This work examined the effect of sodium carbonate (Na(2)CO(3)) on the topical delivery of methotrexate (MTX) from a loaded nanogel in vitro and the modulation of prostaglandin E(2) (PGE(2)) production in skin ex vivo. A nanogel based on co-polymerised N-isopropylacrylamide (NIPAM) and butylacrylate (BA) was synthesized, characterized and loaded with MTX. Finite doses were then applied to excised porcine epidermal membranes mounted in Franz diffusion cells, followed by the addition of saturated aqueous Na(2)CO(3). For comparison, the addition of half-saturated Na(2)CO(3) was examined along with loaded nanogel alone. The same treatments were applied to Silastic membrane and full-thickness porcine ear skin ex vivo, which was then treated with radioimmunoprecipitation buffer and probed for levels of PGE(2) using a commercial enzyme immunoassay kit. The MTX-loaded nanogel, which demonstrated de-swelling by 7% over the range 25-37°C, provided a MTX flux of 1.4±0.3ngcm(-2)h(-1); this increased to 3.1±0.22ngcm(-2)h(-1) upon the addition of saturated aqueous Na(2)CO(3) (p<0.05). Lag times were 6 and ∼0h, respectively. Similar results were obtained using half-saturated aqueous Na(2)CO(3). No permeation was detected across Silastic membrane. PGE(2) levels for water (control) and saturated aqueous Na(2)CO(3) were similar, but reduced by 33% when the MTX-loaded nanogel was applied, and by 57% when this was followed by the application of saturated aqueous Na(2)CO(3) (p<0.01). A novel mechanism is proposed whereby the change in temperature experienced by the nanogel as it penetrated skin induced de-swelling and expulsion of MTX in situ. The added Na(2)CO(3) lead to further solubilisation and MTX release, hence increasing the concentration gradient, flux and reducing PGE(2) production.
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