A preparation method of Astragalus Essence oral liquid

Abstract

The present invention relates to the technical field of Chinese medicine oral liquids, and discloses a method for preparing an astragalus essence oral liquid, comprising the following steps: (1) using astragalus coarse powder, percolating and blending to prepare an astragalus essence liquid; (2) adding a stabilizer to the astragalus essence liquid, mixing it, and then high-pressure homogenizing it to obtain the astragalus essence oral liquid; the stabilizer is a polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer having phytic acid and polyglutamic acid grafted sequentially at one or both ends of the molecular chain. By using a special stabilizer, the present invention can form effective medicinal ingredients with poor water solubility into nanoparticles with smaller particle size, and prolong the retention time of the nanoparticles in the gastrointestinal tract, thereby significantly improving the bioavailability of the poorly water-soluble ingredients in the astragalus essence oral liquid.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine oral liquid, in particular to a preparation method of astragalus essence oral liquid. Background Art

[0002] Astragalus, the root of the leguminous plant Astragalus mongolica or Astragalus membranaceus, possesses benefits such as tonifying qi and strengthening the exterior, strengthening the spleen and replenishing the middle, promoting diuresis and detoxification, stopping bleeding, and stabilizing pregnancy. Recent research on the composition and pharmacological effects of Astragalus has shown that its main components include saponins, flavonoids, and polysaccharides, as well as coumarins, trace amounts of folic acid, and various vitamins. Its active ingredients can enhance cardiac contraction, dilate blood vessels, improve skin circulation and nutritional status, protect the liver, prevent hepatic glycogen depletion, lower blood pressure, and promote diuresis. Astragaloside IV is one of the main active ingredients in Astragalus that enhances immune function and is also a quantitative indicator component in various Astragalus preparations.

[0003] Astragalus Essence Oral Liquid is made from Astragalus as raw material through leaching and other processes. It can play the role of nourishing blood and qi, strengthening the body and stopping sweating, and can enhance the body's immune function and cardiac contraction function, improve the body's ability to tolerate hypoxia, reduce platelet adhesion function, and increase red blood cell Na + Pump activity, promote glycosaminoglycan synthesis and inhibit cancer cells, etc.

[0004] Currently, astragalus extract oral liquids are often prepared through percolation, concentration, and liquid preparation. For example, patent CN108066393A discloses a sugar-free astragalus extract oral liquid and its preparation method. The liquid comprises astragalus root as the main ingredient and aspartame, ethylparaben, and lemon essence as the auxiliary ingredients. The liquid is then pre-treated, separated, impregnated, percolated, concentrated, mixed, liquid prepared, filtered, and then bottled to produce the sugar-free astragalus extract oral liquid. In astragalus extract oral liquids prepared using this method, some active ingredients (such as astragaloside IV) are poorly water-soluble, limiting their absorption in the gastrointestinal tract and resulting in low bioavailability. Summary of the Invention

[0005] To address the technical issue of low bioavailability of poorly water-soluble active ingredients in Huangqijing oral liquid, the present invention provides a method for preparing Huangqijing oral liquid. This method utilizes a special stabilizer to transform the poorly water-soluble active ingredients into nanoparticles with a smaller particle size, prolonging their retention time in the gastrointestinal tract and thereby improving the bioavailability of the active ingredients.

[0006] The specific technical solutions of the present invention are:

[0007] A method for preparing Astragalus Extract Oral Liquid comprises the following steps:

[0008] (1) Astragalus coarse powder is used, filtered and blended to prepare an Astragalus extract;

[0009] (2) adding a stabilizer to the astragalus essence liquid, mixing, and then performing high-pressure homogenization to obtain the astragalus essence oral liquid; the stabilizer is a polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer with phytic acid and polyglutamic acid grafted sequentially at one or both ends of the molecular chain.

[0010] Studies have shown that combining water-insoluble drug ingredients with stabilizers to form nanosuspensions can accelerate drug dissolution rates and improve oral bioavailability. The stabilizer used in the present invention includes hydrophobic polypropylene oxide segments in the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer (PEOn-PPOn-PEOn), which can bind to poorly water-soluble ingredients in the Astragalus Extract liquid. The hydrophilic polyethylene oxide segments also enable the components to be well dispersed in water. Combined with high-pressure homogenization, the nanosuspension can be formed, allowing the poorly water-soluble active ingredients to be dispersed in the Astragalus Extract oral liquid as nanoparticles, thereby accelerating their dissolution rate and improving bioavailability.

