Synergic enhancing-effect of DEET and dodecylamine on the skin permeation of testosterone from a matrix-type transdermal delivery system

The synergic in vitro skin permeation enhancing-effect of N,N-diethyl-m-toluamide (DEET) and dodecylamine was investigated in order to develop a novel non-scrotal matrix-type transdermal delivery system of testosterone (TS). When DEET was loaded in DuroTak^® 87-2510 together with 2% TS and 3% dodecylamine, the in vitro rat skin permeation rate of TS synergistically increased as DEET concentration increased up to 0.5%. No further increase in permeation was observed thereafter and a plateau was observed up to 3.8% DEET. Moreover, compared to 0.5% DEET concentration, the addition of 3.8% of DEET in combination with 3% dodecylamine and 6% TS further increased the permeation rate of TS, and the maximum permeation rate of 11.21 μg/cm²/h was achieved. The in vitro skin permeation rates of TS from a transdermal delivery system of DuroTak^® 87-2510 containing 6% TS, 3% dodecyamine, and 3.8% DEET were in the following order: hairless mouse skin > rat skin > human cadaver skin. Assuming that a system with a surface area of 60 cm² is applied, the human cadaver skin permeation rate of 5.74 μg/cm²/h achieved in this study can be interpreted as being equivalent to delivering ～ 8.?27?mg of TS per day. Considering that the commercially available product (Testoderm^®TTS) for non-scrotal skin of the same surface area is designed to administer 5?mg of TS per day, the new formulation could maintain therapeutic plasma concentration of TS at a smaller surface area of 40 cm².     

Formulation and in vitro evaluation of pentazocine transdermal delivery system

The aim of this study was to prepare a pentazocine (PTZ) matrix-type transdermal drug delivery system (TDDS) using acrylic pressure-sensitive adhesives. Among the five Duro-Tak adhesive polymers tested (87-9301, 87-2677, 87-201A, 87-2196, 87-2852), in vitro dissolution studies demonstrated the highest PTZ release flux from the Duro-Tak 87-9301 matrix. In addition, the effects of permeation enhancers, isopropyl myristate (IPM) and glyceryl monocaprylate (GEFA-C(8)), and drug content on PTZ skin permeation from prepared patches were evaluated using Franz diffusion cells fitted with hairless mouse skin. IPM and GEFA-C(8) were found to produce effective flux of PTZ at a patch concentration of 10% w/w and 5% w/w, respectively. The PTZ flux increased linearly as the loading dose increased up to 30%, whereas no further increase in flux was observed at loading doses of 40% and 50% due to drug crystallization in the matrix. Thus, the highest skin permeation rate (24.2 microg/cm(2)/h) was achieved when 30% of PTZ was loaded in Duro-Tak 87-9301 with 10% IPM and 5% GEFA-C(8). These results demonstrate the feasibility of a novel narcotic-antagonist analgesic matrix-type TDDS for PTZ.     

Pharmacokinetics and pharmacodynamics of ketoprofen plasters

Ketoprofen plasters of 70 cm(2) size using DuroTak acrylic adhesive polymers were developed either containing 30 mg (Ketotop-L) or 60 mg drug (Ketotop-P). The in vitro skin permeation profile was obtained in hairless mouse skin and showed the permeation rate of Ketotop-P to be twice that of Ketotop-L. The plasma concentration profile of ketoprofen was determined in Sprague-Dawley rats after applying a 3 x 3 cm(2) plaster. AUC(0-24h) and C(max) of Ketotop-P were 260.92 microg.h/ml and 25.09 microg/ml, respectively, which were about twice the values of Ketotop-L. The hind paw edema induced by carrageenan injection was measured for 6 h after applying a 2 x 2 cm(2) plaster, and the area under the time-response curve (AUR) value was significantly lower in Ketotop-P attached rats (180.70%.h) than in those with the Ketotop-L (298.65%.h) and the control (407.04%.h) groups, indicating a stronger anti-inflammatory action of Ketotop-P. However, the analgesic effect of the two formulations did not show a statistically significant difference. In conclusion, Ketotop-P was able to achieve higher plasma concentration of ketoprofen, thereby exhibiting higher and more constant anti-inflammatory effect compared with Ketotop-L.     

