ZA200305086B

ZA200305086B - Pharmaceutical composition having reduced tendency for drug crystallization.

Info

Publication number: ZA200305086B
Application number: ZA200305086A
Authority: ZA
Inventors: Ping Gao; Michael J Hageman; Walter Morozowich; Robert J Dalga; Kevin J Stefanski; Tiehua Huang; Aziz Karim; Fred Hassan; James C Forbes
Original assignee: Pharmacia Corp
Priority date: 2001-01-18
Filing date: 2003-06-30
Publication date: 2004-06-30
Also published as: JP2004520398A; MXPA03006404A; WO2002064132A3; CA2434641A1; NZ539046A; PE20020833A1; WO2002064132A2; AR032642A1; EP1365759A2

Description

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PHARMACEUTICAL COMPOSITION HAVING REDUCED TENDENCY FOR

DRUG CRYSTALLIZATION

FIELD OF THE INVENTION

! The present invention relates to orally deliverable pharmaceutical compositions that comprise a drug of low water solubility, more particularly to such compositions where the drug is in dissolved form.

BACKGROUND OF THE INVENTION

Liquid dosage forms, for example solutions suitable for oral administration, have become an important method by which drugs are delivered to subjects, particularly where rapid onset of therapeutic effect is desired. As an alternative to directly imbibable liquid formulations of a drug, it is also known to encapsulate liquid formulations, for example in soft or hard gelatin capsules, to provide a discrete dosage form.

Unfortunately, many useful drugs have low solubility in water and, therefore, are difficult to formulate at convenient concentrations as solutions in an aqueous vehicle. Even when a suitable solvent is found as a vehicle for such a drug, there is often a tendency, particularly for a crystalline drug of low water solubility, to precipitate out of solution and/or crystallize when the drug comes in contact with water, for example in the aqueous environment of the gastrointestinal tract. Such precipitation and/or re-crystallization can offset or reduce the potential rapid onset benefits sought by formulating the drug as a solution.

It is known to provide liquid dosage forms, including encapsulated liquid dosage forms, of poorly water-soluble drugs as self-emulsifying formulations. These formulations are generally designed to form an emulsion, in some cases a microemulsion, when mixed with gastrointestinal fluid. Even with a self-emulsifying formulation, however, certain drugs still have a tendency to precipitate and/or crystallize in gastrointestinal fluid.

Accordingly there remains a need in the art for a means to inhibit precipitation i and/or crystallization in gastrointestinal fluid of a poorly water-soluble drug, and in particular for such a means that can be incorporated in a self-emulsifying liquid ‘ dosage form.

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An illustrative class of drugs for which this need is apparent is the class of selective cyclooxygenase-2 (COX-2) inhibitory drugs of low water solubility.

Numerous compounds have been reported having therapeutically and/or \ prophylactically useful selective COX-2 inhibitory effect, and have been disclosed as having utility in treatment or prevention of specific COX-2 mediated disorders or of ' such disorders in general. Among such compounds are a large number of substituted pyrazolyl benzenesulfonamides as reported in U.S. Patent No. 5,466,823 to Talley ef al., including for example the compound 4-[5-(4-methylphenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as celecoxib (I), and the compound 4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1- yl]benzenesulfonamide, also referred to herein as deracoxib (II).

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2 NZ

HN QO

NZ

7 0

NTN

_N CF,H

N \ =

CF; a

HsC 3 ~o

HsC Wy i (1

Other compounds reported to have therapeutically and/or prophylactically useful selective COX-2 inhibitory effect are substituted isoxazolyl benzenesulfonamides as reported in U.S. Patent No. 5,633,272 to Talley et al., including the compound 4-[5-methyl-3-phenylisoxazol-4-ylJbenzenesulfonamide, also : referred to herein as valdecoxib (IIT).

