Ultrasound-enhanced ocular delivery of dexamethasone sodium phosphate: an in vivo study

Journal of Therapeutic Ultrasound

Vesna Zderic¹  Craig Geist²  Ji Liu²  Sankaranarayana Mahesh²  Shawn Chawla¹  Aditi Shenoy¹  Marjan Nabili¹ 

[1] Department of Electrical and Computer Engineering, George Washington University, Washington, DC 20052, USA;Department of Ophthalmology, George Washington University, Washington, DC 20052, USA

关键词: Dexamethasone sodium phosphate;    Sonophoresis;    Ocular diseases;    Cornea;    Drug delivery;    Therapeutic ultrasound;   

Others  :  804249
DOI  :  10.1186/2050-5736-2-6

 received in 2013-11-09, accepted in 2014-02-04,  发布年份 2014

【 摘 要 】

Background

The eye's unique anatomy and its physiological and anatomical barriers can limit effective drug delivery into the eye.

Methods

An in vivo study was designed to determine the effectiveness and safety of ultrasound application in enhancing drug delivery in a rabbit model. Permeability of a steroid ophthalmic drug, dexamethasone sodium phosphate, was investigated in ultrasound- and sham-treated cases. For this study, an eye cup filled with dexamethasone sodium phosphate was placed on the cornea. Ultrasound was applied at intensity of 0.8 W/cm² and frequency of 400 or 600 kHz for 5 min. The drug concentration in aqueous humor samples, collected 90 min after the treatment, was determined using chromatography methods. Light microscopy observations were done to determine the structural changes in the cornea as a result of ultrasound application.

Results

An increase in drug concentration in aqueous humor samples of 2.8 times (p < 0.05) with ultrasound application at 400 kHz and 2.4 times (p < 0.01) with ultrasound application at 600 kHz was observed as compared to sham-treated samples. Histological analysis showed that the structural changes in the corneas exposed to ultrasound predominantly consisted of minor epithelial disorganization.

Conclusions

Ultrasound application enhanced the delivery of an anti-inflammatory ocular drug, dexamethasone sodium phosphate, through the cornea in vivo. Ultrasound-enhanced ocular drug delivery appears to be a promising area of research with a potential future application in a clinical setting.

