| The release of risperidone microspheres for injection of commercially available products from Janssen Company has a delayed release.This research topic is based on the preparation process of the previous generic product"Risperdal Consta".The project aims to develop risperidone/PLGA microspheres with no release delay period and long-term release by preparing and mixing three microspheres with different release rates.Long-acting slow-release risperidone microspheres M1 and medium-release risperidone microspheres M2 were prepared by O/W preparation methods using PLGA(120 k D)and PLGA(50 k D)respectively.S/O/W emulsion solvent evaporation method,risperidone crystals(particle size 2～5μm)were suspended in ethyl acetate to prepare risperidone microspheres M3.Three types of homemade microspheres were mixed in an appropriate ratio to obtain non-release delay and meet the release cycle long-acting microsphere preparation.M1 type microspheres PLGA(120 k D),with good wrinkles on the surface and good monodispersion,median particle size D50=109.9μm,drug loading 36.58%,encapsulation efficiency 80.93%,benzyl alcohol solvent residue 1.09%meets standard requirements.In vitro the release curve is"S"type,similar to commercial preparations,with early release delay and long release cycle;M2 microspheres PLGA(50 k D),good monodispersity,D50=92.1μm,drug loading 34.25%,encapsulation efficiency 76.87%,benzyl alcohol residual 1.09%<1.7%,meet the limit requirements,accelerated early release and long release cycle;single-factor exploration of the preparation of M3 microspheres,combined with software Design-Expert 8.0.6 design center experiment.The cross-cutting factors predict the optimal prescription,verify the optimal prescription process,and examine the microsphere quality characteristics.M3 microspheres are monodisperse,with a drug loading of 32.32%,an encapsulation rate of 78.34%,D50 is about 100μm,a fast release rate,release on the first day,and a shorter release cycle,indicating that the preparation process is stable with small differences between batches.Three kinds of homemade microspheres were combined in different proportions to obtain the target microspheres(M).The drug loading and encapsulation rate were high without significant differences;the particle size distribution was uniform,and the median particle diameter D50 was about 100μm;the solvent residue less than 1.7%meet the standard requirements.When the combination ratio is M1:M2:M3=2:6:2,the drug loading of M microspheres is 37.44%,the encapsulation efficiency is 81.21%,the particle size distribution is uniform,D50=98.3μm,and the solvent residue is 0.89%<1.7%.It meets the standard requirements.There is no release delay in the early stage.The release amount at the first day of in vitro release at 37℃is about 9%,the burst effect is small,and the release rate is gentle afterwards.It has a good sustained release effect and release uniformity.The microsphere preparation should be stored in a refrigerator at a low temperature of 2～8℃,sealed and protected from light.The release behavior in vitro at 37℃conforms to the Ritger-Peppas model.The Ritger-Peppas equation ln Q=0.88153lnt+1.23173,n=0.88153,0.43<n<0.89,that is,the drug release mechanism is a synergy between diffusion and matrix dissolution.There is no delay in the release of microspheres,and the release cycle lasts about 40 days.The correlation coefficient between accelerated release and normal release R~2=0.99022>0.99has a good correlation.Under this release condition,accelerated release can be used to simulate normal release. |
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