Evaluating the Effects of Crystallinity on Drug Release Behaviour in Itraconazole- or Miconazole-Loaded PLGA Microparticles Prepared Using a Co-Grinding Method

This study aimed to prepare and characterize itraconazole (ITCZ)- or miconazole (MCZ)-loaded poly (lactide-co-glycolide) (PLGA) microparticles (MP) using a co-grinding method with ball milling, which is a solvent-free and convenient procedure. PLGA MP was prepared by grinding for 60 min, and the fixed theoretical drug loading was set at 9.1% and 16.7% for both drugs. The obtained loading efficiency for both drugs was estimated to be approximately 100%. The average diameters of the drug-loaded PLGA MP were approximately 20 - 35 μm. Powder X-ray diffraction (PXRD) or differential scanning calorimetry (DSC) confirmed amorphization of ITCZ and MCZ in ITCZ- or MCZ-loaded PLGA MP in all formulations. The drug release percentage from 9.1%-loaded ITCZ-PLGA7505 MP at 24 h was almost 50%, which was higher than that of ITCZ powder. The drug release percentage from MCZ-loaded PLGA7505 MP at 4 h was over 80%, which was higher than that of MCZ powder. This enhancement of release rate is caused by the amorphization of ITCZ or MCZ in the PLGA matrix. MCZ-loaded PLGA7510 MP showed a sustained release profile up to 24 h, suggesting that MCZ exists in an amorphous form in the PLGA matrix;however, the release rate declined owing to the large molecular weight of PLGA. Therefore, the release enhancement of antifungal drugs loaded on PLGA MP could be achieved by their amorphization using a co-grinding method with ball milling.

Inhibitory Effect of 5-Adenylic Acid on Bitter Taste of Antipsychotic Drugs

The purpose of the present study was to examine the effect of adenylic acid (adenosine 5-monophosphate;AMP), a known nutritional enhancer, on inhibiting the bitterness of antipsychotic medicines administered to patients with mental illnesses, including children. First, we chose four antipsychotic medicines, amitriptyline hydrochloride (AMT), chlorpromazine hydrochloride (CPZ), haloperidol (HPD) and risperidone (RIS) and evaluated the inhibition of their bitterness by AMP through taste sensor measurements. AMP showed a significant bitterness inhibition effect on all drugs. Second, MarvinSketch analysis revealed the potential formation of electrostatic interactions between ionic forms (IV) of AMP and ionic (cationic) forms of each drug, which resulted in bitterness suppression. Third, chemical shift perturbations in 1H-NMR studies suggested an interaction between the phosphate group of AMP and amino group of AMT, CPZ, HPD and RIS. Last, conventional elution experiments of up to 1 min simulating oral cavity conditions were performed for 1 whole AMT tablet, half AMT tablet, crushed half AMT tablet, and crushed AMT tablet containing AMP powder/solution (1, 3 mM potency). The taste sensor output values of the crushed AMT tablet containing AMP powder/solution (1, 3 mM potency) were significantly lower than those of the crushed tablet.

The Effect of Food Thickeners on the Bitterness and Dissolution of Amlodipine Besilate Loaded Oral Disintegration Tablets: Assessment of Potential Suitability for Patients with Dysphagia

The purpose of this research was to evaluate the effect of starch- and xanthan gum-based food thickeners on the bitterness and dissolution of amlodipine besilate (AMPB) loaded orally disintegrating tablets (ODT) for potential use with patients with dysphagia. A conventional dissolution test simulating the oral cavity was performed and the taste sensor output of the dissolved sample was evaluated over a 60-seconds period. When four types of AMPB loaded ODTs were tested alone, at 60 seconds, branded product (A) was the least bitter, followed by generic product (B)/generic product (C) which were equal, and finally generic product (D) which was the most bitter. Inhibition of bitterness of AMPB loaded ODTs mixed thickeners, 1.0 (w/v) % xanthan gum-based food thickener solution was significantly strong. The 7.1 (w/v) % and 4.7 (w/v) % starch-based food thickeners solution also effective in bitterness inhibition compared to the 2.4 (w/v) % starch-based food thickener solution. The dissolution test under pH 1.2 in related to 7.1 (w/v) % and 4.7 (w/v) % starch-based thickener contained each of AMPB loaded ODTs were associated with an almost complete amlodipine (AMP) dissolution (almost 90% at 10 minutes), whereas the 1.0, 2.0, 3.0 (w/v) % xanthan gum-based food thickener solution containing AMPB loaded ODTs did not show complete AMP dissolution and there were large variations in the initial dissolution stage. This suggests that a mixture of xanthan gum-based thickener and AMPB loaded ODT poses a risk of reduction of bioavailability. In conclusion, a mixture of 4.7 (w/v) % or 7.1 (w/v) % starch-based thickener with ODTs provides complete release of AMP and superior bitterness inhibition, so is the best choice for administration to patients with dysphagia.

