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。     

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.     

Effect of permeation enhancers on dynamic mechanical properties of acrylate pressure sensitive adhesives

Physico-chemical properties of permeation enhancers like molecular weight/size, hydrophobicity/hydrophilicity, co-solvency, etc. are necessary during their selection for pharmaceutical product development. Chemical permeation enhancers modulate the viscoelastic properties of pressure sensitive adhesives. The extent of this modulation depends upon the molecular size and branching of the polymeric chains. The functional nature of this branching additionally changes the peel and tack properties of PSA's. Chemical permeation enhancers alone are not able to modify viscoelastic properties of aqueous based PSA's as compared with their solvent based counterparts. These modulated mechanical aspects need to be maintained throughout development of transdermal patch along with other pharmaceutical aspects like drug release and drug stability.     

Effect of vehicles and pressure sensitive adhesives on the permeation of tacrine across hairless mouse skin

The purpose of this study was to investigate the feasibility of developing transdermal drug delivery (TDD) system for tacrine used for treating the symptoms of Alzheimer's disease. The effects of various vehicles on the percutaneous absorption of tacrine in solution formulation and in pressure sensitive adhesive (PSA) matrix across the hairless mouse skin were evaluated using flow-through diffusion cell system at 37 degrees C. The permeation profiles of tacrine from solutions were different depending on vehicles used. The flux of tacrine increased significantly as its concentration in the solutions increased. The permeation rate of tacrine was higher in acrylic adhesives with hydroxyl functional group and without functional group than in polyisobutylene adhesive matrix. Incorporation of vehicles into the acrylic adhesive matrix significantly enhanced the permeation rate and shortened the lag time of tacrine. The maximum flux obtained from pressure sensitive adhesive matrix seemed to be high enough to obtain therapeutic effect.     

Effect of some enhancers on the permeation of haloperidol through rat skin in vitro

The objective of this work is to enhance the permeation of haloperidol through the rat skin in vitro by using various enhancers at a concentration of 1 mg/ml in the saturated drug solution and analysing the dose-dependent diffusion profile for the enhancers which significantly increased permeation at this concentration compared with the control. Enhancers belonging to various chemical classes like the vitamins (ascorbic acid), surfactants (cetrimide, polysorbate 20), sulfoxides (dimethyl sulfoxide), glycols (polyethylene glycol 400, propylene glycol) and amides (urea) were used. Amber glass Franz-type diffusion cells were used for the permeation studies and haloperidol was made soluble in aqueous solution with the aid of lactic acid. Ascorbic acid and cetrimide increased flux and permeability coefficient significantly. From the dose-dependent permeation studies, it was concluded that ascorbic acid enhanced the permeation by increasing the solubility of the drug in the vehicle thus providing a high concentration gradient across the skin, whereas cetrimide enhanced the permeation by increasing the thermodynamic activity which may be due to solubilization of skin lipids by micelles. Polysorbate 20 decreased the enhancer index by decreasing the thermodynamic activity. None of the enhancers changed the lag time except for urea which decreased the lag time probably by its binding with keratin. Dimethyl sulfoxide, polyethylene glycol 400 and propylene glycol did not have a significant effect on haloperidol permeation compared with control.     

Synergistic effects of ethosomes and chemical enhancers on enhancement of naloxone permeation through human skin

The purpose of this study was to investigate the effects of ethosomes, chemical enhancers and their binary combination on the in vitro permeability enhancement of naloxone through human skin. Franz diffusion cells were used for the percutaneous absorption studies. Propylene glycol (PG), N,N-dimethyl formamide (N,N-DMF), N,N-dimethyl acetamide (N,N-DMA), dimethyl sulfoxide (DMSO), Azone and polyethylene glycol 400 (PEG400), were chosen as the chemical enhancers. Naloxone ethosomes showed 11.68 times increase in steady-state flux compared to phosphate buffered solution (PBS). Ethosomes in combination with chemical enhancers synergistically increased (p < 0.05) in vitro flux of naloxone. Azone 3% + PG7% pretreated in ethosomal form dramatically enhanced the skin permeation of naloxone in vitro compared with ethosomes (steady-state flux: 96.75 +/- 5.70 microg x cm(-2) x h(-1) vs 20.56 +/- 1.67 microg x cm(-2) x h(-1)). Ethosomal carrier and enhancers accumulated in the skin after 24 h were greater than that of PBS.     

