Improved method for preparing exenatide sustained release microspheres

A technology for exenatide and sustained-release microspheres, which is applied in the field of improved preparation of exenatide sustained-release microspheres, which can solve the problems of reduced polymer dissolution rate, long dissolution time, and exacerbated polypeptide denaturation, achieving a production cycle The effect of shortening, accelerating the dissolution rate, and simple preparation process

Inactive Publication Date: 2014-02-19
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the solubility of exenatide in methanol is limited. If you want to increase the drug loading capacity, you must increase the temperature or long-term oscillating ultrasonic treatment, which intensifies the denaturation of the peptide.
In the report of Li, Xingang et al. Application of model-based methods to characterize exenatide-loaded double-walled microspheres: In vivo release, pharmacokinetic / pharmacodynamic model, and in vitro and in vivo correlation (see Journal of Pharmaceutical Sciences, 2012, 10 (101), 3946-3961), exenatide and polymer are simultaneously dissolved in a mixed solvent of dichloromethane / methanol and then emulsified with the external water phase to form microspheres, and the dissolution rate of the polymer is greatly reduced
The problems in these methods are either that the drug is difficult to dissolve in the solvent, or that the polymer is difficult to dissolve in the solvent, so that the polypeptide drug is denatured in the dissolution process of the organic solvent, or the dissolution time of the polymer in the solvent is longer, and the organic Solvent volatilization makes it difficult to reproduce the process of polymer concentration change, which eventually causes problems such as affecting the physical and chemical properties of the preparation
In addition, due to the limitation of drug solubility, it is difficult to increase the drug loading of microspheres.

Method used

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  • Improved method for preparing exenatide sustained release microspheres

Examples

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Effect test

Embodiment 1

[0034] Example 1: Preparation of Exenatide Sustained Release Microspheres by Ordinary Single Emulsion Solvent Evaporation Method

[0035] Weigh 0.75 g of exenatide and dissolve it in 75 mL of methanol by ultrasonication for 30 min. Weigh 24g of poly(lactic-co-glycolic acid) copolymer (75 / 25, 0.2dL / g) and dissolve it in 75mL of dichloromethane. Vortex and mix methanol and dichloromethane for 10s to form a clear solution, pour it into 15L of 1% polyvinyl alcohol aqueous solution under mechanical stirring to obtain double emulsion, keep stirring the double emulsion for more than 3 hours to remove the organic solvent, centrifuge and wash , the microspheres were collected, the average particle size of the microspheres was about 34 μm, the drug loading capacity was 2.60%, the encapsulation efficiency was 85.9%, and the total impurity content was 3.04%.

Embodiment 2

[0036] Example 2: Preparation of Exenatide Sustained Release Microspheres by Improved Single Emulsion Solvent Evaporation Method

[0037] Weigh 24g of poly(lactic-co-glycolic acid) copolymer (75 / 25, 0.2dL / g) and dissolve it in 75mL of dichloromethane, add 75mL of methanol, vortex the mixed solution for 10s to form a clear solution, weigh 2.00g of exenatide , add the mixed solution, vortex for 10s to form a clear solution, pour it into 15L of 1% polyvinyl alcohol aqueous solution under mechanical stirring to obtain double emulsion, keep stirring the double emulsion for more than 3 hours to volatilize and remove the organic solvent, centrifuge, wash, and collect to obtain Microspheres, the average particle size of the microspheres is about 39 μm, the drug loading capacity is 6.65%, the encapsulation efficiency is 86.4%, and the total impurity content is 0.55%.

Embodiment 3

[0038] Example 3: Preparation of Exenatide Sustained Release Microspheres by Improved Single Emulsion Solvent Evaporation Method

[0039] Weigh 24g of poly(lactic-co-glycolic acid) copolymer (50 / 50, 0.2dL / g) and dissolve it in 100mL of dichloromethane, add 50mL of methanol, vortex the mixed solution for 10s to form a clear solution, weigh 2.00g of exenatide and micronized zinc acetate 1.50g, add the mixed solution, vortex to form a suspension, inject it into 15L of 0.5% polyvinyl alcohol and 5% sodium chloride aqueous solution under mechanical stirring to obtain double emulsion, and make this compound The milk was continuously stirred for more than 3 hours to volatilize the organic solvent, centrifuged, washed, and collected to obtain microspheres. The average particle size of the microspheres was about 41 μm, the drug loading was 6.94%, the encapsulation efficiency was 90.2%, and the total impurity amount was 0.98%.

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Abstract

The invention belongs to the field of pharmaceutic preparations, and discloses an improved method for preparing exenatide sustained release microspheres and exenatide sustained release microspheres prepared by the method. In the method of the invention, after being dissolved in dichloromethane, a polymer is mixed with methanol solution;after quicker dissolving of the polymer is guaranteed, exenatide or exenatide and protective agent are added, so that the dissolving speed of the exenatide and the polymer is quickened, the contact time of the exenatide with organic solvent and the volatilization loss of solvent in the polymer dissolving process are reduced, and the solubility of the exenatide in oil phase is largely improved. The method improves the drug loading capacity, reduces the degradation of drugs in the preparation process, simplifies the process, and shortens the preparation period.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to an improved method for preparing exenatide sustained-release microspheres. Background technique [0002] Sustained-release microspheres are an important sustained-release drug delivery system. By encapsulating the active ingredient in the polymer, the active ingredient can be released from the microspheres stably for a long time, so as to achieve the purpose of slow release and controlled release. [0003] There are many methods for the preparation of microspheres that have been reported, such as solvent evaporation, phase separation, spray drying, low temperature spray extraction and so on. [0004] The basic steps of the phase separation method are: dissolve or disperse the drug into a suspension or emulsion in the polymer material solution, and increase the solubility of the polymer material by lowering the temperature, adjusting the pH value, or adding a dehydratin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/16A61K38/22
Inventor 刘慧陶安进马亚平袁建成
Owner HYBIO PHARMA
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