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.
2.
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.
3.
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).
4.
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.
5.
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.
6.
Alvebratt, Caroline, et al.
(författare)
A Modified In Situ Method to Determine Release from a Complex Drug Carrier in Particle-Rich Suspensions
2018
Ingår i: AAPS PharmSciTech. - : Springer Science and Business Media LLC. - 1530-9932. ; 19:7, s. 2859-2865
Tidskriftsartikel (refereegranskat) abstract
Effective and compound-sparing methods to evaluate promising drug delivery systems are a prerequisite for successful selection of formulations in early development stages. The aim of the study was to develop a small-scale in situ method to determine drug release and supersaturation in highly concentrated suspensions of enabling formulations. Mesoporous magnesium carbonate (MMC), which delivers the drug in an amorphous form, was selected as a drug carrier. Five model compounds were loaded into the MMC at a 1:10 ratio using a solvent evaporation technique. The μDiss Profiler was used to study the drug release from MMC in fasted-state simulated intestinal fluid. To avoid extensive light scattering previously seen in particle-rich suspensions in the μDiss Profiler, an in-house-designed protective nylon filter was placed on the in situ UV probes. Three types of release experiments were conducted for each compound: micronized crystalline drug with MMC present, drug-loaded MMC, and drug-loaded MMC with 0.01% w/w hydroxypropyl methyl cellulose. The nylon filters effectively diminished interference with the UV absorption; however, the release profiles obtained were heavily compound dependent. For one of the compounds, changes in the UV spectra were detected during the release from the MMC, and these were consistent with degradation of the compound. To conclude, the addition of protective nylon filters to the probes of the μDiss Profiler is a useful contribution to the method, making evaluations of particle-rich suspensions feasible. The method is a valuable addition to the current ones, allowing for fast and effective evaluation of advanced drug delivery systems.
7.
Alvebratt, Caroline, et al.
(författare)
In Vitro Performance and Chemical Stability of Lipid-Based Formulations Encapsulated in a Mesoporous Magnesium Carbonate Carrier
2020
Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923 .- 1999-4923. ; 12:5
Tidskriftsartikel (refereegranskat) abstract
Lipid-based formulations can circumvent the low aqueous solubility of problematic drug compounds and increase their oral absorption. As these formulations are often physically unstable and costly to manufacture, solidification has been suggested as a way to minimize these issues. This study evaluated the physicochemical stability and in vitro performance of lipid-loaded mesoporous magnesium carbonate (MMC) particles with an average pore size of 20 nm. A medium chain lipid was loaded onto the MMC carrier via physical adsorption. A modified in vitro lipolysis setup was then used to study lipid release and digestion with 1H nuclear magnetic resonance spectroscopy. The lipid loading efficiency with different solidification techniques was also evaluated. The MMC, unlike more commonly used porous silicate carriers, dissolved during the lipolysis assay, providing a rapid release of encapsulated lipids into solution. The digestion of the dispersed lipid-loaded MMC therefore resembled that of a coarse dispersion of the lipid. The stability data demonstrated minor degradation of the lipid within the pores of the MMC particles, but storage for three months did not reveal extensive degradation. To conclude, lipids can be adsorbed onto MMC, creating a solid powder from which the lipid is readily released into the solution during in vitro digestion. The chemical stability of the formulation does however merit further attention.
8.
Amidon, Gregory E., et al.
(författare)
Fifty-Eight Years and Counting : High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling
2019
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 108:1, s. 2-7
Tidskriftsartikel (refereegranskat) abstract
With this issue of the Journal of Pharmaceutical Sciences, we celebrate the nearly 6 decades of contributions to mechanistic-based modeling and computational pharmaceutical sciences. Along with its predecessor, The Journal of the American Pharmaceutical Association: Scientific Edition first published in 1911, JPharmSci has been a leader in the advancement of pharmaceutical sciences beginning with its inaugural edition in 1961. As one of the first scientific journals focusing on pharmaceutical sciences, JPharmSci has established a reputation for publishing high-quality research articles using computational methods and mechanism-based modeling. The journal’s publication record is remarkable. With over 15,000 articles, 3000 notes, and more than 650 reviews from industry, academia, and regulatory agencies around the world, JPharmSci has truly been the leader in advancing pharmaceutical sciences.
9.
Asad, Shno, et al.
(författare)
Proteomics-Informed Identification of Luminal Targets For In Situ Diagnosis of Inflammatory Bowel Disease
2021
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier. - 0022-3549 .- 1520-6017. ; 110:1, s. 239-250
Tidskriftsartikel (refereegranskat) abstract
Inflammatory bowel disease (IBD) is a chronic condition resulting in impaired intestinal homeostasis. Current practices for diagnosis of IBD are challenged by invasive, demanding procedures. We hypothesized that proteomics analysis could provide a powerful tool for identifying clinical biomarkers for non-invasive IBD diagnosis. Here, the global intestinal proteomes from commonly used in vitro and in vivo models of IBD were analyzed to identify apical and luminal proteins that can be targeted by orally delivered diagnostic agents. Global proteomics analysis revealed upregulated plasma membrane proteins in intestinal segments of proximal- and distal colon from dextran sulfate sodium-treated mice and also in inflamed human intestinal Caco-2 cells pretreated with pro-inflammatory agents. The upregulated colon proteins in mice were compared to the proteome of the healthy ileum, to ensure targeting of diagnostic agents to the inflamed colon. Promising target proteins for future investigations of non-invasive diagnosis of IBD were found in both systems and included Tgm2/TGM2, Icam1/ICAM1, Ceacam1/CEACAM1, and Anxa1/ANXA1. Ultimately, these findings will guide the selection of appropriate antibodies for surface functionalization of imaging agents aimed to target inflammatory biomarkers in situ.
10.
