CN117618482A

CN117618482A - Pharmaceutical composition of celery-locust extract and benzbromarone and application thereof

Info

Publication number: CN117618482A
Application number: CN202210955006.9A
Authority: CN
Inventors: 高永良
Original assignee: Beijing Tianheng Junwei Pharmaceutical Technology Development Co ltd
Current assignee: Beijing Tianheng Junwei Pharmaceutical Technology Development Co ltd
Priority date: 2022-08-10
Filing date: 2022-08-10
Publication date: 2024-03-01

Abstract

The invention provides a pharmaceutical composition and/or a pharmaceutical kit for treating both symptoms and root causes of hyperuricemia and gout and a fenbromouron, and application thereof. The invention has the advantages that the celery-locust extract and the small-dose benzbromarone are given to patients, on one hand, the action mechanisms of the celery-locust extract and the small-dose benzbromarone are complementary, the clinical effect is quick, the long-acting effect can be maintained, the effects of dissolving kidney stones and tophus are also realized, on the other hand, the toxic and side effects are obviously reduced, and the invention is more suitable for long-term maintenance treatment and medication.

Description

Pharmaceutical composition of celery-locust extract and benzbromarone and application thereof

Technical Field

The invention relates to the technical field of medicines for treating gout or hyperuricemia, in particular to a medicine composition or a combined medicine box for treating gout and/or hyperuricemia of human beings. In particular, the invention also relates to a pharmaceutical composition or a combined kit of the celery-locust extract and the benzbromarone and application thereof in combined medication and/or pharmacy for treating gout or hyperuricemia.

Background

Gout and hyperuricemia are common metabolic diseases and are important public health problems in the global scope.

Gout is a group of metabolic diseases that result in elevated blood uric acid due to purine metabolic disorders. An important cause of gout is that the patient's blood uric acid level exceeds normal, and is often accompanied by an induction of the cause before onset. If the patient drinks and binges before onset of the disease, the patient takes excessive food with high purine content, such as broth, seafood, etc., and drinks and smokes frequently, excessive fatigue, wind-cold, etc. Under normal purine dietary conditions, fasting blood uric acid levels are above 420 μmol/L for two times not on the same day, known as hyperuricemia.

The natural course of gout is divided into four phases:

first, asymptomatic phase

In this case, blood uric acid is higher than normal, and is therefore called hyperuricemia. The patient usually has no clinical manifestations, no pain in joints, no other discomfort, commonly known as silent killers. However, the damage to the body caused by hyperuricemia has begun to appear, and the damage to blood vessels and kidneys appear slowly in the body of the patient. The serum uric acid concentration in the patient in this period increases, but clinical symptoms such as arthritis, tophus, or uric acid stones do not appear. Some male patients develop this condition during puberty and may be related to family history, and female patients are more often than not during menopause. Asymptomatic hyperuricemia may exist throughout life, but may also be converted to acute gouty arthritis or kidney stones, with most asymptomatic hyperuricemia patients experiencing gout symptoms before other conditions, but noting that about 10% to 40% of patients experience kidney stone symptoms.

(II) acute arthritis stage

Patients in this period can develop severe pain symptoms at affected joint parts, single joints (accounting for 90%) are relatively often infringed at early stages of the disease, about half of the cases occur at a metacarpal joint, so that the patients are hard to get painful, cannot wear shoes, often wear slippers for treatment before going on, but possibly infringe a plurality of joints after going on, sometimes infringe other parts only, gout often infringed parts comprise big toes, insteps, ankle, heel, knee, wrist, finger, elbow and other parts, and other parts can also attack.

In general, patients with gout begin to experience severe pain and joint inflammation at night, and sometimes fever symptoms occur at the same time, and the onset of the cases is often caused by overeating, especially after banquet, drinking, medicines, trauma or surgery, and sometimes also caused after ankle sprain, especially dehydration. Clinically, the patient may not have any abnormality before sleeping, but the severe pain caused by gout attack may cause the patient to wake from dream, severe red swelling and hot pain occur in affected joints, the pain is hard to endure, the symptoms are light and heavy, the phenomena of coldness and trembling are aggravated, the pain is tearing at the most, the patient cannot tolerate the pain, and then the symptoms are slowly relieved.

(III) intermittent period

Intermittent phase refers to the period of disappearance of symptoms between two episodes, i.e. clinically the patient does not have any symptoms; intermittent periods of varying length may last from one, two days to several weeks and then reoccur, with very few patients having gout attacks once for life, no symptoms, but most patients having recurrences. The recurrent attacks tend to be multi-articular, with severe attacks, longer attacks, and concomitant fever.

(IV) period of chronic arthritis

Long-term onset of gout, untreated or irregular treatment, causes uric acid crystals to deposit in cartilage, synovial membrane and soft tissues in vivo to form tophus; and the higher the uric acid concentration in blood, the longer the period of illness, the more tophus may be deposited, resulting in chronic gouty arthritis, sometimes affecting blood vessels and kidneys, causing serious renal failure, making kidney disease worse, and causing malignant circulation of uric acid which is not easy to excrete, and the more tophus is deposited.

Often, there are many areas where tophus is deposited, including auricle, hand, elbow, achilles tendon, ankle or toe, sometimes causing localized ulcers, not easily healed, and even requiring amputation. Serious patients and may cause joint deformation or chronic symptoms, and serious problems in wearing shoes by patients may be caused when foot deformation is serious. In addition, the risk of kidney stones increases with increasing uric acid concentration in serum and also often causes kidney disease, which may require hemodialysis after renal failure, which is also one of the major causes of death in gout patients.

In addition, gout is common in obese, hypertriglyceridemia and hypertensive patients. The obese people have increased uric acid production and decreased excretion, causing hyperuricemia and gout. If these diseases occur clinically at the same time, the situation of difficult control may also be caused, so that the evaluation should be paid attention to at the same time during the examination.

Hyperuricemia and gout cannot be marked with equal signs, and hyperuricemia is not necessarily gout, but patients with gout have certain hyperuricemia, and are generally called gout only when arthritis occurs clinically. Hyperuricemia of 5% -12% can progress to gout. Therefore, in clinical diagnosis of pain and wind, doctors pay attention to uric acid elevation, but also include the onset of acute monoarthritis and even the discovery of urate crystals, so that gout can be diagnosed under the guidance of specialists. In gout attack, patients often have uric acid and hematuric acid in normal range due to organism compensation.

Along with the rapid development of economy and the obvious change of the life style of people, the prevalence rate of Chinese hyperuricemia and gout is remarkably increased, and according to the latest research result, the hyperuricemia patients account for 13.3 percent of the total population, and particularly in economically developed cities and coastal areas, the prevalence rate of the hyperuricemia is as high as 5 to 23.5 percent. The prevalence rate of gout is 1-3%, and the prevalence rate of gout rises year by year. According to 2017, the current status report of gout in China, the number of patients with hyperuricemia in China reaches 1.7 hundred million, wherein the number of patients with gout exceeds 8000 ten thousand, and the annual growth rate of 9.7% per year is rapidly increasing.

