Mechanism of Transdermal Controlled Nitroglycerin Administration (III) Control of Skin Permeation Rate and Optimization

A mathematical model was developed to correlate the drug permeation rate through the skin with the drug release rate from a matrix-type drug delivery system. Experiments were carried out using hairless mouse abdominal skin mounted on a recently-developed and hydrodynamically well-calibrated Keshary-Chien skin permeation system. A matrix-type drug delivery system was designed to contain different loading doses of nitroglycerin and to study the effect of drug loading variation on the rate of drug release, the rate of skin permeation and the equilibrium concentration of nitroglycerin in the skin.

Results indicated that the stratum corneum plays a significant rate-limiting role in the skin permeation of nitroglycerin across the intact skin, yielding a constant skin permeation profile. The permeation rate across the intact skin was observed to increase with the increase in the drug release flux initially and then levelled off in a hyperbolic fashion. Various constants were obtained from the reciprocal plot of skin permeation rate vs. drug release flux. These constants could be used for the prediction of the skin permeation rate. A very good correlation between the predicted and the observed values of skin permeation rates was observed.

After the stratum corneum was removed by stripping technique, the mechanism and the rate of skin permeation became dominated by the mechanism and the release rate of the delivery system.

A linear correlation was observed between the drug permeation rate through the skin and the equilibrium concentration of drug in the skin. This correlation was observed in both intact and viable skins.     

Mechanisms of Transdermal Controlled Nitroglycerin Administration (I): Development of a Finite-Dosing Skin Permeation System

A new finite-dosing cell for in vitro skin permeation studies was recently developed to overcome the deficiencies observed in the commercially available Franz diffusion cell and to accomplish the solution hydrodynamics and temperature control required in studying the rate profiles of skin permeation.

Results of comparative studies indicated that the improved diffusion cell, named Keshary-Chien diffusion cell, can achieve and maintain the target body temperature on the skin surface and in the receptor solution, which cannot be accomplished by the Franz diffusion cell. Solution mixing efficiency was substantially improved, so the drug distribution and concentration homogeneity could be achieved in the Keshary-Chien diffusion cell within a duration four times shorter than in the Franz diffusion cell; and a 3-fold reduction in the thickness of the hydrodynamic boundary layer was achieved, so the effect of mass transfer in the hydrodynamic boundary layer on the skin permeation rate profiles was minimized.     

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.     

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.     

Long-Term Permeation Kinetics of Estradiol: (III) Kinetic Analyses of the Simultaneous Skin Permeation and Bioconversion of Estradiol Esters

Abstract

The skin permeation system developed earlier in this laboratory was utilized to study the kinetics of the simultaneous skin permeation and bioconversion of 5 estradiol esters. The equilibrium solubility of estradiol esters in the lipophilic silicone fluid and in hydrophilic PEG 400/saline solution was found to be dependent upon the alkyl chain length of the esters. Estradiol-3,17-diacetate had a greater solubility in silicone fluid and a lower solubility in PEG 400/saline solution than estradiol-17-acetate. The (skin/silicone fluid) partition coefficients were observed to decrease as the alkyl chain increased in length. During the course of skin permeation, the estradiol esters were metabolized by esterase to regenerate estradiol. The rate of appearance of estradiol from the estradiol esters was observed to be dependent upon the ester concentration on stratum corneum surface and to follow the order of: diacetate > valerate > heptanoate > cypionate > acetate. From the dermal uptake and metabolism studies of estradiol esters the first-order rate constants for the metabolism of estradiol esters were determined. The rate constant for the metabolism of estradiol-3,17-diacetate to form estradiol acetate was observed to be about 22 times faster than the rate constant for the metabolism of estradiol acetate to generate estradiol. The enzymatic hydrolysis of the ester group at 17th position was found also to follow a first-order kinetic process and the rate constants varied with the variation in alkyl chain length.     

