Ocular emulsions and dry eye: a case study of a non-biological complex drug product delivered to a complex organ to treat a complex disease

Gore, Anu; Attar, Mayssa; Pujara, Chetan P.; Neervannan, Sesha

doi:10.5639/gabij.2017.0601.004

Cited by 18 publications

(21 citation statements)

References 17 publications

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“…A recent publication suggested that salt sensitivity of carbomer copolymer type A would lead to degradation of the polymer in the ion-rich tear film and produce a subsequent reduction in viscosity, although no data were presented to quantify this effect. 59 To estimate the impact of this mechanism in the context of this study, human bioavailability predictions were produced for the reference product and test 3 with permeability case 1 and ε ¼ 1, where it was assumed that after 5 min, 50% of the viscosity enhancer degraded instantaneously. This degradation produced an approximate 50% decrease in viscosity and similarly, surface tension and osmolality were brought 50% closer to baseline values.…”

Section: Discussionmentioning

confidence: 99%

Impact of Vehicle Physicochemical Properties on Modeling-Based Predictions of Cyclosporine Ophthalmic Emulsion Bioavailability and Tear Film Breakup Time

Walenga

Babiskin

Zhang

et al. 2019

Journal of Pharmaceutical Sciences

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Several physicochemical parameters are thought to affect in vivo performance of cyclosporine ophthalmic emulsion, including globule size distribution, viscosity profile as a function of applied shear, pH, zeta potential, osmolality, and surface tension. Using a modeling approach, this study predicts cyclosporine ophthalmic emulsion drug bioavailability to the cornea and conjunctiva and tear film breakup time for human subjects as a function of the vehicle physicochemical properties viscosity, surface tension, and osmolality for products that are qualitatively (Q1) and quantitatively (Q2) the same. The change in tear film breakup time from baseline, a potential indirect measure of therapeutic benefit, was predicted to characterize the direct effect of the vehicle on efficacy. Bioavailability predictions showed that while individual predictions were sensitive to variations in corneal and conjunctival permeabilities, geometric mean ratios of the test-to-reference comparisons for formulations that are Q1 and Q2 the same showed little sensitivity. Parameter sensitivity analysis showed that bioavailability and change in tear film breakup time from baseline values were both very sensitive to viscosity, slightly sensitive to surface tension, and insensitive to osmolality. With further improvements, the modeling framework developed for this study may be useful for informing future recommendations of cyclosporine ophthalmic emulsion bioequivalence for potential generic drug products.

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Section: Discussionmentioning

confidence: 99%

Impact of Vehicle Physicochemical Properties on Modeling-Based Predictions of Cyclosporine Ophthalmic Emulsion Bioavailability and Tear Film Breakup Time

Walenga

Babiskin

Zhang

et al. 2019

Journal of Pharmaceutical Sciences

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“…We suggest that tolerability issues are likely caused by the formulation, as complex emulsions have free surfactants and free drug in the aqueous phase, which could damage the cornea and induce pain 14 ( Fig. 1B ).…”

Section: Discussionmentioning

confidence: 99%

“…Restasis is a complex emulsion with components distributed in various phases determined by the their physicochemical properties as well as the process used for manufacturing the emulsion 14 ( Fig. 1B ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, CsA-MiDROPS has distinct advantages over complex emulsions, such as Restasis, because they are dilutable isotropic microemulsions that do not break down when exposed to the tear film. Such breakdown leads to the release of free surfactants that may cause irritation to the ocular surface 14 ( Fig. 1B ).…”

Section: Introductionmentioning

confidence: 99%

“…With complex emulsions like Restasis, the CsA is present in multiple phases and could possess a different biological activity in each phase, which may limit the effective delivery of CsA to the affected tissues. 14 Additionally, MiDROPS are thermodynamically stable with a potentially long shelf life, spontaneously form under the correct conditions, and are easy and cheap to manufacture, in stark contrast to the complicated manufacturing process of other complex CsA emulsions. 14 The availability of a more efficacious, better tolerated, and cost-effective formulation of CsA could improve the lives of millions of patients that suffer from DED.…”

Section: Introductionmentioning

confidence: 99%

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Once-Daily Cyclosporine-A-MiDROPS for Treatment of Dry Eye Disease

Coursey¹,

Wassel²,

Quiambao³

et al. 2018

Trans. Vis. Sci. Tech.

