CN108992456B - Pharmaceutical composition containing diosmetin sulfate derivative and application thereof - Google Patents

Pharmaceutical composition containing diosmetin sulfate derivative and application thereof Download PDF

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CN108992456B
CN108992456B CN201810797403.1A CN201810797403A CN108992456B CN 108992456 B CN108992456 B CN 108992456B CN 201810797403 A CN201810797403 A CN 201810797403A CN 108992456 B CN108992456 B CN 108992456B
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pharmaceutical composition
poisoning
formula
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application
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CN108992456A (en
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孙明杰
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Xiangbei Wellman Pharmaceutical Co ltd
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Xiangbei Wellman Pharmaceutical Co ltd
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Abstract

The invention provides a pharmaceutical composition containing diosmetin sulfate derivatives and application thereof, and the derivatives or the pharmaceutical composition thereof can be used for preventing or treating poisoning. The diosmin derivative and the pharmaceutical composition have good detoxification effect, can obviously relieve poisoning caused by various factors, effectively recover impaired liver function, and provide a new drug choice for clinically preventing or treating poisoning or digestive tract ulcer combined poisoning.

Description

Pharmaceutical composition containing diosmetin sulfate derivative and application thereof
Technical Field
The invention relates to a pharmaceutical composition containing diosmetin sulfate derivatives, and also relates to application of the pharmaceutical composition.
Background
Poisoning refers to a process in which foreign substances (toxic substances) enter a human body and react with tissues to cause temporary or permanent damage to the functions of the tissues.
After entering the human body, toxic substances often damage vital organs and systems, such as gastrointestinal tract, liver, kidney, nervous system, etc. The liver, the largest metabolic organ in the human body, is said to have "detoxifying" functions. But as such, the liver also suffers most of the toxicant's damage to the human body.
Poisoning is very common in daily life. Besides causing gastrointestinal reactions such as diarrhea and vomiting, toxic food can cause organ damage in vivo. Excessive alcohol can stimulate the gastrointestinal tract, cause liver injury, cognitive dysfunction and the like, and alcoholic fatty liver caused by long-term drinking becomes one of the liver diseases with extremely high morbidity at present. The drugs are usually metabolized by the liver, and many drugs have adverse reactions such as hepatotoxicity and the like, and particularly some chemotherapy drugs for treating cancers can cause hepatitis and hepatic fibrosis and seriously affect the life quality of patients.
There is a general need to prevent or treat poisoning. Currently, acute poisoning generally discharges toxicants out of the body by means of emetic, gastric lavage, catharsis and the like; although specific antagonists of toxicants have been used to reduce the level of toxicants in humans to mitigate their damage, antagonists themselves may have toxicity problems. There remains an urgent need to find more effective and safe antidotes in the clinic.
Disclosure of Invention
The invention aims to provide a medicinal composition containing diosmetin sulfate derivatives, and also aims to provide application of the medicinal composition in medicines.
In a first aspect, the present invention provides a pharmaceutical composition for preventing or treating poisoning, which comprises a diosmin sulfate derivative as an active ingredient.
Preferably, the diosmetin sulfate derivative refers to a metal salt of diosmetin sulfate or a metal complex of diosmetin sulfate.
Preferably, the diosmetin sulfate derivative is a compound represented by formula I:
Figure RE-GDA0001832114280000011
in the formula I, R is SO3M，R1Selected from H or SO3M, wherein M is a metal ion or a metal complex group.
Preferably, the metal is sodium, potassium, calcium, aluminum or magnesium.
Further preferably, R in the compound of formula I of the invention is SO3Na，R1Is H.
Further preferably, R in the compound of formula I of the invention is SO3Na，R1Is SO3Na。
Further preferably, R in the compound of formula I of the invention is SO3[Al2(OH)5]，R1Is H.
Further preferably, R in the compound of formula I of the invention is SO3[Al2(OH)5]，R1Is SO3[Al2(OH)5]。
The diosmetin sulfate derivative shown in the formula I can also comprise a solvate, a polymorphic substance, an isomer, a prodrug, an active metabolite and a derivative with similar pharmacological activity. One skilled in the art, in light of the present disclosure, would expect these variations to have prophylactic or therapeutic effects on poisoning.
Preferably, the pharmaceutical composition is in the form of an oral formulation. For example, the pharmaceutical composition may be in the form of tablets, chewable tablets, dispersible tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions and the like according to specific needs.
Preferably, the pharmaceutical composition may further comprise pharmaceutically suitable excipients. For example, excipients, preservatives, solubilizers, fillers, binders, adsorbents, disintegrants, lubricants, other carriers, other inert ingredients, or combinations thereof can be included in the pharmaceutical composition according to particular needs.
Further preferably, the pharmaceutical composition of the present invention is a general tablet. Each tablet contains 0.1g to 1g of a compound of formula I. The further preferred pharmaceutical composition may also contain pharmaceutically acceptable excipients such as one or more of diluents, binders, disintegrants or lubricants, for example microcrystalline cellulose, lactose, hypromellose, polyvinylpyrrolidone or magnesium stearate. Coating can also be carried out by conventional methods.
Further preferably, the pharmaceutical composition of the present invention is a dispersible tablet. The dispersible tablet may contain pharmaceutically acceptable adjuvants such as one or more of dispersant, disintegrant, binder or lubricant.
Further preferably, the pharmaceutical composition of the present invention is a capsule. The capsule may contain pharmaceutically acceptable excipients such as one or more of a filler, a disintegrant, a binder or a lubricant.
