CN112870332B - Glutathione-containing pharmaceutical composition for treating fatty liver - Google Patents
Glutathione-containing pharmaceutical composition for treating fatty liver Download PDFInfo
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- CN112870332B CN112870332B CN202110389703.8A CN202110389703A CN112870332B CN 112870332 B CN112870332 B CN 112870332B CN 202110389703 A CN202110389703 A CN 202110389703A CN 112870332 B CN112870332 B CN 112870332B
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- 150000003641 trioses Chemical class 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000001113 umbilicus Anatomy 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
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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 has the advantages that the preparation method is simple, the compatibility is reasonable, and the two active ingredients can produce a synergistic effect while exerting respective effects, so that the fatty liver can be obviously treated. Wherein, the glutathione and the salvianolic acid B are natural in source, safe and nontoxic, and have no side effect; because the pharmaceutical composition has no western medicine component, the medicine has no drug resistance.
Description
Technical Field
The invention relates to the field of medicines, in particular to a pharmaceutical composition for treating fatty liver.
Background
Fatty liver is a liver steatosis caused by various diseases and causes, and epidemiologically investigates mainly chronic fatty liver caused by alcohol, obesity, etc. Fatty Liver (FLD) is classified clinically into Alcoholic Fatty Liver (AFLD) and non-alcoholic fatty liver (NAFLD) or both, depending on the history of excessive drinking in the patient. AFLD refers to fatty liver caused by long-term drinking. NAFLD refers to liver cirrhosis caused by alcohol and other well-defined liver damage factors, including simple fatty liver, steatohepatitis (NASH), and NASH-related cirrhosis. FLD in China is becoming one of the most common chronic liver diseases in China and seriously harms the health of people, and the incidence rate of FLD in China is increasing.
Toxic metabolites produced by the metabolism of ethanol in hepatocytes and the resulting metabolic disorders are the main causes of alcoholic liver injury. The metabolite acetaldehyde of ethanol is hepatotoxic and promotes liver fat accumulation by impairing the function of peroxisome proliferator-activated receptor α (PPAR- α) and increasing the expression of sterol regulatory element binding protein-1 (SREBP-1). When the level of fatty acids increases, PPAR-alpha is activated, inducing an increase in fatty acid metabolizing enzyme synthesis, regulating fatty acids to normal levels. Under induction of acetaldehyde, PPAR-alpha function decreases, SREBP-1 expression increases, enzyme synthesis associated with fat metabolism decreases, enzyme expression associated with fat synthesis increases, and fat synthesis increases. Endotoxemia caused by ethanol may be related to the pathogenesis of alcoholic fatty liver, and Endotoxin (ET) can stimulate liver macrophages (KC) to release cytokines such as tumor necrosis factor (TNF-alpha), interleukin-8 (IL-8) and inflammatory mediators. TNF-alpha binds to TNF-alpha receptors on cell membranes, increasing the formation of active oxygen in the liver, inducing apoptosis in hepatocytes. IL-8 is an inflammatory chemokine that causes neutrophils to accumulate at the inflammatory site, exacerbating hepatocyte damage. TNF-alpha, IL-8 damage to the liver may be one of the important mechanisms for AFLD to occur.
The theory of complex pathogenesis of NAFLD, the second hit, has been accepted by most scholars, that primary hit is primarily Insulin Resistance (IR), which causes hepatic cell steatosis by promoting peripheral lipolysis and hyperinsulinemia, and initiates a cell adaptation procedure, whereas the relative lack of viability of steatosis hepatocytes provides a sufficient response matrix for oxygen stress, with increased sensitivity of steatosis hepatocytes to internal and external damaging factors; the secondary striking is mainly accompanied by the increase of reactive oxidative metabolites, so that lipid peroxidation with cytokines, mitochondrial uncoupling protein 2 and fas ligand are induced and activated, and further, the hepatic cells causing steatosis generate inflammation, necrosis and even fibrosis. Reactive Oxygen Species (ROS) are considered to be the most important factor in the occurrence of NAFLD. ROS production occurs at the primary stroke, and at the secondary stroke, in addition to fibrosis of liver tissue by modulating mitochondrial membrane permeability, inducing apoptosis and producing a series of cytokines and inflammatory adhesion factors, it also attacks unsaturated fatty acids itself, producing a large number of peroxidation products, and under the action of possible genetic hemochromatosis gene mutations, renin-angiotensin-aldosterone system and leptin, activates Hepatic Stellate Cells (HSCs), induces autoimmunity, decreases the body's antioxidant capacity, and continues to produce a large number of ROS, causing severe malignant circulation, promoting the development of hepatic fibrosis.
