Shendan brain-dredging dropping pill for treating stroke and preparation method thereof

Abstract

The invention relates to the technical field of traditional Chinese medicines, and discloses a ginseng-salvia miltiorrhiza brain-dredging dropping pill for treating apoplexy and a preparation method thereof, and the preparation method comprises the following steps: (1) preparing ginseng, salvia miltiorrhiza and ligusticum wallichii into clear paste, and crushing to obtain paste powder; (2) carrying out reaction on epoxy modified glyceryl trioleate, poloxamer and triethylamine in DMF (Dimethyl Formamide), adding glyceryl monooleate, and carrying out secondary reaction; performing reduced pressure distillation and purification to obtain a mixture; stirring and mixing the mixture, a polymer of 2-methacryloyloxyethyl phosphorylcholine and polyethylene glycol to obtain a matrix; and (3) heating and mixing the paste powder and the matrix, and dripping into a cooling agent to prepare the dropping pill. The dropping pill has the effects of promoting blood circulation, tonifying qi, dispelling wind and removing obstruction in the meridians, can be used for treating stroke diseases, has high drug loading capacity and good appearance quality, is quick to dissolve and take effect quickly in the initial stage, is stable and slow-released in the later stage, ensures the long-term drug effect, and remarkably improves the bioavailability of drugs.

Description

Technical Field

[0001] This invention relates to the technical field of traditional Chinese medicine, and in particular to a Shendan Tongnao Dripping Pill for treating stroke and its preparation method. Background Technology

[0002] In recent years, traditional Chinese medicine (TCM) compositions have shown unique advantages in the treatment of stroke. Existing treatments mainly fall into three categories: (1) Blood-activating and stasis-removing: with Danshen, Sanqi, and Chuanxiong as core ingredients, they exert their therapeutic effect by improving cerebral microcirculation; (2) Qi-tonifying and meridian-clearing: for stroke patients in the recovery period, Astragalus membranaceus is used as the principal ingredient, combined with earthworm, leech, etc., to achieve nerve function repair; (3) Brain-awakening and orifice-opening: containing aromatic orifice-opening drugs such as Acorus tatarinowii and Polygala tenuifolia. Studies have shown that TCM compound prescriptions produce comprehensive therapeutic effects through the synergistic effects of multiple components and multiple targets (such as inhibiting inflammatory factors and regulating hemodynamics), but there are bottlenecks such as low bioavailability and difficulty in quality control.

[0003] Droplet formulations are important carriers for traditional Chinese medicine compositions. Their core process involves dispersing the drug within a matrix using a melt method to form a solid solution. However, traditional PEG matrices have insufficient drug loading efficiency. Physical mixing of the drug and matrix leads to high porosity, making the active ingredients prone to oxidative degradation, thus limiting drug loading. Furthermore, the dissolution behavior of the matrix is ​​unstable, exhibiting a significant burst release effect and large fluctuations in drug release concentration, affecting dissolution time and droplet stability. Patent CN101543549A discloses a droplet containing total flavonoids from *Saururus chinensis* and its preparation method. This droplet consists of the raw material *Saururus chinensis* total flavonoid extract and a droplet matrix of polyethylene glycol and poloxamer. Preparation involves adding the *Saururus chinensis* total flavonoid extract powder to a molten matrix, which is then dripped into a cooling liquid. Although this droplet uses a polyethylene glycol-poloxamer blend as a composite matrix, it also suffers from low drug loading and a significant burst release effect, thus limiting its application. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a ginseng-danshen-tongnao dripping pill for treating stroke and its preparation method. The pill uses ginseng, danshen, and chuanxiong as a drug composition for stroke treatment, possessing the effects of invigorating blood circulation, replenishing qi, dispelling wind, and unblocking collaterals. By synergistically regulating the component formulation in the dripping pill matrix, the drug loading is increased, resulting in dripping pills with good appearance quality. Furthermore, the pills exhibit rapid dissolution and quick efficacy in the initial stage, followed by stable and sustained release to ensure long-term efficacy, and significantly improve drug bioavailability and mucosal safety.

