Biomedical subjects

Yoshiharu Machida

Publications and source records attributed to Yoshiharu Machida.

At least 37 records · Page 2Linked to original sources

PubMed2004

Acetaminophen-containing chewable tablets with suppressed bitterness and improved oral feeling.

The aim of this study was to develop acetaminophen chewable tablets with suppressed bitterness and improved oral feeling by examination of hard fats as the matrix base and of sweetening agents as corrigents. Witepsol H-15, W-35, S-55, E-75 and E-85, and Witocan H and 42/44 were used as hard fats. Witocan H and 42/44 were selected in view of improved oral feeling. Witocan H/Witocan 42/44 mixture tablets showed different melting characteristics and drug release rates dependent on their ratios, and those with the Witocan H/Witocan 42/44 ratio of 92.5% (w/w) and more showed good drug release. Sucrose, xylitol, saccharin, saccharin sodium, aspartame and sucralose were used as sweetening agents, and applied alone or with Benecoat BMI-40 or cocoa powder. The Witocan H tablet with 1% (w/w) saccharin plus 5% (w/w) Benecoat BMI-40 (Sc1-B5), and the Witocan H/Witocan 42/44 (92.5:7.5, w/w) mixture tablet with 1% (w/w) aspartame plus 5% (w/w) Benecoat BMI-40 suppressed bitterness and sweetness excellently, but the former tablet showed better drug release. Thus, the Witocan H tablet with Sc1-B5 is suggested as the best acetaminophen chewable tablet, exhibiting suppressed bitterness, low sweetness, improved oral feeling and good drug release.

Acetaminophen↗

PubMed2004

Antitumor characteristics of methoxypolyethylene glycol-poly(DL-lactic acid) nanoparticles containing camptothecin.

The novel nanoparticles (CPT-NP) were prepared by the solvent evaporation method using methoxypolyethylene glycol-poly(DL-lactic acid) block copolymer as a matrix and camptothecin (CPT) as an antitumor agent, and the antitumor characteristics were examined in vitro and in vivo. The mean diameter of CPT-NP was approximately 250 nm. The drug release from CPT-NP in phosphate-buffered saline, pH 7.4, depended on the particle concentration; in the diluted condition, the initial rapid release was greater and subsequent gradual release was faster. After i.v. administration (0.5 mg CPT eq./kg) in rats, CPT-NP showed a longer plasma retention than CPT solution. In both single (2.5 mg CPT eq./kg) and double (2.5 mg CPT eq./kg x 2) administration to mice bearing sarcoma 180 solid tumor, CPT-NP were much more effective than CPT solution; especially, the tumor disappeared completely in three of the four mice in twice administration of CPT-NP, when the body weight did not decrease markedly. After i.v. administration to the tumor-bearing mice, CPT-NP showed better plasma retention, and high and long tumor localization. CPT-NP are suggested to greatly improve the efficacy of CPT due to their pharmacokinetic features.

Animals↗

PubMed2004

Comparison of intraperitoneal continuous infusion of floxuridine and bolus administration in a peritoneal gastric cancer xenograft model.

PURPOSE: To identify the optimal schedule for intraperitoneal (i.p.) infusion of floxuridine (FUDR) against peritoneal micrometastases from gastric cancer. METHODS: The efficacy of continuous i.p. infusion of FUDR was compared with that of bolus i.p. administration in peritoneal gastric cancer (MKN45) xenografts. The FUDR continuous delivery system in this study was in the form of injectable poly(lactic-coglycolic) acid (PLGA) microspheres intended for i.p. injection. Animals were treated by continuous i.p. infusion using FUDR-loaded microspheres or bolus i.p. administration of FUDR. RESULTS: In vitro testing demonstrated that FUDR was released slowly from the microspheres at a rate of approximately 5% of the total encapsulated drug per day. In in vivo studies, the peritoneal level was found to persist and was approximately 5- to 50-fold higher than that of plasma for more than 2 weeks following a single injection of the microspheres. An in vitro MTT assay showed that exposure time clearly influenced the cytotoxic potency of FUDR. In vivo, continuous infusion was more effective against peritoneal tumor than bolus administration at equivalent doses. However, compared with bolus administration, toxicity was increased, resulting in a reduced maximum tolerated dose (MTD) with continuous infusion. When the treatment was carried out at each MTD (continuous 1 mg/kg, bolus 600 mg/kg), continuous infusion had no advantage in inhibiting tumor growth. CONCLUSIONS: Owing to the higher toxicity and the equal efficacy of continuous infusion compared with bolus administration, continuous infusion is not recommended in i.p. FUDR treatment.

