Traditional chinese medicine compositions and extracts comprising vitex agnus-castus and uses thereof for treating pulmonary arterial hypertension

Abstract

The present application relates to the technical field of medicine, and relates to a traditional Chinese medicine formula containing vitex and an extract, and a use of the traditional Chinese medicine formula and the extract in treating pulmonary arterial hypertension. Specifically, the present application relates to an application of a traditional Chinese medicine formula containing vitex and an extract in preparing a medicine for preventing, alleviating and / or treating pulmonary arterial hypertension and complications thereof. The present application shows that the water extract of the formula and components thereof can be absorbed through the oral cavity and the gastrointestinal tract, can reduce pulmonary arterial pressure, can inhibit right ventricular wall hypertrophy, can reduce pulmonary edema, and can play a significant pharmacological role in preventing and treating pulmonary arterial hypertension and complications thereof. The present application shows that the formula can be an ideal medicine for preventing and treating pulmonary arterial hypertension and complications thereof, and can be used in preparing products for preventing, alleviating and / or treating pulmonary arterial hypertension and complications thereof, chronic obstructive emphysema, chronic pulmonary heart disease, high altitude disease, hypoxic injury, right heart failure and immune function injury.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to traditional Chinese medicine formulations and extracts containing Vitex trifolia, and their use in the preparation of drugs for the prevention, relief and / or treatment of pulmonary hypertension and its complications. Background Technology

[0002] Pulmonary hypertension (PH) is a disease characterized by a progressive increase in pulmonary artery pressure. The clinical diagnostic criteria are a mean pulmonary artery pressure (mPAP) ≥25 mmHg measured via right heart catheterization at rest. The incidence of PH has been increasing in recent years, and it is a disease with a high rate of disability and mortality. Unlike cardiovascular diseases such as hypertension, PH has a complex pathogenesis. Drugs generally used to treat hypertension cannot lower pulmonary artery pressure, and existing treatments do not fully meet clinical needs. PH has a poor prognosis and an extremely low 5-year survival rate, making it a very serious disease involving both the cardiovascular and respiratory systems.

[0003] When pulmonary hypertension occurs, patients exhibit symptoms such as shortness of breath, palpitations, chest pain, hemoptysis, and syncope. In later stages, symptoms may include hypoxia, right ventricular hypertrophy, and even right heart failure, potentially leading to death. Currently, treatment options and medications for this disease are severely lacking, resulting in a poor prognosis. Only about 20% of patients achieve effective control, and most die within 2-3 years of diagnosis. Bosentan is currently the first-line drug for treating pulmonary hypertension, but its efficacy is unsatisfactory. Developing new drugs that can effectively treat pulmonary hypertension is a crucial and urgent task.

[0004] The traditional Chinese medicine formula containing Vitex trifolia includes six herbs: Vitex trifolia, Citrus reticulata peel, Ginseng, Prepared Licorice Root, White Peony Root, and Astragalus Root. In our previous work, we investigated the pharmacological effects of each component of this formula and found that its effective extracts may play a therapeutic role in various cardiovascular diseases. Our unit prepared the Vitex trifolia formula, obtaining stable quality Vitex trifolia formula and granules, and analyzed and identified its effective components. Preliminary experiments showed that the Vitex trifolia formula has a protective effect on pulmonary vessels. Through analysis of its characteristics, we hypothesize that it has a preventive or therapeutic effect on pulmonary hypertension, an effect not currently reported in the literature. Summary of the Invention

[0005] The technical problem solved by this invention is to develop a traditional Chinese medicine formula and extract containing Vitex trifolia, and to apply it to the preparation of drugs for the prevention, relief and / or treatment of pulmonary hypertension and its complications.

[0006] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0007] The first aspect of the technical solution of the present invention is to provide a traditional Chinese medicine formula containing Vitex trifolia, wherein every 100 parts by weight of the Vitex trifolia composition is made from the following raw materials in parts by weight: 1-20 parts by weight of Vitex trifolia, 5-10 parts by weight of dried tangerine peel, 8-20 parts by weight of ginseng, 10-20 parts by weight of prepared licorice root, 10-20 parts by weight of white peony root, and 20-50 parts by weight of astragalus root.

