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Sökning: WFRF:(Bergström Christel A. S.)

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1.
  • 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. ; 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.
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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.
  • Alhalaweh, Amjad, et al. (författare)
  • Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.
  • 2016
  • Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 229, s. 172-182
  • Tidskriftsartikel (refereegranskat)abstract
    • Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.
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4.
  • Bergström, Christel A S, et al. (författare)
  • Absorption classification of oral drugs based on molecular surface properties
  • 2003
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 46:4, s. 558-570
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate whether easily calculated and comprehended molecular surface properties can predict drug solubility and permeability with sufficient accuracy to allow theoretical absorption classification of drug molecules. For this purpose, structurally diverse, orally administered model drugs were selected from the World Health Organization (WHO)'s list of essential drugs. The solubility and permeability of the drugs were determined using well-established in vitro methods in highly accurate experimental settings. Descriptors for molecular surface area were generated from low-energy conformations obtained by conformational analysis using molecular mechanics calculations. Correlations between the calculated molecular surface area descriptors, on one hand, and solubility and permeability, on the other, were established with multivariate data analysis (partial least squares projection to latent structures (PLS)) using training and test sets. The obtained models were challenged with external test sets. Both solubility and permeability of the druglike molecules could be predicted with high accuracy from the calculated molecular surface properties alone. The established correlations were used to perform a theoretical biopharmaceutical classification of the WHO-listed drugs into six classes, resulting in a correct prediction for 87% of the essential drugs. An external test set consisting of Food and Drug Administration (FDA) standard compounds for biopharmaceutical classification was predicted with 77% accuracy. We conclude that PLS models of easily comprehended molecular surface properties can be used to rapidly provide absorption profiles of druglike molecules early on in drug discovery.
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5.
  • Wright, Leah, et al. (författare)
  • A comparison of chitosan, mesoporous silica and poly(lactic-co-glycolic) acid nanocarriers for optimising intestinal uptake of oral protein therapeutics
  • 2021
  • Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier. - 0022-3549 .- 1520-6017. ; 110:1, s. 217-227
  • Tidskriftsartikel (refereegranskat)abstract
    • Efficacious oral delivery of therapeutic proteins remains challenging and nanoparticulate approaches are gaining interest for enhancing their permeability. In this study, we explore the ability for three comparably sized nanocarriers, with diverse physicochemical properties (i.e., chitosan (CSNP), mesoporous silica nanoparticles (MSNP) and poly(lactic-co-glycolic) acid (PLGA-NP)), to successfully facilitate epithelial uptake of a model protein, ovalbumin (OVA). We report the effect of nanoparticle surface chemistry and nanostructure on protein release, cell toxicity and the uptake mechanism in a Madin Darby Canine Kidney (MDCK) cell model of the intestinal epithelium. All nanocarriers exhibited bi-phasic OVA release kinetics with sustained and incomplete release after 4 days, and more pronounced release from MSNP than either polymeric nanocarriers. CSNP and MSNP displayed the highest cellular uptake, however CSNP was prone to significant dose-dependent toxicity attributed to the cationic surface charge. Approximately 25% of MSNP uptake was governed by a clathrin-independent endocytic mechanism, while CSNP and PLGA-NP uptake was not controlled via any endocytic mechanisms investigated herein. Furthermore, endosomal localisation was observed for CSNP and MSNP, but not for PLGA-NP's. These findings may assist in the optimal choice and engineering of nanocarriers for specific intestinal permeation enhancement for oral protein delivery.
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6.
  • Ahlin, Gustav, et al. (författare)
  • Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
  • 2008
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:19, s. 5932-5942
  • Tidskriftsartikel (refereegranskat)abstract
    • The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
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7.
  • Alhalaweh, Amjad, et al. (författare)
  • Computational predictions of glass-forming ability and crystallization tendency of drug molecules
  • 2014
  • Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 11:9, s. 3123-3132
  • Tidskriftsartikel (refereegranskat)abstract
    • Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt-quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Hückel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds.
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8.
  • 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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9.
  • Alhalaweh, Amjad, et al. (författare)
  • Physical stability of drugs after storage above and below the glass transition temperature : Relationship to glass-forming ability
  • 2015
  • Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 495:1, s. 312-317
  • Tidskriftsartikel (refereegranskat)abstract
    • Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (T-g) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [ 18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12 h at temperatures 20 degrees C above or below the T-g. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20 degrees C below the T-g. Fourteen of the Class II compounds crystallized when stored above the T-g whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e. g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the T-g. The use of a large dataset revealed that molecular features related to aromaticity and pi-pi interactions reduce the inherent physical stability of amorphous drugs.
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10.
  • 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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11.
  • 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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12.
  • Alskär, Linda C., et al. (författare)
  • Tools for Early Prediction of Drug Loading in Lipid-Based Formulations
  • 2016
  • Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 13:1, s. 251-261
  • Tidskriftsartikel (refereegranskat)abstract
    • Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R-2 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R-2 0.85; Polysorbate 80, R-2 0.90; Cremophor EL, R-2 0.93). A melting point below 150 degrees C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R-2 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R-2 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug.
