In this review, the authors review and explain their research on “Discovery of Bonding Active Species Containing Nitrogen Atoms” from the past to the present. The authors are interested in new chemical phenomena, especially in the activation of chemical bonds containing nitrogen atoms, and have conducted research to discover chemical bonds with new properties. The activated chemical bonds containing nitrogen atoms are the following (Fig. 1). (1) Rotationally activated C–N bonds by pyramidalization of amide nitrogen atoms (2) N–N bond cleavage ability with reduced bond strength by pyramidalization of nitrosamine nitrogen atoms (3) Transient hetero atom-N bond formation by neighboring group participation of a halogen electron to the nitrogen cation. (4) A unique carbon cation reaction involving nitrogen atoms, especially nitro groups (C–NO₂ bond) and ammonium ions (C–NH₃⁺ bond). These purely basic chemistry discoveries unexpectedly led to the creation of functional materials, especially biologically active molecules. We will explain how new chemical bonds led to the creation of new functions.

In recent years, the number of patients undergoing outpatient cancer treatment has been increasing. Community pharmacies, have been increasingly involved in cancer treatment and home palliative care. However, there are several hurdles to overcome, such as logistical support during non-standard working hours (at night or during holidays), emergency visits, and for aseptic dispensing. In this paper, we describe a model of medical coordination for emergency home visits during non-standard working hours in which opioid injections need to be dispensed. The study was conducted using a mixed methods approach. We investigated the need for a medical coordination model in home palliative care as well as the issues that need to be improved upon. We constructed, implemented, and assessed the effectiveness of our medical coordination model in a research setting. The medical coordination model reduced the sense of difficulty for general practitioners and community pharmacists in dealing with patients during non-standard working hours and strengthened the degree of cooperation within the coordination team. The activities of the collaborative team saved patients from emergency hospitalization and enabled them to receive end-of-life care at home in accordance with their wishes. The basic framework of the medical coordination model can be adapted according to regional needs and will help promote home palliative care in the future.

Since oral bioavailability of peptides is extremely low, self-injectable and intranasal formulations have been developed; however, these treatments have problems such as storage and discomfort. The sublingual route is considered suitable for peptide absorption because there is less peptidase and it is not subject to hepatic first-pass effects. In this study, we attempted to develop a new jelly formulation for sublingual delivery of peptides. Gelatins with molecular weights of 20000 and 100000 were used as the jelly base. The gelatin was dissolved in water with a small amount of glycerin and air-dried for at least 1 d to form a thin jelly formulation. A mixed base of locust bean gum and carrageenan was used as the outer layer of the two-layer jelly. Jelly formulations with various compositions were prepared, and we evaluated the dissolution time of the jelly formulations and urinary excretion. It was found that the dissolution time of the jelly became slower as the amount of gelatin and the molecular weight increased. Using cefazolin as a model drug, urinary excretion after sublingual administration was measured, and it was found that urinary excretion tended to increase when using a two-layer jelly covered with a mixed base of locust bean gum and carrageenan compared to oral administration of an aqueous solution. Our findings suggest that sublingual drug absorption could be improved by allowing the drug eluted from the jelly formulation to remain in sublingual region for a longer time.

The mucosal drug delivery system (mDDS) is one of the promising approaches to control the pharmacokinetic behavior of drugs. In this approach, surface properties of drug nanoparticles are key determinants to provide particles with mucoadhesive and mucopenetrating properties for prolonged retention at mucosal tissue and rapid mucosal absorption, respectively. In this paper, we would like to discuss the preparation of mDDS formulations by flash nanoprecipitation using a four-inlet multi-inlet vortex mixer, in vitro and ex vivo evaluation of mucopenetrating and mucoadhesive properties of polymeric nanoparticles as well as the application of mDDS to the pharmacokinetic control of cyclosporine A after oral administration to rats. We also share our current research on in silico modeling and prediction of the pharmacokinetic behavior of drugs after intratracheal administration to rats.

Biopharmaceuticals, including therapeutic genes and proteins, are characterized by highly-targeted, specific action and flexible pharmacological design and have a rapidly growing market share; however, because of high molecular weight and low stability, injection is the most common delivery route of biopharmaceuticals. Thus, pharmaceutical innovations are required to provide alternative delivery routes for biopharmaceuticals. Pulmonary drug delivery via inhalation is a promising approach, particularly for targeting local diseases of the lung, because it can exert therapeutic effects in small doses and can noninvasively and directly deliver drugs to airway surfaces. However, biopharmaceutical inhalers must ensure that the biopharmaceuticals maintain their integrity as they are subjected to several types of physicochemical stress, such as hydrolysis, ultrasound, and heating, at various stages during the process from manufacturing to administration. In this symposium, I present a novel dry powder inhaler (DPI) preparation method without heat-drying, with the goal of developing biopharmaceutical DPIs. Spray-freeze-drying is a nonthermal drying technique that produces a powder with porous shapes; this powder has suitable inhalation characteristics for DPI. A model drug, plasmid DNA (pDNA), was stably prepared as a DPI using the spray-freeze-drying process. Under dry conditions, the powders maintained high inhalation characteristics and maintained pDNA integrity for 12 months. The powder induced pDNA expression in mouse lungs that exceeded at higher levels than the solution did. This novel preparation method is suitable for DPI preparation for various drugs and may help expand the clinical application of DPIs.

