Patent Grant
11865179
This disclosure relates to progesterone formulations, methods of using these formulations, and their related pharmacokinetic parameters. Various progesterone formulations may be used in hormone therapies for menopausal, peri-menopausal and post-menopausal females, for example, to mitigate side effects from estrogen replacement therapy. In addition, various progesterone formulations may be used to prevent preterm delivery in pregnant women having a shortened cervix. Progesterone can likewise be used to treat endometrial hyperplasia and amenorrhea.
It is not uncommon for pre-menopausal, peri-menopausal, menopausal, or postmenopausal females, to experience vaginal dryness, vaginal odor, vulvar irritation and itching, dysuria (pain, burning or stinging when urinating), dysparuenia (vaginal pain associated with sexual activity), or vaginal bleeding associated with sexual activity. They may also experience night sweats and menopausal hot flashes (vasomotor symptoms), soreness, increased or variant urinary frequency and urgency, urinary discomfort and incontinence (“estrogen-deficient urinary state(s)”), mood disturbances, and symptoms related vulvo-vaginal atrophy, endometrial hyperplasia, endometrial cancer, and other symptoms of estrogen-related disorders. These symptoms, and other symptoms known to those skilled in the art, are believed to be induced as a result of inadequate or irregular hormone production. As a result, prophylactic methods and treatment regimens to alleviate these symptoms frequently include low dosages of estrogens.
But increased levels of estrogens, including estradiol, whether due to prescription or naturally-occurring increases, may lead to the symptoms and disorders previously mentioned. To mitigate the effect of increased estradiol levels on the endometrium, progesterone administration is often a prophylactic method or prescribed treatment to prevent the negative effects of estrogens such as endometrial hyperplasias and related disorders.
These prophylactic methods and prescribed treatments involving the use of one or more of a group of medications designed to supplement hormone levels in women who experience irregular or decreased hormone production or who lack adequate hormone production, may generally be referred to as hormone replacement therapy (HRT).
Hormone replacement therapy (HRT) is a medical treatment that involves the use of one or more of a group of medications designed to supplement hormone levels in women who lack adequate hormone production. It can mitigate and prevent symptoms caused by diminished circulating estrogen and progesterone hormones.
HRT is available in various forms. One therapy involves administration of low dosages of one or more estrogen(s) or one or more chemical analogues. Another involves administration of progesterone or one or more chemical analogues. Among other effects, progesterone administration acts to mitigate certain undesirable side effects from estradiol administration or naturally-occurring elevated blood levels including endometrial hyperplasia (thickening) and prevention or inhibition of endometrial cancer. Progesterone is a C-21 steroidal sex hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. Like other steroids, progesterone consists of four interconnected cyclic hydrocarbons. Progesterone is hydrophobic, having a reported aqueous solubility of 0.007±0.0 mg/ml. Progesterone is poorly absorbed when administered orally.
Existing progesterone prophylactic methods and prescribed treatments inconsistently or irregularly achieve high levels of absorbed progesterone at low dosages of progesterone. Existing methods and treatments often use synthetic progestins. Synthetic progestins such as medroxyprogesterone acetate or norethindrone acetate have been specifically designed to resist enzymatic degradation and remain active after oral administration. However, these compounds exert undesirable effects on the liver (notably on lipids) and often cause psychological side effects that can be severe enough to contraindicate their use.
One conventional progesterone therapeutic is PROMETRIUM (progesterone, USP) (Abbott Laboratories, Chicago, IL). PROMETRIUM is an FDA-approved drug, formulated in a peanut oil-based medium, containing micronized progesterone, but with a relatively large particle size fraction. The active ingredient in PROMETRIUM is considered to be structurally identical to naturally occurring progesterone produced by a woman's body (also known as a “bioidentical”).
Clinical trials involving PROMETRIUM have shown significant intra- and inter-patient variability. For example, a clinical trial involving postmenopausal women who were administered PROMETRIUM once a day for five days resulted in the mean pharmacokinetic parameters listed in Table 1 (see Table 1, package insert for PROMETRIUM).
The unusually high variability in Cmax and AUC, as evidenced by the large reported standard deviation, may indicate that a significant percentage of patients are overdosed or receive a sub-optimal dose.
The presence of peanut oil in the formulation excludes patients who are allergic to peanut oil. Peanut oil, like other peanut products, may act as an allergen. Indeed, there is a portion of the population that has severe reactions to peanut oil. Peanut allergies are becoming a significant health concern. Food allergies are a leading cause of anaphylaxis, with approximately 200 deaths occurring annually in the United States. While incidence and prevalence are not entirely known, it is suspected that about 6% of children and 4% of adults in North America are affected by food allergies. Many food allergies experienced by children are generally outgrown in adulthood with the exception of peanut allergies.
Progesterone and its analogues can be used to treat a variety of medical conditions, including acute diseases or disorders, as well as chronic diseases and disorders associated with long-term declines of natural progesterone levels.
Accordingly, improved formulations of progesterone would be advantageous. To that end, and disclosed herein, are, among other things, a new softgel progesterone pharmaceutical composition containing solubilized or partially solubilized progesterone, suspended progesterone, a solubilizing agent, and a non-ionic surfactant.
Various pharmaceutical formulations are disclosed herein. For example, pharmaceutical formulations are disclosed comprising ultra-micronized progesterone. Moreover, pharmaceutical formulations are disclosed comprising formulations of ultra-micronized progesterone, wherein the ultra-micronized progesterone is combined with a suitable excipient.
Thus, in various illustrative embodiments, the invention comprises an encapsulated liquid pharmaceutical formulation for orally administering progesterone to a mammal in need thereof, said formulation comprising: progesterone, as the sole active pharmaceutical ingredient. The progesterone can be fully solubilized, or, more typically, partially solubilized, in a solubilizing agent, with any insoluble progesterone being suspended in the solubilizing agent. The solubilizing agent can comprise a medium chain fatty acid-polyolester or a mixture of medium chain fatty acid-polyol esters. The polyol can be, for example, a glycol such as ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, etc. In other embodiments, the polyol can be a triol such as glycerol. When the polyol is a glycol, the glycol can be mono- or di-esterified with a given fatty acid (simple) or can be a mixed di-ester using different medium chain fatty acids. When the polyol is glycerol, the glycerol can be mono-, di-, or tri-esterified giving a monoglyceride, diglyceride, or triglyceride. Typical di- and triglycerides are simple triglycerides, though in certain embodiments, the di- and triglycerides can be mixed. In particular, embodiments, the solubilizing agent can comprise a simple, mixed, or combination simple and mixed glycol di-ester. In still other embodiments, the solubilizing agent can be a simple, mixed, or combination simple and mixed triglyceride. For example, in a particular embodiment, the solubilizing agent can comprise an oil having simple and mixed triglycerides prepared from predominantly C8 and C10 fatty acids. An example of such a triglyceride is MIGLYOL® 812.
In certain embodiments, the formulation can further comprise a non-ionic surfactant. As discussed elsewhere herein, the non-ionic surfactant can comprise GELUCIRE 44/14.
In certain embodiments the progesterone is micronized or ultra-micronized. In certain embodiments, at least about 80 wt % of the total progesterone is micronized. The fatty acids can be predominantly (>50 wt %): C6 to C12 fatty acids, C6 to C10 fatty acids, C8 to C12 fatty acids, or C8 to C10 fatty acids. Some embodiments comprise a non-ionic surfactant that comprises C8 to C18 fatty acid esters of glycerol and polyethylene glycol.
In other embodiments, a softgel progesterone pharmaceutical composition as a hormone replacement therapy (HRT), or as a prophylactic method or a prescribed treatment to mitigate the associated symptoms associated with irregular or inadequate hormone levels is provided.
In particular embodiments, this disclosure provides a pharmaceutical composition for orally administering progesterone to a subject in need thereof, the composition comprising: an amount of progesterone; a solubilizing agent; and a nonionic surfactant selected from the group consisting of lauroyl macrogol-32 glycerides EP (GELUCIRE 44/11), lauroyl polyoxyl-32 glycerides (GELUCIRE 44/14), and caprylocaproyl macrogol-8 glycerides EP; wherein the solubilizing agent comprises at least one C6-C12 fatty acid mono-, di-, or tri-ester of glycerol and wherein the composition has a total mass.
In one embodiment, the solubilizing agent comprises at least one C6-C12 fatty acid mono-ester of glycerol.
In another embodiment, the solubilizing agent comprises at least one C6-C12 fatty acid di-ester of glycerol.
In another embodiment, the solubilizing agent comprises at least one C6-C12 fatty acid tri-ester of glycerol.
In yet another embodiment, the tri-ester of glycerol comprises predominantly esters of caprylic fatty acid (C8) and capric fatty acid (C10).
In a further embodiment, the tri-ester of glycerol is MIGLYOL® 812.
In certain embodiments, the solubilizing agent is medium chain triglycerides (MIGLYOL® 812).
In certain embodiments, the nonionic surfactant is lauroyl polyoxyl-32 glycerides (GELUCIRE® 44/14).
In some embodiments, the amount of progesterone is from 25 mg to 200 mg.
In particular embodiments, the amount of progesterone is 75 mg or 150 mg.
In some embodiments, the amount of progesterone includes a solubilized amount of progesterone and a suspended amount of progesterone.
In certain embodiments, the composition is provided in a gelatin capsule.
In some embodiments, the total mass of the composition is less than 500 mg.
In other embodiments, the composition provides increased progesterone bioavailability compared to micronized progesterone suspended in peanut oil.
In certain embodiments, the solubilizing agent comprises predominantly at least one C6-C12 fatty acid mono-, di-, or tri-ester of glycerol.
In other embodiments, this disclosure provides a pharmaceutical composition for orally administering progesterone to a subject in need thereof, the composition comprising: 75, 150, 200, or 300 mg of progesterone; a solubilizing agent comprising predominantly a triglyceride oil of C8 and C10 fatty acid esters; and lauroyl polyoxyl-32 glycerides (GELUCIRE 44/14).
This disclosure also provides a method of preventing endometrial hyperplasia, the method comprising administering to a patient in need thereof a composition comprising: an amount of progesterone; a solubilizing agent; and a nonionic surfactant selected from the group consisting of lauroyl macrogol-32 glycerides EP (GELUCIRE 44/11), lauroyl polyoxyl-32 glycerides (GELUCIRE 44/14), and caprylocaproyl macrogol-8 glycerides EP; wherein the solubilizing agent comprises at least one C6-C12 fatty acid mono-, di-, or tri-ester of glycerol and wherein the composition has a total mass.
In certain embodiments of the method, the amount of progesterone is 150 mg.
In other embodiments, this disclosure provides a method of treating amenorrhea, the method comprising administering to a patient in need thereof a composition comprising: an amount of progesterone; a solubilizing agent; and a nonionic surfactant selected from the group consisting of lauroyl macrogol-32 glycerides EP (GELUCIRE 44/11), lauroyl polyoxyl-32 glycerides (GELUCIRE 44/14), and caprylocaproyl macrogol-8 glycerides EP; wherein the solubilizing agent comprises at least one C6-C12 fatty acid mono-, di-, or tri-ester of glycerol and wherein the composition has a total mass.
In certain embodiments of the noted method, the amount of progesterone is 150 mg or 300 mg.
In certain embodiments, the amount of progesterone comprises about 33% by weight of the composition; the solubilizing agent comprises about 65% by weight of the composition, the non-ionic surfactant comprises about 1.7% by weight of the composition.
In further embodiments, the amount of progesterone comprises about 33.33% by weight of the composition; the solubilizing agent comprises about 64.93% by weight of the composition, the non-ionic surfactant comprises about 1.67% by weight of the composition.
In certain embodiments, the composition further comprises an antioxidant.
In particular embodiments, the antioxidant is butylated hydroxy toluene.
In certain embodiments, the solubilizing agent is MIGLYOL 812.
In certain embodiments, the non-ionic surfactant is lauroyl polyoxyl-32 glycerides (GELUCIRE 44/14).
In some embodiments, the amount of progesterone is 200 mg.
In other embodiments, the amount of progesterone is 150 mg.
The accompanying drawings are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure, and together with the description serve to explain the principles of the disclosure.
This disclosure provides a pharmaceutical formulation comprising progesterone and a solubilizing agent. In some embodiments, a pharmaceutical formulation comprising ultra-micronized progesterone is provided. As described in detail herein, various solubilizing agents, lubricants, and other excipients may be included. In further embodiments, ultra-micronized progesterone formulations provide improved bioavailability and other pharmacokinetic improvements. These embodiments are described in sufficient detail to enable those skilled in the art to practice these embodiments. Further, other embodiments may be used and other changes may be made without departing from the scope of this disclosure. The following detailed description is therefore not to be taken in a limiting sense. As used in this disclosure, the term “or” is a logical disjunction and does not indicate an exclusive disjunction unless expressly indicated as such with the terms “either,” “unless,” “alternatively,” and words of similar effect.
Unless otherwise specified, the following definitions apply.
The phrase “active pharmaceutical ingredient” or “API” as used herein, means the active compound(s) used in formulating a drug product. In exemplary embodiments, the API is progesterone.
The term “bioequivalent” has the meaning prescribed in 21 CFR § 320.1(e), e.g. the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain extended release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug. In practice, two products are considered bioequivalent if the 90% confidence interval of the Cmax, AUC, or, optionally, Tmax is within 80.00% to 125.00%.
The term “bioidentical” or “natural” used in conjunction with the hormones disclosed herein, means hormones that are identical to or match the chemical structure and effect of those that occur naturally or endogenously in the human body. An exemplary natural estrogen is estradiol.
The term “drug product” as used herein means at least one API in combination with at least one excipient, wherein the API and at least one excipient are provided in unit dosage form.
The term “estrogen” means generally the different hormone types of estrogen, synthetically or naturally occurring, including estradiol, estriol, and estrone.
The term “estradiol” means (17B)-estra-1,3,5(10)-triene-3,17-diol. Estradiol is also called 17ß-estradiol, oestradiol, or E2 and is found endogenously in the human body. Irrespective of the what it is called, estradiol refers to the bio-identical form of estradiol found in the human body having the structure:
Estradiol is supplied in an anhydrous or a hemi-hydrate form; for the purposes of this disclosure, the anhydrous form or the hemihydrate form can be substituted for the other by accounting for the water or lack of water according to well-known and understood techniques.
The phrase “equivalent dosage form” as used herein refers to a dosage form that is identical to a reference dosage form in composition (e.g. identical solubilizing agent(s), non-ionic surfactant(s), and API), but differs from the reference dosage form in the amount of API present or in the ratio of the various components in the reference dosage form.
The term “ultra-micronized progesterone,” as used herein, refers to micronized progesterone having an X50 particle size value below about 20 microns or having an X90 value below about 25 microns. The term “X50” as used herein, means that half of the particles in a sample are smaller in diameter than a given number. For example, ultra-micronized progesterone having an X50 of 5 microns means that, for a given sample of ultra-micronized progesterone, half of the particles have a diameter of less than 5 microns. In that regard, similar terms, in the form XYY mean that YY percent of the particles in the sample are smaller in diameter than a given number. For example, X90 means that ninety percent of the particles in a sample are smaller in diameter than a given number.
The term “administer,” “administration,” “deliver” or “delivery” (collectively “administration”), as used herein, means oral administration of the formulation disclosed herein, preferably in a soft gelatin capsule.
The term “glyceride” is an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids and is also known as an acylglycerol. If only one position of the glycerol molecule is esterified with a fatty acid, a “monoglyceride” is produced; if two positions are esterified, a “diglyceride” is produced; and if all three positions of the glycerol are esterified with fatty acids, a “triglyceride” or “triacylglycerol” is produced. A glyceride is “simple” if all esterified positions contain the same fatty acid; whereas a glyceride is “mixed” if the esterified positions contained different fatty acids. The carbons of the glycerol backbone are designated sn-1, sn-2 and sn-3, with sn-2 being in the middle carbon and sn-1 and sn-3 being the end carbons of the glycerol backbone.
The term “medium chain” is used to describe the aliphatic chain length of fatty acid containing molecules. “Medium chain” specifically refers to fatty acids, fatty acid esters, or fatty acid derivatives that contain fatty acid aliphatic tails or carbon chains that contain 6 (C6) to 14 (C14) carbon atoms, 8 (C8) to 12 (C12) carbon atoms, or 8 (C8) to 10 (C10) carbon atoms.
The terms “medium chain fatty acid” and “medium chain fatty acid derivative” are used to describe fatty acids or fatty acid derivatives with aliphatic tails (i.e., carbon chains) having 6 to 14 carbon atoms. Fatty acids consist of an unbranched or branched aliphatic tail attached to a carboxylic acid functional group. Fatty acid derivatives include, for example, fatty acid esters and fatty acid containing molecules, including, without limitation, mono-, di- and triglycerides that include components derived from fatty acids. Fatty acid derivatives also include fatty acid esters of ethylene or propylene glycol. The aliphatic tails can be saturated or unsaturated (one or more double bonds between carbon atoms). In some embodiments, the aliphatic tails are saturated (i.e., no double bonds between carbon atoms). Medium chain fatty acids or medium chain fatty acid derivatives include those with aliphatic tails having 6-14 carbons, including those that are C6-C14, C6-C12, C8-C14, C8-C12, C6-C10, C8-C10, or others. Examples of medium chain fatty acids include, without limitation, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and derivatives thereof.
The term “oil,” as used herein, refers to any pharmaceutically acceptable oil, especially medium chain oils, and specifically excluding peanut oil, that can suspend and/or solubilize bioidentical progesterone and/or estradiol, including starting materials and/or precursors thereof, including micronized progesterone and/or micronized estradiol as described herein.
The term “medium chain oil” refers to an oil wherein the composition of the fatty acid fraction of the oil is predominantly medium chain (i.e., C6 to C14) fatty acids, i.e., the composition profile of fatty acids in the oil is predominantly medium chain. As used herein, “predominantly” means that between 20% and 100% (inclusive of the upper and lower limits) of the fatty acid fraction of the oil is made up of medium chain fatty acids, i.e., fatty acids with aliphatic tails (i.e., carbon chains) having 6 to 14 carbons. In some embodiments, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 85%, about 90% or about 95% of the fatty acid fraction of the oil is made up of medium chain fatty acids. Those of skill in the art that will readily appreciate that the terms “alkyl content” or “alkyl distribution” of an oil can be used in place of the term “fatty acid fraction” of an oil in characterizing a given oil or solubilizing agent, and these terms are used interchangeable herein. As such, medium chain oils suitable for use in the formulations disclosed herein include medium chain oils wherein the fatty acid fraction of the oil is predominantly medium chain fatty acids, or medium chain oils wherein the alkyl content or alkyl distribution of the oil is substantially medium chain alkyls (C6-C12 alkyls). It will be understood by those of skill in the art that the medium chain oils suitable for use in the formulations disclosed herein are pharmaceutical grade (e.g., pharmaceutical grade medium chain oils). Examples of medium chain oils include, for example and without limitation, medium chain fatty acids, medium chain fatty acid esters of glycerol (e.g., for example, mono-, di-, and triglycerides), medium chain fatty acid esters of propylene glycol, medium chain fatty acid derivatives of polyethylene glycol, and combinations thereof.
The term “ECN” or “equivalent carbon number” means the sum of the number of carbon atoms in the fatty acid chains of an oil, and can be used to characterize an oil as, for example, a medium chain oil or a long-chain oil. For example, tripalmitin (tripalmitic glycerol), which is a simple triglyceride containing three fatty acid chains of 16 carbon atoms, has an ECN of 3×16=48. Conversely, a triglyceride with an ECN=40 may have “mixed” fatty acid chain lengths of 8, 16 and 16; 10, 14 and 16; 8, 14 and 18; etc. Naturally occurring oils are frequently “mixed” with respect to specific fatty acids, but tend not to contain both long chain fatty acids and medium chain fatty acids in the same glycerol backbone. Thus, triglycerides with ECN's of 21-42 typically contain predominately medium chain fatty acids; while triglycerides with ECN's of greater than 43 typically contain predominantly long chain fatty acids. For example, the ECN of corn oil triglyceride in the USP would be in the range of 51-54. Medium chain diglycerides with ECN's of 12-28 will often contain predominately medium chain fatty chains, while diglycerides with ECN's of 32 or greater will typically contain predominately long chain fatty acid tails. Monoglycerides will have an ECN that matches the chain length of its sole fatty acid chain. Thus, monoglyceride ECN's in the range of 6-14 contain mainly medium chain fatty acids, and monoglycerides with ECN's 16 or greater will contain mainly long chain fatty acids.
The average ECN of a medium chain triglyceride oil is typically 21-42. For example, as listed in the US Pharmacopeia (USP), medium chain triglycerides having the following composition as the exemplary oil in the table below
would have an average ECN of 3*[(6*0.02)+(8*0.70)+(10*0.25)+(12*0.02)+(14*0.01)]=25.8. The ECN of the exemplary medium chain triglycerides oil can also be expressed as a range (per the ranges set forth in the USP) of 24.9-27.0. For oils that have mixed mono-, di-, and trigylcerides, or single and double fatty acid glycols, the ECN of the entire oil can be determined by calculating the ECN of each individual component (e.g., C8 monoglycerics, C8 diglycerides, C10 monoglycerides, and C10 monoglycerides) and taking the sum of the relative percentage of the component multiplied by the ECN normalized to a monoglyceride for each component. For example, the oil having C8 and C10 mono- and diglycerides shown in the table below has an ECN of 8.3, and is thus a medium chain oil.
Expressed differently, ECN can be calculated as each chain length in the composition multiplied by its relative percentage in the oil: (8*0.85)+(10*0.15)=8.3.
The term “patient” refers to a human individual who has received, who might receive, or is receiving health or pharmaceutical care, or is under the supervision and care of a physician, pharmacist, or medically trained professional. This individual may be expecting this care, may be currently receiving it, or may have already received it.
The term “progesterone” refers to pregn-4-ene-3,20-dione. Progesterone is also interchangeably called P4 and is found endogenously in the human body. As used herein, progesterone refers to the bio-identical or body-identical form of progesterone found in the human body having the structure:
The term “solubilized progesterone” means that the progesterone or a portion thereof is solubilized or dissolved in the solubilizing agent(s) or the formulations disclosed herein. In some embodiments, the progesterone is “partially solubilized” with a portion of the progesterone being solubilized or dissolved in the solubilizing agent and a portion of the progesterone being suspended in the solubilizing agent. Partially solubilized progesterone may include progesterone that is about 1% solubilized, about 5% solubilized, about 10% solubilized, about 15% solubilized, or about 20% solubilized, about 30% solubilized, about 40% solubilized, about 50% solubilized, about 60% solubilized, about 70% solubilized, about 80% solubilized, about 85% solubilized, about 90% solubilized or about 95% solubilized. In other embodiments, the progesterone is “fully solubilized” with all or substantially all of the progesterone being solubilized or dissolved in the solubilizing agent. Fully solubilized progesterone may include progesterone that is about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized. In particular embodiments, the progesterone is less than about 20% solubilized. Solubility can be expressed as a mass fraction (% w/w, which is also referred to as wt %).
The term “pharmaceutical composition” refers to a composition comprising at least a solubilizing agent and progesterone. As used herein, pharmaceutical compositions are delivered, for example via oral administration. Furthermore, as used herein, “pharmaceutical composition” and “formulation” are used interchangeably.
The term “uniform distribution” means at least one of uniform dispersion, solubility, or lack of agglomeration of progesterone in gastric juices compared to PROMETRIUM.
The term “gastric juices” means the watery, acidic digestive fluid that is secreted by various glands in the mucous membrane of the stomach and consists chiefly of hydrochloric acid, pepsin, rennin, and mucin.
The term “excipients,” as used herein, refers to non-API substances such as solubilizing agents, anti-oxidants, oils, lubricants and others used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration.
The term “carrier,” as used herein, means any substance or mixture of substances that may be mixed with or contain an API (e.g., ultra-micronized progesterone). The term carrier is interchangeable with solubilizing agent.
The term “capsule,” as used herein, refers to a generally safe, readily dissolvable enclosure for carrying certain pharmaceutical products, and includes hard or soft shell capsules.
The term “softgel,” includes soft shell capsules, including soft-gelatin capsules and soft vegetable-based capsules, and soft capsules made from other materials providing the composition of such soft capsules are compatible with the formulations of the various embodiments described herein. A softgel may comprise two primary phases: a gel or vegetable-based capsule and a fill material of the pharmaceutical formulation as described herein. In particular embodiments, the weight of the fill material does not exceed 500 mg, i.e. the fill material weighs less than 500 mg, less than 450 mg, less than 400 mg, less than 350 mg, less than 300 mg, less than 250 mg, less than 200 mg, or less than 150 mg.
The term “bioavailability” has the meaning prescribed in 21 CFR § 320.1(a): the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. For example, bioavailability can be measured as the amount of API in the blood (serum or plasma) as a function of time. Pharmacokinetic (PK) indicators such as AUC, Cmax, or Tmax may be used to measure and assess bioavailability. Absorption as used in this definition can include absorption in the stomach, intestines, or other tissue that help facilitate absorption of the API into the bloodstream.
The term “co-administered” as used herein, means that two drug products are administered simultaneously or sequentially on the same or different days.
The terms “pharmacokinetics,” “pharmacokinetic measurements,” “pharmacokinetic parameters,” and “PK parameters” refers to parameters or measures used to assess bioavailability such as AUC, Cmax, or Tmax include assessments and determinations to study absorption, distribution, metabolism, and excretion of a drug.
The term “reference listed drug product” (“RLD”) means PROMETRIUM (progesterone, USP) (Abbott Laboratories, Chicago, IL). PROMETRIUM is an FDA-approved drug, formulated in a peanut oil-based medium, containing micronized progesterone, but with a relatively large particle size fraction.
The term “secretory activity” refers to complete and partial secretory activity of the endometrium as is well understood in the art and as is discussed at length in Noyes, R. W., Hertig, A. T. and Rock, J. (1950), Dating the endometrial biopsy. Fertil. Steril., 1, 3-25, which is incorporated herein by reference. See also, Deliqdisch, L., (1993), Effects of hormone therapy on the endometrium. Mod Pathol. January, vol. 6(1), pp 94-106, which is incorporated herein by reference. Noyes et al., is also referenced for additional information regarding endometrial biopsies.
The term “solubilized” refers to the amount of an API that is in solution. Solubility and percent solubility are expressed herein as a mass fraction (mg/g) or (% w/w, also referred to as wt. %).
The term “solubilizing agent” refers to an agent or combination of agents that solubilize an active pharmaceutical ingredient (e.g., estradiol or progesterone). For example and without limitation, suitable solubilizing agents include medium chain oils and other solvents and co-solvents that solubilize or dissolve an active pharmaceutical ingredient to a desirable extent. Solubilizing agents suitable for use in the formulations disclosed herein are pharmaceutical grade solubilizing agents (e.g., pharmaceutical grade medium chain oils). It will be understood by those of skill in the art that other excipients or components can be added to or mixed with the solubilizing agent to enhance the properties or performance of the solubilizing agent or resulting formulation. Examples of such excipients include, but are not limited to, surfactants, emulsifiers, thickeners, colorants, flavoring agents, etc. In some embodiments, the solubilizing agent is a medium chain oil and, in some other embodiments, the medium chain oil is combined with a co-solvent(s) or other excipient(s).
The term “subject” refers to both human and non-human animal subjects who are administered the pharmaceutical composition of this disclosure. Specifically intended are mammalian subjects. More specifically intended are human subjects.
The term “area under the curve” or “AUC” refers to the area under the curve defined by changes in the blood concentration of an active pharmaceutical ingredient (e.g., progesterone), or a metabolite of the active pharmaceutical ingredient, over time following the administration of a dose of the active pharmaceutical ingredient. “AUC0-∞” is the area under the concentration-time curve extrapolated to infinity following the administration of a dose. “AUC0-t” is the area under the concentration-time curve from time zero to time t following the administration of a dose, wherein t is the last time point with a measurable concentration.
The term “Cmax” refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of an active pharmaceutical ingredient (e.g., progesterone), or a metabolite of the active pharmaceutical ingredient, over time.
The term “Tmax” refers to the time that it takes for the blood concentration of an active pharmaceutical ingredient (e.g., estradiol or progesterone), or a metabolite of the active pharmaceutical ingredient, to reach the maximum value.
Optionally, the term, “T1/2” as used herein, refers to the time that it takes for progesterone blood concentration to decline to one-half of the maximum level.
Collectively AUC, Cmax, and optionally Tmax and T1/2, are the principle pharmacokinetic parameters that can characterize the pharmacokinetic responses of a particular drug product such as progesterone in an animal or human subject.
Provided herein are oral pharmaceutical compositions comprising solubilized or partially solubilized progesterone. Further disclosed herein are data demonstrating the efficacy of these pharmaceutical compositions, as well as methods of using the described pharmaceutical compositions. Generally, the pharmaceutical compositions disclosed herein can be useful in mitigating the symptoms and effects of increased, decreased, or irregular estrogen levels.
Additional aspects and embodiments of this disclosure include: providing increased patient ease of use while potentially minimizing certain side effects from erroneous use, providing reduced metabolic and vascular side effects of commonly used synthetic progesterone, providing reduced food and allergy effects, providing improved bioavailability of progesterone as compared to the PROMETRIUM®, and in some embodiments providing for improved bioavailability of progesterone or a bioequivalent progesterone product at a reduced dose of API compared to the RLDs.
Various embodiments are improvements over exiting progesterone formulations, treatments, and methods of using these formulations and treatments. While not bound by theory, the elements of the pharmaceutical compositions of this disclosure provide improved bioavailability, improved pharmacokinetics, bioequivalent pharmaceutical compositions, and the potential to reduce the administered dosage strength. Bioavailability comparisons to commercially available forms, such as tablet and capsule forms, may be determined by standard pharmacokinetic techniques.
In embodiments, progesterone is solubilized or partially solubilized (partially suspended) when administered. The type of progesterone used, the form of that progesterone (i.e., solubilized or suspended), the different solubilizing agent used, the different excipients used, and the administration under proper conditions (i.e. fed, absence of concomitant medications, etc.) contribute, in part, to the improvements over existing progesterone compositions, methods, and treatments.
In embodiments, the pharmaceutical compositions do not include peanut oil.
In certain embodiments, the API is progesterone, which is solubilized or partially solubilized (partially suspended). In embodiments, progesterone is the sole API.
Generally, the pharmaceutical formulations described herein are prepared and administered as filled capsules, typically soft capsules or softgels of one or more materials well known in the art including, for example and without limitation, soft gelatin capsules. Ultra-micronized progesterone, as described herein, may also be prepared for administration in tablets or other well-known orally administered dosage forms using standard techniques.
In illustrative embodiments, total progesterone, i.e., dissolved and suspended progesterone, can be 20 to 50 wt %, e.g., 30 to 35 wt %, based on the weight of the entire fill, i.e., the liquid pharmaceutical formulation.
Other embodiments disclosed herein further provide more uniform dissolution of progesterone and reduced intra- and inter-patient PK parameters when compared to equal dosages of PROMETRIUM. Dissolution uniformity of progesterone in a formulation of this disclosure compared to PROMETRIUM at equal dosage strengths and using the same USP apparatus can be determined using standard techniques established for API dissolution testing, including that which is described in the examples below.
According to the PROMETRIUM prescribing information, progesterone absorption is highly variable from patient to patient and within the same patient. A clinical trial involving postmenopausal women who were administered PROMETRIUM once a day for five days resulted in the mean PK parameters listed in the following table:
These values are highly variable as demonstrated by their standard deviations which, in some cases, exceed 100% of the noted mean value. In particular illustrative aspects and embodiments of this invention, it is possible, though not necessary, to reduce the standard deviations in one or more of these PK parameters.
Reduced intra- and inter-patient variability of progesterone according to this disclosure compared to PROMETRIUM can be assessed using techniques known to those of ordinary skill in the art and described elsewhere herein.
Other aspects of this disclosure include the use of formulations as described herein wherein progesterone is at least one API in said formulation for the treatment of an animal, especially a mammal, including humans: for endometrial hyperplasia; for secondary amenorrhea; as a method of treatment for preterm birth, when said animal has a shortened cervix, and other disease states or conditions treated with supplemental progesterone (collectively, “Progesterone-deficient States”) in a subject in need of treatment, and with a non-toxic effective amount of said formulations.
The terms “treat,” “treating,” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, disease, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, disease, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subject parameters, including the results of a physical examination, neuropsychiatric examinations, or psychiatric evaluation.
For purposes of this disclosure, “prophylaxis” refers to administration of the progesterone, to an animal, especially a mammal, and in particular a human, to protect the animal from any of the disorders set forth herein, as well as others, before or after the disorder has occurred in the subject.
Exemplary dosage strengths for progesterone for use in the formulations described herein include, without limitation, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg and 400 mg. In embodiments, progesterone dosage strength is from at least 25 mg to at least 200 mg. Specific dosage embodiments contain at least: 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, or 200 mg of progesterone per capsule.
In certain embodiments, the pharmaceutical compositions can contain at least about 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg of progesterone. In certain embodiments, the pharmaceutical compositions contain from about 25 mg to about 50 mg, from about 75 mg to 100 mg, from about 50 mg to about 100 mg, about 75 mg, about 150 mg, about 200 mg, from about 100 mg to 150 mg, from about 150 mg to 200 mg, from 100 mg to 200 mg of progesterone. The lowest clinically effective dose of progesterone is used for treatment symptoms occurring due to irregular or inadequate hormone production, or for estrogen HRT patients. In one embodiment, the progesterone dosage is about 75 mg. In another embodiment, the progesterone dosage is about 150 mg. In another embodiment, the progesterone dosage is about 200 mg. In particular embodiments, the dosage is 75 mg, 150 mg, or 200 mg.
