Honghua Xiaoyao composition and its use in treating thyroid nodules

Abstract

The present invention provides a safflower xiaoyao composition and its use in treating thyroid nodules, and relates to the field of pharmaceutical compositions. The raw materials of the safflower xiaoyao composition include: angelica, white peony root, poria, sapodilla thorn, mint, saikosaponin A, atractylodes ketone, glycyrrhizic acid and safflower yellow. The safflower xiaoyao composition can effectively inhibit the proliferation of thyroid FRTL cells, thereby playing a role in dispersing nodules, and has a good effect on thyroid nodules. In addition, the composition of the present invention can also reduce the relative mass of the thyroid gland, and also has a certain effect on the treatment of goiter.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compositions, and in particular to a safflower xiaoyao composition and use thereof in treating thyroid nodules. Background Art

[0002] Honghua Xiaoyao tablets are a kind of medicine for soothing the liver and regulating qi. Its raw materials include angelica, white peony root, atractylodes, poria, safflower, honeysuckle, bupleurum, mint, and licorice. It has the effects of soothing the liver, regulating qi, and promoting blood circulation. The uses that have been discovered so far include the treatment of dysmenorrhea, breast hyperplasia, and breast cancer, as well as the treatment of thyroid nodules. Thyroid nodules are lumps in the thyroid gland that can move up and down with the thyroid gland during swallowing. They are common clinical diseases. Currently, the treatment of thyroid nodules is mostly surgical, supplemented by drug therapy. For the treatment of thyroid nodules with Honghua Xiaoyao preparations, relevant studies are as follows: Literature: Yuan Yalan, Zheng Qian, Liu Bo, et al. Clinical efficacy of Honghua Xiaoyao tablets combined with levothyroxine sodium tablets in the treatment of patients with qi stagnation and blood stasis type thyroid nodules [J]. World Traditional Chinese Medicine, 2023, 18(4): 5. It records the use of Honghua Xiaoyao tablets in combination with levothyroxine sodium tablets to treat patients with perimenopausal qi stagnation and blood stasis type thyroid nodules, and found that it has good clinical efficacy.

[0003] Another example is the literature: Zhang Qianqian, Sun Sutao, Gu Lina, et al. Effect of Honghua Xiaoyao Tablets combined with Levothyroxine Sodium Tablets in the treatment of benign thyroid nodules with qi stagnation and blood stasis syndrome and its effect on thyroid function [J]. Clinical Misdiagnosis and Mistreatment, 2022, 35(9): 5. The clinical effect of Honghua Xiaoyao Tablets combined with Levothyroxine Sodium Tablets on patients with benign thyroid nodules with qi stagnation and blood stasis syndrome and its effect on thyroid function were discussed. It was found that Honghua Xiaoyao Tablets combined with Levothyroxine Sodium Tablets were effective in the treatment of benign thyroid nodules with qi stagnation and blood stasis syndrome, and could improve thyroid function and thyroid autoantibody levels with good safety.

[0004] Literature: Gai Lizhen, Ning Rihong, Zhang Qianqian, et al. Clinical observation on Honghua Xiaoyao tablets in the treatment of Hashimoto's thyroiditis with nodules [J]. Journal of Traditional Chinese Medicine, 2023, 29(2): 5. This article explores the clinical effect of Honghua Xiaoyao tablets combined with levothyroxine sodium tablets in the treatment of patients with Hashimoto's thyroiditis with nodules and qi stagnation and blood stasis syndrome. The results showed that the combination of Honghua Xiaoyao tablets with levothyroxine sodium tablets had no significant effect on thyroid function, but could more effectively regulate the body's immunity, inhibit inflammatory response, shrink thyroid nodules, reduce the risk of nodule malignancy, relieve clinical symptoms, and was safe and reliable.