盐酸川芎嗪经皮给药系统的制备及体外释放和透皮研究

用盐酸川芎嗪作为模型药物,将阿拉伯胶与聚丙烯酸酯压敏胶共混,制备了一种微观非均相、宏观均相的经皮给药系统,并考察了非均相结构对药物体外释放及透皮速率的影响。结果表明,阿拉伯胶含量为15%时可抑制载药量为5%的贴片中药物析晶,同时增加盐酸川芎嗪的体外释放与裸鼠皮肤的透过量,且阿拉伯胶的加入量对于贴片的黏附性无明显影响。     

跌打止痛巴布剂体外透皮吸收实验

目的：研究跌打止痛巴布剂体外经皮渗透吸收特征。方法：以Franz扩散池和离体裸鼠皮肤进行体外渗透试验，采用高效液相色谱法法同时测定蛇床子素和水杨酸甲酯的累积透皮量。结果：两种成分的体外经皮渗透均符合零级动力学方程，蛇床子素和水杨酸甲酯在15h内的透过率分别为13．50％和49．62％。二者在皮肤的蓄积量分别为17．56％和23．23％。结论：跌打止痛巴布剂中的有效成分在皮肤内有较强的蓄积作用，在15h内药物持续恒速释放，为控释长效和局部作用的制剂。     

Skin permeation and metabolism of a new antipsoriatic vitamin D(3) analogue of structure 16-en-22-oxa-24-carboalkoxide with low calcemic effect

A new vitamin D(3) analogue, SMD-429, is an antipsoriatic candidate of structure 16-en-22-oxa-24-carboalkoxide exhibiting fewer side effects than known vitamin D(3) analogues. In this study, the permeation of SMD-429 through excised rat skin and three-dimensional cultured human skin model (LSE-high) was evaluated. The cumulative amount of SMD-429 permeated through the skin membranes was lower than that of either maxacalcitol or calcipotriol, whereas the amount of SMD-429 in the skin was the same. It was found from in vitro rat skin permeation experiment using [(3)H]SMD-429 that SMD-429 was permeated through skin mainly in its metabolized form. The skin permeation profiles of vitamin D(3) analogues obtained were analyzed based on a one-layer diffusion model to estimate permeation parameters. The apparent diffusion coefficient of SMD-429 was 1.30 x 10(-5) cm(2)/h, which was 10-fold lower than that of maxacalcitol. The apparent metabolic rate constant of SMD-429 in skin was 1.01 x 10(-1) h(-1), the same as maxacalcitol. Low apparent diffusivity of SMD-429 in skin might cause an increase in the probability of bioconversion. The same amount of SMD-429 in skin as known vitamin D(3) analogues would achieve sufficient therapeutic efficacy in skin. Such low skin permeability and high metabolic conversion in skin of SMD-429 would contribute to a reduction in the systemic side effects.     

In Vitro Percutaneous absorption of tenoxicam from pressure-sensitive adhesive matrices across the hairless mouse skin

To investigate the feasibility of developing a new tenoxicam plaster, the effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from a pressure-sensitive adhesive (PSA) matrices across the dorsal hairless mouse skin were studied. Vehicles employed in this study were propylene glycol (PG)-oleyl alcohol (OAI), PG-oleic acid (OA), and diethylene glycol monoethyl ether (DGME)-propylene glycol monolaurate (PGML) cosolvents with/without fatty acids. In this study, amines such as triethanolamine (TEA) and tromethamine (TM) were additionally used as a solubilizer. Among PSAs used, Duro-Tak 87-2510 showed much higher release rate than either Duro-Tak 87-2100 or Duro-Tak 87-2196. The relatively high flux rate was obtained with the formulation of DGME-PGML (40:60, v/v) with 3% OA and 5% TM, and the flux increased as a function of the dose; the initial flux up to 12 h was 4.98 +/- 1.38 microg/cm2/h at the tenoxicam dose of 50 mg/70 cm2. This flux was much higher than that of a commercial piroxicam patch (Trast) (1.24 +/- 0.73 microg/ cm2/hr) with almost only one-third that of the commercial patch. Therefore, these observations indicated that these composition of tenoxicam plaster may be practically applicable.     

