References of "Evrard, Brigitte"
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See detailHot melt extrusion as a solvent-free technique for the formation of a polymeric amorphous solid dispersion of atorvastatin
Jennotte, Olivier ULiege; Koch, Nathan ULiege; Collard, Laurence ULiege et al

Scientific conference (2018, December 19)

Water-solubility enhancement of atorvastatin using the hot melt extrusion for the production of a polymeric amorphous solid dispersion

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See detailCationic Liposomes Carrying siRNA: Impact of Lipid Composition on Physicochemical Properties, Cytotoxicity and Endosomal Escape
Lechanteur, Anna ULiege; Sanna, Vincent; Duchemin, Amandine ULiege et al

Conference (2018, August)

In recent year, cationic liposomes have gained a lot of attention for siRNA delivery using different local routes of administration as the vaginal [1] or the pulmonary routes. However, lipoplexes have to ... [more ▼]

In recent year, cationic liposomes have gained a lot of attention for siRNA delivery using different local routes of administration as the vaginal [1] or the pulmonary routes. However, lipoplexes have to face several biological and intracellular barriers before releasing the genetic cargo. In this study, we focus our effort on intracellular barriers and more specifically on endosomal escape and cytosolic delivery of siRNA as well as on the cytotoxicity due to cationic lipids. Indeed, we have previously demonstrated that the surface charge of liposomes composed of the cationic lipid DOTAP is correlated to the induction of cytotoxicity [2]. In the present study, we have investigated the impact of different cationic lipids and co-lipids on the cytotoxicity and also on the endosomal escape of siRNA by flow cytometry, qRT-PCR and Western Blot assays [3]. To address these issues, we developed four liposomal formulations composed of two different cationic lipids (DOTAP and DC-Cholesterol) and different ratio of co-lipids (cholesterol and DOPE). Formulations were DOTAP/Cholesterol/DOPE 1/0.75/0.5, DOTAP/Cholesterol/DOPE 1/0.5/0.5, DOTAP/DOPE 1/1 and DC-Cholesterol/DOPE 1/1. Each type of liposomes were complexed to siRNA at six different N/P molar ratios and physico-chemical properties were characterized in terms of Z-average size, Zeta potential and complexation efficiency by gel retardation assay. Consequently, three N/P ratios (2.5, 5 and 10) were selected for in vitro experiments on A549 cells. First, we studied the cell viability of A549 cells treated during 24 h with liposomes complexed to inactive siRNA at different N/P molar ratios at siRNA concentrations of 40 and 100 nM. We have shown that the cytotoxicity is influenced by the N/P ratio, the concentration of cationic lipid as well as the nature of the cationic lipid. Secondly, the cellular uptake were evaluated by flow cytometry using the dry Trypan Blue® to quench the external fluorescence. Despite the fact the transfection rate were not significantly different, the mRNA knock-down efficiency were not similar between formulations. Liposomes containing 50% of DOPE induced a mRNA silencing of around 80% as well as the protein knock-down. This study allowed to highlight crucial parameters in order to develop lipoplexes which are safe and induce an efficient intracytoplasmic release of siRNA. Acknowledgments: The authors thank the Belgium National Fund for Scientific Research (FNRS, http://www.frs-fnrs.be) –Télévie for financial support and the Giga Cell Imaging and Flow Cytometry Platform for their collaboration. Anna Lechanteur is a FNRS-Télévie post-doctoral researcher. Amandine Duchemin is a FRIA FNRS Fellow. Denis Mottet is a FNRS Research Associate. References: 1. Lechanteur, A., Furst, T. Delvenne, P. et al., Promoting vaginal distribution of E7 and MCL-1 siRNA-silencing nanoparticles for cervical cancer treatment Molecular Pharmaceutics, 2017. 14: p. 1706-1717. 2. Lechanteur, A., Furst, T. Evrard, B. et al., PEGylation of lipoplexes: The right balance between cytotoxicity and siRNA effectiveness. Eur J Pharm Sci, 2016. 93: p. 493-503. 3. Lechanteur, A., Sanna, V. Duchemin, A. et al., Cationic Liposomes Carrying siRNA: Impact of Lipid Composition on Physicochemical Properties, Cytotoxicity and Endosomal Escape. Nanomaterials (Basel), 2018. 8(270): p. 1-12. [less ▲]

