促渗剂对后交联祖师麻凝胶贴膏体外经皮渗透影响的研究

目的 考察不同促渗剂对后交联祖师麻凝胶贴膏中药效成分祖师麻甲素体外经皮渗透特性的影响,筛选出其最佳的透皮促渗剂。方法 采用Franz扩散池法,以离体小鼠皮肤和Strat-M™膜为渗透屏障进行体外透皮试验,采用单因素及正交试验法,以祖师麻甲素72 h内单位面积的累积透过量为评价指标,考察冰片、薄荷脑、樟脑对祖师麻甲素的促渗效果。结果 以离体小鼠皮肤和Strat-M™人工膜为透皮屏障时,祖师麻甲素72 h内单位面积的累积透过量分别为33.85,15.96 μg·cm^-2,稳态透皮速率分别为4.451 2,2.394 5 μg·cm^-2·h^-1,增渗倍数分别可达4.255 0,1.746 4。结论 后交联祖师麻凝胶贴膏以1%薄荷脑、1%冰片、2%樟脑联用时促渗效果最佳。     

基于透皮离子导入技术的戒烟药物金雀花碱的可控递送研究

目的 探索烟碱乙酰胆碱受体部分激动剂金雀花碱(cytisine，CTS)经阳极离子导入透过离体猪皮。方法 采用HPLC-PDA建立并验证CTS的分析方法。研究了电流密度、药物浓度和药物基质对CTS透皮离子导入的影响。采用标志物对乙酰氨基酚解析CTS离子导入过程中电迁移和电渗的贡献。结果 CTS从水溶液中被动透皮不佳，但在离子导入条件下CTS的透皮递送量显著增加，将电流密度从0.15 mA·cm^–2增加到0.5 mA·cm^–2可使离子导入CTS的稳态流量呈线性增加(J=452.8I+31.51，r=0.998 3)。在使用0.5 mA·cm^–2电流密度的条件下，给药池药物浓度的增加(2.5，5.0，10.0 mg·mL^–1)可使累积透皮递送量显著增加。共离子导入对乙酰氨基酚证实了电迁移是CTS的主要递送机制(˃90%)。CTS的传导效率良好(6.63%~8.82%)。递送效率，即递送药物占所给予的制剂中的药物的百分数较高(在0.5 mA·cm^–2时>40%)。CTS从离子导入贮库HEC水凝胶中递送时的累积透皮递送量为(1 551.94±322.19)μg×cm^–2，与从CTS溶液中递送时的累积透皮递送量无统计学差异。结论 体外数据表明，使用较小面积的凝胶贴片通过透皮离子导入可以方便地递送治疗剂量的CTS。     

十一酸睾酮二元醇质体体外透皮特性及其安全性研究

摘 要 目的： 对十一酸睾酮（TU）二元醇质体的体外透皮特性进行考察,并对其皮肤安全性进行研究。方法: 采用注入法制备TU二元醇质体;以小鼠皮肤为屏障,采用Franz扩散池法对其体外透皮特性进行考察;以豚鼠为实验动物,对其皮肤刺激性、过敏性、毒性进行考察。结果: TU二元醇质体平均包封率为（79.14±0.66）%;体外透皮实验中,累积释药百分率Q与时间t的关系符合一级动力学方程：Q=8.57t+8.26（r=0.998 6）,稳态透皮速率为8.57 μg·cm^-2·h^-1;24 h后TU在皮肤中的滞留量为（208.8±55.26）μg·g^-1;TU二元醇质体无明显局部刺激性、致敏性及急性毒性。结论: TU二元醇质体表现出较好的体外透皮渗透性,且安全性理想,值得进一步研究。     

硝苯地平微乳凝胶的制备及其质量评价

目的 将硝苯地平制备成微乳凝胶，以提高其生物利用度。方法 进行凝胶基质以及透皮吸收促进剂的筛选，确定硝苯地平微乳凝胶的最佳处方，并进行初步质量评价。结果 硝苯地平微乳的处方为乳化剂OP∶无水乙醇∶油酸乙酯∶水=27∶13.5∶4.5∶55；硝苯地平微乳凝胶的处方为1.2%卡波姆940，2.5%氮酮。所制得的硝苯地平微乳平均粒径为9.963 nm，大小均匀；硝苯地平微乳凝胶24 h的累积渗透量（Q_{24 h}）达到（296.35±34.66）μg·cm^-2，稳态透皮速率为（14.20±0.23）μg·cm^-2·h^-1；经高速离心、低温、高温试验考察，硝苯地平微乳凝胶稳定性良好；经小鼠皮肤刺激性试验考察，硝苯地平微乳凝胶对皮肤刺激性和毒性较小。结论 将硝苯地平制成微乳凝胶，药物的溶解度提高，制剂质量优良。     

