General Pharmacokinetic Model for Topically Administered Ocular Drug Dosage Forms

Deng, Feng; Ranta, Veli‐Pekka; Kidron, Heidi; Urtti, Arto

doi:10.1007/s11095-016-1993-2

Cited by 18 publications

(8 citation statements)

References 36 publications

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“…Since water solubility of indomethacin at neutral pH is 43 µg/mL, we conclude that dissolution of suspended particles is affected by the dissolved drug in the tear fluid and the sink conditions may not prevail in vivo. Earlier publications suggest that only a fraction of fluorometholone particles dissolve after topical administration in the rabbit eyes [8,10,28]. We can reach this conclusion because the AUC in aqueous humor increased only ≈2-4-fold with suspensions as compared to the fluorometholone solution, even though the drug dose in the suspensions (25 µg) was 67 times higher than in the solution (0.375 µg).…”

Section: Discussionmentioning

confidence: 56%

Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin

et al. 2021

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Eye drops of poorly soluble drugs are frequently formulated as suspensions. Bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid, but these factors are still poorly understood. We investigated seven ocular indomethacin suspensions (experimental suspensions with two particle sizes and three viscosities, one commercial suspension) in physical and biological tests. The median particle size (d50) categories of the experimental suspensions were 0.37–1.33 and 3.12–3.50 µm and their viscosity levels were 1.3, 7.0, and 15 mPa·s. Smaller particle size facilitated ocular absorption of indomethacin to the aqueous humor of albino rabbits. In aqueous humor the AUC values of indomethacin suspensions with different particle sizes, but equal viscosity, differed over a 1.5 to 2.3-fold range. Higher viscosity increased ocular absorption 3.4–4.3-fold for the suspensions with similar particle sizes. Overall, the bioavailability range for the suspensions was about 8-fold. Instillation of larger particles resulted in higher tear fluid AUC values of total indomethacin (suspended and dissolved) as compared to application of smaller particles. Despite these tear fluid AUC values of total indomethacin, instillation of the larger particles resulted in smaller AUC levels of indomethacin in the aqueous humor. This suggests that the small particles yielded higher concentrations of dissolved indomethacin in the tear fluid, thereby leading to improved ocular bioavailability. This new conclusion was supported by ocular pharmacokinetic modeling. Both particle size and viscosity have a significant impact on drug concentrations in the tear fluid and ocular drug bioavailability from topical suspensions. Viscosity and particle size are the key players in the complex interplay of drug retention and dissolution in the tear fluid, thereby defining ocular drug absorption and bioequivalence of ocular suspensions.

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Section: Discussionmentioning

confidence: 56%

Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin

et al. 2021

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“…302 The FDA has developed a regulatory guidance for some dosage forms, for example, to validate the use of dissolution models to establish dissolution specifications, 302 and to reduce the number clinical bioequivalence studies to support biowaivers and bioequivalence criteria. 302,303 Ocular models for topical or anterior segment delivery are more established than models for the posterior segment. For example, in vitro models using isolated corneal epithelial cells from rabbits 301 mimic the corneal barrier for use to develop of topically administered medicines such as eyedrops.…”

Section: In Vitro Models As Preclinical Tools To Develop Intraocular Therapiesmentioning

confidence: 99%

Preclinical challenges for developing long acting intravitreal medicines

Awwad

Henein

Ibeanu

et al. 2020

European Journal of Pharmaceutics and Biopharmaceutics

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…However, rabbits are generally used as surrogates for drug devices and pharmacokinetic studies as their eye anatomy and physiology resemble those in humans. 41 In addition, the NVCM level in solid ocular tissue cannot be measured in vivo at different time-points on the same rabbit by the HPLC-PDA method because the solid ocular tissues can only be obtained when the animal is humanely killed. Generalization of these data from rabbits to humans would be influenced by lower rabbit tear volumes and blink rate, which may affect the dynamics of NVCM dissolution, and the release and ocular absorption of the impregnated drugs.…”

Section: Dovepressmentioning

confidence: 99%

<p>Comparative Assessment of Distribution Characteristics and Ocular Pharmacokinetics of Norvancomycin Between Continuous Topical Ocular Instillation and Hourly Administration of Eye Drop</p>

Lin

Zhao

Huang

et al. 2020

DDDT

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Background: The aim of this study was to compare the distribution characteristics and ocular pharmacokinetics of norvancomycin (NVCM) in ocular tissues of the anterior segment between continuous topical ocular instillation and hourly administration of eye drop in rabbits. Methods: Sixty rabbits were randomly divided into two groups: continuous topical ocular instillation drug delivery (CTOIDD) group and eye drop (control) group. In the CTOIDD group, NVCM solution (50 mg/mL) was perfused to the ocular surface using the CTOIDD system at 2 mL/ h up to 10 h and the same solution was administered at one drop (50 μL) per hour for 10 h in the control group. Animals (N=6 per time-point per group) were humanely killed at 2, 4, 6, 10, and 24 h to analyze their ocular tissues and plasma. The concentrations of NVCM in the conjunctiva, cornea, aqueous humour, iris, ciliary body and plasma were measured by HPLC with photodiode array detector. The pharmacokinetic parameters were calculated by Kinetica 5.1. Results: The highest concentrations of NVCM for the CTOIDD group and control group were 2105.45±919.89 μg/g and 97.18±43.14 μg/g in cornea, 3033.92±1061.95 μg/g and 806.99 ±563.02 μg/g in conjunctiva, 1570.19±402.87 μg/g and 46.93±23.46 μg/g in iris, 181.94 ±47.11 μg/g and 15.38±4.00 μg/g in ciliary body, 29.78±4.90 μg/mL and 3.20±1.48 μg/mL in aqueous humour, and 26.89±5.57 μg/mL and 1.90±1.87 μg/mL in plasma, respectively. The mean NVCM levels significantly increased at all time-points in cornea, iris, and ciliary body (p<0.05) in the CTOIDD group. The AUC 0-24 values in the CTOIDD group were 27,543.70 μg•h/g in cornea, 32,514.48 μg•h/g in conjunctiva, 8631.05 μg•h/g in iris, 2194.36 μg•h/g in ciliary body and 343.9 μg•h/mL in aqueous humour, which were higher than for the eye drop group in all tissues. Conclusion: Since continuous instillation of NVCM with CTOIDD could reach significantly higher concentrations and was sustained for a longer period compared with hourly administration of eye drop, CTOIDD administered NVCM could be a possible method to treat bacterial keratitis.

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General Pharmacokinetic Model for Topically Administered Ocular Drug Dosage Forms

Abstract: The model is suitable for the development of ophthalmic formulations and the planning of bioequivalence studies.

Cited by 18 publications

References 36 publications

Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin

Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin

Preclinical challenges for developing long acting intravitreal medicines

<p>Comparative Assessment of Distribution Characteristics and Ocular Pharmacokinetics of Norvancomycin Between Continuous Topical Ocular Instillation and Hourly Administration of Eye Drop</p>

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