Insulin-lipid complex,preparation method therefor, and preparation thereof

Abstract

Provided are an insulin-lipid complex, a preparation method thereof, and a formulation thereof. The insulin-lipid complex is prepared by compounding insulin and a lipid material in an organic solvent system containing a low boiling point acid, and drying. The mass ratio of insulin to the lipid material is 1:3˜1:20. An oil solution of the insulin-lipid complex and vesicles containing insulin are further provided.

1 . A insulin-lipid complex, wherein the insulin-lipid complex is composed of insulin and lipid material, the mass ratio of insulin to the lipid material being 1:3˜1:20. 
     
     
         2 . The insulin-lipid complex according to  claim 1 , wherein
 said insulin is selected from the group consisting of natural insulin, porcine insulin, bovine insulin, recombinant human insulin and medium or long-acting insulin, and;   said lipid material is selected from the group consisting of natural phospholipids, synthetic phospholipids, cholesterol, cholic acid and salts thereof.   
     
     
         3 . The insulin-lipid complex according to  claim 2 , wherein said insulin is recombinant human insulin, said lipid material is natural phospholipids, and the mass ratio of insulin to the natural phospholipids is 1:5˜1:10. 
     
     
         4 . The insulin-lipid complex according to  claim 1 , wherein said insulin-lipid complex contains at least one of antioxidants, metal-chelators or protease inhibitors. 
     
     
         5 . The insulin-lipid complex according to  claim 1 , wherein said insulin-lipid complex uses an organic solvent system containing a low boiling point acid as a complex solvent. 
     
     
         6 . The insulin-lipid complex according to  claim 5 , wherein said low boiling point acid is selected from the group consisting of trifluoroacetic acid, hydrogen chloride gas, and a combination thereof, and said organic solvent is the group consisting of methanol, tetrahydrofuran, DMSO, chloroform, dichloromethane, and a combination thereof. 
     
     
         7 . An insulin-lipid complex oil solution, wherein said solution contains an insulin-lipid complex oil according to  claim 1 . 
     
     
         8 . The insulin-lipid complex oil solution according to  claim 7 , wherein said oil is selected from the group consisting of LCT, MCT, Glyceryl monooleate, GMS, ethyl oleate, isopropyl myristate, and a combination thereof. 
     
     
         9 . The insulin-lipid complex oil solution according to  claim 7 , wherein said oil contains an emulsifier. 
     
     
         10 . The insulin-lipid complex oil solution according to  claim 9 , wherein said emulsifier is selected from the group consisting of Tween 80, Span 20, Brij, Ethoxylated hydrogenated castor oil, polyoxyethylated castor oil, and Labrosal. 
     
     
         11 . The insulin-lipid complex oil solution according to  claim 7 , wherein said oil contains a co-emulsifier. 
     
     
         12 . The insulin-lipid complex oil solution according to  claim 11  wherein said co-emulsifier is selected from the group consisting of propanediol, PEG400, and Transcutol P. 
     
     
         13 . Use of the oil solution containing insulin-lipid complex according to  claim 7  in the manufacture of insulin sustained-released injection. 
     
     
         14 . Use of the oil solution containing insulin-lipid complex according to  claim 7  in the manufacture of non-injectable formulation for oral, percutaneous, mucosal, and lung inhalation administration. 
     
     
         15 . A novel insulin vesicle, comprising an insulin-lipid complex according to  claim 1  and phospholipids. 
     
     
         16 . The novel insulin vesicle according to  claim 15 , further comprising a surfactant. 
     
     
         17 . The novel insulin vesicle according to  claim 16  wherein, said surfactant is selected from the group consisting of Tween20 and Span60. 
     
     
         18 . The novel insulin vesicle according to  claim 15  wherein said vesicle is an aqueous dispersion, or prepared into a powder by freeze drying or spray drying. 
     
     
         19 . The novel insulin vesicle according to  claim 15 , used in the preparation of non-injectable formulation for oral, percutaneous, mucosal, and lung inhalation administration. 
     
     
         20 . A process for preparation of the insulin-lipid complex according to  claim 1 , comprising the following steps: taking an organic solvent, adding a suitable amount of low boiling point acid, then adding insulin and lipid material, stirring fully to form a clear, transparent solution, removing the organic solvent by the rotary evaporation method or spray drying, and obtaining by drying the residual material; wherein the organic solvent is selected from the group consisting of methanol, tetrahydrofuran, DMSO, and a combination thereof, with methanol being preferred. 
     
     
         21 . A process for preparation of the insulin-lipid complex according to  claim 1 , comprising the following steps: dissolving lipid material in an organic solvent, adding insulin, stirring and adding low boiling point acid until the solution is clear and transparent, stirring at room temperature or ultrasonic processing for a given time, to fully compound the insulin and lipid material, removing the organic solvent by distillation or spray drying, and obtaining said complex by drying the residual material; wherein the organic solvent is selected from the group consisting of methanol, tetrahydrofuran, DMSO, and a combination thereof, with methanol being preferred. 
     
     
         22 . A process for preparation of the insulin-lipid complex according to  claim 1 , comprising the following steps: dissolving insulin in a solvent A containing a suitable amount of a low boiling point acid to form a clear and transparent insulin solution, dissolving the lipid material in a solvent B to form a clear and transparent lipid solution, evenly mixing the insulin solution and lipid solution, and thereafter distilling at reduced pressure in a water bath, further processing by pump extraction, and obtaining said complex by drying; wherein the solvent A is selected from the group consisting of methanol, tetrahydrofuran, DMSO, and a combination thereof, with methanol being preferred; and solvent B is selected from the group consisting of chloroform, dichloromethane, ether, and a combination thereof, with dichloromethane being preferred. 
     
     
         23 . A process for preparation of the insulin-lipid complex according to  claim 1 , comprising the following steps: dissolving insulin in a solvent A containing a suitable amount of a low boiling point acid to form a clear and transparent insulin solution, dissolving the lipid material in a solvent B to form a clear and transparent lipid solution, mixing the insulin solution and lipid solution, thereafter performing reduced pressure distillation in a water bath at a fixed temperature, gradually adding a suitable amount of solvent B during the distillation process, continuing the distillation, then removing the solvent by pumping and obtaining said complex by drying, wherein the solvent A is selected from the group consisting of methanol, tetrahydrofuran, DMSO, and a combination thereof, with methanol being preferred; and solvent B is selected from the group consisting of chloroform, dichloromethane, ether, and a combination thereof, with dichloromethane being preferred.