CN105727251B - Pharmaceutical composition for treating fatty liver - Google Patents

Pharmaceutical composition for treating fatty liver Download PDF

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CN105727251B
CN105727251B CN201610222110.1A CN201610222110A CN105727251B CN 105727251 B CN105727251 B CN 105727251B CN 201610222110 A CN201610222110 A CN 201610222110A CN 105727251 B CN105727251 B CN 105727251B
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liver
salvianolic acid
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glutathione
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CN105727251A (en
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潘宏涛
卢亚萍
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Zhejiang Aegis Biological Science & Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Abstract

The invention relates to a pharmaceutical composition for treating fatty liver, wherein the weight ratio of active ingredients of glutathione to salvianolic acid B is (1:20) - (20: 1). Compared with western medicine preparations, the pharmaceutical composition provided by the invention is simple in preparation method and reasonable in compatibility, and the two active ingredients can generate a synergistic interaction effect while exerting respective effects, so that the fatty liver is remarkably treated. Wherein the glutathione and the salvianolic acid B are natural in source, safe and nontoxic and have no side effect; the medicine composition has no western medicine component, so that the medicine has no drug resistance.

Description

Pharmaceutical composition for treating fatty liver
Technical Field
The invention relates to the field of medicines, and in particular relates to a medicinal composition for treating fatty liver.
Background
Fatty liver is a fatty liver caused by various diseases and causes, and epidemiologically researched chronic fatty liver mainly caused by alcohol, obesity and the like. Fatty Liver (FLD) is classified broadly into Alcoholic Fatty Liver (AFLD) and non-alcoholic fatty liver (NAFLD) or both clinically according to the presence or absence of excessive drinking history of a patient. AFLD refers to fatty liver caused by long-term drinking. NAFLD refers to a condition that is caused by, in addition to alcohol and other well-defined liver damage factors, including simple fatty liver, steatohepatitis (NASH), and NASH-associated cirrhosis. The incidence of FLD in China is increasing day by day, and FLD is becoming one of the most common chronic liver diseases in China and seriously harms the health of people.
Toxic metabolites produced by the metabolism of ethanol in liver cells and the resulting metabolic disorders are the main causes of alcoholic liver injury. Acetaldehyde, a metabolite of ethanol, is hepatotoxic and contributes to liver fat accumulation by impairing the function of peroxisome proliferator-activated receptor alpha (PPAR- α) and increasing the expression of sterol regulatory element binding protein-1 (SREBP-1). When the level of fatty acids is increased, PPAR- α is activated, inducing an increase in synthesis of fatty acid metabolizing enzymes, and regulating fatty acids to normal levels. Under the induction of acetaldehyde, PPAR-alpha function is reduced, SREBP-1 expression is enhanced, enzyme synthesis related to fat metabolism is reduced, enzyme expression related to fat synthesis is increased, and fat synthesis is increased. Endotoxemia caused by ethanol is possibly related to the pathogenesis of alcoholic fatty liver, and Endotoxin (ET) can stimulate hepatomegaphagy cells (KC) to release cytokines such as tumor necrosis factor (TNF-alpha) and interleukin-8 (IL-8) and inflammatory mediators. TNF-alpha is combined with TNF-alpha receptor on cell membrane to increase the formation of active oxygen in liver and induce liver cell apoptosis. IL-8 is an inflammatory chemokine, which causes neutrophils to accumulate at inflammatory sites, exacerbating hepatocyte injury. The damage of TNF-alpha and IL-8 to the liver may be one of the important mechanisms for the occurrence of AFLD.
