(12) Patent Application Publication (10) Pub. No.: US 2002/0013357 A1 Nadkarni Et Al

US 2002001.3357A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0013357 A1 Nadkarni et al. (43) Pub. Date: Jan. 31, 2002 (54) VALDECOXIB COMPOSITIONS 60/169,856, filed on Dec. 9, 1999. Non-provisional of provisional application No. 60/181,635, filed on Feb. (76) Inventors: Sreekant Nadkarni, Gurnee, IL (US); 10, 2000. Non-provisional of provisional application Mark J. Kontny, Libertyville, IL (US) No. 60/202,269, filed on May 5, 2000. Correspondence Address: Publication Classification Pharmacia Corporation Patent Department Central, 1820 (51) Int. Cl." .......................... A61K 31/415; A61 K 9/22 P.O. BOX 5110 (52) U.S. Cl. ............................................ 514/406; 424/468 Chicago, IL 60680-5110 (US) (21) Appl. No.: 09/731,349 (57) ABSTRACT (22) Filed: Dec. 6, 2000 Pharmaceutical compositions are provided comprising par ticulate Valdecoxib in an amount of about 1 mg to about 100 Related U.S. Application Data mg and one or more pharmaceutically acceptable excipients. The compositions are useful in treatment or prophylaxis of (63) Non-provisional of provisional application No. cyclooxygenase-2 mediated conditions and disorders. Patent Application Publication Jan. 31, 2002 Sheet 1 of 3 US 2002/0013357 A1 Micronizing Valdecoxib (Pin mill) Primary diluent Mixing Secondary diluent (Planetary mixer) Binding agent Wet granulation (Planetary mixer) Water Drying (Owen) Dry sizing (Comil) Blending Disintegrant (V-blender) Blending Lubricant (W-blender) Tableting (Rotary press) Fig. 1 Patent Application Publication Jan. 31, 2002. Sheet 2 of 3 US 2002/0013357 A1 Micronizing Valdecoxib (Pin mill) Primary diluent Mixing Binding agent Secondary diluent Disintegrant (intragranular) (High shear mixer) (intragranular) Wet granulation (High shear mixer) Water Drying (Fluid bed drier) Dry sizing (Fitzmill) Secondary diluent Blending Disintegrant (extragranular) (V-blender) (extragranular) Blending Lubricant (V-blender) Tableting (Rotary press) Fig. 2 Patent Application Publication Jan. 31, 2002 Sheet 3 of 3 US 2002/0013357 A1 300 25 O 2O O 150 100 5O O O 5 1 O 15 20 25 Time (hr) Fig. 3 300 25 O 2 OO 515100OO O Time (hr) Fig. 4 US 2002/OO13357 A1 Jan. 31, 2002 WALDECOXB COMPOSITIONS parenterally a much more Soluble prodrug, parecoxib, that 0001. This application claims priority of U.S. provisional cleaves to form Valdecoxib. See for example Dionne (1999), application Ser. No. 60/169,856 filed on Dec. 9, 1999, U.S. “COX-2 inhibitors-IBC Conference, 12-13 April 1999, provisional application Ser. No. 60/181,635 filed on Feb. 10, Coronado, Calif., U.S.A.”, IDrugs, 207), 664-666. 2000, and U.S. provisional application Ser. No. 60/202,269 0008. However, it would be beneficial to have an orally filed on May 5, 2000. deliverable dosage form of Valdecoxib that exhibits good bioavailability and immediate-release properties. FIELD OF THE INVENTION 0009 AS is indicated hereinbelow, Valdecoxib adminis 0002 The present invention relates to orally deliverable tration is indicated or potentially indicated in a very wide pharmaceutical compositions containing Valdecoxib as an array of COX-2 mediated conditions and disorders. It would active ingredient, to processes for preparing Such composi therefore be of great benefit to provide orally deliverable tions, to methods of treatment of cyclooxygenase-2 medi formulations having bioavailability characteristics tailored ated disorders comprising orally administering Such com to such indications. It would be of especial benefit to provide positions to a Subject, and to use of Such compositions in immediate-release oral formulations exhibiting pharmaco manufacture of medicaments. kinetics consistent with a rapid onset effect. 0010. Such formulations would represent a significant BACKGROUND OF THE INVENTION advance in the treatment of COX-2 mediated conditions and 0003) The compound 4-(5-methyl-3-phenyl-4-isox disorders. azolyl)benzenesulfonamide, also referred to herein as val decoxib, was disclosed in U.S. Pat. No. 5,633,272 to Talley SUMMARY OF THE INVENTION et al. together with processes for preparing this and related 0011. There is now provided a pharmaceutical composi compounds. Valdecoxib has the Structure: tion comprising particulate Valdecoxib in an amount of about 1 mg to about 100 mg per dose and one or more pharmaceutically acceptable excipients. (I) 0012. In one embodiment, a single dose, upon oral HN/ administration to a fasting Subject, provides a time course of blood Serum concentration of Valdecoxib having at least one / CH3 of the following: e 0013 (a) a time to reach a threshold concentration S / for therapeutic effect not greater than about 0.5 h N after administration; 0014 (b) a time to reach maximum concentration (T) not greater than about 5 h after administra tion; and 0004. The compounds reported in above-cited U.S. Pat. 0015 (c) a maximum concentration (C ) not less No. 5,633,272, including Valdecoxib, are disclosed therein than about 100 ng/ml. as useful anti-inflammatory, analgesic and antipyretic drugs having a high degree of Selectivity for inhibition of 0016. By “a threshold concentration for therapeutic cyclooxygenase-2 (COX-2) over cyclooxygenase-1 (COX effect” is meant a minimum concentration of Valdecoxib in 1). Above-cited U.S. Pat. No. 5,633,272 also contains gen blood serum consistent with therapeutic benefit for the eral references to formulations for the administration of Such particular indication for which the Valdecoxib is adminis compounds, including orally deliverable dosage forms Such tered. Typically this threshold concentration is at least about as tablets and capsules. 