Weakly acidic pH-responsive liposomal content release induced by histidine-modified agents.

Internal stimuli-responsive controlled release from liposomal vesicles is an innovative approach for site-specific delivery of therapeutic drugs. In this study, to enhance the endosomal pH control of drug release from liposomes, a series of histidine-modified pH-sensitive Cn-His (n = 8, 12, 18) agents were designed and utilized as triggers for liposomal content release. The pH-dependent properties of Cn-His-incorporated liposomes were characterized using dynamic light scattering, ζ-potential, and fluorescence spectroscopy. The liposomes maintained a relatively uniform size across all pH conditions. However, the ζ-potential exhibited positive values at endosomal acidic pH levels and neutral or negative values at physiological pH levels. Furthermore, acidic pH-dependent release of both polar content (carboxyfluorescein) and nonpolar content (Nile red) was observed from the Cn-His-incorporated liposomes. Notably, with C12-His as the pH sensitizer, the pH dependence of liposomal content release was significantly evident. This work establishes endosomal pH-controllable liposome platforms, laying the groundwork for developing clinically applicable triggered release formulations.

Utility of a Novel Micro-Spraying Device for Intranasal Administration of Drug Solutions to Mice.

Intranasal administration has attracted attention as a means of delivering drugs because it bypasses the blood-brain barrier. However, conventional intranasal administration of drug solutions to mice using the micropipette method (MP method) is complicated and time-consuming because it requires small doses to be administered under inhalation anesthesia. This study evaluated the effectiveness of a novel intranasal administration method using Micro FPS™, a novel micro-spraying device (the MSD method). The MSD method allowed more reliable administration of the solution to the nasal mucosa than the MP method did. The transfer of inulin, a model water-soluble macromolecule compound, to the olfactory bulb and brain (cerebrum, cerebellum, brainstem, and striatum) was similar with the two methods. It also allowed the drug to be administered in a shorter time. These results suggest that the MSD method is simpler and more rapid than the MP method for intranasal administration of drugs to mice and achieves comparable delivery of inulin to the olfactory bulb and brain. Therefore, the Micro FPS™ device is a potentially useful tool for intranasal drug administration to rodents and could facilitate the development of intranasal formulations, contributing to drug development for central nervous system diseases.

Anti-Inflammatory Effects of Miyako Bidens pilosa in a Mouse Model of Amyotrophic Lateral Sclerosis and Lipopolysaccharide-Stimulated BV-2 Microglia.

Neuroinflammation is a fundamental feature in the pathogenesis of amyotrophic lateral sclerosis (ALS) and arises from the activation of astrocytes and microglial cells. Previously, we reported that Miyako Bidens pilosa extract (MBP) inhibited microglial activation and prolonged the life span in a human ALS-linked mutant superoxide dismutase-1 (SOD1G93A) transgenic mouse model of ALS (G93A mice). Herein, we evaluated the effect of MBP on microglial activation in the spinal cord of G93A mice and lipopolysaccharide-stimulated BV-2 microglial cells. The administration of MBP inhibited the upregulation of the M1-microglia/macrophage marker (interferon-γ receptor (IFN-γR)) and pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6) in G93A mice. However, MBP did not affect the increase in the M2-microglia/macrophage marker (IL-13R) and anti-inflammatory cytokines (transforming growth factor (TGF)-ß and IL-10) in G93A mice. BV-2 cell exposure to MBP resulted in a decrease in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) reduction activity and bromodeoxyuridine incorporation, without an increase in the number of ethidium homodimer-1-stained dead cells. Moreover, MBP suppressed the production of lipopolysaccharide-induced pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in BV-2 cells. These results suggest that the selective suppression of M1-related pro-inflammatory cytokines is involved in the therapeutic potential of MBP in ALS model mice.

Intranasal Administration of N-acetyl-L-cysteine Combined with Cell-Penetrating Peptide-Modified Polymer Nanomicelles as a Potential Therapeutic Approach for Amyotrophic Lateral Sclerosis.