[0005] At present, there are relatively few in-depth studies on the raw materials of Honghua Xiaoyao preparation for the treatment of thyroid nodules. The main research is on the combined use of Honghua Xiaoyao preparation and levothyroxine sodium tablets. There is still a lot of room for research on Honghua Xiaoyao preparation itself. To address this problem, it is necessary to find a Honghua Xiaoyao composition and its use in the treatment of thyroid nodules. Summary of the invention

[0006] In view of the problems existing in the prior art, the present invention provides a safflower xiaoyao composition and its use in the treatment of thyroid nodules. The safflower xiaoyao composition can effectively inhibit the proliferation of thyroid FRTL cells, thereby playing a role in dispersing nodules and having a good effect on thyroid nodules. In addition, the composition of the present invention can also reduce the relative mass of the thyroid gland and also has a certain effect on the treatment of goiter.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] The invention provides a safflower xiaoyao composition, the raw materials of which include: angelica sinensis, white peony root, tuckahoe, sapodilla thorn, mint, saikosaponin A, atractylodes ketone, glycyrrhizic acid and safflower yellow pigment.

[0009] Furthermore, the Honghua Xiaoyao composition comprises, by weight: 50-65 parts of angelica sinensis, 20-30 parts of white peony root, 10-18 parts of Poria cocos, 10-25 parts of Gleditsia sinensis thorns, 35-45 parts of mint, 0.2-0.6 parts of bupleurum saponin A, 0.1-0.3 parts of atractylodes ketone, 0.05-0.15 parts of glycyrrhizic acid and 0.08-0.18 parts of safflower yellow.

[0010] Preferably, the Honghua Xiaoyao composition comprises, by weight: 55 parts of angelica sinensis, 25 parts of white peony root, 15 parts of Poria cocos, 20 parts of Gleditsia sinensis thorns, 40 parts of peppermint, 0.5 parts of saikosaponin A, 0.2 parts of atractylodes ketone, 0.1 parts of glycyrrhizic acid and 0.15 parts of safflower yellow.

[0011] Furthermore, the weight ratio of saikosaponin A, atractylodesone and safflower yellow is 0.2-0.6:0.1-0.3:0.08-0.18, preferably 0.5:0.2:0.15.

[0012] Furthermore, the present invention also provides a method for preparing the above-mentioned Honghua Xiaoyao composition, comprising the following steps: mixing angelica, white peony root, Poria cocos, Gleditsia sinensis and mint, extracting with water and concentrating to obtain a mixture A; mixing the mixture A with bupleurum saponin A, atractylodes ketone, glycyrrhizic acid and safflower yellow to obtain.

[0013] Furthermore, the concentration is specifically concentrated to a relative density of 1.3-1.5 (60° C.).

[0014] Furthermore, the water extraction is specifically performed by adding water and heating the temperature to 75-85° C., keeping the temperature for 15-25 minutes, filtering to obtain a water extract, repeating 2-3 times, and combining the water extracts.

[0015] Preferably, the water extraction comprises adding water, raising the temperature to 80° C., keeping the temperature for 20 minutes, filtering to obtain a water extract, repeating the process three times, and combining the water extracts.

[0016] Furthermore, the Honghua Xiaoyao composition provided by the present invention or the Honghua Xiaoyao composition prepared by the above preparation method can be used to prepare drugs for treating thyroid nodules.

[0017] Furthermore, the dosage form of the drug includes tablets, ointments, granules, pills or capsules.

[0018] Furthermore, the present invention has conducted a study on precise medication. The raw materials of saikosaponin A (also known as saikosaponin A) are derived from the effective component of bamboo leaf bupleurum in Honghua Xiaoyao preparation, atractylodesone is derived from the effective component of white atractylodes in Honghua Xiaoyao preparation, glycyrrhizic acid is derived from the effective component of licorice in Honghua Xiaoyao preparation, and safflower yellow is derived from the effective component of safflower in Honghua Xiaoyao preparation. The dosage of each component is accurate and the effect is better when compounded.

[0019] Furthermore, the present invention also provides a medicine, comprising the above-mentioned Honghua Xiaoyao composition or the Honghua Xiaoyao composition prepared by the above-mentioned preparation method and medically acceptable excipients.

