ZA200307575B - Orally deliverable pharmaceutical composition comprising a drug of low water solubility (cox-2inhibitor), a solvent, a fatty acid and an organic amine. - Google Patents

Description

FINELY SELF-EMULSIFIABLE PHARMACEUTICAL COMPOSITION

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. Upon precipitation and/or crystallization, the drug can then agglomerate to form larger particles that further retard absorption. Such precipitation and/or crystallization, especially if accompanied by agglomeration, can offset or reduce the potential rapid onset benefits sought by formulating the drug as a solution.

Attempts have been made to facilitate gastrointestinal absorption of poorly water-soluble drugs from solution formulations, by adding relatively large amounts of surfactant; however, these attempts have achieved only limited success. Additionally, the usefulness of surfactants in large amounts can be limited by problems such as foaming, which can cause gas entrapment, and irritation of the gastrointestinal tract.

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. Such self-emulsifying formulations can help to maintain the drug in solubilized form for a sufficient period of time to provide enhanced absorption but, even when formulated in this way, certain drugs still have a tendency to precipitate and/or crystallize in gastrointestinal fluid.

Furthermore, high surfactant loadings are often necessary to provide acceptable self- emulsifying behavior, with the attendant problems indicated above.

There is therefore a need in the art for improved liquid formulations of poorly water-soluble drugs, particularly for such formulations that are finely self-emulsifiable in gastrointestinal fluid. The term “finely self-emulsifiable” herein means capable of forming an emulsion wherein at least about 25% by volume of the emulsion particles have a diameter not greater than about 1 pm. Where emulsion particle size distribution includes a greater proportion of larger particles, it is believed that a greater tendency exists for drug particle aggregation and/or the potential for rapid absorption is reduced.

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). "MN A

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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-yl]benzenesulfonamide, also referred to herein as valdecoxib (III).

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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).

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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]-5H-furan-2-one and 3-(1-cyclopropylethoxy)-5,5-dimethyl-4- [4-(methylsulfonyl)phenyl}-5H-furan-2-one.

U.S. Patent No. 5,861,419 to Dube et 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).

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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.

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)

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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- 8 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 ) 20 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

) SHT; 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 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.

Cited in above-referenced U.S. Patent No. 5,993,858 is prior work by Farah et 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 HIB 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 (Tmax) Was shorter for the solution composition than for the suspension.

Above-cited U.S. Patent No. 5,760,068 discloses that its subject pyrazolyl . 30 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 example, such a compound is dispersed in HPMC.

Above-cited U.S. Patent No. 5,474,995 discloses that its subject (methylsulfonyl)phenyl 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 pyridines, 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 . 30 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 an improved self-emulsifying formulation, particularly a finely self-emulsifying formulation, of such a drug could be provided, 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 and a solvent liquid that comprises at least one pharmaceutically acceptable solvent, at least one pharmaceutically acceptable fatty acid and at least one pharmaceutically acceptable organic amine, 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 fatty acid and the organic amine are present in total and relative amounts such that the composition is finely self-emulsifiable in simulated gastric fluid.

The term “solvent liquid” herein encompasses all of the components of the liquid medium in which a particular drug is dissolved or solubilized. Thus the “solvent liquid” includes not only one or more solvents, fatty acids and organic amines, but optionally additional excipients such as co-solvents, surfactants, co-surfactants, stabilizing agents, crystallization inhibitors, antioxidants, sweeteners, flavoring agents, colorants, etc. ’ 30 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”.

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 isin 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.

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 vention, a drug of low water solubility is now provided in a finely self-emulsifiable solution formulation. Preferably such a formulation is 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 formation of a fine emulsion in the aqueous environment of the gastrointestinal tract. 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. ‘ 30 : 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 vasomeodulator 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.

. 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, measured at 37°C, not greater than about 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, 24th ed. (USP 24), 2000; The Extra Pharmacopoeia, 29th ed., 1989 (published by

Pharmaceutical Press, London); and the Physicians Desk Reference (PDR), 2001 ed. : (published by Medical Economics Co., Montvale, NJ), each of which is individually incorporated herein by reference.

