~™ mil mum mi illinium (19) J European Patent Office Office europeen des brevets (11) EP 0 644 755 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publicationation and mention (51 ) |nt. CI.6: A61 K 9/1 4 of the grant of the patent: 19.03.1997 Bulletin 1997/12 (86) International application number: PCT/US93/05082 (21) Application number: 93914224.6 (87) International publication number: (22) Date of filing : 01 .06.1 993 WO 93/25190 (23.12.1993 Gazette 1993/30) (54) SURFACE MODIFIED NSAID NANOPARTICLES OBERFLAECHENMODIFIZIERTE NSAID NANOPARTIKELN NANOPARTICULES DE MEDICAMENTS ANTI-INFLAMMATOIRES NON STEROIDIENS MODIFIEES EN SURFACE (84) Designated Contracting States: • SARPOTDAR, Pramod, P. AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL Rochester, New York 14650-2201 (US) PTSE (74) Representative: Baillie, lain Cameron et al (30) Priority: 10.06.1992 US 897193 c/o Ladas & Parry Altheimer Eck 2 (43) Date of publication of application: 80331 Munchen (DE) 29.03.1995 Bulletin 1995/13 (56) References cited: (73) Proprietor: NanoSystems L.L.C. EP-A-0169 618 EP-A- 0 371 431 Collegeville, Pennsylvania 19426 (US) EP-A- 0 499 299 WO-A-90/15593 WO-A-91/06292 WO-A-92/00725 (72) Inventors: WO-A-92/03380 • LIVERSIDGE, Gary, G. Rochester, New York 14650-2201 (US) Remarks: • CONZENTINO, Philip The file contains technical information submitted Rochester, New York 14650-2201 (US) after the application was filed and not included in • CUNDY, Kenneth this specification Rochester, New York 14650-2201 (US) CO 10 10 Note: Within nine months from the publication of the mention of the grant of the European patent, give CO2 any person may notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in ^o a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. Q. 99(1) European Patent Convention). Printed by Rank Xerox (UK) Business Services 2.13.17/3.4 EP 0 644 755 B1 Description BACKGROUND OF INVENTION 5 Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used and therapeutically effective groups of drugs. However, gastric irritation problems constitute the most frequently recognized adverse side effect fol- lowing oral administration of NSAIDs. Such side effects are well recognized and must be weighed against the clinical efficacy of the drugs. A great amount of research has been undertaken in an attempt to understand the underlying mechanism respon- 10 sible for these effects. For example, Cioli et al, Tox. andAppl. Pharm., 50, 283-289 (1979) suggest that gastrointestinal lesions in laboratory animals resulting from the oral administration of acidic NSAIDs may depend on two different mech- anisms: a local action exerted by contact with the gastric mucosa and a generalized/centrally mediated (systemic) action, taking place following oral administration. More recently, Price et al, Drugs 40 (Suppl. 5) : 1 - 1 1 , 1990, suggest that NSAID-induced gastric damage occurs as 15 a result of NSAID-mediated direct and indirect acidic damage followed almost simultaneously by the deleterious sys- temic effect of prostaglandin inhibition. A variety of strategies have been used in the management of NSAID-induced gastric damage. These include: 1) the development and use of NSAIDs with less toxic potential; 2) the reduction or elimination of the agent that actually causes the injury; and 3) the enhancement of the mucosal defense. However, these approaches have not proven 20 entirely successful. For example, the most effective means of preventing gastric damage, i.e., by eliminating the primary aetiological agent is rarely feasible with NSAIDs inasmuch as patients with severe inflammatory disease are rarely able to cease using these drugs. Although selection of less toxic NSAIDs should prove useful, the only practical solution, at present, is to treat the NSAID induced gastric damage. Misoprostol (a methylated prostaglandin Ei) has been approved by the 25 FDA for use in preventing NSAID gastropathy. However, Misoprostol is expensive, must be administered multiple times daily and can cause unacceptable side effects. Thus it would be highly desirable to provide NSAID formulations that can exhibit a reduction in gastric irritation. Moreover, it would be desirable to provide NSAID formulations exhibiting hastened onset of action. 