酮洛芬不同透皮制剂的体外透皮性和释放性

分别制备含1%、3%、5%酮洛芬的混合型巴布剂、交联型巴布剂、透皮贴剂,以同浓度的酮洛芬凝胶剂作为对照组,采用改良Franz透皮扩散池,以离体小鼠皮肤为透皮屏障,考察酮洛芬在不同制剂中的体外透皮和释放性能.结果表明,同浓度酮洛芬在不同受试制剂的透皮速率依序为交联型巴布剂＞混合型巴布剂＞凝胶剂＞透皮贴剂;3%酮洛芬在不同贴膏剂中的释放速率依序为混合型巴布剂＞交联型巴布剂＞透皮贴剂.     

基于热塑弹性体的辣椒素贴剂的制备及评价

目的:以热塑弹性体为骨架材料,采用熔融共混法制备贴剂基质,制备辣椒素热熔压敏胶贴剂。方法:用红外光谱和偏振光显微镜考察药物在贴剂基质中的存在状态,同时以国外上市贴剂为对照,采用Franz扩散池考察贴剂中辣椒素的释放和体外透皮特性。以SD大鼠为模型动物,考察贴剂的体内透皮吸收行为。结果:辣椒素药物与热熔压敏胶基质相容性好,但贴剂的稳定性有待进一步提高。药物在两者种贴剂中的释放遵循Higuchi方程。实验室自制热熔胶贴剂的体内外透皮行为与国外市售贴剂相比无显著性差异。结论:热熔胶贴剂基质与皮肤和药物的相容性较好,具有良好的体外-体内透皮相关性。     

右旋酮洛芬氨丁三醇水凝胶贴剂的制备及体外透皮研究

摘 要 目的：制备右旋酮洛芬氨丁三醇水凝胶贴剂,优化其处方并评价其体外透皮性能。方法: 选择NP 800为水凝胶骨架材料,甘羟铝为交联剂,EDTA为交联剂调节剂,甘油为保湿剂,制备右旋酮洛芬氨丁三醇水凝胶贴剂,以初黏力、持黏力、剥离强度和12 h累积透皮量为评价指标,进行正交优化试验,筛选出最佳处方。用改良的Franz扩散池进行透皮吸收试验,比较氮酮、油酸及薄荷脑对贴剂中右旋酮洛芬氨丁三醇的促渗作用。结果: 优选的最佳处方为：NP 800、甘羟铝、甘油、EDTA的质量百分含量分别为5%、0.3%、25%、0.15%。透皮促进剂对右旋酮洛芬氨丁三醇有透皮作用,其中以3%氮酮的作用最显著,其促渗倍数达3.26倍。结论: 制备的右旋酮洛芬氨丁三醇水凝胶贴剂处方工艺稳定,合理可行。     

非洛地平-美托洛尔复方贴剂的透皮吸收促进剂优化

目的：优化复合透皮吸收促进剂，制备非洛地平-美托洛尔复方贴剂，并对其外观、物理特性、体外药物释放和经皮渗透性能进行综合评价。方法：以药物体外释放速率和稳态透皮速率为指标，通过正交设计试验考察桉叶油醇、月桂氮[艹卓]酮和丙二醇体系对贴剂质量的影响，优选最佳复合透皮吸收促进剂构成。结果：优选的透皮吸收促进剂最佳含量分别为桉叶油醇5％、月桂氮[艹卓]酮3％和丙二醇12%，以该促透体系制备的贴剂药物体外释放速率和稳态透皮速率高，外观和理化特性较佳，物理黏性适宜，各指标均达到预期设计要求。结论：桉叶油醇-月桂氮[艹卓]酮-丙二醇（5：3：12）复合体系对非洛地平和关托洛尔的协同促透作用显著，且稳定可靠，是非洛地平关托洛尔复方贴剂的优良透皮吸收促进剂。     

广藿香酮透皮贴剂成型工艺探讨

目的:制备广藿香酮透皮贴剂并优化其处方。方法:通过单因素考察,筛选透皮贴剂的压敏胶基质组成及载药量,采用均匀设计法筛选贴剂透皮促进剂。结果:采用压敏胶A为控释骨架和压敏胶材料,载药量为4%。透皮促进剂最优组合为月桂氮芯卓酮-油酸-丙二醇为6%∶5%∶5%。药物从压敏胶层恒速释放。结论:所研制的透皮贴剂具有理想的释药特性。     