New drug modalities such as nucleic acid, gene, cells, and nanoparticles are expected for treating refractory diseases. However, these drugs have larger size and low cell membrane permeability; therefore, drug delivery systems (DDS) are essential for delivery to the intended site at the organ and cellular level. In case of the brain, drug migration to the brain from blood circulation is extremely limited by the blood–brain barrier (BBB). Therefore, brain-targeted DDS technologies with the ability to overcome the BBB are being intensively developed. Ultrasound-mediated BBB opening can transiently permeabilize the BBB via cavitation and oscillation and is expected to transfer drugs into the brain. Besides several fundamental studies, clinical studies on BBB opening have also been undertaken, proving its efficacy and safety. Our group has developed an ultrasound-mediated DDS to the brain for low-molecular weight drugs as well as plasmid DNA and mRNA intended for gene therapy. We also evaluated the distribution of gene expression to obtain essential information for applying gene therapy. Here, I provide general information on DDS to the brain, and describe our research progress in brain-targeted delivery of plasmid DNA and mRNA using BBB opening.

Extracellular vesicles (EV) are nanoparticles secreted from cells that are involved in biological functions by transferring their cargo to target cells. Novel disease diagnostic and therapeutic methods may be developed utilizing EV derived from specific cells. In particular, mesenchymal stem cell-derived EV have several useful effects, including tissue repair. Several clinical trials are currently underway. Recent studies have demonstrated that EV secretion is not limited to mammals but also occurs in microorganisms. Since EV from microorganisms contain various bioactive molecules, elucidation of their effects on the host and their practical use is of great interest. On the other hand, for EV utilization, it is necessary to clarify their basic characteristics, such as physical properties and effects on target cells, and to develop a drug delivery system that can manipulate and utilize EV functions. However, the current state of knowledge on EV derived from microorganisms is very limited compared to that of mammalian cell-derived EV. Therefore, we focused on probiotics, microorganisms that have beneficial effects on living organisms. Since probiotics are widely used as pharmaceuticals and functional foods, the utilization of EV secreted from probiotics is expected to benefit clinical fields. In this review, we describe our research on elucidating the effects of probiotic-derived EV on the innate immune response of the host and evaluating their availability as a novel adjuvant.

Today computational chemistry has become an established tool for medicinal chemists. However, softwares are becoming more sophisticated, and in order to master the tools, a wide range of fundamental competency such as thermodynamics, statistics, and physical chemistry are required in addition to chemical creativity. As a result, a software might be used as a black box. In this article, I would like to introduce what a simple computational conformation analysis can do and my experience of using it in actual wet research.

Plasma concentrations of mycophenolic acid (MPA), an immunosuppressive agent, have been measured in clinical settings using immunoassay methods or HPLC. However, immunoassay methods show cross-reactivity with metabolites of MPA glucuronide. Recently, the LM1010 high-performance liquid chromatography instrument was approved as a new general medical device. In this study, we compared the results of MPA plasma concentrations analyzed using the LM1010 method and the previously described HPLC method. Plasma samples obtained from 100 renal transplant patients (32 women and 68 men) were evaluated using both HPLC instruments. Deming regression analyses showed a very high correlation between the two instruments, with a slope of 0.9892 and an intercept of 0.0235 µg/mL (r²=0.982). Bland–Altman analysis showed an average of −0.0012 µg/mL between the LM1010 method and the previously described HPLC method. For the LM1010 method, the total run time for MPA analysis was 7 min, and the analytical time was short; however, the extraction recovery when using a spin column was extremely low for frozen plasma samples stored at −20°C for 1 month, and the volume required for the assay (150 µL) could not be collected. Thus, for the LM1010 method, analysis using fresh plasma samples was optimal. Overall, our findings showed that the LM1010 method was a rapid, accurate HPLC assay for MPA analysis and could be used in clinical practice for routine monitoring of MPA in fresh plasma samples.

