Use of amino acids as counterions improves the solubility of the BCS II model drug, indomethacin

The number of new chemical entities (NCE) is increasing every day after the introduction of combinatorial chemistry and high throughput screening to the drug discovery cycle. One third of these new compounds have aqueous solubility less than 20µg/mL [1]. Therefore, a great deal of interest has been forwarded to the salt formation technique to overcome solubility limitations. This study aims to improve the drug solubility of a Biopharmaceutical Classification System class II (BCS II) model drug (Indomethacin; IND) using basic amino acids (L-arginine, L-lysine and L-histidine) as counterions. Three new salts were prepared using freeze drying method and characterised by FT-IR spectroscopy, proton nuclear magnetic resonance ((1)HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The effect of pH on IND solubility was also investigated using pH-solubility profile. Both arginine and lysine formed novel salts with IND, while histidine failed to dissociate the free acid and in turn no salt was formed. Arginine and lysine increased IND solubility by 10,000 and 2296 fold, respectively. An increase in dissolution rate was also observed for the novel salts. Since these new salts have improved IND solubility to that similar to BCS class I drugs, IND salts could be considered for possible waivers of bioequivalence.

Fixed-dose single tablet antidiabetic combinations

Combinations of two or more oral agents with different mechanisms of action are often used for the management of hyperglycaemia in type 2 diabetes. While these combinations have customarily been taken as separate tablets, several fixed-dose single tablet combinations are now available. These are based on bioequivalence with the separate tablets, giving similar efficacy to the separate tablets and necessitating the same cautions and contraindications that apply to each active component. Fixed-dose combinations can offer convenience, reduce the pill burden and simplify administration regimens for the patient. They increase patient adherence compared with equivalent combinations of separate tablets, and this is associated with some improvements in glycaemic control. Presently available antidiabetic fixed-dose combinations include metformin combined with a sulphonylurea, thiazolidinedione, dipeptidylpeptidase-4 inhibitor or meglitinide as well as thiazolidinedione-sulphonylurea combinations, each at a range of dosage strengths to facilitate titration. Anticipated future expansion of multiple drug regimens for diabetes management is likely to increase the use of fixed-dose single tablet combinations. © 2009 Blackwell Publishing Ltd.

In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

Introduction: The In vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance.

Equivalence tests to support environmental biosafety decisions:theory and examples.

2016