Nanodispersion of lutein with use of metastable polymorph for improved dissolution and oral absorption

Abstract

Lutein (LT) is an attractive nutrient for eye health, although it has low water solubility and poor oral absorption. The present study aimed to develop a novel nanodispersion (ND) of LT using a metastable polymorph, offering improved oral absorption of LT. A metastable crystalline form of LT (LT-II) and hydroxypropyl cellulose were subjected to wet-milling followed by freeze-drying to obtain the ND of LT-II (ND/LT-II), and its physicochemical, photochemical, and pharmacokinetic properties of LT samples were evaluated. The mean particle size of LT-II in ND/LT-II was 354 ​nm, and there was no significant change in the crystalline form of LT-II, even after wet milling and freeze-drying. LT generated significant amounts of superoxide anions upon exposure to pseudo-sunlight (250 ​W/m²), indicating high photoreactivity. After irradiation with pseudo-sunlight (250 ​W/m², 30 ​min), the percentages of LT remaining in the LT solution, amorphous LT, and ND/LT-II were 75, 79, and 92%, respectively. LT-II dissolved slightly faster than the stable crystalline form of LT (LT-I) in the dissolution media. ND/LT-II further improved the dissolution property of LT-II, and the dissolved amount of LT was 137- and 7.2-fold higher than that of LT-I and LT-II, respectively, at 2 ​h after dispersion in water. After administration of LT samples (100 ​mg-LT/kg), systemic exposure to LT in the LT-I and LT-II was negligible, whereas a marked improvement in oral absorption was observed in the ND/LT-II groups. Thus, applying ND technology to LT-II may improve oral absorption, and thus the nutrient function of LT.

Keywords

Dissolution / Lutein / Metastable polymorph / Nanodispersion / Oral absorption / Photostability

References

[1] E.S.M. Abdel-Aal, H. Akhtar, K. Zaheer, R. Ali, Dietary sources of lutein and zeaxanthin carotenoids and their role in eye health, Nutrients 5 (2013) 1169-1185, https://doi.org/10.3390/nu5041169.

[2] L.H. Li, J.C.Y. Lee, H.H. Leung, W.C. Lam, Z. Fu, A.C.Y. Lo, Lutein supplementation for eye diseases, Nutrients 12 (2020) 1721, https://doi.org/10.3390/nu12061721.

[3] S. Richer, W. Stiles, L. Statkute, J. Pulido, J. Frankowski, D. Rudy, K. Pei, M. Tsipursky, J. Nyland, Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (lutein Antioxidant Supplementation Trial), Optometry 75 (2004) 216 230, https://doi.org/10.1016/-s1529-1839(04)70049-4.

[4] S. Buscemi, D. Corleo, F. Di Pace, M.L. Petroni, A. Satriano, G. Marchesini, The effect of lutein on eye and extra-eye health, Nutrients 10 (2018) 1321, https://doi.org/10.3390/nu10091321.

[5] Y. Sato, M. Kobayashi, S. Itagaki, T. Hirano, T. Noda, S. Mizuno, M. Sugawara, K. Iseki, Pharmacokinetic properties of lutein emulsion after oral administration to rats and effect of food intake on plasma concentration of lutein, Biopharm. Drug Dispos. 32 (2011) 151-158, https://doi.org/10.1002/bdd.746.

[6] S. Itagaki, W. Ogura, Y. Sato, T. Noda, T. Hirano, S. Mizuno, K. Iseki, Characterization of the disposition of lutein after i.v. administration to rats, Biol. Pharm. Bull. 29 (2006) 2123-2125, https://doi.org/10.1248/bpb.29.2123.

[7] C. Lim, D. Kim, T. Sim, N.H. Hoang, J.W. Lee, E.S. Lee, Y.S. Youn, K.T. Oh, Preparation and characterization of a lutein loading nanoemulsion system for ophthalmic eye drops, J. Drug Deliv. Sci. Technol. 36 (2016) 168-174, https://doi.org/10.1016/j.jddst.2016.10.009.

