Kazuhiro Morimoto

Publications (51)130.34 Total impact

• Article: Enantioselective uptake of fexofenadine by Caco-2 cells as model intestinal epithelial cells.

  Kohei Togami, Yuka Tosaki, Sumio Chono, Kazuhiro Morimoto, Masataka Hayasaka, Hitoshi Tada
  [show abstract] [hide abstract]
  ABSTRACT: Objectives  Fexofenadine contains a chiral carbon in its chemical structure and is orally administered as a racemic mixture. This study evaluated the selective uptake of fexofenadine enantiomers by Caco-2 cells as a model of intestinal epithelial cells. Methods  R(+)-fexofenadine or S(-)-fexofenadine was applied to Caco-2 cells, followed by incubation. After incubation, the amounts of fexofenadine enantiomers in cells were determined. The kinetic parameters for the uptake of fexofenadine enantiomers by Caco-2 cells were estimated using the Michaelis-Menten equation. Key findings  The transporter-mediated uptake rate of R(+)-fexofenadine was 1.7-fold higher than that of S(-)-fexofenadine. The difference in transporter-mediated R(+)-fexofenadine and S(-)-fexofenadine uptake was completely diminished under ATP-depleted conditions and in the presence of organic anion transporter peptide (OATP) inhibitors. Also, a Dixon plot showed that each fexofenadine enantiomer was competitively inhibited by the other enantiomer. The ratio of R(+)-fexofenadine uptake to S(-)-fexofenadine uptake in the case of a racemic mixture was higher than that in the case of a single enantiomer. Conclusion  This study suggested that the selective absorption of fexofenadine enantiomers by intestinal epithelial cells might have been due to the selective uptake mediated by OATPs and that the difference in intestinal absorption was enhanced with a racemic mixture.
  The Journal of pharmacy and pharmacology. 01/2013; 65(1):22-29.
• Article: Aerosol-based efficient delivery of azithromycin to alveolar macrophages for treatment of respiratory infections.

  Kohei Togami, Sumio Chono, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The efficacy of aerosol-based delivery of azithromycin (AZM) for the treatment of respiratory infections caused by pathogenic microorganisms infected in alveolar macrophages (AMs) was evaluated by comparison with oral administration. The aerosol formulation of AZM (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer(®). The oral formulation of AZM (50 mg/kg) was used for comparison. Time-courses of concentrations of AZM in AMs following administration were obtained, and then the therapeutic availability (TA) was calculated. In addition, the area under the concentrations of AZM in AMs - time curve/minimum inhibitory concentration at which 90% of isolates ratio (AUC/MIC(90)) were calculated to estimate the antibacterial effects in AMs. The TA of AZM in AMs following administration of aerosol formulation was markedly greater than that following administration of oral formulation. In addition, the AUC/MIC(90) of AZM in AMs was markedly higher than the effective values. This indicates that the aerosol formulation could be useful for the treatment of respiratory infections caused by pathogenic microorganisms infected in AMs. This study suggests that aerosolized AZM is an effective pulmonary drug delivery system for the treatment of respiratory infections.
  Pharmaceutical Development and Technology 07/2012; · 1.36 Impact Factor
• Article: Aerosol-based efficient delivery of clarithromycin, a macrolide antimicrobial agent, to lung epithelial lining fluid and alveolar macrophages for treatment of respiratory infections.