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See detailAssessment of skin penetration of classical and deformable liposomes
Bellefroid, Coralie ULiege; Lechanteur, Anna ULiege; Evrard, Brigitte ULiege et al

Conference (2018, July 12)

The skin is the largest organ of the human body representing an alternative route of administration by providing an easy and pain-free drug delivery option. Cutaneous drug delivery is not associated with ... [more ▼]

The skin is the largest organ of the human body representing an alternative route of administration by providing an easy and pain-free drug delivery option. Cutaneous drug delivery is not associated with a significant drug loss compared to systemic administration due to low enzymatic degradation and a negligible clearance. Moreover, the systemic toxicity resulting from cutaneous application is limited and side effects are easy to observe and to handle [1]. Thanks to these advantages there is a great interest in using the skin as a route of administration. Besides physical and active methods involving the disruption of the stratum corneum (SC) to increase the penetration of drugs in the underlying layers, passive methods using of non-viral vectors, particularly lipid-based nanovectors, is one of the most attractive method [2]. They were developed to increase topical macromolecules penetration through the SC barrier and to promote the intracellular delivery of large molecules such as nucleic acids. However, it has become obvious that conventional liposomes do not promote the skin penetration without enhancement techniques [3]. The aim of this study is to assess the skin penetration of lipid-based nanocarriers according to their composition. The skin penetration of conventional liposomes was compared to the penetration of deformable liposomes with ethanol and/or edge activators (EA). 25% (w/w) of ethanol was added to conventional liposomes (DOTAP/DOPE) to form ethosomes. Sodium Cholate and Tween®80 were used as EA to develop deformable liposomes. Formulations were characterized in terms of size, polydispersity index and surface charge. Ex vivo skin penetration experiment were performed using pig ear skin on Franz cells. In order to visualize the penetration through the skin using confocal microscopy, nanocarriers were fluorescently labeled with a fluorescent lipid (NBD-PC). A kinetic of application was performed (from 3h to 24h) and each condition was done with or without tape stripping. In this study, we showed that all the formulations were not able to penetrate the skin, even for deformable formulations. However, when the SC was removed, formulations containing ethanol allowed penetration into the epidermis. Moreover, the addition of an EA seems to encourage deeper penetration. Acknowledgments: Authors thank the Walloon Region and FEDER for financial supports. References: 1. Zakrewsky, M., S. Kumar, and S. Mitragotri, Nucleic acid delivery into skin for the treatment of skin disease: Proofs-of-concept, potential impact, and remaining challenges. J Control Release, 2015. 219: p. 445-56. 2. Geusens, B., et al., Lipid-mediated gene delivery to the skin. Eur J Pharm Sci, 2011. 43(4): p. 199-211. 3. Sala, M., et al., Lipid nanocarriers as skin drug delivery systems: Properties, mechanisms of skin interactions and medical applications. Int J Pharm, 2018. 535(1-2): p. 1-17. [less ▲]

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See detailCyclodextrin and Budesonide derivative compositions and methods
Cataldo, Didier ULiege; Evrard, Brigitte ULiege; Dufour, Gilles et al

Patent (2018)

The present invention relates to novel and useful pharmaceutical compositions formulated with a cyclodextrin compound and a budesonide derivative for the treatment and/or prevention of pulmonary ... [more ▼]

The present invention relates to novel and useful pharmaceutical compositions formulated with a cyclodextrin compound and a budesonide derivative for the treatment and/or prevention of pulmonary inflammatory disease. The present invention also relates to a novel and useful analytical technique for the detection and the quantification of ΗΡ-β-CD in solution. More specifically, the present invention relates to the use of a validated 1H NMR analysis for the detection and quantification of cyclodextrins directly in pharmaceutical formulations without any extraction or separation steps for liquid formulations. [less ▲]

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See detailInclusion of 17β-estradiol into liposome : a tool to study the molecular mechanisms of estrogen receptors
Gallez, Anne ULiege; Palazzo, Claudio; Primac, Irina et al

Conference (2018, May 24)

