CN111714487B - Hyperuricemia pharmaceutical composition - Google Patents

Hyperuricemia pharmaceutical composition Download PDF

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CN111714487B
CN111714487B CN201910213595.1A CN201910213595A CN111714487B CN 111714487 B CN111714487 B CN 111714487B CN 201910213595 A CN201910213595 A CN 201910213595A CN 111714487 B CN111714487 B CN 111714487B
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hyperuricemia
dosage ratio
tribromone
leifenesin
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CN111714487A (en
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徐海霞
陈佳玲
逄龙
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SUZHOU KAIXIANG BIOTECHNOLOGY CO Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
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    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • 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
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    • 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
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    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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Abstract

The invention belongs to the field of chemical medicines, and in particular relates to a hyperuricemia medicine composition, which comprises a sesquiterpene lactone compound with a structure shown in a formula (I) and application of pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparation of a combined medicine for treating hyperuricemia, and also provides a hyperuricemia medicine composition, which comprises the compound and one of tribromone or Levenard. The hyperuricemia medicine composition can play a role in reducing uric acid equivalent to or even better than the hyperuricemia medicine in the prior art, but can obviously reduceThe hyperuricemia medicament in the prior art has the advantages of toxic and side effects, improves the safety, and can be used for treating hyperuricemia and gout or gout complications caused by hyperuricemia.

Description

Hyperuricemia pharmaceutical composition
Technical Field
The invention relates to the field of chemical medicines, in particular to a hyperuricemia pharmaceutical composition.
Background
Uric acid is the final metabolite of human purine compounds in the field of chemical medicine. Purine metabolic disorders lead to hyperuricemia. Under normal purine diet, men with fasting blood uric acid levels of more than 416. Mu. Mol/L for two times a day and 360. Mu. Mol/L for women are called hyperuricemia (hyperuricemia). In general, the hyperuricemia state is simply a hyperuricemia state without subjective symptoms, but if the hyperuricemia state is maintained for a long time, urate in blood will crystallize and deposit on joints, subcutaneous tissues, kidneys and other parts, and a series of clinical manifestations such as gout and gout complications occur. The recently published white paper for reporting the status of gout in China in 2017 shows that 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. It is expected that the number of gout persons will reach 1 million in 2020. Gout is the second most metabolic disease in China after diabetes mellitus, and seriously endangers the life and health of people.
Currently, in the treatment of hyperuricemia, gout and complications of gout caused by hyperuricemia, uric acid in blood needs to be controlled: for uric acid excretion-promoting drugs for uric acid excretion-defective patients (90%), such as: tribromone, ramonade, and the like; drugs (mainly xanthine oxidase inhibitors) that inhibit uric acid production are suitable for patients with excessive uric acid production, such as: allopurinol and febuxostat. However, as the clinical use of these drugs increases, adverse effects are gradually exposed.
The tribromone is a medicament for promoting uric acid excretion, is marketed in France in 1976, brings a new way for treating chronic gout, has a remarkable curative effect for treating hyperuricemia, but can cause gastrointestinal discomfort, particularly diarrhea; in 2003, it was reported that it may cause serious liver function damage and is limited to use by the european market, and FDA refuses its application to market due to adverse reactions, however, some countries including China still allow use, but require the use of pharmaceutical doses to reduce uric acid effect according to the rate of muscular intoxication clearance.
Lesinurad (Lesinurad) was originally developed by Aspirikang (AstraZeneca), marketed in the United states in 2015, month 2016 and European Union, respectively, under the trade name Zuramphic, and was the first uric acid transporter 1 inhibitor marketed, and was used clinically in combination with xanthine oxidase inhibitors (e.g., allopurinol, febuxostat) for the treatment of gout-related hyperuricemia, common adverse effects caused by Lesinurad including headache, influenza, increased blood creatinine, and gastroesophageal reflux disease, which alone increased the risk of developing acute renal failure.
The traditional medicine has larger toxic and side effects and generally lower tolerance, and limits the clinical application of the medicines to a certain extent.
Sesquiterpene lactone compounds are compounds of various structural types evolved from the structure of geranyl lactone (Germacranolide), are one of the bioactive components of medicinal plants, and are widely found in plants of Compositae, umbelliferae, magnoliaceae, menispermaceae, euphorbiaceae, acanthaceae, and Leguminosae. Sesquiterpene lactones isolated from Compositae plants alone are more than 3000. According to their structures, guaiacolide (Guaianolide), pseudo guaiacolide (Pesudoguaianolide), germacrolide (germaniconolide), elemene lactone (Elemonolide), eucalyptolide (eudomanide), eremophiladide (Eremophiladien) and the like can be classified. The research shows that the sesquiterpene lactone has various biological activities, such as anti-tumor, heart-strengthening, neurotoxicity, antimalarial, antibacterial and the like, and the Chinese patent document CN103251667A, CN103417532A also discloses that the sesquiterpene lactone can be used for developing medicaments for treating rheumatoid arthritis and tumors.
