Investigation into the mechanism by which cyclodextrins influence transdermal drug delivery

The objective of this study was to investigate the mechanism by which hydroxypropyl-beta-cyclodextrin (HPCD) increases transdermal permeation. Hairless mouse skin was pretreated with HPCD solutions for up to 4 h. After removing the HPCD, corticosteroid-containing suspensions were applied and the transdermal flux and skin accumulation of two model drugs were investigated. After pretreatment, changes to the stratum corneum endothermic melting transitions were determined as an indication of HPCD-induced lipid disorganization. Results demonstrated that HPCD pretreatment had no significant effect on the transdermal permeation or skin accumulation of the model corticosteroids. These findings suggest that HPCD functions to enhance the apparent solubility of the drug in the formulation, thus increasing transdermal permeation rather than extracting lipids from the skin.     

Influence of hydroxypropyl-beta-cyclodextrin on the transdermal permeation and skin accumulation of oxybenzone

The objective of the present study was to determine the effects of hydroxypropyl-β-cyclodextrin (HPCD) concentration on the transdermal permeation and skin accumulation of a model ultraviolet (UV) absorber, oxybenzone. The concentration of oxybenzone was held constant at 2.67 mg/mL for all formulations, while the HPCD concentrations varied from 0 to 20% (w/w). Complexation of oxybenzone by HPCD was demonstrated by differential scanning calorimetry. A modified Franz cell apparatus was used in the transdermal experiments, with aliquots of the receptor fluid assayed for oxybenzone by high-performance liquid chromatography. From the permeation data, flux of the drug was calculated. Skins were removed from the diffusion cells at specified time points over a 24-hr period and the oxybenzone content in the skin determined. The aqueous solubility of oxybenzone increased linearly with increasing HPCD concentration, following a Higuchi A_L-type complexation. The stability constant of the reaction was calculated from the phase-solubility diagram and found to be 2047 M^-1. As the concentration of HPCD was increased from 0 to 10%, transdermal permeation and skin accumulation of oxybenzone increased. Maximum flux occurred at 10% HPCD, where sufficient cyclodextrin was added to completely solubilize all oxybenzone. When the concentration of HPCD was increased to 20%, both transdermal permeation and skin accumulation decreased. These data suggest the formation of a drug reservoir on the surface of the skin.     

Influence of Hydroxypropyl- β-Cyclodextrin on the Transdermal Permeation and Skin Accumulation of Oxybenzone

ABSTRACT

The objective of the present study was to determine the effects of hydroxypropyl-β-cyclodextrin (HPCD) concentration on the transdermal permeation and skin accumulation of a model ultraviolet (UV) absorber, oxybenzone. The concentration of oxybenzone was held constant at 2.67 mg/mL for all formulations, while the HPCD concentrations varied from 0 to 20% (w/w). Complexation of oxybenzone by HPCD was demonstrated by differential scanning calorimetry. A modified Franz cell apparatus was used in the transdermal experiments, with aliquots of the receptor fluid assayed for oxybenzone by high-performance liquid chromatography. From the permeation data, flux of the drug was calculated. Skins were removed from the diffusion cells at specified time points over a 24-hr period and the oxybenzone content in the skin determined. The aqueous solubility of oxybenzone increased linearly with increasing HPCD concentration, following a Higuchi A_L-type complexation. The stability constant of the reaction was calculated from the phase-solubility diagram and found to be 2047 M^?1. As the concentration of HPCD was increased from 0 to 10%, transdermal permeation and skin accumulation of oxybenzone increased. Maximum flux occurred at 10% HPCD, where sufficient cyclodextrin was added to completely solubilize all oxybenzone. When the concentration of HPCD was increased to 20%, both transdermal permeation and skin accumulation decreased. These data suggest the formation of a drug reservoir on the surface of the skin.     

Improvement in Transdermal Bioavailability of Nitroglycerin by Formulation Design

Controlled skin permeation kinetics of nitroglycerin delivered by the three once-a-day transdermal therapeutic systems was recently evaluated and compared using the freshly excised hairless mouse abdominal skin mounted in a finite-dosing Frantz diffusion cell assembly. The kinetics of skin permeation from the conventional ointment formulation was also studied using the same in vitro skin permeation system.

