Journal - Association of Official Analytical Chemists, Jul 1, 1976
Pancuronium bromide (PCBr), a neuro-muscular blocking agent, was determined quantitatively in aqu... more Pancuronium bromide (PCBr), a neuro-muscular blocking agent, was determined quantitatively in aqueous solution by ion-pair extraction. Separate determination of PCBr and degradation products was possible after thin layer chromatography. The procedure was developed by using a theoretical approach. Favorable conditions were calculated from the ion-pair extraction constant. The drug was determined with bromothymol blue at pH 9.0, using one extraction in the direct procedure and 2 successive extractions in the combined elution-extraction process after thin layer chromatography. In the direct method, 0.100 mg PCBr was determined with a reproducibility of +/- 1.0%.
The purpose of this study was to elucidate the physical structure of solid dispersions of the ant... more The purpose of this study was to elucidate the physical structure of solid dispersions of the antiviral agent phenyl]-2-methyl-3-furancarbothioamide) with polyvinylpyrrolidone (PVP K30). Solid dispersions were prepared by coevaporating UC-781 with PVP K30 from dichloromethane. The physicochemical properties of the dispersions were evaluated in comparison with the physical mixtures by differential scanning calorimetry (DSC), X-ray powder diffraction, and FT-IR spectroscopy. We investigated the single crystal structure of pure UC-781. The data from single crystal analysis showed that UC-781 crystallized with orthorhombic symmetry in the space group Pcab. Its cell parameters were found to be ; a l 8.1556(7) A / , b l 17.658(2) A / and c l 23.609(2) A / ; the unit cell was made up of eight molecules of UC-781. The molecules formed intermolecular hydrogen bonds between NH and thio groups, and were packed in a herringbone-like structure. The data from X-ray powder diffraction showed that crystalline UC-781 was changed into the amorphous state by co-evaporating it with PVP K30. From differential scanning calorimetry analysis, UC-781 peaks were observed in the DSC curves of all physical mixtures, while no peaks corresponding to the drug could be observed in the solid dispersions with the same drug composition up to the concentration of 50 % w/w. The data from FT-IR spectroscopy showed the distortions and disappearance of some bands from the drug, while other bands were too broad or significantly less intense compared with the physical mixtures of the crystalline drug in PVP K30. Furthermore, the results from IR spectroscopy demonstrated that UC-781 interacted with PVP K30 in solid dispersions through intermolecular H-bonding.
International Journal of Pharmaceutics, Mar 1, 2002
The aim of this study was to determine the intestinal absorption characteristics of the antiviral... more The aim of this study was to determine the intestinal absorption characteristics of the antiviral agent UC-781 and to optimize the experimental conditions of the in vitro system for low solubility compounds. The absorption potential of UC-781 was studied with the Caco-2 system and with the rat intestinal perfusion technique. The low solubility of UC-781 required the use of solubility/dissolution rate enhancing agents (e.g. VitE-TPGS, Gelucire 44/14). The creation of sink conditions in the receiver compartment of the Caco-2 system was a prerequisite to reliably study the transport of this poorly soluble compound. After inclusion of VitE-TPGS in the acceptor solution, UC-781 could be characterized as a class II drug of the Biopharmaceutical Classification System (low solubility, high permeation across membranes). A significant concentration-dependent decrease in transport of UC-781 was observed upon increasing the concentration of VitE-TPGS in the apical compartment. This observation contrasts to the absorption enhancing properties of VitE-TPGS, and can probably be attributed to a decrease in the concentration of free UC-781 when using higher concentrations of the solubility/dissolution rate enhancing agents. The use of Gelucire 44/14 as a solubilizing agent resulted in a batch-dependent degradation of UC-781. The inclusion of the solubility/dissolution rate-enhancing agent VitE-TPGS did not result in absorption enhancement in the intestinal perfusion technique.
European Journal of Pharmaceutics and Biopharmaceutics, Jul 1, 1999
The enthalpic relaxation of three amorphous benzodiazepines, diazepam, temazepam and triazolam wa... more The enthalpic relaxation of three amorphous benzodiazepines, diazepam, temazepam and triazolam was studied using differential scanning calorimetry for ageing temperatures which were below the glass transition temperature, and ageing times up to 16 h. Experimental determination of the relaxation enthalpy and the heat capacity change, both accompanying the glass transition, enabled us to calculate the extent of relaxation of the amorphous drugs at specific ageing conditions. Fitting of the relaxation function to the Williams-Watts two parameter decay function led to calculation of the mean relaxation time constant tau and the molecular relaxation time distribution parameter beta. The mean relaxation time constants for the three drugs increased from approximately ten h at the glass transition temperature with more than eight orders of magnitude at 66 K below the glass transition temperature. It was found that the benzodiazepines exhibited significant molecular mobility until approximately 50 K below the glass transition temperature; below this temperature molecular mobility becomes unimportant with respect to the shelf life stability. Hence the presented procedure provides the formulation scientist with a tool to set storage conditions for amorphous drugs and glassy pharmaceutical products.