[0008] A further preferred embodiment is that each 100 parts by weight of the traditional Chinese medicine formula containing Vitex trifolia is made from the following parts by weight of raw materials: 2 parts by weight of Vitex trifolia, 10 parts by weight of dried tangerine peel, 15 parts by weight of ginseng, 18 parts by weight of prepared licorice root, 18 parts by weight of white peony root, and 37 parts by weight of astragalus root.

[0009] The second aspect of the present invention provides a traditional Chinese medicine extract containing Vitex trifolia, characterized in that the extract is prepared by water extraction or water extraction with alcohol precipitation of the traditional Chinese medicine formula described in the first aspect of the present invention.

[0010] The method for preparing the extract obtained from the traditional Chinese medicine formula containing Vitex trifolia includes water extraction: add water with a weight of 10 times the total weight of the raw materials, soak for 12 hours, boil for 1 hour to obtain a medicinal liquid; add water with a weight of 8 times the weight of the remaining residue, boil for 1 hour to obtain a medicinal liquid; add water with a weight of 8 times the weight of the remaining residue, boil for 1 hour to obtain a medicinal liquid; combine all the medicinal liquids, concentrate, and pass through a 20-mesh sieve to obtain a concentrated water extract.

[0011] The method for preparing the extract of the traditional Chinese medicine formula containing Vitex trifolia includes water extraction and alcohol precipitation: add water with a weight of 10 times the total weight of the raw materials, soak for 12 hours, boil for 1 hour to obtain the medicinal liquid; add water with a weight of 8 times the weight of the remaining residue, boil for 1 hour to obtain the medicinal liquid; add water with a weight of 8 times the weight of the remaining residue, boil for 1 hour to obtain the medicinal liquid; combine all the medicinal liquids, concentrate them, add edible alcohol to the alcohol content of the medicinal liquid to 70%, stir thoroughly, let stand for 12 hours, discard the precipitate, and pass through a 20-mesh sieve to obtain the concentrated water extraction and alcohol precipitation solution.

[0012] A third aspect of the present invention is to provide a pharmaceutical composition comprising the traditional Chinese medicine formula containing Vitex trifolia as described in the first aspect of the invention, or an extract of the traditional Chinese medicine formula containing Vitex trifolia as described in the second aspect, or a pharmaceutically acceptable carrier or excipient.

[0013] Furthermore, the pharmaceutical composition includes granules, and the preparation method of the granules includes: granulating the Vitex trifolia compound solution and starch in a fluidized bed at a ratio of 2:1 to 3:1, mixing the resulting granules after passing them through a 16-mesh sieve, and packaging them to obtain Vitex trifolia compound granules, wherein the Vitex trifolia compound solution includes a traditional Chinese medicine compound containing Vitex trifolia or its extract.

[0014] And optional pharmaceutically acceptable carriers and / or excipients.

[0015] In this invention, depending on the route of administration, the pharmaceutical composition containing the extract of Vitex trifolia from a traditional Chinese medicine formula may be selected from the following dosage forms: granules, pills, solutions, suspensions, lyophilized powder for injection, emulsions, pills, capsules, powders, controlled-release or sustained-release formulations.

[0016] The pharmaceutical composition of the present invention, which contains extracts of Vitex trifolia from traditional Chinese medicine, can be prepared by known methods and administered to subjects via several routes, including but not limited to parenteral, oral, local, intradermal, intramuscular, intraperitoneal, subcutaneous, intravenous, and intranasal routes.

[0017] The extract of the traditional Chinese medicine formula containing Vitex trifolia in this invention can be prepared by known methods.

[0018] The extracts of the traditional Chinese medicine formulations containing Vitex trifolia of the present invention can optionally be formulated by any conventional method using one or more pharmaceutically acceptable carriers and / or excipients. Therefore, Vitex trifolia formulations and their pharmaceutically acceptable derivatives can be specifically formulated for, for example, inhalation or blowing (through the mouth or nose) or oral, sublingual, parenteral, or rectal administration.

