α-细辛脑纳米粒离子敏感型鼻用原位凝胶的制备及体外释药性能

目的:制备α-细辛脑纳米粒离子敏感型鼻用原位凝胶并考察其体外释放行为。方法:采用去乙酰结冷胶(DGG)为凝胶基质,以凝胶黏度,形成凝胶的能力及持水力为考察指标筛选去乙酰结冷胶的用量;采用纳米沉淀法制备α-细辛脑纳米粒,与凝胶基质混合后制得α-细辛脑纳米粒离子敏感型原位凝胶;以人工模拟鼻液为释放介质、考察制剂的体外释放特性。结果:确定0.5%的结冷胶作为α-细辛脑纳米粒离子敏感型原位凝胶的基质,在非生理状态为自由流动的液体,生理状态下能够发生相变形成凝胶。体外释放结果表明α-细辛脑纳米粒离子敏感型鼻用原位凝胶具有较好的缓释作用。结论:α-细辛脑纳米粒离子敏感型原位凝胶的胶凝效果良好,缓释作用明显且制备工艺简单可行。     

辛芷离子敏感型鼻用原位凝胶的研制及体外释药评价

目的:开发一种新型的中药鼻腔给药系统剂型—原位凝胶。方法:采用去乙酰结冷胶为材料制备辛芷离子敏感型鼻用原位凝胶。研究不同浓度去酰基结冷胶原位凝胶的黏度特性,采用扩散池法考察其体外释药规律,并用无膜溶出法研究其释药机制。结果:辛芷离子敏感型鼻用原位凝胶的黏度随去酰基结冷胶的浓度增加而增大,其释药量随结冷胶的浓度增加而减少,其释药符合一级释药模型,其溶蚀度较小且与释放率无明显相关性(r=0.986)。结论:应用去酰基结冷胶可成功制备离子敏感型中药鼻用原位凝胶,为中药鼻腔给药提供了一种新剂型。     

离子敏感型吲哚美辛眼用原位凝胶的制备与质量控制

目的以海藻酸钠为凝胶基质,羟丙基甲基纤维素（hydroxypropyl methyl cellulose,HPMC）为增黏剂,制备吲哚美辛离子敏感型眼用原位凝胶,并进行质量标准研究及释放度测定。方法通过对海藻酸钠与HPMC的配比研究,筛选最佳凝胶基质,制备吲哚美辛离子敏感型眼用原位凝胶;采用紫外分光光度法测定含量,用透析袋法进行体外释药实验,研究体外释药特性与机制。结果与吲哚美辛溶液相比,吲哚美辛离子敏感型眼用原位凝胶释药时间延长至8 h, 释药量均＞93%,而且具有良好的缓释效果。结论以海藻酸钠与HPMC制备的吲哚美辛离子敏感型眼用原位凝胶质量稳定,对眼部无刺激,且具有缓释、长效作用。     

复方甲硫酸新斯的明眼用原位凝胶的处方工艺研究

目的 筛选用于治疗近视的复方甲硫酸新斯的明眼用原位凝胶处方。方法 温度敏感型凝胶以泊洛沙姆P407和泊洛沙姆P188为基质;离子敏感型凝胶以去乙酰结冷胶为基质;pH敏感型凝胶以卡波姆P934、卡波姆P940和羟丙基甲基纤维素为基质,以胶凝的黏度与成分的相溶性为考察指标,筛选最佳基质处方。采用美国药典溶出度测定法第三法的改良法,作缓释制剂的释放度考察。结果 以温度敏感型的泊洛沙姆P407 24%和P188 10%合用的基质制备复方甲硫酸新斯的明眼用原位凝胶最为适合。结论 本法制备眼用原位凝胶的工艺可行,并具有较好的缓释效果。     

