Veterinary nano-phase Ma Xing Shi Gan decoction preparation and its preparation method

Abstract

The application discloses a traditional Chinese medicine preparation, namely, a nano-phase Maxing Shigan decoction and a preparation method thereof, and belongs to the field of veterinary drugs. The four medicinal materials, namely, Ephedra, bitter apricot kernel, gypsum and licorice, are decocted and extracted together, centrifuged, and dialyzed to obtain the nano-phase Maxing Shigan decoction, which is prepared into a pharmaceutical preparation according to the conventional technical of pharmacy. The nano-phase Maxing Shigan decoction is used for treating fever diseases of livestock and poultry, has a definite curative effect, and has a cure rate of more than 88%, has small side effects, and can be prepared into various dosage forms, such as a powder, a premix, a soluble powder, granules, an oral liquid, an injection, a powder injection, tablets and the like.

Description

Technical Field

[0001] This invention belongs to the fields of traditional Chinese medicine technology and veterinary medicine, specifically relating to a nano-phase Ma Xing Shi Gan Tang preparation and its preparation method. Background Technology

[0002] Fever is the most common symptom associated with infection in livestock and poultry. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice, but the use of chemical drugs is prone to drug resistance and recurrent fever. Large doses or long-term use can cause digestive system ulcers, hypothermia, and other symptoms. No innovative drugs in this field have been developed and marketed in recent decades. Therefore, developing antipyretic and anti-inflammatory drugs with definite efficacy and few side effects is one of the hot topics in the research and development of this type of drug.

[0003] Traditional Chinese medicine (TCM) possesses excellent antipyretic and anti-inflammatory effects. The Artemisia annua and Glycyrrhiza uralensis granules, previously developed by the inventors, exhibit excellent antipyretic and anti-inflammatory effects, with advantages such as low toxicity and long-lasting effects. This invention has been granted a patent (patent number: CN201410322023.4), providing a new direction for the development of novel clinical antipyretic and anti-inflammatory drugs. TCM decoctions are one of the most common dosage forms in clinical practice. As early as thousands of years ago, there was a saying that "Yi Yin created decoctions," highlighting their significant efficacy and rapid absorption. Ma Xing Shi Gan Tang is one of the classic formulas in the *Shang Han Lun* (Treatise on Cold Damage), composed of gypsum, ephedra, licorice, and bitter apricot kernel. It is mainly used to treat fever, cough, and asthma caused by external pathogens invading the lungs, or by stagnation transforming into heat, leading to heat accumulation in the lungs. To improve its clinical efficacy, the preparation process of Ma Xing Shi Gan Tang nano-phase formulations based on the correlation between "decoction phase-material composition-biological effect" urgently needs to be developed.

[0004] The literature reports the preparation process of Ma Xing Shi Gan oral liquid and Ma Xing Shi Gan injection: gypsum is crushed, wrapped in gauze, and decocted twice with the other three ingredients in water. The decoctions are combined, filtered, and the filtrate is concentrated to about 900ml. After filtration, water is added to make 1000ml. This process mainly focuses on extraction (Reference: Veterinary Drug Quality Standards 2017). Guo Yanqin et al. reported the optimal extraction process for veterinary Ma Xing Shi Gan oral liquid: gypsum is crushed into small pieces with a diameter of no more than 1cm, and bitter almonds are crushed into coarse particles with a particle size of 1 / 8 to 1 / 4 of the original medicinal material before feeding (Reference: Research on the extraction process of veterinary Ma Xing Shi Gan oral liquid [J]. Chinese Veterinary Medicine Journal, 2022, 41(3): 58-62.). Zeng Xiong-hui et al. reported a method for preparing a Ma Xing Shi Gan Tang preparation, which involved water extraction and decoction three times, each time for 2 hours, followed by ultrafiltration of the filtrate using a cyanoethyl acetate cellulose membrane with a molecular weight cutoff of 6000 (Patent Application No. 200810000990.3). Wang Peng-long et al. reported the preparation and application of a carrier-free metal-organic small molecule supramolecular hydrogel with antipyretic and anti-inflammatory effects derived from Ma Xing Shi Gan Tang (Patent Application No. 202310267040.1), prepared using pseudoephedrine, amygdalin, glycyrrhizic acid, and magnesium ions. Shi An-long et al. reported a supramolecular hydrogel with antipyretic and anti-inflammatory effects derived from Ma Xing Shi Gan Tang (Patent Application No. 202310430487.6), prepared using pseudoephedrine, amygdalin, glycyrrhizic acid, and calcium ions. Tan Dengping et al. reported a method for preparing and controlling the quality of Ma Xing Shi Gan Tang formula granules (patent application number 201510597933.8), which describes a one-step granulation method involving decoction, concentration, spray drying, and granulation. The methods reported in the above literature either employ traditional decoction methods or only extract chemical components for preparation. These methods cannot truly reflect the nano-preparation process of Ma Xing Shi Gan Tang based on a decoction. To reflect the "decoction characteristics" of "phase-component-efficacy," further improvements to the preparation process are needed. Summary of the Invention

