温敏在体凝胶给药系统的研究与应用

综述N-异丙基丙烯酰胺类聚合物、聚氧乙烯-聚氧丙烯共聚物、聚氧乙烯-聚乳酸羟基乙酸共聚物和多糖类衍生物等温敏聚合物的性质、特点、胶凝机制及在温敏在体凝胶给药系统中的应用进展。温敏在体凝胶作为一种智能水凝胶,可用作药物缓、控释和靶向输送的有效载体。     

利培酮纳米混悬原位凝胶的制备与释药特性研究

目的 制备利培酮纳米混悬原位凝胶剂并考察其体外释放行为。方法 采用反溶剂沉淀法,以粒径为指标,药物浓度(A)、二十二碳六烯酸浓度(B)、水相与油相的比例(C)及搅拌速度(D)为因素,采用正交设计法优化利培酮纳米混悬剂的处方及工艺;进一步制备利培酮纳米混悬原位凝胶剂并考察其体外释药行为。结果 优化处方及工艺为：A 5 mg·mL^-1,B 10 mg·mL^-1,C 1∶1,D 600 r·min^-1,所制备利培酮纳米混悬剂平均粒径176 nm,PI 0.19,Zeta 电位-22.4 mV,利培酮为棒状结晶,在4 ℃条件下,3个月内稳定性较好,且能够显著增加利培酮的体外溶出速率;含有20%泊洛沙姆407的纳米混悬凝胶剂中,30 d内利培酮累积释放度>90%,符合Higuchi释放模型。结论 利培酮纳米混悬处方及工艺简单易行,制剂稳定性较好,进一步制备的原位凝胶剂具有良好的缓释效果。     

川陈皮素温敏型鼻用原位凝胶体外释药行为研究

分别采用扩散池法、无膜溶出法以及渗析池法考察川陈皮素温敏型鼻用原位凝胶的体外释药特性与机制.结果表明,川陈皮素原位凝胶通过扩散释放的药物量较少,150 min仅为1.4%;通过无膜溶出法药物释放完全,120 min时药物基本释放完全,且药物的释放量与溶蚀量具有良好的相关性.渗析池法药物的释放量较扩散池法多,120min可释放8%的药物.因此,本实验室研制的川陈皮素温敏型鼻用原位凝胶可能主要通过溶蚀方式释药.     

灯盏花素微乳凝胶剂的体外释放度考察

目的 考察灯盏花素微乳凝胶剂体外释放度。方法 以pH 6.8的磷酸盐缓冲溶液为释放介质,分别采用正向透析扩散法和反向透析扩散法进行药物体外释放度试验。结果 采用反向透析扩散法测得的药物释放速率显著高于正向透析扩散法,采用反向透析扩散法时灯盏花素微乳凝胶剂在2 h内的累积释放量>60%,10 h的累积释放量>90%,其体外释药符合一级动力学方程。结论 采用反向透析扩散法方便快捷,能较好地模拟灯盏花素微乳凝胶剂的释药行为,灯盏花素微乳凝胶剂体外释药性能良好。     

In Vitro Properties of an In Situ Forming Gel for the Parenteral Delivery of Macromolecular Drugs*

The purpose of this research was to (i) formulate a solution of a water-insoluble interpolymeric complex (IPC) containing poly(methacrylic acid) (PMA), 15 kDa, and poly(ethylene glycol) (PEG), 20 kDa, in a biocompatible cosolvent system; (ii) demonstrate that the IPC solution can transform into a gel, in situ, at physiological pH; and (iii) determine the ability of the gel to entrap, protect, and control the release of macromolecular drugs such as proteins and oligonucleotides. Ternary phase diagrams were prepared to identify cosolvent composition containing N-methylpyrrolidone (NMP), ethanol, and water that dissolve the IPC. IPC solutions (40, 50, or 60% w/v) each containing 1 mg of either model proteins, fluorescein isothiocyanate (FITC)–insulin and FITC–albumin, or 24-mer phosphorothioate oligonucleotides, were placed in containers that were immersed in buffer, pH 7.4. Aliquots of the buffer were sampled periodically and analyzed for the macromolecular content. In addition, in vitro bioactivity of another model protein, α-amylase, contained in the IPC solution was also determined. The studies demonstrated that a cosolvent containing 1:1:2 ratio of NMP/ethanol/water was most suitable for dissolving the IPC. Concentrations >30% w/v IPC were required to form the gel, however, those mixtures containing >60% w/v IPC could not be easily injected via 18–22 gauge needle. The gel can entrap and control the release of the model macromolecules for up to 6 days, in vitro. In addition, the gel can maintain the bioactivity of the protein, α-amylase, for 6 days. Therefore, an IPC gel can entrap, protect, and control the release of macromolecular drugs over a period of 6 days, in vitro, and therefore can be considered for in vivo investigation.     

