CN101049294A - Medication composition in use for treating liver disease - Google Patents
Medication composition in use for treating liver disease Download PDFInfo
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- CN101049294A CN101049294A CN 200610043505 CN200610043505A CN101049294A CN 101049294 A CN101049294 A CN 101049294A CN 200610043505 CN200610043505 CN 200610043505 CN 200610043505 A CN200610043505 A CN 200610043505A CN 101049294 A CN101049294 A CN 101049294A
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Abstract
A composite medicine for treating hepatism, especially the early phase of liver failure is composed of acetylcysteine or its pharmacologically acceptable salt and at least one medicine for treating hepatism, which is chosen from kurarinol, tiopronin and monoammonium glycyrrhizinate. Its preparing process is also disclosed.
Description
[technical field]
The invention belongs to medical technical field, relate to pharmaceutical composition of a kind of medicine that contains N-acetylcystein and at least a treatment hepatopathy and its production and use.
[background technology]
The major function of liver is generation and elimination, biliary generation and the drainage that participates in substance metabolism, biotransformation (detoxifcation and deactivation), blood coagulation substance.Liver has abundant mononuclear phagocyte, has important effect in special and nonspecific immunity.When liver is subjected to the infringement of some paathogenic factor, can cause the unusual of the destruction (degeneration, necrosis, liver cirrhosis) of liver morphosis and liver function.If hepatic injury is relatively serious and extensively (once or prolonged and repeated infringement), cause that tangible substance metabolism obstacle, function of detoxification reduction, biliary formation and abnormal liver function such as acatharsia and bleeding tendency change, and are called hepatic insufficiency (hepatic insufficiency).Serious liver function injury can not be eliminated deleterious metabolite in the blood, or the substance metabolism dysequilibrium, causes central nervous system function disorder (hepatic encephalopathy), is called liver failure (hepaticfailure).
All can cause liver injury when infecting parasite, leptospira, antibacterial, virus (as hepatitis virus), chemical drugs poisoning, immunologic dysfunction, undernutrition shortage choline, methionine.Liver function reduces behind the hepatic injury, in the time of serious even liver failure, causes patient death etc.Therefore research and develop hepatoprotective and become the big focus that medical worker pays close attention to.
Acetylcysteine (N acetylcysteine, NAC) be the precursor of glutathion inside cell, can improve the glutathion inside cell biosynthesis, recent studies proof NAC in vivo can be as the carrier performance nitric oxide physiological effect of nitric oxide molecule, promote the microcirculatory vascular that shrinks to expand, effectively increase blood tissue oxygen is carried and release, correct histanoxia, reduce the generation of multiple organ dysfunction syndrome.Abroad it is caused as drug intoxication and the curative of acute fulminant hepatic failure recorded by British Pharmacopoeia 1993 and version in 1998, its curative effect and safety get the nod abroad.Hepatitis b virus infected back is chronicity easily, in case develop into hepatitis gravis, poor prognosis, case fatality rate height, and the treatment aspect does not still have breakthrough measure so far.In recent years external clinical research proof NAC can not only successfully treat the liver failure of acetaminophen due to excessive, and the liver failure that other reason is caused also shows good efficacy.The N-acetylcystein structural formula is as follows:
The N-acetylcystein structural formula
Kurarinone is the alkaloid that extracts from leguminous plant Herba Sophorae alopecuroidis, Radix Sophorae Flavescentis, and Main Ingredients and Appearance is the N-oxysophocarpine of oxymatrine and minute quantity.Kurarinone has recorded into the 16th 363 pages of national drug standards chemical drugs provincial standard rising national standards of National Drug Administration (Chinese Pharmacopoeia Commission's volume), and wherein regulation contains oxymatrine (C
15H
24N
2O
2) must not be less than 98.0%.Kurarinone is mainly used in the leukopenia that low leukocyte counts that the treatment of chronic viral hepatitis B and tumor radiotherapy, chemotherapy cause and other reasons cause.Use the clinical symptoms of Oxymatrine in Treating Chronic Hepatitis B, as weak, poor appetite and abdominal distention etc., effective percentage is about 90%.The structural formula of oxymatrine is as follows:
The oxymatrine structural formula
Tiopronin chemistry N-(2-mercapto radical propionyl group) by name-glycine is a kind of glycine derivative that contains free sulfhydryl groups.The clinical liver function that is used to improve all kinds of acute, chronic hepatitis, the treatment of fatty liver, alcoholic liver, drug induced hepatic injury and the detoxifcation of heavy metal; Tiopronin can reduce the toxic and side effects of chemicotherapy, and can prevent the peripheral leukocytes minimizing of caused by radiotherapy and chemotherapy and the generation of secondary tumor; Early senile cataract and vitreous opacity are had significant therapeutic effect.The tiopronin structural formula is as follows:
The tiopronin structural formula
Glycyrrhizic acid is the refining extract of the root and rhizome of glycyrrhizic legume, Glycyrrhiza glabra L., Glycyrrhiza inflata Bat..Glycyrrhizic acid has the effect of 17-hydroxy-11-dehydrocorticosterone sample, can improve the concentration of hepatitis patient serum's hydrocortisone, reduce interleukin-6 and tumor necrosis factor in chronic hepatitis patient serum and the periphery mononuclearcell, alleviate the immunopathogenesis reaction, promote liver function recovery, remove symptom, dwindle hepatosplenomegaly, it is fast to fall enzyme, and the jaundice eliminating subcutaneous ulcer is remarkable.Monoammonium glycyrrhizinate is to various acute, chronic hepatitis, hepatic fibrosis, and toxic hepatitis, traumatic hepatitis and cancer have certain auxiliary treatment effect.The structural formula of monoammonium glycyrrhizinate is as follows:
The monoammonium glycyrrhizinate structural formula
Utilize one or more the interaction in N-acetylcystein and kurarinone, tiopronin, the monoammonium glycyrrhizinate at present, composition of prescription is used for the treatment of hepatic disease and yet there are no report.
