Atractylodes macrocephala preparation and use thereof

Abstract

The application discloses atractylodes rhizome preparation and application thereof, and belongs to the technical field of medical drugs, and particularly relates to atractylodes rhizome preparation which is prepared by compounding atractylodes rhizome active substance and auxiliary agents. After the atractylodes rhizome is cleaned and dried, atractylodes rhizome powder is prepared, and then is subjected to reflux extraction treatment by mixing with water, reflux extraction treatment by mixing with an alcohol solution and water vapor distillation treatment by mixing with water, so as to obtain atractylodes rhizome water extraction product, atractylodes rhizome alcohol extraction product and atractylodes rhizome water vapor product; the atractylodes rhizome preparation is prepared by mixing the three products; and the atractylodes rhizome preparation can be compounded with auxiliary agents by adding the auxiliary agents and the atractylodes rhizome active substance; the auxiliary agents can be microbial lipopeptide, lipopeptide derivative and medical solvent, etc. The atractylodes rhizome preparation can prevent and treat peripheral nerve injury caused by tumor drugs, promote the repair of peripheral nerve apoptosis caused by antitumor drugs, promote the expression level of nerve trophic factors of nerve cells and promote the repair and regeneration of nerve tissues.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical drugs, and particularly relates to a white atractylodes preparation and use thereof. BACKGROUND

[0002] Antitumor drugs play an important role in cancer treatment, but their side effects cannot be ignored, especially chemotherapy-induced peripheral neuropathy (CIPN). CIPN is damage to the peripheral nervous system caused by chemotherapy drugs, mainly manifested as numbness, pain, paresthesia and other symptoms in the limbs, which seriously affects the quality of life and treatment effect of patients. At present, the treatment of CIPN in Western medicine mainly relies on symptomatic treatment, and there is a lack of specific drugs, while traditional Chinese medicine shows unique advantages in relieving CIPN.

[0003] CIPN is a common dose-limiting toxicity of chemotherapy, with an incidence rate as high as 70%. Platinum drugs (such as cisplatin and oxaliplatin) and taxol drugs are the main drugs that induce CIPN. The pathogenesis of CIPN has not been fully elucidated, which may be related to oxidative stress, mitochondrial dysfunction, inflammatory response and nerve axon damage. The clinical manifestations of CIPN are diverse, including sensory abnormalities (such as numbness, tingling), motor disorders (such as muscle weakness) and autonomic nervous dysfunction (such as constipation, dizziness). These symptoms not only reduce the quality of life of patients, but also may lead to a reduction or interruption of chemotherapy doses, thereby affecting the treatment effect of tumors. At present, the treatment of CIPN in Western medicine mainly relies on symptomatic treatment, and common drugs include analgesics, antidepressants and anticonvulsants, but these drugs have limited efficacy and may cause side effects. Therefore, the development of safe and effective treatment methods is the focus of current research.

[0004] According to traditional Chinese medicine theory, CIPN belongs to the category of "Bi syndrome", and its pathogenesis is closely related to deficiency of qi and blood, stagnation of cold evil and blood stasis. Traditional Chinese medicine can effectively relieve CIPN symptoms through the effects of regulating qi and blood, warming the meridians, promoting blood circulation and removing blood stasis. In recent years, many studies have confirmed the efficacy of traditional Chinese medicine compounds (such as Jiawei Huangqi Guizhi Wuwu Decoction) in improving CIPN symptoms. In addition, single herb extracts (such as angelica, astragalus and caulis spathulatae) have also been proven to have neuroprotective effects. However, existing researches mainly focus on compound traditional Chinese medicines, and the research on single traditional Chinese medicines and their active ingredients is relatively insufficient.

[0005] At present, the main prevention means for peripheral neuropathy caused by antitumor drugs is mainly ice gloves, and the clinical treatment is mainly observation and symptomatic treatment. At present, the prevention of peripheral neuropathy caused by antitumor drugs in the clinic is mainly ice gloves, and the ice gloves are used to reduce the blood flow speed of limbs to reduce the damage of antitumor drugs to the nervous system. At present, the main treatment for peripheral neuropathy caused by antitumor drugs in the clinic is mainly oral nerve-nourishing drugs, and the treatment effect is poor. SUMMARY

[0006] The purpose of the present application is to provide a Baizhu preparation which can improve the diameter of blood vessels, improve blood speed, improve blood vessel pulsatility index, reduce peripheral blood inflammatory factors, prevent and treat peripheral nerve damage caused by tumor drugs, promote the repair of peripheral nerve apoptosis caused by antitumor drugs, promote the expression level of neurotrophic factors of nerve cells, and promote the repair and regeneration of nerve tissue, and the use thereof.

[0007] The purpose of the present application is to provide a Baizhu preparation which can improve the diameter of blood vessels, improve blood speed, improve blood vessel pulsatility index, reduce peripheral blood inflammatory factors, prevent and treat peripheral nerve damage caused by tumor drugs, promote the repair of peripheral nerve apoptosis caused by antitumor drugs, promote the expression level of neurotrophic factors of nerve cells, and promote the repair and regeneration of nerve tissue, and the use thereof.

[0008] The technical scheme adopted by the present application to achieve the above-mentioned purposes is as follows:

[0009] A Baizhu preparation, comprising: Baizhu active substance and adjuvant, the use amount of the adjuvant is 0.01-150wt% of the Baizhu active substance. The present application finds through clinical trials that the external use of Baizhu extract can significantly improve peripheral neuropathy and inflammatory damage of peripheral nerve tissue caused by antitumor chemotherapy drugs, improve the nerve conduction velocity of peripheral nerve tissue and inflammatory damage, and promote the growth of nerve cells.

[0010] The Baizhu preparation protects the peripheral nerve tissue damaged by antitumor chemotherapy drugs, promotes the repair and proliferation of nerve tissue, inhibits the inflammatory damage and apoptosis of peripheral nerves caused by antitumor chemotherapy drugs, and achieves the effect of protecting peripheral nerve tissue from apoptosis.

[0011] The present application provides a safe, effective and economic new method for the prevention and treatment of peripheral neuropathy caused by antitumor chemotherapy drugs in the clinic.

