WO2021143919A1 - 一种药物组合物及其应用 - Google Patents

一种药物组合物及其应用 Download PDF

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WO2021143919A1
WO2021143919A1 PCT/CN2021/072630 CN2021072630W WO2021143919A1 WO 2021143919 A1 WO2021143919 A1 WO 2021143919A1 CN 2021072630 W CN2021072630 W CN 2021072630W WO 2021143919 A1 WO2021143919 A1 WO 2021143919A1
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patients
pharmaceutical composition
hemorrhoids
injection
patient
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PCT/CN2021/072630
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English (en)
French (fr)
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沙薇
张艳军
宋佳
李婷
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河南泰丰生物科技有限公司
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Priority to US17/793,918 priority Critical patent/US20230065462A1/en
Publication of WO2021143919A1 publication Critical patent/WO2021143919A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention belongs to the field of medical technology. Specifically, the present invention relates to a pharmaceutical composition and the use of the pharmaceutical composition in the treatment of rectal hemangioma and hemorrhoids, especially in patients who are not suitable for surgical treatment, such as the treatment of hemorrhoids in patients with leukemia and hemophilia .
  • Rectal hemangioma is a non-single-cell benign tumor.
  • the main cell components include endothelial cells, fibroblasts, and adipocytes.
  • the etiology of rectal hemangioma is still unclear. It is generally considered to be a hamartoma originating from the remnants of the mesoderm embryo, and it is a very rare benign vascular lesion.
  • the clinical manifestations of rectal hemangioma lack specificity.
  • the main clinical manifestations are recurrent painless blood in the stool. Some patients have abdominal pain, perianal swelling and other discomforts, recurring attacks, long course of disease, progressive aggravation, and clinical manifestations of chronic anemia. Because some of the clinical manifestations are similar to hemorrhoids, it is easy to be misdiagnosed as hemorrhoids or rectal inflammation.
  • sclerosing agent injection The treatment of rectal hemangioma is currently mainly sclerosing agent injection.
  • the principle of action of sclerosing agent is: after sclerosing agent acts on local tissues, it first destroys endothelial cells, causing tissues to undergo swelling, degeneration, necrosis, and inflammatory cell infiltration to different degrees, and then fibrosis, fibroblast proliferation, and blood vessels Compression, occlusion, or embolization, and then cause tissue to shrink and fall off, thereby gradually regressing the hemangioma.
  • the sclerosing agent has a significant therapeutic effect, simple operation and no complicated equipment, there is a lot of bleeding during and after the operation, and it is easy to relapse. It can also cause local phlebitis, inflammatory reactions, and even serious adverse reactions such as infection and necrosis.
  • Hemorrhoids is a common disease located in the anal area. It can occur at any age, but with age, the incidence gradually increases.
  • the accepted theory Thomson's theory of anal cushion shifting down believes that hemorrhoids are originally the normal anatomical structure of the anal canal, that is, the vascular cushion, which is a circular spongy tissue band 1.5 cm above the dentate line.
  • the treatment of hemorrhoids includes surgical treatment and non-surgical treatment, of which surgical treatment is the main one, including thrombotic external hemorrhoid dissection, traditional hemorrhoidectomy, hemorrhoidectomy and PPH surgery; non-surgical treatment also includes topical medication and oral Drug therapy, physical therapy, rubber band ligation, and injection therapy.
  • Conventional injection therapy is to inject sclerosing agent around the submucosal venous plexus to cause inflammation and fibrosis, thereby compressing the varicose veins, but the sclerosing agent is injected into the mucosal layer Will cause necrosis.
  • Hemophilia is a group of bleeding disorders with inherited coagulation dysfunction. Its common features are the generation of active thromboplastin, prolonged coagulation time, and lifelong tendency to bleeding after minor trauma. Severe patients can also have "spontaneous" without obvious trauma. Sexual" bleeding. The severely ill patients will bleed as long as the skin is slightly wounded. In addition to the general symptoms of hemorrhoids in patients with hemophilia and hemorrhoids, the risk of bleeding is particularly serious. Patients with hemophilia and hemorrhoids are prone to repeated heavy bleeding after hemorrhoid surgery, which makes the patient very scared, causing severe psychological and physical injuries to the patient; and repeated operations are required, which also brings additional financial burdens. In addition, the colostomy also brings inconvenience to patients' life and care. Therefore, the risk of surgical treatment for such patients is relatively high, and more serious patients are prone to death, and they need to be injected with expensive clotting factors.
  • Leukemia is a malignant clonal disease of hematopoietic stem cells. Because of mechanisms such as uncontrolled proliferation, impaired differentiation, and blocked apoptosis, leukemia cells accumulate in bone marrow and other hematopoietic tissues, and infiltrate other non-hematopoietic tissues and organs, while inhibiting normal hematopoietic function. Leukemia and hemophilia are similar to blood diseases. The treatment principle is to eliminate the leukemia cell population and control the proliferation of leukemia cells. Therefore, similar to hemophilia with hemorrhoids, leukemia with hemorrhoids also poses a bleeding risk.
  • Surgical treatment often causes great damage to the patient, resulting in a decrease in resistance, resulting in complications and other undesirable consequences.
  • patients with coagulation disorders such as hemophilia and leukemia are not suitable for surgical treatment
  • medical practice has proved that they have a bleeding tendency (patients with coagulation disorders (such as aplastic anemia, leukemia or hemophilia), receiving antithrombotic Treatment (such as cardiac stent surgery, cardiac pacemaker surgery, myocardial infarction, cerebral infarction), hypertension, diabetes, portal hypertension, renal dysfunction, myasthenia gravis, immune deficiency (such as AIDS, systemic Lupus erythematosus), and patients undergoing chemotherapy and radiotherapy should not undergo surgery.
  • patients if they have rectal hemangioma or hemorrhoids at the same time, they should not undergo surgery.
  • the inventors conducted research on the basis of the prior art and found that the use of a three-component composition (especially injection) of citric acid, gallic acid and paeoniflorin can treat the above-mentioned diseases instead of surgical treatment.
  • composition of citric acid, gallic acid and paeoniflorin is different from the necrosis or hardening mechanism of sclerosing agent, but through a series of changes of tissue protein coagulation, lysis, absorption, and capillary angiogenesis, the entire rectal hemangioma or hemorrhoid "shrinks" It does not leave induration and other sequelae after treatment, and also greatly reduces the risk of bleeding; among them, the organic acids citric acid and gallic acid make blood vessels constrict, blood flow decreases, blood vessel permeability decreases, blood clotting time is shortened, and blood vessel damage is promoted.
  • the inventors also found that a specific ratio of citric acid, gallic acid and paeoniflorin, as well as the ratio of gallic acid and paeoniflorin can produce a synergistic effect and achieve a better therapeutic effect.
  • the present invention provides a pharmaceutical composition containing citric acid, paeoniflorin and gallic acid in a weight ratio of about 100:(1-8):(0.1-5).
  • the present invention provides a preparation comprising the pharmaceutical composition of the present invention and pharmaceutically acceptable excipients.
  • the present invention provides the use of the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of rectal hemangioma or hemorrhoids.
  • the present invention provides the pharmaceutical composition of the present invention, which is used to treat rectal hemangioma or hemorrhoids.
  • the present invention provides a method for treating rectal hemangioma or hemorrhoids, which comprises administering the pharmaceutical composition of the present invention or the preparation of the present invention.
  • Citric acid is also called citric acid, and its chemical name is 2-hydroxypropane-1,2,3-tricarboxylic acid. Citric acid is widely distributed in nature. Natural citric acid exists in the bones, muscles and blood of plants such as lemons, citrus, pineapples and other fruits and animals. Citric acid is an edible acid, mainly used in the food industry, such as sour agents, solubilizers, buffers, antioxidants, deodorants, flavor enhancers, gelling agents, toners, etc. Adding citric acid to some foods has a good taste and can promote appetite. It is often used in jams, beverages, cans and candies.
  • Paeoniflorin derived from the roots of Paeonia lactiflora, Paeonia lactiflora, and Paeonia lactiflora, has the following chemical structure:
  • paeoniflorin can resist the oxidative stress damage of tissue cells, inhibit the activation of astrocytes, and enhance the protection of nerves. It has obvious antagonistic effects on the damage of striatum and substantia dopaminergic nerve cells, and can improve motor retardation. It can be used to treat brain diseases such as Alzheimer's disease, Parkinson's disease and epilepsy. In addition, paeoniflorin can also fight tumors, rheumatoid arthritis and ankylosing spondylitis and other autoimmune diseases. Animal experiments also proved that paeoniflorin can significantly reduce blood sugar levels and has an important protective effect on heart and lung cells.
  • Gallic acid is also called gallic acid.
  • the chemical name is 3,4,5-trihydroxybenzoic acid. It is widely present in plants such as palm leaf rhubarb, Eucalyptus grandiflora, dogwood and other plants. It is a polyphenolic compound that exists in nature and has a wide range of applications in food, biology, medicine, chemical and other fields.
  • Gallic acid has various biological activities such as anti-inflammatory, anti-mutation, anti-oxidation and anti-free radicals; at the same time, gallic acid has anti-tumor effects, which can inhibit the metastasis of mast cell tumors, thereby prolonging the survival period; it is also relatively suitable for killing trypanosoma Candidate drug; has a protective effect on the liver, can resist carbon tetrachloride-induced physiological and biochemical changes in the liver; can induce endothelial-dependent contraction and endothelial-dependent relaxation by inhibiting the production of endothelial NO.
  • the mechanism of action of the three components is: organic acid citric acid and gallic acid make blood vessels constrict, blood flow decrease, blood vessel permeability decrease, blood clotting time shorten, platelet aggregation at damaged blood vessels, coagulation and degeneration of large blood vessel walls, and interstitial tissue coagulation Degeneration and tissue disintegration; while paeoniflorin promotes blood circulation to remove blood stasis, inhibits acute inflammation, promotes the proliferation of interstitial fibroblasts, induces macrophages to clear disintegrated tissue, promotes capillary proliferation, and inhibits hypertrophic scar fibrosis.
  • the three components are mixed in a specific ratio to produce biological effects such as reducing the number of capillaries, proliferating collagen fibers, and apoptosis of vascular endothelial cells.
  • biological effects such as reducing the number of capillaries, proliferating collagen fibers, and apoptosis of vascular endothelial cells.
  • the weight ratio of citric acid, gallic acid and paeoniflorin is about 100:(1-8):(0.1-5); in another specific embodiment, the weight ratio of the three Is about 100:(1.5 ⁇ 7.5):(0.2 ⁇ 4); in another specific embodiment, the weight ratio of the three is about 100:(2 ⁇ 7):(0.5 ⁇ 3.5); in another embodiment In the solution, the weight ratio of the three is about 100:(2 ⁇ 6.5):(0.5 ⁇ 3); in another specific embodiment, the weight ratio of the three is about 100:(2 ⁇ 6):(1 ⁇ 2).
  • the specific ratio of gallic acid and paeoniflorin is also critical. Therefore, in a specific embodiment of the present invention, the weight ratio of paeoniflorin to gallic acid is about (1-6):1; in another specific embodiment, the weight ratio of the two is about (1-5) :1; In another specific embodiment, the weight ratio between the two is about (1 ⁇ 4):1; in another specific embodiment, the weight ratio between the two is about (1.5 ⁇ 3.5):1; In another specific embodiment, the weight ratio of the two is about (2-3):1.
  • the weight ratio of citric acid, gallic acid and paeoniflorin is about 100:4:1.5, 100:5.6:2, 100:2.2:1, 100:3.6:1.8, 100:3.6:1.3 , 100:2:1.2, 100:6.2:2, 100:2.5:0.8, and 100:5.3:2.6, preferably about 100:4:1.5, 100:5.6:2 and 100:2.2:1, particularly preferably about 100:4:1.5.
