Ocular biocompatibility of novel Cyclosporin A formulations based on methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide) micelle carriers

Tommaso, Claudia Di; Torriglia, Alicia; Furrer, Pascal; Behar‐Cohen, Francine; Gurny, Robert; Möller, Michael

doi:10.1016/j.ijpharm.2011.01.004

Cited by 71 publications

(58 citation statements)

References 48 publications

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“…These findings would stem from the fact that owing to their remarkably greater hydrodynamic diameter, micelles do not cross the dialysis membrane and serve as reservoirs, making the drug 120 108 96 84 72 60 48 36 24 12 T904 T908 T1107 T1307 T1107 : T1307 (50:50 120 108 96 84 72 60 48 36 24 12 T904 T908 T1107 T1307 T1107 : T1307 ( release process more sustained. If applied ocularly, polymeric micelles can remain in the apical zone of the eye or slowly penetrate inside the cornea, releasing the drug over time, as previously found for other micellar carriers [49]. In other words, once formulated in poloxamine micelles, the drug could be absorbed either in its free form or encapsulated in the carrier.…”

Section: ð3:2þmentioning

confidence: 73%

Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy

Ribeiro

Sosnik

Chiappetta

et al. 2012

J. R. Soc. Interface.

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Polymeric micelles of single and mixed poloxamines (Tetronic) were evaluated regarding their ability to host the antiglaucoma agent ethoxzolamide (ETOX) for topical ocular application. Three highly hydrophilic varieties of poloxamine (T908, T1107 and T1307) and a medium hydrophilic variety (T904), possessing a similar number of propylene oxide units but different contents in ethylene oxide, were chosen for the study. The critical micellar concentration and the cloud point of mixed micelles in 0.9 per cent NaCl were slightly greater than the values predicted from the additive rule, suggesting that the co-micellization is hindered. Micellar size ranged between 17 and 120 nm and it was not altered after the loading of ETOX (2.7-11.5 mg drug g -1 poloxamine). Drug solubilization ability ranked in the order: T904 (50-fold increase in the apparent solubility) . T1107 ffi T1307 . T908. Mixed micelles showed an intermediate capability to host ETOX but a greater physical stability, maintaining almost 100 per cent drug solubilized after 28 days. Furthermore, the different structural features of poloxamines and their combination in mixed micelles enabled the tuning of drug release profiles, sustaining the release in the 1-5 days range. These findings together with promising hen's egg test-chorioallantoic membrane biocompatibility tests make poloxamine micelles promising nanocarriers for carbonic anhydrase inhibitors in the treatment of glaucoma.

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Section: ð3:2þmentioning

confidence: 73%

Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy

Ribeiro

Sosnik

Chiappetta

et al. 2012

J. R. Soc. Interface.

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“…12 To decrease local side effects and to enhance the patient's comfort, CyA colloidal drug delivery systems are an interesting option for formulations to enable them to overcome ocular barriers. [13][14][15][16] The present work is focused on a novel topical micelle formulation based on methoxy poly(ethylene) glycol (MPEG)-hexyl-substituted poly(lactides) (hexPLA) to treat immunerelated ocular diseases and, in particular, dry eye syndrome. The formulation presented here has already shown excellent in vitro and in vivo ocular biocompatibility and efficiency in CyA solubilization.…”

Section: Discussionmentioning

confidence: 99%

“…The formulation presented here has already shown excellent in vitro and in vivo ocular biocompatibility and efficiency in CyA solubilization. 10,16 Here, in vitro and in vivo tests were performed to evaluate the suitability of this micelle formulation for dry eye treatment. The capacity of MPEG-hexPLA micelles to penetrate into primary corneal cells was investigated.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Cyclosporin A Aqueous Formulation for Dry Eye Treatment: In Vitro and In Vivo Evaluation

