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The effects of pH changes and saccharin (SAC) addition on the nanostructure and mobility of the cationic aminoalkyl methacrylate copolymer Eudragit E PO (EUD-E) and its drug solubilization ability were investigated. Small-angle X-ray scattering performed using synchrotron radiation and atomic force microscopy showed that the EUD-E nanostructure, which has a size of approximately several nanometers, changed from a random coil structure at low pH (pH 4.0-5.0) to a partially folded structure at high pH (pH 5.5-6.5). The EUD-E also formed a partially folded structure in a wide pH range of 4.5-6.5 when SAC was present, and the coil-to-globule transition was moderate with pH increase, compared with that when SAC was absent. The equilibrium solubility of the neutral drug naringenin (NAR) was enhanced in the EUD-E solution and further increased as the pH increased. The enlargement of the hydrophobic region of EUD-E in association with the coil-to-globule transition led to efficient solubilization of NAR. The interaction with SAC enhanced the mobility of the EUD-E chains in the hydrophobic region of EUD-E, resulting in changes in the drug-solubilizing ability. 1H high-resolution magic-angle spinning NMR measurements revealed that the solubilized NAR in the partially folded structure of EUD-E showed higher molecular mobility in the presence of SAC than in the absence of SAC. This study highlighted that solution pH and the presence of SAC significantly changed the drug solubilization ability of EUD-E, followed by changes in the EUD-E nanostructure, including its hydrophobic region.

Recently, choline and geranic acid (CAGE), an ionic liquid (IL), has been recognized to be a superior biocompatible material for oral and transdermal drug delivery systems (DDS). When CAGE is administered, CAGE would be exposed to various types of physiological fluids, such as intestinal and intradermal fluids. However, the effect of physiological fluids on the structure of CAGE remains unclear. In the present study, molecular structures of CAGE with different ratios of water were investigated using small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR). The SAXS pattern of CAGE showed an IL-specific broad peak derived from nanoscale aggregation until 17 vol % water. Meanwhile, narrow peaks were observed in samples with 25-50 vol % water, showing a transition to the lamellar phase. With more than 67 vol % water, CAGE was found to exist as micelles in water. The 1H NMR spectra indicated that protons of H2O, OH in choline (CH), and COOH in geranic acid (GA) were observed as only one peak up to 17 vol % water. This peak shifted to a high magnetic field, and the integral values increased with the water content, speculating that water is localized close to the COOH and OH groups to allow proton exchange. The 13C NMR spectra showed that peaks related to the carboxyl group shifted with adding water. Moreover, only GA peaks were observed in the lamellar phase through 13C cross-polarization magic-angle spinning NMR, suggesting that the main rigid component of the lamellar phase was GA. Taken together, this study suggested that CAGE still maintained its IL structure up to 17 vol % water, then transitioned to the lamellar phase with 25-50 vol % water, and finally changed to the micellar phase with more than 67 vol % water. This information would be useful in the formulation and development of DDS using CAGE.

Home medical care (HMC) is advancing not only in Japan but also throughout the world. In Japan, HMC waste is legally classified as municipal waste. Nevertheless, some municipalities do not collect some or all the HMC waste because of fear of infection. Therefore, this study was conducted to clarify the following two issues: First, have the municipalities made progress in collecting and appropriate disposal of HMC waste in the past 13 years? Second, is there a difference between a large city and a small city in terms of appropriate disposal progress? A total of 687 municipalities published the treatment of HMC waste. Currently, 42 municipalities collected all HMC waste. 236 municipalities were collecting HMC waste except for self-injection needle. 117 municipalities were collecting HMC waste except for self-injection needle and Syringe. The collection status of HMC waste was better in cities with high population than in cities with low population. HMC waste collection status was progressed over 13 years. However, more than 60% of the municipality staff stated that they could not avoid being anxious about infection caused by HMC waste. We suggest that providing HMC waste education to the municipalities wherein these efforts have not yet progressed is important.

