Development and validation of a novel system that combines a new masticatory simulator and analysis method for modeling the human gummy candy masticatory process.

During mastication, food undergoes state and texture changes influenced by various mechanical properties, including compression and fracturing of the molar teeth, mixing with saliva, and oral temperature. Prior studies have explored mastication simulators, however, no studies have assessed the forces and duration applied to the molars by the food during bolus formation. In this study, we developed a novel system that integrates a masticatory simulator and analysis method to evaluate mechanical properties. We developed ORAL-MAPS which is equipped with 6-axis force sensor, pneumatic pressure control mechanism, vertical movement, molar-like module, artificial saliva injection unit, and temperature control apparatus. A gap exists between the upper and lower unit at the closest point, allowing the sensor to measure vertical upward force and duration from food, while compressed air provides constant downward pressure. We hypothesized a correlation between the total integrated muscle activity ratio obtained from the human masseter muscle electromyography (iEMG). We compared the normalized impulse obtained from ORAL-MAPS with the normalized total iEMG obtained from human studies with four different types of gummy candies. As a result, the normalized total impulse of gummy candies A, B, C, and D were 1.00 ± 0.00, 1.29 ± 0.06, 0.95 ± 0.00, and 0.39 ± 0.0, respectively. The normalized total iEMG of the same gummy candies were 1.00 ± 0.00, 1.23 ± 0.15, 0.98 ± 0.09, and 0.45 ± 0.07, respectively. Thus, no significant difference was observed between the normalized total impulse obtained in vitro and the normalized total iEMG values for masticating the gummy candies B, C, and D (p > .05).

Factors contributing to carboplatin blockade and interruption in its route of administration in paclitaxel-carboplatin therapy.

The interruption of anticancer infusion processes in patients undergoing chemotherapy may affect their quality of life and the efficacy and safety of the therapy. We experienced several interruptions of carboplatin infusion in multiple patients receiving paclitaxel-carboplatin combination therapy. Therefore, we investigated the causes of these interruptions. The filter and catheter surfaces were evaluated by scanning electron microscopy. Moreover, using a texture analyzer, the mechanical strengths of catheter-attached syringes were compared pre- and post-administration. We observed that the syringe pushing force requirement was higher following dripping failure. However, precipitates were not evident on the filter surfaces, regardless of the dripping failure route. In this case, some of the drug adhered to the catheters' surfaces and interrupted the carboplatin titration. Consequently, in patients receiving combination therapy with paclitaxel and carboplatin, and experiencing interruptions in carboplatin infusion, attention should be paid to the catheter.

SEM Observation of the Filter after Administration of Blinatumomab: A Possibility of Leakage during Home Administration Using a Portable Infusion Pump.

Blinatumomab (Blincyto® injection solution) is classified as a bispecific T-cell engaging (BiTE) antibody and is intended for the treatment of relapsed/refractory acute lymphoblastic leukemia. It requires continuous infusion to maintain therapeutic levels. Therefore, it is often administered at home. Monoclonal antibodies, which are administered intravenously, have the potential to leak depending on the nature of the administration devices. Therefore, we investigated device-associated causes of blinatumomab leakage. We observed no apparent changes to the filter and its materials after exposure to the injection solution and surfactant. From scanning electron microscopic images, precipitate on the surface of the filters was observed after physical stimulation of the injection solution. Therefore, physical stimulations should be avoided during the prolonged administration of blinatumomab. In conclusion, the findings of this study assist in the safe administration of antibodies using portable infusion pumps, taking into consideration the composition of drug excipients and the choice of filter type and structure.

Quantitative Monitoring of Cocrystal Polymorphisms in Model Tablets Using Transmission Low-Frequency Raman Spectroscopy.

Cocrystallization is a technique for improving the physical properties of active pharmaceutical ingredients. However, cocrystals can transform into more stable polymorphs as well as dissociate to original materials. Therefore, an analytical technique is required to determine the polymorphic transformation quickly and accurately in tablets. The purpose of this study is to develop a method to monitor cocrystal polymorphs in model tablets using transmission low-frequency Raman spectroscopy. The tablets, consisting of only metastable polymorphs of caffeine-glutaric acid cocrystals, were stored under various relative humidity levels. The composition of the cocrystal polymorphs were calculated from a calibration curve relating the actual composition to the predicted values calculated by partial least squares regression processing of low-frequency Raman spectra. The metastable form gradually converted to a stable form, and polymorphic phase transformation occurred with increasing relative humidity. Ninety-six percent of the metastable form converted into a stable form stored at 25 °C after 3 h at 95% RH. In conclusion, transmission low-frequency Raman spectroscopy can be used to quantitatively monitor cocrystal polymorphs. This technique is one of the candidate techniques to quantifiably evaluate the physico-chemical stability of cocrystal polymorphs in tablets.

