A pharmaceutical composition for treating abnormal uterine bleeding and its preparation method and application

Abstract

The present invention provides a pharmaceutical composition for treating abnormal uterine bleeding, a preparation method and an application thereof, and belongs to the technical field of traditional Chinese medicine preparations. The pharmaceutical composition provided by the present invention comprises the following ingredients: madder extract, rehmannia extract, cooked rhubarb extract, sanguisorba officinalis extract, notoginseng extract, cuttlebone extract and stir-fried pollen extract. The present invention improves the content of relevant effective ingredients and the dissolution effect of tablets while improving the utilization rate of traditional Chinese medicine through optimized extraction process. Clinical trials show that the tablets prepared from the pharmaceutical composition provided by the present invention can effectively treat abnormal uterine bleeding.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine preparations, and relates to a pharmaceutical composition for treating abnormal uterine bleeding, and a preparation method and application thereof. Background Art

[0002] Normal uterine bleeding, or menstruation, is the periodic shedding and bleeding of the endometrium under the cyclical regulation of ovarian hormones. The normal menstrual cycle is 21-35 days, lasting 2-8 days, with a bleeding volume of 20-60 mL. Abnormal uterine bleeding (AUB) refers to uterine bleeding in which at least one of the frequency, regularity, bleeding volume, and duration of menstruation is inconsistent with normal uterine bleeding. Abnormal uterine bleeding is more common in adolescents and premenopausal women. Depending on the cause, abnormal uterine bleeding may be accompanied by symptoms such as abdominal pain, dysmenorrhea, increased leucorrhea, infertility, hot flashes, anemia, and fatigue. "Metrorrhagia" in traditional Chinese medicine also belongs to the category of abnormal uterine bleeding in the modern sense. The Neijing Suwen Yinyang Bielun, which was written during the Spring and Autumn Period and the Warring States Period, first pointed out that yin deficiency and yang strife are called metrorrhagia. The pathogenesis of metrorrhagia includes spleen deficiency, kidney deficiency, blood heat, and blood stasis.

[0003] Chinese patent application 201110285752.3 provides a method for preparing a drug for treating metrorrhagia, which uses rhubarb, cooked rhubarb, sanguisorba officinalis, Panax notoginseng, cuttlebone, madder and pollen cattail (fried) as raw materials, and is mixed, plasmidized, tableted and coated by ultrafine grinding, supercritical fluid extraction, ultrasonic extraction, microporous membrane filtration, water extraction and alcohol precipitation.

[0004] Chinese patent application 202010019359.9 provides an application of Xueping tablets in the preparation of drugs for treating uterine ectopic, which relates to the field of medicine. The Xueping tablets include the following components in parts by weight: 30-50 parts of Rehmannia root, 15-20 parts of Rhubarb, 30-50 parts of Sanguisorba officinalis, 15-20 parts of Panax notoginseng, 20-40 parts of Cuttlefish sheath, 20-40 parts of Rubia cordifolia, and 20-40 parts of Pollen Typhae (fried). In the preparation process of Xueping tablets, this technology uses a method of enzymatic hydrolysis and mixed large-pore resin for extraction, and uses a microwave-ultraviolet cycle treatment process to treat the drug, which significantly improves the release of the active ingredients of the drug, solves the technical drawbacks of the low extraction amount of the active ingredients of traditional Chinese medicine from the root, and improves the therapeutic effect of uterine ectopic symptoms on the basis of reducing the overall dosage of traditional Chinese medicine, thereby more effectively treating uterine ectopic.

[0005] However, the prior art fails to provide a pharmaceutical composition with a higher content of active ingredients, better dissolution effect, and good effect in treating abnormal uterine bleeding. Summary of the invention

[0006] In view of this, in view of the problem that the prior art has not yet provided a pharmaceutical composition with a higher content of active ingredients, better dissolution effect, and good effect in treating abnormal uterine bleeding, the purpose of the present invention is to provide a pharmaceutical composition for treating abnormal uterine bleeding, and a preparation method and application thereof.

[0007] To achieve the above-mentioned object of the invention, on the one hand, the present invention provides a pharmaceutical composition for treating abnormal uterine bleeding, comprising the following components:

[0008] Rubia cordifolia extract, Rehmannia glutinosa extract, Rhubarb extract, Sanguisorba officinalis extract, Panax notoginseng extract, Cuttlebone extract and Fried Pollen Typhae extract.

[0009] Preferably, the pharmaceutical composition comprises the following ingredients by mass:

[0010] 4-6 parts of Rubia cordifolia extract, 2-4 parts of Rehmannia glutinosa extract, 2-4 parts of Rhubarb extract, 2-4 parts of Sanguisorba officinalis extract, 3-5 parts of Panax notoginseng extract, 5-7 parts of Cuttlebone extract and 1-3 parts of Stir-fried Pollen Typhae extract.

[0011] More preferably, the pharmaceutical composition comprises the following ingredients by mass:

[0012] 5 parts of Rubia cordifolia extract, 3 parts of Rehmannia glutinosa extract, 3 parts of Rhubarb extract, 3 parts of Sanguisorba officinalis extract, 4 parts of Panax notoginseng extract, 6 parts of Cuttlebone extract and 2 parts of Stir-fried Pollen Typhae extract.

[0013] Preferably, the preparation method of the Rubia cordifolia extract comprises the following steps:

[0014] The madder root is mixed with an acidic aqueous solution, stirred, filtered, the filter residue is mixed with an alkaline solution, refluxed for extraction, the filtrate is collected, concentrated, and dried to obtain the madder root extract.

[0015] More preferably, the acidic aqueous solution is an acetic acid aqueous solution with a mass fraction of 0.01%-0.1%.

[0016] More preferably, the mass of the acidic aqueous solution is 1.5-2 times that of the madder.

[0017] More preferably, the stirring is performed at room temperature for 10-30 min.

[0018] More preferably, the alkaline solution is an alcoholic aqueous solution of sodium hydroxide.

[0019] More preferably, the alcohol aqueous solution of sodium hydroxide is an isopropanol aqueous solution of sodium hydroxide.

[0020] Further preferably, and as an example of the present invention, in the isopropanol aqueous solution of sodium hydroxide, the mass concentration of sodium hydroxide is 3%-6%, and the mass concentration of isopropanol is 15%-25%.

[0021] More preferably, the mass of the alkaline solution is 7-9 times the mass of the filter residue.

[0022] More preferably, the reflux extraction is performed 2-3 times.

[0023] More preferably, the pH of the filtrate is adjusted to 7-9 before the concentration.

[0024] More preferably, the concentration is concentrated under reduced pressure until there is no alcohol taste.

[0025] More preferably, the concentration is to a density of 1.2-1.3 g / mL.

[0026] Preferably, the drying is freeze-drying.

[0027] Preferably, the preparation method of the Rehmannia glutinosa extract comprises the following steps:

[0028] The Rehmannia root is heat-treated in a nitrogen atmosphere, mixed with water, refluxed for extraction, the filtrate is collected, the supernatant is taken by centrifugation, and dried to obtain the Rehmannia root extract.

[0029] More preferably, the heat treatment is performed at 70-90°C for 2-4h.

[0030] More preferably, after the heat treatment, the mixture is cooled to room temperature and pulverized.

[0031] More preferably, the amount of water used is 6-8 times the mass of the Rehmannia root.

[0032] More preferably, the reflux extraction is performed 2-3 times.

[0033] More preferably, the centrifugation is performed at 3000 rpm for 2-4 min.

[0034] More preferably, the drying is freeze-drying.

[0035] Preferably, the method for preparing the cooked rhubarb extract comprises the following steps:

[0036] The cooked rhubarb is soaked in liquid nitrogen, crushed, mixed with water, refluxed for extraction, the filtrate is collected, the supernatant is taken by centrifugation, and dried to obtain the cooked rhubarb extract.

[0037] More preferably, the immersion in liquid nitrogen is immersion in liquid nitrogen for 5 minutes.