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Tg on 0 ~./ . N (Im)

Still other compounds reported to have therapeutically and/or prophylactically useful selective COX-2 inhibitory effect are substituted (methylsulfonyl)phenyl furanones as reported in U.S. Patent No. 5,474,995 to Ducharme et al., including the : compound 3-phenyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one, also referred to herein as rofecoxib (IV). : HiC jo] 3 \ Vi

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U.S. Patent No. 5,981,576 to Belley et al. discloses a further series of (methylsulfonyl)phenyl furanones said to be useful as selective COX-2 inhibitory drugs, including 3-(1-cyclopropylmethoxy)-5,5-dimethyl-4-[4- (methylsulfonyl)phenyl]-SH-furan-2-one and 3-(1-cyclopropylethoxy)-5,5-dimethyl-4- [4-(methylsulfonyl)phenyl]-SH-furan-2-one.

U.S. Patent No. 5,861,419 to Dube er al. discloses substituted pyridines said to be useful as selective COX-2 inhibitory drugs, including for example the compound 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine, also referred to herein as etoricoxib (V). 0)

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Cl =

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HaC N (V)

European Patent Application No. 0 863 134 discloses the compound 2-(3,5- difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one said to be useful \ as a selective COX-2 inhibitory drug.

= WO 02/056878 PCT/US02/00971

U.S. Patent No. 6,034,256 to Carter et al. discloses a series of benzopyrans said to be useful as selective COX-2 inhibitory drugs, including the compound (S)- 6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (VI). 0) ° $ x OH 0” “Scr, cl (VD)

International Patent Publication No. WO 00/24719 discloses substituted pyridazinones said to be useful as selective COX-2 inhibitory drugs, including the compound 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4- (methylsulfonyl)phenyl]-3-(2H)-pyridazinone.

A need for formulated compositions of selective COX-2 inhibitory drugs, particularly rapid-onset compositions of such drugs, exists. Rapid-onset drug delivery systems can provide many benefits over conventional dosage forms. Generally, rapid- onset preparations provide a more immediate therapeutic effect than standard dosage forms. For example, in the treatment of acute pain, for example in headache or migraine, rapid-onset dosage forms would be useful to provide fast pain relief.

Australian Patent Applications No. 200042711, No. 200043730 and No. 200043736 disclose compositions comprising a selective COX-2 inhibitory drug, a } 5HT, receptor agonist and caffeine, said to be useful for treating migraine.

U.S. Patent No. 5,993,858 to Crison & Amidon discloses an excipient formulation for increasing bioavailability of a poorly water-soluble drug. The formulation is said to be self-microemulsifying and to comprise an oil or other lipid material, a surfactant and a hydrophilic co-surfactant. The choice of surfactant is said to be less critical than the choice of co-surfactant, which reportedly should have an

HLB (hydrophilic-lipophilic balance) number greater than 8. A preferred example of such a co-surfactant is said to be Labrasol™ of Gattefossé, identified as a product “comprised of medium-chain triglycerides derived from coconut oil” having HLB of a 14. A formulation prepared containing 15 mg nifedipine in a size 1 (0.5 ml) capsule, i.e., at a concentration of 30 mg/ml, is described as a “clear solution” at 70°C but a “semi-solid” at room temperature.

~ WO 02/056878 PCT/US02/00971

Cited in above-referenced U.S. Patent No. 5,993,858 is prior work by Farah ef al. in which a self-microemulsifying formulation was investigated for improving in vitro dissolution of indomethacin. The formulation of Farah et al. reportedly . comprised an oil phase material Gelucire™ of Gattefossé Corporation, together with a polyethylene glycol capric/caprylic glyceride product having HLB of 10, a propylene : glycol laurate product having HLB of 4, and diethylene glycol monoethyl ether.

Drugs of low water solubility are sometimes orally administered in suspension in an imbibable aqueous liquid. For example, a suspension of particulate celecoxib in a vehicle of apple juice is disclosed in co-assigned International Patent Publication

No. WO 00/32189, incorporated herein by reference. Also disclosed therein is a dilute solution of celecoxib in a mixture of PEG-400 (polyethylene glycol having an average molecular weight of about 400) and water in a 2:1 ratio by volume.

