[Effect of Shelf Life on the Physical Stability of Suspended Ophthalmic Solutions].

Quality changes associated with physical changes in suspended eye drops are difficult to predict. In this study, we attempted to evaluate the aggregation and redispersability in commercially available suspended eye drops (fluorometholone ophthalmic solutions). The 0.1% fluorometholone ophthalmic solutions (the original product and 4 generic products) were gently mixed by hand after short-term (4 months) or long-term (40 months) storage, and the drug concentration in the first drop and physical stability (redispersability and particle size) were measured. All eye drops produced a cloudy precipitate on the bottom surface of the container, and the amount of precipitate decreased with mixing time. The drug concentration per drop in the original product was approximately 70% of the labeled value after mixing 10 times, and the drug particle size was approximately 4 µm. After mixing the generic products stored short-term 10 times, the concentration ranged from less than 50% to almost 100%. In addition, some generic products after long-term storage had a reduced redispersion ability and labeled concentration. These results suggested that at least 10 mixing were required before the using of fluorometholone original product. In addition, some generic products may not provide sufficient drug exposure even when mixed in the same manner as the original products.

Ocular penetration of fluorometholone-loaded PEG-PLGA nanoparticles functionalized with cell-penetrating peptides.

Aim: Development of fluorometholone-loaded PEG-PLGA nanoparticles (NPs) functionalized with cell-penetrating peptides (CPPs) for the treatment of ocular inflammatory disorders. Materials & methods: Synthesized polymers and peptides were used for elaboration of functionalized NPs, which were characterized physicochemically. Cytotoxicity and ability to modulate the expression of proinflammatory cytokines were evaluated in vitro using human corneal epithelial cells (HCE-2). NPs uptake was assayed in both in vitro and in vivo models. Results: NPs showed physicochemical characteristics suitable for ocular administration without evidence of cytotoxicity. TAT-NPs and G2-NPs were internalized and displayed anti-inflammatory activity in both HCE-2 cells and mouse eye. Conclusion: TAT-NPs and G2-NPs could be considered a novel strategy for the treatment of ocular inflammatory diseases of the anterior and posterior segment.

In-situ forming gels containing fluorometholone-loaded polymeric nanoparticles for ocular inflammatory conditions.

Thermosensitive gels have been developed and optimized in such a way that they become gels at corneal temperature and with a viscosity that allows the adequate release of the Fluorometholone (FMT)-loaded PLGA nanoparticles (NPs) in order to improve ocular anti-inflammatory efficacy against a commercial formulation. It has been shown that gels avoid burst release of the drug in the first hours with a slow and increasing profile after administration. NPs have maintained their average size and spherical shape within the gels as confirmed by transmission electron microscopy (TEM). In turn, the in-situ gelling of the formulations allows the administration in eye drops dosage form due to its state of sol at temperatures below 25 °C. Ocular tolerance studies have shown that no formulation causes eye irritation. The administration of the developed formulations has improved the precorneal residence time reflected in the ocular bioavailability, where deep tissues as aqueous humour and crystalline were reached. In conclusion, the use of thermosensitive gels for the topical application of NPs has demonstrated their effectiveness in the acute and preventive treatment of ocular inflammatory conditions.

General Pharmacokinetic Model for Topically Administered Ocular Drug Dosage Forms.

PURPOSE: In ocular drug development, an early estimate of drug behavior before any in vivo experiments is important. The pharmacokinetics (PK) and bioavailability depend not only on active compound and excipients but also on physicochemical properties of the ocular drug formulation. We propose to utilize PK modelling to predict how drug and formulational properties affect drug bioavailability and pharmacokinetics. METHODS: A physiologically relevant PK model based on the rabbit eye was built to simulate the effect of formulation and physicochemical properties on PK of pilocarpine solutions and fluorometholone suspensions. The model consists of four compartments: solid and dissolved drug in tear fluid, drug in corneal epithelium and aqueous humor. Parameter values and in vivo PK data in rabbits were taken from published literature. RESULTS: The model predicted the pilocarpine and fluorometholone concentrations in the corneal epithelium and aqueous humor with a reasonable accuracy for many different formulations. The model includes a graphical user interface that enables the user to modify parameters easily and thus simulate various formulations. CONCLUSIONS: The model is suitable for the development of ophthalmic formulations and the planning of bioequivalence studies.

Evaluation of ophthalmic suspensions using surface tension.

Uniformity and precision of single dose are required for ophthalmic suspensions including water-insoluble ingredients. Solid sediments formed after standing still must be immediately re-dispersible and distributed homogeneously before use. However, selection of an appropriate water-soluble polymer as suspending agent is a challenging problem. In this report, the relationship between the surface tension and the re-dispersibility of suspensions was investigated. The surface tension of 0.1 w/v% fluorometholone suspensions began to decline from 74 mN/m at 0.0001 w/v% of hydroxypropylmethylcellulose (HPMC) and became almost constant at 52 mN/m at 0.01 w/v% of HPMC. Re-dispersion time was less than 4 s when HPMC was present at concentrations between 0.0001 w/v% and 0.01 w/v%. At these concentrations, aggregation of suspended particles was not observed. When indomethacin suspensions at 1.0 w/v% concentration were used, the surface tension began to decline from 73 mN/m at 0.0005 w/v% HPMC and became constant at 50 mN/m at 0.005 w/v% HPMC. The suspension also showed good re-dispersibility, and a uniform suspension was obtained between 0.0005 w/v% and 0.005 w/v% of HPMC. The time required for re-dispersion was less than 17 s. The change of surface tension showed a good correlation with the concentration of HPMC in ophthalmic suspensions having good re-dispersibility. Measurement of the surface tension of suspensions provided the optimal concentration of the water-soluble polymers for the suspensions of well re-dispersible characteristics. Evaluation of ophthalmic suspension using surface tension is a good strategy for formulation of suspending pharmaceutical products in the ophthalmic area.

Controlled comparison of two fluorometholone formulations in the antigen challenge model of allergic conjunctivitis.

We compared the safety and efficacy of MethaSite, a gel-forming suspension (0.1% fluorometholone), to a commercially available 0.1% fluorometholone ointment, FML S.O.P., using an antigen challenge model. Subjects with known allergic histories were exposed to increasing concentrations of cat dander, ragweed, or grass at visits 1 and 2. Allergic responses of conjunctival injection, chemosis, and subjective itching were quantified on a scale from zero to 3; the sum of these ratings constituted the total allergic score. At visit 3, 105 subjects with total scores of > or = 5 received a drop of MethaSite in one eye and a 0.5 inch ribbon of FML ointment in the other eye. Three and 6 hours postdose, the eyes were challenged with the antigen concentration that provoked significant allergic response at visit 2. We determined safety by evaluating changes in visual acuity, intraocular pressure, and biomicroscopy that occurred between visits 1 and 3. Eyes treated with MethaSite and FML responded similarly to the antigen challenges. Both groups demonstrated suppression of allergic response 3 and 6 hours postdose through equivalent and significant reductions in total allergy scores and individual ratings of injection, chemosis, and itching. In this population, MethaSite was equivalent to FML ointment in safety and efficacy.