Zimmermannstout9380

The injection of the two NIS underneath the SC monolayers proved their potential to penetrate into the SC model at the air-water interface having a maximum insertion pressure (MIP) above the assumed lateral pressure of biological membranes. The NIS adsorbed preferentially into packing defects seen in epifluorescence microscopy studies with Sucrose monolaurate being more active than Polysorbate 80 in disordering the SC monolayer.

The waiver of bioequivalence (BE) studies is well accepted for Biopharmaceutics Classification System (BCS) class I drugs in form of immediate-release solid oral products. This study aimed to assess whether the rapid dissolution profiles (≥85% in 30 min) was crucial to guarantee bioequivalence of isosorbide mononitrate (ISMN) and then established a clinically relevant dissolution specification (CRDS) for screening BE or non-BE batches.

A physiologically based pharmacokinetic (PBPK) model was constructed by integrating clinical and non-clinical data by B

O simulator. The model was verified by an actual clinical study (NMPA registration number CTR20191360) with 28 healthy Chinese subjects. Then a virtual BE study was simulated to evaluate the bioequivalence of 7 virtual batches of ISMN tablets with different dissolution profiles, and the CRDS was established by integrating the results.

The simulated PK behavior of ISMN was comparable to the observed. Even though the batches with slower dissolution were not equivalent to a rapid dissolution profile (≥85% in 30 min), it was demonstrated these batches would exhibit the similar in vivo performance. selleck products Meanwhile, the in vitro dissolution specification time point and the percentage of drug release (75% in 45 min) proved to have clinical relevance.

The virtual BE simulation by integrating in vitro dissolution profiles into the PBPK model provided a powerful tool for screening formulations, contributing to gaining time and reducing costs in BE evaluations.

The virtual BE simulation by integrating in vitro dissolution profiles into the PBPK model provided a powerful tool for screening formulations, contributing to gaining time and reducing costs in BE evaluations.Non-bioequivalent plasma concentration profiles among different dosage forms of the salt of raltegravir, a poorly soluble acidic drug, were investigated using biorelevant in vitro testing combined with the commercial in silico software, Simcyp®. A suspension and a tablet dosage forms of raltegravir potassium were selected as the test formulations. While dissolution from the suspension was rapid, dissolution from the tablets was slow and delayed by pre-exposure to an acidic environment. Although the tablet was expected to have complex in vivo performance, plasma concentration profiles were successfully simulated when gastric emptying was taken into account as a key physiological factor in in vitro and in silico trials. The effect of pre-exposure to acid in the stomach on dissolution behavior in the intestine was estimated by two-stage in vitro dissolution testing. Based on these results, theoretical in vivo dissolution profiles for different gastric emptying times were inputted into the in silico model and plasma concentration profiles were simulated taking the distribution of individual gastric emptying times into account. The in vitro and in silico method presented in this report would be a practical approach to simulate oral absorption from various formulations of poorly soluble weak acids and their salts.Vulvovaginal candidosis (VVC), caused mainly by the yeast Candida albicans, is the second most prevalent vaginal infection. It has been found to have a large impact on women's quality of life, self-esteem and routines. The prevalence of recurrent vulvovaginal candidosis (RVVC) remains high so the development of alternative treatments is needed. The main objective of this study was to develop and characterize sodium bicarbonate gels to treat VVC. We described key formulation characteristics and analyzed their influence on in vitro performance evaluations. The potential to inhibit Candida albicans's growth, the pH, osmolality, viscosity and rheological performance in contact with vaginal fluid simulant and the bioadhesion's profile (using a vaginal ex vivo porcine model) were studied for all formulations. Among the formulations, formulation C (5% sodium bicarbonate, 1% carbomer and 94% water) was the most effective in inhibiting the C. albicans' growth. This gel presented the same potential (the same MIC 2.5%) to inhibit other etiological agents of VVC (C. glabrata, C. krusei, C. tropicalis and C. parapsilosis) for all species tested. Additionally, sensorial characteristics of gel C were in accord with users' preferences. This gel exhibited physicochemical characteristics acceptable for short term treatments, suggesting good overall performance for the treatment of VVC. Furthermore, Gel C was biocompatible with the HeLa cell line (MTT assay) and was classified as a non-severe irritant in the HET-CAM assay (irritation score 4 ± 1). Overall, gel C was deemed the best performing of the set tested, and suitable for further development.SYL927 and SYL930, two aminopropanediol analogues, are novel Sphingosine-1-phosphate receptor 1 (S1P1) modulators with higher selectivity and pharmacological activity compared with FTY720. Although the immunosuppressive activity of SYLs has been well demonstrated, information regarding the metabolic fates of the two chemicals is limited except for the CYP-catalyzed hydroxylation of SYL930. In this study, the biotransformation schemes of the two promising chemicals were investigated and compared using liver microsomes, S9 fractions and recombinant enzymes, and relevant molecular mechanism was primarily demonstrated by ligand-enzyme docking analysis (CDOCKER). As a result, the hydroxylation at alkyl chain on oxazole ring by the action of CYPs was found for both SYLs in vivo. The SULT-catalyzed sulfonation of the hydroxide was observed for SYL927 while the ADH/ALDH-catalyzed oxidation was only discovered for SYL930. The docking analysis suggested that specific non-covalent forces and/or bonding conformations of the hydroxides with biomacromolecules might be involved in the disparate metabolism of SYLs.