Patent Grant
11351182
This application is directed to pharmaceutical compositions, methods, and devices related to hormone replacement therapy.
Postmenopausal women frequently suffer from atrophic vaginitis or vulvar and vaginal atrophy (hereinafter “vulvovaginal atrophy” or “VVA”) with symptoms including, for example, vaginal dryness, vaginal odor, vaginal or vulvar irritation or itching, dysuria (pain, burning, or stinging when urinating), dysparuenia (vaginal pain associated with sexual activity), or vaginal bleeding associated with sexual activity. Other symptoms include soreness; with urinary frequency and urgency; urinary discomfort and incontinence also occurring (“estrogen-deficient urinary state(s)”). One symptom of vaginal atrophy is an increased vaginal pH, which creates an environment more susceptible to infections. The mucosal epithelium of the VVA patients also reported to show signs of severe atrophy and upon cytological examination accompanied by an increased number of the parabasal cells and a reduced number of superficial cells.
Each of these VVA-related states manifest symptoms associated with decreased estrogenization of the vulvovaginal tissue, and can even occur in women treated with oral administration of an estrogen-based pharmaceutical drug product. Although VVA is most common with menopausal women, it can occur at any time in a woman's life cycle.
Estrogen treatment has proven to be very successful in controlling menopausal symptoms, including vaginal atrophy (VVA). Several studies have shown that the symptoms connected with vaginal atrophy are often relieved by estrogen treatment given either systemically or topically. The existing treatments have numerous problems, for example compliance issues with patients not completing or continuing treatment due to the problems associated with the form of treatment.
Accordingly, disclosed herein is, among other things, a new soft gel vaginal pharmaceutical composition and dosage form containing solubilized estradiol for the treatment of VVA. The soft gel vaginal pharmaceutical composition has been designed to mitigate common limitations found with other vaginal forms of estradiol. The soft gel vaginal pharmaceutical composition is expected to ease vaginal administration, provide improved safety of insertion, minimize vaginal discharge following administration, and provide a more effective dosage form with improved efficacy, safety and patient compliance.
According to various aspects and embodiments of this disclosure, a soft gel vaginal pharmaceutical composition as a potential treatment for post-menopausal women suffering with moderate to severe symptoms of VVA is provided.
Provided herein is a pessary comprising: a) a therapeutically effective amount of estradiol; and b) a solubilizing agent comprising a medium chain oil.
In some embodiments, the pessary comprises about 1 μg to about 25 μg of estradiol. For example, the pessary can include about 1 μg to about 10 μg of estradiol; and about 10 μg to about 25 μg of estradiol.
In some embodiments, the estradiol is solubilized.
In some embodiments, the medium chain oil comprises at least one C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, or triglyceride ester thereof.
In some embodiments, the solubilizing agent comprises at least one ester selected from the group consisting of: an ester of caproic fatty acid, an ester of caprylic fatty acid, an ester of capric fatty acid, and combinations thereof. For example, the solubilizing agent can include a caprylic/capric triglyceride.
In some embodiments, the pessary further comprises a capsule. For example, the capsule can be a soft gelatin capsule.
Also provided herein is a pessary comprising: a) a therapeutically effective amount of estradiol; b) a caprylic/capric triglyceride; c) a non-ionic surfactant comprising PEG-6 palmitostearate and ethylene glycol palmitostearate; and d) a soft gelatin capsule.
In some embodiments, a pessary provided herein comprises about 25 μg of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 19 pg*hr/ml to about 29 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estradiol of about 75 pg*hr/ml to about 112 pg*hr/ml.
In some embodiments, a pessary provided herein comprises about 25 μg of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 9 pg*hr/ml to about 14 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone of about 43 pg*hr/ml to about 65 pg*hr/ml.
In some embodiments, a pessary provided herein comprises about 25 μg of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 416 pg*hr/ml to about 613 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate of about 3598 pg*hr/ml to about 5291 pg*hr/ml.
In some embodiments, a pessary provided herein comprises about to g of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 12 pg*hr/ml to about 18 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estradiol of about 42 pg*hr/ml to about 63 pg*hr/ml. In some embodiments, the pessary further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estradiol of about 1 hrs to about 3 hrs.
In some embodiments, a pessary provided herein comprises about 10 μg of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 4 pg*hr/ml to about 7 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone of about 20 pg*hr/ml to about 31 pg*hr/ml. In some embodiments, the pessary further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estrone of about 4 hrs to about 8 hrs.
In some embodiments, a pessary provided herein comprises about 10 μg of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 10 pg*hr/ml to about 16 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate of about 56 pg*hr/ml to about 84 pg*hr/ml. In some embodiments, the pessary further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estrone sulfate of about 4 hrs to about 7 hrs.
In some embodiments, a pessary provided herein comprises about 4 μg of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 4 pg*hr/ml to about 8 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estradiol of about 16 pg*hr/ml to about 26 pg*hr/ml. In some embodiments, the pessary further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estradiol of about 0.25 hrs to about 2 hrs.
In some embodiments, a pessary provided herein comprises about 4 μg of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 1 pg*hr/ml to about 3 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone of about 8 pg*hr/ml to about 13 pg*hr/ml. In some embodiments, the pessary further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estrone of about 1 hrs to about 4 hrs.
In some embodiments, a pessary provided herein comprises about 4 μg of estradiol, wherein administration of the pessary to a patient provides, in a plasma sample from the patient: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 4 pg*hr/ml to about 7 pg*hr/ml; and 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate of about 22 pg*hr/ml to about 34 pg*hr/ml. In some embodiments, the pessary further provides a corrected geometric mean time to peak plasma concentration (Tmax) of estrone sulfate of about 1 hrs to about 3 hrs.
Also provided herein is a pessary comprising about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estradiol that is less than about 30 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estradiol that is less than about 18 pg*hr/ml.
In some embodiments, a pessary comprising about 1 μg to about 25 μg of estradiol is provided, wherein administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estradiol that is less than about 112 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estradiol that is less than about 63 pg*hr/ml.
In some embodiments, a pessary comprising about 1 μg to about 25 μg of estradiol is provided, wherein administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone that is less than about 14 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone that is less than about 7 pg*hr/ml.
In some embodiments, a pessary comprising about 1 μg to about 25 μg of estradiol is provided, wherein administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone that is less than about 65 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone that is less than about 31 pg*hr/ml.
In some embodiments, a pessary comprising about 1 μg to about 25 μg of estradiol is provided, wherein administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate that is less than about 613 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate that is less than about 16 pg*hr/ml.
In some embodiments, a pessary comprising about 1 μg to about 25 μg of estradiol is provided, wherein administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate that is less than about 5291 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate that is less than about 84 pg*hr/ml.
Further provided herein is a pessary comprising about 1 μg to about 25 μg of estradiol, wherein administration of the pessary to the proximal region of the vagina of a patient provides a therapeutically effective concentration of estradiol over 24 hours in the proximal region of the vagina.
This disclosure also provides a method of treating an estrogen-deficient state, the method comprising administering to a patient in need thereof, a pessary as provided herein. In some embodiments, a method of treating vulvovaginal atrophy is provided, the method comprising administering to a patient in need thereof, a pessary as provided herein.
In some embodiments of the methods provided herein, treatment comprises reducing the severity of one or more symptoms selected from the group consisting of: vaginal dryness, dyspareunia, vaginal or vulvar irritation, vaginal or vulvar burning, vaginal or vulvar itching, dysuria, and vaginal bleeding associated with sexual activity.
In some embodiments of the methods provided herein treatment comprises reducing the vaginal pH of the patient. For example, treatment comprises reducing the vaginal pH of the patient to a pH of less than about 5.0.
In some embodiments of the methods provided herein treatment comprises a change in cell composition of the patient. For example, the change in cell composition comprises reducing the number of parabasal vaginal cells or increasing the number of superficial vaginal cells. In some embodiments, the number of parabasal vaginal cells in the patient are reduced by at least about 35% (e.g., at least about 50%). In some embodiments, the number of superficial vaginal cells are increased by at least about 5% (e.g., at least about 35%).
Further provided herein is a method for reducing vaginal discharge following administration of a pessary, the method comprising administering to a patient in need thereof, a pessary provided herein, wherein the vaginal discharge following administration of the pessary is compared to the vaginal discharge following administration of a reference drug.
The above-mentioned features and objects of the this disclosure will become more apparent with reference to the following description taken in conjunction with the accompanying drawings wherein like reference numerals denote like elements and in which:
In the following detailed description of embodiments of this disclosure, reference is made to the accompanying drawings in which like references indicate similar elements, and in which is shown by way of illustration specific embodiments in which the this disclosure may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the this disclosure, and it is to be understood that other embodiments may be utilized and that other changes may be made without departing from the scope of the this disclosure. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of this disclosure is defined only by the appended claims. As used in this disclosure, the term “or” shall be understood to be defined as a logical disjunction (i.e., and/or) and shall not indicate an exclusive disjunction unless expressly indicated as such with the terms “either,” “unless,” “alternatively,” and words of similar effect.
The term “active pharmaceutical ingredient” (“API”) as used herein, means the active compound(s) used in formulating a drug product.
The term “co-administered” as used herein, means that two or more drug products are administered simultaneously or sequentially on the same or different days.
The term “drug product” as used herein means at least one active pharmaceutical ingredient in combination with at least one excipient and provided in unit dosage form.
The term “area under the curve” (“AUC”) refers to the area under the curve defined by changes in the blood concentration of an active pharmaceutical ingredient (e.g., estradiol or 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 estradiol), or a metabolite of the active pharmaceutical ingredient, over time.
The term “Tmax” refers to the time that it takes for the blood concentration an active pharmaceutical ingredient (e.g., estradiol or progesterone), or a metabolite of the active pharmaceutical ingredient, to reach the maximum value.
The term “bioavailability,” which has the meaning defined in 21 C.F.R. § 320.1(a), refers to the rate and extent to which an API or active ingredient or active moiety is absorbed from a drug product and 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) parameters such as AUC, Cmax, or Tmax may be used to measure and assess bioavailability. 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 API or active ingredient or active moiety becomes available at the site of action.
The term “bioequivalent,” which has the meaning defined in 21 C.F.R. § 320.1(e), refers to the absence of a significant difference in the rate and extent to which the API or 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 AUC, Cmax, or optionally Tmax is within 80.00% to 125.00%.
The term “bio-identical,” “body-identical,” or “natural” used in conjunction with the hormones disclosed herein, means hormones that 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 “bio-identical hormone” or “body-identical hormone” refers to an active pharmaceutical ingredient that is structurally identical to a hormone naturally or endogenously found in the human body (e.g., estradiol and progesterone).
The term “estradiol” refers to (17β)-estra-1,3,5(10)-triene-3,17-diol. Estradiol is also interchangeably called 17β-estradiol, oestradiol, or E2, and is found endogenously in the human body. As used herein, estradiol refers to the bio-identical or body-identical form of estradiol found in the human body having the structure:
Estradiol is supplied in an anhydrous or 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 term “solubilized estradiol” means that the estradiol or a portion thereof is solubilized or dissolved in the solubilizing agent(s) or the formulations disclosed herein. Solubilized estradiol may include estradiol that is about 80% solubilized, about 85% solubilized, about 90% solubilized, about 95% solubilized, about 96% solubilized, about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized. In some embodiments, the estradiol is “fully solubilized” with all or substantially all of the estradiol being solubilized or dissolved in the solubilizing agent. Fully solubilized estradiol may include estradiol that is about 97% solubilized, about 98% solubilized, about 99% solubilized or about 100% solubilized. Solubility can be expressed as a mass fraction (% w/w, which is also referred to as wt %).
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, 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. Solubility can be expressed as a mass fraction (% w/w, which is also referred to as wt %).
The terms “micronized progesterone” and “micronized estradiol,” as used herein, include micronized progesterone and micronized estradiol having an X50 particle size value below about 15 microns or having an X90 particle size value below about 25 microns. The term “X50” means that one-half of the particles in a sample are smaller in diameter than a given number. For example, micronized progesterone having an X50 of 5 microns means that, for a given sample of micronized progesterone, one-half of the particles have a diameter of less than 5 microns. Similarly, the term “X90” means that ninety percent (90%) of the particles in a sample are smaller in diameter than a given number.
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” or “monoacylglycerol” is produced; if two positions are esterified, a “diglyceride” or “diacylglycerol” 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 “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 “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 (i.e., having 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 or solubilize bioidentical progesterone or estradiol, including starting materials or precursors thereof, including micronized progesterone 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 substantially medium chain (i.e., C6 to C14) fatty acids, i.e., the composition profile of fatty acids in the oil is substantially medium chain. As used herein, “substantially” 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 substantially 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 the 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 have the following composition as the exemplary oil set forth in the table below:
and 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 “excipients,” as used herein, refers to non-API ingredients such as solubilizing agents, anti-oxidants, oils, lubricants, and others used in formulating pharmaceutical products.
The term “patient” or “subject” refers to an individual to whom the pharmaceutical composition is administered.
The term “pharmaceutical composition” refers to a pharmaceutical composition comprising at least a solubilizing agent and estradiol. As used herein, pharmaceutical compositions are delivered, for example via pessary (i.e., vaginal suppository), or absorbed vaginally.
The term “progestin” means any natural or man-made substance that has pharmacological properties similar to progesterone.
The term “reference listed drug product” (“RLD”) means VAGIFEM® (estradiol vaginal tablets) or ESTRACE® vaginal cream.
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.
The terms “atrophic vaginitis,” “vulvovaginal atrophy,” “vaginal atrophy,” and “VVA” are used herein interchangeably. The molecular morphology of VVA is well known in the medical field.
Provided herein are pharmaceutical compositions comprising solubilized estradiol designed to be absorbed vaginally. The pharmaceutical compositions disclosed herein are designed to be absorbed and have their therapeutic effect locally, e.g., in vaginal or surrounding tissue. Further disclosed herein are data demonstrating efficacy of the pharmaceutical compositions disclosed, as well as methods relating to the pharmaceutical compositions. Generally, the pharmaceutical compositions disclosed herein are useful in VVA, dysparuenia, and other indications caused by decrease or lack of estrogen.
Additional aspects and embodiments of this disclosure include: providing increased patient ease of use while potentially minimizing certain side effects from inappropriate insertion, minimizing incidence of vulvovaginal mycotic infection compared to incidence of vulvovaginal mycotic infection due to usage of other vaginally applied estradiol products; and, improved side effect profile (e.g., pruritus) compared to the reference drug: VAGIFEM® (estradiol vaginal tablets, Novo Nordisk; Princeton, N.J.).
Functionality
According to embodiments, the pharmaceutical compositions disclosed herein are alcohol-free or substantially alcohol-free. The pharmaceutical compositions offer provide for improved patient compliance because of improvements over the prior offering. According to embodiments, the pharmaceutical compositions disclosed herein are encapsulated in soft gelatin capsules, which improve comfort during use. According to embodiments, the pharmaceutical compositions are substantially liquid, which are more readily absorbed in the vaginal tissue, and also are dispersed over a larger surface area of the vaginal tissue.
Estradiol
According to embodiments, the pharmaceutical compositions disclosed herein are for vaginal insertion in a single or multiple unit dosage form. According to embodiments, the estradiol in the pharmaceutical compositions is at least about: 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% solubilized. According to embodiments and where the estradiol is not 100% solubilized, the remaining estradiol is present in a micronized (crystalline) form that is absorbable by the body and retains biological functionality, either in its micronized form or in another form which the micronized form is converted to after administration.
According to embodiments, all or some of the estradiol is solubilized in a solubilizing agent during manufacturing process. According to embodiments, all or some of the estradiol is solubilized following administration (e.g., the micronized portion where the estradiol is not 100% solubilized is solubilized in a body fluid after administration). According to embodiments, because the estradiol is solubilized, the solubilizing agents taught herein, with or without additional excipients other than the solubilizing agents, are liquid or semi-solid. To the extent the estradiol is not fully solubilized at the time of administration/insertion, the estradiol should be substantially solubilized at a body temperature (average of 37° C.) and, generally, at the pH of the vagina (ranges from 3.8 to 4.5 in healthy patients; and 4.6 to 6.5 in VVA patients).
According to embodiments, the estradiol can be added to the pharmaceutical compositions disclosed herein as estradiol, estradiol hemihydrate, or other grade estradiol forms used in pharmaceutical compositions or formulations.
According to embodiments, estradiol dosage strengths vary. Estradiol (or estradiol hemihydrate, for example, to the extent the water content of the estradiol hemihydrate is accounted for) dosage strength of is from at least about 1 microgram (μg or μg) to at least about 50 μg. Specific dosage embodiments contain at least about: 1 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg, 11 μg, 12 μg, 13 μg, 14 μg, 15 μg, 16 μg, 17 μg, 18 μg, 19 μg, 20 μg, 21 μg, 22 μg, 23 μg, 24 μg, 25 μg, 26 μg, 27 μg, 28 μg, 29 μg, 30 μg, 31 μg, 32 μg, 33 μg, 34 μg, 35 μg, 36 μg, 37 μg, 38 μg, 39 μg, 40 μg, 41 μg, 42 μg, 43 μg, 44 μg, 45 μg, 46 μg, 47 μg, 48 μg, 49 μg, or 50 μg estradiol. According to embodiments, the pharmaceutical compositions contain at least about 2.5 μg; 4 μg 6.25 μg, 7.5 μg, 12.5 μg, 18.75 μg of estradiol. According to embodiments, the pharmaceutical compositions contain from about 1 μg to about 10 μg, from 3 μg to 7 μg, from about 7.5 μg to 12.5 μg, from about 10 μg to about 25 μg, about 1 μg, about 2.5 μg, from about 23.5 μg to 27.5 μg, from about 7.5 μg to 22.5 μg, from 10 μg to 25 μg of estradiol. The lowest clinically effective dose of estradiol is used for treatment of VVA and other indications set forth herein. In some embodiments, the estradiol dosage is about 4 μg. In one embodiment, the estradiol dosage is about 10 μg. In another embodiment, the estradiol dosage is about 25 μg.
Solvent System
According to embodiments, the solvent system that solubilizes the estradiol are medium chain fatty acid based solvents, together with other excipients. According to embodiments, the solvent system comprises non-toxic, pharmaceutically acceptable solvents, co-solvents, surfactants, and other excipients suitable for vaginal delivery or absorption.
According to embodiments, oils having medium chain fatty acids as a majority component are used as solubilizing agents to solubilize estradiol. According to embodiments, the solubilizing agents comprise medium chain fatty acid esters (e.g., esters of glycerol, ethylene glycol, or propylene glycol) or mixtures thereof. According to embodiments, the medium chain fatty acids comprise chain lengths from C6 to C14. According to embodiments the medium chain fatty acids comprise chain lengths from C6 to C12. According to embodiments the medium chain fatty acids substantially comprise chain lengths from C8-C10. ECN's for medium chain oils will be in the range of 21-42 for triglycerides, 12-28 for diglycerides, and 6-14 for monoglycerides.
According to embodiments, the medium chain fatty acids are saturated. According to embodiments, the medium chain fatty acids are predominantly saturated, i.e., greater than about 60% or greater than about 75% saturated.
According to embodiments, estradiol is soluble in the solubilizing agent at room temperature, although it may be desirable to warm certain solubilizing agents during manufacture to improve viscosity. According to 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.
According to embodiments, the solubility of estradiol in the medium chain oil, medium chain fatty acid, or solubilizing agent (or oil/surfactant) is at least about 0.01 wt %, 0.02 wt %, 0.05 wt %, 0.06 wt %, 0.08 wt %, 0.1 wt %, 0.2 wt %, 0.3 wt %, 0.4 wt %, 0.5 wt %, 0.6 wt %, 0.7 wt %, 0.8 wt %, 0.9 wt %, 1.0 wt %, or higher.
According to embodiments, medium chain solubilizing agents include, for example and without limitation saturated medium chain fatty acids: caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), or myristic acid (C14). According to embodiments, the solubilizing agent comprises oils made of these free medium chain fatty acids, oils of medium chain fatty acid esters of glycerin, propylene glycol, or ethylene glycol, or combinations thereof. These examples comprise predominantly saturated medium chain fatty acids (i.e., greater than 50% of the fatty acids are medium chain saturated fatty acids). According to embodiments, predominantly C6 to C12 saturated fatty acids are contemplated. According to embodiments, the solubilizing agent is selected from at least one of a solvent or co-solvent.
According to embodiments, glycerin based solubilizing agents include: mono-, di-, or triglycerides and combinations and derivatives thereof. 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. According to embodiments, CAPMUL MCM, medium chain mono- and di-glycerides, is the solubilizing agent. Other and triglycerides of fractionated vegetable fatty acids, and combinations or derivatives thereof can be the solubilizing agent, according to embodiments. For example, the solubilizing agent can be 1,2,3-propanetriol (glycerol, glycerin, glycerine) esters of saturated coconut and palm kernel oil and derivatives thereof.
Ethylene and propylene glycols (which include polyethylene and polypropylene glycols) solubilizing agents include: glyceryl mono- and di-caprylates; propylene glycol monocaprylate (e.g., CAPMUL® PG-8 (the CAPMUL brands are owned by ABITEC, Columbus, Ohio)); propylene glycol monocaprate (e.g., CAPMUL PG-10); propylene glycol mono- and dicaprylates; propylene glycol mono- and dicaprate; diethylene glycol mono ester (e.g., TRANSCUTOL®, 2-(2-Ethoxyethoxy)ethanol, GATIEFOSSÉ SAS); and diethylene glycol monoethyl ether. Other combinations of mono- and di-esters of propylene glycol or ethylene glycol are expressly contemplated are the solubilizing agent.
According to embodiments, the solubilizing agent comprises combinations of mono- and di-propylene and ethylene glycols and mono-, di-, and triglyceride combinations. According to embodiments, polyethylene glycol glyceride (GELUCIRE®, GATIEFOSSÉ SAS, Saint-Priest, France) can be used herein as the solubilizing agent or as a surfactant. For example, GELUCIRE 44/14 (PEG-32 glyceryl laurate EP), a medium chain fatty acid esters of polyethylene glycol, is a polyethylene glycol glyceride composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol.
According to embodiments, commercially available fatty acid glycerol and glycol ester solubilizing agents are often prepared from natural oils and therefore may comprise components in addition to the fatty acid esters that predominantly comprise and characterize the solubilizing agent. Such other components may be, e.g., other fatty acid mono-, di-, and triglycerides; fatty acid mono- and diester ethylene or propylene glycols, free glycerols or glycols, or free fatty acids, for example. In some embodiments, when an oil/solubilizing agent is described herein as a saturated C8 fatty acid mono- or diester of glycerol, the predominant component of the oil, i.e., >50 wt % (e.g., >75 wt %, >85 wt % or >90 wt %) is 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.
For example, MIGLYOL 812 is a solubilizing agent that is generally described as a C8-C10 triglyceride because the fatty acid composition is at least about 80% triglyceride esters of caprylic acid (C8) and capric acid (C10). However, it also comprises small amounts of other fatty acids, e.g., less than about 5% of caproic acid (C6), lauric acid (C12), and myristic acid (C14). The product information sheet for various MIGLYOLs illustrate the various fatty acid components as follows:
According to embodiments, anionic or non-ionic surfactants may be used in pharmaceutical compositions containing solubilized estradiol. Ratios of solubilizing agent(s) to surfactant(s) vary depending upon the respective solubilizing agent(s) and the respective surfactant(s) and the desired physical characteristics of the resultant pharmaceutical composition. For example and without limitation, CAPMUL MCM and a non-ionic surfactant may be used at ratios including 65:35, 70:30, 75:25, 80:20, 85:15 and 90:10. Other non-limiting examples include: CAPMUL MCM and GELUCIRE 39/01 used in ratios including, for example and without limitation, 6:4, 7:3, and 8:2; CAPMUL MCM and GELUCIRE 43/01 used in ratios including, for example and without limitation, 7:3, and 8:2; CAPMUL MCM and GELUCIRE 50/13 used in ratios including, for example and without limitation, 7:3, and 8:2, and 9:1.
Other Excipients
According to embodiments, the pharmaceutical composition further comprises a surfactant. The surfactant can be a nonionic surfactant, cationic surfactant, anionic surfactant, or mixtures thereof. Suitable surfactants include, for example, water-insoluble surfactants having a hydrophilic-lipophilic balance (HLB) value less than 12 and water-soluble surfactants having a HLB value greater than 12. Surfactants that have a high HLB and hydrophilicity, aid the formation of oil-water droplets. The surfactants are amphiphilic in nature and are capable of dissolving or solubilizing relatively high amounts of hydrophobic drug compounds.
Non-limiting examples, include, Tween, Dimethylacetamide (DMA), Dimethyl sulfoxide (DMSO), Ethanol, Glycerin, N-methyl-2-pyrrolidone (NMP), PEG 300, PEG 400, Poloxamer 407, Propylene glycol, Phospholipids, Hydrogenated soy phosphatidylcholine (HSPC), Distearoylphosphatidylglycerol (DSPG), L-α-dimyristoylphosphatidylcholine (DMPC), L-α-dimyristoylphosphatidylglycerol (DMPG), Polyoxyl 35 castor oil (CREMOPHOR EL, CREMOPHOR ELP), Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), Polyoxyl 60 hydrogenated castor oil (CREMOPHOR RH 60), Polysorbate 20 (TWEEN 20), Polysorbate 80 (TWEEN 80), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, Sorbitan monooleate (SPAN 20), PEG 300 caprylic/capric glycerides (SOFTIGEN 767), PEG 400 caprylic/capric glycerides (LABRASOL), PEG 300 oleic glycerides (LABRAFIL M-1944CS), Polyoxyl 35 Castor oil (ETOCAS 35), Glyceryl Caprylate (Mono- and Diglycerides) (IMWITOR), PEG 300 linoleic glycerides (LABRAFIL M-2125CS), Polyoxyl 8 stearate (PEG 400 monosterate), Polyoxyl 40 stearate (PEG 1750 monosterate), and combinations thereof. Additionally, suitable surfactants include, for example, polyoxyethylene derivative of sorbitan monolaurate such as polysorbate, caprylcaproyl macrogol glycerides, polyglycolyzed glycerides, and the like.
