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CN117186058A - Lipoic acid nanoparticle and preparation method thereof - Google Patents

Lipoic acid nanoparticle and preparation method thereof Download PDF

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Publication number
CN117186058A
CN117186058A CN202311052636.6A CN202311052636A CN117186058A CN 117186058 A CN117186058 A CN 117186058A CN 202311052636 A CN202311052636 A CN 202311052636A CN 117186058 A CN117186058 A CN 117186058A
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lipoic acid
nano
nano particles
nanoparticles
solution
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唐昊
梁瑱
钱栋
邵仲昆
范柯
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JIANGSU TOHOPE PHARMACEUTICAL CO Ltd
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JIANGSU TOHOPE PHARMACEUTICAL CO Ltd
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Abstract

The application relates to the technical field of lipoic acid, in particular to lipoic acid nano particles and a preparation method thereof, and the preparation method of the lipoic acid nano particles comprises the following steps: adding lipoic acid powder into an organic solvent, and stirring and dissolving to form lipoic acid solution; adding the nano particles into a solvent to enable the nano particles to be dispersed in the solvent, so as to obtain a nano carrier solution; dripping lipoic acid solution into nano carrier solution and stirring and mixing to form lipoic acid nano particles; the lipoic acid nano particles are subjected to curing treatment by adopting a heat treatment or chemical crosslinking method; and (3) centrifuging or filtering the solidified lipoic acid nano particles and washing to obtain the lipoic acid nano particles. According to the application, nanoparticles are used as the carrier of the lipoic acid, and the lipoic acid is adsorbed on the surfaces of the nanoparticles, so that lipoic acid molecules are protected by the nanoparticles, the influence of illumination and temperature on the lipoic acid molecules is effectively reduced, and the stability of the lipoic acid is improved.

Description

一种硫辛酸纳米粒子及其制备方法Lipoic acid nanoparticles and preparation method thereof

技术领域Technical field

本申请涉及硫辛酸技术领域,尤其是涉及一种硫辛酸纳米粒子及其制备方法。The present application relates to the technical field of lipoic acid, and in particular to a lipoic acid nanoparticle and a preparation method thereof.

背景技术Background technique

硫辛酸是天然还原剂,被人体吸收后,可以在细胞内迅速转化为二氢硫辛酸,并排出细胞外。硫辛酸和二氢硫辛酸的联合作用可清除体内几乎所有的氧化自由基。硫辛酸因其强抗氧化能力在医药、食品、化妆品等领域得到了广泛的研究和应用。Lipoic acid is a natural reducing agent. After being absorbed by the human body, it can be quickly converted into dihydrolipoic acid within the cells and excreted out of the cells. The combined action of lipoic acid and dihydrolipoic acid scavenges nearly all oxidative free radicals in the body. Lipoic acid has been widely researched and used in medicine, food, cosmetics and other fields due to its strong antioxidant capacity.

由于硫辛酸具有强的抗氧化性,这便导致暴露在空气中的硫辛酸极易受到光照和温度的影响而被氧化,形成硫辛酸的氧化自由基,导致真正能够到达人体内的硫辛酸的有效含量大幅减少,同时氧化后的硫辛酸会发出一种刺鼻的气味。Because lipoic acid has strong antioxidant properties, lipoic acid exposed to the air is easily oxidized by light and temperature, forming oxidative free radicals of lipoic acid, which can actually reach the human body. The effective content is greatly reduced, and the oxidized lipoic acid emits a pungent smell.

因此,提高硫辛酸的稳定性对于其应用和发展具有重要的意义。Therefore, improving the stability of lipoic acid is of great significance for its application and development.

发明内容Contents of the invention

为了提高硫辛酸的稳定性,本申请提供一种硫辛酸纳米粒子及其制备方法。In order to improve the stability of lipoic acid, this application provides lipoic acid nanoparticles and a preparation method thereof.

第一方面,本申请提供一种硫辛酸纳米粒子的制备方法,采用如下的技术方案:In the first aspect, this application provides a method for preparing lipoic acid nanoparticles, adopting the following technical solution:

一种硫辛酸纳米粒子的制备方法,包括以下步骤:A preparation method of lipoic acid nanoparticles, including the following steps:

制备硫辛酸溶液:将硫辛酸粉末加入有机溶剂中,搅拌溶解形成70-80g/L硫辛酸溶液;Prepare lipoic acid solution: Add lipoic acid powder to an organic solvent, stir and dissolve to form a 70-80g/L lipoic acid solution;

制备纳米载体溶液:将纳米粒子加入溶剂中,使纳米粒子分散在溶剂中,得到6-10mg/ml的纳米载体溶液;Preparing the nanocarrier solution: Add the nanoparticles to the solvent to disperse the nanoparticles in the solvent to obtain a nanocarrier solution of 6-10 mg/ml;

制备硫辛酸纳米粒子:将硫辛酸溶液滴加到纳米载体溶液中并搅拌混合形成硫辛酸纳米粒子;Preparing lipoic acid nanoparticles: Drop lipoic acid solution into the nanocarrier solution and stir and mix to form lipoic acid nanoparticles;

固化硫辛酸纳米粒子:将硫辛酸纳米粒子采用热处理或化学交联的方法对硫辛酸纳米粒子进行固化处理;Curing lipoic acid nanoparticles: The lipoic acid nanoparticles are cured by heat treatment or chemical cross-linking;

硫辛酸纳米粒子提纯:通过离心或过滤的方法将固化后的硫辛酸纳米粒子分离得到硫辛酸纳米粒子与溶剂,再对分离得到的硫辛酸纳米粒子进行洗涤,以去除残余的有机溶剂和杂质。Purification of lipoic acid nanoparticles: Separate the solidified lipoic acid nanoparticles by centrifugation or filtration to obtain lipoic acid nanoparticles and solvent, and then wash the separated lipoic acid nanoparticles to remove residual organic solvents and impurities.