<Emphasis Type="Italic">In vitro</Emphasis> Percutaneous absorption of ondansetron hydrochloride from pressure-sensitive adhesive matrices through hairless mouse skin

To investigate the feasibility of developing a new ondansetron transdermal system, the effects of vehicles and penetration enhancers on the in vitro permeation of ondansetron hydrochloride (OS) from a pressure-sensitive adhesive (PSA) matrices across dorsal hairless mouse skin were studied. Vehicles employed in this study consisted of various ratios of propylene glycol monocaprylate (PGMC)-diethylene glycol monoethyl ether (DGME) co-solvents and PGMC-propylene glycol (PG) co-solvents with 3% oleic acid. Duro-Tak 87-2100 and Duro-Tak 87-2196 were used as PSAs. The concentration of DGME in PGMC-DGME co-solvent system affected the release rate; as the concentration of DGME increased, the release rate decreased. The cumulative release amount of OS increased as the ratio of PSA to drug solution decreased. The permeation flux was also primarily affected by the amount of PSAs; as the amount decreased, the permeation flux increased. The overall fluxes from matrix formulations were significantly lower when compared to those obtained from solution formulations. The ratio of PG to PGMC did not affect permeation flux, while the lag time decreased significantly from 5.14 +/- 3.31 to 0.31 +/- 0.12 h as the PG increased from 40% to 60%.     

Enhancement of the transdermal delivery of catechins by liposomes incorporating anionic surfactants and ethanol

The aim of this study was to develop and evaluate liposomal formulations encapsulating tea catechins, which possess antioxidant and chemopreventive activities. Liposomes were characterized for size, zeta potential, and entrapment efficiency. Both in vitro and in vivo skin permeation were examined using nude mouse skin as a model. The results suggested that the liposomal composition plays an important role in affecting the efficiency of transdermal catechin delivery. Incorporation of anionic surfactants such as deoxycholic acid (DA) and dicetyl phosphate (DP) in the liposomes in the presence of 15% ethanol increased the (+)-catechin permeation by five to seven-fold as compared to the control. The flexibility of bilayers is suggested as an important factor governing the enhancing effect of liposomes. Intercellular spaces within the stratum corneum but not shunt routes are the major pathways for catechin delivery from liposomes. (+)-Catechin and (−)-epicatechin are isomers which showed similar encapsulation efficiencies and skin permeation in liposomes. (−)-Epigallocatechin-3-gallate showed the highest encapsulation rate and in vivo skin deposition level in liposomes among all catechins tested. The stability and in vitro tranepidermal water loss test indicated the safety of the practical use of liposomes developed in this study.     

醋酸曲安奈德固体脂质纳米粒卡波姆凝胶的性能及经皮给药研究

目的　以醋酸曲安奈德 (TAA)为模型药物 ,以三棕榈酸甘油酯为脂质材料制备醋酸曲安奈德固体脂质纳米粒(SLN)卡波姆凝胶 ,考察其特性以及药物经皮渗透性能。方法　采用高压乳匀技术制得TAA SLN分散液 ,并制成卡波姆凝胶 ,考察了卡波姆凝胶中SLN的微观形态、粒径、Zeta电位、包封率等理化特性和稳定性、体外药物释放行为。采用改进的Franz扩散池研究了SLN卡波姆凝胶的药物经皮渗透性能。结果　制得的TAA SLN为均匀的球形粒子 ,不同载药量SLN粒径为 95 . 5～ 186 . 2nm ,Zeta电位为 - 2 6 .3～ - 15 . 7mV ,包封率为 6 7. 4 3%～ 90 . 3% ;SLN卡波姆凝胶 37℃储存三个月后SLN粒径略有增大 ,Zeta电位无明显变化 ;SLN卡波姆凝胶体外药物释放符合Higuchi方程 (DR % =6 . 3979t1/2 3. 15 2 9,r2 =0 . 95 18) ;经皮渗透实验结果表明 ,与相同药物浓度的普通卡波姆凝胶比较 ,SLN卡波姆凝胶药物经皮渗透速率和药物 2 4h累积渗透量显著提高。结论　TAA SLN卡波姆凝胶稳定性好 ,对药物释放具有缓控释作用 ,能显著促进药物经皮渗透 ,有望成为新型经皮给药制剂。     

