ABSTRACT
This work presents a comparative study of various hyaluronic acids (HA) produced by fermentation of either Bacillus subtilis or Streptococcus towards the selection of an optimal molecular weight (MW) HA for the preparation of topical ophthalmic formulations. The influence of HA MW on water binding capacity, sterile filtration, rheological properties, precorneal residence time and ocular tolerance of ophthalmic solutions was investigated. Molecular weight did not affect hydration of hyaluronic acid according to differential scanning calorimetry (DSC). In general, medium MW HA (0.6-1 MDa) resulted in solutions that were superior in terms of sterile filtration and kinematic viscosity requirements compared to high MW HA (>1 MDa). Moreover, all HA-based solutions exhibited well-defined viscoelastic properties that depend on MW. Gamma scintigraphic data indicated that HA MW at 0.1% concentration (w/v) and HA origin did not significantly affect the corneal residence time on rabbit eyes. A 0.3% solution of high MW HA had a prolonged residence time in the precorneal area compared to a medium MW HA at the same concentration. Finally, an in vivo ocular irritation test based on confocal laser scanning ophthalmoscopy (CLSO) conclusively showed the excellent tolerance of both Bacillus-derived HA and Streptococcus-derived HA after topical instillation onto the corneal surface. Overall, this comprehensive work highlights the superiority of medium MW hyaluronic acid for topical ophthalmic formulations based on their physico-chemical and biological properties, tolerance and handling. Such solutions are expected to enhance tear film stability, to allow for maximum comfort, and to exhibit high residence times, while being biocompatible and easy to sterile filter.
Subject(s)
Bacillus subtilis , Fermentation , Hyaluronic Acid/chemistry , Hyaluronic Acid/metabolism , Ophthalmic Solutions/chemistry , Ophthalmic Solutions/metabolism , Streptococcus , Animals , Bacillus subtilis/chemistry , Bacillus subtilis/metabolism , Biocompatible Materials/chemistry , Biocompatible Materials/metabolism , Drug Carriers/chemistry , Drug Carriers/metabolism , Drug Carriers/therapeutic use , Dry Eye Syndromes/drug therapy , Elasticity , Eye Diseases/drug therapy , Female , Humans , Hyaluronic Acid/therapeutic use , Male , Materials Testing , Molecular Weight , Ophthalmic Solutions/therapeutic use , Rabbits , Rheology , Streptococcus/chemistry , Streptococcus/metabolism , ViscosityABSTRACT
PURPOSE: To assess ex vivo human scleral permeability to triamcinolone acetonide (TA). METHODS: The experiments were carried out using scleral samples and a Franz-type vertical diffusion cell. A suspension containing TA was prepared and placed in the donor chamber. The concentration of TA in the receptor chamber was measured by high-performance liquid chromatography (HPLC) assay and expressed as a percentage relative to TA concentration dissolved in the donor chamber. Control experiments using a commercial TA suspension were performed. RESULTS: TA (+/-SEM) dissolved in the donor suspension was 10.69 +/- 1.28 microg/ml. The diffusion rate of TA varied from 30% after 1 day to 72% after 4 days, after which equilibrium was reached. The human scleral permeability coefficient (P(s) +/- SEM) was 1.47+/- 0.17 x 10(- 5) cm/s. CONCLUSIONS: TA crossed human sclera. The mean amount of drug retained in the sclera increased with time, 4 days being necessary to equilibrate the unidirectional flux. The TA permeability coefficient was comparable to that of other corticosteroids.
Subject(s)
Glucocorticoids/pharmacokinetics , Sclera/metabolism , Triamcinolone Acetonide/pharmacokinetics , Chromatography, High Pressure Liquid , Diffusion , Humans , Middle Aged , PermeabilityABSTRACT
UNIL088 is a water-soluble prodrug of cyclosporine A (CsA) developed for topical eye delivery. Such a prodrug has to fulfil two paradoxical requirements as it must be rapidly hydrolysed under physiological conditions but also retain a long shelf-life in aqueous media. This study has been conducted to explore the stability of UNIL088 formulated as an eyedrop solution. The stability study of the prodrug was performed over a pH range of 5-7 at 20 degrees C and at various ionic strengths. The molecule was more stable at pH 5 than at pH 7 with conversion rate constant of 3.2 x 10(-3) and 26.0 x 10(-3)days(-1), respectively. The effect of temperature was studied at four different temperatures and activation energy was determined. Conversion of UNIL088 followed a pseudo-first-order kinetic with an activation energy of 79.4 kJ mol(-1). Due to its low solubility, CsA generated precipitated in the solution. The average size of CsA precipitates, determined by photon spectroscopy, was 0.22 and 1.08 microm at 7 and 14 days, respectively. The hydrolysis mechanism was partially elucidated by identification of the intermediate pSer-Sar-CsA.