The states of amorphous drug and/or newly generated crystalline drug on the surface of amorphous drug samples must be carefully characterized to validate the quality of pharmaceutical amorphous drugs. In this study, we investigated whether individual mechanical properties of amorphous and crystalline drugs could be discerned by an atomic force microscope (AFM) with a mapping. Among mechanical properties, the amorphous and crystal drugs were quantitatively distinguished by elastic modulus using PeakForce

The clustered regularly interspaced short palindromic repeats-CRISPR associated protein9 (CRISPR-Cas9) system, which includes a single guide RNA (sgRNA) and a Cas9 protein, is an emerging and promising gene editing technology that produces specific changes, including insertions, deletions, or substitutions, in desired targets. This approach can be applied in novel therapeutic areas for multiple cancers and genetic diseases, including Parkinson's disease, sickle cell disease, and muscular dystrophy. However, there are many limitations to its potential application to therapeutics. CRISPR-Cas9 activity without side effects, delivery of CRISPR-Cas9 to the target cell within the desired tissue including liver, lungs, brain and muscle and the expression of Cas9 endonuclease in the target cell are key factors in achieving therapeutic efficacy. Generally, single-stranded RNA is immediately degraded in cells and biological fluids such as serum, as chemically unmodified single-stranded RNA shows extremely poor stability against nuclease degradation. To overcome this limitation, sgRNA is chemically modified to obtain a highly stable sgRNA for efficient gene editing in cells and in vivo. Here, we identified the cleavage site of sgRNA for pinpoint modification in biological tissues using mass spectrometry and improved stability of pinpoint modified sgRNA in these fluids. Although improved efficiency provided by modified sgRNA has already been reported, we identified the cleavage site by mass spectrometry and revealed that the stability increased with the pinpoint modification strategy for the first time in this study. In future studies, the efficiency of pinpoint modification strategy for the potential application of sgRNA by systematic routes, including intravenous and subcutaneous administration will be assessed.

Introduction: Infectious medical waste management in hospitals is very important. The potential impacts of infectious medical waste discharged from hospitals on populations and society are considered greater than those of general industrial waste. Therefore, the estimation of infectious medical waste discharged from healthcare facilities should be accurate. The present study reports the quantity of infectious medical waste discharged per ward per day per inpatient by weight. Methods: In medical wards, the digestive surgery ward discharged the most infectious medical waste. In addition, the digestive surgery ward had the highest quantity of infectious medical waste per day per inpatient. Infectious medical waste quantity estimates based on beds were lower than those based on inpatients, with minimum and maximum underestimates of 6% and 21%, respectively. Results & Discussion: Infectious medical waste discharged per patient per day was low in the outpatient department. The operating room and the emergency department discharged 10-fold more infectious medical waste than the wards. The operating room, the emergency department, and the clinical inspection department accounted for 60% of infectious medical waste discharged from hospitals. Conclusion: Notably, there are considerable differences among departments when evaluating hospital waste, particularly in hospitals with surgery and critical care departments, which is different in the case of evaluations based on bed counts.

ATP1A3, a mutated gene for AHC, RDP, and CAPOS, is also associated with polymicrogyria by different functional variants., Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

The detailed structure of a pharmaceutical nanosuspension was investigated using three nuclear magnetic resonance (NMR) methods: solid-state, solution-state, and high resolution-magic angle spinning (HR-MAS) NMR. Carbamazepine (CBZ) and CBZ-saccharin (SAC) cocrystal nanosuspensions were prepared by wet-milling with hydroxypropyl methylcellulose (HPMC) and sodium dodecyl sulfate (SDS) as stabilizing agents. Solid-state 13C NMR indicated the presence of not only the crystalline drug substance but also solid-state HPMC, even though HPMC was used as an aqueous solution to prepare the nanosuspensions. Solution-state 1H NMR of the nanosuspensions with and without ultracentrifugation pretreatment indicated that a fraction of the CBZ, SAC, and SDS formed a solid or semisolid phase on the surface of the nanoparticles and was in equilibrium between the dissolved and undissolved states. 1H HR-MAS NMR was highly effective in detecting and quantifying the semisolid phase on the surface of the nanoparticles. From these comprehensive NMR studies, it was concluded that the nanosuspension was composed of crystalline drug core particles surrounded by a semisolid phase consisting of the drug and stabilizing agents. The semisolid phase on the nanoparticle surface was in equilibrium with the solution phase and contributed to the stabilization of the nanoparticle by steric hindrance and electrostatic repulsion.

