A Study on Pharmacokinetics of Acetylsalicylic Acid Mini-Tablets in Healthy Adult Males-Comparison with the Powder Formulation.

Children with Kawasaki disease are prescribed acetylsalicylic acid powder as an antipyretic analgesic and antiplatelet agent; however, some of it remains in the mouth, leading to a bitter or sour taste. To address this issue, an in-hospital mini-tablet formulation of acetylsalicylic acid was developed. In order to use the mini-tablets safely and effectively, dissolution tests alone are not sufficient. Therefore, an open-label crossover study on six healthy participants was conducted to evaluate comparative pharmacokinetic parameters. The pharmacokinetic parameters of salicylic acid were Cmax: 4.80 ± 0.79 mg/L (powder; P), 5.03 ± 0.97 mg/L (mini-tablet; MT), AUC0-12: 18.0 ± 3.03 mg-h/L (P), 18.9 ± 4.59 mg-h/L (MT), those of acetylsalicylic acid Cmax: 0.50 ± 0.20 mg/L (P), 0.41 ± 0.24 mg/L (MT), AUC0-12: 0.71 ± 0.27 mg-h/L (P), 0.61 ± 0.36 mg-h/L (MT), with no significant differences between the mini-tablet and powder formulations. Although pharmacokinetic results obtained from adults cannot be directly applied to children, the results of this study are important for predicting pharmacokinetics. Furthermore, a formulation that can improve medication adherence in children who have difficulty taking acetylsalicylic acid powder, thus contributing to pediatric drug therapy.

Q-learning model of insight problem solving and the effects of learning traits on creativity.

Despite the fact that insight is a crucial component of creative thought, the means by which it is cultivated remain unknown. The effects of learning traits on insight, specifically, has not been the subject of investigation in pertinent research. This study quantitatively examines the effects of individual differences in learning traits estimated using a Q-learning model within the reinforcement learning framework and evaluates their effects on insight problem solving in two tasks, the 8-coin and 9-dot problems, which fall under the umbrella term "spatial insight problems." Although the learning characteristics of the two problems were different, the results showed that there was a transfer of learning between them. In particular, performance on the insight tasks improved with increasing experience. Moreover, loss-taking, as opposed to loss aversion, had a significant effect on performance in both tasks, depending on the amount of experience one had. It is hypothesized that loss acceptance facilitates analogical transfer between the two tasks and improves performance. In addition, this is one of the few studies that attempted to analyze insight problems using a computational approach. This approach allows the identification of the underlying learning parameters for insight problem solving.

Comparison of Bitterness Intensity between Prednisolone and Quinine in a Human Sensory Test Indicated Individual Differences in Bitter-Taste Perception.

Prednisolone is a frequently prescribed steroid with a bitter, unpalatable taste that can result in treatment refusal. Oral suspensions or powder dosage forms are often prescribed, particularly to pediatric patients, as they improve swallowability and ease of dose adjustment. Consequently, the bitterness of prednisolone is more apparent in these dosage forms. Few studies have investigated prednisolone's bitterness. Thus, in this study, 50 adults evaluated the bitterness of prednisolone using the generalized Labeled Magnitude Scale (gLMS), in comparison with quinine, a standard bitter substance. Overall, prednisolone-saturated solution demonstrated the same extent (mean gLMS score: 46.8) of bitterness as 1 mM quinine solution (mean gLMS score: 40.1). Additionally, large individual differences were observed in the perception of the bitterness of prednisolone and quinine. Perceived flavors of some drugs are reportedly associated with bitter-taste receptor (TAS2Rs) polymorphisms. Therefore, we investigated the relationship between subjects' genetic polymorphisms of TAS2R19, 38, and 46, and their sensitivity to bitterness. Although a relationship between TAS2R19 polymorphisms and the perception of quinine bitterness was observed, no significant relationship was found between the perceived bitterness of prednisolone and the investigated genes. Ultimately, the results show that despite individual differences among subjects, the cause of prednisolone's strong bitterness is yet to be elucidated.

Stability Study of Baclofen in an Oral Powder Form Compounded for Pediatric Patients in Japan.

Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients and pediatric patients with cerebral palsy and is prescribed to pediatric patients at 0.3 to 1.0 mg/kg/dose. Baclofen tablets, an oral drug, are usually administered as a powder in pediatric wards after a formulation change by the pharmacist. However, there is no information about stability and assurance of quality for compounded products. The purpose of this study was to design a 10 mg/g oral powder of baclofen and to investigate the stability and changes in the physical properties of this compounded product. A 10 mg/g baclofen powder was prepared by adding extra-fine crystal lactose hydrate to crushed and filtrated baclofen tablets and was stored in a polycarbonate amber bottle with desiccant or in a coated paper laminated with cellophane and polyethylene. The stability of baclofen at 25 ± 2 °C/60 ± 5%RH was tested for 120 days in 'bottle (closed)', 'bottle (in use)', and 'laminated' storage conditions. Baclofen concentrations ranged from 90.0% to 110.0% of the initial concentration under all storage conditions. No crystallographic or dissolution changes were observed after storage. This information can help with the management of baclofen compounded powder in pharmacies.

Visualizing fluid transport inside orally disintegrating tablets and changes in tablets using real-time X-ray radiography and X-ray computed tomography.

OBJECTIVE: To investigate the disintegration of wet- and dry-compressed orally disintegrating (OD) tablets, with synchrotron radiation as the X-ray source. SIGNIFICANCE: Pharmaceutical tablets are vital for the treatment of various diseases. Therefore, they are constantly developed to ensure desirable characteristics. In particular, OD tablets need to disintegrate immediately after absorbing saliva. How these tablets absorb saliva is key to enhancing rapid product development. Recently, absorption processes have been investigated using various noninvasive techniques, including X-ray radiography and X-ray computed tomography. However, X-ray radiography studies on how water without a contrast agent is absorbed, moves, and causes a tablet to swell are scarce. The use of a contrast agent is associated with some shortcomings, including complex data analysis in some instances, alterations in the viscosity of water, and potential influence on fluid transport inside the tablet, thus possibly affecting the disintegration process. METHODS: Real-time X-ray radiography was used to monitor the disintegration of various tablets, while X-ray computed tomography and software were used to create 3 D images. RESULTS: We demonstrated how pure water penetrated the wet-compressed tablet faster than inside the dry-compressed tablet, and how the latter swelled more. X-ray computed tomography showed the presence of voids in the tablets following water absorption. CONCLUSION: Our methods are promising for nondestructive fluid absorption and transport investigations inside OD tablets.

Characteristics of Vibrating Fluidization and Transportation for Al2O3 Powder.

This study focused on the vibrating fluidized-bed-type powder feeder used in HVAF thermal spraying equipment. This feeder has been used in thermal spraying equipment and industrial applications. However, particulate materials' flow mechanism and stable transport characteristics have not been fully understood. This study experimentally investigated the fluidization characteristics, powder dispersion state, and powder transportation characteristics of Al2O3 particles during vertical vibration fluidization. The material used was Al2O3 particles of 2.9 µm and 3808 kg/m3, classified as the group C particles in the Geldart diagram. As experimental conditions, the fluidized air velocity to the bottom of the powder bed and the vibration intensity in the vertical direction changed. The critical fluidization air velocity was defined to evaluate the generating powder flow by vertical vibrating fluidization. As a result, good fluidization of the powder bed of Al2O3 was obtained by the vertical vibration, as well as an airflow that was higher than the critical fluidization air velocity. Regarding powder transportation characteristics, it was clarified that the fluidized air velocity at the bottom of the powder dispersion vessel and the pressure difference from the powder dispersion vessel to the transportation part significantly affect the mass flow rate.

Swallowability of Minitablets among Children Aged 6-23 Months: An Exploratory, Randomized Crossover Study.

