渗透促进剂对利多卡因经皮渗透的促进作用

考察了7种渗透促进剂对利多卡因游离碱的促渗作用，并提出了一促渗作用参数对油溶性和水溶性促渗剂的促渗作用进行系统比较，结果发现渍溶性促渗剂的促渗作用强于水溶性促渗剂（P＜0．05），但对药物经皮渗透的滞后时间无改善作用，水溶性促渗剂可使滞后时间有所缩短。     

肠吸收促进剂的研究进展

肠吸收促进剂可改善肠粘膜透过能力低药物的口服生物利用度。本文综述了肠吸收促进剂研究的实验方法、制剂及生理因素对其促吸收作用的影响、安全性问题以及近年重点研究的促进剂类型。     

Structure-Function Analysis of Phenylpiperazine Derivatives as Intestinal Permeation Enhancers

Purpose

A major obstacle preventing oral administration of macromolecular therapeutics is poor absorption across the intestinal epithelium into the bloodstream. One strategy to improve transport across this barrier is the use of chemical permeation enhancers. Several molecular families with permeation enhancing potential have been identified previously, including piperazines. In particular, 1-phenylpiperazine has been shown to enhance transepithelial transport with minimal cytotoxicity compared to similarly effective molecules. To better understand how the chemistry of 1-phenylpiperazine affects its utility as an intestinal permeation enhancer, this study examined a small library of 13 derivatives of 1-phenylpiperazine.

Methods

The efficacy and cytotoxicity of 13 phenylpiperazine compounds were assessed in a Caco-2 model of the intestinal epithelium. Efficacy was measured using the paracellular diffusion marker calcein as well as by immunostaining and confocal imaging of Caco-2 monolayers.

Results

Of the 13 derivatives, two enhanced the permeability of the fluorescent marker calcein over 100-fold. It was found that hydroxyl or primary amine substitutions on the phenyl ring significantly increased toxicity, while aliphatic substitutions resulted in efficacy and toxicity profiles comparable to 1-phenylpiperazine.

Conclusions

Several potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications.

     

促透剂对血竭素透皮影响的研究

目的：研究几种常用的促透剂对血竭素体外经皮透过的影响，优化健骨膏的处方。方法：采用Franz扩散池，HPLC测定血竭紊的浓度，考察促透剂对血竭素透过离体SD大鼠腹部皮肤的影响。结果：不同促透剂的促透效果依次为：月桂氮革酮〉丙二醇〉松节油〉油酸〉薄荷醇，月桂氮革酮不同浓度的促透效果依次为：2％〉1％〉0.5％〉3％。结论：选择2％氮酮为健骨膏的促透剂时，透皮效果较好。     

透皮促进剂对萘普生的促透效果研究

目的研究透皮促进剂月桂氮酮、油酸、月桂醇与1,2-丙二醇单独使用或混合使用对萘普生经皮渗透的促透效果。方法采用Valia-Chien双室渗透池,以10%聚乙二醇400生理盐水为接收介质,经大鼠腹部离体皮肤渗透,高效液相色谱法测定接受液中药物含量,计算药物累积透皮量和稳态透皮速率。结果 5%月桂氮酮+20%1,2-丙二醇达最大促透效果。结论脂溶性促进剂月桂氮酮、油酸,联合1,2-丙二醇使用对萘普生促透效果显著。     

Effectiveness and Toxicity Screening of Various Absorption Enhancers in the Rat Small Intestine: Effects of Absorption Enhancers on the Intestinal Absorption of Phenol Red and the Release of Protein and Phospholipids from the Intestinal Membrane

Sodium glycocholate, sodium taurocholate, sodium deoxycholate, EDTA, sodium salicylate, sodium caprate, diethyl maleate, N-lauryl-β-D-maltopyranoside, linoleic acid polyoxyethylated (60 mol) mixed micelles (all 20 mM) have been ranked in order of their effectiveness as enhancers of the absorption of drugs in the rat small intestine, by use of an in-situ loop model with phenol red as a model drug. Local toxicity in rats was examined by assessing protein and phospholipid release as biological markers. Of the absorption enhancers, sodium deoxycholate, EDTA and N-lauryl-β-D-maltopyranoside were the most effective; sodium deoxycholate and EDTA, however, caused significant release of protein and phospholipids. N-lauryl-β-D-maltopyranoside, on the other hand, did not damage the small intestinal membrane. Sodium taurocholate enhanced phenol red absorption from the small intestine and resulted in little or no protein and phospholipids release. Sodium salicylate, diethyl maleate and the mixed micelles had no absorption-promoting effects on phenol red. There was good correlation between the area under the plasma concentration-time curve for phenol red and the amounts of protein and phospholipid released in the presence of absorption enhancers. From these results it might be concluded that N-lauryl-β-D-maltopyranoside and sodium taurocholate are effective absorption enhancers which have low toxicity levels at a concentration of 20 mM.     

