Effect of Particle Size on Ophthalmic Bioavailability of Dexamethasone Suspensions in Rabbits

doi:10.1002/jps.2600690407

Journal of Pharmaceutical Sciences

Volume 69, Issue 4, April 1980, Pages 391-394

https://doi.org/10.1002/jps.2600690407 Get rights and content

Abstract

Three suspensions of 0.1% [³H]dexamethasone were prepared with mean particle sizes of 5.75, 11.5, and 22.0 μm. The suspensions were dosed topically to the right eyes of rabbits. Their bioavailability was compared by measuring aqueous humor and corneal levels over 5 hr. A statistically significant rank-order correlation was observed between increasing drug levels and decreasing particle size.

References (13)

SiegJ.W. et al.
J. Pharm. Sci.
(1977)
SkauenD.M.
J. Pharm. Sci.
(1967)
PrincipeJ.R. et al.
J. Pharm. Sci.
(1962)
FincherJ.
J. Pharm. Sci.
(1968)
J. Pharm. Sci.
(1975)
CohenR.M. et al.
J. Pharm. Sci.
(1964)

There are more references available in the full text version of this article.

Cited by (94)

Topical pharmacokinetics of brinzolamide suspensions in rabbits and variability analysis for sample size and design considerations
2023, International Journal of Pharmaceutics
Identifying critical attributes for complex locally acting ophthalmic formulations and establishing in vitro-in vivo correlations can facilitate selection of appropriate thresholds for formulation changes that reflect lack of impact on in vivo performance. In this study the marketed antiglaucoma product Azopt® (1% brinzolamide suspension) and five other brinzolamide formulations varying in particle size distributions and apparent viscosities were topically administered in rabbits, and their ocular pharmacokinetics was determined in multiple ocular tissues. Statistical evaluation with ANOVA showed no significant differences between the formulations in the peak drug concentration (C_max) in the aqueous humor and iris-ciliary body. As a post-hoc analysis, the within animal and total variability was determined for C_max in the aqueous humor and iris-ciliary body. Based on the observed variability, we investigated the sample size needed for two types of study designs to observe statistically significant differences in C_max. For the sample size calculations, assuming both 25% and 50% true differences in C_max between two formulations, two study designs were compared: paired-eye dosing design (one formulation in one eye and another formulation in the other eye of the same animal at the same time) versus parallel-group design. The number of rabbits needed in the paired-eye dosing design are much lower than in the parallel-group design. For example, when the true difference in aqueous humor C_max is 25%, nine rabbits are required in the paired-eye design versus seventy rabbits (35 per treatment) in the parallel-group design to observe a statistically significant difference with a power of 80%. Therefore, the proposed paired-eye dosing design is a viable option for the design of pharmacokinetic studies comparing ophthalmic products to determine the impact of formulation differences.
Fathoming biopharmaceutical tenets and characterization techniques for the plausible ophthalmic drug delivery performance
2023, Nanotechnology in Ophthalmology
Drugs utilized for ocular drug delivery therapeutics are typically transported directly into the eye. The ocular bioavailability, potency, and clearance of the locally administered drugs at the target site govern the drug loading efficiency, sustained release, and ocular drug retention time of delivery systems. The drug entrapment efficiency of the formulation is further reliant on the excipient's properties and manacles of the ocular system. The design aid for ocular drug delivery systems described herein is the computation of steady-state drug concentrations in the ocular compartments by taking bioavailability, drug dosage, and clearance into account. An appropriate dosing rate can be adjusted to achieve the target site drug concentrations, thereby leading to the development of topical, intravitreal, and subconjunctival drug delivery systems. Several ophthalmic dosage forms based on conventional and nanotherapeutic drug delivery systems have been designed in the early phases of drug development without much expertise in pharmacodynamic and pharmacokinetic modeling. Further, it is also imperative to evaluate the biopharmaceutical, formulation, and pharmacokinetic parameters (such as dosage pattern, particle size and its morphology, clarity, pH, viscosity, the gel-forming capacity of polymer, and drug excipient interactions) for designing a robust system. This present chapter aims to summarize biopharmaceutical aspects and characterization techniques employed in ophthalmic drug delivery therapeutics indispensable for its cost-effective design and development, better quality control, and targeted therapeutic drug delivery within the safety spectrum.