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.     

Combined effect of ultrasound and chemical enhancers on the skin permeation of aminopyrine

The combined effect of 150 kHz ultrasound with 111 mW/cm²intensity and chemical enhancers on the skin permeation of aminopyrine (AMP) was investigated using excised hairless rat skin. Monoterpenes (l-menthol, l-calvone and D-limonene), laurocapram (Azone®), glycerol monocaprylate (Sefsol-318®), isopropyl myristate and ethanol were selected as enhancers. Combined application of ultrasound and enhancers increased the skin permeation rate (flux) of AMP compared with ultrasound or enhancers alone. Better effects were obtained by the combination with monoterpenes. The influence of detailed conditions of ultrasound and enhancer applications on the AMP flux was further investigated using l-menthol. The enhancement effect by this combination was increased with an increase in ultrasonic application duration and l-menthol concentration, suggesting that these conditions might be used to achieve the controlled drug delivery. A pretreatment experiment with ultrasound or l-menthol was carried out, and l-menthol content in the skin and the skin permeation of deuterium oxide (D₂O), used as a donor vehicle, were measured to understand the role of ultrasound in the combined effect. Application of ultrasound to the l-menthol-pretreated skin increased the AMP flux, while the effect of l-menthol on ultrasonic-pretreated skin was similar to that of l-menthol alone. The ultrasound increased the l-menthol content in the skin as well as the skin permeation of D₂0 from a vehicle with l-menthol. These results suggested that simultaneous application of ultrasound and enhancers is essential to obtain the pronounced effect. Ultrasound application also strongly assisted migration of l-menthol into skin, which increases the enhancing action on the skin permeation for a drug.     

渗透促进剂对葛根素角膜透过性的影响

目的研究葛根素(puerarin)的角膜透过性,为其处方设计提供理论基础。方法采用体外扩散实验以林格溶液为扩散介质考察在多种渗透促进剂条件下PUE的离体兔眼角膜透过性。结果10 g.L-1吐温80和5 g.L-1乙二胺四乙酸二钠(EDTA)分别使PUE的表观渗透系数增加到1.69和2.10倍,与对照组呈现显著性差异(P<0.01),而20 g.L-1羟丙基-β-环糊精(HP-β-CD)与1 g.L-1月桂氮卓酮(azone)未能显著增大PUE的表观渗透系数(P>0.05);5 g.L-1乙二胺四乙酸二钠(EDTA-2Na),10 g.L-1吐温80能显著缩短PUE透过角膜的滞后时间(P<0.01);而20 g.L-1羟丙基-β-环糊精(HP-β-CD)与1 g.L-1月桂氮卓酮(azone)未能显著缩短PUE的滞后时间(P>0.05);所有渗透促进剂对眼组织均没有显著刺激性。结论5 g.L-1的EDTA-2Na能够显著增加PUE的表观渗透系数并能显著缩短其角膜透过时间,且对角膜无明显刺激性。     

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。     

Effect of permeation enhancers and organic acids on the skin permeation of indapamide

The aim of present study was to investigate the transdermal properties of indapamide and to explore the efficacy of various permeation enhancers and organic acids with regard to the percutaneous absorption of indapamide. Permeation experiments were performed in vitro, using rat abdominal skin as a barrier. In the permeation studies, 2-chamber diffusion cells were used. The results obtained indicate that N-dodecylazepan-2-one, N-methyl-2-pyrrolidone, menthol and oleic acid had a strong enhancing effect on the permeation of indapamide and N-dodecylazepan-2-one exhibited the most potent enhancing effect. All eight of the organic acids chosen had a potent enhancing effect on the permeation of indapamide across rat abdominal skin. Among the organic acids examined, lactic acid had the greatest enhancing effect. The formation of an ion-pair between indapamide and organic acids may be responsible for the enhanced skin permeation of indapamide. Although the exact reason remains unknown, it is worth carrying out further investigations.     

