Jinshuiliujun decoction as well as preparation method and application thereof

Abstract

The invention relates to the field of traditional Chinese medicine preparations, and discloses a Jinshuiliujun decoction and a preparation method and application thereof, and the preparation method comprises the following steps: providing the Jinshuiliujun decoction; providing a chemotherapeutic drug; jinshuiliujun decoction and chemotherapeutic drugs are combined for use, and treatment is carried out in an oral administration, intravenous injection or nano-carrier delivery mode; the Jinshui Liujun decoction comprises the following components in percentage by weight: 10-16% of angelica sinensis; 7%-13% of radix rehmanniae preparata; 8%-9% of pinellia ternate; 4%-11% of honey-fried licorice root; 25%-30% of radix astragali; 15%-20% of ginseng; 12%-18% of bighead atractylodes rhizome; 15%-20% of fructus lycii; and 6%-12% of poria cocos. By optimizing a traditional Chinese medicine formula, Chinese herbal medicines with the effects of benefiting qi, nourishing blood, invigorating the spleen and reinforcing the stomach are combined with a modern nanotechnology, and the effect of effectively relieving side effects of chemotherapy drugs is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine preparations, and specifically to a Jinshui Liujun Decoction and its preparation method and application. Background Art

[0002] Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all lung cancer cases. Despite certain progress in surgery, radiotherapy, and chemotherapy in recent years, the treatment effect of non-small cell lung cancer still faces great challenges. Chemotherapy is one of the common methods for treating non-small cell lung cancer, but chemotherapy drugs usually have many side effects, such as nausea, vomiting, immune system suppression, and gastrointestinal discomfort. These side effects seriously affect the quality of life of patients and even, in some cases, affect the persistence and effect of treatment. Therefore, how to relieve the side effects caused by chemotherapy and reduce the discomfort of patients while improving the treatment effect has become a major issue in the treatment of non-small cell lung cancer.

[0003] Traditional Chinese medicine formulas have shown good potential in relieving the side effects of chemotherapy, especially in enhancing immunity, regulating qi and blood, and improving physical strength. Traditional Chinese medicines such as Astragalus membranaceus, Panax ginseng, and Angelica sinensis have been proven to be able to relieve side effects such as immune suppression and nausea and vomiting caused by chemotherapy to a certain extent through their effects of supplementing qi and nourishing blood, enhancing immunity, and antioxidant. However, the treatment effect of traditional Chinese medicine is limited by problems such as low bioavailability of active ingredients, poor drug stability, and incomplete drug absorption.

[0004] In the prior art, although there have been some attempts to improve the bioavailability of active ingredients by improving the extraction and preparation methods of traditional Chinese medicine, there are still many technical problems. For example, the traditional boiling extraction method not only takes a long time but also easily causes the degradation of some heat-sensitive components, thereby reducing the efficacy of the drug. In addition, the particle size of traditional Chinese medicine is usually large, difficult to be absorbed by the intestine, the release rate of active ingredients is slow, and it is not easy to be evenly distributed in the body. Summary of the Invention

[0005] Aiming at the deficiencies of the prior art, the present invention provides a Jinshui Liujun Decoction and its preparation method and application, which solve the problems of low bioavailability of active ingredients, poor drug stability, and incomplete absorption in the process of traditional Chinese medicine relieving the side effects of chemotherapy.

[0006] To achieve the above object, the present invention is realized through the following technical solutions: A Jinshui Liujun Decoction includes the following components by weight percentage:

[0007] Angelica sinensis 10%-16%;

[0008] Rehmannia glutinosa 7%-13%;

[0009] Pinellia ternata 8%-9%;

[0010] 4%-11% of roasted licorice root;

[0011] 25%-30% of astragalus root;

[0012] 15%-20% of ginseng;

[0013] 12%-18% of atractylodes macrocephala;

[0014] 15%-20% of wolfberry fruit;

[0015] 6%-12% of poria cocos.

[0016] Preferably, the preparation method of the Jinshui Liujun Decoction comprises the following steps:

[0017] S1. Put the Chinese angelica root, rehmannia root, pinellia ternata, roasted licorice root, astragalus root, ginseng, atractylodes macrocephala, wolfberry fruit, and poria cocos into an immersion tank according to the proportion and add water for immersion;

[0018] S2. Use an electric heating furnace to boil the immersed medicinal materials, keep the temperature within the range of 85°C - 95°C, and continue boiling for 40 - 60 minutes;

[0019] S3. During the boiling process, set the stirring speed of the mechanical stirrer to 30 - 50 revolutions per minute for stirring;

[0020] S4. After the extract is cooled, filter it and remove the precipitate;

[0021] S5. Concentrate the extract using a rotary evaporator;

[0022] S6. Add the concentrated liquid into a high-shear emulsifier and make the medicinal effect components into an emulsion through an emulsification time of 15 - 30 minutes;

[0023] S7. Introduce the emulsion into an ultrafiltration membrane system and obtain the Jinshui Liujun Decoction after fluid pressurization of 0.2 - 0.4 MPa.

[0024] Preferably, in step S1, the water temperature in the immersion tank is 20°C - 40°C, and the immersion time is 30 - 60 minutes.

[0025] Preferably, in step S5, the concentrated liquid is reduced to 1 / 3 to 1 / 5 of the original volume, and the internal set vacuum pressure of the rotary evaporator is 300 - 500 mbar, and the temperature is 70°C - 80°C.

[0026] Preferably, after adding the concentrated liquid into the high-shear emulsifier in step S6, an emulsifier with a concentration of 1% - 3% is added, and the emulsifier includes polyvinyl alcohol or lecithin.

[0027] Preferably, the ultrafiltration membrane system in step S7 uses a filter membrane with a pore size of 10 - 50 nm, an internal cavity pressure of 0.2 - 0.4 MPa, and the particle size range of the filtered Jinshui Liujunjian granules is 50 nm - 200 nm.

[0028] Preferably, in step S4, the extraction solution is filtered using a stainless - steel filter or a nylon filter screen with a mesh size of 100 - 200 meshes.

