2,001 research outputs found
When Interactions Between Bile Salts and Cyclodextrin Cause a Negative Food Effect: Dynamic Dissolution/Permeation Studies with Itraconazole (Sporanox®) and Biomimetic Media
Full text linkThe marketed oral solution of itraconazole (Sporanox®) contains 40% (259.2 mM) of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The obvious role of HP-β-CD is to solubilize itraconazole and to overcome its poor aqueous solubility that restricts its absorption. In this study, we investigated the biorelevance of in vitro experiments by the influence of biomimetic media (containing bile salts and phospholipids) on the predicted itraconazole absorption from the commercial HP-β-CD-based Sporanox® solution. We performed phase-solubility studies of itraconazole and dynamic 2-step-dissolution/permeation studies using a biomimetic artificial barrier, Sporanox® solution, and fasted state simulated intestinal fluid (FaSSIF_V1). Both FaSSIF_V1 and HP-β-CD increased the apparent solubility of itraconazole when used individually. In combination, their solubility-enhancing effects were not additive probably due to the competition of bile salts with itraconazole for the hydrophobic cavity of HP-β-CD. Our combined dissolution/permeation experiments indicated the occurrence of a transient supersaturation from Sporanox® upon two-step dissolution. Through systematic variation of bile salt concentrations in the biomimetic media, it was observed that the extent and the duration of supersaturation depend on the concentrations of bile salts: supersaturation was rather stable in the absence of bile salts and phospholipids. The higher the bile salt concentration, the faster the collapse of the transient supersaturation occurred, an effect which is nicely mirrored by reduced in vitro permeation across the barrier. This is an indication of a negative food effect, which in fact correlates well with what earlier had been observed in clinical studies for Sporanox® solution. In essence, we could demonstrate that in vitro two-stage dissolution/permeation experiments using an artificial barrier and selected biomimetic media may predict the negative effects of the latter on cyclodextrin-based drug formulations like Sporanox® Oral Solution and, at the same time, provide a deeper mechanistic insight
Annette Harvey Diary, 1906-1910
No full textAnnette Harvey, of Arkansas, West Virginia, and Ohio, recounts events of her daily life in this 'Line a Day' diary. She was the daughter of William Hope Harvey, aka 'Coin' Harvey, a well-known businessman, politician, author and founder of the resort of Monte Ne and the Ozark Association. Annette's brief entries record visits, housework, dances, parties, a train trip to New York, weather, church services and socials over a 5 year period, 1906-1910. Addresses and miscellaneous thoughts, quotations, poems, are recorded at the end of the volume. A photograph of her home made in 1906 is tipped in at the front of the diary
Modulation of Paracellular-like Drug Transport across an Artificial Biomimetic Barrier by Osmotic Stress-Induced Liposome Shrinking
Full text linkVarious types of artificial biomimetic barriers are widely utilized as in vitro tools to predict the passive “transcellular” transport of drug compounds. The current study investigated if the sandwich barrier PermeaPad®, which is composed of tightly packed phospholipid vesicles enclosed between two support sheets, contributes to a transport mechanism that is paracellular-like, representing one of the alternative pathways of passive transport in vivo, primarily of relevance for hydrophilic drug compounds. To this end, we pretreated the commercial PermeaPad® barrier with NaCl solutions of either high or low osmolality prior to permeation experiments on reversed Franz cell setups with hydrophilic model compounds calcein and acyclovir and hydrophobic model compounds hydrocortisone and celecoxib. Our starting hypothesis was that the liposomes formed in the barrier during the hydration step should either shrink or swell upon contact with test media (drug solutions) due to osmotic pressure difference as compared to the pretreatment solutions. Apparent permeabilities for calcein and acyclovir across the PermeaPad® barrier were found to increase approximately 2.0 and 1.7 fold, respectively, upon hypo-osmotic pretreatment (soaking in hypotonic medium, while the permeation of hydrocortisone and celecoxib remained unchanged. A control experiment with lipid-free barriers (support sheets) indicated that the permeation of all the compounds was virtually unchanged upon hypo-osmotic pretreatment. In conclusion, soaking PermeaPad® in a medium of lower osmotic pressure than that used during the permeation study appears to induce the osmotic shrinking of the lipid vesicles in the barrier, leaving wider water channels between the vesicles and, thus, allowing hydrophilic compounds to pass the barrier in a paracellular-like manner
A Novel Method for the Investigation of Liquid/Liquid Distribution Coefficients and Interface Permeabilities Applied to the Water-Octanol-Drug System
No full textDrug delivery to the brain: In situ gelling formulation enhances carbamazepine diffusion through nasal mucosa models with mucin