The suspension and solution compositions of WO 00/32189 are indicated therein to have comparable bioavailability. However, following oral administration to dogs, the time taken for blood serum celecoxib concentration to reach a maximum level (Tax) was shorter for the solution composition than for the suspension.

Above-cited U.S. Patent No. 5,760,068 discloses that its subject pyrazolyl benzenesulfonamide compounds, of which celecoxib and deracoxib are examples, can be administered parenterally as isotonic solutions in a range of solvents including polyethylene glycol and propylene glycol. It is also disclosed therein that the subject compounds can alternatively be present in a controlled-release capsule or tablet formulation for oral administration wherein, for example, such a compound is dispersed in hydroxypropylmethylcellulose (HPMC).

Above-cited U.S. Patent No. 5,633,272 discloses that its subject isoxazolyl benzenesulfonamides, of which valdecoxib is an example, can be administered parenterally as isotonic solutions in a range of solvents including polyethylene glycol and propylene glycol. It is also disclosed therein that the subject compounds can alternatively be present in a controlled-release capsule or tablet formulation for oral administration wherein, for exampie, such a compound is dispersed in HEMT. ‘ 30 Above-cited U.S. Patent No. 5,474,995 discloses that its subject (methylsulfonyl)pheny! furanones, of which rofecoxib is an example, can be ’ administered parenterally in an isotonic solution in 1,3-butanediol. Also disclosed therein are oil-in-water emulsions, syrups and elixirs for oral administration, formulated with a sweetening agent such as propylene glycol, and aqueous suspensions formulated with suspending agents including methylcellulose and HPMC. : Above-cited U.S. Patent No. 5,861,419 discloses that its subject substituted pyndines, of which etoricoxib is an example, can be administered parenterally in an ’ isotonic solution in 1,3-butanediol. Also disclosed therein are oil-in-water emulsions, syrups and elixirs for oral administration, formulated with a sweetening agent such as propylene glycol, and aqueous suspensions formulated with suspending agents including methylcellulose and HPMC.

Many selective COX-2 inhibitory compounds, including celecoxib, deracoxib, valdecoxib, rofecoxib and etoricoxib, have low solubility in aqueous media. In addition, some, for example celecoxib, have relatively high dose requirements. These properties present practical problems in formulating concentrated solutions of selective COX-2 inhibitory drugs for rapid-onset, oral administration. With respect to such high dose, low solubility drugs, the size of the capsule or volume of solution required to provide a therapeutic dose becomes a limiting factor. For example, a drug that has a solubility of 10 mg/ml in a given solvent and a therapeutic dose of 400 mg/day would require ingestion of 40 ml of solution. Such a volume can be inconvenient or unacceptable for consumption in imbibable form; this volume also presents particular problems where an encapsulated dosage form is desired because capsules that contain more than about 1.0 ml to about 1.5 ml of liquid are generally considered to be too large for comfortable swallowing. Thus, where a solution is administered in capsule form, multiple capsules would need to be ingested in order to provide the required dose. To avoid such problems, a solvent must be selected wherein the drug has relatively high solubility.

As described hereinbelow, treatment with selective COX-2 inhibitory drugs of low water solubility is indicated in a very wide array of COX-2 mediated disorders and conditions. Therefore, if the problem of precipitation or crystallization in gastrointestinal fluid from a solution formulation, for example a self-emulsitying : 30 formulation, could be overcome, a significant advance would be realized in treatment of COX-2 mediated conditions and disorders, particularly in treatment of acute ' disorders where early relief from pain or other symptoms is desired. It would represent an especially important advance in the art to provide an effective method of treatment of acute pain, for example in headache or migraine, using such a formulation.