Six experimental formulations of nitroglycerin were developed, aiming to enhance the permeation rate of nitroglycerin through intact skin. The kinetics of skin permeation of nitroglycerin from these experimental formulations was also investigated, using the same in vitro skin permeation system, and compared to the conventional ointment formulation as well as the newly marketed once-a-day transdermal therapeutic systems. Results indicated that the rates of skin permeation can be greatly improved by proper formulation design.     

The Enhanced Iontophoretic Transport of TRH and Its Impedance Study

The transdermal drug delivery of iontophoresis provides a noninvasive method for the administration of effective drugs. The enhanced iontophoretic transport of thyrotropin-releasing hormone (TRH), a tripeptide with molecular weight of 362 and a pK_a of 6.2, through an excised rabbit skin has been achieved by in vitro iontophoresis. The results indicate that the steady-state flux of TRH in a diffusion cell is proportional to the current density. In addition, the electrochemical properties of rabbit skin were studied with impedance spectroscopy, and it was found that the skin impedance decreased to a low and stable value with respect to its initial skin impedance while a current was applied through the rabbit skin. This is in good agreement with our experimental results on iontophoretic transport. As compared to passive diffusion, the iontophoresis dramatically increased the transport fluxes of TRH, and ethanol pretreatment further enhanced its iontophoretic transport. A practical implication of these results is that iontophoresis with a chemical permeation enhancer (ethanol pretreatment) can be applied to enhance and control the transdermal delivery of peptides.     

Improvement in Transdermal Bioavailability of Nitroglycerin by Formulation Design

Abstract

Controlled skin permeation kinetics of nitroglycerin delivered by the three once-a-day transdermal therapeutic systems was recently evaluated and compared using the freshly excised hairless mouse abdominal skin mounted in a finite-dosing Frantz diffusion cell assembly. The kinetics of skin permeation from the conventional ointment formulation was also studied using the same in vitro skin permeation system.

Six experimental formulations of nitroglycerin were developed, aiming to enhance the permeation rate of nitroglycerin through intact skin. The kinetics of skin permeation of nitroglycerin from these experimental formulations was also investigated, using the same in vitro skin permeation system, and compared to the conventional ointment formulation as well as the newly marketed once-a-day transdermal therapeutic systems. Results indicated that the rates of skin permeation can be greatly improved by proper formulation design.     

The Enhanced Iontophoretic Transport of TRH and Its Impedance Study

Abstract

The transdermal drug delivery of iontophoresis provides a noninvasive method for the administration of effective drugs. The enhanced iontophoretic transport of thyrotropin-releasing hormone (TRH), a tripeptide with molecular weight of 362 and a pK_a of 6.2, through an excised rabbit skin has been achieved by in vitro iontophoresis. The results indicate that the steady-state flux of TRH in a diffusion cell is proportional to the current density. In addition, the electrochemical properties of rabbit skin were studied with impedance spectroscopy, and it was found that the skin impedance decreased to a low and stable value with respect to its initial skin impedance while a current was applied through the rabbit skin. This is in good agreement with our experimental results on iontophoretic transport. As compared to passive diffusion, the iontophoresis dramatically increased the transport fluxes of TRH, and ethanol pretreatment further enhanced its iontophoretic transport. A practical implication of these results is that iontophoresis with a chemical permeation enhancer (ethanol pretreatment) can be applied to enhance and control the transdermal delivery of peptides.     

Development of a Skin Permeation cell to Simulate Clinical Study of Iontophoretic Transdermal Delivery

A new single-compartment iontophoretic skin permeation cell was developed to simulate the clinical application of iontophoretic devices. The stability and permeation kinetics of LHRH, the model peptide, were investigated in this new permeation cell (cell design A) using two analytical methods and compared with a commonly used skin permeation cell (cell design B). A polyacrylamide-based hydrogel device was fabricated as the drug reservoir for the iontophoretic transdermal delivery of LHRH. The skin permeation profiles of LHRH were found identical for both permeation cells when assayed by radioactivity measurement. However, cell design A gave a skin permeation profile that was substantially higher than that obtained in cell design B when assayed by HPLC. This is because the electrochemical degradation of LHRH occurred in the receptor compartment of the Valia-Chien permeation cell (cell design B). This degradation could be overcome by using the new single-compartment iontophoretic permeation cell.     