A Novel In Situ Gel Formulation of Ranitidine for Oral Sustained Delivery

The main purpose of this study was to develop a novel, in situ gel system for sustained delivery of ranitidine hydrochloride. Ranitidine in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of preparation, viscosity and in vitro release. The viscosity of the gellan gum formulations in solution increased with increasing concentrations of gellan gum. In vitro study showed that the release of ranitidine from these gels was characterized by an initial phase of high release (burst effect) and translated to the second phase of moderate release. Single photon emission computing tomography technique was used to evaluate the stomach residence time of gel containing ^99mTc tracer. The animal experiment suggested in situ gel had feasibility of forming gels in stomach and sustained the ranitidine release from the gels over the period of at least 8 h. In conclusion, the in situ gel system is a promising approach for the oral delivery of ranitidine for the therapeutic effects improvement.     

In Vitro Myotoxicity of Selected Cationic Macromolecules Used in Non-Viral Gene Delivery

Purpose. Cationic lipid/DNA complexes have been proposed as a method of in vivo gene delivery via intravenous or intramuscular injection. A concern with using these polycationic molecules is whether they are associated with tissue toxicity at the injection site. Therefore, the objective of these studies was to investigate the myotoxic potential of selected non-viral gene delivery macromolecules (e.g., cationic lipids and polymers) with and without plasmid DNA (pDNA) in vitro. Methods. Myotoxicity was assessed by the cumulative release of creatine kinase (CK) over 90 minutes from the isolated rodent extensor digitorum longus muscle into a carbogenated balanced salt solution (BBS, pH 7.4, 37°C) following a 15 L injection of the test formulation. Phenytoin (Dilantin^®) and normal saline served as positive and negative controls, respectively. Results. The myotoxicity of plasmid DNA (pDNA, ~5000bp, 1 mg/ ml) was not statistically different from normal saline. However, the myotoxicity of Dilantin^® was 16-times higher than either normal saline or pDNA (p < 0.05). Cationic liposomes were found to be less myotoxic than polylysine and PAMAM dendrimers. Polylysine's myotoxicity was found to be dependent upon concentration and molecular weight. The myotoxicity of formulations of cationic liposomes(s), lower molecular weight polylysine (25,000) and higher concentration of PAMAM dendrimers with pDNA were found to be statistically less significant than those formulations without pDNA. Conclusions. The cationic liposomes were less myotoxic compared to the dendrimers and polylysine. Myotoxicity was dependent upon the type of cationic lipid macromolecule, concentration, molecular weight and the presence of pDNA. A possible explanation for this reduced tissue damage in cationic lipids complexed with pDNA is that the formation of complex reduces the overall positive charge of the injectable system resulting in less damage.     

氢溴酸高乌甲素鼻用原位凝胶剂的制备及其处方评价

目的：制备氢溴酸高乌甲素（LH）鼻用原位凝胶剂,并进行处方考察以提高其鼻腔给药的镇痛效果。方法：采用在体蟾蜍上腭纤毛法考察不同LH处方对鼻黏膜纤毛的毒性、大鼠在体鼻腔循环实验考察处方中3种吸收促进剂（β-环糊精、吐温-80和冰片）对LH的鼻黏膜吸收的促进作用以及小鼠扭体法实验考察不同LH处方的镇痛药效,从而确定LH鼻用原位凝胶剂的最佳处方工艺。结果：处方中LH和所选用的辅料对鼻黏膜纤毛均无显著毒性;3种吸收促进剂对LH的鼻黏膜吸收速率常数无显著影响（P〉0．05）;在所有受试处方中,结冷胶和β-环糊精联用处方制剂的镇痛效果最佳,其药效与腹腔注射相同剂量的LH注射液无显著差异（P〉0．05）。结论：结冷胶和β-环糊精联用是制备LH鼻用原位凝胶剂的最佳处方组合。     

