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Rene Holm - One of the best experts on this subject based on the ideXlab platform.
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Buccal Absorption of diazepam is improved when administered in bioadhesive tablets an in vivo study in conscious gottingen mini pigs
International Journal of Pharmaceutics, 2016Co-Authors: Emil Menglund, Rene Holm, Erling B Jorgensen, Jette Jacobsen, Anette MüllertzAbstract:Buccal delivery may be clinically beneficial for compounds with a high gastrointestinal and hepatic first pass metabolism or in situations where a fast systemic Absorption is desired. The delivery of a crystalline low soluble compounds, e.g. diazepam, may be limited due to the low volume of saliva available to facilitate solvation in order to drive the permeation of drug through the Buccal mucosa. Therefore, the present study investigated the potential benefits of administering diazepam either as an amorphous or as a crystalline form in mucoadhesive tablets to conscious Gottingen mini-pigs. Presentation of the compound in the amorphous form lead to a very fast Absorption, however, the obtained bioavailability was at the same level observed following Buccal administration of a commercially immediate release tablet. Addition of chitosan, as a mucoadhesive excipient, resulted in a higher absolute bioavailability compared to tablets without chitosan. The Absorption rate for the chitosan-based tablets was significant slower, probably due to the slower diffusion of the compound out of the tablet. In vitro release data was able to predict the variations in tmax, but otherwise no correlation could be found between in vitro and in vivo data.
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use of permeapad for prediction of Buccal Absorption a comparison to in vitro ex vivo and in vivo method
European Journal of Pharmaceutical Sciences, 2016Co-Authors: Hanady Ajine Bibi, Rene Holm, Annette BauerbrandlAbstract:Abstract The present work explores the usefulness of Permeapad® for prediction of Buccal Absorption. Permeability studies with the model drug metoprolol were carried out using the Permeapad® barrier at pH values 7.4; 8.5; 9.0, and 9.5. It was confirmed that Permeapad® can withstand these conditions, and as expected, a clear increase in permeability was found with increasing pH. The permeation results across Permeapad® were compared to published in vitro, ex vivo and in vivo studies for the same formulations. Results showed that the permeability of metoprolol using the Permeapad® barrier correlated very well to both in vitro and ex vivo studies, (r2 = 0.98 and 0.97), respectively. Furthermore, excellent in vitro in vivo correlation IVIVC (r2 = 0.98) was obtained when comparing apparent permeability coefficient to the absolute bioavailability of metoprolol administered Buccally to mini-pigs. Results indicate that Permeapad® can be used to mimic the Buccal Absorption of metoprolol as a faster and less laborious method as compared to any of the other mentioned methods.
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Ex Vivo Correlation of the Permeability of Metoprolol Across Human and Porcine Buccal Mucosa
Journal of Pharmaceutical Sciences, 2014Co-Authors: Emil Meng-lund, Rene Holm, Eva Marxen, Anne Marie Lynge Pedersen, Anette Müllertz, Birgitte Hyrup, Jette JacobsenAbstract:ABSTRACT The pH partition theory proposes a correlation between fraction of unionized drug substance and permeability. The aim of this study was to compare the permeability of metoprolol and mannitol in ex vivo human and porcine Buccal mucosa models at varying pH to validate whether the porcine permeability model is predictive for human Buccal Absorption. Human ( n = 9-10) and porcine ( n = 6-7) Buccal mucosa were mounted in a modified Ussing chamber, and the kinetics of metoprolol and mannitol transport was assessed for a period of 5.5 h with the pH values of donor medium set at 7.4, 8.5, and 9.0. In addition, hematoxylin-eosin and Alcian blue-van Gieson were used as tissue stains to evaluate the histology and the presence of acidic polysaccharides (e.g., mucins), respectively. The permeability of metoprolol was decreased in human Buccal mucosa by almost twofold when compared with porcine Buccal mucosa with a positive correlation ( r 2 = 0.96) between the permeability assessed in porcine and human Buccal mucosa. There was no change in the degree of either epithelial swelling or desquamation when treating with the pH 9.0 donor medium for 5.5 h. These data suggest that Buccal mucosa from pigs can be used to predict human Buccal Absorption.
