To study the release of verapamil hydrochloride gel through cellulose membrane and human cadaver skin using different permeability enhancers.

摘要

Optimal therapeutic outcomes require not only proper drug selection, but also effective drug delivery. In many instances, oral administration of drugs is considered as less than optimal medication delivery system due to extensive first pass metabolism. In these cases, delivering medicine into the general circulation through the skin is a desirable alternative to oral administration.;Verapamil has a very short biological half-life. Additionally it undergoes extensive first pass metabolism resulting in a low systemic bioavailability by oral route. These properties make it a very ideal candidate for transdermal drug delivery. The present study is about the transdermal delivery of verapamil hydrochloride gels and the effect of permeation enhancers.;All in-vitro permeation studies were conducted by using Franz-diffusion apparatus. During the entire study, verapamil hydrochloride concentration in gel formulation was kept constant which is 6% w/v. Initially, the gelling agent was selected by conducting several experiments with different gelling agents at different concentrations using cellulose membrane permeability studies. The gel was placed in the donor compartment and the receptor compartment was filled with PEG 400: Water (40:60). The release profile of Klucel (0.25%, 0.5% and 1%), Methocel (0.25%, 0.5% and 1%), and CMC (3%, 4% and 5%) was studied. Klucel gave the maximum flux among these gelling agents. Moreover, 0.25% Klucel gave a flux of 1845.67microg/cm2hr, while the 1% Klucel gave a flux of 1690.45microg/cm2hr. The higher flux of 0.25% Klucel gel was probably due to its low viscosity. The 1% Klucel gel had a viscosity of 0.528+/-0.02 centipoise, which is more suitable for topical applications. Therefore, the gel formulation with 1% Klucel was selected from the data obtained. Further studies were performed using different concentrations of oleic acid (1%, 2% and 3%) and capric acid (1%, 2% and 3%) as permeability enhancers. During these studies it was observed that these fatty acids had no effect on the release profile of the gel. With human cadaver skin the study was carried out with different permeation enhancers like sodium salt of capric acid (1%), sodium dodecanoate (1%), sodium salt of myristic acid (1%), methyl decanoate (1%), olanzapine (1%) and oleic acid (1%), and lauric acid (1%). The observed fluxes were 3.52microg/cm2hr for sodium salt of capric acid (1%), 8.10microg/cm2hr for sodium dodecanoate (1%), 8.78microg/cm 2hr for sodium salt of myristic acid (1%), 39.8microg/cm 2hr for methyl decanoate (1%), 96.3microg/cm2hr olanzapine (1%) and oleic acid (1 %), and 2.8microg/cm2hr for lauric acid (1%). From all the above permeability enhancers the maximum flux was observed with olanzapine (1%) and oleic acid (1%). Moreover sodium dodecanoate has shown to have a very low lag time (17.56 hr) as compared to the other permeability enhancers. For this reason, additional permeability studies through human cadaver skin were conducted for the 6% verapamil hydrochloride and 1% Kiucel gel added with oleic acid (1%, 3%, and 5%) and sodium dodecanoate (1%, 3%, and 5%).;The targeted flux for cardiovascular therapeutic effect was calculated to be 315microg/cm2hr. The studies showed that 5% oleic acid gave the maximum flux of 229.2+/-15microg/cm2hr that is about 72% of the target. Therefore, the theoretical flux may be obtained by either increasing the concentration of oleic acid or using other enhancers in combination or increase the concentration of drug in the gel or by increasing the size of application area. The study leads to the conclusion that verapamil hydrochloride is a good candidate for transdermal drug delivery when formulated with 1% Kiucel as a gelling agent and oleic acid as a permeation enhancer.