通过采用上述技术方案,采用纳米粒子作为硫辛酸的载体,将硫辛酸吸附在纳米粒子表面,使得硫辛酸分子受到纳米粒子的保护,有效地降低了光照和温度对其的影响,提高了硫辛酸的稳定性,使其能够在外部环境变化较大的情况下保持活性和纯度;本申请制备方法简单高效,适用于工业化生产,可大规模制备,可用于制备稳定的硫辛酸药物制剂,适用于药物制造、保健品和化妆品等领域。By adopting the above technical solution, nanoparticles are used as the carrier of lipoic acid, and lipoic acid is adsorbed on the surface of the nanoparticles, so that the lipoic acid molecules are protected by the nanoparticles, effectively reducing the effects of light and temperature on them, and improving the efficiency of lipoic acid. The stability enables it to maintain activity and purity under large changes in the external environment; the preparation method of the present application is simple and efficient, suitable for industrial production, can be prepared on a large scale, and can be used to prepare stable lipoic acid pharmaceutical preparations, suitable for Pharmaceutical manufacturing, health care products and cosmetics and other fields.

在一个具体的可实施方案中,所述制备硫辛酸溶液制备步骤中,所述有机溶剂为质量比为(5-15):1的乙醇和二甲基亚砜的混合物。In a specific embodiment, in the step of preparing lipoic acid solution, the organic solvent is a mixture of ethanol and dimethyl sulfoxide with a mass ratio of (5-15):1.

通过采用上述技术方案,由于乙醇和二甲基亚砜对硫辛酸存在二聚缔合作用,一定比例的乙醇和二甲基亚砜可以减少硫辛酸分子之间的聚合,提高硫辛酸分子在纳米粒子表面的包覆率,从而提高硫辛酸的稳定性。By adopting the above technical solution, due to the dimerization effect of ethanol and dimethyl sulfoxide on lipoic acid, a certain proportion of ethanol and dimethyl sulfoxide can reduce the polymerization between lipoic acid molecules and increase the concentration of lipoic acid molecules in nanometers. The coating rate of the particle surface improves the stability of lipoic acid.

在一个具体的可实施方案中,所述制备纳米载体溶液制备步骤中,所述纳米粒子为纳米二氧化硅、纳米氧化钛、纳米淀粉、纳米盐类中的一种。In a specific embodiment, in the step of preparing the nanocarrier solution, the nanoparticles are one of nanosilica, nanotitanium oxide, nanostarch, and nanosalts.

通过采用上述技术方案,纳米二氧化硅表面的羟基可以和分子以氢键形成结合而具有很强的吸附性,可将硫辛酸分子吸附到其表面,提高硫辛酸的稳定性。By adopting the above technical solution, the hydroxyl groups on the surface of nanosilica can form hydrogen bonds with molecules and have strong adsorption properties, which can adsorb lipoic acid molecules to its surface and improve the stability of lipoic acid.

纳米氧化钛表面具有活性位点和很多孔洞,这些活性位点和孔洞对硫辛酸分子具有很强的吸附性,硫辛酸分子会吸附在纳米氧化钛表面,形成稳定的硫辛酸纳米粒子。The surface of nano-titanium oxide has active sites and many holes. These active sites and holes have strong adsorption properties for lipoic acid molecules. Lipoic acid molecules will be adsorbed on the surface of nano-titanium oxide to form stable lipoic acid nanoparticles.

纳米淀粉是一种原料价格低廉、生物兼容性较好并可生物降解的药物载体,由于纳米淀粉粒径很小,具有巨大的自由表面,使纳米淀粉具有较高的胶体稳定性和优异的吸附性能,因而对硫辛酸分子具有很强的吸附性。Nanostarch is a drug carrier with low raw material price, good biocompatibility and biodegradability. Due to the small particle size of nanostarch and its huge free surface, nanostarch has high colloidal stability and excellent adsorption. performance, and therefore has strong adsorption to lipoic acid molecules.

纳米盐类在气化过程中,会形成一种强附着的固体磁膜层,上面布满了数以亿计的纳米级细小针刺,可主动吸附硫辛酸纳米粒子,具有较强的吸附性。During the gasification process, nano-salts will form a strongly adherent solid magnetic film layer, which is covered with hundreds of millions of nano-scale tiny needles, which can actively adsorb lipoic acid nanoparticles and has strong adsorption properties. .

在一个具体的可实施方案中,所述纳米粒子的粒径为10-20nm,比表面积为200-300m2/g,所述纳米盐类为纳米氧化铝。In a specific embodiment, the particle size of the nanoparticles is 10-20 nm, the specific surface area is 200-300 m 2 /g, and the nano-salt is nano-alumina.

通过采用上述技术方案,随着粒径的不断减小,纳米粒子的比表面积急剧变大,高的比表面积使处于粒子表面的原子数增多,导致表面能和表面结合能的迅速增加。由于粒子表面原系数量增多,原子配位的不足及高的表面能,使粒子表面原子具有很高的化学活性,极不稳定,很容易与其他原子结合。所以,选择合适的纳米粒子粒径和比表面积,使硫辛酸分子很容易吸附于其表面,以提高硫辛酸的稳定性。By adopting the above technical solution, as the particle size continues to decrease, the specific surface area of the nanoparticles increases sharply. The high specific surface area increases the number of atoms on the surface of the particles, resulting in a rapid increase in surface energy and surface binding energy. Due to the increased number of original systems on the particle surface, insufficient atomic coordination and high surface energy, the atoms on the particle surface have high chemical activity, are extremely unstable, and can easily combine with other atoms. Therefore, the appropriate particle size and specific surface area of the nanoparticles should be selected so that lipoic acid molecules can be easily adsorbed on their surface to improve the stability of lipoic acid.

纳米氧化铝表面的活性位点非常多,可以与硫辛酸发生化学反应;同时其表面具有微纳结构,形成了许多孔道和微孔,这些孔道和微孔的大小不同,可以进一步增加氧化铝的表面积,进一步提高其吸附性,将硫辛酸分子吸附在其表面,提高硫辛酸的稳定性。There are many active sites on the surface of nano-alumina, which can react chemically with lipoic acid; at the same time, its surface has a micro-nano structure, forming many channels and micropores. The sizes of these channels and micropores are different, which can further increase the strength of alumina. The surface area further improves its adsorption, adsorbs lipoic acid molecules on its surface, and improves the stability of lipoic acid.