Disclosure of Invention
The first technical problem to be solved by the invention is to overcome the defect that medicines for treating hyperuricemia have toxic and side effects in the prior art, so as to provide a sesquiterpene lactone compound with a structure shown as a formula (I) and application of pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparing combined medicines for treating hyperuricemia, wherein the compounds are used as active ingredients and combined with the hyperuricemia medicines, so that the toxic and side effects of the single hyperuricemia medicines can be reduced while the ideal uric acid reducing effect is maintained.
The second technical problem to be solved by the invention is to overcome the defect that the medicines for treating hyperuricemia have toxic and side effects in the prior art, so as to provide the hyperuricemia medicine composition capable of reducing the toxic and side effects while maintaining the ideal uric acid reducing effect.
The third technical problem to be solved by the invention is to overcome the defect that the medicament for treating hyperuricemia has toxic and side effects in the prior art, thereby providing the medicament for treating hyperuricemia, which can reduce the toxic and side effects while maintaining the ideal uric acid reducing effect.
The invention also provides application of the hyperuricemia pharmaceutical composition.
Therefore, the invention provides the application of sesquiterpene lactone compounds with the structure shown in the formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparing combined medicines for treating hyperuricemia. Further, the hyperuricemia medicine is one of tribromone or Leifenesin.
The invention provides a hyperuricemia pharmaceutical composition, which comprises: active ingredients having a synergistic effect with hyperuricemia drugs, and hyperuricemia drugs; wherein the hyperuricemia medicine is uric acid excretion promoting medicine; the active ingredient is sesquiterpene lactone compound with a structure shown in a formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof:
Figure GDA0004144165020000031
wherein:
Figure GDA0004144165020000037
represents a group selected from =or->
Figure GDA00041441650200000311
Represents a member selected from the group consisting of-or no bond; two adjacent->
Figure GDA00041441650200000313
Not at the same time =; />
Figure GDA00041441650200000315
Representation of-when, and->
Figure GDA00041441650200000317
Adjacent->
Figure GDA0004144165020000039
Not at the same time =;
R 1 、R 2 、R 3 、R 4 、R 6 independently of one another, selected from H, OH, unsubstituted or substituted C 1 -C 4 Alkyl, unsubstituted or substituted C 1 -C 4 Alkoxy, OAc or
Figure GDA0004144165020000032
One of the following; />
R 8 、R 9 Independently of one another, from one of H, OH, or R 8 、R 9 Forming an unsubstituted or substituted ethylene oxide group;
Figure GDA0004144165020000033
to form C=C or C-R 7a ；
Figure GDA0004144165020000034
Form C=O or C-R 11a ；
R 7a 、R 11a Independently of one another selected from H, unsubstituted or substituted C 1 -C 4 One of the alkyl groups of (a);
R 9 ,R 10 forming a five-membered ring
Figure GDA0004144165020000035
Figure GDA0004144165020000038
Form->
Figure GDA0004144165020000036
Or c=c; r is R 12a 、R 12b Independently of one another selected from H, OH or C 1 -C 4 One of the alkyl groups of (a);
R 10 ,R 11 forming a five-membered ring
Figure GDA0004144165020000041
Wherein X is selected from N or O, X is O, and X is attached +.>
Figure GDA00041441650200000411
Figure GDA00041441650200000410
Different times are =and-; />
Figure GDA0004144165020000043
Form C=O or C-R 13a ；/>
Figure GDA0004144165020000045
To form C=C or C-R 14a ；R 13a 、R 14a Independently of one another selected from H, unsubstituted or substituted C 1 -C 4 Is one of the alkyl groups of (a).
The active ingredients of the hyperuricemia medicine composition have the following structures:
Figure GDA0004144165020000047
Figure GDA0004144165020000051
the hyperuricemia medicine composition is one of tribromone or Leidecinard.
The mass of the active ingredient of the hyperuricemia medicine composition accounts for 14% -91% of the sum of the mass of the active ingredient and the mass of the hyperuricemia medicine.
The hyperuricemia pharmaceutical composition also comprises a pharmaceutically acceptable carrier.
The invention also provides a medicine for treating hyperuricemia, which comprises the hyperuricemia medicine composition, wherein the medicine is prepared by adding conventional auxiliary materials into the hyperuricemia medicine composition and preparing clinically acceptable tablets, capsules, pills, granules, ointment, mixture or suspension according to a conventional process.
The invention also provides application of the hyperuricemia pharmaceutical composition in preparing hyperuricemia medicines.