紫杉醇纳米脂质体凝胶剂的制备及体外透皮研究

目的制备紫杉醇纳米脂质体凝胶剂,考察其粒径、粒径分布、包封率、体外释放度及透皮特性。方法采用薄膜蒸发高压微射流法制备紫杉醇纳米脂质体,以卡波姆为凝胶基质,研制紫杉醇纳米脂质体凝胶剂,采用正交试验探索最佳工艺。用粒径测定仪测定脂质体的粒径及其粒径分布,低速-超速相结合法测定包封率,透析膜扩散法进行体外释放试验,以离体小鼠皮结合改良Franz扩散装置考察其体外透皮特性。结果紫杉醇纳米脂质体的最佳工艺:卵磷脂的含量为2%,药物与磷脂质量比为1∶30,磷脂与胆固醇的质量比为10∶1。测得的粒径为81.8 nm;粒径分布系数为0.180;平均包封率73.2%。纳米脂质体凝胶剂72 h累积释放百分率为79.04%;48 h的单位面积累积渗透量为429.68μg·cm?2。结论该制剂制备工艺简单,易于涂布,具有较高的包封率,粒径较小且分布均匀,体外释放缓慢。纳米脂质体能促进脂溶性药物紫杉醇透过皮肤。     

磷酸川芎嗪缓释透皮贴剂的制备及体外释放度测定

目的制备磷酸川芎嗪缓释透皮贴剂并优化其处方。方法通过正交实验,筛选缓释透皮贴剂的处方组成。结果采用聚丙烯酸树脂EUDRAGITE100为控释骨架和压敏胶材料,1.0%氮酮作为渗透促进剂制备胶粘剂骨架型经皮给药系统,药物从胶粘剂骨架/药物储库(压敏胶层)中恒速释放,体外释放度表明,贴剂的释放符合零级方程。结论所研制的磷酸川芎嗪缓释透皮贴剂具有理想的释药特性。     

痛舒凝胶膏剂的制备及体外透皮研究

目的 痛舒方为治疗痛经的临床常用方,为了提高治疗效果,本研究将该散剂改良为凝胶膏剂,并考察其体外透皮吸收性能,为其开发和利用提供科学依据。方法 建立综合评分标准,结合单因素实验与响应面法确定凝胶膏剂的基质用量。进行体外透皮实验,以延胡索乙素、芍药苷、粉防己碱、乌药醚内酯为评价指标,考察加入不同比例氮酮促渗剂对凝胶膏剂体外透皮渗透量的影响。结果 痛舒凝胶膏剂基质的最优处方为聚丙烯酸钠0.50 g、甘氨酸铝0.1 g、保湿剂8.00 g（甘油∶丙二醇=8∶2）、酒石酸0.1 g、羧甲基纤维素钠（CMC-Na）、明胶1.75 g(CMC-Na∶明胶=1∶3),体外透皮吸收实验结果表明,透皮促渗剂比例为3%时药物透皮效果最好。结论 用最优处方制备的痛舒凝胶膏剂,具有骨架型缓释制剂的特性,为痛舒方外用新剂型的开发奠定了基础。     

促渗剂对贴剂中双氯芬酸二乙胺的经皮促渗作用

目的 制备双氯芬酸二乙胺(DDEA)水凝用胶贴剂,研究不同促渗剂对水凝胶贴剂中DDEA体外透皮吸收的影响.方法 以具有良好生物相容性的亲水性高分子材料为基质材料制备DDEA水凝胶贴剂;用离体大鼠腹部皮肤为模型,采用改良Franz扩散池装置进行经皮渗透实验.HPLC法测定不同时间点接收池中DDEA的浓度,计算药物的累积渗透量和经皮渗透动力学参数.结果 不同促渗剂对DDEA的经皮渗透有不同程度的促进作用,其中薄荷脑的促渗作用最为显著.薄荷脑对DDEA的促渗在1%～5%,呈正相关剂量效应关系,薄荷脑用量为5%时,药物的稳态透皮速率可达18.121 μg·cm-2·h-1,与空白对照组相比增渗倍数为5.45.结论 薄荷脑可作为DDEA水凝胶贴剂的促渗剂,并可开发此新型水凝胶贴剂.     