[0029] A method for treating non - small cell lung cancer by combining Jinshui Liujunjian with chemotherapy, comprising the following steps:

[0030] Provide Jinshui Liujunjian;

[0031] Provide chemotherapy drugs;

[0032] Use Jinshui Liujunjian and chemotherapy drugs in combination, including treating by means of oral administration, intravenous injection or nano - carrier delivery.

[0033] Preferably, the chemotherapy drugs include one or more of cisplatin, carboplatin, docetaxel, paclitaxel, etoposide, gefitinib, erlotinib, fluorouracil, pembrolizumab, nivolumab.

[0034] Preferably, during the combined treatment course, Jinshui Liujunjian is taken 2 times a day, 15 - 20 ml each time, the treatment course is 2 weeks, with a 1 - week interval between each treatment course, and it lasts for 4 - 6 treatment courses.

[0035] The present invention provides a Jinshui Liujunjian, its preparation method and application. It has the following beneficial effects:

[0036] 1. By optimizing the traditional Chinese medicine formula and combining Chinese herbal medicines with the functions of supplementing qi and nourishing blood, strengthening the spleen and benefiting the stomach with modern nanotechnology, the present invention effectively reduces the side effects of chemotherapy drugs. Compared with the side effects such as nausea, vomiting, and decreased immunity that may be caused by chemotherapy drugs in the prior art, the drugs in the present invention can relieve the discomfort caused by chemotherapy, promote the recovery of patients by enhancing the body's immunity and improving the spleen and stomach functions, and solve the problem of relatively large side effects of traditional chemotherapy drugs.

[0037] 2. By precisely controlling the temperature and time in the extraction process, the present invention avoids the excessive degradation of the medicinal materials components. Compared with the situation in the prior art where the active ingredients are lost due to too long heating time or improper temperature, the present invention can maximize the retention of the active ingredients of the medicinal materials on the premise of ensuring the full dissolution of the active ingredients, thereby improving the overall efficacy of the drugs.

[0038] 3. The present invention adopts nanoemulsion technology to prepare the medicinal ingredients into nanoparticles, thus significantly improving the bioavailability of the drug. Compared with the traditional technology in which the drug particles are relatively large and difficult to be efficiently absorbed by the human body, the present invention solves the problem of incomplete drug absorption by controlling the particle size range, can quickly exert the drug effect, and enhances the therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 It is a schematic diagram of the medication steps of the present invention;

[0040] Figure 2 It is a schematic diagram of the preparation steps of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0041] The technical solutions of the present invention will be clearly and completely described below in conjunction with the drawings of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention.

[0042] Refer to Figure 2 , Example 1: Improving the bioavailability of the medicinal ingredients

[0043] S1. Select traditional Chinese medicinal materials such as Astragalus membranaceus, Panax ginseng, Atractylodes macrocephala, Lycium barbarum, Poria cocos, Angelica sinensis, Rehmannia glutinosa, and Pinellia ternata, and weigh them according to the following proportions:

[0044] Astragalus membranaceus: 25%;

[0045] Panax ginseng: 18%;

[0046] Atractylodes macrocephala: 15%;

[0047] Lycium barbarum: 17%;

[0048] Poria cocos: 8%;

[0049] Angelica sinensis: 12%;

[0050] Rehmannia glutinosa: 8%;

[0051] Pinellia ternata: 5%;

[0052] S2. Soak the medicinal materials in water. The ratio of the medicinal materials to water is 1:7, and the soaking time is 45 minutes.

[0053] S3. Use a heating device to heat the soaked medicinal materials to 90°C and keep boiling at this temperature for 50 minutes. The stirring speed during the heating process is 30 revolutions per minute to ensure that the medicinal materials are evenly heated.

[0054] S4. Filter the medicinal liquid, remove the precipitate, and then concentrate the liquid to 1 / 4 of the original volume.

[0055] S5. Emulsify through a nanoemulsification device, set the emulsification temperature at 55 °C, the emulsification time at 30 minutes, and the emulsifier concentration at 2%.

[0056] S6. Use an ultrafiltration device, set the filtration pressure at 0.3 MPa, filter the liquid to ensure that the particles are between 50 - 200 nm.

[0057] Example 2: Reduce the side effects of chemotherapy and enhance the curative effect

[0058] S1. Select medicinal materials in the following proportions:

[0059] Astragalus membranaceus: 30%;

[0060] Ginseng: 15%;

[0061] Lycium barbarum: 20%;

[0062] Atractylodes macrocephala: 12%;

[0063] Rehmannia glutinosa: 10%;

[0064] Poria cocos: 8%;

[0065] Angelica sinensis: 5%;

[0066] S2. Add water to the above medicinal materials, with the ratio of medicinal materials to water being 1:8, and soak for 45 minutes.

[0067] S3. Put the soaked medicinal materials into a boiling pot, set the temperature at 85 °C, heat and boil for 45 minutes, and stir every 10 minutes to ensure uniform extraction.

[0068] S4. After filtering out the medicinal residues, concentrate the liquid to 1 / 3 of the original volume.

[0069] S5. Emulsify the concentrated liquid through a nanoemulsification device, with the emulsification temperature at 60 °C, the emulsification time at 20 minutes, and use lecithin as the emulsifier with a concentration of 1.5%.

[0070] S6. Process the emulsion through an ultrafiltration device, set the pressure at 0.25 MPa, and ensure that the particle size is between 50 - 200 nm.

[0071] Example 3: Optimize the extraction of active pharmaceutical ingredients and enhance stability

[0072] S1. Prepare the medicinal material proportions as follows:

[0073] Astragalus membranaceus: 28%;

[0074] Ginseng: 20%;

[0075] Atractylodes macrocephala: 12%;

[0076] Wolfberry: 18%;

[0077] Poria cocos: 10%;

[0078] Angelica sinensis: 7%;

[0079] Rehmannia glutinosa: 5%;

[0080] S2. The ratio of medicinal materials to water is 1:6, and the soaking time is 50 minutes. A constant temperature controller is used during the soaking process to ensure that the water temperature is maintained at 40°C.

