氟尿嘧啶-羟丙基-β-环糊精包合物温敏凝胶生物黏附力及溶出度研究

目的：考察不同生物黏附材料对氟尿嘧啶-羟丙基-β-环糊精包合物温敏凝胶剂粘附性及溶出度的影响。方法：以羟丙基甲基纤维素（HPMC）、海藻酸钠、透明质酸钠、卡波姆、聚卡波菲为生物黏附材料制备氟尿嘧啶-羟丙基-β-环糊精包合物温敏凝胶剂,测定各处方的黏附力,并在溶出介质p H 7.2磷酸盐缓冲液中,用透析袋法进行体外释药试验。结果：以0.2%聚卡波菲为生物黏附材料的处方黏附力为32.3 g·ml^-1,药物释放时间延长至8 h,采用不同的生物黏附材料对制剂溶出行为没有显著影响。结论：以0.2%聚卡波菲为生物黏附材料,制备氟尿嘧啶-羟丙基-β-环糊精包合物温敏凝胶剂黏附力高,且具有良好的缓释效果。     

阴道生物黏附缓释制剂的研究进展

综述了近年来国内外阴道生物黏附缓释新型制剂的进展,包括生物黏附性缓释乳膏、生物黏附阴道片、缓释凝胶剂等。     

阴道生物黏附缓释制剂的研究进展

综述了近年来国内外阴道生物黏附缓释新型制剂的进展,包括生物黏附性缓释乳膏、生物黏附阴道片、缓释凝胶剂等.     

5-氟尿嘧啶直肠温敏胶膜剂的制备

目的:制备5-氟尿嘧啶(5-FU)直肠温敏胶膜剂。方法:以泊洛沙姆407(P407)和泊洛沙姆188(P188)为温敏材料制备5-FU直肠温敏胶膜剂,以溶液-凝胶的相变温度、凝胶强度、生物黏附力为指标,对温敏材料的比例、5-FU质量浓度、p H、生物黏附剂种类进行筛选。结果:以P407-P188(17∶2.5)为温敏材料,2%卡波姆940为生物黏附剂,p H为7.1,制得规格为500 mg/30 ml的5-FU温敏凝胶剂。所制凝胶在室温下为自由流动的液体,在生理条件下相变形成胶膜,相变温度为35~36.6℃,凝胶强度为20~60 g,生物黏附力为20~100 g,均符合直肠应用要求。结论:成功制得5-FU直肠温敏胶膜剂。     

姜黄素鼻用微乳凝胶剂的制备及性质考察

目的制备载药量高、纤毛毒性低、生物黏附性好的姜黄素鼻用制剂,以提高姜黄素脑部生物利用度。方法通过溶解度实验、纤毛毒性试验和三元相图进行微乳处方筛选,以载药量、载油量及粒径等为指标,应用单纯形网格法优化处方;采用直接溶胀法制备微乳凝胶并对该微乳凝胶进行影响因素考察;采用在体法纤毛毒性试验,以中华大蟾蜍的上颚黏膜为模型考察制剂的纤毛毒性;以转篮法测定微乳凝胶剂及混悬凝胶剂中药物释放度。结果姜黄素微乳凝胶剂最优处方为泊洛沙姆188-中碳链三甘酯-聚乙二醇400-水-卡波姆940的质量比为21.7∶5.0∶48.2∶25∶1,最大载药量68.97 mg.g-1;60℃、光照下含量明显下降;制剂组纤毛持续运动时间为生理盐水组的95.14%;微乳凝胶剂和混悬凝胶剂24 h累积药物释放量分别为100%、41.1%。结论所制备的姜黄素微乳凝胶剂具有载药量高、纤毛毒性低、可生物黏附的特点且较混悬剂释放完全,符合鼻用制剂标准。     

生物黏附制剂的研究进展

生物黏附制剂是一类药物以水凝胶聚合物为载体,通过生物黏附作用长时间黏附于黏膜而发挥疗效的药物制剂[1]。目前,人们已研制了生物黏附性散剂、片剂、凝胶、脂质体及微球等制剂,国外已有激素的口腔溃疡粘贴膜剂和片剂商品。生物黏附制剂在延长药物的作用时间,减轻药物不良反应,提高生物利用度等方面取得了十分显著的效果。1　生物黏附机制人与动物的口腔、鼻、眼、阴道、消化道等组织的黏膜可分泌黏液。黏液的主要成分是水(95%以上),还有黏蛋白(0.5%～5%)及少量的脂质、无机盐和游离蛋白质。黏蛋白是产生黏性的主要成分,它是由蛋白质主链和…     

卡波姆在药剂学中的应用

综述了卡波姆在生物黏附释药系统、缓控释释药系统、外用凝胶剂及混悬剂中应用的研究进展.     

