Self-Emulsifying Formulations to Increase the Oral Bioavailability of 4,6,4'-Trimethylangelicin As a Possible Treatment for Cystic Fibrosis

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2022 Sep 23

PMID 36145554

Authors

Erica Franceschinis

Marco Roverso

Daniela Gabbia

Sara De Martin

Matteo Brusegan

Christian Vaccarin

Sara Bogialli

Adriana Chilin

Affiliations

Soon will be listed here.

Abstract

4,6,4'-trimethylangelicin (TMA) is a promising pharmacological option for the treatment of cystic fibrosis (CF) due to its triple-acting behavior toward the function of the CF transmembrane conductance regulator. It is a poorly water-soluble drug, and thus it is a candidate for developing a self-emulsifying formulation (SEDDS). This study aimed to develop a SEDDS to improve the oral bioavailability of TMA. Excipients were selected on the basis of solubility studies. Polyoxyl-35 castor oil (Cremophor EL) was proposed as surfactant, diethylene glycol-monoethyl ether (Transcutol HP) as cosolvent, and a mixture of long-chainmono-,di-, and triglycerides (Maisine CC) or medium-chain triglycerides (Labrafac lipophile) as oil phases. Different mixtures were prepared and characterized by measuring the emulsification time, drop size, and polydispersity index to identify the most promising formulation. Two formulations containing 50% surfactant (/), 40% cosolvent (/), and 10% oil (/) (Maisine CC or Labrafac lipophile) were selected. The results showed that both formulations were able to self-emulsify, producing nanoemulsions with a drop size range of 20-25 nm, and in vivo pharmacokinetic studies demonstrated that they were able to significantly increase the oral bioavailability of TMA. In conclusion, SEEDS are useful tools to ameliorate the pharmacokinetic profile of TMA and could represent a strategy to improve the therapeutic management of CF.

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References

Tamanini A, Borgatti M, Finotti A, Piccagli L, Bezzerri V, Favia M . Trimethylangelicin reduces IL-8 transcription and potentiates CFTR function. Am J Physiol Lung Cell Mol Physiol. 2010; 300(3):L380-90. DOI: 10.1152/ajplung.00129.2010. View

Guiotto A, Rodighiero P, Manzini P, Pastorini G, Bordin F, Baccichetti F . 6-Methylangelicins: a new series of potential photochemotherapeutic agents for the treatment of psoriasis. J Med Chem. 1984; 27(8):959-67. DOI: 10.1021/jm00374a005. View

Orlando R, De Martin S, Andrighetto L, Floreani M, Palatini P . Fluvoxamine pharmacokinetics in healthy elderly subjects and elderly patients with chronic heart failure. Br J Clin Pharmacol. 2010; 69(3):279-86. PMC: 2829698. DOI: 10.1111/j.1365-2125.2009.03587.x. View

Dahan A, Hoffman A . The effect of different lipid based formulations on the oral absorption of lipophilic drugs: the ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats. Eur J Pharm Biopharm. 2007; 67(1):96-105. DOI: 10.1016/j.ejpb.2007.01.017. View

Holm R . Bridging the gaps between academic research and industrial product developments of lipid-based formulations. Adv Drug Deliv Rev. 2019; 142:118-127. DOI: 10.1016/j.addr.2019.01.009. View

Pouton C . Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006; 29(3-4):278-87. DOI: 10.1016/j.ejps.2006.04.016. View

De Boeck K, Amaral M . Progress in therapies for cystic fibrosis. Lancet Respir Med. 2016; 4(8):662-674. DOI: 10.1016/S2213-2600(16)00023-0. View

Han S, Yao T, Zhang X, Gan L, Zhu C, Yu H . Lipid-based formulations to enhance oral bioavailability of the poorly water-soluble drug anethol trithione: effects of lipid composition and formulation. Int J Pharm. 2009; 379(1):18-24. DOI: 10.1016/j.ijpharm.2009.06.001. View

Ditzinger F, Price D, Ilie A, Kohl N, Jankovic S, Tsakiridou G . Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review. J Pharm Pharmacol. 2018; 71(4):464-482. DOI: 10.1111/jphp.12984. View

10.

Porter C, Pouton C, Cuine J, Charman W . Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev. 2007; 60(6):673-91. DOI: 10.1016/j.addr.2007.10.014. View

11.

Huang Y, Yu Q, Chen Z, Wu W, Zhu Q, Lu Y . and correlation for lipid-based formulations: Current status and future perspectives. Acta Pharm Sin B. 2021; 11(8):2469-2487. PMC: 8424225. DOI: 10.1016/j.apsb.2021.03.025. View

12.

Caffieri S . Reversed-phase high-performance liquid chromatography (RP-HPLC) determination of lipophilicity of furocoumarins: relationship with DNA interaction. J Pharm Sci. 2001; 90(6):732-9. DOI: 10.1002/jps.1029. View

13.

Baloch J, Sohail M, Sarwar H, Kiani M, Khan G, Jahan S . Self-Nanoemulsifying Drug Delivery System (SNEDDS) for Improved Oral Bioavailability of Chlorpromazine: In Vitro and In Vivo Evaluation. Medicina (Kaunas). 2019; 55(5). PMC: 6572212. DOI: 10.3390/medicina55050210. View

14.

Thomas N, Mullertz A, Graf A, Rades T . Influence of lipid composition and drug load on the In Vitro performance of self-nanoemulsifying drug delivery systems. J Pharm Sci. 2012; 101(5):1721-31. DOI: 10.1002/jps.23054. View

15.

Abou Assi R, Abdulbaqi I, Seok Ming T, Siok Yee C, Wahab H, Asif S . Liquid and Solid Self-Emulsifying Drug Delivery Systems (SEDDs) as Carriers for the Oral Delivery of Azithromycin: Optimization, In Vitro Characterization and Stability Assessment. Pharmaceutics. 2020; 12(11). PMC: 7693798. DOI: 10.3390/pharmaceutics12111052. View

16.

Khoo S, Shackleford D, Porter C, Edwards G, Charman W . Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs. Pharm Res. 2003; 20(9):1460-5. DOI: 10.1023/a:1025718513246. View

17.

Laselva O, Marzaro G, Vaccarin C, Lampronti I, Tamanini A, Lippi G . Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators. Front Pharmacol. 2018; 9:719. PMC: 6039571. DOI: 10.3389/fphar.2018.00719. View

18.

Lopes-Pacheco M . CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine. Front Pharmacol. 2020; 10:1662. PMC: 7046560. DOI: 10.3389/fphar.2019.01662. View

19.

Rege B, Kao J, Polli J . Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci. 2002; 16(4-5):237-46. DOI: 10.1016/s0928-0987(02)00055-6. View

20.

Hong J, Kim J, Song Y, Park J, Kim C . A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption. J Control Release. 2005; 110(2):332-338. DOI: 10.1016/j.jconrel.2005.10.002. View