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Sustained Release Micro-implants for Delivery of Hydrophilic Drugs to Treat Vitreoretinal Diseases

Manna, Soumyarwit
http://orcid.org/0000-0003-0971-5830
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1471346005

Abstract Details

2016, PhD, University of Cincinnati, Engineering and Applied Science: Materials Science.
A drug delivery device (micro-implant) providing sustained release of hydrophilic drugs has the potential to improve the therapeutic outcome for treatment of vitreoretinal (VR) diseases such as primary intraocular lymphoma, uveitis and proliferative retinopathy. At present, the preferred treatment of VR diseases is intravitreal methotrexate (MTX) injection. Each intravitreal injection of MTX is associated with potentially toxic and sub-therapeutic MTX concentrations. Repetitive intravitreal injections are required to maintain therapeutic MTX concentration. A drug delivery system is desired for sustained therapeutic release (0.2-2.0 µg/day) of MTX for >1 month to achieve effective treatment of VR diseases. In an in vitro study, chitosan (CS) and polylactic acid (PLA)-based micro-implants were fab-ricated for different MTX loadings (10%, 25% and 40% w/w). The micro-implant structure was characterized using optical and scanning electron microscopy, time of flight-secondary ions mass spectroscopy and differential scanning calorimetry techniques. The MTX release rate studies were evaluated using a UV-Visible Spectrophotometer. It was observed that uncoated CS-MTX micro-implant released MTX rapidly (~1 day) because of the hydrophilic nature of both CS and MTX. However, the CS-MTX micro-implant with a lipophilic coating of PLA showed therapeu-tic MTX release (0.2–2 µg/day) for >50 days. The MTX release kinetics from the coated micro-implants is explained by a) the Korsmeyer Peppas and zero order model fit (R2~0.9) of the first 60% of MTX release which indicates the swelling of polymer and initial burst release of MTX; and b) the first order and Higuchi model fit (R2 ~ 0.9) from the 10th day to the end of drug release, implying the therapeutic MTX release depends on its concentration and follows diffusion kinetics. The pharmacokinetics and toxicity of the PLA-coated CS-MTX micro-implant (40% w/w MTX) was evaluated in rabbit eyes. High performance liquid chromatography showed a thera-peutic release of MTX (0.1–1.0 µM) in the vitreous of the rabbit eyes for 33 days following first order kinetics (R2~0.88). Histopathology analysis of the enucleated eyes failed to show any signs of toxicity and clinically significant inflammation. Electroretinography (ERG), a non invasive technique, confirmed no functional toxicity in the retina for the entire duration of study. Ultrasonography (US) showed the micro-implant did not disintegrate or dislocate during the course of the study. The PLA-coated CS-MTX micro-implant is therefore non-toxic and the lip-ophilic PLA coating enables sustained release of MTX (>1 month) in vivo. Further lipophilic surface modification of the CS-MTX micro-implant surface is shown to improve and optimize the release duration of MTX. It was investigated that with an increase in the PLA content in poly-(lactic-co-glycolic acid) PLGA and with an elevated molecular weight of PLA, a) the initial burst of MTX and the mean release rate of MTX from the micro-implants can be reduced; b) the release duration can be improved from 2 to >5 months; and c) the swelling and biodegradation of the micro-implants can be delayed. The findings of this study can be used to develop a generic platform for sustained release of hydrophilic drugs with widespread clinical application.
Rupak Banerjee, Ph.D P.E. (Committee Chair)
Zelia Correa, M.D. Ph.D. (Committee Member)
James Augsburger, M.D. (Committee Member)
Relva Buchanan, Sc.D. (Committee Member)
Jude Iroh, Ph.D. (Committee Member)
179 p.
Materials Science
Vitreoretinal; Chitosan; Methotrexate; Polylactic acid; Implant; Drug delivery

Recommended Citations

Citations

  • Manna, S. (2016). Sustained Release Micro-implants for Delivery of Hydrophilic Drugs to Treat Vitreoretinal Diseases [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1471346005

    APA Style (7th edition)

  • Manna, Soumyarwit. Sustained Release Micro-implants for Delivery of Hydrophilic Drugs to Treat Vitreoretinal Diseases. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1471346005.

    MLA Style (8th edition)

  • Manna, Soumyarwit. "Sustained Release Micro-implants for Delivery of Hydrophilic Drugs to Treat Vitreoretinal Diseases." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1471346005

    Chicago Manual of Style (17th edition)

ucin1471346005
176
© 2016, some rights reserved.Creative Commons License Sustained Release Micro-implants for Delivery of Hydrophilic Drugs to Treat Vitreoretinal Diseases by Soumyarwit Manna is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.