Controlled In Vivo Release of Nicorandil from a Carvone-Based Transdermal Therapeutic System in Human Volunteers

The aim of our present study was to prepare and evaluate a carvone-based transdermal therapeutic system (TTS) of nicorandil to find its ability in providing the desired in vivo controlled release profile on dermal application to human volunteers. The effect of EVA 2825, and adhesive-coated EVA 2825, and adhesive-coated EVA 2825-rat skin composite on the in vitro permeation of nicorandil from a carvone-based HPMC gel drug reservoir was studied against a control (rat abdominal skin alone). The carvone-based drug reservoir system was sandwiched between adhesive-coated EVA 2825-release liner composite and a backing membrane. The resultant drug reservoir sandwich was heat-sealed to produce a circle-shaped TTS (20 cm²) that was subjected to in vivo evaluation on dermal application to human volunteers against oral administration of immediate-release tablets of nicorandil. The carvone-based TTS provided a steady-state plasma concentration of 20.5 ng/ml for ～24 hr in human volunteers. We concluded that the carvone-based TTS of nicorandil provided the desired in vivo controlled-release profile of the drug for the predetermined period of time.     

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.     

Limonene enhances the in vitro and in vivo permeation of trimetazidine across a membrane-controlled transdermal therapeutic system

The objective of the study was to design membrane-controlled transdermal therapeutic system (TTS) for trimetazidine. The optimization of (i) concentration of ethanol-water solvent system, (ii) HPMC concentration of drug reservoir and (iii) limonene concentration in 2% w/v HPMC gel was done based on the in vitro permeation of trimetazidine across excised rat epidermis. A limonene-based membrane-controlled TTS of trimetazidine was fabricated and evaluated for its in vivo drug release in rabbit model. The in vitro permeation of trimetazidine from water, ethanol and selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent systems showed that 50% v/v of ethanol-water solvent system provided an optimal transdermal flux of 233.1+/-3.8 microg/cm(2.)h. The flux of the drug decreased to 194.1+/-7.4 microg/cm(2.)h on adding 2% w/v of HPMC to ethanolic (50% v/v ethanol-water) solution of trimetazidine. However, on adding selected concentrations of limonene (0, 2, 4, 6 and 8% w/v) to 2% w/v HPMC gel drug reservoir, the flux of the drug increased to 365.5+/-7.1 microg/cm(2.)h. Based on these results, 2% w/v HPMC gel drug reservoir containing 6% w/v of limonene was chosen as an optimal formulation for studying the influence of rate-controlling EVA2825 membrane and adhesive-coated EVA2825 membrane. The flux of the drug across EVA2825 membrane (mean thickness 31.2 microm) decreased to 285.8+/-2.2 microg/cm(2.)h indicating that the chosen membrane was effective as rate-controlling membrane. On applying an adhesive coat (mean thickness 10.2 microm) to EVA2825 membrane, the drug flux further decreased to 212.4+/-2.6 microg/cm(2.)h. However, the flux of the drug across adhesive-coated EVA2825 membrane-rat epidermis composite was 185.9+/-2.9 microg/cm(2.)h, which is about 2-times higher than the desired flux. The fabricated limonene-based TTS patch of trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL for about 14 h with minimal fluctuation when tested in rabbits. It was concluded from the investigation that the limonene-based TTS patch of trimetazidine provided constant drug delivery across the skin in rabbit model.     

Formulation and in vivo evaluation of membrane-moderated transdermal therapeutic systems of nicardipine hydrochloride using carvone as a penetration enhancer

A membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride was developed using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 8%w/w of carvone as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38, or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28%w/w vinyl acetate) or EVA 2825 membrane/skin composite also was studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED and 2%w/w HPC gel as reservoir containing 8%w/w of carvone as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 23 hr with improved bioavailability in comparison with the immediate-release capsule dosage form.     

Influence of menthol and pressure-sensitive adhesives on the in vivo performance of membrane-moderated transdermal therapeutic system of nicardipine hydrochloride in human volunteers.