According to embodiments, the non-ionic surfactant is selected from one or more of glycerol and polyethylene glycol esters of long chain fatty acids, for example, lauroyl macrogol-32 glycerides or lauroyl polyoxyl-32 glycerides, commercially available as GELUCIRE, including, for example, GELUCIRE 39/01 (glycerol esters of saturated C12-C18 fatty acids), GELUCIRE 43/01 (hard fat NF/JPE) and GELUCIRE 50/13 (stearoyl macrogol-32 glycerides EP, stearoyl polyoxyl-32 glycerides NF, stearoyl polyoxylglycerides (USA FDA IIG)). These surfactants may be used at concentrations greater than about 0.01%, and typically in various amounts of about 0.01%-10.0%, 10.1%-20%, and 20.1%-30%. In some embodiments, surfactants may be used at concentrations of about 1% to about 10% (e.g., about 1% to about 5%, about 2% to about 4%, about 3% to about 8%).
According to embodiments, non-ionic surfactants include, for example and without limitation: one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid. According to embodiments, non-ionic surfactants comprise polyethylene sorbitol esters, including 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%, and according to embodiments, about 30% of the pharmaceutical composition total mass.
According to embodiments, the non-ionic surfactant includes PEG-6 palmitostearate and ethylene glycol palmitostearate, which are available commercially as TEFOSE® 63 (GATTEFOSSÉ 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. According to embodiments, other solubilizing agents/non-ionic surfactants combinations include, for example, MIGLYOL 812:GELUCIRE 50/13 or MIGLYOL 812:TEFOSE 63.
According to 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. Cationic surfactants are also contemplated.
According to embodiments, non-ionic or anionic surfactants 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 estradiol. The combination of solubilizing agent, surfactant, and other excipients should be designed whereby the estradiol is absorbed into the vaginal tissue. According to embodiments, the pharmaceutical composition will result in minimal vaginal discharge.
According to embodiments, the pharmaceutical composition further comprises at least one thickening agent. Generally, a thickening agent is added when the viscosity of the pharmaceutical composition results less than desirable absorption. According to embodiments, the surfactant(s) disclosed herein may also provide thickening of the pharmaceutical composition that, upon release, will aid the estradiol in being absorbed by the vaginal mucosa while minimizing vaginal discharge. 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, GATTEFOSSÉ, 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); a non-ionic surfactant comprising PEG-6 stearate, ethylene glycol palmitostearate, and PEG-32 stearate; TEFOSE 63 or a similar product; and a mixture of various hard fats (WITEPSOL®, Sasol Germany GmbH, Hamburg, Germany). Other thickening agents such as the alginates, certain gums such as xanthan gums, agar-agar, iota carrageenans, kappa carrageenans, etc. Several other compounds can act as thickening agents like gelatin, and polymers like HPMC, PVC, and CMC. According to 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.
According to 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 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.
According to 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.
According to embodiments, the pharmaceutical composition further comprises one or more mucoadherent agents to improve vaginal absorption of the estradiol. For example, a mucoadherent agent can be present to aid the pharmaceutical composition with adherence to the mucosa upon activation with water. According to embodiments, polycarbophil is the mucoadherent agent. According to embodiments, other mucoadherent agents include, for example and without limitation: poly (ethylene oxide) polymers having a molecular weight of from about 100,000 to about 900,000; chitosans carbopols including polymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol; polymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol; carbomer homopolymer or copolymer that contains a block copolymer of polyethylene glycol and a long chain alkyl acid ester; and the like. According to embodiments, various hydrophilic polymers and hydrogels may be used as the mucoadherent agent. According to certain embodiments, the polymers or hydrogels can swell in response to contact with vaginal tissue or secretions, enhancing moisturizing and mucoadherent effects. The selection and amount of hydrophilic polymer may be based on the selection and amount of solubilizing agent. In some embodiments, the pharmaceutical composition includes 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 some embodiments, a mucoadherent agent is present in the pharmaceutical formulation, in the soft gel capsule, or both.
According to embodiments, the pharmaceutical compositions 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 by reference).
According to embodiments, the pharmaceutical composition further comprises a lubricant. In some embodiments, a lubricant can be present to aid in formulation of a dosage form. For example, a lubricant may be added to ensure that capsules or tablets do not stick to one another during processing or upon storage. Any suitable lubricant may be used. For example, lecithin, which is a mixture of phospholipids, is the lubricant.
According to embodiments, the pharmaceutical composition further comprises an antioxidant. Any suitable anti-oxidant may be used. For example, butylated hydroxytoluene, butylated hydroxyanisole, and Vitamin E TPGS.
According to embodiments, the pharmaceutical composition 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.
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 and preservatives. Examples of colorants include FD&C colors (e.g., blue No. 1 and Red No. 40), D&C colors (e.g., Yellow No. 10), and opacifiers (e.g., Titanium dioxide). According to embodiments, colorants, comprise about 0.1% to about 2% of the pharmaceutical composition by weight. According to 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.
Solubility of Estradiol
According to embodiments, solubilizing agents comprising mixtures of medium chain fatty acid glycerides, e.g., C6-C12, C8-C12, or C8-C10 fatty acid mono- and diglycerides or mono-, di-, and triglycerides dissolve estradiol. As illustrated in the Examples, good results were obtained with solubilizing agents that are predominantly a mixture of C8-C10 saturated fatty acid mono- and diglycerides, or medium chain triglycerides (e.g., Miglyol 810 or 812). Longer chain glycerides appear to be not as well suited for dissolution of estradiol.
A solubilizing agent comprising propylene glycol monocaprylate (e.g., CAPRYOL) and 2-(2-Ethoxyethoxy)ethanol (e.g., TRANSCUTOL) solubilized estradiol well.
According to embodiments, the pharmaceutical composition is prepared via blending estradiol 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. According to 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, as discussed further herein. Optionally added are other excipients including, for example and without limitation, anti-oxidants, lubricants, and the like. According to embodiments, the pharmaceutical composition comprises sufficient solubilizing agent to fully solubilize the estradiol. It is expressly understood, however, the other volumes of solubilizing agent can be used depending on the level of estradiol 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 estradiol 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 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.
Specific Examples disclosed herein provide additional principles and embodiments illustrating the manufactures of the pharmaceutical compositions disclosed herein.
Generally, the pharmaceutical compositions described herein delivered intravaginally inside of a delivery vehicle, for example a capsule. According to embodiments, the capsules are soft capsules made of materials well known in the pharmaceutical arts, for example, gelatin. However, according to embodiments, the delivery vehicle is integral with the pharmaceutical composition (i.e., the pharmaceutical composition is the delivery vehicle). In such embodiments the pharmaceutical compositions is a gel, cream, ointment, tablet, or other preparation that is directly applied and absorbed vaginally.
According to embodiments, pharmaceutical compositions disclosed herein are contained in capsules, such as soft gelatin capsules. According to embodiments, the capsules contain one or more of the following: hydrophilic gel-forming bioadhesive (e.g., mucoadhesive) agents; a lipophilic agent; a gelling agent for the lipophilic agent, or a hydrodispersible agent. According to embodiments, the hydrophilic gel-forming bioadhesive agent is carboxyvinylic acid; hydroxypropylcellulose; carboxymethylcellulose; gelatin; xanthane gum; guar gum; aluminum silicate; or mixtures thereof. According to 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 mixtures thereof. According to embodiments, the gelling agent is a hydrophobic colloidal silica. According to embodiments, the hydrodispersible agent is: polyoxyethylene glycol; polyoxyethylene glycol 7-glyceryl-cocoate; or mixtures thereof.
According to embodiments, the delivery vehicle is designed for ease of insertion. According to embodiments, the delivery vehicle is sized whereby it can be comfortably inserted into the vagina. According to embodiments, the delivery vehicle is prepared in a variety of geometries. For example, the delivery vehicle is shaped as a tear drop, a cone with frustoconical end, a cylinder, a cylinder with larger “cap” portion, or other shapes suitable for and that ease insertion into the vagina. According to embodiments, delivery vehicle is used in connection with an applicator. According to other embodiments, delivery vehicle is inserted digitally.
With reference to
According to embodiments, the delivery vehicle is designed to remaining in the vagina until the pharmaceutical compositions are released. According to embodiments, delivery vehicle dissolves intravaginally and is absorbed into the vaginal tissue with the pharmaceutical composition, which minimizes vaginal discharge. In such embodiments, delivery mechanism is made from constituents that are non-toxic, for example, gelatin.
According to embodiments, the pharmaceutical composition is designed to maximize favorable characteristics that lead to patient compliance (patients that discontinue treatment prior to completion of the prescribed course of therapy), without sacrificing efficacy. Favorable characteristics include, for example, lack of or reduction of irritation relative to other hormone replacement pessaries, lack of or reduction in vaginal discharge of the pharmaceutical composition and delivery vehicle relative to other hormone replacement pessaries, lack of or reduction of pharmaceutical composition or delivery vehicle residue inside the vagina, ease of administration compared to other hormone replacement pessaries, or improved efficacy of drug product relative to otherwise similar pharmaceutical compositions.
According to embodiments, the pharmaceutical composition is non-irritating or minimizes irritation. Patient irritation comprises pain, pruritis (itching), soreness, excessive discharge, swelling, or other similar conditions. Patient irritation results in poor compliance. Non-irritating or reduced irritation pharmaceutical compositions are measured relative to competing hormone pessaries, including tablets, creams, or other intravaginal estrogen delivery forms.
According to embodiments, the pharmaceutical compositions does not result in systemic exposure (e.g., blood circulation of estradiol), which improves safety. According to other embodiments, the pharmaceutical compositions disclosed herein result in significantly reduced systemic exposure (e.g., blood circulation of estradiol) when compared to RLDs.
According to embodiments, the pharmaceutical composition does not leave residue inside the vagina. Rather, the pharmaceutical composition and delivery vehicle are substantially absorbed or dispersed without resulting in unabsorbed residue or unpleasant sensations of non-absorbed or non-dispersed drug product. Measurement of lack of residue is relative to other vaginally inserted products or can be measured objectively with inspection of the vaginal tissues. For example, certain other vaginally inserted products contain starch which can result in greater discharge from the vagina following administration than. In some embodiments, the pharmaceutical compositions provided herein provide a lower amount, duration, or frequency of discharge following administration compared to other vaginally inserted products (e.g., compressed tablets).
According to embodiments, the pharmaceutical composition improves vaginal discharge compared to other pessaries, including pessaries that deliver hormones. Ideally, vaginal discharge is eliminated, minimized, or improved compared to competing products.
According to embodiments, the pharmaceutical compositions disclosed herein are inserted digitally. According to embodiments, the pharmaceutical compositions are digitally inserted approximately two inches into the vagina without a need for an applicator. According to embodiments, the pharmaceutical compositions are designed to be also inserted with an applicator, if desired. According to some embodiments, because the site of VVA is in the proximal region of the vagina (towards the vaginal opening), the pharmaceutical compositions disclosed herein are designed to be inserted in the proximal portion of the vagina.
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. According to embodiments, 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.
According to embodiments, the pharmaceutical composition is delivered via a gelatin capsule delivery vehicle. According to these embodiments, the pharmaceutical composition is a liquid pharmaceutical composition. According to embodiments, the delivery vehicle is a soft capsule, for example a soft gelatin capsule. Thus, the pharmaceutical composition of such embodiments is encapsulated in the soft gelatin capsule or other soft capsule.
According to embodiments, the pharmaceutical composition comprises estradiol that is at least about 80% solubilized in a solubilizing agent comprising one or more C6 to C14 medium chain fatty acid mono-, di-, or triglycerides and, optionally, a thickening agent. According to embodiments, the pharmaceutical composition comprises estradiol that is at least about 80% 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 estradiol being at least 80% solubilized. These embodiments specifically contemplate the estradiol being at least 90% solubilized. These embodiments specifically contemplate the estradiol being at least 95% solubilized. These embodiments specifically contemplate the estradiol being fully solubilized.
As noted above, liquid pharmaceutical compositions are liquid at room temperature or at body temperature. For example, in some embodiments, a pharmaceutical composition provided herein is a liquid formulation contained within a soft gel capsule. 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.
The thickening agent serves to increase viscosity, e.g., up to about 10,000 cP (10,000 mPa-s), typically to no more than about 5000 cP, and more typically to between about 50 and 1000 cP. In embodiments, the non-ionic surfactant, e.g., GELUCIRE or TEFOSE, may be solid at room temperature and require melting to effectively mix with the solubilizing agent. However, in these embodiments, the resultant pharmaceutical composition remains liquid, albeit with greater viscosity, not solid.
According to embodiments, the pharmaceutical composition comprises estradiol, the medium chain solubilizing agent, and the thickening agent as the ingredients delivered via a soft capsule delivery vehicle. Other ingredients, e.g., colorants, antioxidants, preservatives, or other ingredients may be included as well. However, the addition of other ingredients should be in amounts that do not materially change the solubility of the estradiol, the pharmacokinetics of the pharmaceutical composition, or efficacy of the pharmaceutical composition. Other factors that should be considered when adjusting the ingredients of the pharmaceutical composition include the irritation, vaginal discharge, intravaginal residue, and other relevant factors, for example those that would lead to reduced patient compliance. Other contemplated ingredients include: oils or fatty acid esters, lecithin, mucoadherent agents, gelling agents, dispersing agents, or the like.
According to embodiments, the pharmaceutical compositions disclosed herein can be used for the treatment of WA, including the treatment of at least one WA symptom including: vaginal dryness, vaginal or vulvar irritation or itching, dysuria, dysparuenia, and vaginal bleeding associated with sexual activity, among others. According to embodiments the methods of treatment are generally applicable to females.
According to embodiments, the pharmaceutical compositions disclosed herein can be used for the treatment of estrogen-deficient urinary states. According to embodiments, the pharmaceutical compositions disclosed herein can be used for the treatment of dysparuenia, or vaginal bleeding associated with sexual activity.
According to embodiments, treatment of the VVA, estrogen-deficient urinary states, and dysparuenia and vaginal bleeding associated with sexual activity occurs by administering the pharmaceutical compositions intravaginally. According to embodiments where the delivery vehicle is a capsule, the patient obtains the capsule and inserts the capsule into vagina, where the capsule dissolves and the pharmaceutical composition is releases into the vagina where it is absorbed into the vaginal tissue. In some embodiments, the pharmaceutical composition is completely absorbed into the vaginal tissue. In some embodiments, the pharmaceutical composition is substantially absorbed into the vaginal tissue (e.g., at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, at least about 98% by weight, or at least about 99% by weight of the composition is absorbed). According to embodiments, the capsule is inserted about two inches into the vagina digitally, however the depth of insertion is generally any depth that allows for adsorption of substantially all of the pharmaceutical composition. According to embodiments, the capsule can also be applied using an applicator that deposits the capsule at an appropriate vaginal depth as disclosed herein.
According to embodiments where the pharmaceutical composition is a cream, gel, ointment, or other similar preparation, the pharmaceutical composition is applied digitally, as is well known and understood in the art.
Upon release of the pharmaceutical composition in the vagina, estradiol is locally absorbed. For example, following administration of the pessary to the proximal region of the vagina of a patient provides a therapeutically effective concentration of estradiol over 24 hours in the proximal region of the vagina.
According to embodiments, the timing of administration of the pharmaceutical composition of this disclosure may be conducted by any safe means as prescribed by an attending physician. According to embodiments, a patient will administer the pharmaceutical composition (e.g., a capsule) intravaginally each day for 14 days, then twice weekly thereafter.
According to embodiments, the pharmaceutical compositions are vaginally administered with co-administration of an orally administered estrogen-based (or progestin-based or progestin- and estrogen-based) pharmaceutical drug product, or patch, cream, gel, spray, transdermal delivery system or other parenterally-administered estrogen-based pharmaceutical drug product, each of which can include natural, bio-similar, or synthetic or other derived estrogens or progestins. According to embodiments, modulation of circulating estrogen levels provided via the administration of the pharmaceutical compositions disclosed herein, if any, are not intended to be additive to any co-administered estrogen product and its associated circulating blood levels. According to other embodiments, co-administrated estrogen products are intended to have an additive effect as would be determined by the patient physician.
According to embodiments, the efficacy and safety of the pharmaceutical compositions described herein in the treatment of the symptoms of VVA may be determined. According to embodiments, the size, effect, cytology, histology, and variability of the VVA may be determined using various endpoints to determine efficacy and safety of the pharmaceutical compositions described herein or as otherwise accepted in the art, at present or as further developed. On source of endpoints is with the US Food and Drug Administration's (FDA) published guidelines for treatment of VVA with estradiol.
According to embodiments, administration of the pharmaceutical compositions described herein resulted in treatment of the WA, as well as improvement of one or more of the associated symptoms. Patients with WA experience shrinking of the vaginal canal in both length and diameter and the vaginal canal has fewer glycogen-rich vaginal cells to maintain moisture and suppleness. In addition, the vaginal wall can become thin, pale, dry, or sometimes inflamed (atrophic vaginitis). These changes can manifest as a variety of symptoms collectively referred to as VVA. Such symptoms include, without limitations, an increase in vaginal pH; reduction of vaginal epithelial integrity, vaginal secretions, or epithelial surface thickness; pruritis; vaginal dryness; dyspareunia (pain or bleeding during sexual intercourse); urinary tract infections; or a change in vaginal color. According to embodiments, efficacy is measured as a reduction of vulvar and vaginal atrophy in a patient back to premenopausal conditions. According to embodiments, the change is measured as a reduction in the severity of one or more atrophic effects measured at baseline (screening, Day 1) and compared to a measurement taken at Day 15 (end of treatment). Severity of the atrophic effect may be measured using a scale of 0 to 3 where, for example, none=0, mild=1, moderate=2, or severe=3. Such scoring is implemented to evaluate the pre-treatment condition of patients; to determine the appropriate course of a treatment regime; such as dosage, dosing frequency, and duration, among others; and post-treatment outcomes.
One of the symptoms of VVA is increased vaginal pH. In further aspects of this disclosure, treatment with the pharmaceutical compositions described herein resulted in a decrease in vaginal pH. A decrease in vaginal pH is measured as a decrease from the vaginal pH at baseline (screening) to the vaginal pH at Day 15, according to embodiments. In some embodiments, a pH of 5 or greater may be associated with WA. In some embodiments, pH is measured using a pH indicator strip placed against the vaginal wall. In some embodiments, a change in vaginal pH is a change in a patient's vaginal pH to a pH of less than about pH 5.0. In some embodiments, a subject's vaginal pH may be less than about pH 4.9, pH 4.8, pH 4.7, pH 4.6, pH 4.5, pH 4.4, pH 4.3, pH 4.2, pH 4.1, pH 4.0, pH 3.9, pH 3.8, pH 3.7, pH 3.6, or pH 3.5.
According to embodiments, treatment with the pharmaceutical compositions described herein resulted in improvements in the vaginal Maturation Index. The Maturation Index is measured as a change in cell composition. According to embodiments and as related to VVA, a change in cell composition is measured as the change in percent of composition or amount of parabasal vaginal cells, intermediate cells, and superficial vaginal cells, such as a change in the composition or amount of parabasal vaginal cells compared with or, relative to, a change in superficial vaginal cells. A subject having VVA symptoms often has an increased number of parabasal cells and a reduced number of superficial cells (e.g., less than about 5%) compared with women who do not suffer from VVA. Conversely, a subject having decreasing VVA symptoms, or as otherwise responding to treatment, may demonstrate an improvement in the Maturation Index, specifically a decrease in the amount of parabasal cells or an increase in the amount of superficial cells compared to baseline (screening). In embodiments, a decrease in parabasal cells is measured as a reduction in the percent of parabasal cells; the percent reduction may be at least about an 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% reduction in the number of parabasal cells. In embodiments, a percent reduction may be at least about a 54% reduction in the number of parabasal cells. In embodiments, an increase in superficial cells is measured as an increase in the percent of superficial cells; the percent increase in superficial cells may be at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase in the number of superficial cells. In further embodiments, a percent increase may be at least about a 35% increase in the number of superficial cells.
In some embodiments, an improvement in the Maturation Index is assessed as a change over time. For example, as a change in cell composition measured at a baseline (screening) at Day 1 compared to the cell composition measured at Day 15. The change in cell composition may also be assessed as a change in the amount of parabasal cells over time, optionally in addition to measuring changes in parabasal cells and superficial cells as described above. Such cells may be obtained from the vaginal mucosal epithelium through routine gynecological examination and examined by means of a vaginal smear.
In various further aspects of this disclosure, treatment with the pharmaceutical compositions described herein resulted in any of: an increase in superficial cells; a decrease in parabasal cells; and an increase in intermediate cells.
In further aspects of this disclosure, samples may be collected to determine hormone levels, in particular, estradiol levels. In some embodiments, blood samples may be taken from a subject and the level of estradiol measured (pg/ml). In some embodiments, estradiol levels may be measured at 0 hours (for example, at time of first treatment), at 1 hour (for example, post first treatment), at 3 hours, and at 6 hours. In some embodiments, samples may be taken at day 8 (for example, post first treatment) and at day 15 (for example, one day post the last treatment on day 14). In some embodiments, descriptive statistics of plasma estradiol concentrations at each sampling time and observed Cmax and Tmax values may be measured and the AUC calculated.
In some embodiments, a pessary can comprise about 25 μg of estradiol. In such cases, administration of the pessary to a patient can provide, in a plasma sample from the patient, parameters including one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 19 pg*hr/ml to about 29 pg*hr/ml (e.g., 19.55 pg*hr/ml to about 28.75 pg*hr/ml); or 2) a corrected geometric mean area under the curve (AUC)0-24 of estradiol of about 75 pg*hr/ml to about 112 pg*hr/ml (e.g., 75.82 pg*hr/ml to about 111.50). In some embodiments, administration of the pessary to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 9 pg*hr/ml to about 14 pg*hr/ml (e.g., 9.17 pg*hr/ml to about 13.49 pg*hr/ml); and 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone of about 43 pg*hr/ml to about 65 pg*hr/ml (e.g., 43.56 pg*hr/ml to about 64.06 pg*hr/ml). In some embodiments, administration of the pessary to a patient provides, in a plasma sample from the patient, provides one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 416 pg*hr/ml to about 613 pg*hr/ml (e.g., 416.53 pg*hr/ml to about 612.55 pg*hr/ml); and 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate of about 3598 pg*hr/ml to about 5291 pg*hr/ml (e.g., 3598.04 pg*hr/ml to about 5291.24 pg*hr/ml).
In some embodiments, a pessary can comprise about 10 μg of estradiol. In such cases, administration of the pessary to a patient can provide, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 12 pg*hr/ml to about 18 pg*hr/ml (e.g., 12.22 pg*hr/ml to about 17.98 pg*hr/ml); 2) a corrected geometric mean area under the curve (AUC)0-24 of estradiol of about 42 pg*hr/ml to about 63 pg*hr/ml (e.g., 42.18 pg*hr/ml to about 62.02 pg*hr/ml); and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estradiol of about 1 hrs to about 3 hrs (e.g., 1.49 hrs to about 2.19 hrs). In some embodiments, administration of the pessary to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 4 pg*hr/ml to about 7 pg*hr/ml (e.g., 4.38 pg*hr/ml to about 6.44 pg*hr/ml); 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone of about 20 pg*hr/ml to about 31 pg*hr/ml (e.g., 20.60 pg*hr/ml to about 30.30 pg*hr/ml); and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estrone of about 4 hrs to about 8 hrs (e.g., 4.99 hrs to about 7.34 hrs). In some embodiments, administration of the pessary to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 10 pg*hr/ml to about 16 pg*hr/ml (e.g., 10.34 pg*hr/ml to about 15.20 pg*hr/ml); 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate of about 56 pg*hr/ml to about 84 pg*hr/ml (e.g., 56.61 pg*hr/ml to about 83.25 pg*hr/ml); and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estrone sulfate of about 4 hrs to about 7 hrs (e.g., 4.67 hrs to about 6.86 hrs).
In some embodiments, a pessary can comprise about 4 μg of estradiol. In such cases, administration of the pessary to a patient can provide, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estradiol of about 4 pg*hr/ml to about 8 pg*hr/ml; 2) a corrected geometric mean area under the curve (AUC)0-24 of estradiol of about 16 pg*hr/ml to about 26 pg*hr/ml; and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estradiol of about 0.25 hrs to about 2 hrs. In some embodiments, administration of the pessary to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone of about 1 pg*hr/ml to about 3 pg*hr/ml; 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone of about 8 pg*hr/ml to about 13 pg*hr/ml; and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estrone of about 1 hrs to about 4 hrs. In some embodiments, administration of the pessary to a patient provides, in a plasma sample from the patient, one or more parameters selected from: 1) a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate of about 4 pg*hr/ml to about 7 pg*hr/ml; 2) a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate of about 22 pg*hr/ml to about 34 pg*hr/ml; and 3) a corrected geometric mean time to peak plasma concentration (Tmax) of estrone sulfate of about 1 hrs to about 3 hrs.
