Traditional Chinese medicine compound oral liquid and preparation process thereof

Abstract

Compared with the prior art, the traditional Chinese medicine compound oral liquid is mainly used for invigorating qi and blood, regulating yin and yang, nourishing liver and kidney, strengthening spleen and stomach, strengthening muscles and bones and the like, a plurality of traditional Chinese medicine components are compounded and decocted to obtain liquid medicine, and finally specific modified polysaccharide, steviosin, sodium benzoate and ethylparaben are added, so that the traditional Chinese medicine compound oral liquid is prepared. The modified polysaccharide is screened and optimized and is added into the compound oral liquid, and the problems of serious wall hanging and high liquid medicine waste rate in the prior art are solved by reducing the low-temperature storage wall hanging rate and the hydrolysis rate in storage stability on the premise of not influencing the medicine effect and safety.

Description

Technical Field

[0001] The present invention relates to the technical field of oral liquids, and particularly relates to a traditional Chinese medicine compound oral liquid and a preparation process thereof. Background Art

[0002] Traditional Chinese medicine compound oral liquids may face the problem of waste in the bottle due to factors such as the characteristics of the ingredients, the production process, and the storage conditions. Polysaccharides, mucilages, etc. in their ingredients are likely to make the liquid medicine viscous, with poor fluidity and wall sticking; or if the concentration and drying processes are not properly controlled during production, such as too high heating temperature and too long time in the concentration stage, resulting in excessive evaporation of water, the liquid medicine will become too thick; and low storage temperature in winter will also increase the viscosity of the liquid medicine, making it easy to cause residue in the bottle and waste during consumption.

[0003] In the prior art, the above situation can be alleviated by the following methods. For example, from the packaging aspect, superhydrophobic coating treatment is used to reduce the residue on the bottle wall; natural surfactants or cyclodextrin carriers can also be added to form an inclusion system to improve fluidity; or natural plant extracts are added to construct a dynamic rheological balance to improve solubility and stability; appropriately shaking the medicine bottle before use by the patient also helps to reduce wall sticking and suck out as much liquid medicine as possible. Production enterprises can optimize the production process, adjust the formula, etc. to control the viscosity and fluidity of the liquid medicine, significantly improving economy, convenience, and safety while ensuring the efficacy.

[0004] CN108403760A discloses a preparation method of a compound sedative traditional Chinese medicine oral liquid. The method includes steps such as weighing traditional Chinese medicine raw materials according to the prescription ratio, performing water decoction and alcohol precipitation extraction on the traditional Chinese medicine raw materials, adding flavoring agents and pH regulators, and filling and sterilizing. The preparation method disclosed by the invention improves the problem of poor clarity of the oral liquid produced by the same type of prescription process in the prior art through process improvements such as the concentration degree after water decoction extraction of the medicinal materials, the alcohol precipitation concentration, the concentration degree after alcohol precipitation, and the sterilization process conditions. The method of the invention not only improves the appearance and properties of the oral liquid preparation product, but also improves the storage stability of the preparation.

[0005] CN113350459A discloses a preparation method and a quality control method of a traditional Chinese medicine oral liquid for treating lung cancer. The invention selects two traditional Chinese medicines, ginseng and coix seed, and obtains the finished product through steps such as decocting, filtering, concentrating, alcohol precipitation, formulation, three-phase separation, and filtering; solves the problems of turbidity and easy precipitation of the liquid medicine in the original process, optimizes the product process, improves the product taste, uses fewer raw materials, and has simple process operation, suitable for industrial production. The traditional Chinese medicine oral liquid of the invention invigorates the spleen and benefits the lung, can significantly improve symptoms such as weakness of the body, shortness of breath and spontaneous sweating, and loss of appetite, has no toxic and side effects, and is beneficial to popularization and application. Summary of the Invention

[0006] In view of the above defects of the prior art, the technical problem to be solved by the present invention is to provide a traditional Chinese medicine compound oral liquid, which is mainly used for tonifying qi and blood, regulating yin and yang, nourishing the liver and kidneys, strengthening the spleen and stomach, strengthening the muscles and bones, etc. Optimizing the components can reduce the problems of serious wall sticking, high liquid waste rate, and high hydrolysis rate in storage stability caused by low-temperature storage at 5-10°C.

[0007] To achieve the above object, the present invention provides a traditional Chinese medicine compound oral liquid.

[0008] The preparation method of the traditional Chinese medicine compound oral liquid is as follows: it is obtained by the steps of soaking the medicinal materials, decocting the liquid medicine, and combining the liquid medicine. In the step of combining the liquid medicine, modified polysaccharide is added.

[0009] The preparation method of the modified polysaccharide is as follows, by weight:

[0010] Add 4-6 parts of polysaccharide to 80-120 parts of water, add 15-20 parts of sodium hydroxide, stir at 45-55°C for 1-2 hours, add 1-2 parts of chloroacetic acid, stir at 50-60°C for 2-4 hours, dropwise add glacial acetic acid to adjust the pH to neutral, add 80-120 parts of absolute ethanol and let stand for 24 hours, centrifuge 2-4 times, collect the precipitate and dry it at 40-50°C to obtain the modified polysaccharide.