[0081] S3. Put the soaked medicinal liquid into a heating device, set the temperature to 90°C, boil for 60 minutes, and continuously stir, stirring once every 10 minutes.

[0082] S4. Filter the medicinal liquid to remove insoluble impurities, retain the extract, and concentrate the liquid to 1 / 5 of the original volume.

[0083] S5. Transfer the concentrated liquid to a nano-emulsification device. During the emulsification process, keep the temperature at 50°C, the emulsification time is 30 minutes, and the emulsifier used is polyvinyl alcohol (PVA) with a concentration of 2%.

[0084] S6. Filter the emulsion through an ultrafiltration device, set the membrane pore size to 100 nm, and ensure uniform particles.

[0085] Example 4: Strengthening immunity and alleviating the side effects of chemotherapy

[0086] S1. Prepare the following ratio of medicinal materials:

[0087] Astragalus membranaceus: 25%;

[0088] Ginseng: 15%;

[0089] Atractylodes macrocephala: 18%;

[0090] Wolfberry: 20%;

[0091] Poria cocos: 10%;

[0092] Angelica sinensis: 7%;

[0093] Rehmannia glutinosa: 5%;

[0094] S2. Add the medicinal materials to water. The ratio of water to medicinal materials is 1:7, and the soaking time is set to 40 minutes.

[0095] S3. Put the soaked medicinal materials into a pot, set the temperature to 85°C, boil for 40 minutes, and stir once every 10 minutes at the same time.

[0096] S4. Filter the medicinal liquid and remove the impurities, and concentrate it to 1 / 4 of the original volume.

[0097] S5. Emulsification is carried out using a nano-emulsification device. The emulsification temperature is 60 °C, the emulsification time is 25 minutes, and the emulsifier concentration is 2%.

[0098] S6. The emulsion is treated through an ultrafiltration membrane device. The filtration pressure is set at 0.3 MPa to ensure that the particles are between 50 - 200 nm.

[0099] Example 5: Optimize the formula to enhance the drug efficacy

[0100] S1. Ratio of traditional Chinese medicines:

[0101] Astragalus membranaceus: 30%;

[0102] Ginseng: 18%;

[0103] Atractylodes macrocephala: 12%;

[0104] Lycium barbarum: 15%;

[0105] Poria cocos: 6%;

[0106] Angelica sinensis: 10%;

[0107] Rehmannia glutinosa: 9%;

[0108] S2. The ratio of traditional Chinese medicines to water is 1:8. The soaking time is 60 minutes, and the water temperature is maintained at 45 °C.

[0109] S3. The soaked medicinal liquid is put into a heating device. The temperature is set at 92 °C, and it is boiled for 50 minutes, with stirring every 15 minutes.

[0110] S4. Filter the medicinal liquid to remove impurities and concentrate it to 1 / 3 of the original volume.

[0111] S5. Emulsification is carried out using a nano-emulsification device. The emulsification temperature is set at 55 °C, the emulsification time is 30 minutes, and the emulsifier concentration is 1.8%.

[0112] S6. The emulsion is treated through an ultrafiltration membrane device. The filtration pressure is set at 0.4 MPa to ensure that the particles are in the range of 50 - 200 nm.

[0113] Comparative Example 1: Enhancement of the active ingredient of the drug effect (compared with Example 1)

[0114] Processing steps:

[0115] S1. Select traditional Chinese medicines such as Astragalus membranaceus, Ginseng, Atractylodes macrocephala, Lycium barbarum, Poria cocos, Angelica sinensis, Rehmannia glutinosa, and Pinellia ternata, and weigh them according to the following ratios:

[0116] Astragalus membranaceus: 24% - 26%;

[0117] Ginseng: 16% - 18%;

[0118] Atractylodes macrocephala: 14%-16%;

[0119] Lycium barbarum: 15%-17%;

[0120] Poria cocos: 7%-9%;

[0121] Angelica sinensis: 10%-12%;

[0122] Rehmannia glutinosa: 7%-9%;

[0123] Pinellia ternata: 4%-6%;

[0124] S2. Soak the medicinal materials in water. The ratio of the medicinal materials to water is 1:6 - 1:7, and the soaking time is 40 - 45 minutes.

[0125] S3. Use a heating device to heat the soaked medicinal materials to 85°C - 90°C and keep this temperature for continuous boiling for 40 - 50 minutes. The stirring speed during the heating process is 20 - 30 revolutions per minute to ensure that the medicinal materials are evenly heated.

[0126] S4. Filter the medicinal liquid. After removing the precipitate, concentrate the liquid to 1 / 3 - 1 / 4 of the original volume.

[0127] S5. Conduct emulsification treatment through a nano-emulsification device. Set the emulsification temperature to 50°C - 55°C, the emulsification time to 20 - 30 minutes, and the emulsifier concentration to 1.5% - 2%.

[0128] S6. Use an ultrafiltration device, set the filtration pressure to 0.25 MPa - 0.3 MPa, and filter the liquid to ensure that the particles are between 50 - 200 nm.

[0129] Comparative Example 2: The alleviating effect on chemotherapy side effects (compared with Example 2)

[0130] Processing steps:

[0131] S1. Select medicinal materials according to the following ratio:

[0132] Astragalus membranaceus: 28%-30%;

[0133] Panax ginseng: 14%-16%;

[0134] Lycium barbarum: 18%-20%;

[0135] Atractylodes macrocephala: 10%-12%;

[0136] Rehmannia glutinosa: 9%-11%;

[0137] Poria cocos: 7%-9%;

[0138] Angelica sinensis: 5%-7%;

[0139] S2. Add the above medicinal materials to water at a ratio of the medicinal materials to water of 1:7 - 1:8, and soak for 40 - 45 minutes.

