7 Transscleral Drug Delivery |
169 |
transscleral drug delivery. In our OGTA studies, peak choroid/retinal following subtenon injection in euthanized rabbits was observed to be approximately 3 times greater compared to injection in vivo. Vitreous concentrations with euthanization were 12 times greater than observed after in vivo injection. These results the significance of the dynamic barriers presented by the conjunctival and choroidal circulations as demonstrated by Robinson et al. (2006).
Taken together, the results of these in vivo studies have investigated and defined the diffusion characteristics of several agents administered by periocular injection. The dynamic barriers to transscleral drug delivery are clearly significant and are best studied in an in vivo model. If a drug is formulated in a sustained delivery vehicle or system, significant vitreous concentrations could be maintained over longer periods, as demonstrated with carboplatin in a fibrin sealant vehicle (Simpson et al. 2002). These studies also demonstrate that periocular drug delivery can achieve effective local delivery, with significant vitreous drug concentrations and minimal systemic levels. Limitations of the anatomic and dynamic barriers to the transscleral approach must be considered. Additionally, potential delivery limitations include drug/solute molecular weight, radius, partition coefficient, and charge. Despite potential limitations, however, periocular drug delivery can provide effective drug delivery to the posterior segment tissues of the eye.
7.7 Conclusions and Future Directions
Much experimental evidence currently indicates that transscleral delivery of therapeutic solutes can be achieved. This approach to intraocular drug delivery shows great promise in providing new therapeutic approaches for treating diseases of the posterior segment of the eye. The past results of these experiments have added to the understanding of solute flux across the sclera and provide new data on in vivo transscleral drug permeability and sustained-release delivery of drugs and therapeutic agents for retinal degenerations and disease. The longterm goal of these transscleral delivery studies is to provide a more effective drug delivery to the retina and posterior eye for the treatment of retinal degenerations and posterior segment disease. Delivering drugs across the permeable sclera would be safer and less invasive than intravitreal injection or devices, yet potentially could provide a more effective retinal dose than systemic or topical delivery.
Ultimately, a delivery device (biodegradable and/or refillable) needs to be developed that will provide a sustained release of the drug or protein to the episclera. In this case the sclera will come in equilibrium with the delivery device and provide a slow release of the drug to the suprachoroidal space, where it can then directly diffuse to the choroid, RPE, and neuroretina.
Acknowledgments Supported in part by R24EY017045 and Research to Prevent Blindness Inc.
170 |
D.H. Geroski and H.F. Edelhauser |
References
Ahmed I, Patton TF (1985) Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest Ophthalmol Vis Sci 26:584–587
Ahmed I, Gokhale RD, Shah MV, Patton TF (1987) Physico-chemical determinants of drug difusion across the conjunctive, sclera, and cornea. J Pharm Sci 76:583–586
Borcherding MS, Blacik LJ, Sittig RA, Bizzell JW, Breen M, Weinstein HG (1975) Proteoglycans and collagen fibre organization in human corneoscleral tissue. Exp Eye Res 21:59–70
Cruysberg LPJ, Nuyts RM, Geroski DH, Koole LH, Hendrikse F, Edelhauser HF (2002) In vitro human scleral permeability of fluorescein, methotrexate–fluorescein and rhodamine 6 G and the use of: coated coil as a new drug delivery system. J Ocul Pharmacol Ther 18:559–569
Cruysberg LPJ, Nuyts RMMA, Gilbert JA, Geroski DH, Hendricks F, Edelhauser HF (2005) In vitro sustained human transscleral drug delivery of fluorescein labeled dexamethasone and methotrexate with fibrin sealant. Curr Eye Res 30:653–660
Edwards A, Prausnitz MR (1998) A fiber matrix model of sclera and corneal stroma for drug delivery to the eye. AIChE J 44:214–225
Ghate D, Brooks W, McCarey BE, Edelhauser HF (2007) Pharmacokinetics of intraocular drug delivery by periocular injections using ocular flurophotometry. Invest Ophthalmol Vis Sci 48:2230–2237
Gilbert JA, Simpson AE, Rudnick DE, Geroski DH, Aaberg TM, Edelhauser HF (2003) Transscleral permeability and intraocular concentration of cisplatin from a collagen matrix. J Control Release 89:409–417
Jiang J, Geroski DH, Edelhauser HF, Prausnitz MR (2006) Measurement and Prediction of lateral diffusion within human sclera. Invest Ophthalmol Vis Sci 47:3011–3016
Kau JC, Geroski DH, Edelhauser HF (2005) Trans-scleral permeability of fluorescent antibiotics. J Ocul Pharmacol Ther 21:1–10
Kim ES, Dkurairaj C, Kadam RS, Lee SJ, Mo Y, Geroski DH, Kompella UB, Edelhauser HF (2009) Human scleral diffusion of anticancer drugs from solution and nanoparticle formulation. Pharm Res 26(5):1155–1161
Lang JC (1995) Ocular drug delivery conventional ocular formulations. Adv Drug Delivery Rev 16:39–43
