Application of polypeptide polymer in improving stability of traditional Chinese medicine preparation and preparation method of traditional Chinese medicine preparation

Abstract

The invention belongs to the technical field of traditional Chinese medicine production, and particularly relates to application of a polypeptide polymer in improving stability of a traditional Chinese medicine preparation and a preparation method of the traditional Chinese medicine preparation. The polypeptide polymer is used for preparing the traditional Chinese medicine preparation; the polypeptide polymer comprises one or more of 3-9 peptide polymers; the molecular weight of the polypeptide polymer is 200 to 5000Da. The polypeptide polymer is helpful for constraining small molecules in traditional Chinese medicines (constraining by utilizing cavity structures in polypeptide molecules and covalent bonds formed by lone pair electron pairs of N on peptide bonds and the small molecules of the traditional Chinese medicines) and uniformly dispersing components of the traditional Chinese medicine preparation, so that the traditional Chinese medicines can form ointment, powder and water aqua more easily, and compared with a traditional medicine preparation method, the method has the advantages of less pollution and low cost. The traditional Chinese medicine preparation is short in preparation time, easy to store and carry and good in stability, and the medicine effect is slightly affected.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine production, and specifically relates to the application of polypeptide polymer in improving the stability of traditional Chinese medicine preparations and a preparation method of traditional Chinese medicine preparations. Background Art

[0002] Chinese medicine preparations refer to drugs that are processed into certain specifications and can be directly used in clinical practice under the guidance of traditional Chinese medicine theory and in accordance with the prescriptions specified in the Chinese Pharmacopoeia and Chinese Hospital Preparation Standards. Due to the complexity and diversity of the formula and brewing process of Chinese medicine, as well as the lack of relevant talents, the development of stable aqueous preparations, ointments, and powders of Chinese medicine is difficult. The complexity of industrial equipment is not conducive to large-scale production, which is also an important factor restricting the development of Chinese medicine.

[0003] Although there are technical solutions for extracting Chinese herbal medicine slices in the prior art, a large amount of impurities and macromolecular substances are usually obtained when the ingredients are obtained, resulting in patients needing to take a larger dose to ensure the efficacy. In addition, due to the strong hygroscopicity of the extract powder, it will show too much instability in the actual production process of the preparation. Although the hygroscopicity of the extract can be reduced to a certain extent by adding excipients, the effect is often not good, and the addition of excipients will also increase the volume of the preparation, thereby increasing the dosage for patients. Summary of the invention

[0004] The purpose of the present invention is to make up for the deficiencies of the prior art, ensure the efficacy of Chinese medicine preparations, and make the Chinese medicine preparations more stable.

[0005] The present invention provides application of polypeptide polymer in improving the stability of traditional Chinese medicine preparations; the polypeptide polymer comprises one or more of 3-9 peptide polymers; the molecular weight of the polypeptide polymer is 200-5000Da.

[0006] Preferably, the dosage form of the traditional Chinese medicine preparation includes aqueous solution, ointment or powder.

[0007] Preferably, the polypeptide polymer is one or more of a 4-peptide polymer, a 6-peptide polymer, a 7-peptide polymer and a 9-peptide polymer;

[0008] The 4-peptide polymer includes tetrapeptide-21 and / or tetrapeptide-7;

[0009] The 6-peptide polymer includes hexapeptide-3;

[0010] The 7-peptide polymer includes β-amyloid peptide fragment polypeptides 4-10;

[0011] The 9-peptide polymer includes nonapeptide-1.

[0012] The present invention also provides a method for preparing a Chinese medicine preparation, comprising the following steps:

[0013] The Chinese medicine and the solvent are mixed and boiled, the solid and the liquid are separated, and the liquid medicine is collected;

[0014] The drug solution and the polypeptide polymer are mixed and then subjected to ultrafiltration treatment to obtain a Chinese medicine aqueous solution;

[0015] The polypeptide polymer includes one or more of 3-9 peptide polymers;

[0016] The molecular weight of the polypeptide polymer is 200-5000Da.

[0017] Preferably, after obtaining the Chinese medicine aqueous solution, the process further comprises: freeze-drying the Chinese medicine aqueous solution at -15 to -25°C for 45 to 75 minutes, heating the temperature to 0 to 5°C at a heating rate of 3 to 5°C / 10 minutes, and filtering at a pressure of -0.10 to -0.09 MPA to obtain a Chinese medicine ointment.

