Comparison of Skin Permeation of Dideoxynucleoside-Type Anti-HIV Drugs: Alone Versus Combination

Abstract

The effects of vehicles and skin permeation enhancer on the skin permeation of dideoxynucleoside-type anti-HN drugs, Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT), alone and in combination, were compared using hairless rat and human cadaver skins. Each drug alone or a combination of three drugs was added to various compositions of ethanol/water or ethanol/tricaprylin cosolvent system to saturation, and in vitro skin permeation studies were conducted using Valia-Chien skin permeation cells. In both ethanol/water and ethanol/tricaprylin systems, the hairless rat skin permeation rates achieved by each drug alone and three drugs in combination were not significantly different. Addition of oleic acid [1.0% (v/v) for each drug alone and 5.0% (v/v) for drug combination] in ethanol/tricaprylin (50:50) could not significantly enhance the skin permeation of these drugs. In hairless rat skin permeation of each drug alone, the permeation rates of all three drugs were dramatically enhanced with the addition of oleic acid in ethanol/water (60:40) cosolvent system and reached plateau level with oleic acid as low as 0.3% (v/v). However, in the case of drug combination, the enhancement of skin permeation rates of these drugs with the addition of oleic acid in ethanol/water (80:20) cosolvent system was not as high as that observed for each drug alone, and plateau level was not observed even at 5.0% (v/v) of oleic acid. Human cadaver skin permeation rates of each drug alone saturated in ethanol/ water (60:40) cosolvent system containing 1.0% (v/v) of oleic acid were 3-4 times lower than those of hairless rat skin. However, in skin permeation of three drugs in combination, saturated in ethanol/water (80:20) cosolvent system containing 5.0% (v/v) of oleic acid, human cadaver skin permeation rates of DDC and DDI were slightly lower than those of hairless rat skin, and there was no significant difference between the two skins for AZT. These results show that mutual skin permeation-enhancing effects of oleic acid and an ethanol/water cosolvent system Made the transdermal delivery of anti-HIV drugs, alone and in combination, feasible.     

Effect of Fatty Acid Diesters on Permeation of Anti-Inflammatory Drugs Through Rat Skin

ABSTRACT

Four fatty acid diesters (diethyl succinate, diethyl adipate, diethyl sebacate, and diisopropyl adipate) were used to study their enhancement effect on the permeation of four non-steroidal anti-inflammatory drugs (NSAIDs: ketoprofen, indomethacin, diclofenac sodium, and ibuprofen) through rat abdominal skin. With the diester pretreatment, drug permeation increased and the lag times decreased. No relationship was observed between the solubilities of the drugs in the diesters and the diester enhancement effects. The enhancement effect decreased with an increase of the drug lipophilicity, but increased with an increase of the lipophilic index of the diester up to about 3.5, after which the enhancement effect decreased or remained constant. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to investigate the biophysical changes in the stratum corneum lipids caused by the diesters. The FTIR results showed that treatment of the skin with diesters did not produce a blue shift in the asymmetric and symmetric C–H stretching peak positions. However, all of the above diesters showed a decrease in peak heights and areas for both asymmetric and symmetric C–H stretching absorbances in comparison with water treatment.

These results suggested that the diesters were more effective for enhancing the penetration of hydrophilic drugs than lipophilic drugs, and the enhancing effect of lipophilic diesters was more effective than that of hydrophilic diesters. The enhancement effects of diesters may be due to their causing lipid extraction in the skin.     

Development of a Dynamic Skin Permeation System for Long-Term Permeation Studies

Abstract

A dynamic skin permeation system was developed aiming to eliminate the deficiencies observed in the apparatus currently available. It consists of two half-cells in mirror image, each contains a stirring platform to permit a starhead magnet to rotate at a synchronous speed. The solution chamber is equipped with a sampling port, which can be tightly closed with glass stopper. The design characteristics of this new system was calibrated, using the commercially available Franz diffusion cell as the reference. The results clearly suggested that this newly developed skin permeation system shows consistently superior than the Franz diffusion cell in terms of the control of skin surface temperature and the efficiency of solution mixing. To investigate the potential effect of environment, the temperature on the stratum corneum surface was varied, while the dermal solution was maintained at constant body temperature, and its effect on the kinetics of skin permeation was studied. The energy requirements for various steps of skin permeation were determined. The results suggested that the skin permeation system developed in this investigation can be useful for the mechanistic analysis of long-term skin permeation kinetics.     