Intranasal administration is a promising route for direct drug delivery to the brain; its combination with nanocarriers enhances delivery. We have previously shown that intranasal administration combined with PEG-PCL-Tat (a nanocarrier) efficiently delivers drugs to the brain and exhibits excellent therapeutic efficacy against brain diseases. We aimed to clarify whether intranasal administration combined with PEG-PCL-Tat represents a useful drug delivery system (DDS) for amyotrophic lateral sclerosis (ALS) pharmacotherapy. We used N-acetyl-L-cysteine (NAC) as a model drug with low transferability to the spinal cord and determined the physicochemical properties of NAC/PEG-PCL-Tat. After intranasal administration of NAC/PEG-PCL-Tat, we measured the survival duration of superoxide dismutase-1 G93A mutant transgenic mice (G93A mice), widely used in ALS studies, and quantitatively analyzed the tissue distribution of NAC/PEG-PCL-Tat in ddY mice. The mean particle size and zeta potential of NAC/PEG-PCL-Tat were 294 nm and + 9.29 mV, respectively. Treatment with repeated intranasal administration of NAC/PEG-PCL-Tat considerably prolonged the median survival of G93A mice by 11.5 days compared with that of untreated G93A mice. Moreover, the highest distribution after a single administration of NAC/PEG-PCL-Tat was measured in the spinal cord. These results suggest that intranasal administration combined with PEG-PCL-Tat might represent a useful DDS for ALS therapeutics.

Application of ionic liquid to enhance the nose-to-brain delivery of etodolac.

The purpose of this study was to enhance the delivery of Etodolac (ETD) to the brain through intranasal administration using an ionic liquid (IL) consisting of ETD and proline ethyl ester. The IL of ETD was prepared by mixing ETD with proline ethyl ester as a counterion in a molar ratio of 1:2.The formation of the IL was confirmed by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and proton nuclear magnetic resonance (1H-NMR).The solubility of ETD in simulated nasal fluids was improved by approximately 200-fold due to the formation of IL. The intranasal administration of ETD-containing IL, which is viscous, increased the nose-to-brain delivery by approximately 7-fold 30 min after an administration of the ETD solution alone. The enhancement of ETD delivery to the brain from the nose was attributed to the enhanced retention of ETD in the nasal mucosal surface due to the viscosity of IL. The induction of prostaglandin E2 in the brain inflammation that was induced by lipopolysaccharides was significantly suppressed by up to 40% in the IL-treated group compared with the drug-untreated group. Therefore, ETD-containing IL were suggested to be useful in designing intranasal formulations for the nasal delivery of ETDs to the brain.

Efficacy of Zinc Acetate in the Treatment of Zinc Deficiency in Elderly Inpatients and Effect of Total Dose on Its Replacement Therapy.

We aimed to determine the efficacy of zinc acetate hydrate (ZAH) treatment for hypozincemia in elderly inpatients and to identify the factors affecting its therapeutic effect. We enrolled 79 patients with a mean age of 82 years. The mean serum zinc level before ZAH administration was 53.4 ± 11.5 µg/dL. More than half of the patients (67%) had zinc deficiency (<60 µg/dL), whereas 33% had subclinical zinc deficiency (60-80 µg/dL). The median increase in serum zinc level per ZAH tablet (25 mg) was 1.00 µg/dL. Based on the cutoff value, two groups were identified: slight increase (<1.00 µg/dL) and marked increase (≥1.00 µg/dL) groups; the difference between the two groups was significant (0.57 ± 0.22 µg/dL, n = 39 vs. 1.68 ± 0.70 µg /dL, n = 40; p < 0.0001, Wilcoxon rank sum test). Logistic regression analysis using total zinc dose, serum albumin level, impaired renal function, and diuretics as multivariate variables revealed a significant difference in total zinc dose (total number of tablets per 25 mg tablet: odds ratio 1.056, 95% confidence interval 1.019-1.095, p = 0.003). A significant increase in serum zinc levels was observed in the group with a total zinc dose of less than 1000 mg. The results suggest that an increasing trend in total zinc dose is associated with a low increase in serum zinc levels. Therefore, for the treatment of zinc deficiency in elderly inpatients, serum zinc levels need to be measured once, at a total dose of 1000 mg after initiation of ZAH.