Utterances as Signals for Sharing Tacit Images in Collective Interaction.

In ball games, individuals collaborate to enhance their team's performance by sharing images and ideas that have not been verbalized. One of a coach's roles is to ascertain whether players share a common understanding of their team's images so as to devise tactics. Accordingly, this study aimed to verify the hypothesis that sharing images such as tacit knowledge that has not been verbalized occurs in collective interaction when utterances increase substantially during problem-solving. The participants were 13 male university handball players whose teams were championship contenders in Japan. A mixed methods research design was employed. Scenes in which two groups engaged in problem-solving were recorded and data of each participant's utterances were obtained. The utterances were analyzed quantitatively by employing Smirnoff-Grubbs and the time periods including those with a substantial number of utterances were identified. What happened during the identified time periods verified as outliers including the high frequency utterances were analyzed qualitatively by employing consensual qualitative analysis. Finally, the results of the consensual qualitative analysis were used to examine statistically to determine whether specific events occurred during times of extreme high frequency utterances. The exact binomial test was used to determine the 95% confidence interval of the population ratio and the effect size (g) of the mother ratio (0.05) to determine whether non-verbalized images such as tacit knowledge were being shared among members. Of the 26 time periods, 22 were supported the hypothesis. Of the time periods with extremely high utterances, the population ratio of the time periods supporting the hypothesis was 0.846 (CI = 0.681-1.00, g = 0.80). The results revealed that tacit image sharing occurred when there were a substantial number of utterances. This study demonstrated the possibility that sharing images that have not been verbalized occurs in collective interaction when there is a hotspot of utterances.

Solid-State Analysis of Alpha-Cyclodextrin Inclusion Complexes Using Low-Frequency Raman Spectroscopy.

A rapid and nondestructive analytical technique is critical for the analysis of cyclodextrin inclusion complexes in solid dosage forms. This study proposed a newly developed low-frequency Raman spectroscopy as a candidate technique for the analysis of cyclodextrin inclusion complexes. In this study, we selected a typical series of five crystalline cyclodextrin inclusion complexes and reported the usefulness of Raman spectroscopy for analyzing these inclusion complexes. Some inclusion complexes clearly differed from the raw materials in conventional Raman spectra. In another case, though specific differences were not observed between inclusion complexes and raw materials in conventional Raman spectra, clear differences were observed in low-frequency Raman spectra. Moreover, no characteristic differences between inclusion complexes consisting of different guest molecules were observed in conventional Raman spectra. The characteristic differences were observed only in low-frequency Raman spectra. Therefore, low-frequency Raman spectroscopy is a useful technique for solid-state analysis of crystalline inclusion complexes.

Mechanistic study of preparation of drug/polymer/surfactant ternary hot extrudates to obtain small and stable drug nanocrystal suspensions.

We studied optimized conditions for preparing ternary hot extrudates (HEs) of glibenclamide (GLB)/polyvinylpyrrolidone (PVP)/sodium dodecyl sulfate to generate stable nanocrystal suspensions following aqueous dispersion. Raman and solid-state NMR measurements of ternary HEs prepared by altering HE conditions revealed that GLB crystallinity in HEs reduced with increased extrusion temperature and count and decreased screw speed. Aqueous dispersions of all HEs temporarily formed GLB nanoparticles with a diameter of 75-420 nm. The suspension from the HEs with the low GLB crystallinity (<22%) precipitated after 4-h storage, while the HEs with the high GLB crystallinity (>22%) formed stable nanocrystal suspension. Interestingly, the number of GLB nanoparticles <150  nm was different despite aqueous dispersion of HEs with similar GLB crystallinity, reflecting the different GLB crystalline size in those HEs. Although both the crushing by shear force and GLB dissolution into PVP reduced GLB crystalline size, the crushing GLB crystal by the shear force has a relatively high ability to decrease GLB crystalline size without excess amorphization of GLB. Performing the hot extrusion at a low temperature, a high screw speed, and maximizing extrusion count with GLB crystallinity >22% led to formation of small and stable nanocrystal suspensions.