[0019] Herbal extracts containing Vitex trifolia can also be available in granules, pellets, solutions, suspensions, emulsions, pills, capsules, powders, controlled-release or sustained-release formulations. These formulations will contain a therapeutically effective amount of the herbal extract containing Vitex trifolia, along with an appropriate carrier, to provide a suitable form of administration to the patient.

[0020] The herbal extract containing Vitex trifolia is used in granule form. The preparation method includes: granulating the herbal extract containing Vitex trifolia in a fluidized bed with starch at a ratio of 2:1 to 3:1; mixing the resulting granules after passing them through a 16-mesh sieve; and packaging.

[0021] The fourth aspect of the present invention is the use of the traditional Chinese medicine formula containing Vitex trifolia as described in the first aspect, the extract of the traditional Chinese medicine formula containing Vitex trifolia as described in the second aspect, and the pharmaceutical composition as described in the third aspect in the preparation of a medicament for the prevention, relief, and / or treatment of pulmonary hypertension and its complications. The pulmonary hypertension and its complications are selected from hypoxic pulmonary hypertension, arterial pulmonary hypertension, chronic obstructive pulmonary emphysema, chronic cor pulmonale, altitude sickness, hypoxic injury, right heart failure, and immune dysfunction.

[0022] The effects of preventing, alleviating and / or treating pulmonary hypertension and its complications are achieved by reducing pulmonary artery pressure, inhibiting right ventricular hypertrophy, and reducing pulmonary edema through a traditional Chinese medicine formula extract containing Vitex trifolia.

[0023] This invention can be achieved through the following technical solution: A mouse model of hypoxic pulmonary hypertension is established using a hypoxic chamber. Animals in the model group and treatment group are placed in a hypoxic chamber with a 10% oxygen concentration for 4 weeks. Simultaneously, the treatment group is administered a lyophilized suspension of Vitex trifolia extract via gavage at a dose of 5 g / kg / day. On day 29, various indicators of the animals are measured, including body weight, right ventricular systolic pressure, right ventricular hypertrophy index, and organ indices, to determine the preventive, alleviating, and therapeutic effects of the Vitex trifolia extract on hypoxic pulmonary hypertension.

[0024] A rat model of arterial pulmonary hypertension was established using lily alkaloids. Animals in both the model and treatment groups received a single subcutaneous injection of 50 mg / kg lily alkaloids. The day after model establishment, the treatment group began receiving a lyophilized suspension of Vitex trifolia extract via gavage at a dose of 3.2 g / kg / day. On day 29, various indicators of the animals were measured, including body weight, right ventricular systolic pressure, right ventricular hypertrophy index, and organ indices, to assess the preventive, alleviating, and therapeutic effects of the Vitex trifolia extract on arterial pulmonary hypertension.

[0025] Beneficial Technical Effects: The characteristics and advantages of this invention are that the Vitex trifolia formula is a traditional Chinese medicine compound with high safety, reliable ingredient sources, and low production costs, possessing good market development prospects. Oral administration of the Vitex trifolia formula can improve cardiopulmonary function in animals, reduce pulmonary artery pressure and right ventricular remodeling, and can be applied to the preparation of products for the prevention, relief, and / or treatment of pulmonary hypertension and its complications, chronic obstructive pulmonary emphysema, chronic cor pulmonale, altitude sickness, hypoxia injury, right heart failure, and immune dysfunction. Attached Figure Description

[0026] Figure 1 Effects of extracts from traditional Chinese medicine formulas containing Vitex trifolia on right ventricular systolic pressure in hypoxic pulmonary hypertension mice.

[0027] Figure 2 Effects of extracts from traditional Chinese medicine formulas containing Vitex trifolia on right ventricular remodeling in hypoxic pulmonary hypertension mice.

[0028] Figure 3 Effects of extracts from traditional Chinese medicine formulas containing Vitex trifolia on pulmonary vascular remodeling in mice with hypoxic pulmonary hypertension.

[0029] Figure 4 Effects of extracts from traditional Chinese medicine formulas containing Vitex trifolia on right ventricular systolic pressure in rats with lily alkaloid-induced pulmonary hypertension.

[0030] Figure 5 Effects of extracts from traditional Chinese medicine formulas containing Vitex trifolia on right ventricular remodeling in rats with lily alkaloid-induced pulmonary hypertension.