[0011] On this basis, the present invention sequentially grafts phytic acid and polyglutamic acid onto the ends of the PEOn-PPOn-PEOn molecular chain. Polyglutamic acid has good cell adhesion. When the stabilizer of the present invention combines with the poorly water-soluble active pharmaceutical ingredient to form nanoparticles, the large number of polyglutamic acid segments on the surface of the nanoparticles enable them to adhere well to the gastrointestinal mucosa, prolonging the nanoparticles' gastrointestinal retention time, thereby increasing drug absorption in the digestive tract and further improving oral bioavailability.

[0012] In addition, since hydrogen bonds are easily formed between the adhesion groups and the nanoparticles have a very small particle size, the nanoparticles are prone to agglomeration. However, the present invention uses polyglutamic acid as the adhesive group and introduces phytic acid. The phosphate groups in the phytic acid and the carboxyl groups in the polyglutamic acid can both produce electrostatic repulsion. At the same time, the stabilizer molecular chain can produce steric hindrance. Under the combined effect of the above-mentioned electrostatic repulsion and steric hindrance, the nanoparticles can be effectively prevented from agglomerating, thereby reducing the nanoparticles to a smaller particle size, which is conducive to accelerating drug dissolution.

[0013] Preferably, the astragalus coarse powder is prepared by crushing astragalus slices.

[0014] Preferably, the specific process of step (1) includes the following steps:

[0015] (1.1) Percolation: Use 30-35 vol% alcohol to infiltrate and swell the astragalus powder and percolate to obtain a percolate.

[0016] (1.2) Concentration: The percolate is concentrated to obtain an astragalus concentrate having a relative density of 1.00 to 1.10 at 80°C;

[0017] (1.3) Preparation: Mix the astragalus concentrate with the auxiliary materials, add water and boil, then adjust the pH to 5.5-6.5 to obtain an astragalus extract with a relative density of 1.03-1.09 at 20°C.

[0018] Preferably, in the stabilizer, the polyglutamic acid is poly-L-glutamic acid formed by connecting L-glutamic acid residues through α-amide bonds.

[0019] The poly-L-glutamic acid used in the present invention is composed of L-glutamic acid residues connected by α-amide bonds. It has good adhesion, which enables the nanoparticles to adhere well to the mucosa after entering the gastrointestinal tract, allowing the digestive tract sufficient time to absorb the nanoparticles, thereby effectively improving the bioavailability of the drug. At the same time, poly-L-glutamic acid is highly sensitive to digestive enzymes and will be gradually degraded under the action of digestive enzymes, thereby weakening the adhesion. Therefore, it can prevent the nanoparticles from stably adhering to the mucosa for a long time, which is not conducive to the digestive tract's overall absorption of the nanoparticles.

[0020] Preferably, in the stabilizer, the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer is Pluronic F68 and / or Pluronic F127.

[0021] Preferably, in step (2), the method for preparing the stabilizer comprises the following steps:

[0022] (2.1) Phytic acid is grafted onto the molecular chain ends of polyethylene oxide-polypropylene oxide-polyethylene oxide copolymers through the reaction between hydroxyl groups and phosphoric acid groups to obtain PA-PEOn-PPOn-PEOn-PA;

[0023] (2.2) Through the reaction between amino groups and phosphate groups, polyglutamic acid is grafted onto the molecular chain end of PA-PEOn-PPOn-PEOn-PA to obtain a stabilizer.

[0024] Preferably, in step (2.2), the weight average molecular weight of the polyglutamic acid is 1000 to 2000 Da.

[0025] Preferably, the preparation method of the stabilizer specifically comprises the following steps:

[0026] (2.1) Dissolving polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer in water to obtain solution A; dissolving phytic acid in water, and adding sodium carbonate until the pH of the solution is 7.5-8.5 to obtain solution B; controlling the temperature at 70-90°C, adding solution A dropwise to solution B in batches while stirring, stirring for 0.5-1 hour after each addition, and then removing impurities to obtain a PA-PEOn-PPOn-PEOn-PA solution;

[0027] (2.2) Dissolve polyglutamic acid in water to obtain solution C; control the temperature to 80-90°C, and add solution C dropwise to the PA-PEOn-PPOn-PEOn-PA solution while stirring. After the addition is complete, continue stirring for 1.5-2.5 hours, and then separate the product to obtain a stabilizer.

[0028] Preferably, in steps (2.1) to (2.2), the molar ratio of the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer, phytic acid and polyglutamic acid is 1:2.5-3.5:1.5-2.0.

[0029] The molar amounts of the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer and polyglutamic acid are calculated by dividing the mass by the weight average molecular weight.