Full text linkThe objective of this work was to optimize a thermosensitive in situ gelling formulation to improve intranasal and nose-to-brain delivery of the antiepileptic drug carbamazepine (CBZ). A preliminary procedure of vehicles obtained just mixing different fractions of poloxamer 407 (P407) and poloxamer 188 (P188) revealed preparations with phase transition temperatures, times to gelation and pH values suitable for nasal delivery. Subsequently, the mucoadhesive properties of the most promising formulations were tuned by adding hydroxypropylmethylcellulose types of different viscosity grades, and the effect of the adhesive polymers was evaluated by testing in vitro time and strength of mucoadhesion on specimens of sheep nasal mucosa. The formulation that showed the greatest mucoadhesive potential in vitro, with a time and force of mucoadhesion equal to 1746,75 s and 3.66 × 10-4 N, respectively, was that composed of 22% P407, 5% P188 and 0.8% HPMC low-viscous and it was further investigated for its ability to increase drug solubility and to control the release of the drug. Lastly, the capability of the candidate vehicle to ensure drug permeation across the biomimetic membrane Permeapad®, an artificial phospholipid-based barrier with a stratified architecture, and the same barrier enriched with a mucin layer was verified. The final formulation was characterized by a pH value of 6.0, underwent gelation at 32.33°C in 37.85 s, thus showing all the features required by in situ gelling thermosensitive preparations designed for nasal delivery and, more notably, it conserved the ability to favor drug permeation in the presence of mucin. These findings suggest that the optimized gelling system could be a promising and easy to realize strategy to improve CBZ delivery to the brain exploiting both a direct and indirect pathway
Solubilization of ibuprofen with β-cyclodextrin derivatives: Energetic and structural studies
No full textPermeation behavior and supramolecular structures of mono- / diacyl solid phospholipid dispersions of celecoxib in simulated intestinal fluid.
No full textPhospholipid-based oral formulations are generally regarded advantageous for poorly soluble drugs, potentially increasing solubility, permeability and bioavailability, although translation of solubility enhancement into permeability/bioavailability enhancement is not straightforward [1]. Solid phospholipid dispersions (SPDs) are especially promising in oral applications. A recent study indicates that the enhancing effect of SPDs can be ascribed to two mechanisms: 1. Encapsulation of the drug into colloids after hydration and 2. Amorphization of the drug induced by the preparation method and stabilized by the phospholipid (PL) matrix [2]. The permeation behavior of celecoxib (CXB) (BCS class II) formulated as either mono- or diacyl based SPDs was studied using a side-by-side diffusion set-up employing Permeapad® as artificial, biomimetic diffusion barrier. To this end CXB SPDs with various ratios of CXB to PL (phosphatidylcholine (PC) or lyso-phosphatidylcholine) were prepared by freeze-drying from a tert-butanol co-solvent system. To investigate the impact of intestinal fluids, permeation studies were carried out both, in presence or absence of fasted state simulated intestinal fluid (FaSSIF). In an attempt to elucidate supramolecular structures, the colloidal phases formed by dispersing CXB SPDs were studied utilizing the combined technique of asymmetrical flow field-flow fractionation (AF4) connected to static light scattering instrumentation i.e. multi-angle laser light scattering (MALLS). CXB permeation was found significantly changed when formulated as SPD with varying CXB to PL ratios compared to the pure (crystalline) drug. Generally, a permeation-enhancing effect was seen with higher CXB/PL-ratios, irrespective of the type of PL used (mono- vs. diacyl). But, no direct correlation between the amount of PL used and permeation enhancement was observed highlighting the complex interplay between the two enhancing mechanisms of SPDs. The presence of FaSSIF had a significant influence on CXB permeation for CXB SPDs with a low PC content. AF4/MALLS analysis of mono- or diacyl based CXB SPDs dispersed in buffer or FaSSIF revealed not more than two distinct particle fractions in all cases. The question, how differences in supramolecular structures influence the permeation of CXB was not fully resolved, but important hints were obtained on how future research activities should be designed to yield a better insight into this highly complex scenario. References: [1] Fong, S. Y. K., Brandl, M. & Bauer-Brandl, A. 2015. Phospholipid-based solid drug formulations for oral bioavailability enhancement: A meta-analysis. European Journal of Pharmaceutical Sciences, 80, 89-110. [2] Fong, S.Y.K., Martins, S.M., Brandl, M., Bauer-Brandl, A. 2016. Solid Phospholipid Dispersions for Oral Delivery of Poorly Soluble Drugs: Investigation into Celecoxib Incorporation and Solubility-In Vitro Permeability Enhancement. Journal of Pharmaceutical Sciences, 105 (3), pp. 1113-1123. DOI: 10.1016/S0022-3549(15)00186-
Permeation behavior and supramolecular structures of mono- / diacyl solid phospholipid dispersions of celecoxib in simulated intestinal fluid.
