WO2023284426A1 - 一种抗痛风的芹槐提取物与非布司他药物组合物及其用途 - Google Patents
一种抗痛风的芹槐提取物与非布司他药物组合物及其用途 Download PDFInfo
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- extract
- celery
- febuxostat
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- gout
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
-
- 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)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/489—Sophora, e.g. necklacepod or mamani
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/04—Drugs for disorders of the urinary system for urolithiasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Definitions
- the invention relates to the technical field of medicines for treating gout or hyperuricemia, in particular, the invention relates to medicines or combination kits for treating gout and/or hyperuricemia in humans.
- the present invention also relates to the combined medicine and pharmaceutical application of the celery locust extract and febuxostat for treating gout or hyperuricemia.
- Gout and hyperuricemia are common metabolic diseases and important public health problems worldwide.
- Gout is a group of metabolic diseases that lead to elevated blood uric acid due to purine metabolism disorders. Therefore, an important cause of gout is that the patient's blood uric acid level exceeds the normal value, and before the onset, it is often accompanied by an inducing cause. Such as overeating before the onset, excessive consumption of high-purine foods such as broth, seafood, etc., frequent drinking, smoking, overwork, and exposure to wind and cold. Under a normal purine diet, if the fasting blood uric acid level is higher than 420 ⁇ mol/L twice on different days, it is called hyperuricemia.
- the blood uric acid is higher than the normal level, so it is called hyperuricemia.
- patients usually have no clinical manifestations, no joint pain, and no other discomforts, commonly known as the silent killer.
- the damage of high uric acid to the body has begun to appear, and slowly damage to blood vessels and kidneys in the patient's body.
- the concentration of uric acid in the serum of patients will increase, but clinical symptoms such as arthritis symptoms, tophi, or uric acid stones do not appear.
- Asymptomatic hyperuricemia may exist throughout life, but it may also turn into acute gouty arthritis or kidney stones. Most patients with asymptomatic hyperuricemia will first develop gout symptoms before changing to other conditions , but note that about 10% to 40% of patients will first develop symptoms of kidney stones.
- gout patients will start to experience severe pain and joint inflammation at night, and sometimes fever symptoms at the same time.
- the onset of this kind of situation often occurs after eating too much, especially after a banquet, drinking, drugs, trauma Or after surgery, and sometimes after an ankle sprain, especially if you're dehydrated.
- Clinically there may be no abnormality before the patient goes to bed, but the severe pain caused by gout attack may wake the patient up from sleep, and severe redness, swelling and heat pain will appear in the affected joints, which is unbearable pain. Symptoms will progress from mild to severe, and the chills and tremors will also increase. At the most painful time, it will be like tearing, which is unbearable, and then the symptoms will gradually decrease.
- the intermission period refers to the period during which symptoms disappear between two attacks, that is, the patient does not have any symptoms clinically.
- the length of the intermittent period varies, and may last for one or two days to several weeks, and then there will be another attack.
- uric acid crystals will deposit in the cartilage, synovial membrane, and soft tissues in the body, forming tophi.
- the higher the concentration of uric acid in the blood and the longer the duration of the disease the more tophi may be deposited, leading to chronic gouty arthritis, sometimes affecting blood vessels and kidneys, causing severe renal failure, making the kidney disease more serious, and This creates a vicious cycle where it is difficult to excrete uric acid, resulting in more tophi deposits.
- tophi There are often many places where tophi is deposited, including the pinnae, hands, elbows, Achilles tendons, ankles or toes. Sometimes it will cause local ulcers, which are not easy to heal, and even require amputation. Serious patients can cause joint deformation or chronic symptoms. When the foot deformation is serious, it may cause serious problems for the patient to wear shoes. In addition, the risk of kidney stones increases with the increase of serum uric acid concentration, and it often causes kidney disease. Hemodialysis may be required after kidney failure, which is also one of the main causes of death in gout patients.
- gout is common in obese, hypertriglyceridemia and hypertensive patients. Obese people will increase uric acid production and decrease excretion, causing hyperuricemia and gout. If these diseases appear clinically at the same time, it may also cause uncontrollable situations, so attention should be paid to the evaluation during the examination.
- Hyperuricemia and gout cannot be equated.
- High blood uric acid is not necessarily gout, but gout patients must have high blood uric acid. Clinically, it is generally only called gout when arthritis occurs. 5%-12% of hyperuricemia can develop into gout. Therefore, when doctors diagnose gout clinically, in addition to paying attention to high uric acid levels, they also need to include the onset of acute monoarthritis, and even the discovery of urate crystals, so that they can diagnose gout under the guidance of specialists. When gout attacks, some patients often have uric acid and blood uric acid in the normal range due to body compensation.
- Another epidemiological feature of gout is that the age of onset is getting younger.
- CRDC National Rheumatology Data Center
- the average age of gout patients in my country is 48.28 years old, which is gradually increasing. younger.
- a survey by the China-Japan Friendship Hospital found that in less than 20 years, the average age of onset of gout patients has dropped by 6.3 years, and the number of people suffering from gout for the first time before the age of 40 has increased by 26.3%.
- gout has become the second largest metabolic disease in my country after diabetes, and it is a systemic disease involving multi-system functions.
- hyperuricemia and gout are independent risk factors for diseases such as chronic kidney disease, hypertension, cardiovascular and cerebrovascular diseases, and diabetes, and are independent predictors of premature death.
- CKD chronic kidney disease
- CKD chronic kidney disease
- the risk of cardiovascular death increases by 16%
- the risk of all-cause death increases by 17%.
- Gouty nephropathy with a course of more than 10 years can easily lead to renal colic, hematuria, renal failure and uremia, and ultimately necessitates a kidney transplant to sustain life. About 15% of patients die from renal failure.
- gout In addition to the involvement of multiple system functions, gout also leads to joint deformities, which seriously affects the patient's limb function, which in turn causes huge obstacles and difficulties in daily life, and makes the patient lose the ability to work.
- hyperuricemia/gout also affects the sexual function of male patients.
- 76% of gouty men had erectile dysfunction (ED), compared with 51% of normal men.
- Gouty men have a higher rate of organic ED than other men. ED in these men was likely due to hyperuricemia, which is elevated uric acid years before the onset of gout symptoms.
- the treatment of gout with hyperuricemia is generally drug therapy and general treatment.
- the common therapeutic drugs in clinical practice include: non-steroidal anti-inflammatory drugs, colchicine, and glucocorticoids in the acute attack phase, and febuxostat, allopurinol, and benzbromarone in the remission phase of gout.
- patients should eat a low-purine diet, take baking soda tablets to alkalize the urine, drink plenty of water, exercise properly, and keep warm in the joints to promote the excretion of uric acid and prevent gout from recurring.
- the core of the treatment method is to reduce the blood uric acid level first, so as to reduce the attack of acute arthritis, prevent urate deposition, prevent the formation of tophi and renal function damage.
- Uric acid-lowering drugs commonly used in clinical practice are mainly divided into two categories: inhibiting uric acid production and promoting uric acid excretion.
- Drugs that inhibit the production of uric acid play a role in lowering uric acid by inhibiting xanthine oxidase.
- the initial dose of allopurinol is 50mg once, 1-2 times a day, and can be increased by 50-100mg every week to 200-300mg a day, divided into 2-3 times. Measure blood and urine uric acid levels every 2 weeks. If they have reached normal levels, do not increase them. If they are still high, they can be increased. But the maximum daily dose should not exceed 600mg. Side effects: gastrointestinal reactions, leukopenia, thrombocytopenia, anemia, bone marrow suppression. Others include hair loss, fever, lymphadenopathy, liver toxicity, interstitial nephritis and allergic vasculitis. It can also lead to exfoliative dermatitis, toxic epidermal necrolysis, severe erythema multiforme drug eruption, drug hypersensitivity syndrome, liver function damage, renal function damage, etc.
- the initial dose of febuxostat is 20 mg once a day, and the dosage can be gradually increased according to the blood uric acid value after 4 weeks of administration, with each increment of 20 mg, and the maximum daily dose is 80 mg.
- Side effects cardiovascular risk, abnormal liver function, nausea, arthralgia, rash.
- Both febuxostat and allopurinol monotherapy have serious side effects, and they are all dose-related. The greater the dose, the greater the side effects.
- febuxostat The main adverse reaction of febuxostat is cardiovascular toxicity.
- cardiovascular thrombotic events including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke
- Febuxostat was 0.74/100 patient-years (95% CI: 0.36-1.37)
- allopurinol was 0.60/100 patient-years (95% CI: 0.16-1.53).
- a causal relationship between febuxostat and cardiovascular thrombotic events has not been established. Pay attention to monitor the symptoms and signs of myocardial infarction and stroke when taking medicine.
- febuxostat In the latest treatment guidelines in the United States, febuxostat has been reduced to the second-line treatment drug, and for gout patients with cardiovascular disease, it is recommended to replace febuxostat with other urate-lowering drugs. In the revised U.S. label, febuxostat is only used in patients who cannot tolerate allopurinol or whose use is not recommended.
- Allopurinol may cause adverse reactions ranging from mild rash (MPE) to severe skin adverse reactions (SCAR). Specifically Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and rare but potentially life-threatening allopurinol allergy Syndrome (AHS).
- MPE mild rash
- SCAR severe skin adverse reactions
- SJS/TEN Stevens-Johnson syndrome/toxic epidermal necrolysis
- DRESS drug reaction with eosinophilia and systemic symptoms
- AHS rare but potentially life-threatening allopurinol allergy Syndrome
- AHS is a rare adverse reaction, but special attention should be paid to the use of it in the Chinese population (the incidence rate in Taiwan, China is 2.7%). Once it occurs, the fatality rate is as high as 30%. It has been confirmed that the occurrence of AHS is significantly correlated with HLA-B*5801, and the frequency of carrying this genotype in the Han population
- the combination of the two medicines can search for rheumatism-heat toxins in the meridians and joints, thereby treating the syndrome of wind pain and spasm in the past. It is a kind of anti-gout traditional Chinese medicine that treats both symptoms and root causes.
