CN115607588B - Anti-gout apiary extract and non-bestatin pharmaceutical composition for treating both symptoms and root causes and application thereof - Google Patents
Anti-gout apiary extract and non-bestatin pharmaceutical composition for treating both symptoms and root causes and application thereof Download PDFInfo
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- CN115607588B CN115607588B CN202110790637.5A CN202110790637A CN115607588B CN 115607588 B CN115607588 B CN 115607588B CN 202110790637 A CN202110790637 A CN 202110790637A CN 115607588 B CN115607588 B CN 115607588B
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- febuxostat
- apices
- gout
- uric acid
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- 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
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Abstract
The invention provides a medicine composition of a celery-locust extract and febuxostat for treating gout and treating both symptoms and root causes and application thereof. The invention also provides a combined medicine box for treating gout or hyperuricemia, which comprises the apices extract preparation and a small dose of febuxostat or the preparation.
Description
Technical Field
The invention relates to the technical field of medicines for treating gout or hyperuricemia, in particular to a medicine or a combined medicine box for treating gout and/or hyperuricemia of human beings. The invention also relates to application of the apices and the extracts of the febuxostat in preparing medicines 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 often invade a single joint (accounting for 90%) at the early stage of the disease, and about half of the cases occur in a metacarpal joint, so that the patients are hard to pain, cannot wear shoes, often get a diagnosis before wearing slippers, but develop later, are likely to invade a plurality of joints, sometimes only invade other parts, and gout often invade parts including big toe, instep, ankle, heel, knee, wrist, finger, elbow and the like, but other parts 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 mild and heavy, the phenomena of coldness and tremors 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. The drug for inhibiting uric acid generation plays a role in reducing uric acid by inhibiting xanthine oxidase, and (1) the initial dose of allopurinol is 50mg once a day and 1 to 2 times a day, and can be increased by 50 to 100mg every week to 200 to 300mg a day and taken for 2 to 3 times. Blood and urine acid levels were measured every 2 weeks and were no longer increased if normal levels had been reached, and were still high and were allowed to be increased again. But the maximum daily amount must not be greater than 600mg. Side effects: 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.
Allopurinol has the following structural formula:
(2) the initial dose of febuxostat was 20mg 1 time a day, and the dose could be gradually increased by 20mg each time according to the blood uric acid level 4 weeks after the start of administration, with a maximum daily dose of 80mg. Side effects: cardiovascular risk, liver dysfunction, nausea, arthralgia, and rash.
The febuxostat has the following structural formula:
2. the medicament for promoting uric acid excretion (1) is taken orally by an adult 50mg (one tablet) 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.
The defects of the prior art are that in the clinical treatment field of gout and hyperuricemia, medicines for inhibiting uric acid generation, such as: the amount of febuxostat and allopurinol used is quite large. Clinical studies over the years have shown that febuxostat and allopurinol can reduce blood uric acid levels, but the disadvantages are also apparent:
1. has limited curative effect
Febuxostat and allopurinol have limited efficacy alone. Even after a large dose is added, millions of patients still cannot control the disease 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 single drug of febuxostat and allopurinol has great toxic and side effects and is dose-dependent. The larger the dosage, the larger the toxic and side effects.
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 causal relationship of febuxostat with cardiovascular thrombotic events has not been established. The symptoms and signs of myocardial infarction and cerebral apoplexy are monitored during administration.
In the CARES study with gout patients with cardiovascular disease as the target group, the incidence of cardiovascular death was higher in the febuxostat group compared to the allopurinol group. Therefore, gout patients with cardiovascular diseases should take the herb with cautions. If clinical doctors evaluate that the benefit of the product is greater than the risk, patients should pay close attention to the deterioration of the original cardiovascular diseases and the new cardiovascular diseases during the use of the product, and medical treatment should be carried out in time once the above conditions occur.
On 11 and 15 2017, the us FDA issued a warning of the cardiovascular risk of febuxostat, known as increasing the risk of total cause death associated with the heart compared to allopurinol. Although 56.6% of the clinical data published by the U.S. FDA discontinued treatment, 45% lost visit, and there was a significant bias, this still reminded that during clinical use, the occurrence of cardiovascular disease in patients needs to be monitored, attention was paid to the preventive work of cardiovascular risk patients, and the medication needs to be sufficiently balanced against the 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, and for gout patients who incorporate cardiovascular disease, it has been suggested to replace febuxostat with other uric acid lowering agents. In the revised us specification, febuxostat is used only for patients who are intolerant to allopurinol or who are not advised to use allopurinol.