SUMMARY OF THE INVENTION

There is now provided an orally deliverable pharmaceutical composition comprising a drug of low water solubility, a solvent liquid that comprises at least one pharmaceutically acceptable solvent, and a turbidity-decreasing polymer. In a preferred embodiment, the polymer is a cellulosic polymer having at least a portion of substitutable hydroxyl groups substituted by methoxyl and/or hydroxypropoxyl groups, wherein (a) a substantial portion, for example at least about 15% by weight, of the drug is in dissolved or solubilized form in the solvent liquid, and (b) the polymer is present in an amount sufficient to substantially inhibit crystallization and/or precipitation of the drug in simulated gastric fluid.

Whether a given polymer is a "turbidity-decreasing polymer" herein can be determined according to Test I described hereinbelow.

The term “solvent liquid” herein encompasses all of the components of the liquid medium in which a particular drug is dissolved or solubilized, with the exception of a polymer component as defined above. Thus the “solvent liquid” includes not only one or more solvents but optionally additional excipients such as co- solvents, surfactants, co-surfactants, antioxidants, sweeteners, flavoring agents, colorants, etc. :

In a presently preferred composition of the invention, substantially all of the drug is in dissolved or solubilized form in the solvent liquid and substantially none of the drug is in solid particulate form. Such a composition is referred to herein as a “solution”. It is particularly preferred that the solution is finely self-emulsifiable in simulated gastric fluid, as described hereinbelow.

An alternative composition of the invention comprises, in addition to a first portion of the drug in dissolved or solubilized form, a second portion of the drug in particulate form dispersed in the solvent liquid. In this embodiment, part of the drug is in solution and part is in suspension. Such a composition is referred to herein as a “solution/suspension”. “Simulated gastric fluid”, abbreviated herein to “SGF”, is an aqueous solution of 0.01M hydrochloric acid and 0.15M sodium chloride, having a pH of about 2.

In a presently preferred embodiment, the solution or solution/suspension is encapsulated in one or more capsules having a wall that breaks down in gastrointestinal fluid to release the drug within a short period of time after entry into the gastrointestinal tract.

The turbidity-decreasing polymer as defined above is sometimes herein referred to as a “crystallization inhibitor”. This crystallization inhibitor can be present (a) in solution or suspension in the solvent liquid, and/or (b) as a component of a capsule wall.

In one embodiment, there is provided an orally deliverable pharmaceutical composition comprising a finely self-emulsifiable liquid formulation of a drug of low water solubility, encapsulated within a capsule wall that comprises a turbidity- decreasing polymer, preferably a turbidity-decreasing cellulosic polymer having at least a portion of substitutable hydroxyl groups substituted by methoxyl and/or hydroxypropoxyl groups, in an amount effective to substantially inhibit crystallization and/or precipitation of the drug in simulated gastric fluid. Preferably the capsule wall consists predominantly of a turbidity-decreasing cellulosic polymer, for example

HPMC.

This embodiment can be seen to be part of a broader embodiment of the invention, according to which there is provided an orally deliverable pharmaceutical composition comprising a drug of low water solubility in a high energy phase together with one or more pharmaceutically acceptable excipients, encapsulated within a capsule wall that comprises a turbidity-decreasing polymer, preferably a turbidity- decreasing cellulosic polymer having at least a portion of substitutable hydroxyl groups substituted by methoxyl and/or hydrox ypropoxyl groups, in an amount effective to substantially inhibit crystallization and/or precipitation of the drug in simulated gastric fluid.

A “high energy phase” herein is any form of the drug, including solids, salts of bases or acids, semi-solids and liquids, that exhibits a more rapid dissolution rate and/or a greater tendency for supersaturation in an aqueous medium than the most thermodynamically stable crystalline form of the drug. Thus in this embodiment, the drug can be in any high energy phase, for example in a solid state particulate form other than the lowest energy crystalline form (e.g., in amorphous form).

