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CN117562869B - Magnesium hydroxide nanoparticles for treating joint pain, preparation method and application thereof - Google Patents

Magnesium hydroxide nanoparticles for treating joint pain, preparation method and application thereof Download PDF

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CN117562869B
CN117562869B CN202310496323.3A CN202310496323A CN117562869B CN 117562869 B CN117562869 B CN 117562869B CN 202310496323 A CN202310496323 A CN 202310496323A CN 117562869 B CN117562869 B CN 117562869B
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CN117562869A (en
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雷光华
曾超
邓彩凤
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Xiangya Hospital of Central South University
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    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

本发明属于医药领域,具体涉及一种治疗关节疼痛的氢氧化镁纳米粒及其制备方法。所述制备方法为:将可溶性镁盐溶于纯化水中,得到镁盐溶液;将可溶性金属氢氧化物溶于纯化水中,得到金属氢氧化物溶液;将磷脂溶于有机溶剂中,得到磷脂溶液;对磷脂溶液进行旋蒸除去有机试剂,待形成薄膜后加入镁盐溶液进行水化,得到水化液;向水化液中加入金属氢氧化物溶液进行纳米化处理,完成后即可。所述制备方法简单易控,仅通过镁盐、氢氧化物和磷脂即可制备得到氢氧化镁纳米粒,且经过大鼠试验验证得,通过药物制剂技术手段将镁盐制备成纳米级别的氢氧化镁后,其具有关节镇痛的作用,而且镇痛作用时间显著延长,将极大降低给药频率,进而将减少患者痛苦。

The present invention belongs to the field of medicine, and specifically relates to a magnesium hydroxide nanoparticle for treating joint pain and a preparation method thereof. The preparation method is as follows: dissolving a soluble magnesium salt in purified water to obtain a magnesium salt solution; dissolving a soluble metal hydroxide in purified water to obtain a metal hydroxide solution; dissolving a phospholipid in an organic solvent to obtain a phospholipid solution; subjecting the phospholipid solution to rotary evaporation to remove organic reagents, adding a magnesium salt solution to hydration after a thin film is formed to obtain a hydration liquid; adding a metal hydroxide solution to the hydration liquid for nano-treatment, and the preparation method is simple and easy to control, and magnesium hydroxide nanoparticles can be prepared only by magnesium salt, hydroxide and phospholipid, and rat experiments have verified that after magnesium salt is prepared into nano-scale magnesium hydroxide by means of pharmaceutical preparation technology, it has the effect of joint analgesia, and the analgesic effect time is significantly prolonged, which will greatly reduce the frequency of administration, and thus reduce the pain of patients.

Description

一种治疗关节疼痛的氢氧化镁纳米粒、其制备方法及应用Magnesium hydroxide nanoparticles for treating joint pain, preparation method and application thereof

技术领域Technical Field

本发明属于医药领域,具体涉及一种治疗关节疼痛的氢氧化镁纳米粒、其制备方法及应用。The invention belongs to the field of medicine, and specifically relates to magnesium hydroxide nanoparticles for treating joint pain, a preparation method and application thereof.

背景技术Background technique

骨关节炎(Osteoarthritis,OA)是一种由多因素引起的关节软骨纤维化、皲裂、溃疡和脱失而导致的以关节疼痛为主要症状的退行性疾病,常累及膝关节、髋关节、脊柱和手等部位,其病理特点主要为关节软骨变性破坏、软骨下骨硬化或囊性变、关节边缘骨质增生以及滑膜炎等。OA严重影响患者关节功能和生活质量,且研究发现,OA尤其是症状性膝OA可显著升高患者全因死亡率。但遗憾的是,目前国内外尚无安全有效可延缓OA病情进展的治疗方法。Osteoarthritis (OA) is a degenerative disease with joint pain as the main symptom caused by fibrosis, cracking, ulceration and loss of articular cartilage caused by multiple factors. It often affects the knee joint, hip joint, spine and hands. Its pathological characteristics are mainly degeneration and destruction of articular cartilage, subchondral bone sclerosis or cystic changes, bone hyperplasia at the joint edge and synovitis. OA seriously affects the joint function and quality of life of patients. Studies have found that OA, especially symptomatic knee OA, can significantly increase the all-cause mortality of patients. Unfortunately, there is currently no safe and effective treatment that can delay the progression of OA at home and abroad.

