Study On The Design, Preparation And Related Problems Of A Polysaccharide-based PH-bacterially Triggered OCDDS

Oral colon-specific drug delivery system (OCDDS) is one of important gastrointestinal drug delivery systems and one of the important advanced techniques in contemporary drug dosage. OCDDS is adopted by the special technique through single carrier to avoid to release in upper digestive tract. The drug will start disintegrate and release when it arrives at the caecum to reach the goal for the colon-specific drug delivery and elevate therapeutic effects. Konjac glucomannan (KGM) is a natural polysaccharide having excellent biodegradability, biocompatibility, and many unique pharmacological functions. It is not degraded by digestive enzyme in the upper gastrointestinal tract of humans but can be degraded byβ-mannanase to produce manno-oligosaccharides. Recently, KGM has been paid special attention to use for a potential carrier in OCDDS.In this research, a novel pH-bacterially triggered having a spatial arm colon-specific drug delivery system based on konjac glucomannan was designed and prepared by means of oxidation, coupling reaction, and so on. On the basis of the investigation on the fluorescence properties of the carriers of konjac glucomannan solutions and dialdehyde konjac glucomannan solutions, the interactions of all kinds of compositions in the resulted OCDDS were studied, including carrier, model drug and auxiliary materials. The studied results plays great significance for applying in the field of auxiliary materials, improving the qualities of medicine preparation and exploiting the new medicine preparation. The main contents of the research were as follows:1. A novel pH-bacterially triggered having a spatial arm oral colon-specific drug delivery system based on konjac glucomannan was prepared and characterized.Firstly, konjac glucomannan (KGM) was oxidized to dialdehyde konjac glucomannan (DAKGM) via sodium periodate. Secondly, the model drug of 4-aminosalicylic acid (4-ASA) was connected to dialdehyde konjac glucomannan by covalent bond to prepare oral colon-specific drug delivery system which having a spatial arm with adipic dihydrazides (ADH) between DAKGM chain and 4-ASA. The effects of oxidizing agent, pH values and reaction time on the content of dialdehyde were studied. The optimum oxidation conditions were pH=7, NaIO4 : KGM=1.5:1 (mol : mol), and the dialdehyde content of dialdehyde konjac glucomannan was controlled by the reaction time. Thirdly, the structure and properties of the resulted products were characterized by FTIR, 1H NMR, 13C NMR, thermogravimetric analysis (TGA), and wide angle X-ray diffraction (WAXRD). The oxidation positions are occurred between C2 and C3 in the sugar hexahydroxy-ring. There are not any obvious crystal diffraction occurred in DAKGM and KGM, which illuminated DAKGM and KGM are amorphous. And finally, the mechanism of oxidation were discussed.2. The fluorescence properties of KGM solutions were systematically investigated.The fluorescence properties of KGM solutions were investigated via steady fluorescence spectra. Firstly, the excited wavelength dependence of the fluorescence of KGM solutions was measured. The results indicate that the maximum emission appears at about 334 nm when excited by the wavelength range from 200 to 300 nm. It can conclude that fluorescence of KGM can attribute to the n→σ* transition of ether oxygen (C-O-C) in the sugar hexahydroxy-ring. Secondly, the concentration dependence of fluorescence of KGM solutions was studied in detail, and a three-stage change of the concentration was showed as follows: (1) The concentration is lower than 1.0 g/L in the range from 0.05 to 1.0 g/L, the fluorescence intensity increases linearly with rising KGM concentration. (2) In the concentration range from 1.0 to 7.0 g/L, an unconspicuous enhancement in intensity with increasing concentration was observed. (3) The fluorescence intensity decreased with further rising KGM concentration in the solutions is greater than 7.0 g/L. The effect of solvent on the fluorescence properties of KGM was also investigated. The dielectirc constant, dipolarity and spatial effect of solvent will affect the fluorescence properties of KGM greatly. Moreover, the influence of the pH value on fluorescence of KGM was discussed. A maximum intensity appeared at pH 7.0. However, the intensity decreased dramatically at other pH values except for 7.0. A blue-shift of