肝动脉栓塞用顺铂白蛋白微球的研究

按正交设计筛选乳化热固化法制备顺铂白蛋白微球的最佳工艺,并对影响微球粒径大小和体外释药速率的诸多因素进行了研究。该微球粒径范围为50.8～256μm。平均粒径为148.46μm,药物含量为51.16%(W/W)。兔肝动脉栓塞后,与对照组相比铂的分布半衰期延长336%,消除半衰期延长123%,体内最高血浓仅为对照组的30%。肝组织顺铂量显著增加(P<0.01),肾组织药物量明显降低(P<0.05),体内外相关性研究表明顺铂白蛋白微球体外累积溶出百分率与兔体内药物吸收分数呈显著相关(P<0.01)。     

盐酸川芎嗪肺靶向微球的研究

用乳化法制备盐酸川芎嗪明肢微球,优化了工艺。对微球的外观、粒径与其分布、含量、体外释药、稳定性及体内分布等进行研究。结果表明平均粒径为12.65μm,粒径范围5.0～24.9μm占总数的87.5%,球内含药量平均为16.49%±0.49%(n=3),冰箱或室温放置稳定,体外释药符合一级动力学规律,释药t_1/2比原药延长约5倍。小鼠静注微球后20 min,在肺内的相对分布百分率明显高于其它组织与血液,与溶液对照组相比,提高近6倍。     

肺靶向卡铂明胶微球的研究

目的:为提高卡铂的疗效,降低毒副作用,制备了该药的明胶微球。方法:用乳化法制备卡铂明胶微球,紫外分光光度法测定药物的含量,二阶导数法测定体外释药情况;用静脉注射肿瘤细胞建立了肺肿瘤模型,计算瘤结节数来考察疗效。结果:卡铂明胶微球平均粒径为13-20 μm ,粒径范围5-0～28-6 μm 的微球数占总数的91-8% 。微球平均载药量为23-76%(n=3) 。冰箱、室温和37℃,RH75% 考察3个月,几乎无变化,体外释药符合一级动力学规律,释药T_1/2 比原药延长约10倍。药效学实验表明,卡铂明胶微球对小鼠肺部S180肿瘤生长有明显的抑制作用,抑瘤作用较原药卡铂大大提高。结论:卡铂明胶微球在体内有良好的肺靶向性,对提高药物的疗效,降低药物毒副作用等方面有重大意义。     

新型可降解聚酯材料地西泮缓释微球的研制

目的　优化制备工艺,用新型的生物可降解材料聚羟基丁酸酯—羟基戊酸酯共聚物（PHBV）与D,L-聚乳酸（PLA）共混物为基材制备以地西泮（diazepam,DZP）为模型药物的缓释微球（MS）。方法　用正交设计优化微球制备工艺,用扫描电镜（SEM）观察微球表面形态。对微球粒径及其分布、体外释药、稳定性及在动物体内药动学进行了测定。结果　微球平均粒径为(20.45±4.50) μm,粒径在15.5～35.2 μm占总数88%以上。载药量为(16.95±0.80)%,包封率为(69.68±1.13)%;体外释药方程为Q=2.7027t+13.50(γ=0.9827),动物体内实验表明,微球的血药浓度-时间曲线下面积AUC是溶液对照组的2.35倍,平均驻留时间MRT是对照组的3.62倍。微球在冰箱4℃与室温（20～25℃）条件下性质稳定。结论　微球制备工艺稳定,与DZP针剂相比,具有明显缓释作用。     

关节腔注射用氟比洛芬PLGA缓释微球的制备及体外释放特性研究

目的制备关节腔注射用氟比洛芬(FP)缓释微球并研究其体外释药特性。方法以聚乳酸-羟基乙酸共聚物(PLGA)为材料,采用乳化-溶剂挥发法制备微球;正交设计法优化微球的制备工艺;采用透析法研究体外释药特性,UV法测定FP的含量。结果正交试验表明,PLGA的浓度是影响微球包封率的非常显著性因素。微球粒径范围为1.5~24.3μm,平均粒径为10.6μm,载药量为7.1%(W/W),包封率为92.7%,体外释药符合Higuchi方程,释放时间显著延长。结论本法制备的FP微球粒径大小适宜,具有明显的缓释作用,符合关节腔注射给药设计要求。     

