Research Of Preparation Method And Characteratization Of Triptorelin Acetate Microspheres

Preparation of triptorelin acetate sustain-released microsphere has been a hot point inmedical research field since the1980s. In this study, preparation methods fortriptorelin acetate microsphere and its related properties have been explored.Three different methods (Multiple Emulsion, Phase Separation, hot melt extrusionintegrating with grinding) have been choosed to prepare triptorelin acetate microsphere. Thenatures of various prepared microspheres has been compared，including morphologicalobservation，particle size and in vitro sudden release. The microspheres prepared byourselves have been compared with diphereline which is on the market. The surfacemorphology and the particle size of microsphere are the main factors for its releasing invitro. The releasing condition of microspheres in vitro is closely related to the drugsrelease in vivo，which is also a prerequisite for the drug’s good therapeutic effect. Based onthe above studies, the triptorelin acetate microspheres prepared by melt extrusion integratingwith grinding method can reach the similar releasing level in vitro as compared that ofdiphereline, but the other two methods can’t achieve the standard. So we choose meltextrusion integrating with grinding method as the final method to prepare triptorelin acetatemicrospheres.On the basis of above research, preparation method of melt extrusion integrating withgrinding has been further optimized, including pre-cooling temperature, time and frequencyof grinding, sudden-release washing condition (time, temperature and water volume), etc.Through the optimization of preparation conditions of microspheres, the triptorelin acetatemicrosphere was ascertained to achieve the best characterizations, including morphology,particle size and in vitro drug release.After establishing the preparation method for triptorelin acetate microsphere, a series ofcomprehensive in vitro studies for the natures of triptorelin acetate microspheres have beencarried out. The studies included suspension property, identification of triptorelin acetate inmicrospheres, molecular weight of triptorelin acetate in microspheres, encapsulationefficiency of triptorelin acetate microspheres, relevant substances and influence factors of relevant substances formed, moisture detection, intrinsic viscosity determination of PLGA,asepsis test, pyrogen test, drug releasing detection in vitro and the stability determinations oftriptorelin acetate microspheres. The results showed that triptorelin acetate microsphereshave a good suspension properties, triptorelin acetate extacted from microspheres has thesame retention time as compared with that of triptorelin acetate standard, molecular weightof triptorelin acetate extacted from microspheres was1311.498, the same as that oftriptorelin acetate standard. The mean drug-loading rate was4.29±0.18%and the meanentrapment efficiency was85.78±1.64%. Content of relavant substances in triptorelin acetatemicrospheres were lower than5%by controlling the preparation conditions of hot meltextrusion temperature, irradiation intensity for sterilization, grinding method, and washingmethod for drug sudden release. Result of moisture dectection for triptorelin acetatemicrospheres was1.2%. Results of asepsis test and pyrogen test were all eiligible accordingto the standared described in Chinese Pharmacopoeia. Drug’s releasse from microspheres inneutral buffer system can keep a effective concentration for a month. The triptorelin acetatemicrospheres prepared had a good stability under the storage conditions of25℃±2℃temperature/60%±10%humidity for12months and of6℃±2℃temperature/60%±10%huimidity for6months, respectively.Also, drug-release studies in vivo for triptorelin acetate microsphere have been carriedout using diphereline as positive standard. The results showed that drug-releasing curve oftriptorelin acetate microsphere prepared was similar as compared with that of diphereline.All above results indicate that triptorelin acetate microsphere prepared could be a promisingcandidate for its further clinical applications.