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13.
  • 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.
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14.
  • Alzghoul, Ahmad, et al. (författare)
  • Experimental and Computational Prediction of Glass Transition Temperature of Drugs
  • 2014
  • Ingår i: JOURNAL OF CHEMICAL INFORMATION AND MODELING. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 54:12, s. 3396-3403
  • Tidskriftsartikel (refereegranskat)abstract
    • Glass transition temperature (T-g) is an important inherent property of an amorphous solid material which is usually determined experimentally. In this study, the relation between T-g and melting temperature (T-m) was evaluated using a data set of 71 structurally diverse druglike compounds. Further, in silico models for prediction of T-g were developed based on calculated molecular descriptors and linear (multilinear regression, partial least-squares, principal component regression) and nonlinear (neural network, support vector regression) modeling techniques. The models based on T-m predicted T-g with an RMSE of 19.5 K for the test set. Among the five computational models developed herein the support vector regression gave the best result with RMSE of 18.7 K for the test set using only four chemical descriptors. Hence, two different models that predict T-g of drug-like molecules with high accuracy were developed. If T-m is available, a simple linear regression can be used to predict T-g. However, the results also suggest that support vector regression and calculated molecular descriptors can predict T-g with equal accuracy, already before compound synthesis.
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15.
  • 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.
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16.
  • Andersson, Sara B. E., et al. (författare)
  • Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs
  • 2016
  • Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 105:9, s. 2864-2872
  • Tidskriftsartikel (refereegranskat)abstract
    • The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured at multiple laboratories using the same experimental protocol. Dissolution was studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly showed a need for a standardized protocol including both the experimental assay and the data analysis. Standardization at both these levels decreased the interlaboratory variability. The results also illustrated the difficulties in performing disc IDR on poorly water-soluble drugs because the concentrations reached are typically below the limit of detection. The following guidelines were established: for compounds with Sapp > 1 mg/mL, the disc method is recommended. For compounds with Sapp <100 μg/mL, IDR is recommended to be performed using powder dissolution. Compounds in the interval 100 μg/mL to 1 mg/mL can be analyzed with either of these methods.
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17.
  • Ansari, Shaquib Rahman, 1993-, et al. (författare)
  • Hyperthermia-Induced In Situ Drug Amorphization by Superparamagnetic Nanoparticles in Oral Dosage Forms
  • 2022
  • Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 14:19, s. 21978-21988
  • Tidskriftsartikel (refereegranskat)abstract
    • Superparamagnetic iron oxide nanoparticles (SPIONs) generate heat upon exposure to an alternating magnetic field (AMF), which has been studied for hyperthermia treatment and triggered drug release. This study introduces a novel application of magnetic hyperthermia to induce amorphization of a poorly aqueous soluble drug, celecoxib, in situ in tablets for oral administration. Poor aqueous solubility of many drug candidates is a major hurdle in oral drug development. A novel approach to overcome this challenge is in situ amorphization of crystalline drugs. This method facilitates amorphization by molecular dispersion of the drug in a polymeric network inside a tablet, circumventing the physical instability encountered during the manufacturing and storage of conventional amorphous solid dispersions. However, the current shortcomings of this approach include low drug loading, toxicity of excipients, and drug degradation. Here, doped SPIONs produced by flame spray pyrolysis are compacted with polyvinylpyrrolidone and celecoxib and exposed to an AMF in solid state. A design of experiments approach was used to investigate the effects of SPION composition (Zn0.5Fe2.5O4 and Mn0.5Fe2.5O4), doped SPION content (10–20 wt %), drug load (30–50 wt %), and duration of AMF (3–15 min) on the degree of drug amorphization. The degree of amorphization is strongly linked to the maximum tablet temperature achieved during the AMF exposure (r = 0.96), which depends on the SPION composition and content in the tablets. Complete amorphization is achieved with 20 wt % Mn0.5Fe2.5O4 and 30 wt % celecoxib in the tablets that reached the maximum temperature of 165.2 °C after 15 min of AMF exposure. Furthermore, manganese ferrite exhibits no toxicity in human intestinal Caco-2 cell lines. The resulting maximum solubility of in situ amorphized celecoxib is 5 times higher than that of crystalline celecoxib in biorelevant intestinal fluid. This demonstrates the promising capability of SPIONs as enabling excipients to magnetically induce amorphization in situ in oral dosage forms.
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18.
  • 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.
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19.
  • 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.
  •  
20.
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21.
  • Bergström, Christel A S, et al. (författare)
  • Accuracy of calculated pH-dependent aqueous drug solubility.
