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(12) United States Patent (10) Patent No.: US 6,183,779 B1 10 11 12 USOO6183779B1 (12) United States Patent (10) Patent No.: US 6,183,779 B1 Ouali et al. (45) Date of Patent: Feb. 6, 2001 (54) STABILIZED PHARMACEUTICAL 5,698,225 12/1997 Gimet et al. ......................... 424/475 COMPOSITION OF ANONSTEROIDAL ANTI-NFLAMMATORY AGENT AND A FOREIGN PATENT DOCUMENTS PROSTAGLANDIN 91/16895 11/1991 (WO). 99/12524 3/1999 (WO). (75) Inventors: Aomar Ouali, Boisbriand; Abul Kalam 99/65496 12/1999 (WO). Azad, Montreal, both of (CA) 00/01368 1/2000 (WO). 00/15200 3/2000 (WO). (73) Assignee: Pharmascience Inc., Montreal (CA) OTHER PUBLICATIONS (*) Notice: Under 35 U.S.C. 154(b), the term of this Searle HealthNet Prescribing Information for Arthrotec(R) patent shall be extended for 0 days. (downloaded from http://www.searlehealthnet.com/pi/ar throtec.html on Oct. 27, 1998). (21) Appl. No.: 09/273,692 Information for the Patient: ControtecTM. (22) Filed: Mar. 22, 1999 * cited by examiner Primary Examiner James M. Spear (51) Int. Cl. ............................... A61K 9/22; A61 K9/24; (74) Attorney, Agent, or Firm-Dianne E. Reed; J. Elin A61 K9/52; A61 K9/54 Hartrum; Reed & Associates (52) U.S. Cl. .......................... 424/472; 424/451; 424/457; 424/458; 424/465; 424/468; 424/470; 424/474; (57) ABSTRACT 424/489; 514/772.3; 514/781; 514/970 A pharmaceutical composition is provided for the oral (58) Field of Search ..................................... 424/472, 474, administration of an NSAID and a prostaglandin. The com 424/451, 464, 465, 489, 470, 457, 468, position is a solid dosage form wherein the NSAID is 458 enterically coated and the prostaglandin is present along with an effective Stabilizing amount of a prostaglandin (56) References Cited Stabilizing agent Such as hydroxypropyl methylcellulose or U.S. PATENT DOCUMENTS polyvinylpyrrollidone. Exemplary dosage forms are bilayer tablets in which the prostaglandin is misoprostol and the 3,781,429 12/1973 Partridge ............................., 424/234 3,927,213 12/1975 Lippman .............................. 424/234 NSAID is diclofenac, piroxicam, or a pharmaceutically 3,928,588 12/1975 Robert .................................. 424/234 acceptable Salt thereof. Methods for using the composition 3,954,787 5/1976 Monkhouse ....... 260/308 D to treat NSAID-responsive conditions, disorders and dis 4,301,146 11/1981 Sanvordeker .......................... 424/80 eases are provided as well. 5,015,481 5/1991 Franz et al. ....... ... 424/494 5,601,843 2/1997 Gimet et al. ......................... 424/475 35 Claims, 1 Drawing Sheet 10 TN 11 12 U.S. Patent Feb. 6, 2001 US 6,183,779 B1 10 NS C 12 S 9 FIG. 1 10 US 6,183,779 B1 1 2 STABILIZED PHARMACEUTICAL hydroxypropyl methylcellulose (HPMC) or polyvinylpyr COMPOSITION OF ANONSTEROIDAL rolidone (PVP) which can, in turn, lessen the activity of an ANTI-INFLAMMATORY AGENT AND A NSAID. See, for example, U.S. Pat. No. 4,301,146 to PROSTAGLANDIN Sanvordeker, which discloses prostaglandin E-type com pounds stabilized with hydroxypropyl methylcellulose or TECHNICAL FIELD polyvinylpyrrolidone before being pressed into tablets, U.S. This invention relates generally to pharmaceutical Pat. No. 3,954,787 to Monkhouse, which discloses that compositions, and more particularly relates to a pharmaceu lyophilized compositions of prostaglandin E and Sodium tical composition containing a combination of a nonsteroidal chloride, cyclodextrin or polyvinylpyrrollidone are stable, anti-inflammatory drug (NSAID) and a prostaglandin. and U.S. Pat. No. 5,015,481 to Franz et al., which discusses BACKGROUND the destabilization of prostaglandins in the presence of the NSAIDs diclofenac and piroxicam. Nonsteroidal anti-inflammatory agents Such as There is, accordingly, a need in the art to provide a diclofenac, difenpiramide, fenbufen, flufenamic acid, 15 composition for administering an NSAID wherein the unde ibuprofen, indomethacin, ketoprofen, meclofenamate Sirable gastrointestinal Side effects of the drug are minimized Sodium, mefenamic acid, nabumetone, naproxen, piroXicam, but wherein the drugs therapeutic effectiveness is main Suprofen and tiaprofenic acid, are widely used to relieve tained. The present invention is addressed to the aforemen mild to moderate pain, for fever, and to treat inflammatory tioned need in the art and provides a Stabilized pharmaceu conditions. Sodium diclofenac, for example, is particularly tical composition of an NSAID and a prostaglandin, i.e., a effective for relief of musculoskeletal and joint disorders composition in which the prostaglandin is Stabilized and the Such as rheumatoid arthritis, an autoimmune disease, Osteoarthritis and ankylosing spondilitis, periacicular disor efficacy of the NSAID is maintained. derS Such as bursitis and tenditis, Soft-tissue