Minitablets have garnered interest as a new paediatric formulation that is easier to swallow than liquid formulations. In Japan, besides the latter, fine granules are frequently used for children. We examined the swallowability of multiple drug-free minitablets and compared it with that of fine granules and liquid formulations in 40 children of two age groups (n = 20 each, aged 6-11 and 12-23 months). We compared the percentage of children who could swallow minitablets without chewing with that of children who could swallow fine granules or liquid formulations without leftover. The children who visited the paediatric department of Showa University Hospital were enrolled. Their caregivers were allowed to choose the administration method. In total, 37 out of 40 caregivers dispersed the fine granules in water. Significantly more children (80%, 95% CI: 56-94%) aged 6-11 months could swallow the minitablets than those who could swallow all the dispersed fine granules and liquid formulations (22%, 95% CI: 6-47% and 35%, 95% CI: 15-59%, respectively). No significant differences were observed in children aged 12-23 months. Hence, minitablets may be easier to swallow than dispersed fine granules and liquid formulations in children aged 6-11 months.

Exploring the effects of risk-taking, exploitation, and exploration on divergent thinking under group dynamics.

This study examined the effects of risk-taking and exploitation/exploration trade-off on divergent thinking in individuals, dyads, and triads. We adopted a simple Q-learning model to estimate risk attitudes, exploitation, and exploration parameters. The results showed that risk-taking, exploitation, and exploration did not affect divergent thinking in dyads. Instead, loss aversion was negatively related to divergent thinking. In contrast, risk attitudes and the inverse temperature as a ratio between exploitation and exploration were significant but with contrasting effects in individuals and triads. For individuals, risk-taking, exploitation and loss aversion played a critical role in divergent thinking. For triads, risk aversion and exploration were significantly related to divergent thinking. However, the results also indicated that balancing risk with exploitation/exploration and loss aversion is critical in enhancing divergent thinking in individuals and triads when learning coherence emerges. These results could be interpreted consistently with related literature such as the odd-vs. even-numbered group dynamics, knowledge diversity in group creativity, and representational change theory in insight problem-solving.

Examining learning coherence in group decision-making: triads vs. tetrads.

This study examined whether three heads are better than four in terms of performance and learning properties in group decision-making. It was predicted that learning incoherence took place in tetrads because the majority rule could not be applied when two subgroups emerged. As a result, tetrads underperformed triads. To examine this hypothesis, we adopted a reinforcement learning framework using simple Q-learning and estimated learning parameters. Overall, the results were consistent with the hypothesis. Further, this study is one of a few attempts to apply a computational approach to learning behavior in small groups. This approach enables the identification of underlying learning parameters in group decision-making.

Stability of clonidine hydrochloride in an oral powder form compounded for pediatric patients in Japan.

BACKGROUND: Clonidine hydrochloride is used to treat sedative agent withdrawals, malignant hypertension, and anesthesia complications. Clonidine is also prescribed off-label to pediatric patients at a dose of 1 µg/kg. The commercially available enteral form of clonidine, Catapres® tablets, is often compounded into a powder form by pharmacists to achieve dosage adjustments for administration to pediatric patients. However, the stability and quality of compounded clonidine powder have not been verified. The objectives of this study were to formulate a 0.2 mg/g oral clonidine hydrochloride powder and assess the stability and physical properties of this compounded product in storage. METHODS: A 0.2 mg/g clonidine powder was prepared by adding lactose monohydrate to crushed and filtrated clonidine tablets. The powder was stored in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. The stability of clonidine at 25 °C ± 2 °C and 60% ± 5% relative humidity was examined over a 120-d period in "bottle (closed)," "bottle (in use)," and "laminated paper" storage conditions. Drug dissolution and powder X-ray diffraction analysis were conducted to assess physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify clonidine and its degradation product, 2,6-dichloroaniline (2,6-DCA). RESULTS: Clonidine content was maintained between 90.0 and 110.0% of the initial contents in all packaging and storage conditions. After 120 d of storage, 2,6-DCA was not detected, and no crystallographic and dissolution changes were observed. CONCLUSIONS: Compounded clonidine powder stability was maintained for 120 d at 25 °C ± 2 °C and 60% ± 5% relative humidity. This information may contribute to the management of clonidine compounded powder in community and hospital pharmacies in Japan.

Stability of Hydrocortisone in Oral Powder Form Compounded for Pediatric Patients in Japan.