A pharmaceutical composition provided herein can result in substantially local delivery of estradiol. For example, plasma concentrations of estradiol, estrone, and estrone sulfate measured in the plasma of a patient following administration of a pharmaceutical composition as provided herein be statistically similar to those measured following administration of a placebo formulation (i.e. a similar formulation lacking the estradiol). Accordingly, in some embodiments, the plasma concentrations of estradiol, estrone, or estrone sulfate measured following administration of a pharmaceutical composition provided herein may be low compared to RLD formulations.
In some embodiments, a pessary can include about 1 μg to about 25 μg of estradiol. Upon administration the pessary to a patient, a plasma sample from the patient can provide a corrected geometric mean peak plasma concentration (Cmax) of estradiol that is less than about 30 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estradiol that is less than about 18 pg*hr/ml. In some embodiments, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estradiol that is less than about 112 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estradiol that is less than about 63 pg*hr/ml.
In some embodiments, administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone that is less than about 14 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone that is less than about 7 pg*hr/ml. In some embodiments, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone that is less than about 65 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone that is less than about 31 pg*hr/ml.
In some embodiments, administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate that is less than about 613 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean peak plasma concentration (Cmax) of estrone sulfate that is less than about 16 pg*hr/ml. In some embodiments, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate that is less than about 5291 pg*hr/ml. For example, administration of the pessary to a patient provides a corrected geometric mean area under the curve (AUC)0-24 of estrone sulfate that is less than about 84 pg*hr/ml.
In further aspects of this disclosure, capsule disintegration may be determined. In some embodiments, delivery vehicle disintegration or absorption (presence or absence of the delivery vehicle after administration) at day 1 of treatment (for example, at 6 hours post first treatment) and at day 15 (for example, one day post the last treatment on day 14).
Statistical Measurements
According to embodiments, pharmacokinetics of the pharmaceutical composition disclosed herein are measured using statistical analysis. According to embodiments, Analysis of Variance (“ANOVA”) or Analysis of CoVariance (“ANCOVA”) are used to evaluate differences between a patient receiving treatment with a pharmaceutical composition comprising an active pharmaceutical composition (for example, a pharmaceutical composition comprising estradiol) and a patient receiving treatment with a placebo (for example, the same pharmaceutical composition but without estradiol) or a reference drug. A person of ordinary skill in the art will understand how to perform statistical analysis of the data collected.
The following examples are of pharmaceutical compositions, delivery vehicles, and combinations thereof. Methods of making are also disclosed. Data generated using the pharmaceutical compositions disclosed herein are also disclosed.
In embodiments, estradiol is procured and combined with one or more pharmaceutically acceptable solubilizing agents. The estradiol is purchased as a pharmaceutical grade ingredient, often as micronized estradiol, although other forms can also be used. In embodiments, the pharmaceutical composition comprises estradiol in a dosage strength of from about 1 μg to about 50 μg. In embodiments, the pharmaceutical composition comprises 10 μg of estradiol. In embodiments, the pharmaceutical composition comprises 25 μg of estradiol.
In embodiments, the estradiol is combined with pharmaceutically acceptable solubilizing agents, and, optionally, other excipients, to form a pharmaceutical composition. In embodiments, the solubilizing agent is one or more of CAPMUL MCM, MIGLYOL 812, GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13, and TEFOSE 63.
GELUCIRE 39/01 and GELUCIRE 43/01 each have an HLB value of 1. GELUCIRE 50/13 has an HLB value of 13. TEFOSE 63 has an HLB value of between 9 and 10.
Various combinations of pharmaceutically acceptable solubilizing agents were combined with estradiol and examined as shown in Table 1.
Pharmaceutical compositions in Table 1 that were liquid or semisolid at room temperature were tested using a Brookfield viscometer (Brookfield Engineering Laboratories, Middleboro, Mass.) at room temperature. Pharmaceutical compositions appearing in Table 1 that were solid at ambient temperature were tested using a Brookfield viscometer at 37° C.
Pharmaceutical compositions appearing in Table 1 that were solid at room temperature were assessed at 37° C. to determine their melting characteristics. The viscosity of the gels can be important during encapsulation of the formulation. For example, in some cases, it is necessary to warm the formulation prior to filing of the gelatin capsules. In addition, the melting characteristics of the composition can have important implications following administration of the formulation into the body. For example, in some embodiments, the formulation will melt at temperatures below about 37° C. Pharmaceutical Composition 11 (Capmul MCM/Tefose 63), for example, did not melt at 37° C. or 41° C.
A dispersion assessment of the pharmaceutical compositions appearing in Table 1 was performed. The dispersion assessment was performed by transferring 300 mg of each vehicle system in 100 ml of 37° C. water, without agitation, and observing for mixing characteristics. Results varied from formation of oil drops on the top to separation of phases to uniform, but cloudy dispersions. Generally speaking, it is believed that formulations able to readily disperse in aqueous solution will have better dispersion characteristics upon administration. It was surprisingly found, however, as shown below in Examples 7-9, that formulations that did not readily disperse in aqueous solution (e.g., Formulation 13) and instead formed two phases upon introduction to the aqueous solution were found to be the most effective when administered to the human body.
In embodiments, the pharmaceutical composition is delivered in a gelatin capsule delivery vehicle. The gelatin capsule delivery vehicle comprises, for example, gelatin (e.g., Gelatin, NF (150 Bloom, Type B)), hydrolyzed collagen (e.g., GELITA®, GELITA AG, Eberbach, Germany), glycerin, sorbitol special, or other excipients in proportions that are well known and understood by persons of ordinary skill in the art. Sorbitol special may be obtained commercially and may tend to act as a plasticizer and humectant.
A variety of delivery vehicles were developed, as show in Table 2, Gels A through F. In Table 2, each delivery vehicle A through F differs in the proportion of one or more components.
Each delivery vehicle A through F was prepared at a temperature range from about 45° C. to about 85° C. Each molten delivery vehicle A through F was cast into a film, dried, and cut into strips. The strips were cut into uniform pieces weighing about 0.5 g, with about 0.5 mm thickness. Strips were placed into a USP Type 2 dissolution vessel in either water or pH 4 buffer solution and the time for them to completely dissolve was recorded (see TABLE 2). Delivery vehicle A had the fastest dissolution in both water and pH 4 buffer solution.
Various combinations of the pharmaceutical compositions from TABLE 1 and from TABLE 2 were prepared. The combinations are shown in TABLE 3.
Each aliquot of the pharmaceutical compositions of Table 3 about 300 mg to about 310 mg. Batch size was as listed in TABLE 3. To encapsulate the vehicle system, each 300 mg to about 310 mg pharmaceutical composition aliquot was encapsulated in about 200 mg of the gelatin capsule delivery vehicle. Thus, for example, in Trial 1, the pharmaceutical composition denoted by MCM:39/01 was encapsulated in gelatin capsule delivery vehicle A for a total encapsulated weight of about 500 mg to about 510 mg. The aliquot size is arbitrary depending on the concentration of the estradiol and the desired gelatin capsule delivery vehicle size. Artisans will readily understand how to adjust the amount of estradiol in the pharmaceutical composition to accommodate a given size of delivery vehicle, when the delivery vehicle encapsulates the pharmaceutical composition.
In various experiments, solubilizing agents were tested to determine whether they were able to solubilize 2 mg of estradiol for a total pharmaceutical composition weight of 100 mg. The solubilizing agents were considered suitable if estradiol solubility in the solubilizing agent was greater than or equal to about 20 mg/g. Initial solubility was measured by dissolving micronized estradiol into various solubilizing agents until the estradiol was saturated (the estradiol/solubilizing agent equilibrated for three days), filtering the undissolved estradiol, and analyzing the resulting pharmaceutical composition for estradiol concentration by HPLC.
The following pharmaceutical compositions are contemplated.
Gel Mass
Pharmaceutical Composition 1: 10 μg Estradiol
Pharmaceutical Composition 2: 10 μg Estradiol
Pharmaceutical Composition 3: 25 μg Estradiol
Pharmaceutical Composition 4: 4 μg Estradiol
In operation 104, GELUCIRE is mixed with the CapmulMCM to form the finished solubilizing agent. As used herein, any form of GELUCIRE may be used in operation 104. For example, one or more of GELUCIRE 39/01, GELUCIRE 43/01, GELUCIRE 50/13 may be used in operation 104. Mixing is performed as would be known to persons of ordinary skill in the art, for example by impeller, agitator, stirrer, or other like devices used to mix pharmaceutical compositions. Operation 104 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas. Mixing may be performed in any vessels that are known to persons of ordinary skill in the art, such as a stainless steel vessel or a steel tank.
In operation 106 estradiol is mixed into the solubilizing agent. In embodiments, the estradiol in micronized when mixed into the solubilizing agent. In other embodiments, the estradiol added is in a non-micronized form. Mixing may be facilitated by an impeller, agitator, stirrer, or other like devices used to mix pharmaceutical compositions. Operation 106 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas.
In embodiments, however, the addition of estradiol may be performed prior to operation 104. In that regard, operations 104 and 106 are interchangeable with respect to timing or can be performed contemporaneously with each other.
In operation 110, the gelatin delivery vehicle is prepared. Any of the gelatin delivery vehicles described herein may be used in operation 110. In embodiments, gelatin, hydrolyzed collagen, glyercin, and other excipients are combined at a temperature range from about 45° C. to about 85° C. and prepared as a film. Mixing may occur in a steel tank or other container used for preparing gelatin delivery vehicles. Mixing may be facilitated by an impellor, agitator, stirrer, or other devices used to combine the contents of gelatin delivery vehicles. Operation 110 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas. In embodiments, the gelatin delivery vehicle mixture is degassed prior to being used to encapsulate the pharmaceutical composition.
In operation 112, the gelatin delivery vehicle encapsulates the pharmaceutical composition, according to protocols well known to persons of ordinary skill in the art. In operation 112, a soft gelatin capsule delivery vehicle is prepared by combining the pharmaceutical composition made in operation 106 with the gelatin delivery vehicle made in operation 110. The gelatin may be wrapped around the material, partially or fully encapsulating it or the gelatin can also be injected or otherwise filled with the pharmaceutical composition made in operation 106.
In embodiments, operation 112 is completed in a suitable die to provide a desired shape. Vaginal soft gel capsules may be prepared in a variety of geometries. For example, vaginal soft gel capsules may be shaped as a tear drop, a cone with frustoconical end, a cylinder, a cylinder with larger “cap” portion as illustrated in
The objective of this study was designed to evaluate the efficacy and safety of a pharmaceutical composition comprising 10 μg estradiol (i.e., Pharmaceutical Composition 2) in treating moderate to severe symptoms of VVA associated with menopause after 14 days of treatment, and to estimate the effect size and variability of vulvovaginal atrophy endpoints. In addition, the systemic exposure to estradiol from single and multiple doses of the pharmaceutical composition was investigated.
This study was a phase 1, randomized, double-blind, placebo-controlled trial to evaluate safety and efficacy of the pharmaceutical composition in reducing moderate to severe symptoms of vaginal atrophy associated with menopause and to investigate the systemic exposure to estradiol following once daily intravaginal administrations of a pharmaceutical composition for 14 days.
Postmenopausal subjects who met the study entry criteria were randomized to one of two treatment groups (pharmaceutical composition or placebo). During the screening period subjects were asked to self-assess the symptoms of VVA, including vaginal dryness, vaginal or vulvar irritation or itching, dysuria, vaginal pain associated with sexual activity, and vaginal bleeding associated with sexual activity. Subjects with at least one self-assessed moderate to severe symptom of VVA identified by the subject as being most bothersome to her were eligible to participate in the study.
Clinical evaluations were performed at the following time points:
Screening Period (up to 28 days);
Visit 1—Randomization/Baseline (day 1);
Visit 2—Interim (day 8); and
Visit 3—End of the treatment (day 15).
Eligible subjects were randomized in a 1:1 ratio to receive either pharmaceutical composition comprising estradiol 10 μg or a matching placebo vaginal softgel capsule, and self-administered their first dose of study medication at the clinical facility under the supervision of the study personnel. Serial blood samples for monitoring of estradiol level were collected at 0.0, 1.0, 3.0, and 6.0 hours relative to first dose administration on day 1. Subjects remained at the clinical site until completion of the 6-hour blood draw and returned to clinical facility for additional single blood draws for measurement of estradiol concentration on day 8 (before the morning dose) and day 15. Subjects were provided with enough study medication until the next scheduled visit and were instructed to self-administer their assigned study treatment once a day intravaginally at approximately the same time (±1 hour) every morning. Each subject was provided with a diary in which she was required to daily record investigational drug dosing dates and times. Subjects returned to clinical facility on day 8 for interim visit and on day 15 for end of treatment assessments and post study examinations. Capsule disintegration state was assessed by the investigator at day 1 (6 hours post-dose) and day 15.
The study involved a screening period of up to 28 days before randomization and treatment period of 14 days. Selection of dosage strength (estradiol 10 μg) and treatment regimen (once daily for two weeks) was based on the FDA findings on safety and efficacy of the RLD.
Number of Subjects (Planned and Analyzed)
Up to 50 (25 per treatment group) postmenopausal female subjects 40 to 75 years old with symptoms of moderate to severe VVA were randomized. 50 subjects were enrolled, 48 subjects completed the study, and 48 subjects were analyzed.
Diagnosis and Main Criteria for Inclusion
Fifty female subjects were enrolled in the study. Post-menopausal female subjects 40 to 75 years of age, with a mean age was 62.3 years were enrolled. Subjects' mean weight (kg) was 71.2 kg with a range of 44.5-100 kg. Subjects' mean height (cm) was 162.6 cm with a range of 149.9-175.2 cm, and the mean BMI (kg/m2) was 26.8 kg/m2 with a range of 19-33 kg/m2. Criteria of inclusion in the study included: self-identification of at least one moderate to severe symptom of VVA, for example, vaginal dryness, dysparuenia, vaginal or vulvar irritation, burning, or itching, dysuria, vaginal bleeding associated with sexual activity, that was identified by the subject as being most bothersome to her; ≤5% superficial cells on vaginal smear cytology; vaginal pH>5.0; and estradiol level ≤50 pg/ml. Subject who were judged as being in otherwise generally good health on the basis of a pre-study physical examination, clinical laboratory tests, pelvic examination, and mammography were enrolled.
Estradiol 10 μg or Placebo, Dose, and Mode of Administration
Subjects were randomly assigned (in 1:1 allocation) to self-administer one of the following treatments intravaginally once daily for 14 days:
The estradiol formulation was a tear drop shaped light pink soft gel capsule. Treatment B had the same composition, appearance, and route of administration as the Treatment A, but contained no estradiol.
Duration of Treatment
The study involved a screening period of up to 28 days before randomization and a treatment period of 14 days.
Criteria for Evaluation
Efficacy Endpoints:
Unless otherwise noted, the efficacy endpoints were measured as a change-from Visit 1—Randomization/Baseline (day 1) to Visit 3—End of the treatment (day 15), except for vaginal bleeding which was expressed as either treatment success or failure.
Other endpoints include:
Results from the assessment of plasma concentrations of estradiol are presented in Table 5.
Other Endpoints:
Maturation Index Results
Vaginal cytology data was collected as vaginal smears from the lateral vaginal walls according to standard procedures to evaluate vaginal cytology at screening and Visit 3—End of treatment (day 15). The change in the Maturation Index was assessed as a change in cell composition measured at Visit 1—Baseline (day 1) compared to the cell composition measured at Visit 3—End of treatment (day 15). The change in percentage of superficial, parabasal, and intermediate cells obtained from the vaginal mucosal epithelium from a vaginal smear was recorded. Results from these assessments are presented in Tables 6, 7, and 8.
1 Confidence interval for the estradiol 10 μg-Placebo from ANCOVA with treatment as a fixed effect and baseline as a covariate.
2 P-value for treatment comparison from ANCOVA with treatment as a fixed effect and baseline as a covariate.
1 Confidence interval for the estradiol 10 μg-Placebo from ANOVA with treatment as a fixed effect.
2 P-value for treatment comparison from ANOVA with treatment as a fixed effect.
1 Confidence interval for the estradiol 10 μg-Placebo from ANCOVA with treatment as a fixed effect and baseline as a covariate.
2P-value for treatment comparison from ANCOVA with treatment as a fixed effect and baseline as a covariate.
Change in pH Results
Vaginal pH was measured at Screening and Visit 3—End of treatment (day 15). The pH measurement was obtained by pressing a pH indicator strip against the vaginal wall. The subjects entering the study were required to have a vaginal pH value greater than 5.0 at screening. pH values were recorded on the subject's case report form. The subjects were advised not to have sexual activity and to refrain from using vaginal douching within 24 hours prior to the measurement. Results from these assessments are presented in Table 9.
1Confidence interval for the estradiol 10 μg-Placebo from ANCOVA with treatment as a fixed effect and baseline as a covariate.
2P-value for treatment comparison from ANCOVA with treatment as a fixed effect and baseline as a covariate.
Most Bothersome Symptoms Data
Subjects were asked to specify the symptom that she identified as the “most bothersome symptom.” During the screening period all of the subjects were provided with a questionnaire to self-assess the symptoms of VVA: (1) vaginal dryness; (2) vaginal or vulvar irritation, burning, or itching; (3) dysuria; (4) dysparuenia; (5) vaginal bleeding associated with sexual activity. Each symptom, with the exception of vaginal bleeding associated with sexual activity, was measured on a scale of 0 to 3, where 0=none, 1=mild, 2=moderate, and 3=severe. Vaginal bleeding associated with sexual activity was measured in a binary scale: N=no bleeding; Y=bleeding. The subject's responses were recorded. All randomized subjects were also provided a questionnaire to self-assess the symptoms of VVA at Visit 1—Randomization/Baseline (day 1) and at Visit 3—End of the treatment (day 15). Subjects recorded their self-assessments daily in a diary and answers were collected on days 8 and 15 (end of treatment). Pre-dose evaluation results obtained at Visit 1 were considered as baseline data for the statistical analyses. Data from these assessments are presented in Tables 10 and 11.
1P-value for treatment comparison from ANOVA/ANCOVA with treatment as a fixed effect and Baseline as a covariate when appropriate.
2N = number of subjects sexually active at baseline.
3Percent of subjects with bleeding, evaluated using Fisher's Exact Test.
1ANOVA model contained a fixed effect for treatment. ANCOVA added baseline as a covariate to the model.
2Confidence interval for the difference between estradiol 10 μg and Placebo treatment least-squares means.
Changes to the most bothersome symptom from the baseline was scored according to the evaluation of VVA symptoms generally set forth above. Tables 13 and 14 show a comparison between the pharmaceutical composition 1 and placebo generally for most bothersome symptom and vaginal atrophy symptom. It is noteworthy to point out that these measurement demonstrated a trend of improvement, though not statistically significant, at day 15.
1Confidence interval for the estradiol 10 μg-Placebo from ANOVA with treatment as a fixed effect.
2P-value for treatment comparison from ANOVA with treatment as a fixed effect.
1ANOVA model contained a fixed effect for treatment. ANCOVA added baseline as a covariate to the model.
2Confidence interval for the difference between TX-12-004-HR and Placebo treatment least-squares means.
With respect to the most bothersome symptoms data presented in Tables 13 and 14, the period over which the data was measured is generally considered insufficient to make meaningful conclusions. However, the trends observed as part of this study suggest that the data will show improvement of the most bothersome symptoms when data for a longer time period is collected.
The absence or presence of any vaginal bleeding associated with sexual activity was also measured as one of the most bothersome symptoms. The data for vaginal bleeding associated with sexual activity is reported in Table 15.
1P-value for treatment comparison from Fisher's Exact Test.
2Percent is based on the number of subjects classified as either a Success or a Failure (N = 2 for estradiol 10 μg; N = 5 for Placebo
Estradiol Level/Pharmacokinetics Data
In this study, the systemic exposure to estradiol following once daily intravaginal administration of estradiol 10 μg for 14 days was investigated. Descriptive statistics of the plasma estradiol concentrations taken at each sampling time and the observed Cmax and Tmax values were recorded in Tables 16 and 17. No statistically significant difference in the systemic concentration of estradiol 10 μg versus the placebo group was observed, which suggests the estradiol is not carried into the blood stream where it will have a systemic effect. Rather, it remains in localized tissues; the effect of estradiol is therefore believed be local to the location of administration (i.e., the vagina). The lower limits of detection of the assays used to measure the pharmacokinetic data may have affected the measured the accuracy of the pk values presented. Additional pk studies were performed with more accurate assays in Examples 8 and 9.
For the purpose of monitoring the estradiol level during the study blood samples were collected at 0.0, 1.0, 3.0, and 6.0 hours relative to dosing on day 1; prior to dosing on day 8; and prior to dosing on day 15. Efforts were made to collect blood samples at their scheduled times. Sample collection and handling procedures for measurement of estradiol blood level was performed according to procedure approved by the sponsor and principal investigator. All baseline and post-treatment plasma estradiol concentrations were determined using a validated bioanalytical (UPLC-MS/MS) methods. These data are shown in Tables 16 and 17.
Assessment of Vaginal Mucosa Data
The investigators rated the vaginal mucosal appearance at day 1 (pre-dose) and day 15. Vaginal color, vaginal epithelial integrity, vaginal epithelial surface thickness, and vaginal secretions were evaluated according to the following degrees of severity: none, mild, moderate, or severe using scales 0 to 3, where 0=none, 1=mild, 2=moderate, and 3=severe. Results from these investigators rated assessments are presented in Tables 18, 19, 20, and 21.
1Confidence interval for the estradiol 10 μg-Placebo from ANCOVA with treatment as a fixed effect and baseline as a covariate.
2P-value for treatment comparison from ANCOVA with treatment as a fixed effect and baseline as a covariate.
1Confidence interval for the estradiol 10 μg-Placebo from ANCOVA with treatment as a fixed effect and baseline as a covariate.
2P-value for treatment comparison from ANCOVA with treatment as a fixed effect and baseline as a covariate.
1Confidence interval for the estradiol 10 μg-Placebo from ANCOVA with treatment as a fixed effect and baseline as a covariate.
2P-value for treatment comparison from ANCOVA with treatment as a fixed effect and baseline as a covariate.
1Confidence interval for the estradiol 10 μg-Placebo from ANCOVA with treatment as a fixed effect and baseline as a covariate.
2P-value for treatment comparison from ANCOVA with treatment as a fixed effect and baseline as a covariate.
Delivery Vehicle Disintegration Data
Assessment of capsule disintegration in the vagina (presence or absence) at Day 1 (6 hours after dosing) and Day 15. Results of this assessment is presented in Table 22.
Serum hormone level data was collected to measure the serum concentrations of estradiol. These data were used for screening inclusion and were determined using standard clinical chemistry methods.
Appropriateness of Measurements
The selection of the efficacy measurements used in this study was based on FDA's recommendations for studies of estrogen and estrogen/progestin drug products for the treatment of moderate to severe vasomotor symptoms associated with the menopause and moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause (Food and Drug Administration, Guidance for Industry, Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms and Vulvar and Vaginal Atrophy Symptoms—Recommendations for Clinical Evaluation. January 2003, hereby incorporated by reference).
Standard clinical, laboratory, and statistical procedures were utilized in the trial. All clinical laboratory procedures were generally accepted and met quality standards.
Statistical Methods:
Efficacy:
Analysis of variance (ANOVA) was used to evaluate the change from baseline differences between the subjects receiving estradiol 10 μg and placebo capsules for all efficacy endpoints, except for vaginal bleeding, to estimate the effect size and variability of the effect. In some cases, for example, for some vaginal atrophy symptoms, the change from baseline (post dose response) was correlated with the baseline value (p<0.05), so baseline was included as a covariate to adjust for this correlation (Analysis of Covariance, ANCOVA). The 90% confidence intervals on the differences between estradiol 10 μg and placebo endpoint means were determined to evaluate the effect size. The change from baseline in vaginal bleeding associated with sexual activity was evaluated in terms of the proportion of subjects who had treatment success or failure. Any subject reporting bleeding at baseline who did not report bleeding at Day 15 was considered to have been successfully treated. Any subject reporting bleeding at day 15 was considered a treatment failure, regardless of whether they reported baseline bleeding or not. Subjects reporting no bleeding at both baseline and day 15 were classified as no-change and were excluded from the statistical evaluation. The difference in the proportion of subjects with success between the two treatment groups was statistically evaluated using Fisher's Exact Test. Results of this difference in proportion are presented in Table 10.
Measurements of Treatment Compliance
Subjects were required to complete a diary in order to record treatment compliance. Diaries were reviewed for treatment compliance at day 8 and day 15 visits. A total of 45 subjects (21 subjects in the estradiol 10 μg group and 24 subjects in the placebo group) were 10% compliant with the treatment regimen.
Due to the investigative nature of the study, no adjustments were made for multiplicity of endpoints.
Safety:
The frequency and severity of all adverse events were summarized descriptively by treatment group.
Results: All forty eight (48) subjects who completed the study were included in the primary efficacy analyses. The results of efficacy analyses are presented throughout Tables 5, 6, and 7.
Efficacy
The two-week treatment with pharmaceutical composition 10 μg led to a statistically significant greater mean decrease in percent of parabasal cells than did placebo treatment (54% vs. 5%, p<0.0001), as illustrated in Table 6. At the same time, a significantly greater mean increase in the percent of superficial cells was observed with the pharmaceutical composition (35%) than with the placebo capsules (9%), with the difference being highly statistically significant (p=0.0002), as illustrated in Table 7. The difference in pH reduction between the pharmaceutical composition (0.97 units) compared to that for the placebo (0.34 units) was only slightly greater than 0.5 units, but the difference was detected as statistically significant (p=0.0002), as illustrated in Table 9.
