柔红霉素聚氰基丙烯酸正丁酯毫微粒制备工艺的优化

用乳液聚合法制备柔红霉素聚氰基丙烯酸正丁酯毫微粒,在单因素试验基础上,通过系统全面反馈动态技术优化,确定了处方和制备工艺。载药毫微粒平均粒径６０ｎｍ,分布范围３０～２２０ｎｍ,表观包封率９６．３６％,表观载药量５５．３３％（ｇ／ｇ）;有效包封率７４．１１％,有效载药量４２．２５％（ｇ／ｇ）。     

异烟肼肺靶向性微球的制备及其小鼠体内分布

目的：制备异烟肼肺靶向性微球,评价其体外释药特性及在动物体内的肺靶向性。方法：采用溶剂挥发法制备微球,动态透析法考察其体外释药性能,实验动物静脉注射后测定其各组织的药物浓度,研究其体内相对分布百分率及肺靶向性。结果：制得的微球粒径在7～30μm的占微球总数的88．8％,平均粒径为（16.7±4．6）μm,包封率为86．92％,载药量为（40．7±3.6）％（n=5）,体外释药T50为68min,轻对照组延长了4.5倍。动物实验表明,制得微球后,药物在肺内的相对分布百分率明显高于其它组织与血液,并轻对照组提高了4倍。结论：本法制得的异烟肼微球具有明显的缓释性及肺靶向性。     

阿柔比星A聚乳酸毫微粒主要性质研究

目的：对载药毫微粒主要质量指标载药量、包封率及其关系,粒径及其分布进行研究,方法：以阿柔比星Ａ聚乳酸微粒为研究对象,以分光光度测定载药量与包封率,以激光粒度分析仪测定粒径及其分布。结果：阿柔比星Ａ聚乳酸毫微粒平均载药量为１８．５％。平均包封率为８６．７％,平均数目径为８０ｎｍ,平均体积径为２３０ｎｍ。结论：载药量与包封率之间具有一定关系。体积径分布是载药毫微粒粒径分布评价不可忽视的内容。     

盐酸川芎嗪肺靶向微球理化性质的研究

考察了盐酸川芎嗪肺靶向微球的微粉学性质、热解稳定性、载药量和体外释药模式。结果表明，微球为类白色圆球状粉末，平均算术粒径为１２．６５μｍ，５～２４．９μｍ，粒径范围的微球数占总数的８７．５％，平均堆密度为０．５９ｇ／ｍｌ，休止角为６８．６３°，临界相对湿度为５６％，热解活化能为８１．６ｋＪ／ｍｏｌ，反应级数为１。用ＵＶ法测得微球载药量为１７．０％，微球体外释药符合一级动力学规律。微球粒径符合肺靶向要求     

柔红霉素隐形脂质体的药剂学性质

本文研究了柔红霉素隐形脂质体的药剂学性质。考察了柔红霉素隐形脂质体的形态和粒径分布;考察了柔红霉素隐形脂质体的包封率和脂质体在Hepes缓冲液(pH 7.5)和大鼠血清中的体外释放行为。结果表明所制备的柔红霉素隐形脂质体包封率高(>85%),平均粒径为56.3 nm,体外释放慢。结论认为制备的隐形脂质体包封率较高,药剂学性质较好,适于临床使用。     

23—H1基因在膀胱癌中的表达及意义

目的 研究ｎｍ２３－Ｈ１基因在膀胱癌中的表达并探讨其临床意义。方法 用免疫组化ＬＳＡＢ法分析ｎｍ２３－Ｈ１基因表达与膀胱癌多种指标的关系。结果 ｎｍ２１－Ｈ１基因在５６例膀胱癌中的阳性表达率为６９．６％。在高、中及低分化癌中的阳性率分别有３Ｒ５．０％、８４．６％、９０．０％,ｎｍ２３－Ｈ１基因高度表达与膀胱癌的分级及淋巴结转移有关,与年龄、性别、肿瘤大小及复发无关。结论ｎｍ２３－Ｈ１基因可能在膀胱     

