Abstract
A major issue of the pharmaceutical industry is the poor solubility, permeability, and bioavailability of most active ingredients. These properties also induce the accumulation of pharmaceuticals in groundwater, surface water, wastewater, soils and biota. Therefore, enhancing the solubility and bioavailability of pharmaceuticals could allow the prescription of lower doses, and could reduce environmental impact. Pharmaceutical solubility can be increased by pH modification, salt formation, ionization, complexation, and co-solvency. Here we report for the first time the use of cyclodextrin-based low-melting mixtures for the solubilization of four steroids: beclomethasone dipropionate, budesonide, fluticasone propionate and mometasone furoate. First, a low-melting mixture was prepared from sulfobutylether-β-cyclodextrin and levulinic acid, and characterized. Then, the shake flask method was used to determine the solubility of the drugs in this low-melting mixture. Results show a 4000-fold increase of the solubility of fluticasone propionate using the low-melting, cyclodextrin-based mixture versus water. This huge solubility enhancement could be explained by the formation of an inclusion complex with the cyclodextrin within the low-melting mixture.
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Abbreviations
- APIs:
-
Active pharmaceutical ingredients
- CDs:
-
Cyclodextrins
- DESs:
-
Deep eutectic solvents
- DSC:
-
Differential scanning calorimetry
- HyperDSC®:
-
High-speed differential scanning calorimetry
- NADES:
-
Natural deep eutectic solvents
- NMR:
-
Nuclear magnetic resonance
- SBE-β-CD:
-
Sulfobutylether-β-cyclodextrin
References
Abbott AP, Capper G, Davies DL et al (2003) Novel solvent properties of choline chloride/urea mixtures. Chem Commun. https://doi.org/10.1039/b210714g
Al-Akayleh F, Mohammed Ali HH, Ghareeb MM, Al-Remawi M (2019) Therapeutic deep eutectic system of capric acid and menthol: characterization and pharmaceutical application. J Drug Deliv Sci Technol 53:101159. https://doi.org/10.1016/j.jddst.2019.101159
Arora D, Saneja A, Jaglan S (2019) Cyclodextrin-based delivery systems for dietary pharmaceuticals. Environ Chem Lett 17:1263–1270. https://doi.org/10.1007/s10311-019-00878-w
Athanasiadis V, Grigorakis S, Lalas S, Makris DP (2018) Methyl β-cyclodextrin as a booster for the extraction for Olea europaea leaf polyphenols with a bio-based deep eutectic solvent. Biomass Convers Biorefin 8:345–355. https://doi.org/10.1007/s13399-017-0283-5
Brewster ME, Loftsson T (2007) Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev 59:645–666. https://doi.org/10.1016/j.addr.2007.05.012
Caban M, Stepnowski P (2021) How to decrease pharmaceuticals in the environment? A review. Environ Chem Lett 19:3115–3138. https://doi.org/10.1007/s10311-021-01194-y
Choi YH, van Spronsen J, Dai Y et al (2011) Are natural deep eutectic solvents the missing link in understanding cellular metabolism and physiology? Plant Physiol 156:1701–1705. https://doi.org/10.1104/pp.111.178426
Crini G (2014) Review : a history of cyclodextrins. Chem Rev 114:10940–10975. https://doi.org/10.1021/cr500081p
Di Pietro ME, Colombo Dugoni G, Ferro M et al (2019) Do cyclodextrins encapsulate volatiles in deep eutectic systems? ACS Sustain Chem Eng 7:17397–17405. https://doi.org/10.1021/acssuschemeng.9b04526
Dugoni GC, Di Pietro ME, Ferro M et al (2019) Effect of water on deep eutectic solvent/β-cyclodextrin systems. ACS Sustain Chem Eng 7:7277–7285. https://doi.org/10.1021/acssuschemeng.9b00315
El Achkar T, Moufawad T, Ruellan S et al (2020a) Cyclodextrins: from solute to solvent. Chem Commun 56:3385–3388. https://doi.org/10.1039/d0cc00460j
El Achkar T, Moura L, Moufawad T et al (2020b) New generation of supramolecular mixtures: Characterization and solubilization studies. Int J Pharm 584:119443. https://doi.org/10.1016/j.ijpharm.2020.119443
