USOO945218OB2 (12) United States Patent (10) Patent No.: US 9,452,180 B2 Tei et al. (45) Date of Patent: Sep. 27, 2016 (54) NSAIDS-INDUCED GASTROINTESTINAL (52) U.S. Cl. MUCOSAL DISORDERALLEVATOR AND CPC ......... A6 IK3I/7016 (2013.01); A61K 31/192 MANUFACTURING METHOD THEREOF (2013.01); A61K 31/196 (2013.01); A61 K 31/405 (2013.01); A61K 3.1/5415 (2013.01); (71) Applicant: Next21 K.K., Tokyo (JP) A6 IK3I/616 (2013.01); A61K 45/06 (2013.01); A61K 47/26 (2013.01); C07H 3/04 (72) Inventors: Yuichi Tei, Tokyo (JP); Nobuo Sasaki, (2013.01) Tokyo (JP); Shigeki Suzuki, Tokyo (JP) (58) Field of Classification Search None (73) Assignee: Next21 K.K., Bunkyo-Ku, Tokyo (JP) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 77 days. U.S. PATENT DOCUMENTS (21) Appl. No.: 14/295,154 2005/0003000 A1*ck 1/2005 Einig ..................... A612.3 (22) Filed: Jun. 3, 2014 OTHER PUBLICATIONS O O Zhang et al., The effects of cryoprotectants on the freeze-drying of (65) Prior Publication Data ibuprofen-loaded solid lipid microparticles (SLM) European Jour US 2014/0323429 A1 Oct. 30, 2014 nal of Pharmaceutics and Biopharmaceutics (2008) vol. 69 pp. 750-759.* Related U.S. Application Data * cited by examiner (62) Division of application No. 13/132,613, filed as application No. PCT/JP2009/006603 on Dec. 3, 2009, Primary Examiner — Eric Olson now abandoned. (74) Attorney, Agent, or Firm — Osha Liang LLP (30) Foreign Application Priority Data (57) ABSTRACT A method of manufacturing a medical drug of alleviating Dec. 4, 2008 (JP) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 2008-310O85 damage of gastrointestinal mucosal induced by a O steroidal anti-inflammatory drug, NSAID, the medical drug (51) Int. Cl. being able to induce anti-inflammatory effect of the NSAID C7H 3/04 (2006.01) and being able to alleviate damage induced by the NSAID A6 IK3I/706 (2006.01) includes dissolving trehalose and the NSAID into one or A6 IK3I/92 (2006.01) more solutions, so as to obtain an approximately homog A6 IK3I/I96 (2006.01) enously-mixed liquid mixture of the trehalose and the A6 IK 3/405 (2006.01) NSAID; in which the liquid mixture contains an intermo A6 IK3I/545 (2006.01) lecular compound with the trehalose and the NSAID; and A6 IK3I/66 (2006.01) drying the liquid mixture so as to obtain the medical drug. A6 IK 45/06 (2006.01) A6 IK 47/26 (2006.01) 5 Claims, 13 Drawing Sheets U.S. Patent Sep. 27, 2016 Sheet 1 of 13 US 9,452,180 B2 5s NE CN () O) O s CN C (UIUI) be Ib Ieon U.S. Patent US 9,452,180 B2 UTU ) ea.It loon U.S. Patent Sep. 27, 2016 Sheet 4 of 13 US 9,452,180 B2 (guu) belie JeoIn U.S. Patent Sep. 27, 2016 Sheet 5 of 13 US 9,452,180 B2 Fig. 5A 12O 1CO s 80 £C 60 3 40 20 Control DiC LyO DC Mix U.S. Patent US 9,452,180 B2 U.S. Patent Sep. 27, 2016 Sheet 7 of 13 US 9,452,180 B2 Oul/ W. OSO U.S. Patent Sep. 27, 2016 Sheet 9 of 13 US 9,452,180 B2 0,( Otiu/ (W OSO U.S. Patent US 9,452,180 B2 U.S. Patent US 9,452,180 B2 U.S. Patent Sep. 27, 2016 Sheet 13 of 13 US 9,452,180 B2 ?I‘61 CY) CN (Uu) Bo Je Joon US 9,452,180 B2 1. 2 NSAIDS-INDUCED GASTRONTESTINAL medical drugs comprise an intermolecular compound of MUCOSAL DISORDERALLEVATOR AND NSAIDs and a disaccharide; thereby the medical drugs have MANUFACTURING METHOD THEREOF anti-inflammatory effect of the NSAIDs and can reduce damage induced by the NSAIDs. The medical drugs are CROSS-REFERENCE TO RELATED manufactured by the method of the invention. The method APPLICATIONS comprises a step of mixing a disaccharide and the NSAIDs So as to obtain a liquid mixture of the disaccharide and the This application is a Divisional of U.S. patent application NSAIDs; and a step of drying the liquid mixture so as to Ser. No. 13/132,613, filed Jun. 3, 2011, which is a national obtain the medical drugs. stage application of PCT/JP2009/006603, filed Dec. 3, 2009, 10 As shown in the following examples, the intermolecular which claims priority of Japanese Patent Application No. compounds, new compounds, have extremely high effect to 2008-310085, filed Dec. 4, 2008. This application claims the alleviate damage of gastrointestinal mucosal induced by priorities and benefits of all these prior applications and NSAIDs. The examples of medical drugs, which reduce incorporates the disclosures of these prior applications by 15 damage of gastrointestinal mucosal induced by NSAIDs, are reference in their entireties. medical drugs, which reduce damage of gastric mucosal induced by NSAIDs. BACKGROUND OF INVENTION As shown in the following examples, the drug medicine 1. Field of the Invention of the present invention which is manufactured by the above The present invention relates to medical drugs which method interacts with molecular. As shown in the following reduce damage of gastrointestinal mucosal induced by non examples, the drug medicine (lyophilized agent) has reduce steroidal