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See detailCationic Liposomes Carrying siRNA: Impact of Lipid Composition on Physicochemical Properties, Cytotoxicity and Endosomal Escape
Lechanteur, Anna ULiege; Sanna, Vincent; Duchemin, Amandine ULiege et al

in Nanomaterials (2018), 8(5),

Abstract: In recent year, cationic liposomes have gained a lot of attention for siRNA delivery. Despite this, intracellular barriers as endosomal escape and cytosolic delivery of siRNA still represent a ... [more ▼]

Abstract: In recent year, cationic liposomes have gained a lot of attention for siRNA delivery. Despite this, intracellular barriers as endosomal escape and cytosolic delivery of siRNA still represent a challeng, as well as the cytotoxicity due to cationic lipids. To address these issues, we developed four liposomal formulations, composed of two different cationic lipids (DOTAP and DC-Cholesterol) and different ratio of co-lipids (cholesterol and DOPE). The objective is to dissect these impacts on siRNA efficacy and cytotoxicity. Liposomes were complexed to siRNA at six different N/P molar ratios, physico-chemical properties were characterized, and consequently, N/P 2.5, 5 and 10 were selected for in vitro experiments. We have shown that cytotoxicity is influenced by the N/P ratio, the concentration of cationic lipid, as well as the nature of the cationic lipid. For instance, cell viability decreased by 70% with liposomes composed of DOTAP/Cholesterol/DOPE 1/0.75/0.5 at a N/P ratio 10, whereas the same formulation at a N/P ratio of 2.5 was safe. Interestingly, we have observed differences in terms of mRNA knock-down efficiency, whereas the transfection rate was quite similar for each formulation. Liposomes containing 50% of DOPE induced a mRNA silencing of around 80%. This study allowed us to highlight crucial parameters in order to develop lipoplexes which are safe, and which induce an efficient intracytoplasmic release of siRNA. [less ▲]

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See detailCationic Liposomes Carrying siRNA: Impact of Lipid Composition on Physicochemical Properties, Cytotoxicity and Endosomal Escape
Lechanteur, Anna ULiege; Sanna, Vincent; Duchemin, Amandine ULiege et al

in Cationic liposomes carrying siRNA: impact of lipid composition on physicochemical properties, cytotoxicity and endosomal escape (2018, April)

In recent year, cationic liposomes have gained attention for siRNA delivery using different local routes of administration as the vaginal [Lechanteur et al, Mol Pharm.2017] or the pulmonary routes ... [more ▼]

In recent year, cationic liposomes have gained attention for siRNA delivery using different local routes of administration as the vaginal [Lechanteur et al, Mol Pharm.2017] or the pulmonary routes. However, lipoplexes have to face several biological and intracellular barriers before releasing the genetic cargo. In this study, we focus our effort on intracellular barriers and more specifically on endosomal escape and cytosolic delivery of siRNA as well as on the cytotoxicity due to cationic lipids. Indeed, we have previously demonstrated that the surface charge of liposomes composed of the cationic lipid DOTAP is correlated to the induction of cytotoxicity [Lechanteur et al. EJPS.2016]. In the present study, we have investigated the impact of different cationic lipids and co-lipids on the cytotoxicity and also on the endosomal escape of siRNA by flow cytometry, qRT-PCR and Western Blot assays [Lechanteur et al. Nanomat.2018]. To address these issues, we developed four liposomal formulations composed of two different cationic lipids (DOTAP and DC-Cholesterol) and different ratio of co-lipids (cholesterol and DOPE). Formulations were DOTAP/Cholesterol/DOPE 1/0.75/0.5, DOTAP/Cholesterol/DOPE 1/0.5/0.5, DOTAP/DOPE 1/1 and DC-Cholesterol/DOPE 1/1. Each type of liposomes were complexed to siRNA at six different N/P molar ratios and physico-chemical properties were characterized in terms of Z-average size, Zeta potential and complexation efficiency. Consequently, three N/P ratios (2.5, 5 and 10) were selected for in vitro experiments on A549 cells. We studied the cell viability of cells with liposomes complexed to inactive siRNA at different N/P molar ratios at two siRNA concentrations. We have shown that the cytotoxicity is influenced by the N/P ratio, the concentration of cationic lipid as well as the nature of the cationic lipid. The cellular uptake were evaluated using the dye Trypan Blue® to quench the external fluorescence. Despite the fact the transfection rate were not significantly different, the mRNA knock-down efficiency were not similar between formulations. Liposomes containing 50% of DOPE induced a mRNA silencing of around 80% as well as the protein knock-down. This study allowed to highlight crucial parameters in order to develop lipoplexes which are safe and induce an efficient intracytoplasmic release of siRNA. [less ▲]

