Cyclodextrin nanoparticles for targeted ocular drug delivery of kinase inhibitors

Abstract

Background: Age-related macular degeneration (AMD) causes vision loss in elderly people due to neovascularization. The first line treatments are intravitreal injections which can induce severe pain. Oral administration still produces side effects. Cyclodextrins (CDs) can self-assemble into aggregates or larger nanoparticle platform that can deliver drugs to the back of eye. Thus, CD-based eye drops can be a more favorable formulation for AMD.

Introduction: Tyrosine kinase inhibitors (KIs) suppress the growth of new blood vessels in AMD. The obstacle of delivery of KIs is their very low aqueous solubility. Here γCD was used as a solubilizing complexing agent but the efficiency remained inadequate. In addition, the KI salt tended to degrade at elevated temperatures during preparation of KI/γCD complexes. Hence, the aim of this research was to enhance the γCD solubilization of KIs by additional techniques such as by including hydrophilic polymers or counter ions, and to develop the thermally stable eye drops for delivery of KI to the targeted site.

Method: Two different heating methods were used in preparation of KI/CD complexes. Mild heat in the form of ultrasonication at 30oC for 30 min, was applied to thermolabile drugs while heat stable drugs were autoclaved at 121oC for 20 min which was also beneficial for sterilization of eye drops. All complex characterizations used samples from the supernatants. The physicochemical properties of the aqueous eye drop micro-suspensions were also evaluated.

Results: Dovitinib had the best solubility performance due to the high affinity for γCD, followed by motesanib. KIs were more soluble at low pH. The tested hydrophilic polymers affected the KI solubility in complexation media. Besides that, the formulation vehicle could also solubilize KI/γCD complexes, mainly influenced by salt formation. Hexadimethrine bromide (HDMBr) generally enhanced the γCD solubilization via a synergist effect. The presence of HDMBr increased γCD solubilization and formed ternary complex.

Salt formation was observed in formulation vehicle systems and, thus, several acidic counter ions were introduced to enhance the solubility of the weakly basic drug/CD complex. Citrate was the most powerful counter ion that reinforced CD efficiency by salt formation and/or charge-charge interactions. In vitro drug permeation did not increase as result of increased CD solubilization.

KI salt was used in formulation studies because salt formation had a greater capacity to solubilize the drug. An unexpected problem occurred regarding the dovitinib salt. Here cediranib maleate (CM) was selected for eye drops due to its noteworthy performance and high intrinsic solubility. Riboflavin could thermally stabilize CM dissolved in 15% (w/v) γCD solution. The combination of riboflavin and other excipients (i.e. polymer and co-solvent) reduced the thermal degradation in micro-suspensions. The optimized eye drops did deliver the drug into the back of eye. This product was stable at 25oC for six months.

Conclusion: The γCD solubilization and complexation of KIs was increased by additional techniques including the addition of hydrophilic polymers or counter ions. An appropriate stabilizer could protect the KI salt from thermal degradation in a concentrated complexation media. The thermally stable eye drops achieved ocular delivery and had a shelf life of at least six months.