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(12) United States Patent (10) Patent No.: US 8,715,735 B2 Funke Et Al

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(12) United States Patent (10) Patent No.: US 8,715,735 B2 Funke Et Al US008715735B2 (12) United States Patent (10) Patent No.: US 8,715,735 B2 Funke et al. (45) Date of Patent: May 6, 2014 (54) STABILISED SUPERSATURATED SOLIDS OF OTHER PUBLICATIONS LIPOPHILIC DRUGS V. Buehler, “Kollidon (R). Polyvinylpyrrollidone for the pharmaceu (75) Inventors: Adrian Funke, Berlin (DE); Torsten tical industry.” Mar. 1998, BASF AG Fine Chemicals, Ludwigshafen, Wagner, Berlin (DE); Ralph Lipp, Germany, pp. 88-116, XP002297940. Zionsville, IN (US) K. Khougaz et al., “Crystallization inhibition in solid dispersions of (73) Assignee: Bayer Intellectual Property GmbH, MK-0591 and poly(vinylpyrrollidone)polymers,” Journal of Pharma Monehim (DE) ceutical Sciences, Oct. 2000, vol. 89, No. 10, pp. 1325-1334. XP002297939, the whole document. (*) Notice: Subject to any disclaimer, the term of this T. Watanabe et al., "Stability of amorphous indomethacin com patent is extended or adjusted under 35 pounded with silica.” International Journal of Pharmaceutics, U.S.C. 154(b) by 759 days. 2001, vol. 226, pp. 81-91, XP002310637. (21) Appl. No.: 11/076,022 T. Watanabe et al., “Prediction of apparent equilibrium solubility of indomethacin compounded with silica by 13C solid state NMR.” Int. (22) Filed: Mar 10, 2005 J. Pharmaceutics, 2002, vol. 248, pp. 123-129, XP002310638. (65) Prior Publication Data T. Watanabe et al., “Comparison between polyvinylpyrrollidone and silica nanoparticles as carriers for indomethacin in a solid state dis US 2005/02O7990 A1 Sep. 22, 2005 persion.” Int. J. Pharmaceutics, 2003, vol. 250, pp. 283-286, XPOO23 10639. Related U.S. Application Data H. Takeuchi et al., “Spherical Solid dispersion containing amorphous tolbutamide embedded in enteric coating polymers or colloidal silica (60) Provisional application No. 60/551.330, filed on Mar. prepared by spray-drying technique.” Chemical and Pharmaceutical 10, 2004. Bulletin, Pharmaceutical Society of Japan, Tokyo, 1987, vol. 35. No. (51) Int. Cl. 9, pp. 3800-3806. XP001 183548, ISSN: 0009-2363. A6 IK9/00 (2006.01) K.P.R. Chowdary et al., “Enhancement of dissolution rate of A6 IK 9/14 (2006.01) meloxicam.” Indian Journal of Pharmaceutical Sciences, Mar. 2001, A6 IK9/20 (2006.01) vol. 63, pp. 150-154, XP009037083, ISSN: 0250-474X. A6 IK9/48 (2006.01) H. Nakagami. “Solid dispersions of indomethacin and griseofulvin in non-porous fumed silicon dioxide, prepared by melting.” Chemical (52) U.S. Cl. and Pharmaceutical Bulletin, Pharmaceutical Society of Japan, USPC ............ 424/489: 424/400; 424/451; 424/464 Tokyo, Sep. 1991, vol. 39, No. 9, pp. 2417-2421, XP001 183546, (58) Field of Classification Search ISSN: 0009-2363. USPC .................................. 424/464, 400, 451, 489 D.C. Monkhouse et al., “Use of adsorbents in enhancement of drug See application file for complete search history. dissolution I.” Journal of Pharmaceutical Sciences, American Phar maceutical Association, Washington, US, Sep. 1972, vol. 61, No. 9. (56) References Cited pp. 1430-1435, XP001105645, ISSN: 0022-3549. Degussa AG, Duesseldorf, "Aerosil (R)—Internet presentation—En U.S. PATENT DOCUMENTS try No. 5 Dry binder: A new concept of pressed powders,” "Online 4,013,785 A 3, 1977 Weintraub et al. Retrieved from the internet: URL:https://www1.sivento.com/wps3/ 4,254,099 A 3/1981 Asmussen et al. portal/action/ChangePage?.pg/85/..reqid-1?cqurl=/en/aerosil?ebusi 4,639,370 A 1, 1987 Carl ness/news0> retrieved on 12-114-2004 See "Aeroperl (R)'. 5,569,652 A 10, 1996 Beier et al. Cab-O-Sil M5 (C) Product Inforamtion Sheet. Retrieved from http:// 5,656,622 A 8, 1997 Bullet al. talasonlinen.com/photos?inatructions/fumed silica info.pdf Pub 5,789,442 A 8, 1998 Garfield et al. lished 2004. 6,027,747 A 2/2000 Ducloset al. Syloid 244 FPSilica Product Information Sheet. Retrieved from 6,787,531 B1* 9/2004 Hilman et al. ................ 514,171 2002/0142032 A1* 10, 2002 Sherwood et al. ............ 424/465 http://www.discoverysciences.com/uploadedFiles/Preparative 2003/OO54037 A1 3/2003 Babcock et al. and Process/B561 SYLOID US ver FINAL.pdf Published 2003/01 19798 A1* 6/2003 Heil et al. ..................... 514f175 2011. 2006,0182691 A1 8, 2006 Besse et al. Limnel, Tarja. Mesoporous silica and silicon based materials as car riers for poorly water soluble drugs. Retrieved from https://helda. FOREIGN PATENT DOCUMENTS helsinki.fi/bitstream/handle/10138/27709/rnesoporo. pdf?sequence=1 published 2011. EP O336014 10, 1989 EP O474098 3, 1992 EP O492007 A1 * T 1992 * cited by examiner EP 1 260 225 11, 2002 EP 1380 301 1, 2004 Primary Examiner — Barbara P Badio GB 1365,661 9, 1974 (74) Attorney, Agent, or Firm — Millen, White, Zelano, JP 2006 505704 2, 2006 Branigan, P.C. JP 200651982O 8, 2006 KR 10 2000 OO16 3, 2000 (57) ABSTRACT WO WO-97 47290 12/1997 WO WO O1, 52857 T 2001 Methods for improving solubility and bioavailability of lipo WO WOO152857 T 2001 philic compounds are described. Particularly, described are WO WOO3O43630 5, 2003 WO WO 2004/O22065 3, 2004 stabilized Supersaturated Solid solutions, particularly in WO WO 2004/041289 5, 2004 power from, of lipophilic drugs, such as Steroidal molecules. WO WO 2004/073689 9, 2004 WO WO 2005/087.194 9, 2005 17 Claims, 2 Drawing Sheets U.S. Patent US 8,715,735 B2 U.S. Patent May 6, 2014 Sheet 2 of 2 US 8,715,735 B2 Figure 2 He et al. ert Carrier Solvent layer containing dissolved drospirenone Renova of solvent net. Carrier Solid drospirer one deposited on Surface of inert Carrier US 8,715,735 B2 1. 