Patent Grant
9358214
A major objective of chronotherapy for cardiovascular diseases is to deliver the drug in higher concentrations during the time of greatest need, typically during the early morning hours, and in lesser concentrations when the need is less, such as during the late evening and early sleep hours. This can be accomplished by administration of the release dosage form of the present invention, which relates to a controlled absorption of propranolol from dosage forms. The release dosage form of the present invention, which relates to a controlled absorption of propranolol from dosage form, comprises an assembly of Timed, Sustained Release (TSR) Beads, each of which is designed to release as a sustained release pulse after a predetermined delay (“time-controlled” drug delivery instead of “rate-controlled”) with resulting plasma concentration(s) of propranolol varying in a circadian rhythm fashion following administration of a single dosage form at bedtime, thereby minimizing potential risks of a cardiovascular disease, such as stroke, heart attack and myocardial infarction, decreasing systolic blood pressure, or reducing hypertension or beta-adrenergic stimulation, treating cardiac arrhythmia, hypertrophic subaortic stenosis or angina, or preventing migraine and thus enhancing patient compliance and therapeutic efficacy, while reducing cost of treatment.
Many therapeutic agents are most effective when made available at a constant rate at or near the absorption site. The absorption of therapeutic agents thus made available generally results in desired plasma concentrations leading to maximum efficacy and minimum toxic side effects. Much effort has been devoted to developing sophisticated drug delivery systems, such as osmotic devices, for oral application. However, there are instances where maintaining a constant blood level of a drug is not desirable. For example, a “position-controlled” drug delivery system (e.g., treatment of colon disease or use of colon as an absorption site for peptide and protein based products) may prove to be more efficacious. A pulsatile delivery system is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. However, there are only a few such orally applicable pulsatile release systems due to the potential limitation of the size or materials used for dosage forms. Ishino et al. disclose a dry-coated tablet form in Chemical Pharm. Bull. Vol. 40 (11), 3036-041 (1992). U.S. Pat. No. 4,851,229 to Magruder et al., U.S. Pat. No. 5,011,692 to Fujioka et al., U.S. Pat. No. 5,017,381 to Maruyama et al., U.S. Pat. No. 5,229,135 to Philippon et al., and U.S. Pat. No. 5,840,329 to Bai disclose preparation of pulsatile release systems. Some other devices are disclosed in U.S. Pat. No. 4,871,549 to Ueda et al. and U.S. Pat. Nos. 5,260,068; 5,260,069; and 5,508,040 to Chen. U.S. Pat. Nos. 5,229,135 and 5,567,441 both to Chen disclose a pulsatile release system consisting of pellets coated with delayed release or water insoluble polymeric membranes incorporating hydrophobic water insoluble agents or enteric polymers to alter membrane permeability. U.S. Pat. No. 5,837,284 to Mehta et al. discloses a dosage form which provides an immediate release dose of methylphenidate upon oral administration, followed by one or more additional doses spread over several hours.
There is a well-established circadian variation in frequency of onset of cardiovascular events including ventricular arrhythmias, stroke, angina, and myocardial infarction. The peak frequency of such events is exhibited in the morning hours, theoretically in conjunction with the morning surge in systolic blood pressure and heart rate. There is also some evidence of a secondary peak in frequency of such events in the late afternoon or evening hours. Although there is some evidence which suggests that long acting propranolol may blunt the circadian variability of sudden cardiac death, it does not appear to attenuate early morning increases in blood pressure observed in hypertensive patients. Thus it would be physiologically advantageous to tailor plasma concentrations of propranolol to the typical circadian patterns of blood pressure and heart rate.
Chronotherapeutics is a means of proportioning plasma drug concentrations during a 24 hour period, relative to the biological rhythm determinates of disease activity. The objective of chronotherapy is to deliver the drug in higher concentrations during the time of greatest need, and in lesser concentrations when the need is less. The dosage forms disclosed in the prior arts above are not specifically designed to provide drug release profiles varying predictably in time over 24 hours, i.e., in a circadian rhythm fashion to effectively treat cardiovascular diseases. The dosage forms of the present invention, Propranolol Hydrochloride ER Capsules, 80, 120, and 160 mg), which are typically administered at bedtime, i.e., at about 10:00 PM, are novel formulations designed to provide reductions in blood pressure and heart rate over 24 hours, including optimal protection in the early morning hours when patients are most vulnerable to cardiovascular events. At steady state, blood levels of propranolol begin to increase approximately 4 hours after bedtime administration of these capsules and rise progressively over the early morning hours to reach peak plasma concentrations approximately 14 hours after dosing. These capsules produce peak plasma propranolol levels that rise slowly to attenuate the rapid increase in blood pressure and heart rate that precedes and follows waking. This increase is associated with circadian variation in catecholamine secretion and in rennin release. The rise in plasma propranolol concentration after dosing with these capsules parallel the circadian rise in morning blood pressure associated with target organ damage in patients with hypertensive and ischemic cardiovascular disease.
Propranolol [1-(isopropyl amino)-3-(1-naphthyloxy)-2-propanol] is a betaadrenergic blocking agent and as such is a competitive inhibitor of the effects of catecholamines at beta-adrenergic receptor sites. The principal effect of propranolol is to reduce cardiac activity by diminishing or preventing beta-adrenergic stimulation. By reducing the rate and force of contraction of the heart, and decreasing the rate of conduction of impulses through the conducting system, the response of the heart to stress and exercise is reduced. These properties are used in the treatment of angina in an effort to reduce the oxygen consumption and increase the exercise tolerance of the heart. Propranolol is also used in the treatment of cardiac arrhythmias to block adrenergic stimulation of cardiac pacemaker potentials. Propranolol is also beneficial in the long term treatment of hypertension. Other uses of propranolol are in the treatment of migraine and anxiety.
The preparation of the dosage form of the present invention is fully described in U.S. Pat. No. 6,500,454 assigned to Eurand Pharmaceuticals, Ltd., which is incorporated here by reference in its entirety. The dosage form, a hard gelatin capsule, is a timed, sustained release multi-particulate dosage form comprising a propranolol core having a first membrane of a sustained release polymer and a second membrane of a mixture of water insoluble polymer and an enteric polymer (2nd or outer coating), wherein the water insoluble polymer and the enteric polymer may be present at a weight ratio of from 10:1 to 1:2, and the total weight of the coatings is 10 to 60 weight % based on the total weight of the coated beads. In some cases depending on the type of drug release profile needed, an immediate release component may be included to provide a modified, timed, sustained release dosage form. When administered at bedtime, the dosage form comprising Timed, Sustained Release Capsule, commercially known as TSR Formulation XL, is designed to provide reductions in blood pressure and heart rate over 24 hours, including optimal protection in the early morning hours when patients are most vulnerable to cardiovascular events. At steady state, blood levels of propranolol begin to increase approximately 4 hours after bedtime administration of TSR Formulation XL and rise progressively over the early morning hours to reach peak plasma concentrations approximately 14 hours after dosing. TSR Formulation XL produces peak plasma propranolol levels that rise slowly to attenuate the rapid increase in blood pressure and heart rate that precedes and follows waking. This increase is associated with circadian variation in catecholamine secretion and in rennin release. The rise in plasma propranolol concentration after dosing with TSR Formulation XL parallels the circadian rise in morning blood pressure associated with target organ damage in patients with hypertensive and ischemic cardiovascular disease.