30 SUMMARY OF THE INVENTION We have discovered that pharmaceutical compositions containing surface modified crystalline NSAID nanoparti- cles exhibit reduced gastric irritation following oral administration and/or more rapid onset of action. More particularly, in accordance with this invention, there are provided particles consisting essentially of a crystal- 35 line NSAID having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an average particle size of less than about 400 nm, wherein said NSAID is selected from nabumetone, tiaramide, proquazone, bufexamac, flumizole, epirazole, tinoridine, timegadine, dapsone, benorylate, fosfosal, alclofenac, fenclofenac, etodolac, sulindac, tolmetin, fentiazac, tilomisole, carprofen, fenbufen, oxaprozin, suprofen, tiaprofenic acid, fenoprofen, indoprofen, pirprofen, flufenamic, mefenamic, meclofenamic, niflumic, oxyphenbutazone, phenylbutazone, apazone, 40 feprazone, piroxicam, sudoxicam, isoxicam and tenoxicam. This invention further provides a pharmaceutical composition comprising the above-described particles and a phar- maceutical^ acceptable carrier. In another embodiment of the invention, there is provided the use of the above-described particles or a pharma- ceutical composition thereof for the preparation of a medicament for the treatment of a mammal and in particular for the 45 reduction of gastric irritation in a mammal. In further embodiments of the invention, there are provided the use of particles consting essentially of a drug sub- stance, such as a crystalline NSAID, having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an average particle size of less than about 400 nm or a pharmaceutical composition thereof for the prepa- ration of a medicament for hastening the onset of action after administration to a mammal, with the proviso that the drug so substance is other than naproxen or indomethacin. In yet another embodiment of the invention, there is provided a method of preparing the above-described particles consisting of a crystalline NSAID having a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an average particle size of less than 400 nm, the method comprising the steps of dispersing the NSAID in a liquid dispersion medium and wet grinding the NSAID in the presence of rigid grinding media, to an effective average 55 particle size of less than about 400 nm, wherein the pH of said medium is maintained within the range of from 2 to 6 during said wet grinding, with the proviso that the NSAID is other than ibuprofen. It is an advantageous feature of this invention that pharmaceutical compositions containing NSAIDs are provided which exhibit reduced gastric irritation following oral administration. It is another advantageous feature of this invention that pharmaceutical compositions are provided exhibiting has- 2 EP 0 644 755 B1 tened onset of action. Other advantageous features will become readily apparent upon reference to the following description of preferred embodiments. 5 DESCRIPTION OF THE PREFERRED EMBODIMENTS This invention is based partly on the discovery that surface modified nanoparticles comprising an NSAID demon- strate reduced gastric irritation and/or a more rapid onset of action following oral administration. While the invention is described herein primarily in connection with its preferred class of drugs, i.e., NSAIDs, it is also useful in conjunction 10 with other classes of drug substances, e.g., antibiotics, quinolones, antilipemics and roentgenographies. The particles of this invention comprise an NSAID. The NSAID exists as a discrete, crystalline phase. The crystal- line phase differs from an amorphous or noncrystalline phase which results from conventional solvent precipitation techniques, such as described in U.S. Patent 4,826,689. The NSAID can be present in one or more suitable crystalline phases. 15 The invention can be practised with a wide variety of NSAIDs. However, the NSAID must be poorly soluble and dis- persible in at least one liquid medium. By poorly soluble" it is meant that the NSAID has a solubility in the liquid disper- sion medium, e.g., water, of less than about 10 mg/ml, and preferably of less than about 1 mg/ml at processing temperature, e.g., room temperature. The preferred liquid dispersion medium is water, however, the invention can be practised with other liquid media in which the NSAID is poorly soluble and dispersible including, for example, aqueous 20 salt solutions, safflower oil and solvents such as ethanol, t-butanol, hexane and glycol. The pH of the aqueous disper- sion media can be adjusted by techniques known in the art. The NSAIDs that are useful for the purpose can be selected from suitable acidic and nonacidic compounds. Suita- ble acidic compounds include carboxylic acids and enolic acids. Suitable nonacidic compounds include, for example, nabumetone, tiaramide, proquazone, bufexamac, flumizole, epirazole, tinoridine, timegadine and dapsone. 25 Suitable carboxylic acid NSAIDs include, for example, salicylic acids and esters thereof, such as aspirin, diflunisal, benorylate