All medical enteral nutrition products contain phosphorus and when administered to patients with chronic kidney disease (CKD) and on dialysis, they lead to the risk of elevated serum phosphorus levels. Thus, serum phosphorus levels should be monitored, and phosphorus adsorbents should be used in cases of high serum phosphorus levels. In this study, we investigated the effect of phosphorus adsorbents on enteral nutrition, using Ensure Liquid^®, a medical nutritional formula, for patients with CKD and those on dialysis. Additionally, we compared the effects of the simple suspension method, in which various phosphorus-adsorbing agents are suspended and mixed directly with the nutritional formula for tube administration (hereafter referred to as the “pre-mix method”), and the conventional method, in which only the phosphorus-adsorbing agents are administered separately from the nutritional formula for tube administration (hereafter referred to as the “normal administration method”). The administration of various phosphorus adsorbents using the pre-mix technique resulted in a phosphorus removal rate of 8–15% (approximately 12% on average). Therefore, through the pre-mix method, maintaining the phosphorus content of Ensure Liquid^® below the daily phosphorus intake standard was possible for patients on dialysis. The pre-mix method via the simple suspension method of administering phosphorus adsorbent with Ensure Liquid^® resulted in less drug adsorption to the injector and tube and a higher phosphorus removal rate than the normal administration method.

Community pharmacists in Japan participate in many important clinical cases involving drug therapies. This involvement should be researched and widely publicized to promote evidence-based medicine (EBM). However, the awareness level about the establishment of clinical evidence among community pharmacists remains unknown. Therefore, this large-scale questionnaire survey was conducted among members of the Okayama Pharmaceutical Association to clarify the awareness about the establishment of clinical evidence among community pharmacists to determine the major factors affecting their awareness. Questionnaires requiring open-ended responses were developed in Google Forms. Finally, 366 valid answers were obtained and statistically analyzed based on three aspects: academic conference presentation, research article publication, and research conduct. More than 50% of the participants agreed that they must engage in the establishment of clinical evidence. However, they were unwilling to engage in it by themselves. Additionally, the awareness about the establishment of clinical evidence among participants aged <40 years, who underwent a 6-year course, and with presentation experience was greater than that among participants aged ≥40 years, who underwent a 4-year course and without presentation experience. Thus, age, course duration, and presentation experience are important factors influencing awareness about the establishment of clinical evidence. Further, >70% of the participants did not have enough time to engage in the establishment of clinical evidence, suggesting that reducing workload and ensuring adequate time are necessary for such engagements. Our novel findings may increase the establishment of clinical evidence by community pharmacists, improve community pharmacists’ social standing, and promote EBM in Japan.

In Japan, pharmacists have begun working in emergency departments (ED) over the last decade. However, no reports exist on the contribution of pharmacists’ activities in the ED to patient safety. We investigated whether pharmacists’ long-term duties influence the number of incident reports in the ED. Of the 862 incidents reported, 152 (17.6%) were drug-related reports. Further investigations revealed that 42 cases occurred during pharmacists’ usual working hours, four cases (9.5%) occurred when a pharmacist was present in the ED, and 38 cases (90.5%) occurred in the absence of a pharmacist in the ED. The number of incident reports was significantly reduced by pharmacists optimizing pharmacotherapy in the ED (p=0.002). There was a decrease in the degree of impact on patients through pharmacist duties compared to pharmacist absence (intercepting errors prior to patient administration: 4.8 vs. 31%; medication misadministration: 4.8 vs. 59.4%). Medical staff-associated factors and time of patient arrival at the ED did not have a significant impact on incident reports for any time. Long-term pharmacist duties in the ED can reduce the number of incident reports and contribute to safe medication care in the ED.

Eleven major cannabinoids from each subdivided tissue of drug-type and fiber-type cannabis plants were determined by means of a liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). The cannabinoids analyzed in this study were tetrahydrocannabinol acid (THCA), Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol acid (CBDA), cannabidiol (CBD), Δ⁸-tetrahydrocannabinol (Δ⁸-THC), cannabinol (CBN), cannabichromene (CBC), cannabidivarin (CBDV), cannabigerolic acid (CBGA), cannabigerol (CBG) and tetrahydrocannabivarin (THCV). As a result, THCA was detected in the bracts at 28.4 µg/mg, in the buds at 24.8 µg/mg, and in the leaves at 5.1 to 10.5 µg/mg in the drug-type cannabis plant. In addition, Δ⁹-THC, CBGA, CBN, CBG, CBC, and THCV were mainly detected in bracts, buds, and leaves. On the other hand, as for the fiber-type cannabis plant, CBDA was detected in the bracts at 27.5 µg/mg, in the buds at 10.6 µg/mg, and in the leaves at 1.5–3.3 µg/mg. In addition, Δ⁹-THCA, CBD, Δ⁹-THC, CBC, and CBG were mainly detected in bracts, buds, and leaves.