Blog 6: Chitosan-based Micro- and Nanoparticle Systems
In this unit, we learned about two types of new materials: composite and natural. Of particular interest are natural materials that we can modify to fit our needs. These include proteins, polysaccharides, and polynucleotides. Natural materials have several benefits, among which the lower chances of immunorejection and the cheaper costs are key. In keeping with my theme, I will discuss recent advances on chitosan-based micro- and nanoparticles for drug delivery.
Chitosan is a polysaccharide commonly associated and similar in structure to cellulose. An important difference between the two is the primary amine group on chitosan gives it special properties that are very useful in pharmaceutical applications. Similarly, unlike many other natural polymers, chitosan has a positive charge and is mucoadhesive. an important adhesive property that allows for prolonged duration of drug release. Chitosan is derived from chitin, which is naturally abundant and biocompatible but inert. When treated in a concentrated alkali solution, chitin becomes chitosan, a long-chain polymer that is reactive and can be produced in forms such as powdder, paste, film, fiber, etc. Chitosan is highly biocompatible with living tissues. It breaks down slowly to harmless amino sugars that are completely absorbed into the body. It is also nontoxic and can be easily removed without causing side-effects. In addition, chitosan is anti-microbial and known to absorb toxic metals. And finally, as mentioned, it has high adhesion and coagulation due to its muchoadhesive qualities.
With respect to nano- or micro-particles, Chitosan also has several advantages. (1) such particles provide controlled release, (2) don’t need toxic organic solvents since it can readily dissolve in aqueous acidic solution, (3) has a linear polamine that can be easily cross-linked, (4) its cationic nature promotes additional ionic cross-linking, (5) it is mucoadhesive, so it can readily adhere to the site of absorption. Added to these are chitosan’s numerous biocompatibilities and antimicrobial advantages
. Above are a list of chitosan-based drug delivery systems and the methods used to formulate them, as well as the drugs they were used to deliver. In this blog, I will discuss a couple formulation methods that I found interesting or valuable.
Emulsion cross-linking:
Similar to traditional nanoparticle formulation methods, water-in-oil emulision is prepared by emulsifying the CS aqueous solution at an interface with oil. A surfactant is used to decrease surface energy and stabilize aqueous droplets. This emulsion is then cross-linked with an agent to harden the droplets. Based on the emulsification intensity, the size of the particles can be controlled; but size also depends on the extent of cross-linking agent used. Some drawbacks to this method are its tedious process and the use of the harsh agents that can chemically react to disrupt the particle morphology, if nothing worse. That said, the method is cheaper and a proven technique. It is shown below in a diagram:
Spray-drying
This is a common technique to produce powders, granules, or agglomerates from a solution mixture of drug and excipient. First, chitosan is dissolved in acid, dispersed in solution, and cross-linked. A stream of hot air is then used to atomize the solution. This leads to small droplet formation; the solvent evaporates instantaneously, revealing free flowing particles. Basic parameters, such as the size of the nozzle, spray flow rate, atomization pressure, air temperature, and again, the extent of cross-linking all can be controlled to precisely determine size. 
Reverse Micellar Method
The micelle method is also one that we briefly covered in class. Reverse micelles are highly favorable because they are thermodynamically stable mixtures of water, oil, and surfactant arranged in an amphiphilic way. Unlike normal micelles, reverse micelles have an aqueous core; they are “homogenous structures at a microscopic scale in aqueous and oil micro-domains” separated by surfactant-rich films. This aqueous core can be used as a nanoreactor. Because the particles are highly monodispersed, reverse micelles will produce fine nanoparticles. While vortexing in this mircroemulsion phase, chitosan and drugg are added, and a cross-linking agent follows.
In addition to particle formulation, drug loading in these systems can be done during preparation or after. The drug is either embedded in the matrix or adsorbed on the surface. Both have advantages and disadvantages: maximum drug loading is achieved when added during formation, but adding on the sruface protexts the durg from being affected by formation parameters.
Finally, drug release from chitosan systems either (a) releases from the surface of the particles, in a burst effect; (b) by diffusion through the rubbery matrix, caused by water penetrating the system, transforming it into a rubbery matrix, and allowing the drug to diffuse through in an initially slow but later, rapid release profile; (c) due to erosion of the system, followed by rapid release.
Overall, chitosan has been proven to be a safe, biocompatible, and advantageous material to use in pharmaceutical applications. The study of chitsan-based nano- and micro-particle systems shows a lot of potential for being new solutions to the table in the future!
Source:
Agnihotri, Sunil A, Nadagouda Mallikarjuna, Tejraj Aminabhavi. “Recent advances on chitosan-based micro- and nanoparticles in drug delivery.” Jounral of Controlled Release, 2004.