The adverse reactions that allopurinol can cause range from mild rash (MPE) to severe adverse skin reactions (SCARs). Specifically Stevens Johnson syndrome/toxic epidermolysis necrotica (SJS/TEN), eosinophilia and systemic symptomatic Drug Response (DRESS), and rare but life-threatening allopurinol allergy syndrome (AHS). AHS is a rare adverse reaction, but is of particular concern for use in the chinese population (incidence in taiwan of china is 2.7%), once it occurs, mortality is as high as 30%. It has been shown that there is a clear correlation between the occurrence of AHS and HLA-B5801, and that the frequency of carrying this genotype is 10% -20% in the han population. Therefore, for HLA-B5801 positive patients, the guidelines at home and abroad do not recommend allopurinol.
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 invention 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 ZL 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 celery-sophora japonica extract 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 celery-sophora japonica extract 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 is to provide a pharmaceutical composition of apices and non-bust for treating both symptoms and root causes of gout, which is characterized by comprising 225-2250mg of apices and 5-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the apices and the root causes are apices (celery seeds) and flos sophorae (sophora flower bud) alcohol extracts in a weight ratio of 2:1-4:1.
Preferably, the anti-gout drug combination is characterized by comprising 450-1800mg of the celery-locust extract, 10-20mg of febuxostat 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.
Particularly preferred are: the medicine composition is characterized by comprising 900-1350mg of the apices, 10-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the apices extract is a celery seed (celery seeds) and a pagodatree flower bud (sophora flower bud) alcohol extract 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 apices, 5-20mg of febuxostat, a pharmaceutically acceptable carrier and a medicine instruction, wherein the apices extract is an alcohol extract of apices seeds and flos sophorae (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 apices, 10-20mg of febuxostat, a pharmaceutically acceptable carrier and a medicine instruction, wherein the apices extract is an alcohol extract of celery seeds (celeries) and pagodatree flower buds (sophora flower bud) 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 consisting of 900-1350mg of apices, 10-20mg of febuxostat and a pharmaceutical specification, wherein the apices extract is an alcohol extract of apices seeds and pagodatree flower bud (sophora flower bud) in a weight ratio of 2:1-4:1.
The invention also provides application of the pharmaceutical composition of the apiacea extract and the febuxostat in preparing medicines for treating gout and/or hyperuricemia of mammals or humans, wherein the pharmaceutical composition consists of 225-2250mg of apiacea extract, 5-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the apiacea extract is prepared from apiacea seed and pagodatree flower bud alcohol extract in a weight ratio of 2:1-4:1.
In other words, the present invention provides a pharmaceutical composition of an extract of apices comprising febuxostat 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 apiacea and febuxostat, comprising administering to the patient a pharmaceutically effective dose of the extract of apiacea and febuxostat, wherein the daily dose of febuxostat tablet is in the range of 5mg to 20mg and the daily dose of the extract of apiacea 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 + small dose febuxostat pharmaceutical composition.
The daily dose of the febuxostat tablet ranges from 5mg to 20mg. Further preferred ratios are 10mg to 20mg.
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 Apii is 900mg and the daily dose of febuxostat is 5mg to 20mg. Further preferably, the daily dose of 900mg of the apices extract and 20mg of febuxostat are firstly given to the patient for a period of time, so that the blood uric acid level is quickly reduced to a reasonable level, and then the daily dose of 900mg of the apices extract and 10mg of febuxostat are given to the patient, so that the blood uric acid level is kept stable and does not rebound. For patients with stable partial blood uric acid level, the maintenance dose can be 900mg of the celery-locust extract daily dose and 5mg of the febuxostat daily dose.
As a first embodiment of the present invention, the present invention provides a combination of administration. The extract of apices and the febuxostat can be respectively prepared into solid preparation compositions, such as tablets, capsules, granules and other dosage forms, and are provided for patients in a combined mode. Preferably, the extract of the apices sophorae is added with proper pharmaceutically acceptable auxiliary materials to be prepared into capsules, and the febuxostat is prepared into tablets or capsules. The combination forms include, but are not limited to, simultaneous administration, sequential administration, intermittent administration, alternating administration, and other combination modes.
