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(12) United States Patent (10) Patent No.: US 8,685,947 B2 Mathiowitz Et Al

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(12) United States Patent (10) Patent No.: US 8,685,947 B2 Mathiowitz Et Al US008685947B2 (12) United States Patent (10) Patent No.: US 8,685,947 B2 Mathiowitz et al. (45) Date of Patent: Apr. 1, 2014 (54) COMPOSITIONS AND METHODS FOR LOOP Dormans etal. “Diuretic Etificacy of High Dose Furosemide in Severe DURETCS WITH CONSISTENT Heart Failure: Bolus Injection Versus Continuous Infusion' J. Am BOAVAILABILITY Coll Cardiol, 1996, vol. 28, pp. 376-382. Gimenez et al. “Molecular mechanisms and regulation of (75) Inventors: Edith Mathiowitz, Brookline, MA (US); furosemide-sensitive Na-K-Cl cotransporters' Curr Op Nephrol Bryan Laulicht, Great Neck, NY (US) Hyperten, 2006, vol. 15, pp. 517-523. Gohary et al. “Release of furosemide from sustained release (73) Assignee: Brown University, Providence, RI (US) microcapsules prepared by phase separation technique' Drug Develop Industrial Pharm, 1991, vol. 17, pp. 443-450. (*) Notice: Subject to any disclaimer, the term of this Hammarlund et al. "Acute tolerance to furosemide diuresis in patent is extended or adjusted under 35 humans. Pharmacokinetic-Pharmacodynamic Modeling” J Pharm U.S.C. 154(b) by 33 days. Exp Thera, 1985, vol. 233, pp. 447-453. Kislalioglu et al. Physical characteristics and dissolution properties (21) Appl. No.: 13/217,764 of ibuprofen: eudragit coprecipitates, J Pharm Sci, 1991, vol. 80, pp. (22) Filed: Aug. 25, 2011 T99-804. Laulicht et al. "Are in vivo gastric bioadhesive forces accurately (65) Prior Publication Data reflected by in vitro experiments?” JControl Release, 2009, vol. 134. pp. 103-110. US 2012/OO53156A1 Mar. 1, 2012 Laulicht et al. “Diuretic bioactivity optimization of furosemide in rats' EurJ Pharm Biopharm, 2011, vol. 79, pp. 314-319. Related U.S. Application Data Moustafine et al. “Characteristics of interpolyelectrolyte complexes (60) Provisional application No. 61/376,737, filed on Aug. of Eudragit E 100 with Eudragit L100” J. Control Release, 2005, vol. 103, pp. 191-198. 25, 2010. Murray et al. “Variable furosemide absorption and poor predictability (51) Int. Cl. of response in elderly patients' Pharmacotherapy, 1997, vol. 17, pp. AOINSI/00 (2006.01) 98-106. A6 IK3I/655 (2006.01) Ozdemir et al. “Studies of Floating Dosage Forms of Furosemide: In Vitro and InVivo Evaluations of Bilayer Tablet Formulations Nurten” A6 IK 47/32 (2006.01) Drug Develop Industr Pharm, 2000, vol. 26, pp. 857-866. B32B5/16 (2006.01) Sakkinen et al. “Evaluation of microcrystalline chitosans for gastro B32B 9/00 (2006.01) retentive drug delivery” Eur J Pharm Sci., 2003, vol. 19, pp. 345-353. B32B 5/02 (2006.01) Sakkinen et al. "Are chitosan formulations mucoadhesive in the B32B 17/02 (2006.01) human Small intestine'? An evaluation based on gamma Scintigraphy Intl J Pharm, 2006, vol. 307, pp. 285-291. B32B 9/00 (2006.01) Salvador et al. “Continuous infusion versus bolus injection of loop B32B 2/02 (2006.01) diuretics in congestive heart failure (Review)” The Cochrane Col B32B 23/02 (2006.01) laboration, 2009. B32B 27/02 (2006.01) Santus et al. "An in vitro-in vivo investigation of oral bioadhesive controlled release furosemide formulations' Eur J Pharm Biopharm. C07D 307/02 (2006.01) 1997, vol. 44, pp.39-52. (52) U.S. Cl. Shin et al. “Enhanced dissolution of furosemide by coprecipitating or USPC ............................ 