Further preferably, the pharmaceutical composition of the invention is a suspension comprising 0.5g to 3g of the compound of formula I per bottle. The further preferred pharmaceutical composition may further comprise pharmaceutically acceptable excipients, such as one or more of a suspending agent, a surfactant or a preservative. Such as sucrose, sodium saccharin, tris, sorbitol, xanthan gum, glycerol, sodium benzoate, paraben or propyl benzoate, and the like.
Preferably, 0.05g to 50g of a compound of formula I per day may be administered to said human as specifically required.
Further preferably, the amount of 0.1g to 30g per day is administered to the human body.
Still more preferably, the amount of 1g to 18g per day is administered to said human.
Preferably, the compound of formula I is administered to said human 1-3 times per day, depending on the particular need.
Preferably, the intoxication is food-, drug-or alcohol-induced intoxication.
Preferably, the symptoms of poisoning include impaired liver function.
Preferably, the poisoning refers to impaired liver function.
In addition, given that the compounds of formula I are useful per se in the treatment of gastrointestinal disorders including peptic ulcers, therefore:
preferably, the pharmaceutical composition of the invention, said intoxication is also associated with gastrointestinal disorders. Further preferably, the gastrointestinal disorder is an ulcer of the digestive tract, such as a gastric ulcer or a duodenal ulcer.
In a second aspect, the invention also provides a new application, namely the application of the diosmin sulfate derivative shown in the formula I in preparing a medicament for preventing or treating poisoning.
In the alternative, the first and second sets of the first,
the invention provides application of a pharmaceutical composition taking diosmin sulfate derivatives shown in formula I as active ingredients in preparation of drugs for preventing or treating poisoning.
Preferably, in the application of the present invention, the technical features of intoxication, pharmaceutical composition and the like can be adopted in various preferred manners already mentioned above.
The pharmaceutical composition and the application thereof provided by the invention have the beneficial technical effects that:
we find a pharmaceutical composition which takes the compound of the formula I as an active ingredient and can be used for preventing or treating poisoning for the first time, and provide a new pharmaceutical choice for clinic. The pharmaceutical composition can obviously relieve the toxic symptoms caused by various reasons. It has been found through experimentation that preferred pharmaceutical compositions are effective in restoring impaired liver function. In particular, the values of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) can be reduced by more than 30-60% compared with a model group without using the pharmaceutical composition.
Detailed Description
To better illustrate the objects, aspects and effects of the present invention, the present invention will be further described with reference to the following specific examples. It should be noted that the embodiments are only examples and not exhaustive.
EXAMPLE 1 preparation of a Compound of formula I according to the invention
Figure RE-GDA0001832114280000031
The diosmin sulfate derivative shown in the formula I comprises a metal salt of diosmin sulfate and a metal compound of diosmin sulfate. In the formula I, R is SO3M, R1 is selected from H or SO3M, wherein M is a metal ion or a metal complex group.
Reference is made to European patent EP0302155 and European patent EP0558435, the entire contents of which are incorporated herein by reference. Referring to the following reaction formula, Diosmin (Diosmin) is used as a raw material, sulfation is carried out, and alkalization is carried out to obtain the metal salt of Diosmin sulfate, namely R ═ SO3M, R1 ═ H or SO3M is a compound of formula I, wherein M may be a common metal ion, such as sodium, potassium, calcium, aluminum or magnesium, and different metal salts may be obtained by selecting different alkalizing agents, such as sodium hydroxide. On the basis of this, a metal complex can be obtained by further treatment, for example an aluminum complex of diosmin sulphate, i.e. R ═ SO, can be obtained by further treatment with an alkaline aluminum chloride3[Al2(OH)5]R1 ═ H or SO3[Al2(OH)5]A compound of formula I.
Figure RE-GDA0001832114280000041
Several representative specific compounds of the compounds of formula I are listed below:
a compound I: r is SO3Na and R1 are H.
And (2) a compound II: r is SO3Na, R1 is SO3Na。
Compound three: r is SO3[Al2(OH)5]And R1 is H.
Compound iv: r is SO3[Al2(OH)5]R1 is SO3[Al2(OH)5]。
Example 2 pharmaceutical composition-tablet of the invention
Prescription: 500g of compound III, 30g of microcrystalline cellulose, 20.2g of hydroxypropyl methylcellulose, 10.3g of polyvinylpyrrolidone and 3.5g of magnesium stearate. The preparation method comprises the following steps: taking compound III and microcrystalline cellulose, preparing into soft mass with 5% hydroxypropyl methylcellulose ethanol solution, granulating, drying, adding sodium carboxymethyl starch and magnesium stearate, and tabletting to obtain 1000 tablets.
Example 3 pharmaceutical composition-Capsule of the invention
Prescription: 500g of compound II, 30g of microcrystalline cellulose and 10g of silicon dioxide. The preparation method comprises the following steps: mixing the compound II, microcrystalline cellulose and silicon dioxide uniformly, sieving, and encapsulating to obtain 1000 granules.
Example 4 pharmaceutical composition-suspension of the invention
Prescription: compound three 1500g, sucrose 30g, saccharin sodium 40g, trihydroxymethyl aminomethane 5g, sorbitol 50g, xanthan gum 2500g, nipagin methyl ester 10g, and appropriate amount of deionized water. The preparation method comprises the following steps: according to the conventional preparation method of the suspension, the raw and auxiliary materials are taken to prepare 1000 bottles of suspension, and each bottle contains 10ml of suspension.
Example 5 protective Effect of the pharmaceutical composition of the present invention on animals with drug intoxication
Test drugs: the pharmaceutical compositions of examples 2, 3, and the control drug diosmin.
Test animals: two-week-old Wister rats, half male and half female, were randomly divided into 7 groups: normal group, model group, control group, prevention group, treatment group, and treatment group.
The test method comprises the following steps:
molding: except for the normal group, animals in each group were gavaged with 110mg/kg (based on cyclophosphamide) of 5% methylcellulose solution of cyclophosphamide per day, and the next normal group was gavaged with the same volume of 5% methylcellulose solution. The molding was completed for 3 consecutive days (D1, D2, D3).
