美欧关于透皮贴剂临床研究要求的探究与思考

目的：为我国透皮贴剂的研发提供参考。方法：通过查阅美国和欧盟药监机构官网,就欧美关于透皮贴剂临床研究的要求及已上市透皮贴剂产品案例进行讨论和分析。结果与结论：结合欧美经验及我国法规现状,对我国透皮贴剂创新药、改良型透皮贴剂和透皮贴剂仿制药的临床研究要求分别提出了相应的思考建议：透皮贴剂创新药需开展充分的体内外研究以揭示其安全性和有效性;改良型透皮贴剂应与对照药开展桥接试验,并侧重于揭示经皮给药的临床特点和特有的不良反应;透皮贴剂仿制药可开展生物等效性试验、黏附性、皮肤刺激性和致敏性研究。     

第二军医大学长海医院2004-2013年新剂型药物用药金额及用药频度分析

目的：分析缓释剂、控释剂及透皮贴剂在第二军医大学长海医院的临床应用情况及使用中出现的问题。方法：对本院2004-2013年缓释剂、控释剂及透皮贴剂的品种、用药金额、用药频度等指标进行回顾性分析。结果：上述3类新剂型药物用药金额和用药频度逐年增长,其中透皮贴剂用药频度的增幅最大。临床应用新剂型仍存在不合理现象。结论：新剂型药物临床应用逐渐增多,其合理应用仍需药师进一步宣传,以便更好地提高疗效。     

透皮贴剂渗透性研究进展

与传统注射剂和口服制剂相比，透皮贴剂具有避免首过消除效应、维持稳定的血药浓度以及提高患者的用药依从性等许多优势，其研发和产业化发展近年来受到了广泛的关注，但经皮吸收这一过程的存在使得透皮贴剂的生物利用度难以达到临床要求。因此，如何改善药物的经皮渗透以及如何评价药物的体外渗透成为透皮贴剂开发的关键和难点。本文结合国内外相关文献将现阶段透皮贴剂的促透方法及其机制进行归纳，为开发新的促透方法，提高药物的生物利用度提供思路；同时总结了体外渗透试验主要方法及常用皮肤模型、用于体外渗透分析的成像技术等，为解决目前关于透皮贴剂渗透性存在的诸多问题与挑战，制定更为完善的关于透皮贴剂渗透性的要求和标准提供参考。     

基于FAERS数据库的两种剂型卡巴拉汀风险信号数据挖掘与比较

目的:挖掘和分析卡巴拉汀透皮贴剂和胶囊上市后的风险信号与不良事件(ADE)特征,为两种剂型的卡巴拉汀临床安全用药提供参考。方法:对美国食品药品管理局(FDA)不良事件报告系统(FAERS)数据库2007年1月1日～2021年3月31日两种剂型卡巴拉汀的ADE进行数据挖掘,采用报告比值比法(ROR)比较两种剂型卡巴拉汀的风险。结果:共得到卡巴拉汀透皮贴剂的ADE报告40 839份,卡巴拉汀胶囊的ADE报告13 742份。严重的ADE报告中男性更多,年龄主要集中在高龄老年(75～89岁),卡巴拉汀透皮贴剂和胶囊ADE上报数最多的地区分别为北美洲和南美洲,胶囊发生严重的ADE占比大于透皮贴剂。卡巴拉汀透皮贴剂和胶囊可能的风险信号常见于胃肠系统疾病、精神病类、各类神经系统疾病等。卡巴拉汀透皮贴剂需关注产品附着力问题以及皮肤刺激,卡巴拉汀胶囊致呕吐和呼吸衰竭的风险可能较高。结论:卡巴拉汀透皮贴剂和胶囊ADE警戒尚不完善,需更多的临床监护,以降低ADE风险。     

透皮贴剂特性质量研究方法及控制标准

作为非侵入型药物递送系统,透皮贴剂可通过皮肤以固定剂量和可调节的速率递送药物,从而产生全身或局部的治疗作用。本文聚焦透皮贴剂关键质量属性,阐述其检测方法及试验中的关键点,同时参考国内外药典及现行政策法规,简述部分其他特性质量的检测方法及控制标准,以期为企业及相关部门完善质量检测体系及控制标准提供参考。     