[0020] The technical effects achieved by the present invention are:

[0021] 1. The present invention further refines the formula of the Honghua Xiaoyao preparation, by extracting some of the raw materials such as angelica, white peony, Poria, Gleditsia sinensis and mint with water, and then using them in combination with effective extracts of some components in the raw materials (safflower, licorice, Atractylodes macrocephala, Bupleurum chinense), so as to use the medicine more accurately and make the efficacy of the medicine better under the premise of saving resources. Studies have shown that the raw materials of the Honghua Xiaoyao composition complement each other and synergize with each other. The final drug product can promote blood circulation and remove blood stasis, regulate the liver and spleen, and effectively control the further growth of nodules. Preliminary in vitro tests and animal tests have found that the Honghua Xiaoyao composition in the present invention can effectively inhibit the proliferation of thyroid FRTL cells, thereby playing a role in dispersing nodules, and has a good effect on thyroid nodules. In addition, the composition of the present invention can also reduce the relative mass of the thyroid gland, and also has a certain effect on the treatment of goiter, thereby having a good therapeutic effect on the concomitant goiter caused by severe thyroid nodules.

[0022] 2. The present invention has found that Bupleurum saponin A has a certain effect on the thyroid gland. When used in combination with atractylodes lancea ketone and safflower yellow pigment, the effect is more prominent. Combined with the extracts of other raw materials of the safflower Xiaoyao composition, the effect can be made more precise and efficient, effectively saving the waste of drug raw materials and making drug compounding more reasonable. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The figure shows the comparison of the inhibition rate of thyroid FRTL cell proliferation of the samples to be tested in each example. DETAILED DESCRIPTION

[0024] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0025] Before further describing the specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the examples of the present invention are for describing specific embodiments rather than for limiting the scope of protection of the present invention.

[0026] When the embodiment gives a numerical range, it should be understood that, unless otherwise specified in the present invention, the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs.

[0027] It is worth noting that the raw materials used in the present invention are all common commercially available products, so their sources are not specifically limited.

[0028] Table 1 Prescription of the safflower Xiaoyao composition of Examples 1-3 of the present invention (unit: portion)

[0029]

[0030]

[0031] The preparation method of the Honghua Xiaoyao composition of Example 1 in the above table comprises the following steps: after mixing angelica, white peony root, Poria, Gleditsia sinensis and mint, adding water and heating to 75°C, keeping warm for 25 minutes, filtering to obtain a water extract, repeating twice, combining the water extracts, and concentrating to obtain a mixture A (relative density of 1.3, 60°C); mixing the mixture A with saikosaponin A, atractylodes ketone, glycyrrhizic acid and safflower yellow to obtain.

[0032] The preparation method of the Honghua Xiaoyao composition of Example 1 in the above table comprises the following steps: after mixing angelica, white peony root, Poria cocos, Gleditsia sinensis and mint, adding water and heating to 85°C, keeping warm for 15 minutes, filtering to obtain a water extract, repeating 3 times, combining the water extracts, and concentrating to obtain a mixture A (relative density of 1.5, 60°C); mixing the mixture A with saikosaponin A, atractylodes ketone, glycyrrhizic acid and safflower yellow to obtain.

[0033] The preparation method of the Honghua Xiaoyao composition of Example 3 in the above table comprises the following steps: after mixing angelica, white peony root, Poria, Gleditsia sinensis and mint, adding water and heating to 80°C, keeping warm for 20 minutes, filtering to obtain a water extract, repeating 3 times, combining the water extracts, and concentrating to obtain a mixture A (relative density of 1.4, 60°C); mixing the mixture A with saikosaponin A, atractylodes ketone, glycyrrhizic acid and safflower yellow to obtain.

[0034] Table 2 Prescription of the safflower Xiaoyao composition of comparative examples 1-3 of the present invention (unit: portion)

[0035]

[0036]

[0037] The preparation method of the Honghua Xiaoyao composition of Comparative Example 1 in the above table comprises the following steps: after mixing angelica, white peony root, Poria, Gleditsia sinensis and mint, adding water and heating to 80°C, keeping warm for 20 minutes, filtering to obtain a water extract, repeating 3 times, combining the water extracts, and concentrating to obtain a mixture A (relative density of 1.4, 60°C); mixing the mixture A with saikosaponin A, atractylodes lactone II, glycyrrhizic acid, and safflower yellow to obtain.