医薬保健研究域薬学系, The World Health Organization has warned that substandard and falsified medical products (SFs) can harm patients and fail to treat the diseases for which they were intended, and they affect every region of the world, leading to loss of confidence in medicines, health-care providers, and health systems. Therefore, development of analytical procedures to detect SFs is extremely important. In this study, we investigated the quality of pharmaceutical tablets containing the antihypertensive candesartan cilexetil, collected in China, Indonesia, Japan, and Myanmar, using the Japanese pharmacopeial analytical procedures for quality control, together with principal component analysis (PCA) of Raman spectrum obtained with handheld Raman spectrometer. Some samples showed delayed dissolution and failed to meet the pharmacopeial specification, whereas others failed the assay test. These products appeared to be substandard. Principal component analysis showed that all Raman spectra could be explained in terms of two components: the amount of the active pharmaceutical ingredient and the kinds of excipients. Principal component analysis score plot indicated one substandard, and the falsified tablets have similar principal components in Raman spectra, in contrast to authentic products. The locations of samples within the PCA score plot varied according to the source country, suggesting that manufacturers in different countries use different excipients. Our results indicate that the handheld Raman device will be useful for detection of SFs in the field. Principal component analysis of that Raman data clarify the difference in chemical properties between good quality products and SFs that circulate in the Asian market. Copyright © 2018 by The American Society of Tropical Medicine and Hygiene.

Sulfathiazole forms II, III and IV are polytypes where common monolayers accumulate in different stacking modes. These polytypes are difficult to identify using conventional analytical techniques when they concomitantly crystallize. However, the use of low-frequency Raman spectroscopy enables discrimination of these polytypes and can determine the ratio of forms III and IV, which are the most challenging pair for quantification. A Hydrogen/deuterium exchange study suggests that characteristic patterns below 100 cm−1 predominantly come from differences of superstructure geometries, especially layer stacking, rather than hydrogen-bond geometries. This study demonstrates that low-frequency Raman spectroscopy has advantages for both polytypic discrimination and quantification.

Micronized cocrystal powders and amorphous spray-dried formulations were prepared and evaluated in vivo and in vitro as pulmonary absorption enhancement formulations of poorly soluble itraconazole (ITZ). ITZ cocrystals with succinic acid (SA) or l-tartaric acid (TA) with a particle size diameter of

Background: Domestic medical waste from Home Medical Care (HMC) is a concern in Japan. In 2005, the Japanese government provided that HMC waste is collected by municipalities. HMC waste includes infectious or sharps, thus such waste should be collected by doctor or nurse. Nevertheless, no studies have examined the collection of separate HMC waste items, such as needles and infectious agents. Objective: To demonstrate the current HMC waste collection status for individual items and to assess whether HMC waste collection rate by nurses has been changed since the initial study. Methods: A questionnaire was mailed and delivered 1,022 offices, from which 677 office nurses replied for the follow-up study, 27 had closed down, and five had integrated with other offices. Thus, the final analysis was conducted in 645 offices. Offices were classified into three groups according to the size of the local population. Results: Most of the used syringes and needles, were collected by a nurse or doctor. More nurses in small-sized cities collected used syringes and needles from patients’ homes than nurses in medium- or large-sized cities. In contrast, more doctors in large-sized cities collected used syringes and needles from patients’ homes than doctors in small- or medium-sized cities. HMC waste collection rates by nurses for all city sizes had decreased since the baseline study. Both 2009 and 2015 study, the collection rate of HMC waste by nurse was as high as small-sized city and lower as large-sized city. The trend of this did not change over six years. Conclusion: The collection rate of HMC waste by nurses has declined in the last six years. This indirectly indicated that the HMC waste collection rate of municipalities improved in six years. Safe HMC waste collection program awareness should be promoted among nurses, doctors and patients. It is necessary for healthcare workers to work in cooperation with municipalities. The development of standardized guidelines for HMC waste handling protocols should be a priority for all municipalities.

金沢大学医薬保健研究域薬学系, Analytical methods for the detection of substandard and falsified medical products (SFs) are important for public health and patient safety. Research to understand how the physical and chemical properties of SFs can be most effectively applied to distinguish the SFs from authentic products has not yet been investigated enough. Here, we investigated the usefulness of two analytical methods, handheld Raman spectroscopy (handheld Raman) and X-ray computed tomography (X-ray CT), for detecting SFs among oral solid antihypertensive pharmaceutical products containing candesartan cilexetil as an active pharmaceutical ingredient (API). X-ray CT visualized at least two different types of falsified tablets, one containing many cracks and voids and the other containing aggregates with high electron density, suchasfrom the presence of theheavy elements. Generic products that purported to contain equivalent amounts of A PIto the authentic products were discriminated from the authentic products by the handheld Raman and the different physical structure on X-ray CT. Approachto investigate both the chemical and physical properties with handheld Raman and X-ray CT, respectively, promise the accurate discrimination of the SFs, even if their visual appearance is similar with authentic products. We present a decision tree for investigating the authenticity of samples purporting to be authentic commercial tablets. Our results indicate that the combination approach of visual observation, handheld Raman and X-ray CT is a powerful strategy for nondestructive discrimination of suspect samples. © Copyright 2017 by The American Society of Tropical Medicine and Hygiene., Embargo Period 12 months

