Simulation of oral absorption from non-bioequivalent dosage forms of the salt of raltegravir, a poorly soluble acidic drug, using a physiologically based biopharmaceutical modeling (PBBM) approach.

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.

Nanosuspension formulations of poorly water-soluble compounds for intravenous administration in exploratory toxicity studies: in vitro and in vivo evaluation.

This study was conducted to investigate the use of a nanosuspension for intravenous injection into dogs to increase exposure without toxic additives for preclinical studies in the discovery stage. Nanosuspensions were prepared with a mixer mill and zirconia beads with a vehicle of 2% (w/v) poloxamer 338, which was confirmed to lead to no histamine release in dogs. Sterilized nanosuspensions of poorly water-soluble compounds, cilostazol (Cil), spironolactone (Spi) and probucol (Pro), at 10 mg ml(-1) were obtained by milling for 30 min, followed by autoclaving for 20 min at 121 °C and milling for 30 min (mill-autoclave-mill method). The particle sizes (d50) of Cil, Spi and Pro were 0.554, 0.484 and 0.377 µm, respectively, and the percentages of the nominal concentration were 79.1%, 99.6% and 75.4%, respectively. In chromatographic data, no extra peaks were observed. The particle size of Cil was 0.564 µm after storage for 16 days at 2-8 °C. Cil in nanosuspension, but not in microsuspension, rapidly dissolved in dog plasma. Cil nanosuspension at 0.4 mg kg(-1) and Cil saline solution at 0.03 mg kg(-1) , around the saturation solubility, were intravenously administered to dogs. Nanosuspension increased exposure. The versatility of the mill-autoclave-mill method was checked for 15 compounds, and the particle size of 12 compounds was in the nano range. The nanosuspension optimized in this study may be useful for intravenous toxicological and pharmacological studies in the early stage of drug development. Copyright © 2016 John Wiley & Sons, Ltd.

Practical method for preparing nanosuspension formulations for toxicology studies in the discovery stage: formulation optimization and in vitro/in vivo evaluation of nanosized poorly water-soluble compounds.

The present study aimed to develop a practical method for preparing nanosuspension formulations of poorly water-soluble compounds for enhancing oral absorption in toxicology studies in the discovery stage. To obtain a suitable nanosuspension formulation for the intended purpose, formulations were optimized with a focus on the following characteristics: i) containing a high drug concentration, ii) consisting of commonly used excipient types in proper quantities for toxicology studies, iii) having long-term stability, and iv) having versatility for use with diverse compounds. Test compounds were milled with various excipients by wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). As a result, 100 mg/mL nanosuspensions of all 11 test compounds could be prepared with an optimized dispersing agent, 0.5% hydroxypropyl methylcellulose (HPMC) (3 cP)-0.5% Tween 80. Notably, it was found that the molecular weight of HPMC influenced not only particle size but also the stability of nanosuspensions and they were stable for 4 weeks at 5°C. The nanosuspensions increased in vitro dissolution rates and provided 3.9 and 3.0 times higher Cmax and 4.4 and 1.6 times higher area under the concentration-time curve from 0-24 h (AUC0-24 h) in rats (oral dose of 300 mg/kg) for cilostazol and danazol, respectively. In conclusion, applying a wet media milling method with the combination of HPMC of a small molecular weight and Tween 80 as a dispersing agent, nanosuspensions can be practically prepared and conveniently utilized for enhancing the oral absorption of poorly water-soluble compounds in toxicology studies in the discovery stage.

Reevaluation of solubility of tolbutamide and polymorphic transformation from Form I to unknown crystal form.

Thermodynamic stability order of tolbutamide between polymorphs was evaluated using calorimetry and spectroscopic analysis. The heat of solution (DeltaH) of Forms I-III measurements were carried out in dimethylsulfoxide between 298.2K and 319.2K. It was found that the DeltaH of Forms II and III was increased nearly parallel with a temperature rise. However, change of the DeltaH of Form I with a temperature rise was not in correspondence with that of other forms. Solubility data confirmed the change in DeltaH of Form I around 308.2K. XRD-DSC measurement of Form I detected a polymorphic transformation (Form I(L)-->unknown form) at 311K. Obtained data suggested that the new crystal form (Form I(H)) would exist above 311K, and the order of thermodynamic stability was "Form III