Solubilized compositions of this disclosure can be formulated for administration using techniques disclosed herein, and also using techniques well known in the art. Thus, an illustrative embodiment of a pharmaceutical composition of the invention comprises progesterone, at least 75% of the progesterone being solubilized (the balance being suspended/ultra-micronized as discussed elsewhere herein), and an oil, wherein the oil is medium chain fatty acid mono- and di-esters of one or more glycols, with or without surfactant.
In other embodiments, the progesterone in the pharmaceutical compositions is not more than about 20% solubilized, not more than about 19% solubilized, not more than about 18% solubilized, not more than about 17% solubilized, not more than about 16% solubilized, not more than about 15% solubilized, not more than about 14% solubilized, not more than about 13% solubilized, not more than about 12% solubilized, not more than about 11% solubilized, not more than about 10% solubilized, not more than about 9% solubilized, not more than about 8% solubilized, not more than about 7% solubilized, not more than about 6% solubilized, or not more than about 5% solubilized, with the balance being suspended in the formulation as discussed elsewhere herein. The suspended/ultra-micronized progesterone is absorbable by the body and retains biological functionality despite not being soluble in the formulation. In a particular embodiment, the progesterone is about 15% solubilized in the formulation, with balance (about 85%) being suspended/ultra-micronized. In another embodiment, the progesterone is about 5% solubilized in the formulation, with balance (about 95%) being suspended/ultra-micronized.
In certain embodiments, progesterone solubility in various solubilizing agents ranges from 27 mg/g to 95 mg/g. More specifically, in certain embodiments, progesterone's solubility in solubilizing agents is from 27.8 mg/g, 57.4 mg/g, 70.5 mg/g, 73.4 mg/g, 86.4 mg/g, to 95 mg/g.
Progesterone may be micronized/ultra-micronized via any one of the multiple methods typically utilized by the ordinarily skilled artisan.
Particle size may be determined in any suitable manner. For example, a Beckman Coulter LS 13 320 Laser Diffraction Particle Size Analyzer (the “Beckman Device”) may be used to determine particle size. Particle size may be represented by various metrics, for example, through an X50 particle size, or X90 particle size, or similar descriptions of particle size.
The Beckman Device may be used with various modules for introducing a sample for analysis. The Beckman Device may be used with the LS 13 320 Universal Liquid Module (“ULM”). The ULM is capable of suspending samples in the size range of 0.017 μm to 2000 μm. The ULM is a liquid based module that allows for delivery of the sample to the sensing zone. The ULM recirculates the sample through the Beckman Device. The ULM comprises two hoses, one for fluid delivery and another for waste. The total volume used may be 125 mL or less. A sample mass of from about 1 mg to about 10 g may be used. The ULM may interact with the Beckman Device via pins that fit into slots on the ULM. The ULM may use a variety of suspension fluids, for example, water, butonol, ethanol, chloroform, heptanes, toluene, propanol, COULTER Type 1B Dispersant (“Coulter 1B”), and a variety of other suspension fluids. Surfactants may also be used, though pump speed should be adjusted to prevent excessive bubbling. Coulter 1B may comprise one or more of acetaldehyde, ethylene oxide, or 1,4-dioxane. The Beckman Device may be configured to use a variety of optical theories, including the Fraunhofer optical model and the Mie Theory.
The Beckman Device may comprise software to control the Beckman Device while the ULM is in use. The software may control, for example, pump speed, use of de-bubble routine, rinse routine, sonicate routine, and fill routine, among others. Parameters regarding the sample run may also be configured. For example, run length may be set. Though any suitable run length may be used, in various embodiments, a time period of 30 seconds to 120 seconds, and preferably between 30 seconds and 90 seconds may be used.
The Beckman Device may be used with the LS 13 320 Micro Liquid Module (“MLM”). The MLM is capable of suspending samples in the size range of 0.4 μm to 2000 μm. The MLM is a liquid based module that allows for delivery of the sample to the sensing zone. The MLM includes a stirrer. The total volume used may be 12 mL or less. The MLM may use a variety of suspension fluids, both aqueous and non-aqueous.
In various embodiments, ultra-micronized progesterone has an X50 value of less than about 15 microns, less than about 10 microns, less than about 5 microns or less than about 3 microns; and an X90 value of less than about 25 microns, less than about 20 microns, or less than about 15 microns.
In various embodiments, ultra-micronized progesterone is formulated with peanut and peanut-oil free excipients.
Solvent System
In various embodiments, a solvent system solubilizes one or more APIs, and in particular, progesterone. The solvent system is a mixture of solubilizing agents, together with co-solvents, surfactants, or other excipients. In certain embodiments, the solvent system comprises non-toxic, pharmaceutically acceptable solvents (alternatively referred to as “carriers”), co-solvents, surfactants, and excipients suitable for oral administration or absorption.
In embodiments, oils having medium chain fatty acids as a predominant or majority component are used as solubilizing agents/carriers to solubilize the one or more APIs. In certain embodiments, the solubilizing agents comprise medium chain fatty acid esters (e.g., esters of glycerol, ethylene glycol, or propylene glycol) or mixtures thereof. In certain embodiments, the medium chain fatty acids comprise chain lengths from C6 to C14. In certain embodiments the medium chain fatty acids comprise chain lengths from C6 to C12. In still other embodiments, the medium chain fatty acids are mono-, di-, or triglycerides predominately with chain lengths from C8 to C10. As noted elsewhere herein, the medium chain fatty acids can be saturated. In certain embodiments, the medium chain fatty acids are predominantly saturated, i.e., greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, or greater than about 95% saturated. In particular embodiments, the solubilizing agent comprises a mixed triglyceride predominantly comprising C8 and C10 fatty acids. In other particular embodiments, the solubilizing agent comprises both simple and mixed triglycerides predominately comprising C8 and C10 fatty acids. In particular embodiments, the solubilizing agent comprises a mixed triglyceride predominantly comprising saturated C8 and C10 fatty acids. In other particular embodiments, the solubilizing agent comprises both simple and mixed triglycerides predominately comprising saturated C8 and C10 fatty acids.
In some embodiments, the solubilizing agent/carrier is selected to enhance dissolution or suspension of progesterone. In further various embodiments, the solubilizing agent/carrier is selected to enhance absorption of the API by cells of a mammal. For example, certain carriers may be selected to enhance absorption of the other formulation components, including the API. Absorption may comprise absorption into any cell and particularly absorption into digestive system cells, such as intestinal cells, and cells of the female reproductive system, such as the vagina and the cervix. Selected mono-, di-, or triglyercides are particularly suited to aid in cellular absorption.
In certain embodiments, a surfactant is used to aid in solubilizing, partially solubilizing, or suspending progesterone in the solubilizing agent. For example, a surfactant, such as GELUCIRE 44/14, can be used. In certain embodiments, GELUCIRE 44/14 may be heated to approximately 45-50° C. When the surfactant is completely melted, it is added to an appropriate container that contains the solubilizing agent. The solubilizing agent and surfactant are mixed. During this mixing process the progesterone is added, thus, solubilizing, partially solubilizing, or suspending progesterone. In certain embodiments, the solubilizing agent is liquid at between room temperature and about 50° C., at or below 50° C., at or below 40° C., or at or below 30° C.
In various embodiments, the solubilizing agent/carrier can be an oil having medium chain fatty acids as a majority or predominant component. Suitable medium chain fatty acids include caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), and myristic acid (C14). In use, these fatty acids are predominantly saturated (e.g., greater than 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 95%, or about 100%). In certain embodiments, predominantly C6 to C12 saturated fatty acids are contemplated. In certain embodiments, predominately C8 to C10 saturated fatty acids are contemplated. In certain embodiments, these fatty acids may be bound to glycerin, propylene glycol, ethylene glycol, or polyethylene glycol. In certain embodiments, the solubilizing agent is selected from at least one of a solvent or co-solvent.
In particular embodiments, the solubilizing agent can comprise a mixture of caprylic/capric triglycerides; caproic/caprylic/capric/lauric triglycerides; caprylic/capric/linoleic triglycerides; caprylic/capric/succinic triglycerides; propylene glycol dicaprylate/dicaprate; and combinations and derivatives thereof. In further embodiments, in addition to the various mixtures of the specified triglycerides, the solubilizing agent can further include polyethylene glycol.
Suitable carriers/solubilizing agents further include esters of saturated coconut and palm kernel oil and derivatives thereof, including fractionated coconut oils and palm kernel oils; and triglycerides of fractionated vegetable fatty acids, and derivatives thereof and combinations thereof. In further various embodiments, the carrier/solubilizing agent may comprise one or more monoglycerides, diglycerides, triglycerides, and combinations thereof having predominately C6-C12 fatty acid esters. Specifically contemplated as the solvent are mono-, di-, and triglycerides of saturated C8-C10 (caprylic/capric) fatty acids. Exemplary glycerin based solubilizing agents include MIGLYOLs®, which are caprylic/capric triglycerides (SASOL Germany GMBH, Hamburg). MIGLYOLs includes MIGLYOL 810 (caprylic/capric triglyceride), MIGLYOL 812 (caprylic/capric triglyceride), MIGLYOL 816 (caprylic/capric triglyceride), and MIGLYOL 829 (caprylic/capric/succinic triglyceride). Other caprylic/capric triglyceride solubilizing agents are likewise contemplated, including, for example: caproic/caprylic/capric/lauric triglycerides; caprylic/capric/linoleic triglycerides; caprylic/capric/succinic triglycerides. In certain embodiments, CAPMUL MCM, medium chain mono- and di-glycerides of caprylic/capric fatty acids, is the solubilizing agent. In other embodiments, CAPMUL PG-8 (Propylene Glycol Monocaprylate), CAPMUL PG-10 (Propylene Glycol Monocaprate), or other caprylic/capric CAPMULs is the solubilizing agent. Triglycerides of fractionated vegetable fatty acids, and combinations or derivatives thereof can be the solubilizing agent, in certain embodiments.
Additional examples of solubilizing agents include a polyethylene glycol glyceride (Gelucire®; GATTEFOSSE SAS, Saint-Priest, France); a propylene glycol; a caproic/caprylic/capric/lauric triglyceride; a caprylic/capric/linoleic triglyceride; a caprylic/capric/succinic triglyceride; propylene glycol monocaprylate; propylene glycol monocaprate; (Capmul® PG-8 and 10; the CAPMUL brands are owned by ABITEC, Columbus Ohio); propylene glycol dicaprylate; propylene glycol dicaprylate; a diethylene glycol mono ester (including 2-(2-Ethoxyethoxy)ethanol (also referred to as TRANSCUTOL®); diethylene glycol monoethyl ether; esters of saturated coconut and palm kernel oil and derivatives thereof; triglycerides of fractionated vegetable fatty acids, and combinations and derivatives thereof.
In other aspects and embodiments, progesterone is fully solubilized using, for example and without limitation, sufficient amounts of: TRANSCUTOL and MIGLYOL; TRANSCUTOL, MIGLYOL and CAPMUL PG-8 or CAPMUL PG-10; CAPMUL MCM (Medium Chain Mono- and Diglycerides); CAPMUL MCM and a non-ionic surfactant; and CAPMUL MCM and GELUCIRE.
In particular embodiments, the solubilizing agent comprises combinations of mono- and di-esters of propylene glycol or ethylene glycol or mono-, di-, and triglyceride combinations.
In certain embodiments, polyethylene glycol glyceride (GELUCIRE®, GATTEFOSSE SAS, Saint-Priest, France) can be used as the solubilizing agent or as a surfactant. For example, GELUCIRE 44/14 can be used. GELUCIRE 44/14 is a non-ionic water dispersible surfactant, also known as lauroyl macrogol-32 glycerides EP and lauroyl polyoxyl-32 glycerides NF. For example, in certain embodiments, a non-ionic surfactant is selected from one or more of glycerol and polyethylene glycol esters of long chain fatty acids, such GELUCIRE 44/14 (discussed previously herein), GELUCIRE 44/11, GELUCIRE 39/01 (glycerol esters of saturated C12-C18 fatty acids), GELUCIRE 43/01 (hard fat NF/JPE), GELUCIRE 50/13 (stearoyl macrogol-32 glycerides EP, stearoyl polyoxyl-32 glycerides NF, and stearoyl polyoxylglycerides (USA FDA IIG)). These surfactants may be used at concentrations greater than about 0.01 wt. %, and typically in various amounts of about 0.01 wt. %; about 10.0 wt. %; about 10.1 wt. %; about 20 wt. %; about 20.1 wt. %; and about 30 wt. %. More specifically, these surfactants may be used at concentrations between 0.01 wt. % to 5.00 wt. %.
Other non-ionic surfactants include, for example and without limitation one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid. In other embodiments, non-ionic surfactants can comprise polyethylene sorbitol esters, such as polysorbate 80, which is commercially available under the trademark TWEEN® 80 (polysorbate 80) (Sigma Aldrich, St. Louis, MO). Polysorbate 80 comprises approximately 60%-70% oleic acid with the remainder comprising primarily linoleic acids, palmitic acids, and stearic acids. Polysorbate 80 may be used in amounts ranging from about 5 to 50% of the pharmaceutical composition by mass, and in particular embodiments, about 30% of the pharmaceutical composition total mass.
Yet another non-ionic surfactants is PEG-6 palmitostearate and ethylene glycol palmitostearate, which is available commercially as TEFOSE® 63 (GATTEFOSSE SAS, Saint-Priest, France), which can be used with, for example, CAPMUL MCM having ratios of MCM to TEFOSE 63 of, for example, 8:2 or 9:1. In other embodiments, other solubilizing agents/non-ionic surfactants combinations include, for example, MIGLYOL 812: GELUCIRE 50/13 or MIGLYOL 812: TEFOSE 63.
In still further embodiments, the surfactant can be an anionic surfactant, for example: ammonium lauryl sulfate, dioctyl sodium sulfosuccinate, perfluoro-octane sulfonic acid, potassium lauryl sulfate, or sodium stearate.
In certain embodiments, the non-ionic or anionic surfactant(s) can be used alone with at least one solubilizing agent or can be used in combination with other surfactants. Accordingly, such surfactants, or any other excipient as set forth herein, may be used to solubilize one or more APIs. In this disclosure, the API is progesterone. The combination of solubilizing agent, surfactant, and other excipients should be designed whereby the one or more APIs are delivered to the target tissue and result the intended effect of the API.
Various ratios of the noted solubilizing agents can be used for suspension or solubilization of progesterone. CAPMUL MCM and a non-ionic surfactant, e.g., GELUCIRE 44/14 (Lauroyl macrogol-32 glycerides EP Lauroyl polyoxyl-32 glycerides NF Lauroyl polyoxylglycerides (USA FDA IIG)), can be used at ratios of about 9:1, 7:3, 6:4, and 6:3 when progesterone is the sole API and at ratios of 65:35, 70:30, 75:25, 80:20, 85:15 and 90:10 with estradiol as the sole API. Other non-limiting examples include CAPMUL MCM and GELUCIRE 44/14 used in ratios including, for example, and without limitation, 99:1 to 2:1, including, for example and without limitation: 60:40, 65:35, 70:30, 75:25, 80:10, 80:15, 85:20, 90:10, and 98:1; CAPMUL MCM and GELUCIRE 39/01 can be used in ratios including, for example and without limitation, 6:4, 7:3, and 8:2 (one or more API composition); CAPMUL MCM and GELUCIRE 43/01 can be used in ratios including, for example and without limitation, 7:3, and 8:2 (one or more API composition); and CAPMUL MCM and GELUCIRE 50/13 can be used in ratios including, for example and without limitation, 7:3, and 8:2, and 9:1. In other embodiments, CAPMUL MCM and GELUCIRE were used in ratios of up to about 65:1, e.g., 8:1, 22:1, 49:1, 65:1 and 66:1. Thus, useful ratios can be, e.g., 8:1 or greater, e.g., 60 to 70:1.
Combinations of these solubilizing agents can produce solubilized or partially solubilized progesterone, depending upon the desired unit dosage amount of progesterone. The greater the amount of progesterone per unit dosage form, the less progesterone may be solubilized. The upward limit of dosage strength per unit dose it generally limited only by the practical size of the final dosage form.
In illustrative embodiments, solubilizing agents used to suspend, partially solubilize, or fully solubilize progesterone include medium chain fatty acid esters, (e.g., esters of glycerol, ethylene glycol, polyethylene glycol, or propylene glycol) and mixtures thereof. In illustrative embodiments, the medium chain fatty acids are C6 to C14 or C6 to C12 fatty acids. In illustrative embodiments, the medium chain fatty acids are saturated, or predominantly saturated, e.g., greater than about 60% or greater than about 75% saturated. In illustrative embodiments, progesterone is soluble in the oils at room temperature, although it may be desirable to warm certain oils initially during manufacture to improve viscosity. In illustrative embodiments, the oil or oil/surfactant is liquid at between room temperature and about 50° C., e.g., at or below 50° C., at or below 40° C., or at or below 30° C. In illustrative embodiments, GELUCIRE 44/14 is heated to about 65° C. and CAPMUL MCM is heated to about 40° C. to facilitate mixing of the oil and non-ionic surfactant, although such heating is not necessary to dissolve the estradiol or progesterone.
In illustrative embodiments, the solubility of estradiol in the solubilizing agent or combination of solubilizing agents is at least about 0.5 wt %, e.g., 0.8 wt % or higher, or 1.0 wt % or higher. Illustrative examples of mono- and diglycerides of medium chain fatty acids include, among others, CAPMUL MCM, CAPMUL MCM C10 (Glyceryl Monocaprate), CAPMUL MCM C8 (Glyceryl Monocaprylate), and CAPMUL MCM C8 EP (Glyceryl Monocaprylate). These oils are C8 and C10 fatty acid mono- and diglycerides. Illustrative examples of oils that are triglycerides of medium chain fatty acids include, among others, MIGLYOL 810 and MIGLYOL 812.
Illustrative examples of solubilizing agents that are medium chain fatty acid esters of propylene glycol include, among others, CAPMUL PG-8, CAPMUL PG-2L EP/NF (Propylene Glycol Dilaurate), CAPMUL PG-8 NF (Propylene Glycol Monocaprylate), CAPMUL PG-12 EP/NF (Propylene Glycol Monolaurate) and CAPRYOL (Propylene glycol monocaprylate (type II) NF). Other illustrative examples include MIGLYOL 840 (Propylene Glycol Dicaprylate/Dicaprate).
Illustrative examples of solubilizing agents that are medium chain fatty acid esters of polyethylene glycol include, among others, GELUCIRE 44/14 (PEG-32 glyceryl laurate EP), which is polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol. Without intending to be bound to any particular mechanism, it appears that at least in formulations comprising small amounts of GELUCIRE, e.g., 10 wt % or less, the primary function of this oil is as a non-ionic surfactant.
These illustrative examples comprise predominantly medium chain length, saturated, fatty acids, specifically predominantly C8 to C12 saturated fatty acids. In particular embodiments, the predominantly C8 to C12 saturated fatty acids comprise not less than 50 wt %, not less than 75 wt %, not less than 85 wt %, not less than 90 wt %, or not less than 95 wt % of the solubilizing agent.
It will be understood that commercially available fatty acid esters of glycerol and other glycols are often prepared from natural oils and therefore may comprise components additional to the fatty acid esters that comprise the predominant (by weight) component(s) and that therefore are used to characterize the product. Such other components may be, e.g., other fatty acid triglycerides, mono- and diesters, free glycerol, or free fatty acids. So, for example, when an oil/solubilizing agent is described herein as a saturated C8 fatty acid mono- or diester of glycerol, it will be understood that the predominant component of the oil, i.e., >50 wt % (e.g., >75 wt %, >85 wt % or >90 wt %) are caprylic monoglycerides and caprylic diglycerides. For example, the Technical Data Sheet by ABITEC for CAPMUL MCM C8 describes CAPMUL MCM C8 as being composed of mono and diglycerides of medium chain fatty acids (mainly caprylic) and describes the alkyl content as <=1% C6, >=95% C8, <=5% C10, and <=1.5% C12 and higher.
By way of further example, MIGLYOL 812 is generally described as a C8-C10 triglyceride because the fatty acid composition is at least about 80% caprylic (C8) acid and capric (C10) acid. However, it can also comprise small amounts of other fatty acids, e.g., less than about 5% of caproic (C6) acid, lauric (C12) acid, and myristic (C14) acid.
Specifically, a product information sheet for MIGLYOL by SASOL provides the composition of fatty acids as follows:
Where certain embodiment of this invention are described as comprising (or consisting essentially of) a capsule shell, estradiol solubilized in C8-C10 triglycerides, and a thickening agent, it will be understood that the fatty acid esters component of the formulation may be, e.g., MIGLYOL 812 or a similar product.
By way of further illustration, GELUCIRE 44/14 is generally described as lauroyl polyoxyl-32 glycerides, i.e., polyoxyethylene 32 lauric glycerides (which is a mixture of mono-, di-, and triesters of glycerol and mono- and diesters of PEGs) because the fatty acid composition is 30 to 50% lauric acid and smaller amounts of other fatty acids, e.g., up to 15% caprylic acid, up to 12% capric acid, up to 25% myristic acid, up to 25% palmitic acid, and up to 35% stearic acid. The product may also contain small amounts of non-esterified glycols.
Similarly, where certain embodiment of this invention are described as comprising (or consisting essentially of) a capsule shell, estradiol solubilized in triglycerides, and a thickening agent that is a non-ionic surfactant comprising PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate, it will be understood that the thickening agent component of the formulation may be, e.g., TEFOSE 63 (PEG-6 palmitostearate and ethylene glycol palmitostearate) or a similar product.
In illustrative embodiments of the invention, the selected solubilizing agent does not require excessive heating in order to solubilize progesterone. For example, when the formulation comprises medium chain fatty acid mono- and diglycerides (e.g., CAPMUL MCM) and polyethylene glycol glycerides (e.g., GELUCIRE) as a surfactant, the oil or the surfactant can be warmed up, e.g., to about 65 C in the case of the surfactant and less in the case of the oil, to facilitate mixing of the oil and surfactant. The progesterone can be added as the mixture cools, e.g., to below about 40 C or to below about 30 C, even down to room temperature.
In various embodiments, a lubricant is used. Any suitable lubricant may be used, such as, for example and without limitation, lecithin, and in various embodiments, a mixture of polyethylene glycol (“PEG”) esters, glycerides, and PEG, such as is commercially available under the trade name GELUCIRE (Gattefosse, FR) may also be used as a lubricant. Suitable lubricants may also comprise calcium stearate, ethyl oleate, ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium, oxide, magnesium stearate, poloxamer, glycols, and phospholipid mixtures. In particular, a mixture of polyethylene glycol esters, glycerides, and PEG such as GELUCIRE 44/14, may be used as a lubricant. GELUCIRE 44/14 is a non-ionic water dispersible surfactant, also known as lauroyl macrogol-32 glycerides EP and lauroyl polyoxyl-32 glycerides NF. In various embodiments, GELUCIRE 44/14 acts as a suspension agent.
In various embodiments, an antioxidant is used. Any suitable antioxidant may be used, such as, for example and without limitation, butylated hydroxytoluene, also commercially referred to as BHT. Butylated hydroxytoluene, a derivative of phenol, is lipophilic and is thus suited to being intermixed with ultra-micronized progesterone and carriers disclosed or contemplated herein.
For example, in various embodiments, a pharmaceutical formulation comprises about 20% to about 80% solubilizing agent by weight, about 0.1% to about 5% lubricant by weight, and about 0.01% to about 0.1% antioxidant by weight.
In certain embodiments, the pharmaceutical composition further comprises at least one thickening agent. Generally, a thickening agent is added when the viscosity of the pharmaceutical composition provides less than desirable absorption following administration. Examples of thickening agents include: hard fats; propylene glycol; a mixture of hard fat EP/NF/JPE, glyceryl ricinoleate, ethoxylated fatty alcohols (ceteth-20, steareth-20) EP/NF (available as OVUCIRE® 3460, GATTEFOSSE, Saint-Priest, France); a mixture of hard fat EP/NF/JPE, glycerol monooleate (type 40) EP/NF (OVUCIRE WL 3264; a mixture of hard fat EP/NF/JPE, glyceryle monooleate (type 40) EP/NF (OVUCIRE WL 2944); and a mixture of various hard fats (WITEPSOL®, Sasol Germany GmbH, Hamburg, Germany). In certain embodiments, the viscosity of pharmaceutical compositions in accordance with various embodiments may comprise from about 50 cps to about 1000 cps at 25° C. A person of ordinary skill in the art will readily understand and select from suitable thickening agents.
In other embodiments, the thickening agent is a non-ionic surfactant. For example, polyethylene glycol saturated or unsaturated fatty acid ester or diester is the non-ionic surfactant thickening agent. In some embodiments, the non-ionic surfactant comprises a polyethylene glycol long chain (C16-C20) fatty acid ester and further comprises an ethylene glycol long chain fatty acid ester, such as PEG-fatty acid esters or diesters of saturated or unsaturated C16-C18 fatty acids, e.g., oleic, lauric, palmitic, and stearic acids. In embodiments, the non-ionic surfactant comprises a polyethylene glycol long chain saturated fatty acid ester and further comprises an ethylene glycol long chain saturated fatty acid ester, such as PEG- and ethylene glycol-fatty acid esters of saturated C16-C18 fatty acids, e.g., palmitic and stearic acids. Such non-ionic surfactant can comprise PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate, such as but not limited to TEFOSE 63.
In certain embodiments, the non-ionic surfactant used as a thickening agent is not hydrophilic and has good emulsion properties. An illustrative example of such surfactant is TEFOSE 63, which has a hydrophilic-lipophilic balance (HLB) value of about 9-10.
The selection and amount of hydrophilic polymer may be based on the selection and amount of solubilizing agent. The pharmaceutical composition can include a hydrophilic polymer but optionally excludes a gelling agent. In embodiments having a hydrogel, from about 5% to about 10% of the total mass may comprise the hydrophilic polymer. In further embodiments, hydrogels may be employed. A hydrogel may comprise chitosan, which swell in response to contact with water. In various embodiments, a cream pharmaceutical composition may comprise PEG-90M.
In addition to the above, the pharmaceutical compositions described herein can include one or more thermoreversible gels, typically of the hydrophilic nature including for example and without limitation, hydrophilic sucrose and other saccharide-based monomers (U.S. Pat. No. 6,018,033, which is incorporated herein by reference).
The choice of excipient will depend on factors such as, for example, the effect of the excipient on solubility and stability. Additional excipients used in various embodiments may include colorants, flavoring agents, taste-masking agents and preservatives. In certain embodiments, colorants, comprise about 0.1% to about 2% of the pharmaceutical composition by weight. In certain embodiments, preservatives in the pharmaceutical composition comprise methyl and propyl paraben, in a ratio of about 10:1, and at a proportion of about 0.005% and 0.05% by weight.
Generally, the solubilizing agents, excipients, other additives used in the pharmaceutical compositions described herein, are non-toxic, pharmaceutically acceptable, compatible with each other, and maintain stability of the pharmaceutical composition and the various components with respect to each other. Additionally, the combination of various components that comprise the pharmaceutical compositions will maintain will result in the desired therapeutic effect when administered to a subject.
The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Excipients used in various embodiments may include colorants, flavoring agents, preservatives and taste-masking agents. Colorants, for example, may comprise about 0.1% to about 2% by weight. Preservatives may comprise methyl and propyl paraben, for example, in a ratio of about 10:1, and at a proportion of about 0.005% and 0.05% by weight.
As is with all oils, solubilizers, excipients and any other additives used in the formulations described herein, each is to be non-toxic and pharmaceutically acceptable.
As referenced above, the formulations of this disclosure are generally orally administered, typically via, for example, capsules such as soft capsules.
In certain embodiments, a pharmaceutical composition of this disclosure comprises progesterone, (with about 15% or less, and in particular embodiments, about 5% or less of the progesterone being solubilized—the balance being ultra-micronized/suspended as discussed elsewhere herein), and an oil, wherein the oil is medium chain fatty acid mono- and diesters of one or more glycols, with or without surfactant.
Pharmaceutical formulations in accordance with various embodiments comprise ultra-micronized progesterone. In further embodiments, a pharmaceutical formulation comprises ultra-micronized progesterone, a carrier, and a lubricant. In still further embodiments a pharmaceutical formulation comprises ultra-micronized progesterone, a carrier, a lubricant, and optionally an antioxidant. In still further embodiments, a pharmaceutical formulation comprises ultra-micronized progesterone, and a medium chain triglyceride as a carrier. In still further embodiments, a pharmaceutical formulation comprises ultra-micronized progesterone, and mono-, di-, or triglycerides of caprylic/capric acid as a carrier. Various further embodiments also comprise lecithin and optionally butylated hydroxytoluene.
In additional embodiments, a pharmaceutical formulation comprises ultra-micronized progesterone and at least one carrier, a lubricant, optionally an antioxidant, and other pharmaceutically acceptable excipients. For example, in various embodiments, a pharmaceutical formulation comprises about 20% to about 80% carrier by weight, about 0.1% to about 5% lubricant by weight, and about 0.01% to about 0.1% antioxidant by weight.
According to embodiments, a pharmaceutical formulation comprises ultra-micronized progesterone, at least one carrier, and a non-ionic surfactant.
The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Excipients used in various embodiments may include colorants, flavoring agents, preservatives, and taste-masking agents. Colorants, for example, may comprise about 0.1% to about 2% by weight. Preservatives may comprise methyl and propyl paraben, for example, in a ratio of about 10:1, and at a proportion of about 0.005% and 0.05% by weight.
In various embodiments, ultra-micronized progesterone is administered in a capsule. Capsules may be prepared using one or more film forming polymers. Suitable film forming polymers include natural polymers, such as gelatin, and synthetic film forming polymers, such as modified celluloses. Suitable modified celluloses include, but are not limited to, hydroxypropyl methyl cellulose, methyl cellulose.
Manufacturing
In certain embodiments, the pharmaceutical composition is prepared by blending progesterone with a pharmaceutically acceptable solubilizing agent, including for example and without limitation, at least one medium chain fatty acid such as medium chain fatty acids consisting of at least one mono-, di-, or triglyceride, or derivatives thereof, or combinations thereof. In particular embodiments, the pharmaceutical composition also comprises at least one glycol or derivatives thereof or combinations thereof or combinations of at least one glyceride and glycol. The glycol(s) may be used as solubilizing agents or to adjust viscosity and, thus, may be considered thickening agents. Other excipients can optionally be included, including, for example and without limitation, anti-oxidants, lubricants, and the like. In some embodiments, the pharmaceutical composition includes sufficient solubilizing agent(s) to fully solubilize the progesterone. It is expressly understood, however, that other volumes of solubilizing agent can be used depending on the level of progesterone solubilization desired. Persons of ordinary skill in the art will know and understand how to determine the volume of solubilizing agent and other excipients depending on the desired percent of progesterone to be solubilized in the pharmaceutical composition.
In illustrative embodiments, GELUCIRE 44/14 (lauroyl macrogol-32 glycerides EP, lauroyl polyoxyl-32 glycerides NF, lauroyl polyoxylglycerides (USA FDA IIG)) is heated to about 45-65° C. and CAPMUL MCM or MIGLYOL 812 is heated to about 40° C. to facilitate mixing of the oil and non-ionic surfactant, although such heating is not necessary to dissolve the progesterone.
Specific Examples disclosed herein provide additional principles and embodiments illustrating processes for manufacturing the pharmaceutical compositions disclosed herein.
Delivery Vehicle
The pharmaceutical compositions described herein can be delivered orally inside of a delivery vehicle, for example a capsule. In certain embodiments, the capsules are soft capsules made of materials well known in the pharmaceutical arts such as gelatin. In other embodiments, the delivery vehicle is integral with the pharmaceutical composition (i.e., the pharmaceutical composition is the delivery vehicle). Hard or soft shell capsules can be used to administer the API. In certain embodiments, capsules may be prepared by forming the two capsule halves, filling one of the halves with a fill solution, and then sealing the capsule halves together to form the finished capsule.
Hard shell capsules may be prepared by combining the “Body” and the “Cap”. The “Body” of the capsule is filled with the “fill mass” and then closed with the “Cap”. The “Body”/“Cap” interface is then sealed/banded.
Soft gelatin (“softgel”) capsules may be prepared using a rotary die encapsulation process, as further described below. Softgel capsules may contain the formulation disclosed herein as a “fill material.” The soft gelatin capsule do not contain one or more of the following as the fill material: hydrophilic gel-forming bioadhesive (e.g., mucoadhesive) agents; a lipophilic agent and a gelling agent for the lipophilic agent, or a hydrodispersible agent. In some embodiments, the hydrophilic gel-forming bioadhesive agent is carboxyvinylic acid; hydroxypropylcellulose; carboxymethylcellulose; gelatin; xanthane gum; guar gum; aluminum silicate; or mixtures thereof. In still other embodiments, the lipophilic agent is a liquid triglyceride; solid triglyceride (e.g., with a melting point of about 35° C.); carnauba wax; cocoa butter; or a mixture thereof. In certain embodiments, the gelling agent is a hydrophobic colloidal silica. And in still other embodiments, the hydrodispersible agent can be polyoxyethylene glycol; polyoxyethylene glycol 7-glyceryl-cocoate; or a mixture thereof.
The softgel capsule itself may comprise a gelatin material in a relatively solid or stiff form. The gel capsule defines an inner volume that contains the fill material. Dissolution of the gelatin material may commence at various points after administration, such as in the digestive tract (mouth, esophagus, stomach and intestines), or in another body cavity, such as the vaginal tract.
Gel capsules may be prepared using one or more film forming polymers. Suitable film forming polymers include, but are not limited to, natural polymers, such as gelatin, and synthetic film forming polymers, such as modified celluloses. Suitable modified celluloses include, but are not limited to, hydroxypropyl methyl cellulose, methyl cellulose.
Suitable shell additives, for either a hard or soft shell capsules, may include plasticizers, opacifiers, colorants, humectants, preservatives, flavorings, and buffering salts and acids, and combinations thereof. The main ingredients of the capsule shell is primarily gelatin (or a gelatin substitute for non-gelatin capsules), plasticizer, and purified water. Hard shell and soft shell capsules differ primarily in the amount of plasticizer present that is used in the capsule shell.
