阅读说明：本技术 二蒽酮类化合物在制备抗炎保肝药物中的应用 (Application of dianthrone compound in preparation of anti-inflammatory and liver-protecting drugs ) 是由 马双成 孙华 魏锋 杨建波 欧阳婷 汪褀 陈子涵 王莹 宋云飞 陈智伟 高慧宇 于 2021-09-14 设计创作，主要内容包括：尤其涉及二蒽酮类化合物在制备抗炎保肝药物中的应用,属于生物医药技术领域。本发明提供了二蒽酮类化合物在制备抗炎保肝药物中的应用；所述二蒽酮类化合物包括Trans-大黄素二蒽酮和/或Cis-大黄素二蒽酮。本发明提供了二蒽酮类化合物在制备抗炎保肝药物中的应用,由实施例的结果表明,二蒽酮类化合物在药理上具有以下显著活性：显著改善小鼠免疫性肝脏损伤,改善肝组织病理损伤,降低血清肝损伤生物标记物。(In particular to application of dianthrone compounds in preparing anti-inflammatory and liver-protecting medicaments, belonging to the technical field of biological medicines. The invention provides application of dianthrone compounds in preparing anti-inflammatory and liver-protecting medicaments; the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone. The invention provides application of dianthrone compounds in preparing anti-inflammatory and liver-protecting medicaments, and results of examples show that the dianthrone compounds have the following remarkable activities in pharmacology: obviously improve the immune liver injury of mice, improve the pathological injury of liver tissues and reduce the biomarkers of serum liver injury.)

1. The application of dianthrone compounds in preparing anti-inflammatory and liver-protecting medicaments;

the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone.

2. The use according to claim 1, wherein when the dianthrone compounds include Trans-emodin dianthrone and Cis-emodin dianthrone, the ratio of the amounts of the substances of Trans-emodin dianthrone and Cis-emodin dianthrone is 1 (0.5-1).

3. The use according to claim 2, wherein the substance amounts of Trans-emodin dianthrone and Cis-emodin dianthrone are in a ratio of 56: 38.

4. The use according to any one of claims 1 to 3, wherein the anti-inflammatory liver protection medicament is used for the treatment of one or more of viral hepatitis, drug-induced liver injury, fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis.

5. The use according to any one of claims 1 to 4, wherein the mass percentage of the dianthrone compound in the medicament is 0.1% to 95%.

6. The use according to claim 5, wherein the content of dianthrone compounds in the medicament is 30-90% by mass.

7. The use according to any one of claims 1 to 4, wherein the medicament is in a dosage form selected from the group consisting of oral preparation, external preparation, injection and cavity administration preparation.

8. The use according to claim 7, wherein the oral formulation comprises a tablet, capsule, pill, granule, oral liquid or suspension.

9. The use of claim 7, wherein the injection comprises a liquid injection, a powder injection or an infusion solution.

Technical Field

The invention relates to the technical field of biological medicines, in particular to application of dianthrone compounds in preparation of anti-inflammatory and liver-protecting medicines.

Background

In recent years, the incidence of drug-induced liver diseases, alcoholic liver diseases, metabolic-related fatty liver diseases and autoimmune liver diseases has also been increasing year by year. As is well known, liver disease is a progressive disease and there are several evidences suggesting that inflammation of the liver occurs in liver disease due to almost all causes and often throughout the course of liver disease.

The anti-inflammatory liver protection treatment is an important component of the comprehensive treatment of the liver inflammation, and for the liver inflammation, whether an effective etiology treatment exists or not, the anti-inflammatory liver protection treatment is considered to be implemented; anti-inflammatory and hepatoprotective therapies are more considered for some patients who lack effective etiological treatment or who are temporarily unable to do so.

However, the progress of anti-inflammatory liver protection is not ideal for a long time, and the clinical selection of anti-inflammatory liver protection medicines is limited.

Disclosure of Invention

The invention aims to provide application of dianthrone compounds in preparing anti-inflammatory and liver-protecting medicaments.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides application of dianthrone compounds in preparing anti-inflammatory and liver-protecting medicaments;

the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone.

Preferably, when the dianthrone compound comprises Trans-emodin dianthrone and Cis-emodin dianthrone, the mass ratio of the Trans-emodin dianthrone to the Cis-emodin dianthrone is 1 (0.5-1).

Preferably, the mass ratio of the Trans-emodin dianthrone to the Cis-emodin dianthrone is 56: 38.