[0038] The preparation method of the Honghua Xiaoyao composition of Comparative Example 1 in the above table comprises the following steps: after mixing angelica, white peony root, Poria, Gleditsia sinensis and mint, adding water and heating to 80°C, keeping warm for 20 minutes, filtering to obtain an aqueous extract, repeating 3 times, combining the aqueous extracts, and concentrating to obtain a mixture A (relative density of 1.4, 60°C); mixing the mixture A with saikosaponin A, atractylodes ketone, chrysophanol and luteolin to obtain the mixture.

[0039] The preparation method of the Honghua Xiaoyao composition of comparative example 3 in the above table comprises the following steps: after mixing angelica, white peony root, Poria cocos, Gleditsia thorn, mint, Bupleurum and Atractylodes macrocephala, adding water and heating to 80°C, keeping warm for 20 minutes, filtering to obtain a water extract, repeating 3 times, combining the water extracts, concentrating to obtain a mixture A (relative density of 1.4, 60°C); mixing the mixture A with glycyrrhizic acid and safflower yellow to obtain.

[0040] Table 3 Prescription of the safflower Xiaoyao composition of comparative examples 4-6 of the present invention (unit: portion)

[0041]

[0042]

[0043] The preparation method of the Honghua Xiaoyao composition of comparative example 4 in the above table comprises the following steps: after mixing angelica, white peony root, Poria cocos, Gleditsia sinensis and mint, adding water and heating to 80°C, keeping warm for 20 minutes, filtering to obtain a water extract, repeating 3 times, combining the water extracts, concentrating to obtain a mixture A (relative density of 1.4, 60°C); mixing the mixture A with saikosaponin A and glycyrrhizic acid to obtain.

[0044] The preparation method of the Honghua Xiaoyao composition of comparative example 5 in the above table comprises the following steps: after mixing angelica, white peony root, Poria cocos, Gleditsia sinensis and mint, adding water and heating to 80°C, keeping warm for 20 minutes, filtering to obtain a water extract, repeating 3 times, combining the water extracts, and concentrating to obtain a mixture A (relative density of 1.4, 60°C); mixing the mixture A with atractylodes ketone and glycyrrhizic acid to obtain.

[0045] The preparation method of the safflower Xiaoyao composition of comparative example 6 in the above table comprises the following steps: after mixing angelica, white peony, Poria, Gleditsia sinensis and mint, adding water and heating to 80°C, keeping warm for 20 minutes, filtering to obtain a water extract, repeating 3 times, combining the water extracts, and concentrating to obtain a mixture A (relative density of 1.4, 60°C); mixing the mixture A with glycyrrhizic acid and safflower yellow to obtain.

[0046] 1. In vitro testing

[0047] 1.1 Thyroid cell culture: The thyroid FRTL cell line was cultured in complete culture medium (F-12 culture medium containing 5% fetal bovine serum) in a 5% carbon dioxide incubator at 37°C.

[0048] 1.2 Samples to be tested: the Honghua Xiaoyao compositions obtained in Examples 1-3 and Comparative Examples 1-6.

[0049] 1.3 Experimental method: 5×10 3 FRTL cells were cultured for 24 hours until the cells adhered to the wall. 3 mg / mL of the sample to be tested was added to each well of the test group. Each sample to be tested was designed in 6 parallel groups. No sample to be tested was added to each well of the control group. Then 20 μL of 5 mg / mL MTT solution was added to each well. After 4 hours of culture, the supernatant was discarded, and 150 μL DMSO was added. After mixing evenly, the absorbance (A) was measured and the inhibition rate was calculated; wherein, The results are as follows Figure 1 shown.

[0050] Depend on Figure 1 It can be seen that the Honghua Xiaoyao composition of the present invention can effectively inhibit the proliferation of thyroid FRTL cells, and thus has a good effect on thyroid nodules.

[0051] 2. Animal testing

[0052] 2.1 Experimental animals: Wistar rats, 4 weeks old, male;

[0053] 2.2 Samples to be tested: the Honghua Xiaoyao compositions obtained in Examples 1-3 and Comparative Examples 1-6.

[0054] 2.3 Test methods:

[0055] 2.3.1 Modeling: After one week of adaptive feeding, the rats were fed with low-iodine feed (corn, millet, and soybeans were mixed in a weight ratio of 75:18:7, and 6 mg of vitamin B, 1 g of yeast, 5.5 mg of calcium pantothenate, 0.5 g of calcium carbonate, 0.15 g of disodium hydrogen phosphate, 50 mg of manganese sulfate, and 0.1 mg of folic acid were added per 100 grams, with a total iodine content of less than 20 μg / kg), and sodium perchlorate was given simultaneously for 19 days, and then hydrogen peroxide was given for 2 days to obtain a goiter model.