Nose-to-brain/spinal cord delivery kinetics of liposomes with different surface properties.

The administration of liposomes via nose-to-brain delivery is expected to become a strategy for efficient drug delivery to the central nervous system. Efficient nose-to-brain delivery and the kinetics of drugs administered in this manner depend on the properties of liposomes. However, there is a lack of basic knowledge of which liposomes are suitable for this purpose. Here, a qualitative study of intranasally administered liposomes (positively charged, neutral, and negatively charged, with or without polyethylene glycol [PEG] modification; particle size <100 nm) was performed to elucidate their dynamics in the brain and spinal cord. Additionally, a quantitative investigation was performed to ascertain their distribution in each part of the brain and spinal cord. The effects of liposome surface charge and PEG modification on the kinetics and distribution post intranasal administration were investigated via two experiments. Qualitative evaluation was performed via ex vivo observation after intranasal administration of fluorescently labeled liposomes. Neutral PEG-modified liposomes were distributed throughout the brain and spinal cord 60 min after administration, and the fluorescence intensity increased with time. By contrast, non-PEG-modified neutral liposomes showed particularly strong fluorescence in the olfactory bulb, and the fluorescence was localized in the anterior part of the brain. Positively charged liposomes showed low fluorescence around the lateral part of the brain and lumbar spinal cord 60 min after administration. Low fluorescence was observed in the whole brain and spinal cord, with strong fluorescence being observed in the olfactory bulb after 120 min of administration. Negatively charged liposomes showed no fluorescence at 60 min after administration, but low fluorescence was observed throughout the brain and spinal cord 120 min after administration. We quantified the radioactivity in the brain and spinal cord after intranasal administration of radioisotope-labeled liposomes. Neutral liposomes showed the highest distribution by area under the drug concentration-time curve (AUC60-120) in the brain and spinal cord compared to other liposomes. Compared with negatively charged liposomes, positively charged liposomes had a higher distribution in the olfactory bulb and forebrain, while negatively charged liposomes had a higher distribution in the hindbrain and bulbospinal tract cord. In addition, the distribution of PEG-modified neutral liposomes in the brain and spinal cord was significantly enhanced compared to that of non-PEG-modified neutral liposomes after 90 min of intranasal administration. These results indicate that surface charge and PEG modification strongly affect the efficiency of nose-to-brain delivery kinetics, and that PEG-modified neutral liposomes are excellent carriers for drug delivery to a wide area of the brain and spinal cord.

Monitoring of Cocrystal Dissociation during the Wet Granulation Process in the Presence of Disintegrants by Using Low-Frequency Raman Spectroscopy.

The aim of this study was to evaluate the effect of three coformers and five disintegrants in the granulation formulation on the dissociation of cocrystal during the granulation process by monitoring wet granulation with probe-type low-frequency Raman (LF-Raman) spectroscopy. As model cocrystals, paracetamol (APAP)-oxalic acid (OXA), APAP-maleic acid (MLA), and APAP-trimethylglycine (TMG) were used. The monitoring of the granulation recipe containing cocrystals during wet granulation was performed over time with high-performance LF-Raman spectrometry and the dissociation rate was calculated from the results of multivariate analysis of LF-Raman spectra. The dissociation rate decreased in the order of APAP-TMG, APAP-OXA, and APAP-MLA, showing the same order as observed in Powder X-ray diffraction measurements. Furthermore, to compare the effect of disintegrants on the dissociation rate of APAP-OXA, LF-Raman monitoring was performed for the granulation recipes containing five typical disintegrants (two low-substitution hydroxypropyl cellulose (HPC), cornstarch (CSW), carmellose sodium (CMC), and crospovidone (CRP)). The dissociation rate of APAP-OXA decreased in the order of CSW, HPCs, CMC, and CRP. This difference in the dissociation rate of APAP-OXA was thought to be due to the disintegration mechanism of the disintegrants and the water absorption ratio, which was expected to affect the water behavior on the disintegrant surface during wet granulation. These results suggested that probe-type LF-Raman spectroscopy is useful to monitor the dissociation behavior of cocrystals during wet granulation and can compare the relative stability of cocrystal during wet granulation between different formulations.