可乐定透皮贴剂体外透皮性能研究

目的:研究可乐定透皮贴剂体外透皮性能.方法:用离体豚鼠皮肤为透皮屏障,采用改进Franz扩散池,比较康倍得公司研制的可乐定透皮贴剂(C-TTS)、美国的可乐定透皮贴剂(Catapres-TTS)和国内的可乐定透皮贴剂(N-TTS)的体外透皮性能.检测方法为高效液相色谱法.结果:C-TTS与Catapres-TTS两种贴剂体外经皮渗透曲线符合零级方程(Q=kt),两者透皮速率无显著性差异(P>0.05);N-TTS体外经皮渗透曲线符合Ritger-peppas方程(Q=ktm),其透皮速率与C-TTS比较有显著性差异(P<0.01).3种样品试验结束揭去贴片后,皮肤中有一定的药物残留量,并且残留量与贴片面积呈线性关系.结论:C-TTS可以维持7d的恒定经皮渗透,与Catapres-TTS体外透皮行为相似.     

复方利多卡因乳膏联合芬太尼透皮贴剂治疗老年患者带状疱疹后遗神经痛的临床观察

目的：观察复方利多卡因乳膏联合芬太尼透皮贴剂治疗带状疱疹后遗神经痛的疗效。方法60例临床诊断为带状疱疹后遗神经痛患者随机分为三组（复方利多卡因组、芬太尼透皮贴剂组和复方利多卡因联合芬太尼透皮贴剂组）,利多卡因乳膏组：在最痛的皮肤区涂抹复方利多卡因乳膏,根据皮肤大小涂抹,保留时间最大不超过12 h,每次间隔时间大于12 h,每天涂抹次数不超过3次;芬太尼透皮贴剂组：使用芬太尼初始剂量为12．5μg·h－1,如疼痛控制不满意,逐渐增加剂量（每72 h增加12．5μg·h－1）;利多卡因乳膏联合芬太尼透皮贴剂组：使用芬太尼初始剂量为12．5μg·h－1,如疼痛控制不满意,在最痛的皮肤区涂抹复方利多卡因乳膏。观察并记录治疗前三组的VAS（视觉模拟尺）评分及治疗4周后三组的VAS评分、统计三组中的芬太尼及利多卡因用量、并发症。结果三组患者疼痛均获得了明显缓解（P＜0．05）,利多卡因乳膏联合芬太尼透皮贴剂组的治疗满意度与芬太尼透皮贴剂组及利多卡因乳膏组相比,有统计学差异（P＜0．05）。结论复方利多卡因乳膏联合芬太尼透皮贴剂治疗带状疱疹后遗神经痛取得了较好的疗效,值得临床推广。     

长春西汀透皮贴剂的研制及体外释药机理的探讨

目的:制备长春西汀透皮贴剂,研究其体外释药机理.方法:在单层贴剂优化处方的基础上制备了单层、双层和三层贴剂,比较不同类型贴剂经不同皮肤的体外渗透速率,对三层贴剂进行了质量考察并研究了其释药机理.结果:三层贴剂和双层贴剂的经皮渗透量大于单层贴剂.去除角质层的皮肤对药物经皮渗透的屏障作用明显小于完整皮肤. 结论:长春西汀贴剂质量可控,刺激性小,药物经皮吸收的主要屏障为角质层,在经皮渗透中有较微弱的储库效应,其渗透行为主要是零级释药模式.     

中药复方制剂心安康贴剂的透皮吸收促进剂选择研究

目的：对中药复方制剂心安康贴剂的透皮吸收促进剂的选择进行研究。方法：采用Franz渗透扩散装置的气相色谱法，进行了大鼠皮肤贴剂的体外释放与渗透试验，对氮酮、十六醇、月桂醇硫酸钠，丙二醇4种透皮吸收促进剂单独应用和任意两种舍用的促进效果进行考察。结果：氮酮和丙二醇以2％：15％褥合，促进效果最强。结论：透皮促进剂对中药贴剂中的成分有较好的促透作用。     

盐酸特拉唑嗪贴剂的制备及质量控制

目的：制备盐酸特唑嗪贴剂，研究其耐热，耐寒性，刺激性及透皮吸收性能，方法：以PVA制备盐酸特拉唑嗪贴剂，小鼠皮为模型皮肤，采用Franz扩散池分别进行药物经皮释放试验和渗透试验，并测定了人体透皮速率。结果：盐酸特拉唑嗪贴剂耐热和耐寒性质良好。对皮肤无刺激性。体外释放速率为13．52ug.cm^-2.h^-1，体外透皮速率为11．87ug.cm^-2.h^-1，人体平均透平速率为11．25ug.cm^-2.h^-1，结论：盐酸特拉唑嗪贴剂是一种有效的控释型外用制剂。     

Spray-on transdermal drug delivery systems

Introduction: Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems.