- the applicant systematically optimized the ratio of celery seed and sophora japonica, and conducted pharmacodynamic experiments and clinical studies on the compound extract. The results showed that the compound was reasonable in compatibility and had synergistic Sustained effect of lowering uric acid. Because it is a product of the same origin as medicine and food, it has basically no toxic and side effects, and it also shows good druggability, and can be made into medicines in the form of tablets, capsules, and granules.
- celery locust extract has a slow onset, mild effect, and basically no toxic side effects.
- it needs to be overcome before it can be expanded.
- the scope of application can better meet the clinical needs.
- the technical solution of the present invention is to provide a kind of pharmaceutical composition of Acacia celery extract and febuxostat that treats both the symptoms and root causes of gout, and is characterized in that
- the pharmaceutical composition is composed of 225-2250mg celery extract, 5-20mg febuxostat and a pharmaceutically acceptable carrier, wherein the celery extract is celery with a weight ratio of 2:1-4:1 Alcoholic extracts of celery seeds and sophora flower bud.
- a pharmaceutical composition of Acacia celery extract and febuxostat for treating both symptoms and root causes of gout characterized in that the pharmaceutical composition consists of 450-1800mg of Acacia celery extract, 10-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the celery locust extract is the alcohol extract of celery seeds and sophora flower bud in a weight ratio of 2:1-4:1.
- a pharmaceutical composition of Acacia celery extract and febuxostat for treating both symptoms and root causes of gout is characterized in that the pharmaceutical composition consists of 900-1350mg of Acacia celery extract, 10-20mg of febux It consists of a pharmaceutically acceptable carrier, wherein the celery locust extract is the alcohol extract of celery seeds and sophora flower bud in a weight ratio of 2:1-4:1.
- the present invention further provides a kit for treating gout and/or hyperuricemia in mammals or humans, the kit is composed of 225-2250mg celery locust extract, 5-20mg febuxostat and a pharmaceutically acceptable carrier and
- the drug instructions consist of the extract of celery locust being the alcohol extract of celery seeds and sophora flower bud with a weight ratio of 2:1-4:1.
- the present invention provides a kit for treating gout and/or hyperuricemia in mammals or humans.
- the present invention further provides a kit for treating gout and/or hyperuricemia in mammals or humans, the kit is composed of 900-1350mg celery locust extract, 10-20mg febuxostat and a drug instruction , wherein the celery locust extract is an alcoholic extract of celery seeds and sophora flower bud in a weight ratio of 2:1–4:1.
- the present invention also provides the use of a pharmaceutical composition of Acacia celery extract and febuxostat in the preparation of medicines for treating gout and/or hyperuricemia in mammals or humans, wherein the pharmaceutical composition consists of 225-2250mg of Acacia celery Extract, 5-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the celery extract is the alcohol extract of celery seed and sophora japonica with a weight ratio of 2:1-4:1.
- the present invention provides a pharmaceutical composition of Acacia celery extract and febuxostat, which is used to treat gout and/or hyperuricemia in mammals or humans, wherein the pharmaceutical composition consists of 225- 2250mg of Acacia celery extract, 5-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the Acacia celery extract is celery seed and Sophora japonica alcohol extract with a weight ratio of 2:1-4:1.
- the present invention provides a method for treating gout and/or hyperuricemia in mammals or humans in combination with acacia extract and febuxostat, comprising administering an effective dose of acacia extract and febuxostat to the patient , the daily dose of febuxostat tablets ranges from 5 mg to 20 mg, and the daily dose of celery locust extract in terms of extracts ranges from 225 mg to 2250 mg.
- the present invention also provides a combination of acacia extract and febuxostat in the preparation of medicines for the treatment of gout and/or hyperuricemia in mammals or humans, wherein the extract of acacia is in a weight ratio of 2: 1–4:1 celery seed and sophora japonica alcohol extract, preferably the daily dose of febuxostat tablet ranges from 5 mg to 20 mg, and the daily dose of celery locust extract in terms of extract ranges from 225 mg to 2250 mg .
- the present invention provides a combination of celery locust extract and febuxostat for use in the treatment of gout and/or hyperuricemia in mammals or humans, wherein the celery locust extract has a weight ratio of 2 :1–4:1 celery seed and sophora japonica alcohol extract, preferably the daily dosage range of the febuxostat tablet is 5 mg to 20 mg, and the daily dosage range of the celery locust extract is 225 mg to 20 mg in terms of extract. 2250mg.
- the present invention provides a method for treating gout and/or hyperuricemia in a mammal or a human, comprising administering to a patient an effective amount of a combination of acacia extract and febuxostat, wherein the acacia extract It is the alcohol extract of celery seed and sophora japonica with a weight ratio of 2:1-4:1, preferably the daily dosage range of the febuxostat tablet is 5mg to 20mg, and the daily dose of celery locust extract is calculated by extract.
- the dose ranges from 225 mg to 2250 mg, and the extract of celery locust and febuxostat are administered simultaneously, sequentially or separately.
- the present invention also provides the use of a locust extract in the preparation of a drug for improving febuxostat's treatment effect on gout and/or hyperuricemia and/or reducing its toxic and side effects, wherein the extract of locust
- the substance is the alcohol extract of celery seed and sophora japonica with a weight ratio of 2:1–4:1, preferably, the daily dosage range of the febuxostat tablet is 5mg to 20mg, and the celery locust extract is calculated as the extract The daily dosage range of 225mg to 2250mg.
- the present invention provides an extract of Acacia celery, which is used to improve the therapeutic effect of febuxostat on gout and/or hyperuricemia and/or reduce its toxic and side effects, wherein the extract of Acacia celery is The weight ratio is 2:1-4:1 of celery seed and sophora japonica alcohol extract, preferably, the daily dose range of the febuxostat tablet is 5 mg to 20 mg, and the daily dose of celery locust extract in terms of extract Dosage ranges from 225mg to 2250mg.
- the present invention provides a method for improving the therapeutic effect of febuxostat on gout and/or hyperuricemia and/or reducing its toxic and side effects, which includes administering effective doses of acacia extract and febuxostat to patients wherein the extract of Acacia celery is 2:1-4:1 weight ratio of celery seed and sophora alcohol extract, preferably the daily dosage range of the febuxostat tablet is 5mg to 20mg, The daily dosage range of the extract of celery locust is 225 mg to 2250 mg in terms of extract, and the extract of celery locust and febuxostat are administered simultaneously, sequentially or separately.
- the toxic and side effects of febuxostat can be cardiovascular toxicity, especially cardiovascular thrombotic events (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), as well as stomach discomfort, abnormal liver function, Abnormal renal function, etc.; especially cardiovascular toxicity.
- the celery locust extract of the present invention is obtained according to the formula and method of Chinese patent ZL201610313303.8.
- Celery seed and Sophora japonica alcohol extract of the present invention is the extract of celery seed or Sophora japonica in alcohol solvent, and the ratio of celery seed and Sophora japonica in the Sophora celery extract is 2:1 ⁇ 4: 1.
- the alcoholic solvent can be C1 ⁇ C4 alcoholic solvent, preferably methanol, ethanol, isopropanol, n-butanol, or an aqueous alcoholic solution, and the concentration of the aqueous alcoholic solution is preferably 50% by volume ⁇ 80%.
- the extract of Acacia celery in the present invention can be in the form of granules, tablets, dropping pills, or capsules, preferably capsules.
- the daily dose of febuxostat tablets ranges from 5 mg to 20 mg.
- a further preferred ratio is 10 mg to 20 mg.
- the daily dosage range of celery locust extract is 225mg to 2250mg (based on extract), the preferred daily dosage range is 450mg to 1800mg (based on extract), and the further preferred daily dosage range is 900mg to 1350mg (based on extract) ), the most preferred daily dosage of celery locust extract is 900 mg (in terms of extract).
- the daily dosage of the extract of celery locust is 900 mg, and the daily dosage of febuxostat is 5 mg-20 mg. Further preferably, first give the patient a daily dose of celery locust extract of 900 mg + a daily dose of febuxostat of 20 mg for a period of time, so that the blood uric acid level is rapidly reduced to a reasonable level, and then give the patient a daily dose of celery locust extract of 900 mg + febuxostat daily Dose 10mg, keep blood uric acid level stable and not rebound. For some patients with stable blood uric acid levels, the daily dose of celery locust extract 900 mg + febuxostat daily dose 5 mg can be selected as the maintenance dose.
- the present invention provides a combination of combined administration.
- the extract of celery locust and febuxostat can be made into solid preparation compositions, such as tablets, capsules, granules and other dosage forms, and provided to patients in the form of combined medication.
- the extract of celery locust is made into capsules by adding appropriate pharmaceutically acceptable excipients, and febuxostat is made into tablets or capsules.
- the forms of the combined medication include but not limited to simultaneous administration, sequential administration, interval administration, alternate administration and other forms of combined administration.
- the daily dosage range of febuxostat is 5mg to 20mg; the daily dosage range of celery locust extract is 225mg to 2250mg (extract), and the preferred daily dosage range is 450mg to 1800mg (extract In terms of extracts), the further preferred daily dosage range is 900 mg to 1350 mg (in terms of extracts), and the most preferred daily dose of the extract of Acacia celery is 900 mg (in terms of extracts).
- the present invention provides a combination medicine box product.
- the present invention provides a kit for treating gout and/or hyperuricemia in mammals and/or humans, the kit consists of 225-2250mg celery extract, 5-20mg febuxostat and a pharmaceutically acceptable carrier And the composition of the drug instructions, wherein the extract of celery locust is the extract of celery seed and sophora japonica alcohol with a weight ratio of 2:1-4:1.
- the kit is composed of 450-1800mg of celery locust extract, 10-20mg of febuxostat, a pharmaceutically acceptable carrier and a drug instruction, wherein the weight ratio of celery locust extract is 2:1-4:1 or, the kit consists of 900–1350mg celery extract, 10-20mg febuxostat and a pharmaceutically acceptable carrier and drug instructions, wherein the celery extract is Alcohol extracts of celery seed and sophora japonica in a weight ratio of 2:1–4:1.
- the extract of Acacia celery and febuxostat can be made into solid preparation compositions, such as tablets, capsules, granules and other dosage forms, and provided to patients in the form of a complete combination kit.