关节疼痛是OA最为常见的临床表现,镇痛是OA患者就诊的最主要诉求。且随着病情进展,OA患者常常出现持续性疼痛,因此,实现长效安全镇痛对OA患者具有重要意义。Joint pain is the most common clinical manifestation of OA, and analgesia is the main demand of OA patients when they seek medical treatment. As the disease progresses, OA patients often experience persistent pain. Therefore, achieving long-term and safe analgesia is of great significance to OA patients.

目前,针对OA患者的治疗方法以关节镇痛为主,虽种类繁多,但却存在诸多问题。例如,对乙酰氨基酚过去一直是治疗OA疼痛的一线药物,但近年的高质量研究证据显示,其相比安慰剂不但对缓解OA疼痛无效反而显著升高胃肠道副作用风险;口服非甾体抗炎药缓解OA疼痛疗效明确,但长期服用所引起的心血管和胃肠道等副作用令人担忧;口服曲马多被2013版美国骨科医师协会和2012版美国风湿病学会OA指南均推荐为“一线药物”,但近年研究发现口服曲马多相比非甾体抗炎药可显著升高全因死亡率、心肌梗死发生率和髋部骨折发生率(已写入2019版美国风湿病学会OA指南并不再推荐曲马多为“一线药物”);关节腔注射激素使用广泛且短期止痛效果显著,但关节腔注射激素存在镇痛效果维持时间较短、效果不够显著以及存在安全性隐患等亟待解决的重要问题。因此,亟待进一步探索疗效显著且安全性高的可用于OA长效镇痛的治疗药物。At present, the treatment methods for OA patients are mainly joint analgesia. Although there are many types, there are many problems. For example, acetaminophen has always been the first-line drug for the treatment of OA pain, but high-quality research evidence in recent years shows that it is not only ineffective in relieving OA pain compared with placebo, but also significantly increases the risk of gastrointestinal side effects; oral non-steroidal anti-inflammatory drugs have a clear effect on relieving OA pain, but the cardiovascular and gastrointestinal side effects caused by long-term use are worrying; oral tramadol is recommended as a "first-line drug" by the 2013 edition of the American Orthopaedic Association and the 2012 edition of the American College of Rheumatology OA Guidelines, but recent studies have found that oral tramadol can significantly increase all-cause mortality, myocardial infarction, and hip fracture incidence compared with non-steroidal anti-inflammatory drugs (it has been written into the 2019 edition of the American College of Rheumatology OA Guidelines and no longer recommends tramadol as a "first-line drug"); intra-articular injection of hormones is widely used and has a significant short-term analgesic effect, but intra-articular injection of hormones has important problems that need to be solved, such as a short-term analgesic effect, insufficient effect, and safety risks. Therefore, there is an urgent need to further explore therapeutic drugs with significant efficacy and high safety for long-term analgesia of OA.

故基于此,提出本发明技术方案。Therefore, based on this, the technical solution of the present invention is proposed.

发明内容Summary of the invention

为了解决现有技术存在的问题,本发明提供了一种治疗关节疼痛的氢氧化镁纳米粒及其制备方法。所述制备方法简单易控,仅通过镁盐、氢氧化物和磷脂即可制备得到氢氧化镁纳米粒,且经过大鼠试验验证得,通过药物制剂技术手段将镁盐制备成纳米级别的氢氧化镁后,其具有关节镇痛的作用,而且镇痛作用时间显著延长,将极大降低给药频率,进而将减少患者痛苦。In order to solve the problems existing in the prior art, the present invention provides a magnesium hydroxide nanoparticle for treating joint pain and a preparation method thereof. The preparation method is simple and easy to control, and magnesium hydroxide nanoparticles can be prepared only by magnesium salt, hydroxide and phospholipid, and rat experiments have verified that after magnesium salt is prepared into nano-scale magnesium hydroxide by means of pharmaceutical preparation technology, it has the effect of joint analgesia, and the analgesic effect time is significantly prolonged, which will greatly reduce the frequency of administration, thereby reducing the pain of patients.

本发明的方案是,提供一种治疗关节疼痛的氢氧化镁纳米粒,所述氢氧化镁纳米粒包含氢氧化镁和磷脂。The present invention provides magnesium hydroxide nanoparticles for treating joint pain, wherein the magnesium hydroxide nanoparticles contain magnesium hydroxide and phospholipids.

