Transdermal drug delivery not only has contributed immensely to medical practice, but has enjoyed enormous interest in the field of cosmetic and pharmaceutical industries. Nevirapine, a non‐nucleoside reverse transcriptase inhibitor (NNRTI) is used clinically for the treatment of HIV‐ 1 infection. The aim of the present study is to investigate the influence of cosolvents (glycerol, propylene glycol, ethanol, polyethylene glycol 400) and surfactants (polysorbate 20, polysorbate 80, sodium lauryl sulfate, sodium cholate and cetrimide) on the dermal permeability coefficient of nevirapine by utilizing established and recognized mathematical model that employs partition coefficient as one of its molecular descriptors. The partition coefficient of nevirapine is determined in chloroform-water system at room temperature using the shake flask method. The results show that all the cosolvents used in this study decrease the partition coefficient of nevirapine. The same decrease in the partition coefficient of nevirapine is observed with all the surfactants investigated. The order of dermal enhancement potential of the vehicles studied based on the predicted permeability coefficient is glycerol > propylene glycol > ethanol > polyethylene glycol 400 for the cosolvents while tween 20 > tween 80 > sodium lauryl sulfate > sodium cholate > cetrimide for the surfactants. The maximum predicted flux through skin was obtained by multiplying the predicted permeability coefficient and the drug aqueous solubility. As the rate of penetration into the skin is quantitatively assessed by the use of permeability coefficient, the findings suggest that for dermal formulation of nevirapine, glycerol and tween 20 are the most preferred vehicles out of the vehicles investigated. Furthermore, the results of the correlation coefficients obtained by plotting permeability coefficient or maximum predicted flux, versus logarithm partition coefficient indicate that permeability coefficient can be a more reliable parameter to predict transdermal absorption of nevirapine than flux.
Nevirapine, chemically defined as 11-cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido{3,2-b:2’,3’-e}{1,4}di- azepine-6-one has chemical structure presented in
Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used clinically to treat HIV-1 infection. Its mechanism of action involves direct binding to reverse transcriptase (RT) thereby blocking the RNA- dependent and DNA-dependent DNA polymerase activities resulting in the disruption of the enzyme’s catalytic site [
This route of drug delivery is easy to use and noninvasive, increases patient compliance, increases therapeutic index with simultaneous decrease in side effects and provides steady plasma level [
The skin is composed of two layers namely the epidermis (nonvascular layer of about 100 µm thick) and the dermis (highly vascularized layer of about 500 to 3000 µm thick). However, the layer reported [
The permeability coefficient is the principal factor used to estimate movements of drugs through the skin [
number of hydrogen bond donors (nNHOH) and number of rotational bonds (nrotb), polar surface area etc. have also been used to determine dermal permeability coefficient. These additional models have shown that the application of more descriptors for dermal permeability coefficient determination increases the correlation coefficient (r2) of determination.
Cosolvents and surfactants are often employed in cosmetic or pharmaceutical formulations to serve various purposes including percutaneous enhancement [
In the present study, we investigate the effect of these vehicles on the partition coefficient of nevirapine while envisaging that the results of the study will provide some knowledge on the dermal enhancement potentials of the studied vehicles and invariably the dermal permeability coefficient of nevirapine. Potts and Guy [
Nevirapine (Boehringer Ingelhem, USA), glycerol, propylene glycol, polyethylene glycol 400, polysorbate 20 (tween 20), polysorbate-80 (tween 80), sodium lauryl sulfate, sodium cholate, cetrimide were purchased from Sigma-Aldrich (USA), chloroform was purchased from Fisher Scientific (USA) and other chemicals were of analytical reagent grade.
Stock solution of nevirapine (10 µg/ml) was prepared in methanol. Aliquots (1.0 - 5.0 µg/ml) of the standard stock solution were pipetted into a 10 ml volumetric flask diluted to volume with methanol.
The partition coefficient of nevirapine was determined in a chloroform-water system. To 5 ml of chloroform (saturated with different vehicles studied) containing 100 µg/m of nevirapine was added 5 ml of aqueous solution (saturated with chloroform) of different concentrations of glycerol, propylene glycol, ethanol, polyethylene glycol 400, polysorbate-20, polysorbate-80, sodium lauryl sulfate, sodium cholate and cetrimide. The vials were capped and agitated at room temperature for 2 h to achieve complete equilibration. The aqueous phase was analyzed using UV/Vis spectrophotometer at a maximum wavelength of 275 nm. The drug concentration in the aqueous layer was obtained from the calibration graph. The partition coefficient of nevirapine was calculated using this equation [
where P = partition coefficient; C1 = total concentration of gemifloxacin; Cw = concentration of gemifloxacin in aqueous phase; Vw = volume of the aqueous phase; Vo = volume of the organic phase.
