Multiscale structure analysis of a pH-responsive gelatin/hydroxypropyl methylcellulose phthalate blend using small-angle scattering.

HYPOTHESIS: Hydroxypropyl methylcellulose phthalate (HPMCP) is an enteric polymer that has been employed in drug delivery systems to delay the release of the encapsulated active pharmaceutical ingredients through its pH-responsive solubility change. This has been recently demonstrated as an effective means for delaying the drug release from gelatin/HPMCP hydrogels at gastric pH values. However, structural characteristics of HPMCP agglomeration in gelatin/HPMCP hydrogels is not well understood thus limiting further tailoring of their material properties. EXPERIMENTS: We investigated the multiscale structure of a gelatin/HPMCP hydrogel (1:1 by weight) between pH 2 and 6 at 37 °C, i.e. above the upper critical solution transition temperature of gelatin, using small-angle X-ray scattering and contrast-variation small-angle neutron scattering to understand the pH-responsive structure of HPMCP and the cross-correlation between gelatin and HPMCP. FINDINGS: Agglomeration of HPMCP between pH 2 and 4 was evidenced by the formation of mass fractal structures, with a fractal dimension ranging from 1.5 to 2.7, comprising primary particles with a radius of gyration ranging from 70 to 140 Å. Blending with gelatin influenced the fractal structure of HPMCP and the primary particle size. Gelatin and HPMCP exhibited negative cross-correlation in all probed length scales and pH values, which was attributed to volume-exclusion interaction in a double-network-like solution architecture.

Development of Bitter-Taste Masked Instant Jelly Formulations of Diphenhydramine Hydrochloride with Easy-to-Consume Granules.

This study developed easy-to-consume bitter taste-masking granules for the preparation of instant jelly formulations. Composite granules containing diphenhydramine hydrochloride (DPH) and polymers were prepared via spray drying. The taste-masking effect on DPH was evaluated with acceptable linearity between DPH concentration and intensity of bitterness using an electronic tongue sensor. The results indicated that ι-carrageenan could provide the greatest suppression effect on the DPH bitterness among the polymers selected for preparing spray-dried particles (SDPs). The thixotropic index (TI) of ι-carrageenan was higher than that of the other polymers. In addition, two sulfate groups per two galactose molecules in one unit of ι-carrageenan improved interaction with DPH. Compared to κ-carrageenan, the electrostatic interaction with DPH may be stronger. Easy-to-consume SDPs with ι-carrageenan were used to prepare instant jelly formulations. The instant jelly formulation containing DPH with ι-carrageenan (3.0%) met the criteria for texture properties (hardness, adhesiveness, and cohesiveness) for patients with difficulty swallowing, as specified by the Consumer Affairs Agency. Furthermore, instant jelly enhanced the bitter taste suppression of DPH. Overall, using spray-dried granules with ι-carrageenan, this technique for preparing instant jelly formulations is simple and inhibits the bitter taste of drugs, contributing to the development of oral dosage forms suitable for patients of all ages.

Current status of delirium assessment tools in the intensive care unit: a prospective multicenter observational survey.

Delirium is a critical challenge in the intensive care unit (ICU) or high care unit (HCU) setting and is associated with poor outcomes. There is not much literature on how many patients in this setting are assessed for delirium and what tools are used. This study investigated the status of delirium assessment tools of patients in the ICU/HCU. We conducted a multicenter prospective observational study among 20 institutions. Data for patients who were admitted to and discharged from the ICU/HCU during a 1-month study period were collected from each institution using a survey sheet. The primary outcome was the usage rate of delirium assessment tools on an institution- and patient-basis. Secondary outcomes were the delirium prevalence assessed by each institution's assessment tool, comparison of delirium prevalence between delirium assessment tools, delirium prevalence at the end of ICH/HCU stay, and the relationship between potential factors related to delirium and the development of delirium. Result showed that 95% of institutions used the Intensive Care Delirium Screening Checklist (ICDSC) or the Confusion Assessment Method for the ICU (CAM-ICU) to assess delirium in their ICU/HCU, and the remaining one used another assessment scale. The usage rate (at least once during the ICU/HCU stay) of the ICDSC and the CAM-ICU among individual patients were 64.5% and 25.1%, and only 8.2% of enrolled patients were not assessed by any delirium assessment tool. The prevalence of delirium during ICU/HCU stay was 17.9%, and the prevalence of delirium at the end of the ICU/HCU stay was 5.9%. In conclusion, all institutions used delirium assessment tools in the ICU/HCU, and most patients received delirium assessment. The prevalence of delirium was 17.9%, and two-thirds of patients had recovered at discharge from ICU/HCU.Trial registration number: UMIN000037834.