[0030] Preferably, in step (2.1), in the solution A, the mass ratio of the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer to water is 1 to 5:100.

[0031] Preferably, in step (2.1), the mass ratio of phytic acid to water in the solution B is 20-25:100.

[0032] Preferably, in step (2.2), in the solution C, the mass ratio of polyglutamic acid to water is 1 to 5:100.

[0033] Preferably, the specific process of step (1.1) includes the following steps:

[0034] (1.1.1) Add 30-35 vol% alcohol to the astragalus powder, mix thoroughly, and allow to soak for 20-30 minutes. Then, place the mixture in a percolation apparatus. Open the outlet and add 30-35 vol% alcohol to the percolation apparatus. Once the percolation liquid flows out of the outlet, close the outlet and continue adding 30-35 vol% alcohol to the percolation apparatus. Allow the mixture to soak for 20-30 hours.

[0035] (1.1.2) Open the outlet of the percolation device and perform percolation, continuously adding 30-35 vol% alcohol, sieve, and collect the percolation liquid.

[0036] Preferably, in step (1.1.2), the diafiltration flow rate is 2 to 4 mL / (min·kg).

[0037] Preferably, the mass ratio of the astragalus coarse powder to the stabilizer is 1000:2-10.

[0038] Preferably, in step (2), the pressure of the high-pressure homogenization is 80 to 90 MPa, and the number of cycles is 15 to 30 times.

[0039] Compared with the prior art, the present invention has the following advantages:

[0040] (1) The stabilizer used in the present invention can prolong the retention time of the nanoparticles containing the active pharmaceutical ingredient in the gastrointestinal tract by sequentially grafting phytic acid and polyglutamic acid onto the ends of the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer molecular chain, while also preventing the nanoparticles from agglomerating, thereby significantly improving the bioavailability of the poorly water-soluble components in the Huangqijing oral liquid.

[0041] (2) The present invention uses poly-L-glutamic acid as an adhesion group in the stabilizer, which can moderately prolong the retention time of the nanoparticles in the gastrointestinal tract. While increasing the absorption of the nanoparticles by extending the retention time, it also prevents the nanoparticles from stably adhering to the gastrointestinal mucosa for a long time, which is not conducive to their absorption. Therefore, the oral bioavailability of the drug can be better improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The blood drug concentration-time curve of the Astragalus Essence oral solution after administration prepared according to the steps of Examples 1 and 4 and Comparative Examples 1 and 2;

[0043] Figure 2 This is the blood concentration-time curve of the Astragalus Essence Oral Liquid after administration, prepared according to the steps of Example 2;

[0044] Figure 3 The blood concentration-time curve of the Astragalus Essence oral solution prepared according to the steps of Example 3 after administration. DETAILED DESCRIPTION

[0045] The present invention will be further described below with reference to the embodiments.

[0046] Overall embodiment

[0047] A method for preparing Astragalus Extract Oral Liquid comprises the following steps:

[0048] (1) Astragalus coarse powder is used, filtered and blended to prepare an Astragalus extract;

[0049] (2) adding a stabilizer to the astragalus essence liquid, mixing, and then performing high-pressure homogenization to obtain the astragalus essence oral liquid; the stabilizer is a polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer with phytic acid and polyglutamic acid grafted sequentially at one or both ends of the molecular chain.

[0050] As a specific implementation, the specific process of step (1) includes the following steps:

[0051] (1.1) Grinding: Grinding the Astragalus membranaceus slices to obtain coarse Astragalus membranaceus powder;

[0052] (1.2) Percolation:

[0053] (1.2.1) Add 30-35 vol% alcohol to the astragalus powder, mix well, and allow to soak for 20-30 minutes. Then, place the mixture in a percolation apparatus. Open the outlet and add 30-35 vol% alcohol to the percolation apparatus. When the percolation liquid flows out of the outlet, close the outlet and continue adding 30-35 vol% alcohol to the percolation apparatus. Allow the mixture to soak for 20-30 hours.

[0054] (1.2.2) Open the outlet of the percolation apparatus and perform percolation at a flow rate of 2–4 mL / (min·kg), continuously adding 30–35 vol% alcohol. Sieve and collect the percolate.

[0055] (1.3) Concentration: The percolate is concentrated to obtain an astragalus concentrate having a relative density of 1.00 to 1.10 at 80°C;

[0056] (1.4) Preparation: Mix the astragalus concentrate with the auxiliary materials, add water and boil, then adjust the pH to 5.5-6.5 and control the relative density at 20°C to 1.03-1.09.

