Convolution- and Deconvolution-Based Approaches for Prediction of Pharmacokinetic Parameters of Diltiazem Extended-Release Products in Flow-Through Cell Dissolution Tester.

The present study evaluated the effect of different configuration setups of the Flow-Through Cell (USP IV) dissolution tester in developing in vitro-in vivo correlation (IVIVC). A Biopharmaceutics Classification System (BCS) Class I Diltiazem (DTZ), formulated in extended-release (ER) gel-matrix system, was employed for this purpose. The study also assessed the validity and predictability of IVIVC employing both deconvolution- and convolution-based approaches. In vitro release was conducted in USP IV as open- or closed-loop setups, while the pharmacokinetic (PK) data were obtained from a previous fasted-state cross-over study conducted on 8 healthy male volunteers, after oral administration of ER matrix tablets against market product (Tildiem Retard® 90 mg). PK parameters (Cmax, AUC0-t and AUC0-∞) were predicted, and compared with actual data to establish the strength of correlation models. Results showed that DTZ release from ER products was influenced by operating the FTC in different configuration-setups, where ≥ 75% of labeled DTZ was released after 6 h and 12 h using the open- and closed-loop settings, respectively. Correlation between fraction-dissolved versus fraction-absorbed for both ER products displayed linear relation upon employing FTC open-loop setup. Convolution-based approach was more discriminative in predicting DTZ in vivo PK parameters with a minimal prediction error, compared to deconvolution-based approach. A successful trial to predict DTZ PKs from individual in vitro data performed in USP IV dissolution model was established, employing convolution technique. Basic principle of the convolution approach provides a simple and practical method for developing IVIVC, hence could be utilized for other BCS Class I extended-release drug products.

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.

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.

A novel combination of Soluplus®/Poloxamer for Meloxicam solid dispersions via hot melt extrusion for rapid onset of action. Part 2: comparative bioavailability and IVIVC.

OBJECTIVE: Bioavailability of Meloxicam (MLX) from solid dispersions (SDs), against innovator product Mobic® in humans was conducted. Furthermore, to establish a good in vitro-in vivo correlation (IVIVC); dissolution studies were carried-out in different media. METHODS: MLX/SDs was prepared using Soluplus/Poloxamer via hot-melt-extrusion (EXT-SD) and fusion melt (FUS-SD) techniques. A single oral dose (15 mg), three periods, crossover study of MLX/SDs and Mobic® in four healthy humans under fed conditions was carried-out. In vitro dissolution was studied in pH 1.2, distilled water (pH 6.4), and biorelevant simulated gastric media in pre- and post-prandial states. Level A IVIVC was carried-out by comparing time-scaled fraction dissolved versus fraction absorbed and calculated using the Wagner-Nelson method. Multiple level C models were developed for C max and AUC0-96 versus % dissolved at different time-points. Internal predictability was evaluated for both IVIVC models. RESULTS: MLX rate of absorption (T max) from EXT-SD, FUS-SD, and Mobic® was 1.5, 3.0, and 4.0 h, respectively. Moreover, 1.45- and 1.40-folds increase in AUC0-∞ and C max, was obtained for EXT-SD versus Mobic®, respectively, while FUS-SD gave the lowest extent of drug absorption. EXT-SD provided highest dissolution profiles in all studied media. IVIVC models showed linear-regression (R 2≥0.90) and prediction errors (≤10%) in water and post-prandial simulated gastric media. CONCLUSION: Hot-melt-extrusion technology promises an ideal alternative for enhancing MLX extent of absorption compared to Mobic® with T max value almost equal to the reported intramuscular injection. Predictive IVIVC was established for in vitro dissolution profile and in vivo performance.

Stability and bioavailability of diltiazem/polyethylene oxide matrix tablets.

The aim of this study was to prepare and evaluate in vitro and in vivo; Diltiazem-Hydrochloride (DTZ) in sustained-release matrix tablets. Stability of DTZ tablets prepared with polyethylene oxide (MWs 900 000, 4 000 000, and 8 000 000) with or without addition of electrolytes was carried-out for 1-month, under short-term storage at 40 °C/75% RH. Stability was evaluated by DTZ content, DSC and drug release using the Flow-Through Cell (USP # IV). The majority of stored tablets were stable for 1-month under short-term storage with respect to DTZ content and drug release. DSC curves of stored samples showed appearance of new exothermic peak after 1-month storage at 40 °C/75% RH, which was not observed after 5 years storage at room temperature. A selected formula was tested in vivo against reference product on eight healthy human volunteers. DTZ-plasma profiles were different between the two formulae. However, no statistically significant differences were detected between Cmax, AUC0-48 and AUC0-∞. The two products were therapeutically in-equivalent, as 90% confidence intervals "T/R" were 88.82-205.76, 91.40-139.94, and 93.73-134.97 for Cmax, AUC0-48 and AUC0-∞, respectively. This study highlighted possible differences observed between the two regimes frequently applied for stability testing.

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.