  Kohei Togami, Sumio Chono, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: Macrolide antimicrobial agents are generally given by the oral route for the treatment of respiratory infections caused by pathogenic microorganisms infected in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs). However, because macrolides distribute to many different tissues via the blood after oral administration, systemic side effects are frequently induced. In contrast with oral administration, aerosolization may be an efficient method for delivering macrolides directly to ELF and AMs. In this study, the efficacy of aerosol-based delivery of clarithromycin (CAM), as a model macrolide, for the treatment of respiratory infections was evaluated by comparison with oral administration. The aerosol formulation of CAM (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer(®). The oral formulation of CAM (50 mg/kg) was used for comparison. Time courses of concentrations of CAM in ELF and AMs following administration were obtained, and then the bioavailability (BA) was calculated. In addition, the area under the concentrations of CAM in ELF and AMs-time curve/minimum inhibitory concentration at which 90% of isolates ratio [area under the curve (AUC/MIC(90))] were calculated to estimate the antibacterial effects in ELF and AMs. The BA of CAM in ELF and AMs following administration of aerosol formulation were markedly greater than that following administration of oral formulation. This indicates that the aerosol formulation is more effective in delivering CAM to ELF and AMs, compared with the oral formulation, despite a low dose. The AUC/MIC(90) of CAM in ELF and AMs were markedly higher than the effective values. This indicates that the aerosol formulation could be useful for the treatment of respiratory infections caused by pathogenic microorganisms infected in ELF and AMs. This study suggests that aerosol formulation of macrolides is an effective pulmonary drug delivery system for the treatment of respiratory infections.
  Journal of Aerosol Medicine and Pulmonary Drug Delivery 02/2012; 25(2):110-5. · 2.20 Impact Factor
• Article: Distribution characteristics of clarithromycin and azithromycin, macrolide antimicrobial agents used for treatment of respiratory infections, in lung epithelial lining fluid and alveolar macrophages.

  Kohei Togami, Sumio Chono, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The distribution characteristics of clarithromycin (CAM) and azithromycin (AZM), macrolide antimicrobial agents, in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) were evaluated. In the in vivo animal experiments, the time-courses of the concentrations of CAM and AZM in ELF and AMs following oral administration (50 mg/kg) to rats were markedly higher than those in plasma, and the area under the drug concentration-time curve (AUC) ratios of ELF/plasma of CAM and AZM were 12 and 2.2, and the AUC ratios of AMs/ELF were 37 and 291, respectively. In the in vitro transport experiments, the basolateral-to-apical transport of CAM and AZM through model lung epithelial cell (Calu-3) monolayers were greater than the apical-to-basolateral transport. MDR1 substrates reduced the basolateral-to-apical transport of CAM and AZM. In the in vitro uptake experiments, the intracellular concentrations of CAM and AZM in cultured AMs (NR8383) were greater than the extracellular concentrations. The uptake of CAM and AZM by NR8383 was inhibited by ATP depletors. These data suggest that the high distribution of CAM and AZM to AMs is due to the sustained distribution to ELF via MDR1 as well as the high uptake by the AMs themselves via active transport mechanisms.
  Biopharmaceutics & Drug Disposition 08/2011; 32(7):389-97. · 2.07 Impact Factor
• Source

  Available from: 217.219.214.30

  Article: Efficient drug delivery to lung epithelial lining fluid by aerosolization of ciprofloxacin incorporated into PEGylated liposomes for treatment of respiratory infections.

  Sumio Chono, Hirokazu Suzuki, Kohei Togami, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The efficacy of aerosolization of ciprofloxacin (CPFX) incorporated into PEGylated liposomes (PEGylated CPFX-liposomes) for the treatment of respiratory infections was evaluated. PEGylated CPFX-liposomes with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000] (particle size: 100 nm) were prepared, and the drug distribution characteristics in lung epithelial lining fluid (ELF) following aerosolization of PEGylated CPFX-liposomes were examined in rats. Furthermore, the antibacterial effects of PEGylated CPFX-liposomes in ELF were evaluated by pharmacokinetic/pharmacodynamic analysis. The elimination rate of CPFX from ELF following aerosolization of PEGylated CPFX-liposomes was significantly slower than that of CPFX incorporated into unmodified liposomes (unmodified CPFX-liposomes; particle size: 100 nm). According to pharmacokinetic/pharmacodynamic analysis, the PEGylated CPFX-liposomes exhibited potent antibacterial effects against pathogenic microorganisms in ELF. This study shows that PEGylated CPFX-liposomes are a useful aerosol-based pulmonary drug delivery system for the treatment of respiratory infections.
  Drug Development and Industrial Pharmacy 04/2011; 37(4):367-72. · 1.49 Impact Factor
• Source

  Available from: pharm.or.jp

  Article: [Effects of sperminated pullulans on the pulmonary absorption of insulin].

