發(fā)布時(shí)間：2018-06-06 03:34

  本文選題：聚乳酸/羥基乙醇酸 + 利福平��； 參考：《第二軍醫(yī)大學(xué)》2014年碩士論文

【摘要】：研究目的：通過制備聚乳酸/羥基乙醇酸共聚物（PLGA）-利福平緩釋微球，研究微球的粒徑、包封率、載藥量和體外釋放特點(diǎn)，同時(shí)兔椎旁植入PLGA-利福平緩釋微球后，觀察局部組織中的利福平濃度以及微球突釋和緩釋特點(diǎn)，研究微球的體內(nèi)釋放特點(diǎn)，從而明確利福平緩釋微球在脊柱結(jié)核治療中的作用和應(yīng)用前景，并且為將來進(jìn)行同類實(shí)驗(yàn)以及臨床應(yīng)用奠定實(shí)驗(yàn)基礎(chǔ)。 研究內(nèi)容及結(jié)果： 研究內(nèi)容：（1）用乳化溶劑揮發(fā)法（W/O/W）制備PLGA-利福平緩釋微球；（2）以包封率、載藥量和體外釋放度為評(píng)價(jià)指標(biāo)，單因素考察PLGA平均分子量（Mw）、初乳制備方式、攪拌速度、內(nèi)水相體積等因素對(duì)微球粒徑、包封率和釋放度的影響，優(yōu)化微球制備處方；（3）采用紫外分光光度計(jì)測(cè)定PLGA-利福平緩釋微球的載藥量和包封率；（4）使用掃描電鏡對(duì)PLGA-利福平緩釋微球進(jìn)行形態(tài)學(xué)觀察，并測(cè)量其粒徑大小及分布；（5）使用PBS液為釋放介質(zhì)，觀察PLGA-利福平緩釋微球在不同溫度下的穩(wěn)定情況，并研究其體外釋放特點(diǎn)；（6）應(yīng)用高效液相色譜法（HPLC）建立利福平標(biāo)準(zhǔn)曲線，以測(cè)量血漿及組織標(biāo)本中利福平藥物濃度；（7）兔脊柱旁開槽，局部給予PLGA-利福平緩釋微球，，研究PLGA-利福平緩釋微球在體內(nèi)的釋放特點(diǎn)。 結(jié)果：（1）PLGA-利福平緩釋微球形態(tài)圓整，表面光滑，肉眼觀呈橙紅色；（2）優(yōu)化的處方：1:1的PLGA503H（Mw65000）和PLA共200mg，溶解于2ml二氯甲烷中，再加入1%PVA飽和溶液20ml中，400rpm攪拌20min，再轉(zhuǎn)移至100ml0.2%PVA飽和溶液中，600rpm攪拌揮發(fā)溶劑4h；（3）PLGA-利福平緩釋微球的載藥量為42.95%，包封率為87.83%；（4）微球粒徑分布呈近似正態(tài)分布，平均粒徑124um；（5）利福平緩釋微球體外釋放特點(diǎn)：微球體外釋放呈零級(jí)模式，24h突釋低于25%，兩周釋放可達(dá)81%；（6）利福平緩釋微球的體內(nèi)釋放特點(diǎn)：將利福平緩釋微球和利福平原藥按比例植入兔椎旁后，腰6椎體及腰大肌測(cè)得的利福平濃度均可維持在結(jié)核桿菌最低抑菌濃度（MIC）以上持續(xù)到術(shù)后28d，但是利福平緩釋微球椎旁給藥組的腰6椎體及腰大肌的利福平濃度下降趨勢(shì)較利福平原藥椎旁給藥組更平緩，持續(xù)時(shí)間更長，同時(shí)肝、肺等其它組織未見明顯蓄積。 結(jié)論：(1)用乳化溶劑揮發(fā)法（W/O/W）制備的PLGA-利福平緩釋微球，平均粒徑為124u m，其外觀、載藥量、包封率等評(píng)價(jià)指標(biāo)優(yōu)良；(2)適當(dāng)比例的投藥比、內(nèi)水相體積、攪拌速度、載體材料等參數(shù)值對(duì)微球的包封率、載藥量及釋放行為的影響很大；（3）PLGA-利福平緩釋微球體外釋放穩(wěn)定，微球的釋放呈零級(jí)模式，24h突釋低，釋放周期長；（4）PLGA-利福平緩釋微球在兔椎旁用藥后，腰6椎體及腰大肌測(cè)得的利福平濃度可維持在結(jié)核桿菌最低抑菌濃度（MIC）以上持續(xù)到術(shù)后28d，并且局部利福平濃度下降趨勢(shì)平穩(wěn)，肝、肺等其它組織未見明顯蓄積。
[Abstract]:Objective: to study the particle size, encapsulation efficiency, drug loading and release characteristics of poly (lactic acid) / hydroxy glycolic acid copolymers (PLGA-rifampicin) sustained-release microspheres. To observe the concentration of rifampicin in local tissues and the characteristics of sudden and sustained release of microspheres, and to study the characteristics of release of microspheres in vivo, so as to clarify the role and application prospect of rifampicin microspheres in the treatment of spinal tuberculosis. And lay the experimental foundation for the similar experiment and clinical application in the future. Contents and results of the study: Preparation of PLGA-rifampicin sustained-release microspheres by emulsified solvent volatilization method (W / O / W). The encapsulation efficiency, drug loading and release rate in vitro were used as the evaluation indexes. The average molecular weight of PLGA, the preparation method of colostrum, and the stirring rate were investigated by single factor. The effects of the volume of internal water phase on the particle size, encapsulation efficiency and release rate of the microspheres, The optimized preparation of microspheres was used to determine the drug loading and encapsulation efficiency of PLGA-rifampicin sustained-release microspheres by UV spectrophotometer. The morphology of PLGA-rifampicin sustained-release microspheres was observed by scanning electron microscope (SEM). The particle size and distribution of the microspheres were measured. The stability of PLGA-rifampicin sustained release microspheres at different temperatures was observed by using PBS solution as the release medium, and the release