In the combination, the daily dosage of febuxostat is in the range of 5mg to 20mg; 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 second embodiment of the invention, the invention provides a combination kit product.
The invention provides a medicine box for treating gout and/or hyperuricemia of mammals and/or humans, which consists of 225-2250mg of apiacea extract, 5-20mg of febuxostat, a pharmaceutically acceptable carrier and a medicine instruction, wherein the apiacea extract is an alcohol extract of apiacea seed and pagoda flower bud in a weight ratio of 2:1-4:1. Further, the medicine box consists of 450-1800mg of the celery fruit extract, 10-20mg of febuxostat, a pharmaceutically acceptable carrier and a medicine instruction book, wherein the celery fruit extract is a celery seed and pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1; or the medicine box consists of 900-1350mg of the celery-locust extract, 10-20mg of febuxostat, a pharmaceutically acceptable carrier and a medicine instruction, wherein the celery-locust extract is a celery seed and pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1.
In the kit, the apices extract and the non-bucindoles can be respectively prepared into solid preparation compositions, such as tablets, capsules, granules and other dosage forms, and are provided for patients in the form of a complete set of combined kit. In the dosage form, the extract of the apices, preferably, is added with proper pharmaceutically acceptable auxiliary materials (carriers) to prepare capsules, and the febuxostat is added with proper pharmaceutically acceptable auxiliary materials (carriers) to prepare tablets or capsules. The daily dose range of the two preparations in the combined medicine box is 5mg to 20mg; 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 apices extract preparation is 900mg and the daily dose of the febuxostat preparation is 5mg to 20mg. 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 extract and 20mg of febuxostat daily dose, and then, the patient is administered with a combined medicine box with 900mg of the apices extract and 10mg of febuxostat daily dose, so that the blood uric acid level is kept stable and does not rebound. For patients with stable partial blood uric acid level, the maintenance dose can be selected from a combined medicine box of 900mg of the apices extract daily dose and 5mg of febuxostat daily dose.
As a third embodiment of the invention, the invention provides a compound pharmaceutical composition. Mixing the herba Apii Graveolentis extract with non-bucindolt, adding pharmaceutically acceptable carrier or adjuvant, 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 apices and the non-bestrol is (225-2250): (5-20); the preferable proportion is (450-1800): (5-20), more preferably (900-1350): (5-20), the most preferred ratio is 900: (5-20).
As a preferred embodiment, the weight ratio of the apices extract to the non-bestrol in the compound pharmaceutical composition is 900:5 or 900:10 or 900:20. further preferably, the patient is administered first the celery sophora extract and the non-bestrol in a weight ratio of 900:20, 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 apices extract to non-beset of 900:10, and can keep the blood uric acid level stable and free from rebound. For patients with stable partial blood uric acid level, the maintenance dose can be selected from 900mg of the apices sophorae extract and 5mg of febuxostat daily dose.
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.
The formulation of the extract of the celery-locust is preferably prepared into capsules (hereinafter referred to as celery-locust capsules). As one embodiment, each capsule contains 100-300mg, preferably 225mg, of the extract of Apium graveolens. The febuxostat can be prepared from a commercially available tablet, and is subjected to dose division according to specifications, and further preferably, a small-dose febuxostat tablet is specially prepared so as to ensure accurate dose.
When co-administration is used, a specific treatment regimen for one embodiment is as follows:
1. apices sophorae capsule and febuxostat tablet
Apices sophorae capsule (225 mg,4 granules/day, 2 granules each in the morning and evening) and non-bestatin tablet (20 mg,1 tablet/day) based on the extract; after the treatment scheme is implemented for 4 weeks, the preparation is adjusted to 4 apices/day of apices and sophorae capsules, and 2 apices and febuxostat tablets (specification: 20mg, half tablet/day) are used together.
Through preclinical and preliminary clinical studies, the inventors have unexpectedly found that the combination or co-administration of the apices and the non-bestatin has the following unexpected advantages:
1. superposition of mechanisms of action
The action mechanisms of the celery-locust extract and the febuxostat are that the synthesis of uric acid is reduced and the content of blood uric acid is reduced by inhibiting the activity of xanthine oxidase, so that the deposition of uric acid salt on bones, joints and kidneys is reduced, and the re-dissolution of gout nodules and uric acid crystals is facilitated. Therefore, the two medicines are combined, and the dosage of the febuxostat is possible to be reduced due to the superposition of action mechanisms.