Artemisinin and its derivatives are becoming interesting alternatives to the commonly used antima... more Artemisinin and its derivatives are becoming interesting alternatives to the commonly used antimalarial drugs because they are efficient in treating severe and multidrug resistant forms of Plasmodium falciparum malaria. A major drawback is the occurrence of recrudescence some time after treatment. Moderate oral bioavailability has been suggested as a possible cause. As one of the factors that might limit absorption after oral administration, we studied the intestinal permeability using an in vitro system of the intestinal mucosa, Caco-2. Concentrations of artemisinin were determined by UV after alkaline degradation, while for sodium artesunate, a capillary electrophoresis method was developed. Artemisinin easily crossed the epithelial cells by passive diffusion (P app ) 30.4 ± 1.7 × 10 -6 cm s -1 , pH 7.4). Permeability of the hemisuccinate analogue, sodium artesunate, was 8-fold lower (P app ) 4.0 ± 0.4 × 10 -6 cm s -1 at pH 7.4) and strongly dependent on pH, which might result in site dependent resorption in an in vivo situation. Enzyme catalyzed ester hydrolysis of sodium artesunate in Caco-2 monolayers to the biologically active metabolite, dihydroartemisinin, was moderate. The results indicate that the transepithelial permeability is probably not a limiting factor in the overall absorption process after oral administration of artemisinin or sodium artesunate. Solubility, dissolution rate, stability, and first-pass metabolism are suggested as alternative limiting factors.
ABSTRACT Eight different formulations for the oral administration of 8-methoxypsoralen (8-MOP) we... more ABSTRACT Eight different formulations for the oral administration of 8-methoxypsoralen (8-MOP) were compared in rabbits. Plasma levels of 8-MOP were measured using a high-performance liquid chromatography method. Partly dissolved 8-MOP resulted in higher plasma levels than the solid form. Addition of corn oil to a semisolid matrix (SSM) increased AUC values and peak plasma concentrations indicating that the oil component has an important influence on the absorption of 8-MOP in the rabbit. No marked differences were found using oils with differing fatty acid composition.
International Journal of Pharmaceutics, Nov 1, 1992
In order to develop a colon-specific drug delivery system, copolymers of 2-hydroxyethyl methacryl... more In order to develop a colon-specific drug delivery system, copolymers of 2-hydroxyethyl methacrylate and methyl methacrylate were prepared in the presence of bis(methacryloylamino)azobenzene. The conditions of polymerization were optimized to prevent crosslinking. Film coatings were prepared with the azo polymers. The films were insoluble in simulated gastric and intestinal juice. Dependent on the content of the hydrophilic groups in the polymers, the films were more or less permeable to water. In vitro and in vivo tests prove that it is possible to use the polymers to deliver drugs to the large intestine. Due to the presence of the azo compound, the azo polymer coatings can be degraded by intestinal bacteria.
To explore the usefulness of fruit extracts as enhancers of the oral absorption of esterase-sensi... more To explore the usefulness of fruit extracts as enhancers of the oral absorption of esterase-sensitive prodrugs. Inhibition of esterase-mediated degradation by nature-identical fruit extracts was evaluated using 1) p-nitrophenylacetate (model substrate for esterase-activity) in rat intestinal homogenates and 2) bis(isopropyloxycarbonyloxymethyl)-(R)-9-[(2-phosphonomethoxy++ +)propyl]adenine [bis(POC)-PMPA] (esterase-sensitive prodrug of the antiviral agent PMPA) in Caco-2 cell homogenates and in intestinal homogenates from rat, pig and man. Subsequently, transport of the ester prodrug was studied across Caco-2 monolayers in the presence or absence of fruit extracts. In homogenates from rat ileum, the esterase activity could be reduced significantly by the inclusion of fruit extracts (1%): the initial enzymatic degradation of p-nitrophenylacetate was inhibited by 77% (strawberry), 16% (passion fruit) and 57% (banana). A similar inhibition of bis(POC)-PMPA metabolism by fruit extracts was observed in intestinal homogenates from several species and in homogenates from Caco-2 cells. Transport of total PMPA across Caco-2 monolayers was enhanced 3-fold by co-incubation with strawberry extract (1%). The fraction of intact prodrug appearing in the acceptor compartment increased from virtually zero to 67%. The results suggest that co-incubation with nature-identical fruit extracts might be useful as a strategy to enhance the transepithelial transport of esterase-sensitive prodrugs through inhibition of intracellular metabolism of the prodrug.