characteristics in vitro were studied. The standard curve of rifampicin was established by high performance liquid chromatography (HPLC). To study the release characteristics of PLGA-rifampicin sustained-release microspheres (PLGA-rifampicin sustained-release microspheres) were used to measure the concentration of rifampicin in plasma and tissue samples. Results the microspheres with smooth shape, smooth surface and orange red eye were optimized for the formulation: 1: 1: 1: 1 PLGA 503H Mw65000) and PLA 200mg, dissolved in 2ml dichloromethane. After stirring for 20 minutes in the saturated solution of 1%PVA, 20ml, and then transferred to the saturated solution of 100ml0.2%PVA for 20 minutes, the amount of drug loaded in the volatile solvent of 4hu ~ (3) and lifampicin was 42.95 and the entrapment efficiency was 87.83 ~ (3) the particle size distribution of the microspheres was approximately normal, and the particle size distribution of the microspheres was similar to that of the 100ml0.2%PVA saturated solution, and the particle size distribution of the microspheres was approximately normal. Characteristics of in vitro release of rifampicin sustained-release microspheres: in vitro release of rifampicin microspheres was in a zero-order mode with a sudden release of less than 25% in 24 hours and up to 81% in two weeks. In vivo release characteristics of rifampicin sustained-release microspheres: rifampicin sustained-release microspheres and rifampicin microspheres were released in vivo: rifampicin sustained release microspheres and rifampicin microspheres were released in vivo. The original drug was implanted into rabbit paravertebral vertebrae in proportion. The concentration of rifampicin measured in lumbar 6 vertebra and psoas major muscle can be maintained above the minimum inhibitory concentration of Mycobacterium tuberculosis (MIC) until 28 days after operation, but the rifampicin concentration in the lumbar 6 vertebrae and psoas major muscle of rifampicin sustained-release microsphere paravertebral delivery group is below the concentration of rifampicin in the lumbar vertebrae and psoas major muscle. The descending trend was more gentle than that of rifampicin paravertebral administration group. It lasted longer, while other tissues, such as liver and lung, did not accumulate significantly. Conclusion the PLGA-rifampicin sustained-release microspheres prepared by the emulsified solvent volatilization method (W / O / W) have an average particle size of 124u m.The appearance, drug loading and encapsulation efficiency of PLGA-rifampicin microspheres are excellent. The effects of carrier material and other parameters on encapsulation efficiency, drug loading and release behavior of microspheres were significant. The release of PLGA-rifampicin sustained-release microspheres was stable in vitro, and the release of microspheres was in zero order mode. After sustained release of PLGA-rifampicin microspheres in rabbit paravertebral, the concentration of rifampicin measured in lumbar 6 vertebrae and psoas major muscle could be maintained above the minimum inhibitory concentration of Mycobacterium tuberculosis (MIC) until 28 days after operation, and the decrease of local rifampicin concentration was stable. There was no obvious accumulation of liver, lung and other tissues.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943

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