  • the pharmaceutical composition of the present invention is preferably used in the form of injection.
  • Injections refer to sterile solutions (including emulsions and suspensions) made of medicines for injection into the body, and sterile powders or concentrated solutions that are prepared into solutions or suspensions immediately before use. It mainly includes liquid injection, powder for injection, and tablet for injection.
  • Liquid injections are also called injections, commonly known as “water injections”.
  • the drug is formulated into a solution (aqueous or non-aqueous), suspension or emulsion, and filled into ampoules or multi-dose containers.
  • water-soluble drugs are required to achieve quick-acting effects after injection, so they are often formulated into aqueous solutions or water composite solutions (eg, ethanol, propylene glycol, glycerin, etc.) are added to the aqueous solution.
  • Some medicines are not suitable to be made into aqueous solutions, such as being insoluble in water or prolonging their efficacy after injection, etc. They can be made into oil solutions, water or oil suspensions, or emulsions. But these injections are generally only for intramuscular injection.
  • Powder for injection commonly known as "powder injection”.
  • Some drugs have poor stability and are easy to decompose and deteriorate after being made into solutions.
  • Such drugs generally can be sterilized by using sterile powdered drugs for injection into ampoules or other suitable containers, and dissolve or suspend them in a suitable solvent before use.
  • Tablets for injection refer to molded tablets or machine-pressed tablets made by aseptic operation of drugs, which are dissolved in water for injection before use and are used for subcutaneous or intramuscular injection.
  • the "method” or “use” of the present invention refers to administering the pharmaceutical composition of the present invention to a subject who has a corresponding disease or a tendency of the disease, with the purpose of imparting a therapeutic effect, such as curing, alleviating, changing, affecting, improving Or prevent the symptoms or tendencies of the aforementioned diseases.
  • a therapeutic effect such as curing, alleviating, changing, affecting, improving Or prevent the symptoms or tendencies of the aforementioned diseases.
  • Those skilled in the art can easily determine the specific effective dose according to the type of disease to be treated, the route of administration, and the use of excipients. The dose may vary due to the simultaneous use of other drugs.
  • Rectal hemangioma is a congenital non-hereditary disease, which is rare in clinical practice. Because of its non-progressive growth characteristics, rectal hemangioma is generally considered to be a hamartoma, rather than a new tumor. The disease usually occurs in the rectum. It is more common in adolescents aged 10 to 20, with more men than women. According to the morphology of blood vessels in hemangioma, it can be divided into three categories: capillary hemangioma, cavernous hemangioma, and mixed hemangioma.
  • rectal hemangioma The cause of rectal hemangioma is still unclear. It is generally believed that it originated from embryonic vascular hamartosis buds. Under the action of certain factors, it leads to tumor-like proliferation. Capillary hemangioma causes slow bleeding, and cavernous hemangioma causes massive bleeding, which is gradually severe and frequent bleeding. Polyp-type colonic hemangioma can cause intestinal obstruction due to intussusception, and volvulus occurs in a few cases. Extensive diffuse rectal hemangioma manifests as systemic coagulation mechanism disorder, aggravating intestinal bleeding, accompanied by thrombocytopenia, hypofibrinogenemia, and decreased blood coagulation factors V and VIII levels. After the rectal hemangioma is removed, it can be restored to normal.
  • rectal hemangioma The clinical manifestations of rectal hemangioma vary with the type, size and location of the hemangioma. For those with a history of hemangioma, mucosal or skin similar lesions, and signs of hematochezia, anemia, and intestinal obstruction, especially young children or young adults, the possibility of this disease should be considered. Fiber endoscopy, lower gastrointestinal angiography, and mesenteric angiography, etc., can be used as a basis for lesion location and diagnosis. This disease should be distinguished from internal and external hemorrhoids, colorectal inflammation, ulcers, rectal villous adenoma, rectal polyps, and anorectal prolapse.
  • Rectal hemangioma requires active treatment. Among untreated patients, 40% of patients die from bleeding caused by hemangioma. According to the patient's general condition, the size and location of the hemangioma, non-surgical treatment or surgical treatment can be used.
  • Non-surgical treatments include sclerosing agent injection, freezing, diathermy or electrocautery, electrocoagulation and other therapies to make the tumor fibrosis, reduce the tumor and stop bleeding. It is suitable for patients with low-level hemangioma, poor general condition, and rectal hemangioma who cannot tolerate surgical resection. The hemostatic effect is better in the short term, the long-term effect and radical cure are poor, and the recurrence rate is high.
  • the best way to treat rectal hemangioma is surgical removal. Partial intestinal resection is feasible for colonic hemangioma; small rectal hemangiomas can be resected under local submucosal, preserving the muscle layer and serous membrane; upper rectal lesions undergo anterior rectal resection via abdomen; diffuse or multiple types of middle and lower rectal lesions, the most The best surgical method is combined rectal-abdominal-perineum resection, but since most patients are young, it is difficult to accept a permanent abdominal colostomy, which causes postoperative sexual dysfunction, so it should be avoided.
  • Hemorrhoids (commonly known as hemorrhoids) is a common disease located in the anus. It can be affected at any age, but with age, the incidence gradually increases.
  • hemorrhoids There are two main theories about the cause of hemorrhoids. The first is the theory of varicose veins, which believes that hemorrhoids are venous clusters formed by congestion, expansion and flexion of the venous plexus under the mucosa of the rectum and under the skin of the anal canal.
  • the currently widely accepted theory is Thomson's theory of anal cushion downward shift, which believes that hemorrhoids are originally the normal anatomical structure of the anal canal, that is, the vascular cushion, which is a circular spongy tissue band 1.5 cm above the dentate line. Only when the anal pad tissue is abnormal and symptomatic can it be called hemorrhoids and need treatment. The purpose of treatment is to relieve the symptoms, not to eliminate the hemorrhoids.
  • Asymptomatic hemorrhoids do not need treatment; symptomatic hemorrhoids do not need radical treatment; non-surgical treatment is the main treatment.
  • the medications include suppositories, ointments and lotions, most of which contain Chinese herbal ingredients.
  • Oral drug treatment generally use drugs for the treatment of varicose veins.
  • Injection therapy injecting sclerosing agent around the submucosal venous plexus to cause inflammation and fibrosis, thereby compressing the varicose veins; but injection of sclerosing agent into the mucosal layer will cause necrosis.
  • Rubber band ligation ligate the roots of the hemorrhoids to block the blood supply to make the hemorrhoids fall off and necrotic; it is more suitable for huge internal hemorrhoids and fibrotic internal hemorrhoids.
  • PPH operation stapler hemorrhoids and rectal mucosa circumcision and nailing. Created by the Italian doctor Longo, it was promoted in 1998. It is mainly suitable for prolapsed type III-IV mixed hemorrhoids, circular hemorrhoids, and partially bleeding serious internal hemorrhoids.
  • the mechanism of PPH in the treatment of prolapsed hemorrhoids circular excision of the 2 to 3 cm lower rectal mucosa and submucosal tissue to restore the normal anatomical structure, that is, the anal cushion return; the resection of the submucosal tissue blocks the blood flow from the suprahemorrhoidal artery to the hemorrhoid area Supply, so that postoperative hemorrhoids atrophy.
  • PPH surgery has shorter operation time, less postoperative pain, faster recovery, and fewer complications, but the equipment is more expensive.
  • bleeding tendency with coagulation dysfunction (such as aplastic anemia, leukemia or hemophilia patients), receiving antithrombotic therapy (such as cardiac stent surgery, cardiac pacemaker surgery, myocardial infarction, Patients with cerebral infarction), hypertension, diabetes, portal hypertension, renal dysfunction, myasthenia gravis, immunodeficiency (such as AIDS, systemic lupus erythematosus), and patients receiving chemotherapy and radiotherapy.
  • coagulation dysfunction such as aplastic anemia, leukemia or hemophilia patients
  • antithrombotic therapy such as cardiac stent surgery, cardiac pacemaker surgery, myocardial infarction, Patients with cerebral infarction
  • hypertension diabetes
  • portal hypertension renal dysfunction
  • myasthenia gravis such as AIDS, systemic lupus erythematosus
  • immunodeficiency such as AIDS, systemic lupus erythematosus
  • Bleeding tendency refers to the spontaneous bleeding of the skin and mucous membranes, or a clinical manifestation in which the bleeding is not easy to stop spontaneously when the tiny blood vessels suffer minor trauma.
  • the causes of bleeding tendency are generally divided into three categories: abnormal blood coagulation function, abnormal platelet, and abnormal blood vessel wall function.
  • Coagulation dysfunction refers to a bleeding disorder caused by a deficiency or abnormal function of coagulation factors. Including hemophilia, vitamin K deficiency, and coagulation abnormalities caused by severe liver disease. Platelet abnormalities mainly include thrombocytopenia and platelet dysfunction.
  • Abnormal blood vessel wall function such as Henoch-Schonlein purpura.
  • some other diseases and their treatment process can also cause bleeding tendency.
  • one of the common symptoms of leukemia patients is thrombocytopenia, followed by a tendency to blood.
  • Another example is that for various cardiovascular and cerebrovascular diseases such as coronary heart disease, heart bypass surgery, coronary stent surgery, heart valve replacement surgery and large vessel disease surgery, long-term use of antithrombotic drugs such as aspirin and warfarin is required for treatment. , And the use of antithrombotic drugs has led to bleeding tendency.
  • Hemophilia is a group of bleeding disorders with inherited coagulation dysfunction. The common features are the generation of active thromboplastin, prolonged coagulation time, lifelong tendency to bleeding after minor trauma, and "spontaneous" can occur in severely ill patients without obvious trauma. Sexual" bleeding. Hemophilia is a group of bleeding disorders that are inherited in a sex-linked recessive manner. It is clinically divided into two types, hemophilia A and hemophilia B, which are caused by mutations in coagulation factor VIII and coagulation factor IX genes, respectively.
  • hemophilia suffers from hemorrhoids, its treatment is more difficult than ordinary people. Patients with hemophilia have a higher risk of surgical treatment, which can easily lead to bleeding, and patients with more serious conditions are likely to die. When treating hemorrhoids, patients with hemophilia need to inject expensive coagulation factors; when undergoing surgical treatment, in addition to coagulation factors, they also need to prepare fresh plasma in order to prevent postoperative bleeding.
  • Leukemia is a malignant clonal disease of hematopoietic stem cells. Due to mechanisms such as uncontrolled proliferation, differentiation disorder, and obstructed apoptosis, clonal leukemia cells accumulate in bone marrow and other hematopoietic tissues, and infiltrate other non-hematopoietic tissues and organs, while inhibiting normal hematopoietic function. Clinically, various degrees of anemia, hemorrhage, infection, fever, liver, spleen, and lymphadenopathy and bone pain can be seen.
  • Leukemia and hemophilia are similar to blood diseases. One thing they have in common is that leukemia patients have thrombocytopenia, blood vessel damage and blood clotting dysfunction, which lead to the risk of bleeding. Nearly 40% of leukemias have bleeding as the early manifestation. Bleeding can occur in various parts of the body, common with unexplained skin bruises, oral cavity, nasal cavity, bleeding gums, menorrhagia, etc. Blurred retina often indicates that the patient has fundus hemorrhage; severe headache, nausea, and vomiting often indicate that the patient has intracranial hemorrhage.