【 授权许可】

   
2014 Nabili et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Mundt GH, Hugues WE: Ultrasonics in ocular diagnosis. Am J Ophthalmol. 1956, 41:488-98.
• [2]Allemann N, Silverman RH, Reinstein DZ, Coleman DJ: High-frequency ultrasound imaging and spectral analysis in traumatic hyphema. Ophthalmology. 1993, 100:1351-7.
• [3]Aptel F, Lafon C: Therapeutic applications of ultrasound in ophthalmology. Int J Hyperthermia. 2012, 28:405-18. doi:10.3109/02656736.2012.665566
• [4]Sterk CC, vd Valk PH, van Hees CL, van Delft JL, van Best JA, Oosterhuis JA: The effect of therapeutic ultrasound on the average of multiple intraocular pressures throughout the day in therapy-resistant glaucoma. Graefes Arch Clin Exp Ophthalmol 1989, 227(1):36-8.
• [5]Silverman RH, Vogelsang B, Rondeau MJ, Coleman DJ: Therapeutic ultrasound for the treatment of glaucoma. Am J Ophthalmol 1991, 111(3):327-37.
• [6]Aptel F, Charrel T, Lafon C, Romano F, Chapelon JY, Blumen-Ohana E, Nordmann JP, Denis P: Miniaturized high-intensity focused ultrasound device in patients with glaucoma: a clinical pilot study. Invest Ophthalmol Vis Sci. 2011, 52:8747-53. doi:10.1167/iovs.11-8137
• [7]Sonoda S, Tachibana K, Uchino E, Okubo A, Yamamoto M, Sakoda K, Hisatomi T, Sonoda KH, Negishi Y, Izumi Y, Takao S, Sakamoto T: Gene transfer to corneal epithelium and keratocytes mediated by ultrasound with microbubbles. Invest Ophthalmol Vis Sci 2006, 47(2):558-64.
• [8]Park J, Zhang Y, Vykhodtseva N, Akula JD, McDannold NJ: Targeted and reversible blood-retinal barrier disruption via focused ultrasound and microbubbles. PloS One 2012, 1932-6203. doi:10.1371/journal.pone.0042754
• [9]Eljarrat-Binstock E, Pe’er J, Domb AJ: New techniques for drug delivery to the posterior eye segment. Pharm Res. 2010, 27:530-43. doi:10.1007/s11095-009-0042-9
• [10]Sasaki H, Igarashi Y, Nagano T, Nishida K, Nakamura J: Different effects of absorption promoters on corneal and conjunctival penetration of ophthalmic beta-blockers. Pharm Res 1995, 12(8):1146-50.
• [11]Achouri D, Alhanout K, Piccerelle P, Andrieu V: Recent advances in ocular drug delivery. Drug Dev Ind Pharm 2012, 1-19. doi:10.3109/03639045.2012.736515
• [12]Gaudana R, Ananthula HK, Parenky A, Mitra AK: Ocular drug delivery. AAPS J. 2010, 12:348-60. doi:10.1208/s12248-010-9183-3
• [13]Kompella UB, Kadam RS, Lee VH: Recent advances in ophthalmic drug delivery. Ther Deliv. 2010, 1:435-56. doi:10.4155/TDE.10.40
• [14]Ke TL, Clark AF, Gracy RW: Age-related permeability changes in rabbit corneas. J Ocul Pharmacol Ther. 1999, 15:513-23.
• [15]Robinson JR: Ocular anatomy and physiology relevant to ocular drug delivery. In Ophthalmic Drug Delivery Systems. Edited by Mitra AK. New York: Marcel Dekker; 1993:1929-57.
• [16]Hu X, Hao L, Wang H, Yang X, Zhang G, Wang G, Zhang X: Hydrogel contact lens for extended delivery of ophthalmic drugs. Int J Polymer Science 2011, 1-9. doi:10.1155/2011/814163
• [17]Mishra GP, Bagui M, Tamboli V, Mitra AK: Recent applications of liposomes in ophthalmic drug delivery. Journal of Drug Delivery 2011:1-14. doi:10.1155/2011/863734
• [18]Cohen AE, Assang C, Patane MA, From S, Korenfield M: Evaluation of dexamethasone phosphate delivered by ocular iontophoresis for treating noninfectious anterior uveitis. Ophthalmology. 2012, 119:66-73. doi:10.1016/j.ophtha.2011.07.006
• [19]Eljarrat-Binstock E, Raiskup F, Stepensky D, Domb AJ, Frucht-Pery J: Delivery of gentamicin to the rabbit eye by drug-loaded hydrogel iontophoresis. Invest Ophthalmol Vis Sci. 2004, 45:2543-8.
• [20]Lam TT, Fu J, Chu R, Stojack K, Siew E, Tso MOM: Intravitreal delivery of ganciclovir in rabbits by transscleral iontophoresis. J Ocul Pharmacol. 1994, 10:571-5.