一测多评法测定茵栀黄颗粒中4个环烯醚萜苷类成分

目的 建立同时测定茵栀黄颗粒中栀子苷、山栀苷、去乙酰车叶草苷酸甲酯和京尼平-1-β-D-龙胆二糖苷的一测多评法,验证该方法在茵栀黄颗粒质量控制应用中的科学性和可行性。方法 采用高效液相色谱法,以栀子苷为内参物,建立该成分与山栀苷、去乙酰车叶草苷酸甲酯和京尼平-1-β-D-龙胆二糖苷的相对校正因子,利用相对校正因子来计算各成分的质量分数,同时用外标法测定茵栀黄颗粒中栀子苷等4个成分的质量分数,对一测多评的计算值和外标法实测值进行比较,验证一测多评法在茵栀黄颗粒中应用的科学性和准确性。结果 各相对校正因子重复性良好,一测多评法测定结果与外标法测定结果无显著差异。结论 在缺少对照品的情况下,以栀子苷为内标同时测定栀子苷、山栀苷、去乙酰车叶草苷酸甲酯和京尼平-1-β-D-龙胆二糖苷的一测多评法可用于茵栀黄颗粒的定量分析。     

水溶性帕利哌酮前体药物的合成及其体外透皮研究

目的 合成帕利哌酮（PPD）的水溶性前体药物,使其能通过离子导入技术快速透过皮肤。方法 合成PPD的水溶性前体药物,即PPD的β-丙氨酸酯（PPD-β-Ala）,并对前药进行结构确证;利用高效液相色谱（HPLC）建立PPD及PPD-β-Ala的定量分析方法,并进行方法学验证;测定PPD及PPD-β-Ala的饱和溶解度,并对PPD-β-Ala的脂水分配系数（P_o/w）和pKa进行考察;进行PPD-β-Ala体外透皮实验,包括被动透皮吸收和离子导入透皮研究;在体外离子导入研究中,考察给药池介质[纯水、HEPES溶液（pH 5.5）或HEPES溶液（pH 6.5）]、给药池药物浓度（10、20、30 mmol·L^-1）和电流密度（0.1、0.3、0.5 mA·cm^-2）对PPD-β-Ala透皮递送量的影响。结果 前体药物PPD-β-Ala结构通过核磁共振氢谱得以确证。建立的HPLC法可对PPD及PPD-β-Ala同时检测,方法专属性、精密度和检测限均满足实验要求。PPD-β-Ala在纯水中的饱和溶解度为33.46 mmol·L^-1,远高于PPD的水溶解度;PPD-β-Ala的lg P_o/w小于PPD;PPD-β-Ala可充分质子化,带1个正电荷,PPD不具备易解离或易质子化的基团。PPD-β-Ala不易透皮吸收,但在离子导入条件下可在接收池中检出大量PPD-β-Ala,如在施加电流0.5 mA·cm^-2条件下,当给药池中PPD-β-Ala的浓度为30 mmol·L^-1时,7 h后的累积透皮递送量可达250 nmol·cm^-2。所选给药池介质的变化未对PPD-β-Ala的累积透皮递送量产生明显改变,但给药池药物浓度和电流强度的增加均能提高PPD-β-Ala的累积透皮递送量。在体外离子导入研究各组中均发现大量的PPD和PPD-β-Ala蓄积于皮肤,以0.5 mA·cm^-2电流强度、给药池药物浓度为20 mmol·L^-1（HEPES溶液为介质,pH 5.5）的给药条件为例,蓄积于皮肤中的PPD和PPD-β-Ala的量分别可达（144.21±41.73）、（890.61±106.40） nmol·cm^-2。结论 水溶性离子化的PPD前药PPD-β-Ala可在离子导入过程中通过电迁移作用快速透皮,理论上可利用尺寸适中的离子导入透皮贴片满足PPD的最小日给药剂量。     

