Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Patent
1996-03-27
1999-05-11
Webman, Edward J.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
424484, 514944, A61K9/10;47/42;47/36
Patent
active
059026073
DESCRIPTION:
BRIEF SUMMARY
This invention concerns a method for producing a drug system for delivering a drug or other agent for the treatment of a condition in a controlled release manner.
Most known `controlled-release` drug systems are constant slow-release mechanisms (U.S. Pat. No. 4,145,410). These systems do not react to any inherent substances in the body to release the drug appropriately in response to that substance, ie. there is no feedback mechanism. Feedback mechanisms have been suggested to be of interest in vivo to maintain general homeostasis.
U.S. Pat. No. 4,348,387 discloses a feedback controlled insulin delivery system wherein glucose-insulin conjugates are displaced from glucose binding sites on a binding molecule by free glucose. The conjugated insulin retains its biological activity once released. However, it is not known whether other agents or drugs can be so conjugated or whether such a conjugated form of any drug or other agent would be effective.
The present invention provides a delivery system for the controlled release of an unconjugated drug or other agent for possible use in vivo.
According to the present invention there is provided a method for producing a system for delivering a drug for the treatment of a condition, comprising immobilising a drug or other agent in a bio-compatible matrix containing at least one receptor for a physiological substance which will be in the environment of the matrix when administered, said receptor being anchored within the matrix but remaining biologically active being activated in response to the levels of said physiological substance to effect a conformational change in the matrix allowing mobilisation and release of the drug only into the environment.
The agent may comprise a naturally occurring biological agent, for example, a hormone, which may, of course, be insulin, as in U.S. Pat. No. 4,348,387, but now in unconjugated form. Because there is now no need for conjugation, other hormones or drugs which it may not be possible to conjugate or which will not work in the system of U.S. Pat. No. 4,348,387 even if they can be conjugated, or which may be physiologically ineffective or less effective or even harmful when conjugated, may be used according to the invention.
The receptor may be a binding macromolecule, for example, a lectin, which may be concanavalin-A, a lectin produced from the jack bean. Because the binding macromolecule is anchored within the matrix, it is not necessary to enclose the system within a semi-permeable membrane, tube or other device, as is the case in the system of U.S. Pat. No. 4,348,387. Such a method of restraining the drug system may alter the kinetics of the drug releasing mechanism and result in reduced sensitivity. Additionally, should the retaining device disintegrate, toxic lectin molecules would be released into the general circulation. The present invention provides a system which overcomes these disadvantages and allows lectins to be used more safely.
The receptor may reversibly bind the physiological substance, which may be a carbohydrate, preferably glucose, fructose or mannose or a carbohydate polymer containing glucose moieties, such as branched starches, dextrans, mannans and levans or synthetic carbohydrates, for example, ficoll-400, a synthetic polysucrose.
Insulin, or any other agent or drug, may be immobilised in the matrix when terminal glucose molecules on dextran bind to concanavalin-A to form a gel.
Concanavalin-A molecules are anchored within the matrix by covalent bonding to the polymeric chains of dextran without forming insoluble aggregates. Such a system allows maintenance of the structure and function of the matrix. The concanavalin-A may be covalently bonded to the dextran in any conventional manner, for example; dextran, followed by reduction and purification by precipitation;
The conformational change in the matrix may be brought about by the displacement of terminal dextran-glucose molecules from the receptor by free glucose in the physiological environment which may of course be blood or other tissue fluid
De Montfort University
Webman Edward J.
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