The current medicine for treating fatty liver mainly comprises western medicines which can be divided into several kinds according to the action mechanism:
(1) Insulin sensitizers: the lipid metabolism abnormality caused by insulin resistance is the first hit in FLD formation. Insulin sensitizers may therefore be an effective method of treating FLD. (1) Biguanides: the representative drug is metformin, which can obviously enhance the sensitivity of peripheral tissues to insulin and has certain effects of reducing weight and hyperinsulinemia. (2) Thiazolidinediones: reducing the release of free fatty acids from adipocytes and tumor necrosis factor, increasing glucose utilization, simultaneously increasing insulin sensitivity, inhibiting lipid peroxidation and TNF-alpha activity, and selectively transferring fat from viscera to subcutaneous tissue.
(2) Lipid-lowering drugs: (1) gemfibrozil: has effects in promoting fatty acid intake, transportation, oxidation and utilization of liver, and maintaining lipid balance in cell environment. (2) Clofibrate: mainly, by inhibiting adenylate cyclase, cAMP content in fat cells is reduced, fat tissue hydrolysis is inhibited, non-acetified fatty acid content in blood is reduced, and thus synthesis and secretion of Very Low Density Lipoprotein (VLDL) in liver are reduced, and simultaneously, activity of lipoprotein lipase is enhanced, catabolism of VLDL and Triglyceride (TG) is 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 that hydrolyzes food fat in the small intestine and facilitates fat absorption (as monoglyceride). Studies have demonstrated that inhibition of lipase activity can limit the absorption of triacylglycerols in the diet, thereby inhibiting the intake of exogenous fat. (4) Elastase: the elastase-elastase inhibitor in normal human blood is a balance system, and supplementing elastase can regulate balance of the system, prevent synthesis of cholesterol, promote conversion of cholesterol into cholic acid, and promote bile excretion, so that TG and TC contents in blood are reduced, high-density lipoprotein cholesterol (HDL-C) level is raised, and fat transported to liver is reduced.
(3) Antioxidant: vitamin E, betaine, spirulina maxima, etc.: oxygen stress and lipid peroxidation play an important role in NASH formation as secondary hits, and blocking oxygen stress and lipid peroxidation may have a therapeutic effect on NASH, and thus antioxidants may be an effective method of treating NASH. Vitamin E has a certain antioxidant effect, but it is noted that the long-term and high-volume supplementation of vitamin E can also increase the death rate. In the treatment of NAFLD patients with the spirulina maxima, the spirulina maxima is found to have good treatment effect on NAFLD patients by B-ultrasonic and biochemical examination, and can be used as an auxiliary treatment drug of NAFLD.
(4) Cytochrome P 450 Inhibitors: cimetidine is H 2 Receptor antagonists, also cytochrome P 450 An inhibitor. Experiments prove that cimetidine can inhibit NAFLD rat liver microsome CYP 450 And the expression of the isozyme CYP2E1, reduces the content of Hyaluronic Acid (HA) in serum, improves liver function, and further reduces NAFLD liver tissue inflammation. (5) probiotics: the probiotics have a regulating effect on intestinal flora interfering with intestinal liver axis. And 4 liver disease research center data are searched, and only 2 preliminary data of non-random experimental researches indicate that probiotics have better tolerance, so that the liver function conventional index can be improved, and lipid peroxidation markers can be reduced. However, the possibility of supporting or refuting probiotics for NAFLD or NASH has not been made due to the lack of randomized clinical trials. The normal intestinal flora has an important therapeutic effect on hyperlipidemia.
