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Purpose: The potential of sucrose fatty acid esters (SEs) to enhance intestinal absorption was investigated in order to identify their utility for the intestinal absorption of water-soluble high molecular weight compounds. Methods: Fluorescein isothiocyanate-labeled dextran (FD) with a molecular weight (MW) of 4,000 (FD-4) was used as a model compound, and several SEs were tested as absorption enhancers. After FD-4 was administered intra-duodenally at 10 % (w/v) with the non-loop method in situ in rats in the absence or presence of SEs, the plasma concentration-time profiles of FD-4 were examined. As to sucrose laurate (L-1695), the relationship between concentration and enhancement effect was investigated. In addition, the enhancement effect after dosing into the different small intestinal regions, the effect on FDs with different MWs and the influence of N-acetyl-cysteine (NAC) co-existence were examined. Results: Low watersoluble SEs exhibited slight and/or slow absorption enhancement effects, while L-1695, being highly water-soluble, had good potential to enhance the absorption rate and extent. The enhancement effect became greater as the concentration of L1695 increased. L-1695 displayed high enhancement potential in wide intestinal areas. The enhancement effect of L-1695 (10 %, w/v) depended on MWs of FDs; the mean values of the area under the plasma concentration curve from 0-120 min (AUC0-120 mins) increased by 14 and 8 times for FD-4 and FD-10 (MW 10,000), while it was hardly changed as for FD-70 (MW 70,000). The enhancement effect of L-1695 (10 %, w/v) was similar to that of sodium caprate (10 %, w/v), and was influenced to some extent by the co-existence of NAC (5 %, w/v). Conclusion: The absorption enhancement potential of SEs depended on their water-solubility. L-1695, being highly water-soluble, showed a good enhancement effect, and its absorption profiles were elucidated. This study proposes the possibility of SEs, in particular, L-1695, as intestinal absorption enhancers. As far as the present non-loop method is concerned, the intestinal damage was not observed macroscopically with the addition of L1695 at 2.5-20 % (w/v).

Recently, many people have developed rheumatoid arthritis (RA), and prednisolone (PD) is often used for treatment; however, long use and a large dose of PD can cause toxic side effects. In this study, in order to enhance the therapeutic effects and to suppress the toxic side effects, the conjugate (GC-SP) was prepared by coupling between glycol-chitosan (GC) and succinyl-prednisolone (SP). The drug-release properties of GC-SP were examined and analyzed kinetically. The plasma concentration-time profiles of GC-SP and released PD were investigated after i.v. injection to normal rats, and their pharmacokinetic profiles were analyzed. PD was stable and released gradually (ca. 1%/h) from GC-SP at physiological pH, while PD was unstable at basic pH and the release from GC-SP was accelerated at basic pH. GC-SP showed good systemic retention (more than 16-fold area under the plasma concentration-time curve (AUC) as compared to PD alone), and released PD gradually in vivo. The in vivo release rate was calculated to be much faster than the in vitro rate. From these results, it is expected that GC-SP will be accumulated at inflammatory sites based on enhanced permeability and retention (EPR) effects, and release PD there effectively.

Using furosemide (FU) as a model drug, we examined the wet granulation method as a way to improve the taste masking and physical characteristics of orally disintegrating tablets (ODTs). In the wet granulation method, yogurt powder (YO) was used as a corrective and maltitol (MA) was used as a binding agent. The taste masked FU tablets were prepared using the direct compression method. Microcrystalline cellulose (Avicel® PH-302) and mannitol were added as excipients at a mixing ratio of 1/1 by weight. Based on the results of sensory test on taste, the prepared granules markedly improved the taste of FU, and a sufficient masking effect was obtained at the YO/FU ratio of 1 or more. Furthermore, it was found that the masking effect achieved by YO granules made with the wet granulation method was similar to or better than that produced by the granules made with dry granulation method. All types of tablets displayed sufficient hardness (over 3.5×10(-2) kN), and rapidly disintegrating tablets were obtained with YO granules produced at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s. Disintegration time lengthened as the mixing ratio of YO to FU increased. In the mixing ratio of FU/YO=1/1, the hardness of tablets with granules made by the wet granulation method exceeded that of tablets with granules made by the dry granulation method, with minimal differences in disintegration time. The hardness and disintegration time of the tablets with granules made by the wet granulation method could be controlled by varying the compression force. In conclusion, YO was found to be a useful additive for masking unpleasant tastes. FU ODTs with improved taste, rapid disintegration and greater hardness could be prepared with YO-containing granules made by the wet granulation method using MA as a binding agent.