The invention will be described in further detail with reference to the accompanying Figures wherein:
The active core of the novel dosage form of the present invention may comprise an inert particle or an acidic or alkaline buffer crystal, which is coated with a propranolol-containing film-forming formulation and preferably a water-soluble film forming composition to form a water-soluble/dispersible particle. Alternatively, the active core may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing propranolol. Generally, the individual polymeric coating on the active core will be from 1 to 50% based on the weight of the coated particle. Those skilled in the art will be able to select an appropriate amount of propranolol for coating onto or incorporating into the core to achieve the desired dosage. In one embodiment, the inactive core may be a sugar sphere, a buffer crystal or an encapsulated buffer crystal, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. Buffer crystals are useful to alter the microenvironment.
In accordance with one embodiment of the present invention, the water soluble/dispersible drug-containing particle is first coated with a water insoluble polymer (1st or inner coating), and further coated with a mixture of a water insoluble polymer and an enteric polymer (2nd or outer coating). The water insoluble polymer and enteric polymer may be present at a weight ratio of from 10:1 to 1:2, more preferably 2:1 to 1:1, and the total weight of the coatings is 10 to 60 weight % based on the total weight of the coated beads. The polymeric coatings typically contain plasticizers and may be applied from aqueous and/or solvent based systems.
The composition of the outer layer and the individual weights of the inner and outer layers of the polymeric membrane are optimized for achieving desired drug release profiles. The unit dosage form according to certain embodiments of the present invention may comprise an immediate release bead population which provides an immediate release component of propranolol to act as a bolus dose.
The invention also provides a method of making a timed, sustained release dosage form comprising the steps of:
1. preparing an active-containing core by coating an inert particle such as a nonpareil seed, an acidic buffer crystal or an alkaline buffer crystal, with propranolol and polymeric binder or by granulation and milling or by extrusion/spheronization to form an immediate release (IR) bead;
2. coating the core with a plasticized solution or suspension of a water insoluble polymer to form sustained release (SR) coated drug particle;
3. coating the SR coated particle with a mixture of plasticized water insoluble and enteric polymers to form a Timed Sustained Release (TSR) coated drug particle; and filling capsules with TSR particles to produce Timed, Sustained Release (TSR) capsules.
The release profile for TSR beads can be determined according to the following procedure:
Dissolution testing is conducted with a USP Apparatus 2 (Paddles at 50 rpm) using a two-stage dissolution medium (first 2 hours in 700 mL 0.1N HC1 at 37° C. followed by dissolution at pH=6.8 obtained by the addition of 200 mL of pH modifier). Drug release with time is determined by HPLC on samples pulled at selected intervals.
The TSR Beads prepared in accordance with present invention release not more than 20%, more preferably not more than 10%, and most preferably not more than 5% in 2 hours, about 5-35%, more preferably about 5-25%, and most preferably about 5-15% in 4 hours, about 10-60%, more preferably about 20-45%, and most preferably about 25-35% in 6 hours, about 4090%, more preferably about 50-80%, and most preferably about 55-70% in 10 hours, and not less than 60%, more preferably not less than 70%, and most preferably not less than 75% in 16 hours.
In accordance with the present invention, the desired release properties are obtained as a result of the different characteristics of the two coating layers. The inner layer membrane provides sustained or extended drug release over several hours, while the second or outer membrane provides a lag time of three to four hours. Typical release profiles for SR beads (ethylcellulose coated drug particle) and TSR beads when tested by the two-stage dissolution medium are provided in Table 1, below:
It is also possible that the TSR Capsule may optionally also contain a population of Immediate Release (IR) beads or particles to provide an immediate release component of active to act as a bolus dose in addition to the timed, sustained release of active provided by the TSR beads. These dosage forms provide a Modified Timed Sustained Release (MTSR) profile.
An aqueous or a pharmaceutically acceptable solvent medium may be used for preparing drug containing core particles. The type of film forming binder that is used to bind propranolol to the inert sugar sphere is not critical but usually water-soluble, alcohol-soluble or acetone/water soluble binders are used. Binders such as polyvinylpyrrolidone (PVP), polyethylene oxide, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polysaccharides, such as dextran, and corn starch may be used at concentrations of from about 0.5 to 10 weight %. Propranolol may be present in the coating formulation in solution form or may be suspended at a solids content up to about 35 weight % depending on the viscosity of the coating formulation.
Dissolution rate controlling polymers suitable for incorporating in the formulation for producing granules by high shear or fluid bed granulation or by dry granulation include high molecular weight hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, alginic acid, polymethylmethacrylate copolymers and polyvinyl acetate/crotonic acid copolymer or combinations thereof. Acidic buffers, which help maintain an acidic microenvironment within drug containing particles, include fumaric acid, tartaric acid, maleic acid, succinic acid and mixtures thereof. An acidic microenvironment helps dissolve basic drugs with poor solubility at the intestinal pHs and become available for absorption. Examples of alkaline buffers include sodium bicarbonate, calcium carbonate, and sodium dihydrogen phosphate.
Propranolol, a binder such as PVP, a buffer, a dissolution rate controlling polymer (if used), and optionally other pharmaceutically acceptable excipients are blended together in a high shear granulator such as Fielder or a fluid bed granulator such as Glatt GPCG 5 and granulated to form agglomerates by adding/spraying a granulating fluid such as water or alcohol and dried. The wet mass can be extruded and spheronized to produce spherical particles (beads) using an extruder/marumerizer. In these embodiments, the drug load could be as high as 90% by weight based on the total weight of the extruded/spheronized core. The blend can also be used to produce dry granules by slugging in a tablet press or a chilsonator, without the addition of any granulating fluid.
The active containing cores (beads, pellets or granular particles) thus obtained may be coated with one or two layers of polymers to obtain desired release profiles with or without a lag time. The inner layer membrane, which largely controls the rate of release following imbibition of water or body fluids into the core, comprises a water insoluble polymer, such as ethylcellulose, at a thickness of from 1 weight % up to 6 weight %, preferably from 1.5 to 4% and most preferably about 2%, depending on the solvent or latex suspension based coating formulation used.