While the decrease in severity of the most bothersome symptom was essentially the same (˜1 unit) for both pharmaceutical composition and placebo, the reductions in the severity of the individual symptoms of vaginal dryness, irritation and pain during sexual activity were all marginally better for the active treatment than for the placebo treatment. None of the differences between the two treatments, all of which were ≤0.3 units, were detected as statistically significant. There was no difference between the two treatments in regard to reduction of pain/burning/stinging during urination (˜0.4 unit reduction). The length of the study was not long enough to show a separation between the most bothersome symptoms in the pharmaceutical composition and placebo. However, the trends of most bothersome symptoms suggest that with a suitable period of time, significantly significant differences between the two treatments would be observed.
The two-week treatment with estradiol 10 μg capsules showed no statistically detectable difference in regard to reduction of severity from baseline according to the investigator's assessment of vaginal color or vaginal epithelial surface thickness. Pharmaceutical composition capsules did demonstrate a statistically significant greater reduction than did placebo in severity of atrophic effects on vaginal epithelial integrity (−0.34 vs. 0.18, p=0.0001) and vaginal secretions (−0.64 vs. −0.27, p=0.0401).
Descriptive statistical analyses (mean, median, geometric mean, standard deviation, CV, minimum and maximum, Cmax, and Tmax) were conducted on the estradiol concentrations at each sampling time, the peak concentration on day 1 and the time of peak concentration. Results from this assessment are presented in Tables 16 and 17.
A pharmaceutical composition comprising estradiol 10 μg outperformed placebo treatment in regard to improvement in the Maturation Index, reduction in vaginal pH, reduction in the atrophic effects on epithelial integrity and vaginal secretions. The lack of statistical significance between the two treatments in regard to reduction of severity for the most bothersome symptom, and the individual vaginal atrophy symptoms of dryness, irritation, pain associated with sexual activity, and pain/burning/stinging during urination, is not unexpected given the small number of subjects in the study and the short duration of therapy. Too few subjects in the study had vaginal bleeding associated with sexual activity to permit any meaningful evaluation of this vaginal atrophy symptom.
Of the 48 subjects enrolled in the study, 45 subjects were 100% compliant with the treatment regimen. Of the remaining three subjects, one removed herself from the study due to personal reasons and the other two subjects each missed one dose due to an adverse event.
Safety
Although the Day 1 mean plasma estradiol peak concentration for the pharmaceutical composition was somewhat higher than that for the Placebo (ratio of geometric means=1.21:Test Product (estradiol 10 μg) 21%>Placebo), no statistically significant difference was determined. However, the assay methods were questionable, resulting in questionable pk data. Additional pk studies were performed in Examples 8 and 9.
There were no serious adverse events in the study.
Overall, the pharmaceutical composition comprising estradiol 10 μg was well tolerated when administered intravaginally in once daily regimen for 14 days.
A pk study was undertaken to compare the 25 μg formulation disclosed herein (Pharmaceutical Composition 3) to the RLD. The results of the pk study for estradiol are summarized in Table 23. The p values for these data demonstrate statistical significance, as shown in Table 24.
As illustrated in Table 23, baseline adjusted pk data illustrates that the formulations disclosed herein unexpectedly show a 54% decrease in Cmax and a 31% decrease in the AUC relative to the RLD. This result is desirable because the estradiol is intended only for local absorption. These data suggest a decrease in the circulating levels of estradiol relative to the RLD. Moreover, it is noteworthy to point out that the Cmax and AUC levels of estradiol relative to placebo are not statistically differentiable, which suggests that the formulations disclosed herein have a negligible systemic effect. As shown in Table 24, there was no significant difference between the test and reference products due to sequence and period effects. However, there was a significant difference due to treatment effect for both Cmax and AUC.
Pharmacokinetics for circulating total estrone, a metabolite of estradiol, is show in Table 25. These data show that the total circulating estrone for the formulations disclosed herein resulted in a 55% decrease in the Cmax for circulating estrone, and a 70% decrease in the AUC for circulating estrone.
There was a significant difference between test and reference products due to treatment effect whereas there was no significant difference due to sequence and period effects for Cmax. For AUC, there was a significant difference between test and reference products due to treatment, sequence, and period effects.
pk for circulating total estrone sulfate is shown in Table 27. These data show that the total circulating estrone sulfate for the pharmaceutical compositions disclosed herein resulted in a 33% decrease in the Cmax and a 42% decrease in the AUC for circulating estrone sulfate.
There was a significant difference between test and reference products due to treatment effect whereas there was no significant difference due sequence and period effects for both Cmax and AUC.
A pk study was undertaken to compare the 10 μg formulation disclosed herein (Pharmaceutical Composition 2) to the RLD. The results of the pk study for estradiol are summarized in Table 29-40, and
A pk study was undertaken to compare pharmaceutical compositions disclosed herein having 10 μg of estradiol to the RLD. The results of the pk study for estradiol are summarized in tables 29-34, which demonstrate that the pharmaceutical compositions disclosed herein more effectively prevented systemic absorption of the estradiol. Table 35 shows that the pharmaceutical compositions disclosed herein had a 28% improvement over the RLD for systemic blood concentration Cmax and 72% AUC improvement over the RLD.
The pk data for total estrone likewise demonstrated reduced systemic exposure when compared to the RLD. Table 33 shows the pharmaceutical compositions disclosed herein reduced systemic exposure by 25% for Cmax and 49% for AUC.
The pk data for estrone sulfate likewise demonstrated reduced systemic exposure when compared to the RLD. Table 37 shows the pharmaceutical compositions disclosed herein reduced systemic exposure by 25% for Cmax and 42% for AUC.
While the pharmaceutical compositions and methods have been described in terms of what are presently considered to be practical and preferred embodiments, it is to be understood that the disclosure need not be limited to the disclosed embodiments. It is intended to cover various modifications and similar arrangements included within the spirit and scope of the claims, the scope of which should be accorded the broadest interpretation so as to encompass all such modifications and similar embodiments. This disclosure includes any and all embodiments of the following claims.
This application claims priority to the following U.S. Patent Applications: U.S. Provisional Application Ser. No. 61/932,140, entitled “VAGINAL INSERTED ESTRADIOL PHARMACEUTICAL COMPOSITIONS AND METHODS”, which was filed on Jan. 27, 2014; U.S. Provisional Application Ser. No. 61/894,411, entitled “SOLUBLE ESTRADIOL CAPSULE FOR VAGINAL INSERTION,” which was filed on Oct. 22, 2013; U.S. Provisional Application Ser. No. 61/745,313, entitled “SOLUBLE ESTRADIOL CAPSULE FOR VAGINAL INSERTION,” which was filed on Dec. 21, 2012; U.S. Provisional Application Ser. No. 61/889,483, entitled “Natural Combination Hormone Replacement Pharmaceutical compositions and Therapies,” which was filed on Oct. 10, 2013; U.S. Provisional Application Ser. No. 61/661,302, entitled “ESTRADIOL PHARMACEUTICAL COMPOSITIONS,” which was filed on Jun. 18, 2012; U.S. Provisional Application Ser. No. 61/662,265, entitled “PROGESTERONE PHARMACEUTICAL COMPOSITIONS,” which was filed on Jun. 20, 2012; U.S. patent application Ser. No. 13/684,002, entitled “Natural Combination Hormone Replacement Pharmaceutical compositions 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. All aforementioned applications are hereby incorporated by reference herein in their entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1967351 | Doisy | Jan 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 | Stein et al. | Nov 1969 | A |
| 3526648 | Bertin et al. | Sep 1970 | A |
| 3710795 | Higuchi et al. | Jan 1973 | A |
| 3729560 | Hagerman | Apr 1973 | A |
| 3729566 | Ericsson 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 | Jun 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. | Aug 1977 | A |
| 4071623 | van der Vies | Jan 1978 | A |
| 4093709 | Choi et al. | Jun 1978 | A |
| 4154820 | Simoons | May 1979 | A |
| 4155991 | Schopflin et al. | May 1979 | A |
| 4196188 | Besins | Apr 1980 | A |
| 4215691 | Wong | Aug 1980 | A |
| 4237885 | Wong 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 |
| 5043331 | Hirvonen et al. | Aug 1991 | A |
| 5059426 | Chiang | Oct 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 |
| 5164416 | Nagai et al. | Nov 1992 | A |
| 5208225 | Boissonneault et al. | May 1993 | 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 |
| 5295945 | Miller | Mar 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. | Aug 1994 | A |
| 5382573 | Casper | Jan 1995 | A |
| 5393528 | Staab | Feb 1995 | A |
| 5393529 | Hoffmann et al. | Feb 1995 | A |
| 5419910 | Lewis | May 1995 | A |
| 5453279 | Lee et al. | Sep 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 | Barth et al. | Jul 1996 | A |
| 5543150 | Bologna et al. | Aug 1996 | A |
| 5547948 | Barcomb | Aug 1996 | A |
| 5556635 | Grognet 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 | Liorzou 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 | Math et al. | Feb 1997 | A |
| 5607691 | Solas et al. | Mar 1997 | A |
| 5607693 | Bonte et al. | Mar 1997 | A |
| 5609617 | Cady et al. | Mar 1997 | A |
| 5620705 | Dong et al. | Apr 1997 | A |
| 5626866 | Heiber 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 |
| 5645856 | Lacy et al. | Jun 1997 | A |
| 5653983 | Bonte 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 | Dumas et al. | Sep 1997 | A |
| 5676968 | Lipp et al. | Oct 1997 | A |
| 5677292 | Li et al. | Oct 1997 | A |
| 5686097 | Crisologo 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 | Mantelle 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 | Tipton et al. | Jul 1998 | A |
| 5780050 | Jain et al. | Jul 1998 | A |
| 5788980 | Nabahi | Aug 1998 | A |
| 5788984 | Schmidt 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 | Shinmura et al. | Oct 1998 | A |
| 5827200 | Caillouette | Oct 1998 | A |
| 5840327 | Gale et al. | Nov 1998 | A |
| 5843468 | Yum 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 |
| 5869084 | Paradissis et al. | Feb 1999 | A |
| 5882676 | Yum 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 | Gunther 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 |
| 5942531 | Diaz et al. | Aug 1999 | A |
| 5952000 | Fikstad et al. | Sep 1999 | A |
| 5958446 | Miranda et al. | Sep 1999 | A |
| 5962445 | Stewart | Oct 1999 | A |
| 5968919 | Gyurik 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 |
| 5993856 | Ragavan et al. | Nov 1999 | A |
| 5989568 | De Lacharriere et al. | Dec 1999 | A |
| 6001846 | Edwards et al. | Dec 1999 | A |
| 6007835 | Bon-Lapillonne et al. | Dec 1999 | A |
| 6010715 | Pollock et al. | Jan 2000 | A |
| 6013276 | Teillaud 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 | Garfield et al. | Mar 2000 | A |
| 6056972 | Hermsmeyer | May 2000 | A |
| 6060077 | Meignant | May 2000 | A |
| 6068853 | Berner 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. | Jul 2000 | A |
| 6106848 | Willcox 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 | Tenzel 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 | Rubinstein 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 | MacQueen et al. | Jun 2001 | B1 |
| 6245811 | Horrobin et al. | Jun 2001 | B1 |
| 6262115 | Guittard et al. | Jul 2001 | B1 |
| 6267984 | Hamlin et al. | Jul 2001 | B1 |
| 6274165 | Meconi et al. | Aug 2001 | B1 |
| 6277418 | Marakverich et al. | Aug 2001 | B1 |
| 6283927 | Caillouette | Sep 2001 | B1 |
| 6284263 | Place | 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 | Vo 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 | Leyba 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 | Houze 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 | Seibertz et al. | Feb 2003 | B2 |
| 6526980 | Tracy et al. | Mar 2003 | B1 |
| 6528094 | Savoir et al. | Mar 2003 | B1 |
| 6531149 | Meconi 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 | Murray et al. | Apr 2003 | B1 |
| 6548491 | Tanabe et al. | Apr 2003 | B2 |
| 6551611 | Sen 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 | 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 |
| 6610325 | Meignant | Aug 2003 | B1 |
| 6610652 | Adams et al. | Aug 2003 | B2 |
| 6610670 | Backensfeld et al. | Aug 2003 | B2 |
| 6610674 | Schreiber | Aug 2003 | B1 |
| 6635274 | Carter 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 |
| 6664296 | Meignant | Dec 2003 | B1 |
| 6682757 | Wright | Jan 2004 | B1 |
| 6692763 | Cummings et al. | Feb 2004 | B1 |
| 6708822 | Muni | Mar 2004 | B1 |
| 6716454 | Meignant | Apr 2004 | B2 |
| 6720001 | Chen et al. | Apr 2004 | B2 |
| 6737081 | Avoir 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 | Heubner et al. | Mar 2005 | B2 |
| 6878518 | Whitehead | Apr 2005 | B2 |
| 6901278 | Notelovitz | May 2005 | B1 |
| 6905705 | Palm et al. | Jun 2005 | B2 |
| 6911211 | Tamarkin 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 | Pike 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 | Boyd et al. | Dec 2005 | B2 |
| 6977250 | Rodriguez | Dec 2005 | B2 |
| 6978945 | Wong et al. | Dec 2005 | B2 |
| 6987129 | Mak et al. | Jan 2006 | B2 |
| 6995149 | Reilhac et al. | Feb 2006 | B1 |
| 7004321 | Hackbarth 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 | Paris et al. | Apr 2006 | B2 |
| 7030157 | Ke 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, III et al. | Aug 2006 | B2 |
| 7094228 | Zhang et al. | Aug 2006 | B2 |
| 7097853 | Keister 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 | Dec 2008 | B2 |
| 7470433 | Carrara et al. | Dec 2008 | B2 |
| 7485666 | Villaneuva 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 | Ring et al. | May 2009 | B2 |
| 7550142 | Giles-Komar et al. | Jun 2009 | B2 |
| 7563565 | Matsuo et al. | Jul 2009 | B1 |
| 7569274 | Alphonse 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 | Frye et al. | Nov 2010 | B2 |
| RE42012 | Deaver et al. | Dec 2010 | E |
| 7850992 | Hwang, II 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 Bennink et al. | May 2011 | B2 |
| 7945459 | Grace et al. | May 2011 | B2 |
| 7960368 | Rao 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 | Visser et al. | Dec 2011 | B2 |
| 8071729 | Giles-Komar et al. | Dec 2011 | B2 |
| 8075916 | Park et al. | Dec 2011 | B2 |
| 8075917 | Park et al. | Dec 2011 | B2 |
| 8076317 | Kulmann | Dec 2011 | B2 |
| 8076319 | Leonard | Dec 2011 | B2 |
| 8080553 | Auspitz et al. | Dec 2011 | B2 |
| 8088605 | Beudet et al. | Jan 2012 | B2 |
| 8096940 | Iverson 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 | Lennernaes et al. | Feb 2012 | B2 |
| 8124595 | Boissonneault | Feb 2012 | B2 |
| 8147561 | Binmoeller | Apr 2012 | B2 |
| 8148546 | Baasner 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 | Watkinson et al. | May 2012 | B2 |
| 8182833 | Hermsmeyer | May 2012 | B2 |
| 8187615 | Friedman | May 2012 | B2 |
| 8195403 | Wood, Jr. 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 | Thoene | Jul 2012 | B2 |
| 8222237 | Narkunan 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 | Karan et al. | Sep 2012 | B2 |
| 8268806 | Labrie | Sep 2012 | B2 |
| 8268878 | Johnson et al. | Sep 2012 | B2 |
| 8273730 | Fernandez et al. | Sep 2012 | B2 |
| 8287888 | Song et al. | Oct 2012 | B2 |
| 8288366 | Gonzalez 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 | Chui 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 | Besonov et al. | Jan 2013 | B2 |
| 8372424 | Berry et al. | Feb 2013 | B2 |
| 8372806 | Bragagna et al. | Feb 2013 | B2 |
| 8377482 | Laurie et al. | Feb 2013 | B2 |
| 8377994 | Drechsler et al. | Feb 2013 | B2 |
| 8394759 | Barathur et al. | Mar 2013 | B2 |
| 8415332 | Reape et al. | Apr 2013 | B2 |
| 8420111 | Hermsmeyer | Apr 2013 | B2 |
| 8435561 | Besins et al. | May 2013 | B2 |
| 8435972 | Sayeed et al. | May 2013 | B2 |
| 8449879 | Laurent Applegate et al. | May 2013 | B2 |
| 8450108 | Boyce | May 2013 | B2 |
| 8454945 | Narain et al. | Jun 2013 | B2 |
| 8455468 | Kellermann et al. | Jun 2013 | B2 |
| 8461138 | Boissonneault | Jun 2013 | B2 |
| 8476252 | Pickersgill et al. | Jul 2013 | B2 |
| 8481488 | Carter | Jul 2013 | B2 |
| 8486374 | Zlatkis et al. | Jul 2013 | B2 |
| 8486442 | Yamaji et al. | Jul 2013 | B2 |
| 8492368 | Lewandowski et al. | Jul 2013 | B2 |
| 8507467 | Ueda et al. | Aug 2013 | B2 |
| 8512693 | Azevedo et al. | Aug 2013 | B2 |
| 8512754 | Needham | Aug 2013 | B2 |
| 8518376 | Schuz et al. | Aug 2013 | B2 |
| 8536159 | Zeng et al. | Sep 2013 | B2 |
| 8540967 | Trivedi et al. | Sep 2013 | B2 |
| 8541400 | Joabsson et al. | Sep 2013 | B2 |
| 8551462 | Marenus et al. | Oct 2013 | B2 |
| 8551508 | Lee et al. | Oct 2013 | B2 |
| 8557281 | Tuominen et al. | Oct 2013 | B2 |
| 8568374 | De Graaff et al. | Oct 2013 | B2 |
| 8591951 | Kohn et al. | Nov 2013 | B2 |
| 8613951 | Troiano et al. | Dec 2013 | B2 |
| 8633178 | Cacace et al. | Jan 2014 | B2 |
| 8633180 | Zeng et al. | Jan 2014 | B2 |
| 8636787 | Sabaria | Jan 2014 | B2 |
| 8636982 | Schuz 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 | Moldavski et al. | Mar 2014 | B2 |
| 8664207 | Zheng et al. | Mar 2014 | B2 |
| 8669293 | Sharoni et al. | Mar 2014 | B2 |
| 8679552 | Guthery | Mar 2014 | B2 |
| 8694358 | Tryfon | Apr 2014 | B2 |
| 8697127 | Sah | Apr 2014 | B2 |
| 8697710 | Zeng et al. | Apr 2014 | B2 |
| 8703105 | Besonov et al. | Apr 2014 | B2 |
| 8709385 | Schuz 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 | Eini et al. | May 2014 | B2 |
| 8734846 | Hrkach et al. | May 2014 | B2 |
| 8735381 | Podolski | May 2014 | B2 |
| 8741336 | Dipierro et al. | Jun 2014 | B2 |
| 8741373 | Rao et al. | Jun 2014 | B2 |
| 8753661 | Gassner et al. | Jun 2014 | B2 |
| 8784882 | Mattern | Jul 2014 | B2 |
| 8846648 | Bernick et al. | Sep 2014 | B2 |
| 8846649 | Bernick et al. | Sep 2014 | B2 |
| 8933059 | Bernick et al. | Jan 2015 | B2 |
| 8987237 | Bernick et al. | Mar 2015 | B2 |
| 8987238 | Bernick et al. | Mar 2015 | B2 |
| 8993548 | Bernick et al. | Mar 2015 | B2 |
| 8993549 | Bernick et al. | Mar 2015 | B2 |
| 9005597 | Hansen et al. | Apr 2015 | B2 |
| 9006222 | Bernick et al. | Apr 2015 | B2 |
| 9012434 | Bernick et al. | Apr 2015 | B2 |
| 9114145 | Bernick et al. | Aug 2015 | B2 |
| 9114146 | Bernick et al. | Aug 2015 | B2 |
| 9180091 | Bernick et al. | Nov 2015 | B2 |
| 9248136 | Bernick et al. | Feb 2016 | B2 |
| 9289382 | Bernick et al. | Mar 2016 | B2 |
| 9301920 | Bernick et al. | Apr 2016 | B2 |
| 9931349 | Shadiack et al. | Apr 2018 | B2 |
| 10052386 | Bernick et al. | Aug 2018 | B2 |
| 10098894 | Amadio et al. | Oct 2018 | B2 |
| 10206932 | Bernick et al. | Feb 2019 | B2 |
| 10258630 | Mirkin et al. | Apr 2019 | B2 |
| 10398708 | Mirkin et al. | Sep 2019 | B2 |
| 10471072 | Bernick et al. | Nov 2019 | B2 |
| 10568891 | Mirkin et al. | Feb 2020 | B2 |
| 10835487 | Bernick et al. | Nov 2020 | B2 |
| 10888516 | Bernick et al. | Jan 2021 | B2 |
| 11065197 | Bernick et al. | Jul 2021 | B2 |
| 20010005728 | Guittard et al. | Feb 2001 | A1 |
| 20010009673 | Gunther 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 | de Ziegler et al. | Oct 2001 | A1 |
| 20010032125 | Bhan et al. | Oct 2001 | A1 |
| 20010034340 | Pickar | Oct 2001 | A1 |
| 20120269878 | Cantor et al. | Oct 2001 | A2 |
| 20010053383 | Sablotsky 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 | Garfield 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 | Gunther et al. | Jan 2003 | A1 |
| 20030004145 | Leonard | Jan 2003 | A1 |
| 20030007994 | Bunt et al. | Jan 2003 | A1 |
| 20030027772 | Breton | Feb 2003 | A1 |
| 20030091620 | Venkateshwaran et al. | Feb 2003 | A1 |
| 20030044453 | Volkel et al. | Mar 2003 | A1 |
| 20030049307 | Gyurik | Mar 2003 | A1 |
| 20030052799 | Weigl | 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 et al. | Apr 2003 | A1 |
| 20030078245 | Bennink et al. | Apr 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 | Beckmann 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 | Batycky et al. | Sep 2003 | A1 |
| 20030170295 | Yoon et al. | Sep 2003 | A1 |
| 20030175329 | Mak 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 | Bernstein et al. | Nov 2003 | A1 |
| 20030224057 | Martin-Letellier et al. | Dec 2003 | A1 |
| 20030224059 | Lerner et al. | Dec 2003 | A1 |
| 20030225047 | Friedman et al. | Dec 2003 | A1 |
| 20030225048 | Friedman et al. | Dec 2003 | A1 |
| 20030225050 | Eichardt 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 Chacra-Vernet et al. | Mar 2004 | A1 |