The formation of an inclusion complex of amoxicillin (AMX) with beta-cyclodextrin (beta-CD) in aqueous solution was confirmed by a solubility method and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The apparent stability constant for the inclusion complex was 10.72 M(-1) in water at 25 degrees C. The effect of alpha-CD, beta-CD, and gamma-CD on the degradation of AMX in a pH 1.2 solution at 37 degrees C was investigated. beta-CD and gamma-CD reduced the rate of degradation. alpha-CD had no effect. These results were consistent with those of 1H-NMR spectroscopy. The effect of beta-CD on the degradation rate was studied in more detail. The apparent first order rate constant for the degradation of AMX in the pH 1.2 solution at 37 degrees C was 0.1121 h(-1) (t(1/2)=6.18 h), which decreased with the addition of beta-CD. The rate constants and t(1/2) values for the concentrations of beta-CD added, corresponding to molar ratios of AMX to beta-CD of 1:0.5, 1:1, 1:2, 1:5, and 1:10, were 0.1051 h(-1) and 6.59 h, 0.0992 h(-1) and 6.98 h, 0.0893 h(-1) and 7.76 h, 0.0697 h(-1) and 9.95 h, and 0.0509 h(-1) and 13.61 h, respectively. The activation energy for the degradation of AMX in the pH 1.2 solution was increased from 6.9 x 10(4) J/mol (AMX alone) to 8.0 x 10(4) J/mol (AMX:beta-CD=1:10).

Microcrystalline cellulose (Avicel®PH-302),lactose (Super-Tab®),carboxymethyl cellulose (CMC) and xylitol are added to tablet formulations of precipitated calcium carbonate to achieve rapid disintegration while maintaining sufficient tensile strength,and to allow tablets to be easy to take.We prepared tablets containing 200 mg of precipitated calcium carbonate by the direct compression method and measured their tensile strength,wetting rate and disintegration time.Though precipitated calcium carbonate gave tablets a greater hardness and disintegration time than tablets containing no precipitated calcium carbonate,the disintegration time in the human oral cavity was short enough for them to be rapidly disintegrating tablets.On investigating a correlation between disintegration time in vitro and disintegration time in the oral cavity,we found that disintegration time in vitro was a fairly good predictor of disintegration time in the oral cavity.The sensory test score for the calcium carbonate tablets was excellent.In addition,we demonstrated that it was possible to produce rapidly disintegrating tablets containing precipitated calcium carbonate produced by direct compression when CMC is used as a disintegrant and Super-Tab® and Avicel®PH-302 are used as excipients.

We investigated the preparation of orally disintegrating tablets (ODTs) using furosemide (FU) as a model drug.Preparations were made from granules containing 2 correctives,maltitol (MA) and yogurt powder (YO),in various mixing ratios formed by the wet granulation method,and the taste of each one was evaluated.Though all of the FU preparations had an improved taste,the mixing ratio of MA did not affect the masking effect.It appeared that a sufficient masking effect could be obtained with mixing ratio of YO/MA/FU=0.5/0.5/1 by weight.The taste masked FU tablets were prepared using the direct compression method,and microcrystalline cellulose (Avicel® PH-30citation=2)and mannitol were added as excipients at a mixing ratio of 1/1 by weight.For all formulations,the hardness of tablets exceeded 4.5 kgf.The disintegration time and water absorption time increased as the proportions of YO and MA increased.Tablets made from granules with the mixing ratio YO/MA/FU=0.5/0.5/1 exhibited the greatest hardness (above 6.0 kgf),the shortest disintegration time (within 30 sec) and the shortest water absorption time (about 100 sec).Increasing the compression force had little effect on tablet hardness but increased the disintegration time,though it did not go over 60 sec,and also increased the water absorption time.In conclusion,we found that well taste masked ODTs can be prepared with granules produced by the wet granulation method at a mixing ratio of YO/MA/FU=0.5/0.5/1 by weight.

We investigated several methods of taste masking in the preparation of orally disintegrating tablets (ODTs), using furosemide (FU) as a model drug. Four types of FU preparations were prepared: granules with maltitol (MA), granules with yogurt powder (YO), a physical mixture of FU and MA, and a physical mixture of FU and YO. All taste-masking granules were prepared using the dry granulation method. The taste of each type of preparation was evaluated. All four preparations markedly improved the taste of the FU tablets, but the mixing ratios of the correctives did not affect the masking effect. No difference in masking effect was found between MA and YO in the physical mixtures, but the masking effect in the granules with YO was superior to that of the granules with MA. Taste-masked FU tablets were prepared using the direct compression method; crystalline cellulose (Avicel PH-302) and mannitol were added as excipients at the mixing ratio of 1/1. All four types of tablets displayed sufficient hardness, but MA-containing tablets were harder than YO-containing tablets. The hardness of the tablets prepared from YO granules increased as the YO content increased. The most rapidly disintegrating tablets were those of YO granules prepared at a mixing ratio of FU/YO=1/1, which disintegrated within 20 s, followed by the tablets of MA granules prepared at a mixing ratio of FU/MA=1/1. The disintegration times of the tablets made from physical mixtures, in contrast, were longer than 200 s. Disintegration time lengthened as the mixing ratio of YO or MA increased. The hardness and disintegration time of these tablets could be controlled by varying the compression pressure. We found that YO is more useful than MA in masking unpleasant tastes and confirmed that orally disintegrating tablets with taste-masking function can be prepared using granules of YO prepared using the dry granulation method as a new corrective.