  • 2004
  • Ingår i: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987. ; 22:5, s. 387-98
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of the present study was to investigate the extent to which the Henderson-Hasselbalch (HH) relationship can be used to predict the pH-dependent aqueous solubility of cationic drugs. The pH-dependent solubility for 25 amines, carrying a single positive charge, was determined with a small-scale shake flask method. Each sample was prepared as a suspension in 150 mM phosphate buffer. The pH-dependent solubility curves were obtained using at least 10 different pH values. The intrinsic solubility, the solubility at the pKa and the solubility at pH values reflecting the pH of the bulk and acid microclimate in the human small intestine (pH 7.4 and 6.5, respectively) were determined for all compounds. The experimental study revealed a large diversity in slope, from -0.5 (celiprolol) to -8.6 (hydralazine) in the linear pH-dependent solubility interval, which is in sharp contrast to the slope of -1 assumed by the HH equation. In addition, a large variation in the range of solubility between the completely uncharged and completely charged drug species was observed. The range for disopyramide was only 1.1 log units, whereas that for amiodarone was greater than 6.3 log units, pointing at the compound specific response to counter-ion effects. In conclusion, the investigated cationic drugs displayed compound specific pH-dependent solubility profiles, indicating that that the HH equation in many cases will only give rough estimations of the pH-dependent solubility of drugs in divalent buffer systems.
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22.
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23.
  • Bergström, Christel A. S., 1973- (författare)
  • Computational and Experimental Models for the Prediction of Intestinal Drug Solubility and Absorption
  • 2003
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the number of new drugs undergoing clinical trial has not augmented at the same pace, which in part has been attributed to poor absorption of the compounds.The main objective of this thesis was to investigate whether computer-based models devised from calculated molecular descriptors can be used to predict aqueous drug solubility, an important property influencing the absorption process. For this purpose, both experimental and computational studies were performed. A new small-scale shake flask method for experimental solubility determination of crystalline compounds was devised. This method was used to experimentally determine solubility values used for the computational model development and to investigate the pH-dependent solubility of drugs. In the computer-based studies, rapidly calculated molecular descriptors were used to predict aqueous solubility and the melting point, a solid state characteristic of importance for the solubility. To predict the absorption process, drug permeability across the intestinal epithelium was also modeled.The results show that high quality solubility data of crystalline compounds can be obtained by the small-scale shake flask method in a microtiter plate format. The experimentally determined pH-dependent solubility profiles deviated largely from the profiles predicted by a traditionally used relationship, highlighting the risk of data extrapolation. The in silico solubility models identified the non-polar surface area and partitioned total surface areas as potential new molecular descriptors for solubility. General solubility models of high accuracy were obtained when combining the surface area descriptors with descriptors for electron distribution, connectivity, flexibility and polarity. The used descriptors proved to be related to the solvation of the molecule rather than to solid state properties. The surface area descriptors were also valid for permeability predictions, and the use of the solubility and permeability models in concert resulted in an excellent theoretical absorption classification. To summarize, the experimental and computational models devised in this thesis are improved absorption screening tools applicable to the lead optimization in the drug discovery process.
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24.
  • Bergström, Christel A S, 1973-, et al. (författare)
  • Computational prediction of drug solubility in water-based systems : qualitative and quantitative approaches used in the current drug discovery and development setting
  • 2018
  • Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 540:1-2, s. 185-193
  • Forskningsöversikt (refereegranskat)abstract
    • In this review we will discuss recent advances in computational prediction of solubility in water-based solvents. Our focus is set on recent advances in predictions of biorelevant solubility in media mimicking the human intestinal fluids and on new methods to predict the thermodynamic cycle rather than prediction of solubility in pure water through quantitative structure property relationships (QSPR). While the literature is rich in QSPR models for both solubility and melting point, a physicochemical property strongly linked to the solubility, recent advances in the modelling of these properties make use of theory and computational simulations to better predict these properties or processes involved therein (e.g. solid state crystal lattice packing, dissociation of molecules from the lattice and solvation). This review serves to provide an update on these new approaches and how they can be used to more accurately predict solubility, and also importantly, inform us on molecular interactions and processes occurring during drug dissolution and solubilisation.
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25.
  • Bergström, Christel A. S., et al. (författare)
  • Computational prediction of formulation strategies for beyond-rule-of-5 compounds
  • 2016
  • Ingår i: Advanced Drug Delivery Reviews. - : Elsevier BV. - 0169-409X .- 1872-8294. ; 101, s. 6-21
  • Forskningsöversikt (refereegranskat)abstract
    • The physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of 'formulate-ability' during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets.
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26.
  • Bergström, Christel A. S., et al. (författare)
  • Early pharmaceutical profiling to predict oral drug absorption : Current status and unmet needs
  • 2014
  • Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57, s. 173-199
  • Tidskriftsartikel (refereegranskat)abstract
    • Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silica and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. (C) 2013 Elsevier B.V. All rights reserved.
  •  
27.