法莫替丁生物黏附缓释片释放机制研究

目的探讨法莫替丁生物黏附缓释片的释药机制及影响因素。方法以羟丙基甲基纤维素（HPMC）为骨架材料，卡波姆为生物黏附材料，乳糖为辅料制备生物黏附缓释片，运用Ritger-Peppas方程释放指数n值，评价HPMC、卡波姆和乳糖对释药速率的影响。结果生物黏附片的释药速率随HPMC、卡波姆含量增高而减慢，乳糖可以加快释药速率，经处方筛选优化后制备的法莫替丁生物黏附缓释片的释放，是Fick扩散和凝胶骨架溶蚀两种机制的协同作用结果。结论HPMC、卡波姆和乳糖均可影响法莫替丁生物黏附片中主药的释放，生物黏附缓释片的释药过程可用Ritger—Peppas方程进行描述。     

褐藻酸硫酸酯凝胶剂的质量考察及安全性研究

目的 制备褐藻酸硫酸酯凝胶剂,并对其进行质量考察及安全性评价。方法 以褐藻酸硫酸酯为有效成分制备凝胶剂,从外观、装样量、酸碱度、粘度、有效成分含量及微生物限度方面对凝胶剂质量进行考察,并对其生物安全性进行评价,包括细胞毒性、刺激性及致敏性。结论 制备得到了性状良好、性质稳定的褐藻酸硫酸酯凝胶剂,并且具有较高的生物安全性,为后期褐藻酸硫酸酯药物或医用功能制品的开发奠定了基础。     

法莫替丁生物黏附缓释片释放机制研究木

目的 探讨法莫替丁生物黏附缓释片的释药机制及影响因素.方法 以羟丙基甲基纤维素(HPMC)为骨架材料,卡波姆为生物黏附材料,乳糖为辅料制备生物黏附缓释片,运用Ritger-Peppas方程释放指教n值,评价HPMC、卡渡姆和乳糖对释药速率的影响.结果 生物黏附片的释药速率随HPMC、卡波姆含量增高而减慢,乳糖可以加快释药速率,经处方筛选优化后制备的法莫替丁生物黏附缓释片的释放,是Fick扩散和凝胶骨架溶蚀两种机制的协同作用结果.结论 HPMC、卡波姆和乳糖均可影响法莫替丁生物黏附片中主药的释放,生物黏附缓释片的释药过程可用Ritger-Peppas方程进行描述.     

Development of prilocaine gels for enhanced local anesthetic action

Prilocaine, one of local anesthetics, has been used for regional pain relief. When applied as an ointments or creams, it is hard to expect their effects to last for long time, because they are easily removed by wetting, movement and contacting. For more comfortable and better application, we developed a prilocaine gel system using a bioadhesive polymer, carboxymethyl cellulose (CMC). For suitable bioadhesion, the bioadhesive force of various polymers was tested using an auto-peeling tester. The bioadhesive force of various types of CMC such as 100MC, 150MC and 300MC, was 0.0264, 0.0461 and 0.0824 N, at 1.5% concentration, respectively. The CMC-300MC gels showed the most suitable bioadhesive forces. The effect of drug concentration on drug release was studied from the prepared 1.5% CMC gels using a synthetic cellulose membrane at 37 ± 0.5°C. As the concentration of drug increased, the drug release increased. The effects of temperature on drug release from the 1.0% prilocaine gels were evaluated at 27, 32, 37 and 42°C. As the temperature of the drug gels increased, drug release increased. The enhancing effects of penetration enhancers such as pyrrolidones, non-ionic surfactants, fatty acids and propylene glycol derivatives were studied. Among the enhancers used, polyoxyethylene 2-oleyl ether was superior. The anesthetic effects were studied by a tail flick analgesic meter. In the rat tailflick test, 1.0% prilocaine gels containing polyoxyethylene 2-oleyl ether showed the most prolonged local analgesic effects. The results support the view that prilocaine gels with enhanced local anesthetic action could be developed using CMC bioadhesive polymer.     

Preparation and evaluation of bioadhesive dibucaine gels for enhanced local anesthetic action

In relieving local pains, dibucaine, one of ester type local anesthetics, has been used. In case of their application such as ointments and creams, it is difficult to expect their effects for a required period of time, because they are easily removed by wetting, movement and contacting. To develop suitable bioadhesive gels, the bioadhesive force of hydroxypropyl cellulose (HPC) was tested using auto-peeling tester. The effect of drug concentration on drug release was studied from the prepared 2% HPC-HF gels using synthetic cellulose membrane at 37 ± 0.5°C. We investigated the enhancing effects on drug permeation into skins, using some kind of enhancers such as the glycols, the non-ionic surfactants, the fatty acids, and the propylene glycol derivatives. Anesthetic effects of dibucaine gels containing polyoxyethylene 2-oleyl ether were measured by tail flick analgesic meter. The bioadhesive force of various types of HPC such as GF, MF, and HF, was 0.0131, 0.0501, and 0.1346 N, at 2% HPC concentration, respectively. The HPC-HF gels showed the highest bioadhesive force. As the concentration of HPC-HF increased, the drug release increased. As the temperature increased, the drug release increased. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the highest enhancing effects. According to the rat tail flick test, 1% drug gels containing polyoxyethylene 2-oleyl ether showed the prolonged local anesthetic effects. In conclusion, the dibucaine gel containing penetration enhancer and vasoconstrictor showing enhanced local anesthetic action could be developed by using the bioadhesive polymer, HPC.     