the emission peak was observed with changing the pH value. Finally, the effect of metal ions on emission of KGM was studied. The fluorescence emission of KGM can be quenched effectively by transition metal ions such as Fe3+ and Cu²⁺. According to the Stern-Volmer Equation, the activation energies for the quenching by Fe³⁺ and Cu²⁺ are estimated to be 203.8 and 171.0 L/mol, respectively.3. The fluorescence properties of DAKGM solutions were studied in detail.The fluorescence properties of DAKGM solutions were studied via steady fluorescence spectra. Two emission peaks appeared at 425 and 465 nm, respectively. The peak at 425 nm is attributed to the n→σ* transition of ether oxygen (C-O-C) in the sugar hexahydroxy-ring, and the peak at 465 nm originated from the n→π* transition of aldehyde group. The dependence of fluorescence of DAKGM on concentration was studied. In the experimental concentration range of 0.8 to 10 g/L, the emission intensities at both 425 and 465 nm increased with increasing DAKGM concentration. And the effect of solvent on the fluorescence properties of DAKGM was investigated. The dielectirc constant, dipolarity and spatial effect of solvent will affect the fluorescence properties of DAKGM greatly.4. The drug release of DAKGM-ADH-ASA (K1) was studied in artificial gastrointestinal tract, and compared with embedding delivery system of KGM (K0).The results show that the drug release in vitro of K0 is belonged to burst releasing process. The model drug of 4-ASA released rapidly in 1h with high release rate of 95% in pH 1.0 buffer solution. Drug disintegrates easily in carrier and was almost totally released. The delivery system of K0 had a similar sudden releasing process in pH 6.8 and pH 7.4 buffer solution, and its release rate amount to 50⁶0%. While in the delivery system of K1, the content of 4-ASA release reached 5% at 24h in pH 1.0 buffer solution. However, the release amount of 4-ASA amount to 20% in pH 7.4 buffer solution, and 60% in pH 6.8 buffer solution at 12h. The drug released slowly the system of K1. These results indicate the delivery system of K1 has proficient pH sensitivity and has more efficiency of colon-specific drug delivery system.5. The interactions between three surfactants and 4-ASA were discussed based on the ultraviolet spectrum, the fluorescent spectrum and the fluorescent resonance scatter of 4-ASA aqueous solution in the presence of surfactant.The results demonstrate that the cationic surfactant cetyltrimethyl ammonium bromide (CTAB) has the effect on the spectrum properties of 4-ASA aqueous solution via the static interaction. The non-ionic surfactant polyvinylpyrrolidone (PVP) has the effect on the spectrum properties of 4-ASA aqueous solution via the static interaction and hydrogen-bonding interactions. The anionic surfactant of sodium dodecyl sulfate (SDS) has the effect on the spectrum properties of 4-ASA aqueous solution via the hydrophobic interactions and static interaction. And the interactions between the surfactants and 4-ASA were provided with the schemes.6. The interaction between KGM and 4-ASA was investigated by methods of fluorescence quenching and fluorescence scatter, the combined constant of K and the number of binding sites of n were studied.The results show that the combined constant of K is 77.32 L/mol and the number of binding sites of n is 0.94. While the surfactant is added to the system of 4-ASA-KGM; the above values of K and n are changed. In the system of cationic surfactant (4-ASA-CTAB-KGM), the combined constant of K is 4.26×10⁵ L/mol, and the number of binding sites of n is 1.31. In the system of anionic surfactant (4-ASA-SDS-KGM), the combined constant of K is 0.19×10⁵ L/mol, and the number of binding sites of n is 1.08. In the system of non-ion surfactant (4-ASA-PVP-KGM), the combined constant of K is 4.36×105, the number of binding sites of n is 1.45. The results show that the surfactant can promote the combination between 4-ASA and KGM effectively.7. The molecular conformation of 4-ASA in KGM-surfactant system was investigated via methods of DSC, WAXRD and fluorescent spectra analysis.The results show that there are many kinds of intensive interaction in the system, like the hydrogen bonds and hydrophobic interaction between KGM and ASA, the static interaction and hydrophobic interaction between ASA and surfactant, the static interaction between KGM and surfactant, all of which will affect the control-release of ASA directly.