CN109453249B - Pharmaceutical composition for preventing and treating drug-induced liver injury and preparation method of different dosage forms - Google Patents

Abstract

The invention discloses a pharmaceutical composition for preventing and treating drug-induced liver injury and a preparation method of different dosage forms, wherein the pharmaceutical composition takes roxburgh rose and schisandra chinensis as effective medicinal components and consists of the active medicinal components and acceptable auxiliary additive components in the drugs; the effective medicinal components are calculated by the dry weight of the raw materials of the roxburgh rose and the Chinese magnoliavine fruit, and the mass ratio of the roxburgh rose to the Chinese magnoliavine fruit is 1: 0.1-10. The fructus Rosae Normalis and fructus Schisandrae chinensis can be mixed at a certain proportion to make into tablet, capsule, powder, etc. The pharmaceutical composition has remarkable prevention and treatment effects on drug-induced liver injury, especially alcoholic liver injury, and can also remarkably resist the side effect of schisandra chinensis on increasing liver index.

Description

Pharmaceutical composition for preventing and treating drug-induced liver injury and preparation method of different dosage forms

Technical Field

The invention relates to a pharmaceutical composition for preventing and treating drug-induced liver injury and a preparation method of different dosage forms, in particular to the pharmaceutical composition which enhances the liver protection effect by the combined use of roxburgh rose and schisandra chinensis and simultaneously remarkably resists the side effect of schisandra chinensis on increasing the liver index.

Background

The medicinal liver injury (DILI) refers to the diseases of hepatic cell injury necrosis, liver enzyme abnormality and related clinical manifestations induced by various chemical drugs, biological drugs, Chinese herbal medicines and preparations, health products, dietary supplements and metabolites thereof, and the like. The clinical symptoms mainly comprise digestive tract symptoms such as jaundice, aversion to oil, nausea and the like, and some patients can have anaphylactic reactions such as fever, rash and the like; the biochemical index is mainly changed by the increase of transaminase and bilirubin level. The action mechanism is complex and various, and at present, no drug has the effect of preventing and treating all drug-induced liver injuries. Among them, alcoholic liver injury is the most attractive.

Alcoholic liver disease (alcoholic liver disease) refers to a liver disease caused by excessive ethanol intake for a long time, and the initial stage of the disease generally shows alcoholic fatty liver, and then can develop into alcoholic hepatitis, alcoholic liver fibrosis and alcoholic cirrhosis, and can cause extensive hepatocyte necrosis and liver failure when severe alcoholism occurs. The liver cirrhosis caused by the alcoholic liver damage finally needs a long process, and a clinician needs to take active prevention and treatment measures at the reversible stage of alcoholic liver patients, so that the occurrence and development of the liver cirrhosis are reduced.

Alcoholic cirrhosis constitutes an increasing proportion of the causes of cirrhosis. The analysis of the etiology composition and the change trend of liver cirrhosis patients in northern China in 2002-2010 shows that the alcoholic liver cirrhosis is increased from 3% to 7.7%. In developed regions such as north america and europe, alcoholic liver disease is the leading cause of cirrhosis. In 2010, the number of people who die of alcoholic liver diseases is about 493300, the number of people who have diseases caused by alcohol is about 1450000, and the alcoholic cirrhosis accounts for 47.9% of patients who die of cirrhosis. Korean research on the decade survey between 2000 and 2010 has shown that the rate of cirrhosis in alcoholic liver disease rises from 6.3% to 78.1%. In the united states, cirrhosis was located at the 12 th cause of death in the population in 2002, with a mortality rate that fluctuated at the same level since 1973, with approximately 27794 deaths per year. More than 43.6% of the causes of cirrhosis death are alcohol-related and account for 60.2% of younger cirrhosis people (age 35-45). In 2009 alone, the number of deaths from cirrhosis in the united states reached 31522, 48.2% of which were associated with alcohol, with an socio-economic burden of nearly $ 223.5 million per year due to alcoholic liver disease.

