Insulin derivatives having a rapid onset of action

Details Insulin derivatives having a rapid onset of action Insulin derivatives having a rapid onset of action

1998-06-18

2001-04-24

Saoud, Christine J. (Department: 1646)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S243000, C435S320100, C435S325000, C536S023510, C530S303000, C514S003100, C514S866000

Reexamination Certificate

active

06221633

ABSTRACT:

The present invention relates to insulin derivatives which, in comparison to human insulin, have an accelerated onset of action, to a process for their preparation and to their use, in particular in pharmaceutical preparations for the treatment of diabetes mellitus.
Approximately 120 million people worldwide suffer from diabetes mellitus. Among these are approximately 12 million type I diabetics, for whom the administration of insulin is the only therapy possible at present. The affected people are assigned insulin injections, as a rule several times daily, for life. Although type II diabetes, from which approximately 100 million people suffer, is not fundamentally accompanied by an insulin deficiency, in a large number of cases, however, treatment with insulin is regarded as the most favorable or only possible form of therapy.
With increasing length of the disease, a large number of the patients suffer from so-called diabetic late complications. These are essentially micro- and macrovascular damage, which depending on the type and extent, result in kidney failure, blindness, loss of extremities or an increased risk of heart/circulation disorders.
As a cause, chronically increased blood glucose levels are primarily held responsible, since even with careful adjustment of the insulin therapy a normal blood glucose profile, such as would correspond to physiological regulation, is not achieved (Ward, J. D. (1989) British Medical Bulletin 45, 111-126; Drury, P. L. et al. (1989) British Medical Bulletin 45, 127-147; Kohner, E. M. (1989) British Medical Bulletin 45, 148-173)
In healthy people, insulin secretion is closely dependent on the glucose concentration of the blood. Increased glucose levels, such as occur after meals, are rapidly compensated by an increased release of insulin. In the fasting state, the plasma insulin level falls to a basal value, which is sufficient to guarantee a continuous supply of insulin-sensitive organs and tissue with glucose. An optimization of the therapy, the so-called intensified insulin therapy, is today primarily aimed at keeping variations in the blood glucose concentration, especially deviations upward, as low as possible (Bolli, G. B. (1989) Diabetes Res. Clin. Pract. 6, p. 3-p. 16; Berger, M. (1989) Diabetes Res. Clin. Pract. 6, p. 25-p. 32). This leads to a significant decrease in the occurrence and the progression of diabetic late damage (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986).
From the physiology of insulin secretion, it can be deduced that for an improved, intensified insulin therapy using subcutaneously administered preparations, two insulin preparations having different pharmacodynamics are needed. To compensate the blood glucose rise after meals, the insulin must flow in rapidly and must only act for a few hours. For the basal supply, in particular in the night, a preparation should be available which acts for a long time, has no pronounced maximum and only infuses very slowly.
The preparations based on human and animal insulins only fulfill the demands of an intensified insulin therapy, however, in a restricted manner. After subcutaneous administration, rapidly acting insulins (unmodified insulins) pass too slowly into the blood and to the site of action and have too long an overall duration of action. The result is that the postprandial glucose levels are too high and the blood glucose begins to fall severely several hours after the meal (Kang, S. et al. (1991) Diabetes Care 14, 142-148; Home, P. J. et al. (1989) British Medical Bulletin 45, 92-110; Bolli, G. B. (1989) Diabetes Res. Clin. Pract. 6, p. 3-p. 16). The available basal insulins in turn, especially NPH insulins, have too short a duration of action and have a too severely pronounced maximum.
Beside the possibility of affecting the profile of action by means of pharmaceutical principles, the alternative presents itself today of designing insulin derivatives, with the aid of genetic engineering, which achieve specific properties such as onset and duration of action solely by means of their structural properties. By the use of suitable insulin derivatives, a significantly better adjustment of the blood glucose more closely adapted to the natural conditions could therefore be achieved.
Insulin derivatives having an accelerated onset of action are described in EP 0 214 826, EP 0 375 437 and EP 0 678 522. EP 0 214 826 relates, inter alia, to substitutions of B27 and B28, but not in combination with the substitution of B3. EP 0 678 522 describes insulin derivatives which have various amino acids, preferably proline, but not glutamic acid, in the position B29. EP 0 375 437 encompasses insulin derivatives having lysine or arginine in B28, which can optionally be additionally modified in B3 and/or A21.
EP 0 419 504 discloses insulin derivatives which are protected against chemical modifications by changing asparagine in B3 and at least one further amino acid in the positions A5, A15, A18 or A21. Combinations with modifications in positions B27, B28 or B29 are, however, not described. An indication that these compounds have modified pharmacodynamics resulting in a more rapid onset of action is not given.
WO 92/00321 describes insulin derivatives in which at least one amino acid of the positions B1-B6 is replaced by lysine or arginine. According to WO 92/00321, insulins of this type have a prolonged action. Combinations with modifications of the positions B27, 28, 29, however, are not disclosed.


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