US 2002OO15735A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0015735A1 Hedden et al. (43) Pub. Date: Feb. 7, 2002 (54) SUSTAINED-RELEASE FORMULATION OF A of provisional application No. 60/181,635, filed on CYCLOOXYGENASE-2 INHIBITOR Feb. 10, 2000. Non-provisional of provisional appli cation No. 60/202,269, filed on May 5, 2000. (76) Inventors: David B. Hedden, Ann Arbor, MI (US); Sreekant Nadkarni, Gurnee, IL Publication Classification (US) (51) Int. Cl." ........................... A61K 9/14; A61K 31/44; Correspondence Address: A61K 31/415; A61K 31/135 Pharmacia Corporation (52) U.S. Cl. ......................... 424/488; 424/487; 514/406; Patent Department Central, 1820 514/349; 514/352; 514/646 P.O. BOX 5110 Chicago, IL 60680-5110 (US) (57) ABSTRACT (21) Appl. No.: 09/742,906 (22) Filed: Dec. 20, 2000 There is provided an orally deliverable pharmaceutical com position comprising a Selective cyclooxygenase-2 inhibitory Related U.S. Application Data drug of low water Solubility Such as celecoxib and a release extending polymer. The composition is useful in treatment (63) Non-provisional of provisional application No. of cyclooxygenase-2 mediated conditions and disorders by 60/171,738, filed on Dec. 22, 1999. Non-provisional once-a-day administration. Patent Application Publication Feb. 7, 2002 Sheet 1 of 5 US 2002/0015735 A1 % dissolution s... ', ... % is iss's S. O 2 4 6 8 10 12 14 16 18 Time (hours) -0-M4 --M5 -a-M6 -e-M7 --M8 -b-M9 -A-M10 -O-M11 Fig. 1 Patent Application Publication Feb. 7, 2002 Sheet 2 of 5 US 2002/0015735 A1 % dissolution 120 is: 100 O 2 4 6 8 10 12 14 16 18 Time (hours) -0-M12 -a-M13 --M14 -A-M15 -B-M16 -e-M17 -H-M18 -O-M19 -be-M2O --M21 Fig. 2 Patent Application Publication Feb. 7, 2002. Sheet 3 of 5 US 2002/0015735 A1 % dissolution 3& - s six. S- i. & ... Time (hours) -- S1 -- S2 -- S3 -- S4 -A-S5 -- S6 -e-S7 -o-S8 Fig. 3 Patent Application Publication Feb. 7, 2002 Sheet 4 of 5 US 2002/0015735A1 AssistsYESS ash 8 : : Time (hours) -A-Q5 (20-5-A) -e-Q6 (20-5-L) --Q7 (20-35-A) -O-O8 (20-35-L) Fig. 4 S.S.S.S. 8%. 8. gap". 2:2 . $33.33. Say s Time (hours) -A-Q11 (1,25) -A-Q12 (1,65) --Q13 (25,25) -HQ14 (25,65) -e-Q15 (13,45) -O-O 16 (1345) Fig. 5 Patent Application Publication Feb. 7, 2002 Sheet 5 of 5 US 2002/0015735 A1 - Time (hr) Fig. 6 -0-R tablet -HQ17 -A-Q18 US 2002/OO15735 A1 Feb. 7, 2002 SUSTAINED-RELEASE FORMULATION OFA 0004) Other compounds reported to have therapeutically CYCLOOXYGENASE-2 INHIBITOR and/or prophylactically useful selective COX-2 inhibitory 0001. This application claims priority of U.S. provisional effect are Substituted isoxazolyl benzeneSulfonamides as application Ser. No. 60/171,738 filed on Dec. 22, 1999, U.S. reported in U.S. Pat. No. 5,633,272 to Talley et al., including provisional application Ser. No. 60/181,635 filed on Feb. 10, the compound 4-5-methyl-3-phenylisoxazol-4-ylbenzene 2000, and U.S. provisional application Ser. No. 60/202,269 sulfonamide, also referred to herein as Valdecoxib (III). filed on May 5, 2000. FIELD OF THE INVENTION 0002 This invention relates to orally deliverable phar (III) maceutical compositions containing a Selective cyclooxyge nase-2 (COX-2) inhibitory drug as an active ingredient, to processes for preparing Such compositions, to methods of treatment of COX-2 mediated disorders comprising orally administering Such compositions to a Subject, and to use of Such compositions in manufacture of medicaments. BACKGROUND OF THE INVENTION 0003) Numerous compounds have been reported having therapeutically and/or prophylactically useful Selective COX-2 inhibitory effect, and 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 0005 Still other compounds reported to have therapeu reported in U.S. Pat. No. 5,760,068 to Talley et al., including tically and/or prophylactically useful selective COX-2 for example the compound 4-5-(4-methylphenyl)-3-(trif inhibitory effect are substituted (methylsulfonyl)phenyl luoromethyl)-1H-pyrazol-1-ylbenzenesulfonamide, also furanones as reported in U.S. Pat. No. 5,474,995 to Ducha referred to herein as celecoxib (I), and the compound rme et al., including the compound 3-phenyl-4-4-(methyl 4-5-(3-fluoro-4-methox yphenyl)-3-difluoromethyl)-1H sulfonyl)phenyl-5H-furan-2-one, also referred to herein as pyrazol-1-ylbenzenesulfonamide, also referred to herein as rofecoxib (IV). deracoxib (II). (IV) H2N O (I) S. HC (II) 0006 U.S. Pat. 