[Introduction of "Access to Health" Initiatives for Neglected Tropical Diseases (NTDs)～R&D of NTD Medicines～].

Astellas regards the situation where there still remain barriers for many people who have difficulty accessing the healthcare they need due to the lack of available treatments, poverty, healthcare system challenges and insufficient healthcare information. Astellas recognizes this problem as the Access to Health issue. To improve Access to Health, Astellas has identified four areas where we can leverage our strengths and technologies, and is working to solve issues, making full use of external partnerships. These areas are "creating innovation", "enhancing availability", "strengthening healthcare system" and "improving health literacy". In March 2018, Astellas participated in the Neglected Tropical Diseases Drug Discovery Booster, a consortium whose purpose is to identify lead compounds for leishmaniasis and Chagas disease, both of which are neglected tropical diseases (NTDs). Moreover, within the pediatric praziquantel consortium, involving pharmaceutical companies, research institutions and international non-profit organizations, Astellas has developed a pediatric formulation of praziquantel for the treatment of schistosomiasis. In this report, we will introduce concretely how Astellas has promoted new drug development projects for NTDs in collaboration with various external partners, giving the projects as examples.

Release mechanisms of tacrolimus-loaded PLGA and PLA microspheres and immunosuppressive effects of the microspheres in a rat heart transplantation model.

The objective of this study was to elucidate the release and absorption mechanisms of tacrolimus loaded into microspheres composed of poly(lactic-co-glycolic acid) (PLGA) and/or polylactic acid (PLA). Tacrolimus-loaded microspheres were prepared by the o/w emulsion solvent evaporation method. The entrapment efficiency correlated with the molecular weight of PLGA, and the glass transition temperature of PLGA microspheres was not decreased by the addition of tacrolimus. These results indicate that intermolecular interaction between tacrolimus and the polymer would affect the entrapment of tacrolimus in the microspheres. Tacrolimus was released with weight loss of the microspheres, and the dominant release mechanism of tacrolimus was considered to be erosion of the polymer rather than diffusion of the drug. The whole-blood concentration of tacrolimus in rats was maintained for at least 2 weeks after a single subcutaneous administration of the microspheres. The pharmacokinetic profile of tacrolimus following subcutaneous administration was similar to that following intramuscular administration, suggesting that the release and dissolution of tacrolimus, rather than the absorption of the dissolved tacrolimus, were rate-limiting steps. Graft-survival time in a heart transplantation rat model was prolonged by the administration of tacrolimus-loaded microspheres. The microsphere formulation of tacrolimus would be expected to precisely control the blood concentration while maintaining the immunosuppressive effect of the drug.

Effects of physicochemical properties of salting-out layer components on drug release.

A "Salting-out Taste-masking System" generates a long lag time for numbness and bitterness masking, with subsequent immediate drug release to exert pharmacological effects. In this study, the effects of physicochemical properties of salting-out agents and water-soluble polymers in the salting-out layer on the dissolution behaviors of acetaminophen were investigated and predominant factors for lag time generation (Lag time index, hereafter LI) and subsequent drug release (Rapid release index, hereafter RI) were discussed. Each prepared formulation showed a different dissolution profile of acetaminophen with a lag time and subsequent immediate release. Significant correlations between both LI and RI and DeltaCST (the salting-out power of salting-out agents) (r(2)=0.90, 0.67, respectively) and between both LI and RI and CST(1) (the sensitivity of water-soluble polymers to a salting-out effect) (r(2)=0.98, 0.71, respectively) were shown. These results suggest that the components showing a strong salting-out effect inside the beads lead to extended lag times and slow drug releases after the lag times. Results further suggest the use of CST(1) to evaluate suitable combinations of salting-out agents and water-soluble polymers in this system.

Optimization of salting-out taste-masking system for micro-beads containing drugs with high solubility.

The salting-out taste-masking system is a multiparticulate system consisting of a drug core, a salting-out layer containing salts and water-soluble polymers, and a water-penetration control layer containing water-insoluble materials. The system generates a long lag time (time when released drug is less than 1%) for numbness masking, and a subsequent immediate drug release for high bioavailability. Aiming to contain the system and drugs that cause numbness in oral disintegrating tablets, the system was optimized to reduce the particle size and contain drugs with high water solubility in this study. The amount of coating on the layers, the coating solvent, and the positioning of the components were also optimized. The findings in this study will lead to the provision of numbness-masked oral disintegrating tablets to patients.

Mechanism of controlled drug release from a salting-out taste-masking system.

A "salting-out taste-masking system" is a multiparticulate system consisting of a drug core, a salting-out layer containing salts and water-soluble polymers, and a water-penetration control layer containing water-insoluble materials. The system generates a long lag time for numbness masking, with subsequent immediate drug release for high bioavailability. In this study, sodium carbonate (Na2CO3) and hydroxypropylmethylcellulose (HPMC) were used as the salt and water-soluble polymer in the salting-out layer, respectively. The drug release rate from the formulation containing the HPMC layer was affected by the Na2CO3 concentrations in the media used in the drug dissolution tests. The HPMC layer suppressed drug release in a medium with a high Na2CO3 concentration, and subsequently increased the drug release rate in a medium with a low Na2CO3 concentration. Drug release from the system was suppressed while Na2CO3 remained in the formulations. Microscopic changes in HPMC in the salting-out layers correlated well with changes in the drug release rate. These results indicate that, in the salting-out taste-masking system, the drug release suppression and the immediate release are caused by insolubilization and dissolution of the water-soluble polymer respectively. These findings will allow for smarter formulation design.