Free radical polymerization converts aqueous solutions of methacrylated inulin into cross-linked ... more Free radical polymerization converts aqueous solutions of methacrylated inulin into cross-linked hydrogels. The purpose of this work was to study the hydrogel formation and to characterize the fully cured hydrogels. The gelation process of aqueous solutions of methacrylated inulin was monitored as a function of time by means of linear oscillatory shear measurements, at a fixed frequency and amplitude. The fully cured inulin hydrogels were characterized by measurement of the frequency-dependency of the linear elastic modulus G′. The effects of the degree of substitution and feed concentration of methacrylated inulin on both the gelation kinetics and the rigidity of the obtained hydrogels were determined. The effect of the concentration of the initiators of the radical polymerization reaction has been studied as well. The weight fraction of polymer which was not incorporated in the hydrogel networks was determined using the anthrone reaction, and physical chain entanglements were determined by solution viscosity measurements. The gelation kinetics and the elastic modulus were proportional to the degree of substitution and feed concentration of methacrylated inulin. Increasing concentrations of radical-forming compounds also accelerated the hydrogel formation, but lowered the elastic modulus of the obtained hydrogels. The amount of polymer chains incorporated in the hydrogel network seemed to be especially influenced by the degree of substitution of the derivatized inulin, and for a feed concentration of 27% w/w of methacrylated inulin, entanglements have to be accounted for. The gelation kinetics and the elastic modulus of inulin hydrogels are not only affected by the degree of substitution and the feed concentration of methacrylated inulin, but also by the concentration of the initiators of the free radical polymerization reaction.
Journal - Association of Official Analytical Chemists, Jul 1, 1976
Pancuronium bromide (PCBr), a neuro-muscular blocking agent, was determined quantitatively in aqu... more Pancuronium bromide (PCBr), a neuro-muscular blocking agent, was determined quantitatively in aqueous solution by ion-pair extraction. Separate determination of PCBr and degradation products was possible after thin layer chromatography. The procedure was developed by using a theoretical approach. Favorable conditions were calculated from the ion-pair extraction constant. The drug was determined with bromothymol blue at pH 9.0, using one extraction in the direct procedure and 2 successive extractions in the combined elution-extraction process after thin layer chromatography. In the direct method, 0.100 mg PCBr was determined with a reproducibility of +/- 1.0%.
The purpose of this study was to elucidate the physical structure of solid dispersions of the ant... more The purpose of this study was to elucidate the physical structure of solid dispersions of the antiviral agent phenyl]-2-methyl-3-furancarbothioamide) with polyvinylpyrrolidone (PVP K30). Solid dispersions were prepared by coevaporating UC-781 with PVP K30 from dichloromethane. The physicochemical properties of the dispersions were evaluated in comparison with the physical mixtures by differential scanning calorimetry (DSC), X-ray powder diffraction, and FT-IR spectroscopy. We investigated the single crystal structure of pure UC-781. The data from single crystal analysis showed that UC-781 crystallized with orthorhombic symmetry in the space group Pcab. Its cell parameters were found to be ; a l 8.1556(7) A / , b l 17.658(2) A / and c l 23.609(2) A / ; the unit cell was made up of eight molecules of UC-781. The molecules formed intermolecular hydrogen bonds between NH and thio groups, and were packed in a herringbone-like structure. The data from X-ray powder diffraction showed that crystalline UC-781 was changed into the amorphous state by co-evaporating it with PVP K30. From differential scanning calorimetry analysis, UC-781 peaks were observed in the DSC curves of all physical mixtures, while no peaks corresponding to the drug could be observed in the solid dispersions with the same drug composition up to the concentration of 50 % w/w. The data from FT-IR spectroscopy showed the distortions and disappearance of some bands from the drug, while other bands were too broad or significantly less intense compared with the physical mixtures of the crystalline drug in PVP K30. Furthermore, the results from IR spectroscopy demonstrated that UC-781 interacted with PVP K30 in solid dispersions through intermolecular H-bonding.