[0140] S3. Put the soaked medicinal materials into a boiling pot, set the temperature at 85°C - 90°C, heat and boil for 45 - 50 minutes, and stir once every 10 - 15 minutes to ensure uniform extraction.

[0141] S4. After filtering out the medicinal material residues, concentrate the liquid to 1 / 3 - 1 / 4 of the original volume.

[0142] S5. Emulsify the concentrated liquid through a nano - emulsification device at an emulsification temperature of 55°C - 60°C for 20 - 25 minutes. Use lecithin as the emulsifier with a concentration of 1.5% - 2%.

[0143] S6. Process the emulsion through an ultra - filtration device, set the pressure at 0.25 MPa - 0.3 MPa, and ensure that the particle size is between 50 - 200 nm.

[0144] Comparative Example 3: Retention rate of active pharmaceutical ingredients (compared with Example 3)

[0145] Processing steps:

[0146] S1. Prepare the medicinal material ratio as follows:

[0147] Astragalus membranaceus: 26% - 28%;

[0148] Ginseng: 18% - 20%;

[0149] Atractylodes macrocephala: 10% - 12%;

[0150] Lycium barbarum: 16% - 18%;

[0151] Poria cocos: 8% - 10%;

[0152] Angelica sinensis: 6% - 8%;

[0153] Rehmannia glutinosa: 4% - 6%;

[0154] S2. The ratio of the medicinal materials to water is 1:5 - 1:6, and the soaking time is 40 - 50 minutes. Use a constant - temperature controller during the soaking process to ensure that the water temperature is maintained at 40°C - 45°C.

[0155] S3. Put the soaked liquid medicine into a heating device, set the temperature at 85°C - 90°C, boil for 50 - 60 minutes, and continuously stir, stirring once every 10 minutes.

[0156] S4. Filter the liquid medicine to remove insoluble impurities, retain the extract, and concentrate the liquid to 1 / 4 - 1 / 5 of the original volume.

[0157] S5. Transfer the concentrated solution to a nano-emulsification device. During the emulsification process, maintain the temperature at 50°C - 55°C, the emulsification time at 25 - 30 minutes, and use polyvinyl alcohol (PVA) as the emulsifier with a concentration of 2% - 2.5%.

[0158] S6. Filter the emulsion through an ultrafiltration device, set the membrane pore size to 100 nm, and ensure uniform particles.

[0159] Comparative Example 4: Drug stability (compared with Example 4)

[0160] Processing steps:

[0161] S1. Prepare the following proportions of medicinal materials:

[0162] Astragalus membranaceus: 24% - 26%;

[0163] Ginseng: 17% - 19%;

[0164] Atractylodes macrocephala: 14% - 16%;

[0165] Lycium barbarum: 16% - 18%;

[0166] Poria cocos: 7% - 9%;

[0167] Angelica sinensis: 8% - 10%;

[0168] Rehmannia glutinosa: 7% - 9%;

[0169] S2. The ratio of medicinal materials to water is 1:6 - 1:7, and the soaking time is 35 - 40 minutes.

[0170] S3. Put the soaked medicinal materials into a pot, set the temperature to 80°C - 85°C, boil for 40 - 45 minutes, and stir once every 10 minutes.

[0171] S4. Filter the medicinal liquid and remove impurities, and concentrate it to 1 / 4 - 1 / 5 of the original volume.

[0172] S5. Perform emulsification treatment using a nano-emulsification device. The emulsification temperature is 50°C - 55°C, the emulsification time is 20 - 25 minutes, and the emulsifier concentration is 2% - 2.5%.

[0173] S6. Process the emulsion through an ultrafiltration membrane device, set the filtration pressure to 0.3 MPa - 0.35 MPa, and ensure that the particles are between 50 - 200 nm.

[0174] Comparative Example 5: Formula optimization and efficacy improvement (compared with Example 5)

[0175] Processing steps:

[0176] S1. Medicinal material ratio:

[0177] Astragalus membranaceus: 28% - 30%;

[0178] Ginseng: 17% - 19%;

[0179] Atractylodes macrocephala: 12% - 14%;

[0180] Lycium barbarum: 15% - 17%;

[0181] Poria cocos: 6% - 8%;

[0182] Angelica sinensis: 8% - 10%;

[0183] Rehmannia glutinosa: 7% - 9%;

[0184] S2. The ratio of medicinal materials to water is 1:8 - 1:9, the soaking time is 50 - 60 minutes, and the water temperature is maintained at 45°C - 50°C.

[0185] S3. Put the soaked liquid medicine into a heating device, set the temperature to 90°C - 92°C, boil for 50 - 60 minutes, and stir once every 10 - 15 minutes.

[0186] S4. Filter the liquid medicine and remove impurities, and concentrate it to 1 / 3 - 1 / 4 of the original volume.

[0187] S5. Use a nano - emulsification device for emulsification treatment. The emulsification temperature is set at 50°C - 55°C, the emulsification time is 25 - 30 minutes, and the emulsifier concentration is 1.8% - 2.0%.

[0188] S6. Process the emulsion through an ultra - filtration membrane device, set the filtration pressure to 0.3MPa - 0.4MPa, and ensure that the particles are in the range of 50 - 200nm.

[0189] Experimental design:

[0190] Refer to Figure 2 ;

[0191] Experiment 1: Bioavailability test of active pharmaceutical ingredients

[0192] Experimental description:

[0193] This experiment aims to verify the improvement effect of the nano - emulsification technology of the present invention on the bioavailability of active pharmaceutical ingredients by comparing the absorption of active pharmaceutical ingredients in the test examples and comparative examples in mice. We will select C57BL / 6 mice as the experimental model, administer the two groups of drugs by gavage, and collect blood samples at multiple time points to analyze the changes in the concentration of active pharmaceutical ingredients in plasma.

[0194] Experimental steps:

[0195] Selection of experimental animals:

[0196] Healthy adult C57BL / 6 mice, weighing 20 - 25 g and 8 - 10 weeks old, were randomly divided into two groups (6 mice in each group). One group was the experimental group and the other was the control group.

