Enhancement of in vitro skin permeation of verapamil

A number of compounds including aliphatic esters, alkanols and amides were investigated for their ability to enhance the in vitro permeation rate of verapamil across hairless mouse skin. While several of them did enhance the permeation rate, the best results were obtained with the lauric acid derivatives. On analysis of the permeation rate data it was found that while most of the compounds increased the solubility of verapamil in skin and hence its partition coefficient from the delivery system, the lauric acid derivatives also increased its diffusivity in skin. Permeation of verapamil from delivery systems containing these lauric derivatives was further investigated through delipidized and stripped skin. It was found that most of these derivatives enhanced the permeation of verapamil across both whole and delipidized skin, indicating that in addition to their action on the skin lipids, they must also have some effect on the proteins in the stratum corneum.     

Enhancement of in vitro skin permeation of verapamil

Abstract

A number of compounds including aliphatic esters, alkanols and amides were investigated for their ability to enhance the in vitro permeation rate of verapamil across hairless mouse skin. While several of them did enhance the permeation rate, the best results were obtained with the lauric acid derivatives. On analysis of the permeation rate data it was found that while most of the compounds increased the solubility of verapamil in skin and hence its partition coefficient from the delivery system, the lauric acid derivatives also increased its diffusivity in skin. Permeation of verapamil from delivery systems containing these lauric derivatives was further investigated through delipidized and stripped skin. It was found that most of these derivatives enhanced the permeation of verapamil across both whole and delipidized skin, indicating that in addition to their action on the skin lipids, they must also have some effect on the proteins in the stratum corneum.     

Effects of some hydrophilic permeation enhancers on the absorption of bepridil through excised human skin

The permeation of Bepridil through excised human skin was measured from vehicles composed of various mixtures of aqueous buffer and the permeation enhancers ethanol, DMSO or DMF. Only DMSO was found to act as a true permeation enhancer for the drug, the magnitude of its action depending on its concentration in the vehicle. At concentrations greater than 50% DMSO the permeability coefficient of the drug was increased over and above that which could be accounted for by changes in partitioning of the drug between vehicle and skin. The effects of ethanol could be related to changes in the measured skin/vehicle partition coefficients of the drug. DMF showed a complicated, concentration dependent influence on permeation.     

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.     

Effects of some hydrophilic permeation enhancers on the absorption of bepridil through excised human skin

Abstract

The permeation of Bepridil through excised human skin was measured from vehicles composed of various mixtures of aqueous buffer and the permeation enhancers ethanol, DMSO or DMF. Only DMSO was found to act as a true permeation enhancer for the drug, the magnitude of its action depending on its concentration in the vehicle. At concentrations greater than 50% DMSO the permeability coefficient of the drug was increased over and above that which could be accounted for by changes in partitioning of the drug between vehicle and skin. The effects of ethanol could be related to changes in the measured skin/vehicle partition coefficients of the drug. DMF showed a complicated, concentration dependent influence on permeation.     

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.     

In Vitro and In Vivo Percutaneous Absorption Studies of Ketotifen Patches

The purpose of the study is to develop a suitable transdermal delivery system for ketotifen. The physicochemical properties and skin penetration of ketotifen were evaluated for the optimization of the method of patch preparation. The distribution coefficients of ketotifen were determined in octanol/phosphate buffer systems, the partition coefficient and pka value of ketotifen were obtained as 120 and 6.73, respectively. In vitro skin penetration of ketotifen solution was determined at 35°C in the Valia-Chien diffusion cell by using the abdominal skin of nude mouse. The results showed that ketotifen had an optimal skin permeability at pH 7.5. In addition, ketotifen had higher rate of penetration through stripped skin, it was suggested that the main barrier for percutaneous absorption of ketotifen is stratum corneum. Ketotifen patch was fabricated in a stainless mold containing Eudragit S-100 and PEG 400. Other components, tween, span and fatty acids were also incorporated into the patch as penetration enhancers. For animal study, a patch with area of 30 cm² was applied on the dorsal skin of rabbit. The plasma level, after 10 hrs administration were reached 60 ng/mL and maintained a constant level. The results proposed that ketotifen was successfully absorbed through the skin from the applied patch.     