Quantitative analysis of inulin distribution in the brain focused on nose-to-brain route via olfactory epithelium by reverse esophageal cannulation.

This study aimed to determine the effect of intranasal dosing speed and administrating volume of nose-to-brain delivery on candidates for peptide drugs (molecular weight ca. 1-10 kDa). Using inulin as the model molecule of a peptide drug, intranasal administration by cannulation from the airway side through the esophagus was tested in mice. This was done to determine the quantitative distribution levels of the drug in the brain and cerebral spinal fluid (CSF). Distribution levels were increased with slower and constant speed (5 µL/min), with higher dosing volume equivalent to nasal volume per body weight in mice (25 µL), and were recorded 0.27% injected dose per gram of tissue (ID/g) in the brain, and 0.24% injected dose per milliliter (ID/mL) in the CSF at 60 min. Then, brain distribution resulting from reverse cannulation was two times more than that of the typical intranasal administration method using a micropipette. In addition, the percentage of inulin estimated to reach the brain via direct transport (%DTP) during reverse cannulation was estimated to be 93%, suggesting that ~95% of the total dose was transferred directly to the brain via the olfactory mucosa. These results show that distribution of the peptide drug in the brain was increased through constant administration at a slow and constant speed.

[Establishment of a Novel Method to Evaluate Water Permeation Rates by Combining the Dynamic Contact Angle and Thermographic Approach: Significance of Disintegration Properties of Orally Disintegrating Tablets].

The purpose of the present study was to establish a novel method to evaluate water penetration rates by combining the local dynamic contact angle and thermographic approach to characterize water conduction properties in orally disintegrating (OD) tablets. The OD tablet tester OD-mate was used to measure the disintegration times of OD tablets. Other formulation characteristics, such as tablet hardness and friability, were evaluated. By examining three formulation characteristics, such as the disintegration time, tablet hardness, and friability, of 33 OD tablets for generic drugs, four characteristic OD tablets containing aripiprazole were selected. To quantitatively evaluate water penetration rates into the tablet interior, we measured the dynamic contact angle after dropping water locally on the tablet surface. Linearity with a high correlation coefficient was observed for each of the initial time-dependent changes in the dynamic contact angle. Water penetration rates into tablets were approximately twice as fast for Pharmaceuticals A and B than for Pharmaceuticals C and D. These rates were consistent with changes observed in tablet thermographic imaging. The relationship between the rapid disintegration of the tablet and its physical strength was discussed based on the internal structure of the tablet by X-ray CT and the additives of each OD tablet. The present results demonstrated that the water penetration rates of OD tablets, as measured by dynamic contact angle, may accurately detect differences in disintegration times in the human oral cavity.

The Molecular Mechanisms Underlying Prostaglandin D2-Induced Neuritogenesis in Motor Neuron-Like NSC-34 Cells.