Development of a Dynamic Skin Permeation System for Long-Term Permeation Studies

A dynamic skin permeation system was developed aiming to eliminate the deficiencies observed in the apparatus currently available. It consists of two half-cells in mirror image, each contains a stirring platform to permit a starhead magnet to rotate at a synchronous speed. The solution chamber is equipped with a sampling port, which can be tightly closed with glass stopper. The design characteristics of this new system was calibrated, using the commercially available Franz diffusion cell as the reference. The results clearly suggested that this newly developed skin permeation system shows consistently superior than the Franz diffusion cell in terms of the control of skin surface temperature and the efficiency of solution mixing. To investigate the potential effect of environment, the temperature on the stratum corneum surface was varied, while the dermal solution was maintained at constant body temperature, and its effect on the kinetics of skin permeation was studied. The energy requirements for various steps of skin permeation were determined. The results suggested that the skin permeation system developed in this investigation can be useful for the mechanistic analysis of long-term skin permeation kinetics.     

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.     

Evaluation of Verapamil Hydrochloride Permeation Through Human Cadaver Skin

Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of verapamil hydrochloride (VPHC1). The apparent partition coefficient (octanol/water or buffer) of VPHC1 in buffers of different Ph values was determined. The saturation solubility of VPHC1 in different buffers and propylene glycol was determined. The target drug flux through the human skin to attain therapeutic concentrations in blood was determined. The maximum flux attainable through the human skin was determined. An attempt was made to increase the flux of the drug using azone as a penetration enhancer. The rate limiting barrier for the permeation of VPHC1 through the skin was determined.     

Skin Permeation of Lidocaine from Crystal Suspended Oily Formulations

ABSTRACT

In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, J_app, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2 = IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0–20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest J_app among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.     

Synthesis and Skin Permeation Study of Lidocaine Organic Salts

Four organic quarternary ammonium salts of lidocaine, lidocaine adipate, lidocaine maleate, lidocaine malonate and lidocaine tosylate were prepared in this study. These compounds were regarded as prodrugs of lidocaine and were expected to enhance skin permeability by ion-pair approach. In vitro permeation study through pig skin and determination of partition coefficients were carried out. The skin permeation of lidocaine adipate and lidocaine malonate after 12 hours of application was significantly higher than lidocaine hydrochloride but was not significantly different from lidocaine (α < 0.05). The increase in permeation of organic salts from lidocaine hydrochloride and the different profile of permeation from lidocaine may be the result of prodrug structure contributing ion-pair transportation beside normal route of transportation.     

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.     

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.     

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: (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.     

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

Abstract

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.     

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.     

Topical Delivery of Fluconazole: In Vitro Skin Penetration and Permeation Using Emulsions as Dosage Forms

ABSTRACT

We investigated in vitro skin penetration and permeation of fluconazole from emulsions containing different penetration enhancers. Fluconazole permeation was high (15–65% of the applied dose) across hairless mouse skin and low (8–9%) across pig ear skin. Permeation across mice skin from a formulation containing propyleneglycol and isopropyl myristate was significantly higher than that observed with the paraffin oil and propyleneglycol or Transcutol® emulsions. With pig skin, the paraffin oil or isopropyl myristate and propyleneglycol emulsions showed similar skin permeation and penetration. However, these emulsions provided epidermal concentrations higher than the minimal inhibitory concentrations for most dermatophytes.     

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.     

Permeation of Zidovudine and Probenecid from Oily Bases Containing Alcohols Through Rat Skin

Permeation of zidovudine (3'-azido-3'-deoxythymidine, AZT) and probenecid from oily bases containing an alcohol through rat skin was examined. Isopropyl myristate (IPM), as an oily vehicle, showed a penetration enhancing effect for AZT and probenecid. Ethanol, n-propanol, and n-butanol were used as additives in IPM and were examined for their own permeation and the enhancing effect on the permeation of AZT and probenecid. The skin permeation of AZT and probenecid from IPM was enhanced by addition of the alcohol in IPM. The degree of the enhancement was decreased with increasing lipophilicity of the alcohol used. me permeation rate of the drug from those systems was shown to be governed by penetration-enhancing effects of the oily base and alcohol, and the penetration of the alcohol itself through the skin.     

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.     

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.     

Comparison of Milling Processes: Ball Mill Versus Air Classifying Mill

Abstract

A study was initiated to compare the milling process and equivalence of mills for milling a fibrous material. In this study, milling processes using either a ball mill (Abbe Model Number 2) or an air classifying mill (Mikro ACM 10) were compared. Samples from both processes were evaluated by appropriate physical and chemical analyses such as particle size, surface area, densities, and potency. The particle size distribution and surface area analysis showed equivalence between the two milling processes. Scanning electron micrographs (SEM) showed that the samples had similar morphology. The potency of samples obtained from either of the milling processes was not affected by differences in the milling processes. In addition, results of milled samples that were subsequently granulated and compressed into tablets showed no difference in assay, content uniformity or disintegration time. Based on these results, it is concluded that the ball mill and the air classifying mill produce material that is equivalent in terms of physical and chemical properties, and therefore the processes of milling are interchangeable.