The mechanism of alcohol-induced liver damage is mainly characterized by the following aspects. Ethanol and metabolite toxic effects: early researches show that in the process of generating acetaldehyde by oxidizing ethanol, the ratio of liver NADH/NAD is increased, and NADH can promote the synthesis of fatty acid and inhibit the fatty acid from being oxidized to cause liver steatosis. Meanwhile, the generation of oxygen free radicals is increased, the consumption of antioxidants is increased, the generation of oxidative stress is induced, the respiratory function of cells and the generation of ATP are influenced, and the necrosis or the apoptosis of liver cells is caused. NADH can react with Reactive Oxygen Species (ROS) to cause a cascade inflammatory reaction, releasing more inflammatory factors to damage liver cells. Recent studies have found that ethanol regulates transcription factors associated with fat metabolism, and activation of these transcription factors can promote fat synthesis and inhibit lipolysis. In addition, acetaldehyde can be covalently bound to various proteins in the body to produce acetaldehyde-protein adduct (APA) and DNA adduct, which affect protein function and cause damage to hepatocytes by enzyme inactivation, DNA repair protein dysfunction, lipid peroxidation, and mitochondrial destruction. The acetaldehyde protein adduct is mainly positioned around the central vein, and the liver cells at the position are obviously damaged, so that the collagen synthesis is further stimulated, and the alcoholic liver fibrosis is caused. In addition, alcoholic liver injury is closely related to factors such as endotoxin and abnormal nutrient components.

At present, there is no particularly effective method for preventing and treating alcoholic liver injury, and although abstinence is the best method for preventing and treating alcoholic liver injury, the number of people who drink alcohol and the proportion thereof are increasing year by year due to the increase of social pressure: in recent years, the yield and consumption of alcohol in China tend to increase. Survey data show that the liquor yield in China is 711.3 ten thousand tons in 1984, the yield is increased to 3069.87 ten thousand tons in 2001, and the yield is increased by more than 4 times in nearly 20 years. From the 80 s to the 90 s of the 20 th century, the proportion of alcoholics in the general population rose from 0.21% to 14.3%. Epidemiological investigation and research of part of provinces and cities in China at the beginning of the 21 st century show that the population who drink alcohol is increased to 26.98-43.4%.

Rosa roxburghii Tratt (Rosa roxburghii Tratt), also known as Senchu, Fangji fruit, reeling silk flower, belongs to perennial deciduous shrub of Rosa in Rosaceae, and mainly grows in Guizhou, Sichuan, Yunnan and other places in China.

The roxburgh rose has higher edible value and medicinal value, and modern researches show that fresh roxburgh rose fruits contain abundant substances such as vitamins, polyphenol, flavone, organic acid, polysaccharide, amino acid, trace elements and the like. The fructus Rosae Normalis contains flavonoids up to 0.8%, and its aglycones are myricetin, quercetin and kaempferin; the triterpene compounds mainly comprise roxburgh rose glycoside, pentacyclic triterpene ester glycoside, Euscaphic acid, tormentic acid, roxburgh rose glycoside, and multiflora rose glycoside. The organic acid contained in fructus Rosae Normalis is mainly malic acid, lactic acid, tartaric acid, citric acid, oxalic acid and succinic acid; also contains linoleic acid, linolenic acid, oleic acid, palmitic acid and stearic acid; it also contains superoxide dismutase (SOD) and 18 amino acids, wherein SOD exists mainly in the form of Mn-SOD.

Modern pharmacological research shows that the roxburgh rose has the effects of regulating the immune function of an organism, delaying senility, resisting oxidation, protecting the liver and the like.

Fructus Schisandrae chinensis is dried mature fruit of Schisandra chinensis (Turcz.) Baill. of Magnoliaceae, and is known as "Schisandra chinensis"; it is a commonly used Chinese medicine, and its application history is long, and it is recorded in Shen nong's herbal Jing; the Chinese medicinal herbs are superior in taste, sour and warm in nature, and enter lung, heart and kidney meridians; has the effects of astringing, arresting discharge, benefiting qi, promoting fluid production, invigorating kidney, calming heart, etc.; it can be used for treating chronic cough, asthma, nocturnal emission, enuresis, chronic diarrhea, spontaneous perspiration, night sweat, thirst due to body fluid consumption, palpitation, and insomnia. The schisandra fruit mainly contains lignan compounds accounting for 2-8%, and also contains various components such as volatile oil, polysaccharides, organic acids, fatty acids, proteins and the like. The quality of the Chinese magnoliavine fruit is slightly inferior to that of the northern schisandra fruit.

Modern pharmacological research shows that the schisandra chinensis and the active substances thereof have better effects of resisting oxidation, resisting fatigue, detoxifying, protecting the liver, tranquilizing, hypnotizing and protecting the cardiovascular system.