Administration: example 2 and example 3 groups 1000mg/kg (active ingredient) of 5% methylcellulose solution of the test drug per day were started on day 7 before molding (D1-7), until the day before molding was started (D1-1), and then the same volume of 5% methylcellulose solution was gavaged per day. Example 2, example 3 two groups were gavaged with 5% methylcellulose solution daily from D1-7 until the day of molding (D1) was changed to 5% methylcellulose solution of the daily gavage test drug at a dose of 1000mg/kg (as active ingredient) and continued until day 5 after molding was completed (D3+ 5). Wherein, the diosmin is used for the control group, the pharmaceutical composition in the example 2 is used for the prevention group and the pharmaceutical composition in the example 3 is used for the treatment group, and the pharmaceutical composition in the example 3 is used for the prevention group and the therapeutic group. The model group and the normal group were gavaged daily with an equal volume of 5% methylcellulose solution.
Detection and results: animals in each group were bled on day 5 after molding and the levels of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) were determined. The main results of the tests are shown in table 1.
TABLE 1 protective action of the pharmaceutical silk compound of the present invention on cyclophosphamide poisoned rats
Figure RE-GDA0001832114280000051
The test results show that the composition has better detoxification effect on drug poisoning. Cyclophosphamide is an alkylating agent, belongs to a broad-spectrum anticancer drug with wide application, but has larger hepatotoxicity. Cyclophosphamide poisoning may be manifested as an abnormality of the relevant indicators in the body. In the test, cyclophosphamide causes great elevation of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) of rats, and severe toxic reaction is generated. Significant improvement of the symptoms of poisoning, i.e., significant reduction in ALT and AST values in the prevention and treatment groups, compared to the model group, was observed with the pharmaceutical composition of the present invention before or after cyclophosphamide administration, indicating that the pharmaceutical composition of the present invention has effects of preventing and treating cyclophosphamide poisoning and liver protecting effects. The control drug group did not decrease ALT and AST, but increased them.
Example 6 protective Effect of the pharmaceutical composition of the present invention on Alcoholic animals
Test drugs: pharmaceutical compositions of examples 2 and 3
Test animals: two-week-old Wister rats, half male and half female, were randomly divided into 6 groups: normal group, model group, prevention group, treatment group.
The test method comprises the following steps:
molding: except for normal group, each group of animals was gavaged with 55 ° distilled spirit at a dose of 10 ml/kg. The normal group was gavaged with the same volume of deionized water.
Administration: the 5% methylcellulose solution of the gastric lavage test medicament is used for preventing one group and two groups before 40min of the model building, and the 5% methylcellulose solution of the gastric lavage test medicament is used for treating one group and two groups after 40min of the model building, and the dosage is 800mg/kg (calculated by active ingredients). Wherein the pharmaceutical composition of example 2 is used in the preventive group and the therapeutic group, and the pharmaceutical composition of example 3 is used in the preventive group and the therapeutic group. The model group and the normal group were gavaged daily with an equal volume of 5% methylcellulose solution.
Detection and results: blood was collected 7h after molding for each group of animals, and the contents of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) in serum were determined. The main results of the tests are shown in table 2.
TABLE 2 protective effect of the pharmaceutical composition of the present invention on alcoholism rats
Figure RE-GDA0001832114280000061
Alcohol is metabolized mainly by liver, and animals produce toxic reaction after intragastric administration of alcohol with medium concentration in the test, which is marked by obvious increase of ALT and AST. The use of the pharmaceutical composition of the present invention can effectively reduce the elevation values of ALT and AST. The test result shows that the pharmaceutical composition has the effects of preventing or treating alcoholism and protecting liver.
Example 7 protective Effect of the pharmaceutical composition of the present invention on food poisoning animals
Test drugs: pharmaceutical compositions of examples 2 and 3
Test animals: two-week-old Wister rats, half male and half female, were randomly divided into 4 groups: normal group, model group, treatment group, and treatment group.
The test method comprises the following steps:
molding: aspergillus flavus (CICC2219) is selected to ferment the aflatoxin B1, and the aflatoxin B1 is added into normal animal feed to prepare toxic feed. Animals in each group were fed with the poisonous diet daily (20. mu.g/kg calculated as aflatoxin B1) except for the normal group.
Administration: after continuously feeding the poisonous feed for 10 days, 5% methylcellulose solution of the test drug for the first and second groups of the treatment is used as the drug for the daily gavage test, and the dosage is 800mg/kg (calculated by active ingredients). One group of treatments uses the pharmaceutical composition of example 2 and two groups of treatments use the pharmaceutical composition of example 3. The model group and the normal group were gavaged daily with an equal volume of 5% methylcellulose solution. The administration was continued for 5 days, during which time each group of animals was fed normal diet.
Detection and results: blood was collected 5 days after administration, and the contents of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) in the serum were measured. The main results of the tests are shown in table 3.
TABLE 3 protective effect of the pharmaceutical composition of the present invention on food poisoning rats
Figure RE-GDA0001832114280000062
Figure RE-GDA0001832114280000071
After most foods are deteriorated, aspergillus flavus is easy to breed, and after the foods are eaten, the foods are easy to be poisoned by the aspergillus flavus. After the rats in the experiment are fed with the poisonous feed, the liver function damage caused by the poisoning is shown. After the medicine composition is taken, the liver function damage of animals is obviously reduced, and the detoxification function is achieved.
The present invention has been described in detail with reference to the general description, the specific embodiments, and the like. Those skilled in the art can make reasonable modifications or improvements based on the present invention, and such modifications or improvements do not depart from the spirit of the present invention.