Effect of some penetration enhancers on the permeation of glibenclamide and glipizide through mouse skin

The purpose of this investigation was to study the effect of some penetration enhancers on in vitro permeation of glibenclamide and glipizide through mouse skin. Ethanol in various concentrations, N-methyl-2-pyrrolidinone, transcutol, propylene glycol and terpenes like citral, geraniol and eugenol were used as penetration enhancers. The in vitro skin permeation experiments were conducted by both simultaneous application of drug and enhancer solution and by pretreatment of the skin with neat enhancer. At the end of the experiment drug retained in the skin was estimated. The flux values (microg/cm2/h) of both drugs significantly (p < 0.05) increased in the presence of penetration enhancers, except transcutol and propylene glycol. The glibenclamide flux values ranged from 1.42 +/- 0.09 without enhancer, to 18.25 +/- 1.21 in a combination of 50% ethanol and 5% eugenol. Glipizide flux values ranged from 3.21 +/- 0.51 without enhancer, to 57.21 +/- 5.25 in a combination of 50% ethanol and 5% eugenol. Skin retention and solubility of both drugs increased with all penetration enhancers compared to control (except propylene glycol). As the target permeation rates for glibenclamide and glipizide were calculated to be 193.8 and 184.8 microg/h respectively, the present study showed that the required permeation rates for both drugs could be achieved with the aid of enhancers by increasing the area of application in an appreciable range.     

The effect of vehicles and pressure sensitive adhesives on the percutaneous absorption of quercetin through the hairless mouse skin

To investigate the feasibility of developing a new quercetin transdermal system, a preformulation study was carried out. Therefore, the effects of vehicles and pressure-sensitive adhesives (PSA) on the in vitro permeation of quercetin across dorsal hairless mouse skin were studied. Among vehicles used, propylene glycol monocaprylate (PGMC) and propylene glycol monolaurate were found to have relatively high permeation flux from solution formulation (i.e., the permeation fluxes were 17.25 +/- 1.96 and 9.60 +/- 3.87 microg/cm2/h, respectively). The release rate from PSA formulations followed a matrix-controlled diffusion model and was mainly affected by the amount of PSA and drug loaded. The overall permeation fluxes from PSA formulations were less than 0.30 microg/cm2/h, which were significantly lower compared to those obtained from solution formulations. The lower permeation fluxes may be due to the decrease of solubility and diffusivity of quercetin in the PSA layer, considering the fact that the highest flux of 0.26 microg/cm2/h was obtained with the addition of 0.2% butylated hydroxyanisole in PGMC-diethylene glycol monoethyl ether co-solvents (80-85 : 15-20, v/v). Taken together, these observations indicate that improvement in the solubility and diffusivity of quercetin is necessary to realize fully the clinically applicable transdermal delivery system for the drug.     

Effects of vehicles and pressure sensitive adhesives on the penetration of isosorbide dinitrate across the hairless mouse skin

The effects of various vehicles and adhesives on the percutaneous absorption of isosorbide dinitrate (ISDN) were evaluated. Lauroglycol ® FCC showed the highest flux among vehicles tested. The flux of ISDN from silicone and acrylic adhesive matrices was found to be higher than that from other types of adhesive matrices. No statistically significant relationship between the flux from acrylic PSA and the flux from a solution formulation was observed. A highly cross-linked acrylic adhesive gave higher permeation rates than the other acrylic adhesives examined. N-decylmethyl sulfoxide showed the highest enhancing effect on the flux of ISDN from acrylic adhesive. The relationship between the HLB values of vehicles and the measured flux showed a decrease of flux at HLB values greater than 12.     