A membrane-moderated transdermal therapeutic system of nicardipine hydrochloride was developed using 2% w/w hydroxypropylcellulose (HPC) gel as a reservoir system containing 5% w/w of menthol as a penetration enhancer. The permeability flux of nicardipine hydrochloride through the ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28% w/w vinyl acetate) or EVA 2825 membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new transdermal therapeutic system for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED, and 2% w/w HPC gel as reservoir containing 5% w/w of menthol as a penetration enhancer. In vivo studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 26h with improved bioavailability in comparison with the immediate release capsule dosage form.     

Effect of carvone on the permeation of nimodipine from a membrane-moderated transdermal therapeutic system

The purpose of this investigation was to develop a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2% w/w hydroxypropylmethylcellulose (HPMC) gel as a reservoir system containing 10% w/w of carvone (penetration enhancer) in 60% v/v ethanol. The flux of nimodipine through an ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of a pressure-sensitive adhesive (TACKWHITE A 4MED) on the permeability of nimodipine through an EVA 2825 membrane (28% w/w vinyl acetate) or an EVA 2825 membrane/skin composite was also studied. An EVA 2825 membrane coated with TACKWHITE 4A MED was found to provide the required flux of nimodipine (117 +/- 5 microg/cm2/h) across rat abdominal skin. Thus a new transdermal therapeutic system for nimodipine was formulated using EVA 2825 membrane, coated with a pressure-sensitive adhesive TACKWHITE 4A MED, and 2% w/w HPMC gel as reservoir containing 10% w/w of carvone as a penetration enhancer. Studies in healthy human volunteers indicated that the TTS of nimodipine, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations.     

Influence of limonene on the bioavailability of nicardipine hydrochloride from membrane-moderated transdermal therapeutic systems in human volunteers

The aim of the present study was to develop a membrane-moderated transdermal therapeutic system (TTS) of nicardipine hydrochloride using 2%w/w hydroxy propyl cellulose (HPC) gel as a reservoir system containing 4%w/w of limonene as a penetration enhancer. The permeability flux of nicardipine hydrochloride through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate (VA) content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED) on the permeability of nicardipine hydrochloride through EVA membrane 2825 (28% w/w VA) or membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE 4A MED/skin composite was higher than that coated with MA-31or MA-38. Thus a new TTS for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED and 2%w/w HPC gel as reservoir containing 4%w/w of limonene as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady state plasma concentration of the drug with minimal fluctuations for 20 h with improved bioavailability in comparison with the immediate release capsule dosage form.     

Studies on the transdermal delivery of nimodipine from a menthol-based TTS in human volunteers

The purpose of the present study was to design a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2%w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing menthol as penetration enhancer and 60%v/v ethanol-water as solvent system. The flux of nimodipine was markedly increased from 35.51 microg/cm2/h to 167.53+/-3.69 microg/cm2/h with the addition of 8%w/w menthol to HPMC drug reservoir. There was an increase in the flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane with an increase in vinyl acetate content (9 to 28%w/w) of the copolymer. The permeability flux of nimodipine from the chosen EVA 2825 (with 28%w/w vinyl acetate content) was 152.05+/-2.68 microg/cm2/h, and this flux decreased to 132.69+/-1.45 microg/cm2/h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat. However, the transdermal flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED/ rat skin composite was found to be 116.05+/-2.39 microg/cm2/h, which is about 1.4 times greater than the required flux. Thus a new transdermal therapeutic system for nimodipine was designed using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED, and 2%w/w HPMC gel as reservoir containing 8%w/w of menthol as a penetration enhancer. The in vivo evaluation of nimodipine TTS patch was carried out to find the ability of the fabricated menthol-based TTS patch in providing the predetermined plasma concentration of the drug in human volunteers. The results showed that the menthol-based TTS patch of nimodipine provided steady plasma concentration of the drug with minimal fluctuations with improved bioavailability in comparison with the immediate release tablet dosage form.     

