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United States Patent (10) Patent No.: US 8,329,217 B2 Vergezz

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United States Patent (10) Patent No.: US 8,329,217 B2 Vergezz US008329217B2 (12) United States Patent (10) Patent No.: US 8,329,217 B2 VergezZ. et all e 45) Date of Patent:e Dec.e 11, 2012 (54) DUAL CONTROLLED RELEASE DOSAGE 5, 190,765 A 3, 1993 Jao et al. FORM 5,208,037 A 5/1993 Wright et al. 5,252.338 A 10, 1993 Jao et al. 5,399,359 A 3, 1995 Baichwal (75) Inventors: Juan A. Vergez, Buenos Aires (AR): 5,543,155 A 8, 1996 Fekete et al. Marcelo A. Ricci, Buenos Aires (AR) 5,674,895 A 10/1997 Guittard et al. 5,788,987 A 8, 1998 Busetti et al. (73) Assignee: Osmotica Kereskedelmi es Szolgaltato 5,840,754. A 1 1/1998 Guittard et al. Kft, Budapest (HU) 5,866,164 A 2/1999 Kuczynski et al. s 5,912,268 A 6/1999 Guittard et al. 6,106,864 A 8, 2000 Dolan et al. (*) Notice: Subject to any disclaimer, the term of this 6,207,191 B1* 3/2001 Crison et al. .................. 424,472 patent is extended or adjusted under 35 2002/0010216 A1 1/2002 Rogosky et al. U.S.C. 154(b) by 1407 days. 2006/0177510 A1 8/2006 Vergez (21) Appl. No.: 11/355,315 FOREIGN PATENT DOCUMENTS y x- - - 9 JP 2646170 8, 1997 JP 2665858 10, 1997 (22) Filed: Feb. 15, 2006 WO 96.12477 5, 1996 WO 97.18814 5, 1997 (65) Prior Publication Data WO OOf 12069 3, 2000 WO OOf 18997 4/2000 US 2006/0204578 A1 Sep. 14, 2006 WO WOO1/51036 * 7/2OO1 Related U.S. Application Data OTHER PUBLICATIONS (60) Continuation-in-part of application No. 1 1/321,736, Santus et al., Osmotic drug delivery: a review of the patent literature, filed on Dec. 29, 2005, which is a division of Journal of controlled release 35 (1995), 1-21.* application No. 09/992.488, filedon Nov. 6, 2001, now Santus et al., (Journal of Controlled Release 1995, 35, 1-21).* abandoned. Herbig et al., (Journal of Controlled Release 1995, 35, 127-136).* Dmochowski, R. et al., Advancements in Pharmacologic Manage (51) Int. C. ment of the Overactive Bladder, Urology, Dec. 2000, vol. 56 (Supple A69/24 (2006.01) ment 6A), 41-49. Appell, R.A. et al., Clinical Evaluation of a Sustained-Release Form (52) U.S. Cl. ....................................................... 424/473 of Oxybutynin (Ditropan SR) for the Treatment of Detrusor Hyper (58) Field of Classification Search ........................ None reflexia in Neuropathic Patients, Urodynamics Society Symposium See application file for complete search history. Abstracts, 1990, 228. Sirkia, T. etal, use of Hydrophilic Polymers to Control Drug Release (56) References Cited from Press-Coated Oxybutynin Hydrochloride Tablets, S.T.P. Pharmacia Sci., 1993, 21, 3-8. U.S. PATENT DOCUMENTS Nilsson, C. G. et al., Comparison of a 10-mg Controlled Release 2,853,418 A 9, 1958 Smith Oxybutynin Tablet with a 5-mg Oxybutynin Tablet in Urge Inconti 3,184.386 A * 5/1965 Stephenson ................... 424/471 nent Patients, 1997, 16:533-542. 4,111.202 A 9, 1978 Theeuwes 4,309,996 A 1, 1982 Theeuwes * cited by examiner 4,327,725 A 5, 1982 Cortese et al. 4,449,983. A * 5/1984 Cortese et al. ............. 604/892.1 Primary Examiner — David J Blanchard 4,455,143 A 6, 1984 Theeuwes Assistant Examiner — Tigabu Kassa 4,612,008 A 9/1986 Wong et al. 4,624,847 A 1 1/1986 Ayer et al. (74) Attorney, Agent, or Firm — Rick Matos: Innovar, 4,627,971 A 12/1986 Ayer L.L.C. 4,662,880 A * 5/1987 Hamel et al. .................. 424/467 4,681,583 A 7/1987 Urquhartet al. (57) ABSTRACT 4,723,957 A 2/1988 Magruder et al. 4,765,989 A 8/1988 Wong et al. A dosage form that provides a controlled release of at least 4,814, 181 A 3, 1989 Jordan et al. .................. 424/473 two different active agents is provided. Particular embodi 4,863,456 A 9/1989 Stephens et al. ments include a dosage form that provides therapeutically 4,867,969 A 9/1989 Magruder et al. 4,904,474 A 2f1990 Theeuwes et al. effective levels of a first active agent and a second active agent 4.915,954 A 4/1990 Ayer et al. in a mammal for an extended period of time following oral 4,931,285 A 6/1990 Edgren et al. administration. An osmotic device containing a bi-layered 4,960.416 A 10/1990 Stephens et al. core is provided. The osmotic device provides a dual con 4,971,790 A 1 1/1990 Magruder et al. trolled release of both drugs from the core. The layers of the 4,996,061 A * 2/1991 Webb et al. ................... 