Transdermal Delivery of Tadalafil. I. Effect of Vehicles on Skin Permeation

Transdermal delivery that avoids the presystemic disposition can provide an alternative to oral administration of tadalafil. Accordingly, the aim of this study was to select the best vehicle as the first step in optimization of tadalafil transdermal delivery. The vehicles were used neat or in selected binary combinations and were evaluated for drug solubilization and transdermal delivery. The drug solubility in pure vehicles were ranked as polyethylene glycol (PEG) 400 >?propylene glycol (PG) >?ethanol >?ethyl oleate (EO) >?isopropyl myristate (IPM) >?water. The solubility in binary systems containing ethanol at 2:1 ratios with EO or IPM was greater than that obtained with pure ethanol, EO, or IPM. This effect could be due to the cosolvency effect. The transdermal drug delivery from pure vehicles was ranked as IPM >?EO >?ethanol >?PG >?PEG >?water. The delivery from binary mixtures of ethanol with either IPM or EO was higher than that obtained from pure solvents with the delivery increasing with increasing ethanol concentration in the mixtures. The delivery from binary mixtures was synergistic rather than additive. The study thus demonstrated a potential of tadalafil transdermal delivery. Binary combinations of ethanol with either IPM or EO provided the first step forward toward the development of transdermal delivery system for tadalafil.     

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.     

Intravaginal Controlled Administration of Flurogestone Acetate: (III) Development of Rate-Control Vaginal Devices

A Rate-Control vaginal device was developed which overcomes the low bioavailability and unpredictable Q - t^1/2 type release and absorption rate profiles of flurogestone acetate delivered by the currently marketed Syncro-Mate pessary.

The in vitro release and vaginal absorption profiles from the Rate-Control vaginal device were run simultaneously, a linear Q - t relationship was obtained with a significant improvement in bioavailability. A mathematical model was developed to correlate the in vitro drug release and the vaginal absorption profiles of flurogestone acetate from the vaginal devices.

The design, development and the simultaneous release and absorption profiles of flurogestone acetate from this new vaginal device were outlined and discussed.     

Intravaginal Controlled Administration of Flurogestone Acetate: (III) Development of Rate-Control Vaginal Devices

Abstract

A Rate-Control vaginal device was developed which overcomes the low bioavailability and unpredictable Q – t^1/2 type release and absorption rate profiles of flurogestone acetate delivered by the currently marketed Syncro-Mate pessary.

The in vitro release and vaginal absorption profiles from the Rate-Control vaginal device were run simultaneously, a linear Q – t relationship was obtained with a significant improvement in bioavailability. A mathematical model was developed to correlate the in vitro drug release and the vaginal absorption profiles of flurogestone acetate from the vaginal devices.

The design, development and the simultaneous release and absorption profiles of flurogestone acetate from this new vaginal device were outlined and discussed.     

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.     

Long-Tern Skin Permeation Kinetics of Estradiol: (II) Kinetics of Skin Uptake, Binding, and Metabolism

The in vitro skin permeation system developed in this laboratory was utilized to investigate the kinetics of uptake, binding, and metabolism of estradiol, the female hormone, by the hairless mouse skin. The kinetics of uptake of estradiol and its subsequent metabolism to estrone by the skin were examined by exposing one side of a freshly excised skin to an estradiol solution, while the other side of the skin was protected with an impermeable aluminum foil.

The results concluded that the stratum corneum plays a rate-limiting role in the uptake and binding of estradiol and its metabolism to estrone by the skin. The mechanisms of the uptake and binding of estradiol to whole skin tissue (with stratum corneum) showed a sex dependence, with the rate higher in the female than in the male mouse. On the other hand, no sex-dependent difference was observed in the mechanism and rate of metabolism to estrone.

After stripping off the rate-limiting stratum corneum, the mechanisms of the uptake, binding and metabolism of estradiol all became sex dependent with identical rates observed between male and female mice in the initial 14 hrs of the experiment; Between 14 to 21 hrs, the rates increased substantially with the female skin, but not with the male skin. The increase in the rate of uptake of estradiol by the female skin was related primarily to the increased rate of metabolism of estradiol to estrone.     

