阅读说明：本技术 一种强心抗疲劳聚合物纳米颗粒及其制备方法 (Heart-strengthening anti-fatigue polymer nano-particles and preparation method thereof ) 是由 汤佳鹏 葛彦 朱俐 胡亦雯 于 2020-04-30 设计创作，主要内容包括：本发明公开了一种强心抗疲劳聚合物纳米颗粒及其制备方法,将对甲苯磺酸和硼酸溶于DMF中制得复合催化剂；随后将DL-酒石酸、丹参素、咖啡酸、阿魏酸、二十八烷醇、CTAB分别依次加入甲苯中,油浴加热,搅拌至DL-酒石酸溶解后,滴加氯化亚砜,再滴加复合催化剂,加热回流,反应过程中分出多余水,直到没有多余的水产生时反应结束；反应结束后,减压除溶剂得到固体粉末,用乙酸乙酯回流带走残留溶剂,饱和NaHCO<Sub>3</Sub>水溶液和蒸馏水洗涤后离心,干燥制得强心抗疲劳聚合物纳米颗粒。本发明强心抗疲劳聚合物纳米颗粒以DL-酒石酸和丹参素作为聚合中心,接枝咖啡酸、阿魏酸和二十八烷醇,具有长循环效果,能够一次大剂量给药,长期维持体内药物浓度,获得理想的缓释效果。(The invention discloses a cardiotonic anti-fatigue polymer nanoparticle and a preparation method thereof, wherein p-toluenesulfonic acid and boric acid are dissolved in DMF to prepare a composite catalyst; sequentially adding DL-tartaric acid, tanshinol, caffeic acid, ferulic acid, octacosanol and CTAB into toluene respectively, heating in an oil bath, stirring until the DL-tartaric acid is dissolved, dropwise adding thionyl chloride, dropwise adding a composite catalyst, heating and refluxing, and separating excessive water in the reaction process until no excessive water is generated, wherein the reaction is finished; after the reaction is finished, decompressing and removing the solvent to obtain solid powder, refluxing and taking away residual solvent by ethyl acetate, and taking saturated NaHCO 3 And washing the aqueous solution and the distilled water, centrifuging and drying to obtain the cardiotonic anti-fatigue polymer nanoparticles. The cardiotonic anti-fatigue polymer nanoparticle takes DL-tartaric acid and danshensu as polymerization centers, is grafted with caffeic acid, ferulic acid and octacosanol, has a long circulation effect, can be administered at a large dose once, maintains the in-vivo drug concentration for a long time, and obtains an ideal slow release effect.)

1. A preparation method of a cardiotonic anti-fatigue polymer nanoparticle is characterized by comprising the following steps:

s1, preparing a composite catalyst: dissolving p-toluenesulfonic acid and boric acid in DMF to prepare a composite catalyst;

s2, respectively and sequentially adding DL-tartaric acid, tanshinol, caffeic acid, ferulic acid, octacosanol and CTAB into toluene, heating in an oil bath, stirring, slowly dripping thionyl chloride after the DL-tartaric acid is dissolved, then slowly dripping a composite catalyst, heating and refluxing, controlling the temperature at 130-140 ℃, separating excess water in the reaction process until the reaction is finished when no excess water is generated, and decompressing and removing the solvent to obtain solid powder;

s3, refluxing the solid powder in ethyl acetate for 3-4 hours, removing the ethyl acetate under reduced pressure, and using saturated NaHCO₃Washing with water solution for 2-3 times, and washing with distilled water for 1-2 times to obtain crude suspension;

and S4, centrifuging the crude suspension obtained in the step S3, collecting supernatant, and performing spray drying to obtain the cardiotonic anti-fatigue polymer nanoparticles.

2. The method according to claim 1, wherein in step S1, the ratio of p-toluenesulfonic acid to boric acid to DMF is (15.48-18.92) g to (5.56-6.80) g to 50 ml.

3. The method according to claim 1, wherein the DL-tartaric acid, danshensu, caffeic acid, ferulic acid, octacosanol, CTAB and toluene are used in a ratio of (13.5-16.5) g, (8.91-10.89) g, (8.1-9.9) g, (8.73-10.67) g, (18.49-22.60) g, (0.08-0.10) g and 90ml in step S2.

4. The method according to claim 1, wherein in step S2, the thionyl chloride is added in an amount of 0.9 to 1.1ml per 90ml of toluene.

5. The method according to claim 1, wherein the amount of the composite catalyst added in step S2 is 5.6-6.8ml per 90ml of toluene.

6. The method as claimed in claim 1, wherein the rotation speed of the centrifugation step S4 is 10000-15000 r/min.

7. The preparation method as claimed in claim 1, wherein in step S4, the inlet temperature of spray drying is 180-220 ℃, the outlet temperature is 50-80 ℃, and the feeding rate is 5-10 ml/S.

