US 2004.0005359A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0005359 A1 Cheng et al. (43) Pub. Date: Jan. 8, 2004 (54) CONTROLLED RELEASE ORAL DOSAGE (22) Filed: Jun. 27, 2002 FORM Publication Classification (76) Inventors: Xiu Xiu Cheng, Davie, FL (US); Chih Ming Chen, Davie, FL (US); Dacheng (51) Int. Cl.' ..................... A61K 31/554; A61K 31/277; Tian, Miramar, FL (US) A61K 31/455; A61K 9/24 (52) U.S. Cl. .................... 424/471; 514/211.07: 514/355; Correspondence Address: 514/523 Martin P. Endres, Esq. HEDMAN & COSTIGAN, PC. (57) ABSTRACT 1185 Avenue of the Americas A Sustained-release pharmaceutical preparation is disclosed New York, NY 10036 (US) in which a calcium channel blocker, preferably Verapamil, core is Surrounded by an optional Seal coat layer and a (21) Appl. No.: 10/183,776 water-insoluble coating. 8 O S.3S O C 2 6 O O f 92 O o O E CC 1O Dissolution Time (Hour) -e- SF -a - SGF Patent Application Publication Jan. 8, 2004 Sheet 1 of 5 US 2004/0005359 A1 st N 1-N h OS O O w N1 O) E co C .9 --d 2 C d V2 O O O O CO CO r (%) panoSSIO unouw Patent Application Publication Jan. 8, 2004 Sheet 2 of 5 US 2004/0005359 A1 8|910Z -OZ}ºddy:-IL@Zºtud- -±- 08 09$ 0?7± Š „~, C) 9. % S? 8 Patent Application Publication Jan. 8, 2004 Sheet 3 of 5 US 2004/0005359 A1 S : 1N No1T D - S.Sst O pm g OO O ca .2 VO A o d C CO Vo rt (%) peAIOSSCI Junou IV Patent Application Publication Jan. 8, 2004 Sheet 4 of 5 US 2004/0005359 A1 Mean Verapamil Concentration of Example 1 vs. Time Fasting 150 E 1 OO dh S. 2 3 16, 20 Time (hours) FG. 4 Patent Application Publication Jan. 8, 2004 Sheet 5 of 5 US 2004/0005359 A1 Mean Verapamil Concentration of Example 1 vs. Time Fed e 1 OO d S US 3 50 2O 24 28 Time (hours) -a- Covera HS (8J127) F.G. 5 US 2004/0005359 A1 Jan. 8, 2004 CONTROLLED RELEASE ORAL DOSAGE FORM layer and a push layer containing pharmacologically inert (but osmotically active) components. However, the manu BACKGROUND OF THE INVENTION facturing of this multi-layer core System proves to be difficult and expensive. This system, disclosed in U.S. Pat. 0001) 1. Field of the Invention No. 5,252.338 is incorporated herein by reference. Varia 0002 The present invention relates to oral controlled tions on the osmotic System are also disclosed in U.S. Pat. release dosage formulations containing a calcium channel No. 4,783,337 and 4,753,802 which are incorporated herein blocking agent. More specifically, the present invention by reference. relates to an oral dosage formulation in the form of a coated 0008 Another Sustained release formulation disclosed in Single composition core tablet comprising a calcium channel U.S. Pat. No. 4,863,742 (incorporated herein by reference) blocking agent, Such as amlodipine, diltiazem, nicardipine, requires a core comprised of layers of polymeric material nifedipine, Verapamil, felodipine, isradipine, nisoldipine, Superimposed on layers of Verapamil. The core is Sur nimodipine, nilvadipine, flunarizine, norVerapamil, nitre rounded by a multi-layer membrane with a major portion of dipine, cinnarizine, fendiline or their pharmaceutically a water Soluble polymer and a minor portion of a water acceptable derivatives, Salts and Stereoisomers. Preferably, insoluble polymer. The formulation contains a first compo the calcium channel blocking agent is Verapamil. nent that provides an effective amount of Verapamil within 0003 2. Description of the Prior Art one hour after administration and a Second component that 0004 Verapamil (+/-)-5-[(3,4-Dimethoxyphenethyl)m- provides an effective amount of Verapamil 6-16 hours after ethylamino-2-(3,4-dimethoxyphenyl)-2-isopropylvaleroni administration. trile monohydrochloride or iproveratril is a nondihydropy 0009. One limitation associated with these prior art dos ridine calcium channel blocking agent that inhibits the age forms is that many of the multi-walled preparations transmembrane influx of extracellular calcium ions acroSS described above do not provide a therapeutic release of the the membranes of the myocardial cells and vascular Smooth drug prior to initiation of Sustained release, which is impor muscle cells, without changing Serum calcium concentra tant when biphasic release profiles are desired. tions. By inhibiting calcium influx, Verapamil inhibits the 0010. Other systems are essentially “delayed' release contractile processes of cardiac and vascular Smooth muscle, thereby dilating the main coronary and Systemic arteries. mechanisms wherein there is a delay of drug release in the Verapamil is a class IV antiarrhythmic. It reduces afterload Stomach but once the coated drug reaches the intestines, the and myocardial contractility. release of medication is rapid. 