Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1999-07-16
2003-04-01
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S400000, C424S452000, C424S443000, C514S773000
Reexamination Certificate
active
06541031
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a further development in the area of active substance systems with delayed and gentle release of active substances from a carrier material, in particular from the sector of medical and/or biological products. Combination materials of this type, in particular from the sector both of pharmaceutical ancillary substances and biological preparations, for example crop protection agents, are the subject of numerous investigations and printed publications. They are referred to, for example, by the terms controlled release systems, depot or slow release materials or, very generally, as compositions with delayed release of product.
DESCRIPTION OF THE RELATED ART
The release-controlling action can be brought about for example, by a coating process in which granules or a tablet which has already been shaped is coated with an enveloping layer through which the active substance diffuses over a lengthy period (compare, for example, DE-A 4239244). In order to achieve release of active substance which is controlled as possible, U.S. Pat. No. 3,916,899 describes, for example, a release-controlling form for active substances in which the active substance reservoir is surrounded by a semipermeable coating layer which is impermeable to the active substance but permeable to the particular liquid in the surrounding medium. The surrounding coating layer additionally contains a geometrically well-defined orifice through which the active substance, which is dissolved in the surrounding liquid, can reach the outside. After the composition is taken, the digestive fluids diffuse through the semipermeable coating layer into the interior of the capsule. The active substance in the interior of the capsule is continuously dissolved in the in flowing liquid and reaches the outside through the geometric orifice in the coating layer at a defined rate.
However, with this system there is repeatedly local irritation of the tissue in the gastric or intestinal tract, depending on the capsule contents employed, due to elevated concentrations. In addition, part of the active substance as a rule remains in the medicinal form and is thus not available for the desired absorption. In addition, the production of the release-controlling form is very elaborate because the coating layer must be provided with the defined orifices.
In another process, the depot materials consist of a carrier with or without its own action, into which the product which is to undergo delayed release is incorporated. Particular attention has been paid in the literature in recent years to polymeric compounds based on polyesters from lower hydroxy carboxylic acids with, in particular 2-6 C atoms in the hydroxy carboxylic acid molecule as carrier material. Carrier materials of this type are in turn labile to hydrolysis and subject to biological mechanisms.
From the recent relevant literature, reference may be made, for example, to U.S. Pat. No. 4,011,312 which discloses solid formulations of copolyesters of glycolic acid and lactic acid with molecular weights below 2,000 as carrier material mixed with antibiotic active substances such as tetracycline, neomycin and other antibiotics. Numerous investigations deal with the use of absorbable polyesters based on glycolic acid/lactic acid as carrier material with delayed release of active substance (compare, for example, D. L. Wiese et al. in: Drugs Carriers in Medicine Academic Press London 1979, pages 237-270).
A specific manner of controlling release by means of carrier-bound active substances is disclosed in DE-A 4413350. This describes a controlled release form in which the active substance is embedded in a mixture of a water-insoluble polymer, a lipid and a polymer which is soluble in water to form a highly viscous colloid, forms a gel or is at least able to swell in water. The basic principle of the polymer matrix described therein is a matrix which is classified by suitable lipophilic substances and consists of a polymer which is insoluble in water and gastrointestinal fluids. Additionally incorporated into this matrix of insoluble polymer and lipophilic component is a gel former, that is to say a polymer which forms a highly viscous solution, or is at least able to swell, in water. This gel former brings about breaking open of the release-controlling matrix by the swelling on contact with gastric fluid, so that the active substance can be released.
A disadvantage of this design of a controlled release form is the very complicated mode of production, in particular the matching of the various components responsible for the release-controlling action. An additional factor is that all the controlled release forms hitherto described reach the stomach in the form of small-volume structures and, as a rule, their volume does not increase considerably there either. The medicinal compositions may therefore be deposited in folds of the intestine and the stomach. The consequence may be irritation or even perforation of the gastric and intestinal walls. In addition, with the small-volume medicines hitherto, there is not the required uniform distribution of the delayed released active substances in the gastrointestinal tract.
SUMMARY OF THE INVENTION
It is accordingly an object of the present invention to provide a composition with delayed and gentle release of the active substances, containing a swelling carrier material which is insoluble, or soluble after a delay, in water and gastrointestinal fluids, active substances and where appropriate, conventional ancillary substances and, where appropriate, a coating which is soluble in water and gastrointestinal fluids, which does not have the disadvantages described for controlled release forms hitherto. In particular, the intention is that the composition prevent, by its large-volume form, local irritation occurring due to deposition on the walls of the stomach and intestine. In addition, the intention is to achieve distribution of the released active substances over an area as large as possible in the gastrointestinal tract.
This object is achieved by a composition which is obtainable by a large-volume, sponge-like structure of a carrier material which is loaded with active substance being partly compressed to various shapes and, where appropriate, being provided with the coating.
Sponge-like structures mean according to the invention foams which consist of gas-filled spherical/polyhedral cells which are limited by highly viscous or solid cell walls. It is possible to employ according to the invention both naturally occurring sponges and synthetically produced sponge-like structures.
The sponge-like structures are produced by methods known per se from the state of the art. Depending on the starting material employed, in the simplest case a foam can be obtained by blowing in, by beating, shaking, spraying or stirring in the relevant gas atmosphere. In the case of polymers, the foam structure arises due to chemical reactions. Thus, polyurethanes are foamed by adding blowing agents which decompose at a particular temperature during the processing to form a gas, or by adding liquid solvents during the polymerization. The foaming takes place either on leaving the extrusion die, that is to say following the extrusion or injection moulding or in open moulds. Curing takes place under the conditions characteristic of the particular chemical compound of the carrier material.
An indispensable prerequisite for the employability of the carrier material according to the invention and of the sponge structure is that the material can be compressed without the cell walls breaking. This is because in order to be able to employ the carrier material according to the invention for a composition, the foam-like carrier material must be compressed to a size which is suitable for oral or enteral administration. The carrier material is normally compressed to a volume not exceeding 2 cm
3
. For usual dosage forms the volume should be below 3 cm
3
.
The compression consists of the carrier material being pressed or compressed in a
Kueffner Friedrich
Webman Edward J.
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