20 ng/ml, for example about 25 to about 75 ng/ml. 0005 European Patent Application No. 0 863 134 dis 0017. The composition can be in the form of discrete closes orally deliverable compositions comprising a Selec Solid articles Such as tablets, pills, hard or Soft capsules, tive COX-2 inhibitory drug, specifically 2-(3,5-difluorophe lozenges, Sachets or pastilles, one to a Small plurality of nyl)-3-(4-methyl-Sulfonyl)phenyl)-2-cyclopenten-1-one, in which constitute a single dose, alternatively the composition combination with excipient ingredients including microc can be in the form of a Substantially homogeneous flowable rystalline cellulose, lactose monohydrate, hydroxypropyl mass, Such as a particulate or granular Solid or a liquid cellulose, croScarmellose Sodium and magnesium Stearate. Suspension, from which Single doses are measurably remov able. 0006 International Patent Publication No. WO 00/32189 discloses orally deliverable compositions comprising a 0018. In a presently preferred embodiment, the compo selective COX-2 inhibitory drug, specifically celecoxib, in sition is in the form of tablets wherein the excipients include combination with excipient ingredients Selected from exten a water-Soluble diluent, a disintegrant, a binding agent and Sive lists of Suitable diluents, disintegrants, binding agents, a lubricant. Most preferably the binding agent comprises wetting agents, lubricants, etc. pregelatinized Starch. 0007 Valdecoxib has extremely low solubility in water, 0019. Also provided is a method of treating a medical and for this reason it has been proposed to administer condition or disorder in a Subject where treatment with a US 2002/OO13357 A1 Jan. 31, 2002 COX-2 inhibitor is indicated, comprising orally administer the Subject is a child or a small animal (e.g., a dog), for ing a composition of the invention one to about four times example, an amount of Valdecoxib relatively low in the a day. indicated range of about 1 mg to about 100 mg is likely to provide blood Serum concentrations consistent with at least 0020. Other features of the invention will be in part one of criteria (a) to (c). Where the subject is an adult human apparent and in part pointed out hereinafter. or a large animal (e.g., a horse), the indicated blood Serum BRIEF DESCRIPTION OF THE DRAWINGS concentrations of Valdecoxib are likely to require a relatively greater dosage amount of Valdecoxib. For an adult human, a 0021 FIG. 1 is a flow diagram illustrating a representa Suitable amount of Valdecoxib per dose in a composition of tive method for preparation of Valdecoxib tablets of the the present invention to provide the indicated blood Serum invention. concentrations is typically about 5 mg to about 40 mg. 0022 FIG. 2 is a flow diagram illustrating an alternative 0032. In a preferred embodiment, the bioavailability of method for preparation of Valdecoxib tablets of the inven the composition is Such that, when a 20 mg dose is admin tion. istered orally to a fasting adult human Subject: 0023 FIG. 3 is a graph showing plasma concentration of 0033 (a) a valdecoxib blood serum concentration of Valdecoxib in dogs following oral administration of Valde 20 ng/ml, more preferably of 50 ng/ml, is reached coxib tablets of the invention. not more than about 0.5 h after administration; 0024 FIG. 4 is a graph showing plasma concentration of Valdecoxib in humans following oral administration of Val 0034 (b) T is not greater than about 3 h after decoxib tablets of the invention. administration; and 0035) (c) C is not less than about 100 ng/ml. DETAILED DESCRIPTION OF THE INVENTION 0036 Compositions of the invention contain valdecoxib in particulate form. Primary Valdecoxib particles, generated 0.025 A composition of the invention comprises particu for example by milling or grinding, or by precipitation from late Valdecoxib in a dosage amount of about 1 mg to about Solution, can agglomerate to form Secondary aggregate 100 mg. Such a composition is a Superior immediate-release particles. The term "particle Size' as used herein refers to dosage form capable of providing rapid relief from a COX-2 size, in the longest dimension, of primary particles, unless mediated disorder when orally administered to a Subject, the context demands otherwise. Particle size is believed to more particularly a human Subject, Suffering from Such a be an important parameter affecting clinical effectiveness of disorder.

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