The application of the hyperuricemia medicine composition in preparing hyperuricemia medicines comprises gout or gout complications caused by hyperuricemia.
The application of the hyperuricemia pharmaceutical composition in preparing hyperuricemia medicaments, wherein the gout comprises acute gout or chronic gout; the gout complications comprise gouty arthritis, gout attack, gouty nephropathy or uric acid kidney stone disease.
The technical scheme of the invention has the following advantages:
1. the invention provides a hyperuricemia medicine composition, which can achieve the effect of reducing uric acid equivalent to or even better than that of hyperuricemia medicines in the prior art, but can obviously reduce the toxic and side effects of the hyperuricemia medicines in the prior art, improve the safety, and can be used for treating hyperuricemia and gout or gout complications caused by the hyperuricemia.
2. The invention provides a medicament for treating hyperuricemia, which can achieve the effect of reducing uric acid equivalent to or even better than that of hyperuricemia medicaments in the prior art, but can obviously reduce the toxic and side effects of the hyperuricemia medicaments in the prior art, improve the safety, and can be used for treating hyperuricemia and gout or gout complications caused by hyperuricemia.
Detailed Description
Example 1
The embodiment provides an extraction method and characterization of the compound 1 and the compounds 4-8 in the active ingredients.
The ethanol, ethyl acetate, petroleum ether and methanol used in this example were all commercial products, and the silica gel column used was a 3.5L-silica gel column (Φ8cm. Times.70cm).
Taking 50kg of dry rhizome of bighead atractylodes rhizome, crushing, soaking and extracting for 3 times by using 90% ethanol solution with the volume of 8 times, and concentrating under reduced pressure to remove organic solvent (solid content is 2.5 kg); passing the concentrated solution through 50L-D101 column (phi 22 cm. Times.150cm), washing 4 column volumes with 40% ethanol and 95% ethanol respectively, collecting 95% ethanol part, concentrating under reduced pressure to remove organic solvent (solid content 1 kg); adding 3 times volume of ethyl acetate into the concentrated solution for extraction, collecting an ethyl acetate part, and concentrating under reduced pressure to remove an organic solvent (solid content 400 g); separating the obtained concentrated solution by silica gel column chromatography, sequentially carrying out gradient elution by using petroleum ether and ethyl acetate mixed solutions with volume ratios of 10:1, 5:1, 3:1 and 1:1, and then eluting by using ethyl acetate to sequentially obtain 5 parts: fr.a-E.
Separating Fr.B by silica gel column chromatography, and performing gradient elution by using petroleum ether and ethyl acetate mixed solution with the volume ratio of 10:1-5:1 to obtain compounds 7 and 8 in sequence; separating Fr.C by silica gel column chromatography, and gradient eluting with petroleum ether and ethyl acetate mixed solution with volume ratio of 5:1-3:1 to obtain compounds 1 and 6 in sequence; separating Fr.D by silica gel column chromatography, and performing gradient elution by using petroleum ether and ethyl acetate mixed solution with the volume ratio of 3:1-1:1 to obtain a compound 4; fr.E was separated by ODS preparative chromatography eluting with 75% and 85% methanol-water gradient, respectively, to give compound 5.
The isolated components were identified by multidimensional NMR spectroscopy (1H, 13C, COSY, HMBC, HSQC) and mass spectrometry, and the structure of the compounds was determined by data comparison with the following prior art documents:
compound 1,4: huang Baoshan, sun Jianshu separation and identification of atractylenolide IV [ J ]. Plant ecological journal (English edition), 1992 (8): 614-617.
Compound 5: ding H Y, liu M Y, chang W L, et al New Sesquiterpenoids from the Rhizomes of Atractylodes macrocephala [ J ]. Chinese Pharmaceutical Journal,2005,57 (1): 37-42.
Compound 6: chen Z L, cao W Y, zhou G X, et al A sesquiterpene lactam from Artractylodes macrocephala [ J ]. Phytochectry, 1997,45 (4): 765-767.
Compound 7: chen Jianmin, minqian, shen Yinzhu, et al comparison of chemical compositions of tissue culture and natural bighead atractylodes rhizome [ J ]. Plant ecological journal (English edition), 1991 (2): 164-167.
Compound 8: lin Yongcheng, jin Tao, yuan Zhi Mei, et al A new double sesquiterpene lactone [ J ] in Atractylodis rhizoma, university of Zhongshan university (Nature science edition), 1996 (2): 75-76.
Example 2
The embodiment provides an extraction method and characterization of the compounds 9-14 in the active ingredients.
The ethanol, petroleum ether, ethyl acetate and methanol used in this example were all commercial products, and the silica gel column used was a 3.5L-silica gel column (Φ8cm. Times.70cm).
