Abstract
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.
Highlights
Applied eyedrops are the most commonly used dosage form in ocular drug Topically applied eyedrops aretreatment the most commonly used dosagediseases, form in ocular drug treatment.They are used in the of anterior segment such as infections treatment.They are used in the treatment of anterior segment diseases, such as infections, inflammatory conditions, and glaucoma
hydroxypropyl methylcellulose (HPMC) E5 was obtained from Dow Chemicals (Dow Chemicals, Midland, MI, USA), HPMC 4000 was obtained from Sigma-Aldrich
(260 μg/mL) in Indom were measured by ultra-performance liquid chromatography (UPLC)
Summary
Applied eyedrops are the most commonly used dosage form in ocular drug Topically applied eyedrops aretreatment the most commonly used dosagediseases, form in ocular drug treatment.They are used in the of anterior segment such as infections treatment.They are used in the treatment of anterior segment diseases, such as infections, inflammatory conditions, and glaucoma. Applied eyedrops are the most commonly used dosage form in ocular drug Topically applied eyedrops aretreatment the most commonly used dosagediseases, form in ocular drug treatment They are used in the of anterior segment such as infections treatment. Ocular bioavailability of drugs af inflammatory conditions, and glaucoma. 5% of theofinstilled dose, often eyedrop administration to rabbits is limited to less than 5% of the instilled dose, often less less than 1% [1]. This is due to several limiting factors: (1) the permeation barrier of the than 1% [1]. This is due to several limiting factors: (1) the permeation barrier of the corneal corneal epithelium [2]; (2) rapid drainage of the instilled drug from the ocular surface [3]
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