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(12) United States Patent (10) Patent No.: US 8,039,019 B2 Hahn (45) Date of Patent: Oct

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(12) United States Patent (10) Patent No.: US 8,039,019 B2 Hahn (45) Date of Patent: Oct USO08039019B2 (12) United States Patent (10) Patent No.: US 8,039,019 B2 Hahn (45) Date of Patent: Oct. 18, 2011 (54) PHARMACEUTICAL FORMULATION (56) References Cited CONTAINING A BIGUANDE AND AN ANGOTENSIN ANTAGONST U.S. PATENT DOCUMENTS 5,196,444 A 3, 1993 Naka et al. (75) Inventor: Elliot F. Hahn, North Miami Beach, FL 5,534,534 A 7/1996 Makino et al. (US) 5,650,170 A 7/1997 Wright et al. 5,705,517 A 1/1998 Naka et al. (73) Assignee: Andrx Labs, LLC, Davie, FL (US) 6,099,859 A 8/2000 Cheng et al. 6,099,862 A 8, 2000 Chen et al. 6,682,759 B2 1/2004 Lim et al. (*) Notice: Subject to any disclaimer, the term of this 7,588,779 B2 9, 2009 Hahn patent is extended or adjusted under 35 2001 OO24659 A1 9, 2001 Chen et al. U.S.C. 154(b) by 54 days. 2004.0034.065 A1 2/2004 Allison et al. 2004/0106660 A1 6/2004 Kositprapa et al. (21) Appl. No.: 12/535,833 2004O161462 A1 8/2004 Kositprapa et al. 2004/0219209 A1 11/2004 Chen et al. (22) Filed: Aug. 5, 2009 2005/0226928 A1 10, 2005 LOdin et al. FOREIGN PATENT DOCUMENTS Prior Publication Data (65) WO WO9947 125 9, 1999 US 2009/O2976OO A1 Dec. 3, 2009 WO WOO215933 2, 2002 Related U.S. Application Data OTHER PUBLICATIONS Graffeo, M., International Search Report, PCT/US05/18939, Mar. 9. (62) Division of application No. 1 1/628,066, filed as 2006. application No. PCT/US2005/018939 on May 27, Graffeo, M., Written Opinion of the International Searching Author 2005, now Pat. No. 7,588,779. ity, PCT/US05/18939, Mar. 9, 2006. (60) Provisional application No. 60/575,259, filed on May http://en.wikipedia.org/wiki/Biguanide (2007). 28, 2004. Primary Examiner — Kevin E Weddington (51) Int. Cl. (74) Attorney, Agent, or Firm — Florek & Endres PLLC A6 IK9/20 (2006.01) A6 IK3I/44 (2006.01) ABSTRACT A6 IK3I/4I (2006.01) (57) A6 IK3I/55 (2006.01) A pharmaceutical dosage form comprising a controlled (52) U.S. C. ........ 424/464; 514/342: 514/381: 514/635; release component comprising an antihyperglycemic drug in 514/866 combination with a second component comprising a angio (58) Field of Classification Search .................. 514/342, tensin antagonist is herein disclosed and described. 514/381, 635, 824,866; 424/464 See application file for complete search history. 24 Claims, No Drawings US 8,039,019 B2 1. 2 PHARMACEUTICAL FORMULATION Certain controlled or sustained release formulations that CONTAINING A BIGUANDE AND AN employ antihyperglycemic drugs such as metformin hydro ANGOTENSIN ANTAGONST chloride have been limited to the use of an expanding or gelling agent to control the release of the drug from the CROSS REFERENCE TO RELATED dosage form. This limited research is exemplified by the APPLICATIONS teachings of WO 96/08243 and by the product insert for GLUCOPHAGETM XR, which is a controlled release met The present application is a divisional application of U.S. formin HCl product commercially available from Bristol patent application Ser. No. 1 1/628,066, which was filed on Myers Squibb Co. Nov. 28, 2006 now U.S. Pat. No. 7,588,779. U.S. patent 10 Angiotensin antagonists have been described in U.S. Pat. Nos. 5,196,444; 5,534,534 and 5,705,517. The therapeutic application Ser. No. 1 1/628,066 was a U.S. National Stage value of these compounds in combination therapy has further filing of International Patent Application No. PCT/US05/ been described in published PCT application WO 0215933. 18939, which was filed on May 27, 2005 and which claimed However, none of these patents, or the publication describe a the benefits of U.S. Provisional Patent Application Ser. No. 15 dosage form having the advantages of the Subject invention. 60/575,259, filed on May 28, 2004. Angiotensin antagonists are compounds functioning to control the renin-angiotensin System as well as being clini BACKGROUND OF THE INVENTION cally useful for the treatment of circulatory diseases Such as hypertensive diseases, heart diseases (e.g. hypercardia, heart The present invention relates to a pharmaceutical dosage failure, cardiac infarction, etc.), strokes, cerebral apoplexy, form comprising an antihyperglycemic drug, in combination etc. These compounds are required to have potent angiotensin with a second drug. More specifically, the present invention II receptor antagonistic activity and to exert strong oral and relates to an oral dosage form comprising a biguanide, e.g., long-lasting angiotensin II antagonist action. Several 2-sub metformin or buformin or a pharmaceutically acceptable salt stituted benzimidazole derivatives possessing highly angio thereof e.g., metformin hydrochloride or the metformin salts 25 tensin II receptor antagonistic activity as well as exerting described in U.S. Pat. Nos. 3,957,853 and 4,080,472, which strong oral and long-lasting angiotensin II antagonistic and are incorporated herein by reference in combination with an anti-hypertensive action have been developed. These com angiotensin antagonist as described in U.S. Pat. Nos. 5,196, pounds are potent angiotensin II antagonists that are of value 444; 5,534,534; 5,703,110; and 5,705,517 also incorporated in the treatment of circulatory system diseases such as hyper herein by reference. 