Dynamic permeation method to determine partition coefficients of highly hydrophobic chemicals between poly(dimethylsiloxane) and water

Measurement of partition coefficients between poly(dimethylsiloxane) (PDMS) and water (KPDMSw) becomes more and more difficult as the hydrophobicity of the compound increases. Experimental challenges include long extraction times, sorption to various surfaces and materials, and incomplete dissolution of the compound in the aqueous phase. In order to avoid these artifacts and to shorten experimental time, a dynamic permeation method was developed. According to steady-state diffusion theory, KPDMSw is inversely proportional to the permeation rate through the aqueous boundary layer (ABL) from the donor PDMS to the acceptor PDMS. A simple ABL permeation reactor can thus be applied to determine KPDMSw values of hydrophobic chemicals within a few days. The obtained values were in good agreement with those obtained using a conventional shaking method and the partition controlled delivery system. A good linear correlation was obtained between the logarithm of the 1-octanol/water partition coefficient (log Kow) from the literature and log KPDMSw over 6 orders of magnitude.     

In Vitro and In Vivo Percutaneous Absorption Studies of Ketotifen Patches

Abstract

The purpose of the study is to develop a suitable transdermal delivery system for ketotifen. The physicochemical properties and skin penetration of ketotifen were evaluated for the optimization of the method of patch preparation. The distribution coefficients of ketotifen were determined in octanol/phosphate buffer systems, the partition coefficient and pka value of ketotifen were obtained as 120 and 6.73, respectively. In vitro skin penetration of ketotifen solution was determined at 35°C in the Valia-Chien diffusion cell by using the abdominal skin of nude mouse. The results showed that ketotifen had an optimal skin permeability at pH 7.5. In addition, ketotifen had higher rate of penetration through stripped skin, it was suggested that the main barrier for percutaneous absorption of ketotifen is stratum corneum. Ketotifen patch was fabricated in a stainless mold containing Eudragit S-100 and PEG 400. Other components, tween, span and fatty acids were also incorporated into the patch as penetration enhancers. For animal study, a patch with area of 30 cm² was applied on the dorsal skin of rabbit. The plasma level, after 10 hrs administration were reached 60 ng/mL and maintained a constant level. The results proposed that ketotifen was successfully absorbed through the skin from the applied patch.     

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.     

Evaluation of salicylic acid fatty ester prodrugs for UV protection

The purpose of this study was to investigate the physicochemical properties and in vitro evaluation of fatty ester prodrugs of salicylic acid for ultraviolet (UV) protection. The physicochemical properties such as lipophilicity, chemical stability and enzymatic hydrolysis were investigated with the following fatty ester prodrugs of salicylic acid: octanoyl (C8SA), nonanoyl (C9SA), decanoyl (C10SA), lauroyl (C12SA), myristoyl (C14SA) and palmitoyl oxysalicylate (C16SA). Furthermore, their skin permeation and accumulation were evaluated using a combination of common permeation enhancing techniques such as the use of a lipophilic receptor solution, removal of stratum corneum and delipidization of skin. Their k' values were proportional to the degree of carbon-carbon saturation in the side chain. All these fatty esters were highly stable in 2-propanol, acetonitrile and glycerin, but unstable in methanol and ethanol. They were relatively unstable in liver and skin homogenates. In particular, C16SA was mostly hydrolyzed to its parent compound in hairless mouse liver and skin homogenates, suggesting that it might be converted to salicylic acid after its topical administration. In the skin permeation and accumulation study, C16SA showed the poorest permeation in all skins, suggesting that it could not be permeated in the skin. Furthermore, C14SA and C16SA were less accumulated in delipidized skin compared with normal skin or stripped skin, suggesting that these esters had relatively strong affinities for lipids compared with the other prodrugs in the skin. C16SA showed significantly higher dermal accumulation in all skins compared with its parent salicylic acid. Thus, the palmitoyl oxysalicylate (C16SA) might be a potential candidate for UV protection due to its absence of skin permeation, smaller uptake in the lipid phase and relatively lower skin accumulation.     

Novel method to evaluate moisture permeation of the metal barrier coating on polymer substrate

Water is detrimental to the performance of organic light-emitting devices and organic solar cells. A novel weight gain test (WGT) was introduced and demonstrated to measure the low permeation of water vapor through a metallic barrier coating on a polymer substrate. By using the WGT, the values of solubility, diffusivity and permeability for a sample are obtained with a simple experimental setup and diffusion equation. The WGT method has potential for the measurement of water-vapor permeation properties for samples with good barrier properties and irregular shape.     