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See detailInclusion of 17β-estradiol into liposome prevent the activation of membrane initiated signaling of ERalpha
Gallez, Anne ULiege; Palazzo, Claudio ULiege; Evrard, Brigitte ULiege et al

Poster (2018)

Estrogens are implicated in many physiological and pathological processes thanks to their interaction with estrogen receptors (ERs). The estrogen receptor alpha (ERα) controls reproduction, normal mammary ... [more ▼]

Estrogens are implicated in many physiological and pathological processes thanks to their interaction with estrogen receptors (ERs). The estrogen receptor alpha (ERα) controls reproduction, normal mammary gland development and breast cancer progression. The activation of ERα by estrogens, especially by 17β-estradiol (E2), leads to two major pathways: (1) the genomic effects associated to the transcriptional activity of the ERα and (2) the MISS (Membrane Initiated Steroid Signaling) effects related to the induction of fast signaling pathways occurring when ERα is anchored to the plasma membrane. Liposome are small non-toxic and biodegradable vectors widely studied for treatment of pathologies, like multiple sclerosis, Parkinson and Alzheimer disease and cancer. The encapsulation of several types of molecules (proteins, DNA and steroids), the protection of the activity and the improvement of the pharmacokinetic properties of these compounds represent the main advantages of liposome’s use. However, the impact of the encapsulation on molecular mechanisms is not yet established. As a proof of concept, we evaluate the impact of E2 inclusion into liposome (named POPC E2) in vitro and in vivo on ERα signaling pathway activation. [less ▲]

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See detailSafety and tolerance of cidofovir as a 2% gel for local application in high-grade cervical intraepithelial neoplasia: A phase 1 investigation.
Bossens, Michel; Jost, Maud; Van Pachterbeke, Catherine et al

in International Journal of Clinical Pharmacology and Therapeutics (2018), 56(3), 134-141

OBJECTIVES: The primary objective was to evaluate the safety and local tolerance of a topical 2% (w/w) cidofovir gel, applied directly to the cervices of women with high-grade cervical intraepithelial ... [more ▼]

OBJECTIVES: The primary objective was to evaluate the safety and local tolerance of a topical 2% (w/w) cidofovir gel, applied directly to the cervices of women with high-grade cervical intraepithelial neoplasia (CIN 2+). The secondary objective was to evaluate the pharmacokinetics of cidofovir during the treatment. MATERIALS AND METHODS: Nine women with CIN 2+, were treated with a course of 3 g of cidofovir gel, applied locally once per week for 3 weeks in total (9 g). The treatment was administered in a cervical cap, applied to the cervix for 5 or 10 hours (n = 6 and 3 patients, respectively). Follow-up included a structured questionnaire, a gynecological examination, blood analysis for hematology, C-reactive protein (CRP), and renal function assessment plus pharmacokinetic analyses of cidofovir after each treatment and at the end of the full course. RESULTS: No clinically significant hematological/biochemical abnormalities or serious adverse events (SAE) were reported, although 6 mild to moderate adverse events (AE) occurred in relation to the study drug: 1 flu-like syndrome and 5 local AEs. Plasma concentrations of cidofovir were very low (mean Cmax of 103.0 and 99.2 ng/mL after 5 and 10 hours of exposure, respectively). CONCLUSION: Cidofovir, directly applied on CIN 2+, is reasonably well tolerated and the systemic exposure following topical application is much lower than that seen with intravenous administration, at the approved dose.. [less ▲]

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See detailPromoting vaginal distribution of two active siRNA-complexed in liposomes for cervical cancer treatment
Lechanteur, Anna ULiege; Furst, Tania; Delvenne, Philippe ULiege et al

Conference (2017, December 07)

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See detailPromoting vaginal distribution of two active siRNA-complexed in liposomes for cervical cancer treatment
Lechanteur, Anna ULiege; Furst, Tania; Delvenne, Philippe ULiege et al