[0005] Based on the current state of the technology, the present invention aims to provide a preparation process for efficiently obtaining nano-phase formulations of Ma Xing Shi Gan Tang; another objective is to provide veterinary nano-phase formulations of Ma Xing Shi Gan Tang.

[0006] To achieve the objective of this invention, this invention, for the first time, obtains nano-phase Ma Xing Shi Gan Tang from the decoction of an ancient prescription. The specific preparation process is as follows:

[0007] A. Weigh the medicinal materials according to the formula of ephedra, bitter almond, gypsum, and licorice in a mass ratio of 1-5:1-3:5-10:1-4. Add purified water at a ratio of 8-15 times the mass of the medicinal materials. First, decoct the ephedra for 1-5 hours, then add the other three ingredients and decoct for 1.0-2.0 hours. Filter to obtain the decoction.

[0008] B. The decoction is concentrated to a specific gravity of 1.0-1.05, which is called Ma Xing Shi Gan Yuan Tang.

[0009] C. Centrifuge the original decoction of Ma Xing Shi Gan Tang, and take the supernatant to obtain a colloidal phase solution.

[0010] D. The above colloidal solution was dialyzed using a dialysis bag to obtain a nano-phase Ma Xing Shi Gan Tang. A dialysis bag with a molecular weight of 15000 was preferred for dialysis.

[0011] The nano-phase Ma Xing Shi Gan Tang can be prepared into various dosage forms, such as powders, premixes, soluble powders, granules, oral liquids, injections, powder injections, tablets, etc., for the treatment of febrile diseases in livestock and poultry.

[0012] This invention uses the classic formula Ma Xing Shi Gan Tang from Zhang Zhongjing's *Treatise on Febrile and Miscellaneous Diseases* as its raw material. Through dialysis separation and phase characterization, a liquid preparation with a nanophase structure was prepared. This preparation has no toxic side effects and a long-lasting antipyretic effect. Compared with existing technologies, this invention has the following advantages: This invention is the first to obtain a nanophase Ma Xing Shi Gan Tang preparation from the decoction of an ancient formula through separation and dialysis. The preparation process is simple and convenient, with definite efficacy, a cure rate of over 88%, and few side effects. It belongs to a natural nanophase structure. This provides a new method for the development of new traditional Chinese medicine preparations. Attached Figure Description

[0013] Figure 1 This is a TEM image of the nano-phase Ma Xing Shi Gan Tang prepared according to the present invention;

[0014] Figure 2 This is a TEM image of the nano-phase Ma Xing Shi Gan Tang prepared by this invention at magnification.

