氮酮对丙酸氯倍他索乳膏经皮渗透和吸收的影响

目的：考察氮酮对丙酸氯倍他索乳膏经皮渗透的作用,通过比较累积通过量和皮层中量,分析在该制剂中使用氮酮的利弊。方法：采用直立式扩散池,考察氮酮在０．５％、１．０％、２．０％和５．０％浓度下０．０５％丙酸氯倍他索乳膏经皮渗透２、４、６、８、１０、２４ｈ后累积透过量和稳态流量;分别测定了经皮渗透２４ｈ后每克皮肤组织中部他索的量。结果：４个浓度氮酮均极显著促进ＣＢＴ乳膏经皮渗透（Ｐ〈０．０１）,Ｑ２４分别     

氯霉素透皮吸收作用研究

本文对氯霉素的透皮吸收作用作了进一步观察,用95%乙醇配制的含月桂氮酮溶液与不含月桂氮酮的溶液对氯霉素的透皮吸收作用没有显著性影响,24h 前者透过量虽较高,但经统计学检验没有显著性意义,而用50%乙醇配制的溶液在24h 则有显著的促进氯霉素透皮吸收作用(P<0.01),提示单用该浓度的乙醇有显著促进氯霉素的透皮吸收。     

γ-亚麻油酸对血脂的调节作用

目的研究γ 亚麻油酸对机体血脂的调节作用。方法利用口服高脂饲料所致大鼠及家兔实验性高脂血症模型。结果γ 亚麻油酸预防性给药，可显著降低大鼠血清ＴＧ，ＴＣＨ，ＬＤＬ ｃｈ及ＶＬＤＬ ｃｈ含量；对家兔血清ＴＣＨ，ＬＤＬ ｃｈ及ＶＬＤＬ ｃｈ含量也有显著降低作用，但对ＴＧ水平无明显影响；γ 亚麻油酸治疗性给药，对家兔血脂中，ＴＧ，ＴＣＨ，ＬＤＬ ｃｈ及ＶＬＤＬ ｃｈ含量有显著降低作用，对心肌组织中ＴＧ和ＴＣＨ含量也有明显降低，并可显著降低家兔全血粘度低切变率。结论γ 亚麻油酸具有显著调节高脂血症模型大鼠及家兔血脂的作用，延缓组织血脂沉积，并可有效降低血液粘度。     

pH对甘草次酸经皮渗透性的影响

目的考察介质的pH对甘草次酸经皮渗透性的影响。方法采用HPLC法测定甘草次酸在不同pH介质中的饱和溶解度,采用摇瓶法测定其在不同pH正辛醇/PBS缓冲液中的表观油水分配系数,采用体外Franz扩散池法考察不同pH的甘草次酸饱和溶液在离体小鼠皮上的经皮渗透性。结果 pH5.0～10.8时,甘草次酸饱和溶液的稳态透皮速率随pH升高而增大,而表观渗透系数随pH升高而减小。结论甘草次酸在介质中饱和时,可通过调节pH来改善甘草次酸的稳态透皮速率。     

Effect of chemical penetration enhancer and iontophoresis on the in vitro percutaneous absorption enhancement of insulin through porcine epidermis

The purpose of this study was to investigate the effect of chemical enhancers (fatty acids and limonene) and iontophoresis on the in vitro permeability enhancement of insulin through porcine epidermis. The following fatty acids were used: palmitic (C16:0), palmitoleic (C16:1), stearic (C18:0), oleic (C18:1), linoleic (C18:2), and linolenic (C18:3). Franz diffusion cells and the Scepter iontophoretic power source were used for the percutaneous absorption studies. Cathodal iontophoresis was performed at 0.2 mA/cm2 current density. Iontophoresis in combination with chemical enhancers synergistically increased (p<0.05) the in vitro permeability of insulin. Linolenic acid (C18:3) produced greater permeability of insulin through epidermis than did other fatty acids during passive (44.45 x 10(-4) cm/h) and iontophoretic (78.03 x 10(-4) cm/h) transport. Lispro insulin flux was significantly (p<0.05) greater through linolenic acid and limonene pretreated epidermis compared to untreated controls during both passive and iontophoretic transports. Using limonene as a penetration enhancer, a linear increase in the passive and iontophoretic flux of lispro insulin was observed with donor concentrations increasing from 100 IU/mL to 300 IU/mL. Iontophoretic flux through limonene-treated epidermis using 0.5 mA/cm2 current density and 300 IU/mL insulin donor solution was 45.63 IU/cm2/day. Using an iontophoretic patch size of 10 cm2, we would be able to deliver 50 IU of insulin within 3 h.     