disorderS Such 25 SUMMARY OF THE INVENTION as sprains and Strains, and other painful conditions Such as Accordingly, it is a primary object of the invention to renal colic, acute gout, dySmenorrhoea, and for relieving provide a Stabilized pharmaceutical composition for oral pain following some surgical disorders. The NSAIDs are administration of an NSAID and a prostaglandin. non-habit forming drugs and thus offer a significant advan It is another object of the invention to provide such a tage over traditional opioid-based drugs; furthermore, as composition wherein the NSAID is enterically coated. NSAIDs are by definition “nonsteroidal,” the side effects It is yet another object of the invention to provide Such a commonly associated with oral administration of Steroids composition that additionally includes a prostaglandin are avoided as well. However, it is recognized that NSAIDs Stabilizing agent. also exhibit Some undesirable Side effects, particularly at 35 high dosages and/or with chronic oral administration. It is still another object of the invention to provide such Generally, high dosages and chronic use of NSAIDS are a composition in which the enterically coated NSAID and asSociated with problems. Such as gastrointestinal and duode the prostaglandin are present in discrete regions of the nal bleeding, ulceration and perforation. composition, Such as in a bilayer tablet wherein the enteri In view of the advantages of NSAIDs over opioid-based 40 cally coated NSAID is present in a first layer and the drugs and Steroidal agents, Steps have been undertaken to prostaglandin and the prostaglandin Stabilizing agent are minimize the drugs adverse effects. In one approach, present in a Second layer. NSAIDs have been administered locally, such as by Another object of the invention is to provide a method for injection, by topical administration of, for example, an 45 treating a patient with an NSAID-responsive condition, ointment or cream, by use of a transdermal patch, or by an disease or disorder, wherein the method comprises admin inhalation device. Although local administration is istering an NSAID to the patient in a Stabilized pharmaceu desirable, administration of an effective amount of the active tical composition as provided herein. agent is difficult or inconvenient. In another approach to Still another object of the invention is to provide a method reduce the adverse effects of NSAIDs, the agents are 50 for reducing the undesirable gastrointestinal Side effects ingested after food or milk, or are taken in combination with associated with the oral administration of an NSAID, antacids, histamine H-receptor antagonists, omeprazole, or wherein the method comprises co-administering a proStag Sucralefate. landin with the NSAID in a stabilized pharmaceutical com In yet another approach to reduce the undesirable gas 55 position as provided herein. trointestinal effects resulting from the oral administration of Additional objects, advantages and novel features of the NSAIDs, the agents have been co-administered with some invention will be set forth in part in the description which prostaglandins, particularly "E-Series' prostaglandins Such follows, and in part will become apparent to those skilled in as PGE, PGE, misoprostol, and derivatives thereof; See, the art upon examination of the following, or may be learned e.g., U.S. Pat. No. 3,781,429 to Partridge, U.S. Pat. No. 60 by practice of the invention. 3,927,213 to Lippman, U.S. Pat. No. 3,928,588 to Robert, In one embodiment, the first layer of the bilayer tablet and U.S. Pat. No. 5,015,481 to Franz et al. Administration of comprises an enterically coated nonsteroidal anti a prostaglandin with an NSAID has been shown to reduce inflammatory agent, and the Second layer comprises a pros the ulcerogenicity of the NSAID. However, prostaglandins 65 taglandin and a Stabilizing agent. are unstable compounds and degrade readily in the presence In another embodiment, a method of treating a patient is of NSAIDS, thus requiring a Stabilizing agent Such as provided for carrying out the present therapeutic method US 6,183,779 B1 3 4 comprising administering to the patient a pharmaceutical nontoxic but Sufficient amount of the agent to provide the composition bilayer tablet as described herein. desired therapeutic effect. As will be pointed out below, the exact amount required will vary from Subject to Subject, BRIEF DESCRIPTION OF THE DRAWINGS depending on the age, weight, and general condition of the FIGS. 1 and 2 are Schematic representations of dosage Subject, the Severity of the condition being treated, and the forms of the invention. like. Thus, it is not possible to specify an exact “effective DETAILED DESCRIPTION OF THE amount.” However, an appropriate “effective” amount in INVENTION any individual
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