0.011 Verapamil is also available as controlled and 0005 Verapamil is used orally to treat Prinzmetal variant extended release capsules (Verelan SRE) containing pellets angina and unstable and chronic Stable angina pectoris, the and as extended release caplets (Calan SRCR), Isoptin SR(R). management of hypertension, for the prevention of recurrent The extended release capsules contain controlled release premature Supraventricular tachycardia (PSVT) and, in com beads, a portion of which are uncoated for immediate bination with a cardiac glycoside, to control ventricular rate release. The remainder consists of a drug core with rate at rest and during StreSS in patients with atrial flutter and/or controlling polymeric coating. The extended release caplets fibrillation. It has been used as adjunctive therapy in the contain alginate which SWells in water and forms a gelati management of hypertrophic cardiomyopathy or in certain nous like substance. Verapamil is released both by diffusion patients after myocardial infarction when beta-adrenergic out of the gel and by erosion of the tablet. Verapamil shows blocking agents are ineffective or contraindicated for the linear pharmacokinetics for Single dosing, but Saturation and relief of ongoing ischemia. Benefit has also been demon increased bioavailability with multiple dosing. Because of Strated in the management of manic manifestations of bipo their pharmacokinetic profile, these are dosed early in the lar disorder. morning, rather than at bedtime. For many patients, these are 0006 Numerous techniques are in the prior art for pre dosed every twelve hours in the morning and in the evening. paring Sustained or controlled release pharmaceutical for Additionally, the caplets should be administered with food to mulations. One common technique involves Surrounding an prevent wide differences between peak and trough Serum oSmotically active drug core with a Semipermeable mem Verapamil concentrations. brane or wall. The drug is released from the core by allowing 0012. The need exists for a sustained release pharmaceu a fluid Such as gastric or intestinal fluid to permeate the tical preparation which provides constant blood levels, and coating membrane and dissolve the drug So dissolved drug is Simply and economically produced. Such a delivery can permeate the membrane. In Some cases a hydrogel is dosage form has a practical application, and it represents a employed to push the active ingredient through the passage valuable contribution to the medical arts. The present inven way in the membrane. The hydrogel imbibes fluid and tion provides Such a composition, and offers an efficient and expands thereby pushing the active ingredient through the cost effective method of preparation. membrane or passageway formed in the membrane and from the dosage form. 0013. Accordingly, it is an object of this invention to provide a novel and useful dosage form for administering a 0007. Several different Sustained release formulations of calcium channel blocking agents are patented. Commer calcium channel blocker, preferably Verapamil, that repre cially available extended-release tablets of Verapamil hydro Sents an unexpected improvement in the art and Substantially chloride (Covera-HS(R) contain drug in an osmotic delivery overcomes the disadvantages known to the prior art. System consisting of an OSmotically active core Surrounded 0014. It is an object of this invention to provide a by a semipermeable membrane with a laser-drilled delivery Sustained release form of a calcium channel blocker, pref orifice. The core itself is divided into 2 layers: an active drug erably Verapamil, Suitable for bedtime administration, which US 2004/0005359 A1 Jan. 8, 2004 is Substantially invariable from Subject to Subject, and pro antihypertensive effect remaining at the end of the dosing vides Significant plasma levels of the calcium channel interval. Release of the calcium channel blocker does not blocker which are maintained for an extended period after occur until about two hours after administration. The prod administration. uct peaks and maintains levels from 10-24 hours. The usual 0.015. Another object of the invention is to provide bed dosage range is 80 mg-480 mg. time dosing of Verapamil resulting in therapeutic morning levels to reduce the early morning rise in blood pressure and BRIEF DESCRIPTION OF THE DRAWINGS heart rate. 0022 FIG. 1 is a graph depicting the dissolution profile in Simulated intestinal fluid (pH 6.8) and Simulated gastric 0016. Another object of this invention is to provide 24 fluid (pH 1.2) of the formulation as described in Example 1 hour control of hypertension and angina. as tested according to the procedure described in United 0.017. Other objects, features and advantages of the States Pharmacopoeia (USP) XXIII, Apparatus 2 (a 75 rpm. invention are not taught in the prior art but will be more 0023 FIG. 2 is a graph depicting the dissolution profile apparent to those versed in the art from the following in a pH 7.5 buffer of the formulation in Example 2 as tested Specification, taken in conjunction with the drawings and the according to the procedure described in USP XXIII, Appa accompanying claims.