Vitreous Pharmacokinetics and Retinal Safety of Intravitreal Preserved Versus Non-preserved Triamcinolone Acetonide in Rabbit Eyes

Oliveira, R. C.; Messias, André; Siqueira, Rubens Camargo; Bonini-Filho, Marco A.; Haddad, Antônio; Damico, Francisco Max; Maia-Filho, A; Crispim, Pedro di Tárique Barreto; Saliba, Juliana Barbosa; Ribeiro, J.A.; Silva-Cunha, Armando; Jorge, Rodrigo

doi:10.3109/02713683.2011.593722

Cited by 15 publications

(11 citation statements)

References 21 publications

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“…6) of the nanoparticle-within-microparticle drug delivery system was measured to assess the suitability for IVT. The particle sizes were in the range of 3.04 -6.04 µm which is considerably smaller than previously reported particles of sizes 14 -21 μm (9,67) which showed no effects on the retinal in vivo studies. Thus, based on the size, the particles appear to be suitable for IVT.…”

Section: Particle Size and Zeta Potentialmentioning

confidence: 68%

PLGA Microparticles Entrapping Chitosan-Based Nanoparticles for the Ocular Delivery of Ranibizumab

et al. 2016

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Age-related macular degeneration (AMD) is the leading cause of certified vision loss worldwide. The standard treatment for neovascular AMD involves repeated intravitreal injections of therapeutic proteins directed against vascular endothelial growth factor, such as ranibizumab. Biodegradable polymers, such as poly(lactic-co-glycolic acid) (PLGA), form delivery vehicles which can be used to treat posterior segment eye diseases, but suffer from poor protein loading and release. This work describes a 'system-within-system', PLGA microparticles incorporating chitosan-based nanoparticles, for improved loading and sustained intravitreal delivery of ranibizumab. Chitosan-N-acetyl-L-cysteine (CNAC) was synthesized and its synthesis confirmed using FT-IR and 1 H NMR. Chitosan-based nanoparticles comprised of CNAC, CNAC/tripolyphosphate (CNAC/TPP), chitosan, chitosan/TPP (chit/TPP) or chit/TPP-hyaluronic acid (chit/TPP-HA) were incorporated in PLGA microparticles using a modified w/o/w double emulsion method. Nanoparticles and final nanoparticles-within-microparticles were characterized for their protein-nanoparticle interaction, size, zeta potential, morphology, protein loading, stability, in vitro release, in vivo anti-angiogenic activity and effects on cell viability. The prepared nanoparticles were 17 -350 nm in size and had zeta potentials of -1.4 to +12 mV. Microscopic imaging revealed spherical nanoparticles on the surface of PLGA microparticles for preparations containing chit/TPP, CNAC and CNAC/TPP. Ranibizumab entrapment efficiency in the preparations varied between 13 -69% and was highest for the PLGA microparticles containing CNAC nanoparticles. This preparation also showed the slowest release with no initial burst release compared to all other preparations. Incorporation of TPP to this formulation increased the rate of protein release and reduced entrapment efficiency. PLGA microparticles containing chit/TPP-HA showed the fastest and near-complete release of ranibizumab. All of the prepared empty particles showed no effect on cell viability up to a concentration of 12.5 mg/mL. Ranibizumab released from all preparations maintained its structural integrity and in vitro activity. The chit/TPP-HA preparation enhanced anti-angiogenic activity and may provide a potential biocompatible platform for enhanced anti-angiogenic activity in combination with ranibizumab. In conclusion, the PLGA microparticles containing CNAC nanoparticles, showed significantly improved ranibizumab loading and release profile. This novel drug delivery system may have potential for improved intravitreal delivery of therapeutic proteins, thereby reducing the frequency, risk and cost of burdensome intravitreal injections.