International Journal of Pharmaceutics, Mar 1, 2002
The aim of this study was to determine the intestinal absorption characteristics of the antiviral... more The aim of this study was to determine the intestinal absorption characteristics of the antiviral agent UC-781 and to optimize the experimental conditions of the in vitro system for low solubility compounds. The absorption potential of UC-781 was studied with the Caco-2 system and with the rat intestinal perfusion technique. The low solubility of UC-781 required the use of solubility/dissolution rate enhancing agents (e.g. VitE-TPGS, Gelucire 44/14). The creation of sink conditions in the receiver compartment of the Caco-2 system was a prerequisite to reliably study the transport of this poorly soluble compound. After inclusion of VitE-TPGS in the acceptor solution, UC-781 could be characterized as a class II drug of the Biopharmaceutical Classification System (low solubility, high permeation across membranes). A significant concentration-dependent decrease in transport of UC-781 was observed upon increasing the concentration of VitE-TPGS in the apical compartment. This observation contrasts to the absorption enhancing properties of VitE-TPGS, and can probably be attributed to a decrease in the concentration of free UC-781 when using higher concentrations of the solubility/dissolution rate enhancing agents. The use of Gelucire 44/14 as a solubilizing agent resulted in a batch-dependent degradation of UC-781. The inclusion of the solubility/dissolution rate-enhancing agent VitE-TPGS did not result in absorption enhancement in the intestinal perfusion technique.
European Journal of Pharmaceutics and Biopharmaceutics, Jul 1, 1999
The enthalpic relaxation of three amorphous benzodiazepines, diazepam, temazepam and triazolam wa... more The enthalpic relaxation of three amorphous benzodiazepines, diazepam, temazepam and triazolam was studied using differential scanning calorimetry for ageing temperatures which were below the glass transition temperature, and ageing times up to 16 h. Experimental determination of the relaxation enthalpy and the heat capacity change, both accompanying the glass transition, enabled us to calculate the extent of relaxation of the amorphous drugs at specific ageing conditions. Fitting of the relaxation function to the Williams-Watts two parameter decay function led to calculation of the mean relaxation time constant tau and the molecular relaxation time distribution parameter beta. The mean relaxation time constants for the three drugs increased from approximately ten h at the glass transition temperature with more than eight orders of magnitude at 66 K below the glass transition temperature. It was found that the benzodiazepines exhibited significant molecular mobility until approximately 50 K below the glass transition temperature; below this temperature molecular mobility becomes unimportant with respect to the shelf life stability. Hence the presented procedure provides the formulation scientist with a tool to set storage conditions for amorphous drugs and glassy pharmaceutical products.
Artemisinin and its derivatives are becoming interesting alternatives to the commonly used antima... more Artemisinin and its derivatives are becoming interesting alternatives to the commonly used antimalarial drugs because they are efficient in treating severe and multidrug resistant forms of Plasmodium falciparum malaria. A major drawback is the occurrence of recrudescence some time after treatment. Moderate oral bioavailability has been suggested as a possible cause. As one of the factors that might limit absorption after oral administration, we studied the intestinal permeability using an in vitro system of the intestinal mucosa, Caco-2. Concentrations of artemisinin were determined by UV after alkaline degradation, while for sodium artesunate, a capillary electrophoresis method was developed. Artemisinin easily crossed the epithelial cells by passive diffusion (P app ) 30.4 ± 1.7 × 10 -6 cm s -1 , pH 7.4). Permeability of the hemisuccinate analogue, sodium artesunate, was 8-fold lower (P app ) 4.0 ± 0.4 × 10 -6 cm s -1 at pH 7.4) and strongly dependent on pH, which might result in site dependent resorption in an in vivo situation. Enzyme catalyzed ester hydrolysis of sodium artesunate in Caco-2 monolayers to the biologically active metabolite, dihydroartemisinin, was moderate. The results indicate that the transepithelial permeability is probably not a limiting factor in the overall absorption process after oral administration of artemisinin or sodium artesunate. Solubility, dissolution rate, stability, and first-pass metabolism are suggested as alternative limiting factors.
