Enhanced In Vitro Percutaneous Absorption and In Vivo Anti-Inflammatory Effect of a Selective Cyclooxygenase Inhibitor Using Microemulsion

Celecoxib, a specific COX-2 inhibitor, was recently approved for the treatment of rheumatoid and osteoarthritis, acute pain, familial adenomatous polyposis and primary dysmenorrhea. Oral administration of celecoxib is effective against ultraviolet B radiation (UVB)-induced skin carcinogenesis; however, its clinical use is restricted because of its failure to block the characteristic cutaneous inflammatory response and lower availability at the site of inflammation. Topical application of celecoxib has been effective compared with oral in certain clinical conditions. The present study was undertaken to develop and investigate the development of microemulsion system (isopropyl myristate/medium-chain glyceride/polysorbate 80/water) for topical delivery of celecoxib. The pseudoternary phase diagram was constructed with constant surfactant concentration, and several compositions were identified and characterized by using dynamic light scattering. The in vitro permeation rate of celecoxib through rat skin was determined for microemulsions, microemulsion gel, and cream by using the modified Franz-type diffusion cell. In all formulations tested, celecoxib permeated more quickly, and the microemulsions increased the permeation rate of celecoxib up to 5 and 11 times compared with those of microemulsion gel and cream, respectively. Increasing the concentration of medium-chain mono-/di-glyceride in microemulsion imparted increased droplet size and viscosity and decreased diffusion coefficient. In vivo anti-inflammatory study suggested that the developed microemulsion formulations might serve as potential drug vehicle for the prevention of UVB-induced skin cancer.     

Enhanced In Vitro Percutaneous Absorption and In Vivo Anti-Inflammatory Effect of a Selective Cyclooxygenase Inhibitor Using Microemulsion

Celecoxib, a specific COX-2 inhibitor, was recently approved for the treatment of rheumatoid and osteoarthritis, acute pain, familial adenomatous polyposis and primary dysmenorrhea. Oral administration of celecoxib is effective against ultraviolet B radiation (UVB)-induced skin carcinogenesis; however, its clinical use is restricted because of its failure to block the characteristic cutaneous inflammatory response and lower availability at the site of inflammation. Topical application of celecoxib has been effective compared with oral in certain clinical conditions. The present study was undertaken to develop and investigate the development of microemulsion system (isopropyl myristate/medium-chain glyceride/polysorbate 80/water) for topical delivery of celecoxib. The pseudoternary phase diagram was constructed with constant surfactant concentration, and several compositions were identified and characterized by using dynamic light scattering. The in vitro permeation rate of celecoxib through rat skin was determined for microemulsions, microemulsion gel, and cream by using the modified Franz-type diffusion cell. In all formulations tested, celecoxib permeated more quickly, and the microemulsions increased the permeation rate of celecoxib up to 5 and 11 times compared with those of microemulsion gel and cream, respectively. Increasing the concentration of medium-chain mono-/di-glyceride in microemulsion imparted increased droplet size and viscosity and decreased diffusion coefficient. In vivo anti-inflammatory study suggested that the developed microemulsion formulations might serve as potential drug vehicle for the prevention of UVB-induced skin cancer.     

Enhancement of the Skin Permeation of Clindamycin Phosphate by Aerosol OT/1-Butanol Microemulsions

Microemulsions of water/isopropyl palmitate (IPP)/Aerosol OT (AOT)/1-butanol were developed as alternative formulations for topical delivery of clindamycin phosphate. Effect of AOT:1-butanol ratios on microemulsion region existence in the pseudoternary phase diagrams was investigated. The 2:1 AOT:1-butanol provided the largest microemulsion region. Five microemulsions of 1% w/w clindamycin phosphate were prepared and characterized. The permeation through human epidermis of the microemulsions was evaluated and compared with the 70% isopropanol solution using modified Franz diffusion cells. The drug permeation from all microemulsions was found to be significantly greater than that from the solution, indicating the enhancement of the skin permeation by the microemulsions. Within the same microemulsion type, the drug permeation increased with increasing the amount of AOT:1-butanol. The drug permeation from oil-in-water (o/w) microemulsions was relatively higher than that from water-in-oil (w/o) microemulsions. In addition, all microemulsions were stable for at least three months at 30 ± 1°C.     