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conscious and anaesthetised gottingen mini pigs as an in vivo model for Buccal Absorption ph dependent Absorption of metoprolol from bioadhesive tablets
Drug Development and Industrial Pharmacy, 2014Co-Authors: Emil Menglund, Morten B Andersen, Mads L Jespersen, Jensjakob Karlsson, Mats Garmer, Erling B Jorgensen, Jette Jacobsen, Rene HolmAbstract:AbstractThe potential of Buccal mucosa as a site for systemic Absorption has attracted increased attention in recent years creating a need for new predictive in-vivo models. The aim of this study was to evaluate anaesthetised and conscious Gottingen mini-pigs as a model for Buccal drug Absorption by testing pH-dependent Absorption of metoprolol from a solid dosage form. Buccal tablets buffered to pH 6.2 and pH 8.9, oral liquid and intravenous injection were tested in four conscious and anaesthetised Gottingen mini-pigs in a non-randomised cross-over study. Blood samples were collected and processed before analysis by ultra-performance liquid chromatography with tandem mass spectrometry detection. An ex-vivo flow retention model was applied to study release and retention of the bioadhesive Buccal tablets. The Tmax obtained from the two Buccal conscious groups (55 ± 5 and 35 ± 5 min) were significantly different to the Buccal anaesthetised groups (120 ± 0 and 165 ± 15 min) for Buccal tablet pH 6.2 and pH 8....
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Buccal Absorption of propofol when dosed in 1 perfluorobutylpentane to anaesthetised and conscious wistar rats and gottingen mini pigs
European Journal of Pharmaceutics and Biopharmaceutics, 2013Co-Authors: Charalambos Tsagogiorgas, Sonja Theisinger, Per Holm, Manfred Thiel, Michael Quintel, Rene HolmAbstract:Abstract The purpose of this study was to evaluate whether propofol could be absorbed Buccally when administered in semifluorinated alkanes (SFAs), here specifically perfluorobutylpentane (F4H5). This was evaluated in anesthetised and conscious rats and mini-pigs, to measure the relative bioavailability of propofol following Buccal administration, but also partly to evaluate the animal models used for this investigation. The absolute bioavailability in the conscious animals was approximately 10% for both species and approximately 50% and 30% in the anesthetised rats and mini-pigs, respectively. This clearly demonstrates that propofol can be absorbed Buccally, and F4H5 appears to be a relevant excipient for Buccal administration of lipophilic drugs like propofol. The lower Absorption in the conscious animals clearly indicates the need for an optimisation of the formulation.
Hans Bundgaard - One of the best experts on this subject based on the ideXlab platform.
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enhanced delivery of ketobemidone through porcine Buccal mucosa in vitro via more lipophilic ester prodrugs
International Journal of Pharmaceutics, 1992Co-Authors: Laila Bach Hansen, Lona L. Christrup, Hans BundgaardAbstract:The in vitro penetration of ketobemidone and various ester prodrugs through porcine Buccal mucosa in a modified Ussing chamber was investigated in order to support the selection of a prodrug derivative with optimal Buccal Absorption. The nine esters studied included carboxylic acid and carbonate esters formed at the phenolic hydroxy group of ketobemidone. The esters were all rapidly hydrolyzed to the parent drug in a porcine Buccal epithelial homogenate and only free ketobemidone was detected in the receptor compartment of the Ussing chamber. All the ester prodrugs showed enhanced rates of permeation relative to ketobemidone, the permeability coefficients being 3–30-times higher than that of ketobemidone. The permeability coefficients increased with increasing lipophilicity, expressed in terms of octanol-buffer (pH 7.4) partition coefficients (P), up to log P values of about 1.5 whereupon a plateau or a slight decrease occurred. No toxic effects of ketobemidone or the prodrugs on the Buccal membrane were observed as judged from monitoring of the electrical properties of the membrane.
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Buccal Absorption of ketobemidone and various ester prodrugs in the rat
International Journal of Pharmaceutics, 1992Co-Authors: Laila Bach Hansen, Lona L. Christrup, Aksel Jorgensen, Soren N Rasmussen, Hans BundgaardAbstract:Abstract The Buccal Absorption of ketobemidone, a strong narcotic analgesic, and various carboxylate and carbonate ester prodrugs was studied in rats. The compounds were administered in the form of aqueous solutions of pH 7.4. The absolute bioavailability of ketobemidone following Buccal dosing was 26% whereas the bioavailability of ketobemidone following Buccal administration of the prodrugs ranged from 37 to 98%. The highest bioavailability was obtained with the ethyl carbonate ester. An apparent parabolic correlation between bioavailability and lipophilicity of the compounds was seen. All esters were rapidly hydrolyzed to ketobemidone after both Buccal and intravenous administration. The acute toxicity of the esters after i.v. administration to mice and rats was similar to that of the parent drug. It is concluded that esterification of the phenolic hydroxyl group in ketobemidone to give a more lipophilic prodrug may be a useful approach to improve the Buccal delivery of this analgesic.