| 20040073024 | Metcalf, III 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 |
| 20040147578 | Calvet | 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 | Sciano 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 | Deaver et al. | Jan 2005 | A1 |
| 20050004088 | Hesch | Jan 2005 | A1 |
| 20050009800 | Thumbeck et al. | Jan 2005 | A1 |
| 20050014729 | Pulaski | Jan 2005 | A1 |
| 20050020550 | Latif et al. | Jan 2005 | A1 |
| 20050020552 | Aschkenasay et al. | Jan 2005 | A1 |
| 20050021009 | Massara et al. | Jan 2005 | A1 |
| 20050025833 | Aschkenasay et al. | Feb 2005 | A1 |
| 20050031651 | Gervais et al. | Feb 2005 | A1 |
| 20050042173 | Besse et al. | Feb 2005 | A1 |
| 20050042268 | Aschkenasay et al. | Feb 2005 | A1 |
| 20050048116 | Straub et al. | Mar 2005 | A1 |
| 20050054991 | Paterson 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 Bennink | 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 | Wuttke et al. | Oct 2005 | A1 |
| 20050222106 | Bracht | Oct 2005 | A1 |
| 20050228692 | Hodgdon | Oct 2005 | A1 |
| 20050228718 | Austin | Oct 2005 | A1 |
| 20050239747 | Le 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. | Nov 2005 | A1 |
| 20050266088 | Frijlink 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 | 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 |
| 20060040904 | Ahmed et al. | 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 | Seibertz et al. | Apr 2006 | A1 |
| 20060089337 | Casper et al. | Apr 2006 | A1 |
| 20060093678 | Chickering, III et al. | May 2006 | A1 |
| 20060100180 | Bohlmann 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 | Jun 2006 | A1 |
| 20060134188 | Podhaisky et al. | Jun 2006 | A1 |
| 20060135619 | Kick et al. | Jun 2006 | A1 |
| 20060165744 | Anyarambhatla 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 | Pushpala 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 Bennink et al. | Nov 2006 | A1 |
| 20060251581 | Madenjian et al. | Nov 2006 | A1 |
| 20060252049 | Shuler et al. | Nov 2006 | A1 |
| 20060257472 | Neilsen | Nov 2006 | A1 |
| 20060275218 | Besonov et al. | Dec 2006 | A1 |
| 20060275360 | Ahmed et al. | Dec 2006 | A1 |
| 20060276414 | Coelingh Bennink 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 | Mc Ilroy et al. | Dec 2006 | A1 |
| 20070004693 | Woolfson et al. | Jan 2007 | A1 |
| 20070004694 | Woolfson et al. | Jan 2007 | A1 |
| 20070009559 | Alosio et al. | Jan 2007 | A1 |
| 20070009594 | Grubb et al. | Jan 2007 | A1 |
| 20070010550 | McKenzie | Jan 2007 | A1 |
| 20070014839 | Bracht | Jan 2007 | A1 |
| 20070015698 | Goldstein 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 |
| 20070036843 | Hirsh et al. | Feb 2007 | A1 |
| 20070037780 | Anigbogu et al. | Feb 2007 | A1 |
| 20070037782 | Suzuki et al. | Feb 2007 | A1 |
| 20070042038 | Besse | Feb 2007 | A1 |
| 20070049567 | Wiley | Mar 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 |
| 20070071777 | Bromer 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 | Wall 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 | Chiao et al. | Aug 2007 | A1 |
| 20070191319 | Ke et al. | Aug 2007 | A1 |
| 20070191321 | Ahmed | Aug 2007 | A1 |
| 20070196415 | Houston 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 | Bernard et al. | Oct 2007 | A1 |
| 20070238713 | Gast et al. | Oct 2007 | A1 |
| 20070243229 | Smith et al. | Oct 2007 | A1 |
| 20070248658 | Bracht et al. | Oct 2007 | A1 |
| 20070254858 | Cronk | Nov 2007 | A1 |
| 20070255197 | Wilkins 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 |
| 20070270394 | El-Alfy et al. | Nov 2007 | A1 |
| 20070281008 | Lin | Dec 2007 | A1 |
| 20070286819 | DeVries et al. | Dec 2007 | A1 |
| 20070287688 | Chan et al. | Dec 2007 | A1 |
| 20070287789 | Jones et al. | Dec 2007 | A1 |
| 20070292359 | Schuz et al. | Dec 2007 | A1 |
| 20070292387 | Jon et al. | Dec 2007 | A1 |
| 20070292461 | Danziger et al. | Dec 2007 | A1 |
| 20070292493 | Brierre | Dec 2007 | A1 |
| 20070298089 | Yoshinaga et al. | Dec 2007 | A1 |
| 20080026035 | Chollet et al. | Jan 2008 | A1 |
| 20080026040 | Rivera et al. | Jan 2008 | A1 |
| 20080026062 | Farr et al. | Jan 2008 | A1 |
| 20080038219 | Carlson et al. | Feb 2008 | A1 |
| 20080038350 | Gerecke et al. | Feb 2008 | A1 |
| 20080039405 | Joseph et al. | Feb 2008 | A1 |
| 20080050317 | Besonov et al. | Feb 2008 | A1 |
| 20080051351 | Ghisalberti | Feb 2008 | A1 |
| 20080063607 | Berman et al. | Mar 2008 | A1 |
| 20080069779 | Schuz et al. | Mar 2008 | A1 |
| 20080069791 | Beissert | Mar 2008 | A1 |
| 20080085877 | Bortz | Apr 2008 | A1 |
| 20080095831 | Mc Graw | Apr 2008 | A1 |
| 20080095838 | Abou Chacra-Vernet | Apr 2008 | A1 |
| 20080119537 | Zhang et al. | May 2008 | A1 |
| 20080125402 | Dilberti | May 2008 | A1 |
| 20080138379 | Jennings-Spring | Jun 2008 | A1 |
| 20080138390 | Gricenko et al. | Jun 2008 | A1 |
| 20080139392 | Yuan 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 | Baksh et al. | Jul 2008 | A1 |
| 20080175908 | Baksh et al. | Jul 2008 | A1 |
| 20080188829 | Creasy | Aug 2008 | A1 |
| 20080206156 | Cronk | Aug 2008 | A1 |
| 20080206159 | Schuz 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 | Beste et al. | Sep 2008 | A1 |
| 20080227763 | Paris 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 | Stenlof et al. | Oct 2008 | A1 |
| 20080113953 | DeVries et al. | Dec 2008 | A1 |
| 20080114050 | Fensome et al. | Dec 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 | Peyrot et al. | Jan 2009 | A1 |
| 20090011041 | Musaeva et al. | Jan 2009 | A1 |
| 20090017120 | Brisco et al. | Jan 2009 | A1 |
| 20090022683 | Park 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 | Kresevic et al. | Apr 2009 | A1 |
| 20090130029 | Tamarkin et al. | May 2009 | A1 |
| 20090131385 | Voskuhl | May 2009 | A1 |
| 20090136574 | Diaz-Astruc et al. | May 2009 | A1 |
| 20090137478 | Bernstein et al. | May 2009 | A1 |
| 20090137538 | Klamerus et al. | May 2009 | A1 |
| 20090143344 | Chang | Jun 2009 | A1 |
| 20090164341 | Sunvoid et al. | Jun 2009 | A1 |
| 20090175799 | Tamarkin et al. | Jul 2009 | A1 |
| 20090181088 | Song et al. | Jul 2009 | A1 |
| 20090186081 | Slot et al. | Jul 2009 | A1 |
| 20090197843 | Notelovitz et al. | Aug 2009 | A1 |
| 20090203658 | Rose 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 | 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 | Kresevic et al. | Dec 2009 | A1 |
| 20090325916 | Zhang et al. | Dec 2009 | A1 |
| 20100008985 | Vermeulen 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 | Jacobs 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 | Lee 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 Bennink et al. | Jul 2010 | A1 |
| 20100190758 | Fauser et al. | Jul 2010 | A1 |
| 20100204326 | D Souza | Aug 2010 | A1 |
| 20100210994 | Zarif | Aug 2010 | A1 |
| 20100221195 | Ziv et al. | Sep 2010 | A1 |
| 20100227797 | Danielsson et al. | Sep 2010 | A1 |
| 20100240626 | Kulkarni et al. | Sep 2010 | A1 |
| 20100247482 | Chen et al. | Sep 2010 | A1 |
| 20100247632 | Dong et al. | Sep 2010 | A1 |
| 20100247635 | Schmidt et al. | Sep 2010 | A1 |
| 20100255085 | Liu et al. | Oct 2010 | A1 |
| 20100273730 | Hsu et al. | Oct 2010 | A1 |
| 20100278759 | Murad | Nov 2010 | A1 |
| 20100279988 | Setiawan et al. | Nov 2010 | A1 |
| 20100291191 | Lapitsky 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 | Wilkins et al. | Dec 2010 | A1 |
| 20100330168 | Gicquel et al. | Dec 2010 | A1 |
| 20110028439 | Witt-Enderby et al. | Feb 2011 | A1 |
| 20110039814 | Ross 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 | Canet et al. | Apr 2011 | A1 |
| 20110098631 | McIntyre et al. | Apr 2011 | A1 |
| 20110104268 | Segot et al. | May 2011 | A1 |
| 20110104289 | Savoir Vilboeuf et al. | May 2011 | A1 |
| 20110130372 | Marliani 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 | Fisher et al. | Jun 2011 | A1 |
| 20110171140 | Illum et al. | Jul 2011 | A1 |
| 20110182997 | Lewis et al. | Jul 2011 | A1 |
| 20110190201 | Wood, Jr. 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 | Karabelas et al. | Sep 2011 | A1 |
| 20110244043 | Wang 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 Millet | Oct 2011 | A1 |
| 20110262494 | Achleitner et al. | Oct 2011 | A1 |
| 20110268665 | Tamarkin et al. | Nov 2011 | A1 |
| 20110275584 | Volkmann et al. | Nov 2011 | A1 |
| 20110281832 | Wennogle et al. | Nov 2011 | A1 |
| 20110287094 | Penhasi et al. | Nov 2011 | A1 |
| 20110293720 | General et al. | Dec 2011 | A1 |
| 20110294738 | Kuliopulos et al. | Dec 2011 | A1 |
| 20110300167 | Covic 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 | Takruri et al. | Feb 2012 | A1 |
| 20120028936 | Popova et al. | Feb 2012 | A1 |
| 20120045532 | Cohen | Feb 2012 | A1 |
| 20120046264 | Lieb et al. | Feb 2012 | A1 |
| 20120046518 | Yoakum et al. | Feb 2012 | A1 |
| 20120052077 | Truitt, III et al. | Mar 2012 | A1 |
| 20120058171 | Zeeman et al. | Mar 2012 | A1 |
| 20120058962 | Sparrow et al. | Mar 2012 | A1 |
| 20120058979 | Auspitz et al. | Mar 2012 | A1 |
| 20120064135 | Harms et al. | Mar 2012 | A1 |
| 20120065179 | Andersson | Mar 2012 | A1 |
| 20120065221 | Babul | Mar 2012 | A1 |
| 20120087872 | Schuz et al. | Apr 2012 | A1 |
| 20120101073 | Mannion et al. | Apr 2012 | A1 |
| 20120121517 | Kim et al. | May 2012 | A1 |
| 20120121692 | Fang et al. | May 2012 | A1 |
| 20120122829 | Masini 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 | Wennogle et al. | May 2012 | A1 |
| 20120142645 | Marx | Jun 2012 | A1 |
| 20120148670 | Lee et al. | Jun 2012 | A1 |
| 20120149748 | Shanler et al. | Jun 2012 | A1 |
| 20120172343 | Schuermann et al. | Jul 2012 | A1 |
| 20120184515 | Schwede et al. | Jul 2012 | A1 |
| 20120231052 | Brinton et al. | Sep 2012 | A1 |
| 20120232011 | Kneissel | Sep 2012 | A1 |
| 20120232042 | Krenz et al. | Sep 2012 | A1 |
| 20120263679 | Wallace et al. | Oct 2012 | A1 |
| 20120269721 | Weng et al. | Oct 2012 | A1 |
| 20120277249 | Tarrand 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 | Warner et al. | Nov 2012 | A1 |
| 20120301538 | Latere et al. | Nov 2012 | A1 |
| 20120302535 | Caufriez et al. | Nov 2012 | A1 |
| 20120316130 | Hendrix | Dec 2012 | A1 |
| 20120316496 | Horres 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 | Goh et al. | Jan 2013 | A1 |
| 20130011342 | Hazot et al. | Jan 2013 | A1 |
| 20130017239 | Fernandez et al. | Jan 2013 | A1 |
| 20130022674 | Dudley et al. | Jan 2013 | A1 |
| 20130023505 | Garfield et al. | Jan 2013 | A1 |
| 20130023823 | Volland et al. | Jan 2013 | A1 |
| 20130028850 | Hazot et al. | Jan 2013 | A1 |
| 20130029947 | Nachaegari et al. | Jan 2013 | A1 |
| 20130029957 | Venkateshwaran et al. | Jan 2013 | A1 |
| 20130045266 | Kang et al. | Feb 2013 | A1 |
| 20130045953 | Grenier 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 | Zhao et al. | Apr 2013 | A1 |
| 20130089574 | Stock et al. | Apr 2013 | A1 |
| 20130090318 | Gainer et al. | Apr 2013 | A1 |
| 20130102781 | Ely et al. | Apr 2013 | A1 |
| 20130108551 | Gruell et al. | May 2013 | A1 |
| 20130116215 | Lleo et al. | May 2013 | A1 |
| 20130116222 | Altomari et al. | May 2013 | A1 |
| 20130122051 | Gullapalli et al. | May 2013 | A1 |
| 20130123175 | McKee et al. | May 2013 | A1 |
| 20130123220 | Queiroz et al. | May 2013 | A1 |
| 20130123351 | Dewitt | May 2013 | A1 |
| 20130129818 | Bernick et al. | May 2013 | A1 |
| 20130131027 | Schmitz et al. | May 2013 | A1 |
| 20130131028 | Snyder et al. | May 2013 | A1 |
| 20130131029 | Baltussen et al. | May 2013 | A1 |
| 20130149314 | Bullerdiek et al. | Jun 2013 | A1 |
| 20130150334 | Sun et al. | Jun 2013 | A1 |
| 20130164225 | Besonov et al. | Jun 2013 | A1 |
| 20130164346 | Son et al. | Jun 2013 | A1 |
| 20130165744 | Carson et al. | Jun 2013 | A1 |
| 20130178452 | King | Jul 2013 | A1 |
| 20130183254 | Cochran et al. | Jul 2013 | A1 |
| 20130183325 | Sforzini et al. | Jul 2013 | A1 |
| 20130189193 | Besonov et al. | Jul 2013 | A1 |
| 20130189196 | Tamarkin et al. | Jul 2013 | A1 |
| 20130189230 | Kooy et al. | Jul 2013 | A1 |
| 20130189368 | Mosqueira et al. | Jul 2013 | A1 |
| 20130210709 | Covic et al. | Aug 2013 | A1 |
| 20130216550 | Penninger et al. | Aug 2013 | A1 |
| 20130216596 | Fernandez et al. | Aug 2013 | A1 |
| 20130224177 | Kim et al. | Aug 2013 | A1 |
| 20130224257 | Sah et al. | Aug 2013 | A1 |
| 20130224268 | Jaikaria et al. | Aug 2013 | A1 |
| 20130224300 | Maggio | Aug 2013 | A1 |
| 20130225412 | Sardari Lodriche et al. | Aug 2013 | A1 |
| 20130225542 | Frick et al. | Aug 2013 | A1 |
| 20130226113 | Langguth et al. | Aug 2013 | A1 |
| 20130243696 | Wang et al. | Sep 2013 | A1 |
| 20130245253 | Mook et al. | Sep 2013 | A1 |
| 20130245570 | Jackson | Sep 2013 | A1 |
| 20130261096 | Merian et al. | Oct 2013 | A1 |
| 20130266645 | Schoenecker et al. | Oct 2013 | A1 |
| 20130267485 | Da Silva Maia Filho et al. | Oct 2013 | A1 |
| 20130273167 | Kim et al. | Oct 2013 | A1 |
| 20130274211 | Prusthy et al. | Oct 2013 | A1 |
| 20130280213 | Voskuhl | Oct 2013 | A1 |
| 20130316374 | Menon et al. | Nov 2013 | A1 |
| 20130317065 | Seto et al. | Nov 2013 | A1 |
| 20130317315 | Tsang et al. | Nov 2013 | A1 |
| 20130324565 | Zhao et al. | Dec 2013 | A1 |
| 20130331363 | Zhao et al. | Dec 2013 | A1 |
| 20130338122 | Bernick et al. | Dec 2013 | A1 |
| 20130338123 | Bernick et al. | Dec 2013 | A1 |
| 20130338124 | Zhao et al. | Dec 2013 | A1 |
| 20130345187 | Rodriguez Oquendo | Dec 2013 | A1 |
| 20140018335 | Keto et al. | Jan 2014 | A1 |
| 20140024590 | Taylor et al. | Jan 2014 | A1 |
| 20140031289 | Kim et al. | Jan 2014 | A1 |
| 20140031323 | Perez | Jan 2014 | A1 |
| 20140066416 | Leunis et al. | Mar 2014 | A1 |
| 20140072531 | Oh et al. | Mar 2014 | A1 |
| 20140079686 | Prouty et al. | Mar 2014 | A1 |
| 20140088051 | Bernick et al. | Mar 2014 | A1 |
| 20140088058 | Maurizio | Mar 2014 | A1 |
| 20140088059 | Santha 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 | Cacace et al. | Apr 2014 | A1 |
| 20140113889 | Haine et al. | Apr 2014 | A1 |
| 20140127185 | Sayeed et al. | May 2014 | A1 |
| 20140127280 | Jukarainen et al. | May 2014 | A1 |
| 20140127308 | Opara et al. | May 2014 | A1 |
| 20140128798 | Malanchine 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 | Wennogle et al. | Jul 2014 | A1 |
| 20140206616 | Ko et al. | Jul 2014 | A1 |
| 20140213565 | Bernick et al. | Jul 2014 | A1 |
| 20140329783 | Bernick 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 |
| 20150133421 | Bernick et al. | May 2015 | A1 |
| 20150148323 | Bernick et al. | May 2015 | A1 |
| 20150164789 | Bernick et al. | Jun 2015 | A1 |
| 20150224117 | Bernick et al. | Aug 2015 | A1 |
| 20150224118 | Bernick et al. | Aug 2015 | A1 |
| 20150297733 | Oberegger et al. | Oct 2015 | A1 |
| 20150302435 | Bernick et al. | Oct 2015 | A1 |
| 20150342963 | Bernick et al. | Dec 2015 | A1 |
| 20150352126 | Bernick et al. | Dec 2015 | A1 |
| 20150359737 | Bernick et al. | Dec 2015 | A1 |
| 20160030449 | Persicaner et al. | Feb 2016 | A1 |
| 20160213685 | Bernick et al. | Jul 2016 | A1 |
| 20170056418 | Thorsteinsson et al. | Mar 2017 | A1 |
| 20170216310 | Mirkin et al. | Aug 2017 | A1 |
| 20170281645 | Shadiack et al. | Oct 2017 | A1 |
| 20170281646 | Inskeep et al. | Oct 2017 | A1 |
| 20170281647 | Shadiack et al. | Oct 2017 | A1 |
| 20170281776 | Shadiack et al. | Oct 2017 | A1 |
| 20180161343 | Mirkin et al. | Jun 2018 | A1 |
| 20180161344 | Bernick et al. | Jun 2018 | A1 |
| 20180161345 | Bernick et al. | Jun 2018 | A1 |
| 20180221389 | Amadio et al. | Aug 2018 | A1 |
| 20180256598 | Mirkin et al. | Sep 2018 | A1 |
| 20180280410 | Amadio et al. | Oct 2018 | A1 |
| 20180289723 | Bernick et al. | Oct 2018 | A1 |
| 20190022107 | Mirkin et al. | Jan 2019 | A1 |
| 20190046542 | Bernick et al. | Feb 2019 | A1 |
| 20190070197 | Amadio et al. | Mar 2019 | A1 |
| 20190142844 | Bernick et al. | May 2019 | A1 |
| 20190247401 | Amadio et al. | Aug 2019 | A1 |
| 20190343771 | Mirkin et al. | Nov 2019 | A1 |
| 20190343845 | Bernick et al. | Nov 2019 | A1 |
| 20190358243 | Mirkin et al. | Nov 2019 | A1 |
| 20200069700 | Bernick et al. | Mar 2020 | A1 |
| 20200147104 | Bernick | May 2020 | A1 |
| 20200230153 | Bernick et al. | Jul 2020 | A1 |
| 20200230154 | Bernick et al. | Jul 2020 | A1 |
| 20200276210 | Amadio et al. | Sep 2020 | A1 |
| 20200281849 | Bernick et al. | Sep 2020 | A1 |
| 20200297736 | Bernick et al. | Sep 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| PI1001367 | Jul 2012 | BR |
| 2044371 | Dec 1991 | CA |
| 2612380 | Dec 2006 | CA |
| 102258455 | Nov 2011 | CN |
| 0261429 | Mar 1988 | EP |
| 275716 | Jul 1988 | EP |
| 0279977 | Aug 1988 | EP |
| 622075 | Nov 1994 | EP |
| 785211 | Jul 1997 | EP |
| 785212 | Jul 1997 | EP |
| 811381 | Dec 1997 | EP |
| 0904064 | Mar 1999 | EP |
| 0813412 | Dec 1999 | EP |
| 0750495 | Dec 2002 | EP |
| 1300152 | Apr 2003 | EP |
| 1094781 | Jul 2008 | EP |
| 2191833 | Jun 2010 | EP |
| 452238 | Aug 1936 | GB |
| 720561 | Dec 1954 | GB |
| 848881 | Sep 1960 | GB |
| 874368 | Aug 1961 | GB |
| 1589946 | May 1981 | GB |
| 2005KO00053 | Aug 2005 | IN |
| 216026 | Mar 2008 | IN |
| 244217 | Nov 2010 | IN |
| H4-503810 | Sep 1990 | JP |
| H2-264725 | Oct 1990 | JP |
| 2002 510336 | Apr 2002 | JP |
| 2006 513182 | Apr 2006 | JP |
| 2155582 | Sep 2000 | RU |
| 199010425 | Sep 1990 | WO |
| 1990011064 | Oct 1990 | WO |
| 1993017686 | Sep 1993 | WO |
| 1994022426 | Oct 1994 | WO |
| 1995005807 | Mar 1995 | WO |
| 1995030409 | Nov 1995 | WO |
| 1996009826 | Apr 1996 | WO |
| 1996019975 | Jul 1996 | WO |
| 1996030000 | Oct 1996 | WO |
| 1997005491 | Feb 1997 | WO |
| 1997040823 | Nov 1997 | WO |
| 1997043989 | Nov 1997 | WO |
| 1998010293 | Mar 1998 | WO |
| 1998032465 | Jul 1998 | WO |
| 1998041217 | Sep 1998 | WO |
| 1998051280 | Nov 1998 | WO |
| 199922680 | May 1999 | WO |
| 1999032072 | Jul 1999 | WO |
| 1999039700 | Aug 1999 | WO |
| 1999042109 | Aug 1999 | WO |
| 1999043304 | Sep 1999 | WO |
| 1999048477 | Sep 1999 | WO |
| 1999052528 | Oct 1999 | WO |
| 1999053910 | Oct 1999 | WO |
| 1999055333 | Nov 1999 | WO |
| 1999062497 | Dec 1999 | WO |
| 1999063974 | Dec 1999 | WO |
| 2000001351 | Jan 2000 | WO |
| 2000006175 | Feb 2000 | WO |
| 2000038659 | Jun 2000 | WO |
| 2000045795 | Aug 2000 | WO |
| 2000050007 | Aug 2000 | WO |
| 2000059577 | Oct 2000 | WO |
| 2000076522 | Dec 2000 | WO |
| 2001037808 | May 2001 | WO |
| 2001054699 | Aug 2001 | WO |
| 2001060325 | Aug 2001 | WO |
| 2001087276 | Nov 2001 | WO |
| 2001091757 | Dec 2001 | WO |
| 2002007700 | Jan 2002 | WO |
| 2002011768 | Feb 2002 | WO |
| 2002022132 | Mar 2002 | WO |
| 2002040008 | May 2002 | WO |
| 2002041878 | May 2002 | WO |
| 2002053131 | Jul 2002 | WO |
| 2002078602 | Oct 2002 | WO |
| 2002078604 | Oct 2002 | WO |
| 2003028667 | Apr 2003 | WO |
| 2003041718 | May 2003 | WO |
| 2003041741 | May 2003 | WO |
| 2003068186 | Aug 2003 | WO |
| 2003077923 | Sep 2003 | WO |
| 2003082254 | Oct 2003 | WO |
| 2003092588 | Nov 2003 | WO |
| 2004014397 | Feb 2004 | WO |
| 2004014432 | Feb 2004 | WO |
| 2004017983 | Mar 2004 | WO |
| 2004032897 | Apr 2004 | WO |
| 2004032942 | Apr 2004 | WO |
| 2004052336 | Jun 2004 | WO |
| 2004054540 | Jul 2004 | WO |
| 2004054576 | Jul 2004 | WO |
| 2004080413 | Sep 2004 | WO |
| 2004105694 | Dec 2004 | WO |
| 2004110402 | Dec 2004 | WO |
| 2004110408 | Dec 2004 | WO |
| 2005027911 | Mar 2005 | WO |
| 2005030175 | Apr 2005 | WO |
| 2005081825 | Sep 2005 | WO |
| 2005087194 | Sep 2005 | WO |
| 2005087199 | Sep 2005 | WO |
| 2005105059 | Nov 2005 | WO |
| 2005115335 | Dec 2005 | WO |
| 2005120470 | Dec 2005 | WO |
| 2005120517 | Dec 2005 | WO |
| 2006013369 | Feb 2006 | WO |
| 2006034090 | Mar 2006 | WO |
| 2006036899 | Apr 2006 | WO |
| 2006053172 | May 2006 | WO |
| 2006105615 | Oct 2006 | WO |
| 2006113505 | Oct 2006 | WO |
| 2006138686 | Dec 2006 | WO |
| 2006138735 | Dec 2006 | WO |
| 2007045027 | Apr 2007 | WO |
| 2007076144 | Jul 2007 | WO |
| 2007103294 | Sep 2007 | WO |
| 2007120868 | Oct 2007 | WO |
| 2007123790 | Nov 2007 | WO |
| 2007124250 | Nov 2007 | WO |
| 2007144151 | Dec 2007 | WO |
| 2008049516 | May 2008 | WO |
| 2008152444 | Dec 2008 | WO |
| 2009002542 | Dec 2008 | WO |
| 2009036311 | Mar 2009 | WO |
| 2009040818 | Apr 2009 | WO |
| 2009069006 | Jun 2009 | WO |
| 2009098072 | Aug 2009 | WO |
| 2009133352 | Nov 2009 | WO |
| 2010033188 | Mar 2010 | WO |
| 2010146872 | Dec 2010 | WO |
| 2011000210 | Jan 2011 | WO |
| 2011073995 | Jun 2011 | WO |
| 2011120084 | Oct 2011 | WO |
| 2011128336 | Oct 2011 | WO |
| 2012009778 | Jan 2012 | WO |
| 2012024361 | Feb 2012 | WO |
| 2012055814 | May 2012 | WO |
| 2012055840 | May 2012 | WO |
| 2012065740 | May 2012 | WO |
| 2012098090 | Jul 2012 | WO |
| 2012116277 | Aug 2012 | WO |
| 2012118563 | Sep 2012 | WO |
| 2012120365 | Sep 2012 | WO |
| 2012127501 | Sep 2012 | WO |
| 2012156561 | Nov 2012 | WO |
| 2012156822 | Nov 2012 | WO |
| 2012158483 | Nov 2012 | WO |
| 2012166909 | Dec 2012 | WO |
| 2012170578 | Dec 2012 | WO |
| 2013011501 | Jan 2013 | WO |
| 2013025449 | Feb 2013 | WO |
| 2013028639 | Feb 2013 | WO |
| 2013035101 | Mar 2013 | WO |
| 2013044067 | Mar 2013 | WO |
| 2013045404 | Apr 2013 | WO |
| 2013059285 | Apr 2013 | WO |
| 2013063279 | May 2013 | WO |
| 2013064620 | May 2013 | WO |
| 2013071281 | May 2013 | WO |
| 2013078422 | May 2013 | WO |
| 2013088254 | Jun 2013 | WO |
| 2013102665 | Jul 2013 | WO |
| 2013106437 | Jul 2013 | WO |
| 2013112947 | Aug 2013 | WO |
| 2013113690 | Aug 2013 | WO |
| 2013124415 | Aug 2013 | WO |
| 2013127727 | Sep 2013 | WO |
| 2013127728 | Sep 2013 | WO |
| 2013144356 | Oct 2013 | WO |
| 2013149258 | Oct 2013 | WO |
| 2013158454 | Oct 2013 | WO |
| 2013170052 | Nov 2013 | WO |
| 2013178587 | Dec 2013 | WO |
