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Potential Use of Cyclodextrin Complexes for Enhanced Stability, Anti-inflammatory Efficacy, and Ocular Bioavailability of Loteprednol Etabonate

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Abstract

Loteprednol etabonate (LE) is a soft corticosteroid that maintains therapeutic activity with much reduced adverse effects. Yet, its ocular bioavailability is hindered by its poor aqueous solubility. Early attempts of LE complexation with cyclodextrins (CDs) did not involve the study of the effects of various complexation methods on the characteristics of the complexes formed. Formulation of complexes into different delivery systems as well in vitro and in vivo assessments has not been accomplished in the earlier studies. In this study, complexation of LE with each of hydroxypropyl-β-cyclodextrin (HP-β-CD) and β-cyclodextrin (β-CD) by kneading, freeze drying, and co-precipitation was attempted. These complexes were incorporated into gels, drops, and ocuserts using hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), and sodium alginate (ALG). These formulae were examined with respect to drug content, pH, viscosity, in vitro release, and stability for 6 months. Kinetic analysis of release data was done. Selected formulations were assessed for their efficacy in the treatment of ocular allergic conjunctivitis and their ocular bioavailability in rabbits’ eyes. All formulations exhibited accepted drug content, pH, and viscosity. The drug release was increased by complexation particularly with HP-β-CD in the order of ocuserts ≥ drops > gels, being the highest for HPMC preparations that also exhibited the greatest stability and anti-inflammatory activity especially in case of LE-HP-β-CD complexes. Ocuserts of co-precipitated LE-HP-β-CD using HPMC (5% w/w) and Carbopol 934P (0.1% w/w) provided a significantly enhanced stability (p < 0.05), ocular anti-inflammatory efficacy (p < 0.05), and ocular bioavailability (p < 0.0001), to be represented as a potential ocular delivery system of LE.

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References

  1. Bodor N, Buchwald P. Ophthalmic drug design based on the metabolic activity of the eye: soft drugs and chemical delivery systems. AAPS J. 2005;7:820–33.

    Article  Google Scholar 

  2. Bodor NS. Soft steroids having anti-inflammatory activity. US patent No. 4996335 A, 1991.

  3. Bartels SP. Use of loteprednol etabonate for the treatment of dry eye. European patent No. EP 2 127 655 A1, 2009.

  4. Chowdhury P, Borah JM, Goswami P, Das AM. A convenient synthesis of the side chain of loteprednol etabonate—an ocular soft corticosteroid from 20-oxopregnanes using metal-mediated halogenation as a key reaction. Steroids. 2011;76:497–501.

    Article  CAS  PubMed  Google Scholar 

  5. Howes JF. Loteprednol etabonate: a review of ophthalmic clinical studies. Pharmazie. 2000;55:178–83.

    CAS  PubMed  Google Scholar 

  6. Shirasaki Y, Inada K, Inoue J, Nakamura M. Isolation and structure elucidation of the major photodegradation products of loteprednol etabonate. Steroids. 2004;69:23–34.

    Article  CAS  PubMed  Google Scholar 

  7. Ilyas H, Slonim CB, Braswell GR, Favetta JR, Schulman M. Long-term safety of loteprednol etabonate 0.2% in the treatment of seasonal and perennial allergic conjunctivitis. Eye Contact Lens. 2004;30:10–3.

    Article  PubMed  Google Scholar 

  8. Pflugfelder SC, Maskin SL, Anderson B, Chodosh J, Holland EJ, De Paiva CS, et al. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J Ophthalmol. 2004;138:444–57.

    Article  CAS  PubMed  Google Scholar 

  9. Dubey R. Pure drug nanosuspension: impact of nanotechnology on drug discovery and development. Drug Deliv Technol. 2006;6:65–71.

    CAS  Google Scholar 

  10. Druzgala P, Hochhaus G, Bodor N. Soft drugs—10. Blanching activity and receptor binding affinity of a new type of glucocorticoid. Loteprednol etabonate. J Steroid Biochem Mol Biol. 1991;38:149–54.

