透皮贴剂的技术及质量控制进展

目的：介绍透皮贴剂的上市药品进展、剂型技术进展与质量控制要求。方法：检索并梳理归纳透皮贴剂上市情况以及贴剂类型、基质种类、皮肤吸收、促渗技术、质量控制方面的研究文献和相关技术指导原则。结果与结论：综述了透皮贴剂的剂型特点、技术进展以及系统总结了透皮贴剂的质量控制指标，建议应重点关注透皮贴剂的体外药物释放度、皮肤渗透性、黏附力、冷流和药物残留等关键质量属性。     

非洛地平-美托洛尔复方贴剂经不同动物皮肤的药物渗透性

目的制备非洛地平-美托洛尔复方透皮贴剂并研究经不同动物皮肤的体外药物渗透特性。方法采用改良的Franz透皮扩散装置,分别以离体小鼠、大鼠和兔皮肤为渗透屏障,生理盐水-乙醇(60:40)为接受液,用HPLC同时测定经皮渗透液中两药物的浓度,并计算渗透动力学参数。结果贴剂中,非洛地平和美托洛尔48 h内均以零级动力学经不同动物皮肤转运,并具一定同步性,动物皮肤对药物渗透性依次为:小鼠>大鼠>兔。结论非洛地平-美托洛尔复方透皮贴剂缓释长效特征明显,药物体外经皮渗透性稳定,各指标均可满足治疗血药浓度的要求。     

联苯乙酸透皮贴剂的体外透皮性能研究

目的:研究促进渗透剂对联苯乙酸贴剂(BPAA-TTS)体外透皮性能的影响.方法:用高体豚鼠皮肤为透皮屏障,采用改进的Franz扩散池,通过体外渗透性实验对含有不同处方的BPAA-TTS进行了透皮性能的研究.结果:体外渗透曲线符合平方根方程(Q=k×t1/2),含10%乙醇和8%的1,2-丙二醇的复合促进渗透剂的BPAATTS具有良好的透皮性能.结论:将加入复合促进渗透剂的贴剂中的BPAA的透皮速率与不加促进渗透剂贴剂的透皮速率进行比较,贴剂中药物的透皮性能有明显提高.     

非洛地平-美托洛尔复方经皮给药系统的制备及其兔体内生物利用度

制备了非洛地平-美托洛尔复方经皮给药系统，并研究其药剂学性质及经兔皮肤给药的药代动力学和生物利用度。先建立了同时测定贴剂和经皮渗透液中非洛地平与美托洛尔含量的RP-HPLC方法，以考察贴剂的药物体外稳态透皮速率和经皮渗透机制，并进行质量控制和评价；再以高灵敏度的GC-ECD方法分别测定非洛地平和美托洛尔的血药浓度，研究贴剂经皮给药后在兔体内的药代动力学和生物利用度。结果显示，该给药系统的复方药物体外透皮转运具有零级动力学特征，其含量均匀度检查符合2005版中国药典规定，稳定性好；经皮给药的血药浓度明显较口服平稳，且波动性小，达峰时间推后，持效时间延长，非洛地平与美托洛尔的相对生物利用度分别为275.37%和189.76%。以上结果表明，非洛地平-美托洛尔复方经皮给药系统具有明显缓释特征，可较长时间维持稳定有效的血药浓度。     

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。     

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.     

非洛地平/美托洛尔复方贴剂体外透皮特性及皮肤刺激性考察

目的 制备非洛地平/美托洛尔复方透皮贴剂,考察其对离体兔皮的经皮渗透性及对家兔皮肤的刺激性.方法 采用改良的Franz透皮扩散装置,以离体兔皮为渗透屏障,NS-乙醇(6040)为接受液,用HPLC法同时测定经皮渗透液中两药浓度并计算其渗透动力学参数.通过皮肤刺激性试验法考察该贴剂对家兔皮肤的刺激性.结果 非洛地平/美托洛尔复方透皮贴剂中非洛地平和美托洛尔48h内均以零级动力学经兔皮转运,并具一定同步性;该贴剂对家兔皮肤无刺激性.结论 非洛地平/美托洛尔复方透皮贴剂缓释长效特征明显,药物体外经皮渗透性较好且稳定,符合经皮给药系统应对皮肤无刺激性的设计要求.     