The outer membrane, which largely controls the lag time of up to 6 hours, comprises an enteric polymer and a water insoluble polymer at a thickness of 10 to 60, preferably from 10 to 56 weight % based on the total weight of the coated beads. The ratio of water insoluble polymer to enteric polymer may vary from 10:1 to 1:2, preferably from 2:1 to 1:1.
Representative examples of water insoluble polymers useful in the invention include cellulose derivatives (e.g. ethylcellulose), polyvinyl acetate (Kollicoat SR30D from BASF), neutral copolymers based on ethyl acrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups, such as Eudragit NE, RS or RS30D, RL or RL30D and the like.
Representative examples of enteric polymers useful in the invention include esters of cellulose and its derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, pHsensitive methacrylic acid-methamethacrylate copolymers and shellac. These polymers may be used as a dry powder or an aqueous dispersion. Some commercially available materials that may be used are methacrylic acid copolymers sold under the trademark Eudragit (L100, S100, L30D) manufactured by Rhom Pharma, Cellacefate (cellulose acetate phthalate) from Eastman Chemical Co., Aquateric (cellulose acetate phthalate aqueous dispersion) from FMC Corp. and Aqoat (hydroxypropyl methylcellulose acetate succinate aqueous dispersion) from Shin Etsu K.K.
Both enteric and water insoluble polymers used in forming the membranes are usually plasticized. Representative examples of plasticizers that may be used to plasticize the membranes include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate diethyl phthalate, castor oil, dibutyl sebacate, acetylated monoglycerides and the like or mixtures thereof. The plasticizer may comprise about 3 to 30 wt. % and more typically about 10 to 25 wt. % based on the polymer. The type of plasticizer and its content depends on the polymer or polymers, nature of the coating system (e.g., aqueous or solvent based, solution or dispersion based and the total solids).
In general, it is desirable to prime the surface of the particle before applying the pulsatile release membrane coatings or to separate the different membrane layers by applying a thin hydroxypropyl methylcellulose (HPMC) (Opadry Clear) film. While HPMC is typically used, other primers such as hydroxypropylcellulose (HPC) can also be used.
The membrane coatings can be applied to the core using any of the coating techniques commonly used in the pharmaceutical industry, but fluid bed coating is particularly useful.
The present invention is applied to multi-dose forms, i.e., drug products in the form of multi-particulate dosage forms (pellets, beads, granules or mini-tablets) or in other forms suitable for oral administration.
The following non-limiting examples illustrate the capsule dosage forms manufactured in accordance with the invention, which exhibit in vitro drug release profiles, similar to that predicted by performing modeling exercises, and in vivo plasma concentrations following circadian rhythm pharmaco-dynamic profile of angina attacks. Such dosage forms when administered at bed time, would enable maintaining drug plasma concentration at a level potentially beneficial in minimizing the occurrence of heart attacks in the early hours of the morning.
Modified Timed, Sustained Release (MTSR) capsules of Propranolol Hydrochloride may contain a mixture of two sets of beads: The first set is referred to as immediate release (IR) Beads and are designed to provide a loading dose by releasing all of the drug within the first hour, preferably within the first 30 minutes. The second set is referred to as Timed Sustained Release (TSR) Beads and are designed to release the remainder of the dose slowly over a period of 12-15 hours after a 3-5-hour lag time. The TSR Beads are produced by applying an inner layer of sustained release coating (with a dissolution rate controlling polymer such as ethylcellulose) (producing IntR Beads, intermediate release beads) and then an outer layer of pulse coating (with a blend of an enteric polymer such as HPMCP and a water-insoluble polymer such as ethylcellulose) on IR Beads. The two sets of beads (IR and TSR) when filled into capsule shells at an appropriate ratio will produce the target circadian rhythm release profile required for maintaining drug plasma concentrations at potentially beneficial levels in minimizing the occurrence of heart attacks. Alternatively, the capsules may comprise only the TSR Beads, the capsules containing only the TSR Beads are referred to as TSR Formulation. It is well known that the blood pressure begins to drop as the night advances, and consequently, only the Formulations containing only the TSR beads for oral administration are described below.
Propranolol HCl (45.2 kg) was slowly added to an aqueous solution of polyvinylpyrrolidone (2.34 kg Povidone K-30) and mixed well. # 25-30 mesh sugar spheres (31.6 kg) were coated with the drug solution in a Glatt fluid bed granulator. The drug containing pellets were dried, and a seal coat of Opadry Clear (2% w/w) was first applied (batch size: 80.75 kg). The inner sustained release coating was applied to the active particles (73.7 kg) by spraying a solution of ethylcellulose and diethyl phthalate in 98/2 acetone/water. The outer coating of a blend of ethylcellulose and HPMCP plasticized with diethyl phthalate was sprayed onto the active particles having the inner coating to produce TSR Beads (batch size: 82.5 kg). These TSR Beads were filled into hard gelatin capsules using an MG capsule filling equipment to produce Propranolol hydrochloride TSR Capsules, 80, 120, and 160 mg.
These Propranolol TSR Capsules were tested for drug release profiles by the two-stage dissolution method, wherein capsules were dissoluted at pH 1.5 in 700 mL 0.1N HCl for two hours followed by testing at pH 6.8 in 900 mL obtained by adding 200 mL of concentrated buffer modifier.
A double-blind, randomized, placebo-controlled, 4-period crossover study to assess the efficacy and dose proportionality of TSR Formulation 80 mg, 120 mg, and 160 mg in 39 healthy male and female subjects of ages 18 to 40 was carried out. In each study period a single dose of one strength of TSR Formulation or placebo was administered at approximately 10:00 PM. There was a minimum of 7 days between the administration of each dose of TSR Formulation or placebo. Efficacy was assessed by the mean change in post-exercise heart rate, heart rate pressure product, and systolic blood pressure from pre-dose to Hour 24 post-dose (trough) assessments. The secondary efficacy variable was the mean change in post-exercise heart rate from pre-dose to Hour 12. Post-exercise heart rate was used as a surrogate marker for antianginal efficacy.
Analyses for concentrations of total plasma propranolol (conjugated and unconjugated) on the blood samples collected were carried out using a validated high performance liquid chromatography (HPLC) method. Plasma samples were collected pre-dose and up to 72 hours post-dose. The limit of quantitation was 2 ng/mL.
at is the last time point with measurable propranolol concentration
Linear regression analyses on untransformed pharmacokinetic parameters showed dose proportionality and a linear dose-response relationship between the TSR Formulation dosage strengths and the pharmacokinetic parameters AUC0-T (area under the concentration-time curve to the last measurable time point calculated by the linear trapezoidal rule), AUC0-∞ (are under the concentration-time curve to infinity), and Cmax. Results of linear regression and ANOVA after log-transformation and dose-normalization confirmed a dose proportional relationship between AUC0-T, AUC0-∞, and Cmax and TSR Formulation 80 mg, 120 mg, and 160 mg doses.
