Production method of oral liquid medicine for nourishing yin and strengthening body

Abstract

The invention relates to the technical field of medicines, in particular to a production method of a yin-nourishing and body-strengthening oral liquid medicine. The method comprises the following steps: clarifying the Chinese magnoliavine fruit clear paste, the Chinese yam clear paste and the polygonatum sibiricum decoction with tannin and polyvinylpyrrolidone in sequence; cooling, filtering, and preparing the oral liquid with a fish extract and a turtle extract; the fish extract and the turtle extract are respectively subjected to micro-enzymolysis by chymotrypsin and cathepsin and then are extracted. The quality guarantee period of the yin-nourishing and health-strengthening oral liquid prepared by the invention can be prolonged to 24 months, and the oral liquid is free from suspended solids, turbidity, layering or precipitation; in addition, peculiar smells such as fishy smell and bitter taste are removed, the taste is improved, and the medicine taking compliance is improved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a production method of Ziyin Qiangshen Oral Liquid. Background Art

[0002] Retarding aging, enhancing the body's resistance and improving immune function are important health goals that people widely concern. Especially in modern society, factors such as environmental pollution, life pressure and bad eating habits have accelerated the aging process of the body and weakened the body's natural immune barrier. Therefore, people pay more and more attention to scientific and reasonable health preservation methods, hoping to maintain the body's vitality, enhance disease resistance and reduce the occurrence of chronic diseases through the combination of dietary conditioning, traditional Chinese medicine conditioning and healthy lifestyle, so as to achieve longer-term health and high-quality life.

[0003] CN1820778A discloses a production method of Ziyin Qiangshen Oral Liquid. By weight ratio, taking 80 - 120 g of turtle extract, 80 - 120 g of fish extract, 5 - 15 g of Schisandra chinensis, 10 - 30 g of Dioscorea opposita and 50 - 70 g of Polygonatum sibiricum as main raw materials, Schisandra chinensis is crushed into coarse powder and extracted with ethanol to obtain clear paste, then gelatin solution is added to make emulsion. Dioscorea opposita is extracted with ethanol to obtain clear paste, Polygonatum sibiricum is cut into thin slices and decoction is taken. While the decoction of Polygonatum sibiricum is hot, fish extract, Schisandra chinensis emulsion, Dioscorea opposita clear paste and turtle extract are added, mixed evenly, filtered, 5 - 7 g of aspartame is added, water is added to 1000 ml, stirred evenly, filled and sealed, and sterilized to obtain the product. This oral liquid has the function of nourishing yin and replenishing qi, and is used for the adjuvant treatment of symptoms such as low immunity, reduction of platelets and white blood cells and low organ function caused by senility and debility or being weak after illness. Summary of the Invention

[0004] During the long-term research on Ziyin Qiangshen Oral Liquid of CN1820778A, the inventors found that the oral liquid prepared by the existing production method becomes turbid or precipitates during long-term storage, affecting the taste of the product. Therefore, the inventors improved the original production method.

[0005] The original formula of Ziyin Qiangshen Oral Liquid is relatively complex, including not only plant-based Chinese medicinal materials such as Schisandra chinensis, Dioscorea opposita and Polygonatum sibiricum, but also animal-derived raw materials such as turtle and fish extracts. Its components are diverse and the system is complex. Since it is difficult for the conventional production method to balance the technical requirements of drug efficacy stability and long-term preservation, ensuring its efficacy and maintaining its stability has become a major challenge. To solve this technical problem, the inventors systematically optimized the original production process based on long-term and extensive experimental research, and finally achieved the stable release of drug efficacy and the long-term stability of the preparation.

[0006] Specifically, the present invention provides a production method of Ziyin Qiangshen Oral Liquid, including:

[0007] 1) Take 5 - 15 g of Schisandra chinensis, impregnate and extract it with ethanol with a concentration of 90 - 95%, and make a clear extract of Schisandra chinensis with a relative density of 1.10 - 1.15 at 60°C;

[0008] Take 10 - 30 g of Chinese yam, impregnate and extract it with ethanol with a concentration of 60 - 80%, and make a clear extract of Chinese yam with a relative density of 1.10 - 1.15 at 60°C;

[0009] Take 50 - 70 g of Polygonatum sibiricum, soak it in water, decoct it, and make a decoction of Polygonatum sibiricum;

[0010] 2) Mix the clear extract of Schisandra chinensis, the clear extract of Chinese yam and the decoction of Polygonatum sibiricum to obtain a mixed solution; first add tannin for clarification; filter; then add polyvinylpyrrolidone for clarification; filter; cool the filtrate to 5 - 15°C, let it stand for 4 - 6 hours, and filter again to obtain a mixed extract of Schisandra chinensis, Chinese yam and Polygonatum sibiricum;

[0011] 3) Mix the mixed extract of Schisandra chinensis, Chinese yam and Polygonatum sibiricum, 80 - 120 g of fish extract and 80 - 120 g of turtle extract, filter, add a sweetening agent, stir well, add water to 1000 mL, stir well, seal, sterilize, and you will get it;

[0012] The preparation method of the fish extract includes: take 100 g of fresh meat of Aristichthys nobilis or Hypophthalmichthys molitrix, pound it into meat paste with water, and carry out micro - enzymatic hydrolysis with chymotrypsin and cathepsin, control the pH to be 6.8 - 7.2, the temperature to be 20 - 25°C, and the time to be 20 - 30 minutes; after micro - enzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 300 g - 500 g of extraction solution, mix well, impregnate for 1 - 3 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to obtain 25 - 30 g of fish extract; the extraction solution is an aqueous solution containing 1 wt% - 10 wt% of sodium citrate and 0.5 wt% - 5 wt% of sodium chloride;

[0013] The preparation method of the turtle extract includes: take 100 g of fresh meat of Chinemys reevesii, Mauremys mutica or Cuora flavomarginata, pound it into meat paste with water, and carry out micro - enzymatic hydrolysis with chymotrypsin and cathepsin, control the pH to be 6.8 - 7.2, the temperature to be 20 - 25°C, and the time to be 20 - 30 minutes; after micro - enzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 300 - 500 g of extraction solution, mix well, impregnate for 1 - 3 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to obtain 10 - 20 g of turtle extract; the extraction solution is an aqueous solution containing 1 wt% - 10 wt% of sodium citrate and 0.5 wt% - 5% of sodium chloride.