在一个具体的可实施方案中,所述制备硫辛酸纳米粒子制备步骤中,所述硫辛酸溶液与纳米载体溶液的体积比为(70-80):(6-10)。In a specific embodiment, in the step of preparing lipoic acid nanoparticles, the volume ratio of the lipoic acid solution to the nanocarrier solution is (70-80): (6-10).

通过采用上述技术方案,优化硫辛酸溶液与纳米载体溶液的质量比,可提高硫辛酸分子在纳米粒子表面的包覆率,从而提高硫辛酸的稳定性。By adopting the above technical solution and optimizing the mass ratio of lipoic acid solution and nanocarrier solution, the coating rate of lipoic acid molecules on the surface of nanoparticles can be increased, thereby improving the stability of lipoic acid.

在一个具体的可实施方案中,所述制备硫辛酸纳米粒子制备步骤中,硫辛酸溶液以2-5ml/min的速度滴加到纳米载体溶液中并搅拌18-24h。In a specific embodiment, in the step of preparing lipoic acid nanoparticles, the lipoic acid solution is dropped into the nanocarrier solution at a speed of 2-5 ml/min and stirred for 18-24 hours.

通过采用上述技术方案,滴加速度和搅拌时间的组合可以影响硫辛酸与纳米粒子之间的接触时间和频率。适当的条件有助于在合适的时间内使硫辛酸分子与纳米粒子表面发生相互作用,从而实现较好的包覆。By adopting the above technical solution, the combination of dropping speed and stirring time can affect the contact time and frequency between lipoic acid and nanoparticles. Proper conditions help lipoic acid molecules interact with the nanoparticle surface in the right amount of time, resulting in better coating.

适当的搅拌时间能够将硫辛酸分子在纳米粒子悬浮液中均匀分散,从而提高包覆的均匀性;过快或过慢的搅拌可能会导致硫辛酸在溶液中分散不均匀。Appropriate stirring time can evenly disperse lipoic acid molecules in the nanoparticle suspension, thereby improving the uniformity of coating; stirring too fast or too slow may cause lipoic acid to be unevenly dispersed in the solution.

同时适当的搅拌时间可以影响硫辛酸分子在纳米粒子表面的吸附和排斥行为;适当的搅拌时间有助于防止硫辛酸分子在纳米粒子表面过度聚集,从而实现更好的包覆效果。At the same time, appropriate stirring time can affect the adsorption and repulsion behavior of lipoic acid molecules on the surface of nanoparticles; appropriate stirring time can help prevent excessive aggregation of lipoic acid molecules on the surface of nanoparticles, thereby achieving better coating effects.

在一个具体的可实施方案中,所述固化硫辛酸纳米粒子制备步骤中,所述热处理时的温度为60-100℃,时间为10-30min。In a specific embodiment, in the preparation step of solidified lipoic acid nanoparticles, the temperature during the heat treatment is 60-100°C and the time is 10-30 minutes.

通过采用上述技术方案,在固化过程中,适当的温度可以影响反应速率;较高的温度通常会促进反应速率,有助于在相对短的时间内形成更稳定的包覆结构。温度可以影响包覆物分子的构象,从而影响其在纳米载体表面的吸附和包覆率;不同温度下,包覆物可能有不同的构象,这可能会影响其在载体表面的分布和相互作用。适当的固化温度可以促进包覆物与纳米载体之间的交联、键合或其他相互作用,这些化学反应有助于提高包覆物在载体表面的稳定性。By adopting the above technical solution, during the curing process, appropriate temperature can affect the reaction rate; higher temperatures usually promote the reaction rate and help form a more stable coating structure in a relatively short time. Temperature can affect the conformation of coating molecules, thereby affecting its adsorption and coating rate on the surface of the nanocarrier; at different temperatures, the coating may have different conformations, which may affect its distribution and interaction on the surface of the carrier . Appropriate curing temperature can promote cross-linking, bonding or other interactions between the coating and the nanocarrier. These chemical reactions help to improve the stability of the coating on the carrier surface.

固化时间决定了包覆物与纳米载体之间的相互作用程度;适当的固化时间可以确保足够的反应发生,从而形成稳定的包覆层。适当的固化时间可以允许包覆物分子之间的交联或交联到载体表面,从而形成更为紧密的结构,提高包覆物的稳定性。不同的固化时间可以实现不同程度的固化。较短的固化时间可能导致未完全反应的包覆物分子仍存在,而较长的固化时间可能导致过度固化,影响包覆物的分散性和稳定性。The curing time determines the degree of interaction between the coating and the nanocarrier; an appropriate curing time ensures that sufficient reaction occurs to form a stable coating. Appropriate curing time can allow cross-linking between coating molecules or to the surface of the carrier, thereby forming a tighter structure and improving the stability of the coating. Different curing times can achieve different degrees of curing. A shorter curing time may cause incompletely reacted coating molecules to still exist, while a longer curing time may result in over-curing, affecting the dispersion and stability of the coating.

在一个具体的可实施方案中,所述固化硫辛酸纳米粒子制备步骤中,所述化学交联法是指用化学交联剂对硫辛酸纳米粒子进行改性处理,所述化学交联剂包括戊二醛、羧酸交联剂、碳酸二酐中的一种。In a specific embodiment, in the preparation step of solidified lipoic acid nanoparticles, the chemical cross-linking method refers to modifying lipoic acid nanoparticles with a chemical cross-linking agent, and the chemical cross-linking agent includes One of glutaraldehyde, carboxylic acid cross-linking agent, and carbonic dianhydride.

通过采用上述技术方案,采用化学交联法使得硫辛酸纳米粒子通过化学键联结而形成交联网络的方法,从而可防止吸附在纳米粒子表面的硫辛酸分子发生脱落,提高硫辛酸在纳米粒子表面的吸附效果。By adopting the above technical solution and using a chemical cross-linking method to connect lipoic acid nanoparticles through chemical bonds to form a cross-linked network, it is possible to prevent the lipoic acid molecules adsorbed on the surface of the nanoparticles from falling off and improve the adhesion of lipoic acid on the surface of the nanoparticles. adsorption effect.