anti-inflammatory drugs, NSAIDs, and the method damage of gastrointestinal mucosal induced by NSAID for manufacturing thereof. better than the mixture of NSAIDs and a disaccharide 2. Background Art (mixture of powders). In other words, the drug medicine of NSAIDs, non-steroidal anti-inflammatory drugs, are com 25 the present invention, which is manufactured by the above monly used as a pain killer, antipyretic, and anti-inflamma method, has intermolecular compound between NSAIDs tory drugs. Even though the NSAIDs have a suitable effect, and a disaccharide, thereby the intermolecular compound it has a drawback to induce damage of gastrointestinal effectively reduce damage of gastrointestinal mucosal mucosal. induced by NSAIDs. Japanese Patent Publication 2005-343886 disclose that 30 As shown in the following working examples preferred damage of gastrointestinal mucosal induced by Ibuprofen, NSAIDs are acidic NSAIDs. The example of the NSAIDs is which is categorized in NSAIDs, is reduced by mixing one or more selected from the group of "aspirin, sodium sugars (Patent document 1). However the alleviative effect salicylate, salicylamide, Sazapirin, diflunisal, ethenZamide, caused by the mixture of Ibuprofen and Sugars at a dry state aluminum aspirin, 5-amino salicylic acidic, indomethacin, is not sufficient. 35 etodolac, Sodium diclofenac, Sulindac, Sodium anfenac, pro Japanese Patent Publication 2005-1391.65 disclose that glumetacin maleate, acemetacin, nabumeton, mofeZolac, damage of gastrointestinal mucosal induced by NSAIDs ibuprofen, naproxen, loxoprofen, flurbiprofen, flurbiprofen including Loxoprofen is reduced by mixing Sugars (Patent axetil, oxaprozin, tiaprofenic acidic, pranoprofen, alumino document 2). However the alleviative effect caused by the prophen, Zaltoprofen, Mefenamic acidic, tolFenamic acidic, mixture of NSAIDs and sugars at a dry state is not sufficient. 40 alminum flufenamate, ketophenylbutaZone, clofeZone, Patent document 1: Japanese Patent Publication 2005 bucolome, piroXicam, lornoxicam, tenoxicam, meloxicam, 343886 ampiroXicam, epirizole, tiaramide, and elmofazon.” Within Patent document 2: Japanese Patent Publication 2005 the above compounds, the preferred NSAIDs are one or 1391.65 more of aspirin, indomethacin, Sodium diclofenac, ibupro 45 fen, piroXicam, loxoprofen and Mefenamic acidic. The drug SUMMARY OF INVENTION medicine can effectively reduce damage of gastrointestinal mucosal induced by NSAIDs by using the above NSAIDs. Problems to be Solved by the Invention A preferred working example of the first aspect of the invention is that the drug medicine comprises, as the disac The object of the present invention is to provide medical 50 charide, one or more selected from trehalose, maltose, drugs, which reduce damage of gastrointestinal mucosal lactose and Sucrose. Trehalose is more preferred as the induced by NSAIDs. disaccharide. A preferred working example of the first aspect of the Means for Solving Problems invention is that the form of the medical drugs is tablets, 55 granules, or capsules. The disaccharides and NSAIDs are The present invention is basically based on the new attached by means of molecular interactions by dissolving substance that is intermolecular compounds with NSAIDs disaccharides and NSAIDs jointly, drying the dissolved and a disaccharide. As shown in the following examples, the disaccharides and NSAIDs and forming them into tablets, intermolecular compounds, new compounds, have granules or capsules. Thus Such forms of medical drugs extremely high effect to alleviate damage of gastrointestinal 60 bring high reduction effect for damage of gastrointestinal mucosal induced by NSAIDs. The present invention is also mucosal induced NSAIDs. related to a method for manufacturing the drug medicine A preferred working example of the first aspect of the which includes a step of manufacturing the intermolecular invention is that the NSAIDs are Indomethacin and the compounds. disaccharide is trehalose. Further, the DSC curve of the The first aspect of the invention relates to medical drugs 65 intermolecular compound obtained by the method of differ which reduce damage of gastrointestinal mucosal induced ential scanning calorimetry, DSC, has a first peak and a by non-steroidal anti-inflammatory Drugs, NSAIDs, the second peak at 80 to 95°C. and 260 to 270° C., respectively. US 9,452,180 B2 3 4 A preferred working example of the first aspect of the more of aspirin, indomethacin, Sodium diclofenac, ibupro invention is that the NSAID is ibuprofen and the disaccha fen, piroXicam, loxoprofen and Mefenamic acidic. The drug ride is trehalose. Further the DSC curve of the intermolecu medicine can effectively reduce damage of gastrointestinal lar compound obtained by the method of differential scan mucosal induced by NSAIDs by using the above NSAIDs.