Another epidemiological feature of gout is the younger and younger age of onset. The stage data of national rheumatism data center (CRDC) network registration and follow-up study show that based on the effective case discovery of 6814 gout patients in 100 hospitals in province, city and municipality of 27 nations, the average age of gout patients in China is 48.28 years, and the gout patients gradually trend to be younger. One investigation in a middle day friendly hospital found that gout decreased the average age of onset of the patient by 6.3 years in less than 20 years, and increased the number of people with gout 1 st time before 40 years by 26.3%.

Gout is the second most metabolic disease in China and is a systemic disease with multiple system functions. Many evidences indicate that hyperuricemia and gout are independent risk factors for chronic kidney disease, hypertension, cardiovascular and cerebrovascular diseases, diabetes and other diseases, and are independent predictors of premature death. In the case of Chronic Kidney Disease (CKD), the cardiovascular risk of death increases by 16% and the total risk of death increases by 17% for every 1mg/dL increase in blood uric acid levels in patients at stage 3-4. Gouty kidney disease with the disease course exceeding 10 years is easy to cause renal colic and hematuria until renal failure and uremia, and finally the kidney has to be replaced to sustain life. Approximately 15% of patients die from renal failure.

Besides the function of multiple systems is affected, gout also causes joint deformity, seriously affects the limb functions of patients, further causes great obstruction and difficulty in living and living, and causes the patients to lose working capacity. News reports have been presented for gout patients claiming disability. Hyperuricemia/gout also affects the sexual function of male patients. In one study of middle-aged men in the hospital rheumatology, 76% of gout men suffer from Erectile Dysfunction (ED), while the average men are 51%. The probability of organic ED is higher for gout men than for other men. ED in these men is likely to be due to hyperuricemia, which increases uric acid a few years before gout symptoms appear.

The treatment methods for gout accompanied with hyperuricemia are generally drug treatment and general treatment. Clinically common therapeutic agents include: the acute stage uses non-steroidal anti-inflammatory drugs, colchicine, glucocorticoid, febuxostat, allopurinol, benzbromarone and the like in the remission stage of gout. In general treatment, patients need to eat low-purine diet daily, and can take sodium bicarbonate tablets to alkalize urine and drink more water daily, and proper exercise is performed, and joint parts pay attention to keep warm so as to promote excretion of uric acid and prevent gout recurrence.

At present, gout cannot be radically treated, and the core of the treatment method is to reduce the blood uric acid level at first, so that the acute arthritis attack can be reduced, the deposition of the uric acid salt can be prevented, and the tophus formation and the kidney function damage can be prevented. Clinically commonly used uric acid lowering drugs are mainly divided into two main classes: inhibit uric acid production and promote uric acid excretion.

1. Drugs that inhibit uric acid production: the representative drugs are allopurinol and febuxostat, and play a role in reducing uric acid by inhibiting xanthine oxidase;

side effects of allopurinol: gastrointestinal tract response, leukopenia, thrombocytopenia, anemia, and bone marrow depression. Other diseases include alopecia, fever, lymphadenectasis, hepatotoxicity, interstitial nephritis, and allergic vasculitis. Can also cause exfoliative dermatitis, toxic epidermonecrosis, severe erythema multiforme drug eruption, drug hypersensitivity syndrome, liver function injury, kidney function injury, etc.

The main adverse effect of febuxostat is cardiovascular toxicity. In the randomized controlled study, patients treated with febuxostat, where febuxostat was 0.74/100 patients-year (95% CI: 0.36-1.37) and allopurinol was 0.60/100 patients-year (95% CI: 0.16-1.53), had a higher probability of cardiovascular thrombotic events (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) than allopurinol. The us FDA issued febuxostat cardiovascular risk warning on 11 and 15 2017, and the medication needed to be balanced against the full benefit and disadvantage of patients with high cardiovascular risk. In the latest therapeutic guidelines in the united states, febuxostat has been reduced to a second line therapeutic agent, requiring attention to monitor symptoms and signs of myocardial infarction and stroke when administered. And for gout patients with cardiovascular diseases, it is recommended to replace febuxostat with other uric acid lowering drugs.

2. Medicament for promoting uric acid excretion:

(1) the tribromone is orally taken by 50mg (one tablet) for adults once a day after breakfast. The patient is checked for serum uric acid concentration 1 week after administration, or 100mg (two tablets) can be taken orally daily at the beginning of the treatment, after breakfast, and 50mg (one tablet) daily when the blood uric acid falls to the normal range. Side effects: hepatotoxicity, uric acid calculus, and liver and kidney calculus.

(2) Probenecid and buprofezin are only used for patients with normal renal function, and liver damage is more common.

Uric acid in humans is excreted about 70% by the kidneys. The urate anion transporter (urate anion transporters, URAT1) is an important kidney urate transporter, and is mainly located at the epithelial cell brush-like edge of the renal cortex proximal tubule and mainly involved in reabsorption of uric acid in the renal proximal tubule. A drug for promoting uric acid excretion is benzbromarone, and can inhibit reabsorption of uric acid by renal tubules by inhibiting activity of uric acid salt anion transporter 1, thereby reducing uric acid.

The structural formula of the benzbromarone is as follows:

the benzbromarone is a benzofuran derivative, 50mg is orally taken by a healthy adult, the peak value of blood concentration is reached after about 2-3 hours, the clearance rate of uric acid is reached to the maximum value after 4-5 hours, and the half life period is 12-13 hours. The dosage method comprises the following steps: the dosage is increased by 40-80 mg each time, 1 time a day, and the dosage is continuously used for 3-6 months. The indications are as follows: primary hyperuricemia and gouty arthritis intermittent stage.

Clinical studies for many years have shown that benzbromarone can reduce blood uric acid levels, but has the following disadvantages:

1. the curative effect is limited, even if the dosage is increased greatly, millions of patients still cannot control the illness state every year, and the blood uric acid does not reach the standard (lower than 360 mu mol/L);

2. poor safety and aggravated adverse reactions after increasing doses.

The safety of benzbromarone is poor, and the main adverse reaction is hepatotoxicity. After 1976, the drug was marketed in france, severe cytolytic liver damage occurred, some patients died, and the rest required liver transplantation. The tags were modified in 1997 and 2002, respectively, to warn of this adverse effect, but severe liver damage reports still appear, and finally in france. 4 cases of suspected liver damage occurred after the suspected administration of the phenylbromarone of celecoxib in the netherlands in 2003, and sales were stopped by themselves (because the patent had expired). After that, only after 10 months, no medicine which can reduce uric acid better can be found, and the sales of the benzbromarone can be restarted by the celecoxib. European countries use it as a second line therapy, and need to closely monitor liver function, especially for patients with chronic liver disease, and should be carefully used.