在一个具体的可实施方案中,所述硫辛酸纳米粒子提纯制备步骤中:将固化后的硫辛酸纳米粒子通过在转速为10000-15000rpm下将硫辛酸纳米粒子与溶剂离心分离,再对分离得到的硫辛酸纳米粒子采用丙酮洗1-3次,再用去离子水洗3次以去除残余的有机溶剂和杂质。In a specific embodiment, in the purification and preparation step of lipoic acid nanoparticles: the solidified lipoic acid nanoparticles are centrifuged from the solvent at a rotation speed of 10,000-15,000 rpm, and then separated to obtain The lipoic acid nanoparticles were washed 1-3 times with acetone and then 3 times with deionized water to remove residual organic solvents and impurities.

通过采用上述技术方案,采用高速离心分离的方法不仅分离速度快,分离效率高,而且溶剂去除较彻底,可提高硫辛酸纳米粒子的纯度,提高硫辛酸对纳米粒子的包覆率。By adopting the above technical solution, the high-speed centrifugal separation method not only has fast separation speed and high separation efficiency, but also removes the solvent more thoroughly, which can improve the purity of lipoic acid nanoparticles and improve the coating rate of lipoic acid on the nanoparticles.

第二方面,本申请提供一种硫辛酸纳米粒子,采用如下的技术方案:In the second aspect, this application provides lipoic acid nanoparticles, adopting the following technical solution:

一种硫辛酸纳米粒子,采用上述制备方法制备得到。A lipoic acid nanoparticle is prepared using the above preparation method.

综上所述,本申请包括以下至少一种有益技术效果:To sum up, this application includes at least one of the following beneficial technical effects:

1.本申请采用纳米粒子作为硫辛酸的载体,将硫辛酸吸附在纳米粒子表面,使得硫辛酸分子受到纳米粒子的保护,有效降低了光照和温度对硫辛酸的影响,提高了硫辛酸的稳定性;1. This application uses nanoparticles as the carrier of lipoic acid, and adsorbs lipoic acid on the surface of the nanoparticles, so that the lipoic acid molecules are protected by the nanoparticles, effectively reducing the effects of light and temperature on lipoic acid, and improving the stability of lipoic acid. sex;

2.本申请中优化硫辛酸溶液滴加到纳米载体溶液中的速度和搅拌时间,有助于在合适的时间内使硫辛酸分子与纳米粒子表面发生相互作用,从而实现较好的包覆;2. In this application, the speed and stirring time of lipoic acid solution dripping into the nanocarrier solution are optimized, which will help the lipoic acid molecules interact with the surface of the nanoparticles within a suitable time, thereby achieving better coating;

3.本申请在固化过程中,优化热处理时的温度和时间,适当的温度可以影响反应速率;较高的温度通常会促进反应速率,有助于在相对短的时间内形成更稳定的包覆结构,提高包覆率,从而进一步提高硫辛酸的稳定性。3. During the curing process of this application, the temperature and time of the heat treatment are optimized. Appropriate temperature can affect the reaction rate; higher temperature usually promotes the reaction rate and helps to form a more stable coating in a relatively short time. structure, improve the coating rate, thereby further improving the stability of lipoic acid.

具体实施方式Detailed ways

以下实施例对本申请作进一步详细说明。The following examples further illustrate this application in detail.

实施例Example

实施例1Example 1

本实施例公开了一种硫辛酸纳米粒子的制备方法,具体包括以下步骤:This embodiment discloses a method for preparing lipoic acid nanoparticles, which specifically includes the following steps:

S1,将70g硫辛酸粉末加入833ml乙醇和167ml二甲基亚砜混合形成的1L有机溶液中,搅拌使硫辛酸完全溶解在有机溶剂中,得到70g/L硫辛酸溶液;S1, add 70g lipoic acid powder to 1L organic solution formed by mixing 833ml ethanol and 167ml dimethyl sulfoxide, stir to completely dissolve lipoic acid in the organic solvent, and obtain a 70g/L lipoic acid solution;

S2,将6㎎粒径为10nm、比表面积为300m2/g的纳米二氧化硅加入1ml去离子水中,搅拌使纳米二氧化硅分散在去离子水中,得到6㎎/ml纳米载体溶液;S2, add 6㎎ of nano-silica with a particle size of 10 nm and a specific surface area of 300 m 2 /g into 1 ml of deionized water, and stir to disperse the nano-silica in the deionized water to obtain a 6㎎/ml nano-carrier solution;

S3,将70ml上述硫辛酸溶液以2ml/min的速度滴加到上述6ml纳米载体溶液中,搅拌24h形成硫辛酸纳米粒子;S3, add 70 ml of the above-mentioned lipoic acid solution dropwise into the above-mentioned 6 ml nanocarrier solution at a speed of 2 ml/min, and stir for 24 hours to form lipoic acid nanoparticles;

S4,将上述硫辛酸纳米粒子在温度为60℃的温度下,热处理30min,将硫辛酸分子固化在纳米粒子表面,形成固化硫辛酸纳米粒子;S4, heat-treat the above-mentioned lipoic acid nanoparticles at a temperature of 60°C for 30 minutes to solidify lipoic acid molecules on the surface of the nanoparticles to form solidified lipoic acid nanoparticles;

S5,将固化后的硫辛酸纳米粒子在10000rpm的转速下将硫辛酸纳米粒子与溶剂分离;再对分离得到的硫辛酸纳米粒子用丙酮清洗1次后再用去离子水反复清洗3次即可。S5, separate the solidified lipoic acid nanoparticles from the solvent at a rotation speed of 10,000 rpm; then wash the separated lipoic acid nanoparticles once with acetone and then wash them three times with deionized water. .

实施例2Example 2

本实施例与实施例1不同的是,S1,将70g硫辛酸粉末加入818ml乙醇和182ml二甲基亚砜混合形成的1L有机溶液中,搅拌使硫辛酸完全溶解在有机溶剂中,得到70g/L硫辛酸溶液。The difference between this example and Example 1 is that in S1, 70g lipoic acid powder is added to 1L organic solution formed by mixing 818ml ethanol and 182ml dimethyl sulfoxide, and stirred to completely dissolve lipoic acid in the organic solvent to obtain 70g/ L lipoic acid solution.

