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(12) United States Patent (10) Patent No.: US 9.474,719 B2 Mullen Et Al

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(12) United States Patent (10) Patent No.: US 9.474,719 B2 Mullen Et Al US009474719B2 (12) United States Patent (10) Patent No.: US 9.474,719 B2 Mullen et al. (45) Date of Patent: Oct. 25, 2016 (54) PULSATILE DRUG RELEASE 2009,02976O1 A1 12/2009 Vergnault et al. 2010.0040557 A1* 2/2010 Ke et al. ...................... 424,103 (75) Inventors: Alexander Mullen, Glasgow (GB); 2013, OO17262 A1 1/2013 Mullen et al. Howard Stevens, Glasgow (GB); 2013/0022677 A1 1/2013 Mullen et al. Sarah Eccleston, Glasgow (GB) FOREIGN PATENT DOCUMENTS (73) Assignee: UNIVERSITY OF STRATHCLYDE, Glasgow (GB) EP O 546 593 A1 6, 1993 EP 1 064 937 A1 1, 2001 (*) Notice: Subject to any disclaimer, the term of this EP 1607 092 A1 12/2005 EP 2 098 250 A1 9, 2009 patent is extended or adjusted under 35 WO WO 99.12524 A1 3, 1999 U.S.C. 154(b) by 0 days. WO WO 01 00181 A2 1, 2001 WO WO O3,O266.15 A2 4/2003 (21) Appl. No.: 131582.913 WO WO O3,O26625 A1 4/2003 (22) PCT Filed: Mar. 4, 2011 WO WO 03/026626 A2 4/2003 WO WO 03/030920 A1 4/2003 (86). PCT No.: PCT/GB2O11AOOO3O6 WO WO 2006/045618 A1 5, 2006 WO WO 2008/0791O2 A1 T 2008 S 371 (c)(1), WO WO 2008/081891 A1 T 2008 (2), (4) Date: Oct. 2, 2012 WO WO 2008, 129517 A2 10, 2008 WO WO 2009,1548O1 12/2009 (87) PCT Pub. No.: WO2011/107749 OTHER PUBLICATIONS PCT Pub. Date: Sep. 9, 2011 Fukui et al. Journal of Controlled Release 2000 68:215-223. (65) Prior Publication Data Shin-Etsu Guide on Low-Substituted Hydroxypropyl Cellulose NF (2008).* US 2013 FOO22676 A1 Jan. 24, 2013 Alvarez-Lorenzo et al. International Journal of Pharmaceutics 2000 (30) Foreign Application Priority Data 197: 107-116. International Search Report and the Written Opinion of the Inter national Searching Authority for International Application No. Mar. 5, 2010 (GB) ................................... 10O3766.1 PCT/GB2011/000307, mailed Mar. 12, 2012, 14 pages. (51) Int. Cl. International Search Report and the Written Opinion of the Inter A6 IK 9/28 (2006.01) national Searching Authority for International Application No. PCT/GB2011/000314, mailed Mar. 12, 2012, 14 pages. A6 IK 9/20 (2006.01) Stevens, H.N.E., "Chronopharmaceutical Drug Delivery,” Journal A61 K 9/24 (2006.01) of Pharmacy and Pharmacology, 1998, 50 (Supplement 9), 5. (52) U.S. Cl. Ghimire, M. et al. “In-vitro/In-vivo Correlation of Pulsatile Drug CPC ............. A61K 9/2866 (2013.01); A61K 9/282 Release from Press-Coated Tablet Formulations: A (2013.01); A61K 9/288 (2013.01); A61 K9/209 Pharmacoscintigraphic Study in the Beagle Dog.' European Journal of Pharmaceutics and Biopharmaceutics, 2007, vol. 67, No. 2, (2013.01) 515-523. (58) Field of Classification Search Written Opinion of the International Searching Authority (Form None PCT/ISA/237) mailed Mar. 12, 2012, for International Application See application file for complete search history. No. PCT/GB2011/000306, 15 pages. Kleinebudde, P. “Application of Low Substituted (56) References Cited Hydroxypropylcellulose (L-HPC) in the Production of Pellets. Using Extrusion/Spheronization'. International Journal of Pharmaceutics, U.S. PATENT DOCUMENTS 1993, 96, 119-128. English-language abstract of JP 2001-322927. Date of publication 4,832,958 A 5, 1989 Baudier et al. of application Nov. 20, 2001, 1 page. 4,871,549 A * 10/1989 Ueda et al. ................... 424/494 English-language machine translation of JP 2001-322927, retrieved 5,145,644 A 9, 1992 Park et al. from the Japanese Patent Office website on May 2, 2015, 15 pages. 5,508,044 A 4, 1996 Buxton et al. Rowe, R. et al., Eds. Handbook of Pharmaceutical Excipients, Sixth 5,558,879 A 9, 1996 Chen et al. Edition, Pharmaceutical Press, London, 2009, pp. 317-324. 5,614,220 A * 3/1997 Hirakawa et al. ............ 424/480 5,788,987 A * 8/1998 Busetti et al. ................ 424/480 * cited by examiner 6,312,724 B1 1 1/2001 Odidi et al. 6,610,323 B1 8/2003 Lundberg et al. Primary Examiner — Robert A Wax 6,632,451 B2 10/2003 Penhasi et al. Assistant Examiner — Caralynne Helm 6,740,339 B1* 5/2004 Ohkouchi et al. ............ 424/464 (74) Attorney, Agent, or Firm — Hoxie & Associates LLC 8, 168,218 B2 5/2012 Vergnault et al. 2004.0062804 A1 4/2004 Lee et al. (57) ABSTRACT 2004/0241100 A1* 12/2004 Kramer et al. ................. 424/45 2005, 0112201 A1* 5, 2005 Baichwal ............... A61K 9,286 In one aspect, the present invention is concerned with a 424/470 treatment where it is desired that an active agent is designed 2005/O152974 A1 7/2005 Boehm et al. to be released in a pulse at a time point some time after 2005/022O877 A1 10/2005 Patel et al. administration of the active agent. The present invention is 2006/O127475 A1* 6/2006 Makino ................ A61K9/2027 particularly Suited to administering an agent which may be 424/464 released while a subject is sleeping. As well as treating 2006/0177506 A1 8, 2006 Yanai et al. certain conditions by a particular regime, the invention also 2006/0257482 A1* 11/2006 Kumar et al. ................ 424/469 provides novel formulations for a delayed, followed by a 2007/OO98788 A1 5, 2007 Gore et al. 2009.0053308 A1 2/2009 Ishida et al. pulsed release of drug. 2009. O1553.58 A1 6, 2009 Diaz et al. 22 Claims, 7 Drawing Sheets U.S. Patent Oct. 25, 2016 Sheet 1 of 7 US 9,474,719 B2 1OO BO c S 60 8 O) O 40 O C N O - 1 OO O 1OO 2OO 3OO AOO SOO SOO 7OO BOO Time (min) Figure 1 U.S. Patent Oct. 25, 2016 Sheet 2 of 7 US 9,474,719 B2 O & 80 S 60 S D 40 Ol cs N 2O O - 10 O 1OO 2DO SOO 4D 5OO SOO FOO BOO Time (min) Figure 2 U.S. Patent Oct. 25, 2016 Sheet 3 of 7 US 9,474,719 B2 1OO 8O s 9. 60 40 S O - OO O 1 OO 2OO 3OO 4OO 5DO SOD O) BOO Time (min) Figure 3 U.S. Patent Oct. 25, 2016 Sheet 4 of 7 US 9,474,719 B2 100 Sla 80 c) ;s 6O A. E 9 40 O N 2D O -1DO O 1OO 2OO 3OO ADO 5OO SOO FOO BOO Time (min) Figure 4 U.S. Patent Oct. 25, 2016 Sheet S of 7 US 9,474,719 B2 O min 120 min 135 min 165 min Figure 5 U.S. Patent Oct. 25, 2016 Sheet 6 of 7 US 9,474,719 B2 Zolpidem PK ro-Subject OO1 Subject 002 S r r i ral sess 200 400 SOO 800 1000 1200 1400 15 Time (mins) Figure 6 US 9,474,719 B2 1. 2 PULSATLE DRUG RELEASE art, many Such devices/methods were highly complex and there is distinct advantage in providing a simpler press CROSS REFERENCE TO RELATED coated tablet formulation. APPLICATIONS One particularly preferred embodiment relates to treating subjects who wake during the night, but have no or little This application is a United States Application under 35 difficulty in initially falling asleep, commonly termed sleep U.S.C. 371 claiming the benefit of PCT Application No. maintenance insomnia. In a preferred embodiment therefore, PCT/GB2011/000306, filed on Mar. 4, 2011, which claims the formulations of the present invention are for treating the benefit of GBApplication No. 1003766.1, filed on Mar. sleep maintenance insomnia. Such formulations therefore 10 comprise a pharmaceutically active agent for inducing and/ 5, 2010, the contents of each of which are incorporated or facilitating sleep. Typically this may be a sedative or herein by reference. hypnotic agent, Such as a benzodiazepine, chloral hydrate, melatonin and analogues thereof. Zolpidem, Zopiclone or FIELD OF INVENTION Zaleplon. 15 Thus, in a first aspect, the present invention provides a In one aspect, the present invention is concerned with a sleep inducing and/or maintaining formulation agent such as treatment where it is desired that an active agent is designed a sedative or hypnotic agent, formulated as a component of to be released in a pulse at a time point some time after a press-coated tablet for treating sleep maintenance insom administration of the active agent. The present invention is nia, wherein the formulation is intended to be administered particularly Suited to administering an agent which may be immediately prior to a subject going to sleep (i.e. when a released whilst a Subject is sleeping. As well as treating Subject goes to bed at night for a prolonged period of sleep, certain conditions by a particular regime, the invention also such as 6-10 hours and hence is distinguished over shorter provides novel formulations for a delayed, followed by a sleeping periods) and wherein the hypnotic agent is Sub pulsed release of drug. stantially not released from the formulation for a period 25 between 1-8 hours, such as 1.5-4 hours after administration BACKGROUND TO THE INVENTION of the formulation to the subject and thereafter the agent is released from the formulation as a pulse Such that at least Time-dependent release mechanisms of drugs have been 70-90%, for example 80% of the agent within the formula described in the literature for tablet, pellet and capsule tion is released within 5-80 mins, such as 10-45, or 10-30 formulation utilising a wide range of physicochemical and 30 mins. physicomechanical strategies. The common feature of all In a further aspect there is provided a method of treating such formulations is that they are activated by contact with sleep maintenance insomnia, the method comprising admin fluids following ingestion by the patient and the drug will be istering a press-coated tablet comprising a sleep inducing released at the predetermined time after administration.
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