优选地,所述氢氧化镁纳米粒包含“核-壳”结构,其中:Preferably, the magnesium hydroxide nanoparticles comprise a "core-shell" structure, wherein:

核层为氢氧化镁,壳层为磷脂。The core layer is magnesium hydroxide and the shell layer is phospholipid.

优选地,所述磷脂为天然大豆磷脂、天然蛋黄磷脂或合成磷脂(如氢化磷脂)中的一种。Preferably, the phospholipid is one of natural soybean phospholipid, natural egg yolk phospholipid or synthetic phospholipid (such as hydrogenated phospholipid).

优选地,所述磷脂为磷脂S45、S75、S100、SPC、E80、EPCS、EPG、SPC-3、PC98-T、PL-100M、HSPC、PGE、PGSH、DS-PL95E、DSPE、DPPA、DSPA或DMPC中的一种。Preferably, the phospholipid is one of phospholipids S45, S75, S100, SPC, E80, EPCS, EPG, SPC-3, PC98-T, PL-100M, HSPC, PGE, PGSH, DS-PL95E, DSPE, DPPA, DSPA or DMPC.

优选地,所述氢氧化镁纳米粒的平均粒径为50~550nm。Preferably, the average particle size of the magnesium hydroxide nanoparticles is 50 to 550 nm.

基于相同的技术构思,本发明再提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:Based on the same technical concept, the present invention further provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将可溶性镁盐溶于纯化水中,得到镁盐溶液;(1) dissolving a soluble magnesium salt in purified water to obtain a magnesium salt solution;

(2)将可溶性金属氢氧化物溶于纯化水中,得到金属氢氧化物溶液;(2) dissolving a soluble metal hydroxide in purified water to obtain a metal hydroxide solution;

(3)将磷脂溶于有机溶剂中,得到磷脂溶液;(3) dissolving the phospholipid in an organic solvent to obtain a phospholipid solution;

(4)对所述磷脂溶液进行旋蒸除去有机试剂,待形成薄膜后,加入所述镁盐溶液进行水化,得到水化液;(4) performing rotary evaporation on the phospholipid solution to remove the organic reagent, and after a thin film is formed, adding the magnesium salt solution to hydrate the solution to obtain a hydrated solution;

(5)向所述水化液中加入所述金属氢氧化物溶液进行纳米化处理,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒。(5) Adding the metal hydroxide solution to the hydration liquid for nano-processing, and obtaining the magnesium hydroxide nanoparticles for treating joint pain.

优选地,步骤(1)中,所述可溶性镁盐为无水硫酸镁、一水硫酸镁、七水硫酸镁、氯化镁、六水氯化镁中的一种或多种的组合。Preferably, in step (1), the soluble magnesium salt is a combination of one or more of anhydrous magnesium sulfate, magnesium sulfate monohydrate, magnesium sulfate heptahydrate, magnesium chloride, and magnesium chloride hexahydrate.

优选地,步骤(2)中,所述金属氢氧化物为氢氧化钠或氢氧化钾中的一种或两种的组合。Preferably, in step (2), the metal hydroxide is sodium hydroxide or potassium hydroxide, or a combination of both.

优选地,步骤(3)中,所述有机溶剂具有挥发性且可溶解磷脂,其为乙醇、二氯甲烷或丙酮中的一种或多种的组合。Preferably, in step (3), the organic solvent is volatile and can dissolve phospholipids, and is a combination of one or more of ethanol, dichloromethane or acetone.

优选地,步骤(5)中,所述纳米化处理的方式为探头超声处理、高压均质处理或球磨仪处理中的一种。Preferably, in step (5), the nano-treatment is carried out by one of probe ultrasonic treatment, high-pressure homogenization treatment or ball mill treatment.

基于相同的技术构思,本发明再提供一种所述治疗关节疼痛的氢氧化镁纳米粒的应用,所述氢氧化镁纳米粒用于制备治疗骨关节炎的关节疼痛的药物。Based on the same technical concept, the present invention further provides an application of the magnesium hydroxide nanoparticles for treating joint pain, wherein the magnesium hydroxide nanoparticles are used to prepare a drug for treating joint pain caused by osteoarthritis.

