Microcapsules for administration of neuroactive agents

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert

Reexamination Certificate

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C424S451000, C424S490000, C424S496000, C424S497000, C514S963000

Reexamination Certificate

active

06517859

ABSTRACT:

It has long been recognized that delivering a drug to its therapeutic site of action within the central nervous system 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 number of methods have been designed to overcome some of these barriers to central nervous system drug delivery as, for instance, the use of liposomes to surmount the blood-brain barrier. However, the disadvantages of a liposome delivery system, including low drug loadings, short duration of action, limited ways to manipulate the rate of drug release, poor storage stability, and problems with scale-up, have precluded the use of such a system. Another method to overcome some of the barriers to central nervous system drug delivery consists of chemically modifying the active drug to a form, called a prodrug, that is capable of crossing the blood-brain barrier, and once across this barrier the prodrug reverts to its active form. One 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.
The most common method to surmount some of the physical barriers preventing drug delivery to the central nervous system has been through the use of pumps. A variety of pumps have been designed to deliver drugs from an externally worn reservoir through a small tube into the central nervous system. Although such pump delivery systems can be externally controlled to a certain degree, the potential for infection directly within the central nervous system is great and the exact site of action of the drug within the central nervous system is largely beyond control.
To be successful, it does not suffice just to deliver the drug within the central nervous system. The drug must be delivered to the intended site of action, at the required rate of administration, and in the proper therapeutic dose. Commercially, the Alzetosmotic mini-pump has become an acceptable, very useful, and successful means of delivering drugs at a controlled rate and dose over extended periods within the central nervous system. However, adapting this device to deliver the desired drug to discrete brain nuclei presents vast difficulties such as implanting cannulas directly within the designated brain regions.
Still another technique that has been developed to deliver neuro-active agents, such as neurotransmitters, to the central nervous system is with the use of neural transplants. Viable neuronal tissue can be implanted directly within discrete brain nuclei. The duration of substance delivery from the transplanted tissue does not present a problem because implanted tissue may survive for a long time in the host's central nervous system. This technique surmounts a number of obstacles cited above, however, despite claims that neuronal grafts from fetal dopamine cells exhibit some of the autoregulatory feedback properties that are normally found in intact dopamine neuronal systems, the exact rate at which the neurotransmitters are delivered from neuronal transplants at their site of action can not be predetermined.
In 1817, James Parkinson described a disease which he termed “shaking palsy”. This condition is presently known as Parkinson's disease and occurs in the middle-aged and elderly. While its onset is insidious, often beginning with tremor in one hand followed by increasing bradykinesia and rigidity, it is slowly progressive and may become incapacitating after several years. In idiopathic Parkinson's disease, there is usually a loss of cells in the substantia nigra, locus ceruleus and other pigmented neurons, and a decrease of dopamine content in axon terminals of cells projecting from the substantia nigra to the caudate nucleus and putamen commonly referred to as the nigrostriatal pathway.
Some symptoms of Parkinson's disease can be treated by the administration of L-3,4-dihydroxyphenylalanine (levodopa or L-dopa). L-dopa, the metabolic precursor of dopamine, is used for replacement therapy because dopamine itself does not cross the blood-brain barrier. However, it must be given in large doses of 3 to 15 grams per day because much of the drug is metabolized before it reaches the site of action in the brain. Alternatively, it is often given in combination with a dopa decarboxylase inhibitor, such as carbidopa, which prevents the metaboligm of L-dopa until it crosses the blood-brain barrier. Its greatest effect is on bradykinesic symptoms. After about five years of treatment, side effects develop and the treatment becomes less and less effective even with increasing doses of the drug. These problems have raised the question of whether or not it would be possible to replace the lost dopamine by other means which would deliver the drug to its therapeutic site of action within the central nervous system.
The discovery that a unilateral lesion of the nigrostriatal pathway by the neurotoxin 6-hydroxy-dopamine produced an asymmetry of movement and posture in the rat, provided an animal model for Parkinson's disease. This asymmetry of movement is employed in the rotometer model developed to measure rotational behavior induced by drugs that interfere with dopamine neurotransmission such as apomorphine. The characteristic apomorphine-induced rotational behavior is only observed in animals with a 90 to 95% reduction of dopamine levels in the striatum, and replacement dopamine in this tissue either by transplants of fetal dopamine-producing cells or adrenal medullary tissue results in significant decreases in apomorphine-induced rotational behavior.
Even though these approaches are well documented for experimental animal models, their use as therapy for neurodegenerative disorders such as Parkinson's disease present a number of practical as well as ethical considerations. Not only is the use of human aborted fetal tissue a controversial issue, but this technique involves complicated surgical procedures. Furthermore, although clinical trials of adrenal and fetal tissue implants in Parkinsonian patients are being conducted, the mechanism and long-term efficacy of tissue transplants within the nervous system remain unclear and is still a matter of medical debate. The best theoretical approach for treatment of such central nervous system pathologies continues to be one which would deliver the biologically active agent directly to the damaged region of the central nervous system.
Although a number of different methods have been proposed and are presently being utilized for the delivery of pharmaceutically active compounds to the central nervous system (as used herein, “nervous system” and “central nervous system” are generally used interchangeably indicating that although one aspect of the present invention is to provide for a means of delivering a neuro-active agent directly into the central nervous system, another aspect is to provide for uptake of the microspheres according to the present invention by astrocytes wherever they may occur in the nervous system), there are sufficient disadvantages to each method that the need for delivering biologically active substances to the central nervous system still exists. The present invention addresses this need in a unique manner.
Broadly defined, the present invention relates, in part, to microspheres that have been developed as injectable, drug-delivery vehicles in which bioactive agents are contained within a polymer compatible with nerve tissues. As used with regard to the present invention, the term microsphere includes microcapsules, nanocapsules, microparticles, nanoparticles and nanospheres.
Microcapsules, microspheres, and microparticles are conventionally free-flowing powders consisting of spherical particles of 2 millimeters or less in diameter, usually 500 microns or less in diameter. Particles less than 1 micron are conventionally referred to as nanocapsules, nanopar

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