[0012] Preferably, the Baizhu active substance comprises at least one of Baizhu water extraction product, Baizhu alcohol extraction product and Baizhu water vapor product.

[0013] More preferably, the Baizhu active substance is Baizhu water extraction product, Baizhu alcohol extraction product and Baizhu water vapor product.

[0014] The use amount of the alcohol extraction product of Atractylodes Macrocephala Koidz is 50-150 vol% of the water extraction product of Atractylodes Macrocephala Koidz; or, the use amount of the water steam product of Atractylodes Macrocephala Koidz is 50-150 vol% of the water extraction product of Atractylodes Macrocephala Koidz.

[0015] More preferably, in the preparation of the water extraction product of Atractylodes Macrocephala Koidz, Atractylodes Macrocephala Koidz is mixed with water, and reflux extraction is performed to obtain the water extraction product of Atractylodes Macrocephala Koidz; or,

[0016] In the preparation of the alcohol extraction product of Atractylodes Macrocephala Koidz, Atractylodes Macrocephala Koidz is mixed with an alcohol solution, and reflux extraction is performed to obtain the alcohol extraction product of Atractylodes Macrocephala Koidz; or,

[0017] In the preparation of the water steam product of Atractylodes Macrocephala Koidz, Atractylodes Macrocephala Koidz is mixed with water, and water steam distillation is performed to obtain the water steam product of Atractylodes Macrocephala Koidz.

[0018] Preferably, in the preparation of the powder of Atractylodes Macrocephala Koidz, the rhizome of Atractylodes Macrocephala Koidz is cleaned and dried, and is broken by a pulverizer to 20-40 meshes to obtain the powder of Atractylodes Macrocephala Koidz. In the drying process, the rhizome of Atractylodes Macrocephala Koidz is dried to less than 8% of water content.

[0019] Preferably, in the preparation of the water extraction product of Atractylodes Macrocephala Koidz, the powder of Atractylodes Macrocephala Koidz is mixed with pure water, reflux extraction is performed at 90-100 DEG C for 2-8 hours, residues are removed by filtration, and the supernatant is obtained by centrifugation after polysaccharide is precipitated by adding ethanol at 20-60 DEG C, to obtain the water extraction product of Atractylodes Macrocephala Koidz.

[0020] More preferably, in the preparation of the water extraction product of Atractylodes Macrocephala Koidz, the use amount of the powder of Atractylodes Macrocephala Koidz is 5-15 wt% of the pure water. The use amount of ethanol is 400-600 wt% of the pure water.

[0021] Preferably, in the preparation of the alcohol extraction product of Atractylodes Macrocephala Koidz, the powder of Atractylodes Macrocephala Koidz is mixed with an ethanol solution, reflux extraction is performed at 60-80 DEG C for 2-8 hours, residues are removed by filtration, and the alcohol extraction product of Atractylodes Macrocephala Koidz is obtained by recovering ethanol by concentration.

[0022] More preferably, in the preparation of the alcohol extraction product of Atractylodes Macrocephala Koidz, the ethanol solution is obtained by mixing ethanol and water, and the content of ethanol in the ethanol solution is 60-70 wt%.

[0023] More preferably, in the preparation of the alcohol extraction product of Atractylodes Macrocephala Koidz, the use amount of the powder of Atractylodes Macrocephala Koidz is 5-25 wt% of the ethanol solution.

[0024] Preferably, in the preparation of the water steam product of Atractylodes Macrocephala Koidz, the powder of Atractylodes Macrocephala Koidz is mixed with pure water, water steam distillation is performed for 2-8 hours, volatile oil is collected by oil-water separation, and the water steam product of Atractylodes Macrocephala Koidz is obtained by dehydration with anhydrous sodium sulfate.

[0025] More preferably, in the preparation of the water steam product of Atractylodes Macrocephala Koidz, the use amount of the powder of Atractylodes Macrocephala Koidz is 10-30 wt% of the pure water.

[0026] The application discloses a preparation method of Atractylodes Macrocephala Koidz preparation.

[0027] Preferably, the atractylodes rhizome active includes atractylodes rhizome water extraction product, atractylodes rhizome alcohol extraction product, and atractylodes rhizome steam extraction product, the use amount of the atractylodes rhizome alcohol extraction product is 50-150vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome steam extraction product is 50-150vol% of the atractylodes rhizome water extraction product.

[0028] Preferably, the adjuvant includes at least one of water, alcohol agent, ester agent, ether agent, and biological agent.

[0029] More preferably, the alcohol agent includes at least one of methanol, ethanol, propylene glycol, isopropyl alcohol, ethylene glycol, and polyethylene glycol; or,

[0030] The ether agent includes at least one of diethyl ether, diethylene glycol monoethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monobutyl ether, and ethylene glycol dibutyl ether; or,

[0031] The ester agent includes at least one of polyethylene glycol laurate, propylene glycol laurate, and glyceryl caprylate; or,

[0032] The biological agent includes at least one of microbial lipopeptide, lipopeptide derivative, polypeptide, and polypeptide derivative.

[0033] The atractylodes rhizome active can reduce the inflammation of the nervous system caused by the antitumor drug, protect the nerve cells from inflammatory death, activate the neurotrophic growth factor transmission of the nerve cells, and play a role in protecting the nerve cells from nervous system damage. After the microbial lipopeptide and / or lipopeptide derivative are compounded with the atractylodes rhizome active to form the atractylodes rhizome preparation, the atractylodes rhizome preparation has more excellent effects on reducing the inflammation of the nervous system caused by the antitumor drug, protecting the nerve cells from inflammatory death, activating the neurotrophic growth factor transmission of the nerve cells, and playing a role in protecting the nerve cells from nervous system damage.

[0034] More preferably, the adjuvant is microbial lipopeptide, which is obtained by fermenting and culturing Bacillus licheniformis.

[0035] More preferably, in the preparation of the microbial lipopeptide, the Bacillus licheniformis strain is inoculated into the fermentation medium at a volume fraction of 1%, and cultured for 0.5-7d. The bacterial bodies and supernatant are separated by centrifugation, the bacterial bodies are broken to obtain a broken liquid, the supernatant and the broken liquid are mixed, an extractant is used for extraction, the organic phase is separated, reduced pressure distillation is performed, and freeze-drying is performed to obtain the microbial lipopeptide.