Development of matrix-membrane transdermal drug delivery system for atenolol

A polymer matrix system for transdermal delivery of Atenolol was developed for its prolonged and controlled release systemic availability. To achieve the desired and controlled release rate, different combinations of Eudragit RL with polyvinyl pyrrolidone and polyethylene glycol 4000 were used in the preparations of polymeric matrix system. These preparations were evaluated for in vitro release and permeation of the drug across pig skin. The desired systems exhibited linear relationship between drug release (Q) versus ne^0.8(hr^0.8). The product exhibiting required skin permeation 64 mcg/h/cm² to achieve an effective plasma concentration was selected for the in vivo performance evaluation. The drug plasma profile was compared with the plasma profile obtained following the administration of a conventional oral dose of Atenolol. The study revealed that the designed polymeric matrix transdermal drug delivery system of Atenolol could be successful with improved performance.     

Transdermal atenolol releasing system: an approach towards its development

A polymer matrix system for transdermal delivery of atenolol was developed for its prolonged and controlled release using different ratios of ethylcellulose and hydroxypropyl methylcellulose. These polymeric matrix films were characterized for thickness, tensile strength, moisture content and drug content. They were also studied for in vitro drug release and in vitro drug skin permeation. The drug release from the films was found to be Fickian diffusion type and exhibiting linear relationship between drug release (Q) vs. square root of time (t0.5). The in vitro skin permeation of drug from transdermal drug delivery system (TDDS) was evaluated using dermatomed pig skin. The product which shows in vitro drug skin permeation near to 64 mcg/h/ml was selected for in vivo studies. The in vivo studies revealed that Ma EC HPMC 46 is most effective among the other polymeric matrix TDDS. The AUC0-28 with Ma EC HPMC 46 was better than orally administered conventional doses at twelve hours interval (AUC0-28 1587 ng h/ml) as well as no trough and peaks in drug plasma level was recorded with TDDS. Hence, it could be concluded that the designed polymeric matrix TDDS of atenolol could be used successfully for effective and prolonged delivery of atenolol. However, it further demands exploration in clinic, an insight vision towards the development of TDDS for commercial use.     

Deformable liposomes and ethosomes as carriers for skin delivery of ketotifen

Deformable liposomes and ethosomes were investigated as carriers for skin delivery of ketotifen (KT) in terms of vesicle size, entrapment efficiency, stability, in vitro permeation and skin deposition properties. Phosphatidylcholine (PC) from soybean lecithin was used in the preparation of all vesicles. Sodium cholate, sodium deoxycholate and Tween 80 were investigated as edge activators in preparation of KT deformable liposomes. KT ethosomes were prepared in two PC concentrations, 2% and 4.25% w/v, in 30% v/v ethanol. KT deformable liposomes showed improved entrapment efficiency over KT ethosomes. KT deformable liposomes with Tween 80 as an edge activator were more stable upon storage at 5 +/- 1 degree C than those prepared using sodium cholate or sodium deoxycholate and were more stable than KT ethosomes. In vitro permeation and skin deposition studies employed only deformable liposomes with Tween 80 as an edge activator and ethosomes with 4.25% w/v PC concentration. Both of them improved skin delivery of KT over controls and over traditional liposomes, with greater improvement of KT skin deposition than KT skin permeation, hence are more useful for dermal than for transdermal delivery of KT.     

固体脂质纳米粒作为水杨酸经皮给药载体的研究

目的 考察固体脂质纳米粒作为经皮给药载体对水杨酸经皮吸收的促渗透作用.方法 采用薄膜超声法制备水杨酸固体脂质纳米粒,以改良的Franz扩散池考察其体外透皮特性;并与水杨酸软膏剂比较,考察其促渗作用.结果 制备的水杨酸固体脂质纳米粒均匀圆整,包封率为46.4%,体外透皮特性优于普通软膏剂,24 h后皮肤药物累积透过量为654.3 μg/cm2,皮肤中药物残留量为22.99 μg,均分别显署高于软膏剂组(128.0 μg/cm2和0.84 μg,P<0.05).结论 固体脂质纳米粒作为水杨酸经皮给药载体,可有效促进药物透皮吸收和增加药物在皮肤中储留量,而且可延缓药物的释放,从而有效提高药物疗效及患者依从性.     

