Polymer-inducing chemical degradation of amorphous solid dispersions driven by drug-polymer interactions for physical stabilization.

Intermolecular interactions between active pharmaceutical ingredients (APIs) and carrier polymers are important for the long-term physical stability of amorphous solid dispersions (ASDs). However, the negative impact of intermolecular interactions on chemical stability has rarely been reported. In this study, the relationship between intermolecular interactions and physical and chemical stability was investigated using two ASDs composed of API and hydroxypropyl methylcellulose acetate succinate (HPMCAS) with different stabilities: ASD1 was physically stable but chemically unstable, whereas ASD2 was physically unstable but chemically stable. Ionic-bonding between the pyridine nitrogen in the API and succinyl group in HPMCAS was found in both ASDs. The additional interaction between the succinyl group in HPMCAS and the hydroxyl group in the API was suggested only in ASD1. It was concluded that the additional interaction contributed to the physical stability of ASD1; however, it accelerated the chemical reaction between the succinyl and hydroxyl groups to generate succinyl ester owing to its close proximity. This study shows that the intermolecular interaction between the API and carrier polymer is not always beneficial for chemical stability. Understanding the molecular states of APIs and polymers in ASDs is important for their successful development.

Efficient Drug Loading Method for Poorly Water-Soluble Drug into Bicelles through Passive Diffusion.

The bicelle, a type of solid lipid nanoparticle, comprises phospholipids with varying alkyl chain lengths and possesses the ability to solubilize poorly water-soluble drugs. Bicelle preparation is complicated and time-consuming because conventional drug-loading methods in bicelles require multiple rounds of thermal cycling or co-grinding with drugs and lipids. In this study, we proposed a simple drug-loading method for bicelles that utilizes passive diffusion. Drug-unloaded bicelles were placed inside a dialysis device and incubated in a saturated solution of ketoconazole (KTZ), which is a model drug. KTZ was successfully loaded into bare bicelles over time with morphological changes, and the final encapsulated concentration was dependent on the lipid concentration of the bicelles. When polyethylene glycol (PEG) chains of two different lengths (PEG2K and 5K) were incorporated into bicelles, PEG2k and PEG5k bicelles mitigated the morphological changes and improved the encapsulation rate. This mitigation of morphological changes enhanced the encapsulated drug concentration. Specifically, PEG5k bicelles, which exhibited the greatest prevention of morphological changes, had a lower encapsulated concentration after 24 h than that of PEG2k bicelles, indicating that PEGylation with a longer PEG chain length improved the loading capacity but decreased the encapsulation rate owing to the presence of a hydration layer of PEG. Thus, PEG with a certain length is more suitable for passive loading. Moreover, loading factors, such as temperature and vehicles used in the encapsulation process, affected the encapsulation rate of the drug. Taken together, the passive loading method offers high throughput with minimal resources, making it a potentially valuable approach during early drug development phases.

Preparation of Cubosomes with Improved Colloidal and Structural Stability Using a Gemini Surfactant.

Cubosomes are nanoparticles with bicontinuous cubic internal nanostructures that have been considered for use in drug delivery systems (DDS). However, their low structural stability is a crucial concern for medical applications. Herein, we investigated the use of a gemini surfactant, sodium dilauramidoglutamide lysine (DLGL), which is composed of two monomeric surfactants linked with a spacer to improve the structural stability of cubosomes prepared with phytantriol (PHY). Uniform nanosuspensions comprising a specific mixing ratio of DLGL and PHY in water prepared via ultrasonication were confirmed by using dynamic light scattering. Small-angle X-ray scattering and cryo-transmission electron microscopy revealed the formation of Pn3̅m cubosomes in a range of DLGL/PHY solid ratios between 1 and 3% w/w. By contrast, cubosome formation was not observed at DLGL/PHY solid ratios of 5% w/w or higher, suggesting that excess DLGL interfered with cubosome formation and caused them to transform into small unilamellar vesicles. The addition of phosphate-buffered saline to the nanosuspension caused aggregation when the solid ratio of DLGL/PHY was less than 5% w/w. However, Im3̅m cubosomes were obtained at solid ratios of DLGL/PHY of 6, 7.5, and 10% w/w. The lattice parameters of the Pn3̅m and Im3̅m cubosomes were approximately 7 and 11-13 nm, respectively. The lattice parameters of Im3̅m cubosomes were affected by the concentration of DLGL. Pn3̅m cubosomes were surprisingly stable for 4 weeks at both 25 and 5 °C. In conclusion, DLGL, a gemini surfactant, was found to act as a new stabilizer for PHY cubosomes at specific concentrations. Cubosomes composed of DLGL are stable under low-temperature storage conditions, such as in refrigerators, making them a viable option for heat-sensitive DDS.