不同透皮吸收促进剂对黄绵马酸BB乳膏体外透皮吸收的影响

目的:研究不同透皮吸收促进剂对黄绵马酸BB乳膏体外透皮吸收的影响。方法:分别制备含1%氮酮、2%氮酮、3%氮酮、4%氮酮、1%薄荷醇、1%丙二醇、1%油酸、1%氮酮+1%薄荷醇、1%氮酮+1%丙二醇、1%氮酮+1%油酸、1%薄荷醇+1%丙二醇等11种不同透皮吸收促进剂的黄绵马酸BB乳膏。采用改良Franz扩散池,以离体雄性大鼠腹部皮肤为透皮屏障,通过超高效液相色谱法测定接受液中黄绵马酸BB含量,并计算24 h内的单位面积累积透过量(Q_24h)和经皮渗透速率(J_ss);同时与无透皮吸收促进剂的黄绵马酸BB乳膏进行比较,计算增渗比(ER)。结果:含上述11种透皮吸收促进剂的黄绵马酸BB乳膏的Q_24h分别为(82.96±7.15)、(80.17±0.66)、(78.22±1.87)、(73.53±1.24)、(35.65±2.23)、(34.02±1.73)、(42.68±2.66)、(33.94±1.37)、(34.16±1.54)、(46.78±1.21)、(43.66±1.69)μg/cm²,Jss...     

不同促渗剂对马钱子碱贴剂体外透皮吸收的影响

目的:研究不同促渗剂对马钱子碱贴剂体外透皮促渗作用的影响.方法:采用不同浓度、不同种类促渗剂制备马钱子碱贴剂;采用改良Franz扩散池,以离体雄性大鼠皮肤为模型,通过高效液相色谱法测定药物浓度,拟合马钱子碱透皮吸收的累积透过量和透过速率.结果:以3%氮酮制备的马钱子碱贴剂具有较好的体外透过速率及累积透过量;促渗剂合用时...     

Effects of Dimethylformamide and L-Menthol Permeation Enhancers on Transdermal Delivery of Quercetin

In this work a feasibility study of transdermal delivery system for quercertin (Q) in carbopol gel through abdominal hairless pig skin in vitro was performed. Dimethylformamide (DMF) and L-menthol (M) were selected as enhancers. Permeation experiences were carried out by using Franz-type diffusion cells. Phosphate saline buffer (pH 7.4) was used in the receptor compartments. All the system was maintained at 32 ± 0.5°C with a circulating water jacket and magnetic stirring (180 rpm). Samples were analysed by UV-VIS spectrophotometer at 255 nm. Flux (J_m) values, permeation (P) and diffusion (D) coefficients were obtained. Results of Q in CG permeation experiences with different percentages of DMF and M showed that 16.7% DMF and 1.95% L-menthol enhancers were the best quantities for the system tested. Enhancer effect can be attributed to direct action on membrane structure by promoting its distension. Therefore, enhancer substitutes for water in pores, improving active principal permeation through pig skin. M significantly increases Q permeation about 17 times higher than control. The results of permeation experiments with M and DMF using the same enhancer concentration (1.42%) conclude that M action is 9 times higher than DMF, approximately, indicating that M is an effective enhancer for a transdermal therapeutic system of Q in CG as vehicle.     

