Takehisa Hanawa

Investigation of the release behavior of diethylhexyl phthalate from the polyvinyl-chloride tubing for intravenous administration

The release behavior of diethylhexyl phthalate (DEHP) from a polyvinyl-chloride (PVC) tube, which is part of an intravenous administration set, was investigated with the coexistence of polysorbate 80 (Tween 80) in various solutions such as physiological saline (PS), distilled water for injection (DWI) and glucose solution (TZ). The cumulative amount of DEHP released after 5 h was in the following order; PS, DWI > 50% TZ. From a comparison of the amount of released DEHP and the critical micelle concentration (CMC) of various solutions, the lower the CMC of the solution, the higher the amount of DEHP released from the PVC tubing. When the concentration of Tween 80 was kept constant at 1 mg/ml, the cumulative amount of DEHP released with a flow rate 90 ml/h was higher than that at 60 ml/h. These results suggest that the release of DEHP from the PVC tubing is closely correlated with the interaction of Tween 80 and DEHP such as the formation of micelles, the collision of micelles against the surface of the PVC tubing and the diffusion properties of DEHP and or Tween 80 in the liquid medium.

(S)-1-(4-Dimethylaminophenylcarbonyl)-3-aminopyrrolidine: a derivatization reagent for enantiomeric separation and sensitive detection of chiral carboxylic acids by LC/ESI-MS/MS.

A novel derivatization reagent, (S)-1-(4-dimethylaminophenylcarbonyl)-3-aminopyrrolidine (1-DAPAP), was developed for increasing the detection sensitivity and enantiomeric separation of chiral carboxylic acids by liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS). 1-DAPAP reacted with carboxylic acids at room temperature within 5min in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The epimerization (racemization) during the derivatization reaction was negligible. The resulting derivatives were highly responsive during the ESI-MS operating in the positive-ion mode and gave a characteristic product ion during the MS/MS, which enabled the sensitive detection using selected reaction monitoring; the detection responses of the 1-DAPAP-derivatives were increased by 10-1100-fold over the intact carboxylic acids and the limits of detection ranged from 0.97 and 5.2fmol on the column. The 1-DAPAP-derivatization was also effective for the enantiomeric separation of chiral carboxylic acids; the resolution values were 1.2-4.3 for the evaluated carboxylic acids. The derivatization procedure was successfully applied to biological sample analyses; the derivatization followed by LC/ESI-MS/MS enabled the separation and detection of trace amounts of ibuprofen and naproxen in human saliva with a simple pretreatment and small sample volume.

Development of Patient‐Friendly Preparations: Preparation of a New Allopurinol Mouthwash Containing Polyethylene(oxide) and Carrageenan

Stomatitis is a harmful side effect induced by high and/or multiple dosing of cytotoxic drugs such as 5‐fluorouracil. Allopurinol mouthwash has been used to prevent stomatitis induced by cancer chemotherapy. In the present study, the pharmaceutical utility of allopurinol mouthwash (Alkox‐mw), which consists of polyethylene(oxide) (Alkox®) and iota‐carrageenan (INA), was investigated as a possible material for a new oral dosage preparation for improving the adhesiveness onto the oral mucosa. From the observation of the gel formation, which was studied as a function of the variety of the added Alkox® and/or INA, the preferential compositions of Alkox®‐mw (Alkox®:INA% ratio) seemed to be 1.0:(0–1.0) and (0–3.0):0.4, respectively. The adhesiveness and the spinnability of various allopurinol mouthwashes were also investigated using a creep meter. The adhesiveness of Alkox‐mw increased with the increase in the amount of added Alkox®. Furthermore, the adhesion force of Alkox®‐mw was greater than that of allopurinol mouthwash consisting of sodium carboxymethylcellulose (CMC–Na). From the in vitro assessment of mimicking the effusion of the allopurinol mouthwashes from the surface of the oral mucosa, the effusion of Alkox®‐mws was retarded by the added Alkox. The results obtained in the present study suggest that Alkox®‐mws may be useful as a new dosage form that adheres to the oral mucosa.