眼用维生素A棕榈酸酯阳离子脂质体-原位凝胶的研制及体外释药研究

目的：以维生素A棕榈酸酯（VAP）为模型,制备眼用阳离子脂质体-原位凝胶系统,并对其体外释药行为进行考察。方法：采用薄膜分散法制备VAP脂质体,根据胶凝温度筛选泊洛沙姆407的最佳处方浓度,采用无膜溶出模型对该制剂的体外释放行为进行考察。结果：透射电镜显示VAP脂质体-原位凝胶（VAPL—ISG）粒径分布均匀,经N-三甲基壳聚糖（TMC）包衣后Zeta电位〉40mV,泊洛沙姆407的最佳浓度为25％,VAPL—ISG中药物释放和凝胶溶蚀均呈现良好的零级释放特征。结论：VAPL—ISG具有阳离子脂质体和原位凝胶的优势,延缓了药物释放,为下一步研究其延长角膜滞留时间打下基础。     

天麻素鼻腔原位凝胶的基质筛选

摘 要 目的：对天麻素鼻腔原位凝胶（ISG）的基质进行优选,为研发天麻素新型制剂奠定基础。方法: 分别选用两种复合基质,N-三甲基壳聚糖（TMC）-聚乙二醇4000（PEG 4000）-甘油磷酸钠（GP）和TMC-泊洛沙姆407（P407）-泊洛沙姆188（P188）-卡波姆,以鼻腔温度35℃为试验温度,检测两种基质的胶凝时间,以筛选出其最佳配比;分别在两种基质中加入主药天麻素,同法进行胶凝时间的考察,以优选出天麻素ISG的最佳基质组成。 结果: 在空白TMC-PEG 4000-GP基质中加入天麻素后,在鼻腔温度下无法胶凝;而在空白TMC-P407-P188-卡波姆基质中加入天麻素后,在鼻腔温度下可以迅速发生胶凝。结论:本处方选择TMC-P407-P188-卡波姆为天麻素ISG的基质。     

rhEGF原位凝胶的生物学效应研究初探

目的 探讨rhEGF原位凝胶及对大鼠烧伤创面愈合的生物学功能.方法 通过对大鼠烧伤模型来对比rhEGF原位凝胶及复方凝胶的创口愈合效果,动态观察烧伤后使用原位凝胶及复方凝胶在不同时间点的创口愈合时间、羟脯氨酸(OHP)含量和Ⅰ/Ⅲ型胶原比值变化及病理组织学等指标的变化.结果 动物实验表明使用rhEGF原位凝胶对大鼠烧伤创口修复作用类同于复方凝胶,而明显优于生理盐水对照组.结论 鉴于原位凝胶在使用和生产上的便利性,可望在剂型上替代传统的rhEGF复方凝胶.     

pH-Induced In Situ Gel for Periodontal Anesthesia

A pH mediated in situ gelling system was developed using prilocaine hydrochloride for periodontal anesthesia using combination of chitosan and hydroxypropylmethylcellulose. The gel so developed can be used as anaesthetic in lengthy dental surgery. The gel was evaluated for many parameters like gelation pH, viscosity, physicochemical properties, in vitro release, sterility and stability. Gel with chitosan (0.25% w/v) and hydroxypropylmethylcellulose (0.25% w/v) was found to have good gelation near pH 7.4 (pH of mucous) with prolonged action.     

苄达赖氨酸温敏型眼用原位凝胶的体外释放性及角膜渗透性考察

目的 研究苄达赖氨酸温敏型眼用原位凝胶体外释放性及离体角膜渗透性。方法 考察泊洛沙姆P407及P188用量对处方凝胶温度的影响,并对结果进行二项式拟合筛选出最优处方;以市售滴眼液或溶液剂为对照,采用无膜法、透析袋法、透析膜法考察了该处方的体外释放性;采用Franz扩散池对该处方进行了离体角膜渗透研究。结果 该优选处方对角膜刺激性较小,胶凝温度为31.5 ℃,pH为6.95,渗透压为397 mOsmol·kg^-1;相比于对照组,该处方缓释效果明显,未出现突释效应;离体角膜渗透研究结果表明,该优选处方6 h角膜累积渗透率及渗透速率均低于市售处方。结论 温敏型原位凝胶缓释效果明显,有望成为治疗白内障药物苄达赖氨酸的新剂型。     

甲氧沙林脂质体凝胶的体外释药与稳定性研究

目的 对甲氧沙林脂质体凝胶体外释药模式进行定量考察。方法 以相同浓度甲氧沙林凝胶为对照，用透析法检测甲氧沙林脂质体凝胶的体外释药模式，并对其在4 ℃下贮存3周的释药稳定性进行研究。结果与甲氧沙林凝胶比较，甲氧沙林脂质体凝胶具有明显的缓释及长效作用，且前3 h释药符合Higuchi扩散模式（k＝4.07%·h 1/2），3 h后遵循零级释药模式（k＝0.66%·h 1）。而甲氧沙林凝胶在实验24 h内释药均符合Higuchi扩散模式（k＝6.91%·h 1/2）。在贮存期内，甲氧沙林脂质体凝胶的释药模式及包封率均维持稳定。结论 甲氧沙林脂质体凝胶体外释药具有明显的缓释特征，稳定性理想，值得进一步研究开发。     