[0005] The objective of this invention is achieved through the following technical solution: In a first aspect, the present invention provides a method for preparing Shendan Tongnao Dripping Pills for treating stroke, comprising the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer and triethylamine were reacted in DMF, and a second reaction was carried out after the addition of monooleic acid glyceride. The mass ratio of epoxy-modified trioleic acid glyceride, poloxamer and monooleic acid glyceride was 1-1.5:1:0.3-0.5. After vacuum distillation and purification, a mixture was obtained. The mixture, the polymer of 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol were stirred and mixed at a mass percentage of 10-15%:8-10%:75-82% to obtain the matrix. (3) Heat and mix the powder and matrix, and drip them into the coolant to make droplets.

[0006] This invention uses ginseng, salvia miltiorrhiza, and chuanxiong as a drug composition for treating stroke. Ginseng has the effects of greatly replenishing vital energy, restoring pulse and consolidating the body, tonifying the spleen and lungs, promoting body fluid production and nourishing blood, and calming the mind and improving intelligence. Salvia miltiorrhiza has the effects of promoting blood circulation and removing blood stasis, clearing the meridians and relieving pain, clearing the heart and relieving irritability, cooling the blood and reducing swelling. Chuanxiong has the effects of promoting blood circulation and regulating qi, dispelling wind and relieving pain. Therefore, the combination of these three herbs has the effects of promoting blood circulation and replenishing qi, dispelling wind and clearing the meridians, thus exerting a comprehensive therapeutic effect in the treatment of stroke.

[0007] Furthermore, the droplet formulation uses a mixture of polymers of 2-methacryloyloxyethyl phosphorylcholine and polyethylene glycol as the matrix. Polyethylene glycol is a commonly used matrix for droplets, exhibiting good water solubility and moderate viscosity after melting, which facilitates droplet preparation and drug encapsulation. 2-methacryloyloxyethyl phosphorylcholine possesses good biocompatibility; its phosphorylcholine structure promotes the fusion of the droplets with the intestinal mucosa, significantly improving mucosal safety. Simultaneously, after polymerization, 2-methacryloyloxyethyl phosphorylcholine forms a hydration layer that acts as a diffusion barrier, allowing the drug in the droplets to diffuse through this layer for effective sustained release. The addition of PEG, however, meets the requirements for immediate release. The addition of the mixture ensures a high drug loading capacity for the pellets. Epoxy-modified trioleic acid ester, poloxamer, and monooleic acid ester are combined through epoxy and hydroxyl reactions. The long alkyl chain structure of trioleic acid ester can form a hydrophobic core, allowing for tighter adsorption to drug particles and increasing drug loading. The introduction of monooleic acid ester extends the hydrophobic segments to form a layered structure, which is beneficial for physical drug retention during pellet formation and slow drug release during pellet dissolution. Furthermore, the introduction of poloxamer improves the compatibility of the mixture with the other two components in the matrix, enhancing pellet stability. Poloxamer also significantly reduces surface tension, promoting drug wetting and dissolution, and improving bioavailability. Therefore, the components in the pellet matrix of this invention can synergistically regulate and increase drug loading, achieving rapid initial dissolution, rapid onset of action, and stable sustained release in the later stages, ensuring long-term efficacy and significantly improving drug bioavailability and mucosal safety.

[0008] Preferably, in step (2), the preparation of the epoxy-modified trioleic acid glyceride includes the following steps: adding trioleic acid glyceride and m-chloroperoxybenzoic acid to chloroform, stirring and reacting at room temperature, then distilling under reduced pressure, adding the product to n-hexane for low-temperature crystallization, filtering and washing to obtain epoxy-modified trioleic acid glyceride.

[0009] Preferably, the ratio of trioleic acid glyceride to chloroform is 1g:30-40mL; the amount of m-chloroperoxybenzoic acid added is 0.5-2% of the mass of trioleic acid glyceride; the stirring reaction time is 10-14h; the low-temperature crystallization temperature is -25℃ to -15℃, and the time is 10-14h.

