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 parecoxib 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 - - ValdeCOxib 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 analgesics 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 cyclooxygenase-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) enzymes 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 analgesic Solids content of the original product must be between effects, through inhibition of prostaglandin Synthesis. Con approximately 5 and 25%. Among the Substances found ventional NSAIDS Such as ketorolac, diclofenac, naproxen 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 prostaglandins 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 celecoxib and rofecoxib, 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 medication. 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