Optimization of Subconjunctival Biodegradable Microfilms for Sustained Drug Delivery to the Anterior Segment in a Small Animal Model

Liu, Yu-Chi; Peng, Yan; Lwin, Nyein Chan; Wong, Tina; Venkatraman, Subbu S.

doi:10.1167/iovs.12-11466

Cited by 19 publications

(20 citation statements)

References 36 publications

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“…However, using the same implant, we have previously shown resolution of this inflammatory response by 3 months. 16 Compared to the Te and Tm groups, as expected, the De and TeþDe groups demonstrated more inhibitory effects on the expression of CD11c, CD4, and IL-4 after 4 weeks of treatment. Corticosteroids are known to provide dramatic improvement in acute symptoms and signs of ocular allergic diseases.…”

Section: Discussionsupporting

confidence: 68%

“…Our in vivo drug release profiles showed that the tacrolimus microfilm reached and maintained above the daily target dose up to week 6. We have previously shown that the amount of loaded drug is proportional to the size of the microfilms, 16 and the size of the microfilms in the present study was limited to the eyeball of the mice. For future studies and clinical trials, larger microfilms with greater amount of loaded drug will be designed, and the drug concentration in the target tissue (i.e., conjunctiva) will be analyzed.…”

Section: Discussionmentioning

confidence: 67%

“…14,15 Our previous work has shown that subconjunctival poly [d,l-lactide-co-e-caprolactone] (PLC) microfilms were biodegradable and displayed good biocompatibility and feasibility. 16 We further loaded the PLC microfilms with prednisolone acetate (PA) and demonstrated that the PA microfilms significantly reduced corneal graft rejection after corneal transplantation, 17 reduced postoperative inflammation and prolonged bleb survival following glaucoma filtering surgery, 18 and suppressed the severity of uveitis in animal models. 19 We have also loaded the PLC microfilms with timolol maleate and demonstrated the sustained intraocular pressurelowering effects.…”

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confidence: 99%

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A Biodegradable, Sustained-Released, Tacrolimus Microfilm Drug Delivery System for the Management of Allergic Conjunctivitis in a Mouse Model

Liu

Teo

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To investigate the drug release profiles of a tacrolimus-loaded poly(D,L-lactide-co-ecaprolactone) (PLC) microfilm, and to evaluate its efficacy on the treatment of allergic conjunctivitis using a mouse model. METHODS.The in vitro and in vivo drug release profiles were first characterized. Balb/c mice were immunized with short ragweed (SRW) injection followed by re-challenges with topical SRW solution. The mice were divided into six groups (n ¼ 12 in each): negative control (NC); positive control (PC); tacrolimus eye drops (Te); subconjunctival tacrolimus microfilm (Tm); dexamethasone eye drops (De); and tacrolimus þ dexamethasone eye drops (TeþDe). The mice were evaluated for 28 days by a scoring system for allergic conjunctivitis. Histopathologic and immunohistochemical staining with CD11c, CD4, and IL-4 were performed.RESULTS. The microfilms were biocompatible and delivered clinically sufficient dose in a sustained manner, with a steady rate of 0.212 to 0.243 lg/day in vivo. Compared to the PC groups, the Te, Tm, De, and TeþDe groups significantly reduced the allergic clinical scores throughout the study period (all P < 0.01; 0.0 6 0.0, 5.6 6 0.9, 3.3 6 0.9, 3.2 6 0.9, 1.9 6 0.4 and 1.7 6 0.8 for the NC, PC, Tm, Te, De, and TeþDe groups, respectively, at 4 weeks after treatment). The suppressed eosinophils, CD11c, CD4, and IL-4 expression were also observed in all treatment groups, with more reduction in the TeþDe group.CONCLUSIONS. Tacrolimus-loaded microfilms display good biocompatibility and desirable sustained drug release. It was as effective as conventional tacrolimus eye drops on the treatment of allergic conjunctivitis, providing a promising clinically applicable alternative for controlling allergic disease activity, or other immune-mediated ocular diseases.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

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A Biodegradable, Sustained-Released, Tacrolimus Microfilm Drug Delivery System for the Management of Allergic Conjunctivitis in a Mouse Model

Liu

Teo

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…We have demonstrated in previous studies the anti-fibrotic and anti-inflammatory properties of a subconjunctivally implanted prednisolone acetate (PA)-preloaded microfilm in the rabbit model of subconjunctival scarring following glaucoma filtration surgery [6] and rat keratoplasty model[7]. Our in vivo studies have shown that PA-loaded poly[d,l-lactide-co-ε-caprolactone] (PLC) microfilms display good biocompatibility, feasibility, and desirable sustained drug release profiles, maintaining high anterior chamber PA levels at 76.7±5.9, 70.3±2.3, and 42.7±4.1 ng/mL at 2, 4, and 12 weeks, respectively[8], [9].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a Prednisolone Acetate-Loaded Subconjunctival Implant for the Treatment of Recurrent Uveitis in a Rabbit Model