不同透皮促进剂对双氯芬酸钾凝胶体外透皮效果的影响研究

目的:考察氮酮(Azone)、丙二醇(PG)、油酸(OA)3种透皮促进剂一元、二元、三元联合对双氯芬酸钾凝胶的体外促透作用。方法:配制以下13种含不同透皮促进剂的双氯芬酸钾凝胶处方:空白,3%Azone,5%OA,12%PG,6%PG+2.5%OA,12%PG+5%OA,1.5%Azone+2.5%OA,1.5%Azone+6%PG+5%OA,1.5%Azone+12%PG,3%Azone+5%OA,3%Azone+6%PG,3%Azone+6%PG+5%OA,3%Azone+12%PG,以透皮速率J等为指标,采用改良的Franz扩散池,以离体人皮肤为透皮屏障,测定并计算双氯芬酸钾凝胶加入上述不同透皮促进剂处理后药物的透皮性能。结果:与空白组比较,其它各组J值均升高,其中以3%Azone+12%PG组的J值最高,达10.253 0μg.cm-2.h-1。结论:3种透皮促进剂对双氯芬酸钾凝胶均有不同程度促透效果,但以Azone和PG二元联用效果最佳。     

Effects of Penetration Enhancers on the In-vitro Percutaneous Absorption of Progesterone

Because progesterone seems suitable for treatment of premenstrual syndrome, the influence of penetration enhancers such as propylene glycol, urea and laurocapram (Azone) on the percutaneous absorption of progesterone from carbopol hydroalcoholic gels and from poly(ethylene glycol) ointments has been investigated. Skin experiments were performed using excized abdominal rat and porcine skin. Addition of 10% laurocapram was found to be the most efficient enhancer for progesterone from carbopol hydroalcoholic gels, for both rat and porcine skin; the next most efficient enhancer was urea in poly(ethylene glycol) bases. This enhanced the diffusion rates 2.5 fold, compared with pure poly(ethylene glycol) alone. The results show that hydroalcoholic gels and poly(ethylene glycol) ointments are both suitable vehicles for progesterone and that premenstrual syndrome might be treated effectively by use of hydroalcoholic gels containing 10% laurocapram.     

Absorptive-Mediated Endocytosis of an Adrenocorticotropic Hormone (ACTH) Analogue,Ebiratide, into the Blood–Brain Barrier: Studies with Monolayers of Primary Cultured Bovine Brain Capillary Endothelial Cells

The internalization of a neuromodulatory adrenocorticotropic hormone (ACTH) analogue, [¹²⁵I]ebiratide (H-Met(O₂)-Glu[¹²⁵I]His-Phe-D-Lys-Phe-NH(CH₂)₈NH₂), was examined in cultured mono-layers of bovine brain capillary endothelial cells (BCEC). HPLC analysis of the incubation solution showed that [¹²⁵I]ebiratide was not metabolized during the incubation with BCEC. The acid-resistant binding of [¹²⁵I]ebiratide to BCEC increased with time for 120 min and showed a significant dependence on temperature and medium osmolarity. Pretreatment of BCEC with dansylcadaverine or phenylarsine oxide, endocytosis inhibitors, and 2,4-dinitrophenol, a metabolic inhibitor, decreased significantly the acid-resistant binding of [¹²⁵I]ebiratide. The acid-resistant binding of [¹²⁵I]ebiratide was saturable in the presence of unlabeled ebiratide (100 nM–1 mM). The maximal internalization capacity (B _max) at 30 min was 7.96 ± 3.27 µmol/mg of protein with a half-saturation constant (K _d) of 15.9 ± 6.4 µM. The acid-resistant binding was inhibited by basic peptides such as poly-L-lysine, protamine, histone, and ACTH but was not inhibited by poly-L-glutamic acid, insulin, or transferrin. These results confirmed that ebiratide is transported through the blood-brain barrier via an absorptive-mediated endocytosis.     

促渗剂对司来吉兰贴片透皮性能的影响

目的:考察不同质量分数的氮酮、油酸和肉豆蔻酸异丙酯3种促渗剂对司来吉兰贴片经离体豚鼠皮渗透性的影响。方法:采用Franz扩散池进行体外经皮渗透试验,利用高效液相色谱法为浓度测定方法,以不含促渗剂的司来吉兰贴片为对照计算氮酮、油酸和肉豆蔻酸异丙酯的增渗比及表观扩散系数比较促渗剂渗透效果。结果:与对照组比较,质量分数为3%的3种促渗剂增渗倍数分别为1.53、1.37和1.26,表观扩散系数分别增至2.37、1.65、1.13倍。结论:3种促渗剂均可提高司来吉兰贴片的透皮性能,其中以3%氮酮的促渗效果较好。     