| 2013181449 | Dec 2013 | WO |
| 2013192248 | Dec 2013 | WO |
| 2013192249 | Dec 2013 | WO |
| 2013192250 | Dec 2013 | WO |
| 2013192251 | Dec 2013 | WO |
| 2014001904 | Jan 2014 | WO |
| 2014004424 | Jan 2014 | WO |
| 2014009434 | Jan 2014 | WO |
| 2014018569 | Jan 2014 | WO |
| 2014018570 | Jan 2014 | WO |
| 2014018571 | Jan 2014 | WO |
| 2014018856 | Jan 2014 | WO |
| 2014018932 | Jan 2014 | WO |
| 2014031958 | Feb 2014 | WO |
| 2014041120 | Mar 2014 | WO |
| 2014052792 | Apr 2014 | WO |
| 2014056897 | Apr 2014 | WO |
| 2014066442 | May 2014 | WO |
| 2014074846 | May 2014 | WO |
| 2014076231 | May 2014 | WO |
| 2014076569 | May 2014 | WO |
| 2014081598 | May 2014 | WO |
| 2014086739 | Jun 2014 | WO |
| 2014093114 | Jun 2014 | WO |
| 2014104784 | Jul 2014 | WO |
| 2015179782 | Nov 2015 | WO |
| 2016018993 | Feb 2016 | WO |
| Entry |
|---|
| US 6,214,374 B1, 04/2001, Schmirler et al. (withdrawn) |
| UNC, “Inserting of suppositories”, Nov. 3, 2008, https://pharmlabs.unc.edu/labs/suppository/inserting.htm, retrieved on Apr. 4, 2021. (Year: 2008). |
| Office Action dated Jan. 30, 2017, in U.S. Appl. No. 14/649,818 Inventors, Bernick, B.A., Jun. 4, 2015, 12 pages. |
| Office Action dated Nov. 2, 2017, in U.S. Appl. No. 14/649,818 Inventors, Bernick, B.A., Jun. 4, 2015, 21 pages. |
| Office Action dated Jun. 15, 2018, in U.S. Appl. No. 14/649,818 Inventors, Bernick, B.A., Jun. 4, 2015, 21 pages. |
| Office Action dated Jun. 3, 2017, in U.S. Appl. No. 14/649,818 Inventors, Bernick, B.A., Jun. 4, 2015, 15 pages. |
| Office Action dated Jan. 5, 2016, in U.S. Appl. No. 14/521,002 Inventors, Bernick, B.A., Oct. 22, 2014, 9 pages. |
| Office Action dated Jan. 6, 2017, in U.S. Appl. No. 14/521,002 Inventors, Bernick, B.A., Oct. 22, 2014, 10 pages. |
| Office Action dated Oct. 5, 2017, in U.S. Appl. No. 14/521,002 Inventors, Bernick, B.A., Oct. 22, 2014, 13 pages. |
| Office Action dated Jul. 20, 2018, in U.S. Appl. No. 14/521,002 Inventors, Bernick, B.A., Oct. 22, 2014, 16 pages. |
| Office Action dated Jun. 3, 2019, in U.S. Appl. No. 14/521,002 Inventors, Bernick, B.A., Oct. 22, 2014, 12 pages. |
| Office Action dated Apr. 2, 2020, in U.S. Appl. No. 14/521,002 Inventors, Bernick, B.A., Oct. 22, 2014, 6 pages. |
| Kingsburg, S.A et al., “Treating dyspareunia caused by vaginal atrophy: a review of treatment options using vaginal estrogen therapy,” International Journal of Women's Health 1:105-111, Dove Press, England (2009). |
| ACTIVELLA® (estradiol/ norethindrone acetate) prescribing information (Nov. 2017) FDA Label, 39 pages. |
| PROMETRIUM® (progesterone, USP) prescribing information (Jun. 2009) FDA Label, 33 pages. |
| VAGIFEM® (estradiol vaginal tablets) prescribing information (Nov. 2009) FDA Label, 14 pages. |
| MacBride, M.B., et al., “Vulvovaginal Atrophy,” Mayo Clinic Proceedings, 85(1): 87-94, Elsevier, Netherlands (2010). |
| De Vries, T.P.G.M., et al., “Guide to Good Prescribing: A Practical Manual,” Essential Medicines and Health Products Information Portal, World Health Organization, Annex 3 (“How to explain the use of some dosage forms”), Checklist 11 (“Vaginal tablet without applicator”) available at https://apps.who.int/iris/handle/10665/59001 (4 pages)(1994). |
| Rioux, J.E., et al “17 beta-Estradiol Vaginal Tablet Versus Conjugated Equine Estrogen Vaginal Cream to Relieve Menopausal Atrophic Vaginitis,” Menopause, 7(3): 156-161, The North American Menopause Society, United States (2000). |
| Cicinelli, E. et al “Placement of the vaginal 17 beta-estradiol tablets in the inner or outer one third of the vagina affects the preferential delivery of 17 beta-estradiol toward the uterus or periurethral areas, thereby modifying efficacy and endometrial safety,” Am. J. Obstet. Gynecol, 189: 55-58 (2003). |
| Office Action dated Apr. 30, 2021, in U.S. Appl. No. 16/834,780, Bernick, B. A., et al., filed Apr. 30, 2021, 13 pages. |
| Office Action dated Jun. 25, 2020, in U.S. Appl. No. 16/834,844, Bernick, B. A., et al., filed Mar. 30, 2020, 12 pages. |
| Notice of Allowance dated Aug. 21, 2020, in U.S. Appl. No. 16/834,844, Bernick, B. A., et al., filed Mar. 30, 2020, 6 pages. |
| Office Action dated Aug. 7, 2020, in U.S. Appl. No. 16/833,213, Bernick, B. A., et al., filed Mar. 27, 2020, 14 pages. |
| Bassi, P., and Kaur, G., “Innovations in bioadhesive vaginal drug delivery system,” Expert Opinion on Therapeutic Patents 22(9): 1019-1032, Taylor and Francis Ltd., United Kingdom (published online Aug. 2012, published in print Sep. 2012). |
| Office Action dated Apr. 8, 2021, in U.S. Appl. No. 16/833,188, Bernick, B. A., et al., filed Mar. 27, 2020, 16 pages. |
| UNC School of Pharmacy, “Preparation of Suppositories,” PharmLabs.unc.edu, accessed at http://pharmlabs.unc.edu/labs/suppository/inserting.htm on Apr. 16, 2021, 1 page. |
| Final Office Action dated Oct. 8, 2021, in U.S. Appl. No. 16/834,780, Bernick, B. A., et al., filed Mar. 30, 2020, 12 pages. |
| Notice of Allowance dated Oct. 7, 2020, in U.S. Appl. No. 16/833,213, Bernick, B. A., et al., filed Mar. 27, 2020, 5 pages. |
| Gullapalli, R.P., “Soft Gelatin Capsules (Softgels),” J. Pharm. Sci., 99, No. 10, Oct. 2010. |
| Office Action dated Nov. 27, 2020, in U.S. Appl. No. 16/837,929, Bernick, B. A., et al., filed Apr. 1, 2020, 15 pages. |
| Notice of Allowance dated Mar. 12, 2021, in U.S. Appl. No. 16/837,929, Bernick, B. A., et al., filed Apr. 1, 2020, 8 pages. |
| Office Action dated Jul. 10, 2020, in U.S. Appl. No. 16/837,937, Bernick, B. A., et al., filed Apr. 1, 2020, 14 pages. |
| Final Office Action dated Nov. 30, 2020, in U.S. Appl. No. 16/837,937, Bernick, B. A., et al., filed Apr. 1, 2020, 15 pages. |
| Notice of Allowance dated Mar. 17, 2021, in U.S. Appl. No. 16/837,937, Bernick, B. A., et al., filed Apr. 1, 2020, 7 pages. |
| Office Action dated Oct. 6, 2020, in U.S. Appl. No. 16/837,933, Bernick, B. A., et al., filed Apr. 1, 2020, 14 pages. |
| Final Office Action dated Feb. 4, 2021, in U.S. Appl. No. 16/837,933, Bernick, B. A., et al., filed Apr. 1, 2020, 15 pages. |
| Notice of Allowance dated Mar. 12, 2021, in U.S. Appl. No. 16/837,933, Bernick, B. A., et al., filed Apr. 1, 2020, 7 pages. |
| Office Action dated Apr. 30, 2021 in U.S. Appl. No. 16/875,030, Bernick, B. A., et al., filed May 15, 2020, 17 pages. |
| Dugal et al., “Comparison of usefulness of estradiol vaginal tablets and estriol vagitories for treatment of vaginal atrophy” Acta Obstericia et Gynecologia Scandinavica, 79, 2000, pp. 293-297. |
| Office Action dated Apr. 8, 2021, in U.S. Appl. No. 16/677,831, Bernick, B. A., et al., filed Nov. 8, 2019, 19 pages. |
| Rodriguez-Tenreiro, C. et al., “Cyclodextrin/carbopol micro-scale interpenetrating networks for dmg delivery” J. of Controlled Release 123, 2007, pp. 56-66. |
| Rodriguez-Tenreiro, C. et al., “Estradiol sustained release from high affinity cyclodextrin hydrogels” Eur. J. of Pharmaceutics and Biopharmaceutics 66, 2007, 55-62. |
| Notice of Allowance dated Sep. 8, 2020, in U.S. Appl. No. 14/521,002, Bernick, B. A., et al., filed Oct. 22, 2014, 6 pages. |
| Office Action dated Apr. 7, 2021, in U.S. Appl. No. 16/746,434, Bernick, B. A., et al., filed Jan. 17, 2020, 14 pages. |
| Notice of Allowance dated Oct. 6, 2021 in U.S. Appl. No. 16/746,434, Bernick, B. A., et al., filed Jan. 17, 2020, 10 pages. |
| Notice of Allowance dated Oct. 20, 2021 in U.S. Appl. No. 16/677,831, Bernick, B. A., et al., filed Oct. 20, 2021, 7 pages. |
| Notice of Allowance dated Oct. 6, 2021 in U.S. Appl. No. 16/833,188, Bernick, B. A., et al., filed Mar. 27, 2020, 10 pages. |
| Abbas et al., “Regression of endometrial implants treated with vitamin D3 in a rat model of endometriosis,” European J of Pharma, Elsevier, 2013, 715:72-75. |
| Abitec, CapmulMCM, EP, Technical Data Sheet, version 10, 2014, Columbus, OH, 1 page. |
| Abitec, CapmulMCM, NF, Technical Data Sheet, version 6, 2014, Columbus, OH. 1 page. |
| Abitec, CapmulMCM, Safety Data Sheet, 2011, Janesville, WI, 5 pages. |
| Abitec, CapmulMCM, Technical Data Sheet, version 17, 2014, Columbus, OH, 1 page. |
| Abitec, CapmulPG8, CAS No. 31565-12-5, version 11, 2006, Columbus, OH, 2 pages. |
| Abitec, Excipients for the Pharmaceutical Industry—Regulatory and Product Information, 2013, 2 pages. |
| Acarturk, Fusun, “Mucoadhesive Vaginal Drug Delivery System,” Recent Patents on Drug Delivery & Formulation, 2009, 3:193-205. |
| Alabi et al., “Analysis of Fatty Acid Composition of Thevetia peruviana and Hura crepitans Seed oils using GC-FID,” Fountain Journal of Nat. and Appl. Sciences, 2013, 2(2):32-37. |
| Alexander, KS, Com Oil, CAS No. 8001-30-7, Jan. 2009, 2 pages. |
| Alvarez et al., “Ectopic uterine tissue as a chronic pain generator,” Neuroscience, Dec. 6, 2012, 225:269-282. |
| Application Note FT-IR: JI-Ap-FT0508-008, CD spectra of pharmaceuticals substances—Steroids (2), JASCO International Co., Ltd., 2 pages. |
| Araya-Sibaja, Andrea Manela, et al., “Chemical Properties of Progesterone Selected Refer.,” SciFinder, 2014, American Chemical Society & US Natl. Lib. of Med., 6 pages. |
| Araya-sibaja, andrea m.a., “Morphology Study of Progesterone Polymorphs Prepared by Polymer-Induced Heteronucleation (PIHn),” Scanning, 2013, 35:213-21, Wiley Period., Inc. |
| Araya-sibaja, andrea manela, et al., “Polymorphism in Progesterone Selected References,” SciFinder, Feb. 24, 2014, pp. 1-12, American Chem. Society & Natl. Lib. of Med. |
| Araya-sibaja, andrea manela, et al., “Polymorphism in Progesterone,” SciFinder, Feb. 24, 2014, pp. 1-46, American Chem. Society & Natl. Lib. of Med. |
| Araya-sibaja et al., “Crystallization of progesterone polymorphs using polymer-induced heteronucleation (PIHn) method,” Drug Development and Industrial Pharmacy, Early Online, 2014, pp. 1-8. |
| Archer et al., “Effects of ospemifene on the female reproductive and urinary tracts: translation from preclinical models into clinical evidence,” Menopause: The Journal of the North American Menopause Society, 2015, 22(77):1-11. |
| Archer et al., “Estrace® vs Premarin® for Treatment of Menopausal Symptoms: Dosage Comparison Study,” Advances In Therapy®, Jan./Feb. 1992, 9(1):21-31. |
| Ashburn et al., “Cardiovascular, Hepatic and Renal Lesions in Mice Receiving Cortisone, Estrone and Progesterone,” Yale J Bilogy and Medicine, Feb. 1963, 35:329-340. |
| Azeem, adnan et al., “Microemulsions as a Surrogate Carrier for Dermal Drug Delivery” (abstract only), Drug Development and Industrial Pharmacy, May 2000, 35(5):525-547 http://informahealthcare.com/doi/abs/10.1080/03639040802448646. |
| Azure Pharma, Inc., ELESTRINTM—Estradiol Gel, Drug Info, http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=11885, Aug. 2009, 25 pages. |
| Bakhmutova-albert, Ekaterina, et al., “Enhancing Aqueous Dissolution Rates of Progesterone via Cocrystallization,” SSCI, Division of Aptuit, Poster No. R6247, West Lafayette (publicly available before application filing date of Oct. 22, 2014), 1 page. |
| Banerjee, Sila, et al., On the Stability of Salivary Progesterone Under Various Conditions of Storage, Steroids, Dec. 1985, 46(6):967-974. |
| Barnett, Steven M, “Pressure-tuning infared and solution Raman spectroscopic studies of 17β-estradiol and several A-ring . . . ,” Vibrational Spectroscopy 8, Elsevier, 1995, pp. 263-277. |
| Bartosova, “Transdermal Drug Delivery In Vitro Using Diffusion Cells,” Current Medicinal Chemistry, 2012, 19:4671-4677, Bentham Science Publishers. |
| Benbow et al., “Distribution and Metabolism of Maternal Progesterone in the Uterus, Placenta, and Fetus during Rat Pregnancy,” Biology of Reproduction, 1995, 52:1327-1333. |
| Bernabei et al., “Release of progesterone polymorphs from dimethylpoly siloxane polymeric matrixes,” Bollettino Chimico Farmaceutico, 1983, 122(1):20-6, SciFinder (abstract only). |
| Bhavnani et al., “Misconception and Concerns about Bioidentical Hormones Used for Custom-Compounded Hormone Therapy,” J Clin Endocrin Metab, first published ahead of print Dec. 28, 2011 as doi: 10.1210/jc.2011-2492, Mar. 2012, 97(3), 4 pages. |
| Bhavnani et al., “Structure Activity Relationships and Differential Interactions and Functional Activity of Various Equine Estrogens Mediated via Estrogen Receptors (ERs) ERα and ERβ,” Endocrinology, Oct. 2008, 149(10):4857 4870. |
| Bhavnani, b.r., Stanczyk, f.z., “Pharmacology of conjugated equine estrogens: Efficacy, safety and mechanism of action,” J. Steroid Biochem. Mol. Biol., 2013, 14 pages. Elsevier. |
| Bhavnani, B.R., Stanczyk, F.Z., “Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: Is it safe?, ” J. Steroid Biochem. Mol. Biol., 2013, 9 pages, Elsevier. |
| BioMed Central, Solubility of Progesterone in Organic Solvents, Online PDF, http://www.biomedcentral.com/content/supplementary/1475-2859-11-106-S2.pdf, 1 page (publicly available before application filing date of Oct. 22, 2014). |
| Blake et al., “Single and multidose pharmacokinetic study of a vaginal micronized progesterone insert (Endometrin) compared with vaginal gel in healthy reproductiveaged female subjects,” Fertility and Sterility#, 94(4), Sep. 2010, Elsevier, 6 pages. |
| Borka, laszlo, “Crystal Polymorphism of Pharmaceuticals,” Acta Pharm. Jugosl., 1990, 40:71-94. |
| Brandstatter-kuhnert, M, “Zur mikroskopischen Identitatsprufung und zur Polymorphie der Sexualhormone,” Acta, vol. 6, pp. 847-853, 1959, Univ. Innsbruck. |
| Brinton, l.a., felix, a.s., “Menopausal hormone therapy and risk of endometrial cancer,” 2013, J. Steroid Biochem. Mol. Biol., Elsevier, 7 pages. |
| British Pharmacopoeia 2014 Online, Refined Maize Oil, Ph. Eur. Monograph 1342, vol. I & II, Monographs: Medicinal and Pharmaceutical Substances, http://www.pharmacopoeia.co.uk/bp2014/ixbin/bp.cgi?a=print&id=7400&tab=a-z%20index[Feb. 3, 2014 1:37:50 PM], 2 pages. |
| Burry, “Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen,” Am J Obstet Gynecol, 1999, vol. 180(6) part 1, pp. 1504-1511. |
| Busetta, “Structure Cristalline et Moleculair de 1'Oestradiol Hemihydrate,” Acta Cryst., B28 pp. 560, 1972, Bis(dimethyl-o-thiolophenylarsine)palladium(II). |
| Busetta, “Structure Cristalline et Moleculaire du Complexe Oestradiol-Propanol,” Acta Cryst., B28 pp. 1349, 1972, J.A. Kanters and J. Kroon. |
| Campsteyn et al., “Structure Cristalline et Moleculaire de la Progesterone C21H30O2,” Acta Cryst., B28 pp. 3032-3042, 1972 (with English abstract). |
| Cendejas-Santana et al., “Growth and characterization of progesterone crystallites,” Revista Mexicana de Fisica, 2004, 50, Suplemento 1 pp. 1-3. |
| ChemPro, Top-Notch Technology in Production of Oils and Fats, Chempro-Edible-Oil-Refining-ISO-TUV-Austria, 3 pages (publicly available before application filing date of Oct. 22, 2014). |
| Christen et al., “Phase I/Pharmacokinetic Study of High-Dose Progesterone and Doxorubicin,” J Clin Oncol, 1993, 11:2417-2426. |
| Christensson et al., “Limonene hydroperoxide analogues differ in allergenic activity,” Contact Dermatitis 2008, 59:344-352. |
| Christensson et al., “Limonene hydroperoxide analogues show specific patch test reactions,” Contact Dermatitis, 2014, 70, 291-299. |
| Christensson et al., “Positive patch test reactions to oxidized limonene: exposure and relevance,” Contact Dermatitis, 2014, 71, 264-272. |
| Chun et al., “Transdermal Delivery of Estradiol and Norethrindrone Acetate: Effect of Vehicles . . . , ” J. Kor. Pharm. Sci., 2005, 35(3):173-174. |
| Cicinelli et al., “Direct Transport of Progesterone From Vagina to Uterus, Obstetrics & Gynecology,” 95(3), Mar. 2000, pp. 403-406. |
| Cole, Wayne & Julian, Percy l, Sterols. I. A Study of the 22-Ketosteroids, Cont. of the Research Lab. of the Glidden Co., Soya Prod. Div., vol. 67 pp. 1369-1375, Aug. 1945, Chicago. |
| Committee Opinion, Incidentally Detected Short Cervical Length, Committee of Obstetric Practice, Obstetrics & Gynecology, Acog, vol. 119, No. 4, Apr. 2012, pp. 879-882. |
| Commodari, Fernando, “Comparison of 17β-estradiol structures from x-ray diffraction and solution NMR,” Magn. Reson. Chem., 2005, 43:444-50, Wiley InterScience. |
| Cooper et al., “Systemic absorption of progesterone from Progest cream in postmenopausal women,” The Lancet, vol. 351, pp. 1255-1256, Research Letters, Apr. 25, 1998. |
| Corbett et al., “Trends in Pharmacy Compounding for Women's Health in North Carolina: Focus on Vulvodynia,” Southern Medical Journal, Jul. 2014, 107(7):433-436. |
| Corn Refiners Association, Corn Oil, 5th Edition, Washington, D.C., 2006, 24 pages. |
| Critchley et al., “Estrogen Receptor β, But Not Estrogen Receptor α, Is Present in the Vascular Endothelium of the Human and Nonhuman Primate Endometrium,” The Journal of Clinical Endocrinology & Metabolism, 2001, 86(3): 1370-1378. |
| Dauqan, Eqbal m. A., et al., “Fatty Acids Composition of Four Different Vegetable Oils (Red Palm Olein, Palm Olein, Corn Oil,” IPCBEE, vol. 14, 2011, pp. 31-34 IACSIT Press, Singapore. |
| Dideberg et al., “Crystal data on progesterone (C21H30O2), desoxycorticosterone (C21H30O3), corticosterone (C21H30O4) and aldosterone . . . ,” J. Appl. Cryst., 1971, 4:80. |
| Diramio, “Polyethylene Glycol Methacrylate/Dimetacrylate Hydrogels for Controlled Release of Hydrophobic Drugs,” Masters of Science Thesis, University of Georgia, Athens, Georgia, 2002, 131 pages. |
| Drakulic, “Role of complexes formation between drugs and penetration enhancers in transdermal . . . ,” Inter. Journal of Pharmaceutics, Elsevier, 2009, 363:40-49. |
| Du 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: The Journal of the North American Menopause Society, 2013, 20(11):1-7. |
| Duax et al., “Conformation of Progesterone Side Chain: Conflict between X-ray Data and Force-Field Calculations,” J. Am. Chem. Soc., Jun. 1981, 103, pp. 6705-6712. |
| Duclos et al., “Polymorphism of Progesterone: Influence of the carrier and of the solid dispersion manufacturing . . . ,” J. Thermal Anal., 1991, 37:1869-75, Wiley. |
| Ebian, “Ebian Article: Polymorphism and solvation of ethinyl estradiol,” SciFinder, Pharmaceutica Acta Helvetiae, vol. 54(4), pp. 111-114, 1979, Alexandria, Egypt (abstract only). |
| Eisenberger, a., Westhoff, c., “Hormone replacement therapy and venous thromboembolism,” J. Steroid Biochem. Mol. Biol., 2013, Elsevier, 7 pages. |
| Engelhardt et al., “Conceptus Influences the Distribution of Uterine Leukocytes During Early Porcine Pregnancy,” Biology of Reproduction, 2002, 66:1875-1880. |
| Ettinger et al., “Comparison of endometrial growth produced by unopposed conjugated estrogens or by micronized estradiol in postmenopausal women,” Am J Obstet Gynecol 1997, 176:112-117. |
| Excipients for Pharmaceuticals, Sasol Olefins & Surfactants Gmbh, 2010, 28 pages. |
| Faassen, Fried, “Physicochemical Properties and Transport of Steroids across Caco-2 Cells,” Pharmaceutical Research, vol. 20(2), 2003, Plenum Pub. Corp., 10 pages. |
| FDA, Draft Guidance on Progesterone, Recommended Apr. 2010, Revised Feb. 2011 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM209294.pdf, 8 pages. |
| Ferrari, Roseli Ap., et al., “Oxidative Stability of Biodiesel From Soybean Oil Fatty Acid Ethyl Esters,” Sci. Agric., 2005, vol. 62(3), pp. 291-295, Piracicaba, Braz. |
| Filipsson et al., “Concise International Chemical Assessment Document 5: Limonene,” first draft, World Health Organization, Geneva, 1998, 36 pages. |
| Final Report on the Safety Assessment of BHT, International Journal of Toxicology, 2002, 21(Suppl. 2):19-94. |
| Flyvholm, “Sensitizing risk of butylated hydroxytoluene based on exposure and effect data,” Contact Dermatitis, 1990:23:341-345. |
| Fotherby, “Bioavailability of Orally Administered Sex Steroids Used in Oral Contraception and Hormone Replacement Therapy,” Contraception, 1996; 54:59-69. |
| Franklin et al., “Characterization of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones,” Journal of Reproductive Immunology, 1999, 42: 93-106, Elsevier. |
| Franz et al., “Use of Excised Human Skin to Assess the Bioequivalence of Topical Products,” Skin Pharmacol Physiol 2009, 22:276-286. |
| Freedman, “Menopausal hot flashes: Mechanisms, endocrinology, treatment,” J. Steroid Biochem. Mol. Biol., 2013, 6 pages, Elsevier. |
| Fuchs et al., “The Effects of an Estrogen and Glycolic Acid Cream on the Facial Skin of Postmenopausal Women: A Randomized Histologic Study,” Cutis. Jun. 2003, 71(6):481-8. |
| Fugh-Berman, Adriane, “Bioidentical Hormones for Menopausal Hormone Therapy: Variation on a Theme, Journal of General Internal Medicine,” 2007, vol. 1030-34. |
| Furness et al.,“Hormone therapy in postmenopausal women and risk of endometrial hyperplasia (Review),” 2012, 208 pages, The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. |
| Gäfvert et al., “Free radicals in antigen formation: reduction of contact allergic response to hydroperoxides by epidermal treatment with antioxidants,” British Journal of Dermatology, 2002, 146:649-656. |
| Ganam-Quintanar et al., “Evaluation of the transepidermal permeation of diethylene glycol monoethyl ether and skin water loss,” International Journal of Pharmaceutics, 147(2), Feb. 28, 1997, pp. 165-171 (abstract only). |
| Gattefossé SAS, Material Safety Data Sheet, Gelot 64, 2012, 8 pages. |
| Gattefossé SAS, Regulatory Data Sheet, Gelot 64, 2012, 6 pages. |
| Gattefossé SAS, Regulatory Data Sheet, Lauroglycol 90, 2012, 5 pages. |
| Gattefossé, “Excipients for Safe and Effective Topical Delivery, Drug Development and Delivery” Jul./Aug. 2012, http://drug-dev.com/Main/Back-Issues/Transdermal-Topical-Sutecutaneous-NonInvasive-Deliv-5.aspx#, 2 pages. |
