Formulation and Evaluation of Hydrophilic Polymer Based Methotrexate Patches: In Vitro and In Vivo Characterization

Abstract

This study attempted to develop and evaluate controlled-release matrix-type transdermal patches with different ratios of hydrophilic polymers (sodium carboxymethylcellulose and hydroxypropyl methylcellulose) for the local delivery of methotrexate. Transdermal patches were formulated by employing a solvent casting technique using blends of sodium carboxymethylcellulose (CMC-Na) and hydroxypropylmethylcellulose (HPMC) polymers as rate-controlling agents. The F1 formulated patch served as the control formulation with a 1:1 polymer concentration. The F9 formulation served as our optimized formulation due to suitable physicochemical properties yielded through the combination of CMC-Na and HPMC (5:1). Drug excipient compatibilities (ATR-FTIR) were performed as a preformulation study. The ATR-FTIR study depicted great compatibility between the drug and the polymers. Physicochemical parameters, kinetic modeling, in vitro drug release, ex vivo drug permeation, skin drug retention, and in vivo studies were also carried out for the formulated patches. The formulated patches exhibited a clear, smooth, elastic nature with good weight uniformity, % moisture uptake, drug content, and thickness. Physicochemical characterization revealed folding endurance ranging from 62 ± 2.21 to 78 ± 1.54, tensile strength from 9.42 ± 0.52 to 12.32 ± 0.72, % swelling index from 37.16 ± 0.17 to 76.24 ± 1.37, and % drug content from 93.57 ± 5.34 to 98.19 ± 1.56. An increase in the concentration of the CMC-Na polymer (F9) resulted in increased drug release from the formulated transdermal patches. Similarly, drug permeation and retention were found to be higher in the F9 formulation compared to the other formulations (F1–F8). A drug retention analysis revealed that the F9 formulation exhibited 13.43% drug retention in the deep layers of the skin compared to other formulations (F1–F8). The stability study indicated that, during the study period of 60 days, no significant changes in the drug content and physical characteristics were found. ATR-FTIR analysis of rabbit skin samples treated with the formulated transdermal patches revealed that hydrophilic polymers mainly affect the skin proteins (ceramide and keratins). A pharmacokinetic profile revealed Cmax was 1.77.38 ng/mL, Tmax was 12 h, and t1/2 was 17.3 ± 2.21. In vivo studies showed that the skin drug retention of F9 was higher compared to the drug solution. These findings reinforce that methotrexate-based patches can possibly be used for the management of psoriasis. This study can reasonably conclude that methotrexate transdermal matrix-type patches with CMC-Na and HPMC polymers at different concentrations effectively sustain drug release with prime permeation profiles and better bioavailability. Therefore, these formulated patches can be employed for the potential management of topical diseases, such as psoriasis.

Formulation of Polymers-Based Methotrexate Patches and Investigation of the Effect of Various Penetration Enhancers: In Vitro, Ex Vivo and In Vivo Characterization

“…Analytical weighing balance (Shimadzu AX 200, Kyoto, Japan, +81-75-823-1111) was used for the investigation of weight variations in between formulated patches. The data obtained was averaged for confirming weight variation values [ 16 ].…”

“…Uniformity of patch thickness was ensured by measuring patches thickness at different six places. The result obtained was calculated and averaged (mean ± SD) [ 16 ].…”

“…The folding of formulated transdermal patches at same place were carried out until breaking and cracking in the patch formulations appears, and the number of folding of patch showed value of folding endurance. Following equation best demonstrate folding endurance [ 16 ]. F = d where F is folding endurance and d is number of folds required to break or crack the patch.…”

“…After 2 h, filtration was carried out for removal of excess water. The obtained results were calculated and averaged (mean ± SD) [ 16 ].…”

“…In warm water, the excised rabbit skin was placed for removal of adhered fats. The excised skin was washed with 0.9% sodium chloride solution and was kept at −20 ± 1 °C [ 16 ].…”