Correlation between drug dissolution and resistance to water-induced phase separation in solid dispersion formulations revealed by solid-state NMR spectroscopy.

We aimed to elucidate the dissolution mechanism of solid dispersions (SDs) according to the carrier polymers used. Nifedipine (NIF) and polymers dissolved simultaneously from NIF/Eudragit® S (EUD-S), NIF/Eudragit® L (EUD-L), and NIF/hypromellose (HPMC)/EUD-S spray-dried samples (SPDs). In contrast, NIF dissolved separately from polymers from NIF/HPMC and NIF/HPMC/EUD-L SPDs due to the formation of an amorphous NIF-rich interface. Solid-state NMR spectroscopy indicated that NIF-EUD interactions were stronger than NIF-HPMC interactions. NIF/HPMC SPD exhibited weak interactions; thus, it failed to inhibit phase separation during the dissolution process and control NIF dissolution. The hygroscopicity of SPDs was higher with HPMC mixing and increased substitution ratio of methacrylic acid in EUD. Moreover, solid-state NMR spectroscopy revealed that the NIF-EUD interactions were hindered to a large extent by the absorbed water. During the dissolution process of NIF/HPMC/EUD-L SPD, the introduction of water to the NIF-EUD-L interaction site could induce the phase separation and poor controllability of NIF dissolution. Water-induced phase separation should be considered based on molecular-level characterization to obtain SDs with enhanced drug dissolution. An investigation of the molecular state change caused by the absorbed water using solid-state NMR spectroscopy will be helpful in understanding the dissolution mechanism of SDs.

Quantification of a cocrystal and its dissociated compounds in solid dosage form using transmission Raman spectroscopy.

The performance of transmission Raman spectroscopy (TRS) for quantifying a cocrystal and its dissociation in solid dosage form was investigated. Some tablets containing 0%-20% (w/w) of a cocrystal of carbamazepine (CBZ)/succinic acid (SUC), 0%-4% of CBZ, 0%-4% of SUC, and 75%-99% of D-mannitol were prepared. The Raman spectra of these tablets were preprocessed using the standard normal variate (SNV) or multiplicative scatter correction (MSC) as well as the Savitzky Golay second derivative, and then, these were used to generate calibration models using partial least squares (PLS) regression. The performance of the model was superior when the MSC preprocessing spectra of the cocrystal between 200 and 1800 cm-1 were used for calibration. The determination coefficient of the PLS calibration curve for the CBZ/SUC cocrystal between 200 and 1800 cm-1 with MSC was 0.97, root mean square error of cross validation (RMSECV) was 1.16, and root mean square error of prediction (RMSEP) was 1.10. As in the case of the CBZ/SUC cocrystal, the performance of the model was superior when the MSC preprocessing spectra of CBZ and SUC between 200 and 1800 cm-1 were used for calibration. These data suggest that TRS is useful for quantifying a cocrystal and its dissociation compounds in solid dosage forms.

Solid-State Quantification of Cocrystals in Pharmaceutical Tablets Using Transmission Low-Frequency Raman Spectroscopy.

To enable the continuous production of cocrystal-containing pharmaceutical tablets, guaranteeing the cocrystal content of the final pharmaceutical tablets in the solid state is critical. This study demonstrates the quantification of caffeine-glutaric acid cocrystals in model tablets using transmission low-frequency Raman spectroscopy. Although distinguishing between cocrystals and raw materials using conventional Raman spectroscopy is difficult, the use of low-frequency Raman spectroscopy enables the discrimination of cocrystals and raw materials. Low-frequency Raman spectra were analyzed by the partial least-squares method (PLS) to obtain the predicted contents in the model tablets. To evaluate the quantitative ability of this method, the root means square error of cross-validation (RMSECV) was determined by comparing the actual concentration and predicted content with a calibration curve. For cocrystal-containing tablets, the quantitative ability of the transmission mode (RMSECV = 2.06- 3.17) was 13.4-31.4% higher than that of the backscattering mode (RMSECV= 2.37- 3.91). The coexistence of raw crystalline materials did not affect the quantitative ability for cocrystals.

Pharmaceutical quantification with univariate analysis using transmission Raman spectroscopy.