| Gillet et al., “Induction of amenorrhea during hormone replacement therapy: optimal micronized progesterone dose,” A multicenter study, 1994, Maturitas, 19:103-115. |
| Giron-Forest et al., “Thermal analyis methods for pharmacopoeial materials,” J. Pharmaceutical & Biomedical Anal., 1989, vol. 7(12) pp. 1421-1433, Pergamon Press, Gr. Britain. |
| Giron-Forest, “Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates,” Thermochimica Acta, 1995, 248:1-59, Elsevier. |
| Glaser 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,” Gynecol Obstet Invest 2008; 66:111-118. |
| Golatowski et al., “Comparative evaluation of saliva collection methods for proteome analysis,” Clinica Chimica Acta, 2013, 419:42-46. |
| Graham et al., “Physiological Action of Progesterone in Target Tissues, Endocrine Reviews,” 1997, 18(4):502-519. |
| Groothuis et al., “Estrogen and the endometrium: lessons learned from gene expression profiling in rodents and human,” Human Reproduction Update, 2007, 13(4):405-417. |
| Gunstone et al., “Vegetable Oils in Food Technology: Composition, Properties and Uses, Blackwell Publishing,” CRC Press, 2002, 21 pages. |
| Gurney et al., “The Women's Health Initiative trial and related studies: 10 years later: A clinician's view,” J.Steroid Biochem. Mol. Biol., 2013, 8 pages Elsevier. |
| Hamid et al. “The Effects of Common Solubilizing Agents on the Intestinal Membrane Barrier Functions and Membrane Toxicity in Rats,” International Journal of Pharmaceutics, 2009 379:100-108, Elsevier. |
| Haner, “Crystal data (I) for some pregnenes and pregnadienes,” Acta Cryst., 1964, 17:1610. |
| Hapgood et al., “Potency of progestogens used in hormonal therapy: Toward understanding differential actions,” J. Steroid Biochem. Mol. Biol., 2013, Elsevier, 9 pages. |
| Hargrove et al., “Menopausal Hormone Replacement Therapy with Continuous Daily Oral Micronize Estradiol and Progesterone,” Obstet Gynecol, Apr. 1989, 73(4):606-612. |
| Hatton et al., “Safety and efficacy of a lipid emulsion containing medium-chain triglycerides,” Clinical Pharmacy, 1990, 9(5):366-371. |
| He et al., “Apoptotic Signaling Pathways in Uteri of Rats with Endometrial Hyperplasia Induced by Ovariectomy Combined with Estrogen,” Gynecol Obstet Invest 2013;76:51-56. |
| Helbling et al., “The Optimization of an Intravaginal Ring Releasing Progesterone Using a Mathematical Model,” Pharm Res, 2014, 31:795-808, Springer Science. |
| Helmy et al., “Estrogenic Effect of Soy Phytoestrogens on the Uterus of Ovariectomized Female Rats,” Clinic Pharmacol Biopharmaceut, 2014, S2, 7 pages. |
| Henderson, “Alzheimer's disease: Review of hormone therapy trials and implications for treatment and prevention after . . . ,” J. Steroid Biochem. Mol. Biol., 2013, 8 pages, Elsevier. |
| Henriksen et al., “An ENDOR Sturdy of Radiation-Induced Molecular Damage to Progesterone,” Jour. of Mag. Resonance, 1985, 63:333-42, Acedemic Press, Inc. |
| Hodis, H.N., Mack, W.J., “Hormone replacement therapy and the association with heart disease and overall mortality: Clinical . . . ,” J. Steroid Biochem. Mol. Biol., 2013, 8 pages, Elsevier. |
| Hospital et al., “X-ray Crystallography of Estrogens and Their Binding to Receptor Sites,” Mol. Pharmacology, 1972, 8:438-45, Acedemic Press, Inc. |
| Hostynek, “Predicting absorption of fragrance chemicals through human skin,” J. Soc.CosmeCt.hem.,4 6, 221-229, Jul./Aug. 1995. |
| Hulsmann, “Stability of Extruded 17B-Estradiol Solid Dispersions,” Pharmaceutical Development and Tech., 2001, 6(2):223-29, (9 total pages), Marcel Dekker, Inc. |
| Hurn et al., “Estrogen as a Neuroprotectant in Stroke,” Journal of Cerebral Blood Flow and Metabolism, 2000, 20:631-652, Lippincott Williams & Wilkins, Inc., Philadelphia. |
| Hyder et al., “Synthetic Estrogen 17α-Ethinyl Estradiol Induces Pattern of Uterine Gene Expression Similar to Endogenous Estrogen 17β-Estradiol,” JPET, 1999, 290(2):740-747. |
| Idder et al., “Physicochemical properties of Progesterone,” SciFinder, Feb. 24, 2014, pp. 1-26, American Chem. Society & US Natl. Lib. of Med. |
| International Search Report issued in International Application No. PCT/US12/66406, dated Jan. 24, 2013, 3 pages. |
| International Search Report issued in International Application No. PCT/US13/023309, dated Apr. 9, 2013, 12 pages. |
| International Search Report and written Opinion issued in PCT/US/13/46442, dated Nov. 1, 2013, 10 pages. |
| International Search Report and written Opinion issued in PCT/US/13/46443, dated Oct. 31, 2013, 11 pages. |
| International Search Report and written Opinion issued in PCT/US/13/46444, dated Oct. 31, 2013, 10 pages. |
| International Search Report and written Opinion issued in PCT/US/13/46445, dated Nov. 1, 2013, 9 pages. |
| Johanson, “Toxicity Review of Ethylene Glycol Monomethyl Ether and its Acetate Ester,” Critical Reviews in Toxicology, 2000, 30(3):307-345 (abstract only). http://informahealthcare.com/doi/abs/10.1080/10408440091159220. |
| Johnson et al., “Racemic Progesterone,” Tetrahedron Letters No. 4, 1963, pp. 193-196, Pergamon Press Ltd., Great Britain. |
| Joshi et al., “Detection and synthesis of a progestagen-dependent protein in human endometrium,” J Reprod Fert, 1980, 59:273-285. |
| Kanno et al., “The OECD Program to Validate the Rat Uterotrophic Bioassay to Screen Compounds for in Vivo Estrogenic Responses: Phase 1,” Environmental Health Perspectives, Aug. 2001, 109(8):785-794. |
| Karlberg et al., “Air oxidation of d-limonene (the citrus solvent) creates potent allergens,” Contact Dermatitis, 1992:26:332-340. |
| Karlberg et al., “Influence of an anti-oxidant on the formation of allergenic compounds during auto-oxication of d-limonene,” Ann. Occup. Hyg., 1994, 38(2):199-207. |
| Kaunitz, “Extended duration use of menopausal hormone therapy,” Menopause: The Journal of the North American Menopause Society, 2014, 21(6):1-3. |
| Khalil, “Stability and Dissolution Rates of Corticosteroids in Polyethylene Glycol Solid Dispersions,” Drug Dev. & Indus. Pharm., 1984, 10(5):771-87, Marcel Dekker. |
| Kharode 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, 2008, 149(12):6084-6091. |
| Kim et al., “Safety Evaluation and Risk Assessment of d-Limonene,” Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 2013, 16:1, pp. 17-38 http://dx.doi.org/10.1080/10937404.2013.769418. |
| Kincl et al., “Increasing Oral Bioavailability of Progesterone by Formulation,” Journal of Steroid Biochemistry, 1978, 9:83-84. |
| Knuth et al., “Hydrogel delivery systems for vaginal and oral applications: Formulation and biological considerations,” Advanced Drug Delivery Reviews, Jul.-Aug. 1993, 11(1-2):137-167 (abstract only). |
| Koga et al., “Enhancing mechanism of Labrasol on intestinal membrane permeability of the hydrophilic drug gentamicin sulfate,” European Journal of Pharmaceutics and Biopharmaceutics, 2006, 64:82-91. |
| Komm et al., “Bazedoxifene Acetate: A Selective Estrogen Receptor Modulator with Improved Selectivity,” Endocrinology, 2005, 146(9):3999-4008. |
| Korkmaz, “Byophysical Studies of Progesterone-Model Membrane Interactions,” Thesis, Grad. School of Nat. and App. Sci. of the Middle East Tech. University, Sep. 2003, 143 pages. |
| Kotiyan, “Stability indicating HPTLC method for the estimation of estradiol,” Journal of Pharmaceutical and Biomedical Analysis, 2000, 22: 667-671, Elsevier. |
| Krzyminiewski et al., “EPR Study of the Stable Radical in a y-Irradiated Single Crystal of Progesterone,” Jour. of Mag. Resonance, 1982, 46:300-05, Acedemic Press. |
| Kubli-Garfias et al., “Ab initio calculations of the electronic structure of glucocorticoids,” Jour. of Mol. Structure, Theochem, 1998, 454:267-75, Elsevier. |
| Kubli-Garfias, “Ab initio study of the electronic structure of progesterone and related progestins, Jour. of Mol. Structure,” Theochem, 1998, 425:171-79, Elsevier. |
| Kuhnert-Brandstaetter and Kofler, Zur Unterscheidung von losungsmittelhaltigen pseudopolymorphen Kristallformen und polymorphen Modiflkationen bei Steroidhormonen.II. vol. 1 pp. 127-139, 1968, Mikrochimica Acta. |
| Kuhnert-Brandstaetter, M & Lnder, R, Zur Hydratbildung bei Steroidhormonen, Sci. Pharm., vol. 41(2) pp. 109-116, 1973. |
| Kuhnert-Brandstatter, “Thermo-microscopic and spectrophotometric: Determination of steroid hormones,” Microchemical Journal, 1965, 9:105-33. |
| Kumasaka et al., “Effects of Various Forms of Progestin on the the Estrogen-Primed, Ovariectomized Rat,” Endocrine Journal, 1994, 41(2):161-169. |
| Kuon 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,” Am J Obstet Gynecol. Jul. 2011, 205(1): 82.e15-82.e20. |
| Kuon et al., “Actions of progestins for the inhibition of cervical ripening and uterine contractions to prevent preterm birth,” FVV in Obgyn, 2012, 4 (2):110-119. |
| Kuon et al., “Pharmacological actions of progestins to inhibit cervical ripening and prevent delivery depend upon their properties, the route of administration and the vehicle,” Am J Obstet Gynecol. May 2010, 202(5):455.e1-455.e9. |
| 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, 2013, 38:359-67, Elsevier. |
| Lacey, “The WHI ten year's later: An epidemiologist's view,” J. Steroid Biochem. Mol. Biol., 2013, 4 pages, Elsevier. |
| Lahiani-Skiba, “Solubility and Dissolution Rate of Progesterone-Cyclodextrin . . . , Drug Development and Industrial Pharmacy,” Informa Healthcare, 2006, 32:1043-1058. |
| Lancaster et al., “The Polymorphism of Progesterone: Stabilization of a ‘Disappearing’ Polymorph by . . . ,” Jour. of Pharm. Sci., 2007, 96(12):3419-31, Wiley-Liss. |
| Land, “The influence of water content of triglyceride oils on the solubility of steriods,” Pharmaceutical Research, May 2005, 22(5) Springer Science+Business Media, pp. 784-788. |
| Lauer et al., “Evaluation of the hairless rat as a model for in vivo percutaneous absorption,” Journal of Pharmaceutical Sciences, Jan. 1997, 86(1):13-18. |
| Leonetti et al., “Transdermal progesterone cream as an alternative progestin in hormone therapy,” Alternative Therapies, Nov./Dec. 2005, 11(6):36-38. |
| Leonetti, “Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium,” Fertility and Sterility, Jan. 2003, 79(1):221-222. |
| Lewis et al., “Caution on the use of saliva measurements to monitor absorption of progesterone from transdermal creams in postmenopausal women,” Maturitas, The European Menopause Journal, 2002, 41:1-6. |
| Li, “Solid-state NMR analysis of steroidal conformation of 17a- and 17B-estradiol in the absence and presence of lipi . . . ,” Steroids, Elsevier, 2012, 77:185-92. |
| Lobo, Foreword, J. Steroid Biochem. Mol. Biol., 2014, 1 page, Elsevier. |
| López-Belmonte, “Corrigendum to Comparative uterine effects on ovariectomized rats after repeated treatment with different vaginal estrogen formulations,” [Maturitas 72 (2012) 353-358], Maturitas 74, 2013, p. 393, Elsevier. |
| Lucy et al., “Gonadotropin-releasing hormone at estrus: lutenizing hormone, estradiol, and progesterone during, . . . ,” Biol Reprod, Sep. 1986;35(2):300-311 (abstract only). |
| LVova, “Thermal Analysis in the Quality Control and Standardization of Some Drugs,” J Thermal Anal., 1993, 40:405-11, Wiley. |
| Madishetti et al., “Development of domperidone bilayered matrix type transdermal patches physicochemical,” in vitro and ex vivo characterization, DARU, 2010, 18(3):221-229. |
| Magness et al., “Estrone, Estradiol-17β and Progesterone Concentrations in Uterine Lymph and Systematic Blood throughout the Porcine Estrone Estrous Cycle,” Journal of Animal Science, 1983, 57:449-55, ISU. |
| Mcguffy, “Softgel Technology as a Lipid-Based Delivery Tool for Bioavailability Enhancement,” Catalent Pharma Solutions, Somerset, NJ, Mar. 2011, 35 pages. |
| Estradiol, The Merck Index Online, Royal Society of Chemistry, https://www.rsc.org/Merck-Index/monograph/mono1500003758/estradiol?q=unauthorize, 2013, 2 pages. |
| Progesterone, The Merck Index Online, Royal Society of Chemistry, 2013, search Feb. 17, 2014 https://www.rsc.org/Merck-Index/monograph/print/mono1500007889/progesterone?q=authorize, 2 pages. |
| Mesley, “Clathrate Formation from Steroids,” Chemistry and Industry, Sep. 1965, 37:1594-95. |
| Miao et al., “Chemical Properties of Progesterone,” SciFinder, 2014, American Chemical Society & US Natl. Lib. of Med., 36 pages. |
| Miles et al., “Pharmacokinetics and endometrial tissue levels of progesterone after administration bv'Intramuscular and vaginal routes: a comparative study,” Fertility and Sterility, Sep. 1994, 62(3):485-490. |
| Miller et al., “Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast,” Journal of Cancer Therapy, 2012, 3:749-754. |
| Mueck et al., “Genomic and non-genomic actions of progestagens in the breast,” J. Steroid Biochem. Mol.Biol, 2013, Elsevier, 6 pages. |
| Muramatsu, “Thermodynamic Relationship between a- and B—Forms of Crystalline Progesterone,” J. Pharmaceutical Sciences, 1979, 68(2):175-76, Amer. Pharm. Assoc. |
| Ng et al., “Advances in biodiesel fuel for application in compression ignition engines,” Clean Techn Environ Policy, 2010, 12:459-93, Springer-Verlag. |
| Nicklas, “Preparation and characterization of marine sponge collagen nanoparticles and employment for the trans . . . ,” Drug Devel. & Indust. Pharmacy, 2009, 35(9):1035-1042. |
| Nilsson et al., “Analysis of Contact Allergenic Compounds in Oxidized d-Limonene,” Chromatographia, Feb. 1996, 42(3/4):199-205. |
| Notelovitz et al., “Initial 17-b-Estradiol Dose for Treating Vasomotor Symptoms, Obstetrics & Gynecology,” vol. 95(5):726-31, part 1, May 2000, Elsevier. |
| NuGen, What is NuGen HP Hair Growth System, accessed from the Internet on Mar. 7, 2013, copyright 1997-2013, 3 pages. |
| NuGest900, NuGest 900™, accessed Mar. 5, 2013, copyright 1998-2009, 4 pages. |
| O'leary, “Salivary, but not serum or urinary levels of progesterone are elevated after topical application of pregersterone cream to pre-and post-menopausal women,” Clinical Endocrinology, 2000, 53: 615-20, Blackwell Science (abstract only). |
| Open Notebook, Science Solubility Challenge, Jul. 16, 2013, Solubility of progesterone in organic solvents, http://lxsrv7.oru.edu/˜alang/onsc/solubility/allsolvents.php?solute=progesterone, 1 page. |
| Opinion on the Diethylene Glycol Momoethyl Ether (DEGEE), Scientific Committee on Consumer Products, Dec. 19, 2006, 27 pages. |
| Outterson, “The Drug Quality and Security Act—Mind the Gaps,” NEngl J med , Jan. 9, 2014, 370(2):97-99, nejm.org. |
| Palamakula et al., “Preparation and In Vitro Characterization of Self-Nanoemulsified Drug Delivery Systems of Coenzyme Q10 Using Chiral Essential Oil Components,” Pharmaceutical Technology Oct. 2004, pp. 74-88. |
| Panay 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, 11 pages. |
| Panchangnula et al., “Development and evaluation of an intracutaneous depot formulation of corticosteroids using Transcutol . . . ,” J Pharm Pharmacol. Sep. 1991, 43(9):609-614 (abstract only). |
| Parasuraman et al., “Blood sample collection in small laboratory animals,” Journal of Pharmacology & Pharmacotherapeutics, Jul.-Dec. 2010, 1(2):87-93. |
| Park, “Solvent effects on physicochemical behavior of estradiols recrystalized for transdermal delivery,” Arch Pharm Res, 2008, 31(1): 111-16. |
| Park, “Use of CP/MAS solid-state NMR for the characterization of solvate . . . ,” European Journal of Pharmaceutics and Biopharmaceutics, 2005, 60:407-12. |
| Parrish, “A new estra—1,3,5(10)-triene-3,17b-diol solvate: estradiol-methanol-water, Crystal Structure Comm.,” Intn'l Union of Crystallography, ISSN 0108-2701, 2003, pp. o80-o82. |
| Patel et al., “Transdermal Drug Delivery System: A Review,” www.thepharmajournal.com, vol. 1, No. 4, 2012, pp. 78-87. |
| Payne et al., “Examples of successful crystal structure prediction: polymorphs of primidone and progesterone,” Intl. Jourl of Pharma., 1999, 177:231-45, Elsevier. |
| PCCA, Apothogram, PCCA, May 2014, 14 pages, Houston, TX. |
| Persson et al., “Physicochemical Properties of Progesterone Selecte,” SciFinder, pp. 1-5, Feb. 24, 2014, American Chem. Society & US Natl. Lib. of Med. |
| Pfaus et al., “Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist,” PNAS, Jul. 6, 2004, 101(27):10201-10204. |
| Pheasant, “Polymorphism of 17-Ethinylestradiol, Schering Corporation,” Bloomfield, NJ, May 1950, pp. 4303-4304. |
| Pickles, “Cutaneous reactions to injection of progesterone solutions into the skin,” Br Med Journal, Aug. 16, 1952, pp. 373-374. |
| Pinkerton et al., “What are the concerns about custom-compounded “bioidentical” hormone therapy?” Menopause: The Journal of the North American Menopause Society, 2014, 21(12):1-3. |
| Pinkerton, J.V., Thomas, S., “Use of SERMs for treatment in postmenopausal women,” J. Steroid Biochem. Mol. Biol., 2014, 13 pages Elsevier. |
| Pisegna, “A High-pressure Vibrational Spectroscopic Study of Polymorphism in Steroids . . . ,” Thesis, McGill University, Dept. of Chem, Nov. 1999, Natl. Lib. of Canada, 134 pages. |
| Position Statement, Management of symptomatic vulvovaginal atrophy: 2013 position statement of the North American Menopause Society (NAMS), Menopause, 2013, 20(9):888-902. |
| Practice Bulletin No. 141, Management of Menopausal Symptoms, Obstetrics & Gynecology, Acog, Jan. 2014, 123(1): 202-216. |
| Prajapati et al., “A comparative Evaluation of Mono-, Di- and Triglyceride of Medium Chain Fatty Acids by Lipid/Surfactant/Water Phase Diagram, Solubility Determination and Dispersion Testing for Application in Pharmaceutical Dosage Form Development,” Springerlink.com, Apr. 2011, 21 pages. |
| Prausnitz et al., “Transdermal drug delivery,” Nat Biotechnol. Nov. 2008 ; 26(11), 18 pages. |
| Price, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Adv. Drug Delivery Reviews, 2004, 56:301-19, Elsevier. |
| Product Information Sheet, Body Balance Cream, Tahitian Noni International, 2013, 1 page. |
| Product Safety Assessment: Diethylene Glycol Monoethyl Ether, Created: Sep. 24, 2007 the Dow Chemical Company Page, 5 pages. |
| Progynova TS 100, available online at file:///C:/Users/Call%20Family/Desktop/Progynova%/20TS%20100%2012%20Patches_Pack%20%28Estradiol%20Hemihydrate%29.html, 2010, 6 pages. |
| Provider Data Sheet, About Dried Blood Spot Testing, ZRT Laboratory, 2014, 3 pages. |
| Rahn et al., “Vaginal Estrogen for Genitourinary Syndrome of Menopause a Systematic Review,” Obstet Gynecol, 2014, 124(6):1147-56. |
| Reisman et al., “Topical Application of the Synthetic Triterpenoid RTA 408 Protects Mice from Radiation-Induced Dermatitis,” Radiation Researc, 2014, 181:512-520. |
| Rosilio et al., “Physical Aging of Progesterone-Loaded Poly(D,L,-lactide-co-glycolide) Microspheres,” Pharmaceutical Research, 1998, 15(5):794-99, Plenum Pub. Corp. |
| Ross et al., “Randomized, double-blind, dose-ranging study of the endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women,” AnnJ Obstet Gynecol, Oct. 1997, 177(4):937-941. |
| Ruan et al., “Systemic progesterone therapy—Oral, vaginal, injections and even transdermal?” Maturitas, 2014, 79:248-255, Elsevier. |
| Salem, “Sustained-release progesterone nanosuspension following intramuscular injection in ovariectomized rats,” International Journal of Nanomedicine 2010, 5:943-954, Dove Press. |
| Salole, “Estradiol, Analytical Profiles of Drug Substances,” 1986, 15:283-318. |
| Salole, “The physicochemical properties of oestradiol, Journal of Pharmaceutical & Biomedical Analysis,” 1987, 5(7):635-648. |
| Santen, “Menopausal hormone therapy and breast cancer,” J. Steroid Biochem. Mol. Biol., 2013, Elsevier, 10 pages. |
| Santen, “Vaginal administration of estradiol: effects of dose, preparation and timing on plasma estradiol levels,” CLIMACTERIC, 2014; 17:1-14. |
| Sarkar et al., “Chemical Stability of Progesterone in Compounded Topical Preparations using PLO Transdermal Cream™ and HRT Cream™ Base . . . ,” J Steroids Horn Sci, 2013, 4:2, 3 pages. |
| Sarrel et al., “The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years,” American Journal of Public Health, Research and Practice, Published online ahead of print Jul. 18, 2013, pp. e1-e6. |
| Satyanarayana et al., “Aqueous Solubility Predictions of Aliphatic Alcohols, Alkyl Substituted Benzoates and Steroids,” Asian J. Chem., 1997, 9(3):418-26. |
| Scavarelli et al., “Progesterone and Hydrate or Solvate,” SciFinder, pp. 1-2, Feb. 24, 2014, American Chem. Society. |
| Schindler, “The “newer” progestogens and postmenopausal hormone therapy (HRT),” J. Steroid Biochem.Mol. Biol., 2013, Elsevier, 4 pages. |
| Schutte et al., “A tissue engineered human endometrial stroma that responds to cues for secretory differentiation, decidualization and menstruation,” Fertil Steril, Apr. 2012 ; 97(4):997-1003, Elsevier. |
| Schweikart et al., “Comparative Uterotrophic Effects of Endoxifen and Tamoxifen in Ovariectomized Sprague-Dawley Rats, Toxicologic Pathology,” 2014, 42: 1188-1196. |
| SciFinder Scholar Prednisone Chemical Properties, SciFinder, 2014, pp. 1-7, National Library of Medicine. |
| SciFinder Scholar Prednisone Physical Properties, SciFinder, 2014, pp. 1-10, Natioinal Library of Medicine. |
| SciFinder Scholar Progesterone Experimental Properties, SciFinder, pp. 1-9, Feb. 24, 2014, American Chem. Society. |
| Serantoni et al., “4-Pregnen-3,20-dione (progesterone, form II),” Crystal Structure Comm., 1975, 4(1):189-92, CAPLUS Database (abstract only). |
| Shao et al., “REVIEW Open Access 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, 2014, 33(1):41, 11 pages. |
| Sharma et al., “Physical Properties of Progesterone Selected Refer,” SciFinder, pp. 1-5, Feb. 24, 2014, American Chern. Society & US Natl. Lib. of Med. |
| Shrier et al., “Mucosal Immunity of the Adolescent Female Genital Tract,” Journal of Adolescent Health, 2003, 32:183-186. |
