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Long acting insulin composition

An insulin and composition technology, applied in the field of long-acting insulin compositions, can solve the problems of reducing the frequency of insulin administration, not providing continuous release, not providing, etc., to reduce the risk of hypoglycemia, reduce the risk of hyperglycemia, The effect of reducing the frequency of injections

Inactive Publication Date: 2015-05-27
SANOFI AVENTIS DEUT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the aim of the invention was to provide formulations with a similar pharmacokinetic profile to the native protein, thus not providing sustained release
US2007 / 0207210A1 therefore does not provide a solution to reduce the frequency of insulin dosing

Method used

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  • Long acting insulin composition
  • Long acting insulin composition
  • Long acting insulin composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0501] Synthesis of Backbone Reagent 1g

[0502]

[0503] Backbone reagent 1g was synthesized from amino 4-branch PEG5000 1a according to the following scheme:

[0504]

[0505] For the synthesis of compound 1b, amino 4-arm PEG5000 1a (MW about 5200 g / mol, 5.20 g, 1.00 mmol, hydrochloride) was dissolved in 20 mL DMSO (anhydrous). A solution of Boc-Lys(Boc)-OH (2.17 g, 6.25 mmol) in 5 mL DMSO (anhydrous), EDC HCl (1.15 g, 6.00 mmol), HOBt·H 2 O (0.96 g, 6.25 mmol) and collidine (5.20 mL, 40 mmol). The reaction mixture was stirred at RT for 30 minutes.

[0506] The reaction mixture was diluted with 1200 mL of dichloromethane and washed with 600 mL of 0.1N H 2 SO 4 (2x), brine (1x), 0.1M NaOH (2x) and 1 / 1 (v / v) brine / water (4x) washes. The aqueous layer was extracted again with 500 mL DCM. The organic phase was subjected to Na 2 SO 4 Drying, filtration and evaporation gave 6.3 g of crude product 1b as a colorless oil. Compound 1b was purified by RP-HPLC.

[0507] Yi...

Embodiment 2

[0547] Synthesis of crosslinking reagent 2d

[0548] Crosslinking reagent 2d was prepared from monobenzyl adipate (English, Arthur R. et al., Journal of Medicinal Chemistry, 1990, 33(1), 344-347) and PEG2000 according to the following protocol:

[0549]

[0550] A solution of PEG 2000(2a) (11.0 g, 5.5 mmol) and benzyl adipate half ester (4.8 g, 20.6 mmol) in dichloromethane (90.0 mL) was cooled to 0°C. Dicyclohexylcarbodiimide (4.47 g, 21.7 mmol) was added followed by a catalytic amount of DMAP (5 mg) and the solution was stirred and allowed to reach room temperature overnight (12 hours). The flask was stored at +4°C for 5 hours. The solid was filtered and the solvent was completely removed by vacuum distillation. The residue was dissolved in 1000 mL of 1 / 1 (v / v) ether / ethyl acetate and kept at RT for 2 hours while a small amount of flaky solid formed. filter the solid through Filler removed. The solution was kept in a closed flask in a -30°C freezer for 12 hours unti...

Embodiment 3

[0558] Preparation of hydrogel beads (3) and (3a) containing free amino groups

[0559] A solution of 275 mg 1g and 866 mg 2d in 14 mL DMSO was added to a solution of 100 mg Arlacel P135 (Croda International Plc) in 60 mL heptane. The mixture was stirred at 700 rpm for 10 minutes at 25°C with a conventional metal stirrer to form a suspension. Add 1.0 mL of N,N,N',N'-tetramethyl-ethylenediamine to effect polymerization. After 2 hours, the stirrer speed was reduced to 400 rpm and the mixture was stirred for an additional 16 hours. 1.5 mL of acetic acid was added and after 10 minutes, 50 mL of water was added. After 5 minutes, the stirrer was stopped and the aqueous phase was drained.

[0560] For bead size fractionation, the water-hydrogel suspension was wet sieved on 75, 50, 40, 32 and 20 μm mesh steel sieves. The bead fractions retained on the 32, 40 and 50 μm sieves were pooled and washed 3 times with water, 10 times with ethanol and dried at 0.1 mbar for 16 hours to give...

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Abstract

The present invention relates to a pharmaceutical composition comprising an insulin compound in a concentration that is sufficient to maintain a therapeutically effective level of the insulin compound in blood plasma for at least 3 days characterized by having a pharmacokinetic profile in vivo with substantially no burst of the insulin compound. The present invention further relates to the use of an insulin compound for preparing said pharmaceutical composition as well as a kit of parts comprising said pharmaceutical composition.

Description

technical field [0001] The present invention relates to pharmaceutical compositions comprising insulin compounds, uses of said compositions, methods of treatment, kits and combination therapy with GLP-1 compounds such as GLP-1 agonists. The pharmaceutical composition can be administered less frequently than current long-acting insulins and is characterized by the release of structurally intact insulin throughout the time between administrations with essentially no burst of insulin compound. The treatment helps patients reduce the frequency of injections so that optimal control of plasma levels of insulin and thus blood sugar can be maintained. Background technique [0002] Insulin therapy is characterized by a high need to maintain insulin drug release at very stringent levels due to a narrow therapeutic window, and the adverse effects of hyperinsulinemia can be potentially life threatening. A variety of insulin preparations are already commercially available with different...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/06A61K47/48A61K9/00
CPCA61K9/0019A61K9/19A61K38/28A61K38/26A61K45/06A61K47/60A61K47/69A61K9/06Y10T428/13A61K47/50A61P3/04A61P3/10A61K2300/00
Inventor K.斯普罗格F.克里曼U.赫赛尔S.卡登-瓦格特T.莱斯曼H.劳T.韦格
Owner SANOFI AVENTIS DEUT GMBH
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