[0031] Figure 6The protective effect of extracts from traditional Chinese medicine formulas containing Vitex trifolia on the lungs of rats with purpuric alkaloid-induced pulmonary hypertension.

[0032] Figure 7 Effects of extracts from traditional Chinese medicine formulas containing Vitex trifolia on pulmonary vascular remodeling in rats with lily alkaloid-induced pulmonary hypertension. Detailed Implementation

[0033] The following description, in conjunction with the present invention, further illustrates the pharmacological effects and drug uses of extracts from traditional Chinese medicine formulations containing Vitex trifolia in vivo for the prevention, relief, and / or treatment of pulmonary hypertension and its complications.

[0034] The following embodiments illustrate the invention in more detail, but are not intended to limit the invention in any way.

[0035] Example 1

[0036] The extract of a traditional Chinese medicine formula containing Vitex trifolia fruit was prepared by water extraction. The formula was prepared according to the following weight ratio: Vitex trifolia fruit: Citrus reticulata peel: Ginseng: Prepared licorice root: White peony root: Astragalus membranaceus = 1:5:8:10:10:20. The preparation method is as follows:

[0037] ① After mixing the medicinal materials according to the above proportions, add 10 times the amount of water, soak overnight, and then transfer to the extraction tank;

[0038] ② Boil (simmer) for 1 hour, then vacuum filter and transfer the liquid to a concentration tank.

[0039] ③ Add 8 times the amount of water to the remaining dregs in the extraction tank, boil (simmer) for 1 hour, filter under vacuum, and then transfer the liquid to the concentration tank.

[0040] ④ Add 8 times the amount of water to the remaining dregs in the extraction tank, boil (simmer) for 1 hour, vacuum filter, and then transfer the liquid to the concentration tank.

[0041] ⑤ Combine all the liquids, concentrate under reduced pressure, and pass through a 20-mesh sieve to obtain the liquid.

[0042] Example 2

[0043] The extract of the traditional Chinese medicine formula containing Vitex trifolia was prepared by water extraction and alcohol precipitation. The formula was prepared according to the following weight ratio: Vitex trifolia: Citrus reticulata peel: Ginseng: Prepared licorice root: White peony root: Astragalus membranaceus = 1:5:8:10:10:20. The preparation method is as follows:

[0044] ① After mixing the medicinal materials according to the above proportions, add 10 times the amount of water, soak overnight, and then transfer to the extraction tank;

[0045] ② Boil (simmer) for 1 hour, then vacuum filter and transfer the liquid to a concentration tank.

[0046] ③ Add 8 times the amount of water to the remaining dregs in the extraction tank, boil (simmer) for 1 hour, filter under vacuum, and then transfer the liquid to the concentration tank.

[0047] ④ Add 8 times the amount of water to the remaining dregs in the extraction tank, boil (simmer) for 1 hour, vacuum filter, and then transfer the liquid to the concentration tank.

[0048] ⑤ Combine all the liquids, concentrate them under reduced pressure to one-third of their original volume, and then transfer them to the extraction tank;

[0049] ⑥ Add edible alcohol until the alcohol content of the medicine solution reaches 70%, stir thoroughly, and let it stand overnight;

[0050] ⑦ Transfer the supernatant to the concentration tank and discard the precipitate;

[0051] ⑧ Concentrate under reduced pressure until the alcohol content is 0%, then pass through a 20-mesh sieve to obtain the medicinal solution.

[0052] Example 3

[0053] The preparation method of a traditional Chinese medicine extract granule containing Vitex trifolia fruit for the prevention and treatment of pulmonary hypertension is as follows:

[0054] The extract of the drug solution according to the method of Example 1 or 2 was granulated in a fluidized bed at a ratio of drug solution to starch of 2:1 to 3:1. The resulting granules were passed through a 16-mesh sieve, mixed, and packaged.

[0055] Example 4: Pharmacological effects of a traditional Chinese medicine formula containing Vitex trifolia extract on a mouse model of hypoxic pulmonary hypertension.

