Statistical Sequential Experimentation: Preliminary Mixed Factorial Design, I-Optimal Mixture Design Then Finally Novel Design Space Expansion for Optimization of Tazarotene Cubosomes.

Objective: This study aims to illustrate the potential of sequential experimentation for statistically scientific based optimization of Tazarotene (TAZA) cubosomes. Methods: Hot melt emulsification method was used for cubosomes preparation. A preliminary (3.2) mixed factorial design (MFD) was conducted to choose suitable types of stabilizer and surfactant that maximize entrapment efficiency (EE) and minimize particle size (PS). These chosen stabilizer and surfactant were to be used in the statistical design proposed for optimization of TAZA cubosomes (I-optimal mixture design) (IOMD). Glyceryl monooleate (GMO), stabilizer and surfactant amounts were the three mixture components (MixCs) studied in that design. Responses (EE, PS and drug percent released after 24 hours (Q24h)) were statistically analyzed. Numerical optimization using desirability function based on different responses' importance was used to find an IOMD-optimized formulation (IOMD-OF) with the predetermined characters. Then, a novel statistical methodology of design space expansion was adopted to enhance Q24h. Suitable models to express EE, PS and Q24h were elucidated over the expanded mixture design (EMD) space. Validity of derived models was verified via prediction intervals and percent deviations of actual values from predicted ones for all the EMD design points. EMD was then navigated to find EMD-OF. Results: Analysis of MFD showed that Pluronic-F68 and polyvinyl alcohol were the best stabilizer and surfactant to be used. First stage optimization after IOMD analysis led to a formulation with unsatisfactory Q24h of 58.8%. After design space expansion adoption, re-analysis and re-optimization, a satisfactory EMD-OF having EE of 82.1%, PS of 273.0 nm and Q24h of 68.8% was found. Conclusion: Statistical sequential experimentation with the novel design space expansion approach proved to be a successful paradigm for enhancing TAZA cubosomes optimization. Thus, this paradigm is expected to have promising future applications in various pharmaceutical formulations optimization.

Formulation, characterization, optimization, and in-vivo performance of febuxostat self-nano-emulsifying system loaded sublingual films.

Febuxostat (FXS) is a potent antigout drug with poor water solubility and relative high first-pass effect leading to moderate oral bioavailability (<49%). This study aimed to increase FXS solubility and bioavailability by optimizing sublingual fast-dissolving films (SFs) containing a selected FXS self-nano-emulsifying system (s-SNES) previously prepared by our team. The s-SNES was loaded into SFs by solvent casting technique. A full factorial design (32) was applied to study the effects of polymer and plasticizer types on mechanical characteristics and the dissolution profile of FXS from the SFs. Numerical optimization was performed to select the SF having highest desirability according to predetermined characteristics. The optimized SF (O-SF) contained 1 g of s-SNES, polyvinylpyrrolidone K30 (6%w/v), polyethylene glycol 300 (20%w/w of polymer wt.), and Avicel PH101 (0.5%w/v). O-SF showed good permeation of FXS through sheep sublingual tissue. Storage of O-SF for three months showed no significant change in the FXS dissolution profile. In-vivo performance of O-SF in rabbits was compared to that of oral marketed tablets (Staturic® 80 mg). A cross-over design was applied and pharmacokinetic parameters were calculated after ensuring absence of sequence effect. Statistical analysis revealed better performance for O-SF with significantly higher Cmax, AUC0-24, AUC0-∞, apparent t1/2 together with lower tmax, and apparent kel than marketed tablets. Relative bioavailability of O-SF compared to the marketed tablet was found to be 240.6%. This confirms the achievement of the study aims of improving dissolution rate and bioavailability of FXS using a patient-wise convenient formula.

Development and characterization of sponge-like acyclovir ocular minitablets.

For the treatment of ocular keratitis acyclovir, as a highly specific inhibitor of herpes virus replication, is applied topically into the eye. The objective of this study was to design and evaluate freeze-dried, bioadhesive and biodegredable acyclovir ocular minitablets for prolonged local drug action. The sponge-like nature of the lyophilized ocular minitablets ensures rapid hydration and gelation of these tablets in the eye and thus would reduce the foreign body sensation. The polymers used were sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), xanthan gum, chitosan and Carbopol 943P. The minitablets were evaluated for drug content, weight variation, bioadhesion, water uptake and in vitro drug release. In addition, the rheological characteristics of the polymers solutions were investigated. Rheological data revealed that all tested polymers exhibited pseudoplastic behaviour which is required to minimize interference with blinking. Drug release was found to be affected by the type and concentration of polymer. The order of sustainment was chitosan > xanthan > HPMC > Carbopol > NaCMC. Water uptake study, dissolution rate of the polymers and viscosity measurements could explain the different release profiles of the drug from the polymers. Chitosan minitablet was chosen for its significant sustained release and good bioadhesive property for in vivo study in rabbits. The tablet showed a good permeation into the cornea in comparison to the commercially available Zovirax(®) eye ointment. In conclusion, chitosan ocular minitablets containing acyclovir could be considered as a promising sustained drug delivery system for ocular keratitis treatment.