摘要
本研究针对目前缓控释制剂中存在的载药量低、突释现象严重的问题，将微球传统制备方法复乳-溶剂挥发法进行了优化，采用旋转蒸发法制备高浓度内水相。优化后的方法具有较高的载药量和较低的突释。在工艺优化过程中兼顾载药量、突释、收率、粒径等关键质量控制点，并对影响质量控制点的因素进行细致的分析和讨论。工艺过程及参数确定后，进行了系统的工艺验证及无菌验证，并将优化的制备工艺放大到生产规模，在GMP条件下进行生产。此后，对制备的微球进行表征，建立了多种适用于微球的检测方法，并参照2010年版《中国药典》对微球进行质量研究。质量研究内容包括：微球无菌检测和稳定性试验。在药物释放研究中，通过体内药代动力学研究，摸索出体外长期和加速释放方法，建立了体内外相关性，长期释放方法可以对体内释放进行模拟和预测；加速释放方法便于快速筛选制剂处方和成品检验。
本研究创新点：1、将传统的复乳-溶剂挥发法进行了优化，采用旋转蒸发法制备高浓度内水相，内水相浓度达到2.5g/ml；2、首次获得高载药量（11.2%）、低突释（8.6%）的醋酸奥曲肽微球；3、设计了一套适用于缓释制剂的生产线，并进行了验证；4、建立了加速释放方法，能够预测长期体外释放，极大的缩短了微球的释放检测周期。
Octreotide (OT) is a kind of artificial growth hormone release inhibitinghormone with eight peptides. It can bring about biological effects by connecting withacceptors of central nervous system, hypophysis and abdominal salivary gland cell.Because of its short half-value period, retaining long-term plasma drug level requiresmany injection-times every day. Common preparations will easily occur wave-crestand wave-trough phenomenons. So sustained release dosage forms will make theadministration more convenience.
Sustained release dosage forms’ preparations were researched several years. Thedouble emulsion solvent-evolution method is developed and deeply researched. Itneeds the loaded-drug with a high water-solubility and stability. These may match thecharactors of Octreotide acetate (OTA). So, in this paper, the double emulsionsolvent-evolution method was employed to prepare OTA loaded-microspheres and anoptimized method (W1/O/W2) was created. The obvious difference between the twomethods was the preparation of W1. Using a rotary evaporation method instead oftraditional dissolve method can lead to a series of adventages, such as: the degradationof OTA was decreased; the viscosity was increased and the homogeneity of drugbecame better, so the burst release was decreased and the safty of drug was increased.After the microspheres were obtained, the morphologic was studied by microscope.We found that the surface of the microspheres were smooth without pore anddispersed well. At the same time, the course of flat-sphere phenomenon wasdiscovered: during the freeze drying procession, the temperature increased too fastwill lead to the PLGA skeleton’s retracted delayed and shaped pores inside themicrospheres. Then falt spheres were formed under the vacuum condition. Furthermore, this study investigated the influence of double-emulsion procession parametersto the key quality points of microspheres, such as: the particle size, drug loadingcapacity, recovery rate and release amount. The results indicated that: the particle size decreased with the concentration of W2increased. And with the CH2Cl2disappearedand the solidity of the microspheres, the particle size of microspheres was alsodecreased.
In order to ensure the process environment is sterile, after the preparation processwas determined, a series of process qualifications were carried out. Before the regularpreparetion of microspheres, an aseptic production was simulated by using mannitolinstead of the raw meterials and excipients. This paper, we used a conviction ofprocess control. The workshop was under the condition of GMP and the wholeprecess was under the close and sterile situation. The raw materials and excipientswere moist heat sterilized. OTA and PLGA were aseptic filtrated. The instrumentswere sterilized online and the intermediates and finished products were all detected.
For sustained release dosage forms, the release amount is an important charactor.The drug release will concentrated on the first day of the release course and this burstrelease may raise the challenges of the drug’s safety. The mechanism is dispersing. Sothe research on burst release is very necessary. Through the release test, we foundedthat the burst release occurs during the first6h mainly. Meanwhile, we alsodiscovered that: the molecular weight of PLGA, the volatilize speed of CH2Cl2, thevolume of W1, the PVA concentration of W2, the particle size, washing-time of burstrelease and the pH value of the buffer will affect the burst release profiles of themicrospheres. Moreover, the in vivo release test was carried out using beagle dogsthrough one-dosing and multiple-dosing. The results indicated that: the bioavailabilityof microspheres made by the optimized method was98%and their action equaled toSandostatin. At the aspect of release determination, this paper founded an acceleratedmethod to evaluate the release profiles of microspheres. Firstly, according to thedurg-time curve of in vivo one-dosing, the in vivo release amount was calculated bythe Wagner-Nelson method. Secondly, a long-term release model was founded inorder to match the in vivo release profiles, so the correlation between in vivo and invitro relwas founded (r=0.9876). Finally, an accelerated release method was founded,and the release profiles correlated well with the long-term release obtained by thepaddle method (r=0.9540). Therefore, by the optimization of release conditions, an accelerated release method could be founded to evaluate release profiles from PLGAmicrospheres.
At the aspect of microspheres’ quality controlling, according to CHP, thedetective items are: microspheres’ shape, sterile detection, endotoxin detection,degradation products, moisture, residual solvent and the molecure mass of PLGA. Inthis study, the sterile detection method and degradation products were researcheddeeply. Other items were defined in CHP, so the research were not carried out. In thisstudy, the sterile detection and degradation products were researched deeply. Forsterile detection, the microspheres were dissolved by the solvent and filtered bymembrane filter method. The microbe will remained at the surface of the filtermembrane. For the comparative study of degradation products, the sandostatin wasused as the reference drug. Deduced the structures of degradation products accordingto the meterials’ chemical charactors, then synthesised the impurity to carry out masschromatographic analysis. The results indicated that the degradation products ofmicrospheres made by the optimized method were less than that of sandostatin.
In order to ensure that the detection methods could describe the production’squality truly and reliably, according to ICH and CHP, the analytical methodvalidations were carried out in specificity, degree of accuracy, reproducibility,precision, durability and linear. The results indicated that: the detection methods couldmeet the needs of controling the production’s quality. In order to determine thedeposit condition of the microspheres, the stability was studied. The targets were: theamount of OTA, degradation products and release amount. The conditions wereaccelerating experimentation and long-term experimentation under deposit condition.It contains influencing factors detection, such as: high temperature, high moist,illumination, oxidation. The stability study results indicated that: theOTA-microspheres could be stored for12months at2-8℃，the relative humidity of10±3%. The microspheres were sensitive to temperature and water, so should bestored at a low temperature and drying condition.
引文
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