格列美脲凝胶骨架控释贴剂的制备及体内外评价

目的研究格列美脲凝胶骨架控释贴剂的药剂学性质及其经大鼠皮肤给药的药代动力学和相对于口服水溶液的生物利用度。方法建立格列美脲体外含量测定的HPLC方法，考察贴剂的体外透皮吸收速率和经皮渗透机制，并进行质量控制和评价；建立高灵敏度的HPLC柱前衍生化方法测定格列美脲血药浓度，研究贴剂经皮给药后在大鼠体内的药代动力学和生物利用度。结果该控释贴剂具零级动力学特征，其含量测定和重量差异检查符合2000年版中国药典规定，稳定性好；贴片给药的血药浓度明显较口服平稳，达峰时间推后，持效时间延长，相对生物利用度为20.3%。结论格列美脲凝胶骨架型贴剂经皮给药后，能使药物的吸收和消除较口服缓慢而持久，具明显的控释特征。     

醋氯芬酸贴剂的制备

目的以体外释放度和经皮渗透性为指标,制备醋氯芬酸贴剂并优化压敏胶和促渗剂的处方。方法采用不同类型丙烯酸酯压敏胶为基质制备醋氯芬酸贴剂,以体外释放度为指标考察筛选压敏胶;以不同种类促渗剂制备醋氯芬酸贴剂,采用改良Franz扩散池,以离体大鼠皮肤为渗透屏障,考察其经皮渗透性能,筛选经皮渗透促进剂。结果醋氯芬酸贴剂在12 h内体外释放曲线遵循Higuchi动力学方程,经皮渗透曲线遵循零级动力学方程,且以Duro Tak 87-2677为压敏胶基质、质量分数为5%的氮酮为促渗剂时醋氯芬酸贴剂具有较快的释放和经皮渗透速率。结论醋氯芬酸贴剂为皮肤控释型骨架释药系统,选择适宜的基质和促渗剂可保证足够的药物释放并穿透皮肤发挥理想的治疗作用。     

骨质增生透皮贴剂的制备

目的将传统的骨质增生膏改进为骨质增生透皮贴剂。方法利用挥发油提取方法提取药材中的有效成分,将其制成贴剂;以君药细辛中的主要成分甲基丁香酚作为药物经皮渗透的评价指标,进行体外经皮渗透实验以筛选贴剂中干姜挥发油的用量与透皮促进剂月桂氮卓酮的用量。结果贴剂处方中含2倍量干姜挥发油和2%氮酮时具有最佳的药物渗透量和渗透速度。结论筛选制得骨质增生透皮吸收贴剂的透皮效果较好,具有广阔的应用前景。     

皮肤给药的经皮吸收与测量技术研究进展

经皮给药系统（TDDS）可避免首关效应、胃肠道破坏，为新型皮肤给药系统，可通过控制释放而延长治疗效果，成为药物制剂开发研究的热点之一。但是，药物的理化性质以及皮肤屏障影响药物的经皮吸收。综述了TDDS常用的促渗透技术，包括化学、物理、纳米、天然促渗透技术；介绍了促渗透能力的测定方法，包括体外、离体和体内评估皮肤渗透性的方法。通过对经皮药物递送系统和经皮吸收能力测定方法的归纳与总结，以期为TDDS的合理使用和快速发展提供参考。     