[0057] In the above specific embodiment, optionally, in step (1.4), the auxiliary materials include honey and ethylparaben; the mass ratio of the astragalus coarse powder, honey and ethylparaben is 1000:100-150:0.30-0.35; and the specific process of mixing the astragalus concentrate with the auxiliary materials includes the following steps:

[0058] (1.4.1) Dissolve honey in 1 to 1.5 times its mass of water and sieve to obtain honey water;

[0059] (1.4.2) Dissolve ethyl paraben in 3.5 to 4.5 times its mass of alcohol to obtain an ethyl paraben solution;

[0060] (1.4.3) Mix the Astragalus concentrate, honey water and ethylparaben solution evenly.

[0061] As a specific implementation manner, the mass ratio of the astragalus coarse powder to the stabilizer is 1000:2-10.

[0062] As a specific implementation, in step (2), the pressure of the high-pressure homogenization is 80 to 90 MPa, and the number of cycles is 15 to 30 times.

[0063] As a specific embodiment, in the stabilizer, the polyglutamic acid is poly-L-glutamic acid formed by connecting L-glutamic acid residues through α-amide bonds, and the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer is Pluronic F68 and / or Pluronic F127.

[0064] As a specific embodiment, in step (2), the method for preparing the stabilizer comprises the following steps:

[0065] (2.1) Phytic acid is grafted onto the molecular chain ends of polyethylene oxide-polypropylene oxide-polyethylene oxide copolymers through the reaction between hydroxyl groups and phosphoric acid groups to obtain PA-PEOn-PPOn-PEOn-PA;

[0066] (2.2) Through the reaction between amino groups and phosphate groups, polyglutamic acid is grafted onto the molecular chain end of PA-PEOn-PPOn-PEOn-PA to obtain a stabilizer.

[0067] In the above specific implementation:

[0068] Optionally, the specific process of step (2.1) includes the following steps: dissolving polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer in water at a mass ratio of 1 to 5:100 to obtain solution A; dissolving phytic acid in water at a mass ratio of 20 to 25:100, controlling the molar ratio of polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer to phytic acid to be 1:2.5 to 3.5, adding sodium carbonate to the solution pH to 7.5 to 8.5, and obtaining solution B; controlling the temperature to 70 to 90°C, adding solution A dropwise to solution B in batches under stirring, stirring for 0.5 to 1 hour after each batch is added, and then removing impurities to obtain a PA-PEOn-PPOn-PEOn-PA solution.

[0069] Optionally, the specific process of step (2.2) includes the following steps: dissolving polyglutamic acid in water at a mass ratio of 1 to 5:100, controlling the molar ratio of polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer to polyglutamic acid to be 1:1.5 to 2.0, and obtaining solution C; controlling the temperature to 80 to 90°C, and adding solution C dropwise to the PA-PEOn-PPOn-PEOn-PA solution under stirring. After the dropwise addition is completed, stirring is continued for 1.5 to 2.5 hours, and then the product is separated to obtain a stabilizer.

[0070] Optionally, in step (2.2), the weight average molecular weight of the polyglutamic acid is 1000 to 2000 Da.

[0071] Example 1

[0072] The stabilizer PGlu-PA-Pluronic F68-PA-PGlu was prepared by the following steps:

[0073] (I) Take 20g of Pluronic F68 (M w =8400Da), add 30 times the mass of purified water, stir to dissolve, and obtain solution A for standby use.

[0074] (II) 4.0 g of phytic acid was added to 5 times its mass of purified water, stirred to dissolve, and sodium carbonate was added until the pH of the solution reached 7.5 to obtain Solution B, which was set aside.

[0075] (III) Controlling the temperature at 85 ± 5°C, solution A was added dropwise to solution B in three batches with stirring. Stirring was continued for 0.5 h after each addition. The solution was then dialyzed in purified water using a 7000 molecular weight cutoff dialysis bag for three days, with the purified water replaced every 12 h, to obtain a PA-Pluronic F68-PA solution.

[0076] (IV) Take 4.0g poly-L-glutamic acid (M w =1100Da; composed of L-glutamic acid residues connected by α-amide bonds), added to 20 times the mass of purified water, stirred to dissolve, and obtained solution C for standby use.

[0077] (V) Controlling the temperature at 85±5°C, solution C was added dropwise to the PA-Pluronic F68-PA solution with stirring. After the addition was complete, stirring was continued for 1.5 hours. The solution was then dialyzed in purified water using a dialysis bag with a molecular weight cutoff of 7000 for 5 days, with the purified water replaced every 12 hours. The solution was then freeze-dried to obtain the stabilizer PGlu-PA-Pluronic F68-PA-PGlu.