The determination was carried out in triplicates.
The results of the present study are presented in Tables 1-3 respectively. In
Conc (% w/v) | Log Partition Coefficient (mean ± SD) | Log Dermal Permeability Coefficient | ||||||
---|---|---|---|---|---|---|---|---|
Glycerol | Propylene glycol | Ethanol | Polyethylene glycol 400 | Glycerol | Propylene glycol | Ethanol | Polyethylene glycol 400 | |
0.0 | 2.7680 ± 0.036 | 2.768 ± 0.036 | 2.768 ± 0.036 | 2.768 ± 0.036 | −2.379 | −2.379 | −2.379 | −2.379 |
5.0 | 2.5709 ± 0.041 | 2.5327 ± 0.016 | 2.3712 ± 0.048 | 1.9977 ± 0.038 | −2.5191 | −2.5462 | −2.6609 | −2.9261 |
10.0 | 2.5234 ± 0.007 | 2.4627 ± 0.031 | 2.2325 ± 0.026 | 1.5629 ± 0.029 | −2.5528 | −2.5959 | −2.7594 | −3.2348 |
15.0 | 2.4707 ± 0.011 | 2.0623 ± 0.025 | 1.9499 ± 0.021 | 1.4026 ± 0.002 | −2.5902 | −2.8802 | −2.9600 | −3.3486 |
20.0 | 2.3368 ± 0.063 | 2.0414 ± 0.021 | 1.7043 ± 0.008 | 1.2004 ± 0.006 | −2.6853 | −2.8950 | −3.1344 | −3.4921 |
25.0 | 2.1944 ± 0.056 | 1.9941 ± 0.013 | 1.3671 ± 0.029 | 0.9841 ± 0.015 | −2.7864 | −2.9286 | −3.3738 | −3.6457 |
SD = standard deviation.
Conc (% w/v) | log Partition Coefficient (mean ± SD*) | log Dermal Permeability Coefficient | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Tween 20 | Tween 80 | Sodium lauryl sulfate | Sodium cholate | Cetrimide | Tween 20 | Tween 20 | Sodium lauryl sulfate | Sodium cholate | Cetrimide | |
0.0 | 2.7680 | 2.7680 | 2.7680 | 2.7680 | 2.7680 | −2.3790 | −2.3790 | 2.7680 | −2.3790 | −2.3790 |
0.05 | 2.2270 | 2.1999 | 2.3169 | 2.1536 | 1.9292 | −2.7633 | −2.7825 | −2.6994 | −2.8154 | −2.9747 |
0.10 | 2.2158 | 2.1840 | 1.9056 | 1.9499 | 1.6450 | −2.7712 | −2.7938 | −2.9915 | −2.9600 | −3.1765 |
0.20 | 2.0665 | 1.8701 | 1.8080 | 1.8283 | 1.4814 | −2.8772 | −3.0167 | −3.0463 | −3.0463 | −3.2926 |
0.50 | 1.7364 | 1.6427 | 1.5864 | 1.5534 | 1.2144 | −3.1116 | −3.1781 | −3.2181 | −3.2415 | −3.4822 |
1.00 | 1.6538 | 1.5515 | 1.4713 | 1.3528 | 1.0522 | −3.1702 | −3.2429 | −3.2998 | −3.3839 | −3.5974 |
2.00 | 1.5384 | 1.3966 | 1.2700 | 1.2465 | 0.9141 | −3.2522 | −3.3528 | −3.4427 | −3.4594 | −3.6954 |
SD* = standard deviation range: 0.002 - 0.067.