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saliva catalyzed hydrolysis of a ketobemidone ester prodrug factors influencing human salivary esterase activity
International Journal of Pharmaceutics, 1992Co-Authors: Laila Bach Hansen, Lona L. Christrup, Hans BundgaardAbstract:Abstract Saliva enzyme-catalysed hydrolysis of ester prodrugs containing sensitive ester groups may be a limiting factor to the Buccal Absorption of such compounds. Using the isopropyl carbonate ester of ketobemidone as a model substance of a hydrolysis-sensitive prodrug the esterase activity of human saliva has been characterized as a function of various factors. The esterase activity was found to decrease rapidly upon storage of the saliva at 37°C. The activity increased with increasing pH in the range 4.5–7.4 and with increasing salivation flow rate up to a rate of 0.9 ml min −1 . Under resting conditions, the flow rate was about 0.2 ml min −1 which implied a greatly decreased esterase activity. The activity was highest after fasting and decreased after intake of a meal. The intraindividual variation in the saliva esterase activity was small whereas a larger interindividual variation was found.
Jette Jacobsen - One of the best experts on this subject based on the ideXlab platform.
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Buccal Absorption of diazepam is improved when administered in bioadhesive tablets an in vivo study in conscious gottingen mini pigs
International Journal of Pharmaceutics, 2016Co-Authors: Emil Menglund, Rene Holm, Erling B Jorgensen, Jette Jacobsen, Anette MüllertzAbstract:Buccal delivery may be clinically beneficial for compounds with a high gastrointestinal and hepatic first pass metabolism or in situations where a fast systemic Absorption is desired. The delivery of a crystalline low soluble compounds, e.g. diazepam, may be limited due to the low volume of saliva available to facilitate solvation in order to drive the permeation of drug through the Buccal mucosa. Therefore, the present study investigated the potential benefits of administering diazepam either as an amorphous or as a crystalline form in mucoadhesive tablets to conscious Gottingen mini-pigs. Presentation of the compound in the amorphous form lead to a very fast Absorption, however, the obtained bioavailability was at the same level observed following Buccal administration of a commercially immediate release tablet. Addition of chitosan, as a mucoadhesive excipient, resulted in a higher absolute bioavailability compared to tablets without chitosan. The Absorption rate for the chitosan-based tablets was significant slower, probably due to the slower diffusion of the compound out of the tablet. In vitro release data was able to predict the variations in tmax, but otherwise no correlation could be found between in vitro and in vivo data.
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Ex Vivo Correlation of the Permeability of Metoprolol Across Human and Porcine Buccal Mucosa
Journal of Pharmaceutical Sciences, 2014Co-Authors: Emil Meng-lund, Rene Holm, Eva Marxen, Anne Marie Lynge Pedersen, Anette Müllertz, Birgitte Hyrup, Jette JacobsenAbstract:ABSTRACT The pH partition theory proposes a correlation between fraction of unionized drug substance and permeability. The aim of this study was to compare the permeability of metoprolol and mannitol in ex vivo human and porcine Buccal mucosa models at varying pH to validate whether the porcine permeability model is predictive for human Buccal Absorption. Human ( n = 9-10) and porcine ( n = 6-7) Buccal mucosa were mounted in a modified Ussing chamber, and the kinetics of metoprolol and mannitol transport was assessed for a period of 5.5 h with the pH values of donor medium set at 7.4, 8.5, and 9.0. In addition, hematoxylin-eosin and Alcian blue-van Gieson were used as tissue stains to evaluate the histology and the presence of acidic polysaccharides (e.g., mucins), respectively. The permeability of metoprolol was decreased in human Buccal mucosa by almost twofold when compared with porcine Buccal mucosa with a positive correlation ( r 2 = 0.96) between the permeability assessed in porcine and human Buccal mucosa. There was no change in the degree of either epithelial swelling or desquamation when treating with the pH 9.0 donor medium for 5.5 h. These data suggest that Buccal mucosa from pigs can be used to predict human Buccal Absorption.