[0010] Preferably, in step (2), the ratio of the epoxy-modified trioleic acid glyceride, triethylamine, and DMF is 1g: 0.005-0.02g; 50mL; the reaction is carried out at 70-80℃ for 5-7h; the secondary reaction is carried out at 70-80℃ for 3-5h; and the purification is carried out by extracting the reaction solution with ice-cold diethyl ether, shaking to separate the layers, washing the diethyl ether phase with ice water, and then drying.

[0011] Preferably, in step (2), the preparation of the polymer of 2-methacryloyloxyethyl phosphorylcholine includes the following steps: adding 2-methacryloyloxyethyl phosphorylcholine and an initiator to an ethanol-water mixed solution, refluxing for 4-8 hours, and dialysis purification and drying of the product.

[0012] Preferably, the initiator is azobisisobutyronitrile; the amount of the initiator added is 0.5-1.5% of the molar amount of 2-methacryloyloxyethylphosphorylcholine; the volume ratio of ethanol to water in the ethanol-water mixture is 3-4:1; and the ratio of 2-methacryloyloxyethylphosphorylcholine to the ethanol-water mixture is 1g:30-40mL.

[0013] Preferably, in step (2), the polyethylene glycol is PEG4000 and / or PEG6000.

[0014] Preferably, in step (3), the pellets comprise 35-50% of ointment powder and 65-80% of matrix by mass percentage.

[0015] Preferably, in step (3), the pills contain 80-130 mg / g of total ginsenosides, 4-10 mg / g of ferulic acid, and 80-125 mg / g of salvianolic acid B.

[0016] Preferably, in step (3), the temperature of the heating and mixing is 60-80℃; the dripping rate is 20-25 drops / min, and the dripping distance is 3-5cm.

[0017] Preferably, in step (3), the coolant is dimethyl silicone oil or liquid paraffin; the temperature of the coolant is 0-10℃.

[0018] Secondly, the present invention provides a ginseng and brain-clearing pill prepared by the above-mentioned preparation method.

[0019] Compared with the prior art, the present invention has the following beneficial effects: (1) The combination of ginseng, salvia miltiorrhiza and chuanxiong as a drug for treating stroke has the effects of promoting blood circulation and qi, dispelling wind and unblocking collaterals; (2) Through the reaction of epoxy-modified trioleic acid glyceride, poloxamer and monooleic acid glyceride, the resulting hydrophobic core can significantly increase the drug loading capacity and ensure its compatibility with other components in the pellet matrix, improve the stability of the pellet, promote drug wetting, dissolution and ensure stable sustained release; (3) By adding a polymer of 2-methacryloyloxyethylphosphorylcholine, a hydration layer can be formed to create a diffusion barrier. The drug in the pellet diffuses through the hydration layer to achieve a good sustained-release effect. The addition of PEG can meet the requirements for rapid release, so that the resulting pellets dissolve quickly and take effect in the early stage, and release steadily in the later stage to ensure long-term efficacy, and significantly improve drug bioavailability and mucosal safety. Detailed Implementation

[0020] The technical solution of the present invention will be illustrated below with specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0021] The preparation method of the Shendan Tongnao Dripping Pills for treating stroke in this invention includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer, and triethylamine were added to DMF in a ratio of 1 g: 0.005-0.02 g; 50 mL was added, and the mixture was reacted at 70-80℃ for 5-7 h. After the reaction was completed, monooleic acid glyceride was added to the reaction product in a mass ratio of 1-1.5:1:0.3-0.5. The reaction was continued at 0-80℃ for 3-5 hours. After vacuum distillation, the reaction solution was extracted 2-3 times with ice-cold ether. After each extraction, the mixture was allowed to stand and separate into layers. The ether phases were combined and washed repeatedly with ice water and dried to obtain a mixture. The mixture, the polymer of 2-methacryloyloxyethylphosphonic choline, and polyethylene glycol (PEG4000 and / or PEG6000) were stirred and mixed at a mass percentage of 10-15%: 8-10%: 75-82% to obtain the matrix. (3) After mixing the powder and the matrix evenly, heat it to 60-80℃ and keep it warm. Then, drop it into a coolant (dimethyl silicone oil or liquid paraffin) at 0-10℃. The dropping rate is 20-25 drops / min and the dropping distance is 3-5cm. After the pellet cools down, take it out, drain it and wipe off the coolant to obtain the pellet.

