上市新型经皮递药系统的研究进展

对近几年来上市的经皮制剂进行文献整理和归纳，通过查阅相关文献，对贴剂、软膏剂、凝胶剂、乳膏剂、泡沫剂、洗剂等经皮给药制剂的特点、上市时间、作用、不良反应等进行总结。经皮制剂是药物通过皮肤吸收的一类外用递药给药系统，可以局部给药也可以全身给药，具有安全性高、毒副作用小、使用方便的优点，是目前国内外研究的热点。     

Synthesis and Charactersiation of Chitosan conjugate; Design and Evaluation of Membrane Moderated Type Transdermal Drug Delivery System

The purpose of the present research investigation was to synthesis, characterisation of chitosan conjugates and its effect on drug permeation from transdermal rate controlling membrane. Chitosan conjugate was synthesised by conjugation with thioglycolic acid. The prepared chitosan conjugate was characterised by determining the charring point, Fourier transmission-infrared and differential scanning calorimetric analysis. The rate controlling membranes were prepared by various proportions of chitosan and chitosan conjugate, to moderate drug permeation through rate controlling membrane. The membrane moderated transdermal system consists of reservoir to hold the drug gel was prepared by 20% w/v ethylcellulose with a cavity in its center. An impermeable backing layer was prepared by 2% w/v ethylcellulose. Gel consists of carvedilol was prepared by sodium alginate and sodium carboxymethylcellulose in ethanol:water solvent system The rate controlling membranes prepared were evaluated by various parameters like thickness, folding endurance, swelling index, moisture content, moisture uptake, water vapor transmission rate, tensile strength test, measurement of gel strength, in vitro permeation study, ex vivo permeation study, compatibility study using differential scanning calorimetry and stability studies. All physical parameters evident that prepared membranes have good folding endurance and sufficient tensile strength. As the proportion of chitosan conjugate increases in membrane swelling index, moisture content, moisture uptake and permeability coefficient increases. The gel strength of chitosan conjugate was considerable less compared with chitosan.     

Numerical Investigation of Analytical Models of Drug Flux Through Microporated Skin

In this study, drug flux through microporated skin was modeled using detailed numerical solution of the diffusion equation. The results of the modeling were compared to previously published simplified and easy to use analytical equations. Limitations and accuracy of these equations were investigated. Appropriate modifications of the equations were identified to expand them to wider practical applications when pore shape is not circular. Numerical simulations have shown a good accuracy of the new simple equations when these are used within their limits of application.     

Effect of transdermal estrogen dose regimen for endometrial preparation of frozen-thawed embryo transfer on reproductive and obstetric outcomes

PurposePrevious studies have reported different methods of estrogen administration during endometrial preparation for frozen‐thawed embryo transfer (FET). This study aimed to investigate a beneficial regimen of transdermal estrogen administration for FET.MethodsWe investigated the reproductive and obstetric outcomes of FET by comparing the increasing dose (ID) group that mimics changes in serum estradiol during the menstrual cycle and the constant dose (CD) group. Transdermal patches were used for estrogen administration in both groups. In our hospital, we targeted 315 cycles of the ID group in which FET was performed in 2017 and 324 cycles of the CD group in which FET was performed in 2018. In all cases, single embryo transfer was performed.ResultsAll were singleton pregnancies. There was no difference in clinical pregnancy rate (28.9% vs 28.2%, P =.837) and live birth rate (17.3% vs 21.4%, P =.201) between the ID and CD groups. Spontaneous abortion rate was significantly lower in the CD group than in the ID group (37.2% vs 23.0%, P =.041). There was no difference in obstetrical outcomes.ConclusionsIt was considered that the simple CD regimen may be more beneficial than the complicated ID regimen.     