[0038] More preferably, the amount of water used is 6-8 times the mass of the cooked rhubarb.

[0039] More preferably, the reflux extraction is performed 2-3 times.

[0040] More preferably, the centrifugation is performed at 3000 rpm for 2-4 min.

[0041] More preferably, the drying is freeze-drying.

[0042] Preferably, the preparation method of the Sanguisorba officinalis extract comprises the following steps:

[0043] The Sanguisorba officinalis extract is obtained by mixing the Sanguisorba officinalis with 8-10 times the mass of water, performing ultrasonic extraction, filtering, and drying the filtrate.

[0044] More preferably, the ultrasonic extraction time is 30-60 min, the temperature is 40-50° C., and the power is 100-150W.

[0045] More preferably, the drying is freeze-drying.

[0046] Preferably, the preparation method of the Panax notoginseng extract comprises the following steps:

[0047] (1) Mix the Panax notoginseng extract with 6-8 times methanol aqueous solution, extract for 2-3 times, filter, and obtain Panax notoginseng filtrate and Panax notoginseng residue;

[0048] (2) heating and drying 20%-30% (preferably 30%) of the Panax notoginseng residue obtained in step (1), freeze-drying 20%-30% (preferably 30%) of the Panax notoginseng residue obtained in step (1), mixing the products obtained by the heating and drying and the freeze-drying, grinding and sieving, and obtaining Panax notoginseng powder;

[0049] (3) The Panax notoginseng filtrate obtained in step (1) is concentrated, dried, and mixed with the Panax notoginseng powder obtained in step (2) to obtain a Panax notoginseng extract.

[0050] More preferably, in step (1), the methanol aqueous solution is a methanol aqueous solution with a volume fraction of 60%-70%; and the leaching is performed at 20-30°C.

[0051] More preferably, in step (2), the heating and drying is specifically: heating and drying on a heating plate at 60-80° C. in an air atmosphere for 3-4 hours.

[0052] More preferably, in step (2), the grinding and screening is grinding through a 20-mesh sieve.

[0053] More preferably, in step (3), the drying is freeze-drying.

[0054] Preferably, the method for preparing the cuttlebone extract comprises the following steps:

[0055] The cuttlebone is mixed with 3-4 times the mass of a hydrochloric acid aqueous solution with a mass concentration of 10%-15%, ultrasonicated for 3-5 minutes, the solid is filtered out, washed with water, freeze-dried and ground to obtain a cuttlebone extract.

[0056] Preferably, the method for preparing the stir-fried Pollen Typhae extract comprises the following steps:

[0057] The stir-fried pollen puhuang is mixed with 8-10 times the mass of water, subjected to ultrasonic extraction, filtered, and the filtrate is dried to obtain the stir-fried pollen puhuang extract.

[0058] More preferably, the ultrasonic extraction time is 30-60 min, the temperature is 40-50° C., and the power is 100-150W.

[0059] More preferably, the drying is freeze-drying.

[0060] In another aspect, the present invention provides a method for preparing the above-mentioned pharmaceutical composition.

[0061] In yet another aspect, the present invention provides a medicine, the active ingredient of which includes the above-mentioned pharmaceutical composition.

[0062] The drug can be prepared into dosage forms such as pills, capsules, granules, oral liquids, powders, tablets, lozenges, etc., and suitable drug carriers in the art can be selected for different dosage forms.

[0063] The pharmaceutical carrier used can be solid, liquid or gas. Examples of solid carriers include lactose, kaolin, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0064] When preparing the composition for oral dosage form, any convenient pharmaceutical medium can be used. For example, water, ethanol, oil, alcohol, flavoring agent, preservative, coloring agent, etc. can be used to form oral liquid preparations, such as suspensions, elixirs and solutions; while carriers, such as starch, sugars, microcrystalline cellulose, diluents, granulating agents, emulsifiers, lubricants, binders, disintegrants can be used to form oral solid preparations, such as powders, capsules and tablets. Tablets and capsules are preferred oral dosage units using solid pharmaceutical carriers due to their ease of administration. Tablets can be coated using standard aqueous or non-aqueous techniques.

[0065] Tablets containing the Chinese medicine composition of the present invention can be prepared by tableting or molding, and one or more auxiliary ingredients or adjuvants can be used. The active ingredient can be tableted in a free-flowing form (such as powder or granules) in a suitable machine, and can be mixed with an adhesive, a lubricant, an inert diluent, a surfactant or a dispersant to prepare a tablet. Molded tablets can be molded in a suitable machine, i.e., a powdered compound mixture moistened with an inert liquid diluent. Each tablet preferably contains about 0.05 mg to about 5 g of active ingredient, and each sachet or capsule preferably contains about 0.05 mg to about 5 g of active ingredient. For example, a preparation intended for oral administration to humans may contain about 0.5 mg to about 5 g of active drug, mixed with an appropriate and convenient carrier material, which may account for about 5% to 95% of the total composition. The unit dosage form usually contains about 1 mg to about 2 g of active ingredient, usually 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0066] The pharmaceutical composition suitable for parenteral administration of the present invention can be prepared as an aqueous solution or suspension of the active compound. Suitable surfactants such as hydroxypropylcellulose can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol and oil mixtures thereof. In addition, preservatives can be added to prevent the harmful growth of microorganisms.

[0067] Medicine of the present invention can be in the form suitable for topical use, for example aerosol, cream, ointment, lotion, powder or the like. In addition, composition can be in the form suitable for transdermal administration device. Can use Chinese medicine composition of the present invention, prepare these prescriptions by conventional processing method. For example, by mixing hydrophilic material and water, and about 5wt% to about 10wt% of compound, prepare cream or ointment with required consistency.

[0068] The medicine of the present invention can be in a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture is made into a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be prepared by first forming a composition containing a softened or melted carrier, followed by cooling and shaping in a mold.

[0069] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may include (if applicable) one or more additional carrier components, such as diluents, buffers, flavoring agents, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other excipients, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc., colorants and flavoring agents, etc., may be added. The preparation is made isotonic with the blood of the intended recipient. The components containing the Chinese medicine composition of the present invention can also be prepared in the form of powder or concentrate.

[0070] Preferably, the pharmaceutical preparation is an oral pharmaceutical preparation.

[0071] More preferably, the oral pharmaceutical preparation is any one of a decoction, a pill, a tablet, a capsule, a powder, a granule, and an oral liquid.

[0072] More preferably, the oral pharmaceutical preparation is a tablet.

[0073] Preferably, the oral pharmaceutical preparation further contains excipients.

[0074] In yet another aspect, the present invention provides the use of the above-mentioned pharmaceutical composition, preparation method and drug in the preparation of a drug for treating abnormal uterine bleeding.

[0075] Compared with the prior art, the present invention has the following beneficial effects:

[0076] (1) The present invention provides a novel pharmaceutical composition for treating abnormal uterine bleeding, which has a better extraction effect of active ingredients than traditional extraction technology.

[0077] (2) The preparation method of the pharmaceutical composition provided by the present invention is simple and easy, does not require large-scale equipment, and is low in cost. The prepared pharmaceutical tablets make fuller use of the components of traditional Chinese medicine, and the content of rhubarb, hydroxyrubiacin and rubiacin is higher, and the dissolution effect of the tablets is better.

[0078] (3) Clinical experiments have shown that the tablets prepared from the pharmaceutical composition provided by the present invention have better effects in treating abnormal uterine bleeding. DETAILED DESCRIPTION

[0079] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0080] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0081] Functions of each raw material medicine in the Xueping tablets of the present invention:

[0082] Rehmannia root: Fresh Rehmannia root: sweet, bitter, cold; Raw Rehmannia root: sweet, cold; Cooked Rehmannia root: sweet, slightly warm. It enters the heart, liver, and kidney meridians. Functions and indications: Rehmannia root is cool in nature, sweet and bitter in taste, and has the effects of nourishing yin and kidney, nourishing blood and cooling blood. It is quite beneficial for people with yin deficiency, blood deficiency, and kidney deficiency. In addition, Rehmannia root has the effects of strengthening the heart and promoting diuresis, relieving fever and inflammation, promoting blood coagulation, and lowering blood sugar.

