It is well known that the oral bioavailability of peptide and protein drugs is generally poor because they are extensively degraded by proteases in the gastrointestinal tract and impermeable through the intestinal mucosa. Therefore, various approaches have been examined to overcome the delivery problems of these peptides and to improve their absorption via the gastrointestinal tract. Of these approaches, a potentially useful approach to solve these delivery problems may be chemical modification of peptides and proteins to produce prodrugs and analogues. Thus, it is plausible that this chemical approaches may protect peptides against degradation by peptidases and other enzymes present at the mucosal barrier and renders the peptides and proteins more lipophilic, resulting in increased bioavailability. From these standpoints, we synthesized lipophilic derivatives of peptides and proteins such as thyrotropin-releasing hormone (TRH), tetragastrin (TG), calcitonin and insulin by chemical modification with fatty acids. The pharmacological activities of these derivatives were relatively high as compared with the native peptides. A significant increase in the intestinal absorption of these derivatives of peptides was observed in comparison with native peptides. Overall, the effects of acylation on the intestinal absorption of these peptides were more predominant in the large intestine than those in the small intestine. In addition, these derivatives were more stable than the parent peptides in homogenates of the various intestinal mucosae. We also examined the intestinal transport characteristics of TG and its acyl derivatives using Caco-2 cell monolayer system in order to assess the contribution of enzymatic and transport barriers on their intestinal absorption. The degradation clearance of TG on the apical membrane was decreased by chemical modification with fatty acids. In addition, the permeability clearance of TG was improved by the acylation. On the other hand, CLp value of carboxyfluorescein, a paracellular transport marker, was increased by the coadministration with acyl-TGs, suggesting that these derivatives have absorption enhancing actions and may enhance themselves across the Caco-2 cell monolayers. In summary, this chemical modification approaches may be useful to improve the intestinal absorption of peptides and proteins.

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Polymeric prodrugs having a basic side chain were synthesized by mechanochemical solid-state polymerization, and the nature of drug release of these polymeric prodrugs was investigated. Two kinds of methods, flow-through-cell and flask-shaking method, were used for hydrolysis of polymeric prodrugs. Drug release in flow-through-cell method can be considered to be a model experiment under in vivo condition, and the polymeric prodrugs synthesized in the present reactions eventually released the drugs quantitatively. It was also shown that the hydrolysis (drug release) profiles apparently follow a first-order kinetics. On the other hand, the drug release in flask-shaking method ceased before its completion due to lack of sink conditions. The flask-shaking method, however, was used in this study, since the 100% drug release time can be deduced by the rate constant of apparent first-order reaction calculated from the data of initial stage of drug release. The polymeric prodrugs having 5-fluorouracil (5-FU) and pyridyl group as a side chain were prepared by mechanochemical polymerization. The rate of drug release increased with an increase in the content of basic group in the copolymer. The plots of the rate constant as a function of the ratio of the basic monomer in copolymer exhibited exponential curves under the present experimental conditions. It was also shown that the rate of drug release is influenced by the nature of the basic group. The hybrid polymeric prodrugs were synthesized by mechanochemical polymerization of the methacryloyl derivatives of 5-FU and pyridoxamine which possesses a pyridyl group. Although pyridoxamine was not released from the hybrid polymeric prodrugs thus obtained, the rate of drug release of 5-FU can be controlled by the amount of the pyridoxamine in polymeric prodrug. These results provided the fundamental and significant information for the syntheses of novel hybrid polymeric prodrugs possessing a wide variety of drug as a side chain.

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We have developed a physiological model for free and liposomal DOX to calculate the time course of free DOX in extracellular space of tumor tissue and to calculate area under the curve as an index of antitumor effect of doxorubicin. Simulations were performed to clarify the relationship between antitumor effect and pharmacokinetic or physicochemical parameters of liposomes under different physiological conditions of tumor tissues. The importance of long circulation time of liposomes was confirmed and the optimum rate of drug release from long circulating liposomes was found to depend on tumor sensitivity to the antitumor agent. This simulation can provide useful information in development of optimized drug carrier for antitumor agents.

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[in Japanese]

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The effects of ultrasonic irradiation on the skin-moisturing and the skin penetration of sodium hyaluronate (HA) were measured in hairless rats. Ultrasound (2.15 MHz) with different power and pulse duty was applied for 10 min on the abdominal site which was pretreated with 1% HA for 3 h. Relative conductance on the skin surface was increased by the ultrasonication. The content of HA in the stratum corneum (measured using fluorescence-labeled HA) was also increased by the treatment. In addition, a good relationship was observed between the two values. The ultrasonic treatment may be utilized as a new tool to increase the HA penetration and the humectant efficacy into and on the skin surface.

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To develop new dosage form of pirarubicin (THP) for hepatic arterial infusion chemotherapy, we investigated constituents of THP-emulsion, stability of THP in emulsions, and release characteristics of THP from emulsions. The THP-emulsion was prepared by high pressure homogenization using three-way cock. Water and non-ionic contrast media (CM), which are Iopamidol, Iohexol and Ioversol, were used as solvents for THP. Sesame oil, soybean oil, and Lipiodol-ultrafluid (LPD) were used as oily phase, and surfactants and saccharides were used as additives to make the emulsion stable. Stable w/o and o/w types of emulsions were obtained only when THP was dissolved in CM and mixed with LPD. Stability of THP in CM was examined and Iopamidol (Iopamiron 300) was selected as the solvent. Release characteristics of THP from the emulsion consisted of Iopamiron 300 and LPD was examined by means of multistoried method using saline. THP was released rapidly from the o/w type of emulsion, but gradually from the w/o type of emulsion. In this study, we could propose o/w and w/o types of THP-emulsions using Iopamiron 300 and LPD as constituents to carry preclinical study for hepatic arterial infusion chemotherapy.

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In order to achieve optimum drug delivery for clinical application, the bioconjugated drugs with polymeric modifiers must be designed to show desirable biopharmaceutical characteristics. Pharmacokinetics of bioconjugated drugs is greatly affected by physicochemical characteristics of polymeric modifiers themselves. Therefore, it is very important to study the relationships between pharmacokinetics of polymeric modifiers and their physicochemical properties typified with molecular weight, electric charge, and hydrophilic-lipophilic balance and so on. In the present study, we synthesized two anionized polyvinylpyrrolidone (PVP) by radical copolymerization between vinylpyrrolidone monomer and acrylic acid or vinylsulfonic acid co-monomer to assess the influence of anionic groups on pharmacokinetics of polymeric modifiers. The resulting anionized PVPs were eliminated from the circulation more rapidly than nonionic PVP. An increase of negative charge on polymeric modifier occurred a decrease of circulation life-time. In addition, though PVP showed no specific tissue distribution, anionized PVP was markedly accumulated to kidney at 3 hr after iv injection. These fundamental approach will enable to chose the optimum polymeric modifiers for features of drugs or for purposes of bioconjugation.

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[in Japanese]

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