El Achkar T, Greige-Gerges H, Fourmentin S (2021) Basics and properties of deep eutectic solvents: a review. Environ Chem Lett 19:3397–3408. https://doi.org/10.1007/s10311-021-01225-8
Fenyvesi É, Puskás I, Szente L (2019) Applications of steroid drugs entrapped in cyclodextrins. Environ Chem Lett 17:375–391. https://doi.org/10.1007/s10311-018-0807-7
Ferreira M, Jérôme F, Bricout H et al (2015) Rhodium catalyzed hydroformylation of 1-decene in low melting mixtures based on various cyclodextrins and N, N′-dimethylurea. Catal Commun 63:62–65. https://doi.org/10.1016/j.catcom.2014.11.001
Fourmentin S, Outirite M, Blach P et al (2007) Solubilisation of chlorinated solvents by cyclodextrin derivatives. A study by static headspace gas chromatography and molecular modelling. J Hazard Mater 141:92–97. https://doi.org/10.1016/j.jhazmat.2006.06.090
Fourmentin S, Landy D, Moura L et al (2016) Procédé d’épuration d’un effluent gazeux. FR3058905B1
Hădărugă NG, Bandur GN, David I, Hădărugă DI (2019) A review on thermal analyses of cyclodextrins and cyclodextrin complexes. Environ Chem Lett 17:349–373. https://doi.org/10.1007/s10311-018-0806-8
Imperato G, Eibler E, Niedermaier J, König B (2005) Low-melting sugar-urea-salt mixtures as solvents for Diels-Alder reactions. Chem Commun. https://doi.org/10.1039/b414515a
Jain H, Chella N (2021) Methods to improve the solubility of therapeutical natural products: a review. Environ Chem Lett 19:111–121. https://doi.org/10.1007/s10311-020-01082-x
Jeliński T, Przybyłek M, Cysewski P (2019) Natural deep eutectic solvents as agents for improving solubility, stability and delivery of curcumin. Pharm Res 36:116. https://doi.org/10.1007/s11095-019-2643-2
Kalepu S, Nekkanti V (2015) Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B 5:442–453. https://doi.org/10.1016/j.apsb.2015.07.003
Kfoury M, Pipkin JD, Antle V, Fourmentin S (2017) Captisol ® : an efficient carrier and solubilizing agent for essential oils and their components. Flavour Fragr J 32:1–7. https://doi.org/10.1002/ffj.3395
Kfoury M, Auezova L, Greige-Gerges H, Fourmentin S (2018) Encapsulation in cyclodextrins to widen the applications of essential oils. Environ Chem Lett. https://doi.org/10.1007/s10311-018-0783-y
Khaoulani S, Chaker H, Cadet C et al (2015) Wastewater treatment by cyclodextrin polymers and noble metal/mesoporous TiO2 photocatalysts. Comptes Rendus Chim 18:23–31. https://doi.org/10.1016/j.crci.2014.07.004
Landy D, Mallard I, Ponchel A et al (2012) Remediation technologies using cyclodextrins: an overview. Environ Chem Lett 10:225–237. https://doi.org/10.1007/s10311-011-0351-1
Laquintana V, Asim MH, Lopedota A et al (2019) Thiolated hydroxypropyl-β-cyclodextrin as mucoadhesive excipient for oral delivery of budesonide in liquid paediatric formulation. Int J Pharm 572:118820. https://doi.org/10.1016/j.ijpharm.2019.118820
Legrand FX, Sauthier M, Flahaut C et al (2009) Aqueous hydroformylation reaction mediated by randomly methylated beta-cyclodextrin: how substitution degree influences catalytic activity and selectivity. J Mol Catal A Chem 303:72–77. https://doi.org/10.1016/j.molcata.2008.12.017
Li Z, Lee PI (2016) Investigation on drug solubility enhancement using deep eutectic solvents and their derivatives. Int J Pharm 505:283–288. https://doi.org/10.1016/j.ijpharm.2016.04.018
Lu C, Cao J, Wang N, Su E (2016) Significantly improving the solubility of non-steroidal anti-inflammatory drugs in deep eutectic solvents for potential non-aqueous liquid administration. Medchemcomm 7:955–959. https://doi.org/10.1039/c5md00551e
McCune JA, Kunz S, Olesińska M, Scherman OA (2017) DESolution of CD and CB macrocycles. Chem - A Eur J 23:8601–8604. https://doi.org/10.1002/chem.201701275
Mokhtarpour M, Shekaari H, Martinez F, Zafarani-Moattar MT (2019) Study of naproxen in some aqueous solutions of choline-based deep eutectic solvents: solubility measurements, volumetric and compressibility properties. Int J Pharm 564:197–206. https://doi.org/10.1016/j.ijpharm.2019.04.029