8. The cardiotonic anti-fatigue polymer nanoparticles prepared by the preparation method of any one of claims 1 to 7.

9. The cardiotonic anti-fatigue polymeric nanoparticle of claim 8 having a particle size distribution of 50-100 nm.

Technical Field

The invention belongs to the field of medicinal preparations, and relates to a cardiotonic anti-fatigue polymer nanoparticle and a preparation method thereof.

Background

Heart failure, heart failure for short, refers to a heart circulatory disturbance syndrome caused by insufficient discharge of venous return blood volume from the heart due to the failure of the systolic and/or diastolic functions of the heart, resulting in venous system blood stasis and arterial system blood perfusion deficiency, which is manifested as pulmonary congestion and vena cava congestion. Heart failure is not an independent disease, but is the terminal stage of progression of heart disease, with high disability rate and mortality, severely impacting the quality of life and prognosis of the patient.

Fatigue is a subjective feeling of discomfort, but objectively loses its ability to perform the normal activities or work originally undertaken under the same conditions. Excessive fatigue may be one of the causes of heart failure. Persistent fatigue may be a manifestation of heart failure.

Disclosure of Invention

In view of the above, the present invention aims to provide a cardiotonic anti-fatigue polymer nanoparticle and a preparation method thereof, wherein the cardiotonic anti-fatigue polymer nanoparticle has a slow release property and can maintain a long-term drug effect.

In order to solve the technical problem, the invention provides a preparation method of a cardiotonic anti-fatigue polymer nanoparticle, which comprises the following steps:

s1, preparing a composite catalyst: dissolving p-toluenesulfonic acid and boric acid in DMF (dimethylformamide) to prepare a composite catalyst;

s2, respectively and sequentially adding DL-tartaric acid, tanshinol, caffeic acid, ferulic acid, octacosanol and CTAB (cetyl trimethyl ammonium bromide) into toluene, heating in an oil bath, stirring, slowly dripping thionyl chloride after the DL-tartaric acid is dissolved, then slowly dripping a composite catalyst, heating and refluxing, controlling the temperature at 130-140 ℃, separating excessive water in the reaction process until the reaction is finished when no excessive water is generated, and decompressing and removing the solvent to obtain solid powder;

s3, refluxing the solid powder in ethyl acetate for 3-4 hours, removing the ethyl acetate under reduced pressure, and using saturated NaHCO₃Washing with water solution for 2-3 times, and washing with distilled water for 1-2 times to obtain crude suspension;

and S4, centrifuging the crude suspension obtained in the step S3, collecting supernatant, and performing spray drying to obtain the cardiotonic anti-fatigue polymer nanoparticles.

Preferably, in step S1, the ratio of p-toluenesulfonic acid to boric acid to DMF is (15.48-18.92) g (5.56-6.80) g to 50 ml.

Preferably, in step S2, the dosage ratio of DL-tartaric acid, danshensu, caffeic acid, ferulic acid, octacosanol, CTAB and toluene is (13.5-16.5) g, (8.91-10.89) g, (8.1-9.9) g, (8.73-10.67) g, (18.49-22.60) g, (0.08-0.10) g and 90 ml.

Preferably, in step S2, the thionyl chloride is added in an amount of 0.9 to 1.1ml per 90ml of toluene.

Preferably, in step S2, the amount of the composite catalyst added is 5.6-6.8ml per 90ml of toluene.

Preferably, in step S4, the rotation speed of the centrifugation is 10000-.

Preferably, in step S4, the inlet temperature of the spray drying is 180-220 ℃, the outlet temperature is 50-80 ℃, and the feeding rate is 5-10 ml/S.

The invention also provides the cardiotonic anti-fatigue polymer nanoparticles prepared by the preparation method.

Preferably, the cardiotonic anti-fatigue polymer nanoparticles have a particle size distribution of 50-100 nm.

Compared with the prior art, the invention has the following beneficial effects:

1. the invention utilizes three catalysts of p-toluenesulfonic acid, boric acid and thionyl chloride to catalyze the esterification reaction among tartaric acid, tanshinol, caffeic acid, ferulic acid and octacosanol to form copolymer polymer nanoparticles taking tartaric acid and tanshinol as cores, and the particle size is maintained at 50-100 nm. The reaction can obtain cardiotonic anti-fatigue polymer nanoparticles with uniform particle size and good dispersion.

2. The addition of CTAB promotes the dissolution of the reactants in the reaction medium, promotes the esterification reaction and optimizes the reaction.

3. In vivo, the cardiotonic anti-fatigue polymer nanoparticles can be gradually degraded under the action of plasma esterase to release active molecules of tanshinol, caffeic acid, ferulic acid and octacosanol. These molecules, at certain concentrations, can synergistically improve cardiac function and relieve fatigue.

Detailed Description

For a further understanding of the invention, reference will now be made to the preferred embodiments of the present invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the present invention and is not intended to limit the scope of the claims which follow.

All of the starting materials of the present invention, without particular limitation as to their source, may be purchased commercially or prepared according to conventional methods well known to those skilled in the art.