Regarding efficacy, maximum decreases in systolic blood pressure were noted at 8-10 hours post-dose in all treatment groups. Maximum decreases in diastolic blood pressure were noted at 8-10 hours post-dose in the TSR Formulation 120 mg and placebo groups and at 14 hours post-dose in the TSR Formulation 80 mg and 160 mg groups. Maximum decreases in heart rate were observed at 10 hours post-dose in all treatment groups. Mean changes in systolic and diastolic blood pressure and heart rate showed increases from pre-dose values at 72 hours post-dose in all treatment groups. No subject experienced postural hypotension during the study.
Only the TSR Formulation 80 mg dose group showed a statistically significant decrease in the adjusted mean change in exercise-induced heart rate from baseline at 24 hours post-dose, relative to placebo (primary end point) and in 12-hour post-exercise heart rate (secondary end point). No dose response was observed for heart rate. Statistically significant changes, relative to placebo, were observed for two primary end points: hour 24 heart rate-pressure product seen for the lowest and highest doses and hour 24 heart rate at the lowest dose of TSR Formulation; these data support the efficacy of TSR formulations in the prevention and treatment of angina. Demonstration of blunting of exercise response to beta blockade for the 12-hour post p.m. dosing exercise challenge also supports the efficacy of the TSR Formulation in protection against morning ischemic events.
A randomized, open-label, two-period crossover study to evaluate the single and multiple dose bioavailability and safety of TSR Formulation 160 mg compared to Inderal® LA 160 mg capsules was carried out. The primary objective of this study was to evaluate the relative bioavailability of TSR Formulation 160 mg to Inderal® LA 160 mg as assessed by an ANOVA on AUCs after single and multiple dose administrations. The secondary objective was to explore the pharmacokinetics of TSR Formulation and Inderal® LA after single and multiple dose administrations. Safety and tolerability were measured by evaluating adverse events, laboratory values, physical examinations, electrocardiograms, and vital signs.
Subjects were healthy, adult, males between 18 and 45 years of age who met the study eligibility criteria. In Period 1 of the study, following a 4-hour fasting period on Day 1, subjects received a single dose of the study drug (TSR Formulation or Inderal® LA) between 9:30 and 10:30 PM. Serial blood samples for plasma total propranolol determinations were collected for 72 hours. Subjects received a daily dose of their Period 1 drug on Days 4 to 8 and 24-hour trough blood samples were collected. A seven-day washout period followed, and the same procedures were followed for Period 2 with the other study drug as determined by the sequence to which the subjects were randomized. Analyses for concentrations of total plasma propranolol (conjugated and unconjugated) on the blood samples collected were carried out using a validated high performance liquid chromatography (HPLC) method. The limit of quantitation was 2 ng/mL.
Plots of the mean propranolol plasma concentration over time following a single dose of 160 mg propranolol TSR Formulation or 160 mg Inderal® LA are presented in
A summary of the single dose pharmacokinetic parameters of AUC0-T, AUC0-∞ and Cmax following an Analysis of Variance (ANOVA) is given in Table 3. The adjusted mean Cmax values were 131.0 ng/mL and 171.3 ng/mL for subjects administered Inderal® LA and TSR Formulation, respectively.
1Adjusted mean and 90% CI calculated from ANOVA on log-transformed parameter with subject, period, sequence, and treatment as fixed effects. Adjusted means and CIs displayed have been transformed from the log to the arithmetic scale.
Table 4 describes a summary of the results of the ANOVA performed on the pharmacokinetic parameters AUCo-TSS, CAV SS, Rac SS, and FiSS.
1Adjusted mean and 90% CI calculated from ANOVA on log-transformed parameter with subject, period, sequence, and treatment as fixed effects. Adjusted means and CIs displayed have been transformed from the log to the arithmetic scale.
A randomized, double-blind, parallel, placebo-controlled, multicenter trial to study the efficacy, safety and steady state pharmacokinetics of 80 mg, 120 mg, 160 mg, and 640 mg TSR Formulation in patients with essential hypertension was carried out. The primary objective of this study was to assess the efficacy of the TSR Formulation in subjects with essential hypertension by evaluating the mean change from Baseline to Week 8 in morning sitting diastolic pressure. Subjects were randomized to one of the five double-blind treatment groups: placebo, TSR Formulation 80 mg/day, TSR Formulation 120 mg/day, TSR Formulation 160 mg/day, and TSR Formulation 640 mg/day taken once daily before bedtime. During Week 1 and Week 2 subjects were up titrated to the appropriate dose for 6 weeks, and then they were down titrated for the last two weeks of the study.
Morning sitting diastolic pressure, the measure of primary efficacy, decreased from Baseline to Endpoint for the placebo and all four TSR Formulation groups. Statistically significant differences in the magnitude of the decrease between the placebo group and the 120 mg, 160 mg, and 640 mg TSR Formulation groups were observed. Statistical trends were observed for the 80 mg TSR Formulation dose group. These results demonstrate that the TSR Formulation, administered once daily at bedtime in dosage strengths of 80 mg to 640 mg propranolol is an effective antihypertensive agent.