- solid preparation compositions such as tablets, capsules, granules and other dosage forms
- the daily dosage range of the febuxostat equivalent of the two preparations in the combination kit is 5 mg to 20 mg; the daily dosage range of the celery locust extract is 225 mg to 2250 mg (calculated as an extract), and the preferred daily dosage range is 450 mg to 1800 mg ( In terms of extract), the further preferred daily dosage range is 900 mg to 1350 mg (in terms of extract), and the most preferred daily dose of the extract of Acacia celery is 900 mg (in terms of extract).
- the daily dosage of the preparation of the celery locust extract is 900 mg, and the daily dosage of the febuxostat preparation is 5 mg-20 mg. It is further preferred that after giving the patient a daily dose of 900 mg of celery locust extract + febuxostat daily dose of 20 mg combination kit for a period of time, the blood uric acid level is quickly reduced to a reasonable level, and then the patient is given a daily dose of celery locust extract
- the combination kit of 900mg + febuxostat daily dose of 10mg keeps the blood uric acid level stable and does not rebound.
- the maintenance dose can be a combination kit with a daily dose of celery extract 900 mg + a daily dose of febuxostat 5 mg.
- the present invention provides a compound pharmaceutical composition.
- Acacia celery extract and febuxostat are mixed, a pharmaceutically acceptable carrier or adjuvant is added, and compound pharmaceutical compositions such as tablets, capsules, granules and other solid dosage forms are further prepared.
- the weight ratio of celery locust extract to febuxostat is (225-2250): (5-20); the preferred ratio is (450-1800): (5-20), and more preferably The ratio is (900-1350):(5-20); the most preferred ratio is 900:(5-20).
- the weight ratio of Acacia celery extract to febuxostat in the compound pharmaceutical composition is 900:5 or 900:10 or 900:20. It is further preferred that after giving the patient a medicinal composition with a weight ratio of celery locust extract and febuxostat of 900:20 for a period of time, the blood uric acid level is rapidly reduced to a reasonable level, and then the patient is given the celery locust extract and febuxostat.
- the pharmaceutical composition with the weight ratio of sestat being 900:10 keeps the blood uric acid level stable and does not rebound.
- the maintenance dose can be selected from the pharmaceutical composition of celery locust extract daily dose 900 mg + febuxostat daily dose 5 mg.
- the extract of celery locust used in the present invention is prepared by the method described in the inventor’s previous Chinese patent application CN201610313303.8, and the ratio of celery seed and pagoda japonica in the extract of celery locust is 2:1–4:1.
- the dosage form of the celery locust extract is preferably made into capsules (hereinafter referred to as celery locust capsules).
- each capsule contains 100-300 mg, preferably 225 mg, of the celery locust extract.
- febuxostat commercially available tablets can be used, and the dose can be divided according to the specifications. It is further preferred to prepare small-dose febuxostat tablets specially to ensure accurate dosage.
- the specific treatment plan of one embodiment is as follows:
- Qinhuai Capsules + Febuxostat Tablets Qinhuai Capsules (each based on extract: 225mg, 4 capsules per day, 2 capsules in the morning and evening) and Febuxostat Tablets (specification: 20mg, 1 tablet per day); After 4 weeks of implementation of the above treatment plan, it was adjusted to 4 capsules of Qinhuai Capsules per day, 2 capsules in the morning and evening + febuxostat tablets (specification: 20mg, half a tablet per day,) in combination.
- locust locust extract and febuxostat The mechanism of action of locust locust extract and febuxostat is through inhibiting the activity of xanthine oxidase, reducing uric acid synthesis and blood uric acid content, thereby reducing the deposition of urate in bones, joints and kidneys, and helping In the redissolution of gouty nodules and uric acid crystals. Therefore, the combined use of the two drugs makes it possible to reduce the dose of febuxostat due to the superposition of the mechanism of action.
- celery locust extract is a pure traditional Chinese medicine preparation with mild effects.
- the advantage is that the sharp drop in blood uric acid in a short period of time will not destroy the uric acid balance between blood and tissues and induce acute gout; the disadvantage is that the onset of action is slow, and the patient's blood uric acid level is slow to reach the standard.
- the combination of Qinhuai Capsules and febuxostat can produce a moderate uric acid-lowering effect relatively quickly, and has a strong ability to control the temporary fluctuation of blood uric acid level caused by diet.
- Maintaining the blood uric acid level ⁇ 360 ⁇ mol/L is the key to the treatment of gout.
- the blood uric acid concentration can reach the normal range, which is conducive to the dissolution of tophi and reduces the onset of gout, so as to effectively prevent various chronic diseases caused by hyperuricemia. damage.
- Clinical studies have shown that the combination of Acacia celery extract and a small dose of febuxostat can produce long-term and stable uric acid-lowering effect, and the fluctuation of blood uric acid is small.
- the blood uric acid level can be rapidly reduced, and at the same time, the urate deposited in the body can be quickly released, but it will not cause acute gout symptoms.
- Acute gout attacks can cause severe pain, which is unbearable. In severe cases, it can cause joint deformities, making it impossible to walk normally. Difficulty, if not treated in time, it will rupture on its own, the wound will not heal after years, and eventually amputation will be forced due to infection.
- gout In the field of gout treatment, the patient base is large, the growth rate is fast, and the market demand is broad. In the field of gout treatment, gout cannot be cured and requires life-long medication, so safety is particularly important. Most of the existing drugs have obvious defects in safety. Due to its high cardiovascular toxicity, febuxostat tablets have been downgraded to second-line drugs by the US gout treatment guidelines.
- patients with gout and hyperuricemia were randomly divided into three groups, and the patients in the test group were combined with extract of celery locust tree (2 capsules/time, 2 times/day) and small dose of febuxostat (before 20mg/day for 4 weeks, and 10mg/day for the next 8 weeks), the control group was only treated with celery locust extract (2 capsules/time, 2 times/day) or high-dose febuxostat tablets (40mg/day), the course of treatment for 12 weeks.
- the results showed that there was no abnormality in the electrocardiogram examination of patients in the combined medication group and the Qinhuai capsule group alone, and only mild gastrointestinal adverse reactions were found.
- the sources of experimental equipment are as follows:
- Swing pellet machine YK-160, Jiangyin Kanghe Machinery Manufacturing Factory
- Dry granulator RCG100-25L, Chongqing Yingge Granulation Coating Technology Co., Ltd.
- Fluidized bed WBF-2G, Chongqing Yingge Granulation Coating Technology Co., Ltd.
- Hopper mixer HSD5, Zhejiang Canaan Technology Co., Ltd.
- the Qinhuai capsules used in the following test examples can be prepared in the following manner.
- the extract of celery locusts used in the present invention can be prepared by the method described in the inventor's previous Chinese patent application CN201610313303.8.
- the ratio of celery seed and sophora japonica in the celery locust extract is 3:1, and the operation is as follows:
- Solution preparation Weigh the polysorbate 80 of prescription quantity, dissolve in appropriate amount of absolute ethanol, set aside.
- Acid-making granules Weigh tartaric acid, low-substituted hydroxypropyl cellulose and lactose, place them in a high-speed mixing granulator, and mix for 5 minutes; add the polysorbate 80 absolute ethanol solution prepared above, stir for 3 minutes, and discharge. Pour into a swinging granulator, granulate with a 20-mesh sieve, and dry in an oven at 55°C.
- Blending Put the prescription amount of celery extract, hydroxypropyl beta cyclodextrin, sodium bicarbonate and the acid granules prepared above in a high-speed mixer and mix for 5 minutes; then add magnesium stearate and continue mixing for 5 minutes , the material is ready for use.
- Dry granulation Add the blended granules prepared above to a dry granulator for granulation.
- Encapsulation Take the zero-size capsule and fill it with the above-mentioned dry granulated granules to obtain the product. Each capsule contains 225mg of celery locust extract.
- the febuxostat tablets used in the following test examples 20 mg, can be commercially available, or can be prepared in the following manner.
- Fluidized bed granulation put the prescribed amount of febuxostat, lactose monohydrate, pregelatinized starch, and hydroxypropyl cellulose in the fluidized bed, the air inlet temperature is 60°C, and granulate in one step, and the dry granules are sized at high speed Machine granulation.
- the granules prepared above are mixed with the prescription amount of lactose and croscarmellose sodium in a hopper mixer; the prescription amount of magnesium stearate is weighed and added to the materials for total mixing.
- Tablet compression Transfer the blended granules prepared above to the hopper of a tablet press (ZPS016 Shanghai Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd.) for tablet compression.
- Embodiment 3 comprises the compound preparation of celery locust extract and febuxostat
- the extract of celery locusts used in the present invention can be prepared by the method described in the inventor's previous Chinese patent application CN201610313303.8.
- Example 3-1 the ratio of celery seed and Sophora japonica in the extract of celery locust is 2:1, the ratio of Example 3-2 is 3:1, and the ratio of Example 3-3 is 4:1, prepared by the following process :
- Solution preparation Weigh the prescribed amount of polysorbate 80, dissolve in an appropriate amount of absolute ethanol, and set aside.
- Preparation of acid granules containing febuxostat Weigh febuxostat, tartaric acid, low-substituted hydroxypropyl cellulose and lactose, place them in a high-speed mixing granulator, start the mixing granulator, and stir for 5 minutes; add the above-prepared The polysorbate 80 absolute ethanol solution was stirred for 3 minutes, discharged, poured into a swinging granulator, granulated with a 20-mesh sieve, and dried in an oven at 55°C.
- Total mixing put the prescription amount of celery extract, hydroxypropyl beta cyclodextrin, sodium bicarbonate and magnesium stearate in a high-speed mixer, start the mixer, and mix for 5 minutes; add the acid granules prepared above , continue mixing for 5 minutes, stop stirring, and discharge for later use.
- Dry granulation Add the blended granules prepared above to a dry powder granulator for dry granulation.
- Encapsulation Take the zero-size capsule and fill it with the above-mentioned dry granulated granules to obtain the product.
- the extract of celery locust was prepared according to Example 1, and the ratio of celery seed and sophora japonica in the celery locust extract was 3:1. Sealed and protected from light, stored in a dry place at room temperature.
