Oral lipid-based drug delivery approaches to improve the intestinal lymphatic transport and systemic bioavailability of a highly lipophilic drug cannabidiol

Feng, Wanshan (2022) Oral lipid-based drug delivery approaches to improve the intestinal lymphatic transport and systemic bioavailability of a highly lipophilic drug cannabidiol. PhD thesis, University of Nottingham.

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Abstract

Lipid-based formulations play a significant role in oral delivery of lipophilic drugs. Previous studies have shown that natural sesame oil promotes the intestinal lymphatic transport and oral bioavailability of highly lipophilic drug cannabidiol (CBD). However, both lymphatic transport and systemic bioavailability were also associated with considerable variability. The first aim of this thesis was to test the hypothesis that pre-digested lipid formulations (oleic acid, linoleic acid, oleic acid with 2-oleoylglycerol, oleic acid with 2-oleoylglycerol and oleic acid with glycerol) could reduce variability and increase the extent of the intestinal lymphatic transport and oral bioavailability of CBD. In vivo studies in rats showed that pre-digested or purified triglyceride did not improve the lymphatic transport and bioavailability of CBD in comparison to sesame oil. Moreover, the results suggest that both the absorption of lipids and the absorption of co-administered CBD were more efficient following administration of natural sesame oil vehicle compared with pre-digested lipids or purified trioleate. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD [1]. Therefore, the second approach in this thesis was to test the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and mesenteric lymph nodes (MLN), but with reduced variability. MCT improves the emulsification and micellar solubilisation of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle [2].

These results lead to the hypothesis that differences in composition of vegetable oils lead to differences in promotion of intestinal lymphatic transport of lipophilic drugs. Therefore, the differences in composition of sesame, sunflower, peanut, soybean, olive and coconut oils and their corresponding role as vehicles in promoting CBD lymphatic targeting and bioavailability were investigated in this thesis. The comparative analysis suggested that the fatty acids profile of vegetable oils is overall similar to the fatty acids profile in the corresponding chylomicrons in rat lymph. However, arachidonic acid (C20:4), was introduced to chylomicrons from endogenous nondietary sources in all cases. Overall, fatty acid composition of natural vegetable oils vehicles affected the intestinal lymphatic transport and bioavailability of CBD following oral administration in this work. Olive oil led to the highest concentration of CBD in the lymphatic system and systemic circulation and low variability in comparison to other natural vegetable oils following oral administration in rats.

The natural rapeseed oil bodies also used as lipid-based vehicles to facilitate CBD oral bioavailability and lymphatic transport in this thesis. The oral bioavailability of CBD was 1.7-fold higher in oil bodies-based formulation than rapeseed oil-based formulation in rats. This finding indicates that oil bodies could potentially to improve lipophilic drug systemic exposure and lymphatic targeting in comparison to simple oils, and their other pharmaceutical properties as a drug delivery carrier needs to be further investigated.

Overall in this thesis, olive oil and oil bodies are preferred lipid vehicles for improving intestinal lymphatic transport and bioavailability of co-administered CBD following oral administration.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Gershkovich, Pavel
Fischer, Peter
Barrett, David
Constantinescu, Cris
Stocks, Michael
Keywords: Drug delivery, Lipid-based, Intestinal lymphatic transport
Subjects: R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 68717
Depositing User: Feng, Wanshan
Date Deposited: 28 Jul 2022 04:40
Last Modified: 28 Jul 2022 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/68717

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