1.
Diakidou, Amalia, et al.
(författare)
Characterization of the contents of ascending colon to which drugs are exposed after oral administration to healthy adults
2009
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 26:9, s. 2141-2151
Tidskriftsartikel (refereegranskat) abstract
PURPOSE: To characterize the contents of the ascending colon in healthy adults under fasting and fed state conditions, with a view to designing in vitro studies to explain/predict dosage form performance in the lower gut. METHODS: Twelve healthy adults participated in a two-phase crossover study. In Phase A, subjects were fasted (water allowed) overnight plus 5 h in the morning prior to colonoscopy (fasted state). In Phase B, subjects were fasted overnight, consumed a standard breakfast (960 kcal) in the morning, and were offered a light lunch 4.5 h later. In this phase, colonoscopy was performed 1 h after lunch (fed state). Volume, pH, and buffer capacity of colonic contents were measured immediately upon collection. After ultracentrifugation, the supernatant was further characterized. RESULTS: Free water content, pH, surface tension, and isobutyrate levels were lower in fed than in fasted subjects. On the other hand, buffer capacity, osmolality, acetate, butyrate, cholate, and chenodeoxycholate levels were higher in fed subjects. Carbohydrate content; protein content; and levels of long chain fatty acids, phosphatidylcholine, and cholesterol were not affected significantly by prandial state. CONCLUSION: Composition of fluids in the ascending colon is affected by feeding. This may affect the performance of products designed to deliver drug to the colon.
2.
Diakidou, A, et al.
(författare)
Simulation of gastric lipolysis and prediction of felodipine release from a matrix tablet in the fed stomach
2009
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 37:2, s. 133-140
Tidskriftsartikel (refereegranskat) abstract
The importance of intragastric lipolysis to felodipine release from a hydrophilic, extended release tablet in the fed stomach was assessed in USP II apparatus with the tablet fixed on a steel wire above the paddle. The release medium, homogenized long-life milk, was gradually digested with shots of acidic solutions of pepsin over the course of the experiment in absence and in presence of biorelevant concentrations of a lipase that was similar to human gastric lipase. Percentage tablet erosion at specific times in the same media was measured in separate experiments. The data were compared to published data for intragastric release in fed healthy adults. In all cases, felodipine release occurred under sink conditions. Lipase facilitated felodipine release from the eroded polymer, bringing the release profile closer to the in vivo data. Likewise, the relationship between tablet erosion and amount of released felodipine reflected the in vivo data only when lipase was added to the medium. It was concluded that modelling intragastric lipolysis is necessary in order to simulate felodipine release from the extended release tablets in the fed stomach.
3.
Dickinson, Paul A, et al.
(författare)
Clinical relevance of dissolution testing in quality by design
2008
Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 10:2, s. 380-390
Forskningsöversikt (refereegranskat) abstract
Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.
4.
Garbacz, Grzegorz, et al.
(författare)
Comparison of dissolution profiles obtained from nifedipine extended release once a day products using different dissolution test apparatuses
2009
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 38:2, s. 147-155
Tidskriftsartikel (refereegranskat) abstract
In order to improve the predictability of dissolution testing new apparatuses have been proposed that mimic hydrodynamic and mechanical conditions in the gastrointestinal tract. In this study tested were four different nifedipine extended release (ER) formulations using the paddle apparatus and the reciprocating cylinder as pharmacopoeial test devices as well as two newly developed test apparatuses: the rotating beaker apparatus and the dissolution stress test apparatus. Investigated were Adalat OROS in strengths of 30 and 60 mg, and two hydrophilic matrix formulations: 60 mg nifedipine Coral and Nifedipin Sandoz 40 mg retard. The results demonstrate that the dissolution characteristic of the ER tablets is strongly dependent on the applied test conditions. The dosage form related food effects for Coral 60 mg tablets that were previously observed in human bioequivalence studies could be predicted with the two non-compendial dissolution test devices. The dissolution of Sandoz 40 mg tablets was very sensitive to all applied test conditions. The stable drug delivery characteristics of Adalat OROS observed in numerous in vivo studies was also observed in all of the dissolution tests. In conclusion, the present study shows that besides pH dependency the aspect of the mechanical robustness may be an essential factor affecting the dissolution characteristic of hydrogel matrix formulations.