[0018] Preferably, after obtaining the Chinese medicine aqueous solution, it also includes: freeze-drying the Chinese medicine aqueous solution at -20°C for 45 to 75 minutes, heating it to 0 to 5°C at a heating rate of 1 to 3°C / 10min, treating it at a pressure of -0.10 to -0.09MPA for 50 to 65 minutes, heating it to 0 to 5°C at a heating rate of 1 to 3°C / 10min, and filtering it at a pressure of -0.10 to -0.09MPA to obtain a Chinese medicine powder.

[0019] Preferably, the boiling step comprises: boiling the mixture of the traditional Chinese medicine and the solvent for 5 to 15 minutes under high-temperature steam at 175 to 190° C., adjusting the high-temperature steam flow rate to maintain a slightly boiling state, and boiling for 0.5 to 1 hour.

[0020] Preferably, the mass ratio of the traditional Chinese medicine to the solvent is (175-340):(400-600).

[0021] Preferably, the raw materials of the Chinese medicine include angelica dahurica, ginger, dried rehmannia root, peony root, siler, cinnamon heart, trichosanthes root, liquorice, ephedra and dried kudzu root; or include rhubarb, liquorice, jujube and honey; or include pinellia, ginger, platycodon, evodia rutaecarpa, peucedanum, turtle shell, immature bitter orange, ginseng and betel nut;

[0022] The solvent includes water and / or anhydrous ethanol.

[0023] Preferably, when the Chinese medicinal raw materials are Angelica dahurica, ginger, dried rehmannia root, peony root, saposhnikovia root, cinnamon bark, trichosanthes root, liquorice, ephedra and dried kudzu, the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is (300-370): (50-70), the polypeptide polymer is a 4-peptide polymer; the solvent is water and anhydrous ethanol;

[0024] When the Chinese medicinal raw materials are rhubarb, liquorice, jujube and honey, the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is (160-190): (40-60), the polypeptide polymer is a 6-peptide polymer and / or a 7-peptide polymer; and the solvent is water;

[0025] When the Chinese medicinal raw materials are pinellia, ginger, platycodon, evodia rutaecarpa, peucedanum chinense, turtle shell, immature bitter orange, ginseng and betel nut, the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is (190-230): (90-120), the polypeptide polymer is a 9-peptide polymer; and the solvent is water.

[0026] Beneficial effects:

[0027] The present invention provides an application of a polypeptide polymer in improving the stability of a traditional Chinese medicine preparation; the polypeptide polymer includes one or more of 3-9 peptide polymers; the molecular weight of the polypeptide polymer is 200-5000Da. The present invention uses polypeptide polymers for the preparation of traditional Chinese medicine preparations, and the addition of polypeptide polymers helps to bind small molecules in traditional Chinese medicine (using the cavity structure in the polypeptide molecule and the lone pair of electrons of N on the peptide bond to form covalent bonds with the traditional Chinese medicine small molecules for binding), uniformly disperses the components of the traditional Chinese medicine preparation, and makes it easier for the traditional Chinese medicine to form ointments, powders, and aqueous preparations. Compared with traditional pharmaceutical methods, the pollution is less, the preparation time is shortened, and it is easy to store and carry, the efficacy is less affected, and the formed traditional Chinese medicine preparation has good stability. DETAILED DESCRIPTION

[0028] The present invention provides application of polypeptide polymer in improving the stability of traditional Chinese medicine preparations; the polypeptide polymer comprises one or more of 3-9 peptide polymers; the molecular weight of the polypeptide polymer is 200-5000Da.

[0029] In the present invention, as an embodiment, the dosage form of the Chinese medicine preparation is an aqueous solution, an ointment or a powder.

[0030] In the present invention, as an embodiment, the polypeptide polymer is one or more of a 4-peptide polymer, a 6-peptide polymer, a 7-peptide polymer and a 9-peptide polymer; as another embodiment, the polypeptide polymer is one or two of a 4-peptide polymer, a 6-peptide polymer, a 7-peptide polymer and a 9-peptide polymer. As an embodiment, the 4-peptide polymer includes tetrapeptide-21 and / or tetrapeptide-7. As an embodiment, the 6-peptide polymer includes hexapeptide-3. As an embodiment, the 7-peptide polymer includes beta-amyloid peptide fragment polypeptide 4-1. As an embodiment, the 9-peptide polymer includes nonapeptide-1.

[0031] The present invention also provides a method for preparing a Chinese medicine preparation, comprising the following steps:

[0032] The Chinese medicine and the solvent are mixed and boiled, the solid and the liquid are separated, and the liquid medicine is collected;

[0033] The drug solution and the polypeptide polymer are mixed and then subjected to ultrafiltration treatment to obtain a Chinese medicine aqueous solution;

[0034] The polypeptide polymer includes one or more of 3-9 peptide polymers;

[0035] The molecular weight of the polypeptide polymer is 200-5000Da.

