Mitsuaki Kuwano

Cyclosporine A Formulation Affects Its Ocular Distribution in Rabbits

Systemic Cyclosporine A (CsA) administration averts graft rejection after organ transplantation. In the eye, CsA is also beneficial in the treatment of autoimmune diseases, uveitis, Bechet’s disease, Sjögren’s syndrome, keratoconjunctivis sicca, and corneal transplantation (1). It has been suggested that topical rather than systemic CsA application could also be therapeutic, without causing systemic side effects, in the treatment of ocular disease. This may be possible because much less CsA can penetrate into the bloodstream after its topical instillation in either an aqueousor oil-based medium. It is expected that penetration from an aqueous medium will be even less than in oil because its solubility in water is much less. Various attempts were made to develop ophthalmic formulations that improve ocular CsA penetration, including an alpha-cyclodextrin vehicle (2), vegetable oils (3), liposomes (4), collagen shields (5), microor nanospheres (6), and oilin-water emulsion (7). However, none of these deliver therapeutic amounts of CsA into target ocular tissues with low ocular toxicity. In this work, we compared in rabbit ocular tissues CsA pharmacokinetics and distribution resulting from its topical application as an oil-based medium, o/w emulsion, and CsA aqueous clear solution containing a surfactant. Our results suggest that only an aqueous solution containing the nonionic surfactant MYS-40 delivers therapeutic levels of CsA.

Pharmaceutical design of Kary Uni® ophthalmic suspension

Pirenoxine ophthalmic solution was developed based on the quinoid theory which is one of the theories for development mechanism of senile cataracts, and its usefulness for treatment of cataracts has been proved. Since pirenoxine is unstable in aqueous solution, conventional products are required the reconstitution procedure of tablet (or granule) with accompanied solvent before use. Therefore, there are some problems with respect to good patients compliance. Under these circumstances, one bottle type and stable pirenoxine ophthalmic product has been desired. Our concepts for designing new pirenoxine ophthalmic product are as follows, (1) To be one bottle type product, (2) To stabilize pirenoxine in aqueous media for three years at room temperature, (3) To keep its bioequivalence to conventional products. Pirenoxine showed very low solubility in acidic aqueous solution and good stability in aqueous suspension (pH 3.4-4.0) for three years at room temperature in our study. On the other hand, pirenoxine showed good solubility in neutral aqueous solution. We applied these unique properties and developed a new pirenoxine ophthalmic product, Kary Uni® ophthalmic suspension. As no buffer agent is contained in Kary Uni® ophthalmic suspension, the pH of the solution is elevated to the physicological pH of tears immediately after instillation, and pirenoxine microparticles rapidly dissolve in tears. As a result, the bioequivalence to conventional products can be obtained. Kary Uni® is a one bottle type ophthalmic suspension in ready to use, without the reconstitution procedure required for conventional products and is especially evaluated as a new type DDS pharmaceutical product taking advantage of the transformation on the living environment of ocular surface.