Preferably, the anti-inflammatory liver protection medicament is used for treating one or more of viral hepatitis, drug-induced liver injury, fatty liver disease, autoimmune hepatitis, hepatic fibrosis and liver cirrhosis.

Preferably, the mass percent of the dianthrone compound in the medicine is 0.1-95%.

Preferably, the mass percentage of the dianthrone compound in the medicine is 30-90%.

Preferably, the dosage form of the medicament comprises an oral preparation, an external preparation, an injection or a cavity administration preparation.

Preferably, the oral preparation comprises tablets, capsules, pills, granules, oral liquid or suspension.

Preferably, the injection comprises water injection, powder injection or infusion solution.

The invention provides application of dianthrone compounds in preparing anti-inflammatory and liver-protecting medicaments; the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone. In the invention, the dianthrone compound has the following significant activity in pharmacology: obviously improve the immune liver injury of mice, improve the pathological injury of liver tissues and reduce the biomarkers of serum liver injury.

Drawings

Figure 1 is a graph of the effect of gluten Aminotransferase (ALT) on the serum liver function biomarker of mice with acute immunological liver injury induced by phytohemagglutinin (ConA) (n-7-8); (^*P is less than 0.05, compared with a blank control group;^#p < 0.05, compared to model group);

figure 2 is a graph of the effect of glutamic-oxaloacetic transaminase (AST) on a lectin (ConA) -induced acute immune liver injury mouse serum liver function biomarker (n-7-8); (^*P is less than 0.05, compared with a blank control group;^#p < 0.05, compared to model group);

FIG. 3 shows the pathological improvement effect on the liver tissue of a mouse with acute immunological liver injury induced by phytohemagglutinin (ConA).

Detailed Description

The invention provides application of dianthrone compounds in preparing anti-inflammatory and liver-protecting medicaments;

the dianthrone compound comprises Trans-emodin dianthrone and/or Cis-emodin dianthrone.

In the invention, the chemical structural formula of the Trans-emodin dianthrone (HSW-W-25) is shown as a formula I; the chemical structural formula of the Cis-emodin dianthrone (HSW-W-26) is shown as a formula II;

the sources of Cis-emodin dianthrone and Trans-emodin dianthrone are not particularly limited in the present invention and are derived from conventional commercial sources or prepared according to methods well known in the art.

In the present invention, the Trans-emodin dianthrone is a mixture of racemates of Trans-emodin dianthrone; the Cis-emodin dianthrone is a meso-form mixture of the Cis-emodin dianthrone.

In the invention, when the dianthrone compound comprises Trans-emodin dianthrone and Cis-emodin dianthrone, the mass ratio of the Trans-emodin dianthrone to the Cis-emodin dianthrone is preferably 1 (0.5-1), and more preferably 56: 38.

In the present invention, the anti-inflammatory liver protection drug is preferably used for treating one or more of viral hepatitis, drug-induced liver injury, fatty liver disease, autoimmune hepatitis, hepatic fibrosis and hepatic cirrhosis.

In the present invention, the mass percentage of the dianthrone compound in the drug is preferably 0.1% to 95%, more preferably 30% to 90%, and most preferably 50% to 80%.

In the present invention, the dosage form of the drug preferably includes an oral preparation, a topical preparation, an injection or a cavity administration preparation.

In the present invention, the oral formulation preferably includes a tablet, a capsule, a pill, a granule, an oral liquid or a suspension.

In the invention, the injection preferably comprises water injection, powder injection or infusion solution.

In the present invention, the dosage form of the drug preferably includes a gaseous dosage form, a liquid dosage form, a solid dosage form or a semisolid dosage form.

In the present invention, the gaseous dosage form preferably comprises an aerosol or spray.

In the present invention, the liquid dosage form preferably includes a solution, an emulsion, a suspension, an injection, an eye drop, a nasal drop, a lotion or a liniment. In the present invention, the solution preferably comprises a true solution or a colloidal solution; the emulsion preferably comprises o/w type living compound emulsion or w/o type living compound emulsion; the injection preferably comprises water injection, powder injection or infusion solution.

In the present invention, the solid dosage form preferably comprises tablets, capsules, granules, powders, pellets, dripping pills, suppositories, films, patches or powder sprays; in the present invention, the tablet preferably includes a general tablet, an enteric coated tablet, a buccal tablet, a dispersible tablet, a chewable tablet, an effervescent tablet or an orally disintegrating tablet. In the present invention, the capsule preferably includes a hard capsule, a soft capsule or an enteric capsule.