| Shufelt et al., “Hormone therapy dose, formulation, route delivery, and risk of cardiovascular events in women: findings from the Women's Health Initiative Observational Study,” Menopause: The Journal of The North American Menopause Society, 2014, 21(3): 1-7. |
| Siew, “Adeline, moderator, Bioavailability Enhancement with Lipid-Based Drug-Delivery Systems,” Pharmaceutical Technology, Aug. 2014, pp. 28, 30-31. |
| Sigma-Aldrich, Progesterone-Water Soluble: powder, BioReagent, suitable for cell culture), MSDS available online: hitp://www.sigmaaldrich.com/catalog/product/sigma/p7556,, 2015, 1 page. |
| Simon et al., “Effective Treatment of Vaginal atrophy with an Ultra-low-dose estradiol vaginal tablet,” Obstetrics & Gynocology, Nov. 2008, 112(5):1053-1060. |
| Simon, “What if the Women's Health Initiative had used transdermal estradiol and oral progesterone instead?” Menopause: The Journal of The North American Menopause Society, 2014, 21(7):1-15. |
| Sitruk-Ware et al., “Progestogens in hormonal replacement therapy: new molecules, risks, and benefits,” Menopause: The Journal of The North American Menopause Society. 2002, 9(1):6-15, 2002. |
| Sitruk-Ware, “Oral Micronized Progesterone—Bioavailability pharmacokinetics, pharmacological and therapeutic implications—A review,” Contraception, Oct. 1987, 36(4):373-402. |
| Smith et al., “Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared with Oral Conjugated Equine Estrogens,” JAMA Internal Medicine, Published online Sep. 30, 2013, E1-E7. jamainternalmedicine.com. |
| Smyth et al., “Summary of Toxicological Data, A 2-Yr Study of Diethylene Glycol Monoethyl Ether in Rats,” Fd Cosmet. Toxicol., 1964, vol. 2, pp. 641-642. |
| Stanczyk et al., “Therapeutically equivalent pharmacokinetic profile across three application sistes for AG200-15, a novel low-estrogen dose contraceptive patch,” Contraception, 2013, 87:744-749. |
| Stanczyk et al., Ethinyl estradiol and 17β-estradiol in combined oral contraceptives pharmacokinetics, pharmacodynamics and risk assessment, Contraception, Jun. 2013, 87(6):706-727. |
| Stanczyk, F.Z., Bhavnani, B.R., “Current views of hormone therapy for the management and treatment of postmenopausal women,” J. Steroid Biochem. Mol. Biol., 2014, Elsevier, 3 pages. |
| Stein et al., Progesterone Physical Properties, SciFinder, pp. 1-46, Feb. 24, 2014, American Chem. Society & US Natl. Lib. of Med. |
| Strickley, “Solubilizing excipients in oral and injectable formulations,” Pharmaceutical Research Feb. 2004, 21 (2):201-230 (abstract only). |
| Strocchi, “Fatty Acid Composition, and Triglyceride Structure of Corn Oil, Hydrogenated Corn Oil, and Corn Oil Margarine,” Journal of Food Science, 1981, 47:36-9. |
| Struhar et al., “Estradiol Benzoate: Preparation of an injection suspension . . . ,” SciFinder, Cesko-Slovenska Farmacie, 1978, 27(6):245-9, Bratislava, Czech (abstract only). |
| Sullivan 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, 2014, 72:40-50. |
| Sun, D-Limonene: Safety and Clinical Applications, Alternative Medicine Review, 2007, 12(3):259-264. |
| Tait, “Characterization of the Prod. from the Oxidation of Progesterone with Osmium Tetroxide,” Dept of Investigative Med., Univ. Cambridge, Gt. Britain, 1972, pp. 531-542. |
| Takacs M. et al., “The light sensitivity of corticosteroids in crystalline form,” Pharmaceutica acta Helvetiae, vol. 66 (5-6) pp. 137-140, 1991, Hardin Library. |
| Tan et al., “A Sensitive Method for the Determination of Progesterone in Human Plasma by LC-MS-MS,” M1025, Cedra Corporation, Austin, Texas (publicly available before application filing date of Oct. 22, 2014), 1 page. |
| Tang et al., “Effect of Estrogen and Progesterone on the Development of Endometrial Hyperplasia in the Fischer Rat,” Biology of Reproduction, 1984, 31:399-413. |
| Tas et al., “Comparison of antiproliferative effects of metformine and progesterone on estrogen-induced endometrial hyperplasia in rats,” Gynecol Endocrinol, Early Online: pp. 1-4, 2013. http://informahealthcare.com/gye. |
| Telia, S.H., Gallagher, J.C., “Prevention and treatment of postmenopausal osteoporosis,” J. Steroid Biochem. Mol. Biol., 2013, Elsevier, 16 pages. |
| Thomas et al., The effect of water solubility of solutes on their flux through human skin in vitro: An . . . , Intl. J. of Pharmaceut., 2007, vol. 339 pp. 157-167, Elsevier. |
| Thomas, “Characteristics of membrane progestin receptor alpha (mPRα) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions,” Frontiers in Neuroendocrinology, 2008, 29:292-312. |
| Tripathi et al., “Study of Polymorphs of Progesterone by Novel Melt Sonocrystallization Technique: A Technical Note,” AAPS PhamSciTech, Sep. 2010, 11(3):1493-1498. |
| Trommer et al., “Overcoming the stratum Comeum: The modulation of Skin Penetration,” Skin Pharmacol Physiol, 2006, 19:106-121. |
| Tuleu 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, Jun. 2004, 93(6):1495-1502. |
| Ueda et al., “Topical and Transdermal Drug Products,” Pharmacopeial Forum, vol. 35(3), May-Jun. 2009, 750-764. |
| USP, 401 Fats and Fixed Oils, Chemical Tests, Second Suplement to USP36-NF 31, pp. 6141-6151, 2013. |
| USP, Lauroyl Polyoxylglycerides, Safety Data Sheet, US, 5611 Version #02, pp. 1-9, 2013. |
| USP, Official Monographs, Corn Oil, NF 31, pp. 1970-1971, Dec. 2013. |
| USP, Official Monographs, Lauroyl Polyoxylglycerides, NF 31, pp. 2064-2066, Dec. 2013. |
| USP, Official Monographs, Medium Chain Triglycerides, NF 31, pp. 2271-2272, Dec. 2013. |
| USP, Official Monographs, Mono- and Di-glycerides, NF 31, p. 2101, Dec. 2013. |
| USP, USP Certificate-Corn Oil, Lot G0L404, Jul. 2013, 2 pages. |
| USP Monographs: Progesterone, USP29, www.pharmacopeia.cn/v29240/usp29nf24s0_m69870.html, search done: Feb. 25, 2014, 2 pages. |
| USPTO, Final Office Action issued in U.S. Appl. No. 13/684,002, dated Jul. 16, 2013, 13 pages. |
| USPTO, Non-Final Office Action issued in U.S. Appl. No. 13/684,002, dated Mar. 20, 2013, 14 pages. |
| USPTO, Notice of Allowance issued in U.S. Appl. No. 13/684,002, dated Dec. 6, 2013, 7 pages. |
| USPTO, Non-Final Office Action issued in U.S. Appl. No. 14/099,545, dated Feb. 18, 2014, 7 pages. |
| USPTO, Restriction/Election Requirement issued in U.S. Appl. No. 14/099,562, dated Feb. 20, 2014, 6 pages. |
| USPTO, Restriction/Election Requirement issued in U.S. Appl. No. 14/099,623, dated Mar. 5, 2014, 9 pages. |
| USPTO, Office Action issued in U.S. Appl. No. 12/561,515, dated Dec. 12, 2011, 14 pages. |
| USPTO, Final Office Action issued in U.S. Appl. No. 12/561,515, dated Oct. 26, 2013, 14 pages. |
| USPTO, Advisory Action issued in U.S. Appl. No. 12/561,515, dated Jan. 29, 2013, 3 pages. |
| USPTO, Notice of Allowance issued in U.S. Appl. No. 12/561,515, dated Sep. 11, 2013, 12 pages. |
| Utian et al., “Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens,” Fertility and Sterility, Jun. 2001, 75(6), 15 pages. |
| Voegtline et al., “Dispatches from the interface of salivary bioscience and neonatal research,” Frontiers in Endocrinology, Mar. 2014, vol. 5, article 25, 8 pages. |
| Waddell et al., “Distribution and metabolism of topically applied progesterone in a rat model,” Journal of Steroid Biochemistry & Molecular Biology, 2002, 80:449-455. |
| Waddell et al., “The Metabolic Clearance of Progesterone in the Pregnant Rat: Absence of a Physiological Role for the Lung,” Biology of Reproduction, 1989, 40:1188-1193. |
| Walter et al., “The role of progesterone in endometrial angiogenesis in pregnant and ovariectomised mice,” Reproduction, 2005, 129:765-777. |
| Weber, “Corn Lipids,” Cereal Chem.,Sep.-Oct. 1978, 55(5):572-584, The American Assoc of Cereal Chem. |
| Weber, et al., “Cognition and mood in perimenopause: A systematic review and meta-analysis,” J. Steroid Biochem. Mol. Biol., 2013, 9 pages, Elsevier. |
| Whitehead et al., “Absorption and metabolism of oral progesterone,” The British Medical Journal, vol. 280, No. 6217 (Mar. 22, 1980), pp. 825-827, BMJ Publishing Group. |
| Wiranidchapong, “Method of preparation does not affect the miscibility between steroid hormone and polymethacrylate,” Thermochimica Acta 485, Elsevier, 2009, p. 57. |
| Wood et al., “Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys,” Breast Cancer Res Treat, 2007, 101:125-134. |
| Wren et al., “Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women,” Climacteric, 2000, 3(3), pp. 155-160. http://dx.doi.org/10.1080/13697130008500109. |
| Wu et al., “Gene Expression Profiling of the Effects of Castration and Estrogen Treatment in the Rat Uterus,” Biology of Reproduction, 2003, 69:1308-1317. |
| Yalkowsky, Samuel H, & Valvani, Shri C, “Solubility and Partitioning I: Solubility of Nonelectrolytes in Water,” J. of Pharmaceutical Sciences, 1980, 69(8):912-22. |
| Yalkowsky, Handbook of Acqueous Solubility Data, Solutions, pp. 1110-1111, CRC Press, Boca Raton, London, New York, Wash. D.C., Jan. 2003. |
| Yue, “Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis,” Journal of Steroid Biochem & Mol Biology, 2003, 86:477-86. |
| Zava et al.,“Percutaneous absorption of progesterone,” Maturitas, 2014, 77:91-92, Elsevier. |
| Zava, “Topical Progesterone Delivery and Levels in Serum, Saliva, Capillary Blood, and Tissues,” Script, ZRT Laboratory, pp. 4-5. (publicly available before application filing date of Oct. 22, 2014). |
| Geelen, Math 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, 1995, 125(10):2449-2456. |
| Herman, Anna et al., “Essential oils and their constituents as skin penetration enhancer for transdermal drug delivery: a review,” 2014 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, pp. 1-13. |
| Manson, JoAnn E. et al., “Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women's health initiative randomized trials,” JAMA, Oct. 2, 2013, vol. 310, No. 13, pp. 1353-1368. |
| Portman, David et al., One-year treatment persistence with local estrogen therapy in postmenopausal women diagnosed as having vaginal atrophy, Menopause, vol. 22, No. 11, 2015, pp. 000/000 (8 pages). |
| Rao, Rajeswara et al., “Intra Subject Variability of Progesterone 200 mg Soft Capsules in Indian Healthy Adult Postmenopausal Female Subjects under Fasting Conditions,” J Bioequiv Availab. 2014, 6: 139-143. |
| Schindler, Aldof E. et al., Classification and pharmacology of progestins, Maturitas 46S1 (2003) S7-S16. |
| Sitruk-Ware, Regine, “Pharmacological profile of progestins,” Maturitas 47 (2004) 277-283. |
| Stanczyk, F.Z. et al., “Percutaneous administration of progesterone: blood levels and endometrial protection,” Menopause: The Journal of The North American Menopause Society, 2005, vol. 12, No. 2, pp. 232-237. |
| Stanczyk, F.Z., “All progestins are not created equal,” Steroids 68 (2003) 879-880. |
| Stanczyk, F.Z., “Treatment of postmenopausal women with topical progesterone creams and gels: are they effective?” Climacteric 2014; 17(Suppl 2):8-11. |
| Stephenson et al., “Transdermal progesterone: Effects on Menopausal symptoms and on thrombotic, anticoagulant, and inflammatory factors in postmenopausal women,” Int J Pharmaceutical Compounding, vol. 12, No. 4, Jul./Aug. 2008, pp. 295-304. |
| U.S. Appl. No. 13/843,362_Mar. 16, 2015_Restriction_Requirement. |
| U.S. Appl. No. 13/843,428_Apr. 14, 2015_Restriction_Requirement. |
| U.S. Appl. No. 14/099,545_Jul. 14, 2014_Notice_of_Allowance. |
| U.S. Appl. No. 14/099,562_Mar. 27, 2014_Non-Final_Office_Action. |
| U.S. Appl. No. 14/099,562_Jul. 2, 2014_Final_Office_Action. |
| U.S. Appl. No. 14/099,562_Dec. 10, 2014_Notice_of_Allowance. |
| U.S. Appl. No. 14/099,571_Mar. 28, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/099,571_Jul. 15, 2014_Notice_of_Allowance. |
| U.S. Appl. No. 14/099,582_Apr. 29, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/099,582_Jun. 17, 2014_Non-Final_Office_Action. |
| U.S. Appl. No. 14/099,582_Nov. 7, 2014_Notice_of_Allowance. |
| U.S. Appl. No. 14/099,582_Jan. 22, 2015_Notice_of_Allowance. |
| U.S. Appl. No. 14/099,598_May 13, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/099,598_Jul. 3, 2014_Non-Final_Office_Action. |
| U.S. Appl. No. 14/099,598_Dec. 10, 2014_Notice_of_Allowance. |
| U.S. Appl. No. 14/099,612_Mar. 20, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/099,612_Oct. 30, 2014_Non-Final_Office_Action. |
| U.S. Appl. No. 14/099,612_Nov. 26, 2014_Notice_of_Allowance. |
| U.S. Appl. No. 14/099,623_Jul. 18, 2014_Non-Final_Office_Action. |
| U.S. Appl. No. 14/099,623_Dec. 15, 2014_Notice_of_Allowance. |
| U.S. Appl. No. 14/103,355_Dec. 8, 2014_Non-Final_Office_Action. |
| U.S. Appl. No. 14/106,655_Jul. 3, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/125,554_Dec. 5, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/125,554_Apr. 14, 2015_Non-Final_Office_Action. |
| U.S. Appl. No. 14/136,048_Nov. 4, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/136,048_Mar. 12, 2015_Non-Final_Office_Action. |
| U.S. Appl. No. 14/475,814_Oct. 1, 2014_Non-Final_Office_Action. |
| U.S. Appl. No. 14/475,814_Feb. 13, 2015_Notice_of_Allowance. |
| U.S. Appl. No. 14/475,864_Feb. 11, 2014_Notice_of_Allowance. |
| U.S. Appl. No. 14/475,864_Oct. 2, 2014_Non-Final_Office_Action. |
| U.S. Appl. No. 14/476,040_Mar. 26, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/521,230_Dec. 12, 2014_Restriction_Requirement. |
| U.S. Appl. No. 14/521,230_Feb. 18, 2015_Non-Final_Office_Action. |
| U.S. Appl. No. 14/624,051_Apr. 7, 2015_Non-Final_Office_Action. |
| Weintraub, Arlene, “Women fooled by untested hormones from compounding pharmacies,” Forbes, Feb. 20, 2015; retrieved online at http://onforb.es/1LIUm1V on Feb. 23, 2015, 3 pages. |
| Castelo-Branco Camil et al., “Treatment of atrophic vaginitis,” Therapy, 2007, vol. 4, No. 3, pp. 349-353. |
| Chambin et al., Interest of Multifunctional Lipid Excipients: Case of Gelucire® 44/14, Drug Development and Industrial Pharmacy, vol. 31, No. 6, pp. 527-534 (Year: 2005). |
| Cho, Y.A. et al., Transdermal Delivery of Ketorolac Tromethamine: Effects of Vehicles and Penetration Enhancers, Drug Development and Industrial Pharmacy, 30(6):557-564, Jun. 2004. |
| Cicinelli et al., “First uterine pass effect” is observed when estradiol is placed in the upper but not lower third of the vagina, Fertility and Sterility, vol. 81, No. 5, May 2004, pp. 1414-1416. |
| Cicinelli, Intravaginal oestrogen and progestin administration: advantages and disadvantages, Best Practices & Research Clinical Obstretrics and Gynaecology vol. 22, No. 2, 2008, pp. 391-405. |
| Crandall, Carolyn, “Vaginal Estrogen Preparations: A Review of Safety and Efficacy for Vaginal Atrophy,” Journal of Women's Health, 2002, vol. 11, No. 10, pp. 857-877. |
| Garad S. et al., “Preclinical Development for Suspensions,” A.K. Kulshreshtha et al. (eds), Pharmaceutical Suspensions: From Formulation Development to Manufacturing, Springer, New York 2010, pp. 127-176. |
| Holm et al., “Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides,” European Journal of Pharmaceutical Sciences 20 (2003) 91-97. |
| Humberstone, Andrew et al., “Lipid-based vehicles for the oral delivery of poorly water soluble drugs,” Advanced Drug Delivery Reviews, 25 (1997) 103-128. |
| Karande, et al., Enhancement of transdermal drug delivery via synergistic action of chemicals, Biochimica et Biophysica Acta, 1788:2362-2373, Sep. 2009. |
| Knuth et al., Hydrogel delivery systems for vaginal and oral applications: Formulation and biological considerations, Advanced Drug Delivery Reviews, vol. 11, No. 1-2, Jul.-Aug. 1993, pp. 137-167. |
| Lane, Majella E., “Skin penetration enhancers,” International Journal of Pharmaceutics 447 (2013) 12-21. |
| Lindmark, Tuulikki et al., “Absorption Enhancement through Intracellular Regulation of Tight Junction Permeability by Medium Chain Fatty Acids in Caco-2 Cells,” JPET 284(1):362-369, 1998. |
| Lindmark, Tuulikki et al., “Mechanisms of Absorption Enhancement by Medium Chain Fatty Acids in Intestinal Epithelial Caco-2 Cell Monolayers,” JPET 275(2):958-964, 1995. |
| Lopes, Luciana B. et al., Enhancement of transdermal delivery of progesterone using medium-chain mono and diglycerides as skin penetration enhancers, Pharmaceutical Development and Technology, 14:5, 524-529, Mar. 2009. |
| Mac Bride, Maire B. et al., “Vulvovaginal Atrophy,” Mayo Clin Proc, Jan. 2010, 85(1):87-94. |
| Monti, D. et al., Effect of different terpene-containing essential oils on permeation of estradiol through hairless mouse skin, International Journal of Pharmaceutics, 237:209-24, 2002. |
| Pachman et al., “Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions,” International Journal of Women's Health, May 7, 2010. |
| Potluri, Praveen and Guru V. Betageri, “Mixed-micellar proliposomal systems for enhanced oral delivery of progesterone,” Drug Delivery, 2006, vol. 13, No. 3, pp. 227-232. |
| Prajapati Hetal N. et al., “A Comparative Evaluation of Mono-, Di- and Triglyceride of Medium Chain Fatty Acids by Lipid/Surfactant/Water Phase Diagram, Solubility Determination and Dispersion Testing for Application in Pharmaceutical Dosage Form Development,” Pharm Res. Jan. 2012; 29(1): 285-305. Published online Aug. 23, 2011. doi: 10.1007/s11095-011-0541-3. |
| Prajapati Hetal N. et al., “Effect of Difference in Fatty Acid Chain Lengths of Medium-Chain Lipids on Lipid/Surfactant/Water Phase Diagrams and Drug Solubility,” J. Excipients and Food Chem. 2 (3) 2011:73-88. |
| Rao, R. et al., “The Affect of Capmul, Labrafil and Transcutol on Progesterone 100 Mg Soft Capsules Bioavailability in Indian Healthy Adult Postmenopausal Female Subjects Under Fasting Conditions,” Bioequivalence & Bioavailability, 7(2):095-107, 2015. |
| Sallee, Verney L. et al., “Determinants of intestinal mucosal uptake of short- and medium-chain fatty acids and alcohols,” Journal of Lipid Research, 1973, vol. 14, 475-484. |
| Sarpal, K. et al., “Self emulsifying drug delivery systems: a strategy to improve oral bioavailability,” Current Research & Information on Pharmaceuticals Sciences (CRIPS), 2010, vol. 11, No. 3, pp. 42-49. |
| Search Report, Extended European Search Report for EP13741053.6, dated Jul. 1, 2015. |
| Search Report, Extended European Search Report for EP13807188.1, dated Nov. 23, 2015. |
| Search Report, International Search Report and Written Opinion for PCT/US14/61811, dated Jan. 21, 2015. |
| Search Report, International Search Report and Written Opinion for PCT/US15/23041, dated Jun. 30, 2015. |
| Search Report, International Search Report and Written Opinion for PCT/US15/42621, dated Oct. 29, 2015. |
| U.S. Appl. No. 12/561,515 Dec. 12, 2011 Non-Final Office Action. |
| U.S. Appl. No. 12/561,515 Oct. 26, 2012 Final Office Action. |
| U.S. Appl. No. 12/561,515 Sep. 11, 2013 Notice of Allowance. |
| U.S. Appl. No. 13/843,428 Jul. 2, 2015 Non-Final Office Action. |
| U.S. Appl. No. 14/106,655 Jun. 19, 2015 Final Office Action. |
| U.S. Appl. No. 14/690,955 Feb. 1, 2016 Non-Final Office Action. |
| Ettinger et al., “Measuring symptom relief in studies of vaginal and vulvar atrophy: the most bothersome symptom approach,” Menopause, vol. 15, No. 5, 2008, pp. 885-889. |
| Eugster-Hausmann et al., “Minimized estradiol absorption with ultra-low-dose 10 μg 17β-estradiol vaginal tablets,” Climacteric 2010;13:219-227. |
| Martelli, Mary Elizabeth, “Vaginal Medicine Administration,” The Gale Encyclopedia of Nursing and Allied Health, Gale Group, 2002, pp. 2542-2543. |
| Regidor, P., “Progesterone in Peri- and Postmenopause: A Review,” Geburtshilfe Frauenheilkd, Nov. 2014. 74(11):995-1002. |
| Simon, James A. et al., “A vaginal estradiol softgel capsule, TX-004HR, has negligible to verylow systemic absorption of estradiol: Efficacy and pharmacokineticdata review,” Maturitas 99 (2017) 51-58. |
| Stefanick, “Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration,” The American Journal of Medicine (2005) vol. 118 (12B), 64S-73S. |
| Hitchcock, Christine L. et al., “Oral micronized progesterone for vasomotor symptoms—a placebo-controlled randomized trial in healthy postmenopausal women,” Menopause: The Journal of The North American Menopause Society. 19(8):886-893, Aug. 2012. |
| Hosmer, Jaclyn et al., “Microemulsions Containing Medium-Chain Glycerides as Transdermal Delivery Systems for Hydrophilic and Hydrophobic Drugs,” AAPS PharmSciTech, 2009, vol. 10, No. 2, pp. 589-596. |
| March, Charles M. et al., “Roles of Estradiol and Progesterone in Eliciting the Midcycle Luteinizing Hormone and Follicle-Stimulating Hormone Surges,” The Journal of Clinical Endocrinology & Metabolism, vol. 49, Issue 4, Oct. 1, 1979, pp. 507-513. |
| Sofi, Showkat Hussain et al., “Gelucire: A Versatile Formulation Excipient,” Ijppr.Human, 2017; vol. 10 (3): 55-73. |
| Tang et al., “Pharmacokinetics of different routes of administration of misoprostol,” Human Reproduction, 2002; 17(2):332-226. |
| Wang et al., “Pharmacokinetics of hard micronized progesterone capsules via vaginal or oral route compared with soft micronized capsules in healthy postmenopausal women: a randomized open-label clinical study,” Drug Des Devel Ther., 2019; 13: 2475-2482. |
| Number | Date | Country | |
|---|---|---|---|
| 20200297735 A1 | Sep 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61932140 | Jan 2014 | US | |
| 61894411 | Oct 2013 | US | |
| 61745313 | Dec 2012 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16746434 | Jan 2020 | US |
| Child | 16833186 | US | |
| Parent | 14521230 | Oct 2014 | US |
| Child | 16746434 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2013/046443 | Jun 2013 | US |
| Child | 14521230 | US |
