Skip to main content
SpringerLink
Log in

Molecular Modeling-Based Inclusion Mechanism and Stability Studies of Doxycycline and Hydroxypropyl-β-Cyclodextrin Complex for Ophthalmic Delivery

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The aim of the present study was to prepare a stable complex of doxycycline (Doxy) and hydroxypropyl-β-cyclodextrin (HPβCD) for ophthalmic delivery and investigate the inclusion mechanism and the inclusion effects on the stability of Doxy. The Doxy/HPβCD complex was prepared by solution stirring and then characterized by scanning electron microscopy and ultraviolet spectroscopy. Based on results of nuclear magnetic resonance, molecular model of Doxy/HPβCD complex was established using computational simulation of PM3 method implemented in Gaussian 03. Stabilities of Doxy/HPβCD complex in both aqueous solution and solid state at 25°C were evaluated by HPLC. Finally, in vitro antibacterial activity of the Doxy/HPβCD complex was evaluated by disk diffusion test. It was found that the stabilities of Doxy/HPβCD complex in both aqueous solution and solid state were improved obviously as compared with Doxy alone. This stability enhancement is consistent with the inclusion mechanism between HPβCD and Doxy, which showed that the unstable site of Doxy molecule at 6-CH3 was protected in the hydrophobic cavity of HPβCD, additionally, the chelation of Mg2+ provided a synergetic protection of the other unstable site of Doxy at 4-N(CH3)2. The antibacterial activity results indicated that Doxy/HPβCD complex might have potential for clinical applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

REFERENCES

  1. Ferreri AJ, Ponzoni M, Guidoboni M, Resti AG, Politi LS, Cortelazzo S, et al. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst. 2006;98(19):1375–82.

    Article  PubMed  CAS  Google Scholar 

  2. Smith VA, Cook SD. Doxycycline-a role in ocular surface repair. Br J Ophthalmol. 2004;88(5):619–25.

    Article  PubMed  CAS  Google Scholar 

  3. Libinson GS, Ushakova TA. Doxycycline. Stability in solutions. Pharm Chem J. 1976;10(8):1076–8.

    Article  Google Scholar 

  4. Carrier RL, Miller LA, Ahmed M. The utility of cyclodextrins for enhancing oral bioavailability. J Control Release. 2007;123(2):78–99.

    Article  PubMed  CAS  Google Scholar 

  5. Loftsson T, Duchene D. Cyclodextrins and their pharmaceutical applications. Int J Pharm. 2007;329(1–2):1–11.

    Article  PubMed  CAS  Google Scholar 

  6. Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007;59(7):645–66.

    Article  PubMed  CAS  Google Scholar 

  7. Mady FM, Abou-Taleb AE, Khaled KA, Yamasaki K, Iohara D, Taguchi K, et al. Evaluation of carboxymethyl-beta-cyclodextrin with acid function: improvement of chemical stability, oral bioavailability and bitter taste of famotidine. Int J Pharm. 2010;397(1–2):1–8.

    Article  PubMed  CAS  Google Scholar 

  8. Stella VJ, Rao VM, Zannou EA, Zia V. Mechanisms of drug release from cyclodextrin complexes. Adv Drug Deliv Rev. 1999;36(1):3–16.

    Article  PubMed  CAS  Google Scholar 

  9. Cal K, Centkowska K. Use of cyclodextrins in topical formulations: practical aspects. Eur J Pharm Biopharm. 2008;68(3):467–78.

    Article  PubMed  CAS  Google Scholar 

  10. Armstrong WW, Neck M. Oxytetracycline compositions. US patent. 1976;646,295.

  11. Nosworthy MM, Ferry G. Doxycycline parenteral compositions. US patent. 1976;477,703.

  12. Su WR, Li ZR, Lin ML, Li YP, He ZX, Wu CB, et al. The effect of doxycycline temperature-sensitive hydrogel on inhibiting the corneal neovascularization induced by BFGF in rats. Graefes Arch Clin Exp Ophthalmol. 2011;249(3):421–7.