Development of matrix patches for transdermal delivery of a highly lipophilic antiestrogen

The aim of this study was to develop matrix-type transdermal systems (TDSs) containing the highly lipophilic (log P = 5.82) antiestrogen (AE) and the permeation enhancers propylene glycol and lauric acid. For that purpose, permeation of AE from various adhesive matrices through excised skin of hairless mice was evaluated. It was found that pretreatment of the skin with permeation enhancers raised the transdermal flux of subsequently applied antiestrogen. Highest steady-state transdermal fluxes (1.1 µg cm^-2 h^-1) were obtained from Gelva®, polyacrylate adhesive, followed by 0.55 µg cm^-2 h^-1 from Oppanol® polyisobutylene, 0.31 µg cm^-2 h^-1 from BIO-PSA® silicone, and 0.12 µg cm^-2 h^-1 from Sekisui polyacrylate matrices. In order to develop TDS with high content of fluid permeation enhancer propylene glycol, two different strategies were investigated. One strategy was the addition of hydroxypropyl cellulose (HPC) as thickening agent to Gelva matrices. This allowed for propylene glycol loading levels of up to 30%, resulting in transdermal AE fluxes of 0.09 µg cm^-2 h^-1. On the other hand, a fleece-laminated backing foil was loaded with the described permeation enhancer formulation and laminated with polyacrylate adhesive layer, resulting in transdermal AE fluxes of 0.06 µg cm^-2 h^-1. However, application of these TDSs on skin pretreated with permeation enhancers raised the fluxes to 2.6 µg cm^-2 h^-1 from Gelva/HPC and 0.46 µg cm^-2 h^-1 from fleece/Sekisui.     

人体组织液的微创透皮抽取技术

对人体组织液的微创透皮抽取技术进行了研究.首先对皮肤进行低频超声预处理,提高皮肤表层对组织液的通透性,然后利用文氏管真空负压实现组织液的抽取、收集和输运.搭建了低频超声皮肤预处理系统,设计了基于文氏管的真空负压一体化装置,研究了组织液透皮抽取效果的评价方法.通过实验验证了组织液的抽取效果,研究了抽取时机、抽取频率对组织液渗透速率的影响,验证了文氏管真空负压作为组织液抽取、收集和输运驱动力的作用效果,研究了利用真空负压控制液体输运速度的方法.研究成果在微创血糖监测技术中具有重要的应用价值.     

Transdermal Dual-Controlled Delivery of Testosterone and Estradiol: (I) Impact of system Design

Abstract

A multilaminate-type transdermal drug delivery (m-TDD) system was designed with the objective of delivering testosterone and estradiol simultaneously but at different daily dosage rates. To achieve such a dual-controlled transdermal delivery, skin permeation enhancer and permselective membrane were incorporated into the system. The results demonstrated that skin permeation enhancer, which is incorporated into the testosterone reservoir layer, and permselective membrane, which is added onto the drugreleasing surface of estradiol reservoir layer, can both alter the overall rate of skin permeation for both drugs. The skin permeation enhancer was observed to enhance the skin permeation rate of testosterone, while the permselective membrane was shown to reduce the skin permeation rate of estradiol. The addition of permselective membrane was observed to modify the release kinetics of estradiol from the matrix diffusion-controlled drug delivery to membrane permeation-controlled drug delivery. Other factors which may affect the deliver rate of drug, e.g., the thickness of permselective membrane and loading dose of drugs, were also studied. Furthermore, evaluation of physical stability of this mTDD system demonstrated that the inter-layer migration of drugs is at minimum.     

Transdermal Dual-Controlled Delivery of Testosterone and Estradiol: (I) Impact of system Design

A multilaminate-type transdermal drug delivery (m-TDD) system was designed with the objective of delivering testosterone and estradiol simultaneously but at different daily dosage rates. To achieve such a dual-controlled transdermal delivery, skin permeation enhancer and permselective membrane were incorporated into the system. The results demonstrated that skin permeation enhancer, which is incorporated into the testosterone reservoir layer, and permselective membrane, which is added onto the drugreleasing surface of estradiol reservoir layer, can both alter the overall rate of skin permeation for both drugs. The skin permeation enhancer was observed to enhance the skin permeation rate of testosterone, while the permselective membrane was shown to reduce the skin permeation rate of estradiol. The addition of permselective membrane was observed to modify the release kinetics of estradiol from the matrix diffusion-controlled drug delivery to membrane permeation-controlled drug delivery. Other factors which may affect the deliver rate of drug, e.g., the thickness of permselective membrane and loading dose of drugs, were also studied. Furthermore, evaluation of physical stability of this mTDD system demonstrated that the inter-layer migration of drugs is at minimum.     