Enhancement of the skin permeation of clindamycin phosphate by Aerosol OT/1-butanol microemulsions

Microemulsions of water/isopropyl palmitate (IPP)/Aerosol OT (AOT)/1-butanol were developed as alternative formulations for topical delivery of clindamycin phosphate. Effect of AOT:1-butanol ratios on microemulsion region existence in the pseudoternary phase diagrams was investigated. The 2:1 AOT:1-butanol provided the largest microemulsion region. Five microemulsions of 1% w/w clindamycin phosphate were prepared and characterized. The permeation through human epidermis of the microemulsions was evaluated and compared with the 70% isopropanol solution using modified Franz diffusion cells. The drug permeation from all microemulsions was found to be significantly greater than that from the solution, indicating the enhancement of the skin permeation by the microemulsions. Within the same microemulsion type, the drug permeation increased with increasing the amount of AOT:1-butanol. The drug permeation from oil-in-water (o/w) microemulsions was relatively higher than that from water-in-oil (w/o) microemulsions. In addition, all microemulsions were stable for at least three months at 30 ± 1°C.     

Microemulsion for Intradermal Delivery Of Cetyl Alcohol and Octyl Dimethyl PABA

A water-in-oil microemulsion was prepared to deliver cetyl alchohol [I] octyl dimethyl PABA or Padimate-O [II] in vitro using human and hairless mouse skin. A standard Franz diffusion cell and a microsectiong cryostat microtome were used to quantify the rate and the depth of penetration and the results were compared in the percent does penetrated for this microemulsion and two macroemulsion formulations, namely a cream and a lotion. It appeared that the microemulsion had the ability to deliver [I] into the skin 2-6 times faster and at least twice as much as that with the other two formulations. Furthermore, the absorption of [I] from the cream or lotion product could bel enhanced by as much as 50-250% if the skin had been pretreated with microemulsion prior to product application. The advantage of using a microemulison to acheieve deeper and faster penetratin of the permeating compunds was clearly demonstreated in this study.     

Preparation,Evaluation, and NMR Characterization of Vinpocetine Microemulsion for Transdermal Delivery

A novel microemulsion was prepared to increase the solubility and the in vitro transdermal delivery of poorly water‐soluble vinpocetine. The correlation between the transdermal permeation rate and structural characteristics of vinpocetine microemulsion was investigated by pulsed field gradient nuclear magnetic resonance (PFG‐NMR). For the microemulsions, oleic acid was chosen as oil phase, PEG‐8 glyceryl caprylate/caprate (Labrasol®) as surfactant (S), purified diethylene glycol monoethyl ether (Transcutol P®) as cosurfactant (CoS), and the double‐distilled water as water phase. Pseudo‐ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of various oils and different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of vinpocetine were investigated. Self‐diffusion coefficients were determined by PFG‐NMR in order to investigate the influence of microemulsion composition with the equal drug concentration on their transdermal delivery. Finally, the microemulsion containing 1% vinpocetine was optimized with 4% oleic acid, 20.5% Labrasol, 20.5% Transcutol P, and 55% double‐distilled water (w/w), in which drug solubility was about 3160‐fold higher compared to that in water and the apparent permeation rate across the excised rat skin was 36.4?±?2.1 µg/cm²/h. The physicochemical properties of the optimized microemulsion were examined for the pH, viscosity, refractive index, conductivity, and particle size distribution. The microemulsion was stable after storing more than 12 months at 25°C. The irritation study showed that the optimized microemulsion was a nonirritant transdermal delivery system.     

The effect of component of microemulsion for transdermal delivery of nicardipine hydrochloride

Purpose: Nicardipine hydrochloride has been used widely for the treatment of angina pectoris and hypertension. Because of its extensive first pass metabolism after oral administration, the transdermal administration of nicardipine microemulsions was developed in this study. Methods: Microemulsions consisted of isopropyl myristate (IPM), surfactant mixture of Tween 80/Span 80 and/or Tween 80/Span 20, co-surfactant (ethanol) and aqueous phase. Pseudo-ternary phase diagrams were constructed using water titration method. The effect of component of microemulsion on the percutaneous absorption of drug was evaluated by in vitro permeation study. Results: The area of microemulsion isotropic region in the presence of ethanol was comparably larger in the absence of ethanol. The mean droplet size of nicardipine microemulsions ranged from 70 to 123 nm. With addition of ethanol, the droplet size became smaller. The permeation rate and extent of nicardipine microemulsion transport across rat skin was affected by the components of microemulsion. Nicardipine microemulsion had higher flux at surfactant mixture with lower hyrophile-lipophile balance (HLB) value and Tween content. Conclusions: The microemulsion consisted of 52% IPM, 35% surfactant mixture and 13% water had higher permeation rate through rat skin above 122.53±1.87 μg/cm2/h and was expected to develop a transdermal delivery system.     

