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R Kinget

Publications and source records attributed to R Kinget.

At least 55 records · Page 3Linked to original sources
PubMed1998

Carrier mechanisms involved in the transepithelial transport of bis(POM)-PMEA and its metabolites across Caco-2 monolayers.

PURPOSE: To investigate the role of carrier mechanisms in: [1] the polarized transport of the bis(pivaloyloxymethyl)- [bis(POM)-] ester prodrug of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA] and [2] the directional secretion of its metabolites. METHODS: Caco-2 monolayers were used to study the modulation effect of carriers on the transport of bis(POM)-PMEA and the efflux of intracellularly formed metabolites mono(POM)-PMEA and PMEA from the cells. The interaction of bis(POM)-PMEA and its metabolites with the efflux mechanisms present in Caco-2 monolayers was investigated by testing the effect of various concentrations of verapamil (30, 100, 300, microns) or indomethacin (10-500 microns) on transport and efflux. RESULTS: Polarity in transport of bis(POM)-PMEA (50 micron) across Caco-2 monolayers was noted: transport of total PMEA [=bis(POM)-PMEA, mono(POM)-PMEA and PMEA] was significantly higher in basolateral (BL) to apical (AP) direction (14.5 +/- 0.4%) than transport in the opposite (AP to BL) direction (1.7 +/- 0.2%). This difference was reduced in a concentration dependent way when verapamil (0-100 microns) was included in both AP and BL incubation media. After loading the cells with bis(POM)-PMEA (100 micron) for 1 hr, studies on efflux of PMEA and mono(POM)-PMEA from the Caco-2 monolayers over a 3 hr period, revealed that both metabolites were preferentially secreted towards the AP compartment. Efflux of PMEA toward AP and BL compartments amounted to 14.6 +/- 1.1% and 5.3 +/- 0.4, respectively, of the initial intracellular amount of total PMEA, while efflux of mono(POM)-PMEA towards AP and BL compartments was limited to 2.3 +/- 0.1% and 0.5 +/- 0.1%, respectively. When 10 micron indomethacin was included in the AP incubation medium, efflux of PMEA was decreased to 7.8 +/- 0.3% and 3.3 +/- 0.3% towards the AP and BL compartments, respectively. The decrease in efflux by indomethacin was concentration-dependent up to 100 micron. Transepithelial transport of total PMEA was also reduced in the presence of 30 micron indomethacin, as reflected in smaller concentrations of PMEA and mono(POM)-PMEA in the acceptor compartment, irrespective of the transport direction. CONCLUSIONS: The data obtained in this study suggest that bis(POM)-PMEA is substrate for a P -glycoprotein-like carrier mechanism in Caco-2 monolayers, while its metabolites mono(POM)-PMEA and PMEA are transported by a non-P-glycoprotein efflux protein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Colonic drug targeting.

Specific targeting of drugs to the colon is recognized to have several therapeutic advantages. Drugs which are destroyed by the stomach acid and/or metabolized by pancreatic enzymes are slightly affected in the colon, and sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Treatment of colonic diseases such as ulcerative colitis, colorectal cancer and Crohn's disease is more effective with direct delivery of drugs to the affected area. Likewise, colonic delivery of vermicides and colonic diagnostic agents require smaller doses. This article is aimed at providing insight into the design considerations and evaluation of colonic drug delivery systems. For this purpose, the anatomy and physiology of the lower gastrointestinal tract are surveyed. Furthermore, the biopharmaceutical aspects are considered in relation to drug absorption in the colon and hence various approaches to colon-specific drug delivery are discussed.

Biodegradation, Environmental↗
PubMed1998

The release mechanism of an oral controlled-release delivery system for indomethacin.

This study was carried out to fully characterize the release kinetics of an oral controlled-release tablet formulation of indomethacin with xanthan gum. Matrix swelling, matrix erosion, and drug diffusion studies were performed to elucidate the operative release mechanisms of a tablet compressed from a ternary mixture of indomethacin-xanthan gum-lactose. Drug release tests were performed according to the USP paddle method in phosphate buffer pH 7.4, concurrently with the dissolution of the gum. Mean dissolution time (MDT) of the drug was calculated from the release profile and it was used as a parameter to evaluate the influence of (a) polymer content in the dosage form, (b) ionic strength of the medium, and (c) the rotation speed of the paddle on the release characteristics of the drug. There is a linear relationship between MDT and the inverse of polymer content. Within the range of ionic strength of the gastrointestinal tract, the salt concentration of the dissolution medium has a negative (inhibitory) effect on release rate of the drug and on matrix swelling. A positive (enhancing) influence of the salt concentration on drug diffusion in the hydrated matrices was noted. The polymer dissolution follows almost immediately the dissolution of the drug. A linear relationship between MDT and the inverse of paddle rotation speed has been observed. Swelling-controlled erosional process is the operative mechanism for indomethacin release from xanthan gum matrices.