Evaluation of the Transdermal Permeation Behavior of Proterguride from Drug in Adhesive Matrix Patches Through Hairless Mouse Skin

The transdermal in vitro permeation behavior of the highly potent dopamine agonist Proterguride was investigated using hairless mouse skin as a model membrane. Drug in adhesive matrix formulations based on different types of pressure-sensitive adhesives (Eudragit® E 100 and Gelva®7883 as acrylates, Oppanol® B 15 SFN as polyisobutylene, and BioPSA® 7-4202 as silicone) with a drug load of 3% by weight were manufactured. All patches were examined for drug crystallization by polarized microscopy immediately after the manufacturing process and after storage for 30 days in sealed aluminium laminate bags at ambient temperature and at 40°C, respectively. Furthermore, the influence of the drug load in acrylate-based formulations onto the steady-state flux of Proterguride was examined. The Eudragit® E 100 system delivered a significantly higher steady-state flux than the systems based on Oppanol® B 15 SFN and also a somewhat higher steady-state flux than the Gelva®-based patch. An addition of 10% by weight of the crystallization inhibitor povidone 25 did not significantly influence the steady-state flux of Proterguride from acrylate matrices. The lipophilic silicone and polyisobutylene adhesives facilitated drug crystallization within the short storage periods at both conditions, probably due to the absence of povidone 25, which was incompatible with these polymers. Varying the drug load in acrylate-based formulations led to a linear increase of the steady-state flux until the steady-state flux of Proterguride leveled off and the patches tended to drug crystallization. It was found that Gelva®-based patches show good physical stability, good skin adhesion, and moderate flux values and, thus, can be evaluated as a basis for a suitable formulation for the transdermal administration of Proterguride.     

Long-Tern Skin Permeation Kinetics of Estradiol: (II) Kinetics of Skin Uptake,Binding, and Metabolism

Abstract

The in vitro skin permeation system developed in this laboratory was utilized to investigate the kinetics of uptake, binding, and metabolism of estradiol, the female hormone, by the hairless mouse skin. The kinetics of uptake of estradiol and its subsequent metabolism to estrone by the skin were examined by exposing one side of a freshly excised skin to an estradiol solution, while the other side of the skin was protected with an impermeable aluminum foil.

The results concluded that the stratum corneum plays a rate-limiting role in the uptake and binding of estradiol and its metabolism to estrone by the skin. The mechanisms of the uptake and binding of estradiol to whole skin tissue (with stratum corneum) showed a sex dependence, with the rate higher in the female than in the male mouse. On the other hand, no sex-dependent difference was observed in the mechanism and rate of metabolism to estrone.

After stripping off the rate-limiting stratum corneum, the mechanisms of the uptake, binding and metabolism of estradiol all became sex dependent with identical rates observed between male and female mice in the initial 14 hrs of the experiment; Between 14 to 21 hrs, the rates increased substantially with the female skin, but not with the male skin. The increase in the rate of uptake of estradiol by the female skin was related primarily to the increased rate of metabolism of estradiol to estrone.     

Long-Term Permeation Kinetics of Estradiol: (V) Development and Evaluation of Transdermal Bioactivated Hormone Delivery System

Abstract

Based on the results of simultaneous skin permeation and bioconversion profiles, a Transdermal Bioactivated Hormone Delivery (TBHD) System was developed from the microreservoir partition-controlled drug delivery technology for the transdermal controlled delivery of estradiol prodrugs.

Using the in vitro skin permeation apparatus developed earlier, the kinetics of release and skin permeation of estradiol prodrugs from the TBHD system and the regeneration of estradiol were simultaneously studied. Results indicated that all prodrugs are totally converted by the esterase to estradiol during the course of skin permeation.

The release rate of estradiol was found to be first enhanced by the esterification of the OH groups at 3- and 17-position and then decreased as the alkyl chain length increased.

The rate of regeneration of estradiol from the prodrugs was found to follow the order of: diacetate > valerate > heptanoate > acetate > cypionate.     

Effects of Adhesives and Permeation Enhancers on the Skin Permeation of Captopril

To formulate a transdermal drug delivery system of captopril, monolithic adhesive matrix type patches containing 20% captopril, different pressure-sensitive adhesives, and various permeation enhancers were prepared using a labcoater. The effects of the adhesives and permeation enhancers on skin permeation of captopril from the prepared patches were evaluated using Franz diffusion cells fitted with excised rat skins. The permeation rate of the drug through the excised skin was dependent on the type of polyacrylate copolymers studied. Fatty alcohols resulted in a pronounced enhancing effect on the skin permeation of captopril, while dimethyl sulfoxide,N-methyl-2-pyrrolidone, oleic acid, Transcutol, and polysorbate 20 showed no significant enhancing effect. The permeation-enhancing effect of the fatty alcohols reached the maximum at the level of 10%. Based on these results, a captopril patch may be developed with further optimization.     

Long-Term Permeation Kinetics of Estradiol: (IV) A Theoretical Approach to the Simultaneous Skin Permeation and Bioconversion of Estradiol Esters

Abstract

A theoretical non-steady-state treatment was developed to analyze the kinetics of metabolism during the course of dermal uptake or skin permeation of estradiol esters across the hairless mouse skin. The first-order rate constants for the metabolism reaction of estradiol acetate → estradiol and estradiol diacetate → estradiol acetate → estradiol were determined. The theoretical drug concentration profile calculated from the present model was found to be agreed reasonably well with the experimental data determined in the early stage of skin uptake/metabolism studies (<24 hr). For the skin permeation of estradiol acetate and diacetate and their concurrent metabolism, the experimental Q vs. t profiles were also observed to agree well with the theoretical results for a period of up to 28 hr. A deviation was observed at later phase of experiments, which can be attributed to the reduction in enzyme activity during the permeation studies, possibly due to the result of skin aging.     

Transdermal Dual-Controlled Delivery of Testosterone and Estradiol: (II) Enhanced Skin Permeability and Membrane-Moderated Delivery

In the second report of this series of investigations, series of alkanols, alkanoic acids and propyl alkanoates were evaluated for their potential as skin permeation enhancers for testosterone and estradiol delivered from a multilaminate-type transdermal drug delivery (m-TDD) system. Results indicated that permeation rates vary with the length of alkyl chain and the maximum enhancement effect is attained with alkanol having n=6-8 (n is the number of methylene groups), alkanoic acid having n=8-10, and propyl alkanoate having n=10-12. The enhancing effect of series of sorbitan esters and polysorbates on the skin permeation of testosterone was also studied; and the results indicated that sorbitan esters are effective skin permeation enhancer, while polysorbates are not. The effect of enhancer loading on the skin permeation rates of testosterone and estradiol, the barrier property of permselective membrane, the dosage rate ratio of testosterone/estradiol was extensively studied; and the effect of variation in the location of enhancer in the m-TDD system on the skin permeation of estradiol and testosterone was also investigated. The permselective membrane has been shown to be effective in controlling the delivery and skin permeation of estradiol. By simultaneous application of an appropriate skin permeation enhancer in testosterone reservoir layer and a permselective membrane with controlled thickness sandwiched between the estradiol- and testosterone-reservoir layer, the skin permeation rates of testosterone and estradiol from the m-TDD system can be modulated and the dosage rate ratio of testosterone/estradiol can be varied to suite for a particular therapeutic application.     

Long-Term Skin Permeation Kinetics of Estradiol (I): Effect of Drug Solubilizer-Polyethylene Glycol 400

A skin permeation cell was recently developed to overcome the deficiencies noted in the currently available in vitro diffusion cells, and to provide a cell design which is suitable for studying the long-term drug permeation kinetics through the skin and is also sensitive enough for assessing the mechanisms of skin permeation by a high performance liquid chromatography.

To evaluate the rote of drug reservoir concentration in the kinetics of skin permeation as well as to maintain a sink condition in the receptor solution, the water-miscible polyethylene glycol (PEG) 400 was incorporated into the saline solution to act as a solubilizer to enhance the aqueous solubility of the relative water-insoluble estradiol. The equilibrium solubility of estradiol at 37°C was observed to in crease exponentially as increasing the volume fraction of PEG 400 added.

The rates o f permeation of estradiol across the male and female hairless mouse, whole and stripped skins excised freshly from the abdominal region, were measured a t various PEG concentrations and the permeability coefficients were determined. The permeability co-efficients were found t o decrease as increasing the PEG concentration. A linear relationship was established between th e permeability co-efficients and the skin /solution partition coefficients and the steady-stated if fusivity was calculated. Effect of sex was assessed.

The rate of permeation and the permeability coefficient across the stratum corneum were determined, using t h e multi-laminated dif-fusional resistance model. Results demonstrated that the stratum corneum acts as the rate-limiting barrier in the skin permeation of estradiol and the incorporation of upto 40% v/v PEG 400 does not in-fluence the barrier propertiesof stratum corneum, even though PEG 400 has been found to affect the aqueous solubility, permeability co-efficient, and skin /solution partition coefficient of estradiol.