[0083] Cooked rhubarb: bitter, cold. Enters the spleen, stomach, large intestine, liver, and pericardium meridians. Functions and indications: purging heat and clearing the intestines, cooling blood and detoxifying, removing blood stasis and dredges the menstrual cycle. Used for constipation due to excess heat, abdominal pain due to stagnation, diarrhea, jaundice due to damp heat, vomiting and bleeding due to blood heat, red eyes, swollen throat, abdominal pain due to intestinal carbuncle, carbuncle furuncle, amenorrhea due to blood stasis, traumatic injury, external treatment of burns caused by water or fire; upper gastrointestinal bleeding. Wine rhubarb is good at clearing heat and toxicity from the upper jiao blood. Used for red eyes, swollen throat, and swollen and painful gums. Cooked rhubarb has a slow purgative effect, purging fire and detoxifying. Used for fire toxicity sores. Rhubarb charcoal cools blood, removes blood stasis, and stops bleeding. Used for blood heat with blood stasis and bleeding.

[0084] Sanguisorba officinalis: cold in nature, bitter and sour in taste, non-toxic; enters the liver, lung, kidney and large intestine meridians. It has the effects of cooling blood and stopping bleeding, clearing away heat and detoxifying, nourishing yin, and reducing swelling and healing sores.

[0085] Panax notoginseng: sweet, slightly bitter, warm; enters the liver and stomach meridians; Efficacy: dissipates blood stasis and stops bleeding, reduces swelling and relieves pain; used for hemoptysis, hematemesis, epistaxis, bloody stool, metrorrhagia, bleeding from trauma, stabbing pain in the chest and abdomen, and swelling and pain from falls.

[0086] Cuttlebone: salty, slightly warm; enters the liver and kidney meridians; main functions: dehumidification, acid retardation, hemostasis, sore astringent. Treats stomachache, acid regurgitation, vomiting, epistaxis, vomiting blood, blood in the stool, metrorrhagia, amenorrhea, abdominal pain, abdominal masses, malaria, diarrhea, genital ulcers. Astringent and hemostatic, astringent and leukorrhea, used for stomachache, acid regurgitation, vomiting blood, epistaxis, metrorrhagia, blood in the stool, spermatorrhea, leukorrhea; ulcers. External treatment of bleeding injuries and pus-filled sores.

[0087] Rubia cordifolia: Main functions: used for hematemesis, epistaxis, metrorrhagia, traumatic bleeding, amenorrhea, arthralgia, and swelling and pain caused by falls. Used for cooling blood and stopping bleeding, promoting blood circulation and removing blood stasis, fever-induced bleeding, amenorrhea, abdominal pain, and injuries caused by falls.

[0088] Puhuang (fried): Mainly cools blood and stops bleeding, activates blood circulation and removes blood stasis. Raw use is used to treat amenorrhea and abdominal pain, postpartum blood stasis pain, blood congestion due to falls, sores, carbuncle and swelling; fried until black, it can stop vomiting blood, epistaxis, metrorrhagia, hematuria, bloody diarrhea, and leucorrhea; externally used to treat heavy tongue, mouth sores, pus discharge from the ears, bleeding from the ears, and itchy genitals. Stop bleeding, remove blood stasis, and relieve stranguria. Used for vomiting blood, epistaxis, hemoptysis, metrorrhagia, traumatic bleeding, amenorrhea, dysmenorrhea, abdominal pain, swelling and pain due to falls, and pain due to blood. Stop bleeding and activate blood circulation; used for various bleeding, dysmenorrhea, falls, and carbuncle pain.

[0089] Example 1

[0090] A pharmaceutical composition for treating abnormal uterine bleeding.

[0091] 5 parts of Rubia cordifolia extract, 3 parts of Rehmannia glutinosa extract, 3 parts of Rhubarb extract, 3 parts of Sanguisorba officinalis extract, 4 parts of Panax notoginseng extract, 6 parts of Cuttlebone extract and 2 parts of Stir-fried Pollen Typhae extract.

[0092] Preparation method of madder extract:

[0093] Mix Rubia cordifolia with 2 times the mass of 0.05% acetic acid aqueous solution, stir at room temperature for 20 minutes, filter, mix the filter residue with 8 times the mass of 5% (w / w) sodium hydroxide in 20% isopropanol (w / w) aqueous alkaline solution, reflux extraction 3 times, collect the filtrate, adjust the pH to 8 with hydrochloric acid, concentrate under reduced pressure until there is no alcohol taste and the density is 1.3 g / mL, and freeze-dry to obtain Rubia cordifolia extract.

[0094] Preparation method of Rehmannia glutinosa extract:

[0095] The Rehmannia root was heat treated at 80°C for 3 hours in a nitrogen atmosphere, cooled to room temperature and crushed, mixed with water 7 times the mass of the Rehmannia root, refluxed and extracted 3 times, the filtrate was collected, centrifuged at 3000 rpm for 3 minutes, the supernatant was taken, and freeze-dried to obtain the Rehmannia root extract.

[0096] Preparation method of cooked rhubarb extract:

[0097] The cooked rhubarb was soaked in liquid nitrogen for 5 minutes, crushed, mixed with 7 times the mass of water, refluxed and extracted 3 times, the filtrate was collected, centrifuged at 3000 rpm for 3 minutes, the supernatant was taken, and freeze-dried to obtain the cooked rhubarb extract.

[0098] Preparation method of Sanguisorba officinalis extract:

[0099] Mix the Sanguisorba officinalis with 8-10 times the mass of water, perform ultrasonic extraction (ultrasonic extraction time is 45 min, temperature is 45° C., power is 125 W), filter, and freeze-dry the filtrate to obtain the Sanguisorba officinalis extract.

[0100] Preparation method of Panax notoginseng extract:

[0101] (1) Mix the Panax notoginseng extract with 7 times 65% (v / v) methanol aqueous solution, extract for 3 times at 20-30°C, and filter to obtain Panax notoginseng filtrate and Panax notoginseng residue;

[0102] (2) drying 30% of the Panax notoginseng residue obtained in step (1) using a heating plate and heating at 70° C. in an air atmosphere for 4 h; freeze-drying 30% of the Panax notoginseng residue obtained in step (1), mixing the products obtained by the heating drying and the freeze-drying, grinding and passing through a 20-mesh sieve to obtain Panax notoginseng powder;

[0103] (3) The Panax notoginseng filtrate obtained in step (1) is concentrated, freeze-dried, and mixed with the Panax notoginseng powder obtained in step (2) to obtain a Panax notoginseng extract.

[0104] Preparation method of cuttlebone extract:

[0105] The cuttlebone was mixed with 3 times the mass of a 15% hydrochloric acid aqueous solution, ultrasonicated for 3 minutes, the solid was filtered out, washed with water to remove the acid, freeze-dried and ground to obtain a cuttlebone extract.

[0106] Preparation method of stir-fried pollen extract:

[0107] The stir-fried pollen was mixed with 8-10 times the mass of water, subjected to ultrasonic extraction (ultrasonic extraction time was 45 min, temperature was 45° C., power was 125 W), filtered, and the filtrate was freeze-dried to obtain the stir-fried pollen extract.

[0108] Example 2

[0109] A pharmaceutical composition for treating abnormal uterine bleeding.

[0110] 4 parts of Rubia cordifolia extract, 4 parts of Rehmannia glutinosa extract, 2 parts of Rhubarb extract, 4 parts of Sanguisorba officinalis extract, 3 parts of Panax notoginseng extract, 7 parts of Cuttlebone extract and 2 parts of Stir-fried Pollen Typhae extract.

[0111] The preparation method of the above extract is the same as that of Example 1.

[0112] Example 3

[0113] A pharmaceutical composition for treating abnormal uterine bleeding.

