复合中空微球的制备、改性与药物缓释性能研究
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摘要
无机中空微球具有结构稳定,空腔和孔道尺寸可调控和表面易于修饰等优点,在药物缓控释方面有良好的应用前景。但是,单一壳层的中空微球在结构和表面改性方面存在一定不足,难以满足不同药物在载入、储存和释放时不同的要求。本文制备了具有复合结构的TiO2/SiO2中空微球,并针对壳层材料不同,选择性的对内层TiO2进行各种改性,考察了它们在药物缓释上的应用。同时,通过对CaCO3/SiO2核壳微球的选择性改性,对相关结论作了进一步验证。
1.以共聚物微球为模板,制备了TiO2/SiO2复合中空微球。电镜和氮气吸附／脱附结果表明,其具有完整的球形空腔和多孔的壳层孔道结构,孔径分布良好。
2.分别采用硬脂酸和无机磷酸盐对复合中空微球内层的TiO2进行疏水和亲水改性。以脂溶性药物布洛芬为对象,考察了不同改性基团对载药量及释药速率的影响,结果表明：硬脂酸改性的中空微球内表面疏水,具有萃取、浓缩作用,可以增大载药量(189.8 mg／g),同时降低释药速率；而磷酸改性的中空微球内表面亲水,且由于电荷排斥,药物释放加快,同时载药量减少(153.5 mg／g)。
3.利用TiO2对卵磷脂(PC)的化学吸附作用,对TiO2/SiO2复合中空微球的内层进行了选择性改性。研究表明,由于疏水长链的引入,改性后的微球载药量增大,释药速率减慢。实验结果还表明,当采用高浓度的PC,同时加入胆固醇时,体系的释药速率进一步减缓。推测其机理,除了疏水作用外,较大浓度的PC可能在中空微球内形成了一定数量的脂质体囊泡。
4.为深入探讨选择性改性对缓释性能的影响,制备了CaCO3/SiO2核壳微球,分别采用硬脂酸和无机磷酸盐对其内核CaCO3进行了选择性改性,考察了三种体系对脂溶性药物布洛芬和水溶性药物心得安的释放机理。对于布洛芬：由于电荷排斥,无机磷酸改性体系释放速率最快；由于COO与CaCO3存在化学吸附,未改性体系释放速率最慢。对于心得安：由于无机磷酸改性后对药物的碱性基团具有较强化学吸附,该体系释放速率最慢；未改性体系释放速率最快,其释放主要受扩散控制。由于硬脂酸改性的体系对有机药物存在萃取、浓缩作用,但疏水作用较化学吸附弱,该体系对两种药物的释放速率居中。
因此,制备双层结构的中空和核壳微球,并进行选择性改性,可以使载体既具有和环境相容的外表面,又具有适合药物储存的内部微环境,同时还可以实现对载药量及药物释放速率的有效调控。
Inorganic hollow spheres are promising for controlled and sustained drug release applications due to their characteristics such as high structure stability, controlled morphologies, adjustable pore size, facile surface modification. Recently, more and more research groups have reported drug delivery vehicles based on hollow spheres with single shell material. However, the desirable loading, storage and release environment of various drugs is widely divergent from each other. Obviously, single shell spheres, even if a modification is processed, could hardly meet the complicated demands, since it has only one shell and as a result every modification takes place on the whole shell. Therefore, hollow and core-shell spheres with composite structure, which have advantages in selective modification due to their distinctive properties of inner and outer materials, are synthesized in this paper. Herein, their drug loading amounts and release behaviors, for both unmodified and modified systems have been investigated.
1. Using spherical P(St-co-AA) particles as templates, TiO2/SiO2 composite hollow spheres(CHSs) have been successfully synthesized via sol-gel method. Their hollow and porous structures were confirmed by transmission electron microscope (TEM) and N2 sorption analysis. Furthermore, they are highly intact and have suitable pore size distribution.
