A simple method to improve the dissolution of repaglinide and exploration of its mechanism

In the present study, a simple and rapid method was developed to improve the in vitro dissolution of repaglinide, an oral antidiabetic drug, which was based on addition of meglumine in 50% (v/v) ethanol to dissolve repaglinide, and the drug dissolved in meglumine/50% ethanol was used directly with a binder to prepare tablets. The mechanism of solubilization of repaglinide by meglumine was studied by using infrared spectrum (IR), ultraviolet (UV) measurement through dual wavelength, differential scanning calorimetry (DSC) and X-ray powder diffraction methods. Dissolution tests of repaglinide tablets were performed in the media with different pH values and the repaglinide concentrations were analyzed by High Performance Liquid Chromatography (HPLC) method. The solubility data showed that with the meglumine concentration increasing, the solubility of repaglinide was increased. Meanwhile, tablets with the molar ratio of repaglinide and meglumine 1:2 (n/n) resulted in a significant increase in dissolution compared to the repaglinide tablets without using meglumine, and nearly equal to the commercial preparations of NovoNorm®, which concluded that meglumine had a great role in promoting the dissolution of repaglinide. The results of IR and UV dual wavelength methods suggested the formation of repaglinide–meglumine (REP–MEG) molecular complex. DSC results showed that the melting peak of repaglinide disappeared in the REP–MEG coprecipitate, which indicated that repaglinide was stable when existing at amorphous or molecular state. The experiment of X-ray powder diffraction showed that with the solubilization of meglumine, the crystal diffraction peak of repaglinide disappeared, which further inferred that repaglinide was formed complexes with meglumine. It was demonstrated that the method of improving repaglinide with meglumine was reliable and could be suitable for repaglinide tablets production in industry. This study also provides a feasible way to enhance the dissolution of drugs with low solubility, which will be leading to improved bioavailability of these drugs

Development and validation of a rapid and sensitive UHPLC–MS/MS method for the determination of paliperidone in beagle dog plasma

In order to evaluate the pharmacokinetic profile of paliperidone extended-release tablets in vivo, a simple and rapid ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) method was developed and validated for the determination of paliperidone in beagle dog plasma. Paliperidone and diazepam (internal standard) were extracted from plasma samples with diethyl ether, and then separated on a C18 column (2.1 × 50 mm, 2.6 μm) under gradient elution with methanol–0.1% formic acid at a flow rate of 0.3 ml/min. The compounds were detected using a triple-quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source. The validated method was linear over the concentration range of 1.00–1000.00 ng/ml and the lower limit of quantitation was 1.00 ng/ml. The intra-day and inter-day precision values were not more than 15% (relative standard deviation < 20% at low levels), while the accuracy was within ±10% of nominal values. The validated UHPLC–MS/MS method was successfully applied to an oral pharmacokinetic study of paliperidone extended-release tablets in a beagle dog

A Comparative Study between A Protein Based Amorphous Formulation and Other Dissolution Rate Enhancing Approaches: A Case Study with Rifaximin

Amorphous solid dispersions (ASDs) based on proteins as co-formers have previously shown promising potential to improve the solubility and bioavailability of poorly water-soluble drugs. In particular, whey proteins have shown to be promising co-formers and amorphous stabilizers in ASD formulations, including at high drug loading. In this study, the feasibility of the whey protein β-lactoglobulin (BLG) as a co-former in ASDs was compared to the more traditional ASD co-formers based on synthetic polymers (hydroxypropyl methylcellulose acetate succinate and Eudragit® L) as well as to a nanocrystalline formulation. The poorly water-soluble drug rifaximin (RFX) was chosen as the model drug. All drug/co-former formulations were prepared as fully amorphous ASDs by spray drying at 50% (w/w) drug loading. The BLG-based ASD had the highest glass transition temperature and showed a faster dissolution rate and higher drug solubility in three release media with different pH values (1.2, 4.5, and 6.5) compared to the polymer-based ASDs and the nanocrystalline RFX. In conclusion, BLG is a promising co-former and amorphous stabilizer of RFX in ASD formulations, superior to the selected polymer-based ASD systems or the nanocrystalline formulation

Can semipermeable membranes coating materials influence in vivo performance for paliperidone tri-layer ascending release osmotic pump tablet: In vitro evaluation and in vivo pharmacokinetics study

One purpose of this study was to develop a paliperidone (PAL) tri-layer ascending release push–pull osmotic pump (TA-PPOP) tablet which could meet the needs of clinical applications. And another purpose was to investigate whether different coating materials influenced in vivo performance of TA-PPOP. The ascending release mechanism of this tri-layer delivery system on theory was elaborated. TA-PPOP was prepared by means of coating with cellulose acetate (CA) or ethyl cellulose (EC). Several important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated. The optimization of formulation and process was conducted by comparing different in vitro release behaviors of PAL. In vitro dissolution studies indicated that both the two formulations of different coating materials were able to deliver PAL at an ascending release rate during the whole 24 h test. The in vivo pharmacokinetics study showed that both self-made PPOP tablets with different coating had a good in vitro-in vivo correlation (IVIVC) and were bioequivalent with the brand product, which demonstrated no significant influence of the coating materials on the in vivo release acceleration of TA-PPOP