The traditional Chinese medicine considers that the cause of FLD is overfeeding fat, sweet and thick, or obesity, excessive drinking, or emotional disorder, or feeling damp-heat epidemic toxin, or chronic disease body deficiency, food stagnation, qi stagnation, epidemic qi and the like, thereby causing liver failure, spleen dysfunction, damp evil generation, phlegm turbidity accumulation, kidney essence deficiency, phlegm turbidity incapacitation and the like. The bupleurum root is used for soothing liver and dispelling stasis, the phlegm-dampness and spleen-affecting type is used for calming stomach and dispelling stasis, the flavored bupleurum root decoction is used for damp-heat accumulation type, the blood stasis and collateral obstruction type is used for restoring and activating blood decoction, and the yin deficiency and liver depression type is used for nourishing water and clearing liver-fire yin. The eight acupoints (moisture, yin-crossing, ganshu, sunling, tianshu, ganshu, ganli, zusanli, fenglong, quchi, sanyinjiao) around the umbilicus are used for treating 32 cases of obesity FLD, the method of lifting, inserting, twisting, reinforcing and reducing is applied, electric needle continuous wave is applied, the patient can endure for 30min, 1 time every other day, and 12 times are 1 course of treatment, generally 2-3 courses of treatment. As a result, 18 cases were clinically cured, 8 cases were significantly effective, 4 cases were effective, and 2 cases were ineffective. 28 NAFLD patients were randomized into 2 groups. 12 control groups are treated by basic liver protection, and 16 treatment groups are orally taken with liver-strengthening capsules on the basis of the control groups. The clinical symptoms, liver functions, serum liver fibrosis indexes, oxidative stress indexes and liver pathological changes of biopsy of patients are observed before and after 6 months of treatment. The results show that all indexes are obviously improved, and the comparison difference between the treated group and the treated group has statistical significance (P is less than 0.05). The liver strengthening capsule can improve liver inflammation, promote fat metabolism in liver, protect liver cells and reverse liver fibrosis.
In the common medicines for treating fatty liver, western medicines have obvious curative effects, but are easy to generate drug resistance after long-term administration, and traditional Chinese medicine compounds have limited curative effects although low toxicity and no drug resistance, so that scientific researchers focus on the research of fatty liver treatment on medicines with natural sources, and glutathione and traditional Chinese medicine natural products are particularly attractive.
Glutathione is a peptide naturally synthesized in human cells and consists of glutamic acid, cysteine and glycine, and is ubiquitous in 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 in an inactive state, accounting for about 1%. According to studies, GSH contains sulfhydryl (-SH) groups, which are the main groups that play a role in the human body through enzyme activation and free radical scavenging. When human tissue cells are aged, infected, poisoned and stressed by oxidation, the biosynthesis capacity and content of intracellular GSH can be reduced. Timely supplementing exogenous GSH can prevent, alleviate and terminate tissue cell injury, and change pathophysiological process.
GSH, an important metabolic regulating substance in cells, is a prosthetic group of glyceraldehyde phosphate dehydrogenase, a coenzyme for glyoxalase and triose dehydrogenase, participates in tricarboxylic acid cycle and sugar metabolism in vivo, and can activate various enzymes such as Sulfhydryl (SH) enzyme-coenzyme, etc., thereby promoting carbohydrate, fat and protein metabolism. GSH molecule is characterized by having active sulfhydryl (-SH), is the most important functional group, can participate in various important biochemical reactions of organisms, protects important enzyme protein sulfhydryl in vivo from oxidation and inactivation, and ensures energy metabolism and cell utilization. Meanwhile, the thiol is combined with free radicals in the body, so that the free radicals can be directly reduced into acidic substances, thereby accelerating the excretion of the free radicals and resisting the damage of the free radicals to important organs. GSH has been found to be involved in lipopolysaccharide-induced regulation of cytokine transcription and in the I-KB/NF-KB signaling pathway. It has also been found that a decrease in GSH content is a potential early activation signal for apoptosis, with subsequent generation of oxygen radicals that promote apoptosis.
GSH, which is an important metabolic agent and antioxidant for intracellular regulation, has the effects of scavenging oxygen free radicals, enhancing antioxidant enzyme activity, improving the antioxidant defenses of organisms and the like, is a medicament for the consistent treatment and adjuvant treatment of various diseases, and is widely applied to liver damage, kidney damage, lung diseases, eye diseases, cardiovascular and cerebrovascular diseases, parkinsonism and other multi-system and multi-organ diseases at present. GSH has also been reported to have an AIDS inhibiting effect. As research continues, the application range may be further expanded.