Analysis of the national drug adverse reaction monitoring database shows that the liver damage problem in the serious adverse reaction of the benzbromarone is more prominent. The general medical staff, medicine production and management enterprises and the public should know the liver damage risk of the tribromone, and when the tribromone is used, the tribromone should be used from a small dosage, so that the tribromone is prevented from being used together with other medicines with liver toxicity, and the liver function should be monitored periodically during treatment; during the administration period of patients, attention should be paid to symptoms and signs of liver injury, such as anorexia, nausea, emesis, general listlessness, abdominal pain, diarrhea, fever, urine staining, conjunctival yellow, etc., and patients should take a doctor in time to check liver function and perform corresponding treatment if necessary; the production enterprises should strengthen the monitoring of adverse drug reactions and the propaganda of clinical safe medication, take effective measures and reduce the occurrence of serious adverse reactions.

Pathogenesis of tribromone hepatotoxicity: the structure of benzbromarone is similar to that of amiodarone, a mitochondrial toxic drug, and mitochondrial toxicity can be an important cause of liver injury caused by benzbromarone. Studies have shown that benzbromarone causes mitochondrial damage to hepatocytes, which in turn induces apoptosis necrosis. Kaufmann et al found that the hepatotoxicity of benzbromarone depends on the side chain groups at position 1 and/or 2 of the furan ring, whereas the bromine atom on the hydroxybenzene can enhance hepatotoxicity.

The tribromone is used as uric acid reducing medicine for promoting uric acid excretion, has definite mechanism, quick response and definite curative effect, but in order to achieve satisfactory curative effect, a large dosage is required, side effects are increased along with the increase of dosage, clinical use is required, and the dosage is increased for 3-6 months, so that the possibility of occurrence of toxic and side effects is further increased. Especially toxic and side effects of liver severely limit the clinical use of benzbromarone and even lead to market withdrawal in European and American markets for a short time. There are 8 cases of severe hepatitis caused by benzbromarone reported in the Ministry of thick students in Japan, of which 6 cases die.

Chinese traditional medicine has a long history of preventing and treating gout, and through thousands of years of clinical practice, abundant medical experience is accumulated, and a theoretical system and a treatment method of the system are formed. Under the conditions that the curative effect and the safety of western medicines for reducing uric acid are not ideal, but the clinical requirements are urgent, the applicant invents a pure traditional Chinese medicine preparation, and the celery seed and the pagodatree flower bud are combined according to the traditional Chinese medicine theory (Chinese patent CN 201610313303.8). The celery seeds can clear heat and relieve restlessness, induce diuresis to alleviate edema, dispel qi, alleviate edema and unblock stagnation. The pagodatree flower bud is good at clearing heat and promoting diuresis, cooling blood and stopping bleeding, and can clear heat of blood system. The two medicines are mutually matched, so that the wind-damp heat toxin of the meridian joint can be searched, thereby treating the syndrome of wind pain and contracture of the meridian joint, and being an anti-gout traditional Chinese medicine for treating both symptoms and root causes. The applicant carries out systematic optimization proportioning on two medicines of celery seed and pagodatree flower bud under the guidance of pharmacodynamics, and carries out pharmacodynamics experiments and clinical researches on the compound extract, and the result shows that the compound has reasonable compatibility and has the effect of synergetic continuous uric acid reduction. Because of being a medicine and food homologous product, the medicine has no toxic and side effects basically, also has good medicine forming property, and can be prepared into medicines in the forms of tablets, capsules, granules and the like.

Like most traditional Chinese medicines, the compound extract of the celery-sophora japonica has slow effect and mild effect, basically has no toxic or side effect, but has insufficient control on acute episode of gout and temporary fluctuation caused by influence of diet on blood uric acid level, and needs to be overcome so as to expand the applicable range of the compound extract of the celery-sophora japonica and better meet clinical needs.

At present, a medicament or a medicament combination for treating both symptoms and root causes, which has stronger and more durable uric acid reducing effect and smaller toxic and side effects, is urgently needed clinically.

Disclosure of Invention

In order to overcome the defects of curative effect and safety of the traditional western medicines and traditional Chinese medicines for reducing uric acid, the technical scheme of the invention aims at providing a pharmaceutical composition for treating both symptoms and root causes of gout, in particular to a pharmaceutical composition of a celery-locust extract and benzbromarone, which is characterized by comprising 225-2250mg of the celery-locust extract, 12.5-25mg of benzbromarone and a pharmaceutically acceptable carrier, wherein the celery-locust extract is an alcohol extract of celery seeds (celery seeds) and pagodatree flower buds (sophora flower bud) in a weight ratio of 2:1-4:1.

Preferably, the pharmaceutical composition of the celery sophora extract and the benzbromarone is characterized by comprising 450-1800mg of the celery sophora extract, 12.5-25mg of the benzbromarone and a pharmaceutically acceptable carrier, wherein the celery sophora extract is an alcohol extract of celery seeds (celery seeds) and sophora japonica (sophora flower bud) in a weight ratio of 2:1-4:1.

Particularly preferred are: the pharmaceutical composition is characterized by comprising 900-1350mg of the celery-sophora japonica extract, 12.5-25mg of the benzbromarone and a pharmaceutically acceptable carrier, wherein the celery-sophora japonica extract is an alcohol extract of celery seeds and sophora japonica (sophora flower bud) in a weight ratio of 2:1-4:1.

The invention further provides a medicine box for treating gout and/or hyperuricemia of mammals or humans, which consists of 225-2250mg of celery sophora extract, 12.5-25mg of benzbromarone, a pharmaceutically acceptable carrier and a medicine instruction, wherein the celery sophora extract is an alcohol extract of celery seeds and sophora flower buds (sophora flower bud) in a weight ratio of 2:1-4:1.

Preferably, the invention provides a medicine box for treating gout and/or hyperuricemia of mammals or humans, which consists of 450-1800mg of celery-locust extract, 12.5-25mg of benzbromarone, a pharmaceutically acceptable carrier and a medicine instruction, wherein the celery-locust extract is an alcohol extract of celery seeds (celeries) and pagodatree flower buds (sophora flowerbud) in a weight ratio of 2:1-4:1.

It is particularly preferred that the present invention further provides a kit for treating gout and/or hyperuricemia in a mammal or human, the kit comprising 900-1350mg of the extract of apium graveolens, 12.5-25mg of benzbromarone and a pharmaceutical specification, wherein the extract of apium graveolens is an alcohol extract of apium graveolens seeds and sophora japonica (sophora flower bud) in a weight ratio of 2:1-4:1.

