眼后节疾病经巩膜给药的影响因素与提高经巩膜给药利用率的途径_Chinese Journal of Ocular Fundus Diseases

Authors：

顾冰 , 兰碧菲 ,  程凌云

325027 温州医科大学眼科药物研究所;

Corresponding author：

程凌云, Email: lingyunc@hotmail.com

Keywords：

眼疾病/药物疗法; 投药, 眼; 巩膜; 影响因素; 综述

DOI：

10.3760/cma.j.issn.1005-1015.2015.02.029

Video：

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目的经巩膜眼后节给药因其靶向传递较好、创伤相对较小等优点在眼后节疾病的治疗中备受关注。然而, 在治疗视网膜疾病时, 经巩膜给药的临床有效性不及玻璃体腔注药。其原因在于药物经巩膜向眼内传递的过程不仅受到巩膜、脉络膜、视网膜色素上皮(RPE)和眼内色素等解剖屏障的影响, 而且还受到RPE转运蛋白、代谢酶系统以及前列腺素等代谢化学屏障的影响。了解药物经巩膜向眼后节递放的各种影响因素的研究和相关生物材料方面的进展, 为进一步明确经巩膜给药机制, 更有效治疗眼后节疾病提供科学思考素材和启迪。

Citation： 顾冰, 兰碧菲, 程凌云. 眼后节疾病经巩膜给药的影响因素与提高经巩膜给药利用率的途径. Chinese Journal of Ocular Fundus Diseases, 2015, 31(2): 205-208. doi: 10.3760/cma.j.issn.1005-1015.2015.02.029 Copy