• [21]Yasukawa T, Ogura Y, Kimura H, Sakurai E, Tabata Y: Drug delivery from ocular implants. Expert Opin Drug Deliv 2006, 3(2):261-3.
• [22]Du J, Shi QS, Sun Y, Lui PF, Zhu MJ, Du LF, Duan YR: Enhanced delivery of monomethoxypoly (ethylene glycol)-poly(lactic-co-glycolic acid)-poly l-lysine nanoparticles loading platelet-derived growth factor BB small interfering RNA by ultrasound and/or microbubbles to rat retinal pigment epithelium cells. J Gene Med 2011:312-323. doi:10.1002/jgm.1574
• [23]Hiscott P, Armstrong D, Batterbury M, Kaye S: Repair in avascular tissue: fibrosis in the transparent structures of the eye and thrombospondin 1. Histol Histopathol. 1999, 14:1309-20.
• [24]Zderic V, Clark JI, Vaezy S: Drug delivery into the eye with the use of ultrasound. J Ultrasound Med. 2004, 23:1349-59.
• [25]Nuritdinov VA: Phonophoresis and cavitation [in Russian]. Vestn Oftalmol 1981, 56-58.
• [26]Nabili M, Patel H, Mahesh SP, Liu J, Geist C, Zderic V: Ultrasound-enhanced delivery of antibiotics and anti-inflammatory drugs into the eye. Ultrasound Med Biol 2013, 39(4):638-46. doi:10.1016/j.ultrasmedbio.2012.11.010
• [27]Gwon A: The rabbit in cataract/IOL surgery. In Animal Models in Eye Research. Edited by Panagiotis A. San Diego: Elsevier; 2008:184-99.
• [28]Cheung ACY, Yu Y, Tay D, Wong HS, Ellis-Behnke R, Chau Y: Ultrasound enhanced intrascleral delivery of protein. Int J Pharm. 2010, 401:16-24. doi:10.1016/j.ijpharm.2010.09.001
• [29]Christensen DA: Ultrasonic Bioinstrumentation. 1st edition. Hoboken: Wiley; 1988.
• [30]Silverman RH, Lizzi FL, Ursea BG, Cozzarelli L, Ketterling JA, Deng CX, Folberg R, Coleman DJ: Safety levels for exposure of cornea and lens to very high-frequency ultrasound. J Ultrasound Med 2001, 20(9):979-986.
• [31]Polat BE, Hart D, Langer R, Blankschtein D: Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. J Control Release. 2011, 152:330-48. doi:10.1016/j.jconrel.2011.01.006
• [32]Mitragotri S, Edwards D, Blankschtein D, Langer R: A mechanistic study of ultrasound-enhanced transdermal drug delivery. J Pharm Sci. 1995, 84:697-706.
• [33]Paliwal S, Mitragotri S: Ultrasound-induced cavitation: applications in drug and gene delivery. Expert Opin Drug Deliv 2006, 3(6):713-26.
• [34]Ahmadi F, McLoughlin IV, Chauhan S, terHaar G: Bio-effects and safety of low-intensity, low-frequency ultrasonic exposure. Prog Biophys Mol Biol. 2012, 108:119-38.
• [35]Dijkmans PA, Juffermans LJ, Musters RJ, van Wamel A, ten Cate FJ, van Gilst W, Visser CA, de Jong N, Kamp O: Microbubbles and ultrasound: from diagnosis to therapy. Eur J Echocardiogr. 2004, 5:245-56.
• [36]Tang H, Wang CC, Blankschtein D, Langer R: An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport. Pharm Res 2002, 19(8):1160-9.
• [37]Miller DL: A review of the ultrasonic bioeffects of microsonation, gas-body activation, and related cavitation-like phenomena. Ultrasound Med Biol. 1987, 13:443-70.
• [38]Postema M, Gilja OH: Ultrasound-directed drug delivery. Curr Pharm Biotechnol 2007, 8(6):355-61.
• [39]Peach R, Gompf B: Microimplosions: cavitation collapse and shock wave emission on a nanosecond time scale. Phys Rev Lett 2000, 84(6):1328-30.
• [40]Martin RW, Hwang JH: Therapeutic potential and consideration of high intensity ultrasound in gastroenterology. In Basic and New Aspects of Gastrointestinal Ultrasonography, Advanced Series in Biomechanics. 2005 edition. Edited by Odegaard S, Gilja OH, Gregersen H. Singapore: World Scientific; 2005:211-42.
• [41]Saroha K, Sharma B, Yadav B: Sonophoresis: an advanced tool in transdermal drug delivery system. Int J Curr Pharm Res 2011, 3(3):89-97.
• [42]Nyborg WL: Physical Mechanisms for Biological Effects of Ultrasound. Department of Health, Education, and Welfare. Washington, DC: U.S. FDA; 1978:78-8062.
