Application of PRINT Microparticle and Nanoparticle Technology Toward Preparation of Ophthalmic Suspension Formulations with Improved Tolerability and Efficacy

Abstract

 

Purpose

 

To use PRINT technology to produce micro and nanoparticles of controlled microstructure and nanostructure that are suitable for the preparation of aqueous ophthalmic suspension formulations without use of solubilizing excipients (e.g. cremaphor, oils, cyclodextrins).

 

Methods

 

PRINT technology, a novel drug/excipient micromolding approach, was used to produce monodisperse nonspherical particles of itraconazole, cyclosporine, and tacrolimus. Specifically, 10 micron triangular templates, 3 micron toroids, 200 nm cylindrical and 1 micron cylindrical polymeric templates were used to prepare particles of cyclosporine, tacrolimus, and itraconazole, respectively. Dissolution characteristics of itraconazole suspensions were evaluated and compared to bulk and micronized itraconazole using standard dissolution test methods.

 

Results

 

Monodisperse, shape-specific microparticles and nanoparticles were successfully prepared of cyclosporine, tacrolimus, and itraconazole. Characterization of these particles using microscopy confirms that monodisperse populations of 10 micron triangles, 3 micron toroids, and 200 nm and 1 micron cylinders were produced of cyclosporine, tacrolimus, and itraconazole, respectively. The sizes and shapes of these microparticles and nanoparticles are suitable for use in ophthalmic suspension dosage forms. Dissolution studies of itraconazole cylinder suspensions indicate that these particles dissolve faster under sink conditions than traditional micronized itraconazole (50% dissolution at 5 min for PRINT-itraconazole cylinders vs. 15 minutes for micronized itraconazole), suggesting that itraconazole PRINT formulations may have greater ocular surface bioavailability than micronized formulations.

 

Conclusions

 

We demonstrate that PRINT technology is a promising approach for the development of improved suspension formulations of compounds such as cyclosporine, tacrolimus, and itraconazole. Dissolution experiments show enhanced dissolution time of these particles compared to traditional micronized drug formulations, without the use of excipients with poor tolerability profile.

 

 

A) Scanning electron microscopy images of PRINT microparticles composed of cyclosporine and tacrolimus; B) Aqueous dissolution characteristics of PRINT-itraconazole microparticles and comparison to micronized suspensions.

 

Keywords: 489 cyclosporine