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conscious and anaesthetised gottingen mini pigs as an in vivo model for Buccal Absorption ph dependent Absorption of metoprolol from bioadhesive tablets
Drug Development and Industrial Pharmacy, 2014Co-Authors: Emil Menglund, Morten B Andersen, Mads L Jespersen, Jensjakob Karlsson, Mats Garmer, Erling B Jorgensen, Jette Jacobsen, Rene HolmAbstract:AbstractThe potential of Buccal mucosa as a site for systemic Absorption has attracted increased attention in recent years creating a need for new predictive in-vivo models. The aim of this study was to evaluate anaesthetised and conscious Gottingen mini-pigs as a model for Buccal drug Absorption by testing pH-dependent Absorption of metoprolol from a solid dosage form. Buccal tablets buffered to pH 6.2 and pH 8.9, oral liquid and intravenous injection were tested in four conscious and anaesthetised Gottingen mini-pigs in a non-randomised cross-over study. Blood samples were collected and processed before analysis by ultra-performance liquid chromatography with tandem mass spectrometry detection. An ex-vivo flow retention model was applied to study release and retention of the bioadhesive Buccal tablets. The Tmax obtained from the two Buccal conscious groups (55 ± 5 and 35 ± 5 min) were significantly different to the Buccal anaesthetised groups (120 ± 0 and 165 ± 15 min) for Buccal tablet pH 6.2 and pH 8....
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in vitro ex vivo and in vivo examination of Buccal Absorption of metoprolol with varying ph in tr146 cell culture porcine Buccal mucosa and gottingen minipigs
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Rene Holm, Emil Menglund, Morten B Andersen, Mads L Jespersen, Jensjakob Karlsson, Mats Garmer, Erling B Jorgensen, Jette JacobsenAbstract:Abstract This work studied the Buccal Absorption of metoprolol in vitro, ex vivo and in vivo as a function of buffered pH at 7.4, 8.5, 9.0 and 9.5. Permeability studies showed a correlation (r2 = 0.92) between in vitro TR146 cell culture and ex vivo porcine Buccal mucosa in a modified Ussing chamber. A higher apparent permeability was observed at higher pH values, i.e. the more compound that was unionised the higher the permeability. In vivo studies were conducted in anaesthetised Gottingen mini-pigs. A clear influence of pH on the Absorption was seen and a significant higher absolute bioavailability was obtained after Buccal dosing (58–107%) compared to oral (3%) administration, ranging 58–107% and 3%, respectively. Macroscopically, no local toxic effects were observed by visual inspection of mini-pig cheeks. A very clear level C in vitro in vivo correlation (r2 = 0.98) was obtained between the observed in vitro permeabilities and the bioavailability observed in vivo, suggesting that the two in vitro models have good predictive power for drug delivery, which could be a useful tool for future formulation developments intended for Buccal delivery.
Tsuneji Nagai - One of the best experts on this subject based on the ideXlab platform.
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Buccal Absorption of ergotamine tartrate using the bioadhesive tablet system in guinea-pigs.
International journal of pharmaceutics, 2002Co-Authors: Keiko Tsutsumi, Tsuneji Nagai, Yasuko Obata, Thorsteinn Loftsson, Kozo TakayamaAbstract:The Buccal administration of ergotamine tartrate (ET) combined with polyvinyl alcohol (PVA) gel brought about higher plasma concentration of ET compared with that of oral administration of capsules in guinea-pigs. T(max) of ET in plasma of Buccal administration was significantly smaller than that of oral administration. For the Buccal dosage form of ET, the bioadhesive tablet system (BTS) was newly developed. It consisted of a reservoir of drug and an adhesive region. BTS showed better Absorption of ET compared with PVA gel in guinea pigs. Among several pharmaceutical bases in the reservoir of BTS, Witepsol W-35 was most effective. It is likely that the high lipophilic property of Witepsol W-35 in which ET was dissolved facilitated the drug release by its relatively low melting point (around 35 degrees C), consequently a rapid Absorption. In addition, the enhancing activity of the cod-liver oil extract (CLOE) in hydrophilic ointment on the in vivo Buccal ET Absorption was clarified to be comparable to that in the in vitro study utilizing the keratinized epithelial-free membrane (KEF-membrane) of the hamster cheek pouch.