Enhancement of Percutaneous Absorption of Propranolol Hydrochloride by Iontophoresis

Iontophoresis is defined as the migration of ions when an electric current passes through a solution containing ionized species. When applied transdermally, iontophoresis may reduce the barrier porperties of skin and may enhance the transdermal permeation of drugs. This research work was aimed at exploring the factors which influence the effectiveness of iontophoresis facilitated transport of ionized species across the skin, and comparing it with that by passive diffusion. Propranolol hydrochloride was selected as the model drug, and rat abdominal skin as the in-vitro animal model. Pulse dc was applied, at 2.16/3/6/9 mA/cm²; 1:1 or 4:1 duty cycle and 20 KHz frequency for 15/25 minutes. Factors which modify the iontophoretic drug delivery, such as drug concentration, current density, duty-cycle of pulse dc, and duration of iontophoresis, were also evaluated. It was found that iontophoresis causes a significant increase in transdermal permeation of Propranolol hydrochloride in-vitro through rat abdominal skin, as compared to that by passive diffusion.     

Mechanism of Transdermal Controlled Nitroglycerin Administration (II) Assessment of Rate-Controlling Steps

The mechanisms and the rates of skin permeation of nitroglycerin delivered by four transdermal therapeutic systems were investigated using hairless mouse skin mounted on a newly-developed and well-calibrated Keshary-Chien skin permeation system. Experiments were carried out to identify and characterize the rate-controlling roles of stratum corneum, controlled-release drug delivery system and dermal solution sink in the transdermal controlled administration of nitroglycerin.     

Effect of borneol on the transdermal permeation of drugs with differing lipophilicity and molecular organization of stratum corneum lipids

The aim of the present paper was to investigate the promoting activity of borneol on the transdermal permeation of drugs with differing lipophilicity, and probe its alterations in molecular organization of stratum corneum (SC) lipids. The toxicity of borneol was evaluated in epidermal keratinocyte HaCaT and dermal fibroblast CCC-HSF-1 cell cultures and compared to known enhancers, and its irritant profile was also assessed by transepidermal water loss (TEWL) evaluation. The promoting effect of borneol on the transdermal permeation of five model drugs, namely 5-fluorouracil, antipyrine, aspirin, salicylic acid and ibuprofen, which were selected based on their lipophilicity denoted by logp value, were performed using in vitro skin permeation studies. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to monitor the borneol-induced alteration in molecular organization of SC lipids. The enhancer borneol displayed lower cytotoxicity or irritation in comparison to the well-established and standard enhancer Azone. Borneol could effectively promote the transdermal permeation of five model drugs, and its enhancement ratios were found to be parabolic curve with the logp values of drugs, which exhibited the optimum permeation activity for relatively hydrophilic drugs (an estimated logp value of??0.5 ～0.5). The molecular mechanism studies suggested that borneol could perturb the structure of SC lipid alkyl chains, and extract part of SC lipids, resulting in the alteration in the skin permeability barrier.     

Effect of Penetration Enhancers on Transdermal Absorption of Insulin Across Human Cadaver Skin

The transdermal diffusion of insulin, a model polypeptide drug, across the human cadaver skin (HCS) was evaluated in vitro, in presence of penetration enhancing solvents, anionic surfactants, biosurfactants, a natural moisturizing agent and combinations thereof. Also, an attempt was made to relate the enhanced penetration to physical parameters like distribution coefficient, surface tension and viscosity. The results of the permeation experiments indicate that the permeation enhancers used in the present investigation significantly enhance the amount of drug entering into the HCS and the amount reaching to the skin. A synergistic effect on permeation enhancement was observed in cases where combination of permeation enhancers were selectively used. Reasons for this synergism were critically examined and established.     