[0022] In a specific embodiment of the present invention, the preparation of the ointment powder includes the following steps: Step 1: Extract 1389g of Ligusticum chuanxiong and 139g of Salvia miltiorrhiza twice with 8 times the amount of 75% ethanol, 1 hour each time. Filter the extract, combine the filtrates, recover the ethanol and concentrate to a relative density of 1.05-1.08 (50℃). Extract the concentrate twice with ethyl acetate, 278mL each time. Combine the ethyl acetate extracts, recover the ethyl acetate under reduced pressure and concentrate to a clear extract with a relative density of 1.05-1.08 (40℃) for later use. Step 2: Concentrate the aqueous solution from Step 1 under reduced pressure until the recovered solution has no ethyl acetate odor (concentration approximately 1 g crude drug / mL). Centrifuge the solution under conditions where the filter cloth pore size is 3 μm. Pass the centrifuged solution through a D101 type macroporous adsorption resin column. After adsorption for 12 h, wash the solution with 1 column volume (1 BV) of water and discard the water. Then elute with 1 BV of 70% ethanol. Collect the eluent, recover the ethanol, and concentrate it to a clear extract with a relative density of 1.10-1.15 (50℃) for later use. Step 3: Extract 93g of ginseng three times with 8 times the amount of 80% ethanol by reflux, 2 hours each time. Filter the extract, combine the filtrates, recover the ethanol and concentrate to a relative density of 1.04-1.06 (50℃). Centrifuge at a filter cloth pore size of 3μm, and take the centrifuged liquid (concentration of about 1g crude drug / mL). Pass it through a D101 macroporous adsorption resin column. After adsorption for 12 hours, wash with 2BV of water and discard the water wash. Then elute with 2BV of 75% ethanol, collect the eluent, recover the ethanol and concentrate to a clear extract with a relative density of 1.10-1.15 (50℃) for later use.

[0023] Step 4: Combine the three types of ointment, mix them well, dry under reduced pressure, and pulverize them into a fine powder to obtain ointment powder.

[0024] In a specific embodiment of the present invention, the preparation of epoxy-modified trioleic acid glyceride includes the following steps: Trioleic acid ester and m-chloroperoxybenzoic acid were added to chloroform at a ratio of 1 g: 40 mL. The amount of m-chloroperoxybenzoic acid added was 1.1% of the mass of trioleic acid ester. The mixture was stirred at room temperature for 10 h. After the reaction was completed, the mixture was distilled under reduced pressure. The product was added to n-hexane and crystallized at -20 °C. After filtration, washing with ice water three times, and drying, epoxy-modified trioleic acid ester was obtained.

[0025] In a specific embodiment of the present invention, the preparation of the polymer of 2-methacryloyloxyethyl phosphorylcholine includes the following steps: 2-Methacryloxyethylphosphorylcholine and azobisisobutyronitrile were added to an ethanol-water mixture (volume ratio 4:1), with the ratio of 2-methacryloxyethylphosphorylcholine to the ethanol-water mixture being 1 g: 35 mL. The amount of azobisisobutyronitrile added was 0.8% of the molar amount of 2-methacryloxyethylphosphorylcholine. The mixture was then refluxed for 6 h. After the reaction was completed, the product was placed in a dialysis bag with a molecular weight cutoff of 3500 Da for dialysis purification, and then dried to obtain the polymer.

[0026] In a specific embodiment of the present invention, the droplets comprise 35-50% of powder and 65-80% of matrix by weight percentage. The droplets contain 80-130 mg / g of total ginsenosides, 4-10 mg / g of ferulic acid, and 80-125 mg / g of salvianolic acid B.