Although the roxburgh rose has the effect of protecting the liver, the curative effect is weaker; although the liver-protecting effect of schisandra chinensis is stronger than that of rosa roxburghii tratt, schisandra chinensis has the side effect of causing the liver tissue to be remarkably increased.

Disclosure of Invention

In order to obtain a medicine with strong liver protection effect and no side effect of liver tissue enlargement, the invention provides a pharmaceutical composition for preventing and treating drug-induced liver injury and preparation methods of different dosage forms.

The specific technical scheme of the pharmaceutical composition for preventing and treating the drug-induced liver injury is as follows:

a pharmaceutical composition for preventing and treating drug induced hepatic injury comprises fructus Rosae Normalis and fructus Schisandrae as effective medicinal components, and pharmaceutically acceptable auxiliary additive components; the effective medicinal components are calculated by the dry weight of the raw materials of the roxburgh rose and the Chinese magnoliavine fruit, and the mass ratio of the roxburgh rose to the Chinese magnoliavine fruit is 1: 0.1-10.

The effective components of fructus Schisandrae can be obtained by various methods, such as directly using fructus Schisandrae powder as medicine, or extracting fructus Schisandrae with 0-100% water, ethanol water solution or ethanol to obtain fructus Schisandrae extract, and adding fructus Schisandrae extract into medicine.

The fructus Schisandrae chinensis in the effective medicinal components is fructus Schisandrae chinensis or fructus Schisandrae Sphenantherae. The schisandra fruit is usually the northern schisandra fruit, and the quality of the schisandra fruit is better than that of the southern schisandra fruit, and the effective components are more.

The active ingredients of the rosa roxburghii tratt can also be obtained in various ways, such as:

the first method is as follows: the fructus Rosae Normalis in the effective medicinal components is extract obtained by extracting with 0-100% water, ethanol water solution or ethanol.

The second method comprises the following steps: the fructus Rosae Normalis in the effective medicinal components is fructus Rosae Normalis powder obtained by drying and pulverizing fructus Rosae Normalis.

The third method comprises the following steps: the fructus Rosae Normalis in the effective medicinal components is squeezed from fresh fructus Rosae Normalis to obtain juice, or the juice is concentrated and dried to obtain the final product.

The pharmaceutical composition of the invention can be prepared into oral pharmaceutical preparations including common dosage forms such as tablets, dripping pills, capsules, pellets and the like by the pharmaceutical ingredients with drug effect and corresponding auxiliary additives acceptable in the medicaments, such as disintegrating agents, excipients, lubricants, binders, fillers and the like according to the use requirements in the conventional mode.

The invention provides a preparation method of different drug formulations of a drug composition for preventing and treating drug-induced liver injury, which comprises the following specific contents:

the preparation method of the pharmaceutical composition capsule for preventing and treating the drug-induced liver injury comprises the following steps: drying fresh fructus Rosae Normalis, and pulverizing; reflux-extracting fructus Schisandrae with ethanol water solution, recovering extractive solution, and removing ethanol to obtain fructus Schisandrae ethanol extract; adding fructus Rosae Normalis powder into fructus Schisandrae chinensis ethanol extract, mixing, drying, pulverizing, and making into capsule; the dry weight mass ratio of the roxburgh rose powder to the schisandra chinensis is 1: 0.1-10.

In the above preparation method, preferably, the dry weight mass ratio of the roxburgh rose powder to the schisandra chinensis is more than 1; the ethanol water solution is ethanol water solution with ethanol volume fraction of 70%.

The preparation method of the pharmaceutical composition tablet for preventing and treating the drug-induced liver injury comprises the following steps: drying fresh fructus Rosae Normalis, and pulverizing; decocting fructus Schisandrae Sphenantherae with water, removing water decoction, drying the residue, pulverizing, extracting with ethanol water solution under reflux, recovering extractive solution and removing ethanol, standing or centrifuging the water solution, collecting fructus Schisandrae Sphenantherae precipitate, adding fructus Rosae Normalis powder, mixing, drying, pulverizing, and making into tablet; the mass ratio of the roxburgh rose powder to the schisandra chinensis is 1: 0.1-10.

In the above preparation method, preferably, the dry weight mass ratio of the roxburgh rose powder to the schisandra chinensis is less than or equal to 1; the ethanol water solution is ethanol water solution with ethanol volume fraction of 70%.

70% ethanol can extract more effective components from fructus Rosae Normalis or fructus Schisandrae chinensis.