[0036] The invention comprises the following steps: mixing the traditional Chinese medicine and the solvent, boiling the mixture, separating the solid from the liquid, and collecting the liquid medicine.

[0037] The present invention has no strict requirements on the boiling method, and the conventional boiling method in the art can be used. In the present invention, as an embodiment, the boiling step includes: boiling the mixed solution of the Chinese medicine and the solvent for 5 to 15 minutes under high-temperature steam at 175 to 190°C, adjusting the high-temperature steam flow rate, maintaining a slightly boiling state, and boiling for 0.5 to 1 hour; as another embodiment, the boiling step includes: boiling the mixed solution of the Chinese medicine and the solvent for 5 minutes under high-temperature steam at 180°C, adjusting the high-temperature steam flow rate, maintaining a slightly boiling state, and boiling for 0.8 hours. The boiling of the Chinese medicine of the present invention only requires one step to boil it into a decoction, and there is no need to boil and concentrate repeatedly. The present invention is only described by taking the above method as an example, and it cannot be understood as the entire protection scope of the present invention.

[0038] As an embodiment, the solid-liquid separation method is filtration. As an embodiment, the filtration uses a basket filter, a plate filter, a bag filter or a core filter. As an embodiment, the filter mesh number of the filtration is 80 mesh or more, and the membrane is selected to be 0.001 to 0.01 μm.

[0039] After obtaining the medicinal solution, the present invention mixes the medicinal solution with a polypeptide polymer and then performs ultrafiltration treatment to obtain a Chinese medicine aqueous solution.

[0040] In the present invention, as an embodiment, the pore size of the ultrafiltration membrane used in the ultrafiltration is 1 to 20 nm; as another embodiment, the pore size of the ultrafiltration membrane used in the ultrafiltration is 5 to 15 nm; as another embodiment, the pore size of the ultrafiltration membrane used in the ultrafiltration is 10 nm. As an embodiment, the water flow direction is set to be parallel to the membrane surface of the ultrafiltration membrane during the ultrafiltration process. The present invention has no special requirements for the horizontal rotor used. When using an angular rotor, the placement of the double-sided vertical membrane ultrafiltration tube requires the filter membrane to be laterally opposite and the window to face upward; the single-sided vertical membrane requires the printed scale side to face upward and the membrane surface to face downward. The two symmetrical ultrafiltration tubes need to be balanced, and the mass and center of gravity must be balanced. Ensure that the placement position and direction of the filter elements of the two symmetrical ultrafiltration tubes are consistent. In the present invention, as an embodiment, the ultrafiltration pressure is 0.5 to 0.7 MPA; as another embodiment, the ultrafiltration pressure is 0.6 MPA. As one embodiment, the ultrafiltration uses a swinging bucket rotor and is centrifuged at 4000g for 10 to 40 minutes; as another embodiment, the ultrafiltration uses a swinging bucket rotor and is centrifuged at 4000g for 20 to 30 minutes. As one embodiment, the ultrafiltration uses a fixed angle rotor and is centrifuged at 5000g to 7500g for 10 to 40 minutes; as another embodiment, the ultrafiltration uses a fixed angle rotor and uses an ultrafiltration tube of 3 to 50K and is centrifuged at 7500g for 10 to 40 minutes; as another embodiment, the ultrafiltration uses a fixed angle rotor and uses an ultrafiltration tube of 100K and is centrifuged at 5000g for 10 to 20 minutes.

[0041] In the present invention, as an embodiment, the raw materials of the Chinese medicine include angelica dahurica, ginger, dried rehmannia, peony, siler, cinnamon heart, trichosanthes, licorice, ephedra and dried kudzu; as another embodiment, the raw materials of the Chinese medicine include rhubarb, licorice, jujube and honey; as another embodiment, the raw materials of the Chinese medicine include pinellia, ginger, platycodon, evodia rutaecarpa, peucedanum, turtle shell, immature bitter orange, ginseng and betel nut. As an example, the mass ratio of angelica dahurica, ginger, dried rehmannia, peony, siler, cinnamon heart, trichosanthes, licorice, ephedra and dried kudzu is 30:60:50:40:30:30:30:20:20:30. As an example, the mass ratio of rhubarb, licorice, jujube and honey is 30:20:5:120. As an embodiment, the mass ratio of the pinellia tuber, ginger, platycodon, evodia rutaecarpa, peucedanum chinense, turtle shell, immature bitter orange, ginseng and betel nut is 30:40:20:20:30:30:20:10:10.