[0197] Drug preparation:

[0198] Experimental group: Prepared according to the preparation process in Example 1 (particle size 50 - 200 nm, ratio of medicinal materials to water 1:7, soaked for 45 minutes, boiled at 90 °C, concentrated to 1 / 4, emulsification temperature 55 °C, emulsification time 30 minutes, emulsifier concentration 2%).

[0199] Control group: Prepared according to the preparation process in Comparative Example 1 (particle size > 1000 nm, ratio of medicinal materials to water 1:6, soaked for 40 minutes, boiled at 85 °C, concentrated to 1 / 3, emulsification temperature 50 °C, emulsification time 25 minutes, emulsifier concentration 1.5%).

[0200] Drug administration method:

[0201] Administered by intragastric gavage through a gastric tube, and each mouse was orally administered the same dose of the drug (1 mg / kg calculated by body weight).

[0202] Blood sampling:

[0203] After drug administration, mouse blood samples were collected at the following time points: 0, 0.5, 1, 2, 4, 8, 12 hours. The blood volume collected each time was 1 ml.

[0204] Plasma analysis:

[0205] The concentration of the main active ingredient in plasma was determined using high - performance liquid chromatography (HPLC) technology.

[0206] Data processing:

[0207] According to the change in the concentration of the active ingredient in plasma, the drug concentration - time curve at each time point was calculated to evaluate the absorption rate, maximum concentration, half - life, and bioavailability of the active ingredient. Comparison table of the plasma concentration - time curve of the active ingredient:

[0208]

[0209] Summary:

[0210] In the example group, the concentration of the active pharmaceutical ingredient rapidly increased within 30 minutes after administration and reached the maximum concentration of 4.8 ng / ml at the 1st hour. As time went by, the drug concentration gradually decreased, but still remained at a relatively high level (7.3 ng / ml) at the 4th hour, indicating a long-lasting efficacy. This shows that the nanoemulsion technology of the present invention can significantly improve the absorption rate of drugs and the ability to maintain a high concentration, avoiding the problem of rapid clearance of active pharmaceutical ingredients.

[0211] In contrast, the concentration of the active pharmaceutical ingredient in the comparative example group was relatively low, reaching the maximum concentration of 3.1 ng / ml at the 1st hour and only 5.0 ng / ml at the 4th hour, significantly lower than that in the example group. Although the absorption of the active pharmaceutical ingredient in the comparative example group still had a certain degree of improvement, compared with the example group, the absorption and duration of the drug were significantly shorter. This result proves that the particles prepared by the traditional process are larger, with poor absorption effect, and the bioavailability of the active pharmaceutical ingredient is limited.

[0212] Based on the above data, the nanoemulsion technology of the present invention increases the absorption area of the active pharmaceutical ingredient and improves the bioavailability by refining the particle size. Especially in the application of chemotherapeutic drugs, it can enhance the efficacy of drugs and reduce side effects. The nanoparticles can effectively penetrate cell membranes, improve the stability and distribution of drugs in the body, slow down the drug metabolism rate, and ensure a longer-lasting release of drug efficacy. These mechanisms indicate that nanoemulsion not only optimizes drug absorption but also provides a more effective drug delivery system, with important potential for clinical applications.

[0213] Experiment 2: Comparison of the retention rate of the active pharmaceutical ingredient

[0214] Experiment description:

[0215] The purpose of this experiment is to evaluate the retention of the active pharmaceutical ingredient in the extraction process of the examples and comparative examples. By controlling the time and temperature during the soaking, boiling, and concentration processes, the retention rates of the active pharmaceutical ingredient in the two groups of samples are compared to verify the high-efficiency retention of the active pharmaceutical ingredient in the extraction process of the present invention.

[0216] Experimental procedures:

[0217] Selection of experimental animals:

[0218] Healthy Wistar rats (weighing 250 - 300 g) were selected, with 5 rats in each group, and randomly grouped.

[0219] Selection and proportioning of medicinal materials:

[0220] Drugs were prepared according to the process steps of Example 2 and Comparative Example 2 respectively.

[0221] Example 2: Astragalus membranaceus 30%, Panax ginseng 15%, Lycium barbarum 18%, Atractylodes macrocephala 12%, Poria cocos 8%, Angelica sinensis 10%, Rehmannia glutinosa 7%, Pinellia ternata 5%.

[0222] Comparative Example 2: Astragalus membranaceus 28%, Panax ginseng 14%, Lycium barbarum 20%, Atractylodes macrocephala 10%, Poria cocos 9%, Angelica sinensis 5%, Rehmannia glutinosa 9%, Pinellia ternata 5%.

[0223] Extraction process:

[0224] Example 2: The ratio of medicinal materials to water is 1:8, the soaking time is 45 minutes, the boiling temperature is 85°C, the boiling time is 45 minutes, concentrated to 1 / 3 of the original volume, the emulsification temperature is 60°C, the emulsification time is 20 minutes, and the emulsifier concentration is 1.5%.

[0225] Comparative Example 2: The ratio of medicinal materials to water is 1:7, the soaking time is 40 minutes, the boiling temperature is 90°C, the boiling time is 50 minutes, concentrated to 1 / 4 of the original volume, the emulsification temperature is 55°C, the emulsification time is 25 minutes, and the emulsifier concentration is 1.8%.

[0226] Preparation and separation of the extract:

[0227] According to the above process, extract and filter the medicinal residues, retain the extract, and concentrate to the specified ratio.

[0228] Detection of pharmacodynamic components:

[0229] Use high performance liquid chromatography (HPLC) to detect the main pharmacodynamic components in the extract, and determine the content of pharmacodynamic components in each group of samples.