ABSTRACT Eight different formulations for the oral administration of 8-methoxypsoralen (8-MOP) we... more ABSTRACT Eight different formulations for the oral administration of 8-methoxypsoralen (8-MOP) were compared in rabbits. Plasma levels of 8-MOP were measured using a high-performance liquid chromatography method. Partly dissolved 8-MOP resulted in higher plasma levels than the solid form. Addition of corn oil to a semisolid matrix (SSM) increased AUC values and peak plasma concentrations indicating that the oil component has an important influence on the absorption of 8-MOP in the rabbit. No marked differences were found using oils with differing fatty acid composition.
International Journal of Pharmaceutics, Nov 1, 1992
In order to develop a colon-specific drug delivery system, copolymers of 2-hydroxyethyl methacryl... more In order to develop a colon-specific drug delivery system, copolymers of 2-hydroxyethyl methacrylate and methyl methacrylate were prepared in the presence of bis(methacryloylamino)azobenzene. The conditions of polymerization were optimized to prevent crosslinking. Film coatings were prepared with the azo polymers. The films were insoluble in simulated gastric and intestinal juice. Dependent on the content of the hydrophilic groups in the polymers, the films were more or less permeable to water. In vitro and in vivo tests prove that it is possible to use the polymers to deliver drugs to the large intestine. Due to the presence of the azo compound, the azo polymer coatings can be degraded by intestinal bacteria.
To explore the usefulness of fruit extracts as enhancers of the oral absorption of esterase-sensi... more To explore the usefulness of fruit extracts as enhancers of the oral absorption of esterase-sensitive prodrugs. Inhibition of esterase-mediated degradation by nature-identical fruit extracts was evaluated using 1) p-nitrophenylacetate (model substrate for esterase-activity) in rat intestinal homogenates and 2) bis(isopropyloxycarbonyloxymethyl)-(R)-9-[(2-phosphonomethoxy++ +)propyl]adenine [bis(POC)-PMPA] (esterase-sensitive prodrug of the antiviral agent PMPA) in Caco-2 cell homogenates and in intestinal homogenates from rat, pig and man. Subsequently, transport of the ester prodrug was studied across Caco-2 monolayers in the presence or absence of fruit extracts. In homogenates from rat ileum, the esterase activity could be reduced significantly by the inclusion of fruit extracts (1%): the initial enzymatic degradation of p-nitrophenylacetate was inhibited by 77% (strawberry), 16% (passion fruit) and 57% (banana). A similar inhibition of bis(POC)-PMPA metabolism by fruit extracts was observed in intestinal homogenates from several species and in homogenates from Caco-2 cells. Transport of total PMPA across Caco-2 monolayers was enhanced 3-fold by co-incubation with strawberry extract (1%). The fraction of intact prodrug appearing in the acceptor compartment increased from virtually zero to 67%. The results suggest that co-incubation with nature-identical fruit extracts might be useful as a strategy to enhance the transepithelial transport of esterase-sensitive prodrugs through inhibition of intracellular metabolism of the prodrug.
Free radical polymerization converts aqueous solutions of methacrylated inulin into cross-linked ... more Free radical polymerization converts aqueous solutions of methacrylated inulin into cross-linked hydrogels. The purpose of this work was to study the hydrogel formation and to characterize the fully cured hydrogels. The gelation process of aqueous solutions of methacrylated inulin was monitored as a function of time by means of linear oscillatory shear measurements, at a fixed frequency and amplitude. The fully cured inulin hydrogels were characterized by measurement of the frequency-dependency of the linear elastic modulus G′. The effects of the degree of substitution and feed concentration of methacrylated inulin on both the gelation kinetics and the rigidity of the obtained hydrogels were determined. The effect of the concentration of the initiators of the radical polymerization reaction has been studied as well. The weight fraction of polymer which was not incorporated in the hydrogel networks was determined using the anthrone reaction, and physical chain entanglements were determined by solution viscosity measurements. The gelation kinetics and the elastic modulus were proportional to the degree of substitution and feed concentration of methacrylated inulin. Increasing concentrations of radical-forming compounds also accelerated the hydrogel formation, but lowered the elastic modulus of the obtained hydrogels. The amount of polymer chains incorporated in the hydrogel network seemed to be especially influenced by the degree of substitution of the derivatized inulin, and for a feed concentration of 27% w/w of methacrylated inulin, entanglements have to be accounted for. The gelation kinetics and the elastic modulus of inulin hydrogels are not only affected by the degree of substitution and the feed concentration of methacrylated inulin, but also by the concentration of the initiators of the free radical polymerization reaction.
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