萜烯类手性促进剂对氟比洛芬经皮渗透对映体选择性的影响

目的:考察萜烯类手性促进剂芳樟醇和薄荷醇对氟比洛芬(flurbiprofen,FP)经皮渗透的对映体选择性作用.方法:采用Valia-Chien双室渗透扩散池,以大鼠离体皮肤为渗透屏障,以稳态经皮渗透速率为评价指标,用对映体选择性高效液相色谱法对FP对映体进行浓度测定,考察手性促进剂芳樟醇或薄荷醇对FP对映体选择性的影响.结果:无论供给液是否含单个对映体或消旋体,若供给液中不含促透剂,FP经大鼠离体皮肤渗透未见对映体选择性.当供给液中含有dl-薄荷醇时,RS-FP的稳态渗透速率分别为R-FP、S-FP的1.34,1.27倍,差异有显著性(P <0.05);而供给液中含有l-薄荷醇时,FP对映体及消旋体间的皮肤渗透速率无显著差异(P >0.05).l-薄荷醇和dl-薄荷醇对同一药物构型R-FP或S-FP 的促透效果相当;然而,dl-薄荷醇对RS-FP的促透作用是l-薄荷醇的1.44倍.l-芳樟醇或dl-芳樟醇作为手性促透剂时,未发现对映体选择性渗透现象.结论:dl-薄荷醇对FP的促透作用出现了对映体选择性,而l-薄荷醇、l-芳樟醇和dl-芳樟醇未引起FP的对映体选择性渗透,且所有渗透实验均未发现对映体转化.     

不同透皮吸收促进剂对士的宁透过离体猪皮的影响

目的初步探索开发士的宁透皮给药系统的可能性。方法采用体外透皮扩散法在规定时间点取样,高效液相色谱法测样品中士的宁的含量;以时间为横坐标,士的宁累积透皮量为纵坐标作图求透皮吸收速率、滞后时间等参数。结果各促透剂对士的宁促渗作用由弱至强依次为吐温-80<桉叶素<薄荷醇<香芹酮<油酸<柠檬烯<萜品油烯。结论选用适当的透皮吸收促进剂,士的宁体外透皮吸收速率可达到开发透皮给药系统的需要。     

丙二醇-肉豆蔻酸异丙酯系统中促透剂对来曲唑经皮透过性的影响

目的考察在丙二醇(propylene glycol,PG)-肉豆蔻酸异丙酯(isopropyl myristate,IPM)系统(简称PI系统)中经皮促透剂对来曲唑经皮透过性的影响。方法采用水平双室扩散池,以离体大鼠皮肤作为透过屏障进行体外透过实验。结果在不含经皮促透剂时,来曲唑的累积透过量随体系中PG浓度的增加而增大。在PI系统[m(PG)∶m(IPM)=20∶100]中,N-甲基-2-吡咯烷酮、月桂氮卓酮、乳酸对来曲唑的透过具有显著的促进作用,司盘-80和二乙二醇单乙基醚具有轻微抑制作用,而油酸和吐温-80则有显著的抑制作用。结论在PI系统中经皮促透剂对来曲唑的经皮透过性具有不同的促透作用,为开发来曲唑的透皮给药贴剂提供参考数据。     

Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens,permeation enhancers,and solvents from liquid formulations

Purpose. Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Methods. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Results. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 g·cm^–2·h^–1 and 3.2 g·cm^–2·h^–1, respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Conclusion. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.     

Transdermal delivery of praziquantel: effects of solvents on permeation across rabbit skin

To explore a new method for the transdermal delivery of praziquantel (PZQ), the effects of solvents on permeation across rabbit skin were investigated. The solubility of PZQ in five different solvents, ethylene glycol monophenyl ether (EGPE), 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, and oleic acid, were measured with a UV-Vis spectrophotometer. The determination of the n-octanol/water partition coefficient of PZQ in the five different solutions and assay of serum concentration following PZQ transdermal administration in rabbits were performed using HPLC. The results indicated that the transdermal absorption of the drug was related to the partition coefficient and lipophilic characteristics of the solvent. The optimal solvent for PZQ transdermal delivery was EGPE in our protocol. The solubility of PZQ in EGPE is >400 mg/ml, and the apparent partition coefficient of PZQ in the solution is 0.895 (log P value). After transdermal administration of PZQ in EGPE solution, the bioavailability is 2.85-fold that after oral administration. The serum drug concentration was maintained at 4.0 mug/ml over 4 h, which is sufficient for the treatment of schistosomiasis. At the same time, no apparent side effects were found on the skin. EGPE may thus be a promising vehicle for the transdermal delivery of PZQ in the future.     