Development and Optimization of a Methotrexate Topical Formulation

A topical methotrexate (MTX) formulation that would achieve optimal drug buildup in the epidermis and diminish potential systemic toxicity could be of great utility in the treatment of a variety of hyperproliferative skin disorders. In an attempt to develop an optimized MTX topical formulation containing pharmaceutically acceptable excipients, a 2³ factorial design was used to investigate the effects of a fatty alcohol, propylene glycol, and ethanol on the in vitro skin permeation and uptake of MTX. In vitro skin permeation studies were performed using excised human epidermis mounted in flow-through diffusion cells. The results of steady-state flux and skin uptake of MTX from these formulations ranged from 0.035 to 0.315 μg/cm²/hr and 1.146 to 7.929 μg/cm², respectively. Response surface analysis was used to determine the optimum formulation in terms of skin permeation and uptake of MTX.

An optimized cream formulation was developed and compared to a gel formulation containing 3% Azone in hairless mice to evaluate the uptake of MTX in the treated and untreated skin sites as well as the distribution of MTX in the blood and liver following topical application. The results of the in vivo study demonstrated the localization of MTX at the treated site for both formulations without significant uptake of MTX in the distant untreated epidermis and dermis. The levels of MTX in the blood and liver following topical application of the optimized cream were significantly less than those of the gel formulation with 3% Azone.     

Preparation, evaluation, and NMR characterization of vinpocetine microemulsion for transdermal delivery

A novel microemulsion was prepared to increase the solubility and the in vitro transdermal delivery of poorly water-soluble vinpocetine. The correlation between the transdermal permeation rate and structural characteristics of vinpocetine microemulsion was investigated by pulsed field gradient nuclear magnetic resonance (PFG-NMR). For the microemulsions, oleic acid was chosen as oil phase, PEG-8 glyceryl caprylate/caprate (Labrasol®) as surfactant (S), purified diethylene glycol monoethyl ether (Transcutol P®) as cosurfactant (CoS), and the double-distilled water as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of various oils and different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of vinpocetine were investigated. Self-diffusion coefficients were determined by PFG-NMR in order to investigate the influence of microemulsion composition with the equal drug concentration on their transdermal delivery. Finally, the microemulsion containing 1% vinpocetine was optimized with 4% oleic acid, 20.5% Labrasol, 20.5% Transcutol P, and 55% double-distilled water (w/w), in which drug solubility was about 3160-fold higher compared to that in water and the apparent permeation rate across the excised rat skin was 36.4 ± 2.1 µg/cm²/h. The physicochemical properties of the optimized microemulsion were examined for the pH, viscosity, refractive index, conductivity, and particle size distribution. The microemulsion was stable after storing more than 12 months at 25°C. The irritation study showed that the optimized microemulsion was a nonirritant transdermal delivery system.     

Development and Optimization of a Methotrexate Topical Formulation

Abstract

A topical methotrexate (MTX) formulation that would achieve optimal drug buildup in the epidermis and diminish potential systemic toxicity could be of great utility in the treatment of a variety of hyperproliferative skin disorders. In an attempt to develop an optimized MTX topical formulation containing pharmaceutically acceptable excipients, a 2³ factorial design was used to investigate the effects of a fatty alcohol, propylene glycol, and ethanol on the in vitro skin permeation and uptake of MTX. In vitro skin permeation studies were performed using excised human epidermis mounted in flow-through diffusion cells. The results of steady-state flux and skin uptake of MTX from these formulations ranged from 0.035 to 0.315 μg/cm²/hr and 1.146 to 7.929 μg/cm², respectively. Response surface analysis was used to determine the optimum formulation in terms of skin permeation and uptake of MTX.

An optimized cream formulation was developed and compared to a gel formulation containing 3% Azone in hairless mice to evaluate the uptake of MTX in the treated and untreated skin sites as well as the distribution of MTX in the blood and liver following topical application. The results of the in vivo study demonstrated the localization of MTX at the treated site for both formulations without significant uptake of MTX in the distant untreated epidermis and dermis. The levels of MTX in the blood and liver following topical application of the optimized cream were significantly less than those of the gel formulation with 3% Azone.     

Prolonged skin retention of clobetasol propionate by bio-based microemulsions: a potential tool for scalp psoriasis treatment

Novel effective and cosmetically acceptable formulations are needed for the treatment of scalp psoriasis, due to the poor efficacy of the current products. The challenge in developing safe, efficient, and convenient delivery systems for this drug was addressed in the present work by formulating clobetasol propionate-loaded W/O microemulsions (MEs). Pseudo-ternary phase diagrams were constructed by using a combination of biocompatible and biodegradable excipients. Characterization studies demonstrated that selected MEs had suitable technological features such as being Newtonian fluids, possessing low viscosity, and high thermodynamic stability. Photomicrographs showed a significant alteration of the skin structure after treatment with MEs, and a preferential concentration of these in the stratum corneum and epidermis. These data, together with ex vivo permeation results, suggested an enhanced topical targeted effect due to an increased drug retention efficacy in the upper skin layers, as desired. Moreover, the bio-based excipients selected could contribute to the healing of the psoriatic scalp. In this way, the improvement of clobetasol efficacy is combined with the useful properties of the microemulsion components and with environmental safety.     