[0036] More preferably, in the preparation of the microbial lipopeptide, the fermentation medium contains 20 g / L of corn syrup, 20 g / L of glucose, 3 g / L of sodium gluconate, 2 g / L of yeast powder, 2 g / L of ammonium sulfate, 2 g / L of disodium hydrogen phosphate, 2 g / L of dipotassium hydrogen phosphate, 2 g / L of calcium chloride, 1 g / L of calcium carbonate, 0.5 g / L of magnesium sulfate, 0.5 g / L of potassium chloride, 0.03 g / L of ferric chloride, and the pH is adjusted to neutral, and the balance is water.

[0037] More preferably, the adjuvant is a lipopeptide derivative, which is derived from the microbial lipopeptide and a derivatizing agent.

[0038] More preferably, in the preparation of the lipopeptide derivative, the derivatizing agent is mixed with deionized water, the pH is adjusted to 4-6, an EDC / NHSS solution is added and stirred, the mixture is treated at 30-50°C for 10-60 min, then the microbial lipopeptide is added, and the reaction is carried out at 30-50°C for 2-8 h, after the reaction is completed, EDC and NHSS are removed by ultrafiltration, and freeze-drying is performed to obtain the lipopeptide derivative.

[0039] More preferably, in the preparation of the lipopeptide derivative, the derivatizing agent includes D-glucosamine acid and N,N-dimethylglycine, the use amount of the D-glucosamine acid is 0.05-0.5 wt% of the deionized water, and the use amount of the N,N-dimethylglycine is 20-100 wt% of the D-glucosamine acid.

[0040] More preferably, in the preparation of the lipopeptide derivative, the use amount of the EDC is 10-50 wt% of the D-glucosamine acid.

[0041] More preferably, in the preparation of the lipopeptide derivative, the use amount of the NHSS is 10-50 wt% of the D-glucosamine acid.

[0042] More preferably, in the preparation of the lipopeptide derivative, the use amount of the microbial lipopeptide is 400-1000 wt% of the D-glucosamine acid.

[0043] More preferably, the derivatizing agent includes D-glucosamine acid and / or N,N-dimethylglycine.

[0044] More preferably, the adjuvant includes a medical solvent or a pharmaceutical solvent.

[0045] The application also discloses a preparation method of the atractylodes rhizome preparation, which comprises mixing the atractylodes rhizome active substance with an adjuvant to obtain the atractylodes rhizome preparation.

[0046] Preferably, the active material of Atractylodes includes Atractylodes water extract, Atractylodes alcohol extract and Atractylodes steam product, the use amount of Atractylodes alcohol extract is 50-150vol% of Atractylodes water extract, and the use amount of Atractylodes steam product is 50-150vol% of Atractylodes water extract.

[0047] Preferably, the use amount of the adjuvant is 0.02-150wt% of the active material of Atractylodes.

[0048] More preferably, the adjuvant includes microbial lipopeptide, and the use amount of microbial lipopeptide is 0.5-10wt% of the active material of Atractylodes.

[0049] More preferably, the adjuvant includes lipopeptide derivative, and the use amount of lipopeptide derivative is 0.5-10wt% of the active material of Atractylodes.

[0050] More preferably, the adjuvant includes 2-acetylamino-2-deoxy-D-galactosamide, and the use amount of 2-acetylamino-2-deoxy-D-galactosamide is 0.02-1wt% of the active material of Atractylodes. After using the active material of Atractylodes and lipopeptide derivative, 2-acetylamino-2-deoxy-D-galactosamide can be further added, and the further compounding of 2-acetylamino-2-deoxy-D-galactosamide under the use of the active material of Atractylodes and lipopeptide derivative has more excellent use effect.

[0051] The application discloses a use of an Atractylodes preparation in preparation of a medicine for preventing and treating neuropathy caused by a tumor medicine.

[0052] The application has the following beneficial effects: can improve the inner diameter of blood vessels, improve blood speed, improve the pulsatility index of blood vessels, reduce peripheral blood inflammatory factors, prevent and treat peripheral nerve damage caused by a tumor medicine, promote the repair of peripheral nerve apoptosis caused by an anti-tumor medicine, promote the expression level of neurotrophic factors of nerve cells, and promote the repair and regeneration of nerve tissues. BRIEF DESCRIPTION OF DRAWINGS

[0053] Figure 1Graph for microbial lipopeptide wavelength scanning.

[0054] Figure 2 Graph for peripheral blood inflammatory factor reduction rate. DETAILED DESCRIPTION

[0055] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work are within the protection scope of the present application.

[0056] The concepts involved in the present application will be described below in combination with the drawings. It should be noted that the following descriptions of the concepts are only for the purpose of making the content of the present application easier to understand, and do not represent a limitation on the protection scope of the present application. Meanwhile, the embodiments in the present application and the features in the embodiments can be combined with each other without conflict. The present application will be described in detail below with reference to the drawings and in combination with the embodiments.

[0057] Research basis and results of the present application:

[0058] From January 2024 to December 2024, 100 female breast cancer patients with CIPN caused by taxane chemotherapy drugs were recruited in the Affiliated Hospital of Zhejiang Chinese Medical University. SPASS 26.0 software was used to generate random numbers, and the random numbers and groups were placed in opaque envelopes, the serial numbers were attached to the envelopes, and the corresponding serial numbers were selected according to the patient's visiting order. The patients were randomly divided into Baizhu group and western medicine group at a ratio of 1:1, with 50 patients in each group. During the implementation of the study, the treatment personnel and the evaluation personnel were separated, that is, the evaluation personnel did not know the grouping and treatment of the patients, and the data analyst was a third party.

[0059] Diagnostic criteria

[0060] The diagnostic criteria for breast cancer refer to Breast Disease Diagnosis and Treatment and Comprehensive Treatment of Breast Cancer. The CIPN evaluation classification refers to the National Cancer Institute-common terminology criteria for adverse events Version 5.0 (NCI-CTCAE V5.0).

