Design, Development and Optimization of Novel Anti-acne Formulations of Dapsone

Abstract

Backgound: Acne is a most common and multifactorial disorder which is currently incurable with available treatment and knowledge. Acne treatment lasts from months to years. To avoid systemic side effects of anti-acne agents, topical route is the most preferred way to provide local treatment which has bioavailability issues. In recent scenarios, most physicians use combination therapy (systemic and topical) to quickly get rid of acne. Successful management of acne needs careful selection of anti-acne agents for treatment according to type/level of acne and individual patient needs. To overcome these challenges, it was hypothesized to prepare one-month depot injection in the form of microspheres which provides long term treatment and to prepare topical dosage form with higher skin penetration and retention. Aim and Objective: Aim was to prepare dapsone containing intramuscular microspheres for long term treatment and topical nanogel with high retention and penetration effect for the management of acne vulgaris. So, the objective is to develop and optimize the microspheres as depot injection and to develop and optimize topical nanogel followed by In-vivo evaluation. Materials and methods: Formulation 1: Dapsone for injectable suspension (Microspheres) In the present study, dapsone was selected as an active model drug because of its activity against P. acne (Propionibacterium acne) bacteria. Microsphere as injectable suspension was selected as a dosage form to improve patient compliance by providing long term treatment with minimum systemic side effects. Poly (lactide-co-glycolic acid) (50:50) was selected as a polymeric carrier as it is biocompatible and biodegradable in nature. Solvent extraction and evaporation techniques were used to prepare microspheres by adopting risk based systemic approaches like identification of critical quality attributes, risk assessment, identification of critical process parameters, optimization using design expert software. Further optimized formulation was evaluated using free drug analysis, entrapment efficiency, surface morphology by SEM, particle size analysis, molecular weight, residual solvents and In-vitro dissolution study. The formulation was compared with API suspension for controlled release through in-vivo study in Sprague Dawley rats. Formulation 2: Dapsone topical nanogel Dapsone topical gel is available as commercial formulation. In the present study, dapsone topical gel was compared with marketed formulation (e.g. Aczone, Acnedap) to increase dapsone penetration and retention. Polymeric nanoparticles were prepared to increase penetration through skin barrier and charge particles through steric effect to increase retention in the dermis layer. Nanogel was prepared using emulsification technique followed by solvent evaporation by adopting risk based systemic approaches like identification of critical quality attributes, risk assessment, identification of critical process parameters, optimization using design expert software. Further optimized formulation was evaluated using free drug analysis, entrapment efficiency, pH, particle size analysis, viscosity, residual solvents, In-vitro diffusion study and Ex-vivo permeation study. The formulation was applied topically and compared with marketed formulation (e.g. Acozone) through in-vivo study in Sprague Dawley rats. Result and discussion: Formulation 1: Dapsone for injectable suspension (Microspheres) (Formulation and Development) results of 33 central-composite design experiments revealed that Temperature of quench phase, flow rate of dispersed phase and Drug: polymer ratio were found critical process parameters (CPPs) while residual ethyl acetate, particle size and drug release at T24 were found critical quality attributes (CQAs). Further identified CQA and CPP were optimized along with the drug concentration by employing the Response Surface Methodology (RSM) design using Design Expert software. The physicochemical properties of the resultant optimized microspheres were found as per the desired target product profile (TPP). In-vitro release profile of microspheres shows controlled release up to 30 days as compared to API solution. Thus, it was concluded that the resultant data are in accordance with the proposed hypothesis and found the potential to evaluate further for In-vivo release. (In-vivo evaluation) API solution and microsphere suspension were injected in animals through intra-muscular route. It reveals that the microspheres show controlled release over API solution. The concentration of dapsone was maintained within the therapeutic window throughout 30 days while API solution shows concentration above maximum safe concentration. Hence, resultant data confirms that dapsone entrapped in PLGA microspheres is able to control the release of API up to 1 month. Formulation 2: Dapsone topical nanogel (Formulation and Development) results of 32 factorial design revealed that polycaprolactone concentration and temperature during solvent evaporation were found critical process parameters (CPPs) while Time at 100% release, Residual acetone and % Assay were found critical quality attributes (CQAs). Further identified CQA and CPP were optimized along with the drug concentration by employing the Response Surface Methodology (RSM) design using Design Expert software. The physicochemical properties of the resultant optimized nanogel were found as per the desired target product profile (TPP). Ex-vivo study was conducted with and without dermis layer which confirms that formulation increases retention in skin layer. (In-vivo evaluation) In-house nanogel and marketed formulation were applied on animals for 24 days once daily. It reveals that nanogel has 3.5 times higher retention as compared to marketed formulation. In-vivo, nanogel shows less systemic concentration as compared to marketed formulation which concludes more local retention of dapsone. Hence, resultant data confirms that dapsone entrapped in polycaprolactone shows higher penetration and retention as compared to marketed formulation (e.g. Aczone). Conclusion: The overall results strengthen the present concept of long-term depot injection and nanogel formulation with higher penetration and retention efficiency. The combination of systemic and topical delivery system can provide effective treatment in acne.