514/158; 428/402; 549/494 cogrinding with crospovidone” Intl J Pharm, 1998, vol. 175, pp. (58) Field of Classification Search 17-24. None Sistovaris et al. “Multifunctional Substances-Determinational of pKa-values by various methods' Fresnius J Anal Chem, 1991, vol. See application file for complete search history. 340, pp. 345-349. (56) References Cited Terao et al. “Improvement in site-specic intenstinal absorption of furosemide by Eudragit L100-55'J Pharm Pharmacol. 2001, vol.53, U.S. PATENT DOCUMENTS pp. 433-440. Thoma et al. “Photostabilization of drugs in dosage forms without 2006/0057197 A1 3f2006 Han et al. ...................... 424/468 protection from packaging materials' Intl J Pharm, 1991, vol. 67, pp. 169-175 2007/028.1007 A1* 12, 2007 Jacob et al. .... 424/452 2009/0011019 A1* 1/2009 Jahagirdar et al. ............ 424,472 VanDerWatt et al. “The effect of mixing variables on the dissolution properties of direct compression formulations of furosemide” 1995, OTHER PUBLICATIONS vol. 21, pp. 2047-2056. Lee etal. (ACTAPaediatr Sin, Zhonghua MinGuo Xiao Er Keyi Xue * cited by examiner Zai Zhi May-Jun. 1994 35 (3) 215-220).* Primary Examiner — James D Anderson Aceves et al. "Preparation and characterization of Furosemide Eudragit controlled release systems' Intl.JPharm, 2000, vol. 195, pp. Assistant Examiner — William Lee 45-53. (74) Attorney, Agent, or Firm — Lawson & Weitzen, LLP: Bardonnet et al. "Gastroretentive dosage forms: Overview and spe Sonia K. Guterman; Anna E. Stanford cial case of Helicobacter pylori” J. Control Release, 2006, vol. 111, pp. 1-18. (57) ABSTRACT Beyersetal. “Structure-Solubility Relationship and Thermal Decom position of Furosemide' Drug Develop Industrial Pharm, 2000, vol. Diuretic bioactivity profiles of phase inversion micronized 26, pp. 1077-1083. furosemide and furosemide co-precipitated with Eudragit Carino et al. “Nanosphere based oral insulin delivery' J Control L100, and mixtures of those formulations with stock furo Release, 2000, vol. 65, pp. 261-269. semide, reduced or eliminated the rapid spike in diuresis Cilurzo et al. “Polymethacrylate salts as new low-swellable associated with immediate release formulations and main mucoadhesive materials' JControl Release, 2003, vol. 88, pp. 43-53. tained cumulative urine output. Of the formulations tested, Davis et al. “Formulation strategies for absorption windows' Drug each of a mixture of micronized furosemide with stock furo Disc Today, 2005, vol. 10, pp. 249-257. semide, and Eudragit L100 polymer with stock furosemide Di Colo et al. “In vitro evaluation of a system for pH-controlled peroral delivery of metformin' J. Control Release, 2002, vol. 80, pp. demonstrated optimal diuretic bioactivity profiles in subjects. 119-128. 