[0014] In the original production process of CN1820778A, gelatin was used, and its main function was to form a colloidal solution-like substance, which helped emulsify and stabilize the Schisandra chinensis extract, making it easier to mix with other ingredients, preventing layering or precipitation, and thus improving the solubility and stability of the ingredients. However, the inventor found that although this emulsifying and stabilizing effect of gelatin could keep Ziyin Qiangshen Oral Liquid stable in the short term, during long-term storage (for example, after 6 months), the stability of the oral liquid decreased, and turbidity or precipitation occurred, which affected both the taste and efficacy of the product. Through extensive research, the inventor unexpectedly found that by abandoning the use of gelatin, the mixed solution of Schisandra chinensis extract, Chinese yam extract, and Polygonatum sibiricum Decne. decoction was successively clarified with tannin and polyvinylpyrrolidone, and further cooled (5 - 15°C, preferably 10 - 15°C) and allowed to stand. The mixed extract of Schisandra chinensis, Chinese yam, and Polygonatum sibiricum obtained after filtration was then mixed with the fish extract and tortoise extract of the original process, which could significantly improve the stability of the oral liquid, and no turbidity or precipitation would occur even after 6 months of storage.

[0015] In the original production process of CN1820778A, fish extract and tortoise extract were prepared using an extract solution (containing 1 - 10% by weight of sodium citrate and 0.5 - 5% by weight of sodium chloride). The inventor found that components such as proteins in this extract were also one of the important reasons for the inability of the oral liquid to maintain long-term stability (i.e., layering or precipitation). The inventor tried to use enzymatic hydrolysis methods (using pepsin, trypsin, papain, bromelain, carica papaya protease, etc.) to hydrolyze fish meat and tortoise meat. Although to a certain extent, it could improve the stability of the oral liquid, the efficacy of the oral liquid decreased. The inventor unexpectedly found that by first performing micro-enzymatic hydrolysis on fish meat and tortoise meat using chymotrypsin and cathepsin, and then extracting with the extract solution, the oral liquid could maintain long-term stability without affecting its efficacy. Further research found that the degree of micro-enzymatic hydrolysis was very crucial. If the enzymatic hydrolysis was excessive, the efficacy of the oral liquid would decrease; if the degree of enzymatic hydrolysis was insufficient, the oral liquid could not maintain long-term stability. The optimal conditions for micro-enzymatic hydrolysis were: controlling the pH at 6.8 - 7.2, the temperature at 20 - 25°C, and the time at 20 - 30 minutes. Under these conditions, micro-enzymatic hydrolysis could appropriately decompose the proteins in fish meat and tortoise meat, and was beneficial for dissolving them into the extract solution in the subsequent extraction step. Surprisingly, after this micro-enzymatic hydrolysis treatment, the specific fishy, bitter and other unpleasant tastes of fish meat and tortoise meat were removed, and almost no fishy, tortoise-like or other strange smells could be smelled in the final oral liquid product. Thus, it was easier for patients to accept, and significantly improved the compliance of taking medicine.

[0016] In particular, the Chinese medicinal materials Schisandra chinensis, Chinese yam, and Polygonatum sibiricum were subjected to the above-mentioned tannin and polyvinylpyrrolidone clarification treatment and further cooling treatment, and then mixed with the fish extract and tortoise extract of the improved process above to prepare an oral liquid that could be stored for 24 months without turbidity or precipitation.

[0017] As a preferred embodiment of the present invention, the preparation method of the Schisandra chinensis paste comprises: taking 5-15g of Schisandra chinensis, crushing it into coarse powder, adding 3-5 times the weight concentration of 90-95% ethanol, soaking it for 20-40 days, filtering the soaking liquid, recovering the ethanol, and concentrating the soaking liquid under reduced pressure to a paste with a relative density of 1.10-1.15 at 60°C.

[0018] As a preferred embodiment of the present invention, the concentration of ethanol in preparing the Schisandra chinensis paste is 92%.

[0019] As a preferred embodiment of the present invention, the preparation method of the yam paste comprises: taking 10-30g of yam, crushing it into coarse powder, adding 3-5 times the weight concentration of 60-80% ethanol, soaking for 20-40 days, filtering the soaking liquid, recovering ethanol, and decompressing and concentrating the soaking liquid to a paste with a relative density of 1.10-1.15 at 60°C.

[0020] As a preferred embodiment of the present invention, the concentration of ethanol in preparing the yam paste is 70%.

[0021] As a preferred embodiment of the present invention, when preparing the polygonatum sibiricum decoction, the amount of water added is 5-7 times the weight of the polygonatum sibiricum.

[0022] As a preferred embodiment of the present invention, the preparation method of the polygonatum decoction comprises: taking 50-70g of polygonatum, cutting into thin slices, adding 5-7 times the weight of water to soak for 0.5-1 hour, decocting twice, each time for 1-1.5 hours, combining the two decoctions, filtering, and cooling to 60-80°C.

[0023] In the present invention, tannin mainly combines with proteins and colloids (such as mucus and polysaccharides in yam) in the liquid medicine to form precipitation, thereby improving clarity; it can also reduce high molecular impurities in the decoction of polygonatum, and avoid the subsequent precipitation. As a preferred embodiment of the present invention, the amount of tannin added is 0.05%-0.08% of the weight of the mixed liquid made of Schisandra chinensis paste, Chinese yam paste and polygonatum decoction. If the amount of tannin added is less than 0.05%, the clarification effect is not good, and the stability of the oral liquid is also affected. Because Schisandra chinensis and polygonatum contain more flavonoids and polyphenols, if the amount of tannin added is higher than 0.08%, tannin may combine with part of the flavonoids, affecting the content of the effective ingredients, and may produce excessive precipitation, affecting subsequent filtration.

