US 2003OO78266A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0078266A1 Kararli et al. (43) Pub. Date: Apr. 24, 2003

(54) RECONSTITUTABLE PARENTERAL Publication Classification COMPOSITION 51)1) Int. Cl.'C.7 ...... A61K 31/5050; A61K 31/415;5 A61K 31/353; A61K 31/12 (76) Inventors: Tugrul T. Kararli, Skokie, IL (US); (52) U.S. Cl...... 514/247; 514/406; 514/456; Sandeep Nema, Grayslake, IL (US); 514/690 Aziz Karim, Skokie, IL (US) (57) ABSTRACT Correspondence Address: Pharmacia Corporation Corporate Patent Department A pharmaceutical composition comprises, in powder form, (a) at least one water-Soluble therapeutic agent Selected from 800 N. Lindbergh Boulevard - 04B Selective COX-2 inhibitory drugs and prodrugs and Salts St. Louis, MO 63167 (US) thereof, for example Sodium, in a therapeutically effective total amount constituting about 30% to about 90% (21) Appl. No.: 10/113,281 by weight, (b) a parenterally acceptable buffering agent in an amount of about 5% to about 60% by weight, and optionally (22) Filed: Apr. 1, 2002 (c) other parenterally acceptable excipient ingredients in a total amount not greater than about 10% by weight, of the Related U.S. Application Data composition. The composition is reconstitutable in a parenterally acceptable Solvent liquid to form an injectable (60) Provisional application No. 60/281,058, filed on Apr. Solution. Alyophilization process is provided for preparation 3, 2001. of Such a composition. Patent Application Publication Apr. 24, 2003 US 2003/0078266A1

-0-parecoxib IV

233 OOO - - - O - - oral 200 -

150 -

100 -

5 O

O O 4 8 12 16 20 24 hours after administration

Fig. 1 US 2003/0078266 A1 Apr. 24, 2003

RECONSTITUTABLE PARENTERAL use are effective but have been associated with COMPOSITION side effects typical of Such non-selective NSAIDs. These 0001. This application claims priority of U.S. provisional Side effects have included upper gastrointestinal tract ulcer application Serial No. 60/281,058, filed on Apr. 3, 2001. ation and bleeding, particularly in elderly Subjects, reduced renal function, potentially leading to fluid retention and FIELD OF THE INVENTION exacerbation of hypertension; and inhibition of platelet function, potentially predisposing the Subject to increased 0002 The present invention relates to water-soluble Selective -2 (COX-2) inhibitory drugs and bleeding, for example during Surgery. Such side effects have Salts and prodrugs thereof and in particular to parecoxib, for Seriously limited the use of parenteral formulations of non example in the form of its Sodium salt (parecoxib Sodium). Selective NSAIDs. Parecoxib is a water-soluble prodrug of the selective COX-2 inhibitory drug Valdecoxib. More particularly, the invention 0006. It would therefore represent a further significant relates to parenterally deliverable, for example injectable, advance in the art if a parenterally deliverable formulation of formulations of water-soluble selective COX-2 inhibitory a selective COX-2 inhibitory drug could be provided. drugs and Salts and prodrugs thereof. Even more particu larly, the invention relates to Such formulations that are 0007. It is known to prepare parenteral formulations by a prepared as powders for reconstitution in an aqueous carrier process of lyophilization (freeze-drying) of an aqueous prior to parenteral administration. The invention also relates Solution of the therapeutic agent. See for example Reming to processes for preparing Such reconstitutable formulations, ton. The Science and Practice of Pharmacy, 19th edition to therapeutic methods of use of Such formulations and to (1995), Mack Publishing, pp. 1544-1546. According to use of Such formulations in manufacture of medicaments. Remington, excipients often are added to the therapeutic agent to increase the amount of Solids, So that the resulting BACKGROUND OF THE INVENTION powder is more readily visible when the amount of the 0003) Inhibition of cyclooxygenase (COX) is therapeutic agent is very Small. "Some consider it ideal for believed to be at least the primary mechanism by which the dried-product plug to occupy essentially the same Vol nonsteroidal anti-inflammatory drugs (NSAIDs) exert their ume as that of the original Solution. To achieve this, the characteristic anti-inflammatory, antipyretic and Solids content of the original product must be between effects, through inhibition of Synthesis. Con approximately 5 and 25%. Among the Substances found ventional NSAIDS Such as , , and salts thereof inhibit both the constitutively expressed most useful for this purpose, usually as a combination, are COX-1 and the inflammation-associated or inducible Sodium or potassium phosphates, citric acid, tartaric acid, COX-2 isoforms of cyclooxygenase at therapeutic doses. gelatin and carbohydrates Such as dextrose, mannitol and Inhibition of COX-1, which produces that are dextran.'Remington, loc. cit. necessary for normal cell function, appears to account for certain adverse side effects that have been associated with 0008 Parecoxib, disclosed in U.S. Pat. No. 5,932,598 to use of conventional NSAIDs. By contrast, selective inhibi Talley et al., is one of a class of water-Soluble prodrugs of tion of COX-2 without Substantial inhibition of COX-1 leads selective COX-2 inhibitory drugs. Parecoxib rapidly con to anti-inflammatory, antipyretic, analgesic and other useful verts to the Substantially water-insoluble selective COX-2 therapeutic effects while minimizing or eliminating Such inhibitory drug Valdecoxib following administration to a adverse side effects. Selective COX-2 inhibitory drugs such Subject. Parecoxib also converts to Valdecoxib upon expo as and , first commercially available in Sure to water, for example upon dissolution in water. The 1999, have therefore represented a major advance in the art. high water Solubility of parecoxib, particularly of Salts of These drugs are formulated in a variety of orally deliverable parecoxib Such as the Sodium Salt, by comparison with most dosage forms. selective COX-2 inhibitory drugs such as celecoxib and 0004 Parenteral routes of administration, including Sub Valdecoxib, has led to interest in developing parecoxib for cutaneous, intramuscular and intravenous injection, offer parenteral use. Parecoxib, having the structural formula (I) numerous benefits over oral delivery in particular situations, below, itself shows weak in vitro inhibitory activity against for a wide variety of drugs. For example, parenteral admin both COX-1 and COX-2, while Valdecoxib (II) has strong istration of a drug typically results in attainment of a inhibitory activity against COX-2 but is a weak inhibitor of therapeutically effective blood Serum concentration of the COX-1. drug in a shorter time than is achievable by oral adminis tration. This is especially true of intravenous injection, whereby the drug is placed directly in the bloodstream. (I) Parenteral administration also results in more predictable blood Serum concentrations of the drug, because losses in the gastrointestinal tract due to metabolism, binding to food and other causes are eliminated. For similar reasons, O M parenteral administration often permits dose reduction. / CH Parenteral administration is generally the preferred method e of drug delivery in emergency situations, and is also useful O in treating Subjects who are uncooperative, unconscious, or S. M otherwise unable or unwilling to accept oral . N 0005 Relatively few NSAIDs are commercially avail able in injectable form. Non-selective NSAIDs such as ketorolac tromethamine Salt that are available for parenteral US 2003/0078266 A1 Apr. 24, 2003

0013 A still further embodiment of the invention is an -continued injectable Solution prepared by reconstitution of the com (II) position. O 0014) A still further embodiment of the invention is an H.N/ article of manufacture comprising a Sealed vial having 4 CH contained there within a unit dosage amount of the compo Sition in a Sterile condition. e O S / 0015. A still further embodiment of the invention is a N method of treating or preventing a COX-2 mediated disease or disorder in a Subject, the method comprising (a) recon Stituting a unit dosage amount of the composition in a physiologically acceptable Volume of a parenterally accept able Solvent liquid to form an injectable Solution, and (b) injecting the Solution parenterally into the Subject. 0009. Other water-soluble selective COX-2 inhibitory drugs and prodrugs are known. For example, U.S. Pat. No. 0016. In all of the above embodiments, an especially 6,034,256 to Carter et al. discloses a series of water-soluble preferred therapeutic agent is a water-Soluble Salt of pare benzopyrans said to be useful as selective COX-2 inhibitory coxib. It is Surprisingly found that parecoxib, upon drugs, including the compound (S)-6,8-dichloro-2-(trifluo parenteral administration, exhibits through conversion to romethyl)-2H-1-benzopyran-3-carboxylic acid (Ell) and Valdecoxib Substantially equal anti-inflammatory and anal salts thereof. gesic effect at equal dose to Valdecoxib itself. Thus, accord ing to a yet further embodiment of the invention, there is provided a method of treating or preventing a COX-2 (III) mediated disease or disorder in a Subject, the method com prising parenterally administering parecoxib or a Salt thereof to the Subject at a parecoxib dosage equal in molar amount to a therapeutically effective dosage of Valdecoxib. 0017. A yet further embodiment of the invention is an article of manufacture comprising a Sealed vial having contained there within a sterile parenterally deliverable com Cl position that comprises parecoxib or a Salt thereof in a parecoxib dosage amount equal to a therapeutically effective 0010 While these and other selective COX-2 inhibitory dosage of Valdecoxib. drugs and prodrugs have been proposed in general terms for parenteral administration, no pharmaceutically acceptable BRIEF DESCRIPTION OF THE DRAWING injectable formulation of Such drugs or prodrugs has hitherto 0018 FIG. 1 presents data from the human pharmaco been described. As will be clear from the disclosure that kinetic Study of Example 3, showing mean blood plasma follows, numerous problems have beset the formulator concentrations of Valdecoxib from 0 to 72 hours following attempting to prepare Such a formulation, illustratively of (a) intravenous (IV) injection of 20 mg parecoxib in a 1 ml parecoxib. The present invention provides a Solution to these bolus; and (b) oral administration of 20 mg Valdecoxib problems. formulated as an immediate-release tablet.

SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION 0.011 There is now provided, in one embodiment, a pharmaceutical composition comprising, in powder form, 0019. A pharmaceutical composition of the present (a) at least one water-Soluble therapeutic agent Selected from invention comprises as the therapeutic agent: Selective COX-2 inhibitory drugs and prodrugs and Salts 0020 (a) a water-soluble selective COX-2 inhibi thereof, in a therapeutically effective total amount consti tory drug, tuting about 30% to about 90% by weight, (b) a parenterally acceptable buffering agent in an amount of about 5% to 0021 (b) a water-soluble salt of a selective COX-2 about 60% by weight, and optionally (c) other parenterally inhibitory drug, whether or not Such drug is itself acceptable excipient ingredients in a total amount not greater water-soluble; than about 10% by weight, of the composition. The com position is reconstitutable in a parenterally acceptable Sol 0022 (c) a water-soluble prodrug of a selective vent liquid, preferably an aqueous liquid, to form an inject COX-2 inhibitory drug, whether or not such drug is able Solution. itself water-soluble; or 0012. The composition described above can be prepared 0023 (d) a water-soluble salt of a prodrug of a by a proceSS comprising a Step of lyophilization of an selective COX-2 inhibitory drug, whether or not aqueous Solution comprising the therapeutic agent, the buff Such prodrug is itself water-Soluble. ering agent and optionally other excipient ingredients to 0024 More than one such therapeutic agent can be form a readily reconstitutable powder, Such a process rep present, but in general it is preferred to include only one Such resents a further embodiment of the present invention. selective COX-2 inhibitory drug or prodrug or salt thereof in US 2003/0078266 A1 Apr. 24, 2003

the composition. A composition comprising a prodrug of a 0054) Pat. 5,633,272 to Talley et al. selective COX-2 inhibitory drug or a salt of such drug or prodrug may contain a Small quantity of the drug itself, for 0055) Pat. . 5,639,780 to Lau et al. example if the prodrug or Salt readily converts to the drug 0056) Pat. 5,643,933 to Talley et al. during manufacture, Storage, handling or use. 0057) Pat. . 5,658,903 to Adams et al. 0.025 The term “water-soluble” as applied to a therapeu tic agent herein means that the agent, in an amount that is 0058 Pat. . 5,668,161 to Talley et al. therapeutically effective in a Subject, is Soluble in water at 0059) Pat. 5,670,510 to Huang & Reitz. 20-25 C. and at a parenterally acceptable pH, the water being in a Volume less than a maximum volume acceptable 0060) Pat. . 5,677,318 to Lau. for parenteral administration of a Single dose to the Subject. 0061 Pat. . 5,681,842 to Dellaria & Gane. Preferred therapeutic agents have a solubility in water at 20 C. and pH 7.4 of greater than about 0.1 mg/ml. More 0062) Pat. . 5,686,460 to NicolaY et al. preferred therapeutic agents have a Solubility in water at 20 0063) Pat. . 5,686,470 to Weier et al. C. and pH 7.4 of greater than about 0.5 mg/ml. 0.064 Pat. 5,696,143 to Talley et al. 0026. A selective COX-2 inhibitory drug useful herein, or to which a prodrug or Salt useful herein is converted in Vivo, 0065 Pat. . 5,710,140 to Ducharme et al. exhibits selective inhibition of COX-2 relative to COX-1 0.066) Pat. . 5,716,955 to Adams et al. with a selectivity factor of at least 50, preferably at least 100. Such drugs include without limitation compounds disclosed 0067 Pat. . 5,723,485 to Guiigör & Teulon. in the patents and publications listed below, each of which 0068) Pat. . 5,739,166 to Reitz et al. is individually incorporated herein by reference. 0069 Pat. . 5,741,798 to Lazer et al. 0027 U.S. Pat. No. 5,344.991 to Reitz & Li. 0070) Pat. . 5,756,499 to Adams et al. 0028 U.S. Pat. No. 5,380,738 to Norman et al. 0.071) Pat. . 5,756,529 to Isakson & Talley. 0029 U.S. Pat. No. 5,393,790 to Reitz et al. 0072) Pat. 5,776,967 to Kreft et al. 0030 U.S. Pat. No. 5,401,765 to Lee. 0073) Pat. 5,783,597 to Beers & Wachter. 0031 U.S. Pat. No. 5,418,254 to Huang & Reitz. 0074) Pat. . 5,789,413 to Black et al. 0032 U.S. Pat. No. 5,420,343 to Koszyk & Weier. 0075) Pat. . 5,807.873 to NicolaY & Teulon. 0033 U.S. Pat. No. 5,434,178 to Talley & Rogier. 0076) Pat. . 5,817,700 to Dube et al. 0034 U.S. Pat. No. 5,436,265 to Black et al. 0.077 Pat. . 5,830,911 to Failli et al. 0035 U.S. Pat. No. 5,466,823 to Talley et al. 0078 Pat. . 5,849,943 to Atkinson & Wang. 0036 U.S. Pat. No. 5,474,995 to Duchanne et al. 0079 Pat. . 5,859,036 to Sartori et al. 0037 U.S. Pat. No. 5,475,018 to Lee & Bertenshaw. 0080) Pat. . 5,861,419 to Dube et al. 0038 U.S. Pat. No. 5,486,534 to Lee et al. 0081) Pat. . 5,866,596 to Sartori & Teulon. 0039 U.S. Pat. No. 5,510,368 to Lau et al. 0082) Pat. . 5,869,524 to Failli. 0040 U.S. Pat. No. 5,521,213 to Prasit et al. 0083) Pat. . 5,869,660 to Adams et al. 0041 U.S. Pat. No. 5,536,752 to Ducharme et al. 0084) Pat. . 5,883,267 to Rossen et al. 0042 U.S. Pat. No. 5,543,297 to Cromlish et al. 0085 Pat. . 5,892,053 to Zhi et al. 0043 U.S. Pat. No. 5,547,975 to Talley et al. 0086) Pat. . 5,922,742 to Black et al. 0044) U.S. Pat. No. 5,550,142 to Ducharme et al. 0087 .S. Pat. No. 5,929,076 to Adams & Garigipati. 0045 U.S. Pat. No. 5,552,422 to Gauthier et al. 0088) Above-cited U.S. Pat. No. 5,932,598. 0046 U.S. Pat. No. 5,585,504 to Desmond et al. 0089) .S. Pat. No. 5,935,990 to Khanna et al. 0047 U.S. Pat. No. 5,593,992 to Adams et al. 0090) S. Pat No. 5,945,539 to Haruta et al. 0048 U.S. Pat. No. 5,596,008 to Lee. 0091) .S. Pat. . 5,958,978 to Yamazaki et al. 0049 U.S. Pat. No. 5,604,253 to Lau et al. 0092) Pat. . 5,968,958 to Guay et al. 0050 U.S. Pat. No. 5,604.260 to Guay & Li. 0093) Pat. . 5,972,950 to Nicolal & Teulon. 0051 U.S. Pat. No. 5,616,458 to Lipsky et al. 0094) Pat. . 5,973,191 to Mamett & Kalgutkar. 0.052 U.S. Pat. No. 5,616,601 to Khanna et al. O095 Pat. . 5,981,576 to Belley et al. 0053 U.S. Pat. No. 5,620,999 to Weier et al. 0096) Pat. . 5,994,381 to Haruta et al. US 2003/0078266 A1 Apr. 24, 2003

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0176 A preferred selective COX-2 inhibitory drug useful 0184) R' is selected from hydrido and halo. herein, or to which a prodrug or Salt useful herein is 0185. Compositions of the invention are especially useful converted in vivo, is a compound of formula (IV): for water-Soluble Salts, prodrugs and Salts of prodrugs of selective COX-2 inhibitory drugs having the formula (V): (IV) R1 (V) R An ^, R3 O R51Y-N4 \ 4 O S X