本发明的有益效果为:The beneficial effects of the present invention are:

本发明所述的制备方法简单易控,仅通过镁盐、氢氧化物和磷脂即可制备得到氢氧化镁纳米粒,且经过大鼠试验验证得,通过药物制剂技术手段将镁盐制备成纳米级别的氢氧化镁后,其具有关节镇痛的作用,而且镇痛作用时间显著延长,将极大降低给药频率,进而将减少患者痛苦。The preparation method of the present invention is simple and easy to control. Magnesium hydroxide nanoparticles can be prepared only by magnesium salt, hydroxide and phospholipids. It has been verified through rat experiments that after magnesium salt is prepared into nano-scale magnesium hydroxide by means of pharmaceutical preparation technology, it has the effect of joint analgesia, and the analgesic effect time is significantly prolonged, which will greatly reduce the frequency of drug administration and thus reduce the pain of patients.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

图1是试验例1中,氢氧化镁纳米粒的TEM图片。FIG. 1 is a TEM image of magnesium hydroxide nanoparticles in Experimental Example 1.

图2是试验例2中,各组大鼠的机械缩足阈值结果数据图。FIG. 2 is a data diagram showing the mechanical withdrawal threshold results of rats in each group in Experimental Example 2.

图3是试验例2中,各组大鼠的双足负重差值结果数据图。FIG. 3 is a data diagram showing the difference in weight bearing between the two feet of rats in each group in Experimental Example 2.

具体实施方式Detailed ways

为使本发明的目的、技术方案和优点更加清楚,下面将对本发明的技术方案进行详细的描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式,都属于本发明所保护的范围。To make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

实施例1Example 1

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将393.6mg七水硫酸镁与4mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 393.6 mg of magnesium sulfate heptahydrate in 4 mL of purified water to obtain a magnesium sulfate solution;

(2)将8mg氢氧化钠与1mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 8 mg of sodium hydroxide and 1 mL of purified water to obtain a sodium hydroxide solution;

(3)将125mg蛋黄磷脂E80溶于20mL二氯甲烷,得到磷脂溶液;(3) Dissolve 125 mg of egg yolk phospholipid E80 in 20 mL of dichloromethane to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后以220W的功率探头超声10min,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为338.5nm。(5) The sodium hydroxide solution is quickly added to the hydration solution, and then ultrasonicated for 10 minutes with a 220 W power probe. After completion, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 338.5 nm as measured by a laser particle size analyzer.

实施例2Example 2

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将393.6mg七水硫酸镁与4mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 393.6 mg of magnesium sulfate heptahydrate in 4 mL of purified water to obtain a magnesium sulfate solution;

(2)将12mg氢氧化钠与1mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 12 mg of sodium hydroxide and 1 mL of purified water to obtain a sodium hydroxide solution;

(3)将125mg蛋黄磷脂E80溶于30mL二氯甲烷,得到磷脂溶液;(3) Dissolve 125 mg of egg yolk phospholipid E80 in 30 mL of dichloromethane to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated solution;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后以220W的功率探头超声10min,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为445.0nm。(5) The sodium hydroxide solution is quickly added to the hydration solution, and then ultrasonicated for 10 minutes with a 220 W power probe. After completion, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 445.0 nm as measured by a laser particle size analyzer.

实施例3Example 3

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将393.6mg七水硫酸镁与4mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 393.6 mg of magnesium sulfate heptahydrate in 4 mL of purified water to obtain a magnesium sulfate solution;

(2)将16mg氢氧化钠与1mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 16 mg of sodium hydroxide and 1 mL of purified water to obtain a sodium hydroxide solution;

(3)将125mg蛋黄磷脂E80溶于20mL二氯甲烷,得到磷脂溶液;(3) Dissolve 125 mg of egg yolk phospholipid E80 in 20 mL of dichloromethane to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后以220W的功率探头超声10min,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为539.5nm。(5) The sodium hydroxide solution is quickly added to the hydration solution, and then ultrasonicated for 10 minutes with a 220 W power probe. After completion, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 539.5 nm as measured by a laser particle size analyzer.