The pathogenesis of NAFLD is a complex "secondary hit" theory that is recognized by most scholars, where the primary hit is mainly Insulin Resistance (IR), which causes hepatic cell steatosis by promoting peripheral lipolysis and hyperinsulinemia and initiates cell adaptation programs, while the relative lack of viability of the steatosis hepatic cells provides sufficient reaction matrix for oxygen stress, resulting in increased sensitivity of the steatosis hepatic cells to internal and external damaging factors; the secondary hit is mainly caused by the increase of reactive oxidative metabolites, so that lipid peroxidation is induced and activated by the cytokine, the mitochondrial uncoupling protein 2 and the fas ligand, and further, the inflammation, necrosis and even fibrosis of the fatty degeneration liver cells are caused. Reactive Oxygen Species (ROS) are considered to be the most important factor for the development of NAFLD. ROS are generated in one stroke, and in the second stroke, in addition to fibrosis of liver tissues caused by regulation of mitochondrial membrane permeability, induction of apoptosis and generation of a series of cytokines and inflammatory adhesion factors, unsaturated fatty acids can be attacked by self to generate a large amount of peroxidation products, Hepatic Stellate Cells (HSC) are activated under the action of genetic hemochromatosis gene mutation, a renin-angiotensin-aldosterone system and leptin, autoimmunity is induced, the oxidation resistance of an organism is reduced, a large amount of ROS are continuously generated, severe vicious circle is caused, and the development of hepatic fibrosis is promoted.
At present, the medicines for treating fatty liver mainly take western medicines, which can be divided into several types according to the action mechanism:
(1) insulin sensitizer: the abnormality of lipid metabolism caused by insulin resistance is the first hit in the formation of FLD. Insulin sensitizers may therefore be an effective method of treating FLD. A biguanide: the representative medicine is metformin, which can obviously enhance the sensitivity of peripheral tissues to insulin and has certain functions of reducing weight and reducing hyperinsulinemia. Thiazolidinediones: reduce the release of free fatty acids and tumor necrosis factor from adipocytes, increase glucose utilization, while increasing insulin sensitivity, inhibiting lipid peroxidation and TNF- α activity, and enabling selective transfer of fat from the gut to the subcutaneous tissue.
(2) Lipid-lowering drugs: gemfibrozil: has effects in promoting fatty acid uptake, transport, oxidation and utilization of liver, and maintaining lipid balance in cell. ② clofibrate: mainly through inhibiting adenylate cyclase, cAMP content in fat cells is reduced, fat tissue hydrolysis is inhibited, non-acetified fatty acid content in blood is reduced, so that Very Low Density Lipoprotein (VLDL) synthesis and secretion of liver are reduced, lipoprotein lipase activity is enhanced, decomposition and metabolism of VLDL and Triglyceride (TG) are accelerated, and contents of blood Low Density Lipoprotein (LDL), TG, low density lipoprotein cholesterol (LDL-C) and Total Cholesterol (TC) are reduced. ③ orlistat: orlistat is a potent inhibitor of pancreatic lipase, an important enzyme in the small intestine that hydrolyzes food fat and facilitates fat absorption (as monoglycerides). Studies have demonstrated that inhibition of lipase activity can limit the absorption of dietary triacylglycerols, thereby inhibiting the intake of exogenous fat. Fourthly, elastase: the elastase-elastase inhibitor is a balance system in normal human blood, and can regulate the balance of the system, prevent the synthesis of cholesterol, promote the conversion of cholesterol into bile acid, accelerate the excretion of bile, reduce the contents of TG and TC in blood, increase the level of high density lipoprotein cholesterol (HDL-C), and reduce fat transported to liver by supplementing elastase.
(3) Antioxidant: vitamin E, betaine, spirulina maxima, etc.: oxygen stress and lipid peroxidation play an important role as secondary attacks in the formation of NASH, and blocking oxygen stress and lipid peroxidation may have a therapeutic effect on NASH, and thus antioxidants may become an effective method for treating NASH. Vitamin E has a certain antioxidant effect, but it should be noted that long-term massive vitamin E supplementation can also increase mortality. When the patient suffering from NAFLD is treated by the spirulina maxima, the B-ultrasonic and biochemical examination finds that the spirulina maxima really has good treatment effect on the patient suffering from NAFLD and can be used as an auxiliary treatment medicine for NAFLD.
(4) Cytochrome P450Inhibitor (B): cimetidine is H2Receptor antagonists and also cytochrome P450And (3) an inhibitor. Experiments prove that cimetidine can inhibit NAFLD rat liver microsome CYP450And isoenzyme CYP2E1 expression, reducing Hyaluronic Acid (HA) content in serum, and improving liverFunction, thereby reducing NAFLD liver tissue inflammation. (5) And (3) probiotics: the probiotics have the function of regulating intestinal flora interfering with the intestinal and hepatic axis. Data of 4 liver disease research centers are searched, and results only include preliminary data of 2 non-random experimental researches, which suggest that probiotics have better tolerance, can improve conventional liver function indexes and reduce lipid peroxidation markers. But the lack of randomized clinical trials has not made the possibility to support or refute probiotics for NAFLD or NASH. The normal intestinal flora has an important therapeutic effect on hyperlipidemia.
