Polymer carrier systems
Chitosan is a biodegradable, biocompatible polymer that is considered safe for human dietary use and approved for the application of wound dressing, produced by removing the acetate moiety from chitin Chitosan has been used in polymeric nanoparticles as a carrier for the delivery of drugs through different routes of administration. Chitosan has chemical functional groups that can be modified to accomplish specific objectives, making it a polymer with a huge range of potential applications. To form a complex through ionic or hydrogen bonding as well as through hydrophobic interactions, chitosan interacts with mucus (negatively charged). Depending on the degree of N deacetylation, the pKa of the primary amine of chitosan is 6.5. The solubility of chitosan in acidic pH environments is also contributed by this group, and the partial neutralization of this primary amine may also explain why chitosan has been reported to aggregate at neutral to high pH .
Drug Release from Chitosan Nanoparticles
There are several mechanisms that regulate the release of medication from chitosan nanoparticles, such as Polymer swelling, adsorbed drug diffusion, drug diffusion through the polymer matrix, erosion or degradation of the polymer and a combination of erosion . The initial burst release from the nanoparticles of chitosan is either due to Polymer swelling, the creation of pores, or the diffusion of the drug from the polymer surface.
Chitosan in Oral Drug Delivery
There are several challenges in achieving oral delivery such as varying pH, the presence of enzymes, first-pass effect in the liver and the intestinal barrier Pharmaceutics to drug absorption. The above challenges limit the drug from entering the systemic circulation thereby reducing oral bioavailability.
Chitosan in Nasal Drug Delivery
Chitosan is biodegradable, biocompatible, has low toxicity, adheres to mucus and
opens the nasal membrane's tight junctions and has applications in nasal delivery
due to these properties.
Chitosan in Pulmonary Drug Delivery
The positive charge is beneficial for the delivery of pulmonary drugs. Muco-adhesive properties are provided on the surface of chitosan. The potential for drug absorption is increased by this adherence to the lung mucosa; the positive charge on chitosan has previously been shown to open the intercellular tight junctions of the lung epithelium, thereby increasing uptake  . chitosan possesses antibacterial activity by binding to phosphoryl groups and lipopolysaccharides on bacterial cell membranes, which is an additional benefit in fighting pulmonary bacterial infections.
Pharmacokinetics (PK) of Chitosan Based Formulations
The pharmacokinetics of chitosan-based NPs are comparable to those of other
polymeric NPs because, as discussed above, the same principles of drug release apply. Its mucoadhesion is the most significant characteristic of chitosan to be exploited. In beagle dogs, a PK study was conducted to assess the bioavailability of Consisting of chitosan, gelatin-A or sodium glycocholate, cyclosporin-A (Cy-A) encapsulated in NPs (SGC). The standard oral microemulsion formulation (Neoral®) was received from a control group. In the case of both chitosan and gelatin NP formulations, the Cmax was markedly increased, while the Cmax decreased compared to Neoral with SGC NPs. Compared with SGC NPs, there was a 2.6-fold increase in the AUC of Cy-A from chitosan NPs and a 1.8-fold increase in the AUC of gelatin NPs compared to SGC NPs.The relative bioavailability of Cy-A from SGC NPs was decreased by 36% when compared to marketed formulation. This could be due to the SGC NPs' negative charge, which could have prevented the NPs from adhering to the intestinal mucus and thus reduced the absorption of drugs throughout the intestinal epithelium. This supports the idea that a positive charge on NPs of chitosan can contribute to mucoadhesion and increase relative bioavailability, improving in this case by 73% .
Toxicity and Safety of Chitosan
Chitosan is biodegradable, and either chemical or enzyme catalysis occurs in the process. Chitosan degradation relies on the degree of deacetylation and the availability of amino groups. In addition, for dietary use and wound dressing applications, chitosan is approved as safe by the US-FDA and the EU. The toxicity of chitosan, however, increases by increasing the density of charge and degree of deacetylation . We did not find any published data showing human toxicity of formulations based on chitosan or questioning the safety of human use of chitosan. There are, however, several studies of animal toxicity reporting good safety in vivo and in vitro .
Preparation of Chitosan Nanoparticles:
The most common methods for preparing chitosan-based nanoparticles are ionotropic gelation, microemulsion, emulsification solvent diffusion and emulsion based solvent evaporation. Some of the main benefits offered by most of these techniques are the use of less organic solvent and lower force. The main features that have been found to affect the particle size and surface charge of chitosan NPs prepared by these methods are molecular weight and the degree of acetylation of the chitosan. not only ionic strength, or the presence of salts, enzymes and proteins but also pH stability (consider the milieu of the eye vs. the GI tract). Fortunately, we now have multiple formulation methods to choose from.
1. Ionotropic gelation
The method uses the electrostatic relationship between the group of amines
Chitosan and a negatively charged polyanion group, such as tripolyphosphate, are used. Chitosan may, in the absence or presence of stabilizing agents such as poloxamer, be dissolved in acetic acid. Polyanion was then added, spontaneously forming nanoparticles at room temperature under mechanical stirring. The size and surface charge of particles can be modified by changing the ratio of chitosan to the stabilizer.
2. Microemulsion Method
Chitosan in acetic acid solution and glutaraldehyde in an organic solvent such as hexane are added to a surfactant in this method. This mixture is maintained at room temperature under continuous stirring, allowing the nanoparticles to form overnight as the cross-linking process is completed. By evaporating under low pressure, the organic solvent is then removed. At this point, the product has excess surfactant that can be removed by calcium chloride precipitation, followed by centrifugation. The final nanoparticle suspension is then dialyzed and then lyophilized .
3. Emulsification Solvent Diffusion Method
By mixing organic solvent into a solution of chitosan with stabilizer under mechanical stirring followed by high pressure homogenization, an o/w emulsion is prepared. This method could be used to achieve a size range of 300-500 nm. When a large amount of water is added to the emulsion, polymer precipitation occurs, forming nanoparticles.
4. Polyelectrolyte complex (PEC)
Polyelectrolyte complexes formed by self-assembly of the cationic charged polymer and plasmid DNA as a result of fall in hydrophilicity due to charge neutralization between cationic polymer and DNA.
5. Reverse micellar method
The major highlight is the absence of both crosslinker and toxic organic solvents. Also, ultrafine nanoparticles within a narrow size range can be obtained with this method.
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