In the present invention, the semisolid dosage form preferably comprises an ointment, gel or paste.

In the present invention, the dosage form of the drug preferably includes a general formulation, a sustained release formulation, a controlled release formulation, a targeted formulation or a microparticle delivery system.

In the present invention, the medicament preferably further comprises pharmaceutically acceptable excipients.

In the present invention, when the dosage form of the drug is preferably a tablet, the auxiliary material preferably includes one or more of a diluent, a binder, a wetting agent, a disintegrant, a lubricant, and a glidant.

In the present invention, the diluent preferably includes one or more of starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and calcium carbonate; the humectant preferably comprises one or more of water, ethanol and isopropanol; the binder preferably comprises one or more of starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, acrylic resins, carbomers, polyvinylpyrrolidone and polyethylene glycol; the disintegrant preferably comprises one or more of dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate, citric acid, polyoxyethylene sorbitol fatty acid ester and sodium dodecyl sulfate; the lubricant preferably comprises one or more of talc, silica, stearate, tartaric acid, liquid paraffin and polyethylene glycol; the glidant preferably comprises one or more of talc, silicon dioxide, stearate, tartaric acid, liquid paraffin and polyethylene glycol.

In the present invention, the tablet preferably includes a coated tablet, and the coated tablet preferably includes a sugar-coated tablet, a film-coated tablet or an enteric-coated tablet.

In the present invention, the tablet preferably comprises a single-layer tablet or a multi-layer tablet.

In the present invention, when the dosage form of the drug is preferably a capsule, the adjuvant preferably includes one or more of a diluent, a glidant, a wetting agent, a binder, and a disintegrant.

In the present invention, when the dosage form of the drug is preferably an injection, the solvent of the injection preferably includes one or more of water, ethanol, isopropanol, and propylene glycol; the auxiliary materials of the injection preferably comprise one or more of solubilizer, cosolvent, pH regulator and osmotic pressure regulator. The solubilizer preferably comprises one or more of poloxamer, lecithin and hydroxypropyl-beta-cyclodextrin, and the cosolvent preferably comprises one or more of poloxamer, lecithin and hydroxypropyl-beta-cyclodextrin; the pH regulator preferably comprises one or more of phosphate, acetate, hydrochloric acid and sodium hydroxide; the osmolality adjusting agent preferably comprises one or more of sodium chloride, mannitol, glucose, phosphate and acetate.

In the invention, when the dosage form of the medicament is preferably a freeze-dried powder injection, the auxiliary material preferably comprises a propping agent. The proppant preferably comprises mannitol and/or glucose.

In the present invention, the adjuvant of the drug preferably further comprises one or more of a coloring agent, a preservative, a fragrance and a flavoring agent.

The method of administration of the drug is not particularly limited in the present invention, and a method of administration known in the art may be used.

In the present invention, the route of administration of the drug preferably includes enteral administration or parenteral administration. The enteral administration preferably comprises oral administration or rectal administration; said parenteral administration preferably comprises: intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin or vagina.

In the present invention, the drug is preferably administered at a daily dose of 0.001 to 150mg/kg body weight, more preferably 0.1 to 100mg/kg body weight, still more preferably 1 to 60mg/kg body weight, and most preferably 2 to 30mg/kg body weight, and the above dose may be administered in one dosage unit or divided into several dosage units depending on the clinical experience of the doctor and the administration regimen including the use of other therapeutic means.

The medicine of the invention can be taken alone or combined with other therapeutic medicines or symptomatic medicines. When the medicament of the invention has synergistic effect with other therapeutic drugs, the dosage of the medicament is adjusted according to actual conditions.

The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The following examples and pharmacological activity experiments are intended to further illustrate the invention, but are not intended to limit the invention in any way. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, the full names or corresponding Chinese names of the partial substances are as follows:

HSW-W-25: trans-emodin dianthrone

HSW-W-26: cis-emodin dianthrone

HSW-W-25/26: trans-emodin dianthrone and Cis-emodin dianthrone (dianthrone for short)

ConA: plant agglutinin

ALT: glutamic-pyruvic transaminase

AST: glutamic-oxalacetic transaminase

The room temperature described in the examples below is as conventional in the art and is typically 15-25 ℃.

