Potential combination topical therapy of anal fissure: development, evaluation, and clinical study†

To treat anal fissure, internal anal sphincterotomy may be associated with surgical risks and incidence of incontinence. Botulinum toxin injection into the anal sphincter is invasive and expensive. Headache and hypotension hindered topical treatment with glyceryl trinitrate. Greater patient compliance, potentiated efficacy, reduced side effects, and lower cost are the major advantages offered by the combination therapy. Therefore, combination topical gels of nifedipine (NIF), lidocaine hydrochloride (LDH) and betamethasone valerate (BMV) were prepared and evaluated regarding viscosity, pH, drug content, and in vitro release. Compatibility study of drug–drug and drug-excipient mixtures preceded the formulation. Stability study was performed. A prospective randomized clinical trial was conducted for six weeks to assess the efficacy of the optimized formula in the treatment of anal fissure either acute (AAF, 37 patients) or chronic (CAF, 34 patients) in comparison with three single drug market products. The compatibility was indicated except in case of LDH with each of poloxamer 407 (P407), methylparaben, and propylparaben as well as BMV with P407. The gels showed acceptable viscosity ranges, tolerated pH values, and drugs content limits complying with the pharmacopeial limit. The gel containing 10% Transcutol(®) (F2) was selected as optimized formula due to the significant (p < 0.05) enhancement in NIF release. The recommended storage temperature was 8 °C. In comparison with the market products, the optimized gel can be represented as a potential combination therapy of acute and chronic anal fissures as suggested by significantly increased healing% and significantly reduced pain, bleeding, anal discharge and itching without side effects.