RGD修饰的多柔比星脂质体的制备及荷瘤动物活体成像研究

目的制备精氨酸-甘氨酸-天冬氨酸环状三肽(arginine-glycin-aspartic acid,RGD)序列修饰的多柔比星(doxorubicin,DOX)脂质体(RGD-DOX-LP),考察其粒径、zeta电位、包封率,并探究其肿瘤细胞摄取率及在荷瘤裸鼠中的靶向分布情况。方法采用薄膜分散法制备RGD-DOX-LP及多柔比星脂质体(DOX-LP)。荧光分光光度法研究SUP-M2细胞对RGD-DOX-LP,DOX-LP及DOX溶液的摄取效率。以Cyp790为染料,采用近红外小动物活体成像仪研究比较Cyp靶向脂质体(Cyp-RGDDOXLP)与Cyp常规脂质体(Cyp-DOX-LP)在荷瘤裸鼠体内的分布情况。结果 RGD-DOX-LP粒径为(117±1.8)nm,zeta电位为(-12.46±0.86)mv。细胞摄取实验结果显示,SUP-M2细胞对RGDDOXLP的摄取率是DOX-LP的2.8倍,差异有统计学意义(P<0.05)。在荷瘤裸鼠中,Cyp-RGDDOXLP组在肿瘤部位的荧光强度显著高于Cyp-DOX-LP组,荧光持续时间也显著延长。结论 RGD修饰载多柔比星的脂质体能够高效、靶向性地富集于肿瘤组织,是一种有效的抗肿瘤给药系统。     

米托蒽醌聚乳酸缓释毫微粒针剂的制备

在单因素实验的基础上用均匀设计优化了米托蒽醌聚乳酸缓释微粒的制备方法。空白和载药微粒的平均粒径分别为１２９．９６和１３３．１５ｎｍ;包封率为９９．２３％;载药量为１３．５６％;制备收率为９９．３％。以乳和支架剂制得的冻干针剂外型美观、理化性质稳定,再分散后平均粒径为１５２．０２ｎｍ。用动态透析系统考察了不同分子量聚乳酸毫微粒冻干针剂的体外释药特性,结果显示高分子量聚乳酸微粒的释药速度明显慢于低分子     

不同浓度吐温—80对红霉素口腔药膜的均匀度与释放率的影响

红霉素口腔药膜处方中加入适量表面活性剂吐温－８０，可提高膜剂中主药分布均匀度与释放率。本文以０．１％、０．３％、０．５％、１％四种不同浓度分别进行考察，实验结果表明，０．５％吐温－８０的膜剂最为理想，符合膜剂的质量要求。     

柔红霉素长循环脂质体的药剂学性质及大鼠体内药代动力学研究

目的研究柔红霉素长循环脂质体的药剂学性质及大鼠体内药代动力学。方法考察柔红霉素长循环脂质体的形态和粒径分布、包封率和加速实验稳定性;建立脂质体中柔红霉素含量测定的可见分光光度法和HPLC方法;考察脂质体在Hepes缓冲液(pH 7.5)和大鼠血清中的体外释放行为。考察脂质体在大鼠体内的药代动力学行为。结果制备的柔红霉素长循环脂质体包封率高(>85%)、稳定性好,平均粒径为56.3 nm,体外释放慢;长循环脂质体的T_1/2α和AUC分别是注射剂的17.6和96倍。结论制备的长循环脂质体包封率较高,药剂学性质稳定,在大鼠体内的药代动力学参数优于注射剂,能达到长循环目的。     

肝靶向羟基喜树碱缓释毫微粒的研究

采用吸附—包裹法制备了聚乙烯吡啶烷酮包被的羟基喜树碱聚氰基丙烯酸正丁酯毫微粒。研究了该毫微粒的形态、粒径及粒径分布、载药量、体外释药特征、动物体内的分布与药代动力学参数。结果表明平均粒径dav=81.2nm,载药量为1.22%,体外释药速率符合Higuchi方程:Q=0.0615+0.0940t,静脉注射后15min,即有68.2%羟基喜树碱浓集于肝脏。血浆药浓—时间曲线符合二室开放药动学模型。主要药动学参数为:Vc=3.548L,T_1/2β=146.99h,CL=0.1788L·h^-1。说明该载药毫微粒具有明显的肝靶向和缓释作用。本文报道的吸附─包裹法对水、脂不溶性药物聚氰基丙烯酸酯毫微粒的制备具有一定参考价值。     

Improved targeting of antimony to the bone marrow of dogs using liposomes of reduced size

A novel liposomal formulation of meglumine antimoniate (MA), consisting of vesicles of reduced size, has been evaluated in dogs with visceral leishmaniasis to determine its pharmacokinetics as well as the impact of vesicle size on the targeting of antimony to the bone marrow. Encapsulation of MA in liposomes was achieved through freeze-drying of empty liposomes in the presence of sucrose and rehydration with a solution of MA. The resulting formulation, with a mean vesicle diameter of about 400 nm, was given to mongrel dogs with visceral leishmaniasis as an i.v. bolus injection at 4.2 mgSb/kg of body weight. The pharmacokinetics of antimony were assessed in the blood and in organs of the mononuclear phagocyte system and compared to those achieved with the free drug and the drug encapsulated in large sized liposomes (mean diameter of 1200 nm). The targeting of antimony to the bone marrow was improved (approximately three-fold) with the novel liposomal formulation, when compared to the formulation of MA in large sized liposomes. This study provides the first direct experimental evidence that passive targeting of liposomes to the bone marrow of dogs is improved by the reduction of vesicle size from the micron to the nanometer scale.     

