温度敏感原位凝胶在眼部给药系统中的研究进展

温度敏感原位凝胶可随温度变化发生凝胶反应,从而缓慢持久地释放药物,提高药物的生物利用度,是一种很有开发价值的新型药物传递系统.本文主要对温度敏感原位凝胶中聚合物的种类及应用,以及该剂型在眼部给药系统中的应用进行了综述.     

阴道用塞克硝唑温敏型原位凝胶的研制

目的:以温敏性聚合物泊洛沙姆407和黏附性聚合物羟丙基甲基纤维素为载体制备阴道用塞克硝唑温敏型原位凝胶,使凝胶在阴道壁原位凝胶化并迅速黏附于黏膜表面,延长药物在黏膜表面吸收时间。方法:采用单因素考察泊洛沙姆407浓度及药物对凝胶相变温度的影响,确定最佳处方;采用冷法制备载塞克硝唑温敏型原位凝胶,考察凝胶的流变学特性;采用紫外分光光度法测定原位凝胶中药物的含量。结果:当泊洛沙姆407浓度为20%时,载塞克硝唑温敏型凝胶的胶凝相变温度为(31.7±0.5)℃,可满足阴道用药后迅速相变为凝胶的条件,流变学行为显示塞克硝唑阴道凝胶的黏度随温度的变化均呈S形曲线,相变温度与转子法测得值相近。含量测方法在4.99~24.96mg.L-1范围内线性关系良好,平均回收率为98.47%,RSD为2.73%(n=6)。结论:阴道用塞克硝唑温敏型原位凝胶制备工艺简单,能在生理温度下迅速原位凝胶化,建立的含量测定方法简便可靠。     

注射用可降解原位水凝胶的研究进展

介绍注射用可降解原位水凝胶的分类及其应用情况。通过查阅国内外的相关文献,对其中的37篇研究进行分析,归纳。总结了温敏型和p H/温敏型的注射用可降解原位水凝胶的聚合物种类,各自主要特点,并对各聚合物的应用研究加以综述。可知注射用可降解原位水凝胶具有广泛的应用和发展前景。     

昂丹司琼温度敏感型原位凝胶体外释药动力学研究

目的：制备昂丹司琼温度敏感型原位凝胶并研究其体外释药动力学。方法采用温度敏感型原位凝胶为载体,制备昂丹司琼原位凝胶控释给药系统,建立昂丹司琼高效液相色谱测定方法,探索温度、转速、聚合物浓度及不同介质等因素对释药行为的影响。结果制得的昂丹司琼/泊洛沙姆407原位凝胶在pH 6.25的0.9％氯化钠溶液中,室温时为液体状态,在接近体温条件下转化为半固体状态,释药规律具有Highchi平方根定律模型特征。结论该制剂具有显著的温度敏感型控制缓释特征,且制备方法简单,用药剂量易于控制,极具应用前景。     

注射用原位凝胶的研究进展

主要介绍了注射用原位凝胶中聚合物的种类,综述了该剂型在给药系统中的应用以及近年来的研究热点.作为一种新型的药物传递系统,注射用原位凝胶凭借其独特的优势,在药剂学领域有着广阔的应用前景.     

瘀肿消温度敏感型原位凝胶的基质配比优选

目的优选瘀肿消温度敏感型原位凝胶的基质配比。方法以温度敏感型原位凝胶的胶凝温度、胶凝强度、生物黏附力为考察指标,优选出瘀肿消温度敏感型原位凝胶基质配比。结果瘀肿消温度敏感型原位凝胶基质配方Poloxamer407、Poloxamer188、卡波姆分别为22%、3%、0.7%。结论瘀肿消温度敏感型原位凝胶成型工艺简单、性质稳定。     

原位凝胶在黏膜给药制剂中的研究进展

原位凝胶是一种新型给药系统,按其形成机制可分为温度敏感型、离子敏感型、pH敏感型等类型。该文就原位凝胶在眼部给药、鼻腔给药及直肠给药方面的应用作一概述,提出原位凝胶应用中存在的问题,并对其良好应用前景进行展望。     