1.	Vemulakonda GA, Hariprasad SM, Mieler WF, et al.Aqueous and vitreous concentrations following topical administration of 1% voriconazole in humans[J]. Arch Ophthalmol, 2008, 126(1):18-22.
2.	Raghava S, Hammond M, Kompella UB. Periocular routes for retinal drug delivery[J]. Expert Opin Drug Del, 2004, 1(1):99-114.
3.	Anderson OA, Jackson TL, Singh JK, et al. Human transscleral albumin permeability and the effect of topographical location and donor age[J]. Invest Ophthalmol Vis Sci, 2008, 49(9):4041-4045.
4.	Nan K, Sun S, Li Y, et al.Characterisation of systemic and ocular drug level of triamcinolone acetonide following a single sub-Tenon injection[J].Br J Ophthalmol, 2010, 94(5):654-658.
5.	Shen L, You Y, Sun S, et al.Intraocular and systemic pharmacokinetics of triamcinolone acetonide after a single 40-mg posterior subtenon application[J]. Ophthalmology, 2010, 117(12):2365-2371.
6.	Ambati J, Canakis CS, Miller JW, et al. Diffusion of high molecular weight compounds through sclera[J]. Invest Ophthalmol Vis Sci, 2000, 41(5):1181-1185.
7.	Kansara V, Mitra AK.Evaluation of an ex vivo model implication for carrier-mediated retinal drug delivery[J]. Curr Eye Res, 2006, 31(5):415-426.
8.	Cheruvu NP, Kompella UB.Bovine and porcine transscleral solute transport:influence of lipophilicity and the Choroid-Bruch's layer[J]. Invest Ophthalmol Vis Sci, 2006, 47(10):4513-4522.
9.	Hillenkamp J, Hussain AA, Jackson TL, et al.The influence of path length and matrix components on ageing characteristics of transport between the choroid and the outer retina[J]. Invest Ophthalmol Vis Sci, 2004, 45(5):1493-1498.
10.	Kadam RS, Tyagi P, Edelhauser HF, et al.Influence of choroidal neovascularization and biodegradable polymeric particle size on transscleral sustained delivery of triamcinolone acetonide[J]. Int J Pharm, 2012, 434(1-2):140-147.
11.	Pitkänen L, Ranta VP, Moilanen H, et al.Permeability of retinal pigment epithelium:effects of permeant molecular weight and lipophilicity[J]. Invest Ophthalmol Vis Sci, 2005, 46(2):641-646.
12.	Hu DN, Simon JD, Sarna T.Role of ocular melanin in ophthalmic physiology and pathology[J]. Photochem Photobiol, 2008, 84(3):639-644.
13.	Cheruvu NP, Amrite AC, Kompella UB. Effect of eye pigmentation on transscleral drug delivery[J].Invest Ophthalmol Vis Sci, 2008, 49(1):333-341.
14.	Du W, Sun S, Xu Y, et al.The effect of ocular pigmentation on transscleral delivery of triamcinolone acetonide[J]. J Ocul Pharmacol Ther, 2013, 29(7):633-638.
15.	Rudnick DE, Noonan JS, Geroski DH, et al.The effect of intraocular pressure on human and rabbit scleral permeability[J].Invest Ophthalmol Vis Sci, 1999, 40(12):3054-3058.
16.	Cruysberg LP, Nuijts RM, Geroski DH, et al. The influence of intraocular pressure on the transscleral diffusion of high-molecular-weight compounds[J].Invest Ophthalmol Vis Sci, 2005, 46(10):3790-3794.
17.	Duvvuri S, Gandhi MD, Mitra AK.Effect of P-glycoprotein on the ocular disposition of a model substrate, quinidine[J]. Curr Eye Res, 2003, 27(6):345-353.
18.	Attar M, Shen J, Ling KH, et al.Ophthalmic drug delivery considerations at the cellular level:drug-metabolising enzymes and transporters[J].Expert Opin Drug Deliv, 2005, 2:891-908.
19.	Kumar G.Drug metabolizing enzyme systems in the eye[M]//Leino M, Urtti A.Ocular therapeutics and drug delivery:a multi-disciplinary approach. Indra K. Reddy:Lancaster, Technomic Publishing Company, 1996:149-167.
20.	Kim JW, Lindsey JD, Wang N, et al.Increased human scleral permeability with prostaglandin exposure[J].Invest Ophthalmol Vis Sci, 2001, 42(7):1514-1521.
21.	Shen L, Mao J, Chen Y, et al. Transscleral permeation of subtenon triamcinolone in different vitreoretinal diseases[J]. Ophthalmology, 2015, 122(3):649-651.
22.	Cellini M, Pazzaglia A, Zamparini E, et al. Intravitreal vs. subtenon triamcinolone acetonide for the treatment of diabetic cystoid macular edema[J]. BMC Ophthalmol, 2008, 8:5.
23.	Thakur A, Kadam RS, Kompella UB. Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids[J]. Drug Metab Dispos, 2011, 39(5):771-781.
24.	Kadam RS, Cheruvu NP, Edelhauser HF, et al. Sclera-choroid-RPE transport of eight beta-blockers in human, bovine, porcine, rabbit, and rat models[J]. Invest Ophthalmol Vis Sci, 2011, 52(8):5387-5399.