[0015] Figure 3 This is the EDS-Mapping elemental distribution diagram of the nano-phase Ma Xing Shi Gan Tang prepared by this invention;

[0016] Figure 4-1 This is the HPLC chromatogram of the nano-phase Ma Xing Shi Gan Tang containing ephedrine and pseudoephedrine prepared by this invention;

[0017] Figure 4-2 This is the HPLC chromatogram of the nano-phase ephedra, amygdalin-containing ginseng prepared by this invention;

[0018] Figure 4-3 This is the HPLC chromatogram of the nano-phase Ma Xing Shi Gan Tang containing glycyrrhizin and ammonium glycyrrhizate prepared by this invention;

[0019] Figure 5 The body temperature change curve of rats prepared with nano-phase Ma Xing Shi Gan Tang (n=5) according to the present invention;

[0020] Figure 6 This is a standard curve of tumor necrosis factor-α;

[0021] Figure 7 This is the standard curve of interleukin-1β;

[0022] Figure 8-1 The bar chart shows the tumor necrosis factor-α (TNF-α) bars for the blank group, model group, positive group (acetaminophen), Ma Xing Shi Gan Tang group, and nano-phase group.

[0023] Figure 8-2 The bar chart shows the interleukin-1β bars for the blank group, model group, positive group (acetaminophen), Ma Xing Shi Gan Tang group, and nano-phase group.

[0024] Figure 8-3 The bar chart shows the blood calcium ion content of the blank group, model group, positive group (acetaminophen), Ma Xing Shi Gan Tang group, and nano-phase group.

[0025] Figure 9 This is a comparison of body temperature before and after treatment within the same group. Detailed Implementation

[0026] To better illustrate the present invention, the following embodiments are provided:

[0027] Example 1

[0028] The preparation method of the nano-phase Ma Xing Shi Gan Tang is as follows:

[0029] A. Place 60-80g of ephedra in an extraction vessel, add 1400-1800mL of water, stir and soak for half an hour, then heat and boil for 0.5-5 hours, filter to obtain 1000-1400mL of decoction; then add 120-160g of gypsum, 30-40g of licorice, and 20-30g of bitter apricot kernel, decoct for 40-90 minutes, filter to obtain the original decoction of Ephedra, Apricot Kernel, Gypsum and Licorice Decoction;

[0030] B. The above decoction is concentrated by multi-effect distillation to a specific gravity of 1.0-1.05 and a volume of 500-800mL, which is called Ma Xing Shi Gan Yuan Tang.

[0031] C. After centrifuging the original decoction of Ma Xing Shi Gan Tang at 9000 rpm for 10 min, the supernatant is taken to obtain the colloidal phase solution;

[0032] D. Dialyze the above colloidal phase solution once using a dialysis bag with a molecular weight of 15000 to obtain a nanophase solution.

[0033] Example 2

[0034] The nano-phase ephedra, apricot kernel, and licorice decoction was prepared by the following method:

[0035] Take 60g of ephedra and add it to 1400mL of water. After boiling, decoct for 30 minutes. Then add 120g of gypsum (wrapped in cotton), 30g of licorice root, and 20g of bitter almond, and decoct for 1 hour. Combine the decoctions and concentrate to a specific gravity of 1.0-1.05 to obtain 550mL of Ephedra-Apricot-Gypsum-Licorice Decoction. Centrifuge the Ephedra-Apricot-Gypsum-Licorice Decoction at 9000rpm / min for 10 minutes. The supernatant is the colloidal phase, and the precipitate is the precipitate phase. Place the colloidal phase of Ephedra-Apricot-Gypsum-Licorice Decoction in a dialysis bag with a molecular weight cutoff of 15000Da. Clamp both ends with dialysis bag clamps and place it in a beaker containing 1000mL of distilled water. Dialyze for 30 minutes and remove the liquid from the dialysis bag to obtain 550mL of nano-phase Ephedra-Apricot-Gypsum-Licorice Decoction.

[0036] Example 3

[0037] The preparation method is the same as above. The formula is: 60g of ephedra, 20g of bitter almond, 120g of gypsum, and 30g of licorice. Weigh the medicinal materials and add them to purified water at 15 times the amount of medicinal materials. Decoction.

