Effect of ethanol pretreatment on skin permeation of drugs

It has been demonstrated that ethanol (EtOH) can enhance skin permeation of drugs when simultaneously applied with drugs. However, only a few studies have reported on the pretreatment effect of EtOH on skin permeations. In this study, the pretreatment effects of EtOH on skin permeation of drugs were investigated by measuring changes in skin permeation and electrical skin resistance. Permeabilities of deuterium oxide (D2O), isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), calcein sodium (CA-Na), and fluorescein isothiocyanate-dextran 4?kDa (FD-4, 3.3-4.4?kDa) were evaluated through Yucatan micropig skin pretreated with different concentrations of EtOH solution. From the results, almost constant skin permeabilities of D2O and ISDN were observed independent of EtOH concentration. Skin permeabilities of ISMN, CA, and FD-4 increased with low concentrations of EtOH, but decreased with high concentrations of EtOH. At 99.5% EtOH pretreatment, skin permeabilities of hydrophilic compounds (ISMN, CA, and FD-4) decreased to non-detectable levels. In addition, low molecular ion transports were almost constant at any EtOH concentration. Since molecular (ion) sizes of ISMN, CA, and FD-4 are larger than Na⁺, Cl^－, and D2O, permeation pathway sizes for hydrophilic compounds in the skin barrier may be remarkably decreased by pretreatment with high concentrations of EtOH. However, the permeability coefficient of ISDN was not influenced by any EtOH concentration, since ISDN is a lipophilic, low-molecular compound that permeated through the lipophilic stratum corneum pathway. The present results show useful information for repeatedly and topically applied formulations containing EtOH, and also contribute to the effective use of alcohol formulations.     

Effect of positively and negatively charged liposomes on skin permeation of drugs

To clarify the effect of the surface charge of liposomes on percutaneous absorption, the permeation of liposomal drugs through rat skin was investigated in vitro and in vivo. Liposomes were prepared using egg yolk lecithin (EPC, phase transition temperature, -15 to -17 degrees C), cholesterol and dicetylphosphate (DP) or stearylamine (SA) (10:1:1, mol/mol). Also examined was the penetration behavior of positively and negatively charged liposomes, using a fluorescent probe (Nile Red). The in vitro penetration rate of melatonin (MT) entrapped in negatively charged liposomes was higher than that of positively charged ones (p<0.05). When the percutaneous absorption of ethosuximide (ES) encapsulated was estimated in vivo, the absorption of ES from negatively charged liposomes was slightly higher than that from positively charged liposomes. Additionally, the absorption of ES from both types of liposomes was superior to that from the lipid mixtures consisting of the same composition as the vesicles. The percutaneous absorption of betahistine (BH) from a gel formulation containing negatively charged liposomes of BH was much more than that from the formulation with positively charged ones, with 2-fold higher AUC (p<0.05). Histological studies revealed that the negatively charged liposomes diffused to the dermis and the lower portion of hair follicles through the stratum corneum and the follicles much faster than the positive vesicles at the initial time stage after application. Thus, the rapid penetration of negatively charged liposomes would contribute to the increased permeation of drugs through the skin.     

Effect of pH on skin permeation enhancement of acidic drugs by l-menthol-ethanol system

The effect of pH on the skin permeation enhancement of three acidic drugs by the l-menthol-ethanol system was investigated. The total flux of acidic drugs from the system remarkably varied over the pH range 3.0-8.0, and the permeation enhancement factor depended on the system pH and drug. A skin permeation model, which consists of two permeant (unionized and ionized) species, two system (oily and aqueous) phases, and two permeation (lipid and pore) pathways, was developed. The assumptions were made that only the unionized species can distribute to the oily phase and transport via the lipid pathway. The model explained the relationship between the concentration of drug in the aqueous phase and system pH. The skin permeability data were also described by the model and permeability coefficients corresponding to the physicochemical properties of permeant were calculated for the lipid and pore pathways. The model simulation showed that the permeation of acidic drugs occurred from the aqueous phase and the oily phase acted as a reservoir. Whether the total flux increased with increase of pH was dependent on the lipophilicity of drug. These results suggest that the pH of l-menthol-ethanol system should be given attention to elicit the maximum permeation enhancement.     

