CN115120601A - Application of mesalazine in preparation of anti-hyperuricemia and anti-gout drugs - Google Patents
Application of mesalazine in preparation of anti-hyperuricemia and anti-gout drugs Download PDFInfo
- Publication number
- CN115120601A CN115120601A CN202110313376.8A CN202110313376A CN115120601A CN 115120601 A CN115120601 A CN 115120601A CN 202110313376 A CN202110313376 A CN 202110313376A CN 115120601 A CN115120601 A CN 115120601A
- Authority
- CN
- China
- Prior art keywords
- gout
- hyperuricemia
- mesalazine
- uric acid
- blood
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Abstract
The invention belongs to the technical field of medicines, and discloses application of mesalazine in preparation of anti-hyperuricemia and/or anti-gout medicines. Specifically, the application of 5-aminosalicylic acid shown as a formula I or a salt thereof or a pharmaceutical composition thereof in preparing a medicament for preventing and/or treating hyperuricemia or/and gout diseases is disclosed. Hyperuricemia comprises primary hyperuricemia and secondary hyperuricemia, and high uric acid concentration in blood caused by various factors, wherein gout comprises primary gout and secondary gout. The invention discovers that mesalazine can obviously reduce the serum uric acid level of a hyperuricemia model mouse, and indicates that the mesalazine can be used for preparing anti-hyperuricemia and/or anti-gout drugs, and provides a safe, effective and economic active substance for preparing drugs for preventing and/or treating hyperuricemia and/or gout diseases.
Description
Technical Field
The invention relates to an application of mesalazine in preparing a medicament, mainly relates to an application of mesalazine in preparing a medicament for resisting hyperuricemia and gout, and belongs to the technical field of medicines.
Background
Gout is a joint disease caused by the deposition of mono-natriuretic urate to form crystals, and is directly related to hyperuricemia caused by purine metabolic disorder and/or reduction of uric acid excretion.
Hyperuricemia means that the uric acid concentration of adult plasma is higher than 420 mu mol/L in male blood and higher than 357 mu mol/L in female blood when the uric acid concentration of adult plasma is determined by a phosphotungstic acid reduction method, or is higher than 420 mu mol/L and higher than 357 mu mol/L in male blood and female blood when the uric acid concentration of adult plasma is determined by a uricase-peroxidase coupling method, and is caused by the increase of uric acid production and (or) reduction of excretion in a human body.
The treatment of hyperuricemia can be divided into drug therapy and non-drug therapy. Clinical research reports show that non-drug treatment can only reduce plasma uric acid levels by about 10-18%, and therefore is essential for drug treatment of hyperuricemia.
The therapeutic drugs for hyperuricemia can be divided into uric acid lowering drugs and anti-inflammatory drugs for controlling acute inflammatory attack. The uric acid lowering drugs can be classified into a xanthine oxidase inhibitor for reducing the production of uric acid, a uricosuric drug for increasing the excretion of uric acid and a uricase for decomposing uric acid according to the action mechanism. However, the existing medicines have adverse reactions with different degrees, such as hypersensitivity syndrome of allopurinol, so the traditional medicines are not ideal.
Mesalazine (mesalazine) with molecular formula of C 7 H 7 NO 3 CAS number: 89-57-6. The chemical structure is as follows:
at present, mesalazine is mainly used for treating active colitis clinically, and the action principle of the mesalazine is to inhibit prostaglandin synthesis in a dose-dependent manner and reduce the release of PGE2 on the colon mucosa of a human. The content of prostaglandin E2(PGE2) and leukotriene B4(LTB4) in the colon mucosa of a colitis patient is high, mesalazine can inhibit the synthesis of mesalazine, inhibit the activity of lipoxygenase of neutrophils, inhibit the functions of migration, degranulation, phagocytosis, oxygen free radical synthesis and the like of human neutrophils, and inhibit the synthesis of Platelet Activating Factor (PAF) which plays an important role in inflammation occurrence, thereby playing a role in treating colitis and having better effect on the connective tissue of the intestinal wall with inflammation. Currently used for the treatment of ulcerative colitis, ulcerative proctitis and Crohn's Disease. The clinical dosage of the mesalazine is 1.5-3.0 g/day. The effects of mesalazine in anti-hyperuricemia and/or anti-gout drugs have not been reported.