Prostaglandins are a group of physiologically active lipid compounds derived from arachidonic acid. Our previous study has found that prostaglandin E2 promotes neurite outgrowth in NSC-34 cells, which are a model for motor neuron development. However, the effects of other prostaglandins on neuronal differentiation are poorly understood. The present study investigated the effect of prostaglandin D2 (PGD2) on neuritogenesis in NSC-34 cells. Exposure to PGD2 resulted in increased percentages of neurite-bearing cells and neurite length. Although D-prostanoid receptor (DP) 1 and DP2 were dominantly expressed in the cells, BW245C (a DP1 agonist) and 15(R)-15-methyl PGD2 (a DP2 agonist) had no effect on neurite outgrowth. Enzyme-linked immunosorbent assay demonstrated that PGD2 was converted to 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) under cell-free conditions. Exogenously applied 15d-PGJ2 mimicked the effect of PGD2 on neurite outgrowth. GW9662, a peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist, suppressed PGD2-induced neurite outgrowth. Moreover, PGD2 and 15d-PGJ2 increased the protein expression of Islet-1 (the earliest marker of developing motor neurons), and these increases were suppressed by co-treatment with GW9662. These results suggest that PGD2 induces neuritogenesis in NSC-34 cells and that PGD2-induced neurite outgrowth was mediated by the activation of PPARγ through the metabolite 15d-PGJ2.

Correction: Therapeutic Effects in a Transient Middle Cerebral Artery Occlusion Rat Model by Nose-To-Brain Delivery of Anti-TNF-Alpha siRNA with Cell-Penetrating Peptide-Modified Polymer Micelles. Pharmaceutics, 2019, 11(9), 478.

The appropriate information for the reprint used with permission from [...].

Therapeutic Effects in a Transient Middle Cerebral Artery Occlusion Rat Model by Nose-To-Brain Delivery of Anti-TNF-Alpha siRNA with Cell-Penetrating Peptide-Modified Polymer Micelles.

We previously reported that siRNA delivery to the brain is improved by the nose-to-brain delivery route and by conjugation with polyethylene glycol-polycaprolactone (PEG-PCL) polymer micelles and the cell-penetrating peptide, Tat (PEG-PCL-Tat). In this study, we evaluated the nose-to-brain delivery of siRNA targeting TNF-α (siTNF-α) conjugated with PEG-PCL-Tat to investigate its therapeutic effects on a transient middle cerebral artery occlusion (t-MCAO) rat model of cerebral ischemia-reperfusion injury. Intranasal treatment was provided 30 min after infarction induced via suturing. Two hours after infarction induction, the suture was removed, and blood flow was released. At 22 h post-reperfusion, we assessed the infarcted area, TNF-α production, and neurological score to determine the therapeutic effects. The infarcted area was observed over a wide range in the untreated group, whereas shrinkage of the infarcted area was observed in rats subjected to intranasal administration of siTNF-α with PEG-PCL-Tat micelles. Moreover, TNF-α production and neurological score in rats treated by intranasal administration of siTNF-α with PEG-PCL-Tat micelles were significantly lower than those in untreated and naked siTNF-α-treated rats. These results indicate that nose-to-brain delivery of siTNF-α conjugated with PEG-PCL-Tat micelles alleviated the symptoms of cerebral ischemia-reperfusion injury.

Imaging Analysis Enables Differentiation of the Distribution of Pharmaceutical Ingredients in Tacrolimus Ointments.

We demonstrated the difference in the distribution state of pharmaceutical ingredients between tacrolimus (TCR) original ointment and six kinds of generic medicines. Two-dimensional imaging and depth analysis using attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy and confocal Raman microscopy were used, in addition to the evaluation of pharmaceutical properties, including spreading properties, rheological properties, and amount of solvent. The solvents, such as propylene carbonate and triacetin, in TCR ointments formed liquid droplets and dispersed in hydrocarbon oils. Waxes, white beeswax and beeswax, formed other domains. Confocal Raman microscopy could detect liquid droplet size without coalescence of that on germanium or glass surfaces. The combination of ATR FT-IR and confocal Raman imaging would be a powerful tool to reveal the size and shape of liquid droplets of pharmaceutical ingredients in semisolid formulations.