Hydrocortisone has been utilized in the management of adrenal insufficiency. For pediatric patients, the commercially available enteral form of hydrocortisone tablets (Cortoril®) is administered in powder form after being compounded by a pharmacist. However, the stability and quality of compounded hydrocortisone powder have not been verified. In this study, we formulated a 20 mg/g oral hydrocortisone powder by adding lactose monohydrate to crushed and filtered hydrocortisone tablets and assessed the stability and physical properties of this compounded product in polycarbonate amber bottles or coated paper packages laminated with cellophane and polyethylene. Stability was examined over 120 days in three storage conditions: closed bottle, in-use bottle, and laminated paper. Drug dissolution and powder X-ray diffraction analysis were conducted to assess its physicochemical stabilities. Validated liquid chromatography-diode array detection was used to detect and quantify hydrocortisone and its degradation products. Although impurity B (cortisone) and G (hydrocortisone-21-aldehyde) were found after 120 days of storage, no crystallographic and dissolution changes were noted. Hydrocortisone content was maintained between 90% and 110% of initial contents for 120 days at 25 ± 2 °C and 60 ± 5% relative humidity in all packaging conditions.

Three heads are better than two: Comparing learning properties and performances across individuals, dyads, and triads through a computational approach.

Although it is considered that two heads are better than one, related studies argued that groups rarely outperform their best members. This study examined not only whether two heads are better than one but also whether three heads are better than two or one in the context of two-armed bandit problems where learning plays an instrumental role in achieving high performance. This research revealed that a U-shaped correlation exists between performance and group size. The performance was highest for either individuals or triads, but the lowest for dyads. Moreover, this study estimated learning properties and determined that high inverse temperature (exploitation) accounted for high performance. In particular, it was shown that group effects regarding the inverse temperatures in dyads did not generate higher values to surpass the averages of their two group members. In contrast, triads gave rise to higher values of the inverse temperatures than their averages of their individual group members. These results were consistent with our proposed hypothesis that learning coherence is likely to emerge in individuals and triads, but not in dyads, which in turn leads to higher performance. This hypothesis is based on the classical argument by Simmel stating that while dyads are likely to involve more emotion and generate greater variability, triads are the smallest structure which tends to constrain emotions, reduce individuality, and generate behavioral convergences or uniformity because of the ''two against one" social pressures. As a result, three heads or one head were better than two in our study.

Effect of xanthan gum-based food thickeners on the dissolution profile of fluoroquinolones oral formulations.

BACKGROUND: Xanthan gum-based food thickeners (XG-FTs) are often ingested by patients with dysphagia to prevent aspiration during drug treatment. Reportedly, XG-FTs affect tablet disintegration, drug dissolution rates, and reduce the efficacy of postprandial antihyperglycemic agents. The absorption rate and quantity of fluoroquinolone antimicrobial agents correlate with drug efficacy, raising concern about the impact of XG-FTs. Previously, we reported that film-coated tablets were less susceptible to the effects of XG-FT than conventional and orally disintegrating tablets. Here, we compare the effect of XG-FTs on dissolution profiles of three oral fluoroquinolone-based film-coated tablets by evaluating the dissolution of crushed products, fine granules, and film-coated fine granules. METHODS: We examined formulations of tosufloxacin tosylate monohydrate (TFLX), levofloxacin hemihydrate (LVFX), and ciprofloxacin hydrochloride hydrate (CPFX). The formulations were immersed in 20 mL of 1.5% (w/v) XG-FT aqueous solution for 2.5 min followed by a dissolution test using the paddle method according to the Japanese Pharmacopoeia (dissolution test solution pH 1.2; volume 900 mL; temperature 37 ± 0.5 °C). The dissolution profile was evaluated according to the dissolution quantity indicated in product specifications and guidelines for bioequivalence testing of generic drugs. The 15-min mean dissolution rate was determined for a formulation immersed in 1.5% (w/v) XG-FT aqueous solution and compared with that for a non-immersed formulation (control). Fluoroquinolone film-coated tablets were mixed with starch-based FTs, guar gum-based FTs, or XG-FTs to observe their appearances. RESULTS: The dissolution profile of LVFX film-coated tablets was not affected by XG-FTs, but the dissolution of TFLX and CPFX was delayed. For crushed film-coated tablets, the 15-min mean dissolution rate was significantly delayed for all three fluoroquinolones when compared with that of uncrushed products. The dissolution profile of TFLX film-coated fine granules was unchanged by XG-FTs. CPFX film-coated tablets and crushed products produced a gel-like precipitate when mixed with XG-FTs and failed to meet product-dissolution specifications. A gel-like precipitate was also observed with guar gum-based FTs. CONCLUSION: The effect of XG-FTs on the dissolution profile of film-coated fluoroquinolone formulations varied depending on the formulation. The CPFX formulation formed a gel-like precipitate when immersed in XG-FTs resulting in a significantly delayed dissolution.