[0027] Example 1 The preparation of Shendan Tongnao Dripping Pills includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer 188 and triethylamine were added to DMF. The ratio of epoxy-modified trioleic acid glyceride, triethylamine and DMF was 1g:0.01g. 50mL was stirred at 70℃ for 6h. After the reaction was completed, monooleic acid glyceride was added to the reaction product. The mass ratio of epoxy-modified trioleic acid glyceride, poloxamer and monooleic acid glyceride was 1.2:1:0.3. The reaction was then stirred at 75℃ for 3h. After vacuum distillation, the reaction solution was extracted three times with ice-cold ether. After each shaking, the mixture was allowed to stand and separate into layers. The ether phases were combined and washed five times with ice water and dried to obtain a mixture. The mixture, the polymer of 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol (PEG4000 and PEG6000 in a mass ratio of 1:1) were stirred and mixed at a mass percentage of 10%:10%:80% to obtain the matrix. (3) After mixing the paste powder and the matrix evenly, heat it to 70°C and keep it warm. Then, drop it into a coolant (dimethyl silicone oil) at 10°C at a dropping rate of 20 drops / min and a dropping distance of 4cm. After the pellet cools down, take it out, drain it and wipe off the coolant to obtain the pellet.

[0028] Example 2 The preparation of Shendan Tongnao Dripping Pills includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer 188 and triethylamine were added to DMF. The ratio of epoxy-modified trioleic acid glyceride, triethylamine and DMF was 1g:0.012g. 50mL was stirred at 70℃ for 6h. After the reaction was completed, monooleic acid glyceride was added to the reaction product. The mass ratio of epoxy-modified trioleic acid glyceride, poloxamer and monooleic acid glyceride was 1.4:1:0.5. The reaction was then stirred at 75℃ for 5h. After vacuum distillation, the reaction solution was extracted three times with ice-cold ether. After each shaking, the mixture was allowed to stand and separate into layers. The ether phases were combined and washed five times with ice water and dried to obtain a mixture. The mixture, the polymer of 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol (PEG4000 and PEG6000 in a mass ratio of 1:1) were stirred and mixed at a mass percentage of 10%:10%:80% to obtain the matrix. (3) After mixing the paste powder and the matrix evenly, heat it to 70°C and keep it warm. Then, drop it into a coolant (dimethyl silicone oil) at 10°C at a dropping rate of 20 drops / min and a dropping distance of 4cm. After the pellet cools down, take it out, drain it and wipe off the coolant to obtain the pellet.

[0029] Example 3 The preparation of Shendan Tongnao Dripping Pills includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer 188 and triethylamine were added to DMF. The ratio of epoxy-modified trioleic acid glyceride, triethylamine and DMF was 1g:0.012g. 50mL was stirred at 70℃ for 6h. After the reaction was completed, monooleic acid glyceride was added to the reaction product. The mass ratio of epoxy-modified trioleic acid glyceride, poloxamer and monooleic acid glyceride was 1.4:1:0.5. The reaction was then stirred at 75℃ for 5h. After vacuum distillation, the reaction solution was extracted three times with ice-cold ether. After each shaking, the mixture was allowed to stand and separate into layers. The ether phases were combined and washed five times with ice water and dried to obtain a mixture. The mixture, the polymer of 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol (PEG4000 and PEG6000 in a mass ratio of 1:1) were stirred and mixed at a mass percentage of 14%:8%:78% to obtain the matrix. (3) After mixing the paste powder and the matrix evenly, heat it to 70°C and keep it warm. Then, drop it into a coolant (dimethyl silicone oil) at 10°C at a dropping rate of 20 drops / min and a dropping distance of 4cm. After the pellet cools down, take it out, drain it and wipe off the coolant to obtain the pellet.

[0030] Comparative Example 1 The difference from Example 1 is that 2-methacryloyloxyethyl phosphorylcholine is added to replace the polymer of 2-methacryloyloxyethyl phosphorylcholine.

