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Positively Charged Polymeric Nanoparticle Reservoirs of Terbinafine Hydrochloride: Preclinical Implications for Controlled Drug Delivery in the Aqueous Humor of Rabbits

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Abstract

Frequent instillation of terbinafine hydrochloride (T HCl) eye drops (0.25%, w/v) is necessary to maintain effective aqueous humor concentrations for treatment of fungal keratitis. The current approach aimed at developing potential positively charged controlled-release polymeric nanoparticles (NPs) of T HCl. The estimation of the drug pharmacokinetics in the aqueous humor following ocular instillation of the best-achieved NPs in rabbits was another goal. Eighteen drug-loaded (0.50%, w/v) formulae were fabricated by the nanopreciptation method using Eudragit® RS100 and chitosan (0.25%, 0.5%, and 1%, w/v). Soybean lecithin (1%, w/v) and Pluronic® F68 (0.5%, 1%, and 1.5%, w/v) were incorporated in the alcoholic and aqueous phases, respectively. The NPs were evaluated for particle size, zeta potential, entrapment efficiency percentage (EE%), morphological examination, drug release in simulated tear fluid (pH 7.4), Fourier-transform IR (FT-IR), X-ray diffraction (XRD), physical stability (2 months, 4°C and 25°C), and drug pharmacokinetics in the rabbit aqueous humor relative to an oily drug solution. Spherical, discrete NPs were successfully developed with mean particle size and zeta potential ranging from 73.29 to 320.15 nm and +20.51 to +40.32 mV, respectively. Higher EE% were achieved with Eudragit® RS100-based NPs. The duration of drug release was extended to more than 8 h. FT-IR and XRD revealed compatibility between inactive formulation ingredients and T HCl and permanence of the latter’s crystallinity, respectively. The NPs were physically stable, for at least 2 months, when refrigerated. F5-NP suspension significantly (P < 0.05) increased drug mean residence time and improved its ocular bioavailability; 1.657-fold.

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References

  1. Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. World Health Organization. 2001;79:214–21.

    CAS  Google Scholar 

  2. Bhatta RS, Chandasana H, Chhonker YS, Rathi C, Kumar D, Mitra K, et al. Mucoadhesive nanoparticles for prolonged ocular delivery of natamycin: In vitro and pharmacokinetics studies. Int J Pharm. 2012;432:105–12.

    Article  CAS  PubMed  Google Scholar 

  3. Tuli SS. Fungal keratitis. Clin Ophthalmol. 2011;5:275–79.

    Article  PubMed  Google Scholar 

  4. Shukla PK, Kumar M, Keshava GB. Mycotic keratitis: an overview of diagnosis and therapy. Mycoses. 2008;51:183–99.

    Article  CAS  PubMed  Google Scholar 

  5. Sweetman CS. Martindale: the complete drug reference. 37th ed. London: Pharmaceutical Press; 2011.

    Google Scholar 

  6. Xuguang S, Zhixin W, Zhiqun W, Shiyun L, Ran L. Ocular fungal isolates and antifungal susceptibility in Northern China. Am J Ophthalmol. 2007;143:131–33.

    Article  PubMed  Google Scholar 

  7. Liang QF, Jin XY, Wang XL, Sun XG. Effect of topical application of terbinafine on fungal keratitis. Chin Med J. 2009;122(16):1884–88.

    PubMed  Google Scholar 

  8. Sun XG, Wang ZX, Wang ZQ, Deng SJ, Li R, Luo SY, et al. Pharmacokinetics of terbinafine in the rabbit ocular tissues after topical administration. Ophthalmic Res. 2007;39:81–3.

    Article  CAS  PubMed  Google Scholar 

  9. Pignatello R, Ricupero N, Bucolo C, Maugeri F, Maltese A, Puglisi G. Preparation and characterization of Eudragit retard nanosuspensions for the ocular delivery of cloricromene. AAPS PharmSciTech. 2006;7(1):E27.

    Article  PubMed  Google Scholar 

  10. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular Drug Delivery. AAPS J. 2010;12(3):348–60.

    Article  CAS  PubMed  Google Scholar 

  11. Motwani SK, Chopra S, Talegaonkar S, Kohli K, Ahmad FJ, Khar RK. Chitosan–sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: formulation, optimization and in vitro characterization. Eur J Pharm Biopharm. 2008;68:513–25.

    CAS  PubMed  Google Scholar 

  12. Hirano S, Seino H, Akiyama I, Nonaka I. Chitosan: a biocompatible material for oral and intravenous administration. In: Gebelein CG, Dunn RL, editors. Progress in biomedical polymers. New York: Plenum Press; 1990. p. 283–89.

    Google Scholar 

  13. Artursson P, Lindmark T, Davis SS, Illum L. Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm Res. 1994;11:1358–61.

    Article  CAS  PubMed  Google Scholar 

  14. De Campos AM, Sanchez A, Alonso MJ. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A. Int J Pharm. 2001;224:159–68.