R6

0177 wherein: 0186 where R is a methyl or amino group, R is hydrogen or a C- alkyl or alkoxy group, X" is N or 0.178 A is a substituent selected from partially CR" where R is hydrogen or halogen, and Y and Z unsaturated or unsaturated heterocyclyl and partially are independently carbon or nitrogen atoms defining unsaturated or unsaturated carbocyclic rings, prefer adjacent atoms of a five- to six-membered ring that ably a heterocyclyl group Selected from pyrazolyl, is optionally Substituted at one or more positions furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl with OXO, halo, methyl or halomethyl groups, or an and pyridaZinonyl groups, isomer or tautomer thereof. Preferred Such five- to Six-membered rings are cyclopentenone, furanone, 0179 X is O, S or CH; methylpyrazole, isoxazole and pyridine rings Substi 0180 n is 0 or 1; tuted at no more than one position. 0181) R' is at least one substituent selected from 0187 Illustratively, compositions of the invention are heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and Suitable for water-Soluble Salts, prodrugs and Salts of pro drugs of celecoxib, , Valdecoxib, rofecoxib, etori is optionally Substituted at a Substitutable position coxib, 2-(3,5-difluorophenyl)-3-4-(methylsulfonyl)phe with one or more radicals Selected from alkyl, nyl-2-cyclopenten-1-one and 2-(3,4-difluorophenyl)-4-(3- haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxy-3-methyl-1-butoxy)-5-4-(methylsulfonyl)phenyl hydroxyl, hydroxyalkyl, haloalkoxy, amino, alky 3-(2H)-pyridaZinone, most particularly Valdecoxib. A lamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, particularly useful prodrug of Valdecoxib for use in compo halo, alkoxy and alkylthio; Sitions of the invention is parecoxib, more particularly a 0182 R is methyl, amino or aminocarbonylalkyl; water-Soluble Salt thereof, for example parecoxib Sodium. 0188 Parecoxib used in compositions and methods of the 0183) R is one or more radicals selected from hydrido, invention can illustratively be prepared in the manner Set halo, alkyl, alkenyl, alkynyl, OXO, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcar forth in above-cited U.S. Pat. No. 5,932,598. bonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalk 0189 Compositions of the invention are also useful for enyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, compounds having the formula (VI): hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbo nyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, (VI) alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-ary RIQ COOH laminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N- aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylami noalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, R12 aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminoSulfonyl, alkylaminoSulfonyl, N-arylaminoSulfonyl, 0190 where X" is O, S or N-lower alkyl; R is lower arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R being haloalkyl; R is hydrogen or halogen; R' is hydrogen, optionally Substituted at a Substitutable position with one or halogen, lower alkyl, lower alkoxy or haloalkoxy, lower more radicals Selected from alkyl, haloalkyl, cyano, car aralkylcarbonyl, lower dialkylaminoSulfonyl, lower alky boxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, laminoSulfonyl, lower aralkylaminoSulfonyl, lower het amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkyl eroaralkylaminoSulfonyl, or 5- or 6-membered nitrogen Sulfinyl, halo, alkoxy and alkylthio; and containing heterocyclosulfonyl; and R'' and R'' are US 2003/0078266 A1 Apr. 24, 2003 independently hydrogen, halogen, lower alkyl, lower from the composition, or if included, is present at no more alkoxy, or aryl; and for pharmaceutically acceptable Salts than about 10%, preferably no more than about 5%, by thereof. weight of the composition. According to the present inven 0191) A particularly useful compound of formula (VI) is tion, it is believed that by minimizing the amount of, or (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3- excluding altogether, Such bulking agents, especially man carboxylic acid, particularly in the form of a water-Soluble nitol, as components of the composition, acceptable chemi Salt thereof, for example the Sodium Salt. This compound can cal Stability of the therapeutic agent can be assured. illustratively be prepared in the manner set forth in above 0198 Optionally, one or more preservatives can be cited U.S. Pat. No. 6,034,256. included in the composition at up to about 0.5% by weight. 0.192 One or more therapeutic agents selected from those Suitable illustrative preservatives include methylparaben, disclosed hereinabove are present in a reconstitutable pow propylparaben, phenol and benzyl . der composition of the invention in a total amount of about 0199 A reconstitutable powder composition of the inven 30% to about 90%, preferably about 40% to about 85%, and tion preferably contains less than about 5%, more preferably more preferably about 50% to about 80%, by weight of the less than about 2%, and most preferably less than about 1%, composition. by weight of water. Typically the moisture content is about 0193 The buffering agent, which is present in an amount 0.5% to about 1% by weight. It is especially important to of about 5% to about 60%, preferably about 10% to about keep the amount of water to such a low level where the 60%, and more preferably about 20% to about 50%, by therapeutic agent has a tendency to degrade or convert to a weight of the composition, is typically the predominant leSS Soluble form in presence of water. Powder compositions excipient ingredient. In one embodiment of the invention, of the invention exhibit acceptable chemical stability of the the reconstitutable powder composition consists essentially therapeutic agent for at least about 30 days, preferably at of the therapeutic agent and the buffering agent. least about 6 months, most preferably at least about 2 years, when stored at room temperature (about 20-25 C.) in a 0194 The buffering agent is selected to provide a pH of Sealed vial. the composition, upon reconstitution in a physiologically acceptable Volume of a parenterally acceptable Solvent liq 0200 " Acceptable chemical stability” herein means that uid, that (a) is parenterally acceptable, (b) is consistent with the composition, following the defined time period (e.g., the therapeutic agent being entirely in Solution in the Solvent about 30 days, about 6 months or about 2 years), passes a liquid, and (c) provides a medium wherein the therapeutic Standard test for chemical purity of the therapeutic agent, for agent exhibits acceptable chemical stability for at least about example as may be required for approval by a regulatory one hour following reconstitution. Suitable buffering agents authority. An example of such a test is the “5% total, 1% can illustratively be Selected from Sodium and potassium Single impurity rule', whereby a preparation of a candidate phosphates, Sodium and potassium citrates, mono-, di- and drug must contain not more than 5% total impurities, and not triethanolamines, 2-amino-2-(hydroxymethyl)-1,3-pro more than 1% of any Single impurity. panediol (tromethamine), etc. and mixtures thereof. Pre 0201 Where the therapeutic agent is parecoxib, for ferred buffering agents are dibasic Sodium and potassium example in the form of parecoxib Sodium, partial conversion phosphates and tromethamine. An especially preferred buff to Valdecoxib can occur in a composition over a period of ering agent is dibasic Sodium phosphate, for example dibasic time. AS Valdecoxib is itself therapeutically active as a Sodium phosphate anhydrous, heptahydrate, dodecahydrate, selective COX-2 inhibitory drug (indeed the therapeutic etc. efficacy of parecoxib is dependent upon conversion in the 0.195. In one embodiment, the pH of the composition body to Valdecoxib), Such conversion does not result in a upon reconstitution is about 7 to about 9, preferably about loss of therapeutic effect. However, as Valdecoxib has 7.5 to about 8.5, for example about 8. If desired, pH can be extremely low solubility in water, it is desirable to minimize adjusted by including in the composition, in addition to the Such conversion prior to reconstitution, So that complete buffering agent, a Small amount of an acid, for example dissolution of the therapeutic agent is assured. The presence phosphoric acid, and/or a base, for example Sodium hydrox of particulates, Such as would result from the presence of ide. Significant quantities of Valdecoxib, is generally undesirable 0196. Excipients other than the buffering agent, if in a Solution intended for parenteral administration. present, constitute not more than about 10%, preferably not 0202) It is surprisingly found that conversion of pare more than about 5%, by weight of the composition prior to coxib to Valdecoxib in a reconstitutable powder composition reconstitution. The term “excipient herein embraces all can be greatly reduced by reduction or, preferably, elimina non-therapeutically active components of the composition tion from the composition of bulking agents Such as man except for water. In one embodiment of the invention, no nitol. This is illustrated in Examples 1 and 2 hereinbelow. excipients other than the buffering agent are Substantially Compositions of the invention, having no more than 10% by present. weight of excipients other than buffering agents, exhibit a very high degree of chemical Stability of parecoxib, as 0.197 Surprisingly, it has been found important to include shown in Example 1, whereas compositions having higher in the composition no more than about 10% by weight, preferably no more than about 5% by weight, and most levels of excipients other than buffering agents exhibit a preferably Substantially no amount, of ingredients com greater degree of conversion of parecoxib to Valdecoxib, as monly used as bulking agents in reconstitutable parenteral shown in Example 2. formulations, other than buffering agents. In particular, the 0203) An injectable solution composition prepared by widely used bulking agent mannitol is preferably excluded reconstituting a powder composition as herein provided in a US 2003/0078266 A1 Apr. 24, 2003 parenterally acceptable Solvent, preferably an aqueous Sol adapted to other therapeutic agents and/or other buffering vent, is a further embodiment of the present invention. In agents in accordance with the invention. Such a Solution composition the therapeutic agent can have 0209. In this process, parecoxib sodium and dibasic limited chemical Stability, in which case it is preferred to Sodium phosphate heptahydrate as buffering agent are dis reconstitute the composition within a short period of time, solved in water to form an aqueous solution. Preferably for example within about one hour, before administration. In water for injection is used as the Solvent. Parecoxib Sodium other cases the therapeutic agent can exhibit a relatively high and the buffering agent are present in the Solution at con degree of chemical Stability in Solution, and in Such cases it centrations relative to each other consistent with the desired is not critical to administer within a short period of time after relative concentrations of these ingredients in the final reconstitution. composition. Absolute concentrations of these ingredients 0204. Where the therapeutic agent is parecoxib, for are not critical; however, in the interest of process efficiency example in the form of parecoxib Sodium, partial conversion it is generally preferred that the concentration of parecoxib to highly insoluble Valdecoxib can occur in aqueous Solution Sodium be as high as can be conveniently prepared without over a period of time, resulting in formation of Solid risking exceeding the limit of solubility. Other formulation particulates. AS indicated above, the presence of Solid par ingredients can be added in this step if desired. Order of ticulates is generally undesirable in injectable formulations, addition is not critical but it is Strongly preferred to add the thus in the particular case of parecoxib compositions of the parecoxib Sodium last to ensure rapid and complete disso invention, injectable Solutions are preferably administered lution. within a short period of time, for example within about one 0210. The solution is optionally but preferably sterilized, hour, following reconstitution. for example by passing through one or more Sterilizing 0205 Rate of conversion of parecoxib to Valdecoxib in an filters, and is then metered into one or more Vials. Each vial aqueous medium can be greatly reduced by maintaining the receives a measured Volume of Solution having a desired medium at a pH of about 7 or higher. Furthermore, aqueous unit dosage amount of parecoxib Sodium. Lyophilization solubility of parecoxib sodium itself is strongly affected by StopperS having an opening to allow Sublimation to occur are pH. For example, equilibrium solubility at 20° C. rises from placed on the Vials. Preferably the Vials and stopperS are 1.0 mg/ml at pH 7.3 to 18 mg/ml at pH 7.8 and to 220 mg/ml Sterile and filling is conducted under aseptic conditions. at pH 8.2. SuperSaturated Solutions of parecoxib Sodium can also be prepared at much higher concentrations. A preferred 0211 The stoppered vials are then placed in a lyophiliza pH range providing physiological acceptability, good short tion chamber and the contents of the Vials lyophilized, term chemical stability and good solubility of parecoxib preferably in a three-phase cycle. Sodium is about 7.5 to about 8.5, more preferably about 7.8 0212. In a first phase of the lyophilization cycle, the to about 8.2, for example about 8.0. Solution in each vial is frozen to a temperature below the glass transition temperature of the Solution. For composi 0206. Any known parenterally acceptable solvent liquid tions of the invention comprising parecoxib Sodium and can be used to reconstitute a powder composition of the dibasic Sodium phosphate, the glass transition temperature is invention. Water for injection can be suitable, but will about -20° C. Glass transition temperature can be measured generally provide a hypotonic Solution. Accordingly, it is by any technique known in the art, for example by use of a generally preferred to use an aqueous liquid containing a freeze-drying microScope or by electrical resistance mea Solute Such as dextrose or Sodium chloride. Illustratively, Surement. A Suitable temperature for this freezing phase is 0.9% sodium chloride injection USP, bacteriostatic 0.9% typically about -30°C. to about -60C., for example about Sodium chloride injection USP, 5% dextrose injection USP, -40 C. to about -50° C. Temperature is gradually lowered and 5% dextrose and 0.45% sodium chloride injection USP from room temperature to the desired freezing temperature, are suitable. Lactated Ringer's injection USP is less Suitable, typically over a period of about 1 to about 5 hours, more at least where the therapeutic agent is parecoxib Sodium, typically about 2 to about 4 hours. The temperature is then because of a tendency to form crystals. held at the freezing temperature, typically for a period of 0207. A suitable volume of the solvent liquid for recon about 0.5 to about 24 hours, more typically about 0.75 to Stitution depends on the age and body weight of the Subject, about 3 hours. the Solubility and dosage amount of the therapeutic agent 0213. In the freezing phase of a preferred lyophilization and other factors, but is generally about 0.25 ml to about 5 process, temperature is first lowered from room temperature ml, preferably about 0.5 ml to about 2 ml. For example, in to about -20° C. fairly rapidly, e.g., over a period of about the case of parecoxib Sodium, a 20 mg dose can generally be 0.25 to about 1 hour, more preferably about 0.5 to about 0.75 conveniently reconstituted in about 1 ml of any of the above hour. Temperature is then lowered more gradually from solvent liquids, while for a 40 mg dose a 2 ml volume of the about -20° C. to about -30°C., e.g., over a period of about Solvent liquid is generally Suitable. 1 to about 4 hours, more preferably about 1.5 to about 3 0208. A powder composition of the invention preferably hours. Without being bound by theory, it is believed that this has Sufficient porosity to permit rapid dissolution of the gradual lowering of temperature ensures that the Solution is therapeutic agent upon reconstitution in the Solvent liquid. A completely frozen. Temperature is then lowered fairly rap high degree of porosity is obtainable by using a process to idly from about -30° C. to the final freezing temperature, prepare the powder as described hereinbelow. Such a pro preferably about -40°C., e.g., over a period of about 0.1 to ceSS is a further embodiment of the present invention and is about 1 hour, more preferably about 0.25 to about 0.5 hour. described herein with particular reference to parecoxib It has been found that a stepwise freezing phase as described Sodium and dibasic Sodium phosphate heptahydrate; how above tends to provide a final lyophilized product that ever, it will be understood that the process can be readily appears Solid with no cracking. US 2003/0078266 A1 Apr. 24, 2003