[Optimum Volume of Water Needed for the Paste State of Pediatric Powders: Considerations Based on Yield Values and Applications to Generic Medicine].

To clarify the volume of water required to paste pediatric powders, we herein established a standard for the powder paste state by measuring yield values when water was added to powders. The powders used in the present study were selected from 8 types including original and generic drugs. Tipepidine hibenzate is prescribed in the pediatric field in combination with ambroxol hydrochloride and l-carbocysteine. The volumes of water needed to achieve the paste state of ambroxol hydrochloride between the original and generic drugs were similar. However, the volumes of water needed for l-carbocysteine markedly differed between the original and generic drugs due to differences in their additives. The spreadability of the mixture when water was added to the powders was evaluated using a spread meter. Among the powders tested in the present study, the yield value to achieve a paste state with the addition of water was approximately 1000 dyne/cm2. The optimum volume of water estimated from this yield value using the linear proportional relationship for the amount of powder may be applied to the mixture of each pediatric power for dosage/body weight.

Novel Methods for Intranasal Administration Under Inhalation Anesthesia to Evaluate Nose-to-Brain Drug Delivery.

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain barrier. However, there have been few reports regarding not only the quantitative analysis but also optimal administration conditions and dosing regimens for investigations of nose-to-brain delivery. The limited progress in research on nose-to-brain pathway mechanisms using rodents represents a significant impediment in terms of designing nose-to-brain delivery systems for candidate drugs. To gain some headway in this regard, we developed and evaluated two novel methods of stable intranasal administration under inhalation anesthesia for experimental animals. We also describe a method for the evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radio-labeled [14C]-inulin (molecular weight: 5,000) as a model substrate of water-soluble macromolecules. Initially, we developed a pipette-based intranasal administration protocol using temporarily openable masks, which enabled us to perform reliable administration to animals under stable anesthesia. Using this system, [14C]-inulin could be delivered to the brain with little experimental error. We subsequently developed an intranasal administration protocol entailing reverse cannulation from the airway side through the esophagus, which was developed to minimize the effects of mucociliary clearance (MC). This technique led to significantly higher levels of [14C]-inulin, which was quantitatively detected in the olfactory bulb, cerebrum, and medulla oblongata, than the pipette method. This appears to be because retention of the drug solution in the nasal cavity was substantially increased by active administration using a syringe pump in a direction opposite to the MC into the nasal cavity. In conclusion, the two methods of intranasal administration developed in this study can be expected to be extremely useful techniques for evaluating pharmacokinetics in rodents. The reverse cannulation method, in particular, could be useful for evaluating the full potential of nose-to-brain delivery of drug candidates.

Molecular State of Active Pharmaceutical Ingredients in Ketoprofen Dermal Patches Characterized by Pharmaceutical Evaluation.

The molecular states of ketoprofen and the interaction between ketoprofen and other pharmaceutical excipients in the matrix layer were examined to determine their effect on the pharmaceutical properties of original and generic ketoprofen dermal patches (generic patches A and B). Molecular states of ketoprofen were evaluated using polarized light microscopy, Raman spectroscopy and powder X-ray diffraction. For the original ketoprofen patch, crystalline components were not observed in the matrix layer. However, crystalline ketoprofen was observed in the two generic ketoprofen patches. Moreover, the ketoprofen exhibited hydrogen bonding with the pharmaceutical excipients or patch materials in the generic products. Skin permeation of ketoprofen from the patches was evaluated using hairless mouse skin. Twelve hours after application, the original patch demonstrated the highest level of cumulative skin permeation of ketoprofen. This was followed by generic patch B while generic patch A showed the lowest level of permeation. Fluxes were calculated from the skin permeation profiles. The original patch was approx. 2.4-times faster compared with generic patch A and approximately 1.9-times faster compared with generic patch B. This investigation suggested that pharmaceutical properties such as skin permeability for these types of products are affected by the precipitation of crystalline ketoprofen in the matrix layer and the interaction of ketoprofen with the pharmaceutical excipients or patch materials.