  Toshinobu Seki, Nanako Fukushi, Hiroto Maru, Soichiro Kimura, Sumio Chono, Yuya Egawa, Kazuhiro Morimoto, Hideo Ueda, Yasunori Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: Sperminated pullulans (SP) having different molecular weights (MWs) were prepared, and the enhancing effect on the pulmonary absorption of insulin in rats was examined. SP acted as enhancers of insulin absorption when a 0.1% solution was applied with insulin simultaneously and their enhancing effects depended on the MW of the SP; the same solutions exhibited low toxicity in the in vivo LDH leaching test. In the in vitro experiments using Calu-3 cells, tight junction-opening effects and a toxic effect of SP in the MTT assay were observed at lower concentrations compared with the in vivo experiments. A mucus layer might interfere with the interaction between SP and the cell surface and might suppress both these effects and toxicity. SP having a high MW will be useful for preparing safe and efficient formulations of peptide and protein drugs. The change in the localization of the tight junction proteins may be related to the permeation-enhancing mechanism of SP.
  Yakugaku zasshi journal of the Pharmaceutical Society of Japan 02/2011; 131(2):307-14. · 0.39 Impact Factor
• Article: Aerosol-based efficient delivery of telithromycin, a ketolide antimicrobial agent, to lung epithelial lining fluid and alveolar macrophages for treatment of respiratory infections.

  Kohei Togami, Sumio Chono, Toshinobu Seki, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The efficacy of aerosol-based delivery of telithromycin (TEL), as a model antimicrobial agent, for the treatment of respiratory infections was evaluated by comparison with oral administration. The aerosol formulation (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer. The time courses of the concentration of TEL in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) following administration of an aerosol formulation to rat lungs were markedly higher than that following the administration of an oral formulation (50 mg/kg). The time course of the concentrations of TEL in plasma following administration of the aerosol formulation was markedly lower than that in ELF and AMs. These results indicate that the aerosol formulation is more effective in delivering TEL to ELF and AMs, compared to the oral formulation, despite a low dose and it avoids distribution of TEL to the blood. In addition, the antibacterial effects of TEL in ELF and AMs following administration of the aerosol formulation were estimated by pharmacokinetics/pharmacodynamics analysis. The concentrations of TEL in ELF and the AMs time curve/minimum inhibitory concentration of TEL ratio were markedly higher than the effective values. This study indicates that an antibiotic aerosol formulation may be an effective pulmonary drug delivery system for the treatment of respiratory infections.
  Drug Development and Industrial Pharmacy 07/2010; 36(7):861-6. · 1.49 Impact Factor
• Article: Intracellular pharmacokinetics of telithromycin, a ketolide antibiotic, in alveolar macrophages.

  Kohei Togami, Sumio Chono, Toshinobu Seki, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: Telithromycin, a ketolide antibiotic, has an antibacterial range that covers intracellular parasitic pathogens that survive or multiply intracellularly in alveolar macrophages. The intracellular pharmacokinetics of TEL in alveolar macrophages was evaluated in vitro. Telithromycin (50 microm) was applied to NR8383 as cultured alveolar macrophages, followed by incubation at 37 degrees C or 4 degrees C. After incubation, the amount of telithromycin in cells was determined. Telithromycin exhibited high accumulation in NR8383 and its intracellular accumulation was temperature dependent. Also, telithromycin distributed to the organelles and cytosol in NR8383 and, in particular, it accumulated in the acidic organelle compartments. This study suggests that the high accumulation of telithromycin in NR8383 is due to its high influx via active transport systems and trapping in acidic organelles, such as lysosomes. Moreover, this study provides important information for optimizing the treatment of respiratory intracellular parasitic infections based on the intracellular pharmacokinetics of antibiotics and parasitic sites.
  The Journal of pharmacy and pharmacology. 01/2010; 62(1):71-5.
• Article: Effect of surface-mannose modification on aerosolized liposomal delivery to alveolar macrophages.