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 slow to reach the standard. After clinical researches, the apiacea capsule and the non-bestatin are combined, so that moderate uric acid reducing effect can be rapidly generated, and the control force for temporary fluctuation caused by the influence of diet on the 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 the apices extract can produce long-term stable uric acid reducing effect after being combined with small-dose febuxostat, 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 form uric acid stones, leading to the development and progression of obstructive nephropathy, and ultimately 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 a long-term combination of the celery-locust extract and the small-dose febuxostat is adopted by some patients with gout accompanied with hyperuricemia, the blood uric acid level 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, and has effect in dissolving uric acid calculus. 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. Febuxostat tablets have been reduced to two-line administration by U.S. guidelines for gout treatment due to high cardiovascular toxicity.
According to the clinical observation study of the inventors, patients with gout accompanied by hyperuricemia were randomly divided into three groups, and patients in the test group were combined with the apices extract (2 grains/time, 2 times/day) and the febuxostat in a small dose (20 mg/day for the first 4 weeks and 10 mg/day for the subsequent 8 weeks), and the patients in the control group were combined with the apices extract (2 grains/time, 2 times/day) or the febuxostat tablet in a large dose (40 mg/day) for the treatment course of 12 weeks. The results show that the electrocardiographic examination of the patients of the combined drug group and the single apices and the capsule group does not see any abnormality, and only slight adverse reaction of the gastrointestinal tract is found. A few patients in the large-dose febuxostat group had electrocardiographic abnormalities. The combination of the apices and the small-dose febuxostat is prompted, so that the heart toxicity of the large-dose febuxostat tablet can be obviously reduced, and the long-term maintenance treatment of gout patients is facilitated.
The specific embodiment is as follows:
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. sealing and keeping in dark place and at room temperature.
Positive drug information
Febuxostat tablet, manufacturer: japanese teijn PHARMA LIMITED. Specification of: 20mg; lot number: 6484, expiration date to 2022 month 02. Sealing and preserving at 25 deg.C.
Detection kit
Uric acid detection kit: north-control biotechnology, inc, lot number: 19251.
solvent(s)
0.5% cmc-Na aqueous solution; CMC-Na lot number: 20190123, national pharmaceutical systems and chemicals Co., ltd.
Animal test data
1. Combination of apices and non-bucindoles tablet
The method comprises the following steps: male SD rats were selected for the study. 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 rats in the model group were randomly grouped, with 10 rats in each group, including 1 for the model control group and 27 for the experimental group. The normal group and the model control group are subjected to gastric lavage by using 0.5% CMC-Na aqueous solution, and the other groups are subjected to gastric lavage by dissolving the corresponding medicines 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 dosage procedure for conversion from human to animal according to the apices in the form of apices capsules (225 mg per capsule based on extract) was 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 dosing process of febuxostat from human to animal is as follows:
the daily dose of the febuxostat is calculated as 10mg-40mg, and the dose converted into rats is 10mg x 0.018/0.2 kg=0.9 mg/kg to 40mg x 0.018/0.2 kg=3.6 mg/kg.
The dosing amounts for each experimental group are shown in table 1 below:
table 1 dosing amounts for each experimental group
Note that: the dosage of the celery-sophora japonica extract is equivalent to the number of the celery-sophora japonica capsules (225 mg in specification) after the dosage is reduced for human use: a1:1 grain; a2:2 grains; a3:4 grains; a4:6 grains; a5:8 grains; a6:10 granules
The febuxostat group dose corresponds to B1 after dose conversion for human: 10mg; b2:20mg; b3:40mg.
Experimental results: see table 2.
Table 2 effects of apices in combination with non-bucindoles on blood uric acid levels in hyperuricemic rats (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. As the febuxostat dose increases, the effect increases, the large dose effect is stronger, but the side effects start 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 febuxostat dose is large, no synergy is found from the A1+B3 group to the A6+B3 group, and presumably, the synergy is not found in the whole group because the large-dose effect of febuxostat is too strong.
