WO2008058234A2

WO2008058234A2 - Pharmaceutical formulations for 1,4-dihyrdropyridine compounds having improved solubility

Info

Publication number: WO2008058234A2
Application number: PCT/US2007/084068
Authority: WO
Inventors: Ashok Tehim
Original assignee: Memory Pharmaceuticals Corporation
Priority date: 2006-11-08
Filing date: 2007-11-08
Publication date: 2008-05-15
Also published as: WO2008058234A3

Abstract

A pharmaceutical composition comprising a 1,4-dihydropyridine pharmaceutical agent, particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate), a mixture of glycerol and PEG1500 esters of long fatty acids having a melting point of approximately 44 °C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14) and d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), and further optionally comprising polyethylene glycol-15-hydroxystearate (Solutol-HS 15) and/or polyoxyl castor oil (Cremophor-EL), exhibits enhanced solubility characteristics.

Description

PHARMACEUTICAL FORMULATIONS FOR 1,4-DIHYDROPYRIDINE COMPOUNDS HAVING IMPROVED SOLUBILITY

The present invention relates to pharmaceutical formulations comprising at least one 1,4-dihydropyridine compound, particularly the compound (+)-isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)- 1 ,4-dihydro-2,6-dimethyl-pyridine-3 ,5- dicarboxylate, having enhanced solubility.

1,4-Dihydropyridine compounds are used as potassium channel modulators and calcium channel blockers in the treatment of various diseases and conditions. See, e. g., US 6,147, 087 and US 5,665,740. 1,4-dihydropyridine compounds are known to have vasodilating activity and can be used as coronary agents and antihypertensive agents. 1,4-Dihydropyridines inhibit contractility of smooth and cardiac muscles and thus can be used in the treatment of coronary and vascular disease. See, e.g., US 5,629,320 and US 5,420,142. Additionally, 1,4-dihydropyridine s may be used to treat disorders of the central nervous system. Thus, 1,4-Dihydropyridine compounds are suitable for use in the treatment of various diseases and conditions.

For example, US 6,147,087 discloses a genus of 1,4-bridged 1 ,4-dihydropyridines as selective potassium channel modulators suitable for treating disorders of the central nervous system, such as dementias (for example, multiinfarct dementia (MID), primary degenerative dementia (PDD), pre- and senile Alzheimer's disease, HIV dementia, etc.), Parkinson's disease, amyotropic lateral sclerosis (ALS) and multiple sclerosis (MS). The compounds can also be used, for example, in the treatment of brain function disorders in old age, organic brain syndrome (OBS), and age-related memory disorders such as age- associated memory impairment (AAMI).

US 5,629,320 discloses a genus of 3-quinolyl-substituted dihydropyridines. The compounds are said to be cardiovascular agents and thus suitable for use in influencing pathologically altered blood pressure, treating of cardiac insufficiency, and treating disturbances in cardiac rhythm. US 5,420,142 discloses a genus of 3-formyl-l,4-dihydropyridine. These compounds are also said to be useful in the treatment of cardiovascular diseases. Additional 1 ,4-dihydropyridine compounds for use as pharmaceutical agents are described in, for example, US 6,995,179, US 6,852,742, US 6,653,313, and US 6,306,853.

There are many known 1 ,4-dihydropyridine calcium channel blocker agents, for example, amlodipine (antihypertensive), felodipine (vasodilater), isradipine (antihypertensive), lacidipine (antihypertensive), lercanidipine (antihypertensive), nicardipine(vasodilater), nifedipine (vasodilater), nimodipine (vasodilater), nitrendipine(antihypertensive), and nisoldipine (vasodilater).

