Studies of in vitro skin permeation and retention of a leukotriene antagonist from topical vehicles with a hairless guinea pig model.

A leukotriene antagonist [Ro 23-3544; 6-acetyl-7-[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyloxy] -3,4-dihydro-2H-1-benzopyran-2-carboxylic acid; 1] was studied in vitro for its permeation through and retention in hairless guinea pig skin from various topical vehicles. Both the free acid and the sodium salt forms of the drug were used. The vehicles evaluated were polyethylene glycol 400, propylene glycol, dimethyl sulfoxide (DMSO), C12-C15 alcohol lactates, dimethyl isosorbide, butyrolactone, methylpyrrolidone, hexyl laurate, isopropyl myristate, and caprylic/capric triglyceride (Neobee M5). For the salt form of the drug, the highest permeability coefficient and retention were obtained from DMSO and methylpyrrolidone, respectively. For the acid form, however, the highest permeability coefficient and retention were obtained from hexyl laurate and DMSO, respectively. The highest permeation and retention values were not obtained from the same vehicle for either the salt or the acid form of the drug. This observation questions the validity of using permeation (flux) measurements to screen topical drugs and formulations. Although the precise reasons for this lack of correlation between permeation and retention are not known at this time, this study has shown that the solubility parameters of the drug and the vehicles used may play an important role. It seems logical to conduct skin retention studies rather than flux measurements in evaluating drug delivery from dermatological products.     

Ketorolac trometamol topical formulations: release behaviour,physical characterization,skin permeation,efficacy and gastric safety

Objectives The objective of this study was to improve systemic delivery of the highly analgesic ketorolac trometamol (ketorolac tromethamine) via the transdermal route, through cost‐effective topical formulations, to avoid most of the problems associated with ketorolac trometamol therapy. Methods In‐vitro release behaviour of the drug from different microemulsion and emulgel formulations was evaluated. E2 emulgel (based on isopropyl myristate as penetration enhancer) and E7 emulgel (based on Brij 92 as penetration enhancer) were evaluated for their physical properties, rat skin permeation, in‐vivo analgesic effect (hot‐plate test and the paw pressure test), acute and chronic anti‐inflammatory activity and gastric safety. Key findings Isopropyl myristate and the synergistic effect of the two known penetration enhancers (propylene glycol and Brij 92) significantly modulated drug permeation and may be a promising approach for the transdermal delivery of ketorolac trometamol and other drugs. Selected in‐vivo tested formulae (E2 and E7) caused significantly less ulcer score and less gastric erosion compared with oral ketorolac trometamol. E7 showed significantly higher analgesic and anti‐inflammatory activity compared with E2 with no significant difference compared with oral ketorolac trometamol. Conclusions The developed ketorolac trometamol E7 emulgel appeared promising for dermal and transdermal delivery of ketorolac trometamol, which would circumvent most of the problems associated with drug therapy.     

Effect of penetration enhancers on in vitro percutaneous penetration of nimesulide through rat skin

The influence of several penetration enhancers alone and/or in various combinations on the percutaneous penetration of nimesulide (NM) from Carbopol 934 based gel formulations was investigated. Skin permeation studies were performed using Franz-type diffusion cells and full-thickness abdominal rat skin. Various types of compounds such as ethanol, isopropyl alcohol, propylene glycol, Transcutol, Tween 80 and oleic acid were employed as penetration enhancers. The steady-state flux, the lag time and permeability coefficients of NM for each formulation were calculated. The results showed that the skin permeability of NM from gels tested was significantly increased (P < 0.05) by isopropyl alcohol (40%) and the combination of oleic acid (3%) with Transcutol (30%) when compared with the control formulation. In conclusion, these substances could be considered as penetration enhancers for NM topical formulations.     

The Influence of Cosolvents on the In-vitro Percutaneous Penetration of Diclofenac Sodium From a Gel System

Abstract— The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system was studied using a simplex lattice experimental design. Gel formulations were prepared by gelling the vehicle mixture of water, alcohol and propylene glycol with Carbomer 940. The synthetic membrane Durapore and hairless mouse skin were employed as barriers in a Franz-type diffusion cell. It was found that the penetration through the synthetic membrane was well described by the Higuchi model. There existed a better inverse relationship between the penetration rate and the drug solubility in the respective vehicle. It appeared to be a membrane-controlled mechanism when using hairless mouse skin as the barrier. The penetration rates in steady-state for nine formulations were fitted to a polynomial equation based on this simplex lattice method. A three-dimensional plot was constructed in this simplex surface studied. The maximal penetration rate was found to be from the vehicle containing water and ethanol in an exact volume ratio of 3:1 and the minimal penetration rate was observed from the vehicle containing water only.     

