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Improved Molecular Understanding of Lipid-Based Formulations: for Enabling Oral Delivery of Poorly Water-Soluble Drugs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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 [en]
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: urn:nbn:se:uu:diva-366586ISBN: 978-91-513-0509-7 (print)OAI: oai:DiVA.org:uu-366586DiVA, id: diva2:1264989
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
List of papers
1. Computational Prediction of Drug Solubility in Lipid Based Formulation Excipients
Open this publication in new window or tab >>Computational Prediction of Drug Solubility in Lipid Based Formulation Excipients
2013 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 30, no 12, p. 3225-3237Article in journal (Refereed) Published
Abstract [en]

To investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties. Solubility was measured for 30 structurally diverse drug molecules in soybean oil (SBO, long-chain triglyceride; TG(LC)), Captex355 (medium-chain triglyceride; TG(MC)), polysorbate 80 (PS80; surfactant) and PEG400 co-solvent and used as responses during PLS model development. Melting point and calculated molecular descriptors were used as variables and the PLS models were validated with test sets and permutation tests. Solvation capacity of SBO and Captex355 was equal on a mol per mol scale (R (2) = 0.98). A strong correlation was also found between PS80 and PEG400 (R (2) = 0.85), identifying the significant contribution of the ethoxylation for the solvation capacity of PS80. In silico models based on calculated descriptors were successfully developed for drug solubility in SBO (R (2) = 0.81, Q (2) = 0.76) and Captex355 (R (2) = 0.84, Q (2) = 0.80). However, solubility in PS80 and PEG400 were not possible to quantitatively predict from molecular structure. Solubility measured in one excipient can be used to predict solubility in another, herein exemplified with TG(MC) versus TG(LC), and PS80 versus PEG400. We also show, for the first time, that solubility in TG(MC) and TG(LC) can be predicted from rapidly calculated molecular descriptors.

Keywords
computational prediction, lipid based formulation, loading capacity, molecular properties, solubility
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-213917 (URN)10.1007/s11095-013-1083-7 (DOI)000327878300019 ()
Available from: 2014-01-06 Created: 2014-01-05 Last updated: 2018-11-21Bibliographically approved
2. Tools for Early Prediction of Drug Loading in Lipid-Based Formulations
Open this publication in new window or tab >>Tools for Early Prediction of Drug Loading in Lipid-Based Formulations
2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 1, p. 251-261Article in journal (Refereed) Published
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.

Keywords
lipid-based formulations, solubility prediction, loading capacity, molecular properties, in silico prediction
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-275856 (URN)10.1021/acs.molpharmaceut.5b00704 (DOI)000367866200026 ()26568134 (PubMedID)
Funder
Swedish Research Council, 621-2011-2445 621-2014-3309EU, European Research Council, 638965
Available from: 2016-02-16 Created: 2016-02-08 Last updated: 2018-11-21Bibliographically approved
3. Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations
Open this publication in new window or tab >>Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations
Show others...
2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 10, p. 4733-4744Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
Keywords
Poorly water-soluble drugs, lipid digestion, physicochemical properties, precipitation, solid state, supersaturation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-366563 (URN)10.1021/acs.molpharmaceut.8b00699 (DOI)000446413400041 ()30142268 (PubMedID)
Funder
EU, European Research Council, 638965Swedish Research Council, 621-2011-2445, 621-2014-3309
Available from: 2018-11-21 Created: 2018-11-21 Last updated: 2018-12-03Bibliographically approved
4. Effect of Lipids on Absorption of Carvedilol in Dogs: Is Coadministration of Lipids as Efficient as a Lipid-Based Formulation?
Open this publication in new window or tab >>Effect of Lipids on Absorption of Carvedilol in Dogs: Is Coadministration of Lipids as Efficient as a Lipid-Based Formulation?
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

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 lipid-based 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 acid) and bile salt. 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 acid and bile salt 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 solid form, e.g. due to chemical instability in the lipid vehicle. Finally, the in vitro lipolysis-permeation used herein established IVIVC for carvedilol in the presence of LBFs.       

Keywords
Intestinal digestion, in vivo dog study, lipid-based formulation, coadministration, absorption, in vitro in vivo correlation (IVIVC)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-366566 (URN)
Available from: 2018-11-21 Created: 2018-11-21 Last updated: 2018-11-21

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