26 Claims, 7 Drawing Sheets U.S. Patent Apr. 1, 2014 Sheet 1 of 7 US 8,685,947 B2 TOP ROW OOOx NAGNCAON SS BOTTOM ROW S3% s MAGNIFICATION5,000x SASA3 x: Figure 1A -o-, ROSVDE - or MCRONE FUR OSEMOE -er DRAC - O "r L. O.O.FUR.OSEMDE CO-PRECIPIATON r OOF UROSEMDESOLID DSPERSION Os s 5 soo-------------- f O ----------- E. ... ...e. e. e. “ -------------------r** 50 r. xxx w8* &&ssexx-x-xx-xxx: ses s gs se O O OO SO 2OO 250 TEMPERATURE (CELSUS) Figure 1B U.S. Patent US 8,685,947 B2 009||000€ (uup/l)H10NHTHAVNA DI?In6|+ 008: 00017 DNWLWSNW. N. Did U.S. Patent Apr. 1, 2014 Sheet 3 of 7 US 8,685,947 B2 Figure 2 U.S. Patent Apr. 1, 2014 Sheet 4 of 7 US 8,685,947 B2 EBASA O2.5 mg/kg STOCKFURoSEMIDE EN2.5 mg/kg MICRONIZED FURCSEMIDE 32.5 mg/kg 50% STOCK/50% MICRONIZED FUR.OSEMIDE O 5 4. 6 8 O HOURS AFTER DOSING Figure 3A 15 E. BASA O2.5 mg/kg STOCKFURCSEMIDE EJ2.5 mg/kg L100 CO-PRECIPITATED FURoSEMIDE 22.5 mg/kg 50% L100/50% STOCKFURCSEMIDE O. 5 2 4. s 8. O HOURS AFTER DOSING Figure 3B U.S. Patent Apr. 1, 2014 Sheet 5 Of 7 US 8,685,947 B2 E BASA 15 D5 mg/kg STOCKFURCSEMDE ES5 mg/kg MICRONIZED FUROSEMIDE (25 mg/kg 50% STOCK/50% MICRONIZED FUR.OSEMIDE o e O A 10 O 2 O 5 5 O O-lis to- O. OURS AFTER DOSING Figure 4A 15 O5BASA mg/kg STOCKFU ROSEMIDE ES5 mg/kg L100 CO-PRECIPITATED FURCSEMIDE E35 mg/kg 50% L100/50% STOCKFU ROSEMIDE O 5 OURSA ER DOSING Figure 4B U.S. Patent Apr. 1, 2014 Sheet 6 of 7 US 8,685,947 B2 2. BASA «s O 10 mg/kg STOCKFURoSEMIDE o 20 - EN 10 mg/kg MICRONIZED FURCSEMIDE 5 210 mg/kg 50% STOCK/50% MICRONIZED FUR.OSEMIDE o 15 2. O g 10 R s s 5 HOURS AFTER DOSING Figure 5A 25 EBASA D10 mg/kg STOCKFURCSEMIDE E10 mg/kg L100 CO-PRECIPITATED FURoSEMIDE | Ed 10 mg/kg EUDRAGITL100 2.O a 10 mg/kg 50%L100/50% STOCKFURCSEMIDE 15 O 6 8 OURS AFTER DOSING Figure 5B U.S. Patent Apr. 1, 2014 Sheet 7 Of 7 US 8,685,947 B2 20 - EOBASAL O10 mg/kg: STOCKFURCSEMIDE E 10 mg/kg:50% STOCK/50% MICRONIZED FURCSEMIDE 210 mg/kg:50% L-100/50% STOCKFURCSEMIDE 1. 5 10 8 HOURS AFTER DOSING Figure 6 US 8,685,947 B2 1. 2 COMPOSITIONS AND METHODS FOR LOOP form particles that have a size of at least about 1 micrometer DURETCS WITH CONSISTENT which improves the bioactivity of the hydrophobic agent for BOAVAILABILITY administration to a Subject. The improved bioactivity regu lates diuresis in Subjects, an advantage compared to current RELATED APPLICATIONS diuretics which cause excessive and inconsistent fluid loss. An embodiment of the invention provides a pharmaceuti The present utility application claims the benefit of U.S. cal composition formulating a mixture of a hydrophobic provisional application Ser. No. 61/376,737 filed Aug. 25. agent, such as furosemide, and a phase inverted micronized 2010, which is hereby incorporated herein by reference in its form of the agent with an acceptable salt or buffer, wherein entirety. 10 the composition has an average particle size of at least about 1 micrometer and is formulated as a unit dosage of a range TECHNICAL FIELD selected from about 0.05 mg/kg (50 ug/kg), about 0.1 mg/kg (100 ug/kg), about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, or The invention relates to formulations of a composition to contain a hydrophobic agent and a micronized phase inverted 15 about 10 mg/kg. The term “at least about 1 micrometer', as form of the hydrophobic agent, and methods regulating diure provided herein means about 1 um to about 4 um; about 1 um sis to decrease or eliminate diuretic spike.
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