25.	Krishnadev N, Forooghian F, Cukras C, et al. Subconjunctival sirolimus in the treatment of diabetic macular edema[J]. Graefe's Arch Clin Exp Ophthalmol, 2011, 249(11):1627-1633.
26.	Bochot A, Fattal E, Boutet V, et al. Intravitreal delivery of oligonucleotides by sterically stabilized liposomes[J].Invest Ophthalmol Vis Sci, 2002, 43 (1):253-259.
27.	Kim S, Kim JH, Jeon O, et al. Engineered polymers for advanced drug delivery[J]. Eur J Pharm Biopharm, 2009, 71(3):420-430.
28.	Kim YM, Lim JO, Kim HK, et al. A novel design of one-side coated biodegradable intrascleral implant for the sustained release of triamcinolone acetonide[J]. Eur J Pharm Biopharm, 2008, 70(1):179-186.
29.	Meng Y, Sun S, Li J, et al.Sustained release of triamcinolone acetonide from an episcleral plaque of multilayered poly-epsilon-caprolactone matrix[J].Acta biomaterialia, 2014, 10(1):126-133.
30.	Amrite AC, Kompella UB. Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration[J]. J Pharm Pharmacol, 2005, 57(12):1555-1563.
31.	Ayalasomayajula SP, Kompella UB. Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration[J]. Pharm Res, 2004, 21(10):1797-1804.
32.	Ayalasomayajula SP, Kompella UB. Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model[J]. Eur J Pharmacol, 2005, 511(2-3):191-198.
33.	Booth BA, Vidal Denham L, Bouhanik S, et al. Sustained-release ophthalmic drug delivery systems for treatment of macular disorders:present and future applications[J]. Drugs Aging, 2007, 24(7):581-602.
34.	Lin CC, Metters AT. Hydrogels in controlled release formulations:network design and mathematical modeling[J]. Adv Drug Deliv Rev, 2006, 58(12-13):1379-1408.
35.	Raiskup-Wolf F, Eljarrat-Binstock E, Rehak M, et al.Transcorneal and transscleral iontophoresis of the dexamethasone phosphate into the rabbit eye[J]. Cesk Slov Oftalmol, 2007, 63(5):360-368.
36.	Eljarrat-Binstock E, Orucov F, Frucht-Pery J, et al. Methylprednisolone delivery to the back of the eye using hydrogel iontophoresis[J]. J Ocul Pharmacol Ther, 2008, 24(3):344-350.
37.	Myles ME, Neumann DM, Hill JM. Recent progress in ocular drug delivery for posterior segment disease:emphasis on transscleral iontophoresis[J]. Adv Drug Deliv Rev, 2005, 57(14):2063-2079.
38.	Tsutsui JM, Grayburn PA, Xie F, et al.Drug and gene delivery and enhancement of thrombolysis using ultrasound and microbubbles[J].Cardiol Clin, 2004, 22(2):299-312.
39.	Mayer CR, Geis NA, Katus HA., et al. Ultrasound targeted microbubble destruction for drug and gene delivery[J]. Expert Opin Drug Deliv, 2008, 5(10):1121-1138.
40.	Chen ZY, Yang F, Lin Y, et al. New development and application of ultrasound targeted microbubble destruction in gene therapy and drug delivery[J]. Curr Gene Ther, 2013, 13(4):250-274.
41.	Patel SR, Lin AS, Edelhauser HF, et al. Suprachoroidal drug delivery to the back of the eye using hollow microneedles[J]. Pharm Res, 2011, 28(1):166-176.
42.	Kadam RS, Williams J, Tyagi P, et al. Suprachoroidal delivery in a rabbit ex vivo eye model:influence of drug properties, regional differences in delivery, and comparison with intravitreal and intracameral routes[J]. Mol Vis, 2013, 19:1198-1210.
43.	Patel SR, Berezovsky DE, McCarey BE, et al.Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye[J]. Invest Ophthalmol Vis Sci, 2012, 53(8):4433-4441.
44.	Chen M, Li X, Liu J, et al.Safety and pharmacodynamics of suprachoroidal injection of triamcinolone acetonide as a controlled ocular drug release model[J]. J Control Release, 2015, 203:109-117.
45.	Gu B, Liu J, Li X, et al. Real time monitoring of suprachoroidal space by ultra-high resolution Optical Coherence Tomography (UHR-OCT) in guinea pig eyes[J]. Inves Ophthalmol Vis Sci, 2015, In Press.
46.	李杰, 兰碧菲, 赵春晖, 等.灰兔眼巩膜厚度测量[J].中华眼视光学与视觉科学杂志, 2013, 15(9):551-554.
47.	Serpe L, Canaparo R, Foglietta F, et al. Innovative formulations for the controlled and site-specific delivery of antiinflammatory drugs[J]. Curr Pharm Des, 2013, 19(41):7219-7236.
48.	Kovacs K, Wagley S, Quirk MT, et al. Pharmacokinetic study of vitreous and serum concentrations of triamcinolone acetonide after posterior sub-tenon's injection[J]. Am J Ophthalmol, 2012, 153(5):939-948.