No full textPhospholipid-based oral formulations are generally regarded advantageous for poorly soluble drugs, potentially increasing solubility, permeability and bioavailability, although translation of solubility enhancement into permeability/bioavailability enhancement is not straightforward [1]. Solid phospholipid dispersions (SPDs) are especially promising in oral applications. A recent study indicates that the enhancing effect of SPDs can be ascribed to two mechanisms: 1. Encapsulation of the drug into colloids after hydration and 2. Amorphization of the drug induced by the preparation method and stabilized by the phospholipid (PL) matrix [2]. The permeation behavior of celecoxib (CXB) (BCS class II) formulated as either mono- or diacyl based SPDs was studied using a side-by-side diffusion set-up employing Permeapad® as artificial, biomimetic diffusion barrier. To this end CXB SPDs with various ratios of CXB to PL (phosphatidylcholine (PC) or lyso-phosphatidylcholine) were prepared by freeze-drying from a tert-butanol co-solvent system. To investigate the impact of intestinal fluids, permeation studies were carried out both, in presence or absence of fasted state simulated intestinal fluid (FaSSIF). In an attempt to elucidate supramolecular structures, the colloidal phases formed by dispersing CXB SPDs were studied utilizing the combined technique of asymmetrical flow field-flow fractionation (AF4) connected to static light scattering instrumentation i.e. multi-angle laser light scattering (MALLS). CXB permeation was found significantly changed when formulated as SPD with varying CXB to PL ratios compared to the pure (crystalline) drug. Generally, a permeation-enhancing effect was seen with higher CXB/PL-ratios, irrespective of the type of PL used (mono- vs. diacyl). But, no direct correlation between the amount of PL used and permeation enhancement was observed highlighting the complex interplay between the two enhancing mechanisms of SPDs. The presence of FaSSIF had a significant influence on CXB permeation for CXB SPDs with a low PC content. AF4/MALLS analysis of mono- or diacyl based CXB SPDs dispersed in buffer or FaSSIF revealed not more than two distinct particle fractions in all cases. The question, how differences in supramolecular structures influence the permeation of CXB was not fully resolved, but important hints were obtained on how future research activities should be designed to yield a better insight into this highly complex scenario. References: [1] Fong, S. Y. K., Brandl, M. & Bauer-Brandl, A. 2015. Phospholipid-based solid drug formulations for oral bioavailability enhancement: A meta-analysis. European Journal of Pharmaceutical Sciences, 80, 89-110. [2] Fong, S.Y.K., Martins, S.M., Brandl, M., Bauer-Brandl, A. 2016. Solid Phospholipid Dispersions for Oral Delivery of Poorly Soluble Drugs: Investigation into Celecoxib Incorporation and Solubility-In Vitro Permeability Enhancement. Journal of Pharmaceutical Sciences, 105 (3), pp. 1113-1123. DOI: 10.1016/S0022-3549(15)00186-
New biomimetic barrier Permeapad™ for efficient investigation of passive permeability of drugs
No full textIn this work the suitability of a newly invented physical patch comprising a biomimetic barrier (named Permeapad™) for drug permeability tests has been investigated. Exemplars of Permeapad™ were adapted to Franz diffusion cells and apparent permeability (Papp) of a series of drugs were measured and compared with calculated partition coefficients (log Pcal) of the investigated drugs as well as literature reference values obtained from Parallel Artificial Membrane Permeation Assay (PAMPA) and the cellular based method Caco-2. Moreover, tightness of the barrier to hydrophilic marker's permeation, resistance of these barriers to proton permeation (pH changes) and shelf-life functionality were also investigated. Comparison with the published data indicated a good correlation between the permeability values measured and partition coefficients (log Pcal). Moreover, a good correlation between the permeabilities measured with the new barrier and well-established in vitro permeability methods (PAMPA and Caco-2 respectively) was found for both highly absorbed and poorly permeable compounds. Permeapad™ also proved to maintain high integrity over time and in different pH environments. In conclusion, Permeapad™ as an innovative barrier appears to be a promising tool for fast, cost effective and reliable screening of drugs and chemical entities' passive permeability.</p
Many young people’s mental health suffered during COVID. They need more help
No full textYoung people’s mental health and wellbeing suffered during the pandemic, and we do not yet know what the long-term consequences will be. Annette Bauer (LSE) looks at which groups have been most affected and calls for support that extends beyond 2022
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