[0024] As a preferred embodiment of the present invention, when adding tannin for clarification, the temperature of the mixed solution is controlled to 25-35° C., more preferably 30-35° C. Within this temperature range, tannin is more conducive to the clarification effect.

[0025] In the present invention, polyvinylpyrrolidone can selectively adsorb the excessive tannins and polyphenols in Schisandra chinensis and Polygonatum sibiricum, reduce the subsequent precipitation risk, and improve the stability of the oral liquid; and can further remove the components that may cause color deepening, making the medicinal liquid clearer. Although increasing the addition amount of polyvinylpyrrolidone is beneficial to improving the clarification effect, it will affect the content of active ingredients. As a preferred embodiment of the present invention, the addition amount of polyvinylpyrrolidone is 0.1%-0.15% of the weight of the mixed solution prepared from the Schisandra chinensis extract, Dioscorea opposita extract and Polygonatum sibiricum decoction.

[0026] To further improve the clarification effect and the stability of the oral liquid, the present invention adds steps of cooling (5-15°C, preferably 10-15°C), standing and re-filtering after clarification with polyvinylpyrrolidone, which not only helps to improve the stability but also avoids the loss of active ingredients.

[0027] Experiments show that clarifying the medicinal liquid by first adding tannin, filtering and then adding polyvinylpyrrolidone for clarification, and further performing cooling, standing and re-filtering treatment significantly improves the stability and taste of the oral liquid and does not affect its medicinal efficacy.

[0028] The fresh meat of Aristichthys nobilis or Hypophthalmichthys molitrix described in the present invention is obtained by removing the head, tail, skin, bones and internal organs from Aristichthys nobilis or Hypophthalmichthys molitrix in Cyprinidae.

[0029] The fresh meat of Chinemys reevesii, Mauremys mutica or Cuora flavomarginata described in the present invention is obtained by removing the head, shell, plate, bones and internal organs from Chinemys reevesii, Mauremys mutica or Cuora flavomarginata in Testudinidae.

[0030] As a preferred embodiment of the present invention, relative to the weight of fish meat, the dosage of chymotrypsin is 0.05%-0.1%, and the dosage of cathepsin is 0.01%-0.05%.

[0031] As a preferred embodiment of the present invention, relative to the weight of turtle meat, the dosage of chymotrypsin is 0.05%-0.1%, and the dosage of cathepsin is 0.01%-0.05%.

[0032] In the present invention, chymotrypsin mainly hydrolyzes the peptide bonds of aromatic amino acids (tyrosine, tryptophan, phenylalanine), which helps to improve the protein structure; cathepsin can degrade myofibrillar protein and collagen, promote the degradation of fish meat and turtle meat proteins, and is used for softening tissues or producing small molecule peptides. Through the combined microenzymolysis of chymotrypsin and cathepsin, the present invention significantly reduces the unpleasant tastes such as fishy smell and bitterness unique to fish meat and turtle meat.

[0033] As a preferred embodiment of the present invention, the Ziyin Qiangshen Oral Liquid is prepared from the following raw materials by weight ratio: 5-15 g of Schisandra chinensis, 10-30 g of Dioscorea opposita, 50-70 g of Polygonatum sibiricum, 80-120 g of turtle extract, 80-120 g of fish extract, and made into 1000 mL of oral liquid.

[0034] As a further preferred embodiment of the present invention, the Ziyin Qiangshen Oral Liquid is prepared from the following raw materials by weight ratio: 10-15 g of Schisandra chinensis, 15-30 g of Dioscorea opposita, 55-60 g of Polygonatum sibiricum, 80-120 g of turtle extract, 80-120 g of fish extract, and made into 1000 mL of oral liquid.

[0035] As a further preferred embodiment of the present invention, the Ziyin Qiangshen Oral Liquid is prepared from the following raw materials by weight ratio: 10 g of Schisandra chinensis, 20 g of Dioscorea opposita, 60 g of Polygonatum sibiricum, 100 g of turtle extract, 100 g of fish extract, and made into 1000 mL of oral liquid.

[0036] The filtration method described in the present invention can be selected from Buchner filtration or diatomaceous earth filtration.

[0037] The sweetening agent described in the present invention can be aspartame.

[0038] The sterilization of the present invention can be high-pressure steam sterilization, for example, at 105-115 °C for 20-30 minutes.

[0039] By improving the original production method, the shelf life of the Ziyin Qiangshen Oral Liquid prepared in the present invention can be increased to 24 months, without suspension, turbidity, delamination or precipitation; and the fishy smell, bitter taste and other abnormal odors are removed, the taste is improved, and the compliance of taking medicine is improved. Detailed Embodiments

[0040] In order to make the above objects, features and advantages of the present invention more obvious and understandable, the detailed embodiments of the present invention will be described below. Many specific details are set forth in the following description in order to fully understand the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0041] For the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or range of values, and each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded within the range.

[0042] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although this invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of this invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the said documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0043] Without departing from the scope or spirit of this invention, various improvements and changes can be made to the specific embodiments of the description of this invention, which are obvious to those skilled in the art. Other embodiments obtained from the description of this invention are obvious to those skilled in the art. The description and examples of this application are merely exemplary.

[0044] Regarding the use of "comprising", "including", "having", "containing", etc. in this article, they are all open-ended terms, meaning including but not limited to.

[0045] The technical solutions described in this invention, unless otherwise specified, are all conventional solutions in the art. The reagents or raw materials used, unless otherwise specified, are all purchased from commercial channels or have been made public.