  Sumio Chono, Keita Kaneko, Eri Yamamoto, Kohei Togami, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The effect of surface-mannose modification on aerosolized liposomal delivery to alveolar macrophages (AMs) was evaluated in vitro and in vivo. 4-Aminophenyl-α-D-mannopyranoside (Man) was used for surface-mannose modification, and mannosylated liposomes with various mannosylation rates (particle size: 1000 nm) were prepared. In the in vitro uptake experiments, the uptake of mannosylated liposomes by AMs was increased with the increase in the mannosylation rate over the range 2.4-9.1 mol% Man and became constant at over 9.1%. Thus, the most efficient mannosylation rate was 9.1 mol% Man. Furthermore, free mannose inhibited the uptake of mannosylated liposomes by AMs. This indicates that the uptake mechanism of mannosylated liposomes by AMs is mannose receptor-mediated endocytosis. In the in vivo animal experiments, the mannosylated liposomes (mannosylation rate, 9.1 mol% Man) were more efficiently delivered to AMs after pulmonary aerosolization to rats than nonmodified liposomes and did not harm lung tissues. These results indicate that surface-mannose modification is useful for efficient aerosolized liposomal delivery to AMs.
  Drug Development and Industrial Pharmacy 09/2009; 36(1):102-7. · 1.49 Impact Factor
• Article: Aerosolized liposomes with dipalmitoyl phosphatidylcholine enhance pulmonary insulin delivery.

  Sumio Chono, Rie Fukuchi, Toshinobu Seki, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The pulmonary insulin delivery characteristics of liposomes were examined. Aerosolized liposomes containing insulin were administered into rat lungs and the enhancing effect on insulin delivery was evaluated by changes of plasma glucose levels. Liposomes with dipalmitoyl phosphatidylcholine (DPPC) enhanced pulmonary insulin delivery in rats, however, liposomes with dilauroyl, dimyristoyl, distearoyl or dioleoyl phosphatidylcholine did not. Liposomes with DPPC also enhanced the in vitro permeation of FITC dextran (Mw 4400, FD-4) through the calu-3 cell monolayer by reducing the transepithelial electrical resistance and did not harm lung tissues in rats. These findings suggest that liposomes with DPPC enhance pulmonary insulin delivery by opening the epithelial cell space in the pulmonary mucosa not mucosal cell damage. Liposomes with DPPC could be useful as a pulmonary delivery system for peptide and protein drugs.
  Journal of Controlled Release 05/2009; 137(2):104-9. · 5.73 Impact Factor
• Article: Distribution characteristics of telithromycin, a novel ketolide antimicrobial agent applied for treatment of respiratory infection, in lung epithelial lining fluid and alveolar macrophages.

  Kohei Togami, Sumio Chono, Toshinobu Seki, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The distribution characteristics of telithromycin (TEL), a novel ketolide antimicrobial agent, in lung epithelial fluid (ELF) and alveolar macrophages (AMs) were evaluated. In vivo animal experiments, the time-courses of the concentrations of TEL in ELF and AMs following oral administration of TEL solution (50 mg/4 mL/kg) to rats were markedly higher than in plasma, and areas under drug concentration-time curve (AUC) ratios of ELF/plasma and AMs/plasma were 2.4 and 65.3, respectively. In vitro transport experiments, the basolateral-to-apical transport of TEL through model lung epithelial cell (Calu-3) monolayers was greater than apical-to-basolateral transport. Rhodamine123 and verapamil, MDR1 substrates, reduced the basolateral-to-apical transport of TEL. In vitro uptake experiments, the intracellular equilibrated concentration of TEL in cultured AMs (NR8383) was approximately 40 times the extracellular concentration. The uptake of TEL by NR8383 was inhibited by rotenone and FCCP, ATP depletors and was temperature-dependent. These data suggest that the high distribution of TEL to AMs is due to the sustained distribution to ELF via MDR1 as well as the high uptake by AMs themselves via active transport mechanisms.
  Drug Metabolism and Pharmacokinetics 01/2009; 24(5):411-7. · 2.32 Impact Factor
• Article: Efficient drug delivery to alveolar macrophages and lung epithelial lining fluid following pulmonary administration of liposomal ciprofloxacin in rats with pneumonia and estimation of its antibacterial effects.

