Date of Award

5-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Tao L. Lowe, Ph.D.

Committee

Joel Bumgardner, Ph.D. James R. Johnson, Ph.D. Bernd Meibohm, Ph.D. Duane D. Miller, Ph.D.

Keywords

blood-brain barrier, In situ depot, levonorgestrel, ocular, polyester, polysaccharide

Abstract

Efficacy of many of the new and existing therapeutics is often hampered by the lack of an effective and compliant method of delivery. Typically, drugs have poor water solubility, short half-lives, and low permeability across the biological membranes. The result is low bioavailability of the drugs at the target site and can cause toxicity and side effects at high doses. Often the conventional dosage forms fail to overcome these limitations. In the recent decades, biodegradable polymeric drug delivery systems have emerged as promising candidates to solve the challenges of poor solubility, low permeability and sustained release owing to the advantages of biocompatibility, versatility, and tunable drug release. Polyesters and polysaccharides are the most common polymers that were explored for drug delivery applications because of their unique advantages including non-toxic nature, wide availability, relatively low cost, and flexibility in chemistry. Although a major progress has been in the field of drug delivery, still there are unmet medical needs which require new materials for delivering drugs such as, injectable systems that can achieve long-term contraception (five months or longer) at low cost, and drug delivery systems that can enhance the permeability of drugs across ocular/blood-brain barriers and sustain release as well for treating chronic diseases such as diabetic retinopathy in the eye and Alzheimer’s disease in the brain. Therefore, this research has evaluated the potential of different biodegradable polymeric biomaterials based on polyesters or polysaccharides for long-acting contraception and drug delivery to the eye and brain to resolve the issues such as poor compliance and adherence to the existing contraceptive dosage forms or poor solubility and permeability of the drugs across ocular/blood-brain barriers. The first system includes polyester-based injectable in situ forming depot systems (ISD) for long-acting contraception. The aim of this project was to develop injectable ISD system containing levonorgestrel (LNG) for contraceptive effect for five months or longer after single shot that helps to reduce unintended pregnancies with high patient compliance and low cost. A series of LNG-containing ISD formulations were designed by employing unique strategies which include the use of poly(lactic acid-co-glycolic acid), poly(lactic acid) with different biodegradable properties, and blends of these polyesters, use solvent mixtures of N-methyl-2-pyrrolidone, triethyl citrate, benzyl benzoate, and vary the polymer/solvent ratios, and various drug loadings. The formulations were evaluated for viscosity, initial burst, in vitro and in vivo long-term release. In vivo investigation in rats showed the sustained-release pharmacokinetic profile of LNG from the ISD formulations for at least five months and continued for more than seven months depending on the composition, and the vaginal cytology studies have demonstrated that formulations have successfully suppressed the rat estrous cycle. After the end of the treatment, a rapid and predictable return of fertility was observed in rats. The optimized lead formulation has shown promising injectability (23 G) and low initial in vivo burst profiles. The results suggested that the developed LNG-ISD formulations have a great potential for developing into future robust affordable long-acting contraceptive products for improving patient compliance and adherence. Another type of polymeric biomaterial systems that were evaluated in this study includes polysaccharide-based biodegradable nanoparticles for drug delivery across ocular and blood-brain barriers. Depending on the need of the therapeutic application, two types of polysaccharide-based nanoparticles were investigated for their drug delivery feasibility which includes: (a) Poly(N-isopropylacrylamide-co-Dextran-lactateHEMA) nanogels for the potential delivery of hydrophilic peptide (insulin) across ocular barriers for the treatment of diabetic retinopathy. The in vitro, and ex vivo studies showed that the developed nontoxic nanogels have great potential to enhance the drug permeability across ocular barriers including the in vitro retinal pigment epithelium, sclera and cornea barriers for treating diabetic retinopathy; and (b) β-cyclodextrin-poly(β-amino ester) nanoparticles as potential drug carriers to enhance the solubility and blood-brain barrier (BBB) permeability of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) to treat Alzheimer’s disease. The nanoparticles sustained the release of 17-AAG for at least one week in vitro and showed increased permeability (2-fold) of the 17-AAG across BBB in vivo in mice, and resulted in enhanced expression of the Hsp70 protein in the brain. In conclusion, the developed biodegradable polymeric biomaterials have shown potential to be used in long-acting contraception and drug delivery to the eye and brain.

ORCID

http://orcid.org/0000-0002-7235-7709

DOI

10.21007/etd.cghs.2017.0429

Comments

Two year embargo expires February 2019.

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