[0011] Or, add 4-6 parts of polysaccharide to 300-400 parts of water, add 1-2 parts of sodium sulfate and 40-60 parts of 0.1-0.2 g / mL sodium tripolyphosphate aqueous solution, adjust the pH to neutral with food-grade sodium hydroxide, stir at 75-85°C for 1-3 hours, cool to room temperature, dialyze to remove salts, and freeze-dry to obtain the modified polysaccharide;

[0012] Or, add 4-6 parts of polysaccharide to 80-120 parts of water, add sodium hydroxide to adjust the pH to 8.5-9.5 and stir for 10-30 minutes, keep the pH between 8.0-8.5 and dropwise add 80-120 parts of acetic anhydride, stir at 35-45°C for 1-3 hours, cool to room temperature, dropwise add citric acid aqueous solution to adjust the pH to neutral, centrifuge 2-4 times to remove insoluble impurities, concentrate to 40-60 parts at 40-50°C, add 40-60 parts of ethanol aqueous solution and stir for 0.5-1 hour, centrifuge 2-4 times to remove insoluble impurities, concentrate and dry at 40-50°C, then add it to 80-120 parts of water and continue to stir for 0.5-1.5 hours to obtain a clear liquid, and concentrate and dry at 70-80°C to obtain the modified polysaccharide;

[0013] Alternatively, add 4 - 6 parts of polysaccharide to 80 - 120 parts of water, add 15 - 20 parts of sodium hydroxide, stir at 45 - 55 °C for 1 - 2 hours, add 1 - 2 parts of chloroacetic acid, stir at 50 - 60 °C for 2 - 4 hours, adjust the pH to neutral by dropping glacial acetic acid, add 80 - 120 parts of absolute ethanol, let stand for 24 hours, centrifuge 2 - 4 times, collect the precipitate, dry at 40 - 50 °C, take 4 - 6 parts of carboxymethylated modified Tremella polysaccharide and mix and compound it with 0.2 - 0.6 parts of fucoidan to obtain the modified polysaccharide.

[0014] The citric acid aqueous solution is a 20 - 40 wt% citric acid aqueous solution.

[0015] The ethanol aqueous solution is a 60 - 80 wt% ethanol aqueous solution.

[0016] Specifically, the preparation method of the traditional Chinese medicine compound oral liquid includes the following steps, by weight:

[0017] (1) Medicinal material soaking: Put 6 - 10 parts of ginseng, 3 - 5 parts of black wolfberry, 6 - 10 parts of rehmannia root, 4 - 8 parts of anemarrhena rhizome, 4 - 8 parts of phellodendron bark, 6 - 10 parts of astragalus root, 4 - 6 parts of Chinese yam, 6 - 10 parts of glossy privet fruit, 4 - 6 parts of bird vetch root, 6 - 10 parts of polygonatum rhizome into a container, add 150 - 250 parts of water to submerge the medicinal materials, soak for 30 - 60 minutes to obtain a mixed medicinal liquid;

[0018] (2) Medicinal liquid decocting: Decoct the mixed medicinal liquid twice. For the first decoction, add 300 - 500 parts of water and decoct for 90 - 120 minutes; for the second decoction, add 200 - 400 parts of water and decoct for 90 - 120 minutes, and combine to obtain the decocted medicinal liquid;

[0019] (3) Medicinal liquid combination: Add 4 - 8 parts of modified polysaccharide, 1 - 2 parts of steviol glycoside, 0.1 - 0.3 parts of sodium benzoate, 0.05 - 0.1 parts of ethylparaben to the decocted medicinal liquid, continue to stir for 10 - 20 minutes, let stand for 24 hours, filter through a 0.3 - 0.5 μm nylon membrane, collect the filtrate to obtain the traditional Chinese medicine compound oral liquid.

[0020] In the step (1), the height of the water submerging the medicinal materials is 2 - 4 cm.

[0021] The traditional Chinese medicine compound oral liquid is a brown to yellowish - brown clear liquid, with a slight odor and a sweet and slightly bitter taste.

[0022] The usage of the traditional Chinese medicine compound oral liquid is oral administration; the dosage is 10 mL once, 2 - 3 times a day.

[0023] The traditional Chinese medicine compound oral liquid is mainly used for: tonifying qi and blood, regulating yin and yang, nourishing the liver and kidney, strengthening the spleen and stomach, and strengthening the muscles and bones; it is used for the symptoms of weakness in the elderly, mental fatigue, dizziness, soreness and weakness of the waist and legs, blurred vision and tinnitus, forgetfulness and insomnia, palpitations, shortness of breath, edema, frequent urination at night, etc. caused by the deficiency of the liver and kidney due to physical weakness; it can also be used as adjuvant treatment for hypertensive patients with hyperlipidemia.

[0024] The traditional Chinese medicine compound oral liquid of the present invention is obtained by soaking and decocting the traditional Chinese medicine components of ginseng, black fruit wolfberry, rehmannia root, anemarrhena rhizome, phellodendron bark, astragalus root, Chinese yam, glossy privet fruit, golden bract tree root, and polygonatum rhizome to obtain a medicinal liquid, and adding modified polysaccharide, steviol glycoside, sodium benzoate, and ethylparaben, mixing and then filtering to obtain the traditional Chinese medicine compound oral liquid.

[0025] Ginseng: Slightly warm in nature, sweet and slightly bitter in taste, belonging to the spleen, lung, heart, and kidney meridians, greatly tonifying primordial qi, invigorating the spleen and benefiting the lung, calming the mind and improving intelligence, being a key herb for supplementing qi, and having a significant curative effect on fatigue and shortness of breath caused by qi deficiency.

[0026] Black fruit wolfberry: Neutral in nature and sweet in taste, entering the liver and kidney meridians, nourishing the liver and kidney, benefiting essence and improving eyesight, being good at treating dizziness and blurred vision caused by yin deficiency of the liver and kidney, and its sweet and moist nature can nourish yin and moisten dryness.

[0027] Schisandra chinensis: Warm in nature and sour in taste, belonging to the lung, kidney, and heart meridians, astringing and consolidating, replenishing qi and promoting fluid production, being good at treating spontaneous sweating and night sweating, chronic cough and deficiency panting, and also being able to calm the mind and soothe the nerves.

[0028] Rehmannia root: Cold in nature, sweet and bitter in taste, belonging to the liver and kidney meridians, clearing heat and cooling blood, nourishing yin and promoting fluid production, being able to nourish yin and reduce fire when used raw, and tonifying blood and filling essence when used cooked, mainly treating yin deficiency and excessive fire, soreness and weakness of the waist and knees.

[0029] Anemarrhena rhizome: Cold in nature, bitter and sweet in taste, belonging to the lung, stomach, and kidney meridians, clearing heat and purging fire, nourishing yin and moistening dryness, being good at treating steaming bone fever and internal heat diabetes.

