Development and evaluation of desoximetasone loaded niosomes for topical drug delivery using quality by design (QbD) approach
Creators: name: Shah, Parinbhai B.
Publisher: name: No Publisher Supplied
Year: 2021

description: Drug delivery via the transdermal and topical routes offers many advantages, including improved patient acceptance, targeted local delivery, reduced systemic toxicity/side-effects, avoidance of the hepatic first-pass metabolism, and enablement of sustained or controlled drug release. However, skin functions as a barrier which poses a major challenge to the delivery of therapeutically significant amounts of drug into and across the skin. This barrier property of the upper skin layer (stratum corneum) also affects the deposition of a drug within the lower skin layers. Therefore, it is critical to select a suitable carrier and approach which can enhance drug deposition in the skin. The approaches include among others, the use of chemical permeation enhancers and vesicle based drug delivery. One example of the latter is niosomal topical formulations. This research work was focused on the systematic development of non-ionic surfactant based niosomal formulations using Quality by Design (QbD) principles. The research was subdivided into three phases as described below. In the first phase of the study, niosomes were prepared by considering various Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs). Organic solvent selection, drug concentration, surfactant concentration, cholesterol concentration, and type of lipids used in the formulation were considered as CMAs. Systematically, experiments were performed by changing the concentrations of drug, surfactant, and cholesterol to evaluate the impact of these changes on the final drug product. Mixing parameters (speed and time), internal and external phase volume, external phase temperature, and organic phase addition rate were considered as CPPs. Various formulations were manufactured by changing process parameters to evaluate their impact on the final drug product. Each formulation was evaluated for entrapment efficiency, particle size, polydispersity index (PDI), and zeta potential. The result from these initial trial formulations showed that the concentration of surfactant and cholesterol, mixing parameters (time and speed), and organic phase addition rate have a significant impact on the final niosomal formulations produced. In the second phase of the study, parameters impacted in the first phase were exhaustively studied by a 25 full factorial design using JMP® statistical software. Experiments were performed as per the formulation combination proposed by the design of the experiments. The formulations were evaluated for niosomal entrapment efficiency, particle size, polydispersity index (PDI), and zeta potential. All the data were added into the JMP study design and the profile predictor was generated based on the experimental data. The ideal formulation profile was predicted using the profile predictor features from JMP statistical software. The suggested ideal formulation was manufactured to validate the study design. The test results obtained from the formulation were in-line with the predicted results, which represent an accuracy of design of experiments (DoE) study. An additional batch was manufactured by changing the grade of surfactant to verify the impact of surfactant (principal component) chemistry on the niosomal formulation characteristics. In the final phase of the study, topical gels were manufactured with niosomal dispersion using various synthetic or natural gelling agents. Various topical gels were manufactured by changing the concentration or grade of the Carbomer or changing the gelling agent. Different gelling agents were used in identical concentrations to examine the impact of various gelling material on the final product. In these preparations, Carbomer 980 was used as the reference gelling agent since it was used in the marketed drug product which is used as a reference listed drug (RLD) in this study. Various concentrations of Carbomer 980 were also evaluated to match the physical characteristics of the gel with the reference drug product. Topical gel formulations were evaluated for chemistry parameters (assay, content uniformity, pH), physical parameters (yield stress, viscosity, rheology, flow curves, specific gravity, spreadability), and organoleptic properties. Finally, studies were performed for delivery of desoximetasone (anti-inflammatory glucocorticoid) to human cadaver skin using a topical gel dosage form prepared with niosomal microstructures and compared to the RLD. Topicort® Gel (desoximetasone) USP, 0.05% marketed drug product manufactured by Taro Pharmaceuticals was used as the reference drug product for comparison of the niosome based topical gel product (the FDA has listed Topicort® Gel (desoximetasone) USP, 0.05% as a reference drug in the Orange Book). Topical gel formulations were prepared and evaluated in such a way as to match with the reference product. Based on their performance, results showed that topical gel formulations with 0.7% Carbomer 980 were in complete concordance with the reference product. The results also showed that the rheological testing provided additional advantages over conventional methods for being sensitive, accurate, and versatile. Additionally, permeation experiments on human cadaver skin were conducted in order to compare the niosome containing topical gel and the reference product. Dermal delivery of desoximetasone in the niosome-containing topical gel formulation was found to be slower in comparison with the reference product. The result also showed a statistically significant increase in the amount of drug retained in the skin in the niosome-containing topical gel formulation, which showed a sustained drug release pattern. The stability study of the niosomal dispersion and niosome-containing topical gel shows that the niosome vesicle dispersion and topical gel products were stable at room temperature (20-25°C) and at accelerated temperature (40°C) conditions with no significant change occurring in the final drug product. Results from the present study highlight that optimized ideal niosome formulations can efficiently deliver a hydrophilic/hydrophobic drug to the target site with improved stability. Also, the niosomal topical gel was able to have a reduced drug concentration and dose frequency, and this was achieved by controlling drug release from the niosome matrix to gain maximum therapeutic effectiveness.