Plasticizers are chemical agents added to gelatin to make the material softer and more flexible. Suitable plasticizers include, but are not limited to, glycerin, sorbitol solutions which are mixtures of sorbitol and sorbitan, and other polyhydric alcohols such as propylene glycol and maltitol or combinations thereof.
Opacifiers are used to opacify the capsule shell when the encapsulated active agents are light-sensitive. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate and combinations thereof.
Colorants can be used for marketing and product identification/differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof.
Flavorings can be used to mask unpleasant odors and tastes of fill formulations. Suitable flavorings include synthetic and natural flavorings. The use of flavorings can be problematic due to the presence of aldehydes which can cross-link gelatin. As a result, buffering salts and acids can be used in conjunction with flavorings that contain aldehydes in order to minimize cross-linking of the gelatin.
In accordance with various embodiments, a softgel dosage form is used.
As the softgel dissolves, the inner volume may come into fluid communication with the digestive system, allowing the fill material to leach outside the softgel. A softgel may also be punctured, cut, or otherwise opened outside a body. The fill material may then be poured or squeezed outside the gel capsule and applied on or in the body, such as within the vaginal cavity.
Humectants can be used to suppress the water activity of the softgel. Suitable humectants include glycerin, sorbitol, propylene glycol, microcrystalline cellulose, silica, mineral oil, and combinations thereof which are often components of the plasticizer composition. Regulated water activity in pharmaceutical compositions and dosage forms, such as capsules, can improve the compatibility and stability of the compositions and forms. This is because when hydrolosis is regulated chemical degradation caused by water is also regulated (or slowed, as is desirable in the present case). Thus, by regulating water in the present compositions, the capsule shells are less likely to soften, dissolve, break, or leak during storage. Moreover, due to the low water activity of dried, properly stored softgels, the greatest risk from microorganisms comes from molds and yeasts. For this reason, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxy benzoic acid such as methyl, ethyl, propyl, butyl and heptyl esters (collectively known as “parabens”) or combinations thereof.
The fill material may comprise a liquid, such as an oil, a solution, a suspension, or other acceptable forms. The active ingredient or active ingredient may be contained within the liquid.
Hard and softgel capsules can be manufactured according to various techniques known in the art. In particular embodiments, softgel capsules can be prepare using a rotary die encapsulation process. An exemplary process is disclosed in Wilkinson, P. K. et al., 1990, “Softgels: manufacturing considerations.” In: Specialized Drug Delivery Systems, P. Tyle (Ed.), pp. 409-449, Marcel Dekker, Inc., New York, the entirety of which is hereby incorporated by reference.
In other embodiments, softgels can be prepared according to the process disclosed in PCT/US2000/005178, the entirety of which is incorporated herein by reference.
Hard shell capsules can also be used as the delivery vehicle. These capsules may be prepared by forming the two capsule halves, filling one half with the fill material, and then sealing the halves together to form the finished capsule. In other embodiments, hard shell capsules may be prepared by combining a “body” and a “cap.” The “body” of the capsule is filled with the fill material and then closed with the cap. The body/cap interface is then sealed or banded.
Drawings
Methods of manufacture in accordance with various embodiments are shown in
Operation 104 may comprise mixing progesterone (progesterone) into the mixture of the solubilizing agent, the surfactant (i.e. lubricant), and the antioxidant. A pasty substance is thus formed. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Operation 104 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Operation 106 comprises degasing. The resulting mixture from operation 106 may comprise a pharmaceutical composition suitable for production into a softgel capsule.
With reference to
Operation 204 comprises the addition of gelatin to the glycerin water mixture. Mixing may be facilitated by an impellor, agitator, or other suitable means. Operation 204 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. A vacuum may be drawn in operation 204 to de-aerate.
Operation 206 comprises addition of an excipient (i.e. coloring agent) such as a dye. A coloring agent may comprise products sold under the trademark OPATINT or the suitable agent. Operation 206 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Operation 208 comprises degasing. The resulting mixture from operation 208 may comprise a gel capsule material suitable for use as a gel capsule in production of a softgel capsule.
With reference to
Operation 304 comprises filling a gel mass. A gel mass may be taken from the gel capsule material produced in operation 208 of
Operation 306 comprises drying the softgel capsules. Drying may be performed in a tumble dryer, tray dryer, or combinations thereof. For example, drying may be performed in a tumble drying basket for between about 10 minutes and about 120 minutes. Drying may continue in a drying room for about 24 hours to about 72 hours. Polishing may be performed with isopropyl alcohol.
Design Factors for Encapsulated Pharmaceutical Compositions
In certain embodiments, the pharmaceutical composition is designed to maximize API solubility, and other favorable characteristics without sacrificing efficacy, while simultaneously improving bioavailability in subjects. Other favorable characteristics, besides improving bioavailability as compared to the RLD, include, for example, bioavailability that is bioequivalent to the RLD, improved subject compliance (i.e., ability to easily take the right capsule during the correct period), reducing food and allergy effects due to administration, and reducing required prescribed dosage levels in order to achieve efficacy of the drug product.
In some embodiments, progesterone is fully or partially solubilized. The form of the API (i.e., being in solution), and other factors and conditions, may account for the increased bioavailabilty of progesterone as compared to the RLD.
In some embodiments, the pharmaceutical composition is delivered via a gelatin capsule delivery vehicle. In these embodiments, the pharmaceutical composition is a liquid pharmaceutical composition. Accordingly, the pharmaceutical composition of such embodiments is encapsulated in the gelatin capsule. The inclusion of the capsules in blister packs, as described elsewhere herein, ensures that subjects will receive the right dosage during the correct period of time.
In some embodiments, the gelatin capsules are softgels. Other forms of administration (i.e. injection, intra-muscular, etc.) can cause pain, discomfort, or irritation, especially when frequent administration is required. Softgels eliminate these problems, while minimizing adverse tastes. Softgels can be administered orally or can be administered locally. In some embodiments, the softgel is administered orally.
Through extensive experimentation, various medium chain fatty acid esters of glycerol and propylene glycol demonstrated one or more favorable characteristics for development as a human drug product. In one embodiment, the solubilizing agent was selected from at least one of a solvent or co-solvent. Suitable solvents and co-solvents include any mono-, di-, or triglyceride and glycols, and combinations thereof.
In other embodiments, the solubilizing agent was selected from one or more C6 to C12 fatty acid mono-, di-, or triesters of glycerol, e.g., one or more C6 to C14 triglycerides, e.g., one or more C6 to C12 triglycerides, such as one or more C8-C10 triglycerides. Thus, in certain embodiments, the pharmaceutical composition comprises progesterone that is at least about 75% solubilized in a solubilizing agent comprising one or more C6 to C14 medium chain fatty acid mono-, di-, or triglycericdes and, optionally, a thickening agent.
In still other embodiments, the pharmaceutical composition comprises progesterone that is at least about 75% solubilized one or more C6 to C12 medium chain fatty acid mono-, di-, or triglycerides, e.g., one or more C6 to C14 triglycerides, e.g., one or more C6 to C12 triglycerides, such as one or more C8-C10 triglycerides. These embodiments specifically contemplate the progesterone being at least 85% solubilized, at least 90% solubilized, at least 95% solubilized, and in certain instances, 100% solubilized. In other embodiments, estradiol or a combination of progesterone and estradiol is included in the pharmaceutical compositions as the one or more APIs.
As noted previously herein, liquid pharmaceutical compositions are preferably liquid at room temperature. Accordingly, gels, hard fats, or other solid forms that are not liquid at room or body temperature are less desirable in embodiments of the pharmaceutical composition that are liquid. In certain embodiments, where a non-ionic surfactant such as GELUCIRE or TEFOSE to increase viscosity, the non-ionic surfactant may be solid at room temperature. In those situations, the non-ionic surfactant may require melting to mix with one or more APIs solubilized in a fatty acid-glycol ester. In this embodiment, the resultant composition is advantageously liquid, not solid. However, in these embodiments, the resultant pharmaceutical composition remains liquid, albeit with greater viscosity, although it is still not a solid.
In other embodiments, the pharmaceutical composition comprises progesterone, a medium chain solubilizing agent, and a thickening agent as the only essential ingredients delivered via a softgel delivery vehicle. Non-essential ingredients, e.g., colorants, antioxidants, preservatives, or other excipients may be included as well. Other embodiments comprise one or more APIs.
Additional ingredients can be incorporated in amounts that do not materially change the solubility of the progesterone, the pharmacokinetics of the pharmaceutical composition, or the efficacy of the pharmaceutical composition. Other factors that should be considered when adjusting the ingredients of the pharmaceutical composition include taste, water regulation, and other relevant factors, for example those that would lead to reduced patient compliance.
In softgel embodiments, mucoadhesive agents, gelling agents, dispersing agents, or the like would not be included because of effects some of these ingredients may have on bioavailability of the API(s) in the digestive system.
Methods
Pharmaceutical compositions in different embodiments may be administered alone or combination with one or more other drugs (or as any combination thereof). For example, compositions in accordance with embodiments including one or more other drugs may also comprise estradiol. In such compositions, estradiol is also an API.
In certain embodiments, and as discussed elsewhere herein, the pharmaceutical composition disclosed herein can be administered orally in a softgel. As the softgel dissolves after administration, the inner volume may come into fluid communication with the digestive system such that the progesterone present in the pharmaceutical composition can be absorbed systemically. Oral administration may involve swallowing, so that the pharmaceutical composition enters the gastrointestinal tract. Alternatively, buccal or sublingual administration may be employed such that the pharmaceutical composition enters the bloodstream directly from the mouth.
In embodiments where hard shell capsules are employed, the method of administration is typically oral. Hard capsules or softgels may be arranged in blisters or cartridges or bottles.
In certain embodiments, a 28-day or monthly regimen of capsules can be packaged in a single kit (e.g., a blister pack) having delivery days identified to improve subject compliance. One or more of the capsules may contain no progesterone. A blister pack can have a plurality of scores or perforations separating blister pack into 28 days. Each day may further comprise a single blister or a plurality of blisters. In various embodiments, each dose (e.g., each softgel) may contain solubilized, partially solubilized, or partially suspended progesterone in any of the amounts previously set forth herein, though may, in certain instances, include 100, 150, or 200 mg of progesterone. In addition, kits having other configurations are also contemplated herein. For example, without limitation, kits having such blister packs may contain any number of capsules.
In additional embodiments, progesterone is formulated for intraperitoneal, percutaneous, subcutaneous, intra-muscular, and atomization administration (i.e. such as with nasal mist administration).
In still other embodiments, the pharmaceutical compositions are administered according to other techniques known to those skilled in the art, which may include, but are not limited to: tablets, film-coated tablets, prolonged-release tablets, modified-released tablets, effervescent tablets, orodispersible tablets, sachets, dry powders used to form suspension; or liquid dosage forms.
Compositions in accordance with the various embodiments disclosed herein may be used to treat or prevent endometrial hyperplasia, prevent secondary amenorrhea, or mitigate or treat the effects of estradiol supplementation. In certain embodiments, compositions comprising progesterone may be co-administered with estradiol or co-formulated with estradiol.
In other embodiments, formulations in accordance with various embodiments may be used to treat or prevent preterm delivery in pregnant women, including in certain women having a shortened cervix. In various embodiments, a capsule, for example a softgel capsule, may be opened and the fill material applied in or around the vagina. However, in various embodiments the capsules are taken orally.
In still further embodiments, formulations in accordance with various embodiments may be used to treat menopause-related symptoms, including vasomotor symptoms, for example, in relation to treatment of hypoestrogenism related symptoms including hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes, vulvo-vaginal atrophy; and osteoporosis and endometrial hyperplasia reduction.
In still further embodiments, formulation in accordance with various embodiments may be used to treat amenorrhea.
Additional objects of this disclosure include: providing increased patient compliance secondary to ease of use; providing increased physician adoption secondary to ease of use/instruction with less worry of side effects from inappropriate usage; providing decreased side-effects from erroneous use (decreased irregular bleeding); providing better efficacy/control of symptoms secondary to appropriate use; reducing the metabolic and vascular side effects of the commonly used synthetic progestins when administered alone or in combination with an estrogen (norethindrone acetate, medroxyprogesterone acetate, etc.) including, for example, stroke, heart attacks, blood clots and breast cancer.
Enhanced Bioavailability
In certain embodiments, the formulations disclosed herein provide enhanced bioavailability of progesterone when compared to conventional progesterone formulations. As a result of this improved bioavailability, certain embodiments of the formulations disclosed herein allow for a reduction in the quantity of progesterone administered to a person in need thereof while still providing the providing the benefits of a dosage form containing the greater amount of progesterone.
As such, and in certain embodiments, a formulation of this disclosure can include less than 200 mg of progesterone while still having an acceptable PK profile. In particular, embodiments, the formulation can include about 175 mg of progesterone, about 170 mg of progesterone, about 165 mg of progesterone, about 160 mg of progesterone, about 159 mg of progesterone, about 158 mg of progesterone, about 157 mg of progesterone, about 156 mg of progesterone, about 155 mg of progesterone, about 154 mg of progesterone, about 153 mg of progesterone, about 152 mg of progesterone, about 151 mg of progesterone, about 150 mg of progesterone, about 149 mg of progesterone, about 148 mg of progesterone, about 147 mg of progesterone, about 146 mg of progesterone, about 145 mg of progesterone, about 170 mg of progesterone, about 140 mg of progesterone, about 135 mg of progesterone, about 170 mg of progesterone, about 130 mg of progesterone, about 125 mg of progesterone, about 120 mg of progesterone, about 115 mg of progesterone, about 110 mg of progesterone, about 105 mg of progesterone, or about 100 mg of progesterone. In still further embodiments, the formulation can have exactly the amounts of progesterone noted above, e.g. exactly 175 mg of progesterone, exactly 170 mg of progesterone, etc.
In certain embodiments, this disclosure provides a formulation including less than 200 mg of progesterone having an AUC0-∞ in (ng/ml)*hr of from about 5 to about 500, from about 5 to about 400, from about 5 to about 300, from about 5 to about 270, from about 20 to about 200, from about 25 to about 150, or from about 25 to about 140. In particular embodiments, the formulation including less than 200 mg progesterone can have an AUC0-∞ of about 137 (ng/ml)*hr±95%. In particular embodiments, the formulation can have about 150 or exactly 150 mg progesterone.
In certain embodiments, this disclosure provides a formulation including less than 200 mg of progesterone having an AUC0-t in (ng/ml)*hr of from about 5 to about 500, from about 5 to about 400, from about 5 to about 300, from about 5 to about 240, from about 20 to about 200, from about 25 to about 150, or from about 25 to about 140. In particular embodiments, the formulation including less than 200 mg progesterone can have an AUC0-t of about 120 (ng/ml)*hr±95%. In particular embodiments, the formulation can have about 150 or exactly 150 mg progesterone.
In certain embodiments, this disclosure provides a formulation including less than 200 mg of progesterone having a Cmax in ng/ml of from about 3 to about 350, from about 3 to about 325, from about 3 to about 300, from about 3 to about 250, from about 3 to about 240, and from about 3 to about 230. In particular embodiments, the formulation including less than 200 mg progesterone can have a C. of about 75 ng/ml±95%. In particular embodiments, the formulation can have about 150 or exactly 150 mg progesterone.
Although the amount of progesterone is typically less than 200 mg, in certain embodiments, the amount of progesterone can be about 300 mg. In such embodiments, the formulation can have the PK parameters discussed below upon administration.
In certain embodiments, this disclosure provides a formulation including about 300 mg of progesterone having an AUC0-∞ in (ng/ml)*hr of from about 10 to about 1000, from about 10 to about 800, from about 10 to about 600, from about 10 to about 540, from about 40 to about 400, from about 50 to about 300, or from about 50 to about 280. In particular embodiments, the formulation including about 300 mg progesterone can have an AUC0-∞ of about 274 (ng/ml)*hr±95%.
In certain embodiments, this disclosure provides a formulation including about 300 mg of progesterone having an AUC0-t in (ng/ml)*hr of from about 10 to about 1000, from about 10 to about 800, from about 10 to about 600, from about 10 to about 480, from about 40 to about 400, from about 50 to about 300, or from about 50 to about 280. In particular embodiments, the formulation including about 300 mg progesterone can have an AUC0-t of about 240 (ng/ml)*hr±95%.
In certain embodiments, this disclosure provides a formulation including about 300 mg of progesterone having a Cmax in ng/ml of from about 6 to about 700, from about 6 to about 650, from about 6 to about 600, from about 6 to about 500, from about 6 to about 480, and from about 6 to about 460. In particular embodiments, the formulation including about 300 mg progesterone can have a C. of about 150 ng/ml±95%.
Bioavailability comparisons to commercially available forms, such as tablet forms, may be determined by standard pharmacokinetic techniques.
In accordance with various embodiments, food effects are reduced, e.g., relative to comparative progesterone products.
In accordance with various embodiments, formulations do not include peanut oil. The lack of peanut oil obviates the risk posed to those having peanut-based allergies.
Measurement of Efficacy
Efficacy can be measured using standard techniques known in the art. However in certain embodiments, subjects are administered progesterone. After administration of the progesterone, endometrial biopsies can be performed by a board-certified gynecologist. Procedures, instruments used, and observations are documented in the subject's file.
The resulting biopsy specimens can then processed by a central laboratory. The central laboratory includes a chartered pathology committee of independent pathologists who are experts in the field of endometrial pathology to assess all endometrial biopsy sample.
In certain embodiments, treatment with the pharmaceutical compositions described herein resulted in complete and partial secretory activity. In cases of complete secretory activity, subjects experienced 1) glands with secretory changes, and 2) stromal predecidual changes. In cases of partial secretory activity, subjects experienced 1) glands with secretory changes, or 2) stromal predecidual changes.
In certain embodiments, subjects are administered pharmaceutical compositions as described herein, while other subjects are administered placebos. Exemplary test scenarios are described in the Example section, below. In these embodiments, secretory activity is measured as a proportion of subjects at Cycle 3 Day 24±1 day on active treatment (200 mg progesterone/day, 225 mg progesterone/day, or 300 mg progesterone/day) compared to placebo with complete secretory activity on endometrial biopsy (referenced in the examples as the “primary efficacy endpoint”).
In these embodiments, secretory activity is also measured as a proportion of subjects at Cycle 3 Day 24±1 day on active treatment (200 mg progesterone/day, 225 mg progesterone/day, or 300 mg progesterone/day) compared to placebo with total secretory activity (defined as the aggregate of partial and complete secretory activity) on endometrial biopsy. Included in this measurement is an observation of the proportion of subjects reporting withdrawal bleeding at cycle 2 on or after cycle day 21 or within 7 days (including 7th day) after completion of blinded treatment at cycle 2 (this and the secretory measurement of the preceding sentence are referenced in the examples as the “secondary efficacy endpoints”).
Statistical Measurements
Pharmacokinetics of the pharmaceutical composition disclosed herein can be calculated using statistical analyses. In particular embodiments, Analysis of Variance (“ANOVA”) or Analysis of CoVariance (“ANCOVA”) are used to evaluate differences between a subject receiving treatment with a pharmaceutical composition comprising an active pharmaceutical composition (for example, a pharmaceutical composition comprising progesterone) and a subject receiving treatment with a placebo (for example, the same pharmaceutical composition but without progesterone) or a reference drug. A person of ordinary skill in the art will understand how to perform statistical analysis of the data collected.
Among the data collected or calculated are PK parameters for pharmacokinetic evaluation and analysis, including, but not limited to, AUC, Cmax, and Tmax. The pharmacokinetic evaluation was carried out by a research lab using statistical and analytical software, which could include, but is not limited to, WinNonlin® software (version 5.3), and using SAS version 9.2.
Through extensive trial-and-error testing of various fatty acid esters of glycerol and other glycols, embodiments of the invention have been invented that have one or more favorable characteristics for development as a human drug product. Such favorable characteristics include those described above, e.g., improved PK properties and reduced inter- and intra-patient variability.
Such embodiments include an encapsulated liquid pharmaceutical formulation for orally administering progesterone to a mammal in need thereof, said formulation comprising: progesterone, as the sole active pharmaceutical ingredient, in ultra-micronized form suspended in a carrier that comprises a medium chain fatty acid-glycol ester or mixtures thereof and a non-ionic surfactant comprising a polyethylene glycol fatty acid ester.
In particular embodiments, the progesterone can be ultramicronized.
In certain embodiments, the progesterone is suspended or solubilized in one or more solubilizing agents such as one or more C6 to C14 fatty acid mono-, di-, or triesters of glycerol, including, but not limited to, one or more C6 to C14 triglycerides, one or more C6 to C12 triglycerides, or one or more C8-C10 triglycerides, as well as combinations thereof. An example of a solubilizing agent that provides beneficial properties is MIGLYOL, and in particular MIGLYOL 812.
In such general and more specific embodiments, the non-ionic surfactant is a polyethylene glycol saturated or unsaturated fatty acid ester or diester. In certain such embodiments, the non-ionic surfactant comprises C8 to C18 fatty acid esters of glycerol and polyethylene glycol. An example of a non-ionic surfactant that provides beneficial properties is GELUCIRE, e.g., GELUCIRE 44/14.
In certain such embodiments, the non-ionic surfactant has a HLB value of about 15. An illustrative example of such surfactant is GELUCIRE 44/14.
The formulations and methods described herein are now further detailed with reference to the following examples. These examples are provided for the purpose of illustration only and the formulations and methods described herein should in no way be construed as being limited to these examples. Rather, the formulations disclosed herein should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.
In an exemplary embodiment, a capsule is provided containing a fill material comprising a formulation set forth in one of Tables 2, 2A, or 2B
The formulation in Table 2 is prepared as follows: MIGLYOL is heated to about 45° C. GELUCIRE 44/14 is added and mixed until dissolved. BHT is added and mixed until dissolved. Progesterone is suspended and passed through a colloid mill. The resultant fill mass can be used for encapsulation.
The formulations in Tables 2A and 2B are prepared as follows: melt Gelucire 44/14 by heating it to about 45-50° C.; once Gelucire 44/14 is completely melted, add MIGYOL 812 and mix/stir until dissolved; continue mixing/stirring; during the mixing/stirring, slowly add progesterone to the solution; and, after all progesterone has been added, continue mixing for a period of time to ensure proper suspension and near dissolution equilibrium. The suspended progesterone is then passed through a colloid mill. De-gassing and applying a vacuum for complete de-aeration of the fill mass is conducted. The resultant fill mass can be used for encapsulation.
In an exemplary embodiment, a capsule is provided containing a fill material comprising:
In various embodiments, amounts of MIGLYOL may be present in a range from about 35-95% by weight; GELUCIRE 44/14 from about 0.5-30% by weight; and BHT from about 0.01-0.1% by weight.
Progesterone Solubility
In various embodiments, both estradiol and progesterone may be independently dissolved in a solubilizing agent. In various embodiments, the solubility of both estradiol and progesterone will be such that a therapeutically effective dose may be obtained in a reasonably sized mass, generally considered to be between 1 mg and 1200 mg, preferably suitable for encapsulation in a size 3 to 22 oval or oblong capsule. For example, in various embodiments, 50 mg to 100 mg of progesterone may be dissolved in a volume of solubilizing agent; i.e., the solubility would be 50 mg to 100 mg per capsule.
MIGLYOL was attempted, and while it can be considered a good carrier for progesterone, it alone did not provide a desirable level of solubilization of estradiol (e.g., solubility of 12 mg/g may be desirable in various embodiments). Thus, MIGLYOL, including without limitation MIGLYOL 812, may be used in embodiments comprising fully solubilized, partially solubilized, and suspended progesterone.
As can be seen in Table 4, the solubility of progesterone in CAPMUL MCM is ˜73 mg/g. Therefore, by suspending 200 mg progesterone in 400 mg of solvent, part of the dose (˜14%) is already dissolved and the remaining is still a suspension. In some aspects and embodiments, it is desired to minimize the partial solubility of progesterone in the formulation in order to minimize the possibility of recrystallization. Based on 73 mg/g solubility, the capsule size required to make a capsule of 50 mg solubilized progesterone would be 685 mg. Based on 95 mg/g solubility, a 50 mg progesterone capsule would require a 526 capsule size. The other capsule sizes required based on each respective solubility below includes: 1,799 mg, 579 mg, 709 mg, and 871 mg. Capsule size amounts based on respective solubilities will generally be at least 10% greater than the calculated value in order to ensure the progesterone remains in solution. Thus, a 50 mg progesterone capsule based on 73 mg/g solubility would require a 685 mg capsule, and with the at least 10% addition, it would require approximately a 754 mg sized capsule. Based on each respective solubility listed below, the capsule sizes include (approximately): 579 mg, 1979 mg, 637 mg, 780 mg, and 958 mg respectively. These values, and their corresponding 10% additions are shown in Table 4.
In addition, it has been found that the solubility of progesterone in a solvent of CAPMUL MCM in combination with GELUCIRE 44/14 in a 9:1 ratio increases the solubility to approximately 86 mg/g. Therefore, in various embodiments, progesterone or estradiol may be dissolved in a CAPMUL MCM and GELUCIRE 44/14 system, wherein the ratio of CAPMUL MCM to GELUCIRE 44/14 is 9:1.
In an exemplary embodiment, a capsule is provided containing a fill material having suspended progesterone comprising:
The above formulation is prepared as follows: MIGLYOL is heated to about 45° C. GELUCIRE 44/14 is added and mixed until dissolved. BHT is added and mixed until dissolved. Progesterone is suspended and passed through a colloid mill. The resultant fill mass can be used for encapsulation.
In an exemplary embodiment, a capsule is provided containing a fill material having partially solubilized progesterone comprising:
6.0 kg
For suspensions of progesterone and partially solubilized progesterone, GELUCIRE 44/14 may be added at 1% to 2% w/w to increase viscosity. The above formulation is prepared as follows: CAPMUL MCM is heated to about 65° C. GELUCIRE 44/14 is added and mixed until dissolved. Heat is removed. Progesterone is added and the mixture is passed through a colloid mill. The resultant fill mass can be used for encapsulation.
In particular embodiments, a capsule is provided containing a pharmaceutical composition having fully solubilized, partially solubilized, or suspended progesterone comprising the components according to the formulations specified in Tables 8 and 9:
The pharmaceutical composition above can be prepared in accordance with the procedures noted in prior examples.
A gel mass can be prepared in order to encapsulate the pharmaceutical compositions of the various Examples herein.
Gel mass compositions were formulated and produced according to the following steps. Purified water (22.2 kg) and glycerin (10.8 kg) were charged into a stainless steel tank with mixing and heated to a temperature of 80±5° C. Hydrolyzed gelatin (1.8 kg) and gelatin 200 bloom limed bone, NF (24.0 kg) were then added to the water/glycerin mixture and were mixed until all solids were completely dissolved. This resulted in the formation of a gel mass. The resulting gel mass was de-gassed under vacuum. Coloring agents OPATINT® white (0.6 kg) and OPATINT® red (0.6 kg) were then added to the gel mass and the resultant was mixed for about 5 minutes. The resultant was then de-gassed under vacuum for a sufficient period of time and ultimately passed to an encapsulation device for preparation of gel capsules of the types disclosed herein.
Bioavailability Assessment—Fasted
A randomized single-dose oral bioequivalence study comparing 200 mg ultra-micronized progesterone capsule test product (T) and 200 mg PROMETRIUM® (progesterone) capsules (Abbott Laboratories, Abbott Park, IL) reference product (R) is conducted. Subjects are administered a single 200 mg dose of either test product (T) or the reference product (R) under fasting conditions, for example, subjects fasted at least 10.0 hours prior to dosing. Blood is collected pre-dose and post-dose. Pre-dose samples are collected at approximately −01.00, −00.50, and 00.00 hours. Post-dose samples are collected at approximately 01.00, 02.00, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00, 09.00, 10.00, 12.00, 18.00, 24.00, 36.00 and 48.00 hours. Standard meals are provided at 04.00, 09.00, 13.00, 25.00, 29.00, 33.00 and 37.00 hours post-dose.
Pharmacokinetic measurements are assessed including Cmax, AUC and optionally Tmax. Comparative bioavailability of the test product (T) and reference product are assessed.
Bioavailability Assessment—Fed
The procedures for determining bioavailability under fasted conditions are repeated except that subjects are administered a single 200 mg dose of either test product (T) or reference product (R) immediately following a high fat meal, for example, within 30 minutes of dosing. Blood is collected pre-dose and post-dose. Pre-dose samples are collected at approximately −01.00, −00.50, and 00.00 hours. Post-dose samples are collected at approximately 01.00, 02.00, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00, 09.00, 10.00, 12.00, 18.00, 24.00, 36.00 and 48.00 hours. Standard meals are provided at 04.00, 09.00, 13.00, 25.00, 29.00, 33.00 and 37.00 hours post-dose. Pharmacokinetic measurements are assessed including Cmax, AUC and optionally Tmax. Bioavailability of the test product (T) in reference to the reference product is assessed. The effect of food on the comparative bioavailability of the test product (T) and the reference product (R) are also assessed.
Method of manufacture in accordance with various embodiments are shown in
Operation 104 may comprise mixing ultra-micronized progesterone into the mixture of the carrier, the lubricant, and the antioxidant. A pasty substance is thus formed. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Operation 104 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Operation 106 comprises degasing. The resulting mixture from operation 106 may comprise a fill material suitable for production into a softgel capsule.
With reference to
Operation 204 comprises the addition of gelatin to the glycerin water mixture. Mixing may be facilitated by an impellor, agitator, or other suitable means. Operation 204 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. A vacuum may be drawn in operation 204 to de-aerate.
Operation 206 comprises addition of a coloring agent such as a dye. A coloring agent may comprise products sold under the trademark OPATINT or other suitable agent. Operation 206 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Operation 208 comprises degasing. The resulting mixture from operation 208 may comprise a gel capsule material suitable for use as a gel capsule in production of a softgel capsule.
With reference to
Operation 304 comprises filling a gel mass. A gel mass may be taken from the gel capsule material produced in operation 208 of
Operation 306 comprises drying the softgel capsules. Drying may be performed in a tumble dryer, tray dryer, or combinations thereof. For example, drying may be performed in a tumble drying basket for between about 10 minutes and about 120 minutes. Drying may continue in a drying room for about 24 hours to about 72 hours. Polishing may be performed with isopropyl alcohol.
Stability Study
In accordance with various embodiments, formulations in accordance with various embodiments have an exemplary shelf life of 3 months with storage at 25±2° C./60±5% RH in 75 cc HDPE white, opaque bottles with a 38/400 mm white child resistant cap.
Packaging during testing comprises a 75 cc round HDPE bottle and 33 mm cap. A Brasken FPT 300F resin is associated with the cap. Testing criteria include visual appearance, assay of progesterone, dissolution, content uniformity and microbial limits testing.
Three test groups are created. Test group 1 comprises a test at 40° C./75% RH. Test group 2 comprises a test at 30° C./65% RH. Test group 3 comprises a test at 25° C./60% RH. Test group 1 is tested for visual appearance, assay of ultra-micronized progesterone, and dissolution at months 1, 2, 3, and 6. Test group 2 is tested for visual appearance, assay of ultra-micronized progesterone, and dissolution at months 0, 1, 2, 3, 6, and 12. Test group 3 is tested for visual appearance, assay of ultra-micronized progesterone, and dissolution at months 0, 1, 2, 3, 6, 12 and 24.
A particle size analysis is conducted by using a Beckman Coulter LS 13 320 Laser Diffraction Particle Size Analyzer (the “Beckman Device”). The Beckman Device uses laser diffraction to determine particle size. A sample of a formulation in accordance with various embodiments is provided. The Beckman Device particle sensor yields that the sample has an X50 of 6.67 μm, an X75 of 14.78 μm, and an X25 of 2.193 μm.
A dissolution study was performed using a formulation in accordance with various embodiments. The results of the dissolution study are shown in
The dissolution study was performed using a United States Pharmacopoeia dissolution apparatus 3 (reciprocating cylinder) (“USP Apparatus 3”). The USP Apparatus 3 was set to 30 dips per minute. Two hundred fifty mL (250 mL) of a solution of. 1N HCL with 3% sodium lauryl sulfate was used at 37° C.
For the purposes of this Example, a particle size analysis is conducted by using the Beckman Device. A sample API comprising ultra-micronized progesterone in accordance with various embodiments is provided for analysis.
Approximately 0.01 g of a sample API in accordance with various embodiments was combined with Coulter 1B and 10 mL of deionized water. Sonication was performed for 15 seconds. The Beckman Device, equipped with a ULM, performed analysis for 90 seconds. The Beckman Device was configured to use the Fraunhofer optical model. The Beckman Device yielded that the sample has an X50 of 4.279 μm, an X75 of 7.442 μm, and an X25 of 1.590 μm. The Beckman Device also yielded that the mean particle size is 4.975 μm, the median particle size is 4.279 μm, the mode particle size is 6.453 μm, and the standard deviation is 3.956 μm. A graph of the particle distribution obtained is shown in
Dissolution
Dissolution studies were performed using a formulation of this invention comparing the dissolution of progesterone to the dissolution of PROMETRIUM and comparing the dissolution of estradiol to the dissolution of Estrace. In one study, a formulation of the invention in capsules comprising 200 mg of progesterone and 2 mg estradiol was used. In a second study, a formulation of the invention in capsules comprising 50 mg of progesterone and 2 mg estradiol was used.
The dissolution study was performed using a USP dissolution apparatus (reciprocating cylinder) (“USP Apparatus 3”). The apparatus was set to 30 dips per minute. 250 mL of a solution of 0.1N HCl with 3% sodium lauryl sulfate was used at 37 C.
