多糖基pH-菌群触发型结肠定位给药体系的设计、合成及其相关问题研究
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摘要
口服结肠定位释药系统(Oral Colon-specific Drug Delivery System,OCDDS)是胃肠道给药系统的重要分支,也是现代药物剂型重要的高新技术之一。它通过专一载体,采用专属释药技术,使药物口服后,避免上消化道释药,只当药物转运到回盲肠部位后,才开始崩解或蚀解并释放出来,达到结肠定位释放给药的目的,提高了药物的治疗效果。魔芋葡甘聚糖来自天然的植物资源,它具有优良的生物相容性、可生物降解性和许多独特的理化性能。尤其特别的是,魔芋葡甘聚糖在经过上消化道时不会被存在于胃及小肠的酶所降解,而到达结肠部位后,则被存在于结肠部位的β-糖苷键酶降解。因此,它被认为是比较有前途的结肠定位给药新载体材料,近年得到了广泛关注。
本工作以魔芋葡甘聚糖为原料,通过氧化、桥联等方法,制备了一种具有一定长度空间臂的新型pH-菌群触发型结肠定位给药体系;并在系统研究载体葡甘聚糖溶液和醛基葡甘聚糖溶液荧光光谱特性的基础上,从药剂学角度探讨了载体、模型药物、药用辅料之间相互作用问题。这对于进一步开发与合理应用辅料,提高药物制剂质量,开发新剂型和研制药物制剂新品种具有非常重要的意义,也为提高魔芋资源的综合利用价值及丰富制剂辅料品种提供了重要依据。具体的研究工作如下:
1、以魔芋葡甘聚糖(KGM)为原料,制备了一种具有一定长度空间臂的结肠定位给药体系。采用高碘酸钠氧化方法制备了醛基葡甘聚糖(DAKGM);以己二酰肼(ADH)为空间臂,通过偶合桥联的方式,将4-氨基水杨酸(4-ASA)通过共价键连接的方式引入醛基葡甘聚糖,制备出具一定长度空间臂的结肠定位给药体系。以醛基含量为指标,考察了氧化剂用量、反应体系pH值和反应时间对醛基含量的影响,得到了较佳的氧化工艺条件:pH=7,氧化剂高碘酸钠:葡甘聚糖=1.5:1(mol:mol);通过控制反应时间即可得到不同醛基含量的醛基葡甘聚糖。通过FTIR、1H NMR、13C NMR、DSC、WAXRD等手段表征了产物结构。结果表明,高碘酸钠氧化主要发生在糖单元上的2位和3位碳原子,醛基葡甘聚糖和葡甘聚糖一样无明显的结晶特征峰出现,均为无定形聚合物,在此基础上对氧化机理进行了初步探讨。
2、系统地研究了葡甘聚糖溶液的荧光光谱特性。采用稳态荧光光谱研究葡甘聚糖溶液的荧光光谱特性,发现激发波长在210～280 nm范围内,葡甘聚糖溶液的最强荧光波长峰值均在334 nm左右,并对葡甘聚糖溶液进行波长依赖性研究,初步判断KGM荧光主要是六元环结构中醚键C-O-C的氧未共享电子发生n→σ*跃迁。研究还发现,葡甘聚糖水溶液荧光光谱随浓度变化出现三段规律。在0.05～1.0 g/L低浓度范围内,KGM随浓度的升高,其荧光强度变大且有较好的线性关系。在1.0～7.0 g/L浓度范围内,随浓度升高荧光强度变大,但没有浓度小于1.0 g/L时明显。当KGM浓度大于7.0 g/L时,出现了荧光强度随着浓度增大而下降的现象。探讨了不同溶剂对魔芋葡甘聚糖化合物的荧光性质的影响,溶剂的介电常数、极性、空间结构等因素都对KGM的荧光性质产生影响。而且KGM的荧光特性受溶液pH值影响很大,在pH为7时荧光强度最大,当pH大于或小于7时,KGM荧光强度急剧下降;且最大发射峰有所蓝移。过渡金属离子Fe~(3+)和Cu~(2+)能显著降低KGM的荧光强度,根据Stern-Volmer方程得到了Fe~(3+)和Cu~(2+)对KGM的淬灭常数分别为203.8 L/mol和171.0 L/mol。
3、系统地研究了醛基葡甘聚糖溶液的荧光光谱特性。采用稳态荧光光谱研究醛基葡甘聚糖溶液的荧光光谱特性,发现DAKGM溶液的最大荧光波长出现在425 nm和465 nm;在此基础探讨了DAKGM的荧光机理,即425 nm附近的发射峰主要是六元环结构中醚键C-O-C的氧未成键电子发生n→σ*跃迁所致,而465 nm附近的发射峰则归属于醛基C=O氧未共价成键电子发生n→π*跃迁。研究了DAKGM浓度对荧光强度的影响,在本实验浓度为0.8～10 g/L的范围内,DAKGM在425 nm和465 nm处的荧光强度均随浓度的增大而荧光强度都增强,且荧光强度与溶液浓度之间呈两段变化。探讨了不同溶剂对醛基葡甘聚糖荧光性质的影响,溶剂的极性、介电常数、空间效应等因素都对DAKGM的荧光性质产生影响。
4、研究了DAKGM-ADH-4-ASA(K1)结肠定位给药体系的体外药物释放行为,并与KGM包埋给药体系(K0)的体外释放行为进行了对比分析,结果表明,对于包埋型给药载体K0,释放行为基本属于突释行为。在pH=1.0时,4-ASA在1h内迅速释放,释放率高达95%,药物很容易从给药载体中崩解出来。同样,K0体系在pH 6.8和pH 7.4的环境中释放行为相似,释放率约达到50～60%,也属于突释行为。而K1在pH 1.0的环境中,4-ASA释放量在24h时只有少量释放,释放量仅约为5%;而在pH 6.8和pH 7.4时,4-ASA在pH 7.4时的12小时内的总释放量约为20%;在pH 6.8时12小时内则约为60%,药物从体系内部缓慢地释放出来。说明该结肠定位给药体系具有更强的定位给药功能。