Medicinal carbon (MC) films, which can be taken more easily than other dosage forms, were prepared using sodium carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC) and alginic acid sodium (ALG) as film base materials. Brilliant blue FCF (BB) was used as a model drug. The films containing MC had sufficient strength and disintegration time, but their ability to adsorb BB was clearly inhibited compared to that of MC in powder form. When ALG was used as the film base, the BB adsorption capacity of MC film was approximately 50% of that of MC powder. In an attempt to improve this adsorption ability, two saccharides, sorbitol (SOR) and maltitol (MT), were separately added to MC at a mixing ratio of 1 : 1 by weight. When ALG was the film base, MC films containing SOR or MT showed rapid adsorption profiles and had greatly increased capacities for BB adsorption compared with films containing MC alone. SOR was superior to MT as an additive, though both gave MC-containing films a BB adsorption capacity almost equal to that of MC powder after 24 h, and physical mixtures tended to have better BB adsorption capacities than pre-treatment mixture. In addition, both SOR and MT tended to increase vertical strength of films, but neither additive in either type of mixture had a clear effect on disintegration time. When CMC or HPMC was used as the film base, on the other hand, the addition of SOR or MT caused hardly any improvement in adsorption ability. The above results demonstrate that ALG is useful as a film base material for the preparation of MC films, and that MC films with sufficient strength and adsorption capacities equal to those of MC powders can be produced using a physical mixture of MC and SOR on an ALG base.

An attempt was made to prepare FITC-labeled-lactoferrin (LF-FTC)-loaded microparticles, durable under gastrointestinal conditions, first by the combination of alginate/calcium complexation and emulsification-evaporation and next by treatment with chitosan solution. The obtained microparticles were examined for particle characteristics, in vitro release profiles and physical stability in solutions of pH 1.2 and 6.8. The obtained chitosan-coated alginate/calcium complex microparticles (Ch/Al/Ca-MP) showed almost uniform size of 1-2 μm and a spherical shape with a non-smooth surface. The content and recovery of LF-FTC in Ch/Al/Ca-MP fell as the concentration of chitosan solution used in chitosan coating increased. The release rate of LF-FTC was faster in Ch/Al/Ca-MP prepared with more chitosan at pH 1.2 and 6.8. Ch/Al/Ca-MP coated with 0.25 and 0.5% (w/v) chitosan solution showed good gradual release characteristics in vitro. Furthermore, they were durable at pH 1.2 and 6.8, though swelling and softening of the microparticles occurred at pH 6.8. It is suggested that alginate/calcium complex microparticles coated with 0.25-0.5% (w/v) chitosan solution would be useful for the intestinal delivery of LF.

Fast-disintegrating tablets of furosemide (FS) were prepared by the novel direct compression method. FS, microcrystalline cellulose (MC), croscarmellose sodium (CC), xylitol (XL) and sucrose stearic acid esters (SSEs) with an hydrophilic-lipophilic balance (HLB) of 16, 15 and 11, named S1670, S1570 and S1170, were used. An FS/SSE/MC mixed powder was obtained by solvent evaporation of a suspension of MC in ethanol solution containing FS and SSE, and the resultant mixed powder was mixed with CC and XL, and directly compressed. The tablets with hardness of more than 40 N and disintegration time of less than 20 s were obtained at the addition of SSE at 0--0.5% (w/w). A tablet with S1670 at 0.1% (w/w), named TA2, dissolved faster than a commercial FS tablet, Lasix. TA2 tended to show higher plasma concentration than Lasix after intragastric administration to rats. It was demonstrated that the present direct compression using homogeneous FS/S1670/MC powder mixture could give an excellent fast-disintegrating tablet of FS.

To develop a transdermal dosage form of propofol (PF), in vitro skin permeability and in vivo absorbability of PF were investigated in rats, and the effectiveness of enhancers on the transdermal delivery of PF was estimated. Propylene glycol (PG), isopropyl myristate and macrogol were used as co-solvent type enhancers. L(-)-Menthol (MEN), D(+)-limonene, oleic acid, stearic acid, sucrose fatty acid esters and sodium dodecyl sulfate (SDS) were used as membrane-acting type enhancers. Among the co-solvent type enhancers, PG showed the highest enhancing effect in vitro. Furthermore, the synergistic effect of the combined use of PG and membrane-acting type enhancers was confirmed. Higher values of permeation parameters were observed with the combined use of PG and MEN, sucrose fatty acid esters or SDS. For the in vivo experiment, the addition of a smaller amount of PG was preferable to the amount used in the in vitro experiment. The synergistic effect of enhancers was observed with the combined use of PG and MEN. Our findings suggest that the combination of PG and MEN was useful as enhancers for the transdermal absorption of PF. These results provide useful information to develop a transdermal dosage form of PF as a sedative or a hypnotic.

A targeted delivery system for inflammatory bowel disease (IBD), Eudragit L100 (EuL)-coated chitosan (Ch)-succinyl-prednisolone (SP) conjugate microspheres (Ch-SP-MS/EuL), were designed and examined in vivo for efficacy and toxicity. Their preparation was conducted in the same manner as previously; that is, by synthesis of the conjugate by carbodiimide coupling of Ch and SP, conversion into microspheres (Ch-SP-MS), and coating of Ch-SP-MS with EuL. Experimental colitis was induced by instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) into the colon in rats. Drugs were administered once or twice a day intragastrically for three consecutive days. Visible colitis severity, colon/body weight ratio and myeloperoxidase activity were measured as inflammatory indices. Toxicity was examined from the decrease in the thymus/body weight ratio. Efficacy was dose-dependent and the greatest in the order Ch-SP-MS/EuL>Ch-SP-MS>prednisolone (PD) alone, and Ch-SP-MS/EuL showed excellent recovery of colitis states. Toxicity was the greatest in the order PD>>Ch-SP-MS>Ch-SP-MS/EuL. Ch-SP-MS and Ch-SP-MS/EuL reduced significantly the thymic atrophy caused by PD. It was demonstrated that Ch-SP-MS/EuL enhanced effectiveness of PD and reduced toxic side effects of PD greatly. Also, these results established the prediction by previous in vitro and in vivo studies.