Pulverizing 50kg of radix Inulae, soaking and extracting with 8 times of 90% ethanol solution for 3 times, concentrating under reduced pressure to remove organic solvent; the concentrated solution is passed through 50L-D101 column (phi 22 cm. Times.150cm), 4 column volumes are respectively washed by 40% and 95% ethanol, 95% ethanol parts are collected, the organic solvent (solid content is 3.2 kg) is removed by decompression concentration, 3 times of petroleum ether with volume of 3 times is added into the concentrated solution for extraction for 3 times, and the extraction solvent is recovered by decompression, so as to obtain 2kg of petroleum ether parts. Separating petroleum ether part by silica gel column chromatography, gradient eluting with petroleum ether and ethyl acetate mixed solution with volume ratio of 100:1-1:1, combining the same parts by TLC detection, sequentially obtaining 5 parts: fr.a-E.
Separating Fr.A again by silica gel column chromatography, performing gradient elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 100:1-20:1, combining the same parts by TLC detection, and sequentially obtaining 4 parts: fr.a1-A4; wherein fr.a2 is separated by ODS preparative chromatography and eluted with 30%, 40%, 65% methanol-water gradient to give compounds 9, 10 in sequence; a3 was purified by ODS preparative chromatography eluting with a 45%, 60%, 95% methanol-water gradient to give Compound 11.
Separating Fr.B again by silica gel column chromatography, performing gradient elution by using a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 50:1-10:1, combining the same parts by TLC detection, and sequentially obtaining 3 parts: fr.b1-B3; wherein Fr.B1 is subjected to ODS preparation chromatography, and eluted with 55% methanol-water to sequentially obtain compounds 12 and 13; fr.b3 was chromatographed on ODS and eluted with 60% methanol-water to give compound 14.
The isolated components were identified by multidimensional NMR spectroscopy (1H, 13C, COSY, HMBC, HSQC) and mass spectrometry, and the structure of the compounds was determined by data comparison with the following prior art documents:
compounds 9-14: xu Hui, yang Xiaoling, liu Shengsheng, et al, sesquiterpene chemical composition of Inula, J. Shizhen national medicine, 2007,18 (11): 2738-2740.
Example 3
The embodiment provides a hyperuricemia medicine composition which is formed by mixing tribromouron and a compound 1 in a weight ratio of 3:5. The compound 1 used in this example was prepared according to example 1, and the structural formula of the compound 1 was as follows:
Figure GDA0004144165020000081
as an alternative to this example, compound 1 may be replaced with one of compounds 2-14 and benzbromarone may be replaced with ramonade.
Example 4
The embodiment provides a hyperuricemia medicine composition which is formed by mixing benzbromarone and a compound 2 in a weight ratio of 1:10. Compound 2 used in this example was purchased from tuina biotechnology limited, su, and the structural formula of compound 2 was as follows:
Figure GDA0004144165020000082
as an alternative to this example, the compound 2 may be replaced with one of the compounds 1 and 3 to 14, and the tribromone may be replaced with ramonade.
Example 5
The embodiment provides a hyperuricemia medicine composition which is formed by mixing benzbromarone and a compound 3 in a weight ratio of 1:5. Compound 3 used in this example was purchased from shanghai source leaf biotechnology limited, and the structural formula of compound 3 was as follows:
Figure GDA0004144165020000083
as an alternative to this example, the compound 3 may be replaced with one of the compounds 1 to 2 and the compounds 4 to 14, and the tribromone may be replaced with ramonade.
Example 6
The embodiment provides a hyperuricemia medicine composition which is formed by mixing benzbromarone and a compound 4 in a weight ratio of 8:5. The compound 4 used in this example was prepared according to example 1, the structural formula of compound 4 being as follows:
Figure GDA0004144165020000091
as an alternative to this example, the compound 4 may be replaced with one of the compounds 1 to 3 and the compounds 5 to 14, and the tribromone may be replaced with ramonade.
Example 7
The embodiment provides a hyperuricemia medicine composition which is formed by mixing tribromouron and a compound 5 in a weight ratio of 8:15. The compound 5 used in this example was prepared according to example 1, the structural formula of compound 5 being as follows:
Figure GDA0004144165020000092
as an alternative to this example, the compound 5 may be replaced with one of the compounds 1 to 4 and the compounds 6 to 14, and the tribromone may be replaced with ramonade.
Example 8
The embodiment provides a hyperuricemia pharmaceutical composition which is prepared by mixing tribromouron and a compound 6 according to a weight ratio of 4:15. The compound 6 used in this example was prepared according to example 1, the structural formula of compound 6 being as follows:
Figure GDA0004144165020000101
as an alternative to this example, the compound 6 may be replaced with one of the compounds 1 to 5 and the compounds 7 to 14, and the tribromone may be replaced with ramonade.