[summary of the invention]
In order to meet clinical needs, to the invention provides a kind of new pharmaceutical composition that is mainly used in the treatment hepatopathy, and its preparation method is provided.
Pharmaceutical composition of the present invention contains the acetylcysteine of effective dosage or the medicine of its pharmaceutically acceptable salt and at least a treatment hepatopathy, and the medicine of wherein treating hepatopathy is selected from: kurarinone, tiopronin or monoammonium glycyrrhizinate.
Aforementioned pharmaceutical compositions, its raw material medicines in portions by weight number is: acceptable salt is 400～40000 parts on acetylcysteine or its materia medica, the medicine of treatment hepatopathy is different and different according to medicine, for kurarinone is 40～4000 parts, for tiopronin is 1～100 part, is 4～400 parts for glycyrrhizic acid monoammonium.
Aforementioned pharmaceutical compositions, its raw material medicines in portions by weight number is preferably: acceptable salt is 1000～8000 parts on acetylcysteine or its materia medica, the medicine of treatment hepatopathy is different and different according to medicine, for kurarinone is 80～2000 parts, for tiopronin is 2～50 parts, is 8～200 parts for glycyrrhizic acid monoammonium.
Aforementioned pharmaceutical compositions, its raw material medicines in portions by weight number is more preferably: acceptable salt is 4000 parts on acetylcysteine or its materia medica, and the medicine of treatment hepatopathy is different and different according to medicine, is 400 parts for kurarinone, for tiopronin is 10 parts, is 40 parts for glycyrrhizic acid monoammonium.
Aforementioned pharmaceutical compositions, its raw material medicines in portions by weight number is particularly preferred to be: the compositions of 400 parts of 4000 parts of acceptable salt and kurarinones on acetylcysteine or its materia medica; Perhaps be: the compositions of 10 parts of 4000 parts of acceptable salt and tiopronins on acetylcysteine or its materia medica; Perhaps be: the compositions of 40 parts of 4000 parts of acceptable salt and monoammonium glycyrrhizinates on acetylcysteine or its materia medica.
More than form to be by weight as proportioning, when producing, can or reduce according to the corresponding proportion increase, as large-scale production can be unit with the kilogram, or be unit with the ton, small-scale production can be unit with the gram also, weight can increase or reduce, but the constant rate of weight proportion between each composition.
More than form,, can make the preparation of 100～10000 consumptions,, can be made into 100～10000,1～10 of each consumption as injection as if being unit with the gram.
The ratio of above weight proportion obtains through science screening, and for especial patient, the ratio of can corresponding adjustment forming increases or reduce being no more than 100%.
The consumption of drug component of the present invention is groped to sum up to draw through the inventor in a large number, and each amounts of components all has better curative effect in above-mentioned weight portion scope.
Pharmaceutical composition of the present invention, the acetylcysteine pharmaceutically acceptable salt can be preferably N-acetylcystein for organic nitrogen salt, hydrochlorate, sulfate, acetate, mesylate, tartrate, maleate, fumarate, hydrobromate, aspartate.
Aforementioned pharmaceutical compositions can be made clinically any or pharmaceutically acceptable dosage form with mixing acceptable accessories, is preferably injection and oral formulations.
Medicine of the present invention can adopt the conventional method production in the existing pharmaceutical field, can add various pharmaceutically acceptable carriers when needing.Described carrier comprises diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant of pharmaceutical field routine etc.