[0056] Thirty male C57 mice, weighing approximately 25g, were divided into three groups of 10 mice each: a normal group, a model group, and a group treated with Vitex trifolia extract. After 3 days of acclimatization, the model group and the group treated with Vitex trifolia extract (administered with granules of a traditional Chinese medicine formula containing Vitex trifolia extract) were placed in a hypoxic chamber with 10% oxygen for 28 days. The chamber door was briefly opened daily to change food, water, bedding, and administer medication. Simultaneously with the hypoxia, the mice were administered 5g / kg of the traditional Chinese medicine formula extract granules containing Vitex trifolia extract prepared in Example 3 (granules prepared by mixing the extract solution containing Vitex trifolia extract obtained from the water extraction and alcohol precipitation in Example 2 with starch in a 2:1 ratio) via gavage for 28 consecutive days.

[0057] 1. Effects of Vitex trifolia extract on right ventricular systolic pressure in animals:

[0058] On day 29, various physiological indicators of the animals were tested. After the mice were anesthetized and fixed, the right jugular vein was bluntly dissected, and the right ventricular systolic pressure was measured using a Miller catheter and the classic right heart catheterization method. The average right ventricular systolic pressure of each group was calculated to represent the pulmonary artery pressure. (See attached image) Figure 1As shown, after 4 weeks of hypoxia, the right ventricular systolic pressure of the animals increased significantly. The increase in right ventricular systolic pressure was controlled in animals treated with the Vitex trifolia formula, demonstrating that the Vitex trifolia formula can effectively prevent and treat pulmonary artery pressure elevation caused by hypoxia. The right ventricular systolic pressure of each group of animals is shown in Appendix Table 1.

[0059] Table 1. Effects of Vitex trifolia extract on right ventricular systolic pressure in hypoxic pulmonary hypertension mice.

[0060]

[0061] 2. Effects of Vitex trifolia formulation on right ventricular hypertrophy in animals:

[0062] In hypoxic pulmonary hypertension, as the pressure load gradually increases, the right ventricle of the affected animal undergoes remodeling and hypertrophy. The right ventricular index is the ratio of the right ventricular wall mass (RV) to the sum of the left ventricular wall mass (LV) and the interventricular septum mass (S), i.e., RV / (LV+S). (See attached...) Figure 2 As shown, an increase in the right ventricular index was observed at the experimental endpoint, indicating that the administration of the Vitex trifolia formula had a certain inhibitory effect on right ventricular remodeling. Specific data on the right ventricular index for each group are shown in Appendix Table 2.

[0063] Table 2. Effects of Vitex trifolia extract on right heart index in hypoxic pulmonary hypertension mice.

[0064]

[0065] Example 5: Pharmacological effects of Vitex trifolia extract on a rat model of pulmonary hypertension.

[0066] Thirty male SD rats, weighing approximately 220g, were divided into three groups of 10 rats each: a normal group, a model group, and a Vitex trifolia formula group (administered with granules of a traditional Chinese medicine formula containing Vitex trifolia). After 3 days of acclimatization, the model group and the Vitex trifolia formula group were given a single subcutaneous injection of 50mg / kg of limonene. The day after modeling, the Vitex trifolia formula group was given 3.25g / kg of granules of a traditional Chinese medicine formula containing Vitex trifolia by gavage, and this treatment continued for 28 days.

[0067] 1. Effects of Vitex trifolia extract on right ventricular systolic pressure in animals:

[0068] On day 29, various physiological indicators of the animals were measured. After the rats were anesthetized and fixed, the right jugular vein was bluntly dissected, and the right ventricular systolic pressure was measured using a PE50 catheter and the classic right heart catheterization method. The average right ventricular systolic pressure of each group was calculated to represent the pulmonary artery pressure. (See attached image) Figure 3As shown, the right ventricular systolic pressure of the animals in the model group was significantly increased after the establishment of the wild lily alkaloid model. The increase in right ventricular systolic pressure was controlled in the animals given the Vitex trifolia formula, proving that the Vitex trifolia formula can effectively prevent and treat the increase in pulmonary artery pressure caused by wild lily alkaloid. The right ventricular systolic pressure of each group of animals is shown in Appendix Table 3.

[0069] Table 3. Effects of Vitex trifolia extract on right ventricular systolic pressure in rats with pyruvic alkaloid-induced pulmonary hypertension.

