本文選題：異煙肼 + 粉霧劑��； 參考：《重慶醫(yī)科大學(xué)》2014年碩士論文

【摘要】：目的結(jié)核病是治療療程長、不良反應(yīng)多的嚴(yán)重慢性傳染性疾病，異煙肼（isonicotinohydrazide，INH）是治療肺結(jié)核一線用藥，對結(jié)核桿菌殺菌作用強(qiáng)大，但副作用很大，給藥方式多為口服和靜注。因肺部給藥方式可明顯增強(qiáng)INH臨床療效，故本文通過將INH制成超順磁性微球，然后將微球裝入膠囊和裝置制成粉霧劑，在外磁場引導(dǎo)下，肺靶向給藥，以提高藥物局部濃度和生物利用度，減少藥物本身的不良反應(yīng)，減少胃腸道反應(yīng)、降低肝功能損害，并減少給藥次數(shù)。為結(jié)核病的治療和INH用藥新劑型的開發(fā)提供基礎(chǔ)。 方法本課題首先采用去溶劑化-交聯(lián)法制備超順磁性氧化鐵納米粒（Superparamagnetic iron oxide，SPIO），再將INH、SPIO和其他載體制成混合溶液，噴霧干燥得到1μm-5μm超順磁性微球，對微球性質(zhì)進(jìn)行了檢測。然后將微球制成粉霧劑，對粉霧劑質(zhì)量指標(biāo)進(jìn)行了檢測。本文同時(shí)進(jìn)行了外磁場制備并檢測其磁性強(qiáng)度，并進(jìn)行了動(dòng)物體內(nèi)分布的研究和外磁場對微球粉霧劑肺部分布的影響實(shí)驗(yàn)。 結(jié)果所得SPIO的zeta電位絕對值約20，平均粒徑29.39nm，DPI值0.185，飽和磁化強(qiáng)度為8.223emu/g，剩余磁化強(qiáng)度為0.0199emu/g，矯頑HC等于1.7Oe，符合超小型超順磁氧化鐵粒子標(biāo)準(zhǔn)。Halbach磁體磁強(qiáng)度在8-9cm的深度距離上大于等于20mT(200Gs)，符合外磁場在血管內(nèi)束縛磁性納米粒的基本要求。確定了噴霧干燥最優(yōu)工藝，所制微球電鏡下為圓形或者橢圓形小顆粒，Dav=1.552μm，D90=2.351μm，擬合系數(shù)=0.951。休止角=38°，振實(shí)密度=0.298g/cm3，排空率為97.2%，平均體外沉積率為42%。體外實(shí)驗(yàn)中于pH=7.4的PBS液中緩釋時(shí)間為8h。引濕性為12.4%，需保存于內(nèi)放硅膠干燥劑的密閉玻璃缸內(nèi)，，微球在此干燥環(huán)境中的4℃和25℃溫度下，6個(gè)月內(nèi)穩(wěn)定，各項(xiàng)理化性質(zhì)均未發(fā)生改變。體內(nèi)微球肺部濃度明顯高于其他器官，單側(cè)外加Halbach磁場組的微球數(shù)明顯超過不加磁場組。 結(jié)論本課題首次將陡脈沖磁場、磁靶向微球與DPI工藝相結(jié)合，將三者優(yōu)點(diǎn)融合后制備出具有磁靶向的異煙肼超順磁性微球粉霧劑，所得微球粉霧劑各項(xiàng)質(zhì)量評價(jià)指標(biāo)符合中國藥典標(biāo)準(zhǔn)，能在外磁場作用下，靶向給藥于肺部局部，對提高INH藥物療效，降低INH對其他器官的損害，提高患者依從性，為結(jié)核病的治療和INH用藥新劑型的開發(fā)提供了實(shí)驗(yàn)基礎(chǔ)。
[Abstract]:Objective Tuberculosis is a serious chronic infectious disease with long course of treatment and many adverse reactions. Isoniazid isonicotinohydrazidezide (INH) is a first-line drug for the treatment of pulmonary tuberculosis, which has a strong bactericidal effect on Mycobacterium tuberculosis, but has great side effects. Because the pulmonary administration can obviously enhance the clinical efficacy of INH, the superparamagnetic microspheres were prepared by INH, then the microspheres were put into capsules and devices to make powder aerosols. Under the guidance of the external magnetic field, the drug was targeted to the lung. In order to improve the local concentration and bioavailability of drugs, reduce the adverse reactions of the drugs themselves, reduce gastrointestinal reactions, reduce liver function damage, and reduce the times of administration. To provide a basis for the treatment of tuberculosis and the development of new dosage forms of INH. Methods the superparamagnetic ferric oxide nanoparticles superparamagnetic iron oxide-SPIOO were prepared by desolvation-crosslinking method. The superparamagnetic microspheres were prepared by spray drying, and the properties of the superparamagnetic microspheres were determined. Then the microspheres were made into powder aerosol and the quality index of powder aerosol was determined. At the same time, the external magnetic field was prepared and its magnetic intensity was measured. The distribution in vivo and the effect of external magnetic field on the pulmonary distribution of microsphere aerosol were studied. Results the absolute value of zeta potential of SPIO is about 20, the average particle size is 29.39 nm, the saturation magnetization is 8.223emu / g, the residual magnetization is 0.0199emu / g, the coercive HC is 1.7Oe, and the magnetic intensity of the superparamagnetic iron oxide particle standard. Halbach magnet is within the depth of 8-9cm. The separation is more than or equal to 20 Mt / 200GsL, which meets the basic requirement of external magnetic field binding magnetic nanoparticles in blood vessel. The optimum technology of spray drying was determined. The microspheres prepared were circular or elliptical small particles Davan 1.552 渭 m D90D902.351 渭 m under electron microscope, and the fitting coefficient was 0.951 渭 m. The angle of repose is 38 擄, the vibrational density is 0.298g / cm ~ 3, the emptying rate is 97.2and the average deposition rate is 42g / cm ~ 3. In vitro, the sustained release time in PBS solution of pH=7.4 was 8 h. The hygroscopicity is 12.4, which needs to be stored in the closed glass cylinder containing silica gel desiccant. The microspheres are stable in this drying environment at 4 鈩

本文編號：1934533