Regarding the prior mesalazine patents, a plurality of patents have been disclosed, which mainly focus on the synthesis prescription of mesalazine (CN201610380200.3 a synthesis method of 5-aminosalicylic acid as a mesalazine drug intermediate), industrial preparation (for example, CN202020109156.4 an industrial mesalazine preparation system, CN201580020277.3 a method for preparing mesalazine composition and mesalazine composition prepared by the method), dosage form improvement (CN201610424518.7 a drug composition for colon-specific delivery, CN201610269892.4 a mesalazine enteric-coated positioning controlled-release preparation and its preparation method, CN201610310802.1 mesalazine temperature-sensitive gel enema and its preparation method, etc.), external packaging (CN201430501403.5 packaging box (24 mesalazine enteric coated tablets), CN201430501793.6 packaging box (36 mesalazine enteric coated tablets), etc.), and inflammatory bowel disease and other symptoms treatment (CN201810607144.1 a traditional Chinese medicine composition for preventing or treating ulcerative colitis canceration and its application, cn201610876703.x a pharmaceutical composition for preventing and treating ulcerative colitis and its application), and the like, there is no patent related or similar to the present invention.
Disclosure of Invention
The invention aims to provide the application of mesalazine in preparing anti-hyperuricemia and/or anti-gout drugs, thereby providing a solution with slight adverse reaction for reducing the concentration of uric acid in blood and treating gout.
Therefore, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides application of 5-aminosalicylic acid (mesalamine) shown as a formula I or salt thereof in preparing medicines for preventing and/or treating hyperuricemia or/and gout diseases
Further, the hyperuricemia comprises but is not limited to primary and secondary hyperuricemia and the concentration of uric acid in blood caused by various factors is higher than (male) 420 mu mol/L, (female) 357 mu mol/L (determined by phosphotungstic acid reduction method) or (female) 357 mu mol/L determined by uricase-peroxidase coupling method.
Further, the gout includes but is not limited to primary gout and secondary gout. The gout is primary gout induced by uric acid in joints becoming crystals due to the fact that the concentration of uric acid in blood is increased and secondary gout caused by various factors.
The salt of the 5-aminosalicylic acid comprises pharmaceutically acceptable salt consisting of the 5-aminosalicylic acid and basic ions or organic basic substances and crystal forms of the salt, wherein the basic ions comprise sodium, potassium, magnesium and calcium.
The second aspect of the technical scheme of the invention provides application of a pharmaceutical composition in preparing a medicament for preventing and/or treating hyperuricemia or/and gout diseases, which is characterized in that the pharmaceutical composition contains effective dose of 5-aminosalicylic acid shown in formula I or salt thereof and other active substances, and a pharmaceutically acceptable carrier or excipient.
The other active substances comprise compounds with the effect of reducing uric acid, or components capable of influencing uric acid metabolism or influencing the pathological process or the pathological manifestations of gout.
The salt of the 5-aminosalicylic acid comprises pharmaceutically acceptable salt consisting of the 5-aminosalicylic acid and basic ions or organic basic substances and crystal forms of the salt, wherein the basic ions comprise sodium, potassium, magnesium and calcium.
Further, the pharmaceutical composition may be prepared according to methods well known in the art. The content of the compound of the invention in the pharmaceutical composition is usually 0.1-99%, and the compound can be prepared into pharmaceutical composition dosage forms for human or animal use.
Further, the salts of 5-aminosalicylic acid include, but are not limited to, pharmaceutically acceptable salts with ions including sodium, potassium, magnesium, calcium or organic bases and crystalline forms thereof.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by a route which may be gastrointestinal or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal and the like.