- mice Male SD rats (provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were selected for the experiment. They were randomly divided into normal group and model group according to body weight. The normal group (10 rats) was given normal diet and drinking water; the model group (280 rats) was given normal diet and 10% fructose aqueous solution. After successful modeling, the rats in the model group were randomly divided into 10 rats in each group, including 1 rat in the model control group and 27 rats in the experimental group. The normal group and the model control group were given 0.5% CMC-Na aqueous solution for intragastric administration, and the remaining groups were administered by intragastric administration according to the corresponding drug dissolved in 0.5% CMC-Na aqueous solution (ultrasonic dissolution). Once, administration for 28 days. Before administration and 28 days after administration, the blood uric acid (SUA) level was detected by biochemical method.
- SUA blood uric acid
- the dose of celery locust extract group is equivalent to the human dose equivalent to the number of celery locust capsules (specification 225mg): A1: 1 capsule; A2: 2 capsules; A3: 4 capsules; A4: 6 capsules; A5: 8 capsules ; A6: 10 capsules; the dose of febuxostat group equivalent to the human dose is equivalent to B1: 10 mg; B2: 20 mg; B3: 40 mg.
- the synergistic effect is not obvious due to the small dose of celery locust extract in group A1+B1 and A1+B2 group, and the excessive dose of celery locust extract in group A6+B1 and A6+B2 , the synergistic effect is not obvious, and the middle dose has obvious synergistic effect.
- the reduction effect of the blood uric acid level in the combination group is greater than the sum of the effects of the two single drugs administered separately, and there is an obvious synergistic effect.
- test example 2 Clinical effect
- febuxostat single drug produces uric acid-lowering effect at conventional doses, it is also accompanied by strong side effects, especially cardiovascular toxicity, which can be fatal in severe cases.
- a treatment plan for the combination of Qinhuai Capsules and low-dose febuxostat was developed, and Qinhuai capsules were taken orally or combined with small-dose febuxostat tablets to investigate the effectiveness of treating gout with hyperuricemia. sex and safety.
- Gender 24 males and 6 females, including 5 patients with high uric acid and 25 patients with gout diagnosed by the hospital (21 males and 4 females).
- Group 1 (Qinhuai capsule group): 4 capsules per day, 2 capsules in the morning and evening.
- Group 2 (combined use of Qinhuai Capsules and small-dose febuxostat tablets): the initial dose is 4 capsules per day, 2 capsules in the morning and evening + 1 febuxostat tablet (specification: 20mg) per day . After one month, depending on the level of uric acid, continue to reduce the dosage of febuxostat, and adjust it to 4 capsules of Qinhuai capsules per day, 2 capsules in the morning and evening + half a tablet of febuxostat (specification: 20mg) per day. After 1 month, depending on the level of uric acid, continue the maintenance treatment.
- Group 3 high-dose febuxostat tablet group: the initial dose is 20 mg/day, once/day. After 1 month, gradually increase the dosage according to the blood uric acid value, each increment is 20mg, and the maximum daily dose is 80mg.
- febuxostat is an effective drug for lowering uric acid, but the safety of the drug has attracted attention, especially because of the cardiovascular toxicity of febuxostat, it is difficult for patients with gout and hyperuricemia Adhere to long-term medication. Some gout patients would rather endure severe pain than take medicine because they are afraid of the adverse reactions of gout medicine.
- Results The trial enrolled 30 patients, among whom the gout patients all suffered from gout attacks due to the lack of timely and standardized treatment of hyperuricemia.
- the patients were divided into three groups, the first group was Qinhuai Capsules alone, the second group was Qinhuai Capsules combined with low-dose febuxostat tablets, and the third group was large-dose febuxostat tablets alone. Dose febuxostat group.
- Qinhuai Capsules are combined with low-dose febuxostat tablets.
- 30 patients with gout and hyperuricemia were enrolled, and the combination of Qinhuai Capsules and low-dose febuxostat tablets was compared and observed.
- the curative effect and safety of the drug on patients with hyperuricemia and gout were compared with Qinhuai Capsule alone and high-dose febuxostat tablets.
- This combination kit includes:
- Acacia extract is used as a capsule of active substance, and each capsule contains 225mg of Acacia extract.
- the ratio of the number of capsules of celery locust extract as the active substance to the number of febuxostat tablets is 2:1 or 4:1, or 6:1 or 8:1.