Animals↗

PubMed2004

Evaluation of the bioavailability of flurbiprofen and its beta-cyclodextrin inclusion complex in four different doses upon oral administration to rats.

The dissolution profiles of flurbiprofen (Flu) and its beta-cyclodextrin inclusion complex (Flu/beta-CD) in buffer solutions at various pH values were examined. The percent dissolved at 15 min for Flu and Flu/beta-CD was almost 100% at pH 6.8 and 8.0 but the dissolution rate of Flu was extremely reduced at pH 1.2 and 4.0. In these lower pH conditions, Flu/beta-CD improved the dissolution rate of Flu. The percent dissolved at 1 h for Flu/beta-CD at pH 1.2 and 4.0 were 33.4 and 41.3%, respectively, and about 10 times larger than those for Flu. The oral bioavailability of Flu from Flu or Flu/beta-CD at doses of 1, 3, 10, and 30 mg/kg (as Flu) was examined in rats. An apparent linear relationship between doses and C(max) and AUC was observed after administration of Flu and Flu/beta-CD. The Flu C(max) and AUC values at 30 mg/kg, however, were much lower than would have been predicted from doses of 1-10 mg/kg. Those of Flu/beta-CD were also lower than the predicted values, but the gap was quite small. The results suggest that the absorption of Flu in rats was saturated at 10 mg/kg, and that the enhanced dissolution rate of Flu/beta-CD increased the saturation dose to 30 mg/kg.

Administration, Oral↗

PubMed2004

N-succinyl-chitosan as a drug carrier: water-insoluble and water-soluble conjugates.

N-succinyl-chitosan (Suc-Chi) has favourable properties as a drug carrier such as biocompatibility, low toxicity and long-term retention in the body. It was long retained in the systemic circulation after intravenous administration, and the plasma half-lives of Suc-Chi (MW: 3.4 x 10(5); succinylation degree: 0.81 mol/sugar unit; deacetylation degree: 1.0 mol/sugar unit) were ca. 100.3h in normal mice and 43 h in Sarcoma 180-bearing mice. The biodistribution of Suc-Chi into other tissues was trace apart from the prostate and lymph nodes. The maximum tolerable dose for the intraperitoneal injection of Suc-Chi to mice was greater than 2 g/kg. The water-insoluble and water-soluble conjugates could be prepared using a water-soluble carbodiimide and mitomycin C (MMC) or using an activated ester of glutaric MMC. In vitro release characteristics of these conjugates showed similar patterns, i.e. a pH-dependent manner, except that water-insoluble conjugates showed a slightly slower release of MMC than water-soluble ones. The conjugates of MMC with Suc-Chi showed good antitumour activities against various tumours such as murine leukaemias (L1210 and P388), B16 melanoma, Sarcoma 180 solid tumour, a murine liver metastatic tumour (M5076) and a murine hepatic cell carcinoma (MH134). This review summarizes the utilization of Suc-Chi as a drug carrier for macromolecular conjugates of MMC and the therapeutic efficacy of the conjugates against various tumours.

Animals↗

PubMed2004

Glycyrrhetic acid-loaded microparticles: liver-specific delivery and therapeutic potential against carbon tetrachloride-induced hepatitis.

