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 C_max was 1.77.38 ng/mL, T_max was 12 h, and t_1/2 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.

Keywords: hydroxypropyl methylcellulose (HPMC); methotrexate; sodium carboxymethylcellulose (CMC-Na); transdermal drug deliveries (TDDs); transdermal patches.

Figure 1

ATR-FTIR spectra of (a) pure drug methotrexate, (b) F1, (c) F2, (d) F3, (e) F4, (f) F5, (g) F6, (h) F7, (i) F8, and (j) F9.

Figure 2

Skin irritation study: edema and erythema. Data are expressed as mean ± SD; n = 3. The results were significant compared to formalin (one-way ANOVA followed by post hoc Tukey test; p < 0.05).

Figure 3

Release profiles of methotrexate from formulated patches (F1–F9). Data are expressed as mean ± SD; n = 3. One-way ANOVA followed by post hoc Tukey test (p < 0.05), F9 vs. F1.

Figure 4

Permeation profiles of methotrexate from formulated patches (F1–F9). Data are expressed as mean ± SD; n = 3. One-way ANOVA followed by post hoc Tukey test (p < 0.05), F9 vs. F1.

Figure 5

Skin drug retention analysis of methotrexate patches (F1–F9). Dataare expressed as mean ± SD; n = 3. One-way ANOVA followed by post hoc Tukey test (p < 0.05), F9 vs. F1.

Figure 6

Representation of rabbit skin FTIR: (a) epidermis untreated, (b) epidermis treated with F1, (c) epidermis treated with F5, (d) epidermis treated with F9, (e) dermis untreated (f) dermis treated with F1, (g) dermis treated with F5, and (h) dermis treated with F9. Data are expressed as mean ± SD; n = 3.

Figure 7

Methotrexate concentration in the skin from the methotrexate solution and methotrexate-optimized patch formulation (F9). Data are expressed as mean ± SD; n = 3. One-way ANOVA followed by post hoc Tukey Test (p < 0.05).