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United States Patent [19] [11] Patent Number: 6,149,923 Shirahase Et Al

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United States Patent [19] [11] Patent Number: 6,149,923 Shirahase Et Al US006149923A United States Patent [19] [11] Patent Number: 6,149,923 Shirahase et al. [45] Date of Patent: Nov. 21, 2000 [54] ANTIRHEUMATIC AGENT OTHER PUBLICATIONS [75] Inventors: Hiroaki Shirahase, Nagaokakyo; Yoshimi et al Importance of Hydrolysis of Amino Acid Akihisa Yoshimi, Takatsuki; Fumio Moiety in Water—Soluble Prodrugs of Disodium Cromogly Fukata, Osaka; Hideki Okunishi; Yuta cate for Increased Oral Bioavailability 1992 J. Pharmaco Kobayashi, both of IZumo, all of Japan bio—Dyn 15:339—345. Mori et al Pro—drugs for the Oral Deliver of Disodium [73] Assignee: Kyoto Pharmaceutical Industries, Cromoglycate 1988 Chem. Pharm. Bull. 36:338—344. Ltd., Kyoto, Japan Primary Examiner—Thurman K. Page Appl. N0.: Assistant Examiner—Todd D. Ware 09/202,368 Attorney, Agent, or Firm—Leydig, Voit & Mayer, Ltd. PCT Filed: Jun. 6, 1997 [57] ABSTRACT PCT No.: PCT/JP97/01974 An antirheumatic agent comprising diethyl § 371 Date: Dec. 10, 1998 L-lysylcromoglycate of the following formula § 102(e) Date: Dec. 10, 1998 NH; PCT Pub. No.: WO97/47297 [87] OCOCH(CH2)4NH2 PCT Pub. Date: Dec. 18, 1997 o OCHZCHCHZO o [30] Foreign Application Priority Data Jun. 11, 1996 [JP] Japan .................................. .. 8-149549 [51] Int. Cl.7 .......................... .. A61K 9/00; A61K 31/35; A01N 43/16 H5c2ooc o o cooczns US. Cl. ......................... .. 424/400; 514/825; 514/456 Field of Search ........................... .. 424/400; 514/825, or a nontoxic salt thereof as an active ingredient. This 514/456 compound has an anti-in?ammatory action and immuno modulating action, is absorbed by oral administration to be References Cited delivered efficiently to local sites, and is associated With feWer side effects, so that it serves Well as an antirheumatic U.S. PATENT DOCUMENTS agent that can be administered orally. 4,066,756 1/1978 Orr et a1. .............................. .. 514/161 4,847,286 7/1989 Tamaki et a1. ........................ .. 514/456 6 Claims, No Drawings 6,149,923 1 ANTIRHEUMATIC AGENT (I) This application is a 371 of PCT/JP97/01974, ?led Jun. NH2 6, 1997. OCOCH(CH2)4NH2 TECHNICAL FIELD o OCHZCHCHZO o The present invention relates to an antirheumatic agent comprising diethyl L-lysylcromoglycate or a nontoxic salt 10 thereof as an active ingredient. H5c2ooc o o cooczn5 BACKGROUND ART namely, diethyl L-lysylcromoglycate and a nontoxic salt thereof, are efficiently absorbed from the digestive tract, 15 delivered to local sites and suppress the symptoms of Atypical rheumatic disease—chronic rheumatoid arthritis polyarthritis, Which is the main symptom of RA, and devel (hereinafter RA)—is a systemic connective-tissue disease oped further studies to result in the completion of the present having a main symptom of polyarthritis chronica, and is one invention. of the autoimmune diseases. The disease type thereof is That is, the present invention provides the folloWing. generally polyarthritis Which is progressive and chronic. It (1) An antirheumatic agent comprising diethyl L-lysylcromoglycate or a nontoxic salt thereof as an active includes various clinical types such as one shoWing spon ingredient. taneous remission, one shoWing highly progressive destruc (2) The antirheumatic agent of (1) above, Which is an oral tion and absorption of joints (e. g., arthritis dissecans) and the preparation. like. Clinical symptoms thereof include arthritis, sWelling of 25 (3) The antirheumatic agent of (1) or (2) above, further joint, pain, deformation, morning stiffness, rheumatoid comprising an organic acid. nodule, angiitis and the like. (4) The antirheumatic agent of (3) above, Wherein the organic acid is at least one organic carboxylic acid selected For internal therapy of RA at present, nonsteroidal anti from the group consisting of maleic acid, fumaric acid, ?ammatory agents (e.g., aspirin, indometacin, diclofenac tartaric acid, citric acid, succinic acid, malic acid, oxalic sodium, ibuprofen, loxoprofen sodium, piroxicam, acid, mandelic acid, malonic acid and benZoic acid. ampiroxicam, naproxen, and the like), adrenocorticosteroi (5) A pharmaceutical composition for the therapy of dal agents (e.g., intraarticular injection and oral administra rheumatism, comprising diethyl L-lysylcromoglycate or a tion of prednisolone, and the like), immunomodulators (e.g., nontoxic salt thereof, and a pharmaceutically acceptable gold preparation, D-penicillamine, bucillamine, actarit and 35 carrier. the like), immunosuppressive agents (e.g., methotrexate, (6) The pharmaceutical composition for the therapy of rheumatism according to (5) above, Which is an oral prepa miZoribine and the like), and the like are used. These