According to traditional Chinese medicine, FLD is caused by overeating fat, sweet and thick taste, obesity, excessive drinking, emotional disorder, or feeling of damp-heat and epidemic toxicity, or body deficiency due to long-term illness, food stagnation, qi stagnation, epidemic qi and the like, so that liver dysfunction, spleen dysfunction, endogenous damp evil, phlegm stagnation, kidney essence deficiency, phlegm stagnation and the like are caused. Modified chaihu Shugan san for liver qi stagnation, modified Pingwei san for phlegm-dampness stagnancy in spleen, modified chaihu Tang for damp-heat retention, modified Fuyuan Huoxue Tang for blood stasis obstruction of collaterals, and modified water-nourishing and liver-clearing decoction for yin deficiency and liver qi stagnation. Eight acupuncture points (moisture, Yinjiao, Tinsmen, Wailing, Tianshu, Ganshu, Qimen, Zusanli, Fenglong, Quchi and Sanyinjiao) around the umbilicus are selected for treating obesity FLD32 cases, a reinforcing and reducing method of lifting, inserting and twirling is applied, and a continuous wave of electric needles is added, so that the patients can tolerate the acupuncture for 30min, 1 time every other day, 12 times of treatment are 1 treatment course, and generally 2-3 treatment courses are adopted. As a result, 18 cases were clinically cured, 8 cases were significantly effective, 4 cases were effective, and 2 cases were ineffective. 28 patients with NAFLD were randomized into 2 groups. 12 control groups are subjected to basic liver protection treatment, and 16 treatment groups are orally taken liver strengthening capsules on the basis of the control groups. Clinical symptoms, liver function, serum hepatic fibrosis index, oxidative stress index and biopsy liver pathological change condition of the patient are observed before and after 6 months of treatment. The results show that all indexes are obviously improved, and the comparative difference between the treatment group and the control group after treatment has statistical significance (P is less than 0.05). The liver strengthening capsule can improve liver inflammation, promote fat metabolism in liver, protect liver cell and reverse hepatic fibrosis.
In common medicines for treating fatty liver, western medicines have obvious curative effect but are easy to generate drug resistance after long-term administration, and a traditional Chinese medicine compound has limited treatment effect although low toxicity and no drug resistance, so that researchers focus on the research of fatty liver treatment on natural-source medicines, and glutathione and natural traditional Chinese medicine products are particularly attracted.
Glutathione is a peptide naturally synthesized in human cells, consisting of glutamic acid, cysteine and glycine, and is present throughout animal tissue cells. Glutathione exists in vivo in both reduced (GSH) and oxidized (GSSG) forms. Reduced Glutathione (GSH) is the predominant active state, accounting for approximately 95%; oxidized glutathione (GSSG) is inactive, accounting for about 1%. It has been studied that the thiol group (-SH) contained in GSH is a group that plays a major role, and plays a role in the activation of enzymes and the scavenging of free radicals in the human body. When human tissue cells are aged, infected, poisoned and subjected to oxidative stress, the biosynthesis capability of GSH in the cells can be reduced and the content of the GSH is reduced. The timely supplement of exogenous GSH can prevent, alleviate and stop the damage of tissue cells and change the pathophysiological process.
GSH, an important intracellular metabolite that regulates, is a prosthetic group of glyceraldehyde phosphate dehydrogenase and a coenzyme of glyoxalase and triose dehydrogenase, participates in the tricarboxylic acid cycle and sugar metabolism in vivo, and activates various enzymes such as thiol (SH) enzyme-coenzyme, thereby promoting the metabolism of sugars, fats and proteins. GSH molecule is characterized by active sulfydryl (-SH), which is the most important functional group, can participate in a plurality of important biochemical reactions of organisms, protects important enzyme protein sulfydryl in vivo from oxidation and inactivation, and ensures energy metabolism and cell utilization. Meanwhile, the sulfhydryl is combined with free radicals in vivo, so that the free radicals can be directly reduced into acidic substances, the excretion of the free radicals is accelerated, and the damage of the free radicals to important organs is resisted. GSH has been found to be involved in regulation of lipopolysaccharide-induced cytokine transcription and regulation of the I-KB/NF-KB signaling pathway. Studies have also found that a reduction in GSH levels is a potential early activation signal for apoptosis, with subsequent generation of oxygen radicals that contribute to apoptosis.