0214. In a second phase of the lyophilization cycle, 0220 An article of manufacture comprising a Sealed Vial, freeze-drying is effected by drawing a vacuum in the lyo preferably a glass Vial, having enclosed therewithin a pow philization chamber. This phase is described herein as the der composition as herein provided in a unit dosage amount “primary drying phase. A vacuum of about 25 to about 500 and in a Sterile condition, is a further embodiment of the um Hg (about 25 to about 500 millitorr), preferably about 50 present invention. In a particular embodiment, Such an to about 300 um Hg, is generally suitable. During the article of manufacture is provided, prepared by a process as primary drying phase, temperature is gradually raised, described above. The vial preferably has a capacity sufficient optionally in Stages Separated by periods when the tempera to enable reconstitution of the composition in situ. Generally ture is held constant. Preferably the vacuum is maintained a capacity of about 1 ml to about 10 ml, preferably about 2 with a nitrogen Sweep. Ice Sublimates from the frozen ml to about 5 ml, will be found convenient. Solution during this phase, forming a partially dried cake. 0221) The term “vial” herein is used to denote any small 0215. In the primary drying phase of a preferred lyo container, having a closure, that is Suitable for packaging a philization process, temperature is first raised from the unit dosage amount of a reconstitutable powder, preferably freezing temperature, e.g., about -40°C., to about 0°C. Over in a sterile condition. It will be understood that equivalent a period of about 1 to about 5 hours, preferably about 2 to forms of packaging, Such as an ampoule, a disposable about 4 hours, and is then held at about 0°C. for a prolonged Syringe and a Syringe cartridge, are encompassed by this period, for example about 6 to about 12 hours, preferably embodiment of the invention. about 8 to about 10 hours. Preferably a vacuum of about 150 to about 300 um Hg is used during the primary drying phase. 0222 Optionally the vial can comprise two compart 0216) In a third phase of the lyophilization cycle, drying ments, one to contain the reconstitutable powder and one to is completed under Vacuum. This phase is described herein contain a Solvent liquid in an amount Sufficient to dissolve as the "Secondary drying phase. Again a vacuum of about the powder. In Such a vial the two compartments are 25 to about 500 um Hg, preferably about 50 to about 300 um interconnected by an aperture wherein a stopper can be Hg, is generally Suitable, preferably maintained with a engaged to prevent contact of the powder and the Solvent nitrogen Sweep. Temperature is raised during the Secondary liquid until the Vial is ready for use. In use, the liquid is drying phase, preferably to a level above room temperature, brought into contact with the powder by disengagement or for example about 40 C., to drive off remaining moisture puncture of the Stopper by any Suitable means, for example and provide a powder having a moisture content of less than a device Such as a plunger that exerts pressure or drives a about 5%, preferably less than about 2%, more preferably needle through the Stopper. Examples of Such multi-com less than about 1%, by weight. partment vials include a dual-chamber cartridge for a 0217. In the secondary drying phase of a preferred lyo Syringe and a dual-chamber vial Such as that available under philization process, temperature is first raised from about 0. the trademark Act-O-Vial(R) of Pharmacia Corporation. C. to about 40 C. over a period of about 1 to about 4 hours, 0223) A unit dosage amount of a powder composition of preferably about 1.5 to about 3 hours, and is then held at the invention, Suitable for preparation and or placement in a about 40 C. for about 3 to about 12 hours, preferably about Vial to form an article of manufacture of the invention, is an 4 to about 8 hours. Preferably a vacuum of about 150 to amount that comprises Sufficient of the therapeutic agent to about 300 um Hg is used during the Secondary drying phase. provide a therapeutic benefit upon parenteral administration Optionally during the last part of the Secondary drying to a subject having a COX-2 mediated condition or disorder. phase, while temperature is being held at about 40 C., the For example, in the case of a parecoxib Sodium composition vacuum is lowered to about 25 to about 75 um Hg. of the invention, a Suitable unit dosage amount is generally 0218. The overall lyophilization cycle time is typically one containing about 1 mg to about 200 mg, preferably about 18 to about 36 hours. Extending the cycle time is about 5 mg to about 120 mg, and more preferably about 10 generally not deleterious to quality of the finished product mg to about 100 mg, for example about 20 mg, about 40 mg but increaseS proceSS cost. The best combination of product or about 80 mg, parecoxib. Where the therapeutic agent is quality and process economics can be found by routine other than parecoxib, a Suitable unit dosage amount is one testing based on the information presented herein, and will that is therapeutically equivalent to parecoxib at the dosage vary depending on Several factors, including the particular ranges indicated above. lyophilization equipment used, the precise composition and 0224 Compositions of the invention are useful in treat concentration of ingredients in the Solution being lyo ment and prevention of a very wide range of disorders philized, the therapeutic agent and buffering agent Selected, mediated by COX-2, including but not restricted to disorders etc. In general, however, a cycle time of about 18 to about characterized by inflammation, pain and/or fever. Such 24 hours will be found suitable. In the case of parecoxib compositions are especially useful as anti-inflammatory Sodium compositions having dibasic Sodium phosphate as agents, Such as in treatment of arthritis, with the additional the buffering agent, it has been found that shortening cycle benefit of having Significantly leSS harmful Side effects than time substantially below about 18 hours, for example to 16.5 compositions of conventional NSAIDs that lack selectivity hours, leads to increased incidence of collapse of the fin for COX-2 over COX-1. In particular, compositions of the ished product, which in turn is not conducive to the desired invention have reduced potential for gastrointestinal toxicity rapid dissolution upon reconstitution. and gastrointestinal irritation, including upper gastrointesti 0219. On completion of the lyophilization cycle, the nal ulceration and bleeding, by comparison with composi Vacuum is released and temperature is permitted to return to tions of conventional NSAIDs. Thus compositions of the room temperature. The Vials are then capped and Sealed to invention are particularly useful as an alternative to conven prevent reabsorption of moisture from the atmosphere and to tional NSAIDs where Such NSAIDs are contraindicated, for maintain Sterility. example in patients with peptic ulcers, gastritis, regional US 2003/0078266 A1 Apr. 24, 2003