Conc (% w/v) | Flux (µg/cm2/h) | Conc (% w/v) | Flux (µg/cm2/h) | |||||
---|---|---|---|---|---|---|---|---|
Glycerol | Propylene glycol | Polyethylene glycol 400 | Tween 20 | Tween 80 | Sodium lauryl sulfate | Cetrimide | ||
0.0 | 0.3282 | 0.3282 | 0.3282 | 0.0 | 0.3282 | 0.3282 | 0.3282 | 0.3282 |
5.0 | 0.4423 | 0.5318 | 0.4581 | 0.05 | 0.2902 | 0.3553 | 0.3636 | 0.1960 |
10.0 | 0.5582 | 0.9604 | 0.2477 | 0.10 | 0.3707 | 0.4160 | 0.3027 | 0.0893 |
15.0 | 0.8489 | 0.6697 | 0.3184 | 0.20 | 0.3265 | 0.2855 | 0.3993 | 0.1088 |
20.0 | 0.9719 | 1.0179 | 0.5690 | 0.50 | 0.3108 | 0.3305 | 0.3938 | 0.0970 |
25.0 | 1.1276 | 1.6084 | 0.6847 | 1.00 | 0.4387 | 0.4435 | 0.5132 | 0.1111 |
2.00 | 0.6850 | 0.6418 | 0.7040 | 0.1721 |
glycol, ethanol and polyethylene glycol 400 respectively. The results might be explained if we assume that the squeezing out of the drug from the aqueous phase decreased as the polarity of the vehicles decreases thereby resulting in the drug partitioning less into the organic phase.
Previous report has shown diffusion coefficients of alcohols in hydrated skin were ten times that observed in dry skin [
The results in
However, the surfactants gave less linear relationship with correlation coefficients of −0.7885, −0.7780, −0.7772, −0.7713 and −0.7257 for tween 20, tween 80, sodium cholate, sodium lauryl sulfate and cetrimide respectively. Plot of concentration of surfactant versus logarithm of partition coefficient is not shown due to lack of uniformity in point scattering. The experimental logarithm partition coefficient values were utilized to predict the dermal permeability coefficient of nevirapine through the skin. This was accomplished by the application of Potts and Guy equation:
where Kp is the dermal permeability coefficient, P is the partition coefficient and MW is the molecular weight of nevirapine respectively. Permeability coefficient has been reported to be a useful parameter in evaluating dermal absorption of drugs and has produced effective results [
In an effort to ascertain which of the two parameters namely permeability coefficient and flux would be the better parameter to describe the potential dermal absorption of nevirapine, we chose polyethylene glycol 400 and sodium lauryl sulfate at their different concentration levels. These vehicles were found in the previous report [
when the maximum predicted flux was plotted against logarithm partition coefficient. A similar plot with the results of sodium lauryl sulfate gave correlation coefficients (r2) of 0.9473 and −0.7219 for predicted permeability coefficient and maximum predicted flux respectively. An increase in correlation coefficient (r2) indicates an improved fit of the raw data and substantiates the accuracy of that model in the prediction of dermal permeability coefficient. The results of the correlation coefficients therefore suggest that permeability coefficient could be a more reliable parameter than flux in describing the percutaneous absorption of nevirapine.
Amongst the cosolvents studied, polyethylene glycol 400 showed the highest decreasing effect on the partition coefficient of nevirapine. With the surfactants, the highest decrease was observed with cetrimide. The maximum predicted flux (µg/cm2/h) was obtained from the product of predicted permeability coefficient and the drug aqueous solubility. The results of the correlation coefficients obtained by plotting predicted permeability coefficient or maximum predicted flux versus logarithm partition coefficient indicated that permeability coefficient could be a more reliable parameter than the flux in predicting transdermal absorption of nevirapine. Thus, if permeability coefficient is to be used to predict the transdermal absorption of nevirapine, the results then suggest that glycerol and polysorbate 20 when compared to other vehicles investigated, are potential transdermal absorption enhancers of nevirapine and hence the preferred vehicles to be employed in the formulation of topical pharmaceutical products containing nevirapine. The results also suggest that: 1) nevirapine can be formulated into a transdermal dosage form containing glycerol and/or tween 20 as potential dermal enhancers of the drug for the treatment of HIV patients; 2) pharmaceutically, nevirapine can be fabricated into a transdermal patch. Finally, based on the significance of the findings, future work shall involve both in vitro and in vivo investigations.
Chika J. Mbah,Theophilus C. Onyekaba,Agatha O. Uwakwe, (2016) Prediction of Dermal Permeability Coefficient of Nevirapine—Effect of Cosolvents, Anionic, Nonionic and Cationic Surfactants. Pharmacology & Pharmacy,07,283-289. doi: 10.4236/pp.2016.77035