    Article  PubMed  CAS  Google Scholar 

  13. Cho HJ, Balakrishnan P, Shim WS, Chung SJ, Shim CK, Kim DD. Characterization and in vitro evaluation of freeze-dried microparticles composed of granisetron-cyclodextrin complex and carboxymethylcellulose for intranasal delivery. Int J Pharm. 2010;400(1–2):59–65.

    Article  PubMed  CAS  Google Scholar 

  14. Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci. 1996;85(10):1017–25.

    Article  PubMed  CAS  Google Scholar 

  15. de Paula WX, Denadai AML, Santoro MM, Braga ANG, Santos RAS, Sinisterra RD. Supramolecular interactions between losartan and hydroxypropyl-beta-CD: ESI mass-spectrometry, NMR techniques, phase solubility, isothermal titration calorimetry and anti-hypertensive studies. Int J Pharm. 2011;404(1–2):116–23.

    Article  PubMed  Google Scholar 

  16. Mura P, Bettinetti G, Melani F, Manderioli A. Interaction between naproxen and chemically modified [beta]-cyclodextrins in the liquid and solid state. Eur J Pharm Sci. 1995;3(6):347–55.

    Article  CAS  Google Scholar 

  17. Yap KL, Liu X, Thenmozhiyal JC, Ho PC. Characterization of the 13-cis-retinoic acid/cyclodextrin inclusion complexes by phase solubility, photostability, physicochemical and computational analysis. Eur J Pharm Sci. 2005;25(1):49–56.

    Article  PubMed  CAS  Google Scholar 

  18. Xing SK, Zhang C, Ai HQ, Zhao Q, Zhang Q, Sun DZ. Theoretical study of the interactions of beta-cyclodextrin with 2 ′-hydroxyl-5 ′-methoxyacetophone and two of its isomers. J Mol Liq. 2009;146(1–2):15–22.

    Article  CAS  Google Scholar 

  19. Shi JH, Ding ZJ, Hu Y. Theoretical study on chiral recognition mechanism of methyl mandelate enantiomers on permethylated beta-cyclodextrin. J Mol Model. 2012;18(2):803–13.

    Article  PubMed  CAS  Google Scholar 

  20. Chen MW, Pan X, Wu HM, Han K, Xie XB, Wedge DE, et al. Preparation and anti-bacterial properties of a temperature-sensitive gel containing silver nanoparticles. Pharmazie. 2011;66(4):272–7.

    PubMed  Google Scholar 

  21. Rios JL, Recio MC, Villar A. Screening methods for natural products with antimicrobial activity: a review of the literature. J Ethnopharmacol. 1988;23(2–3):127–49.

    Article  PubMed  CAS  Google Scholar 

  22. He ZX, Wang ZH, Zhang HH, Pan X, Su WR, Liang D, et al. Doxycycline and hydroxypropyl-β-cyclodextrin complex in poloxamer thermal sensitive hydrogel for ophthalmic delivery. Acta Pharmacol Sin B. 2011;1(4):254–60.

    Article  CAS  Google Scholar 

  23. Gibaud S, Ben ZS, Mutzenhardt P, Fries I, Astier A. Melarsoprol-cyclodextrins inclusion complexes. Int J Pharm. 2005;306(1–2):107–21.

    Article  PubMed  CAS  Google Scholar 

  24. Zhao M, Wang H, Yang B, Tao H. Identification of cyclodextrin inclusion complex of chlorogenic acid and its antimicrobial activity. Food Chem. 2010;120(4):1138–42.

    Article  CAS  Google Scholar 

  25. Yang B, Lin J, Chen Y, Liu Y. Artemether/hydroxypropyl-beta-cyclodextrin host-guest system: characterization, phase-solubility and inclusion mode. Bioorg Med Chem. 2009;17(17):6311–7.

    Article  PubMed  CAS  Google Scholar 

  26. Torri G, Bertini S, Giavana T, Guerrini M, Puppini N, Zoppetti G. Inclusion complex characterization between progesterone and hydroxypropyl-beta-cyclodextrin in aqueous solution by NMR study. J Incl Phenom Macrocycl Chem. 2007;57(1–4):317–21.