实施例3Example 3

本施例与实施例1不同之处在于,S1,将70g硫辛酸粉末加入937.5ml乙醇和62.5ml二甲基亚砜混合形成的1L有机溶液中,搅拌使硫辛酸完全溶解在有机溶剂中,得到70g/L硫辛酸溶液。The difference between this example and Example 1 is that, in S1, 70g lipoic acid powder is added to 1L organic solution formed by mixing 937.5ml ethanol and 62.5ml dimethyl sulfoxide, and stirred to completely dissolve lipoic acid in the organic solvent. Obtain 70g/L lipoic acid solution.

实施例4Example 4

本实施例与实施例2不同之处在于,S1,将75g硫辛酸粉末加入818ml乙醇和182ml二甲基亚砜混合形成的1L有机溶液中,搅拌使硫辛酸完全溶解在有机溶剂中,得到75g/L硫辛酸溶液。The difference between this example and Example 2 is that in S1, 75g lipoic acid powder is added to 1L organic solution formed by mixing 818ml ethanol and 182ml dimethyl sulfoxide, and stirred to completely dissolve lipoic acid in the organic solvent to obtain 75g /L lipoic acid solution.

实施例5Example 5

本实施例与实施例2不同之处在于,S1,将80g硫辛酸粉末加入818ml乙醇和182ml二甲基亚砜混合形成的1L有机溶液中,搅拌使硫辛酸完全溶解在有机溶剂中,得到80g/L硫辛酸溶液。The difference between this example and Example 2 is that in S1, 80g lipoic acid powder is added to 1L organic solution formed by mixing 818ml ethanol and 182ml dimethyl sulfoxide, and stirred to completely dissolve lipoic acid in the organic solvent to obtain 80g /L lipoic acid solution.

实施例6Example 6

本实施例与实施例4不同之处在于,S2,将8㎎粒径为10nm、比表面积为300m2/g纳米二氧化硅加入1ml去离子水中,搅拌使纳米二氧化硅分散在去离子水中,得到8㎎/ml纳米载体溶液。The difference between this example and Example 4 is that in S2, 8 mg of nano-silica with a particle size of 10 nm and a specific surface area of 300 m 2 /g is added to 1 ml of deionized water, and stirred to disperse the nano-silica in the deionized water. , to obtain 8㎎/ml nanocarrier solution.

实施例7Example 7

本实施例与实施例4不同之处在于,S2,将10㎎粒径为10nm、比表面积为300m2/g纳米二氧化硅加入1ml去离子水中,搅拌使纳米二氧化硅分散在去离子水中,得到10㎎/ml纳米载体溶液。The difference between this example and Example 4 is that in S2, 10 mg of nano-silica with a particle size of 10 nm and a specific surface area of 300 m 2 /g is added to 1 ml of deionized water, and stirred to disperse the nano-silica in the deionized water. , to obtain a 10㎎/ml nanocarrier solution.

实施例8Example 8

本实施例与实施例6不同之处在于,S2,将8㎎粒径为10nm、比表面积为300m2/g纳米二氧化硅加入1ml去离子水中,超声处理使纳米二氧化硅分散在去离子水中,得到8㎎/ml纳米载体溶液。The difference between this example and Example 6 is that, in S2, 8 mg of nano-silica with a particle size of 10 nm and a specific surface area of 300 m 2 /g is added to 1 ml of deionized water, and the nano-silica is dispersed in deionized water through ultrasonic treatment. In water, an 8㎎/ml nanocarrier solution was obtained.

实施例9Example 9

本实施例与实施例6不同之处在于,S2,将8㎎粒径为10nm、比表面积为300m2/g纳米氧化钛加入1ml去离子水中,搅拌使纳米氧化钛分散在去离子水中,得到8㎎/ml纳米载体溶液。The difference between this example and Example 6 is that in S2, 8 mg of nano-titanium oxide with a particle size of 10 nm and a specific surface area of 300 m 2 /g is added to 1 ml of deionized water, and stirred to disperse the nano-titanium oxide in the deionized water to obtain 8㎎/ml nanocarrier solution.

实施例10Example 10

本实施例与实施例6不同之处在于,S2,将8㎎粒径为10nm、比表面积为300m2/g纳米氧化铝加入1ml去离子水中,搅拌使纳米氧化铝分散在去离子水中,得到8㎎/ml纳米载体溶液。The difference between this example and Example 6 is that, in S2, 8 mg of nano-alumina with a particle size of 10 nm and a specific surface area of 300 m 2 /g is added to 1 ml of deionized water, and stirred to disperse the nano-alumina in the deionized water to obtain 8㎎/ml nanocarrier solution.

实施例11Example 11

本实施例与实施例6不同之处在于,S2,将8㎎粒径为10nm、比表面积为300m2/g纳米淀粉加入1ml去离子水中,搅拌使纳米淀粉分散在去离子水中,得到8㎎/ml纳米载体溶液。The difference between this example and Example 6 is that in S2, 8㎎ of nanostarch with a particle size of 10nm and a specific surface area of 300m 2 /g is added to 1 ml of deionized water, and stirred to disperse the nanostarch in the deionized water to obtain 8㎎ /ml nanocarrier solution.

实施例12Example 12

本实施例与实施例6不同之处在于,S2,将8㎎粒径为20nm、比表面积为200m2/g纳米二氧化硅加入1ml去离子水中,搅拌使纳米二氧化硅分散在去离子水中,得到8㎎/ml纳米载体溶液。The difference between this example and Example 6 is that in S2, 8 mg of nano-silica with a particle size of 20 nm and a specific surface area of 200 m 2 /g is added to 1 ml of deionized water, and stirred to disperse the nano-silica in the deionized water. , to obtain 8㎎/ml nanocarrier solution.

实施例13Example 13

本实施例与实施例6不同之处在于,S3,将75ml上述硫辛酸溶液以2ml/min的速度滴加到上述8ml纳米载体溶液中,搅拌24h形成硫辛酸纳米粒子。The difference between this embodiment and Example 6 is that in S3, 75 ml of the above-mentioned lipoic acid solution was dropped into the above-mentioned 8 ml nanocarrier solution at a speed of 2 ml/min, and stirred for 24 hours to form lipoic acid nanoparticles.

