Table 1 - uploaded by Ragna Berthelsen
Content may be subject to copyright.
Source publication
The aim of this study was to develop a sensitive and discriminative in vitro-in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of th...
Contexts in source publication
Context 1
... main difference between the three formulations was the choice and contents of surfactants. Table 1 lists the surfactants and contents of the three formulations. In each of the formulations, the content of surfactants ranged from 6.4 to 8.8% (w/w) of the total content. ...
Context 2
... 6 shows this relation with the data fitted by linear regression producing a fine correlation for MD formula- tion A and B. For formulation C, the apparent solubility basically remained unchanged throughout the dissolution experiments. Fig. 7 shows the simulated plasma profiles when employing the smaller volume for total intestinal volume in the in silico model, combined with apparent solubility input calculated for each GI- Sim compartment based on linear regression fits from Fig. 6 (input values are available in the Supplementary material, Table 1). The simulations based on multiple experiments produced the overall best correlations, with right C max rank order and AUC 0-8 h within the std. ...
Citations
... proposed to predict ADMET properties without the need for in vitro and in vivo experiments [8][9][10]. In silico approaches offer several advantages over experimental methods, including lower costs and the ability to process a large number of compounds in a highthroughput manner [11]. ...
Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims to present an innovative approach for predicting ADMET properties using attention-based graph neural networks (GNNs). The model utilizes a graph-based representation of molecules directly derived from Simplified Molecular Input Line Entry System (SMILE) notation. Information is processed sequentially, from substructures to the whole molecule, employing a bottom-up approach. The developed GNN is tested and compared with existing approaches using six benchmark datasets and by encompassing regression (lipophilicity and aqueous solubility) and classification (CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibition) tasks. Results show the effectiveness of our model, which bypasses the computationally expensive retrieval and selection of molecular descriptors. This approach provides a valuable tool for high-throughput screening, facilitating early assessment of ADMET properties and enhancing the likelihood of drug success in the development pipeline.
... It is a broad spectrum antihyperlipidaemic drug that not only attenuates the elevated plasma level of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL), but also augments the optimum level of essential cholesterols, for example high-density lipoprotein (HDL) in plasma. [1][2][3] Due to having a profound TG lowering-effect FF has the greatest worth of use in patients with hypertriglyceridaemia with or without hypercholesterolaemia associated with type 2 diabetes. It is also used in the treatment of familial dysbetalipoproteinaemia, combined hyperlipidaemia and primary hypercholesterolaemia. ...
Objectives Hyperlipidaemia is a common phenomenon in diabetes mellitus. Fenofibrate (FF) is a good candidate for the treatment of lipid abnormalities in patients with type 2 diabetes. But the bioavailability as well as therapeutic efficacy of this drug is limited to its dissolution behaviour. Here, the authors assess the therapeutic efficacy of a newly formulated solid dispersion of fenofibrate (SDF) having enhanced dissolution profiles in contrast to pure FF using fructose-induced diabetic rat model. Methods Fructose-induced diabetic rat model was developed to assess the pharmacological efficacy of the formulated SDF, and the results were compared with the effects of conventional FF therapy. Key findings The 14 days treatment showed better improvement in lipid-lowering potency of SDF than pure FF. SDF containing one-third dose of pure FF showed similar effect in terms of triglyceride, total cholesterol and low-density lipoprotein lowering efficacy, whereas increased high-density lipoprotein at same extent. The similar dose of SDF produced more prominent effect than FF. Histo-logical studies also demonstrated the enhanced lipid clearance from liver by SDF than FF that was concordant with the biochemical results. Conclusions This newly formulated SDF would be a promising alternative for conventional fenofibrate in treating hyperlipidaemia.
... Additionally, the in vivo relevant dissolution setup, displaying nonsink conditions using a 50 mL dissolution volume and a clinically relevant dose of approx. 110 mg CCX, was selected to allow evaluation of the possible supersaturating effect of the prepared ASDs [53,54]. The dissolution experiments were performed in triplicate (n = 3). ...
In the current study, the concept of multiparticulate drug delivery systems (MDDS) was applied to tablets intended for the amorphisation of supersaturated granular ASDs in situ, i.e. amorphisation by microwave irradiation within the final dosage form. The MDDS concept was hypothesised to ensure geometric and structural stability of the dosage form and to improve the in vitro disintegration and dissolution characteristics. Granules were prepared in two sizes (small and large) containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) at a 50 % w/w drug load as well as sodium dihydrogen phosphate monohydrate as the microwave absorbing excipient. The granules were subsequently embedded in an extra-granular tablet phase composed of either the filler microcrystalline cellulose (MCC) or mannitol (MAN), as well as the disintegrant crospovidone and the lubricant magnesium stearate. The tensile strength and disintegration time were investigated prior to and after 10 min of microwave irradiation (800 and 1000 W) and the formed ASDs were characterised by X-ray powder diffraction and modulated differential scanning calorimetry. Additionally, the internal structure was elucidated by X-ray micro-Computed Tomography (XµCT) and, finally, the dissolution performance of selected tablets was investigated. The MDDS tablets displayed no geometrical changes after microwave irradiation, however, the tensile strength and disintegration time increased. Complete amorphisation of CCX was achieved only for the MCC-based tablets at a power input of 1000 W, while MAN-based tablets displayed partial amorphisation independent of power input. The complete amorphisation of CCX was associated with the fusion of individual ASD granules within the tablets, which impacted the subsequent disintegration and dissolution performance. For these tablets, supersaturation was only observed after 60 min. On the other hand, the partially amorphised MDDS tablets displayed complete disintegration during the dissolution experiments, resulting in a fast onset of supersaturation within 5 min and an approx. 3.5-fold degree of supersaturation within the experimental timeframe (3 h). Overall, the MDDS concept was shown to potentially be a feasible dosage form for in situ amorphisation, however, there is still room for improvement to obtain a fully amorphous and disintegrating system.
