Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Abstract Probiotics have become one of the most consumed food supplements worldwide. Many probiot... more Abstract Probiotics have become one of the most consumed food supplements worldwide. Many probiotic strains are sensitive to low pH and bile concentrations encountered in the gastrointestinal tract upon oral ingestion. This study aimed at developing gastro-resistant probiotic granulates releasing viable cells in the small intestine. Fatty alcohols were investigated as potential coating materials. Cetostearyl alcohol was selected and combined with different plasticizers to further optimize the coating properties. Combining cetostearyl alcohol with olive oil and beeswax in selected concentrations was found promising, and the coatings were applied to L. acidophilus LA3 and B. longum BB536, using hot-melt fluid bed coating. Viability in and release from the coated probiotic granulate was investigated, using a physiological relevant in vitro model simulating conditions in the human stomach, duodenum, jejunum and ileum. L. acidophilus LA3 coated with cetostearyl alcohol and olive oil in the ratio 95:5 (w/w) resulted in significantly higher viability after simulated gastrointestinal transit, compared to the uncoated probiotic powder. The coating showed no release of viable cells after simulation of the stomach. Released viable cells were detected after the remaining steps in the in vitro model, indicating that the coating system provides gastric protection and release during intestinal transit.
Intake of probiotics is associated with many health benefits, which has generated an interest in ... more Intake of probiotics is associated with many health benefits, which has generated an interest in formulating viable probiotic supplements. The present study had two aims. The first aim was to achieve gastrointestinal protection and delayed release of viable probiotics by pelletizing and coating freeze-dried probiotic strains, using riboflavin as a marker for release. The second aim was to set up a dynamic three-step in vitro model simulating the conditions in the human gastric, duodenum/jejunum and ileum compartments using physiologically relevant media to evaluate delayed release of the formulations. To simulate lowered bile acid concentrations in the ileum area of the gastrointestinal tract, a novel method using the bile acid sequestrant cholestyramine to lower bile acid concentrations in the small intestinal medium to physiologically relevant levels was attempted. Granulation, extrusion and spheronization was used to develop pellets containing viable probiotics using freeze-dried Lactobacullus reuteri as a model strain. Fluid bed coating the pellets with the pH-sensitive polymers Eudragit S100 or Eudragit FS30D resulted in targeted release in the ileum step of the three-step in vitro model based on release of the marker riboflavin.
Journal of Drug Delivery Science and Technology, 2020
Lipid based drug delivery systems (LbDDSs) present an effective solution for increasing the appar... more Lipid based drug delivery systems (LbDDSs) present an effective solution for increasing the apparent solubility and eliminating the slow dissolution process of many poorly water-soluble compounds. Typically, an initial step in designing a LbDDS is to measure the equilibrium solubility of the compound in various LbDDS excipients, which often are viscous. Equilibrium solubility is usually measured by the classical saturation shake-flask (SSF) method with centrifugation for phase separation. The concentration of the compound in the supernatant is determined as the solubility. As complete phase separation is necessary to determine the equilibrium solubility, but difficult to achieve in viscous solvents, the aim of the present study was to evaluate the effect of centrifugation speed on the measured solubility. In the present study, the solubility of seven poorly water-soluble compounds: amphotericin B, nystatin, β-carotene, curcumin, itraconazole, cinnarizine and fenofibrate was measured in five viscous solvents using the SSF method. For five out of the seven compounds (amphotericin B, nystatin, β-carotene, curcumin and itraconazole) the centrifugation speed had a significant effect on the measured solubility, i.e. different centrifugation speeds led to differences in the measured solubility. The supernatants of all the tested samples, following 15 min of centrifugation at 900 � g (3K RPM), 4.7K � g (7K RPM) and 17K � g (13.3K RPM), were evaluated for particle presence by polarized light microscopy. Presence of particles in the supernatants of the five affected compounds indicated that complete phase separation was not obtained, and that the measured solubility did not represent the true equilibrium solubility. Studying the physicochemical properties of the tested compounds, it was found, that the compounds, for which the measured solubility was affected by the centrifugation speed, all display high melting points. In conclusion, to avoid overestimating the equilibrium solubility, especially for compounds with high melting points, it is recommended to use the highest possible centrifugation speed, and to evaluate the effect of centrifugation speed on the solubility measurement, when conducting solubility experiments in viscous solvents using centrifugation for phase separation.