    Article  CAS  PubMed  Google Scholar 

  11. Bodor N, Drustrup J, Wu W. Effect of cyclodextrins on the solubility and stability of a novel soft corticosteroid, loteprednol etabonate. Pharmazie. 2000;55:206–9.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Rajewski RA, Stella VJ. Pharmaceutical applications of cyclodextrins, 2. In-vivo drug delivery. J Pharm Sci. 1996;85:1017–25.

    Article  Google Scholar 

  14. Loftsson T, Brewster ME, Masson M. Role of cyclodextrins in improving oral drug delivery. Am J Drug Deliv. 2004;2:261–75.

    Article  CAS  Google Scholar 

  15. Loftsson T, Jarvinen T. Cyclodextrins in ophthalmic drug delivery. Adv Drug Deliv Rev. 1999;36:59–79.

    Article  Google Scholar 

  16. Loftsson T, Masson M. Cyclodextrins in topical drug formulations: theory and practice. Int J Pharm. 2001;225:15–30.

    Article  CAS  PubMed  Google Scholar 

  17. Loftsson T, Stefánsson E. Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye. Acta Ophthalmol Scand. 2002;80:144–50.

    Article  CAS  PubMed  Google Scholar 

  18. Lang JC, Stiemke MM. Biological barriers to ocular delivery. In: Reddy IK, editor. Ocular therapeutics and drug delivery. A multidisciplinary approach. Lancaster: Technomic; 1996. p. 51–132.

    Google Scholar 

  19. European Medicine Agency. Background review for cyclodextrins used as excipients. EMA/CHMP/333892/2013.

  20. Washington N, Washington C, Wilson CG. Ocular drug delivery. In: Physiological pharmaceutics. USA: Taylor and Francis Inc; 2001. p. 249–270.

  21. Kaur IP, Singh M, Kanwar M. Formulation and evaluation of ophthalmic preparations of acetazolamide. Int J Pharm. 2000;199:119–27.

    Article  CAS  PubMed  Google Scholar 

  22. Reddy IK, Khan MA, Wu WM, Bodor NS. Permeability of a soft steroid, loteprednol etabonate, through an excised rabbit cornea. J Ocul Pharmacol Ther. 1996;12:159–67.

    Article  CAS  PubMed  Google Scholar 

  23. Doile MM, Fortunato KA, Schmücker IC, Schucko SK, Silva MA, Rodrigues PO. Physicochemical properties and dissolution studies of dexamethasone acetate-β-cyclodextrin inclusion complexes produced by different methods. AAPS PharmSciTech. 2008;9:314–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ribeiro A, Figueiras A, Santos D, Veiga F. Preparation and solid-state characterization of inclusion complexes formed between miconazole and methyl-β-cyclodextrin. AAPS PharmSciTech. 2008;9:1102–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jansen T, Xhonneux B, Mesens J, Borgers M. Beta-cyclodextrins as vehicles in eye-drop formulation: an evaluation of their effects on rabbit corneal epithelium. Lens Eye Toxic Res. 1990;7:459–68.

    CAS  PubMed  Google Scholar 

  26. Kanai A, Alba RM, Takano T, Kobayashi C, Nakajima A, Kurihara K, et al. The effect on the cornea of alpha cyclodextrin vehicle for cyclosporine eye drops. Transplant Proc. 1989;21:3150–2.

    CAS  PubMed  Google Scholar 

  27. Loftsson E, Stefansson E. Effect of cyclodextrin on topical drug delivery to the eye. Drug Dev Ind Pharm. 1997;23:473–81.

    Article  CAS  Google Scholar 

  28. Javitt JC, Javitt NB, McDonnell P. Topical compositions for the eye comprising a beta-cyclodextrin derivative and a carbonic anhydrase inhibitor, International patent application No. WO 94/15582, 1994.

  29. Loftsson T, Stefansson E, Kristinsson JK, Fridriksdottir H, Sverrisson T, Gudmundsdottir G, et al. Topically effective acetazolamide eye-drop solution in man. Pharm Sci. 1996;6:277–9.

    Google Scholar 

  30. Saarinen-Savolainen P, Järvinen T, Araki-Sasaki K, Watanabe H, Urtti A. Evaluation of cytotoxicity of various drugs, eye drop excipients and cyclodextrins in immortalized human corneal epithelial cell line. Pharm Res. 1998;15:1275–80.