[8] J.H. Yoo, S. Shanmugam, P. Thapa, E.S. Lee, P. Balakrishnan, R. Baskaran, S.K. Yoon, H.G. Choi, C.S. Yong, B.K. Yoo, K. Han, Novel self-nanoemulsifying drug delivery system for enhanced solubility and dissolution of lutein, Arch Pharm. Res. (Seoul) 33 (2010) 417-426, https://doi.org/10.1007/s12272-010-0311-5.

[9] C. Lim, J.K. Kang, C.E. Jung, T. Sim, J. Her, K. Kang, E.S. Lee, Y.S. Youn, H.G. Choi, K.T. Oh, Preparation and characterization of a lutein solid dispersion to improve its solubility and stability, AAPS PharmSciTech 22 (2021) 169, https://doi.org/10.1208/s12249-021-02036-4.

[10] J.M.M. Salmani, S. Asghar, H. Lv, J. Zhou, Aqueous solubility and degradation kinetics of the phytochemical anticancer thymoquinone; probing the effects of solvents, pH and light, Molecules 19 (2014) 5925-5939, https://doi.org/10.3390/molecules19055925.

[11] D. jian Jv, T. Hao Ji, Z. Xu, A. Li, Z. Chen yi, The remarkable enhancement of photo-stability and antioxidant protection of lutein coupled with carbon-dot, Food Chem. 405 (2023) 134551, https://doi.org/10.1016/j.foodchem.2022.134551.

[12] H. Sato, T. Matsushita, K. Ueno, H. Kikuchi, K. Yamada, S. Onoue, Oily suspension of micronized crystalline lutein for the improvement of dissolution and oral bioavailability, ACS Food Sci. Technol. 2 (2022) 272-279, https://doi.org/10.1021/acsfoodscitech.1c00377.

[13] S. Onoue, N. Terasawa, T. Nakamura, K. Yuminoki, N. Hashimoto, S. Yamada, Biopharmaceutical characterization of nanocrystalline solid dispersion of coenzyme Q10 prepared with cold wet-milling system, Eur. J. Pharmaceut. Sci. 53 (2014) 118-125, https://doi.org/10.1016/j.ejps.2013.12.013.

[14] Y. Kawabata, K. Yamamoto, K. Debari, S. Onoue, S. Yamada, Novel crystalline solid dispersion of tranilast with high photostability and improved oral bioavailability, Eur. J. Pharmaceut. Sci. 39 (2010) 256-262, https://doi.org/10.1016/j.ejps.2009.12.009.

[15] J.I. Jinno, N. Kamada, M. Miyake, K. Yamada, T. Mukai, M. Odomi, H. Toguchi, G.G. Liversidge, K. Higaki, T. Kimura, Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs, J. Contr. Release 111 (2006) 56-64, https://doi.org/10.1016/j.jconrel.2005.11.013.

[16] S. Onoue, H. Sato, Y. Kawabata, T. Mizumoto, N. Hashimoto, S. Yamada, In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy, J. Contr. Release 138 (2009) 16-23, https://doi.org/10.1016/j.jconrel.2009.04.014.

[17] S. Onoue, Y. Tsuda, Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances, Pharm. Res. 23 (2006) 156-164, https://doi.org/10.1007/s11095-005-8497-9.

[18] L. Nicoud, F. Licordari, A.S. Myerson, Estimation of the solubility of metastable polymorphs: a critical review, Cryst. Growth Des. 18 (2018) 7228-7237, https://doi.org/10.1021/acs.cgd.8b01200.

[19] J. de Cassia Zaghi Compri, V.M. Andres Felli, F.R. Lourenço, T. Takatsuka, N. Fotaki, R. L€obenberg, N.A. Bou-Chacra, G.L. Barros de Araujo, Highly watersoluble orotic acid nanocrystals produced by high-energy milling, J. Pharm. Sci. 108 (2019) 1848-1856, https://doi.org/10.1016/j.xphs.2018.12.015.

