Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-07-21
2002-12-31
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S470000, C424S472000, C424S475000, C514S770000, C514S772300, C514S777000, C514S778000, C514S779000, C514S780000, C514S781000, C514S782000
Reexamination Certificate
active
06500459
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to dosage forms for controlled onset and sustained release of active ingredients for human or animal use.
BACKGROUND OF THE INVENTION
The goal of any drug delivery system is to provide an effective therapeutic amount of a drug to a targeted site in the body to obtain quickly, and then maintain, the desired drug concentration. The two most important aspects of drug delivery are spatial placement and temporal delivery of a drug. Spatial placement relates to the targeting of a drug to a specific organ or tissue, while temporal delivery refers to controlling the rate of drug delivery to the target tissue.
Sustained release drug delivery systems are designed in an attempt to satisfy the spatial placement and temporal delivery of a drug. Sustained release drug delivery systems include any drug delivery system that achieves slow release of a drug over an extended period of time. If these sustained release drug delivery systems can provide some control of drug release in the body, whether this be of a temporal or spatial nature, or both, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells, it is considered to be a controlled release drug delivery system.
Some therapeutic programs require that the dose of a drug be administered in a time varying pattern of delivery such as a drug free interval followed by a sustained release of the drug for an extended period of time. The science of chronotherapeutics relies on the practice of delivering an effective therapeutic amount of a drug to the desired site of action at the most appropriate time period for a particular disease condition. For example, the greatest incidence of cardiovascular disorders including angina, stroke, heart attack, etc., typically occur during the early morning hours when blood pressure is rising in response to an animal's natural circadian rhythm. This rise in blood pressure, which occurs at waking, requires a dosage form that is administered upon retiring which dosage form delivers its drug before waking but after a drug free interval during sleep. This time varying pattern or controlled onset of drug delivery provides the required therapy at the appropriate time, thereby substantially lessening the instance of a waking elevated blood pressure.
It is well known in the prior art to provide dosage forms that deliver their contents at a desired rate after a predetermined time delay. Applicant is aware of two such controlled onset and sustained release drug delivery systems currently on the market namely, Verelan® PM by Schwarz Pharma and Covera-HS™ by G.D. Searle & Co. Verelan® PM is a verapamil hydrochloride capsule formulation utilizing the proprietary CODAS™ (Chronotherapeutic Oral Drug Absorption System) technology, developed by Elan Corporation PLC and which technology is based on U.S. Pat. No. 4,863,742. U.S. Pat. No. 4,863,742 relates to a controlled absorption verapamil containing pellet formulation for oral administration comprising: (i) a core of (a) a powder mixture containing verapamil or a salt thereof and an organic acid, and (b) a polymeric material containing a major proportion of a water soluble polymer and a minor proportion of a water insoluble polymer, the core comprising layers of the powder mixture and the polymeric material superimposed one upon the other; and (ii) a multi-layer membrane surrounding the core and containing a major proportion of a film-forming, water insoluble polymer and a minor proportion of a film forming water soluble polymer; the release of the verapamil from the pellet being substantially independent of pH and at a rate allowing controlled absorption thereof over a 24 hour period following oral administration.
The individual pellets formulated according to U.S. Pat. No. 4,863,742 may be filled into hard or soft gelatin capsules or may be compressed into tablets. The pellets in the formulation may consist of a blend of pellets formulated to provide various release rates of verapamil. Upon ingestion, the hard or soft gelatin capsules dissolve immediately, thus releasing the individual pellets into the gastrointestinal tract. Likewise, upon ingestion, the compressed tablets are designed to fall apart immediately, thus releasing the individual pellets into the gastrointestinal tract.
The Verelan® PM capsule formulation, which is based on the teachings of U.S. Pat. No. 4,863,742, is a controlled onset sustained release drug delivery system designed for bed time administration, which incorporates a 4 to 5 hour delay in drug delivery. The Verelan® PM capsule formulation initiates the release of verapamil hydrochloride 4 to 5 hours after ingestion and results in a maximum plasma concentration (C
max
) of verapamil hydrochloride in the morning hours. The pellet filled, hard gelatin capsules provide for extended release of verapamil hydrochloride in the gastrointestinal tract. The delay is introduced by the level of non-enteric release controlling polymer applied to the verapamil hydrochloride loaded beads. The release controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer coated beads, the water soluble polymer slowly dissolves and the verapamil hydrochloride diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the verapamil hydrochloride. The rate of release is essentially independent of pH, posture, and gastrointestinal motility in fed or fasting conditions.
The formulation disclosed in U.S. Pat. No. 4,863,742 and thus the currently marketed Verelan® PM capsule formulation, has several limitations. In the acidic environment of the stomach (pH 1 to 3) where the verapamil is water soluble, the gastric fluid diffuses through the permeable membrane of each pellet, dissolves the verapamil, and diffuses out through the permeable membrane of each pellet with the dissolved verapamil. The purpose of the organic acid is purportedly to maintain an acidic micro-environment in the pellet core to keep the verapamil soluble, even when the pellet is introduced into the alkaline environment of the lower gastrointestinal tract. Thus, when the pellets descend through the stomach into the alkaline environment of the lower gastrointestinal tract (pH 5 to 7), the verapamil purportedly continues to be dissolved because of the purported continued presence of the organic acid in the core which organic acid maintains the acidity of the micro-environment (assuming the acid has not diffused out). Fluid entering the pellet from the lower gastrointestinal tract (even though more basic) is purportedly neutralized by the presence of the organic acid and the relatively low pH maintained so that the verapamil can purportedly remain in its more soluble state in the maintained acidic micro-environment. Thus, the verapamil purportedly continues to dissolve and diffuse through the multi-layer permeable membrane into the lower gastrointestinal tract.
The difficulty of the approach used in the formulation disclosed in U.S. Pat. No. 4,863,742 and thus the approach used in the Verelan® PM capsule formulation, is two-fold. Firstly, the organic acid is soluble. Therefore, the organic acid dissolves and diffuses out from the core through the multi-layer permeable membrane as the pellets pass through the gastrointestinal tract. Secondly, the organic acid is subject to neutralization as a result of its contact with the alkaline environment of the lower gastrointestinal tract, where the effectiveness of the organic acid is most needed. At the time when only a percentage of the original amount of verapamil is present in the core, there is a stronger need for solubilization because the less product inside the core, the higher the osmotic pressure needed to permit the verapamil to be pushed out. However, at that point, the quantity of organic acid has had time to diffuse out and another quantity of organic acid has had
Chhabra Harinderpal
Sarkar Shyamal K.
Hughes Ivor M.
Sarkis Marcelo K.
Sinden Kitt
Spear James M.
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