[0042] In the present invention, as an embodiment, the solvent includes water and / or anhydrous ethanol; as another embodiment, the solvent is water and anhydrous ethanol; as another embodiment, the solvent is water and. As an embodiment, the mass ratio of the traditional Chinese medicine to the solvent is (175-340): (400-600); as another embodiment, the mass ratio of the traditional Chinese medicine to the solvent is 210:450.

[0043] In the present invention, as an embodiment, the Chinese medicinal raw materials are Angelica dahurica, ginger, dried Rehmannia root, peony root, Saposhnikovia divaricata, cinnamon bark, Trichosanthes kirilowii, liquorice, ephedra and dried kudzu; the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is 300-370:50-70; the polypeptide polymer is a 4-peptide polymer; the solvent is water and anhydrous ethanol; as another embodiment, when the Chinese medicinal raw materials are rhubarb, liquorice, jujube and honey, the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is (160-190): (40-60), and the polypeptide polymer is a 6-peptide polymer and / or a 7-peptide polymer; the solvent is water; as another embodiment, when the Chinese medicinal raw materials are Pinellia ternata, ginger, Platycodon grandiflorum, Evodia rutaecarpa, Peucedanum scutellariae, Carapax trichosanthis, Citrus aurantium, Ginseng and Areca catechu, the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is (190-230): (90-120), and the polypeptide polymer is a 9-peptide polymer; the solvent is water.

[0044] After obtaining the Chinese medicine aqueous solution, as one embodiment, the present invention freeze-dries the Chinese medicine aqueous solution at -15 to -25°C for 45 to 75 minutes, heats the temperature to 0 to 5°C at a heating rate of 3 to 5°C / 10min, and filters at a pressure of -0.10 to -0.09MPA to obtain a Chinese medicine ointment; as another embodiment, the present invention freeze-dries the Chinese medicine aqueous solution at -20°C for 60 minutes, heats the temperature to 0°C at a heating rate of 4°C / 10min, and filters at a pressure of -0.10MPA to obtain a Chinese medicine ointment. In the present invention, as another embodiment, after freeze-drying the Chinese medicine aqueous solution at -20°C for 45 to 75 minutes, the temperature is increased to 0 to 5°C at a temperature increase rate of 1 to 3°C / 10min, treated at a pressure of -0.10 to -0.09MPA for 50 to 65 minutes, the temperature is increased to 0 to 5°C at a temperature increase rate of 1 to 3°C / 10min, and the pressure is filtered at -0.10 to -0.09MPA to obtain a Chinese medicine powder; as another embodiment, after freeze-drying the Chinese medicine aqueous solution at -20°C for 1 hour, the temperature is increased to 0°C at a temperature increase rate of 2°C / 10min, treated at a pressure of -0.10MPA for 60 minutes, the temperature is increased to 0°C at a temperature increase rate of 1°C / 10min, and the pressure is filtered at -0.10MPA to obtain a Chinese medicine powder.

[0045] The present invention adds polypeptide polymers during the preparation of Chinese medicine preparations, which can overcome the complexity and diversity of Chinese medicine formulas and boiling processes, the difficulty in making the finished products into pastes, powders, and stable aqueous preparations that are easy to transport, and the problems of being unfavorable for production. The preparation method provided by the present invention is simple, has low requirements on equipment, and can be industrialized for production. The Chinese medicine preparation obtained by the preparation method of the present invention has strong stability, and at the same time, through methods such as concentration and paste collection, pastes and powders are easier to prepare.

[0046] In order to further illustrate the present invention, the application of the polypeptide polymer provided by the present invention in improving the stability of traditional Chinese medicine preparations and a method for preparing a traditional Chinese medicine preparation are described in detail below in conjunction with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0047] Example 1

[0048] (1) 30 kg of Angelica dahurica, 60 kg of ginger, 50 kg of dried Rehmannia root, 40 kg of Paeonia lactiflora, 30 kg of Saposhnikovia divaricata, 30 kg of Cassia bark, 30 kg of Trichosanthes kirilowii, 20 kg of Licorice root, 20 kg of Ephedra sinica, and 30 kg of Radix Puerariae are crushed with a wall-breaking machine and added into a boiling kettle. 400 kg of deionized water and 50 kg of anhydrous ethanol are added, and 180°C high-temperature steam is quickly introduced into the kettle to heat the Chinese medicine in the kettle. After the Chinese medicine in the kettle boils for 5 minutes, the switch opening is adjusted to 10-30%, the temperature is 100-120°C, and the mixture is carefully boiled for 1 hour. After boiling, the mixture is introduced into a filter to remove the Chinese herbal medicine residue and collect the liquid medicine.

