• Journal of Pharmaceutical Investigation
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• v.37 no.1
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• pp.45-49
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• 2007

Dextran-5-aminosalicylic acid conjugate (dextran-5-ASA) was in vitro-evaluated as a polymeric colon-spe-cific prodrug of 5-aminosalicylic acid (5-ASA). Chemical stability of dextran-5-ASA in the pH 1.2 or 6.8 buffer solutions was investigated at 37 for 6 hrs. The dextran backbone was not degraded and no 5-ASA release was detected. Moreover, dextran-5-ASA neither liberated 5-ASA in the homogenates of the small intestine of rats nor was transported across Caco-2 cell monolayers, suggesting no significant loss of dextran-5-ASA during transit through the upper intestine. Furthermore, incubation of dextran-5-ASA in 10% cecal contents of rats released about 37% and 55% of 5-ASA bound to dextran in 8 hr and 24 hr, respectively. While that with either esterase or dextranase failed to liberate 5-ASA from the polymeric prodrug, incubation of dextran-5-ASA with both esterases and dextranse released 5-ASA up to about 24% of 5-ASA bound to dextran. These results suggest that, after oral administration of dextran-5-ASA, the polymeric prodrug is delivered specifically to and releases 5-ASA in the large intestine, and reveal that the 5-ASA release by cleavage of the ester bond requires precedent depolymerization of the dextran backbone.

• Macromolecular Research
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• v.12 no.1
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• pp.71-77
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• 2004

We have synthesized various types of poly(ethylene glycol) (PEG)-ibuprofen conjugates by nucleophilic substitution of bromo-terminated PEG with ibuprofen-Cs salt. The conversion of the terminal hydroxyl groups to bromo-termini was quantitative, as was the drug conjugation process, which suggests that the present synthetic method is very useful for the preparation of PEG-based prodrugs from pharmaceuticals having carboxyl functionalities. The drug-release behavior of the prodrugs was examined in both phosphate buffer (PBS, pH 7.4) and rat plasma. From the drug-release behavior in PBS, we determined that each prodrug has high storage stability. The drug-release rate was observed to be much faster in rat plasma than in buffer solution as a result of the acceleration effect provided by enzymes present in the plasma. The drug-release rate in rat plasma depends on the degree of molecular aggregation of the prodrugs, which can be changed effectively by the nature of their spacer groups or by the use of Pluronic as the polymer carrier.

• Macromolecular Research
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• v.12 no.1
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• pp.63-70
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• 2004

We have synthesized various types of poly(ethylene glycol) (PEG)-ibuprofen conjugates by the nucleophilic substitution of bromo-terminated PEG with ibuprofen-Cs salt; PN (Pluronic) was also used in place of PEG. All the bromo-terminated PEGs and PN were obtained in high yield. Conversions of the terminal hydroxyl groups to bromo-termini were quantitative, as were the drug conjugation processes. The Ι$_1$/Ι$_3$values obtained from solutions of the ibuprofen-conjugated prodrugs are summarized in relation to those of ibuprofen in water and in aqueous solutions of the original PEG, PN, and several ordinary surfactants. We believe that the fully hydrophilic PEG is completely hydrated and forms no hydrophobic pocket by segment aggregation. These results indicate that the probe environment is significantly hydrophobic, particularly in the solution of prodrug PN, for which the ratio is similar to that obtained from typical micelles of surfactants. The results suggest, therefore, that the present synthetic method is very useful for preparing PEG-based prodrugs from pharmaceuticals having carboxyl functionalities.

• Journal of Biomedical Engineering Research
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• v.28 no.4
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• pp.484-493
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• 2007

Two polymeric prodrugs of PGE1 (prodrugs IVg and PNg) were newly synthesized. The drug conjugation proceeded in quantitative yield without decomposition of PGE1 to PGA1. With two types conjugates, PEG-PGE1 and PN-PGE1 with different spacer groups, we first discovered a possibility of slow release of PGE1 in blood circulatory system. PGE1 is conjugated with PEG and PN through the long alkylene spacers, and their availability as polymeric prodrugs is evaluated. Their drug-releasing behavior was examined both in phosphate buffer (pH=7.4) and rat plasma. Each prodrug was known to be highly stabile in the buffer solution. The drug-releasing rate became much faster in rat plasma than in the buffer solution due to the acceleration by the plasma enzymes. The drug-release was found to reach a plateau in rat plasma because the released PGE1 or its derivatives may be captured or decomposed by the plasma proteins. The slower drug-releasing rate of pro drug PNg in rat plasma is reasonably attributed to the molecular aggregation due to the hydrophobic bonding between the PGE1 moieties and spacers.