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Section: Particle Size and Zeta Potentialmentioning

confidence: 68%

PLGA Microparticles Entrapping Chitosan-Based Nanoparticles for the Ocular Delivery of Ranibizumab

et al. 2016

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“…There have been no prior reports of Naka-Rushton analysis in preclinical studies involving intravitreal administrations of MTX. However, research by Oliveira et al 8 on intravitreal administration of triamcinolone acetonide in normal rabbit eyes reported ''-log K'' values in the range of 2.82-3.37 for both treated and nontreated eyes. The range of ''-log K'' values obtained in the photopic protocol of the current study (2.92-2.97) is similar to that obtained in the study of Oliveira et al 8 Furthermore, the Naka-Rushton analysis showed that there is no significant difference in the means of the ''n'' values and the means of the ''-log K'' values in any of the eyes for both the scotopic and the photopic protocols, which also implies no significant change in the retinal sensitivity because of the presence of the PLAcoated CS-MTX microimplant or the placebo microimplants.…”

Section: Author Disclosure Statementmentioning

confidence: 97%

“…Prior studies that involved assessment of the safety of the intravitreal implants using ERG were involved with sustained administration of lipophilic drugs, such as dexamethasone, triamcinolone, and 2-methoxyestradiol. [6][7][8][9] There has been no report of evaluation of the safety of sustained-release hydrophilic drugs, such as MTX, over a long duration using ERG.…”

Section: Assessment Of Toxicity From Mtx Delivery Systemmentioning

confidence: 99%

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Noninvasive Electroretinography Assessment of Intravitreal Sustained-Release Methotrexate Microimplants in Rabbit Eyes

Manna

Augsburger

Corrêa

et al. 2016

Journal of Ocular Pharmacology and Therapeutics

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“…Some in vivo experimental studies suggest that TA intravitreal injection, which formula contains PS80, is safe [10][11][12] . However, other experimental studies suggest that TA formulation without preservative is less toxic to retina after intravitreal injection than most common formulas [13][14][15] .…”

mentioning

confidence: 99%

Intravitreal injection of polysorbate 80: a functional and morphological study

Damico¹,

Gasparin²,

Ioshimoto³

et al. 2017

Rev. Col. Bras. Cir.

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Objective : to determine the functional and morphological effects at rabbits retina of PS80 concentration used in the preparation of intravitreal drugs. Methods: eleven New Zealand rabbits received a intravitreal injection of 0.1ml of PS80. As control, the contralateral eye of each rabbit received the same volume of saline. Electroretinography was performed according to a modified protocol, as well as biomicroscopy and retina mapping before injection and seven and ten days after. Animals were euthanized in the 30th day and the retinas were analyzed by light microscopy. Results: eyes injected with PS80 did not present clinical signs of intraocular inflammation. Electroretinography did not show any alteration of extent and implicit time of a and b waves at scotopic and photopic conditions. There were no morphological alterations of retinas at light microscopy. Conclusion: intravitreal injection of PS80 in the used concentration for intravitreal drug preparations do not cause any functional or morphological alterations of rabbit retinas. These results suggest that PS80 is not toxic to rabbit retinas and may be safely used in the preparation of new lipophilic drugs for intravitreal injection.

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Vitreous Pharmacokinetics and Retinal Safety of Intravitreal Preserved Versus Non-preserved Triamcinolone Acetonide in Rabbit Eyes

Abstract: Following a single intravitreal injection, the median concentration of triamcinolone acetonide is significantly higher in the TA-BA compared to the TA-PF group at 7 days post-injection. No toxic reactions in the retina were observed in either group.

Cited by 15 publications

References 21 publications

PLGA Microparticles Entrapping Chitosan-Based Nanoparticles for the Ocular Delivery of Ranibizumab

PLGA Microparticles Entrapping Chitosan-Based Nanoparticles for the Ocular Delivery of Ranibizumab

Noninvasive Electroretinography Assessment of Intravitreal Sustained-Release Methotrexate Microimplants in Rabbit Eyes

Intravitreal injection of polysorbate 80: a functional and morphological study

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