Delivery of Model Lipophilic Compounds from Poloxamer 407 Thermoreversible Gels

Permeation into the skin from topical drug application favors highly lipophilic drugs due to the low water content and intercellular lipids of the stratum corneum (outermost layer of the skin). However, many lipophilic drugs are BCS Class II or IV with low water solubility that limits their bioavailability in the hydrophilic dermal environment. Thermoreversible poloxamer gels are well tolerated topical delivery systems that can concentrate drug in the epidermis and dermis. Addition of excipients and drugs can significantly affect the solution to gel transition temperature (T_solâ??gel), and the effect may be dependent upon the physicochemical properties of the active ingredient. In this work, two model lipophilic compounds, loperamide hydrochloride and diclofenac sodium, were used to formulate thermoreversible gels. These compounds were chosen for their comparable lipophilicity (logP 4.51 and 5.5 for diclofenac and loperamide, respectively) but varying water solubility (0.0086mg/mL and 50mg/mL for loperamide and diclofenac, respectively). Gels were prepared with a poloxamer 407 base to make thermoreversible aqueous solutions. Due to its nearly negligible water solubility, the mixed solvency concept was initially used to enhance the solubility of loperamide in aqueous solutions. Maximum loperamide solubility occurred in a 40% solution of propylene glycol (10 w/w %) and PEG 400 (30 w/w %), increasing its solubility by nearly 1,500 times compared to water. Solubility results informed formulations of thermoreversible gels, prepared using the cold technique with poloxamer 407. A loperamide-incorporated gel (16% w/w Poloxamer 407, 0.5% loperamide, 8% PEG 400, 24% propylene glycol, 4% ethanol) and two diclofenac sodium-incorporated gels (17% poloxamer 407, 0.5% or 1% diclofenac sodium) were investigated for solution to gel transition temperatures (T_solâ??gel) and in vitro drug release. Solution to gel transition temperatures were 23 ± 3.5°C, 29.3 ± 0.6°C, and 31°C for the 0.5% and 1% diclofenac and 0.5% loperamide gels, respectively. In vitro drug release studies were conducted using excised porcine skin and resulted in an unexpectedly rapid lag time of less than three hours for both drugs.