[0061] Inclusion criteria

[0062] ① Female breast cancer patients, aged 18 to 75 years; ② Grade I and above CIPN symptoms due to the use of taxane chemotherapy drugs (including paclitaxel, albumin-bound paclitaxel, docetaxel, paclitaxel liposome, etc.); ③ Have the ability to live daily, Karnofsky Performance Status (KPS) score > 60 points, can independently complete all treatments; ④ No serious heart, liver, brain, kidney and other organ diseases, no serious mental illness; ⑤ No use of analgesics within 2 weeks before enrollment; ⑥ Voluntarily participate in this study, and sign the informed consent form.

[0063] Exclusion criteria

[0064] ① CIPN caused by non-taxane chemotherapy drugs; ② Pregnant women, or combined with other serious diseases, end-stage cachexia, etc.; ③ CIPN caused by other diseases, such as diabetic peripheral neuropathy; ④ Do not cooperate with treatment or are participating in other acupuncture or drug clinical trials.

[0065] Exclusion criteria

[0066] ① Do not meet the inclusion criteria and are mistakenly included; ② Poor compliance, or cannot tolerate drug treatment, or allergic to atractylodes-related components, cannot complete treatment and follow-up as required, patients voluntarily withdraw.

[0067] Stopping criteria

[0068] Progression of disease or occurrence of serious complications during the study, which is not suitable for further treatment after evaluation.

[0069] Treatment method

[0070] Western medicine group

[0071] Give mecobalamin tablets (China Pharmaceutical Co., Ltd., National Drug Code H20143107, 0.5 mg) orally, 0.5 mg each time, 3 times a day, for 4 weeks of continuous treatment.

[0072] Traditional Chinese medicine group

[0073] Take 15 g of atractylodes preparation, smear the limbs and rub for 15 min in the morning and before going to bed, 2 times a day, for 4 weeks of continuous treatment.

[0074] The preparation of the atractylodes preparation is as follows: the atractylodes rhizome is washed and dried, and then broken by a pulverizer to 30 mesh to obtain atractylodes powder. In the drying process, the atractylodes rhizome is dried to a moisture content of less than 8%; the atractylodes powder is mixed with pure water, and extracted at 100°C for 4h, and the residue is removed by filtration, and concentrated to 20vol% at 40°C, and then polysaccharide is precipitated by adding ethanol, and the supernatant is obtained by centrifugation to obtain the atractylodes water extract. The amount of atractylodes powder used is 10wt% of pure water. The amount of ethanol used is 500wt% of pure water; the atractylodes powder is mixed with an ethanol solution, and extracted at 70°C for 4h, and the residue is removed by filtration, and the ethanol is recovered by concentration to obtain the atractylodes ethanol extract. The ethanol solution is obtained by mixing ethanol and water, and the content of ethanol in the ethanol solution is 70wt%. The amount of atractylodes powder used is 12.5wt% of the ethanol solution; the atractylodes powder is mixed with pure water, and steam distillation is performed for 4h, and the volatile oil is collected by oil-water separation, and dehydrated with anhydrous sodium sulfate to obtain the atractylodes steam distillation product. The amount of atractylodes powder used is 20wt% of pure water; the atractylodes water extract, the atractylodes ethanol extract and the atractylodes steam distillation product are mixed in a volume ratio of 1:1:1 to obtain the atractylodes preparation.

[0075] Therapeutic effect observation

[0076] Observation index

[0077] The following indexes were evaluated before treatment, after treatment and 4 weeks after all treatment.

[0078] Primary outcome index

[0079] Functional assessment of cancer therapy / gynaecologic oncology group-neurotoxicity (FACT / GOG-Ntx) score: the scale has a total of 11 items, including 4 sensory items, 2 hearing items, 3 movement items and 2 dysfunction items, and has good reliability and validity in Chinese cancer population. Each item is scored from 0 to 4, and the total score ranges from 0 to 44, with higher scores indicating more severe neuropathy.

[0080] Secondary outcome index

[0081] (1) National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V5.0) grading of peripheral neurotoxicity: peripheral neuropathy caused by chemotherapy is divided into 4 grades from mild to severe, which is the standard scale for judging the severity of CIPN. Grade I: tendon reflex disappears or sensory numbness (including tingling), but does not affect function; Grade II: sensory loss or sensory numbness (including tingling), affecting function but not affecting daily life activities; Grade III: sensory loss or sensory numbness (including tingling), affecting daily life activities; Grade IV: sensory motor neuropathy, significantly interfering with daily life activities. In addition to the above 4 grades, 0 in this study means that the patient has no CIPN symptoms or CIPN is completely recovered.

[0082] (2) Visual Analogue Scale (VAS) score of peripheral neuropathic pain: VAS is used to evaluate peripheral neuropathic pain caused by chemotherapy at each time point. The total score ranges from 0 to 10, 0 for no pain, 1-3 for mild pain, 4-6 for moderate pain, and 7-10 for severe pain.

[0083] (3) European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN 20) for evaluating patient quality of life: The evaluation scale mainly includes sensory nerves, motor nerves and autonomic nerves, a total of 20 items, and the disease description is divided into 4 grades from mild to severe, with a total score of 20-80.

[0084] (4) ECOG score: ECOG score is divided into 0-5 points according to the activity state of the patient, a total of 6 grades. 0 points represent normal activity, and 5 points represent death. The higher the score, the worse the quality of life.

[0085] (5) Safety evaluation: observe and record various adverse events such as allergies and subcutaneous hematomas that occur during the study, record the processing process, and evaluate whether this patient can continue to participate in the study.

[0086] (6) Efficacy evaluation criteria: according to the experience of clinical practice, the efficacy evaluation criteria are self-made, and the clinical efficacy is evaluated after treatment. Marked effect: FACT / GOG-Ntx score decreased by ≥6 points compared with before treatment; Effective: FACT / GOG-Ntx score decreased by 3-<6 points compared with before treatment; Ineffective: FACT / GOG-Ntx scale score decreased by <3 points or aggravated.

[0087] Mechanism indicators

[0088] (1) Doppler ultrasound examination of the blood vessels of the extremities: before and after treatment, color Doppler ultrasound diagnostic instrument was used to examine the lower extremity arteries, and the dorsalis pedis artery was examined about 3 cm distal to the ankle joint. The blood vessel diameter, blood flow velocity and pulsatility index were recorded.