[0030] Phellodendron bark: Cold in nature, bitter in taste, belonging to the kidney, bladder, and large intestine meridians, clearing heat and drying dampness, purging fire and detoxifying, being good at treating dampness heat in the lower energizer.

[0031] Epimedium: Warm in nature, pungent and sweet in taste, belonging to the kidney and liver meridians, tonifying the kidney and strengthening yang, strengthening the muscles and bones, mainly treating impotence, premature ejaculation, and soreness and cold pain of the waist and knees caused by kidney yang deficiency, being a key herb for warming the kidney and assisting yang.

[0032] Astragalus root: Slightly warm in nature, sweet in taste, belonging to the spleen and lung meridians, tonifying qi and lifting yang, securing the exterior and stopping sweating, being good at treating qi deficiency and fatigue, spontaneous sweating due to exterior deficiency, and can tonify both qi and blood when combined with angelica.

[0033] Chinese yam: Neutral in nature, sweet in taste, belonging to the spleen, lung, and kidney meridians, strengthening the spleen and nourishing the stomach, promoting fluid production and benefiting the lung, being a product for evenly tonifying the three energizers, and being good at treating weakness of the spleen and stomach, yin deficiency of the lung and kidney.

[0034] Drynaria rhizome: Warm in nature, bitter in taste, belonging to the liver and kidney meridians, promoting blood circulation and healing injuries, tonifying the kidney and strengthening bones, being good at treating kidney deficiency and low back pain, bone and muscle injuries, and can reduce swelling and stasis of bone injuries when used externally.

[0035] Cistanche deserticola: It is warm in nature, sweet and salty in taste, and belongs to the kidney and large intestine meridians. It tonifies the kidney and boosts yang, moistens the intestines and promotes defecation. It is mainly used for impotence and infertility due to insufficient kidney yang, and intestinal dryness and constipation. It is mild and not dry.

[0036] Ligustrum lucidum: It is neutral in nature, sweet and bitter in taste, and belongs to the liver and kidney meridians. It nourishes the liver and kidney, improves eyesight and blackens hair. It is good at treating unclear vision and premature whitening of hair and beard due to yin deficiency of the liver and kidney, and also clears deficiency heat.

[0037] Caragana sinica root: It is neutral in nature, pungent, sweet in taste, and belongs to the lung, spleen and kidney meridians. It dispels wind and dampness, promotes blood circulation and relieves pain. It is good at treating edema with less urine and rheumatic arthralgia due to spleen deficiency and dampness entrapment, and can also disperse swelling and dissipate nodules.

[0038] Polygonatum sibiricum: It is neutral in nature, sweet in taste, and belongs to the spleen, lung and kidney meridians. It supplements qi and nourishes yin, strengthens the spleen and moistens the lung. It is a product that supplements both qi and yin. It is good at treating spleen and stomach weakness, pulmonary tuberculosis with hemoptysis, and consumptive thirst with spermatorrhea.

[0039] In the traditional Chinese medicine compound oral liquid of the present invention, adding different types of polysaccharides and different modification methods will affect its wall adhesion rate, storage stability, etc. Different types of polysaccharides include Tremella polysaccharide, Taraxacum polysaccharide, and Lilium brownii polysaccharide. Different modification methods include carboxymethylated modified polysaccharide, phosphorylated modified polysaccharide, and acetylated modified polysaccharide. In the carboxymethylated modified polysaccharide, the hydroxyl group of the polysaccharide is activated under alkaline conditions and reacts with chloroacetic acid to generate a carboxymethyl group. By introducing the carboxymethyl group, the solubility and water solubility of the polysaccharide are improved, and at the same time its electronegativity is enhanced, so that Tremella polysaccharide, Taraxacum polysaccharide or Lilium brownii polysaccharide can be more easily dispersed in the solution at low temperature, reducing the occurrence of wall adhesion phenomenon of the oral liquid; at the same time, the carboxymethylated modified polysaccharide can also improve the homogeneity, stability and hydrolysis rate of the solution by increasing the intermolecular electrostatic repulsion and reducing particle aggregation. In the phosphorylated modified polysaccharide, the hydroxyl group reacts with the phosphate group to generate a phosphoester bond. By introducing the phosphate group and introducing negative charges to enhance the electrostatic repulsion, the aggregation of the liquid medicine components is inhibited by the electrostatic repulsion. At the same time, phosphorylation improves the water solubility of the polysaccharide and forms a more stable dispersion system, thus reducing the occurrence of wall adhesion phenomenon. In the acetylated modified polysaccharide, the hydroxyl group in the polysaccharide molecule is activated under alkaline conditions and reacts with acetic anhydride to generate an acetyl group. By introducing the acetyl group, the intermolecular electrostatic attraction is reduced, the balance of intermolecular forces is changed, particle aggregation is reduced, and at the same time the overall stability of the solution is improved.

[0040] The beneficial effects of the present invention:

[0041] Compared with the prior art, the traditional Chinese medicine compound oral liquid of the present invention mainly treats supplementing qi and blood, regulating yin and yang, nourishing the liver and kidneys, strengthening the spleen and stomach, strengthening the bones and muscles, etc. The medicinal liquid is obtained by compound decocting of various traditional Chinese medicine components, and finally specific modified polysaccharides, steviol glycosides, sodium benzoate, and ethylparaben are added. The present invention also screens and optimizes the modified polysaccharides and adds them to the compound oral liquid. On the premise of not affecting the drug effect and safety, the problem of serious wall sticking and high waste rate of the medicinal liquid faced in the prior art is solved by improving the low-temperature storage stability. Detailed implementation manners

[0042] The parameters and sources of the specific chemical substances used in the examples are as follows:

[0043] The preparation method of tremella polysaccharide is as follows:

[0044] The whole tremella is crushed by a pulverizer and then passed through a 40-mesh sieve. 3 g of the treated tremella is weighed and extracted with hot water. The ratio of liquid to material for extraction is 60:1 mL / g, the extraction temperature is 90 °C, and the extraction time is 4 h; it is filtered through gauze, the filtrate is made up to 250 mL, 3 mL of the filtrate is placed in a 50-mL centrifuge tube, 15 mL of absolute ethanol is added and shaken well, taken out after refrigeration for 1 h, centrifuged at 4000 r / min for 20 min, the supernatant is discarded, the precipitate is washed twice with 80 wt% ethanol, 8 mL each time, centrifuged, the supernatant is removed, the precipitate is dissolved in hot water, transferred to a 25-mL volumetric flask, cooled, made up to the mark, shaken well, and concentrated to obtain tremella polysaccharide.

