Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2002-02-01
2004-01-27
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S469000, C424S470000, C424S472000, C424S474000, C424S479000, C424S480000, C424S486000, C424S488000
Reexamination Certificate
active
06682759
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is in the field of pharmacology, and relates to drug dosage forms that are designed to deliver the drugs to human patients at particular rates.
2. Description of the Prior Art
Certain pharmacological therapies either require or benefit from the administration of drugs in a sequential manner. This can be done by a regimen in which the patient follows a prescribed time schedule, but because of patient non-compliance, scrupulous adherence to a schedule often requires the assistance of a medical professional. Even those therapies that involve only two dosages, such as an immediate but rapidly declining high-level dosage combined with a prolonged low-level or moderate-level dosage, either of the same drug or of two different drugs, can be a nuisance to the individual or troublesome to maintain if the individual is required to take separate unitary dosage forms. Certain pharmaceutical formulations have therefore been developed that combine both functions into a single dosage form. This simplifies the therapy and reduces or eliminates the chances of improper administration.
Many unitary dosage forms that have been proposed for combining immediate release with prolonged release do so by the placement of the drugs in different layers of a tablet or by placing one drug in a quickly-dissolving or quickly-dispersing coating over the surface of a slowly dissolving or swellable core that contains the other drug. With its high initial release concentration and rapid rate of decline, the immediate-release drug is often provided in a much lower amount than the prolonged-release drug. The immediate-release portion of the dosage form is therefore either a very thin layer or coating or a layer or coating with a very low concentration of the drug relative to the drug in the prolonged-released portion. It is common, for example, to design the dosage form such that the amount of drug intended for immediate release is {fraction (1/100)}th or less of the amount intended for prolonged release.
This large imbalance in the amounts of immediate-release and controlled-release drug creates problems in manufacturing, particularly in achieving uniformity from one tablet to the next. It is difficult to achieve uniform immediate-release coatings or layers of uniform drug content when the drug is so low in quantity or concentration. The problem is exacerbated when the drug in the immediate-release portion is one that has little or no solubility in water.
SUMMARY OF THE INVENTION
It has now been discovered that a dosage form that includes a core from which drug is released on a prolonged basis and a coating or layer from which drug is released on an immediate-release basis can be made in a manner that provides a high degree of uniformity in the immediate-release portion, even when the drug in the immediate-release portion is either insoluble or only sparingly soluble in water. This is achieved by limiting the drug particle diameter in the immediate-release coating or layer to 10 microns or less. The coating or layer is either the particles themselves, applied as an aqueous suspension, or a solid composition that contains the drug particles incorporated in a solid material that disintegrates rapidly in gastric fluid. Either mixture can be applied as a coating or layer over a core or coherent mass of the prolonged-release drug. When an aqueous suspension is used and applied as a coating, a suspending agent, binder, or both can be included to improve the procedure, and in either case, other excipients can be included to facilitate the manufacturing process.
Details on these and other features, advantages, and embodiments of the invention will be apparent from the description that follows.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The dosage forms of this invention are designed for oral ingestion, and the prolonged-release portion of the dosage form is one that delivers its drug to the digestive system continuously over a period of time of at least an hour and preferably several hours. The drug is retained in a matrix or supporting body of pharmaceutically inert solid, and the controlled delivery rate can be achieved by using a matrix that allows the gastric fluid to permeate the matrix and leach out the drug (i.e., allow the drug to diffuse out from the matrix as the drug slowly dissolves in the permeating fluid), or a matrix that slowly dissolves or erodes to expose the drug to the gastric fluid, or one that does both of these at once. The delivery rate is preferably slow enough that at least about 40% of the drug remains unreleased one hour after ingestion, more preferably at least about 60% and most preferably at least about 80%. In general, the drug will be substantially all released within about ten hours and preferably within about eight hours, and in most cases, the matrix supporting the drug will remain substantially intact until all of the drug is released. “Substantially intact” in this sense means that the matrix retains its size and shape without dissolving or disintegrating into fragments.
The immediate-release portion of the dosage form is either a coating applied or deposited over the entire surface of a unitary prolonged-release core, or a single layer of a tablet constructed in two or more layers, one of the other layers of which is the prolonged-released portion. Immediate release of the drug from the immediate-release layer is achieved by any of various methods known in the art. One example is the use of a very thin layer or coating which by virtue of its thinness is quickly penetrated by gastric fluid allowing fast leaching of the drug. Another example is by incorporating the drug in a mixture that includes a supporting binder or other inert material that dissolves readily in gastric fluid, releasing the drug as the material dissolves. A third is the use of a supporting binder or other inert material that rapidly disintegrates upon contact with gastric fluid, with both the material and the drug quickly dispersing into the fluid as small particles. Examples of materials that rapidly disintegrate and disperse are lactose and microcrystalline cellulose. An example of a suspending agent and binder is hydroxypropyl methyl cellulose.
The dosage forms of this invention include those in which the same drug is used in both the immediate-release and the prolonged-release portions as well as those in which one drug is formulated for immediate release and another drug, different from the first, for prolonged release. This invention is particularly directed to dosage forms in which the immediate-release drug is at-most sparingly soluble in water, i.e., either sparingly soluble or insoluble in water, while the prolonged-release drug can be of any level of solubility. The immediate-release drug is of sufficiently low solubility that it remains a solid particle during the preparation of the dosage form when the dosage form is prepared without the use of organic solvents. The only dispersing medium, when one is used, is water or an aqueous solution that may contain other components. The term “at most sparingly soluble” as used herein denotes a drug having a solubility in water at 37° C. that is generally less than 2% by weight, preferably less than 0.5% by weight. The particle size of the drug as it is used in the practice of this invention is equal to or less than about 10 microns in diameter, preferably within the range of from about 0.3 micron to about 10 microns in diameter, and most preferably with the range of from about 1 micron to about 5 microns in diameter.
The immediate-release drug can thus be deposited as a suspension over a unitary core of the controlled-release drug, with deposition being achieved by coating techniques known in the pharmaceutical formulation art such as spraying, pan coating, and the like, or the drug can be combined with particles of a binding matrix and compressed over a preformed layer of the controlled-release drug to form a layered tablet. In either case, the immediate-release coating o
Lim Jong C.
Shell John N.
DepoMed, Inc.
Heines M. Henry
Spear James M.
Townsend and Townsend / and Crew LLP
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