实施例4Example 4

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将393.6mg七水硫酸镁与4mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 393.6 mg of magnesium sulfate heptahydrate in 4 mL of purified water to obtain a magnesium sulfate solution;

(2)将32mg氢氧化钠与1mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 32 mg of sodium hydroxide and 1 mL of purified water to obtain a sodium hydroxide solution;

(3)将125mg蛋黄磷脂E80溶于20mL二氯甲烷,得到磷脂溶液;(3) Dissolve 125 mg of egg yolk phospholipid E80 in 20 mL of dichloromethane to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后通过高压均质机以6000psi的条件处理5min,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为398.5nm。(5) The sodium hydroxide solution is quickly added to the hydration liquid, and then treated by a high-pressure homogenizer at 6000 psi for 5 minutes. After completion, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 398.5 nm as measured by a laser particle size analyzer.

实施例5Example 5

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将192mg无水硫酸镁与4mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 192 mg of anhydrous magnesium sulfate in 4 mL of purified water to obtain a magnesium sulfate solution;

(2)将8mg氢氧化钠与1mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 8 mg of sodium hydroxide and 1 mL of purified water to obtain a sodium hydroxide solution;

(3)将125mg蛋黄磷脂E80溶于20mL二氯甲烷,得到磷脂溶液;(3) Dissolve 125 mg of egg yolk phospholipid E80 in 20 mL of dichloromethane to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后以220W的功率探头超声10min,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为313.6nm。(5) The sodium hydroxide solution is quickly added to the hydration solution, and then ultrasonicated for 10 minutes with a 220 W power probe. After completion, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 313.6 nm as measured by a laser particle size analyzer.

实施例6Example 6

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将1.2g七水硫酸镁与12mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 1.2 g of magnesium sulfate heptahydrate in 12 mL of purified water to obtain a magnesium sulfate solution;

(2)将48mg氢氧化钠与3mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 48 mg of sodium hydroxide and 3 mL of purified water to obtain a sodium hydroxide solution;

(3)将350mg大豆磷脂S100溶于60mL二氯甲烷,得到磷脂溶液;(3) Dissolve 350 mg of soybean lecithin S100 in 60 mL of dichloromethane to obtain a lecithin solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后通过高压均质机以6000psi的条件处理5min,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为363.9nm。(5) The sodium hydroxide solution is quickly added to the hydration liquid, and then treated by a high-pressure homogenizer at 6000 psi for 5 minutes. After completion, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 363.9 nm as measured by a laser particle size analyzer.

实施例7Example 7

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将393.6mg七水硫酸镁与4mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 393.6 mg of magnesium sulfate heptahydrate in 4 mL of purified water to obtain a magnesium sulfate solution;

(2)将8mg氢氧化钠与1mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 8 mg of sodium hydroxide and 1 mL of purified water to obtain a sodium hydroxide solution;

(3)将60mg蛋黄磷脂E80溶于20mL二氯甲烷,得到磷脂溶液;(3) Dissolve 60 mg of egg yolk phospholipid E80 in 20 mL of dichloromethane to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated solution;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后以220W的功率探头超声10min,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为411.7nm。(5) The sodium hydroxide solution is quickly added to the hydration solution, and then ultrasonicated for 10 minutes with a 220 W power probe. After completion, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 411.7 nm as measured by a laser particle size analyzer.

实施例8Example 8

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将440mg一水硫酸镁与8mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 440 mg of magnesium sulfate monohydrate in 8 mL of purified water to obtain a magnesium sulfate solution;

(2)将16mg氢氧化钠与2mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 16 mg of sodium hydroxide and 2 mL of purified water to obtain a sodium hydroxide solution;

(3)将200mg蛋黄卵磷脂PC98-T溶于50mL无水乙醇,得到磷脂溶液;(3) dissolving 200 mg of egg yolk lecithin PC98-T in 50 mL of anhydrous ethanol to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后通过球磨仪(德国Retsch公司Emax型球磨仪)以800rpm处理2h,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为206.5nm。(5) The sodium hydroxide solution is quickly added to the hydration liquid, and then the hydration liquid is processed by a ball mill (Emax ball mill produced by Retsch, Germany) at 800 rpm for 2 h. After the process is completed, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 206.5 nm as measured by a laser particle size analyzer.