  • the patient adopts the side lying position, the folding knife position and the bladder lithotomy position and other treatment positions, routine disinfection, and then anal local anesthesia or anal canal anesthesia, anesthetic with 0.5-1% lidocaine;
  • stage III hemorrhoids Retract anoscopy to expose the hemorrhoids, and the injection method for stage III hemorrhoids is the same as that of stage I and II;
  • Each patient is about 10-20ml at a time, with an average of 15ml, and the maximum dosage does not exceed 40ml;
  • Each patient generally only has one injection.
  • the pharmaceutical composition of the present invention is administered to patients with rectal hemangioma. In another embodiment, the pharmaceutical composition of the present invention is administered to a patient with hemorrhoids. In another embodiment, the pharmaceutical composition of the present invention is administered to patients with rectal hemangioma or hemorrhoids who are not suitable for surgical treatment. In another embodiment, the pharmaceutical composition of the present invention is administered to patients with rectal hemangioma or hemorrhoids who are prone to bleeding. In another embodiment, the pharmaceutical composition of the present invention is administered to patients with rectal hemangioma or hemorrhoids who have hemophilia or leukemia. In another embodiment, the pharmaceutical composition of the present invention is administered to patients with rectal hemangioma or hemorrhoids receiving antithrombotic therapy.
  • the patient when the pharmaceutical composition of the present invention is administered, the patient does not stop the original drug treatment, such as antithrombotic drugs.
  • the patient when administering the pharmaceutical composition of the present invention, the patient does not need to supplement clotting factors or undergo blood transfusion.
  • the pharmaceutical composition of the present invention when the pharmaceutical composition of the present invention is administered, the patient's coagulation factor VIII activity is above 30%, such as 50% or 80%.
  • Scheme 1 A pharmaceutical composition containing citric acid, paeoniflorin and gallic acid in a weight ratio of about 100:(1-8):(0.1-5), preferably about 100:(1.5-7.5): (0.2 to 4), more preferably about 100: (2 to 7): (0.5 to 3.5).
  • Scheme 2 The pharmaceutical composition of Scheme 1, wherein the weight ratio of paeoniflorin to gallic acid is about (1-6):1, preferably about (1-5):1, more preferably about (1-4) ):1.
  • Scheme 3 The pharmaceutical composition of Scheme 1, wherein the weight ratio of citric acid, paeoniflorin and gallic acid is about 100:(2 ⁇ 6.5):(0.5 ⁇ 3), and the weight ratio of paeoniflorin to gallic acid is Approximately (1.5 ⁇ 3.5):1.
  • Scheme 4 The pharmaceutical composition of Scheme 1, wherein the weight ratio of citric acid, paeoniflorin and gallic acid is about 100:(2 ⁇ 6):(1 ⁇ 2), and the weight ratio of paeoniflorin to gallic acid is Approximately (2 ⁇ 3):1.
  • Scheme 5 The pharmaceutical composition of Scheme 1, wherein the weight ratio of citric acid, paeoniflorin, and gallic acid is about 100:4:1.5, 100:5.6:2, 100:2.2:1, 100:3.6:1.8, 100:3.6:1.3, 100:2:1.2, 100:6.2:2, 100:2.5:0.8, 100:5.3:2.6, preferably about 100:4:1.5, 100:5.6:2 or 100:2.2:1 , Especially preferably about 100:4:1.5.
  • Scheme 6 A preparation comprising the pharmaceutical composition according to any one of Schemes 1-5 and pharmaceutically acceptable excipients.
  • Scheme 7 The formulation of Scheme 6, which is an injection.
  • Scheme 8 The formulation of Scheme 7, which comprises the pharmaceutical composition and water for injection.
  • Scheme 9 The injection according to Scheme 7 or 8, which is in a 5 mL or 10 mL dosage format and contains 132 mg ⁇ 0.5 mg or 264 mg ⁇ 0.5 mg of the pharmaceutical composition, respectively.
  • Scheme 10 Use of the pharmaceutical composition of any one of schemes 1-5 in the preparation of a medicament for treating rectal hemangioma or hemorrhoids.
  • Scheme 11 The use of Scheme 10, wherein the drug is used for patients who are not suitable for surgery.
  • Scheme 12 The use of Scheme 11, wherein the patients who are not suitable for surgery include patients with bleeding tendency, hypertension, diabetes, portal hypertension, renal dysfunction, myasthenia gravis, immunodeficiency, and patients who are receiving chemotherapy and radiotherapy.
  • Scheme 13 The use of Scheme 12, wherein the patients with bleeding tendency include patients with coagulation dysfunction (such as aplastic anemia, leukemia or hemophilia patients), receiving antithrombotic therapy (such as cardiac stent surgery, heart disease) Patients after cardiac surgery, myocardial infarction, cerebral infarction).
  • patients with coagulation dysfunction such as aplastic anemia, leukemia or hemophilia patients
  • receiving antithrombotic therapy such as cardiac stent surgery, heart disease
  • Scheme 14 The use of Scheme 12, wherein the immunodeficiency patients include AIDS and systemic lupus erythematosus patients.
  • Scheme 15 The use of any one of schemes 10-14, wherein the drug is used to treat rectal hemangioma.
  • Scheme 16 The use of any one of Schemes 10-14, wherein the drug is used to treat hemorrhoids in patients with coagulopathy (such as aplastic anemia, leukemia, or hemophilia).
  • coagulopathy such as aplastic anemia, leukemia, or hemophilia
  • Scheme 17 The pharmaceutical composition according to any one of schemes 1-5 or the preparation according to any one of schemes 6-9, which is used to treat rectal hemangioma or hemorrhoids.
  • Scheme 18 Use of the pharmaceutical composition or preparation of Scheme 17, which is used to treat patients who are not suitable for surgery.
  • Scheme 19 Use of the pharmaceutical composition or preparation of Scheme 18, wherein the patients who are not suitable for surgery include bleeding tendency, hypertension, diabetes, portal hypertension, renal dysfunction, myasthenia gravis, immunodeficiency, and those who are receiving radiotherapy Patients on chemotherapy.
  • Scheme 20 Use of the pharmaceutical composition or preparation of Scheme 19, wherein the patients with bleeding tendency include patients suffering from coagulopathy (such as aplastic anemia, leukemia or hemophilia), receiving antithrombotic therapy (such as cardiac Patients after stenting, pacemaker surgery, myocardial infarction, cerebral infarction).
  • coagulopathy such as aplastic anemia, leukemia or hemophilia
  • antithrombotic therapy such as cardiac Patients after stenting, pacemaker surgery, myocardial infarction, cerebral infarction.
  • Scheme 21 Use of the pharmaceutical composition or preparation of Scheme 19, wherein the immunodeficiency patients include AIDS and systemic lupus erythematosus patients.
  • Scheme 22 Use of the pharmaceutical composition or preparation of any one of schemes 17-21, which is used to treat rectal hemangioma.
  • Scheme 23 Use of the pharmaceutical composition or preparation of any one of schemes 17-21 for the treatment of hemorrhoids in patients with coagulation dysfunction (such as aplastic anemia, leukemia or hemophilia).
  • coagulation dysfunction such as aplastic anemia, leukemia or hemophilia.
  • Scheme 24 A method for treating rectal hemangioma or hemorrhoids in a patient, comprising the pharmaceutical composition of any one of regimens 1-5 or the preparation of any one of regimens 6-9.
  • Scheme 25 The method of Scheme 24, in which the patient is a patient who is not suitable for surgery.
  • Scheme 26 The method of Scheme 25, wherein the patients who are not suitable for surgery include patients with bleeding tendency, hypertension, diabetes, portal hypertension, renal dysfunction, myasthenia gravis, immunodeficiency, and patients who are receiving chemotherapy and radiotherapy.
  • Scheme 27 The method of Scheme 26, wherein the patients with bleeding tendency include patients with coagulopathy (such as aplastic anemia, leukemia or hemophilia patients), receiving antithrombotic therapy (such as cardiac stent surgery, heart disease) Patients after cardiac surgery, myocardial infarction, cerebral infarction).
  • patients with coagulopathy such as aplastic anemia, leukemia or hemophilia patients
  • antithrombotic therapy such as cardiac stent surgery, heart disease
  • Scheme 28 The method of Scheme 26, wherein the immunodeficiency patients include AIDS and systemic lupus erythematosus patients.
  • Scheme 29 A method for treating rectal hemangioma in a patient, comprising the pharmaceutical composition of any one of regimens 1-5 or the preparation of any one of regimens 6-9.
  • Scheme 30 A method for treating hemorrhoids in patients with coagulopathy (such as aplastic anemia, leukemia, or hemophilia), including the pharmaceutical composition of any one of dosing regimens 1-5 or regimens 6-9 Any formulation.
  • coagulopathy such as aplastic anemia, leukemia, or hemophilia
  • Scheme 31 The method of any one of Schemes 24-30, wherein the administered pharmaceutical composition or preparation is an injection in water for injection, wherein the drug concentration is 22-30 mg/mL, preferably 24-27 mg/mL, preferably 26.5 mg/mL.
  • Scheme 32 The method of Scheme 31, wherein the injection is used after being diluted with a volume ratio of 1: (0.8 to 1.2), preferably 0.5% to 1% of lidocaine at 1:1.
  • Scheme 33 The method of Scheme 31 or 32, wherein the injection is injected to the patient 1-3 times, preferably once.
  • Scheme 34 A method for treating hemorrhoids in patients with coagulation dysfunction, including the pharmaceutical composition of any one of regimens 1-5 or the preparation of any one of regimens 6-9, including the following steps:
  • the patient adopts the side lying position, the folding knife position and the bladder lithotomy position and other treatment positions, routine disinfection, and then anal local anesthesia or anal canal anesthesia, anesthetic with 0.5-1% lidocaine;
  • stage III hemorrhoids Retract anoscopy to expose the hemorrhoids, and the injection method for stage III hemorrhoids is the same as that of stage I and II;
  • Each patient is about 10-20ml at a time, with an average of 15ml, and the maximum dosage does not exceed 40ml;
  • Each patient generally only has one injection.
  • Scheme 35 The method of Scheme 34, wherein the patient is a patient with aplastic anemia, leukemia, or hemophilia.
  • Example 1 Cockscomb hemangioma model experiment
  • Test drug Each component of the drug composition is commercially available. Mix citric acid, paeoniflorin, and gallic acid according to the ratio described in the following table to obtain compositions 1-9 of group A-I, respectively. Then, each composition was dissolved in water for injection to obtain an injection with a concentration of 13.2 mg/mL.
  • the positive control group used polycinnamyl alcohol injection (specification: 10 mL: 100 mg, Shaanxi Tianyu Pharmaceutical Co., Ltd.) as a hardening agent, and was prepared into a 5 mg/ml injection with water for injection before use.
  • Table 1 The distribution ratio (weight ratio) of each group in the pharmaceutical composition
  • the clean-grade male Laihen chickens were selected and randomly divided into a blank control group, a positive control group and a pharmaceutical composition A-I group, a total of 11 groups, each with 8 chickens.
  • Four points were selected for the cockscomb of each rooster as the drug injection point, and the cockscomb was observed, photographed, and taken before the experiment and 3 days, 7 days, 14 days, and 28 days after the experiment.
  • the thickness of the comb is 8-10mm, only one side of the comb is injected subcutaneously, and the non-injected side of the contralateral side is used as the self-control group. After the injection, continue to raise under uniform conditions, eat and drink freely until the material is obtained.
  • the observation contents include: the color change of the comb, whether the epidermis has white spots, whether it is edema, whether there is tissue necrosis on the surface, whether there is scab, whether there is scar, and whether the scab falls off, and the time distribution of fall off.
  • the pictures were taken and recorded at four time points, 3 days, 7 days, 14 days, and 28 days after the drug injection.