The microparticles (MPs) of an anti-hepatotoxic drug, glycyrrhetic acid (GLA), were prepared using poly(DL-lactic acid-co-glycolic acid) as a drug carrier, and their in-vitro properties, biodistribution and therapeutic effects were investigated. The MPs showed a particle diameter distribution of 1.0-1.4 microm and a drug content of approximately 10% (w/w). In the in-vitro release in a mixture of methanol and phosphate-buffered saline pH 7.4 (3:7, v/v), slow release was observed after an initial burst release of approximately 30% (w/w). After i.v. administration of MPs in normal mice, GLA was mainly distributed to the liver. After i.v. administration in normal mice, the MPs maintained a much higher liver concentration than did GLA solution, and the plasma concentration also tended to be higher for MPs than for GLA solution. As to therapeutic effect, the liver was damaged by repeated injection of carbon tetrachloride (CCl(4)) in mice every 48 h, and the drugs were administered intravenously as a single dose 3 h after the first injection of CCl(4). At 10 mg GLA eq. kg(-1), the MPs significantly suppressed the plasma level of glutamic pyruvic transaminase for at least 141 h after administration, while GLA solution did not become significantly effective within 45 h post-administration. MPs are suggested as a possible useful system to prolong the therapeutic effect of GLA.

Animals↗

PubMed2003

In vitro characteristics of liposomes and double liposomes prepared using a novel glass beads method.

A novel preparative method for liposomes and double liposomes (DL) using glass beads was superior to a glass-filter method developed previously. Lipid dissolved in chloroform was poured into a kjeldahl flask with glass beads (BZ-04, 0.350-0.500 mm phi; BZ-3, 2.794-3.962 mm phi; or BZ-6, 5.613-6.680 mm phi), and the organic solvent was evaporated. The lipid layer that formed on the glass beads was hydrated with 1.5 ml of the suspension of inner liposomes at a temperature above the phase transition temperature of the lipids employed, and was agitated vigorously. Erythrosine (ER) was used as a model drug. The size of liposomes prepared by the glass beads method depended on the size of the glass beads. The size of the liposomes became smaller as glass beads with a smaller size were used. A high encapsulation efficiency was observed when glass bead blends consisting of two different sizes were used. Large sizes (BZ-3/BZ-6) had a tendency to show high encapsulation efficiency and size also played an important role in the formation of liposomes. DL formation inhibited the release of ER and DL formative efficiency was markedly improved by means of the glass beads method. These findings suggested that the glass beads method developed in this study conferred a high drug loading and a high DL formation on liposomes compared with ordinary methods.

Erythrosine↗

PubMed2003

Potentiality of double liposomes containing salmon calcitonin as an oral dosage form.

The hypocalcemic effects of salmon calcitonin (SCT) after oral administration in rats by means of SCT-loading double liposomes (DL) which consist of liposomes containing small liposomes were investigated. SCT-loading DL consisted of four types of the inner liposomes such as neutral liposomes (NL) and cationic charged liposomes (CL) prepared using Coatsome, and neutral (VET) and cationic charged (c-VET) liposomes prepared using a mechanochemical method and sizing to 100 nm by the extrusion procedure were prepared. DL could be prepared by a combination of mechanochemical and glass-beads methods at a high efficiency. DL produced the increase in bioavailability in all groups treated with SCT-loading liposomes except for c-VET. The bioavailability of VET-DL was not significantly different but the greatest among the samples used in this study regardless of the similar size of NL-DL and CL-DL, and was approx. 6.8-fold higher than that of SCT solution when taken orally. The group treated with c-VET showed the strongest hypocalcemic effects among the inner liposomes examined (P>0.05). Therefore, it is speculated that not only the size of liposomes but also the cationic charge plays an important role in the intestinal absorption of DL. These findings suggested the utility of DL as an oral dosage form of SCT.

Administration, Oral↗

PubMed2003

Development of oral acetaminophen chewable tablets with inhibited bitter taste.

