期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 103, 期 8, 页码 2296-2306出版社
WILEY-BLACKWELL
DOI: 10.1002/jps.24026
关键词
drug delivery systems; polymer synthesis; viscosity; thermal analysis; nanoparticles; quaternary ammonium palmitoyl glycol chitosan (GCPQ); pKa; polymeric micelles; micellar networks
资金
- University Translational Award from the Wellcome Trust
- UCL studentship
- Engineering and Physical Sciences Research Council [EP/L024748/1, EP/G061483/1, GR/T20410/01, EP/K502340/1, GR/T20410/02] Funding Source: researchfish
- EPSRC [EP/K502340/1, EP/G061483/1, EP/L024748/1] Funding Source: UKRI
N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) is a self-assembling polymer, which enables the oral bioavailability of peptide and hydrophobic drugs. In preparation for clinical testing, here we examine GCPQ's synthesis reproducibility, pKa, thermal, and rheological properties. GCPQ was synthesised by acid degradation of glycol chitosan (GC), reaction with palmitic acid N-hydroxysuccinimide (PNS) and methylation. A GC monomer, PNS molar feed ratio of 0.92 together with a gravimetric feed ratio for N-palmitoyl-6-O-glycolchitosan, methyl iodide of 3.3, reproducibly produces GCPQ48 (M-w = 19.9 +/- 9.9 kDa, M-n = 13.1 +/- 2.4 kDa, mol % palmitoylation = 23 +/- 2.7, mol % quaternisation = 10 +/- 0.23, n = 56). GCPQ48 decomposes at 218 +/- 4.3 degrees C, is glassy at room temperature (T-g = 164.4 +/- 8.5 degrees C), is a weak base (pKa = 5.99 +/- 0.15), and produces micellar dispersions at neutral pH. Below a concentration of 0.07 g mL(-1), GCPQ48 dispersions showed Newtonian rheological behaviour but at higher concentrations, the polymer undergoes shear thinning because of the chain disentanglement at high shear rates. GCPQ48 forms a network of micelles and concentrated (0.09 g mL(-1)) dispersions are viscoelastic, with the storage modulus exceeding the loss modulus at high frequencies. Solid GCPQ48 was stable when stored at room temperature for 18 months. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2296-2306, 2014
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