The kit of the invention is selected from:

(1) Consists of independent 450-1800mg of celery seed extract, a pharmaceutically acceptable carrier, independent 12.5-25mg of benzbromarone and a drug instruction, wherein the celery seed extract is a celery seed extract and a pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1;

(2) Consists of 900-1350mg of isolated celery seed extract, a pharmaceutically acceptable carrier, 12.5-25mg of tribromone and a drug instruction, wherein the isolated celery seed extract is a celery seed extract and a pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1;

(3) Consists of 450-1800mg of celery seed extract, 12.5-25mg of benzbromarone and a mixture of pharmaceutically acceptable carriers and a drug instruction, wherein the celery seed extract is a celery seed and pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1; or,

(4) Consists of 900-1350mg of the celery seed extract, 12.5-25mg of the benzbromarone and a mixture of pharmaceutically acceptable carriers and a drug instruction, wherein the celery seed extract is a celery seed and pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1.

In other words, the invention provides a pharmaceutical composition of an extract of apices, comprising benzbromarone, for the treatment of gout and/or hyperuricemia in a mammal or human.

In other words, the present invention provides a method for treating gout and/or hyperuricemia in a mammal or human by combining the extract of apices and tribromone, comprising administering to the patient a pharmaceutically effective dose of the extract of apices and tribromone, wherein the daily dose of tribromone is in the range of 12.5mg to 25mg, and the daily dose of the extract of apices is in the range of 225mg to 2250mg, based on the extract.

The extract of herba Apii Graveolentis can be granule, tablet, dripping pill, or capsule, preferably capsule.

Wherein the celery-locust extract is obtained according to the formula and method of Chinese patent ZL 201610313303.8.

Further, a novel pharmaceutical composition is invented: the celery locust extract and the small dosage of the benzbromarone pharmaceutical composition.

The daily dosage of benzbromarone ranges from 12.5mg to 25mg.

The daily dosage of the extract of the celery tree is 225mg to 2250mg (calculated as extract), preferably the daily dosage is 450mg to 1800mg (calculated as extract), further preferably the daily dosage is 900mg to 1350mg (calculated as extract), most preferably the daily dosage of the extract of the celery tree is 900mg (calculated as extract).

As one embodiment of the preferred combination, the daily dose of the extract of apices et radix Apii is 900mg and the daily dose of benzbromarone is 12.5mg to 25mg. Further preferably, after the daily dose of 900mg of the celery sophora extract and 25mg of the benzbromarone are firstly given to the patient for a period of time, the blood uric acid level is quickly reduced to a reasonable level, and then the daily dose of 900mg of the celery sophora extract and 12.5mg of the benzbromarone are given to the patient, so that the blood uric acid level is kept stable and does not rebound.

As a first embodiment of the present invention, the present invention provides a combination of administration. The herba Apii Graveolentis extract and the benzbromarone can be respectively made into solid preparation composition, such as tablet, capsule, granule and other dosage forms, and can be provided for patients in the form of combined administration. Preferably, the extract of the apices sophorae is added with proper pharmaceutically acceptable auxiliary materials to be prepared into capsules and the benzbromarone is prepared into tablets. The combination forms include, but are not limited to, simultaneous administration, sequential administration, intermittent administration, alternating administration, and other combination modes. In the combined administration form, the daily dosage of the benzbromarone is in the range of 12.5mg to 25mg; the daily dosage of the extract of the celery tree is 225mg to 2250mg (calculated as extract), preferably the daily dosage is 450mg to 1800mg (calculated as extract), further preferably the daily dosage is 900mg to 1350mg (calculated as extract), most preferably the daily dosage of the extract of the celery tree is 900mg (calculated as extract).

As a preferred embodiment of the above combination, the daily dose of the extract of apices et radix Apii is 900mg and the daily dose of benzbromarone is 12.5mg to 25mg. Further preferably, after a period of time when 900mg of the celery sophora extract and 25mg of the tribromone are administered to the patient, the blood uric acid level is quickly reduced to a reasonable level, and then 12.5mg of the celery sophora extract and 900mg of the tribromone are administered to the patient, so that the blood uric acid level is kept stable and does not rebound.

As a second embodiment of the invention, the invention provides a combination kit product. In the kit product, the celery-sophora extract and the benzbromarone can be respectively prepared into solid preparation compositions, such as tablets, capsules, granules and other dosage forms, and the solid preparation compositions are provided for patients in the form of a complete set of combined kit. In the dosage form, the extract of the apices, preferably the apices, is added with proper pharmaceutically acceptable auxiliary materials to prepare capsules and the tribromone is prepared into tablets. The daily dosage range of the two preparations in the combined medicine box is 12.5mg to 25mg; the daily dosage of the extract of the celery tree is 225mg to 2250mg (calculated as extract), preferably the daily dosage is 450mg to 1800mg (calculated as extract), further preferably the daily dosage is 900mg to 1350mg (calculated as extract), most preferably the daily dosage of the extract of the celery tree is 900mg (calculated as extract).

As a preferred embodiment of the above combination kit embodiment, the daily dose of the preparation of the extract of apices et radix Apii Graveolentis is 900mg and the daily dose of the preparation of benzbromarone is 12.5mg to 25mg. Further preferably, after a period of time, the blood uric acid level is rapidly reduced to a reasonable level by firstly administering to a patient a combined medicine box with 900mg of the apices and 25mg of the tribromone daily dose, and then, the patient is administered with a combined medicine box with 900mg of the apices and 12.5mg of the tribromone daily dose, so that the blood uric acid level is kept stable and does not rebound.

As a third embodiment of the invention, the invention provides a compound pharmaceutical composition. Mixing the herba Apii Graveolentis extract with benzbromarone, adding pharmaceutically acceptable adjuvants, and further making into compound pharmaceutical composition such as tablet, capsule, granule and other solid dosage forms. In the compound pharmaceutical composition, the weight ratio of the celery-locust extract to the benzbromarone is (225-2250): (12.5-25); the preferable proportion is (450-1800): (12.5 to 25), and more preferably (900 to 1350): (12.5 to 25), the most preferable ratio is 900: (12.5-25).

As a preferred embodiment, the weight ratio of the apices extract to the benzbromarone in the compound pharmaceutical composition is 900:12.5 or 900:25. further preferably, the weight ratio of the celery sophora extract to the benzbromarone is 900:25, which after a period of time, rapidly reduces the blood uric acid level to a reasonable level, and then administering to the patient a weight ratio of the celery sophora extract to the benzbromarone of 900:12.5, the blood uric acid level is kept stable and does not rebound.

The celery-locust extract adopted by the invention is prepared by adopting a method described in Chinese patent CN201610313303.8 before the inventor, wherein the ratio of celery seeds to pagodatree flower buds in the celery-locust extract is 2:1-4:1.

When the combination is used, the formulation of the extract of apices Apii is preferably formulated into a capsule (hereinafter referred to as apices Apii capsule). As one embodiment, each capsule contains 100-300mg, preferably 225mg, of the extract of Apium graveolens. The tribromone can be prepared from commercial tablets, and the tribromone can be divided into dosage according to the specification and daily dosage, and further preferably, small dosage tribromone tablets are specially prepared to ensure accurate dosage.

