Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-07
2002-09-24
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06455526
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods for the production of sustained release compositions containing a biodegradable polymer and a pharmaceutically active molecule, which are useful in the treatment of a variety of diseases, including certain psychoses such as, for example, schizophrenia, obsessive compulsive disorder, anxiety, and bipolar disorders. More specifically, the present invention relates to sustained release compositions of a biodegradable polyester and a pharmaceutically active molecule capable of exerting serotonin receptor antagonist activity at the 5HT
2
receptor, method of making the same, and method of treating patients in need of such compositions.
2. Description of the Prior Art
It has long been appreciated that the continuous release of certain drugs over an extended period following a single administration could have significant practical advantages in clinical practice. It is also well recognized in the art that delivering a drug to its therapeutic site of action, such as, for example, the central nervous system (CNS) can be a very difficult task because of the numerous chemical and physical barriers which must be overcome in order for such delivery to be successful. A particularly difficult problem is in long term administration of a drug to patients suffering from CNS related diseases. This is particularly true for patients suffering from various CNS related diseases, such as schizophrenia, obsessive compulsive disorders, sleep disorders, depression, anxiety, anorexia and drug addiction. In addition, there is a need to maintain a steady drug level in patients suffering with these diseases so as to provide an improved efficacy in treatment with lower peak drug concentrations.
As a result, many methods have been developed to deliver drugs to the CNS effectively. One such method involves preparation of sustained release formulations. The sustained release formulations may however be of various different types. For example, a drug may be chemically modified into a form called a prodrug, that is capable of transforming into its active form slowly, either before or after crossing the blood-brain barrier. An example of such a prodrug delivery system consists of the neurotransmitter dopamine attached to a molecular mask derived from the fat-soluble vitamin niacin. The modified dopamine is taken up into the brain where it is then slowly stripped from its prodrug mask to yield free dopamine.
Other common methods used to prepare sustained release formulations include formation of microparticles in which bioactive agents are contained within a compatible biodegradable polymer. A number of methods are reported in the art, which use a wide range of organic solvents to prepare such microparticles. For example, U.S. Pat. No. 4,389,330 describes a method of forming microcapsules by dissolving or dispersing an active agent along with a wall forming material in a solvent. Common solvents used for the formation of such microcapsules include chlorinated hydrocarbons, particularly, methylene chloride, acetone, alcohols, and the like. However, due to environmental and toxicological considerations it is not possible to make certain of these drug formulations using solvents. Particularly, there are a number of regulatory restrictions in disposing of the solvent and solid wastes produced during the manufacture of these drug formulations.
In addition, there are many disadvantages to the solvent method of producing microparticle drug formulations. First, this method is uneconomical for an industrial size scale-up. Second, there are also quality concerns such as reproducibility and consistency of the drug distribution in the polymer matrix, thus causing serious regulatory compliance problems. Finally, the solvent method generally produces only the microspheres in powder form.
To overcome some of the problems of the solvent method of producing microparticles, there are methods known in the art to melt extrude a solid mixture of drug molecules and a variety of polymeric binders. For example, U.S. Pat. No. 5,439,688 describes a process for preparing a pharmaceutical composition for the sustained release of a drug molecule. However, all of the drug molecules described therein are synthetic or naturally occurring peptides. U.S. Pat. No. 5,456,923 describes a process for producing a solid dispersion of a drug dissolved or dispersed in a polymer or a diluent using a twin screw extruder. However, none of these prior art references teaches a formation of sustained release pharmaceutical compositions using a melt extrusion process wherein such compositions are suitable for the treatment of any of the CNS diseases described hereinabove. Furthermore, none of the prior art references describes a method for the formation of microparticles wherein the drug molecules are dissolved in the polymeric matrix and are useful in forming injectable formulations for the treatment of CNS related diseases.
The following references are disclosed as background.
U.S. Pat. No. 4,389,330 describes a microencapsulation process for the formation of microcapsules laden with an active agent involving a series of steps using a solvent.
U.S. Pat. No. 4,801,460 describes a process for the preparation of solid pharmaceutical forms by an injection molding or an extrusion process.
U.S. Pat. No. 5,360,610 describes polymeric microspheres as injectable, drug-delivery systems for use to deliver bioactive agents to sites within the central nervous system.
U.S. Pat. No. 5,439,688 and references cited therein describe processes for preparing pharmaceutical compositions for the sustained and/or controlled release of a drug using a biodegradable polymer and incorporating as the active substance the salts of a natural or synthetic peptide.
U.S. Pat. No. 5,456,917 describes a method for making an implantable bioerodible material for the sustained release of a medicament.
U.S. Pat. No. 5,456,923 describes a method of manufacturing solid dispersion in which a drug is dissolved or dispersed in a polymer carrier or a diluent. The solid dispersions are formed in a twin screw extruder.
U.S. Pat. No. 5,505,963 describes a method for making a pharmaceutical composition free of organic solvents useful for oral administration. The method employs a solidified granulates of an active ingredient in admixture with a meltable auxiliary substance which is soluble in the active ingredient at elevated temperatures.
J. Controlled Release, 28 (1994) 121-129 describes a review of drug delivery systems using various kinds of biodegradable polymers.
Pharmacy International, (1986), 7 (12), 316-18, describes a review of controlled drug release from monolithic bioerodible polymer devices.
All of the references cited herein are incorporated herein by reference in their entirety.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a melt extrusion method for the formation of microparticles in which the drug molecules are substantially dissolved in the polymer matrix forming a solid solution. It is further an object of the present invention to provide microparticles capable of releasing the drug molecules at a sustained release rate over an extended period of time. Finally, it is also an object of the present invention to provide injectable microparticle formulations for the treatment of various CNS diseases including diseases or conditions treatable by antagonizing the effects of serotonin at the 5HT
2
receptor, such as schizophrenia, obsessive compulsive disorders, sleep disorders, depression, anxiety, anorexia and drug addiction.
Surprisingly, it has now been found that solid solution of a biodegradable polymer and a pharmaceutically active molecule can be made by a melt extrusion process. Some of the advantages gained by the practice of the method of the present invention, individually and/or in combinations, are: a) the pharmaceutically active compound is essentially dissolved in the biodegradable polymer matrix forming a solid solution; b) the compositions of the p
Comiskey Stephen J.
Hanley Stephen J.
Kohn Rachel S.
Aventis Pharmaceuticals Inc.
Gupta Balaram
Pryor Alton
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