[0049] (2) The drug solution collected in step (1) is introduced into a prefabricated kettle, 60 kg of a tetrapeptide polymer with a molecular weight of 389.4 Da (tetrapeptide-21, CAS number: 960608-17-7, purchased from Nanjing Leon Biotechnology Co., Ltd.) is added, and stirred evenly. When the stirred drug solution is cooled to below 45°C, most of the water is removed from the drug solution using an ultrafiltration machine, and the mother liquor after ultrafiltration is introduced into a freeze dryer, and the temperature is set to -20°C. After freeze drying for 1 hour, the temperature is increased to 0°C at a rate of 2°C / 10min, and the pressure is -0.10MPA. The temperature is maintained at 0°C for 1 hour, and the temperature is increased from 0 to 10°C at a rate of 1°C / 10min and a pressure of -0.10MPA, and then filtered to obtain a freeze-dried powder product.

[0050] Comparative Example 1

[0051] The same as Example 1, the only difference is that in step (2), no tetrapeptide polymer is added, and the liquid medicine collected in step (1) is directly treated in the manner of step (2) to obtain a lyophilized powder product.

[0052] Example 2

[0053] (1) 30 kg of Angelica dahurica, 60 kg of ginger, 50 kg of dried Rehmannia root, 40 kg of Paeonia lactiflora, 30 kg of Saposhnikovia divaricata, 30 kg of Cassia bark, 30 kg of Trichosanthes kirilowii, 20 kg of Licorice root, 20 kg of Ephedra sinica, and 30 kg of Radix Puerariae are crushed with a wall-breaking machine and added to a boiling kettle. 400 kg of deionized water and 50 kg of anhydrous ethanol are added, and 180°C high-temperature steam is quickly introduced into the kettle to heat the Chinese medicine in the kettle. After the Chinese medicine in the kettle boils for 5 minutes, the flow rate of high-temperature steam is adjusted to maintain a slightly boiling state. The mixture is carefully boiled for 1 hour. After boiling, the mixture is introduced into a filter to remove the Chinese herbal medicine residue and collect the liquid medicine.

[0054] (2) The drug solution collected in step (1) is introduced into the prefabricated kettle, 60 kg of a tetrapeptide polymer with a molecular weight of 456.5 Da (tetrapeptide-7, CAS number: 77727-17-4, purchased from Shanghai Hongpeptide Biotechnology Co., Ltd., item number: 164P19) is added, and stirred evenly. When the stirred drug solution is cooled to below 45°C, most of the water is removed from the drug solution using an ultrafilter, and the mother liquor after ultrafiltration is introduced into a freeze dryer, and the temperature is set to -20°C. After freeze drying for 1 hour, the temperature is increased to 0°C at a rate of 2°C / 10min, and the pressure is -0.10MPA. The temperature is maintained at 0°C for 1 hour, and the temperature is increased from 0 to 10°C at a rate of 1°C / 10min and a pressure of -0.10MPA. The product is filtered to obtain a freeze-dried powder product.

[0055] Comparative Example 2

[0056] The same as Example 2, the only difference is that in step (2), no tetrapeptide polymer is added, and the drug solution collected in step (1) is directly treated in the manner of step (2) to obtain a lyophilized powder product.

[0057] Example 3

[0058] (1) 30 kg of rhubarb, 20 kg of licorice, 5 kg of jujube, and 120 kg of honey were crushed with a wall-breaking machine and added to a boiling kettle. 400 kg of deionized water was added and 180 °C high-temperature steam was quickly introduced into the kettle to heat the Chinese medicine in the kettle. After the Chinese medicine in the kettle boiled for 5 minutes, the flow rate of high-temperature steam was adjusted to maintain a slight boiling state. The mixture was carefully boiled for 1 hour. After boiling, the mixture was introduced into a filter to remove the Chinese herbal medicine residue and collect the liquid medicine.

[0059] (2) The drug solution collected in step (1) is introduced into a prefabricated kettle, 50 kg of a hexapeptide polymer with a molecular weight of 846.96 Da (hexapeptide-3, CAS No.: 1205679-02-2, purchased from Nanjing Peptide Industry Biotechnology Co., Ltd.) is added, and stirred evenly. When the stirred drug solution is cooled to below 45°C, most of the water is removed from the drug solution using an ultrafilter, and the mother liquor after ultrafiltration is introduced into a freeze dryer, the temperature is set to -20°C, and after freeze drying for 1 hour, the temperature is increased to 0°C at a rate of 2°C / 10min, and the pressure is -0.10 MPA, and suction filtration is performed to obtain a paste product.