[0045] The preparation methods of dandelion polysaccharide and lily polysaccharide are the same as above.

[0046] Example 1

[0047] A preparation method of a traditional Chinese medicine compound oral liquid includes the following steps:

[0048] (1) Medicinal material soaking: 8 g of ginseng, 4 g of black wolfberry, 8 g of rehmannia root, 6 g of anemarrhena rhizome, 6 g of phellodendron bark, 8 g of astragalus root, 5 g of Chinese yam, 8 g of glossy privet fruit, 5 g of sericea lespedeza root, and 8 g of polygonatum rhizome are put into a container, 200 g of water is added to submerge the medicinal materials by 3 cm, and soaked for 45 minutes to obtain a mixed medicinal liquid;

[0049] (2) Medicinal liquid decocting: The mixed medicinal liquid is decocted twice. 400 g of water is added for the first decoction, the decocting temperature is 70 °C, and the decocting time is 100 minutes; 300 g of water is added for the second decoction, the decocting temperature is 65 °C, and the decocting time is 100 minutes. After combining, the decocted medicinal liquid is obtained;

[0050] (3) Liquid medicine combination: Add 5 g of carboxymethylated modified tremella polysaccharide, 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben to the decocted liquid medicine, stir for another 15 minutes, let it stand for 24 hours, filter through a 0.4-μm nylon membrane, collect the filtrate to obtain the traditional Chinese medicine compound oral liquid.

[0051] The preparation method of the carboxymethylated modified tremella polysaccharide is as follows:

[0052] Add 6 g of tremella polysaccharide to 100 g of water, add 18 g of food-grade sodium hydroxide, stir at 50 °C for 1.5 hours, add 1.5 g of chloroacetic acid, stir at 55 °C for 3 hours, add glacial acetic acid dropwise to adjust the pH to neutral, add 100 g of absolute ethanol, let it stand for 24 hours, centrifuge 3 times, collect the precipitate, and dry it at 45 °C to obtain the carboxymethylated modified tremella polysaccharide.

[0053] Comparative Example 1

[0054] A preparation method of a traditional Chinese medicine compound oral liquid, comprising the following steps:

[0055] (1) Medicinal material soaking: Put 8 g of ginseng, 4 g of black wolfberry, 8 g of rehmannia root, 6 g of anemarrhena rhizome, 6 g of phellodendron bark, 8 g of astragalus root, 5 g of Chinese yam, 8 g of glossy privet fruit, 5 g of broomrape root, and 8 g of polygonatum rhizome into a container, add 200 g of water to cover the medicinal materials by 3 cm, soak for 45 minutes to obtain a mixed liquid medicine;

[0056] (2) Liquid medicine decoction: Decoct the mixed liquid medicine twice. For the first decoction, add 400 g of water, the decoction temperature is 70 °C, and the decoction time is 100 minutes; for the second decoction, add 300 g of water, the decoction temperature is 65 °C, and the decoction time is 100 minutes. After combining, obtain the decocted liquid medicine;

[0057] (3) Liquid medicine combination: Add 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben to the decocted liquid medicine, stir for another 15 minutes, let it stand for 24 hours, filter through a 0.4-μm nylon membrane, collect the filtrate to obtain the traditional Chinese medicine compound oral liquid.

[0058] Comparative Example 2

[0059] A preparation method of a traditional Chinese medicine compound oral liquid, comprising the following steps:

[0060] (1) Medicinal material soaking: Put 8 g of ginseng, 4 g of black wolfberry, 8 g of rehmannia root, 6 g of anemarrhena rhizome, 6 g of phellodendron bark, 8 g of astragalus root, 5 g of Chinese yam, 8 g of glossy privet fruit, 5 g of broomrape root, and 8 g of polygonatum rhizome into a container, add 200 g of water to cover the medicinal materials by 3 cm, soak for 45 minutes to obtain a mixed liquid medicine;

[0061] (2) Decoction of medicinal liquid: The mixed medicinal liquid is decocted twice. For the first decoction, 400 g of water is added, the decoction temperature is 70 °C, and the decoction time is 100 minutes; for the second decoction, 300 g of water is added, the decoction temperature is 65 °C, and the decoction time is 100 minutes. After combination, the decocted medicinal liquid is obtained;

[0062] (3) Combination of medicinal liquids: 5 g of tremella polysaccharide, 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben are added to the decocted medicinal liquid, and stirring continues for 15 minutes. After standing for 24 hours, filtration is carried out through a 0.4 μm nylon membrane, and the filtrate is collected to obtain the traditional Chinese medicine compound oral liquid.

[0063] Example 2

[0064] A preparation method of a traditional Chinese medicine compound oral liquid, comprising the following steps:

[0065] (1) Soaking of medicinal materials: 8 g of ginseng, 4 g of black wolfberry, 8 g of rehmannia root, 6 g of anemarrhena rhizome, 6 g of phellodendron bark, 8 g of astragalus root, 5 g of Chinese yam, 8 g of glossy privet fruit, 5 g of sericea lespedeza root, and 8 g of polygonatum rhizome are placed in a container, 200 g of water is added to submerge the medicinal materials by 3 cm, and soaking is carried out for 45 minutes to obtain the mixed medicinal liquid;

[0066] (2) Decoction of medicinal liquid: The mixed medicinal liquid is decocted twice. For the first decoction, 400 g of water is added, the decoction temperature is 70 °C, and the decoction time is 100 minutes; for the second decoction, 300 g of water is added, the decoction temperature is 65 °C, and the decoction time is 100 minutes. After combination, the decocted medicinal liquid is obtained;

[0067] (3) Combination of medicinal liquids: 5 g of carboxymethylated modified dandelion polysaccharide, 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben are added to the decocted medicinal liquid, and stirring continues for 15 minutes. After standing for 24 hours, filtration is carried out through a 0.4 μm nylon membrane, and the filtrate is collected to obtain the traditional Chinese medicine compound oral liquid.