This application is a continuation-in-part application of U.S. application Ser. No. 10/334,052 filed Dec. 30, 2002, now abandoned, which is a continuation of U.S. application Ser. No. 09/971,167 filed Oct. 4, 2001, now U.S. Pat. No. 6,500,454. Each of the foregoing applications, each document cited or referenced in each of the foregoing applications and during the prosecution of each of the foregoing applications (“application cited documents”), each document referenced or cited in each of the application cited documents, each document cited or referenced in this application (“herein cited documents”) and each document cited or referenced in each of the herein cited documents are all incorporated herein by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3184386 | Stephenson | May 1965 | A |
| 3558768 | Klippel | Jan 1971 | A |
| 3885026 | Heinemann et al. | May 1975 | A |
| 4078051 | Pomot et al. | Mar 1978 | A |
| 4138475 | McAinsh et al. | Feb 1979 | A |
| 4248857 | DeNeale et al. | Feb 1981 | A |
| 4292017 | Doepel | Sep 1981 | A |
| 4305502 | Gregory et al. | Dec 1981 | A |
| 4369172 | Schor et al. | Jan 1983 | A |
| 4371516 | Gregory et al. | Feb 1983 | A |
| 4389330 | Tice et al. | Jun 1983 | A |
| 4389393 | Schor et al. | Jun 1983 | A |
| 4542042 | Samejima et al. | Sep 1985 | A |
| 4556678 | Hsiao | Dec 1985 | A |
| 4587118 | Hsiao | May 1986 | A |
| 4628098 | Nohara et al. | Dec 1986 | A |
| 4661647 | Serpelloni et al. | Apr 1987 | A |
| 4670459 | Sjoerdsma | Jun 1987 | A |
| 4689333 | Nohara et al. | Aug 1987 | A |
| 4698101 | Koivurinta | Oct 1987 | A |
| 4708867 | Hsiao | Nov 1987 | A |
| 4713248 | Kjornaes et al. | Dec 1987 | A |
| 4716041 | Kjornaes et al. | Dec 1987 | A |
| 4728512 | Mehta et al. | Mar 1988 | A |
| 4743248 | Bartoo et al. | May 1988 | A |
| 4752470 | Mehta | Jun 1988 | A |
| 4757090 | Salpekar et al. | Jul 1988 | A |
| 4760093 | Blank et al. | Jul 1988 | A |
| 4780318 | Appelgren et al. | Oct 1988 | A |
| 4786508 | Ghebre-Sellassie et al. | Nov 1988 | A |
| 4800087 | Mehta | Jan 1989 | A |
| 4803213 | Iida et al. | Feb 1989 | A |
| 4824675 | Wong et al. | Apr 1989 | A |
| 4832880 | Staniforth | May 1989 | A |
| 4840799 | Appelgren et al. | Jun 1989 | A |
| 4851226 | Julian et al. | Jul 1989 | A |
| 4851229 | Magruder et al. | Jul 1989 | A |
| 4863742 | Panoz et al. | Sep 1989 | A |
| 4871549 | Ueda et al. | Oct 1989 | A |
| 4874613 | Hsiao | Oct 1989 | A |
| 4886669 | Ventouras | Dec 1989 | A |
| 4892741 | Ohm et al. | Jan 1990 | A |
| 4894240 | Geoghegan et al. | Jan 1990 | A |
| 4898737 | Panoz et al. | Feb 1990 | A |
| 4915949 | Wong et al. | Apr 1990 | A |
| 4938968 | Mehta | Jul 1990 | A |
| 4946684 | Blank et al. | Aug 1990 | A |
| 4957745 | Jonsson et al. | Sep 1990 | A |
| 4968508 | Oren et al. | Nov 1990 | A |
| 4971805 | Kitanishi et al. | Nov 1990 | A |
| 4983401 | Eichel et al. | Jan 1991 | A |
| 5006345 | Lang | Apr 1991 | A |
| 5011692 | Fujioka et al. | Apr 1991 | A |
| 5013557 | Tai | May 1991 | A |
| 5013743 | Iwahi et al. | May 1991 | A |
| 5017122 | Staniforth | May 1991 | A |
| 5017381 | Maruyama et al. | May 1991 | A |
| 5026559 | Eichel et al. | Jun 1991 | A |
| 5026560 | Makino et al. | Jun 1991 | A |
| 5039540 | Ecanow | Aug 1991 | A |
| 5045321 | Makino et al. | Sep 1991 | A |
| 5073374 | McCarty | Dec 1991 | A |
| 5075114 | Roche | Dec 1991 | A |
| 5079018 | Ecanow | Jan 1992 | A |
| 5082669 | Shirai et al. | Jan 1992 | A |
| 5084278 | Mehta | Jan 1992 | A |
| 5093132 | Makino et al. | Mar 1992 | A |
| 5104648 | Denton et al. | Apr 1992 | A |
| 5112616 | McCarty | May 1992 | A |
| 5133974 | Paradissis et al. | Jul 1992 | A |
| 5137733 | Noda et al. | Aug 1992 | A |
| 5149542 | Valducci | Sep 1992 | A |
| 5160680 | Serpelloni et al. | Nov 1992 | A |
| 5169640 | France et al. | Dec 1992 | A |
| 5178878 | Wehling et al. | Jan 1993 | A |
| 5204121 | Bucheler et al. | Apr 1993 | A |
| 5211957 | Hagemann et al. | May 1993 | A |
| 5213808 | Bar-Shalom et al. | May 1993 | A |
| 5229131 | Amidon et al. | Jul 1993 | A |
| 5229135 | Philippon et al. | Jul 1993 | A |
| 5238686 | Eichel et al. | Aug 1993 | A |
| 5252337 | Powell | Oct 1993 | A |
| 5256699 | Murphy et al. | Oct 1993 | A |
| 5260068 | Chen | Nov 1993 | A |
| 5260069 | Chen | Nov 1993 | A |
| 5275827 | Spinelli et al. | Jan 1994 | A |
| 5376384 | Eichel et al. | Dec 1994 | A |
| 5409711 | Mapelli et al. | Apr 1995 | A |
| 5433959 | Makino et al. | Jul 1995 | A |
| 5439689 | Hendrickson et al. | Aug 1995 | A |
| 5445829 | Paradissis et al. | Aug 1995 | A |
| 5464632 | Cousin et al. | Nov 1995 | A |
| 5466464 | Masaki et al. | Nov 1995 | A |
| 5470584 | Hendrickson et al. | Nov 1995 | A |
| 5472708 | Chen | Dec 1995 | A |
| 5478573 | Eichel et al. | Dec 1995 | A |
| 5489436 | Hoy et al. | Feb 1996 | A |
| 5501861 | Makino et al. | Mar 1996 | A |
| 5506345 | Riley et al. | Apr 1996 | A |
| 5508040 | Chen | Apr 1996 | A |
| 5529790 | Eichel et al. | Jun 1996 | A |
| 5536507 | Abramowitz et al. | Jul 1996 | A |
| 5567441 | Chen | Oct 1996 | A |
| 5576014 | Mizumoto et al. | Nov 1996 | A |
| 5609883 | Valentine et al. | Mar 1997 | A |
| 5612059 | Cardinal et al. | Mar 1997 | A |