Various formulations with some matrix bases and corrigents were examined for development of oral chewable tablets which suppressed the bitter taste of acetaminophen, often used as an antipyretic for infants. Corn starch/lactose, cacao butter and hard fat (Witepsol H-15) were used for matrix bases, and sucrose, cocoa powder and commercial bitter-masking powder mixture made from lecithin (Benecoat BMI-40) were used for corrigents against bitter taste. The bitter taste intensity was evaluated using volunteers by comparison of test samples with standard solutions containing quinine at various concentrations. For the tablets made of matrix base and drug, Witepsol H-15 best inhibited the bitter taste of the drug, and the bitter strength tended to be suppressed with increase in the Witepsol H-15 amount. When the inhibitory effect on the bitter taste of acetaminophen solution was compared among the corrigents, each tended to suppress the bitter taste; especially, Benecoat BMI-40 exhibited a more inhibitory effect. Further, chewable tablets were made of one matrix base and one corrigent, and of one matrix base and two kinds of corrigents, their bitter taste intensities after chewing were compared. As a result, the tablets made of Witepsol H-15/Benecoat BMI-40/sucrose, of Witepsol H-15/cocoa powder/sucrose and of Witepsol H-15/sucrose best masked the bitter taste so that they were tolerable enough to chew and swallow. The dosage forms best masking bitter taste showed good release of the drug, indicating little change in bioavailability by masking.

Acetaminophen↗

PubMed2003

Preparation and characterization of chitosan microspheres containing doxifluridine.

Chitosan microspheres containing 5-fluorouracil (5-FU), tegafur (FT), and doxifluridine (DFUR) were prepared by the dry-in-oil method using silicone oil with no surfactant as a dispersion medium. For DFUR-containing chitosan microspheres (DFUR-M), reacetylation with acetic anhydride or coating using chitosan and glutaraldehyde was performed. DFUR-M, reacetylated DFUR-M, and chitosan-coated DFUR-M were investigated on in vitro drug release, and the former two microspheres were examined for in vivo degradation after subcutaneous (s.c.) implantation in mice, and in vivo plasma concentration-time profiles after s.c. implantation in rats. The present method gave fairly large microspheres purely composed of chitosan and drug because of no use of surfactant, which showed the mean particle diameters of 300-900 microm and the drug contents of 4-22% (w/w). Encapsulation efficiency of DFUR was higher than that of 5-FU and FT. DFUR-M and reacetylated DFUR-M exhibited spherical shape except chitosan-coated DFUR-M. DFUR-M showed high initial rapid release, which was suppressed to some extent by reacetylation or chitosan coating. DFUR-M and reacetylated DFUR-M subcutaneously implanted were gradually degraded, and approximately half or a little more of the microspheres disappeared from the implanted site at 3 weeks postimplantation. DFUR-M and reacetylated DFUR-M implanted subcutaneously gave similar plasma concentration-time profiles of DFUR, which did not indicate prolonged release in vivo. DFUR-containing chitosan microspheres with fairly large size and good drug content could be obtained by the present preparation but remained to be improved for drug release properties.

Animals↗

PubMed2003

Double liposomes: hypoglycemic effects of liposomal insulin on normal rats.

The biopharmaceutical characteristics of double liposomes (DLs) containing insulin were examined, and the usefulness of DLs in combination with aprotinin is discussed. Encapsulation of insulin was influenced by lipid composition, and the highest efficiency was observed with positively charged liposomes. Insulin encapsulated in liposomes, especially in DLs, was protected from enzymatic proteolysis. A portion of insulin molecules was adsorbed on the surface of the membrane when liposomes were prepared using a lipid with a positive charge and was degraded by enzymes. Remarkable hypoglycemic effects were observed after intragastric administration of DLs containing insulin at a dose of 20 IU/kg to normal male Wistar rats. The highest mean relative efficacy to administration was obtained with insulin-loading DLs containing aprotinin as a protease inhibitor. These results suggest that DLs are applicable as an oral dosage form for peptide drugs such as insulin etc., especially in combination with protease inhibitors.

Animals↗

PubMed2003

Antitumor properties of irinotecan-containing nanoparticles prepared using poly(DL-lactic acid) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol).

Irinotecan-containing nanoparticles (NP) were prepared by coprecipitation with addition of water to acetone solution of poly(DL-lactic acid), poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) and irinotecan, and subsequent evaporation of organic solvent. NP were purified by gel filtration and used for experiments after condensation by evaporation. The obtained NP showed the drug content of 4.5% (w/w) and the mean particle diameter of 118 nm with the particle diameter distribution between 80-210 nm. When the antitumor effect was examined at a repeated dose of 20 mg irinotecan eq/kg for 3 d (3 x 20 mg/kg) using mice bearing Sarcoma 180 subcutaneously, only NP suppressed tumor growth significantly. After i.v. injection in rats, NP maintained irinotecan plasma concentration longer than CPT-11 aqueous solution. The present nanoparticle formation is suggested as a possibly useful dosage form of irinotecan against solid tumor.