The degree of deacetylation and molecular weight of carboxymethyl-chitin (CM) were manipulated using 10% (w/v) NaOH aqueous solution at 25˚C and 5 M HCl aqueous solution at 40˚C, respectively. The resultant CMs were char- acterized by 1 H-NMR spectroscopy and size exclusion chromatography/multi-angle light scattering. The degree of deace- tylation of 7 - 35% (mol/mol) and molecular weight of 43,000 - 449,000 were achieved. Nanoparticles were prepared us- ing W/O emulsification and amide coupling. Nanoparticles with the size of less than 400 nm were obtained using CM with a high degree of deacetylation and low molecular weight, CM48-L. When the mixture of CM-mitomycin C conjugate and CM48-L underwent W/O emulsification and amide coupling, nanoparticles with the size of ca. 350 nm were obtained, and released mitomycin C fairly fast but gradually. CM with a high degree of deacetylation and low molecular weight was suggested to be useful for the production of CM nanoparticles.

After chitosan-succinyl-prednisolone conjugate (Ch-SP) was synthesized, conjugate microspheres (Ch-SP-MS), Eudragit L100-coated Ch-SP-MS and Eudragit S100-coated Ch-SP-MS, were prepared under novel preparative conditions. Namely, sonication was utilized to prepare finer Ch-SP-MS, and the addition ratio of Eudragit was reduced to yield Eudragit-coated Ch-SP-MS with higher drug content. Ch-SP-MS and Eudragit-coated Ch-SP-MS had mean sizes of 1.3microm and approximately 30microm, respectively, and showed prednisolone (PD) contents of 4.6% (w/w) and approximately 3% (w/w), respectively. Morphological changes of all the types of microparticles in different pH media were observed by scanning electron microscopy and confocal laser scanning microscopy. Both methods gave similar results. Both types of Eudragit-coated Ch-SP-MS protected Ch-SP-MS from morphological change at pH 1.2, and regenerated Ch-SP-MS fast at pH 6.8 and 7.4. For all types of microparticles, release of PD was suppressed at pH 1.2, but caused gradually at pH 6.8. These particle characteristics and in vitro behaviors demonstrated that the present Eudragit-coated Ch-SP-MS were considered potentially suitable for in vivo or practical application as a specific delivery system of PD to IBD sites.

The effect of iontophoresis and switching iontophoresis on the skin accumulation of drugs was investigated. An acrylic diffusion cell mounted with electrode cells (bore: 2.2 cm) with circular platinum electrodes (diameter: 2.0 cm) was used for the skin accumulation study. The skin accumulation of fluorescein after non-switching and switching iontophoresis was macroscopically compared with that achieved by passive diffusion (control). Intense fluorescence was observed after the application of non-switching and switching iontophoresis. Furthermore, fluorescence was observed just under the electrode cell and hardly spread in the skin beyond the area of the electrode cell. The skin accumulation of ketoprofen after non-switching and switching iontophoresis was also compared with control data. Although non-switching iontophoresis showed the highest amount of ketoprofen accumulated in skin, skin irritation was observed. Among the various switching intervals, switching iontophoresis using 10-min intervals achieved the highest value, and there was no skin irritation. Furthermore, the amount of ketoprofen accumulated was maintained after switching iontophoresis at 10-min intervals up to 180 min. Since the amount of ketoprofen in skin after switching iontophoresis was greater than that after intermittent iontophoresis, switching iontophoresis should increase the amount of ketoprofen due to enhancement of skin penetration by skin hydration. These findings suggest that switching iontophoresis using an optimal switching interval can prevent skin irritation and enhance drug accumulation in the skin.

The use of competing agents is considered a powerful tool for the development of a drug-delivery system with drug/cyclodextrin inclusion complexes. However, there are very few studies examining this issue. To explain this phenomenon, it was thought that a competing agent with a sufficiently high stability constant had not yet been reported. In this study, cinnarizine (CN), which has a high stability constant with beta-cyclodextrin (beta-CD) and unique solubility characteristics, was selected, and its ability as a competing agent was examined in a membrane permeability study. The permeability study showed that the permeation rates of the drugs flurbiprofen, progesterone, and spironolactone decreased with their stability constants with the addition of beta-CD. In one of the drugs, progesterone (Pro), the decrease was restored by the addition of CN. The amount of CN added was a 1:1 molar ratio to the amount of Pro. However, no similar action was induced with the addition of DL-phenylalanine (Phe) in the permeation study at the 1:5 (Pro:Phe) molar ratio. These finding indicate that CN acts as a competing agent, and its action is much stronger than that of Phe.