甲巯咪唑水凝胶贴剂的制备和体外透皮性能

目的制备甲巯咪唑水凝胶贴荆,研究不同促渗剂对甲巯咪唑经皮渗透的促进作用,并与市售甲巯咪唑软膏进行比较,对甲巯咪唑水凝胶贴剂的体外透皮性能进行评价.方法以具有良好生物相客性的亲水性高分子材料制备甲巯咪唑水凝胶贴剂,采用透皮扩散试验仪,以离体大鼠皮肤为屏障进行经皮渗透实验,高效液相色谱法测定接收池中药物的浓度,计算药物累积渗透量.结果甲巯咪唑水凝胶贴剂制备工艺简单,各类促渗剂对甲巯咪唑的经皮渗透有不同程度的促进作用,其中月桂氮革酮的促渗作用最为显著.以2%月桂氮革酮为促渗剂的甲巯咪唑水凝胶贴剂的经皮渗透符合零级动力学过程,药物经皮渗透速率为39.60 μg·cm-2·h-1,其24 h单位面积累积渗透量为950.39 μg·cm-2,高于对照制剂甲巯咪唑软膏.结论甲巯咪唑水凝胶贴剂可以开发为甲巯咪唑的新型经皮给药制剂.     

中药骨伤凝胶贴剂的经皮渗透性研究

目的 探讨药粉目数及透皮吸收促进剂对中药骨伤凝胶贴剂经皮渗透作用的影响。方法 以羟基红花黄色素A和血竭素为评价指标，采用桨碟法评价凝胶贴剂的体外释放行为，采用Franz扩散池法考察药粉目数及透皮吸收促进剂对凝胶贴剂透皮吸收的影响。结果 与氮酮和薄荷脑相比，肉豆蔻酸异丙酯对于羟基红花黄色素A和血竭素的促渗作用最好，其最佳用量为3%，200目的药粉相对于80目在体外释放及有效成分的经皮吸收方面没有明显影响。结论 药粉目数对凝胶贴剂经皮渗透作用的影响不显著，肉豆蔻酸异丙酯透皮吸收促进剂能显著提高凝胶贴剂的透皮吸收。     

小茴香油微乳凝胶的制备及其体外透皮促渗行为研究

目的 优化筛选出小茴香油微乳凝胶的最佳处方组成，并考察小茴香油微乳凝胶的体外透皮性能。方法 采用星点设计效应面法分别优化了微乳和微乳凝胶的处方，Franz扩散池法考察小茴香油微乳及其凝胶的体外透皮性能。结果 微乳最优处方为油相∶乳化剂和助乳化剂(吐温-80︰二乙二醇单乙基醚=2.5︰1)∶水=20︰27.6︰52.4，进一步制备得到了小茴香油微乳凝胶。小茴香油微乳的流动性及稳定性好，平均粒径为(42.03±0.9)nm、多分散性指数为(0.154±0.005)。小茴香油微乳凝胶均匀细腻，易涂展，有一定流动性，为乳白色半透明半固体凝胶。体外透皮性能结果表明小茴香油作为油相，制备成微乳和微乳凝胶，其体外透皮吸收量分别提高了3，4倍。结论 该研究为小茴香油的制剂技术奠定了基础，也为挥发油类药物的广泛应用提供了理论依据。     

正交设计优选化瘀散凝胶贴膏基质配方

目的 优选化瘀散凝胶贴膏基质配方制备工艺的最佳条件。方法 采用正交设计试验,以凝胶贴膏的初黏力、持黏力、剥离强度及追随性为考察指标,对聚丙烯酸钠、明胶、甘油和丙二醇的用量进行优选,确定基质中不同辅料的最佳配比。结果 优选出化瘀散凝胶贴膏最佳基质处方配比为聚丙烯酸钠∶明胶∶甘油∶丙二醇=4∶3∶3∶2。结论 以最优处方基质配比制备的凝胶贴膏,表面平整光滑,具有良好的黏附性和保湿性。     

Randomized,double-blind,crossover study of the adhesiveness of two formulations of rotigotine transdermal patch in patients with Parkinson’s disease

Objective: In patch-based transdermal drug delivery, adhesiveness is critical for safe and effective treatment, especially in Parkinson’s disease (PD) where excessive sweating is common. This study compared the adhesiveness of two transdermal patch formulations of rotigotine (improved room temperature-stable [PR2.3.1/Treatment A] and intermediate cold storage product [PR2.1.1/Treatment B]), using the largest patch size (40?cm²).