[0078] The stabilizer prepared in this example was used to prepare the Astragalus Extract oral solution. The specific steps are as follows:

[0079] (1) Crushing: Take 1000g of Astragalus slices and crush them to make Astragalus coarse powder.

[0080] (2) Percolation:

[0081] (2.1) Wetting and Soaking: Place the coarse Astragalus powder in a soaking tank, add 1.35 L of 30 vol% alcohol, mix thoroughly, and soak for 30 minutes. Load the moistened and expanded powder into the percolation tank in batches, flattening and compacting the powder after each addition. Open the percolation outlet valve and slowly add 30 vol% alcohol to the percolation tank. Once the percolation liquid flows out of the outlet, close the valve and continue adding 30 vol% alcohol until it is 20 cm above the powder, for a total of 1.35 L of 30 vol% ethanol. Soak for 24 hours to allow the powder to fully expand.

[0082] (2.2) Percolation: Open the percolation tank outlet and percolate at a theoretical flow rate of 2-4 mL / (min·kg). That is, control the flow rate within the range of 2.7-5.0 L / min during percolation. Continuously add 30 vol% alcohol. Adjust the high-level tank valve so that the liquid level in the percolation tank is always more than 20 cm above the powder. Pass the percolate through a 120-mesh sieve and collect the percolate.

[0083] (3) Concentration: The percolate obtained in step (2) was transferred to an evaporation concentrator for concentration, during which the temperature was controlled at 80±5°C and the vacuum degree was 0.065±0.015 MPa to obtain an astragalus concentrate having a relative density of 1.10 (measured at 80°C). The astragalus concentrate was refrigerated and allowed to stand for more than 10 hours to keep the temperature of the astragalus concentrate below 10°C.

[0084] (4) Preparation:

[0085] (4.1) Preparation of honey water: Take 150g honey, add 1 times the weight of purified water, place in a sugar dissolving tank, heat and stir, boil for 30 minutes, filter through a 120-mesh sieve, and obtain honey water for later use.

[0086] (4.2) Preparation of ethyl hydroxybenzoate solution: Take 0.35 g of ethyl hydroxybenzoate and add it to 4 times the mass of 95 vol% alcohol. Stir to dissolve the mixture to obtain the ethyl hydroxybenzoate solution, which is set aside.

[0087] (4.3) The astragalus concentrate prepared in step (3) was extracted into a preparation tank, honey and ethylparaben were added, and the mixture was stirred evenly. The total volume was adjusted to 2.1 L with purified water, and the mixture was boiled for 30 minutes. The pH value was adjusted to 6.0 with medicinal sodium hydroxide to obtain an astragalus extract liquid with a relative density of 1.06 (measured at 20°C).

[0088] (4.4) 8 g of the stabilizer PGlu-PA-Pluronic F68-PA-PGlu prepared in this example was added to the Astragalus extract liquid, stirred evenly, and then subjected to high-pressure homogenization at 90 MPa for 15 cycles to obtain the Astragalus extract oral liquid.

[0089] Example 2

[0090] The stabilizer PGlu-PA-Pluronic F68-PA-PGlu was prepared by the following steps:

[0091] (I) Take 20g of Pluronic F68 (M w =8400Da), add 30 times the mass of purified water, stir to dissolve, and obtain solution A for standby use.

[0092] (II) 4.5 g of phytic acid was added to 5 times the mass of purified water, stirred to dissolve, and sodium carbonate was added until the pH of the solution reached 8.5 to obtain Solution B, which was set aside.

[0093] (III) Controlling the temperature at 75 ± 5°C, solution A was added dropwise to solution B in three batches with stirring. Stirring was performed for 1 hour after each addition. The solution was then dialyzed in purified water using a 7000 molecular weight cutoff dialysis bag for 3 days, with the purified water replaced every 12 hours, to obtain a PA-Pluronic F68-PA solution.

[0094] (IV) Take 4.5g poly-L-glutamic acid (M w =1100Da; composed of L-glutamic acid residues connected by α-amide bonds), added to 20 times the mass of purified water, stirred to dissolve, and obtained solution C for standby use.

[0095] (V) Controlling the temperature at 85±5°C, solution C was added dropwise to the PA-Pluronic F68-PA solution with stirring. After the addition was complete, stirring was continued for 1.5 hours. The solution was then dialyzed in purified water using a dialysis bag with a molecular weight cutoff of 7000 for 5 days, with the purified water replaced every 12 hours. The solution was then freeze-dried to obtain the stabilizer PGlu-PA-Pluronic F68-PA-PGlu.

