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(12) United States Patent (10) Patent No.: US 6,472,433 B2 Wechter (45) Date of Patent: Oct

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(12) United States Patent (10) Patent No.: US 6,472,433 B2 Wechter (45) Date of Patent: Oct USOO6472433B2 (12) United States Patent (10) Patent No.: US 6,472,433 B2 Wechter (45) Date of Patent: Oct. 29, 2002 (54) METHOD FOR TREATMENT OF Variability of Inversion of (R)-Flurbiprofen in Different NFLAMMATION WITH R-NSAIDS Species, Sabine Menzel-Soglowek, Gerd Geisslinger, Win fried S. Beck, and Kay Brune-Journal of Pharmaceutical (75) Inventor: William J. Wechter, Ojai, CA (US) Sciences vol. 81, No. 9, Sep. 1992. Disposition and Pharmacokinetics of R-flurbiprofen in (73) Assignee: Loma Linda University Medical Three Species: Demonstration of R- to S-Flurbiprofen Center, Loma Linda, CA (US) Inversion in the Mouse, Rat and Monkey-William J. Wechter, E. David Murray, Jr. Karina M. Gibson, David D. (*) Notice: Subject to any disclaimer, the term of this Quiggle, and Douglas L. Leipold-Laboratory of Chemical patent is extended or adjusted under 35 Endocrinology, Loma Linda University School of Medicine, U.S.C. 154(b) by 0 days. 1998. Superaspirin, Jerome Groopman The New Yorker, Jun. 15, (21) Appl. No.: 09/797,022 1998 pp. 32–35. (22) Filed: Mar. 1, 2001 Building a Better Aspirin, Science, vol. 280, May 22, 1998. (65) Prior Publication Data R-Flurbiprofen Chemoprevention and Treatment of Intesti nal Adenomas in the APC Min/+ Mouse Model: Implica US 2001/0012849 A1 Aug. 9, 2001 tions for Prophylazis and Treatment of Colon Caner, Will iam Wechter, Darko Kantoci, E. David Murray, Jr. David D. Related U.S. Application Data Quiggle, Douglas D. Leipold, Karina M. Gibson, and John D. McCracker-Cancer Research 57, 4316-4324, Oct. 1, (63) Continuation of application No. PCT/US99/20261, filed on 1997. Sep. 3, 1999. (60) Provisional application No. 60/155,217, filed on Jul. 8, Aspirin-like drugs may block pain idependently of proStag 1999. landin synthesis inbibition, K. Brune, W.S. Beck, G. Gei sslinger, S. Menzel-Soglowek, B.M. Peskar and B.A. Pes (51) Int. Cl." ........................ A61K 31/19; A61K 31/42; kar-Experientia 47 (1991). A61K 31/40; A61K 31/38 PIII–82 Effect of Flurbiprofen (FLU) Enantiomers on Pros taglandin E2 (POE2) and Substance P(SP) Levels in Human (52) U.S. Cl. ....................... 514/570; 514/375; 514/411; Suction Blister, G. Geisslinger, Ph.D., R. Oelkers, MD, W. 514/413; 514/429; 514/448 Neupert, Ms. K.M. Williams, Ph.D., K. Brune, MD. Dept. of Exp & Clinical Pharmacology-Clinical Pharmacology & (58) Field of Search ................................. 514/570,375, Therapeutics Feb. 1996. 514/411, 413, 429, 448 XP-O00874955 Pharmacoloical Differences Between the Optical Isomers if Ibufprofen: Evidence for Metabolic (56) References Cited Inversion of the (-)-isomer, S.S. Adams, PBresloff, C.G. Mason, Research Department, The Boots Company Ltd., U.S. PATENT DOCUMENTS Nottingham, U.K.-Communications, J.Pharm. Pharmac., 5,200,198 A 4/1993 Geisslinger et al. 1976, 28,256. 5,206,029 A 4/1993 Brune et al. 5,331,000 A 7/1994 Young et al. (List continued on next page.) 6,069,172 A 5/2000 Bertini et al. Primary Examiner William R. A. Jarvis FOREIGN PATENT DOCUMENTS (74) Attorney, Agent, or Firm-Knobbe Martens Olson & EP O 935961 A2 1/1999 Bear LLP WO WO 94/28890 12/1994 (57) ABSTRACT WO WO 98/09603 3/1998 OTHER PUBLICATIONS This invention relates to the use of enantiomerically pure R-NSAIDs for the treatment of inflammation. Preferably, the Schaible et al, Chemical Abstracts, vol. 129, abstract No. R-NSAID used is R-flurbiprofen and is administered in a 197755, 1998.* dose of at least 5 milligrams per kilogram of body weight per Buritova et al., Chemical Abstracts, vol. 129, abstract No. day. The anti-inflammatory action of R-NSAIDs is due to 326025, 1998.* their ability to interfere with the biosynthesis of COX-2 by New Insights into the Site and Mode of Antinociceptive inhibiting COX-2 mRNA synthesis, rather than by just Action of Flurbiprofen Enantiomers, Gerd Geisslinger, blocking the action of the enzyme itself. In order to effect the Ph.D. and Hans-Georg Schaible, MD, J Clin Pharmacol inhibition of COX-2 mRNA synthesis, the R-NSAID must 1996. 36. 51352O. be present at relatively high doses. Because the R-NSAID is Pure Enantiomers of 2-Arylpropionic Acid: Tools in Pain Selective in its action, that is, it does not inhibit either Research and Improved Drugs in Rheumatology, Kay COX-1 mRNA synthesis or the COX-1 enzyme itself, it can Brune, MD, Gerd Geisslinger, Ph.D. and S. Menzel-Soglo be administered in the required high doses because the tissue wek, Ph.D-J Clin Pharmacol 1992:32:944–952. protective effects of prostaglandins made through the Clinical Pharmacokinetics of Flurbiprofen and its Enanti COX-1 pathway are not interfered with. momers, Neal M. Davies-Drug Disposition, Clin Pharma cokinet 28 (2) 1995. 