纳米微针透皮技术联合郑氏新伤软膏贴敷治疗急性踝关节扭伤的临床研究

目的:探讨纳米微针透皮技术联合郑氏新伤软膏贴敷治疗急性踝关节扭伤的临床疗效和安全性。方法:将80例急性踝关节扭伤患者随机分为2组,每组40例。软膏贴敷组采用郑氏新伤软膏贴敷治疗,每晚贴敷8~10h,共2周;联合治疗组在贴敷郑氏新伤软膏前先采用纳米微针透皮技术治疗,每晚1次,每次3min,共2周。分别于治疗前、治疗结束后记录并比较2组患者足踝部周径、踝部疼痛视觉模拟量表(visual analogue scale,VAS)评分及Kofoed踝关节评分,并观察并发症发生情况。结果:①足踝部周径。治疗前2组患者足踝部周径比较,差异无统计学意义[(35.08±2.39)cm,(34.93±2.44)cm,t=0.278,P=0.782];治疗结束后,联合治疗组患者足踝部周径小于软膏贴敷组[(28.63±1.40)cm,(30.18±1.60)cm,t=-4.626,P=0.000],2组患者足踝部周径均小于治疗前(t=17.338,P=0.000;t=14.162,P=0.000)。②踝部疼痛VAS评分。治疗前2组患者踝部疼痛VAS评分比较,差异无统计学意义[(7.08±1.14)分,(7.05.±1.13)分,t=-0.308,P=0.758];治疗结束后,联合治疗组患者踝部疼痛VAS评分低于软膏贴敷组[(2.03±0.73)分,(3.10±1.17)分,t=-4.467,P=0.000],2组患者踝部疼痛VAS评分均低于治疗前(t=-5.591,P=0.000;t=-5.690,P=0.000)。③Kofoed踝关节评分。治疗前2组患者Kofoed踝关节评分比较,差异无统计学意义[(50.18±5.49)分,(50.23±5.26)分,t=-0.042,P=0.967];治疗结束后,联合治疗组患者Kofoed踝关节评分高于软膏贴敷组[(89.95±1.74)分,(82.18±1.88)分,t=19.205,P=0.000],2组患者Kofoed踝关节评分均高于治疗前(t=-40.124,P=0.000;t=-37.709,P=0.000)。④综合疗效。治疗结束后,联合治疗组优15例、良18例、及格6例、差1例,软膏贴敷组优9例、良16例、及格11例、差4例;联合治疗组的综合疗效优于软膏贴敷组(Z=-2.100,P=0.036)。⑤并发症发生情况。2组患者均未出现药物过敏反应;联合治疗组2例遗留踝关节轻微疼痛,软膏贴敷组7例遗留踝关节轻微疼痛,因不影响日常生活,均未给予特殊处理。2组并发症发生率比较,差异无统计学意义(χ²=2.003,P=0.157)。结论:纳米微针透皮技术联合郑氏新伤软膏贴敷治疗急性踝关节扭伤,能缓解疼痛、减轻肿胀和改善关节功能,其疗效优于单纯郑氏新伤软膏贴敷治疗,但两者安全性相当。     

Evaluation of Transdermal Drug Permeation as Modulated by Lipoderm and Pluronic Lecithin Organogel

The transdermal delivery of 2 fluorescent probes with similar molecular weight but different lipophilicity, into and through the skin from 2 commercially available transdermal bases, pluronic lecithin organogel, and Lipoderm^® has been evaluated. First, in vitro penetration of fluorescein sodium and fluorescein (free acid) through porcine skin was evaluated. Retention and depth distribution profiles in skin were obtained by tape stripping and then followed by optical sectioning using multiphoton microscopy. The results showed that Lipoderm^® led to an enhanced penetration of the hydrophilic compound, fluorescein sodium. For the lipophilic compound fluorescein (free acid), Lipoderm^® performed similar to pluronic lecithin organogel base, where minimal drug was detected in either receptor phase. The skin retention and depth distribution results also showed that the hydrophilic fluorescein sodium had high skin retention with Lipoderm^®, whereas fluorescein (free acid) had very low penetration and retention with increasing skin depth. Moreover, optical sectioning by multiphoton microscopy revealed an uneven distribution of probes across the skin in the x-y plane for both transdermal bases. This work showed that a hydrophilic compound has significantly increased skin penetration and retention when formulated with Lipoderm^®, and the skin retention of the probe was the main determinant of its skin flux.     