Meier at al. (US 5,665,740), the entire disclosure of which is hereby incorporated by reference, disclose that the compound, (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3- cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate, has a positive effect on learning and memory powers and has antidepressant potential. US 5,665,740 further discloses that (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro- 2,6-dimethyl-pyridine-3,5-dicarboxylate can be employed for: the treatment of central degenerative disorders, as, for example, occur in dementias (multi-infarct dementia, MID, primary degenerative dementia PDD, pre- and senile Alzheimer's disease, HIV dementia and other forms of dementia), Parkinson's disease or tropic lateral sclerosis; the treatment of cerebral function disorders in old age, of organic brain syndrome (OBS) and of age- associated memory impairment (AAMI); the prophylaxis and control of the sequelae of cerebral circulatory disorders such as cerebral ischaemias, strokes and of subarachnoid haemorrhages; the treatment of depressions and of mania; the treatment of migraines; the treatment of neuropathies, which are caused, e.g., by metabolic disorders such as diabetes mellitus, traumas, intoxifications, microorganisms or autoimmune disorders; the treatment of addictive disorders; and the treatment of withdrawal symptoms. US 2005/0153953 discloses, among other things, the use of L-type calcium channel blockers, such as (+)-isopropyl 2-methoxyethyl-4-(2-chloro-3-cyano-phenyl)- l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate, in combination with a cholinesterase inhibitor for the treatment of memory and/or cognitive impairment.

WO 2005/051389 discloses the use (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3- cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate for the treatment of various memory and cognitive disorders.

However, while 1 ,4-dihydropyridine derivatives are known for use as pharmaceutical agents, such compounds often have poor solubility in water. For example, US 4,976,964 discloses that due to their poor solubility, 1 ,4-dihydropyridines were often formulated with organic solvents to prepare parenteral formulations. However, organic solvents can lead to adverse effects. To address this problem, US 4,976,964 provides a liposomal formulation of dihydropyridines. However, there are disadvantages associated with the use of liposomes. For example, liposomes formulations can be unstable, and, in general, only small amounts of agent can be incorporated in a liposome. Further, liposomes may also present manufacturing disadvantages. Difficulties in using liposomes as drug delivery systems have also been reported by Meisner in Chapter 3, page 31 of Pharmaceutical Particulate Carriers- Therapeutic Applications, A. Roland, ed., Marcel Dekker, 1993.

The enhancement of oral bioavailability of drugs that are poorly water soluble remains one of the most challenging aspects of drug development. Although salt formation, solubilization and micronization have commonly been used to enhance the in vitro dissolution rate and thereby oral absorption and bioavailability, there are practical difficulties. The use of very fine powders may still be problematic to handle due to poor wettability characteristics.

There is therefore a need for formulations for 1 ,4-dihydropyridine pharmaceutical agents, in particular (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4- dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate, that possess greater solubility in pharmaceutically acceptable carriers and excipients.

Thus, according to an aspect of the invention, there is provided a formulation containing a 1 ,4-dihydropyridine pharmaceutical agent (such as (+)-isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)- 1 ,4-dihydro-2,6-dimethyl-pyridine-3 ,5- dicarboxylate), pharmaceutically acceptable excipients, and a carrier, wherein the agent exhibits greater solubility. In particular, the formulation is one suitable for use filling hard capsules. Thus, another aspect of the invention is a dosage unit form containing the above-mentioned formulation in a hard capsule.

According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)- isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)- 1 ,4-dihydro-2,6-dimethyl- pyridine-3,5-dicarboxylate), a mixture of glycerol and PEG1500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14) and d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), and further optionally comprising polyethylene glycol- 15- hydroxystearate (Solutol-HS 15) and/or polyoxyl castor oil (Cremophor-EL).

According to a further aspect of the invention there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)- isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)- 1 ,4-dihydro-2,6-dimethyl- pyridine-3,5-dicarboxylate), Gelucire 44/14, Vitamin E TPGS, and Solutol-HS 15, and further optionally comprising Cremophor-EL.

According to a further aspect of the invention there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)- isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)- 1 ,4-dihydro-2,6-dimethyl- pyridine-3,5-dicarboxylate), Gelucire 44/14, Vitamin E TPGS, and Cremophor-EL, and further optionally comprising Solutol-HS 15. In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing 25-90 wt.% Gelucire 44/14, 10-75 wt.% Vitamin E TPGS, 0-50 wt.% Cremophor-EL, and 0-50 wt.% Solutol-HS 15, based on the total weight of the mixture.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent

(particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing 25-90 wt.% Gelucire 44/14, 10-75 wt.% Vitamin E TPGS, 10-50 wt.% Cremophor-EL, and 0-50 wt.% Solutol-HS 15, based on the total weight of the mixture.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing 25-90 wt.% Gelucire 44/14, 10-75 wt.% Vitamin E TPGS, 0-50 wt.% Cremophor-EL, and 10-50 wt.% Solutol-HS 15, based on the total weight of the mixture.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing 25-90 wt.% Gelucire 44/14, 10-75 wt.% Vitamin E TPGS, 10-50 wt.% Cremophor-EL, and 10-50 wt.% Solutol-HS 15, based on the total weight of the mixture.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing 40-75 wt.% Gelucire 44/14, 7-40 wt.% Vitamin E TPGS, 0-35 wt.% Cremophor-EL, and 0-20 wt.% Solutol-HS 15, based on the total weight of the mixture.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing 50-70 wt.% Gelucire 44/14, 10-40 wt.% Vitamin E TPGS, 0-35 wt.% Cremophor-EL, and 0-20 wt.% Solutol-HS 15, based on the total weight of the mixture.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing 45-55 wt.% Gelucire 44/14, 10-15 wt.% Vitamin E TPGS, 20-30 wt.% Cremophor-EL, and 10-15 wt.% Solutol-HS 15, based on the total weight of the mixture.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing 60-70 wt.% Gelucire 44/14, 30-40 wt.% Vitamin E TPGS, 0-5 wt.% Cremophor-EL, and 0-5 wt.% Solutol-HS 15, based on the total weight of the mixture.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing about 50 wt.% Gelucire 44/14, about 25 wt.% Vitamin E TPGS, and about 25 wt.% Cremophor-EL, based on the total weight of the mixture. In this context, "about" means + 2.0 wt.%.

(particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing about 50 wt.% Gelucire 44/14, about 18.8 wt.% Vitamin E TPGS, about 12.5 wt.% Cremophor-EL, and 18.8 wt.% Solutol-HS 15, based on the total weight of the mixture. In this context, "about" means + 2.0 wt.%.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing about 50 wt.% Gelucire 44/14, about 12.5 wt.% Vitamin E TPGS, about 12.5 wt.% Cremophor-EL, and about 12.5 wt.% Solutol-HS 15, based on the total weight of the mixture. In this context, "about" means + 2.0 wt.%.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition comprising a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture containing about 65 wt.% Gelucire 44/14, about 35 wt.% Vitamin E TPGS, 0-2 wt.% Cremophor-EL, and 0-2 wt.% Solutol-HS 15, based on the total weight of the mixture. In this context, "about" means + 2.0 wt.%.

It is known that dissolution of poorly soluble drugs can be improved by incorporating the drugs in liquid/semi solid formulations that are then used to fill hard capsules. Liquid-filled capsule technology (LFC) can be used for liquid and semi-solid fills in two-piece gelatin or hydroxypropyl methylcellulose (HPMC) capsules with or without banding. Liquid-filled, hard-shell capsule technology has recently gained greater popularity due to its ability to improve bioavailability, enhance chemical stability, improve content uniformity, and its suitability for use in controlled release applications.

Despite the many benefits, developing a two piece capsule for holding a liquid formulation still presents challenges. The most critical step in designing a liquid based formulation is determining a vehicle/solvent system. A wide array of solubilizers, co- solvents, surfactants and emulsifying agents are available to achieve the desired solubility and pharmacokinetics characteristics. The use of these materials is limited by their permissible daily intake levels, individual solubilizing capacities, and compatibility with the shell.

The following discussion describes the analysis used to arrive at an improved formulation for a 1 ,4-dihydropyridine agent. In this analysis, (+)-isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5- dicarboxylate was used as the 1,4-dihydropyridine agent, however, the formulation is believed to be suitable for use with other 1,4-dihydropyridine agents. Additional details regarding the following experiments are described in Kiran Kumar Tumbalam, Unmesh Deodhar, Anil Kane, Mougang Hu, Tanya Tadey, Kadriye Ciftci, Stuart Madden "AN EXCIPIENT MIXTURE APPROACH TO IMPROVE SOLUBILITY, DRUG

LOADING AND DISSOLUTION OF A BCS CLASS II COMPOUND IN LIQUID FILLED HARD GELATIN CAPSULES," poster presented at AAPS, Nashville, TN on November 9, 2005; and Anil Kane, Kiran Kumar Tumbalam, Mougang Hu, Tanya Tadey "A STATISTICAL MIXTURE DESIGN APPROACH FOR FORMULATING POORLY SOLUBLE COMPOUNDS IN LIQUID FILLED HARD SHELL CAPSULE" Bulletin Technique Gattefosse No. 99(2006) 43-49.