Ang

Wong

et al. 2014

PLoS ONE

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AimTo assess the efficacy of a biodegradable, prednisolone acetate implant in a rabbit uveitis model.MethodsRandomized, controlled study of biodegradable microfilms preloaded with prednisolone acetate (PA) in a rabbit uveitis model. Experimental uveitis was induced by unilateral intravitreal injection of Mycobacterium tuberculosis H37Ra antigen (50 ug; 1 ug/uL) in preimmunized rabbits. PA-loaded poly[d,l-lactide-co-ε-caprolactone] (PLC) microfilms (n = 10) and blank microfilms (n = 6) were implanted subconjunctivally. An estimate of PA release in vivo was calculated from measured residual PA amounts in microfilms after the rabbits were sacrificed. The eyes were clinically monitored for ocular inflammation for 28 days. Histopathological examination of the enucleated eyes was performed at the end of the study period.Results In vitro studies revealed that sandwich PA-loaded microfilm formulations exhibited higher release kinetic compared to homogenous PA-loaded microfilms. The 60–40–60% microfilm released an average of 0.034 mg/day of PA over the period of 60 days in vitro; and we found that approximately 0.12 mg/day PA was released in vivo. Animals implanted with the PA-loaded microfilms exhibited significantly lowered median inflammatory scores when compared against the control group in this model for recurrent uveitis (P<0.001). The implants were clinically well tolerated by all the animals. Histology results showed no significant scarring or inflammation around the PA-loaded microfilms.ConclusionOur pilot study demonstrated that a subconjunctival PA-loaded implant is effective in suppressing inflammation in the rabbit model of uveitis, by providing therapeutic levels of PA that attenuated the inflammatory response even after a rechallenge. Longer term studies are now needed to establish the therapeutic potential of such a delivery system for treatment of ocular inflammation.

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“…Perhaps the water-soluble nature of vitamin B12 is an obstacle to penetration into the ocular compartment, and the use of repeated subconjunctival injection, 55 small-volume nebulizer, 56 and more recently, periocular injection of in situ hydrogels 57 or subconjunctival biodegradable microfilms 58 may be a more efficient means to deliver the cofactor in these patients. Clearly, research on potential therapeutics would be enhanced significantly if a viable animal model of cblC deficiency could be generated and studied.…”

Section: Discussionmentioning

confidence: 99%

Ophthalmic Manifestations and Long-Term Visual Outcomes in Patients with Cobalamin C Deficiency

et al. 2016

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Ocular manifestations of cobalamin C deficiency include a developmental as well as a degenerative phenotype and lack strict correlation to metabolic status, but may be mitigated by prenatal or early treatment. Purpose To explore the ocular manifestations of cobalamin C (cblC) deficiency, an inborn error of intracellular vitamin B12 metabolism caused by mutations in the MMACHC gene. Design Retrospective, observational case series. Participants Twenty-five cblC patients underwent clinical and ophthalmic examination at the National Institutes of Health Clinical Center between August 2004 and September 2012. Patient ages ranged from 2 to 27 years at last ophthalmic visit, and follow-up ranged from 0 to 83 months (median, 36 months; range, 13–83 months) over a total of 69 visits. Methods Best-corrected Snellen visual acuity, slit-lamp biomicroscopy, dilated fundus examination, wide-field photography, fundus autofluorescence imaging, sedated electroretinography, spectral-domain optical coherence tomography, and metabolite assessment. Main Outcome Measures Visual acuity and presence and degree of retinal degeneration and optic nerve pallor. Results Nystagmus (64%), strabismus (52%), macular degeneration (72%), optic nerve pallor (68%), and vascular changes (64%) were present. c.271dupA (p.R91KfsX14) homozygous patients (n = 14) showed early and extensive macular degeneration. Electroretinography showed that scotopic and photopic responses were reduced and delayed, but were preserved remarkably in some patients despite severe degeneration. Optical coherence tomography images through the central macular lesion of a patient with severe retinal degeneration showed extreme thinning, some preservation of retinal lamination, and nearly complete loss of the outer nuclear layer. Despite hyperhomocysteinemia, no patients exhibited lens dislocation. Conclusions This longitudinal study reports ocular outcomes in the largest group of patients with cblC deficiency systematically examined at a single center over an extended period. Differences in progression and severity of macular degeneration, optic nerve pallor, and vascular attenuation between homozygous c.271dupA (p.R91KfsX14) patients and compound heterozygotes were noted. The pace and chronicity of ophthalmic manifestations lacked strict correlation to metabolic status as measured during visits. Prenatal or early treatment, or both, may have mitigated ocular disease, leading to better functional acuity, but patients still progressed to severe macular degeneration. The effects of prenatal or early treatment, or both, in siblings, the manifestation of severe disease in infancy, the presence of comorbid developmental abnormalities (e.g., microcephaly, cardiac noncompaction), and the possible laminar structural defect noted in many patients are findings showing that cblC deficiency displays a developmental as well as a degenerative ocular phenotype.

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Optimization of Subconjunctival Biodegradable Microfilms for Sustained Drug Delivery to the Anterior Segment in a Small Animal Model

Cited by 19 publications

References 36 publications

A Biodegradable, Sustained-Released, Tacrolimus Microfilm Drug Delivery System for the Management of Allergic Conjunctivitis in a Mouse Model

A Biodegradable, Sustained-Released, Tacrolimus Microfilm Drug Delivery System for the Management of Allergic Conjunctivitis in a Mouse Model

Evaluation of a Prednisolone Acetate-Loaded Subconjunctival Implant for the Treatment of Recurrent Uveitis in a Rabbit Model

Ophthalmic Manifestations and Long-Term Visual Outcomes in Patients with Cobalamin C Deficiency

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