Effect of Disintegrants on Prolongation of Tablet Disintegration Induced by Immersion in Xanthan Gum-Containing Thickening Solution: Contribution of Disintegrant Interactions with Disintegration Fluids.

In clinical practice, a thickening solution is frequently used to allow easy swallowing of tablets by patients suffering from dysphagia. This study investigated the effect of the thickening solution on tablet disintegration. Model tablets containing different disintegrants were prepared and their disintegration times (DTs) measured using standard methods. We also performed an additional disintegration test on the model tablets after immersing them for 1 min in thickening solution containing xanthan gum (XTG-SOL) ("modified disintegration test"). The DTs of the test tablets were substantially prolonged by immersion in XTG-SOL. Furthermore, the effect of the XTG-SOL on the DTs differed depending on the type of disintegrant contained in the tablets. To investigate in more detail this prolongation of tablet disintegration, we examined the contribution of tablet properties to their DTs. The properties analyzed included contact angle, T2 relaxation time, wetting time, and water absorption ratio. The contributions of these properties to the DTs were analyzed using multiple regression analysis. This analysis clarified that the tablet properties affecting DTs changed after immersion in XTG-SOL: wetting time significantly affected the DTs measured in the normal disintegration test, while T2 was crucial for the DTs of tablets immersed in XTG-SOL. These findings provide valuable information for design of tablet formulations, and for clinical medication management for older patients with dysphagia.

Learning From Success or Failure? - Positivity Biases Revisited.

The purpose of this study was to reexamine positivity learning biases through a Q learning computation model and relate them to behavioral characteristics of exploitation and exploration. It was found that while the positivity learning biases existed in the simple asymmetric Q learning model, they completely disappeared once the time-varying nature of learning rates was incorporated. In the time-varying model, learning rates depended on the magnitudes of success and failure. The corresponding positive and negative learning rates were related to high and low performance, respectively, indicating that successes and failures were accounted for by positive and negative learning rates. Moreover, these learning rates were related to both exploitation and exploration in somewhat balanced ways. In contrast, under the constant learning parameter model, positivity biases were associated only with exploration. Therefore, the results in the time-varying model are more intuitively appealing than the simple asymmetric model. However, the statistical tests indicated that participants eclectically selected between the asymmetric learning model and its time-varying version, a frequency of which differed across participants.

The effects of risk-taking, exploitation, and exploration on creativity.

The purpose of this paper was to investigate the effects of risk-taking, exploitation, and exploration on creativity by taking a model-based computational approach to both divergent and convergent thinking as primary ingredients of creativity. We adopted a reinforcement learning framework of Q learning to provide a simple, rigorous account of behavior in the decision-making process and examined the determinants of divergent and convergent thinking. Our findings revealed that risk-taking has positive effects on divergent thinking, but not related to convergent thinking. In particular, divergent thinkers with a high learning capacity were more likely to engage in risk-taking when facing losses than when facing gains. This risk-taking behavior not only contributes to the rapid achievement of learning convergence, but is also associated with high performance in divergent thinking tasks. Conversely, both exploitation and exploration had no significant effects on creativity once these risk attitudes were considered. Moreover, while convergent thinking relied on personality characteristics, it was not associated with risk-taking, exploitation, or exploration.

Mood and Risk-Taking as Momentum for Creativity.