[0089] (2) Peripheral blood inflammatory factors: the contents of interleukin-1 and interleukin-6 in peripheral blood before treatment were detected.

[0090] Statistical processing

[0091] SPSS 23.0 software was used for statistical analysis of the data. First, normal distribution test was performed on all data, and different test methods were used according to whether the data was normally distributed. For normally distributed data, `x ± s was used, and for non-normally distributed data, median and interquartile range were used. Two independent sample t test was used for comparison between two groups of count data, and paired sample t test was used for comparison within two groups of count data. For non-normally distributed data, median and interquartile range were used to represent the change level, and Mann-whitney U test was used for comparison between non-normally distributed data. Chi-square test was used for count data.

[0092] Results of the study

[0093] A total of 100 cases were included in this study, and all patients completed the treatment-related research. The age, disease duration, body mass index (BMI), KPS score, number of chemotherapy and regimen, and tumor metastasis of patients in each group were compared, and the differences were not statistically significant (P>0.05), which were comparable, as shown in Table 1.

[0094] Table 1. Patient data of peripheral neuropathy caused by taxane chemotherapy in female breast cancer patients in each group

[0095]

[0096] The FACT / GOG-Ntx score, VAS score, EORTC QLQ-CIPN 20 score and ECOG score of patients in each group before and after treatment were compared, as shown in Table 2.

[0097] There was no significant difference in FACT / GOG-Ntx score, VAS score, EORTC QLQ-CIPN 20 score and ECOG score of patients in each group before treatment (P>0.05), which was comparable. After treatment, the levels of FACT / GOG-Ntx score and EORTC QLQ-CIPN 20 score of patients in two groups were significantly decreased (P<0.05), while there was no significant difference in VAS score and ECOG score (P>0.05). Compared with western medicine group, the levels of FACT / GOG-Ntx score and EORTC QLQ-CIPN 20 score of patients in traditional Chinese medicine group were decreased more obviously (P<0.05).

[0098] Table 2 Score results of patients in each group before and after treatment

[0099]

[0100] Note: Compared with this group before treatment, *P<0.05; compared with the control group at the same period, #P<0.05;

[0101] The comparison of blood flow of limbs and peripheral blood inflammatory factors of patients in each group at each time point before and after treatment is shown in Table 3.

[0102] Before treatment, there was no significant difference in blood vessel conditions (vessel diameter, blood flow velocity, pulsatility index) and peripheral blood inflammatory factors (IL-6, IL-1) of patients in each group (P>0.05), which was comparable. After treatment, the blood vessel conditions (vessel diameter, blood flow velocity, pulsatility index) and peripheral blood inflammatory factors (IL-6, IL-1) of patients in two groups were significantly improved (P<0.05). Compared with western medicine group, the blood vessel conditions (vessel diameter, blood flow velocity, pulsatility index) and peripheral blood inflammatory factors (IL-6, IL-1) of patients in traditional Chinese medicine group were improved more obviously (P<0.05).

[0103] Table 3 Comparison results of blood flow of limbs and peripheral blood inflammatory factors of patients in each group at each time point before and after treatment

[0104]

[0105] Note: Compared with this group before treatment, *P<0.05; compared with the control group at the same period, #P<0.05;

[0106] The effective rate of patients in each group after treatment is shown in Table 4.

[0107] After treatment, the overall effective rate of traditional Chinese medicine group was 88.0%, which was significantly higher than that of western medicine group (70.0%) (P<0.05).

[0108] Table 4 Effective rate results of patients in each group after treatment

[0109]

[0110] Compared with the contemporary control group, #P<0.05.

[0111] Example 1: A preparation method of atractylodes rhizome preparation

[0112] Preparation of atractylodes rhizome powder: The atractylodes rhizome was washed and dried, and then broken by a pulverizer to 30 mesh to obtain atractylodes rhizome powder. In the drying process, the atractylodes rhizome was dried to less than 8% of moisture.

[0113] Preparation of atractylodes rhizome water extraction product: The atractylodes rhizome powder was mixed with pure water, and refluxed at 100°C for 4h. The residue was removed by filtration, and concentrated to 20vol% at 40°C. Ethanol was added to precipitate polysaccharides, and the supernatant was obtained by centrifugation to obtain the atractylodes rhizome water extraction product. The use amount of the atractylodes rhizome powder was 10wt% of the pure water. The amount of ethanol was 500wt% of the pure water.

[0114] Preparation of atractylodes rhizome ethanol extraction product: The atractylodes rhizome powder was mixed with an ethanol solution, and refluxed at 70°C for 4h. The residue was removed by filtration, and the ethanol was recovered by concentration to obtain the atractylodes rhizome ethanol extraction product. The ethanol solution was mixed by ethanol and water, and the content of ethanol in the ethanol solution was 70wt%. The use amount of the atractylodes rhizome powder was 12.5wt% of the ethanol solution.

[0115] Preparation of atractylodes rhizome water distillation product: The atractylodes rhizome powder was mixed with pure water, and water distillation was performed for 4h. The volatile oil was collected by oil-water separation, and dehydrated by anhydrous sodium sulfate to obtain the atractylodes rhizome water distillation product. The use amount of the atractylodes rhizome powder was 20wt% of the pure water.

[0116] Preparation of atractylodes rhizome preparation: The atractylodes rhizome active substances were mixed to obtain the atractylodes rhizome preparation. The atractylodes rhizome active substances included the atractylodes rhizome water extraction product, the atractylodes rhizome ethanol extraction product, and the atractylodes rhizome water distillation product. The use amount of the atractylodes rhizome ethanol extraction product was 100vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome water distillation product was 100vol% of the atractylodes rhizome water extraction product.

[0117] Example 2: A preparation method of atractylodes rhizome preparation

[0118] The difference between this embodiment and example 1 is the preparation of the atractylodes rhizome preparation. Microbial lipopeptide is added in the preparation of the atractylodes rhizome preparation.

