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Insoluble insulin compositions

An insulin analog, insulin technology, applied in the direction of insulin, drug combination, hormone peptide, etc., can solve the problems of insufficient time effect, inability to provide, poor effective insulin, etc.

Inactive Publication Date: 2000-12-13
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the time action of these formulations may not be long enough, or flat enough, to provide ideal basal control, and they are less effective than insulin, requiring administration of larger amounts of the drug [Radziuk, J. et al., Diabetologia41: 116-120, 489-490 (1998)]

Method used

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  • Insoluble insulin compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0324] In vivo testing in diabetic dogs

[0325] Suspension formulations containing microcrystals prepared as described in any of the preparations herein are tested for prolonged action by comparing their ability to control hyperglycemia with that of a control compound in diabetic dogs. A once-daily dose of about 0.2 units / kg body weight is used. This dose is equal to about 1.2 nmol / kg. On the test day, blood glucose was monitored for 24 hours after subcutaneous injection of the suspension formulation. Control compounds were human insulin and NPH human insulin. The microcrystalline suspension formulations of the present invention will lower blood glucose levels and have a prolonged duration of action compared to human insulin NPH when tested at comparable doses.

Embodiment 2

[0327] Temporal effects of crystalloids in rats

[0328] To 1.898 ml of the crystal formulation prepared according to Preparation 19, add 3.102 ml of diluent (16 mg / ml glycerol, 20 mM TRIS, 1.6 mg / ml m-cresol, 0.65 mg / ml phenol, 40 mM trisodium citrate, pH 7.4) . This provided 5 ml of the U40 formulation, which was tested in BBDP / Wor rats, a genetically characterized animal model developed by the University of Massachusetts Medical Center (Worchester) in association with Biomedical Research Models, Inc. (Rutland, MA). , MA) to maintain and provide. The DPBB / Wor rat line is diabetic, exhibiting insulin-dependent (autoimmune) diabetes.

[0329] 40 BBDP / Wor rats [20 males / 20 females, 4-5 months old, maintenance long-acting insulin (PZI)] were randomly assigned to generate 8 experimental groups - A, B, C, D, E, F , G and H. Group A (5 males) and Group B (5 females) were tested for 2 days with U40 human insulin ultra-low composition with 2.5 mg / ml zinc. Group C (5 ...

Embodiment 3

[0332] Temporal effects of crystalloids in rats

[0333] The above test procedure in Example 2 was repeated with a second 5 ml sample of the U40 suspension formulation prepared as described above.

[0334] 35 BBDP / Wor rats [18 males / 17 females, 4-5 months old, maintenance long-acting insulin (PZI)] were randomly assigned to generate 6 experimental groups - I, J, K, L, M and N . Group I (8 males) and Group J (8 females) were tested for 3 days with the crystal formulation according to the invention as described above in this example. Group K (5 males) and Group L (4 females) were tested for 3 days with U40 human insulin ultra-low composition with 2.5 mg / ml zinc. Group M (5 males) and Group N (5 females) were tested with U40 beef-pork PZI insulin (PZI) for 3 days. Before measuring blood glucose and on the day of measuring blood glucose, each rat was injected with its preparation every day for 3 days.

[0335] Blood was obtained half an hour before administration...

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Abstract

The present invention relates to an insoluble composition comprising an acylated protein selected from the group consisting of acylated insulin, acylated insulin analogs and acylated proinsulin and preparations thereof. The formulations are suitable for parenteral or other delivery to a patient for prolonged control of blood glucose levels. More specifically, the present invention relates to compositions comprising an acylated protein complexed with zinc, protamine and a phenolic compound such that the resulting microcrystals resemble the neutral protamine zinc (NPH) insulin crystalline form. Surprisingly; this acylated protein composition has been found to have therapeutically superior subcutaneous release pharmacokinetics, and longer and flatter glucose kinetics than currently marketed NPH insulin formulations. Furthermore, the crystals of the present invention retain some of the advantageous properties of NPH crystals, namely being able to be easily resuspended and also mixed with soluble insulin.

Description

[0001] This application claims priority to US Provisional Application Serial No. 60 / 063104, filed October 24, 1997, and US Provisional Application Serial No. 60 / 088930, filed June 11, 1998. Background of the invention [0002] 1. Field of invention. The present invention belongs to the field of human medicine. More specifically, the invention is in the field of drug treatment of diabetes and hyperglycemic disorders. [0003] 2. Description of related technologies. The goal of insulin therapy has long been to mimic the endogenous insulin secretion pattern in normal individuals. Physiological daily insulin requirements fluctuate and can be divided into two periods: (a) the absorption phase, which requires pulses of insulin to deal with meal-related blood glucose surges, and (b) the post-absorption phase, which requires continuous delivery of insulin, To regulate hepatic glucose output to maintain optimal fasting blood glucose. [0004] Thus, effective ...

Claims

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Application Information

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IPC IPC(8): A61K9/10A61K38/00A61K38/28A61K47/10A61P3/10C07K14/62
CPCC07K14/62A61K38/28A61P5/50A61P3/10
Inventor M·L·布拉德
Owner ELI LILLY & CO
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