Compositions of the invention are illustratively useful where the drug is a selective COX-2 inhibitory drug, and have been found to resolve at least some of the : difficulties alluded to above in a surprisingly effective manner. Thus, according to the invention, a drug of low water solubility is now presented in a high energy phase, for example in a finely self-emulsifiable solution formulation, with greatly reduced tendency to precipitate and/or crystallize upon release into gastrointestinal fluid, as indicated for example by in vitro release into SGF. Preferably such formulations are presented in a dosage form that is convenient for oral administration. Formulations of the invention are particularly advantageous because they permit a high concentration of the drug, are suitable for encapsulation and, following oral administration thereof, can permit rapid absorption of the drug into the bloodstream through inhibition of precipitation and/or crystallization of the drug. By virtue of this rapid absorption, formulations of the invention can provide rapid onset of therapeutic action.

It can be theorized that a poorly water-soluble drug can provide more rapid onset of therapeutic effect when orally administered in solution, particularly a self- emulsifiable solution, than in particulate form because the process of dissolution in the gastrointestinal tract is not required. An even greater advantage by comparison with a solid formulation such as a tablet can be postulated because neither disintegration nor dissolution is required in the case of the solution composition.

Additionally, a drug administered in imbibable solution can be available for absorption higher in the alimentary tract, for example, in the mouth and esophagus, than one that becomes available for absorption only upon disintegration of the carrier formulation in the stomach or bowel.

A further advantage of liquid dosage forms such as imbibable solutions and solution/suspensions for many subjects is that these dosage forms are easy to swallow.

A yet further advantage of imbibable liquid dosage forms is that metering of doses is continuously variable, providing infinite dose flexibility. The benefits of ease of swallowing and dose flexibility are particularly advantageous for infants, children and the elderly.

When encapsulated, a solution or solution/suspension can provide the subject with the beneficial rapid absorption characteristics associated with liquid formulations in addition to the convenience of a discrete, easy to swallow capsule form.

The highly concentrated solutions permitted by the present invention are beneficial for several reasons. First, concentrated solutions are less costly to package and easier to transport and handle than dilute solutions. Second, concentrated solutions provide flexibility in administration as they can be administered with any desired degree of dilution. And third, concentrated drug solutions, especially when encapsulated, do not require consumption of large volumes of fluid, which can be uncomfortable for many patient populations.

In one embodiment, a method of analgesia is provided comprising orally administering, to a subject in need of analgesia, an effective pain-relieving amount of a selective COX-2 inhibitory drug composition of the invention. In another embodiment, a method of treatment and/or prevention of headache or migraine is provided comprising orally administering, to a subject in need of such treatment or prevention, a selective COX-2 inhibitory drug composition of the invention and a vasomodulator, for example a methylxanthine, wherein the selective COX-2 inhibitory drug and the vasomodulator are administered in effective pain-relieving total and relative amounts. The selective COX-2 inhibitory drug and the vasomodulator can be administered as components of separate compositions or of a single composition. Such a single composition comprising (a) a selective COX-2 inhibitory drug, formulated as provided herein, and (b) a vasomodulator, is a further embodiment of the invention. A presently preferred methylxanthine is caffeine.

Other features of this invention will be in part apparent and in part pointed out hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows in vitro dissolution behavior in SGF of celecoxib compositions

SF-1A, SF-1B, and SF-1C of Example 2.

Fig. 2 shows in vitro dissolution behavior in SGF of celecoxib compositions

SF-2A and SF-3B of the invention by comparison with celecoxib composition SF-3A, all as described in Example 3.

Fig. 3 shows in vitro dissolution behavior in SGF of celecoxib composition

SF-4A of the invention by comparison with celecoxib composition SF-4B, both as described in Example 4.

Fig. 4 shows in vivo bioavailability of celecoxib after oral administration of celecoxib test compositions SF-5A and SF-7A of the invention by comparison with celecoxib composition SF-6A, all as described in Example S, to fasting dogs. y Fig. 5 shows in vitro dissolution behavior of comparative paclitaxel solution formulation SF-8 and of solution formulation SF-9 of the invention, both as described ) in Example 7, in SGF.

