Scleral Plug of Biodegradable Polymers Containing Tacrolimus (FK506) for Experimental Uveitis

Sakurai, Eiji; Nozaki, Miho; Okabe, Komei; Kunou, Noriyuki; Kimura, Hideya; Ogura, Yuichiro

doi:10.1167/iovs.02-1228

Cited by 68 publications

(43 citation statements)

References 12 publications

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Section: Discussionmentioning

confidence: 99%

“…25,26 Souza et al 25 reported an intravitreal tacrolimus-loaded poly(d,l-lactide-coglycolide) (PLGA) implant provided prolonged release of drug up to 6 weeks, and there was no evidence of toxic effects of implants. Sakurai et al 26 also reported a scleral PLGA plug containing tacrolimus was effective in suppressing the inflammation of experimental uveitis in a rabbit model for at least 6 weeks. 26 Compared to those designs, the subconjunctival microfilm reported in the present study is more ideal for conjunctival diseases like allergic conjunctivitis, and this is the first described tacrolimus drug delivery system inserted subconjunctivally to our knowledge.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…26 There are also reports of trans-scleral delivery of betamethasone from implant devices, 15 sodium fl uorescein, 27 and ganciclovir. 28 One of the proposed barriers to trans-scleral delivery is represented by the choroidal blood fl ow clearance mechanism. Perhaps, the ovalbumin protein is large enough to breach this clearance mechanism and escapes rapid removal by the choroidal blood.…”

Section: Discussionmentioning

confidence: 99%

Sustained Subconjunctival Protein Delivery Using a Thermosetting Gel Delivery System

Rieke

Amaral

Becerra

et al. 2010

Journal of Ocular Pharmacology and Therapeutics

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Purpose: An effective treatment modality for posterior eye diseases would provide prolonged delivery of therapeutic agents, including macromolecules, to eye tissues using a safe and minimally invasive method. The goal of this study was to assess the ability of a thermosetting gel to deliver a fl uorescently labeled protein, Alexa 647 ovalbumin, to the choroid and retina of rats following a single subconjunctival injection of the gel. Additional experiments were performed to compare in vitro to in vivo ovalbumin release rates from the gel. Methods: The ovalbumin content of the eye tissues was monitored by spectrophotometric assays of tissue extracts of Alexa 647 ovalbumin from dissected sclera, choroid, and retina at time points ranging from 2 h to 14 days. At the same time points, fl uorescence microscopy images of tissue samples were also obtained. Measurement of intact ovalbumin was verifi ed by LDS-PAGE analysis of the tissue extract solutions. In vitro release of Alexa 488 ovalbumin into 37ºC PBS solutions from ovalbumin-loaded gel pellets was also monitored over time by spectrophotometric assay. In vivo ovalbumin release rates were determined by measurement of residual ovalbumin extracted from gel pellets removed from rat eyes at various time intervals. Results: Our results indicate that ovalbumin concentrations can be maintained at measurable levels in the sclera, choroid, and retina of rats for up to 14 days using the thermosetting gel delivery system. The concentration of ovalbumin exhibited a gradient that decreased from sclera to choroid and to retina. The in vitro release rate profi les were similar to the in vivo release profi les. Conclusions: Our fi ndings suggest that the thermosetting gel system may be a feasible method for safe and convenient sustained delivery of proteins to choroidal and retinal tissue in the posterior segments of the eye.

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“…A biocompatibilidade e a biodegradação in vivo de implantes intravítreos preparados com diferentes ésteres de ácido hialurônico foi avaliada em olhos de coelhos (Avitabile et al, 2001 A segurança e a eficácia de um sistema biodegradável composto de PLGA e contendo 0,5 mg de ciclosporina (CsA) foram avaliadas após sua implantação na câmara anterior de olhos de coelhos (Theng et al, 2003 A eficácia de um implante polimérico biodegradável contendo tacrolimus foi avaliada em um modelo animal de uveíte experimental (Sakurai et al, 2003 A uveíte recorrente equina (URE), também conhecida como cegueira da lua, iridociclite e oftalmia periódica é a causa mais comum de cegueira em BIONDI, F. et al Implantes poliméricos intraoculares de fármacos na medicina veterinária, revisão de literatura e relato de um caso. PUBVET, Londrina, V. 6, N. 23, Ed.…”

