球结膜下注射用西罗莫司缓释微球的制备及其体外释药性能

目的使用3-羟基丁酸-co-3-羟基戊酸共聚物制备西罗莫司缓释微球,为预防和治疗角膜移植术后免疫排斥反应奠定基础。方法采用乳化-溶剂挥发法制备微球,正交实验法优化,测得载药量、包封率等指标,结合光镜观察其形态特征,得出最佳制备条件后,模拟眼内前房环境检测其体外释药性能。结果微球制备工艺稳定,重复性好。微球成球率高,形态圆整,表面光滑,载药量为(37.34±1.25)%,包封率为(99.63±0.93)%,能够在体外稳定缓释,500 h累积释药率为71%。结论西罗莫司缓释微球表征良好,载药量、包封率较高,有望发挥稳定释药的临床作用。     

大蒜素/有机凹凸棒黏土/海藻酸钠/壳聚糖复合微球的制备及其性能

目的制备大蒜素/有机凹凸棒黏土/海藻酸钠/壳聚糖复合微球(ASCM),并研究其载药性能。方法采用复凝聚法制备了ASCM,以复合微球的载药量和包封率为指标,以大蒜素(DATS)为模型药物,考察了有机凹土(OA)/海藻酸钠(SA)质量比、药物含量、复合温度对微球载药性能的影响,并比较了OA加入前后微球的溶胀性能和缓释性能。结果加入OA后,当复合微球中OA:SA为1:3,OA:DATS为1:1时,其载药量和包封率由原来的12.3%和42.3%分别提高到16.8%和66.5%,而在pH 6.8的磷酸盐缓冲溶液中累积释放率降低。结论复合微球可以作为药物的缓释载体。     

奥沙普秦壳聚糖-海藻酸钠缓释微球的制备

目的：目的：选择奥沙普秦作为模型药制备壳聚糖-海藻酸钠缓释微球。方法：采用滴制法制备奥沙普秦壳聚糖-海藻酸钠缓释微球，通过正交试验设计优化了处方和工艺，考察其理化特征及体外释药行为。结果：优化处方制得的微球包封率及载药量分别为98．36％和16．26％，平均粒径为（346．6±164．1）μm；1h药物释放达到36％，随后药物的释药行为是一个缓释过程。结论：制得了载药量较大，包封率较高的奥沙普秦壳聚糖-海藻酸钠缓释微球。     

双氯芬酸钠/海藻酸钠微球的制备与体外释药行为考察

目的以海藻酸钠为载体材料,双氯芬酸钠为模型药物,制备载药微球并考察其性质及体外释放行为。方法本文采用海藻酸钠为药物载体,采用喷雾干燥法制备双氯芬酸钠/海藻酸钠微球。考察于双氯芬酸钠/海藻酸钠投料比对载药微球理化性质的影响。采用扫描电镜对所得到的微球进行形貌观察。同时考察其体外药物释放行为。结果所得到的载药微球形态呈不规则的扁平状,粒径分布较为均匀。通过控制投料比,可以得到不同粒径(5.64～9.58μm),载药量(5.76～18.43%)和包封率(35.45～43.92%)的载药微球。体外药物释放行为结果显示微球在含有0.5%氯化钙的PBS(pH=7.4)溶液的药物释放时间可以持续96h,具有一定的缓释效果。结论通过喷雾干燥法制备的双氯芬酸钠/海藻酸钠载药微球具有较高载药量和一定的药物缓释效果。     

替莫唑胺壳聚糖缓释微球的制备及体外释药特性

目的:制备替莫唑胺壳聚糖缓释微球,并对其体外释药模式进行研究.方法:以替莫唑胺为模型药物,采用乳化交联法制备壳聚糖微球,两步优化法优化处方和制备工艺.通过测定微球的粒径及其分布、载药量、包封率和体外释放速度对微球进行质量评价.结果:优化工艺制得的微球平均粒径为(3.9±1.6)μm,载药量为(7.1±0.5)%(n=3),包封率为(25.0±0.8)%(n=3),体外释药特性研究具有良好的缓释特性,在0～8 h符合Higuchi方程,Q=11.717 26.951t1/2(r=0.980),8～24 h符合一级释放曲线,lnQ=4.37 0.007 5t(r=0.983).结论:通过优化处方和制备工艺,采用乳化交联法可制备出以壳聚糖为载体、替莫唑胺为模型药物的缓释微球,其体外释药具有明显的缓释作用.     

