Sýklódextrín nanóagnir fyrir markbundna lyfjagjöf í augu - verkefni lokið

Fréttatilkynning verkefnisstjóra

5.8.2021

Aðferð: Kínasahemlar (KI) bæla vöxt nýrra æða hjá sjúklingum með augnbotnahrörnun (Age related Macular Degeneration eða AMD). Kínasahemlar eru mjög torleysanlegir í vatni en aðeins uppleyst lyf getur flætt frá yfirborði augans inn í augað. Því þarf að beita aðferðum sem bæði auka leysanleika lyfjanna í táravökvanum og aðgengi lyfjanna frá yfirborðinu inn í augað. Í þessu verkefni var náttúrulegt γ-sýklódextrín valið til að auka vatnleysanleika og aðgengi kínasahemla. Myndaðar voru kínasahemla/γ-sýklódextrín fléttur og flétturnar síðan hópaðar saman til að mynda vatnsleysanlegar nanóagnir sem bundust yfirborði augans eftir gjöf augndropanna. Nanóagnirnar juku það magn lyfs sem frásogaðist inn í augað og jók styrk þess í sjónhimnu. Auk γ-sýklódextríns innihéldu augndroparnir ýmsar fjölliður og önnur hjálparefni sem auka geymsluþol augndropanna. Alls voru um 10 mismunandi kínasahemlarar rannsakaðir.
Niðurstöður: Augndroparnir juku styrk kínasahemla í sjónhimnu og öðrum vefjum bakhluta
augans. Sýnt var fram á að geymsluþol augndropanna var að minnsta kosti 6 mánuðir við
stofuhita.

English:

I. Background
The most leading cause of blindness, age-related macular degeneration (AMD) affects elderly population worldwide. AMD is a neurodegenerative disease associated with neovascularization in the posterior segment of the eye. Systemic drug administration produces side effects while current drug delivery to the target site requires a regular injection into the eye (intravitreal route). The invasive technique leads burden and discomfort to patients. To avoid these problems, topical ophthalmic formulation like eyedrop is favorable.

II. Introduction
Commercial eyedrops do not reach the back of the eye due to inability of drugs. Previous studies have shown that cyclodextrin (CD) can self-assemble to form nanoaggregates (diameter 20 to 200 nm), then nanoparticles and microparticles (diameter 1000 to 3000 nm) under certain conditions. This self-assembly formation behaves as non-invasive platform for targeted drug delivery. Main objection of this project is to develop and test aqueous eyedrops containing poorly soluble drugs in drug/CD nano- or micro-suspensions.

III. Material and method
The study will involve formation of drug/CD nanoparticles, more specifically nanoparticles
containing kinase inhibitor (KI), and eyedrop formulations of such nanoparticles in aqueous
particulated system containing stabilizers and other excipients. Nano- or micro-suspensions
will be tested the physicochemical stability and required tests according to the European
Pharmacopoeia. Finally, the formulation will be tested in rabbits.

IV. Results
In this project, natural γCD was selected to increase the water solubility and bioavailability of KIs. The complexes were initially prepared by mild heating technique. Aqueous KI/γCD complexes were formed, then they were self-assembled to form water-soluble nanoparticles which bound to the surface of the eye after topical administration. Supporting techniques (i.e.addition of hydrophilic polymers, and salt formation with acidic counter ion) can promote the solubilization and complexation of γCD on KIs. KI salt was selected to formulate the eyedrop due to very high solubility. According to the criteria for sterile product, the complex preparation changed to autoclaving. Stabilizers were needed to prevent or retard the drug loss under hightemperature process. In addition to γCD, the eyedrops containing various polymers and other excipients can increase the shelf life of the eye drops. The nanoparticles increased the amount of drug absorbed into the eye and increased its concentration in the retina.

V. Conclusion
γCD along with supportive technique could solubilize KI to reach the suitable solubility. A combination of stabilizers and other excipients such as polymer, and co-solvent helped prevent drug degradation under heat process. Final micro-suspension was stable over 6 months. This non-invasive product successfully delivered KI to the targeted site.

VI. Impacts
• γCD platform has been proved to deliver poorly soluble drug with not only small molecular weight (i.e., steroid) but also larger one (i.e., KI) to the back of the eye.
• In vivo results support the design for testing on humans. 
• The optimal formulation can be a prototype for product development in industrial scale.

VII. Information on how the results will be applied
• The results of tested KIs, hydrophilic polymers, acidic counter ions, and stabilizers can
be organized into a library for further aqueous γCD formulations.
• In vitro data will be useful for computer-aided product design.
• Basic modeling may be applied to in vitro-in vivo studies and find their correlations.

VIII. A list of the project's outputs
• KIs can be solubilized by using γCD as complexing agent.
• Hydrophilic polymers help enhance the solubilization and complexation of γCD on KIs via synergist effect.
• γCD increases the drug solubility even further when acidic counter ions are used due to salt formation and charge-charge interaction.
• Stabilizers can prevent or retard thermal degradation of KI during autoclaving.
• Successful eyedrop micro-suspension containing aqueous γCD nanoparticles can deliver KI to the back of the eye.

Heiti verkefnis: Sýklódextrín nanóagnir fyrir markbundna lyfjagjöf í augu/Cyclodextrin nanoparticles for targeted ocular delivery of kinase inhibitors
Verkefnisstjóri: Pitsiree Praphanwittaya, Háskóla Íslands 
Tegund styrks: Doktorsnemastyrkur
Styrktímabil: 2017-2019
Fjárhæð styrks: 14,945 millj. kr. alls
Tilvísunarnúmer Rannís: 173841