Example 9
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing a 2:1 Leifenesin and a compound 7. The compound 7 used in this example was prepared according to example 1, the structural formula of compound 7 being as follows:
Figure GDA0004144165020000102
as an alternative to this example, the compound 7 may be replaced with one of the compounds 1 to 6 and the compounds 8 to 14, and the rabinamide may be replaced with benzbromarone.
Example 10
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing a compound 8 and a Leifenesin in a weight ratio of 6:1. The compound 8 used in this example was prepared according to example 1, the structural formula of compound 8 being as follows:
Figure GDA0004144165020000103
as an alternative to this example, the compound 8 may be replaced with one of the compounds 1 to 7 and the compounds 9 to 14, and the rabina may be replaced with benzbromarone.
Example 11
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing a 2:3 Leifenesin and a compound 9 in a weight ratio. The compound 9 used in this example was prepared according to example 2, the structural formula of the compound 9 being as follows:
Figure GDA0004144165020000111
as an alternative to this example, the compound 9 may be replaced with one of the compounds 1 to 8 and the compounds 10 to 14, and the rabina may be replaced with benzbromarone.
Example 12
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing Leifenesin and a compound 10 in a weight ratio of 1:3. The compound 10 used in this example was prepared according to example 2, the structural formula of the compound 10 being as follows:
Figure GDA0004144165020000112
as an alternative to this example, the compound 10 may be replaced with one of the compounds 1 to 9 and the compounds 11 to 14, and the rabina may be replaced with benzbromarone.
Example 13
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing a 2:1 Leifenesin and a compound 11. The compound 11 used in this example was prepared according to example 2, the structural formula of the compound 11 being as follows:
Figure GDA0004144165020000113
as an alternative to this embodiment, the compound 11 may be replaced with one of the compounds 1 to 10 and the compounds 12 to 14, and the rabina may be replaced with benzbromarone.
Example 14
The embodiment provides a hyperuricemia pharmaceutical composition, which is prepared by mixing Leifenesin and a compound 12 in a weight ratio of 1:1. The compound 12 used in this example was prepared according to example 2, the structural formula of the compound 12 being as follows:
Figure GDA0004144165020000121
as an alternative to this embodiment, the compound 12 may be replaced with one of the compounds 1 to 11 and the compounds 13 to 14, and the rabina may be replaced with benzbromarone.
Example 15
The present embodiment provides a pharmaceutical tablet for treating hyperuricemia.
[ formula ]
Figure GDA0004144165020000122
Weighing a prescribed amount of hyperuricemia pharmaceutical composition, hydroxypropyl cellulose, starch, lactose and povidone, mixing, sieving with a 60-mesh sieve for three times, and uniformly mixing; adding 10% starch slurry to make soft material, sieving with 24 mesh sieve, granulating, drying, adding silica gel micropowder and magnesium stearate, mixing, granulating, tabletting, and coating with film.
Example 16
The embodiment provides a pharmaceutical capsule for treating hyperuricemia.
[ formula ]
Figure GDA0004144165020000131
Weighing a prescribed amount of hyperuricemia pharmaceutical composition, lactose, povidone, microcrystalline cellulose and sodium carboxymethyl starch, sieving with a 100-mesh sieve respectively, and uniformly mixing; adding hypromellose solution to make soft mass, sieving with 24 mesh sieve, granulating, drying in oven at 50-60deg.C for about 2-3 hr, adding silica gel micropowder and magnesium stearate, mixing, granulating, and making into capsule.
The pharmaceutical compositions of the present invention may be administered by any means known in the art, including but not limited to oral, nasal, parenteral, topical, transdermal or rectal routes of administration. The pharmaceutical compositions of the present invention are preferably suitable for oral or topical administration in dosage forms such as tablets, capsules (including hard capsules, soft capsules), pills, solutions, powders or granules, suspensions, patches, and the like, and the medicaments of the present invention may be formulated into corresponding dosage forms using methods well known in the art.
As an alternative implementation manner of this embodiment, the above-mentioned pharmaceutical excipients such as microcrystalline cellulose may be replaced with other commonly used excipients, and the "conventional excipients" described in the present invention refers to pharmaceutically acceptable materials, compositions or vehicles, such as liquid or solid fillers, diluents, excipients (such as cocoa butter and plug wax), solvents or packaging materials. The pharmaceutically acceptable carrier is compatible with the other ingredients of the composition, with the mode of administration, and is not deleterious to the patient. The pharmaceutically acceptable carrier may be aqueous or non-aqueous. Conventional excipients include gelatin, for example gelatin; starches, such as corn starch, potato starch; sugars such as lactose, glucose, and sucrose; cellulosic materials and mixtures thereof, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate. Materials that may be used as pharmaceutically acceptable carriers include, but are not limited to, tragacanth, malt, talc, oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, and the like), alcohols (e.g., propylene glycol, ethanol, glycerol, sorbitol, mannitol, polyethylene glycol, and the like), esters (e.g., ethyl oleate, ethyl laurate, agar), buffers (e.g., magnesium hydroxide, aluminum hydroxide, boric acid, and sodium borate, and phosphate buffers), alginic acid, non-heat source water, isotonic saline, ringer's solution.