[0046] Example 1

[0047] This example provides a production method for Ziyin Qiangsheng Oral Liquid medicine, which is as follows:

[0048] 1) Take 10 g of Schisandra chinensis, crush it into coarse powder, add 40 g of ethanol with a concentration of 92%, soak for 30 days, filter the soaking solution, recover the ethanol, and concentrate the soaking solution under reduced pressure to obtain Schisandra chinensis clear paste with a relative density of 1.12 at 60 °C.

[0049] Take 20 g of Dioscorea opposita, crush it into coarse powder, add 80 g of ethanol with a concentration of 70%, soak for 30 days, filter the soaking solution, recover the ethanol, and concentrate the soaking solution under reduced pressure to obtain Dioscorea opposita clear paste with a relative density of 1.12 at 60 °C.

[0050] Take 60 g of Polygonatum sibiricum, cut it into thin slices, soak it in 360 g of water for 0.5 hour, decoct it twice, each time for 1 hour, combine the decoction liquids of the two times, filter, and cool down to 70 °C to obtain Polygonatum sibiricum decoction liquid.

[0051] 2) Mix the Schisandra chinensis clear paste, Dioscorea opposita clear paste and Polygonatum sibiricum decoction liquid to obtain a mixed liquid, and cool it down to 30 - 35 °C; first add 0.08% of tannin based on the weight of the mixed liquid for clarification; filter; then add 0.15% of polyvinylpyrrolidone based on the weight of the mixed liquid for clarification; filter; cool the filtrate down to 10 - 15 °C, let it stand for 4 hours; filter again to obtain Schisandra chinensis - Dioscorea opposita - Polygonatum sibiricum mixed extract.

[0052] 3) Mix 100 g of the mixed extract of Schisandra chinensis, Dioscorea opposita, and Polygonatum sibiricum, 100 g of fish extract, and 100 g of tortoise extract, filter the mixture, add 6 g of aspartame, stir well, add water to make 1000 ml, stir well, fill into 10-ml bottles, seal the bottles, and sterilize to obtain Ziyin Qiangshen Oral Liquid.

[0053] Preparation method of fish extract: Take 357 g of fresh meat of silver carp, mash it into meat paste with water, add 0.05% of chymotrypsin based on the weight of the fish meat and 0.01% of cathepsin based on the weight of the fish meat, conduct microenzymatic hydrolysis, control the pH at 7, the temperature at 25°C, and the time at 25 minutes; after microenzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 1400 g of the extract, mix well, soak for 2 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to 100 g to obtain fish extract; the extract is an aqueous solution containing 3% by weight of sodium citrate and 2% by weight of sodium chloride.

[0054] Preparation method of tortoise extract: Take 714 g of fresh meat of tortoise, mash it into meat paste with water, add 0.08% of chymotrypsin based on the weight of the tortoise meat and 0.02% of cathepsin based on the weight of the tortoise meat, conduct microenzymatic hydrolysis, control the pH at 7, the temperature at 25°C, and the time at 30 minutes; after microenzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 2800 g of the extract, mix well, soak for 2 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to 100 g to obtain tortoise extract; the extract is an aqueous solution containing 5 wt% of sodium citrate and 1 wt% of sodium chloride.

[0055] Example 2

[0056] This example provides a production method of Ziyin Qiangshen Oral Liquid medicine, which is as follows:

[0057] 1) Take 10 g of Schisandra chinensis, crush it into coarse powder, add 40 g of ethanol with a concentration of 92%, soak for 30 days, filter the soaking solution, recover the ethanol, and concentrate the soaking solution under reduced pressure to obtain Schisandra chinensis clear paste with a relative density of 1.12 at 60°C.

[0058] Take 20 g of Dioscorea opposita, crush it into coarse powder, add 80 g of ethanol with a concentration of 70%, soak for 30 days, filter the soaking solution, recover the ethanol, and concentrate the soaking solution under reduced pressure to obtain Dioscorea opposita clear paste with a relative density of 1.12 at 60°C.

[0059] Take 60 g of Polygonatum sibiricum, cut it into thin slices, soak it in 360 g of water for 0.5 hour, decoct it twice, each time for 1 hour, combine the two decoction liquids, filter, and cool down to 70°C to obtain Polygonatum sibiricum decoction liquid.

[0060] 2) Mix the Schisandra chinensis extract, Chinese yam extract, and Polygonatum sibiricum decoction, to obtain a mixed solution, and cool it to 30 - 35 °C; first add tannin accounting for 0.05% of the weight of the mixed solution for clarification; filter; then add polyvinylpyrrolidone accounting for 0.12% of the weight of the mixed solution for clarification; filter; cool the filtrate to 10 - 15 °C, let it stand for 4 hours; filter again to obtain the Schisandra chinensis, Chinese yam, and Polygonatum sibiricum mixed extract.

[0061] 3) Mix the Schisandra chinensis, Chinese yam, and Polygonatum sibiricum mixed extract, 100 g of fish extract, and 100 g of turtle extract, filter, add 6 g of aspartame, stir well, add water to 1000 ml, stir well, fill into 10 - ml bottles, seal the bottles, and sterilize to obtain the Ziyin Qiangshen Oral Liquid.

[0062] Preparation method of the fish extract: Take 357 g of fresh meat of silver carp, add water and mash it into a meat paste, add chymotrypsin accounting for 0.08% of the weight of the fish meat and cathepsin accounting for 0.02% of the weight of the fish meat, carry out micro - enzymatic hydrolysis, control the pH to be 6.8, the temperature to be 25 °C, and the time to be 20 minutes; after micro - enzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 1400 g of the extraction solution, mix well, soak for 2 hours, centrifuge to obtain the extract, and concentrate the extract under reduced pressure to 100 g to obtain the fish extract; the extraction solution is an aqueous solution containing 3% by weight of sodium citrate and 2% by weight of sodium chloride.