Section: Desenvolvimentounclassified

“…210, Art. 1399, 2012 em severos efeitos adversos (Fialho e Cunha Júnior, 2007 Devido a todas as dificuldades encontradas, algumas pesquisas têm sido realizadas no sentido de desenvolver sistemas de administração intraoculares que permitam liberar concentrações terapêuticas dos fármacos por um período prolongado e adequado (Rubsamen et al, 1994;Hashizoe et al, 1994;Chang e Wong, 1999;Gilger et al, 2000;Avitabile et al, 2001;Okabe et al, 2003;Sakurai et al, 2003;Saliba et al, 2008;Choonara et al, 2011;Haghjou et al, 2011). Tais sistemas podem proporcionar inúmeras vantagens, como aumentar a biodisponibilidade do fármaco, no sentido de obter uma liberação constante e prolongada; aumentar as concentrações locais, sem a ocorrência de efeitos adversos sistêmicos; atingir mais especificamente um tipo de tecido ou célula; reduzir a freqüência de injeções intraoculares.…”

Section: Introductionunclassified

Untitled

2012

Pubvet

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ResumoDoenças do segmento posterior do bulbo do olho são responsáveis pela maioria dos casos de cegueira irreversível no mundo inteiro e, até o momento, BIONDI, F. et al. Implantes poliméricos intraoculares de fármacos na medicina veterinária, revisão de literatura e relato de um caso. PUBVET, Londrina, V. 6, N. 23, Ed. 210, Art. 1399, 2012 apresentam sucesso terapêutico limitado devido à dificuldade de penetração dos fármacos neste local. Na medicina veterinária, as doenças oculares crônicas apresentam frequente insucesso terapêutico por conta da frequência e via de administração, além do alto custo das medicações. Visando a obtenção de níveis terapêuticos adequados de fármacos por períodos prolongados e a diminuição de efeitos colaterais indesejados, alguns sistemas de liberação poliméricos de implantação intraocular estão sendo investigados. Eles são preparados na forma de implantes a partir de polímeros que podem ser biodegradáveis ou não biodegradáveis, e pretendem revolucionar a oftalmologia humana e veterinária, aumentando o conforto do paciente e a eficácia medicamentosa no tratamento de doenças até o momento tidas como irreversíveis por conta das dificuldades terapêuticas á elas relacionadas.Palavras-chave: doenças oculares; medicação intraocular; sistemas de liberação. Polymeric implants for intraocular administration of drugs inveterinary medicine -review of the literature and report of a case AbstractDiseases of the posterior segment of the eye are responsible for most cases of irreversible blindness, and until at the present moment, have limited therapeutic success due to the difficulty of penetration of drugs in this site. In veterinary medicine, chronic eye diseases are often frustrating to treat due to the frequency and route of administration, besides the high cost of the drugs involved. In order to obtain therapeutic levels of these drugs for prolonged periods and to promote reduction of unwanted side effects, some polymeric delivery systems designed for intraocular implantation are currently being investigated. They are prepared in the form of implants from polymers that can be classified in biodegradable or nonbiodegradable, and are aimed to revolutionize medical and veterinary ophthalmology, increasing patient comfort BIONDI, F. et al. Implantes poliméricos intraoculares de fármacos na medicina veterinária, revisão de literatura e relato de um caso. PUBVET, Londrina, V. 6, N. 23, Ed. 210, Art. 1399, 2012 and effectiveness of drugs in the treatment of diseases, which are so far regarded as irreversible because of the difficulties therapies related to them.Keywords: eye diseases; intraocular medication; systems release. INTRODUÇÃOAs doenças oculares acometem as mais diversas espécies, incluindo a espécie humana, podendo causar intenso desconforto, comprometimento da acuidade visual e, por fim, cegueira. Sabe-se que as doenças do segmento posterior do olho são responsáveis pela maioria dos casos de cegueira irreversível no mundo (Fialho e Cunha Júnior, 2007). Em seres humanos, crescem os caso...

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Scleral Plug of Biodegradable Polymers Containing Tacrolimus (FK506) for Experimental Uveitis

Abstract: Intravitreal sustained-release of FK506 from a biodegradable polymeric scleral plug was highly effective in suppressing the inflammation of experimental uveitis in a rabbit model for at least 6 weeks. This device may be useful in the management of patients with severe chronic uveitis.

Cited by 68 publications

References 12 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

Sustained Subconjunctival Protein Delivery Using a Thermosetting Gel Delivery System

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