    Article  CAS  PubMed  Google Scholar 

  31. Higuchi T, Connors KA. Phase solubility techniques. Adv Anal Chem Instrum. 1965;4:117–22.

    CAS  Google Scholar 

  32. Loftsson T, Hreinsdottir D, Masson M. Evaluation of cyclodextrin solubilization of drugs. Int J Pharm. 2005;302:18–28.

    Article  CAS  PubMed  Google Scholar 

  33. Missel PJ, Lang JC, Rodeheaver DP, Jani R, Chowhan MA, Chastain J, et al. Design and evaluation of ophthalmic pharmaceutical products. In: Florence AT, Siepmann J, editors. Modern pharmaceutics. New York: Informa Healthcare; 2009. p. 101–89.

    Google Scholar 

  34. Gilhotra RM, Gilhotra N, Mishra DN. Piroxicam bioadhesive ocular inserts: physicochemical characterization and evaluation in prostaglandin-induced inflammation. Curr Eye Res. 2009;34:1065–73.

    Article  CAS  PubMed  Google Scholar 

  35. Gilhotra RM, Nagpal K, Mishra DN. Azithromycin novel drug delivery system for ocular application. Int J Pharm Investig. 2011;1:22–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Davies NM, Farr SJ, Hadgraft J, Kellaway IW. Evaluation of mucoadhesive polymers in ocular drug delivery, I. Viscous solutions. Pharm Res. 1991;8:1039–43.

    Article  CAS  PubMed  Google Scholar 

  37. Habib FS, Attia MA, El-Shanawany SM. In-vitro study of physostigmine salicylate and pilocarpine hydrochloride release from different gel formulations. Pharmazie. 1986;41:124–5.

    CAS  PubMed  Google Scholar 

  38. Levy MY, Benita S. Drug release from submicronized o/w emulsion: new in-vitro kinetic evaluation model. Int J Pharm. 1990;66:29–37.

    Article  CAS  Google Scholar 

  39. Loftsson T, Masson M, Sigurdsson HH. Cyclodextrins and drug permeability through semipermeable cellophane membranes. Int J Pharm. 2002;232:35–43.

    Article  CAS  PubMed  Google Scholar 

  40. Moya-Ortega MD, Alves TF, Alvarez-Lorenzo C, Concheiro A, Stefánsson E, Thorsteinsdóttir M, et al. Dexamethazone eye drops containing γ-cyclodextrin-based nanogels. Int J Pharm. 2013;441:507–15.

    Article  CAS  PubMed  Google Scholar 

  41. Martin A, Bustamante P, Chun AHC. Kinetics. In: Physical pharmacy. Philadelphia: Lea and Febiger; 1993. p. 284–323.

  42. Higuchi T. Mechanism of sustained action medication. J Pharm Sci. 1963;52:1145–9.

    Article  CAS  PubMed  Google Scholar 

  43. Ritger PL, Peppas NA. Simple equation for description of solute release: part 1, Fickian and non-Fickian release from nonswellable devices in the form of slab, spheres, cylinders or disk. J Control Release. 1987;5:23–36.

    Article  CAS  Google Scholar 

  44. Winston PW, Bates DH. Saturated solutions for the control of humidity in biological research. Ecology. 1960;41:232–7.

    Article  Google Scholar 

  45. Garrett ER, Carper RF. Prediction of stability in pharmaceutical preparations I. Color stability in a liquid multisulfa preparation. J Am Pharm Assoc. 1955;44:515–8.

    Article  CAS  Google Scholar 

  46. Anderson G, Scott M. Determination of product shelf life and activation energy for five drugs of abuse. Clin Chem. 1991;37:398–402.

    CAS  PubMed  Google Scholar 

  47. Lund W. Ophthalmic products. In: The pharmaceutical codex. London: The Pharmaceutical Press; 1994. p. 160–169.

  48. Saxena V, Singh A. Development and validation of HPLC method for the simultaneous estimation of loteprednol and gatifloxacin. IJSR. 2013;2:252–5.