Molecular-Level Structural Analysis of siRNA-Loaded Lipid Nanoparticles by 1H NMR Relaxometry: Impact of Lipid Composition on Their Structural Properties.

1H NMR relaxometry was applied for molecular-level structural analysis of siRNA-loaded lipid nanoparticles (LNPs) to clarify the impact of the neutral lipids, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol, on the physicochemical properties of LNP. Incorporating DSPC and cholesterol in ionizable lipid-based LNP decreased the molecular mobility of ionizable lipids. DSPC reduced the overall molecular mobility of ionizable lipids, while cholesterol specifically decreased the mobility of the hydrophobic tails of ionizable lipids, suggesting that cholesterol filled the gap between the hydrophobic tails of ionizable lipids. The decrease in molecular mobility and change in orientation of lipid mixtures contributed to the maintenance of the stacked bilayer structure of siRNA and ionizable lipids, thereby increasing the siRNA encapsulation efficiency. Furthermore, NMR relaxometry revealed that incorporating those neutral lipids enhanced PEG chain flexibility at the LNP interface. Notably, a small amount of DSPC effectively increased PEG chain flexibility, possibly contributing to the improved dispersion stability and narrower size distribution of LNPs. However, cryogenic transmission electron microscopy represented that adding excess amounts of DSPC and cholesterol into LNP resulted in the formation of deformed particles and demixing cholesterol within the LNP, respectively. The optimal lipid composition of ionizable lipid-based LNPs in terms of siRNA encapsulation efficiency and PEG chain flexibility was rationalized based on the molecular-level characterization of LNPs. Moreover, the NMR relaxation rate of tertiary amine protons of ionizable lipids, which are the interaction site with siRNA, can be a valuable indicator of the encapsulated amount of siRNA within LNPs. Thus, NMR-based analysis can be a powerful tool for efficiently designing LNP formulations and their quality control based on the molecular-level elucidation of the physicochemical properties of LNPs.

Amorphous characterization of pharmaceutical drug substances enabled by the elastic modulus mapping of atomic force microscope.

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 PeakForceTM quantitative nanomechanical mapping. The elastic modulus of the crystals exceeded 10 GPa-significantly higher than that of the amorphous, which was ≤5 GPa in all five model drugs; consequently, ≤200 nm scale crystals were detected on amorphous surfaces. Furthermore, the elastic modulus reflected the difference in the amorphous states between the molten and the solvent-evaporated preparations in the microscopic area, thereby demonstrating the ability of AFM to characterize amorphous states. Taken together, AFM measurements using elastic modulus can be an effective analytical tool to provide microscale mapping and characterization of amorphous surfaces, leading to enhanced amorphous drug development.

Pinpoint modification strategy for stabilization of single guide RNA.

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.

Nanostructure and Molecular-Level Characterization of Aminoalkyl Methacrylate Copolymer and the Impact on Drug Solubilization Ability.

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.

De novo ATP1A3 variants cause polymicrogyria.

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.

Structural Evaluation of the Choline and Geranic Acid/Water Complex by SAXS and NMR Analyses.

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.

Improvement plan for professionalism course guidance based on adult learning theory.