Effect of chitosan on a periodontal pathogen Porphyromonas gingivalis

Local delivery systems of antimicrobial agents for treatment of the periodontal diseases received considerable attention during the past decade due to the disadvantages of the systemic administration. An ideal formulation should exhibit ease of delivery, a good retention at the application site, and a controlled release of the drug. The application of bioadhesive gels provides a long stay in the oral cavity, adequate drug penetration, high efficacy and acceptability. In dentistry and oral medicine, various applications of chitosan, which is a bioadhesive polymer have been proposed due to its favorable properties such as biocompatibility and biodegradability. The aim of this study was to determine the antimicrobial activity of chitosan formulations either in gel or film form against a periodontal pathogen, Porphyromonas gingivalis. The viscosity, bioadhesive properties and antimicrobial activity of chitosans at different molecular weight and deacetylation degree were evaluated in the absence or presence of chlorhexidine gluconate (Chx), incorporated into the formulations at 0.1 and 0.2% concentrations. The flow property of the gels were found to be suitable for topical application on the oral mucosa and to syringe into the periodontal pocket. Bioadhesion of the gels and films examined ex-vivo using fresh porcine buccal mucosa showed that both the film and gel formulations exert bioadhesive properties and was not affected by incorporation of Chx. Chitosan is shown to have an antimicrobial activity against P. gingivalis and this was higher with high molecular weight chitosan. The combination of chitosan with Chx showed a higher activity when compared to that of Chx alone, which would provide Chx application at lower concentrations thus avoiding its unwanted side effects. Chitosan films and gels seem to be promising delivery systems for local therapy of periodontal diseases with its bioadhesive property and antimicrobial activity.     

Enhanced permeation of triamcinolone acetonide through the buccal mucosa.

To develop new formulations that have suitable bioadhesive force and provide sustained release in buccal area for an extended period of time, bioadhesive gels containing triamcinolone acetonide were prepared using two polymers, carbopol 934 and poloxamer 407 which were selected for their bioadhesiveness and gelling property, respectively. The drug release profiles from the gels were studied as a function of drug concentration and temperature. Different enhancers such as bile salts, glycols and non-ionic surfactants were used for the enhancement of its permeation through buccal mucosa. Among the enhancers used, sodium deoxycholate showed the best enhancing effects.     

Rheological, mucoadhesive and release properties of pluronic F-127 gel and pluronic F-127/polycarbophil mixed gel systems

This study was designed to combine the mucoadhesive property of Noveon and the thermosensitive property of Pluronic F-127 into one gel system. A rheological study of Pluronic aqueous sols (10-35%), Noveon gels (0.5-2%) and of mixed gels containing Pluronic (10-17.5%) and polycarbophil (0.5-2.5%) was conducted at different temperatures (15-35 degrees C). The viscosity of Pluronic sols increased with an increase in temperature and the mixed gels had thermoreversible property. The viscosity of mixed gels was higher than that of the Pluronic sols containing only Pluronic because of the increase in total polymer concentration. No interaction was found between -COOH groups of Noveon and Pluronic molecules at the studied concentrations of polymers; the viscosity of mixed gels containing un-neutralized Noveon was lower than that of the neutralized mixed gels. The effect of Pluronic F-127 on the mucoadhesive property of Noveon was investigated. The mucoadhesive properties of Pluronic and Noveon gels were compared by a force of detachment test. It was found that Pluronic and Noveon gels showed approximately the same mucoadhesive strength. However, there were significant differences in the viscosity of Noveon and Pluronic gels. The adhesive force of the mixed gel was almost same as that of the Noveon gel. The Pluronic did not affect the adhesive power of Noveon and the increased viscosity did not affect the bioadhesive force of the mixed gels. In spite of increasing viscosity of the gel, the percentage of released model material (mannitol) increased with increasing temperature. This is based on the previously reported observation that the interaction between the Pluronic molecules squeezed mannitol molecules out of the polymer chains. The mannitol release obeyed zero-order kinetics and the flux values of mixed gels at 15 and 35 degrees C were very similar. The Noveon chains among Pluronic chains probably hindered the diffusion of mannitol molecules and the release was thus controlled by Noveon. The combination of a thermosensitive polymer like Pluronic and a bioadhesive polymer like Noveon appears promising from a pharmaceutical viewpoint. These gel systems may find use in the development of bioadhesive, thermosensitive and controlled release formulations.     