[0096] The stabilizer prepared in this example was used to prepare the Astragalus Extract oral solution. The specific steps are as follows:

[0097] (1) Using the same steps as in Example 1, prepare the Astragalus extract solution;

[0098] (2) 8 g of the stabilizer PGlu-PA-Pluronic F68-PA-PGlu prepared in this example was added to the Astragalus extract liquid, stirred evenly, and then subjected to high-pressure homogenization at a pressure of 90 MPa for 20 cycles to obtain the Astragalus extract oral liquid.

[0099] Example 3

[0100] The stabilizer PGlu-PA-Pluronic F68-PA-PGlu was prepared by the following steps:

[0101] (I) Take 20g of Pluronic F68 (M w =8400Da), add 30 times the mass of purified water, stir to dissolve, and obtain solution A for standby use.

[0102] (II) 5.5 g of phytic acid was added to 4 times its mass of purified water, stirred to dissolve, and sodium carbonate was added until the pH of the solution reached 8.0 to obtain Solution B, which was set aside.

[0103] (III) Controlling the temperature at 85 ± 5°C, solution A was added dropwise to solution B in three batches with stirring. Stirring was continued for 0.5 h after each addition. The solution was then dialyzed in purified water using a 7000 molecular weight cutoff dialysis bag for three days, with the purified water replaced every 12 h, to obtain a PA-Pluronic F68-PA solution.

[0104] (IV) Take 5.2g poly-L-glutamic acid (M w =1100Da; composed of L-glutamic acid residues connected by α-amide bonds), added to 20 times the mass of purified water, stirred to dissolve, and obtained solution C for standby use.

[0105] (V) Controlling the temperature at 75±5°C, solution C was added dropwise to the PA-Pluronic F68-PA solution with stirring. After the addition was complete, stirring was continued for 2.5 hours. The solution was then dialyzed in purified water using a dialysis bag with a molecular weight cutoff of 7000 for 5 days, with the purified water replaced every 12 hours. The solution was then freeze-dried to obtain the stabilizer PGlu-PA-Pluronic F68-PA-PGlu.

[0106] The stabilizer prepared in this example was used to prepare the Astragalus Extract oral solution. The specific steps are as follows:

[0107] (1) Using the same steps as in Example 1, prepare the Astragalus extract solution;

[0108] (2) 8 g of the stabilizer PGlu-PA-Pluronic F68-PA-PGlu prepared in this example was added to the Astragalus extract liquid, stirred evenly, and then subjected to high-pressure homogenization with the pressure set to 80 MPa and the number of cycles being 15 to obtain the Astragalus extract oral liquid.

[0109] Example 4

[0110] The stabilizer PGlu-PA-Pluronic F68-PA-PGlu was prepared by the following steps:

[0111] (I) Take 20g of Pluronic F68 (M w =8400Da), add 30 times the mass of purified water, stir to dissolve, and obtain solution A for standby use.

[0112] (II) 4.0 g of phytic acid was added to 5 times its mass of purified water, stirred to dissolve, and sodium carbonate was added until the pH of the solution reached 7.5 to obtain Solution B, which was set aside.

[0113] (III) Controlling the temperature at 85 ± 5°C, solution A was added dropwise to solution B in three batches with stirring. Stirring was continued for 0.5 h after each addition. The solution was then dialyzed in purified water using a 7000 molecular weight cutoff dialysis bag for three days, with the purified water replaced every 12 h, to obtain a PA-Pluronic F68-PA solution.

[0114] (IV) Take 4.0g γ-polyglutamic acid (M w =1100Da; composed of D-glutamic acid residues connected by γ-amide bonds), added to 20 times the mass of purified water, stirred to dissolve, and obtained solution C for standby use.

[0115] (V) Controlling the temperature at 85±5°C, solution C was added dropwise to the PA-Pluronic F68-PA solution with stirring. After the addition was complete, stirring was continued for 1.5 hours. The solution was then dialyzed in purified water using a dialysis bag with a molecular weight cutoff of 7000 for 5 days, with the purified water replaced every 12 hours. The solution was then freeze-dried to obtain the stabilizer PGlu-PA-Pluronic F68-PA-PGlu.

[0116] The stabilizer prepared in this example was used to prepare the Astragalus Extract oral solution. The specific steps are as follows:

[0117] (1) Using the same steps as in Example 1, prepare the Astragalus extract solution;

[0118] (2) 8 g of the stabilizer PGlu-PA-Pluronic F68-PA-PGlu prepared in this example was added to the Astragalus extract liquid, stirred evenly, and then subjected to high-pressure homogenization at a pressure of 90 MPa for 15 cycles to obtain the Astragalus extract oral liquid.