眼用即型凝胶基质的成胶性研究

目的:研究眼用原位凝胶基质的成胶性,并建立温度敏感型、离子敏感型和pH敏感型眼用原位凝胶的基质处方。方法:使用人工泪液,模拟眼部生理条件综合考虑黏度、突跃点等因素来考察各类基质处方的成胶性并筛选基质处方。结果:眼部生理条件下,0.02%卡波姆P934、0.02%卡波姆P940和0.5%羟丙基甲基纤维素(HPMC)-K4M合用、0.45%的去乙酰结冷胶、24%泊洛沙姆P407与10%泊洛沙姆P188合用等三种情况下有合适的成胶性。结论:pH敏感型、离子敏感型、温度敏感型眼用原位凝胶的适用基质处方分别为0.02%卡波姆P934+0.02%卡波姆P940+0.5%羟丙基甲基纤维素(HPMC)-K4M合用、0.45%的去乙酰结冷胶、24%泊洛沙姆P407+10%泊洛沙姆P188合用。     

口腔溃疡原位凝胶的研制及体外质量评价

摘要：目的:优化口腔溃疡原位凝胶的制备工艺,研究口腔溃疡不同剂型体外释药规律及机制。方法:以泊洛沙姆188（P188）和泊洛沙姆407（P407）为凝胶基质,胶凝温度为考察指标,采用星点设计-效应面法优选凝胶处方。采用改良桨法,研究口腔溃疡原位凝胶的经皮渗透过程,探索口腔溃疡原位凝胶的缓释机制。结果:口腔溃疡原位凝胶的最优处方为:P188用量为4.0%,P407用量为12.5%,形成凝胶相转变温度范围为33～37℃。口腔溃疡原位凝胶体外释药行为遵循一级动力学方程。结论:口腔溃疡原位凝胶的制剂处方设计合理,质量可控,具有一定的缓释性,是可替代口腔溃疡液用于临床的一种新剂型。     

胰岛素纳米粒温敏凝胶的制备及体外释药性能

目的:制备胰岛素壳聚糖温度敏感型原位凝胶(INS-CS-NP-TISG)并进行体外释药动学考察。方法:采用离子凝胶化法制备胰岛素壳聚糖纳米粒;均匀设计法优化其处方及制备工艺,观察形态,测定粒径、表面电位、包封率和载药量;冷法配液的方法制备温度敏感型原位凝胶,改进透析袋-恒温水浴法研究胰岛素壳聚糖纳米粒温度敏感型原位凝胶溶液的体外释药动学。结果:优化制得的纳米粒呈类球形,均匀圆整,分散性好;平均粒径为(255.3±143.5)nm,在175.2~349.6nm范围内的纳米粒子达99.4%,大小均匀,分布较窄;高效液相色谱法(HPLC)测定胰岛素壳聚糖纳米粒平均包封率和载药量分别为75.84%与58.52%;表面电位(ζ)为+32.67;在人工鼻黏液中,胰岛素壳聚糖纳米粒温度敏感型原位凝胶的体外释药符合双相动力学方程,且持续释药24h。结论:选用合适的处方制备胰岛素壳聚糖纳米粒温度敏感型原位凝胶,方法简便,药物载药量高,具有较好的生物黏附性,并有一定的缓释作用。     

盐酸格拉司琼鼻用温敏型凝胶的制备及其体外释放度研究

目的研制盐酸格拉司琼鼻用温敏型凝胶并考察其体外释药行为。方法以泊洛沙姆407为凝胶材料，泊洛沙姆188及聚乙二醇6000调节胶凝温度，正交试验法优选处方，并采用数学模型拟合体外释放曲线。结果盐酸格拉司琼鼻用温敏型凝胶在32～33％胶凝，体外释药行为符合Higuchi方程。结论盐酸格拉司琼鼻用温敏型凝胶处方设计合理，可进一步研究开发。     

利巴韦林温度-离子敏感型鼻用原位凝胶喷雾剂的制备及体外性质考察

目的制备具有适宜临界相变温度和临界相变阳离子强度,及适宜的喷雾粒度、使用方便、缓慢释放药物的温度-离子敏感复合型鼻用原位凝胶。方法以临界相变温度、临界相变阳离子强度、喷雾粒度为考察指标筛选温敏及离子敏材料的用量,制备利巴韦林温度-离子敏感复合型原位凝胶。以透析袋法评价该复合凝胶的凝胶外排水量、溶蚀速率、体外释放度,并以断裂距离为指标评价凝胶的黏膜黏附力。结果以质量分数为0.3%的去乙酰化结冷胶和质量分数为18.0%的泊洛沙姆407制备的温度-离子敏感复合型原位凝胶,临界相变温度为32.6℃,临界相变阳离子强度为93.4 mmol.kg-1,喷雾粒度为68.0μm,凝胶外排水质量分数为(13.8±0.8)%,溶蚀速度常数为1×10-4min-1,断裂距离为(1.60±0.06)mm。该混合凝胶具有良好的体外缓释特征。结论该复合型原位凝胶剂适宜作为水溶性药物的鼻用缓释载体。     