[0060] Comparative Example 3

[0061] The same as Example 3, the only difference is that in step (2), no tetrapeptide polymer is added, and the liquid medicine collected in step (1) is directly treated in the manner of step (2) to obtain a paste product.

[0062] Example 4

[0063] (1) 30 kg of rhubarb, 20 kg of licorice, 5 kg of jujube, and 120 kg of honey were crushed with a wall-breaking machine and added to a boiling kettle. 400 kg of deionized water was added and 180 °C high-temperature steam was quickly introduced into the kettle to heat the Chinese medicine in the kettle. After the Chinese medicine in the kettle boiled for 5 minutes, the flow rate of high-temperature steam was adjusted to maintain a slight boiling state. The mixture was carefully boiled for 1 hour. After boiling, the mixture was introduced into a filter to remove the Chinese herbal medicine residue and collect the liquid medicine.

[0064] (2) The drug solution collected in step (1) is introduced into a prefabricated kettle, and 30 kg of a hexapeptide polymer with a molecular weight of 846.96 Da (hexapeptide-3, CAS number: 1205679-02-2, purchased from Nanjing Peptide Industry Biotechnology Co., Ltd., CAS number: 1205679-02-2) and 20 kg of a heptapeptide polymer with a molecular weight of 880.917 Da (β-amyloid peptide fragment polypeptide 4-10, CAS number: 477284-32-5, purchased from Nantong Eastern Amino Acid Co., Ltd.) are added, and stirred evenly. When the stirred drug solution is cooled to below 45° C., most of the water is removed from the drug solution using an ultrafilter, and the mother liquor after ultrafiltration is introduced into a freeze dryer, and the temperature is set to -20° C. After freeze drying for 1 hour, the temperature is increased to 0° C. at a heating rate of 2° C. / 10 min, and the pressure is -0.10 MPA, and suction filtration is performed to obtain a paste product.

[0065] Comparative Example 4

[0066] The same as Example 4, the only difference is that in step (2), no tetrapeptide polymer is added, and the liquid medicine collected in step (1) is directly treated in the manner of step (2) to obtain a paste product.

[0067] Example 5

[0068] (1) 30 kg of Pinellia ternata, 40 kg of ginger, 20 kg of Platycodon grandiflorum, 20 kg of Evodia rutaecarpa, 30 kg of Peucedanum chinense, 30 kg of Carapax Trionycis, 20 kg of Citrus aurantium, 10 kg of Ginseng, and 10 kg of Areca nut were crushed with a wall-breaking machine and added to a boiling kettle. 600 kg of deionized water was added and 180°C high-temperature steam was quickly introduced into the kettle to heat the Chinese medicine in the kettle. After the Chinese medicine in the kettle boiled for 5 minutes, the flow rate of high-temperature steam was adjusted to maintain a slightly boiling state. The mixture was carefully boiled for 30 minutes. After boiling, the mixture was introduced into a filter to remove the Chinese herbal medicine residue and collect the liquid medicine.

[0069] (2) The drug solution collected in step (1) is introduced into a prefabricated kettle, 100 kg of a nonapeptide polymer with a molecular weight of 1206.6 Da (nonapeptide-1, CAS number: 158563-45-2, purchased from Hangzhou Gutuo Biotechnology Co., Ltd., item number: GT-082) is added, and stirred evenly. When the stirred drug solution is cooled to below 45°C, most of the water is removed from the drug solution using an ultrafilter, and the mother liquor after ultrafiltration is introduced into a freeze dryer, the temperature is set to -20°C, and after freeze drying for 1 hour, the temperature is increased to 0°C at a rate of 2°C / 10min, and the pressure is -0.10MPA, and suction filtration is performed to obtain a paste product.

[0070] Comparative Example 5

[0071] The same as Example 5, the only difference is that in step (2), no tetrapeptide polymer is added, and the liquid medicine collected in step (1) is directly treated in the manner of step (2) to obtain a paste product.

[0072] Test Example 1

[0073] 1. Freeze-dried powder product testing

[0074] (1) With reference to the Technical Guidelines for Production Quality of Freeze-dried Powder Injections (Chemical Preparations), the freeze-dried powder products of Test Examples 1 and 2 and Comparative Examples 1 and 2 were tested. The results are shown in Table 1.