5 Claims, No Drawings US 6,472.433 B2 Page 2 OTHER PUBLICATIONS The Effects of S- and R-flurbiprofen on the inflammation Differential Contribution of R and S Isomers in Ketoprofen evoked intraspinal release of immunoreactive Substance P-a Anti-inflammatory Activity: Role of Cytokine Modulation, study with antibody microphobes, Brain Research 798 Pietro Ghezzi, et al. -The Journal of Pharmacology and (1998) 287–293; Hans-Georg Schaible, et al. Experimental Therapeutics vol. 287, No. 8, 1998. Stereoselective Cyclooxygenase Inhibition in Cellular Peripheral and/or central effects of racemic-S(+)- and Modeels by the Enantiomers of Ketoprofen, Nuria Suesa, et R(-)-flurbiprofen on inflammatory nociceptive processes: a al-Chirality 5:589–595 (1993). c-Fos protein study in the rat spinal cord; British Journal of Pharmacokinetics of Enantiomers of Chrial Non-Steroidal Phamacology vol. 125(1), pp. 87-101; Jaroslava Buritova & Anti-Inflammatory Drugs, Fakhreddin Jamali-European Jean-Marie Besson, 1998. Journal of Drug Metabolism and Pharmacokinetics, 1998, vol. 13, No. 1, pp 1-9. * cited by examiner US 6,472.433 B2 1 2 METHOD FOR TREATMENT OF as to say that “at best, the R-isomers of APAS function as NFLAMMATION WITH R-NSAIDS prodrugs for the therapeutically active S-forms” when the racemic drug is administered to the host, and that the RELATED APPLICATION INFORMATION R-enantiomers are “undesirable impurities in the active This application is a continuation of PCT International drug.” Caldwell et al., Biochem. Pharmacol. 37:105-114 Patent Application No. PCT/US99/20261, filed Sep. 3, 1999, (1988). and claims priority under 35 U.S.C. S 119(e) to U.S. Although the S-NSAIDs have the desired effect of inhib application Ser. No. 09/146,395, filed Sep. 3, 1998, now iting production of prostaglandins through the COX-2 abandoned, which was converted to Provisional Application pathway, they also inhibit the production through the COX-1 Ser. No. 60/155,217 on Jul. 8, 1999. pathway and thus the bad side effects of NSAID use gen erally are also associated with the use of S-enantiomers. FIELD OF THE INVENTION Earlier studies by researchers in this field, as well as by the inventor himself, found that R-NSAIDs had little or no The present invention relates to pharmaceutical compo inhibiting effect on COX enzymes and prostaglandin pro Sitions comprising enantiomerically pure R-NSAIDS and the 15 methods of their use for the treatment of inflammation. duction. What little anti-inflammatory effect existed was Preferably, the R-NSAID used is R-flurbiprofen which is either found to be Statistically insignificant or attributed to administered in a dose of at least 2.5 milligrams per kilo the S-enantiomer, the presence of which was due to either an gram of body weight per day. enantiomerically impure dose of R-NSAID or inversion of the R-enantiomer in vivo. See K. Brune et al., Pure Enanti BACKGROUND OF THE INVENTION omers of 2-Arylpropionic Acids: Tools in Pain Research and Improved Drugs in Rheumatology, J. Clin. Pharmacol. Nonsteriodal anti-inflammatory drugs (NSAIDs) have 32:944-52,946 (1992); K. Brune et al., Aspirin-like drugs been in use for Over a century beginning with aspirin. In may block pain independently of prostaglandin Synthesis recent decades the arylpropionic acid (APA) class of these inhibition, Experentia 47:257-61, 260 (1991); U.S. Pat. No. drugs has gained Wide acceptance. 25 5,200,198 to Geisslinger et al.; and U.S. Pat. No. 5,206,029 Although the NSAIDs are known to be effective against to Brune et al. pain and inflammation, there are often Severe side effects Although the researchers did not find Significant anti and toxicity associated with chronic use of these drugs. inflammatory activity, there was evidence of other activity Chronic NSAID use is known to cause gastric and duodenal attributable to the R-enantiomer, Such as amelioration of ulceration, which may be Severe enough to result in Signifi pain (see U.S. Pat. Nos. 5,200,198 and 5,206,029), treatment cant morbidity and mortality. Furthermore, NSAID use has and prevention of cancer (see Wechter et al., R-Flurbiprofen been reported to be associated with renal and hepatic Chemoprevention and Treatment of Intestinal Adenomas in toxicities, increase in bleeding times due to disruption of the APC"/+Mouse Model, Cancer Research 57.4316–24 platelet function, prolongation of gestation due to uterine (1997)), treatment of cystic fibrosis (see U.S. Pat. No. effects, and a decreased white cell count in the blood. 35 5,981,592) and treating or delaying the onset of Alzheimer's Because of the side effects and toxicity, many NSAIDs are Disease (see U.S. Pat. No. 6,160,018). no longer in use in human medicine as analgesics. Some of these include tiaprofenic acid, Suprofen, carprofen, U.S. Pat. Nos. 5,200,198 and 5,206,029 disclose the use pirprofen, benoxaprofen, and indoprofen.
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