氯霉素温敏型眼用原位凝胶的研制

目的制备氯霉素泊洛沙姆眼用原位温敏型凝胶并建立其质量控制方法。方法以泊洛沙姆P407和P188为温敏材料,通过测定溶液-凝胶相转变温度优化处方;采用紫外分光光度法测定氯霉素含量。结果氯霉素温敏型原位凝胶的胶凝温度随P407浓度增大而降低,随P188浓度增加先升高后降低,模拟泪液的稀释可使胶凝温度升高,建立了泪液稀释后相变温度与泊洛沙姆浓度的拟合方程,经Design-Expert软件优化出的氯霉素温敏型原位凝胶最佳处方为25%P407和4.19%P188;优化处方在29.5℃时为自由流动的液体,泪液稀释后在34.6℃能够发生相变形成凝胶。结论该眼用温敏凝胶符合眼部应用要求,体现出良好的应用前景。     

奥洛他定温度敏感眼用原位凝胶的制备

目的:研制奥洛他定温度敏感眼用原位凝胶。方法:采用泊洛沙姆P407和P188为温敏材料,以胶凝温度为指标,通过星点设计-效应面法优化处方。结果:经过优化筛选出的处方在室温条件下是自由流动的液体,在生理条件下发生胶凝形成凝胶。结论:所研制奥洛他定眼用温度敏感原位凝胶符合眼部应用要求,体现出良好的临床应用前景。     

原位凝胶的研制及临床应用研究新进展

原位凝胶(in situ gel)又称即型凝胶、在位凝胶,是指将其以溶液或半固体状态给药,当接触用药部位的机体生理条件或受到其他环境因素的影响后,即发生相转变,形成半固体凝胶状态的制剂。原位凝胶是一种具有给药方便、剂量准确、患者顺应性好、灌装生产方便等诸多优势的剂型,从制备基质所需的聚合物材料选用到其在各种临床给药途径中的应用,一直是研究的热点。以泊     

Thermosensitive and mucoadhesive in situ gel based on poloxamer as new carrier for rectal administration of nimesulide

Poloxamer 407 has excellent thermo-sensitive gelling properties. Nevertheless, these gels possess inadequate poor bioadhesiveness and high permeability to water, which limited its' application as a thermoresponsive matrix. The main aim of the present investigation was to develop thermosensitive and mucoadhesive rectal in situ gel of nimesulide (NM) by using mucoadhesive polymers such as sodium alginate (Alg-Na) and HPMC. These gels were prepared by addition of mucoadhesive polymers (0.5%) to the formulations of thermosensitive gelling solution containing poloxamer 407 (18%) and nimesulide (2.0%). Polyethylene glycol (PEG) was used to modify gelation temperature and drug release properties. The gelation temperature and drug release rate of the prepared in situ gels were evaluated. Gelation temperature was significantly increased with incorporation of nimesulide (2.0%) in the poloxamer solution, while the addition of the mucoadhesive polymers played a reverse role on gelation temperature. The addition of PEG polymers increased the gelation temperature and the drug release rate. Among the formulations examined, the poloxamer 407/nimesulide/sodium alginate/PEG 4000 (18/2.0/0.5/1.2%) exhibited the appropriate gelation temperature, acceptable drug release rate and rectal retention at the administration site. Furthermore, the micrographic results showed that in situ gel, given at the dose of 20mg/kg, was safe for no mucosa irritation. In addition, it resulted in significantly higher initial serum concentrations, C(max) and AUC of NM compared to the solid suppository.     

Injectable in situ forming drug delivery system for cancer chemotherapy using a novel tissue adhesive: characterization and in vitro evaluation.