[0075] Table 1 Test items and test results of freeze-dried powder products

[0076] sample Effective drug suspension rate Moisture content Residue after dumping Residue after washing Example 1 ＞95％ ＜3％ ＜5％ ＜0.5％ Comparative Example 1 92.3％ 4.2％ 8.5％ 2.4％ Example 2 ＞94％ ＜2.8％ ＜4.8％ ＜0.6％ Comparative Example 2 91.5％ 5.1％ 9.6％ 3.3％

[0077] As can be seen from Table 1, this solution uses polypeptide polymers for preparation. Compared with traditional pharmaceutical methods, the prepared products have simple production processes, less pollution, are easy to store and carry, and have less impact on efficacy.

[0078] (2) The freeze-dried powder products of Examples 1 and 2 and Comparative Examples 1 and 2 were stored in a low-temperature, dry and ventilated place to avoid high temperature and sunlight. After 6 days of storage, the effective ingredients were detected. The results showed that the dissolution rate of the effective ingredients of the freeze-dried powder products obtained in Examples 1 and 2 was improved. The dissolution rates of Examples 1 and 2 were 95.6% and 94.8%, respectively, and the dissolution rates of Comparative Examples 1 and 2 were 92.3% and 91.5%, respectively. After taking the paste products of Examples 1 and 2, the patients' symptoms of fatigue and limb pain were further alleviated compared with Comparative Examples 1 and 2.

[0079] 2. Paste product testing

[0080] (1) Paste fluidity: The finished paste is semi-fluid and has a certain viscosity. If measured with a densitometer, the density should be between 1.3 and 1.4 kg / m 3 , there is no special requirement that the density does not exceed 1.45kg / m 3 The paste product obtained in Examples 3 and 4 has a solid content of 60-75% and a relative density of 1.3-1.5 kg / m at room temperature of 25°C. 3 .

[0081] (2) With reference to the Good Manufacturing Practice for Pharmaceuticals, the paste products of Examples 3 to 4 and Comparative Examples 3 to 4 were tested. The results are shown in Table 2.

[0082] Table 2 Test items and test results of paste products

[0083] sample Effective drug suspension rate Moisture content Residue after dumping Residue after washing Example 3 ＞95％ ＜2.7％ ＜4.9％ ＜0.5％ Comparative Example 3 89.6％ 5.9％ 9.6％ 4.7％ Example 4 ＞95％ ＜2.9％ ＜5％ ＜0.5％ Comparative Example 4 88.5％ 6.9％ 9.3％ 5.4％

[0084] It can be seen from Table 2 that compared with the traditional paste product pharmaceutical method, this process has a simpler production process, less pollution, is easy to store and carry, has less impact on the efficacy, and can retain more effective ingredients.

[0085] (3) The paste products of Example 3 and Comparative Example 3 were respectively stored in a low-temperature, dry and ventilated place to avoid high temperature and sunlight. After storage for 6 days, the effective ingredients were detected. The results showed that the dissolution rate of the effective ingredients of the paste products obtained in Example 3 and Example 4 was improved. The dissolution rates of Examples 3 and 4 were 95.6% and 95.9%, respectively, and the dissolution rates of Comparative Examples 3 and 4 were 89.6% and 88.5%, respectively. After taking the paste products of Examples 3 and 4, the patients' symptoms such as dry mouth, thirst, irritability, and nausea were further alleviated compared with Comparative Examples 3 and 4.

[0086] 3. Paste product testing

[0087] (1) With reference to the Good Manufacturing Practice for Pharmaceuticals, the paste products of Example 5 and Comparative Example 5 were tested. The results are shown in Table 3.

[0088] Table 3 Paste product test items and test results

[0089] sample Effective drug suspension rate Moisture content Residue after dumping Residue after washing Example 5 ＞96％ ＜31％ ＜5％ ＜0.5％ Comparative Example 5 90.9％ 66.5％ 15.8％ 13.5％

[0090] It can be seen from Table 3 that compared with traditional pharmaceutical methods, this process has a simpler production process, less pollution, the drug can be fully concentrated and refined, easy to store and carry, the efficacy is less affected, and more active ingredients can be retained.

[0091] (2) The paste products of Example 5 and Comparative Example 5 were respectively stored in a low-temperature, dry and ventilated place to avoid high temperature and sunlight. After storage for 6 days, the effective ingredients were detected. The results showed that the dissolution rate of the effective ingredients in the paste product obtained in Example 5 was improved, specifically 96.6, and the dissolution rate of Comparative Example 5 was 90.9%. After taking the paste product of Example 5, the patient's symptoms such as abdominal distension, chills, and nausea were further alleviated compared with Comparative Example 5.

