Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-04-12
2003-10-21
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S457000, C424S461000, C424S462000, C424S494000, C424S497000
Reexamination Certificate
active
06635277
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field Of The Invention
A three-pellet, pulsatile drug delivery system results in bioequivalence to Cardizem® CD. The fast release membrane (FRF) composition includes an anionic surface active agent which assures complete drug release after providing a desired lag time. The medium release fraction (MRF) and the slow release fraction (SRF) are plasticized with decreased concentrations of triethyl citrate and increased concentrations of silicone dioxide powder for improved process performance.
2. Background Of The Art
Diltiazem is a benzothiazine derivative possessing calcium antagonist activity. Diltiazem blocks the influx of calcium ions in smooth and cardiac muscle and thus exerts potent cardiovascular effects. Diltiazem has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris and myocardial ischemia and hypertension, while displaying a low incidence of side effects. The first dosage forms of diltiazem sold in the United States were tablets containing 30 mg or 60 mg of diltiazem hydrochloride sold under the tradename Cardizem® by Marion Laboratories Inc. Single oral doses of 30 mg and to 120 mg of Cardizem® tablets result in peak plasma levels about 2 to 3 hours after ingestion, and the elimination half-life is about 3 to 5 hours. Because of the relatively rapid absorption of diltiazem hydrochloride from such tablets and rapid elimination, the usual dosage regimen for immediate release tablets is for a dose to be taken three or four times daily. The need for such frequent administration may reduce patient compliance. Thus adverse therapeutic effects can arise. It thus became apparent that it would be preferable to administer diltiazem hydrochloride in a dosage form that releases the diltiazem hydrochloride much more slowly than Cardizem® tablets, so as to enable the frequency of ingestion by the patient to be reduced to once daily.
A formulation of diltiazem hydrochloride that controls the rate of release to enable once daily administration is sold in the United States under the tradename Dilacor® XR by Rhone-Poulenc Rorer Pharmaceuticals Inc. Dilacor® XR is produced as two-piece hard gelatin capsules, with each capsule containing a plurality of tablets. The 180 mg strength of Dilacor® XR contains three tablets and the 240 mg strength contains four tablets. The same tablets are used in both capsules, and each tablet contains 60 mg of diltiazem hydrochloride.
The tablets used in Dilacor® XR are made in accordance with the invention of U.S. Pat. No. 4,839,177. Each tablet is comprised of a cylindrical core containing diltiazem hydrochloride mixed with inactive ingredients that include a polymer that swells and forms a gel upon contact with aqueous fluids. Because the gel has high viscosity, it swells and dissolves only very slowly in the gastrointestinal fluids to thereby retard the rate of release of the diltiazem hydrochloride. To further retard the release, insoluble polymeric platforms are affixed to the top and bottom of the cylindrical core, thus leaving only the periphery exposed to the gastrointestinal fluid. The formulation of Dilacor® XR capsules successfully accomplishes gradual release to enable once daily dosing, but the Dilacor® XR formulation requires complex and expensive procedures to produce. In particular, production of the tablets contained in Dilacor® XR capsules requires production of cores containing the diltiazem hydrochloride and the affixing thereto of the insoluble platforms.
Another formulation of diltiazem hydrochloride suitable for once daily administration is now sold in the United States under the trademark Cardizem® CD, by Marion Laboratories Inc. Cardizem® CD is sold as capsules containing a multitude of beads. The composition of the beads contained in Cardizem® CD capsules is described in U.S. Pat. No. 5,286,497. The beads are made using core seeds to which is applied a first coating containing the diltiazem hydrochloride. Over the first coating, further coatings of polymers are applied which serve to slow down and control the rate at which the diltiazem hydrochloride is released from the beads in gastrointestinal fluids.
As explained in U.S. Pat. No. 5,286,497, there is a particular dissolution profile found to be optimum for once daily administration. This desired dissolution profile, when measured in a type 2 dissolution apparatus according to U.S. Pharmacopoeia XXII, in 0.1 NHCL at 100 rpm is as follows:
a) from 20-45% released after 6 hours;
b) from 25-50% released after 12 hours;
c) from 35-70% released after 18 hours;
d) not less than 70% released after 24 hours;
e) not less than 85% released after 30 hours;
The invention of U.S. Pat. No. 5,286,497 achieves this dissolution profile by using a mixture of beads with two differing amounts of coating. The beads with the lesser amount of coatings are referred to as “rapid release diltiazem beads” and the beads with the greater amount of coating are referred to as “delayed release diltiazem beads”. It is disclosed that by making each of these types of beads so as to comply with particular dissolution requirements, the mixture of the two types of beads produces the desired dissolution profile for the final composition.
A difficulty with the invention of U.S. Pat. No. 5,286,497 is that it is difficult to reliably make the two types of beads so as to get the required dissolution profile for the final mixture. In particular, the desired dissolution profile requires that the amount released must exceed 20% after 6 hours, but must not exceed 50% after 12 hours. This requires that the “rapid release diltiazem beads” give a sharp, step-like release of the diltiazem. Otherwise, if the amount released increases only gradually with time, beads formulated to assure that at least 20% of the diltiazem is released from the final mix after 5 hours will also cause more than 50% to be released after 10 hours, thus causing the final composition to fail to meet the defined requirements.
U.S. Pat. No. 5,968,552 discloses beads containing diltiazem hydrochloride made by processes the same as or similar to those disclosed in U.S. Pat. No. 5,286,497. However, instead of mixing only two types of beads, referred to as “rapid release beads” and “delayed release bead”, three types of beads are made which will be referred to herein as “rapid release beads”, “intermediate release beads”, and “delayed release beads”. By using an appropriate mixture of these three types of beads, with three different amounts of coating, it is possible to obtain the desired dissolution profile for the final mix, without the need for the individual types of beads to have the sharp step-like release profile required by the invention of U.S. Pat. No. 5,286,497.
The three bead combination (rapid release, intermediate release, and delayed release beads) of U.S. Pat. No. 5,968,552 will typically exhibit in vitro dissolution profiles as shown in the Patent when measured in 0.1 NHCL using a type 2 apparatus at 100 rpm according to U.S. Pharmacopoeia XXII. A typical profile (preferred profile) composition is Rapid Release at 3 hours 40-100% (70%), Intermediate Release at 6 hours 0 to 30% (17%), Delayed Release at 18 hours 30 to 60% (45%). The beads are provided in a manner so that the available diltiazem HCl from each set is approximately 18% in rapid release beads, about 20% in intermediate release beads, and 65% delayed release beads. This distribution cannot possibly provide bioequivalence to the biphasic plasma profile of Cardizem® CD. The release profile is only more similar to the release profile of Cardizem®, as compared to that of U.S. Pat. No. 5,286,497. Even 100% release of the fast release fraction in three hours could contribute a maximum of about 28% of the diltiazem HCl (18%×the 40-100% release rate of the fast release fraction plus 15%×the 0-15% release rate in the intermediate release fraction and 67×0-10% of the delayed release fraction) in three hours. This profile is asserted to provide a better dissolution profile for the final mix,
Hussain Javed
Khorakiwala Habil F.
Sharma Vinay K.
Schwegman Lundberg Woessner & Kluth P.A.
Spear James M.
Wockhardt Limited
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