Experimental example 1 HSW-W-25/26 Activity test for lectin (ConA) -induced immunological liver injury in mice

The experimental method comprises the following steps:

SPF male ICR mice (20-22 g) are randomly grouped after being adapted to the environment, a blank control group, a 20% phytohemagglutinin (ConA) model group, a positive control medicament bicyclol 200mg/kg group, an HSW-W-25/260.1mg/kg group, an HSW-W-25/261mg/kg group and 7-8 mice in each group. The test substance is administrated in each dosage group by gavage 1 time respectively in the afternoon, the morning and afternoon of the model before the model building, 3 times in total, and the blank control group and the model group are administrated with the same amount of 0.5% CMC-Na solution. After 2h of the last administration, mice in each group were injected with 20% ConA 10ml/kg once in the tail vein except for the blank control group. After the mice are fasted for 16 hours without water supply, the mice are sacrificed, blood is taken to prepare serum, the ALT and AST content of the serum is detected by a full-automatic biochemical analyzer, and the liver lobules are fixed by 10 percent paraformaldehyde.

The experimental results are as follows:

effect of HSW-W-25/26 on serum biomarker of alanine Aminotransferase (ALT) elevation of mice immune liver injury caused by ConA

The serum ALT level is directly and positively correlated with the liver injury degree, and is an internationally accepted serum biomarker of liver injury. The results are shown in Table 1 and FIG. 1, and ConA20mg/kg caused significant liver injury in mice, and serum ALT content was significantly increased compared with that in the blank control group. The serum ALT rise caused by ConA can be obviously reduced by HSW-W-25/260.1mg/kg and 1mg/kg, and the ALT level can be reduced to be close to the level of normal animals by HSW-W-25/261 mg/kg. The reduction effect of HSW-W-25/260.1mg/kg on the serum liver injury biomarker ALT is equivalent to that of the positive control medicament bicyclol 200mg/kg, and the reduction effect of HSW-W-25/261mg/kg on the serum liver injury biomarker ALT is superior to that of the positive control medicament bicyclol 200 mg/kg.

Table 1 effect of HSW-W-25/26 on serum liver function biomarker glutamic-pyruvic transaminase (ALT) in ConA-induced acute immune liver injury mice (n-7-8).

^*P is less than 0.05, compared with a blank control group;^#p is less than 0.05, compared with the model group.

Effect of HSW-W-25/26 on serum biomarker of glutamic-oxaloacetic transaminase (AST) elevation of mice immune liver injury caused by ConA

The increase of serum AST level is also one of important markers of hepatocyte damage, especially hepatocyte mitochondrial damage, and the serum AST level is obviously increased when mitochondria are damaged, which reflects the severity of hepatocyte damage. The results are shown in Table 2 and FIG. 2, and ConA20mg/kg caused significant damage to mouse hepatocyte mitochondria and significantly increased serum AST levels compared with the blank control group. HSW-W-25/261mg/kg can obviously reduce serum AST rise caused by ConA, has statistical difference compared with a model group, and shows obvious protective effect on liver cell mitochondria damage. The reduction activity of HSW-W-25/261mg/kg on serum liver injury biomarker AST is better than that of 200mg/kg of bicyclol.

Table 2 effect of HSW-W-25/26 on the serum liver function biomarker, aspartate Aminotransferase (AST), in ConA-induced acute immune liver injury mice (n-7-8).

P < 0.05, compared to a blank control group; # P < 0.05, compared to model group.

Effect of HSW-W-25/26 on ConA-induced immune liver injury in mice

The results are shown in fig. 3, the lobular structure of the liver of the blank control group animal is completed, the liver cell cords are arranged regularly, the structure is clear, the structural morphology of the central hepatic vein and the vascular region is normal, and the liver cells are not degenerated and necrotized. The phytohemagglutinin (ConA) model group of animal liver cells showed massive apoptosis-like necrosis, liver cell shrinkage, deep cytoplasm, red stain, and nucleus shrinkage, and some were observed as apoptotic bodies. The necrotic area has liver sinuses with distending congestion and moderate infiltration of hepatic interstitial inflammatory cells. HSW-W-25/260.1mg/kg and 1mg/kg have obvious improvement effect on liver histopathology, which is shown in that inflammatory cell infiltration is reduced, the degeneration and necrosis degree of liver cells is reduced, and the accumulation area of inflammation/necrosis lesion is obviously reduced. The pathological improvement of liver tissue by HSW-W-25/261mg/kg is more obvious.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.