Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1987-01-28
1991-07-02
Moezie, F. T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 4, 514866, 530303, A61K 3702, A61K 3726, C07K 740
Patent
active
050285866
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel insulin derivatives and to insulin preparations showing protracted action and comprising at least one of the novel insulin derivatives and, if desired, a fast acting insulin.
BACKGROUND ART
In severe or chronic cases the disease of Diabetes is usually treated with injection preparations containing insulin, e.g. porcine insulin, bovine insulin or human insulin. Soluble insulin preparations are usually fast acting, but in return the action ceases after few hours. Therefore, it is necessary to give frequent injections, normally several times a day.
In order to overcome this disadvantage insulin preparations with protracted action have been formulated so that the action is maintained for several hours or even up to 24 hours or longer. Using such protracted preparations some diabetic patients only have to receive a small number of injections, e.g. a single or two injections during 24 hours.
Such a protracted action can be achieved by converting the insulin to a slightly soluble salt, such as zinc insulin or protamin insulin. The slightly soluble insulin salts are used in the form of suspensions from which the insulin is gradually released e.g. after subcutaneous injection.
Recently other methods have been invoked to achieve a protracted action. An example hereof is the encapsulation of insulin crystals in polymerized serum albumin. Another example is continuously acting infusion devices, so-called insulin pumps, which however may be uncomfortable and entail a risk to the patient.
The specifications of Danish patent applications No. 3582/84, No. 3583/84 and No. 3757/84 disclose the preparation and use of insulin derivatives wherein the C-terminus of the B-chain is extended with an organic group carrying at least one positive charge, preferably Arg--OH or Arg--Arg--OH. Preparations containing suspensions of such insulin derivatives exhibit a protracted action.
However, the preferred methods for preparing the insulin derivatives disclosed in the specification of Danish patent application No. 3582/84 in an industrial scale involve the use of trypsin-like enzymes which implies that enzymatic activity may contaminate the final preparations, cf. examples of execution in the specification of Danish patent application No. 3757/84. The protracted action of the above-mentioned insulin derivatives wherein the C-terminus of the B-chain is extended with an organic group carrying at least one positive charge results exclusively from the extension of the B-chain. However, the extended B-chain is sensitive to enzymes which cleave the B-chain, especially at B29-lysine, and consequently, the protracted action may be reduced and even abolished. This enzymatic cleavage can also take place after subcutaneous injection, cf. the specification of Danish patent application No. 3583/84, page 15, line 18. As a result of the enzymatic activity the protracted action of the preparations containing the above-mentioned insulin derivatives wherein the C-terminus of the B-chain is extended with an organic group carrying at least one positive charge may vary considerably.
DISCLOSURE OF THE INVENTION
It has now surprisingly been found that by the use of insulin derivatives, wherein one or more of the four amino acid residues of positions A4, A17, B13 and B21 comprise an uncharged side chain, in insulin preparations, in particular injection preparations, a hitherto unknown and desirably long-lasting protracted action is achieved.
Accordingly, the invention relates to insulin derivatives wherein one or more of the four amino acid residues of positions A4, A17, B13 and B21 comprise an uncharged side chain.
The invention relates specifically to insulin derivatives wherein one or two of the four amino acid residues of positions A4, A17, B13 and B21 comprise an uncharged side chain.
The invention relates in particular to insulin derivatives in which one of the four amino acid residues of positions A4, A17, B13 and B21 comprises an uncharged side chain.
The invention relates particularly to in
REFERENCES:
patent: 3903068 (1975-09-01), Ruttenberg
patent: 4320196 (1982-03-01), Morihara et al.
patent: 4320197 (1982-03-01), Morihara et al.
Daniel Levy, Biochimica et Biophysica Acta, 310 (1973), pp. 406-415.
Balschmidt Per
Hansen Finn B.
Moezie F. T.
Novo Norkisk A/S
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