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Träfflista för sökning "hsv:(MEDICIN OCH HÄLSOVETENSKAP) hsv:(Medicinska och farmaceutiska grundvetenskaper) hsv:(Farmaceutiska vetenskaper) ;pers:(Bergström Christel 1973)"

Sökning: hsv:(MEDICIN OCH HÄLSOVETENSKAP) hsv:(Medicinska och farmaceutiska grundvetenskaper) hsv:(Farmaceutiska vetenskaper) > Bergström Christel 1973

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1.
  • Berg, Staffan, et al. (författare)
  • Evaluation in pig of an intestinal administration device for oral peptide delivery
  • 2023
  • Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 353, s. 792-801
  • Tidskriftsartikel (refereegranskat)abstract
    • The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5–3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability.
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2.
  • Berg, Staffan, et al. (författare)
  • In Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery
  • 2021
  • Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 228-238
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to traditional enteric coated hard gelatin capsules and enteric coated tablets. Paracetamol, which is completely absorbed in dogs, was included in the formulations and used as an absorption marker to give information about the in vivo performance of the dosage forms. The pressure sensitive capsules released drug in 50% of the dogs. In the cases where drug was released, there was no difference in octreotide bioavailability or C-max compared to the enteric coated dosage forms. When comparing all dosage forms, a correlation was seen between paracetamol C-max and octreotide bioavailability, suggesting that a high drug release rate may be beneficial for peptide absorption when delivered together with sodium caprate. (C) 2020 Published by Elsevier Inc.
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3.
  • Boyd, Ben J., et al. (författare)
  • Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems
  • 2019
  • Ingår i: European Journal of Pharmaceutical Sciences. - : ELSEVIER. - 0928-0987 .- 1879-0720. ; 137
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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4.
  • Hedge, Oliver, 1991-, et al. (författare)
  • Investigation of Self-Emulsifying Drug-Delivery System Interaction with a Biomimetic Membrane under Conditions Relevant to the Small Intestine
  • 2021
  • Ingår i: Langmuir. - : American Chemical Society (ACS). - 1520-5827 .- 0743-7463. ; 37:33, s. 10200-10213
  • Tidskriftsartikel (refereegranskat)abstract
    • Self-emulsifying drug-delivery systems (SEDDS) have been extensively shown to increase oral absorption of solvation-limited compounds. However, there has been little clinical and commercial use of these formulations, in large part because the demonstrated advantages of SEDDS have been outweighed by our inability to precisely predict drug absorption from SEDDS using current in vitro assays. To overcome this limitation and increase the biological relevancy of in vitro assays, an absorption function can be incorporated using biomimetic membranes. However, the effects that SEDDS have on the integrity of a biomimetic membrane are not known. In this study, a quartz crystal microbalance with dissipation monitoring and total internal reflection fluorescence microscopy were employed as complementary methods to in vitro lipolysis-permeation assays to characterize the interaction of various actively digested SEDDS with a liquescent artificial membrane comprising lecithin in dodecane (LiDo). Observations from surface analysis showed that interactions between the digesting SEDDS and LiDo membrane coincided with inflection points in the digestion profiles. Importantly, no indications of membrane damage could be observed, which was supported by flux profiles of the lipophilic model drug felodipine (FEL) and impermeable marker Lucifer yellow on the basal side of the membrane. There was a correlation between the digestion kinetics of the SEDDS and the flux of FEL, but no clear correlation between solubilization and absorption profiles. Membrane interactions were dependent on the composition of lipids within each SEDDS, with the more digestible lipids leading to more pronounced interactions, but in all cases, the integrity of the membrane was maintained. These insights demonstrate that LiDo membranes are compatible with in vitro lipolysis assays for improving predictions of drug absorption from lipid-based formulations.
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5.
  • Sou, Tomás, et al. (författare)
  • Model-Based Drug Development in Pulmonary Delivery : Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection
  • 2019
  • Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 108:1, s. 630-640
  • Tidskriftsartikel (refereegranskat)abstract
    • Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.
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6.
  • Sou, Tomás, et al. (författare)
  • Model-Informed Drug Discovery and Development in Pulmonary Delivery : Biopharmaceutical Pharmacometric Modeling for Formulation Evaluation of Pulmonary Suspensions
  • 2020
  • Ingår i: ACS Omega. - : AMER CHEMICAL SOC. - 2470-1343. ; 5:40, s. 25733-25746
  • Tidskriftsartikel (refereegranskat)abstract
    • For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration-time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.
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7.