[0114] 6 parts of Rubia cordifolia extract, 2 parts of Rehmannia glutinosa extract, 4 parts of Rhubarb extract, 2 parts of Sanguisorba officinalis extract, 4 parts of Panax notoginseng extract, 5 parts of Cuttlebone extract and 3 parts of Stir-fried Pollen Typhae extract.

[0115] The preparation method of the above extract is the same as that of Example 1.

[0116] Example 4

[0117] A pharmaceutical composition for treating abnormal uterine bleeding.

[0118] 6 parts of Rubia cordifolia extract, 2 parts of Rehmannia glutinosa extract, 4 parts of Rhubarb extract, 2 parts of Sanguisorba officinalis extract, 5 parts of Panax notoginseng extract, 6 parts of Cuttlebone extract and 1 part of Stir-fried Pollen Typhae extract.

[0119] The preparation method of the above extract is the same as that of Example 1.

[0120] Comparative Example 1

[0121] A pharmaceutical composition for treating abnormal uterine bleeding.

[0122] 1 part of Rubia cordifolia extract, 7 parts of Rehmannia glutinosa extract, 1 part of Rhubarb extract, 1 part of Sanguisorba officinalis extract, 8 parts of Panax notoginseng extract, 2 parts of Cuttlebone extract and 6 parts of Stir-fried Pollen Typhae extract.

[0123] The preparation method of the above extract is the same as that of Example 1.

[0124] Comparative Example 2

[0125] A pharmaceutical composition for treating abnormal uterine bleeding.

[0126] 5 parts of Rubia cordifolia extract, 3 parts of Rehmannia glutinosa extract, 3 parts of Rhubarb extract, 3 parts of Sanguisorba officinalis extract, 4 parts of Panax notoginseng extract, 6 parts of Cuttlebone extract and 2 parts of Stir-fried Pollen Typhae extract.

[0127] The preparation method of the above extract is as follows:

[0128] The seven raw materials were mixed with 8 times the mass of water respectively, refluxed for extraction 3 times, the filtrate was collected, concentrated, and freeze-dried to obtain seven extracts respectively.

[0129] Comparative Example 3

[0130] A pharmaceutical composition for treating abnormal uterine bleeding.

[0131] Compared with Example 1, the only difference is that the preparation method of the Panax notoginseng extract is changed to:

[0132] The Panax notoginseng extract was mixed with 7 times 65% (v / v) methanol aqueous solution, extracted 3 times at 20-30°C, filtered, concentrated, and freeze-dried to obtain the Panax notoginseng extract.

[0133] Comparative Example 4

[0134] A pharmaceutical composition for treating abnormal uterine bleeding.

[0135] Compared with Example 1, the only difference is that the preparation method of the Panax notoginseng extract is changed to:

[0136] (1) Mix the Panax notoginseng extract with 7 times 65% (v / v) methanol aqueous solution, extract for 3 times at 20-30°C, and filter to obtain Panax notoginseng filtrate and Panax notoginseng residue;

[0137] (2) drying 55% of the Panax notoginseng residue obtained in step (1) on a heating plate and heating at 70° C. in an air atmosphere for 4 h; freeze-drying 5% of the Panax notoginseng residue obtained in step (1), mixing the products obtained by heating and drying and freeze-drying, grinding and passing through a 20-mesh sieve to obtain Panax notoginseng powder;

[0138] (3) The Panax notoginseng filtrate obtained in step (1) is concentrated, freeze-dried, and mixed with the Panax notoginseng powder obtained in step (2) to obtain a Panax notoginseng extract.

[0139] Preparation of tablets (blood-level tablets).

[0140] The pharmaceutical compositions obtained in Examples 1-4 and Comparative Examples 1-4 were prepared into tablets:

[0141] The pharmaceutical composition is mixed with an appropriate amount of 30% (v / v) ethanol aqueous solution and starch, granulated, dried, added with magnesium stearate, and pressed into tablets. The mass ratio of the pharmaceutical composition, starch and magnesium stearate is 5:4.5:0.5.

[0142] Comparative Example 5

[0143] Blood level tablets provided by CN111012848A.

[0144] Comparative Example 6

[0145] CN103437401A provides blood level tablets.

[0146] Effect example 1: Evaluation of the contents of madderwright, hydroxymadderwright and rhein in Xueping tablets.

[0147] Test method:

[0148] The content detection method of rubiacin and hydroxyrubiacin was based on the "HPLC method for determination of rubiacin and hydroxyrubiacin in rubiaceae slices" (Beijing Traditional Chinese Medicine, July 2011, Vol. 30, No. 7, 541-543): Chromatographic column: Agilent ZORBAX SB-C18 column. The mobile phase was methanol-acetonitrile-0.2% phosphoric acid (25:52:23). The flow rate was 1 mL / min. The column temperature was 30°C and the detection wavelength was 250 nm.

[0149] The test method of rhein (calculated as the total amount of rhein and chrysophanol) refers to the method provided in CN111012848A.

[0150] The test results of the content of madderin, hydroxymadderin and rhamnosin in the blood-leveling tablets prepared according to the preparation example in Examples 1-4, Comparative Example 1 and Comparative Example 2, and the blood-leveling tablets obtained in Comparative Example 5 and Comparative Example 6 are shown in Table 1 (content per tablet in mg, tablet weight 0.35 g):

[0151] Table 1

[0152]

[0153] It can be seen that the contents of rhubarb, marigoldin and hydroxyrubiacin in the Xueping tablets prepared by the preparation method provided in Examples 1-4 of the present invention are higher than the contents of rhubarb, rhubarb, marigoldin and hydroxyrubiacin in the Xueping tablets prepared in Comparative Examples 1-4.

[0154] Effect example 2: Dissolution rate test of rhubarb, madderwine and hydroxymadderwine in Xueping tablets.

[0155] The Xueping tablets prepared by the preparation method of Preparation Example 1 and the Xueping tablets provided by the pharmaceutical compositions provided in Test Examples 1-4 and Comparative Examples 1-6 and Comparative Examples 5 and 6 were subjected to in vitro dissolution experiments in acetate buffer solution at pH 4.5.

[0156] The dissolution test evaluation method refers to the general dissolution method 2 of the 2020 edition of the Chinese Pharmacopoeia, the paddle method, the medium is an acetate buffer solution with a pH of 4.5, and the volume is 900 mL. The speed is 50 rpm. The content detection method of marigoldin, hydroxymarigoldin, and rhubarb in effect example 1 is adopted. Each group of experiments is put into 1 blood tablet / cup, and sampling and testing are carried out at various time points.

[0157] The test results of rheum officinale are shown in Table 2:

[0158] Table 2

[0159]

[0160] The test results of hydroxyrubiacein are shown in Table 3:

[0161] Table 3

[0162]

[0163] The test results of rubiacein are shown in Table 4:

[0164] Table 4

[0165]

[0166] It can be seen that the Xueping tablets prepared by the pharmaceutical composition provided in Examples 1-4 according to the method of the preparation example can release rubiacein, hydroxyrubiacein and rhein more quickly within 15 minutes under the condition of pH 4.5.

[0167] Clinical effect evaluation

[0168] The blood-level tablets used in the following clinical trials are all blood-level tablets prepared from the pharmaceutical composition provided in Example 1 of the present invention according to the method described in the preparation example.

[0169] 1. Clinical data

[0170] 1.1. Source of cases

[0171] Patients with blood-heat syndrome endometrial hyperplasia and abnormal uterine bleeding who visited the gynecology outpatient clinic of Dongzhimen Hospital of Beijing University of Chinese Medicine from January 2023 to January 2024 were collected.

[0172] This study was reviewed and approved by the Ethics Committee of Dongzhimen Hospital of Beijing University of Chinese Medicine, project number: 2023DZMEC-122-02.

