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Ocular topical application of alpha-glucosyl hesperidin as an active pharmaceutical excipient: in vitro and in vivo experimental evaluation

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Abstract

Alpha-glucosyl hesperidin (GH) is an aqueous soluble, amphipathic hesperidin derivative with several pharmacological effects, and it is postulated in this manuscript that GH could potentially be utilized as an active pharmaceutical excipient in eyedrops. The ocular safety of GH was evaluated according to in vitro cytotoxicity and in vivo ocular tolerance. The in vivo corneal permeation of coumarin-6 (Cou-6) with or without GH was characterized, and the in vivo inducing corneal wound healing using bisdemethoxycurcumin (BDMC) with or without GH was also evaluated to determine whether GH is an active pharmaceutical excipient in eyedrops. The results demonstrated that as high as 30 mg/ml of GH exhibits high-level in vitro and in vivo safety profiles according to four in vitro and in vivo evaluations. GH improved the corneal permeation of Cou-6 in mice, as well as demonstrated in vitro antioxidant activity. Concerning in vivo activity, a BDMC–GH suspension was shown to be synergistic in promoting corneal wound healing in mice, as well as restoring corneal sensitivity, promoting corneal epithelial wound healing, and restoring the corneal tissue structure without inflammatory cell infiltration. Overall, GH could be a novel and promising active excipient in eyedrops.

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Data availability statement

The data and materials of this study are available on reasonable request.

References

  1. Buzdagli Y, Eyipinar CD, Kaci FN, Tekin A. Effects of hesperidin on anti-inflammatory and antioxidant response in healthy people: a meta-analysis and meta-regression. Int J Environ Health Res. 2022:1–16. https://doi.org/10.1080/09603123.2022.2093841.

  2. Homayouni F, Haidari F, Hedayati M, Zakerkish M, Ahmadi K. Blood pressure lowering and anti-inflammatory effects of hesperidin in type 2 diabetes; a randomized double-blind controlled clinical trial. Phytother Res. 2018;32(6):1073–9. https://doi.org/10.1002/ptr.6046.

    Article  CAS  PubMed  Google Scholar 

  3. Lu B, Wang X, Ren Z, Jiang H, Liu B. Anti-glaucoma potential of hesperidin in experimental glaucoma induced rats. AMB Express. 2020;10(1):94. https://doi.org/10.1186/s13568-020-01027-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Karimi N, Monfared AS, Haddadi GH, Soleymani A, Mohammadi E, Hajian-Tilaki K, et al. Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats. Int J Pharm Investig. 2017;7(3):149–54. https://doi.org/10.4103/jphi.JPHI_60_17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Majumdar S, Srirangam R. Solubility, stability, physicochemical characteristics and in vitro ocular tissue permeability of hesperidin: a natural bioflavonoid. Pharm Res. 2009;26(5):1217–25. https://doi.org/10.1007/s11095-008-9729-6.

    Article  CAS  PubMed  Google Scholar 

  6. Nakazawa Y, Aoki M, Ishiwa S, Morishita N, Endo S, Nagai N, et al. Oral intake of alpha-glucosyl-hesperidin ameliorates selenite-induced cataract formation. Mol Med Rep. 2020;21(3):1258–66. https://doi.org/10.3892/mmr.2020.10941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nakazawa Y, Aoki M, Doki Y, Morishita N, Endo S, Nagai N et al. Oral consumption of alpha-glucosyl-hesperidin could prevent lens hardening, which causes presbyopia. Biochem Biophys Rep. 2021;25:100885. https://doi.org/10.1016/j.bbrep.2020.100885.

  8. de Souza VT, de Franco EP, de Araujo ME, Messias MC, Priviero FB, Frankland Sawaya AC, et al. Characterization of the antioxidant activity of aglycone and glycosylated derivatives of hesperetin: an in vitro and in vivo study. J Mol Recognit. 2016;29(2):80–7. https://doi.org/10.1002/jmr.2509.

    Article  CAS  PubMed  Google Scholar 

  9. Huang Y, Zhou W, Sun J, Ou G, Zhong NS, Liu Z. Exploring the potential pharmacological mechanism of hesperidin and glucosyl hesperidin against COVID-19 based on bioinformatics analyses and antiviral assays. Am J Chin Med. 2022;50(2):351–69. https://doi.org/10.1142/S0192415X22500148.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang J, Tozuka Y, Uchiyama H, Higashi K, Moribe K, Takeuchi H, et al. NMR investigation of a novel excipient, alpha-glucosylhesperidin, as a suitable solubilizing agent for poorly water-soluble drugs. J Pharm Sci. 2011;100(10):4421–31. https://doi.org/10.1002/jps.22606.

