Study On Amphiphilic Copolymer Micelles Applied In Coating Pharmaceuticals

Polymeric micelle is a novel nano-drug carrier developing in recent years, which is self-assembled with amphiphilic copolymer in the selective solvent when micro-phase separation occurs. The micelle has a hydrophobic core and a hydrophilic shell; the special structure can enhance the solubilities of water-insoluble drugs. However, the present researches are more concentrated in the studies of the block copolymers. While synthesis of the block copolymers is complicated, and harsh conditions required, production for large scale is limited. In contrast, the random copolymers can be easily synthesized, which have huge potentials. However, few work related in the area was reported. In this thesis, the pH-responsive poly(methyl methacrylate-co-methacrylic acid) self-assembled micelles chosen as the research object, a linear solvation energy equation (LSER) model was established. According to LSER model, three pharmaceuticals with appropriate groups were selected to be encapsulated by the copolymer, and their releases from micelles have been investigated systematically. There were four sections in the thesis as follows:(1) The poly(methyl methacrylate-co-methacrylic acid) micelles were used as pseudosta-tionary phase (PSP) in electrokinetic chromatography capillary (EKC). A series of26different kinds of solutes were determined with EKC to obtain their retention behaviors. According to the retention factors and the descriptors of the solutes, the multiple linear regressions were investigated to obtain the contributions of various forces between molecules when drug molecule was distributed between the PSP and water phase. The multiple linear regression equation is as follows:logk=2.27Vs+0.39R2+0.10πH2+0.33ΣαH2-2.25ΣβH2-2.71This LSER model revealed that the copolymer micelle has a good encapsulation capability for pharmaceuticals with moderately polar, unsaturated double bond and unshared pair of electrons, protons available.(2) Retinol, i.e. vitamin A, fat-soluble and containing hydrogen bond (-CH2OH), was selected as the first kind of drug to be coated by the copolymer micelles. CMC values of polymers with the different monomer ratio were measured using pyrene fluorescence probe method. The effects of monomer ratio of copolymer and the amount of drug added on the drug encapsulation efficiency and drug loading content were investigated. The particle size, zeta potential, and TEM were determined and compared between vitamin A coated copolymer micelle and the blank one. The results revealed the CMC value decreases with the increase of the methyl methacrylate monomer ratio. Drug loading content and encapsulation efficiency reach to12.9%and81.9%, respectively, using polymer with monomer ratio of7:3as packing material and adding15%vitamin A. The micelle coating vitamin A is larger, and zeta potential is more negative than the blank micelle. Encapsulation with the polymeric micelle could improve the storage stability of vitamin A, and release76.1%vitamin A in simulated the human skin pH environments within10hours.(3) All-trans retinoic acid, fat-soluble and containing hydrogen bonding (-COOH), was selected as the second kind of drug to be coated by the copolymer micelles. The effect of the amount of drug added on the drug encapsulation efficiency and drug loading content was investigated. The particle size and zeta potential were determined and compared between retinoic acid coated copolymer micelle and the blank one. The analysis of DSC and the characterization of IR were investigated between retinoic acid and the copolymer micelle coating one. Drug loading content and encapsulation efficiency reach24.8%and92.5%, respectively, using polymer with monomer ratio of7:3as packing material and adding27%retinoic acid. The micelle coating retinoic acid is larger, and zeta potential is more negative than the blank micelle. In the micelles, retinoic acid forms dimer firstly, and then forms hydrogen bonds with the micelles, leading to an obvious redshift in UV spectrum. The micelle can release63.1%retinoic acid in the simulated human skin pH environment within10hours.(4) Paclitaxel, water-insoluble, containing fews hydrogen bondings (-CH2OH) and having a larger spatial structures, was selected as the third kind of drug to be coated by the copolymer micelles. The effect of the amount of paclitaxel added on the encapsulation efficiency and loading content was investigated. The particle size and zeta potential were determined and compared between paclitaxel coated copolymer micelle and the blank one. The analysis of DSC was investigated between paclitaxel and the copolymer micelle coating one. Drug loading content and encapsulation efficiency reach18%and85.2%, respectively, using polymer with monomer ratio of7:3as packing material and adding21%paclitaxel. The micelle coating paclitaxel is larger, and zeta potential is more negative than the blank micelle. The results revealed that the7:3copolymers’drug loading content and encapsulation efficiency reach18%and85.2%, respectively, with21%paclitaxel added in. And the micelle’s particle size becomes larger, and zeta potential more negative. Micelle coating paclitaxel in a simulated body fluid pH environment show stable sustained-release of paclitaxel within140hours.The three kinds of pharmaceuticals, selected according to LSER model, could be well encapsulated by poly(methyl methacrylate-co-methacrylic acid) micelles, which, in turn, verified the reasonableness of the LSER model.