DD286509A5 - METHOD FOR THE PRODUCTION OF ACTIVITY-STABILIZED, EFFICIENT-EXPLOSED RECTALLY APPLICABLE INSULIN PREPARATIONS - Google Patents

Abstract

The invention relates to a process for the preparation of activity-stabilized, effect-prolonged rectally administrable insulin preparations from complexes between insulin and polyamine acids, which are used in diabetes therapy. The object of the present invention is achieved by using the polyamine acids having an insulin content of 50-60% together with a resorption mediator * relative to the total suppository mass) in hydrophilic suppositories. Advantages of the invention are that dose savings can be achieved with concomitant prolongation of action. {Rectal Insulin Preparation; Polyamino-insulin complexes; Diabetes therapy; Wirkungsverlaengerung; Dose reduction}

Description

Body weight received. The controls were suppositories same insulin dosage and surfactant concentration, but applied without complexation of the hormone. The blood glucose levels were determined after normalization to the initial fasting blood glucose level using the Fermognost blood sugar control kit

 There was no significant improvement in the blood glucose lowering profile over the control group.

Example 2

According to Example 1, a 20% insulin-polyglycine complex is prepared by suspending 165 mg of polyglycine (M = 4000) in 5 ml of 85% formic acid with the addition of 0.16 ml of insulin solution (250 mg / ml of 85% formic acid). 15.6 mg of the complex thus obtained are suspended in 3 ml of citrate-phosphate buffer and added together with 1.5 g of lauroylleucin to the casting mixture, mixed homogeneously and then poured into suppositories. At an insulin dose of 1.2 ΙΕ / kg, there was no significant change in the blood glucose lowering profile compared to the control group.

Belsptel 3

Analogous to Example 1, a 55% insulin-polyglycine complex was prepared by suspending 260 mg of polyglycine (M = 4000) in

7.5 ml of 85% formic acid with the addition of 1.1 ml of insulin solution (250 mg / ml of 85% formic acid). 5.7 mg of this

Complexes were added to the casting batch as in Example I and shed into suppositories. With an insulin dosage

of 1.2 IU / kg of body weight resulted in a 3-hour blood glucose lowering by 40% upon reaching the initial level

5 hours. The control animals showed a 1-hour glucose lowering by 30% with reaching the initial level

2.5 hours.

Example 4

11.4 mg of a 55% insulin-polyglycine complex and 300 mg of lauroylleucine were added to the suppository formulation in analogy to Example 1 in such a way that suppositories were obtained with a dosage of 10 IU insulin

 After administration, with an insulin dosage of 2.5 IU / kg body weight, the experimental animals showed a 4-hour reduction in blood glucose by 50% when reaching the initial level after 7 hours. In the control experiment, there was a 45% blood glucose reduction over 2 hours after reaching the initial value after 4 hours.

Example 5

To hurl a 55% insulin-polylysine complex, 450 mg polylysine (M = 4000) was dissolved in 20 ml distilled water and 560 mg insulin was added to the solution. It was stirred for a further 30 minutes and then freeze-dried. The inslethal content of the complex was confirmed by amino acid analysis. 11.4 mg of the complex thus obtained were added together with 300 mg of lauroylleucine to the casting batch and worked up as in Example 1. At an insulin dosage of 2.5 ΙΕ / kg body weight, the test animals showed a 60% blood glucose reduction over 3 hours, the initial level after 6 hours was reached again. The control experiment is selected under Example 4-n.

Example β

Suspend 75 mg polyglycine (M = 4000) in 2.5 ml 85% formic acid and add 0.7 ml insulin solution

(250 mg / ml 85% formic acid), a 70% insulin-polyglycine complex was obtained. 8.9 mg of this complex was added to the casting mix as in the example and suppositories were prepared with an insulin dosage of 2.5 ΙΕ / kg, the eight

male rabbits were administered. There was no improvement in the blood glucose reduction profile compared to

Control group.

Claims (2)

For the preparation of activity-stabilized, effect-prolonged, rectally administrable preparations of complexes between insulin and polyamino acids, in particular polyglycine or polylysine having average molecular weights of 2000-4000 and gelatin or agar as suppository base and absorption mediator, characterized in that the polyamino acid with an insulin content of 50-60% and be used as a resorption promoter stearoyl, pajmitoyl or Lauroylaminosäuren. 2. The method according to claim 1, characterized in that 1-5% of the absorption promoter, based on the total suppository mass, are used. Field of application of the invention The invention relates to a process for the preparation of insulin-containing suppositories for diabetes therapy with improved pharmacological properties. Characterization of the known prior art The patent DD 257197 describes a process for the production of immobilized, in their biological activity stabilized and modified in their pharmacological properties insulin preparations whose essential feature is the complexation of the hormone with polyamino acids and is suitable for parenteral administration. For the use of these insulin-polyamino acid complexes for rectally administrable insulin preparations are there additional, this application form specially adapted and not readily apparent prerequisites necessary. Object of the invention The aim of the invention is to develop a production process which makes it possible to obtain especially rectally administrable insulin preparations with improved pharmacological properties. Explanation of the essence of the invention The object of the invention is to develop a process for the preparation of rectally administrable insulin preparations with activity-stabilized and effect-prolonged properties. According to the invention, the object is achieved by using insulin-polyamino acid complexes having an insulin content of 50-60% and an average molar mass of the polyamino acids polyglycine or polylysine of 2000-4000, the respective complex being in a hydrophilic, water-receptive gel, e.g. Gelatin or agar while maintaining neutral pH values are dispersed while maintaining a quantitative ratio, which ensures per dose suppositories S2.5IE insulin / kg body weight. At the same time the overall approach of the suppository base 1-5% of a resorption mediator, in particular by higher fatty acids acylated amino acids such. B. stearoyl, palmitoyl or Lauroylaminosäuren added. Surprisingly, it has been found that only within a narrow range of the variable loading level of the complex and the concentration of resoroption mediator achieved by the immobilization and stabilization effect of the complex compared to suppositories with the same recipe, but with free, not complexed insulin considerable dose saving or extended Wirkgenängert to let. It is characteristic of the process that the pharmacological benefits are achieved only in the specific combination of the claimed composition and thereby a rectal, adapted to the specific clinical needs of diabetics insulin application is possible. Ausführungsbeisplele example 1 For the preparation of insulin-polyglycine complexes 1.9g Poiyglycin (M = 4000) in 57 ml 85% formic acid at 25 ⁰ C (ml 85% formic acid 250mg /) are suspended and 0.4 ml of insulin solution were added. After stirring for 3 minutes, the complex is precipitated with further stirring with 380 ml of absolute ether. Still aspirate the complex is washed 5x with 50ml sbiolutom ether and dried in vacuo over P ₂ O ₅ at 1 Torr and 20 ° C to constant weight. The insulin-polyglycine complexes prepared in this way contain 5% insulin according to amino acid analysis. To prepare the insulin-containing suppositories, a mixture of 7.5 g of glycerol and 8.9 g of citrate-phosphate buffer (pH 7.5) was introduced, 9 g of gelatin were stirred in and allowed to stand for 1 h at room temperature to swell. The mixture is then homogenized at 60 ^c C within 30 minutes, the weight loss added by distilled water and cooled to 40 ° C. The mixture is homogeneously mixed with 1.5 g Lauroyllßucin and stirred under 62.5 mg of the insulin-polyglycine complex of the sieve fraction 0-160pm in 3 ml citrate-phosphate buffer and then poured into suppositories. In the case of male rabbits of about 4 kg body mass of the same breed, the suppositories were applied so that each test animal had an insulin dose of 1.2 IU / kg