  Sumio Chono, Tomoharu Tanino, Toshinobu Seki, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The efficacy of pulmonary administration of liposomal ciprofloxacin (CPFX) in pneumonia was evaluated. In brief, the pharmacokinetics following pulmonary administration of liposomal CPFX (particle size, 1,000 nm; dose, 200 microg/kg) were examined in rats with lipopolysaccharide-induced pneumonia as an experimental pneumonia model. Furthermore, the antibacterial effects of liposomal CPFX against the pneumonic causative organisms were estimated by pharmacokinetic/pharmacodynamic (PK/PD) analysis. The time-courses of the concentration of CPFX in alveolar macrophages (AMs) and lung epithelial lining fluid (ELF) following pulmonary administration of liposomal CPFX to rats with pneumonia were markedly higher than that following the administration of free CPFX (200 microg/kg). The time course of the concentrations of CPFX in plasma following pulmonary administration of liposomal CPFX was markedly lower than that in AMs and ELF. These results indicate that pulmonary administration of liposomal CPFX was more effective in delivering CPFX to AMs and ELF compared with free CPFX, and it avoids distribution of CPFX to the blood. According to PK/PD analysis, the liposomal CPFX exhibited potent antibacterial effects against the causative organisms of pneumonia. This study indicates that pulmonary administration of CPFX could be an effective technique for the treatment of pneumonia.
  Drug Development and Industrial Pharmacy 10/2008; 34(10):1090-6. · 1.49 Impact Factor
• Article: Efficient drug targeting to rat alveolar macrophages by pulmonary administration of ciprofloxacin incorporated into mannosylated liposomes for treatment of respiratory intracellular parasitic infections.

  Sumio Chono, Tomoharu Tanino, Toshinobu Seki, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The efficacy of pulmonary administration of ciprofloxacin (CPFX) incorporated into mannosylated liposomes (mannosylated CPFX-liposomes) for the treatment of respiratory intracellular parasitic infections was evaluated. In brief, mannosylated CPFX-liposomes with 4-aminophenyl-a-d-mannopyranoside (particle size: 1000 nm) were prepared, and the drug targeting to alveolar macrophages (AMs) following pulmonary administration was examined in rats. Furthermore, the antibacterial and mutant prevention effects of mannosylated CPFX-liposomes in AMs were evaluated by pharmacokinetic/pharmacodynamic (PK/PD) analysis. The targeting efficiency of CPFX to rat AMs following pulmonary administration of mannosylated CPFX-liposomes was significantly greater than that of CPFX incorporated into unmodified liposomes (unmodified CPFX-liposomes; particle size: 1000 nm). According to PK/PD analysis, the mannosylated CPFX-liposomes exhibited potent antibacterial effects against many bacteria although unmodified CPFX-liposomes were ineffective against several types of bacteria, and the probability of microbial mutation by mannosylated CPFX-liposomes was extremely low. The present study indicates that mannosylated CPFX-liposomes as pulmonary administration system could be useful for the treatment of respiratory intracellular parasitic infections.
  Journal of Controlled Release 05/2008; 127(1):50-8. · 5.73 Impact Factor
• Article: Effects of sperminated polymers on the pulmonary absorption of insulin.

  Toshinobu Seki, Nanako Fukushi, Sumio Chono, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: Sperminated pullulans (SP) and gelatin (SG) having different numbers of amino groups were prepared as sperminated polymers for absorption enhancement and the absorption-enhancing effects on the pulmonary absorption of insulin in rats and the permeation of FITC-dextran (MW 4400, FD4) through Calu-3 cell monolayers were evaluated. In both in vivo and in vitro experimental systems, SP and SG acted as enhancers and their enhancing effects correlated with the amino group content. The zeta potential of red blood cells treated with SP and SG was positive and the degree was also correlated with the amino group content. SP and SG interact directly with the luminal surface of mucus membranes via an ion-ion interaction and then may induce signals that open tight junctions resulting in intercellular permeation of water soluble drugs.
  Journal of Controlled Release 03/2008; 125(3):246-51. · 5.73 Impact Factor
• Article: Design of cationic microspheres based on aminated gelatin for controlled release of peptide and protein drugs.

