(W1030-12-72) Nanostructured Lipid Carriers Enriched Gel for Enhancing Topical Delivery of Betamethasone Dipropionate in Treatment of Atopic Dermatitis

Purpose: Atopic dermatitis (AD) also called atopic eczema is a chronic, relapsing skin inflammation disease that affects children and adults. Topical corticosteroids are the mainstay of treatment for Atopic dermatitis. Betamethasone dipropionate is a highly potent corticosteroid used in the treatment of skin inflammation diseases but has certain drawbacks such as low epidermal targeting, skin atrophy and irritation and systemic side effects on long term use. Hence, there is an urging need for developing an alternative delivery system over the conventional therapy. Nano drug delivery approach is a widely raising technique with possible applications in medicine and clinical use. Lipid formulations like nanostructured lipid carriers (NLCs) mainly enhances solubility and bioavailability of poorly water-soluble drugs. The lipophilic nature of Betamethasone dipropionate lends itself for solubilizing in the lipids of NLC, thereby increasing the drug loading capacity. The aim of the researchers was encapsulation of the drug in the NLC core to control the permeation and provide higher concentration of the drug at the target site, thereby eliminating the risk of systemic side effects. The developed formulation was evaluated for physicochemical, in vitro, ex vivo and cytotoxicity studies. Developed drug loaded NLC gel showed promising results as compared to marketed product showing potential for better therapy management of Atopic dermatitis.

Methods: Based on the results of the solubility studies and literature search, solid lipids, liquid lipids and surfactants were selected for the development of Betamethasone dipropionate loaded nanostructured lipid carrier. After the selection, maximum solubility of Betamethasone dipropionate was determined in various ratios of solid lipid and liquid lipid with desired dose of drug. NLCs were then formulated using hot melt emulsification followed by probe sonication homogenization technique. Central Composite Design (CCD) using two full level factorial was applied for the optimization of Betamethasone dipropionate loaded NLCs. NLCs were characterized using Malvern zeta sizer for particle size, polydispersity index (PDI) and zeta potential. Various grades of Carbopol® such as Carbopol® 971, Carbopol® Ultrez 10 NF and Carbopol® 974 were employed to prepare NLC-based gel in different concentration range. Two drug loaded batches with and without jojoba oil were prepared. The optimized NLC based gel was characterized for appearance, spreadability, viscosity, drug content, occlusive effect and pH. In vitro diffusion studies, ex vivo skin permeation studies, skin retention studies and HET CAM was carried out for NLC and NLC based gel. The test compounds are evaluated at concentrations 6, 25, 12.5, 25, 50 and 100µG/mL to analyse the cytotoxicity effect on HACAT cell line. The final formulation was charged for stability for 3 months as per ICH Q1A (R2) guidelines.

Results: NLC of Betamethasone dipropionate were prepared using Compritol ATO 888 as solid lipid, Caproyl 90 as liquid lipid and Tween 80 as surfactant. NLC of Betamethasone dipropionate showed particle size of 164 nm, PDI 0.188, zeta potential -11.6 mV, entrapment efficiency of 92.65% and in-vitro release of 90.62% at the end of 12 hrs. Carbopol ® Ultrez 10 NF 1% gelling agent was selected for incorporating Betamethasone dipropionate loaded NLCs (BD-NLCs). NLC incorporated in jojoba oil gel showed spreadability of 675 gm.cm/4secs, occlusive effect of 58.67 ± 1.02 and controlled release of 91.28 % at the end of 2 hrs compared to the marketed gel. The ex-vivo study on porcine ear skin revealed the improved permeation and retention of betamethasone dipropionate in skin layers. There was no sign of skin irritation indicating safe for topical application. The results of cytotoxicity study (MTT assay) suggested NLC dispersion had cell proliferation potency on HaCaT cells and were non-toxic up till the concentration of 100ug/ml after the treatment period of 24hrs respectively.

Conclusion: This study entails a great promise of reducing skin inflammation for atopic dermatitis patients. We have explored the potency of drug Betamethasone dipropionate by loading it into nanostructured lipid carriers (NLCs) and incorporating into the gel. The studies showed that there were no signs of irritation and depicted high permeation and retention indicating its safety and efficacy as a topical formulation.


Fig. 1. Development of Betamethasone dipropionate NLCs using Central Composite Design (A) Contour plot and 3D surface plot of Particle size (B) Contour plot and 3D surface plot of polydispersibility index (C) Contour plot and 3D surface plot of EE


Fig. 2. (A) Particle size and Polydispersity index (PDI) by Malvern Zetasizer (B) % drug release of BD-NLC dispersion (C) % drug release of Betamethasone dipropionate loaded NLC gels and Marketed gel (D) TEM images of Betamethasone dipropionate loaded NLC


Fig. 3. (A) Skin irritation studies on HetCam egg (B) & (C) % cell viability of NLC dispersion