Discovery and Model-Informed Drug Development of a Controlled-Release Formulation of Nonracemic Amisulpride that Reduces Plasma Exposure but Achieves Pharmacodynamic Bioequivalence in the Brain.

Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II.

Changes in mobility amid the COVID-19 pandemic in Sapporo City, Japan: An investigation through the relationship between spatiotemporal population density and urban facilities.

By the end of 2021, the Omicron variant of coronavirus disease 2019 had become the dominant cause of a worldwide pandemic crisis. This demands a deeper analysis to support policy makers in creating interventions that not only protect people from the pandemic but also remedy its negative effects on the economy. Thus, this study investigated people's mobility changes through the relationship between spatiotemporal population density and urban facilities. Results showed that places related to daily services, restaurants, commercial areas, and offices experienced decreased visits, with the highest decline belonging to commercial facilities. Visits to health care and production facilities were stable on weekdays but increased on holidays. Educational institutions' visits decreased on weekdays but increased on holidays. People's visits to residential housing and open spaces increased, with the rise in residential housing visits being more substantial. The results also confirmed that policy interventions (e.g., declaration of emergency and upgrade of restriction level) have a great impact on people's mobility in the short term. The findings would seem to indicate that visit patterns at service and restaurant places decreased least during the pandemic. The analysis outcomes suggest that policy makers should pay more attention to risk perception enhancement as a long-term measure. Furthermore, the study clarified the population density of each facility type in a time series. Improving model performance would be promising for tracking and predicting the spread of future pandemics.

Changes in urban mobility in Sapporo city, Japan due to the Covid-19 emergency declarations.

At the time of writing, the world is facing the new coronavirus pandemic, which has been declared one of the most dangerous disasters of the 21st century. All nations and communities have applied many countermeasures to control the spread of the epidemic. In terms of countermeasures, lockdowns and reductions of social activities are meant to flatten the curve of infection. Nevertheless, to date, there has been no evaluation of the effectiveness of these methods. Thus, the present study aims to interpret the change in the population density of Sapporo city in the emergency's period declaration using big data obtained from mobile spatial statistics. The results indicate that, in the time of refraining from traveling, the city's residents have been more likely to stay home and less likely to travel to the center area. This has led to a decrease of up to 90% of the population density in crowded areas. The study's outcomes partly explain the statement of reducing 70%-80% of contact between people in line with the purpose of the emergency declaration. Moreover, these findings establish the primary step for further analysis of estimating the efficiency of policy in controlling the epidemic.

Formulation of a poorly water-soluble drug in sustained-release hollow granules with a high viscosity water-soluble polymer using a fluidized bed rotor granulator.

Water-soluble polymers with high viscosity are frequently used in the design of sustained-release formulations of poorly water-soluble drugs to enable complete release of the drug in the gastrointestinal tract. Tablets containing matrix granules with a water-soluble polymer are preferred because tablets are easier to handle and the multiple drug-release units of the matrix granules decreases the influences of the physiological environment on the drug. However, matrix granules with a particle size of over 800 µm sometimes cause a content uniformity problem in the tableting process because of the large particle size. An effective method of manufacturing controlled-release matrix granules with a smaller particle size is desired. The aim of this study was to develop tablets containing matrix granules with a smaller size and good controlled-release properties, using phenytoin as a model poorly water-soluble drug. We adapted the recently developed hollow spherical granule granulation technology, using water-soluble polymers with different viscosities. The prepared granules had an average particle size of 300 µm and sharp particle size distribution (relative width: 0.52-0.64). The values for the particle strength of the granules were 1.86-1.97 N/mm2, and the dissolution profiles of the granules were not affected by the tableting process. The dissolution profiles and the blood concentration levels of drug released from the granules depended on the viscosity of the polymer contained in the granules. We succeeded in developing the desired controlled-release granules, and this study should be valuable in the development of sustained-release formulations of poorly water-soluble drugs.

Mechanism of the formation of hollow spherical granules using a high shear granulator.