As a preferred embodiment, when co-administration is employed, the specific treatment regimen for one embodiment is as follows: apiary capsule (225 mg,4 granules/day, 2 granules each in the morning and evening) and tribromone tablet (specification: 50mg, half tablet/day; or specification: 25mg,1 tablet/day); in a further preferred embodiment, the above treatment regimen is carried out for 4 weeks, and then the composition is adjusted to 4 apices/day of apices and/or stigmata/2 apices/night (specification: 50mg, half tablet/2 day; or specification: 25mg, half tablet/day; or specification: 12.5mg,1 tablet/day) for use.

Through preclinical and preliminary clinical studies, applicants have unexpectedly found that the combination or co-administration of two drugs has the following unexpected advantages:

1. complementary mechanism of action

The extract of Apium graveolens reduces uric acid synthesis and blood uric acid content by inhibiting xanthine oxidase activity, thereby reducing the deposition of uric acid salts on bones, joints and kidneys, and facilitating the re-dissolution of gout nodules and uric acid crystals. The tribromoron can inhibit reabsorption of uric acid by renal tubules, so that excretion of uric acid is promoted, and concentration of uric acid in serum is reduced. Therefore, the two medicines are combined together, and have the dual pharmacological effects of reducing uric acid generation and promoting uric acid excretion.

Clinical studies show that after some patients use the pharmaceutical composition of the invention, blood uric acid is still maintained in a normal range after eating high purine diets such as seafood and beer, and the life quality of patients suffering from hyperuricemia is stably improved.

2. Has rapid clinical onset, long-acting maintenance, and kidney stone and tophus dissolving effects

(1) Quick acting

As described above, the extract of the celery-locust is a pure Chinese medicinal preparation, and has mild effect. The preparation method has the advantages that uric acid in blood is not greatly reduced in a short time, so that uric acid balance between blood and tissues is damaged, and acute gout is induced; the disadvantage is slow onset of action, and the blood uric acid level of the patient is delayed and cannot reach the standard. After clinical researches, the two medicines are combined, so that moderate uric acid reducing effect can be rapidly generated, and the control force for treating temporary fluctuation caused by the influence of diet on blood uric acid level is strong.

(2) Has lasting effect

Maintaining blood uric acid level <360 mu mol/L is a key point in gout treatment, and the blood uric acid concentration reaches a normal range through acid reduction treatment, so that tophus can be dissolved and the onset of gout can be reduced, and various chronic damages caused by hyperuricemia can be effectively prevented. Clinical researches show that after the combination of the celery-locust extract and the small-sized benzbromarone tablet, the celery-locust extract can produce a long-term stable uric acid reducing effect, and the fluctuation of blood uric acid is small. The blood uric acid level can be rapidly reduced during the combined therapy, and the uric acid salt deposited in the body can be rapidly released, but the acute gout symptom can not be caused. Some patients with gout accompanied by hyperuricemia have a maximum period of 10 years when combined, and the blood uric acid is always kept at a normal level. In the long-term administration process, the acute gout is occasionally caused, the symptoms are lighter than before, the recovery period is short, and the attack interval is prolonged.

(3) Dissolving kidney stones and tophus

Urate deposits in the kidneys produce urate crystals and stones, leading to the development and progression of obstructive nephropathy, ultimately leading to end stage renal disease. Typically 25% of gout patients have kidney stones 200 times higher than normal. At present, the modes of shock wave lithotripsy, minimally invasive stone extraction operation and the like are the main means of clinical treatment of kidney stones, but do not radically twist the cause of stone formation, and still have a certain recurrence rate.

In addition, urate is easy to deposit at joints to form 'tophus', severe pain is caused during acute gout attack, the acute gout attack is difficult to tolerate, joint deformity can be caused during severe cases, normal walking cannot be realized, even things such as pens, books, chopsticks and the like are difficult to hold, if the treatment is not in time, the wound can be automatically broken, the wound is not healed for a long time, and finally amputation is forced to be disabled due to infection.

Clinical researches show that after long-term combination of the celery-locust extract and the small-dose benzbromarone tablet, the blood uric acid level of some patients with gout accompanied with hyperuricemia can be rapidly reduced, and after the uric acid level in blood is reduced, the uric acid balance deposited in tissues is broken, so that uric acid is gradually dissolved from the tissues into the blood, and the deposited uric acid is gradually dissolved and becomes smaller to disappear. Can promote gradual disintegration of formed uric acid calculus crystals, has uric acid calculus dissolving effect, comprises urine acidic kidney calculus and tophus in joint cavity, and can restore joint flexibility, and avoid deformation, deformity, disability, etc.

3. Obviously reduce toxic and side effects, and is suitable for long-term administration

The patient base in the gout treatment field is large, the growth speed is high, and the market demand is wide. In the field of gout treatment, gout cannot be cured, and medicines are required to be taken for a lifetime, so that the safety is particularly important. The existing medicines have obvious defects in the aspect of safety. Taking tribromone tablet as an example, conventional dosage of tribromone tablet has liver toxicity, and liver dysfunction and elevation of glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase and alkaline phosphatase are clinically observed. Severe liver injury such as fulminant hepatitis and jaundice may occur. Patients with gout can not tolerate the medicine for long-term administration, and the disease condition is not controlled perfectly.

Early people have insufficient knowledge of liver toxicity of the tribromoron, and patients have serious liver injury after long-term use of the tribromoron, so that the aim of even liver transplantation is achieved. And the longer the administration time, the more severe the liver damage, the worse the prognosis. At present, clinicians need to closely monitor liver functions of patients while using old drugs such as benzbromarone and the like, and perform liver function examination every month.

According to the clinical observation study of the inventor, patients with gout accompanied by hyperuricemia are randomly divided into three groups, the patients in the test group are combined with the apices carbostyril compound extract (2 grains/time, 2 times/day) and the small dosage of the tribromotime (25 mg/day for the first 4 weeks and 12.5 mg/day for the subsequent 8 weeks), and the patients in the control group are respectively combined with the apices carbostyril compound extract (2 grains/time, 2 times/day) or the large dosage of the tribromotime tablet (25-50 mg/day) for the treatment course of 12 weeks. The results show that the liver function of the patients of the combined drug group and the single apices and the capsule group is checked without any abnormality, and only slight adverse reaction of the gastrointestinal tract is found. The large-dose benzbromarone group has liver enzyme abnormality, gastrointestinal adverse reaction and kidney function injury. The combination of the celery-locust extract and the small-dose benzbromarone is suggested, so that the hepatotoxicity of the large-dose benzbromarone tablet can be obviously reduced, and the long-term maintenance treatment of gout patients is facilitated.