According to research, when liver cells are damaged, intracellular GSH is depleted or synthesized to be reduced, various oxidation free radicals are increased, when the concentration of GSH in vivo is lower than a critical value, various GSH dependent enzyme systems are deactivated, protection of 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 the activity of thiol enzymes of the liver cells is directly changed to cause degeneration and necrosis of the liver cells. The exogenous GSH can be supplemented to provide a reducing agent for GSH oxidase, and the activity of GSH enzyme system is recovered, so that the generation of free radicals is inhibited or reduced, the damage of oxygen free radicals to liver cells is blocked, and meanwhile, the excretion of the free radicals is accelerated, so that the liver cells are protected.
When patients with acute viral hepatitis are treated, 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 the patients in a control group, and adverse reactions of the patients during the administration period are lighter, so that the method is safe and reliable. In observing the curative effect of GSH on alcoholic liver disease, the treatment group is additionally treated by GSH on the basis of conventional treatment. The results showed different degrees of improvement in liver function in both groups, but the treated group was superior to the control group (P < 0.05). In observing the clinical effect of alcoholic cirrhosis, the treatment group was treated with GSH. The clinical effect of the result observation group and the liver fibrosis index of the liver function are obviously superior to those of the control group, which shows that the reduced glutathione has good effect of treating alcoholic cirrhosis, can obviously inhibit liver fibrosis and improve liver function.
Gouty nephropathy is caused by long-term hyperuricemia, and the generation of kidney NO is inhibited. It is considered that GSH can stabilize endothelial cell function by scavenging free radicals, antagonize the inhibition of high uric acid to kidney NO, and alleviate damage to renal tubule and interstitium and toxicity of drug to kidney. In the treatment of gouty kidney disease patients, GSH was added to 18 observations. The results were observed that the group showed 7 cases (38.9%), the total showed 14 cases (77.8%), the control group showed 3 cases (16.7%), the total showed 10 cases (55.6%). The blood creatinine reduction, urine protein reduction, renal function improvement and other aspects of the observed group are obviously superior to those of the control group (P < 0.05), and no adverse reaction is found.
The action mechanism of GSH for treating lung diseases is not clear at present, and research considers that GSH can completely eliminate oxygen free radicals, hydrogen peroxide and hydrogen free radicals, and can also derive various oxides with peroxidase produced by leucocytes in an oxygen stress state, thereby having a certain inhibition effect on oxygen free radical generation reaction in a body. Patients with chronic obstructive pulmonary disease are treated with a combination of mechanical ventilation and GSH, which combination is treated with a combination of mechanical ventilation and GSH. Results the combined group of patients showed significantly better symptom control effect (total effective rate 93.3%) than the ventilated group (total effective rate 75.5%), the ventilated treatment time and hospitalization time were significantly shorter than those of the ventilated group (P < 0.05), and no adverse reactions occurred during treatment of both groups of patients. In treating severe pneumonia patients, the observations group received conventional therapy while being adjunctively treated with GSH. The results show that the total effective rate (77.78%) of the treatment of the patients in the observation group is obviously higher than that of the control group (66.67%), and meanwhile, each body measurement index of the patients in the observation group after the treatment is better than that of the control group (P < 0.05).
GSH has protective effect on chemotherapy patients, when tumor patients receive chemotherapy for a long time, a large amount of oxygen free radicals and other active oxygen free radicals can be generated in the organism, so that peroxidation damage is caused to organism tissues, liver functions are seriously affected, and organism immunity is reduced, cell metabolism is disordered, DNA damage, protein damage, cell damage and death are caused when illness is serious. GSH can remove oxygen self-group, has detoxification effect, and effectively protects normal functions of liver cells in a body. When the influence of GSH on bone marrow function and liver function damage caused by chemotherapy of tumor patients is studied, the indexes such as white blood cell number, glutamic pyruvic transaminase and the like are better than those of a control group after GSH is added into a prevention group.