Doxorubicin skin penetration from monoolein-containing propylene glycol formulations

Topical chemotherapy with the antineoplastic doxorubicin (DXR) could be an alternative to treat skin cancer, however its poor skin penetration often limits the efficacy of topical formulations. The aim of this work was to study the effect of monoolein (MO), a penetration enhancer, on the in vitro skin permeation and retention of DXR. DXR was incorporated in a propylene glycol preparation containing 0-20% of MO. DXR release rate and topical delivery were evaluated in vitro using acetate cellulose membrane and porcine skin, respectively, mounted in a Franz diffusion cell. At 5%, MO did not significantly change DXR release rate, but MO concentrations larger than 10% decreased almost twice its release. In vitro skin penetration studies showed that the presence of MO in the propylene glycol formulations markedly increased DXR presence in the stratum corneum (SC). At 5%, MO significantly increased the amount of DXR in the SC already in the first hours, attained a maximum in 6h. Comparing propylene glycol formulations containing more than 10% MO with that containing 5%, the former took the double of the time (12h) to reach the same amount of DXR in the skin, result that is in agreement with in vitro release studies. Interesting, despite the fact that MO significantly increased the amount of DXR in the SC, drug transdermal delivery did not change. These findings suggest a cutaneous delivery of DXR that is an important condition for topical treatment of skin tumors. Further in vivo experiments can show DXR delivery to deeper skin layers.     

不锈钢微针经皮给药的研究

目的：将不锈钢微针阵列应用于经皮给药。考察离体大鼠皮肤经不同针形微针预处理相同时间、相同针形微针预处理不同时间后，模型药物鬼臼毒素经大鼠皮肤的透皮能力。方法：微针预处理大鼠皮肤后，用改进的Franz扩散池研究鬼臼毒素对皮肤的透皮速率。高效液相色谱法测定鬼臼毒素的含量。结果：皮肤经微针预处理后进行鬼臼毒素透皮，其透皮速率比未经微针处理时有明显提高。三角形微针、梯形微针、矛形微针对鬼臼毒素的促渗能力依次增强；三者所引起的鬼臼毒素在皮肤中的滞留量有显著差异。同种针形微针预处理皮肤时间越长，鬼臼毒素的透皮速率越大；但微针预处理时间对皮肤中的药物滞留量无显著影响。结论：微针用于药物经皮给药时，微针针形、微针的预处理时间对药物的经皮渗透具有重要影响。     

Effect of fatty acids on the transdermal delivery of donepezil: in vitro and in vivo evaluation

The effect of fatty acids on the skin permeation of donepezil base (DPB) and its hydrochloride salt (DPH) were studied in vitro using hairless mouse and human cadaver skin. DPB and DPH were solubilized in propylene glycol (PG) containing 1% (w/v) fatty acid, after which the in vitro permeation through hairless mouse skin and human cadaver skin were evaluated using Keshary-Chien diffusion cells. The optimized formulation obtained from the in vitro study was then tested in rats for an in vivo pharmacokinetic study. The relative in vitro skin permeation rate of donepezil (DP) through the hairless mouse skin showed a parabolic relationship with increased carbon length of the fatty acid enhancers. Among the fatty acids tested, oleic acid for DPB and palmitoleic acid for DPH showed the highest enhancing effect, respectively. Both the permeation rates of DPB and DPH evaluated in human cadaver skin were in good correlation with those in hairless mouse skin, regardless of the presence of fatty acids. This suggests that the mouse skin model serves as a useful in vitro system that satisfactorily represents the characteristics of the human skin. Moreover, based on the in vitro results, the optimal formulation that could maintain the human plasma concentration of 50 ng/mL was determined to be 10mg DP with 1% (w/v) enhancer. When the DP transdermal formulations were applied to the abdominal skin of rats (2.14 cm(2)), the C(ss) was maintained for 48 h, among which the highest value of 52.21 ± 2.09 ng/mL was achieved with the DPB formulation using oleic acid. These results showed that fatty acids could enhance the transdermal delivery of DP and suggested the feasibility of developing a novel transdermal delivery system for clinical use.     