enteritis, ulcerative colitis, diverticulitis or with a recurrent tias, including Alzheimer's disease, vascular dementia, history of gastrointestinal lesions, gastrointestinal bleeding, multi-infarct dementia, pre-Senile dementia, alcoholic coagulation disorders including anemia Such as hypopro dementia and Senile dementia. thrombinemia, hemophilia or other bleeding problems, kid 0232 Such compositions are useful in treatment of aller ney disease; or in patients prior to Surgery or patients taking gic rhinitis, respiratory distress Syndrome, endotoxin shock anticoagulants. Syndrome and liver disease. 0225 Contemplated compositions are useful to treat a 0233. Such compositions are useful in treatment of pain, variety of arthritic disorders, including but not limited to including but not limited to postoperative pain, dental pain, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, muscular pain, and pain resulting from cancer. For example, Such compositions are useful for relief of pain, fever and Osteoarthritis, Systemic lupus erythematosus and juvenile inflammation in a variety of conditions including rheumatic arthritis. fever, influenza and other viral infections including common 0226. Such compositions are useful in treatment of cold, low back and neck pain, dysmenorrhea, headache, asthma, bronchitis, menstrual cramps, preterm labor, ten toothache, Sprains and Strains, myositis, neuralgia, Synovitis, dinitis, bursitis, allergic neuritis, cytomegalovirus infection, arthritis, including rheumatoid arthritis, degenerative joint apoptosis including HIV-induced apoptosis, lumbago, liver diseases (osteoarthritis), gout and ankylosing spondylitis, disease including hepatitis, Skin-related conditions Such as bursitis, burns, and trauma following Surgical and dental pSoriasis, eczema, acne, burns, dermatitis and ultraViolet procedures. radiation damage including Sunburn, and post-operative 0234. Such compositions are useful for treating and pre inflammation including that following ophthalmic Surgery venting inflammation-related cardiovascular disorders, Such as cataract Surgery or refractive Surgery. including vascular diseases, coronary artery disease, aneu rysm, vascular rejection, arteriosclerosis, atherOSclerosis 0227 Such compositions are useful to treat gastrointes including cardiac transplant atherosclerosis, myocardial inf tinal conditions Such as inflammatory bowel disease, arction, embolism, Stroke, thrombosis including venous Crohn's disease, gastritis, irritable bowel Syndrome and thrombosis, angina including unstable angina, coronary ulcerative colitis. plaque inflammation, bacterial-induced inflammation 0228 Such compositions are useful in treating inflam including Chlamydia-induced inflammation, Viral induced mation in Such diseases as migraine headaches, periarteritis inflammation, and inflammation associated with Surgical nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, procedures Such as vascular grafting including coronary Sclerodoma, rheumatic fever, type I diabetes, neuromuscular artery bypass Surgery, revascularization procedures includ junction disease including myasthenia gravis, white matter ing angioplasty, Stent placement, endarterectomy, or other disease including multiple Sclerosis, Sarcoidosis, nephrotic invasive procedures involving arteries, veins and capillaries. Syndrome, Behcet's Syndrome, polymyositis, gingivitis, 0235 Such compositions are useful in treatment of angio nephritis, hyperSensitivity, Swelling occurring after injury genesis-related disorders in a Subject, for example to inhibit including brain edema, myocardial ischemia, and the like. tumor angiogenesis. Such compositions are useful in treat ment of neoplasia, including metastasis, ophthalmological 0229 Such compositions are useful in treatment of oph conditions Such as corneal graft rejection, ocular neovascu thalmic disorders, including without limitation inflamma larization, retinal neovascularization including neovascular tory disorderS Such as endophthalmitis, episcleritis, retinitis, ization following injury or infection, diabetic retinopathy, iriditis, cyclitis, choroiditis, keratitis, conjunctivitis and ble macular degeneration, retrolental fibroplasia and neovascu pharitis, inflammatory disorders of more than one part of the lar glaucoma; ulcerative diseaseS Such as gastric ulcer, eye, e.g., retinochoroiditis, iridocyclitis, iridocyclochoroidi pathological, but non-malignant, conditions Such as heman tis (also known as uveitis), keratoconjunctivitis, blepharo giomas, including infantile hemangiomas, angiofibroma of conjunctivitis, etc.; other COX-2 mediated retinopathies the nasopharynx and avascular necrosis of bone; and disor including diabetic retinopathy, ocular photophobia, acute ders of the female reproductive System Such as endometrio trauma of any tissue of the eye including postSurgical SS. trauma, e.g., following cataract or corneal transplant Sur 0236 Such compositions are useful in prevention and gery; postSurgical ocular inflammation; intraoperative mio treatment of benign and malignant tumors and neoplasia sis, corneal graft rejection; ocular, for example retinal, including cancer, Such as colorectal cancer, brain cancer, neovascularization including that following injury or infec bone cancer, epithelial cell-derived neoplasia (epithelial tion, macular degeneration; cystoid macular edema, retro carcinoma) Such as basal cell carcinoma, adenocarcinoma, lental fibroplasia; neovascular glaucoma, and ocular pain. gastrointestinal cancer Such as lip cancer, mouth cancer, 0230. Such compositions are useful in treatment of pull esophageal cancer, Small bowel cancer, Stomach cancer, monary inflammation, Such as that associated with viral colon cancer, liver cancer, bladder cancer, pancreas cancer, infections and cystic fibrosis, and in bone resorption Such as Ovary cancer, cerVical cancer, lung cancer, breast cancer, that associated with Osteoporosis. skin cancer Such as Squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known 0231. Such compositions are useful for treatment of cancers that effect epithelial cells throughout the body. certain central nervous System disorders, Such as cortical Neoplasias for which compositions of the invention are dementias including Alzheimer's disease, neurodegenera contemplated to be particularly useful are gastrointestinal tion, and central nervous System damage resulting from cancer, Barrett's esophagus, liver cancer, bladder cancer, Stroke, ischemia and trauma. The term “treatment” in the pancreatic cancer, OVarian cancer, prostate cancer, cerVical present context includes partial or total inhibition of demen cancer, lung cancer, breast cancer and skin cancer. Such US 2003/0078266 A1 Apr. 24, 2003