Animals↗

PubMed2003

Application of chitin and chitosan derivatives in the pharmaceutical field.

Chitin and chitosan derivatives are used as excipients and drug carriers in the pharmaceutical field. Their derivatization contributed to expansion of application and decrease toxicity. Chitosan is used as an excipient in oral dosage form. Chitosan tablet can exhibit a sustained drug release compared to commercial products. Films prepared using chitin or chitosan have been developed as wound dressings, oral mucoadhesive and water-resisting adhesive by virtue of their release characteristics and adhesion. Intratumoral administration of gadopentetic acid-chitosan complex nanoparticles (approximately 430 nm in diameter) has been more effective for gadolinium neutron-capture therapy compared with a group treated with the solution. Compared to intragastrical feeding with diphtheria toxoid (DT) in PBS, a strong enhancement of the systemic (IgG) and local (IgA) immune responses against DT has been observed in mice fed with DT loaded chitosan microparticles (approximately 4.7 microm in size). When DNA-loaded chitosan microspheres (1.15 - 1.28 microm) were intramuscularly administrated into mice, high beta-galactosidase and luciferase productions were obtained even after a long post-transfection period (12 weeks). N-Succinyl-chitosan (Suc-Chi) has been studied for cancer chemotherapy as a drug carrier and the conjugates of mitomycin C with Suc-Chi exhibited good antitumor activities against various tumors. Furthermore, trimethyl-chitosan and monocarboxymethyl-chitosan has been shown to be effective as intestinal absorption enhancers due to their physiological properties. Chitosan-thioglycolic acid conjugates has been found to be a promising candidate as scaffold material in tissue engineering due to their physicochemical properties. This review summarizes the application of chitin and chitosan derivatives for hospital preparations and drug carriers.

Adjuvants, Pharmaceutic↗

PubMed2002

Enhancement of transdermal absorption by switching iontophoresis.

The enhancing effect of switching iontophoresis on transdermal absorption of phthalic acid (PA), benzoic acid (BA), salicylic acid (SA), p-phenylenediamine (PD), aniline (AN) and verapamil (VR) and its mechanism were examined. An electric current with pulsed waveform (4 kHz, 50% duty) was passed through the skin for 2 h at 10 V. Iontophoretic application was carried out with switching at intervals of 5, 10 and 20 min, or without switching. Each drug solution was injected into the donor side of the cell, and phosphate buffer (pH 7.4) was injected into the receiver side. Transport of PA, BA and VR was affected by switching the polarity of electrodes but no effect was observed on that of SA, PD and AN. Cumulative amount permeated and apparent permeability coefficients were apparently high at switching intervals with a short period. The partition coefficient suggested that there was no interrelation between the affinity for skin and the permeability of each drug. The resistance values of PA and glucose were low at intervals of 5 min suggesting the participation of enhanced hydration of the skin. These results suggested that enhancement of skin hydration plays an important role in the enhancing effect of switching iontophoresis on skin permeation.

Administration, Cutaneous↗

PubMed2002

Preparation of novel double liposomes using the glass-filter method.

The glass-filter method, a newly developed preparative method for liposomes, was applied for preparation of novel double liposomes. Double liposomes were prepared by filtering a suspension of liposomes prepared using a G4 filter (pore size: 10-16 microm) into a G3 filter (pore size: 40-100 microm) coated with a similar lipid layer. The morphological structure of the double liposomes was confirmed using scanning electron microscopy by the freeze-fracture method to be multivesicular vesicles consisting of small liposomes enveloped in larger liposomes. The diameter of liposomes prepared using the G4 filter was 0.8-2 microm and that of liposomes prepared using the G3 filter or double liposomes was 5-10 microm. These results suggested that the particle size of liposomes is dependent on the pore size of the glass-filter. The encapsulation efficiencies of double liposomes for brilliant blue FCF (BB) and erythrosine (ER) were higher than those of liposomes prepared by the standard Bangham method. Double liposomes showed suppressed release of BB or ER compared with normal liposomes. In particular, no release of BB was observed from the double liposomes prepared with stearylamine. These findings implied that the outer lipid layer protects the inner liposomes. The glass-filter method is the only method that we can get the double liposomes in a short period, and double liposomes prepared by this novel method had adequate size and good stability in vitro.

