摘要
缓控释给药体系是指在水中或特定介质中缓慢释放药物的给药体系,由于具有诸多优点,包括减少给药次数,提高病人依从性,保持平稳而有效的血药浓度,提高药物的安全性和有效性,同时能够降低药物对胃肠道的不良反应,越来越受到人们的关注。最初的药物释放体系是非降解的,随后逐渐被生物降解聚合物所取代,近年来随着纳米技术的发展,许多有机纳米材料被作为药物载体得到广泛研究。尽管作为药物载体生物降解纳米材料的优点毋庸置疑,但是由于有机材料化学稳定性差,释放速率的可控性差,相容性不理想等明显不足,近年来对无机纳米材料在药物缓控释放方面的应用越来越重视。随着1992年介孔纳米材料M41S的出现,科学家们注意到这种新型的无机纳米孔道材料能够克服上述缺陷,成为性能更加优异的载体之一。自从2001年西班牙Vallet-Regí教授首次报道应用介孔纳米材料MCM-41作为布洛芬载体,介孔纳米材料与上述其他纳米材料相比,由于自身优异的结构特性,例如孔道内表面充足的硅羟基为药物的装载提供了足够的活性位;可进行调控的介孔孔道为不同的药物分子“量身”匹配孔径;理想的生物适应性与安全性,在药物缓控释的研究应用中占据了重要的地位。双模型介孔材料(BMMs)是一种新型介孔材料,它具有双孔道结构:3 nm左右的蠕虫状一级孔与10-30 nm左右的球形颗粒堆积孔。由于BMMs有别于单一孔道介孔材料,具有结构可控和粒度可控等许多独特性质,通过进一步表面改性,能够针对特定的药物分子,尤其是不溶性药物分子进行装载与可控释放,具有很好的专一性。与MCM-41和SBA-15相比较,在模拟人体环境下可实现对多种药物的缓控释放,是药物缓控释的良好载体。
我们主要制备BMMs,通过两种硅烷偶联剂3-氨丙基三乙氧基硅烷或3-(2-氨基乙基氨基)丙基三甲氧基硅烷对其表面进行功能化处理,作为阿司匹林,布洛芬和紫杉醇的载体,同时以MCM-41和SBA-15作为比较,研究介孔孔道结构,表面性能,以及释放介质对分子尺寸,溶解度不同药物的缓控释作用规律。应用Korsmeyer–Peppas方程计算释放动力学常数k研究药物缓控释过程,同时结合密度泛函理论,Flynn-Wall-Ozawa方法和Kissinger方法,研究介孔表面氨基改性和药物装载释放过程中表面能的变化规律,以及相应的表观活化能,从而获得介孔材料缓控释的影响因素和控制机制。
首先对于小分子的微水溶性药物阿司匹林,与MCM-41和SBA-15相比,BMMs由于具有双孔结构,虽然装载量不及具有较大介孔孔道的SBA-15,但是能够在较大载药量的基础上实现较好的缓控释;通过改变BMMs表面功能基团的种类和数量,可以提高BMMs的表面能量从而有利于与阿司匹林分子发生相互作用,实现高载药量。因此选择孔结构不同的介孔材料并应用不同功能基团对介孔表面进行修饰是控制药物装载与释放的有效手段。
在上述研究结论的基础上,对于难溶性药物布洛芬,由于分子尺寸增大阻碍了药物的多层物理吸附,因此BMMs的装载量大于SBA-15;同时通过改变颗粒尺寸得到具有不同二级堆积孔的BMMs应用于布洛芬的缓控释,研究表明功能基团和药物分子进入3 nm的一级孔中,而颗粒堆积孔的大小直接影响药物分子的扩散行为,因此增大BMMs颗粒尺寸可提高布洛芬释放速率;除此之外基于药物分子与表面有机基团之间的相互作用可知,释放过程中由介孔表面脱附的布洛芬以离子态存在,因此与模拟体液和模拟胃液相比,以水为释放介质有益于离子态布洛芬的释放;相反由于布洛芬分子难溶于水,在酸性模拟胃液中分子态布洛芬的释放受到阻碍,释放率低,说明释放介质的pH值和组成同样会影响药物释放性能。
将BMMs应用为天然产物紫杉醇载体时,由于紫杉醇分子尺寸更大,且不溶于水,在装载过程中主要被吸附在介孔孔口部分,说明介孔孔径除了会影响药物分子的扩散行为,对药物尺寸的限制同样明显;由于紫杉醇分子为非极性,当纳米材料表面嫁接极性氨丙基时,对紫杉醇的装载量明显减小,再一次验证药物分子与表面功能基团的相互作用是实现药物装载的重要因素。除此之外初步探索了BMMs紫杉醇载药体系在水中的释放性能,发现BMMs作为紫杉醇载体能够实现药物的释放,但是对释放速率的控制有待进一步的研究。
应用多种表征手段,如X-射线衍射、高分辨率扫描电子显微镜、透射电子显微镜、氮气吸附-脱附,热重分析,固态硅核磁共振、元素分析、红外光谱、紫外光谱等对功能化处理,以及药物装载与释放后的介孔材料进行表征。
依据上述研究所提出的药物缓控释模型为实现介孔纳米材料作为药物缓控释载体的实际应用提供了可靠的实验依据,并通过密度泛函理论和热分解动力学从微观层次上探索了介孔材料作为药物载体在药物装载与释放过程中的作用机制。
Controlled drug-delivery systems, a kind of drug-delivery systems which could release drug slowly in water or specific medium, because of its advantage such as reducing administration, improving patients compliance, keeping stable and effective plasma concentration, enhancing the drug safety and effect, and reducing drug side effects on the gastrointestinal tract, have received more and more attention. The initial controlled drug-delivery systems were non-degradable, and then were substituted by biodegradable polymers. Recently, with the development of nano-technology, lots of organic nano-materials have been studied as drug carriers. Although the advantages of biodegradable nano-materials are undoubted, more and more researches have been focusing on the applications of inorganic nano-materials in the research field of controlled drug delivery in recent years, due to the obvious shortcoming such as poor chemical stability, difficult control over the release rate and imperfect compatibility,. With the appearance of the mesoporous materials M41S, the scientist realized that this new kind of inorganic porous materials could overcome the weaknesses mentioned above, and become one of the excellent carriers. Since the first report from Spanish professor Vallet-Regíof the application of MCM-41 as ibuprofen carrier, mesoporous nano-materials occupied important position in the research of controlled drug delivery because of its excellent features, for example, the adequate silanols on the inner surface could provide adequate active sites for drug molecules; the tuneable porous channels could be designed for different drug molecules, and also the ideal biocompatibility and safety compared with other nano-materials. Bimodal mesoporous material (BMMs) is a new mesoporous material consisting of worm-like mesopores of 3nm as well as large inter-particles pores around 10-30 nm. Different from mesoporous materials with only one pore distribution, BMMs could realize the loading and controlled release of specific drug molecules, especially for the insoluble drugs, through surface modification, due to the unique characteristics such as the controllable structure and particles size. In comparison with MCM-41 and SBA-15, BMMs could also achieve controlled delivery of many kinds of drug in simulated body environment, and therefore could serve as a benign drug carrier.