Usefulness and limitations of taste sensors in the evaluation of palatability and taste-masking in oral dosage forms

The purpose of this review is to discuss the advantages and limitations of taste sensors in the evaluation of the taste of palatability of different oral dosage forms. First, we consider some ways in which the palatability of various pharmaceutical formulations including orally disintegrating tablets(ODTs) are tested using two different taste sensors. Second, we focus on the evaluation of palatability of ODTs. We compare the usefulness of three pieces of apparatus for estimating the disintegration time of ODTs. Finally, we compare the characteristics of the two taste sensors in the evaluation of palatability of various kinds of drug formulations.

Preparation and Evaluation of Poly-γ-Glutamic Acid Hydrogel Mixtures with Basic Drugs or Acidic Drugs: Effect on Ease of Swallowing and Taste Masking

The purpose of this study was to prepare a poly-γ-glutamic acid hydrogel (PGA gel), to examine its ease of swallowing using texture profile analysis (TPA) and to evaluate its taste-masking effects on basic or acidic drugs using the artificial taste sensor. Using TPA, 0.5% and 1.0% PGA gels, 0.5% and 1.0% agar and 1.0% ι-carrageenan in the absence of drug was examined the hardness, adhesiveness and cohesiveness, ranked according to permission criteria published by the Japanese Consumers Affairs Agency. 0.5% PGA gel and 1.0% agar were classified into grade II. In the taste sensor measurement, the bitterness suppressions by 0.5% PGA gel were larger than that by 1.0% agar in all drugs and the bitterness suppressions of basic drugs in 0.5% PGA gel were more potent than those of acidic drugs in 0.5% PGA gel. 1H-nuclear magnetic resonance spectroscopic analysis was carried out to examine the difference in mechanism of bitterness suppression between basic drugs and acidic drugs mixed with PGA gel. The signals of the proton nearest to the nitrogen atom of basic drugs shifted clearly upfield, suggesting an interaction between the amino group of basic drugs and the carboxyl group of PGA gel. In conclusion, PGA gel is expected to be a useful excipient in formulations contained various drugs, especially basic drugs;it also has advantage for not only increasing ease of swallowing but also masking the bitterness of drugs even though a small amount of a single drug dose might be preferred.

The Effect of Food Thickeners on the Bitterness and Dissolution of Amlodipine Besilate Powder When Co-Administered with Thickeners to Patients with Dysphagia

Purpose: The present research was performed to evaluate the effect of food thickeners on the bitterness and dissolution of bitter drugs when co-administered to patients with dysphagia. Methods: Amlodipine besilate (AMPB) powder was used as a model drug. Starch- and xanthan gum-based food thickeners were examined, with swallowing-aid jelly as a reference. The line-spread test (LST), texture prolife analysis (TPA) were done firstly. In related to AMPB powder mixed with food thickeners solution, a conventional dissolution test simulating the oral cavity was performed, the amlodipine (AMP) concentration and taste sensor output for dissolved medium versus time profiles were developed. The dissolution test at pH 1.2 and 4.5, representing typical gastric conditions for younger or elderly people, was performed in two kinds of thickener solution and swallowing-aid jelly those were mixed with AMPB powder. Results: LST demonstrated that xanthan gum-based food thickeners fulfilled the requirements for patients with dysphagia but that starch-based food thickeners did not. In TPA, hardness and adhesiveness decreased proportionally as the concentration increased for both kinds of food thickener. Conventional dissolution test simulating oral cavity demonstrated the following bitterness ranking: xanthan gum-based food thickener Conclusion: Although xanthan gum-based food thickeners were successful in masking the bitterness of AMP, they may reduce its bioavailability in humans. The 7.1 and 4.7 (w/v) % starch-based thickener show bitterness inhibition under simulated oral cavity conditions and complete dissolution of AMP under simulated gastric conditions.

Prevalence of left ventricular dyssynchrony in patients with heart failure assessed by a novel programmer-cardioGRAF

Objectives Left ventricular systolic dyssynchrony is the most important determinant of response to cardiac resynchronization therapy （CRT）, playing a vital role to predict improvement of systolic function or LV reverse remodeling. CardioGRAF is a novel programmer based on the ECG gated single photon emission computed tomography （G-SPECT） imaging to detect LV systolic and diastolic dyssynchrony simultaneously. This study was to investigate the prevalence of systolic and diastolic left ventricular （LV） dyssynchrony in patients with heart failure. Methods We retrospectively studied 69 patients with heart disease, including 31 patients who had symptoms of heart failure （NYHA class Ⅱ-Ⅲ）, and 38 patients who had no symptoms of heart failure. （NYHA class Ⅰ）. G- SPECT data were analyzed by cardiaGRAF, and measurements included the time to end systole （TES）, the time to peak ejection （TPE）, the time to peak filling （TPF）, TES＋TPF and maximal difference （MD） of each parameters were obtained, using the 95th percentile of the control group as a cutoffof 150 ms for MD-TES, 139 ms for MD-TPE, 345 ms for MD-TPF and 315 ms for MD-TES＋TPF. Results The prevalence of LV systolic dyssynchrony was significantly higher in heart failure patients with reduced LV ejection fraction （LVEF）〈45% （72% for MD-TES; 64% for MD-TPE） compared with heart failure patients with preserved LVEF=45% （14% for both MD-TES and MD-TPE; P=0.002, P=0.005, respectively）; The prevalence of MD-TES〈150 ms was higher in NYHA class Ⅲ patients （64%） compared with NYHA class Ilpatients （27%, P=0.049）. However, the prevalence of the LV diastolic dyssynchrony were high but not difference between NYHA class III（47% for both MD-TPF and MD-TES＋TPF） and class Ⅲ（63% for MD-TPF; 69% for MD-TES＋TPF; P=NS） patients as well as between patients with preserved LVEF （43% for both MD-TPF and MD-TES＋TPF） and patients with reduced LVEF（64% for MD-TPF; 72% for MD-TES＋TPF; P=NS）. Conclusions The prevalence of LV systolic dyssynchrony was high in heart failure patients with reduced LVEF. Diastolic dyssynchrony was common in patients with heart failure. CardioGRAF maybe a useful method to detect LV dyssynchrony （J Gerlatr Cardio12009; 6：151-156）.

