Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1994-07-22
2001-11-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S400000, C424S423000, C424S468000, C424S486000, C424S487000, C424S488000
Reexamination Certificate
active
06322815
ABSTRACT:
BACKGROUND OF THE INVENTION
The blood-brain barrier, which results from the low permeability of brain capillaries to most drug molecules, prevents systemically delivered agents from reaching the parenchymal tissue of the brain. Because of this barrier, conventional modes of drug delivery often fail to provide therapeutic drug doses to the brain. Recently, implantable or injectable polymeric controlled release systems have been developed for achieving high concentrations of agents within the brain tissue over an extended period of time (Sabel, et al., 1989
, Annals of Neurology
, 25:351-356; Saltzman, et al., 1991
, Chemical Engineering Science
, 46:2429-2444; Reinhard, et al., 1991
, Journal of Controlled Release
, 16:331-340; Brem, et al., 1991
, Journal of Neurosurgery
, 74:441-446; Powell, et al., 1990
, Brain Research
, 515:309-311). Controlled release polymers are designed to release precisely defined quantities of agents over an extended period. When these polymeric systems are inserted directly into the brain tissue, they release a biologically active agent into the brain extracellular space—already past the blood-brain barrier—where they can diffuse within the tissue and provide their therapeutic effect.
While controlled release may be important for treating certain disease of the brain with some specific agents, it has important limitations. Therapeutic agents are released into the brain extracellular space. To be effective, the released agent must diffuse within the extracellular space to reach its site of action. In many cases, this site of action may be many millimeters or centimeters from the polymer matrix. Unfortunately most agents of interest will be removed from the brain by the capillary system or destroyed by brain metabolic processes before they can diffuse far enough to be effective. For example, five chemotherapeutic compounds (hydroxyurea, MTX, thiotepa, BCNU, and cytosine arabinoside) penetrated only 1-5 mm from the ependymal surface following intrathecal perfusion (Blasberg, et al., 1975
, J. Pharmacol. Exp. Ther
., 195:73-83). Autoradiography following surgically implantation of degradable radiolabeled BCNU-loaded polymers in rabbits revealed that the bulk of the BCNU was within several mm of the implant site (Grossman, et al., 1992
, J. Neurosurg
., 76:640-647). Similarly, the diffusion distance for cisplatin was <1 mm following direct microinfusion in the rat brain (Morrison, et al., 1986
, J. Pharm. Sci
., 75:120-128). These small penetration distances for anticancer drugs in brain tissue may limit the effectiveness of polymer matrices for tumor therapy. This limitation may be particularly significant for the treatment of glioblastoma, which can recur several cm from the original primary tumor site (Hochberg, et al., 1980
, Neurology
30:907-911).
Thus there is a need in the art for drug delivery vehicles which achieve a larger area of penetration of drug than simple drug-releasing polymer matrices.
SUMMARY OF THE INVENTION
It is an object of the invention to provide an implantable multipart drug delivery system having a reduced rate of drug elimination from its target tissue and an enhanced penetration volume from its implantation site relative to free drug.
It is another object of the invention to provide a method of treating a human having a brain disease.
It is yet another object of the invention to provide a drug-polymer conjugate for delivering free drug to the extracellular space of a tissue with a reduced rate of elimination.
It is still another object of the invention to provide a method for administering intrathecal therapy.
These and other objects of the invention are provided by one or more of the embodiments described below. In one embodiment of the invention an implantable multipart drug delivery system is provided. The system provides a reduced rate of drug elimination from its target tissue and an enhanced penetration volume from its implantation site relative to free drug. The system comprises:
(a) a drug covalently attached via a hydrolytically labile bond to (b) a water soluble, high molecular weight first polymer, forming a first drug-polymer conjugate, said conjugate being incorporated in (c) a controlled-release matrix comprising a biocompatible second polymer.
In another embodiment of the invention a method of treating a human having a brain disease is provided. The method comprises: implanting into the brain of said human a multipart drug delivery system having a reduced rate of drug elimination from its target tissue and an enhanced penetration volume from its implantation site relative to free drug. The multipart drug delivery system comprises: (a) a drug covalently attached via a hydrolytically labile bond to (b) a water soluble, high molecular weight first polymer forming a first drug-polymer conjugate, said conjugate being incorporated in (c) a controlled-release matrix comprising a biocompatible second polymer.
In still another embodiment of the invention a method of performing intrathecal therapy is provided. The method comprises the step of:
administering directly to an intrathecal space a drug-polymer conjugate, said drug-polymer conjugate providing a reduced rate of drug elimination from its target tissue relative to free drug, said drug-polymer conjugate comprising: (a) a drug attached via an hydrolytically labile bond to (b) a water-soluble, high molecular weight polymer.
These and other embodiments of the invention provide the art with the means to treat more effectively localized and disseminated diseases which respond to sustained exposure to therapeutic agents.
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Yang et al.
Colvin O. Michael
Dang Wenbin
Ludeman Susan
Saltzman W. Mark
Banner & Witcoff
Page Thurman K.
Tran S.
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