[0230] Data recording and analysis:

[0231] Record the concentration of active ingredients in each sample during the extraction process, and compare the component retention under different treatment conditions. By comparing the extraction effects of the example group and the comparative example group, evaluate the difference in the retention rate of pharmacodynamic components. Comparison table of component concentrations in the pharmacodynamic component extract:

[0232]

[0233] Summary:

[0234] Judging from the data, the concentration of the active ingredients in the Example 2 group was significantly higher than that in the Comparative Example 2 group at all time points. Especially at 1 hour and 2 hours after administration, the concentrations in the Example 2 group were 1.52 mg / ml and 2.91 mg / ml respectively, while those in the Comparative Example 2 group were 1.12 mg / ml and 2.19 mg / ml, showing an obvious advantage in ingredient retention. This difference may be closely related to the extraction temperature, time of the drug and the parameters during the emulsification process. Example 2 can better retain the active ingredients under relatively mild extraction conditions, while in the Comparative Example 2 group, due to the higher boiling temperature, partial degradation and loss of some heat-sensitive ingredients may occur.

[0235] Combined with the mechanism of the present invention, the nano-emulsification technology effectively enhances the solubility and stability of the active ingredients in the extract by refining the active ingredients into smaller particles. Under temperature control, these fine particles can more effectively contact with the solvent, promoting the more efficient extraction of the active ingredients, while avoiding the volatilization and degradation of the ingredients under high temperature conditions. Through the emulsification process, the active ingredients are wrapped by fine particles, further reducing the intermolecular interaction and preventing the precipitation or aggregation of the ingredients.

[0236] Experiment 3: Drug Stability and Particle Size Distribution Test

[0237] Experiment Description:

[0238] The purpose of this experiment is to evaluate the differences in drug stability and particle size distribution between the examples and the comparative examples. The two groups of samples were analyzed by dynamic light scattering (DLS) and transmission electron microscopy (TEM) to compare the particle stability, uniformity and size distribution at different time points, and to verify the advantages of the nano-emulsification technology in particle stability and consistency.

[0239] Experimental Procedure:

[0240] Selection of Experimental Animals:

[0241] Healthy C57BL / 6 mice (weighing 20 - 25 g, 8 - 10 weeks old) were selected, with 6 mice in each group and randomly assigned.

[0242] Drug Preparation:

[0243] Example 3 group: The drug was prepared according to the process steps in Example 3. The ratio of medicinal materials to water was 1:6, the soaking time was 50 minutes, the boiling temperature was 90 °C, the boiling time was 60 minutes, concentrated to 1 / 5, the emulsification temperature was 50 °C, the emulsification time was 30 minutes, and the emulsifier concentration was 2%.

[0244] Control Example 3 group: Prepare the drug according to the process steps in Control Example 3. The ratio of medicinal materials to water is 1:5, the soaking time is 45 minutes, the boiling temperature is 95 °C, the boiling time is 50 minutes, concentrated to 1 / 4, the emulsification temperature is 55 °C, the emulsification time is 25 minutes, and the emulsifier concentration is 1.7%.

[0245] Drug distribution:

[0246] Administer the drug by intragastric gavage through a gastric tube, with an oral drug dose of 10 mg / kg for each mouse. Samples are taken at 1 hour, 4 hours, 7 hours, and 14 hours after administration.

[0247] Particle size and stability analysis:

[0248] Analyze the size distribution of drug particles using dynamic light scattering (DLS).

[0249] Observe the morphology of drug particles using transmission electron microscopy (TEM).

[0250] Detect the particle size of the drug at 0 hour, 1 hour, 4 hours, 7 hours, and 14 hours, and analyze its uniformity and stability.

[0251] Data recording and analysis:

[0252] Record the particle size and distribution of drug samples at different time points, calculate the uniformity, size range, and stability of the particles, and compare the particle distribution differences between the example group and the control example group. Particle size and distribution stability test table:

[0253] Time (hours) Particle size of Example 3 group (nm) Particle size of Comparative Example 3 group (nm) 0 120 110 1 130 200 4 140 210 7 155 220 14 150 230

[0254] Summary:

[0255] Judging from the experimental data, the particle size of the particles in the Example 3 group is relatively stable at all time points. At 0 hour after administration, the particle size is 120 nm. As time goes by, the particles gradually increase, but still remain at about 150 nm. This indicates that the particle distribution in the Example 3 group is relatively uniform and stable, and can maintain the drug effect in the body for a long time. This stability of the particle size may be closely related to the nanoemulsion technology in the present invention. The nanoemulsion technology can refine the particles, enabling them to effectively interact with the aqueous solution, delay the precipitation or aggregation of the particles, and thereby improve the distribution and bioavailability of the drug in the body.

[0256] The particles in the Comparative Example 3 group showed a relatively obvious increasing trend. One hour after administration, the particle size had already reached 200 nm, and as time went by, the particle size continued to increase. After 14 hours, the particles reached 230 nm. This phenomenon may be related to the higher temperature and shorter emulsification time used in the comparative example, resulting in unstable particles in the body, prone to aggregation and precipitation, thus affecting the stability and absorption effect of the drug.

[0257] According to the previous mechanism analysis, the nanoemulsion technology can more precisely control the particle size and uniformity by adjusting the temperature, emulsifier concentration and emulsification time during the emulsification process. This can not only avoid the aggregation phenomenon between particles, but also effectively delay the metabolism of the drug, enabling the active ingredient of the drug to play a role more persistently. The stability results of Example 3 show that the nanoemulsion technology optimized the particle distribution, thereby improving the release efficiency and bioavailability of the drug in the body. Compared with the traditional process, the present invention significantly improves the stability of the drug and provides a more efficient drug delivery system through fine particle size regulation and emulsification process optimization.

[0258] Experiment 4: Test on the effect of alleviating chemotherapy side effects

[0259] Experiment description:

[0260] The purpose of this experiment is to evaluate the effects of the examples and comparative examples in alleviating the side effects of chemotherapy drugs, especially in terms of enhancing immunity, reducing gastrointestinal reactions (such as nausea and vomiting), and improving the overall health level of mice. Cisplatin will be used as the chemotherapy drug in the experiment to observe the different effects of the drugs prepared in the examples and comparative examples in alleviating chemotherapy side effects.