  • the experimental cock was anesthetized and the tissues at the injection site were cut and examined by light microscope.
  • the tissues at the injection site were cut out, fixed in 10% neutral formaldehyde fixative for 48 hours, embedded in paraffin, tissue sections, conventional HE staining, and light microscopy examine.
  • the TUNEL method is used for cell apoptosis detection, including cell detection and tissue specimen detection.
  • the principle is that deoxyuridine triphosphate is catalyzed by deoxyribonucleotide terminal transferase and connects to the 3'-OH end of broken DNA in apoptotic cells, and then deoxyuridine triphosphate is also bound to horseradish peroxidase.
  • deoxyuridine triphosphate is catalyzed by deoxyribonucleotide terminal transferase and connects to the 3'-OH end of broken DNA in apoptotic cells, and then deoxyuridine triphosphate is also bound to horseradish peroxidase.
  • the combination of luciferin antibody and horseradish peroxidase substrate diaminobenzidine can accurately locate apoptotic cells.
  • Five fields of view are randomly selected under the field of view, and the image is analyzed using Tmage Proplus 6.0 software.
  • the treated combs of the blank control group showed no abnormal changes after naked eye observation.
  • Positive control group White skin hills can be seen at the injection site after the drug injection; 3 days after the injection, the drug injection site was dark red with mild edema; 7 days after the injection, the drug injection site was light yellow and the edema decreased; 14 days after the injection, the center of the drug injection site Part of the scab was black, and the surrounding part was yellow, and the edema gradually decreased. 28 days after the injection, the black scab at the injection site was light yellow, with no edema or scar; the appearance of the comb remained normal throughout the experiment.
  • the overall condition of the AI group of the pharmaceutical composition was similar to that of the positive control group.
  • the blank control group showed neatly arranged epithelial cells, abundant subcutaneous capillaries, regular morphology, loose connective tissue and adipose tissue, and some collagen fibers were seen between the blood vessels.
  • the overall trend of each group was that the capillaries gradually decreased, the collagen fibers gradually increased, and the changes of inflammatory cell infiltration and interstitial edema appeared in the early stage.
  • Positive control group Subcutaneous capillaries were destroyed and fused 3 days after injection, inflammatory cells in the peripheral tissues were infiltrated, interstitial edema was obvious, and a small amount of collagen fibers proliferated; 7 days later, capillaries were further reduced, collagen fibers were further proliferated, and inflammatory cells infiltrated and interspersed. The qualitative edema has been reduced; 14 days later, the number of blood vessels continued to decrease, and collagen fibers continued to proliferate; after 28 days, the capillaries were significantly reduced, and they were filled with a large number of collagen fibers.
  • the overall situation of the pharmaceutical composition A-I group is similar to that of the positive control group; and compared with the D-I group, the number of capillaries in the ABC group is reduced and the proliferation of collagen fibers is more obvious.
  • Table 7 The internal and external conditions of subcutaneous capillary lumen of cockscomb after drug injection
  • the capillary reduction of cockscomb was observed at the four time points of 3d, 7d, 14d, 28d after drug injection, as shown in Table 8.
  • Each group showed a trend of gradual increase in capillary reduction, and the capillary reduction in each group was more obvious in the first 7 days , After 7 days, the capillary decreases and slows down.
  • the A-I group significantly reduced the number of capillaries, and reached a significant difference P ⁇ 0.05 after 7 days, and reached a significant difference P ⁇ 0.01 after 14 days.
  • a significant difference P ⁇ 0.05 was reached after 3 days, and a significant difference P ⁇ 0.01 after 7 days.
  • the decrease in the number of capillaries is basically consistent with the results of visual inspection and histopathology of the comb.
  • the details of the results obtained through 2.3.2 HE staining and 2.3.4 computer image analysis are shown in Table 8 below.
  • compositions 1-9 of the present invention can all have significant effects on cockscombs, such as reducing the number of capillaries, proliferating collagen fibers, and apoptotic vascular endothelial cells.
  • cockscombs such as reducing the number of capillaries, proliferating collagen fibers, and apoptotic vascular endothelial cells.
  • the composition 1-3 in the cockscomb hemangioma model, it has a better effect in the disappearance time of the vascular wall structure, damages the vascular endothelium and induces the apoptosis of capillary endothelial cells, and reduces the number of capillaries. Will not change the shape of the comb.
  • citric acid, paeoniflorin and gallic acid produces a synergistic effect, especially when the weight ratio of citric acid, paeoniflorin, and gallic acid is about 100:(2.2 ⁇ 5.7):(1 ⁇ 2), and The weight ratio of paeoniflorin and gallic acid is about (2.31-2.89):1 o'clock.