In-vitro release of diclofenac diethylammonium from lipid-based formulations

This article presents the preparation and topical performance of some new lipid-based formulations of diclofenac, namely (a) a diclofenac aqueous gel containing mixed micelles (sodium cholate:egg lecithin molar ratio 0.55); (b) diclofenac lotion that contains soya lecithin, ethanol and buffer; and (c) diclofenac lipogel containing egg lecithin, isopropyl myristate, propylene glycol and ethanol. Gel formulations were prepared using Carbomer 934. Release of diclofenac from all formulations was monitored via dialysis through Spectra/por membrane into phosphate buffer (0.2 M pH=7.4) using a Franz cell. Drug release profile and diffusion coefficients were compared with brand formulation (Geigy's Vlotaren Emulgel). Statistical analysis of data show that the diffusion coefficient of the drug from these formulations rank according to the following order: Diclofenac lotion (D=5.308x10(-7) cm(2)/s) >lipogel (D=2.102 x 10(-7) cm(2)/s) >Voltaren Emulgel (1.518 x 10(-7) cm(2)/s) >aqueous gel mixed micelle (0.966 x 10(-7) cm(2)/s). These results show that diclofenac lotion and lipogel maybe more suitable formulations than the conventional topical dosage form.     

Formulation and evaluation of once-a-day transdermal gels of diclofenac diethylamine

The present study was undertaken to prepare and evaluate transdermal gels of diclofenac diethylamine (DDEA) containing penetration enhancers such as olesan oil and dimethyl sulfoxide (DMSO). Transdermal gels were prepared using different polymers such as carbopol-940, polyvinyl alcohol (PVA), hydroxy propyl methyl cellulose-K(4) M, hydroxy propyl cellulose-M, and sodium carboxy methyl cellulose. The formulated gels were subjected to physicochemical studies, in vitro release studies and in vitro skin permeations studies and were evaluated for drug content, viscosity, extrudability, spreadability, and pH. The in vitro release studies of prepared gels were performed using specially designed Fites cell and in vitro skin permeation studies were performed using keshary-chien diffusion cell through rat skin. Selected formulations were evaluated for their antiinflammatory activity using the carrageenan-induced paw edema in rats. The carbopol-940 and PVA gels containing 10% DMSO showed best in vitro skin permeation of DDEA. In vivo study for the selected formulation showed a sustained reduction in inflammation in the carrageenan induced paw edema in rats. The efficacies of carbopol-940 and PVA gels were also compared with that of the marketed Voveran gel,(R) and it was found that carbopol and PVA gels produced better results than the Voveran gel. (c) 2006 Prous Science. All rights reserved.     

Doxorubicin skin penetration from monoolein-containing propylene glycol formulations

Topical chemotherapy with the antineoplastic doxorubicin (DXR) could be an alternative to treat skin cancer, however its poor skin penetration often limits the efficacy of topical formulations. The aim of this work was to study the effect of monoolein (MO), a penetration enhancer, on the in vitro skin permeation and retention of DXR. DXR was incorporated in a propylene glycol preparation containing 0-20% of MO. DXR release rate and topical delivery were evaluated in vitro using acetate cellulose membrane and porcine skin, respectively, mounted in a Franz diffusion cell. At 5%, MO did not significantly change DXR release rate, but MO concentrations larger than 10% decreased almost twice its release. In vitro skin penetration studies showed that the presence of MO in the propylene glycol formulations markedly increased DXR presence in the stratum corneum (SC). At 5%, MO significantly increased the amount of DXR in the SC already in the first hours, attained a maximum in 6h. Comparing propylene glycol formulations containing more than 10% MO with that containing 5%, the former took the double of the time (12h) to reach the same amount of DXR in the skin, result that is in agreement with in vitro release studies. Interesting, despite the fact that MO significantly increased the amount of DXR in the SC, drug transdermal delivery did not change. These findings suggest a cutaneous delivery of DXR that is an important condition for topical treatment of skin tumors. Further in vivo experiments can show DXR delivery to deeper skin layers.     

Topical delivery of cyclosporin A: an in vitro study using monoolein as a penetration enhancer.