[0068] The preparation method of the carboxymethylated modified dandelion polysaccharide is as follows:

[0069] 6 g of dandelion polysaccharide is added to 100 g of water, 18 g of food-grade sodium hydroxide is added, and stirring is carried out at 50 °C for 1.5 hours. Then 1.5 g of chloroacetic acid is added, and stirring is carried out at 55 °C for 3 hours. Glacial acetic acid is added dropwise to adjust the pH to neutral. 100 g of absolute ethanol is added, and standing is carried out for 24 hours. Centrifugation is carried out 3 times, and the precipitate is collected and dried at 45 °C to obtain the carboxymethylated modified dandelion polysaccharide.

[0070] Example 3

[0071] A preparation method of a traditional Chinese medicine compound oral liquid, comprising the following steps:

[0072] (1) Medicinal material soaking: Put 8 g of ginseng, 4 g of black wolfberry, 8 g of rehmannia root, 6 g of anemarrhena rhizome, 6 g of phellodendron bark, 8 g of astragalus root, 5 g of Chinese yam, 8 g of glossy privet fruit, 5 g of sericea lespedeza root, and 8 g of polygonatum rhizome into a container, add 200 g of water to submerge the medicinal materials by 3 cm, and soak for 45 minutes to obtain a mixed medicinal liquid;

[0073] (2) Medicinal liquid decocting: Decoct the mixed medicinal liquid twice. For the first decoction, add 400 g of water, the decocting temperature is 70 °C, and the decocting time is 100 minutes; for the second decoction, add 300 g of water, the decocting temperature is 65 °C, and the decocting time is 100 minutes. After combining, obtain the decocted medicinal liquid;

[0074] (3) Medicinal liquid combination: Add 5 g of carboxymethylated modified lily polysaccharide, 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben to the decocted medicinal liquid, continue to stir for 15 minutes, let it stand for 24 hours, filter through a 0.4 μm nylon membrane, collect the filtrate, and obtain the traditional Chinese medicine compound oral liquid.

[0075] The preparation method of the carboxymethylated modified lily polysaccharide is as follows:

[0076] Add 6 g of lily polysaccharide to 100 g of water, add 18 g of food-grade sodium hydroxide, stir at 50 °C for 1.5 hours, add 1.5 g of chloroacetic acid, stir at 55 °C for 3 hours, dropwise add glacial acetic acid to adjust the pH to neutral, add 100 g of absolute ethanol, let it stand for 24 hours, centrifuge 3 times, collect the precipitate, and dry it at 45 °C to obtain the carboxymethylated modified lily polysaccharide.

[0077] Example 4

[0078] A preparation method of a traditional Chinese medicine compound oral liquid, comprising the following steps:

[0079] (1) Medicinal material soaking: Put 8 g of ginseng, 4 g of black wolfberry, 8 g of rehmannia root, 6 g of anemarrhena rhizome, 6 g of phellodendron bark, 8 g of astragalus root, 5 g of Chinese yam, 8 g of glossy privet fruit, 5 g of sericea lespedeza root, and 8 g of polygonatum rhizome into a container, add 200 g of water to submerge the medicinal materials by 3 cm, and soak for 45 minutes to obtain a mixed medicinal liquid;

[0080] (2) Medicinal liquid decocting: Decoct the mixed medicinal liquid twice. For the first decoction, add 400 g of water, the decocting temperature is 70 °C, and the decocting time is 100 minutes; for the second decoction, add 300 g of water, the decocting temperature is 65 °C, and the decocting time is 100 minutes. After combining, obtain the decocted medicinal liquid;

[0081] (3) Medicinal liquid combination: Add 5 g of phosphorylated modified tremella polysaccharide, 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben to the decocted medicinal liquid, continue to stir for 15 minutes, let it stand for 24 hours, filter through a 0.4 μm nylon membrane, collect the filtrate, and obtain the traditional Chinese medicine compound oral liquid.

[0082] The preparation method of the phosphorylated modified Tremella polysaccharide is as follows:

[0083] Add 6 g of Tremella polysaccharide into 350 g of water, add 1.5 g of sodium sulfate and 50 g of 0.1 g / mL sodium tripolyphosphate aqueous solution, adjust the pH to neutral with food-grade sodium hydroxide, stir at 80 °C for 2 hours, cool to room temperature, dialyze to remove salts with a dialysis bag (MW 3500), and freeze-dry to obtain the phosphorylated modified Tremella polysaccharide.

[0084] Example 5

[0085] A preparation method of a traditional Chinese medicine compound oral liquid comprises the following steps:

[0086] (1) Medicinal material soaking: Put 8 g of ginseng, 4 g of Lycium ruthenicum Murr., 8 g of Rehmannia glutinosa, 6 g of Anemarrhena asphodeloides, 6 g of Phellodendron amurense, 8 g of Astragalus membranaceus, 5 g of Dioscorea opposita, 8 g of Ligustrum lucidum, 5 g of Pueraria lobata, and 8 g of Polygonatum sibiricum into a container, add 200 g of water to submerge the medicinal materials by 3 cm, and soak for 45 minutes to obtain a mixed medicinal liquid;

[0087] (2) Medicinal liquid decocting: Decoct the mixed medicinal liquid twice. For the first decoction, add 400 g of water, the decocting temperature is 70 °C, and the decocting time is 100 minutes; for the second decoction, add 300 g of water, the decocting temperature is 65 °C, and the decocting time is 100 minutes. Combine them to obtain the decocted medicinal liquid;

[0088] (3) Medicinal liquid combination: Add 5 g of acetylated modified Tremella polysaccharide, 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben to the decocted medicinal liquid, continue to stir for 15 minutes, let it stand for 24 hours, filter through a 0.4 μm nylon membrane, and collect the filtrate to obtain the traditional Chinese medicine compound oral liquid.

