Ocular distribution, bactericidal activity and settling characteristics of TobraDex ST ophthalmic suspension compared with TobraDex ophthalmic suspension.

INTRODUCTION: TobraDex ophthalmic suspension (tobramycin 0.3%, dexamethasone 0.1%; Alcon Laboratories Inc, Fort Worth, Tex) is frequently used for inflammatory ocular conditions where a risk of bacterial ocular infection exists. A new formulation, TobraDex ST ophthalmic suspension (tobramycin 0.3%, dexamethasone 0.05%, Alcon), utilises a novel suspension technology to reduce viscosity and help prevent settling in the container. METHODS: A rabbit model that closely mimics the human eye and a clinical study with cataract patients was used to compare the pharmacokinetics and tissue permeability of TobraDex ST and TobraDex. An in-vitro model was used to assess the bactericidal activity using the rabbit tear concentrations of tobramycin 10 minutes after a single topical dose. RESULTS: Concentrations of both tobramycin and dexamethasone were greater in the tear film and ocular tissues of rabbits treated with TobraDex ST. There was an 8.3-fold increase in tobramycin concentration in the rabbit tear film 10 minutes after dosing with TobraDex ST compared with TobraDex. Concentrations of tobramycin and dexamethasone in ocular tissues from rabbits exposed to TobraDex ST were up to 12.5-fold greater relative to TobraDex. The in-vitro bactericidal activity (>99.9% kill, 3-log reduction) of TobraDex ST toward tobramycin-resistant and methicillin-resistant Staphylococcus aureus occurred in 90 minutes. TobraDex ST killed Streptococcus pneumoniae 3-log in 5 minutes. TobraDex had no activity toward tobramycin-resistant, methicillin-resistant S. aureus and required approximately 120 minutes for 3-log reduction of S. pneumoniae. In humans, the mean ratio of dexamethasone levels in the aqueous humour at 1 hour was 1.17 in favour of TobraDex ST. CONCLUSION: TobraDex ST demonstrated improved suspension formulation characteristics, enhanced pharmacokinetic distribution and improved bactericidal characteristics, and may provide a useful alternative as compared to TobraDex.

Development of a liquid enzyme-based ceruminolytic product.

Various compositions for removal of human cerumen are marketed but they are not very effective. Therefore, a proteolytic enzyme-based ceruminolytic product was developed containing the enzyme, methyl trypsin, and sodium bicarbonate. Efficacy was optimized based on in vitro testing using both human and artificial cerumen preparations. Both qualitative (visual observation) and quantitative (spectrophotometric) assessments of ceruminolytic efficacy were employed. Optimal enzyme stability was observed for the aqueous formulation at pH 4, while greater ceruminolytic efficacy was observed at pH 8. The optimal concentration range of enzyme was 150-300 absorbance U/mL based on efficacy and stability considerations. An aqueous formulation containing both methyl trypsin and sodium bicarbonate was shown to be more effective than two commercial products, Murine Ear Wax Removal Drops and Cerumenex Ear Drops. A two-part packaging system was employed to provide adequate shelf-life. Long-term stability studies confirmed that the formulation maintained >75% enzyme stability for 24 months at 5 and 25 degrees C and after reconstitution at room temperature for up to 1 day.

A novel in vivo rabbit model that mimics human dosing to determine the distribution of antibiotics in ocular tissues.

PURPOSE: The aim of this study was to establish a novel method to predict the human ocular penetration and distribution of topical antibiotics by using a controlled rabbit model that mimics the human eye with manual blinking and tear flow. METHODS: After anesthetizing the rabbits, a single dose of commercial antibiotic formulations was given with precision directly onto the cornea. This was followed by a 30-min controlled period applying manual blinking (4 blinks/min) and a supplementary tear flow (2 microL/min) that mimics the human eye. Tear samples were collected every 5 min and after euthanasia, conjunctival, aqueous humor, iris-ciliary body, and scleral samples were collected. The corneas were mounted in perfusion chambers to determine the level and continuing rate of release of the antibiotics, the levels of which were all determined using high-performance liquid chromatography analysis. RESULTS: U.S. formulations achieved conjunctival and corneal levels (µg/g) as follows: moxifloxacin, 6.6 +/- 0.3 and 50 +/- 5; tobramycin, 3.1 +/- 1.4 and 20 +/- 5; gentamicin, <2 and <2; levofloxacin, 1.5 +/- 0.3 and 19 +/- 2; gatifloxacin, 0.9 +/- 0.1 and 11 +/- 1; and trimethoprim, <0.1 and 2 +/- 1. Japan formulations achieved conjunctival and corneal levels as follows: levofloxacin 2.1 +/- 0.8 and 12 +/- 2; gatifloxacin, 2.2 +/- 0.9 and 7 +/- 1; ofloxacin, 1.6 +/- 0.5 and 7 +/- 1; and tosufloxacin, 0.7 +/- 0.1 and 1.5 +/- 0.3 (mean +/- standard error, n = 4). CONCLUSIONS: Moxifloxacin achieved the highest levels of antibiotic in ocular tissues. In the conjunctiva and cornea, the moxifloxacin level was 3-30 times the level of other fluoroquinolones, at least twice the level of the aminoglycosides, and 25 times the level of the antibacterial trimethoprim.

Ocular pharmacokinetics of moxifloxacin after topical treatment of animals and humans.

The ocular penetration and pharmacokinetics of moxifloxacin in comparison to other fluoroquinolones (ofloxacin, ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, and lomefloxacin) have been determined by in vitro and ex vivo techniques, as well as in animal and human studies. This article reviews the original pharmacokinetics work performed by Alcon and other studies reported in the ocular fluoroquinolone literature. The results consistently demonstrate higher maximum concentrations for moxifloxacin relative to the other fluoroquinolones in ocular tissues with levels well above its minimum inhibitory concentrations for relevant ocular pathogens. This superior performance is due to the unique structure of moxifloxacin that combines high lipophilicity for enhanced corneal penetration with high aqueous solubility at physiological pH. The latter property creates a high concentration gradient at the tear film/corneal epithelial interface providing a driving force for better ocular penetration for moxifloxacin. In addition, the higher concentration of moxifloxacin in VIGAMOX (i.e., 0.5% vs. 0.3%) allows more antibiotic to be available to ocular tissues. It is clear from the array of studies summarized in this report that moxifloxacin penetrates ocular tissues better (two- to three-fold) than gatifloxacin, ciprofloxacin, ofloxacin, or levofloxacin. This consistent, enhanced penetration of topical moxifloxacin offers powerful advantages for ophthalmic therapy.