Claims (6)

1. The application of a pharmaceutical composition in preparing a medicament for preventing or treating poisoning, wherein the pharmaceutical composition takes diosmetin sulfate derivatives shown in formula I as active ingredients;
Figure FDA0002987872430000011
in the formula I, R is SO3M，R1Selected from H or SO3M, wherein M is a metal ion, and the metal is sodium, potassium, calcium, aluminum or magnesium;
the poisoning is food-, drug-or alcohol-induced poisoning.
2. The application of a pharmaceutical composition in preparing a medicament for preventing or treating poisoning, wherein the pharmaceutical composition takes diosmetin sulfate derivatives shown in formula I as active ingredients;
Figure FDA0002987872430000012
in the formula I, R is SO3[Al2(OH)5]，R1Selected from H or SO3[Al2(OH)5]；
The poisoning is food-, drug-or alcohol-induced poisoning.
3. The use as claimed in claim 1, wherein R is SO3Na，R1Is H; or R is SO3Na，R1Is SO3Na。
4. The use according to claim 1 or 2, wherein the pharmaceutical composition is an oral formulation.
5. Use according to claim 1 or 2, wherein the pharmaceutical composition is a plain tablet, chewable tablet, dispersible tablet, granule, solution, capsule or suspension.
6. Use according to claim 1 or 2, wherein the poisoning is impaired liver function.
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