正辛胺改性海藻酸钠凝胶微球的制备及其性质研究

目的:制备正辛胺改性海藻酸钠凝胶微球,并研究其性质。方法:以超声波辅助氧化法制备多醛基海藻酸钠,通过希夫碱反应制备正辛胺改性海藻酸钠,并表征其结构;以乳化-内部凝胶化技术制备负载小分子抗肿瘤药物β-榄香烯的改性海藻酸钠凝胶微球,采用气相色谱法测定其8、15、24、48h时的累积释放率及海藻酸钠和正辛胺改性海藻酸钠凝胶微球中β-榄香烯的包封率。结果:表征并证实了多醛基海藻酸钠和正辛胺改性海藻酸钠的结构;制备得到的改性海藻酸钠凝胶微球中8、15、24、48h时β-榄香烯的累积释放率分别为16%、28%、40%、83%;海藻酸钠和正辛胺改性海藻酸钠凝胶微球中β-榄香烯的包封率分别为36%、73%。结论:制备的正辛胺改性海藻酸钠凝胶微球,具有优良的缓释性能,对β-榄香烯的包封率高。     

龟板水提物缓释微球的制备及其特性

目的：制备高包封率的龟板水提物缓释微球。方法：分别采用海藻酸钙凝胶珠、海藻酸钙-壳聚糖微胶囊和海藻酸钙-羧甲基纤维素钠微胶囊体系制备龟板水提物缓释微球,并考察其外观形态、包封率和体外释药等特性。结果：制得的龟板-海藻酸钙凝胶珠、龟板-海藻酸钙—壳聚糖微球和龟板-海藻酸钙-羧甲基纤维素钠微球外观圆整,表面光滑,且粒径均匀;包封率分别是46．7％、49．9％和82．3％;海藻酸钙凝胶珠有明显的突释现象,海藻酸钠—壳聚糖微球的突释现象和缓释效果有所改善,而海藻酸钙-羧甲基纤维素钠微球无突释现象,其缓释可达14小时以上。结论：龟板-海藻酸钙-羧甲基纤维素钠微球包封率高,同时具有优良的缓释性能。     

多西他赛人血白蛋白微球的制备及体外释药性质的评价

目的：通过优选工艺条件制备多西他赛人血白蛋白微球,并考察其体外缓释特性。方法：以人血白蛋白为药物载体,采用乳化-化学交联法制备多西他赛蛋白微球,HPLC测定多西他赛的浓度,通过L₁₆（4⁵）正交设计试验考察药质比、交联剂用量、交联时间、搅拌转速、酸碱度等因素对微球载药量和包封率的影响,利用极差分析和方差分析优选最佳工艺条件;扫描电镜观察微球形态;以累积释药百分率为指标考察微球体外释药特性。结果：最佳工艺条件为药质比为1：7、交联剂用量为2.0 mL、交联时间为1.5 h、搅拌转速为300 r·min^-1、反应介质pH值为7.5;以优化工艺制备的微球在扫描电镜下可见为表面光滑的类球体,平均粒径为36.16 μm,载药量为（11.74±0.26）%,包封率为（65.24±1.24）%,体外释药模式符合Higuchi方程Q=14.34t^1/2+0.21 （r=0.994 5）,48 h体外累积释药百分率为82.8%。结论：本实验通过优化工艺条件,制备完成载药量、包封率和缓释性均较为理想的多西他赛人血蛋白微球。     