| 5616345 | Geoghegan et al. | Apr 1997 | A |
| 5629017 | Pozzi et al. | May 1997 | A |
| 5639475 | Bettman et al. | Jun 1997 | A |
| 5643630 | Hinzpeter et al. | Jul 1997 | A |
| 5700492 | Morimoto et al. | Dec 1997 | A |
| 5720974 | Makino et al. | Feb 1998 | A |
| 5738875 | Yarwood et al. | Apr 1998 | A |
| 5747068 | Mendizabal | May 1998 | A |
| 5762961 | Roser et al. | Jun 1998 | A |
| 5788987 | Busetti et al. | Aug 1998 | A |
| 5807577 | Ouali | Sep 1998 | A |
| 5837284 | Mehta et al. | Nov 1998 | A |
| 5837285 | Nakamichi et al. | Nov 1998 | A |
| 5837379 | Chen et al. | Nov 1998 | A |
| 5840329 | Bai | Nov 1998 | A |
| 5876759 | Gowan, Jr. | Mar 1999 | A |
| 5891474 | Busetti et al. | Apr 1999 | A |
| 5900252 | Calanchi et al. | May 1999 | A |
| 5908638 | Huber et al. | Jun 1999 | A |
| 5968554 | Beiman et al. | Oct 1999 | A |
| 6024981 | Khankari et al. | Feb 2000 | A |
| 6024982 | Oshlack et al. | Feb 2000 | A |
| 6033687 | Heinicke et al. | Mar 2000 | A |
| 6039979 | Gendrot et al. | Mar 2000 | A |
| 6096340 | Chen et al. | Aug 2000 | A |
| 6099859 | Cheng et al. | Aug 2000 | A |
| 6099863 | Gilis et al. | Aug 2000 | A |
| 6099865 | Augello et al. | Aug 2000 | A |
| 6103263 | Lee et al. | Aug 2000 | A |
| 6106861 | Chaveau et al. | Aug 2000 | A |
| 6106862 | Chen et al. | Aug 2000 | A |
| 6123962 | Makino et al. | Sep 2000 | A |
| 6129933 | Oshlack et al. | Oct 2000 | A |
| 6136345 | Grimmett et al. | Oct 2000 | A |
| 6139865 | Friend et al. | Oct 2000 | A |
| 6139877 | Debregeas et al. | Oct 2000 | A |
| 6153220 | Cumming et al. | Nov 2000 | A |
| 6162463 | Lippa | Dec 2000 | A |
| 6169105 | Wong et al. | Jan 2001 | B1 |
| 6183776 | Depui et al. | Feb 2001 | B1 |
| 6190692 | Busetti et al. | Feb 2001 | B1 |
| 6221392 | Khankari et al. | Apr 2001 | B1 |
| 6221402 | Itoh et al. | Apr 2001 | B1 |
| 6228398 | Devane et al. | May 2001 | B1 |
| 6269615 | Amborn et al. | Aug 2001 | B1 |
| 6287599 | Burnside et al. | Sep 2001 | B1 |
| 6316029 | Jain et al. | Nov 2001 | B1 |
| 6328994 | Shimizu et al. | Dec 2001 | B1 |
| 6344215 | Bettman et al. | Feb 2002 | B1 |
| 6350470 | Pather et al. | Feb 2002 | B1 |
| 6350471 | Seth | Feb 2002 | B1 |
| 6365182 | Khankari et al. | Apr 2002 | B1 |
| 6368625 | Siebert et al. | Apr 2002 | B1 |
| 6368628 | Seth | Apr 2002 | B1 |
| 6372253 | Daggy et al. | Apr 2002 | B1 |
| 6391335 | Pather et al. | May 2002 | B1 |
| 6413549 | Green et al. | Jul 2002 | B2 |
| 6420473 | Chittamuru et al. | Jul 2002 | B1 |
| 6432534 | Hayakawa et al. | Aug 2002 | B1 |
| 6465009 | Liu et al. | Oct 2002 | B1 |
| 6465010 | Lagoviyer et al. | Oct 2002 | B1 |
| 6495160 | Esposito et al. | Dec 2002 | B2 |
| 6500454 | Percel et al. | Dec 2002 | B1 |
| 6509036 | Pather et al. | Jan 2003 | B2 |
| 6531152 | Lerner et al. | Mar 2003 | B1 |
| 6551617 | Corbo et al. | Apr 2003 | B1 |
| 6579535 | Valentine et al. | Jun 2003 | B2 |
| 6596311 | Dobetti | Jul 2003 | B1 |
| 6602521 | Ting et al. | Aug 2003 | B1 |
| 6627223 | Percel et al. | Sep 2003 | B2 |
| 6641838 | Pather et al. | Nov 2003 | B2 |
| 6660382 | Nouri et al. | Dec 2003 | B2 |
| 6663888 | Percel et al. | Dec 2003 | B2 |
| 6663893 | Corbo et al. | Dec 2003 | B2 |
| 6740341 | Holt et al. | May 2004 | B1 |
| 6897205 | Beckert et al. | May 2005 | B2 |
| 7048945 | Percel et al. | May 2006 | B2 |
| 20010007680 | Kolter et al. | Jul 2001 | A1 |
| 20010014340 | Ohta et al. | Aug 2001 | A1 |
| 20010046964 | Percel et al. | Nov 2001 | A1 |
| 20020054907 | Devane et al. | May 2002 | A1 |
| 20020077348 | Dean et al. | Jun 2002 | A1 |
| 20020142034 | Shimizu et al. | Oct 2002 | A1 |
| 20020187190 | Cade et al. | Dec 2002 | A1 |
| 20030064108 | Lukas et al. | Apr 2003 | A1 |
| 20030096791 | Gupte et al. | May 2003 | A1 |
| 20030113374 | Percel et al. | Jun 2003 | A1 |
| 20030134884 | Hazama et al. | Jul 2003 | A1 |
| 20030157173 | Percel et al. | Aug 2003 | A1 |
| 20030161888 | Fernandez et al. | Aug 2003 | A1 |
| 20030215500 | Ohta et al. | Nov 2003 | A1 |
| 20040121010 | Hirsh et al. | Jun 2004 | A1 |
| 20040122106 | Ohta et al. | Jun 2004 | A1 |
| 20040126427 | Venkatesh et al. | Jul 2004 | A1 |
| 20040131682 | Percel et al. | Jul 2004 | A1 |
| 20040137156 | Lee et al. | Jul 2004 | A1 |
| 20040242536 | Khoo et al. | Dec 2004 | A1 |
| 20050025824 | Percel et al. | Feb 2005 | A1 |
| 20050118268 | Percel et al. | Jun 2005 | A1 |
| 20050152974 | Boehm et al. | Jul 2005 | A1 |
| 20050232988 | Venkatesh et al. | Oct 2005 | A1 |
| 20050269722 | De Luigi Brushci et al. | Dec 2005 | A1 |
| 20060057199 | Venkatesh et al. | Mar 2006 | A1 |
| 20060078614 | Venkatesh et al. | Apr 2006 | A1 |
| 20060105038 | Lai et al. | May 2006 | A1 |
| 20060105039 | Lai et al. | May 2006 | A1 |
| 20060246134 | Venkatesh | Nov 2006 | A1 |
| 20060269607 | Percel et al. | Nov 2006 | A1 |
| 20090263480 | Lai et al. | Oct 2009 | A1 |
| Number | Date | Country |
|---|---|---|
| 0052492 | Feb 1984 | EP |
| 0166440 | Jan 1986 | EP |
| 0239361 | Sep 1987 | EP |
| 0349103 | Jan 1990 | EP |
| 0357369 | Mar 1990 | EP |
| 0391518 | Oct 1990 | EP |
| 0431877 | Jun 1991 | EP |
| 0516345 | Dec 1992 | EP |
| 0538034 | Apr 1993 | EP |
| 0553777 | Aug 1993 | EP |
| 0650826 | May 1995 | EP |