    Article  CAS  PubMed  Google Scholar 

  11. Letchmanan K, Shen SC, Ng WK, Tan RBH. Application of transglycosylated stevia and hesperidin as drug carriers to enhance biopharmaceutical properties of poorly-soluble artemisinin. Colloids Surf B Biointerfaces. 2018;161:83–93. https://doi.org/10.1016/j.colsurfb.2017.10.020.

    Article  CAS  PubMed  Google Scholar 

  12. Tozuka Y, Imono M, Uchiyama H, Takeuchi H. A novel application of alpha-glucosyl hesperidin for nanoparticle formation of active pharmaceutical ingredients by dry grinding. Eur J Pharm Biopharm. 2011;79(3):559–65. https://doi.org/10.1016/j.ejpb.2011.07.006.

    Article  CAS  PubMed  Google Scholar 

  13. Uchiyama H, Tozuka Y, Asamoto F, Takeuchi H. Alpha-glucosyl hesperidin induced an improvement in the bioavailability of pranlukast hemihydrate using high-pressure homogenization. Int J Pharm. 2011;410(1–2):114–7. https://doi.org/10.1016/j.ijpharm.2011.03.017.

    Article  CAS  PubMed  Google Scholar 

  14. Uchiyama H, Tozuka Y, Imono M, Takeuchi H. Improvement of dissolution and absorption properties of poorly water-soluble drug by preparing spray-dried powders with alpha-glucosyl hesperidin. Int J Pharm. 2010;392(1–2):101–6. https://doi.org/10.1016/j.ijpharm.2010.03.037.

    Article  CAS  PubMed  Google Scholar 

  15. Bachu RD, Chowdhury P, Al-Saedi ZHF, Karla PK, Boddu SHS. Ocular drug delivery barriers-role of nanocarriers in the treatment of anterior segment ocular diseases. Pharmaceutics. 2018;10(1). https://doi.org/10.3390/pharmaceutics10010028.

  16. Li Y, Zhou L, Zhang M, Li R, Di G, Liu H et al. Micelles based on polyvinylpyrrolidone VA64: A potential nanoplatform for the ocular delivery of apocynin. Int J Pharm. 2022;615:121451. https://doi.org/10.1016/j.ijpharm.2022.121451.

  17. Li Q, Wu X, Xin M. Strengthened rebamipide ocular nanoformulation to effectively treat corneal alkali burns in mice through the HMGB1 signaling pathway. Exp Eye Res. 2021;213:108824. https://doi.org/10.1016/j.exer.2021.108824.

  18. Badr MY, Halwani AA, Odunze U, Eskandarpour M, Calder VL, Schatzlein AG et al. The topical ocular delivery of rapamycin to posterior eye tissues and the suppression of retinal inflammatory disease. Int J Pharm. 2022;621:121755. https://doi.org/10.1016/j.ijpharm.2022.121755.

  19. Sharif NA, Li L, Katoli P, Xu S, Veltman J, Li B, et al. Preclinical pharmacology, ocular tolerability and ocular hypotensive efficacy of a novel non-peptide bradykinin mimetic small molecule. Exp Eye Res. 2014;128:170–80. https://doi.org/10.1016/j.exer.2014.10.008.

    Article  CAS  PubMed  Google Scholar 

  20. Chen W, Zhang Z, Hu J, Xie H, Pan J, Dong N, et al. Changes in rabbit corneal innervation induced by the topical application of benzalkonium chloride. Cornea. 2013;32(12):1599–606. https://doi.org/10.1097/ICO.0b013e3182a8196f.

    Article  PubMed  Google Scholar 

  21. Dubey V, Mohan P, Dangi JS, Kesavan K. Brinzolamide loaded chitosan-pectin mucoadhesive nanocapsules for management of glaucoma: formulation, characterization and pharmacodynamic study. Int J Biol Macromol. 2020;152:1224–32. https://doi.org/10.1016/j.ijbiomac.2019.10.219.

    Article  CAS  PubMed  Google Scholar 

  22. Tanito M, Takanashi T, Kaidzu S, Yoshida Y, Ohira A. Cytoprotective effects of rebamipide and carteolol hydrochloride against ultraviolet B-induced corneal damage in mice. Invest Ophthalmol Vis Sci. 2003;44(7):2980–5. https://doi.org/10.1167/iovs.02-1043.

    Article  PubMed  Google Scholar 

  23. Li M, Xin M, Guo C, Lin G, Wu X. New nanomicelle curcumin formulation for ocular delivery: improved stability, solubility, and ocular anti-inflammatory treatment. Drug Dev Ind Pharm. 2017;43(11):1846–57. https://doi.org/10.1080/03639045.2017.1349787.