The research of the project group finds that the effect of singly using the roxburgh rose to prevent and treat the drug-induced liver injury is weak, and the expected effect under the ideal dosage is difficult to achieve. The schisandra chinensis has a good prevention and treatment effect on the drug-induced liver injury, but the schisandra chinensis can cause the remarkable enlargement of liver tissues while playing the prevention and treatment effect, and the phenomenon causes new adverse reactions. By combining the schisandra chinensis and the rosa roxburghii tratt, the liver-protecting function can be shown, the side effect of the schisandra chinensis on increasing the liver index can be resisted remarkably, and the application value is good.

Compared with the prior art, the invention has at least the following beneficial effects: the invention provides a pharmaceutical composition with remarkable prevention and treatment effects on drug-induced liver injury, in particular alcoholic liver injury, and meanwhile, the pharmaceutical composition can remarkably resist the side effect of increasing liver index of schisandra chinensis.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Preparation examples of different dosage forms of pharmaceutical composition

Example 1

Taking dried fructus Schisandrae chinensis and fructus Rosae Normalis according to a dry weight ratio of 10:1, pulverizing, sieving with 100 mesh sieve, packaging, and making into powder.

Example 2

According to the following steps: 10, pulverizing dried fructus Rosae Normalis and fructus Schisandrae chinensis, adding 70% ethanol 8 times the amount of the pulverized fructus Rosae Normalis and fructus Schisandrae chinensis, soaking overnight, heating and reflux-extracting for 3 times, mixing filtrates, recovering ethanol, concentrating, drying, adding excipient such as dextrin, and tabletting to obtain 0.5g tablet.

Example 3

According to the following steps: 5 taking dried roxburgh rose and Chinese magnoliavine fruit according to the proportion, and crushing the roxburgh rose into fine powder for later use. Reflux-extracting fructus Schisandrae with 6 times of 70% ethanol for 3 times, recovering solvent to obtain fructus Schisandrae extract, adding the above fructus Rosae Normalis fine powder, mixing, drying, pulverizing, and making into capsule.

Example 4

According to the following steps: 1, taking dried roxburgh rose and kadsura longepedunculata, and crushing the roxburgh rose into fine powder for later use. Decocting fructus Schisandrae Sphenantherae with 8 times of water for 1 time, removing water decoction, drying the residue, pulverizing, extracting with 10 times of 70% ethanol under reflux for 2 times, recovering ethanol, centrifuging the aqueous solution, collecting fructus Schisandrae Sphenantherae precipitate, adding the above fructus Rosae Normalis fine powder, mixing, drying, pulverizing, and making into tablet.

Second, study of the Effect of the drugs of the examples on the liver injury model

1 test Material

1.1 test drugs

Bicyclol sheets: the national standard of medicine H20040467, 25 mg/tablet, lot number 090307, is produced by Beijing collaborating pharmaceutical factory. The suspension is prepared with 0.5CMC to the required concentration before use.

1.2 test animals

Kunming mouse, SPF grade, production certificate number SCXK (Sichuan 2018-19), provided by the Experimental animals center of the academy of traditional Chinese medicine and sciences of Sichuan province.

1.3 test apparatus

An electronic balance: shimadzu EB-3200, produced in Japan.

2 methods and results

2.1 Effect on Alcoholic liver injury mice

Male mice with the weight of 18-22g are taken, randomly grouped, and respectively administered by intragastric administration 1 time a day for 7 days. On the 4 th day of administration, the groups except the normal control group were each gavaged with 0.1ml/10g of 50% ethanol in a weight-average manner in mice for 4 times. After 24h after the last administration and 16h after fasting without water prohibition, blood is taken to measure ALT and AST serum, the animal is killed, the liver is taken to weigh the wet weight, and the organ index is calculated. The results are shown in Table 1.