Formulation and evaluation of limonene-based membrane-moderated transdermal therapeutic system of nimodipine

The aim of the present study was to design a membranemoderated transdermal therapeutic system (TTS) of nimodipine using 2% w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing 4% w/w of limonene as a penetration enhancer. The permeability flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer (9 to 28%). The effect of pressure-sensitive adhesives such as TACKWHITE A 4MED® on the permeability of nimodipine through EVA membrane 2825 (28% w/w vinyl acetate) or membrane/rat skin composite also was studied. The permeability flux of nimodipine from the chosen EVA 2825 (with 28% vinyl acetate content) was 159.72 ± 1.96 μg/cm²/hr, and this flux further decreased to 141.85 ± 1.54 μg/cm²/hr on application of pressure-sensitive adhesive (TACKWHITE A 4MED®). However, the transdermal permeability flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED®/rat skin composite was found to be 126.59 ± 2.72 μg/cm²/hr, which is 1.3-fold greater than the required flux. Thus, a new transdermal therapeutic system for nimodipine was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED® and 2% w/w HPMC gel as reservoir containing 4% w/w of limonene as a penetration enhancer. The bioavailability studies in healthy human volunteers indicated that the TTS of nimodipine, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 20 hr with improved bioavailability in comparison with the immediate release tablet dosage form.     

Effect of PEG6000 on the in vitro and in vivo transdermal permeation of ondansetron hydrochloride from EVA1802 membranes

The objective was to evaluate ethylene vinyl acetate (EVA) copolymer membranes with vinyl acetate content of 18% w/w (EVA1802) for transdermal delivery of ondansetron hydrochloride. The EVA1802 membranes containing selected concentrations (0, 5, 10 and 15% w/w) of PEG6000 were prepared, and subjected to in vitro permeation studies from a nerodilol-based drug reservoir. Flux of ondansetron from EVA1802 membranes without PEG6000 was 64.1 +/- 0.6 microg/cm(2.)h, and with 10%w/w of PEG6000 (EVA1802-PEG6000-10) it increased to 194.9 +/- 4.6 microg/cm(2.)h. However, with 15%w/w of PEG6000, EVA1802 membranes produced a burst release of drug which in turn decreased drug flux. The EVA1802-PEG6000-10 membrane was coated with an adhesive emulsion, applied to rat epidermis and subjected to in vitro permeation studies against controls. Flux of ondansetron from transdermal patch across rat epidermis was 111.7 +/- 1.3 microg/cm(2.)h, which is about 1.3 times the required flux. A TTS was fabricated using adhesive-coated EVA1802-PEG6000-10 membrane and other TTS components, and subjected to in vivo delivery in human volunteers against a control. It was concluded from the comparative pharmacokinetic study that TTS of ondansetron, prepared with EVA1802-PEG6000-10 membrane, provided average steady-state plasma concentration on par with multiple-dosed oral tablets, but with a low percent of peak-to-trough fluctuation.     

Effect of PEG6000 on the In Vitro and In Vivo Transdermal Permeation of Ondansetron Hydrochloride from EVA1802 Membranes

The objective was to evaluate ethylene vinyl acetate (EVA) copolymer membranes with vinyl acetate content of 18% w/w (EVA1802) for transdermal delivery of ondansetron hydrochloride. The EVA1802 membranes containing selected concentrations (0, 5, 10 and 15% w/w) of PEG6000 were prepared, and subjected to in vitro permeation studies from a nerodilol-based drug reservoir. Flux of ondansetron from EVA1802 membranes without PEG6000 was 64.1 ± 0.6 μg/cm^2·h, and with 10%w/w of PEG6000 (EVA1802-PEG6000-10) it increased to 194.9 ± 4.6 μg/cm^2·h. However, with 15%w/w of PEG6000, EVA1802 membranes produced a burst release of drug which in turn decreased drug flux. The EVA1802-PEG6000-10 membrane was coated with an adhesive emulsion, applied to rat epidermis and subjected to in vitro permeation studies against controls. Flux of ondansetron from transdermal patch across rat epidermis was 111.7 ± 1.3 μg/cm^2·h, which is about 1.3 times the required flux. A TTS was fabricated using adhesive-coated EVA1802-PEG6000-10 membrane and other TTS components, and subjected to in vivo delivery in human volunteers against a control. It was concluded from the comparative pharmacokinetic study that TTS of ondansetron, prepared with EVA1802-PEG6000-10 membrane, provided average steady-state plasma concentration on par with multiple-dosed oral tablets, but with a low percent of peak-to-trough fluctuation.     