Influence of cyclodextrins on in vitro human skin absorption of the sunscreen, butyl-methoxydibenzoylmethane

The effects of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-CD (SBE7-β-CD) on in vitro human skin penetration and retention of the sunscreen agent butyl-methoxydibenzoylmethane (BM-DBM) were investigated. The interaction between the UV filter and the cyclodextrins was studied in water by phase-solubility analysis. Solid complexes were prepared by the co-evaporation method and characterized by ¹H NMR spectroscopy, thermal analysis and powder X-ray diffraction. Solutions containing BM-DBM free or complexed with cyclodextrins were applied to excised human skin in Franz diffusion cells and the amount of sunscreen permeated after 6 h into the stratum corneum, viable epidermis, dermis and receptor fluid was assessed by HPLC. As much as 14.10–16.78% of the applied dose of BM-DBM penetrated within the skin tissue. No sunscreen was detected in the dermis and in the receiver phase. The greater proportion (84.6–95.5%) of the absorbed UV filter was localized in the stratum corneum with no significant differences between uncomplexed or complexed BM-DBM. Notable levels (2.29% of the applied dose) of the sunscreen agent accumulated in the epidermis from the preparation containing free BM-DBM. The epidermal concentration of the UV filter was markedly reduced (0.66% of the applied dose) by complexation with SBE7-β-CD, whereas HP-β-CD had no effect. The decreased BM-DBM retention in the epidermal region achieved by SBE7-β-CD limits direct contact of the sunscreen and of its reactive photolytic products with the skin viable tissues.     

Prior iontophoresis of saline enhances vasoconstriction to phenylephrine and clonidine in the skin of the human forearm

AIMS: To determine whether postjunctional alpha1- and alpha2-adrenoceptors mediate vasoconstrictor responses in the cutaneous vasculature of the human forearm. METHODS: Drugs were administered transdermally by iontophoresis in the forearm of 20 healthy participants. Phenylephrine and clonidine were administered at sites pretreated with the relevant antagonist (terazosin and rauwolscine), and at additional untreated sites and sites pretreated with saline. To enhance the contrast between sites, the forearm was heated to 42 degrees C before flow was measured with the laser Doppler technique. RESULTS: After the iontophoresis of phenylephrine, blood flow at the site pretreated with terazosin was 24+/-37% (+/-95% confidence interval) greater than flow at the reference site, whereas flow was 53+/-24% lower than reference flow at the previously untreated site and 77+/-10% lower than reference flow at the site pretreated with saline (P<0.001). After the iontophoresis of clonidine, blood flow at the site pretreated with rauwolscine was 25+/-21% greater than flow at the reference site, whereas flow was 56+/-15% lower than reference flow at the previously untreated site and 72+/-8% lower than reference flow at the site pretreated with saline (P<0.001). The saline pretreatment enhanced vasoconstriction to phenylephrine (P<0.05) and clonidine (P=0.05). CONCLUSIONS: Pre-treatment with the appropriate antagonist blocked vasoconstrictor responses to phenylephrine and clonidine, consistent with the presence of both alpha-adrenoceptor subtypes in cutaneous vessels of the human forearm. In addition, iontophoretic pretreatment with saline facilitated vasoconstrictor responses, suggesting that a nonspecific effect of iontophoresis may enhance drug penetration through the stratum corneum.     