Topical delivery of cyclosporin A (CysA) is of great interest for the treatment of autoimmune skin disorders, but it is frequently ineffective due to poor drug penetration in the skin. The present study was aimed at investigating whether the presence of monoolein (a lipidic penetration enhancer) in a preparation of propylene glycol can improve CysA delivery to the skin. CysA was incorporated in a propylene glycol preparation containing 5-70% (w/w) of monoolein. The topical (to the skin) and transdermal (across the skin) delivery of CysA were evaluated in vitro using porcine ear skin mounted in a Franz diffusion cell. CysA was quantified by UV-HPLC. At 5%, monoolein increased only the transdermal delivery of CysA. At 10%, it increased both topical and transdermal delivery. When the concentration of monoolein was further increased (20-70% w/w), an interesting phenomenon was observed: the topical delivery of CysA was still elevated but its transdermal delivery was substantially reduced. It was concluded that monoolein (in propylene glycol formulations) can promote the topical delivery of CysA, with reduced transdermal delivery.     

Preparation of hydrogels of griseofulvin for dermal application

In an attempt to prepare topical formulations of griseofulvin that can deliver the drug locally in effective concentration, various hydrogel formulations were prepared using carbomer (940 NF) as base; essential oils, propylene glycol (PG), N-methyl-2-pyrrolidone (NMP) as penetration enhancers. The in vitro skin permeation studies through Laca mouse skin were performed using vertical type cells. PG in the hydrogel formulation was found to influence drug release rate by increasing its solubility and partitioning. Further combinations of PG with varying amounts of NMP in the hydrogel formulations exhibited a significantly greater increase in the flux on comparison with the control and formulation containing PG alone. The diffusion samples obtained by in vitro permeation studies through mouse skin when subjected to microbioassay using Microsporum gypseum as tester microorganism exhibited antifungal activity. This indicates that the drug permeated through the mouse skin possess sufficient antifungal activity in vitro against the tested microorganism. The prepared hydrogels did not show any skin sensitization and histological studies were carried out to check the safety of permeation enhancers used. Further these formulations were found to be stable at three different temperatures 4, 25 and 40 degrees C with respect to percent drug content, release characteristics, pH, transparency, feel and viscosity.     

双氯芬酸钠自乳化给药系统的研制

目的研制双氯芬酸钠自乳化给药系统。方法通过测定双氯芬酸钠在各种溶剂中的平衡溶解度,选择适宜油相、乳化剂、助乳化剂,并在此基础上绘制伪三元相图。通过对各处方比例的筛选,结合各处方载药量以及所形成微乳的稳定性,确定最佳处方。结果以油相为三辛酸/癸酸甘油酯,乳化剂为Cremophor EL,助乳化剂为丙二醇,Km1为4∶1,Km2为1∶9,双氯芬酸钠在微乳中的质量浓度为25g.L-1,该处方为最佳处方。结论所研制的自乳化给药系统具有粒径小、载药量高、性质稳定的优势,可作为进一步研究的基础。     

Characterisation of microemulsions containing orange oil with water and propylene glycol as hydrophilic components

The current study aims to investigate the effect of incorporation of orange oil, mainly consisting of the cyclic mono-terpene linolene, a known skin penetration enhancer, as oil component on microemulsion formation both in water and propylene glycol containing systems. Phase diagrams of pseudoternary mixtures containing orange oil, ethyloleate or a 1:1 mixture (w/w) of orange oil and ethyloleate as oil components, a 6:4 (w/w) mixture of polyoxyethylene 20 sorbitan monooleate and sorbitan monolaurate as surfactant components and water or propylene glycol as hydrophilic components were investigated. Smaller microemulsion regions were observed when orange oil was used as a substitute for ethyloleate in both water and propylene glycol containing systems. Polarising light microscopy, viscosity measurements, electrical conductivity measurements and cryo-field emission scanning electron microscopy were used to identify structural features of the microemulsions. Solution-type, w/o droplet-type microemulsions and microemulsion areas containing liquid crystals were found in varying areas in the phase diagrams of water containing systems. Liquid crystals formation occurs when the water concentration reaches 20%-22.5% (w/w). Only solution-type microemulsions were observed in propylene glycol containing systems. The dimension of solution-type microemulsion areas in the phase diagrams is likely to depend on the miscibility of components and larger microemulsion areas were found when ethyloleate was used instead of orange oil and propylene glycol was used instead of water. W/o droplet-type microemulsions of systems containing orange oil and ethyloleate as oil components appear in different areas of the phase diagrams. Incorporation of orange oil as a penetration enhancer into a topical microemulsion affects its physical characteristics. This in turn may lead to instability of the microemulsion and/or can influence the release patterns of drugs from these microemulsions when applied as topical formulations.     