[0092] Based on the above content, it can be seen that polypeptide polymers help make traditional Chinese medicine easier to form ointments, powders, and aqueous solutions. Compared with traditional pharmaceutical methods, they are less polluting and have a shorter preparation time. They are also easier to store and carry, with less impact on efficacy, and the resulting traditional Chinese medicine preparations have good stability.

[0093] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. Application of polypeptide polymers in improving the stability of traditional Chinese medicine preparations; the polypeptide polymers include one or more of 3-9 peptide polymers; the molecular weight of the polypeptide polymers is 200-5000Da.

2. The use according to claim 1, characterized in that: The dosage form of the traditional Chinese medicine preparation includes aqueous solution, ointment or powder.

3. The use according to claim 1 or 2, characterized in that: The polypeptide polymer is one or more of a 4-peptide polymer, a 6-peptide polymer, a 7-peptide polymer and a 9-peptide polymer; The 4-peptide polymer includes tetrapeptide-21 and / or tetrapeptide-7; The 6-peptide polymer includes hexapeptide-3; The 7-peptide polymer includes β-amyloid peptide fragment polypeptides 4-10; The 9-peptide polymer includes nonapeptide-1.

4. A method for preparing a Chinese medicine preparation, characterized in that: The steps include: The Chinese medicine and the solvent are mixed and boiled, the solid and the liquid are separated, and the liquid medicine is collected; The drug solution and the polypeptide polymer are mixed and then subjected to ultrafiltration treatment to obtain a Chinese medicine aqueous solution; The polypeptide polymer includes one or more of 3-9 peptide polymers; The molecular weight of the polypeptide polymer is 200-5000Da.

5. The preparation method according to claim 4, characterized in that: After obtaining the Chinese medicine aqueous solution, the method further comprises: freeze-drying the Chinese medicine aqueous solution at -15 to -25°C for 45 to 75 minutes, heating the temperature to 0 to 5°C at a heating rate of 3 to 5°C / 10 minutes, and filtering at a pressure of -0.10 to -0.09 MPA to obtain a Chinese medicine ointment.

6. The preparation method according to claim 4, characterized in that: After obtaining the Chinese medicine aqueous solution, the method further includes: freeze-drying the Chinese medicine aqueous solution at -20°C for 45 to 75 minutes, heating it to 0 to 5°C at a heating rate of 1 to 3°C / 10min, treating it at a pressure of -0.10 to -0.09MPA for 50 to 65 minutes, heating it to 0 to 5°C at a heating rate of 1 to 3°C / 10min, and filtering it at a pressure of -0.10 to -0.09MPA to obtain a Chinese medicine powder.

7. The preparation method according to claim 4, characterized in that: The boiling step comprises: boiling the mixture of the Chinese medicine and the solvent for 5 to 15 minutes under high-temperature steam at 175 to 190° C., adjusting the flow rate of the high-temperature steam to maintain a slightly boiling state, and boiling for 0.5 to 1 hour.

8. The preparation method according to claim 4, characterized in that: The mass ratio of the traditional Chinese medicine to the solvent is (175-340):(400-600).

9. The preparation method according to any one of claims 4 to 7, characterized in that: The raw materials of the Chinese medicine include angelica dahurica, ginger, dried rehmannia root, peony root, fangfeng root, cinnamon heart, trichosanthes root, liquorice, ephedra and dried kudzu root; or include rhubarb, liquorice, jujube and honey; or include pinellia tuber, ginger, platycodon, evodia rutaecarpa, peucedanum chinense, turtle shell, immature bitter orange, ginseng and betel nut; The solvent includes water and / or anhydrous ethanol.

10. The preparation method according to claim 9, characterized in that: When the Chinese medicinal raw materials are Angelica dahurica, ginger, dried rehmannia root, peony root, saposhnikovia root, cinnamon bark, trichosanthes root, liquorice, ephedra and dried kudzu, the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is (300-370): (50-70), the polypeptide polymer is a 4-peptide polymer; the solvent is water and anhydrous ethanol; When the Chinese medicinal raw materials are rhubarb, liquorice, jujube and honey, the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is (160-190): (40-60), the polypeptide polymer is a 6-peptide polymer and / or a 7-peptide polymer; and the solvent is water; When the Chinese medicinal raw materials are pinellia, ginger, platycodon, evodia rutaecarpa, peucedanum chinense, turtle shell, immature bitter orange, ginseng and betel nut, the mass ratio of the Chinese medicinal raw materials to the polypeptide polymer is (190-230): (90-120), the polypeptide polymer is a 9-peptide polymer; and the solvent is water.