眼镜蛇毒细胞毒素缓释微球制备及体外性质研究

目的研究眼镜蛇毒细胞毒素(Cytotoxin,CTX)聚乳酸/羟基乙酸缓释微球的制备方法,考察其一般性质、体外释药特性及生物学活性。方法采用色谱方法纯化眼镜蛇CTX,MTT方法检测细胞毒活性,复乳-溶剂挥发法制备载药微球,考察微球表面形态、粒径、包封率、载药率、体外释药行为及释放眼镜蛇CTX细胞毒活性。结果纯化眼镜蛇CTX具有明显的细胞毒作用,对肝癌HepG2细胞12,24 h的IC50分别为1.43,1.12μg/mL,对L02肝细胞12,24 h的IC50分别为1.37,1.01μg/mL。微球表面光滑圆整,粒径2.1~7.8μm,包封率和载药率分别为(74.10±9.92)%和(0.72±0.09)%,30 d药物累积释放84.3%,释放眼镜蛇CTX保持较好的生物学活性。结论采用复乳-溶剂挥发法可制备具有较高包封率,良好缓释效果,保持完整生物学活性的眼镜蛇CTX缓释微球。     

制备工艺对石杉碱甲微球体外释药机制的影响

目的考察制备工艺对石杉碱甲(Hup)乳酸-羟基乙酸共聚物(PLGA)微球体外释药机制的影响。方法 采用两种O/O型乳化溶剂挥发法工艺(A法和B法)制备Hup微球。考察微球的体外释药曲线，结合微球在释放介质中的降解速度和溶胀速度曲线以及微球的形态和微球中药物的分布情况阐述微球的释药机制。结果采用A法制备的微球包封率为47.60%，体外无明显突释现象，可缓释35 d，符合零级动力学方程，通过扩散和降解两种机制释药。采用B法制备的微球包封率为83.50%，体外可缓释21 d，整体释药曲线符合Higuchi方程，主要以扩散机制释药。结论采用A法制备的微球具有更理想的缓释效果。     

Preparation of sodium alginate microspheres containing hydrophilic β-lactam antibiotics

Alginate microspheres were prepared by the emulsification process as a drug delivery system of ampicillin sodium (AMP-Na). The preparation parameters such as the concentration of calcium chloride, the stirring time and the amount of AMP-Na were investigated. The alginate microspheres containing hydroxypropylmethylcellulose (HPMC) were found to be generally spherical, discrete and had smoother surfaces when compared to without HPMC. However, there was no significant difference in the release profile of AMP-Na from alginate microspheres prepared with or without HPMC. The concentration of calcium chloride solution and the stirring time in the preparation of alginate microspheres influenced the aggregation of alginate microspheres. The amount of AMP-Na in alginate microspheres influenced the surface morphology and the practical drug content in microspheres.     

α-细辛脑海藻酸钙微球的制备及体外释放药物考察

目的研究α-细辛脑海藻酸钙微球的制备工艺,测定微球中α-细辛脑的体外释放度。方法采用乳化-内部凝胶化法制备海藻酸钙微球,正交试验设计优化制备工艺,分光光度法测定α-细辛脑的含量。结果最优工艺微球球形圆整,载药量为1.17%,包封率为2.40%,微球的平均粒径为17.97μm,大部分微球粒径分布在7~30μm（93.67%）,体外释放符合双相动力学方程Q/100=0.8276-0.0506exp（-1909t）-0.777exp（-0.4405t）。结论以海藻酸钠为载体、乳化-内部凝胶化法制备了海藻酸钙微球,获得微球制备工艺。     

Sodium alginate microspheres of metformin HCl: formulation and in vitro evaluation