  • Clinical case 1 Treatment of rectal hemangioma
  • the main symptoms hematochezia, anemia and blood in the stool.
  • the blood in the stool is persistent, and the bleeding is dark red or bright red.
  • Fiber colonoscopy was performed before treatment. It was characterized by ring-shaped, irregular purple bumps in the rectum, smooth mucosal surface, mucosal erosion accompanied by active bleeding, and the diagnosis was rectal hemangioma.
  • Treatment method The injection (concentration 2.635%) of the pharmaceutical composition 1 of the present invention and 0.5% lidocaine are prepared as a 1:1 mixture according to the volume ratio.
  • the patient takes a folding knife position, the protective film pulls both buttocks to expose the anus, and the anus automatic retractor is used to expose the lesion area.
  • the normal rectal mucosa at 0.5 cm from the edge of the hemangioma is punctured with a No. 7 puncture needle in the direction of the center of the hemangioma , As deep as the muscle layer, and when there is no blood in the withdrawal, inject the above-prepared mixed solution and inject it at points along the edge of the hemangioma, and inject about 5 mL of the mixed solution in total.
  • the main symptoms the perianal mass prolapsed after defecation, and can be absorbed by itself, accompanied by bleeding for two days, each bleeding about 3mL, the local clinic prescribed oral medications, and the symptoms were relieved, but the symptoms were not controlled.
  • Treatment method conventional disinfection, or anal canal anesthesia.
  • the injection of the pharmaceutical composition 1 of the present invention (concentration 2.635%) and 0.5% lidocaine were prepared as a 1:1 mixture according to the volume ratio, and the hemorrhoids were exposed under anoscope, and the raised part of the hemorrhoids surface was obliquely A needle is inserted, and the amount of injection at each location is that the hemorrhoids are uniform, full, and filled, and the surface mucosa is pink. A total of about 10 mL is injected.

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Abstract

一种药物组合物，该药物组合物包含柠檬酸、芍药苷和没食子酸，其中柠檬酸、芍药苷和没食子酸的重量比为约100:(1~8):(0.1~5)。还提供了该药物组合物治疗直肠血管瘤的用途，以及在白血病及血友病患者中治疗痔疮的用途。

Description

一种药物组合物及其应用 技术领域
本发明属于医药技术领域。具体地，本发明涉及一种药物组合物，以及该药物组合物在治疗直肠血管瘤、痔疮中的用途，尤其是在不宜手术治疗的患者中使用，具体如治疗白血病和血友病患者的痔疮。
背景技术
直肠血管瘤是一种非单一细胞的良性肿瘤，主要细胞成分包括内皮细胞、成纤维细胞、脂肪细胞等。直肠血管瘤病因尚不明确，一般认为是起源于中胚层胚胎残余的错构瘤，是一种非常罕见的血管良性病变。直肠血管瘤的临床表现缺乏特异性，主要临床表现为反复无痛性便血，部分患者有腹痛、肛周坠胀等不适，反复发作，病程长，进行性加重，多有慢性贫血的临床表现。由于部分临床表现与痔疮相似，容易被误诊为痔疮或直肠炎症。
直肠血管瘤的治疗目前主要为硬化剂注射治疗。硬化剂的作用原理为：硬化剂作用于局部组织后，首先破坏内皮细胞，促使组织发生不同程度的肿胀、变性、坏死、炎症细胞浸润，继而产生纤维化，成纤维化细胞增生，并导致血管紧缩、闭塞或栓塞，然后致使组织萎缩、脱落，从而将血管瘤逐步消退。虽然硬化剂治疗效果显著、操作简单，无需复杂设备，但是术中、术后出血多，且易复发。而且也会造成局部静脉炎，造成炎症反应，甚至会出现感染坏死等严重不良反应。
痔疮是一种位于肛门部位的常见疾病，任何年龄都可发病，但随着年龄增长，发病率逐渐增高。关于痔的病因主要有两种学说，一种是静脉曲张学说，认为痔是直肠下段黏膜下和肛管皮肤下的静脉丛淤血、扩张和屈曲所形成的静脉团；另一种是目前广为接受的理论Thomson肛垫下移学说，认为痔疮原本是肛管部位正常的解剖结构，即血管垫，是齿状线及以上1.5cm的环状海绵样组织带。
痔疮的治疗包括手术治疗和非手术治疗两种，其中以手术治疗为主，包括血栓性外痔剥离术、传统痔切除术、痔环切术和PPH手术；非手术治疗又包括局部用药治疗、口服药物治疗、物理疗法、胶圈套扎以及注射疗法，常规的注射疗法为将硬化剂注射于黏膜下层静脉丛周围，使引起炎症反应及纤维化，从而压闭曲张的静脉，但硬化剂注入黏膜层会造成坏死。
血友病为一组遗传性凝血功能障碍的出血性疾病，其共同的特征是活性凝血活酶生成障碍，凝血时间延长，终身具有轻微创伤后出血倾向，重症患者没有明显外伤也可发生“自发性”出血。病情严重的患者只要皮肤受到轻微创伤就会流血不止。血友病伴痔疮患者除了痔疮患者的一般症状外，尤其严重的是出血风险。血友病伴痔疮患者在进行痔疮手术后，容易发生反复大出血，使患者十分恐惧，给患者的心理及身体造成重创；而且需要反复手术，还带来额外经济负担。此外，对于结肠造口也给患者带来生活和护理的不便。因此，此类患者进行手术治疗的风险比较大，比较严重的患者容易致死，而且需要注射昂贵的凝血因子。
白血病是一类造血干细胞恶性克隆性疾病。因为增殖失控、分化障碍、凋亡受阻等机制，白血病细胞在骨髓和其他造血组织中大量累积，并浸润其他非造血组织和器官，同时抑制正常造血功能。白 血病与血友病类似都属于血液方面的疾病，治疗原则为消灭白血病细胞群体和控制白血病细胞的大量增生。因而，与血友病伴痔疮相似，白血病伴痔疮也会产生出血风险。针对白血病伴痔疮的患者进行手术治疗时，一方面由于其凝血功能问题，会引起出血不止，另一方面由于免疫功能下降，可能引起肛周感染，波及全身感染，或诱发败血症而危及生命。
手术治疗往往对患者造成较大损伤，导致抵抗力下降，产生并发症等不良后果。除上述患有血友病、白血病等凝血功能障碍的患者不宜手术治疗外，医疗实践证明具有出血倾向(患有凝血功能障碍(如再生障碍性贫血、白血病或血友病患者)、接受抗栓治疗(如心脏支架术后、心脏起搏器术后、心肌梗塞、脑梗塞)的患者)、高血压、糖尿病、门脉高压、肾功能障碍、重症肌无力、免疫缺陷(如艾滋病、系统性红斑狼疮)，以及正在接受放化疗的患者也不宜进行手术。对于这些患者如果同时患有直肠血管瘤或者痔疮，则不宜进行手术治疗。
目前，对于直肠血管瘤、不宜手术治疗患者伴有的痔疮尚无可靠的治疗方法。因此，迫切需要找到一种不需要手术便能治疗的方法。
发明内容
本发明人在现有技术的基础上进行了研究，发现使用柠檬酸、没食子酸和芍药苷的三组分组合物(尤其是注射剂)可以治疗上述疾病，取代手术治疗。
柠檬酸、没食子酸和芍药苷的组合物不同于硬化剂的坏死或硬化机理，而是经过组织蛋白凝固、裂解、吸收、毛细血管新生这一系列变化而使整个直肠血管瘤或痔核“萎缩”，达到治疗后不留硬结和其他后遗症，同时也大大降低了出血风险；其中，有机酸柠檬酸、没食子酸使血管收缩、血流量下降、血管通透性下降，凝血时间缩短，促进血管破损处血小板凝聚，大血管壁凝固变性，间质组织凝固变性、组织崩解；而芍药苷活血化瘀、抑制急性炎症反应，促进间质纤维细胞增生，诱导巨噬细胞清除崩解组织，促进毛细血管增生，抑制增生性瘢痕成纤维。
此外，本发明人还发现，特定的柠檬酸、没食子酸和芍药苷比例，以及没食子酸和芍药苷比例能产生协同作用，取得更好的治疗效果。
因此，在一个方面，本发明提供了一种药物组合物，其含有柠檬酸、芍药苷和没食子酸，其重量比为约100:(1～8):(0.1～5)。
在另一个方面，本发明提供了一种制剂，其中包含本发明所述的药物组合物，以及药学上可接受的辅料。
在另一个方面，本发明提供了本发明所述的药物组合物在制备用于治疗直肠血管瘤或痔疮的药物中的用途。
在另一个方面，本发明提供了本发明所述的药物组合物，其用于治疗直肠血管瘤或痔疮。
在另一个方面，本发明提供了一种治疗直肠血管瘤或痔疮的方法，包括给药本发明所述的药物组合物或本发明所述的制剂。
具体实施方案
定义
除非另有说明，本文使用的所有技术和科学术语具有与本发明所属领域的技术人员通常理解相同的含义，但如有冲突，则以本说明书中的定义为准。
如说明书和权利要求书中所用，单数形式“一”、“一个”和“该(所述)”包括复数形式，除非上下文另有明确说明。
如无特殊说明，本说明书中的百分比(％)均为重量百分比(重量％)。
在说明书和权利要求书中使用的涉及组分量的所有数值或表述在所有情形中均应理解被“约”修饰。术语“约”当指数量或数值范围时，意思是所指数量或者数值范围是在统计学实验误差内的近似值，因此该数量或者数值范围可以在所述数量或数值范围的例如±5％之间变化。
涉及相同组分的所有范围均包括端点，该端点可独立地组合。由于这些范围是连续的，因此它们包括在最小值与最大值之间的每一数值。还应理解的是，本申请引用的任何数值范围预期包括该范围内的所有子范围。
本发明使用的缩写具有在医药、化学、生物领域的通常含义。
活性成分
柠檬酸
柠檬酸又称枸橼酸，化学名称为2-羟基丙烷-1,2,3-三羧酸。柠檬酸在自然界中分布很广，天然的柠檬酸存在于植物如柠檬、柑橘、菠萝等果实和动物的骨骼、肌肉、血液中。柠檬酸为可食用酸类，主要用于食品工业，如酸味剂、增溶剂、缓冲剂、抗氧化剂、除腥脱臭剂、风味增进剂、胶凝剂、调色剂等。在某些食品中加入柠檬酸后口感好，并可促进食欲，在果酱、饮料、罐头和糖果中经常使用。
芍药苷
芍药苷，来源于芍药科植物芍药根、牡丹根、紫牡丹根，具有以下化学结构：
Figure PCTCN2021072630-appb-000001
