Cellulose and Its Use for Drug Delivery

Cellulose, a natural polymer, is the most renewable and abundant polysaccharide. Cellulose has been used as an immunoprotective macrocapsule because it does not form a hydrogel and it is mostly applied in inert diffusion chambers. As an encapsulating agent, it is beneficial for cytotoxic epithelial cells in the treatment of pancreatic cancer, insulin-producing cell lines (HIT-T15), embryonic kidney cells, and hybridoma cells. It is recognized as a new nanovehicle for oral colorectal cancer treatment with high drug release at a neutral pH compared to acid pH, being proposed as a safe oral delivery system for controlled colon cancer treatment [159].

Cellulose is the structural part of the cell wall of green plants, algae, or oomycetes. It is part of the polysaccharide group and is composed of a linear chain of β (1 → 4)-linked D-glucose units. Considering it has an amphiphilic character, it can be used as a surfactant and/or stabilizer at the water–oil interface in pickering emulsions [160]. Cellulose is insoluble in water and most organic solvents. The cellulose derivative, carboxy-methylcellulose (CMC), contains carboxymethyl groups bound to the OH-groups of glucopyranose monomers on the cellulose backbone. CMC is mostly applied as a matrix molecule and, in order to ensure mechanical stability and immunoprotection, requires surface coating. CMC has been used as an encapsulating agent for probiotics, but due to the hydrophilicity of the cellulose derivatives, physical degradation occurs when passing through the digestive system. Combined with alginate, it provides a better medium system for probiotics with

enhanced tolerance at low pH and a more durable delivery of probiotic cells. Long-term storage stability depends on low water activity and low temperature. The most used dehydration methods to reduce water activity are freeze-drying, spray-drying, vacuumdrying, convective air-drying, and fluidized bed-drying. Among all, freeze-drying is the best method for preserving cells' viability because it reduces the damage to biological structures by eliminating water through sublimation [155].

Cellulose crystals have been used in combination with chitosan to encapsulate vitamin C. Stability of vitamin C is highly dependent on light, pH, and the dissolved oxygen in the environment, but is maintained due to the encapsulation with cellulose and chitosan crystals, and this may be a way to preserve highly unstable compounds during long-term storage in functional systems [161]. Similarly, nanofibrillated cellulose, combined with soybean oil-in-water emulsion and whey protein isolate, was used to encapsulate vitamin D3. Vitamin D3 encapsulation efficiency has improved with increasing emulsifier concentrations. Increasing the concentration of nanofibrillated cellulose has improved the stability and efficiency of encapsulation against environmental stresses (pH changes, salt addition, and thermal processing). The procedure may be the basis for more suitable encapsulation technologies for liposoluble vitamins in emulsion-based food products [162].

In addition to encapsulating vitamins, cellulose and cellulose derivatives have been used as agents to encapsulate drugs and probiotics with active substances. For example, ethyl cellulose nanoparticles have been shown to be effective in encapsulating clarithromycin (3:1 weight ratio of ethyl cellulose:clarithromycin). Once encapsulated, clarithromycin was more effective against *Helicobacter pylori* gastric infections. Tests performed in vivo on laboratory mice have clearly indicated better elimination of bacteria from the stomach by encapsulated clarithromycin compared to the nonencapsulated drug [163]. Ethyl cellulose and microcrystalline cellulose were also used for the encapsulation of antihypertensive drugs. This is important considering that, in the standard method of manufacturing microspheres involving emulsification and solvent evaporation, the solvents used are usually dichloromethane or chloroform, which are hazardous for the environment. Therefore, less toxic substances such as ethyl acetate are used to prepare the microspheres. Furthermore, the drug release from the microspheres is faster than the tableted ones, suggesting that tableting of the microparticulate systems may be optimal [163].