The present invention in order to increase its dissolubility, can add solubilizing agents such as Tween-80 when making injection.Can add the isoosmotic adjusting agent that is used to regulate osmotic pressure in the transfusion, for example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol and dextran etc., preferred sodium chloride or glucose.Can add excipient in the powder pin, for example, mannitol, glucose etc.
Aforementioned pharmaceutical compositions has good hepatoprotective effect, can be used for the liver failure early treatment on the Comprehensive Treatment basis, to reduce bilirubin, to improve the thrombinogen mobility.
The invention has the advantages that:
1. a kind of compound medicine of new treatment hepatic disease is provided, has satisfied urgent clinical needs.
2. pharmaceutical composition of the present invention has been carried out pharmaceutical research, the result shows: pharmaceutical composition of the present invention can extremely significantly reduce the ALT and the AST (p＜0.01) of immunologic liver injury mice serum, and the mouse immune liver damage is had significant protective effect; Can significantly reduce hepatic injury mice serum ALT due to the acetaminophen and the activity (p＜0.01) of hepatic tissue LPO, the mouse liver injury due to the acetaminophen has significant protective effect; Can significantly reduce D-Gal and cause acute liver damage mice serum serum AST, ALB content (p＜0.01), significantly shorten clotting time (p＜0.01), the chmice acute hepatic injury due to the D-Gal is had significant protective effect; Acute hepatic failure mortality of mice due to the remarkable reduction acetaminophen; the blood plasma amino acid content significantly increases (p＜0.01); branched-chain amino acid/ArAA (BCAA/AAA) ratio significantly raises, and the chmice acute liver failure due to the acetaminophen is had significant protective effect.N-acetylcystein and kurarinone or tiopronin or monoammonium glycyrrhizinate drug combination; mouse liver injury to multiple drug-induced has significant protective effect; drug combination is evident in efficacy, has produced beyond thought effect, and this is that those of ordinary skills are unexpected.
3. the various preparations of the present composition, preparation method is simple, and quality is easy to control, can be widely used in big production.
4. the present composition has been carried out acute toxicity test, the result shows that present composition toxicity is little, and safety range is big.
5. the stability test result that pharmaceutical composition of the present invention is carried out shows that every index is all more stable, has guaranteed safety of clinical administration.
Below further set forth the beneficial effect of medicine of the present invention by testing example.The compositions of N-acetylcystein and kurarinone is hereinafter to be referred as the bitter compositions of Guang, and the compositions of N-acetylcystein and tiopronin is hereinafter to be referred as Guang sulfur compositions, and the compositions of N-acetylcystein and monoammonium glycyrrhizinate is hereinafter to be referred as the sweet compositions of Guang.
The bitter compositions of test example 1 Guang is to the protective effect of mouse immune liver damage
Test sample: 0.9% normal saline, self-control;
N-acetylcystein injection: 20ml:4g, self-control;
Matrine Injection: 2ml:0.2g, the Tianjin Biochemical Pharmaceutical Factory;
The bitter composite injection of Guang, 20ml contains N-acetylcystein 4g, kurarinone 400mg.
Reagent: bacillus calmette-guerin vaccine (BCG), Shanghai Vaccine and Serum Institute; Lipopolysaccharide (LpS), Sigma company.
Animal subject: ICR kind, body weight 16～20g, male and female half and half.
Test method: get 70 of mices, mice is divided into normal saline matched group, model group, N-acetylcystein group, kurarinone group, the basic, normal, high dosage group of the bitter compositions of Guang, 10 every group at random.Except that the every caudal vein injecting normal saline of matched group 0.2ml, other is respectively organized every caudal vein injection 0.2ml bacillus calmette-guerin vaccine and (contains 5 * 10
7Viable bacteria).Play begin treatment next day, the every Mus of matched group and model group intraperitoneal injection of saline every day 0.5ml, other is respectively organized dosage and sees Table 1.After 12 days, except that matched group gave a normal saline 0.2ml/ tail vein injection, all the other each Mus by tail vein injection lipopolysaccharide 0.2ml/7.5 μ g/ only.After 12 hours, eye socket is got blood, and conventional separation of serum is used IFCC recommendation method and measured serum glutamic pyruvic transminase (ALT) and glutamic oxaloacetic transaminase, GOT (AST) activity.The results are shown in Table 1.
The bitter compositions of table 1 Guang is to the influence of immunologic liver injury mice serum ALT and AST (n=10)
| Group | Dosage (mg/kg) | ALT | AST |
| The bitter composition low dose group of dosage group Guang in the bitter composition of the bitter composition high dose group of physiological saline control group model group (BCG+LpS) N-acetylcystein group kushenin group Guang Guang | - - 2400 240 880 1760 2640 | 41.25±7.54 314.56±47.28 △△ 189.54±35.46 ** 229.34±32.61 ** 102.35±16.89 **bd 138.67± **bd 158.64±23.15 **ac | 168.46±28.96 524.63±138.46 △△ 396.67±64.36 ** 413.14±113.54 ** 224.15±75.65 **bd 276.34±98.96 **bd 335.46±126.59 **ac |
Compare with the normal saline matched group
△ △P＜0.01; Compare with model group
*P＜0.01; Compare with the N-acetylcystein group
aP＜0.05,
bP＜0.01; Compare with the kurarinone group
cP＜0.05,
dP＜0.01.