Areas covered: A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.

Expert opinion: TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.     

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.     

Drug crystallization – implications for topical and transdermal delivery

ABSTRACT

Introduction: Crystallization of actives in skin following topical application was suggested by studies in the 1950s and 1960s but is poorly understood. In contrast, the problem of crystallization of actives on skin and in transdermal formulations has been known for many years.

Areas covered: With respect to crystallization in skin, this review describes early reports of a skin ‘reservoir’ and possible reasons underlying its genesis. Techniques to study crystallization on and in skin and in transdermal patches are outlined. The role of the vehicle in skin delivery is emphasised. Studies which have investigated permeation from crystalline particles are described. Approaches to limit crystallization of actives are discussed. Using supersaturation and antinuclean polymers, control of crystal size is possible; controlled release from crystals is also employed in transdermal patches.

Expert Opinion: Drug crystallization has significant implications for topical and transdermal delivery. Approaches have been developed to counteract the issue for transdermal patches but crystallization in and on the skin for other formulations remains unresolved. Greater knowledge of residence time of excipients and their interaction with skin at the molecular level is critical in order to address the problem. This will lay the foundations for better design of topical/transdermal formulations.     

Optimization of self-nanoemulsifying systems for the enhancement of in vivo hypoglycemic efficacy of glimepiride transdermal patches

Objectives: To optimize and use of glimepiride (GMD)-loaded self-nanoemulsifying delivery systems (SNEDs) for the preparation of transdermal patches.

Methods: Mixture design was utilized to optimize GMD-loaded SNEDs in acidic and aqueous pH media. Optimized GMD-loaded SNEDs were used in the preparation of chitosan (acidic) and hydroxypropyl methyl cellulose (HPMC) (aqueous) films. The prepared optimized formulations were investigated for ex vivo skin permeation, for in vivo hypoglycemic activity and for their pharmacokinetic parameters using animal model.

Results: The optimized formulations showed flux value of (2.88 and 4.428 μg/cm²/h) through rat skin for chitosan and HPMC films, respectively. The pattern of GMD release from both formulations was in favor of Higuchi and approaching zero order models. The n values for Korsmeyer–Peppas equation were characteristic of anomalous (non-Fickian) release mechanism. Moreover, HPMC patches have shown significant reductions (p < 0.05) in blood glucose levels; (213.33 ± 15.19) mg/100 ml from the base-line measurement after 12 h of application.

Conclusions: Optimized GMD SNEDs patches were found to improve GMD skin permeability and the essential pharmacokinetic parameters. Further extensive pre/clinical studies are necessary prior to use transdermal GMD as a valuable alternative to peroral dosage forms with improved bioavailability, longer duration of action and more patient convenience.     

Synthesis of Conjugated Chitosan and its Effect on Drug Permeation from Transdermal Patches

The aim of this study was to synthesis the conjugated chitosan by covalent attachment of thiol moieties to the cationic polymer, mediated by a carbodiimide to improve permeation properties of chitosan. Thioglycolic acid was covalently attached to chitosan by the formation of amide bonds between the primary amino groups of the polymer and the carboxylic acid groups of thioglycolic acid. Hence, these polymers are called as thiomers or thiolated polymers. Conjugation of chitosan was confirmed by Fourier transform-infrared and differential scanning calorimetric analysis. Matrix type transdermal patches of carvedilol were prepared using the different proportions of chitosan and chitosan-thioglycolic acid conjugates (2:0, 1.7:0.3, 1.4:0.6, 1:1, 0.6:1.4 and 0.3:1.7) by solvent casting technique. Prepared matrix type patches were evaluated for their physicochemical characterization followed by in vitro evaluation. Selected formulations were subjected for their ex vivo studies on Wistar albino rat skin and human cadaver skin using the modified Franz diffusion cell. As the proportion of conjugated chitosan increased, the transdermal patches showed increased drug permeation. The mechanism of drug release was found to be nonFickian profiles. The present study concludes that the transdermal patches of carvedilol using conjugated chitosan with different proportions of chitosan were successfully developed to provide improved drug permeation. The transdermal patches can be a good approach to improve drug bioavailability by bypassing the extensive hepatic first-pass metabolism of the drug.     