Matrix type transdermal drug delivery systems of metoprolol tartrate: in vitro characterization

The monolithic matrix type transdermal drug delivery system of metoprolol tartrate were prepared by the film casting on a mercury substrate and characterised in vitro by drug release studies, skin permeation studies and drug-excipients interaction analysis. Four formulations were developed, which differed in the ratio of matrix-forming polymers. Formulations MT-1, MT-2, MT-3 and MT-4 were composed of Eudragit RL-100 and polyvinyl pyrrolidone K-30 with the following ratios: 2:8, 4:6, 6:4 and 8:2, respectively. All the four formulations carried 10% (m/m) of metoprolol tartrate, 5% (m/m) of PEG-400 and 5% (m/m) of dimethyl sulfoxide in isopropyl alcohol: dichloromethane (40:60). Cumulative amounts of the drug released in 48 hours from the four formulations were 61.5, 75.4, 84.3 and 94.5%, respectively. The corresponding values for cumulative amounts of the permeated drug for the said formulations were 53.5, 62.5, 69.8 and 78.2%. On the basis of in vitro drug release and skin permeation performance, formulation MT-4 was found to be better than the other three formulations and it was selected as the optimized formulation.     

Studies on the In-vitro Percutaneous Penetration of Indomethacin from Gel Systems in Hairless Mice

The influence of co-solvents on the in-vitro percutaneous penetration of indomethacin from gel systems was studied using a simplex lattice experimental design. Gel formulations were prepared by gelling the vehicle mixture of water, either alcohol or isopropanol and either propylene glycol or PEG 400 with 1% w/w Carbomer 940. Hairless mouse skin was employed as the barrier in a Franz-type diffusion cell. The penetration rates at steady state for seven formulations were fitted to a polynomial equation based on this simple lattice method and a three-dimensional plot was constructed. The formulation having the maximal penetration rate was determined to be the vehicle with a solvent ratio of water: alcohol: propylene glycol equal to 15:33:52, and which possessed a solubility parameter of 15 and a drug solubility of around 10 mg mL^?1. When the solubility parameter of the vehicle was > 15, the drug solubility increased. However, the penetration rate decreased with an increasing solubility parameter. For those vehicles with a solubility parameter < 15, both the drug solubility and the penetration rate decreased with a decrease in the solubility parameter. There was shown to be an approximately 20-fold increase in the relative enhancement factor when using both alcohol and isopropanol, but only a threefold increase for both propylene glycol and PEG 400, when compared with water.     

薄荷醇及其二组分系统对双氯芬酸钠的促透作用

目的：以双氯芬酸钠作为模型药物，通过研究薄荷醇及其二组分系统对双氯芬酸钠的促透作用，比较薄荷醇与其二组分系统对某些药物促进作用的强弱。方法：采用两室扩散池体外实验装置，以兔皮为屏障，使用薄荷醇及其二组分系统，作为促透剂，测定双氯芬酸的渗透系数。结果：单独使用丙二醇、薄荷醇和月桂氮 酮的药物渗透作用没有它们与薄荷醇联合使用时明显。结论：薄荷醇－月桂氮 酮、薄荷醇－丙二醇系统能增加药物的皮肤通透性。     

Influence of propylene glycol and isopropyl myristate on the in vitro percutaneous penetration of diclofenac sodium from carbopol gels

The influence of propylene glycol (PG) on the in vitro penetration of diclofenac sodium (DFS) through a synthetic membrane and abdominal rat skin from carbopol gels was investigated using Franz-type diffusion cells. The combined effect of isopropyl myristate (IPM) and PG was also evaluated. It was found that the penetration through the synthetic membrane was well described by the Higuchi model. The gel containing 40% PG showed the highest release rate, indicating that a releasing maximum exists for PG content which provides the fully solubilized drug in the vehicle. When using rat skin as the barrier, the penetration rate was controlled by the membrane. DFS flux decreased with increasing PG content of the gels due to an increase of the drug affinity to the vehicle. A cosolvent action of PG was evident. However, the combination of PG and IPM resulted in a synergistic enhancement of DFS flux. Maximum enhancing activity was obtained from gels containing 40% PG, which yielded an enhancement ratio of about 8. Increasing IPM content from 3 to 5% increased the flux and decreased the lag time taken to reach a steady-state level.     

Assessment of diclofenac permeation with different formulations: anti-inflammatory study of a selected formula.