    Article  PubMed  Google Scholar 

  15. De la Fuente M, Raviña M, Paolicelli P, Sanchez A, Seijo B, Alonso MJ. Chitosan-based nanostructures: a delivery platform for ocular therapeutics. Adv Drug Del Rev. 2010;62:100–17.

    Article  Google Scholar 

  16. Rowe RC, Sheskey PJ, Owen SC. Handbook of pharmaceutical excipients. 5th edn. Pharmaceutical Press and American Pharmacists Association; 2006. Electronic version.

  17. Mandal B, Alexander KS, Riga AT. Sulfacetamide loaded Eudragit® RL100 nanosuspension with potential for ocular delivery. J Pharm Pharmaceut Sci. 2010;13(4):510–23.

    CAS  Google Scholar 

  18. Bhagav P, Upadhyay H, Chandran S. Brimonidine tartrate-Eudragit long-acting nanoparticles: formulation, optimization, in vitro and in vivo evaluation. AAPS PharmSciTech. 2011;12(4):1087–101.

    Article  CAS  PubMed  Google Scholar 

  19. Ibrahim HK, El-Leithy IS, Makky AA. Mucoadhesive nanoparticles as carrier systems for prolonged ocular delivery of gatifloxacin/prednisolone bitherapy. Mol Pharm. 2010;7(2):576–85.

    Article  CAS  PubMed  Google Scholar 

  20. Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm. 1989;55(1):r1–4.

    Article  CAS  Google Scholar 

  21. El-Shabouri MH. Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Int J Pharm. 2002;249:101–08.

    Article  CAS  PubMed  Google Scholar 

  22. Shegokar R, Singh KK, Müller RH. Production & stability of stavudine solid lipid nanoparticles-From lab to industrial scale. Ibid. 2011;416:461–70.

    CAS  Google Scholar 

  23. Roland JC, Lembi CA, Morré DJ. Phosphotungstic acid-chromic acid as a selective electron-dense stain for plasma membranes of plant cells. Stain Technol. 1972;47(4):195–200.

    CAS  PubMed  Google Scholar 

  24. Rozier A, Mazuel C, Grove J, Plazonnet B. A novel ion-activated, in-situ gelling polymer for ophthalmic vehicles. Effect on bioavailability of timolol. Int. J. Pharm. 1989;57:163–68.

    Article  CAS  Google Scholar 

  25. Miyazaki S, Suzuki S, Kawasaki N, Endo K, Takahashi A, Attwood D. In situ gelling xyloglucan formulations for sustained release ocular delivery of pilocarpine hydrochloride. Int J Pharm. 2001;229(1–2):29–36.

    Article  CAS  PubMed  Google Scholar 

  26. Abd-Elbary A, El-laithy HM, Tadros MI. Sucrose stearate-based proniosome-derived niosomes for the nebulisable delivery of cromolyn sodium. Ibid. 2008;357:189–98.

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Piao H, Ouyang M, Xia D, Quan P, Xiao W, Song Y, et al. In vitro–in vivo study of CoQ10-loaded lipid nanoparticles in comparison with nanocrystals. Int J Pharm. 2011;419(1–2):255–9.

    Article  CAS  PubMed  Google Scholar 

  29. Denouël J, Keller HP, Schaub P, Delaborde C, Humbert H. Determination of terbinafine and its desmethyl metabolite in human plasma by high-performance liquid chromatography. J Chromatography B. 1995;663:353–9.

    Article  Google Scholar 

  30. El-Laithy HM, Nesseem DI, El-Adly AA, Shoukry M. Moxifloxacin–Gelrite in situ ophthalmic gelling system against photodynamic therapy for treatment of bacterial corneal inflammation. Arch. Pharm. Res. 2011;34(10):1663–78.

    Article  CAS  PubMed  Google Scholar 

  31. Asasutjarita R, Thanasanchokpibull S, Fuongfuchat A, Veeranondha S. Optimization and evaluation of thermoresponsive diclofenac sodium ophthalmic in situ gels. Int. J. Pharm. 2011;411:128–35.

    Article  Google Scholar 

  32. Bonferoni MC, Chetoni P, Giunchedi P, Rossi S, Ferrari F, Burgalassi S, et al. Carrageenan–gelatin mucoadhesive systems for ion-exchange based ophthalmic delivery: in vitro and preliminary in vivo studies. Eur. J Pharm. Biopharm 2004;57:465–72.

    Article  CAS  PubMed  Google Scholar 

  33. Hornig S, Heinze T, Becer CR, Schubert US. Synthetic polymeric nanoparticles by nanoprecipitation. J Mater Chem. 2009;19:3838–40.

    Article  CAS  Google Scholar 

  34. Zimmer A, Kreuter J. Microspheres and nanoparticles used in ocular delivery systems. Adv Drug Del Rev. 1995;16(1):61–73.