乙酰半胱氨酸纳米粒的制备及在小鼠体内的分布

以壳聚糖为载体,溶剂扩散法制备乙酰半胱氨酸纳米粒,制得的纳米粒呈大小均匀的球形,平均粒径(163.0±12.8)nm,包封率(81.2+1.2)%,载药量(28.9+0.4)%。用HPLC法测定了小鼠单剂量尾静脉注射乙酰半胱氨酸纳米粒或其注射液后各脏器(心、肝、脾、肺和肾)和血浆中的药物浓度,并以相对摄取量和靶向效率评价纳米粒的靶向性。结果表明,纳米粒明显改变了药物在小鼠体内的生物分布。与注射液组相比,纳米粒组在肝组织中乙酰半胱氨酸浓度明显提高,血浆、心和肾组织中的药物浓度显著降低。     

Distribution and pharmacokinetics of the prodrug daunorubicin-GA3 in nude mice bearing human ovarian cancer xenografts

N-[4-daunorubicin-N-carbonyl (oxymethyl)phenyl] O-beta-glucuronyl carbamate (DNR-GA3) is a glucuronide prodrug of daunorubicin (DNR) which induced a better tumor growth delay than DNR when studied at equitoxic doses in three human ovarian cancer xenografts. These results suggested that the prodrug DNR-GA3 was selectively activated by human beta-glucuronidase present in tumor tissue. We determined the pharmacokinetics and distribution of DNR-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3, FMa, A2780, and MRI-H-207). Administration of DNR at 10 mg/kg i.v. (maximum tolerated dose) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 12.18 microM (t = 1 min). DNR-GA3 at 100 mg/kg i.v. (approximately 50% of the maximum tolerated dose [MTD]) resulted in a peak plasma concentration of DNR that was 28-fold lower than that after DNR itself; in normal tissues, prodrug injection resulted in 5- to 23-fold lower DNR concentrations. DNR showed a relatively poor uptake into OVCAR-3 tumors with a peak concentration of 2.05 nmol x g(-1) after injection. In the same xenograft, DNR-GA3 resulted in a significantly higher DNR peak concentration of 3.45 nmol x g(-1) (P < 0.05). The higher area under the curve of DNR in tumor tissue after DNR-GA3 than after DNR itself would be the result of prodrug activation by beta-glucuronidase. In this respect, a considerably higher beta-glucuronidase activity was found in tumor tissue when compared to plasma. The specific activation of DNR-GA3 by beta-glucuronidase at the tumor site relative to normal organs leads to a more tumor-selective therapy, resulting in greater efficacy without increased toxicity.     

肝靶向万乃洛韦毫微粒的研究

为提高核苷类药物对乙型肝炎的疗效并降低其毒性,用乳化聚合法制备了万乃洛韦聚氰基丙烯酸正丁酯毫微粒,对其形态、大小及其分布、体外释药特性、载药量、初步稳定性、动物体内的分布和体外肝细胞的摄取情况进行了研究。结果表明,该毫微粒粒径d_av=104.77±11.78nm;载药量11.20%;包封率84.85%;体外释药符合双相动力学规律;对肝细胞具有通透性;静注后15min有74.49%集中在肝脏。提示,万乃洛韦毫微粒对于提高万乃洛韦对病毒性乙型肝炎的治疗效果和降低其对肾脏的毒性有意义。     

Targeting bone marrow with the help of polyalkylcyanoacrylate nanoparticles]

Using a mouse model, we examine drug targeting towards bone marrow. One cytotoxic (doxorubicin) and one stimulating (rhG-CSF), bound to polyalkylcyanoacrylate nanoparticles, were studied. Histological studies, using a fluorescence microscope, showed rapid capture of nanoparticles by bone marrow macrophages and granulocytes as soon as 15 minutes after injection into the blood stream. Doxorubicin nanoparticles, administered at a dose of 11 mg/kg were more toxic than free doxorubicin on all blood and marrow cell lines. Moreover, the choice of the nature of the polymer had an influence on toxicity: doxorubicin polyisohexylcyanoacrylate nanoparticles were more toxic than polyisobutylcyanoacrylate particles. Quantification of doxorubicin in bone marrow has confirmed these results. The bone marrow concentrations observed demonstrated that there was a high level of targeting towards the bone marrow that would be very interesting to use for a stimulating drug. Nevertheless, rhG-CSF nanoparticles did not show better efficacy than free rhG-CSF.     