  • Bergström, Christel A S, 1973- (författare)
  • Early recognition of absorption challenges of contemporary targets: : key molecular properties and in silico tools
  • 2013
  • Ingår i: Bulletin Technique Gattefossé. ; 106, s. 50-57
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Oral route is the preferred option for the administration of small molecules due to convenience and good patient compliance. For absorption to occur, a drug compound needs to be dissolved in the gastrointestinal fluid to permeate the intestinal membrane. In recent times large efforts have been directed towards solubility enhancing strategies due to the poor solubility profile of the current pipeline of pharmaceutical companies. The reasons for the poor solubility, from a molecular perspective, are related to whether the compound has a solid-state limited or solvation limited solubility. Recent studies indicate that rather simple characterization of a molecule, including calculated molecular properties such as lipophilicity, charge, flexibility, planarity and size can provide information of whether the solubility is restricted by the strong crystal lattice or by poor hydration. Early assessment of these properties will allow the processes which limit solubility to be considered during the early formulation discussions, ultimately guiding toward optimal formulation approaches for new chemical entities (NCEs). Recently, it was shown that it is possible to predict, from molecular structure alone, i) the glass-forming ability of molecules (as an indicator of the possibility to manipulate the solid state as a means to increase dissolution rate/apparent solubility) and ii) drug solubility in commonly used pharmaceutical lipids (as an indicator of the possibility of utilizing lipids to increase the dissolved amount NCE delivered to the intestine). Through approaches like these, the future of formulation design will be transformed from experimental screening efforts to predictive science, allowing better understanding of the molecular interactions that result in successful performance in vivo.
  •  
28.
  •  
29.
  • Bergström, Christel A S, et al. (författare)
  • Global and local computational models for aqueous solubility prediction of drug-like molecules.
  • 2004
  • Ingår i: Journal of chemical information and computer sciences. - : American Chemical Society (ACS). - 0095-2338 .- 1520-5142. ; 44:4, s. 1477-88
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to develop in silico protocols for the prediction of aqueous drug solubility. For this purpose, high quality solubility data of 85 drug-like compounds covering the total drug-like space as identified with the ChemGPS methodology were used. Two-dimensional molecular descriptors describing electron distribution, lipophilicity, flexibility, and size were calculated by Molconn-Z and Selma. Global minimum energy conformers were obtained by Monte Carlo simulations in MacroModel and three-dimensional descriptors of molecular surface area properties were calculated by Marea. PLS models were obtained by use of training and test sets. Both a global drug solubility model (R(2) = 0.80, RMSE(te) = 0.83) and subset specific models (after dividing the 85 compounds into acids, bases, ampholytes, and nonproteolytes) were generated. Furthermore, the final models were successful in predicting the solubility values of external test sets taken from the literature. The results showed that homologous series and subsets can be predicted with high accuracy from easily comprehensible models, whereas consensus modeling might be needed to predict the aqueous drug solubility of datasets with large structural diversity.
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30.
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31.
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32.
  • Bergström, Christel A S, et al. (författare)
  • Hepatitis C virus NS3 protease inhibitors : large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells
  • 2009
  • Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 38:5, s. 556-563
  • Tidskriftsartikel (refereegranskat)abstract
    • The purpose of this study was to investigate the intestinal absorption of tripeptide-based compounds intended for treatment of hepatitis C virus (HCV) infection. The intestinal permeability of 11 HCV NS3 protease inhibitors (Mw 687-841, ClogD(pH 7.4) 1.2-7.3 and 10-13 hydrogen bond donors/acceptors) was measured using Caco-2 cells. Each compound was investigated in the apical to basolateral (a-b) and basolateral to apical (b-a) direction at pH 7.4. For compounds displaying efflux the experiment was repeated in the presence of 1 microM GF120918 to investigate possible involvement of P-glycoprotein (Pgp; ABCB1). All compounds displayed intermediate to high permeability. Seven of them showed extensive efflux, with 31-114-fold higher permeability in the b-a direction than the a-b direction. Addition of the Pgp inhibitor GF120918 reduced the b-a transport rate for the effluxed compounds. However, for inhibitors with a C-terminal carboxylic acid and the acidic bioisosteres thereof the efflux was still significant. Hence, the negative charge resulted in efflux by other ABC-transporters than Pgp. From this study it can be concluded that small changes in the overall structure can lead to a large variation in permeability and efflux as shown by the inhibitors herein, properties that also may influence the resulting inhibition potency of the compounds when performing cell-based pharmacological assays.
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33.
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34.
  • Bergström, Christel A. S., et al. (författare)
  • Is the full potential of the biopharmaceutics classification system reached?