[0070]

[0071] 2. Effects of Vitex trifolia formulation on right ventricular hypertrophy in animals:

[0072] When pulmonary hypertension develops to a certain stage, the right ventricle of diseased animals gradually thickens due to increased pressure load, leading to right ventricular remodeling. The right ventricular index is the ratio of the right ventricular wall mass (RV) to the sum of the left ventricular wall mass (LV) and the interventricular septum mass (S), i.e., RV / (LV+S). (See attached...) Figure 4 As shown, an increase in the right ventricular index was observed at the experimental endpoint, indicating that the administration of the Vitex trifolia formula had a certain inhibitory effect on right ventricular remodeling. Specific data on the right ventricular index for each group are shown in Appendix Table 4.

[0073] Table 4. Effects of the Vitex trifolia formula on the right heart index in rats with lily alkaloid-induced pulmonary hypertension.

[0074]

[0075] 3. The protective effect of the Vitex trifolia formula on the lungs of animals:

[0076] like Figure 5 As shown, pulmonary hypertension rats exhibited pulmonary edema at the experimental endpoint, with a significantly increased lung index (lung wet weight / body weight * 100%). After intervention with the Vitex trifolia formula, the lung index showed a decreasing trend, suggesting that the Vitex trifolia formula may have a protective effect on the lungs of pulmonary hypertension rats. Specific data on the lung index for each group are shown in Appendix Table 5.

[0077] Table 5. Effects of Vitex trifolia extract on lung index in rats with pyruvic alkaloid-induced pulmonary hypertension.

[0078]

Claims

1. The use of a traditional Chinese medicine composition in the preparation of a medicament for the prevention and / or treatment of hypoxic pulmonary hypertension or arterial pulmonary hypertension, wherein each 100 parts by weight of the traditional Chinese medicine composition is made from the following raw materials in parts by weight: 1-20 parts by weight of Vitex trifolia fruit, 5-10 parts by weight of Citrus reticulata peel, 8-20 parts by weight of ginseng, 10-20 parts by weight of prepared licorice root, 10-20 parts by weight of white peony root, and 20-50 parts by weight of Astragalus membranaceus.

2. The application according to claim 1, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight per 100 parts by weight: 2 parts by weight of Vitex trifolia fruit, 10 parts by weight of dried tangerine peel, 15 parts by weight of ginseng, 18 parts by weight of prepared licorice root, 18 parts by weight of white peony root, and 37 parts by weight of astragalus root.

3. The application according to claim 1 or 2, wherein the preparation method comprises: Add water at a weight of 10 times the total weight of the raw materials, soak for 12 hours, then boil for 1 hour to obtain the medicinal liquid; add water at a weight of 8 times the weight of the remaining dregs, boil for 1 hour to obtain the medicinal liquid; add water at a weight of 8 times the weight of the remaining dregs, boil for 1 hour to obtain the medicinal liquid; combine all the medicinal liquids, concentrate them, and pass them through a 20-mesh sieve to obtain the concentrated medicinal liquid.

4. The application according to claim 1 or 2, wherein the preparation method comprises: Add water at a weight of 10 times the total weight of the raw materials, soak for 12 hours, then boil for 1 hour to obtain the medicinal liquid; add water at a weight of 8 times the weight of the remaining dregs, boil for 1 hour to obtain the medicinal liquid; add water at a weight of 8 times the weight of the remaining dregs, boil for 1 hour to obtain the medicinal liquid; combine all the medicinal liquids, concentrate them, add alcohol, stir and let stand for 12 hours, discard the precipitate, and pass through a 20-mesh sieve to obtain the concentrated medicinal liquid.

5. The application according to claim 3, the preparation method further includes: The concentrated drug solution described in claim 3 and starch were granulated using a fluidized bed in a ratio of 2:1 to 3:

1. The resulting granules were passed through a 16-mesh sieve, mixed, and packaged to obtain granules.

6. The application according to claim 4, the preparation method further includes: The concentrated drug solution of claim 4 and starch are granulated in a fluidized bed at a ratio of 2:1 to 3:

1. The resulting granules are passed through a 16-mesh sieve, mixed, and packaged to obtain granules.

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