  • Alhalaweh, Amjad, et al. (författare)
  • Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions
  • 2019
  • Ingår i: Journal of Pharmaceutical Sciences. - : ELSEVIER SCIENCE INC. - 0022-3549 .- 1520-6017. ; 108:1, s. 252-259
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).
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8.
  • Alskär, Linda C., et al. (författare)
  • Effect of lipids on absorption of carvedilol in dogs : Is coadministration of lipids as efficient as a lipid-based formulation?
  • 2019
  • Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 304, s. 90-100
  • Tidskriftsartikel (refereegranskat)abstract
    • Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly water-soluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipidbased drug formulation containing the pre-dissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acids) and bile salts. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acids and bile salts in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in the solid form, e.g. due to chemical instability in the lipid vehicle. LBFs.
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9.
  • Alskär, Linda C., et al. (författare)
  • Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations
  • 2018
  • Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 15:10, s. 4733-4744
  • Tidskriftsartikel (refereegranskat)abstract
    • In this study we investigated lipolysis-triggered supersaturation and precipitation of a set of model compounds formulated in lipid-based formulations (LBFs). The purpose was to explore the relationship between precipitated solid form and inherent physicochemical properties of the drug. Eight drugs were studied after formulation in three LBFs, representing lipid-rich (extensively digestible) to surfactant-rich (less digestible) formulations. In vitro lipolysis of drug-loaded LBFs were conducted, and the amount of dissolved and precipitated drug was quantified. Solid form of the precipitated drug was characterized with polarized light microscopy (PLM) and Raman spectroscopy. A significant solubility increase for the weak bases in the presence of digestion products was observed, in contrast to the neutral and acidic compounds for which the solubility decreased. The fold-increase in solubility was linked to the degree of ionization of the weak bases and thus their attraction to free fatty acids. A high level of supersaturation was needed to cause precipitation. For the weak bases, the dose number indicated that precipitation would not occur during lipolysis; hence, these compounds were not included in further studies. The solid state analysis proved that danazol and griseofulvin precipitated in a crystalline form, while niclosamide precipitated as a hydrate. Felodipine and indomethacin crystals were visible in the PLM, whereas the Raman spectra showed presence of amorphous drug, indicating amorphous precipitation that quickly crystallized. The solid state analysis was combined with literature data to allow analysis of the relationship between solid form and the physicochemical properties of the drug. It was found that low molecular weight and high melting temperature increases the probability of crystalline precipitation, whereas precipitation in an amorphous form was favored by high molecular weight, low melting temperature, and positive charge.
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10.
  • Alskär, Linda C., 1985- (författare)
  • Improved Molecular Understanding of Lipid-Based Formulations : for Enabling Oral Delivery of Poorly Water-Soluble Drugs
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The majority of emerging drug candidates are not suited for conventional oral dosage forms, as they do not dissolve in the aqueous environment of the gastrointestinal (GI) tract. Consequently, a large number of enabling formulation strategies have emerged. One such strategy is to deliver the drug pre-dissolved in a lipid-based formulation (LBF), thereby bypassing the rate-limiting dissolution step. To date, only about 4% of the marketed oral drugs are delivered as LBFs. The limited use of this strategy is a result of the incomplete understanding of drug solubility in lipid vehicles, the reduced chemical stability of pre-dissolved drug, and the complex interplay between drug and formulation undergoing intestinal lipid processing. Hence, this thesis targeted an improved molecular understanding of lipid-based drug delivery to make an informed formulation development. In the first part of the thesis, drug solubility in LBF excipients and composed formulations was assessed. Through experimental studies of nearly forty compounds in nine excipients drug physicochemical properties related to solubility in these excipients were identified. The obtained data was used to develop in silico tools for prediction of drug solubility in excipients and formulations. The second part of the thesis focused on LBF performance in vitro and in vivo. Factors associated with the type of solid form that is precipitating during digestions was revealed, which provides an initial framework for understanding drug precipitation behaviour under physiological conditions. It was also shown that clinically relevant doses of LBF significantly increases intestinal drug solubilization as a result of GI lipid processing and bile secretion. Moreover, simultaneous assessment of digestion and absorption in vitro provided the same rank order of absorbed drug as the in vivo studies. Coadministration of LBF and drug was shown to be a promising alternative to pre-dissolved drug in the LBF. In summary, this thesis has improved the molecular understanding of factors that govern drug solubility in lipid vehicles and solid form of precipitated drug under digestive conditions. It was also proved that clinically relevant doses of LBFs significantly increase the intestinal drug solubilization, and proof-of-concept was shown for coadministration of LBF with solid drug as an alternative to drug-loaded LBF.  
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