Nanosuspension-loaded dissolving bilayer microneedles for hydrophobic drug delivery to the posterior segment of the eye
2022, Biomaterials Advances
Intravitreal injections (IVT) are regarded as the gold standard for effective delivery of hydrophobic drugs to the back of the eye. However, as a highly invasive procedure, the injection itself may lead to poor patient compliance and severe complications. In this research work, a hybrid system of nanosuspensions (NS) and dissolving microneedles (MNs) was developed as an alternative to conventional hypodermic needles used in IVT for minimally invasive transscleral delivery of hydrophobic drugs. NS of a hydrophobic drug, triamcinolone acetonide (TA), were fabricated using a wet milling technique. TA NS optimised by central composite factorial design had a proven diameter of 246.65 ± 8.55 nm. After optimisation, TA NS were incorporated into MN arrays to form a bilayer structure by high-speed centrifugation. TA NS-loaded MNs were robust enough to pierce excised porcine sclera with insertion depth higher than 80% of the needle height and showed rapid dissolution (<3 min). In contrast, the plain TA-loaded MNs exhibited poor mechanical and insertion performances and took more than 8 min to be fully dissolved in the scleral tissue. Importantly, transscleral deposition studies showed that 56.46 ± 7.76 μg/mm² of TA was deposited into the sclera after 5 min of NS-loaded MN application, which was 4.5-fold higher than plain drug-loaded MNs (12.56 ± 2.59 μg/mm²). An ex vivo distribution study revealed that MN arrays could promote the transscleral penetration of hydrophobic molecules with higher drug concentrations observed in the deep layer of the sclera. Moreover, the developed TA NS-loaded MN array was biocompatible with ocular tissues, as demonstrated using the hens egg-chorioallantoic membrane assay and cytotoxicity test. The results presented here demonstrate that the hybrid system of NS and dissolving MNs can provide a novel and promising technology to alleviate retinal diseases in a therapeutically effective and minimally invasive manner.
Topical pharmacokinetics of dexamethasone suspensions in the rabbit eye: Bioavailability comparison
2022, International Journal of Pharmaceutics
Citation Excerpt :
Early work on topical fluorometholone suspensions in albino rabbits showed that the particles present in an eye drop are retained within the cul‐de‐sac of the eye and contribute significantly to the amount of steroid penetrating the cornea (Sieg and Robinson, 1975). Schoenwald et al observed from their rabbit study with 0.1% [3H] dexamethasone a statistically significant rank-order correlation between increasing drug levels in aqueous humor and decreasing particle size (Schoenwald and Stewart, 1980). With other types of ocular suspensions (indomethacin) the importance of particle size and viscosity on the ocular absorption into rabbit eyes has been shown more recently (Toropainen et al., 2021).
Topical corticosteroids are used to treat inflammation of the anterior segment. Due to their low water-solubility, they are often formulated as suspensions, but ocular bioavailability of the suspensions is not known. Herein, ocular pharmacokinetics of dexamethasone in albino rabbits was investigated following intracameral administration of dexamethasone solution and topical administration of three commercial suspensions: Maxidex®, TobraDex®, and TobraDexST®. Dexamethasone concentrations in tear fluid, cornea, aqueous humor, conjunctiva and iris-ciliary body were determined. Non-compartmental analysis was performed to estimate the pharmacokinetic parameters of dexamethasone. Following intracameral administration, the clearance and the apparent volume of distribution were estimated to be 13.6 µL/min and 990 µL, respectively. After topical administration, the absolute aqueous humor bioavailability for dexamethasone (<2%) is being reported for the first time. The highest value was obtained for TobraDexST® followed by Maxidex® and TobraDex®. This study provides for the first-time comprehensive and quantitative ocular pharmacokinetic parameters (including absolute bioavailability) for topically instilled dexamethasone suspensions. Furthermore, the new intracameral pharmacokinetic parameters allow a rational and quantitative basis for the design of improved ocular dexamethasone delivery systems.
