X‑ray Absorption Near-Edge Spectroscopy Analysis of Indomethacin in Crystalline Forms and in Amorphous Solid Dispersions

Chlorine K-edge X-ray absorption near-edge spectroscopy (XANES) measurements were performed to characterize the crystal polymorphs of identical active pharmaceutical ingredients (APIs) containing chloride atoms and their amorphous solid dispersions (ASDs). Indomethacin (IMC), of which three crystal forms (α, β, and γ) have been reported, was used as a model API. The shape of XANES spectra was unique to each IMC crystal. The analysis of the crystal structures of IMC revealed that chlorine atoms of the IMCα form had unique intermolecular interactions and halogen bonds with oxygen atoms, while those of the IMCγ form do not have any notable interactions. This result showed that XANES measurements can detect weak interatomic interactions. The shapes of the ASD spectra were clearly different from those of the crystals, suggesting that the environment around the Cl atom of IMC was different from that of the crystals. A thermal stress test was then performed to study the transformation from the amorphous form to the crystalline form of IMC in the ASD. The powder X-ray diffraction (PXRD) patterns indicated that amorphous IMC transformed into crystals during the thermal stress test. In accordance with the PXRD results, the XANES spectra also transformed from ASD to crystalline form. These results indicate that the IMC transformation could be monitored by XANES measurement. Our findings led us to conclude that XANES measurement is a novel approach for the evaluation of crystal polymorphs of APIs and the crystalline state of APIs in ASDs

Analysis of Cimetidine Crystal Polymorphs by X‑ray Absorption Near-Edge Spectroscopy

Sulfur K-edge X-ray absorption near-edge spectroscopy (XANES) measurements were performed to characterize the crystal polymorphs of the active pharmaceutical ingredients (APIs) containing sulfur atoms. Cimetidine (CIM) was used as a model API. Each crystal form of CIM has its own XANES spectrum, so we can discriminate the crystal form by its spectrum. The analysis of the crystal structure of CIM revealed that the difference in the shape of XANES spectra was ascribable to the difference in the C–S–C bond angle of CIM molecules and the intermolecular hydrogen bonds, such as C–H···S and N–H···S, and S–S interaction. It was found that the peak shape of the XANES spectrum is gentle when the C–S–C bond angle is large, while the peak shape can be steep when the C–S–C bond angle is small. Furthermore, it was found that the peak energy values varied depending on the hydrogen bonds and S–S interaction. By linear combination fitting using XANES spectra, it was possible to quantify the ratio of CIM form A crystal in mixed powders of form A and monohydrate crystals. These results indicate that XANES measurements can be a useful technique to evaluate the crystal polymorphism of APIs containing S atom in pharmaceutical formulation

Effect of Seed Particles on Precipitation of Weak Base Drugs in Physiological Intestinal Conditions

The purpose of the present study was to investigate the effect of seed particles on the precipitation behavior of weak base drugs in the small intestine. A simple in vitro infusion method was used to mimic in vivo processes. Dipyridamole, pioglitazone, topiroxostat, chlorpromazine, cinnarizine, and ketoconazole were used as model drugs. A drug was dissolved in 0.01 N HCl and infused into a pH 6.5 buffer. The existence of seed particles significantly affected the concentration–time profiles of the model drugs in the buffer. The maximum concentration was significantly reduced in the presence of seed particles (except for cinnarizine). In the case of dipyridamole, pioglitazone, and topiroxostat, the precipitants were crystalline from the beginning of precipitation. In contrast, the precipitants of ketoconazole, cinnarizine, and chlorpromazine were a mixture of amorphous and crystals. In conclusion, the presence of seed particles significantly affected the precipitation behavior of weak base drugs

Characteristics of proliferative diabetic retinopathy (PDR) and control [idiopathic epiretinal membrane (ERM), idiopathic macular hole (MH), and uveitis associated with sarcoidosis] patients.

<p>^* Mean ± standard deviation.</p><p>^† Range.</p><p>^<b>‡</b> Numbers (%).</p><p>^§ IVB = intravitreal injection of bevacizumab.</p><p>Characteristics of proliferative diabetic retinopathy (PDR) and control [idiopathic epiretinal membrane (ERM), idiopathic macular hole (MH), and uveitis associated with sarcoidosis] patients.</p

Comparison of vitreous cytokine levels between proliferative diabetic retinopathy (PDR), idiopathic epiretinal membrane (ERM), idiopathic macular hole (MH), and uveitis associated with sarcoidosis.