Corneal critical barrier against the penetration of dexamethasone and lomefloxacin hydrochloride: evaluation by the activation energy for drug partition and diffusion in cornea

The cornea is a solid barrier against drug permeation. We searched the critical barrier of corneal drug permeation using a hydrophobic drug, dexamethasone (DM), and a hydrophilic drug, lomefloxacin hydrochloride (LFLX). The activation energies for permeability of DM and LFLX across the intact cornea were 88.0 and 42.1 kJ/mol, respectively. Their activation energies for permeability across the cornea without epithelium decreased to 33.1 and 16.6 kJ/mol, respectively. The results show that epithelium is the critical barrier on the cornea against the permeation of a hydrophobic drug of DM as well as a hydrophilic drug of LFLX. The activation energy of partition for DM (66.8 kJ/mol) was approximately 3-fold larger than that of diffusion (21.2 kJ/mol). The results indicate that the partition for the hydrophobic drug of DM to the corneal epithelium is the primary barrier. Thermodynamic evaluation of activation energy for the drug permeation parameters is a good approch to investigate the mechanism of drug permeability.     

Corneal Critical Barrier against the Penetration of Dexamethasone and Lomefloxacin Hydrochloride: Evaluation by the Activation Energy for Drug Partition and Diffusion in Cornea

The cornea is a solid barrier against drug permeation. We searched the critical barrier of corneal drug permeation using a hydrophobic drug, dexamethasone (DM), and a hydrophilic drug, lomefloxacin hydrochloride (LFLX). The activation energies for permeability of DM and LFLX across the intact cornea were 88.0 and 42.1 kJ/mol, respectively. Their activation energies for permeability across the cornea without epithelium decreased to 33.1 and 16.6 kJ/mol, respectively. The results show that epithelium is the critical barrier on the cornea against the permeation of a hydrophobic drug of DM as well as a hydrophilic drug of LFLX. The activation energy of partition for DM (66.8 kJ/mol) was approximately 3-fold larger than that of diffusion (21.2 kJ/mol). The results indicate that the partition for the hydrophobic drug of DM to the corneal epithelium is the primary barrier. Thermodynamic evaluation of activation energy for the drug permeation parameters is a good approch to investigate the mechanism of drug permeability.     

Simple universal permeation apparatus

A number of methods and commercial apparatuses for measuring the permeability of polymeric films and sheet materials have been successfully developed. Generally, the equipment is complex, expensive and specific to certain permeants, but all operate on similar basic principles. Because of our interest in a wide range of permeants, including fixed gases and organic vapours, we have built an inexpensive apparatus that can measure permeation to gas, moisture and organic vapours. We also require outputs that can provide not only permeability data but also proved solubility and diffusion coefficients. The apparatus is built around a commercially available thermal conductivity detector. Copyright © 2003 John Wiley & Sons, Ltd.     

Development of phospholipid vesicle-based permeation assay models capable of evaluating percutaneous penetration enhancing effect

Objectives: The phospholipid vesicle-based permeation assay (PVPA) model has recently been introduced as an in vitro model which can mimic stratum corneum (SC) barriers to estimate the skin permeability of drugs. The aim of this study was to evaluate whether the PVPA model was suitable for the evaluation of penetration enhancing effect of skin penetration enhancers (PE).

Methods: The PVPA model was optimized by changing the lipid composition of both small liposomes (SL), and large liposomes (LL). The barrier properties of the PVPA model were monitored by electrical resistance and permeability measurement of the fluorescent marker Rhodamine B (RB). Then the permeation studies of the five active compounds with different physicochemical properties, namely, ferulic acid, paeoniflorin, albiflorin, tetrahydrocolumbamine, and tetrahydropalmatine, were performed directly on PVPA model to evaluate the penetration enhancing effect of menthol.

Results and discussions: The enhancement ratio (ER) ranking of the five active compounds observed using the optimized PVPA model was in accordance with what observed with Franz diffusion cell device using porcine ear skin. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) analysis of PVPA model and porcine ear skin after treatment with menthol has shown similar mechanism of menthol which perturbs the SC lipid arrangement and extracts the SC lipids.

Conclusions: In summary, the optimized PVPA model was used for the first time for the evaluation of the permeation enhancing effect. The optimized PVPA model has shown potential to be applied in a more standardized, cheaper, and ethical way for the screening of PE.     