Poly(DL-lactic acid) (PLA)/poly(ethylene glycol)-block-poly (propylene glycol)-block-poly(ethylene glycol) copolymer (PEG-PPG-PEG) nanoparticles loaded with camptothecin (CPT), called CPT-NP, were prepared and examined for particle size change and drug release in phosphate-buffered saline, pH 7.4, (PBS), and drug biodistribution profiles in mice bearing sarcoma 180 solid tumor. CPT-NP kept an almost constant mean size and exhibited an initial rapid release of approximately 20%, following by very slow release. As compared with CPT solution, CPT-NP showed higher tissue accumulation and better tumor localization, which were considered essentially associated with the better efficacy of CPT-NP reported in the previous study.

Camptothecin (CPT)-loaded nanoparticles were prepared using poly( dl -lactic acid) (PLA) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) copolymer (PEG-PPG-PEG), and examined for particle characteristics, in vitro release, pharmacokinetics and efficacy. The preparative condition, in which the ratio of PLA/PEG-PPG-PEG/CPT was 35/35/4 (w/w/w) and organic solvent (dichloromethane) was evaporated from the emulsion at 18 °C, gave the nanoparticles with the diameter of approximately 230 nm, fairly high drug content (ca. 1.6% (w/w)) and stable entrapment of the drug, which were used for in vivo studies. After i.v. administration to normal rats, the nanoparticles showed slightly smaller AUC but much larger MRT as compared with CPT solution, and delivered the drug greatly to the surrounding tissues, in particular to the liver. When antitumor effect was examined by i.v. administration to mice bearing sarcoma 180 (S-180) solid tumor, the nanoparticles showed a significant suppression of tumor growth without body weight loss, and their effect was better than that of CPT solution. The PLA/PEG-PPG-PEG nanoparticles were considered potentially useful to enhance the efficacy of CPT, to which the high drug retention in the body and gradual drug release appeared to be importantly related.

Novel wound dressings composed of chitosan (CH) film and minocycline hydrochloride (MH) were prepared using commercial polyurethane film (Tegaderm) as a backing. CHs with deacetylation degrees of 67%, 83% and 96% (mol/mol), named CH67, CH83 and CH96, respectively, were used. Wound dressing with a large piece of Tegaderm film (4 cm x 4 cm), named CH-MH-N, and wound dressing prepared by cutting CH-MH-N to the wound size, named CH-MH-A, were developed. As CH67-MH-N and CH83-MH-N showed the sustained release of minocycline in vitro, CH67 and CH83 were used as chitosan in the in vivo studies. Various formulations were applied to severe burn wounds in rats in the early stage, and the wound status and change in the wound surface area were examined. The use of 10mg of MH and complete sealing with Tegaderm had a negative effect. MH ointment was not effective, but Geben cream was fairly effective. However, CH83-MH-A containing 2mg of MH (CH83-MH2-A) and CH83 film showed an excellent effect. Considering the elimination of pus, CH83-MH2-A tended to be better than CH83 film. CH83-MH2-A is suggested as a useful formulation for the treatment of severe burn wounds.

White petrolatum is widely used as an ointment base.In this study,we examined the quality characteristics of pharmaceutical petrolatums and a cosmetic petrolatum.There are 6 brands of pharmaceutical white petrolatum which are Perfecta and White 1S made by Sonneborn Co.and Ultima,Snow,Snow V and Regent made by Penreco Co. We measured the melting point and viscosity of the white petrolatums.Perfecta had the highest melting point and Ulitima had the lowest.Snow had the highest viscosity and Perfecta the lowest.These results show that the characteristics of white petolatums vary among brands.Spectrophotometry was used to evaluate potential allergenicity.For extracts of Ultima,Regent and a cosmetic petrolatum,absorption was not observed in the 260 to 270 nm range suggesting that Ultima,Regent and the cosmetic petrolatum have a low content of polycyclic aromatic hydrocarbons which cause skin irritation.Upon investigating the brands of white petrolatum used in the base of commercial ointments,we found that the brand of petrolatum varied among the ointments.In order to ensure the proper use of ointments,suitable ointments should therefore be selected in consideration of patient needs.

Kumazasa extract (KE) and its whole solid component (EXT)-containing chitosan films produced by drying in air and lyophilization, abbreviated to ND and FD films, respectively, were examined for efficacy and healing features using a deep skin ulcer model in rats. Their effects were compared with those of clinically available dosage forms, Beschitin W, Geben cream and U-PASTA. KE alone exhibited a better effect as compared with other preparations, and FD films also more effective than control in the early stage. Histological analysis showed that KE alone reduced necrosis rapidly and accelerated granulation. ND films delayed healing rate as compared with control. FD films showed histological features between control and KE alone, but tended to delay healing rate in the later period. Thus, reduction rate of wound area and histological features suggested that KE alone should be excellent for the promotion of wound healing. Although FD films were less effective than KE alone, they were superior as to usability such as changing the preparation.