The present study evaluated the specific intermolecular interactions between carbamazepine (CBZ) and substituents of hypromellose acetate succinate (HPMC-AS), as well as the mechanism of inhibition of recrystallization of solid dispersions (SDs) using Fourier-transform infrared (FTIR) and solid-state nuclear magnetic resonance (NMR) spectroscopy. CBZ and HPMC derivatives, including HPMC, hypromellose acetate (HPMC-A), and hypromellose succinate (HPMC-S), were spray-dried to prepare CBZ/polymer spray-dried samples (SPDs). CBZ/HPMC SPD and CBZ/HPMC-A SPD recrystallized within 10 days at 60 °C and 0% relative humidity, whereas CBZ/HPMC-S SPD maintained its amorphous state for a longer period. FTIR and solid-state NMR measurements using 13C cross polarization (CP), 1H single-pulse, and 1H-15N CP-based heteronuclear single quantum correlation filter experiment with very fast magic angle spinning (MAS) at 70 kHz identified molecular interactions in CBZ/polymer SPDs. Although the HPMC backbone and substituents did not interact notably with CBZ and disrupt CBZ-CBZ intermolecular interactions (formed in the amorphous CBZ), acetate and succinate substituents on HPMC-A and HPMC-S disrupted CBZ-CBZ intermolecular interactions through formation of CBZ/polymer interactions. The acetate substituent formed a hydrogen bond with the NH2 group of CBZ, whereas the succinate substituent formed molecular interactions with both the C═O and NH2 groups of CBZ. Formation of relatively strong molecular interactions between CBZ and the succinate substituent followed by disruption of CBZ-CBZ intermolecular interactions effectively stabilized the amorphous state of CBZ in CBZ/HPMC-S SPD. The correlation between CBZ-polymer interactions and ability of polymers to effectively inhibit CBZ recrystallization is reflected in various commercial HPMC-AS. For example, HPMC-AS LF grade, containing higher amounts of the succinate group, was found to effectively inhibit the recrystallization of CBZ through strong molecular interactions as compared with the HPMC-AS HF grade. The present study demonstrated that a detailed investigation of molecular interactions between the drug and the polymer using FTIR and solid-state NMR spectroscopy could contribute to a suitable selection of the SD carrier.

Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacologica...

TAK-441 was cocrystallized to enhance its aqueous solubility and suppress its high solvatomorphism. A TAK-441/l-malic acid (2:1) cocrystal and a TAK-441/l-tartaric acid (2:1) cocrystal were observed, and they exhibited isomorphism. These cocrystals were 2–3 times more soluble than its free form in aqueous solutions and directly crystallized without solvate formation in various organic solvents. The cocrystals were chemically and physically stable under stress conditions and are predicted to have sufficient stability to ensure an adequate shelf life. The results demonstrated that the cocrystals had a more preferable pharmaceutical profile and that cocrystallization can both improve oral bioavailability and simplify crystal form control simultaneously.

Lipophilicity and solubility are important physicochemical properties of pharmaceutical compounds, especially orally administration drugs. In this study, we developed a chromatographic distribution coefficient (LogD) determination method as lipophilicity evaluation and a kinetic solubility procedure with rapid quantitation by HPLC-UV. Both methods are simple and applicable for use of conventional equipment in early stage of drug discovery and development. Actually both data of model drugs were collected and discussed to improve the physicochemical properties using formulation technologies such as solubilization and enteric coating. The parallel measurement and consideration of both sets of data enables not only detail evaluation of the physicochemical properties but also the perspective of the relevant formulation strategies of drugs. Such rational evaluation will facilitate the development of high quality and effective drugs.

Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

The objective of this study was to improve the solubility of poorly water-soluble drugs by pharmaceutical cocrystal engineering techniques and select the best pharmaceutical forms with high solubility and solubilized formulations for progress from the early discovery stage toward the clinical stage. Several pharmaceutical cocrystals of TAK-020, a Bruton tyrosine kinase inhibitor, were newly discovered in the screening based on the solid grinding method and the slurry method, considering thermodynamic factors that dominate cocrystal formation. TAK-020/gentisic acid cocrystal (TAK-020/GA CC) was selected based on a physicochemical property of enhanced dissolution rate. TAK-020/GA CC was proven to be a reliable cocrystal formation with a definitive stoichiometric ratio by a variety of analytical techniques&mdash, pKa calculation, solid-state nuclear magnetic resonance, and single X-ray structure analysis from the view of regulation. Furthermore, its absorption was remarkable and beyond those achieved in currently existing solubilized formulation techniques, such as nanocrystal, amorphous solid dispersion, and lipid-based formulation, in dog pharmacokinetic studies. TAK-020/GA CC was the best drug form, which might lead to good pharmacological effects with regard to enhanced absorption and development by physicochemical characterization. Through the trials of solid-state optimization from early drug discovery to pharmaceutical drug development, the cocrystals can be an effective option for achieving solubilization applicable in the pharmaceutical industry.

Different crystal packing of hydrates from anhydrate crystals leads to different physical properties, such as solubility and stability. Investigation of the potential of varied hydrate formation, and understanding the stability in an anhydrous/hydrate system, are crucial to prevent an undesired transition during the manufacturing process and storage. Only one anhydrous form of T-3256336, a novel inhibitor of apoptosis (IAP) protein antagonist, was discovered during synthesis, and no hydrate form has been identified. In this study, we conducted hydrate screening such as dynamic water vapor sorption/desorption (DVS), and the slurry experiment, and characterized the solid-state properties of anhydrous/hydrate forms to determine the most desirable crystalline form for development. New hydrate forms, both mono-hydrate and hemi-hydrate forms, were discovered as a result of this hydrate screening. The characterization of two new hydrate forms was conducted, and the anhydrous form was determined to be the most desirable development form of T-3256336 in terms of solid-state stability. In addition, the stability of the anhydrous form was investigated using the water content and temperature controlled slurry experiment to obtain the desirable crystal form in the crystallization process. The water content regions of the stable phase of the desired form, the anhydrous form, were identified for the cooling crystallization process.

In recent years, to guarantee a quality-by-design approach to the development of pharmaceutical products, it is important to identify properties of raw materials and excipients in order to determine critical process parameters and critical quality attributes. Feedback obtained from real-time analyses using various process analytical technology (PAT) tools has been actively investigated. In this study, in situ monitoring using low-frequency (LF) Raman spectroscopy (10–200 cm−1), which may have higher discriminative ability among polymorphs than near-infrared spectroscopy and conventional Raman spectroscopy (200–1800 cm−1), was investigated as a possible application to PAT. This is because LF-Raman spectroscopy obtains information about intermolecular and/or lattice vibrations in the solid state. The monitoring results obtained from Furosemide/Nicotinamide cocrystal indicate that LF-Raman spectroscopy is applicable to in situ monitoring of suspension and fluidized bed granulation processes, and is an effective technique as a PAT tool to detect the conversion risk of cocrystals. LF-Raman spectroscopy is also used as a PAT tool to monitor reactions, crystallizations, and manufacturing processes of drug substances and products. In addition, a sequence of conversion behaviors of Furosemide/Nicotinamide cocrystals was determined by performing in situ monitoring for the first time.

The chapter explores the intellectual background of the shift toward neoliberal policymaking in Japan. There existed a variety of New Liberal and neoliberal traditions in the Japanese economic thought, which meant the transition from one welfare regime to the next did not necessarily rest on imported ideas. The chapter describes New Liberalism and social liberalism between the wars and the intellectual basis of the postwar welfare regime (focusing on Fukuda, Ishibashi, and Ueda). It then describes the New Liberalism and neoliberalism in the postwar business world (focusing on Keizai-doyukai, the Japan Economic Research Institute, and the Institute of World Economy). The chapter describes the rise of neoliberalism, first under the radar, then explicitly after the mid-1970s (when Hayek won the Nobel Prize), focusing on Nishiyama.

Isotope-edited infrared spectroscopy using carboxylic acids selectively labeled with 13C is proposed herein for the efficient discrimination of pharmaceutical salts and cocrystals, whereby proton-transfer probe vibrations are highlighted by isotope shifts. This new technique can accurately discriminate even a confusing salt from a cocrystal for the traditional method, highlighting the diagnostic peaks. In addition, the established technique also provided the OH in-plane bending vibrations corresponding to intermolecular hydrogen bonding at the carbonyl oxygens of the cocrystals. The technique will accelerate the discrimination, which is a critical process in cocrystal development.

