A Controlled Release System for Long-Acting Intravitreal Delivery of Small Molecules
| Autor: | Kyosuke Tanaka, Yoshiyuki Yabe, Atsushi Yamasaki, Koichi Nakamura, Nobuo Machinaga, Yasushi Yoshigae, Gary W. Ashley, Daniel V. Santi, Ralph Reid |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Drug beta-elimination media_common.quotation_subject Biomedical Engineering Pharmacology 03 medical and health sciences 0302 clinical medicine Pharmacokinetics medicine PEG40kDa media_common Chemistry Half-life Articles Controlled release Small molecule intravitreal half life Ophthalmology 030104 developmental biology medicine.anatomical_structure Long acting 030221 ophthalmology & optometry Choroid CFD Conjugate |
| Zdroj: | Translational Vision Science & Technology |
| ISSN: | 2164-2591 |
| Popis: | Purpose The short half lives of small molecules in the vitreous requires frequent repeated intravitreal injections that are impractical for treatment of chronic eye diseases. We sought to develop a method for increasing the intravitreal half-life of small-molecule drugs. Methods We adapted a technology for controlled release of drugs from macromolecular carriers for use as a long-acting intravitreal delivery system for small molecules. As a prototype, a small molecule complement factor D inhibitor with an intravitreal half-life of 7 hours was covalently attached to a 4-arm PEG40kDa by a self-cleaving β-eliminative linker with a cleavage half-life of approximately 1 week. Results After intravitreal injection in rabbits, the drug was slowly released in the vitreous, and equilibrated with the retina and choroid. The intravitreal half-life of the intact PEG-drug conjugate in the rabbit was 7 days, and that of the released drug was 3.6 days. We simulated the anticipated pharmacokinetics of the delivery system in human vitreous, and estimated that the half-life of a 4-arm PEG40kDa conjugate would be approximately 2 weeks, and that of the released drug would be approximately 5 days. Conclusions We posit that a linker with a cleavage half life of 2 weeks would confer a half life of approximately 7 days to a released small molecule drug in humans, comparable to the half life of approved intravitreal injected macromolecular drugs. Translational Relevance With this technology, a potent small molecule with an appropriate therapeutic window should be administrable by intravitreal injections in the human at once-monthly intervals. |
| Databáze: | OpenAIRE |
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