Furthermore, the pharmaceutical composition dosage form comprises an oral preparation, an injection administration dosage form and a skin mucosa administration dosage form.
The oral preparation comprises tablets, sustained-release preparations, capsules, controlled-release preparations, dripping pills and liquid preparations, and the injection administration dosage forms comprise intramuscular injection, intravenous injection and intravenous drip.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, carboxypropylmethylcellulose, ethylcellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.
In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, gallate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, in the preparation of lyophilized powder for injection, mannitol and glucose can also be added as proppant.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired. For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method. The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 100mg/kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The invention has the beneficial effects that: according to the invention, a potassium oxonate induced hyperuricemia mouse model is adopted to investigate the effect of mesalazine on resisting hyperuricemia and/or gout, and the results show that 10mg/kg, 30mg/kg and 100mg/kg of mesalazine can respectively reduce 46%, 63% and 46% of serum uric acid levels, so that a potential safe and effective solution is provided for the treatment, prevention and treatment of hyperuricemia and/or gout.
Drawings
FIG. 1 Mesalazine reduction in vitro(iv) a (iv) oxidase activity.
n＝4。
Fig. 2 mesalazine in vitro experiments scavenging free radicals.
n＝4。
FIG. 3 shows the uric acid-lowering effect of mesalazine mice in vivo.
n＝6-10。
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings.
EXAMPLE 1 Mesalazine reduces xanthine oxidase activity in vitro.
Experimental materials: mesalamine, allopurinol, tert-butylhydroquinone, xanthine oxidase, EDTA available from Sigma Aldrich (Sigma-Aldrich, Germany). WST-1 was purchased from Dongren chemical technology (Shanghai) Inc.
Table 1. reaction system:
after the sample is loaded on a 384-well plate according to the reaction system in the table 1, the reaction system is continuously monitored for 20min, the absorption conditions of 295nm and 450nm are detected, and the change of the absorbance slope of 295nm is calculated. The slope of the 295nm absorption peak represents the rate of uric acid production and can be used for evaluating the xanthine oxidase activity; OD495 represents the amount of formazan generated by WST-1, and can be used for observing the reaction progress and the free radical generation amount.
As a result: after mesalamine (0.3, 1, 3, 10, 30, 100, 300, 1000 μ g/ml) is added in vitro, the xanthine oxidase activity is increased in a dose-dependent manner, and the free radical clearance rate is also increased in a dependent manner, as shown in tables 2 and 3 and fig. 1 and 2, which suggest that oral mesalamine can further exert an anti-hyperuricemic and/or anti-gout effect by scavenging free radicals. IC50 (free radical scavenging) was 690.3. mu.g/ml.
TABLE 2 Mesalazine reduction of xanthine oxidase Activity in vitro
TABLE 3 Mesalazine in vitro scavenging of free radicals
Experimental example 2 uric acid lowering effect in mesalazine mice.
Experimental materials: the c57BL/6J mice were purchased from Wafunkang Biotech GmbH, Beijing. Potassium Oxazinate, benzbromarone, was purchased from Sigma Aldrich (Sigma-Aldrich, Germany). Mesalazine was purchased from Shanghai-derived leaf Biotech, Inc. Sodium carboxymethylcellulose was purchased from national pharmaceutical group chemical reagents, ltd. The uric acid kit is purchased from Zhongsheng Bei Zhi Biotechnology GmbH.
Solution preparation: dissolving 0.5% sodium carboxymethylcellulose, boiling, cooling, and dissolving mesalazine, potassium oxonate, and benzbromarone respectively to obtain suspension.
Grouping experiments: 18g mice were randomly divided into a normal control group, a model group, and a benzbromarone group (20 mg. kg) -1 Positive control), mesalazine low and high dose groups (5, 20mg kg) -1 ) Each group of 5-8Only.