  Kazuhiro Morimoto, Sumio Chono, Tadashi Kosai, Toshinobu Seki, Yasuhiko Tabata
  [show abstract] [hide abstract]
  ABSTRACT: Two different types of cationized microspheres based on a native cationic gelatin (NGMS) and aminated gelatin with ethylendiamine (CGMS) were investigated for the controlled release of three model acidic peptide/protein drugs with different molecular weights (MWs) and isoelectric points (IEPs). Recombinant human (rh)-insulin (MW: 5.8 kDa, IEP: 5.3), bovine milk lactoalbumin, BMLA (MW: 14 kDa, IEP: 4.3), and bovine serum albumin (BSA MW: 67 kDa, IEP: 4.9) were used as model acidic peptide/protein drugs. The in vitro release profiles of these acidic peptide/protein drugs from NGMS and CGMS were compared and different periods of cross-linking were obtained. The slower release of these acidic peptide/protein drugs from CGMS compared with those from NGMS with cross-linking for 48 hr. was caused by the suppression of burst release during the initial phase. The degree of suppression of burst release of the three peptide/protein drugs during the initial phase by CGMS was in the following order: (rh)-insulin > BMLA > BSA. The release of insulin with a lower molecular weight from CGMS was particularly suppressed compared with the other two drugs with higher molecular weights in the initial phase. The control of the release rate of acidic peptide/protein drugs from gelatin microsphere can be achieved by amination of gelatin. Therefore, CGMS is useful for the controlled release of acidic peptide/ protein drugs.
  Drug Delivery 02/2008; 15(2):113-7. · 1.46 Impact Factor
• Article: Evaluation of the establishment of a tight junction in Caco-2 cell monolayers using a pore permeation model involving two different sizes.

  Toshinobu Seki, Sonoko Harada, Osamu Hosoya, Kazuhiro Morimoto, Kazuhiko Juni
  [show abstract] [hide abstract]
  ABSTRACT: The tight junction formation in Caco-2 cell monolayers was compared after 9 and 13 d of culture. Four different sized paracellular markers were simultaneously applied to the apical side of the monolayers. The transepithelial resistance and permeability coefficient of mannitol for the monolayers cultured for 13 d were 17.4 and 0.095 times those after 9 d, respectively. The tight junction structure developed during that period. The pore permeation model involving two different sizes was used to quantitatively evaluate the paracellular pathways. The results suggest that there were two-different sized (large and small) pathways in the monolayers cultured for 13 d, while there was only a single large pathway in those cultured for 9 d. The small pathway in the monolayers cultured for 13 d might be a major permeation pathway for the paracellular permeation of urea and the equivalent cylindrical pore radius of the small pathway was less than 0.4 nm, suggesting development of the tight junctions after 13 d.
  Biological & Pharmaceutical Bulletin 02/2008; 31(1):163-6. · 1.66 Impact Factor
• Article: Enhancement of the dissolution rate and gastrointestinal absorption of pranlukast as a model poorly water-soluble drug by grinding with gelatin.

  Sumio Chono, Eri Takeda, Toshinobu Seki, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The effect of grinding with gelatin on the dissolution behavior and gastrointestinal absorption of a poorly water-soluble drug was evaluated using the antiasthmatic agent, pranlukast, as a model poorly water-soluble drug. A ground pranlukast-gelatin mixture was prepared by grinding equal quantities of pranlukast and gelatin. In the dissolution testing, the dissolution rate of pranlukast in the suspension of the ground pranlukast-gelatin mixture under conditions of pH 3.0, 5.0 and 7.0 was markedly faster than that in the suspension of pranlukast. According to powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC) analysis, the enhanced dissolution rate of pranlukast produced by grinding with gelatin was caused by changing the crystalline state of pranlukast into an amorphous state. In an animal experiment, the bioavailability of pranlukast following oral administration of the ground pranlukast-gelatin mixture to rats was threefold greater than that following administration of pranlukast. In the in vitro permeation experiment, the amount of permeated pranlukast through Caco-2 cell monolayers after application of the ground pranlukast-gelatin mixture was greater than that after application of pranlukast. These results suggest that the enhancement of the gastrointestinal absorption of pranlukast by grinding with gelatin is due to enhancement of the dissolution rate. Grinding a poorly water-soluble drug with gelatin is a useful method of enhancing its gastrointestinal absorption.
  International Journal of Pharmaceutics 02/2008; 347(1-2):71-8. · 3.35 Impact Factor
• Article: Effects of a sperminated gelatin on the nasal absorption of insulin.