EXAMPLE 2 observation of clinical Effect
1. Purpose of observation
As mentioned above, the single febuxostat tablet produces uric acid lowering effect at conventional doses, and is accompanied by strong side effects, especially cardiovascular toxicity and death in severe cases. In view of the above, on the basis of the voluntary of the patient, a treatment scheme of combining the apices and the small-dose febuxostat is formulated, and the effectiveness and the safety of treating gout with hyperuricemia are examined by orally taking the apices and the small-dose febuxostat.
2. Case of patient
The number of people: 30 cases. The random number was divided into 3 groups of 10 cases each.
Gender: 24 men and 6 women, 5 patients with hyperuricemia, 25 patients with gout (21 men and 4 women) were diagnosed in hospitals.
Age range: 18-70 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 febuxostat): the initial dose was 4 tablets/day, 2 tablets each of morning and evening+febuxostat tablets (specification: 20 mg) 1 tablet/day. After 1 month, the uric acid level is considered, the dosage of the febuxostat is continuously reduced, and the dosage is adjusted to 4 pieces/day of the apices and the soyabean capsules, and 2 pieces of febuxostat tablets (specification: 20 mg) are respectively half pieces/day in the morning and evening. After 1 month, the uric acid level was observed and the maintenance treatment was continued.
3. Group 3 (single high dose febuxostat tablet group): the initial dose was 20 mg/day, 1 time/day. After 1 month, the dosage is gradually increased according to the blood uric acid level, 20mg is added each time, and the maximum daily dosage is 80mg.
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 blood uric acid level 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 febuxostat group (p > 0.05), as shown in table 1.
Table 1 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)
5. Adverse reaction observations
After 3 months of continuous oral administration, only 2 patients in the single apices and sophora japonica capsules find adverse reactions of gastrointestinal tracts on the 2 nd day of administration, and the stomach has a transitional burning sensation, is untreated and disappears after continuous administration.
The group of apices and sophorae capsules plus small-dose febuxostat had 1 patient with mild flatulence on day 5 after administration, and symptoms disappeared on day 2 without stopping administration.
1 patient had gastric discomfort in the large-dose febuxostat group at month 2 after dosing; abnormal performance of electrocardiogram occurs in 2 patients in 3 rd month, liver function is abnormal in 2 patients, and kidney function is abnormal in 1 patient, as shown in table 2.
TABLE 2 adverse reaction observations
6. Summary and discussion
Clinical researches at home and abroad for many years show that febuxostat is an effective uric acid reducing drug, but the safety problem of drug administration is concerned, and particularly, patients with gout accompanied with hyperuricemia are difficult to adhere to long-term drug administration due to cardiovascular toxicity of febuxostat. Some gout patients can endure severe pain rather than take medicine because of adverse reactions of unscrupulous gout therapeutic drugs.
In order to reduce the toxic and side effects of febuxostat and continuously exert the clinical value of the old medicine, the apices and the febuxostat are combined, the medicine is continuously administered for 3 months, whether the remarkable uric acid reducing effect exists or not and whether the adverse reaction is reduced or not is observed, and the adverse reaction of febuxostat is emphasized. The control group is a single apices and locust capsule or a large dosage febuxostat tablet.
Results: the patients with gout are 30 patients in the test group, wherein the gout is caused by the fact that hyperuricemia is not treated in time and standard. In clinical trials, patients were divided into three groups, group 1 being a single apices capsule group, group 2 being a combination of apices capsules and small-dose febuxostat tablets, and group 3 being a single large-dose febuxostat group.
After 3 months of treatment, the surprise found that the uric acid reducing effect of the apices sophorae capsule and the small-dose febuxostat is obviously superior to that of the apices sophorae capsule alone, and the apices sophorae capsule and the large-dose febuxostat alone have no obvious difference, so that the two medicines are combined to have the synergistic uric acid reducing effect.
In terms of safety, only 1 patient in the combination group of the apices and the small-dose febuxostat had mild flatulence, and the symptoms disappeared and were not stopped on day 2. And the patients with large dosage of febuxostat have stomach discomfort, abnormal electrocardiogram, liver function abnormality and kidney function abnormality, and are consistent with the report of the literature and are in the expected range. Only 1 patient after using the apices and the sophora japonica capsules has slight burning sensation of stomach transient, and the uric acid reducing effect is weaker than that of the combined administration, and the expected range is also reached.
