Optimization of Meloxicam Solid Dispersion Formulations for Dissolution Enhancement and Storage Stability Using 33 Full Factorial Design Based on Response Surface Methodology.

This study aimed to formulate and optimize solid-dispersion of meloxicam (MX) employing response-surface-methodology (RSM). RSM allowed identification of the main effects and interactions between studied factors on MX dissolution and acceleration of the optimization process. 33 full factorial design with 27 different formulations was proposed. Effects of drug loading percentage (A), carriers' ratio (B), method of preparation (C), and their interactions on percent MX dissolved after 10 and 30 min (Q10min & Q30min) from fresh and stored samples were studied in distilled water. The considered levels were 2.5%, 5.0%, and 7.5% (factor A), three ratios of Soluplus®/Poloxamer-407 (factor B). Physical mixture (PM), fusion method (FM), and hot-melt-extrusion (HME) were considered factor (C). Stability studies were carried out for 3 months under stress conditions. The proposed optimization design was validated by 3-extra checkpoints formulations. The optimized formulation was selected via numerical optimization and investigated by DSC, XRD, PLM, and in vitro dissolution study. Results showed that HME technique gave the highest MX dissolution rate compared to other techniques (FM & PM). At constant level of factor (C), the amount of MX dissolved increased by decreasing MX loading and increasing Soluplus in carriers' ratio. Actual responses of the optimized formulation were in close consistency with predicted data. Amorphous form of MX in the optimized formulation was proved by DSC, XRD, and PLM. Selected factors and their levels of the optimization design were significantly valuable for demonstrating and adapting the expected formulation characteristics for rapid dissolution of MX (Q10min= 89.09%) from fresh and stored samples.

Preparation, characterization and in-Vitro/in-Vivo evaluation of meloxicam extruded pellets with enhanced bioavailability and stability.

OBJECTIVE: The present study involved enhancement of Meloxicam (MX) oral absorption for rapid onset of therapeutic action. A challenging approach using hot-melt-extrusion technique (HME) for production of stable novel preparation of MX pellets was successfully proposed. METHODS: Manipulating HME processing parameters (barrel-temperatures and screw-speed) and proper polymer(s) selection (Soluplus, a combination of Soluplus/Poloxamar and Polyethylene Glycol 6000) were the main strategies involved for productive extrusion of MX. Evaluation of MX solid-state (TGA, DSC and PLM), absolute percent crystallinity, in-vitro dissolution (in acidic/aqueous pHs), and stability testing in accelerated conditions up to 6-months as well as a long-term shelf for 36-months were performed. A comparative bioavailability study of selected MX-Pellets was carried-out against the innovator product (Mobic®) in 6 healthy volunteers under fed-conditions. RESULTS: TGA, DSC and PLM analyses proved the dispersion of MX in amorphous-state within polymeric matrix by HME. MX/Soluplus pellets exhibited the lowest crystallinity % and best dissolution performance among other polymers in both pHs. In addition, presence of Soluplus safeguards final pellets stability under different storage conditions. MX rate of absorption (Tmax) from Soluplus-based pellets attained a value of 45 min, which was 6-times faster than Mobic® (4.5 hr). CONCLUSION: A promising oral MX formula prepared by HME was successfully developed with a rapid onset of analgesic action (Tmax of 45 mins; almost 2-times faster than reported intramuscular injection), hence appropriate in the early relief of pain associated with rheumatoid arthritis and osteoarthritis. Moreover, the proposed formula was physico-chemically stable up to 36 months of shelf-life storage.

Optimization of gliclazide loaded alginate-gelatin beads employing central composite design.