肺靶向利福平聚乳酸微球的研究

在单因素考察的基础上进行正交试验设计,筛选出肺靶向利福平聚乳酸微球的最佳制备工艺条件;利用桨板法研究了微球的体外释药规律;考察了微球在不同温度下的稳定性;用新西兰兔为实验对象,研究了利福平聚乳酸微球的体内药动学及组织药物分布。结果制得的微球形态圆整,粒径在5～15μm范围内的占总体积的86.54%,微球平均粒径为9.00±4.08μm;包封率为31.9%;载药量为16.0%;体外释药方程为Q=20.77+10.12T_1/2(γ=0.9892);微球在冰箱4℃和室温(20～25℃)条件下性质稳定;体内实验表明微球具有长效和肺靶向双重作用。     

左炔诺孕酮-聚3-羟基丁酸酯缓释微球的研究

目的：优化制备工艺,用可生物降解的成球材料制备缓释并有优良抗生育效果的左炔诺孕酮-聚3-羟基丁酸酯微球。方法：以均匀设计优化微球的液中干燥法制备工艺,用DTA确证含药微球的形成,对微球的外观、粒径、载药量、体外释药、稳定性及小鼠体内抗生育等进行了研究。结果：微球平均粒径为64 μm,(28.7～85.8) μm的微球占总数90％以上,微球中氯仿残留量低于0.001％,体外释药符合Higuchi方程,释药T_1/2比原药延长约1.8倍,4,25及40℃(RH 75%)放置3个月稳定。对小鼠具有抗生育效果。结论：微球的制备工艺满意,与原药相比,微球对小鼠有明显的缓释、延长抗生育时间和降低毒性的作用。     

莪术油明胶微球用于肝动脉栓塞

目的　制备符合肝动脉栓塞要求的莪术油明胶微球(ZT-GMS)。方法　用正交设计优化了微球的制备工艺,对微球的制备工艺、粉体学性质、体外释药、初步稳定性和初步药效进行了研究。结果　球径在40～160 μm的微球占97.16%,平均产率为89.73%,平均含药量为2.13%,平均包封率为19.36%(均以莪术醇计)。体外释药12 h达80%,符合一级动力学模型,释药机理为溶蚀加扩散。稳定性考察实验结果表明其稳定性较好。肝动脉栓塞荷瘤大鼠实验结果表明大鼠平均生存率显著延长(P<0.01),肿瘤体积显著减小(P<0.01)。结论　微球的制备工艺及粒径分布较好,体外释药有明显的缓释作用,有一定疗效。     

关节腔内注射用氟比洛芬明胶微球的制备及体外释药的研究

氟比洛芬是布洛芬类非甾体抗炎药物（NSIDs），临床上用于急性或长期类凤湿性关节炎与骨关节炎的治疗，但口服给药对胃肠道有刺激性，且代谢迅速，局部药物浓度低，为了提高局部药物浓度，延长作用时间，探求缓释微球关节腔给药的可行性，我们选用药用A型明胶为材料，氟比洛芬为模型药物制备了粒径大小符合关节腔注射要求的氟比洛芬明胶微球，粒径分布集中在2．5－12．3μm范围内，药物的包封率为5．02％，氟比洛芬明胶微球体外释药缓慢，t70＝12h，符合Higuchi释药规律。     

褪黑激素明胶微球的鼻腔给药

目的　制备经鼻粘膜给药的褪黑激素明胶微球,以提高其生物利用度。方法　用乳化交联技术制备褪黑激素明胶微球,用放射性核素^99mTc标记,用γ射线闪烁显像技术考察微球在鼻粘膜滞留时间,用HPLC法测定药物的体内吸收。结果　褪黑激素明胶微球粒径在30～70 μm,平均粒径为50.2 μm,褪黑激素含量为13.48%。与滴鼻液相比,明胶微球在鼻粘膜滞留时间明显延长。褪黑激素明胶微球的绝对生物利用度为87.47%。结论　鼻粘膜给药明胶微球,能避免肝脏首过作用,延长药物在鼻粘膜滞留时间,提高药物吸收,有很好的应用前景。     

Preparation and evaluation of biodegradable flubiprofen gelatin micro-spheres for intra-articular administration

Purpose: A controlled release delivery system that localizes flurbiprofen (FP) in synovial joint is prefered to treat inflammation in rheumatoid arthritis (RA). The purpose of this study is to develop and characterize FP-loaded gelatin microspheres and evaluate FP plasma concentrations following intra-articular injection into healthy rabbits.

Methods: Flurbiprofen gelatin microspheres (FP-GMS) were prepared by a emulsion-congealing method. The RP-HPLC method was established to determine the FP concentraion in plasma. The particle size of FP-GMS with optimized formulation was 2.5?～?12.3?µm with a mean size of gelatin microspheres of 7.53?µm. The drug loading efficiency was 5.02% (w/w). The dissolution profile of the FP-GMS was depicted by Higuchi kinetics.