<p><b>Detectable samples (%)</b>: Number (%) of samples with detectable cytokine.e</p><p>^*<i>P</i> < 0.05 between PDR, MH, and ERM, by Pearson's chi-squared test.</p><p>^†<i>P</i> < 0.05 between PDR and uveitis, by Pearson's chi-squared test.</p><p>^‡<i>P</i> < 0.05 between PDR, MH, and ERM, by Steel-Dwass multiple comparison test.</p><p>^§<i>P</i> < 0.05 between PDR and uveitis, by Wilcoxon signed-rank test.</p><p>Comparison of vitreous cytokine levels between proliferative diabetic retinopathy (PDR), idiopathic epiretinal membrane (ERM), idiopathic macular hole (MH), and uveitis associated with sarcoidosis.</p

Comparison of vitreous cytokine levels between proliferative diabetic retinopathy (PDR) with and without vitreous hemorrhages (VH).

<p><b>Detectable samples (%)</b>: Number (%) of samples with detectable cytokine.</p><p>Comparison of vitreous cytokine levels between proliferative diabetic retinopathy (PDR) with and without vitreous hemorrhages (VH).</p

CONSORT flowchart.

<p>CONSORT flowchart.</p

Comparison of vitreous cytokine levels between proliferative diabetic retinopathy (PDR), idiopathic epiretinal membrane (ERM), idiopathic macular hole (MH), and uveitis associated with sarcoidosis.

<p><b>Detectable samples (%)</b>: Number (%) of samples with detectable cytokine.e</p><p>^*<i>P</i> < 0.05 between PDR, MH, and ERM, by Pearson's chi-squared test.</p><p>^†<i>P</i> < 0.05 between PDR and uveitis, by Pearson's chi-squared test.</p><p>^‡<i>P</i> < 0.05 between PDR, MH, and ERM, by Steel-Dwass multiple comparison test.</p><p>^§<i>P</i> < 0.05 between PDR and uveitis, by Wilcoxon signed-rank test.</p><p>Comparison of vitreous cytokine levels between proliferative diabetic retinopathy (PDR), idiopathic epiretinal membrane (ERM), idiopathic macular hole (MH), and uveitis associated with sarcoidosis.</p

Direct maintenance of acinar cell activity in lacrimal glands (LGs) by orally administrated royal jelly.

A: Effects of RJ on decreased tear secretion after postganglionic denervation (PGD; six mice). B: LG weight (n = 4–5 lacrimal glands). C: Histopathological changes in LGs Gross appearance of LG (upper) and hematoxylin and eosin staining of LGs (lower). The scale bar is 3 mm (upper) and 50 μm (lower). E: Typical transmission electron microscopy images of an acinar cell after vehicle (left) and RJ (right) treatment. The arrow indicates vesicle-rich acinar cells. The scale bar is 5 µm. All data represent mean ± standard deviation. *pppp<0.01 versus denervation with vehicle</p

Clinical Evaluation of a Royal Jelly Supplementation for the Restoration of Dry Eye: A Prospective Randomized Double Blind Placebo Controlled Study and an Experimental Mouse Model

<div><p>Background</p><p>Dry eye is a multifactorial disease characterized by ocular discomfort and visual impairment. Lacrimal gland function has been shown to decrease with aging, a known potent risk factor for dry eye. We have previously found that orally administrated royal jelly (RJ) restored tear secretion in a rat model of dry eye.</p><p>Methods and Findings</p><p>We examined the effects of RJ oral administration on dry eye in this prospective, randomized, double-blind, placebo-controlled study. Forty-three Japanese patients aged 20–60 years with subjective dry eye symptoms were randomized to an RJ group (1200 mg/tablet, six tablets daily) or a placebo group for 8 weeks. Keratoconjunctival epithelial damage, tear film break-up time, tear secretion volume, meibum grade, biochemical data, and subjective dry eye symptoms based on a questionnaire were investigated at baseline, and at 4 and 8 weeks after intervention. Adverse events were reported via medical interviews. In the RJ group, tear volume significantly increased after intervention (<i>p</i> = 0.0009). In particular, patients with a baseline Schirmer value of ≤10 mm showed a significant increase compared with baseline volume (<i>p</i> = 0.0005) and volume in the placebo group (<i>p</i> = 0.0051). No adverse events were reported. We also investigated the effect of RJ (300 mg/kg per day) administration using a mouse model of dry eye. Orally repeated administration of RJ preserved tear secretion, potentially through direct activation of the secretory function of the lacrimal glands.</p><p>Conclusion</p><p>Our results suggest that RJ improves tear volume in patients with dry eye.</p><p>Trial Registration</p><p>Registered NO. the University Hospital Medical Information Network in Japan (UMIN000014446)</p></div