| 0721777 | Jul 1996 | EP |
| 0815931 | Jan 1998 | EP |
| 0294493 | Dec 1998 | EP |
| 0914818 | May 1999 | EP |
| 0914823 | May 1999 | EP |
| 1010423 | Jun 2000 | EP |
| 0582396 | Jan 2001 | EP |
| 1070497 | Jan 2001 | EP |
| 1072257 | Jan 2001 | EP |
| 1157690 | Nov 2001 | EP |
| 1156786 | Mar 2003 | EP |
| 1366759 | Dec 2003 | EP |
| 0914823 | Dec 2004 | EP |
| 2319498 | May 2011 | EP |
| 2679451 | Jan 1993 | FR |
| 2766089 | Jan 1999 | FR |
| 2778848 | Nov 1999 | FR |
| 2053787 | Feb 1981 | GB |
| 8824392.8 | Sep 1989 | GB |
| 2224207 | May 1990 | GB |
| 41-11273 | Jun 1966 | JP |
| 49-69819 | Jul 1974 | JP |
| 55-129224 | Oct 1980 | JP |
| 56-014098 | Oct 1981 | JP |
| 61-143316 | Jul 1986 | JP |
| 62-50445 | Oct 1987 | JP |
| 62-242616 | Oct 1987 | JP |
| 62-246513 | Oct 1987 | JP |
| 62-252723 | Nov 1987 | JP |
| 63-162619 | Jul 1988 | JP |
| 63-270624 | Nov 1988 | JP |
| 1-503385 | Nov 1989 | JP |
| 1-313420 | Dec 1989 | JP |
| 2-500747 | Mar 1990 | JP |
| 2-164824 | Jun 1990 | JP |
| 2-172918 | Jul 1990 | JP |
| 2-289512 | Nov 1990 | JP |
| 3-240724 | Oct 1991 | JP |
| 5-271054 | Oct 1993 | JP |
| 5-310558 | Nov 1993 | JP |
| 6-53658 | Jul 1994 | JP |
| 6-321790 | Nov 1994 | JP |
| 7-69889 | Mar 1995 | JP |
| 7-124231 | May 1995 | JP |
| 8-503482 | Apr 1996 | JP |
| 8-175978 | Jul 1996 | JP |
| 550608 | Nov 2005 | NZ |
| 554346 | May 2006 | NZ |
| WO 8808703 | Nov 1988 | WO |
| WO 8808704 | Nov 1988 | WO |
| WO 9210173 | Jun 1992 | WO |
| WO 9300097 | Jan 1993 | WO |
| WO 9312769 | Jul 1993 | WO |
| WO 9313758 | Jul 1993 | WO |
| WO 9315724 | Aug 1993 | WO |
| WO 9408576 | Apr 1994 | WO |
| WO 9412180 | Jun 1994 | WO |
| WO 9741878 | Nov 1997 | WO |
| WO 9747287 | Dec 1997 | WO |
| WO 9904763 | Feb 1999 | WO |
| WO 0025752 | May 2000 | WO |
| WO 0033821 | Jun 2000 | WO |
| WO 0042998 | Jul 2000 | WO |
| WO 0051568 | Sep 2000 | WO |
| WO 0059486 | Oct 2000 | WO |
| WO 0113898 | Mar 2001 | WO |
| WO 0172285 | Oct 2001 | WO |
| WO 0180829 | Nov 2001 | WO |
| WO 0213794 | Feb 2002 | WO |
| WO 0243704 | Jun 2002 | WO |
| WO 02057475 | Jul 2002 | WO |
| WO 02085336 | Oct 2002 | WO |
| WO 03013492 | Feb 2003 | WO |
| WO 03039520 | Mar 2003 | WO |
| WO 03026613 | Apr 2003 | WO |
| WO 03041683 | May 2003 | WO |
| WO 03047552 | Jun 2003 | WO |
| WO 2004009058 | Jan 2004 | WO |
| WO 2004022037 | Mar 2004 | WO |
| WO 2004087111 | Oct 2004 | WO |
| WO 2005097064 | Oct 2005 | WO |
| WO 2005105049 | Nov 2005 | WO |
| Entry |
|---|
| “Low Substituted Hydroxypropylcellulose,” Official Monographs for Part II, 2001, NRF, JP XIV, pp. 942-943. |
| Albrecht, “International Search Report,” 6 pages, from International Patent Appl. No. PCT/US02/31535, European Patent Office (Feb. 3, 2003). |
| Anwar et al., “Chronotherapeutics for Cardiovascular Disease,” Drugs 55(5):631-643 (1998). |
| Bauer et al., Pharmarzeutische Technologie, 5th Edition, 1997, Govi Verlag Frankfurt, pp. 164-166. |
| Berigan, “Atomoxetine Used Adjunctively With Selective Serotonin Reuptake Inhibitors to Treat Depression,” Prim. Care. Companion J. Clin. Psychiatry 6(2):93-94 (2004). |
| Bodmeier et al., “Theophylline Tablets Coated with Aqueous Latexes Containing Dispersed Pore Formers,” J. Pharm. Sci. 79(10):925-928 (1990). |
| Database WPI, Section Ch, Week 198748, Derwent Publications, Ltd., London, GB; AN 1987-338131, XP002156870. |
| Fell, Letter to The Editor, J. Pharm. Pharmacol. 1968, vol. 20, pp. 657-658. |
| FMC Corporation Product Specification for Avicel PH, 2005. |
| Foreign non-patent publication from Japanese textbook, 1989, Hirokawa Publishing Co. |
| Foreign non-patent publication Sysmex No. FP30SCJ001. |
| Fubara, “International Preliminary Examination Report,” 3 pages, from International Patent Appl. No. PCT/US02/31535, European Patent Office (Jun. 19, 2003). |
| Gordon et al., “Effect of the Mode of Super Disintegrant Incoproration on Dissolution in Wet Granulated Tables,” J. Pharm. Sci. 82:220-226 (1993). |
| Gorman et al., An Evaluation of Croscarmellose as a Tablet Disintegrant in Direct Compression Systems, Drug. Dev. Ind. Pharm. 1982; vol. 8, pp. 397-410. |
| Handbook (Binran) of Granule, vol. 1, Ohmsha Ltd., p. 434 & 438 (May 3, 1975). |
| Ishino et al., “Design and Preparation of Pulsatile Release Tablet as a New Oral Drug Delivery System,” Chem. Pharm. Bull. 40(11):3036-3041 (1992). |
| Kaneto et al., 2000, Latest Pharmacy, Hirokawa Publishing Co., 1 Edition. |
| Kawashima, “Low-Substituted Hydroxypropylcellulose as a Sustained-Drug Release Matrix Base or Disintegrant Depending on Its Particle Size and Loading in Formulation,” Pharm. Res. 1993, vol. 10(3), pp. 351-355. |
| Kornblum, “A New Tablet Disintegrating Agent,” J. Pharm. Sci., Jan. 1973, vol. 62(1), pp. 43-49. |
| Kratochvil et al., “Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder,” Exp. Opin. Pharmacother. 4(7):1165-1174 (2003). |
| McKenna et al., “Effect of particle size on the compaction mechanism and tensile strength of tablets,” J. Pharm. Pharmacol. Jun. 1982, vol. 34(6), pp. 347-351. |
| McKetta et al., “Table of Contents,” Encyclopedia of Chemical Processing and Design (1989). |