... Bethelsen et al. have evaluated the performance of in-house ASDbased formulations of fenofibrate against marketed nanosized formulation (i.e., Tricor®) (Berthelsen et al., 2014). Dissolution of Tricor® was performed in fasted state simulated upper intestinal medium using USP type II apparatus and mini-paddle assembly with volumes of 1000 mL and 100 or 75 mL, respectively. ...
... The micellar partitioning of fenofibrate due to the presence of phospholipids and bile salt in the simulated medium was also calculated for each dissolution conditions. Dissolution in lower volume (i.e., 100 mL) with the adoption of smaller intestinal volume and micellar partitioning led to the better prediction of in vivo profiles of Tricor® (Berthelsen et al., 2014). Litou et al. developed PBAM of aprepitant to assess the parameters affecting in vivo performance in fasted-and fed-state at a dose of 80 mg and 125 mg (Litou et al., 2019). ...
Supersaturating drug delivery systems (SDDS) enhance the oral absorption of poorly water-soluble drugs by achieving a supersaturated state in the gastrointestinal tract. The maintenance of a supersaturated state is decided by the complex interplay among inherent properties of drug, excipients and physiological conditions of gastrointestinal tract. The biopharmaceutical advantage through SDDS can be mechanistically investigated by coupling biopredictive dissolution testing with physiologically based absorption modeling (PBAM). However, the development of biopredictive dissolution methods possess challenges due to concurrent dissolution, supersaturation, precipitation, and possible redissolution of precipitates during gastrointestinal transit of SDDS. In this comprehensive review, our effort is to critically assess the current state-of-knowledge and provide future directions for PBAM of SDDS. The review outlines various methods used to retrieve physiologically relevant values for input parameters like solubility, dissolution, precipitation, lipid-digestion and permeability of SDDS. SDDS-specific parameterization includes solubility values corresponding to apparent physical form, dissolution in physiologically relevant volumes with biorelevant media, and transfer experiments to incorporate precipitation kinetics. Interestingly, the lack of experimental permeability values and modification of absorption flux through SDDS possess the additional challenge for its PBAM. Supersaturation triggered permeability modifications are reported to fit the observed plasma concentration-time profile. Hence, the experimental insights on good fitting with modified permeability can be potential area of future research for the development of in vitro methods to reliably predict oral absorption of SDDS.
... Berthelsen i wsp. [29] do badania uwalniania substancji czynnej z minitabletek stosowali aparat farmakopealny nr 2 ze zmniejszonymi łopatkami i zlewkami o pojemności 250 mL. Stwierdzono, że dynamika ruchu mieszadła pozostawała taka sama jak w oryginalnym urządzeniu. ...
The individualization of pharmacotherapy including the age and health condition of the patient is a recent trend determining directions of pharmaceutical technology development. Groups of patients that especially need individualization of the therapy include children of different age and elderly with different health condition. Both of them still misses appropriately designed forms of the drugs. One of the dosage forms that enables wide modifications and broad application, convenient for a numerous groups of patients, are minitablets.
Minitablets are a solid dosage form of the drug with a diameter from 1 to 3 mm and a mass ranging from several to several dozens of milligrams. They can be administered orally as a conventional and modified release dosage forms, particularly as sustained or enteral release forms. Orodispersible minitablets suitable for children and people with swallowing disorders are also under development. Numerous studies proved that they are convenient even for newborns, infants and toddlers. What is more, they can be much safer alternative for the liquid dosage forms such as syrups or drops. Fast disintegration of such minitablets causes that they can be mixed with soft foods or liquids, including milk and enteral feeding formulas. They can be put directly in the oral cavity or administered with spoon, bottle, or transferred to the stomach or intestines with feeding tubes. Minitablets intended for the oral administration can be applied as an individual dosage units or as a multicompartment dosage form enclosed in a capsule, sachet or administered with a special dispenser. This allows individual dose adjustment within a very wide range.
The aim of this study is to present, based on the literature review, the current directions of development of minitablets as a drug form, especially beneficial in pediatric and geriatric patients. This paper also describes methods of minitablets production, compendial requirements regarding quality control of the minitablets, and possibilities of their administration to the patients concerning their age and physiological conditions.