In both studies, progesterone was dissolved faster, and with smaller standard deviations, from the capsules of the invention than from PROMETRIUM. Dissolution of estradiol was comparable but marginally slower from the capsules of the invention than from Estrace. For illustrative purposes, a graph showing progesterone dissolution from the 200 mg progesterone capsule of the invention and from PROMETRIUM is attached as
Both capsules of the invention were stable on storage in white HDPE bottles. Positive stability data were obtained with the 200 mg progesterone formulation over 6 months (>6 months data unavailable) and with the 50 mg progesterone formulation over 3 months (>3 months data unavailable).
Bioavailability & Bioequivalence Assessment
This study was conducted to determine bioavailability and bioequivalence of reference product PROMETRIUM “R” (200 mg progesterone) and test product “T” as described in Table 9 herein. T was administered as a softgel capsule.
The study was an open-label, balanced, randomized, single-dose, two-treatment, three-period, three-sequence, crossover, partial replicate, reference-scaled oral bioequivalence study. A total of 72 healthy, adult, human, postmenopausal female subjects were enrolled in the study. Each subject was randomly assigned to a sequence (TRR, RTR, or RRT) such that each subject received T once and R twice during the course of the 32 day study (14 day washout between doses). R was administered twice so that the within subject variance could be calculated for later assessment of bioequivalence of the T and R formulations.
On study days 1, 15, and 29, patients who had been fasting for 10 hours were administered a high fat meal. 30 minutes after the meal, each patient was given a single softgel dose of T or, alternatively, R, in accordance with the patients' randomly assigned sequence. The dosage forms were taken with 240 ml of water. Subjects were housed in a clinical facility for at least 11 hours prior to dosing to at least 24 hours post dose.
A total of 20 (3×8 mL pre-dose and 17×6 mL post dose) blood samples were collected per subject after each dose. Pre-dose samples were collected at −1.00, −0.50, 0 hrs. Post dose samples were collected at 0.25, 0.50, 0.67, 0.83, 1.00, 1.33, 1.67, 2.00, 02.50, 3.00, 4.00, 6.00, 8.00, 12.00 24.00, 36.00 and 48.00 hours after dosing in vacutainers containing K2EDTA. Based on an analysis of the collected blood samples, pharmacokinetic parameters including Cmax, AUC0-t, AUC0-∞, and Tmax were calculated using WinNonlin® version 5.3 (Pharsight Corporation). Although 72 patients were enrolled in the study, only data from the 62 patients who finished the study was used to calculate the values shown in Table 11, below.
Bioequivalence Analysis
In this study, the within-subject standard deviation of the reference formulation (SWR) was found to be ≥0.294 for Cmax and AUC (AUC0-t and AUC0-∞). As a result, the point estimate (test/reference geometric mean ratio) and 95% upper confidence bound for (μT−μR)2−(θS2WR) was determined using ln-transformed data using SAS® statistical software version 9.2 from SAS Institute Inc, USA. This methodology (Scaled-Average Bioequivalence (“SABE”)) is consistent with FDA guidelines for calculating bioequivalence for highly variable drugs, such as progesterone. Using the SABE methodology, T demonstrated improved bioavailability compared to PROMETRIUM and was considered superior to PROMETRIUM. Supporting data is shown in Tables 12 and 13 below.
In view of the data noted above, the appropriate dosage of progesterone in the formulation disclosed herein necessary to achieve bioequivalence to PROMETRIUM was 150 mg. The computed results are shown in Table 14. This suggests that, in certain embodiments, the formulations disclosed herein have nearly 25% greater bioavailability than the current marketed formulation (PROMETRIUM).
Bioavailability Assessment—Fed #3
The amounts progesterone administered include 225 mg/day and 300 mg/day of progesterone. Progesterone capsule sizes are 75 mg and 150 mg capsules. Subjects taking the progesterone capsules are compared to subjects taking placebos. In both cases subjects are estrogen-primed.
The study includes: approximately a 6-week (42 days) screening period before enrolling into the study; approximately 6 weeks of Estrace®-priming before randomization; 6 weeks of blinded treatment (along with Estrace® treatment); and up to approximately 5 weeks of follow-up. The study is a phase 3, randomized, three-cycle, double-blind, placebo-controlled study to evaluate induction of secretory conversion of endometrium and withdrawal bleeding after administration of progesterone in estrogen-primed women with secondary amenorrhea. In clinical facilities, at the first visit (baseline—Cycle 1, day 1) subjects are estrogen-primed using an oral estradiol (i.e. 1.0 mg Estrace®). This priming takes place for 25 days. Compliance with estrogen-priming is determined (throughout, and at day 28 −3 day to +1 day). Subjects will begin cycle 2 of estrogen-priming (Cycle 2, day 1).
After 12 days (±2 days), subjects return to clinic. A transvaginal ultrasound (TVU) is conducted. Estrogen compliant subjects, and subjects meeting other criteria (i.e. double-walled endometrial thickness of ≥5 mm, ≥80% compliant with Estrace®, and negative urine pregnancy test) are randomized for treatment with progesterone.
Subjects begin blinded administration on day 14 of Cycle 2. Subjects continue both Estrace® and blinded administration through day 25 of Cycle 2. No medication is taken from Cycle 2, Day 26-28.
Estrace® 1.0 mg is re-started at Cycle 3, Day 1 and continued until Day 25. Subjects will return to the clinic at Cycle 2, Day 12 (±2d) for study assessments. At Cycle 3, Day 14, subjects will again begin taking blinded study medication through Day 25.
Subjects return to the clinic day 24 (±1 day) of Cycle 3, at which time an endometrial biopsy is conducted.
Subjects complete their final dose of Estrace® and blinded study medication on Day 25 and return to the clinic for a follow-up visit approximately 10 days later (upon receipt of biopsy results). Final visit assessments are conducted. Subjects whose endometrial biopsy results show proliferative endometrium are prescribed a 14 day course of medroxyprogesterone acetate 10 mg [MPA] as standard-of-care treatment to counterbalance the effect of estrogen-induced endometrial proliferation. These subjects receive a follow up telephone call at 2-4 weeks after completion of the MPA course and queried for the incidence of bleeding and adverse events. Unscheduled visits are allowed as needed.
An open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, oral bioequivalence study was conducted with progesterone soft gel capsules having the formulation disclosed in Table 9 as fill material and PROMETRIUM® soft gel capsule 200 mg in normal healthy, adult human male subjects under fasting conditions.
A total of 25 normal healthy, adult, human male subjects were enrolled into the study. All subjects were housed in the clinical facility for at least 11 hours before dosing through a 24 hours post dose. After an overnight fast of at least 10 hours, a single dose of either test product (T) or reference product (R) (as per a randomization schedule) was administered orally to each subject with 240 mL of water. There was a washout period of 14 days between treatments. 18 blood samples were collected at: −1 hours, −0.5 hours, 0 hours, 0.25 hours, 0.5 hours, 0.67 hours, 0.83 hours, 1.00 hours, 1.33 hours, 1.67 hours, 2.00 hours, 2.50 hours, 3.00 hours, 4.00 hours, 6.00 hours, 8.00 hours, 12.00 hours, and 24.00 hours. The testing indicated that T and R had the following PK parameters:
This data indicates that T and R are not bioequivalent because the 90% confidence interval of the least square mean of Cmax, AUC0-t and AUC0-∞ were 34.3% to 62.63%, 25.84% to 90.62%, and 72.18% to 597.25% respectively. They were thus not within the limit of 80.00% and 125.00% used by the FDA to demonstrate bioequivalence.
An open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, oral bioequivalence study was conducted with progesterone soft gel capsules having the formulation disclosed in Table 9 as fill material and PROMETRIUM® soft gel capsule 200 mg in normal healthy, adult human male subjects under fed conditions.
A total of 25 normal healthy, adult, human male subjects were enrolled into the study. All subjects were housed in the clinical facility for at least 11 hours before dosing through a 24 hours post dose. After an overnight fast of at least 10 hours, a high fat, high calorie breakfast was served 30 minutes before administering a single dose of either test product (T) or reference product (R) (as per a randomization schedule). Capsules were given to each subject orally with 240 mL of water. There was a washout period of 14 days between treatments. 18 blood samples were collected at: −1 hours, −0.5 hours, 0 hours, 0.25 hours, 0.5 hours, 0.67 hours, 0.83 hours, 1.00 hours, 1.33 hours, 1.67 hours, 2.00 hours, 2.50 hours, 3.00 hours, 4.00 hours, 6.00 hours, 8.00 hours, 12.00 hours, and 24.00 hours. The testing indicated that T and R had the following PK parameters:
This data indicates that T and R are not bioequivalent because the 90% confidence interval of the least square mean of Cmax, AUC0-t and AUC0-∞ were 79.38% to 351.89%, 85.01% to 239.08%, and 103.59% to 245.94%. They were thus not within the limit of 80.00% and 125.00% used by the FDA to demonstrate bioequivalence. But importantly, and unlike the fasted study, the fed study demonstrated that test product T demonstrated enhanced oral bioavailability vs. PROMETRIUM®.
It will be apparent to those skilled in the art that various modifications and variations can be made in this disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that this disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.
Likewise, numerous characteristics and advantages have been set forth in the preceding description, including various alternatives together with details of the structure and function of the devices or methods. The disclosure is intended as illustrative only and as such is not intended to be exhaustive. It will be evident to those skilled in the art that various modifications may be made, especially in matters of structure, materials, elements, components, shape, size and arrangement of parts including combinations within the principles of the disclosure, to the full extent indicated by the broad, general meaning of the terms in which the appended claims are expressed. To the extent that these various modifications do not depart from the spirit and scope of the appended claims, they are intended to be encompassed therein.
This application claims priority to U.S. Provisional Application 61/972,068 filed 28 Mar. 2014 and is a continuation in part of U.S. Ser. No. 14/125,547 filed 11 Dec. 2013 which is a National Stage application under 35 U.S.C. § 371 of International Application Serial No. PCT/US2013/046442, entitled “PROGESTERONE FORMULATIONS” which was filed on 18 Jun. 2013, and claims priority to the following U.S. Patent Applications: U.S. Provisional Application Ser. No. 61/661,302, entitled “ESTRADIOL FORMULATIONS,” which was filed on Jun. 18, 2012; U.S. Provisional Application Ser. No. 61/662,265, entitled “PROGESTERONE FORMULATIONS,” which was filed on Jun. 20, 2012; U.S. patent application Ser. No. 13/684,002, entitled “NATURAL COMBINATION HORMONE REPLACEMENT FORMULATIONS AND THERAPIES,” which was filed Nov. 21, 2012; U.S. Patent Application Serial No. PCT/US2013/023309, entitled “TRANSDERMAL HORMONE REPLACEMENT THERAPIES,” which was filed Jan. 25, 2013; and U.S. patent application Ser. No. 13/843,362, entitled “TRANSDERMAL HORMONE REPLACEMENT THERAPIES,” which was filed Mar. 15, 2013. This application also claims priority to U.S. patent application Ser. No. 13/843,428, entitled “NATURAL COMBINATION HORMONE REPLACEMENT FORMULATIONS AND THERAPIES,” which was filed Mar. 15, 2013. Each of the aforementioned applications are incorporated herein by reference in their entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1967351 | Doisy | Jul 1934 | A |
| 2232438 | Butenandt | Feb 1941 | A |
| 2379832 | Serini et al. | Jul 1945 | A |
| 2649399 | Beall et al. | Aug 1953 | A |
| 3198707 | Nomine et al. | Aug 1965 | A |
| 3478070 | Reinhardt et al. | Nov 1969 | A |
| 3526648 | Daniel et al. | Sep 1970 | A |
| 3710795 | Higuchi et al. | Jan 1973 | A |
| 3729560 | Hagerman | Apr 1973 | A |
| 3729566 | Youngdale et al. | Apr 1973 | A |
| 3755573 | Berman | Aug 1973 | A |
| 3755575 | Lerner | Aug 1973 | A |
| 3903880 | Higuchi et al. | Sep 1975 | A |
| 3916898 | Robinson | Nov 1975 | A |
| 3916899 | Theeuwes et al. | Nov 1975 | A |
| 3921636 | Zaffaroni | Nov 1975 | A |
| 3923997 | Meuly | Dec 1975 | A |
| 3948254 | Zaffaroni | Apr 1976 | A |
| 3971367 | Zaffaroni | Jul 1976 | A |
| 3977404 | Theeuwes | Aug 1976 | A |
| 3993072 | Zaffaroni | Nov 1976 | A |
| 4008719 | Theeuwes et al. | Feb 1977 | A |
| 4012496 | Schopflin et al. | Mar 1977 | A |
| 4014334 | Theeuwes et al. | Mar 1977 | A |
| 4014987 | Heller et al. | Mar 1977 | A |
| 4016251 | Higuchi et al. | Apr 1977 | A |
| 4071623 | Van Der Vies | Jan 1978 | A |
| 4093709 | Choi et al. | Jun 1978 | A |
| 4154820 | Simoons | May 1979 | A |
| 4155991 | Hartmann et al. | May 1979 | A |
| 4196188 | Besins | Apr 1980 | A |
| 4215691 | Wong | Aug 1980 | A |
| 4237885 | Pharriss et al. | Dec 1980 | A |
| 4310510 | Sherman et al. | Jan 1982 | A |
| 4327725 | Cortese et al. | May 1982 | A |
| 4372951 | Vorys | Feb 1983 | A |
| 4384096 | Sonnabend | May 1983 | A |
| 4393871 | Vorhauer et al. | Jul 1983 | A |
| 4402695 | Wong | Sep 1983 | A |
| 4423151 | Baranczuk | Dec 1983 | A |
| 4449980 | Millar et al. | May 1984 | A |
| 4610687 | Fogwell | Sep 1986 | A |
| 4629449 | Wong | Dec 1986 | A |
| 4732763 | Beck et al. | Mar 1988 | A |
| 4738957 | Laurent et al. | Apr 1988 | A |
| 4756907 | Beck et al. | Jul 1988 | A |
| 4762717 | Crowley, Jr. | Aug 1988 | A |
| 4788062 | Gale et al. | Nov 1988 | A |
| 4816257 | Buster et al. | Mar 1989 | A |
| 4822616 | Zimmermann et al. | Apr 1989 | A |
| 4865848 | Cheng et al. | Sep 1989 | A |
| 4900734 | Maxson et al. | Feb 1990 | A |
| 4906475 | Kim | Mar 1990 | A |
| 4942158 | Sarpotdar et al. | Jul 1990 | A |
| 4961931 | Wong | Oct 1990 | A |
| 5030629 | Rajadhyaksha | Jul 1991 | A |
| 5064654 | Berner et al. | Nov 1991 | A |
| 5108995 | Casper | Apr 1992 | A |
| 5128138 | Blank | Jul 1992 | A |
| 5130137 | Crowley, Jr. | Jul 1992 | A |
| 5140021 | Maxson et al. | Aug 1992 | A |
| 5211952 | Spicer et al. | May 1993 | A |
| 5252334 | Chiang et al. | Oct 1993 | A |
| 5280023 | Ehrlich et al. | Jan 1994 | A |
| 5288496 | Lewis | Feb 1994 | A |
| 5340584 | Spicer et al. | Aug 1994 | A |
| 5340585 | Pike et al. | Aug 1994 | A |
| 5340586 | Pike et al. | Aug 1994 | A |
| 5362497 | Yamada et al. | Nov 1994 | A |
| 5382573 | Casper | Jan 1995 | A |
| 5393528 | Staab | Feb 1995 | A |
| 5393529 | Hoffmann et al. | Feb 1995 | A |
| 5419910 | Lewis | May 1995 | A |
| 5468736 | Hodgen | Nov 1995 | A |
| 5474783 | Miranda et al. | Dec 1995 | A |
| 5480776 | Dullien | Jan 1996 | A |
| 5514673 | Heckenmueller et al. | May 1996 | A |
| 5516528 | Hughes et al. | May 1996 | A |
| 5527534 | Myhling | Jun 1996 | A |
| 5529782 | Staab | Jun 1996 | A |
| 5538736 | Hoffmann et al. | Jul 1996 | A |
| 5543150 | Bologna et al. | Aug 1996 | A |
| 5547948 | Barcomb | Aug 1996 | A |
| 5556635 | Istin et al. | Sep 1996 | A |
| 5565199 | Page et al. | Oct 1996 | A |
| 5567831 | Li | Oct 1996 | A |
| 5569652 | Beier et al. | Oct 1996 | A |
| 5580572 | Mikler et al. | Dec 1996 | A |
| 5582592 | Kendrick | Dec 1996 | A |
| 5585370 | Casper | Dec 1996 | A |
| 5595759 | Wright et al. | Jan 1997 | A |
| 5595970 | Garfield et al. | Jan 1997 | A |
| 5605702 | Teillaud et al. | Feb 1997 | A |
| 5607691 | Hale et al. | Mar 1997 | A |
| 5607693 | Bonte et al. | Mar 1997 | A |
| 5609617 | Shealy et al. | Mar 1997 | A |
| 5620705 | Dong et al. | Apr 1997 | A |
| 5626866 | Ebert et al. | May 1997 | A |
| 5629021 | Wright | May 1997 | A |
| 5633011 | Dong et al. | May 1997 | A |
| 5633242 | Oettel et al. | May 1997 | A |
| 5639743 | Kaswan et al. | Jun 1997 | A |
| 5653983 | Meybeck et al. | Aug 1997 | A |
| 5656286 | Miranda et al. | Aug 1997 | A |
| 5660839 | Allec et al. | Aug 1997 | A |
| 5662927 | Ehrlich et al. | Sep 1997 | A |
| 5663160 | Meybeck et al. | Sep 1997 | A |
| 5676968 | Lipp et al. | Oct 1997 | A |
| 5677292 | Li et al. | Oct 1997 | A |
| 5686097 | Taskovich et al. | Nov 1997 | A |
| 5693335 | Xia et al. | Dec 1997 | A |
| 5694947 | Lehtinen et al. | Dec 1997 | A |
| 5700480 | Hille et al. | Dec 1997 | A |
| 5709844 | Arbeit et al. | Jan 1998 | A |
| 5719197 | Kanios et al. | Feb 1998 | A |
| 5735801 | Caillouette | Apr 1998 | A |
| 5739176 | Dunn et al. | Apr 1998 | A |
| 5744463 | Bair | Apr 1998 | A |
| 5747058 | Tipton et al. | May 1998 | A |
| 5762614 | Caillouette | Jun 1998 | A |
| 5770176 | Nargessi | Jun 1998 | A |
| 5770219 | Chiang et al. | Jun 1998 | A |
| 5770220 | Meconi et al. | Jun 1998 | A |
| 5770227 | Dong et al. | Jun 1998 | A |
| 5776495 | Duclos et al. | Jul 1998 | A |
| 5780044 | Yewey et al. | Jul 1998 | A |
| 5780050 | Jain et al. | Jul 1998 | A |
| 5788980 | Nabahi | Aug 1998 | A |
| 5788984 | Guenther et al. | Aug 1998 | A |
| 5789442 | Garfield et al. | Aug 1998 | A |
| 5811416 | Chwalisz et al. | Sep 1998 | A |
| 5811547 | Nakamichi et al. | Sep 1998 | A |
| 5814329 | Shah | Sep 1998 | A |
| 5820878 | Hirano et al. | Oct 1998 | A |
| 5827200 | Caillouette | Oct 1998 | A |
| 5840327 | Gale et al. | Nov 1998 | A |
| 5843468 | Burkoth et al. | Dec 1998 | A |
| 5843979 | Wille et al. | Dec 1998 | A |
| 5858394 | Lipp et al. | Jan 1999 | A |
| 5863552 | Yue | Jan 1999 | A |
| 5866603 | Li et al. | Feb 1999 | A |
| 5882676 | Lee et al. | Mar 1999 | A |
| 5885612 | Meconi et al. | Mar 1999 | A |
| 5888533 | Dunn | Mar 1999 | A |
| 5891462 | Carrara | Apr 1999 | A |
| 5891868 | Cummings et al. | Apr 1999 | A |
| 5898038 | Yallampalli et al. | Apr 1999 | A |
| 5902603 | Chen et al. | May 1999 | A |
| 5904931 | Lipp et al. | May 1999 | A |
| 5906830 | Farinas et al. | May 1999 | A |
| 5912010 | Wille et al. | Jun 1999 | A |
| 5916176 | Caillouette | Jun 1999 | A |
| RE36247 | Plunkett et al. | Jul 1999 | E |
| 5919477 | Bevan et al. | Jul 1999 | A |
| 5922349 | Elliesen et al. | Jul 1999 | A |
| 5928666 | Farinas et al. | Jul 1999 | A |
| 5942243 | Shah | Aug 1999 | A |
| 5952000 | Venkateshwaran et al. | Sep 1999 | A |
| 5958446 | Miranda et al. | Sep 1999 | A |
| 5962445 | Stewart | Oct 1999 | A |
| 5968919 | Samour et al. | Oct 1999 | A |
| 5972372 | Saleh et al. | Oct 1999 | A |
| 5985311 | Cordes et al. | Nov 1999 | A |
| 5985850 | Falk et al. | Nov 1999 | A |
| 5985861 | Levine et al. | Nov 1999 | A |
| 5989568 | Breton et al. | Nov 1999 | A |
| 5993856 | Ragavan et al. | Nov 1999 | A |
| 6001846 | Edwards et al. | Dec 1999 | A |
| 6007835 | Bon-Lapillonne et al. | Dec 1999 | A |
| 6010715 | Wick et al. | Jan 2000 | A |
| 6013276 | Math et al. | Jan 2000 | A |
| 6022562 | Autant et al. | Feb 2000 | A |
| 6024974 | Li | Feb 2000 | A |
| 6024976 | Miranda et al. | Feb 2000 | A |
| 6028057 | Burns | Feb 2000 | A |
| 6030948 | Mann | Feb 2000 | A |
| 6039968 | Nabahi | Mar 2000 | A |
| 6040340 | Chwalisz et al. | Mar 2000 | A |
| 6056972 | Hermsmeyer | May 2000 | A |
| 6060077 | Meignant | May 2000 | A |
| 6068853 | Giannos et al. | May 2000 | A |
| 6074625 | Hawthorne et al. | Jun 2000 | A |
| 6077531 | Salin-Drouin | Jun 2000 | A |
| 6080118 | Blythe | Jun 2000 | A |
| 6083178 | Caillouette | Jul 2000 | A |
| 6086916 | Agnus et al. | Jul 2000 | A |
| 6087352 | Trout | Jul 2000 | A |
| 6090404 | Meconi et al. | Jul 2000 | A |
| 6096338 | Lacy et al. | Aug 2000 | A |
| 6106848 | Preuilh et al. | Aug 2000 | A |
| 6117446 | Place | Sep 2000 | A |
| 6117450 | Dittgen et al. | Sep 2000 | A |
| 6124362 | Bradbury et al. | Sep 2000 | A |
| 6133251 | Dittgen et al. | Oct 2000 | A |
| 6133320 | Yallampalli et al. | Oct 2000 | A |
| 6139868 | Hoffmann | Oct 2000 | A |
| 6139873 | Hughes, Jr. et al. | Oct 2000 | A |
| 6149935 | Chiang et al. | Nov 2000 | A |
| 6153216 | Cordes et al. | Nov 2000 | A |
| 6165491 | Grasset et al. | Dec 2000 | A |
| 6165975 | Adams et al. | Dec 2000 | A |
| 6187323 | Aiache et al. | Feb 2001 | B1 |
| 6187339 | De Haan et al. | Feb 2001 | B1 |
| 6190331 | Caillouette | Feb 2001 | B1 |
| 6201072 | Rathi et al. | Mar 2001 | B1 |
| 6217886 | Önyüksel et al. | Apr 2001 | B1 |
| 6225297 | Stockemann et al. | May 2001 | B1 |
| 6227202 | Matapurkar | May 2001 | B1 |
| 6228383 | Hansen et al. | May 2001 | B1 |
| 6228852 | Shaak | May 2001 | B1 |
| 6242509 | Berger et al. | Jun 2001 | B1 |
| 6245811 | Horrobin et al. | Jun 2001 | B1 |
| 6262115 | Guittard et al. | Jul 2001 | B1 |
| 6264980 | Hille | Jul 2001 | B1 |
| 6267984 | Beste et al. | Jul 2001 | B1 |
| 6274165 | Meconi et al. | Aug 2001 | B1 |
| 6277418 | Markaverich et al. | Aug 2001 | B1 |
| 6283927 | Caillouette | Sep 2001 | B1 |
| 6287588 | Shih et al. | Sep 2001 | B1 |
| 6287693 | Savoir et al. | Sep 2001 | B1 |
| 6294188 | Ragavan et al. | Sep 2001 | B1 |
| 6294192 | Patel et al. | Sep 2001 | B1 |
| 6294550 | Place et al. | Sep 2001 | B1 |
| 6299900 | Reed et al. | Oct 2001 | B1 |
| 6303132 | Nelson | Oct 2001 | B1 |
| 6303588 | Danielov | Oct 2001 | B1 |
| 6306841 | Place et al. | Oct 2001 | B1 |
| 6306914 | De Ziegler et al. | Oct 2001 | B1 |
| 6309669 | Setterstrom et al. | Oct 2001 | B1 |
| 6309848 | Howett et al. | Oct 2001 | B1 |
| 6312703 | Orthoefer | Nov 2001 | B1 |
| 6328987 | Marini | Dec 2001 | B1 |
| 6342491 | Dey et al. | Jan 2002 | B1 |
| 6344211 | Hille | Feb 2002 | B1 |
| 6372209 | Chrisope | Apr 2002 | B1 |
| 6372245 | Bowman et al. | Apr 2002 | B1 |
| 6372246 | Wei et al. | Apr 2002 | B1 |
| 6387390 | Deaver et al. | May 2002 | B1 |
| 6402705 | Caillouette | Jun 2002 | B1 |
| 6416778 | Ragavan et al. | Jul 2002 | B1 |
| 6420352 | Knowles | Jul 2002 | B1 |
| 6423039 | Rathbone et al. | Jul 2002 | B1 |
| 6423683 | Heaton et al. | Jul 2002 | B1 |
| 6432438 | Shukla | Aug 2002 | B1 |
| 6436633 | Kreider et al. | Aug 2002 | B1 |
| 6440454 | Santoro et al. | Aug 2002 | B1 |
| 6444224 | Rathbone et al. | Sep 2002 | B1 |
| 6444234 | Kirby et al. | Sep 2002 | B1 |
| 6451300 | Dunlop et al. | Sep 2002 | B1 |
| 6451339 | Patel et al. | Sep 2002 | B2 |
| 6451779 | Hesch | Sep 2002 | B1 |
| 6455246 | Howett et al. | Sep 2002 | B1 |
| 6455517 | Tanabe et al. | Sep 2002 | B1 |
| 6465004 | Rossi-Montero et al. | Oct 2002 | B1 |
| 6465005 | Biali et al. | Oct 2002 | B1 |
| 6465006 | Zhang et al. | Oct 2002 | B1 |
| 6468526 | Chrisope | Oct 2002 | B2 |
| 6469016 | Place et al. | Oct 2002 | B1 |
| 6472434 | Place et al. | Oct 2002 | B1 |
| 6479232 | Howett et al. | Nov 2002 | B1 |
| 6495160 | Esposito et al. | Dec 2002 | B2 |
| 6500814 | Hesch | Dec 2002 | B1 |
| 6503896 | Tanabe et al. | Jan 2003 | B1 |
| 6511969 | Hermsmeyer | Jan 2003 | B1 |
| 6521250 | Meconi et al. | Feb 2003 | B2 |
| 6526980 | Tracy et al. | Mar 2003 | B1 |
| 6528094 | Savoir et al. | Mar 2003 | B1 |
| 6531149 | Kirstgen et al. | Mar 2003 | B1 |
| 6537580 | Savoir et al. | Mar 2003 | B1 |
| 6538039 | Laurent | Mar 2003 | B2 |
| 6544196 | Caillouette | Apr 2003 | B2 |
| 6544553 | Hsia et al. | Apr 2003 | B1 |
| 6548053 | Stewart et al. | Apr 2003 | B1 |
| 6548491 | Tanabe et al. | Apr 2003 | B2 |
| 6551611 | Elliesen et al. | Apr 2003 | B2 |
| 6555131 | Wolff et al. | Apr 2003 | B1 |
| 6562367 | Wolff et al. | May 2003 | B1 |
| 6562370 | Luo et al. | May 2003 | B2 |
| 6562790 | Chein et al. | May 2003 | B2 |
| 6569463 | Patel et al. | May 2003 | B2 |
| 6583129 | Mazer et al. | Jun 2003 | B1 |
| 6586006 | Roser et al. | Jul 2003 | B2 |
| 6589549 | Shih et al. | Jul 2003 | B2 |
| 6593317 | De Ziegler et al. | Jul 2003 | B1 |
| 6599519 | Seo et al. | Jul 2003 | B1 |
| 6610652 | Heaton et al. | Aug 2003 | B2 |
| 6610670 | Backensfeld et al. | Aug 2003 | B2 |
| 6610674 | Schreiber | Aug 2003 | B1 |
| 6635274 | Masiz et al. | Oct 2003 | B1 |
| 6638528 | Kanios | Oct 2003 | B1 |
| 6638536 | Savoir et al. | Oct 2003 | B2 |
| 6645528 | Straub et al. | Nov 2003 | B1 |
| 6649155 | Dunlop et al. | Nov 2003 | B1 |
| 6653298 | Potter et al. | Nov 2003 | B2 |
| 6656929 | Agnus et al. | Dec 2003 | B1 |
| 6660726 | Hill et al. | Dec 2003 | B2 |
| 6663608 | Rathbone et al. | Dec 2003 | B2 |
| 6663895 | Savoir et al. | Dec 2003 | B2 |
| 6682757 | Wright | Jan 2004 | B1 |
| 6692763 | Cummings et al. | Feb 2004 | B1 |
| 6708822 | Muni | Mar 2004 | B1 |
| 6720001 | Chen et al. | Apr 2004 | B2 |
| 6737081 | Savoir et al. | May 2004 | B2 |
| 6740333 | Beckett et al. | May 2004 | B2 |
| 6743448 | Kryger | Jun 2004 | B2 |
| 6743815 | Huebner et al. | Jun 2004 | B2 |
| 6747018 | Tanabe et al. | Jun 2004 | B2 |
| 6750291 | Kim et al. | Jun 2004 | B2 |
| 6756208 | Griffin et al. | Jun 2004 | B2 |
| 6776164 | Bunt et al. | Aug 2004 | B2 |
| 6787152 | Kirby et al. | Sep 2004 | B2 |
| 6805877 | Massara et al. | Oct 2004 | B2 |
| 6809085 | Elson et al. | Oct 2004 | B1 |
| 6818226 | Reed et al. | Nov 2004 | B2 |
| 6821524 | Marini | Nov 2004 | B2 |
| 6841716 | Tsutsumi | Jan 2005 | B1 |
| 6844334 | Hill et al. | Jan 2005 | B2 |
| 6855703 | Hill et al. | Feb 2005 | B1 |
| 6860859 | Mehrotra et al. | Mar 2005 | B2 |
| 6866865 | Hsia et al. | Mar 2005 | B2 |
| 6869969 | Huebner et al. | Mar 2005 | B2 |
| 6878518 | Whitehead | Apr 2005 | B2 |
| 6901278 | Notelovitz | May 2005 | B1 |
| 6905705 | Palm et al. | Jun 2005 | B2 |
| 6911211 | Eini et al. | Jun 2005 | B2 |
| 6911438 | Wright | Jun 2005 | B2 |
| 6923988 | Patel et al. | Aug 2005 | B2 |
| 6924274 | Lardy et al. | Aug 2005 | B2 |
| 6932983 | Straub et al. | Aug 2005 | B1 |
| 6939558 | Massara et al. | Sep 2005 | B2 |
| 6943021 | Klausner et al. | Sep 2005 | B2 |
| 6958327 | Hillisch et al. | Oct 2005 | B1 |
| 6960337 | Daniels et al. | Nov 2005 | B2 |
| 6962691 | Lulla et al. | Nov 2005 | B1 |
| 6962908 | Aloba et al. | Nov 2005 | B2 |
| 6967194 | Matsuo et al. | Nov 2005 | B1 |
| 6974569 | Dunlop et al. | Dec 2005 | B2 |
| 6977250 | Rodriguez | Dec 2005 | B2 |
| 6978945 | Wong et al. | Dec 2005 | B2 |
| 6995149 | Endrikat et al. | Feb 2006 | B1 |
| 7004321 | Palm et al. | Feb 2006 | B1 |
| 7005429 | Dey et al. | Feb 2006 | B2 |
| 7011846 | Shojaei et al. | Mar 2006 | B2 |
| 7018992 | Koch et al. | Mar 2006 | B2 |
| 7030104 | Gray et al. | Apr 2006 | B2 |
| 7030157 | Huazhu et al. | Apr 2006 | B2 |