Effect of oleic acid/ethanol and oleic acid/propylene glycol on the in vitro percutaneous absorption of 5-fluorouracil and tamoxifen and the macroscopic barrier property of porcine epidermis

Transdermal delivery of most drugs is precluded due to the impervious nature of the stratum corneum. Chemical penetration enhancers offer an approach to enhance the transdermal transport of drugs by partitioning into and interacting with skin constituents, inducing a temporary reversible increase in skin permeability. The effect of penetration enhancers (e.g. oleic acid/ethanol and oleic acid/propylene glycol) was investigated on the in vitro percutaneous absorption of a hydrophilic (5-fluorouracil) and a lipophilic (tamoxifen) anticancer drug through porcine epidermis. In vitro transepidermal water loss (TEWL) studies were undertaken to investigate the effect of the above enhancers on the macroscopic barrier properties of the epidermis. Oleic acid/ethanol and oleic acid/propylene glycol significantly enhanced (P<0.05) the permeability coefficient of 5-fluorouracil (5-FU) and tamoxifen in comparison to their controls. In vitro TEWL was significantly greater (P<0.01) through epidermis treated with the above enhancers in comparison with control (epidermis that was not treated). However, neither oleic acid/ethanol nor oleic acid/propylene glycol enhanced (P>0.05) TEWL in comparison with ethanol and propylene glycol alone. Thus, changes in the permeability of 5-FU and tamoxifen caused by oleic acid/ethanol or oleic acid/propylene glycol could not be correlated with the in vitro TEWL.     

桉油对丙酸氮倍他索乳膏经皮渗透和吸收的作用

目的：考察促进剂桉油对丙酸氯倍他索（CBT）乳膏经皮渗透的促进作用,通过比较透过量和皮层中量,分析在该制剂中是否透合使用桉油,方法：采用直立式扩散池,考察了桉油在0．5％,1．0％,5．0％浓度下0．05％CBT乳膏经皮渗透2,4,6,8,10,24h后单位面积累积透过量Q(ug.cm^-2)和稳态透皮流量J（ug.cm^-2.h^-1);HPLC法测定经皮渗透24h后每克皮肤组织中CBT的量D（ug.g^-1),结果：4种浓度的桉油均显著促进CBT乳膏透皮吸收（P＜0．01）,其J值约是对照组的3－5倍（P＜0．01）,随浓度增加,陂层量D并不随之相应增加,结论：桉油可加快CBT经皮渗透速度,也能增加皮层中CBT量,但有饱和性,建议CBT 乳膏膏以少加（＜50％）或不加桉油为好。     

不同透皮促进剂对马钱子碱体外透皮吸收的影响

目的考察不同透皮促进剂对马钱子碱体外透皮吸收的影响。方法采用改良Franz扩散池,选用离体猪耳朵皮为屏障,考察不同类型的透皮促进剂对马钱子碱体外透皮吸收速率、增渗倍数等参数的影响。结果除吐温-80外,各透皮促进剂均能提高马钱子碱的透皮速率,促透能力由弱至强依次为桉叶素<油酸<氮酮<肉豆蔻酸异丙酯<柠檬烯。结论本研究可为马钱子碱外用剂型的选择与优化提供指导。     

Effect of exercise and heat exposure on percutaneous absorption of methyl salicylate

Summary The effects of exercise, heat exposure or both on the percutaneous absorption of methyl salicylate were studied in 6 healthy volunteers. Exercise was performed to 30% ofVO_2max, 45 min each hour for 6 h, at ambient temperatures of 22°C or 40°C. Systemic availability was assessed by measurement of plasma salicylate concentrations and cumulative urinary salicyluric acid excretion over an 8-h collection period. The absorption of methyl salicylate was increased to more than 3-times above control in subjects exercising in the heat. It is concluded that exercise and heat exposure, by increasing skin temperature, hydration and blood flow, enhance the percutaneous absorption of methyl salicylate.     

Effect of chemical enhancers on percutaneous absorption of daphnetin in isopropyl myristate vehicle across rat skin in vitro

The percutaneous absorption properties of daphnetin with chemical penetration enhancers were investigated to explore the feasibility of daphnetin as a candidate for transdermal delivery to treat arthritis. Permeation experiments were carried out in vitro using 2-chamber diffusion cells in isopropyl myristate (IPM) vehicle using rat abdominal skin as a barrier. Various enhancers were employed, including O-acylmenthol derivatives synthesized in the laboratory and many conventional enhancers. Among the O-acylmenthol derivatives, 2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) demonstrated a significant enhancing effect on daphnetin permeation. The highest degree of enhancement was obtained when NMP combined with Span 80 and the cumulative transport was 667.29 μg/cm² over 8 h. The solubility parameters, vehicle/stratum corneum partition, and diffusion coefficients were calculated to clarify the enhancing mechanism of classic enhancers on daphnetin. In conclusion, these findings allow a rational approach for designing an effective daphnetin transdermal delivery system.     