5、通过紫外光谱、荧光光谱、荧光共振散射光谱研究方法,探讨了表面活性剂与4-ASA的相互作用。结果表明,阳离子表面活性剂十六烷基三甲基溴化铵(CTAB)主要通过静电相互作用影响着4-ASA的光谱性质;非离子型表面活性剂聚乙烯基吡咯烷酮(PVP)主要通过静电相互作用和氢键相互作用影响着4-ASA的光谱性质;阴离子表面活性剂十二烷基磺酸钠(SDS)则主要依靠疏水相互作用和静电相斥作用影响着4-ASA水溶液体系的光谱性质,并提供了相应的相互作用示意图。
6、采用荧光猝灭方法和荧光散射方法研究了KGM与4-ASA相互作用结合常数及结合位点。结果表明KGM与4-ASA的相互作用结合常数及结合位点分别为:结合常数K=77.32 L/mol,结合位点数n=0.940。当体系中存在表面活性剂时,上述数值有所改变,具体为:阳离子表面活性剂CTAB:K=4.26×10~5 L/mol,结合位点数n=1.31;阴离子表面活性剂SDS:K=0.19×10~5 L/mol,结合位点数n=1.08;非离子型表面活性剂PVP:K=4.36×10~5 L/mol,结合位点数n=1.45。表面活性剂促进了4-ASA与KGM的结合。
7、采用DSC、WAXRD和荧光光谱方法研究了KGM-ASA-表面活性剂体系中的相互作用。结果表明,体系中存在多种相互作用,KGM与4-ASA之间存在氢键和疏水相互作用,4-ASA与表面活性剂之间存在静电相互作用和疏水相互作用,KGM和表面活性剂之间存在疏水相互作用,这些相互作用将直接影响到4-ASA的控释性能。
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 Cu~(2+). According to the Stern-Volmer Equation, the activation energies for the quenching by Fe~(3+) and Cu~(2+) 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 50~60%. 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 4.26×10~5 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 0.19×10~5 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.
本工作以魔芋葡甘聚糖为原料,通过氧化、桥联等方法,制备了一种具有一定长度空间臂的新型pH-菌群触发型结肠定位给药体系;并在系统研究载体葡甘聚糖溶液和醛基葡甘聚糖溶液荧光光谱特性的基础上,从药剂学角度探讨了载体、模型药物、药用辅料之间相互作用问题。这对于进一步开发与合理应用辅料,提高药物制剂质量,开发新剂型和研制药物制剂新品种具有非常重要的意义,也为提高魔芋资源的综合利用价值及丰富制剂辅料品种提供了重要依据。具体的研究工作如下:
1、以魔芋葡甘聚糖(KGM)为原料,制备了一种具有一定长度空间臂的结肠定位给药体系。采用高碘酸钠氧化方法制备了醛基葡甘聚糖(DAKGM);以己二酰肼(ADH)为空间臂,通过偶合桥联的方式,将4-氨基水杨酸(4-ASA)通过共价键连接的方式引入醛基葡甘聚糖,制备出具一定长度空间臂的结肠定位给药体系。以醛基含量为指标,考察了氧化剂用量、反应体系pH值和反应时间对醛基含量的影响,得到了较佳的氧化工艺条件:pH=7,氧化剂高碘酸钠:葡甘聚糖=1.5:1(mol:mol);通过控制反应时间即可得到不同醛基含量的醛基葡甘聚糖。通过FTIR、1H NMR、13C NMR、DSC、WAXRD等手段表征了产物结构。结果表明,高碘酸钠氧化主要发生在糖单元上的2位和3位碳原子,醛基葡甘聚糖和葡甘聚糖一样无明显的结晶特征峰出现,均为无定形聚合物,在此基础上对氧化机理进行了初步探讨。