Improvement in Transdermal Bioavailability of Nitroglycerin by Formulation Design

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

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

Bicontinuous water-AOT/Tween85-isopropyl myristate microemulsion: a new vehicle for transdermal delivery of cyclosporin A

The purpose of this study was to investigate the influence of structure and composition of microemulsions (AOT/Tween85/isopropyl myristate/water) on their transdermal delivery potential of a lipophilic model drug (Cyclosporin A), and to compare the drug delivery potential of microemulsion to the suspension of drug in normal saline containing 20% ethanol. Their type and structure were examined by measuring surface tension, density, viscometry, and electric conductivity; the degree of agreement between the techniques was assessed. Transdermal flux of Cyclosporin A through rat skin was determined in vitro using Franz-type diffusion cells. Results of conducting, viscosity, and surface tension measurement confirmed the prediction transition to a bicontinuous structure. The microemulsions increased transdermal drug delivery of Cyclosporin A up to 10 times compared to the suspension. The increased transdermal delivery was found to be due mainly to water concentration and appeared to be dependent on the structure of the microemulsions.     

Topical permeation characteristics of diclofenac sodium from NaCMC gels in comparison with conventional gel formulations.

Topical gel formulations of diclofenac sodium were prepared by using sodium carboxymethylcellulose (NaCMC), a low-toxicity cellulose polymer as a gel-forming material that is biocompatible and biodegradable. The influence of various formulation variables, such as initial drug concentrations and NaCMC concentration, and certain skin permeation enhancers on release characteristics of the diclofenac sodium from the prepared gels through a standard cellophane membrane was studied in comparison with four commercially available gel formulations of diclofenac sodium,. The cumulative amounts released and the apparent release rates were higher for the prepared gels in comparison with the commercial formulations. Skin permeation studies using abdominal rat skin revealed good improvement of skin permeation characteristics of diclofenac sodium using NaCMC gels as compared to the commercial gels. The cumulative amount permeated at 6 h (microg/cm2), steady-state flux Jss (microg/cm2 h), lag time tL (h), permeability coefficient kp (cm/s), partition coefficient k, and diffusion coefficient D (cm2/s) were determined for the prepared gels in comparison with the commercial gels. Skin permeation enhancers such as isopropyl alcohol (IPA), Tween 80, and alpha-tocopherol polyethylene glycol succinate (TPGS) exhibited little or no effect on the permeation characteristics of diclofenac sodium. Infrared (IR) spectrum and differential scanning calorimetry (DSC) studies on the pure diclofenac sodium, NaCMC, and their physical mixture at a 1:1 ratio revealed that there was no positive evidence for the interactions between the drug and NaCMC, indicating the compatibility of the drug and the vehicle. Based on experimental results, preparation of diclofenac sodium gels using NaCMC vehicle is promising.     

Permeation of piroxicam from the poloxamer gels

Topical formulations of piroxicam were prepared using poloxamer 407 or poloxamer 188 by a cold method, and the permeation characteristics of piroxicam were evaluated. The permeation rate of piroxicam across the synthetic cellulose membrane and the rat skin decreased as the concentration of poloxamer increased. Though poloxamer gel exhibits reversed thermal behavior, the permeation rate of piroxicam increased with increasing temperature, indicating that the diffusional pathway of piroxicam is a water channel within the gel formulation. The pH of the gel did not affect the permeation rate of piroxicam significantly. As the concentration of piroxicam in the gel formulation increased, the permeation rate of piroxicam increased up to 1% and reached a plateau above 1%. Among various enhancers tested, polyoxyethylene-2-oleyl ether showed the highest enhancing effect, with an enhancement ratio of 2.84. Based on experimental results, the permeation rate of piroxicam can be controlled by changing the poloxamer concentration or drug concentration and by the addition of an appropriate enhancer.     