3种青鹏膏剂经皮行为的比较

目的比较3种青鹏膏剂的体外透皮吸收情况。HPIE法检测透过及滞留在皮肤内的没食子酸含量。结果方的青鹏膏剂经皮性质差异显著。方法进行体外透皮实验,以没食子酸为含量测定指标成分,采用样品A透皮效果明显优于其他2种市售样品。结论不同基质处     

Percutaneous penetration and absorption of parathion using human and pig skin models in vitro and human skin grafted onto nude mouse skin model in vivo

This study determined and compared the percutaneous penetration and absorption of an organophosphorus (OP) pesticide, parathion (PA), using three experimental skin models: namely the human abdominal- and pig-ear skin in vitro models and the Human Skin grafted onto a nude mouse (HuSki) in vivo model. The percentage of topically applied dose absorbed and the doses present in the stratum corneum and skin were systematically determined at 24 h under similar experimental conditions. The three experimental skin models were first compared. Then, the advantages of the HuSki model for in vivo PA skin absorption studies were evaluated compared with the pig in vivo model previously used by others. Lastly, the relevance of each skin model to predict the permeability of human skin to PA in vivo was assessed by comparing our results with previously published in vivo human volunteer values. It was demonstrated that (a) pig-ear skin is relevant for predicting the in vitro human abdominal skin absorption taking into account a 2-3 times higher skin permeability to PA, (b) using ethanol as the vehicle, the absorption of PA was 4-5 times higher in the HuSki model than in the pig model but supports the usefulness of the HuSki model to easy mass balance studies, (c) both human in vitro and HuSki models closely predict the in vivo human volunteer absorption at 24 h when acetone is used as a vehicle but the HuSki model overcomes the known limitations of in vitro models for studying the fate of PA in the different skin layers after topical application.     

薄荷醇和氮酮对水杨酸体外透皮吸收的促进作用

目的 研究薄荷醇和氮酮单独使用及合用时对水杨酸的促透作用。方法 采用离体鼠皮作透皮吸收试验。结果 薄荷醇对水杨酸的促透作用强于氮酮,而两药合用时的促透作用并不比分别使用时的促透效果好,在合用浓度较高时,甚至表现促透作用降低。     

Effect of cholestyramine on the gastrointestinal absorption of phenprocoumon and acetylosalicylic acid in man

Summary The effect of cholestyramine on the absorption of phenprocoumon and acetylosalicylic acid has been studied in volunteers by comparing their serum concentrations after a single oral dose either of the drug alone or simultaneously with the resin in a crossover repetition arrangement. In four volunteers cholestyramine 8 g significantly reduced the absorption of a simultaneous 15 mg dose of phenprocoumon. The effect of the latter on coagulation, as measured by the thrombotest method was also diminished. The absorption of acetylosalicylic acid 500 mg was delayed by cholestyramine but there was no appreciable effect on the total amount absorbed. These results are in accordance with the stronger binding of phenprocoumon to cholestyramine inin vitro experiments.     

糖尿病大鼠皮肤的组织学改变及其对糖皮质激素药物经皮吸收的影响

探讨糖尿病大鼠皮肤改变及其对糖皮质激素药物氢化可的松经皮吸收的影响。Wistar雄性大鼠随机 分成正常组及造模1周组 (W1) 、2周组 (W2)、3周组 (W3) 和4周组 (W4), 每组6只, 采用链脲菌素 (STZ, 40 mg·kg⁻¹) 对大鼠进行糖尿病造模, 取大鼠腹部皮肤进行体外透皮扩散实验, 接收液为磷酸盐缓冲液 (PBS, pH 7.4), HPLC法测定接收液中的药物量, 计算出药物渗透速率; 将造模不同时间的大鼠皮肤组织做病理切片, 进行HE染色并观察是否存在组织学差异。结果发现, 正常组、W1、W2、W3和W4组的渗透速率分别为 (2.39 ± 1.25)、(3.22 ± 1.72)、(3.02 ± 1.89)、(3.63 ± 2.02) 和 (5.00 ± 3.36) μg·h⁻¹·cm⁻²。造模4周组与正常组之间存在显著差异   (P < 0.05), 其余各组之间均无显著性差异; 皮肤组织学观察结果显示: 造模1周时大鼠腹部皮肤改变并不明显,  1个月时表皮有变薄的现象, 2个月时这种现象变得尤为明显。与正常皮肤相比, 患糖尿病后的皮肤能引起药物经皮透过性的增加, 这与糖尿病后发生一定程度的皮肤组织学改变关系密切。因此, 提示糖尿病患者在必要时需要调整经皮给药的剂量。     

