Abstract
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.
Highlights
Anal fissure is one of the most painful anal disorders that inversely affect the life quality of the patients
Lidocaine hydrochloride (LDH), poloxamer 407 (P407), titanium dioxide, TweenVR 20 were purchased from Sigma-Aldrich, St
The binary mixtures of lidocaine hydrochloride (LDH)-NIF and LDH-betamethasone valerate (BMV) exhibited one peak at 73.49 and 75.30 C, respectively, corresponding to that of LDH, while those of NIF and BMV disappeared. These results can be referred to the dissolution of the crystalline NIF and BMV in the molten LDH and complete conversion into the amorphous state during differential scanning calorimetry (DSC) run (Liu et al 2013)
Summary
Anal fissure is one of the most painful anal disorders that inversely affect the life quality of the patients. It is an elliptical or longitudinal tear in the anoderm distal to the dentate line, exactly proximal to or at the level of the anal verge (Hall & Kann 2016). Anal fissures can be acute or chronic (Beaty & Shashidharan 2016). Chronic anal fissure (CAF) is present for more than 6–8 weeks and it is characterized by exposed fibers of internal anal sphincters at the base, hypertrophied anal papilla proximally, and a skin tag or sentinel pile distally. Use of topical nitrates is hindered by headache reported in as many as 90% of patients as well as orthostatic hypotension due to possible vasodilatation following systemic absorption (Bulus et al 2013)
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