黄芩苷、黄芩苷磷脂复合物与黄芩苷磷脂复合物鼻用温敏型原位凝胶的鼻黏膜渗透性研究

目的:研究黄芩苷、黄芩苷磷脂复合物与黄芩苷磷脂复合物鼻用温敏型原位凝胶的体外鼻黏膜渗透性,对黄芩苷磷脂复合物温敏型鼻用原位凝胶的处方进行筛选。方法:采用Franz扩散池法进行鼻黏膜渗透试验,高效液相色谱(HPLC)法测定接受池中药物累积渗透量。以单位面积累积渗透量(Q)和稳态透膜速率(Js)为标准考察黄芩苷、黄芩苷磷脂复合物与黄芩苷磷脂复合物鼻用温敏型原位凝胶的体外鼻黏膜渗透性,从而确定三者的体外释药曲线和对黄芩苷磷脂复合物鼻用温敏型原位凝胶处方的筛选结果。结果:各个供试药物的释药符合一级释放模型;与黄芩苷溶液比较,黄芩苷磷脂复合物能明显增加释药量和释药速率。处方二的Q和Js为3种鼻用原位凝胶处方中最高值。结论:黄芩苷磷脂复合物可明显提高黄芩苷的膜渗透性。黄芩苷磷脂复合物鼻用温敏型原位凝胶为处方二最佳,可用于鼻腔给药。     

Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy

AIM: To develop a novel, in situ gel system for nasal delivery of scopolamine hydrobromide (SCOP) and study its efficacy on motion sickness. METHODS: SCOP in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of viscosity, in vitro release, and nasal ciliotoxicity. Single photon emission computing tomography technique was used to evaluate the nasal residence time of gel containing (99m)Tc tracer. The antimotion sickness efficacy produced by the in situ gel formulation was investigated in rats and compared with those achieved after subcutaneous and oral administration. RESULTS: The viscosity of the gellan gum formulations either in solution or in gel increased with increasing concentrations of gellan gum. Its release in vitro was moderate in artificial nasal fluid. The micrographic results showed that in situ gels were safe, without nasal ciliotoxicity. In comparison with phosphate buffer saline, a prolonged radioactivity of (99m)Tc in the rabbit nasal cavity was observed after administration of the gellan gum formulation. Intranasal SCOP in situ gel at a dose of 100 microg/kg decreased symptoms of motion sickness significantly in comparison with subcutaneous and oral administration (P<0.01). CONCLUSION: SCOP nasal in situ gel is a safe and promising therapeutic alternative to existing medications for motion sickness.     

Formulation development of ambroxol hydrochloride soft gel with application of statistical experimental design and response surface methodology