5.
Lennernäs, Hans, et al.
(författare)
Oral drug absorption and the biopharmaceutics classification system
2007
Ingår i: Journal of drug delivery science and technology. - 1773-2247. ; 17:4, s. 237-244
Forskningsöversikt (refereegranskat) abstract
Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Application (NDAs) of new compounds, in supplementary NDAsfor new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediate release (IR) dosage form. The aim of BCS is to provide a regulatory tool for replacing certain BE studies by accurate in vitro dissolution tests. The aim of the present review is to present the status of BCS and discuss its future application in pharmaceutical product development. This will be discussed in relation to novel findings in human intestinal absorption, permeability and solubility. The future application of BCS is likely to be increasingly important if the BCS borders for certain Class II and III drugs are extended. The BCS is also a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. In the future, this increased awareness of a proper biopharmaceutical characterization of new drugs may result in drug molecules with a sufficiently high permeability, solubility and dissolution rate that will automatically increase the importance of BCS as a regulatory tool over time.
6.
Nyberg, Lars, et al.
(författare)
A convenient method for local drug administration at predefined sites in the entire gastrointestinal tract : experiences from 13 phase I studies
2007
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 30:5, s. 432-440
Tidskriftsartikel (refereegranskat) abstract
For local administration of drugs or enzyme inhibitors in the human gut, a small-bore, smooth tube was introduced through the nose, retrieved from the pharynx, equipped with a firm radio-opaque capsule, and swallowed. Peristalsis moves the capsule to the desired location in the gut where it is anchored before administration via the tube. Drug uptake is followed by plasma sampling. One capsule type is used for solutions, another for solid formulations. With solutions, repeated administrations could be done with the capsule being anchored for 24 h or longer or, alternatively, at several locations along the gut. This communication presents the method and an overview of 13 uptake and enzyme/transporter localization studies. Altogether, 268 intubations were undertaken in a total of 128 subjects. Plasma concentrations found with terbutaline and metoprolol are presented showing that terbutaline has its best uptake in the upper small intestine, whereas metoprolol shows the same bioavailability along the whole gut. Subjects could undertake most of their normal activities while carrying the equipment. No serious adverse events (AEs) occurred. Possibly intubation-related AEs were abdominal pain (n = 8) and constipation (n = 5). In conclusion, the method has been found to be safe, convenient and multifunctional for studies of drug uptake at predetermined gut locations in healthy subjects.
7.
Pal, Anupam, et al.
(författare)
A stomach road or "Magenstrasse" for gastric emptying
2007
Ingår i: Journal of Biomechanics. - : Elsevier BV. - 0021-9290 .- 1873-2380. ; 40:6, s. 1202-1210
Tidskriftsartikel (refereegranskat) abstract
Gastric muscle contractions grind and mix solid/liquid meal within the stomach, and move it into the bowels at a controlled rate. Contractions are of two types: slow volume-reducing contractions of the proximal stomach (the fundus), and peristaltic contraction waves in the distal stomach (the antrum). Fundic squeeze maintains gastro-duodenal pressure difference to drive gastric emptying. Emptying is generally assumed to proceed from the antrum to the fundus, so that ingested drugs can take hours to enter the small intestines and activate. Antral contraction waves (ACW), in contrast, generate fluid motions that break down and mix gastric content. Using a computer model of the human stomach, we discover a new function of these contraction waves apart from grinding and mixing. In coordination with fundic contraction, antral contraction waves move liquid content from the fundus along a very narrow path to the duodenum through the center of the antrum. Using physiological data, we show that this gastric emptying “Magenstrasse” (stomach road) can funnel liquid gastric content from the farthest reaches of the fundus directly to the intestines within 10min. Consequently, whereas drugs (tablets, capsules, liquid) released off the Magenstrasse may require hours to enter the duodenum, at low concentration, when released on the Magenstrasse the drug can enter the duodenum and activate within 10min—at high concentration. This discovery might explain observed high variability in drug initiation time, and may have important implications to both drug delivery and digestion, as well as to other wall-driven emptying of elastic containers.