实施例9Example 9

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将200mg无水氯化镁(阿拉丁,纯度99%)与8mL纯化水中混合溶解,得氯化镁溶液;(1) Mix and dissolve 200 mg of anhydrous magnesium chloride (Aladdin, purity 99%) with 8 mL of purified water to obtain a magnesium chloride solution;

(2)将16mg氢氧化钠与2mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 16 mg of sodium hydroxide and 2 mL of purified water to obtain a sodium hydroxide solution;

(3)将200mg蛋黄卵磷脂PC98-T溶于50mL无水乙醇,得到磷脂溶液;(3) dissolving 200 mg of egg yolk lecithin PC98-T in 50 mL of anhydrous ethanol to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述氯化镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium chloride solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后通过球磨仪(德国Retsch公司Emax型球磨仪)以800rpm处理2h,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为228.1nm。(5) The sodium hydroxide solution is quickly added to the hydration liquid, and then the hydration liquid is processed by a ball mill (Emax ball mill produced by Retsch, Germany) at 800 rpm for 2 h. After the process is completed, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 228.1 nm as measured by a laser particle size analyzer.

实施例10Example 10

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将420mg六水氯化镁(阿拉丁,纯度99%)与8mL纯化水中混合溶解,得氯化镁溶液;(1) Mix and dissolve 420 mg of magnesium chloride hexahydrate (Aladdin, purity 99%) in 8 mL of purified water to obtain a magnesium chloride solution;

(2)将16mg氢氧化钠与2mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 16 mg of sodium hydroxide and 2 mL of purified water to obtain a sodium hydroxide solution;

(3)将200mg蛋黄卵磷脂PC98-T溶于50mL无水乙醇,得到磷脂溶液;(3) dissolving 200 mg of egg yolk lecithin PC98-T in 50 mL of anhydrous ethanol to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述氯化镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium chloride solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后通过球磨仪(德国Retsch公司Emax型球磨仪)以800rpm处理2h,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为235.0nm。(5) The sodium hydroxide solution is quickly added to the hydration liquid, and then the hydration liquid is processed by a ball mill (Emax ball mill of Retsch, Germany) at 800 rpm for 2 hours. After completion, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 235.0 nm as measured by a laser particle size analyzer.

实施例11Embodiment 11

本实施例提供一种治疗关节疼痛的氢氧化镁纳米粒的制备方法,所述制备方法包括如下步骤:This embodiment provides a method for preparing magnesium hydroxide nanoparticles for treating joint pain, the preparation method comprising the following steps:

(1)将440mg一水硫酸镁与8mL纯化水中混合溶解,得硫酸镁溶液;(1) Mix and dissolve 440 mg of magnesium sulfate monohydrate in 8 mL of purified water to obtain a magnesium sulfate solution;

(2)将16mg氢氧化钠与2mL纯化水混合溶解,得氢氧化钠溶液;(2) Mix and dissolve 16 mg of sodium hydroxide and 2 mL of purified water to obtain a sodium hydroxide solution;

(3)将800mg蛋黄卵磷脂PC98-T溶于50mL无水乙醇,得到磷脂溶液;(3) dissolving 800 mg of egg yolk lecithin PC98-T in 50 mL of anhydrous ethanol to obtain a phospholipid solution;

(4)将所述磷脂溶液转移至圆底烧瓶中,通过旋转蒸发仪除去有机试剂,从而在瓶壁上形成薄膜,然后使用所述硫酸镁溶液水化薄膜,得到水化液;(4) transferring the phospholipid solution to a round-bottom flask, removing the organic reagent by a rotary evaporator to form a thin film on the flask wall, and then hydrating the thin film with the magnesium sulfate solution to obtain a hydrated liquid;

(5)将所述氢氧化钠溶液快速加入所述水化液中,然后通过球磨仪(德国Retsch公司Emax型球磨仪)以1000rpm处理6h,完成后即得到所述治疗关节疼痛的氢氧化镁纳米粒,经过激光粒度仪测定其平均粒径为65.3nm。(5) The sodium hydroxide solution is quickly added to the hydration liquid, and then the mixture is processed by a ball mill (Emax ball mill of Retsch, Germany) at 1000 rpm for 6 h. After the processing, the magnesium hydroxide nanoparticles for treating joint pain are obtained. The average particle size thereof is 65.3 nm as measured by a laser particle size analyzer.