    Article  CAS  PubMed  Google Scholar 

  24. Sun Z, Zhang M, Wei Y, Li M, Wu X, Xin M. A simple but novel glycymicelle ophthalmic solution based on two approved drugs empagliflozin and glycyrrhizin: in vitro/in vivo experimental evaluation for the treatment of corneal alkali burns. Biomater Sci. 2023;11(7):2531–42. https://doi.org/10.1039/d2bm01957d.

    Article  CAS  PubMed  Google Scholar 

  25. Alshamrani M, Sikder S, Coulibaly F, Mandal A, Pal D, Mitra AK. Self-assembling topical nanomicellar formulation to improve curcumin absorption across ocular tissues. AAPS PharmSciTech. 2019;20(7):254. https://doi.org/10.1208/s12249-019-1404-1.

    Article  CAS  PubMed  Google Scholar 

  26. Park B, Lee IS, Hyun SW, Jo K, Lee TG, Kim JS et al. The protective effect of polygonum cuspidatum (pce) aqueous extract in a dry eye model. Nutrients. 2018;10(10). https://doi.org/10.3390/nu10101550.

  27. El-Kamel AH. In vitro and in vivo evaluation of Pluronic F127-based ocular delivery system for timolol maleate. Int J Pharm. 2002;241(1):47–55. https://doi.org/10.1016/s0378-5173(02)00234-x.

    Article  CAS  PubMed  Google Scholar 

  28. Qu M, Wang Y, Yang L, Zhou Q. Different cellular effects of four anti-inflammatory eye drops on human corneal epithelial cells: independent in active components. Mol Vis. 2011;17:3147–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Scuderi AC, Paladino GM, Marino C, Trombetta F. In vitro toxicity of netilmicin and ofloxacin on corneal epithelial cells. Cornea. 2003;22(5):468–72. https://doi.org/10.1097/00003226-200307000-00014.

    Article  PubMed  Google Scholar 

  30. Steiling W, Bracher M, Courtellemont P, de Silva O. The HET-CAM, a useful in vitro assay for assessing the eye irritation properties of cosmetic formulations and ingredients. Toxicol In Vitro. 1999;13(2):375–84. https://doi.org/10.1016/s0887-2333(98)00091-5.

    Article  CAS  PubMed  Google Scholar 

  31. Alshamsan A, Abul Kalam M, Vakili MR, Binkhathlan Z, Raish M, Ali R et al. Treatment of endotoxin-induced uveitis by topical application of cyclosporine a-loaded polygel in rabbit eyes. Int J Pharm. 2019;569:118573. https://doi.org/10.1016/j.ijpharm.2019.118573.

  32. Salama AH, Shamma RN. Tri/tetra-block co-polymeric nanocarriers as a potential ocular delivery system of lornoxicam: in-vitro characterization, and in-vivo estimation of corneal permeation. Int J Pharm. 2015;492(1–2):28–39. https://doi.org/10.1016/j.ijpharm.2015.07.010.

    Article  CAS  PubMed  Google Scholar 

  33. Romeo A, Bonaccorso A, Carbone C, Lupo G, Daniela Anfuso C, Giurdanella G et al. Melatonin loaded hybrid nanomedicine: DoE approach, optimization and in vitro study on diabetic retinopathy model. Int J Pharm. 2022;627:122195. https://doi.org/10.1016/j.ijpharm.2022.122195.

  34. Liang H, Baudouin C, Daull P, Garrigue JS, Brignole-Baudouin F. Ocular safety of cationic emulsion of cyclosporine in an in vitro corneal wound-healing model and an acute in vivo rabbit model. Mol Vis. 2012;18:2195–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Onizuka N, Uematsu M, Kusano M, Sasaki H, Suzuma K, Kitaoka T. Influence of different additives and their concentrations on corneal toxicity and antimicrobial effect of benzalkonium chloride. Cornea. 2014;33(5):521–6. https://doi.org/10.1097/ICO.0000000000000086.

    Article  PubMed  Google Scholar 

  36. Uematsu M, Kumagami T, Shimoda K, Kusano M, Teshima M, To H, et al. Polyoxyethylene hydrogenated castor oil modulates benzalkonium chloride toxicity: comparison of acute corneal barrier dysfunction induced by travoprost Z and travoprost. J Ocul Pharmacol Ther. 2011;27(5):437–44. https://doi.org/10.1089/jop.2010.0175.