For example, individual drugs of low solubility as defined herein include those drugs categorized as “slightly soluble”, “very slightly soluble”, “practically insoluble” and “insoluble” in USP 24, pp. 2254-2298; and those drugs categorized as requiring

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100 ml or more of water to dissolve 1 g of the drug, as listed in USP 24, pp. 2299- ) 2304. . Nustratively, suitable drugs of low water solubility include, without limitation, : drugs from the following classes: abortifacients, ACE inhibitors, o- and B-adrenergic agonists, o- and B-adrenergic blockers, adrenocortical suppressants, adrenocorticotropic hormones, alcohol deterrents, aldose reductase inhibitors, aldosterone antagonists, anabolics, analgesics (including narcotic and non-narcotic analgesics), androgens, angiotensin II receptor antagonists, anorexics, antacids, anthelminthics, antiacne agents, antiallergics, antialopecia agents, antiamebics,

antiandrogens, antianginal agents, antiarrhythmics, antiarteriosclerotics, antiarthritic/antirheumatic agents (including selective COX-2 inhibitors), antiasthmatics, antibacterials, antibacterial adjuncts, anticholinergics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antidiarrheal agents, antidiuretics, antidotes to poison, antidyskinetics, antieczematics, antiemetics, antiestrogens,

antifibrotics, antiflatulents, antifungals, antiglaucoma agents, antigonadotropins, antigout agents, antihistaminics, antihyperactives, antihyperlipoproteinemics, antihyperphosphatemics, antihypertensives, antihyperthyroid agents, antihypotensives, antihypothyroid agents, anti-inflammatories, antimalarials, antimanics, antimethemoglobinemics, antimigraine agents, antimuscarinics, antimycobacterials,

antineoplastic agents and adjuncts, antineutropenics, antiosteoporotics, antipagetics, antiparkinsonian agents, antipheochromocytoma agents, antipneumocystis agents, antiprostatic hypertrophy agents, antiprotozoals, antipruritics, antipsoriatics, antipsychotics, antipyretics, antirickettsials, antiseborrheics, antiseptics/disinfectants, antispasmodics, antisyphylitics, antithrombocythemics, antithrombotics, antitussives,

antiulceratives, antiurolithics, antivenins, antiviral agents, anxiolytics, aromatase inhibitors, astringents, benzodiazepine antagonists, bone resorption inhibitors, bradycardic agents, bradykinin antagonists, bronchodilators, calcium channel blockers, calcium regulators, carbonic anhydrase inhibitors, cardiotonics, CCK antagonists, chelating agents, cholelitholytic agents, choleretics, cholinergics,

} 30 cholinesterase inhibitors, cholinesterase reactivators, CNS stimulants, contraceptives, debriding agents, decongestants, depigmentors, dermatitis herpetiformis suppressants, digestive aids, diuretics, dopamine receptor agonists, dopamine receptor antagonists,

N ectoparasiticides, emetics, enkephalinase inhibitors, enzymes, enzyme cofactors, estrogens, expectorants, fibrinogen receptor antagonists, fluoride supplements, gastric * and pancreatic secretion stimulants, gastric cytoprotectants, gastric proton pump : inhibitors, gastric secretion inhibitors, gastroprokinetics, glucocorticoids, a-glucosidase inhibitors, gonad-stimulating principles, growth hormone inhibitors, growth hormone releasing factors, growth stimulants, hematinics, hematopoietics, hemolytics, hemostatics, heparin antagonists, hepatic enzyme inducers, hepatoprotectants, histamine H, receptor antagonists, HIV protease inhibitors, HMG

CoA reductase inhibitors, immunomodulators, immunosuppressants, insulin sensitizers, ion exchange resins, keratolytics, lactation stimulating hormones, laxatives/cathartics, leukotriene antagonists, LH-RH agonists, lipotropics, 5-lipoxygenase inhibitors, lupus erythematosus suppressants, matrix metalloproteinase inhibitors, mineralocorticoids, miotics, monoamine oxidase inhibitors, mucolytics, muscle relaxants, mydriatics, narcotic antagonists, neuroprotectives, nootropics, ovarian hormones, oxytocics, pepsin inhibitors, pigmentation agents, plasma volume expanders, potassium channel activators/openers, progestogens, prolactin inhibitors, prostaglandins, protease inhibitors, radio-pharmaceuticals, Sa-reductase inhibitors, respiratory stimulants, reverse transcriptase inhibitors, sedatives/hypnotics, serenics, serotonin noradrenaline reuptake inhibitors, serotonin receptor agonists, serotonin receptor antagonists, serotonin uptake inhibitors, somatostatin analogs, thrombolytics, thromboxane A, receptor antagonists, thyroid hormones, thyrotropic hormones, tocolytics, topoisomerase I and II inhibitors, uricosurics, vasomodulators including vasodilators and vasoconstrictors, vasoprotectants, xanthine oxidase inhibitors, and combinations thereof.

