Nazir, Chaudhry Zahid
(2020)
Design and development of injectable intraperitoneal sustained release drug delivery system for ovarian cancer.
PhD thesis, University of Nottingham.
Abstract
Multiple clinical trials have shown improved survival after IP (intraperitoneal) over IV (intravenous) chemotherapy in women with optimally resected ovarian cancer and the National Cancer Institute (NCI) encourages the use of IP chemotherapy. Despite this, IP chemotherapy has still not been widely accepted due to various concerns.
In this PhD thesis, an injectable intraperitoneal sustained release drug delivery system has been developed for ovarian cancer to address some of these concerns hindering the clinical application of IP chemotherapy e.g. risk of chemical peritonitis due to high drug concentrations, catheter associated infections, bowel obstructions, and lack of dedicated products. The drug delivery system is comprised of paclitaxel and carboplatin encapsulated in PLGA microspheres to provide sustained release over a period of approximately 1 month after single injection. It was also intended to administer microspheres in a hydrogel to prevent microsphere clearance from peritoneal cavity and avoid inflammation and adhesions.
Firstly, an intraperitoneal pharmacokinetic mathematical model was developed to support the formulation design. Secondly, various PLGA microsphere manufacturing methods were evaluated to make controlled, uniform size microspheres. The selected method was then systematically optimised by using a design of experiment (DOE) approach to achieve the particle size (D0.5) between 50 – 200 µm. Thirdly, various hydrogels were developed and/or evaluated, and their stability assessed in the simulated IP fluid at 37 °C, in the presence or absence of PLGA microspheres. Subsequently, the paclitaxel and carboplatin release rates from PLGA microspheres were optimised by using four different grades of PLGA. Finally, the preliminary IP PK mathematical model was adjusted to fit the optimised release rates and a dosage regimen for carboplatin and paclitaxel was determined.
The preliminary IP PK mathematical model predicted doses of 0.84 mg and 82 mg of paclitaxel and carboplatin loaded PLGA microspheres, respectively, assuming a drug loading of 10 % w/w and a zero- order release profile.
From the PLGA microsphere manufacturing method evaluation, a passive flow-focussing droplet microfluidics method was selected. However, none of the tested hydrogels was found to be physically stable in the simulated IP fluid at 37 °C, with or without PLGA microspheres. Therefore, it was decided to exclude the hydrogels from the drug delivery system and carry on the optimisation of PLGA micropsheres manufacturing method(s).
The results from the optimisation of the microfluidics method by using DOE approach clearly identified the PLGA concentration in the organic phase and aqueous to organic flow ratio as the most significant factors that affected the microsphere size. The optimised conditions for the manufacture of paclitaxel loaded PLGA microspheres by single emulsion (O/W) method resulted in approximately 100 % w/w encapsulation efficiency with 10 % w/w drug loading. Whereas, for carboplatin the single emulsion (O/W) method was modified and an innovative method was developed. In this method, carboplatin was first wet-milled to make carboplatin nanocrystals which were then suspended in the organic phase to make S/O/W emulsion. The remainder of the method was same as for paclitaxel. This resulted in approximately 60 % w/w encapsulation efficiency and 6 % w/w carboplatin loading.
From the release rate optimisation experiments it was found that, in general, release rates from PLGA microspheres decreased and the lag phase (i.e. no release) became longer with increasing the PLGA molecular weight (10 to 50 kDa) and/or increasing the lactide to glycolide ratio (50/50 to 75/25).
Finally, by using one formulation of carboplatin and a combination of two paclitaxel formulations, IP PK mathematical model estimated that steady state therapeutic concentrations (exposure) can be maintained in the intraperitoneal cavity for at least 23 days after a single dose of 1 mg of paclitaxel and 28 days after single dose of 330 mg of carboplatin loaded PLGA microspheres. In addition, the simulated data also predicted that the exposure can be maintained for several months by administering multiple doses of paclitaxel and carboplatin (as PLGA microsphere formulations) at a dosing interval of 23 days and 28 days, respectively.
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