2. The inner layers of the CHSs were selectively modified with stearic acid and phosphate. Using water-insoluble ibuprofen (IBU) as a model drug, the investigation of drug loading amounts and release rates of the CHSs shows that they can be regulated by suitable modification. Compare with the unmodified system, the stearic acid modified CHSs exhibit higher drug loading amount(189.8 mg/g) and lower release rate due to the hydrophobic effect. However, the phosphate modified CHSs exhibit relatively low drug loading amount (153.5 mg/g) and increased release rate, probably associated to the hydrophilic shell and charge repulsion.
3. TiO2 can facilely form stable hydrophobic layers by Lewis acid-base interaction with phosphatidylcholine(PC). The CHSs were selectively modified with PC. Studies demonstrate that, due to the introduction of the hydrophobic chains, the system shows higher drug loading amount and lower release rate than that of the unmodified system. More importantly, when modified with high concentration of PC in the existence of cholesterol, the release rate of the system decreased further, it could attribute to the formation of liposome vesicles in the cavities and pore channels.
4. For further study the effect of the selective modification on drug release, CaCO3/SiO2 core-shell spheres have been synthesized. Using water-insoluble ibuprofen and water-soluble propranolol hydrochloride as two kinds of model drugs, the investigation of drug release rates for the CaCO3/SiO2 core-shell spheres shows that they can be regulated by suitable modification. For ibuprofen, the phosphate modified spheres (NaP-CaCO3/SiO2) exhibit the fastest release rate due to the charge repulsion, whereas the unmodified spheres(CaCO3/SiO2) exhibit the slowest release rate due to the chemical adsorption between COO- and CaCO3. For propranolol hydrochloride, NaP-CaCO3/SiO2 system shows the best sustained release behavior, attributed to the chemical adsorption between-NH and PO43-, whereas the unmodified system underwent the fastest release stage. In addition, the stearic acid modified interior can serve as smart nanophase extractor to capture and concentrate organic drug molecules from the aqueous release medium. Since hydrophobic effect is weaker than chemical adsorption, the stearic acid modified system shows sustained release behavior between CaCO3/SiO2 and NaP-CaCO3/SiO2.
Composite hollow and core-shell spheres have distinct inner and outer surface that can be modified differently depending on their roles to obtain adjustable drug loading amounts and release rates, drug-friendly interiors and environment-friendly exteriors. Therefore, they are potential for drug delivery applications.
1.以共聚物微球为模板,制备了TiO2/SiO2复合中空微球。电镜和氮气吸附／脱附结果表明,其具有完整的球形空腔和多孔的壳层孔道结构,孔径分布良好。
2.分别采用硬脂酸和无机磷酸盐对复合中空微球内层的TiO2进行疏水和亲水改性。以脂溶性药物布洛芬为对象,考察了不同改性基团对载药量及释药速率的影响,结果表明：硬脂酸改性的中空微球内表面疏水,具有萃取、浓缩作用,可以增大载药量(189.8 mg／g),同时降低释药速率；而磷酸改性的中空微球内表面亲水,且由于电荷排斥,药物释放加快,同时载药量减少(153.5 mg／g)。
3.利用TiO2对卵磷脂(PC)的化学吸附作用,对TiO2/SiO2复合中空微球的内层进行了选择性改性。研究表明,由于疏水长链的引入,改性后的微球载药量增大,释药速率减慢。实验结果还表明,当采用高浓度的PC,同时加入胆固醇时,体系的释药速率进一步减缓。推测其机理,除了疏水作用外,较大浓度的PC可能在中空微球内形成了一定数量的脂质体囊泡。
4.为深入探讨选择性改性对缓释性能的影响,制备了CaCO3/SiO2核壳微球,分别采用硬脂酸和无机磷酸盐对其内核CaCO3进行了选择性改性,考察了三种体系对脂溶性药物布洛芬和水溶性药物心得安的释放机理。对于布洛芬：由于电荷排斥,无机磷酸改性体系释放速率最快；由于COO与CaCO3存在化学吸附,未改性体系释放速率最慢。对于心得安：由于无机磷酸改性后对药物的碱性基团具有较强化学吸附,该体系释放速率最慢；未改性体系释放速率最快,其释放主要受扩散控制。由于硬脂酸改性的体系对有机药物存在萃取、浓缩作用,但疏水作用较化学吸附弱,该体系对两种药物的释放速率居中。
因此,制备双层结构的中空和核壳微球,并进行选择性改性,可以使载体既具有和环境相容的外表面,又具有适合药物储存的内部微环境,同时还可以实现对载药量及药物释放速率的有效调控。