Experimental example
The tribromone, the Leidener, the analytically pure grade absolute ethyl alcohol, the chloroform, the methanol, the ethyl acetate, the distilled water, the dimethyl sulfoxide, the monopotassium phosphate and the dipotassium phosphate used in the experimental example are all commercial products; the instruments used included Buchi medium pressure preparation liquid phase, ika stirrer, buchi vacuum rotary evaporator, vortex shaker, water bath, biofuge Primo R multipurpose bench-top high-speed centrifuge, mettlerae240 electronic balance, beckman Coulter AU Biochemical analyzer.
Compounds 2 and 3 are commercially available (HPLC > 98%) and are obtained from the following sources:
compound 2: eudesma-4 (14), 7 (11) dien-8-one (CAS: 54707-47-0), available from He-Ming Biotechnology Co., ltd;
compound 3: atractylone (CAS: 6989-21-5), available from Shanghai Seiyaka Biotechnology Co., ltd;
compound 1, compound 4-14 were isolated from the corresponding plants according to examples 1-2 (HPLC > 98%).
Test animals and groupings: taking healthy male KM mice with a weight of 15-18g, which are provided by Beijing vitamin Toril Hua biotechnology Co., ltd; after 5 cages were divided, the animals were adaptively kept in a barrier system of Kaixiang biotechnology Co., ltd, for 4 days, and then, 10 animals were randomly grouped according to body weight, and each group was a blank control group (blank group for short), a hyperuricemia model group (model group for short), a positive control group (tribromoron control group or Levend control group), a compound control group, and a test composition group (test composition for short).
Modeling of hyperuricemia:
firstly, preparing a gastric lavage drug, and suspending the benzbromarone or the Leidecinard by using a positive control group by using a 0.5% sodium carboxymethylcellulose (CMC-Na) solution; compound control compound 1-14 was suspended with 0.5% sodium carboxymethylcellulose (CMC-Na) solution, respectively; the test composition groups each suspended a set dose of the pharmaceutical composition with a 0.5% sodium carboxymethyl cellulose (CMC-Na) solution. Immediately after the adaptation period of the mice, the mice are subjected to gastric lavage, 1 time in the morning and 7 days in succession, and the blank control group and the hyperuricemia model group are subjected to gastric lavage by using 0.5% CMC-Na for comparison; mice were intraperitoneally molded after lavage for 0.5 hours at day 7, with a blank group intraperitoneally injected with a 0.5% sodium carboxymethylcellulose (CMC-Na) solution; the hyperuricemia model group, the positive control group and the tested composition group were all injected with 300mg/kg body weight of potassium Oxazinate (OA) dissolved in CMC-Na solution.
The method comprises the steps of removing eyeballs of mice after intraperitoneal injection for 1.5 hours, taking blood, placing the mice at room temperature for 1 hour after blood collection, centrifuging at 3500rpm/4 ℃ for 10 minutes after blood is completely coagulated, taking serum to be separated for 5 minutes under the same condition, taking 0.2mL of serum, and detecting the levels of Uric Acid (UA), alanine Aminotransferase (ALT), glutamic oxaloacetic Aminotransferase (AST) and Creatinine (CRE) in the serum by using a biochemical analyzer, wherein the alanine Aminotransferase (ALT), glutamic oxaloacetic Aminotransferase (AST) and Creatinine (CRE) are used for representing toxic and side effects of the medicines, and the higher the content is, the greater the toxic and side effects are indicated.
Statistical analysis is carried out on the data by Excel and SPSS, the average number and SD are calculated, the inter-group difference of each experimental group is compared after single-factor variance analysis, and compared with a blank control group, the serum uric acid level of mice in a hyperuricemia model group, a positive control group and a tested composition group is obviously improved, and obvious differences exist, so that the modeling is successful.