Detailed Description

Example 1 animal test data

Experimental materials

Sample information

The celery-locust extract is provided by Beijing human Fu Legiocarb medical technology development Co. Lot number: 190403. sealed and light-proof, and stored at room temperature and dry place

Positive drug information

Tribromone tablets, manufacturer: sano Arzneimittelfabrik GmbH. Specification of: 50mg; lot number: 200116, shading, sealing and preserving, and the effective period is up to 2023, 11 and 26.

Detection kit

Uric acid detection kit: north-control biotechnology, inc, lot number: 141161.

solvent(s)

0.5% cmc-Na aqueous solution; CMC-Na lot number: 20190123, national pharmaceutical systems and chemicals Co., ltd.

Animal test data

The method comprises the following steps: the study was performed using 250 male SD rats. The model groups are randomly divided into normal groups and model groups according to weight layering. Normal group (10) were given normal diet and drinking water; model group (280) was given normal diet and 10% fructose in water. After successful modeling, the model groups of rats were randomly grouped, 10 per group. The normal group and the model group are subjected to gastric lavage by using 0.5% CMC-Na aqueous solution, and the other groups are subjected to gastric lavage by using the corresponding medicines dissolved in 0.5% CMC-Na aqueous solution (ultrasonic dissolution), wherein the dosage capacity is 0.1mL/kg body weight, and the administration is carried out once daily for 28 days. Blood uric acid (SUA) levels were measured biochemically before and 28 days of dosing, respectively.

The course of the dose of the apices sophorae capsule (225 mg per material based on extract) converted from human to animal is as follows:

the daily dose of the apices sophorae capsule is 1 to 10, the dose converted into rats is 225 mg/0.018/0.2 kg=20.25 mg/kg to 225 mg/10 mg/0.018/0.2 kg=202.5 mg/kg

The dosage process of the tribromone converted into animals from human is as follows:

the daily dosage of the tribromone is calculated to be 12.5mg-50mg, and the dosage converted into rats is 12.5mg 0.018/0.2 kg=1.125 mg/kg to 50mg 0.018/0.2 kg=4.5 mg/kg.

The dosing amounts for each experimental group are shown in table 1 below:

table 1 dosing amounts for each experimental group

The experimental results are shown in table 2 below:

table 2 effects of apices extract on blood uric acid levels in hyperuricemic rats (unit mu mol/L,n＝10)/>

experimental data indicate that:

1. as the dose of the fennel extract increases, the effect of lowering the blood uric acid level increases, but the high dose increases to a lesser extent than the low dose;

2. with increasing tribromoron dosage, the effect is increased, the effect of large dosage is stronger, but side effects begin to appear obviously.

3. When the two are combined for administration, the dosage of the apices extract in the A1+B1 group and the A1+B2 group is smaller, the synergistic effect is not obvious, the dosage of the apices extract in the A6+B1 group and the A6+B2 group is too large, the synergistic effect is also not obvious, the intermediate dosage has obvious synergistic effect, and compared with the model group, the reducing effect of the blood uric acid level of the combined group is larger than the sum of the effects of the respective administration of the two single medicines, so that the obvious synergistic effect is realized.

4. When the dosage of the tribromoron is large, no synergistic effect is found from the A1+B3 group to the A6+B3 group, and the synergistic effect is not obvious in the whole group presumably because the large dosage of the tribromoron has too strong effect.

Example 2 clinical data

1. Purpose of observation

As described above, the single drug of the tribromone tablet produces uric acid reducing effect at the same time of conventional dosage, and also has strong side effects, especially liver toxicity, and fulminant liver necrosis occurs when severe, so that the drug is removed from the market in a plurality of countries in European Union. In view of the above, the applicant examined the treatment scheme of combining the apices and the small-dose benzbromarone tablet, and on the basis of the voluntary of the patient, the effectiveness and the safety of treating gout with hyperuricemia were examined by orally taking the apices and the small-dose benzbromarone tablet.

2. Case of patient

The number of people: 30 cases. The random number was divided into 3 groups of 10 cases each.

Gender: 18 men and 12 women, 6 patients with hyperuricemia, 24 patients with gout (18 men and 6 women) are diagnosed in hospitals

Age range: 21-75 years old

3. Dose design scheme

1. Group 1 (apices apiacea capsule group alone): 4 granules/day, 2 granules each in the morning and evening.

2. Group 2 (apices capsule combined with small dose benzbromarone tablet): the initial dose was 4 tablets/day, 2 tablets each in the morning and evening+commercial benzbromarone tablets (specification: 50 mg) half tablets/day. After 1 month, the uric acid level is considered, the dosage of the benzbromarone is continuously reduced, and is adjusted to 4 grains/day of the apices and the locust capsules, and 2 grains of the apices and the night are respectively added with half of the benzbromarone tablets (specification: 50 mg) per 2 days. After 1 month, the uric acid level was observed and the maintenance treatment was continued.

3. Group 3 (single high dose benzbromarone tablet group): the initial dose is 100mg per oral administration, 1 time a day. After 1 month, if uric acid falls to the normal range, 50mg daily is changed, and the maintenance treatment is continued.

4. Observation of curative effect

There was no significant difference in blood uric acid levels (p > 0.05) before treatment for the three groups. After treatment 1, 2 and 3 months, the haematuria value of the combination group was significantly lower than that of the Shan Yong apices capsule group (p < 0.05), and there was no significant difference from the large-dose benzbromarone group (p > 0.05), as shown in table 3.

Table 3 comparison of the blood uric acid level at each time point for three groups (mu mol/L,n＝10)

note that: * Compared with group 2, there was a significant difference (p<0.05)； ^# No significant difference compared to group 2 (p<0.05 Fifth, adverse reaction observation result

After 3 months of continuous oral administration, only 1 patient of the single apices and sophora japonica capsules found adverse reactions of gastrointestinal tract on the 2 nd day of administration, and the stomach had slight transient light burning sensation, and the patients had disappeared after continuing administration without treatment.

The combination of the apices and the small dosage of the benzbromarone has 1 patient with mild intragastric fullness on the 5 th day after administration, and symptoms disappear on the 2 nd day without stopping administration.

1, 2 and 2 patients with liver enzyme abnormality (AST or ALT elevation) in large-dose benzbromarone group 1, 2 and 3 months after administration; creatinine elevation in 1 patient 3 months after dosing; 1 (nausea) and 3 patients showed moderate gastrointestinal reactions (flatulence, nausea, vomiting) 2 and 3 months after administration, respectively, as shown in Table 4.

TABLE 4 adverse reaction observations

6. Summary and discussion

Clinical researches for 40 years at home and abroad show that the benzbromarone is an effective uric acid reducing drug, but the safety of the drug is poor, and particularly, patients with gout accompanied with hyperuricemia are difficult to adhere to long-term administration due to well-known hepatotoxicity. In order to reduce toxic and side effects, particularly hepatotoxicity, of the tribromone and continuously exert the value of the old medicine, a small-scale clinical observation study is carried out, and a new treatment scheme is evaluated, namely, a apices capsule and a small-dose tribromone are combined and continuously administered for 3 months, whether obvious uric acid reducing effect exists or not, whether adverse reactions are reduced or not is observed, and the hepatotoxicity of the tribromone is emphasized. The control group is a single apices sophorae capsule or a large dosage of benzbromarone tablet.