Conference (2017, December 05)

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See detailPulmonary delivery of a liposome formulation encapsulating a natural flavonoid in the treatment of lung cancer
Cao, Martine ULiege; Karim, Reatul ULiege; CATALDO, Didier ULiege et al

Poster (2017, December)

Development of new chemotherapeutic agents remains a continuing challenge in oncology, as the disease represents the major cause of morbidity and mortality worldwide. Lung cancer is the most frequently ... [more ▼]

Development of new chemotherapeutic agents remains a continuing challenge in oncology, as the disease represents the major cause of morbidity and mortality worldwide. Lung cancer is the most frequently diagnosed cancer and was the leading cause of deaths due to cancer in the last recent years [1]. In Belgium, one cancer out of four was associated to lung cancer in 2013 [2]. There is therefore an urgent need to discover new chemotherapeutic options. To date, the treatment of patients with lung cancer is a combination of surgery, radiotherapy and/or oral or IV chemotherapy. But there is currently no direct pulmonary treatment to administer chemotherapeutic drugs. Our project seeks to develop an original formulation for inhalation based on liposomes and a natural compound from the flavonoid class to treat lung cancer. Previous work carried out in our laboratory showed that liposomes with a positive zeta potential and composed of DPPC, DOPE, DC-Cholesterol and DSPE-PEG2000 displayed superior entrapping rate of the active flavonoid. Starting from that formulation, we worked on the optimization with different types and proportions of lipids, and characterized the liposomes in terms of size, PDI, charge, encapsulation efficiency and drug loading capacity. The in vitro therapeutic efficacy and cytotoxicity of the formulations were validated by MTT assays on a lung cancer cell line (LLC - mouse Lewis lung carcinoma cells) and on a lung control cell line (MLE12). The formulation giving the optimal characteristics and response on cells will be then evaluated in vivo for its tumor potential and toxicity in a relevant experimental lung cancer mouse model. [less ▲]

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See detailDevelopment and evaluation of injectable nanosized drug delivery systems for apigenin
Karim, Reatul ULiege; Palazzo, Claudio ULiege; Laloy, Julie et al

in International Journal of Pharmaceutics (2017), 532(2), 757-768

The purpose of this study was to develop different injectable nanosized drug delivery systems (NDDSs) i.e. liposome, lipid nanocapsule (LNC) and polymeric nanocapsule (PNC) encapsulating apigenin (AG) and ... [more ▼]

The purpose of this study was to develop different injectable nanosized drug delivery systems (NDDSs) i.e. liposome, lipid nanocapsule (LNC) and polymeric nanocapsule (PNC) encapsulating apigenin (AG) and compare their characteristics to identify the nanovector(s) that can deliver the largest quantity of AG while being biocompatible. Two liposomes with different surface characteristics (cationic and anionic), a LNC and a PNC were prepared. A novel tocopherol modified poly(ethylene glycol)-b-polyphosphate block-copolymer was used for the first time for the PNC preparation. The NDDSs were compared by their physicochemical characteristics, AG release, storage stability, stability in serum, complement consumption and toxicity against a human macrovascular endothelial cell line (EAhy926). The diameter and surface charge of the NDDSs were comparable with previously reported injectable nanocarriers. The NDDSs showed good encapsulation efficiency and drug loading. Moreover, the NDDSs were stable during storage and in fetal bovine serum for extended periods, showed low complement consumption and were non-toxic to EAhy926 cells up to high concentrations. Therefore, they can be considered as potential injectable nanocarriers of AG. Due to less pronounced burst effect and extended release characteristics, the nanocapsules could be favorable approaches for achieving prolonged pharmacological activity of AG using injectable NDDS. [less ▲]

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See detailSampling only 10 μL of whole blood to study the bioavailability of itraconazole formulations in rats
Kok, Miranda ULiege; Thiry, Justine ULiege; Evrard, Brigitte ULiege et al

Conference (2017, September 12)

Background Volumetric absorptive microsampling (VAMS) offers a unique opportunity to collect small and accurate quantities of biological fluids. This sampling technique is of great interest for volume ... [more ▼]