Recent advances in ophthalmic preparations: Ocular barriers, dosage forms and routes of administration
2021, International Journal of Pharmaceutics
Citation Excerpt :
Ophthalmic suspensions often have improved residence times due to the tendency of drug particles to be retained in the conjunctival cul-de-sac (Peters, 2020). Critical factors in the production of ophthalmic suspensions are particle size, intrinsic solubility and dissolution rate of the drug in the tear fluid (Schoenwald and Stewart, 1980). Usually, smaller drug particle of <10 µm have higher solubility and dissolution rates which lead to poor drug retention on the ocular surface.
The human eye is a complex organ with unique anatomy and physiology that restricts the delivery of drugs to target ocular tissues/sites. Recent advances in the field of pharmacy, biotechnology and material science have led to development of novel ophthalmic dosage forms which can provide sustained drug delivery, reduce dosing frequency and improve the ocular bioavailability of drugs. This review highlights the different anatomical and physiological factors which affect ocular bioavailability of drugs and explores advancements from 2016 to 2020 in various ophthalmic preparations. Different routes of drug administration such as topical, intravitreal, intraocular, juxtascleral, subconjunctival, intracameral and retrobulbar are discussed with their advances and limitations.
Novel water soluble sterile natamycin formulation (Natasol) for fungal keratitis
2021, European Journal of Pharmaceutical Sciences
Citation Excerpt :
It is a known fact that the Physiological factors in eye drains the instilled drug within 1-2 min (Lee and Robinson, 1986). Moreover, the coarse particles in the suspension promotes reflex tearing related drug dilution and drug loss (Schoenwald and Stewart, 1980). Apart from the physiological constraints, suspension formulation needs to be mixed thoroughly before instillation to have a uniform drug content (Nourry et al., 2011).
The purpose of this study was to develop, characterize and evaluate novel water soluble formulation for its topical and intrastromal application. Natamycin complexed with cyclodextrin was characterized by Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The complexed powder was used to formulate 1% w/v aqueous natamycin formulation (Natasol 1%) for topical use. The developed formulation was subjected to stability testing at various conditions. Single and multi-dose trans-corneal permeation of Natasol 1% was evaluated in New Zealand Albino rabbits in comparison with marketed 5% natamycin suspension. Sterile unpreserved Natasol (0.01% w/v natamycin) formulation was also developed for intrastromal injection. Both formulations were evaluated for the ocular toxicity. FTIR and DSC studies revealed successful complexation of natamycin that further protected the degradation at various stability conditions. Single dose trans-corneal permeation studies revealed that Natasol 1% attained Cmax at one hr and maintain its intraocular concentration 5 and 2.5 times higher at 4^th and 6^th hr compared to 5% natamycin suspension. Multi-dose kinetics revealed the steady state pharmacokinetics after hourly and two hourly dosing schedules. Topical Natasol 1% and sterile unpreserved Natasol 0.01% intrastromal injection, did not show any ocular toxicity in the animals. To conclude, the newly developed topical 1% w/v natamycin formulation was found to be non-inferior to 5% natamycin topical suspension. It is expected to increase patient compliance for the treatment of fungal keratitis.

View all citing articles on Scopus

View full text

Research ArticlesEffect of Particle Size on Ophthalmic Bioavailability of Dexamethasone Suspensions in Rabbits

Abstract

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

Research Articles
Effect of Particle Size on Ophthalmic Bioavailability of Dexamethasone Suspensions in Rabbits