| RE39104 | Duclos et al. | May 2006 | E |
| 7074779 | Sui et al. | Jul 2006 | B2 |
| 7083590 | Bunt et al. | Aug 2006 | B1 |
| 7091213 | Metcalf et al. | Aug 2006 | B2 |
| 7094228 | Zhang et al. | Aug 2006 | B2 |
| 7097853 | Garbe et al. | Aug 2006 | B1 |
| 7101342 | Caillouette | Sep 2006 | B1 |
| 7105573 | Krajcik et al. | Sep 2006 | B2 |
| 7135190 | Piao et al. | Nov 2006 | B2 |
| 7153522 | Ikeura et al. | Dec 2006 | B1 |
| 7163681 | Giles-Komar et al. | Jan 2007 | B2 |
| 7163699 | Besse | Jan 2007 | B2 |
| 7175850 | Cevc | Feb 2007 | B2 |
| 7179799 | Hill et al. | Feb 2007 | B2 |
| 7196074 | Blye et al. | Mar 2007 | B2 |
| 7198800 | Ko | Apr 2007 | B1 |
| 7198801 | Carrara et al. | Apr 2007 | B2 |
| 7226910 | Wilson et al. | Jun 2007 | B2 |
| 7247625 | Zhang et al. | Jul 2007 | B2 |
| 7250446 | Sangita et al. | Jul 2007 | B2 |
| 7267829 | Kirby et al. | Sep 2007 | B2 |
| 7300926 | Prokai et al. | Nov 2007 | B2 |
| 7303763 | Ho | Dec 2007 | B2 |
| 7317037 | Fensome et al. | Jan 2008 | B2 |
| 7329654 | Kanojia et al. | Feb 2008 | B2 |
| 7335650 | Potter et al. | Feb 2008 | B2 |
| 7374779 | Chen et al. | May 2008 | B2 |
| 7378404 | Peters et al. | May 2008 | B2 |
| 7381427 | Ancira et al. | Jun 2008 | B2 |
| 7387789 | Klose et al. | Jun 2008 | B2 |
| 7388006 | Schmees et al. | Jun 2008 | B2 |
| 7414043 | Kosemund et al. | Aug 2008 | B2 |
| 7427413 | Savoir et al. | Sep 2008 | B2 |
| 7427609 | Leonard | Sep 2008 | B2 |
| 7429576 | Labrie | Sep 2008 | B2 |
| 7431941 | Besins et al. | Oct 2008 | B2 |
| 7456159 | Houze et al. | Nov 2008 | B2 |
| 7459445 | Hill et al. | Dec 2008 | B2 |
| 7465587 | Imrich et al. | Dec 2008 | B2 |
| 7470433 | Carrara et al. | Dec 2008 | B2 |
| 7485666 | Villanueva et al. | Feb 2009 | B2 |
| 7497855 | Ausiello et al. | Mar 2009 | B2 |
| 7498303 | Arnold et al. | Mar 2009 | B2 |
| 7534765 | Gregg et al. | May 2009 | B2 |
| 7534780 | Wyrwa et al. | May 2009 | B2 |
| 7550142 | Giles-Komar et al. | Jun 2009 | B2 |
| 7563565 | Matsuo et al. | Jul 2009 | B1 |
| 7569274 | Besse et al. | Aug 2009 | B2 |
| 7572779 | Aloba et al. | Aug 2009 | B2 |
| 7572780 | Hermsmeyer | Aug 2009 | B2 |
| 7589082 | Savoir et al. | Sep 2009 | B2 |
| 7671027 | Loumaye | Mar 2010 | B2 |
| 7674783 | Hermsmeyer | Mar 2010 | B2 |
| 7687281 | Roth et al. | Mar 2010 | B2 |
| 7687485 | Levinson et al. | Mar 2010 | B2 |
| 7694683 | Callister et al. | Apr 2010 | B2 |
| 7704983 | Hodgen et al. | Apr 2010 | B1 |
| 7727720 | Dhallan | Jun 2010 | B2 |
| 7732408 | Josephson et al. | Jun 2010 | B2 |
| 7749989 | Hill et al. | Jul 2010 | B2 |
| 7767656 | Shoichet et al. | Aug 2010 | B2 |
| 7799769 | White et al. | Sep 2010 | B2 |
| 7815936 | Hasenzahl et al. | Oct 2010 | B2 |
| 7815949 | Cohen | Oct 2010 | B2 |
| 7829115 | Besins et al. | Nov 2010 | B2 |
| 7829116 | Griswold et al. | Nov 2010 | B2 |
| RE42012 | Deaver et al. | Dec 2010 | E |
| 7850992 | Kim et al. | Dec 2010 | B2 |
| 7854753 | Kraft et al. | Dec 2010 | B2 |
| 7858607 | Mamchur | Dec 2010 | B2 |
| RE42072 | Deaver et al. | Jan 2011 | E |
| 7862552 | McIntyre et al. | Jan 2011 | B2 |
| 7867990 | Schultz et al. | Jan 2011 | B2 |
| 7871643 | Lizio et al. | Jan 2011 | B2 |
| 7879830 | Wiley | Feb 2011 | B2 |
| 7884093 | Creasy et al. | Feb 2011 | B2 |
| 7925519 | Greene | Apr 2011 | B2 |
| 7939104 | Barbera et al. | May 2011 | B2 |
| 7943602 | Bunschoten et al. | May 2011 | B2 |
| 7943604 | Coelingh et al. | May 2011 | B2 |
| 7945459 | Grace et al. | May 2011 | B2 |
| 7960368 | Nickisch et al. | Jun 2011 | B2 |
| 7989436 | Hill et al. | Aug 2011 | B2 |
| 7989487 | Welsh et al. | Aug 2011 | B2 |
| 8022053 | Mueller et al. | Sep 2011 | B2 |
| 8048017 | Xu | Nov 2011 | B2 |
| 8048869 | Bunschoten et al. | Nov 2011 | B2 |
| 8063030 | Ellman | Nov 2011 | B2 |
| 8071576 | Coelingh et al. | Dec 2011 | B2 |
| 8071729 | Giles-Komar et al. | Dec 2011 | B2 |
| 8075916 | Song et al. | Dec 2011 | B2 |
| 8075917 | Chung et al. | Dec 2011 | B2 |
| 8076317 | Kulmann | Dec 2011 | B2 |
| 8076319 | Leonard | Dec 2011 | B2 |
| 8080553 | Keith et al. | Dec 2011 | B2 |
| 8088605 | Beaudet et al. | Jan 2012 | B2 |
| 8096940 | Josephson et al. | Jan 2012 | B2 |
| 8101209 | Legrand et al. | Jan 2012 | B2 |
| 8101773 | Smith et al. | Jan 2012 | B2 |
| 8114152 | Furst | Feb 2012 | B2 |
| 8114434 | Sasaki et al. | Feb 2012 | B2 |
| 8114442 | Tucker et al. | Feb 2012 | B2 |
| 8119741 | Pavlin | Feb 2012 | B2 |
| 8121886 | Azar | Feb 2012 | B2 |
| 8124118 | Lennernas et al. | Feb 2012 | B2 |
| 8124595 | Boissonneault | Feb 2012 | B2 |
| 8147561 | Binmoeller | Apr 2012 | B2 |
| 8148546 | Schuster et al. | Apr 2012 | B2 |
| 8158613 | Staniforth et al. | Apr 2012 | B2 |
| 8158614 | Lambert et al. | Apr 2012 | B2 |
| 8163722 | Savoir et al. | Apr 2012 | B2 |
| 8177449 | Bayly et al. | May 2012 | B2 |
| 8182833 | Hermsmeyer | May 2012 | B2 |
| 8187615 | Friedman | May 2012 | B2 |
| 8195403 | Ishikawa et al. | Jun 2012 | B2 |
| 8202736 | Mousa et al. | Jun 2012 | B2 |
| 8217024 | Ahmed et al. | Jul 2012 | B2 |
| 8221785 | Chien | Jul 2012 | B2 |
| 8222008 | Theone et al. | Jul 2012 | B2 |
| 8222237 | Nickisch et al. | Jul 2012 | B2 |
| 8227454 | Hill et al. | Jul 2012 | B2 |
| 8227509 | Castro et al. | Jul 2012 | B2 |
| 8241664 | Dudley et al. | Aug 2012 | B2 |
| 8247393 | Ahmed et al. | Aug 2012 | B2 |
| 8257724 | Cromack et al. | Sep 2012 | B2 |
| 8257725 | Cromack et al. | Sep 2012 | B2 |
| 8268352 | Vaya et al. | Sep 2012 | B2 |
| 8268806 | Labrie | Sep 2012 | B2 |
| 8268878 | Armer et al. | Sep 2012 | B2 |
| 8273730 | Fernandez et al. | Sep 2012 | B2 |
| 8287888 | Song et al. | Oct 2012 | B2 |
| 8288366 | Chochinov et al. | Oct 2012 | B2 |
| 8318898 | Fasel et al. | Nov 2012 | B2 |
| 8324193 | Lee-Sepsick et al. | Dec 2012 | B2 |
| 8329680 | Evans et al. | Dec 2012 | B2 |
| 8337814 | Osbakken et al. | Dec 2012 | B2 |
| 8344007 | Tang et al. | Jan 2013 | B2 |
| 8349820 | Zeun et al. | Jan 2013 | B2 |
| 8353863 | Imran | Jan 2013 | B2 |
| 8357723 | Satyam | Jan 2013 | B2 |
| 8361995 | Schramm | Jan 2013 | B2 |
| 8362091 | Tamarkin et al. | Jan 2013 | B2 |
| 8372424 | Berry et al. | Feb 2013 | B2 |
| 8372806 | Bohler et al. | Feb 2013 | B2 |
| 8377482 | Laurie et al. | Feb 2013 | B2 |
| 8377994 | Gray et al. | Feb 2013 | B2 |
| 8394759 | Barathur et al. | Mar 2013 | B2 |
| 8415332 | Diliberti et al. | Apr 2013 | B2 |
| 8420111 | Hermsmeyer | Apr 2013 | B2 |
| 8435561 | Besins et al. | May 2013 | B2 |
| 8435972 | Stein et al. | May 2013 | B2 |
| 8449879 | Laurent-Applegate et al. | May 2013 | B2 |
| 8450108 | Boyce | May 2013 | B2 |
| 8454945 | McCook et al. | Jun 2013 | B2 |
| 8455468 | Hoffman et al. | Jun 2013 | B2 |
| 8461138 | Boissonneault | Jun 2013 | B2 |
| 8476252 | Achleitner et al. | Jul 2013 | B2 |
| 8481488 | Carter | Jul 2013 | B2 |
| 8486374 | Tamarkin et al. | Jul 2013 | B2 |
| 8486442 | Matsushita et al. | Jul 2013 | B2 |
| 8492368 | Vanlandingham et al. | Jul 2013 | B2 |
| 8507467 | Matsui et al. | Aug 2013 | B2 |
| 8512693 | Capito et al. | Aug 2013 | B2 |
| 8512754 | Needham | Aug 2013 | B2 |
| 8518376 | Tamarkin et al. | Aug 2013 | B2 |
| 8536159 | Li et al. | Sep 2013 | B2 |
| 8540967 | Barrett et al. | Sep 2013 | B2 |
| 8541400 | Johnsson et al. | Sep 2013 | B2 |
| 8551462 | Goldstein et al. | Oct 2013 | B2 |
| 8557281 | Halliday et al. | Oct 2013 | B2 |
| 8568374 | De Graaff et al. | Oct 2013 | B2 |
| 8591951 | Kohn et al. | Nov 2013 | B2 |
| 8613951 | Zale et al. | Dec 2013 | B2 |
| 8633178 | Bernick | Jan 2014 | B2 |
| 8633180 | Li et al. | Jan 2014 | B2 |
| 8636787 | Sabaria | Jan 2014 | B2 |
| 8636982 | Tamarkin et al. | Jan 2014 | B2 |
| 8653129 | Fein et al. | Feb 2014 | B2 |
| 8658627 | Voskuhl | Feb 2014 | B2 |
| 8658628 | Baucom | Feb 2014 | B2 |
| 8663681 | Ahmed et al. | Mar 2014 | B2 |
| 8663692 | Mueller et al. | Mar 2014 | B1 |
| 8663703 | Lerner et al. | Mar 2014 | B2 |
| 8664207 | Li et al. | Mar 2014 | B2 |
| 8669293 | Levy et al. | Mar 2014 | B2 |
| 8679552 | Guthery | Mar 2014 | B2 |
| 8694358 | Tryfon | Apr 2014 | B2 |
| 8697127 | Sah | Apr 2014 | B2 |
| 8697710 | Li et al. | Apr 2014 | B2 |
| 8703105 | Tamarkin et al. | Apr 2014 | B2 |
| 8709385 | Tamarkin et al. | Apr 2014 | B2 |
| 8709451 | Rapoport et al. | Apr 2014 | B2 |
| 8715735 | Funke et al. | May 2014 | B2 |
| 8721331 | Raghuprasad | May 2014 | B2 |
| 8722021 | Friedman et al. | May 2014 | B2 |
| 8734846 | Ali et al. | May 2014 | B2 |
| 8735381 | Podolski | May 2014 | B2 |
| 8741336 | Dipierro et al. | Jun 2014 | B2 |
| 8741373 | Bromley et al. | Jun 2014 | B2 |
| 8753661 | Steinmuller-Nethl et al. | Jun 2014 | B2 |
| 8784882 | Mattern | Jul 2014 | B2 |
| 8815261 | Hanma | Aug 2014 | B2 |
| 8846648 | Bernick | Sep 2014 | B2 |
| 8846649 | Bernick | Sep 2014 | B2 |
| 8933059 | Bernick | Jan 2015 | B2 |
| 8987237 | Bernick | Mar 2015 | B2 |
| 8987238 | Bernick | Mar 2015 | B2 |
| 8993548 | Bernick et al. | Mar 2015 | B2 |
| 8993549 | Bernick et al. | Mar 2015 | B2 |
| 9006222 | Bernick | Apr 2015 | B2 |
| 9012434 | Bernick | Apr 2015 | B2 |
| 9114145 | Bernick | Aug 2015 | B2 |
| 9114146 | Bernick | Aug 2015 | B2 |
| 9248136 | Bernick | Feb 2016 | B2 |
| 10052386 | Bernick | Aug 2018 | B2 |
| 10471148 | Cacace | Nov 2019 | B2 |
| 10639375 | Bernick | May 2020 | B2 |
| 11033626 | Cacace | Jun 2021 | B2 |
| 20010005728 | Guittard et al. | Jun 2001 | A1 |
| 20010009673 | Lipp et al. | Jul 2001 | A1 |
| 20010021816 | Caillouette | Sep 2001 | A1 |
| 20010023261 | Ryoo et al. | Sep 2001 | A1 |
| 20010027189 | Bennink et al. | Oct 2001 | A1 |
| 20010029357 | Bunt et al. | Oct 2001 | A1 |
| 20010031747 | Deziegler et al. | Oct 2001 | A1 |
| 20010032125 | Bhan et al. | Oct 2001 | A1 |
| 20010034340 | Pickar | Oct 2001 | A1 |
| 20010053383 | Miranda et al. | Dec 2001 | A1 |
| 20010056068 | Chwalisz et al. | Dec 2001 | A1 |
| 20020012710 | Lansky | Jan 2002 | A1 |
| 20020026158 | Rathbone et al. | Feb 2002 | A1 |
| 20020028788 | Bunt et al. | Mar 2002 | A1 |
| 20020035070 | Gardlik et al. | Mar 2002 | A1 |
| 20020058648 | Hammerly | May 2002 | A1 |
| 20020058926 | Rathbone et al. | May 2002 | A1 |
| 20020064541 | Lapidot et al. | May 2002 | A1 |
| 20020076441 | Shih et al. | Jun 2002 | A1 |
| 20020102308 | Wei et al. | Aug 2002 | A1 |
| 20020107230 | Waldon et al. | Aug 2002 | A1 |
| 20020114803 | Deaver et al. | Aug 2002 | A1 |
| 20020119174 | Gardlik et al. | Aug 2002 | A1 |
| 20020119198 | Gao et al. | Aug 2002 | A1 |
| 20020132801 | Heil et al. | Sep 2002 | A1 |
| 20020137749 | Levinson et al. | Sep 2002 | A1 |
| 20020142017 | Simonnet | Oct 2002 | A1 |
| 20020151530 | Leonard et al. | Oct 2002 | A1 |
| 20020156394 | Mehrotra et al. | Oct 2002 | A1 |
| 20020169150 | Pickar | Nov 2002 | A1 |
| 20020169205 | Chwalisz et al. | Nov 2002 | A1 |
| 20020173510 | Levinson et al. | Nov 2002 | A1 |
| 20020193356 | Van Beek et al. | Dec 2002 | A1 |
| 20020193758 | Sandberg | Dec 2002 | A1 |
| 20020197286 | Brandman et al. | Dec 2002 | A1 |
| 20030003139 | Lipp et al. | Jan 2003 | A1 |
| 20030004145 | Leonard | Jan 2003 | A1 |
| 20030007994 | Bunt et al. | Jan 2003 | A1 |
| 20030027772 | Breton | Feb 2003 | A1 |
| 20030044453 | Dittgen et al. | Mar 2003 | A1 |
| 20030049307 | Gyurik | Mar 2003 | A1 |
| 20030064097 | Patel et al. | Apr 2003 | A1 |
| 20030064975 | Koch et al. | Apr 2003 | A1 |
| 20030072760 | Sirbasku | Apr 2003 | A1 |
| 20030073248 | Roth et al. | Apr 2003 | A1 |
| 20030073673 | Hesch | Apr 2003 | A1 |
| 20030077297 | Chen | Apr 2003 | A1 |
| 20030078245 | Bennink et al. | Apr 2003 | A1 |
| 20030091620 | Fikstad et al. | May 2003 | A1 |
| 20030091640 | Ramanathan et al. | May 2003 | A1 |
| 20030092691 | Besse et al. | May 2003 | A1 |
| 20030096012 | Besse et al. | May 2003 | A1 |
| 20030104048 | Patel et al. | Jun 2003 | A1 |
| 20030109507 | Franke et al. | Jun 2003 | A1 |
| 20030113268 | Buenafae et al. | Jun 2003 | A1 |
| 20030114420 | Salvati et al. | Jun 2003 | A1 |
| 20030114430 | MacLeod et al. | Jun 2003 | A1 |
| 20030124182 | Shojaei et al. | Jul 2003 | A1 |
| 20030124191 | Besse et al. | Jul 2003 | A1 |
| 20030130558 | Massara et al. | Jul 2003 | A1 |
| 20030144258 | Heil et al. | Jul 2003 | A1 |
| 20030157157 | Luo et al. | Aug 2003 | A1 |
| 20030166509 | Edwards et al. | Sep 2003 | A1 |
| 20030170295 | Kim et al. | Sep 2003 | A1 |
| 20030175329 | Azarnoff et al. | Sep 2003 | A1 |
| 20030175333 | Shefer et al. | Sep 2003 | A1 |
| 20030180352 | Patel et al. | Sep 2003 | A1 |
| 20030181353 | Nyce | Sep 2003 | A1 |
| 20030181728 | Salvati et al. | Sep 2003 | A1 |
| 20030191096 | Leonard et al. | Oct 2003 | A1 |
| 20030195177 | Leonard et al. | Oct 2003 | A1 |
| 20030215496 | Patel et al. | Nov 2003 | A1 |
| 20030219402 | Rutter | Nov 2003 | A1 |
| 20030220297 | Berstein et al. | Nov 2003 | A1 |
| 20030224057 | Martin-Letellier et al. | Dec 2003 | A1 |
| 20030224059 | Lerner et al. | Dec 2003 | A1 |
| 20030225047 | Caubel et al. | Dec 2003 | A1 |
| 20030225048 | Caubel et al. | Dec 2003 | A1 |
| 20030225050 | Grawe et al. | Dec 2003 | A1 |
| 20030228686 | Klausner et al. | Dec 2003 | A1 |
| 20030229057 | Caubel et al. | Dec 2003 | A1 |
| 20030235596 | Gao et al. | Dec 2003 | A1 |
| 20030236236 | Chen et al. | Dec 2003 | A1 |
| 20040009960 | Heil et al. | Jan 2004 | A1 |
| 20040022820 | Anderson | Feb 2004 | A1 |
| 20040034001 | Karara | Feb 2004 | A1 |
| 20040037881 | Guittard et al. | Feb 2004 | A1 |
| 20040039356 | Maki et al. | Feb 2004 | A1 |
| 20040043043 | Schlyter et al. | Mar 2004 | A1 |
| 20040043943 | Guittard et al. | Mar 2004 | A1 |
| 20040044080 | Place et al. | Mar 2004 | A1 |
| 20040048900 | Flood | Mar 2004 | A1 |
| 20040052824 | Abou et al. | Mar 2004 | A1 |
| 20040073024 | Metcalf et al. | Apr 2004 | A1 |
| 20040077605 | Salvati et al. | Apr 2004 | A1 |
| 20040077606 | Salvati et al. | Apr 2004 | A1 |
| 20040087548 | Salvati et al. | May 2004 | A1 |
| 20040087564 | Wright et al. | May 2004 | A1 |
| 20040089308 | Welch | May 2004 | A1 |
| 20040092494 | Dudley | May 2004 | A9 |
| 20040092583 | Shanahan-Prendergast | May 2004 | A1 |
| 20040093261 | Jain et al. | May 2004 | A1 |
| 20040097468 | Wimalawansa | May 2004 | A1 |
| 20040101557 | Gibson et al. | May 2004 | A1 |
| 20040106542 | Deaver et al. | Jun 2004 | A1 |
| 20040110732 | Masini-Eteve et al. | Jun 2004 | A1 |
| 20040131670 | Gao | Jul 2004 | A1 |
| 20040138103 | Patt | Jul 2004 | A1 |
| 20040142012 | Bunt et al. | Jul 2004 | A1 |
| 20040146539 | Gupta | Jul 2004 | A1 |
| 20040146894 | Warrington et al. | Jul 2004 | A1 |
| 20040161435 | Gupta | Aug 2004 | A1 |
| 20040176324 | Salvati et al. | Sep 2004 | A1 |
| 20040176336 | Rodriguez | Sep 2004 | A1 |
| 20040185104 | Piao et al. | Sep 2004 | A1 |
| 20040191207 | Lipari et al. | Sep 2004 | A1 |
| 20040191276 | Muni | Sep 2004 | A1 |
| 20040198706 | Carrara et al. | Oct 2004 | A1 |
| 20040210280 | Liedtke | Oct 2004 | A1 |
| 20040213744 | Lulla et al. | Oct 2004 | A1 |
| 20040219124 | Gupta | Nov 2004 | A1 |
| 20040225140 | Fernandez et al. | Nov 2004 | A1 |
| 20040234606 | Levine et al. | Nov 2004 | A1 |
| 20040241219 | Hille et al. | Dec 2004 | A1 |
| 20040243437 | Grace et al. | Dec 2004 | A1 |
| 20040253319 | Netke et al. | Dec 2004 | A1 |
| 20040259817 | Waldon et al. | Dec 2004 | A1 |
| 20040266745 | Schwanitz et al. | Dec 2004 | A1 |
| 20050003003 | Basu et al. | Jan 2005 | A1 |
| 20050004088 | Hesch | Jan 2005 | A1 |
| 20050009800 | Thumbeck et al. | Jan 2005 | A1 |
| 20050014729 | Pulaski | Jan 2005 | A1 |
| 20050020550 | Morris et al. | Jan 2005 | A1 |
| 20050020552 | Aschkenasy et al. | Jan 2005 | A1 |
| 20050021009 | Massara et al. | Jan 2005 | A1 |
| 20050025833 | Aschkenasy et al. | Feb 2005 | A1 |
| 20050031651 | Gervais et al. | Feb 2005 | A1 |
| 20050042173 | Besse et al. | Feb 2005 | A1 |
| 20050042268 | Aschkenasy et al. | Feb 2005 | A1 |
| 20050048116 | Straub et al. | Mar 2005 | A1 |
| 20050054991 | Tobyn et al. | Mar 2005 | A1 |
| 20050079138 | Chickering et al. | Apr 2005 | A1 |
| 20050085453 | Govindarajan | Apr 2005 | A1 |
| 20050101579 | Shippen | May 2005 | A1 |
| 20050113350 | Duesterberg et al. | May 2005 | A1 |
| 20050118244 | Theobald et al. | Jun 2005 | A1 |
| 20050118272 | Besse et al. | Jun 2005 | A1 |
| 20050129756 | Podhaisky et al. | Jun 2005 | A1 |
| 20050152956 | Dudley | Jul 2005 | A1 |
| 20050153946 | Hirsh et al. | Jul 2005 | A1 |
| 20050164977 | Coelingh | Jul 2005 | A1 |
| 20050182105 | Nirschl et al. | Aug 2005 | A1 |
| 20050186141 | Gonda et al. | Aug 2005 | A1 |
| 20050187267 | Hamann et al. | Aug 2005 | A1 |
| 20050192253 | Salvati et al. | Sep 2005 | A1 |
| 20050192310 | Gavai et al. | Sep 2005 | A1 |
| 20050196434 | Brierre | Sep 2005 | A1 |
| 20050207990 | Funke et al. | Sep 2005 | A1 |
| 20050209209 | Koch et al. | Sep 2005 | A1 |
| 20050214384 | Juturu et al. | Sep 2005 | A1 |
| 20050220825 | Funke et al. | Oct 2005 | A1 |
| 20050220900 | Popp et al. | Oct 2005 | A1 |
| 20050222106 | Bracht | Oct 2005 | A1 |
| 20050228692 | Hodgdon | Oct 2005 | A1 |
| 20050228718 | Austin | Oct 2005 | A1 |
| 20050239747 | Yang et al. | Oct 2005 | A1 |
| 20050239758 | Roby | Oct 2005 | A1 |
| 20050244360 | Billoni | Nov 2005 | A1 |
| 20050244522 | Carrara et al. | Nov 2005 | A1 |
| 20050245902 | Cornish et al. | Nov 2005 | A1 |
| 20050250746 | Iammatteo | Nov 2005 | A1 |
| 20050250750 | Cummings et al. | Nov 2005 | A1 |
| 20050250753 | Fink et al. | Nov 2005 | A1 |
| 20050256028 | Yun et al. | Nov 2005 | A1 |
| 20050266078 | Jorda et al. | Dec 2005 | A1 |
| 20050266088 | Hinrichs et al. | Dec 2005 | A1 |
| 20050271597 | Keith | Dec 2005 | A1 |
| 20050271598 | Friedman et al. | Dec 2005 | A1 |
| 20050272685 | Hung | Dec 2005 | A1 |
| 20050272712 | Grubb et al. | Dec 2005 | A1 |
| 20060009428 | Grubb et al. | Jan 2006 | A1 |
| 20060014728 | Chwalisz et al. | Jan 2006 | A1 |
| 20060018937 | Friedman et al. | Jan 2006 | A1 |
| 20060019978 | Balog et al. | Jan 2006 | A1 |
| 20060020002 | Salvati et al. | Jan 2006 | A1 |
| 20060030615 | Fensome et al. | Feb 2006 | A1 |
| 20060034889 | Jo et al. | Feb 2006 | A1 |
| 20060034904 | Weimann | Feb 2006 | A1 |
| 20060051391 | Dvoskin et al. | Mar 2006 | A1 |
| 20060052341 | Cornish et al. | Mar 2006 | A1 |
| 20060069031 | Loumaye | Mar 2006 | A1 |
| 20060078618 | Constantinides et al. | Apr 2006 | A1 |
| 20060083778 | Allison et al. | Apr 2006 | A1 |
| 20060084704 | Shih et al. | Apr 2006 | A1 |
| 20060088580 | Meconi et al. | Apr 2006 | A1 |
| 20060089337 | Casper et al. | Apr 2006 | A1 |
| 20060093678 | Chickering, III | May 2006 | A1 |
| 20060100180 | Nubbemeyer et al. | May 2006 | A1 |
| 20060106004 | Brody et al. | May 2006 | A1 |
| 20060110415 | Gupta | May 2006 | A1 |
| 20060111424 | Salvati et al. | May 2006 | A1 |
| 20060121102 | Chiang | Jun 2006 | A1 |
| 20060121626 | Imrich et al. | Jun 2006 | A1 |
| 20060134188 | Podhaisky et al. | Jun 2006 | A1 |
| 20060135619 | Kick et al. | Jun 2006 | A1 |
| 20060165744 | Jamil et al. | Jul 2006 | A1 |
| 20060193789 | Tamarkin et al. | Aug 2006 | A1 |
| 20060194775 | Tofovic et al. | Aug 2006 | A1 |
| 20060204557 | Gupta et al. | Sep 2006 | A1 |
| 20060233743 | Kelly | Oct 2006 | A1 |
| 20060233841 | Brodbeck et al. | Oct 2006 | A1 |
| 20060235037 | Purandare et al. | Oct 2006 | A1 |
| 20060240111 | Fernandez et al. | Oct 2006 | A1 |
| 20060246122 | Langguth et al. | Nov 2006 | A1 |
| 20060247216 | Haj-Yehia | Nov 2006 | A1 |
| 20060247221 | Coelingh et al. | Nov 2006 | A1 |
| 20060251581 | McIntyre et al. | Nov 2006 | A1 |
| 20060252049 | Shuler et al. | Nov 2006 | A1 |
| 20060257472 | Nielsen | Nov 2006 | A1 |
| 20060275218 | Tamarkin et al. | Dec 2006 | A1 |
| 20060275360 | Ahmed et al. | Dec 2006 | A1 |
| 20060276414 | Coelingh et al. | Dec 2006 | A1 |
| 20060280771 | Groenewegen et al. | Dec 2006 | A1 |
| 20060280797 | Shoichet et al. | Dec 2006 | A1 |
| 20060280800 | Nagi et al. | Dec 2006 | A1 |
| 20060292223 | Woolfson et al. | Dec 2006 | A1 |
| 20070004693 | Woolfson et al. | Jan 2007 | A1 |
| 20070004694 | Woolfson et al. | Jan 2007 | A1 |
| 20070009559 | Li et al. | Jan 2007 | A1 |
| 20070009594 | Grubb et al. | Jan 2007 | A1 |
| 20070010550 | McKenzie | Jan 2007 | A1 |
| 20070014839 | Bracht | Jan 2007 | A1 |
| 20070015698 | Kleinman et al. | Jan 2007 | A1 |
| 20070021360 | Nyce et al. | Jan 2007 | A1 |
| 20070027201 | McComas et al. | Feb 2007 | A1 |
| 20070031491 | Levine et al. | Feb 2007 | A1 |
| 20070037780 | Ebert et al. | Feb 2007 | A1 |
| 20070037782 | Hibino et al. | Feb 2007 | A1 |
| 20070042038 | Besse | Feb 2007 | A1 |
| 20070060589 | Purandare et al. | Mar 2007 | A1 |
| 20070066628 | Zhang et al. | Mar 2007 | A1 |
| 20070066637 | Zhang et al. | Mar 2007 | A1 |
| 20070066675 | Zhang et al. | Mar 2007 | A1 |
| 20070078091 | Hubler et al. | Apr 2007 | A1 |
| 20070088029 | Balog et al. | Apr 2007 | A1 |
| 20070093548 | Diffendal et al. | Apr 2007 | A1 |
| 20070116729 | Palepu | May 2007 | A1 |
| 20070116829 | Prakash et al. | May 2007 | A1 |
| 20070128263 | Gargiulo et al. | Jun 2007 | A1 |
| 20070154533 | Dudley | Jul 2007 | A1 |
| 20070167418 | Ferguson | Jul 2007 | A1 |
| 20070178166 | Bernstein et al. | Aug 2007 | A1 |
| 20070184558 | Roth et al. | Aug 2007 | A1 |
| 20070185068 | Ferguson et al. | Aug 2007 | A1 |
| 20070190022 | Bacopoulos et al. | Aug 2007 | A1 |
| 20070191319 | Ke et al. | Aug 2007 | A1 |
| 20070196415 | Chen et al. | Aug 2007 | A1 |
| 20070196433 | Ron et al. | Aug 2007 | A1 |
| 20070207225 | Squadrito | Sep 2007 | A1 |
| 20070225281 | Zhang et al. | Sep 2007 | A1 |
| 20070232574 | Galey et al. | Oct 2007 | A1 |
| 20070238713 | Gast et al. | Oct 2007 | A1 |
| 20070243229 | Smith et al. | Oct 2007 | A1 |
| 20070248658 | Zurdo et al. | Oct 2007 | A1 |
| 20070254858 | Cronk | Nov 2007 | A1 |
| 20070255197 | Humberstone et al. | Nov 2007 | A1 |
| 20070264309 | Chollet et al. | Nov 2007 | A1 |
| 20070264345 | Eros et al. | Nov 2007 | A1 |
| 20070264349 | Lee et al. | Nov 2007 | A1 |
| 20070286819 | Devries et al. | Dec 2007 | A1 |
| 20070287688 | Chan et al. | Dec 2007 | A1 |
| 20070287789 | Jones et al. | Dec 2007 | A1 |
| 20070292359 | Friedman et al. | Dec 2007 | A1 |
| 20070292387 | Jon et al. | Dec 2007 | A1 |
| 20070292461 | Tamarkin et al. | Dec 2007 | A1 |
| 20070292493 | Brierre | Dec 2007 | A1 |
| 20070298089 | Saeki et al. | Dec 2007 | A1 |
| 20080026035 | Chollet et al. | Jan 2008 | A1 |
| 20080026040 | Farr et al. | Jan 2008 | A1 |
| 20080026062 | Farr et al. | Jan 2008 | A1 |
| 20080038219 | Mosbaugh et al. | Feb 2008 | A1 |
| 20080038350 | Gerecke et al. | Feb 2008 | A1 |
| 20080039405 | Langley et al. | Feb 2008 | A1 |
| 20080050317 | Tamarkin et al. | Feb 2008 | A1 |
| 20080051351 | Ghisalberti | Feb 2008 | A1 |
| 20080063607 | Tamarkin et al. | Mar 2008 | A1 |
| 20080069779 | Tamarkin et al. | Mar 2008 | A1 |
| 20080069791 | Beissert | Mar 2008 | A1 |
| 20080085877 | Bortz | Apr 2008 | A1 |
| 20080095831 | McGraw | Apr 2008 | A1 |
| 20080095838 | Abou | Apr 2008 | A1 |
| 20080113953 | De Vries et al. | May 2008 | A1 |
| 20080114050 | Fensome et al. | May 2008 | A1 |
| 20080119537 | Zhang et al. | May 2008 | A1 |
| 20080125402 | Diliberti et al. | May 2008 | A1 |
| 20080138379 | Jennings-Spring | Jun 2008 | A1 |
| 20080138390 | Hsu et al. | Jun 2008 | A1 |
| 20080139392 | Acosta-Zara et al. | Jun 2008 | A1 |
| 20080145423 | Khan et al. | Jun 2008 | A1 |
| 20080153789 | Dmowski et al. | Jun 2008 | A1 |
| 20080175814 | Phiasivongsa et al. | Jul 2008 | A1 |
| 20080175905 | Liu et al. | Jul 2008 | A1 |
| 20080175908 | Liu et al. | Jul 2008 | A1 |
| 20080188829 | Creasy et al. | Aug 2008 | A1 |
| 20080206156 | Cronk | Aug 2008 | A1 |
| 20080206159 | Tamarkin et al. | Aug 2008 | A1 |
| 20080206161 | Tamarkin et al. | Aug 2008 | A1 |
| 20080214512 | Seitz et al. | Sep 2008 | A1 |
| 20080220069 | Allison | Sep 2008 | A1 |
| 20080226698 | Tang et al. | Sep 2008 | A1 |
| 20080227763 | Lanquetin et al. | Sep 2008 | A1 |
| 20080234199 | Katamreddy | Sep 2008 | A1 |
| 20080234240 | Duesterberg et al. | Sep 2008 | A1 |
| 20080255078 | Katamreddy | Oct 2008 | A1 |
| 20080255089 | Katamreddy | Oct 2008 | A1 |
| 20080261931 | Hedner et al. | Oct 2008 | A1 |
| 20080299220 | Tamarkin et al. | Dec 2008 | A1 |
| 20080306036 | Katamreddy | Dec 2008 | A1 |
| 20080312197 | Rodriguez | Dec 2008 | A1 |
| 20080312198 | Rodriguez | Dec 2008 | A1 |
| 20080319078 | Katamreddy | Dec 2008 | A1 |
| 20090004246 | Woolfson et al. | Jan 2009 | A1 |
| 20090010968 | Allart et al. | Jan 2009 | A1 |
| 20090011041 | Musaeva et al. | Jan 2009 | A1 |
| 20090017120 | Trimble et al. | Jan 2009 | A1 |
| 20090022683 | Song et al. | Jan 2009 | A1 |
| 20090047357 | Tomohira et al. | Feb 2009 | A1 |
| 20090053294 | Prendergast | Feb 2009 | A1 |
| 20090060982 | Ron et al. | Mar 2009 | A1 |
| 20090060997 | Seitz et al. | Mar 2009 | A1 |
| 20090068118 | Eini et al. | Mar 2009 | A1 |
| 20090074859 | Patel | Mar 2009 | A1 |
| 20090081206 | Leibovitz | Mar 2009 | A1 |
| 20090081278 | De Graaff et al. | Mar 2009 | A1 |
| 20090081303 | Savoir et al. | Mar 2009 | A1 |
| 20090092656 | Klamerus et al. | Apr 2009 | A1 |
| 20090093440 | Murad | Apr 2009 | A1 |
| 20090098069 | Vacca | Apr 2009 | A1 |
| 20090099106 | Phiasivongsa et al. | Apr 2009 | A1 |
| 20090099149 | Liu et al. | Apr 2009 | A1 |
| 20090130029 | Tamarkin et al. | May 2009 | A1 |
| 20090131385 | Voskuhl | May 2009 | A1 |
| 20090137478 | Bernstein et al. | May 2009 | A1 |
| 20090137538 | Klamerus et al. | May 2009 | A1 |
| 20090143344 | Chang | Jun 2009 | A1 |
| 20090164341 | Sunvold et al. | Jun 2009 | A1 |
| 20090175799 | Tamarkin et al. | Jul 2009 | A1 |
| 20090181088 | Song et al. | Jul 2009 | A1 |
| 20090186081 | Holm et al. | Jul 2009 | A1 |
| 20090197843 | Notelovitz et al. | Aug 2009 | A1 |
| 20090203658 | Marx et al. | Aug 2009 | A1 |
| 20090214474 | Jennings | Aug 2009 | A1 |
| 20090227025 | Nichols et al. | Sep 2009 | A1 |
| 20090227550 | Mattern | Sep 2009 | A1 |
| 20090232897 | Sahoo et al. | Sep 2009 | A1 |
| 20090258096 | Cohen | Oct 2009 | A1 |
| 20090264395 | Creasy et al. | Oct 2009 | A1 |
| 20090269403 | Shaked et al. | Oct 2009 | A1 |
| 20090285772 | Phiasivongsa et al. | Nov 2009 | A1 |
| 20090285869 | Trimble | Nov 2009 | A1 |
| 20090318558 | Kim et al. | Dec 2009 | A1 |
| 20090324714 | Liu et al. | Dec 2009 | A1 |
| 20090325916 | Zhang et al. | Dec 2009 | A1 |
| 20100008985 | Pellikaan et al. | Jan 2010 | A1 |
| 20100028360 | Atwood | Feb 2010 | A1 |
| 20100034838 | Staniforth et al. | Feb 2010 | A1 |
| 20100034880 | Sintov et al. | Feb 2010 | A1 |
| 20100040671 | Ahmed et al. | Feb 2010 | A1 |
| 20100048523 | Bachman et al. | Feb 2010 | A1 |
| 20100055138 | Margulies et al. | Mar 2010 | A1 |
| 20100074959 | Hansom et al. | Mar 2010 | A1 |