    Article  CAS  PubMed  Google Scholar 

  37. Khan W, Aldouby YH, Avramoff A, Domb AJ. Cyclosporin nanosphere formulation for ophthalmic administration. Int J Pharm. 2012;437(1–2):275–6. https://doi.org/10.1016/j.ijpharm.2012.08.016.

    Article  CAS  PubMed  Google Scholar 

  38. Yenice I, Mocan MC, Palaska E, Bochot A, Bilensoy E, Vural I, et al. Hyaluronic acid coated poly-epsilon-caprolactone nanospheres deliver high concentrations of cyclosporine A into the cornea. Exp Eye Res. 2008;87(3):162–7. https://doi.org/10.1016/j.exer.2008.04.002.

    Article  CAS  PubMed  Google Scholar 

  39. Jin F, Chen X, Yan H, Xu Z, Yang B, Luo P et al. Bisdemethoxycurcumin attenuates cisplatin-induced renal injury through anti-apoptosis, anti-oxidant and anti-inflammatory. Eur J Pharmacol. 2020;874:173026. https://doi.org/10.1016/j.ejphar.2020.173026.

  40. Liu J, Wang Q, Omari-Siaw E, Adu-Frimpong M, Liu J, Xu X et al. Enhanced oral bioavailability of Bisdemethoxycurcumin-loaded self-microemulsifying drug delivery system: formulation design, in vitro and in vivo evaluation. Int J Pharm. 2020;590:119887. https://doi.org/10.1016/j.ijpharm.2020.119887.

  41. Ghobadi-Oghaz N, Asoodeh A, Mohammadi M. Fabrication, characterization and in vitro cell exposure study of zein-chitosan nanoparticles for co-delivery of curcumin and berberine. Int J Biol Macromol. 2022;204:576–86. https://doi.org/10.1016/j.ijbiomac.2022.02.041.

    Article  CAS  PubMed  Google Scholar 

  42. Liu W, Pan W, Zou M, Jin S, Mi R, Cheng G, et al. Tacrolimus and paclitaxel co-loaded O/O ointment without surfactant: synergistic combinations for the treatment of psoriasis. Eur J Pharm Biopharm. 2023;185:28–43. https://doi.org/10.1016/j.ejpb.2023.02.007.

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was supported by the National Natural Science Foundation of China (Project no. 82000947), the China International Medical Exchange Foundation (Project no. Z-2021–46-2101), the Research and Development Fund of Peking University People's Hospital (project no. RDJP2022-32), and the Natural Science Foundation of Shandong Province (Grant No. ZR2023MH343).

the National Natural Science Foundation of China,82000947,Meng Xin,the China International Medical Exchange Foundation,Z-2021-46-2101,Mengshuang Li,Research and Development Fund of Peking University People's Hospital,RDJP2022-32,Mengshuang Li

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Authors and Affiliations

  1. College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China

    Linrong Yu, Xianggen Wu & Meng Xin

  2. Department of Ophthalmology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China

    Linrong Yu & Meng Xin

  3. Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China

    Qiliang Zhang & Liping Zhou

  4. Viwit Pharmaceutical Co., Ltd, Zaozhuang, Shandong, China

    Yanjun Wei

  5. Qingdao Women and Children’s Hospital, Qingdao, China

    Mengshuang Li

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  1. Linrong Yu
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Contributions

Linrong Yu: investigation, methodology, validation, writing—original draft. Qiliang Zhang: investigation, methodology. Liping Zhou: investigation, methodology. Yanjun Wei: investigation, methodology. Mengshuang Li: conceptualization, funding acquisition, writing—review & editing. Xianggen Wu: conceptualization, funding acquisition. Meng Xin: conceptualization, funding acquisition, project administration, resources, writing—review & editing.

Corresponding authors

Correspondence to Xianggen Wu or Meng Xin.

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Ethics approval and consent to participate

Male C57BL/6 mice (8 weeks old) and New Zealand white rabbits were used in these manuscript. The animal care procedures complied with the Guide for the Care and Use of Laboratory Animals, and the animal experiment was approved by the Ethics Committee for Animal Experimentation of Qingdao University of Science and Technology (Approval Document No. 2017–1, Qingdao, China).

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Highlights

• Active ocular topical pharmaceutical excipient was highly desired

• GH demonstrated high-level in vitro and in vivo safety profiles

• GH exhibited excellent corneal permeation

• GH marked prompted wound healing in mouse corneas

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Yu, L., Zhang, Q., Zhou, L. et al. Ocular topical application of alpha-glucosyl hesperidin as an active pharmaceutical excipient: in vitro and in vivo experimental evaluation. Drug Deliv. and Transl. Res. 14, 373–385 (2024). https://doi.org/10.1007/s13346-023-01403-x

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