TABLE 1 Effect of the examples on alcoholic liver injury mice (x. + -.s)

Comparison with model groups:^*P<0.05,^**P<0.01,^***P<0.001.

comparison with the group of five flavors:^△P<0.05,^△△P<0.01,^△△△P<0.001.

as can be seen from table 1, the serum transaminase and liver index of the mice significantly increased after 4 days of continuous alcohol administration, which is statistically different from that of the control group. The schisandra chinensis can obviously reduce the serum glutamic-pyruvic transaminase of mice with alcoholic liver when used alone, but can obviously increase the liver index of the mice with alcoholic liver, and compared with a model group, the difference has statistical significance. The roxburgh rose is used alone, has a tendency of reducing transaminase activity, but has weak effect, has no obvious influence on liver index, and has no statistical difference compared with a model group. When the roxburgh rose and the schisandra chinensis are used together, transaminase of an alcoholic liver mouse can be reduced remarkably, liver index of an alcoholic liver injury mouse is reduced, and compared with a model group, the difference has statistical significance, and compared with a single schisandra chinensis group, the difference has statistical significance. The other embodiments also have similar effects.

2.2 protective action on mouse acute liver injury caused by carbon tetrachloride

Taking male mice with weight of 18-22g, randomly grouping, respectively intragastrically administering twice a day, continuously 5 times, 1 hr after the last administration, and intraperitoneally injecting CCl₄After 10uL/kg and fasting for 16 hours without water prohibition, blood is taken for measuring ALT and AST activities of the serum. The results are detailed in table 2.

TABLE 2 Effect on carbon tetrachloride induced acute liver injury in mice (x + -s)

Comparison with model groups:^*P<0.05,^**P<0.01,^***P<0.001.

as can be seen from Table 2, carbon tetrachloride caused a significant increase in serum transaminase activity in mice, which was statistically different from the control group. The examples can significantly reduce serum transaminase of mice with carbon tetrachloride, and have statistical differences compared with a model group.

The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.

Claims (10)

1. The application of a pharmaceutical composition which is composed of the rosa roxburghii tratt and the schisandra chinensis as effective medicinal components and auxiliary additive components acceptable in the medicine in preparing the medicine for preventing and treating the alcoholic liver injury, wherein the mass ratio of the rosa roxburghii tratt to the schisandra chinensis is 1: 0.1-10.

2. The use according to claim 1, wherein the schisandra fruit of the effective pharmaceutical ingredient is an extract of schisandra fruit obtained by extraction with water, aqueous ethanol solution or ethanol with a volume fraction of ethanol of 0-100%.

3. The use according to claim 1, wherein the schisandra fruit in the effective pharmaceutical ingredient is schisandra fruit or schisandra fruit.

4. The use according to claim 1, wherein the Rosa roxburghii Tratt is an extract obtained by extracting with water, ethanol water solution or ethanol with ethanol volume fraction of 0-100%.

5. The use according to claim 1, wherein the Rosa roxburghii Tratt in the effective pharmaceutical ingredient is powder of Rosa roxburghii Tratt obtained by drying and pulverizing Rosa roxburghii Tratt.

6. The use of claim 1, wherein the fructus Rosae Normalis is squeezed from fresh fructus Rosae Normalis to obtain juice, or the juice is concentrated and dried to obtain the final product.

7. The use according to claim 1, characterized in that the preparation method of the pharmaceutical composition capsule comprises the following steps: drying fresh fructus Rosae Normalis, and pulverizing; reflux-extracting fructus Schisandrae with ethanol water solution, recovering extractive solution, and removing ethanol to obtain fructus Schisandrae ethanol extract; adding fructus Rosae Normalis powder into fructus Schisandrae chinensis ethanol extract, mixing, drying, pulverizing, and making into capsule; the dry weight mass ratio of the roxburgh rose powder to the schisandra chinensis is 1: 0.1-10.

8. Use according to claim 7, characterized in that the dry weight to mass ratio of the roxburgh rose powder and the schisandra fruit is greater than 1; the ethanol water solution is ethanol water solution with ethanol volume fraction of 70%.

9. Use according to claim 1, characterized in that the process for the preparation of tablets of the pharmaceutical composition comprises the following steps: drying fresh fructus Rosae Normalis, and pulverizing; decocting fructus Schisandrae Sphenantherae with water, removing water decoction, drying the residue, pulverizing, extracting with ethanol water solution under reflux, recovering extractive solution and removing ethanol, standing or centrifuging the water solution, collecting fructus Schisandrae Sphenantherae precipitate, adding fructus Rosae Normalis powder, mixing, drying, pulverizing, and making into tablet; the mass ratio of the roxburgh rose powder to the schisandra chinensis is 1: 0.1-10.

10. Use according to claim 9, characterized in that the dry weight to mass ratio of the roxburgh rose powder and the schisandra fruit is less than or equal to 1; the ethanol water solution is ethanol water solution with ethanol volume fraction of 70%.