Non-limiting illustrative examples of suitable drugs of low water solubility include, for example, acetohexamide, acetylsalicylic acid, alclofenac, allopurinol, atropine, benzthiazide, carprofen, celecoxib, chlordiazepoxide, chlorpromazine, clonidine, codeine, codeine phosphate, codeine sulfate, deracoxib, diacerein, diclofenac, diltiazem, estradiol, etodolac, etoposide, etoricoxib, fenbufen, fenclofenac, . 30 fenprofen, fentiazac, flurbiprofen, griseofulvin, haloperidol, ibuprofen, indomethacin, indoprofen, ketoprofen, lorazepam, medroxyprogesterone acetate, megestrol, methoxsalen, methylprednisone, morphine, morphine sulfate, naproxen, nicergoline,

i nifedipine, niflumic, oxaprozin, oxazepam, oxyphenbutazone, paclitaxel, phenindione, phenobarbital, piroxicam, pirprofen, prednisolone, prednisone, procaine, progesterone, i pyrimethamine, rofecoxib, sulfadiazine, sulfamerazine, sulfisoxazole, sulindac, : suprofen, temazepam, tiaprofenic acid, tilomisole, tolmetic, valdecoxib, etc.

The amount of drug incorporated in a dosage form of the invention can be selected according to known principles of pharmacy. A therapeutically effective amount of drug is specifically contemplated. The term “therapeutically and/or prophylactically effective amount” as used herein refers to an amount of drug that is sufficient to elicit the required or desired therapeutic and/or prophylactic response.

In a particularly preferred embodiment, the drug is a selective COX-2 inhibitory drug of low water solubility. Any such selective COX-2 inhibitory drug known in the art can be used, including without limitation compounds disclosed in the patents and publications listed below, each of which is individually incorporated herein by reference.

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Above-cited European Patent Application No. 0 863 134. 7 European Patent Application No. 0 985 666. : A preferred selective COX-2 inhibitory drug useful herein is a compound of formula (VI) oo”

R* Aes

RN

O (VID wherein:

A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings, preferably a heterocyclyl group selected from pyrazolyl, furanonyl, : isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups;

X is O, S or CHy; nisOor1;

R' is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;

R? is methyl, amino or aminocarbonylalkyl;

R? is one or more radicals selected from hydrido, halo, alkyl, alkenyl, alkynyl, 0X0, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, } 25 alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyi, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,

R WO 02/083177 PCT/US02/11689 . aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-

N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N- ‘ alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N- aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N- arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkyithio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R? being optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; and

R* is selected from hydrido and halo.

Compositions of the invention are especially useful for selective COX-2 inhibitory drugs having the formula (VIII): 10) \, .

RST N\ eo} Nw xX’

R® (vm) 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 optionally substituted at one or more positions with oxo, halo, methyl or halomethyl groups, or an isomer, tautomer, pharmaceutically-acceptable salt or prodrug thereof.

Preferred such five- to six-membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at no more than one position.

Dlustratively, compositions of the invention are suitable for celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib, 2-(3,5-difluorophenyl)-3-[4- (methylsulfonyl)phenyl]-2-cyclopenten-1-one and 2-(3,4-difluorophenyl)-4-(3- hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinone.

Claims (33)

] WHAT IS CLAIMED IS:

1. An orally deliverable pharmaceutical composition comprising a drug of low water solubility and a solvent liquid that comprises at least one pharmaceutically ) acceptable solvent, at least one pharmaceutically acceptable fatty acid and at ) 5 least one pharmaceutically acceptable organic amine, wherein (a) a substantial portion of the drug is in dissolved or solubilized form in the solvent liquid, and (b) the fatty acid and the organic amine are present in total and relative amounts such that the composition is finely self-emulsifiable in simulated gastric fluid.