compositions can also be used to treat fibrosis that occurs intra-articular, intrasynovial, intraspinal, intrathecal and int with radiation therapy. Such compositions can be used to racardiac administration. Any known device useful for treat Subjects having adenomatous polyps, including those parenteral injection or infusion of drugs can be used to effect with familial adenomatous polyposis (FAP). Additionally, Such administration. Such compositions can be used to prevent polyps from 0243 It has been found that parecoxib, when adminis forming in subjects at risk of FAP. tered parenterally to a human Subject, is rapidly and com 0237 Such compositions inhibit -induced pletely converted to Valdecoxib. Surprisingly, therefore, Smooth muscle contraction by inhibiting Synthesis of con even where rapid onset of therapeutic effect is desired, a tractile and hence can be of use in treatment of therapeutically effective dose of parecoxib, for example in dySmenorrhea, premature labor, asthma and eosinophil-re the form of parecoxib Sodium, is one that is equal to a lated disorders. They also can be of use for decreasing bone therapeutically effective dose of Valdecoxib administered loss particularly in postmenopausal women (i.e., treatment orally. The term “equal” in this context means equal in molar of Osteoporosis), and for treatment of glaucoma. amount or in absolute amount (i.e., in weight). Based on molecular weights, complete conversion of 1 mg parecoxib 0238 Preferred uses for compositions of the invention produces about 0.85 mg Valdecoxib. For practical purposes, are for treatment of rheumatoid arthritis and Osteoarthritis, for pain management generally (particularly post-oral Sur no great error arises from considering 1 mg parecoxib to be gery pain, post-general Surgery pain, post-Orthopedic Sur equivalent to 1 mg Valdecoxib. gery pain, and acute flares of Osteoarthritis), for treatment of 0244 Thus according to an embodiment of the present Alzheimer's disease, and for colon cancer chemoprevention. invention, a method is provided for treatment of a COX-2 mediated disorder in a human Subject comprising parenter 0239 Besides being useful for human treatment, compo ally administering parecoxib or a Salt thereof to the Subject sitions of the invention are useful for veterinary treatment of at a parecoxib dosage equal to a therapeutically effective companion animals, exotic animals, farm animals, and the dosage of Valdecoxib. Preferably, the parecoxib or salt like, particularly mammals. More particularly, compositions thereof, for example the Sodium Salt, is administered in a of the invention are useful for treatment of COX-2 mediated daily dosage amount of about 1 mg to about 200 mg. More disorders in horses, dogs and cats. preferred daily dosage amounts are about 5 mg to about 120 0240 The present invention is further directed to a thera mg, more preferably about 10 mg to about 100 mg, for peutic method of treating a condition or disorder where example about 20 mg, about 40 mg or about 80 mg, treatment with a COX-2 inhibitory drug is indicated, the parecoxib. method comprising parenteral administration of a reconsti 0245. In an especially Surprising finding, illustrated in tuted composition of the invention to a Subject in need FIG. 1, so rapid and complete is the conversion of parecoxib thereof. The dosage regimen to prevent, give relief from, or to Valdecoxib that parenteral, for example intravenous, ameliorate the condition or disorder preferably corresponds administration of parecoxib to a human Subject provides a to once-a-day or twice-a-day treatment, but can be modified Significantly earlier peak of blood plasma concentration of in accordance with a variety of factors. These include the Valdecoxib than does oral administration of Valdecoxib itself type, age, weight, Sex, diet and medical condition of the at equal dose in immediate release form. subject and the nature and severity of the disorder. Thus, the dosage regimen actually employed can vary widely and can 0246. In a further embodiment of the invention, an article therefore deviate from the preferred dosage regimens Set of manufacture is provided comprising a Sealed Vial, pref forth above. erably a glass Vial, containing a sterile parenterally deliver able composition that comprises parecoxib or a Salt thereof 0241 Initial treatment can begin with a dose regimen as in a parecoxib dosage amount equal to a therapeutically indicated above. Treatment is generally continued as neces effective dosage of Valdecoxib. Preferably the dosage Sary over a period of Several weeks to Several months or amount of parecoxib is about 1 mg to about 200 mg, more years until the condition or disorder has been controlled or preferably about 5 mg to about 120 mg, and most preferably eliminated. Subjects undergoing treatment with a reconsti about 10 mg to about 100 mg, for example about 20 mg, tuted composition of the invention can be routinely moni about 40 mg or about 80 mg. Preferably the parecoxib is tored by any of the methods well known in the art to present as parecoxib Sodium. Optionally the Vial is a mul determine effectiveness of therapy. Continuous analysis of ticompartment vial as hereinabove described. data from Such monitoring permits modification of the treatment regimen during therapy So that optimally effective 0247 Therapeutic methods of the present invention fur doses are administered at any point in time, and So that the ther include combination therapies of parecoxib or a com duration of treatment can be determined. In this way, the position of the invention with one or more drugs Selected treatment regimen and dosing Schedule can be rationally from and other analgesics, including narcotic anal modified over the course of therapy so that the lowest gesics, Mu receptor antagonists, Kappa receptor antagonists, amount of the composition exhibiting Satisfactory effective non-narcotic (i.e. non-addictive) analgesics, monoamine neSS is administered, and So that administration is continued uptake inhibitors, adenosine regulating agents, only for So long as is necessary to Successfully treat the derivatives, Substance Pantagonists, neurokinin-1 receptor antagonists and Sodium channel blockers, among others. condition or disorder. Preferred combination therapies comprise use of a compo 0242. The term “parenteral administration” herein Sition of the invention with one or more compounds Selected encompasses injection and/or infusion of a composition into from , , e-acetamidocaproic acid, or through the skin of a Subject, and includes intradermal, acetaminophen, acetaminoSalol, , acetylsalicylic Subcutaneous, intramuscular, intravenous, intramedullary, acid (), S-adenosylmethionine, , , US 2003/0078266 A1 Apr. 24, 2003

allylprodine, , , alphaprodine, alumi acid, , , tropesin, , Xenbucin, Ximo num bis(acetylsalicylate), , aminochlorthenoxazin, profen, and (see The Merck Index, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, amino 12th Edition, Therapeutic Category and Biological Activity propylon, aminopyrine, amiXetrine, ammonium Salicylate, Index, ed. S. Budavari (1996), pp. Ther-2 to Ther-3 and , amtolimetin guacil, anilleridine, antipyrine, Ther-12 (Analgesic (Dental), Analgesic (Narcotic), Analge antipyrine Salicylate, antrafenine, apaZone, , beno sic (Non-narcotic), Anti-inflammatory (Nonsteroidal)). rylate, , benzpiperylon, , benzyl , bermoprofen, , oc-bisabolol, bro 0248 Particularly preferred combination therapies com mfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, prise use of parecoxib or a composition of the invention with bromosaligenin, , bucloxic acid, bucolome, bufeX an compound, more particularly where the opioid amac, bumadizon, , butacetin, butibufen, compound is , meperidine, morphine or a derivative butophanol, calcium acetylsalicylate, , carbi thereof. phene, , carSalam, chlorobutanol, chlorthenoxazin, 0249. The drug being used in combination therapy with choline Salicylate, cinchophen, cinmetacin, ciramadol, clid parecoxib or a composition of the invention can be admin anac, clometacin, clonitaZene, , clopirac, clove, istered by any route, including parenterally, orally, topically, codeine, codeine methyl bromide, codeine phosphate, codeine Sulfate, cropropamide, crotethamide, desomor etc. phine, deXOXadrol, , , diampro mide, diclofenac Sodium, , , EXAMPLES , , dihydrocodeinone enol acetate, , dihydroxyaluminum acetylsalicylate, 0250) The following examples illustrate aspects of the , dimepheptanol, dimethylthiambutene, diox present invention but are not to be construed as limitations. aphetylbutyrate, , diprocetyl, dipyrone, ditazol, , emorfaZone, enfenamic acid, epirizole, eptaZO Example 1 cine, etersalate, , , ethoxazene, ethylmethylthiambutene, , , etofe 0251 Reconstitutable powder compositions, herein iden namate, etonitaZene, eugenol, , , fenclozic tified as Formulations A-D, were prepared as described acid, fendosal, , , , fepradinol, below, containing respectively 5, 10, 20 and 40 mg dosage , , , , amounts of parecoxib in the form of parecoxib Sodium. fluoresone, , flu produaZone, , fosfosal, 0252 First, Solutions for lyophilization were prepared gentisic acid, , glucame tacin, glycol Salicylate, having compositions as shown in Table 1. Solutions A-D for guaiaZulene, , , hydroxypethi lyophilization correspond to Formulations A-D respectively. dine, ibufenac, , , imidazole Salicylate, indomethacin, , isofeZolac, isoladol, isometha done, isonixin, isoxepac, , , ketopro TABLE 1. fen, ketorolac, p-lactophenetide, lefetamine, , Composition of Solutions A-D for lyophilization , , , , lysine acetyl Salicylate, magnesium acetylsalicylate, , Ingredient A. B C D , meperidine, , meSalamine, parecoxib sodium (mg) 5.30 10.59 21.18 42.36 metazocine, hydrochloride, methotrimeprazine, dibasic sodium phosphate heptahydrate (mg) 0.67 1.34 2.68 5.36 phosphoric acid, 1M as required for pH metiazinic acid, metofoline, , , mof adjustment eZolac, , morphine, morphine hydrochloride, mor sodium hydroxide, 1N as required for pH phine Sulfate, morpholine Salicylate, myrophine, nabume adjustment tone, , 1-naphthyl Salicylate, naproxen, narceline, water for injection USP, to make (ml) 1. 1. 1. 2 , , , , nime Sulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, , olSalazine, 0253) In preparation of each of the above solutions for , , Oxametacine, , , lyophilization, dibasic Sodium phosphate heptahydrate was , , papaveretum, paranyline, dissolved in a suitable volume of water for injection and pH parSalmide, , perisoxal, , phenadox of the resulting Solution was adjusted to 8.1 using 1M one, , hydrochloride, pheno phosphoric acid. Parecoxib sodium was dissolved in this coll, , phenopyrazone, phenyl acetylsalicy Solution. The pH was checked and readjusted if necessary late, , phenyl Salicylate, phenyramidol, with 1M phosphoric acid or 1N sodium hydroxide and the , , pipebuZone, piperylone, piprofen, Volume was adjusted to a target Volume by addition of water piraZolac, , , , proglu meta to form the solution for lyophilization. The volume of each cin, , promedol, , , pro Solution prepared was Sufficient to prepare Several unit poxyphene, , produaZone, protizinic acid, dosage compositions (1 ml or 2 ml of Solution per unit dose ramifenaZone, , rimazolium metilsulfate, Salac etamide, , , Salicylamide O-, as indicated in Table 1). Salicylsulfuric acid, Salsalte, Salverine, Simetride, Sodium 0254 The solution for lyophilization was passed through Salicylate, , SulfaSalazine, , Superoxide two 0.2 um Durapore(R) sterilizing filters and 1 ml or 2 ml of dismutase, , , talniflumate, , the solution was aseptically filled into 2 ml or 5 ml, Type I, , terofenamate, tetrandrine, thiazolinobutaZone, untreated, depyrogenated, clear glass Vials, respectively. The , tiaramide, , tinoridine, tolfenamic filling was metered by weight. Average density of Several US 2003/0078266 A1 Apr. 24, 2003