- This combination kit includes:
- Acacia extract is used as a capsule of active substance, and each capsule contains 225mg of Acacia extract.
- the ratio of the number of capsules of celery locust extract as the active substance to the number of febuxostat capsules is 2:1 or 4:1, or 6:1 or 8:1.
- This combination kit includes:
- Acacia extract is used as a capsule of active substance, and each capsule contains 225mg of Acacia extract.
- the ratio of the number of capsules of celery locust extract as the active substance to the number of febuxostat tablets is 2:1 or 4:1, or 6:1 or 8:1.
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Abstract
一种抗痛风的芹槐提取物与非布司他药物组合物及其用途，芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物。将芹槐提取物与小剂量非布司他组合用于治疗哺乳动物或人类痛风、或高尿酸血症，可降低非布司他毒副反应。
Description
本发明涉及治疗痛风或高尿酸血症的药物技术领域，具体的说，本发明涉及用于人类治疗痛风和/或高尿酸血症的药物或组合药盒。本发明还涉及芹槐提取物与非布司他治疗痛风、或高尿酸血症联合用药以及制药的应用。
痛风、高尿酸血症是常见的代谢性疾病，是全球范围内的重要公共卫生问题。
痛风是由于嘌呤代谢紊乱而导致血尿酸升高的一组代谢性疾病。因此痛风的一个重要原因为患者的血尿酸水平超过正常值，同时在发病之前，大多时候还会伴有诱发的原因。如在发病之前暴饮暴食，过量的吃高嘌呤的食物如肉汤、海鲜等，经常饮酒、吸烟，过度劳累以及受风寒等。在正常嘌呤饮食状态下，非同日两次空腹血尿酸水平高于420μmol/L，即称为高尿酸血症。
痛风的临床自然病程分为如下四个阶段：
(一)无症状期
此时血尿酸高于正常的水平，因此叫做高尿酸血症。这个时期通常患者没有任何的临床表现，没有关节的疼痛，没有一些其他的不适，俗称沉默的杀手。但是高尿酸对机体的损害已开始出现，并慢慢的在患者身体内出现对血管的损害、肾脏的损害。在此时期的病人血清中的尿酸浓度会增高，但并未出现临床上的关节炎症状、痛风石、或尿酸结石等临床症状。有些男性病人会在青春期即发生此种情形，且可能与家族史有关，女性病人则较常在停经期才出现。无症状的高尿酸血症情形可能终其一生都会存在，但也可能会转变成急性痛风关节炎或肾结石，临床大多数无症状的高尿酸血症病人会先发生痛风症状，才转变其它情形，但注意约有10％至40％病人则会先发生肾结石症状。
(二)急性关节炎期
此时期的病人会在受累关节部位出现剧痛症状，在病发的早期较 常侵犯单一关节(占90％)，其中约有半数发生于一脚掌骨关节，因此病人疼痛难当，无法穿上鞋子，常会穿著拖鞋前来就诊，但发展到后来，也很可能会侵犯多处关节，有时也可能只侵犯其它部位，痛风常犯部位包括大脚趾、脚背、脚踝、脚跟、膝、腕、手指和肘等部位，但其它部位也会发作。
一般而言，痛风病人会在晚上开始发生剧疼及关节发炎的情形，有时候也会同时出现发烧症状，此种情形的发作常常见于饮食过量，尤其是宴客后发作、饮酒、药物、外伤或手术后，有时在脚踝扭伤后也会引发，尤其是脱水时。临床上在病人就睡前可能尚无任何异样，但痛风发作时所引起的剧痛可能会使病人从睡梦中痛醒，且在受犯关节会出现严重红肿热痛现象，令人疼痛难耐，症状会由轻而重，发冷与颤抖现象也会因而加重，最痛时有如撕裂般，令人无法忍受，而后症状再慢慢减轻。
(三)间歇期
间歇期指的是两次发作的之间症状消失的期间，即临床上病人未出现任何症状。间歇期长短不等，可能会持续一、二天至几周，然后会再次发作，极少数的病人痛风终生只发作一次，不再发作症状，但是绝大多数病人会复发。反复发作后倾向于多关节性，发作较严重，发作期较长，且伴随着发烧。
(四)慢性关节炎期
痛风长期发作，未经治疗或治疗不规则，在体内会有尿酸结晶沉积在软骨、滑液膜、及软组织中，形成痛风石。而且血中的尿酸浓度越高，患病的期间越久，则可能会沉积越多的痛风石，导致慢性痛风关节炎，有时会影响血管与肾，造成严重肾功能衰竭，使肾病越严重，并造成不易排泄尿酸的恶性循环，令痛风石的沉积也就越多。
常常沉积痛风石的部位很多，包括耳廓、手部、肘部、跟腱、脚踝或脚趾，有时候更会引起局部溃疡，不易愈合，甚至于需接受截除手术。严重病人且会引起关节变形或慢性症状，足部变形严重时可能造成病人穿鞋上的严重问题。此外，发生肾结石的危险性随血清中尿酸浓度增高而增加，且也常会引起肾病变，肾衰竭后可能需接受血液透析，这也是引起痛风病人死亡的主要死因之一。
此外，痛风常见于肥胖、高三酸甘油脂血症及高血压病人。肥胖者尿酸产量会增多且排泄会减少，引起高尿酸血与痛风。若临床上同时出现这些疾病，也可能造成不易控制的情形，因此在检查时应同时注意评估。
高尿酸血症和痛风不能划等号，血尿酸高不一定是痛风，但痛风的病人一定血尿酸高。临床上，一般仅在发生关节炎时才称为痛风。5％-12％的高尿酸血症可发展为痛风。因此医生在临床诊断痛风时，除了关注尿酸高，还要包括急性单关节炎的发作，甚至也包括尿酸盐结晶晶体的发现，这样才能在专科医生指导下诊断是痛风。而在痛风发作的时候，往往有的病人因为机体代偿原因，甚至尿酸、血尿酸在正常范围。
随着经济快速发展和人群生活方式的明显改变，中国高尿酸血症和痛风患病率显著增高。根据最新研究结果，高尿酸血症患者已占总人口13.3％，特别是在经济发达的城市和沿海地区，高尿酸血症的患病率高达5％-23.5％。而痛风患病率在1％～3％，且逐年上升。根据2017年《中国痛风现状报告》，我国高尿酸血症患者人数已达1.7亿，其中痛风患者超过8000万人，正以每年9.7％的年增长率迅速增加。
痛风的另一个流行病学特点是发病年龄越来越年轻。国家风湿病数据中心(CRDC)网络注册及随访研究的阶段数据显示，基于全国27个省、市、自治区100家医院的6814例痛风患者有效病例发现，我国痛风患者平均年龄为48.28岁，逐步趋年轻化。中日友好医院的一项调查研究发现，痛风在不到20年的时间里，患者的平均发病年龄下降了6.3岁，40岁以前第1次患上痛风的人数增加了26.3％。
目前痛风已成为我国仅次于糖尿病的第二大代谢类疾病，多系统功能受累的全身性疾病。许多证据表明，高尿酸血症和痛风是慢性肾病、高血压、心脑血管疾病及糖尿病等疾病的独立危险因素，是过早死亡的独立预测因子。以慢性肾病(CKD)为例，3-4期患者血尿酸水平每升高1mg/dL，心血管死亡风险增加16％，全因死亡风险增加17％。病程超过10年以上的痛风性肾病，容易引发肾绞痛、血尿，直至肾功能衰竭及尿毒症，最终不得不换肾来维持生命。大约15％的患者死于肾衰竭。
除多系统功能受累外，痛风还导致关节畸形，严重影响患者的肢体功能，进而造成生活起居遇到巨大阻碍和困难，使患者丧失工作能力。已有痛风患者申领残疾证的新闻报道。高尿酸血症/痛风还对男性患者的性功能造成影响。一项在医院风湿科室对中年男性进行的研究中，76％的痛风男性患有勃起功能障碍(ED)，而普通男性是51％。痛风男性患器质性ED的几率要高于其他男性。这些男性的ED很可能是由于高尿酸血症造成的，这在出现痛风症状之前的几年就会有尿酸增高。
痛风伴发高尿酸血症的治疗方法一般是药物治疗和一般治疗。在临床上常见的治疗药物包括：急性发作期使用非甾类抗炎药、秋水仙碱、糖皮质激素，痛风的缓解期使用非布司他、别嘌醇以及苯溴马隆等。一般治疗，患者日常要低嘌呤饮食，可以服用小苏打片碱化尿液以及日常多喝水，适当运动，关节部位注意保暖，来促进尿酸的排泄，防止痛风复发。
目前痛风尚无法根治，治疗方法的核心首先要降低血尿酸水平，进而才能减少急性关节炎发作，预防尿酸盐沉积，防止痛风石形成及肾功能损害。临床上常用的降尿酸药物主要分为两大类：抑制尿酸生成和促进尿酸排泄。
1、抑制尿酸生成的药物，通过抑制黄嘌呤氧化酶发挥降尿酸作用。
①别嘌醇初始剂量一次50mg，一日1～2次，每周可递增50～100mg，至一日200～300mg，分2～3次服。每2周测血和尿的尿酸水平，如已达正常水平，则不再增量，如仍高可再递增。但一日最大量不得大于600mg。副作用：胃肠道反应、白细胞减少、血小板减少、贫血、骨髓抑制。其他有脱发、发热、淋巴结肿大、肝毒性、间质性肾炎及过敏性血管炎等。还可导致剥脱性皮炎、中毒性表皮坏死松解症、重症多形红斑型药疹、药物超敏综合征、肝功能损伤、肾功能损伤等。
别嘌醇的结构式如下：
②非布司他初始剂量为20mg每日1次，且可在给药开始4周后根据血尿酸值逐渐增加用量，每次增量20mg，每日最大剂量为80mg。副作用：心血管风险、肝功能异常、恶心、关节痛、皮疹。
非布司他的结构式如下：
2、促进尿酸排泄的药物
①苯溴马隆成人每次口服50mg(一片)，每日一次，早餐后服用。服药1周后检查患者血清尿酸浓度，或可在治疗初期每日口服100mg(二片)，早餐后服用，待血尿酸降至正常范围时改为每日50mg(一片)。副作用：肝毒性、尿酸结石、肝肾结石。②丙磺舒、磺吡酮只能用于肾功能正常者，肝损较多见。
现有技术的不足之处在于目前在痛风、高尿酸血症的临床治疗领域，抑制尿酸生成的药物，如：非布司他和别嘌醇的用量相当大。多年来的临床研究表明，非布司他和别嘌醇虽可降低血尿酸水平，但缺点也很明显：
1)疗效有限
非布司他和别嘌醇单药的疗效有限。即使增加剂量较大后，每年仍有数以百万的患者的病情得不到控制，血尿酸不达标(低于360μmol/L)。
2)安全性较差，增加剂量后会加重不良反应。
非布司他和别嘌醇单药的毒副作用都很大，而且都与剂量有关。剂量越大，毒副作用越大。
非布司他的主要不良反应是心血管毒性。在随机对照研究中，相比使用别嘌醇，使用非布司他治疗的患者发生心血管血栓事件(包括心血管死亡、非致死性心肌梗死、非致死性脑卒中)的概率较高，其中非布司他为0.74/100例患者-年(95％CI：0.36～1.37)，别嘌醇为0.60/100例患者-年(95％CI：0.16～1.53)。尚未确定非布司他与心血管血栓事件的因果关系。用药时注意监测心肌梗死和脑卒中的症状及体征。
在以伴有心血管疾病的痛风患者为目标人群的CARES研究中，与别嘌醇组相比，非布司他组中心血管死亡的发生率较高。因此，伴有心血管疾病的痛风患者应慎用本品。如经临床医生评估患者使用本品的获益大于风险，使用本品期间应密切关注原有心血管疾病恶化和新发心血管疾病，一旦发生以上情况须及时进行医疗救治。