Mechanistic and empirical modeling of skin permeation of drugs

The skin forms a barrier to the external environment, maintaining body fluids within our system and excluding harmful substances, while the skin is a site of administration of drugs for topical and systemic chemotherapy. It is an important issue to predict the rate at which drugs or other xenobiotics penetrate the skin. In this article, we review modeling approaches for predicting skin permeation of compounds, including both mechanistic and empirical approaches. Mechanistic approaches can give us much information on understanding of skin permeation of the compounds, such as structure-permeability relationship, contribution of each barrier step, mechanism of penetration enhancers, and in vivo-in vitro relationship. On the other hand, empirical modeling can overcome any inaccuracies of mechanistic models caused by the existence of uncertainties and, therefore, give us better predictions from the practical point of view. Artificial neural networks are being available for empirical modeling of complex skin transport phenomenon.     

Effects of isopropyl palmitate on the skin permeation of drugs

The model penetrants oxaprozin, nimesulide, gliclazide, and ribavirin, because of their different lipophilicities, were selected to assess the enhancing activity of pre-treatment solutions consisting of isopropyl palmitate (IP) in ethanol (5%, 10%, 15%and 20%, w/w, respectively) across excised rat skin using Franz diffusion cells and HPLC detection. All pre-treatment solutions produced a significant increase in the flux and permeation of all four penetrants (p<0.001) and a relationship between penetrant lipophilicity and enhancement effect was observed. The general order of IP effectiveness at concentration was 20%>15%>10%>5% (w/w). The lag-time of drugs did not significantly change except for ribavirin.     

Liposome–skin interactions and their effects on the skin permeation of drugs

The aim of the study was to evaluate the interaction of phospholipid liposomes with skin and stratum corneum lipid liposomes (SCLLs). The influence of phospholipid liposomes on the skin permeability of model drugs was also studied. The transdermal flux of the drugs applied in various phospholipid containing formulations through human epidermis was studied in diffusion chambers. Liposomes in water solutions did not enhance the skin permeability of the drugs, but when ethanol (32% w/v) was present in the donor with EPC (egg yolk lecithin), permeabilities of some model drugs were substantially increased. Confocal microscopy studies revealed that EPC do not penetrate into the skin from water solutions, while from ethanol solutions, EPC penetrates deeply into the stratum corneum. Also, resonance energy transfer between different liposome compositions and the release of calcein from SCLLs showed that interactions between phospholipid liposomes and SCLLs increased with increasing ethanol concentration in the liposome solutions.     

Effect of phosphatidylcholine on skin permeation of indomethacin from gel prepared with liquid paraffin and hydrogenated phospholipid

The effects of hydrogenated and unhydrogenated phosphatidylcholine (HPC, PC) on the permeation of indomethacin (IM) through hairless rat skin were investigated using liquid paraffin (LP) and a gel prepared with LP and hydrogenated soybean phospholipid (HSL). IM solubility at 95 degrees C increased in proportion to the concentration of HPC or PC, whereas solubility at 37 degrees C did not increase with HPC. IM showed no permeation until 10 h from LP without HPC/PC, but permeated at rates of approximately 5 and 10 microg/cm2 within 10 h from LP with HPC and PC, respectively. The permeation from the gel with various formulations (HSL, 15%; PC/HPC, 0-5%; IM, 0.5-2%) was determined. Permeation rates were 1.7-4.8 microg/cm2 per h and were proportional to the skin concentration. Skin concentration was correlated to the release rate from the gel. We concluded that IM was solubilized by phospholipids, high activity in the vehicle led to high partition of IM in skin, and permeation increased due to a high skin concentration.     

The effect of rheological behaviour of a topical anaesthetic formulation on the release and permeation rates of the active compound.

