Co-processing of nateglinide with meglumine for enhanced dissolution rate: in vitro and in vivo evaluation.

OBJECTIVE: The aim of this work was to investigate dry co-grinding of nateglinide with meglumine for enhanced dissolution rate of nateglinide. The study was extended to investigate the effect of this dissolution enhancement on the hypoglycemic effect of the drug in diabetic rats. METHODS: Nateglinide was subjected to dry co-grinding with increasing proportions of meglumine to prepare products containing the drug with meglumine at 1:1, 1:2, and 1:3 molar ratios. These products were evaluated using combined instrumental analysis which employed Fourier transform infrared spectroscopy (FTIR), differential thermal analysis (DTA), and X-ray diffraction (XRD). Drug dissolution was also monitored before and after processing with and without meglumine. The optimum ratio was used to assess the effect of dissolution enhancement on the hypoglycemic effect of nateglinide on diabetic rats. The unprocessed nateglinide was used as control. RESULTS: Co-grinding of nateglinide resulted in changes in the FTIR spectral patterns of nateglinide and meglumine. The changes suggested the formation of amide bond between both compounds at 1:1 molar ratio. The new species was confirmed by DTA and XRD. This species exhibited fast dissolution of nateglinide after incorporation of higher proportions of meglumine. Co-grinding was essential as indicated from slower dissolution from physical mixture containing the highest proportion of meglumine. Enhanced dissolution was reflected in vivo as improved rate and extent of hypoglycemia. CONCLUSION: Dry co-grinding of nateglinide with meglumine developed new species which liberated nateglinide rapidly and enhanced the rate and extent of hypoglycemia of nateglinide.

Simultaneous Pharmacokinetics Estimation of Nateglinide and Pioglitazone by RP-HPLC: Computational Study to Unlock the Synergism.

Nateglinide (NAT) and Pioglitazone (PIO) are an antidiabetic drugs combination and currently under clinical trial in countries like Japan. In this study, an alternative, a simple, sensitive high-performance liquid chromatography method has been developed (limit of detection: 15 ng/mL and limit of quantification: 50 ng/mL) for simultaneous estimation of this drug combination in rat plasma. Most remarkably, bioavailability of NAT has been increased markedly on coadministration with PIO, than when it was administered alone. Thus, PIO is assumed to retard the catabolism of NAT by inhibiting metabolic liver-microsomal enzyme, especially CYP2C9. Using a Waters Nova-Pak C 18 column (150 × 3.9 mm, 4 µm) and a mobile phase of acetonitrile: 10 mM KH2PO4 (60: 40, V/V (volume by volume)) pH 3.5, the analysis was performed at 210 nm with a flow rate of 1.5 mL/min. In silico docking via molecular dynamics simulation revealed that NAT-CYP2C9 binding affinity may be reduced after PIO attachment, presumably due to the binding site overlapping of the two drugs. Thus, it has been proposed that NAT and PIO may be an efficient synergistic fixed dose combination against diabetes mellitus, and the above method can foster a simple but highly sensitive bioanalytical estimation for routine analysis.

QSPR Modeling of Biopharmaceutical Properties of Hydroxypropyl Methylcellulose (Cellulose Ethers) Tablets Based on Its Degree of Polymerization.

Quantitative structure-property relationship (QSPR) approach has been widely used in predicting physicochemical properties of compounds. However, its application in the estimation of formulation properties based on the polymer used in it to achieve desired formulation characteristics is an extremely challenging process. In the present research, predictive QSPR models were developed by correlating the physicochemical properties of varying grades of cellulose ethers (hydroxypropyl methylcellulose, HPMC) with those of nateglinide (NTG) containing tablets (in vitro and in vivo properties). Sustained release tablets of NTG were prepared by using different grades and concentrations of HPMC and subsequently characterized for in vitro as well as in vivo parameters. Further, QSPR models for individual formulation property were developed by correlating the polymeric physicochemical properties with the formulation characteristics. Subsequently, a true external validation method was used to validate the predictability of developed models. The dissolution study indicated Korsmeyer-Peppas as the best fit model following non-Fickian as drug transport mechanism extending the drug release up to 12 h. In vivo studies showed limited absorption of the NTG. Developed QSPR models showed promising validated predictability for formulation characteristics. The applicability of present work in formulation development could significantly reduce the time and cost expenditure on design trials without actually formulating a delivery system.