The clinical test has a few cases, and in the future large-scale clinical research, the curative effect and the safety of the combination of the apices and the febuxostat with small dosage can be further observed.
The small knot: in the clinical test, 30 cases of patients with gout accompanied with hyperuricemia are respectively added, the curative effect and the safety of the combination of the apices and the small-dose febuxostat on patients with hyperuricemia and gout are compared and observed, and meanwhile, the combination of the apices and the small-dose febuxostat is compared with the single administration of the apices and the large-dose febuxostat. The result shows that the combination of the apices and the febuxostat tablet has good curative effect and safety, reduces the possible toxic and side effects of the febuxostat tablet in large dosage, especially does not cause adverse reactions such as cardiotoxicity and the like of the febuxostat tablet, is more suitable for long-term maintenance medication of patients with gout accompanied with hyperuricemia, is a breakthrough in the field of gout treatment, and provides preliminary test data for large-scale clinical tests carried out later.
In addition, it was found that one patient had kidney stones disappeared after 3 months of treatment in the combination group. After the study experiment is finished for 3 months, 3 patients with stable blood uric acid level continue to be treated in the maintenance stage by adopting a combined mode of 900mg of the apices extract daily dose and 5mg of febuxostat daily dose, and the blood uric acid level still keeps reasonable level for a long time.
Example 3 Combined kit
The combined medicine box. Comprising the following steps:
1. the active substance is capsule containing herba Apii Graveolentis extract 225mg per capsule.
2. Febuxostat tablet, specification 5mg.
The number of capsules and the number ratio of the apices sophorae extract to the non-bestat tablets serving as active substances are 2:1 or 4: 1. or 6:1 or 8:1.
3. and (3) a medicine use instruction, wherein when the combined medicine box is used, the patient takes 5mg (1 piece) febuxostat tablets each day, and the number of the apices sophorae extract capsules taken each day is selected from 2, 4, 6 or 8.
Example 4 Combined kit
The combined medicine box. Comprising the following steps:
1. the active substance is capsule containing herba Apii Graveolentis extract 225mg per capsule.
2. Febuxostat capsule with the specification of 10mg.
The number of capsules taking the celery-locust extract as an active substance and the number ratio of the non-bestat capsules are 2:1 or 4: 1. or 6:1 or 8:1.
3. and (3) a medicine use instruction, wherein when the combined medicine box is used, a patient takes one febuxostat capsule daily, and the number of the apices extract capsules taken daily is selected from 2, 4, 6 or 8.
Example 5 Combined kit
The combined medicine box. Comprising the following steps:
1. The active substance is capsule containing herba Apii Graveolentis extract 225mg per capsule.
2. Febuxostat tablet, 20mg gauge.
The number of capsules and the number ratio of the apices sophorae extract to the non-bestat tablets serving as active substances are 2:1 or 4: 1. or 6:
1 or 8:1.
3. instructions for use of the combination kit wherein the patient takes a tablet of febuxostat daily and the number of apices extract capsules taken daily is selected from 2, 4, 6 or 8
Example 6 preparation of apices Apii and Sophora japonica extract Capsule
The apices extract capsules used in examples 2 to 5 above can be prepared as follows:
(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 7 preparation of febuxostat tablet
The febuxostat tablet used in the above example, 20mg, may be commercially available, or may be prepared as follows:
preparation of febuxostat tablet (specification: 5mg, 10mg, 20 mg):
(1) Prescription composition
(2) Preparation process
The 3 specifications are all prepared according to the following process:
granulating by a fluidized bed: the prescription amount of febuxostat, lactose monohydrate, pregelatinized starch and hydroxypropyl cellulose are placed in a fluidized bed, the air inlet temperature is 60 ℃, the granules are granulated in one step, and the dry granules are granulated by a high-speed granulator.
Mixing: mixing the obtained granules with lactose and croscarmellose sodium in a prescribed amount in a hopper mixer; the magnesium stearate with the prescription amount is weighed and added into the materials for total mixing.
Tabletting: the total mixed particles were transferred to a tablet press hopper for tabletting.
Example 8 Compound preparation comprising Aphis Sophora extract and febuxostat
Preparation of Apium graveolens extract 225 mg+febuxostat 1.25mg, 2.5mg and 5mg capsule
(1) Prescription of prescription
(2) Preparation process
The 3 specifications are prepared according to the following process:
Preparing a solution: weighing polysorbate 80 with the prescription amount, and dissolving in a proper amount of absolute ethyl alcohol for standby.