[0063] Preparation method of the turtle extract: Take 714 g of fresh meat of turtle, add water and mash it into a meat paste, add chymotrypsin accounting for 0.1% of the weight of the turtle meat and cathepsin accounting for 0.02% of the weight of the turtle meat, carry out micro - enzymatic hydrolysis, control the pH to be 6.8, the temperature to be 25 °C, and the time to be 20 minutes; after micro - enzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 2800 g of the extraction solution, mix well, soak for 2 hours, centrifuge to obtain the extract, and concentrate the extract under reduced pressure to 100 g to obtain the turtle extract; the extraction solution is an aqueous solution containing 5 wt% of sodium citrate and 1 wt% of sodium chloride.

[0064] Example 3

[0065] This example provides a production method of the Ziyin Qiangshen Oral Liquid medicine, which is as follows:

[0066] 1) Take 10 g of Schisandra chinensis, crush it into coarse powder, add 40 g of ethanol with a concentration of 92%, soak for 30 days, filter the soaking solution, recover the ethanol, and concentrate the soaking solution under reduced pressure to obtain the Schisandra chinensis extract with a relative density of 1.12 at 60 °C.

[0067] Take 20 g of Chinese yam, crush it into coarse powder, add 80 g of ethanol with a concentration of 70%, soak for 30 days, filter the soaking solution, recover the ethanol, and concentrate the soaking solution under reduced pressure to obtain the Chinese yam extract with a relative density of 1.12 at 60 °C.

[0068] Take 60 g of polygonatum sibiricum, cut it into thin slices, soak it in 360 g of water for 0.5 hour, decoct it twice, each time for 1 hour, combine the decoctions of the two times, filter, and cool it to 70 °C to obtain the polygonatum sibiricum decoction.

[0069] 2) Mix the schisandra chinensis extract, Chinese yam extract and polygonatum sibiricum decoction to obtain a mixed solution, and cool it to 30 - 35 °C; first add tannin accounting for 0.06% of the weight of the mixed solution for clarification; filter; then add polyvinylpyrrolidone accounting for 0.1% of the weight of the mixed solution for clarification; filter; cool the filtrate to 10 - 15 °C, stand for 6 hours; filter again to obtain the schisandra chinensis, Chinese yam and polygonatum sibiricum mixed extract.

[0070] 3) Mix the schisandra chinensis, Chinese yam and polygonatum sibiricum mixed extract, 100 g of fish extract and 100 g of tortoise extract, filter, add 6 g of aspartame, stir well, add water to 1000 ml, stir well, fill into 10 - ml bottles, seal the bottles, and sterilize to obtain the Ziyin Qiangshen Oral Liquid.

[0071] Preparation method of fish extract: Take 357 g of fresh meat of silver carp, add water and mash it into meat paste, add chymotrypsin accounting for 0.1% of the weight of the fish meat and cathepsin accounting for 0.05% of the weight of the fish meat, carry out micro - enzymatic hydrolysis, control the pH to 7.2, the temperature to 20 °C, and the time to 25 minutes; after micro - enzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 1400 g of extraction solution, mix well, soak for 2 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to 100 g to obtain the fish extract; the extraction solution is an aqueous solution containing 3% by weight of sodium citrate and 2% by weight of sodium chloride.

[0072] Preparation method of tortoise extract: Take 714 g of fresh meat of tortoise, add water and mash it into meat paste, add chymotrypsin accounting for 0.08% of the weight of the tortoise meat and cathepsin accounting for 0.05% of the weight of the tortoise meat, carry out micro - enzymatic hydrolysis, control the pH to 7.2, the temperature to 20 °C, and the time to 25 minutes; after micro - enzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 2800 g of extraction solution, mix well, soak for 2 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to 100 g to obtain the tortoise extract; the extraction solution is an aqueous solution containing 5 wt% of sodium citrate and 1 wt% of sodium chloride.

[0073] Control Example 1

[0074] The production steps of the Ziyin Qiangshen Oral Liquid in this control example are as follows:

[0075] 1), Take 10 g of schisandra chinensis, crush it into coarse powder, add 40 g of ethanol (concentration 92%), soak for 30 days, filter the soaking solution, recover ethanol, and concentrate the soaking solution under reduced pressure to obtain an extract (schisandra chinensis extract) with a relative density of 1.12 at 60 °C.

[0076] 2), Take 2% of the weight of Schisandra chinensis extract as gelatin, add 5 times the weight of water of gelatin to dissolve the gelatin, add the gelatin solution to the Schisandra chinensis extract, stir to make a Schisandra chinensis emulsion, and set aside;

[0077] 3), Take 20 g of Chinese yam, crush it into coarse powder, add 80 g of ethanol (concentration 70%), soak for 30 days, filter the soaking solution, recover the ethanol, and concentrate the soaking solution under reduced pressure to a clear extract with a relative density of 1.12 at 60 °C (Chinese yam clear extract);

[0078] 4), Take 60 g of Polygonatum sibiricum, cut it into thin slices, add 360 g of water and soak for 0.5 hour, decoct twice, each time for 1 hour, combine the two decoction liquids, filter, and cool down to 70 °C to obtain the Polygonatum sibiricum decoction liquid;

[0079] 5), While the Polygonatum sibiricum decoction liquid is still hot, add 100 g of fish extract, stir, boil for 0.5 hour, then simmer for 15 minutes, successively add the Schisandra chinensis emulsion, Chinese yam clear extract and 100 g of turtle extract, mix well, filter, add 6 g of aspartame, stir well, add water to 1000 ml, stir well, fill into 10 ml bottles, seal the bottles, sterilize to obtain Ziyin Qiangshen Oral Liquid.

[0080] Method for preparing turtle extract: Remove the head, shell, plate, bone and internal organs of the turtle, take 714 g of fresh meat and mash it into meat paste, add 4 times the weight of the extract, mix the meat paste evenly in the extract, soak for 2 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to obtain 100 g of turtle extract. The extract is an aqueous solution containing 5 wt% sodium citrate and 1 wt% sodium chloride.

[0081] Method for preparing fish extract: Remove the head, tail, skin, bone and internal organs of the silver carp, take 357 g of fresh meat and mash it into meat paste, add 4 times the weight of the extract, mix the meat paste evenly in the extract, soak for 2 hours, centrifuge to obtain the extract, and concentrate the extract under reduced pressure to obtain 100 g of fish extract. The extract is an aqueous solution containing 3 wt% sodium citrate and 2 wt% sodium chloride.