The purpose of this study was to investigate the quantification performance of transmission Raman spectroscopy with univariate analysis. Model dosage forms containing acetaminophen and an excipient, lactose monohydrate, were prepared. The Raman spectra of the tablets were obtained using the modes of transmission, backscattering micro-spectroscopy, and wide area illumination. Calibration curves for quantification of acetaminophen in the tablets were created using peak heights of the Raman spectra. Of the three modes of measurement, the quantitative results by transmission had the highest correlation with those by conventional UV-vis methods. In the validation of quantification by the transmission mode with univariate analysis, a certain degree of daily variation was confirmed. Additionally, quantitative results using peak heights were compared with those of partial least squares (PLSs) multivariate analysis. The root mean square error of prediction (RMSEP) suggested that quantification using PLS provided better precision than the peak height method as expected. However, content uniformity test using large sample sizes by the Raman spectra is not required to be very highly predictive because they usually employ non-parametric criteria and include wide specification ranges. Therefore, univariate analysis using transmission Raman spectroscopy was a suitable quantitative method for conducting content uniformity tests of large sample sizes.

Analysis of inline-filter blockage with trastuzumab formulation using scanning-electron microscopy.

The instability of pharmaceutical monoclonal antibodies are affected by physical stimuli including, temperature, denaturant, surfactant, stirring, solid phase adsorption, oxidation, and ultraviolet rays. Clinically, we frequently experience precipitation during preparation of several pharmaceutical monoclonal antibodies for cancer. Although it is possible to remove precipitates in the injection solution during the preparation procedure, potential filter blockade during administration remains a problem with adverse effects on the quality of life of patients. Therefore we sought to investigate factors contributing to this phenomenon. To closely observed the mechanisms involved in blockade of filters during trastuzumab preparation, we prepared samples under the same conditions used in clinical practice and observed them comprehensively. The precipitates that caused filter blockade were observed when the samples were vigorously shaken and left for several hours after dissolving. The precipitates were identified as proteins. The vigorous shaking caused contact between the protein and air, which induced protein precipitation caused by the surfactants derived from the foam formation. We discovered that the external stimulation may cause the instability of monoclonal antibody preparations and, so, it is important for procedures to be as rapid to avoid precipitate formation as much as possible.

Transmission Low-Frequency Raman Spectroscopy for Quantification of Crystalline Polymorphs in Pharmaceutical Tablets.

The purpose of this study was to quantify polymorphs of active pharmaceutical ingredients in pharmaceutical tablets using a novel transmission low-frequency Raman spectroscopy method. We developed a novel transmission geometry for low-frequency Raman spectroscopy and compared quantitative ability in transmission mode versus backscattering mode using chemometrics. We prepared two series of tablets, (1) containing different weight-based contents of carbamazepine form III and (2) including different ratios of carbamazepine polymorphs (forms I/III). From the relationship between the contents of carbamazepine form III and partial least-squares (PLS) predictions in the tablets, correlation coefficients in transmission mode ( R2 = 0.98) were found to be higher than in backscattering mode ( R2 = 0.97). The root-mean-square error of cross-validation (RMSECV) of the transmission mode was 3.9 compared to 4.9 for the backscattering mode. The tablets containing a mixture of carbamazepine (I/III) polymorphs were measured by transmission low-frequency Raman spectroscopy, and it was found that the spectral shape changed according to the ratio of polymorphs: the relationship between the actual content and the prediction showed high correlation. These findings indicate that transmission low-frequency Raman spectroscopy possesses the potential to complement existing analytical methods for the quantification of polymorphs.

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.

[Comparison of Chemical Behavior of Original and Generic Docetaxel Formulations as Non-alcoholic Preparations: Discussion about Diluent Solvents for Docetaxel].

　Although generic anti-tumor agents are in wide clinical use, they have not in all cases been shown to be equivalent to the original agents after preparation. In the present study, original and generic docetaxel formulations were compared with respect to stability when prepared as a non-alcoholic solution for use. When the original formulation was diluted with physiological saline solution to make a non-alcoholic preparation, the concentration decreased with time, whereas no such decrease occurred when a preparation of the generic formulation was made in a similar manner. With both the original and generic formulations, no decrease in docetaxel concentration with time was found after dilution with 5% glucose solution. On the basis of these results, it is concluded that the behaviors of original and generic docetaxel formulations are not equivalent when prepared, but that the original and generic formulations can be taken to be equivalent if they are diluted with 5% glucose solution at preparation.