Inorganic hollow spheres are promising for controlled and sustained drug release applications due to their characteristics such as high structure stability, controlled morphologies, adjustable pore size, facile surface modification. Recently, more and more research groups have reported drug delivery vehicles based on hollow spheres with single shell material. However, the desirable loading, storage and release environment of various drugs is widely divergent from each other. Obviously, single shell spheres, even if a modification is processed, could hardly meet the complicated demands, since it has only one shell and as a result every modification takes place on the whole shell. Therefore, hollow and core-shell spheres with composite structure, which have advantages in selective modification due to their distinctive properties of inner and outer materials, are synthesized in this paper. Herein, their drug loading amounts and release behaviors, for both unmodified and modified systems have been investigated.
1. Using spherical P(St-co-AA) particles as templates, TiO2/SiO2 composite hollow spheres(CHSs) have been successfully synthesized via sol-gel method. Their hollow and porous structures were confirmed by transmission electron microscope (TEM) and N2 sorption analysis. Furthermore, they are highly intact and have suitable pore size distribution.
2. The inner layers of the CHSs were selectively modified with stearic acid and phosphate. Using water-insoluble ibuprofen (IBU) as a model drug, the investigation of drug loading amounts and release rates of the CHSs shows that they can be regulated by suitable modification. Compare with the unmodified system, the stearic acid modified CHSs exhibit higher drug loading amount(189.8 mg/g) and lower release rate due to the hydrophobic effect. However, the phosphate modified CHSs exhibit relatively low drug loading amount (153.5 mg/g) and increased release rate, probably associated to the hydrophilic shell and charge repulsion.
3. TiO2 can facilely form stable hydrophobic layers by Lewis acid-base interaction with phosphatidylcholine(PC). The CHSs were selectively modified with PC. Studies demonstrate that, due to the introduction of the hydrophobic chains, the system shows higher drug loading amount and lower release rate than that of the unmodified system. More importantly, when modified with high concentration of PC in the existence of cholesterol, the release rate of the system decreased further, it could attribute to the formation of liposome vesicles in the cavities and pore channels.
4. For further study the effect of the selective modification on drug release, CaCO3/SiO2 core-shell spheres have been synthesized. Using water-insoluble ibuprofen and water-soluble propranolol hydrochloride as two kinds of model drugs, the investigation of drug release rates for the CaCO3/SiO2 core-shell spheres shows that they can be regulated by suitable modification. For ibuprofen, the phosphate modified spheres (NaP-CaCO3/SiO2) exhibit the fastest release rate due to the charge repulsion, whereas the unmodified spheres(CaCO3/SiO2) exhibit the slowest release rate due to the chemical adsorption between COO- and CaCO3. For propranolol hydrochloride, NaP-CaCO3/SiO2 system shows the best sustained release behavior, attributed to the chemical adsorption between-NH and PO43-, whereas the unmodified system underwent the fastest release stage. In addition, the stearic acid modified interior can serve as smart nanophase extractor to capture and concentrate organic drug molecules from the aqueous release medium. Since hydrophobic effect is weaker than chemical adsorption, the stearic acid modified system shows sustained release behavior between CaCO3/SiO2 and NaP-CaCO3/SiO2.
Composite hollow and core-shell spheres have distinct inner and outer surface that can be modified differently depending on their roles to obtain adjustable drug loading amounts and release rates, drug-friendly interiors and environment-friendly exteriors. Therefore, they are potential for drug delivery applications.
引文
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