    Article  CAS  Google Scholar 

  27. Jullian C, Cifuentes C, Alfaro M, Miranda S, Barriga G, Olea-Azar C. Spectroscopic characterization of the inclusion complexes of luteolin with native and derivatized beta-cyclodextrin. Bioorg Med Chem. 2010;18(14):5025–31.

    Article  PubMed  CAS  Google Scholar 

  28. Li JS, Xiao HN, Li JH, Zhong YP. Drug carrier systems based on water-soluble cationic beta-cyclodextrin polymers. Int J Pharm. 2004;278(2):329–42.

    Article  PubMed  CAS  Google Scholar 

  29. Rojas-Aguirre Y, Yepez-Mulia L, Castillo I, Lopez-Vallejo F, Soria-Arteche O, Hernandez-Campos A, et al. Studies on 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole/2-hydroxypropyl-beta-cyclodextrin association: characterization, molecular modeling studies, and in vivo anthelminthic activity. Bioorg Med Chem. 2011;19(2):789–97.

    Article  PubMed  CAS  Google Scholar 

  30. Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, et al. Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res. 2000;33(12):889–97.

    Article  PubMed  CAS  Google Scholar 

  31. Jullian C, Orosteguis T, Perez-Cruz F, Sanchez P, Mendizabal F, Olea-Azar C. Complexation of morin with three kinds of cyclodextrin. A thermodynamic and reactivity study. Spectrochim Acta A Mol Biomol Spectrosc. 2008;71(1):269–75.

    Article  PubMed  Google Scholar 

  32. Szejtli J. Introduction and general overview of cyclodextrin chemistry. Chem Rev. 1998;98(5):1743–54.

    Article  PubMed  CAS  Google Scholar 

  33. Skulason S, Ingolfsson E, Kristmundsdottir T. Development of a simple HPLC method for separation of doxycycline and its degradation products. J Pharm Biomed Anal. 2003;33(4):667–72.

    Article  PubMed  CAS  Google Scholar 

  34. Newman EC, Frank CW. Circular dichroism spectra of tetracycline complexes with Mg+2 and Ca+2. J Pharm Sci. 1976;65(12):1728–32.

    Article  PubMed  CAS  Google Scholar 

  35. Lambs L, Venturim M, Révérend BDL, Kozlowski H, Berthon G. Metal ion-tetracycline interactions in biological fluids: part 8. Potentiometric and spectroscopic studies on the formation of Ca (II) and Mg (II) complexes with 4-dedimethylamino-tetracycline and 6-desoxy-6-dem. J Inorg Biochem. 1988;33(3):193–209.

    Article  PubMed  CAS  Google Scholar 

  36. Silva PP, Guerra W, Silveira JN, Ferreira AMC, Bortolotto T, Fischer FL, et al. Two new ternary complexes of copper(II) with tetracycline or doxycycline and 1,10-phenanthroline and their potential as antitumoral: cytotoxicity and DNA cleavage. Inorg Chem. 2011;50(14):6414–24.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People’s Republic of China

    Haohao Zhang, Zixin He, Zhouhua Wang, Meimei Zhang, Zhouyang He & Chuanbin Wu

  2. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, People’s Republic of China

    Meiwan Chen

  3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, People’s Republic of China

    Qian Wan & Dan Liang

  4. Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, Oxford, Mississippi, 38677, USA

    Michael A. Repka

Authors
  1. Haohao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meiwan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zixin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhouhua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meimei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhouyang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qian Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dan Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael A. Repka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chuanbin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chuanbin Wu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, H., Chen, M., He, Z. et al. Molecular Modeling-Based Inclusion Mechanism and Stability Studies of Doxycycline and Hydroxypropyl-β-Cyclodextrin Complex for Ophthalmic Delivery. AAPS PharmSciTech 14, 10–18 (2013). https://doi.org/10.1208/s12249-012-9877-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-012-9877-1

KEY WORDS

Search

Navigation