Formulation of an HPMC gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing in vitro transdermal delivery of nicorandil

The objective of the present study was to formulate a hydroxypropyl methylcellulose (HPMC) gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing the transdermal delivery of nicorandil so as to develop and fabricate a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation of nicorandil was determined across rat abdominal skin from a solvent system consisting of ethanol or various proportions of ethanol and water. The ethanol-water (70:30 v/v) solvent system that provided an optimal transdermal permeation was used in formulating an HPMC gel drug reservoir system with selected concentrations (0% w/w, 4% w/w, 6% w/w, 8% w/w or 10% w/w) of limonene as a penetration enhancer for further enhancement of transdermal permeation of nicorandil. The amount of nicorandil permeated in 24 h was found increased with an increase in the concentration of limonene in the drug reservoir system up to a concentration of 6% w/w, but beyond this concentration there was no further increase in the amount of drug permeated. The flux of nicorandil was 370.9 +/- 4.2 microg/cm2 x h from the drug reservoir system with 6% w/w of limonene, which is about 2.6 times the required flux to be obtained across rat abdominal skin for producing the desired plasma concentration for the predetermined period in humans. The results of a Fourier Transform Infrared study indicated that limonene enhanced the percutaneous permeation of nicorandil by partially extracting the stratum corneum lipids. It is concluded that the HPMC gel drug reservoir system prepared with a 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene is useful in designing and fabricating a membrane-moderated TTS of nicorandil.     

Transdermal Delivery of the Synthetic Cannabinoid WIN 55,212-2: In Vitro/in Vivo Correlation

PURPOSE: The aim of the current investigation was to evaluate the percutaneous absorption of the synthetic cannabinoid WIN 55,212-2 in vitro and in vivo. METHODS: The in vitro permeation studies of WIN 55,212-2 in human skin, hairless guinea pig skin, a polymer membrane with adhesive, and a skin/polymer membrane composite were conducted in flowthrough diffusion cells. The pharmacokinetic parameters for WIN 55,212-2 were determined after intravenous administration and topical application of Hill Top Chambers and transdermal therapeutic systems (TTS) in guinea pigs. RESULTS: The in vitro permeation studies indicated that the flux of WIN 55,212-2 through hairless guinea pig skin was 1.2 times more than that through human skin. The flux of WIN 55,212-2 through human and guinea pig skin was not significantly higher than that through the corresponding skin/polymer membrane composites. The mean guinea pig steady-state plasma concentrations after topical 6.3 cm2 chamber and 14.5 cm2 TTS patch applications were 5.0 ng/ml and 8.6 ng/ml, respectively. CONCLUSIONS: The topical drug treatments provided significant steady-state plasma drug levels for 48 h. The observed in vivo results from the Hill Top Chambers and TTS patches in the guinea pigs were in good agreement with the predicted plasma concentrations from the in vitro data.     