[0082] Comparative Example 2

[0083] The difference between the production method of Ziyin Qiangshen Oral Liquid in this comparative example and that in Example 1 is only that: the fish extract and turtle extract are prepared according to the method of Comparative Example 1 respectively.

[0084] Comparative Example 3

[0085] The difference between the production method of Ziyin Qiangshen Oral Liquid in this comparative example and that in Example 1 is only that: in step 2), the step of clarifying with polyvinylpyrrolidone is omitted, that is, only tannin is used for clarification, and the dosage of tannin is 0.15% of the weight of the mixed solution.

[0086] Comparative Example 4

[0087] The difference between the production method of Ziyin Qiangshen Oral Liquid in this comparative example and that in Example 1 is only that: in step 2), the step of clarifying with tannin is omitted, that is, only polyvinylpyrrolidone is used for clarification, and the dosage of polyvinylpyrrolidone is 0.25% of the weight of the mixed solution.

[0088] Comparative Example 5

[0089] The difference between the production method of Ziyin Qiangshen Oral Liquid in this comparative example and that in Example 1 is only that: after clarification with tannin and polyvinylpyrrolidone in step 2), the steps of cooling the filtrate to 10 - 15°C, standing, and filtering again are omitted.

[0090] Comparative Example 6

[0091] The difference between the production method of Ziyin Qiangshen Oral Liquid in this comparative example and that in Example 1 is only that: the preparation methods of fish extract and turtle extract are different, and cathepsin is omitted in both. That is, the difference between the preparation method of fish extract and that in Example 1 is that only chymotrypsin accounting for 0.2% of the weight of fish meat is added for enzymatic hydrolysis, the pH is controlled at 7, the temperature is 25°C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme; the difference between the preparation method of turtle extract and that in Example 1 is that only chymotrypsin accounting for 0.2% of the weight of turtle meat is added for enzymatic hydrolysis, the pH is controlled at 7, the temperature is 25°C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme.

[0092] Comparative Example 7

[0093] The difference between the production method of Ziyin Qiangshen Oral Liquid in this comparative example and that in Example 1 is only that: the preparation methods of fish extract and turtle extract are different, and chymotrypsin is omitted in both. That is, the difference between the preparation method of fish extract and that in Example 1 is that only cathepsin accounting for 0.1% of the weight of fish meat is added for enzymatic hydrolysis, the pH is controlled at 7, the temperature is 25°C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme; the difference between the preparation method of turtle extract and that in Example 1 is that only cathepsin accounting for 0.1% of the weight of turtle meat is added for enzymatic hydrolysis, the pH is controlled at 7, the temperature is 25°C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme.

[0094] Comparative Example 8

[0095] The difference between the production method of Ziyin Qiangshen Oral Liquid in this comparative example and that in Example 1 is only that: chymotrypsin and cathepsin are replaced with pepsin, that is, in the preparation method of fish extract, only pepsin accounting for 1% of the weight of fish meat is added for enzymatic hydrolysis, the pH is controlled at 3, the temperature is 37°C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme, and the pH is adjusted to 7; in the preparation method of turtle extract, only pepsin accounting for 1% of the weight of turtle meat is added for enzymatic hydrolysis, the pH is controlled at 3, the temperature is 37°C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme, and the pH is adjusted to 7.

[0096] Comparative Example 9

[0097] The difference between the production method of Ziyin Qiangsheng Oral Liquid in this comparative example and that in Example 1 is only that: chymotrypsin and cathepsin are replaced by trypsin, that is, in the preparation method of fish extract, only 1% of the weight of fish meat of trypsin is added for enzymatic hydrolysis, the pH is controlled at 7.5, the temperature is 37 °C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme; in the preparation method of turtle extract, only 1% of the weight of turtle meat of trypsin is added for enzymatic hydrolysis, the pH is controlled at 7.5, the temperature is 37 °C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme.

[0098] Comparative Example 10

[0099] The difference between the production method of Ziyin Qiangsheng Oral Liquid in this comparative example and that in Example 1 is only that: chymotrypsin and cathepsin are replaced by papain, that is, in the preparation method of fish extract, only 1% of the weight of fish meat of papain is added for enzymatic hydrolysis, the pH is controlled at 7.0, the temperature is 50 °C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme; in the preparation method of turtle extract, only 1% of the weight of turtle meat of papain is added for enzymatic hydrolysis, the pH is controlled at 7.0, the temperature is 50 °C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme.

[0100] Comparative Example 11

[0101] The difference between the production method of Ziyin Qiangsheng Oral Liquid in this comparative example and that in Example 1 is only that: chymotrypsin and cathepsin are replaced by bromelain, that is, in the preparation method of fish extract, only 1% of the weight of fish meat of bromelain is added for enzymatic hydrolysis, the pH is controlled at 7.0, the temperature is 50 °C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme; in the preparation method of turtle extract, only 1% of the weight of turtle meat of bromelain is added for enzymatic hydrolysis, the pH is controlled at 7.0, the temperature is 50 °C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme.

[0102] Comparative Example 12

[0103] The difference between the production method of Ziyin Qiangsheng Oral Liquid in this comparative example and that in Example 1 is only that: chymotrypsin and cathepsin are replaced by carica papaya protease, that is, in the preparation method of fish extract, only 1% of the weight of fish meat of carica papaya protease is added for enzymatic hydrolysis, the pH is controlled at 7.0, the temperature is 50 °C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme; in the preparation method of turtle extract, only 1% of the weight of turtle meat of carica papaya protease is added for enzymatic hydrolysis, the pH is controlled at 7.0, the temperature is 50 °C, and the time is 60 minutes; after enzymatic hydrolysis, the temperature is raised to inactivate the enzyme.