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Buccal Absorption of ergotamine tartrate using the bioadhesive tablet system in guinea pigs
International Journal of Pharmaceutics, 2002Co-Authors: Keiko Tsutsumi, Tsuneji Nagai, Yasuko Obata, Thorsteinn Loftsson, Kozo TakayamaAbstract:Abstract The Buccal administration of ergotamine tartrate (ET) combined with polyvinyl alcohol (PVA) gel brought about higher plasma concentration of ET compared with that of oral administration of capsules in guinea-pigs. T max of ET in plasma of Buccal administration was significantly smaller than that of oral administration. For the Buccal dosage form of ET, the bioadhesive tablet system (BTS) was newly developed. It consisted of a reservoir of drug and an adhesive region. BTS showed better Absorption of ET compared with PVA gel in guinea pigs. Among several pharmaceutical bases in the reservoir of BTS, Witepsol W-35 was most effective. It is likely that the high lipophilic property of Witepsol W-35 in which ET was dissolved facilitated the drug release by its relatively low melting point (around 35 °C), consequently a rapid Absorption. In addition, the enhancing activity of the cod-liver oil extract (CLOE) in hydrophilic ointment on the in vivo Buccal ET Absorption was clarified to be comparable to that in the in vitro study utilizing the keratinized epithelial-free membrane (KEF-membrane) of the hamster cheek pouch.
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Buccal Absorption through golden hamster cheek pouch in vitro and in vivo of 17β estradiol from hydrogels containing three types of Absorption enhancers
International Journal of Pharmaceutics, 1998Co-Authors: Manabu Kitano, Yoshie Maitani, Kozo Takayama, Tsuneji NagaiAbstract:Abstract The combined effects of hydrogels and Absorption enhancers on the permeability of 17 β -estradiol (E 2 ) through Buccal membrane were investigated by measuring the rate of permeation of E 2 through hamster cheek pouch Buccal mucosa in vitro and in vivo. Glycerylmonolaurate (LAU), l -menthol (MEN) and sodium caprate (CAP) were selected as Absorption enhancers in hydrogels containing ethanol and propylene glycol (PG). Based on the rate of penetration through the Buccal mucosa of E 2 in the PG and ethanol gels containing the enhancers, the permeability of E 2 was observed to be greater in the hydrogel containing ethanol than in that containing PG. CAP increased the permeability of E 2 compared with that of the control in both the PG and ethanol gels. MEN increased the permeability of E 2 in a 40% (w/w) ethanol gel, and LAU was more effective in the ethanol gel than in the PG gel without decreasing the gel strength. Regarding the mechanisms of these Absorption enhancers in the ethanol gel, CAP and MEN mainly contributed to the diffusion of E 2 in the mucosa, but LAU increased the solubility of E 2 in the hydrogel. The Buccal administration of E 2 in the 40% (w/w) ethanol hydrogels containing 2% (w/w) LAU allowed the maintenance of the plasma level at above 300 ng/ml cm 2 for 7 h after application in hamster. No primary morphological change of Buccal membrane was detected using scanning electron microscopy 7 h after application. These findings suggest that the combination of LAU and ethanol is useful and safe in hydrogels containing E 2 for application to the Buccal mucosa.
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combined effects of ph cosolvent and penetration enhancers on the in vitro Buccal Absorption of propranolol through excised hamster cheek pouch
International Journal of Pharmaceutics, 1992Co-Authors: Anne Coutelegros, Yoshie Maitani, Michel Veillard, Yoshiharu Machida, Tsuneji NagaiAbstract:Abstract The combined effect of pH and vehicle composition on the Buccal Absorption of propranolol has been evaluated in vitro using hamster cheek pouch. Ethanol was used as cosolvent in various binary-water mixtures. Lauric acid, 1-menthol, sodium salicylate and phosphatidylcholine were evaluated as penetration enhancers. Isopropyl myristate was used as a model of the mucosal lipid phase in partitioning experiments. Permeation of propranolol increased in extent with increasing pH of the vehicle, as compared with the unionized lipophilic fraction of the drug. Permeation of propranolol was decreased at pH 9.4 and increased at pH 6.8 on the addition of ethanol. Ethanol increases the solubility of propranolol in the aqueous vehicle and reduces the oil/vehicle partitioning of the drug through a thermodynamic effect. In addition, at low concentration, ethanol is assumed to increase the permeability of the Buccal mucosa to the polar ionized form of propranolol, while higher concentration is required to enhance the diffusivity of the nonpolar unionized form. Menthol and lauric acid were effective at promoting the Buccal Absorption of propranolol only when the drug was ionized. It was assumed that the mechanism of permeation enhancement was an interaction with the membrane components for 1-menthol, increasing the diffusibility of propranolol, whereas lauric acid may form a more partitionable complex with the drug without any action on membrane permeability.