The entire disclosures of all applications, patents and publications, cited above and below, are hereby incorporated by reference.

Solubility Studies (+)-Isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate, hereafter called Compound A, has an aqueous solubility of 0.0016 mg/mL. Initially, several possible vehicles were investigated for visual solubility at ambient temperature. These vehicles selected on the basis of compatibility with gelatin. See Table 1.

Table 1: Vehicles evaluated at Ambient Temperature

Also known as polyoxyethylenglyceroltriricinoleat 35 (DAC) or polyoxyl 35 castor oil, Cremophor EL, manufactured by BASF, is a non-ionic solubilizer and emulsifier obtained by causing ethylene oxide to react with castor oil of German Pharmacopoeia (DAB 8) quality in a molar ratio of 35 moles to 1 mole. The main component of Cremophor EL is glycerol-polyethylene glycol ricinoleate, which, together with fatty acid esters of polyethylene glycol, represents the hydrophobic part. The smaller, hydrophilic part is made of polyethylene glycols and ethoxylated glycerol. Cremophor EL is a pale yellow, oily liquid that is clear at temperatures above 26 ⁰C. The hydrophilic-lipophilic balance (HLB) lies between 12 and 14.

Solutions were prepared at approximately a ratio of 1:10 (Compound A: Vehicle). The solutions were further sonicated for 30 minutes and subsequently shaken in a mechanical shaker for ~8 hours. However, none of the vehicles has demonstrated adequate solubility at ambient temperature, i. e., they were not able to solubilize the drug or form a clear solution at the target dosage of 30 mg per capsule. The results are given in Table 2.

Table 2: Solubility Studies at Ambient Temperature

Thereafter, further solubility studies were conducted at elevated temperatures (~

60⁰C) using solutions having an approximate ratio of 1:10 (Compound A: Vehicle). The solutions were formed by indirect heat with intermittent manual stirring. Some of the above excipients were semi-solid at room temperature, but melted above 55°C. Table 3 lists the vehicles evaluated at elevated temperature.

Table 3: Excipients evaluated at Elevated Temperatures

Gelucire 44/14 (Gattefosse S. A., Saint-Priest Cedex, France) is a mixture of glycerol and PEGl 500 esters of long fatty acids (44 and 14 refer, respectively, to its melting point and its hydrophilic/lipophilic balance (HLB)). The main components are polyethylene glycol (PEG), PEG monolaurate and PEG dilaurate (PEG esters), trilaurin (glyceride) and glycerol.

Solutol HS 15(BASF) is polyethylene glycol- 15 -hydroxystearate (also known as Polyethylene glycol 660 12-hydoxystearate, Macrogol-15-hydroxistearate, and Macrogoli 15 hydroxystearas). It is a yellowish white paste at room temperature that becomes liquid at approximately 30⁰C. The hydrophilic-lipophilic balance lies between 14 and 16.

Some of the excipients were able to solubilize Compound A at the target dosage strength of 30 mg/capsule. The results are indicated in Table 4. Table 4: Solubility Studies at Elevated Temperature

Following the solubility tests at elevated temperature, certain vehicles were further evaluated for their solubilizing capacity by saturation with Compound A at elevated temperature (55⁰C - 80⁰C). After initial formation of the solutions, incremental amounts of Compound A were added until a clear residual amount of un- dissolved Compound A was visually observed. The vehicles tested are listed in Table 5. Table 5: Saturation Studies with selected excipients

Gelucire 44/14, Gelucire 50/13, PEG - 400, Cremophor EL, Solutol HS 15, Vitamin E TPGS, and Polysorbate 20 were found to have excellent visual solubility (up to 3 fold increase in drug load). These promising excipients were further encapsulated in

LICAPS® at near saturation point and subjected to an in-vitro dissolution study.

Licaps® capsules (by CAPSUGEL) are two-piece gelatin capsules that have been specially designed to be sealed for secure containment of liquids and semi-solids. The results of the in-vitro dissolution study are presented in Figure 1.