Mechanism of Transdermal Controlled Nitroglycerin Administration (II) Assessment of Rate-Controlling Steps

Abstract

The mechanisms and the rates of skin permeation of nitroglycerin delivered by four transdermal therapeutic systems were investigated using hairless mouse skin mounted on a newly-developed and well-calibrated Keshary-Chien skin permeation system. Experiments were carried out to identify and characterize the rate-controlling roles of stratum corneum, controlled-release drug delivery system and dermal solution sink in the transdermal controlled administration of nitroglycerin.     

The effects of pressure-sensitive adhesives and solubilizers on the skin permeation of testosterone from a matrix-type transdermal delivery system

Matrix-type transdermal delivery systems of testosterone (TS) were formulated with three different pressure-sensitive adhesives (PSA). The effects of PSA, skin permeation enhancers, and solubilizers on the rat skin permeation rate of TS were systematically investigated. Without a solubilizer, the skin permeation rate of TS reached its maximum value when only 2% of TS was loaded in the matrix and the crystal formation in the matrix was very rapid and severe. Two surfactants differing in their hydrophile-lipophile balance (HLB) number were, therefore, considered. Span 80, which was of the lower HLB number, was more effective than Tween 80 in increasing the solubility, and thereby increasing the permeation rate of TS. Moreover, the concentrations of both the solubilizer and the skin permeation enhancer affected the skin permeation rate. Thus, the highest skin permeation rate (4.14 µg/cm²/hr) was achieved when 2% TS was loaded in DuroTak® 87-2516 together with 10% Span 80 and 3% dodecylamine, the permeation enhancer. In vivo study showed that the application of an experimental patch on rat abdominal skin resulted in a prompt and significantly higher plasma concentration of TS than that of a commercial product (Testoderm®) designed to apply on the scrotal skin. The area under the curve (AUC) increased linearly as the loading dose of TS increased up to 6%. Thus, based on these results, a non-scrotal matrix-type transdermal delivery system of TS could be developed.     

The Effects of Pressure-Sensitive Adhesives and Solubilizers on the Skin Permeation of Testosterone from a Matrix-Type Transdermal Delivery System

ABSTRACT

Matrix-type transdermal delivery systems of testosterone (TS) were formulated with three different pressure-sensitive adhesives (PSA). The effects of PSA, skin permeation enhancers, and solubilizers on the rat skin permeation rate of TS were systematically investigated. Without a solubilizer, the skin permeation rate of TS reached its maximum value when only 2% of TS was loaded in the matrix and the crystal formation in the matrix was very rapid and severe. Two surfactants differing in their hydrophile–lipophile balance (HLB) number were, therefore, considered. Span 80, which was of the lower HLB number, was more effective than Tween 80 in increasing the solubility, and thereby increasing the permeation rate of TS. Moreover, the concentrations of both the solubilizer and the skin permeation enhancer affected the skin permeation rate. Thus, the highest skin permeation rate (4.14 µg/cm²/hr) was achieved when 2% TS was loaded in DuroTak® 87-2516 together with 10% Span 80 and 3% dodecylamine, the permeation enhancer. In vivo study showed that the application of an experimental patch on rat abdominal skin resulted in a prompt and significantly higher plasma concentration of TS than that of a commercial product (Testoderm®) designed to apply on the scrotal skin. The area under the curve (AUC) increased linearly as the loading dose of TS increased up to 6%. Thus, based on these results, a non-scrotal matrix-type transdermal delivery system of TS could be developed.     

Effect of Penetration Enhancers on Transdermal Absorption of Insulin Across Human Cadaver Skin

The transdermal diffusion of insulin, a model polypeptide drug, across the human cadaver skin (HCS) was evaluated in vitro, in presence of penetration enhancing solvents, anionic surfactants, biosurfactants, a natural moisturizing agent and combinations thereof. Also, an attempt was made to relate the enhanced penetration to physical parameters like distribution coefficient, surface tension and viscosity. The results of the permeation experiments indicate that the permeation enhancers used in the present investigation significantly enhance the amount of drug entering into the HCS and the amount reaching to the skin. A synergistic effect on permeation enhancement was observed in cases where combination of permeation enhancers were selectively used. Reasons for this synergism were critically examined and established.