Preparing febuxostat-containing acid particles: weighing febuxostat, tartaric acid, low-substituted hydroxypropyl cellulose and lactose, placing in a high-speed mixing granulator, starting the mixing granulator, and stirring 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 magnesium stearate into a high-speed mixer, starting stirring, and mixing and stirring for 5 minutes at a stirring speed; adding acid particles, mixing for 5 min, stopping stirring, and discharging for standby.
Dry granulating: and adding the total mixed particles into a dry powder granulator for dry granulation.
And (3) bagging: and (3) taking a zero-number capsule, and filling the granules subjected to dry granulation.
The daily administration of 4 capsules is equivalent to 900mg of the dry extract of the celery tree and 5mg of febuxostat, or 900mg of the dry extract of the celery tree and 10mg of febuxostat, or 900mg of the dry extract of the celery tree and 20mg of febuxostat.
Claims (6)
1. The anti-gout apiary extract and non-buchneri pharmaceutical composition is characterized by comprising 450-1800mg of apiary extract, 10-20mg of non-buchneri and a pharmaceutically acceptable carrier, wherein the apiary extract is a mixture of apiary seed and pagodatree flower bud alcohol extract in a weight ratio of 2:1-4:1.
2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition consists of 900-1350mg of the extract of apices, 10-20mg of febuxostat and a pharmaceutically acceptable carrier, wherein the extract of apices is an extract of apices and flos Sophorae Immaturus 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 450-1800 mg of celery-locust extract, 10-20mg of febuxostat, a pharmaceutically acceptable carrier and a medicine instruction book, wherein the celery-locust extract is a celery seed and pagodatree flower bud alcohol extract with the weight ratio of 2:1-4:1.
4. A kit according to claim 3, characterized in that the kit consists of 900-1350mg of the extract of apices, 10-20mg of febuxostat and a pharmaceutically acceptable carrier and a pharmaceutical specification, wherein the extract of apices is a mixture of apices and flos sophorae alcohol in a weight ratio of 2:1-4:1.
5. The kit according to claim 3 or 4, wherein the extract of apices in the kit is a granule, a tablet, a dripping pill, or a capsule prepared by adding a pharmaceutically acceptable carrier, and the febuxostat is a tablet or a capsule prepared by adding a pharmaceutically acceptable carrier.
6. Use of a pharmaceutical composition of apices, comprising 450-1800mg of apices, 10-20mg of febuxostat and a pharmaceutically acceptable carrier, in the preparation of a medicament for treating gout and/or hyperuricemia in a mammal or human, wherein the apices are apices and pagodatree flower bud alcohol extracts in a weight ratio of 2:1-4:1.
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| PCT/CN2022/095120 WO2023284426A1 (en) | 2021-07-13 | 2022-05-26 | Anti-gout celery seed-flos sophorae immaturus extract and febuxostat pharmaceutical composition, and use thereof |
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| CN105560262A (en) * | 2016-01-04 | 2016-05-11 | 中国科学院昆明植物研究所 | Application of Graveobioside A in preparation of drugs or healthcare food for preventing hyperuricemia and gout |
| EP3809871B1 (en) * | 2018-06-13 | 2024-02-14 | Baylor College of Medicine | Development of health food supplements and antioxidants for controlling hyperuricemia and oxidative stress |
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| 加味薏苡附子败酱散联合非布司他治疗高尿酸血症33 例临床研究;黎雾峰等;《江苏中医药》;第52卷(第6期);35-38 * |
| 痛风中西医治疗研究进展;李璐瑶等;《中医药信息》;第35卷(第3期);128-131 * |
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| TR01 | Transfer of patent right | ||
| CI03 | Correction of invention patent |
Correction item: transfer of patent right Correct: Beijing Tianheng Junwei Pharmaceutical Technology Development Co.,Ltd.|102629 No.11 Tianrong street, biomedical industry base, Daxing District, Beijing False: Beijing Tianheng Junwei Pharmaceutical Technology Development Co.,Ltd.|102629 No.11 Tianrong street, biomedical industry base, Daxing District, Beijing|Gao Yongliang Number: 49-02 Volume: 39 |
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| CI03 | Correction of invention patent |