[0119] Preparation of microbial lipopeptide: Bacillus licheniformis strain is inoculated into fermentation medium at a volume fraction of 1%, and cultured for 5 days. The bacterial bodies and supernatant are separated by centrifugal separation. The bacterial bodies are crushed to obtain a crushing liquid. The supernatant and the crushing liquid are mixed, extracted by an extracting agent, and separated to obtain an organic phase. The organic phase is distilled under reduced pressure, and freeze-dried to obtain the microbial lipopeptide. The fermentation medium contains 20 g / L of corn syrup, 20 g / L of glucose, 3 g / L of sodium gluconate, 2 g / L of yeast powder, 2 g / L of ammonium sulfate, 2 g / L of disodium hydrogen phosphate, 2 g / L of dipotassium hydrogen phosphate, 2 g / L of calcium chloride, 1 g / L of calcium carbonate, 0.5 g / L of magnesium sulfate, 0.5 g / L of potassium chloride, 0.03 g / L of ferric chloride, and the rest is water. The bacterial bodies are crushed by an ultrasonic crusher at a crushing temperature of 25°C and a crushing frequency of 25 KHz. The extracting agent is dichloromethane. The preservation number of the Bacillus licheniformis is CGMCC No. 5686.

[0120] The prepared microbial lipopeptide is subjected to wavelength scanning, and the results are shown in FIG. 1. Figure 1

[0121] Preparation of atractylodes rhizome preparation: Atractylodes rhizome active substance is mixed with an auxiliary agent to obtain an atractylodes rhizome preparation. The atractylodes rhizome active substance includes atractylodes rhizome water extraction product, atractylodes rhizome alcohol extraction product, and atractylodes rhizome steam extraction product. The use amount of the atractylodes rhizome alcohol extraction product is 100 vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome steam extraction product is 100 vol% of the atractylodes rhizome water extraction product. The auxiliary agent includes microbial lipopeptide, and the use amount of the microbial lipopeptide is 1.2 wt% of the atractylodes rhizome active substance.

[0122] Example 3: a preparation method of an atractylodes rhizome preparation

[0123] The difference between the present example and example 2 is the preparation of the atractylodes rhizome preparation. A lipopeptide derivative is added in the preparation of the atractylodes rhizome preparation.

[0124] Preparation of lipopeptide derivative: A derivative agent is mixed with deionized water, and the pH is adjusted to 5. An EDC / NHSS solution is added and stirred to mix. The mixed solution is treated at 40°C for 30 min. Then, microbial lipopeptide is added, and the reaction is carried out at 40°C for 4 h. After the reaction is completed, EDC and NHSS are removed by ultrafiltration, and freeze-drying is performed to obtain the lipopeptide derivative. The derivative agent includes D-glucosamine acid and N,N-dimethylglycine. The use amount of the D-glucosamine acid is 0.1 wt% of the deionized water, the use amount of the N,N-dimethylglycine is 60 wt% of the D-glucosamine acid, the use amount of the EDC is 30 wt% of the D-glucosamine acid, the use amount of the NHSS is 30 wt% of the D-glucosamine acid, and the use amount of the microbial lipopeptide is 700 wt% of the D-glucosamine acid.

[0125] ​Preparation of the atractylodes rhizome preparation: the atractylodes rhizome active substance is mixed with the adjuvant to obtain the atractylodes rhizome preparation. The atractylodes rhizome active substance includes the atractylodes rhizome water extraction product, the atractylodes rhizome alcohol extraction product, and the atractylodes rhizome steam extraction product. The use amount of the atractylodes rhizome alcohol extraction product is 100 vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome steam extraction product is 100 vol% of the atractylodes rhizome water extraction product. The adjuvant includes the lipopeptide derivative, and the use amount of the lipopeptide derivative is 1.2 wt% of the atractylodes rhizome active substance.

[0126] Example 4: a preparation method of an atractylodes rhizome preparation

[0127] The difference between this example and example 3 is the preparation of the lipopeptide derivative.

[0128] Preparation of the lipopeptide derivative: the derivatizing agent is mixed with deionized water, the pH is adjusted to 5, the EDC / NHSS solution is added and stirred, the mixed solution is treated at 40°C for 30 min, then the microbial lipopeptide is added, and the reaction is carried out at 40°C for 4 h. After the reaction is completed, the EDC and NHSS are removed by ultrafiltration, and then freeze-drying is performed to obtain the lipopeptide derivative. The derivatizing agent includes D-amino glucuronic acid and N, N-dimethylglycine. The use amount of the D-amino glucuronic acid is 0.2 wt% of the deionized water, the use amount of the N, N-dimethylglycine is 80 wt% of the D-amino glucuronic acid, the use amount of the EDC is 30 wt% of the D-amino glucuronic acid, the use amount of the NHSS is 30 wt% of the D-amino glucuronic acid, and the use amount of the microbial lipopeptide is 700 wt% of the D-amino glucuronic acid.

[0129] Example 5: a preparation method of an atractylodes rhizome preparation

[0130] The difference between this example and example 3 is the preparation of the atractylodes rhizome preparation.

[0131] Preparation of the atractylodes rhizome preparation: the atractylodes rhizome active substance is mixed with the adjuvant to obtain the atractylodes rhizome preparation. The atractylodes rhizome active substance includes the atractylodes rhizome water extraction product, the atractylodes rhizome alcohol extraction product, and the atractylodes rhizome steam extraction product. The use amount of the atractylodes rhizome alcohol extraction product is 100 vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome steam extraction product is 100 vol% of the atractylodes rhizome water extraction product. The adjuvant includes the lipopeptide derivative, and the use amount of the lipopeptide derivative is 1.2 wt% of the atractylodes rhizome active substance.

[0132] Example 6: a preparation method of an atractylodes rhizome preparation

[0133] The difference between this example and example 3 is the preparation of the atractylodes rhizome preparation. In the preparation of the atractylodes rhizome preparation, 2-acetylamino-2-deoxy-D-galactosamide is added.