The Saviae Miltiorrhizae radix is dry root and rhizome of Saviae Miltiorrhizae radix (Salvia miltiorrhiza Bunge) of Salvia of Labiatae, the Shen nong Ben Cao Jing (Shen nong's herbal) has the effect of collecting all the herbs in the past. The red sage root is good for heart and liver meridian, has slight cold property, bitter taste and 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 the red sage root 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 the red sage root have phenolic acid structures, wherein the salvianic acid is the basic chemical structure of various salvianolic acids. A series of phenolic acid compounds found hereafter are all named salvianolic acid. The salvianolic acid B is prepared by condensing 3 molecules of salvianic acid A with one molecule of caffeic acid. The content of salvianolic acid B in the medicinal materials can reach 2% -8%, is the most main active ingredient in the water-soluble ingredients of the red sage root, and the content of salvianolic acid B in the total salvianolic acid is the highest and accounts for about 70%. Salvianolic acid B is weakly acidic, and is easily dissolved in water, alcohol, ethyl acetate and other solvents, and is mainly extracted by water, ethanol or ethyl acetate and the like at present. Salvianolic acid B has effects of resisting myocardial ischemia, resisting oxidation, resisting coagulation, resisting thrombi, regulating blood lipid, increasing coronary flow, improving heart function, and relieving inflammation.
The salvianolic acid compounds have strong antioxidation, and in vivo and in vitro experiments prove that the salvianolic acid can remove oxygen free radicals and inhibit lipid peroxidation. Studies show that salvianolic acid B can remove active oxygen in cells by improving the activities of superoxide dismutase (SOD), catalase (CAT) and Glutathione Peroxidase (GPX), so that the oxidation resistance of the whole cells is improved, the action intensity of removing oxygen free radicals and inhibiting lipid peroxidation is higher than that of vitamin C and vitamin E, and the salvianolic acid B is one of the natural products with the strongest oxidation resistance known at present.
Salvianolic acid B inhibits AS production in hypercholesterolemic animals, not only in connection with its cholesterol lowering effect, but also because its antioxidant effect prevents endothelial damage and oxidative modification of LDL. Intravenous injection of salvianolic acid B can reduce myocardial ischemia degree and myocardial ischemia range of coronary ligature dogs, and the action intensity of the salvianolic acid B is dose-dependent. The action mechanism of the medicine is to increase 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 hearts. Myocardial ischemia reperfusion injury produces a large amount of oxygen radicals, which leads to lipid peroxidation of myocardial cell membranes and further exacerbates myocardial injury. Salvianolic acid B can relieve ischemia reperfusion injury by improving SOD activity and inhibiting injury effect of oxygen free radical on myocardium.
Ca 2+ The overload contributes to the formation of oxygen radicals, resulting in reperfusion injury. Studies have shown that intracellular Ca 2+ -Mg 2 + A decrease in ATPase (calmag ATPase) activity may lead to an overload of intracellular calcium, while salvianolic acid B is responsible for intracellular Ca in myocardial ischemia 2 + -Mg 2+ Decreased ATPase activity has a better antagonism, thus reducing intracellular calcium overload during myocardial ischemia. In vitro culture of myocardial cells for simulating myocardial ischemia reperfusion injury calcium overload test proves that salvianolic acid B can obviously reduce intracellular Ca 2+ Is a concentration of (3). Studies show that the salvianolic acid B has better protection effect on the rat cardiac muscle damaged by acute myocardial ischemia reperfusion.
The salvianolic acid has strong antagonism to vascular endothelial cell injury caused by oxidative stress. Salvianolic acid B can promote synthesis of Nitric Oxide (NO) in 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 anoxia injury has the following aspects: (1) is related to the synthesis of stress-induced heat shock protein 70 (HSP 70). (2) Can activate CMEC endogenous delay protection mechanism, improve cell survival rate and SOD activity, reduce Lactate Dehydrogenase (LDH) and NO levels, and antagonize myocardial ischemia and anoxia injury effects. (3) Has remarkable inhibiting effect on Vascular Endothelial Growth Factor (VEGF) -induced vascular endothelial permeability increase. (4) Significantly inhibit the increase of matrix metalloproteinase-2 (MMP-2) activity caused by Lysophosphatidylcholine (LPC), and has a protective effect on LPC-mediated damage to cardiovascular system. (5) Inhibiting the increase of permeability of endothelial cells caused by tumor necrosis factor-alpha (TNF-alpha), and has direct protection effect on damaged rat microvascular endothelial cells.
The intravenous injection of the salvianolic acid B can reduce the myocardial ischemia degree, reduce the myocardial ischemia range, lighten the damage of myocardial cells and has the therapeutic effect on myocardial infarction; can increase coronary flow, reduce myocardial oxygen uptake rate, and protect heart. Pre-adaptation and O-deficiency of salvianolic acid B 2 Pre-adaptation has a similar cytoprotective effect, canEnhancing cell pair followed by prolonged O-deficiency 2 Complex O 2 Tolerance to injury, thereby triggering endogenous protection mechanisms of the cell.
