Abstract
An in situ forming implant (ISFI) for drug delivery combines the potential to improve therapeutic adherence for patients with simple administration by injection. Herein, we describe the preparation of an injectable nanocomposite ISFI composed of thermoresponsive poly(N-isopropylacrylamide) based microgels and solid drug nanoparticles. Monodisperse poly(N-isopropylacrylamide) or poly(N-isopropylacrylamide-co-allylamine) microgels were prepared by precipitation polymerisation with mean diameters of approximately 550 nm at 25 °C. Concentrated dispersions of these microgels displayed dual-stimuli responsive behaviour, forming shape persistent bulk aggregates in the presence of both salt (at physiological ionic strength) and at body temperature (above the lower critical solution temperature of the polymer). These dual-stimuli responsive microgels could be injected into an agarose gel tissue mimic leading to rapid aggregation of the particles to form a drug depot. Additionally, the microgel particles aggregated in the presence of other payload nanoparticles (such as dye-containing polystyrene nanoparticles or lopinavir solid drug nanoparticles) to form nanocomposites with high entrapment efficiency of the payload. The resulting microgel and solid drug nanoparticle nanocomposites displayed sustained drug release for at least 120 days, with the rate of release tuned by blending microgels of poly(N-isopropylacrylamide) with poly(N-isopropylacrylamide-co-allylamine) microgels. Cytotoxicity studies revealed that the microgels were not toxic to MDCK-II cells even at high concentrations. Collectively, these results demonstrate a novel, easily injectable, nanocomposite ISFI that provides long-term sustained release for poorly water-soluble drugs without a burst release.
Highlights
Medication adherence to long-term therapy is vital in the successful treatment of chronic illness
PNIPAm microgels were prepared via precipitation polymerisation before being characterised by dynamic light scattering (DLS), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and potentiometric titration
SEM images show that discrete monodisperse particles were formed for both microgel samples PNA-00 and PNA-25, with a diameter corresponding to the Z-average diameter of the particles above the volume phase transition temperature (VPTT) measured via DLS. 1H nuclear magnetic resonance (NMR) and FTIR spectra is consistent with previous microgel characterisations, with all proton signals of PNIPAM accounted for with a weak signal detected at 2.81 ppm for the CH2 in the side group of the polyallylamine repeat unit.[53,54,55]
Summary
Paper to form a depot, i.e. a site with a large storage of drug from which sustained drug release can occur over a long period of time. Poly(N-isopropylacrylamide) (PNIPAm) is a well-established thermoresponsive polymer that can be prepared in the form of nanoparticles known as microgels.[33,34,35,36,37,38] PNIPAm microgels swell in response to temperature,[39] exhibiting a volume phase transition temperature (VPTT), which is similar to the lower critical solution temperature (LCST) of linear PNIPAm.[40] Below the VPTT the polymer exists as hydrophilic particles, with the network swollen by water molecules. We demonstrate the following: the efficient entrapment of payload nanoparticles within a nanocomposite; that the rate of drug release from a nanocomposite containing SDNs can be controlled by blending microgels with different comonomer compositions and show that such ISFIs display sustained release profiles exceeding 120 days with very little burst release
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