药用库拉索芦荟活性多糖的护肤特性研究

目的 研究库拉索芦荟多糖的保湿特性、经皮吸收特性以及皮肤安全性。方法 采用超声辅助提取芦荟活性多糖,并通过人体皮肤水分含量和水分散失量测试法对所制备的芦荟活性多糖的保湿特性（包括锁水、保水两个方面）进行评价;Franz扩散池体外透皮吸收法评价其透皮吸收特性;人体斑贴试验评价其皮肤安全性。结果 与空白对照组比较,库拉索芦荟多糖可显著提高皮肤水合状态（P＜0.05）,同时降低经皮失水（P＜0.05）;多糖质量浓度为5%时,皮肤渗透速率达到0.251 0 mg/(h?cm²),24 h累计渗透量达（4.151 9±0.046 2）mg/cm²;人体皮肤斑贴试验中全部评定为0级反应。结论 库拉索芦荟活性多糖对皮肤具有显著的保湿功效以及较强的皮肤渗透力,并且高度安全,可作为优良的保湿添加剂在化妆品等肤用产品中广泛应用。     

镰形棘豆总黄酮理化性质及体外经皮渗透性的研究

目的 考察镰形棘豆总黄酮的溶解度、表观油水分配系数等理化常数,研究其体外经皮渗透性能,为指导其经皮给药剂型设计和制备提供参考。方法 采用紫外分光光度法测定镰形棘豆总黄酮在水及不同溶剂中的溶解度,同时测定其在正辛醇/水缓冲溶液中的P值,以大鼠离体皮肤为模型,采用双室渗透扩散装置考察其经皮渗透情况。结果 镰形棘豆总黄酮在甲醇、乙醇及pH 5.0~7.4的磷酸盐缓冲液中溶解度较好。镰形棘豆总黄酮的P值与溶液pH有一定关系,当pH值在2.5~7.4时,随着pH值的增加,总黄酮的logP值逐渐减小且基本控制在0.38~1.34之间。24 h药物累积透过量为155.44 μg/cm²,时滞为（11.52±0.95）h。结论 镰形棘豆总黄酮水溶性差,较易溶于甲醇、乙醇及pH 5.0~7.4的磷酸盐缓冲液,其皮肤透过性不高,累积透过率较低,且有一定的时滞,经皮给药剂型设计时需综合考虑以上特点。     

黄体酮热熔压敏胶透皮贴剂的制备及其体外释药性能研究

目的 制备黄体酮热熔压敏胶透皮贴剂并考察其体外释药性能。 方法 采用苯乙烯-异戊二烯-苯乙烯热塑性弹性体热熔压敏胶为骨架材料,以大鼠离体皮肤为渗透屏障,采用改良Freeze扩散池,用HPLC法测定接收液浓度,筛选促渗剂的种类、浓度和涂布厚度,确定贴剂处方。 结果 促渗剂选择肉豆蔻酸异丙酯(IPM),含量为2%;选择涂布厚度为300 μm,得到累积渗透曲线为Q=6.172 1 t-5.457 7(r=0.998 8);24 h药物累积渗透量为144.17 μg/cm²;稳态渗透速率为(6.17±0.49) μg/(cm²·h)。 结论 制备的黄体酮热熔压敏胶透皮贴剂中的有效成分黄体酮体外经皮渗透良好,具有较好的临床应用前景。     

消喘膏的体外透皮吸收研究

摘 要 目的：研究消喘膏中芥子碱硫氰酸盐、延胡索乙素和细辛脂素成分的体外经皮渗透性,为其临床应用提供参考。方法: 采用Franz扩散池法,用LC-MS/MS法测定膏中芥子碱硫氰酸盐、延胡索乙素和细辛脂素成分在一段时间内对大鼠离体皮肤的透皮吸收量。结果: 不同给药量对各成分的累积渗透量影响不大。模型拟合结果显示芥子碱硫氰酸盐透皮行为符合Higuchi方程,延胡索乙素和细辛脂素符合零级方程,延胡索乙素和细辛脂素的透皮速率分别为0.362×10^-1,0.330×10^-2 μg·cm^-2·h^-1。结论:消喘膏具有经皮渗透性能,为其透皮吸收给药途径提供了依据。     