GSH is used as an important metabolic regulation agent and antioxidant in cells, has the functions of removing oxygen free radicals, enhancing the activity of antioxidant enzyme, improving the antioxidant defense capacity of organisms and the like, becomes a medicine for consistent treatment and adjuvant therapy of various diseases, and is widely applied to liver damage, kidney damage, lung diseases, eye diseases, cardiovascular and cerebrovascular diseases, multi-system and multi-organ diseases such as Parkinson and the like at present. It has also been reported that GSH has the function of inhibiting AIDS. With the continuous and intensive research, the application range can be further expanded.
GSH as an auxiliary drug has good effect on treatment of liver diseases, and according to research, when liver cells are damaged, GSH in the cells can be exhausted or reduced in synthesis, various oxidation free radicals are increased, when the concentration of the GSH in vivo is lower than a critical value, various GSH dependent enzyme systems are inactivated, the protection on the oxidation free radicals is weakened, the free radicals cause damage to liver cell membranes and the like through lipid peroxidation of biological membranes, and directly cause the activity change of liver cell mercaptoenzymes to cause the degeneration and the necrosis of the liver cells. The exogenous GSH can provide reducing agent for GSH oxidase, recover activity of GSH enzyme system, inhibit or reduce free radical generation, block damage of oxygen free radical to liver cell, and accelerate excretion of free radical to protect liver cell.
When treating acute viral hepatitis patients, after GSH is given to a treatment group, the liver function detection index and the effective rate of the patients in an observation group are obviously superior to those of a control group, and the patients have less adverse reaction during medication, and are safe and reliable. When the effect of GSH on alcoholic liver disease is observed, the treatment group is treated by GSH on the basis of conventional treatment. The results showed that both groups improved liver function to different extents, but the treated group was superior to the control group (P < 0.05). When the clinical curative effect of alcoholic cirrhosis is observed, GSH is added to the treatment group for treatment. The clinical curative effect of the result observation group and the index for reducing liver function and hepatic fibrosis are obviously superior to those of the control group, which shows that the effect of reducing glutathione for treating alcoholic cirrhosis is good, hepatic fibrosis can be obviously inhibited, and liver function can be improved.
Gouty nephropathy is caused by long-term hyperuricemia, and inhibits the production of renal NO. The research suggests that GSH can stabilize the function of endothelial cells by removing free radicals, antagonize the inhibition effect of hyperuricemia on kidney NO, and reduce the damage to renal tubules and interstitium and the toxicity of medicaments on kidney. For the treatment of gouty nephropathy patients, 18 patients were observed with GSH. As a result, the observation group showed 7 cases (38.9%) of significant effect, 14 cases (77.8%) of total significant effect, the control group showed 3 cases (16.7%) of comparative significant effect, and 10 cases (55.6%) of total significant effect. The observation group is obviously superior to the control group in the aspects of reduction of blood creatinine, reduction of urine protein, improvement of renal function and the like (P is less than 0.05), and no adverse reaction is found.
The action mechanism of GSH for treating lung diseases is not clear at present, and researches suggest that GSH can completely eliminate oxygen free radicals, hydrogen peroxide and hydrogen free radicals, and can also derive various oxides with peroxidase produced by leukocytes in an oxygen stress state, so that GSH has a certain inhibition effect on further participating in oxygen free radical generation reaction in organisms. Patients with chronic obstructive pulmonary disease are treated with a combination of mechanical ventilation and GSH, and the combination is treated with a combination of mechanical ventilation and GSH. Results the symptom control effect (total effective rate 93.3%) of the patients in the combined group is obviously better than that of the patients in the ventilation group (total effective rate 75.5%), the ventilation treatment time and the hospitalization time are obviously shorter than those of the patients in the ventilation group (P <0.05), and no adverse reaction occurs in the treatment period of the patients in the two groups. In the treatment of patients with severe pneumonia, the observation group received conventional treatment and was treated with GSH for adjuvant treatment. The results show that the total effective rate (77.78%) of the observed patients is obviously higher than that of the control group (66.67%), and simultaneously, each physical index of the observed patients after treatment is also better than that of the control group (P < 0.05).