This article was migrated. The article was marked as recommended. Professionalism is widely known as extremely important to the practice of medicine. However, a methodology has not been established in Japan, such that teachers-in-charge at medical schools are using personal strategies in conducting classes. Evidently, research on professionalism education in Japan is lacking. Therefore, the study aims to report an improvement plan for professionalism education in a certain medical school in Japan with emphasis on practice. Specifically, the study focuses on problem extraction and targets medical students in the first year. The problems of the program were extracted for learner, grouping, facilitator, and presentation. Program improvements were implemented for each of these parts to overcome the problems. The result shows that students gained a better understanding of their roles until graduation. In addition, the number of students who answered that this program was the most memorable in 2019 has tripled compared with that in 2018. Regarding the program improvement, the effect of the program cannot be concluded based on this result alone. In the future, these students should be followed up to investigate any changes. In addition, feedback from each facilitator should be investigated as a future endeavor.

Effect of Drug-Polymer Interactions through Hypromellose Acetate Succinate Substituents on the Physical Stability on Solid Dispersions Studied by Fourier-Transform Infrared and Solid-State Nuclear Magnetic Resonance.

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.

Relationship between evaluation of the teaching environment using DREEM scores and students' school learning scores.

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.

Combination of NMR Methods To Reveal the Interfacial Structure of a Pharmaceutical Nanocrystal and Nanococrystal in the Suspended State.

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.

Survey to Identify Substandard and Falsified Tablets in Several Asian Countries with Pharmacopeial Quality Control Tests and Principal Component Analysis of Handheld Raman Spectroscopy.

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.

In situ monitoring of cocrystals in formulation development using low-frequency Raman spectroscopy.

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.

Classification and Visualization of Physical and Chemical Properties of Falsified Medicines with Handheld Raman Spectroscopy and X-Ray Computed Tomography.

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, such as from the presence of the heavy elements. Generic products that purported to contain equivalent amounts of API to the authentic products were discriminated from the authentic products by the handheld Raman and the different physical structure on X-ray CT. Approach to 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.

Isotope-Edited Infrared Spectroscopy for Efficient Discrimination between Pharmaceutical Salts and Cocrystals.

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.

Enhanced pulmonary absorption of poorly soluble itraconazole by micronized cocrystal dry powder formulations.

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 <2µm were successfully micronized using the jet-milling system. The cocrystal crystalline morphologies observed using scanning electron microscopy (SEM) suggested particle shapes that differed from those of the crystalline or spray-dried amorphous ITZ. The micronized ITZ cocrystal powders showed better intrinsic dissolution rate (IDR) and pulmonary absorption profile in rats than that of the amorphous spray-dried formulation and crystalline ITZ with comparable particle sizes. Specifically, in rat pharmacokinetic studies following pulmonary administration, micronized ITZ-SA and ITZ-TA cocrystals showed area under the curve from 0 to 8h (AUC0-8h) values approximately 24- and 19-fold higher than those of the crystalline ITZ and 2.0- and 1.6-fold higher than the spray-dried ITZ amorphous values, respectively. The amorphous formulation appeared physically instable during the studies due to rapid crystallization of ITZ, which was its disadvantage compared to the crystalline formulations. Therefore, this study demonstrated that micronized cocrystals are promising formulations for enhancing the pulmonary absorption of poorly soluble compounds.

Scoring system for the diagnosis of bilateral primary aldosteronism in the outpatient setting before adrenal venous sampling.

OBJECTIVE: 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 <490 after a captopril challenge test. Receiver operating characteristic curve analysis for the ability to discriminate BHA from UHA showed that a score of 7 points had 50% sensitivity and 100% specificity and a score of 5 points had 67% sensitivity and 94% specificity (area under the curve: 0·922; 95% CI: 0·863-0·980). CONCLUSIONS: Our new, simple criteria specifically distinguished BHA from UHA in the outpatient setting before AVS. Furthermore, not only endocrinologists but also general internists can use this convenient, safe scoring system.

Plasma adrenocorticotropic hormone but not aldosterone is correlated with blood pressure in patients with aldosterone-producing adenomas.

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.