An increasing number of industrial applications, from the manufacturing of long lasting fragrance, to the protection of materials surfaces against bacterial attack, or the targeting of cancer tumours, require the production of delivery systems in particulate form. Although a wide range of organic materials have been used to manufacture capsules and particles, very few inorganic controlled release systems have found their way into industrial products. This is typically the case for ceramics which, despite a number of intrinsic advantages such as high mechanical strength, resistance to corrosion, thermal and electrical stability biocompatibility and an environmentally benign nature, remain an untapped resource for the manufacture of controlled release systems. Using traditional routes, the relative difficulty in manipulating the internal microstructure of ceramics (compared to polymers), as well as high processing temperatures, which are incompatible with the encapsulation of organic molecules, may explain the lack of popularity as a controlled release matrix. Both of these limitations can be overcome by using sol-gel technology.
Sol-gel chemistry has revolutionized ceramic production by enabling ambient temperature, solution-based synthesis of metal oxides with the ability to “tailor” porosity. By combining sol-gel with emulsion chemistry, it is possible to produce spherical particles with a designed microstructure resulting from a judicious choice of solvent/surfactant and sol-gel reaction parameters. By changing the solvent/surfactant combination, the particle size can be varied from 10 nm to 100 m. The size of the particles is controlled by the size of the emulsion droplet, which acts as a nano-reactor for the sol-gel reaction. When an active molecule is located in the aqueous droplet, encapsulation occurs as silicon precursors polymerise to build an oxide cage around the active species. Encapsulation efficiencies for hydrophilic molecules are typically > 85%, with doping levels typically in the range 5 – 30 wt%. The release profiles can be tailored, independently of the particle size, by controlling the internal structure of the particles (pore volume, pore size, tortuosity, and surface chemistry) (e.g. Figure 2). This can be easily achieved by controlling sol gel processing parameters such as the water to alkoxide ratio, pH, alkoxide concentration, ageing, drying time and temperature. Hence, the release rate of the encapsulated species is controlled by adapting the structure of the internal pore network to the physico-chemical properties of the active molecule.
Although the CeramiSphere technology was originally developed for encapsulation and controlled release of small hydrophilic molecules, we have recently expanded our technology to the encapsulation of biomolecules, poorly soluble molecules and the production of nanoparticles with extended release capacity (multi-layered nanoparticles). CeramiSphere has developed an innovative procedure by which biomolecules are entrapped in silica microspheres formed from inorganic suspensions of aqueous silica colloids. The release mechanism is diffusion of the biomolecule through the matrix pores. The particles are in the range of 0.5 – 10 micron in size, with pore size being optimised (2 – 7 nm) to provide an appropriate release rate for the biomolecule of interest. The process has been designed to minimise denaturation of biomolecules during encapsulation. Several methods, were also developed to encapsulate hydrophobic molecules in the form of liquid, solution or solids into silica micro- and nano-particles. The encapsulation in silica offers good protection for sensitive molecules such as retinol against chemical attack, oxidation or decomposition. In addition, the release rate of the molecules can be optimised for specific compounds.
The encapsulation of active pharmaceutical ingredients (API) into nanoparticles enables new routes of administration and treatment. Using room temperature sol-gel polymerisation in reverse emulsions, active pharmaceuticals can be encapsulated inside silica nanoparticles. The surface of the particles can be functionalised to minimise protein interaction and enhance blood circulation, for active targeting. In vitro experiments, show that the particles degrade relatively rapidly (from hours to weeks) in physiological media. In addition, they show good biocompatibility, interfering with cellular processes only at very high doses (20 mg/ml). This combined with the regulatory approval by the FDA of silica for oral, topical and mucosal applications, makes this technology an interesting candidate for drug delivery.
From an industrial perspective, thanks to CeramiSphere micro-reactor approach, no serious scale-up challenges (up to 10,000 ton/year scale) are foreseen and the final cost is expected to be acceptable for all of the applications investigated to date.
State of technology and opportunities
CeramiSphere is seeking to incorporate its technology into the products of commercial partners as well as potentially manufacturing and supplying our own powders. We are currently exploring, in collaboration with various industrials partners around the globe, the potential for our technology to be applied in drug delivery, the protection of surfaces (release of biocides and anti-corrosion), the encapsulation and release of cosmeceuticals and nutraceuticals.