    Google Scholar 

  49. Cheruvu NP, Amrite AC, Kompella UB. Effect of eye pigmentation on transscleral drug delivery. Invest Ophthalmol Vis Sci. 2008;49:333–41.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Yoshida A, Yamamoto M, Irie T, Hirayama F, Uekama K. Some pharmaceutical properties of 3-hydroxypropyl- and 2,3-dihydroxypropyl-beta-cyclodextrins and their solubilizing and stabilizing abilities. Chem Pharm Bull. 1989;37:1059–63.

    Article  CAS  PubMed  Google Scholar 

  51. Granero GE, Maitre MM, Garnero C, Longhi MR. Synthesis, characterization and in vitro release studies of a new acetazolamide-HP-F-CD-TEA inclusion complex. Eur J Med Chem. 2008;43:464–70.

    Article  CAS  PubMed  Google Scholar 

  52. Su J, Chen J, Li L, Li B, Shi L, Zhang H, et al. Preparation of natural borneol/2-hydroxypropyl-β-cyclodextrin inclusion complex and its effect on the absorption of tetramethylpyrazine phosphate in mouse. Chem Pharm Bull. 2012;60:736–42.

    Article  CAS  PubMed  Google Scholar 

  53. Cui L, Zhang ZH, Sun E, Jia XB. Effect of β-cyclodextrin complexation on solubility and enzymatic conversion of naringin. Int J Mol Sci. 2012;13:14251–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. B. P. British pharmacopeia, Vol. III, 6th Ed. London: The Council of Europe, The Stationary Office; 2010. p. 3155–3157.

  55. Amselem SR, Friedman D, Yosef C. Suspension of loteprednol etabonate for ear, eye, or nose treatment. US Patent # 5747061. 1998.

  56. Bilensoy E, Rouf MA, Vural I, Sen M, Hincal AA. Mucoadhesive, thermosensitive, prolonged-release vaginal gel for clotrimazole: β-cyclodextrin complex. AAPS PharmSciTech. 2006;7:38–44.

    Article  Google Scholar 

  57. Abdelkader H, Abdallah OY, Salem HS. Comparison of the effect of tromethamine and polyvinylpyrrolidone on dissolution properties and analgesic effect of nimesulide. AAPS PharmSciTech. 2007;8:1–8.

    Article  Google Scholar 

  58. Mohamed EA, Meshali MM, Foda AM, Borg TM. Improvement of dissolution and hypoglycemic efficacy of glimepiride by different carriers. AAPS PharmSciTech. 2012;13:1013–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Oh A, Jin DH, Yun J, Lee YS, Kim H. Effect of pH-dependent solubility on release behavior of alginate-chitosan blend containing activated carbon. Carbon Lett. 2009;10:208–12.

    Article  Google Scholar 

  60. Durrani MJ, Andrews A, Whitaker R, Benner SC. Studies on drug release kinetics from carbomer matrices. Drug Dev Ind Pharm. 1994;20:2439–47.

    Article  CAS  Google Scholar 

  61. Zhou M, Donovan MD. Intranasal mucociliary clearance of putative bioadhesive polymer gels. Int J Pharm. 1996;135:115–25.

    Article  CAS  Google Scholar 

  62. Budai L, Hajdu M, Budai M, Grof P, Beni S, Noszal B, et al. Gels and liposomes in optimized ocular drug delivery: studies on ciprofloxacin formulations. Int J Pharm. 2007;343:34–40.

    Article  CAS  PubMed  Google Scholar 

  63. Aburahma MH, Mahmoud AA. Biodegradable ocular inserts for sustained delivery of brimonidine tartarate: preparation and in vitro/in vivo evaluation. AAPS PharmSciTech. 2011;12:1335–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Osama Abd El-Aazeem Soliman, Elham Abdel Monem Mohamed, Marwa Salah El-Dahan & Nabil Abdullah Ali Khatera

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  1. Osama Abd El-Aazeem Soliman
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  2. Elham Abdel Monem Mohamed
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Correspondence to Elham Abdel Monem Mohamed.

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Soliman, O.A.EA., Mohamed, E.A.M., El-Dahan, M.S. et al. Potential Use of Cyclodextrin Complexes for Enhanced Stability, Anti-inflammatory Efficacy, and Ocular Bioavailability of Loteprednol Etabonate. AAPS PharmSciTech 18, 1228–1241 (2017). https://doi.org/10.1208/s12249-016-0589-9

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