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。     

青藤碱压敏胶分散型贴剂的制备及体外经皮渗透性考察

目的制备青藤碱压敏胶分散型贴剂并考察其体外经皮渗透性。方法将青藤碱及各种渗透促进剂直接溶于压敏胶中制备压敏胶分散型贴剂;采用卧式双室扩散池,研究青藤碱贴剂的体外经皮渗透行为。结果由DURO-TAK87-4098型压敏胶制备的贴剂的稳态渗透速率显著高于由DURO-TAK 87-2677制备的贴剂。加入各种渗透促进剂后,促渗作用由大到小的排列顺序为(质量分数):15%肉豆蔻酸异丙酯>10%肉豆蔻酸异丙酯>10%氮酮>5%肉豆蔻酸异丙酯>10%油酸>10%N-甲基吡咯烷酮。联合应用促进剂后促渗作用由大到小的排列顺序为(质量分数):10%肉豆蔻酸异丙酯+5%薄荷醇>10%肉豆蔻酸异丙酯+5%氮酮>10%肉豆蔻酸异丙酯+10%薄荷醇>10%肉豆蔻酸异丙酯+10%氮酮,但与10%的豆蔻酸异丙酯或10%氮酮相比,没有协同作用。结论应用DURO-TAK87-4098型压敏胶制备的青藤碱压敏胶分散型贴剂有望制成长效抗炎镇痛贴剂,值得进一步深入研究。     

Structure-activity relationship for chemical skin permeation enhancers: probing the chemical microenvironment of the site of action

Studies were previously conducted in our laboratory on the influence of n-alkanols, 1-alkyl-2-pyrrolidones, N,N-dimethlyalkanamides, and 1,2-alkanediols as skin permeation enhancers on the transport of a model permeant, corticosterone (CS). The experiments were conducted with hairless mouse skin (HMS) in a side-by-side, two-chamber diffusion cell, with enhancer present in an aqueous buffer in both chambers. The purpose of the present study was to extend these studies and investigate in greater detail the hypothesis that a suitable semipolar organic phase may mimic the microenvironment of the site of enhancer action, and that the enhancer partitioning tendency into this organic phase may be used to predict the enhancer potency. CS flux enhancement along the lipoidal pathway of HMS stratum corneum was determined with the 1-alkyl-2-azacycloheptanones, 1-alkyl-2-piperidinones, 1,2-dihydroxypropyl decanoate, 1,2-dihydroxypropyl octanoate, n-alkyl-beta-D-glucopyranosides, 2-(1-alkyl)-2-methyl-1,3-dioxolanes, 1,2,3-nonanetriol, and trans-hydroxyproline-N-decanamide-C-ethylamide as enhancers. Enhancement factors (E values) were calculated from the permeability coefficient and solubility data over a range of E values. Comparisons of the enhancer potencies for all studied homologous series and the carbon number of the n-alkyl group revealed a nearly semilogarithmic linear relationship with a slope of approximately 0.55, which is consistent with the hydrophobic effect. Moreover, comparisons of the enhancer potencies of all the enhancers with the n-hexanol-phosphate buffered saline (PBS), n-octanol-PBS, n-decanol-PBS, and n-hexane-PBS partition coefficients showed very good correlations for the n-alkanol solvents but not for n-hexane. This result supports the interpretation that the enhancer potency is directly related to the ability of the enhancer molecule to translocate to a site of action via its free energy of transfer from the bulk aqueous phase to a semipolar microenvironment in the stratum corneum lipid lamella that is well mimicked by water-saturated n-alkanols.     

Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin

Mannitol, hydrocortisone and progesterone were selected as model penetrants to assess the mode of action of eight potential penetration enhancers in human skin. Their partition coefficients, octanol: water and stratum corneum: water were measured and correlated with their postulated routes of penetration through human skin. The results suggest that mannitol penetrated via a polar route, hydrocortisone by a mainly lipid route and progesterone via a lipid pathway but its penetration rate was probably affected by aqueous layers. From permeation studies through cadaver skin in which an in-vivo mimic method was used, it was concluded that the penetration enhancers fell into three main categories: solvents which enhanced permeation of polar and non-polar compounds e.g. 2-pyrrolidone, N-methylpyrrolidone, N-methylformamide and propylene glycol plus Azone; enhancers which preferentially affected the polar route e.g. propylene glycol plus decylmethylsulphoxide, and accelerants which mainly modified the non-polar route e.g. propylene glycol plus oleic acid, propylene glycol alone and, to a limited extent, water.