Transdermal and dermal delivery of adefovir: Effects of pH and permeation enhancers

The objective of this work was to investigate feasibility of transdermal and dermal delivery of adefovir (9-(2-phosphonomethoxyethyl)adenine), a broad-spectrum antiviral from the class of acyclic nucleoside phosphonates. Transport of 2% adefovir through and into porcine skin and effects of various solvents, pH, and permeation enhancers were studied in vitro using Franz diffusion cell. From aqueous donor samples, adefovir flux through the skin was 0.2-5.4 microg/cm2/h with greatest permeation rate at pH 7.8. The corresponding adefovir skin concentrations reached values of 120-350 microg/g of tissue. Increased solvent lipophilicity resulted in higher skin concentration but had only minor effect on adefovir flux. A significant influence of counter ions on both transdermal and dermal transport of adefovir zwitterion was observed at pH 3.4. Permeation enhancer dodecanol was ineffective, 1-dodecylazepan-2-one (Azone) and dodecyl 2-(dimethylamino)propionate (DDAIP) showed moderate activity. The highest adefovir flux (11.3+/-3.6 microg/cm2/h) and skin concentration (1549+/-416 microg/g) were achieved with 1% Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycarbonyl)pentylcarbamate) at pH 4. This study suggests that, despite its hydrophilic and ionizable nature, adefovir can be successfully delivered through the skin.     

Impacts of chemical enhancers on skin permeation and deposition of terbinafine

Abstract

Context/Objective: The addition of chemical enhancers into formulations is the most commonly employed approach to overcome the skin barrier. The objective of this work was to evaluate the effect of vehicle and chemical enhancers on the skin permeation and accumulation of terbinafine, an allylamine antifungal drug.

Methods: Terbinafine (1% w/w) was formulated as a Carbopol 934?P gel formulation in presence and absence of three chemical enhancers, nerolidol, dl-limonene and urea. Terbinafine distribution and deposition in stratum corneum (SC) and skin following 8-h ex vivo permeation study was determined using a sequential tape stripping procedure. The conformational order of SC lipids was investigated by ATR-FTIR spectroscopy.

Results and discussion: Nerolidol containing gel formulation produced significantly higher enhancement in terbinafine permeation through skin and its skin accumulation was increased. ATR-FTIR results showed enhancer induced lipid bilayer disruption in SC. Urea resulted in enhanced permeation of terbinafine across the skin and a balanced distribution to the SC was achieved. But, dl-limonene could not minimize the accumulation of terbinafine in the upper SC.

Conclusion: Nerolidol dramatically improved the skin permeation and deposition of terbinafine in the skin that might help to optimize targeting of the drug to the epidermal sites as required for both of superficial and deep cutaneous fungal infections.     

不同促渗剂对盐酸氨酮戊酸原位凝胶体外透皮吸收的影响

目的：研究不同透皮促渗剂对盐酸氨酮戊酸原位凝胶体外透皮吸收的影响,为筛选最佳透皮促渗剂提供实验依据。方法：采用Franz扩散池法,以离体大鼠皮肤为模型,选择3种常用透皮促渗剂月桂氮芯卓酮（azone,AZ）、丙二醇（propylene glycol,PG）、二甲亚砜（dimethyl sulfoxide,DMSO）,分别考察单一促渗剂及二元促渗剂对盐酸氨酮戊酸原位凝胶体外透皮吸收的影响。结果：含促渗剂盐酸氨酮戊酸原位凝胶体外透皮吸收显著高于未添加促渗剂盐酸氨酮戊酸原位凝胶及市售制剂;采用单一促渗剂时,1% PG促渗效果最好;采用二元促渗剂时,3% AZ+1% PG促渗效果最好;3% AZ+1% PG促渗效果优于1% PG,含促渗剂3% AZ+1% PG的盐酸氨酮戊酸原位凝胶透皮性优于市售制剂艾拉。结论：添加促渗剂的方法能够显著改善盐酸氨酮戊酸的体外透皮吸收性,3% AZ+1% PG构成的二元促渗剂用于盐酸氨酮戊酸原位凝胶促渗效果最佳;本研究为设计优良的盐酸氨酮戊酸经皮给药系统药物奠定了重要基础。     

不同促渗剂对盐酸芦氟沙星体外经皮渗透的影响

目的　研究几种常用促渗剂对盐酸芦氟沙星体外经皮渗透的影响。方法　用紫外分光光度法检测浓度 ,采用改进Franz扩散池 ,比较几种常用促渗剂对盐酸芦氟沙星渗透系数的影响。结果　1%氮酮和 1%氮酮 10 %丙二醇可显著增大盐酸芦氟沙星的渗透系数 (P <0 .0 1)。结论　 1%氮酮和1%氮酮 10 %丙二醇可作为促渗剂用于盐酸芦氟沙星的透皮吸收制剂     

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。     

A combined approach of chemical enhancers and sonophoresis for the transdermal delivery of tizanidine hydrochloride

