A Biodegradable, Sustained-Released, Prednisolone Acetate Microfilm Drug Delivery System Effectively Prolongs Corneal Allograft Survival in the Rat Keratoplasty Model

Frequent and long-term use of topical corticosteroids after corneal transplantation is necessary to prevent graft rejection. However, it relies heavily on patient compliance, and sustained therapeutic drug levels are often not achieved with administration of topical eye drops. A biodegradable drug delivery system with a controlled and sustained drug release may circumvent these limitations. In this study, we investigated the efficacy of a prednisolone acetate (PA)-loaded poly (d,l-lactide-co-ε-caprolactone) (PLC) microfilm drug delivery system on promoting the survival of allogeneic grafts after penetrating keratoplasty (PK) using a rat model. The drug release profiles of the microfilms were characterized (group 1). Subsequently, forty-eight PK were performed in four experimental groups: syngeneic control grafts (group 2), allogeneic control grafts (group 3), allogeneic grafts with subconjunctivally-implanted PA microfilm (group 4), and allogeneic grafts with PA eye drops (group 5; n = 12 in each). PA-loaded microfilm achieved a sustained and steady release at a rate of 0.006–0.009 mg/day, with a consistent aqueous drug concentration of 207–209 ng/ml. The mean survival days was >28 days in group 2, 9.9±0.8 days in group 3, 26.8±2.7 days in group 4, and 26.4±3.4 days in group 5 (P = 0.023 and P = 0.027 compared with group 3). Statistically significant decrease in CD4+, CD163+, CD 25+, and CD54+ cell infiltration was observed in group 4 and group 5 compared with group 3 (P<0.001). There was no significant difference in the mean survival and immunohistochemical analysis between group 4 and group 5. These results showed that sustained PA-loaded microfilm effectively prolongs corneal allograft survival. It is as effective as conventional PA eye drops, providing a promising clinically applicable alternative for patients undergoing corneal transplantation.

[1]  J. Mehta,et al.  Optimization of subconjunctival biodegradable microfilms for sustained drug delivery to the anterior segment in a small animal model. , 2013, Investigative ophthalmology & visual science.

[2]  Marcus Ang,et al.  Cost-effectiveness of Descemet's stripping endothelial keratoplasty versus penetrating keratoplasty. , 2013, Ophthalmology.

[3]  J. Mehta,et al.  Intraocular lens as a drug delivery reservoir , 2013, Current opinion in ophthalmology.

[4]  Roni M. Shtein,et al.  Comparative cost-effectiveness analysis of descemet stripping automated endothelial keratoplasty versus penetrating keratoplasty in the United States. , 2013, American journal of ophthalmology.

[5]  Rishi P. Singh,et al.  Evaluation of fluocinolone acetonide sustained release implant (Retisert) dissociation during implant removal and exchange surgery. , 2012, American journal of ophthalmology.

[6]  P. Tyagi,et al.  Flt23k nanoparticles offer additive benefit in graft survival and anti-angiogenic effects when combined with triamcinolone. , 2012, Investigative ophthalmology & visual science.

[7]  J. Shimazaki,et al.  Efficacy and safety of long-term corticosteroid eye drops after penetrating keratoplasty: a prospective, randomized, clinical trial. , 2012, Ophthalmology.

[8]  M. Ang,et al.  Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye , 2012, International journal of nanomedicine.

[9]  M. Ang,et al.  Evaluation of Sustained Release of PLC-Loaded Prednisolone Acetate Microfilm on Postoperative Inflammation in an Experimental Model of Glaucoma Filtration Surgery , 2011, Current eye research.

[10]  J. Mehta,et al.  Corneal transplantation: changing techniques. , 2011, Transplantation.

[11]  Marcus Ang,et al.  Biocompatibility and Biodegradation Studies of Subconjunctival Implants in Rabbit Eyes , 2011, PloS one.

[12]  Terry W. J. Steele,et al.  The effect of polyethylene glycol structure on paclitaxel drug release and mechanical properties of PLGA thin films. , 2011, Acta biomaterialia.

[13]  B. Fernandes,et al.  Histopathological Study of Delayed Regraft After Corneal Graft Failure , 2011, Cornea.

[14]  S. Yiu,et al.  Management of Corneal Graft Rejection - A Case Series Report and Review of the Literature. , 2010, Journal of clinical & experimental ophthalmology.

[15]  M. Robinson,et al.  Biodegradable Implants for Sustained Drug Release in the Eye , 2010, Pharmaceutical Research.

[16]  C. Jessup,et al.  Mechanisms of corneal allograft rejection and the development of new therapies , 2010 .

[17]  R. Herrero-Vanrell,et al.  Downregulation of endotoxin-induced uveitis by intravitreal injection of polylactic-glycolic acid (PLGA) microspheres loaded with dexamethasone. , 2009, Experimental eye research.

[18]  G. Dutton,et al.  Penetration of topical and subconjunctival corticosteroids into human aqueous humour and its therapeutic significance , 2009, British Journal of Ophthalmology.

[19]  J. Haller,et al.  EVALUATION OF THE SAFETY AND PERFORMANCE OF AN APPLICATOR FOR A NOVEL INTRAVITREAL DEXAMETHASONE DRUG DELIVERY SYSTEM FOR THE TREATMENT OF MACULAR EDEMA , 2009, Retina.

[20]  M. Dana,et al.  Corneal Graft Rejection , 2009, International ophthalmology clinics.

[21]  Ashim K. Mitra,et al.  Recent Perspectives in Ocular Drug Delivery , 2009, Pharmaceutical Research.