| 20100086501 | Chang et al. | Apr 2010 | A1 |
| 20100086599 | Huempel et al. | Apr 2010 | A1 |
| 20100092568 | Lerner et al. | Apr 2010 | A1 |
| 20100105071 | Laufer et al. | Apr 2010 | A1 |
| 20100119585 | Hille et al. | May 2010 | A1 |
| 20100129320 | Phiasivongsa et al. | May 2010 | A1 |
| 20100136105 | Chen et al. | Jun 2010 | A1 |
| 20100137265 | Leonard | Jun 2010 | A1 |
| 20100137271 | Chen et al. | Jun 2010 | A1 |
| 20100143420 | Shenoy et al. | Jun 2010 | A1 |
| 20100143481 | Shenoy et al. | Jun 2010 | A1 |
| 20100150993 | Theobald et al. | Jun 2010 | A1 |
| 20100152144 | Hermsmeyer | Jun 2010 | A1 |
| 20100168228 | Bose et al. | Jul 2010 | A1 |
| 20100183723 | Laurent-Applegate et al. | Jul 2010 | A1 |
| 20100184736 | Coelingh et al. | Jul 2010 | A1 |
| 20100190758 | Fauser et al. | Jul 2010 | A1 |
| 20100204326 | D'Souza | Aug 2010 | A1 |
| 20100210994 | Zarif | Aug 2010 | A1 |
| 20100221195 | Tamarkin et al. | Sep 2010 | A1 |
| 20100227797 | Axelson et al. | Sep 2010 | A1 |
| 20100240626 | Kulkarni et al. | Sep 2010 | A1 |
| 20100247482 | Cui et al. | Sep 2010 | A1 |
| 20100247632 | Dong et al. | Sep 2010 | A1 |
| 20100247635 | Rosenberg et al. | Sep 2010 | A1 |
| 20100255085 | Liu | Oct 2010 | A1 |
| 20100273730 | Hsu et al. | Oct 2010 | A1 |
| 20100278759 | Murad | Nov 2010 | A1 |
| 20100279988 | Setiawan et al. | Nov 2010 | A1 |
| 20100291191 | Shoichet et al. | Nov 2010 | A1 |
| 20100292199 | Leverd et al. | Nov 2010 | A1 |
| 20100303825 | Sirbasku | Dec 2010 | A9 |
| 20100312137 | Gilmour et al. | Dec 2010 | A1 |
| 20100316724 | Whitfield et al. | Dec 2010 | A1 |
| 20100322884 | Dipietro et al. | Dec 2010 | A1 |
| 20100330168 | Gicquel et al. | Dec 2010 | A1 |
| 20110028439 | Witt-Enderby et al. | Feb 2011 | A1 |
| 20110039814 | Huatan et al. | Feb 2011 | A1 |
| 20110053845 | Levine et al. | Mar 2011 | A1 |
| 20110066473 | Bernick et al. | Mar 2011 | A1 |
| 20110076775 | Stewart et al. | Mar 2011 | A1 |
| 20110076776 | Stewart et al. | Mar 2011 | A1 |
| 20110086825 | Chatroux | Apr 2011 | A1 |
| 20110087192 | Uhland et al. | Apr 2011 | A1 |
| 20110091555 | De Luigi Bruschi et al. | Apr 2011 | A1 |
| 20110098258 | Masini-Eteve et al. | Apr 2011 | A1 |
| 20110098631 | McIntyre et al. | Apr 2011 | A1 |
| 20110104268 | Pachot et al. | May 2011 | A1 |
| 20110104289 | Savoir et al. | May 2011 | A1 |
| 20110130372 | Agostinacchio et al. | Jun 2011 | A1 |
| 20110135719 | Besins et al. | Jun 2011 | A1 |
| 20110142945 | Chen et al. | Jun 2011 | A1 |
| 20110152840 | Lee et al. | Jun 2011 | A1 |
| 20110158920 | Morley et al. | Jun 2011 | A1 |
| 20110171140 | Illum et al. | Jul 2011 | A1 |
| 20110182997 | Lewis et al. | Jul 2011 | A1 |
| 20110190201 | Hyde et al. | Aug 2011 | A1 |
| 20110195031 | Du | Aug 2011 | A1 |
| 20110195114 | Carrara et al. | Aug 2011 | A1 |
| 20110195944 | Mura et al. | Aug 2011 | A1 |
| 20110217341 | Sah | Sep 2011 | A1 |
| 20110238003 | Bruno-Raimondi et al. | Sep 2011 | A1 |
| 20110244043 | Xu et al. | Oct 2011 | A1 |
| 20110250256 | Hyun-Oh et al. | Oct 2011 | A1 |
| 20110250259 | Buckman | Oct 2011 | A1 |
| 20110250274 | Shaked et al. | Oct 2011 | A1 |
| 20110256092 | Phiasivongsa et al. | Oct 2011 | A1 |
| 20110262373 | Umbert | Oct 2011 | A1 |
| 20110262494 | Achleitner et al. | Oct 2011 | A1 |
| 20110268665 | Tamarkin et al. | Nov 2011 | A1 |
| 20110275584 | Wilckens et al. | Nov 2011 | A1 |
| 20110281832 | Li et al. | Nov 2011 | A1 |
| 20110287094 | Penhasi et al. | Nov 2011 | A1 |
| 20110293720 | General et al. | Dec 2011 | A1 |
| 20110294738 | Ren et al. | Dec 2011 | A1 |
| 20110300167 | McMurry et al. | Dec 2011 | A1 |
| 20110301087 | McBride et al. | Dec 2011 | A1 |
| 20110306579 | Stein | Dec 2011 | A1 |
| 20110311592 | Birbara | Dec 2011 | A1 |
| 20110312927 | Nachaegari et al. | Dec 2011 | A1 |
| 20110312928 | Nachaegari et al. | Dec 2011 | A1 |
| 20110318405 | Erwin | Dec 2011 | A1 |
| 20110318431 | Gulati | Dec 2011 | A1 |
| 20120009276 | De Groote | Jan 2012 | A1 |
| 20120015350 | Nabatiyan et al. | Jan 2012 | A1 |
| 20120021041 | Rossi et al. | Jan 2012 | A1 |
| 20120028888 | Janz et al. | Feb 2012 | A1 |
| 20120028910 | Combal et al. | Feb 2012 | A1 |
| 20120028936 | Gloger et al. | Feb 2012 | A1 |
| 20120045532 | Cohen | Feb 2012 | A1 |
| 20120046264 | Simes et al. | Feb 2012 | A1 |
| 20120046518 | Yoakum et al. | Feb 2012 | A1 |
| 20120052077 | Truitt, III et al. | Mar 2012 | A1 |
| 20120058171 | De Graaff et al. | Mar 2012 | A1 |
| 20120058962 | Cumming et al. | Mar 2012 | A1 |
| 20120058979 | Keith et al. | Mar 2012 | A1 |
| 20120064135 | Levin et al. | Mar 2012 | A1 |
| 20120065179 | Andersson | Mar 2012 | A1 |
| 20120065221 | Babul | Mar 2012 | A1 |
| 20120087872 | Tamarkin et al. | Apr 2012 | A1 |
| 20120101073 | Mannion et al. | Apr 2012 | A1 |
| 20120121517 | Song et al. | May 2012 | A1 |
| 20120121692 | Xu et al. | May 2012 | A1 |
| 20120122829 | Taravella et al. | May 2012 | A1 |
| 20120128625 | Shalwitz et al. | May 2012 | A1 |
| 20120128654 | Terpstra et al. | May 2012 | A1 |
| 20120128683 | Shantha | May 2012 | A1 |
| 20120128733 | Perrin et al. | May 2012 | A1 |
| 20120128777 | Keck et al. | May 2012 | A1 |
| 20120129773 | Geier et al. | May 2012 | A1 |
| 20120129819 | Vancaillie et al. | May 2012 | A1 |
| 20120136013 | Li et al. | May 2012 | A1 |
| 20120142645 | Marx | Jun 2012 | A1 |
| 20120148670 | Kim et al. | Jun 2012 | A1 |
| 20120149748 | Shanler et al. | Jun 2012 | A1 |
| 20120172343 | Lindenthal et al. | Jul 2012 | A1 |
| 20120184515 | Klar et al. | Jul 2012 | A1 |
| 20120231052 | Sitruk-Ware et al. | Sep 2012 | A1 |
| 20120232011 | Kneissel et al. | Sep 2012 | A1 |
| 20120232042 | Klar et al. | Sep 2012 | A1 |
| 20120263679 | Marlow et al. | Oct 2012 | A1 |
| 20120269721 | Weng et al. | Oct 2012 | A1 |
| 20120269878 | Cantor et al. | Oct 2012 | A2 |
| 20120277249 | Andersson et al. | Nov 2012 | A1 |
| 20120277727 | Doshi et al. | Nov 2012 | A1 |
| 20120283671 | Shibata et al. | Nov 2012 | A1 |
| 20120295911 | Mannion et al. | Nov 2012 | A1 |
| 20120301517 | Zhang et al. | Nov 2012 | A1 |
| 20120301538 | Gordon-Beresford et al. | Nov 2012 | A1 |
| 20120302535 | Caufriez et al. | Nov 2012 | A1 |
| 20120316130 | Hendrix | Dec 2012 | A1 |
| 20120316496 | Hoffmann et al. | Dec 2012 | A1 |
| 20120321579 | Edelson et al. | Dec 2012 | A1 |
| 20120322779 | Voskuhl | Dec 2012 | A9 |
| 20120328549 | Edelson et al. | Dec 2012 | A1 |
| 20120329738 | Liu | Dec 2012 | A1 |
| 20130004619 | Chow et al. | Jan 2013 | A1 |
| 20130011342 | Tamarkin et al. | Jan 2013 | A1 |
| 20130017239 | Viladot et al. | Jan 2013 | A1 |
| 20130022674 | Dudley et al. | Jan 2013 | A1 |
| 20130023505 | Garfield et al. | Jan 2013 | A1 |
| 20130023823 | Simpson et al. | Jan 2013 | A1 |
| 20130028850 | Tamarkin et al. | Jan 2013 | A1 |
| 20130029947 | Nachaegari et al. | Jan 2013 | A1 |
| 20130029957 | Giliyar et al. | Jan 2013 | A1 |
| 20130045266 | Choi et al. | Feb 2013 | A1 |
| 20130045953 | Sitruk-Ware et al. | Feb 2013 | A1 |
| 20130059795 | Lo et al. | Mar 2013 | A1 |
| 20130064897 | Binay | Mar 2013 | A1 |
| 20130072466 | Choi et al. | Mar 2013 | A1 |
| 20130084257 | Ishida et al. | Apr 2013 | A1 |
| 20130085123 | Li et al. | Apr 2013 | A1 |
| 20130089574 | Schmidt-Gollwitzer et al. | Apr 2013 | A1 |
| 20130090318 | Ulmann et al. | Apr 2013 | A1 |
| 20130102781 | Bevill et al. | Apr 2013 | A1 |
| 20130108551 | Langereis et al. | May 2013 | A1 |
| 20130116215 | Coma et al. | May 2013 | A1 |
| 20130116222 | Arnold et al. | May 2013 | A1 |
| 20130122051 | Abidi et al. | May 2013 | A1 |
| 20130123175 | Hill et al. | May 2013 | A1 |
| 20130123220 | Queiroz | May 2013 | A1 |
| 20130123351 | Dewitt | May 2013 | A1 |
| 20130129818 | Bernick et al. | May 2013 | A1 |
| 20130131027 | Pakkalin et al. | May 2013 | A1 |
| 20130131028 | Snyder et al. | May 2013 | A1 |
| 20130131029 | Bakker et al. | May 2013 | A1 |
| 20130149314 | Bullerdiek et al. | Jun 2013 | A1 |
| 20130164225 | Tamarkin et al. | Jun 2013 | A1 |
| 20130164346 | Lee et al. | Jun 2013 | A1 |
| 20130165744 | Carson et al. | Jun 2013 | A1 |
| 20130178452 | King | Jul 2013 | A1 |
| 20130183254 | Zhou et al. | Jul 2013 | A1 |
| 20130183325 | Bottoni et al. | Jul 2013 | A1 |
| 20130189193 | Tamarkin et al. | Jul 2013 | A1 |
| 20130189196 | Tamarkin et al. | Jul 2013 | A1 |
| 20130189230 | Shoichet et al. | Jul 2013 | A1 |
| 20130189368 | Mosqueira et al. | Jul 2013 | A1 |
| 20130210709 | McMurry et al. | Aug 2013 | A1 |
| 20130216550 | Penninger et al. | Aug 2013 | A1 |
| 20130216596 | Viladot et al. | Aug 2013 | A1 |
| 20130224177 | Kim et al. | Aug 2013 | A1 |
| 20130224257 | Sah et al. | Aug 2013 | A1 |
| 20130224268 | Alam et al. | Aug 2013 | A1 |
| 20130224300 | Maggio | Aug 2013 | A1 |
| 20130225412 | Sardari et al. | Aug 2013 | A1 |
| 20130225542 | Poegh et al. | Aug 2013 | A1 |
| 20130226113 | Schumacher et al. | Aug 2013 | A1 |
| 20130243696 | Wang et al. | Sep 2013 | A1 |
| 20130245253 | Marx et al. | Sep 2013 | A1 |
| 20130245570 | Jackson | Sep 2013 | A1 |
| 20130261096 | Merian et al. | Oct 2013 | A1 |
| 20130266645 | Becker et al. | Oct 2013 | A1 |
| 20130267485 | Da Silva Maia Filho | Oct 2013 | A1 |
| 20130273167 | Lee et al. | Oct 2013 | A1 |
| 20130274211 | Burman et al. | Oct 2013 | A1 |
| 20130280213 | Voskuhl | Oct 2013 | A1 |
| 20130316374 | Penninger et al. | Nov 2013 | A1 |
| 20130317065 | Tatani et al. | Nov 2013 | A1 |
| 20130317315 | Lu et al. | Nov 2013 | A1 |
| 20130324565 | Li et al. | Dec 2013 | A1 |
| 20130331363 | Li et al. | Dec 2013 | A1 |
| 20130338122 | Bernick et al. | Dec 2013 | A1 |
| 20130338123 | Bernick et al. | Dec 2013 | A1 |
| 20130338124 | Li et al. | Dec 2013 | A1 |
| 20130345187 | Rodriguez | Dec 2013 | A1 |
| 20140018335 | Tatani et al. | Jan 2014 | A1 |
| 20140024590 | Weidhaas et al. | Jan 2014 | A1 |
| 20140031289 | Song et al. | Jan 2014 | A1 |
| 20140031323 | Perez | Jan 2014 | A1 |
| 20140066416 | Leunis et al. | Mar 2014 | A1 |
| 20140072531 | Kim et al. | Mar 2014 | A1 |
| 20140079686 | Barman et al. | Mar 2014 | A1 |
| 20140088051 | Bernick et al. | Mar 2014 | A1 |
| 20140088058 | Maurizio | Mar 2014 | A1 |
| 20140088059 | Perumal et al. | Mar 2014 | A1 |
| 20140094426 | Drummond et al. | Apr 2014 | A1 |
| 20140094440 | Bernick et al. | Apr 2014 | A1 |
| 20140094441 | Bernick et al. | Apr 2014 | A1 |
| 20140099362 | Bernick et al. | Apr 2014 | A1 |
| 20140100159 | Conrad | Apr 2014 | A1 |
| 20140100204 | Bernick et al. | Apr 2014 | A1 |
| 20140100205 | Bernick et al. | Apr 2014 | A1 |
| 20140100206 | Bernick et al. | Apr 2014 | A1 |
| 20140113889 | Connor et al. | Apr 2014 | A1 |
| 20140127185 | Stein et al. | May 2014 | A1 |
| 20140127280 | Duesterberg et al. | May 2014 | A1 |
| 20140127308 | Opara et al. | May 2014 | A1 |
| 20140128798 | Janson et al. | May 2014 | A1 |
| 20140148491 | Valia et al. | May 2014 | A1 |
| 20140186332 | Ezrin et al. | Jul 2014 | A1 |
| 20140187487 | Shoichet et al. | Jul 2014 | A1 |
| 20140193523 | Henry | Jul 2014 | A1 |
| 20140194396 | Li et al. | Jul 2014 | A1 |
| 20140206616 | Ko et al. | Jul 2014 | A1 |
| 20140213565 | Bernick et al. | Jul 2014 | A1 |
| 20140288035 | Hübner et al. | Sep 2014 | A1 |
| 20140329783 | Bernick et al. | Nov 2014 | A1 |
| 20140335193 | Rintoul et al. | Nov 2014 | A1 |
| 20140370084 | Bernick et al. | Dec 2014 | A1 |
| 20140371182 | Bernick et al. | Dec 2014 | A1 |
| 20140371183 | Bernick et al. | Dec 2014 | A1 |
| 20140371184 | Bernick et al. | Dec 2014 | A1 |
| 20140371185 | Bernick et al. | Dec 2014 | A1 |
| 20150031654 | Amadio | Jan 2015 | A1 |
| 20150045335 | Bernick et al. | Feb 2015 | A1 |
| 20150133421 | Bernick et al. | May 2015 | A1 |
| 20150148323 | Cacace et al. | May 2015 | A1 |
| 20150202211 | Amadio et al. | Jul 2015 | A1 |
| Number | Date | Country |
|---|---|---|
| PI1001367 | Jul 2012 | BR |
| 102258455 | Nov 2011 | CN |
| 0275716 | Jul 1988 | EP |
| 0622075 | Nov 1994 | EP |
| 0785211 | Jul 1997 | EP |
| 0785212 | Jul 1997 | EP |
| 0811381 | Dec 1997 | EP |
| 0811381 | May 2003 | EP |
| 1094781 | Jul 2008 | EP |
| 2191833 | Jun 2010 | EP |
| 2191833 | Feb 2013 | EP |
| 452238 | Aug 1936 | GB |
| 720561 | Dec 1954 | GB |
| 848881 | Sep 1960 | GB |
| 874368 | Aug 1961 | GB |
| 1589946 | May 1981 | GB |
| 216026 | Mar 2008 | IN |
| 53KOL2005 | Sep 2009 | IN |
| 244217 | Nov 2010 | IN |
| WO-9011064 | Oct 1990 | WO |
| WO-9317686 | Sep 1993 | WO |
| WO-9422426 | Oct 1994 | WO |
| WO-9530409 | Nov 1995 | WO |
| WO-9609826 | Apr 1996 | WO |
| WO-9619975 | Jul 1996 | WO |
| WO-9630000 | Oct 1996 | WO |
| WO-9705491 | Feb 1997 | WO |
| WO-9743989 | Nov 1997 | WO |
| WO-9810293 | Mar 1998 | WO |
| WO-9832465 | Jul 1998 | WO |
| WO-9851280 | Nov 1998 | WO |
| WO-9932072 | Jul 1999 | WO |
| WO-9939700 | Aug 1999 | WO |
| WO-9942109 | Aug 1999 | WO |
| WO-9943304 | Sep 1999 | WO |
| WO-9948477 | Sep 1999 | WO |
| WO-9953910 | Oct 1999 | WO |
| WO-9963974 | Dec 1999 | WO |
| WO-0001351 | Jan 2000 | WO |
| WO-0006175 | Feb 2000 | WO |
| WO-0038659 | Jul 2000 | WO |
| WO-0045795 | Aug 2000 | WO |
| WO-0050007 | Aug 2000 | WO |
| WO-0059577 | Oct 2000 | WO |
| WO-0076522 | Dec 2000 | WO |
| WO-0137808 | May 2001 | WO |
| WO-0154699 | Aug 2001 | WO |
| WO-0160325 | Aug 2001 | WO |
| WO-0207700 | Jan 2002 | WO |
| WO-0211768 | Feb 2002 | WO |
| WO-0222132 | Mar 2002 | WO |
| WO-0240008 | May 2002 | WO |
| WO-0241878 | May 2002 | WO |
| WO-02053131 | Jul 2002 | WO |
| WO-02078604 | Oct 2002 | WO |
| WO-02078602 | Feb 2003 | WO |
| WO-03028667 | Apr 2003 | WO |
| WO-03041718 | May 2003 | WO |
| WO-03041741 | May 2003 | WO |
| WO-03068186 | Aug 2003 | WO |
| WO-03077923 | Sep 2003 | WO |
| WO-03082254 | Oct 2003 | WO |
| WO-03092588 | Nov 2003 | WO |
| WO-2004014397 | Feb 2004 | WO |
| WO-2004014432 | Feb 2004 | WO |
| WO-2004017983 | Mar 2004 | WO |
| WO-2004032897 | Apr 2004 | WO |
| WO-2004052336 | Jun 2004 | WO |
| WO-2004054540 | Jul 2004 | WO |
| WO-2004080413 | Sep 2004 | WO |
| WO-2005027911 | Mar 2005 | WO |
| WO-2005030175 | Apr 2005 | WO |
| WO-2005081825 | Sep 2005 | WO |
| WO-2005087194 | Sep 2005 | WO |
| WO-2005087199 | Sep 2005 | WO |
| WO-2005105059 | Nov 2005 | WO |
| WO-2005115335 | Dec 2005 | WO |
| WO-2005120470 | Dec 2005 | WO |
| WO-2005120517 | Dec 2005 | WO |
| WO-2006013369 | Feb 2006 | WO |
| WO-2006034090 | Mar 2006 | WO |
| WO-2006036899 | Apr 2006 | WO |
| WO-2006053172 | May 2006 | WO |
| WO-2006105615 | Oct 2006 | WO |
| WO-2006113505 | Oct 2006 | WO |
| WO-2006138686 | Dec 2006 | WO |
| WO-2006138735 | Dec 2006 | WO |
| WO-2007045027 | Apr 2007 | WO |
| WO-2007103294 | Sep 2007 | WO |
| WO-2006138735 | Oct 2007 | WO |
| WO-2007120868 | Oct 2007 | WO |
| WO-2007123790 | Nov 2007 | WO |
| WO-2007124250 | Nov 2007 | WO |
| WO-2007124250 | Dec 2007 | WO |
| WO-2007144151 | Dec 2007 | WO |
| WO-2007103294 | Apr 2008 | WO |
| WO-2008049516 | Jun 2008 | WO |
| WO-2008152444 | Dec 2008 | WO |
| WO-2009002542 | Dec 2008 | WO |
| WO-2009036311 | Mar 2009 | WO |
| WO-2009040818 | Apr 2009 | WO |
| WO-2008152444 | Jun 2009 | WO |
| WO-2009069006 | Jun 2009 | WO |
| WO-2009098072 | Aug 2009 | WO |
| WO-2009098072 | Oct 2009 | WO |
| WO-2009069006 | Nov 2009 | WO |
| WO-2009133352 | Nov 2009 | WO |
| WO-2010033188 | Mar 2010 | WO |
| WO-2009133352 | Oct 2010 | WO |
| WO-2010146872 | Dec 2010 | WO |
| WO-2011000210 | Jan 2011 | WO |
| WO-2011073995 | Jun 2011 | WO |
| WO-2011073995 | Aug 2011 | WO |
| WO-2010033188 | Sep 2011 | WO |
| WO-2011120084 | Oct 2011 | WO |
| WO-2011128336 | Oct 2011 | WO |
| WO-2012009778 | Jan 2012 | WO |
| WO-2012024361 | Feb 2012 | WO |
| WO-2012055814 | May 2012 | WO |
| WO-2012055840 | May 2012 | WO |
| WO-2012065740 | May 2012 | WO |
| WO-2012098090 | Jul 2012 | WO |
| WO-2012116277 | Aug 2012 | WO |
| WO-2012118563 | Sep 2012 | WO |
| WO-2012120365 | Sep 2012 | WO |
| WO-2012127501 | Sep 2012 | WO |
| WO-2012156561 | Nov 2012 | WO |
| WO-2012156822 | Nov 2012 | WO |
| WO-2012158483 | Nov 2012 | WO |
| WO-2012166909 | Dec 2012 | WO |
| WO-2012170578 | Dec 2012 | WO |
| WO-2013011501 | Jan 2013 | WO |
| WO-2012009778 | Feb 2013 | WO |
| WO-2013025449 | Feb 2013 | WO |
| WO-2013028639 | Feb 2013 | WO |
| WO-2013035101 | Mar 2013 | WO |
| WO-2013044067 | Mar 2013 | WO |
| WO-2013045404 | Apr 2013 | WO |
| WO-2013059285 | Apr 2013 | WO |
| WO 2013078422 | May 2013 | WO |
| WO-2013063279 | May 2013 | WO |
| WO-2013064620 | May 2013 | WO |
| WO-2013071281 | May 2013 | WO |
| WO-2013088254 | Jun 2013 | WO |
| WO-2013102665 | Jul 2013 | WO |
| WO-2013106437 | Jul 2013 | WO |
| WO-2013113690 | Aug 2013 | WO |
| WO-2013124415 | Aug 2013 | WO |
| WO-2013127727 | Sep 2013 | WO |
| WO-2013127728 | Sep 2013 | WO |
| WO-2013144356 | Oct 2013 | WO |
| WO-2013149258 | Oct 2013 | WO |
| WO-2013158454 | Oct 2013 | WO |
| WO-2013170052 | Nov 2013 | WO |
| WO-2013178587 | Dec 2013 | WO |
| WO-2013181449 | Dec 2013 | WO |
| WO-2013192248 | Dec 2013 | WO |
| WO-2013192249 | Dec 2013 | WO |
| WO-2013192250 | Dec 2013 | WO |
| WO-2013192251 | Dec 2013 | WO |
| WO-2014001904 | Jan 2014 | WO |
| WO-2014004424 | Jan 2014 | WO |
| WO-2014009434 | Jan 2014 | WO |
| WO-2014018569 | Jan 2014 | WO |
| WO-2014018570 | Jan 2014 | WO |
| WO-2014018571 | Jan 2014 | WO |
| WO-2014018856 | Jan 2014 | WO |
| WO-2014018932 | Jan 2014 | WO |
| WO-2014031958 | Feb 2014 | WO |
| WO-2014041120 | Mar 2014 | WO |
| WO-2014052792 | Apr 2014 | WO |
| WO-2014056897 | Apr 2014 | WO |
| WO-2014066442 | May 2014 | WO |
| WO-2014074846 | May 2014 | WO |
| WO-2014076231 | May 2014 | WO |
| WO-2014076569 | May 2014 | WO |
| WO-2014081598 | May 2014 | WO |
| WO-2014086739 | Jun 2014 | WO |
| WO-2014093114 | Jun 2014 | WO |
| WO-2014104784 | Jul 2014 | WO |
| Entry |
|---|
| US 6,214,374 B1, 04/2001, Schmirler et al. (withdrawn) |
| Abbas, M.A., et al., “Regression of Endometrial Implants Treated with Vitamin D3 in a Rat Model of Endometriosis,” European Journal of Pharmacology 715(1-3):72-75, Elsevier Science, Netherlands (2013). |
| Abitec, CapmuiMCM, EP, Technical Data Sheet, version 10, 2014, Columbus, OH. |
| Abitec, CapmuiMCM, NF, Technical Data Sheet, version 6, 2014, Columbus, OH. |
| Abitec, CapmuiMCM, Safley Data Sheet, 2011, Janesville, WI. |
| Abitec, CapmuiMCM, Technical Data Sheet, version 17, 2014, Columbus, OH. |
| Abitec, CapmuiPG8, CAS No. 31565-12-5, version 11,2006, Columbus, OH. |
| Abitec Corporation Excipients for the Pharmaceutical Industry—Regulatory and Product Information, 2 pages (2013). |
| Acarturk, F., “Mucoadhesive Vaginal Drug Delivery Systems,” Recent patents on drug delivery & formulation 3(3):193-205, Bentham Science Publishers, United Arab Emirates (2009). |
| Acog, Mckinlay, et al., “Practice Bulletin, Clinical Management Guidelines for Obstetrician-Gynecologists,”, Obstetrics & Gynecology Agog, No. 141, vol. 123(1), 202-216, (2014). |
| Advisory Action dated Jan. 29, 2007 for U.S. Appl. No. 12/561,515, filed Sep. 17, 2009. |
| Alabi, K. A., et al., “Analysis of Fatty Acid Composition ofThevetia peruviana and Hura crepitans Seed oils using GC-FID,” Fountain Journal of Natural and Applied Sciences 2(2):32-7, Osogbo (2013). |
| Alexander, KS, Corn Oil, CAS No. 8001-30-7, (2009). |
| Alvarez, P., et al., “Ectopic Uterine Tissue as a Chronic Pain Generator,” Neuroscience 225:269-282, Elsevier Science, United States (2012). |
| Application Note JASCO CD Spectra of Pharmaceuticals Substances Steroids, 2 pages. |
| Araya-Sibaja, A.M., et al., “Morphology Study of Progesterone Polymorphs Prepared by Polymer-induced Heteronucleation (Pihn),” Scanning 35(4):213-221, John Wiley & Sons, United States (2013). |
| Araya-Sibaja, Andrea Manela, et al., “Chemical Properties of Progesterone Selected Refer,” SciFinder, American Chemical Society & US National. Library. of Med, (2014). |
| Araya-Sibaja, Andrea Manela, et al., “Polymorphism in Progesterone,” SciFinder, pp. 1-46, American Chemical Society & US National. Library. of Med, (2014). |
| Araya-Sibaja, Andrea Manela, et al., “Polymorphism in Progesterone Selected References,” SciFinder, pp. 1-12, American Chemical Society & US National. Library. of Med, (2014). |
| Araya-Sibaja., et al., “Crystallization of progesterone polymorphs using polymer-induced heteronucleation (PIHn) method,” Drug Development and Industrial Pharmacy, Early Online, pp. 1-8, Informa Healthcare (2014). |
| Archer, D.F., et al., “Effects of Ospemifene on the Female Reproductive and Urinary Tracts : Translation From Preclinical Models into Clinical Evidence,” Menopause, Lippincott-Raven Publishers, United States (2014). |
| Archer, F., et al., Estrace® vs Premarin® for Treatment of Menopausal Symptoms: Dosage Comparison Study 9(1):21-31, (1992). |
| Ashburn, A.D., et al., “Cardiovascular , Hepatic and Renal Lesions in Mice Receiving Cortisone , Estrone and Progesterone,” The Yale Journal of Biology and Medicine 35:329-340, Yale Journal of Biology and Medicine, United States (1963). |
| Azeem, A., et al., “Microemulsions as a Surrogate Carrier for Dermal Drug Delivery,” Drug development and industrial pharmacy 35(5):525-547, Informa Healthcare, England (2009). |
| Azure Pharma, Inc., “Elestrin—estradiol gel” Drug Info, http://dailymed.nlm.nih.gov/dailymed/archives/ fdaDrugInfo.cfm?archiveid=11885, 26 pages, (2009). |
| Bakhmutova-Albert, Ekaterina, et al.,“Enhancing Aqueous Dissolution Rates of Progesterone via Cocrystallization,” SSCI, Division of Aptuit, Poster No. R6247, West Lafayette. |
| Banerjee, S., et al., “on the Stability of Salivary Progesterone Under Various Conditions of Storage,” Steroids 46(6):967-974, Elsevier, United States (1985). |
| Barnett. and Steven, M., “Pressure-tuning infared and solution Raman spectroscopic studies of 17B-estradiol and several A-ring,” Vibrational Spectroscopy, vol. 8, pp. 263, (1995). |
| Bartosova, L. and Bajgar, J., “Transdermal Drug Delivery in Vitro Using Diffusion Cells,” Current Medicinal Chemistry 19(27):4671-4677, Bentham Science Publishers, Netherlands (2012). |
| Benbow, A.L. and Waddell, B.J., “Distribution and Metabolism of Maternal Progesterone in the Uterus, Placenta, and Fetus During Rat Pregnancy,” Biology of Reproduction 52(6):1327-1333, Society for the Study of Reproduction, United States (1995). |
| Bernabei, M.T., et al., “[Release of Polymorphic forms of Progesterone From Dimethylpolysiloxane Matrices],” Bollettino chimico farmaceutico 122(1):20-26, Societa Editoriale Farmaceutica, Italy (1983). |
| Bernard, et al., “Structure Cristalline et Moleculaire du Complexe Oestradiol-Propanol,” Acta Crystallographica B28 :1349, (1972). |
| Bernard Hospital and Michel Busetta, “Structure Cristalline et Moleculair de !'Oestradiol Hemihydrate,” Acta Crystallographica B28 :560-567, (1972). |
| Bhavnani, B.R. and Stanczyk, F.Z., “Misconception and Concerns About Bioidentical Hormones Used for Custom-Compounded Hormone Therapy,” The Journal of clinical endocrinology and metabolism 97(3):756-759, Endocrine Society, United States (2012). |
| Bhavnani, B.R. and Stanczyk, F.Z., “Pharmacology of Conjugated Equine Estrogens: Efficacy, Safety and Mechanism of Action,” The Journal of steroid biochemistry and molecular biology 142:16-29, Pergamon, England (2014). |
| Bhavnani, B.R., et al., “Structure Activity Relationships and Differential interactions and Functional Activity of Various Equine Estrogens Mediated via Estrogen Receptors (Ers) Eralpha and Erbeta,” Endocrinology 149(10):4857-4870, Endocrine Society, United States (2008). |
| BioMed Centrai,Solubility of Progesterone in Organic Solvents, Online PDF, http://www.biomedcentral.com/content/ supplementary/1475-2859-11-106-S2.pdf. |
| Blake, E.J., et al., “Single and Multidose Pharmacokinetic Study of a Vaginal Micronized Progesterone insert (Endometrin ) Compared with Vaginal Gel in Healthy Reproductive-Aged Female Subjects,” Fertility and Sterility 94(4):1296-1301, Elsevier for the American Society for Reproductive Medicine, United States (2010). |
| Borka. and Laszlo., Crystal Polymorphism of Pharmaceuticals, Acta Pharmaceutica Jugoslavia 40:71-94, (1990). |
| Brandstatter-Kuhnert, M., Kofler A., “Zur mikroskopischen ldentitatsprufung und zur Polymorphie der Sexualhormone,” Microchimica Acta 6:847-853, Springer-Verlag, Germany (1959). |
| Brared Christensson, J., et al., “Positive Patch Test Reactions to Oxidized Limonene: Exposure and Relevance,” Contact Dermatitis 71(5):264-272, Wiley, England (2014). |
| Brinton, L.A. and Felix, A.S., “Menopausal Hormone Therapy and Risk of Endometrial Cancer,” The Journal of steroid biochemistry and molecular biology 142:83-89, Pergamon, England (2014). |
| “British Pharmacopoeia 2014 Online, Refined Maize Oil, Ph. Eur. Monograph 1342, voll & II, Monographs: Medicinal and Pharmaceutical Substances, accessed at http:/www.pharmacopoeia.co.uklbp2014/ixbin/bp.egi?a=print&id=7400&tab=a-z% 20index[2/3/2014 1:37:50 PM]”. |
| Burry, K.A., et al., “Percutaneous Absorption of Progesterone in Postmenopausal Women Treated with Transdermal Estrogen,” American journal of obstetrics and gynecology 180(6Pt1):1504-1511, Elsevier, United States (1999). |
| Campsteyn, H., et al., “Structure Cristalline et Molcculaire de Ia Progesterone C21H3002,” Acta Crystallographica B28 :3032-3042, (1972). |
| Cendejas-Santana, G., et al., “Growth and characterization of progesterone crystallites,” Revista Mexicana de Fisica 50 S(1) : 1-3, (2004). |
| ChemPro, Top-Notch Technology in Production of Oils and Fats, Chempro-Edible-Oii-Refining-ISO-TUV-Austria. |
| Christen, R.D., et al., “Phase I/Pharmacokinetic Study of High-Dose Progesterone and Doxorubicin,” Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 11(12):2417-2426, American Society of Clinical Oncology, United States (1993). |
| Christensson, J.B., et al., “Limonene Hydroperoxide Analogues Differ in Allergenic Activity,” Contact Dermatitis 59(6):344-352, Wiley, England (2008). |
| Christensson, J.B., et al., “Limonene Hydroperoxide Analogues Show Specific Patch Test Reactions,” Contact Dermatitis 70(5):291-299, Wiley, England (2014). |
| Chun et al., “Transdermal Delivery of Estradiol and Norethindrone Acetate: Effect of Vehicles and Pressure Sensitive Adhesive Matrix,” Journal of Korean Pharmaceutical Sciences 35(3):173-177, (2005). |
| Cicinelli, E., et al., “Direct Transport of Progesterone From Vagina to Uterus,” Obstetrics and Gynecology 95(3):403-406, Lippincott Williams & Wilkins, United States (2000). |
| Committee of Obstetric Practice, Committee Opinion—No. 522, Obstetrics & Gynecology, 119(4):879-882, (2012). |
| Commodari, F., et al., “Comparison of 17Beta-Estradiol Structures From X-Ray Diffraction and Solution Nmr,” Magnetic resonance in chemistry : MRC 43(6):444-450, Wiley Heyden, England (2005). |