Injectable polymers that are biocompatible and biodegradable are important biomaterials for drug delivery system (DDS) and tissue engineering. We have already developed novel tissue adhesives consisting of biomacromolecules and organic acid derivatives with active ester groups. The resulting tissue adhesive forms in situ as a gel and has high bonding strength for living tissue as well as it has good biocompatibility and biodegradability. Here, we report on the physicochemical properties and in vitro evaluation of this novel tissue adhesive consisting of human serum albumin (HSA) and tartaric acid derivative (TAD) containing doxorubicin hydrochloride (DOX). The results of the measurement of physicochemical characteristics indicate that the gelation time and gel strength of HSA-TAD gels can be controlled according to the material composition. The bonding strength of HSA-TAD adhesives was found to be sufficient to adhere at focus and to correspond with the cross-linking density of HSA-TAD gels. Furthermore, the release of DOX from HSA-TAD gels was sustained for approximately 100 h in an in vitro evaluation. The novel tissue adhesive, therefore, is expected to be applicable for use as an injectable in situ forming DDS.     

Ophthalmic controlled release in situ gelling systems for ciprofloxacin based on polymeric carriers

The objective of the present study was to design controlled release ophthalmic delivery systems for ciprofloxacin based on polymeric carriers that undergo sol-to-gel transition upon change in pH or in the presence of cations in an attempt to prolong the effect of ciprofloxacin and improve its ocular bioavailability. Carbopol and alginates polymers were used to confer gelation properties to the formulations. Hydroxypropyl methylcellulose and methylcellulose were combined with carbopol to increase the viscosity of the gels and to reduce the concentration of the incorporated carbopol. The release exponents (n) for the designed systems were close to 1, indicating that the drug release occurred by zero-order kinetics. Controlled release in situ gels consisting of carbopol and cellulose derivatives showed an increase in viscosity, gelling capacity, and adhesiveness as the concentration of each polymeric component was increased. On the other hand, these parameters possessed lowest values when alginate was used as an in situ gelling agent. The antimicrobial efficiency of the selected formulation against gram-positive and gram-negative organisms including Echerichia coli, staphylococcus strains and Pseudomonas aeruginosa confirmed that the designed formulation has prolonged the antimicrobial effect of ciprofloxacin and retained its properties against bacteria.     

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。     

Percutaneous absorption of non-steroidal anti-inflammatory drugs from in situ gelling xyloglucan formulations in rats

The potential of gels formed in situ by dilute aqueous solutions of a xyloglucan polysaccharide derived from tamarind seed as sustained release vehicles for percutaneous administration of non-steroidal anti-inflammatory drugs has been assessed by in vitro and in vivo studies. Chilled aqueous solutions of xyloglucan that had been partially degraded by beta-galactosidase formed gels at concentrations of 1-2% w/w when warmed to 37 degrees C. The in vitro release of ibuprofen and ketoprofen at pH 7.4 from the enzyme degraded xyloglucan gels and the subsequent permeation of these fully ionized drugs through cellulose membranes followed root-time kinetics over a period of 12 h after an initial lag period. Diffusion coefficients were appreciably higher when the drugs were released from 1.5% w/w xyloglucan gels than when released from 25% w/w Pluronic F127 gels formed in situ under identical conditions. The difference in release rates was attributed to differences in the structure of the gels. The permeation rate of ibuprofen through excised skin was higher than that of ketoprofen when released from both gels, but of similar magnitude through cellulose membranes. Plasma concentrations of ibuprofen and ketoprofen from gels formed in situ following topical application of chilled aqueous solutions of xyloglucan and Pluronic F127 to the abdominal skin of rats were compared. The bioavailabilities of ibuprofen and ketoprofen were significantly higher when released from xyloglucan gels compared to Pluronic F127 gels. Occlusive dressing techniques had a greater enhancing effect on the bioavailability of ibuprofen when released from Pluronic gels.     

In vitro–in vivo evaluation of tetrahydrozoline-loaded ocular in situ gels on rabbits for allergic conjunctivitis management

Ocular allergy is one of the most common disorders of the eye surface. The conventional eye drops lack of therapeutic efficacy due to low ocular bioavailability and decreased drug residence time on eye surface. Hence, the present research work aimed to formulate, optimize, and evaluate the in situ gel for ophthalmic drug delivery. The prepared in situ gel formulations were evaluated for clarity, pH, gelling capacity, viscosity, osmolality, in vitro release study, and kinetic evaluation. ex vivo corneal permeation/penetration study using goat and in vivo studies on rabbits were also performed. Fourier-transformed infrared spectroscopy was also applied to study possible interactions between drug and polymers. The formulations found to be stable, nonirritant, and showed sustained release of the drug for a period of up to 24 hr with no ocular damage. The developed in situ gels loaded with tetrahydrozoline are alternative and promising ocular candidates for the treatment of allergic conjunctivitis.     