Microemulsion-based hydrogel formulation of ibuprofen for topical delivery

The purpose of this study was to construct microemulsion-base hydrogel formulation for topical delivery of ibuprofen. Ethyl oleate (EO) was screened as the oil phase of microemulsions, due to a good solubilizing capacity of the microemulison systems and excellent skin permeation rate of ibuprofen. The pseudo-ternary phase diagrams for microemulsion regions were constructed using ethyl oleate as the oil, Tween 80 as the surfactant, propylene glycol as the cosurfactant. Various microemulsion formulations were prepared and the abilities of various microemulsions to deliver ibuprofen through the skin were evaluated in vitro using Franz diffusion cells fitted with porcine skins. The in vitro permeation data showed that microemulsions increased the permeation rate of ibuprofen 5.72-30.0 times over the saturated solution. The optimum formulation consisted of 3% ibuprofen, 6% EO, 30% Tween 80/PG (2:1) and water, showed a high permeation rate of 38.06 microg cm(-2) h(-1). Xanthan gum as a gel matrix was used to construct the microemulsion-based hydrogel for improving the viscosity of microemulsion for topical administration. The studied microemulsion-based hydrogel showed a good stability. These results indicate that the studied microemulsion-based hydrogel may be a promising vehicle for topical delivery of ibuprofen.     

Effect of electroporation and iontophoresis on skin permeation of Defibrase--a purified thrombin-like enzyme from the venom of Agkistrodon halys ussuriensis Emelianov

The purpose of this study was to investigate electroporation and iontophoresis as a means for in vitro delivery of Defibrase--a thrombin-like enzyme (TLE) from Agkistrodon halys ussuriensis Emelianov snake venom--through human epidermis membrane (HEM). Electroporation was carried out using an exponential decay pulse generator (BioR-ad Genepulser, USA) for a period of 0.5 h, followed by a period of 5.5 h passive diffusion or iontophoresis. The results indicated that the combined use of electroporation and anodal iontophoresis in pH 6.4 permeation medium could effectively enhance the skin permeation of Defibrase, whose apparent permeability coefficient was 1.6 +/- 0.8 x 10(-4) cm.h-1. The delivery of Defibrase by the combined use of electroporation and anodal iontophoresis was more effective than by electroporation alone (P < 0.01) or by the combined use of electroporation and cathodal iontophoresis (P < 0.01). Moreover, when the pH of the permeation medium was raised from 6.4 to 7.4 the permeation of Defibrase caused by a combined use of electroporation and anodal iontophoresis showed a tendency to increase. These results implied that electroosmotic flow effect might be important for the iontophoretic (following electroporation) skin permeation of Defibrase.     

Triclosan: release from transdermal adhesive formulations and in vitro permeation across human epidermal membranes

Malarial resistance is an escalating global problem and consequently new and more efficacious treatments to combat malaria are urgently needed. The transdermal delivery of anti-malarials may provide an effective alternative or adjunct to conventional regimens. Triclosan is widely used as an anti-bacterial agent and it has recently been demonstrated that this compound has anti-malarial properties. Its high lipophilicity makes it a potential candidate for delivery across the skin and this paper examines in vitro the potential for the transdermal delivery of triclosan from 'drug-in-glue' formulations. Model patches were prepared using DuroTak 2287, 2516 and 2051 acrylic polymer adhesives loaded with 0, 30 and 50 mg per 0.785 cm(-2) triclosan and dissolution was measured over a 12-h period. There was no apparent difference between the adhesives at the 30 mg patch loading, but at 50 mg, the trend for increased release was 2051>2516>2287. No significant burst effect was apparent. Patches of 50 mg per 0.785 cm2 were then used to determine the permeation of triclosan across heat-separated human epidermal membranes in Franz diffusion cells, over a period of 48 h. The above general trend was reflected in the steady state flux values obtained: 2051:16.91 microg x cm(-2) x h(-1) (S.E.M. 1.29), 2516:15.05 microg x cm(-2) x h(-1) (S.E.M. 1.00), 2287 12.83 microg x cm(-2) x h(-1) (S.E.M. 2.81). Although pharmacokinetic data are not currently available to permit calculation of an efficacious patch size, the transdermal delivery of triclosan is feasible.