Metformin microspheres with sodium alginate alone and in combination with gellan were prepared using an emulsion-cross linking method. The prepared microspheres were evaluated for their physico-chemical characteristics like particle size, morphology using SEM, incorporation efficiency, equilibrium water content (swelling) and in vitro drug release. The effect of various formulation variables like polymer concentration (sodium alginate; and proportion of gellan in microspheres prepared by a combination of sodium alginate and gellan), drug loading, crosslinking agent concentration and cross-linking time on the in vitro dissolution of the prepared microspheres were evaluated. The results showed that both the particle size and the incorporation efficiency were proportional to the polymer concentration. In case of microspheres containing both sodium alginate and gellan, the mean diameter and the incorporation efficiency were higher than the corresponding microspheres containing only alginate, both increasing with an increase in proportion of gellan. The prepared microspheres were found to be discrete and spherical in shape and were successful in sustaining the drug release for 8 hours. Incorporation of gellan caused a significant decrease in drug release. The release followed a biphasic profile, in all cases, characterized by an initial phase of moderate drug release followed by a phase of higher release. Further, the kinetic treatment of the dissolution data revealed the prevalence of matrix diffusion kinetics.     

Preparation and release characteristics of polymer-coated and blended alginate microspheres

To prevent a rapid drug release from alginate microspheres in simulated intestinal media, alginate microspheres were coated or blended with polymers. Three polymers were selected and evaluated such as HPMC, Eudragit RS 30D and chitosan, as both coating materials and additive polymers for controlling the drug release. This study focused on the release characteristics of polymer-coated and blended alginate microspheres, varying the type of polymer and its concentration. The alginate microspheres were prepared by dropping the mixture of drug and sodium alginate into CaCl(2) solution using a spray-gun. Polymer-coated microspheres were prepared by adding alginate microspheres into polymer solution with mild stirring. Polymer-blended microspheres were prepared by dropping the mixture of drug, sodium alginate and additive polymer with plasticizer into CaCl(2) solution. In vitro release test was carried out to investigate the release profiles in 500 ml of phosphate buffered saline (PBS, pH 7.4). As the amount of polymer in sodium alginate or coating solution increase, the drug release generally decreased. HPMC-blended microspheres swelled but withstood the disintegration, showing an ideal linear release profiles. Chitosan-coated microspheres showed smooth and round surface and extended the release of drug. In comparison with chitosan-coated microspheres, HPMC-blended alginate microspheres can be easily made and used for controlled drug delivery systems due to convenient process and controlled drug release.     

Cross-linking mechanisms of calcium and zinc in production of alginate microspheres

Calcium chloride and zinc sulphate were used to cross-link alginate microspheres prepared by an emulsification method. The microspheres cross-linked by a combination of these two salts showed different morphology and slower drug release compared with those cross-linked by the calcium salt alone. From viscosity study, it was found that zinc cations interacted with the alginate molecules to a greater extent than calcium cations. The varying effects of the salts on the properties of the microspheres were largely attributed to their ability to interact with the alginate molecules.     

Gelatin microspheres crosslinked with D,L-glyceraldehyde as a potential drug delivery system: preparation, characterisation, in vitro and in vivo studies

To overcome the restriction in using crosslinked gelatin in the pharmaceutical field, D,L-glyceraldehyde (GAL), a non-toxic crosslinking agent, was proposed. Gelatin microspheres crosslinked with different concentrations of GAL (0.5, 1 or 2%, w/v) and for different time periods (1 or 24 h) were prepared. The effect of the preparation variables was evaluated analysing the extent of crosslinking, the morphological aspect, the particle size and the swelling behaviour. To evaluate the pharmaceutical properties, an antihypertensive drug, clonidine hydrochloride, was chosen as drug model and loaded into the microspheres. Either the increase of the crosslinker concentration or of the crosslinking time period decreased both the swelling and the in vitro drug release processes of the microspheres. After the subcutaneous injection, the loaded microspheres crosslinked with the lowest GAL concentration (0.5%, w/v) or for the shortest time period (1 h) showed a reduction of systolic blood pressure (SBP) similar to that recorded with a clonidine hydrochloride solution having the same drug concentration. Instead, the microspheres crosslinked for 24 h with concentrations of GAL higher than 0.5% (w/v) produced a more gradual and sustained SBP reduction and the antihypertensive effect was maintained until 52-72 h. The biocompatibility studies showed that the microspheres crosslinked with GAL are well tolerated in vivo. These results suggest the potential application of gelatin microspheres crosslinked with GAL as a suitable drug delivery system for the subcutaneous administration.     

Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide: in-vitro/ex-vivo studies

Microparticulate delivery systems designed for the nasal administration of an antiemetic drug, metoclopramide hydrochloride, were prepared. Microspheres composed of sodium alginate, chitosan hydrochloride, or both, were obtained using a spray-drying method; some batches of drug-free microparticles were prepared as a comparison. The morphology, in-vitro swelling behaviour, mucoadhesive properties and drug release from microparticles were evaluated. Ex-vivo drug permeation tests were carried out using sheep nasal mucosa; permeation test of the drug solution was performed as comparison. During ex-vivo permeation tests, transmission electron microscopy (TEM) analyses were carried out on the nasal mucosa to study the morphological changes of epithelial cells and tight junctions, while the change in microsphere morphology was examined using photostereo microscopy (PM). Spray-dried microparticles had a mean diameter (d(vs)) in the range of about 3-10 microm. They showed good in-vitro mucoadhesive properties. In-vitro release profiles and swelling behaviour depended on their composition: the drug release occurred in 1-3 h. Ex-vivo studies showed that drug permeation through the mucosa from microparticles based on chitosan was higher than from those consisting of alginate alone. This can be related to the penetration enhancing properties of chitosan. Complexation of chitosan with alginate led to a control of the drug release. Microscopy observation of microspheres during the permeation tests revealed that microparticles swelled and gelled, maintaining their shape. TEM analyses of the mucosa after exposure to the microparticles consisting of alginate/chitosan showed opened tight junctions. This preliminary study shows that alginate/chitosan spray-dried microspheres have promising properties for use as mucoadhesive nasal carriers of an antiemetic drug.     

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl(2) was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and approximately 100-400 microm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50-280%. CaCl(2) concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in approximately 30 min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1 h) values.     

Chitosan microspheres for intrapulmonary administration of moxifloxacin: interaction with biomembrane models and in vitro permeation studies.

Chitosan microspheres loaded moxifloxacin were prepared to obtain sustained release of the drug after intrapulmonary administration. The microspheres were produced by the spray-drying method using glutaraldehyde as the crosslinking agent. The particles were spherical with a smooth but distorted surface morphology and were of small size, ranging from 2.5 to 6.0microm, thus suitable for inhalation. In vitro release studies showed a significant burst effect for all crosslinked systems, followed by a prolonged moxifloxacin release, particularly in the presence of the highest glutaraldehyde concentration. Lipid vesicles made of dipalmitoylphosphatidylcholine (DPPC) were used as an in vitro biomembrane model to evaluate the influence of chitosan microspheres on the interaction of moxifloxacin with biological membranes. Differential scanning calorimetry was used as a simple and non-invasive technique of analysis. Moxifloxacin freely permeates through DPPC liposomes, interacting with the hydrophobic zone of the bilayers (lowering of the DeltaH value and loss of the cooperativity of the main transition peak). Uncrosslinked microspheres rapidly swelled and dissolved releasing free chitosan that was able to interact with liposomes (increase of DeltaH value), probably altering the biomembrane permeability to the drug. Crosslinked microspheres did not show this property. Pulmonary absorption of moxifloxacin-loaded chitosan microspheres was evaluated compared to the free drug. A monolayer of Calu-3 human bronchial epithelial cells mounted on Franz diffusion cells was used as an in vitro bronchial epithelium model. Microspheres retard the absorption of moxifloxacin and within 6h the cumulative amount of permeated drug was about 18%, 11% and 7% (w/w) for free moxifloxacin, moxifloxacin-loaded crosslinked and moxifloxacin-loaded uncrosslinked microspheres, respectively.     

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl₂ was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and ～100–400?µm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50–280%. CaCl₂ concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in ～30?min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1?h) values.