LC-MS法研究尼莫地平脂质体原位凝胶在家兔体内的药动学

目的研究尼莫地平脂质体原位凝胶在家兔体内的药动学。方法单剂量(尼莫地平0.5 mg·kg~(-1))于家兔后腿股四头肌肌内注射尼莫地平溶液剂、尼莫地平脂质体、泊洛沙姆188(P188)修饰的尼莫地平脂质体和尼莫地平脂质体原位凝胶,建立高效液相色谱-质谱(LC-MS)法测定血浆中尼莫地平的浓度。结果尼莫地平在0.8～800μg·L~(-1)范围内线性关系良好(r=0.999 2),提取回收率大于90%,日内、日问精密度RSD<15%。尼莫地平脂质体原位凝胶和脂质体的c_(max)分别为(88±s 18)和(224±64)μg·L~(-1);t_(max)分别为(2.0±0.7)和(0.29±0.14)h;AUC_(0-∞)分别为(402±15)和(273±28)μg·h·L~(-1)。尼莫地平脂质体原位凝胶的c_(max)、t_(max)、AUC_(0-∞)等药动学参数与尼莫地平脂质体和P188修饰的尼莫地平脂质体均有显著或极显著差异。结论尼莫地平脂质体原位凝胶经肌内注射后可延长药物在体内的驻留时间,具有一定的缓释作用并提高了尼莫地平的生物利用度。     

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。     

Development and in vitro evaluation of a mucoadhesive vaginal delivery system for nystatin

The purpose of the present study was to design and evaluate a novel vaginal delivery system for nystatin based on mucoadhesive polymers. L-Cysteine and cysteamine, respectively, were covalently attached to poly(acrylic acid), and the two different thiolated polymers were evaluated in vitro regarding their swelling behavior, mucoadhesive properties and release behavior. Tablets comprising these thiolated polymers and nystatin demonstrated a high stability in vaginal fluid simulant pH 4.2 and an increase in weight by swelling whereas control tablets comprising unmodified poly(acrylic acid) disintegrated and dissolved. The mucoadhesion time of tablets on freshly excised bovine vaginal mucosa on a rotating cylinder and the total work of adhesion of gels and tablets increased significantly due to the formation of disulfide bonds between the thiolated polymer and cysteine rich subdomaines of the mucus layer. The drug nystatin was released more slowly out of thiomer tablets and gels than out of PAA control tablets and gels. Therefore these thiolated polymers are promising delivery systems for nystatin providing a prolonged residence time and a sustained drug release in vitro under physiological relevant conditions.     

Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels

A method for the in situ gelation of poloxamers and the mucoadhesive polymer chitosan has been developed by exploiting the tendency of poloxamer solution to form gel at physiological temperatures and of chitosan (CT) to form ionotropic gel structures in the presence of sodium tripolyphosphate (TPP). Novel poloxamer gels containing CT-TPP complex formed in situ during the administration were prepared by mixing poloxamer-CT and poloxamer-TPP solutions in double syringes. The micellization and gelation of poloxamer 407 in the presence of chitosan and/or TPP were studied using differential scanning calorimetry and tube inversion; both additives were found to reduce the critical micellization temperature and critical gelation temperature of poloxamer aqueous solution. The poloxamer gels containing CT-TPP complex formed in situ were found to exhibit reduced dissolution rate and superior release characteristics with three different drugs--metoprolol, doxycycline and flufenamic acid. Furthermore, by varying the compositions of the two solutions independently, it is possible to control the pH in a way to suit the solubilization of a drug as well as the specific environment of a particular application site. By varying the concentrations of chitosan, TPP and poloxamer, the delivery system can be fine-tuned to afford gels with specific properties, ranging from nanoparticle suspensions to semisolid gels. These in situ gels have the potential to increase the utility of thermo-reversible poloxamers in drug delivery.