Application of Response Surface Methodology Using Face-centered Central Composite Design for Studying Long-Term Stability of Gliclazide-Loaded Multiparticulate Systems.

The appropriate design of experiments (DoE) could support post-approval lean-stability approaches. A three-factor three-level face-centered design was constructed to evaluate the long-term stability of gliclazide (GLZ) alginate-gelatin beads. The formulation variables were GLZ%(X1), alginate:gelatin ratio(X2), and glutaraldehyde%(X3). The studied responses included GLZ release at predefined intervals in 0.1 N HCl (2 h) followed by phosphate buffer (pH 7.4). Model-dependent and independent approaches were utilized for comparison. DoE-model validation and reduction were implemented. All the studied formulations showed non-significant changes in the particle size (p > 0.05) and most of them showed similar release profiles before and after storage. The directions of the relationships between the factors' main effects and the responses (Y1:Q0.5h, Y2:Q2h, and Y3:Q4h) remained unchanged after storage. The optimal factor settings based on the proposed optimization criteria were defined. The optimized formulations (OP-1 and OP-2) showed non-significant changes in the particle size after storage. The release profiles and kinetics of OP-1 and OP-2 remained unchanged after storage. No chemical change was indicated (FT-IR). DSC-thermograms of OP-1 indicated GLZ conversion to a more stable polymorph after storage. While OP-2 showed a change in GLZ crystallinity. The stored and fresh beads' surfaces after GLZ release were almost similar. DoE could be utilized to evaluate, optimize, and predict the effects of different formulation variables on the long-term stability of GLZ alginate-gelatin beads.

Formulation and evaluation of alginate-gelatin hydrogel scaffolds loaded with zinc-doped hydroxyapatite and 5-fluorouracil.

Alginate and gelatin are natural macromolecules used to formulate biocompatible drug delivery systems. Hydroxyapatite (HA) is an osteophilic ceramic used to prepare bone scaffolds. The current study aimed at preparing and characterizing HA, zinc-doped HA, and 5-fluorouracil(5-FU)-loaded alginate-gelatin-based hydrogel scaffolds using different crosslinking solutions. 5-FU incorporation efficiency, in-vitro drug release, antitumor bioassays, FTIR, X-ray-diffraction (XRD), High-Resolution Transmission, and Scanning-Electron Microscope (HR-TEM and SEM) studies were conducted. XRD showed the incorporation of Zn2+ into HA structure with a deformity in HA crystal lattice and inhibited crystal growth. FTIR-spectra represented the characteristic bands corresponding to HA structure. HR-TEM showed a decreased HA crystal size and rod-like crystallites that increased with increasing zinc content. Zn2+ content and 5-FU-loading caused significant effects on the scaffolds' thickness (p-value = 0.021 and 0.035, respectively). Burst 5-FU release within 10-15 min followed by 100 % release within 4 h was observed. Zinc content showed a significant positive effect on the cytotoxicity% of the blank and drug-loaded scaffolds. XRD and FTIR studies revealed that 5-FU was completely incorporated into the hydrogel with no chemical interaction. SEM-imaging showed interconnected pores and needle-shaped drug particles. The prepared formulations showed promising physico-chemical properties for targeted delivery of 5-FU in the form of biocompatible bone scaffolds.

Formulation, Pharmacokinetics evaluation, and IVIVC Assessment of Gliclazide Multiparticulates in Rat Model.

In vitro and in vivo studies of gliclazide (GLZ)-loaded freeze-dried alginate-gelatin (AL-GL) beads were carried out, aiming to modify its oral bioavailability. Crosslinked freeze-dried GLZ AL-GL beads (particle size: 1.5- and 3.0-mm) were prepared. In vitro evaluation of GLZ AL-GL beads included SEM, DSC, FT-IR, and release rate study in gradient media. In vivo study was single-dose (4 mg/kg), randomized, parallel-group design, two-treatment (T: test GLZ AL-GL beads and R: reference product Diamicron® 30-mg MR tablet) conducted in 96 healthy rats. Each group was subdivided into 2 sub-groups (G1 and G2) having different blood sampling schemes for up to 72 h. Assessment of level A in-vitro-in-vivo correlation (IVIVC) model was carried out. AL-GL beads successfully increased GLZ release rate compared to R. GLZ percent released (Q4h) was 109.34, 86.85, and 43.43% for 1.5-mm and 3.0-mm beads and R, respectively. DSC analysis confirmed the interaction of AL-GL via crosslinking. No chemical interaction of GLZ has occurred as proved by FT-IR. Relative bioavailability (T/R) for AUC0-∞ was 132.45% for G1 and 146.16% for G2. No significant differences between T and R in the primary pharmacokinetic parameters were determined. Tmax values were found to be earlier in the case of G1 than those of G2. A secondary absorption peak of GLZ was clearly detected in the case of R while its sharpness was minimized in T. High IVIVC was established, and hence, the proposed in vitro release model perfectly correlated with the in vivo study. The current study design might be a platform to enable panoramic view for GLZ variability in vivo.

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.