• [43]American Institute of Ultrasound in Medicine (AIUM) Report: Section 2—definition and description of non-thermal mechanisms. J Ultrasound Med 2000, 19:77-84.
• [44]National Council on Radiation Protection and Measurements (NCRP): Biological effects of ultrasound: mechanical and clinical implications. Recommendations of the National Council on Radiation Protection and Measurements, NCRP Report No.74. Bethesda; 1983:84-86.
• [45]Williams AR: Ultrasound: Biological Effects and Potential Hazards. London: Academic; 1983.
• [46]Tsivgoulis G, Alexandrov A: Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics 2007, 4(3):420-7.
• [47]Fischbarg J: The corneal endothelium. In The Biology of Eye. Edited by Fischbarg J. New York: Academic; 2006:113-25.
• [48]Zderic V, Clark JI, Martin RW, Vaezy S: Ultrasound-enhanced transcorneal drug delivery. Cornea. 2004, 23:804-11.
• [49]Doughty MJ: Evaluation of the effects of saline versus bicarbonate-containing mixed salts solutions on rabbit corneal epithelium in vitro. Ophthalmic Physiol Opt. 1995, 15:585-99.
• [50]Jester JV, Petroll WM, Garana RM, Lemp MA, Cavanagh HD: Comparison of in vivo and ex vivo cellular structure in rabbit eyes detected by tandem scanning microscopy. J Microsc 1992, 165(Pt 1):169-81.
• [51]Ensminger D, Stulen FB: Ultrasonic: Data, Equations, and their Practical Uses. Boca Raton: CRC: Taylor & Francis Group; 2008.
• [52]Green K, Downs SJ: Corneal membrane water permeability as a function of temperature. Invest Ophthalmol. 1976, 15:304-7.
• [53]Palte HD, Gayer S, Arrieta E, Scot Shaw E, Nose I, Lee E, Arheart KL, Dubovy S, Birnbach DJ, Parel JM: Are ultrasound-guided ophthalmic blocks injurious to the eye? A comparative rabbit model study of two ultrasound devices evaluating intraorbital thermal and structural changes. Anesth Analg 2012, 115(1):194-201. doi:10.1213/ANE.0b013e318253622e
• [54]Herman BL, Harris GR: Theoretical study of steady-state temperature rise within the eye due to ultrasound insonation. IEEE Trans Ultrason Ferroelectr Freq Control. 1999, 46:1566-74.
• [55]Food and Drug Administration (FDA): Guidance for Industry and FDA Staff Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers. Silver Spring: U.S. FDA; 2008.
• [56]Barnett SB: World Federation for Ultrasound in Medicine and Biology (WFUMB) Symposium on safety of ultrasound in medicine: conclusions and recommendations on thermal and non-thermal mechanisms for biological effects of ultrasound. Ultrasound Med Biol. 1998, 24:1-55.
• [57]Safety Group of the British Medical Ultrasound Society (BMUS): Guidelines for the safe use of diagnostic ultrasound equipment. Ultrasound 2010, 18:52-59.
• [58]Cucevic V, Brown AS, Foster FS: Thermal assessment of 40 MHz pulsed Doppler ultrasound in human eye. Ultrasound Med Biol. 2005, 31:565-73.
• [59]Kowalczuk L, Boudinet M, El Sanharawi M, Touchard E, Naud MC, Saïed A, Jeanny JC, Behar-Cohen F, Laugier P: In vivo gene transfer into the ocular ciliary muscle mediated by ultrasound and microbubbles. Ultrasound Med Biol. 2011, 37:1814-27. doi:10.1016/j.ultrasmedbio.2011.07.010
• [60]Guy AW, Lin JC, Kramar PO, Emery AF: Effect of 2450-Mhz radiation on the rabbit eye. IEEE Trans Microw Theory Techn. 1975, 23:492-8. doi:10.1109/TMTT.1975.1128606
• [61]Efron N, Young G, Brennan NA: Ocular surface temperature. Curr Eye Res. 1989, 8:901-6.
• [62]Yamaguchi K, Barbe MF, Brown IR, Tytell M: Induction of stress (heat shock) protein 70 and its mRNA in rat corneal epithelium by hyperthermia. Curr Eye Res 1990, 9(9):913-8.
• [63]Rudnick DV, Noonan JS, Geroski DH, Prausnitz MR, Edelhauser HF: The effect of intraocular pressure on human and rabbit scleral permeability. IOVS 1999, 40(12):3054-8.
• [64]Duncalf D: Anesthesia and intraocular pressure. Bull N Y Acad Med 1975, 51(3):374-81.