[0173] 1.2 Diagnostic criteria

[0174] 1.2.1. Disease diagnostic criteria:

[0175] Referring to the 2022 "Diagnosis and Guidelines for Abnormal Uterine Bleeding", the 2018 International Federation of Gynecology and Obstetrics (FIGO) "PALM-COEIN" classification standard for abnormal uterine bleeding, the 2022 "Chinese Consensus on the Diagnosis and Treatment of Endometrial Hyperplasia", and the 9th edition of "Obstetrics and Gynecology", the Western medicine diagnosis is: abnormal uterine bleeding, and the pathological diagnosis: endometrial hyperplasia without atypical hyperplasia.

[0176] Endometrial hyperplasia (EH): The pathological manifestation is excessive proliferation of endometrial epithelial cells and endometrial glands, with a high ratio of glands to stroma, but without obvious atypical cells.

[0177] Abnormal uterine bleeding (AUB) refers to abnormal bleeding originating from the uterine cavity that is inconsistent with any of the normal menstrual cycle frequency, regularity, menstrual duration, and menstrual bleeding volume.

[0178] 1.2.2. TCM diagnostic criteria:

[0179] With reference to the 2010 edition of the “Guidelines for the Clinical Application of New Chinese Patent Medicines” (first edition in 1993), “Chinese Medicine Gynecology” (Zhang Yuzhen edition) and “Guidelines for the Diagnosis and Treatment of Common Gynecological Diseases in Chinese Medicine” (China Association of Traditional Chinese Medicine, 2012), the TCM diagnosis was “metrorrhagia” and “blood heat syndrome”.

[0180] Menorrhagia: refers to the untimely and continuous menstrual blood flow or persistent dripping. The former is called "menorrhagia" and the latter is called "leakage".

[0181] Blood heat syndrome - Main symptoms of excess heat syndrome: menstruation comes without a fixed time, menstrual blood suddenly flows out like a flood, or it lasts for a long time and cannot be stopped;

[0182] Secondary symptoms: ① Heavy menstruation, dark red color, thick menstrual fluid, or with blood clots, ② Thirst and desire to drink, ③ Upset, ④ Red face and dry lips, ⑤ Constipation, ⑥ Short and yellow urine, ⑦ Red tongue, yellow coating, slippery and rapid pulse.

[0183] The above main symptoms are necessary. If the secondary symptoms are ≥ 4, the diagnosis can be made by combining the tongue and pulse.

[0184] 1.3.3 Inclusion criteria

[0185] (1) Female patients aged ≥20 years and ≤50 years who meet the Western medical diagnostic criteria and are pathologically diagnosed with endometrial hyperplasia without atypical hyperplasia within 3 months;

[0186] (2) Patients who meet the diagnostic criteria of Western medicine and are diagnosed with abnormal uterine bleeding, including patients with frequent menstruation (cycle <21 days), oligomenorrhea (cycle >35 days), prolonged menstruation (menstrual period >7 days), menorrhagia (menstrual flow >80ml, or patients who feel that the menstrual flow is too heavy and affects their life), and patients with intermenstrual bleeding;

[0187] (3) Patients who meet the diagnostic criteria of traditional Chinese medicine and are diagnosed with metrorrhagia and syndrome differentiation of blood heat;

[0188] (4) After enrollment, patients began to receive treatment according to regulations and did not take hormones or other related therapeutic drugs in the 3 months before enrollment;

[0189] (5) Informed consent and voluntary participation, able to follow up regularly, and signed the informed consent form.

[0190] 1.3.4 Exclusion criteria

[0191] (1) Patients with endometrial cancer or atypical endometrial hyperplasia (precancerous lesions);

[0192] (2) Patients with amenorrhea (no menstruation for more than 6 months after establishing a regular menstrual cycle, or no menstruation for more than 3 menstrual cycles);

[0193] (3) Patients with oligomenorrhea (menstrual volume <20 ml, or menstruation duration less than 2 days, or patients who feel that the menstrual volume is less than before);

[0194] (4) Patients with postmenopausal uterine bleeding;

[0195] (5) Patients with liver or kidney dysfunction or combined with heart, brain, liver, kidney, thromboembolic diseases and primary blood system diseases;

[0196] (6) Physiological amenorrhea during pregnancy or lactation;

[0197] (7) Patients with bleeding caused by cervical or vaginal diseases;

[0198] (8) Patients with bleeding caused by uterine fibroids, ovarian tumors, etc.;

[0199] (9) Patients with drug-induced endometrial hyperplasia such as tamoxifen;

[0200] (10) Patients with cognitive impairment or mental illness;

[0201] (11) Those who are allergic to or intolerant of the drugs used;

[0202] (12) Patients with abnormal coagulation function.

[0203] 1.3.5. Elimination criteria

[0204] (1) Severe complications or worsening of concurrent diseases or other serious diseases occur during the study and emergency measures are required;

[0205] (2) Those who did not cooperate with treatment and no longer accepted medication and testing were lost to follow-up;

[0206] (3) Taking other drugs that prohibit or affect the research results without the permission of the physician;

[0207] (4) Incomplete or erroneous data records are recorded during the entire observation process, which has an adverse impact on the evaluation of therapeutic efficacy.

[0208] 1.3.6. Dropout and suspension standards

[0209] (1) If the subject voluntarily requests to withdraw from the trial for any reason at any time during the trial;

[0210] (2) During the trial, the subjects had poor compliance and used less than 80% of the prescribed amount or more than 120% of the prescribed amount of medication;

[0211] (3) Subjects who experience serious adverse events (such as liver and kidney damage, thrombosis, etc.);

[0212] (4) During the trial, the subjects had poor compliance and were lost during follow-up.

[0213] 2. Research Methods

[0214] 2.1 Research Design

[0215] This study adopted a prospective, randomized controlled research method. Patients who visited the gynecology outpatient clinic of Dongzhimen Hospital of Beijing University of Chinese Medicine from January 2023 to January 2024 and met the inclusion criteria were selected. Patients with abnormal uterine bleeding caused by EH were randomly divided into a dydrogesterone group and a blood-level tablet group, and the medication was discontinued after 3 consecutive menstrual cycles of treatment.

[0216] 2.2 Sample size

[0217] This study used a superiority trial design and randomly divided the subjects into two groups, a control group and a study group. The main efficacy indicators were menstrual status and symptom scores. If the two groups had equal effects, the equivalence margin δ was 9, the combined standard deviation σ was 11.7, and the mean difference between the two groups ε was 0. The hypothesis test uniformly used a one-sided test α = 0.05, and the one-sided test Z α =Z 0.05 =1.64, confidence level 1-β=90%, the sample size is calculated according to the following formula:

[0218]

[0219] According to the above formula, n=29 cases, clinically taking into account the dropout rate of 15%, the final calculation is: n=33.35≈33 cases. Considering 1:1 random grouping, that is, 33 subjects are required in the control group and the study group respectively, and a total of at least 68 subjects will be included.

[0220] 2.2 Treatment methods

[0221] The control group: the dydrogesterone group, took dydrogesterone tablets (manufacturer: Abbott Biologicals BV, the Netherlands, approval number: National Medicine Standard HJ20170221, specification: 10 mg per tablet) 14 days before menstruation for 12 consecutive days, 2 tablets at a time, once a day.

[0222] Study group: that is, the Xueping tablet group, took dydrogesterone tablets combined with Xueping tablets 14 days before menstruation. The method of taking dydrogesterone was the same as before, and Xueping tablets were taken for 12 consecutive days, three times a day, 4 tablets each time.

[0223] One menstrual cycle was one course of treatment. Both groups were treated for three menstrual cycles in a row and the medicine was discontinued during menstruation.

[0224] 2.3 Observation indicators

[0225] 2.3.1. Main Observation Indexes

[0226] (1) Menstrual status

[0227] Observe the improvement of the subjects' menstruation from the beginning of treatment to 3 months after the end of treatment. The menstrual status includes the number of days of menstrual bleeding (including days of abnormal bleeding), menstrual cycle, menstrual volume, etc. Menstrual bleeding volume: The menstrual blood loss chart (PBAC method) was used to evaluate the improvement of the menstrual volume of the two groups of subjects.

