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Tools for Early Prediction of Drug Loading in Lipid-Based Formulations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. UMonash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia..
2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 1, p. 251-261Article in journal (Refereed) Published
Resource type
Text
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 13, no 1, p. 251-261
Keywords [en]
lipid-based formulations, solubility prediction, loading capacity, molecular properties, in silico prediction
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-275856DOI: 10.1021/acs.molpharmaceut.5b00704ISI: 000367866200026PubMedID: 26568134OAI: oai:DiVA.org:uu-275856DiVA, id: diva2:903629
Funder
Swedish Research Council, 621-2011-2445 621-2014-3309EU, European Research Council, 638965Available from: 2016-02-16 Created: 2016-02-08 Last updated: 2018-11-21Bibliographically approved
In thesis
1. Improved Molecular Understanding of Lipid-Based Formulations: for Enabling Oral Delivery of Poorly Water-Soluble Drugs
Open this publication in new window or tab >>Improved Molecular Understanding of Lipid-Based Formulations: for Enabling Oral Delivery of Poorly Water-Soluble Drugs
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The majority of emerging drug candidates are not suited for conventional oral dosage forms, as they do not dissolve in the aqueous environment of the gastrointestinal (GI) tract. Consequently, a large number of enabling formulation strategies have emerged. One such strategy is to deliver the drug pre-dissolved in a lipid-based formulation (LBF), thereby bypassing the rate-limiting dissolution step. To date, only about 4% of the marketed oral drugs are delivered as LBFs. The limited use of this strategy is a result of the incomplete understanding of drug solubility in lipid vehicles, the reduced chemical stability of pre-dissolved drug, and the complex interplay between drug and formulation undergoing intestinal lipid processing. Hence, this thesis targeted an improved molecular understanding of lipid-based drug delivery to make an informed formulation development. In the first part of the thesis, drug solubility in LBF excipients and composed formulations was assessed. Through experimental studies of nearly forty compounds in nine excipients drug physicochemical properties related to solubility in these excipients were identified. The obtained data was used to develop in silico tools for prediction of drug solubility in excipients and formulations. The second part of the thesis focused on LBF performance in vitro and in vivo. Factors associated with the type of solid form that is precipitating during digestions was revealed, which provides an initial framework for understanding drug precipitation behaviour under physiological conditions. It was also shown that clinically relevant doses of LBF significantly increases intestinal drug solubilization as a result of GI lipid processing and bile secretion. Moreover, simultaneous assessment of digestion and absorption in vitro provided the same rank order of absorbed drug as the in vivo studies. Coadministration of LBF and drug was shown to be a promising alternative to pre-dissolved drug in the LBF. In summary, this thesis has improved the molecular understanding of factors that govern drug solubility in lipid vehicles and solid form of precipitated drug under digestive conditions. It was also proved that clinically relevant doses of LBFs significantly increase the intestinal drug solubilization, and proof-of-concept was shown for coadministration of LBF with solid drug as an alternative to drug-loaded LBF.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 262
Keywords
lipid-based formulation, poorly water-soluble drug, solubility prediction, molecular properties, lipid digestion, precipitation, solid state, intestinal solubilization, in vitro in vivo correlation (IVIVC), coadministration
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-366586 (URN)978-91-513-0509-7 (ISBN)
Public defence
2019-01-18, B:42, Biomedical Center, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-12-20 Created: 2018-11-21 Last updated: 2019-01-21

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Alskär, Linda C.Bergström, Christel A. S.

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