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PurposeTo determine if a Microemulsion Drug Ocular Penetration System (MiDROPS) formulation of cyclosporine A (CsA) delivers more drug and is more efficacious for treatment of dry eye disease (DED) than the current clinical formulation.MethodsTissue distribution of CsA was quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). To assess tolerability, CsA-MiDROPS (0.1%) was applied to the eyes of rabbits twice per day for 14 days and assessed using ophthalmoscopic examinations. Mice were exposed to desiccating stress for 10 days and received daily topical instillation of the vehicle or test agent. Cornea staining was done to quantify corneal permeability. Histologic quantification of goblet cell (GC) density and CD4+ T-cell infiltration in the conjunctiva was performed.ResultsOphthalmic distribution studies indicate significantly increased drug concentration with CsA-MiDROPS compared with Restasis. CsA-MiDROPS is well tolerated with little toxicity in a 2-week tolerability study. In the DED model, both 0.05% and 0.1% CsA-MiDROPS conferred a significant effect and were more effective than Restasis for treating experimental DED when dosed twice per day. As compared with Restasis dosed twice per day, 0.1% CsA-MiDROPS dosed once per day demonstrated superiority.ConclusionsCsA-MiDROPS showed superior drug delivery and efficacy compared with other clinical formulations. As this product is simple to produce and needs to be only applied once daily, the clinical development of CsA-MiDROPS will help to reduce societal and patient burdens by lowering drug costs and accelerating/improving the activity of CsA.Translational RelevanceMiDROPS has broad application concerning the ophthalmic development of lipophilic small molecule therapeutics.

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Potentiality of Q3 characterization of nanosystem: Surrogate data for obtaining a biowaiver

Mohan

Yadav

2020

Drug Development Research

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A tremendous increase in the entry of drug delivery systems (DDSs) based on nanotechnology has been observed as a result of the ability of pharmaceutical nanotechnology to overcome the various drawbacks related to the first generation DDS. The patent period of these proprietary branded drugs gives its manufacturers sole exclusivity of their product in the market. As the patent period of these products expire, the generic players will initiate their attempts to manufacture and bring generic versions of the reference listed drug product (RLD) into the market. The regulatory approval for a generic DDS based on nanotechnology requires proving the therapeutic equivalence of the generic product with that of the RLD via pharmacodynamics clinical endpoint study on healthy subjects or patients. These studies are extremely complex, expensive and time‐consuming and may have uncertain outcomes. Furthermore, development, scale‐up and manufacturing of generic versions of nanotechnology‐based DDS involves complex steps and achieving an optimized formulation heavily depends on the process parameters during manufacturing. The information in this review addresses the said issues above and emphasizes on the possibility of using exhaustive in vitro characterization of the generic versions of nanotechnology‐based DDSs in the current market to obtain a biowaiver. Various processes involved and their importance in obtaining an optimized formulation have been described to address the issue regarding manufacturing complexities.

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Ocular emulsions and dry eye: a case study of a non-biological complex drug product delivered to a complex organ to treat a complex disease

Cited by 18 publications

References 17 publications

Impact of Vehicle Physicochemical Properties on Modeling-Based Predictions of Cyclosporine Ophthalmic Emulsion Bioavailability and Tear Film Breakup Time

Impact of Vehicle Physicochemical Properties on Modeling-Based Predictions of Cyclosporine Ophthalmic Emulsion Bioavailability and Tear Film Breakup Time

Once-Daily Cyclosporine-A-MiDROPS for Treatment of Dry Eye Disease

Potentiality of Q3 characterization of nanosystem: Surrogate data for obtaining a biowaiver

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