[0038] The following tests were conducted to verify the effectiveness of the invention:

[0039] Take an ultrathin carbon film, dilute the nano-phase Ma Xing Shi Gan Tang solution 5 times, and pipette 10 μL directly onto the carbon film. After natural drying, observe the morphology under TEM. The results are as follows: Figure 1 and Figure 2 As shown.

[0040] Depend on Figure 1 and Figure 2 It can be seen that the nanoparticles in the nanophase Ma Xing Shi Gan Tang observed under TEM are spherical, with complete morphology, smooth particle surface and uniform size, and an average particle size distribution of about 500 nm.

[0041] Qualitative and semi-quantitative elemental analysis was performed on the Ma Xing Shi Gan Tang nanoparticles. The EDS-Mapping elemental analysis results of the Ma Xing Shi Gan Tang nanoparticles are shown below. Figure 3 The five elements Ca, O, Bi, K and S are clearly distributed in the Ma Xing Shi Gan Tang nanoparticles.

[0042] The content of ephedrine and pseudoephedrine in nano-phase Ma Xing Shi Gan Tang was determined by high performance liquid chromatography, and the specific steps are as follows:

[0043] Chromatographic conditions: Mobile phase: Acetonitrile (A): 0.2% phosphoric acid solution (B) = 2:98; Flow rate: 1 mL / min; Detection wavelength: 210 nm; Column temperature: 30 ℃; Injection volume: 5 μL; Theoretical plate number calculated based on ephedrine hydrochloride is not less than 4000;

[0044] Preparation of reference solution: Accurately weigh appropriate amounts of ephedrine hydrochloride and pseudoephedrine hydrochloride reference standards, add methanol to prepare a mixed reference solution containing 20 μg of each per 1 mL;

[0045] Preparation of the test solution: Dilute the sample with methanol 10 times, mix well, sonicate for 30 min, filter through a microporous membrane, and collect the filtrate.

[0046] Content determination results: by Figure 4-1 As can be seen from top to bottom, these represent the negative control, blank control, reference standard, and test sample. It can be observed that the negative control and blank control do not interfere with each other. The resolution between pseudoephedrine hydrochloride and adjacent impurities is >1.5, and the baseline is stable, indicating good specificity of the method. The nano-phase Ma Xing Shi Gan Tang contains ephedrine and pseudoephedrine at concentrations of 528.8 μg / mL and 876.4 μg / mL, respectively.

[0047] The glycyrrhizic acid and glycyrrhizin contents of nano-phase Ma Xing Shi Gan Tang were determined by high performance liquid chromatography, and the specific steps are as follows:

[0048] Chromatographic conditions: injection volume: 10 μL; detection wavelength: 237 nm; flow rate: 0.7 mL / min; column temperature: 30 ℃; mobile phase: gradient elution, see Table 1;

[0049] Table 1

[0050]

[0051] Preparation of reference solution: Accurately weigh appropriate amounts of glycyrrhizin and ammonium glycyrrhizate reference standards, and add methanol to prepare a mixed reference solution containing 46.2 μg of glycyrrhizin and 70.5 μg of ammonium glycyrrhizate per 1 mL.

[0052] Preparation of the test solution: Dilute the sample with methanol 10 times, mix well, sonicate for 30 min, filter through a microporous membrane, and collect the filtrate.

[0053] Content determination results: by Figure 4-2 As can be seen from top to bottom, these represent the negative control, blank control, reference standard, and test sample. It can be observed that the negative control and blank control do not interfere with each other. The resolution between glycyrrhizin hydrochloride, ammonium glycyrrhizate, and adjacent impurities is >1.5, and the baseline is stable, indicating that the method has good specificity. The nanophase of Ma Xing Shi Gan Tang contains glycyrrhizin and ammonium glycyrrhizate at concentrations of 64.25 μg / mL and 215.44 μg / mL, respectively.

