Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1996-10-25
2004-07-13
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S499000, C424S464000, C424S444000, C424S426000, C424S428000, C424S045000
Reexamination Certificate
active
06761908
ABSTRACT:
A number of polymers are used in the production of administration forms for pharmaceutical or cosmetic active substances. Depending on the site of application, these are used to impart to the respective administration form the desired properties. Agents for the treatment of wounds and implantable materials should be adapted to the surface of the respective application site, and they should not interfere with the function and activity of body cells, such as keratinocytes, fibroblasts, or endothelial cells. In these cases the spectrum of suitable polymers is therefore limited to those having an excellent compatibility on contact with connective tissue and which preferably are biodegradable.
For quite a long time now, collagen, the main protein of the connective tissue, has gained a special place among the polymers suitable for this purpose. This is due to the biological compatibility and degradability of the administration forms produced therefrom. Such collagen preparations are for the most part used as wound dressings without any additional additives. However, there have also been attempts to charge collagen matrices of most different kinds with biologically active substances and to influence the release of these substances, which in general follows the dissolution and/or enzymatic degradation of the collagen carrier matrix, by the kind, structure and composition of the matrix.
To produce collagen matrices—such as those described in, for example, U.S. Pat. No. 5,024,841, U.S. Pat. No. 4,789,663, U.S. Pat. No. 4,774,091, U.S. Pat. No. 4,563,350 U.S. Pat. No. 5,246,457, or EP 429 438—solutions of telopeptide-free, acid-soluble collagen are used in general. These are used to obtain reconstituted fibrils by means of dialysis, shift of the pH, or other processes; and these fibrils are then processed by means of different methods into preferably porous matrices. These preparations can exhibit an excellent biocompatibility since they consist of pure collagen, but they have the disadvantage that a retardation of the active substance release is limited owing to the use of soluble collagen.
Such a release retardation can be achieved by decreasing the solubility of the collagen matrix by using cross-linking agents or binders, as is described, for example in U.S. Pat. No. 4,409,332, DE 2 843 963, WO 93/00890, or WO 85/04413, or by using coating agents, e.g., described in DE 38 41 397, or by combining water-soluble collagen with other polymers, preferably natural anionic polymers or their derivatives. However, owing to the additional components, additional toxicological risks which, in particular when the known cross-linking agents for collagen are used, should not be underestimated must be accepted in each of these cases.
Another possibility of delaying the active substance release is described in EP 518 697. Here, laminates are produced from water-soluble and/or water-insoluble collagen, which consist of one or several active substance-containing reservoir layers and one layer retarding the active substance supply. As compared to the above-mentioned preparations, a retardation of the release while minimizing the toxicological risks could be achieved with such laminates. However, they have the disadvantage that their production is extremely expensive and that the adherence of the layers can only be achieved with “moist” films. Dry films which are absolutely necessary in case of active substances susceptible to decomposition cannot be joined to form such laminates, for example.
However, a retardation of the active substance release is not always desired. EP 224 453 describes a collagen matrix which mainly consists of water-insoluble, reticulated collagen and additionally comprises water-soluble, non-reticulated collagen. In cosmetic preparations, e.g., face packs, said soluble collagen serves as active substance which, after application, is dissolved out by means of the natural cutaneous moisture or by extremely moistening the preparation which then takes effect on the skin. For pharmaceutical purposes, active substances can be incorporated into the preparation, these are then dissolved out and released from the collagen matrix together with the soluble collagen very quickly after application. Such a collagen preparation can be useful in cases where a rapid release is desired and appropriate.
Mechanisms to delay or accelerate the active substance release from collagen preparations have been described in many ways. However, due to the given composition, each of these prior art collagen preparations offers only one possibility of influencing the release, and therefore they have a given release profile each tailor-made to one specific problem, e.g., a certain active substance or certain active substance group, a certain therapeutic principle, or a certain disease. None of the prior art collagen preparations can achieve a selective and at the same time manifold control of the active substance release, i.e., permit a variable and individual adaptation of the release kinetics of active substances to differing problems, wherein factors, such as different active substance properties and differences in the onset and duration of action, can be considered adequately for each case.
Accordingly, it was the object of the present invention of find a collagen preparation which is not only suitable for a certain active substance, a certain active substance combination, or a certain release profile, but also permits—for a great variety of uses—a wide-ranging, reliable control of the active substance release adapted to the respective problem.
Most surprisingly, the solution of this object has been found in a collagen preparation for the controlled release of active substances, comprising mixtures of acid-insoluble collagens having different molecular weight distributions.
According to one embodiment, the collagen preparation comprises different active substances. It may additionally comprise adjuvants, such as viscosity regulators, binders, humectants, softening agents, penetration enhancers, preservatives, disinfectants, pH-regulators, antioxidants, active substance stabilizers, oils, fats, waxes, emulsion stabilizers, odorous substances, dyes, and/or inert fillers.
According to a preferred embodiment, the insoluble collagen is telopeptide-free, native, uncross-linked Type-1-collagen. This may be an insoluble collagen which is a product obtained from calfskin by means of alkaline decomposition.
Furthermore, the collagen preparation may be present in the form of powders, dusts, microparticles, fibers, flakes, foams, sponges, needles, small rods, tablets, gels, creams, single-layer films, or laminates.
Advantageously, the collagen preparation may include combinations of different administration forms to achieve the desired release kinetics.
It is preferred that the collagen preparation be bioadhesive.
A process for the production of the collagen preparation may comprise spray drying, freeze-drying, coating or casting with subsequent drying, phase separation and coacervation processes, compression, or filling into containers.
According to the process, the active substance release can additionally be influenced and/or controlled by the mixing ratio of acid-insoluble collagens with different molecular weight distributions. According to the process, the active substance release can additionally be controlled by dissolution, swelling, or erosion of the collagen preparation. Another possibility of controlling the active substance release is by biological degradation of the collagen preparation.
The use of the collagen preparation according to the present invention consists in the controlled release of the active substance to wounds. However, the use may also be directed to the controlled release of active substances to intact skin. Finally, the use of the collagen preparation may serve to implant or inject active substances into a living organism.
In general, prior art collagen preparations for the active substance release are produced from acid-soluble collagen, that is collagen which is dissolved clearly in dilu
Lohmann & Rauscher GmbH & Co. KG
Webman Edward J.
Wenderoth , Lind & Ponack, L.L.P.
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