Mixture Experiments

The above studies involved solutions of one vehicle or excipient and Compound A. Since the individual excipients showed varying properties, it was decided to investigate whether a mixture of two or more excipients would achieve desirable in-vitro dissolution and in-vivo bio availability of Compound A.

However, if mixtures of excipients are involve, it is self-evident that changing the proportion of one ingredient will immediately influence the proportion of the others. As a result, different strategies are used in choosing appropriate experimental designs. See, e.g., C. M. Anderson-Cook et al., "Mixture and Mixture-Process Variable Experiments for Pharmaceutical Applications, Pharmaceutical Statistics," 2004; 3: 247-260.

Using experimental data derived from a selected number of formulations, a statistical model can be developed to allow predictions of drug solubility in co-solvent systems. See, e.g., D. Stephens, "A Statistical Experimental Approach to Co-solvent Formulation of a Water-insoluble Drug," Drug Development and Industrial Pharmacy, 25 (8), 961-965 (1999). Based upon the literature, the in-vitro dissolution data obtained from the solubility studies at elevated temperature, and the solubility studies on selected excipients, four excipients, Gelucire 44/14, Solutol-HS 15, Vitamin E TPGS, and Cremophor-EL, were selected as excipients for use in the co-solvent or mixture investigation to determine if mixtures using two or more of the selected four excipients would result in a formulation having desired in-vitro dissolution profile and in-vivo bioavailability characteristics. Gelucire 44/14 demonstrated a promising solubility with respect to Compound A, and thus was used as one of the solvents in each of the solvent mixtures investigated.

It is known that Gelucire 44/14 contains a well balanced proportion of short, medium and long chain fatty acids. The distribution of glyceride esters and mono- and di-esters of polyethylene glycol in this Gelucire grade result in excellent emulsifying properties in contact with physiological liquids at ~37°C. Gelucire 44/14 is also described as a possible enhancer of bio-availability. See, e.g., Technical Brochure of Gelucire® 44/14 IMMEDIATE RELEASE AND ENHANCED BIO AVAILABILITY, Gattefosse Inc., p 13. Solutol HS-15 has been mentioned as a very efficient solubilizing substance for active ingredients of hydrophobic nature. Vitamin E TPGS is itself water soluble and is claimed to enhance the bioavailability of lipid-soluble drugs that are otherwise difficult to absorb. Cremophor-EL is a solubilizer and emulsifier.

To investigate the mixture composition, a set of experiments were performed using the mixtures of the four promising excipients described in proposed as described in Table 6. This series of different mixtures was designed using JMP 5.1 software.

The amount of Compound A dissolved in 60 minutes in the dissolution study was the criteria for this mixture investigation. During these experiments, excipients were heated at a temperature of ~ 60⁰C - 70⁰C and Compound A was added to the molten mixture of excipients and stirred until dissolved. The molten mixture/clear solution was then encapsulated in LICAPS® and subjected for in-vitro dissolution. The in-vitro dissolution data for the mixture experiments is also presented in Table 6. From the series of 26 mixture experiments designed by mixture design, eight combinations had satisfactory in-vitro dissolution values, i.e., mixture nos. 3, 5, 6, 9, 17, 19, 21, and 25. Figure 2 depicts the in-vitro dissolution behavior of these eight mixtures. The target dose per capsule was 75 mg.

Table 6: Mixture Compositions (wt. %)

Prototype Stability Experiments

Based upon the in-vitro dissolution data from the mixture experiments, mixture nos. 3, 5, 6, 9, 17, 19, 21, and 25 were formulated as prototype formulations (Batch size: 1500 capsules; target dose: 60mg/capsule) and the capsules were subjected to banding. The prototype nos. are listed in Table 6. Along with these prototypes, a formulation consisting Gelucire 44/14 as a sole excipient (Prototype # 1) was prepared for purposes of comparison. The prototype formulations were prepared as follows:

1. The excipients were melted at ~ 65°C and mixed to form a clear solution;

2. Compound A was added to the solution and the contents were mixed until a clear solution was obtained; and

3. The mixtures of step 2 were encapsulated in LICAPS® at temperature below 70⁰C.

The prototype formulations were then subjected to accelerated stability studies to evaluate the efficacy of mixture design approach. Initially, the prototypes were subjected to a dissolution study to determine the dissolution profile of nine prototype formulations at T= 0. These dissolution profiles are depicted in Figure 3. The in-vitro dissolution studies involved dissolving the prototypes in a 0.1 N HCl dissolution medium (900 mL) containing 1% SDS (Sodium Dodecyl Sulphate). Dissolution was performed in a USP Apparatus 2 (paddles) at a temperature of 37.0 + 0.5⁰C and a paddle speed of 75 rpm. The dissolution data for T=O is presented in Table 7.