[0056] 2.3.2 Group test: The rats with successful modeling were randomly divided into 10 groups, with 10 rats in each group. Among them, 9 groups were used as experimental groups, and the samples to be tested were gavaged once a day at a dose of 0.3 g / kg / d. One group was used as the model control group and given an equal amount of deionized water. Another group of rats was set up as the normal control group. The rats were selected from normal rats that had been adaptively fed for one week and gavaged with an equal amount of deionized water. The rats in each group were given low-iodine feed at the same time. After 3 weeks, the rats were weighed and then killed. The wet weight of the thyroid gland was weighed, and the relative weight of the thyroid gland was calculated. The results were statistically recorded in Table 4. Among them, the relative weight of the thyroid gland = wet weight of the thyroid gland / body weight of the rat.

[0057] Table 4 Treatment of goiter in rats with the compositions of various examples of the present invention

[0058]

[0059]

[0060] (Note: #: compared with the blank control group, p ≤ 0.05, ##: compared with the blank control group, p ≤ 0.01;

[0061] *: compared with the model control group, p≤0.05, **: compared with the model control group, p≤0.01;

[0062] a: compared with Example 1, p≤0.05; aa: compared with Example 1, p≤0.01;

[0063] b: compared with Example 2, p≤0.05; bb: compared with Example 2, p≤0.01;

[0064] c: compared with Example 3, p≤0.05; cc: compared with Example 3, p≤0.01. )

[0065] According to Table 4, the Honghua Xiaoyao composition of the present invention can effectively reduce the relative weight of the thyroid gland, and then produce a certain effect on goiter, etc., thus having a good therapeutic effect on the concomitant goiter caused by severe thyroid nodules.

[0066] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A safflower Xiaoyao composition, characterized in that: The invention is prepared from 50-65 parts of angelica sinensis, 20-30 parts of white peony root, 10-18 parts of tuckahoe, 10-25 parts of gleditsia thorn, 35-45 parts of mint, 0.2-0.6 parts of bupleurum saponin A, 0.1-0.3 parts of atractylodes ketone, 0.05-0.15 parts of glycyrrhizic acid and 0.08-0.18 parts of safflower yellow pigment by weight.

2. The safflower Xiaoyao composition according to claim 1, characterized in that: The invention is prepared from 55 parts of angelica sinensis, 25 parts of white peony root, 15 parts of tuckahoe, 20 parts of gleditsia thorn, 40 parts of peppermint, 0.5 parts of saikosaponin A, 0.2 parts of atractylodes ketone, 0.1 parts of glycyrrhizic acid and 0.15 parts of safflower yellow pigment by weight.

3. The safflower Xiaoyao composition according to claim 1, characterized in that: The weight ratio of saikosaponin A, atractylodesone and safflower yellow is 0.5:0.2:0.

15.

4. The method for preparing the safflower Xiaoyao composition according to any one of claims 1 to 3, characterized in that: The following steps are involved: Mix angelica sinensis, white peony root, poria cocos, honeysuckle thorn and mint, extract with water and concentrate to obtain mixture A; mix mixture A with saikosaponin A, atractylodes ketone, glycyrrhizic acid and safflower yellow to obtain the product.

5. The preparation method according to claim 4, characterized in that: The concentration is specifically concentrated to a relative density of 1.3-1.

5.

6. Use of the Honghua Xiaoyao composition as described in any one of claims 1 to 3 or the Honghua Xiaoyao composition prepared by the preparation method as described in any one of claims 4 to 5 in the preparation of a drug for treating thyroid nodules.

7. The use according to claim 6, characterized in that: The dosage form of the drug includes tablets, pastes, granules, pills or capsules.

8. A medicine, characterized in that: The invention comprises the Honghua Xiaoyao composition described in any one of claims 1 to 3 or the Honghua Xiaoyao composition prepared by the preparation method described in any one of claims 4 to 5 and medically acceptable auxiliary materials.

Images