The recent development trend of smaller flip chip packages requires narrower gaps and smaller pitches. The capillary type underfill is still mainly used for the flip chip mass-production process. The Non-Conductive Paste (NCP), which is applied before chip attachment, has been introduced for fine pitch applications. These pre-applied type underfills have some advantages, such as no need for dispensing area and no flux cleaning process. However, the NCP has issues for connectivity, void control and low productivity. In this study, Thermal Compression Bonding (TCB) process which ensures high-throughput is presented. The use of constant heating during the TCB process results in shorter die mounting time, achieving high-throughput via the use of mass reflow (MR), which implies a possible high UPH. Optimization of the mounting process eliminated die-shift. We have successfully developed a new Slow Cure Non Conductive Paste (Slow Cure NCP) suitable for the high-throughput process.

Solid form selection of active pharmaceutical ingredients is essential for pharmaceutical development. Solvates, except for hydrates, are rarely selected because of their physical instability and the potential toxicity of solvent. Here, the solid form selection of TAK-441, a highly solvating compound, was conducted. Anhydrate form I and 12 solvates were obtained from solution. The solvates showed isomorphism and could be placed into three categories. Anhydrate forms II, III, and IV were obtained via the desolvation of different type solvates, and anhydrate form V crystallized following thermal conversion of solvates. Equilibrium solubility analysis suggested that certain thermodynamic relationships between anhydrates were enantiotropic in nature. Moreover, form I was more stable than other polymorphs at ambient temperature, and was thus selected for further development. Finally, crystal structure analyses revealed that form I was an isomorphic desolvate of another solvate type (type 4), which immediately ...

The Japanese Population-based Osteoporosis (JPOS) Cohort Study was launched in 1996 to produce a reference database of areal bone mineral density (aBMD) by dual energy X-ray absorptiometry (DXA) and bone turnover markers in the Japanese female population and to determine risk factors for osteoporotic fractures. At baseline, 3984 women aged 15 to 79 years were randomly selected to provide representative bone status data and aBMD values for the diagnosis of osteoporosis. Follow-up surveys were conducted in 1999, 2002, 2006 and 2011/12 to determine changes in aBMD and identify incident morphometry-confirmed vertebral fractures and clinical fractures. These outcomes were obtained from 2174 women who participated in at least one follow-up survey. JPOS is a unique resource of individual-level bone health information with radiological and biological archives that include DXA images, and serum, plasma and DNA for future analyses with emerging radiological and biological techniques. The JPOS dataset is not freely available, but new collaborations are encouraged. Potential collaborators are invited to contact the Secretary General (M.I.) at the administrative office of the JPOS Study Group.

During polymorph screening, the possibility of overlooking the most stable form of a poorly soluble drug is relatively high due to its slow nucleation rate. To develop a rational polymorph screening system applicable to poorly soluble drugs, the slow cooling crystallization of one such compound, mebendazole (MBZ), from diverse organic solvents and solvent mixtures was demonstrated. The most stable form of MBZ was selectively crystallized from toluene and alcohol/antisolvent mixtures, which generated a higher crystallization temperature. In contrast, metastable forms and solvates were crystallized from specific solvents at higher degrees of supersaturation. Several crystallization factors, such as solvent, drug concentration, temperature, and cooling rate, were found to affect the resultant MBZ crystal forms. Solvents that generated weak solute–solvent interactions and high crystallization temperatures were required to predominantly crystallize the most stable form. In particular, it was clarified that solvents having weak hydrogen bonding propensity such as toluene and heptane were effective for shortening the induction time for crystallization, thereby rising the crystallization temperature during slow cooling that ensured the crystallization of the stable form. Furthermore, we demonstrated that the cooling rate slower than 3 °C/h was rational to be predominantly crystallized the stable form of poorly soluble mebendazole.

Measuring the levels of the plasma free metanephrines (PFMs) represents a recently developed and promising test for the diagnosis of pheochromocytoma in the United States and Europe. As this test has not yet been evaluated in Japan, it is necessary to evaluate the diagnostic efficacy of measuring the levels of PFMs compared with the standard measurement of the urinary excretion of metanephrines (uMNs) whose reliability is well established to detect of pheochromocytoma. A total of 101 Japanese subjects clinically suspected of having pheochromocytoma in were included in this study. Subsequently, we prospectively measured the PFMs levels in all patients, compared with those of biochemical markers of the catecholamine secretion and metabolisms in the plasma and urine. All subjects with adrenal tumors underwent tumor excision. Data were available for 84 of the 101 patients, 47 of whom had histopathologically proven pheochromocytoma and 37 were finally diagnosed with non-pheochromocytoma. The results of comparisons in the accuracy of measurement for diagnosis of pheochromocytoma between PFMs and the urinary excretion of metanephrines (uMNs) were 0.980 VS 0.951 for AUC of receiver operatorating characteristic (ROC) curve, 0.957 VS 0.894 for sensitivity, and 0.973 VS 0.946 for specificity, respectively. Although the differences were small, the results of our study definitely demonstrated that measurement of PFMs was not inferior to standard urinary metanephrines (uMNs) measurement, which is established to be the most reliable biochemical method to detect pheochromocytoma. This study clearly shows measuring the PFMs levels to be a reliable and efficient method for diagnosing pheochromocytoma in Japanese patients, as demonstrated in previous reports.