实施例14Example 14

本实施例与实施例6不同之处在于,S3,将80ml上述硫辛酸溶液以2ml/min的速度滴加到上述10ml纳米载体溶液中,搅拌24h形成硫辛酸纳米粒子。The difference between this embodiment and Example 6 is that in S3, 80 ml of the above-mentioned lipoic acid solution was dropped into the above-mentioned 10 ml nanocarrier solution at a speed of 2 ml/min, and stirred for 24 hours to form lipoic acid nanoparticles.

实施例15Example 15

本实施例与实施例13不同之处在于,S3,将75ml上述硫辛酸溶液以5ml/min的速度滴加到上述8ml纳米载体溶液中,搅拌18h形成硫辛酸纳米粒子。The difference between this embodiment and Example 13 is that in S3, 75 ml of the above-mentioned lipoic acid solution was dropped into the above-mentioned 8 ml nanocarrier solution at a speed of 5 ml/min, and stirred for 18 hours to form lipoic acid nanoparticles.

实施例16Example 16

本实施例与实施例13不同之处在于,S4,将上述硫辛酸纳米粒子在温度为100℃的温度下,热处理10min,将硫辛酸分子固化在纳米粒子表面,形成固化硫辛酸纳米粒子。The difference between this embodiment and Example 13 is that in S4, the above-mentioned lipoic acid nanoparticles are heat-treated at a temperature of 100°C for 10 minutes to solidify lipoic acid molecules on the surface of the nanoparticles to form solidified lipoic acid nanoparticles.

实施例17Example 17

本实施例与实施例13不同之处在于,S4,将10g戊二醛添加到上述100g硫辛酸纳米粒子中进行改性处理,得到固化硫辛酸纳米粒子。The difference between this embodiment and Example 13 is that in S4, 10 g of glutaraldehyde is added to the above 100 g of lipoic acid nanoparticles for modification treatment to obtain solidified lipoic acid nanoparticles.

实施例18Example 18

本实施例与实施例17不同之处在于,S4,将10g N-羟基琥珀酰亚胺(羧酸交联剂)添加到上述100g硫辛酸纳米粒子中进行改性处理,得到固化硫辛酸纳米粒子。The difference between this embodiment and Example 17 is that in S4, 10g N-hydroxysuccinimide (carboxylic acid cross-linking agent) is added to the above 100g lipoic acid nanoparticles for modification treatment to obtain solidified lipoic acid nanoparticles. .

实施例19Example 19

本实施例与实施例17不同之处在于,S4,将10g 1-乙基-3-(3-二甲氨基丙基)碳二亚胺(碳酸二酐)添加到上述100g硫辛酸纳米粒子中进行改性处理,得到固化硫辛酸纳米粒子。The difference between this embodiment and Example 17 is that in S4, 10g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (carbonic dianhydride) was added to the above 100g of lipoic acid nanoparticles. Modification treatment is performed to obtain solidified lipoic acid nanoparticles.

实施例20Example 20

本实施例与实施例17不同之处在于,S5,将固化后的硫辛酸纳米粒子在15000rpm的转速下将硫辛酸纳米粒子与溶剂分离;再对分离得到的硫辛酸纳米用丙酮清洗3次后再用去离子水反复清洗3次即可。The difference between this embodiment and Example 17 is that in S5, the solidified lipoic acid nanoparticles are separated from the solvent at a rotation speed of 15,000 rpm; and then the separated lipoic acid nanoparticles are washed three times with acetone. Then wash it 3 times with deionized water.

实施例21Example 21

本实施例与实施例17不同之处在于,S5,将固化后的硫辛酸纳米粒子在过滤并在120℃下干燥将硫辛酸纳米粒子与溶剂分离;再对分离得到的硫辛酸纳米用丙酮清洗3次后再用去离子水反复清洗3次即可。The difference between this embodiment and Example 17 is that in S5, the solidified lipoic acid nanoparticles are filtered and dried at 120°C to separate the lipoic acid nanoparticles from the solvent; and then the separated lipoic acid nanoparticles are washed with acetone. After 3 times, wash it again with deionized water 3 times.

对比例Comparative ratio

对比例1Comparative example 1

本对比例与实施例1不同之处在于,硫辛酸CAS:62-46-4。The difference between this comparative example and Example 1 is that lipoic acid CAS: 62-46-4.

对比例2Comparative example 2

本对比例与实施例13不同之处在于,S3,将70ml上述硫辛酸溶液以1ml/min的速度滴加到上述6ml纳米载体溶液中,搅拌30h形成硫辛酸纳米粒子。The difference between this comparative example and Example 13 is that in S3, 70 ml of the above-mentioned lipoic acid solution was dropped into the above-mentioned 6 ml nanocarrier solution at a speed of 1 ml/min, and stirred for 30 hours to form lipoic acid nanoparticles.

对比例3Comparative example 3

本对比例与对比例13不同之处在于,S3,将70ml上述硫辛酸溶液以6ml/min的速度滴加到上述6ml纳米载体溶液中,搅拌17h形成硫辛酸纳米粒。The difference between this comparative example and Comparative Example 13 is that in S3, 70 ml of the above-mentioned lipoic acid solution was dropped into the above-mentioned 6 ml nanocarrier solution at a speed of 6 ml/min, and stirred for 17 hours to form lipoic acid nanoparticles.

对比例4Comparative example 4

本对比例与对比例13不同之处在于,S4,将上述硫辛酸纳米粒子在温度为50℃的温度下,热处理40min,将硫辛酸分子固化在纳米粒子表面,形成固化硫辛酸纳米粒子。The difference between this comparative example and Comparative Example 13 is that in S4, the above-mentioned lipoic acid nanoparticles are heat-treated at a temperature of 50°C for 40 minutes to solidify lipoic acid molecules on the surface of the nanoparticles to form solidified lipoic acid nanoparticles.

对比例5Comparative example 5

本对比例与对比例13不同之处在于,S4,将上述硫辛酸纳米粒子在温度为110℃的温度下,热处理5min,将硫辛酸分子固化在纳米粒子表面,形成固化硫辛酸纳米粒子。The difference between this comparative example and Comparative Example 13 is that in S4, the above-mentioned lipoic acid nanoparticles are heat-treated at a temperature of 110°C for 5 minutes to solidify lipoic acid molecules on the surface of the nanoparticles to form solidified lipoic acid nanoparticles.