2、系统地研究了葡甘聚糖溶液的荧光光谱特性。采用稳态荧光光谱研究葡甘聚糖溶液的荧光光谱特性,发现激发波长在210～280 nm范围内,葡甘聚糖溶液的最强荧光波长峰值均在334 nm左右,并对葡甘聚糖溶液进行波长依赖性研究,初步判断KGM荧光主要是六元环结构中醚键C-O-C的氧未共享电子发生n→σ*跃迁。研究还发现,葡甘聚糖水溶液荧光光谱随浓度变化出现三段规律。在0.05～1.0 g/L低浓度范围内,KGM随浓度的升高,其荧光强度变大且有较好的线性关系。在1.0～7.0 g/L浓度范围内,随浓度升高荧光强度变大,但没有浓度小于1.0 g/L时明显。当KGM浓度大于7.0 g/L时,出现了荧光强度随着浓度增大而下降的现象。探讨了不同溶剂对魔芋葡甘聚糖化合物的荧光性质的影响,溶剂的介电常数、极性、空间结构等因素都对KGM的荧光性质产生影响。而且KGM的荧光特性受溶液pH值影响很大,在pH为7时荧光强度最大,当pH大于或小于7时,KGM荧光强度急剧下降;且最大发射峰有所蓝移。过渡金属离子Fe~(3+)和Cu~(2+)能显著降低KGM的荧光强度,根据Stern-Volmer方程得到了Fe~(3+)和Cu~(2+)对KGM的淬灭常数分别为203.8 L/mol和171.0 L/mol。
3、系统地研究了醛基葡甘聚糖溶液的荧光光谱特性。采用稳态荧光光谱研究醛基葡甘聚糖溶液的荧光光谱特性,发现DAKGM溶液的最大荧光波长出现在425 nm和465 nm;在此基础探讨了DAKGM的荧光机理,即425 nm附近的发射峰主要是六元环结构中醚键C-O-C的氧未成键电子发生n→σ*跃迁所致,而465 nm附近的发射峰则归属于醛基C=O氧未共价成键电子发生n→π*跃迁。研究了DAKGM浓度对荧光强度的影响,在本实验浓度为0.8～10 g/L的范围内,DAKGM在425 nm和465 nm处的荧光强度均随浓度的增大而荧光强度都增强,且荧光强度与溶液浓度之间呈两段变化。探讨了不同溶剂对醛基葡甘聚糖荧光性质的影响,溶剂的极性、介电常数、空间效应等因素都对DAKGM的荧光性质产生影响。
4、研究了DAKGM-ADH-4-ASA(K1)结肠定位给药体系的体外药物释放行为,并与KGM包埋给药体系(K0)的体外释放行为进行了对比分析,结果表明,对于包埋型给药载体K0,释放行为基本属于突释行为。在pH=1.0时,4-ASA在1h内迅速释放,释放率高达95%,药物很容易从给药载体中崩解出来。同样,K0体系在pH 6.8和pH 7.4的环境中释放行为相似,释放率约达到50～60%,也属于突释行为。而K1在pH 1.0的环境中,4-ASA释放量在24h时只有少量释放,释放量仅约为5%;而在pH 6.8和pH 7.4时,4-ASA在pH 7.4时的12小时内的总释放量约为20%;在pH 6.8时12小时内则约为60%,药物从体系内部缓慢地释放出来。说明该结肠定位给药体系具有更强的定位给药功能。
5、通过紫外光谱、荧光光谱、荧光共振散射光谱研究方法,探讨了表面活性剂与4-ASA的相互作用。结果表明,阳离子表面活性剂十六烷基三甲基溴化铵(CTAB)主要通过静电相互作用影响着4-ASA的光谱性质;非离子型表面活性剂聚乙烯基吡咯烷酮(PVP)主要通过静电相互作用和氢键相互作用影响着4-ASA的光谱性质;阴离子表面活性剂十二烷基磺酸钠(SDS)则主要依靠疏水相互作用和静电相斥作用影响着4-ASA水溶液体系的光谱性质,并提供了相应的相互作用示意图。
6、采用荧光猝灭方法和荧光散射方法研究了KGM与4-ASA相互作用结合常数及结合位点。结果表明KGM与4-ASA的相互作用结合常数及结合位点分别为:结合常数K=77.32 L/mol,结合位点数n=0.940。当体系中存在表面活性剂时,上述数值有所改变,具体为:阳离子表面活性剂CTAB:K=4.26×10~5 L/mol,结合位点数n=1.31;阴离子表面活性剂SDS:K=0.19×10~5 L/mol,结合位点数n=1.08;非离子型表面活性剂PVP:K=4.36×10~5 L/mol,结合位点数n=1.45。表面活性剂促进了4-ASA与KGM的结合。
7、采用DSC、WAXRD和荧光光谱方法研究了KGM-ASA-表面活性剂体系中的相互作用。结果表明,体系中存在多种相互作用,KGM与4-ASA之间存在氢键和疏水相互作用,4-ASA与表面活性剂之间存在静电相互作用和疏水相互作用,KGM和表面活性剂之间存在疏水相互作用,这些相互作用将直接影响到4-ASA的控释性能。
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 Cu~(2+). According to the Stern-Volmer Equation, the activation energies for the quenching by Fe~(3+) and Cu~(2+) 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 50~60%. 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 4.26×10~5 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 0.19×10~5 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.
引文
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