2017年11月15日，美国FDA发布了非布司他的心血管风险警告，称非布司他相较于别嘌醇增加与心脏有关的全因死亡风险。虽然美国FDA公布的临床数据中56.6％的患者中断了治疗，45％的患者失访，存在重大偏倚，但这仍然提醒在临床应用过程中，需要监测患者心血管疾病的发生，注意心血管风险患者的预防工作，对存在高度心血管风险的患者，用药需要充分权衡利弊。在美国的最新治疗指南中，已将非布司他降为二线治疗药，并且对于合并有心血管疾病的痛风患者，建议把非布司他换成其他降尿酸药。在修订后的美国说明书中，非布司他只用于不耐受别嘌醇或不建议使用别嘌醇的患者。
别嘌醇可能导致的不良反应从轻度的皮疹(MPE)到严重皮肤不良反应(SCAR)。具体有史蒂文斯约翰逊综合征/中毒性表皮坏死松解症(SJS/TEN)，嗜酸性粒细胞增多和全身症状的药物反应(DRESS)，以及罕见但发生时可能危及生命的别嘌呤醇过敏综合征(AHS)。AHS是一种罕见的不良反应，但在中国人群中使用应特别关注(中国台湾地区的发生率为2.7％)，一旦发生，致死率高达30％。已证实AHS的发生与HLA-B*5801存在明显相关性，且汉族人群携带该基因型的频率为10％-20％。因此，对于HLA-B*5801阳性患者，国内外指南均不推荐使用别嘌醇。
我国的中医药防治痛风有着悠久的历史，经过数千年的临床实践，积累了丰富的医疗经验，并形成了系统的理论体系和治疗方法。在西药降尿酸的疗效和安全性均不理想，但临床需求迫切的情况下，本发明人发明了一种纯中药制剂，按照中医理论将芹菜籽与槐米进行了组方(中国专利ZL201610313303.8)。芹菜籽清热除烦，利水消肿，能散气，消肿，开通阻滞。槐米善于清热利湿，凉血止血，能清血分之热。两药相伍，可搜经络关节之风湿热毒，从而治疗历节风痛拘挛之证，是一种标本兼治的抗痛风中药。申请人将芹菜籽和槐米二味药在药效 学的指导下进行了系统的优化配比，并对复方提取物进行药效学实验及临床研究，结果表明该复方配伍合理，具有协同持续降尿酸的作用。由于是药食同源产品，因此基本无毒副作用，而且还展现出良好的成药性，可以制成片剂、胶囊、颗粒剂等形式的药品。
像大多数中药那样，芹槐提取物起效慢，作用温和，基本无毒副作用，但是对于痛风急性发作，以及应对血尿酸水平受饮食影响导致的临时波动控制不足，需要加以克服，才能扩大其适用的范围，更好地满足临床上的需要。
目前，临床上迫切需要一种降尿酸作用更强、更持久，同时毒副作用更小的标本兼治的药物或药物组合。
发明内容
为了克服现有西药和中药用于降尿酸的疗效和安全性的缺点，本发明的技术方案在于提供一种标本兼治抗痛风的芹槐提取物与非布司他的药物组合物，其特征在于所述的药物组合物由225–2250mg芹槐提取物、5–20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽(celery seeds)和槐米(sophora flower bud)醇提取物。
优选的是，一种标本兼治抗痛风的芹槐提取物与非布司他的药物组合物，其特征在于所述的药物组合物由450–1800mg芹槐提取物、10–20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽(celery seeds)和槐米(sophora flower bud)醇提取物。
特别优选的是，一种标本兼治抗痛风的芹槐提取物与非布司他的药物组合物，其特征在于所述的药物组合物由900–1350mg芹槐提取物、10–20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽(celery seeds)和槐米(sophora flower bud)醇提取物。
本发明进一步提供一种治疗哺乳动物或人类痛风和/或高尿酸血症的药盒，该药盒由225–2250mg芹槐提取物、5–20mg非布司他和药学上可接受的载体以及药物说明书组成，其中芹槐提取物是重量比为2:1 –4:1的芹菜籽(celery seeds)和槐米(sophora flower bud)醇提取物。
优选的是，本发明提供一种治疗哺乳动物或人类痛风和/或高尿酸血症的药盒，该药盒由450–1800mg芹槐提取物、10–20mg非布司他和药学上可接受的载体以及药物说明书组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽(celery seeds)和槐米(sophora flower bud)醇提取物。
特别优选是，本发明进一步提供一种治疗哺乳动物或人类痛风和/或高尿酸血症的药盒，该药盒由900–1350mg芹槐提取物、10–20mg非布司他和药物说明书组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽(celery seeds)和槐米(sophora flower bud)醇提取物。
本发明还提供一种芹槐提取物和非布司他的药物组合物在制备治疗哺乳动物或人痛风和/或高尿酸血症药物中的用途，其中该药物组合物由225–2250mg芹槐提取物、5–20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物。
换言之，本发明提供一种芹槐提取物与非布司他的药物组合物，该药物组合物用于治疗哺乳动物或人类的痛风和/或高尿酸血症，其中该药物组合物由225–2250mg芹槐提取物、5–20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物。
换言之，本发明提供一种芹槐提取物和非布司他联合用药治疗哺乳动物或人类痛风和/或高尿酸血症的方法，包括向患者施用有效剂量的芹槐提取物和非布司他，非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg。
本发明还提供一种芹槐提取物和非布司他的组合在制备治疗哺乳动物或人痛风和/或高尿酸血症药物中的用途，其中所述芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物，优选地所述非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg。
换言之，本发明提供一种芹槐提取物和非布司他的组合，其用于治疗哺乳动物或人痛风和/或高尿酸血症的用途，其中所述芹槐提取物 是重量比为2:1–4:1的芹菜籽和槐米醇提取物，优选地所述非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg。
换言之，本发明提供一种治疗哺乳动物或人类痛风和/或高尿酸血症的方法，其包括向患者施用有效量的芹槐提取物和非布司他的组合，其中所述芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物，优选地所述非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg，所述芹槐提取物和非布司他同时、相继或分开施用。
本发明还提供一种芹槐提取物在制备用于提高非布司他的痛风和/或高尿酸血症治疗效果和/或降低其毒副作用的药物中的用途，其中，所述芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物，优选地，所述非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg。
换言之，本发明提供一种芹槐提取物，其用于提高非布司他的痛风和/或高尿酸血症治疗效果和/或降低其毒副作用的用途，其中，所述芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物，优选地，所述非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg。
换言之，本发明提供一种提高非布司他的痛风和/或高尿酸血症治疗效果和/或降低其毒副作用的方法，其包括向患者施用有效量的芹槐提取物和非布司他的组合，其中所述芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物，优选地所述非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg，所述芹槐提取物和非布司他同时、相继或分开施用。
所述的非布司他的毒副作用可以是心血管毒性，特别是心血管血栓事件(包括心血管死亡、非致死性心肌梗死、非致死性脑卒中)，以及胃部不适、肝功能异常、肾功能异常等；特别指心血管毒性。
本发明所述的芹槐提取物为按照中国专利ZL201610313303.8的配方和方法获得。
本发明所述的芹菜籽和槐米醇提取物为芹菜籽或槐米在醇类溶剂 中的提取物，芹槐提取物中芹菜籽和槐米的比例为2:1～4:1，所述醇类溶剂可以是C1～C4醇类溶剂，优选甲醇、乙醇、异丙醇、正丁醇，也可以是醇类水溶液，且该醇类水溶液的浓度优选为按体积计50％～80％。本发明所述的芹槐提取物可以是颗粒剂、片剂、滴丸、或者胶囊剂，优选为胶囊剂。
进一步讲，发明了新的药物组合物：芹槐提取物+小剂量非布司他药物组合物。
非布司他片的日剂量范围为5mg至20mg。进一步优选的比例为10mg至20mg。
芹槐提取物的日剂量范围为225mg至2250mg(以提取物计)，优选的日剂量范围为450mg至1800mg(以提取物计)，进一步优选的日剂量范围为900mg至1350mg(以提取物计)，最优选芹槐提取物的日剂量为900mg(以提取物计)。
作为优选联合使用的一个实施方式，芹槐提取物的日剂量为900mg，非布司他日剂量为5mg-20mg。进一步优选，先给予患者芹槐提取物的日剂量900mg+非布司他日剂量20mg一段时间后，使得血尿酸水平快速降低到合理水平，再给予患者芹槐提取物日剂量900mg+非布司他日剂量10mg，保持血尿酸水平平稳不反弹。对于部分血尿酸水平平稳的患者，维持剂量可以选用芹槐提取物日剂量900mg+非布司他日剂量5mg。
作为本发明的第一种实施方式，本发明提供一种联合给药的组合方式。芹槐提取物与非布司他可以分别制成固体制剂组合物，例如片剂、胶囊、颗粒剂及其他剂型，以联合用药的形式，提供给患者。优选芹槐提取物添加适当的药学上可接受的辅料制成胶囊，非布司他制成片剂或者胶囊剂。所述联合用药的形式，包括但不限于同时服用、顺序服用、间隔服用、交替服用以及其他联合用药方式。
联合用药的形式中，非布司他的日剂量范围为5mg至20mg；芹槐提取物的日剂量范围为225mg至2250mg(以提取物计)，优选的日剂量范围为450mg至1800mg(以提取物计)，进一步优选的日剂量范围为900mg至1350mg(以提取物计)，最优选芹槐提取物的日剂量为900mg(以提取物计)。
作为本发明的第二种实施方式，本发明提供了一种组合药盒产品。
本发明提供了一种治疗哺乳动物和/人类痛风和/或高尿酸血症的药盒，该药盒由225–2250mg芹槐提取物、5–20mg非布司他和药学上可接受的载体以及药物说明书组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物。进一步地，该药盒由450–1800mg芹槐提取物，10-20mg非布司他和药学上可接受的载体以及药物说明书组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物；或者，该药盒由900–1350mg芹槐提取物、10-20mg非布司他和药学上可接受的载体以及药物说明书组成，其中芹槐提取物是重量比为2:1–4:1的芹菜籽和槐米醇提取物。