基于药物-皮肤的相互作用探究盐酸特比萘芬体外透皮特性

目的 考察盐酸特比萘芬的体外透皮特性，探究盐酸特比萘芬与皮肤的相互作用，基于药物-皮肤相互作用阐明盐酸特比萘芬透皮特性的机制。方法 比较盐酸特比萘芬经皮渗透及其皮内滞留以及在皮肤各层的分布；利用衰减全反射红外光谱、差示扫描量热、拉曼光谱研究药物与皮肤的相互作用，并对药物与角质层角蛋白及脂质的相互作用进行计算机模拟和计算。结果 盐酸特比萘芬经皮渗透后高滞留低渗透，滞留的药物多分布于角质层。盐酸特比萘芬与角质层中脂质和角蛋白均有相互作用，该作用使药物自身难于透过皮肤，并导致较大的透过变异性。结论 盐酸特比萘芬与皮肤脂质和角蛋白的相互作用是其表现出典型的皮肤低渗透、高滞留特性的机制之一。本研究为盐酸特比萘芬体外透皮高滞留、低渗透特性提供理论依据。     

Development of drug-in-adhesive transdermal patch for α-asarone and in vivo pharmacokinetics and efficacy evaluation

A transdermal drug delivery system has been reported that can increase the bioavailability, reduce the administration duration, and maintain the concentration of drug in blood. In the present study, drug-in-adhesive transdermal patches of α-asarone using Eudragit E100 as pressure-sensitive adhesives and oleic acid plus isopropyl myristate as penetration co-enhancers were developed. In vitro permeation, in vivo pharmacokinetics in rabbits, and efficacy in asthmatic rats were evaluated. The results showed that co-enhancers could induce a synergistic effect on α-asarone permeability. In vivo study suggested that the patch can keep a relatively certain blood level of drug within 10–30?h in rabbits. Furthermore, the patch with the size of 4?cm² containing drug 3?mg/cm² showed a noticeable treating effect on asthmatic rats which is equivalent to the effect of dexamethasone, while avoiding the side-effect induced by the corticorsteroid. This suggests that the drug-in-adhesive transdermal patch is a promising delivery system containing α-asarone to be used for asthma treatment.     

Dermal Penetration of Fentanyl: Inter‐ and Intraindividual Variations

Abstract: Fentanyl is a potent synthetic opioid that is increasingly being used in transdermal drug delivery systems. The target organ concentration of a drug administered dermally will depend on the rate of dermal absorption and the systemic elimination. We have studied the intra‐ and interindividual variation in dermal penetration of fentanyl in an in vitro model (static diffusion cells) with human skin, and compared the absorption of fentanyl from an aqueous solution with absorption from a commercial patch. The intraindividual variation in dermal penetration of fentanyl in aqueous solution was limited (18%) and no differences in penetration characteristics were observed between breast and abdominal skin. The interindividual variation in dermal penetration of fentanyl was extensive, with maximal fluxes ranging from 21–105 ng/cm²/hr following application of an infinite dose of fentanyl to the donor chamber. Use of transdermal drug delivery systems (patches) reduced the inter‐individual variation. The permeability coefficients after application of fentanyl in aqueous solution and through patches were identical (0.0011 cm/hr). One person had a higher than average penetration rate following patch application, which may indicate that the human skin and not the patch barrier was the rate‐determining factor for the other individuals included in this study.     

Dodecyl N,N-Dimethylamino Acetate and Azone Enhance Drug Penetration Across Human,Snake, and Rabbit Skin

The effectiveness of the penetration enhancers, dodecyl N, N-dimethylamino acetate (DDAA) and Azone, on pretreated human epidermis for the permeation of model drugs, indomethacin, 5-fluorouracil, and propranolol-HCl, was studied in in vitro diffusion cells. Snakeskin (Elaphe obsoleta) and rabbit pinna skin were compared as possible models for human skin. The drug concentrations were analyzed by HPLC. With all skins and all model drugs, DDAA increased drug permeability at least as well as Azone, and in most cases it was a more effective permeation enhancer. The relative permeation improvements in human skin, snakeskin, and rabbit skin were 10- to 20-, 5- to 50-, and 20- to 120-fold, respectively. Tritiated water served as an indicator of skin condition. Its penetration in the skin samples was independent of the drugs used, and both penetration enhancers significantly increased the flux of tritiated water through all skins. Thus, DDAA and Azone significantly increased the permeation of lipophilic and hydrophilic model compounds. Rabbit pinna skin was a poor model for human skin in vitro, while snakeskin was much closer to human skin in terms of transdermal permeability. In most cases drug permeability decreased in the order rabbit human > or < snake.     

<Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">in Vivo</Emphasis> Correlation of Transdermal Naltrexone Prodrugs in Hairless Guinea Pigs

Purpose The purpose of this investigation was to evaluate the in vitro and in vivo percutaneous absorption of the following prodrugs of naltrexone (NTX): 2-ethylbutyryl-3-O-ester-NTX (ETBUT-ester), methyl-3-O-carbonate-NTX (ME-carbonate), ethyl-3-O-carbamate-NTX (ET-carbamate), and N,N-dimethyl-3-O-carbamate-NTX (DME-carbamate) in hairless guinea pigs.Methods In vitro fluxes of NTX and its prodrugs through guinea pig skin were determined using a flow-through diffusion cell system. The pharmacokinetics of NTX prodrugs were determined after topical application of transdermal patches in guinea pigs.Results All the prodrugs hydrolyzed to NTX on passing through the skin, and ME-carbonate provided the highest NTX flux and had the highest apparent permeability coefficient (K_p). ME-carbonate and ET-carbamate underwent the highest extent of bioconversion to NTX upon passing through the skin as compared to ETBUT-ester and DME-carbamate. The results of the in vivo studies indicated that a significant amount of NTX was delivered after the application of transdermal patches of NTX prodrugs. A mean steady-state plasma concentration of 7.1 ng/ml was obtained after the application of transdermal patches of ME-carbonate. A good correlation was obtained between the in vitro and in vivo results.Conclusions The results of the in vivo studies indicated that the ME-carbonate prodrug of NTX was the most promising drug candidate for transdermal delivery.     

47肽的微波辅助固相合成工艺研究

目的合成一长链肽47肽。方法采用Fmoc/t-Bu正交保护多肽固相合成策略,使用9-芴甲氧羰基(Fmoc)保护氨基酸的α-氨基,用Liberty微波多肽合成仪,每个耦合循环用20%哌啶脱除Fmoc保护基团,连续添加氨基酸,并用茚三酮法检测反应终点,有效检测反应的进度,最后用82.5%的三氟乙酸将多肽从树脂上切割下来,得到47肽粗品。经过反相高效液相制备系统纯化得到多肽纯品,用反相高效液相分析仪和傅里叶高分辨质谱仪验证该产物。结果高分辨质谱仪验证了该产物,纯品质量分数达98%。结论微波可促进多肽特别是长链肽的合成。     

Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012     

Application of methyl methacrylate copolymers to the development of transdermal or loco-regional drug delivery systems

Introduction: Methyl methacrylate copolymers (Eudragit®) have been exploited to develop transdermal patches, medicated plasters (hereinafter patches) and, more recently, film-forming sprays, microsponges and nanoparticles intended to be applied on the skin.

Areas covered: The article reviews the information regarding the application of Eudragits in the design and development of these dosage forms focusing on the impact of formulative variables on the skin drug penetration and the patch adhesive properties.

Expert opinion: Eudragits combined with a large amount of plasticizers are used to design the pressure-sensitive adhesives, specialized materials used in the patch development. They have to assure the drug skin penetration and the contact with the skin. Most of the studies mainly deal with the former aspect. The authors used a Eudragit type opportunely plasticized to merely investigate the in vitro or in vivo skin permeability of a loaded drug. However, the summa of these data evidenced that a strict connection between the matrix hydrophilicity and drug penetration probably exists. The criticisms of adhesion are addressed in a limited number of papers reporting data on technological properties, namely tack, shear adhesion and peel adhesion, while the structural data of the Eudragit adhesives, rheology and surface free energy are not described, excepting the case of Eudragit E. Among other applications, micro- and nanosystems exploiting the ionizable nature of some Eudragits can offer novel opportunities to develop pH-sensitive drug delivery systems suitable for triggering its release onto the skin.