Solid dispersions of efonidipine hydrochloride ethanolate with improved physicochemical and pharmacokinetic properties prepared with microwave treatment.

Drug absorption into the body is known to be greatly affected by the solubility of the drug itself. The active pharmaceutical ingredient efonidipine hydrochloride ethanolate (NZ-105) is a novel 1,4-dihydropyridine calcium antagonist that has a very low solubility in water. It is classified as a poorly soluble drug, and improvements in its solubility and higher bioavailability with oral administration are needed. In this study, employing microwave technology as a new means to improve solubility, we established a method for preparing solid dispersions using hydroxypropyl methylcellulose acetate succinate as a polymeric carrier and urea as a third component. This effective method has a treatment time of several minutes (simple) and does not require the use of organic solvents (low environmental impact). The third component, urea, acts to lower the melting point of NZ-105, which promotes amorphization. This greatly improves the solubility compared with the microwave-treated product of NZ-105/HPMC-AS binary system. The solid dispersion prepared with this method, in addition to evaluation in vitro, was tested in vivo using beagle dogs and shown to be effective from the eightfold improvement in absorption compared with NZ-105 alone based on the area under the curve.

Characterization and Quality Control of Pharmaceutical Cocrystals.

Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

[Ultrafast-track Anesthesia (UFTA) in the Operating Room and the Anesthetic Management for Off-pump Coronary Artery Bypass (OPCAB)].

Currently, the immediate extubation in the operating room is necessary for the patients undergoing off-pump coronary artery bypass (OPCAB). To achieve UFTA, anesthesiologists should control general anesthesia. We report the case series of UFTA for the patients undergone OPCAB at our hospital. Forty patients receiving OPCAB between April 2012 and April 2014 were retrospectively analyzed. We divided the patients into those extubated in the operating room (Extubation group) and those not (Intubation group). The extubation criteria included adequate revascularization, adequate hemostasis, ratio between Pa(O2) and FI(O2) more than 250, body temperature above 36 degrees C, stable hemodynamics without noradrenaline, without IABP, and normal postoperative chest X-ray. Twenty-three patients (70% of the scheduled and 20% of the emergency patients) were included in our criteria and could be extubated in the operating room. One patient was re-intubated due to asthma attack following extubation in the operating room. The sucess rate of immediate extubation was 95.7% by our criteria. There were no significant differences in age, sex, BMI, duration of anesthesia, and amount of hemorrhage between the 2 groups. We believe that UFTA for OPCAB patients may be possible under carefull decision by extubation criteria.

In vitro and in vivo biocompatibility and corrosion behaviour of a bioabsorbable magnesium alloy coated with octacalcium phosphate and hydroxyapatite.

Octacalcium phosphate (OCP) and hydroxyapatite (HAp) coatings were formed on Mg-3 mass% Al-1 mass% Zn (AZ31) magnesium alloy by a single-step chemical solution deposition method. Chemically polished AZ31 (Cpol-AZ31) and HAp- and OCP-coated AZ31 (HAp- and OCP-AZ31) were immersed in a medium for 52 weeks or implanted in transgenic mice for 16 weeks to examine the long-term corrosion behaviour and in situ inflammation behaviour. In the medium, Mg-ion release was restricted for the initial several days and the corrosion rate thereafter was suppressed by approximately one-half with the HAp and OCP coatings. HAp-AZ31 showed a ∼20% lower corrosion rate than OCP-AZ31. Tissues of the transgenic mouse emit fluorescence in proportion to the degree of inflammation in situ. The luminescence intensity level was too low to be a problem regardless of the coatings. A thinner fibrous tissue layer was formed around OCP- and HAp-AZ31 than around Cpol-AZ31, indicating that the HAp and OCP coatings suppressed corrosion and foreign-body reaction in vivo. Visible pits were formed in filiform and round shapes in vitro and in vivo, respectively. Corrosion was observed underneath the coatings, and almost uniform corrosion took place in vitro, while local corrosion was predominant in vivo. These differences in corrosion morphology are attributed to the adhesion of tissues and the lower diffusivity on the surface in vivo than that in vitro. Dissolution behaviour of OCP crystals in vivo was different from that in vitro. It was demonstrated that the HAp and OCP coatings developed have great potential for a biocompatible and corrosion protection coating.