Transdermal delivery of diltiazem hydrogen chloride through gels and patches: Effect of permeation enhancers, viscosity studies and physicochemical characterization

Diltiazem HCl (DTM HCl) was formulated as a 0.5 % (w/v) hydroxypropyl methylcellulose gel (HPMC, Methocel K15M Premium). The effect of several enhancers on DTM HCl permeability was determined in vitro. The following enhancers were added at a concentration 0.5 (w/w): sodium lauryl sulfate (SLS), DMSO, oleic acid, caprylic acid, myristic acid, Tween 80 (or polysorbate 80), propylene glycol (PG), isopropyl myristate (IPM) and N-methylpyrrolidone (NMP). Permeation studies with cellulose membrane indicated that all the enhancers caused a decrease in the flux. On the other hand, in vitro studies with human cadaver skin indicated that the effect on the flux varied depending on the enhancer. Viscosity studies were also performed to further investigate the effect each enhancer had on the gel's viscosity. The novel findings of this study were the following: (i) Polysorbate 80 was used for the first time as an enhancer with a hydrophilic compound in a hydrophilic carrier and it rendered the highest flux (57.1 +/- 0.9 ug/cm2/hr) comparatively to the rest of the enhancers. (ii) Among the several fatty acids chosen for this study, the saturated myristic fatty acid with 14 carbons in its chain rendered the highest flux (18.4 +/- 0.49 ug/cm2/hr). Viscosity studies of the HPMC gel indicated that myristic acid was the only one of the fatty acids that decreased the viscosity of the gel. (iii) NMP and IPM increased the release rate from the second day onwards i.e.: they caused a delayed permeation enhancement (46.5 +/- 0.34 ug/cm2/hr and 15.3 +/- 0.41 ug/cm2/hr, respectively). During the first 24 hrs, NMP did not alter the flux, whereas IPM decreased it. It was found that both enhancers increased the viscosity of the gel. (iv) Sodium lauryl sulfate also decreased the viscosity of the HPMC gel, but unlike myristic acid, it decreased the flux due to binding with the drug (8.1 +/- 0.21 ug/cm2/hr). (v) PG decreased the flux (10.2 +/- 0.32 ug/cm2/hr) by increasing the gel viscosity. (vi) DMSO increased the flux (13.8 +/- 0.4 ug/cm2/hr) without altering the viscosity. These findings indicate that to formulate DTM HCl into an HPMC gel the enhancers of choice are Tween 80, Myristic acid, DMSO, NMP and IPM or combinations of them.;Diltiazem HCl was also formulated as a transdermal patch. Several factors which may affect the effectiveness and stability of the formulation were tested. After a number of experiments, the following were concluded: The vehicle of choice for the transdermal delivery of DTM HCl was silicone. The patch was loaded with the maximum amount of drug that could technically be dispersed into the polymer solution, which was determined to be 28.8% w/w. The film thickness was 0.75 mm. Addition of PVP was required in the formulation at 1.5% w/w in order to prevent the re-crystallization of the drug. The backing layer was of high oxygen permeability because the study was intended for a prolonged period.;Enhancers could have been added but their addition in this formulation was not considered necessary. The release profile of this formulation (which will be referred as "optimal") was tested to verify that a high flux could be indeed obtained. This is the first report in the literature of the achievement of a DTM HCl flux as high as the one reported in this study (i.e.: 535.7 +/- 8.1 ug/cm2/hr).