芍药苷毒性很低，在正常情况下无明显不良反应。芍药苷可抗组织细胞氧化应激损伤、抑制星形胶质细胞的激活、增强保护神经，对于纹状体及黑质多巴胺能神经细胞的损伤具有明显的拮抗作用，并可改善运动迟缓，因而可用于治疗阿尔茨海默症、帕金森病、癫痫等脑部疾病。此外，芍药苷还可以抗肿瘤、类风湿关节炎和强直性脊柱炎等自身免疫性疾病。动物实验还证明芍药苷可明显降低血糖含量、对心肺细胞具有重要的保护作用。
没食子酸
没食子酸又称五倍子酸。化学名为3,4,5-三羟基苯甲酸。广泛存在于掌叶大黄、大叶桉、山茱萸等植物中，是自然界存在的一种多酚类化合物，在食品、生物、医药、化工等领域有广泛的应用。
没食子酸具有抗炎、抗突变、抗氧化、抗自由基等多种生物学活性；同时没食子酸具有抗肿瘤作用，可以抑制肥大细胞瘤的转移，从而延长生存期；也是相对适宜的杀锥虫候选药物；对肝脏具有保护作用，可以抵抗四氯化碳诱导的肝脏生理和生化的转变；可以通过抑制内皮NO的生成诱导血管内皮依赖性收缩和对内皮依赖性松弛。
三种成分的作用机理为：有机酸柠檬酸、没食子酸使血管收缩、血流量下降、血管通透性下降，凝血时间缩短，促进血管破损处血小板凝聚，大血管壁凝固变性，间质组织凝固变性、组织崩解；而芍药苷活血化瘀、抑制急性炎症反应，促进间质纤维细胞增生，诱导巨噬细胞清除崩解组织，促进毛细血管增生，抑制增生性瘢痕成纤维。
药物组合物和制剂
在本发明中的组合物中，三种成分以特定的比例混合后，产生减少毛细血管数量、增生胶原纤维、凋亡血管内皮细胞等生物作用。当柠檬酸、没食子酸和芍药苷的重量比在特定范围时，以上生物作用更为明显。
在本发明的一个具体实施方案中，柠檬酸、没食子酸和芍药苷的重量比为约100:(1～8):(0.1～5)；在另一个具体实施方案中，三者的重量比为约100:(1.5～7.5):(0.2～4)；在另一个具体实施方案中，三者的重量比为约100:(2～7):(0.5～3.5)；在另一个具体实施方案中，三者的重量比为约100:(2～6.5):(0.5～3)；在另一个具体实施方案中，三者的重量比为约100:(2～6):(1～2)。
在上述具体比例中，没食子酸和芍药苷的特定比例也是关键的。因而，在本发明的一个具体实施方案中，芍药苷与没食子酸的重量比为约(1～6):1；在另一个具体实施方案中，二者的重量比为约(1～5):1；在另一个具体实施方案中，二者的重量比为约(1～4):1；在另一个具体实施方案中，二者的重量比为约(1.5～3.5):1；在另一个具体实施方案中，二者的重量比为约(2～3):1。
在更具体的实施方案中，柠檬酸、没食子酸和芍药苷的重量比为约100:4:1.5、100:5.6:2、100:2.2:1、100:3.6:1.8、100:3.6:1.3、100:2:1.2、100:6.2:2、100:2.5:0.8和100:5.3:2.6，优选为约100:4:1.5、100:5.6:2和100:2.2:1，尤其优选为约100:4:1.5。
注射剂
本发明的药物组合物优选以注射剂的形式使用。
注射剂是指药物制成的供注入体内的无菌溶液(包括乳浊液和混悬液)以及供临用前配成溶液或混悬液的无菌粉末或浓溶液。主要包括液体注射剂、注射用粉剂、注射用片剂等。
液体注射剂也称为注射液，俗称“水针”。系将药物配制成溶液(水性或非水性)、悬液或乳浊液，装入安瓿或多剂量容器中而成的制剂。一般水溶性药物要求在注射后达到速效，故多配成水溶液或水的复合溶液(如水溶液中另加乙醇、丙二醇、甘油等)。有些药物不宜制成水溶液，如在水中难 溶或为注射后能延长药效等，可制成油溶液、水或油混悬液、乳浊液。但这些注射液一般仅供肌肉注射用。
注射用粉剂，俗称“粉针”。某些药物稳定性较差，制成溶液后易于分解变质。这类药物一般可采用无菌操作法，将供注射用的灭菌粉状药物装入安瓿或其他适宜容器中，临用时用适当的溶媒溶解或混悬。
注射用片剂是指药物用无菌操作法制成的模印片或机压片，临用时用注射用水溶解，供皮下或肌肉注射之用。
注射剂的制备方法
a.在温度为20～25℃、相对湿度为45％～65％的洁净室内，称取没食子酸3.75g、芍药苷10g、柠檬酸250g；
b.将上述三个原料加入配液装置中；
c.调整配液装置内的温度为40～50℃，加入注射用水至配液装置内药液的总重量为100kg，保持配液装置内气压、温度稳定；
d.搅拌3～10分钟，调整配液装置内的温度为15～25℃，过滤；
e.将d所得产物无菌灌封装成10mL/支的注射液，100℃检漏、负压60Kpa湿热灭菌20分钟，检验、包装，即得。
治疗方法和用途
本发明所述的“方法”或“用途”是指将本发明药物组合物给予具有相应疾病或该疾病倾向的受试者，其目的为赋予治疗效果，例如治愈、缓解、改变、影响、改善或预防上述疾病的症状或倾向。本领域技术人员，能根据所治疗的疾病的类型、给药途径、赋形剂的使用容易确定具体的有效剂量，该剂量可能会因为同时使用其他药物而有所差异。
疾病
直肠血管瘤
直肠血管瘤是一种先天性非遗传性疾病，临床少见。因其非进行性生长的特点，通常认为直肠血管瘤属错构瘤，而不是肿瘤新生物。本病好发于直肠。10～20岁青少年多见，男性多于女性。根据血管瘤内血管的形态可分为3类：毛细血管状血管瘤、海绵状血管瘤、混合血管瘤。
直肠血管瘤的发病原因尚不清楚，通常认为起源于胚胎性血管错构芽，在某种因素的作用下，导致肿瘤样增生。毛细血管状血管瘤引起缓慢出血，海绵状血管瘤引起大量出血，逐渐严重，出血频繁。息肉型结肠血管瘤因肠套叠可引起肠梗阻，少数出现肠扭转。广泛弥漫型直肠血管瘤的表现为全身凝血机制障碍，加重肠道出血，伴有血小板减少症、低纤维蛋白原血症以及血中凝血因子V和VIII水平降低等。在直肠血管瘤切除后均可恢复正常。
直肠血管瘤的临床表现因血管瘤的类型、大小和所在部位不同而异。对家族内有血管瘤病史，黏 膜或皮肤有类似病变，伴便血、贫血和肠梗阻体征者，尤其是幼儿或青年，应考虑本病的可能性。纤维内镜、下消化道造影以及肠系膜动脉造影等，可作为病变定位和诊断依据。本病应与内、外痔，结直肠炎、溃疡，直肠绒毛状腺瘤、直肠息肉以及肛门直肠脱垂等相区别。
直肠血管瘤需积极治疗，在未治的病人中，40％的患者死于血管瘤引起的出血。根据病人的全身状况、血管瘤的大小、部位可采用非手术治疗或手术治疗。
1.非手术治疗
非手术治疗包括硬化剂注射、冷冻、透热或电灼、电凝等疗法，使瘤体纤维化，达到缩小肿瘤、停止出血的目的。适用于部位比较低的血管瘤、全身情况较差、不能耐受手术切除的直肠血管瘤患者。止血效果在短期内较好，长期效果和根治性差，复发率高。
2.手术治疗
治疗直肠血管瘤的最佳方法是手术切除。结肠血管瘤可行部分肠段切除；直肠的小血管瘤可行局部黏膜下切除，保留肌层和浆膜；直肠上端的病变经腹行直肠前切除术；弥漫型或多发型直肠中下段病变，最佳手术方式为直肠腹会阴联合切除术，但由于多数患者为青年人，对永久性腹部结肠造口难以接受，引起术后性功能障碍，因而应避免。
痔疮
痔(俗称痔疮)是一种位于肛门部位的常见疾病，任何年龄都可发病，但随着年龄增长，发病率逐渐增高。
关于痔的病因主要有两种学说。首先是静脉曲张学说，认为痔是直肠下段黏膜下和肛管皮肤下的静脉丛淤血、扩张和屈曲所形成的静脉团。然而目前广为接受的理论是Thomson的肛垫下移学说，认为痔原本是肛管部位正常的解剖结构，即血管垫，是齿状线及以上1.5cm的环状海绵样组织带。只有肛垫组织发生异常并合并有症状时，才能称为痔，才需要治疗，治疗目的是解除症状，而非消除痔体。
无症状的痔不需治疗；有症状的痔无需根治；以非手术治疗为主。
1.非手术治疗
(1)局部用药治疗：已被广泛采用，药物包括栓剂、膏剂和洗剂，多数含有中药成分。
(2)口服药物治疗：一般采用治疗静脉曲张的药物。
(3)注射疗法：将硬化剂注射于黏膜下层静脉丛周围，使引起炎症反应及纤维化，从而压闭曲张的静脉；但硬化剂注入黏膜层会造成坏死。
(4)物理疗法：激光治疗、冷冻疗法、直流电疗法和铜离子电化学疗法、微波热凝疗法、红外线凝固治疗，较少用。
(5)胶圈套扎：套扎痔根部，阻断其血供以使痔脱落坏死；对于巨大的内痔及纤维化内痔更适合。
2.手术治疗
(1)血栓性外痔剥离术：适用于血栓性外痔保守治疗后疼痛不缓解或肿块不缩小者。
(2)传统痔切除术：即外剥内扎术。
(3)痔环切术(Whitehead术)：教科书上的经典术式，易导致肛门狭窄，目前临床很少应用。
(4)PPH手术：吻合器痔上直肠黏膜环切钉合术。为意大利Longo医生所创，1998年开始推广，主要适用于脱垂型III-IV度混合痔、环形痔，以及部分出血严重的II度内痔。PPH治疗脱垂痔的机理：环形切除直肠下端2～3厘米黏膜和黏膜下组织，恢复正常解剖结构，即肛垫回位；黏膜下组织的切除，阻断了痔上动脉对痔区的血液供应，使术后痔体萎缩。PPH手术与传统痔切除术相比，手术时间短、术后疼痛轻、恢复快、并发症少，但器械的价格较昂贵。
患者
不宜手术治疗的患者
由于具有出血倾向、伤口愈合慢、继发性感染、身体情况差等原因，一些患者不宜进行手术治疗。这些患者主要包括：具有出血倾向(患有凝血功能障碍(如再生障碍性贫血、白血病或血友病患者)、接受抗栓治疗(如心脏支架术后、心脏起搏器术后、心肌梗塞、脑梗塞)的患者)、高血压、糖尿病、门脉高压、肾功能障碍、重症肌无力、免疫缺陷(如艾滋病、系统性红斑狼疮)，以及正在接受放化疗的患者。
出血倾向的患者
出血倾向是指皮肤、粘膜自发性出血，或当微小血管遭受轻微创伤后，出血不易自行停止的一种临床表现。
出血倾向的原因一般分为凝血功能异常、血小板异常、血管壁功能异常3类。凝血功能障碍是指凝血因子缺乏或功能异常所致的出血性疾病。主要包括血友病、维生素K缺乏症、严重肝病所致的凝血异常。血小板异常主要包括血小板减少、血小板功能障碍等。血管壁功能异常例如过敏性紫癜。
此外，一些其他疾病及其治疗过程也会导致出血倾向。例如，白血病患者常见的症状之一是血小板减少，继发出血倾向。又如，各种心脑血管疾病诸如冠心病、心脏搭桥术后、冠脉支架术后、心脏瓣膜置换术及大血管疾病术后等，因治疗需要长期服用阿司匹林、华法林等抗栓药物，而抗栓药物的使用导致了出血倾向。
血友病伴痔疮
血友病为一组遗传性凝血功能障碍的出血性疾病，其共同的特征是活性凝血活酶生成障碍，凝血时间延长，终身具有轻微创伤后出血倾向，重症患者没有明显外伤也可发生“自发性”出血。血友病是一组性联隐性遗传的出血病。其临床上分为血友病A和血友病B两型，分别由凝血因子VIII和凝血因子IX基因突变所致。
血友病患者罹患痔疮后，其治疗较普通人更困难。血友病患者进行手术治疗的风险比较大，容易导致出血，情况比较严重的患者容易致死。血友病患者在进行痔疮治疗时，需要注射昂贵的凝血因子；在进行手术治疗时，除了凝血因子外，还需要准备新鲜血浆，以备术后出血不止。
白血病伴痔疮
白血病是一类造血干细胞恶性克隆性疾病。因为增殖失控、分化障碍、凋亡受阻等机制，克隆性白血病细胞在骨髓和其他造血组织中大量累积，并浸润其他非造血组织和器官，同时抑制正常造血功能。临床可见不同程度的贫血、出血、感染发热以及肝、脾、淋巴结肿大和骨骼疼痛。
白血病与血友病类似都属于血液方面的疾病，其一个共同点在于白血病患者血小板减少、血管的损伤和凝血功能障碍等，导致出血风险。白血病以出血为早期表现者近40％。出血可发生在全身各个部位，常见与皮肤不明原因的瘀斑、口腔、鼻腔、牙龈出血、月经过多等。视网膜模糊往往提示患者有眼底出血；剧烈的头痛拌恶心、呕吐往往提示患者有颅内出血。
若对白血病患者进行痔疮手术治疗，一方面由于其凝血功能问题，会引起出血不止；另一方面可能引起肛周感染，波及全身感染，或诱发败血症而危及生命。
给药方法
具体给药方法如下：
(1)患者采用侧卧位、折刀位及膀胱截石位等治疗体位，常规消毒，然后肛门局部麻醉或肛管麻醉，麻药用0.5-1％利多卡因；
(2)注射液使用时，用0.5％～1％的利多卡因稀释本品，其中药物与利多卡因的体积比为1:(0.8～1.2)；
(3)对I、II期内痔及静脉曲张型混合痔，在肛门镜下暴露每处痔核，于痔核表面斜刺进针；
(4)退肛门镜，暴露痔核，对III期内痔的注射方法同I、II期内痔；
(5)每位患者一次约10-20ml，平均15ml，最大用量不超过40ml；
(6)每位患者一般只注射一次。
在一个实施方案中，本发明的药物组合物给予直肠血管瘤患者。在另一个实施方案中，本发明的药物组合物给予痔疮患者。在另一个实施方案中，本发明的药物组合物给予不宜手术治疗的直肠血管瘤或痔疮患者。在另一个实施方案中，本发明的药物组合物给予具有出血倾向的直肠血管瘤或痔疮患者。在另一个实施方案中，本发明的药物组合物给予具有血友病或白血病的直肠血管瘤或痔疮患者。在另一个实施方案中，本发明的药物组合物给予接受抗栓治疗的直肠血管瘤或痔疮患者。
