Jimenez, Jorge
(2022)
Designing a Thermoresponsive Ocular Drug Delivery System for Rare Corneal Disease Treatment.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cystinosis is a rare, metabolic, genetic disease with less than 2,000 patients in the U.S. Intralysosomal accumulation of cystine leads to system-wide organ and tissue damage in patients. In the eye, cystine accumulates in all ocular tissues and is noticeably present in the cornea as hyperreflective, spindle structured crystals. The crystals cause light sensitivity and impair vision. Untreated, progressive accumulation of crystals leads to foreign body sensation and corneal erosion, further impacting ocular health. These crystals are treated with eyedrops containing the small molecule, cysteamine. Cysteamine therapeutic levels are reached when administered 6 to 12 times daily and used within their 1-week shelf-life. The frequency of administration and poor drug stability add burden to lives of patients, particularly when considering the multifaceted complications arising from a systemic, rare disease.
I hypothesized cysteamine encapsulated into spray-dried poly(lactic-co-glycolic acid) (PLGA) microspheres embedded within a thermoresponsive gel (SD-CMS/Gel) will reduce the dosing frequency and improve drug stability. This delivery system can be topically administered at room temperature (approximately 25°C) in its liquid phase and retained at ocular surface temperatures (32-34°C) as it undergoes a solution-gel transition.
In this thesis, I developed and evaluated this topical drug delivery system using in vitro and in vivo methods. Spray-dried encapsulation of cysteamine was performed and evaluated in vitro for drug release, stability, drug permeation, and ocular irritation. Cysteamine ocular pharmacokinetics and biodistribution were evaluated in rabbit model. Therapeutic efficacy of our formulation was investigated in a genetic knockout mouse model of cystinosis by measuring corneal cystine crystal reduction using optical coherence tomography (OCT).
The data suggest encapsulated cysteamine improves stability to 7-weeks when compared to 1-week aqueous cysteamine eyedrops. One drop of SD-CMS/Gel delivered cysteamine to ocular tissues for 12 hours in vivo compared to 12 drops of traditional eyedrops, providing the first insights into in vivo cysteamine ocular pharmacokinetics. Studies towards efficacy resulted in our ability to measure cystine crystals with longitudinal OCT and informed the translation of our formulation to the mouse eye. In total, the dissertation presents preclinical studies towards a novel drug delivery system for rare corneal disease.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
16 January 2022 |
| Date Type: |
Publication |
| Defense Date: |
3 November 2021 |
| Approval Date: |
16 January 2022 |
| Submission Date: |
5 October 2021 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
204 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ocular drug delivery, controlled release, cornea, rare disease, small molecule, biomaterials |
| Date Deposited: |
16 Jan 2022 14:48 |
| Last Modified: |
16 Jan 2023 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41839 |
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