[0089] The preparation method of the acetylated modified Tremella polysaccharide is as follows:

[0090] Add 6 g of Tremella polysaccharide into 100 g of water, add food-grade sodium hydroxide to adjust the pH to 9.0 and stir for 20 minutes. While maintaining the pH between 8.0 - 8.5, dropwise add 100 g of acetic anhydride, stir at 40 °C for 2 hours, cool to room temperature, dropwise add 30 wt% citric acid solution to adjust the pH to neutral, centrifuge 3 times to remove insoluble impurities, concentrate to 50 g at 45 °C, add 50 g of 70 wt% ethanol aqueous solution and stir for 0.5 hours, centrifuge 3 times to remove insoluble impurities, concentrate and dry at 45 °C, then add it to 100 g of water and continue to stir for 1 hour to obtain a clear solution, and concentrate and dry at 75 °C to obtain the acetylated modified Tremella polysaccharide.

[0091] Example 6

[0092] A preparation method of a traditional Chinese medicine compound oral liquid comprises the following steps:

[0093] (1) Medicinal material soaking: Put 8 g of ginseng, 4 g of black wolfberry, 8 g of rehmannia root, 6 g of anemarrhena rhizome, 6 g of phellodendron bark, 8 g of astragalus root, 5 g of Chinese yam, 8 g of glossy privet fruit, 5 g of sophora flavescens root, and 8 g of polygonatum rhizome into a container, add 200 g of water to submerge the medicinal materials by 3 cm, and soak for 45 minutes to obtain a mixed medicinal liquid;

[0094] (2) Medicinal liquid decocting: Decoct the mixed medicinal liquid twice. For the first decoction, add 400 g of water, the decocting temperature is 70 °C, and the decocting time is 100 minutes; for the second decoction, add 300 g of water, the decocting temperature is 65 °C, and the decocting time is 100 minutes. After combining, obtain the decocted medicinal liquid;

[0095] (3) Medicinal liquid combination: Add 5 g of carboxymethylated modified tremella polysaccharide, 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben to the decocted medicinal liquid, continue to stir for 15 minutes, let it stand for 24 hours, filter through a 0.4 μm nylon membrane, collect the filtrate, and obtain the traditional Chinese medicine compound oral liquid.

[0096] The preparation method of the carboxymethylated modified tremella polysaccharide is as follows:

[0097] Add 6 g of tremella polysaccharide to 100 g of water, add 18 g of food-grade sodium hydroxide, stir at 50 °C for 1.5 hours, add 1.5 g of chloroacetic acid, stir at 55 °C for 3 hours, dropwise add glacial acetic acid to adjust the pH to neutral, add 100 g of absolute ethanol, let it stand for 24 hours, centrifuge 3 times, collect the precipitate, dry it at 45 °C, take 4.6 g of carboxymethylated modified tremella polysaccharide and mix it with 0.4 g of fucoidan to obtain the carboxymethylated modified tremella composite polysaccharide.

[0098] Comparative Example 3

[0099] A preparation method of a traditional Chinese medicine compound oral liquid, comprising the following steps:

[0100] (1) Medicinal material soaking: Put 8 g of ginseng, 4 g of black wolfberry, 8 g of rehmannia root, 6 g of anemarrhena rhizome, 6 g of phellodendron bark, 8 g of astragalus root, 5 g of Chinese yam, 8 g of glossy privet fruit, 5 g of sophora flavescens root, and 8 g of polygonatum rhizome into a container, add 200 g of water to submerge the medicinal materials by 3 cm, and soak for 45 minutes to obtain a mixed medicinal liquid;

[0101] (2) Medicinal liquid decocting: Decoct the mixed medicinal liquid twice. For the first decoction, add 400 g of water, the decocting temperature is 70 °C, and the decocting time is 100 minutes; for the second decoction, add 300 g of water, the decocting temperature is 65 °C, and the decocting time is 100 minutes. After combining, obtain the decocted medicinal liquid;

[0102] (3) Liquid medicine combination: Add 5 g of fucoidan, 1.5 g of steviol glycoside, 0.2 g of sodium benzoate, and 0.08 g of ethylparaben to the decocted liquid medicine, stir for another 15 minutes, let stand for 24 hours, filter through a 0.4 μm nylon membrane, collect the filtrate to obtain the traditional Chinese medicine compound oral liquid.

[0103] Test Example 1

[0104] Use the traditional Chinese medicine compound oral liquids prepared in Comparative Examples 1-3 and Examples 1-6 as test samples to conduct liver function tests on experimental mice. Randomly divide the experimental mice with a body weight of 20-25 g, half male and half female, into a blank group, Comparative Examples 1-3, and Examples 1-6 groups, a total of 10 groups, with 10 mice in each group. The 10 groups of mice are uniformly placed in a breeding box at 25 °C and 60% humidity for breeding, with artificial lighting for 12 hours and ventilation 12 times per hour, and the feeding time is 90 days. The blank group is fed with feed once a day, 6 g of feed each time, and at the same time, 5 mL of water is fed; the groups of Comparative Examples 1-3 and Examples 1-6 are fed with feed once a day, 6 g of feed each time, and at the same time, 3 mL of water and 2 mL of the corresponding traditional Chinese medicine compound oral liquid of Comparative Examples 1-3 and Examples 1-6 are fed. After the feeding is over, take the orbital venous blood and liver tissue of the experimental mice respectively for liver function tests. The test indicators are alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). The test data are averaged and summarized as shown in Table 1.

[0105] Table 1 Liver Function Test

[0106]

[0107] Note: Compared with the blank group, there are statistically significant differences in Examples 1-6 and Comparative Examples 1-3 (P < 0.05).