Proceedings of The 2nd Electronic Conference on Pharmaceutical Sciences, 2012
Using Soluplus ® as a dissolution modifying agent enables tailoring of the release of the API. In... more Using Soluplus ® as a dissolution modifying agent enables tailoring of the release of the API. In this work the release of two water soluble APIs was modified by two different methods. Furthermore, presence of a new previously not identified polymorphic form of GF was identified. This is underpinning the need for careful preformulation of unstable formulations where the possibility for recrystallization of high-energy polymorphic form exists.
Control of drug action through formulation is a vital and very challenging topic within pharmaceu... more Control of drug action through formulation is a vital and very challenging topic within pharmaceutical sciences. Cellulose nanofibers (CNF) is an excipient candidate in pharmaceutical formulations that could be used to easily optimize drug delivery rates. CNF has interesting physico-chemical properties that, when combined with surfactants, can be used to create very stable air bubbles and dry foams. Utilizing this inherent property, it is possible to
To develop a minimally-invasive method for direct visualization of drug delivery systems in the h... more To develop a minimally-invasive method for direct visualization of drug delivery systems in the human stomach and to compare the obtained results with an established in vitro model. The method should provide the capsule rupture, dispersion characteristics, and knowledge regarding the surrounding physiological environment in the stomach. A capsule endoscopic method was developed. The disintegration time, dispersion characteristics and the impact of the physiological environment on different lipid based delivery systems in different gelatin capsules in the fasted stomach of nine healthy volunteers were visualized. Biorelevant dissolution studies using a USP II apparatus and a droplet size analysis of the released SNEDDS were performed. Visualization of the behavior of both hard and soft gelatin capsules formulations was possible. The disintegration and dispersion of EP oil in a soft capsule and SNEDDS in a hard shell capsule were visualized. The in vitro release rates were different from the in vivo release rates of the soft capsule due to volume, fluid composition and motility differences but not for the hard capsule containing SNEDDS. A minimally-invasive capsule endoscopic method was developed for direct visualizing of drug delivery systems in the human stomach and maybe later, in the duodenum.
European Journal of Pharmaceutics and Biopharmaceutics, 2013
To characterize human gastric fluid with regard to rheological properties and gastric lipase acti... more To characterize human gastric fluid with regard to rheological properties and gastric lipase activity. In addition, traditional physicochemical properties were determined. Methods: Fasted HGA were collected from 19 healthy volunteers during a gastroscopic examination. Rheological characterization of the aspirates was conducted on a TA AR-G2 rheometer, using cone and plate geometry. Lipase activity was measured by continuous titration of released free fatty acid from tributyrate. Further, pH, osmolality, buffer capacity, and surface tension were measured and the total protein content and bile salt level were determined using assay kits. Results: Rheological examination of HGA showed non-Newtonian shear-thinning behavior with predominant elastic behavior in the linear range. The apparent viscosity was measured to be in the range of 1.7-9.3 mPa s at a shear rate of 50 s À1. The FaSSGF and HCl pH 1.2 have no shear-thinning properties and showed lower viscosity (1.1 mPa s at 50 s À1). The observed viscosity of the HGA will decrease the intrinsic dissolution rate of drugs. The activity of the gastric lipase was 7.4 ± 4.0 U/mL (N = 6, n = 3) and 99.0 ± 45.3 U/mL (N = 19, n = 3) at pH 2.8 and 5.4, respectively. pH, surface tension, buffer capacity, bile salt concentration, and osmolality were measured and compared with literature data. Conclusion: The rheological behavior and the mean apparent viscosity of HGA are significantly different from that of water and should therefore be considered important during development of gastric simulated media. Further, the activity of the HGL is active even under fasted gastric conditions and might contribute to the digestion and emulsification of lipid-based drug delivery systems in the entire gastrointestinal tract. HGL should therefore be considered in gastric evaluation of lipid-based drug delivery systems.