透皮促渗剂对醋酸地塞米松壳聚糖凝胶透皮特性的影响

目的观察透皮促渗剂对醋酸地塞米松壳聚糖凝胶透皮特性的影响。方法实验分为无促渗剂组和促渗剂组。无促渗剂组为0.75%药物5%壳聚糖凝胶剂;促渗剂组根据含促渗剂不同又分为月桂氮酮+丙二醇、月桂氮酮、丙二醇+二甲亚砜、二甲亚砜+月桂氮酮组。以无毛大鼠皮肤为渗透屏障,进行体外渗透实验,分析该凝胶稳态透皮速率（Js）和Js提高率。结果无促渗剂组①Js为（3.75±0.56） μg•（cm2） 1•h 1。促渗剂组效果明显,其中二甲亚砜+月桂氮酮组②Js为（8.12±0.58） μg•（cm2） 1•h 1,月桂氮酮+丙二醇组③Js为（5.41±0.74） μg•（cm2） 1•h 1,丙二醇+二甲亚砜组④Js为（4.31±0.42） μg•（cm2） 1•h 1,月桂氮酮组⑤Js为（4.35±0.36） μg•（cm2） 1•h 1。与①比较,②的Js提高率为2.17%（P＜0.01）,与③④⑤比较,②的Js分别为1.51,1.89,1.87倍（P＜0.05或P＜0.01）。结论混合促渗剂具有比单一促渗剂更好的促渗效果。     

促渗剂促进氨氯地平凝胶剂透皮作用的研究

目的 :研究促渗剂对氨氯地平凝胶剂透皮作用的影响。方法 :采取简单小室法 ,用离体小鼠皮肤进行体外透皮扩散试验 ,计算含不同促渗剂的 2 %氨氯地平凝胶的累积渗透量Q及渗透速率k。结果 :1%～ 5 %薄荷脑、1%～ 5 %氮酮对 2 %氨氯地平凝胶的累积渗透量Q及渗透速率k均显著地提高 (P <0 0 1) ;10 %～ 30 %丙二醇显著地降低 2 %氨氯地平凝胶的Q与k值 (P <0 0 1) ,并明显抑制薄荷脑、氮酮的促渗作用 ;薄荷脑与氮酮的联用则无联合增效作用。结论 :提示薄荷脑、氮酮可作为促渗剂在氨氯地平凝胶剂中单独使用     

Effects of Proteolytic Enzyme Inhibitors on the Nasal Absorption of Vasopressin and an Analogue

Proteolytic enzyme inhibitors were examined as absorption enhancers for the nasal delivery of vasopressin (AVP) and desmopressin (l-d-8-DAVP) in rats. Aprotinin, soybean trypsin inhibitor, and camostat mesilate were used as enzyme inhibitors. The nasal absorption of AVP and l-d-8-DAVP was evaluated by measuring its antidiuretic effect. Nasal administration of AVP (0.005 IU/kg) or l-d-8-DAVP alone (2.5 ng/kg) produced a small antidiuretic effect. Coadministration with aprotinin (1000 and 10000 KIU/kg) or soybean trypsin inhibitor (1.25 and 6.25 mM) did not change the antidiuretic effect. However, coadministration with camostat mesilate (1 to 50 mM) significantly increased the antidiuretic effect and, thus, the nasal absorption of AVP and l-d-8-DAVP. The activities of aminopeptidase, cathepsin-B, and trypsin in the nasal mucosal tissue of rats were 7 nmol/min/mg protein, 0.7 nmol/min/mg protein, and 4.6 pmol/min/mg protein, respectively. Aprotinin and soybean trypsin inhibitor inhibited only the trypsin activity, whereas camostat mesilate inhibited aminopeptidase and trypsin activities. Aprotinin (MW 6500) and soybean trypsin inhibitor (MW 8000), with relatively high molecular weights, may not permeate into the nasal mucosal tissue. In contrast, camostat mesilate is slowly absorbed (8%/hr) and could inhibit the proteolytic activity in the nasal mucosa, resulting in enhanced nasal absoprtion of AVP and l-d-8-DAVP.     