Background Volumetric absorptive microsampling (VAMS) offers a unique opportunity to collect small and accurate quantities of biological fluids. This sampling technique is of great interest for volume-limited samples and for the collection of multiple samples from the same animal. This serial sample collection may reduce the number of required study animals, thereby fulfilling the three Rs rule (refine, reduce, replace). Here, we demonstrate the applicability of VAMS to study the bioavailability of drug formulations in rats. Methods Four itraconazole-containing formulations were successively administered to rats with a wash-out period of one week. VAMS was used to collect 14 whole blood samples of only 10 μL each within a time frame of 48 hours after administration of the different drug formulations. Particular attention was paid to sample preparation and stability. The extraction of itraconazole and its main metabolite hydroxy-itraconazole was optimized to provide a high recovery and minimal matrix effects. A developed and validated LC–MS/MS method was used for the quantification of the two compounds. Pharmacokinetic profiles for the different formulations were constructed and compared. Results The stability of itraconazole and hydroxy-itraconazole in dried VAMS samples of whole rat blood could not be guaranteed for more than a day when the samples were stored at room temperature. However, samples were stable for at least two weeks when stored at -80°C after sample preparation. Differences in pharmacokinetic profiles were observed for the tested drug formulations. Whole blood concentrations of itraconazole and its main metabolite were significantly higher after administration of three in-house produced formulations compared to concentrations obtained with a commercially available product. Moreover, these in vivo results could be partly related to in vitro dissolution rates of the various formulations. Conclusions VAMS is an attractive approach for bioavailability studies. Due to the low blood volumes per sampling point, the same rats can be used to compare various drug formulations. Therefore, the number of required animals can be drastically reduced. Moreover, this helps to suppress the inter-individual variability and strengthens the validity of results. [less ▲]

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See detailInterest of cylodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide
Bigazzi, William ULiege; Dufour, Gilles; De Tullio, Pascal ULiege et al

Poster (2017, June)

The present study aim at developing cyclodextrin-based spray-dried microparticles containing a corticosteroid (budesonide) with an efficient lung delivery and efficacy. Complexation between budesonide and ... [more ▼]

The present study aim at developing cyclodextrin-based spray-dried microparticles containing a corticosteroid (budesonide) with an efficient lung delivery and efficacy. Complexation between budesonide and hydroxypropyl-beta-cyclodextrin (HPBCD) has been investigated and production of spray-dried powder was optimized based on a design of experiments. Wrinkled particles associated with a low bulk density and improved respirable fraction in comparison to a marketed product were obtained. An in vitro test showed that HPBCD is able to decrease the permeability of budesonide across the bronchial epithelium by a sustained release effect. In conclusion, this work reports that the use of cyclodextrin in the formulation of dry powder for inhalation is of a double interest as it both improves respirable fraction and lung residence time of budesonide. [less ▲]

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See detailIn vitro biphasic dissolution tests and their suitability for establishing in vitro-in vivo correlations: A historical review
Pestieau, Aude ULiege; Evrard, Brigitte ULiege

in European Journal of Pharmaceutical Sciences (2017), 102

For many decades, one of the most critical issues in the pharmaceutical industry has been the poor solubility of some drugs. Indeed, a prerequisite for drug absorption is the presence of dissolved drug at ... [more ▼]

For many decades, one of the most critical issues in the pharmaceutical industry has been the poor solubility of some drugs. Indeed, a prerequisite for drug absorption is the presence of dissolved drug at the absorption site and this can be challenging for compounds with low aqueous solubility such as BCS class II (low solubility, high permeability) and IV (low solubility, low permeability) compounds. If the development of oral delivery formulations of these compounds is frequently challenging to formulation scientists in the pharmaceutical industry, the in vitro evaluation of these new formulations is also a great challenge. One alternative approach to overcome the problems encountered with conventional dissolution methods is the use of biphasic dissolution systems. This review provides an overview of the origin and the evolution over time of the biphasic systems and the growing interest among scientists regarding their suitability for establishing in vitro-in vivo correlations. The evolution of these systems and their applications from the 1960s to the present day, such as in system variants and improvements, analysis of complex formulations, discriminatory power, bio-relevance, precipitation and supersaturation visualization, etc. will be discussed. [less ▲]

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