Date of Award
1-1-2015
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
Department
Biomolecular Sciences
First Advisor
Soumyajit Majumdar
Second Advisor
John O'Haver
Third Advisor
S. Narasimha Murthy
Relational Format
dissertation/thesis
Abstract
Diseases of the posterior segment of the eye such as diabetic retinopathy, age related macular degeneration and glaucoma are the leading causes for blindness throughout the world. Topical eye drops is the most convenient formulation for daily application. The human eye, however, presents major physiological and dynamic barriers for the topically administered drug/molecule from reaching the retina. Similarly, the blood-retinal and blood-aqueous barriers restricts passage of drug from systemic circulation into the eye. Although intravitreal injections are the gold standards for the treatment of posterior segment ocular diseases, they are associated with pain, inflammation, endopthalmitis and infection. So there is a necessity to develop novel noninvasive drug delivery strategies to treat the posterior segment ocular diseases.
In the present study, we have used melt cast technology to develop a polymeric matrix film system to deliver Hesperetin (HT), a bioflavanoid, to the posterior segment of the eye. The film is 4 mm x 2 mm in dimension and 0.2 to 0.4 mm in thickness. When the HT-film was tested in vivo in anesthetized rabbit model, HT levels were maintained above the neuroprotective and antiinflammatory IC50 levels for upto 6 h. We also prepared HT loaded (0.1% w/v) solid lipid nanoparticles (SLN’s) using a combination of 85% glyceryl monostereate and 15% compritol ATO 888. The particle size, zeta potential and entrapment efficiency of the HT-SLN’s was 225 nm, -21 mV and 85% respectively. Although the dose administered in the animal study was approximately 16-fold lower than the HT-Film, SLN’s provided very good HT levels in the anterior segment of the eye. These formulations were tested in the conscious animal model to determine the effect of active lymphatic and tear drainage. Significant elimination of HT was observed in the aqueous humor due to the turnover rate (1.0% to 1.5% of the anterior chamber volume per minute). But the film formulation was able to maintain 2.3 µg of HT/gm of tissue in the retina choroid and 80 ng of HT/gm of vitreous humor upto 3 h. SLN’s were able to deliver 1.9 µg of HT/gm of iris ciliary bodies, but HT levels were below detection limit in the posterior segment of the eye. Thus, polymeric matrix films prove to be a safe and effective platform for the delivery of drugs/drug candidates to the posterior segment of the eye.
Glaucoma is the second leading cause for blindness worldwide. Rise in intraocular pressure (IOP) has been identified as an important risk factor in the pathogenesis of the disease. Δ9-Tetrahydrocannabinol (THC), an active ingredient of the plant cannabis sativa, and an agonist of the cannabinoid receptors, CB1 and CB2, could potentially be such a dual acting anti-glaucoma agent. Delivering therapeutic levels of THC into the inner ocular layers is very challenging due to the extremely lipophilic characteristics of THC. A synthetic amino acid dicarboxylic acid prodrug of THC, Δ9-Tetrahydrocannabinol valine hemisuccinate (THC-Val-HS) was developed. Micellar and nanoemulsion formulations of THC-Val-HS and THC were prepared. These formulations were evaluated for IOP reduction in an alpha chymotrypsin induced rabbit glaucoma model. With the 0.5%w/v THC emulsion formulation drop in IOP was observed at 30 min, but was very minimal and short acting (60 min). With an increase in dose (0.8% w/v THC) a similar effect was observed with a slight increase in the duration of activity (90 min). With THC-Val-HS (0.6% w/v THC equivalent), drop in IOP was observed at 30 min, but the maximum drop was observed at 90 min, lasting upto 3 h (90% of the baseline). The more gradual drop in IOP can be attributed to the fact that THC-Val-HS has to be enzymatically converted into THC to show activity. Receptor binding studies revealed that THC-Val-HS has 21.8 and 38 folds less affinity towards CB1 and CB2 receptors, respectively, than THC. Thus, the present study demonstrates that a rational combination of prodrug design and formulation strategies can effectively deliver THC to the anterior chamber of the eye. An increased IOP reduction with the prodrug at lower equivalent doses of THC, supports improved ocular penetration of the prodrug. Importantly, with most of the conventionally developed anti-glaucoma drugs having no reported neuroprotective action, THC, an established neuroprotectant, has the potential to become an effective glaucoma medication. Further studies are currently aimed at developing and optimizing various formulations with improved THC delivery to the back-of-the eye.
Since the rate of elimination of drug candidates was relatively rapid in the earlier studies, ion exchange resin - drug complexes were incorporated into the matrix film to improve the sustained release profile. Ion exchange resins (IR) are water insoluble cross linked polymers with ionizable groups that can be exchanged to form complexes. Diclofenac sodium (DFS) was used as a model drug. The goal of this study was to develop polymeric matrix films loaded with a combination of free diclofenac sodium (DFS) and DFS-Ion exchange resin (IR) complexes for immediate and sustained release profiles, respectively. Complexation efficiency of DFS-IR was found to be 99% at 1:1 ratio of DFS:IR. Solution and DFS:IR suspension formulations were not able to maintain therapeutic DFS levels in AH and other ocular tissues. The matrix film, as such, was able to achieve high levels of DFS in the ocular tissues, but was not able to overcome the rapid elimination profile. On the other hand, DFS:IR loaded matrix films were able to maintain DFS levels in the inner ocular tissues fairly constant for upto 8h, probably because of continuous release of DFS from the IR and retention of the IR complexes on the ocular surface. Thus, drug IR complexes loaded into matrix films could be a potential sustained ocular delivery platform.
Recommended Citation
Adelli, Goutham Reddy, "Non-invasive drug delivery to the posterior segment of the eye: Development of formulation strategies and evaluation of ocular distribution and pharmacological activity" (2015). Electronic Theses and Dissertations. 1466.
https://egrove.olemiss.edu/etd/1466