Process of preparing microspheres for sustained release having improved dispersibility and syringeability

Abstract

Disclosed is a process of preparing sustained release microspheres, containing a biodegradable polymer as a carrier and a drug, using spray drying. The process comprises preparing a solution, suspension or emulsion containing a biodegradable polymer, a drug and a solvent; spray drying the solution, suspension or emulsion; and suspending spray-dried microspheres in an aqueous solution containing polyvinyl alcohol to remove the residual solvent and increase the hydrophilicity of the microsphere surface. The process enables the preparation of microspheres having high drug encapsulation efficiency, almost not having a toxicity problem due to the residual solvent, and having good syringeability. The microspheres prepared according to the present invention release an effective concentration of a drug in a sustained manner for a predetermined period when administered to the body, and are thus useful in the treatment of diseases.

Description

TECHNICAL FIELD[0001]The present invention relates to a process of preparing sustained release microspheres comprising a biodegradable polymer as a carrier and a drug. Such microspheres are an injectable sustained-release formulation, which enables the sustained and uniform release of a drug so as to maintain its biological activity in the body upon subcutaneous or intramuscular injection.BACKGROUND ART[0002]A number of approaches have been used to encapsulate bioactive agents into microspheres of polymers for sustained release. Most of them are based on phase separation (U.S. Pat. No. 4,673,595, EP 52,510), cryopulverization after melt extrusion (U.S. Pat. Nos. 5,134,122, 5,192,741, 5,225,205, 5,431,348, 5,439,688, 5,445,832 and 5,776,885), double emulsion evaporation (w / o / w, water / oil / water) (U.S. Pat. Nos. 4,652,441, 4,711,782, 4,954,298, 5,061,492, 5,330,767, 5,476,663, 5,480,656, 5,611,971, 5,631,020 and 5,631,021), single emulsion evaporation (o / w, oil / water) (U.S. Pat. Nos. 4...

AI Technical Summary

Benefits of technology

[0013]It is therefore an object of the present invention to provide a process for preparing sustained release microspheres comprising a biodegradable polymer as a carrier and a bioactive drug, the microspheres being easy for mass production, not containing a residual toxic solvent, which is a problem of conventional methods of preparing sustained release microspheres, having high drug encapsulation efficiency, and having a uniform size suitable for injection.

[0014]The present inventors conducted intensive studies, and found that when microspheres, which are obtained by spray drying a solution, suspension or emulsion containing a biodegradable polymer, a drug and a solvent, are suspended in an aqueous solution containing polyvinyl alcohol to remove the residual solvent, the microspheres have improved suspendability and syringeability and high drug encapsulation efficiency with no residual toxic solvent, thereby leading to the present invention.

Problems solved by technology

However, the phase separation method is problematic as follows.

Since the toxic solvent such as methylenechloride is not sufficiently removed by drying under pressure, the residual solvent reduces the stability of formulations, and may also be detrimental to health when administered to the body.

Also, the excessive use of non-solvent, such as freon, hexane, heptane, cyclohexane, and trichlorofluoromethane, for the solidification of embryonic microspheres is not cost-effective upon mass production and causes serious environmental contamination.

However, the procedure for preparing microparticles does not exclude the possibility of an interaction between the polymer and the drug and denaturation of the drug due to high temperature and high pressure upon melt-extrusion, and denaturation of the drug due to heat locally generated during cryopulverization.

This method is also difficult to use to make microspheres having a uniform size, which are thus easy to inject.

The two methods for preparing microspheres, in addition to the problems of residual solvent, difficulty in mass production and drug denaturation, have another disadvantage in that a biodegradable polymer used for the sustainable release of a drug is non-hydrophilic and thus poorly dispersible in an aqueous suspension for injection.

Most hydrophilic drugs leak in large amounts when dispersed in an aqueous phase, resulting in low encapsulation efficiency.

Typically, microspheres prepared by double emulsion evaporation are more porous than those prepared by single emulsion evaporation, and thus have increased surface areas, leading to a relatively high initial release rate of a drug.

However, the single and double emulsion evaporation methods for preparing microspheres, like the phase separation method, have the following disadvantages: difficulty in the removal of an organic solvent used for dissolving a biodegradable polymer, difficulty in mass production procedures due to changes in solvent removal rate, allergic reactions to gelatin used for increasing the viscosity of a primary emulsion, the possibility of a drug becoming denatured and losing its activity due to strong shearing force applied for making small microspheres during primary emulsion preparation, limited drug encapsulation, and the like.

The solvent used is not sufficiently removed merely by spray drying.

The residual solvent causes a problem in the stability of the biodegradable polymer upon long-term storage, leading to changes in drug release profiles of microspheres.

Another disadvantage of this method is that since biodegradable polymers used for drug encapsulation are mostly non-hydrophilic, microspheres prepared are not suspended well and are thus difficult to accurately administer.

As described above, most conventional methods of preparing sustained release microspheres employ a toxic solvent, and have problems including residue of the toxic solvent used, the microsphere size not being suitable for injection, poor suspendability of microspheres, and difficult mass production.

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