    Article  CAS  Google Scholar 

  35. Ghorab DM, Amin MM, Khowessah OM, Tadros MI. Colon-targeted celecoxib-loaded Eudragit® S100-coated poly-ε-caprolactone microparticles: preparation, characterization and in vivo evaluation in rats. Drug Del. 2011;18(7):523–35.

    Article  CAS  Google Scholar 

  36. Castellanos IJ, Carrasquillo KG, de Jesus LJ, Alvarez M, Griebenow K. Encapsulation of bovine serum albumin in poly(lactide-co-glycolide) microspheres by the solid-in-oil-in-water technique. J Pharm Pharmacol. 2001;53:167–78.

    Article  CAS  PubMed  Google Scholar 

  37. Das S, Suresh PK. Nanosuspension: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to amphotericin B. Nanomedicine. 2011;7(2):242–7.

    Article  CAS  PubMed  Google Scholar 

  38. Rodriguez M, Vila-Jato JL, Torres D. Design of new multiparticulate system for potential site specific and controlled drug delivery to the colonic region. J Control Rel. 1998;55:67–77.

    Article  CAS  Google Scholar 

  39. Krishnamachari Y, Madan P, Lin S. Development of pH- and time dependent oral microparticles to optimize budesonide delivery to ileum and colon. Int J Pharm. 2007;348:238–47.

    Article  Google Scholar 

  40. Atef E, Belmonte AA. Formulation and in vitro and in vivo characterization of a phenytoin self-emulsifying drug delivery system (SEDDS). Eur J Pharm Sci. 2008;35(4):257–63.

    Article  CAS  PubMed  Google Scholar 

  41. Pignatello R, Bucolo C, Spedalieri G, Maltese A, Puglisi G. Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials. 2002;23(15):3247–55.

    Article  CAS  PubMed  Google Scholar 

  42. Kumar N, Jain AK, Singh C, Kumar R. Development, characterization and solubility study of solid dispersion of terbinafine hydrochloride by solvent evaporation method. Asian J Pharm. 2008;2:154–8.

    Article  Google Scholar 

  43. Foda NH, El-laithy HM, Tadros MI. Implantable biodegradable sponges: effect of interpolymer complex formation of chitosan with gelatin on the release behavior of tramadol hydrochloride. Drug Dev Ind Pharm. 2007 Jan;33(1):7–17.

  44. Boyer RF. Transitions and relaxations in amorphous and semicrystalline organic polymers and copolymers. In: Mark HF, editor. Encyclopedia of polymer science and technology; vol II. New York: Wiley; 1977. p. 745–839.

    Google Scholar 

  45. Miller MH, Madu A, Samathanam G, Rush D, Madu CN, Mathisson K, et al. Fleroxacin pharmacokinetics in aqueous and vitreous humors determined by using complete concentration-time data from individual rabbits. Antimicrob Agents Chemother. 1992;36(1):32–8.

    Article  CAS  PubMed  Google Scholar 

  46. Mayers M, Rush D, Madu A, Motyl M, Miller MH. Pharmacokinetics of amikacin and chloramphenicol in the aqueous humor of rabbits. Antimicrob Agents Chemother. 1991;35(9):1791–8.

    Article  CAS  PubMed  Google Scholar 

  47. Giannavola C, Bucolo C, Maltese A, Paolino D, Vandelli MA, Puglisi G, et al. Influence of preparation conditions on acyclovir-loaded poly-d,l-lactic acid nanospheres and effect of PEG coating on ocular drug bioavailability. Pharm Res. 2003;20:584–90.

    Article  CAS  PubMed  Google Scholar 

  48. Mannermaa E, Vellonen KS, Urtti A. Drug transport in corneal epithelium and blood–retina barrier: emerging role of transporters in ocular pharmacokinetics. Adv Drug Deliv Rev. 2006;58:1136–63.

    Article  CAS  PubMed  Google Scholar 

  49. Jarvinen K, Jarvinen T, Urtti A. Ocular absorption following topical delivery. Adv Drug Deliv Rev. 1995;16:3–19.

    Article  Google Scholar 

  50. Klang S, Abdulrazik M, Benita S. Influence of emulsion droplet surface charges on indomethacin ocular tissue distribution. Pharm Dev Technol. 2000;5:521–32.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini, 11562, Cairo, Egypt

    Saadia Ahmed Tayel, Mohamed Ahmed El-Nabarawi, Mina Ibrahim Tadros & Wessam Hamdy Abd-Elsalam

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  1. Saadia Ahmed Tayel
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  2. Mohamed Ahmed El-Nabarawi
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  3. Mina Ibrahim Tadros
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  4. Wessam Hamdy Abd-Elsalam
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Correspondence to Mina Ibrahim Tadros.

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Tayel, S.A., El-Nabarawi, M.A., Tadros, M.I. et al. Positively Charged Polymeric Nanoparticle Reservoirs of Terbinafine Hydrochloride: Preclinical Implications for Controlled Drug Delivery in the Aqueous Humor of Rabbits. AAPS PharmSciTech 14, 782–793 (2013). https://doi.org/10.1208/s12249-013-9964-y

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