[0054] The content of amygdalin in nano-phase Ma Xing Shi Gan Tang was determined by high performance liquid chromatography, and the specific steps are as follows:

[0055] Chromatographic conditions: Injection volume: 5 μL; Detection wavelength: 207 nm; Flow rate: 1.0 mL / min

[0056] Column temperature: 30°C; mobile phase: methanol:0.1% phosphoric acid aqueous solution = 20:80

[0057] Content determination results: from Figure 4-3 , it can be known that from top to bottom are negative control, blank control, reference substance and test sample respectively. It can be seen that the negative control and the blank control have no interference; the resolution between amygdalin and adjacent impurities is >1.5, and the baseline is stable, indicating that the method has good specificity. The amygdalin content in the nano-phase of Maxing Shigan Decoction is 43.83 μg / mL;

[0058] Determination of calcium ions in nano-phase Maxing Shigan Decoction: Adopt EDTA-2Na method. Take 25 mL of three batches of nano-phase Maxing Shigan Decoction samples into a conical flask, add 15 mL of dilute hydrochloric acid and 2 drops of methyl red indicator solution, add 20% potassium hydroxide solution until the solution turns yellow, add an additional 5 mL of potassium hydroxide, add an appropriate amount of calcein indicator, and titrate the above solutions with EDTA-2Na standard solution respectively until the yellow-green color fades and the solution turns purplish red. After 3 parallel determinations, take the average value and record it. Calculate the calcium ion content in Maxing Shigan Decoction and its nano-phase according to the consumption of EDTA-2Na standard solution.

[0059] The measured calcium ion content is 214.7 mg / mL.

[0060] Example 4 Pharmacodynamic experiment

[0061] SPF-grade SD rats, male, were purchased from Henan Provincial Experimental Animal Center, production license number: SCXK (Yu) 2017-0001. Room temperature is 24±2°C, relative humidity is 40% to 60%. The rats were placed in an SPF-grade animal room for one week of adaptive feeding, and the rectal temperature of the rats was measured once a day.

[0062] Rats were subcutaneously injected with 15% mass percentage dry yeast suspension (10 mL / kg) on the back, and the blank group was injected with an equal volume of normal saline. After injection, the rectal temperature of rats in each group was measured and recorded every 1 hour, and the monitoring lasted for 12 hours. Record and draw the body temperature change curve, see Figure 5 , Table 2, body temperature change difference (ΔT) = measured body temperature - basal body temperature.

[0063] Table 2 Body temperature change table of rats (n=5)

[0064]

[0065] (Note: Comparison between model group and blank group: # P < 0.05, ## P < 0.01)

[0066] From Figure 5It can be seen that after injection of dry yeast, the body temperature of rats in the model group rose rapidly within 0 to 4 hours, and there was a significant difference between the model group and the blank group, indicating that the fever rat model was successfully established.

[0067] Twenty-five rats were acclimatized for 7 days and then divided into four groups: a control group, a model group, a positive control group (acetaminophen), a Ma Xing Shi Gan Tang (a traditional Chinese medicine formula) group, and a nano-phase group. Except for the control group, the other groups were subcutaneously injected with dried yeast suspension to establish a fever model. Drug administration was carried out at 4-hour intervals, with one dose administered before modeling and another dose administered 4 hours after modeling. The drug-treated groups were administered the corresponding dose by gavage, while the control and model groups were administered physiological saline by gavage. The positive control group received an equal volume of acetaminophen. Results are shown below. Figure 5 .

[0068] Ten hours after drug administration, blood was collected from the abdominal aorta in each group to prepare serum and plasma. The levels of inflammatory factors TNF-α and IL-1β in rat serum were measured using an ELISA kit. Serum calcium levels were measured using a serum calcium assay kit. Standard curves for TNF-α and IL-1β are shown below. Figure 6 and Figure 7 The test results are shown in Table 3.

[0069] Table 3. Results of ELISA and serum calcium tests

[0070]

[0071] Note: Compared with the blank group, the model group: # P < 0.05 ## P < 0.01; compared with the model group, * P < 0.05 ** P < 0.01.