The doses and test results of the drugs and the drug compositions are shown in tables 1-28:
table 1 Effect of Compound 1 and its combination with benzbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000151
Table 2 Effect of Compound 1 and its combination with Ratenard on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000152
Figure GDA0004144165020000161
Table 3 Effect of Compound 2 and its combination with benzbromarone on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000162
Table 4 Effect of Compound 2 and its composition with Ratenard on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000163
Figure GDA0004144165020000171
Table 5 Effect of Compound 3 and combination thereof with benzbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000172
Table 6 Effect of Compound 3 and its combination with Ratenard on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000173
Client case number
Figure GDA0004144165020000181
Table 7 Effect of Compound 4 and its combination with benzbromarone on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000182
Table 8 influence of Compound 4 and its combination with Ratenard on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000183
Table 9 Effect of Compound 5 and combination of phenylbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000184
Figure GDA0004144165020000191
Table 10 influence of Compound 5 and its combination with Ratenard on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000192
Table 11 influence of Compound 6 and its composition with benzbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000193
Table 12 effects of Compound 6 and its combination with Ratenard on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000194
Figure GDA0004144165020000201
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Table 13 Effect of Compound 7 and its combination with benzbromarone on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000202
Table 14 Effect of Compound 7 and its combination with Ratenard on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000203
Figure GDA0004144165020000211
Table 15 Effect of Compound 8 and its combination with benzbromarone on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000212
Table 16 influence of Compound 8 and its combination with Ratenard on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000213
Effect of compound 9 of table 17 and its combination with benzbromarone on hyperuricemia mice blood uric acid level (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000214
Table 18 influence of Compound 9 and its composition with Ratenard on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000221
Table 19 influence of Compound 10 and its composition with benzbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000222
Table 20 influence of Compound 10 and its combination with Ratenard on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000223
Figure GDA0004144165020000231
/>
Effects of Compound 11 of Table 21 and its composition with benzbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST) and Creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000232
Effects of Compound 11 and its combination with Ratenard on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000233
Table 23 influence of Compound 12 and its composition with benzbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000234
/>
Figure GDA0004144165020000241
Table 24 influence of Compound 12 and its combination with Ratenard on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000242
Effects of Compound 13 of Table 25 and its composition with benzbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000243
/>
Figure GDA0004144165020000251
Table 26 influence of Compound 13 and its composition with Ratenard on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000252
Effects of Compound 14 of Table 27 and its composition with benzbromarone on blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE) in hyperuricemic mice
Figure GDA0004144165020000253
Client case number
Figure GDA0004144165020000261
Effects of Compound 14 and its combination with Ratenard on hyperuricemia mice blood uric acid levels (UA), alanine Aminotransferase (ALT), glutamic-oxaloacetic Aminotransferase (AST), creatinine (CRE)
Figure GDA0004144165020000262
(a represents P <0.05 compared with the blank group, b represents P <0.01 compared with the blank group, c represents P <0.05 compared with the hyperuricemia model group, d represents P <0.01 compared with the hyperuricemia model group, e represents P <0.05 compared with the corresponding dose compound control group, f represents P <0.01 compared with the corresponding dose compound control group, # represents P <0.05 compared with the positive control group 1, # represents P <0.01 compared with the positive control group 1, # represents P <0.05 compared with the positive control group 2, and P <0.01 compared with the positive control group 2.
From the above table results, it can be derived that:
1. the compound disclosed by the invention can obviously reduce serum uric acid level of hyperuricemia mice, has statistical significance compared with hyperuricemia model groups, and can be used as a potential uric acid reducing drug for treating hyperuricemia.
2. The low-dose benzbromarone/or the Leifenesin and the compound are combined for use, and the invention shows stronger uric acid reducing effect at various dosage ratios, and has statistical significance compared with hyperuricemia model groups.
3. The compound disclosed by the invention is combined with low-dose benzbromarone and/or Leidecinard, and then the compound is used, so that the compound has stronger uric acid reducing effect than the single use of the compound under the corresponding dose, and has statistical significance.
4. Compared with the corresponding positive control group 1, the uric acid reducing effect of the tested combination 1 is better than that of the corresponding positive control group 1 (tribromone/or Leidecinard), and the ALT, AST, CRE value in each tested combination 1 is obviously lower than that of the corresponding positive control group 1, so that the method has statistical significance.
5. Compared with the corresponding positive control group 2, the uric acid reducing effect of the tested combination group 2 is better than that of the corresponding positive control group 2 (tribromone/or Leidecinard), and the ALT, AST, CRE value in each tested combination group 2 is obviously lower than that of the corresponding positive control group 2, so that the method has statistical significance.
In conclusion, the reduced dosage of the tribromone and/or the Leuconand is combined with the compound of the invention, so that the same or better uric acid reducing effect of the tribromone and/or the Leuconand under the conventional dosage can be obtained, but the lower dosage of the tribromone and/or the Leuconand is combined with the compound for use, so that the increase of CRE, ALT, AST caused by the tribromone and/or the Leuconand can be obviously reduced, further toxic and side effects are reduced, and the safety is higher than that of the tribromone and/or the Leuconand which are singly used under the conventional dosage.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.