[0031] The preparation of Shendan Tongnao Dripping Pills includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer 188 and triethylamine were added to DMF. The ratio of epoxy-modified trioleic acid glyceride, triethylamine and DMF was 1g:0.01g. 50mL was stirred at 70℃ for 6h. After the reaction was completed, monooleic acid glyceride was added to the reaction product. The mass ratio of epoxy-modified trioleic acid glyceride, poloxamer and monooleic acid glyceride was 1.2:1:0.3. The reaction was then stirred at 75℃ for 3h. After vacuum distillation, the reaction solution was extracted three times with ice-cold ether. After each shaking, the mixture was allowed to stand and separate into layers. The ether phases were combined and washed five times with ice water and dried to obtain a mixture. The mixture, 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol (PEG4000 and PEG6000 in a mass ratio of 1:1) were stirred and mixed at a mass percentage of 10%:10%:80% to obtain the matrix. (3) After mixing the paste powder and the matrix evenly, heat it to 70°C and keep it warm. Then, drop it into a coolant (dimethyl silicone oil) at 10°C at a dropping rate of 20 drops / min and a dropping distance of 4cm. After the pellet cools down, take it out, drain it and wipe off the coolant to obtain the pellet.

[0032] Comparative Example 2 The difference from Example 1 is that the mass percentages of the mixture, the polymer of 2-methacryloyloxyethyl phosphorylcholine, and polyethylene glycol exceed the defined range.

[0033] The preparation of Shendan Tongnao Dripping Pills includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer 188 and triethylamine were added to DMF. The ratio of epoxy-modified trioleic acid glyceride, triethylamine and DMF was 1g:0.01g. 50mL was stirred at 70℃ for 6h. After the reaction was completed, monooleic acid glyceride was added to the reaction product. The mass ratio of epoxy-modified trioleic acid glyceride, poloxamer and monooleic acid glyceride was 1.2:1:0.3. The reaction was then stirred at 75℃ for 3h. After vacuum distillation, the reaction solution was extracted three times with ice-cold ether. After each shaking, the mixture was allowed to stand and separate into layers. The ether phases were combined and washed five times with ice water and dried to obtain a mixture. The mixture, the polymer of 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol (PEG4000 and PEG6000 in a mass ratio of 1:1) were stirred and mixed at a mass percentage of 18%:5%:77% to obtain the matrix. (3) After mixing the paste powder and the matrix evenly, heat it to 70°C and keep it warm. Then, drop it into a coolant (dimethyl silicone oil) at 10°C at a dropping rate of 20 drops / min and a dropping distance of 4cm. After the pellet cools down, take it out, drain it and wipe off the coolant to obtain the pellet.

[0034] Comparative Example 3 The difference from Example 1 is that the added poloxamer did not react and bind.

[0035] The preparation of Shendan Tongnao Dripping Pills includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride and triethylamine were added to DMF, with the ratio of epoxy-modified trioleic acid glyceride, triethylamine and DMF being 1g:0.01g; 50mL of monooleic acid glyceride was added, with the mass ratio of epoxy-modified trioleic acid glyceride and monooleic acid glyceride being 1.2:0.3, and the mixture was stirred at 75℃ for 3h; after vacuum distillation, the reaction solution was extracted three times with ice-cold ether, and after each shaking, the layers were allowed to stand and separate, the ether phases were combined, and the ether phases were washed five times with ice water and dried to obtain a mixture; the mixture, poloxamer 188, the polymer of 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol (the mass ratio of PEG4000 and PEG6000 was 1:1) were stirred and mixed at a mass percentage of 5%:5%:10%:80% to obtain the matrix; (3) After mixing the paste powder and the matrix evenly, heat it to 70°C and keep it warm. Then, drop it into a coolant (dimethyl silicone oil) at 10°C at a dropping rate of 20 drops / min and a dropping distance of 4cm. After the pellet cools down, take it out, drain it and wipe off the coolant to obtain the pellet.

[0036] Comparative Example 4 The difference from Example 1 is that no glyceryl monooleate was added.