Laila Bach Hansen - One of the best experts on this subject based on the ideXlab platform.
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enhanced delivery of ketobemidone through porcine Buccal mucosa in vitro via more lipophilic ester prodrugs
International Journal of Pharmaceutics, 1992Co-Authors: Laila Bach Hansen, Lona L. Christrup, Hans BundgaardAbstract:The in vitro penetration of ketobemidone and various ester prodrugs through porcine Buccal mucosa in a modified Ussing chamber was investigated in order to support the selection of a prodrug derivative with optimal Buccal Absorption. The nine esters studied included carboxylic acid and carbonate esters formed at the phenolic hydroxy group of ketobemidone. The esters were all rapidly hydrolyzed to the parent drug in a porcine Buccal epithelial homogenate and only free ketobemidone was detected in the receptor compartment of the Ussing chamber. All the ester prodrugs showed enhanced rates of permeation relative to ketobemidone, the permeability coefficients being 3–30-times higher than that of ketobemidone. The permeability coefficients increased with increasing lipophilicity, expressed in terms of octanol-buffer (pH 7.4) partition coefficients (P), up to log P values of about 1.5 whereupon a plateau or a slight decrease occurred. No toxic effects of ketobemidone or the prodrugs on the Buccal membrane were observed as judged from monitoring of the electrical properties of the membrane.
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Buccal Absorption of ketobemidone and various ester prodrugs in the rat
International Journal of Pharmaceutics, 1992Co-Authors: Laila Bach Hansen, Lona L. Christrup, Aksel Jorgensen, Soren N Rasmussen, Hans BundgaardAbstract:Abstract The Buccal Absorption of ketobemidone, a strong narcotic analgesic, and various carboxylate and carbonate ester prodrugs was studied in rats. The compounds were administered in the form of aqueous solutions of pH 7.4. The absolute bioavailability of ketobemidone following Buccal dosing was 26% whereas the bioavailability of ketobemidone following Buccal administration of the prodrugs ranged from 37 to 98%. The highest bioavailability was obtained with the ethyl carbonate ester. An apparent parabolic correlation between bioavailability and lipophilicity of the compounds was seen. All esters were rapidly hydrolyzed to ketobemidone after both Buccal and intravenous administration. The acute toxicity of the esters after i.v. administration to mice and rats was similar to that of the parent drug. It is concluded that esterification of the phenolic hydroxyl group in ketobemidone to give a more lipophilic prodrug may be a useful approach to improve the Buccal delivery of this analgesic.
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saliva catalyzed hydrolysis of a ketobemidone ester prodrug factors influencing human salivary esterase activity
International Journal of Pharmaceutics, 1992Co-Authors: Laila Bach Hansen, Lona L. Christrup, Hans BundgaardAbstract:Abstract Saliva enzyme-catalysed hydrolysis of ester prodrugs containing sensitive ester groups may be a limiting factor to the Buccal Absorption of such compounds. Using the isopropyl carbonate ester of ketobemidone as a model substance of a hydrolysis-sensitive prodrug the esterase activity of human saliva has been characterized as a function of various factors. The esterase activity was found to decrease rapidly upon storage of the saliva at 37°C. The activity increased with increasing pH in the range 4.5–7.4 and with increasing salivation flow rate up to a rate of 0.9 ml min −1 . Under resting conditions, the flow rate was about 0.2 ml min −1 which implied a greatly decreased esterase activity. The activity was highest after fasting and decreased after intake of a meal. The intraindividual variation in the saliva esterase activity was small whereas a larger interindividual variation was found.