对比例1Comparative Example 1

将125mg蛋黄磷脂E80溶于20mL二氯甲烷中并转移至圆底烧瓶内,通过旋转蒸发仪除去有机试剂从而在瓶壁上形成薄膜,使用5mL纯化水水化薄膜,使之脱落形成水化液,然后以220W的功率探头超声10min,即得空白脂质体。125 mg of egg yolk phospholipid E80 was dissolved in 20 mL of dichloromethane and transferred to a round-bottom flask. The organic reagent was removed by a rotary evaporator to form a thin film on the flask wall. 5 mL of purified water was used to hydrate the thin film to make it fall off to form a hydrated liquid, and then ultrasonicated with a power probe of 220 W for 10 minutes to obtain blank liposomes.

对比例2Comparative Example 2

(1)将393.6mg七水硫酸镁放入4mL纯化水中溶解,得到硫酸镁溶液;(1) dissolving 393.6 mg of magnesium sulfate heptahydrate in 4 mL of purified water to obtain a magnesium sulfate solution;

(2)将8mg氢氧化钠放入1mL纯化水中溶解,得氢氧化钠溶液;(2) Dissolve 8 mg of sodium hydroxide in 1 mL of purified water to obtain a sodium hydroxide solution;

(3)将所述氢氧化钠溶液快速加入到所述硫酸镁溶液中,然后以220W的功率探头超声10min即可。结果显示体系呈现明显的白色沉淀,粒径已超出激光粒度仪测定范围。(3) The sodium hydroxide solution was quickly added to the magnesium sulfate solution, and then ultrasonicated for 10 minutes with a power probe of 220 W. The results showed that the system presented an obvious white precipitate, and the particle size was beyond the measurement range of the laser particle size analyzer.

试验例1Test Example 1

对本发明所述氢氧化镁纳米粒的内部结构进行观察。The internal structure of the magnesium hydroxide nanoparticles of the present invention was observed.

取实施例1所制备的氢氧化镁纳米粒,通过透射电镜(TEM)观察其结构,结果如图1所示,本发明所制备的氢氧化镁纳米粒呈类球形,且氢氧化镁可被磷脂所包覆。The structure of the magnesium hydroxide nanoparticles prepared in Example 1 was observed by transmission electron microscopy (TEM). The result is shown in FIG1 . The magnesium hydroxide nanoparticles prepared in the present invention are spherical in shape, and the magnesium hydroxide can be coated with phospholipids.

试验例2Test Example 2

对本发明所述氢氧化镁纳米粒的效果进行测试。The effect of the magnesium hydroxide nanoparticles of the present invention was tested.

(一)OA大鼠模型1. OA rat model

对SD大鼠膝关节的关节腔注射碘乙酸钠,以构建OA大鼠模型,待大鼠膝关节出现肿胀,痛阈显著降低,即得OA大鼠模型。Sodium iodoacetate was injected into the articular cavity of the knee joint of SD rats to construct an OA rat model. When the rat knee joint became swollen and the pain threshold was significantly reduced, the OA rat model was obtained.

(二)药效学研究(II) Pharmacodynamic studies

通过关节腔注射方式,对OA模型大鼠分别使用生理盐水(记为生理盐水组)、对比例1制备得到的空白脂质体(记为空白脂质体组)、硫酸镁溶液(将七水硫酸镁溶于生理盐水中,记为硫酸镁溶液组)、实施例1制备的氢氧化镁纳米粒液(记为氢氧化镁纳米粒组1)、实施例3制备的氢氧化镁纳米粒液(记为氢氧化镁纳米粒组2)、实施例11制备的氢氧化镁纳米粒液(记为氢氧化镁纳米粒组3)进行治疗。By intra-articular injection, OA model rats were treated with normal saline (referred to as normal saline group), blank liposomes prepared in Comparative Example 1 (referred to as blank liposome group), magnesium sulfate solution (magnesium sulfate heptahydrate was dissolved in normal saline, referred to as magnesium sulfate solution group), magnesium hydroxide nanoparticle liquid prepared in Example 1 (referred to as magnesium hydroxide nanoparticle group 1), magnesium hydroxide nanoparticle liquid prepared in Example 3 (referred to as magnesium hydroxide nanoparticle group 2), and magnesium hydroxide nanoparticle liquid prepared in Example 11 (referred to as magnesium hydroxide nanoparticle group 3).