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Abstract Probiotics have become one of the most consumed food supplements worldwide. Many probiot... more Abstract Probiotics have become one of the most consumed food supplements worldwide. Many probiotic strains are sensitive to low pH and bile concentrations encountered in the gastrointestinal tract upon oral ingestion. This study aimed at developing gastro-resistant probiotic granulates releasing viable cells in the small intestine. Fatty alcohols were investigated as potential coating materials. Cetostearyl alcohol was selected and combined with different plasticizers to further optimize the coating properties. Combining cetostearyl alcohol with olive oil and beeswax in selected concentrations was found promising, and the coatings were applied to L. acidophilus LA3 and B. longum BB536, using hot-melt fluid bed coating. Viability in and release from the coated probiotic granulate was investigated, using a physiological relevant in vitro model simulating conditions in the human stomach, duodenum, jejunum and ileum. L. acidophilus LA3 coated with cetostearyl alcohol and olive oil in the ratio 95:5 (w/w) resulted in significantly higher viability after simulated gastrointestinal transit, compared to the uncoated probiotic powder. The coating showed no release of viable cells after simulation of the stomach. Released viable cells were detected after the remaining steps in the in vitro model, indicating that the coating system provides gastric protection and release during intestinal transit.
Intake of probiotics is associated with many health benefits, which has generated an interest in ... more Intake of probiotics is associated with many health benefits, which has generated an interest in formulating viable probiotic supplements. The present study had two aims. The first aim was to achieve gastrointestinal protection and delayed release of viable probiotics by pelletizing and coating freeze-dried probiotic strains, using riboflavin as a marker for release. The second aim was to set up a dynamic three-step in vitro model simulating the conditions in the human gastric, duodenum/jejunum and ileum compartments using physiologically relevant media to evaluate delayed release of the formulations. To simulate lowered bile acid concentrations in the ileum area of the gastrointestinal tract, a novel method using the bile acid sequestrant cholestyramine to lower bile acid concentrations in the small intestinal medium to physiologically relevant levels was attempted. Granulation, extrusion and spheronization was used to develop pellets containing viable probiotics using freeze-dried Lactobacullus reuteri as a model strain. Fluid bed coating the pellets with the pH-sensitive polymers Eudragit S100 or Eudragit FS30D resulted in targeted release in the ileum step of the three-step in vitro model based on release of the marker riboflavin.
Journal of Drug Delivery Science and Technology, 2020
Lipid based drug delivery systems (LbDDSs) present an effective solution for increasing the appar... more Lipid based drug delivery systems (LbDDSs) present an effective solution for increasing the apparent solubility and eliminating the slow dissolution process of many poorly water-soluble compounds. Typically, an initial step in designing a LbDDS is to measure the equilibrium solubility of the compound in various LbDDS excipients, which often are viscous. Equilibrium solubility is usually measured by the classical saturation shake-flask (SSF) method with centrifugation for phase separation. The concentration of the compound in the supernatant is determined as the solubility. As complete phase separation is necessary to determine the equilibrium solubility, but difficult to achieve in viscous solvents, the aim of the present study was to evaluate the effect of centrifugation speed on the measured solubility. In the present study, the solubility of seven poorly water-soluble compounds: amphotericin B, nystatin, β-carotene, curcumin, itraconazole, cinnarizine and fenofibrate was measured in five viscous solvents using the SSF method. For five out of the seven compounds (amphotericin B, nystatin, β-carotene, curcumin and itraconazole) the centrifugation speed had a significant effect on the measured solubility, i.e. different centrifugation speeds led to differences in the measured solubility. The supernatants of all the tested samples, following 15 min of centrifugation at 900 � g (3K RPM), 4.7K � g (7K RPM) and 17K � g (13.3K RPM), were evaluated for particle presence by polarized light microscopy. Presence of particles in the supernatants of the five affected compounds indicated that complete phase separation was not obtained, and that the measured solubility did not represent the true equilibrium solubility. Studying the physicochemical properties of the tested compounds, it was found, that the compounds, for which the measured solubility was affected by the centrifugation speed, all display high melting points. In conclusion, to avoid overestimating the equilibrium solubility, especially for compounds with high melting points, it is recommended to use the highest possible centrifugation speed, and to evaluate the effect of centrifugation speed on the solubility measurement, when conducting solubility experiments in viscous solvents using centrifugation for phase separation.