芬太尼透皮贴剂联合康莱特注射液治疗晚期癌痛的疗效观察

目的：观察芬太尼透皮贴剂联合康莱特注射液治疗晚期癌痛的疗效与不良反应。方法：将重庆市第九人民医院2016年收治的64例晚期癌痛患者随机分为治疗组和对照组，每组各32例。治疗组给予芬太尼透皮贴剂，每贴8.4 mg，每72 h更换1次，联合康莱特注射液100 ～ 200 mL静脉滴注，每天1次，每周5次。对照组仅给予芬太尼贴剂治疗。两组均治疗28天后，进行评估。观察镇痛效果、生活质量评分和不良反应情况。结果：治疗组的疼痛缓解率和卡氏（KPS）评分明显优于对照组，差异具有统计学意义。两组不良反应均较轻微，差异无统计学意义。结论：芬太尼透皮贴剂联合康莱特注射液能有效缓解癌痛，改善晚期癌症患者的生存质量。     

Dermal Drug Delivery Systems: A Review

Abstract

Systems that deliver drugs through intact skin at a controlled rate are now in routine clinical use. They include a nitroglycerin system for the prophylaxis of angina, and a scopolamine system for the prevention of motion sickness. In addition, there are also published reports on rate-controlled transdermal forms of clonidine and estradiol. Since the trans-dermal mode of drug administration can provide continuity of delivery and precise control of drug plasma concentrations, it offers particular advantages for drugs with short half-lives or narrow therapeutic indices. It is also useful when the oral route is unsuitable. Transdermal rate-controlled therapy appears on the brink of rapid expansion for the administration of potent, nonirritating, nonallergenic agents with suitable physi-cochemical properties. In the case of new agents, rate-controlled transdermal administration may render some drugs routinely usable that otherwise would produce unacceptable side effects or require impractical regimens. Some older agents will gain an increased margin of safety and convenience—as well as expanded therapeutic usefulness—compared with their administration in conventional dosage forms. Owing to constraints arising from drug potency, skin permeability, and/or topical reactions, however, transdermal administration is not expected to become the preferred dosage form for a high percentage of drugs.     

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 calcium channel blockers for hypertension

Introduction: Calcium channel blockers are a very important class of antihypertensive drugs. Most calcium channel blockers (CCBs) exhibiting low oral bioavailability are required to be taken more than once a day due to their short half-lives which result in poor patient compliance. There is an ineluctable requirement for improved drug-delivery devices for CCBs because of the quantum of their utilization and shortcoming associated with their conventional dosage forms.

Areas covered: There have been worthwhile research endeavors worldwide to investigate the skin permeation and to develop transdermal formulations of various categories of CCBs. This review explores the investigations on the feasibility and applicability of systemic delivery of various CCBs via skin.

Expert opinion: Transdermal delivery of CCBs has been particularly acknowledged as a potential drug-delivery route in the therapy of hypertension. Several overtures have been made to enhance delivery of these drugs via skin barrier. There have been remarkable research endeavors worldwide to investigate the skin permeation and to develop transdermal systems of various CCBs. Persistent advancement in this area holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.     

神效散巴布剂的体外透皮吸收研究

目的比较神效散散剂和巴布剂的透皮吸收效果。方法采用HPLC法测定神效散散剂和巴布剂中血竭素、三七皂苷R1。使用扩散池装置,以离体小鼠皮肤为屏障进行体外透皮吸收研究,比较神效散巴布剂和散剂中血竭素、三七皂苷R1的累积渗透量、渗透速率。结果神效散散剂和巴布剂中血竭素、三七皂苷R1累积渗透量随着时间的增加而增大,且两种成分的累积渗透量:巴布剂散剂;渗透速率:巴布剂散剂。结论与神效散散剂比较,神效散巴布剂具有更强的透皮吸收效果。