The aim of this study was to apply quality by design (QbD) for pharmaceutical development of felodipine solid mixture (FSM) containing hydrophilic carriers and/or polymeric surfactants, for easier development of controlled-release tablets of felodipine. The material attributes, the process parameters (CPP), and the critical quality attributes of the FSMs were identified. Box-Behnken experimental design was applied to develop space design and determine the control space of FSMs that have maximum solubility, maximum dissolution, and ability to inhibit felodipine crystallization from supersaturated solution. Material attributes and CPP studied were the amount of hydroxypropyl methylcellulose (HPMC; X(1)), amount of polymeric surfactants Inutec®SP1 (X(2)), amount of Pluronic®F-127 (X(3)) and preparation techniques, physical mixture (PM) or solvent evaporation (SE; X(4)). There is no proposed design space formed if the Pluronic® content was below 45.1 mg and if PM is used as the preparation technique. The operating ranges, for robust development of FSM of desired quality, of Pluronic®, Inutec®SP1, HPMC, and preparation technique, are 49-50, 16-23, 83-100 mg, and SE, respectively. The calculated value of f2 was 56.85, indicating that the release profile of the controlled-release (CR) tablet (CR-6) containing the optimized in situ-formed FSM was similar to that of the target release profile. Not only did the ternary mixture of Pluronic®, HPMC with Inutec®SP1 enhance the dissolution rate and inhibit crystallization of felodipine, but also they aided Carbopol®974 in controlling felodipine release from the tablet matrix. It could be concluded that a promising once-daily CR tablets of felodipine was successfully designed using QbD approach.
A liquisolid orodispersible tablet of felodipine, a BCS Class II drug, was developed to improve drug dissolution and absorption through the buccal mucosa for management of hypertensive crisis. A 24 full-factorial design was applied to optimize felodipine liquisolid systems (FLSs) having acceptable flow properties and possessing enhanced drug dissolution rates. Four formulation variables; The liquid type, X1 (PG or PEG), drug concentration, X2 (10% and 20%), type of coat, X3 (Aerosil® and Aeroperl®) and excipients ratio, X4 (10 and 20) were included in the design. The systems were assessed for dissolution and flow properties. Following optimization, the formulation components (X1, X2, X3 and X4) were PEG, 10%, Aerosil® and 20, respectively. The optimized FLS was compressed into felodipine liquisolid orodispersible tablet using Prosolv® as carrier material (FLODT-2). The in vitro and in vivo disintegration times of FLODT-2 were 9 and 7 s, respectively. The in vivo pharmacokinetic study using human volunteers showed a significant increase in dissolution and absorption rates of the formulation of FLODT-2 compared to soft gelatin capsules filled with felodipine solution in PEG under the same conditions. Our results proposed that the optimized FLODT formulation could be promising to manage hypertensive crisis.
The current study is regarding the development and characterization of Darifenacin-loaded self-assembled liquid crystal cubic nanoparticles (LCCN). An anhydrous approach was used for the preparation of these cubic nanoparticles using a hydrotropic agent (propylene glycol), with minimal energy input. Upon dispersion in aqueous medium, the system was successfully transformed to cubosomal nanoparticles counterpart as depicted by transmission electron micrographs. A Box-Behnken design was used to optimize formulation variables, namely A: amount of GMO, B: amount of Pluronic F127, C: amount of PG, and D: amount of HPMC. The design has generated 29 formulae which were tested regarding drug content uniformity, dispersibility in water, particle size, zeta potential, polydispersity index, and in vitro release behavior. The numerical optimization algorithms have generated an optimized formula with high desirability ≈ 1. The optimized formula displayed small particle size, good homogeneity, and zeta potential along with controlled in vitro release profile and ex vivo permeation through rabbit intestine. Thus, self-assembled LCCN might offer an alternative anhydrous approach for the preparation of cubosomal nanoparticles with controlled release profile for a possibly better control of overactive bladder syndrome which tremendously affect the overall life quality. Graphical Abstract
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