This study examined the effects of mood and risk-taking on divergent and convergent thinking using a Q-learning computation model. The results revealed that while mood was not significantly related to divergent or convergent thinking (as creative thinking types), risk-taking exerted positive effects on divergent thinking in the face of negative rewards. The results were consistent with the representational change theory in insight problem solving. Although this theory accounts directly for insight, the underlying idea of going beyond current contexts and implicit constrains could be applied to creative thinking as well. The results indeed accounted for the relevance of this theory to divergent thinking. The current study is one of the first empirical studies simultaneously examining the role of mood and risk-taking in creativity. In particular, no related studies exist that took a computational approach to estimate the relevant parameters in the framework of dynamic optimization. Our Q learning model enables to distinguish and identify the different roles of mood and risk-taking in updating Q values and making decisions.

[Development of a novel oral jelly formulation for elderly patients].

Deterioration of the swallowing function in elderly persons and drug refusal among the behavioral abnormalities in Alzheimer's disease (AD) are commonly reported. Therefore, we developed an easy-to-swallow jelly formulation of Donepezil HCl which AD patients can take as a dessert. The development process, however, was full of trade-off problems. (1) Need for evaluating the taste of a drug product vs. Safety of human sensory evaluation of the taste. The trade-off was resolved by using a taste sensor. (2) Speed of development vs. Safety of the manufacturing process. We put priority on the safety rather than speed, and a safer antioxidant agent was found. (3) Usability of the container for AD patients with dysphagia vs. Size of the container. We put priority on its being user-friendly rather than on the size and chose a stable wide-mouth cup. (4) Suitable texture of jelly for swallowing the drug product vs. Residual volume of jelly in the cup. We designed the texture so that the residual volume of jelly in the cup was reduced. (5) Easy peeling properties of aluminum seal vs. High sealing strength for sterilization. The sealing strength was adjusted so that it was adequate to sterilize the drug product. (6) One cup in a heat-sealed aluminum pillow package to prevent overdose vs. Seven cups in a pillow package. A single-dose package was relatively expensive, but it was chosen to assure safety. We faced many difficult trade-off problems in the development of process. However, they were resolved using technical innovations and a people-friendly policy. Finally, we were able to launch a novel oral jelly formulation for elderly patients.

[Application of taste sensor to medicines in research, development and market].

Using a taste sensor in the field of medical products has the following four main purposes: (1) Ensuring that investigational product and placebo are indistinguishable; (2) Formulation design; (3) Quality control; (4) Benchmark test. Unlike evaluating a taste of food, roughly predicting a taste of drug without human sensory test and quantitative evaluation using small quantity of drug sample are more important than evaluation of the nuances of homogeneous taste and preference. Here are some examples of using taste sensor for these purposes. (1) We predicted a taste of suspension of phosphatic drug substance in an early phase of development using a taste sensor. As a result, the suspension seemed to have sour and bitter taste. Then we made placebo solution of citric acid similar taste as much like active suspension to ensure indistinguishable taste from each other. (2) A taste of orally disintegrating tablet (ODT) in the mouth is important to drug adherence. The taste of an ODT was then evaluated in chronological order by combining the taste sensor with the new disintegration testing apparatus to design easy-to-take formulation. (3) We evaluated taste variation of a commercial product in batch-to-batch and identified the cause of the variation. (4) We did benchmark test for easy-to-take of commercial ODTs in vitro. There is great variability among these products in the disintegrating profile and the taste.

A new method for evaluating the bitterness of medicines in development using a taste sensor and a disintegration testing apparatus.

The purpose of this study was to demonstrate the usefulness and wide applicability of a taste sensor and a new disintegration testing apparatus in the development and/or evaluation of orally disintegrating tablets (ODTs). In this paper, we described methods for the effective utilization of a taste sensor in the development of a new medicine. First we predicted the taste of propiverine hydrochloride, a model drug substance whose taste is unknown, using a taste sensor. Then we screened masking agents for their ability to suppress the bitterness of propiverine hydrochloride, and manufactured ODTs of propiverine hydrochloride with various masking agents. The tastes of these ODTs were then evaluated in chronological order by combining the taste sensor with the new disintegration testing apparatus, ODT-101, to resemble the oral cavity. As a result, we were able to evaluate the taste of propiverine hydrochloride and the effectiveness of various masking agents in ODTs. The result using this combination of taste sensor and ODT-101 shows good agreement with the results of human gustatory sensation testing, thus demonstrating the usefulness and applicability of the taste sensor and disintegration testing apparatus, ODT-101, in the development of new medicine.