[0108] When the liver has relatively severe necrosis or damage, the concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in the serum will be on the high side. The indicators of Comparative Examples 1-2 and Examples 1-6 are close to those of the blank group, indicating that the traditional Chinese medicine compound oral liquid has a protective effect on the liver function of experimental mice, and the oral liquid does not contain hepatotoxic anthraquinone toxic components.

[0109] Test Example 2

[0110] Respectively take 10 g of the traditional Chinese medicine compound oral liquids prepared in Examples 1-6 and Comparative Example 3, pack them into oral liquid bottles and seal them as test samples. Weigh the initial weight before the test starts, and prepare 5 samples for each example; then store them in an environment of 5-10 °C and 60% humidity for 1 month, suck them out with a syringe with a 2 mm needle, weigh the actual weight after sucking out, and the wall hanging rate is 1 - {(initial weight - actual weight) / 10} × 100%. The test data are averaged and summarized as shown in Table 2.

[0111] Oral liquid bottle: The manufacturer is Cangzhou Rongchang Glass Products Co., Ltd., the model is 10 mL oral liquid bottle (Type A large mouth), the bottle body diameter is 18 mm, the bottle height is 65 mm, the bottle mouth diameter is 15 mm, and the bottle mouth height is 4.0 mm.

[0112] Table 2 Wall - hanging rate test of oral liquid bottles

[0113]

[0114] Tremella polysaccharide, Taraxacum polysaccharide and Lilium polysaccharide, all being natural polymer compounds, mainly improve product performance through physical effects and have little test significance in this test. In Examples 1 - 3, carboxylated modified Tremella polysaccharide, carboxylated modified Taraxacum polysaccharide and carboxylated modified Lilium polysaccharide are added respectively. In Example 1, through carboxymethylation modification, by introducing strongly hydrophilic carboxymethyl groups, the hydrogen - bond interaction force between the polysaccharide molecules and the aqueous phase is enhanced, forming a stable hydration layer. After carboxymethylation, the molecular chain of Tremella polysaccharide unfolds more fully and the steric hindrance effect is stronger, effectively inhibiting the aggregation of molecular chains in the low - temperature environment of 5 - 10 °C; the main chain of Taraxacum polysaccharide in Example 2 is pectin, and after carboxymethylation, the molecular flexibility is lower and the stability of the hydration layer is also improved; the improvement of the solubility of Lilium polysaccharide by carboxymethylation modification is lower than that of Examples 1 - 2. Given that Example 1 is superior to Examples 2 - 3, in Examples 4 - 5, different types of modification are further carried out on Tremella polysaccharide. In Example 4, phosphorylation modification is carried out on Tremella polysaccharide, introducing negative charges to enhance electrostatic repulsion, inhibiting the aggregation of liquid medicine components through electrostatic repulsion, and at the same time phosphorylation improves the water solubility of the polysaccharide, forming a more stable dispersion system; the acetylation modification in Example 5 may reduce the direct contact between macromolecules through the steric hindrance effect, and after modification, the hydroxyl groups are further improved in solubility; in Example 6, fucan is added on the basis of Example 1 for compounding to obtain carboxymethylated modified Tremella composite polysaccharide. The sulfate group of fucan and the carboxymethyl group of carboxymethylated modified Tremella polysaccharide synergistically strengthen the steric hindrance, inhibiting drug sedimentation and further reducing wall - hanging residue; Comparative Example 3, as a comparative example of Example 1 and Example 6, only adds fucan alone. After sucking out after 1 - month storage at 5 - 10 °C low temperature, the average wall - hanging rate reaches 4.0%. It shows that in actual situations, if an oral liquid is 10 g, when taking medicine normally through a straw, 0.4 g of residual waste will be generated, and the wall - hanging rate is low. Test Example 2 shows that adding different types of polysaccharides and different modification methods will affect the low - temperature stability and thus affect the wall - hanging rate.

[0115] Test Example 3

[0116] 10 g of the traditional Chinese medicine compound oral liquids prepared in Examples 1-6 were respectively taken and filled into oral liquid bottles and sealed as test samples to be tested, and 5 groups of samples were prepared for each example; before the test, the moisture content was measured respectively, and then they were uniformly stored in an environment with room temperature and 60% humidity. The moisture content was measured after 6, 12, and 18 months respectively. The hydrolysis rate = [(initial moisture content - actual moisture content) / initial moisture content] × 100%. The test data were averaged and summarized as shown in Table 3.

[0117] Table 3 Hydrolysis rate test in storage stability

[0118]

[0119] The differences in the hydrolysis rates of Examples 1-5 in Test Example 3 mainly stem from the selectivity of polysaccharides, the synergistic effects and influences of the modified polysaccharides obtained by the modification methods of polysaccharides on the formulation stability. Among them, carboxymethylated tremella polysaccharide was used in Example 1, and a stable hydration layer was formed after hydrophilic carboxymethyl modification, significantly reducing the exposure of unstable groups such as hydroxyl groups and lowering the concentration of hydrolysis substrates during storage; while carboxymethylated dandelion polysaccharide and lily polysaccharide were used in Examples 2-3 respectively, and the molecular chain wrapping effect after modification was weaker than that of tremella polysaccharide, and the remaining free hydroxyl groups underwent hydrolysis over time. Given that Example 1 was superior to Examples 2-3, in Examples 4-5, phosphorylation and acetylation modification of tremella polysaccharide were further carried out respectively. The modified phosphate group in Example 5 had a large volume resulting in insufficient steric hindrance, which increased the hydrolysis rate over time; in Example 6, fucoidan was added for compounding. The carboxyl group of carboxymethylated tremella polysaccharide and the sulfate group of fucoidan formed a double negative charge barrier, preventing water molecules from approaching the hydrolysis-sensitive groups such as hydroxyl and carboxyl groups of drug molecules through electrostatic repulsion, thereby improving the storage stability and water resistance.