[0134] Preparation of the atractylodes rhizome preparation: the atractylodes rhizome active substance is mixed with the adjuvant to obtain the atractylodes rhizome preparation. The atractylodes rhizome active substance includes the atractylodes rhizome water extraction product, the atractylodes rhizome alcohol extraction product, and the atractylodes rhizome water distillation product, the use amount of the atractylodes rhizome alcohol extraction product is 100 vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome water distillation product is 100 vol% of the atractylodes rhizome water extraction product. The adjuvant includes the lipopeptide derivative and the 2-acetylamino-2-deoxy-D-galactosamide, the use amount of the lipopeptide derivative is 1.2 wt% of the atractylodes rhizome active substance, and the use amount of the 2-acetylamino-2-deoxy-D-galactosamide is 0.3 wt% of the atractylodes rhizome active substance.

[0135] Example 7: a preparation method of an atractylodes rhizome preparation

[0136] The difference between this example and example 3 is the preparation of the atractylodes rhizome preparation. The 2-acetylamino-2-deoxy-D-galactosamide is added in the preparation of the atractylodes rhizome preparation.

[0137] Preparation of the atractylodes rhizome preparation: the atractylodes rhizome active substance is mixed with the adjuvant to obtain the atractylodes rhizome preparation. The atractylodes rhizome active substance includes the atractylodes rhizome water extraction product, the atractylodes rhizome alcohol extraction product, and the atractylodes rhizome water distillation product, the use amount of the atractylodes rhizome alcohol extraction product is 100 vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome water distillation product is 100 vol% of the atractylodes rhizome water extraction product. The adjuvant includes the lipopeptide derivative and the 2-acetylamino-2-deoxy-D-galactosamide, the use amount of the lipopeptide derivative is 1.2 wt% of the atractylodes rhizome active substance, and the use amount of the 2-acetylamino-2-deoxy-D-galactosamide is 0.5 wt% of the atractylodes rhizome active substance.

[0138] Example 8: a preparation method of an atractylodes rhizome preparation

[0139] The difference between this example and example 1 is the preparation of the atractylodes rhizome preparation. The isopropyl alcohol is added in the preparation of the atractylodes rhizome preparation.

[0140] Preparation of the atractylodes rhizome preparation: the atractylodes rhizome active substance is mixed with the adjuvant to obtain the atractylodes rhizome preparation. The atractylodes rhizome active substance includes the atractylodes rhizome water extraction product, the atractylodes rhizome alcohol extraction product, and the atractylodes rhizome water distillation product, the use amount of the atractylodes rhizome alcohol extraction product is 100 vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome water distillation product is 100 vol% of the atractylodes rhizome water extraction product. The adjuvant includes the isopropyl alcohol, and the use amount of the isopropyl alcohol is 50 wt% of the atractylodes rhizome active substance.

[0141] Example 9: a preparation method of an atractylodes rhizome preparation

[0142] The difference between this example and example 2 is the preparation of the atractylodes rhizome preparation. The isopropyl alcohol is added in the preparation of the atractylodes rhizome preparation.

[0143] Preparation of the atractylodes rhizome preparation: the atractylodes rhizome active substance is mixed with the adjuvant to obtain the atractylodes rhizome preparation. The atractylodes rhizome active substance includes the atractylodes rhizome water extraction product, the atractylodes rhizome alcohol extraction product, and the atractylodes rhizome water distillation product. The use amount of the atractylodes rhizome alcohol extraction product is 100 vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome water distillation product is 100 vol% of the atractylodes rhizome water extraction product. The adjuvant includes the microbial lipopeptide and the isopropyl alcohol. The use amount of the microbial lipopeptide is 1.2 wt% of the atractylodes rhizome active substance, and the use amount of the isopropyl alcohol is 50 wt% of the atractylodes rhizome active substance.

[0144] Example 10: a preparation method of an atractylodes rhizome preparation

[0145] The difference between this example and example 3 is the preparation of the atractylodes rhizome preparation. Isopropyl alcohol is added in the preparation of the atractylodes rhizome preparation.

[0146] Preparation of the atractylodes rhizome preparation: the atractylodes rhizome active substance is mixed with the adjuvant to obtain the atractylodes rhizome preparation. The atractylodes rhizome active substance includes the atractylodes rhizome water extraction product, the atractylodes rhizome alcohol extraction product, and the atractylodes rhizome water distillation product. The use amount of the atractylodes rhizome alcohol extraction product is 100 vol% of the atractylodes rhizome water extraction product, and the use amount of the atractylodes rhizome water distillation product is 100 vol% of the atractylodes rhizome water extraction product. The adjuvant includes the microbial lipopeptide and the isopropyl alcohol. The use amount of the microbial lipopeptide is 1.2 wt% of the atractylodes rhizome active substance, and the use amount of the isopropyl alcohol is 50 wt% of the atractylodes rhizome active substance.

[0147] Comparative example 1: a preparation method of an atractylodes rhizome preparation

[0148] The difference between this example and example 3 is the preparation of the atractylodes rhizome preparation. Isopropyl alcohol is added in the preparation of the atractylodes rhizome preparation.

[0149] Comparative example 2: a preparation method of an atractylodes rhizome preparation

[0150] The difference between this example and example 3 is the preparation of the atractylodes rhizome preparation. Isopropyl alcohol is added in the preparation of the atractylodes rhizome preparation.

[0151] Comparative example 3: a preparation method of an atractylodes rhizome preparation

[0152] The difference between this example and example 3 is the preparation of the atractylodes rhizome preparation. Isopropyl alcohol is added in the preparation of the atractylodes rhizome preparation.

[0153] Comparative example 4: a preparation method of an atractylodes rhizome preparation

[0154] The difference between this embodiment and Example 6 lies in the preparation of the Atractylodes macrocephala preparation. No lipopeptide derivatives were added in the preparation of the Atractylodes macrocephala preparation; other reagents and their amounts are the same as those in Example 6.