Preparation and evaluation of procaine gels for the enhanced local anesthetic action

To develop the new procaine gel formulations with a suitable bioadhesive property, the gel was formulated using hydroxypropyl methylcellulose (HPMC) and poloxamer containing an enhancer and the local anesthetic action were evaluated. As the drug concentration in the gels and the temperature of surrounding solutions increased, the drug release increased. The activation energy of drug permeation was 4.35 kcal/mol for procaine. The effects of permeation enhancers on the permeation rate of drug through skin were studied using various enhancers, such as the glycols, the non-ionic surfactants, and the bile salts. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the most enhancing effects on drug permeation through skin. The analgesic activity was examined using a tail-flick analgesimeter. From the area under the efficacy curve of the rat-tail flick tests, procaine gel containing polyoxyethylene 2-oleyl ether showed about 1.77-fold increase in analgesic activity compared with the control. These results support that the enhanced local anesthetic gels containing an enhancer could be developed using the bioadhesive polymer gels based on HPMC and poloxamer.     

Effect of sodium chloride on the gelation temperature, gel strength and bioadhesive force of poloxamer gels containing diclofenac sodium

Liquid suppository systems composed of poloxamers and bioadhesive polymers were easy to administer to the anus and mucoadhesive to the rectal tissues without leakage after the dose. However, a liquid suppository system containing diclofenac sodium could not be developed using bioadhesive polymers, since the drug was precipitated in this preparation. To develop a liquid suppository system using sodium chloride instead of bioadhesive polymers, the physicochemical properties such as gelation temperature, gel strength and bioadhesive force of various formulations composed of diclofenac sodium, poloxamers and sodium chloride were investigated. The mixtures of P 407 (15%) and P 188 (15-20%) existed as a liquid at room temperature, but gelled at physiological temperature. Diclofenac sodium significantly increased the gelation temperature and weakened the gel strength and bioadhesive force, while sodium chloride did the opposite. Furthermore, the poloxamer gels with less than 1.0% of sodium chloride, in which the drug was not precipitated, were inserted into the rectum of rabbits without difficulty and leakage, and retained in the rectum of rats for at least 6 h. Our results suggested that a thermosensitive liquid suppository system with sodium chloride and poloxamers was a more physically stable and convenient rectal dosage form for diclofenac sodium.     

Development of lidocaine gels for enhanced local anesthetic action

In relieving local pains, lidocaine, one of ester type local anesthetics, has been used. To develop the lidocaine gels of enhanced local anesthetic effects, hydroxypropyl methylcellulose (HPMC) based bioadhesive polymer gel containing an enhancer was formulated. As the drug concentration in the gels increased up to 3%, the permeation rate of drug linearly increased, thereafter reaching a plateau. As the temperature of surrounding solutions increased, the permeation of drug increased. The activation energy of drug permeation was 3.29 kcal/mol for lidocaine. The permeation rate of drug through skin was studied using various enhancers, such as glycols, non-ionic surfactants, and bile salts. Among the enhancers studied, diethylene glycol showed the greatest enhancing effects on drug permeation through skin. The analgesic activity was examined using a tail-flick analgesimeter. In the area under the efficacy curve (AUEC) of the rat-tail flick tests, lidocaine gel containing diethylene glycol showed about 3.89-fold increase in analgesic activity compared with the control. The addition of vasoconstrictor in the gels prolonged the analgesic effects. The result of this study supports that the bioadhesive gel with efficient anesthetic effect could be developed using HPMC with combination of enhancer and vasoconstrictor.     

Nasal route and drug delivery systems

Nasal drug administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including numerous compound, peptide and protein drugs, for systemic medication has been widely investigated in recent years. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption. Several approaches are here discussed for increasing the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. The article highlights the importance and advantages of the drug delivery systems applied via the nasal route, which have bioadhesive properties. Bioadhesive, or more appropriately, mucoadhesive systems have been prepared for both oral and peroral administration in the past. The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. In this review we discuss the effects of microspheres and other bioadhesive drug delivery systems on nasal drug absorption. Drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and that swell easily when in contact with the nasal mucosa. These drug delivery systems have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions. The mechanisms and effectiveness of these drug delivery systems are described in order to guide the development of specific and effective therapies for the future development of peptide preparations and other drugs that otherwise should be administered parenterally. As a consequence, bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems. Although the majority of this work involving the use of microspheres, liposomes and gels is limited to the delivery of macromolecules (e.g., insulin and growth hormone), the general principles involved could be applied to other drug candidates. It must be emphasized that many drugs can be absorbed well if the contact time between formulation and the nasal mucosa is optimized.