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Method for preparing polymeric microspheres and polymeric microspheres produced thereby

A technology for polymer microspheres and polymer compounds, which is applied in the field of preparation methods and polymer microspheres prepared by the method, can solve problems such as poor mixing, decreased drug release reproducibility, and low water solubility.

Active Publication Date: 2013-04-10
SK CHEM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] As mentioned above, although dichloromethane has strong volatility, poor mixing with water, and has a boiling point far lower than water, etc., it is the best organic solvent for preparing emulsions, but it has the following serious problems: (a) is confirmed by experiments (b) damage the ozone layer of the atmosphere, causing environmental toxicity, resulting in an increase in the incidence of human skin cancer; (c) belonging to the US Department of Welfare's Agency for Toxic Substances and Disease Registry (Agency for Toxic Substances and Disease Registry) One of the most dangerous 38 toxic and harmful substances; (d) water solubility is low, about 1.32% by weight, only a very small part dissolves in water and evaporates in the total amount of dichloromethane used, so if you want to completely remove the dichloromethane in the emulsion beads Dichloromethane, takes a considerable amount of time
Therefore, after drying, the microspheres are not dispersed individually, the possibility of problems occurring during the injection process increases, and the reproducibility of drug release decreases. In addition, the amount of residual solvent exceeds the permitted lower limit, and it is difficult to obtain product approval from the regulatory authority. question

Method used

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  • Method for preparing polymeric microspheres and polymeric microspheres produced thereby
  • Method for preparing polymeric microspheres and polymeric microspheres produced thereby
  • Method for preparing polymeric microspheres and polymeric microspheres produced thereby

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Contrast experiment of residual solvent concentration under different concentrations of water-insoluble organic solvent mixed in dispersion solvent

[0122] Measurement of residual solvents when preparing polymer microspheres according to the original method

[0123] An emulsion was prepared by dissolving 0.25 g of 75252.5E PLGA polymer in 4 ml of ethyl formate (EF) and emulsifying it in 40 ml of 0.5% polyvinyl alcohol (PVA). Then, 3.4 ml of 28% NH3 solution was added to the emulsion, reacted for 30 minutes, and filtered after adding distilled water. The microspheres were separated, redispersed in 0.1%PVA80ml and stirred. Information on the 7525 2.5E PLGA polymer used for this experiment is as follows.

[0124] 【Table 1】

[0125] 75252.5E PLGA polymer information

[0126]

[0127] The microsphere residual solvent analysis used the following gas chromatography (GC) method. The GC equipment used GC-2010 of Shimadzu Corporation (Japan), and the column used ZB-624 ...

Embodiment 2

[0139] Contrast experiment of residual solvent concentration at different dispersing solvent temperatures in the redispersing step

[0140] When preparing polymer microspheres, the temperature of the water phase changes due to the reaction of acids or bases used to remove water-insoluble organic solvents, and this is expected to affect the amount of residual solvents. Therefore, the preparation process of polymer microspheres is separated, and the time point until the addition of alkali or acid solution and the reaction is terminated is defined as step 1, and the polymer microspheres separated by filtration are redispersed in the PVA solution after the reaction is terminated. And the time point at which the stirring is terminated is defined as step 2. It is known that temperature in any of these steps plays an important role in reducing residual solvents.

[0141] Comparative experiment of residual solvent concentration at different dispersion solvent temperatures in the redi...

Embodiment 3

[0175] Contrast experiment of residual solvent concentration under different concentrations of water-insoluble organic solvent mixed in dispersion solvent 1

[0176] In the aforementioned , it was confirmed that the concentration of the residual organic solvent decreased when the organic solvent was previously added to the dispersion solvent. Therefore, using different amounts of the water-insoluble organic solvent mixed in the dispersion solvent while maintaining the temperature of the dispersion solvent in the redispersion step high, the corresponding residual solvent amounts were measured and compared.

[0177] Dissolve 500mg of 4.5A PLGA (lactide:glycolide=85:15, 0.45dL / g, SurModics Pharmaceutical Company, the U.S.) in 4ml of ethyl formate to make a dispersed phase, and make the dispersed phase separately in advance It was emulsified in 20 ml of 0.5% PVA aqueous solution to which 0, 1, 2 or 4 ml of ethyl formate was added to prepare an emulsion. Then, 6.2 ml of 10N NaOH w...

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Abstract

The present invention relates to a method for preparing polymeric microspheres and polymeric microspheres produced thereby. More particularly, the present invention relates to a method for preparing a polymeric microsphere comprising the steps of: mixing a water-insoluble organic solvent with a dispersion solvent; mixing a polymer compound, a drug and a water-insoluble organic solvent so as to prepare a dispersed phase; mixing the dispersed phase with the dispersion solvent mixed with the water-insoluble organic solvent so as to prepare an emulsion; and adding a base or an acid to the prepared emulsion so as to remove the water-insoluble organic solvent from the emulsion and a polymeric microsphere thereby, and a composition for drug delivery comprising the microspheres. The invention provides the new polymeric microsphere preparation method by removing water-insoluable organic solvents from emulsions by using base or acids, the polymeric microspheres prepared by the prepration method, and the composition for drug delivery comprising the polymeric microspheres. Therefore, the preparation method of the invention is different from original solvent evaporation or solvent extraction procedures, realizes minimization of waste water generation by using less water, and simply prepares target durg-containing polymeric microspheres within a short period.

Description

technical field [0001] The present invention relates to a preparation method of polymer microspheres and polymer microspheres prepared according to the method, in particular to a step comprising: mixing a water-insoluble organic solvent and a dispersing solvent; mixing a polymer compound, a drug and a water-insoluble organic solvent to prepare a dispersed The step of phase; the step of preparing emulsion by mixing the dispersed phase with the dispersion solvent mixed with water-insoluble organic solvent; and adding alkali or acid to the prepared emulsion to remove the step of water-insoluble organic solvent from the emulsion The preparation method of the method, the polymer microsphere prepared according to the method and the drug delivery composition comprising the microsphere. Background technique [0002] Conventional injectable formulations such as infusion solutions, suspensions, and emulsions are quickly cleared from the body after intramuscular or subcutaneous adminis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14A61K9/22A61K31/57C08J3/12
CPCA61K9/1647A61K31/4196A61K31/551C08J3/05C08J3/12C08J3/16C08J2367/04A61K9/1694A61K9/16
Inventor 史洪基李峰镛严基安吴畯敎黄用渊金洪起李圭镐洪锡炫李允静
Owner SK CHEM CO LTD
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