The aim of this study was to improve the transdermal permeation of sodium diclofenac. Permeation studies were carried out in vitro using human skin (0.4 mm thick) from plastic surgery as a membrane. Four liquid formulations of 1% (w/w) sodium diclofenac were assayed: three ternary solvent systems (M4, M5, M6) and one microemulsion (M3). A 1% (w/w) solution of sodium diclofenac and a commercially available semisolid preparation were tested as reference formulations. The following permeation parameters for diclofenac were assessed: permeability coefficient, flux and drug permeated and retained in the skin at 24 h. The highest values of these parameters were obtained with formula M4, which contains transcutol 59.2%, oleic acid 14.9% and d-limonene 5% (w/w) as permeation enhancers. The anti-inflammatory activity of this formula was compared with that of the semisolid preparation on carrageenan-induced paw edema in rats. As expected from in vitro results, the M4 diclofenac delivery system showed higher activity than the semisolid preparation, both when applied locally (to the inflammation area) and when applied systemically (to the back). Neither treatment irritated the skin when tested on rabbits in a 72-h trial. These results suggest that topical delivery of sodium diclofenac with an absorption enhancer such as a mixture of oleic acid and d-limonene (M4) may be an effective medication for both dermal and subdermal injuries.     

Enhancing effect of terpenes on the in vitro percutaneous absorption of diclofenac sodium

The enhancing effect of naturally occurring terpenes on the in vitro percutaneous absorption of diclofenac sodium (DFS) from carbopol gels containing propylene glycol was investigated. Permeation experiments were performed on excised abdominal rat skin. Terpenes varied in their activities: the alcohol terpenes were effective accelerants for the drug whereas the ketones were much less efficient, providing only a 2-to-3-fold increase in DFS diffusion; limonene showed mild accelerant activity and 1,8-cineole was a poor accelerant. Acyclic alcohols were found to be the best enhancers for DFS, being geraniol, with an almost 20-fold increase, the most outstanding penetration enhancer. However, although the addition of terpenes increased DFS flux, diffusional lag times were longer than for the control gel.     

Enhancement of percutaneous absorption of Finasteride by cosolvents,cosurfactant and surfactants

The enhancing effects of routinely used co-solvents, propylene glycol and 2-propanol, anionic and cationic surfactants and a co-surfactant with different concentrations were evaluated on the skin permeation of Finasteride. In vitro permeation experiments with rat skin revealed that the solvent mixture is a very important factor in the penetration of Finasteride through the skin. Unexpectedly, cationic and anionic surfactants in various concentrations did not show any enhancement effect on drug transdermal absorption but co-surfactant Transcutol P increased skin penetration of Finastride significantly. Transcutol P with 0.25% and 1% showed the best enhancement in the initial and final sampling time, respectively. Transcutol P in a concentration of 0.25% increased skin absorption of the drug nearly 3.6 times in the first 15?min. The highest enhancement ratio (ER) was gained in the presence of 1% Transcutol P (ER?=?5.98). In this study, among the different topical Finastride formulations, Transcutol P 1% in combination with water, propylene glycol and 2-propanol (30, 10, and 60) showed the highest enhancement ratio.     

Microemulsion-based hydrogel formulation of ibuprofen for topical delivery

The purpose of this study was to construct microemulsion-base hydrogel formulation for topical delivery of ibuprofen. Ethyl oleate (EO) was screened as the oil phase of microemulsions, due to a good solubilizing capacity of the microemulison systems and excellent skin permeation rate of ibuprofen. The pseudo-ternary phase diagrams for microemulsion regions were constructed using ethyl oleate as the oil, Tween 80 as the surfactant, propylene glycol as the cosurfactant. Various microemulsion formulations were prepared and the abilities of various microemulsions to deliver ibuprofen through the skin were evaluated in vitro using Franz diffusion cells fitted with porcine skins. The in vitro permeation data showed that microemulsions increased the permeation rate of ibuprofen 5.72-30.0 times over the saturated solution. The optimum formulation consisted of 3% ibuprofen, 6% EO, 30% Tween 80/PG (2:1) and water, showed a high permeation rate of 38.06 microg cm(-2) h(-1). Xanthan gum as a gel matrix was used to construct the microemulsion-based hydrogel for improving the viscosity of microemulsion for topical administration. The studied microemulsion-based hydrogel showed a good stability. These results indicate that the studied microemulsion-based hydrogel may be a promising vehicle for topical delivery of ibuprofen.     

In vitro percutaneous absorption of piroxicam through synthetic membranes and abdominal rat skin

The in vitro release of piroxicam from carbomer gels and its penetration through isopropyl myristate impregnated membranes and abdominal rat skin were investigated. Attempts were made to relate the differences in the release rate with physicochemical properties of the drug and the vehicle. The results showed that piroxicam is released from the topical gel formulations and diffuses through skin. It is suggested that although piroxicam flux across abdominal rat skin was lower than through isopropyl myristate membranes, this kind of membranes can be used in preliminary screening among the different piroxicam formulations.