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Designing a Thermoresponsive Ocular Drug Delivery System for Rare Corneal Disease Treatment

Jimenez, Jorge (2022) Designing a Thermoresponsive Ocular Drug Delivery System for Rare Corneal Disease Treatment. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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:
CreatorsEmailPitt UsernameORCID
Jimenez, Jorgejoj41@pitt.edujoj410000-0001-9347-4376
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorDiLeo, Morgan V.morgandileo@pitt.edu
Committee MemberLittle, Steven R.srlittle@pitt.edu
Committee MemberLathrop, Kiralathropkl@upmc.edu
Committee CoChairSant, Shilpashs149@pitt.edu
Committee MemberNischal, Ken K.nischalkk@upmc.edu
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: 18 Jan 2022 19:24
URI: http://d-scholarship.pitt.edu/id/eprint/41839

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