Structural changes in pH-responsive gelatin/hydroxypropyl methylcellulose phthalate blends aimed at drug-release systems.

The present study aimed to investigate the thermal- and pH-dependent gelation behavior of gelatin/HPMCP blends using ultraviolet (UV) spectrophotometry, viscoelasticity, and dynamic light scattering (DLS). We found that the release of lisinopril from gelatin/HPMCP gels can be inhibited at low pH. UV spectrophotometric analysis showed that pH had a significant effect on the transparency of aqueous HPMCP systems and gelatin/HPMCP gels. The viscoelastic patterns of gelatin/HPMCP at pH 4.6 considerably differed from those of gelatin/HPMCP at pH 5.2 and 6.0. DLS measurements showed that HPMCP molecules in low concentrations underwent strong aggregation below pH 4.8. Such HPMCP aggregation induces a physical barrier in the matrix structures of the gelatin/HPMCP gels, which inhibits the drug release at pH 1.2. This hydrogel delivery system using polymer blends of gelatin/HPMCP can be used in oral gel formulations with pH-responsive properties.

Formulation and evaluation of bitter taste-masked orally disintegrating tablets of high memantine hydrochloride loaded granules coated with polymer via layering technique.

Orally disintegrating tablets (ODTs) improve patient adherence as they can easily disintegrate in the presence of small amount of saliva. However, the bitter taste of the active pharmaceutical ingredient in ODTs reduces patient compliance. The present study aimed to formulate bitter taste-masked ODTs containing high-dose of memantine hydrochloride (MTN) to achieve a balance between bitterness suppression and dissolution rate or disintegration time and mechanical strength. The high MTN-loaded granules were prepared using a fluidized bed granulator. Taste-masking granules coated with the selected polymer were prepared using the layering technique. Three ODTs, composed of granules coated with different polymers, were prepared. The ODT prepared using granules coated with enteric polymers showed the fastest collapse time (>20 s). Dissolution rates of ODTs composed of enteric polymers were reduced by 5 min compared with ODTs composed of non-coated or coated with water-insoluble polymer granules. X-ray computed tomography analysis revealed that low density distribution of ODTs with enteric polymer granules may result in faster disintegration time. Although ODT prepared using enteric polymers had the fastest collapse time, its change in membrane potential caused by adsorption (CPA), corresponding to aftertaste, was the lowest among formulations. This CPA value was lower than the bitterness threshold.

Design of a pH-responsive oral gel formulation based on the matrix systems of gelatin/hydroxypropyl methylcellulose phthalate for controlled drug release.

Extensive efforts have been directed toward developing novel easily digested formulations with desirable controlled-release properties. The present study sought to develop pH-responsive oral gel formulations using combinations of gelatin and enteric polymers for controlled drug release under stimulated gastric conditions using acetaminophen and fluorescein isothiocyanate (FITC)-labeled dextran as model compounds. Hydroxypropyl methylcellulose phthalate (HPMCP) was identified as the optimal excipient for the pH-responsive drug release system because the release rates of acetaminophen in gelatin/HPMCP gels at pH 1.2 were exceedingly lower than those in other polymer-containing gels. Texture profile analysis of gelatin/HPMCP gels revealed the optimal content of excipients concerning ingestibility. FITC-labeled dextran of varying molecular weights was used to investigate the mechanism of compound release from the gelatin/HPMCP system under acidic conditions. The release properties practically depended on the molecular weight of FITC-dextran, and the compound release rate was proportional to the square root of time. The matrix structures of gelatin/HPMCP gels at low pH offer advantageous pH-responsive drug release profiles.

Jelly containing composite based on α-glucosyl stevia and polyvinylpyrrolidone: Improved dissolution property of curcumin.