[0120] The preferred specific embodiments of the present invention have been described in detail above. It should be understood that those of ordinary skill in the art can make many modifications and variations based on the concept of the present invention without creative efforts. Therefore, all technical solutions that can be obtained by those skilled in the art in the technical field of the present invention based on the concept of the present invention through logical analysis, reasoning, or limited experiments on the basis of the prior art should fall within the protection scope determined by the claims.

Claims

1. A method for preparing a Chinese medicine compound oral liquid, characterized in that: The method is obtained by soaking medicinal materials, decocting medicinal liquid, and combining the medicinal liquid, wherein modified polysaccharides are added in the medicinal liquid combination step; The medicinal material soaking step comprises: putting 6-10 parts of ginseng, 3-5 parts of black wolfberry, 6-10 parts of rehmannia root, 4-8 parts of anemarrhena, 4-8 parts of phellodendron, 6-10 parts of astragalus, 4-6 parts of yam, 6-10 parts of privet fruit, 4-6 parts of genista chinensis, and 6-10 parts of polygonatum into a container, adding 150-250 parts of water for soaking, and obtaining a mixed medicinal solution; The medicinal liquid decoction step comprises: decoct the mixed medicinal liquid twice, and combine the mixture to obtain the decoction medicinal liquid; The step of combining the medicinal liquid is as follows: adding 4-8 parts of modified polysaccharide, 1-2 parts of stevioside, 0.1-0.3 parts of sodium benzoate, and 0.05-0.1 parts of ethylparaben to the decocted medicinal liquid, stirring, standing, filtering, collecting the filtrate, and obtaining the Chinese medicine compound oral liquid; The parts are parts by weight.

2. The method for preparing the Chinese medicine compound oral liquid according to claim 1, characterized in that: The preparation method of the modified polysaccharide is as follows, in parts by weight: Add 4-6 parts of polysaccharide to 80-120 parts of water, add 15-20 parts of sodium hydroxide and stir at 45-55°C for 1-2 hours, add 1-2 parts of chloroacetic acid and stir at 50-60°C for 2-4 hours, add glacial acetic acid dropwise to adjust the pH to neutral, add 80-120 parts of anhydrous ethanol and let stand for 24 hours, centrifuge 2-4 times, collect the precipitate and dry at 40-50°C to obtain modified polysaccharide.

3. The method for preparing the Chinese medicine compound oral liquid according to claim 1, characterized in that: The preparation method of the modified polysaccharide is as follows, in parts by weight: 4-6 parts of polysaccharide are added to 300-400 parts of water, 1-2 parts of sodium sulfate, 40-60 parts of 0.1-0.2 g / mL sodium tripolyphosphate aqueous solution are added, food-grade sodium hydroxide is added to adjust the pH to neutral, the mixture is stirred at 75-85° C. for 1-3 hours, cooled to room temperature, dialyzed for desalination, and freeze-dried to obtain the modified polysaccharide.

4. The method for preparing the Chinese medicine compound oral liquid according to claim 1, characterized in that: The preparation method of the modified polysaccharide is as follows, in parts by weight: 4-6 parts of polysaccharide are added to 80-120 parts of water, sodium hydroxide is added to adjust the pH to 8.5-9.5, and stirred for 10-30 minutes, 80-120 parts of acetic anhydride are added dropwise to maintain the pH between 8.0-8.5, stirred at 35-45° C. for 1-3 hours, cooled to room temperature, citric acid aqueous solution is added dropwise to adjust the pH to neutral, centrifuged 2-4 times to remove insoluble impurities, concentrated at 40-50° C. to 40-60 parts, 40-60 parts of ethanol aqueous solution are added, stirred for 0.5-1 hour, centrifuged 2-4 times to remove insoluble impurities, concentrated and dried at 40-50° C., added to 80-120 parts of water, and continued to stir for 0.5-1.5 hours to obtain a clear liquid, and concentrated and dried at 70-80° C. to obtain the modified polysaccharide.

5. The method for preparing the Chinese medicine compound oral liquid according to claim 4, characterized in that: The citric acid aqueous solution is a 20-40wt% citric acid aqueous solution.

6. The method for preparing the Chinese medicine compound oral liquid according to claim 3 or 4, characterized in that: The ethanol aqueous solution is a 60-80wt% ethanol aqueous solution.

7. The method for preparing the Chinese medicine compound oral liquid according to claim 1, characterized in that: The preparation method of the Chinese medicine compound oral liquid, The method comprises the following steps, in parts by weight: (1) Soaking medicinal materials: put 6-10 parts of ginseng, 3-5 parts of black wolfberry, 6-10 parts of rehmannia root, 4-8 parts of anemarrhena, 4-8 parts of phellodendron, 6-10 parts of astragalus, 4-6 parts of yam, 6-10 parts of privet fruit, 4-6 parts of genista chinensis, and 6-10 parts of polygonatum into a container, add 150-250 parts of water to cover the medicinal surfaces, and soak for 30-60 minutes to obtain a mixed medicinal solution; (2) decoction of the medicinal liquid: decoct the mixed medicinal liquid twice, add 300-500 parts of water for the first decoction, and the decoction time is 90-120 minutes; add 200-400 parts of water for the second decoction, and the decoction time is 90-120 minutes, and then combine them to obtain the decoction liquid; (3) Liquid composition: add 4-8 parts of modified polysaccharide, 1-2 parts of stevioside, 0.1-0.3 parts of sodium benzoate, and 0.05-0.1 parts of ethylparaben to the decocted liquid, continue stirring for 10-20 minutes, let stand for 24 hours, filter through a 0.3-0.5 μm nylon membrane, collect the filtrate, and obtain the Chinese medicine compound oral liquid.

8. The method for preparing the Chinese medicine compound oral liquid according to claim 7, characterized in that: The height of the drug surface in step (1) is 2-4 cm.

9. The method for preparing the Chinese medicine compound oral liquid according to claim 7, characterized in that: The Chinese medicine compound oral liquid in step (3) is a brown to yellowish brown clear liquid with a slight odor and a sweet and slightly bitter taste.

10. A Chinese medicine compound oral liquid, characterized in that: The invention is prepared by the preparation method according to any one of claims 1 to 9.

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