在上述实施方案的一个具体实施方案中，在给予本发明的药物组合物时，患者不停止原有的药物治疗，例如抗栓药物。在另一个具体实施方案中，在给予本发明的药物组合物时，患者不必补充凝血因子或进行输血。在另一个具体实施方案中，在给予本发明的药物组合物时，患者的凝血因子VIII活性在30％以上，例如50％或80％。
具体方案
本发明涉及以下技术方案：
方案1：一种药物组合物，其含有柠檬酸、芍药苷和没食子酸，其重量比为约100:(1～8):(0.1～5)，优选为约100:(1.5～7.5):(0.2～4)，更优选为约100:(2～7):(0.5～3.5)。
方案2：方案1所述的药物组合物，其中芍药苷与没食子酸的重量比为约(1～6):1，优选为约(1～5):1， 更优选为约(1～4):1。
方案3：方案1所述的药物组合物，其中柠檬酸、芍药苷和没食子酸的重量比为约100:(2～6.5):(0.5～3)，且芍药苷与没食子酸的重量比为约(1.5～3.5):1。
方案4：方案1所述的药物组合物，其中柠檬酸、芍药苷和没食子酸的重量比为约100:(2～6):(1～2)，且芍药苷与没食子酸的重量比为约(2～3):1。
方案5：方案1所述的药物组合物，其中柠檬酸、芍药苷、没食子酸的重量比为约100:4:1.5、100:5.6:2、100:2.2:1、100:3.6:1.8、100:3.6:1.3、100:2:1.2、100:6.2:2、100:2.5:0.8、100:5.3:2.6，优选为约100:4:1.5、100:5.6:2或100:2.2:1，尤其优选为约100:4:1.5。
方案6：一种制剂，其中包含方案1-5中任一项所述的药物组合物，以及药学上可接受的辅料。
方案7：方案6所述的制剂，其为注射剂。
方案8：方案7所述的制剂，其中包含所述药物组合物和注射用水。
方案9：方案7或8所述的注射剂，其为5mL或10mL剂量规格，分别含有132mg±0.5mg或264mg±0.5mg所述药物组合物。
方案10：方案1-5中任一项的药物组合物在制备用于治疗直肠血管瘤或痔疮的药物中的用途。
方案11：方案10的用途，其中所述药物用于不宜手术的患者。
方案12：方案11的用途，其中所述不宜手术的患者包括具有出血倾向、高血压、糖尿病、门脉高压、肾功能障碍、重症肌无力、免疫缺陷，以及正在接受放化疗的患者。
方案13：方案12的用途，其中所述具有出血倾向的患者包括患有凝血功能障碍(如再生障碍性贫血、白血病或血友病患者)、接受抗栓治疗(如心脏支架术后、心脏起搏器术后、心肌梗塞、脑梗塞)的患者。
方案14：方案12的用途，其中所述免疫缺陷患者包括艾滋病、系统性红斑狼疮患者。
方案15：方案10-14中任一项的用途，其中所述药物用于治疗直肠血管瘤。
方案16：方案10-14中任一项的用途，其中所述药物用于治疗凝血功能障碍(如再生障碍性贫血、白血病或血友病)患者的痔疮。
方案17：方案1-5中任一项的药物组合物或方案6-9中任一项的制剂，其用于治疗直肠血管瘤或痔疮。
方案18：方案17的药物组合物或制剂的用途，其用于治疗不宜手术的患者。
方案19：方案18的药物组合物或制剂的用途，其中所述不宜手术的患者包括具有出血倾向、高血压、糖尿病、门脉高压、肾功能障碍、重症肌无力、免疫缺陷，以及正在接受放化疗的患者。
方案20：方案19的药物组合物或制剂的用途，其中所述具有出血倾向的患者包括患有凝血功能障碍(如再生障碍性贫血、白血病或血友病患者)、接受抗栓治疗(如心脏支架术后、心脏起搏器术后、心肌梗塞、脑梗塞)的患者。
方案21：方案19的药物组合物或制剂的用途，其中所述免疫缺陷患者包括艾滋病、系统性红斑狼疮患者。
方案22：方案17-21中任一项的药物组合物或制剂的用途，其用于治疗直肠血管瘤。
方案23：方案17-21中任一项的药物组合物或制剂的用途，其用于治疗凝血功能障碍(如再生障碍性贫血、白血病或血友病)患者的痔疮。
方案24：一种在患者中治疗直肠血管瘤或痔疮的方法，包括给药方案1-5中任一项的药物组合物或方案6-9中任一项的制剂。
方案25：方案24的方法，其中患者为不宜手术的患者。
方案26：方案25的方法，其中所述不宜手术的患者包括具有出血倾向、高血压、糖尿病、门脉高压、肾功能障碍、重症肌无力、免疫缺陷，以及正在接受放化疗的患者。
方案27：方案26的方法，其中所述具有出血倾向的患者包括患有凝血功能障碍(如再生障碍性贫血、白血病或血友病患者)、接受抗栓治疗(如心脏支架术后、心脏起搏器术后、心肌梗塞、脑梗塞)的患者。
方案28：方案26的方法，其中所述免疫缺陷患者包括艾滋病、系统性红斑狼疮患者。
方案29：一种在患者中治疗直肠血管瘤的方法，包括给药方案1-5中任一项的药物组合物或方案6-9中任一项的制剂。
方案30：一种在凝血功能障碍(如再生障碍性贫血、白血病或血友病)患者中治疗痔疮的方法，包括给药方案1-5中任一项的药物组合物或方案6-9中任一项的制剂。
方案31：方案24-30中任一项的方法，其中所给药的药物组合物或制剂为注射用水中的注射剂，其中药物浓度为22-30mg/mL，优选24-27mg/mL，优选26.5mg/mL。
方案32：方案31的方法，其中所述注射剂用体积比为1:(0.8～1.2)，优选1:1的0.5％～1％的利多卡因稀释后使用。
方案33：方案31或32的方法，其中向患者注射1-3次，优选1次所述注射剂。
方案34：一种在具有凝血功能障碍的患者中治疗痔疮的方法，包括给药方案1-5中任一项的药物组合物或方案6-9中任一项的制剂，包括以下步骤：
(1)患者采用侧卧位、折刀位及膀胱截石位等治疗体位，常规消毒，然后肛门局部麻醉或肛管麻醉，麻药用0.5-1％利多卡因；
(2)注射液使用时，用0.5％～1％的利多卡因稀释本品，其中药物与利多卡因的体积比为1:(0.8～1.2)；
(3)对I、II期内痔及静脉曲张型混合痔，在肛门镜下暴露每处痔核，于痔核表面斜刺进针；
(4)退肛门镜，暴露痔核，对III期内痔的注射方法同I、II期内痔；
(5)每位患者一次约10-20ml，平均15ml，最大用量不超过40ml；
(6)每位患者一般只注射一次。
方案35：方案34的方法，其中所述患者为再生障碍性贫血患者、白血病患者或血友病患者。
实施例
实施例1：鸡冠血管瘤模型实验
1.材料
动物：清洁级、同一批次统一饲养条件饲养的来亨鸡88只，雄性，体重1000～1500g，10～12周 龄，由南京市江宁青龙山动物繁殖场动物实验中心提供。要求鸡冠丰满、光洁、红润、无病损。全部动物均在同一实验室按清洁级要求专人饲养，自由进食、饮水。实验过程符合中华人民共和国《实验动物管理条例》及伦理要求。
受试药物：药物组合物的各组分均为市售获得。按照下表所述比例，混合柠檬酸、芍药苷和没食子酸，分别得到A-I组的组合物1-9。然后将各组合物溶于注射用水，得到浓度为13.2mg/mL的注射剂。阳性对照组使用聚桂醇注射液(规格：10mL:100mg，陕西天宇制药有限公司)作为硬化剂，使用前用注射用水配制成5mg/ml的注射剂。
表1药物组合物中各组分配比(重量比)
Figure PCTCN2021072630-appb-000002
2.方法
2.1动物分组
选取清洁级雄性来亨鸡，随机分为空白对照组、阳性对照组及药物组合物A-I组，共11组，每组8只。每只公鸡鸡冠选取四个点作为药物注射点，并于实验前和实验后3天、7天、14天、28天，对鸡冠行大体观察、照相记录并取材。
2.2模型建立
速眠新0.1mg/kg肌注将实验公鸡麻醉，固定并清洁和消毒鸡冠后，在一侧鸡冠上由前至后用龙胆紫依次标记4个直径1cm的圆圈，于圆心处注射：空白对照组注射0.5mL溶剂(注射用水)，阳性对照组注射0.5mL的5mg/ml聚桂醇注射液、A-I组分别注射0.5mL相应的13.2mg/mL的组合物1-9的注射剂，以鸡冠表面组织发白并产生皮丘为标准。由于鸡冠厚度为8～10mm，故只在一侧鸡冠进行皮下注射，并以对侧未注射侧为自身对照组。注射后继续统一条件饲养，自由进食、饮水，直至取材为止。
2.3指标观察
2.3.1大体观察
药物注射前肉眼观察鸡冠大体情况，包括形状、颜色、厚度、表面情况等，并照相记录。药物注射后每天进行观察，观察内容包括：鸡冠色泽变化，表皮是否有白斑、是否水肿，表面是否有组织坏死、是否有结痂，是否有瘢痕、以及结痂是否脱落、脱落的时间分布等。于药物注射后3天、7天、 14天、28天四个时间点照相并记录，同时将实验公鸡麻醉切取注射部位组织，进行光镜检查。
2.3.2 HE染色
于药物注射后3天、7天、14天、28天，分别切取注射部位组织，放入10％中性甲醛固定液中固定48小时，石蜡包埋，组织切片，常规HE染色，进行光镜检查。
2.3.3细胞凋亡检测
采用TUNEL法进行细胞凋亡检测，包括细胞检测和组织标本检测。原理是脱氧尿苷三磷酸受脱氧核糖核苷酸末端转移酶的催化，与凋亡细胞中断裂DNA的3’-OH末端相互连接，然后脱氧尿苷三磷酸还结合于与辣根过氧化酶连接的荧光素抗体上，荧光素抗体与辣根过氧化酶底物二氨基联苯胺二者结合可准确定位凋亡的细胞。
具体地，于药物注射后3天、7天、14天、28天，分别切取注射部位组织，预处理，色缸中加入2％过氧化氢的PBS，于室温反应5min，PBS清洗；吸取多余液体，加入2滴TDT酶缓冲液，室温1-5min；用滤纸小心吸去切片周围的多余液体，立即在切片上滴加54μl TdT酶反应液，置湿盒中于37C反应1hr；将切片置于染色缸中，加入已预热到37℃的终止反应缓冲液，于37℃保温30min，每10min将载玻片轻轻提起和放下一次，使液体轻微搅动；组织切片用PBS洗3次，每次5min后，直接在切片上滴加两滴过氧化物酶标记的抗地高辛抗体，于湿盒中室温反应30min；用PBS洗4次，每次5min；在组织切片上直接滴加新鲜配制的0.05％DAB溶液，室温显色3～6min；用蒸馏水洗4次，前3次每次1min，最后1次5min；于室温用甲基绿进行复染10min。用蒸馏水洗3次，前两次将载玻片提起放下10次，最后1次静置30s。依同样方法再用100％正丁醇洗三次；用二甲苯脱水3次，每次2min，封片、干燥后，在光学显微镜下观察并记录实验结果。
2.3.4计算机图像分析
将处理好的切片按照标号排序，在光学显微镜下观察，每张切片在已调好的高倍镜视野(DABX400)下观察血管数目变化情况，TUNEL法检测观察细胞凋亡数的变化，在高倍镜视野下随机选取5个视野，采用Tmage Proplus 6.0软件对图像进行分析。
2.3.5统计学分析
所有数据均用SPSS统计学软件处理，数据用x±s表示。应用双因素方差分析做组间数据比较，P＜0.05为差异具有统计学意义。
3.结果
3.1药物注射后鸡冠大体变化
经连续动态肉眼观察，经处理后的公鸡总体情况良好，进食无异常，观察期内未发生死亡事件。
空白对照组经处理后的鸡冠经过肉眼观察无异常变化。阳性对照组：药物注射后即可见注射部位白色皮丘形成；注射3天后药物注射处呈深红色，轻度水肿；注射7天后药物注射部位呈淡黄色，水肿减退；注射14天后药物注射部位中间部分结黑色痂，周边部分呈黄色，水肿逐渐减退；注射28天后药物注射部位的黑色痂脱落，呈淡黄色，未见水肿，有瘢痕；整个实验过程中，鸡冠外形均保持正常。药物组合物A-I组总体情况与阳性对照组相似，14天部分黑色痂脱落；28天黑色痂脱落，未见 明显水肿，且无瘢痕出现；并且相比D-I组，ABC组的起效时间更快，各时间点药物对鸡冠的影响更大。
鸡冠大体变化的详细情况如下表2至表4所示。
表2药物注射后鸡冠外形情况
  0d 3d 7d 14d 28d
空白对照组 正常 正常 正常 正常 正常
阳性对照组 正常 正常 正常 正常 正常
A组 正常 正常 正常 正常 正常
B组 正常 正常 正常 正常 正常
C组 正常 正常 正常 正常 正常
D组 正常 正常 正常 正常 正常
E组 正常 正常 正常 正常 正常
F组 正常 正常 正常 正常 正常
G组 正常 正常 正常 正常 正常
H组 正常 正常 正常 正常 正常
I组 正常 正常 正常 正常 正常
表3药物注射后鸡冠注射处颜色和结痂情况
Figure PCTCN2021072630-appb-000003
表4药物注射后鸡冠水肿情况
  0d 3d 7d 14d 28d
空白对照组 无 无 无 无 无
阳性对照组 无 轻度水肿 水肿减退 水肿不明显 未见水肿，有瘢痕
A组 无 轻度水肿 轻度水肿 水肿减退 未见水肿和瘢痕
B组 无 轻度水肿 轻度水肿 水肿减退 未见水肿和瘢痕