盐酸特比萘芬凝胶的处方优选及释放度研究

目的 研制盐酸特比萘芬凝胶并进行体外释放度考察。方法 以ACOA聚合物为成膜材料,羟丙基纤维素为增稠剂进行处方筛选,用数学模型拟合释放曲线。结果 盐酸特比萘芬处方中ACOA（型号HXF）用量1%,增稠剂用量1%,溶剂是96%的乙醇。盐酸特比萘芬凝胶的体外释药行为符合Higuchi释放模型。结论 盐酸特比萘芬凝胶处方设计合理,可进一步开发。     

PLGA-PEG-PLGA Tri-Block Copolymers as In Situ Gel-Forming Peptide Delivery System: Effect of Formulation Properties on Peptide Release

Various controlled peptide and protein delivery systems have been investigated for their potential for treatment of chronic diseases. In situ gelling systems are very attractive due to their biocompatibility, biodegradability, and simple manufacturing processes. The objective of this work was to investigate the effect of different excipients on release profile of calcitonin as a model protein from PLGA-PEG-PLGA thermally reversible gels. PLGA-PEG-PLGA with the ratio of PLGA to PEG equal to 2.5 was synthesized and characterized by ¹H NMR and gel permeation chromatography (GPC). The PLGA-PEG-PLGA polymeric solutions (25% w/w) containing calcitonin (0.05% w/w) and other excipients in various concentrations were prepared, and drug release from the thermally reversible gels was evaluated. It was shown that drug release from the systems was dramatically reduced when PEG 200 or PEG 1000 was added to the systems. This may be due to the effect of PEG as an internal cross-linking agent or the formation of PEG complexes that decrease the rate of drug release. Sodium laurel sulfate (SLS) was also shown to reduce the rate of drug release from the systems. This may be due to the large ionic heads of SLS that attract counterions of calcitonin. It can be concluded that the drug release rate from the systems can be controlled by using different excipients.     

利福平脂质体温敏型原位凝胶的制备及其体外释药特征研究

目的 制备利福平脂质体温敏型原位凝胶,并对其体外性质进行研究。方法 采用薄膜分散法制备利福平脂质体,并对利福平脂质体进行表征研究;以泊洛沙姆188、泊洛沙姆407为凝胶基质,制备利福平脂质体温敏型原位凝胶;以无膜溶出模型研究温敏型原位凝胶体外累积溶蚀率;采用透析袋法分析药物体外释放情况。结果 制备的利福平脂质体平均粒径、聚分散指数、Zeta电位、包封率和载药量分别为(149.0±5.67)nm、0.275±0.056、-(29.8±1.59)mv、(79.6±2.67)%,(18.6±0.25)%;利福平脂质体温敏型原位凝胶的胶凝温度为(34.3±0.6)℃。体外溶蚀曲线和体外释药曲线均符合零级动力学特征。结论 利福平脂质体温敏型原位凝胶的制备工艺简单易行,体外释放显示其有很好的缓释作用。     

阿霉素海藻酸钙凝胶微丸的释放性

以阿霉素为阳离子模型药物，研究了不同初始浓度海藻酸钠（ＳｏｄｉｕｍＡｌｇｉｎａｔｅ，ＮａＡｌｇ）制备的空白微丸对药物的摄取作用和不同介质中药物的释放过程     

富马酸酮替芬眼用即型凝胶的研制

目的探讨富马酸酮替芬眼用即型凝胶的制备及质量控制方法.方法以卡波姆为基质制备凝胶,采用紫外分光度法测定含量.结果富马酸酮替芬浓度在1.42～11.42μg·ml-1范围内线性关系良好,平均回收率为99.54%.结论本方法处方设计合理,制备方法简便,含量测定方法适用于本品质量控制.     

阿比多尔双层缓释片的研制及体外释药

目的研制阿比多尔双层缓释片并考察其体外释药特性。方法以两种不同处方作湿法制粒、压制双层片,紫外分光光度法测定阿比多尔的释放度。结果阿比多尔双层缓释片的释药曲线用Higuchi方程或Peppas方程拟合,可维持12h持续释放。结论研制的阿比多尔双层缓释片达到设计要求。