Table 7: In-vitro Dissolution data at T= 0 (Mean % dissolved)

1 Infinity - Change of dissolution parameters to paddle speed 250 rpm for 15 minutes after the last sampling point. All the prototypes achieved greater than 60% dissolution in 60 minutes. Of these prototypes, Prototype 2, Prototype 3, Prototype 6 and Prototype 8 achieved >80% dissolution in 60 minutes at start of stability study. The prototypes were subjected to an accelerated stability study by storing the prototypes at 40°C/75%RH (relative humidity) and at 25°C/60% RH. Based upon the dissolution data observed after 2 weeks and 2 months of stability at 40°C/75%RH, three prototypes were selected for further stability studies at T =3 months at 40°C/75%RH. Tables 8-10 present the dissolution data for T= 2 weeks, T= 2 months, and T =3 months, respectively, at 40°C/75%RH.

Table 8: In-vitro Dissolution data at T= 2 weeks at 40°C/75%RH

(Mean % dissolved)

¹ Infinity - Change of dissolution parameters to paddle speed 250 rpm for 15 minutes after the last sampling point.

Table 9: In- vitro Dissolution data at T= 2 months at 40°C/75%RH

(Mean % dissolved)

Table 10: In- vitro Dissolution data at T= 3 months at 40°C/75%RH

(Mean % dissolved)

Infinity - Change of dissolution parameters to paddle speed 250 rpm for 15 minutes after the last sampling point

Thereafter, these same three prototypes were tested at T=6 months at 40°C/75%RH. Additionally, all 9 prototypes were tested at 25°C/60%RH at T=6 months, and the three previously selected prototypes (Prototypes 1, 3, and 6) were tested at T= 12 months at 25°C/60%RH.

At accelerated conditions, the six months stability data for the three selected prototypes, i.e., Prototypes 1, 3, and 6, demonstrated that the formulations are chemically stable. Their in-vitro dissolution at 40°C/75%RH is depicted in Figure 4 (T=6 months). Prototype 1 (Gelucire 44/14 as only excipient) demonstrated a drop in dissolution from 71% at T= 0 to 47% at T= 6 Months at 40°C/75%RH, where as Prototype 3 demonstrated no significant change in dissolution (80% at T=O vs. 79% at T= 6 M). Figure 5 depicts the stability data (in-vitro dissolution) for all 9 prototypes at T=6 months at 25°C/60% RH.

As mentioned, for the three selected prototypes, i.e., Prototypes 1, 3, and 6, were continued for stability studies up to T= 12 Months at 25°C/60% RH. The resultant stability data (in-vitro dissolution) are depicted in Figure 6. It is evident from the T= 12

M stability that Prototype 3 (85.0% release) and Prototype 6 (77.0% release) performed better in comparison with Prototype 1 (52.0% release).

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

WE CLAIM:

1. A pharmaceutical composition comprising: a 1 ,4-dihydropyridine pharmaceutical agent, a mixture of glycerol and PEG 1500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), and optionally polyethylene glycol- 15 -hydroxys tearate (Solutol-HS 15) and/or polyoxyl castor oil (Cremophor-EL).

2. A composition according to claim 1, wherein said composition contains polyethylene glycol- 15 -hydroxys tearate (Solutol-HS 15), and optionally contains polyoxyl castor oil (Cremophor-EL).

3. A composition according to claim 1, wherein said composition contains polyoxyl castor oil (Cremophor-EL) polyethylene glycol- 15 -hydroxystearate (Solutol-HS 15), and optionally contains polyethylene glycol- 15 -hydroxys tearate (Solutol-HS 15).