The purpose of present work was to develop ambroxol hydrochloride soft gel formulation with the application of statistical experimental design and response surface methodology (RSM). A two-factor, three-level (3(2)) full factorial design of experiment with RSM was run to evaluate the main and interaction effect of two independent formulation variables that included the amount of low-acetylated gellan gum and sodium citrate. The dependent variables included viscosity (Y(1)), amount of drug release at 10 min (Y(2)) and 30 min (Y(3)), and gelation time (Y(4)). In order to obtain a formulation having the maximum amount of drug release at 10 min and minimum gelation time, RSM optimization was used. The prepared formulations were evaluated for pH, viscosity, rheological properties, gelation time, drug content, in vitro drug release, appearance, and taste. All the formulations showed a gelation time in the range of 6 to 48 min. The drug content in all the formulations was within limit (99.6 ± 1.56%). The viscosity of all the formulations was found in the range of 1872-12,182 cP. Dissolution studies of the formulations showed drug release in the range of 40.56-72.46% within 10 min and 80.2-100.5% within 30 min. Human evaluation tests revealed that all the gels possessed acceptable characteristics. This study showed that the soft gel formulation GA5, containing 0.3% of gellan gum and 0.4% of sodium citrate, has potential use as an immediate release soft gel for oral drug delivery. LAY ABSTRACT: The objective of this investigation was to develop a new, immediate-release, soft gel dosage form for ambroxol hydrochloride, an oral expectorant and mucolytic agent. This novel soft gel dosage form needs to be suitable for pediatric and geriatric patients as well as patients with dysphagia. A statistical technique was used for optimization of the gel formulation. The methodology, called a design of experiment with response surface methodology, evaluated several independent formulation variables, including the amount of two ingredients, low-acetylated gellan gum and sodium citrate. Their effects were studied by comparing physical properties of the gel such as viscosity, amount of drug release at 10 and 30 min, and gelation time. The final optimized formulation (0.3% of gellan gum and 0.4% of sodium citrate) was chosen to maximize the amount of drug release at 10 min, minimize gelation time, and optimize viscosity in a reasonable range. After this optimization exercise, the prepared ambroxol hydrochloride soft gel formulations were evaluated for pH, viscosity, rheological properties, gelation time, drug content, in vitro drug release, appearance, and taste. Human evaluation tests revealed that all the gels possessed acceptable organoleptic characteristics.     

Ion-activated in situ gelling systems for sustained ophthalmic delivery of ciprofloxacin hydrochloride

The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to precorneal elimination of the drug may be overcome by the use of in situ gel forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac. Our present work describes the formulation and evaluation of an ophthalmic delivery system of an antibacterial agent, CPH, based on the concept of ion-activated in situ gelation. Gelrite gellan gum, a novel ophthalmic vehicle that gels in the presence of mono or divalent cations, present in the lacrimal fluid was used alone and in combinations with sodium alginate as the gelling agent. The developed formulations were therapeutically efficacious and provided sustained release of the drug over an 8-hr period in vitro.     

In vitro and in vivo evaluation of the Gelrite gellan gum-based ocular delivery system for indomethacin

The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of the drug may be overcome by the use of in situ gel forming systems, which upon instillation as drops into the eye undergo a sol-gel transition in the cul-de-sac. This may result in better ocular availability of the drug. The purpose of this work was to develop an ophthalmic delivery system of the NSAID indomethacin, based on the concept of ion activated in situ gelation. Gelrite gellan gum, a novel ophthalmic vehicle, which gels in the presence of mono or divalent cations present in the lacrimal fluid, was used as the gelling agent. The developed formulations were therapeutically efficacious (in a uveitis induced rabbit eye model) and provided sustained release of the drug over an 8-hour period in vitro.     

硝酸毛果芸香碱原位凝胶滴眼剂的制备及体外释放度评价

目的:制备硝酸毛果芸香碱原位凝胶滴眼剂,并评价其体外释放度。方法:采用结冷胶为成胶辅料制备制剂,并将其与普通滴眼液比较进行体外释放度评价。结果:所制制剂为无色、透明、均匀液体,检查符合2005年版《中国药典》中的相关规定;普通滴眼液在3h内药物已完全释放,而原位凝胶滴眼剂在3h时仅释放68%,10h时释放约87%,后者释放机制为Fick扩散。结论:所制硝酸毛果芸香碱原位凝胶滴眼剂具有良好的控制释药性能。     

Novel Nasal in situ Gelling System for Treatment of Sinusitis

In situ gelling systems based on temperature-dependent phase transition containing pheniramine and phenylephrine were developed using combination of Poloxamers, different cellulose polymers (HPMC) and xanthan gum. The formulations were tested for in vitro gelation, appearance, pH, drug content, in vitro drug release, mucoadhesive strength, preservative efficacy and stability. In vitro release studies revealed significant prolonged released of both drugs up to 24 h as against only 2 h with drug solution. Formulations were found to stable over period of 3 months. In vivo nasal residence time of in situ gel by gamma scintigraphy was found to be significantly higher (6 h) in comparison to drug solution (15 min). It can be concluded that Poloxamers in combination with HPMC are suitable to develop stable, safe in situ temperature-based mucoadhesive gelling systems with prolonged nasal residence time.