BMMs have been synthesized and through modifying the mesoporous surface with two silane coupling agent, 3-(2-aminoethylamino)propyltrimethoxysilane and 3-aminopropyltriethoxysilane, were used as carriers of three drug, aspirin, ibuprofen and taxol, with increasing molecular size and reducing solubility, to explore the feasibility of BMMs as different drug carriers. And at the same time MCM-41 and SBA-15 were also synthesized as comparison to study the influence of mesoporous structure, superficial properties and release medium on the controlled release mechanism of drug molecules with different size and solubility. The drug release profiles were fitted with Korsmeyer–Peppas model to obtain the release kinetic constant k. Meanwhile, combined with the density function theory (DFT), the surface energy distributions (SEDs) of samples including before and after modification and drug loading were studied. Besides with Flynn-Wall-Ozawa and Kissinger methods, the apparent activation energies (Ea) were studied during the superficial amino modification and drug adsorption to explore the existence state of the functional groups and drug molecules in the mesoporous channels, and the influence factors and controlling mechanism of mesoporous materials on drug delivery will be obtained.
Firstly for aspirin, a kind of drug with small molecular size and low solubility, BMMs could achieve good controlled release performance with a large drug loading amount based on its bimodal mesoporous structure, although the loading amount was less than SBA-15 with larger mesoporous channels. By changing the types and quantities of superficial functional groups, the surface energy of BMMs would increase which was good for the interaction with aspirin molecules and finally achieved higher drug loading amounts Therefore, choosing various mesoporous materials with different mesoporous structure and functional groups to modify the mesoporous surface is an effective way for controlled drug adsorption and release. Based on the conclusion mentioned above, for ibuprofen with poor solubility, because of the relatively large molecular size obstructing the multilayer physical adsorption, the drug loading amounts of BMMs was more than that of SBA-15. Meanwhile by changing the particle size, BMMs with different inter-particle pores were applied as ibuprofen carrier, and the results demonstrated that the functional groups and drug molecules were introduced into the mesopore around 3 nm, while the inter-particles pores would influence the drug diffusion behaviour in the mesoporous channels directly. Hence the drug release rate could be accelerated by increasing the particles size of BMMs. Besides, based on the interaction between the drug molecules and superficial groups, the desorbed ibuprofen molecular existed in ionic states, so water was better release medium for ionic ibuprofen compared with simulated body fluid and simulated gastric fluid. On the contrary, because of the low solubility of ibuprofen molecules in water, the release process will be obstructed in acid simulated gastric fluid and result in low release percentage. These phenomena indicate that the pH value and composition of release medium would also affect the drug release profiles.
When BMMs was used as the carrier for natural product taxol, the taxol would be mainly adsorbed at the pore opening of BMMs because of their very large molecular size and insolubility, which means the pore size of mesoporous materials will also determines the size of the molecular besides the effect on the drug diffusion. On the other hand, when mesoporous surface was grafted with polar groups, the loading amount of taxol decreased obviously, because of the weak polarity of taxol molecular. This result further verifies that the interaction between the drug molecules and superficial organic groups is an important factor to obtain large drug loaded amounts. Besides, the release behaviour of Taxol/BMMs delivery system was explored preliminarily, and the results confirmed the BMMs is a potential taxol carrier with the successful release of taxol, however the characteristic of taxol after release and controlled release behaviour should be further studied in the future.
All the mesoporous materials before and after modification, and related drug loaded samples were characterized by means of X-ray diffraction, scanning electron microscopy, transmission electron microscopy, N2 adsorption-desorption, thermogravimetric analyses, 29Si NMR, Elemental analysis, Fourier transform-infrared spectroscopy and UV-vis spectra.
The drug loading and controlled release modal based on the research mentioned have supplied reliable experimental foundation for the practical application of mesoporous nano-materials. With the help of the density function theory and the thermal decomposition kinetics analysis, the function mechanism of mesoporous materials as drug carriers was explored and discussed at the micro-level.
引文
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