Objective: The aim of this study was to optimize the formulation of alginate-gelatin (AL-GL) beads containing gliclazide (GLZ) employing design of experiments (DOE).Significance: DOE enabled identification of the interaction between the studied factors, deep understanding of GLZ release pattern and acceleration of the optimization process.Methods: A three-factor, three-level face centered design was employed. The effects of GLZ content (GLZ%, X1), polymer ratio (AL:GL ratio, X2), crosslinker concentration (glutaraldehyde, GA%, X3), and their interaction on incorporation efficiency (IE) and release rate were studied. The optimized formulation was prepared using numerical optimization and evaluated by DSC, FT-IR, SEM and release rate studies.Results: Increasing GA% (X3) decreased IE (Y1) with the highest magnitude of effect among the studied factors. On the other hand, increasing alginate content in AL:GL ratio (X2) increased IE (Y1). The amount of GLZ released Q0.5h, Q2h(pH 1.2) and Q4h(pH 7.4) decreased by increasing GLZ% (X1) and AL:GL ratio (X2). Both drug content and AL:GL ratio appeared to affect water penetration into the gel matrix and drug release. Generally, there was a direct relationship between GA% (X3) and GLZ release in pH 1.2 (Q0.5h and Q2h). However, in pH 7.4 (Q4h), increasing GA% decreased GLZ release. In addition, increasing GA% caused deviation from zero-order release model. The actual responses of the optimized formulation were in close agreement with the predicted ones.Conclusion: The selected factors and their levels studied in the optimization design were useful for tailoring the anticipated formulation characteristics and GLZ release pattern.

Preparation and in vitro/in vivo evaluation of antimicrobial ocular in situ gels containing a disappearing preservative for topical treatment of bacterial conjunctivitis.

The study aimed to formulate and evaluate levofloxacin hemihydrate ocular in situ gels along with freshly prepared disappearing preservative reported to be safer to human eyes. Formulae were prepared using thermosensitive (PF127 and PF68) or ion-activated (Gelrite) polymers. They were evaluated for gelation temperature (GT), capacity, content uniformity, pH, rheological behavior, in vitro drug release with kinetic analysis. Best formulae were exposed to storage effect to select the optimum formula that was subjected to different sterilization methods and in vivo evaluation. The prepared disappearing preservative (sodium perborate monohydrate) proved to be active oxidative preservative and compatible with our formulae. F9 (24% PF127, 15% PF 68, 0.5% levofloxacin hemihydrate, and 0.0025% sodium perborate monohydrate) showed prolonged drug release (12 h), acceptable GT, viscosity, and pH. It remained stable over 3 months at two temperatures and was best sterilized by filtration. It showed longer residence time (12 h) in rabbits' eye fluids compared with the Levoxin® eye drops (4 h). This successful attempt of using thermo-gelling system along with a disappearing type of preservatives would allow the use of these systems to achieve sustained release of antimicrobial drugs with minimum risk of eye damage improving patient compliance and treatment efficacy.

Controlled porosity osmotic pump system for the delivery of diclofenac sodium: in-vitro and in-vivo evaluation.

The objective of this study was to develop controlled porosity osmotic pump (CPOP) tablets of diclofenac sodium (DS). The influence of different cores (polymers and osmogens) and coats (thickness and porosigen content) on DS release were studied. Results revealed that decreasing HPMC viscosity grade from 4000cp (K4M) to 15cp (E15) increased DS release. While increasing the tablet coat thickness decreased DS release. The presence of osmogen increased DS release in the following rank: mannitol > lactose > avicel. There was a direct relationship between increasing PEG-400 in the coating solution and the amount of drug released in all formulations studied, except in one condition. A comparative bioavailability study using a selected CPOP formulation (T) versus the innovator product (R) revealed that CPOP tablet maintained a less fluctuated DS plasma concentration for up to 24 h with a detected mean Cmax of 836.8 ± 142.4 and 445.0 ± 81.0 ng/mL for R and T, respectively. There were no statistically significant differences between R and T, concerning AUC0-24 and AUC0-∞. Moreover, the appearance of the multi-peak phenomenon, which is frequently observed with DS absorption, was found in only 25% of volunteers in case of T versus 75% in case of R.