... By basing PBPK models on biorelevant in vitro data from e.g. dissolution, solubility or supersaturation studies, it is possible to improve the ability to predict the in vivo performance (Berthelsen et al., 2014, Pathak et al., 2017. As an example, Hens et al. ...
Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds.
... Fenofibrate (FF), a fibric acid derivative, is widely used as lipid lowering drug. It is classified as BCS-II drug and its oral absorption and bioavailability is directed by aqueous solubility that is only 0.1 µg/ml [7] [8] [9] [10]. To overcome this limitation, large number of investigations had been conducted. ...
... Fenofibrate (FF), a fibric acid derivative, is widely used as lipid lowering drug. It is classified as BCS-II drug and its oral absorption and bioavailability is directed by aqueous solubility that is only 0.1 µg/ml [7] [8] [9] [10]. To overcome this limitation, large number of investigations had been conducted. ...
Fenofibrate (FF) is an anti-hyperlipidaemic drug belonging to BCS class-II (low solubility, high permeability). Its bioavailability is limited by the dissolution rate. This study was aimed to enhance the rate of dissolution of poorly water soluble drug, FF. Initially, solid dispersions of fenofibrate (SDFs) were formulated with Carplex-80 or PEG-4000 or in combination at various weight ratios and were subjected to dissolution study. On the basis of drug release at various time intervals, the formulation producing maximum drug concentration was evaluated physicochemically using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier-transform infrared spec-troscopy (FTIR), and scanning electron microscopy (SEM). It was observed that the peak drug concentration was obtained at 120 min of dissolution by formulation SDF-7, which contains a mixture of Carplex-80 and PEG-4000 at weight ratio 1:5:6 of FF:PEG-4000:Carplex-80, respectively. Thus, the extent of drug release by SDF-7 was maximized by 2.5-fold than that of pure FF. Physicochemical characterization revealed the reason for this increased drug release as a conversion of crystalline FF to amorphous form and ensured the chemical compatibility among FF and carriers. The results specified the significant improvement of FF release using solid dispersion technique.
... Fenofibrate (FNB) is a potent and well-known cholesterol-reducing agent, a pro-drug of fenofibric acid with neutral charge, lipophilic nature, and a very low water solubility (<0.5 mg/L with logP = 5.2), and is widely applied clinically to treat LDL-C and high triglyceride (TG) levels [1][2][3][4][5][6]. It acts by stimulating the activity of peroxisome proliferator-activated receptor-α (PPAR-α), a member of the PPAR subfamily of nuclear receptors that modulate the transcription of genes that regulate lipid metabolism [1,2]. ...
The aim of the present study was to make a fenofibrate (FNB) nanocrystal (NC) by wet media milling, characterizations and formulates into oral strip-films (OSFs). Mechanical properties, redispersion study, and solid-state characterizations results suggested that reduction of drug crystal size at nanoscale and incorporation into OSFs does not affect the solid-state properties of the drug. In vitro dissolution kinetics showed enhanced dissolution rate was easily manipulated by changing the thickness of the OSF. In situ UV-imaging was used to monitor drug dissolution qualitatively and quantitatively in real time. Results confirm that the intrinsic dissolution rates and surface drug concentration measured with this device were in agreement with the USP-IV dissolution profiles. In vivo pharmacokinetics in rabbits showed a significant difference in the pharmacokinetics parameter (1.4 fold increase bioavailability) of FNB NC-loaded OSFs as compared to the marketed formulation “Tricor” and as-received (pristine) drug. This approach of drug nanocrystallization and incorporation into OSFs may have significant applications in cost-effective tools for bioavailability enhancement of FNB.
... Pharmacokinetic properties have to be assessed in order to model physiological behaviors, such as the absorption and distribution profile of an oral drug [9,10]. The application of mathematical tools to predict in vivo parameters and relate them to in vitro data has demonstrated high significance and applicability in scientific works with different approaches in recent years [11][12][13][14]. ...
Objective: This study aimed to develop and validate an in vitro dissolution method based on in silico-in vivo data to determine whether an in vitro-in vivo relationship could be established for rivaroxaban in immediate-release tablets.
Significance: Oral drugs with high permeability but poorly soluble in aqueous media, such as the anticoagulant rivaroxaban, have a major potential to reach a high level of in vitro-in vivo relationship. Currently, there is no study on scientific literature approaching the development of RIV dissolution profile based on its in vivo performance.
Methods and Results: Drug plasma concentration values were modelled using computer simulation with adjustment of pharmacokinetic properties. Those values were converted into drug fractions absorbed by the Wagner-Nelson deconvolution approach. Gradual and continuous dissolution of RIV tablets was obtained with a 30 rpm basket on 50 mM sodium acetate + 0.2% SDS, pH 6.5 medium. Dissolution was conducted for up to 180 min. The fraction absorbed was plotted against the drug fraction dissolved, and a linear point-to-point regression (R²=0.9961) obtained.
Conclusions: The in vitro dissolution method designed promoted a more convenient dissolution profile of RIV tablets, whereas it suggests a better relationship with in vivo performance.
