Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-08-10
2000-07-18
Lilling, Herbert J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 23, 536 3, 5361231, 424 937, 424445, 435101, 435174, 435178, 435180, 43524022, 435182, 426573, A23L 105, C08B 3704, A61L 1500, A01N 4304
Patent
active
060907932
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a non-mitogenic substance using guluronic acid or mannuronic acid, its preparation and use.
According to standard terminology, the term mitogenic defines those substances that stimulate the division of cells which would otherwise (i.e., without the influence of this substance) not divide. The reactions thereby triggered in the organism are abnormal and may manifest as allergic, immunologic and pyrogenic (inflammatory) reactions. It requires no further explanation that the development and production of non-mitogenic substances are of the greatest interest for the contact with living organisms in biology and medicine.
In the area of implant surgery, the application of non-mitogenic substances is of the greatest importance in order to suppress immunologic reactions that would otherwise be induced causing a rejection of the implant. In the treatment of numerous illnesses, living cells are introduced into the organism which, on the one hand, are supplied with nutrients and, on the other hand, compensate for an underproduction or complete failure of intrinsic cells by producing cell secretions, hormones, etc., according to the individual requirements.
One of the best known illnesses of this type is diabetes. Although the deficiency of insulin can be adjusted by well-dosed exogenous administration in timed intervals, it should be noted that an exact 24-h dosage in the sense of a regulating mechanism can never be achieved, so that fluctuations and deviations from the ideal level are inevitable. This disadvantage can be corrected by implanting living cells into the organism. In order to suppress immunologic reactions, however, the cells must be placed in capsules which, in turn, must meet the following requirements: uninhibited diffusion through the walls to permit the supply with nutrients on the one hand, and the release of the cell secretions, hormones, etc. on the other hand, must be ensured. In addition, it must be ensured that the implant does not cause immunologic reactions (i.e., it must be non-mitogenic), which would manifest in a fibrotic growth on the capsule surface after a certain period of time, obstructing the required circulation and exchange of nutrients and cell secretions.
The objective of this invention is the development, preparation and application of a non-mitogenic substance which does not cause allergic, immunologic and pyrogenic reactions, even after prolonged contact with the living organism.
According to the invention, this objective is met with copolymers of a molecular weight between 10,000 and 500,000 dalton, which consist of 10 to 90 mol % of guluronic acid, each supplemented to 100% with mannuronic acid.
The only component of the non-mitogenic substance may be a copolymer of guluronic acid and mannuronic acid with a molecular composition of 10 to 90 mol % of guluronic acid and the remainder being mannuronic acid. Because of the given molar ratio of both acids, the size of the copolymer that is formed during polymerization has not been determined. Consequently, copolymers with a low molecular weight which do not meet the requirements can also be identified. Therefore, an additional requirement is a molecular weight of the copolymer between 10,000 and 500,000 dalton. Such molecular weights are relatively easy to obtain by dialysis using membranes and filters with suitable permeability and pore radius.
Non-mitogenicity is determined by testing the substance that was polymerized with calcium for in vitro induction of measurable proliferation of spleen lymphocytes. For this purpose, splenocytes are collected from mice of the inbred strain Balb-c. Cells at a count of 1.multidot.10.sup.6 ml.sup.-1 were cultivated at 37.degree. C. in the presence of 100 .mu.g ml.sup.-1 of the mitogenic substance in the following growth medium: RPMI 1640 medium, 10% fetal bovine serum (Boehringer, Mannheim, Germany), 2 mM L-glutamine, 2 mM sodium pyruvate, non-essential amino acid (1x, Boehringer, Mannheim, Germany), 50 .mu.M 2-mercaptoethanol, 100 units ml.sup.-1 of penicillin and 1
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Federlin Konrad
Klock Gerd
Zekorn Tobias
Zimmermann Ulrich
Lilling Herbert J.
Monsanto Europe S.A.
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