Neuroprotective Effect of a Prostacyclin Agonist (ONO-1301) with Thromboxane Synthase Inhibitory Activity in Rats Subjected to Cerebral Ischemia

ONO-1301 has been developed as a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. In the present study, we investigated the cerebroprotective effect of ONO-1301 on post-ischemic injury induced by cerebral ischemia in rats. ONO-1301 (1 and 10 mg/kg) was administrated orally at reperfusion and then twice a day for 42 days. The cell damage induced by cerebral ischemia in the hippocampal CA1 was evaluated using both Nissl staining and proliferating cell nuclear antigen (PCNA) staining on the 42 days after cerebral ischemia. Activated astrocytes were evaluated using immunofluorescence staining with GFAP on the 42 days after cerebral ischemia. Spatial learning was assessed using a Morris water maze (MWM) task on the 56 days (i.e. after a 14 days washout period). ONO-1301- treated rats (1 and 10 mg/kg) significantly improved cell death in the hippocampal CA1, the number of PCNA-positive cells and astrocyte activation. The spatial learning of ONO-1301-treated rats compared with vehicle- treated rats in the MWM task. These results suggest that repeated treatment with oral ONO-1301 could prevent or limit post-ischemic brain damage. In particular, treatment with ONO-1301 within 7 days after ischemia is most effective to improve ischemic damage.

Evaluation of the Palatability of Dry Syrups and the Bitterness Intensities of Dry Syrups Mixed with Various Beverages

The purpose of this study was to evaluate the palatability of dry syrups for pediatric use by human gustatory sensation testing and the artificial taste sensor. The bitterness intensities of dry syrups mixed with various beverages were also evaluated using the taste sensor. Twenty dry-syrup formulations of antibacterial and anti-allergic drugs containing bitter active ingredients, frequently used in pediatric medicine in Japan, were selected for testing. The main factors influencing palatability were determined by factor analysis of data from human gustatory sensation testing using the semantic differential method. It was shown that the bitterness intensity of dry syrups in water could be predicted by the artificial taste sensor. The influence of different beverages (orange juice, milk or cocoa) mixed with the dry syrups was evaluated using the artificial taste sensor. Taste and texture were found to be the principal factors influencing the palatability of dry syrups. While the bitterness intensities of some dry syrups were increased by mixing with orange juice, the bitterness intensities of most dry syrups were decreased by mixing with milk or cocoa. This suggests that one or more constituents of milk or cocoa may reduce the bitterness intensities of dry syrups.

Preparation and Characterization of Orally Fast-Disintegrating Mini-Tablets Containing Diphenhydramine Hydrochloride and Aspartic or Glutamic Acid as an Umami Amino Acid

The aim of this study was to prepare diphenhydramine hydrochloride (DPH)-loaded orally fast-disintegrating mini-tablets (OFDMTs) containing either L-aspartic acid (Asp) or L-glutamic acid (Glu) as bitterness-suppressant, to characterize the prepared tablets and to evaluate their bitterness under conditions mimicking those of the oral cavity. The preparation of five formulation batches of the OFDMTs involved mixing DPH, with or without two different concentrations of Asp or Glu, and a premix containing a disintegrating agent. When all ingredients were well mixed, the mixture was directly compacted to form small (4 mm diameter) DPH-loaded OFDMTs. There were only small differences between the tablets with respect to mass, diameter, width and hardness. The disintegration times of the five formulation batches of DPH-loaded OFDMTs were measured using the OD-mate, a disintegration test apparatus in which conditions resemble those of the oral cavity. The disintegration times were all within 10 s of exposure to a medium representing the inside of the oral cavity. Rapid release profiles were observed for DPH, Asp and Glu in these dissolution tests. The taste sensor outputs of samples taken at different times (5 - 30 s) from the dissolution test solutions of the four DPH-loaded OFDMTs containing Asp or Glu were significantly inhibited compared with those of control DPH-loaded OFDMT. These results suggest that the inclusion of Asp or Glu in DPH-loaded OFDMTs is sufficient to mask bitterness in the oral cavity for the first 30 s after the tablet is placed in the mouth. It is anticipated that swallowing will have taken place within 30 s.