[0228] (2) TCM syndrome score

[0229] The changes in the TCM blood-heat syndrome scores of the patients before and after treatment were recorded. The scores of cycle, menstrual period, menstrual volume and accompanying symptoms were calculated according to the "Guidelines for Clinical Research of New Chinese Medicines" (China Medical Science and Technology Press, 2002) and the "Guidelines for Diagnosis and Treatment of Common Gynecological Diseases in TCM".

[0230] 2.3.2. Secondary Observation Index

[0231] (1) Endometrial thickness

[0232] Before and after treatment, and 3-5 days after the end of menstruation, transvaginal ultrasound was performed to detect the thickness of the endometrium and record it.

[0233] (2) Sex hormones

[0234] Before and after treatment, fasting venous blood was drawn from the two groups of patients on the morning of the 2nd to 4th day of menstruation, and the upper serum was retained by centrifugation for testing six serum neutral hormone levels: follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), progesterone (P), prolactin (PRL), and testosterone (T).

[0235] (3) Symptoms associated with menstruation

[0236] Before and after treatment, the two groups of patients used the Menstrual Distress Questionnaire (MDQ) to self-assess and record their symptoms. The Menstrual Symptom Questionnaire contains six aspects: pain before and after menstruation, attention, behavior, autonomic nervous reaction, water and sodium loss, and emotions. It can scientifically and effectively evaluate menstrual symptoms and provide validity and feasibility for the evaluation of premenstrual syndrome (PMS).

[11] .

[0237] (4) VAS score for dysmenorrhea

[0238] Before and after treatment, the two groups of patients were evaluated and recorded using the visual analogue scale (VAS) dysmenorrhea scoring method. 0-10 points, 0 points means no pain; 1-3 points means mild pain, which is tolerable; 4-6 points means moderate pain, which affects learning but is tolerable; 7-10 points means severe pain, which affects daily life.

[0239] (5) Mood improvement

[0240] Before and after treatment, the Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA) scores were recorded for the two groups of patients. A total score of less than 7 on the HAMD scale indicates normal; a total score of 7-17 points may indicate depression; a total score of 17-24 points indicates depression. A score of 0-7 on the HAMA scale indicates no anxiety symptoms; a score of 7-14 points indicates mild anxiety; and a score of 14 or more indicates anxiety symptoms.

[0241] (6) Evaluation of quality of life and satisfaction with happiness

[0242] Before and after treatment, the two groups of patients recorded their scores on the quality of life and satisfaction evaluation form. The score ranged from 16 to 80, with 16 to 32 being very dissatisfied, 32 to 48 being generally dissatisfied, 48 to 64 being generally satisfied, and 64 to 80 being very satisfied.

[0243] 2.3.3 Safety indicators

[0244] (1) Safety indicators: general vital signs (pulse, body temperature, respiration, blood pressure); routine blood, urine and stool tests, liver and kidney function, etc.;

[0245] (2) Adverse reaction records: For subjects who are found to have abnormal safety indicators after taking the medication, the clinical symptoms and treatment measures should be recorded in a timely manner.

[0246] 2.4 Follow-up

[0247] The patients were followed up for 8 weeks after the end of the treatment course to analyze the safety, recurrence rate and pregnancy rate.

[0248] 2.5 Comprehensive efficacy evaluation criteria

[0249] The efficacy evaluation is formulated in accordance with the Guiding Principles for the Clinical Application of New Chinese Patent Medicines as follows:

[0250] Markedly effective: clinical symptoms and signs improved, with the total symptom score reduced by ≥70%;

[0251] Effective: related symptoms and signs are alleviated, and the total syndrome score reduction rate is: 30%-70%;

[0252] Ineffective: Clinical symptoms and signs remain unchanged or even worsen, and the total symptom score decreases by <30%.

[0253] The TCM syndrome efficacy evaluation index (n) was calculated using the nimodipine method, and the specific formula was: n = (score before treatment - score after treatment) / score before treatment × 100%.

[0254] 2.6 Statistical Methods

[0255] After collecting all the data, an Excel electronic database was established, and SPSS 22.0 statistical software was used to analyze the data. After the data were sorted, normal distribution and variance homogeneity tests were first performed. The measurement data were expressed as mean ± standard deviation and the t test was used. If the normal distribution or variance was not homogeneous, non-parametric tests were used, and the chi-square test was used for comparison of count data. The test level α = 0.05, when p < 0.05, the difference was considered statistically significant.

[0256] 3. Research Results

[0257] 3.1 Descriptive analysis of clinical data

[0258] The 68 patients with abnormal uterine bleeding caused by endometrial hyperplasia due to blood-heat syndrome were selected from the gynecology outpatient clinic of Dongzhimen Hospital of Beijing University of Chinese Medicine from January 2023 to January 2024. During the study, 6 patients dropped out, 2 patients dropped out of the control group, and 4 patients dropped out of the study group. Finally, 62 patients completed the treatment. A before-and-after control trial design was adopted.

[0259] 3.1.1 Age distribution

[0260] Comparing the ages of the two groups of patients, the youngest in the control group was 24 years old, the oldest was 48 years old, and the average age was 34.00 years old; the youngest in the study group was 26 years old, the oldest was 47 years old, and the average age was 33.16 years old. According to the t-test, the age difference between the two groups of patients was not statistically significant (p>0.05), and they were comparable. See Table 5 (Age comparison of the two groups of patients (mean ± standard deviation)):

[0261] Table 5

[0262]

[0263] 3.1.2 BMI distribution

[0264] Comparing the difference in BMI between the two groups of patients, the minimum in the control group was 17.63, the maximum was 28.34, and the average BMI was 22.58; the minimum in the study group was 17.16, the maximum was 28.44, and the average BMI was 22.26. According to the t-test, the difference in BMI between the two groups of patients was not statistically significant (p>0.05), and they were comparable. See Table 6 (BMI comparison between the two groups of patients (mean ± standard deviation)):

[0265] Table 6

[0266]

[0267] 3.2 Comparison of clinical symptoms before and after treatment

[0268] 3.2.1. Comparison of menstrual improvement in the two groups of patients before and after treatment. The results are shown in Table 7 (mean ± standard deviation):

[0269] Table 7

[0270]

[0271] Note: Superscript a Compared with the group before treatment, p < 0.05.

[0272] As shown in Table 3, there was no significant difference in the number of bleeding days, menstrual cycle, and menstrual blood loss (PBAC score) between the two groups of EH patients before treatment (p>0.05), and they were comparable.

[0273] Control group: Compared with before treatment, the bleeding days, menstrual cycle and PBAC score of patients were significantly reduced, and the difference was statistically significant (p < 0.05).

[0274] Study group: Compared with before treatment, the patients' bleeding days, menstrual cycle and PBAC score were significantly reduced, and the differences were statistically significant (p < 0.05).

[0275] Compared with the control group, the PBAC score in the study group was significantly reduced, and the difference was statistically significant (p < 0.05), indicating that Xueping tablets can significantly reduce menstrual blood loss.

[0276] 3.2.2. Comprehensive comparison of clinical efficacy between the two groups of patients

[0277] After clinical treatment, 4 cases in the control group showed marked effect, 27 cases were effective, and the total effective rate was 87.10%. There were 14 cases in the research group with marked effect, 14 cases with effective effect, and the total effective rate was 90.32%. After treatment, compared with the control group, the research group had a higher marked effect, and the difference was statistically significant (p < 0.05); compared with the control group, the research group had a higher total effective rate, but the difference was not statistically significant (p > 0.05), see Table 8 (Comparison of clinical efficacy between the two groups of patients, number of cases (percentage)):

[0278] Table 8

[0279]

[0280] Note: Superscript a Compared with the control group, p < 0.05.

[0281] 3.2.3. Comparison of TCM syndrome scores between the two groups before and after treatment. The results are shown in Table 9 (mean ± standard deviation):

[0282] Table 9

[0283]

[0284] Note: Superscript a Compared with the group before treatment, p < 0.05.

