Advanced materials and processing for drug delivery: the past and the future

Abstract

Design and synthesis of efficient drug delivery systems are of vital importance for medicine and healthcare. Materials innovation and nanotechnology have synergistically fueled the advancement of drug delivery. Innovation in material chemistry allows the generation of biodegradable, biocompatible, environment-responsive, and targeted delivery systems. Nanotechnology enables control over size, shape and multi-functionality of particulate drug delivery systems. In this review, we focus on the materials innovation and processing of drug delivery systems and how these advances have shaped the past and may influence the future of drug delivery.

Figure 1

Timeline showing FDA approved DDS in the market.

Figure 2

Conventional nanoparticle fabrication methods. a) Nanoprecipitation. Polymer dissolved in organic solvent is added to an aqueous solution in a dropwise manner under constant agitation. Nanoparticles containing drugs form instantaneously as the polymer diffuses to the aqueous phase. b) Layer-by-Layer assembly. Solid form of drugs are used as the core. A polymer layer is first adsorbed onto the drug colloidal template by incubating in polymer solution and transferred to the oppsitely charged polymer solution for additional layering. This process is repeated until nanoparticles of desired sizes are formed. c) Emulsion-based two step methods. Emulsified oil-in-water droplets containing polymer and drugs are formed in the first step. In the second step, different methods are applied to remove the solvent and precipitate nanoparticles. Top pannel: Solvent evapoaration method. Solvents are gradually evaporated under vacuum and high pressure. Middle panel: Solvent diffusion method. The solvent used to prepare emulsion drops is partially miscible with water. When the emulsion droplets are diluted with water containing stablizer, organic solvent rapidly diffuses out from the droplets, leading to condensation of the materials within and formation of polymer nanoparticles. Bottom pannel: Salting out. The solvent used to prepare polymer and drug solution is totally miscible with water. Emulsification is conducted with aqueous phase containing high concentration of salt. The saturated aqueous phase prevents solvent from mixing with water. The emulsified droplets are then diluted in water. A sudden drop of salt concentration in continous phase causes extraction of organic solvent and precipiation of polymer drug nanoparticles.

Figure 3

Common types of microfluidics design. (a) Flow focusing (b) T-junction (c) Concentric capillaries.

Figure 4

Schematic illustration of the microfluidics preparation process of various drug carriers. (a) Nanocomplex. During hydrodynamic flow focusing, precursors self-assemble into nanoparticles when precursor-solvent solution is mixed with buffer, in which the precursor is poorly soluble. The process occurs in three stages involving nucleation of nanoparticles, growth through aggregation and stabilization. (b) Microparticle/microsphere. Disperse phase is broken up by the continuous phase to form droplets which in turn give rise to microparticles upon solidification. (c) Core-shell structure. Sequential encapsulation generates double emulsion after which the shell is solidified to produce a shell layer with a liquid core. (d) Janus particle. The disperse phase comprises two distinct inputs is broken up by the continuous phase to produce particle with two distinct phases.

Figure 5

Potential platform for customized drug carrier synthesis and sorting. Mass production of microdroplets is achieved by incorporation of multiple droplet generators, with valves installed at the inlets of continuous and disperse phases to precisely control the size of particles. A continuous sorting component is included to sort particles according to their properties.

Figure 6

Particle Replication In Non-wetting Template (PRINT). A non-wetting PFPE mold with cavities of predesigned patterns is pressed against a polymer solution deposited on another non-wetting surface. The liquid polymer solution is then solidified by applying pressure or temperature. The solidified particles could be recovered from the mold by using an adhesive film.

Figure 7

Step-Flash Imprint Lithography (S-FIL). A quartz mold with cavities of predesigned shapes is pressed against a photo-crosslinkable monomer solution on top of a silica wafer. A PVA layer is put beneath the polymer solution for the release of imprinted particles. The monomers are cross linked by applying UV light. Residual layer from crosslinking reaction is removed by oxygen plasma etching and particles are freed by dissolving away the PVA layer.

Figure 8

Continuous Flow Photolithography. A stream of photo-crosslinkable monomer solution continuously flows through the rectangular channel of microfluidic device. A photomask with defined patterns is placed underneath through which pulses of UV light are applied. Particles of defined shapes are formed via cross-linking reaction and are flushed out for collection.