The effects of chemical enhancers and sonophoresis on the transdermal permeation of tizanidine hydrochloride (TIZ) across mouse skin were investigated. Parameters including drug solubility, apparent partition coefficient (APC), drug permeation, and degradation in skin were determined. Low frequency ultrasound was also applied in the presence and absence of chemical enhancers to assess whether drug permeation improved. APC values indicated that TIZ preferentially partitions into intercellular spaces and does not form a reservoir, with the drug also exhibiting good enzymatic stability in skin. Most of the enhancers studied significantly increased the permeation rate of TIZ through full thickness mouse skin in comparison with TIZ formulated in phosphate buffer. Maximum enhancement was observed for TIZ formulated as a suspension in 50% v/v aqueous ethanol containing 5% v/v citral. Sonophoresis significantly (p < 0.05) increased the cumulative amount of TIZ permeating through the skin at 15 and 30 min in comparison to passive diffusion. A synergistic effect was noted when sonophoresis was applied in the presence of chemical enhancers. The results suggest that the formulation of TIZ with an appropriate penetration enhancer may be useful in the development of a therapeutic system to deliver TIZ across the skin for a prolonged period, i.e. 24 hr. The application of ultrasound in association with chemical enhancers, such as the combination of 5% v/v citral in 50% v/v aqueous ethanol, could further serve as a non-oral and non-invasive drug delivery modality for the immediate therapeutic effect of muscle relaxants such as TIZ.     

渗透促进剂对美洛昔康经皮渗透的促进作用

目的研究氮酮、薄荷、羟丙基β环糊精等10种常用渗透促进剂对美洛昔康经皮渗透的促进作用。方法应用改良的Valia Chiem扩散池为实验装置,pH 8.0的磷酸盐缓冲液为研究介质,以稳态流量(Js)、增渗倍数(ER)及滞后时间为考察指标,将渗透促进剂分油溶性与水溶性两大类进行了系统地比较。结果油溶性促渗剂对美洛昔康经皮渗透促进作用强于水溶性促渗剂(P<0.05),但滞后时间后者小于前者。以丙二醇为溶剂时,油溶性促渗剂与丙二醇有协同作用;油酸与薄荷合用时二者具有较强的协同作用。以乙醇为溶剂时,氮酮渗透促进作用最显著(P<0.01),薄荷油次之(P<0.05),且二者的渗透促进作用均具有浓度依赖性。结论油溶性氮酮和薄荷油是美洛昔康经皮给药的理想渗透促进剂。     

酮咯酸氨丁三醇凝胶剂体外经皮渗透研究

目的：考察凝胶剂作为酮咯酸氨丁三醇透皮给药载体的可行性。方法：制备卡波姆940药物凝胶，采用Franz扩散池用离体大鼠皮肤进行体外经皮渗透实验，以HPLC法测定渗透介质中药物含量并求算累积渗透量及稳态透皮速率。结果：以1．0％卡波姆940为凝胶基质，以硼砂溶液调节凝胶的pHN6．0时所制备的凝胶为最佳凝胶基质。3％的月桂氮革酮及5％的丙二醇均可以显著提高凝胶中药物的经皮渗透，且两者联用存在协同作用。结论：本实验的凝胶基质可为生产提供参考依据。     

Effect of propylene glycol,Azone and n-decylmethyl sulphoxide on skin permeation kinetics of 5-fluorouracil

The effect of propylene glycol (PG), azone (LDA) and n-decylmethyl sulfoxide (LDB) on the permeation course of fluorouracil through the hairless mouse skin was studied. Steady-state fluxes and permeability coefficients were measured in buffer solutions and in systems containing the enhancing agents. The permeation rates of fluorouracil have been shown to be highly pH dependent in the pH range of 5–9, the rate decreases with an increase in pH. The solubility of fluorouracil in pure propylene glycol at equilibrium measured by the solubility method was found to be 2.2 mg · ml^?1 at 25°C which is a relatively low value as compared to the solubility in water. The effect of various concentrations of propylene glycol in aqueous donor solutions on the drug permeation rate was examined at pH's 5.7 and 9.0. It was found that propylene glycol decreases the permeation flux when increasing concentrations are added to the aqueous pH 5.7 system; however, at pH 9, a strong enhancement effect was shown. PG was also found to decrease the drug reservoir in the hairless mouse skin e.g. 8.4 and 2.8 mg · (mg skin)^?1 for buffer pH 9 and PG/aqueous solution pH 9 systems, respectively. The concentration dependent enhancement effects of azone and n-decylmethyl sulfoxide have been measured. Both have been found to be potent enhancing agents. However, at relatively low concentrations such as 5%, Azone induced a 50-fold and n-decylmethyl sulfoxide only a two-fold enhancement of the drug steady-state flux. At high concentrations as much as 40%, n-decylmethyl sulfoxide appears to be more effective than Azone. The fluxes measured with these systems were 0.21, 0.17 and 0.003 mg · cm^?2 · h^?1 for the n-decylmethyl sulphoxide, Azone and PG/H₂O systems, respectively.     