Methods: PD0018 (NCT02230904) was a multicenter, randomized, double-blind, crossover study. PD patients received Treatments A and B in randomized order for 2 days each. Patch adhesiveness was measured immediately after patch application and 24 hours thereafter (before removal). Primary variable: change in average investigator-rated adhesiveness score between treatments, per modified European Medicines Agency scale (EMA/CHMP/QWP/911254/2011, 2012).

Results: Fifty-seven patients were randomized; 56 patients completed the study. Five patients were excluded from analysis for accidental unblinding. Treatment A had better average adhesiveness score (mean?±?SD Treatment A – Treatment B: 1.115?±?1.635). A higher percentage of patients on both days had patch adhesiveness ≥95% at 24 hours for Treatment A (first day: 65.4%, second day: 71.2%) vs. Treatment B (46.2%, 36.5%), and were satisfied with patch adhesiveness of Treatment A (first day: 75.0%, second day: 73.1%) vs. Treatment B (65.4%, 59.6%). Average patch-wear duration was similar between formulations (23.761 hours vs. 23.495 hours per patch). Both formulations were well tolerated with no new safety observations.

Conclusion: Results indicated greater adhesiveness for the improved room temperature-stable formulation (PR2.3.1) vs. intermediate cold storage product (PR2.1.1) using the largest patch-size, with comparable safety and skin tolerability.     

Skin tolerability of transdermal patches

Introduction: Transdermal patch systems are an effective method of administering active ingredients through the skin, with considerable advantages over other drug delivery routes, for example, maintenance of constant plasma drug levels and avoidance of first-pass metabolism. However, repeated epicutaneous application may be associated with local skin reactions.

Areas covered: This review addresses current issues regarding the effective/safe use of transdermal patch systems, and provides a critical analysis of the addition of ‘skin-caring’ ingredients to patch systems. Effective use of transdermal systems includes choosing an appropriate body area for application, maintaining regular skin care regimens before application and not replacing a patch in the same area (rotation) within 7 days. Another strategy, developed in an attempt to improve the tolerability of transdermal systems, is the addition of assumed ‘skin-caring’ ingredients (e.g., Aloe Vera) to patch systems. However, at present there is neither proof nor clinical evidence of any benefit. On the contrary, plant-derived ingredients might be associated with allergenic potential.

Expert opinion: Transdermal systems are generally well tolerated; physicians must adequately inform patients of the most effective ways to use these formulations for maximum therapeutic benefit, while minimising local adverse events. Skin-caring agents, including Aloe Vera, cannot be recommended until well-controlled clinical trials with standardised extracts are available.     

盐酸罗哌卡因透皮凝胶剂的初步药效学研究

摘 要 目的：初步评价盐酸罗哌卡因透皮凝胶剂的镇痛作用以及对皮肤的刺激性。方法: 采用热板法和醋酸扭体法考察给药后不同时间点1%、3%和5%的盐酸罗哌卡因透皮凝胶对小鼠的镇痛作用。结果: 1%、3%、5%的盐酸罗哌卡因透皮凝胶均能显著提高热板法小鼠的痛阈,显著抑制醋酸引起的小鼠疼痛扭体反应（P<0.01或P<0.05）。载药凝胶对小鼠的镇痛作用具有一定的量效关系,随着罗哌卡因浓度的增加,镇痛作用加强,镇痛持续时间延长,其中5%盐酸罗哌卡因透皮凝胶可持续镇痛24 h。不同浓度的盐酸罗哌卡因透皮凝胶剂对皮肤均无明显的刺激性。结论:5%的盐酸罗哌卡因透皮凝胶具有明显的镇痛作用且维持时间长,基本符合每天给药1次的设计要求。     

A systematic review of medication administration errors with transdermal patches

Introduction: Transdermal patches provide an attractive route of drug delivery with considerable advantages over other routes of administration, for example maintenance of constant plasma drug levels and convenient usage. However, medication administration errors abound with this dosage form and frequently result in harm or treatment failure.