For the treatment of chronic inflammation in the oral cavity, we attempted to develop bioadhesive tablets of bovine lactoferrin (B-LF). Pectin was used as a bioadhesive polymer, and the influence of the degree of esterification and the molecular weight of pectins on the characteristics of B-LF tablets were investigated. Concerning bioadhesive force, a tendency increasing the value according to increase of the esterification of the pectin was confirmed. Sustained release of B-LF from the tablets was observed as the esterification increased, and a possibility for prediction of the time required to release 50% of B-LF by using the equation given by the degree of esterification and the logarithm of the molecular weight was suggested. Pectin cross-linked with Ca(2+) (Ca-PC) was also used for the preparation of the B-LF tablets. Prolonged release of B-LF from the tablets was observed as the Ca(2+) in Ca-PC increased. Our findings suggest that pectin with a high degree of esterification is suitable as a bioadhesive polymer since high bioadhesive force and sustained release are shown. Furthermore, a possibility that the B-LF release could be controlled by adjusting the Ca(2+) concentration in Ca-PC was suggested.

Medicinal carbon (MC) granules were prepared by wet granulation using maltitol (MT), and the MC tablet was produced by compression of the granules. The physical properties and the in vitro adsorption capacity for AA of the formulations were examined. Further, the effects of MC alone and the granules on gastrointestinal absorption of AA were examined in rats when they were administered intragastrically at 15 or 45 min after the intragastrical administration of AA. AA was rapidly adsorbed by MC, and the maximum adsorption capacity of MC was 0.329 g AA per gram MC. The granules and tablet exhibited adequate strength, and the tablet disintegrated rapidly. The granules and tablet showed similar adsorption profiles, but somewhat lower adsorption capacity than MC alone. MC alone and granules administered at 15 min reduced the AUC(0–∞) significantly against the control (no treatment); however, the suppression effect on the plasma concentration was lower with the granules than with MC alone. Thus, granules and tablet are useful as a compact dosage form of MC; though the reduced adsorption capacity must be taken into account in order to expect efficacy equivalent to that of MC alone.

Medicinal carbon (MC) tablets were prepared to obtain an oral dosage form that can be easily taken. The MC tablets were made by the wet granule compression method, in which hydroxypropyl cellulose (HPC), carboxymethyl cellulose sodium (CMC-Na) and maltitol (MT) were applied as binders. Brilliant Blue FCF (BB) was used as a model drug. The binders were evaluated in terms of formability of the granules and tablets, their strength, disintegration of the tablets, and their effect on the adsorption potential of MC. HPC and CMC-Na gave the strong granules at a fairly low concentration, but more MT was needed to obtain the strong granules. The tablets could be formed only when using MT at 120% (w/w) of the MC amount. The tablet displayed good hardness and rapid disintegration. The adsorption potential was not affected by CMC-Na, and slightly prevented by MT. However, the adsorption ability of MC was lowered more with the increase in HPC. The granules and tablets exhibited similar adsorption potentials, which were a little lower than that of MC suspended in MT aqueous solution. Similar adsorption characteristics were also observed in a real drug, acetaminophen. It is suggested that the MC tablets prepared by the wet granule compression using MT as a binder should be useful as a compact dosage form of MC.

Microparticulate dosage forms for liver-specific delivery of a liver-protective drug, glycyrrhetic acid (GLA), were prepared and evaluated in vitro and in vivo. Poly(DL-lactic acid-co-glycolic acid (7:3, mol/mol)) microparticles, produced by the combination of emulsification-solvent evaporation and sonication and washed using the mixture of methanol-phosphate buffered saline pH 7.4 (3:7, v/v), showed a diameter of approximately 1.0 µm, moderate drug content, and prolonged drug release, and were used for in vivo analyses. The long-term pharmacokinetic profiles in plasma and liver were investigated after i.v. administration. The microparticles gave much higher GLA concentration in the liver than did GLA solution, and maintained plasma and liver concentrations of GLA at levels of >1 and 3 mg/mL, respectively, for at least 6 days. Furthermore, therapeutic effect against consecutive carbon tetrachloride-induced murine hepatitis was evaluated based on the plasma level of glutamic oxalacetic transaminase (GOT) after i.v. administration. The microparticles with 10 mg GLA maintained liver-protective effect for approximately 1 week, while the GLA solution with the same dose was scarcely effective from 3 days after the administration. These data suggest that the microparticles should be useful as a prolonged liver-protective system. Drug Dev. Res. 66:189–199, 2006. © 2006 Wiley-Liss, Inc.

The influence of a low-frequency massage device on transdermal absorption of sodium benzoate, ketoprofen and diclofenac sodium was investigated in rats. Electrode pads spread with a hydroxypropyl cellulose gel containing the drug model were placed on excised skin in vitro. The transdermal permeation studies were carried out in the treatment group with the pulse applied through electrode pads spread with the gel, the pretreatment group with the gel applied after the application of the pulse and in the control group in which the gel was applied without the pulse. In vivo, transdermal absorption of ketoprofen was examined in the same groups used for the in vitro study. The pharmacokinetics of ketoprofen in plasma after intravenous injection was also studied. The treatment group showed higher cumulative permeated amounts of the drug models than the control in vitro. However, the enhancing effect was not observed in the pretreatment group. In vivo, the plasma ketoprofen level increased temporarily after the pulse was applied and then increased gradually as compared with the control. Since the distribution of ketoprofen from the central to the peripheral compartment was enhanced by the pulse in the injection study, enhancement of the biodistribution of ketoprofen by the low-frequency pulse was suggested.