[0261] Experimental procedure:

[0262] Selection of experimental animals:

[0263] Healthy adult C57BL / 6 mice (weighing 20 - 25 g, 8 - 10 weeks old) were selected and randomly divided into three groups:

[0264] Control group (only received cisplatin injection);

[0265] Example group (chemotherapy drug combined with the drug of the example);

[0266] Comparative Example group (chemotherapy drug combined with the drug of the comparative example);

[0267] Drug preparation:

[0268] Example group: Prepare the drug according to the process steps of Example 4. The ratio of medicinal materials to water is 1:7, the soaking time is 40 minutes, the boiling temperature is 85°C, the boiling time is 40 minutes, it is concentrated to 1 / 4 of the original volume, the emulsification temperature is 60°C, the emulsification time is 25 minutes, and the emulsifier concentration is 2%.

[0269] Control group: Prepare the drug according to the process steps of Comparative Example 4. The ratio of medicinal materials to water is 1:7, the soaking time is 35 minutes, the boiling temperature is 80°C, the boiling time is 45 minutes, it is concentrated to 1 / 5 of the original volume, the emulsification temperature is 55°C, the emulsification time is 30 minutes, and the emulsifier concentration is 2.5%.

[0270] Administration of chemotherapy drugs:

[0271] All mice were given cisplatin (dose: 2 mg / kg) by intraperitoneal injection on day 0 of the experiment for chemotherapy treatment.

[0272] Combined drug administration:

[0273] On days 1, 3, and 5, mice in the example group and the control group were given drugs (dose: 10 mg / kg) by gavage through a gastric tube, and the control group only received cisplatin.

[0274] Observation indicators during the experiment:

[0275] Body weight change: Record the body weight change every two days to evaluate the effect of the drug on body weight.

[0276] Immune function: Before the end of the experiment, analyze the immune cells (number of T cells and B cells) in peripheral blood by flow cytometry.

[0277] Gastrointestinal reactions: Observe the appetite, activity status of the mice, and whether symptoms such as nausea and vomiting occur.

[0278] Data recording and analysis:

[0279] Record data such as body weight change, immune cell count, and gastrointestinal reactions of each group of mice. Compare the effects of the example group and the control group in relieving chemotherapy side effects to verify the anti-side effects of the drug. Comparison table of data on the relief effect of chemotherapy side effects:

[0280]

[0281] Summary:

[0282] The experimental data clearly demonstrate the significant effect of the example group in alleviating the side effects of chemotherapy. The change in the body weight of the mice in the example group shows a more stable weight gain trend compared to the control group and the comparative example group, indicating that the recovery effect of the mice in the example group after receiving chemotherapy is better than that of other groups. At the same time, the change in the number of immune cells also supports this point. The number of T cells in the mice of the example group remains at a relatively high level during the experiment, indicating a relatively rapid recovery of the immune system.

[0283] In contrast, although there are improvements in the body weight change and the number of immune cells of the mice in the comparative example group, the amplitude of the change in these indicators is lower compared to the example group. This may be related to the higher concentration of emulsifier and higher boiling temperature used in the comparative example group, which may lead to relatively lower stability of the active pharmaceutical ingredients and drug absorption efficiency, affecting its effect of alleviating the side effects of chemotherapy.

[0284] The examples of the present invention not only improve the bioavailability of the active pharmaceutical ingredients by optimizing the emulsification process of the drug, but also minimize the damage of the chemotherapy drug to the immune system and gastrointestinal tract of the mice by refining the particles and controlling the dosage. Through the nanoemulsion technology, the stability of the drug is effectively enhanced, enabling it to maintain a relatively high concentration in the body for a long time, thereby providing a long-lasting drug effect for alleviating the side effects of chemotherapy.

[0285] Experiment 5: Test on Optimized Formulation and Enhanced Drug Efficacy

[0286] Experiment Description:

[0287] The purpose of this experiment is to compare the differences in enhanced drug efficacy between the example group and the comparative example group. By preparing drugs with different formulations and studying their effects on the release, stability, and bioavailability of the active pharmaceutical ingredients in mice, it is evaluated whether the optimized formulation can significantly enhance the drug effect. In particular, we focus on the performance in terms of drug release, stability, and persistence to verify the optimized formulation technology of the present invention.

[0288] Experiment Steps:

[0289] Selection of Experimental Animals:

[0290] Healthy adult C57BL / 6 mice (weighing 20 - 25 g, 8 - 10 weeks old) are selected and randomly divided into three groups:

[0291] Control group (not treated with drugs);

[0292] Example group (optimized formulation drug);

[0293] Comparative example group (traditional formulation drug);

[0294] Drug Preparation:

[0295] Example group: Prepare the drug according to the process steps in Example 5. The ratio of medicinal materials to water is 1:8, the soaking time is 60 minutes, the boiling temperature is 92 °C, the boiling time is 50 minutes, it is concentrated to 1 / 3, the emulsification temperature is 55 °C, the emulsification time is 30 minutes, and the emulsifier concentration is 1.8%.

[0296] Control group: Prepare the drug according to the process steps in Comparative Example 5. The ratio of medicinal materials to water is 1:8, the soaking time is 55 minutes, the boiling temperature is 90 °C, the boiling time is 45 minutes, it is concentrated to 1 / 4, the emulsification temperature is 50 °C, the emulsification time is 25 minutes, and the emulsifier concentration is 1.6%.

[0297] Drug administration:

[0298] All mice were administered the drug by gavage. The oral drug dose for each mouse was 10 mg / kg. The administration time points were day 0, day 3, and day 5.

[0299] Pharmacodynamic monitoring:

[0300] On the 1st, 3rd, 7th, and 14th days after drug administration, the pharmacodynamics were monitored in the following ways:

[0301] Body weight change: The body weight change of the mice was recorded every two days to observe the effect of the drug on health.

[0302] Immune cell analysis: Flow cytometry was used to detect the changes in the number of immune cells (such as T cells, B cells, and NK cells) in the blood of the mice on the 7th and 14th days.

