| 1. |
- Lennernäs, Hans, et al.
(författare)
-
Oral biopharmaceutics tools - Time for a new initiative - An introduction to the IMI project OrBiTo
- 2014
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57:SI, s. 292-299
-
Forskningsöversikt (refereegranskat)abstract
- OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silica biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
|
|
| 2. |
- Abrahamsson, B., et al.
(författare)
-
Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project
- 2020
-
Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER. - 0939-6411 .- 1873-3441. ; 152, s. 236-247
-
Tidskriftsartikel (refereegranskat)abstract
- OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.
|
|
| 3. |
- Bredenberg, S., et al.
(författare)
-
In vitro and in vivo evaluation of a new sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the active substance
- 2003
-
Ingår i: Eur J Pharm Sci. - 0928-0987. ; 20:3, s. 327-34
-
Tidskriftsartikel (refereegranskat)abstract
- Oromucosal delivery of drugs promotes rapid absorption and high bioavailability, with subsequent almost immediate onset of pharmacological effect. However, many oromucosal delivery systems are compromised by the possibility of the patient swallowing the active substance before it has been released and absorbed locally into the systemic circulation. This paper introduces a new tablet system for sublingual administration and rapid drug absorption. The tablet is based on interactive mixtures of components, consisting of carrier particles partially covered by fine dry particles of the drug, in this case fentanyl citrate. In the interests of increasing retention of the drug at the site of absorption in the oral cavity, a bioadhesive component was also added to the carrier particles. Tablets containing 100, 200 and 400 microg of fentanyl were tested both in vitro and in vivo. The tablets disintegrated rapidly and dissolution tests revealed that fentanyl citrate was dissolved from the formulation almost instantly. Plasma concentrations of fentanyl were obtained within 10 min, with no second peak. These results indicated that the bioadhesive component prevented the fentanyl from being swallowed (the fraction swallowed was considered smaller compared to other mucosal delivery systems), without hindering its release and absorption. This new sublingual tablet formulation may also hold potential for other substances where a rapid onset of effect is desirable.
|
|
| 4. |
- Dahan, Arik, et al.
(författare)
-
High-Permeability Criterion for BCS Classification : Segmental/pH Dependent Permeability Considerations
- 2010
-
Ingår i: Molecular pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 7:5, s. 1827-1834
-
Tidskriftsartikel (refereegranskat)abstract
- The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F-abs) in humans is 90% or higher. This direct correlation between human permeability and Fab, has been recently controversial, since the beta-blocker sotalol showed high F-abs (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F-abs. The effective permeabilities (P-eff) of sotalol and metoprolol, a FDA standard for the low/high P-off class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P-eff at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol's at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK(a) and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolol's P-eff, value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalol's permeability is low at pH 6,5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high Faros, In conclusion, we have shown that, in fact, there is no discrepancy between P-eff and F-abs, in sotalol's absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.
|
|
| 5. |
- Dahlgren, David, et al.
(författare)
-
Fasted and fed state human duodenal fluids : Characterization, drug solubility, and comparison to simulated fluids and with human bioavailability
- 2021
-
Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier. - 0939-6411 .- 1873-3441. ; 163, s. 240-251
-
Tidskriftsartikel (refereegranskat)abstract
- Accurate in vivo predictions of intestinal absorption of low solubility drugs require knowing their solubility in physiologically relevant dissolution media. Aspirated human intestinal fluids (HIF) are the gold standard, followed by simulated intestinal HIF in the fasted and fed state (FaSSIF/FeSSIF). However, current HIF characterization data vary, and there is also some controversy regarding the accuracy of FaSSIF and FeSSIF for predicting drug solubility in HIF. This study aimed at characterizing fasted and fed state duodenal HIF from 16 human volunteers with respect to pH, buffer capacity, osmolarity, surface tension, as well as protein, phospholipid, and bile salt content. The fasted and fed state HIF samples were further used to investigate the equilibrium solubility of 17 representative low-solubility small-molecule drugs, six of which were confidential industry compounds and 11 were known and characterized regarding chemical diversity. These solubility values were then compared to reported solubility values in fasted and fed state HIF, FaSSIF and FeSSIF, as well as with their human bioavailability for both states. The HIF compositions corresponded well to previously reported values and current FaSSIF and FeSSIF compositions. The drug solubility values in HIF (both fasted and fed states) were also well in line with reported solubility data for HIF, as well as simulated FaSSIF and FeSSIF. This indicates that the in vivo conditions in the proximal small intestine are well represented by simulated intestinal fluids in both composition and drug equilibrium solubility. However, increased drug solubility in the fed vs. fasted states in HIF did not correlate with the human bioavailability changes of the same drugs following oral administration in either state.
|
|
| 6. |
- Darwich, Adam S., et al.
(författare)
-
IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3 : Identifying gaps in system parameters by analysing In Silico performance across different compound classes
- 2017
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 626-642
-
Tidskriftsartikel (refereegranskat)abstract
- Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.
|
|
| 7. |
- Edgren, M, et al.
(författare)
-
Angiogenic factors: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) are not necessarily elevated in patients with advanced renal cell carcinoma.
- 2001
-
Ingår i: Anticancer research. - 0250-7005. ; 21, s. 1423-
-
Tidskriftsartikel (refereegranskat)abstract
- Serum analysis of Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (b-FGF) levels were studied in 53 patients with renal cell carcinoma (RCC). Approximately 2/3 of the patients had disseminated disease at diagnosis, the remainder had no evidence of metastases. The results confirmed that VEGF has a major role in the angiogenesis of RCC. No correlation was observed between VEGF and/or b-FGF and the presence or absence of metastases, nor was any correlation observed between VEGF and/or b-FGF and patient survival. Thus, to utilise VEGF and/or b-FGF as a tumour marker at the time of diagnosis to predict patients with a high risk of progression, where an adjuvant therapeutic approach would be of great value, seems to be limited. Not all patients with RCC exhibited elevated serum levels of VEGF and/or b-FGF. No correlation was observed between tumour stage and serum levels of these angiogenic peptides.
|
|
| 8. |
- Edgren, M, et al.
(författare)
-
Postoperative radiotherapy after prostatectomy can be associated with severe side effects.
- 2001
-
Ingår i: Anticancer research. - 0250-7005. ; 21, s. 2231-
-
Tidskriftsartikel (refereegranskat)abstract
- This retrospective study was initiated to evaluate the efficacy and side effects of post-prostatectomy external beam radiation therapy (XRT) with a short time interval between surgery and irradiation in patients with prostate adenocarcinoma. Sixteen patients were investigated. The overall results in this study were 3 deaths due to recurring disease and two relapses after an average follow-up of 60 months. Severe side effects were observed. Two patients required surgical intervention due to severe post-radiotherapy side effects. The reason for this could be the high dose delivered to peripheral organs and/or a too short time interval between surgery and postoperative XRT. The results of this study confirmed that postoperative XRT can improve local control frequency in prostate carcinomas. It is recommended that the time interval between surgery and postoperative radiotherapy should to be 3-6 month.
|
|
| 9. |
|
|
| 10. |
|
|