1. Vemulakonda GA, Hariprasad SM, Mieler WF, et al.Aqueous and vitreous concentrations following topical administration of 1% voriconazole in humans[J]. Arch Ophthalmol, 2008, 126(1):18-22.
2. Raghava S, Hammond M, Kompella UB. Periocular routes for retinal drug delivery[J]. Expert Opin Drug Del, 2004, 1(1):99-114.
3. Anderson OA, Jackson TL, Singh JK, et al. Human transscleral albumin permeability and the effect of topographical location and donor age[J]. Invest Ophthalmol Vis Sci, 2008, 49(9):4041-4045.
4. Nan K, Sun S, Li Y, et al.Characterisation of systemic and ocular drug level of triamcinolone acetonide following a single sub-Tenon injection[J].Br J Ophthalmol, 2010, 94(5):654-658.
5. Shen L, You Y, Sun S, et al.Intraocular and systemic pharmacokinetics of triamcinolone acetonide after a single 40-mg posterior subtenon application[J]. Ophthalmology, 2010, 117(12):2365-2371.
6. Ambati J, Canakis CS, Miller JW, et al. Diffusion of high molecular weight compounds through sclera[J]. Invest Ophthalmol Vis Sci, 2000, 41(5):1181-1185.
7. Kansara V, Mitra AK.Evaluation of an ex vivo model implication for carrier-mediated retinal drug delivery[J]. Curr Eye Res, 2006, 31(5):415-426.
8. Cheruvu NP, Kompella UB.Bovine and porcine transscleral solute transport:influence of lipophilicity and the Choroid-Bruch's layer[J]. Invest Ophthalmol Vis Sci, 2006, 47(10):4513-4522.
9. Hillenkamp J, Hussain AA, Jackson TL, et al.The influence of path length and matrix components on ageing characteristics of transport between the choroid and the outer retina[J]. Invest Ophthalmol Vis Sci, 2004, 45(5):1493-1498.
10. Kadam RS, Tyagi P, Edelhauser HF, et al.Influence of choroidal neovascularization and biodegradable polymeric particle size on transscleral sustained delivery of triamcinolone acetonide[J]. Int J Pharm, 2012, 434(1-2):140-147.
11. Pitkänen L, Ranta VP, Moilanen H, et al.Permeability of retinal pigment epithelium:effects of permeant molecular weight and lipophilicity[J]. Invest Ophthalmol Vis Sci, 2005, 46(2):641-646.
12. Hu DN, Simon JD, Sarna T.Role of ocular melanin in ophthalmic physiology and pathology[J]. Photochem Photobiol, 2008, 84(3):639-644.
13. Cheruvu NP, Amrite AC, Kompella UB. Effect of eye pigmentation on transscleral drug delivery[J].Invest Ophthalmol Vis Sci, 2008, 49(1):333-341.
14. Du W, Sun S, Xu Y, et al.The effect of ocular pigmentation on transscleral delivery of triamcinolone acetonide[J]. J Ocul Pharmacol Ther, 2013, 29(7):633-638.
15. Rudnick DE, Noonan JS, Geroski DH, et al.The effect of intraocular pressure on human and rabbit scleral permeability[J].Invest Ophthalmol Vis Sci, 1999, 40(12):3054-3058.
16. Cruysberg LP, Nuijts RM, Geroski DH, et al. The influence of intraocular pressure on the transscleral diffusion of high-molecular-weight compounds[J].Invest Ophthalmol Vis Sci, 2005, 46(10):3790-3794.
17. Duvvuri S, Gandhi MD, Mitra AK.Effect of P-glycoprotein on the ocular disposition of a model substrate, quinidine[J]. Curr Eye Res, 2003, 27(6):345-353.
18. Attar M, Shen J, Ling KH, et al.Ophthalmic drug delivery considerations at the cellular level:drug-metabolising enzymes and transporters[J].Expert Opin Drug Deliv, 2005, 2:891-908.
19. Kumar G.Drug metabolizing enzyme systems in the eye[M]//Leino M, Urtti A.Ocular therapeutics and drug delivery:a multi-disciplinary approach. Indra K. Reddy:Lancaster, Technomic Publishing Company, 1996:149-167.
20. Kim JW, Lindsey JD, Wang N, et al.Increased human scleral permeability with prostaglandin exposure[J].Invest Ophthalmol Vis Sci, 2001, 42(7):1514-1521.
21. Shen L, Mao J, Chen Y, et al. Transscleral permeation of subtenon triamcinolone in different vitreoretinal diseases[J]. Ophthalmology, 2015, 122(3):649-651.
22. Cellini M, Pazzaglia A, Zamparini E, et al. Intravitreal vs. subtenon triamcinolone acetonide for the treatment of diabetic cystoid macular edema[J]. BMC Ophthalmol, 2008, 8:5.
23. Thakur A, Kadam RS, Kompella UB. Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids[J]. Drug Metab Dispos, 2011, 39(5):771-781.
24. Kadam RS, Cheruvu NP, Edelhauser HF, et al. Sclera-choroid-RPE transport of eight beta-blockers in human, bovine, porcine, rabbit, and rat models[J]. Invest Ophthalmol Vis Sci, 2011, 52(8):5387-5399.