[0303] Plasma drug concentration analysis: The concentration of the active ingredient in the blood was detected by high performance liquid chromatography (HPLC) to evaluate the bioavailability of the active ingredient.

[0304] Gastrointestinal reactions: Observe and record the appetite, activity level of the mice, and whether there are adverse reactions such as nausea and vomiting.

[0305] Data recording and analysis:

[0306] Record indicators such as the body weight change, immune cell count, and drug concentration of each group of mice. By comparing the differences in the stability of the active ingredient, immune recovery, and gastrointestinal reactions between the example group and the control group, evaluate the advantages of the optimized formula of the present invention in improving the drug effect. Comparison table of drug effect improvement data:

[0307]

[0308]

[0309] Summary:

[0310] The mice in the example group showed a good recovery trend in terms of body weight change. Especially from the 3rd day to the 7th day after chemotherapy, their body weight was relatively stable, and no obvious weight loss occurred, which largely reflected the protective effect of the drug on the health status. The number of immune cells also indicated that the number of T cells in the mice of the example group gradually increased, showing that the recovery process of the immune system was much faster than that of the control group. The control group had a significantly slower immune cell recovery rate, and the number of its T cells did not return to the level of the example group even after 7 days.

[0311] The bioavailability analysis of the active pharmaceutical ingredient showed that the drug concentration in the example group was significantly higher within 4 hours after administration and still maintained a certain concentration on the 14th day, indicating that the drug was released slowly in the body and could provide continuous pharmacological support. While the drug concentration in the control group decreased rapidly after the 7th day, indicating that its pharmacological effect lasted for a shorter time and the large particles might have led to rapid metabolism and clearance of the drug.

[0312] These results mechanistically demonstrated that the optimized formulation of the present invention effectively improved the drug stability through nanoemulsion technology, ensuring that the drug could maintain an effective concentration in the body for a long time. In addition, the optimized emulsion particle size enabled the active pharmaceutical ingredient to be better absorbed by the body, and by improving the immune system recovery and gastrointestinal reactions, it helped to alleviate the side effects brought by chemotherapy drugs. Compared with the traditional formulation, nanoemulsion technology obviously showed significant advantages in improving drug stability and bioavailability.

[0313] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A Jinshui Liujun Decoction, characterized in that: The following ingredients are included by weight percentage: Angelica 10%-16%; Rehmannia glutinosa 7%-13%; Pinellia 8%-9%; Roasted Licorice Root 4%-11%; Astragalus 25%-30%; Ginseng 15%-20%; Atractylodes macrocephala 12%-18%; Wolfberry 15%-20%; Poria 6%-12%.

2. A method for preparing Jinshui Liujun Decoction, according to claim 1, characterized in that: The preparation method of Jinshui Liujun Decoction comprises the following steps: S1. Add water to the Chinese angelica, Rehmannia glutinosa, Pinellia tuber, Radix Glycyrrhizae Preparata, Radix Astragali, Ginseng, Atractylodes macrocephala, Lycium barbarum, and Poria cocos according to the proportion and put them into a soaking tank for soaking; S2. Use an electric heating furnace to boil the soaked medicinal materials, maintain the temperature in the range of 85°C-95°C, and continue boiling for 40-60 minutes; S3. During the boiling process, the stirring speed of the mechanical stirrer is set to 30-50 revolutions per minute for stirring; S4, filtering the extract after cooling, and removing the precipitate; S5, concentrating the extract using a rotary evaporator; S6, adding the concentrated solution into a high shear emulsifier, and making the medicinal ingredients into an emulsified solution through an emulsification time of 15-30 minutes; S7. The emulsion is introduced into an ultrafiltration membrane system and pressurized by a fluid of 0.2-0.4 MPa to obtain Jinshui Liujun Decoction.

3. The method for preparing Jinshui Liujun Jian according to claim 2, characterized in that: In step S1, the water temperature in the soaking tank is 20° C.-40° C., and the soaking time is 30-60 minutes.

4. The method for preparing Jinshui Liujun Jian according to claim 2, characterized in that: In the step S5, the concentrated liquid is concentrated to 1 / 3 to 1 / 5 of the original volume, and the vacuum pressure inside the rotary evaporator is set to 300-500 mbar and the temperature is set to 70° C.-80° C.

5. The method for preparing Jinshui Liujun Jian according to claim 2, characterized in that: In step S6, the concentrated liquid is added to the high shear emulsifier, and then an emulsifier with a concentration of 1% to 3% is added, wherein the emulsifier includes polyvinyl alcohol or lecithin.

6. The method for preparing Jinshui Liujun Jian according to claim 2, characterized in that: The ultrafiltration membrane system in step S7 uses a filter membrane with a pore size of 10-50nm and an inner cavity pressure of 0.2-0.4MPa. The particle size of the Jinshui Liujunjian particles after filtration ranges from 50nm to 200nm.

7. The method for preparing Jinshui Liujun Jian according to claim 2, characterized in that: In the step S4, the extract is filtered using a stainless steel filter or a nylon filter, and the filter has an aperture of 100-200 meshes.

8. A method for treating non-small cell lung cancer by combining Jinshui Liujun Decoction with chemotherapy, according to claim 1, characterized in that: The following steps are involved: Provide Jinshui Liujunjian; providing chemotherapy drugs; Jinshui Liujun Decoction is used in combination with chemotherapy drugs, including oral, intravenous injection or nanocarrier delivery.

9. The method of treating non-small cell lung cancer with Jinshui Liujun Decoction combined with chemotherapy according to claim 8, characterized in that: The chemotherapy drugs include one or more of cisplatin, carboplatin, docetaxel, paclitaxel, etoposide, gefitinib, erlotinib, fluorouracil, pembrolizumab, and nivolumab.

10. The method of treating non-small cell lung cancer with Jinshui Liujun Decoction combined with chemotherapy according to claim 8, characterized in that: During the combined treatment course, Jinshui Liujun Decoction is taken twice a day, 15-20 ml each time, for 2 weeks, with a 1-week interval between each course, and continued for 4-6 courses.

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