Mixtures of betamethasone butyrate propionate ointments and heparinoid oil-based cream: Physical stability evaluation.

Betamethasone butyrate propionate ointment (BBPO) is mainly used for adult patients in dermatology and is often prescribed as a mixture containing a base or moisturizing cream for various reasons. However, in the case of a moisturizing cream, since this formulation is composed of various ingredients, a physical change is expected to occur by mixing it with an ointment. Therefore, in the present study, the physical stability of a mixture of four BBPO formulations and heparinoid oily cream (HPOC) was examined. Layer separation was observed in all mixtures following centrifugation. The near-infrared (NIR) measurement showed a peak at 5200 cm-1 on the lower layer side, which strongly suggests the presence of water. The peak at 5200 cm-1 in the middle layer was hardly observed in the mixtures of two BBPO generic formulations and HPOC, thus suggesting that the separation was more advanced in those mixtures than in the others. These two mixtures separated into a semisolid layer (upper side) and a liquid layer (lower side) after 3 h of storage at 37 °C. The NIR measurement of each layer revealed that most of the semisolid layer was oil while the liquid layer was water. Furthermore, backscattered light measurements were conducted to monitor the behavior of the mixture's layer separation. An evaluation using model formulations revealed that the layer separation of the mixtures was due to the propylene glycol (PG) and surfactant content of the two generic BBPO formulations. Thus, these findings suggest that excipients need to be considered in selecting formulations for mixtures of skin preparations.

[Retrospective Analysis of Factors Decreasing the Efficacy of Tazobactam/Piperacillin for Pneumonia in Elderly Patients].

　Tazobactam/piperacillin (TAZ/PIPC) is an antimicrobial drug agent with a broad spectrum of antibacterial activity and is recommended as first-line therapy for hospital-acquired pneumonia, nursing- and healthcare-associated pneumonia, and other severe pneumonias. Nevertheless, in clinical settings, TAZ/PIPC is not fully effective in the treatment of pneumonia in the elderly. In the present study, we retrospectively investigated the efficacy of TAZ/PIPC for pneumonia in elderly patients and identified factors that reduced its efficacy. Ninety-nine patients (mean age of 83.4 years and no significant difference in the sex ratio) were included in the present study. The efficacy rate of TAZ/PIPC for pneumonia in elderly patients was 81.8%, which was approximately 7 to 10% lower than that in domestic phase III trials. A multivariate analysis identified the complications of chronic respiratory disease as a significant factor attenuating the therapeutic effects of TAZ/PIPC [odds ratio 4.050, 95% confidence interval (CI) 1.008-16.271]. In conclusion, TAZ/PIPC may not be sufficiently effective for pneumonia in elderly patients with the complications of chronic respiratory disease as a background.

Comparison of the relative stability of pharmaceutical cocrystals consisting of paracetamol and dicarboxylic acids.

OBJECTIVE: The aim of this study is to evaluate the relative stability of pharmaceutical cocrystals consisting of paracetamol (APAP) and oxalic acid (OXA) or maleic acid (MLA). SIGNIFICANCE: These observations of cocrystal stability under various conditions are useful coformer criteria when cocrystals are selected as the active pharmaceutical ingredient in drug development. METHOD: The relative stability was determined from the preferentially formed cocrystals under various conditions. RESULT: Cocrystal of APAP-OXA was more stable than that of APAP-MLA in a ternary cogrinding system and possessed thermodynamical stability. On the other hand, when grinding with moisture or maintaining at high temperatures and relative humidity conditions, APAP-MLA was more stable, and OXA converted to OXA dihydrate. In the slurry method, APAP-OXA was more stable in aprotic solvents because the APAP-OXA with low-solubility product precipitated. CONCLUSIONS: The relative stability order was affected by preparing conditions of presence of moisture. This order might attribute to the small difference of crystal structure in the extension of the hydrogen bond network.