GSH has protective effect on chemotherapy patients, and when tumor patients receive chemotherapy for a long time, a large amount of oxygen free radicals and other active oxygen free radicals are generated in the organism, so that peroxidation damage is caused to organism tissues, liver function is seriously affected, and immunity reduction, cell metabolism disorder, DNA damage, protein damage, cell damage and death can be caused when the disease condition is serious. GSH can remove oxygen radicals, has detoxifying effect, and effectively protects normal function of liver cells in organism. When the influence of GSH on the damage of bone marrow function and liver function caused by chemotherapy of tumor patients is researched, the indexes of white blood cell amount, glutamic-pyruvic transaminase and the like are better in the treatment group than the control group after the GSH is added in the prevention group.
Salvia miltiorrhiza, which is the dried root and rhizome of Salvia miltiorrhiza (Salvia millirrhiza Bunge) belonging to Salvia of Labiatae, was recorded in Shennong Ben Cao Jing, the ancient herbal thereof. The salvia miltiorrhiza, which is slightly cold in property and bitter in taste, has no toxicity and has the effects of removing blood stasis, relieving pain, promoting blood circulation, regulating menstruation, nourishing heart and relieving restlessness. The red sage root is widely used for treating cardiovascular system diseases clinically, and has the functions of dilating coronary artery, increasing coronary blood flow, improving microcirculation, reducing myocardial oxygen consumption, preventing and treating myocardial ischemia and myocardial infarction, etc.
The main chemical components of Saviae Miltiorrhizae radix include water soluble phenolic acid compounds represented by salvianolic acid B and alcohol soluble phenanthrenequinone compounds represented by tanshinone IIA. The water-soluble components of Saviae Miltiorrhizae radix have phenolic acid structure, wherein tanshinol has basic chemical structure of various salvianolic acids. A series of phenolic acids found hereafter are named salvianolic acid (salvianolic acid). The salvianolic acid B is prepared by condensing 3 molecules of tanshinol and one molecule of caffeic acid. The content of salvianolic acid B in the medicinal materials can reach 2% -8%, which is the most main active component in the water-soluble components of the salvia miltiorrhiza, and the content of salvianolic acid B in the total salvianolic acids is the highest, and accounts for about 70%. Salvianolic acid B is weakly acidic, is easily soluble in water, alcohol, ethyl acetate and other solvents, and is mainly extracted by water, ethanol or ethyl acetate at present. Salvianolic acid B has effects of resisting myocardial ischemia, resisting oxidation, resisting coagulation, resisting thrombi, regulating blood lipid, increasing coronary artery flow, improving heart function, and resisting inflammation.
The salvianolic acid compounds have strong antioxidation, and in vivo and in vitro experiments prove that the salvianolic acid can clear oxygen free radicals and inhibit lipid peroxidation. Research shows that the salvianolic acid B can eliminate active oxygen in cells and improve the oxidation resistance of the whole cells by improving the activities of superoxide dismutase (SOD), Catalase (CAT) and Glutathione Peroxidase (GPX), has higher action strength of eliminating oxygen free radicals and inhibiting lipid peroxidation than vitamin C and vitamin E, and is one of the currently known natural products with the strongest oxidation resistance.
Salvianolic acid B inhibits AS production in hypercholesterolemic animals, and is not only related to its cholesterol-lowering effect, but also because its antioxidant effect prevents endothelial damage and prevents oxidative modification of LDL. The intravenous injection of salvianolic acid B can reduce myocardial ischemia degree of coronary artery ligation dog and reduce myocardial ischemia range, and the action intensity is dose-dependent. The action mechanism of the medicine is probably to improve the SOD content in cells, reduce the toxic action of free radicals on myocardial cells, and effectively promote the proliferation of fibroblasts in infarct foci, thereby accelerating the repair process of the heart. Myocardial ischemia reperfusion injury can generate a large amount of oxygen free radicals, which cause lipid peroxidation of myocardial cell membranes, thereby causing aggravation of myocardial injury. Salvianolic acid B can relieve ischemia reperfusion injury by increasing SOD activity, inhibiting oxygen free radical injury to myocardium.