The objective of this study was to investigate the possibility of developing a topical cream that allows maximum release rate of the active compound while having suitable consistency, i.e., sufficient apparent plasticity. A submicron (o/w) emulsion containing a model compound was investigated in the presence and absence of different polymers: sodium carboxymethylcellulose (CMC), Carbopol 934P (C934), polyethylene glycol 400 (PEG400) and polyethylene glycol 4000 (PEG4000). Various concentrations of the polymers were used in order to produce different rheological behaviours. The amount of drug passing through the membrane was measured as a function of time, using static diffusion cells with either Silastic sheeting 500-1 or guinea pig skin as membrane. The emulsion without polymer was used as reference. Rheological measurements were performed, giving the viscosity and the apparent yield stress of the formulations. Furthermore, theoretical values for diffusion coefficients and diffusion pathways were estimated and compared with the experimental data to discuss different diffusion models. Gelling polymers have been shown to produce an increase in the macroviscosity, thus inhibiting the diffusion of the oil droplets in the formulation without affecting the molecular diffusion. However, we suggest that when a compound of limited solubility is emulsified, the intact oil droplets contribute to the transport of the compound through the formulation. Thus, both release and permeation rates are decreased as the apparent yield stress, i.e., the macroviscosity of the formulation, is increased sufficiently by addition of gelling polymers.     

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 N-methyl-2-pyrrolidone on skin permeation of estradiol.

N-Methyl-2-pyrrolidone (NMP) increased the skin permeation of estradiol (E2) in Yucatan micropig epidermis using a modified Franz-type diffusion cell. The addition of NMP significantly increased the fluxes of E2 from water and soybean oil. The flux and skin concentration of E2 were higher from soybean oil than from water and increased with increasing NMP concentrations in soybean oil. Correlation was observed with E2 flux and skin concentration (R(2) = 0.804) NMP enhanced E2 skin permeation because NMP made E2 skin concentration higher. Thus, NMP (10%) was added to the oily gel made by isocetyl isostearate and hydrogenated phospholipid. E2 permeation from the gel without NMP was the same as that from soybean oil suspension. The flux of E2 from the gel with NMP was 0.6 microg/h per cm(2) and might be sufficient for estrogen replacement therapy.     

盐酸尼卡地平凝胶的体外家兔皮肤渗透动力学

目的：研究盐酸尼卡地平（下简称为尼卡地平）凝胶的家兔皮肤渗透,评价月桂氮Zhuo酮的透皮促进作用。方法：采用Ｋeshary-Chien扩散池和高效液相色谱法,测定单位面积皮肤的药物透过量。结果：在月桂氮Ｚhuo酮存在下,尼卡地平的透皮流量增加20．8倍。结论：月桂氮Zhuo酮可作为尼卡地平透皮给药的渗透促进剂。     

青霉素类抗生素皮试药物选用的临床研究

目的探讨青霉素类抗生素使用前的皮试药物选用。方法对1960例住院患者,采用自身对照,先后使用青霉素及青霉素类药物进行皮内注射。具体每例患者均用双敏方法 ：即先用青霉素G钠做皮试,结果为阴性后,再遵医嘱用青霉素类抗生素（以下简称原药）做皮试。结果出现两种情况：A两种药物皮试结果都为阴性;B青霉素G钠皮试结果为阴性,原药皮试结果为阳性。总结B类情况的发生概率。结论建议使用青霉素类抗生素之前,用原药进行皮试更具有科学性,从而能有效降低医疗纠纷发生率。     

离子导入对降纤酶经皮渗透的影响

目的研究离子导入对降纤酶经皮渗透的影响。方法利用水平式扩散池，对降纤酶进行离子导入透过大鼠皮肤和人尸表皮的渗透性试验，对电极极性、渗透介质的pH以及离子强度等影响进行考察。结果离子导入阳极转运时，在pH 6.4的磷酸盐缓冲介质中，降纤酶的表观经皮渗透系数为（1.2±0.4）×10^-4 cm·h^-1，明显高于阴极转运［（4.3±1.4）×10^-5 cm·h^-1］；在pH 7.4磷酸盐缓冲介质中，降纤酶阳极离子导入经皮渗透量为（25±5）×10^-14 mol·cm^-2高于pH 6.4介质经皮渗透量［(15±4)×10^-14 mol·cm^-2］。结论离子导入阳极转运能够促进降纤酶的经皮渗透，电渗作用有重要影响。     