[0285] 3.2.4 Comparison of endometrial thickness between the two groups before and after treatment. The results are shown in Table 10 (mean ± standard deviation):

[0286] Table 10

[0287]

[0288] Note: Superscript a Compared with the group before treatment, p < 0.05.

[0289] As shown in Table 6, there was no statistically significant difference in endometrial thickness before treatment between the two groups of patients with abnormal uterine bleeding caused by endometrial hyperplasia (p>0.05), and they were comparable.

[0290] Control group: Compared with before treatment, the thickness of endometrium was significantly reduced after treatment, and the difference was statistically significant by t-test (p < 0.05).

[0291] Study group: Compared with before treatment, the thickness of the endometrium decreased significantly after treatment, and the difference was statistically significant (p < 0.05). Compared with the control group, the thickness of the endometrium in the study group showed a decreasing trend after treatment, but the difference was not statistically significant (p > 0.05).

[0292] 3.2.5. Comparison of serum sex hormone levels between the two groups before and after treatment.

[0293] Six serum sex hormones: follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), progesterone (P), L-prolactin (PR), and testosterone (T).

[0294] The results are shown in Table 11 (mean ± standard deviation):

[0295] Table 11

[0296]

[0297] Note: Superscript a Compared with the group before treatment, p < 0.05.

[0298] As can be seen from Table 7, there was no significant difference in the levels of six serum sex hormones before treatment between the two groups of patients with abnormal uterine bleeding caused by endometrial hyperplasia: follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), progesterone (P), L-prolactin (PR), and testosterone (T), (p>0.05), so they were comparable.

[0299] Control group: Compared with before treatment, the levels of serum sex hormones E2 and P in patients after treatment were significantly lower than before treatment, and the difference was statistically significant (p < 0.05).

[0300] Study group: Compared with before treatment, the levels of serum sex hormones E2 and P in patients after treatment were significantly lower than before, and the difference was statistically significant (p < 0.05).

[0301] 3.2.6. Comparison of the scores of the menstrual symptom scale between the two groups before and after treatment. The results are shown in Table 12 (mean ± standard deviation):

[0302] Table 12

[0303]

[0304] Note: Superscript a Compared with the group before treatment, p < 0.05.

[0305] As shown in Table 8, there was no significant difference in the scores of the Menstrual Symptom Scale between the two groups of EH patients before treatment (p>0.05), and they were comparable.

[0306] Control group: Compared with before treatment, the menstrual symptom scores decreased after treatment, and the difference was statistically significant (p < 0.05). Study group: Compared with before treatment, the menstrual symptom scores decreased after treatment, and the difference was statistically significant (p < 0.05). Compared with the control group, the menstrual symptom scores in the study group were significantly reduced, and the difference was statistically significant (p < 0.05).

[0307] 3.2.7. Comparison of VAS scores of dysmenorrhea between the two groups before and after treatment. The results are shown in Table 13 (mean ± standard deviation):

[0308] Table 13

[0309]

[0310] Note: Superscript a Compared with the group before treatment, p < 0.05.

[0311] As shown in Table 9, there was no significant difference in the VAS scores of dysmenorrhea between the two groups of EH patients before treatment (p>0.05), which was comparable. Control group: Compared with before treatment, the VAS scores of dysmenorrhea decreased after treatment, and the difference was statistically significant (p<0.05). Study group: Compared with before treatment, the VAS scores of dysmenorrhea decreased after treatment, and the difference was statistically significant (p<0.05). Compared with the control group, the symptom scores before and after menstruation in the study group were significantly reduced, and the difference was statistically significant (p<0.05).

[0312] 3.2.8. Comparison of Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale scores between the two groups before and after treatment. The results are shown in Table 14 (mean ± standard deviation):

[0313] Table 14

[0314]

[0315] Note: Superscript a Compared with the group before treatment, p < 0.05.

[0316] As shown in Table 10, there was no significant difference in the Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA) scores between the two groups of EH patients before treatment (p>0.05), and they were comparable.

[0317] Control group: Compared with before treatment, the HAMD score of patients was significantly reduced, and the difference was statistically significant (p < 0.05); compared with before treatment, the HAMA score of patients showed a downward trend, and the difference was not statistically significant (p > 0.05).

[0318] Study group: Compared with before treatment, the HAMD and HAMA scores of the patients were significantly reduced, and the difference was statistically significant (p < 0.05). Compared with the control group, the HAMD score of the study group decreased significantly, and the difference was statistically significant (p < 0.05).

[0319] 3.2.9 Comparison of quality of life and satisfaction scores between the two groups before and after treatment. The results are shown in Table 15 (mean ± SD).

[0320] Table 15

[0321]

[0322] Note: Superscript a Compared with the group before treatment, p < 0.05.

[0323] There was no significant difference in the quality of life and satisfaction scores of the two groups of EH patients before treatment (p>0.05), and they were comparable.

[0324] Control group: Compared with before treatment, the scores of quality of life and satisfaction were increased, and the difference was statistically significant (p<0.05).

[0325] Study group: Compared with before treatment, the scores of quality of life and satisfaction increased, and the difference was statistically significant (p < 0.05). Compared with the control group, the scores of quality of life and satisfaction in the study group increased significantly, and the difference was statistically significant (p < 0.05).

[0326] 3.3 Adverse Reactions

[0327] During the medication period, one patient in the dydrogesterone group experienced nausea, which disappeared after the medication was adjusted. Four patients in the Xueping tablet group experienced diarrhea and loose stools, which disappeared after the medication dosage was adjusted. The remaining patients did not have allergic reactions or adverse reactions during the medication period. This shows that Xueping tablets are safe in clinical application.

[0328] 3.4 Recent follow-up

[0329] For patients with effective and markedly effective AUB caused by EH with blood-heat syndrome, follow-up was performed 8 weeks after drug withdrawal. Five patients in the dydrogesterone group had abnormal uterine bleeding again, with a recurrence rate of 18.52%. Two patients in the Xueping tablets group had recurrence, with a recurrence rate of 7.14%. One patient in the Xueping tablets group became pregnant.

[0330] 4 Discussion

[0331] After clinical treatment, 4 cases of marked effect were observed in the dydrogesterone group, with a marked effect rate of 12.90%, 27 cases of effective treatment, and a total effective rate of 87.10%. 14 cases of effective treatment were observed in the Xueping tablet combined medication group, with a marked effect rate of 45.16%, 28 cases of effective treatment, and a total effective rate of 90.32%. The marked effect rate of the Xueping tablet combined with dydrogesterone group was significantly higher than that of the dydrogesterone group (p < 0.05), and the total effective rate had a significant advantage, indicating that the clinical efficacy of the Xueping tablet combined with dydrogesterone in the treatment of abnormal uterine bleeding caused by endometrial hyperplasia is significant.

[0332] Xueping tablets combined with dydrogesterone can significantly improve multiple clinical symptoms and signs of patients with abnormal uterine bleeding caused by endometrial hyperplasia due to blood-heat syndrome, improve excessive menstrual bleeding, reduce endometrial thickness, relieve patients' menstrual symptoms and menstrual pain, improve patients' negative emotions such as depression, improve patient satisfaction, have high safety, and have considerable long-term efficacy.

