Formulation Development and Systemic Optimization of Hydroxychlotoquine Loaded Ethosomal Gel For the Management of Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease manifested by chronic joint inflammation leading to severe disability and premature mortality. With a global prevalence of about 0.3%–1% RA is 3–5 times more prevalent in women than in men. There is no known cure for RA; the ultimate goal for treatment of RA is to provide symptomatic relief. Hydroxychloroquine is an BCS Class Ⅲ. It is also used for the treatment of rheumatoid arthritis. Hydroxychloroquine is only available in tablets (FDA: Plaquenil summary of product characteristics). HCQ is only marketed as HCQ sulphate in film-coated or coated tablets for oral use. It have short half-life and insufficient concentration of drug at the site of action, frequent dosing, poor bioavailability, degradation by gastrointestinal enzymes, food interactions, renal impairment and hepatic injury. To overcome these barriers, we have turned to transdermal route of drug administration, which has superior patience compliance and they bypass the first past effect experienced with conventional oral administration. Furthermore, to enhance the permeation of drug through the layers of the skin and reach the site of inflammation, Nano-sized carriers have been designed i.e. ethosomes. This drug delivery system is non-toxic and have high drug encapsulation efficiency and they also provide sustained release of drug. Therefore, the Ethosomes were incorporated in the Carbopol gel for better penetrability and to gain prolonged residence time for efficient reduction of RA induced inflammation. So the aim of the study was to Formulate, Develop and Systemic Optimization of Hydroxychloroquine Ethosomal Gel for The Management of Rheumatoid Arthritis. HCQ is a white, crystalline compound. It has a calculated molecular weight of 335.872 g/mol. It is easily soluble in water and organic solvents. At Preformulation stage various tests such as melting point determination, solubility studies, identification of drug sample by FT-IR and finding Absorption maxima (λ-max) by UV spectrophotometer were carried out. The UV method was developed and validated as per ICH Q2(R1) guidelines. The melting point of drug was found to be 90°C.The UV absorption maxima was found to be 343nm and the same was used for development of the UV methods. Various other parameters such as accuracy, precision, stability and robustness were also carried out. The LOD and LOQ were found to be 0.958 µg/ml, and 2.905 µg /mL, respectively which indicate the sensitivity of the method. Calibration curve equation and the corresponding R2 values were found to be y = 0.034 x - 0.019 and coefficient of correlation value (R2) =0. 998. Optimized Ethosomal formulation. The HCQ loaded ethosomes were prepared by cold method. Central Composite design was used for the optimization of the ethosomes using Design-Expert® software. The Optimized formulation(F6) was characterized for vesicle size, size distribution, shape, zeta potential, entrapment efficiency. The entrapment efficiency was found to be 86±0.03. The Average size of Optimized ethosomes (F6) was found to be 415 nm while the Poly-dispersity Index (PDI) was 0.385. The zeta-potential of the optimised formulation was -5.30 mV. The entrapment efficiency was found to be 86±0.03. The drug release of (F6) was found to be 88%. Further (F6) was incorporated in the Carbopol 934(1.5w/v). The HCQ loaded gel was characterised for Organoleptic properties, Ph Drug content, Spreadability, InVitro and Ex-Vivo studies. The gel was Transparent, Non greasy, Free from grittiness, smoothly and having No skin irritation. pH value of ethosomal gel was found to 6.8±0.01. As this pH value is close to neutral it can prevent the risk of skin irritation at the application site. The drug content was 92.89± 0.95. In-Vitro Drug Release of Ethosomal Gel was 86%. Ex-vivo drug permeation studies showed 60% of the drug permeated the skin in 6 hours and more than 25% of the drug was found to be deposited in the pig ear skin showing 85% of the drug permeation. This formulation as it provides better bioavailability, ease of permeability, patient compliance, avoids first metabolism in GI tract and at the same time is more effective from the Pharmacoeconomics point of view when compared to the conventional market formulation of Hydroxychloroquine.