[0072] Figure 5 The results showed that both Ma Xing Shi Gan Tang and nano-phases had antipyretic effects in a yeast-induced fever rat model, with nano-phases exhibiting a significant antipyretic effect. Table 3 shows that the levels of inflammatory factors were significantly reduced after intervention with Ma Xing Shi Gan Tang and nano-phases. 2+ By participating in the regulation of numerous signaling pathways in the body, it participates in inflammatory responses in various pathological processes, and affects the level of calcium in rat plasma. 2+ Content determination showed that both Ma Xing Shi Gan Tang and nano-phases could increase the calcium content in the plasma of febrile rats. 2+ The concentrations of the above results all demonstrate that the nanophase of Ma Xing Shi Gan Tang has significant antipyretic and anti-inflammatory effects.

[0073] Example 5: Expanded Clinical Trial of Nanoparticle-Based Oral Liquid in Pigs

[0074] Two Duroc × Landrace × Large White fattening pigs weighing approximately 35 kg each were selected from a pig farm in a county of Henan Province. The main symptoms of the diseased pigs included cold ear tips and the lower hindquarters of the limbs, uneven skin temperature, and rectal temperature exceeding 40℃. Some of the diseased pigs were removed and moved to another pigpen for separate rearing to evaluate the efficacy of the methimazole-amylose nanoparticle formulation. Results compared with acetaminophen tablets are shown in Tables 4 and 5.

[0075] Table 4. Effects of nano-phase Ma Xing Shi Gan Tang preparation on body temperature in pigs ( n=50)

[0076]

[0077] The effect of the nano-phase Ma Xing Shi Gan Tang preparation on the body temperature of pigs is shown in Table 4. As can be seen from the table, the body temperature of pigs with fever decreased significantly 4 hours after administration of the nano-phase Ma Xing Shi Gan Tang preparation (P<0.05). Compared with the acetaminophen tablet control group, there were no significant differences in body temperature at any time point (P>0.05). This indicates that the antipyretic effect of the nano-phase Ma Xing Shi Gan Tang preparation is comparable to that of acetaminophen tablets.

[0078] Table 5. Clinical efficacy of nano-phase Ma Xing Shi Gan Tang preparation in treating febrile pigs.

[0079]

[0080] Table 5 shows that in the nano-phase Ma Xing Shi Gan Tang preparation experimental group, 50 pigs with fever were treated, with 44 cured, 2 showing significant improvement, 2 showing improvement, and 2 showing no improvement, resulting in a cure rate of 88.0% and a total effective rate of 98%. In the acetaminophen tablet control group, 50 pigs were treated, with 43 cured, 1 showing significant improvement, 2 showing improvement, and 4 showing no improvement, resulting in a cure rate of 86% and a total effective rate of 92%. The cure rate and total effective rate of the nano-phase Ma Xing Shi Gan Tang preparation were higher than those of the acetaminophen tablet group, but there was no significant difference between the two groups (P>0.05), indicating that the nano-phase Ma Xing Shi Gan Tang preparation has a better effect on fever in pigs, and no adverse reactions were observed during treatment.

[0081] Example 6: Expanded Clinical Trial of Nanophase Formulation in Pigs

[0082] Duroc-Landrace-Large White piglets weighing approximately 15 kg were selected from a pig farm in a county of Henan Province. The main symptom of the disease was fever, with body temperatures exceeding 39.5℃. Some of the diseased pigs were removed and moved to another pigpen for separate rearing to evaluate the efficacy of the nano-phase Ma Xing Shi Gan Tang preparation. Results compared with commercially available Ma Xing Shi Gan Tang oral liquid are shown in Table 6. Figure 9 .

[0083] Table 6 Comparison of body temperature between the two groups before treatment and between the two groups after treatment ( n=50)

[0084]

[0085] Note: Different uppercase letters in the same row subscript indicate extremely significant differences (P < 0.01), different lowercase letters in the subscript indicate significant differences (P < 0.05), and the same letter or no letter in the subscript indicates no significant differences (P > 0.05).