Formulation optimization and stability study of transdermal therapeutic system of nicorandil

The aim of this research investigation was to fabricate acrylate-based stable transdermal therapeutic system (TTS) of nicorandil, which could deliver drug through transdermal route. Monolithic TTS was fabricated in pressure sensitive adhesives (PSAs)--(a) terpolymer (PSA1) of 2-ethylhexyl acrylate, methyl methacrylate, and acrylic acid, (b) copolymer (PSA2) of 2-ethylhexyl acrylate, methyl methacrylate, acrylic acid, and vinyl acetate, and (c) Eudragit E100 pressure sensitive adhesive (PSA3). To enhance the flux of nicorandil, skin permeation enhancer N-methyl-2-pyrrolidone (NMP) was investigated at different concentrations (0.05-5%) in PSAs. Fabricated TTS was evaluated for in-vitro release and skin permeation through guinea pig skin. Maximum flux of nicorandil was observed from Eudragit E100 based TTS and kept for stability study at refrigeration, 25 degrees C/30% RH and 30 degrees C/60% RH. Patches were evaluated for various physicochemical parameters. Formulation was observed to be relatively more stable at refrigeration. Shelf life of the formulation was found to be 270, 270, and 30 days at refrigeration, 25 degrees C/30% RH and 30 degrees C/60% RH conditions, respectively. Nicorandil could be successfully derived from Eudragit E100 based TTS, but attention needs to be given to improve its chemical stability in formulation.     

Diffusion model for the study of a drug from the hydrophilic matrix of a transdermal therapeutic system through a model polymeric membrane

Conclusions The kinetics of drug supply described above from gel-like hydrophilic matrices of a TTS through human skin, or a polymeric membrane imitating itin vitro, are analogous to the kinetics of the release of a drug from a reservoir TTS through an attached polymeric membrane controlling the rate. Studying the kinetics of drug supply from diffusion matrices of TTS through a polymeric membrane imitating skin enables modeling of the kinetics of transdermal drug supplyin vitro andin vivo. The adequacy of such modeling is determined by the correlation between the diffusion coefficients of the drug in the membrane and skin epidermis and the distribution coefficients of the drug between skin and matrix or between membrane and matrix, which are subject to experimental determination.The transdermal supply of drug with kinetics of zero order (i.e. at a rate constant with time) may be effected from a TTS of the membrane-reservoir type containing a membrane specially controlling the rate or from a matrix TTS. In the latter case the function of the membrane controlling the rate of drug supply is fulfilled by the human skin at the point of application of the TTS, while the TTS diffusion matrix acts as a reservoir containing drug on the skin surface and limits the maximally achievable rate of drug release from the TTS to the skin according to equation 12. The competence of such an approach is occasionally questioned because of fears that the permeability of skin for a drug depends markedly on the point of application of the TTS and on the special features of the patient's skin. The effect of skin permeability at the point of application on the rate of transdermal drug supply has been studied well in [21] and a standard place for the application of a TTS may be the correct choice. The vast scope for the clinical application of the various TTS available at the present time indicates that individual variability of skin permeability is not so great and may be displayed mainly by a reduced permeability of the skin for a drug. Unlike membrane-reservoir TTS the majority of matrix TTS may be divided into portions of various size without disturbing their efficiency. This raises the possibility of continuously regulating the dose (by the area of application for TTS of this type).Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 28, No. 10, pp. 38–45, October, 1994.     

Prediction of plasma concentration of GTS-21 in hairless rats following monolithic transdermal delivery

The transdermal therapeutic systems (TTS) usually achieve constant plasma concentration for an extended period of time. This is because a sufficient drug stored in the device can keep the constant concentration on the surface of the stratum corneum during the system application. When the drug molecules are not enough to provide the constant surface concentration, the rate of drug penetration decreases with time because of decreased supply of the drug molecules from the delivery device. This paper has proposed an empirical simple approach to predict the plasma concentration for such a TTS. A novel compound, GTS-21, for Alzheimers' disease currently under development was used as a model drug. In vivo and in vitro experiments were carried out in hairless rats. The in vivo plasma concentration-time profile in hairless rats following the application of TTS well agreed with the predicted profile based on the skin pharmacokinetic model together with the model parameters determined from the in vitro experiment.     