2 STABLISED SUPERSATURATED SOLIDS OF Solvent together with a hydrophilic polymer and evaporating LIPOPHILIC DRUGS the solvent to dryness to form a co-precipitate of the drug with the hydrophilic polymer. This application claims the benefit of the filing date of U.S. Khougaz Ketal. relates to the formulation of solid disper Provisional Application Ser. No. 60/551.330 filed Mar. 10, 5 sions comprising a hardly soluble drug Substance together 2004. with a carrier (PVP), wherein the drug substance is present in amorphous form or in crystalline form (Khougaz K et al. FIELD OF INVENTION Crystallisation inhibition in solid dispersions of MK-0591 and PVP polymers, J Pharm Sci vol.89, October 2000, pages The present invention relates to the field of pharmaceutical 10 1325-1334). formulation Science, in particular with respect to methods of Watanabe Tet al. relates to the formulation of solid com improving solubility and bioavailability of lipophilic com positions comprising indomethacin and silica. The pounds. The specific formulation technique of the present indomethacin is physically mixed with the silica by co-grind invention relates to stabilised Supersaturated Solid solutions ing or melting resulting in amorphous form of indometacin 15 (Watanabe Tetal. Stability of amorphous indomethacincom oflipophilic drugs, such as steroidal molecules and hormones pounded with silica, IntJ Pharm, 226, 2001, pages 81-91). in general. The Solid solutions are suitable for being pro Watanabe Tet al. also relates to the formulation of solid cessed into tablets or other Solid dosage forms. compositions comprising indomethacin and silica. The indomethacin is physically mixed with the silica by co-grind BACKGROUND ing or melting resulting in amorphous form of indometacin (Watanabe T et al. Prediction of apparent equilibrium solu Poor bioavailability of lipophilic compounds is a well bility of indometacin compounded with silica by 13C solid known problem, in particular in connection with per oral state NMR, IntJ Pharm, 248, 2002, pages 123-129). administration, wherein the compound is to be dissolved in Watanabe Tetal relates to the formulation of solid com the gastric fluid and/or intestinal fluid before being absorbed 25 positions comprising indomethacin and silica or PVP. The from the gastro-intestinal tract into the blood circulation. indomethacin is physically mixed with the silica or PVP by Thus, the rate-limiting step in the absorption of compounds co-grinding or melting resulting in amorphous form of from the gastro-intestinal tract is often the dissolution rate of indometacin (Watanabe Tet al. Comparision between Poly the compound in water and other liquids, which are similar to vinylpyrrolidone and silica nano particles as carriers for the ones found in the gastro-intestinal tract. 30 indomethacin in a solid state dispersion. Int J Pharm, 250, Many attempts at increasing the Solubility of a lipophilic 2003, pages 283-286). compound have been suggested and used in the past years. GB 1365 661 relates to the formulation of solid composi Examples are attempts to increase the Surface area of a com tions comprising a drug Substance with low water Solubility pound, either by spraying the amorphous compound onto an (Cholesteryl beta-glucoside) and a carrier (Silica (Aerosil TM). inert carrier or by micronising the compound. Other attempts 35 The composition is prepared by dissolving the betaglucoside in hot ethanol and Subsequently adding this solution to the have been directed to inclusion complexes with cyclodex aerosol powder and evaporate the solvent from the resulting trins. A common feature of the conventional techniques is that slurry. The resulting composition has a slower release rate the compound is in particulate form, eg. in amorphous form or than conventional formulations. in crystalline form. Both forms still require the initial step of 40 Takeuchi et al relates to the formulation of compositions dissolving the particulate compound before being capable of wherein the drug compound (tolbutamide) is presentinamor penetrating the mucosa of the gastro-intestinal tract. phous form (Takeuchi et al. Spherical solid dispersion con Typical examples of pharmaceutical formulation tech taining amorphous tolbutamide embedded in enteric coating niques which result in particulate forms of lipophilic com polymers or colloidal silica prepared by spray-drying tech pounds in the final composition/dosage form rather than in 45 nique. Chem Pharm Bulletin Pharm Soc Japan.
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