| Cooper, A., et al., “Systemic Absorption of Progesterone From Progest Cream in Postmenopausal Women,” Lancet 351(9111):1255-1256, Lancet Publishing Group, England (1998). |
| International Search Report and written opinion for International Application No. PCT/US13/46442, dated Nov. 1, 2013. |
| International Search Report and written opinion for International Application No. PCT/US13/46443, dated Oct. 31, 2013. |
| International Search Report and written opinion for International Application No. PCT/US13/46444, dated Oct. 31, 2013. |
| International Search Report and written opinion for International Application No. PCT/US13/46445, dated Nov. 1, 2013. |
| International Search Report and Written Opinion for related International Application No. PCT/US13/023309, dated Apr. 9, 2013. |
| International Search report for corresponding International Application No. PCT/US12/66406, dated Jan. 24, 2013. |
| Corbett, S.H., et al., “Trends in Pharmacy Compounding for Women'S Health in North Carolina : Focus on Vulvodynia,” Southern Medical Journal 107(7):433-436, Southern Medical Association, United States (2014). |
| Corn Refiners Assoc. Com Oil, Edition 5, United States (2006). |
| Critchley, H.O., et al., “Estrogen Receptor Beta, but Not Estrogen Receptor Alpha, Is Present in the Vascular Endothelium of the Human and Nonhuman Primate Endometrium,” The Journal of Clinical Endocrinology and Metabolism 86(3):1370-1378, Endocrine Society, United States (2001). |
| Dauqan, Eqbal M.A., et al., “Fatty Acids Composition of Four Different Vegetable Oils (Red Palm Olein, Palm Olein, Corn Oil,” IPCBEE, 14, lACSIT Press, Singapore (2011). |
| Dideberg, O., et al., “Crystal data on progesterone (C21H3002), desoxycorticosterone (C21H3003), corticosterone (C21H3004) and aldosterone,” Journal of Applied Crystallography 4:80, (1971). |
| Diramio, J.A., et al., “Poly(Ethylene Glycol) Methacrylate/Dimethacrylate Hydrogels for Controlled Release of Hydrophobic Drugs,” Masters of Science Thesis, University of Georgia, Athens, Georgia, 131 pages (2002). |
| Diramio. “Polyethylene Glycol Methacrylate/Dimetacrylate Hydrogels for Controlled Release of Hydrophobic Drugs,” The University of Georgia-Masters of Science Thesis, http://athenaeum.libs.uga.edu/bitstream/handle/10724/7820/diramio_jackie_a_200412_ms.pdf?sequence=1, , 131 pages, (2004). |
| Drakulic, B.J., et al., “Role of Complexes formation Between Drugs and Penetration Enhancers in Transdermal Delivery,” International journal of pharmaceutics 363(1-2):40-49, Elsevier/North-Holland Biomedical Press., Netherlands (2008). |
| Du, J.Y., et al., “Percutaneous Progesterone Delivery via Cream or Gel Application in Postmenopausal Women : A Randomized Cross-Over Study of Progesterone Levels in Serum , Whole Blood , Saliva , and Capillary Blood,” Menopause 20(11):1169-1175, Lippincott-Raven Publishers, United States (2013). |
| Duclos, R., et al., “Polymorphism of Progesterone: Influence of the carrier and of the solid dispersion manufacturing process. A calorimetric and radiocrystallographic study,” Journal of Thermal Analysis 37:1869-1875, John Wiley & Sons, England (1991). |
| Ebian, A.R., “Ebian Article: Polymorphism and solvation of ethinyl estradiol,” Pharmaceutica Acta Helvetiae 54(4):111-114, (1979). |
| Eisenberger, A. and Westhoff, C., “Hormone Replacement Therapy and Venous Thromboembolism,” The Journal of steroid biochemistry and molecular biology 142:76-82, Pergamon, England (2014). |
| Engelhardt, H., et al., “Conceptus influences the Distribution of Uterine Leukocytes During Early Porcine Pregnancy,” Biology of Reproduction 66(6):1875-1880, Society for the Study of Reproduction, United States (2002). |
| Ettinger, B., et al., “Comparison of Endometrial Growth Produced by Unopposed Conjugated Estrogens or by Micronized Estradiol in Postmenopausal Women,” American Journal of Obstetrics and Gynecology 176(1 Pt1):112-117, Elsevier, United States (1997). |
| Excipients for Pharmaceuticals, Sasol Olefins & Surfactants GMBH, 28 pages (2010). |
| Faassen, F., et al., “Physicochemical Properties and Transport of Steroids Across Caco-2 Cells,” Pharmaceutical research 20(2):177-186, Kluwer Academic/Plenum Publishers, United States (2003). |
| “FDA, Draft Guidance on Progesterone, accessed at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM209294.pdf, accessed on (Recommended) Apr. 2010,(Revised) Feb. 2011,”. |
| Ferrari, Roseli AP., et al., “Oxidative Stability of Biodiesel From Soybean Oil Fatty Acid Ethyl Esters,” Scientia Agricola 62(3):291-95, Piracicaba, brazil (2005). |
| Filipsson,F., et al., “Concise International Chemical Assessment Document 5,” Limonene, first draft, World Health Organization, Geneva, 36 pages (1998). |
| Final Office Action dated Jul. 16, 2013 for U.S. Appl. No. 13/684,002, filed Nov. 21, 2012. |
| Final Office Action dated Oct. 26,2012for U.S. Appl. No. 12/561,515, filed Sep. 17, 2009. |
| Flyvholm, M.A. and Menne, T., “Sensitizing Risk of butylated Hydroxytoluene Based on Exposure and Effect Data,” Contact Dermatitis 23(5):341-345, Wiley, England (1990). |
| Fotherby. K., “Bioavailability of Orally Administered Sex Steroids Used in Oral Contraception and Hormone Replacement Therapy,” Contraception 54(2):59-69, Elsevier, United States (1996). |
| Franklin, R.D. and Kutteh, W.H., “Characterization of Immunoglobulins and Cytokines in Human Cervical Mucus : influence of Exogenous and Endogenous Hormones,” Journal of Reproductive Immunology 42(2):93-106, Elsevier/North-Holland Biomedical Press, Ireland (1999). |
| Franz, T.J., et al., “Use of Excised Human Skin to Assess the Bioequivalence of Topical Products,” Skin Pharmacology and Physiology 22(5):276-286, Karger, Switzerland (2009). |
| Freedman, R.R., “Menopausal Hot Flashes: Mechanisms, Endocrinology, Treatment,” The Journal of steroid biochemistry and molecular biology 142:115-120, Pergamon, England (2014). |
| Fuchs, K.O., et al., “The Effects of an Estrogen and Glycolic Acid Cream on the Facial Skin of Postmenopausal Women: A Randomized Histologic Study,” Aesthetic Dermatology 8(1):14-19, (2006). |
| Fuchs, K.O., et al., “The Effects of an Estrogen and Glycolic Acid Cream on the Facial Skin of Postmenopausal Women: A Randomized Histologic Study,” Cutis 71(6):481-488, Frontline Medical Communications, United States (2003). |
| Fuchs, K.O., et al., “The Effects of an Estrogen and Glycolic Acid Cream on the Facial Skin of Postmenopausal Women: A Randomized Histologic Study,” Pharmacology/Cosmetology 5(1), (2006). |
| Fugh-Berman, A. and Bythrow, J., “Bioidentical Hormones for Menopausal Hormone Therapy: Variation on a Theme,” Journal of general internal medicine 22(7):1030-1034, Springer, United States (2007). |
| Furness, S., et al., “Hormone therapy in Postmenopausal Women and Risk of Endometrial Hyperplasia,” The Cochrane Database of Systematic Reviews 8:1-204, Wiley, England (2012). |
| Gafvert, E., et al., “Free Radicals in Antigen formation: Reduction of Contact Allergic Response to Hydroperoxides by Epidermal Treatment with Antioxidants,” The British Journal of Dermatology 146(4):649-656, Blackwell Scientific Publications, England (2002). |
| Ganem-Quintanar., et al., “Evaluation of the transepidermal permeation of diethylene glycol monoethyl ether and skin water loss,” International Journal of Pharmaceutics, 147(2):165-171, (1997) Abstract Only. |
| Gattefossé SAS, Regulatory Data Sheet, Gelot 64, 6 pages (2012). |
| Gattefossé SAS, Regulatory Data Sheet, Lauroglycol 90, 5 pages (2012). |
| Gattefosse, “Excipients for Safe and Effective Topical Delivery,” http://drug-dev.com/Main/Back-Issues/Transdermal-Topical-Subcutaneous-NonInvasive-Deliv-5.aspx# (2012). |
| Gattefosse SAS, Material Safety Data Sheet, Gelot 64, 8 pages 2012. |
| Gillet, J.Y., et al., “induction of Amenorrhea During Hormone Replacement therapy : Optimal Micronized Progesterone Dose a Multicenter Study,” Maturitas 19(2):103-115, Elsevier/North Holland Biomedical Press, Ireland (1994). |
| Giron, D., “Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates,” Thermochimica Acta 248:1-59, Elsevier B.V., Netherlands (1995). |
| Giron-Forest, D., et al., “Thermal Analysis Methods for Pharmacopoeial Materials,” Journal of pharmaceutical and biomedical analysis 7(12):1421-1433, Elsevier Science, England (1989). |
| Glaser, R.L., et al., “Pilot Study : Absorption and Efficacy of Multiple Hormones Delivered in a Single Cream Applied to the Mucous Membranes of the Labia and Vagina,” Gynecologic and Obstetric Investigation 66(2):111-118,Basel, New York, Karger., Switzerland (2008). |
| Golatowski, C., et al., “Comparative Evaluation of Saliva Collection Methods for Proteome Analysis,” International Journal of Clinical Chemistry 419:42-46,Elsevier., Netherlands (2013). |
| Graham, J.D. and Clarke, C.L., “Physiological Action of Progesterone in Target Tissues,” Endocrine Reviews 18(4):502-519, Endocrine Society, United States (1997). |
| Groothuis, P.G., et al., “Estrogen and the Endometrium : Lessons Learned From Gene Expression Profiling in Rodents and Human,” Human Reproduction Update 13(4):405-417, Published for the European Society of Human Reproduction and Embryology by Oxford University Press, England (2007). |
| Gunstone, Frank, D., et al., “Vegetable Oils in Food Technology: Composition, Properties and Uses,” Blackwell Publishing, CRC Press, (2002). |
| Gurney, E.P., et al., “The Women″S Health initiative Trial and Related Studies: 10 Years Later: A Clinician″S View,” The Journal of steroid biochemistry and molecular biology 142:42105, Pergamon, England (2014). |
| Hamid, K.A., et al., “the Effects of Common Solubilizing Agents on the intestinal Membrane Barrier Functions and Membrane Toxicity in Rats,” International Journal of Pharmaceutics 379(1):100-108,Amsterdam, Elsevier/North-Holland Biomedical Press., Netherlands (2009). |
| Hapgood, J.P., et al., “Potency of Progestogens Used in Hormonal Therapy: Toward Understanding Differential Actions,” The Journal of steroid biochemistry and molecular biology 142:39-47, Pergamon, England (2014). |
| Hargrove, J.T., et al., “Menopausal Hormone Replacement Therapy with Continuous Daily Oral Micronized Estradiol and Progesterone,” Obstetrics and gynecology 73(4):606-612, Lippincott Williams & Wilkins, United States (1989). |
| Harner B.A., and Norton, D.A., “Crystal data (I) for some pregnenes and pregnadienes,” Acta Crystallographica 17:1610, (1964). |
| Hatton, J., et al., “Safety and Efficacy of a Lipid Emulsion Containing Medium-Chain Triglycerides,” Clinical Pharmacy 9(5):366-371, American Society of Hospital Pharmacists, United States (1990). |
| He, F., et al., “Apoptotic Signaling Pathways in Uteri of Rats with Endometrial Hyperplasia induced by Ovariectomy Combined with Estrogen,” Gynecologic and Obstetric Investigation 76(1):51-56,Karger., Switzerland (2013). |
| Helbling, I.M., et al., “The Optimization of an intravaginal Ring Releasing Progesterone Using a Mathematical Model,” Pharmaceutical research 31(3):795-808, Kluwer Academic/Plenum Publishers, United States (2014). |
| Helmy, A., et al., “Estrogenic Effect of Soy Phytoestrogens on the Uterus of Ovariectomized Female Rats,” Clinical Pharmacology & Biopharmaceutics, S2, 7 pages (2014). |
| Henderson, V.W., “Alzheimer″S Disease: Review of Hormone Therapy Trials and Implications for Treatment and Prevention After Menopause,” The Journal of steroid biochemistry and molecular biology 142:99-106, Pergamon, England (2014). |
| Henriksen. Thormod, et al., “An ENDOR Sturdy of Radiation-Induced Molecular Damage to Progesterone,” Journal of Magnetic Resonance 63(2):333-342, Elsevier Inc., United States (1985). |
| Hodis, H.N. and Mack, W.J., “Hormone Replacement Therapy and the association with Coronary Heart Disease and Overall Mortality: Clinical Application of the Timing Hypothesis,” The Journal of steroid biochemistry and molecular biology 142:68-75, Pergamon, England (2014). |
| Hospital, M., et al., “X-Ray Crystallography of Estrogens and Their Binding to Receptor Sites,” Molecular pharmacology 8(4):438-445, American Society for Pharmacology and Experimental Therapeutics, United States (1972). |
| Hostynek, J., et al., “Predictinga bsorptiono f fragrancec hemicalst hrough human skin,” Journal of the Society of Cosmetic Chemists 46:221-229, (1995). |
| Hulsmann, S., et al., “Stability of Extruded 17 Beta-Estradiol Solid Dispersions,” Pharmaceutical Development and Technology 6(2):223-229, Informa Healthcare, England (2001). |
| Hurn, P.D. and Macrae, I.M., “Estrogen as a Neuroprotectant in Stroke,” Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 20(4):631-652, Nature Publishing Group, United States (2000). |
| Hyder, S.M., et al., “Synthetic Estrogen 17Alpha-Ethinyl Estradiol induces Pattern of Uterine Gene Expression Similar to Endogenous Estrogen 17Beta-Estradiol,” The Journal of Pharmacology and Experimental Therapeutics 290(2):740-747, American Society for Pharmacology and Experimental Therapeutics, United States (1999). |
| Johanson, G., “Toxicity Review of Ethylene Glycol Monomethyl Ether and its Acetate Ester,” Critical reviews in toxicology 30(3):307-345, Informa Healthcare, England (2000). |
| Johnson, S., Williams, and John, F.W. Keana, “Racemic Progesterone,” Tetrahedron Letters 4(4):193-196, Pergamon Press Ltd., United Kingdom (1963). |
| Joshi, S.G., et al., “Detection and Synthesis of a Progestagen-Dependent Protein in Human Endometrium,” Journal of Reproduction and Fertility 59(2):273-285, Portland Press, England (1980). |
| Kanno J., et al., “the Oecd Program to Validate the Rat Uterotrophic Bioassay to Screen Compounds for in Vivo Estrogenic Responses : Phase 1,” Environmental Health Perspectives 109(8):785-794,N. C. National Institute of Environmental Health Sciences., United States (2001). |
| Karlberg, A.T., et al., “Air Oxidation of D-Limonene (the Citrus Solvent) Creates Potent Allergens,” Contact Dermatitis 26(5):332-340, Wiley, England (1992). |
| Karlberg, A.T., et al., “influence of an Anti-Oxidant on the formation of Allergenic Compounds During Auto-Oxidation of D-Limonene,” The Annals of Occupational Hygiene 38(2):199-207, Oxford University Press, England (1994). |
| Kaunitz, A.M. “Extended Duration Use of Menopausal Hormone therapy,” Menopause 21(6):679-681, Lippincott-Raven Publishers, United States (2014). |
| Khalil, S.A.H., “Stability and Dissolution Rates of Corticosteroids in Polyethylene Glycol Solid Dispersions,” Drug Development and Industrial Pharmacy 10(5):771-787, Marcel Dekker, New York (1984). |
| Kharode, Y., et al., “the Pairing of a Selective Estrogen Receptor Modulator, Bazedoxifene, with Conjugated Estrogens as a New Paradigm for the Treatment of Menopausal Symptoms and Osteoporosis Prevention,” Endocrinology 149(12):6084-6091, Endocrine Society, United States (2008). |
| Kim, Y.W., et al., “Safety Evaluation and Risk Assessment of D-Limonene,” Journal of Toxicology and Environmental Health. Part B, Critical Reviews 16(1):17-38, Informa Healthcare, England (2013). |
| Kincl, F.A., et al., “Increasing Oral Bioavailability of Progesterone by formulation,” Journal of steroid biochemistry 9(1):83-84, Pergamon Press, England (1978). |
| Knuth., et al., “Hydrogel delivery systems for vaginal and oral applications: Formulation and biological considerations, ” Advanced Drug Delivery Reviews, 11(1-2):137-167, (1993) Abstract Only. |
| Koga, K., et al., “Enhancing Mechanism of Labrasol on intestinal Membrane Permeability of the Hydrophilic Drug Gentamicin Sulfate,” European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V 64(1):82-91, Elsevier Science, Netherlands (2006). |
| Komm, B.S., et al., “Bazedoxifene Acetate : A Selective Estrogen Receptor Modulator with Improved Selectivity,” Endocrinology 146(9):3999-4008, Endocrine Society, United States (2005). |
| Korkmaz, Filiz, “Biophysical Studies of Progesterone-Model Membrane Interactions,” A Thesis Submitted to the Graduate School of Natural and Applied Sciences of the Middle East Technical University (2003). |
| Kotiyan, P.N. and Vavia, P.R., “Stability indicating Hptlc Method for the Estimation of Estradiol,” Journal of pharmaceutical and biomedical analysis 22(4):667-671, Elsevier Science, England (2000). |
| Krzyminiewski, R., et al., “EPR Study of the Stable Radical in a y-lrradialed Single Crystal of Progesterone,” Journal of Magnetic Resonance 46:300-305, Acedemic Press, England (1982). |
| Kubli-Garfias, C., et al., “Ab initio calculations of the electronic structure of glucocorticoids,” Journal of Molecular Structure, Theochem 454(2-3):267-275, Elsevier Science B.V., Netherlands (1998). |
| Kubli-Garfias, Carlos, “Ab initio study of the electronic structure of progesterone and related progestins,” Journal of Molecular Structure, Theochem 425(1-2):171-179, Elsevier B.V., Netherlands (1998). |
| Kuhnert-Brandstaetier, M., Kofler, A., “Zur Unterscheidung von losungsmittelhaltigen pseudopolymorphen Kristallformen und polymorphen Modifikationen bei Steroidhormonen.ll.,” 1:127-139, Mikrochimica Acta (1968). |
| Kuhnert-Brandstaetier, M., Lnder, R., “Zur Hydratbildung bei Steroidhormonen,” Sci. Pharm. 41(2):109-116, (1973). |
| Kuhnert-Brandstatier, M., “Thermo-microscopic and spectrophotometric: Determination of steroid hormones,” Microchemical Journal 9:105-133, (1965). |
| Kumasaka, T., et al., “Effects of Various forms of Progestin on the Endometrium of the Estrogen-Primed , Ovariectomized Rat,” Endocrine Journal 41(2):161-169, Japan Endocrine Society, Japan (1994). |
| Kuon, R.J. and Garfield, R.E., “Actions of Progestins for the inhibition of Cervical Ripening and Uterine Contractions to Prevent Preterm Birth,” Facts, Views &Amp; Vision in Obgyn 4(2):110-119,Flemish Society of Obstetrics & Gynaecology, Belgium (2012). |
| Kuon, R.J., et al., “A Novel Optical Method to Assess Cervical Changes During Pregnancy and Use to Evaluate the Effects of Progestins on Term and Preterm Labor,” American Journal of Obstetrics and Gynecology 205(1):82.e15-82.e20, Elsevier, United States (2011). |
| Kuon, R.J., et al., “Pharmacologic Actions of Progestins to inhibit Cervical Ripening and Prevent Delivery Depend on their Properties , the Route of Administration, and the Vehicle,” American Journal of Obstetrics and Gynecology 202(5):455.e1-455.e9, Elsevier, United States (2010). |
| Labrie, et al., “Intravaginal prasterone (DHEA) provides local action without clinically significant changes in serum concentrations of estrogens or androgens,” Journal of Steroid Biochemistry & Molecular Biology 138:359-367, Elsevier (2013). |
| Lacey, J.V. Jr., “The Whi Ten Year″S Later: An Epidemiologist″S View,” The Journal of steroid biochemistry and molecular biology 142:12-15, Pergamon, England (2014). |
| Lahiani-Skiba, M., et al., “Solubility and Dissolution Rate of Progesterone-Cyclodextrin-Polymer Systems, ” Drug development and industrial pharmacy 32(9):1043-1058, Informa Healthcare, England (2006). |
| Lancaster, R.W., et al., “The Polymorphism of Progesterone: Stabilization of a “Disappearing” Polymorph by Co-Crystallization,” Journal of pharmaceutical sciences 96(12):3419-3431, Wiley-Liss, United States (2007). |
| Land, Laura M., “The influence of water content of triglyceride oils on the solubility of steriods,” Pharmaceutical Research 22(5):Springer Science+Business Media (2005). |
| Lanigan, R.S. and Yamarik, T.A., “Final Report on the Safety Assessment of Bht (1),” International Journal of Toxicology 21(2):19-94, Sage Publications, United States (2002). |
| Lapez-Belmonte, J., et al., “Comparative Uterine Effects on Ovariectomized Rats After Repeated Treatment with Different Vaginal Estrogen formulations,” Maturitas 72(4):353-358, Elsevier/North Holland Biomedical Press, Ireland (2012). |
| Lauer, A.C., et al., “Evaluation of the Hairless Rat as a Model for in Vivo Percutaneous Absorption,” Journal of Pharmaceutical Sciences 86(1):13-18, Wiley-Liss, United States (1997). |
| Idder, Salima, et al., “Physicochemical properties of Progesterone,” 1-26, American Chemical Society & U.S. National Library of Medicine (2014). |
| Leonetti, H.B., et al., “Topical Progesterone Cream Has an Antiproliferative Effect on Estrogen-Stimulated Endometrium,” Fertility and sterility 79(1):221-222, Elsevier for the American Society for Reproductive Medicine, United States (2003). |
| Leonetti, H.B., et al., “Transdermal Progesterone Cream as an Alternative Progestin in Hormone therapy,” Alternative Therapies in Health and Medicine 11(6):36-38, InnoVision Communications, United States (2005). |
| Lewis, J.G., et al., “Caution on the Use of Saliva Measurements to Monitor Absorption of Progesterone From Transdermal Creams in Postmenopausal Women,” Maturitas 41(1):1-6, Elsevier/North Holland Biomedical Press, Ireland (2002). |
| Li, G.C., et al., “Solid-State Nmr Analysis of Steroidal Conformation of 17α- and 17Î2-Estradiol in the Absence and Presence of Lipid Environment,” Steroids 77(3):185-192, Elsevier, United States (2012). |
| Lobo, R.A., “foreword: Hormone Therapy Arms,” The Journal of steroid biochemistry and molecular biology 142:3, Pergamon, England (2014). |
| Lucy., et al., “Gonadotropin-releasing hormone at estrus: luteinizing hormone, estradiol, and progesterone during the periestrual and postinsemination periods in dairy cattle,” Bioi Reprod 35(2):300-11, (1986) Abstract Only. |
| Lvova, M.SH., et al., “Thermal Analysis in the Quality Control and Standardization of Some Drugs,” Journal of Thermal Analysis 40:405-411, Wiley (1993). |
| Madishetti, S.K., et al., “Development of Domperidone Bilayered Matrix Type Transdermal Patches : Physicochemical , in Vitro and Ex Vivo Characterization,” Journal of Faculty of Pharmacy 18(3):221-229, BioMed Central, England (2010). |
| Magness, R.R. and Ford, S.P., “Estrone, Estradiol-17 Beta and Progesterone Concentrations in Uterine Lymph and Systemic Blood Throughout the Porcine Estrous Cycle,” Journal of animal science 57(2):449-455, American Society of Animal Science, United States (1983). |
| “Management of Symptomatic Vulvovaginal Atrophy: 2013 Position Statement of the North American Menopause Society,” Menopause 20(9):888-902, Lippincott-Raven Publishers, United States (2013). |
| Mcguffy, Irena, “Softgel Technology as a Lipid-Based Delivery Tool for Bioavailability Enhancement,” Catalent Pharma Solutions Somerset, NJ (2011). |
| “Merck Index, Estradiol, The Merck Index Online, Royal Society of Chemistry 2014,” https://www.rsc.org/Merck-Index/monograph/mono1500003758/estradiol?q=unauthorize. |
| “Merck Index Online, Progesterone, Royal Society of Chemistry, accessed at https:l/www.rsc.org/Merck-lndeXI monograph/print/mono1500007889/progesterone?q=authorize, accessed on 2013 search Feb. 17, 2014,”. |
| “Merck Index Online, Progesterone, Royal Society of Chemistry, accessed at https://www.rsc.org/Merck-lndex/monograph/print/mono1500007889/progesterone?q=authorize, accessed at 2013, search Feb. 24, 2014 ,”. |
| Mesley, R.J., “Clathrate formation From Steroids,” Chemistry & industry 37:1594-1595, John Wiley & Sons Ltd., England (1965). |
| “Miao, Wenbin, et al.,” Chemical Properties of Progesterone American Chemical Society & U.S. National Library of Medicine (2014). |
| Miles, R.A., et al., “Pharmacokinetics and Endometrial Tissue Levels of Progesterone After Administration by intramuscular and Vaginal Routes : A Comparative Study,” Fertility and Sterility 62(3):485-490, Elsevier for the American Society for Reproductive Medicine, United States (1994). |
| Miller, J.A., et al., “Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast,” Journal Of Cancer Therapy 3(5A), Scientific Research Publishing, United States (2012). |
| Mueck, A.O., et al., “Genomic and Non-Genomic Actions of Progestogens in the Breast,” The Journal of steroid biochemistry and molecular biology 142:62-67, Pergamon, England (2014). |
| Muramatsu, Mitsuo, “Thermodynamic Relationship between a- and B-Forms of Crystalline Progesterone,” Journal of Pharmaceutical Sciences 68(2):175-178, American Pharmacists Association (1979). |
| Ng, Jo-Han., et al., “Advances in biodiesel fuel for application in compression ignition engines,” Clean Technologies and Environmental Policy 12:459-493, Springer-Verlag (2010). |
| Nicklas, M., et al., “Preparation and Characterization of Marine Sponge Collagen Nanoparticles and Employment for the Transdermal Delivery of 17Beta-Estradiol-Hemihydrate,” Drug development and industrial pharmacy 35(9):1035-1042, Informa Healthcare, England (2009). |
| Nilsson, U., et al., “Analysis of Contact Allergenic Compounds in Oxidized d-Limonene,” Chromatographia 42:199-205, (1996). |
| Non Final Office Action dated Dec. 12, 2011 for U.S. Appl. No. 12/561,515, filed Sep. 17, 2009. |
| Non-Final Office Action dated Feb. 18, 2014 for U.S. Appl. No. 14/099,545, filed Dec. 6, 2013. |
| Non-Final Office Action dated Mar. 20, 2013 for U.S. Appl. No. 13/684,002, filed Nov. 21, 2012. |
| Notelovitz, M., et al., “initial 17Beta-Estradiol Dose for Treating Vasomotor Symptoms,” Obstetrics and Gynecology 95(5):726-731, Lippincott Williams & Wilkins, United States (2000). |
| Notice of Allowance dated Dec. 6, 2013 for U.S. Appl. No. 13/684,002, filed Nov. 21, 2012. |
| Notice of Allowance dated Sep. 11, 2013 for U.S. Appl. No. 12/561,515, filed Sep. 17, 2009. |
| NuGen, “What is NuGen HP Hair Growth System? ,” http://www.skinenergizer.com/Nugen-HP-Hair-Grow1h-System-p/ senusystem.htm, 3 pages, undated. |
| NuGest 900™, http://www.lhehormoneshop.nel/nugest900.htm, 4 pages, undated. |
| O'Leary, P., et al., “Salivary, but Not Serum or Urinary Levels of Progesterone are Elevated After Topical Application of Progesterone Cream to Pre- and Postmenopausal Women,” Clinical Endocrinology 53(5):615-620,Blackwell Scientific Publications, England (2000). |
| “Open Notebook, Science Solubility Challenge, Solubility of progesterone in organic solvents, accessed at http:!/ lxsrv7.oru.edu/-alang/onsc/solubility/allsolvents.php?solute=progesterone, accessed on Jul. 16, 2013,”. |
| Opinion on Diethylene glycol monoethyl ether, Scientific Committee on Consumer Products, The SCCP adopted this opinion at its 10th plenary,27 pages (2006). |
| Outterson, K. “the Drug Quality and Security Act—Mind the Gaps,” The New England Journal of Medicine 370(2):97-99,Massachusetts Medical Society., United States (2014). |
| Palamakula, A., et al., “Preparation and In Vitro Characterization of Self-Nanoemulsified Drug Delivery Systems of Coenzyme Q10 Using Chiral Essential Oil Components” Pharmaceutical Technology 74-88, (2004). |
