報告書 H22-2A-09

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のぶあきちとく
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1 TEL % 0.5% in vitro QOL Quality of Life 1

2 MCE mpa s Duck Algin 350M M/G C 20% 50 C 1.0% 5 C SV-10 5 C 10 ml E TV 20H model E 1 34 R24 1 ml 5 C rpm s -1 CR-500DX 8 ml 10 ml 37 C 2.0 cm 60 mm/min 2

3 In vitro 1) Viskase Co., Inc. 4 ml 2.67 cm 2 4 ml 37 C 60 strokes/min 244 nm ph ph 6.8 Higuchi 2) Eq.1 Q = 2C 0 ( ) 1 2 Dt π Eq. 1 Q C 0 t D In vivo g Wistar 1 g/kg i.p. 1.0 ml KN-349D 0.5 ml Ameer 3) HPLC AUC 6 MRT 4) 50 C 2.0% 20% 5) 2.0% 20% 2.0% 34.5 C 1.0% 32.0 C Fig C 3

4 6) ph 37 C ph % 0.25% % 2.0% % 2.0% % Fig % 2.0% 0.25, 0.5, 1.0% 37 C 6.07, 5.38, 8.34, kn/m % % Fig. 2) 2.0% 1.0% 2.0% % American Diabetic Association The National Dysphagic Diet Task Force NDD Task Force thin 1 50mPa s nectar-thick mPa s honey-thick mPa s spoon-thick >1750mPa s 7) 50 s -1 Fig s -1 NDD Task Force 0.25% honey-thick 0.5% spoon-thick 0.25% 4

5 0.75% 2.0% 0.5% in vitro Fig. 4A 2.0% 0.5% 2.0% 0.5% 1.0% in vitro 2.0% 2.0% 0.5% 30 1 ph % ph Fig. 4A Higuchi Fig. 4B 2.0% 2.0% 0.5% 2.0% 2.0% 0.5% Fig. 4B cm 2 /s in vivo Fig % 0.5% 2.0% 0.5% 1.0% 1.0 ml Table µg/ml 2.0% 2.0% 0.5% Fig. 5 Table 1 2.0% 0.5% C max t max MRT AUC (0 6h) 130% 5

6 Shimoyama T., Itoh K., Miyazaki S., D Emanuele A., Attwood D., Oral liquid in situ gelling methylcellulose/alginate formulations for sustained drug delivery to dysphagic patients, Drug Dev. Ind. Pharm., submitted. 1. Miyazaki S., Takeuchi S., Yokouchi C., Takada M., Pluronic F-127 gels as a vehicle for topical administration of anticancer agents, Chem. Pharm. Bull., 32, (1984). 2. Higuchi W. I., Analysis of data on the medicament release from ointments, J. Pharm. Sci., 51, (1962). 3. Ameer B., Greenblatt D. J., Divoll M., Abernethy D. R., Shargel L., High-performance liquid chromatographic determination of acetaminophen in plasma: single-dose pharmacokinetic studies, J. Chromatogr., 226, (1981). 4. Yamaoka K., Nagawara T., Uno T., Statistical moments in pharmacokinetics, J. Pharmacokinet. 6

7 Pharmacodyn., 6, (1978). 5. Itoh K., Hatakeyama T., Kimura T., Shimoyama T., Miyazaki S., D Emanuele A., Attwood D., Effect of D-sorbitol on the thermal gelation of methylcellulose formulations for drug delivery, Chem. Pharm. Bull., 58, (2010). 6. Haque A., Jones A. K., Richardson R. K., Morris E. R., Thermal gelation of methylcellulose: mechanism and structures, Carbohydr. Polym., 22, (1993). 7. National Dysphagia Diet Task Force, National Dysphagia Diet: Standardization for Optimal Care, ed. by Clayton J., American Dieteric Association, Chicago,

8 Fig. 1. Effect of alginate concentration on the gelation temperature of 2.0% methylcellulose solution containing 20% sorbitol. Each value is the mean ± S.E. of three determinations. Fig. 2. Shear rate dependence viscosity at 20 C of ( ) 1.0% alginate, ( ) 2.0% methylcellulose, and 2.0% methylcellulose/alginate solutions containing ( ) 0.25% alginate, ( ) 0.5% alginate, ( ) 0.75% alginate, and ( ) 1.0% alginate. Each value is the mean ± S.E. of three determinations. 8

9 Fig. 3. Stress-strain curves of gels of (a) 2.0% methylcellulose, (b) 2.0% methylcellulose/0.25% alginate, (c) 2.0% methylcellulose/0.5% alginate, and (d) 2.0% methylcellulose/1.0% alginate, prepared at 37 C for 24 h. Fig. 4. (A) Cumulative in vitro release of acetaminophen as a function of time and (B) Cumulative in vitro release of paracetamol per unit area, Q, as a function of square root of time from ( ) acetaminophen aqueous solution, ( ) 2.0% methylcellulose, ( ) 0.5% alginate, and ( ) 2.0% methylcellulose/0.5% alginate. Release was into simulated gastric fluid at ph 1.2, for a period of 1 h and subsequently into simulated intestinal fluid at ph 6.8, 37 C. Each value is the mean ± S.E. of four determinations. 9

10 Fig. 5. Plasma concentrations of acetaminophen in rats after oral administration of from ( ) aqueous solution, ( ) 2.0% methylcellulose, ( ) 0.5% alginate, and ( ) 2.0% methylcellulose /0.5% alginate. Each value is the mean ± S.E. of five determinations. * p<0.05, ** p<0.01, 2.0% methylcellulose/0.5% alginate is compared with aqueous solution. p<0.05, p<0.01, 2.0% methylcellulose is compared with aqueous solution. Table 1. Pharmacokinetic parameters of acetaminophen administrated from aqueous solution, methylcellulose gel, alginate gel and methylcellulose/alginate gel formed in situ in rat stomach. Formulation C max (µg/ml) t max (h) AUC (0-6 h) (µg h/ml) MRT (h) AUC formulation AUC aqueous solution Aqueous solution ± ± ± ± % Methylcellulose 4.98 ± 0.94 ** 0.90 ± ± ± 0.13 ** 0.89 ± % Alginate 7.18 ± 0.71 * 0.70 ± ± ± ± % Methylcellulose /0.5% alginate 5.30 ± 0.39 ** 1.60 ± 0.24 ** ± 1.30 ** 2.51 ± 0.11 ** 1.30 ± 0.13 Each value is the mean ± S.E. of five determinations. * p<0.05, ** p<0.01, compared with aqueous solution. 10

日本化学療法学会雑誌第51巻第2号

日本化学療法学会雑誌第51巻第2号 piperacillin piperacillin PIPC. g Cmax CL PIPC CL CLR CLNR CL PIPC g g Cmax PIPC Key words: piperacillin Piperacillin PIPC PIPC g g PIPC Cmax g g ml g g ml g g ml T T T PIPC g g T Ccr ml min AUCCmax PIPC