Areas covered: A systematic literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using appropriate keywords to identify articles reporting faulty transdermal patch administration. Common pitfalls and errors that were identified through the systematic literature search were discussed alongside individual steps of the transdermal patch administration process.

Expert opinion: The systematic investigation of published errors illustrated that every step in the transdermal patch administration process is prone to errors. Thereby, the lack of knowledge and awareness of the importance of a correct administration practice were a major source of risk. Based on the identified errors and causes of errors prevention strategies were developed as a first step in avoiding transdermal patch administration errors.     

Transdermal delivery of imipramine hydrochloride: development and evaluation (in vitro and in vivo) of reservoir gel formulation

The in vitro permeation studies of imipramine hydrochloride (IMH) reported earlier from our laboratory showed that a combination of menthol (2.5% w/v) and oleic acid (2.5% w/v) worked well in terms of safety and efficacy. The main objective of this study was to evaluate the in vivo performance of this combination; in order to do that, penetration enhancers were incorporated in a hydro-alcoholic gel of hydroxypropylmethyl cellulose along with IMH and used as the drug matrix in a reservoir transdermal patch. A stability study of IMH gel was performed at 40 degrees C/75% RH for 2 months. The results of this study indicate that gels of IMH stored at 40 degrees C/75% RH turned yellow brown in 2 months and the small change in viscosity of gel at 40 degrees C/75% RH had an insignificant effect on the release rate of IMH from the gel (p>0.05). The in vivo performance of the gel was tested in rats using a reservoir transdermal patch, which consisted of a backing membrane, drug matrix and retaining membrane with an area of 12.5 cm2. Plasma concentrations of 3 microg/ml of IMH were achieved and in a histopathological study 24 h occlusion was found to be safe.     

Safety and tolerability of transdermal and oral rivastigmine in Alzheimer's disease and Parkinson's disease dementia

Importance of the field: Cholinesterase inhibitors are the mainstay of symptomatic therapy for Alzheimer's disease (AD). Rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, is available as a transdermal patch and in oral forms. It is also approved for the treatment of Parkinson's disease dementia (PDD) in many countries. The objective of this article is to review the safety and tolerability profile of transdermal and oral rivastigmine in AD and PDD patients.

Areas covered in this review: Articles were identified by searching MEDLINE in July 2009 using the terms rivastigmine, Exelon, ENA 713 and clinical trial. All double-blind, placebo-controlled randomized trials in which rivastigmine monotherapy was administered to AD or PDD patients for longer than 2 weeks were included.

What the reader will gain: This article provides a comprehensive summary of currently available safety data on rivastigmine.

Take home message: The main adverse events reported with rivastigmine therapy are gastrointestinal in nature. However, the transdermal patch appears to reduce these side effects, allowing more patients to access higher therapeutic doses. Overall, the safety profile of rivastigmine is favorable and the improved tolerability offered by the rivastigmine patch suggests that transdermal delivery may be the best way to deliver this drug in AD and PDD patients.     

Enhancement of levodopa stability when complexed with β-cyclodextrin in transdermal patches

Abstract

Levodopa is a promising candidate for administration via the transdermal route because it exhibits a short plasma half-life and has a small window of absorption in the upper section of the small intestine. The aim of this study was to prepare stable levodopa transdermal patches. Both xanthan gum and Carbopol 971 polymers were selected with ethylcellulose constituting the backing layer of the prepared patches. The effect of adding β-cyclodextrin on the prepared patches was investigated. The uniformity in thickness, weight and content of the studied patches was acceptable. Physicochemical characterization revealed that there was no interaction between levodopa and the applied polymer. The results proved that levodopa precipitated as an amorphous form in carbopol patches. Controlled drug release was achieved for all the tested patches over a 6?h period. However, increased permeation was achieved for the carbopol patches. Although cyclodextrin did not enhance levodopa permeation, the stability study confirmed that levodopa stability was enhanced when complexed with β-cyclodextrin. The cumulative amount of drug released from carbopol patches is slightly higher than that of xanthan patches. The optimal stability was achieved in the carbopol/levodopa:β-cyclodextrin patch. The levodopa-β-cyclodextrin complex was successfully characterized using X-ray diffraction, NMR analysis and molecular dynamics simulations. In conclusion, carbopol/levodopa:β-cyclodextrin patches can be considered as a promising stable and effective transdermal drug-delivery system.