Use of Shed Snake Skin as a Model Membrane for in Vitro Percutaneous Penetration Studies: Comparison with Human Skin

The potential usefulness of shed snake skin as a model membrane for transdermal research was examined. There are similarities between shed snake skin and human stratum corneum in terms of structure, composition, lipid content, water permeability, etc. The permeability of various compounds and the contribution of several functional groups to the permeability were also found to be similar between shed snake skin and human skin. Moreover, the permeability of compounds through shed snake skin was increased by Azone, one of the most extensively studied transdermal penetration enhancers. Considering the similarities between shed snake skin and human skin, ease of storage and handling, and low cost, shed snake skin may offer a good model membrane for transdermal research.     

lontophoretic Delivery of Apomorphine I: In Vitro Optimization and Validation

Purpose. To investigate the feasibility of transdermal iontophoretic delivery of apomorphine in patients with Parkinson's disease, transdermal transport rates were optimized and validated across human stratum corneum and freshly dermatomed human skin in vitro. Methods. In all experiments R-apomorphine hydrochloride was applied in the anodal compartment. The effect on the flux of the following parameters was studied, using a flow through transport cell: current density, pH, concentration, ionic strength, osmolarity, buffer strength, temperature and skin type. Results. Transdermal transport of apomorphine was directly controlled by the presence or absence of current. Passive delivery was minimal and no depot effect was observed. A linear relationship was found between current density and steady-state flux. At room temperature the lag time was 30 to 40 minutes. A maximal steady-state flux was obtained when the donor concentration approached maximum solubility. By increasing the temperature of the acceptor chamber to 37°C, the steady-state flux was increased by a factor of 2.3 and the lag time decreased to ± 3 minutes. No effect of osmolarity and buffer strength, and only a small effect of ionic strength and pH on the transport rate were observed. The flux through dermatomed human skin was decreased compared to stratum corneum. This effect was shown not to be caused by skin metabolism. Conclusions. The results obtained in vitroindicate that the iontophoretic delivery of apomorphine can be controlled and manipulated accurately by the applied current. The in vitro flux furthermore depends on the donor composition, temperature and skin type. Under optimized conditions, transport rates resulting in therapeutically effective plasma concentrations are feasible, assuming a one to one in vitro/in vivo correlation.     

A Method to Predict the Percutaneous Permeability of Various Compounds: Shed Snake Skin as a Model Membrane

Penetration of various compounds through shed snake skin was measured in vitro to examine the effect of lipophilicity and molecular size of a compound on permeability through this model membrane. The permeabilities were found to be controlled by the lipophilicity and the molecular size of the permeant. The smaller and the more lipophilic the compound, the greater the permeability. Equations have been developed to predict the permeability from the molecular weight and the distribution coefficient of a compound. Further, the lipophilicity of shed snake skin is similar to that of human skin and the response of shed snake skin to the molecular size of a permeant is more similar to human skin than to hairless mouse skin. Considering the similarities between shed snake skin and human stratum coraeum in terms of structure, composition, and permeability characteristics, the same considerations may apply to permeability through human stratum corneum.     

In Vivo and in Vitro Analysis of Skin Penetration Enhancement Based on a Two-Layer Diffusion Model with Polar and Nonpolar Routes in the Stratum Corneum

In vitro and in vivo skin penetration of three drugs with different lipophilicities and the enhancing effects of l-geranylazacycloheptan-2-one (GACH) were studied in rats. In vivo drug absorption profiles obtained by deconvolution of urinary excretion profiles were compared to the corresponding in vitro data obtained with a diffusion experiment. In vivo skin penetration of lipophilic butylparaben was considerably greater than that observed in vitro, while hydrophilic mannitol and acyclovir showed low penetration in both systems without GACH pretreatment. On the other hand, GACH enhanced mannitol and acyclovir penetration, especially in the in vivo system. Analysis of absorption profiles, using a two-layer skin model with polar and nonpolar routes in the stratum corneum, suggested that the diffusion length of a viable layer (viable epidermis and dermis) was shorter in vivo than in vitro and the effective area of the polar route in the stratum corneum was larger in vitro without GACH pretreatment. GACH increased the partitioning of acyclovir into the nonpolar route to the same extent in both systems. In addition, GACH increased the effective area of the polar route in vivo, probably because of enhanced water permeability; however, this effect was smaller in vitro since the stratum corneum was already hydrated even without GACH pretreatment.     