[0104] Experiment 1 Long-term Stability Test

[0105] Test method: The test samples were placed in an incubator (25°C, relative humidity 60%) and stored for 24 months. Detection was carried out at 0, 3, 6, 9, 12, 18, and 24 months respectively. Check the appearance, identification, and microbial limit.

[0106] This product is a liquid ranging from light brownish yellow to brownish red.

[0107] Appearance: Observe whether there are abnormal color changes, whether there are suspended substances, turbidity, layering, or precipitation.

[0108] Identification: Qualitative identification was carried out by thin layer chromatography, and polygonatum sibiricum and schisandra chinensis should be detected.

[0109] Microbial limit: The method specified in the 2020 edition of the Chinese Pharmacopoeia was adopted.

[0110] The test results are shown in Table 1 below.

[0111] Table 1

[0112]

[0113]

[0114] √ indicates compliance, × indicates non-compliance, and / indicates not tested.

[0115] From the long-term stability test results in Table 1, it can be seen that compared with the existing method, the oral liquid prepared by the improved method of the present invention significantly improves the stability. There are no suspended substances, layering, or precipitation phenomena after 24 months of storage; and the identification and microbial limit also meet the requirements. In Comparative Example 1, layering and precipitation phenomena occurred at 6 months in the original process. In Comparative Example 2, the improved traditional Chinese medicine treatment method and the original preparation methods of fish extract and turtle extract were used, and the shelf life was extended to 6 months, but layering and precipitation phenomena occurred at 9 months. In Comparative Examples 3 to 5, the improved preparation methods of fish extract and turtle extract were used, and the shelf life could be extended to 18 months. In Comparative Examples 6 and 7, chymotrypsin and cathepsin were used respectively to prepare fish extract and turtle extract, and the improved traditional Chinese medicine treatment method was adopted, and the shelf life could be extended to 12 months. In Comparative Examples 8 to 12, pepsin, trypsin, papain, bromelain, and carica papaya protease were used respectively to prepare fish extract and turtle extract, and the improved traditional Chinese medicine treatment method was adopted, and the shelf life could be extended to 9 months.

[0116] Experiment 2 Sensory evaluation

[0117] The blind evaluation method was adopted. 30 evaluators, aged between 25 - 32 years old, with experience in the research and development of oral liquid drugs, were selected to record the taste evaluation and score, and the results were averaged. Scoring criteria: good (10 points), better (8 points), average (5 points), poor (3 points), very poor (1 point). The evaluation results are shown in Table 2.

[0118] Table 2

[0119] Taste evaluation Scoring Example 1 Fragrant smell, sweet taste, slightly astringent taste, no off-flavor 9.2 Example 2 Fragrant smell, sweet taste, slightly astringent taste, no off-flavor 9.1 Example 3 Fragrant smell, sweet taste, slightly astringent taste, no off-flavor 9.1 Comparative Example 1 Obvious bitter taste of traditional Chinese medicine and obvious fishy smell and other off-flavors 5.5 Comparative Example 2 No obvious taste of traditional Chinese medicine, but obvious fishy smell and other off-flavors 5.6 Comparative Example 3 Slightly bitter taste of traditional Chinese medicine, no fishy smell or off-flavor 7.4 Comparative Example 4 Slightly bitter taste of traditional Chinese medicine, no fishy smell or off-flavor 7.1 Comparative Example 5 Slightly bitter taste of traditional Chinese medicine, no fishy smell or off-flavor 7.4 Comparative Example 6 No taste of traditional Chinese medicine, but still has fishy smell and other off-flavors 6.6 Comparative Example 7 No taste of traditional Chinese medicine, but still has fishy smell and other off-flavors 6.5 Comparative Example 8 No taste of traditional Chinese medicine, but has obvious fishy smell and other off-flavors 6.2 Comparative Example 9 No taste of traditional Chinese medicine, but has obvious fishy smell and other off-flavors 6.1 Comparative Example 10 No taste of traditional Chinese medicine, but has obvious fishy smell and other off-flavors 6.0 Comparative Example 11 No taste of traditional Chinese medicine, but has obvious fishy smell and other off-flavors 5.8 Comparative Example 12 No taste of traditional Chinese medicine, but has obvious fishy smell and other off-flavors 5.8

[0120] As can be seen from the sensory evaluation results in Table 2, compared with the existing methods, the oral liquid prepared by the improved method of the present invention significantly improves the taste, removes the peculiar smells such as the traditional Chinese medicine smell and fishy smell, has a harmonious taste, and is more acceptable to patients. The results of Comparative Example 2 to Comparative Example 5 show that by successively using tannin clarification, polyvinylpyrrolidone clarification and further cooling and standing treatment, the traditional Chinese medicine smell can be better removed. The results of Comparative Example 6 and Comparative Example 7 show that only treating with one enzyme such as chymotrypsin or cathepsin cannot completely remove the peculiar smells such as the fishy smell and bitter taste unique to fish meat and turtle meat. The results of Comparative Example 8 to Comparative Example 12 show that pepsin, trypsin, papain, bromelain and carica papaya protease have little or very limited effect on removing the peculiar smells such as the fishy smell and bitter taste unique to fish meat and turtle meat.

[0121] Although the present invention has been described in detail above with general descriptions, specific embodiments and experiments, on the basis of the present invention, some modifications or improvements can be made, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of the present invention claimed.