[0119] Comparative Example 1

[0120] Unmodified Pluronic F68 was used to prepare Astragalus Extract Oral Liquid. The specific steps are as follows:

[0121] (1) Using the same steps as in Example 1, prepare the Astragalus extract solution;

[0122] (2) 8 g of Pluronic F68 (Mw = 8400 Da) was added to the Astragalus extract solution, stirred evenly, and then subjected to high-pressure homogenization with the pressure set to 90 MPa and the number of cycles being 15 to obtain the Astragalus extract oral solution.

[0123] Comparative Example 2

[0124] The stabilizer PGlu-Pluronic F68-PGlu was prepared by the following steps:

[0125] Take 20g of Pluronic F68 (M w =8400Da) and 4.0g poly-L-glutamic acid (M w =1100 Da; composed of L-glutamic acid residues linked by α-amide bonds) was added to 300 mL of DMF and stirred to dissolve. 1.5 g of N,N'-diisopropylcarbodiimide (DIC) and 0.15 g of 4-dimethylaminopyridine (DMAP) were then added. The temperature was controlled at 30±5°C and stirred for 24 hours. Ether was added for precipitation, followed by washing three times with ether and dissolving in purified water. The product was then dialyzed in purified water using a dialysis bag with a molecular weight cutoff of 7000 for five days, with the purified water replaced every 12 hours. The product was then freeze-dried to obtain the stabilizer PGlu-Pluronic F68-PGlu.

[0126] The stabilizer prepared in this comparative example was used to prepare Astragalus Extract Oral Liquid, and the specific steps were as follows:

[0127] (1) Using the same steps as in Example 1, prepare the Astragalus extract solution;

[0128] (2) 8 g of the stabilizer PGlu-Pluronic F68-PGlu prepared in this comparative example was added to the Astragalus extract liquid, stirred evenly, and then subjected to high-pressure homogenization with the pressure set to 90 MPa and the number of cycles being 15 to obtain the Astragalus extract oral liquid.

[0129] Test Example 1: Particle Size Test

[0130] The particle size of the nanoparticles in the Astragalus Extract oral liquid prepared according to the steps of Examples 1 to 4 and Comparative Examples 1 to 2 was detected. The average particle size PS and polydispersity index PDI are shown in Table 1.

[0131] Table 1

[0132]

[0133]

[0134] Test Example 2: Pharmacokinetic Test

[0135] Adult rats were divided into 6 groups (6 rats in each group, half male and half female), and the oral solution of Astragalus Extract prepared according to the steps of Examples 1 to 4 and Comparative Examples 1 to 2 was gavage-administered at a dose of 500 mg / kg. Blood was collected from the orbits at 0 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h, 9 h, 12 h, and 24 h after administration. The blood concentration of Astragaloside IV was detected, and the blood concentration-time curve was plotted. The results are shown in FIG. Figures 1 to 3 .

[0136] According to Table 1 and Figure 1 , we can see that:

[0137] (1) Compared with Comparative Example 1, Example 1 has a higher peak blood drug concentration and can maintain a high blood drug concentration for a longer period of time. This is because Example 1, by grafting phytic acid and polyglutamic acid onto the ends of the PEOn-PPOn-PEOn molecular chain, can utilize the good adhesion of polyglutamic acid to make the nanoparticles containing the active drug ingredient adhere to the gastrointestinal mucosa, prolonging the gastrointestinal retention time of the nanoparticles, thereby increasing drug absorption in the digestive tract.

[0138] (2) Compared with Comparative Example 2, Example 1 has a significantly smaller average particle size and a larger peak blood drug concentration. This is because: Comparative Example 2 does not introduce phytic acid into the hydrophilic segment of the stabilizer, so the electrostatic repulsion between the nanoparticles is weak. Since hydrogen bonds are easily formed between the adhesion groups and the nanoparticle size is very small, the nanoparticles containing the active ingredient of the drug are prone to agglomeration. In contrast, Example 1 introduces phytic acid into the stabilizer, which can increase the electrostatic repulsion between the nanoparticles, prevent their agglomeration, and thus accelerate drug dissolution.