[0037] The preparation of Shendan Tongnao Dripping Pills includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer 188 and triethylamine were added to DMF. The ratio of epoxy-modified trioleic acid glyceride, triethylamine and DMF was 1g:0.01g; 50mL, the mass ratio of epoxy-modified trioleic acid glyceride and poloxamer was 1.2:1. The mixture was stirred at 70℃ for 6h. After the reaction was completed, the reaction solution was distilled under reduced pressure and extracted three times with ice-cold ether. After each shaking, the mixture was allowed to stand and separate into layers. The ether phases were combined and washed five times with ice water and dried to obtain a mixture. The mixture, the polymer of 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol (PEG4000 and PEG6000 in a mass ratio of 1:1) were stirred and mixed at a mass percentage of 10%:10%:80% to obtain the matrix. (3) After mixing the paste powder and the matrix evenly, heat it to 70°C and keep it warm. Then, drop it into a coolant (dimethyl silicone oil) at 10°C at a dropping rate of 20 drops / min and a dropping distance of 4cm. After the pellet cools down, take it out, drain it and wipe off the coolant to obtain the pellet.

[0038] Performance testing: Appearance: Observe the tailing and adhesion of the droplets; take one droplet and measure its radial length in three different directions, take the average value, and the proportion of the data that deviates the farthest from the average radial length to the average radial length is the roundness.

[0039] Disintegration time limit: Tested according to Appendix XIIA of the 2010 edition of the Chinese Pharmacopoeia: Use a stainless steel wire mesh with an inner diameter of 0.42 mm. Take 6 test pellets and place them in a basket without baffles. Suspend the basket on a metal support through a stainless steel shaft and immerse it in a beaker containing an appropriate amount of 37°C water. Adjust the position of the basket so that it is 25 mm from the bottom of the beaker. When it rises, the sieve is 15 mm below the water surface. Perform disintegration test three times.

[0040] Drug release rate: The amount of drug released at 1h, 4h, 12h and 24h in a simulated intestinal fluid environment was measured and the drug release rate was calculated.

[0041] Safety testing: The residual monomers in the matrices from Examples 1-3 were all detected to be <0.1 ppm using nuclear magnetic resonance spectroscopy, and no cytotoxicity was found (CCK-8 assay for IC50). 50 >1000μg / mL), no mucosal irritation (intact mucosa, no inflammatory cell infiltration), and hemolysis rate <5%.

[0042] Table 1. Performance test results of the droplets in Examples 1-3 and Comparative Examples 1-4 As shown in Table 1, the droplets obtained in this invention have a high drug loading capacity (≥38%), good sphericity, no tailing or sticking, and meet the requirements of rapid release with a dissolution time limit (≤5 min). At the same time, they can achieve stable sustained release, with a drug release rate of <19% in 1 h and >95% in 24 h, and high bioavailability.

[0043] In Comparative Example 1, adding only 2-methacryloxyethylphosphorylcholine, rather than its polymer, to the pellet matrix resulted in the inability to form a good hydration layer, affecting the binding between matrix components and leading to poor stability of the resulting pellets. Consequently, this resulted in poor appearance and stable sustained-release properties (the duration of drug release at 100% was less than 20 hours). In Comparative Example 2, because the mass ratio of the mixture, the 2-methacryloxyethylphosphorylcholine polymer, and polyethylene glycol exceeded the specified range, even with excessive addition of the mixture, the components could not achieve good equilibrium stability, thus not significantly increasing the drug loading of the pellets. Instead, it affected the appearance of the pellets and the 24-hour drug release rate. Similarly, the mass ratio of epoxy-modified trioleic acid ester, poloxamer, and monooleic acid ester also affected the appearance and sustained-release effect of the pellets.

[0044] In Comparative Example 3, poloxamer was directly added to the pellet matrix. Since it did not react with the epoxy-modified trioleic acid ester, the compatibility and binding between the mixture and other pellet matrix components were poor, thus affecting the appearance of the pellets and their sustained-release properties. Similarly, in Comparative Example 4, no monooleic acid ester was added to the pellet matrix. Although its impact on the compatibility between the mixture and other matrix components was relatively small, the introduction of monooleic acid ester can extend the hydrophobic segments to form a layered structure, which is beneficial for the physical retention of the drug during pellet formation and the slow release of the drug during pellet dissolution. Therefore, the lack of monooleic acid ester in Comparative Example 4 would affect the drug loading and sustained-release properties of the pellets.