C组 无 轻度水肿 轻度水肿 水肿减退 未见水肿和瘢痕
D组 无 未见明显水肿 未见明显水肿 未见明显水肿 轻度水肿
E组 无 未见明显水肿 未见明显水肿 未见明显水肿 轻度水肿
F组 无 未见明显水肿 未见明显水肿 未见明显水肿 轻度水肿
G组 无 未见明显水肿 未见明显水肿 未见明显水肿 轻度水肿
H组 无 未见明显水肿 未见明显水肿 未见明显水肿 轻度水肿
I组 无 未见明显水肿 未见明显水肿 未见明显水肿 轻度水肿
3.2药物注射后鸡冠光镜下组织病理学变化
光镜下观察，空白对照组可见整齐排列的上皮细胞，皮下毛细血管丰富，形态规则，血管间可见疏松结缔组织和脂肪组织，含部分胶原纤维。药物注射后各组整体趋势为毛细血管逐渐减少，胶原纤维逐渐增多，早期出现炎性细胞浸润及间质水肿变化。阳性对照组：注射3天后皮下毛细血管出现破坏、融合，外周组织炎性细胞浸润，间质水肿明显，胶原纤维少量增生；7天后毛细血管进一步减少，胶原纤维进一步增生，炎性细胞浸润和间质水肿有所减退；14天后血管数量继续减少，胶原纤维继续增生；28天后毛细血管明显减少，均充满大量胶原纤维。药物组合物A-I组总体情况与阳性对照组相似；并且相比D-I组，ABC组毛细血管数量减少和胶原纤维增生更加明显。
鸡冠病理学变化的详细情况如下表5至表7所示。
表5药物注射后鸡冠上皮细胞情况
Figure PCTCN2021072630-appb-000004
Figure PCTCN2021072630-appb-000005
表6药物注射后鸡冠皮下毛细血管形态和数量情况
Figure PCTCN2021072630-appb-000006
表7药物注射后鸡冠皮下毛细血管管腔内部和外部情况
Figure PCTCN2021072630-appb-000007
Figure PCTCN2021072630-appb-000008
3.3药物注射后不同时间点鸡冠毛细血管减少结果
药物注射后在3d、7d、14d、28d四个时间点观察鸡冠毛细血管减少情况如表8所示，各组均呈现毛细血管减少逐渐增加的趋势，各组前7天毛细血管减少均较为明显，7d后毛细血管减少变缓。与空白对照组比较，A-I组均明显减少了毛细血管数目，在7d后均达到显著性差异P<0.05，在14d后均达到显著性差异P<0.01。尤其对于ABC组，在3d后均达到显著性差异P<0.05，在7d后均达到显著性差异P<0.01。
毛细血管数目减少情况与鸡冠目测结果和组织病理学结果基本一致。通过2.3.2 HE染色和2.3.4 计算机图像分析得出的结果详情如下表8所示。
表8各组鸡冠处理后毛细血管数目的变化情况
Figure PCTCN2021072630-appb-000009
3.4药物注射后血管内皮细胞凋亡变化
经光学显微镜连续动态观察，发现空白对照组几乎无细胞凋亡。注射本发明组合物1-9后，可见大量凋亡的血管内皮细胞，并随时间增多。与D-I组相比，ABC组凋亡细胞数明显更多，甚至与阳性对照组相当。与空白对照组比较，A-I组在7d后均达到显著性差异P<0.05，在14d后均达到显著性差异P<0.01。尤其对于ABC组，在3d后均达到显著性差异P<0.05，在7d后均达到显著性差异P<0.01。
通过2.3.3细胞凋亡检测和2.3.4计算机图像分析得出的结果详情如下表9所示。
表9各组鸡冠处理后细胞凋亡数的变化情况
Figure PCTCN2021072630-appb-000010
4.结论
本发明的药物组合物1-9均能对鸡冠产生显著效果，例如减少毛细血管数量、增生胶原纤维、凋亡血管内皮细胞等。尤其对于组合物1-3，其在鸡冠血管瘤模型中，在血管壁结构消失时间，损伤血管内皮并诱导毛细血管内皮细胞凋亡数量，毛细血管数目减少数量方面均有更好的效果，且不会造成 鸡冠外形的改变。因此，柠檬酸、芍药苷和没食子酸三者的组合使用产生了协同作用，尤其当柠檬酸、芍药苷、没食子酸的重量比为约100:(2.2～5.7):(1～2)，且芍药苷和没食子酸的重量比为约(2.31-2.89):1时。
实施例2：临床实施例
临床病例1：直肠血管瘤的治疗
患者：李某，男，22岁。
主要症状：便血、贫血和脓便血。便血为持续性，出血呈暗红色或鲜红色。治疗前进行纤维结肠镜检查，其特点为直肠内可见环形、不规则的紫色隆起、黏膜表面光滑，粘膜糜烂伴有活动性出血，诊断为直肠血管瘤。
治疗方法：将本发明的药物组合物1的注射液(浓度为2.635％)与0.5％的利多卡因按照体积比配制为1:1的混合液。患者取折刀式体位，护皮膜牵拉双侧臀部暴露肛门，以肛门自动牵开器显露病变区域，距血管瘤边缘0.5cm处正常直肠黏膜处用7号穿刺针向血管瘤中心方向作穿刺，深达肌层，回抽无血时，将上述配制的混合液注入，沿血管瘤边缘分点注射，共注入混合液约5mL。
结果：注射三个月后复查，直肠血管瘤症状完全消失，病变部位平整，效果良好。随访一年，无不良反应症状，病变部位无痕迹。
临床病例2：血友病伴痔疮
患者：万某，男，17岁。
主要症状：大便后肛周肿物脱出，能自行回纳，伴出血两天，每次出血约3mL，当地诊所开具口服药物，有所缓解，但症状未控制。
经检查：
(1)T37.0℃P78次/分R 19次/分BP110/70mmHg，全身体格检查未见明显异常；
(2)专科检查：肛门截石位：肛缘欠平整，肛镜下3、7、11点肛管黏膜隆起跨齿线；直肠指诊：直肠下段未触及其他肿物，退出时指套无血迹；
(3)VIII因子活性121.2％、Ⅸ因子活性9.2％，Ⅹ因子活性107.2％。
确诊为乙型血友病伴混合痔。出血风险高，不能进行外科手术治疗。故采用本发明的药物组合物1的注射液。
治疗方法：常规消毒，或肛管麻醉。将本发明的药物组合物1的注射液(浓度为2.635％)与0.5％的利多卡因按照体积比配制为1:1的混合液，在肛门镜下暴露痔核，于痔核表面中心隆起部位斜刺进针，每处注射量以痔核均匀、饱满、充盈，表面粘膜呈粉红色为适宜，共注射约10mL。
结果：术后未出血，三天出院。三个月复查，未见不良反应症状，病变部位平整，痔核脱落，病变部位未见异常。随访一年，无复发。
以上所述的仅是本发明的具体实施方案，在此应当指出，对于本领域的普通技术人员来说，在不 脱离本发明构思的前提下，可以对本发明组合物和方法做出改进，这些均属于本发明的保护范围。

Claims (35)

  1. 一种药物组合物，其含有柠檬酸、芍药苷和没食子酸，其重量比为约100:(1～8):(0.1～5)，优选为约100:(1.5～7.5):(0.2～4)，更优选为约100:(2～7):(0.5～3.5)。
  2. 权利要求1所述的药物组合物，其中芍药苷与没食子酸的重量比为约(1～6):1，优选为约(1～5):1，更优选为约(1～4):1。
  3. 权利要求1所述的药物组合物，其中柠檬酸、芍药苷和没食子酸的重量比为约100:(2～6.5):(0.5～3)，且芍药苷与没食子酸的重量比为约(1.5～3.5):1。
  4. 权利要求1所述的药物组合物，其中柠檬酸、芍药苷和没食子酸的重量比为约100:(2～6):(1～2)，且芍药苷与没食子酸的重量比为约(2～3):1。
  5. 权利要求1所述的药物组合物，其中柠檬酸、芍药苷、没食子酸的重量比为约100:4:1.5、100:5.6:2、100:2.2:1、100:3.6:1.8、100:3.6:1.3、100:2:1.2、100:6.2:2、100:2.5:0.8、100:5.3:2.6，优选为约100:4:1.5、100:5.6:2或100:2.2:1，尤其优选为约100:4:1.5。
  6. 一种制剂，其中包含权利要求1-5中任一项所述的药物组合物，以及药学上可接受的辅料。
  7. 权利要求6所述的制剂，其为注射剂。
  8. 权利要求7所述的制剂，其中包含所述药物组合物和注射用水。
  9. 权利要求7或8所述的制剂，其为5mL或10mL剂量规格，分别含有132mg±0.5mg或264mg±0.5mg所述药物组合物。
  10. 权利要求1-5中任一项的药物组合物在制备用于治疗直肠血管瘤或痔疮的药物中的用途。
  11. 权利要求10的用途，其中所述药物用于不宜手术的患者。
  12. 权利要求11的用途，其中所述不宜手术的患者包括具有出血倾向、高血压、糖尿病、门脉高压、肾功能障碍、重症肌无力、免疫缺陷，以及正在接受放化疗的患者。
  13. 权利要求12的用途，其中所述具有出血倾向的患者包括患有凝血功能障碍(如再生障碍性贫血、白血病或血友病患者)、接受抗栓治疗(如心脏支架术后、心脏起搏器术后、心肌梗塞、脑梗塞)的患者。
  14. 权利要求12的用途，其中所述免疫缺陷患者包括艾滋病、系统性红斑狼疮患者。
  15. 权利要求10-14中任一项的用途，其中所述药物用于治疗直肠血管瘤。
  16. 权利要求10-14中任一项的用途，其中所述药物用于治疗凝血功能障碍(如再生障碍性贫血、白血病或血友病)患者的痔疮。
  17. 权利要求1-5中任一项的药物组合物或权利要求6-9中任一项的制剂，其用于治疗直肠血管瘤或痔疮。
  18. 权利要求17的药物组合物或制剂的用途，其用于治疗不宜手术的患者。
  19. 权利要求18的药物组合物或制剂的用途，其中所述不宜手术的患者包括具有出血倾向、高血压、糖尿病、门脉高压、肾功能障碍、重症肌无力、免疫缺陷，以及正在接受放化疗的患者。
  20. 权利要求19的药物组合物或制剂的用途，其中所述具有出血倾向的患者包括患有凝血功能 障碍(如再生障碍性贫血、白血病或血友病患者)、接受抗栓治疗(如心脏支架术后、心脏起搏器术后、心肌梗塞、脑梗塞)的患者。
  21. 权利要求19的药物组合物或制剂的用途，其中所述免疫缺陷患者包括艾滋病、系统性红斑狼疮患者。
  22. 权利要求17-21中任一项的药物组合物或制剂的用途，其用于治疗直肠血管瘤。
  23. 权利要求17-21中任一项的药物组合物或制剂的用途，其用于治疗凝血功能障碍(如再生障碍性贫血、白血病或血友病)患者的痔疮。
  24. 一种在患者中治疗直肠血管瘤或痔疮的方法，包括给药权利要求1-5中任一项的药物组合物或权利要求6-9中任一项的制剂。
  25. 权利要求24的方法，其中患者为不宜手术的患者。
  26. 权利要求25的方法，其中所述不宜手术的患者包括具有出血倾向、高血压、糖尿病、门脉高压、肾功能障碍、重症肌无力、免疫缺陷，以及正在接受放化疗的患者。
  27. 权利要求26的方法，其中所述具有出血倾向的患者包括患有凝血功能障碍(如再生障碍性贫血、白血病或血友病患者)、接受抗栓治疗(如心脏支架术后、心脏起搏器术后、心肌梗塞、脑梗塞)的患者。
  28. 权利要求26的方法，其中所述免疫缺陷患者包括艾滋病、系统性红斑狼疮患者。
  29. 一种在患者中治疗直肠血管瘤的方法，包括给药权利要求1-5中任一项的药物组合物或权利要求6-9中任一项的制剂。
  30. 一种在凝血功能障碍(如再生障碍性贫血、白血病或血友病)患者中治疗痔疮的方法，包括给药权利要求1-5中任一项的药物组合物或权利要求6-9中任一项的制剂。
  31. 权利要求24-30中任一项的方法，其中所给药的药物组合物或制剂为注射用水中的注射剂，其中药物浓度为22-30mg/mL，优选24-27mg/mL，优选26.5mg/mL。
  32. 权利要求31的方法，其中所述注射剂用体积比为1:(0.8～1.2)，优选1:1的0.5％～1％的利多卡因稀释后使用。
  33. 权利要求31或32的方法，其中向患者注射1-3次，优选1次所述注射剂。
  34. 一种在具有凝血功能障碍的患者中治疗痔疮的方法，包括给药权利要求1-5中任一项的药物组合物或权利要求6-9中任一项的制剂，包括以下步骤：
    (1)患者采用侧卧位、折刀位及膀胱截石位等治疗体位，常规消毒，然后肛门局部麻醉或肛管麻醉，麻药用0.5-1％利多卡因；
    (2)注射液使用时，用0.5％～1％的利多卡因稀释本品，其中药物与利多卡因的体积比为1:(0.8～1.2)；
    (3)对I、II期内痔及静脉曲张型混合痔，在肛门镜下暴露每处痔核，于痔核表面斜刺进针；
    (4)退肛门镜，暴露痔核，对III期内痔的注射方法同I、II期内痔；
    (5)每位患者一次约10-20ml，平均15ml，最大用量不超过40ml；
    (6)每位患者一般只注射一次。
  35. 权利要求34的方法，其中所述患者为再生障碍性贫血患者、白血病患者或血友病患者。
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