New Oral Dosage Form for Elderly Patients. III. Stability of Trichlormethiazide in Silk Fibroin Gel and Various Sugar Solutions

The hydrolysis of trichlormethiazide (TCM) in silk fibroin gel (SFG) prepared in various sugar solutions (such as ribose, fructose, mannose, and glucose solutions) was determined. The hydrolysis rate of TCM differed with the variety of sugars utilized in this study; that is, it decreased in the following order: ribose > fructose > mannose > glucose. To investigate the relationship between the hydrolysis rate of TCM and the physicochemical properties of the sugar molecule, the amount of unfrozen water of sugar molecules was calculated from differential scanning calorimetry (DSC). The amount of unfrozen water increased with an increase in the number of the equatorial OH groups n(e–OH) per sugar molecule that are able to hydrate favorably to the surrounding water molecules. The hydrolysis rate constant decreased with increase in n(e–OH); glucose, having a large n(e–OH) in this study could effectively stabilize TCM.

A comparison of three different concentrations of ropivacaine with fentanyl for patient-controlled epidural analgesia.

BACKGROUND:The optimal concentration of ropivacaine in combination with fentanyl for patient-controlled epidural analgesia focusing on preservation of bowel function, analgesia, and motor function remains unclear. METHODS:Three hundred-twelve women scheduled to undergo gynecologic lower abdominal surgery, were randomly allocated to receive ropivacaine 0.05, 0.075, or 0.1% in combination with fentanyl 4 &mgr;g/mL and droperidol 25 &mgr;g/mL. The settings of patient-controlled epidural analgesia were as follows: initial loading volume 5 mL, background infusion 2 mL/h during night-time, no background infusion during daytime, bolus volume 2 mL, and lockout interval 10 min. Bowel function was evaluated by the first passage of flatus and feces. Pain was assessed with a visual analog scale, and motor function was examined by modified Bromage scale. Data were collected in the evening on the day of surgery, in the morning and in the evening on the first postoperative day, and in the morning on the second postoperative day. RESULTS:Gastrointestinal motility was not different among the three groups. All three solutions produced equivalent analgesia and no motor blockade. CONCLUSION:We conclude that ropivacaine 0.05% is sufficient to preserve gastrointestinal motility, and provides excellent postoperative pain relief without motor blockade.

Preparation and characterization of sealed heated mixture of sublimable compound and porous calcium silicate II: Investigation of the interaction between maltol and porous calcium silicate surface

Abstract A sealed heated mixture of maltol (Mal) and porous calcium silicate (Florite® RE:FR) was prepared by heating the physical mixture in a sealed container. The amorphization of the Mal crystals in the sealed heated mixture (FR:Mal=9:1 or 7:3) was observed by X-ray diffraction and differential scanning calorimetric measurements. At the same time, a marked discoloration was also observed in the sealed heated mixture, which showed a color change from initially white to yellow or light brown. On the basis of Fourier transform infrared spectroscopy, the discoloration seems to be due to the ionization of Mal molecules on the FR surface. The discoloration of the mixture during heating was accelerated by increasing the heating temperature and the heating time. The addition of colloidal silicon dioxide (Reolosil® QS-102:REO) affected the discoloration. It was found that an increase in an amount of REO added inhibited the discoloration during sealed heating.

Stability of the Powdered Dosage Form Prepared by Unsealing the Capsules: Water Vapor Sorption and Discoloration of the Powdery Contents of Clorazepate Dipotassium Capsules

The hygroscopicity of the contents of clorazepate dipotassium (Mendon®) capsules (CM) was investigated by storage at various relative humidities (RHs). The CM adsorbed water vapor significantly at more than 75% RH. At the same time, a marked discoloration of CM from white to yellow was also observed during storage. On the basis of differential scanning calorimetry (DSC) and Fourier transform (FT) Raman spectroscopy, the discoloration seemed to be due to the change in clorazepate dipotassium to nordiazepam and other substances. It was found that, when opening of the Mendon capsule is necessary to prepare the powdered dosage form, the CM should be stored below 60% RH to avoid the adsorption of water vapor and discoloration.

