Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Patent
1996-12-02
1999-08-03
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
424484, 424488, 424490, 424494, A61K 916, A61K 4748
Patent
active
059322489
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the controlled release of active compounds, particularly pharmaceutically active compounds. More particularly, it relates to the use of the interaction of a complexing agent with a pharmaceutically active compound or other active compound as a release control mechanism, in combination with an ionic polymer supporting matrix, for example to improve targeting of the pharmaceutically active compound to the desired site of action of the compound.
BACKGROUND OF THE INVENTION
In its broadest aspect, the present invention extends to a preparation for the controlled release of any chemical compound which has a particular activity, for example in the industrial or agricultural fields as well as in the medical and veterinary fields.
The present invention is described in detail herein with particular reference to the targeting of cytotoxic or cytostatic drugs, particularly the anticancer drugs doxorubicin (DOX) and cisplatin (CDDP), to a tumour site in a human or animal patient, however it will be understood that the present invention is not restricted to delivery of these particular anticancer drugs and in one preferred aspect extends to the delivery of any pharmaceutically active compound. As noted above, in its broadest aspect this invention extends to the controlled release of active compounds in general.
The incorporation of active cytotoxic drugs into controlled release matrices has been demonstrated to have potential useful applications for the treatment of cancer. These drug-polymer complexes can be administered by either direct injection into the tumour, or by embolisation in the form of microspheres into the arterial circulation of the target organ containing the tumour. Both embolisation into the arterial circulation and direct injection into solid tumour deposits are recognised forms of regional cancer therapy.sup.1.2. In the situation where the drug-polymer complex is embolised into the arterial circulation of a cancer bearing organ, the drug-polymer complex is manufactured in the form of small particles or microspheres, usually in the size range of 10-200 micron in diameter. When the drug-polymer complex is administered directly into the tumour, the same formulation may be used but without the necessity to form microspheres.
There are two basic requirements for this form of therapy to be effective. First, there is a need to localise sufficient quantities of the drug at the target site to have the desired cytotoxic effect. Second, there is a need to control the rate of delivery into the tumour milieu that will cause maximal cell destruction. To achieve these, it is essential to design or develop a polymer matrix system that can carry a high load of cytotoxic drug as well as provide a controlled or sustained drug release profile.
This often poses a problem for the formulation of sustained release matrices. It is frequently observed that matrices with a high drug loading release the drug rapidly, known as a "burst release" effect. This is most likely a result of weak bonding or superficial location of drug during the formulation of the high loading matrix. The conventional approach of using a coating technique may sustain the release of drug, but usually decreases the drug loading of the system.sup.3.
In the treatment of patients with cancer using regional chemotherapy, it is desirable for the drug-polymer complex to be degradable so that repeated doses can be given. Therefore, it is necessary to also construct a drug-polymer complex that will degrade within the tissues of the body.
For a sustained/controlled release system, the rate of drug release is determined to a large extent by the interaction between the drug and polymer matrices which is influenced by the method of drug incorporation. Drugs usually can be incorporated into the controlled release systems by the following simplified means: physical entrapment, ionic interaction and covalent binding. Physical entrapment allows medium to high drug loading but usually drug releases too rapidly. Ionic
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Chen Yan
Gray Bruce Nathaniel
Page Thurman K.
Paragon Medical Limited
Seidleck Brian K.
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