US 20090156670A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0156670 A1 Chaudhary (43) Pub. Date: Jun. 18, 2009 (54) NONAQUEOUS LIQUID PARENTERAL Publication Classification ACECLOFENAC FORMULATION (51) Int. Cl. Inventor: Manu Chaudhary, Haryana (IN) A6II 3L/26 (2006.01) (75) A6IP 29/00 (2006.01) Correspondence Address: (52) U.S. Cl. ........................................................ 514/533 Laura A. Chub AMIN HALLIAN, LLC (57) ABSTRACT 217 N. Jefferson Street, Suite 100 A nonaqueous liquid parenterally deliverable pharmaceutical Chicago, IL 60661 (US) formulation, and more particularly a nonaqueous liquid parenteral Aceclofenac formulation comprising the selective (73) Assignee: VENUS REMEDIES LIMITED, NSAID Aceclofenac, is disclosed. A process of preparing Panchkula- Haryana (IN) Aceclofenac formulation, the therapeutic dosage form and storage of dose, and the method of treating a subject having a (21) Appl. No.: 11/719,906 condition or a disorder wherein treatment with NSAID is indicated, are also disclosed. Diclofenac formed by conver (22) PCT Fled: Oct. 19, 2005 sion of Aceclofenac is solubilized by the nonaqueous solubi PCT NO.: PCT/IN05/00339 lizer(s), which are substantially inert with respect to such (86) conversion. The composition has Aceclofenac salt stabilizing S371 (c)(1), means for inhibiting precipitation of Aceclofenac. The com May 22, 2007 positions disclosed in the present invention are stable upon (2), (4) Date: storage at room temperature and at refrigerated temperatures. (30) Foreign Application Priority Data Compositions disclosed in the present invention, whether ready-to-use or requiring dilution prior to administration, can Nov. 22, 2004 (IN) ........................... 2332/DELA2004 be prepared by inexpensive processes disclosed herein. US 2009/0156670 A1 Jun. 18, 2009 NONAQUEOUS LIQUID PARENTERAL drug typically results in attainment of a therapeutically effec ACECLOFENAC FORMULATION tive blood serum concentration of the drug in a shorter time than is achievable by oral administration. This is especially FIELD OF INVENTION true of intravenous injection, whereby the drug is placed 0001. The present invention generally relates to nonaque directly in the bloodstream. Parenteral administration can ous liquid parenterally deliverable pharmaceutical formula also result in more predictable blood serum concentrations of tion and more particularly to nonaqueous liquid parenteral a drug, because losses in the gastrointestinal tract due to metabolism, binding to food and other causes are eliminated. Aceclofenac formulation comprising the selective NSAID For similar reasons, parenteral administration often permits Aceclofenac and still more particularly to pharmaceutically dose reduction. Parenteral administration is generally the pre acceptable salts of Aceclofenac. The invention also relates to ferred method of drug delivery in emergency situations, and is a process of preparing Aceclofenac formulation, the thera also useful in treating Subjects who are uncooperative, uncon peutic dosage form and storage of dose, and the method of scious, or otherwise unable or unwilling to accept oral medi treating a Subject having a condition or a disorder wherein cation, and where a faster relief is required in lesser time, treatment with NSAID is indicated. specially in acute and chronic painful condition. 0022. If a parenteral drug formulation is to be prepared, it BACKGROUND OF INVENTION is preferable from patient convenience and safety standpoints 0002 The non-steroidal anti-inflammatory drug (NSAID) that such a formulation be a ready-to-use formulation, i.e. one has a wide range and it is. available both in non-prescription that does not require dilution or mixing immediately prior to and prescription mode. The major groups of NSAID are as use (as opposed to a reconstitutable formulation). Ready-to follows: use and dilutable liquid parenteral formulations can also be 0003 a. Salicyclic acid group: aspirin (acetyl salicyclic advantageous from a manufacturing standpoint by avoiding acid), Choline magnesium trisalicylate, diflunisal and sal expensive iyophilization and/or other similar manufacturing salate. steps. 