How Sensitive Are Transdermal Transport Predictions by Microscopic Stratum Corneum Models to Geometric and Transport Parameter Input?

While predictive models of transdermal transport have the potential to reduce human and animal testing, microscopic stratum corneum (SC) model output is highly dependent on idealized SC geometry, transport pathway (transcellular vs. intercellular), and penetrant transport parameters (e.g., compound diffusivity in lipids). Most microscopic models are limited to a simple rectangular brick-and-mortar SC geometry and do not account for variability across delivery sites, hydration levels, and populations. In addition, these models rely on transport parameters obtained from pure theory, parameter fitting to match in vivo experiments, and time-intensive diffusion experiments for each compound. In this work, we develop a microscopic finite element model that allows us to probe model sensitivity to variations in geometry, transport pathway, and hydration level. Given the dearth of experimentally-validated transport data and the wide range in theoretically-predicted transport parameters, we examine the model's response to a variety of transport parameters reported in the literature. Results show that model predictions are strongly dependent on all aforementioned variations, resulting in order-of-magnitude differences in lag times and permeabilities for distinct structure, hydration, and parameter combinations. This work demonstrates that universally predictive models cannot fully succeed without employing experimentally verified transport parameters and individualized SC structures.     

乙醇脂质体、二元醇脂质体及传递体对多奈哌齐经皮转运的对比性研究

目的:制备多奈哌齐乙醇脂质体、二元醇脂质体和传递体,并比较皮肤渗透性,从而进一步有效优化药物的经皮转运。方法:通过形态,粒径分布,Zeta电位值和包封率对多奈哌齐乙醇脂质体、二元醇脂质体及传递体进行了初步表征,运用Franz扩散池和共聚焦激光扫描电镜考察了3种囊泡的经皮转运情况。结果:当二元醇脂质体包封率最高(89.1±0.42)%时,乙醇-丙二醇=7∶3,且二元醇脂质体(乙醇-丙二醇为7∶3,W/W)在皮肤中24 h的累积渗透百分数分别是乙醇脂质体和传递体的3.9和5.4倍。结论:二元醇醇脂质体(乙醇-丙二醇为7∶3,W/W)时,有效地改善了药物在醇脂质体中的包封率,且显著增加的药物在皮肤中的累积量。     

马钱子巴布剂体外透皮实验及促透剂的筛选

目的:考察不同促透剂对马钱子巴布剂中马钱子碱、士的宁的体外透皮吸收的影响,筛选合适的促透剂。方法:采用改良Franz扩散池对离体大鼠皮肤进行体外透皮实验,RP-HPLC法测定含不同促透剂的马钱子巴布剂中活性成分的累积渗透量(Q_n)和透过率(T)。结果:马钱子巴布剂体外透皮吸收符合零级动力学方程,不同的促透剂对透皮吸收影响的顺序为:DMF>月桂氮芯卓酮(氮酮)>丙二醇>薄荷醇。在给定的范围内(≤5%),氮酮和薄荷醇的促透性能均是随着浓度增大而先升后降,二甲基甲酰胺和丙二醇的促透效果都是随着浓度增大而增强。结论:不同浓度的促透剂均能一定程度促进马钱子巴布剂活性成分的透皮吸收,其中以5%DMF的促渗效果最好。     

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit^®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit^® RL100 and Eudragit^® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit^® RL100 showed the toughest and softest film, while other formulations containing Eudragit^® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit^® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit^® can be used as a film former for the fabrication of piroxicam films.