性能检测Performance testing

1、稳定性1. Stability

按照《中国药典》2022年版第四部-稳定性试验+方法学验证指导原则来进行稳定性测试。Stability testing was conducted in accordance with the 2022 Edition of the Chinese Pharmacopoeia, Part 4 - Stability Test + Methodological Verification Guiding Principles.

实施例1-21和对比例1-5制备的硫辛酸粒子置于相宜的开口容器中,摊成厚的薄层,疏松原料药物摊成10mm厚的薄层,进展以下试验,具体为:将开口容器放置在装有日光灯(40-50℃)的光照箱中,于照度为4500±500lx的条件下放置10天,于第10天取样,观察硫辛酸是否会散发出刺鼻气味,结果记录在表1中。The lipoic acid particles prepared in Examples 1-21 and Comparative Examples 1-5 are placed in a suitable open container and spread into a thick thin layer. The loose raw materials are spread into a 10mm thick thin layer. The following tests are carried out, specifically: Place the open container in a light box equipped with a fluorescent lamp (40-50°C) and place it for 10 days at an illumination of 4500±500lx. Take a sample on the 10th day to observe whether lipoic acid emits a pungent smell and record the results. in Table 1.

2、包覆率2. Covering rate

计算实施例1-21和对比例2-5所制备的硫辛酸纳米粒子的包覆率,包覆率=(硫辛酸纳米粒子质量-使用的纳米粒子质量)/使用的硫辛酸粉末×100%,结果记录在表1中。Calculate the coating rate of lipoic acid nanoparticles prepared in Examples 1-21 and Comparative Examples 2-5. Covering rate = (mass of lipoic acid nanoparticles - mass of used nanoparticles)/used lipoic acid powder × 100% , the results are recorded in Table 1.

表1实施例1-21及对比例1-5性能检测数据表Table 1 Performance testing data table of Examples 1-21 and Comparative Examples 1-5

参照表1,结合实施例1和对比例1,可以看出,本申请制备的硫辛酸纳米粒子的制备方法得到硫辛酸相比普通的硫辛酸具有很好的稳定性。本申请制备方法采用纳米粒子作为硫辛酸的载体,将硫辛酸吸附在纳米粒子表面,使得硫辛酸分子受到纳米粒子的保护,有效地降低了光照对其的影响,提高了硫辛酸的稳定性。Referring to Table 1, combined with Example 1 and Comparative Example 1, it can be seen that the lipoic acid nanoparticles prepared by the preparation method of the present application have better stability than ordinary lipoic acid. The preparation method of this application uses nanoparticles as the carrier of lipoic acid, and adsorbs lipoic acid on the surface of the nanoparticles, so that the lipoic acid molecules are protected by the nanoparticles, effectively reducing the impact of light on them, and improving the stability of lipoic acid.

参照表1,结合实施例13、15和对比例2-3,可以看出,在制备硫辛酸纳米粒子时,优化硫辛酸溶液滴加到纳米载体溶液中的速度和搅拌时间,可提高硫辛酸的包覆率和所制硫辛酸纳米粒子的稳定性;滴加速度和搅拌时间的组合可以影响硫辛酸与纳米粒子之间的接触时间和频率。适当的条件有助于在合适的时间内使硫辛酸分子与纳米粒子表面发生相互作用,从而实现较高的包覆率。适当的搅拌能够将硫辛酸分子在纳米粒子悬浮液中均匀分散,从而提高包覆的均匀性;过快或过慢的搅拌可能会导致硫辛酸在溶液中分散不均匀。同时搅拌可以影响硫辛酸分子在纳米粒子表面的吸附和排斥行为;适当的搅拌有助于防止硫辛酸分子在纳米粒子表面过度聚集,从而实现更好的包覆效果,进而提高硫辛酸纳米粒子的稳定性。Referring to Table 1, combined with Examples 13, 15 and Comparative Examples 2-3, it can be seen that when preparing lipoic acid nanoparticles, optimizing the speed and stirring time of lipoic acid solution dripping into the nanocarrier solution can improve lipoic acid nanoparticles. The coating rate and the stability of the prepared lipoic acid nanoparticles; the combination of dropping speed and stirring time can affect the contact time and frequency between lipoic acid and nanoparticles. Appropriate conditions help lipoic acid molecules interact with the nanoparticle surface within the right time, thereby achieving a high coating rate. Proper stirring can evenly disperse lipoic acid molecules in the nanoparticle suspension, thereby improving the uniformity of coating; stirring too fast or too slow may cause lipoic acid to be unevenly dispersed in the solution. At the same time, stirring can affect the adsorption and repulsion behavior of lipoic acid molecules on the surface of nanoparticles; appropriate stirring can help prevent excessive aggregation of lipoic acid molecules on the surface of nanoparticles, thereby achieving a better coating effect, thereby improving the performance of lipoic acid nanoparticles. stability.

参照表2,结合实施例13、16和对比例4-5,可以看出,本申请通过优化热处理时的温度和时间,可提高所制硫辛酸纳米粒子的包覆性和稳定性。在固化过程中,适当的温度可以影响反应速率;较高的温度通常会促进反应速率,有助于在相对短的时间内形成更稳定的包覆结构。温度可以影响包覆物分子的构象,从而影响其在纳米载体表面的吸附和包覆率;不同温度下,包覆物可能有不同的构象,这可能会影响其在载体表面的分布和相互作用。适当的固化温度可以促进包覆物与纳米载体之间的交联、键合或其他相互作用,这些化学反应有助于提高包覆物在载体表面的稳定性。Referring to Table 2, combined with Examples 13, 16 and Comparative Examples 4-5, it can be seen that by optimizing the temperature and time during heat treatment, the coating and stability of lipoic acid nanoparticles can be improved. During the curing process, appropriate temperature can affect the reaction rate; higher temperatures generally promote the reaction rate and help form a more stable coating structure in a relatively short time. Temperature can affect the conformation of coating molecules, thereby affecting its adsorption and coating rate on the surface of the nanocarrier; at different temperatures, the coating may have different conformations, which may affect its distribution and interaction on the surface of the carrier . Appropriate curing temperature can promote cross-linking, bonding or other interactions between the coating and the nanocarrier. These chemical reactions help to improve the stability of the coating on the carrier surface.