Camptothecin (CPT) and its analogs are some of the most potent antitumor agents known. However, their poor water-solubility and high toxicity require changes of their physicochemical and biological characteristics. Active lactone forms have provoked interest in the utility of CPT and its analogs again. Macromolecular chemical modifications and nanotechnological formulations have been used to obtain improved systems of CPT-related compounds. In these systems, one of the most important concepts is the enhanced permeability and retention (EPR) effect. The outcomes obtained by these approaches are displayed by introducing concrete examples.

The purpose of the present study was to obtain a novel microparticulate formulation of prednisolone, which was adequate for the treatment of inflammatory bowel disease (IBD). The formulations prepared were evaluated in vitro. Two types of chitosan microspheres containing prednisolone, named Ch-Pred and Ch-SP-MS, were prepared by an emulsification-solvent evaporation method using a chitosan-prednisolone mixture and a chitosan-succinyl-prednisolone conjugate (Ch-SP), respectively. Ch-Pred and Ch-SP-MS were obtained in almost spherical shape. Ch-Pred showed a relatively high drug content of 13.2% (w/w), but the particle size was distributed from 10 to 45 microm, and a large initial burst release of approximately 60% was observed. On the other hand, although Ch-SP-MS exhibited a fairly low drug content of 3.5% (w/w), their particle size ranged from several hundred nanometers to 20 microm, with the mean diameter of 5 microm, and a gradual drug release profile was achieved. These characteristics on particle size and in vitro release suggested that Ch-SP-MS should have good potential as a microparticulate system for the treatment of IBD.

An implant tablet of ketoprofen (KP) was developed in order to achieve its sustained supply for approximately one week, and its release was evaluated in vitro and in vivo. Implant tablets (30 mg) containing 1 and 5 mg of ketoprofen, prepared using poly(DL-lactic acid-co-glycolic acid) copolymer (PLGA; MW 10000; lactic acid : glycolic acid=1 : 1 (mol/mol)) as a matrix, exhibited similar week-long sustained release in vitro. Plasma concentration was monitored after the implant tablet (5 mg of KP) and a KP solution (0.5 mg of KP) were administered subcutaneously to rats, and in vivo release rate was analyzed by deconvolution. The release rate from the implant tablet was faster in vivo than in vitro in the initial phase, but much lower in vivo than in vitro in the later phase. The plasma level decreased to the level less than the minimal effective concentration at 96 h after administration. However, the calculated plasma concentration given by convolution based on in vitro release rate was more than 7 times greater than the minimal effective concentration even at 96 h after administration. As the implant displayed the discrepancy between in vitro and in vivo release rates, the improvement of the in vivo release rate is required.

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.

To identify the optimal schedule for intraperitoneal (i.p.) infusion of floxuridine (FUDR) against peritoneal micrometastases from gastric cancer. 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. 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. 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.

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.

Reductive amination ofN-succinyl-chitosan (1) and lactose using sodium cyanoborohydride in 1/15 M phosphate buffer (pH 6.0) for 6 d was suitable for the preparation of lactosaminated N-succinyl-chitosan (2). At 8, 24 and 48 h after i.v. administration of fluorescently labeled1 (1′) or2 (2′), Peyer’s patch, mesenteric lymph nodes, testes, prostate, preputial grand, intestine (small intestine plus cecum), femoral muscle, backbone and peritoneum were taken. Peyer’s patch and mesenteric lymph nodes were put together as lymph nodes. Over 10% of dose/g tissue was distributed to the prostate and lymph nodes at 48 h post-administration in both1′ and2′. 2′ was easily distributed into not only the liver but also prostate, intestine, preputial gland and lymph nodes. Although galactose receptors are known to exist not only on the liver parenchymal cells but also on prostate and testes, the selective distribution of2′ into the prostate and the testes were not observed clearly. This study suggested that1 and2 should have possibilities for both the prevention and cure of lymph node metastasis as drug carriers.

A simple method for the preparation of the inner liposomes for double liposomes (DL) was developed. The encapsulation efficiency of erythrosine in liposomes prepared by this new method is superior to that of the previous method because of the concentration of the drug in the lipid membrane. To evaluate the usefulness of DL prepared by the glass-filter method modified in this study as an oral dosage form of salmon calcitonin (SCT), a suspension of liposomes containing SCT was administered to rats at a dose of 10 μg SCT/kg. Each type of DL showed better efficacy than its inner liposomes alone. The decrease in plasma calcium level was dependent on the electrical charge and particle size of the inner liposomes. The hypocalcemic efficacy of DL encapsulating SCT-loading cationic liposomes relative to that after subcutaneous administration of SCT at a dose of 1 μg/kg was 6.47%, which was the largest value obtained. These results indicated that not only the particle size but also the electrical charge of inner liposomes affect intestinal absorption. This study verified that the efficacy was increased because of the decrease in diameter of the inner liposomes and the use of lipid with a positive charge. These findings concluded that DL might be useful as an oral dosage form of SCT. Drug Dev. Res. 58:253–257, 2003. © 2003 Wiley-Liss, Inc.

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.

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.