Bicontinuous Water-AOT/Tween85-Isopropyl Myristate Microemulsion: A New Vehicle for Transdermal Delivery of Cyclosporin A

ABSTRACT

The purpose of this study was to investigate the influence of structure and composition of microemulsions (AOT/Tween85/isopropyl myristate/water) on their transdermal delivery potential of a lipophilic model drug (Cyclosporin A), and to compare the drug delivery potential of microemulsion to the suspension of drug in normal saline containing 20% ethanol. Their type and structure were examined by measuring surface tension, density, viscometry, and electric conductivity; the degree of agreement between the techniques was assessed. Transdermal flux of Cyclosporin A through rat skin was determined in vitro using Franz-type diffusion cells. Results of conducting, viscosity, and surface tension measurement confirmed the prediction transition to a bicontinuous structure. The microemulsions increased transdermal drug delivery of Cyclosporin A up to 10 times compared to the suspension. The increased transdermal delivery was found to be due mainly to water concentration and appeared to be dependent on the structure of the microemulsions.     

Development of the bioadhesive tetracaine gels for enhanced local anesthetic effects

To develop the new local anesthetic formulations with a suitable bioadhesive property, hydroxypropyl methylcellulose (HPMC)-based gel was formulated. As the drug concentration in the gels, and the temperature of surrounding solutions increased, the drug release increased. The activation energy of tetracaine permeation was 4.47 kcal/mol. The effects of permeation enhancers on the permeation rate of drug through skin were studied using various enhancers, such as the glycols, the nonionic surfactants, and the bile salts. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the highest enhancing effects on drug permeation through skin. The analgesic activity was examined using a tail-flick analgesimeter. In the AUEC (area under the efficacy curve) of the rat-tail flick test, tetracaine gel containing polyoxyethylene 2-oleyl ether showed about 3.2-fold increase in analgesic activity compared with the control. The results of this study support that the tetracaine gels with efficient anesthetic effects could be developed using HPMC and poloxamer with combination of enhancer and vasoconstrictor.     

Comparison of the transdermal absorption of nimesulide from three commercially available gel formulations

Nimesulide is a non-steroidal anti-inflammatory drug (NSAID) applied topically for a variety of conditions characterized by pain and inflammation. One of the aims of this study was to compare the permeation profile of nimesulide from the commercially available transdermal gel formulations across dermatomed porcine and human skin. The in vitro transdermal absorption of nimesulide formulations across porcine skin and human skin was studiedfor 24 hr using a continuous flow-through diffusion cell. The three commercial gels used in this study were Nimulid, Nise Gel, and Orthobid. All gels contained 1% (w/w) nimesulide. An infinite dose of nimesulide gel (about 300mg) was applied on the skin over 0.636 cm2 surface area. The rank order for the drug permeation from these formulations using porcine skin was: Nimulid > Orthobid > Nise Gel. The rank order of the permeation across human skin was: Nimulid> Nise Gel> Orthobid. The permeation profiles followed zero-order kinetics without any significant lag time. The steady-state flux of nimesulide from Nimulid was significantly higher than that of Nise Gel and Orthobid in both porcine and human skin (p <.05). However, there were no significant differences in the delivery of nimesulide (24 hr) from Nise Gel and Orthobid across both human and porcine skins. The results suggest that the Nimulid gel may have a greater bioavailability of nimesulide compared to the other gels. In addition, permeation profiles of the various gels across porcine skin did show a positive profile behavior to human skin. However, the in vitro drug release of nimesulide gels across a synthetic membrane did not correlate with skin permeation profiles.     

Improvement in Transdermal Bioavailability of Nitroglycerin by Formulation Design

Abstract

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

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

Microemulsion-based patch for transdermal delivery of huperzine A and ligustrazine phosphate in treatment of Alzheimer's disease

The aim of the present study was to construct an innovative microemulsion-based patch for simultaneously transdermal delivery of huperzine A (HA) and ligustrazine phosphate (LP). The pseudo-ternary phase diagrams for microemulsion region were developed using oleic acid as oil, Cremophor RH40 as a surfactant, and ethanol as a cosurfactant. 1,8-cineole was added to the microemulsion as a penetration enhancer. The microemulsion-based transdermal patches were prepared by the lamination technique. The permeation studies were performed in vitro to evaluate the abilities of various microemulsions and transdermal patches to deliver HA and LP across the rat abdominal skin, showing that microemulsions increased the permeation rates of HA and LP compared with the control, and the penetration kinetics of the transdermal patch was in a zero order process. The results of the pharmacodynamic studies indicated that the transdermal combination therapy of HA and LP showed more benefits for fighting against amnesia in comparison with monotherapy. The anti-amnesic effects were also confirmed in scopolamine-induced amnesia rats after transdermal administration at multiple doses for 9 consecutive days, and the efficacy exhibited a dose-dependent manner. As a conclusion, the microemulsion-based transdermal patch containing HA and LP might provide a feasible strategy for the prevention of Alzheimer's disease.