Administration, Oral↗
PubMed1998

Estimation of the amount of water removed by gap and atomization air streams during pelletization in a rotary processor.

The purpose of this study was to estimate the amount of water removed by the gap and atomization air streams during pelletization by the wet granulation technique in a rotary processor and to test the hypothesis that the influence of the water addition rate on the pellet size (1,7) mainly originates from differences in the amount of water removed by these air streams. Estimations from flow, temperature, and relative humidity measurements of the air streams, and estimations from moisture content measurements, indicated that approximately 3.6 g of water/min was removed during spheronization. The estimations from the air streams' characteristics obtained for the water loss during the water addition phase (2.6 g/min) reflected the water removal during the later stages and did not reflect the overall rate of water removal during the total water addition phase as estimated from moisture content measurements (2.0 g/min). This was attributed to the fact that estimations from the air streams' characteristics could not take into account the early stages of the water addition phase. In these early stages, the amount of water removed was very limited. Using the foregoing estimations, differences in amount of water removed by the air streams could be compensated by adding more water when the water addition rate was decreased. This resulted in similar pellet sizes (geometric mean diameter of 800-850 microns) using different water addition rates. Thus, the hypothesis that the major influence of the water addition rate on the pellet size mainly originates from differences in the amount of water removed by the gap and atomization air streams was confirmed.

Air↗
PubMed1997

Transport, uptake, and metabolism of the bis(pivaloyloxymethyl)-ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine in an in vitro cell culture system of the intestinal mucosa (Caco-2).

PURPOSE: To evaluate intestinal transport, uptake and metabolism characteristics of the bis(pivaloyloxymethyl)-ester [bis(POM)-ester] of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA]. METHODS: Intestinal transport, uptake and metabolism of bis(POM)-PMEA were studied using an in vitro cell culture system of the intestinal mucosa (Caco-2 monolayers). Concentrations of bis(POM)-PMEA and its metabolites mono(POM)-PMEA and PMEA were determined using a reversed-phase HPLC method. Enzymatic stability of bis(POM)-PMEA was evaluated by incubation with purified liver carboxylesterase, homogenates of Caco-2 cells and scraped pig small intestinal mucosa. RESULTS: The use of bis(POM)-PMEA as a prodrug of PMEA resulted in a significant increase in transport of total PMEA [bis(POM)-PMEA, mono(POM)-PMEA and PMEA] across Caco-2 monolayers. While transepithelial transport of PMEA (500 microM) was lower than 0.1% during a 3 hr incubation period, transport of total PMEA after addition of bis(POM)-PMEA (100 microM) amounted to 8.8% over the same incubation period. Only 23% of the amount transported appeared as intact bis-ester at the basolateral side, while 33% of this amount was free PMEA and 44% was mono(POM)-PMEA, suggesting susceptibility of the prodrug to chemical and enzymatic degradation. Uptake studies revealed that only negligible amounts of bis(POM)-PMEA (< 0.2%) were present inside the cells. Very high intracellular concentrations of PMEA were found (approximately 1.2 mM, after a 3 hr incubation with 50 microM bis(POM)-PMEA), which suggests that PMEA was trapped inside the cells probably due to its negative charge. This explains that efflux of PMEA was relatively slow (25% of the intracellular amount in 3 hr). Enzymatic degradation of the prodrug by carboxylesterase was confirmed by incubation of bis(POM)-PMEA with purified enzyme (Km = 87 microM and Vmax = 9.5 microM/min). Incubation of bis(POM)-PMEA (10 microM) with cell homogenate of Caco-2 monolayers and pig small intestinal mucosa produced similar degradation profiles. CONCLUSIONS: The use of the bis(POM)-prodrug significantly enhances the intestinal permeability of PMEA. Intracellular trapping of PMEA in the intestinal mucosa may result in slow release of PMEA to the circulation after oral administration of bis(POM)-PMEA.