[20] S. Onoue, H. Takahashi, Y. Kawabata, Y. Seto, J. Hatanaka, B. Timmermann, S. Yamada, Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability, J. Pharm. Sci. 99 (2010) 1871-1881, https://doi.org/10.1002/jps.21964.

[21] Y. Seto, K. Ueno, H. Suzuki, H. Sato, S. Onoue, Development of novel lutein nanocrystal formulation with improved oral bioavailability and ocular distribution, J. Funct. Foods 61 (2019) 103499, https://doi.org/10.1016/j.jff.2019.103499.

[22] F.Y. de Boer, A. Imhof, K.P. Velikov, Photo-stability of lutein in surfactant-free lutein-zein composite colloidal particles, Food Chem. X. 5 (2020) 100071, https://doi.org/10.1016/j.fochx.2019.100071.

[23] S. Onoue, Establishment and international harmonization of photosafety testing strategy, Yakugaku Zasshi 141 (2021) 807-812, https://doi.org/10.1248/yakushi.20-00217-4.

[24] S. Onoue, N. Igarashi, S. Yamada, Y. Tsuda, High-throughput reactive oxygen species (ROS) assay: an enabling technology for screening the phototoxic potential of pharmaceutical substances, J. Pharm. Biomed. Anal. 46 (2008) 187-193, https://doi.org/10.1016/j.jpba.2007.09.003.

[25] H. Suzuki, K. Yakushiji, S. Matsunaga, Y. Yamauchi, Y. Seto, H. Sato, S. Onoue, Amorphous solid dispersion of meloxicam enhanced oral absorption in rats with impaired gastric motility, J. Pharm. Sci. 107 (2018) 446-452, https://doi.org/10.1016/j.xphs.2017.05.023.

[26] T. Nihei, E. Ushiro, H. Sato, S. Onoue, Biopharmaceutical study on nobiletin-loaded amorphous solid dispersion with improved hypouricemic effect, Molecules 26 (2021) 4447, https://doi.org/10.3390/molecules26154447.

[27] Y. Li, P. Zhang, R. Yu, R.Z. Chen, J.P. Si, X.F. Zhang, Effects of different storage conditions on edible quality and antioxidant activity of Polygonatum cyrtonema flowers, Zhongguo Zhongyao Zazhi 46 (2021) 3091-3101, https://doi.org/10.19540/j.cnki.cjcmm.20210319.101.

[28] Y. Sato, T. Joumura, S. Nashimoto, S. Yokoyama, Y. Takekuma, H. Yoshida,M. Sugawara, Enhancement of lymphatic transport of lutein by oral administration

of a solid dispersion and a self-microemulsifying drug delivery system, Eur. J. Pharm. Biopharm. 127 (2018) 171-176, https://doi.org/10.1016/j.ejpb.2018.02.013.

[29] L.B. Da Fonseca, M. Labastie, V.P. De Sousa, N.M. Volpato, Development and validation of a discriminative dissolution test for nimesulide suspensions, AAPS PharmSciTech 10 (2009) 1145-1152, https://doi.org/10.1208/s12249-009-9320-4.

[30] Z. Cai, Y. Wang, L.-J. Zhu, Z.-Q. Liu, Nanocarriers: a general strategy for enhancement of oral bioavailability of poorly absorbed or pre-systemically metabolized drugs, Curr. Drug Metabol. 11 (2010) 197-207, https://doi.org/10.2174/138920010791110836.

[31] E. Loane, J.M. Nolan, O. O'Donovan, P. Bhosale, P.S. Bernstein, S. Beatty, Transport and retinal capture of lutein and zeaxanthin with reference to age-related macular degeneration, Surv. Ophthalmol. 53 (2008) 68-81, https://doi.org/10.1016/j.survophthal.2007.10.008.

[32] Y. Tanaka, T. Hara, R. Waki, S. Nagata, Regional differences in the components of luminal water from rat gastrointestinal tract and comparison with other species, J. Pharm. Pharmaceut. Sci. 15 (2012) 510-518, https://doi.org/10.18433/J3F602.