Poly (DL-lactic acid), irinotecan and polyethylene glycol monostearate were dissolved in acetone, and copre-cipitated by the addition of water. Then, the organic solvent was evaporated. The nanoparticle-containing suspension (NP-S) obtained by that coprecipitation was characterized both in vitro and in vivo. The nanoparticles showed a mean diameter of 150nm with its distribution of 110 to 270nm. At least 20% (w / w) of the drug was incorporated in the nanoparticles. These particle characteristics of NP-S were reproducibly obtained. When the antitumor effect was examined by the i.v. administration at repeated doses of 20mg irinotecan eq. / kg / day for 3 days (20×3 mg irinotecan eq. / kg) using mice bearing sarcoma 180 subcutaneously, NP-S was found to be sig-nificantly effective and it also tended to show a better suppression of tumor growth than an irinotecan hydrochloride (CPT-11) aqueous solution. After i.v. injections in rats, NP-S retained the plasma concentration of irinotecan longer than a CPT-11 aqueous solution. These findings suggest that NP-S may possibly improve the action of irinotecan against solid tumors.

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.

The absorption of amoxicillin (AMX) administered orally was studied in non-fasted rats. The rats received 15 and 50 mg/kg of AMX in two dosage forms, a suspension and a solution. Plasma concentrations of AMX were determined by HPLC. When AMX was administered at 15 mg/kg, there was no significant difference in C max , T max , AUC and MRT values between the dosage forms. No significant difference in C max , T max , AUC 0 -24h , and MRT 0 -24h was observed at 50 mg/kg either. However, the mean plasma concentration at 12 h of the solution was larger than those of the suspension. The difference was considered to be caused by an inadvertent scattering of the data. The AUC 0 -24h , values at 50 mg/kg were 3.17 times larger than those at 15 mg/kg for the solution, and 3.44 times larger for the suspension. A comparison with AUC values in fasted rats reported previously revealed the bioavailability of AMX to decrease due to the effect of food.

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.

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.

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 MMCE-glu-MMCEB-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.

For the self-treatment of hypoglycemia in diabetic patients receiving oral hypoglycemic drugs or insulin injection, we attempted to prepare quickly disintegrating glucose tablets to make them easy to swallow without drinking water. Tablets containing 2, 5 and 10% microcrystalline cellulose were prepared by direct compression at forces of 0.04, 0.06 and 0.12t/cm2. The hardness and water absorption properties were measured as characteristics of the tablets. Changes in the blood glucose level after the oral administration of two tablets were examined using hypoglycemic male rabbits given a subcutaneous injection of one unit of insulin. The intra-oral disintegration time of the glucose tablets was measured in three healthy volunteers who were each administered five tablets.The hardness of the tablets increased as the concentration of microcrystalline cellulose and force of compression increased. The highest value of hardness was 5.27kg (10%, 0.12t/cm2), and the lowest was 1.11kg (2%, 0.04t/cm2). The water absorption rate increased with the concentration of microcrystalline cellulose. The intra-oral disintegration time of the glucose tablets increased as the compression force increased. The minimum value was 83s (2%, 0.04t/cm2) and the maximum 203s (10%, 0.12t/cm2). The results of a multiple regression analysis showed that the tablet hardness correlated closely with the concentration of microcrystalline cellulose in the tablets and the compression force applied. The factors influencing the characteristics of the glucose tablets prepared in this study could be quantitatively analyzed by a multiple regression analysis.

The absorption of amoxicillin (AMX) administered orally was studied in rats. Male Sprague-Dawley rats received 7, 15, 25 and 50 mg/kg of AMX in two dosage forms, a suspension and a solution. Plasma concentrations of AMX were determined by HPLC. When AMX was administered at 7 mg/kg, there was no significant difference in C max , T max , AUC and MRT values between the dosage forms. At 50 mg/kg, there was no significant difference in the plasma concentrations of AMX, but the C max and AUC values of the suspension were significantly higher than those of the solution. The relationship between dose, and C max and AUC values for the suspension had a good linear relationship, y = 0.113642x - 0.05082, r = 0.995, and y = 0.727784x - 0.56625, r = 0.997, respectively. Thus AMX had a linear pharmacokinetic profile at doses from 7 to 50 mg/kg after its oral administration as a suspension, and the dosage form affected the bioavailability of AMX.

The effect of soybean oil refuse powder (SOR) when used as a vehicle on the absorption of oxolinic acid (OXA) powder in chicken, the dissolution profile of OXA and the correlation between in vivo and in vitro study were examined. To examine in vivo bioavailability, chickens fed or fasted were studied using a 2 x 2 crossover design. The OXA was administered OXA or OXA-SOR (1 : 9) mixture 20 mg OXA/kg. In vitro dissolution rates for OXA and OXA-SOR were measured using the paddle (PD) and the rotatory dialysis cell dissolution (PTSW) methods. Maximum plasma concentration (Cmax) and area under the curve (AUC) were significantly increased by the addition of SOR to OXA. Differences between OXA and OXA-SOR were more remarkable under fasted as compared with fed condition. In vitro dissolution rates of OXA-SOR pH 1.2, 6.5 and 7.2 as determined by the PD and the PTSW methods were increased in the presence of SOR vehicle. Differences between OXA and OXA-SOR in vitro dissolution rates were greater than in vivo bioavailability. Correlation between in vitro release (%) and in vivo absorption (%) showed good linearity (gamma=0.8805-0.9999).