Development of a Topically Active Imiquimod Formulation

Abstract

The purpose of this work was to develop a topical formulation of imiquimod, a novel immune response modifier, to induce local cytokine production for the treatment of external genital and perianal warts. A pH-solubility profile and titration data were used to calculate a pKa of 7.3, indicative of a weak base. Solubility experiments were conducted to identify a solvent that dissolves imiquimod to achieve a 5% formulation concentration. Studies to select surfactants, preservatives, and viscosity-enhancing excipients to formulate an oil-in-water cream indicated that fatty acids were the preferred solvent for topical imiquimod formulations, and isostearic acid (ISA) was selected. A relationship existed between the fatty acid composition of four commercially available ISA sources and the solubility of imiquimod. A combination of polysorbate 60, sorbitan monostearate, and xanthan gum was used to produce a physically stable cream. The preservative system included parabens and benzyl alcohol to meet the USP criteria for preservative activity. An in vitro method was developed to demonstrate that imiquimod was released from the formulation. Topical application of the formulation induced local cytokine activity in mice.

Development of Imiquimod-Loaded Mucoadhesive Films for Oral Dysplasia

“…This finding is also supported by CV analysis of drug loading in the films: the films formulated by sonication had a CV of 15, which was twice that for films formulated with cyclodextrin or acetate buffer. Linoleic acid, because of its high solubility for imiquimod (17 mg/mL) 26 and its similarity to the fatty acid oleic acid used in the original Aldara cream, was chosen as the next step for solubilizing imiquimod and mixing it with polymer solutions. The films formulated with linoleic acid were nonuniform, and the oxidation of linoleic acid during drying resulted in a rancid odor from possible degradation into byproducts.…”

TLRs to cytokines: Mechanistic insights from the imiquimod mouse model of psoriasis

“…1‐(2‐methylpropyl)‐1H‐imidazo[4,5‐c]quinolin‐4‐amine is an imadazoquinoline derivative more commonly known as imiquimod or R837. It was originally developed as a low molecular weight nucleoside analog capable of potent induction of IFNs to provide antiviral activity . Because of its relatively small size and high hydrophobicity, imiquimod is well suited for topical administration.…”

“…Isostearic acid was found to act as a safe and effective oil-in-water solvent, providing a stable 5% emulsion. Surfactants were then tested to allow effective release of imiquimod on topical application, a formulation including polysorbate 60 and sorbitan monostearate was found to be stable and effective and possibly to aid penetration of the drug through the skin [12]. Imiquimod 5% cream was first licensed for clinical use in 1997 to treat genital and perianal warts, commonly caused by HSV or human papilloma virus, for which it provides reasonable efficacy and patient tolerance [14,15].…”

In Vitro Analysis of Acetalated Dextran Microparticles as a Potent Delivery Platform for Vaccine Adjuvants

“…Despite the successful use of this molecule in the treatment of several illnesses, it is not without limitations. In particular, imiquimod is a poorly soluble compound limiting parenteral administration in vivo (21). In addition, when delivered systemically, imiquimod initiates a cascade of inflammatory cytokines and pro-apoptotic factors that prove detrimental to the host (22).…”