424/475 5,006,346 A 4, 1991 Edgren et al. core are in Stacked, Substantially concentric or Substantially 5,082,668 A 1/1992 Wong et al. eccentric arrangement. 5,160,743 A 1 1/1992 Edgren et al. 5,160,744 A 11/1992 Jao et al. 33 Claims, 3 Drawing Sheets U.S. Patent Dec. 11, 2012 Sheet 1 of 3 US 8,329,217 B2 FIG. 1 FIG. 2 U.S. Patent Dec. 11, 2012 Sheet 2 of 3 US 8,329,217 B2 FIG. 6 Figure 6. Dissolution profile of example 1 10 12 14 16 18 20 22 24 Time (hrs FG. 7 O 2 4. 6 8 10 12 14 16 18 20 22 24 Time (hrs) -O-Oxybutynin -O-Darifenacin U.S. Patent Dec. 11, 2012 Sheet 3 of 3 US 8,329,217 B2 FIG. 8 10 12 14 is 18 20 22 24 Time (hrs) -O-Oxybutynin-O-Darifenacin 60 FIG. 11 US 8,329,217 B2 1. 2 DUAL CONTROLLED RELEASE DOSAGE The hole(s) can be placed anywhere along the semipermeable FORM membrane. This patent does not disclose a core having two different drug-containing layers, each providing a controlled CROSS-REFERENCE TO EARLIER FILED release of drug through a respective hole in the semiperme APPLICATIONS able membrane. U.S. Pat. No. 4,662,880 to Hamel et al., U.S. Pat. No. This application claims the benefit of and is a continuation 4,723,957, U.S. Pat. No. 4,867,969 and U.S. Pat. No. 4,971, in-part of U.S. application Ser. No. 1 1/321,736 filed Dec. 29, 790 to Magruder et al. disclose osmotic devices comprising a 2005, which is a divisional of U.S. application Ser. No. single-layered core Surrounded by a semipermeable mem 09/992,488 filed Nov. 6, 2001, now abandoned the entire 10 brane having two oppositely placed holes. A drug-containing disclosures of which are hereby incorporated by reference. coat further surrounds the semipermeable membrane. These patents do not disclose a core having two different drug FIELD OF THE INVENTION containing layers, each providing a controlled release of drug This invention pertains to a dosage form that provides a 15 through a respective hole in the semipermeable membrane. controlled release of two different drugs. More particularly, it U.S. Pat. No. 4,624,847 to Ayer et al. discloses an osmotic pertains to a coated dosage form having a bilayered core device comprising a semipermeable membrane Surrounding a wherein each layer includes a respective drug that is released compartment that houses a drug-containing polymer that in a controlled manner. increases in size and releases drug. The semipermeable mem brane has two oppositely placed holes for releasing drug. This BACKGROUND OF THE INVENTION patent does not disclose an osmotic device comprising core having two different drug-containing layers, each providing a Osmotic devices and other tablet formulations are known controlled release of drug through a respective hole in the for their ability to provide a controlled release of a wide range semipermeable membrane. of drugs. Such osmotic devices and other tablet formulations 25 U.S. Pat. No. 4.915,954 to Ayer et al. and U.S. Pat. No. are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., 4,814,181 to Jordan et al. disclose an osmotic device having U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent a bi-layered core Surrounded by a semipermeable membrane. No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. The first layer comprises a first drug that is released from the Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to core rapidly over a period of 2 minto 2 hr. The second layer Ayer et al., U.S. Pat. No. 4,801.461 to Hamel et al., U.S. Pat. 30 comprises a second drug that is released from the core at a No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770 and controlled rate over a long period of time. The layers of the Argentina Patent No. 199,301, the entire disclosures of which core are in intimate contact and are not separated by another are hereby incorporated by reference. layer, lamina or membrane. The semipermeable membrane Osmotic devices have demonstrated utility in delivering can have two holes, one hole adjacent each of the two layers beneficial active agents, such as medicines, nutrients, food, 35 of the core Such that each layer releases drug through its own pesticides, herbicides, germicides, algaecides, chemical respective hole. The Ayer et al. and Jordan et al. patents do not reagents, and others, to an environment of use in a controlled disclose an osmotic device having a bi-layered core, wherein manner over prolonged periods of time.
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