Method for increasing entrapment rate of polylactic acid microspheres to water soluble protein

A technology of water-soluble protein and polylactic acid, which is applied in the direction of peptide/protein components, pharmaceutical formulations, medical preparations of non-active ingredients, etc., can solve the problems of increased drug diffusion, reduced encapsulation rate, and drug loss, and achieves improved Stability, improving encapsulation efficiency, inhibiting the effect of burst release

Inactive Publication Date: 2010-04-14
TSINGHUA UNIV
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Problems solved by technology

For example, the 7th issue (p775-785) of volume 21 of journal J Micoencapsulation and Chinese invention patent CN1460468 have reported a kind of improved double emulsion method, this method adopts Tween to replace PVA as emulsifier, to contain or not contain water-soluble Salt or polyol (or sugar, polysaccharide) aqueous solution is external water phase, can improve the encapsulation efficiency of PLGA microsphere to bovine serum albumin, but this method can not improve the stability of protein; A method for improving the stability of proteins in the encapsulation process, characterized in that nonionic surfactant polyoxyethylene and polyoxypropylene copolymers are added to the internal aqueous phase, but this method does not propose a way to improve the encapsulation efficiency
[0005] From the perspective of the process and principle of double emulsion preparation, the causes of protein inactivation and loss mainly include: 1) The compatibility between the material and the drug is poor, and the protein drug in the inner water phase is in the process of forming microspheres. The water phase diffuses, causing the loss and inactivation of the drug; if the solvent volatilizes slowly, the solidification time in the microspheres is prolonged, which will lead to a further increase in the diffusion of the drug to the outer water phase, and a decrease in the encapsulation efficiency; 2) protein drugs During the emulsification process, it contacts with the oil phase and aggregates at the oil-water interface of the emulsion droplets to cause denaturation, resulting in protein inactivation

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  • Method for increasing entrapment rate of polylactic acid microspheres to water soluble protein

Examples

Experimental program
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Embodiment 1

[0030] This embodiment is an experiment of the influence of O-CMC on the stability of protein lysozyme. Take 1 mL of 50 mg / mL (active concentration) lysozyme aqueous solution, add 0.2% and 0.4% O-CMC in mass fraction respectively, and take the solution without O-CMC as a comparison. In the above solution, add 3mL of dichloromethane, ultrasonically shake in a water bath for 1min, after standing for 5min, then ultrasonically shake for 1min, after standing for 5min, transfer the water phase, and extract the oil phase with aqueous solution for 5 times, and combine the extracts into the water phase , The active concentration of lysozyme was determined by the Schugach method, and the results are shown in Table 1. It can be seen that after adding O-CMC, the content of active lysozyme in the solution is higher.

[0031] Table 1 The active concentration of lysozyme

[0032] O-CMC / %

Embodiment 2

[0034]In this example, the method of the present invention was used to prepare microspheres whose carrier materials were PLGA-mPEG and the model drug lysozyme, and compared with the conventional method. The carrier material is PLGA (50:50, M w =200k)-mPEG(M w =5k), the mass ratio of medicine and material is 1: 6; The oil phase adopts dichloromethane, and wherein the content of PLGA-mPEG is 0.1g / mL; The molecular weight of carboxymethyl chitosan is 250k, and the carboxymethyl substitution degree 0.8; NaCl is used as the osmotically active substance, the volume ratio of the external aqueous phase to colostrum is 1:20, and ultrasonic emulsification is used. The main properties of the lysozyme microspheres obtained under the three formulations with different mass fractions of NaCl and O-CMC are listed in Table 2. Other conditions are the same, but the main properties of lysozyme microspheres obtained under the condition of not adding O-CMC and NaCl are also listed in Table 2. I...

Embodiment 3

[0038] This implementation is the release characteristics of the microspheres prepared by the method of the present invention. The microspheres are: 1) the lysozyme microspheres prepared by the method in Example 1 according to prescription A, 2) the comparison microspheres in Example 1; the conditions for in vitro release are: release medium PBS, temperature 37°C, stirring speed 100rpm; the release rate is represented by the active concentration of lysozyme, and the activity of lysozyme is determined by the Schugard method. The cumulative drug release curve of the microspheres is attached figure 1 shown. The initial "burst release" is suppressed to a certain extent, and the cumulative release time reaches more than 30 days, which can be used as long-acting release particles. At the same time, the microspheres prepared by the present invention can release more active lysozyme, and the cumulative amount of active lysozyme released is significantly higher than that of the contr...

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Abstract

A method for increasing entrapment rate of polylactic acid microspheres to water soluble protein belongs to the field of medicinal preparation. On the basis of the existing multiple emulsion method (W / O / W), water soluble amphiphilic polymer carboxymethyl chitosan (O-CMC) of which the mass fraction ranges from 0.1% to 5% is added in internal water phase medicated solution used for forming multiple emulsion, wherein the molecular weight of the water soluble amphiphilic polymer carboxymethyl chitosan ranges from 15K to 30K, the degree of carboxymethylation ranges from 0.6 to 1, and the degree of deacetylation is 92%. Further, osmotically active substance NaCl or mannitol is added in external water phase solution used for forming multiple emulsions, wherein the mass fraction of NaCl ranges from 0.5% to 1.5%, and the mass fraction of mannitol ranges from 2% to 5%. The method reduces stability of protein during processes of preparation, storage and using of microspheres, and increases the entrapment rate of microspheres to protein and inhibits 'burst effect' of microspheres at initial stage of releasing.

Description

technical field [0001] A method for improving the encapsulation rate of polylactic acid microspheres to water-soluble proteins, to be precise, it is a method to prepare polylactic acid microspheres by improving the double emulsion method (W / O / W) to improve the encapsulation rate of water-soluble proteins The method belongs to the field of pharmaceutical preparations. Background technique [0002] The drug-loaded microspheres of biodegradable materials can significantly improve the safety and effectiveness of clinical medication by controlling or targeting the drug release rate, and are suitable for a variety of drug delivery methods and drug delivery routes. Polylactic acid ball-forming materials, including polylactic acid PLA, lactic acid / glycolic acid copolymer PLGA and their derivatives, are by far the most researched and widely used biodegradable synthetic polymer materials at home and abroad. PLA, PLGA and other polylactic acid materials are currently recognized as goo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/36A61K47/34A61K9/19A61K38/00
Inventor 蒋国强李近孙佳丽丁富新
Owner TSINGHUA UNIV
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