ration. medicaments, nevertheless, fail to provide sufficient thera (7) The pharmaceutical composition for the therapy of peutic effects, but rather, cause various side effects. For rheumatism according to (5) or (6) above, further compris example, nonsteroidal antiin?ammatory agents may cause ing an organic acid. peptic ulcer, nephropathy, hepatopathy and the like, adreno (8) The pharmaceutical composition for the therapy of corticosteroidal agents may induce and exacerbate infec rheumatism according to (7) above, Wherein the organic acid tious diseases, diabetes, moon face, peptic ulcer, adrenocor is at least one organic carboxylic acid selected from the tical insuf?ciency, thrombophlebitis, osteoporosis and the 45 group consisting of maleic acid, fumaric acid, tartaric acid, like, immunomodulators may cause dermatopathy, citric acid, succinic acid, malic acid, oxalic acid, mandelic nephropathy, stomatitis and the like, and immunosuppres acid, malonic acid and benZoic acid. sive agents may cause hepatopathy, leukopenia, thrombocy (9) A method for the therapy of rheumatism comprising topenia and the like, some of Which constituting severe side administering an effective amount of diethyl effects. L-lysylcromoglycate or a nontoxic salt thereof to a patient. (10) Ause of diethyl L-lysylcromoglycate or a nontoxic salt In vieW of the above-mentioned situation, there is a thereof for the therapy of rheumatism. demand for the development of an antirheumatic agent (11) Ause of diethyl L-lysylcromoglycate or a nontoxic salt effective for the alleviation and suppression of the symptoms thereof for the production of a pharmaceutical agent for the of RA and causing feWer side effects. 55 therapy of rheumatism. (12) A commercial package comprising the pharmaceutical It is therefore an object of the present invention to provide composition for the therapy of rheumatism of any of (5)—(8) an antirheumatic agent that is delivered to local sites after above and a Written matter associated thereWith, the Written oral administration, that is effective for the treatment of RA matter stating that said pharmaceutical composition can or and that causes feWer side effects. should be used for the therapy of rheumatism. In the present invention, diethyl L-lysylcromoglycate may be converted to a nontoxic salt, particularly an acid addition DISCLOSURE OF THE INVENTION salt thereof to be mentioned later, to increase absorption efficiency, stabiliZe diethyl L-lysylcromoglycate and facili The present inventors have conducted various studies to 65 tate isolation and production of an oral preparation. solve the above-mentioned problems and found that cro In the present invention, moreover, oral administration of moglycic acid derivatives of the folloWing formula (I): diethyl L-lysylcromoglycate in the presence of an organic 6,149,923 3 4 acid leads to strikingly increased solubility of diethyl administration, such as capsule, tablet, subtiliZed granules, L-lysylcromoglycate in the digestive tract. Therefore, addi granules, dry syrup and the like, according to a knoWn tion of an organic acid to be mentioned later to the anti method. rheumatic agent of the present invention is desirable. Diethyl L-lysylcromoglycate and a nontoxic salt thereof Diethyl L-lysylcromoglycate is a knoWn compound and to be used in the present invention are effective for the can be produced by a method knoWn per se. For example, diethyl cromoglycate and L-lysine are reacted to produce suppression of symptoms of RA and permit high absorption this compound. thereof from the digestive tract and delivery to local sites, so L-Lysine is subjected to the present reaction as a free that they are used as oral antirheumatic agents. carboxylic acid or a reactive derivative thereof. For oral administration of said therapeutic agents, a daily Diethyl L-lysylcromoglycate preferably forms a nontoxic 10 dose is preferably administered orally in one to three doses. salt (acid addition salt) at its amino acid residue. An acid to While the dose varies depending on the condition, age, body form such nontoxic salt is free of any particular limitation as Weight and the like of patients, 20—1000 mg of the active long as it can form a salt With the amino acid residue moiety ingredient—diethyl L-lysylcromoglycate or a nontoxic salt and it is pharmaceutically acceptable. For example, mineral thereof—is administered to an adult daily in one to three acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid; and organic acids such as oxalic acid, 15 doses. fumaric acid, maleic acid, citric acid, tartaric acid, meth anesulfonic acid and toluenesulfonic acid are exempli?ed. EXAMPLES By converting to such salts, absorption from the digestive The present invention is explained in more detail in the tract can be improved and production of the preparation can folloWing by Way of example and experimental
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