所述药盒中，芹槐提取物与非布司他可以分别制成固体制剂组合物，例如片剂、胶囊、颗粒剂及其他剂型，以成套的组合药盒的形式，提供给患者。剂型上，优选芹槐提取物添加适当的药学上可接受的辅料(载体)制成胶囊，非布司他添加适当的药学上可接受的辅料(载体)制成片剂或者胶囊剂。组合药盒中两种制剂折合非布司他的日剂量范围为5mg至20mg；芹槐提取物的日剂量范围为225mg至2250mg(以提取物计)，优选的日剂量范围为450mg至1800mg(以提取物计)，进一步优选的日剂量范围为900mg至1350mg(以提取物计)，最优选芹槐提取物的日剂量为900mg(以提取物计)。
作为上述组合药盒实施方式的一个优选实施方式，芹槐提取物制剂的日剂量为900mg，非布司他制剂日剂量为5mg-20mg。进一步优选，先给予患者使用芹槐提取物的日剂量900mg+非布司他日剂量20mg的组合药盒一段时间后，使得血尿酸水平快速降低到合理水平，再给予患者使用芹槐提取物日剂量900mg+非布司他日剂量10mg的组合药盒，保持血尿酸水平平稳不反弹。对于部分血尿酸水平平稳的患者，维持剂量可以选用芹槐提取物日剂量900mg+非布司他日剂量5mg的组合药盒。
作为本发明的第三种实施方式，本发明提供了一种复方药物组合物。将芹槐提取物与非布司他二者混合，添加药学上可接受的载体或者辅料，并进一步制成复方药物组合物，例如片剂、胶囊、颗粒剂及其他固体剂型。复方药物组合物中，芹槐提取物与非布司他的重量比 为(225～2250)：(5～20)；优选的比例为(450～1800)：(5～20)，进一步优选的比例为(900～1350)：(5～20)；最优选的比例为900：(5～20)。
作为优选的一个实施方式，复方药物组合物中芹槐提取物与非布司他的重量比为900:5或900：10或900：20。进一步优选，先给予患者芹槐提取物与非布司他的重量比为900：20的药物组合物一段时间后，使得血尿酸水平快速降低到合理水平，再给予患者芹槐提取物与非布司他的重量比为900：10的药物组合物，保持血尿酸水平平稳不反弹。对于部分血尿酸水平平稳的患者，维持剂量可以选用芹槐提取物日剂量900mg+非布司他日剂量5mg的药物组合物。
本发明采用的芹槐提取物，采用本发明人之前的中国专利申请CN201610313303.8中所述的方法制备，芹槐提取物中芹菜籽和槐米的比例为2:1–4:1。
芹槐提取物的剂型优选制成胶囊(以下简称芹槐胶囊)。作为一个实施方式，每粒胶囊含有芹槐提取物100–300mg，优选225mg。非布司他可以采用市售片剂，按照规格进行剂量分割，进一步优选专门制备小剂量非布司他片剂，以保证剂量准确。
当采用联合给药时，一种实施方式的具体治疗方案如下：
芹槐胶囊+非布司他片：芹槐胶囊(每粒以提取物计：225mg，4粒/天，早晚各2粒)与非布司他片(规格：20mg，1片/日)；在上述治疗方案实施4周后，调整为芹槐胶囊4粒/天，早晚各2粒+非布司他片(规格：20mg，半片/日，)合用。
经过临床前和初步的临床研究，发明人意外地发现芹槐胶囊与非布司他组合或联合用药，具有如下意料不到的优势：
1、作用机制叠加
芹槐提取物和非布司他的作用机制都是通过抑制黄嘌呤氧化酶的活性，使尿酸合成减少，血尿酸含量降低，从而减少尿酸盐在骨、关节及肾脏的沉着，并有助于痛风结节及尿酸结晶的重新溶解。因此两药合用，由于作用机制叠加，使得减少非布司他的剂量成为可能。
2、临床起效快，能维持长效，还有溶解肾结石和痛风石的作用
(1)起效快
如上所述，芹槐提取物是纯中药制剂，作用温和。优点是不会由 于血尿酸在短时间大幅度下降，破坏了血液和组织间的尿酸平衡，诱发急性痛风；缺点是起效慢，患者的血尿酸水平达标迟缓。经过临床研究后发现，芹槐胶囊与非布司他合用后，能较为迅速的产生适中的降尿酸作用，应对血尿酸水平受饮食影响导致的临时波动的控制力强。
(2)作用持久
维持血尿酸水平<360μmol/L是痛风治疗的关键，经过降酸治疗使血尿酸浓度达到正常范围，有利于痛风石溶解并减少痛风的发作，才能有效防止高尿酸血症带来的各种慢性损害。临床研究表明，芹槐提取物与小剂量的非布司他合用后，能产生长期稳定的降尿酸作用，血尿酸的波动小。联合用药治疗过程中可将血尿酸水平快速降低，同时快速释放体内沉积的尿酸盐，但并不会导致发生急性痛风症状。一些痛风伴发高尿酸血症患者联合用药的最长时间为10年，血尿酸始终保持在正常水平。而且在长期用药过程中，偶尔有急性痛风发作，症状也比以前轻，而且恢复期也短，发病的间隔延长。
(3)溶解肾结石和痛风石
尿酸盐沉积于肾脏产生尿酸盐结晶及形成尿酸结石，导致梗阻性肾病的发生和发展，最终导致终末期肾病。通常25％的痛风患者有肾结石，较正常人高200倍。目前，冲击波碎石、微创取石手术等方式已成肾结石临床治疗的主要手段，但并未从根本上扭转结石形成的诱因，仍有一定的复发率。
此外，尿酸盐极易沉积于关节处而形成“痛风石”，急性痛风发作时导致剧烈疼痛，难以忍受，严重时可导致关节畸形，无法正常行走，甚至手握笔、书、筷子等物困难，如不及时治疗会自行破溃，伤口经年不愈，最终因感染而迫使截肢致残。
经临床研究表明，一些痛风伴发高尿酸血症患者在长期合用芹槐提取物和小剂量非布司他后，可使血尿酸水平迅速下降，当血中的尿酸水平下降后，打破了沉积在组织中尿酸平衡，使得尿酸逐步从组织中溶解进入血液，导致沉积尿酸逐步溶解变小到消失。可促进已形成尿酸结石晶体逐步解体，具有溶尿酸结石的作用。可恢复关节灵活度，避免变形、畸形、致残等状况。
3、显著降低毒副反应，适合长期用药
痛风治疗领域患者基数大，增长速度快，市场需求广阔。而在痛风治疗领域，痛风无法治愈，需要终生服药，因此安全性尤为重要。现有药物多在安全性方面具有明显缺陷。非布司他片由于心血管毒性大，已被美国的痛风治疗指南降为二线用药。
根据发明人的临床观察研究，将痛风伴高尿酸血症患者随机分为三组，试验组患者合用芹槐提取物(2粒/次，2次/天)与小剂量非布司他(前4周为20mg/天，随后8周为10mg/天)，对照组单用芹槐提取物(2粒/次，2次/天)或大剂量非布司他片(40mg/天)，疗程为12周。结果表明，联合用药组和单用芹槐胶囊组患者的心电图检查未见任何异常，只发现轻微的胃肠道不良反应。大剂量非布司他组的少数患者出现心电图异常。提示芹槐提取物与小剂量非布司他合用，可显著降低大剂量非布司他片的心脏毒性，便于痛风患者长期维持治疗。
以下通过具体实施例进一步描述本发明，但应理解这些实施例仅是为了阐明本发明，并不以任何形式限制本发明的范围。
实验材料和仪器：
实验材料来源如下：
实验仪器来源如下：
高速混合制粒机：miniCG，创志机电科技有限公司
摇摆颗粒机：YK-160，江阴市康和机械制造厂
烘箱：DHG-9140A，北京陆希科技有限公司
干法制粒机：RCG100-25L，重庆英格造粒包衣技术有限公司
流化床：WBF-2G，重庆英格造粒包衣技术有限公司
高速整粒机：YZLJ-125型，创志机电科技有限公司
料斗混合机：HSD5，浙江迦南科技股份有限公司
压片机：ZPS016型，上海天祥健台制药机械有限公司
实施例1芹槐提取物胶囊的制备
以下测试例中所使用的芹槐胶囊，可以按照如下方式制备。
(1)处方组成
本发明所用芹槐提取物，可采用本发明人之前的中国专利申请CN201610313303.8中所述的方法制备。
在本实施例中，芹槐提取物中芹菜籽和槐米的比例为3:1，操作如下：
取芹菜籽15kg和槐米5kg，加入10倍重量的60％(V/V)乙醇水溶液50-60℃提取3次，每次60分钟。将提取液合并，减压浓缩，真空干燥，制得本发明芹槐提取物480g。
(2)制备工艺
溶液配制：称取处方量的聚山梨酯80，溶于适量的无水乙醇，备 用。
制酸颗粒：称取酒石酸、低取代羟丙纤维素和乳糖，置于高速混合制粒机中，混合5分钟；加入上述制备的聚山梨酯80无水乙醇溶液，搅拌3分钟，出料，倾入摇摆颗粒机中，20目筛制粒，置于55℃烘箱干燥。
总混：将处方量芹槐提取物、羟丙基倍他环糊精、碳酸氢钠和如上制备的酸颗粒置于高速混合机中，混合5分钟；再加入硬脂酸镁继续混合5分钟，出料备用。
干法制粒：将如上制备的总混颗粒加入到干法制粒机进行制粒。
装囊：取零号胶囊，填充上述干法制粒的颗粒，即得。每粒胶囊含芹槐提取物225mg。
实施例2非布司他片的制备
以下测试例中所使用的非布司他片，20mg可以采用市售品，也可以采用如下方式制备。
非布司他片(规格：5mg、10mg、20mg)的制备：
(1)处方组成
(2)制备工艺
3个规格均按以下工艺制备：
流化床制粒：将处方量非布司他、一水乳糖、预胶化淀粉、羟丙纤维素置于流化床中，进风温度60℃，一步制粒，干颗粒用高速整粒机整粒。
混合：将如上制得的颗粒与处方量的乳糖、交联羧甲基纤维素钠置于料斗混合机中混合；称取处方量的硬脂酸镁加入到物料中进行总混。
压片：将如上制得的总混颗粒转移至压片机(ZPS016型上海天祥健台制药机械有限公司)料斗中压片。
实施例3包含芹槐提取物和非布司他的复方制剂
芹槐提取物225mg+非布司他1.25mg、2.5mg、5mg的胶囊制备。
(1)处方
本发明所用芹槐提取物，可采用本发明人之前的中国专利申请CN201610313303.8中所述的方法制备。
实施例3-1中芹槐提取物中芹菜籽和槐米的比例为2:1，实施例3-2比例为3:1，实施例3-3比例为4:1，采用如下工艺制备：
按照重量比例取芹菜籽和槐米，加入10倍重量的60％(V/V)乙醇水溶液50-60℃提取3次，每次60分钟。将提取液合并，减压浓缩，真空干燥，制得本发明所用的芹槐提取物。
(2)制备工艺
3个规格按以下工艺制备：
溶液配制：称取处方量的聚山梨酯80，溶于适量的无水乙醇，备用。
制含非布司他的酸颗粒：称取非布司他、酒石酸、低取代羟丙纤 维素和乳糖，置于高速混合制粒机中，启动混合制粒机，搅拌5分钟；加入如上制备的聚山梨酯80无水乙醇溶液,搅拌3分钟，出料，倾入摇摆颗粒机中，20目筛制粒，置于55℃烘箱干燥。
总混：将处方量芹槐提取物、羟丙基倍他环糊精、碳酸氢钠和硬脂酸镁置于高速混合机中，启动混合机，混合5分钟；加入如上制得的酸颗粒，继续混合5分钟，停止搅拌，出料备用。
干法制粒：将如上制得的总混颗粒加入到干粉制粒机进行干法造粒。
装囊：取零号胶囊，填充上述干法制粒的颗粒，即得。
每日服用4粒胶囊，分别相当于芹槐提取物日剂量900mg+非布司他剂量5mg或芹槐提取物日剂量900mg+非布司他剂量10mg或芹槐提取物日剂量900mg+非布司他剂量20mg。
测试例1动物试验数据
实验材料
供试品信息：
芹槐提取物，按照实施例1制备，芹槐提取物中芹菜籽和槐米的比例为3:1。密封避光，室温干燥处保存。
阳性药信息：
非布司他片，生产厂家：日本TEIJIN PHARMA LIMITED。规格：20mg；批号：6484，有效期至2022年02月。不超过25℃密闭保存。
检测试剂盒：
尿酸检测试剂盒：中生北控生物科技股份有限公司，批号：19251。
溶媒：
0.5％CMC-Na水溶液；CMC-Na批号：20190123，国药集团化学试剂有限公司。
实验方法