[0333] 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 pharmaceutical composition for treating abnormal uterine bleeding caused by endometrial hyperplasia due to blood-heat syndrome, characterized in that: The invention is composed of dydrogesterone and a traditional Chinese medicine composition, wherein the traditional Chinese medicine composition is prepared from the following ingredients in parts by mass: 4-6 parts of Rubia cordifolia extract, 2-4 parts of Rehmannia glutinosa extract, 2-4 parts of Rhubarb extract, 2-4 parts of Sanguisorba officinalis extract, 3-5 parts of Panax notoginseng extract, 5-7 parts of Cuttlebone extract and 1-3 parts of Stir-fried Pollen Typhae extract; The preparation method of the Rubia cordifolia extract comprises the following steps: Mixing madder with an acidic aqueous solution, stirring, filtering, mixing the filter residue with an alkaline solution, refluxing for extraction, collecting the filtrate, concentrating, and drying to obtain a madder extract, wherein the acidic aqueous solution is an acetic acid aqueous solution with a mass fraction of 0.01% to 0.1%, and the alkaline solution is an isopropanol aqueous solution of sodium hydroxide; The preparation method of the Rehmannia glutinosa extract comprises the following steps: Heat-treating Rehmannia root in a nitrogen atmosphere, mixing with water, extracting by reflux, collecting the filtrate, centrifuging to obtain the supernatant, and drying to obtain Rehmannia root extract; The preparation method of the cooked rhubarb extract comprises the following steps: The cooked rhubarb is soaked in liquid nitrogen, crushed, mixed with water, refluxed for extraction, the filtrate is collected, the supernatant is centrifuged, and dried to obtain the cooked rhubarb extract; The preparation method of the Sanguisorba officinalis extract comprises the following steps: Mixing Sanguisorba officinalis with 8-10 times the mass of water, performing ultrasonic extraction, filtering, and drying the filtrate to obtain the Sanguisorba officinalis extract; the preparation method of the Panax notoginseng extract comprises the following steps: (1) mixing the Panax notoginseng extract with 6-8 times methanol aqueous solution, extracting 2-3 times, filtering, and obtaining Panax notoginseng filtrate and Panax notoginseng residue; (2) heating and drying 20%-30% of the Panax notoginseng residue obtained in step (1), freeze-drying 20%-30% of the Panax notoginseng residue obtained in step (1), mixing the products obtained by the heating and drying and the freeze-drying, grinding and sieving, and obtaining Panax notoginseng powder; (3) concentrating the Panax notoginseng filtrate obtained in step (1), drying it, and mixing it with the Panax notoginseng powder obtained in step (2) to obtain a Panax notoginseng extract; The preparation method of the cuttlebone extract comprises the following steps: Mixing the cuttlebone with 3-4 times the mass of a 10%-15% hydrochloric acid aqueous solution, ultrasonicating for 3-5 minutes, filtering out the solid, washing with water, freeze-drying and grinding to obtain a cuttlebone extract; The preparation method of the stir-fried pollen extract comprises the following steps: The stir-fried pollen puhuang is mixed with 8-10 times the mass of water, subjected to ultrasonic extraction, filtered, and the filtrate is dried to obtain the stir-fried pollen puhuang extract.

2. The pharmaceutical composition according to claim 1, characterized in that The traditional Chinese medicine composition is prepared from the following ingredients by mass: 5 parts of madder extract, 3 parts of rehmannia extract, 3 parts of cooked rhubarb extract, 3 parts of sanguisorba officinalis extract, 4 parts of notoginseng extract, 6 parts of cuttlebone extract and 2 parts of stir-fried pollen extract.

3. The pharmaceutical composition according to claim 1, characterized in that In the preparation method of the Rubia cordifolia extract, The mass of the acidic aqueous solution is 1.5-2 times that of the madder; The stirring is performed at room temperature for 10-30 minutes; The mass of the alkaline solution is 7-9 times the mass of the filter residue; The reflux extraction is performed 2-3 times; Before said concentration, the pH of the filtrate is adjusted to 7-9; The concentration is to concentrate under reduced pressure until there is no alcohol taste; The concentration is concentrated to a density of 1.2-1.3 g / mL; The drying is freeze drying.

4. The pharmaceutical composition according to claim 1, characterized in that In the preparation method of the Rehmannia glutinosa extract, The heat treatment is performed at 70-90° C. for 2-4 hours; After the heat treatment, the mixture is cooled to room temperature and crushed; The amount of water used is 6-8 times the mass of the Rehmannia root; The reflux extraction is performed 2-3 times; The centrifugation is carried out at 3000 rpm for 2-4 min; The drying is freeze drying.

5. The pharmaceutical composition according to claim 1, characterized in that In the preparation method of the Panax notoginseng extract, In step (1), the methanol aqueous solution is a methanol aqueous solution with a volume fraction of 60%-70%; the leaching is performed at 20-30° C.; In step (2), the heating and drying is specifically: heating and drying on a heating plate at 60-80° C. in an air atmosphere for 3-4 hours; In step (2), the grinding and screening is grinding through a 20-mesh sieve; In step (3), the drying is freeze-drying.

6. The method for preparing the pharmaceutical composition according to any one of claims 1 to 5, characterized in that: The pharmaceutical composition is composed of dydrogesterone and a traditional Chinese medicine composition, and the traditional Chinese medicine composition is made of the following ingredients in parts by mass: 4-6 parts of Rubia cordifolia extract, 2-4 parts of Rehmannia glutinosa extract, 2-4 parts of Rhubarb extract, 2-4 parts of Sanguisorba officinalis extract, 3-5 parts of Panax notoginseng extract, 5-7 parts of Cuttlebone extract and 1-3 parts of Stir-fried Pollen Typhae extract; The preparation method of the Rubia cordifolia extract comprises the following steps: Mixing madder with an acidic aqueous solution, stirring, filtering, mixing the filter residue with an alkaline solution, refluxing for extraction, collecting the filtrate, concentrating, and drying to obtain a madder extract, wherein the acidic aqueous solution is an acetic acid aqueous solution with a mass fraction of 0.01% to 0.1%, and the alkaline solution is an isopropanol aqueous solution of sodium hydroxide; The preparation method of the Rehmannia glutinosa extract comprises the following steps: Heat-treating Rehmannia root in a nitrogen atmosphere, mixing with water, extracting by reflux, collecting the filtrate, centrifuging to obtain the supernatant, and drying to obtain Rehmannia root extract; The preparation method of the cooked rhubarb extract comprises the following steps: The cooked rhubarb is soaked in liquid nitrogen, crushed, mixed with water, refluxed for extraction, the filtrate is collected, the supernatant is centrifuged, and dried to obtain the cooked rhubarb extract; The preparation method of the Sanguisorba officinalis extract comprises the following steps: Mixing Sanguisorba officinalis with 8-10 times the mass of water, performing ultrasonic extraction, filtering, and drying the filtrate to obtain the Sanguisorba officinalis extract; the preparation method of the Panax notoginseng extract comprises the following steps: (1) mixing the Panax notoginseng extract with 6-8 times methanol aqueous solution, extracting 2-3 times, filtering, and obtaining Panax notoginseng filtrate and Panax notoginseng residue; (2) heating and drying 20%-30% of the Panax notoginseng residue obtained in step (1), freeze-drying 20%-30% of the Panax notoginseng residue obtained in step (1), mixing the products obtained by the heating and drying and the freeze-drying, grinding and sieving, and obtaining Panax notoginseng powder; (3) concentrating the Panax notoginseng filtrate obtained in step (1), drying it, and mixing it with the Panax notoginseng powder obtained in step (2) to obtain a Panax notoginseng extract; The preparation method of the cuttlebone extract comprises the following steps: Mixing the cuttlebone with 3-4 times the mass of a 10%-15% hydrochloric acid aqueous solution, ultrasonicating for 3-5 minutes, filtering out the solid, washing with water, freeze-drying and grinding to obtain a cuttlebone extract; The preparation method of the stir-fried pollen extract comprises the following steps: The stir-fried pollen puhuang is mixed with 8-10 times the mass of water, subjected to ultrasonic extraction, filtered, and the filtrate is dried to obtain the stir-fried pollen puhuang extract.

7. A drug, characterized in that The active ingredient consists of the pharmaceutical composition according to any one of claims 1 to 5.

8. The drug according to claim 7, characterized in that The dosage form of the drug is tablets.

9. Use of the pharmaceutical composition according to any one of claims 1 to 5 or the drug according to any one of claims 7 to 8 in the preparation of a drug for treating abnormal uterine bleeding caused by endometrial hyperplasia due to blood-heat syndrome.

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