Trimethyl chitosan

Hamman et al. [281,282] tested five trimethyl chitosans with different degrees of quaternization as nasal delivery systems the degree of quaternization had a major role in the absorption enhancement of this polymer across the nasal epithelia in a neutral environment. 

Co-administration of ofloxacin and chitosan in eyedrops increased the bioavailabUity of the antibiotic [290]. Trimethyl chitosan was more effective because of its solubility (plain chitosan precipitates at the pH of the tear fluid). On the other hand, N-carboxymethyl chitosan did not enhance the corneal permeability nevertheless it mediated zero-order ofloxacin absorption, leading to a time-constant effective antibiotic concentration [291]. Also W,0-carboxymethyl chitosan is suitable as an excipient in ophthalmic formulations to improve the retention and the bioavailability of drugs such as pilocarpine, timolol maleate, neomycin sulfate, and ephedrine. Most of the drugs are sensitive to pH, and the composition should have an acidic pH, to enhance stability of the drug. The delivery should be made through an anion exchange resin that adjusts the pH at around 7 [292]. Chitosan solutions do not lend themselves to thermal sterilization. A chitosan suspension, however. 

Sandri G, Poggi P, Bonferoni MC, Rossi S, Ferrari F, and Caramella C (2006) Histological evaluation of buccal penetration enhancement properties of chitosan and trimethyl chitosan. J. Pharm. Pharmacol. 58 1327-1336. 

Kotze AF, Leeuw BJ, Luessen HL, Boer AG, Verhoef JC, Junginger HE (1998) Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J Control Release 51 35—46. 

Thanou, M., Florea, B.I., Langermeyer, M.W.E., Verhoef, J.C., and Junginger, H.E., N-Trimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats), Pharm. Res., 17 27-31 (2000). 

In vitro and ex vivo intestinal tissue models to measure mucoadhesion of poly (methacrylate) and N-trimethylated chitosan polymers. Pharmaceutical Research, 22, 38-49. 

Cationic chitosan derivatives, such as /Y-trimethyl chitosan chloride, increase the paracellular delivery of macromolecules due to the interaction between the positive charges of chitosan and anionic glycoproteins on the surface of the enterocytes. Other chitosans, e.g., chitosan hydrochloride, were reported to shift specific cations required for the efficient closing of tight junctions [21] or reorganize the protein structure of tight junctions [22]. This topic is reviewed in a separate chapter of this book (Chapter 3). 

Kotze, A.F., et al. 1999. Enhancement of paracellular drag transport with highly quatemized, Y-trimethyl chitosan chloride in neutral environments In vitro evaluation in intestinal epithelial cells (Caco-2). J Pharm Sci 88 253. 

FIGURE 3.1 Chemical structures of chitosan, iV-trimethyl chitosan hydrochloride, and chitosan-TBA conjugate. 

Kean T, Roth S, Thanou M (2005) Trimethylated chitosans as non-viral gene delivery vectors cytotoxicity and transfection efficiency. J Control Release 103 643-653... 

A-Trimethyl Chitosan as Absorption Enhancer of Peptide Drugs. Ill... 

Fig. 6.4 Chemical structure of (a) chitosan and (b) N-trimethyl chitosan chloride (from Kotze et al. 1998)...

Just recently a series of other quaternized chitosan derivatives have been synthesized and characterized, namely, A,A-dimethyl, A-ethyl chitosan (DMEC) (Bayat et al. 2006), A-methyl, A,A-diethyl chitosan (DEMC) (Avadi et al. 2004) and A,A,A-triethyl chitosan (TEC) (Avadi et al. 2003). In a comprehensive study (Sadeghi et al. 2008a, b) the four quaternized derivatives of chitosan, trimethyl chitosan (TMC), diethylmethyl chitosan (DEMC), triethyl chitosan (TEC) and dimethylethyl chitosan (DMEC) with degree of substitution of approximately 50% were synthesized and their effect on the permeability of insulin across intestinal Caco-2 monolayers was studied and compared with chitosan both in free-soluble form and in nanoparticulate systems. Trans-epithelial electrical resistance (TEER) studies revealed that all four chitosan derivatives in free-soluble forms were able to decrease the TEER value in the following order TMC>DEMC>TEC = DMEC>chitosan, indicating their... 

Polnok, A., Borchard, G., Verhoef, J.C., Sarisuta, N. and Junginger, H.E. (2004) Influence of methylation process on the degree of quaternization of V-trimethyl chitosan chloride. Eur. J. Pharm. Biopharm. 57 77-83. 

Snyman, D., Hamman, J. H,. Kotze, J.S., Rollings, J.E. and Kotze, A.F. (2002) The relationship between the absolute molecular weight and the degree of quatemization of /V-trimethyl chitosan chloride. Carbohydr. Polym. 50 145-150. 

Thanou, M.M., Kotze, A.F. Scharringhausen, T., LueBen, H.L., de Boer, A.G., Verhoef, J.C. and Junginger, H.E. (2000a). Effect of degree of quatemization of A-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal Caco-2 cell monolayers. J. Control. Release 64 15-25. 

Another very attractive application of nanoparticles is the oral gene delivery. For example, quaternized chitosan-trimethylated chitosan was shown to have... 

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