Ca2+Overloading contributes to the formation of oxygen radicals, leading to reperfusion injury. The study showed that intracellular Ca2+-Mg2 +Decreased ATPase (calcium magnesium ATPase) activity, possibly leading to intracellular calcium overload, while salvianolic acid B on Ca in myocardial ischemia cells2 +-Mg2+The decrease of ATPase activity has better antagonism, thereby reducing the intracellular calcium overload during myocardial ischemia. Calcium overload test of simulating myocardial ischemia reperfusion injury by culturing myocardial cells in vitro proves that salvianolic acid B can obviously reduce intracellular Ca2+The concentration of (c). The research shows that the salvianolic acid B has a better protective effect on the myocardial of a rat with acute myocardial ischemia reperfusion injury.
The salvianolic acid has a strong effect of resisting vascular endothelial cell injury caused by oxidative stress. Salvianolic acid B can promote the synthesis of Nitric Oxide (NO) of endothelial cells, scavenge Reactive Oxygen Species (ROS) in cells, and regulate the action relationship between NO and ROS. The action mechanism of the salvianolic acid B for protecting heart microvascular endothelial cells (CMEC) and resisting myocardial hypoxia injury comprises the following aspects: phi is involved in the synthesis of stress-induced heat shock protein 70(HSP 70). Secondly, the endogenous delayed protection mechanism of CMEC can be activated, the cell survival rate and the SOD activity are improved, the levels of Lactate Dehydrogenase (LDH) and NO are reduced, and the myocardial ischemia and hypoxia injury effect is antagonized. And the inhibitor has obvious inhibition effect on vascular endothelial permeability increase induced by Vascular Endothelial Growth Factor (VEGF). And fourthly, the activity increase of matrix metalloproteinase-2 (MMP-2) caused by Lysophosphatidylcholine (LPC) is obviously inhibited, and the protective effect on the cardiovascular system damage mediated by LPC is possibly realized. Inhibit the permeability increase of endothelial cells caused by tumor necrosis factor-alpha (TNF-alpha), and has direct protection effect on the injured rat microvascular endothelial cells.
The salvianolic acid B can be administered by intravenous injection to reduce myocardial ischemia degree, reduce myocardial ischemia range, and relieve myocardial cell injury, and has therapeutic effect on myocardial infarction; can increase coronary blood flow, reduce oxygen uptake rate of myocardium, and protect heart. Salvianolic acid B preconditioning and O deficiency2The pre-adaptation has similar cytoprotective effect, and can enhance the subsequent O deficiency of cells for a longer time2O complex2Tolerance of the injury, thereby activating the cellular endogenous protective mechanisms.
Under normal physiological conditions, plasma thromboxane A2Prostacyclin (TXA)2/PGI2) The proportion is relatively balanced to keep the internal environment of the body stable. The research finds that the salvianolic acid B can reduce the release of Endothelin (ET) and improve TXA2/PGI2Systemic imbalance, reducing myocardial cell damage; and can improve TXA during ischemia reperfusion2/PGI2The strong constriction of the microvessels, the formation and blockage of thrombus in the microvessels caused by serious unbalance, and the no-reflow phenomenon is restrained. The interaction between the free radical reaction and the arachidonic acid metabolite is probably participated in the formation mechanism of the myocardial ischemia reperfusion without the phenomenon of reflow together.
Salvianolic acid B can reduce leukocyte infiltration by reducing expression of endothelial cell-cell adhesion factor (ICAM-1), thereby relieving myocardial injury. Salvianolic acid B can regulate the release of inflammatory factors during myocardial ischemia, inhibit the transcription and translation of c-fos, IL-1 beta, IL-6 and IL-8, and is one of the mechanisms for improving ventricular remodeling after myocardial infarction and promoting myocardial tissue repair.
At present, the application of the combination of glutathione and salvianolic acid B in the treatment of fatty liver is not reported.
Disclosure of Invention
The invention aims to solve the technical problem of providing a pharmaceutical composition which can effectively treat fatty liver, has no toxic or side effect and drug resistance and has natural active ingredients.