Proceedings of The 2nd Electronic Conference on Pharmaceutical Sciences, 2012
Using Soluplus ® as a dissolution modifying agent enables tailoring of the release of the API. In... more Using Soluplus ® as a dissolution modifying agent enables tailoring of the release of the API. In this work the release of two water soluble APIs was modified by two different methods. Furthermore, presence of a new previously not identified polymorphic form of GF was identified. This is underpinning the need for careful preformulation of unstable formulations where the possibility for recrystallization of high-energy polymorphic form exists.
Control of drug action through formulation is a vital and very challenging topic within pharmaceu... more Control of drug action through formulation is a vital and very challenging topic within pharmaceutical sciences. Cellulose nanofibers (CNF) is an excipient candidate in pharmaceutical formulations that could be used to easily optimize drug delivery rates. CNF has interesting physico-chemical properties that, when combined with surfactants, can be used to create very stable air bubbles and dry foams. Utilizing this inherent property, it is possible to
To develop a minimally-invasive method for direct visualization of drug delivery systems in the h... more To develop a minimally-invasive method for direct visualization of drug delivery systems in the human stomach and to compare the obtained results with an established in vitro model. The method should provide the capsule rupture, dispersion characteristics, and knowledge regarding the surrounding physiological environment in the stomach. A capsule endoscopic method was developed. The disintegration time, dispersion characteristics and the impact of the physiological environment on different lipid based delivery systems in different gelatin capsules in the fasted stomach of nine healthy volunteers were visualized. Biorelevant dissolution studies using a USP II apparatus and a droplet size analysis of the released SNEDDS were performed. Visualization of the behavior of both hard and soft gelatin capsules formulations was possible. The disintegration and dispersion of EP oil in a soft capsule and SNEDDS in a hard shell capsule were visualized. The in vitro release rates were different from the in vivo release rates of the soft capsule due to volume, fluid composition and motility differences but not for the hard capsule containing SNEDDS. A minimally-invasive capsule endoscopic method was developed for direct visualizing of drug delivery systems in the human stomach and maybe later, in the duodenum.
European Journal of Pharmaceutics and Biopharmaceutics, 2013
To characterize human gastric fluid with regard to rheological properties and gastric lipase acti... more To characterize human gastric fluid with regard to rheological properties and gastric lipase activity. In addition, traditional physicochemical properties were determined. Methods: Fasted HGA were collected from 19 healthy volunteers during a gastroscopic examination. Rheological characterization of the aspirates was conducted on a TA AR-G2 rheometer, using cone and plate geometry. Lipase activity was measured by continuous titration of released free fatty acid from tributyrate. Further, pH, osmolality, buffer capacity, and surface tension were measured and the total protein content and bile salt level were determined using assay kits. Results: Rheological examination of HGA showed non-Newtonian shear-thinning behavior with predominant elastic behavior in the linear range. The apparent viscosity was measured to be in the range of 1.7-9.3 mPa s at a shear rate of 50 s À1. The FaSSGF and HCl pH 1.2 have no shear-thinning properties and showed lower viscosity (1.1 mPa s at 50 s À1). The observed viscosity of the HGA will decrease the intrinsic dissolution rate of drugs. The activity of the gastric lipase was 7.4 ± 4.0 U/mL (N = 6, n = 3) and 99.0 ± 45.3 U/mL (N = 19, n = 3) at pH 2.8 and 5.4, respectively. pH, surface tension, buffer capacity, bile salt concentration, and osmolality were measured and compared with literature data. Conclusion: The rheological behavior and the mean apparent viscosity of HGA are significantly different from that of water and should therefore be considered important during development of gastric simulated media. Further, the activity of the HGL is active even under fasted gastric conditions and might contribute to the digestion and emulsification of lipid-based drug delivery systems in the entire gastrointestinal tract. HGL should therefore be considered in gastric evaluation of lipid-based drug delivery systems.
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