Tommaso

Valamanesh

Miller

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The aim of the present study was the in vitro and in vivo evaluation of a novel aqueous formulation based on polymeric micelles for the topical delivery of cyclosporine A for dry eye treatment. METHODS.In vitro experiments were carried out on primary rabbit corneal cells, which were characterized by immunocytochemistry using fluorescein-labeled lectin I/isolectin B4 for the endothelial cells and mouse monoclonal antibody to cytokeratin 3þ12 for the epithelial ones. Living cells were incubated for 1 hour or 24 hours with a fluorescently labeled micelle formulation and analyzed by fluorescence microscopy. In vivo evaluations were done by Schirmer test, osmolarity measurement, CyA kinetics in tears, and CyA ocular distribution after topical instillation. A 0.05% CyA micelle formulation was compared to a marketed emulsion (Restasis). RESULTS. The in vitro experimentsshowed the internalization of micelles in the living cells. The Schirmer test and osmolarity measurements demonstrated that micelles did not alter the ocular surface properties. The evaluation of the tear fluid gave similar CyA kinetics values: AUC ¼ 2339 6 1032 min*lg/mL and 2321 6 881.63; Cmax ¼ 478 6 111 lg/mL and 451 6 74; half-life ¼ 36 6 9 min and 28 6 9 for the micelle formulation and Restasis, respectively. The ocular distribution investigation revealed that the novel formulation delivered 1540 6 400 ng CyA/g tissue to the cornea.CONCLUSIONS. The micelle formulation delivered active CyA into the cornea without evident negative influence on the ocular surface properties. This formulation could be applied for immune-related ocular surface diseases. (Invest Ophthalmol Vis Sci.

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“…33 Cytotoxic effects of unloaded and prodrug-encapsulated nanomicelles were evaluated by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Since eye drops are rapidly cleared from the surface of the eye, 35,36,53 it was assumed that a 1-h incubation time would be sufficient to examine any toxic effects. All the micelle formulations did not affect cell viability after 1 h of incubation.…”

Section: Figmentioning

confidence: 99%

Aqueous Nanomicellar Formulation for Topical Delivery of Biotinylated Lipid Prodrug of Acyclovir: Formulation Development and Ocular Biocompatibility

Vadlapudi

Cholkar

Vadlapatla

et al. 2014

Journal of Ocular Pharmacology and Therapeutics

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Purpose: The objective of this study was to develop a clear, aqueous nanomicellar formulation and evaluate its in vitro ocular biocompatibility as a novel carrier for topical ocular delivery of biotinylated lipid prodrug for the treatment of herpetic keratitis. Methods: Micellar formulation of Biotin-12Hydroxystearic acid-acyclovir (B-12HS-ACV) was prepared by solvent evaporation/film hydration method with two nonionic surfactants, vitamin E TPGS and octoxynol-40. The optimized formulation was characterized for various parameters including micelle size, polydispersity index (PDI), and zeta-potential and in vitro prodrug release. Human corneal epithelial cells (HCECs) were employed for studying the cytotoxicity of the formulation. Further, mRNA expression levels of various cytokines were also studied with quantitative real-time PCR (qPCR). Results: Average size was 10.46 -0.05 nm with a PDI of 0.086 for blank nanomicelles, and 10.78 -0.09 nm with a PDI of 0.075 for prodrug-loaded nanomicelles. Both unloaded and prodrug-loaded nanomicelles had low negative zeta potential. Prodrug encapsulation efficiency of mixed nanomicelles was calculated to be *90%. Transmission electron microscopy analysis revealed that nanomicelles were spherical, homogenous, and devoid of aggregates. B-12HS-ACV release from nanomicelles was slow with no significant burst effect. Results show a sustained release of the prodrug from nanomicelles over a period of 4 days. Neither the blank formulation nor the prodrug-loaded micellar formulation demonstrated any cytotoxic effects. Further, incubation of HCECs with blank and prodrug-loaded nanomicellar groups did not significantly alter the expression levels of IL-1b, IL-6, IL-8, IL-17, TNF-a, and IFN-g. Conclusions: In summary, a topical clear, aqueous nanomicellar formulation comprised of vitamin E TPGS and octoxynol-40 loaded with 0.1% B-12HS-ACV was successfully developed. B-12HS-ACV-loaded nanomicelles are small in size, spherical, and homogenous, without any aggregates. The micellar formulations were perfectly transparent similar to pure water. Ocular biocompatibility studies indicated that mixed nanomicelles were nontoxic and noninflammatory to corneal epithelial cells. Therefore, nanomicellar technology represents a promising strategy for the delivery of biotinylated lipid prodrugs of ACV.

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Ocular biocompatibility of novel Cyclosporin A formulations based on methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide) micelle carriers

Cited by 71 publications

References 48 publications

Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy

Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy

A Novel Cyclosporin A Aqueous Formulation for Dry Eye Treatment: In Vitro and In Vivo Evaluation

Aqueous Nanomicellar Formulation for Topical Delivery of Biotinylated Lipid Prodrug of Acyclovir: Formulation Development and Ocular Biocompatibility

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