0004 b. Propionic acid group: fenoprofen, flurbiprofen, 0023 Aceclofenac is a phenyl acetic acid derivative which ibuprofen, ketoprofen, naproxen, and Oxaprozin. inhibits interleukin 18-induced prostaglandin E2 production 0005 c. Acetic and acid group: diclofenac, aceclofenac, but has poor COX-I inhibitor effect in oral form. This formu indomethacin, Sulindac, and tolmetin. lation converts it to the Diclofenac, the COX-I and COX-II 0006 d. Enolic acid group: meloxicam and piroxicam. inhibitor, following administration to a subject, itself shows 0007 e. Fenamic acid group: meclofenamate and mefe enhanced inhibitory activity against both COX-1 and COX-2. namic acid. 0024. Because Diclofenac has very poor gastrointestinal 0008 f. Napthylalkenone group: nabumetone. (GI) tolerability, it is not particularly well suited for formu 0009. g. Pyarnocarboxylic acid group: etodallac. lation. By contrast, because of the better GI tolerability of 0010 h. Pyrrole group: Keterolac. aceclofenac and lesser side effects than diclofenac, Ace 0011 i. COX-2 inhibitor group: Celecoxib, Valdecoxib clofenac has been proposed by the inventor for liquid formu and rofecoxib. lation. 0012 Some of different NSAIDs are available in one or 0025. Unfortunately, attempts to formulate Aceclofenac more forms like tablets, injections, and dry powder for injec as a ready-to-use solution for injection have heretofore been tion form. The present invention relates to “ready to use complicated by the fact that Aceclofenac, when in solution injection of aceclofenac. and especially in presence of certain excipients, is unstable, 0013 The disadvantages of other NSAIDs as compared to and undergoes degradation which may precipitate out making the present invention are given below. injection unsuitable for use. 0014) 1) Dry powder injectable NSAID needs to be lyo 0026. One potential solution to this problem is to provide philized and then reconstituted before use. The process is a dry reconstitutable Aceclofenac formulation which is mixed costly and cumbersome. with a liquid vehicle just prior to administration but this too is 0015. 2) Injection form is more advantageous over oral not stable for longer period. However, in many situations it is form as serum concentration of oral NSAID is lesser because particularly advantageous to provide a liquid formulation, of intestinal metabolism of the drug. more especially a ready-to-use formulation, as indicated 0016 3) Serum concentration of oral NSAID is unpredict above. able. 0027. If a liquid parenterally deliverable formulation of 0017 4) The frequency of administration of oral NSAID is Aceclofenac or a pharmaceutically acceptable salt thereof, higher. particularly Such a formulation that is ready-to-use, that is 0018 5) Diclofenac has more side-effects than Ace storage stable at room temperature could be prepared, a sig clofenac. nificant advance in treatment of COX-2 mediated conditions 0019 6) NSAID's injections such as indometacin have and disorders would result. This would be especially true for lesser tolerability than Aceclofenac. Such conditions and disorders characterized by or accompa 0020 7) Ketoprofen is less stable than Aceclofenac. nied by pain, particularly where rapid onset of pain relief is 0021 Parenteral drug formulations have become a very desired (as, for example, in migraine and otherforms of acute important component in the arsenal of available drug delivery and/or severe pain). options, particularly for drugs having analgesic effect. (0028 US Patent application publication no. 20040180961 Parenteral routes of administration, including Subcutaneous, of Lee, Beom-Jin, etal discuss the composition and prepara intramuscular and intravenous injection, offer numerous ben tion method for bioavailable oral Aceclofenac dosage forms. efits over oral delivery in particular situations, for a wide The composition contains water-insoluble Aceclofenac, a variety of drugs. For example, parenteral administration of a polymeric base and a Surfactant. It is stated that the oral US 2009/0156670 A1 Jun. 18, 2009 preparation according to this invention has excellent solubil found to be significantly more effective than ketoprofen, both ity in gastrointestinal tract, thereby improving dissolution with regard to the Ritchie Index and morning stiffness. rate and thus bioavailability, as well as rapid dispersion and 0034. The main disadvantage of long-term therapy with dissolution properties in gastrointestinal tract. In addition, NSAIDs is the risk of gastrointestinal disturbances. NSAIDs when being orally administered in an amount much smaller carry a greater risk of inducing upper gastrointestinal bleed than the conventional preparation, the oral preparation is ing than simple analgesics, though the risk is dependent on therapeutically effective, thus minimizing gastrointestinal the dose and is highest in patients who have previously suf disorder. fered bleeding episodes. Ibuprofen and diclofenac have recently been shown to be the NSAIDs, of those most fre 0029 G. Pasero et al., in their paper “A multi-centre, quently used, which have the lowest risk of causing upper double-blind comparative study of the efficacy and safety of gastrointestinal bleeding. Any NSAID which, therefore, has aceclofenac and diclofenac in the treatment of rheumatoid comparable or better gastrointestinal