研究选用雄性SD大鼠(由北京维通利华实验动物技术有限公司提供)进行实验。按体重分层随机分为正常组、模型组。正常组(10只)给予普通饮食、饮水；模型组(280只)给予普通饮食及10％果糖水溶液。造模成功后，模型组大鼠随机分组，每组10只，包括模型 对照组1个，实验组27个。正常组、模型对照组给予0.5％CMC-Na水溶液灌胃，其余组按相应药物溶于0.5％CMC-Na水溶液(超声溶解)灌胃给药，给药容量0.1mL/kg体重，每天灌胃一次，给药28天。分别于给药前和给药28天，采用生化法检测血尿酸(SUA)水平。
按照芹槐胶囊(每粒以提取物计为225mg)由人折算为动物的剂量过程如下：
以芹槐胶囊人的日剂量为1粒至10粒计，折算成大鼠的剂量为225mg×0.018/0.2kg＝20.25mg/kg至225mg×10粒×0.018/0.2kg＝202.5mg/kg。
非布司他由人折算为动物的剂量过程如下：
以非布司他人的日剂量10mg-40mg计算，折算成大鼠的剂量为10mg×0.018/0.2kg＝0.9mg/kg至40mg×0.018/0.2kg＝3.6mg/kg。
各实验组的给药剂量见下表1：
表1各实验组的给药剂量
注：芹槐提取物组剂量折合人用剂量后相当于芹槐胶囊(规格225mg)的个数：A1：1粒；A2：2粒；A3：4粒；A4：6粒；A5：8粒；A6：10粒；非布司他组剂量折合人用剂量后相当于B1：10mg；B2：20mg；B3：40mg。
实验结果：见表2。
表2芹槐胶囊与非布司他片合用对高尿酸血症大鼠血尿酸水平的影响(μmol/L，
n＝10)
注：以上数据均为每组10只大鼠的均值。
实验数据表明：
1、随着芹槐提取物剂量递增，血尿酸水平的降低效果递增，但是高剂量增加的程度比低剂量的少。
2、随着非布司他剂量递增，效果递增，大剂量效果更强，但是副作用开始明显出现。
3、二者合用给药时，A1+B1组和A1+B2组由于芹槐提取物剂量较小，协同作用不明显，A6+B1组和A6+B2组，由于芹槐提取物剂量过大，协同作用也不明显，中间剂量有明显协同作用，与模型组相比较，合用组血尿酸水平的降低效果，大于两个单药分别给药的效果之和，有明显的协同效果。
4、当非布司他剂量较大时，从A1+B3组到A6+B3组，均未发现有协同作用，推测时由于非布司他大剂量的效果过于强烈，整组协同作用都不存在。
测试例2临床效果的观察
一、观察目的
如上所述，非布司他片单药在常规剂量下产生降尿酸作用的同时，也伴有较强的副作用，尤其是心血管毒性，严重时致死。鉴于此，在患者自愿的基础上，制定芹槐胶囊与小剂量非布司他合用的治疗方案，口服芹槐胶囊或与小剂量非布司他片合用，考察治疗痛风伴高尿酸血症有效性和安全性。
二、患者病例情况
人数：30例。随机分为3组，每组10例。
性别：男24例，女6例，其中高尿酸患者5例，医院诊断痛风患者25例(男21例，女4例)。
年龄范围：18-70岁
三、剂量设计方案
1、第1组(单用芹槐胶囊组)：4粒/日，早晚各2粒。
2、第2组(芹槐胶囊与小剂量非布司他片联用组)：起始剂量为4粒/日，早晚各2粒+非布司他片(规格：20mg)1片/日。1个月后视其尿酸水平，继续降低非布司他用量，调整为芹槐胶囊4粒/日，早晚各2粒+非布司他片(规格：20mg)半片/日。1个月后视其尿酸水平，继续维持治疗。
3、第3组(单用大剂量非布司他片组)：起始剂量为20mg/天，1次/天。1个月后根据血尿酸值逐渐增加用量，每次增量20mg，每日最大剂量为80mg。
四、疗效观察结果
三组治疗前的血尿酸值无显著差异(p>0.05)。治疗1、2、3个月后，联合用药组的血尿酸值显著低于单用芹槐胶囊组(p<0.05)，与大剂量非布司他组无显著差异(p>0.05)，见表3。
表3三组各时间点的血尿酸值对比(μmol/L，
n＝10)
注1：*与第2组相比，有显著差异(p<0.05)；
#与第2组相比，无显著差异(p<0.05)
注2：以上数据均为每组10例患者的均值。
五、不良反应观察结果
连续口服给药3个月后，单用芹槐胶囊组只有2例患者在给药第2天发现胃肠道不良反应，胃部有一过性烧灼感，未经治疗，继续用药后消失。
芹槐胶囊+小剂量非布司他组有1例患者在给药后第5天出现轻度的胀气，第2天症状消失，未停药。
大剂量非布司他组在给药后第2个月有1例患者出现胃部不适；第3个月有2例患者的心电图出现异常表现，2例患者的肝功能异常，1例患者的肾功能异常，见表4。
表4不良反应观察结果
六、小结与讨论
国内外多年来的临床研究表明，非布司他是有效的降尿酸药，但用药的安全性问题引起关注，特别是由于非布司他的心血管毒性，使得痛风伴高尿酸血症患者难以坚持长期用药。有的痛风患者就是因为忌惮痛风治疗药的不良反应，宁可忍受剧痛，也不吃药。
为了降低非布司他的毒副作用，继续发挥老药的临床价值，将芹槐胶囊与小剂量非布司他合用，连续给药3个月，观察是否有显著的降尿酸作用，以及不良反应是否下降，重点观察非布司他的不良反应。对照组为单用芹槐胶囊或大剂量非布司他片。
结果：试验入组30例患者，其中痛风患者均是由于高尿酸症没有得到及时、规范的治疗，导致的痛风发作。在临床试验中，分别将患者分为三组，第1组为单用芹槐胶囊组，第2组为芹槐胶囊与小剂量非布司他片联用组，第3组为单用大剂量非布司他组。
经过3个月的治疗，惊喜的发现，芹槐胶囊与小剂量非布司他合用后，降尿酸作用显著优于单用芹槐胶囊，与单用大剂量非布司他无显著差异，提示两药合用有协同降尿酸作用。
在安全性方面，芹槐胶囊与小剂量非布司他联用组只有1例患者出现轻度的胀气，第2天症状消失，未停药。而大剂量非布司他组患者出现胃部不适、心电图出现异常表现、肝功能异常、肾功能异常，与文献报道一致，在预期的范围内。单用芹槐胶囊后只有1例患者出现轻度的胃部一过性烧灼感，降尿酸作用弱于联合用药，也在预期的范围内。
小结：芹槐胶囊与小剂量非布司他片合用，在这项临床试验中，分别入组30例痛风伴高尿酸血症患者，比较并观察了芹槐胶囊与小剂量非布司他联合用药对高尿酸症和痛风患者的疗效和安全性，同时与芹槐胶囊单独用药及大剂量非布司他片进行对比。结果表明，芹槐胶囊与小剂量非布司他片合用的疗效与安全性俱佳，降低了非布司他片在大剂量时可能出现毒副作用，尤其是未见非布司他片的心脏毒性等不良反应，更加适合痛风伴高尿酸血症患者长期维持用药，是痛风治疗领域的一个突破，为日后进行的大规模的临床试验提供了初步的试验数据。
此外，在合用组中还发现一例患者的肾结石在治疗3个月后消失。3个月研究实验结束后，血尿酸水平平稳的3名患者，采用芹槐提取物日剂量900mg+非布司他日剂量5mg的合用方式，继续进行维持阶段的治疗，血尿酸水平依然长期保持合理水平。
实施例4组合药盒
该组合药盒包括：
1、芹槐提取物作为活性物质的胶囊，每粒胶囊含有芹槐提取物225mg。
2、非布司他片剂，规格5mg。
芹槐提取物作为活性物质的胶囊个数与非布司他片剂的数量比例为2：1或4：1、或6：1或8：1。
3、药品使用说明书，其中表述该组合药盒使用时，患者每日服用5mg(1片)非布司他片，每日服用芹槐提取物胶囊个数选自2个、4个、6个或8个。
实施例5组合药盒
该组合药盒包括：
1、芹槐提取物作为活性物质的胶囊，每粒胶囊含有芹槐提取物225mg。
2、非布司他胶囊剂，规格10mg。
芹槐提取物作为活性物质的胶囊个数与非布司他胶囊剂的数量比例为2：1或4：1、或6：1或8：1。
3、药品使用说明书，其中表述该组合药盒使用时，患者每日服用一粒非布司他胶囊，每日服用芹槐提取物胶囊个数选自2个、4个、6个或8个。
实施例6组合药盒
该组合药盒包括：
1、芹槐提取物作为活性物质的胶囊，每粒胶囊含有芹槐提取物225mg。
2、非布司他片剂，规格20mg。
芹槐提取物作为活性物质的胶囊个数与非布司他片剂的数量比例为2：1或4：1、或6：1或8：1。
3、药品使用说明书，其中表述该组合药盒使用时，患者每日服用一片非布司他片，每日服用芹槐提取物胶囊个数选自2个、4个、6个 或8个。
Claims (11)
- 一种标本兼治抗痛风的芹槐提取物与非布司他的药物组合物，其特征在于所述药物组合物由225-2250mg芹槐提取物、5-20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物。
- 根据权利要求1所述的药物组合物，其特征在于所述的药物组合物选自：所述的药物组合物由450-1800mg芹槐提取物、10-20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物；或者所述的药物组合物由900-1350mg芹槐提取物、10-20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物。
- 一种治疗哺乳动物或人类痛风和/或高尿酸血症的药盒，其特征在于该药盒由225-2250mg芹槐提取物、5-20mg非布司他和药学上可接受的载体以及药物说明书组成，其中芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物。
- 根据权利要求3所述的药盒，其特征在于该药盒选自：该药盒由450-1800mg芹槐提取物、10-20mg非布司他和药学上可接受的载体以及药物说明书组成，其中芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物；或者，该药盒由900-1350mg芹槐提取物、10-20mg非布司他和药学上可接受的载体以及药物说明书组成，其中芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物。
- 根据权利要求3或4所述的药盒，其特征在于该药盒中芹槐提取物是添加药学上可接受的载体制成的颗粒剂、片剂、滴丸、或者胶囊剂，非布司他是添加药学上可接受的载体制成的片剂或者胶囊。
- 一种芹槐提取物和非布司他的药物组合物在制备治疗哺乳动物或人痛风和/或高尿酸血症药物中的用途，其中该药物组合物由225-2250mg芹槐提取物、5-20mg非布司他和药学上可接受的载体组成，其中芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物。
- 一种芹槐提取物和非布司他的组合在制备治疗哺乳动物或人痛风和/或高尿酸血症药物中的用途，其中所述芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物，优选地所述非布司他的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg。
- 一种芹槐提取物在制备用于提高非布司他的痛风和/或高尿酸血症治疗效果和/或降低其毒副作用的药物中的用途，其中，所述芹槐提取物是重量比为2:1-4:1的芹菜籽和槐米醇提取物，优选地，所述非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg。
- 根据权利要求7或8所述的用途，其中芹槐提取物和非布司他同时、相继或分开施用。
- 一种芹槐提取物与非布司他的药物组合物，该药物组合物用于治疗哺乳动物或人类的痛风和/或高尿酸血症。
- 一种芹槐提取物和非布司他联合用药治疗哺乳动物或人类痛风和/或高尿酸血症的方法，包括向患者施用有效剂量的芹槐提取物和非布司他，非布司他片的日剂量范围为5mg至20mg，以提取物计芹槐提取物的日剂量范围为225mg至2250mg。
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