4. A composition according to claim 1 , wherein said composition contains a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains 25-90 wt.% of a mixture of glycerol and

PEGl 500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), 10-75 wt.% of d- alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 0-50 wt.% of polyoxyl castor oil (Cremophor-EL), and 0-50 wt.% of polyethylene glycol- 15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

5. A composition according to claim 1, wherein said composition contains a 1,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains 25-90 wt.% of a mixture of glycerol and

PEGl 500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), 10-75 wt.% of d- alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 10-50 wt.% of polyoxyl castor oil (Cremophor-EL), and 0-50 wt.% of polyethylene glycol- 15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

6. A composition according to claim 1 , wherein said composition contains a 1,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains 25-90 wt.% of a mixture of glycerol and PEGl 500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), 10-75 wt.% of d- alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 0-50 wt.% of polyoxyl castor oil (Cremophor-EL), and 10-50 wt.% of polyethylene glycol-15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

7. A composition according to claim 1, wherein said composition contains a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains 25-90 wt.% of a mixture of glycerol and PEGl 500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), 10-75 wt.% of d- alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 10-50 wt.% of polyoxyl castor oil (Cremophor-EL), and 10-50 wt.% of polyethylene glycol-15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

8. A composition according to claim 1, wherein said composition contains a 1,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains 40-75 wt.% of a mixture of glycerol and PEGl 500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), 7-40 wt.% of d- alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 0-35 wt.% of polyoxyl castor oil (Cremophor-EL), and 0-20 wt.% of polyethylene glycol- 15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

9. A composition according to claim 1, wherein said composition contains a

1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains 50-70 wt.% of a mixture of glycerol and PEGl 500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), 10-40 wt.% of d- alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 0-35 wt.% of polyoxyl castor oil (Cremophor-EL), and 0-20 wt.% of polyethylene glycol- 15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

10. A composition according to claim 1, wherein said composition contains a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains 45-55 wt.% of a mixture of glycerol and

PEGl 500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), 10-15 wt.% of d- alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 20-30 wt.% of polyoxyl castor oil (Cremophor-EL), and 10-15 wt.% of polyethylene glycol-15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

11. A composition according to claim 1, wherein said composition contains a 1,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains 60-70 wt.% of a mixture of glycerol and

PEGl 500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), 30-40 wt.% of d- alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 0-5 wt.% of polyoxyl castor oil (Cremophor-EL), and 0-5 wt.% of polyethylene glycol-15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

12. A composition according to claim 1, wherein said composition contains a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains about 50 wt.% of a mixture of glycerol and PEG 1500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), about 25 wt.% of d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), and about 25 wt.% of polyoxyl castor oil (Cremophor-EL), based on the total weight of the mixture.

13. A composition according to claim 1, wherein said composition contains a 1,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains about 50 wt.% of a mixture of glycerol and PEG 1500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), about 18.8 wt.% of d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), about 12.5 wt.% of polyoxyl castor oil (Cremophor-EL), and about 18.8 wt.% of polyethylene glycol- 15 -hydroxys tearate (Solutol-HS 15), based on the total weight of the mixture.

14. A composition according to claim 1, wherein said composition contains a 1,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4-

(2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains about 50 wt.% of a mixture of glycerol and PEG 1500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), about 12.5 wt.% of d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), about 12.5 wt.% of polyoxyl castor oil (Cremophor-EL), and about 12.5 wt.% of polyethylene glycol- 15 -hydroxys tearate (Solutol-HS 15), based on the total weight of the mixture.

15. A composition according to claim 1, wherein said composition contains a 1 ,4-dihydropyridine pharmaceutical agent (particularly (+)-isopropyl 2-methoxyethyl 4- (2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate) and an excipient mixture, wherein said excipient mixture contains about 65 wt.% of a mixture of glycerol and PEG 1500 esters of long fatty acids having a melting point of approximately 44 ⁰C and a hydrophilic/lipophilic balance of approximately 14 (Gelucire 44/14), about 35 wt.% of d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 0-2 wt.% of polyoxyl castor oil (Cremophor-EL), and 0-2 wt.% of polyethylene glycol-15- hydroxystearate (Solutol-HS 15), based on the total weight of the mixture.

16. A composition according to any one of claims 1 to 15, wherein said 1,4- dihydropyridine pharmaceutical agent is (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3- cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate.