The enhancement effect of surfactants on the penetration of lorazepam through rat skin

Lorazepam is an anxiolytic, antidepressant agent, having suitable feature for transdermal delivery. The percutaneous permeation of lorazepam was investigated in rat skin after application of a water:propylene glycol (50:50%v/v). The enhancing effects of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on the permeation of lorazepam were evaluated using Franz diffusion cells fitted with rat skins. Flux, K_p, lag time and enhancement ratios (ERs) of lorazepam were measured over 24 h and compared with control sample. Furthermore, lorazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of lorazepam. The permeation profile of lorazepam in presence of the cationic surfactant, CTAB, reveals that an increase in the concentration of CTAB results in an increase in the flux of lorazepam in comparison with the control. But an increase in concentration of CTAB or benzalkounium chloride from 0.5 to 1% w/w or from 1 to 2.5% w/w resulted in a reduction in ER, respectively. Benzalkonium chloride which possessed the highest lipophilicity (log P=1.9) among cationic surfactants provided the greatest enhancement for lorazepam flux (7.66-fold over control) at 1% w/w of the surfactant. CTAB (log P<1) and sodium lauryl sulphate at a concentration of 5% w/w (the highest concentration) exhibited the greatest increase in flux of lorazepam compared with control (9.82 and 11.30-fold, respectively, over control). This is attributed to the damaging effect of the cationic and anionic surfactants on the skin at higher concentration. The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant molecules to form micelles and is normally observed only if interaction between micelle and the drug occurs.     

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 feasibility study of transdermal drug delivery systems for antidepressants possessing hydrophilicity or hydrophobicity

The feasibility studies on the transdermal drug delivery systems have been performed to avoid the systemic side-effects and gastric disorders that could be occurred due to the transient high blood concentration after oral administration of antidepressants such as venlafaxine HCl and citalopram. When surfactants of tween 80^? and plasticizer of diethyl phthalate were combined with citalopram?Cethylene vinyl acetate (EVA) matrix, the permeation of citalopram showed the best enhancement. As well as, venlafaxine HCl gels were prepared using carbomer, oleic acid and/or propylene glycol to enhance the skin permeation of venlafaxine HCl. The citalopram-EVA matrix containing tween 80^? and diethyl phthalate as permeation enhancers might be a good transdermal delivery system for providing sustained plasma concentrations of citalopram. Also, venlafaxine HCl showed the possibility to be enhanced skin permeation in the formulation of gels with carbomer including penetration enhancer, oleic acid and/or propylene glycol.     

The effect of surfactants on the skin penetration of diazepam

The percutaneous permeation of diazepam was investigated in rat skin after application of a water-propylene glycol (50:50% v/v) using a diffusion cell technique. The effect of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on skin permeability were evaluated. Flux, K(p), lag time and enhancement ratios (ERs) of diazepam were measured over 10 h and compared with control sample (containing no surfactant). Furthermore, diazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of diazepam. Benzalkonium chloride which possessed the highest lipophilicity (logP=1.9) among cationic surfactants provided the greatest enhancement for diazepam flux (7.98-fold over control). CTAB (logP<1) at a concentration of 1% w/w exhibited no significant increase in flux of diazepam compared to control (1.16-fold over control). The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant to form micelles and is normally observed only if interaction between micelle and the drug occurs. The results showed that the nature of enhancer greatly influences cutaneous barrier impairment.     

Effects of pressure sensitive adhesives and chemical permeation enhancers on the permeability of fentanyl through excised rat skin

Drug-in-adhesive patches (DIAPs) of fentanyl were formulated using various pressure sensitive adhesives (PSAs) and various chemical permeation enhancers (CPEs). The effects of PSAs and CPEs on skin permeation of fentanyl from DIAPs were evaluated using modified jacketed Franz diffusion cells fitted with excised rat abdominal skin. It was demonstrated that the permeation rate or steady state flux (J(ss)) of the drug through the excised rat skin was dependent on the viscosity and type of acrylic PSA as well as the type of CPE. Among different acrylic PSAs, Duro-Tak 2054 and Duro-Tak 2516 showed the highest J(ss) of 1.95 microg cm(-2) h(-1) and the lowest J(ss) of 1.43 microg cm(-2) h(-1), respectively. Among the various CPEs used, propylene glycol and polyethylene glycol 400 showed 1.61 and 1.18, the highest and the lowest enhancement ratios (ER) of the skin permeation of fentanyl, respectively. Oleic acid and cetyl alcohol moderately increased the skin permeation of fentanyl. It was also shown that increasing the concentration of CPE led to reduction in the adhesion property of PSA as measured by the 180 degrees peeling strength test. Moreover, it was found that the permeation rate increased as the fentanyl loading increased from 1 to 3%. The skin permeation rate of fentanyl did not increase significantly beyond 3% drug loading. It was concluded that propylene glycol as a CPE and cosolvent in 10% (m/m) with 3% fentanyl loading in Duro-Tak 2054 showed an effective monolithic DIAP for the development of a transdermal therapeutic system for fentanyl.     

Assessment of the percutaneous penetration of cisplatin: The effect of monoolein and the drug skin penetration pathway

It was intended to examine the in vitro penetration of cisplatin (CIS) through porcine skin in the presence of different concentrations of monoolein (MO) as well as to verify the main barrier for CIS skin penetration. In vitro skin penetration of CIS was studied from propylene glycol (PG) solutions containing 0%, 5%, 10%, and 20% of MO using Franz-type diffusion cell and porcine ear skin. Pretreatment experiments with MO and experiments with skin without stratum corneum (SC) were also carried out. Skin penetration studies of CIS showed that the presence of MO doubled the drug permeation through the intact skin. However, permeation studies through the skin without SC caused only a small enhancement of CIS permeation compared to intact skin. Moreover, pretreatment of skin with MO formulations did not show any significant increase in the flux of the drug. In conclusion, MO did not act as a real penetration enhancer for CIS, but it increased the drug partition to the receptor solution improving CIS transdermal permeation. The absence of improvement in drug permeation by MO pretreatment and by the removal of SC indicates that the SC is not the main barrier for the permeation of the metal coordination compound.     

Correlation of water and lidocaine flux enhancement by cationic surfactants in vitro.

The penetration of radiolabeled water and lidocaine through human epidermis was studied simultaneously using a flow-through apparatus under infinite-dose conditions. The donors were suspensions of lidocaine in propylene glycol:water mixtures containing cationic surfactants of varying alkyl chain length from three classes: alkyl dimethylbenzyl ammonium halides, alkyl trimethyl ammonium halides, and alkyl pyridinium halides. Each skin sample served as its own control; each was subjected to sequential treatments of control formulation with no surfactant, test formulation, and then a repeat control. Higher surfactant concentration resulted in greater enhancement ratios for both permeants. Peak surfactant enhancement effects were seen at alkyl chain lengths of 12 or 14 carbons. Strong correlation was noted between the enhancement ratios of water and lidocaine. Water permeation can serve as a predictor of the effects of surface-active compounds on the permeation of drugs. The data suggest that water and lidocaine utilize the same pathway through the horny layer.     

Enhanced transdermal delivery of loratadine from the EVA matrix

Various enhancers, such as fatty acids (saturated, unsaturated), glycerides, propylene glycols, and non-ionic surfactants, have been incorporated in the loratadine-EVA matrix to increase the rate of skin permeation of loratadine from an EVA matrix. The enhancing effects of these enhancers on the skin permeation of loratadine were evaluated using a modified Keshary-Chien cell fitted with intact excised rat skin. The penetration enhancers showed a higher flux, probably due to the enhancing effect on the skin barrier, the stratum corneum. Among the enhancers used, such as the fatty acids, glycols, propylene glycols, and non-ionic surfactants, linoleic acid showed the best enhancement. For the enhanced transdermal delivery of loratadine, application of an EVA matrix containing a permeation enhancer might be useful in the development of a transdermal drug delivery system.     

In Vitro Permeation Screening of a New Formulation of Thiocolchicoside Containing Various Enhancers

Thiocolchicoside, a muscle relaxant agent with anti-inflammatory and analgesic actions, also is used topically for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders. In this study, thiocolchicoside was formulated to use as foam to avoid contact with the afflicted area during the spreading phase. To enhance drug penetration, various enhancers were added to the base formulation. The tested enhancers were ethoxyethylendiglycol (Transcutol ®), highly purified phosphatidylcholine (Lipoid S20), capsaicin, propylene glycol dipelargonate (DPPG), and glycolysed ethoxylated glycerides (Labrafil M1944 CS). The transdermal absorption of the tested formulations containing enhancers, in comparison with base formulation, was evaluated in vitro through rat skin using standard Franz diffusion cells. Base formulation was found to have a higher permeation profile than the simple aqueous and hydroalcoholic solutions of the drug, meaning that the base formulation by itself enhances the drug permeation. Among the tested formulations, only the formulation containing DPPG/ethanol was found to be statistically different, showing an enhancement factor of 3.58. In the same experimental session, Muscoril ® ointment, the commercially available pharmaceutical product containing the same thiocolchicoside concentration (0.25%), also was tested. The formulation containing DPPG/ ethanol showed a 4.86 times increase of permeability constant in comparison with Muscoril ® ointment. The formulation containing DPPG/ethanol as an enhancer could be a good candidate for a new topical foam, considering its good characteristics of permeability and compliance.     

In vitro permeation screening of a new formulation of thiocolchicoside containing various enhancers

Thiocolchicoside, a muscle relaxant agent with anti-inflammatory and analgesic actions, also is used topically for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders. In this study, thiocolchicoside was formulated to use as foam to avoid contact with the afflicted area during the spreading phase. To enhance drug penetration, various enhancers were added to the base formulation. The tested enhancers were ethoxyethylendiglycol (Transcutol ® ), highly purified phosphatidylcholine (Lipoid S20), capsaicin, propylene glycol dipelargonate (DPPG), and glycolysed ethoxylated glycerides (Labrafil M1944 CS). The transdermal absorption of the tested formulations containing enhancers, in comparison with base formulation, was evaluated in vitro through rat skin using standard Franz diffusion cells. Base formulation was found to have a higher permeation profile than the simple aqueous and hydroalcoholic solutions of the drug, meaning that the base formulation by itself enhances the drug permeation. Among the tested formulations, only the formulation containing DPPG/ethanol was found to be statistically different, showing an enhancement factor of 3.58. In the same experimental session, Muscoril ® ointment, the commercially available pharmaceutical product containing the same thiocolchicoside concentration (0.25%), also was tested. The formulation containing DPPG/ ethanol showed a 4.86 times increase of permeability constant in comparison with Muscoril ® ointment. The formulation containing DPPG/ethanol as an enhancer could be a good candidate for a new topical foam, considering its good characteristics of permeability and compliance.     

Effect of penetration enhancers on the release and skin permeation of bupranolol from reservoir-type transdermal delivery systems

A reservoir-type transdermal delivery system (TDS) of bupranolol (BPL) was designed and evaluated for different formulation variables like gel reservoirs (made with anionic and nonionic polymers), rate controlling membranes and penetration enhancers on the drug release and in vitro skin permeation kinetics of the devices. Keshary-Chien type diffusion cells and pH 7.4 phosphate buffered saline (PBS) were used for drug release studies and excised rat skin was used as a barrier for permeation experiments. The release rate of BPL from nonionic polymer gel reservoirs [hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)] was much higher than anionic polymer gel reservoirs [carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (Na CMC) and sodium alginate)]. Among different rate controlling membranes, Cotran-polyethylene microporous membrane demonstrated highest release rate for BPL than all other membranes. An optimized TDS formulation with HPC gel and Cotran-polyethylene microporous membrane was used to study the effect of penetration enhancers on the release and skin permeation rate of BPL from the TDS. Permeation rates of the devices containing 5% (w/v) pyrrolidone (PY) or 1-methyl-2-pyrrolidone (MPY) were about 3- and 1.5-fold higher than control (no enhancer, P<0.01) indicating PY to be better penetration enhancer for BPL than MPY. The permeation rates of devices containing partially methylated beta-cyclodextrin (PMbetaCD) and PMbetaCD-BPL complex were about 2.5- and 1.4-fold higher than control (P<0.01). Inclusion of 10 and 30% w/v propylene glycol (PG) in the devices increased the permeation rate by 1.4- and 1.8-fold higher than control (P<0.05). In conclusion, reservoir-type TDS of BPL was developed and penetration enhancers increased the skin permeation of BPL at 4-5 times higher levels than the desired target delivery rate.     

促渗剂对奥沙普秦体外经皮渗透的影响

目的 研究几种常用促渗剂对奥沙普秦体外经皮渗透的影响。方法 用紫外分光光度法检测浓度,采用改进Franz扩散池,比较几种常用促渗剂对奥沙普秦渗透速率的影响。结果 氮酮(Azone)单独使用不能明显提高奥沙普秦的渗透速率(P>0.05),而丙二醇、薄荷醇、Azone 丙二醇(1:1)、丙二醇 薄荷醇(1:1)能显著提高奥沙普秦的渗透速率(P<0.01)。结论 丙二醇、薄荷醇、Azone 丙二醇(1:1)、丙二醇 薄荷醇(1:1)可作为促渗剂用于奥沙普秦经皮吸收制剂。     

酮咯酸氨丁三醇凝胶剂体外经皮渗透研究

目的：考察凝胶剂作为酮咯酸氨丁三醇透皮给药载体的可行性。方法：制备卡波姆940药物凝胶，采用Franz扩散池用离体大鼠皮肤进行体外经皮渗透实验，以HPLC法测定渗透介质中药物含量并求算累积渗透量及稳态透皮速率。结果：以1．0％卡波姆940为凝胶基质，以硼砂溶液调节凝胶的pHN6．0时所制备的凝胶为最佳凝胶基质。3％的月桂氮革酮及5％的丙二醇均可以显著提高凝胶中药物的经皮渗透，且两者联用存在协同作用。结论：本实验的凝胶基质可为生产提供参考依据。     

Liquid spray formulations of xibornol by using self-microemulsifying drug delivery systems

Xibornol is a lipophilic drug mainly used in Italy and Spain in spray dosage forms for the local treatment of infection and inflammation of the throat. Its poor water solubility makes difficult the development of aqueous formulations of the drug, thus giving rise to a limited number of stable and pharmaceutically accepted preparations. In fact, xibornol is actually marketed only as spray aqueous suspension. The aim of this work was to evaluate the possibility of developing a stable liquid formulation of the drug intended for oral spray administration using a self-microemulsifying drug delivery system (SMEDDS). These systems are able to adequately improve the drug solubility, allowing the introduction of relatively high concentration of drugs in the form of solution. Labrafil M1944, Labrafil M2125 and Labrafac CC were screened as oil phases, Labrasol and Labrafac PG as surfactants and Transcutol as co-surfactant. Pseudo-ternary phase diagrams were constructed, by titration with the aqueous phase of different oil phases and surfactant/co-surfactant mixtures in order to identify the self-microemulsification region and the optimal micro-emulsion composition. Then, complete pharmaceutical formulations were prepared and evaluated for stability and viscosity properties. The final selected formulations, containing Labrafil M1944, Transcutol, Labrafac PG and a hydrophilic co-solvent (propylene glycol or PEG 200) allowed complete solubilization of the required xibornol concentration (3%, w/v) and showed physical good stability up to 2 months at 25 and 4 °C, suitable viscosity and organoleptic properties.     

In vitro percutaneous penetration of acyclovir from solvent systems and Carbopol 971-P hydrogels: influence of propylene glycol

The mechanism underlying propylene glycol (PG) effects on acyclovir (ACV) penetration through human epidermis were studied. Solvent systems and Carbopol gels containing increasing percentage of PG (from 0% to 70%, w/w) were used. Viscosity studies of both vehicles were carried out to characterise the influence of rheological behaviour. In solvent systems skin permeation values of ACV increase as the concentration of PG increase yielding a maximum enhancement ratio (ER = 10) for 70% PG. The release rate of ACV from gels was determined. Higuchi's model was used to estimate the apparent diffusion coefficient of the drug. These values show a decrease as the content of PG in the vehicle increases; this effect could be attributed to the increase of the viscosity in the diffusional pathway. When gels are used skin permeation values of ACV were smaller than those of the solvent systems. This could be attributed to the network structure created by the polymer that increases the length of the diffusional pathway. The maximum ER (= 6.8) was for Carbopol gel containing 50% PG. Therefore, these gels can be considered candidates for further research to confirm their usefulness as delivery systems for ACV topical formulations.     

Cremophor RH40-PEG 400 microemulsions as transdermal drug delivery carrier for ketoprofen

The aim of this study was to prepare novel microemulsion for transdermal drug delivery of ketoprofen (KP). The microemulsion composed of ketoprofen as model drug, isopropyl myristate (IPM) as oil phase, surfactant mixture consisting of polyoxyl 40 hydrogenated castor oil (Cremophor RH40) as surfactant and polyethylene glycol 400 (PEG400) as co-surfactant at the ratio 1:1, and water were prepared. The viscosity, droplet size, pH, conductivity of microemulsions, and skin permeation of KP through shed snake skin were evaluated. The particle size, pH, viscosity and conductivity of microemulsions were in the range of 114-210 nm, 6.3-6.8, 124-799 cPs and 1-45 μS/cm, respectively. The ratio of IPM, and surfactant mixture played the important role in the skin permeation of KP microemulsions. As the amount of surfactant mixture and IPM increased, the skin permeation of KP decreased. The formulation composed of 30% IPM, 45% surfactant mixture and 25% water showed the highest skin permeation flux. The incorporation of terpenes in the 2.5% KP microemulsions resulted in significant enhancement in skin permeation of KP. The rank order of enhancement ratio for skin permeation enhancement of terpenes was α-pinene > limonene > menthone. The results suggested that the novel microemulsion system containing IPM, water, Cremophor RH40:PEG400 and terpenes can be applied for using as a transdermal drug delivery carrier.     

改善美洛昔康体外经皮渗透的研究

目的:研究几种常用促渗剂对美洛昔康体外经皮渗透的影响,改善美洛昔康体外经皮.方法:用紫外分光光度法检测浓度,采用改进Franz扩散池,比较几种常用促渗剂对美洛昔康渗透速率的影响.结果:氮酮(Azone)单独使用不能明显提高美洛昔康的渗透速率(P>0.05),而丙二醇.薄荷醇、丙二醇 Azone(1:1),丙二醇 薄荷醇(1:1)能显著提高美洛昔康的渗透速率(P<0.01).结论:丙二醇、薄荷醇、丙二醇 Azone(1:1)、丙二醇 薄荷肆(1:1)可作为促渗剂用于美洛昔康经皮吸收制剂.     

促渗剂对氟比洛芬体外经皮渗透的影响

目的研究不同的促渗剂对氟比洛芬体外经皮渗透的促渗作用。方法采用TK-6A型透皮扩散仪,用人皮进行体外经皮渗透实验,考察不同的促渗剂[二甲基亚砜、月桂醇、丙二醇、月桂氮酮(氮酮)、尿素、油酸]及其组合对氟比洛芬体外透皮吸收的促渗作用,以HPLC法测定各时间点接受室中药物浓度,求算透皮吸收的有关参数,比较各促渗剂的促渗作用。结果15%二甲基亚砜、3%氮酮、1%尿素可使氟比洛芬经皮渗透速率分别提高1.8,1.5,1.1倍,促渗剂联用取得的促渗效果更佳,5%油酸 20%丙二醇 1%尿素可使该药物的经皮渗透速率提高6倍。结论单用促渗剂对氟比洛芬经皮渗透促渗效果有限,促渗剂联合使用可以显著提高氟比洛芬经皮渗透速率。     

Structure Activity Relationships in Alkylammonium C12-Gemini Surfactants Used as Dermal Permeation Enhancers

The purpose of this study was to determine the ability and the safety of a series of alkylammonium C12-gemini surfactants to act as permeation enhancers for three model drugs, namely lidocaine HCl, caffeine, and ketoprofen. In vitro permeation studies across dermatomed porcine skin were performed over 24 h, after pretreating the skin for 1 h with an enhancer solution 0.16 M dissolved in propylene glycol. The highest enhancement ratio (enhancement ratio (ER) = 5.1) was obtained using G12-6-12, resulting in a cumulative amount of permeated lidocaine HCl of 156.5 μg cm⁻². The studies with caffeine and ketoprofen revealed that the most effective gemini surfactant was the one with the shorter spacer, G12-2-12. The use of the latter resulted in an ER of 2.4 and 2.2 in the passive permeation of caffeine and ketoprofen, respectively. However, Azone was found to be the most effective permeation enhancer for ketoprofen, attaining a total of 138.4 μg cm⁻² permeated, 2.7-fold over controls. This work demonstrates that gemini surfactants are effective in terms of increasing the permeation of drugs, especially in the case of hydrophilic ionized compounds, that do not easily cross the stratum corneum. Skin integrity evaluation studies did not indicate the existence of relevant changes in the skin structure after the use of the permeation enhancers, while the cytotoxicity studies allowed establishing a relative cytotoxicity profile including this class of compounds, single chain surfactants, and Azone. A dependence of the toxicity to HEK and to HDF cell lines on the spacer length of the various gemini molecules was found.     

Transdermal delivery of venlafaxine hydrochloride: the effects of enhancers on permeation across pig ear skin

Venlafaxine representing a new class of antidepressants is a potent serotonin/ norepinephrine reuptake inhibitor. Transdermal delivery of venlafaxine hydrochloride (VHCl) may result in proper patient compliance by reducing the incidence of the undesirable GI problems generally associated with its plural oral dosing. The present study is an attempt to investigate the improvement of the transdermal flux of the hydrophilic VHCl by certain permeation enhancers viz. glycerin, urea, propylene glycol and mixture of propylene glycol and ethanol across pig ear skin. The cumulative drug release was the highest from the formulation F5 consisting of the mixture of propylene glycol and ethanol in sodium alginate gel with a load of 25% w/w VHCl with 96% permeation enhancement. The steady state flux observed with F5 was 0.203 mg cm(-2) hr and an area of 15.27 cm(2) would suffice to arrive at a required therapeutic concentration of VHCl in the blood.