酮洛芬凝胶的制备及体外透皮试验

目的 :为避免酮洛芬口服制剂对胃肠道的刺激作用 ,制备酮洛芬凝胶替代其口服制剂。方法 :以乙醇为溶媒 ,用三乙醇胺中和成中性 ,分散于凝胶基质 ,制成凝胶剂。并对该制剂进行含量测定、动物刺激性试验和体外透皮试验。结果 :表明酮洛芬凝胶处方设计合理 ,无刺激性 ,体外透皮效果良好。结论 :初步认为本制剂可替代口服制剂 ,临床效果有待进一步考察。     

Assessment of in vitro human dermal absorption studies on pesticides to determine default values,opportunities for read-across and influence of dilution on absorption

Dermal absorption is an integral part of non-dietary human safety risk assessments for agrochemicals. Typically, dermal absorption data for agrochemical active substances are generated from the undiluted formulation concentrate and its spray dilutions. European Food Safety Authority (EFSA) guidance, which combines highly conservative default values, very limited opportunities for read-across from existing data and other overly conservative conclusions, was the driver for this assessment. To investigate the reliability of the EFSA guidance, a homogeneous data-set of 190 GLP and OECD guideline compliant in vitro human skin studies, chosen to match the test method preferred by EU data requirements, was evaluated. These studies represented a wide range of active substances, formulation types, and concentrations. In alignment with EFSA guidance on human exposure assessment, a conservative estimate of absorption (95th percentile) was chosen to define defaults, which were also based on the EFSA worst-case assumption that all material in skin, excluding the first two tape strips, is absorbed. The analysis supports dermal absorption defaults of 6% for liquid concentrates, 2% for solid concentrates, and 30% for all spray dilutions, irrespective of the active substance concentration. Relatively high dermal absorption values for organic solvent-based formulations, compared to water-based or solid concentrates, support their use as worst-case surrogate data for read-across to other formulation types. The current review also shows that dermal absorption of sprays does not increase linearly with increasing dilution, and provides a novel, science-based option for extrapolation from existing data.     

In vitro percutaneous absorption and metabolism in man of 2-chloro-4-ethylamino-6-isopropylamine-s-triazine (Atrazine)

Atrazine is an extensively used herbicide in the USA. Our objective was to determine the absorption and metabolism (detoxification) of atrazine in human skin. Percutaneous absorption of atrazine in human skin from four sources was examined utilizing a flow-through in-vitro diffusion system. About 16.4% of the applied dose was absorbed by the skin. Radioactivity in the receptor fluid at 20 h was less than 5% of the administered dose. The highest concentration of the applied dose was found in the skin supernates, where 12.0% of the dose (68 nmol) was recovered. Some metabolites of atrazine were identified by thin layer and high pressure liquid chromatography after extraction of receptor fluid and the skin supernates. Two metabolites of atrazine [2-chloro-4-ethylamino-6-amino-striazine (desisopropylatrazine) and 2-chloro-4,6-diamino-s-triazine] were found in the receptor fluid and the skin supernates. An additional metabolite (2-chloro-4-amino-6-isopropylamino-s-triazine) was found in the skin supernates. Since desisopropylatrazine represented about 50% of the total metabolites formed during percutaneous absorption, cleavage of the N-isopropyl to the amino product was a key step in the metabolism of atrazine. Further metabolism may proceed by cleavage of the N-deethyl group to give totally dealkylated atrazine. The biotransformation of atrazine was studied in skin microsomal fraction supplemented with an NADPH-generating system. In analogy to metabolism during percutaneous absorption, atrazine was metabolized to its deisopropyl and deethylpropyl derivatives. In addition, 2-hydroxy derivatives of atrazine were formed by the skin microsomal fractions. The biotransformation of atrazine by skin microsomal enzymes indicates the metabolic capacity of the tissue. Cutaneous metabolism of atrazine may be an additional route by which human skin detoxifies the pesticide following topical exposure.