Results: the total number of patients is 30, wherein the number of patients with gout is 24, the number of patients with hyperuricemia is 6, the ages are 21-75, 18 men and 12 women. Among 24 cases, gout patients all have gout attacks caused by the fact that hyperuricemia is not treated timely and normally. Patients are divided into three groups, wherein the 1 group is a single-use celery-locust capsule group, the 2 group is a combined group of the celery-locust capsule and the small-dose phenylbromarone tablet, and the 3 group is a single-use large-dose phenylbromarone tablet group.

After 3 months of treatment, we find that the uric acid reducing effect is obviously superior to that of the single-use apices, and has no obvious difference with that of the single-use large-dose apices, after the apices are combined with the small-dose apices, so that the two medicines are combined to have the synergistic uric acid reducing effect. Only 1 patient of the combined administration group has slight gastrointestinal reaction, and symptoms disappear after the treatment, which shows that adverse reaction is not increased after the combined administration, and the advantage of the combined administration, namely the effect of reducing uric acid is improved, and meanwhile, the adverse reaction is not increased. In contrast, the large dosage of the benzbromarone group found that 5 patients had elevated liver enzymes, 4 gastrointestinal adverse reactions and 1 kidney function injury, which were consistent with the literature report and within the expected range. Only 1 patient after using the apices sophorae capsule has slight gastrointestinal reaction, and the uric acid reducing effect is weaker than that of the combined administration, and the application is also within the expected range. The clinical test has a few cases, and in the future large-scale clinical research, the curative effect and the safety of the combined administration of the apices and the small-dose benzbromarone tablet are further observed.

In addition, we also observed that the tophus of one patient was reduced in volume after 3 months of combined administration of the apices in the form of a apices capsule and a small dosage of tribromone tablet, and completely disappeared after 6 months of combined administration.

The small knot: the curative effect and safety of the combination of the apices and the small-dose phenylbromarone tablets on patients with hyperuricemia and gout are compared and observed by 30 selected volunteers, and the combination of the apices and the small-dose phenylbromarone tablets is compared with the single administration of the apices and the large-dose phenylbromarone tablets. The result proves that the combined effect and safety of the two medicines are good, the possible toxic and side effects of the benzbromarone in large dosage are reduced, and especially, the benzbromarone is free from hepatotoxicity, is more suitable for long-term maintenance medication of patients with gout accompanied with hyperuricemia, and is a breakthrough in the field of gout treatment.

Example 3 Combined kit

The combined medicine box. Comprising the following steps:

1. a capsule contains herba Apii Graveolentis extract as active substance, wherein each capsule contains 225mg of herba Apii Graveolentis extract.

2. Tribromone tablet, 25mg gauge.

3. The ratio of the number of capsules containing the celery-locust extract as an active substance to the number of the benzbromarone tablets is 2:1 or 4: 1. or 6:1 or 8:1.

the combined medicine box comprises a medicine use instruction, wherein specific use instruction and a use method are recorded.

When the combined medicine box is used, a patient takes one benzbromarone tablet every day, and the number of the apices sophorae extract capsules taken every day is selected from 2, 4, 6 or 8.

Example 4 Combined kit

The combined medicine box. Comprising the following steps:

2. Tribromone tablets, specification 12.5mg.

The apices extract capsules used in examples 2 to 4 above can be prepared as follows:

example 5 preparation of apices Apii and Sophora japonica extract Capsule

(1) Prescription composition

(2) Preparation process

Preparing a solution: weighing polysorbate 80 with the prescription amount, and dissolving in a proper amount of absolute ethyl alcohol for standby.

Acid preparation particles: weighing tartaric acid, low-substituted hydroxypropyl cellulose and lactose, placing in a high-speed mixer granulator, and mixing for 5 minutes; adding absolute ethanol solution containing polysorbate 80, stirring for 3 min, discharging, pouring into a swing granulator, granulating with a 20 mesh sieve, and drying in a 55 ℃ oven.

Total mixing: placing the prescription amount of the celery-locust extract, the hydroxypropyl betacyclodextrin, the sodium bicarbonate and the acid particles into a high-speed mixer, and mixing for 5 minutes; adding magnesium stearate, mixing for 5 min, and discharging.

Dry granulating: the total mixed granules are added to a dry granulator for carrying out.

And (3) bagging: and (3) taking a zero-number capsule, and filling the granules subjected to dry granulation. Each capsule contains 225mg of the extract of apices Apii.

EXAMPLE 6 preparation of benzbromarone tablet

The tribromone tablets used in examples 2-4 above, 50mg in size, may be commercially available, and other sizes may be prepared according to known techniques, for example, chinese patent 201110392081.0, characterized by being obtained by the steps of:

(1) Superfine pulverizing the tribromoron-benzbromarone raw material by using an air flow pulverizer, wherein the particle size D50 of the micronized raw material is 5 mu m, respectively pulverizing microcrystalline cellulose, hydroxypropyl cellulose and lactose by using a universal high-speed pulverizer, and sieving with a 100-150 mesh sieve by using a vortex oscillating sieve after pulverizing;

(2) Preparing an adhesive, wherein every ten thousand sheets of the adhesive are 400-800ml of 1-3% hydroxypropyl methylcellulose 30% ethanol solution, and 25-45 ml Tween-80 and 10-30g sodium dodecyl sulfate are added as the adhesive;

(3) Spraying the adhesive prepared in the step (2) in 1/3 on the micronized tribromoron raw material in a boiling bed, and passing the prepared material through an 80-target standard sieve;

(4) Transferring the raw materials treated in the step (3), hydroxypropyl cellulose, microcrystalline cellulose and lactose into a high-efficiency wet granulator, starting a shearing blade after dry mixing for 3-5min by starting a stirring paddle, spraying an adhesive from an adhesive adding port of the wet granulator to granulate, adding the adhesive for less than 3min, and continuously granulating for 5-10min after adding the adhesive;

(5) Transferring the prepared wet particles to a high-efficiency boiling dryer for drying, adjusting the frequency of a fan until the materials can be in a good fluidization state in a pot, setting the air inlet temperature of equipment to 80 ℃, drying for 10-15 min, and controlling the particle water to be 2-5%;

(6) Finishing the particles prepared in the step (5) by adopting a finishing machine, wherein the pore diameter of a screen of the finishing machine is 18-20 meshes;

(7) Transferring the particles obtained in the step (6) into a three-dimensional motion mixer, adding weighed magnesium stearate, mixing for 5-10min, and tabletting.

According to the above method, tablets containing 12.5mg, 25mg or 50mg of benzbromarone per tablet can be prepared.