  • 2014
  • Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57, s. 224-231
  • Tidskriftsartikel (refereegranskat)abstract
    • In this paper we analyse how the biopharmaceutics classification system (BCS) has been used to date. A survey of the literature resulted in a compilation of 242 compounds for which BCS classes were reported. Of these, 183 compounds had been reported to belong to one specific BCS class whereas 59 compounds had been assigned to multiple BCS classes in different papers. Interestingly, a majority of the BCS class 2 compounds had fraction absorbed (FA) values >85%, indicating that they were completely absorbed after oral administration. Solubility was computationally predicted at pH 6.8 for BCS class 2 compounds to explore the impact of the pH of the small intestine, where most of the absorption occurs, on the solubility. In addition, the solubilization capacity of lipid aggregates naturally present in the intestine was studied computationally and experimentally for a subset of 12 compounds. It was found that all acidic compounds with FA > 85% were completely dissolved in the pH of the small intestine. Further, lipids at the concentration used in fasted state simulated intestinal fluid (FaSSIF) dissolved the complete dose given of the most lipophilic (logD(6.5) >3) compounds studied. Overall, biorelevant dissolution media (pure buffer of intestinal pH or FaSSIF) identified that for 20 of the 29 BCS class 2 compounds with FA > 85% the complete dose given orally would be dissolved. These results indicate that a more relevant pH restriction for acids and/or dissolution medium with lipids present better forecast solubility-limited absorption in vivo than the presently used BCS solubility criterion. The analysis presented herein further strengthens the discussion on the requirement of more physiologically relevant dissolution media for the in vitro solubility classification performed to reach the full potential of the BCS. (C) 2013 Elsevier B.V. All rights reserved.
  •  
35.
  • Bergström, Christel A. S., et al. (författare)
  • Lipophilicity in Drug Development : Too Much or Not Enough?
  • 2016
  • Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 18:5, s. 1095-1100
  • Tidskriftsartikel (refereegranskat)abstract
    • A round table discussion was held during the AAPS Annual Meeting on October 27, 2015, with the somewhat provocative topic of whether we need more or less lipophilic compounds in drug development. The session was attended by more than 250 participants, and the feedback was very positive as this round table became a forum for the exchange of ideas from scientists within the academia and industry. Most importantly, the discussion highlighted the difference in approaches to compound selection and development strategies in various companies and organizations. As moderators of this session, we are writing this report to highlight the points and counterpoints made at the session and to bring the importance of the dialogue and debate to the forefront of discussions on how to select the best drug development candidates to enable efficient delivery and, hence, treatment of diseases.
  •  
36.
  •  
37.
  • Bergström, Christel A.S. 1973-, et al. (författare)
  • Perspectives in solubility measurement and interpretation
  • 2019
  • Ingår i: ADMET AND DMPK. - : IAPC PUBLISHING. - 1848-7718. ; 7:2, s. 88-105
  • Forskningsöversikt (refereegranskat)abstract
    • Several key topics in solubility measurement and interpretation are briefly summarized and illustrated with case studies drawing on published solubility determinations as a function of pH. Featured are examples of ionizable molecules that exhibit solubility-pH curve distortion from that predicted by the traditionally used Henderson-Hasselbalch equation and possible interpretations for these distortions are provided. The scope is not exhaustive; rather it is focused on detailed descriptions of a few cases. Topics discussed are limitations of kinetic solubility, 'brick-dust and grease-balls,' applications of simulated and human intestinal fluids, supersaturation and the relevance of pre-nucleation clusters and sub-micellar aggregates in the formation of solids, drug-buffer/excipient complexation, hydrotropic solubilization, acid-base 'supersolubilization,' cocrystal route to supersaturation, as well as data quality assessment and solubility prediction. The goal is to highlight principles of solution equilibria - graphically more than mathematically - that could invite better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids. The value of solid state characterizations is stressed but not covered explicitly in this mini-review.
  •  
38.
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39.
  • Clulow, Andrew J., et al. (författare)
  • Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid
  • 2017
  • Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 121:48, s. 10869-10881
  • Tidskriftsartikel (refereegranskat)abstract
    • The absorption of hydrophobic drugs and nutrients from the intestine is principally determined by the amount that can be dissolved by the endogenous fluids present in the gut. Human intestinal fluids (HIFs) comprise a complex mixture of bile salts, phospholipids, steroids and glycerides that vary in composition in the fed and fasted state and between subjects. A number of simulated intestinal fluid (SIF) compositions have been developed to mimic fasted and fed state intestinal conditions and allow the in vitro determination of drug solubility as a proxy for the maximum dissolved concentration it is possible to reach. In particular these solvents are used during the development of lipophilic and poorly water-soluble drugs but questions remain around the differences that may arise from the source and methods of preparation of these fluids. In this work, a range of SIFs were studied using small angle X-ray scattering (SAXS), cryogenic -transmission electron microscopy (cryo-TEM) and molecular dynamics (MD) simulations in order to analyze their structures. In-house prepared SIFs based on sodium taurodeoxycholate (NaTDC) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) formed oblate ellipsoidal micelles irrespective of lipid concentration and preparation conditions. In contrast, commercially available SIFs based on sodium taurocholate and lecithin formed prolate ellipsoidal micelles in the fed state and vesicles in the fasted state. These structural variations are the likely reason for the dramatic differences sometimes observed in the solubility enhancements for hydrophobic drugs, nutrients and digestion products when using different SIFs. However, the structural homogeneity of the NaTDC/DOPC micelles makes them ideal candidates for standardizing SIF formulations as the structures of the solubilizing nanoaggregates therein are not sensitive to the preparation method.
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40.
