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Publications (4)13.61 Total impact

  • Karin Fredholt, Dorrit Høj Larsen, Claus Larsen
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    ABSTRACT: Rate constants for transfer of naproxen and lidocaine from different oils and oil mixtures to aqueous buffer, pH 6.00, were determined using the rotating dialysis cell. Significantly different first-order rate constants related to attainment of equilibrium, kobs, were derived depending on the type of oil/oil mixtures used in the release experiments. For the drugs a linear correlation was found between log kobs and the logarithm of the partition coefficient Papp: log kobs=−0.68 log Papp−0.25 (kobs in h−1, n=26). A linear relationship was observed between the calculated and experimentally determined Papp values for the oil mixtures investigated. The specific rate constants, kow and kwo, related to the partition process were derived from the determined kobs and Papp values. The rate constant kow representing the rate of transfer of the solute from the oil phase to the aqueous buffer was shown to be strongly dependent on the partition coefficient according to the relationship: log kow=−0.68 log Papp−log(Papp+1)−0.25 (kow in h−1, n=26). In particular, diminished release rates were seen for oil mixtures containing castor oil most likely afforded by hydrogen bonding between the solute and the hydroxy groups of the latter vegetable oil. In this study it has been possible to alter Papp for a specific compound up to a factor of 10 by variation of the composition of the oil vehicle. Such a span of Papp values results in in vitro release rates differing a factor of 37. Thus, by proper design of the oil vehicle composition it should be possible to modify the release rate for a specific compound within certain limits.
    European Journal of Pharmaceutical Sciences 10/2000; · 2.99 Impact Factor
  • Dorrit Høj Larsen, Karin Fredholt, Claus Larsen
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    ABSTRACT: The rate constants for transfer of model compounds (naproxen and lidocaine) from oily vehicle (Viscoleo®) to aqueous buffer phases were determined by use of the rotating dialysis cell. Release studies were done for the partly ionized compounds at several pH values. A correlation between the overall first-order rate constant related to attainment of equilibrium, kobs, and the pH-dependent distribution coefficient, D, determined between oil vehicle and aqueous buffer was established according to the equation: log kobs=−0.71 log D−0.22 (kobs in h−1). Based on this correlation it was suggested that the rate constant of a weak electrolyte at a specified D value could be considered equal to the kobs value for a non-electrolyte possessing a partition coefficient, Papp, the magnitude of which was equal to D. Specific rate constants kow and kwo were calculated from the overall rate constant and the pH-dependent distribution coefficient. The rate constant representing the transport from oily vehicle to aqueous phase, kow, was found to be significantly influenced by the magnitude of the partition coefficient Papp according to: log kow=−0.71 log Papp−log(Papp+1)−0.22 (kow in h−1).
    European Journal of Pharmaceutical Sciences 10/2000; · 2.99 Impact Factor
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    ABSTRACT: The Leu-enkephalin analogue (Tyr-D-Ala-Gly-Phe-Leu-NH(2)) was synthesized together with three esters prodrugs hereof. The prodrugs synthesized were the O-acetyl, O-propionyl and O-pivaloyl99%) and in good yields (60-75%). The chemical and enzymatic stability of the prodrugs has been investigated in detail. The prodrugs studied are quite chemically stable and the degradation of the prodrugs follows the pattern previously shown for similar esters (U-shaped pH-profile; maximal stability at pH 4-5). The prodrugs are degraded quantitatively in plasma to the parent peptide with half-lives in the range 2.9 min-2.6 h. Type B esterases were shown to be involved in the degradation as the half-lives increased in the presence of paraoxon. No significant stabilization was seen in 10% porcine gut homogenate. Half-lives in the same order were seen for the analogue and the prodrugs in pure Leucine aminopeptidase solution. The analogue was stable in Carboxypeptidase A solution whereas a faster degradation of the prodrugs was seen in this media. Furthermore the transport properties of the compounds has been studied. A P(app) value of 0.284x10(-6) cm/s for the analogue was obtained for the transport across Caco-2 cell monolayers in the BL-AP direction. The P(app) values were increased by a factor of 2, 7 and 18 for the acetyl-, propionyl- and pivaloylprodrug. The increase could be explained by higher lipofilicities of the prodrugs compared to the analogue.
    Journal of Controlled Release 03/2000; 63(3):261-73. · 7.63 Impact Factor
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    ABSTRACT: The Leu-enkephalin analogue (Tyr-d-Ala-Gly-Phe-Leu-NH2) was synthesized together with three esters prodrugs hereof. The prodrugs synthesized were the O-acetyl, O-propionyl and O-pivaloyl esters of the tyrosine phenolic group. The compounds were isolated in good purity (HPLC purity >99%) and in good yields (60–75%). The chemical and enzymatic stability of the prodrugs has been investigated in detail. The prodrugs studied are quite chemically stable and the degradation of the prodrugs follows the pattern previously shown for similar esters (U-shaped pH-profile; maximal stability at pH 4–5). The prodrugs are degraded quantitatively in plasma to the parent peptide with half-lives in the range 2.9 min–2.6 h. Type B esterases were shown to be involved in the degradation as the half-lives increased in the presence of paraoxon. No significant stabilization was seen in 10% porcine gut homogenate. Half-lives in the same order were seen for the analogue and the prodrugs in pure Leucine aminopeptidase solution. The analogue was stable in Carboxypeptidase A solution whereas a faster degradation of the prodrugs was seen in this media. Furthermore the transport properties of the compounds has been studied. A Papp value of 0.284×10−6 cm/s for the analogue was obtained for the transport across Caco-2 cell monolayers in the BL-AP direction. The Papp values were increased by a factor of 2, 7 and 18 for the acetyl-, propionyl- and pivaloylprodrug. The increase could be explained by higher lipofilicities of the prodrugs compared to the analogue.
    Journal of Controlled Release. 02/2000;