另外,在正常大鼠膝关节腔内注射等体积(100μL)的生理盐水作为对照(记为正常组)。每组的给药浓度为0.4mmol/mL(以镁计算),于造模后第7天给药,共给药1次。从给药第一天起,每周测量一次各组大鼠的机械缩足阈值及双足负重差值。结果分别如图2、图3所示。In addition, an equal volume (100 μL) of normal saline was injected into the knee joint cavity of normal rats as a control (recorded as the normal group). The drug concentration for each group was 0.4 mmol/mL (calculated as magnesium), and the drug was administered on the 7th day after modeling, for a total of 1 dose. From the first day of administration, the mechanical withdrawal threshold and the difference in weight between the two feet of each group of rats were measured once a week. The results are shown in Figures 2 and 3, respectively.

由图2、图3结果可知,本发明制备的氢氧化镁纳米粒可以有效且持久的缓解OA大鼠的关节疼痛,同时这些结果充分说明,本发明的氢氧化镁纳米粒可以用于制备治疗关节镇痛的药物。As shown in Figures 2 and 3, the magnesium hydroxide nanoparticles prepared by the present invention can effectively and durably relieve the joint pain of OA rats. At the same time, these results fully illustrate that the magnesium hydroxide nanoparticles of the present invention can be used to prepare drugs for treating joint analgesia.

以上所述,仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应以所述权利要求的保护范围为准。The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art who is familiar with the technical field can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims (9)

1. A magnesium hydroxide nanoparticle for treating joint pain, wherein the magnesium hydroxide nanoparticle comprises magnesium hydroxide and a phospholipid, the magnesium hydroxide nanoparticle comprising a "core-shell" structure, wherein:
the core layer is magnesium hydroxide, and the shell layer is phospholipid.
2. The magnesium hydroxide nanoparticle for treating joint pain according to claim 1, wherein the phospholipid is one or more of a natural soybean phospholipid, a natural egg yolk phospholipid, or a synthetic phospholipid.
3. The magnesium hydroxide nanoparticle according to claim 2, wherein the phospholipid is one or more of the group consisting of phospholipids S45, S75, S100, SPC, E80, EPCS, EPG, SPC-3, PC98-T, PL-100M, HSPC, PGE, PGSH, DS-PL95E, DSPE, DPPA, DSPA, and DMPC.
4. The magnesium hydroxide nanoparticle for treating joint pain according to claim 3, wherein the average particle size of the magnesium hydroxide nanoparticle is 50-550 nm.
5. The method for preparing the magnesium hydroxide nanoparticles for treating joint pain according to any one of claims 1 to 4, wherein the method comprises the following steps:
(1) Dissolving soluble magnesium salt in purified water to obtain magnesium salt solution;
(2) Dissolving soluble metal hydroxide in purified water to obtain a metal hydroxide solution;
(3) Dissolving phospholipid in an organic solvent to obtain a phospholipid solution;
(4) Performing rotary evaporation on the phospholipid solution to remove an organic reagent, and adding the magnesium salt solution for hydration after a film is formed to obtain hydration liquid;
(5) And adding the metal hydroxide solution into the hydration liquid for nanocrystallization treatment, and obtaining the magnesium hydroxide nanoparticles for treating joint pain after the nanocrystallization treatment is completed.
6. The method of preparing magnesium hydroxide nanoparticles for treating joint pain according to claim 5, wherein in step (1), the soluble magnesium salt is one or more of anhydrous magnesium sulfate, magnesium sulfate monohydrate, magnesium sulfate heptahydrate, anhydrous magnesium chloride, and magnesium chloride hexahydrate.
7. The method for preparing magnesium hydroxide nanoparticles for treating joint pain according to claim 5, wherein in step (2), said metal hydroxide is one or a combination of two of sodium hydroxide and potassium hydroxide.
8. The method for preparing magnesium hydroxide nanoparticles for treating joint pain according to claim 5, wherein in step (5), said nanocrystallization is performed by one of probe sonication, high-pressure homogenization, and ball mill treatment.
9. The use of the magnesium hydroxide nanoparticles for treating joint pain according to any one of claims 1 to 4, wherein the magnesium hydroxide nanoparticles are used for preparing a medicament for treating joint pain of osteoarthritis.
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