  • El Sayed, Mira, et al. (författare)
  • Insights into Dissolution and Solution Chemistry of Multidrug Formulations of Antihypertensive Drugs
  • 2020
  • Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 17:10, s. 4018-4028
  • Tidskriftsartikel (refereegranskat)abstract
    • Using fixed dose combinations of drugs instead of administering drugs separately can be beneficial for both patients and the health care system, but the current understanding of how multidrug formulations work at the molecular level is still in its infancy. Here, we explore dissolution, solubility, and supersaturation of various drug combinations in amorphous formulations. The effect of chemical structural similarity on combination behavior was investigated by using structurally related compounds of both drugs. The effect of polymer type on solution behavior was also evaluated using chemically diverse polymers. Indapamide (IPM) concentration decreased when combined with felodipine (FDN) or its analogues, which occurred even when the IPM solution was undersaturated. The extent of solubility decrease of FDN was less than that of IPM from the dissolution of an equimolar formulation of the drugs. No significant solubility decrease was observed for FDN at low contents of IPM which was also observed for other dihydropyridines, whereas FDN decreases at high contents of IPM. This was explained by the complex nature of the colloidal precipitates of the combinations which impacts the chemical potential of the drugs in solution at different levels. The maximum achievable concentration of FDN and IPM during dissolution of the polyvinylpyrrolidone-based amorphous solid dispersion was higher than the value measured with the hydroxypropyl methylcellulose acetate succinate-based formulation. This emphasizes the significance of molecular properties and chemical diversity of drugs and polymers on solution chemistry and solubility profiles. These findings may apply to drugs administered as a single dosage form or in separate dosage forms and hence need to be well controlled to assure effective treatments and patient safety.
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41.
  • Emeh, Prosper, et al. (författare)
  • Experiences and Translatability of In Vitro and In Vivo Models to Evaluate Caprate as a Permeation Enhancer
  • 2024
  • Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 21:1, s. 313-324
  • Tidskriftsartikel (refereegranskat)abstract
    • Transient permeation enhancers (PEs) have been widely used to improve the oral absorption of macromolecules. During pharmaceutical development, the correct selection of the macromolecule, PE, and the combination needs to be made to maximize oral bioavailability and ensure successful clinical development. Various in vitro and in vivo methods have been investigated to optimize this selection. In vitro methods are generally preferred by the pharmaceutical industry to reduce the use of animals according to the "replacement, reduction, and refinement" principle commonly termed "3Rs," and in vitro methods typically have a higher throughput. This paper compares two in vitro methods that are commonly used within the pharmaceutical industry, being Caco-2 and an Ussing chamber, to two in vivo models, being in situ intestinal instillation to rats and in vivo administration via an endoscope to pigs. All studies use solution formulation of sodium caprate, which has been widely used as a PE, and two macromolecules, being FITC-dextran 4000 Da and MEDI7219, a GLP-1 receptor agonist peptide. The paper shares our experiences of using these models and the challenges with the in vitro models in mimicking the processes occurring in vivo. The paper highlights the need to consider these differences when translating data generated using these in vitro models for evaluating macromolecules, PE, and combinations thereof for enabling oral delivery.
  •  
42.
  • Fagerberg, Jonas H., et al. (författare)
  • Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid
  • 2015
  • Ingår i: Pharmaceutical research. - : Springer. - 0724-8741 .- 1573-904X. ; 32:2, s. 578-589
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeTo develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).MethodsMeasured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.ResultsModest relationships between Sapp in PhBpH6.5 and FaSSIF (R2 = 0.61) or HIF (R2 = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R2 = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R2 = 0.69 and RMSEte of 0.77; HIF, R2 = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R2 = 0.76 and RMSETe of 0.65; HIF, R2 = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.ConclusionComputational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.
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43.
  •  
44.
  • Fagerberg, Jonas H., et al. (författare)
  • Dissolution Rate and Apparent Solubility of Poorly Soluble Drugs in Biorelevant Dissolution Media
  • 2010
  • Ingår i: Molecular pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 7:5, s. 1419-1430
  • Tidskriftsartikel (refereegranskat)abstract
    • A series of poorly soluble BCS class II compounds with "grease ball" characteristics were assessed for solubility and dissolution rate in biorelevant dissolution media (BDM) with the purpose of investigating which molecular structures gain most in solubility when dissolved under physiologically relevant conditions. The compounds were studied in four media (simulated intestinal fluid in fasted (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0), and their corresponding blank buffers (FaSSIF(blk) and FeSSIFblk)) at a temperature of 37 degrees C. The experimental results were used to analyze which molecular characteristics are of importance for the solubility in BDM and for in silico modeling using multivariate data analysis. It was revealed that a majority of the compounds exhibited a higher dissolution rate and higher solubility in the FaSSIF and FeSSIF than in their corresponding blank buffers. Compounds which were neutral or carried a positive charge were more soluble in FeSSIF than FaSSIF. The acidic compounds displayed clear pH dependency, although the higher concentration of solubilizing agents in FeSSIF than FaSSIF also improved the solubility. Five of the ten compounds were upgraded to BCS class I when dissolved in FaSSIF or FeSSIF, i.e., the maximum dose of these compounds given orally was soluble in 250 mL of these BDMs. Lipophilicity as described by the log D-oct value was identified as a good predictor of the solubilization ratio (R-2 = 0.74), and computed molecular descriptors were also shown to successfully predict the solubilities in BDM for this data set. To conclude, the physiological solubility of "grease ball" molecules may be largely underestimated in in vitro solubility assays unless BDM is used. Moreover, the results herein indicate that the improvement obtained in BDM may be possible to predict from chemical features alone.