30 tensive diseases, heart diseases, strokes, nephritis, etc. Many techniques have been used to provide controlled and Also known in the art is WO 99/471.25 and U.S. Pat. No. extended-release pharmaceutical dosage forms in order to 6,099,862 that disclose a metformin osmotic tablet coated maintain therapeutic serum levels of medicaments and to with an immediate release coating containing an antihyperg minimize the effects of missed doses of drugs caused by a lycemic or a hypoglycemic drug. lack of patient compliance. 35 Although the prior art teaches pharmaceutical dosage for For example, extended release tablets have been described mulations that contain both an antihyperglycemic compound which have an osmotically active drug core surrounded by a and an angiotensin antagonist, the present invention provides semi-permeable membrane. These tablets function by allow numerous benefits over the prior art teachings as will be ing the aqueous components of a fluid Such as gastric or described below. intestinal fluid to permeate the coating membrane and dis 40 Solve the active ingredient so the resultant drug solution can SUMMARY OF THE INVENTION be released through a passageway in the coating membrane. Alternatively, if the active ingredient is insoluble in the per The present invention relates to a pharmaceutical dosage meating fluid, it can be pushed through the passageway by an form comprising a first active drug, preferably an antihyper expanding agent Such as a hydrogel. Some representative 45 glycemic drug, in combination with a second active drug. The examples of these osmotic tablet systems can be found in U.S. second active drug may be any drug useful in combination Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and therapy with the first active drug. In one embodiment, the first 4,783,337. U.S. Pat. No. 3,952,741 teaches an osmotic device active drug is a biguanide and the second active drug is an wherein the active agent is released from a core Surrounded angiotensin antagonist. by a semipermeable membrane only after sufficient pressure 50 In certain embodiments, the second active drug may be has developed within the membrane to burst or rupture the selected from antidiabetic agents, cardiovascular agents, anti membrane at a weak portion of the membrane. lipemic agents, or antiplatelet agents. The basic osmotic device described in the above cited The termantidiabetic agent may include, but would not be patents have been refined over time in an effort to provide limited to biguanides (i.e., Metformin, Buformin, Phen greater control of the release of the active ingredient. For 55 formin), Sulfonylureas (i.e., Acetohexamide, Carbutamide, example, U.S. Pat. Nos. 4,777,049 and 4,851,229 describe Chlorpropamide, Glibornuride, Gliclazide, Glimepiride, osmotic dosage forms comprising a semipermeable wall Sur Glipizide, Gliquidone, Glisoxepid, Glyburide, Glybuthiaz rounding a core. The core contains an active ingredient and a ole, Glybuzole, Glyhexamide, Glymidine, Glypinamide, modulating agent wherein the modulating agent causes the Phenbutamide, Tolazamide, Tolbutamide, Tolcyclomide) active ingredient to be released through a passageway in the 60 thiazolidinediones (i.e., PiogliataZone, RosiglitaZone, Trogli semipermeable membrane in a pulsed manner. Further refine taZone), beta andrenergic blockers, and other antidiabetics ments have included modifications to the semipermeable Such as acarbose, calcium mesoxalate, miglitol, nateglinide, membrane Surrounding the active core such as varying the repaglinide, Voglibose. proportions of the components that form the membrane, e.g. The term cardiovascular agent may include, but would not U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625, or 65 be limited to, alpha andrenergic agonists that include, but are increasing the number of coatings Surrounding the active not limited to, Adrafinil, Adrenalone, Amidephrine, Apra core, e.g., U.S. Pat. Nos. 5,650,170 and 4,892,739. clonidine, Budralazine, Clonidine, Cyclopentamine, Dexme US 8,039,019 B2 3 4 detomidine, Dimetofrine, Dipivefrin, Ecabapide, Ephedrine, Inotropic agents include but are not limited to Digoxin, Epinephrine, Fenoxazoline, GuanabenZ, Guanfacine, Milrinone, Dobutamine, and Dopamine. Hydroxyamphetamine, Ibopamine, Indanazoline, Vasodilators include but are not limited to Amotriphene, Isometheptene, Mephentermine, Metaraminol, Methoxam Benfurodil Hemisuccinate,
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