Adenine↗
PubMed1997

Inulin hydrogels as carriers for colonic drug targeting: I. Synthesis and characterization of methacrylated inulin and hydrogel formation.

PURPOSE: Vinyl groups were introduced in inulin chains in order to form hydrogels of this sugar polymer by free radical polymerization. METHODS: Inulin was reacted with glycidyl methacrylate in N,N-dimethylformamide in the presence of 4-dimethylaminopyridine as catalyst. 1H and 13C NMR spectroscopy were used for the characterization of the obtained reaction product. Solid state 13C NMR spectroscopy revealed the conversion of the incorporated vinyl groups into covalent cross-links upon free radical polymerization of aqueous solutions of the derivatized inulin. RESULTS: During reaction of inulin with glycidyl methacrylate, transesterification occurred, leading to the direct attachment of the methacryloyl group to inulin. Consequently, the obtained reaction product is methacrylated inulin. The extent of chemical modification of inulin could be tuned by varying the molar ratio of glycidyl methacrylate to inulin in the reaction mixture. Aqueous solutions of methacrylated inulin were converted into cross-linked hydrogels by free radical polymerization using ammonium persulphate and N,N,N',N'-tetramethylethylenediamine as initiating system. CONCLUSIONS: Inulin hydrogels can be formed by free radical polymerization of aqueous solutions of methacrylated inulin.

4-Aminopyridine↗
PubMed1996

Rheological characterization of xanthan gum and hydroxypropylmethyl cellulose with respect to controlled-release drug delivery.

It has been observed previously that xanthan gum (XG) and hydroxypropylmethyl cellulose (HPMC) show different drug release behavior. In order to clarify these findings, the rheological properties of both polymers have been determined by oscillatory as well as by steady shear measurements. Aqueous solutions of 4 and 7% (w/w) polymer have been used to simulate the outer surface of a hydrated tablet. The dynamic moduli, i.e., storage modulus (G') and loss modulus (G") of the two polymers have been determined in pure water and USP phosphate buffer pH 7.4 at different dilutions. In this concentration range XG solution exhibits "gel-like" behavior, while HPMC behaves as a typical polymer solution. These findings are quite consistent with the reported higher ability of XG matrices to retard drug release than HPMC matrices for controlled-release formulation. The effects of differences in drug solubility and acidity, as well as the addition of lactose, and of the ionic strength of the medium on the rheological properties of XG and HPMC solutions have been studied in detail. Among these parameters, only the salt concentration exerts an enhancing effect on both moduli of XG, while no detectable influence on HPMC solution could be observed.

Chemistry, Pharmaceutical↗
PubMed1996

Transport of artemisinin and sodium artesunate in Caco-2 intestinal epithelial cells.

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 (Papp = 30.4 +/- 1.7 x 10(-6) cm s-1, pH 7.4). Permeability of the hemisuccinate analogue, sodium artesunate, was 8-fold lower (Papp = 4.0 +/- 0.4 x 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.

Antimalarials↗
PubMed1996

Design and evaluation of two-phase partition-dissolution method and its use in evaluating artemisinin tablets.

A method is described for the assessment of the dissolution behavior of solid dosage forms with a high content of a very water insoluble drug. In this method the dissolved drug is continuously extracted from the aqueous dissolution medium into an organic phase. The reported data on the dissolution of artemisinin show that this method guarantees sink conditions in the aqueous dissolution medium during the total duration of the experiment.

Antimalarials↗
PubMed1996

Improvement of the material motion in a rotary processor.

The purpose of this paper is to reject or to confirm the hypothesis that the influence of the water addition rate on the size and size distribution of pellets is caused by insufficient spreading of the added water at higher water addition rates. To overcome insufficient spreading of the added water, the agitation in the rotary processor is intensified by improving the spiral, rope-like movement by means of two baffles and a permanent PTFE coating, and by installing a chopper. Improvement of the spiral, rope-like movement moderates the influence of the water addition rate on the pellet size. The chopper has no significant influence on pellet size, pellet size distribution, or percentage of agglomerates for the pellets, which are investigated in this study. Furthermore, the implementation of the technical modifications does not influence the dissolution characteristics of the pellets directly. It is therefore concluded that the water added is well spread over the mass by ensuring an optimal spiral, rope-like movement, so that incorporation of a chopper is superfluous. The remaining influence of the water addition rate on the pellet size can most probably be explained by differences in processing time, resulting in different volumes of air capable of extracting water from the powder mass.