Effect of 1-O-ethyl-3-butylcyclohexanol on the skin permeation of drugs with different physicochemical characteristics

The effects of 1-O-ethyl-3-butylcyclohexanol (OEBC) on the in vitro skin permeation of ten model drugs with different physicochemical properties across excised rat skin were evaluated. The results showed that the addition of OEBC significantly improved the in vitro skin permeation of the model drugs compared with the control (without OEBC). To clarify the promoting mechanism of OEBC, a multiple regression analysis was employed. When the permeation study was performed without OEBC, the permeability coefficient was quantitatively predicted as a linear function of molecular weight (log MW) and their lipophilicity (partition coefficient of drugs between octanol and water (log K(o/w)) with a sufficiently high correlation coefficient (r=0.842). It was suggested that skin permeation of drugs without OEBC was explained as a function of diffusion of drugs through the skin and partitioning of drugs to the skin. Although OEBC was administered, the permeability coefficient of drugs cannot be predicted as a linear function of log MW and log K(o/w) (r=0.572).     

The effects of selected antidepressant drugs on timing behaviour in rats

It has been suggested that the increased reinforcement rate on a differential-reinforcement-of-low-rate of responding (DRL) schedule observed following acute antidepressant administration in the rat is due to an improvement in timing accuracy. The aim of the present work was to evaluate the effects of antidepressants in another schedule that requires accurate estimation of time intervals, the peak procedure. Three antidepressant drugs were tested, the tricyclic antidepressant imipramine (1.0–10.0 mg/kg, IP) and the 5-HT reuptake inhibitors, zimelidine (10.0–40.0mg/kg, IP) and clomipramine (1.0–10.0 mg/kg, IP). For reference, the full benzodiazepine receptor agonist, diazepam (1.0–5.0 mg/kg, IP) and the psychomotor stimulant, d-amphetamine (0.5–1.5 mg/kg, SC) were also tested. All doses of d-amphetamine tested significantly increased lever-pressing rates, whereas all the other compounds induced significant decreases in lever-pressing rates. Overall, the time at which the maximal lever-pressing rate occurred was not altered by any of the compounds, suggesting that timing accuracy was not significantly affected by any of the compounds administered. The only exception was zimelidine (40.0 mg/kg), which reduced the time at which the maximal lever-pressing rate occurred, although lever-pressing rates were also significantly reduced at this dose. These data suggest that previously reported antidepressant-induced improvement in performance on the DRL schedule may not have been due to improved timing accuracy per se but may have been due to a decrease in lever-pressing rates. Received: 5 December 1996/Final version: 17 June 1997     

Effect of liposomes and niosomes on skin permeation of enoxacin

The skin permeation and partitioning of a fluorinated quinolone antibacterial agent, enoxacin, in liposomes and niosomes, after topical application, were elucidated in the present study. In vitro percutaneous absorption experiments were performed on nude mouse skin with Franz diffusion cells. The influence of vesicles on the physicochemical property and stability of the formulations were measured. The enhanced delivery across the skin of liposome and niosome encapsulated enoxacin had been observed after selecting the appropriate formulations. The optimized formulations could also reserve a large amount of enoxacin in the skin. A significant relationship between skin permeation and the cumulative amount of enoxacin in the skin was observed. Both permeation enhancer effect and direct vesicle fusion with stratum corneum may contribute to the permeation of enoxacin across skin. Formulation with niosomes demonstrated a higher stability after 48 h incubation compared to liposomes. The inclusion of cholesterol improved the stability of enoxacin liposomes according to the results from encapsulation and turbidity. However, adding negative charges reduced the stability of niosomes. The ability of liposomes and niosomes to modulate drug delivery without significant toxicity makes the two vesicles useful to formulate topical enoxacin.     