DETAILED DESCRIPTION OF THE INVENTION

Novel pharmaceutical compositions according to the present invention comprise one or more orally deliverable dose units. The term “orally deliverable” herein means suitable for oral administration. The term “oral administration” herein includes any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed. Thus “oral administration” includes buccal and sublingual as well as esophageal administration. Absorption of the agent can occur in any part or parts of the gastrointestinal tract including the mouth, esophagus, stomach, duodenum, jejunum, ileum and colon. The term “dose unit” herein means a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single oral administration to provide a therapeutic effect. Typically one dose unit, or a small plurality (up to about 4) of dose units, provides a sufficient amount of the agent to result in the desired effect.

Drug of low water solubility

Each dose unit or small plurality of dose units comprises, in a therapeutically and/or prophylactically effective total amount, a drug of low water solubility. A “drug of low water solubility” or “poorly water solubility drug” herein refers to any drug compound having a solubility in water, measured at 37°C, not greater than about 10 mg/ml, and preferably not greater than about 1 mg/ml. It is contemplated that compositions of the invention are especially advantageous for drugs having a solubility in water, measnred at 37°C, not greater than abont 0.1 mg/ml. }

Solubility in water for many drugs can be readily determined from standard pharmaceutical reference books, for example The Merck Index, 11th ed., 1989 (published by Merck & Co., Inc., Rahway, NJ); the United States Pharmacopoeia,

Claims

L] WHAT IS CLAIMED IS:

1. An orally deliverable pharmaceutical composition comprising (a) a drug of low water solubility; ' (b) a pharmaceutically acceptable solvent liquid; and (c) a turbidity-decreasing polymer; wherein at least a substantial portion of the drug is in dissolved or solubilized form in the solvent liquid, and wherein said polymer is present in an amount sufficient to substantially inhibit crystallization and/or precipitation of the drug in simulated gastric fluid.

2. The composition of Claim | wherein the drug is present in a total amount of about 1% to about 75% by weight of the composition.

3. The composition of Claim 1 wherein the drug is a selective cyclooxygenase-2 inhibitory drug.

4. The composition of Claim 3 wherein the selective cyclooxygenase-2 inhibitory drug is a compound having the formula

Y. ry ) 0] Nr RT \ 0 Ne X rR where R? is a methyl or amino group, R* is hydrogen or a C4 alkyl or alkoxy group, X is N or CR’ where R® is hydrogen or halogen, and Y and Z are independently carbon or nitrogen atoms defining adjacent atoms of a five- to six-membered ring that is unsubstituted or substituted at one or more positions with 0x0, halo, methyl or halomethyl groups; or a prodrug of such a compound.

5. The composition of Claim 4 wherein the five- to six-membered ring is selected from cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at no more than one position. : 25 6. The composition of Claim 3 wherein the selective cyclooxygenase-2 inhibitory

< drug is selected from the group consisting of celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib, 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2- cyclopenten-1-one, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3- - carboxylic acid and 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5- [4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinone.

) 7. The composition of Claim 6 wherein the selective cyclooxygenase-2 inhibitory drug is celecoxib.

8. The composition of Claim 7 that comprises one or more dose units each comprising about 10 mg to about 400 mg of celecoxib.

9. The composition of Claim 6 wherein the drug is valdecoxib.

10. The composition of Claim 1 wherein the turbidity-decreasing polymer is selected from the group consisting of polyvinylpyrrolidone and cellulosic polymers.

11. The composition of Claim 1 wherein the turbidity-decreasing polymer is a cellulosic polymer selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose and ethylcellulose.

12. The composition of Claim 11 wherein the cellulosic polymer is hydroxypropylmethylcellulose.

13. The composition of Claim 12 wherein the hydroxypropylmethylcellulose has about 15% to about 35% methoxyl substitution and about 3% to about 15% hydroxypropoxyl substitution.

14. The composition of Claim 1 wherein the turbidity-decreasing polymer is present in the solvent liquid in an amount of about 1% to about 20% by weight of the solvent liquid.

