title: Dual-Stimuli Responsive Nanogels for Injectable Drug Delivery Implants
Creators: name: Town, AR
Publisher: name: University of Liverpool Repository
Year: 2019

description: Chronic conditions are on the rise due to an ageing and increasing global population. Medication adherence to treat chronic conditions is low, with good adherence on average ≤ 50% across a wide range of chronic conditions. Poor adherence is estimated to cost between $100 and $300 billion of avoidable health care costs annually in the US alone. One was to tackle this issue is the use of implants, which provide sustained release of drug over a long time period, removing the reliance on daily oral medication. In situ forming implants are particularly of interest as they can be injected through a standard gauge needle, reducing pain and discomfort for the patient. They are injected as a liquid and then solidify at the injection site. Three different solidification methods were explored to allow a dispersion of poly(N isopropylacrylamide) nanogels to act as an in situ forming implant for drug delivery. Two of these solidification methods were based on the modification of existing methods and utilised the modification of the nanogel behaviour with the incorporation of comonomers of acrylic acid and allylamine. The stabiliser polyvinylpyrrolidone (PVP) was included in the synthesis of these nanogels to attempt to aid nanogel dispersion and formulation with a drug payload. A third novel method of solidification was found to work successfully and so was developed and investigated further. This was based on the aggregation of poly(N-isopropylacrylamide) nanogels to rapidly form a drug depot at an injection site in response to both physiological temperature and ionic strength, giving a new in situ forming implant. Nanogels without surfactant, with sodium dodecyl sulphate (SDS), and with PVP were synthesised to determine if this would effect the suitability of the nanogels to undergo triggered aggregation under the correct conditions. The system was found to be easy to inject, and could be used to deliver hydrophobic drug or hydrophobic drug formulated into solid drug nanoparticles. Unlike the majority of in situ forming implants, a low burst release of drug payload was achievable, &lt; 3.4 wt%, and sustained release was possible for over 120 days. The rate of release could also be tuned by altering the ratio of two different nanogels used to create the depot formulation which has not previously been demonstrated. One of these nanogels contained the comonomer allylamine alongside the monomer N-isopropylacrylamide. This gave a depot with a higher water content and more porosity. Release was also shown to occur through Fickian diffusion. The nanogels were also found not to exhibit any cytotoxicity. Nanogels of different sizes were also synthesised, and it was found that these exhibited different phase behaviour and rheological properties. The rate of drug release from the depot could also be tuned by the size of the nanogel used, which has not previously been demonstrated. Finally nanogels were synthesised with the degradable cross-linking agent N,N’-bis(acryloyl)cystamine (BAC). This allows a depot to degrade into polymeric fragments once it has served its purpose. Alongside BAC, the comonomer N-isopropylmethacrylamide (NIPMAM) was utilised to reduce non-degradable cross linking formation. The NIPAM and NIPMAM monomers were used to create core-shell nanogels. The ratio of each monomer used gave nanogels with a tuneable aggregation temperature. The nanogels were shown to be fully degradable into polymeric fragments beyond the lower detection limit of dynamic light scattering when the count rate of the nanogel dispersion was monitored using DLS. The degradation rate was also very sensitive to temperature, with degradation shown to take place at a much slower rate as temperature increased from 25 °C up to 40 °C, where the nanogels are deswollen and more hydrophobic in nature. This could potentially allow a depot to degrade slowly over a period of months, allowing it to provide a sustained release of drug over this time period, whilst also being fully degradable into polymeric fragments when subjected to an average body temperature of 37 °C.