[0045] The above are merely preferred embodiments of the present invention and do not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made using the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A method for preparing Shendan Tongnao Dripping Pills for treating stroke, characterized in that, Includes the following steps: (1) Ginseng, Salvia miltiorrhiza and Ligusticum chuanxiong are made into a clear paste, and then pulverized to obtain a paste powder; (2) Epoxy-modified trioleic acid glyceride, poloxamer and triethylamine were reacted in DMF, and a second reaction was carried out after the addition of monooleic acid glyceride. The mass ratio of epoxy-modified trioleic acid glyceride, poloxamer and monooleic acid glyceride was 1-1.5:1:0.3-0.

5. After vacuum distillation and purification, a mixture was obtained. The mixture, the polymer of 2-methacryloyloxyethylphosphorylcholine and polyethylene glycol were stirred and mixed at a mass percentage of 10-15%:8-10%:75-82% to obtain the matrix. (3) Heat and mix the powder and matrix, and drip them into the coolant to make droplets.

2. The preparation method of Shendan Tongnao Dripping Pills for treating stroke according to claim 1, characterized in that, In step (2), the preparation of the epoxy-modified trioleic acid glyceride includes the following steps: trioleic acid glyceride and m-chloroperoxybenzoic acid are added to chloroform, stirred and reacted at room temperature, and then distilled under reduced pressure. The product is added to n-hexane for low-temperature crystallization, filtered, washed, and then epoxy-modified trioleic acid glyceride is obtained.

3. The preparation method of Shendan Tongnao Dripping Pills for treating stroke according to claim 2, characterized in that, The amount of m-chloroperoxybenzoic acid added is 0.5-2% of the mass of trioleic acid glyceride; the stirring reaction time is 10-14 h; the low-temperature crystallization temperature is -25℃ to -15℃, and the time is 10-14 h.

4. The preparation method of Shendan Tongnao Dripping Pills for treating stroke according to any one of claims 1-3, characterized in that, In step (2), the ratio of the epoxy-modified trioleic acid glyceride, triethylamine and DMF is 1g: 0.005-0.02g; 50mL; the reaction is carried out at 70-80℃ for 5-7h; the secondary reaction is carried out at 70-80℃ for 3-5h; the purification is carried out by extracting the reaction solution with ice-cold diethyl ether, shaking to separate the layers, washing the diethyl ether phase with ice water and drying it.

5. The method for preparing Shendan Tongnao Dripping Pills for treating stroke according to any one of claims 1-3, characterized in that, In step (2), the preparation of the polymer of 2-methacryloyloxyethyl phosphorylcholine includes the following steps: adding 2-methacryloyloxyethyl phosphorylcholine and an initiator to an ethanol-water mixed solution, refluxing for 4-8 hours, and dialysis purification and drying of the product.

6. The preparation method of Shendan Tongnao Dripping Pills for treating stroke according to claim 1, characterized in that, In step (3), the pellets comprise 35-50% of the powder and 65-80% of the matrix by mass percentage.

7. The preparation method of Shendan Tongnao Dripping Pills for treating stroke according to claim 1 or 6, characterized in that, In step (3), the pills contain 80-130 mg / g of total ginsenosides, 4-10 mg / g of ferulic acid, and 80-125 mg / g of salvianolic acid B.

8. The preparation method of Shendan Tongnao Dripping Pills for treating stroke according to claim 1, characterized in that, In step (3), the temperature of the heating and mixing is 60-80℃; the dripping rate is 20-25 drops / min and the dripping distance is 3-5cm.

9. The preparation method of Shendan Tongnao Dripping Pills for treating stroke according to claim 1 or 8, characterized in that, In step (3), the coolant is dimethyl silicone oil or liquid paraffin; the temperature of the coolant is 0-10℃.

10. A type of Shendan Tongnao Dripping Pill prepared by the preparation method according to any one of claims 1-9.

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