Lee SB, Geroski DH, Prausnitz MR, Edelhauser HF (2004) Drug delivery through the scleral: the effects of thickness, hydration and sustained release systems. Exp Eye Res 78:599–607
Lee SJ, Kim ES, Geroski DH, McCarey BE, Edelhauser HF (2008a) Pharmacokinetics of Intraocular drug delivery of Oregon Green 488® labeled triamcinolone by subtenon injection using ocular fluorophotometry in rabbit eyes. Invest Ophthalmol Vis Sci 49:4506–4514
Lee SJ, Kim SJ, Kim ES, Geroski DH, McCarey BE, Edelhauser HF (2008b) Transscleral permeability of Oregon Green 488®. J Ocul Pharmacol Ther 24:579–586
Maurice DM, Polgar J (1977) Diffusion across the sclera. Exp Eye Res 25:577–582
Miyazaki S, Tkeuchi S, Yokouchi C, Takada M (1984) Pluronic F-127 gels as a vehicle for topical administration of anticancer agents. Chem Pharm Bull 32:4205–4208
Olsen TW, Edelhauser HF, Lim JI, Geroski DH (1995) Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning. Invest Ophthalmol Vis Sci 36:1893–1903
Olsen TW, Aaberg SY, Geroski DH, Edelhauser HF (1998) Human sclera: thickness and surface area. Am J Ophthalmol 125:237–241
Pardue MT, Gilbert JA, Hejny C, Geroski DH, Edelhauser HF (2004) Preservation of retinal function in rabbit after subconjunctival injection of Carboplatin in fibrin sealant. Retina 24:776–782
Prausnitz MR, Noonan JS (1998) Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci 87:1479–1488
Prausnitz MR, Edwards A, Noonan JS, Rudnick DE, Edelhauser HF, Geroski DH (1998) Measurement and prediction of transient transport across sclera for drug delivery to the eye. Ind Eng Chem Res 37:2903–2907
7 Transscleral Drug Delivery |
171 |
Robinson MR, Lee SS, Kim H, Kim S, Lutz RJ, Galban C, Bungay PM, Yuan P, Wang NS, Kim J, Csaky KG (2006) A rabbit model for assessing the ocular barriers to the transscleral delivery of triamcinolone acetonide. Exp Eye Res 82:479–487
Rudnick DE, Noonan JS, Geroski DH, Prausnitz MR, Edelhauser HF (1999) The effect of intraocular pressure on sclera permeability. Invest Ophthalmol Vis Sci 40:3054–3058
Sanborn GE, Anand R, Torti RE (1992) Sustained-release of ganciclovir theraph for treatment of cytomegalovirus retinitis. Arch Ophthal 110:188–195
Shuler RK Jr, Dioguardi PK, Henjy C et al (2004) Scleral permeability of a small single-stranded oligonucleotide. J Ocul Pharmacol Ther 20:159–168
Simpson AE, Gilbert JA, Rudnick DE, Geroski DH, Aaberg TM Jr, Edelhauser HF (2002) Transscleral diffusion of carboplatin: an in vitro and in vivo study. Arch Ophthalmol 120:1069–1074
Tsui YJ, Dalgard C, Van Quill KR, Lee L, Grossniklaus HF, Edelhauser HF, Obrien JM (2008) Subconjunctival topotecan in fibrin sealant in the treatment of transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 29:490–496
Van Quill KR, Dioguardi PK, Tong CT, Gilbert JA, Aaberg TM Jr, Grossniklaus HE, Edelhauser HF, O’Brien JM (2005) Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma. Ophthalmology 112:1151–1158
Yu BG, Kwon IC, Kim YH, Han DK, Park KD, Han K, Jeong SY (1996) Development of a local antibiotic delivery system using fibrin glue. J Control Release 39:65–70
Chapter 8
Suprachoroidal and Intrascleral Drug Delivery
Timothy W. Olsen and Brian C. Gilger
Abstract Local drug delivery to the eye minimizes systemic side effects and targets specific ocular tissue. In preclinical studies, transscleral and suprachoroidal delivery appear to achieve therapeutic drug tissue levels that target specific tissues, such as the choroid and macula. These routes allow minimally invasive sustained delivery of drugs to the ocular posterior segment while minimizing systemic drug levels and the associated side effects.
8.1 Introduction
The suprachoroidal route of delivery as well as deep lamellar scleral delivery are both recently described routes for delivery to the posterior pole of the eye (Einmahl et al. 2002; Gilger et al. 2006; Olsen et al. 2006; Jiang et al. 2007, 2009). Access to these anatomic areas has just recently been explored. Theoretically, this route of delivery has some key advantages. First, the suprachoroidal space is a potential space inside the eye. It does not interfere with the optical pathways as opposed to intravitreal injections. Second, diffusional pathways and pharmacokinetics are clearly different for suprachoroidal than for intravitreal injections. Diffusional access to the choroidal stroma may have advantages, particularly if one is targeting a disease of the choroid. An example might include selective drug delivery in uveitis or in macular diseases that originate in the choroid or retinal pigment epithelium (RPE), respectively. Drugs do not need to cross the internal limiting membrane of the retina in order to gain access to the outer retina, photoreceptors, RPE, and choroid.
T.W. Olsen (*)
Department of Ophthalmology, Emory Eye Center, Emory University School of Medicine, Atlanta, GA, USA
e-mail: tolsen@emory.edu
U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 173 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_8,
© American Association of Pharmaceutical Scientists, 2011