The intraperitoneal injection of 300 mg/kg of Potassium Oxonate is taken daily except for the control group -1 The normal control group is injected with 0.5 percent sodium carboxymethylcellulose solution with the same amount every day, the continuous molding is carried out for 7 days, then the administration is carried out according to groups, the mice are killed after the administration is carried out for 7 days, the blood is taken from the venous plexus behind the eyes, the blood serum is taken after the standing is carried out for 2 hours, the speed is 4500rpm, the centrifugation is carried out for 15min at 4 ℃, and the serum uric acid level is measured by using a uric acid kit.
As a result: after the mesalamine (10, 30 and 100mg/kg) is orally taken by model animals, the serum uric acid level can be respectively reduced by 46%, 63% and 46%, and other results are shown in a table 3 and a figure 3, which indicate that the oral mesalamine can play the role of resisting hyperuricemia and/or gout.
TABLE 3 Effect of mesalazine on serum uric acid levels in hyperuricemia model mice
In conclusion, the invention adopts the potassium oxonate induced hyperuricemia model to investigate the effect of the mesalazine on the anti-hyperuricemia and/or anti-gout drugs, and the result shows that 10, 30 and 100mg of the mesalazine have certain anti-hyperuricemia and/or anti-gout effects. The mesalazine is taken as an active substance, is singly used or/and combined with other compounds and/or extracts with pharmacological activity for compound use, is prepared into anti-hyperuricemia and/or anti-gout drugs in various dosage forms according to the conventional preparation method in the pharmaceutical field, or is prepared into compound preparations with other uricosuric drugs and/or xanthine oxidase inhibitors and the like, is used for reducing adverse reactions in the drug action under the condition of keeping the curative effect, and can provide a safe and effective solution for the treatment, prevention and treatment of hyperuricemia and/or gout.
Finally, while the present invention has been described with reference to a preferred embodiment thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (8)
1. The application of 5-aminosalicylic acid shown as a formula I or a salt thereof in preparing a medicament for preventing and/or treating hyperuricemia or/and gout diseases,
2. use according to claim 1, characterized in that said hyperuricemia is caused by primary, secondary or various factors, by a phosphotungstic acid reduction method determining a uric acid concentration in the blood of adult males higher than 420 μmol/L and in the blood of females higher than 357 μmol/L, or by a uricase-peroxidase coupling method determining a uric acid concentration in the blood of adult males higher than 420 μmol/L and in the blood of females higher than 357 μmol/L.
3. The use according to claim 1, wherein said gout is primary gout induced by uric acid in the joints as crystals due to an increase in the concentration of uric acid in blood and secondary gout caused by various factors.
4. The application of a pharmaceutical composition in preparing a medicine for preventing and/or treating hyperuricemia or/and gout diseases is characterized in that the pharmaceutical composition contains an effective dose of 5-aminosalicylic acid shown as a formula I or a salt thereof and other active substances, and a pharmaceutically acceptable carrier or excipient.
5. The use according to claim 4, wherein said other active substances comprise compounds having a uric acid lowering effect, or components capable of affecting uric acid metabolism, or affecting the pathological course or manifestation of gout.
6. The use according to any one of claims 1 to 5, wherein the salt of 5-aminosalicylic acid comprises a pharmaceutically acceptable salt of 5-aminosalicylic acid with or basic ions comprising sodium, potassium, magnesium, calcium, or an organic basic substance, and crystalline forms thereof.
7. The use according to claim 4, characterized in that said pharmaceutical composition is selected from the group consisting of oral formulations, formulations for administration by injection or formulations for administration by the mucocutaneous route.
8. The use according to claim 7, wherein the oral preparation comprises a tablet, a sustained release formulation, a capsule, a controlled release formulation, an enteric agent, a drop pill or a liquid preparation, and the injection administration comprises intramuscular injection, intravenous injection or intravenous drip.
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| CN1712010A (en) * | 2004-06-14 | 2005-12-28 | 北京化工大学 | 5-amino-salicylic acid intercalation medicinal slow-release agent and production thereof |
| CN106344591A (en) * | 2016-10-25 | 2017-01-25 | 昆明医科大学 | Application of olsalazine sodium in preparation of medicines and health products for preventing and treating hyperuricemia and gout |
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