Recently, we have developed a novel granulation technology to manufacture hollow spherical granules (HSGs) for controlled-release formulations; however, the mechanism of the granulation is still unclear. The aim of this study is to determine the mechanism of the formation of the HSGs using a high shear granulator. Samples of granulated material were collected at various times during granulation and were investigated using scanning electron microscope and X-ray computed tomography. It was observed that the granulation proceeded by drug layering to the polymer, followed by formation of a hollow in the granule. In addition, it was also found that generation of a crack in the adhered drug layer and air flow into the granules might be involved in forming the hollow in the structure. Observation of the granulation of formulations with different types of drugs and polymers indicated that negative pressure in the granules occurred and the granules caved in when the hollow was formed. The hollow-forming speed and the shell density of the hollow granules depended on the particular drug and polymer. Taken together, the granulation mechanism of HSGs was determined and this information will be valuable for HSGs technology development.

An innovative method for the preparation of high API-loaded hollow spherical granules for use in controlled-release formulation.

The aim of this study was to prepare controlled-release (CR) granules with suitable particle strength, flowability, particle size distribution (PSD) and density characteristics for blending with other excipients. We also wanted these CR granules to contain large quantities of active pharmaceutical ingredient (API). A high shear mixer was used to mix an API with various polymers at various feed ratios, and the resulting granulated materials were sprayed with solvent. The wet granules were dried using a fluidized bed dryer to give CR granules. The API content of the granules was determined to be 95wt%. The granules were found to be spherical in shape with smooth surfaces by scanning electron microscopy. The inner structure of each granule was determined to be hollow by X-ray computed tomography, highlighting the unusual mechanism of this granulation process. The PSD of the granules was found to be dependent on that of the constituent polymer, and a narrow PSD was obtained by adjusting the PSD of the polymer. The dissolution profile of the granules was also dependent on the constituent polymer. Taken together, these results show that we have successfully developed a new manufacturing technology for the simple and low-cost preparation of ideal CR granules.

Aggregate formation and radiolytic degradation of amphiphilic DNA block copolymer possessing disulfide bond.

We have designed a novel aggregate of DNA block copolymer (DBC) that is sensitive to hypoxic X-irradiation. The DBC consists of tetrahydropyrane-protected 2-hydroxyethyl methacrylate as a hydrophobic unit and oligodeoxynucleotides as a hydrophilic unit, which are linked to a radiation-sensitive disulfide bond. The DBC self-assembled efficiently to form aggregates that encapsulated small molecules such as nile red and pyrene. Hypoxic X-irradiation could then induce reductive degradation of the DBC aggregates via an exchange reaction of the disulfide bond to release guest molecules.

Facile formation of five-membered N-heterocyclic zirconacycloallenoids.

The reaction of η(2)-iminozirconocene chloride complexes with trimethylsilylethynyl lithium leads to rapid C-C coupling at room temperature to yield the corresponding five-membered aza-zirconacycloallenoids. Such compounds were also obtained by trapping of in situ generated zirconocene with alkynyl imines.

Radiolytic reduction characteristics of drug-encapsulating DNA aggregates possessing disulfide bond.

Radiation-responsive aggregates consisting of artificial DNA were demonstrated. We prepared DNA amphiphiles (DAMs) consisting of oligodeoxynucleotides (ODNs) as the hydrophilic part and an alkyl chain as the hydrophobic part, which were linked by a radiation-sensitive disulfide bond. DAMs assembled to form nanosized aggregates in aqueous solution that encapsulated hydrophobic dyes and drugs. X-irradiation, which triggered selective reduction at the disulfide bond in the DAMs, induced an exchange reaction, resulting in dissociation of the aggregates and release of encapsulated dyes and drugs. Among the DAMs synthesized in this study, DAM 1 possessing 5 mer ODNs showed favorable properties as a nanocarrier; for example, the large amount of drug was encapsulated in the aggregates consisting of DAM 1, and the aggregates showed the high sensitivity to radiolytic reduction. Biological experiments using living A549 cells revealed that the aggregates smoothly penetrated into the cells without the need for transfection reagents, while the drugs inside the aggregates were inert because of the encapsulation. X-irradiation enhanced the cytotoxicity because of dissociation of the aggregates and concomitant release of drugs.