Liposomes↗

PubMed2002

Depolymerization of N-succinyl-chitosan by hydrochloric acid.

N-Succinyl-chitosan (1) was depolymerized with 7.5 M aqueous HCl at room temperature or 3.3 M aqueous HCl at 40 degrees C and the molecular weights (MW) of the products were determined by size-exclusion chromatography-multi angle light scattering (SEC-MALS) and their viscometric features were investigated. The intrinsic viscosity ([eta]) obtained at the concentration of 0.1-0.3% (w/v) in saline showed a linear relationship between log[eta] and log MW, which provided the coefficients in the Mark-Houwink equation.

Biopolymers↗

PubMed2002

Efficacy of lactosaminated and intact N-succinylchitosan-mitomycin C conjugates against M5076 liver metastatic cancer.

In this study,lactosaminated N-succinyl-chitosan (Lac-Suc) was investigated for its liver targeting ability in the early metastatic stage of liver cancer, and subsequently Lac-Suc-mitomycin C conjugate (Lac-Suc-MMC) and highly-succinylated N-succinyl-chitosan (Suc(II))-MMC conjugate (Suc(II)-MMC) were examined for efficacy against the liver metastasis. Mice into which M5076 cells were inoculated intravenously were used as liver metastatic models. Fluorescently labelled Lac-Suc (Lac-Suc-FTC) was intravenously administered at a daily dose of 0.2 mg/mouse for 4 days or at a single dose of 0.8 mg/mouse at 3 days post-inoculation. At a dose of 0.2 mg/mouse for 4 days, liver accumulation of Lac-Suc-FTC was increased after all except the fourth injection, indicating that the capacity of accumulation might be limited to around 110 microg per mouse with repeated daily administration at 0.2 mg/mouse. As to the efficacy of intravenous administration at 7 days post-inoculation, Lac-Suc-MMC was less effective at a dose of 1 mg kg(-1) for 4 days than a single dose of 4 mg kg(-1). This result was not in accordance with that expected from the biodistribution study. On the other hand, with intravenous administration at 3 days post-inoculation, Suc(II)-MMC was more effective on repeated administration, and it showed higher efficacy than Lac-Suc-MMC at both 1 mg kg(-1) for 4 days and 4 mg kg(-1) as a single dose. Further, with intravenous administration at 3 days post-inoculation, Suc(II)-MMC exhibited a much higher survival effect at a dose of 4 mg kg(-1) for 4 days.

Amino Sugars↗

PubMed2002

Antitumor activities of conjugates of mitomycin C with estradiol benzoate and estradiol via glutaric acid in suspension dosage form.

Conjugates of mitomycin C (MMC) with estradiol bezoate and estradiol via glutaric acid (EB-glu-MMC and E-glu-MMC, respectively) were examined for their antitumor activities against P388 leukemia and sarcoma 180. EB-glu-MMC and E-glu-MMC were suspended in 10% (v/v) propylene glycol in saline and administered intraperitoneally to mice bearing P388 leukemia intraperitoneally or to mice bearing sarcoma 180 subcutaneously. The antitumor effect against P388 leukemia was greater in the order MMC>E-glu-MMC>EB-glu-MMC, and only the former two compounds significantly increased life span. On the other hand, EB-glu-MMC and E-glu-MMC showed suppression of sarcoma 180 growth at higher doses close to or better than MMC. In the mixture of 1/15 M phosphate buffer (pH 7.4, ionic strength (mu) adjusted to 0.3 with NaCl)-propylene glycol (9:1, v/v) at 37 degrees C, MMC was released much more slowly from EB-glu-MMC suspension than from E-glu-MMC suspension. With regard to chemotherapy against sarcoma 180, both conjugates were considered to supply MMC slowly but effectively at higher doses.

Animals↗