| McKetta et al., Encyclopedia of Chemical Processing and Design, “Organic Phase Separation Conservation,” p. 167 (1989). |
| Mitsuo et al., Pharmaceutics Manual, 1989, Pharmaceutics Manual, Nanzando Co. Ltd. |
| Nwokole et al., “Tolerance during 29 days of conventional dosing with cimetidine, mizatidine, famotidine or ranitidine,” Aliment. Pharmacol. Ther. 4(Suppl. 1):29-45 (1990) Abstract only. |
| Oh, “International Preliminary Report on Patentability,” 5 pages, from International Appl. No. PCT/US2005/037084, United States Patent and Trademark Office, Alexandria, Virginia, USA (mailed Aug. 24, 2007). |
| Ohira et al., “Effects of Various Histamine H2-Receptor Antagonists on Gastrointestinal Motility and Gastric Emptying,” J. Smooth Muscle Res. 29:131-142 (1993). |
| Pharmaceutical Excipients. London: Pharmaceutical Press. Electronic Version, 2006, Mannitol. |
| Pharmaceutical Excipients. London: Pharmaceutical Press. Electronic Version, 2006, Lactose Monohydrate. |
| Pharmaceutical Excipients. London: Pharmaceutical Press. Electronic Version, 2006, Croscarmellose sodium. |
| Rankin, “International Search Report,” 6 pages, PCT International Application No. PCT/US02/39238, European Patent Office (May 8, 2003). |
| Rudnic et al., “Some Effects of Relatively Low Levels of Eight Tablet Disintegrants on a Direct Compression System,” Drug. Dev. Ind. Pharm. 1981, vol. 7(3), pp. 347-358. |
| Rudnic et al., “Studies of the Utility of Cross Linked Polyvinlpolypyrrolidine as a Tablet Disintegrant,” Drug Development and Industrial Pharmacy, 1980, vol. 6, No. 3, pp. 291-309. |
| Sato et al., “Anticonvulsant effects of tigabine, a new antiepileptic drug: the profile of action in the rat kindling model of epilepsy,” Epilepsia 37(Supp. 3):110-111 (1996). |
| Schifferer, “International Search Report,” 4 pages, from International Appl. No. PCT/US2005/037084, European Patent Office, Rijswijk, The Netherlands (mailed Jun. 1, 2006). |
| Schifferer, “Written Opinion of the International Search Authority,” 6 pges, from International Appl. No. PCT/US2005/037084, European Patent Office, Munich, Germany (mailed Jun. 1, 2006). |
| Shangraw et al., “A new era of tablet disintegrants,” Pharm. Technol. 1980, vol. 4(10), pp. 49-57. |
| Tirkkonen and Paronen, “Enhancement of drug release from ethylcellulose microcapsules using solid sodium chloride in the wall,” Int. J. Pharmaceutics 88:39-51 (1992). |
| Trottier and Wood, 2005, “Particle Size Measurement,” Kirk-Othmer Encyclopedia of Chemical Technology (Extract of 1. Introduction; 2. Data Representation; 4. Measurement Methods; 8. Selection of Equipment). |
| Ueki et al., “Nizatidine Comparably Enhances Postprandial Gastric Motility to Existing Gastroprokinetics in Dogs,” Jpn. Pharmacol. Ther. 28(11):925-930 (2000). |
| Uhl, “International Search Report,” 5 pages, International Patent Appl. No. PCT/US2006/016538, European Patent Office (Feb. 27, 2007). |
| Uhl, “Written Opinion of the International Searching Authority,” 6 pages, International Patent Appl. No. PCT/US2006/016538, European Patent Office (Feb. 27, 2007). |
| van Kamp et al., “Improvement by super disintegrants of the properties of tablets containing lactose, prepared by wet granulation,” Pharmaceutisch Weekblad Scientific Edition; 1983, vol. 5, pp. 165-171. |
| Villa, “International Search Report,” 4 pages, from International Appl. No. PCT/US2005/038328, European Patent Office, Rijswijk, The Netherlands (mailed Sep. 15, 2006). |
| Villa, “Written Opinion of the International Search Authority,” 5 pages, from International Appl. No. PCT/US2005/038328, European Patent Office, Munich, Germany (mailed Sep. 15, 2006). |
| Vromans et al., “Studies on tableting properties of lactose,” Pharmaceutisch Weekblad Scientific Edition; 1985, vol. 7, pp. 186-193. |
| Yamahara et al., “Effect of release rate on bioavailability of control-release multiple unit dosage forms,” Yakuzaigaku 55(2):99-107 (1995). |
| Yamamoto et al., “The Effects of Nizatidine on the Function of Esophageal Motility in Patients with Gastroesophageal Reflux Disease (GERD),” Jpn. Pharmacol. Ther. 28(5):419-424 (2000). |
| Young, “International Preliminary Examination Report” 6 pages, PCT International Application No. PCT/US02/39238, United States Patent and Trademark Office (Apr. 27, 2005). |
| Young, “Written Opinion,” 5 pages, PCT International Application No. PCT/US02/39238, United States Patent and Trademark Office (Jan. 13, 2005). |
| Zheng et al., “Influence of Eudragit® NE 30 D Blended with Eudragit® L 30 D-55 on the Release of Phenylpropanolamine Hydrochloride from Coated Pellets,” Drug Development and Industrial Pharmacy 29(3):357-366 (2003). |
| Zimmer, “European Search Report,” 3 pages, European patent appl. No. 01103129.1, European Patent Office (Jun. 9, 2001). |
| Zimmer, “International Search Report,” 4 pages, PCT International Application No. PCT/US01/04012, European Patent Office (Jun. 19, 2001). |
| Number | Date | Country | |
|---|---|---|---|
| 20040047906 A1 | Mar 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 09971167 | Oct 2001 | US |
| Child | 10334052 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10334052 | Dec 2002 | US |
| Child | 10453848 | US |