固化时间决定了包覆物与纳米载体之间的相互作用程度;适当的固化时间可以确保足够的反应发生,从而形成稳定的包覆层。适当的固化时间可以允许包覆物分子之间的交联或交联到载体表面,从而形成更为紧密的结构,提高包覆物的稳定性。不同的固化时间可以实现不同程度的固化。较短的固化时间可能导致未完全反应的包覆物分子仍存在,而较长的固化时间可能导致过度固化,影响包覆物的分散性和稳定性。The curing time determines the degree of interaction between the coating and the nanocarrier; an appropriate curing time ensures that sufficient reaction occurs to form a stable coating. Appropriate curing time can allow cross-linking between coating molecules or to the surface of the carrier, thereby forming a tighter structure and improving the stability of the coating. Different curing times can achieve different degrees of curing. A shorter curing time may cause incompletely reacted coating molecules to still exist, while a longer curing time may result in over-curing, affecting the dispersion and stability of the coating.

本具体实施例仅仅是对本申请的解释,其并不是对本申请的限制,本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改,但只要在本申请的权利要求范围内都受到专利法的保护。This specific embodiment is only an explanation of the present application, and it is not a limitation of the present application. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contribution as needed, but as long as the rights of this application are All requirements are protected by patent law.

Claims (10)

1. A method for preparing lipoic acid nano particles, which is characterized by comprising the following steps: the method comprises the following steps:
preparation of lipoic acid solution: adding lipoic acid powder into an organic solvent, stirring and dissolving to form 70-80g/L lipoic acid solution;
preparing a nano carrier solution: adding the nano particles into a solvent to enable the nano particles to be dispersed in the solvent, so as to obtain a nano carrier solution with the concentration of 6-10 mg/ml;
preparation of lipoic acid nanoparticles: dripping lipoic acid solution into nano carrier solution and stirring and mixing to form lipoic acid nano particles;
curing lipoic acid nanoparticles: curing the lipoic acid nano particles by adopting a heat treatment or chemical crosslinking method;
purification of lipoic acid nano particles: and separating the solidified lipoic acid nano particles by a centrifugal or filtering method to obtain lipoic acid nano particles and a solvent, and washing the separated lipoic acid nano particles to remove residual organic solvent and impurities.
2. The method for preparing lipoic acid nanoparticles according to claim 1, wherein the method comprises the steps of: in the preparation step of the lipoic acid solution, the organic solvent is prepared from the following components in percentage by mass (5-15): 1 and dimethyl sulfoxide.
3. The method for preparing lipoic acid nanoparticles according to claim 1, wherein the method comprises the steps of: in the preparation step of the nano-carrier solution, the nano-particles are one of nano-silicon dioxide, nano-titanium oxide, nano-starch and nano-salts.
4. A method for preparing lipoic acid nanoparticles according to claim 3, characterized in that: the particle diameter of the nano particles is 10-20nm, and the specific surface area is 200-300m 2 /g。
5. The method for preparing lipoic acid nanoparticles according to claim 1, wherein the method comprises the steps of: in the preparation step of the lipoic acid nanoparticle, the volume ratio of the lipoic acid solution to the nano-carrier solution is (70-80): (6-10).
6. The method for preparing lipoic acid nanoparticles according to claim 5, wherein the steps of: in the preparation step of the lipoic acid nanoparticle, the lipoic acid solution is dripped into the nano-carrier solution at the speed of 2-5ml/min and stirred for 18-24h.
7. The method for preparing lipoic acid nanoparticles according to claim 1, wherein the method comprises the steps of: in the preparation step of the solidified lipoic acid nano particles, the temperature during the heat treatment is 60-100 ℃ and the time is 10-30min.
8. The method for preparing lipoic acid nanoparticles according to claim 1, wherein the method comprises the steps of: in the preparation step of the solidified lipoic acid nano particles, the chemical crosslinking method is to modify the lipoic acid nano particles by using a chemical crosslinking agent, wherein the chemical crosslinking agent comprises one of glutaraldehyde, a carboxylic acid crosslinking agent and carbonic acid dianhydride.
9. The method for preparing lipoic acid nanoparticles according to claim 1, wherein the method comprises the steps of: the lipoic acid nanoparticle purification preparation steps are as follows: centrifuging the solidified lipoic acid nano particles at the rotating speed of 10000-15000rpm to obtain lipoic acid nano particles and solvent, washing the separated lipoic acid nano particles with acetone for 1-3 times, and washing with deionized water for 3 times to remove residual organic solvent and impurities.
10. A lipoic acid nanoparticle characterized by: the lipoic acid nanoparticle according to any one of claims 1 to 9.
CN202311052636.6A 2023-08-21 2023-08-21 Lipoic acid nanoparticle and preparation method thereof Pending CN117186058A (en)

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CN101945654A (en) * 2007-12-14 2011-01-12 江崎格力高株式会社 Alpha-lipoic acid nano-particle and preparation method thereof
CN103417514A (en) * 2012-05-24 2013-12-04 石药集团中奇制药技术(石家庄)有限公司 Microencapsulated butylphthalide medicine composition, preparation method and applications
CN109700779A (en) * 2018-09-14 2019-05-03 苏州科技大学 The degradable polymer microspheres of compound sulfhydryl modified chitosan
CN109908034A (en) * 2019-04-23 2019-06-21 吉林大学珠海学院 A kind of slow-release tea tree ethereal oil microcapsules and preparation method thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101945654A (en) * 2007-12-14 2011-01-12 江崎格力高株式会社 Alpha-lipoic acid nano-particle and preparation method thereof
CN101385713A (en) * 2008-10-24 2009-03-18 苏州纳康生物科技有限公司 Preparation method of lipoic acid lipid nano-particles
KR20090016012A (en) * 2009-01-22 2009-02-12 (주)바이오제닉스 Coated Alpha Lipoic Acid Particles, Compositions Comprising The Same, And Methods For Making The Same
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