Under normal physiological state, plasma thromboxane A 2 Prostacyclin (TXA) 2 /PGI 2 ) The proportion is relatively balanced so as to keep the internal environment of the machine body stable. Studies show that salvianolic acid B can reduce Endothelin (ET) release and improve TXA 2 /PGI 2 The unbalanced state of the system reduces the damage of myocardial cells; and can improve TXA during ischemia reperfusion 2 /PGI 2 The strong constriction of the micro-blood vessels and the thrombosis and blockage in the micro-blood vessels caused by serious unbalance can prevent the phenomenon of no reflow. The interaction between the free radical reaction and the arachidonic acid metabolite may be involved in the mechanism of myocardial ischemia reperfusion without reflow.
Salvianolic acid B can reduce leukocyte infiltration by reducing the expression of endothelial cell adhesion factor (ICAM-1), thereby relieving myocardial injury. Salvianolic acid B can lower 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 treating fatty liver has not been reported yet.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the pharmaceutical composition which can effectively treat fatty liver, has no toxic or side effect and drug resistance and is natural in active ingredient source.
The technical scheme adopted by the invention for solving the problems is to provide 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).
Preferably, the weight ratio of the active ingredients of glutathione to salvianolic acid B is (1:9) - (9:1).
More preferably, the weight ratio of the active ingredients of glutathione to 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 micro silica gel.
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 contains 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 medicines for treating fatty liver.
Preferably, the fatty liver is a non-alcoholic fatty liver.
The invention has the positive beneficial effects that:
surprisingly, through repeated experiments, the invention surprisingly discovers that the combined use of the glutathione and the salvianolic acid B has a synergistic effect on the prevention and treatment of fatty liver, and has better use effect when being matched with other active ingredients. Compared with western medicine preparations, the pharmaceutical composition provided by the invention has the advantages that the preparation method is simple, the compatibility is reasonable, and the two active ingredients can produce a synergistic effect while exerting respective effects, so that the fatty liver can be obviously treated. Wherein, the glutathione and the salvianolic acid B are natural in source, safe and nontoxic, and have no side effect; because the pharmaceutical composition has no western medicine component, the medicine has no drug resistance.
Detailed Description
The present invention will be further described with reference to examples, but the embodiments of the present invention are not limited thereto. The experimental methods used in the following examples are conventional methods unless otherwise specified.
Example 1 preparation of tablets containing reduced glutathione
10 parts by weight of reduced 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 are mixed, wet granulation is carried out, 0.5 part by weight of magnesium stearate and 0.5 part by weight of micro powder silica gel are added into the dried dry granules, and 100 parts by weight of tablet A1 containing the reduced glutathione is prepared by tabletting.
Example 2 preparation of 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, granulating by a wet method, adding 0.5 part by weight of magnesium stearate and 0.5 part by weight of aerosil into the 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 part by weight of reduced glutathione, 9 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 carboxymethyl cellulose and 9 parts by weight of polyvinylpyrrolidone, mixing, granulating by a wet method, adding 0.5 part by weight of magnesium stearate and 0.5 part by weight of micropowder silica gel into the dried granules, and tabletting to prepare 100 parts by weight of tablet A3 containing the reduced glutathione and the salvianolic acid B (weight ratio of 1:9).
Example 4 preparation of tablets containing reduced glutathione and salvianolic acid B (9:1)
9 parts by weight of reduced 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 are taken, mixed, wet granulated, dried and added with 0.5 part by weight of magnesium stearate and 0.5 part by weight of micro-powder silica gel, and tableted into 100 parts by weight of tablet A4 containing the reduced glutathione and the salvianolic acid B (weight ratio of 9:1).
Example 5 preparation of tablets containing reduced glutathione and salvianolic acid B (4:1)
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, wet granulated, dried and added with 0.5 part by weight of magnesium stearate and 0.5 part by weight of micro powder silica gel, and tableted to prepare 100 parts by weight of tablet A5 containing the reduced glutathione and the salvianolic acid B (weight ratio of 4:1).