8.
Persson, Eva M, et al.
(författare)
A clinical single-pass perfusion investigation of the dynamic in vivo secretory response to a dietary meal in human proximal small intestine
2006
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 23:4, s. 742-751
Tidskriftsartikel (refereegranskat) abstract
Purpose To investigate the gastrointestinal secretory and enzymatic responses to a liquid meal during in vivo perfusion of the proximal human jejunum. Methods Human intestinal fluid was collected from the proximal jejunum by single-pass in vivo perfusion (Loc-I-Gut). The fluid was quantitatively collected at 10-min intervals during 90 min while perfusing a nutritional drink at 2 mL/min. Quantification of lipids in the fluid leaving the segment was performed by using novel chromatographic methods. Results The overall bile acid concentration varied between 0.5 and 8.6 mM with a peak level 40 min after the start of the liquid meal perfusion. The total concentration of phospholipids was between 0.1 and 3.9 mM and there was a rapid degradation of phosphatidylcholine to lysophosphatidylcholine. The tri-, di-, monoglycerides and free fatty acid levels increased sharply in the beginning and reached steady-state levels between 7 and 9.5 mM. Conclusions There is a rapid secretion of bile in response to food. Most of the dietary lipids are found in the form of their degradation products in vivo in human jejunum. This novel in vivo characterization, based on direct and high-recovery sampling of intestinal fluids, forms a basis for further development of improved in vitro drug dissolution test media.
9.
Persson, Eva M., et al.
(författare)
Improved understanding of the effect of food on drug absorption and bioavailability for lipophilic compounds using an intestinal pig perfusion model
2008
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 34:1, s. 22-29
Tidskriftsartikel (refereegranskat) abstract
The purpose of this study was to investigate the relative importance of mechanisms behind the effect of food on the intestinal absorption and bioavailability for low solubility compounds by applying a porcine single-pass perfusion model. Nanoparticle suspensions of the model compounds, danazol and cyclosporine were perfused through the jejunum in isotonic fluid alone (control) and isotonic fluid with a P-glycoprotein (P-gp) inhibitor (verapamil) or dietary and endogenous lipids added. The drugs were also administered as saturated solutions in the isotonic fluid containing lipids. Administration of cyclosporine together with verapamil increased the absorption compared to the control (1.6 times) suggesting an effect on jejunal permeability. However, addition of dietary lipids to the media led to a 50% reduction in the absorption of cyclosporine indicating lack of major effects by P-gp inhibition by lipids in vivo. The absorption of danazol was increased (2.6 times) when administered as a nanosuspension in lipid containing media compared to the control, but decreased (60%) when administered as a solution in the same media. This shows how important dissolution of the drug nanoparticles is in drug absorption. The difference in the effect of lipids in the absorption of cyclosporine and danazol when administered as nanosuspensions may be due to different distribution to the colloidal structures present in the media, thereby rendering the drugs' different diffusion rates in the perfused segment. In conclusion, solubilisation seems to be a more important factor than P-gp inhibition as an explanation for the food-drug interaction observed for several low solubility drugs. In addition, the partition into different colloidal structures seems to play a major role in the dissolution and absorption of poorly soluble drugs.
10.
Persson, Eva M, et al.
(författare)
The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids
2005
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 22:12, s. 2141-2151
Tidskriftsartikel (refereegranskat) abstract
Purpose This study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF). Methods Dissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical–chemical characteristics and contents. Results Fed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%). Conclusions Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.