[0155] Experimental example:

[0156] The expression levels of peripheral blood inflammatory factor IL-1 were tested using samples prepared in Examples 1-10 and Comparative Examples 1-4 according to the research method. The expression levels of peripheral blood inflammatory factor IL-1 without using samples were used as a control. The decrease rate of peripheral blood inflammatory factors was obtained as follows: Figure 2 As shown, S1 is Example 1, S2 is Example 2, S3 is Example 3, S4 is Example 4, S5 is Example 5, S6 is Example 6, S7 is Example 7, S8 is Example 8, S9 is Example 9, S10 is Example 10, D1 is Comparative Example 1, D2 is Comparative Example 2, D3 is Comparative Example 3, and D4 is Comparative Example 4. In this invention, after washing and drying the rhizomes of Atractylodes macrocephala, Atractylodes macrocephala powder is prepared. Then, it is subjected to reflux extraction with water, reflux extraction with alcohol solution, and steam distillation with water to obtain Atractylodes macrocephala water extract, Atractylodes macrocephala alcohol extract, and Atractylodes macrocephala steam distillation product. These are mixed to prepare Atractylodes macrocephala preparation. In cell experiments, it can increase the IL-1 reduction rate in cells, indicating that the present invention... Atractylodes macrocephala preparations can reduce IL-1 expression in cells. This invention can also add excipients to the active ingredients of Atractylodes macrocephala. Adding microbial lipopeptides prepared from Bacillus licheniformis can increase the rate of IL-1 reduction in cells, but the effect is relatively low. In this invention, after derivatizing the microbial lipopeptides with D-glucosamine and N,N-dimethylglycine, the resulting lipopeptide derivatives, at the same dosage, show significantly better effects than the microbial lipopeptides. In the preparation of the lipopeptide derivatives, increasing the dosage of D-glucosamine and N,N-dimethylglycine can further improve the effect of the Atractylodes macrocephala preparations. Increasing the dosage of the lipopeptide derivatives during the preparation of Atractylodes macrocephala preparations can also improve the effect. This invention can also use 2-acetamido-2-deoxy-D-galactosamide in combination with the above-mentioned lipopeptide derivatives in Atractylodes macrocephala preparations, which can further increase the rate of IL-1 reduction in cells, indicating that the combined application of 2-acetamido-2-deoxy-D-galactosamide and lipopeptide derivatives in Atractylodes macrocephala preparations can reduce IL-1 expression in cells. In this invention, medical solvents such as isopropanol can also be added. The use of medical solvents cannot increase the rate of IL-1 reduction in cells, that is, medical solvents will not change the expression of IL-1 in cells.

[0157] The above-described embodiments and / or implementations are merely intended to illustrate the preferred embodiments and / or implementations of the present technology, and are not intended to limit the embodiments of the present technology in any form, and any person skilled in the art can make some changes or modifications as other equivalent embodiments without departing from the scope of the technology disclosed in the present disclosure, but should be considered as the same technology or embodiments as the present disclosure.

[0158] The principles and implementations of the present application are described herein using specific examples. The above description of the embodiments is only intended to help understand the method and core idea of the present application. The above description is only the preferred embodiments of the present application. It should be noted that due to the limited nature of the language, there are objectively infinite specific structures. For those skilled in the art, without departing from the principles of the present application, some improvements, refinements or changes can be made, and the above technical features can be combined in an appropriate manner. These improvements, refinements, changes or combinations, or the direct application of the inventive concept and technical solution to other occasions without improvement, shall be considered as the protection scope of the present application.

Claims

1. A white atractylodes preparation, comprising: The auxiliary agent is used in an amount of 0.01-150wt% of the atractylodes rhizome active substance; The atractylodes rhizome active substance is a water-extracted atractylodes rhizome product, an alcohol-extracted atractylodes rhizome product, and a water-steam-extracted atractylodes rhizome product; The alcohol-extracted atractylodes rhizome product is used in an amount of 50-150vol% of the water-extracted atractylodes rhizome product; and the water-steam-extracted atractylodes rhizome product is used in an amount of 50-150vol% of the water-extracted atractylodes rhizome product; The auxiliary agent includes a biological agent, and the biological agent includes a lipopeptide derivative. The derivative agent includes D-amino glucuronic acid and N, N-dimethyl glycine, and the D-amino glucuronic acid is used in an amount of 0.05-0.5wt% of the deionized water, and the N, N-dimethyl glycine is used in an amount of 20-100wt% of the D-amino glucuronic acid. In the preparation of the microbial lipopeptide, Bacillus licheniformis is inoculated into a fermentation medium at a volume fraction of 1%, and is cultured for 0.5-7d, and the bacterial body and supernatant are separated by centrifugation, the bacterial body is crushed to obtain a crushing liquid, the supernatant and the crushing liquid are mixed, an extracting agent is used for extraction, an organic phase is separated, and the microbial lipopeptide is obtained by vacuum distillation and freeze-drying, and the extracting agent is dichloromethane.

2. The atractylodes rhizome preparation of claim 1, wherein: In the preparation of the water-extracted atractylodes rhizome product, the atractylodes rhizome is mixed with water, and is extracted by reflux to obtain the water-extracted atractylodes rhizome product; In the preparation of the alcohol-extracted atractylodes rhizome product, the atractylodes rhizome is mixed with an alcohol solution, and is extracted by reflux to obtain the alcohol-extracted atractylodes rhizome product; In the preparation of the water-steam-extracted atractylodes rhizome product, the atractylodes rhizome is mixed with water, and is distilled by water vapor to obtain the water-steam-extracted atractylodes rhizome product.

3. The Atractylodes Macrocephala Preparation of claim 1, characterized in that: The auxiliary agent includes at least one of water, an alcohol agent, an ester agent, and an ether agent.

4. The Atractylodes Macrocephala Preparation of claim 3, characterized in that: The alcohol agent includes at least one of methanol, ethanol, propylene glycol, isopropyl alcohol, ethylene glycol, and polyethylene glycol; The ether agent includes at least one of diethyl ether, diethylene glycol monoethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monobutyl ether, and ethylene glycol dibutyl ether; The ester agent includes at least one of polyethylene glycol laurate, propylene glycol laurate, and glyceryl caprylate; The biological agent includes at least one of a microbial lipopeptide, a lipopeptide derivative, a polypeptide, and a polypeptide derivative.

5. The Atractylodes Macrocephala Preparation of claim 3, characterized in that: The auxiliary agent is the microbial lipopeptide, which is obtained by fermenting and culturing Bacillus licheniformis.

6. The atractylodes macrocephala preparation of claim 1, characterized in that: The auxiliary agent includes a medical solvent or a pharmaceutical solvent.

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