Development and Characterization of Microstructured, Spray-Dried Co-Amorphous Mixture of Antidiabetic Agents Stabilized by Silicate.

In the present work, co-amorphous mixture (COAM) of poorly soluble nateglinide (NT) and highly soluble Metformin hydrochloride (MT) was prepared by spray drying method to improve the dissolution rate of NT and the processability of COAM. Binary spray-dried COAM of NT and MT (120 mg: 500 mg) was prepared in its clinical dose ratio whereas 20% Neusilin®US2 (NS) was added to prepare non-sticky, free flowing ternary COAM. Solubility studies of binary and ternary COAM exhibited sevenfold and tenfold rise in the solubility of NT. Complete amorphization of NT was revealed in XRPD and DSC studies of both COAM and hydrogen-bonding interactions were reflected in FTIR-spectra. SEM microphotographs illustrated round-shaped microparticles in ternary COAM against the irregular particles in binary COAM. In vitro dissolution of NT was significantly improved in ternary COAM > binary COAM > NT irrespective of dissolution medium. On contrary, MT has partially transformed to the amorphous form in COAM without altering the solubility. In accelerated stability studies, NT and MT devitrification was not observed in XRPD of ternary COAM in contrast to binary COAM. Therefore, enhanced dissolution of NT, stabilization of spray-dried dispersion, and its improved processability can be achieved by preparing ternary COAM of NT:MT:NS.

Enhancing the Pharmaceutical Behavior of Nateglinide by Cocrystallization: Physicochemical Assessment of Cocrystal Formation and Informed Use of Differential Scanning Calorimetry for Its Quantitative Characterization.

The aim of this study was to synthetize cocrystals of nateglinide, an antidiabetic agent of biopharmaceutics classification system Class IIa, as a strategy to improve both the solubility and the dissolution rate of the drug. Benzamide was selected by a screening procedure as a suitable coformer, and binary mixtures with different compositions were prepared and analyzed by differential scanning calorimetry (DSC). An in-depth analysis of DSC data allowed obtaining both the eutectic mixture and cocrystal compositions. The rationale of such an analysis was highlighted and explained. Cocrystals were prepared by kneading and solvent evaporation. Their formation was proved by DSC and confirmed by X-ray powder diffraction, solid-state nuclear magnetic resonance, and Fourier-transform infrared spectroscopy. The functional groups involved in the interaction leading to cocrystals formation were investigated by spectroscopic techniques. The in vitro dissolution profiles show that cocrystals have definite better pharmaceutical performances than the pure drug.

Niosomes for oral delivery of nateglinide: in situ-in vivo correlation.

Niosomes have been claimed to enhance intestinal absorption and to widen the absorption window of acidic drugs. This was reported after monitoring the intestinal absorption in situ. Accordingly, the aim of this work was to investigate the effect of niosomal encapsulation on intestinal absorption and oral bioavailability of nateglinide. This was conducted with the goal of correlation between in situ intestinal absorption and in vivo availability. The drug was encapsulated into proniosomes. The niosomes resulting after hydration of proniosomes were characterized with respect to vesicle size and drug entrapment efficiency. The in situ rabbit intestinal absorption of nateglinide was monitored from its aqueous solution and niosomes. Streptozotocin was used to induce diabetes in albino rats which were then used to assess the hypoglycemic effect of nateglinide after oral administration of aqueous dispersion and niosomal systems. The prepared vesicles were in the nanoscale with the recorded size being 283 nm. The entrapment efficiency depended on the pH of the formulation. The in situ intestinal absorption reflected non-significant alteration in the membrane transport parameters of the drug after niosomal encapsulation compared with the free drug solution. In contrast, niosomes showed significant improvement in the rate and extent of the hypoglycemic effect compared with the unprocessed drug. This discrepancy can be attributed to different transport pathway for the drug after niosomal inclusion with the vesicles undergoing translymphatic transport which can minimize presystemic metabolism. However, this requires confirmatory investigations. In conclusion niosomes can enhance oral bioavailability of nateglinide with the absorption being through nontraditional pathway.