The Relationship of pK a and Acute Skin Irritation in Man

The relationship between pK _a and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15–88 µg/cm²/hr). Skin irritation and pK _a are correlated for pK _a 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pK _a, erythema at 24 hr appears to be the most sensitive parameter to variation in pK _a when pK _a 4.     

FDA的“评估简化新药申请的仿制透皮和局部给药系统可能的刺激性和致敏性的供企业用的指导原则草案”介绍

美国食品药品监督管理局（FDA）于2023年4月发布了“评估简化新药申请仿制透皮和局部给药系统可能的刺激性和致敏性的供企业用的指导原则草案”,全面而又具体地阐明FDA对仿制透皮和局部给药系统（TDS）可能的刺激性和致敏性人体内研究的设计和实施的建议。其中包括一般原则（一般考虑）、研究设计和实施、统计分析（刺激性分析和致敏性分析）、辅料TDS和阳性对照TDS以及部分（切割）TDS等。而中国目前还没有类似的指导原则,详细介绍FDA该指导原则主要内容,期望对中国仿制TDS刺激性和致敏性人体内研究与监管有所裨益。     

Identification and characterisation of a novel antimicrobial polypeptide from the skin secretion of a Chinese frog (Rana chensinensis)

Amphibians secrete small antimicrobial polypeptides from their skin that have been explored as alternatives to conventional antibiotics. In this study, mass spectrometry was used to identify and characterise protein secretions from the skin of a Chinese frog, Rana chensinensis. The skin of this kind of frog has been used in traditional Chinese medicine for centuries as a remedy against inflammation. A novel antimicrobial peptide was identified and the characteristics of this peptide were analysed using far-ultraviolet circular dichroism. When dissolved in aqueous solution, the peptide displayed a high level of random coil structure, in contrast to a more ordered α-helical structure when dissolved in 50% trifluoroethanol. Functional studies showed that this peptide has potent antimicrobial activity both against Gram-positive and Gram-negative bacteria and has extremely low haemolytic activity to human red blood cells. Taken together, these studies suggest that this novel peptide can be further developed as an antimicrobial agent.     

京尼平苷体内外微透析回收率的研究

目的 探究京尼平苷在自制线性微透析探针上的体内外回收率与灌流速度、药物浓度、透析膜长之间的关系。方法 采用HPLC测定微透析样品浓度,考察不同灌流速度、不同药物浓度和不同透析膜长对体外正向和体外反向回收率、体内反向回收率的影响。结果 自制探针性质稳定;探针回收率与京尼平苷的药物浓度无关,与灌流速度成反比,随透析膜长增加而增加;体外的正向与反向探针回收率有显著性差异（P<0.01）,而体内反向回收率低于体外反向回收率,与体外正向回收率无显著性差异;新探针体内回收率大于使用过1次的探针体内回收率（P<0.05）。结论 在京尼平苷的皮肤药动学研究中,宜采用体内反向回收率或体外正向回收率作为药物的探针回收率来校正。     

Vehicle Effects on in Vitro Percutaneous Absorption Through Rat and Human Skin

We studied the effects of three vehicles (propylene glycol, octanol and ethyl decanoate) with differing polarity on the in vitro percutaneous absorption of three chemicals (fluazifop-butyl, dimethyl phthalate and fomesafen sodium salt) with a range of physico-chemical properties. Absorption rate measurements were made from high vehicle volume (200 µl/cm²) and low vehicle volume (<10 µLl/cm²) applications. For the lipophilic fluazifop-butyl absorption rate was highest from the more polar vehicle propylene glycol, but this effect was only significant under high-volume conditions. There was a variable vehicle effect on absorption of the intermediate chemical dimethyl phthalate. The largest vehicle effect was seen for the more hydrophilic fomesafen sodium salt where absorption was fastest from the least polar vehicle ethyl decanoate. These results support the hypothesis that the absorption process can in part be predicted from a knowledge of solute solubility. Vehicle effects were greater from high volume applications than from those more comparable to occupational exposure conditions.