lots of each Solution was 1.005 g/ml. In a separate test, parecoxib Sodium was found not to bind to the Sterilizing TABLE 4 filters. 0255 The vials were partially stoppered with sterilized Stability of Formulation D lyophilization stoppers (having an opening to permit Subli Storage temperature and parecoxib valdecoxib water mation), and were placed in a previously Sterilized lyo time of sampling % % % pH philization chamber and Subjected to a lyophilization cycle. freshly prepared 97.4 O.O3 1.OO 7.9 A typical cycle used is as described in Table 2. Sterile 40 C., 4 weeks 97.1 O.O3 1.06 8.0 nitrogen was used to fill the headspace of the Vials and to 40 C., 8 weeks 96.4 O.O3 1.08 7.8 break the vacuum on completion of the cycle. The Vials were 40 C., 12 weeks 96.9 O.04 1.29 7.8 fully stoppered while in the chamber. Upon removal from 55° C., 4 weeks 96.8 O.OS 1.03 8.0 the chamber the vials were immediately sealed with flip-off 55° C., 8 weeks 96.8 O.O7 O.84 7.8 aluminum Seals crimped into place, and were then Stored at 55° C., 12 weeks 95.4 O.09 0.87 7.9 room temperature, protected from light. 70° C., 4 weeks 97.3 O.14 O.90 8.0 70° C., 8 weeks 96.6 O.2O O.77 7.8 TABLE 2 70° C., 12 weeks no data O.36 no data no data Typical lyophilization cycle Phase Description 0259 Formulations A-C were reconstituted in 1 ml, and freezing room temperature to -50 C. in 1.75 h Formulation D in 2 ml, 0.9% sodium chloride injection USP. hold at -50° C. for 7.0 h. The cakes dissolved instantaneously. primary drying -50° C. to 15° C. in 15 h. hold at 15° C. for 2.25 h. 15° C. to 45° C. in 10 h. Example 2 hold at 45° C. for 16.5 h. vacuum 300 um Hg 0260 Reconstitutable powder compositions, herein iden secondary drying 45 C. to room temperature in 5.0 h tified as Formulations E-J., were prepared as described vacuum 300 um Hg below, each containing 20 mg parecoxib in the form of total cycle time 36 h parecoxib sodium. Solutions for lyophilization were first prepared having compositions as shown in Table 5. Solu 0256 The resulting Formulations A-D formed cakes in tions E-J for lyophilization correspond to Formulations E-J the Vials showing good appearance, i.e., with no cracking or respectively. Preparation of the solutions and of the lyo collapsing of the cake. Powder X-ray diffraction (PXRD) philized powder compositions was by a procedure Similar to analysis indicated that the cakes were amorphous. Even after that for Formulations A-D in Example 1. storage at 70° C. for 12 weeks, PXRD analysis showed no change in physical character of the cakes, and no evidence 0261. It will be noted that each of Formulations E-J of collapse was seen. contains more than about 10% of excipient ingredients other 0257 Formulations A, B and C (5, 10 and 20 mg pare than the buffering agent (dibasic Sodium phosphate or coxib) were analyzed for residual water content and, as an tromethamine). These formulations are presented here for indication of chemical stability, for Valdecoxib. Valdecoxib comparative purposes. analysis, by HPLC, was performed on freshly prepared samples and on samples stored for 12 weeks at 70° C. Data, TABLE 5 shown in Table 3, show excellent chemical stability, with less than 0.5% valdecoxib even after 12 weeks high tem Composition of Solutions E-J for lyophilization perature Storage. Ingredient E F G H I J parecoxib sodium (mg) 21.18 21.18 21.18 21.18 21.18 21.18 TABLE 3 dibasic sodium phosphate 2.68 2.68 2.68 2.68 heptahydrate (mg) Stability of Formulations A–C tromethamine (mg) 1.2 1.2 mannitol (mg) 3O 3O 3O 3O Parameter A. B C glycine (mg) 13.5 13.5 polyethylene glycol 4000 2OO water (%), fresh sample 1.6 1.4 O.8 (mg) valdecoxib (%), fresh sample O.O6 O.O7 O.O3 sulfobutyl-f-cyclodextrin 15 valdecoxib (%), stored 12 weeks at 70° C. O.45 O.37 O.36 (mg) hydrochloric acid, 1N as required for pH adjustment sodium hydroxide, 1N as required for pH adjustment 0258 Formulation D (40 mg parecoxib) was tested for water for injection USP. 1. 1. 1. 1. 1. 1. pH and residual water content and analyzed for parecoxib to make (ml) and Valdecoxib by HPLC when freshly prepared and fol lowing 4, 8 and 12 weekS Storage at various temperatures. Data, shown in Table 4, show excellent chemical stability, 0262 Formulations E-J were analyzed for parecoxib and with less than 0.5% valdecoxib even after 12 weeks high Valdecoxib, when freshly prepared and after 4 weekS Storage temperature Storage. Parecoxib and Valdecoxib percentages at various temperatures. Parecoxib and Valdecoxib percent are expressed on an excipient-free basis. ages are expressed in Table 6 on an excipient-free basis. US 2003/0078266 A1 Apr. 24, 2003

including bony resection, men and women 18-45 years of TABLE 6 age inclusive, were randomized to receive a single preemp tive intravenous dose of 20 mg, 40 mg or 80 mg parecoxib, Stability of Formulations E or placebo, in 4 ml volume of 0.9% sodium chloride. Parameter E F G H I J 0269 Beginning at 30 minutes after closure of Surgery, parecoxib (%), as 99.OO 99.40 104.3 102.2 90.46 99.86 prepared level of pain was assessed every two hours up to 24 hours, parecoxib (%), 5° C., 4 95.71 95.76 100.0 98.04 90.17 98.76 except that patients were not awakened for pain assessments. weeks Pain was assessed by the patient on a 0-3 Scale and on a chart parecoxib (%), 55° C., 4 98.79 99.00 98.37 98.03 87.57 97.41 representing a continuum from "no pain' to "worst pain'. weeks parecoxib (%), 70° C., 4 87.60 98.00 82.77 92.81 85.58 90.OO Rescue medication was administered on demand by the weeks patient. At the last Scheduled assessment, or immediately valdecoxib (%), as O.19 O.17 O.25 O.26 O.16 0.2O prior to administration of rescue medication, the patient was prepared asked to evaluate the effectiveness of the Study medication valdecoxib (%), 5 C., 4 O.2O O.12 O.19 O.19 O.13 O-14 to delay pain. weeks valdecoxib (%), 55° C., 1.43 O.26 1.72 138 0.43 1.04 4 weeks 0270 Time to rescue medication (TRM) was analyzed valdecoxib (%), 70° C., 9.03 O.89 15.08 5.26 O.95 8.81 using Survival analysis techniques. The median time to event 4 weeks for each treatment group was calculated using the Kaplan Meier product limit estimator, including the adjustment described by Miller (1981) in Survival Analysis, pp. 74-75. 0263. It will be noted that Formulations E-J exhibited New York: John Wiley & Sons. Ninety five percent (95%) poorer chemical stability than Formulations A-D of the confidence intervals for the median time to event were invention. Formulations F and I, each of which contained 30 calculated using the method of Simon & Lee (1982), Cancer mg mannitol in addition to dibasic Sodium phosphate, exhib Treat. Rep. 66,37-42. For TRM, patients who did not require ited the greatest stability of the formulations tested in this rescue medication up to the 24 hour assessment were Example, but nonetheless showed a much greater degree of considered censored at 24 hours. Patients who dropped out conversion of parecoxib to Valdecoxib than did Formula for reasons other than administration of rescue medication tions A-D after storage for 4 weeks at 55 C. or 70° C. were censored at the time they dropped out of the Study. Chemical stability of Formulations E, G, H and J was unacceptably poor. 0271) On the basis of median TRM (Table 7), single doses of parecoxib 20 mg, 40 mg and 80 mg resulted in 0264. Furthermore, none of formulations E-J exhibited significantly longer TRM than placebo. Median TRM values instantaneous dissolution upon reconstitution. Formulation for parecoxib 40 mg and 80 mg were not significantly I, which contained 200 mg polyethylene glycol 4000 in different from one another, but both were significantly addition to mannitol and dibasic Sodium phosphate, proved longer than TRM for parecoxib 20 mg. especially slow and difficult to dissolve in attempts to reconstitute the formulation. 0272. The proportion of patients taking rescue medica tion (also shown in Table 7) was significantly lower for the Example 3 parecoxib treatment groups than in the placebo treatment group; there was no significant difference between the 0265 Blood plasma concentration of Valdecoxib in parecoxib 40 mg and 80 mg treatment groups with respect human Subjects was determined in a pharmacokinetic Study. to this parameter. In 11 healthy adult Subjects, a single intravenous (IV) 20 mg dose of parecoxib, as parecoxib Sodium, was administered in TABLE 7 a 1 ml bolus, or a single 20 mg dose of Valdecoxib was administered orally in the form of an immediate-release Time to rescue medication (TRM tablet, with 240 ml water. Subjects drank 180 ml water one, Treatment Median 95% confidence Patients taking two and three hours postdose. group TRM interval rescue medication 0266 Valdecoxib blood plasma concentration was deter Placebo 2 h 51 m 2 h 16 m to 3 h 16 m 93% mined using a validated high performance liquid chroma Parecoxib 20 6 h 17 m 4 h 04 m to 11 h 17 m 78% tography (HPLC) procedure. The mean plasma concentra mg Parecoxib 40 >24 h. 11 h. 04 m to >24 h. 48% tion of Valdecoxib from 0 to 24 hours postdose is shown in mg FIG. 1. Parecoxib 80 12 h OO m 6 h 24 m to 16 h 37 m 59% 0267 Maximum blood plasma concentration of Valde mg coxib was reached earlier when parecoxib Sodium was administered intravenously than when Valdecoxib was administered orally. 0273 With respect to the patient's evaluation of effec tiveness of the Study medication, Scores for patients in each Example 4 of the parecoxib treatment groups were significantly higher than those in the placebo treatment group; there were no 0268. In a single-center, Single-dose, randomized, significant differences between the parecoxib 40 mg and 80 double-blind, placebo-controlled, parallel group 24-hour mg treatment groups. Of the patients in the parecoxib 40 mg Study, a group of 224 patients (56 in each treatment group) treatment group, 92% rated the Study medication as “good” requiring extraction of two ipsilateral impacted third molars or “excellent”. US 2003/0078266 A1 Apr. 24, 2003 14

