Graduate Thesis Or Dissertation


Development of thermosensitive injectable hydrogel and transdermal controlled release formulations for Tacrolimus Public Deposited

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  • TAC is the most commonly used medication in post transplantation maintenance immunosuppression therapy. TAC lipophilicity and its erratic oral absorption especially in the presence of food intake result in great intra- and interpatient pharmacokinetic variations. Complicated dosing and frequent required therapeutic monitoring is thought to be the main cause of non-adherence in the population using this medication. On top of that, being a highly potent drug, it requires a strict control of concentration in whole blood to avoid side effects and graft rejection. Therefore, there is a need to simplify the medication regimen and lower the frequency of medication intake, as such a strategy has been proven to help with increased adherence to medication intake while being less likely to interfere with patient daily schedule. Injectable hydrogels and transdermal drug delivery systems are often employed to deliver drug molecules directly to the blood stream, bypassing GI absorption and hepatic first-pass-effect. This work encompasses the development of a novel biodegradable/biocompatible polyamino-based polymer library for development of thermosensitive hydrogels, the development of nanoparticle-hydrogel composite formulations that eliminate the burst release commonly seen in current hydrogel formulations on the market, and the development of a matrix type transdermal patch utilizing synergistic enhancers to deliver a large molecule such as TAC. A library of polyamino-based polymers is synthesized and characterized for their temperature sensitive gelation. Three polyaspartate polymers are identified to be able to undergo thermosensitive gelation, where the transition temperature is dependent on the polymer concentration and hydrophobicity. The gelation mechanism is shown to be due to aggregation of -sheet formation of the polymer. This phenomenon allows a smaller burst release of TAC from the gel demonstrated both in vitro and in vivo. The aminoGel formulations show a sustained release profile of TAC over a 7-day period in rats. To investigate the effect of NP on reducing the burst effect of drug release from hydrogels, two NP-hydrogel composite platforms capable of delivering TAC within therapeutic window for up to 7 days are developed. By loading TAC into PEG5k-b-PCL10k nanoparticle, the stable formulation allows the incorporation of TAC into the hydrogel solution without using toxic organic solvent. The TAC-NP-hydrogel composites demonstrate no burst effect when compares to the TAC-loaded hydrogel alone. Another formulation that has been developed for TAC in this is a transdermal patch incorporating synergistic penetration enhancers. TAC is a large molecule beyond the ideal molecular size for transdermal delivery. Here we have demonstrated the feasibility of delivering such molecule across the skin barrier using a pair of synergistic enhancers, phenylpiperazine and TPGS. By incorporating the drug and penetration enhancers into a matrix type transdermal patch using Eudragit RL100 and PVP K30 at 2:8 ratio as matrix formers, the patch is found to deliver TAC across pig ear skin in Franz diffusion experiment at a rate of 5.11±0.71 g/cm2/hr. The release rate is confirmed in rat PK studies. The patch size of 2.5 cm2 is shown to be able to maintain TAC concentration within the therapeutic range for up to 7 days. The patch size can be cut to accommodate different release rates, allowing for customized dosing based on weight and scaling to other animal models. Overall, the formulations developed from our studies would add into the repertoires of available formulations for transplantation clinicians. These formulations can be used to maintain patients who demonstrate difficulties in adhering to their oral TAC regimens or variability in their absorption following TAC administration.
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  • Ongoing Research
Embargo date range
  • 2018-04-11 to 2018-11-11



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