This article was migrated. The article was marked as recommended. The results from a comprehensive survey of students' perceptions of their educational environment using the Dundee Ready Educational Environment Measure (DREEM) in our Medical School were compared with students' school learning scores. The subjects (n=495) were medical students beyond their first year of medical school. The students were asked to read each DREEM statement carefully and respond using a 5-point Likert-type scale, with responses ranging from strongly agree to strongly disagree. The mean total DREEM score was 113.4, and there was no significant difference among total DREEM scores for students in different school years. Sixth-year students scored significantly higher than those in the second year for the Academic Self-Perception and Social Self-Perception domains. Females had higher school learning scores and also had better total and Perception of Course Organizers DREEM scores. The DREEM score tended to be lower for those with lower school learning scores, with significant differences found for total, Academic Self-Perception and Social Self-Perception scores. This is the first study to use the DREEM score for Japanese medical students, and further prospective research is required to obtain a complete understanding of the results.

Friedrich Hayek denied that the concept of social justice had any practical meaning in a modern society. He claimed that it can be justified only in those societies in which there is a strict order of preference. This was not the case in a capitalist society. Thus, the concept itself is a typical example of what Hayek called the animistic way of thinking. Using Hayek’s The Road to Serfdom (1944), Law, Legislation and Liberty (1973-79) and The Fatal Conceit (1988), I critically investigate his social and political theories with special attention to this concept.

Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

To judge the developability and analyze functional mechanism of co-amorphouses, we investigated the physicochemical properties of co-amorphouses and compare the properties with the co-crystals having the same drug and counters. Co-amorphous compounds are a novel approach to improve the physicochemical properties of drugs. A co-amorphous is in an amorphous solid state allowing non-ionic interactions between drug molecules and counter molecules. The co-amorphous compounds composed of itraconazole (ITZ) with the organic carboxyl acid, fumaric acid (FA) or L-tartaric acid (TA), were prepared by mechanical grinding. Potential interactions within ITZ-FA co-amorphous were assessed by Raman spectroscopy. ITZ-FA co-amorphous was not crystallized as the co-crystal or as a single ITZ crystal, suggesting that the amorphous state, like the amorphous solid dispersion, was physically stable and that ITZ-FA co-amorphous was also chemically stable. In contrast, no clear interactions were observed within ITZ-TA co-amorphous, and the co-amorphous was physically stable but chemically unstable. The solubility of the co-amorphous state was much higher than those of ITZ crystal and the co-crystals and was almost identical to that of amorphous ITZ. A co-amorphous compound like ITZ-FA co-amorphous might be feasible to implement in the development of solid drug products and bring some merits compared to the co-crystals, and the function is governed by the interaction between a drug and a counter. The co-amorphous approach may be an effective strategy for drug development and can contribute to the production of novel drugs with improved functions.

A questionnaire survey was conducted to determine the current status of home medical care (HMC) waste collection by nurses for individual items and whether the collection rate differs with city size. The questionnaire was mailed to 1,022 nursing offices, of which 645 offices provided valid responses. Offices were classified into three groups according to the local population size. Responses indicated that used syringes and needles, except for pen-type self-injection needles, were collected by50% of HMC nurses. On the other hand, enteral nutrients, nutritional adjustment diet vessels, feeding tubes, portable injectors, ventilator masks, endotracheal suction catheters, tracheal cannulas, continuous ambulatory peritoneal dialysis (CAPD) bags, and urinary catheters and bags had a low collection rate in comparison with syringes or needles. The collection percentage of used syringes, needles, and infusion needles (p0.05) and that for infusion bags, tubes, and catheters (p0.001) differed among the three population groups. Although municipalities are responsible for collect all HMC waste, sharp or infectious items should be collected by HMC doctors or nurses. On the contrary, nonhazardous HMC waste should be collected by municipalities.This paper illustrates the status of waste collection of individual home medical care (HMC) items by HMC nurses. Infectious waste, such as needles and syringes, is collected by nurses. The collection rate of infectious waste by nurses in large cities was low compared with that in small cities. Although municipalities are responsible for collecting all HMC waste, sharp or infectious items should be collected by HMC doctors or nurses, whereas nonhazardous HMC waste should be collected by the municipalities.

Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH

SummaryObjective The only reliable method for subtyping primary aldosteronism (PA) is adrenal venous sampling (AVS), which is costly and time-consuming. Considering the limited availability of AVS, it would be helpful to obtain information on the diagnosis of bilateral hyperaldosteronism (BHA) from routine tests. We aimed to establish new, simple criteria for outpatients to diagnose BHA from PA before AVS. Design We retrospectively analysed 82 patients who were diagnosed with PA and underwent AVS. Thirty-seven patients were diagnosed with unilateral hyperaldosteronism (UHA), and 36 with BHA and nine were undetermined. Among the variables that were significantly different between UHA and BHA in the univariate analysis, we chose three variables to be included in multivariate logistic regression models and constructed a subtype prediction score. Results The subtype prediction score was calculated as follows: 3 points for no adrenal nodules on computed tomography imaging, 2 for serum potassium of ≥3·5 mmol/l and 2 for aldosterone-to-renin ratio of

Although plasma aldosterone concentration (PAC) varies depending on primary aldosteronism (PA) subtypes, patients with different subtypes may have similar blood pressure (BP). The authors hypothesized that hormones other than aldosterone might influence BP in PA patients. A total of 73 PA cases, including 30 cases of aldosterone-producing adenomas (APAs), 29 cases of bilateral hyperaldosteronism, and 24 control cases of essential hypertension were enrolled retrospectively. The authors examined the levels of aldosterone, cortisol, renin, and adrenocorticotropic hormone (ACTH) measured at 12 am, 6 am, 12 pm, and 6 pm and BP in the early morning (6 am to 7 am), late morning (9 am to 11 am), and early evening (5 pm to 7 pm). Results showed no statistically significant correlation between PAC and BP in the patients with PA; however, early and late morning systolic BP strongly correlated with ACTH at 6 am in patients with APA. These results suggest that hormones other than aldosterone, such as ACTH, may affect BP in patients with APA.

Cocrystals (CCs) used in the pharmaceutical industry are defined as complex crystals formed by reaction between an API and a cocrystal former (CCF); unlike salts, CCs do not show proton transfer. Recently, pharmaceutical CCs have been used to improve the drug-likeness of APIs, such as solubility and stability. Grinding is more effective for CC synthesis than crystallization from solution because in the former case, the API can predominantly interact with the CCF without being affected by solvents. However, this method is tedious because the API is ground with only one CCF at a time. We developed a cocktail cocrystal grinding (CCG) method, in which a mixture of CCFs having the same functional group was used. No false negatives/positives were observed in CCG when carbamazepine was used as the model compound. This method could be used to obtain CCs of piroxicam and spironolactone. False negatives were observed for only one compound from among three model compounds, indicating that CCG facilitates efficient CC detection and that it has higher throughput than does the conventional method. Further, CCG is fast and suitable for rational CC screening, and it helps identify the partial structure of CCFs that forms synthons with an API.

A questionnaire survey was conducted with the aim of examining the problems involved in the disposal of infectious waste at home-visit nursing stations and in its handling during home visits by nurses. From among the home-visit nursing stations registered with the National Association for Home-Visit Nursing Care, 1,965 offices were selected at random and questionnaires were sent to the selected offices. Nurses at 1,314 offices (66.9 %) responded to the survey and responses from 1,283 offices were identified as suitable for analysis after excluding 26 offices that closed and five offices whose main field of care was psychiatry. Offices were classified by management configuration. Offices attached to hospitals were classified as “attached office” and all others were classified as “independent office”. More attached office nurses recovered medical waste from patients’ homes than did independent office nurses. They were also more likely to transport waste with them during the course of a day’s visits. There was a significant difference between attached and independent offices in the burden of expense for waste disposal. Both offices have strong concern about waste treatment containers and handling in improvement in home medical care (HMC) waste disposal. Thus, in order to alleviate these concerns, it is necessary to provide nurses with containers for medical waste suited to home-visit nursing care and tools for preventing injuries. Japanese government should address HMC waste disposal more comprehensively through necessary legislation, subsidization and standardization.