Curcumin (CUR) solutions prepared with α-glucosyl stevia (Stevia-G) and polyvinylpyrrolidone K-30 (PVP) by evaporation method showed 11,000-fold higher solubility compared to CUR alone. Tri-component formulations of CUR/Stevia-G/PVP in aqueous solution showed improved CUR stability for precipitation-triggering conditions of CUR, such as aqueous dilution and temperature changes. Fluorescence study with CUR and pyrene indicated that Stevia-G/PVP mixed solutions produce a more hydrophilic microenvironment around their molecules with increasing PVP concentration compared to Stevia-G solution alone. These results suggested the composite formation associated with the adsorption of the aggregated structure of Stevia-G onto PVP molecules. Jelly formulations were prepared with κ-carrageenan, and jelly formulations containing nanocomposites formed by CUR/Stevia-G/PVP obviously enhanced the dissolution properties of CUR compared to CUR powder. This result indicated that the composite formed by CUR/Stevia-G/PVP could be maintained even after the preparation of jelly and release into a dissolution media. Production of jelly formulations using Stevia-G and PVP are a promising way to improve the dissolution properties of CUR.

Comparison of the efficacy of three topical antiseptic solutions for the prevention of catheter colonization: a multicenter randomized controlled study.

BACKGROUND: To compare the efficacy of three antiseptic solutions [0.5%, and 1.0% alcohol/chlorhexidine gluconate (CHG), and 10% aqueous povidone-iodine (PVI)] for the prevention of intravascular catheter colonization, we conducted a randomized controlled trial in patients from 16 intensive care units in Japan. METHODS: Adult patients undergoing central venous or arterial catheter insertions were randomized to have one of three antiseptic solutions applied during catheter insertion and dressing changes. The primary endpoint was the incidence of catheter colonization, and the secondary endpoint was the incidence of catheter-related bloodstream infections (CRBSI). RESULTS: Of 1132 catheters randomized, 796 (70%) were included in the full analysis set. Catheter-tip colonization incidence was 3.7, 3.9, and 10.5 events per 1000 catheter-days in 0.5% CHG, 1% CHG, and PVI groups, respectively (p = 0.03). Pairwise comparisons of catheter colonization between groups showed a significantly higher catheter colonization risk in the PVI group (0.5% CHG vs. PVI: hazard ratio, HR 0.33 [95% confidence interval, CI 0.12-0.95], p = 0.04; 1.0% CHG vs. PVI: HR 0.35 [95% CI 0.13-0.93], p = 0.04). Sensitivity analyses including all patients by multiple imputations showed consistent quantitative conclusions (0.5% CHG vs. PVI: HR 0.34, p = 0.03; 1.0% CHG vs. PVI: HR 0.35, p = 0.04). No significant differences were observed in the incidence of CRBSI between groups. CONCLUSIONS: Both 0.5% and 1.0% alcohol CHG are superior to 10% aqueous PVI for the prevention of intravascular catheter colonization. TRIAL REGISTRATION: Japanese Primary Registries Network; No.: UMIN000008725 Registered on 1 September 2012.

Cloning and expression of the epithelial sodium channel and its role in osmoregulation of aquatic and estivating African lungfish Protopterus annectens.

The epithelial sodium channel (ENaC) is a sodium (Na(+))-selective aldosterone-stimulated ion channel involved in Na(+) transport homeostasis of tetrapods. We examined full-length cDNA sequences and tissue distributions of ENaCα, ENaCß, and ENaCγ subunits in the African lungfish Protopterus annectens. Protopterus ENaC (pENaC) comprises 3 subunits: pENaCα, pENaCß, and pENaCγ. pENaCα, pENaCß, and pENaCγ subunits are closely related to α, ß, and γ subunits of the Australian lungfish Neoceratodus forsteri ENaC (nENaC), respectively. Three ENaC subunit mRNAs were highly expressed in the gills and moderately expressed in the kidney and rectum of P. annectens. During estivation for 2-4weeks and 2-3months, plasma Na(+) concentration was relatively stable, but plasma urea concentration significantly increased in comparison with the control fish kept in a freshwater environment. Plasma aldosterone concentration and mRNA expression of the ENaCα subunit gradually and significantly decreased in the gills and kidney after 2months of estivation. Thus, aldosterone-dependent Na(+) absorption via ENaC probably exists in the epithelial cells of osmoregulatory organs of lungfish kept in fresh water, whereas plasma Na(+) concentration may be maintained by a mechanism independent of aldosterone-ENaC axis during estivation in lungfish.

Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study.

INTRODUCTION: Fever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness. METHODS: We designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring >48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality. RESULTS: We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P=0.028, acetaminophen: 2.05, P=0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P=0.15, acetaminophen: 0.58, P=0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU ≥ 39.5°C increased risk of 28-day mortality in non-septic patients (adjusted odds ratio 8.14, P=0.01), but not in septic patients (adjusted odds ratio 0.47, P=0.11) [corrected]. CONCLUSIONS: In non-septic patients, high fever (≥39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00940654.