Enhanced dissolution rate of nimodipine through ß-lactoglobulin based formulation.

Amorphous solid dispersions (ASD) have been considered as one of the most effective strategies to increase solubility and dissolution rate of poorly water-soluble drugs. Carriers, in which the poorly water-soluble drug is dispersed, contribute a large extent to the solid-state properties, stabilities and dissolution performance of ASDs. This study investigated the solid-state properties, physical stability, and in vitro dissolution behaviour of nimodipine ASDs formulated with a traditional polymeric carrier, i.e., polyvinylpyrrolidone (PVP) and a novel carrier, i.e., ß-lactoglobulin (BLG). The ASDs with both carriers were prepared using ball milling as preparative technique at 10 %, 17.5 %, 25 %, 30 % and 40 % drug loadings (DLs). All the formulations were found to be amorphous upon milling for 60 min based on X-ray powder diffraction measurements, however, the ASDs were found to be homogeneous unequivocally only at DLs below 25 %. After open storage at accelerated conditions (40 °C/75 % relative humidity), only the ASDs formulated with BLG at 10 % and 17.5 % DLs maintained the amorphous form. The dissolution study revealed that all the freshly prepared ASDs formulated with PVP and the ASDs formulated with BLG at or above 25 % DLs, showed a low drug release (<30 µg/mL in simulated gastric fluid, < 70 µg/mL in simulated intestinal fluid). Whilst the ASD formulated with BLG at 10 % DL exhibited a high drug release with a maximum concentration (Cmax) of 251 µg/mL in simulated gastric fluid and 231 µg/mL in simulated intestinal fluid. Surprisingly, the ASD formulated with BLG at 17.5 % DL demonstrated an even higher drug release (Cmax, 643 µg/mL in simulated gastric fluid, 332 µg/mL in simulated intestinal fluid), compared to the ASD of 10 % DL. These findings underline the importance of rationally investigating both carrier types and DL in the design of ASDs, in order to obtain a stable ASD with the desired enhanced dissolution rate of poorly water-soluble drugs.

Characteristics of Contents of Lower intestine in the 65-74 Years of Age Range Could Impact the Performance of Safe and Efficacious Modified Release Products.

We characterized the contents of distal ileum and proximal colon of older people from a pharmaceutical product performance perspective, under two extreme situations, i.e. 5 h after a glass of water to fasted volunteers (fasted state) and 5 h after a high-calorie, high-fat meal to fasted volunteers (fed state). Five males and three females (65-70 y) participated in a two-phase crossover study. Contents were collected via colonoscopy. In distal ileum, luminal pH was lower and buffer capacity was higher than in young adults; differences reached significance for pH in the fed state. In proximal colon, differences reached significance for pH/fasted state and for buffer capacity/both fasted and fed states. Aqueous fraction of contents contained more short chain fatty acids than previously observed in young adults. In distal ileum, osmolality was significantly higher than in young adults. In proximal colon, aqueous fraction in the fasted state was significantly lower and long chain fatty acids 5 h after meal was significantly higher than in young adults. Characteristics of contents of lower intestine that are relevant to the performance of certain modified release products differ between individuals 65-74 years old and young adults, the typical age group employed in safety and efficacy studies of oral drug products.

Potent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF).

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung tissue and constitutes an attractive target for the treatment of fibrotic lung diseases. Herein, we present our research toward novel quinoline-based hFP-R antagonists, including synthesis and detailed structure-activity relationship (SAR). Starting from a high-throughput screening (HTS) hit of our corporate compound library, multiple parameter improvements-including increase of the relative oral bioavailability Frel from 3 to ≥100%-led to a highly potent and selective hFP-R antagonist with complete oral absorption from suspension. BAY-6672 (46) represents-to the best of our knowledge-the first reported FP-R antagonist to demonstrate in vivo efficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.