What is claimed is: 16. The composition of claim 1 having Sufficient porosity 1. A pharmaceutical composition comprising, in powder to permit rapid dissolution of the therapeutic agent upon form: reconstitution. 17. An injectable Solution prepared by reconstituting a (a) at least one water-soluble therapeutic agent Selected composition of claim 1 in a parenterally acceptable Solvent. from selective COX-2 inhibitory drugs and prodrugs and Salts thereof, in a therapeutically effective total 18. The Solution of claim 15 wherein the Solvent is an amount constituting about 30% to about 90% by aqueous Solvent. weight, 19. The solution of claim 16 having pH of about 7.5 to about 8.5. (b) a parenterally acceptable buffering agent in an amount 20. The solution of claim 16 wherein the aqueous solvent of about 5% to about 60% by weight, and contains dextrose and/or Sodium chloride. (c) other parenterally acceptable excipient ingredients in 21. An injectable Solution prepared by reconstituting a a total amount of Zero to about 10% by weight, composition of claim 5 in a parenterally acceptable Solvent. 22. The Solution of claim 21 wherein the Solvent is an of the composition; Said composition being reconstitut aqueous Solvent. able in a parenterally acceptable Solvent liquid to form 23. The solution of claim 22 having pH of about 7.5 to an injectable Solution. about 8.5. 2. The composition of claim 1 wherein the therapeutic 24. The solution of claim 22 wherein the aqueous solvent agent comprises a water-Soluble Salt, prodrug, or Salt of a contains dextrose and/or Sodium chloride. prodrug, of a selective COX-2 inhibitory drug selected from 25. An article of manufacture comprising a Sealed Vial celecoxib, deracoxib, Valdecoxib, rofecoxib, , having contained therewithin a unit dosage amount of a 2-(3,5-difluorophenyl)-3-4-(methylsulfonyl)phenyl)-2-cy composition of claim 1 in a Sterile condition. clopenten-one and 2-(3,4-(difluorophenyl)-4-(3-hydroxy-3- 26. The article of manufacture of claim 25 wherein the methyl-1-butoxy)-5-4-(methylsulfonyl)phenyl-3-(2H)-py Vial is a multicompartment vial. ridaZinone. 27. An article of manufacture comprising a Sealed Vial 3. The composition of claim 1 wherein the therapeutic having contained therewithin a unit dosage amount of a agent comprises a water-Soluble Salt, prodrug, or Salt of a composition of claim 5 in a Sterile condition. prodrug, of Valdecoxib. 28. The article of manufacture of claim 27 wherein the 4. The composition of claim 1 wherein the therapeutic parecoxib Sodium is present in a parecoxib dosage amount agent comprises parecoxib or a Salt thereof. of about 1 mg to about 200 mg. 5. The composition of claim 1 wherein the therapeutic 29. The article of manufacture of claim 27 wherein the agent comprises parecoxib Sodium. parecoxib Sodium is present in a parecoxib dosage amount 6. The composition of claim 1 wherein the therapeutic of about 5 mg to about 120 mg. agent comprises (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1- 30. The article of manufacture of claim 27 wherein the benzopyran-3-carboxylic acid or a water-Soluble Salt parecoxib Sodium is present in a parecoxib dosage amount thereof. of about 10 mg to about 100 mg. 7. The composition of claim 1 wherein the therapeutic 31. The article of manufacture of claim 27 wherein the agent is present in an amount of about 40% to about 85% by Vial is a multicompartment vial. weight of the composition. 32. A process for preparing a reconstitutable Selective 8. The composition of claim 1 wherein the therapeutic COX-2 inhibitory composition, the process comprising a agent is present in an amount of about 50% to about 80% by Step of lyophilizing an aqueous Solution that comprises: weight of the composition. (a) at least one therapeutic agent Selected from Selective 9. The composition of claim 1 wherein the buffering agent COX-2 inhibitory drugs and prodrugs and Salts thereof, is present in an amount of about 10% to about 60% by in a therapeutically effective total amount constituting weight of the composition. about 30% to about 90% by weight, 10. The composition of claim 1 wherein the buffering agent is present in an amount of about 20% to about 50% by (b) a parenterally acceptable buffering agent in an amount weight of the composition. of about 5% to about 60% by weight, and 11. The composition of claim 1 that consists essentially of the therapeutic agent and the buffering agent. (c) other parenterally acceptable excipient ingredients in 12. The composition of claim 1 wherein the buffering a total amount of Zero to about 10% by weight, agent is Selected from the group consisting of Sodium and of the composition, excluding water; Said lyophilizing potassium phosphates, Sodium and potassium citrates, Step resulting in formation of a readily reconstitutable mono-, di- and triethanolamines, tromethamine and mix powder. tures thereof. 33. The process of claim 32 wherein the therapeutic agent 13. The composition of claim 1 wherein the buffering is parecoxib Sodium. agent is Selected from the group consisting of dibasic 34. The process of claim 33 wherein the buffering agent Sodium and potassium phosphates and tromethamine. is dibasic Sodium phosphate. 14. The composition of claim 1 wherein the buffering 35. The process of claim 34 wherein, prior to the lyo agent is dibasic Sodium phosphate. philizing Step, the Solution is prepared by dissolving the 15. The composition of claim 1 that, upon reconstitution, parecoxib Sodium and the dibasic Sodium phosphate in water has a pH of about 7 to about 9. for injection, Sterilized and then metered into Vials, each US 2003/0078266 A1 Apr. 24, 2003 containing a volume of Solution having a unit dosage a unit dosage amount of a composition of claim 5 in a amount of parecoxib Sodium, and the Vials are placed in a physiologically acceptable amount of a parenterally accept lyophilization chamber. able Solvent liquid to form an injectable Solution, and 36. The process of claim 35 wherein, in the step of administering the Solution parenterally to the Subject. preparing the Solution, the parecoxib Sodium is added last. 45. The method of claim 44 wherein the parenteral 37. The process of any claim 34 wherein the lyophilizing administration is by intradermal, Subcutaneous, intramuscu Step comprises a freezing phase, a primary drying phase and lar, intravenous, intramedullary, intra-articular, intrasyn a Secondary drying phase. ovial, intraspinal, intrathecal or intracardiac injection or 38. The process of claim 37 wherein: infusion. 46. The method of claim 44 wherein the parenteral (a) in the freezing phase, temperature is lowered to a administration is by intravenous injection or infusion. freezing temperature of about -30°C. to about -60C. 47. The method of claim 46 wherein the composition is over a period of about 1 to about 5 hours and is held at injected intravenously as a bolus. the freezing temperature for about 0.5 to about 24 48. A method of treating or preventing a COX-2 mediated hours, disorder in a human Subject, the method comprising (b) in the primary drying phase, a vacuum of about 25 to parenterally administering parecoxib or a Salt thereof to the about 500 um Hg is drawn, and temperature is raised Subject at a parecoxib dosage equal to a therapeutically from the freezing temperature to about 0° C. over a effective dosage of Valdecoxib. period of about 1 to about 5 hours; and 49. The method of claim 48 wherein the parecoxib or salt thereof is administered in a daily parecoxib dosage amount (c) in the Secondary drying phase, under vacuum of about of about 1 mg to about 200 mg. 25 to about 500 um Hg, temperature is raised from 50. The method of claim 48 wherein the parecoxib or salt about 0° C. to a level above room temperature over a thereof is administered in a daily parecoxib dosage amount period of about 1 to about 4 hours and is held at the of about 5 mg to about 120 mg. raised level for about 3 to about 12 hours; 51. The method of claim 48 wherein the parecoxib or salt to result in a powder having a moisture content of leSS thereof is administered in a daily parecoxib dosage amount than about 2% by weight. of about 10 mg to about 100 mg. 39. The process of claim 37 wherein overall lyophilization 52. The method of claim 48 wherein the parecoxib or salt cycle time is about 18 to about 24 hours. thereof is injected intravenously as a bolus. 40. A method of treating or preventing a COX-2 mediated 53. An article of manufacture comprising a Sealed Vial disorder in a Subject, the method comprising reconstituting having contained therewithin a sterile parenterally deliver a unit dosage amount of a composition of claim 1 in a able composition that comprises parecoxib or a Salt thereof physiologically acceptable amount of a parenterally accept in a parecoxib dosage amount equal to a therapeutically able Solvent liquid to form an injectable Solution, and effective dosage of Valdecoxib. administering the Solution parenterally to the Subject. 54. The article of manufacture of claim 53 wherein the 41. The method of claim 40 wherein the parenteral parecoxib dosage amount is about 1 mg to about 200 mg. administration is by intradermal, Subcutaneous, intramuscu 55. The article of manufacture of claim 53 wherein the lar, intravenous, intramedullary, intra-articular, intrasyn parecoxib dosage amount is about 5 mg to about 120 mg. ovial, intraspinal, intrathecal or intracardiac injection or 56. The article of manufacture of claim 53 wherein the infusion. parecoxib dosage amount is about 10 mg to about 100 mg. 42. The method of claim 40 wherein the parenteral 57. The article of manufacture of claim 53 wherein the administration is by intravenous injection or infusion. parecoxib is present as parecoxib Sodium. 43. The method of claim 42 wherein the composition is 58. The article of manufacture of claim 53 wherein the injected intravenously as a bolus. Vial is a multicompartment vial. 44. A method of treating or preventing a COX-2 mediated disorder in a Subject, the method comprising reconstituting k k k k k