Drug Compounding↗
PubMed1995

In vivo evaluation of a colon-specific drug delivery system: an absorption study of theophylline from capsules coated with azo polymers in rats.

Azo polymers based upon 2-hydroxyethyl methacrylate, methyl methacrylate, and methacrylic acid, and containing N,N'-bis [(methacryloyloxyethyl)oxy(carbonylamino)]azobenzene as azo aromatic agent were evaluated in vivo as coating for colon-specific drug delivery. The gastrointestinal absorption of theophylline from capsules coated with the azo polymers was examined in the proximal part of the small intestine and the cecum of male Wistar rats. The capsules were surgically inserted in the region of interest. The plasma concentration of the drug was higher when the capsules were inserted in the cecum as compared to the small intestine. The appearance of theophylline in the plasma when capsules were administered in the small intestine can be attributed to simple diffusion of the drug through the swollen polymer coating. Release and absorption from the cecum is the combined results of diffusion and degradation of the azo polymer coatings by bacterial azo reductase.

Animals↗
PubMed1994

Release of indomethacin from transparent oil-water gels.

Within the scope of evaluating transparent oil-water gels (TOW gel) as dermatological vehicles, the release of indomethacin from a model TOW gel into 1-dodecanol is studied at various pH levels of the water phase. Apparent partition coefficient determinations and flame photometrical measurements show that both indomethacin and its sodium salt, as the ion pair, migrate into the 1-dodecanol layer. The pH-dependent release-rate profile is explained in terms of the amount of readily diffusible drug in the water phase of the gel.

Chemical Phenomena↗
PubMed1994

The relation between swelling properties and enzymatic degradation of azo polymers designed for colon-specific drug delivery.

Copolymers of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA), and terpolymers of HEMA, MMA, and methacrylic acid (MA) were synthesized in the presence of N,N'-bis(methacryloyloxyethyloxycarbonylamino)azobenzene (B(MOEOCA)AB) and evaluated as coating materials for colonic targeting. The release of ibuprofen, a model drug, from capsules coated with the azo polymers was investigated in vitro. The release medium was made up of sonicated rat cecal content, benzyl viologen, glucose-6-phosphate, glucose-6-phosphate dehydrogenase, and nicotine amide dinucleotide phosphate (NADP) in phosphate buffer (pH 6.8, 0.05M). The drug-release profiles indicate that the degradation of the azo polymer coatings depends on their degree of swelling, due to a higher accessibility of the azo bonds for the bacterial azo reductase. The best results were obtained with azo polymers containing MA: 98.7 (+/- 1.1) % of ibuprofen was released after 19 hours residence in the release medium, while only 26.2 (+/- 4.9) % in the control experiment. These findings demonstrate that azo polymers are promising materials for delivering drugs selectivity to the colon.

Animals↗
PubMed1989

Comparison of the dissolution behaviour of tablets containing the drug in a polyethyleneglycol solid dispersion with direct compressed tablets.

Higher dissolution rates of diazepam were noted with tablets containing the drug in polyethyleneglycol solid dispersion compared to these containing a physical mixture of the drug granulated with polyethyleneglycol or to directly compressed tablets. The shape factor and t63% depend strongly on the method of incorporation of the drug in the compressed mass. The dissolution of the drug becomes pH independent when it is present as a solid dispersion, which may be advantageous for the bioavailability.

Chemistry, Pharmaceutical↗
PubMed1986

Ethylene chlorohydrin determination in ethylene oxide sterilized polyvinyl chloride tubing.

A convenient rapid gas-chromatographic method is described for the quantitative determination of ethylene chlorohydrin. The method reported herein extracts the ethylene chlorohydrin with water. The method is simple and offers advantages since no elaborate and expensive gas extraction apparatus is required. The ethylene chlorohydrin levels in five different sterilized polyvinyl chloride samples were found to vary between 5 and 25 ppm. The effect of resterilization with ethylene oxide was investigated and was found to produce less ethylene chlorohydrin.

Chlorohydrins↗