| Panay, N., et al., “The 2013 British Menopause Society & Women's Health Concern recommendations on hormone replacement therapy,” DO1: 0.1177/1754045313489645, min.sagepub.com. Menopause International: The Integrated Journal of Post reproductive Health 0(0):1-10, (2013). |
| Panay, N., et al., “The 2013 British Menopause Society & Women″S Health Concern Recommendations on Hormone Replacement Therapy,” Menopause international 19(2):59-68, Sage, England (2013). |
| Panay, N., et al., “The 2013 British Menopause Society & Women's Health Concern recommendations on hormone replacement therapy,” Menopause International: The Integrated Journal of Postreproductive Health, published online May 23, 2013, Sage Publications. http://min.sagepub.com/content/early/2013/05/23/1754045313489645.1. |
| Panchagnula, R. and Ritschel, W.A., “Development and Evaluation of an intracutaneous Depot formulation of Corticosteroids Using Transcutol as a Cosolvent: in-Vitro, Ex-Vivo and in-Vivo Rat Studies,” The Journal of pharmacy and pharmacology 43(9):609-614, Wiley, England (1991). |
| Parasuraman, S., et al., “Blood Sample Collection in Small Laboratory Animals,” Journal of Pharmacology &Amp; Pharmacotherapeutics 1(2):87-93, Medknow Publications and Media, India (2010). |
| Park, J.S., et al., “Solvent Effects on Physicochemical Behavior of Estradiols Recrystallized for Transdermal Delivery,” Archives of pharmacal research 31(1):111-116, Pharmaceutical Society of Korea., Korea (South) (2008). |
| Park, J.S., et al., “Use of Cp/Mas Solid-State Nmr for the Characterization of Solvate Molecules within Estradiol Crystal forms,” European journal of pharmaceutics and biopharmaceutics 60(3):407-412, Elsevier Science, Netherlands (2005). |
| Parrish, D.A. and Pinkerton, A.A., “A New Estra-1,3,5(10)-Triene-3,17Beta-Diol Solvate: Estradiol-Methanol-Water (3/2/1),” Acta crystallographica. Section C, Crystal structure communications 59(Pt2):o80-82, Wiley-Blackwell, United States (2003). |
| Patel., et al., “Transdermal Drug Delivery System: A Review,” The Pharma Innovation, The Pharma Journal 1(4), (2012). |
| Payne, R.S., et al., “Examples of Successful Crystal Structure Prediction: Polymorphs of Primidone and Progesterone,” International Journal of Pharmaceutics 177(2):231-245, Elsevier/North-Holland Biomedical Press., Netherlands (1999). |
| PCCA, Apothogram, PCCA, Houston, TX, (2014). |
| Persson, Linda C, et al., “Physicochemical Properties of Progesterone Selecte,” 1-5, American Chemical Society & U.S. National Library of Medicine (2014). |
| Pfaus, J.G., et al., “Selective Facilitation of Sexual Solicitation in the Female Rat by a Melanocortin Receptor Agonist,” Proceedings of the National Academy of Sciences of the United States of America 101(27):10201-10204, National Academy of Sciences, United States (2004). |
| Pheasant, Richard, , “Polymorphism of 17-Ethinylestradiol,” Schering Corporation, Bloomfield, NJ (1950). |
| Pickles, V.R. “Cutaneous Reactions to injection of Progesterone Solutions into the Skin,” British Medical Journal 2(4780):373-374, British Medical Association, England (1952). |
| Pinkerton, J.V. and Thomas, S., “Use of Serms for Treatment in Postmenopausal Women,” The Journal of Steroid Biochemistry and Molecular Biology 142:142-154, Pergamon, England (2014). |
| Pinkerton, J.V. “What are the Concerns About Custom-Compounded “Bioidentical” Hormone therapy?,” Menopause 21(12):1298-1300, Lippincott-Raven Publishers, United States (2014). |
| Pisegna, Gisia L, “A High-pressure Vibrational Spectroscopic Study of Polymorphism in Steroids,” Thesis, McGill University, Dept. of Chem:National Library of Canada (1999). |
| Prajapati, Hetal N., et al., “A comparative Evaluation of Mono-, Di- and Triglyceride of Medium Chain Fatty Acids by Lipid/Surfactan UWater,” Springerlink.com, pp. 1-21, (2011). |
| Prausnitz, M.R. and Langer, R., “Transdermal Drug Delivery,” Nature Biotechnology 26(11):1261-1268, Nature America Publishing, United States (2008). |
| Price, S.L., “The Computational Prediction of Pharmaceutical Crystal Structures and Polymorphism,” Advanced drug delivery reviews 56(3):301-319, Elsevier Science Publishers, B.V., Netherlands (2004). |
| Product Safety Assessment, Diethylene Glycol Monoethyl Ether, The Dow Chemical Company Page, 5 Pages (2007). |
| Progynova TS 100, available online at file:I//C:!Users/Caii%20Family/Desktop/Progynova%20TS%20100%2012%20Patches_Pack%20%28Estradioi%20Hemihydrate%29.html, 2010. |
| Provider Data Sheet, “About Dried Blood Spot Testing,” ZRT Laboratory, 3 pages (2014). |
| Rahn, D.D., et al., “Vaginal Estrogen for Genitourinary Syndrome of Menopause: A Systematic Review,” Obstetrics and Gynecology 124(6):1147-1156, Lippincott Williams & Wilkins, United States (2014). |
| Reisman, S.A., et al., “Topical Application of the Synthetic Triterpenoid Rta 408 Protects Mice From Radiation-induced Dermatitis,” Radiation Research 181(5):512-520, Radiation Research Society, United States (2014). |
| Restriction/Election Requirement dated Mar. 5, 2014 for U.S. Appl. No. 14/099,623, filed Dec. 6, 2013. |
| Restriction/Election Requirement dated Feb. 20, 2014 for U.S. Appl. No. 14/099,562, filed Dec. 6, 2013. |
| Rosilio, V., et al., “Physical Aging of Progesterone-Loaded Poly(D,L,-Lactide-Co-Glycolide) Microspheres,” Pharmaceutical research 15(5):794-798, Kluwer Academic/Plenum Publishers, United States (1998). |
| Ross, D., et al., “Randomized , Double-Blind , Dose-Ranging Study of the Endometrial Effects of a Vaginal Progesterone Gel in Estrogen-Treated Postmenopausal Women,” American Journal of Obstetrics and Gynecology 177(4):937-941, Elsevier, United States (1997). |
| Ruan, X. and Mueck, A.O., “Systemic Progesterone therapy—Oral, Vaginal , injections and Even Transdermal ?,” Maturitas 79(3):248-255, Elsevier/North Holland Biomedical Press, Ireland (2014). |
| Salem, H.F. “Sustained-Release Progesterone Nanosuspension Following intramuscular injection in Ovariectomized Rats,” International Journal of Nanomedicine 10:943-954,Dove Medical Press, New Zealand (2010). |
| Salole, E.G., “The Physicochemical Properties of Oestradiol,” Journal of Pharmaceutical and Biomedical Analysis 5(7):635-648, Elsevier Science, England (1987). |
| Salole, Eugene G., “Estradiol, Analy lical Profiles of Drug Substances,” vol. 15, pp. 283-318, (1986). |
| Santen, R.J., “Menopausal Hormone Therapy and Breast Cancer,” The Journal of Steroid Biochemistry and Molecular Biology 142:52-61, Pergamon, England (2014). |
| Santen, R.J. “Vaginal Administration of Estradiol : Effects of Dose , Preparation and Timing on Plasma Estradiol Levels,” The Journal of the International Menopause Society :1-14, Informa Healthcare, England (2014). |
| Sarkar, Basu, et al., “Chemical Stability of Progesterone in Compounded Topical Preparations using PLO Transdermal CreamTM and HRT CreamTM Base,” Steroids and Hormonal Science 4:2, (2013). |
| Sarrel. and Philip., “The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomied Women Aged 50 to 59 Years,” American Journal of Public Health, Research and Practice, pp. e1-e6, Published online ahead of print Jul. 18, 2013. |
| Satyanarayana, D, et al., “Aqueous Solubility Predictions of Aliphatic Alcohols, Alkyl Substituted Benzoates and Steroids,” Asian Journal of Chemistry 9(3): 418-26, (1997). |
| Scavarelli, Rosa Maria, et al., Progesterone and Hydrate or Solvate, SciFinder, pp. 1-2, American Chemical Society (2014). |
| Schindler, A.E., “The “Newer” Progestogens and Postmenopausal Hormone Therapy (Hrt),” The Journal of Steroid Biochemistry and Molecular Biology 142:48-51, Pergamon, England (2014). |
| Schutte, S.C. and Taylor, R.N., “A Tissue-Engineered Human Endometrial Stroma That Responds to Cues for Secretory Differentiation , Decidualization , and Menstruation,” Fertility and Sterility 97(4):997-1003, Elsevier for the American Society for Reproductive Medicine, United States (2012). |
| Schweikart, K.M., et al., “Comparative Uterotrophic Effects of Endoxifen and Tamoxifen in Ovariectomized Sprague-Dawley Rats,” Toxicologic Pathology 42(8):1188-1196, Sage Publications, United States (2014). |
| SciFinder Scholar Prednisone Chemical Properties, SciFinde, pp. 1-7, National Library of Medicine (2014). |
| SciFinder Scholar Prednisone Physical Properties, SciFinder, pp. 1-10, Natioinal Library of Medicine (2014). |
| SciFinder Scholar Progesterone Experimental Properties, SciFinder, pp. 1-9, American Chemical Society (2014). |
| Serantoni, Foresti, et al., “4-Pregnen-3, 20-Dione (progesterone, form II),” Crystal Structure Communications 4(1):189-92, CAPLUS Database (1975). |
| Shao, R., et al., “Direct Effects of Metformin in the Endometrium : A Hypothetical Mechanism for the Treatment of Women with Pcos and Endometrial Carcinoma,” Journal of Experimental & Clinical Cancer Research 33:41, BioMed Central, England (2014). |
| Sharma, H.C., et al., “Physical Properties of Progesterone Selected Refer, SciFinder,” pp. 1-5, American Chemical Society & U.S. National Library of Medicine (2014). |
| Shrier, L.A., et al., “Mucosal Immunity of the Adolescent Female Genital Tract,” The Journal of Adolescent Health 32(3):183-186, Elsevier, United States (2003). |
| Shufelt, C.L., et al., “Hormone Therapy Dose , formulation , Route of Delivery , and Risk of Cardiovascular Events in Women : Findings From the Women″S Health initiative Observational Study,” Menopause 21(3):260-266, Lippincott-Raven Publishers, United States (2014). |
| Siew, A, et al.,“Bioavailability Enhancement with Lipid-Based Durg-Delivery Systems” Phamraceutlcal Technology 28,30-31, (2014). |
| Sigma-Aldrich, Progesterone-Water Soluble: powder, BioReagent, suitable for cell culture), MSDS available online: http://www.sigmaaldrich.com/catalog/producl/sigma/p7556. |
| Simon, J., et al., “Effective Treatment of Vaginal Atrophy with an Ultra-Low-Dose Estradiol Vaginal Tablet,” Obstetrics and gynecology 112(5):1053-1060, Lippincott Williams & Wilkins, United States (2008). |
| Simon, J.A. “What If the Women'S Health initiative Had Used Transdermal Estradiol and Oral Progesterone instead?,” Menopause 21(7):769-783, Lippincott-Raven Publishers, United States (2014). |
| Sitruk-Ware. and Regine., “Oral Micronized Progesterone—Bioavailability Pharmacokinetics, Pharmacological and Therapeutic Implications—A Review,” Contraception 36(4):373-402, (1987). |
| Sitruk-Ware, R., “Progestogens in Hormonal Replacement Therapy: New Molecules, Risks, and Benefits,” Menopause 9(1):6-15, Lippincott-Raven Publishers, United States (2002). |
| Smith and Nicholas., “Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared with Oral Conjugated Equine Estrogens,” JAMA Intern Med, pp. e1-e7, published online Sep. 30, 2013. |
| Smyth, H.F., et al., “A 2-Yr Study of Diethylene Glycol Monoethyl Ether in Rats,” Food and Cosmetics Toxicology 2:641-642, Pergamon Press, England (1964). |
| Stanczyk, F.Z. and Bhavnani, B.R., “Current Views of Hormone Therapy for the Management and Treatment of Postmenopausal Women,” The Journal of steroid biochemistry and molecular biology 142:1-2, Pergamon, England (2014). |
| Stanczyk, F.Z. and Bhavnani, B.R., “Use of Medroxyprogesterone Acetate for Hormone Therapy in Postmenopausal Women: Is It Safe?,” The Journal of steroid biochemistry and molecular biology 142:30-38, Pergamon, England (2014). |
| Stanczyk, F.Z., et al., “Ethinyl Estradiol and 17Î2-Estradiol in Combined Oral Contraceptives: Pharmacokinetics, Pharmacodynamics and Risk assessment,” Contraception 87(6):706-727, Elsevier, United States (2013). |
| Stanczyk, F.Z., et al., “therapeutically Equivalent Pharmacokinetic Profile Across Three Application Sites for Ag200-15 , A Novel Low-Estrogen Dose Contraceptive Patch,” Contraception 87(6):744-749, Elsevier, United States (2013). |
| Stein, Emily A., et al., “Progesterone, SciFinder Scholar Search” 1-46, American Chemical Society & U.S. National Library of Medicine, Feb. 24, 2014. |
| Stein, Emily A., et al., “Progesterone Physical Properties,” 1-46, American Chemical Society & U.S. National Library of Medicine, Feb. 24, 2014. |
| Stein, Emily A., et al., “Progesterone Physical Properties,” 1-46, American Chemical Society & U.S. National Library of Medicine,Mar. 3, 2014. |
| Strickley, R.G., “Solubilizing Excipients in Oral and injectable formulations,” Pharmaceutical research 21(2):201-230, Kluwer Academic/Plenum Publishers, United States (2004). |
| Strocchi, Antonino, Fatty Acid Composition, and Triglyceride Structure of Corn Oil, Hydrogenated Corn Oil, and Corn Oil Margarine, Journal of Food Science 47, pp. 36-39, (1981). |
| Struhar, M., et al., “Preparation of the Estradiol Benzoate injection Suspension,” Ceskoslovenska farmacie 27(6):245-249, Ceskoslovenska Lekarska Spolecnost, Czech Republic (1978). |
| Sullivan, D.W.Jr., et al., “A review of the nonclinical safety of Transcutol®, a highly purified form of diethylene glycol monoethyl ether (DEGEE) used as a pharmaceutical excipient,” Food and Chemical Toxicology 72:40-50, Elsevier Science Ltd, England (2014). |
| Sun, J. “D-Limonene : Safety and Clinical Applications,” Alternative Medicine Review 12(3):259-264, Alternative Medicine Review, United States (2007). |
| Tahition Noni. “Body Balance Cream,” http://products.lni.com/dominican_republic/sa_spanish/nonistore/ producl/3438/3416/, 1 page, undated. |
| Tait, A.D., “Characterization of the Products From the Oxidation of Progesterone with Osmium Tetroxide,” Steroids 20(5):531-542, Elsevier, United States (1972). |
| Takacs, M., et al., “The Light Sensitivity of Corticosteroids in Crystalline form Photochemical Studies 59 (1),” Pharmaceutica acta Helvetiae 66(5-6):137-140, Schweizerische Apotheker-Verein, Switzerland (1991). |
| Tan, Melvin, S., et al., “A Sensitive Method for the Determination of Progesterone in Human Plasma by LC-MS-MS, M1025,” Cedra Corporation, Austin. |
| Tang, F.Y., et al., “Effect of Estrogen and Progesterone on the Development of Endometrial Hyperplasia in the Fischer Rat,” Biology of Reproduction 31(2):399-413, Society for the Study of Reproduction, United States (1984). |
| Tas, M., et al., “Comparison of Antiproliferative Effects of Metformine and Progesterone on Estrogen-induced Endometrial Hyperplasia in Rats,” Gynecological Endocrinology 29(4):311-314, Informa Healthcare, England (2013). |
| Tella, S.H., Gallagher, J.C., “Prevention and treatment of postmenopausal osteoporosis,” The Journal of Steroid Biochemistry and Molecular Biology 142:155-170, Elsevier Ltd., United Kingdom (2014). |
| Thomas, J., et al., “The Effect of Water Solubility of Solutes on Their Flux Through Human Skin in Vitro: An Extended Flynn Database Fitted to the Roberts-Sloan Equation,” International Journal of Pharmaceutics 339(1-2):157-167, Elsevier/North-Holland Biomedical Press., Netherlands (2007). |
| Thomas, P. “Characteristics of Membrane Progestin Receptor Alpha (Mpralpha) and Progesterone Membrane Receptor Component 1 (Pgmrc1) and their Roles in Mediating Rapid Progestin Actions,” Frontiers in Neuroendocrinology 29(2):292-312, Academic Press, United States (2008). |
| Tripathi, R., et al., “Study of Polymorphs of Progesterone by Novel Melt Sonocrystallization Technique: A Technical Note,” AAPS PharmSciTech 11(3):1493-1498, Elsevier/North-Holland Biomedical Press., Netherlands (2010). |
| Trommer, H. and Neubert, R.H., “Overcoming the Stratum Corneum : the Modulation of Skin Penetration a Review,” Skin Pharmacology and Physiology 19(2):106-121, Karger, Switzerland (2006). |
| Tuleu, C., et al., “Comparative Bioavailability Study in Dogs of a Self-Emulsifying formulation of Progesterone Presented in a Pellet and Liquid form Compared with an Aqueous Suspension of Progesterone,” Journal of Pharmaceutical Sciences 93(6):1495-1502, Wiley-Liss, United States (2004). |
| Ueda, T., et al., “Topical and Transdermal Drug Products,” Pharmacopeial Forum 35(3):750-764, (2009). |
| USP, 401 Fats and Fixed Oils, Chemical Tests, Second Suplementto USP36-NF 31, pp. 6141-6151, (2013). |
| USP, Lauroyl Polyoxylglycerides, Saftey Data Sheet, US, 5611 Version #02, pp. 1-9, (2013). |
| “USP Monographs: Progesterone. USP29, accessed at www.pharmacopeia.cn/v29240/usp29nf24sO_m69870.html, accessed on Feb. 25, 2014,”. |
| USP, Official Monographs, Corn Oil, NF 31, pp. 1970-1971, (2013). |
| USP. Official Monographs, Lauroyl Polyoxylglycerides, NF 31, pp. 2064-2066, (2013). |
| USP, Official Monographs, Medium Chain Triglycerides, NF 31, pp. 2271-2272, (2013). |
| USP, Official Monographs, Mono- and Di-glycerides, NF 31, pp. 2101, (2013). |
| USP, USP Certificate—Corn Oil, Lot GOL404, Jul. 2013. |
| Utian, W.H., et al., “Relief of Vasomotor Symptoms and Vaginal Atrophy with Lower Doses of Conjugated Equine Estrogens and Medroxyprogesterone Acetate,” Fertility and sterility 75(6):1065-1079, Elsevier for the American Society for Reproductive Medicine, United States (2001). |
| Voegtline, K.M. and Granger, D.A., “Dispatches From the interface of Salivary Bioscience and Neonatal Research,” Frontiers in Endocrinology 5:25,Frontiers Research Foundation, Switzerland (2014). |
| Waddell, B.J. and Bruce, N.W., “the Metabolic Clearance of Progesterone in the Pregnant Rat : Absence of a Physiological Role for the Lung,” Biology of Reproduction 40(6):1188-1193, Society for the Study of Reproduction, United States (1989). |
| Waddell, B.J. and Oleary, P.C., “Distribution and Metabolism of Topically Applied Progesterone in a Rat Model,” The Journal of Steroid Biochemistry and Molecular Biology 80(4-5):449-455, Pergamon, England (2002). |
| Walter, L.M., et al., “the Role of Progesterone in Endometrial Angiogenesis in Pregnant and Ovariectomised Mice,” Reproduction 129(6):765-777,Reproduction and Fertility by BioScientifica, England (2005). |
| Warney Cole and Percy L., Julian , “A Study of the 22-Ketosteroids,” Journal of the American Chemical Society 67(8):1369-1375, (1945). |
| Weber, E.J. “Corn Lipids,” Cereal Chemistry Journal 55(5): 572-584, American Association of Cereal Chemists (1978). |
| Weber, M.T., et al., “Cognition and Mood in Perimenopause: A Systematic Review and Meta-Analysis,” The Journal of Steroid Biochemistry and Molecular Biology 142:90-98, Pergamon, England (2014). |
| Whitehead, M.I., et al., “Absorption and Metabolism of Oral Progesterone,” British medical journal 280(6217):825-827, British Medical Association, England (1980). |
| William, L., Duax, Jane F., Griffin, Douglas, C., Rohrer, “Conformation of Progesterone Side Chain: Conftict between X-ray Data and Force-Field Calculations,” Journal of the American Chemical Society 103(22):6705-6712, (1981). |
| Wiranidchapong, Chutima et al., “Method of preparation does not affect the miscibility between steroid hormone and polymethacrylate,” Thermochimica Acta 485(1-2):57-64, Elsevier B.V., Netherlands (2009). |
| Wood, C.E., et al., “Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys,” Breast Cancer Research and Treatment 101:125-134, Springer Science+ Business Media B.V (2006), published online Jul. 14, 2006. |
| Wren, B.G., et al., “Effect of Sequential Transdermal Progesterone Cream on Endometrium , Bleeding Pattern , and Plasma Progesterone and Salivary Progesterone Levels in Postmenopausal Women,” The Journal of the International Menopause Society 3(3):155-160, Informa Healthcare, England (2000). |
| Wu, X., et al., “Gene Expression Profiling of the Effects of Castration and Estrogen Treatment in the Rat Uterus,” Biology of Reproduction 69(4):1308-1317, Society for the Study of Reproduction, United States (2003). |
| Yalkowsky, Samuel, H. , “Handbook of Acqueous Solubility Data,” 1110-1111, CRC Press, United States. |
| Yalkowsky, S.H. and Valvani, S.C., “Solubility and Partitioning I: Solubility of Nonelectrolytes in Water,” Journal of Pharmaceutical Sciences 69(8):912-922, Wiley-Liss, United States (1980). |
| Yue, W., et al., “Genotoxic Metabolites of Estradiol in Breast: Potential Mechanism of Estradiol induced Carcinogenesis,” The Journal of Steroid Biochemistry and Molecular Biology 86(3-5):477-486, Pergamon, England (2003). |
| Zava, D. “Topical Progesterone Delivery and Levels in Serum, Saliva, Capillary Blood, and Tissues” Script:4-5. |
| Zava, D.T., et al., “Percutaneous absorption of progesterone,” Maturitas 77:91-92, Elsevier/North Holland Biomedical Press, Ireland (2014). |
| Geelen, M.J.H., et al., “Dietary Medium-Chain Fatty Acids Raise and (n-3) Polyunsaturated Fatty Acids Lower Hepatic Triacylglycerol Synthesis in Rats,” The Journal of Nutrition 125:2449-2456, American Institute of Nutrition, United States (1995). |
| Herman, A and Herman, A.P., “Essential oils and their constituents as skin penetration enhancer for transdermal drug delivery: a review,” Journal of Pharmacy and Pharmacology 67(4):473-485, Royal Pharmaceutical Society, England (2014). |
| Manson, J.E., et al., “Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women's Health Initiative Randomized Trials,” The Journal of the American Medical Association 310:1353-1368, American Medical Association, United States (2013). |
| Notice of Allowance, dated Dec. 10, 2014, in U.S. Appl. No. 14/099,562, Bernick, B.A., filed Dec. 6, 2013, 10 pages. |
| Notice of Allowance, dated Dec. 10, 2014, in U.S. Appl. No. 14/099,598, Bernick, B.A., filed Dec. 6, 2013, 8 pages. |
| Notice of Allowance, dated Dec. 15, 2014, in U.S. Appl. No. 14/099,623, Bernick, B.A., filed Dec. 6, 2013, 9 pages. |
| Notice of Allowance, dated Feb. 11, 2015, in U.S. Appl. No. 14/475,864, Bernick, B.A., filed Sep. 3, 2014, 9 pages. |
| Notice of Allowance, dated Feb. 13, 2015, in U.S. Appl. No. 14/475,814, Bernick, B.A., filed Sep. 3, 2014, 6 pages. |
| Notice of Allowance, dated Jan. 22, 2015, in U.S. Appl. No. 14/099,582, Bernick, B.A., filed Dec. 6, 2013, 5 pages. |
| Notice of Allowance, dated Jul. 14, 2014, in U.S. Appl. No. 14/099,545, Bernick, B.A., filed Dec. 6, 2013, 9 pages. |
| Notice of Allowance, dated Jul. 15, 2014, in U.S. Appl. No. 14/099,571, Bernick, B.A., filed Dec. 6, 2013, 11 pages. |
| Notice of Allowance, dated Nov. 26, 2014, in U.S. Appl. No. 14/099,612, Bernick, B.A., filed Dec. 6, 2013, 12 pages. |
| Notice of Allowance, dated Nov. 7, 2014, in U.S. Appl. No. 14/099,582, filed Dec. 6, 2013, 14 pages. |
| Office Action, dated Apr. 14, 2015, in U.S. Appl. No. 14/125,554, Bernick, B.A., filed Dec. 12, 2013, 9 pages. |
| Office Action, dated Apr. 7, 2015, in U.S. Appl. No. 14/624,051, Bernick B.A., filed Feb. 17, 2015, 10 pages. |
| Office Action, dated Dec. 8, 2014, in U.S. Appl. No. 14/106,655, Bernick, B.A., filed Dec. 13, 2013, 9 pages. |
| Office Action, dated Feb. 18, 2015, in U.S. Appl. No. 14/521,230, Bernick, B.A., filed Oct. 22, 2014, 8 pages. |
| Office Action, dated Jul. 18, 2014, in U.S. Appl. No. 14/099,623, Bernick, B.A., filed Dec. 6, 2013, 12 pages. |
| Office Action, dated Jul. 2, 2014, in U.S. Appl. No. 14/099,562, Bernick, B.A., filed Dec. 6, 2013, 9 pages. |
| Office Action, dated Jul. 3, 2014, in U.S. Appl. No. 14/099,598, Bernick, B.A., filed Dec. 6, 2013, 16 pages. |
| Office Action, dated Jul. 30, 2014, in U.S. Appl. No. 14/099,612, Bernick, B.A., filed Dec. 6, 2013, 12 pages. |
| Office Action, dated Jun. 17, 2014, in U.S. Appl. No. 14/099,582, Bernick, B.A., filed Dec. 6, 2013, 14 pages. |
| Office Action, dated Mar. 12, 2015, in U.S. Appl. No. 14/136,048, Bernick, B.A., filed Dec. 20, 2013, 24 pages. |
| Office Action, dated Mar. 27, 2014, in U.S. Appl. No. 14/099,562, Bernick, B.A., filed Dec. 6, 2013, 8 pages. |
| Office Action, dated Oct. 1, 2014, in U.S. Appl. No. 14/475,814, Bernick, B.A., filed Sep. 3, 2014, 6 pages. |
| Office Action, dated Oct. 2, 2014, in U.S. Appl. No. 14/475,864, Bernick, B.A., filed Sep. 3, 2014, 6 pages. |
| Portman, D., et al., “One-year treatment persistence with local estrogen therapy in postmenopausal women diagnosed as having vaginal atrophy,” Menopause 22(11): 7 pages, The North American Menopause Society, United States (2015). |
| Rao, R. and Rao, S., “Intra Subject Variability of Progesterone 200 mg Soft Capsules in Indian Healthy Adult Postmenopausal Female Subjects under Fasting Conditions,” Journal of Bioequivalence & Bioavailability 6(4):139-143, Open Access (2014). |
| Restriction Requirement, dated Apr. 14, 2015, in U.S. Appl. No. 13/843,428, Bernick, B.A., filed Mar. 15, 2013, 7 pages. |
| Restriction Requirement, dated Apr. 29, 2014, in U.S. Appl. No. 14/099,582, Bernick, B.A., filed Dec. 6, 2013, 9 pages. |
| Restriction Requirement, dated Dec. 5, 2014, in U.S. Appl. No. 14/125,554, Bernick, B.A., filed Dec. 12, 2013, 7 pages. |
| Restriction Requirement, dated Dec. 5, 2014, in U.S. Appl. No. 14/521,230, Bernick, B.A., filed Oct. 22, 2014, 9 pages. |
| Restriction Requirement, dated Jul. 3, 2014, in U.S. Appl. No. 14/106,655, Bernick, B.A., filed Dec. 13, 2013, 6 pages. |
| Restriction Requirement, dated Mar. 16, 2015, in U.S. Appl. No. 13/843,362, Bernick, B.A., filed Mar. 15, 2013, 7 pages. |
| Restriction Requirement, dated Mar. 20, 2014, in U.S. Appl. No. 14/099,612, Bernick, B.A., filed Dec. 6, 2013, 9 pages. |
| Restriction Requirement, dated Mar. 26, 2015, in U.S. Appl. No. 14/476,040, Bernick, B.A., filed Sep. 3, 2014, 7 pages. |
| Restriction Requirement, dated Mar. 28, 2014, in U.S. Appl. No. 14/099,571, Bernick, B.A., filed Dec. 6, 2013, 7 pages. |
| International Search Report and Written Opinion of International Application No. PCT/US2015/023041, Korean Intellectual Property Office, Republic of Korea, dated Jun. 30, 2015, 14 pages. |
| Sarpal, K., et al., “Self-Emulsifying Drug Delivery Systems: A Strategy to Improve Oral Bioavailability,” Current Research & Information on Pharmaceuticals Sciences 11(3):42-49, NIPER, India (Jul.-Sep. 2010). |
| Number | Date | Country | |
|---|---|---|---|
| 20220040307 A1 | Feb 2022 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61972068 | Mar 2014 | US | |
| 61662265 | Jun 2012 | US | |
| 61661302 | Jun 2012 | US |
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| Parent | 16578148 | Sep 2019 | US |
| Child | 17348140 | US | |
| Parent | 15454898 | Mar 2017 | US |
| Child | 16578148 | US | |
| Parent | 14671655 | Mar 2015 | US |
| Child | 15454898 | US | |
| Parent | 13843362 | Mar 2013 | US |
| Child | PCT/US2013/046442 | US | |
| Parent | PCT/US2013/023309 | Jan 2013 | US |
| Child | 13843362 | US | |
| Parent | 13684002 | Nov 2012 | US |
| Child | PCT/US2013/023309 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14125547 | US | |
| Child | 14671655 | US | |
| Parent | 13843428 | Mar 2013 | US |
| Child | 14671655 | US |