Effects of Enantiomer and Isomer Permeation Enhancers on Transdermal Delivery of Ligustrazine Hydrochloride

Enantiomers and isomers, such as D-limonene, L-limonene, and α-terpinene, were selected as enhancers. The effects and mechanisms of penetration enhancers on in vitro transdermal delivery of ligustrazine hydrochloride (LH) across hairless porcine dorsal skin were investigated. Transdermal fluxes of LH through porcine skin were determined in vitro by Franz-type diffusion cells. D-limonene, L-limonene, and α-terpinene could significantly promote the transdermal fluxes of LH, but no statistical difference (p > 0.05) between them was found. The lag time of L-limonene and α-terpinene were 2.55 and 2.20 times compared with that of D-limonene. Fourier transform-infrared (FTIR) was carried out to analyze the effects of enhancers on the biophysical natures of the stratum corneum (SC) and the permeation enhancement mechanism. FTIR spectra revealed that the changes of peak shift and peak area due to C-H stretching vibrations in the SC lipids were associated with the selected enhancers. All of them could perturb and extract the SC lipids to different extent and L-limonene showed obvious changes. Morphological changes of the skin treated with enhancers were monitored by a scanning electron microscope (SEM). The extraction of the SC lipids by the enhancers led to the disruption of SC and the desquamated SC flake. Apparent density (AD) was newly proposed to estimate the desquamated extent of SC flake. The results showed that the enantiomers and isomers enhanced the permeation of LH by pleiotropic mechanisms.     

渗透促进剂对盐酸普萘洛尔经皮渗透的影响

目的:研究常用渗透促进剂对盐酸普萘洛尔经皮渗透的影响。方法:采用改良Franz扩散池,以0.9%氯化钠溶液作为接收液,以增渗倍数(ER)为考察指标,考察1%、3%、5%水溶性氮酮溶液,1%、3%、5%油溶性氮酮溶液,1%水溶性氮酮丙二醇溶液,5%、10%油酸溶液,丙二醇等10种渗透促进剂对盐酸普萘洛尔透过离体大鼠腹部皮肤的影响。结果:渗透促进效果分别为3%油溶性氮酮溶液>10%油酸溶液>1%水溶性氮酮丙二醇溶液>5%油溶性氮酮溶液>1%水溶性氮酮溶液>3%水溶性氮酮溶液>1%油溶性氮酮溶液>5%水溶性氮酮溶液>5%油酸溶液>丙二醇。结论:油溶性渗透促进剂对盐酸普萘洛尔的经皮渗透促进作用有强于水溶性渗透促进剂的趋势。     

不同促渗剂对蛇床子软膏透皮吸收特性的影响

目的考察不同促渗剂对蛇床子软膏透皮吸收的影响。方法采用改良Franz扩散池,以离体裸鼠皮肤为屏障,考察氮酮、油酸和高良姜油等不同种类的促渗剂对蛇床子软膏的累积渗透量、渗透吸收速率、增渗倍数等参数的影响。结果几种促渗剂对蛇床子软膏的透皮吸收均有较好的促进作用,其中以3%高良姜油效果最佳。结论高良姜油对蛇床子素经皮吸收具有显著的促进作用,为蛇床子经皮给药制剂处方设计和新药开发提供了依据。     

Absorption Barriers in the Rat Intestinal Mucosa. 3: Effects of Polyethoxylated Solubilizing Agents on Drug Permeation and Metabolism

Modern drug discovery chemical libraries contain a large number of molecular entities exhibiting low aqueous solubility, often necessitating the inclusion of solubilizing agents in preclinical models of absorption or metabolism. The objective of the present study was to investigate the effects of several commonly used polyethoxylated solubilizing agents on P450 (CYP) 3A and P-glycoprotein (P-gp) in the rat intestinal mucosa. Atenolol and verapamil were administered in the in situ perfused rat intestine or incubated with rat intestinal microsomes in the presence or absence of polyethylene glycol (PEG) 400 (2% or 20%, v/v) D-α-tocopheryl polyethylene glycol-1000 succinate (TPGS; 100 µg/mL), Cremophor EL® (47.5 µg/mL) or polysorbate (Tween) 80 (25 µg/mL). Effects on the absorption of unchanged drug were minimal, with the exception of Tween 80 which caused a 5.0-fold increase in paracellular absorption. Rat intestinal CYP3A was significantly inhibited by PEG-400 and in situ, exceeded inhibition observed with ketoconazole. Cremophor and TPGS increased the fraction of norverapamil in the plasma, consistent with excipient-mediated inhibition of P-gp. These results suggest that caution be exercised when these solubilizing agents are included in preclinical oral dosing solutions as the perturbation of drug absorption barriers may heighten the risk of incorrectly classifying drug candidate PK-parameters. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1016–1027, 2010