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45.
  • Fagerberg, Jonas H., et al. (författare)
  • Ethanol Effects on Apparent Solubility of Poorly Soluble Drugs in Simulated Intestinal Fluid
  • 2012
  • Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 9:7, s. 1942-1952
  • Tidskriftsartikel (refereegranskat)abstract
    • Ethanol intake can lead to an unexpected and possibly problematic increase in the bioavailability of druglike compounds. In this work we investigated the effect of ethanol on the apparent solubility and dissolution rate of poorly soluble compounds in simulated intestinal fluid representing a preprandial state. A series of 22 structurally diverse, poorly soluble compounds were measured for apparent solubility and intrinsic dissolution rate (37 degrees C) in phosphate buffer pH 6.5 (PhB6.5) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5) with and without ethanol at 5% v/v or 20% v/v. The obtained data were used to understand for which molecules ethanol results in an increased apparent solubility and, therefore, may increase the amount of drug absorbed. In FaSSIF(20%ethanol) 59% of the compounds displayed >3-fold higher apparent solubility than in pure FaSSIF, whereas the effects of 5% ethanol on solubility, in most cases, were negligible. Acidic and neutral compounds were more solubilized by the addition of ethanol than by lecithin/taurocholate aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. The stronger solubilizing capacity of ethanol as compared to the mixed lipid aggregates in FaSSIF was further identified through Spearman rank analyses, which showed a stronger relationship between FaSSIF(20%ethanol) and PhB6.5,20%ethanol (r(S) of 0.97) than FaSSIF(20%ethanol) and FaSSIF (r(S) of 0.86). No relationships were found between solubility changes in media containing ethanol and single physicochemical properties, but multivariate data analysis showed that inclusion of ethanol significantly reduced the negative effect of compound lipophilicity on solubility. For this data set the higher concentration of ethanol gave a dose number (Do) <1 for 30% of the compounds that showed incomplete dissolution in FaSSIF. Significant differences were shown in the melting point, lipophilicity, and dose profiles between the compounds having a Do < 1 and Do > 1, with the latter having higher absolute values in all three parameters. In conclusion, this study showed that significant effects of ethanol on apparent solubility in the preprandial state can be expected for lipophilic compounds. The results herein indicate that acidic and neutral compounds are more sensitive to the addition of ethanol than to the mixed lipid aggregates present in the fasted intestine.
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46.
  • Fagerberg, Jonas H. (författare)
  • Experimental and Computational Predictions of Drug Solubility in Human Gastrointestinal Fluids
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The aqueous solubility of a drug is viewed as a pivotal property for its oral absorption since only dissolved molecules can permeate the gut wall and reach the systemic circulation. The fluids in the intestine, however, do not only consist of water and therefore poor water solubility may not necessarily imply a poor solubility in the intestinal fluids and resulting low bioavailability. This thesis addresses the determination of drug solubility and dissolution rates in biorelevant dissolution media (BDM) with the aim of applying these methods to the early stages of drug discovery, where there is a need to reduce the volume of the medium and the amount of solid drug used in testing. The thesis also addresses the need for computational methods for predicting solubility in intestinal fluids and, hence, allowing in silico screening of drugs yet to be synthesized. The apparent solubility and dissolution behavior of large series of lipophilic and other diverse compounds in BDM were studied using a miniaturized method developed herein. The media used in the experimental design provided an opportunity to assess the effects of charge, solubilization in mixed lipid aggregates, and ethanol in BDM. Highly lipophilic and uncharged drugs were efficiently solubilized by aggregates in the BDM while solubilization was decreased with charge. The decrease was more pronounced for negatively charged drugs. The solubility of anionic and neutral drugs was significantly increased by the addition of ethanol to the medium and absorption simulations showed that intake of alcohol could lead to increased plasma concentrations of neutral compounds. Statistical models based on calculated molecular descriptors that accurately predicted the apparent solubility in fasted-state simulated intestinal fluid and in aspirated human intestinal fluid were also developed. In summary, the work undertaken in this thesis has resulted in new experimental and computational models for assessment of the dissolution and solubility of poorly water-soluble compounds in BDM. The models are applicable in the early discovery and development phases for predicting physiologically relevant solubility and the effects thereof on drug absorption.  
  •  
47.