The technical scheme adopted by the invention for solving the problems is to provide the pharmaceutical composition for treating the fatty liver, wherein the weight ratio of the active ingredients of glutathione to salvianolic acid B is (1:20) - (20: 1).
Preferably, the weight ratio of the active ingredients of the glutathione to the salvianolic acid B is (1:9) - (9: 1).
More preferably, the weight ratio of the active ingredients of the glutathione to the salvianolic acid B is 4: 1.
Preferably, the glutathione is reduced glutathione.
Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable auxiliary materials.
More preferably, the pharmaceutically acceptable auxiliary materials are selected from one or more of starch, microcrystalline cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, magnesium stearate and aerosil.
Preferably, the dosage form of the pharmaceutical composition is tablets, capsules, injection powder, dripping pills and the like, and more preferably tablets.
Preferably, the pharmaceutical composition comprises 1-10 parts by weight of glutathione and salvianolic acid B in 100 parts by weight of the pharmaceutical composition.
The invention also provides application of the pharmaceutical composition in preparing a medicament for treating fatty liver.
Preferably, the fatty liver is non-alcoholic fatty liver.
The invention has the positive and beneficial effects that:
surprisingly, through repeated experiments, the invention unexpectedly discovers that the combination of the glutathione and the salvianolic acid B has a synergistic effect on the prevention and treatment of the fatty liver, and the effect is better when the combination of the glutathione and the salvianolic acid B is matched with other active ingredients. Compared with western medicine preparations, the pharmaceutical composition provided by the invention is simple in preparation method and reasonable in compatibility, and the two active ingredients can generate a synergistic interaction effect while exerting respective effects, so that the fatty liver is remarkably treated. Wherein the glutathione and the salvianolic acid B are natural in source, safe and nontoxic and have no side effect; the medicine composition has no western medicine component, so that the medicine has no drug resistance.
Detailed Description
The present invention will be further described with reference to the following examples, but the embodiments of the present invention are not limited thereto. The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Example 1 preparation of tablets containing reduced glutathione
Taking 10 parts by weight of reducing glutathione, 50 parts by weight of starch, 20 parts by weight of microcrystalline cellulose, 10 parts by weight of sodium carboxymethylcellulose and 9 parts by weight of polyvinylpyrrolidone, mixing, performing wet granulation, adding 0.5 part by weight of magnesium stearate and 0.5 part by weight of superfine silica gel powder into dried granules, and tabletting to prepare 100 parts by weight of tablets A1 containing reducing glutathione.
Example 2 preparation of a tablet containing Salvianolic acid B
Taking 10 parts by weight of salvianolic acid B, 50 parts by weight of starch, 20 parts by weight of microcrystalline cellulose, 10 parts by weight of sodium carboxymethylcellulose and 9 parts by weight of polyvinylpyrrolidone, mixing, performing wet granulation, adding 0.5 part by weight of magnesium stearate and 0.5 part by weight of aerosil into dried granules, and tabletting to prepare 100 parts by weight of tablet A2 containing salvianolic acid B.
Example 3 preparation of tablets containing reduced glutathione and Salvianolic acid B (1:9)
Taking 1 weight part of reducing glutathione, 9 weight parts of salvianolic acid B, 50 weight parts of starch, 20 weight parts of microcrystalline cellulose, 10 weight parts of sodium carboxymethylcellulose and 9 weight parts of polyvinylpyrrolidone, mixing, performing wet granulation, adding 0.5 weight part of magnesium stearate and 0.5 weight part of superfine silica gel powder into dried granules, and tabletting to obtain 100 weight parts of tablet A3 containing reducing glutathione and salvianolic acid B (the weight ratio is 1: 9).
Example 4 preparation of tablets containing reduced glutathione and Salvianolic acid B (9:1)
Mixing 9 parts by weight of reducing glutathione, 1 part by weight of salvianolic acid B, 50 parts by weight of starch, 20 parts by weight of microcrystalline cellulose, 10 parts by weight of sodium carboxymethylcellulose and 9 parts by weight of polyvinylpyrrolidone, performing wet granulation, adding 0.5 part by weight of magnesium stearate and 0.5 part by weight of aerosil into dried granules, and tabletting to obtain 100 parts by weight of tablet A4 containing reducing glutathione and salvianolic acid B (weight ratio of 9: 1).