Test example 1: application of composition of the invention in treating fatty liver of rats
SD male rats were randomly divided into 7 groups of 10 animals each. The blank control group was given basal feed, and the model control group was given high fat feed (basal feed 85%, lard 10% and cholesterol 5%); each experimental group was given a high fat diet (basal diet 75%, lard 10%, cholesterol 5% and 10% of the inventive tablets A1-A5 ground to a fine powder) with a diet amount of 20 g/day and 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 the iliac veins, serum was isolated, and the triglyceride and cholesterol levels in the serum were determined by the procedure of the kit instructions, with the results shown in table 1. The rats were dissected, the livers were removed, surface tissue fluids were blotted with filter paper, their wet weights were weighed on an electronic balance, and their surface and profile fatness changes were observed and recorded. Taking liver tissue 0.2 g, shearing, placing into 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 specification (see table 2).
TABLE 1 Effect of the compositions of the invention on triglyceride and cholesterol levels in plasma of fatty liver rats
| Triglyceride (mmol/L) | Cholesterol (mmol/L) | |
| Blank control group | 0.61 | 1.88 |
| Model control group | 1.18 | 2.69 |
| A1 experiment group | 0.81 | 1.84 |
| A2 experiment group | 0.97 | 2.06 |
| A3 experiment group | 0.79 | 1.73 |
| A4 experiment group | 0.77 | 1.67 |
| A5 experiment group | 0.70 | 1.44 |
TABLE 2 Effect of the compositions of the invention on triglyceride and cholesterol levels in liver homogenates of fatty liver rats
| Triglyceride (mmol/100 g) | Cholesterol (mmol/100 g) | |
| Blank control group | 2.07 | 1.89 |
| Model control group | 5.89 | 6.94 |
| A1 experiment group | 3.41 | 3.37 |
| A2 experiment group | 3.74 | 3.94 |
| A3 experiment group | 3.05 | 3.27 |
| A4 experiment group | 2.76 | 2.85 |
| A5 experiment group | 1.72 | 1.68 |
As can be seen from tables 1 and 2, the contents of triglyceride and cholesterol in the plasma and liver of rats are reduced to different degrees compared with the model control group after the administration of the pharmaceutical composition of the invention in various proportions, and the pharmaceutical composition of the invention has remarkable effect of preventing and treating fatty liver. Particularly, the combination of the glutathione and the salvianolic acid B produces a synergistic effect, and reduces the dosage of the medicine. Under the condition that the total amount of active ingredients is kept unchanged, the effect of the pharmaceutical composition is obviously improved compared with the effect of singly using a preparation of glutathione and salvianolic acid B for treating fatty liver, wherein the pharmaceutical composition with the weight ratio of the glutathione to the salvianolic acid B of 4:1 has the most outstanding effect, and the excellent effect which is difficult to expect is generated.
Claims (2)
1. The application of the pharmaceutical composition in preparing a medicament for treating fatty liver is characterized in that the weight ratio of active ingredients glutathione to salvianolic acid B in the pharmaceutical composition is 4:1, the glutathione is reduced glutathione, the pharmaceutical composition further comprises pharmaceutically acceptable auxiliary materials, the pharmaceutically acceptable auxiliary materials are selected from one or more of starch, microcrystalline cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, magnesium stearate and micro-powder silica gel, the dosage form of the pharmaceutical composition is a tablet, and the fatty liver is a non-alcoholic fatty liver.
2. The use according to claim 1, characterized in that it contains 1-10 parts by weight of glutathione and salvianolic acid B in 100 parts by weight of the pharmaceutical composition.
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| CN101450051A (en) * | 2007-12-07 | 2009-06-10 | 苑立超 | Monomer salvianolic acid B injection and preparation method thereof |
| WO2009076869A1 (en) * | 2007-12-07 | 2009-06-25 | Lichao Yuan | Salvianolic acid of high purity, preparation method and use thereof |
| CN102139084A (en) * | 2011-04-01 | 2011-08-03 | 南京中医药大学 | Chinese medicinal composition for treating fatty liver and preparation method and application thereof |
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| CN101450051A (en) * | 2007-12-07 | 2009-06-10 | 苑立超 | Monomer salvianolic acid B injection and preparation method thereof |
| WO2009076869A1 (en) * | 2007-12-07 | 2009-06-25 | Lichao Yuan | Salvianolic acid of high purity, preparation method and use thereof |
| CN102139084A (en) * | 2011-04-01 | 2011-08-03 | 南京中医药大学 | Chinese medicinal composition for treating fatty liver and preparation method and application thereof |
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