[0086] Table 5 shows the comparison of body temperature between the two groups of pigs before and after treatment. As can be seen from Table 5, before treatment, there was no significant difference in body temperature between the experimental group (Ma Xing Shi Gan nano-phase preparation) and the control group (commercial Ma Xing Shi Gan oral liquid) (P>0.05); after treatment, the body temperature of the experimental group was significantly lower than that of the control group (P<0.01). This indicates that the experimental group (Ma Xing Shi Gan nano-phase preparation) can reduce the body temperature of sick pigs, and the cooling effect is superior to that of commercially available Ma Xing Shi Gan oral liquid.

[0087] Comparison of body temperature before and after treatment in each group of pigs is shown in the figure. Figure 9 .from Figure 9 It can be seen that, compared with before treatment, the body temperature of both the Ma Xing Shi Gan nano-phase preparation experimental group and the commercial Ma Xing Shi Gan oral liquid control group was significantly reduced after treatment (P<0.01). This indicates that the Ma Xing Shi Gan nano-phase preparation experimental group can reduce the body temperature of diseased pigs, and the cooling effect is better than that of the commercial Ma Xing Shi Gan oral liquid control group.

Claims

1. A veterinary nano-phase state Maxing Shigan Decoction traditional Chinese medicine preparation, characterized in that, The nanoparticles in the nano-phase Ma Xing Shi Gan Tang are spherical, with complete morphology, smooth particle surface, and uniform size. Furthermore, the nanoparticles are distributed with Ca, O, Bi, K, and S. The nano-phase Ma Xing Shi Gan Tang also contains ephedrine, pseudoephedrine, glycyrrhizin, ammonium glycyrrhizate, and calcium ions. The nano-phase Ma Xing Shi Gan Tang is prepared using the following method: A. Weigh the herbs according to the formula of ephedra, bitter almond, gypsum, and licorice in a mass ratio of 1-5:1-3:5-10:1-4. Add purified water at a ratio of 8-15 times the mass of the herbs. For the first decoction, decoct the ephedra for 1-5 hours first, then add the other three herbs and decoct for 1.5-2.0 hours. Filter to obtain the decoction. B. The decoction is concentrated to a specific gravity of 1.0-1.05, which is called Ma Xing Shi Gan Yuan Tang; C. Centrifuge the original decoction of Ma Xing Shi Gan Tang and collect the supernatant to obtain a colloidal phase solution; D. The above colloidal solution was dialyzed using a dialysis bag with a molecular weight of 15,000 to obtain the nano-phase Ma Xing Shi Gan Tang.

2. The veterinary antipyretic nanophase Ma Xing Shi Gan Tang preparation as described in claim 1, characterized in that, It can be made into powders, tablets, granules, capsules, aerosols, injections, ointments, syrups, coatings, liniments, patches, drops, or suppositories.

3. The method for preparing the veterinary antipyretic nanophase Ma Xing Shi Gan Tang preparation as described in claim 1, characterized in that, Prepared using the following method: A. Place 60-80g of ephedra in an extraction tank, add 1400-1800mL of water, stir and soak for half an hour, then heat and cook for 1-5 hours, filter to obtain 1000-1400mL of decoction; then add 120-160g of gypsum, 30-40g of licorice and 20-30g of bitter apricot kernel, decoct for 1-1.5 hours, filter to obtain the Ma Xing Shi Gan Tang decoction; B. The above decoction is concentrated by multi-effect distillation to a specific gravity of 1.0-1.05 and a volume of 500-800mL, which is called Ma Xing Shi Gan Yuan Tang. C. After centrifuging the original decoction of Ma Xing Shi Gan Tang at 9000 rpm for 10 min, the supernatant is taken to obtain the colloidal phase solution; D. Dialyze the above colloidal solution once using a dialysis bag with a molecular weight of 15000 to obtain the nano-phase Ma Xing Shi Gan Tang.

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