Hydrophilic polymeric matrices for enhanced transdermal drug delivery

For many drugs with various chemical structures, delivery rates from the hydrophilic polyvinylpyrrolidone (PVP)-polyethylene oxide (PEO) based pressure sensitive adhesive (PSA) matrices of transdermal therapeutic systems (TTS) are higher compared to the hydrophobic TTS matrices. Delivery of propranolol, glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) from the hydrophilic water soluble TTS matrix across human cadaver skin epidermis or skin-imitating polydimethylsiloxane-polycarbonate block copolymer Carbosil membrane in vitro is characterized by high rate values and zero-order drug delivery kinetics up to the point of 75–85% drug release from their initial contents in matrix. Both in vitro and in vivo drug delivery rates from the TTS hydrophilic diffusion matrix are controlled by the skin or membrane permeability and may be described by Fick's law. The contributions of various physicochemical determinants to the control of transdermal drug delivery kinetics are discussed. Pharmacokinetic and pharmacodynamic properties of hydrophilic TTS matrix with propranolol, GTN and ISDN are described.     

Percutaneous Permeation of Betamethasone 17-Valerate Incorporated in Lipid Nanoparticles

Corticosteroids are therapeutic agents widely used in the pharmacological treatment of skin diseases such as eczema or psoriasis. Unfortunately, their use is restricted by the side effects that frequently occur at the systemic level. The goal of the research described here was to develop and characterize a solid lipid nanoparticle (SLN) system containing corticosteroids for prolonged and localized delivery of the active drugs into the skin. In vitro measurements of Betamethasone 17-valerate (BMV) permeation through human epidermis were conducted using static Franz diffusion cells. The reservoir formation of the drug in the epidermal and dermal layers of the skin was also investigated. Monostearin SLN showed remarkable controlled release properties and a significant epidermis drug reservoir. On the other hand, beeswax SLN could not reduce the drug permeation through the skin, nor increase the drug content in the upper layers of the skin. The diffusion of corticosteroids into the skin appeared to be dependent on the lipid composition of the monostearin SLN. Topical SLN products show great potential for treating dermatological conditions by targeting corticosteroids to epidermal/upper dermal disease sites while minimizing systemic drug absorption.     

Pharmacological evaluation of membrane-moderated transdermal system of glipizide

1. Membrane-moderated transdermal systems of glipizide were prepared using drug-containing carbopol gel (drug reservoir) and ethyl cellulose, as well as Eudragit RS-100, Eudragit RL-100 (Rohm Pharma, Darmstadt, Germany) and ethylene vinyl acetate (EVA; 2, 9 and 19% vinyl acetate content) rate-controlling membranes, and were subsequently evaluated in vitro (drug content and drug permeation studies) and in vivo (acute and long-term hypoglycaemic activity, effect on glucose tolerance, biochemical and histopathological studies, skin irritation test and pharmacokinetic studies in mice). 2. The drug content of the systems was found to be more than 99%. Variations in drug permeation patterns were observed among the formulations containing different rate-controlling membranes. 3. The system with the EVA (19% vinyl acetate) rate-controlling membrane was selected for in vivo experiments. This transdermal system produced better improvement with respect to hypoglycaemic activity, glucose tolerance and tested biochemical, histopathological and pharmacokinetic parameters all compared with oral administration and exhibited negligible skin irritation. 4. The transdermal system successfully prevented severe hypoglycaemia in the initial hours and it was also effective for chronic application.     

Transdermal skin delivery: predictions for humans from in vivo, ex vivo and animal models

The assessment of percutaneous permeation of molecules is one of the main steps in the initial design and later in the evaluation of dermal or transdermal drug delivery systems. The literature reports numerous ex vivo, in vitro and in vivo models used to determine drug skin permeation profiles and kinetic parameters, some studies focusing on the correlation of the data obtained using these models with the dermal/transdermal absorption in humans. This paper reviews work from in vitro permeation studies to clinical performance, presenting various experimental models used in dermal/transdermal research, including the use of excised human or animal skin, cultured skin equivalents and animals. Studies focusing on transdermal absorption of a series of drug molecules and various delivery systems as well as mathematical models for skin absorption are reviewed.