Results: The half time for 50% release of FP from FP-GMS (t₅₀) was 5.58?h. A total of 96% original FP was remained in the microspheres after being stored under 75% humidity and 37°C for 3 months. The pharmacokinetics study demonstrated that the mean resident time (MRT) of FP in the FP-GMS group was prolonged vs. the injection group significantly (p?<?0.01) after intra-articular administration into healthy rabbit hind joints. The T_p of FP-GMS group was prolonged by 2.03-times and the C_max was decreased by 5.57-times vs. that of the injection group, respectively. The FP plasma concentration in FP-GMS was 8-fold higher than that of the FP injection group at 8?h. In addition, FP was rapidly cleared from blood circulation within 8?h with the injection group while FP was retained for more than 24?h with the FP-GMS group.

Conclusions: These data indicate that the simple emulsion-congealing method can be used to encapsulate water soluble drugs such as FP for the treatment of inflammatory disease within the joint cavity.     

Preparation and evaluation of biodegradable flubiprofen gelatin micro-spheres for intra-articular administration

PURPOSE: A controlled release delivery system that localizes flurbiprofen (FP) in synovial joint is prefered to treat inflammation in rheumatoid arthritis (RA). The purpose of this study is to develop and characterize FP-loaded gelatin microspheres and evaluate FP plasma concentrations following intra-articular injection into healthy rabbits. METHODS: Flurbiprofen gelatin microspheres (FP-GMS) were prepared by a emulsion-congealing method. The RP-HPLC method was established to determine the FP concentraion in plasma. The particle size of FP-GMS with optimized formulation was 2.5 approximately 12.3 microm with a mean size of gelatin microspheres of 7.53 microm. The drug loading efficiency was 5.02% (w/w). The dissolution profile of the FP-GMS was depicted by Higuchi kinetics. RESULTS: The half time for 50% release of FP from FP-GMS (t(50)) was 5.58 h. A total of 96% original FP was remained in the microspheres after being stored under 75% humidity and 37 degrees C for 3 months. The pharmacokinetics study demonstrated that the mean resident time (MRT) of FP in the FP-GMS group was prolonged vs. the injection group significantly (p < 0.01) after intra-articular administration into healthy rabbit hind joints. The T(p) of FP-GMS group was prolonged by 2.03-times and the C(max) was decreased by 5.57-times vs. that of the injection group, respectively. The FP plasma concentration in FP-GMS was 8-fold higher than that of the FP injection group at 8 h. In addition, FP was rapidly cleared from blood circulation within 8 h with the injection group while FP was retained for more than 24 h with the FP-GMS group. CONCLUSIONS: These data indicate that the simple emulsion-congealing method can be used to encapsulate water soluble drugs such as FP for the treatment of inflammatory disease within the joint cavity.     

Preparation and evaluation of micro-porous ethylcellulose capsule as oral sustained-release preparation of theophylline

Micro-porous ethylcellulose (EC) membrane capsules were prepared by dissolving polyvinylalcohol (PVA) particles from membranes which were made of a mixture of EC (a water-insoluble polymer). The pore size was approximately 400 μm. Since the dissolution rate of theophylline from the micro-porous EC membrane capsules was fast, gel-forming polymer, poly(acyclic) acid (Carbomer), was incorporated inside the capsule at 10, 20 or 30 mg. Using test capsules containing 100 μm of theophylline, in vitro dissolution studies were performed. By including Carbomer in capsule formulations, the dissolution rate of theophylline was decreased. However, there were not significant differences in dissolution rates between preparations containing the three different amounts of Carbomer. In vivo evaluation studies using beagle dogs showed that AUC, C_max and T_max were inversely proportional to the formulated amount of Carbomer. The capsule containing 20 mg of Carbomer gave plasma theophylline concentrations between 5 and 15 μg mL⁻¹, which reflect levels within the therapeutic window. The effect of food intake on the pharmacokinetics of theophylline was also studied with the same capsule. Food increased AUC, C_max and T_max, although plasma theophylline levels were maintained within the therapeutic range. © 1998 John Wiley & Sons, Ltd.     