不同透皮促进剂及基质对黄体酮透皮作用的影响

目的：观察促进剂及基质对黄体酮凝胶本外透皮作用的影响。方法：采用改良的Ｆｒａｎｚ扩散池,以离体大鼠皮肤为透皮屏障,用高效液相色谱法测定不同种类和浓度的促进剂及不同基质的黄体酮凝胶的体外接受液的含量,进而计算其积累透皮量和稳态透皮速率。结果：３种基质中以Ｃａｒｂｏｐｏｌ＋ＰＶＰ作为基质的渗透作用为好,几种促进剂的促进作用大小顺序为：丙二醇（ＰＧ）＋月桂氮Ｚｈｏｕ酮（Ａｚｏｎｅ）〉月桂氮Ｚｈｏｕ酮〉丙     

促渗剂对奥沙普秦经皮渗透的促进作用

目的：考察几种促渗剂对奥沙普秦透皮作用的影响。方法：采取改良Franz直立式释放池,以离体小鼠皮肤为透皮屏障,计算含不同浓度和组合促透剂的奥沙普秦的累积渗透量Q及渗透速率K,结果;含不同促渗剂奥沙普秦的透皮速率有明显差别,其促进强度依次为油酸＞月桂氮Chuo酮＞薄荷脑;混合促渗剂的促渗效果均比单用时有不同程度的提高;丙二醇有明显的抑制作用,并且抑制油酸,月桂氮Chuo酮及薄荷脑的促渗作用。结论：奥沙普秦透皮吸收符合非极性通道释放的零级动力学方程,其中以10％油酸加1％月桂氮Chuo酮组成的混合促进剂作用最显著。     

Ex vivo buccal drug delivery of ropinirole hydrochloride in the presence of permeation enhancers: the effect of charge

In the current study, the ex vivo permeation of ropinirole hydrochloride (RH) across porcine buccal mucosa in the presence of three permeation enhancers, namely N-trimethyl chitosan (TMC) (positively charged) a chitosan derivative, sulfobutyl ether-β-cyclodextrin (SBE-β-CD) (negatively charged) and hydroxypropyl-β-cyclodextrin (HP-β-CD) (neutral), was investigated. Buccal permeation studies were conducted using Franz diffusion cells. Cumulative amounts of RH were plotted versus time. The presence of the permeation enhancers significantly increased the transport of the drug across the porcine buccal epithelium compared to its plain congener (RH solution). The rank order effect of the permeation enhancers for the transport of RH across buccal epithelium was TMC?≥?SBE-β-CD?>?HP-β-CD?>?RH solution. The presence of TMC increased 1.34-fold the transport of RH across buccal epithelium, whereas an increase of 1.23- and 1.28-fold was reported in the presence of HP-β-CD and SBE-β-CD, respectively. Infrared spectroscopy (IR) was employed to investigate the interaction of permeation enhancers with the epithelial lipids of porcine buccal mucosa corroborating the permeation results. Finally, light microscopy was performed to assess the histological changes in the porcine epithelium. Formation of vacuoles, spongiosis and acantholysis linear detachment and destruction of the epithelium resulted from the presence of the permeation enhancers. The data suggest that all enhancers tested, and particularly TMC, increase the transport of RH across buccal epithelium.     

促渗剂对双氯灭痛透皮吸收的影响

以透皮吸收模型观察了二甲亚砜、1,2-丙二醇及氮酮对搽剂中双氯灭痛透皮吸收的影响。结果表明,1,2-丙二醇或氮酮对双氯灭痛透皮吸收均有促进作用,以氮酮对双氯灭痛的透皮吸收促进作用最强,1,2-丙二醇与氮酮对双氯灭痛透皮吸收无协同作用。     

不同透皮吸收促进剂对左旋肉碱透皮特性的影响

目的:选择适宜的透皮吸收促进剂增加左旋肉碱的透皮百分率。方法:使用改良Franz体外释药装置,用RP-HPLC法检测接收液中左旋肉碱的浓度,计算药物的透皮累积释放量,采用滞留时间法求算经皮渗透相关系数,考察不同用量的丙二醇、尿素、氮酮对左旋肉碱的促透作用。结果:左旋肉碱的溶液在体外透皮释放试验中有透皮吸收。不同种类及不同用量的吸收促进剂对左旋肉碱的促透作用不同,且随着透皮时间的延长,促透量显著增加。3种透皮吸收促进剂中尿素和丙二醇的促透作用较好,氮酮的促透作用稍差。结论:透皮吸收促进剂能够增加左旋肉碱的透皮百分率,其中2.5%的丙二醇促透作用最强。