2. The composition of Claim 1 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 substantially all of the drug is present in the solvent liquid in dissolved or solubilized form.

4. The composition of any of Claims 1 to 3 wherein the drug is a selective cyclooxygenase-2 inhibitory drug.

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

Y. or bi 0) X ~ RN lS xX 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 oxo, halo, methyl or halomethyl groups; or a prodrug of such a compound.

6. The composition of Claim 5 wherein the five- to six-membered ring is selected ) from cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at no more than one position.

. 7. The composition of Claim 4 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.

8. The composition of Claim 4 wherein the selective cyclooxygenase-2 inhibitory drug is celecoxib.

9. The composition of Claim 4 wherein the drug is valdecoxib.

10. The composition of any of Claims 4 to 9 that further comprises 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.

11. The composition of any of Claims 4 to 9 that further comprises 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.

12. The composition of any of Claims 1 to 3 wherein the at least one fatty acid has a saturated or unsaturated Cg_4 carbon chain.

13. The composition of any of Claims 1 to 3 wherein the at least one fatty acid is selected from the group consisting of oleic acid, octanoic acid, caproic acid, caprylic acid, capric acid, eleostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, icosanoic acid, elaidic acid, linoleic acid, linolenic acid, eicosapentaenoic acid and docosahexaenoic acid.

14. The composition of any of Claims 1 to 3 wherein the at least one fatty acid is oleic acid.

15. The composition of any of Claims 1 to 3 wherein the at least one organic amine has a C,_g carbon chain and one or two amine groups.

16. The composition of any of Claims 1 to 3 wherein the at least one organic amine is selected from the group consisting of C,.g alkyl amines, alkylene diamines, alkanol amines, alkylalkanol amines, glycol ether amines and aryl amines. S

17. The composition of any of Claims 1 to 3 wherein the at least one organic amine is selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol and tromethamine.

18. The composition of any of Claims 1 to 3 wherein the at least one organic amine is a tertiary amine.

19. The composition of Claim 18 wherein the tertiary amine is selected from the group consisting of dimethylaminoethanol and triethanolamine. : 15

20. The composition of any of Claims 1 to 3 wherein the mole ratio of fatty acid to amine groups in the at least one organic amine is about 5:1 to about 1:100.

21. The composition of Claim 20 wherein the mole ratio of fatty acid to amine groups in the at least one organic amine is about 1:1.

22. The composition of any of Claims 1 to 3 wherein the fatty acid and organic amine are collectively present in an amount of about 1% to about 50% by weight of the composition.

23. The composition of Claim 22 wherein the fatty acid and organic amine are collectively present in an amount of about 5% to about 15% by weight of the composition.

24. The composition of any of Claims 1 to 3 wherein the solvent liquid comprises a solvent selected from the group consisting of pharmaceutically acceptable glycols and glycol ethers.

25. The composition of Claim 24 wherein the solvent is polyethylene glycol. 60 Amended Sheet — 29-11-2004

26. The composition of Claim 25 wherein the polyethylene glycol is of liquid grade.

27. The composition of Claim 25 wherein the polyethylene glycol has an average molecular weight of about 375 to about 450.

28. A composition of any of Claims 4 to 9 for use in a method of treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated, wherein the method comprises orally administering to the subject the composition.

29. A composition of any of Claims 4 to 9 for use in a method of analgesia, wherein the method comprises orally administering an effective pain- relieving amount of the composition to a subject in need of analgesia.

30. The composition of Claim 29 wherein the subject suffers from headache or migraine and wherein there is further orally administered to the subject a vasomodulator, the selective cyclooxygenase-2 inhibitory drug and the vasomodulator being administered in total and relative amounts effective to relieve pain in the headache or migraine.

31. The composition of Claim 29 wherein the subject suffers from headache or migraine and wherein there is further orally administered to the subject an alkylxanthine compound, the selective cyclooxygenase-2 inhibitory drug and the alkylxanthine compound being administered in total and relative amounts effective to relieve pain in the headache or migraine.

32. A method of use of a composition of any of Claims 4 to 9 in manufacture of a medicament useful for treating a medical condition or disorder in a subject where treatment with a cyclooxygenase-2 inhibitor is indicated.

33. A composition of Claim | substantially as herein described with reference to any one of the illustrative Examples 1 to 7. 61 Amended Sheet — 29-11-2004