15. The composition of Claim 1, further comprising a water-soluble capsule wall wherein the drug and solvent liquid are encapsulated.

16. The composition of Claim 15 wherein the turbidity-decreasing polymer is ‘ present in the capsule wall in an amount of about 5% to about 100% by weight of the wall.

17. The composition of Claim 1 wherein the solvent liquid comprises a solvent selected from pharmaceutically acceptable glycols and glycol ethers.

18. The composition of Claim 17 wherein the solvent is polyethylene glycol. . S

19. The composition of Claim 18 wherein the polyethylene glycol has an average molecular weight of about 100 to about 10,000.

20. An orally deliverable pharmaceutical composition comprising (a) a drug of low water solubility; (b) a pharmaceutically acceptable solvent liquid; and (c) a cellulosic polymer; wherein at least a substantial portion of the drug is in dissolved or solubilized form in the solvent liquid, and wherein said cellulosic polymer is present in an amount sufficient to substantially inhibit crystallization and/or precipitation of the drug in simulated gastric fluid.

21. The composition of Claim 20 wherein the cellulosic polymer is selected from the group consisting of sodium carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and ethylcellulose.

22. The composition of Claim 20 wherein the cellulosic polymer is hydroxypropylmethylcellulose.

23. The composition of Claim 22 wherein the hydroxypropylmethylcellulose has about 15% to about 35% methoxyl substitution and about 3% to about 15% hydroxypropoxy! substitution.

24. The composition of Claim 20 wherein the cellulosic polymer is present in the solvent liquid in an amount of about 1% to about 20% by weight of the solvent liquid.

25. The composition of Claim 20, further comprising a water-soluble capsule wall wherein the drug and solvent liquid are encapsulated. .

26. The composition of Claim 25 wherein the cellulosic polymer is present in the capsule wall in an amount of about 5% to about 100% by weight of the wall,

27. The composition of Claim 3 further comprising a vasomodulator, wherein the selective cyclooxygenase-2 inhibitory drug and the vasomodulator are present in total and relative amounts effective to relieve pain in headache or migraine.

28. The composition of Claim 3 further comprising an alkylxanthine compound, : wherein the selective cyclooxygenase-2 inhibitory drug and the alkylxanthine compound are present in total and relative amounts effective to relieve pain in headache or migraine.

29. The composition of Claim 28 where in the alkylxanthine compound is selected from the group consisting of caffeine, theophylline and theobromine. ‘

30. The composition of Claim 28 wherein the alkylxanthine compound is caffeine.

31. Use of a combination of : B (a) a drug of low water solubility ; (b) a pharmaceutically acceptable solvent liquid; and © (c) aturbidity-decreasing polymer in 2 method of manufacturing an orally deliverable medicament wherein at least a substantial portion of the drug is in dissolved or solubilized form in the solvent liquid, and wherein said polymer is present in an amount sufficient to substantially inhibit crystallization and/or precipitation of the drug in simulated gastric fluid for use in a method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-. 2 inhibitor is indicated. : 32. Use of a combination of : (2) a drug of low water solubility ; : (b) a pharmaceutically acceptable solvent liquid; and {ce} a ccllulosic polymer 61 Amended Sheet — 2004-09-2)

in a method of manufacturing an arally deliverable medicament wherein at : least a substantial portion of the drug is in dissolved or solubilized form in the solvent liquid, and wherein said cellulosic polymer is present in an amount sufficient to substantially inhibit crystallization and/or precipitation of the drug in simulated gastric fluid for use in a method of treating a medical condition or disorder iri a subject where treatment with a cyclooxygenase-2 inhibitor is indicated.

33. An orally deliverable pharmaceutical composition according to claim 1, : substantially as herein described with reference to any one of the illustrative examples.

34. An orally deliverable pharmaceutical composition according to claim 20, oo co substantially as herein described with reference to any one of the - oo illustrative examples. 62 : Amended Sheet — 2004-09-21