In-vitro transdermal permeation of oxycodone: (I) effect of PH, delipidization and skin stripping

The effect of pH, skin stripping and delipidization on the in-vitro transdermal permeation of a weak base analgesic, oxycodone (pKa=8.53), was studied using hydrodynamically calibrated Valia-Chien diffusion cells. Saturated oxycodone. HCl solutions in citrate-phosphate buffers ranging from pH 4 to 10 were used as the donor solution. Skin samples from the abdominal and dorsal sites of hairless rats, abdominal site of hairless mouse, rabbit pinna ear, as well as human cadaver skin were used in permeation studies. The pHs at which maximum flux attained varied from 6.5 to 7.5 depending upon animal model. The permeabilities of protonated form through intact skin of all the animal models used, was about 7-15 fold lower than that of nonionic form. The unexpected high permeation rate at pHs ranges 4 to 6.5 across human cadaver could be attributed to the possible damage upon storage. The skin stripping and delipidizaton process appeared to increase the permeation rates of oxycodone and the degree enhancement is dependent upon the pH in the donor compartment.     

In Vitro Release and Rectal Absorption of Barbital and Aminopyrine from Aqueous Polyacrylic Acid Gel

This study was designed t o evaluate aqueous polyacrylic acid gel (Carbopol gel), relative to its suitability for use as a vehicle for drug delivery. Barbital-Na and aminopyrine, used as model acidic and basic drugs, were completely dissolved into the aqueous gel base at 5 rng/ml and 50 mg/ml, respectively. In the release experiment using micropore membrane, higher concentration of polyacrylic acid in the gel resulted in higher viscosity, and consequently lower release rates of both drugs. Higher pH of barbital gel preparation resulted in higher fraction of ionized molecules of barbital in the gel preparation causing a higher barbital release rate. While the release rate of aminopyrine from gel preparation was the lowest at the region of pH 6.8, the ionized molecules of aminopyrine in gel base was 98.5%. The rectal absorption of barbital from the gel preparation at the pH 5.8-8.3 range had relation with the results of permeability through artificial intestinal lipid barrier and accorded with pH partition hypothesis. The permeability rate of aminopyrine through the artificial intestinal lipid barrier and the rectal absorption of aminopyrine from gel preparations did not have a marked difference at the pH 5.8-8.3 range. The release of both drugs from gel base was not a rate-limiting factor on the rectal absorption of both drugs from the gel bases.     

In-vitro transdermal permeation of oxycodone: (I) effect of PH,delipidization and skin stripping

Abstract

The effect of pH, skin stripping and delipidization on the in-vitro transdermal permeation of a weak base analgesic, oxycodone (pKa=8.53), was studied using hydrodynamically calibrated Valia-Chien diffusion cells. Saturated oxycodone. HCl solutions in citrate-phosphate buffers ranging from pH 4 to 10 were used as the donor solution. Skin samples from the abdominal and dorsal sites of hairless rats, abdominal site of hairless mouse, rabbit pinna ear, as well as human cadaver skin were used in permeation studies. The pHs at which maximum flux attained varied from 6.5 to 7.5 depending upon animal model. The permeabilities of protonated form through intact skin of all the animal models used, was about 7-15 fold lower than that of nonionic form. The unexpected high permeation rate at pHs ranges 4 to 6.5 across human cadaver could be attributed to the possible damage upon storage. The skin stripping and delipidizaton process appeared to increase the permeation rates of oxycodone and the degree enhancement is dependent upon the pH in the donor compartment.     

Microneedles for transdermal drug delivery: a systematic review

Transdermal route has been explored for various agents due to its advantage of bypassing the first pass effect and sustained release of drug. Due to strong barrier properties of the skin, mainly stratum corneum (SC), the delivery of many therapeutic agents across the skin has become challenging. Few drugs with specific physicochemical properties (molecular weight <500?Da, adequate lipophilicity, and low melting point) can be effectively administered via transdermal route. However, delivery of hydrophilic drugs and macromolecular agents including peptides, DNA and small interfering RNA is challenging. Drug penetration through the SC may involve bypass or reversible disruption of SC layer by various means. Recently, the use of micron-scale needles has been proposed in increasing skin permeability and shown to dramatically increase permeation, especially for macromolecules. Microneedles (MNs) can penetrate through the SC layer of the skin into the viable epidermis, avoiding contact with nerve fibers and blood vessels that reside primarily in the dermal layer. This review summarizes the types of MNs and fabrication techniques of different types of MNs. The safety aspects of the materials used for fabrication have been discussed in detail. Biological applications and relevant phase III clinical trials are also highlighted.