Targeted delivery of diclofenac sodium via gelatin magnetic microspheres formulated for intra-arterial administration

In the present work, we have attempted to deliver diclofenac sodium to a target site by intra-arterial injection of gelatin magnetic microspheres and subsequent localization using an external magnet. Drug-loaded magnetic microspheres were prepared by emulsification/cross-linking method, characterized by drug loading, magnetite content, size distribution, optical microscopy, scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) analysis, differential scanning calorimetry (DSC), X-ray diffraction (XRD), absence of glutaraldehyde by gas chromatography, and in vitro release studies. The targeting efficiency and the therapeutic efficacy of microspheres were studied in vivo in rabbits. The microspheres showed drug loading of 9.1, 18.7, 24.9% w/w, magnetite content of 27.8–28.9% w/w with an average size range of 25–30.6 μm, depending upon the drug–polymer ratio. They were spherical in nature as evidenced by optical microscopy and SEM. FT-IR, DSC, and XRD studies revealed the absence of drug–polymer interaction. Gas chromatography confirmed the absence of residual glutaraldehyde. The microspheres were able to prolong the drug release over 24–30 days and the application of sonication during in vitro release study has slightly increased the release rate. After intra-arterial administration of microspheres, 77.7% of injected dose was recovered at the target site which revealed good targeting efficiency. The microspheres effectively reduced joint swelling, but lesser extent than the oral diclofenac sodium in high dose, in antigen induced arthritic rabbits without producing gastric ulceration which was observed in rabbits treated with oral diclofenac sodium.     

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.     

Preparation of magnetic gelatin microspheres for the targeting of drugs

Magnetically responsive gelatin microspheres for the targeting of drugs have been prepared using a water-in-oil emulsion technique with chemical cross-linking of the protein. The manufacturing variables affecting microsphere size, size distribution and surface characteristics have been examined as well as the magnetic responsivenessin vitro. Sesame oil was utilized for non-aqueous phase and magnetic gelatin microspheres of different size from 1.89 to 14.88 μm in mean diameter could be obtained with variation of HLB values of non-ionic surfactants. The content of magnetite which uniformly distributed throughout the microspheres was 26.7% (w/w). It was possible to control the localization of magnetic gelatin microspheres at specific sites within capillary models by using external magnetic field of under 5K gauss.     

IN VIVO/IN VITRO CORRELATIONS FOR FOUR DIFFERENTLY DISSOLVING KETOROLAC TABLETS

This study assesses whether in vitro immediate release ketorolac tablet dissolution profiles (utilizing the recently proposed USP dissolution test for ketorolac tablets) can be correlated with in vivo plasma pharmacokinetic parameters. Four batches of ketorolac tablets were utilized: a ketorolac tablet batch that demonstrated a rapid dissolution rate during USP in vitro dissolution testing, two tablet batches that were manufactured such that they dissolved at moderate rates, and a tablet batch that was manufactured such that it dissolved at a distinctly slow rate. The single-dose mean pharmacokinetic characteristics and relative bioavailability of the four different 10 mg ketorolac tromethamine tablets were evaluated in 12 healthy volunteers in a randomized study of Latin square design. The amount dissolved of the various tablets at 10, 20, and 30 min was in the order of fast-dissolving tablets > medium-1-dissolving tablets=medium-2-dissolving tablets > slow-dissolving tablets. In general, the profiles of the average plasma concentrations for ketorolac were similar for the fast- and the two medium-dissolving tablet batches (even though a statistically significant difference was found between the t_max of the fast-dissolving tablet and one of the medium-dissolving tablet batches). The mean plasma concentrations for the slow-dissolving tablet, however, reached peak levels much later, with the peak also being significantly smaller. There were no statistically significant differences in the total AUC or in the mean plasma half-lives among the four formulations. Good correlations were obtained for mean t_max versus the percentage dissolved at 20, 30, and 45 min. Correlations were generally weaker for percentage dissolved versus C_max or percentage bioavailability. This indicates that in vitro dissolution testing for immediate release ketorolac tablets can be a useful indicator of in vivo time to maximum plasma concentration when comparing similarly formulated tablets. Further, the proposed USP dissolution test and specification would have appropriately failed the slow-dissolving tablet batch, which demonstrated a significantly slower rate of absorption as per t_max and C_max.     

平阳霉素油包明胶微球乳剂(S/O)的研究

用超声分散法制得内相为平阳霉素明胶微球,外相为注射用油的乳剂S/O。其内相独立圆整,在外相中分散均匀,粒径为1.67±0.69μm。乳剂于0℃下贮存稳定,含药量为14.03±0.15mg·ml^-1;体外释药速率符合零级方程,累积释药50%的时间为12.0h。动物实验表明其血药浓度平稳持久,具有极好的淋巴亲和性,并有可能降低肺毒性。