Preparation and Evaluation of Stomatitis Film Using Xyloglucan Containing Loperamide

Stomatitis induced by radiation therapy or cancer chemotherapy is a factor in sleep disorders and/or eating disorders, markedly decreasing patient quality of life. In recent years, disintegrating oral films that are easy to handle have been developed; therefore, we focused on the formulation of these films. We prepared an adhesive film for the oral cavity using xyloglucan (Xylo), which is a water-soluble macromolecule. We used loperamide, which has been reported to relieve pain caused by stomatitis effectively, as a model drug in this study. Films were prepared from Xylo solutions (3% (w/w)) and hypromellose (HPMC) solutions (1% (w/w)). Xylo and HPMC solutions were mixed at ratios of 1 : 1, 2 : 1, or 3 : 1 for each film, and films 2×2 cm weighing 3 g were prepared and dried at 37°C for 24 h. Physicochemical properties such as strength, adhesiveness, disintegration behavior, and dissolution of loperamide from films were evaluated. Films prepared from Xylo solution alone had sufficient strength and mucosal adhesion. On the other hand, films prepared from a mixture of Xylo and HPMC were inferior to those made from Xylo, but showed sufficient strength and mucosal adhesion and were flexible and easy to handle. The films prepared in this study are useful as adhesion films in the oral cavity.

Targeting miR‐223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds

Argonaute 2 bound mature microRNA (Ago2‐miRNA) complexes are key regulators of the wound inflammatory response and function in the translational processing of target mRNAs. In this study, we identified four wound inflammation‐related Ago2‐miRNAs (miR‐139‐5p, miR‐142‐3p, miR‐142‐5p, and miR‐223) and show that miR‐223 is critical for infection control. miR‐223Y/− mice exhibited delayed sterile healing with prolonged neutrophil activation and interleukin‐6 expression, and markedly improved repair of Staphylococcus aureus‐infected wounds. We also showed that the expression of miR‐223 was regulated by CCAAT/enhancer binding protein alpha in human neutrophils after exposure to S. aureus peptides. Treatment with miR‐223Y/−‐derived neutrophils, or miR‐223 antisense oligodeoxynucleotides in S. aureus‐infected wild‐type wounds markedly improved the healing of these otherwise chronic, slow healing wounds. This study reveals how miR‐223 regulates the bactericidal capacity of neutrophils at wound sites and indicates that targeting miR‐223 might be of therapeutic benefit for infected wounds in the clinic.

Study of Interaction between Fluorinated Coating Glass and the Medicines

 The adsorption of active pharmaceutical ingredients on the surface of medical devices such as polyvinl chloride, ethylene-vinyl acetate copolymer and glass often prevent the acuurate dose of drug. At dispensing of pharmaceuticals, mètre glass (MG) has been widely used for dispensing syrup. When measuring the viscous syrup, it often takes long time to dispense the accurate volume due to their adhesiveness on the glass surface. In this study, we investigate the adhesion of various syrups to MG made with uncoated glass or glass with a strongly hydrophobic silicone or fluorinated coating in terms of the following formulation parameters: viscosity, surface tension, contact angle, and surface free energy. The contact angles for syrups on the coated glass surfaces were significantly higher than those on the uncoated glass surface. In addition, the relationship between surface tension and contact angle was examined. We found that the contact angle was independent of surface tension for the uncoated glass, while it increased with increasing surface tension for the coated glasses. These results can be explained as follows: the silicone or fluorinated coatings inhibit the hydrogen bonding that usually takes place between water and silanol and siloxane groups at glass surfaces. The coatings reduced the surface free energy and increased the hydrophobicity of the glass, reduced its wettability by the syrups, and thus reduced the adhesion loss for the syrups. It was considered that as for the hydrophobic action, properties of matter of sample influence the coated device by coating in order that it is reinforced.