  Toshinobu Seki, Hiroshi Kanbayashi, Sumio Chono, Yasuhiko Tabata, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The effects of a sperminated gelatin (SG), which was prepared as a candidate absorption enhancer by the addition of spermine to gelatin, on the nasal absorption of insulin, were examined in rats. The AUC of immuno-reactive insulin levels in the plasma after nasal administration of insulin were increased 5.3-fold by addition of 0.2% SG, and the plasma glucose levels fell in a manner dependent on the insulin levels. In Calu-3 cell monolayer permeation experiments, SG showed significant enhancing effects on 5(6)-carboxyfluorescein (CF), FITC-dextran (MW 4400, FD4) and insulin. Evaluation of the tight junctions in the Calu-3 cell monolayers based on the Renkin molecular sieving function suggests that the pore occupancy/length ratio of the permeation pathways for water-soluble molecules in the tight junctions increases, while the equivalent cylindrical pore radius is not changed by SG treatment. SG may transform the true tight junctions, which act as a barrier for water-soluble molecules, into pathways for CF and FD4 to increase their number. SG is a good candidate for a safe absorption enhancer to produce a slight modification of the permeability of the paracellular pathway of mucosal membranes, while retaining the sieving property of the epithelial membranes.
  International Journal of Pharmaceutics 07/2007; 338(1-2):213-8. · 3.35 Impact Factor
• Article: Pharmacokinetic and pharmacodynamic efficacy of intrapulmonary administration of ciprofloxacin for the treatment of respiratory infections.

  Sumio Chono, Tomoharu Tanino, Toshinobu Seki, Kazuhiro Morimoto
  [show abstract] [hide abstract]
  ABSTRACT: The pharmacokinetic and pharmacodynamic efficacy of intrapulmonary administration of ciprofloxacin (CPFX) for the treatment of respiratory infections caused by pathogenic microorganisms resisting sterilization systems of alveolar macrophages (AMs) was evaluated by comparison with an oral administration. The time-courses of the concentration of CPFX in AMs and lung epithelial lining fluid (ELF) following intrapulmonary administration of CPFX solution to rats (200 microg/kg) were markedly higher than that following oral administration (10 mg/kg). The time-course of the concentrations of CPFX in plasma following intrapulmonary administration was markedly lower than that in AMs and ELF. These results indicate that intrapulmonary administration is more effective in delivering CPFX to AMs and ELF, compared with oral administration, in spite of a low dose and it avoids distribution of CPFX to the blood. In addition, the antibacterial effects of CPFX in AMs and ELF following intrapulmonary administration were evaluated by pharmacokinetics/pharmacodynamics analysis. The concentration of CPFX in AMs and ELF-time curve (AUC)/minimum inhibitory concentration of CPFX (MIC) ratio and the maximum concentration of CPFX in AMs and ELF (Cmax)/MIC ratio were markedly higher than the effective values. The present study indicates that intrapulmonary administration of CPFX is an effective technique for the treatment of respiratory infections.
  Drug Metabolism and Pharmacokinetics 05/2007; 22(2):88-95. · 2.32 Impact Factor
• Article: A novel preparation method for microspheres of water soluble polymers using polypropyleneglycol as the dispersion medium.

  Toshinobu Seki, Katsunori Shinohara, Naoko Kato, Masaki Uchida, Hideshi Natsume, Kazuhiro Morimoto, Kazuhiko Juni
  [show abstract] [hide abstract]
  ABSTRACT: Polypropyleneglycol (PPG) was used as a dispersion medium for the preparation of microspheres (MS) consisting of starch, gelatin, whey protein or dextran. Aqueous solutions of the polymers were dispersed in PPG at various initial temperatures and then the systems were cooled to 0.5 degrees C to allow water in the dispersed phase to dissolve in PPG. The particle size of the starch-MS was dependent on the initial temperature of PPG in the preparation process. There were two different processes for particle generation in the procedure. One of them was via the formation of a temporary emulsion during the early phase of dispersion of the aqueous polymer solution into PPG. The other was via the stable emulsion in which the aqueous polymer solution was dispersed in water-saturated PPG. The particle size generated in the former process was dependent on the initial temperature: a high temperature gave large particles but a low temperature gave small particles, while that in the latter process was temperature-independent. This preparation method for MS will be useful for the formulation of heat-sensitive material, such as protein-containing drugs.
  CHEMICAL & PHARMACEUTICAL BULLETIN 04/2007; 55(3):403-6. · 1.59 Impact Factor