25. Krishnadev N, Forooghian F, Cukras C, et al. Subconjunctival sirolimus in the treatment of diabetic macular edema[J]. Graefe's Arch Clin Exp Ophthalmol, 2011, 249(11):1627-1633.
26. Bochot A, Fattal E, Boutet V, et al. Intravitreal delivery of oligonucleotides by sterically stabilized liposomes[J].Invest Ophthalmol Vis Sci, 2002, 43 (1):253-259.
27. Kim S, Kim JH, Jeon O, et al. Engineered polymers for advanced drug delivery[J]. Eur J Pharm Biopharm, 2009, 71(3):420-430.
28. Kim YM, Lim JO, Kim HK, et al. A novel design of one-side coated biodegradable intrascleral implant for the sustained release of triamcinolone acetonide[J]. Eur J Pharm Biopharm, 2008, 70(1):179-186.
29. Meng Y, Sun S, Li J, et al.Sustained release of triamcinolone acetonide from an episcleral plaque of multilayered poly-epsilon-caprolactone matrix[J].Acta biomaterialia, 2014, 10(1):126-133.
30. Amrite AC, Kompella UB. Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration[J]. J Pharm Pharmacol, 2005, 57(12):1555-1563.
31. Ayalasomayajula SP, Kompella UB. Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration[J]. Pharm Res, 2004, 21(10):1797-1804.
32. Ayalasomayajula SP, Kompella UB. Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model[J]. Eur J Pharmacol, 2005, 511(2-3):191-198.
33. Booth BA, Vidal Denham L, Bouhanik S, et al. Sustained-release ophthalmic drug delivery systems for treatment of macular disorders:present and future applications[J]. Drugs Aging, 2007, 24(7):581-602.
34. Lin CC, Metters AT. Hydrogels in controlled release formulations:network design and mathematical modeling[J]. Adv Drug Deliv Rev, 2006, 58(12-13):1379-1408.
35. Raiskup-Wolf F, Eljarrat-Binstock E, Rehak M, et al.Transcorneal and transscleral iontophoresis of the dexamethasone phosphate into the rabbit eye[J]. Cesk Slov Oftalmol, 2007, 63(5):360-368.
36. Eljarrat-Binstock E, Orucov F, Frucht-Pery J, et al. Methylprednisolone delivery to the back of the eye using hydrogel iontophoresis[J]. J Ocul Pharmacol Ther, 2008, 24(3):344-350.
37. Myles ME, Neumann DM, Hill JM. Recent progress in ocular drug delivery for posterior segment disease:emphasis on transscleral iontophoresis[J]. Adv Drug Deliv Rev, 2005, 57(14):2063-2079.
38. Tsutsui JM, Grayburn PA, Xie F, et al.Drug and gene delivery and enhancement of thrombolysis using ultrasound and microbubbles[J].Cardiol Clin, 2004, 22(2):299-312.
39. Mayer CR, Geis NA, Katus HA., et al. Ultrasound targeted microbubble destruction for drug and gene delivery[J]. Expert Opin Drug Deliv, 2008, 5(10):1121-1138.
40. Chen ZY, Yang F, Lin Y, et al. New development and application of ultrasound targeted microbubble destruction in gene therapy and drug delivery[J]. Curr Gene Ther, 2013, 13(4):250-274.
41. Patel SR, Lin AS, Edelhauser HF, et al. Suprachoroidal drug delivery to the back of the eye using hollow microneedles[J]. Pharm Res, 2011, 28(1):166-176.
42. Kadam RS, Williams J, Tyagi P, et al. Suprachoroidal delivery in a rabbit ex vivo eye model:influence of drug properties, regional differences in delivery, and comparison with intravitreal and intracameral routes[J]. Mol Vis, 2013, 19:1198-1210.
43. Patel SR, Berezovsky DE, McCarey BE, et al.Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye[J]. Invest Ophthalmol Vis Sci, 2012, 53(8):4433-4441.
44. Chen M, Li X, Liu J, et al.Safety and pharmacodynamics of suprachoroidal injection of triamcinolone acetonide as a controlled ocular drug release model[J]. J Control Release, 2015, 203:109-117.
45. Gu B, Liu J, Li X, et al. Real time monitoring of suprachoroidal space by ultra-high resolution Optical Coherence Tomography (UHR-OCT) in guinea pig eyes[J]. Inves Ophthalmol Vis Sci, 2015, In Press.
46. 李杰, 兰碧菲, 赵春晖, 等.灰兔眼巩膜厚度测量[J].中华眼视光学与视觉科学杂志, 2013, 15(9):551-554.
47. Serpe L, Canaparo R, Foglietta F, et al. Innovative formulations for the controlled and site-specific delivery of antiinflammatory drugs[J]. Curr Pharm Des, 2013, 19(41):7219-7236.
48. Kovacs K, Wagley S, Quirk MT, et al. Pharmacokinetic study of vitreous and serum concentrations of triamcinolone acetonide after posterior sub-tenon's injection[J]. Am J Ophthalmol, 2012, 153(5):939-948.

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眼后节疾病经巩膜给药的影响因素与提高经巩膜给药利用率的途径

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