Mokhtarpour M, Shekaari H, Zafarani-Moattar MT, Golgoun S (2020) Solubility and solvation behavior of some drugs in choline based deep eutectic solvents at different temperatures. J Mol Liq 297:111799. https://doi.org/10.1016/j.molliq.2019.111799
Morin-Crini N, Fourmentin S, Fenyvesi É et al (2021) 130 years of cyclodextrin discovery for health, food, agriculture, and the industry: a review. Environ Chem Lett. https://doi.org/10.1007/s10311-020-01156-w
Moufawad T, Moura L, Ferreira M et al (2019) First evidence of cyclodextrin inclusion complexes in a deep eutectic solvent. ACS Sustain Chem Eng 7:6345–6351. https://doi.org/10.1021/acssuschemeng.9b00044
Moura L, Moufawad T, Ferreira M et al (2017) Deep eutectic solvents as green absorbents of volatile organic pollutants. Environ Chem Lett 15:747–753. https://doi.org/10.1007/s10311-017-0654-y
Nguyen C-H, Augis L, Fourmentin S et al (2021) Deep eutectic solvents for innovative pharmaceutical formulations. In: Fourmentin S, Costa Gomes M, Lichtfouse E (eds) Deep eutectic solvents for medicine, gas solubilization and extraction of natural substances. Springer Nature, Switzerland, pp 41–102
Palmelund H, Andersson MP, Asgreen CJ et al (2019) Tailor-made solvents for pharmaceutical use? Experimental and computational approach for determining solubility in deep eutectic solvents (DES). Int J Pharm X 1:100034. https://doi.org/10.1016/j.ijpx.2019.100034
Panda S, Fourmentin S (2022) Cyclodextrin-based supramolecular low melting mixtures: efficient absorbents for volatile organic compounds abatement. Environ Sci Pollut Res 29:264–270. https://doi.org/10.1007/s11356-021-16279-y
Popielec A, Loftsson T (2017) Effects of cyclodextrins on the chemical stability of drugs. Int J Pharm 531:532–542. https://doi.org/10.1016/j.ijpharm.2017.06.009
Stella VJ, He Q (2008) Cyclodextrins. Toxicol Pathol 36:30–42. https://doi.org/10.1177/0192623307310945
Stella VJ, Rajewski RA (2020) Sulfobutylether-β-cyclodextrin. Int J Pharm 583:119396. https://doi.org/10.1016/j.ijpharm.2020.119396
Tokumura T, Isaka H, Kanou M et al (2015) An inclusion complex of fluticasone propionate with γ-cyclodextrin in aqueous solution and in a solid state. J Drug Deliv Sci Technol 26:24–27. https://doi.org/10.1016/j.jddst.2015.02.002
Triolo A, Lo Celso F, Russina O (2020) Structural features of β-cyclodextrin solvation in the deep eutectic solvent, reline. J Phys Chem B 124:2652–2660. https://doi.org/10.1021/acs.jpcb.0c00876
Wang Z, Landy D, Sizun C et al (2020) Cyclodextrin complexation studies as the first step for repurposing of chlorpromazine. Int J Pharm 584:119391. https://doi.org/10.1016/j.ijpharm.2020.119391
Acknowledgements
Canh-Hung NGUYEN from Institut Galien Paris-Saclay (Châtenay-Malabry, France) is greatly acknowledged for his help for rheology experiments.
Funding
This work partially benefited from the support of the project ParasiDES ANR-19-CE18-0027 of the French National Research Agency (ANR). Justine Petitprez is grateful to Ligand pharmaceutical for her master's internship funding.
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JP: Investigation; F-XL: Investigation, Writing- Original draft preparation, Writing—Reviewing and Editing; CT: Investigation; JDP: Resources, Writing—Reviewing and Editing; VA: Resources, Writing- Reviewing and Editing; MK: Methodology, Writing—Reviewing and Editing; SF: Conceptualization, Methodology, Writing—Original draft preparation, Writing—Reviewing and Editing.
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Petitprez, J., Legrand, FX., Tams, C. et al. Huge solubility increase of poorly water-soluble pharmaceuticals by sulfobutylether-β-cyclodextrin complexation in a low-melting mixture. Environ Chem Lett 20, 1561–1568 (2022). https://doi.org/10.1007/s10311-022-01415-y
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DOI: https://doi.org/10.1007/s10311-022-01415-y