Claims (7)

1. A pharmaceutical composition for treating hyperuricemia comprising: active ingredients having synergistic effect with drugs for treating hyperuricemia and drugs for treating hyperuricemia; wherein the drug for treating hyperuricemia is one of tribromone or Leifenesin; the active ingredient is sesquiterpene lactone compound with the following structure and pharmaceutically acceptable salt thereof:
Figure FDA0004144164990000011
/>
Figure FDA0004144164990000021
and the pharmaceutical composition is selected from:
the dosage ratio of the tribromone to the compound 1 is 3mg/kg, 15mg/kg, 3mg/kg, 30mg/kg, 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg and 8mg/kg, 30mg/kg;
the dosage ratio of the Leifenesin to the compound 1 is 10mg/kg, 15mg/kg, 10mg/kg, 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the tribromone to the compound 2 is 3mg/kg, 15mg/kg, 3mg/kg, 30mg/kg, 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg and 8mg/kg, 30mg/kg;
the dosage ratio of the Leifenesin to the compound 2 is 10mg/kg, 15mg/kg, 10mg/kg, 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the tribromone to the compound 3 is 3mg/kg, 15mg/kg, 3mg/kg, 30mg/kg, 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg and 8mg/kg, 30mg/kg;
the dosage ratio of the Leifenesin to the compound 3 is 10mg/kg, 15mg/kg, 10mg/kg, 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the tribromone to the compound 4 is 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg and 8mg/kg, 30mg/kg;
the dosage ratio of the Leifenesin to the compound 4 is 30mg/kg to 30mg/kg;
the dosage ratio of the tribromone to the compound 5 is 8mg/kg and 30mg/kg;
the dosage ratio of the Leifenesin to the compound 5 is 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the tribromone to the compound 6 is 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg and 8mg/kg, 30mg/kg;
the dosage ratio of the Leifenesin to the compound 6 is 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the tribromone to the compound 7 is 3mg/kg, 15mg/kg, 3mg/kg, 30mg/kg, 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg and 8mg/kg, 30mg/kg;
the dosage ratio of the Leifenesin to the compound 7 is 10mg/kg, 15mg/kg, 10mg/kg, 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the Leifenesin to the compound 8 is 30mg/kg to 30mg/kg;
the dosage ratio of the tribromone to the compound 9 is 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg and 8mg/kg, 30mg/kg;
the dosage ratio of the Leifenesin to the compound 9 is 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the tribromone to the compound 10 is 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg, 8mg/kg and 30mg/kg;
the dosage ratio of the Leifenesin to the compound 10 is 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg;
the dosage ratio of the tribromone to the compound 11 is 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg, 8mg/kg and 30mg/kg;
the dosage ratio of the Leifenesin to the compound 11 is 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the tribromone to the compound 12 is 3mg/kg, 15mg/kg, 3mg/kg, 30mg/kg, 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg, 8mg/kg and 30mg/kg;
the dosage ratio of the Leifenesin to the compound 12 is 10mg/kg, 15mg/kg, 10mg/kg, 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg;
the dosage ratio of the tribromone to the compound 13 is 3mg/kg, 15mg/kg, 3mg/kg, 30mg/kg, 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg, 8mg/kg and 30mg/kg;
the dosage ratio of the Leifenesin to the compound 13 is 10mg/kg, 15mg/kg, 10mg/kg, 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg and 30mg/kg;
the dosage ratio of the tribromone to the compound 14 is 3mg/kg, 15mg/kg, 3mg/kg, 30mg/kg, 8mg/kg, 5mg/kg, 8mg/kg, 15mg/kg, 8mg/kg and 30mg/kg;
the dosage ratio of the Leifenesin to the compound 14 is 10mg/kg, 30mg/kg, 5mg/kg, 30mg/kg, 15mg/kg, 30mg/kg.
2. The pharmaceutical composition for treating hyperuricemia according to claim 1, further comprising a pharmaceutically acceptable carrier.
3. A medicament for treating hyperuricemia, which is characterized by comprising the pharmaceutical composition for treating hyperuricemia according to any one of claims 1-2, wherein the medicament is prepared by adding conventional auxiliary materials into the pharmaceutical composition for treating hyperuricemia and preparing clinically acceptable tablets, capsules, pills, granules, ointment, mixture or suspension according to a conventional process.
4. Use of a pharmaceutical composition according to any one of claims 1-2 for the treatment of hyperuricemia in the manufacture of a medicament for the treatment of hyperuricemia.
5. The use of a pharmaceutical composition for treating hyperuricemia according to claim 4, wherein the hyperuricemia is selected from gout or complications of gout caused by hyperuricemia.
6. The use of a pharmaceutical composition for treating hyperuricemia according to claim 5, wherein the gout is selected from acute gout or chronic gout; the gout complications are selected from gouty arthritis, gout flares or gouty nephropathy.
7. The use of a pharmaceutical composition for treating hyperuricemia according to claim 6, wherein the gouty kidney disease is selected from urolithiasis.
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