Development of gelatin microspheres loaded with diclofenac sodium for intra-articular administration

We have previously reported on the targeting of diclofenac sodium in joint inflammation using gelatin magnetic microspheres. To overcome complications in the administration of magnetic microspheres and achieve higher targeting efficiency, the present work focuses on the formulation of gelatin microspheres for intra-articular administration. Drug-loaded microspheres were prepared by the emulsification/cross-linking method, characterized by drug loading, size distribution, scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), gas chromatography, and in vitro release studies. The targeting efficiency of microspheres was studied in vivo in rabbits. The microspheres showed drug loading of 9.8, 18.3, and 26.7% w/w with an average size range of 37–46 µm, depending upon the drug–polymer ratio. They were spherical in nature and free from surface drug as evidenced by the SEM photographs. FT-IR, DSC, and XRD revealed the absence of drug–polymer interaction and amorphous nature of entrapped drug. Gas chromatography confirms the absences of residual glutaraldehyde. The formulated microspheres could prolong the drug release up to 30 days in vitro. About 81.2 and 43.7% of administered drug in the microspheres were recovered from the target joint after 1 and 7 days of postintra-articular injection, respectively, revealing good targeting efficiency.     

脑靶向3′,5′-二辛酰基-5-氟脲嘧啶脱氧核苷药质体研究

目的　为提高氟苷的脑靶向性,以增强疗效,降低毒副作用,制备其前体药物3′,5′-二辛酰基-氟苷的药质体。方法　用薄膜 超声分散法制备药质体,中心组合设计优化制备工艺,反向动态透析法测定体外释药情况,HPLC法测定小鼠iv后在体内各组织的分布。结果　药质体平均粒径为76nm ,载药量为29.02% ,包封率为96.62% ;体外释药过程符合双指数方程;以氟苷注射液为对照,药物在小鼠脑中靶向指数为对照液的10.97倍;并可显著延长药物在血液中的滞留时间。结论　氟苷酯化前体药物的药质体在体内有良好的脑靶向性,可作为新型的脑给药系统     

Injectable actarit-loaded solid lipid nanoparticles as passive targeting therapeutic agents for rheumatoid arthritis

This work systematically studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with actarit, a poor water soluble anti-rheumatic drug. The goal of this study was to design passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects such as nephrotoxicity and gastrointestinal disorders commonly associated with oral formulations of actarit. Based on the optimized results of single-factor and orthogonal design, actarit-loaded SLNs were prepared by a modified solvent diffusion-evaporation method. The formulated SLNs were found to be relatively uniform in size (241+/-23 nm) with a negative zeta potential (-17.14+/-1.6 mV). The average drug entrapment efficiency and loading were (50.87+/-0.25)% and (8.48+/-0.14)%, respectively. The actarit-loaded SLNs exhibited a longer mean retention time in vivo (t(1/2(beta)), 9.373 h; MRT, 13.53 h) compared with the actarit 50% propylene glycol solution (t(1/2(ke)), 0.917 h; MRT, 1.323 h) after intravenous injection to New Zealand rabbits. The area under curve of plasma concentration-time (AUC) of actarit-loaded SLNs was 1.88 times greater than that of the actarit in 50% propylene glycol solution. The overall targeting efficiency (TE(C)) of the actarit-loaded SLNs was enhanced from 6.31% to 16.29% in spleen while the renal distribution of actarit was significantly reduced as compared to that of the actarit solution after intravenous administration to mice. These results indicated that injectable actarit-loaded solid lipid nanoparticles were promising passive targeting therapeutic agents for rheumatoid arthritis.     

Preparation and passive target of 5-fluorouracil solid lipid nanoparticles

This work studied the intravenous injection formulation of solid lipid nanoparticles (SLNs) loaded with 5-fluorouracil (5-FU). The goal was to design longer drug residence in vivo and passive targeting nanoparticles which could improve therapeutic efficacy and reduce side-effects. Based on the optimized results of uniform design experiment, 5-FU-SLNs were prepared by multiple emulsion-ultrasonication (w/o/w). The SLNs were found to be relatively uniform in size (182.1?±?25.8?nm) with a negative zeta potential (?27.89?±?5.1 mV). The average drug entrapment efficiency and loading were 74% and 10%, respectively. Compared with the 5-FU solution (t_1/2β, 0.593h; MRT, 0.358h) after intravenous injection to rats, the pharmacokinetic parameters of 5-FU-SLNs exhibited a longer retention time. (t_1/2β, 4.0628h; MRT, 3.5321h). The area under curve of plasma concentration-time (AUC) of 5-FU-SLNs was 1.48 times greater than that of free drugs. The overall targeting efficiency (TE^C) of the 5-FU-SLNs was enhanced from 13.25–20.45% in the lung and from 11.48–23.16% in kidney while the spleen distribution of 5-FU was significantly reduced as compared with that of the 5-FU solution. These results indicated that 5-FU-SLNs were promising passive targeting therapeutic agents for curing primary lung carcinoma.