[22]  N. Peppas,et al.  Modeling of drug release from biodegradable polymer blends. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[23]  F. Boey,et al.  Hydrolytic degradation characteristics of irradiated multi-layered PLGA films. , 2008, International journal of pharmaceutics.

[24]  Y. Chan,et al.  Penetrating keratoplasty in Asian eyes: the Singapore Corneal Transplant Study. , 2008, Ophthalmology.

[25]  Z. Gao,et al.  Shape-memory behaviors of biodegradable poly(L-lactide-co-ε-caprolactone) copolymers , 2008 .

[26]  Dongwook Han,et al.  The behavior of vascular smooth muscle cells and platelets onto epigallocatechin gallate-releasing poly(l-lactide-co-epsilon-caprolactone) as stent-coating materials. , 2008, Biomaterials.

[27]  Shen‐guo Wang,et al.  Sustained intraocular rapamycin delivery effectively prevents high-risk corneal allograft rejection and neovascularization in rabbits. , 2006, Investigative ophthalmology & visual science.

[28]  B. Ratner,et al.  Protein bonding on biodegradable poly(L-lactide-co-caprolactone) membrane for esophageal tissue engineering. , 2006, Biomaterials.

[29]  D. F. P. Larkin,et al.  Cornea and External Eye Disease , 2006 .

[30]  G. Rao,et al.  Outcome of corneal transplant rejection: a 10‐year study , 2005, Clinical & experimental ophthalmology.

[31]  J. Schouten,et al.  Noncompliance with ocular hypotensive treatment in patients with glaucoma or ocular hypertension an evidence-based review. , 2005, Ophthalmology.

[32]  D. Cohn,et al.  Designing biodegradable multiblock PCL/PLA thermoplastic elastomers. , 2005, Biomaterials.

[33]  W. H. Lee,et al.  Opinions on Risk Factors and Management of Corneal Graft Rejection in the United Kingdom , 2005, Cornea.

[34]  Shen‐guo Wang,et al.  FK506 in a Biodegradable Glycolide-co-Clatide-co-Caprolactone Polymer for Prolongation of Corneal Allograft Survival , 2005, Current eye research.

[35]  Mark R Prausnitz,et al.  Model of transient drug diffusion across cornea. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[36]  F. Claas,et al.  FTY720 prolongs clear corneal allograft survival with a differential effect on different lymphocyte populations , 2004, British Journal of Ophthalmology.

[37]  F. Hoffmann,et al.  Orthotopic corneal transplantation in the mouse — a new surgical technique with minimal endothelial cell loss , 1996, Graefe's Archive for Clinical and Experimental Ophthalmology.

[38]  M. Isobe,et al.  The role of cell adhesion molecules in allograft rejection after penetrating keratoplasty in mice. Clinical and immunohistochemical study , 1996, Graefe's Archive for Clinical and Experimental Ophthalmology.

[39]  Joan W. Miller,et al.  Ocular Tissue Permeabilities , 2004, International ophthalmology clinics.

[40]  M. Ueda,et al.  Rat costochondral cell characteristics on poly (l-lactide-co-ε-caprolactone) scaffolds , 2003 .

[41]  Y. Jie,et al.  Rat corneal allograft survival prolonged by the superantigen staphylococcal enterotoxin B. , 2003, Investigative ophthalmology & visual science.

[42]  M. Ueda,et al.  Rat costochondral cell characteristics on poly (L-lactide-co-epsilon-caprolactone) scaffolds. , 2003, Biomaterials.

[43]  Joan W. Miller,et al.  Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-co-glycolic)acid microspheres. , 2003, Investigative ophthalmology & visual science.

[44]  R. Munger Veterinary ophthalmology in laboratory animal studies. , 2002, Veterinary ophthalmology.

[45]  T. Oshika,et al.  Intraocular Dexamethasone Delivery System for Corneal Transplantation in an Animal Model , 2002, Cornea.

[46]  U. Pleyer,et al.  Corneal Allograft Rejection: Current Understanding , 2002, Ophthalmologica.

[47]  D. Tan,et al.  Randomized clinical trial of Surodex steroid drug delivery system for cataract surgery: anterior versus posterior placement of two Surodex in the eye. , 2001, Ophthalmology.

[48]  Shen‐guo Wang,et al.  Prolongation of Corneal Allograft Survival Using Cyclosporine in a Polylactide-co-glycolide Polymer , 2001, Cornea.

[49]  U. Rehany,et al.  The profile of repeated corneal transplantation. , 2001, Ophthalmology.

[50]  M. Sánchez-Salorio,et al.  Efficacy of subconjunctival cyclosporin-containing microspheres on keratoplasty rejection in the rabbit , 1999, Graefe's Archive for Clinical and Experimental Ophthalmology.

[51]  X Navarro,et al.  Highly permeable polylactide-caprolactone nerve guides enhance peripheral nerve regeneration through long gaps. , 1999, Biomaterials.

[52]  M. Katami The mechanisms of corneal graft failure in the rat , 1995, Eye.

[53]  J. Hill,et al.  Systemic cyclosporine in high-risk keratoplasty. Short- versus long-term therapy. , 1994, Ophthalmology.

[54]  G. Dutton,et al.  Penetration of synthetic corticosteroids into human aqueous humour , 1990, Eye.

[55]  H E Kaufman,et al.  Corneal transplantation. , 1977, Annual review of medicine.

[56]  J. Buxton,et al.  Corticosteroids in 100 keratoplasties. , 1969, American journal of ophthalmology.