  • Fagerberg, Jonas H, et al. (författare)
  • Intestinal solubility and absorption of poorly water soluble compounds : predictions, challenges and solutions
  • 2015
  • Ingår i: Therapeutic delivery. - : Future Science Ltd. - 2041-5990 .- 2041-6008. ; 6:8, s. 935-959
  • Forskningsöversikt (refereegranskat)abstract
    • We have explored for which type of compounds biorelevant dissolution profiling in simulated intestinal fluids would accurately predict solubility in human intestinal fluid. In total, 460 solubility values in simulated and aspirated human intestinal fluid for 78 drugs were compiled and analyzed. Significant solubilization in the colloidal structures was obtained in fasted and fed state fluids for drug compounds with a logD(oct)>3. Highly lipophilic compounds with high melting points (Tm > 200 °C) could also be significantly solubilized, but typically such compounds had solubility values in the lower µg/ml range also in the presence of the colloidal structures. On the basis of our analysis, compounds with a logD(oct)>3 should be explored in biorelevant dissolution media to better predict in vivo performance after oral dosing.
  •  
48.
  • Feeney, Orlagh M, et al. (författare)
  • 50 years of oral lipid-based formulations : Provenance, progress and future perspectives
  • 2016
  • Ingår i: Advanced Drug Delivery Reviews. - : Elsevier BV. - 0169-409X .- 1872-8294. ; 101, s. 167-194
  • Forskningsöversikt (refereegranskat)abstract
    • Lipid based formulations (LBF) provide well proven opportunities to enhance the oral absorption of drugs and drug candidates that sit close to, or beyond, the boundaries of Lipinski's 'rule-of-five' chemical space. Advantages in permeability, efflux and pre-systemic metabolism are evident; however, the primary benefit is in increases in dissolution and apparent intestinal solubility for lipophilic, poorly water soluble drugs. This review firstly details the inherent advantages of LBF, their general properties and classification and provides a brief retrospective assessment of the development of LBF over the past fifty years. More detailed analysis of the ability of LBF to promote intestinal solubilisation, supersaturation and absorption is then provided alongside review of the methods employed to assess formulation performance. Critical review of the ability of simple dispersion and more complex in vitro digestion methods to predict formulation performance subsequently reveals marked differences in the correlative ability of in vitro tests, depending on the properties of the drug involved. Notably, for highly permeable low melting drugs e.g. fenofibrate, LBF appear to provide significant benefit in all cases, and sustained on-going solubilisation may not be required. In other cases, and particularly for higher melting point drugs such as danazol, where re-dissolution of crystalline precipitate drug is likely to be slow, correlations with on-going solubilisation and supersaturation are more evident. In spite of their potential benefits, one limitation to broader use of LBF is low drug solubility in the excipients employed to generate formulations. Techniques to increase drug lipophilicity and lipid solubility are therefore explored, and in particular those methods that provide for temporary enhancement including lipophilic ionic liquid and prodrug technologies. The transient nature of these lipophilicity increases enhances lipid solubility and LBF viability, but precludes enduring effects on receptor promiscuity and off target toxicity. Finally, recent efforts to generate solid LBF are briefly described as a means to circumvent the need to encapsulate in soft or hard gelatin capsules, although the latter remain popular with consumers and a proven means of LBF delivery.
  •  
49.
  • Hedge, Oliver, 1991-, et al. (författare)
  • Suitability of Artificial Membranes in Lipolysis-Permeation Assays of Oral Lipid-Based Formulations
  • 2020
  • Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 37:6
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeTo evaluate the performance of artificial membranes in in vitro lipolysis-permeation assays useful for absorption studies of drugs loaded in lipid-based formulations (LBFs).MethodsPolycarbonate as well as PVDF filters were treated with hexadecane, or lecithin in n-dodecane solution (LiDo) to form artificial membranes. They were thereafter used as absorption membranes separating two compartments mimicking the luminal and serosal side of the intestine in vitro. Membranes were subjected to dispersions of an LBF that had been digested by porcine pancreatin and spiked with the membrane integrity marker Lucifer Yellow (LY). Three fenofibrate-loaded LBFs were used to explore the in vivo relevance of the assay.ResultsOf the explored artificial membranes, only LiDo applied to PVDF was compatible with lipolysis by porcine pancreatin. Formulation ranking based on mass transfer in the LiDo model exposed was the same as drug release in single-compartment lipolysis. Ranking based on observed apparent permeability coefficients of fenofibrate with different LBFs were the same as those obtained in a cell-based model.ConclusionsThe LiDo membrane was able to withstand lipolysis for a sufficient assay period. However, the assay with porcine pancreatin as digestive agent did not predict the in vivo ranking of the assayed formulations better than existing methods. Comparison with a Caco-2 based assay method nonetheless indicates that the in vitro in vivo relationship of this cell-free model could be improved with alternative digestive agents.
  •  
50.
  • Hossain, Shakhawath, et al. (författare)
  • Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers
  • 2020
  • Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8392 .- 1543-8384. ; 17:11, s. 4226-4240
  • Tidskriftsartikel (refereegranskat)abstract
    • Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs-caprylate, caprate, and SNAC-using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.
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