Effect of microneedle treatment on the skin permeation of a nanoencapsulated dye

Objectives The aim of the study was to investigate the effect of microneedle (MN) pretreatment on the transdermal delivery of a model drug (Rhodamine B, Rh B) encapsulated in polylactic‐co‐glycolic acid (PLGA) nanoparticles (NPs) focusing on the MN characteristics and application variables. Methods Gantrez MNs were fabricated using laser‐engineered silicone micro‐mould templates. PLGA NPs were prepared using a modified emulsion–diffusion–evaporation method and characterised in vitro. Permeation of encapsulated Rh B through MN‐treated full thickness porcine skin was performed using Franz diffusion cells with appropriate controls. Key findings In‐vitro skin permeation of the nanoencapsulated Rh B (6.19 ± 0.77 µg/cm²/h) was significantly higher (P < 0.05) compared with the free solution (1.66 ± 0.53 µg/cm²/h). Mechanistic insights were supportive of preferential and rapid deposition of NPs in the MN‐created microconduits, resulting in accelerated dye permeation. Variables such as MN array configuration and application mode were shown to affect transdermal delivery of the nanoencapsulated dye. Conclusions This dual MN/NP‐mediated approach offers potential for both the dermal and transdermal delivery of therapeutic agents with poor passive diffusion characteristics.     

Binding of selected drugs to a "treated" inline filter

The binding of several drugs to an inline i.v. filter that had been treated to inhibit drug-binding was studied. Solutions of mithramycin, vincristine sulfate, digitoxin, insulin, dactinomycin, and nitroglycerin in both 5% dextrose injection and 0.9% sodium chloride injection were allowed to flow through an i.v. administration set containing a 0.22-micron cellulose ester filter that had been treated with a proprietary agent. Actual administration conditions were simulated by using drug concentrations and flow rates commonly employed in clinical practice. The amount of each drug retained by the filter was determined by assaying aliquots of the solutions sampled before and after the solution passed through the filter membrane. In a second experiment, drug binding to the filter membrane was measured by incubating small pieces of the treated membrane in drug solutions and determining concentrations periodically until equilibrium was reached. Untreated filter membrane pieces were used as a control. In the experiment simulating actual i.v. administration, cumulative binding of mithramycin, vincristine sulfate, dactinomycin, and nitroglycerin to the treated filter was less than 6% of the initial dose infused; approximately 8-12% of the initial amounts of digitoxin and insulin were bound to the filter. In the equilibrium binding studies, the untreated filters bound twice as much digitoxin, 5-7 times as much mithramycin, vincristine sulfate, and dactinomycin, and 20 times as much insulin as the treated filters. The amount of nitroglycerin bound to the treated and untreated filters was not substantially different. Insulin had a greater binding tendency in 5% dextrose injection than in 0.9% sodium chloride injection in both experiments regardless of the filter treatment. Treatment of a cellulose ester i.v. filter with the proprietary agent used in this study facilitates drug delivery through this filter.     

Evaluation of excised loach skin for studies on transdermal permeation of drugs in vitro

Transdermal permeation of drug across the excised skin of Asian pond loach (Misgurnus anguillicaudatus Cantor) was studied in vitro. Ten kinds of drugs, D-glucose, L-glucose, sucrose, salicylic acid, cefazolin, urea, antipyrine, naphazoline, propranolol and enviomycin were permeated through the excised loach skin, whereas dextran, a polysaccharide, could not be permeated through the skin. The observed transdermal flux (J), the slope of the line obtained from plots of the cumulative amount of drug permeated vs. time, increased as the drug concentration in the donor compartment solution (50----300 mM), as the temperature of the skin (test solution) increased (4----37 degrees C), or as the molecular weight of compound decreased. These results suggested that the transport of drug across the loach skin was due to the passive diffusion mechanism. The effect of pH on the permeation of drug could not be elucidated since the loach skin was drastically impaired below pH 5.0. The J values of antipyrine and naphazoline varied in proportion to the drug concentration in the donor compartment solution at time zero (C0). The permeability constants (Kp, cm.h-1) of antipyrine and naphazoline were 12.9 x 10(-2) and 9.2 x 10(-2), respectively. However, the J values of salicylic acid and urea were not proportional to C0 in high concentration (300 mM). Probably, these results were related to the irritative effect of salicylic acid or urea on the skin.