Claims

1. A production method of Ziyin Qiangshen oral liquid medicine, characterized in that It includes: 1) Take 5 - 15 g of Schisandra chinensis, impregnate and extract it with ethanol with a concentration of 90 - 95%, and make a Schisandra chinensis clear extract with a relative density of 1.10 - 1.15 at 60 °C; Take 10 - 30 g of Chinese yam, impregnate and extract it with ethanol with a concentration of 60 - 80%, and make a Chinese yam clear extract with a relative density of 1.10 - 1.15 at 60 °C; Take 50 - 70 g of Polygonatum sibiricum, soak it in water, decoct it, and make a Polygonatum sibiricum decoction; 2) Mix the Schisandra chinensis clear extract, Chinese yam clear extract and Polygonatum sibiricum decoction to obtain a mixed solution; first add tannin for clarification; filter; then add polyvinylpyrrolidone for clarification; filter; cool the filtrate to 5 - 15 °C, stand for 4 - 6 hours, and filter again to obtain a mixed extract of Schisandra chinensis, Chinese yam and Polygonatum sibiricum; 3) Mix the mixed extract of Schisandra chinensis, Chinese yam and Polygonatum sibiricum, 80 - 120 g of fish extract and 80 - 120 g of turtle extract, filter, add a sweetening agent, stir well, add water to 1000 mL, stir well, seal, sterilize, and you will get it; The preparation method of the fish extract includes: take 100 g of fresh meat of Aristichthys nobilis or Hypophthalmichthys molitrix, pound it into a meat paste with water, and carry out micro - enzymatic hydrolysis with chymotrypsin and cathepsin, control the pH to be 6.8 - 7.2, the temperature to be 20 - 25 °C, and the time to be 20 - 30 minutes; after micro - enzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 300 g - 500 g of extraction solution, mix well, impregnate for 1 - 3 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to obtain 25 - 30 g of fish extract; the extraction solution is an aqueous solution containing 1 wt% - 10 wt% of sodium citrate and 0.5 wt% - 5 wt% of sodium chloride; The preparation method of the turtle extract includes: take 100 g of fresh meat of Chinemys reevesii, Mauremys mutica or Cuora flavomarginata, pound it into a meat paste with water, and carry out micro - enzymatic hydrolysis with chymotrypsin and cathepsin, control the pH to be 6.8 - 7.2, the temperature to be 20 - 25 °C, and the time to be 20 - 30 minutes; after micro - enzymatic hydrolysis, raise the temperature to inactivate the enzyme, then add 300 - 500 g of extraction solution, mix well, impregnate for 1 - 3 hours, centrifuge to separate the extract, and concentrate the extract under reduced pressure to obtain 10 - 20 g of turtle extract; the extraction solution is an aqueous solution containing 1 wt% - 10 wt% of sodium citrate and 0.5 wt% - 5% of sodium chloride.

2. The production method of the Ziyin Qiangsheng oral liquid drug according to claim 1, characterized in that, The addition amount of tannin is 0.05% - 0.08% of the weight of the mixed solution made from the Schisandra chinensis clear extract, Chinese yam clear extract and Polygonatum sibiricum decoction; and / or, the addition amount of polyvinylpyrrolidone is 0.1% - 0.15% of the weight of the mixed solution made from the Schisandra chinensis clear extract, Chinese yam clear extract and Polygonatum sibiricum decoction.

3. The production method of the Ziyin Qiangshen oral liquid drug according to claim 1 or 2, characterized in that, When adding tannin for clarification, control the temperature of the mixed solution to be 25 - 35 °C, preferably 30 - 35 °C.

4. The production method of the Ziyin Qiangsheng oral liquid drug according to any one of claims 1-3, characterized in that, Relative to the weight of fish meat, the dosage of chymotrypsin is 0.05% - 0.1%, and the dosage of cathepsin is 0.01% - 0.05%; and / or, Relative to the weight of turtle meat, the dosage of chymotrypsin is 0.05% - 0.1%, and the dosage of cathepsin is 0.01% - 0.05%.

5. The production method of the Ziyin Qiangshen Oral Liquid drug according to any one of claims 1-4, characterized in that, The preparation method of the Schisandra chinensis extract includes: taking 5 - 15 g of Schisandra chinensis, pulverizing it into coarse powder, adding 3 - 5 times the weight of ethanol with a concentration of 90 - 95%, impregnating for 20 - 40 days, filtering the impregnation liquid, recovering ethanol, and concentrating the impregnation liquid under reduced pressure to an extract with a relative density of 1.10 - 1.15 at 60°C; Preferably, the concentration of ethanol when preparing the Schisandra chinensis extract is 92%.

6. The production method of Ziyin Qiangsheng Oral Liquid medicine according to any one of claims 1-5, characterized in that The preparation method of the Dioscorea opposita extract includes: taking 10 - 30 g of Dioscorea opposita, pulverizing it into coarse powder, adding 3 - 5 times the weight of ethanol with a concentration of 60 - 80%, impregnating for 20 - 40 days, filtering the impregnation liquid, recovering ethanol, and concentrating the impregnation liquid under reduced pressure to an extract with a relative density of 1.10 - 1.15 at 60°C; Preferably, the concentration of ethanol when preparing the Dioscorea opposita extract is 70%.

7. The production method of Ziyin Qiangshen Oral Liquid drug according to any one of claims 1-6, characterized in that, The preparation method of the Polygonatum sibiricum decoction includes: taking 50 - 70 g of Polygonatum sibiricum, slicing it thinly, soaking it in 5 - 7 times the weight of water for 0.5 - 1 hour, decocting 2 times, each time for 1 - 1.5 hours, combining the decoction liquids of the 2 times, filtering, and cooling to 60 - 80°C.

8. The production method of Ziyin Qiangsheng Oral Liquid drug according to any one of claims 1-7, characterized in that, The Ziyin Qiangshen Oral Liquid, by weight ratio, mainly consists of 10 - 15 g of Schisandra chinensis, 15 - 30 g of Dioscorea opposita, 55 - 60 g of Polygonatum sibiricum, 80 - 120 g of turtle extract, and 80 - 120 g of fish extract, and is made into 1000 mL of oral liquid.

9. The production method of Ziyin Qiangshen Oral Liquid medicine according to any one of claims 1-7, characterized in that, The Ziyin Qiangshen Oral Liquid, by weight ratio, mainly consists of 10 g of Schisandra chinensis, 20 g of Dioscorea opposita, 60 g of Polygonatum sibiricum, 100 g of turtle extract, and 100 g of fish extract, and is made into 1000 mL of oral liquid.

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