The preparation can also be carried out in the following way:

1. Prescription of benzbromarone tablet (specification: 25 mg) and preparation process thereof

(1) Prescription composition

(2) Preparation process

The tribromone is micronized. Weighing micronized benzbromarone with a prescription amount, lactose monohydrate and corn starch, and mixing in a wet granulator for 5min. To the above mixed material was added a 5% aqueous solution of hydroxypropylcellulose by atomization. Granulating the wet granules in a swing granulator, and sieving with a sieve of 20 meshes. The wet granules were dried in a fluidized bed at a drying temperature of 55 ℃. And (3) placing the dried granules into a swinging granule finishing machine for finishing, wherein the mesh number of the screen is 20. Placing the granules after finishing into a three-dimensional mixer, adding magnesium stearate with a prescription proportion, mixing for 5min, and tabletting by adopting a round punching sheet to obtain the finished product.

2. Prescription of benzbromarone tablet (specification: 12.5 mg) and preparation process thereof

(1) Prescription composition

(2) Preparation process

The preparation process is the same as that of 25mg benzbromarone tablet.

Example 7 Compound Capsule preparation comprising 225mg of Aphis Sophora extract and 3.125mg of benzbromarone

(1) Prescription composition

(2) Preparation process

Preparing acid particles containing benzbromarone: weighing micronized benzbromarone, tartaric acid, low-substituted hydroxypropyl cellulose and lactose, placing into a high-speed mixing granulator, and mixing for 5 minutes; adding absolute ethanol solution containing polysorbate 80, stirring for 3 min, discharging, pouring into a swing granulator, granulating with a 20 mesh sieve, and drying in a 55 ℃ oven.

Total mixing: placing the extract of the apices, sodium bicarbonate and acid particles in a high-speed mixer, and mixing for 5 minutes; adding magnesium stearate, mixing for 5 min, and discharging.

And (5) encapsulating: and taking a zero-number capsule, and filling the dry-method granulated particles into the capsule.

Each capsule contains 225mg of the apices sophorae extract and 3.125mg of the benzbromarone, and 4 capsules are taken every day, which is equivalent to 900mg of the apices sophorae extract and 12.5mg of benzbromarone daily dose.

Example 8 Compound Capsule preparation comprising 225mg of Cress Sophora extract and 6.25mg of benzbromarone

(1) Prescription composition

(2) Preparation process

The preparation process was the same as that of example 7.

Each capsule contains 225mg of the apices sophorae extract and 6.25mg of the benzbromarone, and 4 capsules are taken every day, which is equivalent to 900mg of the apices sophorae extract and 25mg of the benzbromarone daily dose.

Claims

1. The pharmaceutical composition of the celery-locust extract and the benzbromarone is characterized by comprising 225-2250mg of the celery-locust extract, 12.5-25mg of the benzbromarone and a pharmaceutically acceptable carrier, wherein the celery-locust extract is an alcohol extract of celery seed and pagodatree flower bud in a weight ratio of 2:1-4:1.

2. The pharmaceutical composition of the extract of apices sophorae and benzbromarone according to claim 1, characterized in that said pharmaceutical composition is selected from the group consisting of:

1) Consists of 450-1800mg of celery sophora extract, 12.5-25mg of benzbromarone and a pharmaceutically acceptable carrier, wherein the celery sophora extract is an alcohol extract of celery seed and pagodatree flower bud in a weight ratio of 2:1-4:1; or alternatively

2) Consists of 900-1350mg of the celery sophora extract, 12.5-25mg of the benzbromarone and a pharmaceutically acceptable carrier, wherein the celery sophora extract is an alcohol extract of celery seed and pagodatree flower bud in a weight ratio of 2:1-4:1.

3. A medicine box for treating gout and/or hyperuricemia of mammals or humans is characterized by comprising 225-2250mg of celery-locust extract, a pharmaceutically acceptable carrier, 12.5-25mg of benzbromarone and a medicine instruction, wherein the celery-locust extract is a celery seed and pagodatree flower bud alcohol extract with a weight ratio of 2:1-4:1.

4. A kit for treating gout and/or hyperuricemia in a mammal or human according to claim 3, wherein the kit is selected from the group consisting of:

1) Consists of independent 450-1800mg of celery seed extract, a pharmaceutically acceptable carrier, independent 12.5-25mg of benzbromarone and a drug instruction, wherein the celery seed extract is a celery seed extract and a pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1;

2) Consists of 900-1350mg of isolated celery seed extract, a pharmaceutically acceptable carrier, 12.5-25mg of tribromone and a drug instruction, wherein the isolated celery seed extract is a celery seed extract and a pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1;

3) Consists of 450-1800mg of celery seed extract, 12.5-25mg of benzbromarone and a mixture of pharmaceutically acceptable carriers and a drug instruction, wherein the celery seed extract is a celery seed and pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1; or,

4) Consists of 900-1350mg of the celery seed extract, 12.5-25mg of the benzbromarone and a mixture of pharmaceutically acceptable carriers and a drug instruction, wherein the celery seed extract is a celery seed and pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1.

5. The kit for treating gout and/or hyperuricemia in mammals or humans according to claim 4, wherein the isolated extract of apiacea is a granule, a tablet, a drop pill, or a capsule prepared by adding appropriate pharmaceutically acceptable excipients, and the tribromone is a tablet or capsule prepared by adding pharmaceutically acceptable carriers.

6. Use of a pharmaceutical composition of apices sophorae extract and tribromone in the preparation of a medicament for treating gout and/or hyperuricemia in a mammal or human, wherein the pharmaceutical composition consists of 225-2250mg of apices sophorae extract, 12.5-25mg of tribromone and a pharmaceutically acceptable carrier, wherein the apices sophorae extract is a mixture of apices and pagodatree flower bud alcohol extract in a weight ratio of 2:1-4:1.

7. The medicine composition for treating gout or hyperuricemia is characterized by comprising the following components in percentage by weight: 12.5 to 25; the preferable proportion is 450-1800: 12.5 to 25, and more preferably 900 to 1350:12.5 to 25, most preferably 900: 12.5-25, wherein the celery seed extract is a celery seed and pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1.

8. The pharmaceutical composition for treating gout or hyperuricemia according to claim 7, wherein the dosage form is a tablet, capsule, granule or other solid dosage form.

9. The pharmaceutical composition for treating gout or hyperuricemia according to claim 7 or 8, wherein the weight ratio of the apices extract to the tribromone in the pharmaceutical composition is 900:12.5 or 900:25.

10. a method of treating gout and/or hyperuricemia in a mammal or human comprising administering to the mammal or patient a pharmaceutically effective amount of a combination of apices comprising a daily dose of from 12.5mg to 25mg and a daily dose of apices comprising a daily dose of from 225mg to 2250mg calculated as extract, wherein the apices comprise apices comprising a combination of apices comprising a weight ratio of from 2:1 to 4:1 and a weight ratio of sophorae flos alcohol.