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-(methylsulfo 21 O nyl)phenyl)-5H-furan-2-one and 3-(1-cyclopropylethoxy)- NN CF2H 5,5-dimethyl-4-4-(methylsulfonyl)phenyl-5H-furan-2- S. OC. HC 0007 U.S. Pat. No. 5,861,419 to Dube et al. discloses No 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-pyridi nyl)pyridine (V). US 2002/OO15735 A1 Feb. 7, 2002 0012 Although the initial cost of Sustained-release deliv ery Systems may be greater than the costs associated with (V) conventional delivery Systems, average costs of extended treatment over time can be lower due to less frequent dosing, HN A” enhanced therapeutic benefit, reduced Side-effects, and a 4. reduction in the time required to dispense and administer the drug and monitor patient compliance. 21 C 0013 Many selective COX-2 inhibitory compounds, in particular those having low Solubility in water, including celecoxib, deracoxib, Valdecoxib and rofecoxib, possess s1S physical and chemical properties which make them poorly 2 amenable to Sustained-release dosage formulation. These HC N physical and chemical properties have presented practical difficulties in formulating longer-acting low Solubility Selec tive COX-2 inhibitory drugs for oral administration. 0008 European Patent Application No. 0 863 134 dis 0014 Illustratively, the formulation of celecoxib for closes the compound 2-(3,5-difluorophenyl)-3-4-(methyl effective Sustained-release oral administration to a Subject Sulfonyl)phenyl-2-cyclopenten-1-one said to be useful as a has hitherto been complicated by the unique physical, selective COX-2 inhibitory drug. chemical and pharmacological properties of celecoxib, par 0009 U.S. Pat. No. 6,034,256 discloses a series of ben ticularly its exceptionally low Solubility in aqueous media, Zopyrans said to be useful as selective COX-2 inhibitory its relatively high dose requirement, and patient-to-patient drugs, including the compound (S)-6,8-dichloro-2-(trifluo variability in its absorption. Drugs with extremely high or romethyl)-2H-1-benzopyran-3-carboxylic acid (VI). low aqueous Solubility are known to be difficult to incorpo rate into effective Sustained-release delivery Systems (Lie berman et al., ed. (1990) Pharmaceutical Dosage Forms: (VI) Tablets, 2nd ed., Vol. 3. Marcel Dekker, Inc., New York.) For example, a lower Solubility limit for Sustained-release prod ucts has been reported to be about 0.1 mg/ml (Fincher (1968) “Particle size of drugs and its relationship to absorp tion and activity”, J. Pharma. Sci., 57, 1825), whereas celecoxib has a Solubility of 5 ug/ml. Drugs having a relatively high oral dose requirement are also known to be poor candidates for Sustained-release Systems, in part Cl because inclusion of a Sufficient dose to provide prolonged therapeutic effect and of the release-Sustaining mechanism tend to result in an unacceptably large Volume of product 0010) A need for formulated compositions of selective (Lieberman et al., op. cit., p. 206). Finally, drugs that are COX-2 inhibitory drugs, in particular Sustained-release absorbed at a rate that varies significantly among treated compositions, exists. Sustained-release drug-delivery Sys Subjects have also been considered inferior candidates for tems can provide many benefits over conventional dosage Sustained-release Systems, in part because Such Systems forms. Generally, Sustained-release preparations provide a normally target a blood concentration of the drug not greatly longer period of therapeutic or prophylactic response com in excess of the threshold concentration for therapeutic pared to conventional rapid release dosage forms. For effectiveness, and Subjects showing relatively poor absorp example, in treatment of pain, Sustained-release formula tions are useful to maintain relatively constant analgesic tion can fail to reach that threshold concentration (Lieber drug release rates over a period of time, for example 12-24 man et al., op. cit., p. 207). hours, So that blood Serum concentration of the drug remains 0015 For these and other reasons, therefore, it would be at a therapeutically effective level for a longer duration than a difficult but much desired advance in the art to provide an is possible with a conventional dosage form of the drug. In effective Sustained-release formulation of a selective COX-2 addition, whereas Standard dosage forms typically exhibit inhibitory drug of low solubility, such as celecoxib. high initial drug release rates that can result in unnecessarily elevated blood Serum levels of the drug, Sustained-release 0016 A wide variety of controlled-release, slow-release, formulations can help maintain blood Serum levels of the programmed-release, timed-release, pulse-release, Sus drug at or slightly above the therapeutically effective thresh tained-release or extended-release technologies are known old.