Example 5 preparation of tablets containing reduced glutathione and Salvianolic acid B (4:1)
Mixing 8 parts by weight of reducing glutathione, 2 parts by weight of salvianolic acid B, 50 parts by weight of starch, 20 parts by weight of microcrystalline cellulose, 10 parts by weight of sodium carboxymethylcellulose and 9 parts by weight of polyvinylpyrrolidone, performing wet granulation, adding 0.5 part by weight of magnesium stearate and 0.5 part by weight of aerosil into dried granules, and tabletting to obtain 100 parts by weight of tablet A5 containing reducing glutathione and salvianolic acid B (weight ratio of 4: 1).
Test example 1: application of composition of the invention in treating fatty liver of rat
SD male rats were randomly divided into 7 groups of 10 rats each. Basal diet was given to the blank control group, and high fat diet (basal diet 85%, lard 10%, and cholesterol 5%) was given to the model control group; high-fat feeds (base feed 75%, lard 10%, cholesterol 5% and 10% of the inventive tablets a1-a5 ground to fine powder) containing the respective active ingredients were administered to each experimental group in an amount of 20 g/day for an experimental period of 30 days. During the experiment, the general situation was observed daily: mental, appetite, hair, activity and stool, body weight was measured and recorded every seven days. At the end of the experiment, blood was collected via iliac vein, serum was separated, and triglyceride and cholesterol contents in serum were measured according to the procedure of kit instructions, and the measurement results are shown in table 1. The rat was dissected, the liver was removed, the surface tissue fluid was aspirated with filter paper, the wet weight was weighed on an electronic balance, and the surface and cross-sectional fatty changes were observed and recorded. Collecting liver tissue 0.2 g, cutting, placing in a homogenizer, adding physiological saline 2.0ml, grinding to obtain 10% liver homogenate, centrifuging at 3500rpm for 10min, collecting supernatant, and determining triglyceride and cholesterol content according to kit instruction (see Table 2).
TABLE 1 Effect of the compositions of the present invention on the plasma triglyceride and cholesterol levels in fatty liver rats
Triglyceride (mmol/L) Cholesterol (mmol/L)
Blank control group 0.61 1.88
Model control group 1.18 2.69
Experimental group A1 0.81 1.84
Experimental group A2 0.97 2.06
Experimental group A3 0.79 1.73
Experimental group A4 0.77 1.67
Experimental group A5 0.70 1.44
TABLE 2 Effect of the compositions of the present invention on the triglyceride and cholesterol levels in liver homogenates of fatty liver rats
Figure BDA0000962711600000081
Figure BDA0000962711600000091
As can be seen from tables 1 and 2, after the pharmaceutical composition of the invention is taken with the reducing glutathione, the salvianolic acid B and various proportions, the contents of triglyceride and cholesterol in the plasma and the liver of the rat are reduced to different degrees compared with the content in the model control group, and the pharmaceutical composition of the invention is proved to have obvious effect on preventing and treating the fatty liver. Particularly, the combined use of the glutathione and the salvianolic acid B generates a synergistic effect, and the use amount of the medicine is reduced. Under the condition that the total amount of active ingredients is kept unchanged, the effect of the pharmaceutical composition is remarkably improved compared with that of a preparation which singly uses the glutathione and the salvianolic acid B to treat the fatty liver, wherein the pharmaceutical composition with the weight ratio of the glutathione to the salvianolic acid B being 4:1 has the most remarkable effect, and produces the excellent effect which is difficult to expect.

Claims (1)

1. An application of a tablet containing reduced glutathione and salvianolic acid B in preparing a medicament for treating non-alcoholic fatty liver is characterized in that 8 parts by weight of reduced glutathione, 2 parts by weight of salvianolic acid B, 50 parts by weight of starch, 20 parts by weight of microcrystalline cellulose, 10 parts by weight of sodium carboxymethylcellulose and 9 parts by weight of polyvinylpyrrolidone are taken, mixed and subjected to wet granulation, 0.5 part by weight of magnesium stearate and 0.5 part by weight of aerosil are added into dried granules, and 100 parts by weight of tablet containing reduced glutathione and salvianolic acid B is prepared by tabletting.
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