[0139] (3) Compared with Example 1, Example 4 has a lower peak blood drug concentration and a lower blood drug concentration in the later period. This is because: Example 4 uses γ-polyglutamic acid, which is composed of D-glutamic acid residues connected by γ-amide bonds and is not easily degraded by digestive tract enzymes. Therefore, the nanoparticles containing the active pharmaceutical ingredient will stably adhere to the gastrointestinal mucosa for a long time and are not easily absorbed by the digestive tract; while the poly-L-glutamic acid used in Example 1 is composed of L-glutamic acid residues connected by α-amide bonds and has good sensitivity to digestive enzymes. Under the action of digestive enzymes, it will be gradually degraded, its adhesion will be weakened, and it will be absorbed by the digestive tract.

[0140] Unless otherwise specified, the raw materials and equipment used in the present invention are commonly used in the art; the methods used in the present invention are conventional methods in the art unless otherwise specified.

[0141] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent transformation made to the above embodiment based on the technical essence of the present invention still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing Astragalus Essence Oral Liquid, characterized in that: The following steps are involved: (1) Astragalus crude powder is used to prepare an Astragalus essence liquid through percolation and blending; wherein the percolation is to soak, swell and percolate the Astragalus crude powder with 30-35 vol% alcohol to obtain a percolation liquid; (2) Add a stabilizer to the Astragalus extract liquid, mix well, and then homogenize under high pressure to obtain the Astragalus extract oral liquid; the stabilizer is a polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer with phytic acid and polyglutamic acid grafted sequentially at one or both ends of the molecular chain, and the preparation steps are as follows: phytic acid is grafted to the molecular chain end of the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer through the reaction between the hydroxyl group and the phosphate group to obtain PA-PEOn-PPOn-PEOn-PA, and polyglutamic acid is grafted to the molecular chain end of PA-PEOn-PPOn-PEOn-PA through the reaction between the amino group and the phosphate group to obtain the stabilizer; polyglutamic acid is poly-L-glutamic acid formed by connecting L-glutamic acid residues through α-amide bonds.

2. The preparation method according to claim 1, wherein In step (1), the astragalus coarse powder is prepared by crushing astragalus slices.

3. The preparation method according to claim 1, wherein The specific process of step (1) includes the following steps: (1.1) Percolation: Use 30-35 vol% alcohol to infiltrate and swell the astragalus powder and percolate to obtain the percolation solution. (1.2) Concentration: The percolate was concentrated to obtain an Astragalus membranaceus concentrate having a relative density of 1.00 to 1.10 at 80°C; (1.3) Preparation: Mix the astragalus concentrate with the excipients, add water and boil, then adjust the pH to 5.5-6.5 to obtain an astragalus extract with a relative density of 1.03-1.09 at 20°C.

4. The preparation method according to claim 1, wherein The preparation method of the stabilizer specifically comprises the following steps: (2.1) Dissolve polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer in water to obtain solution A; dissolve phytic acid in water and add sodium carbonate until the pH of the solution is 7.5-8.5 to obtain solution B; control the temperature at 70-90°C and add solution A dropwise to solution B in batches while stirring. Stir for 0.5-1 h after each addition, and then remove impurities to obtain a PA-PEOn-PPOn-PEOn-PA solution; (2.2) Dissolve polyglutamic acid in water to obtain solution C. Control the temperature to 80-90°C and add solution C dropwise to the PA-PEOn-PPOn-PEOn-PA solution while stirring. After the addition is complete, continue stirring for 1.5-2.5 hours, and then separate the product to obtain a stabilizer.

5. The preparation method according to claim 4, wherein In steps (2.1) to (2.2), the molar ratio of the polyethylene oxide-polypropylene oxide-polyethylene oxide copolymer, phytic acid and polyglutamic acid is 1:2.5~3.5:1.5~2.

0.

6. The preparation method according to claim 3, wherein The specific process of step (1.1) includes the following steps: (1.1.1) Add 30–35 vol% alcohol to the astragalus powder, mix thoroughly, and allow to soak for 20–30 min. Then, place the powder in a percolation apparatus. Open the outlet and add 30–35 vol% alcohol. Once the percolation liquid begins to flow, close the outlet and continue adding 30–35 vol% alcohol to the percolation apparatus. Allow the percolation to soak for 20–30 h. (1.1.2) Open the outlet of the percolation device and perform percolation, continuously adding 30-35 vol% alcohol. Sieve and collect the percolation liquid.

7. The preparation method according to claim 6, wherein In step (1.1.2), the diafiltration flow rate is 2-4 mL / (min•kg).

8. The preparation method according to claim 6 or 7, wherein In step (2), the pressure of the high-pressure homogenization is 80-90 MPa.

9. The preparation method according to claim 8, wherein In step (2), the high-pressure homogenization is repeated 15 to 30 times.

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