Conclusion: by table 1 result as can be seen, compare with the normal saline matched group, model group mice serum ALT and AST activity extremely significantly increase (p＜0.01), and the modeling success is described.Compare with model group, each administration group all can extremely significantly reduce the ALT and the AST (p＜0.01) of immunologic liver injury mice serum.Compare with the N-acetylcystein group, the bitter compositions low dose group of Guang can significantly reduce the ALT and the AST (p＜0.05) of immunologic liver injury mice serum, and the middle and high dosage group of the bitter compositions of Guang can extremely significantly reduce the ALT and the AST (p＜0.01) of immunologic liver injury mice serum.Compare with the kurarinone group, the bitter compositions low dose group of Guang can significantly reduce the ALT and the AST (p＜0.05) of immunologic liver injury mice serum, and the middle and high dosage group of the bitter compositions of Guang can extremely significantly reduce the ALT and the AST (p＜0.01) of immunologic liver injury mice serum.The result shows that the bitter compositions of N-acetylcystein, kurarinone and Guang has protective effect to the mouse immune liver damage, and wherein the curative effect of the bitter compositions of Guang is better than single N-acetylcystein and kurarinone used, and points out two medicines to share synergistic function.
Test example 2 Guang sulfur compositionss are to the protective effect of acetaminophen induced mice hepatic injury
Test sample: 0.9% normal saline, self-control;
N-acetylcystein injection: 20ml:4g, self-control;
Tiopronin injection: 2ml:0.1g; The favorable to the people Pharmaceutical Co in Jinan;
The bitter composite injection of Guang, 20ml contains N-acetylcystein 4g, tiopronin 10mg.
Laboratory animal: ICR mice, body weight 18～25g, male and female half and half.
Experimental technique: get 70 of mices, be divided into 7 groups at random, 10 every group, group sees the following form.Blank group and model group tail vein injection saline every day 20ml/kg Mus are heavy, every day 1 time, 10d continuously; Administration group intraperitoneal injection, every day 1 time, dosage sees the following form, continuously 10d.The blank group is tail vein injection 6h pneumoretroperitoneum injecting normal saline the last time.Model group and administration group lumbar injection 6h pneumoretroperitoneum injection acetaminophen 300mg/kg Mus the last time are heavy, each group breaks end behind intraperitoneal injection of saline and acetaminophen 16h, get blood, liver, carry out the test of biochemical indicator Serum ALT (glutamate pyruvate transaminase) and hepatic tissue LPO (lipid peroxide), the results are shown in Table 2.
Table 2 Guang sulfur compositions is to the influence of hepatic injury murine liver tissue ALT due to the acetaminophen and LPO
| Group | Mice quantity | Dosage (mg/kg) | ALT content (U/L) | LPO content (nmol/L) |
| Dosage group Guang sulphur composition low dose group in the blank group model group N-acetylcystein group Tiopronin group Guang sulphur composition high dose group Guang sulphur composition | 10 10 10 10 10 10 10 | - - 1600 6 2400 1600 800 | 35.27±5.12 281.57±23.64 △△ 179.65±13.02 * 205.68±13.68 * 107.49±11.57 **bf 139.68±12.15 **br 157.34±11.04 **ae | 4.43±0.23 8.62±0.53 △△ 7.48±0.49 * 7.85±0.67 * 5.19±0.19 **bf 5.64±0.42 **be 6.18±0.34 **ae |
Compare with the blank group,
△ △P＜0.01; Compare with model group,
*P＜0.05,
*P＜0.01; Compare with the N-acetylcystein group
aP＜0.05,
bP＜0.01; Compare with the tiopronin group,
eP＜0.05,
fP＜0.01.
Conclusion: compare with the blank group, the active of model group ALT and LPO significantly raises, and significant difference (p＜0.01) illustrates that modeling is reliable.Compare active significantly reduce (p＜0.05, p＜0.01) of each administration group ALT and LPO with model group.Compare with the N-acetylcystein group, active significantly reduce (p＜0.05) of Guang sulfur compositions low dose group ALT and LPO, the activity of middle and high dosage group ALT and LPO extremely significantly reduces (p＜0.01).Compare with the tiopronin group, active significantly reduce (p＜0.05) of Guang sulfur compositions low dose group ALT and LPO, the activity of middle and high dosage group ALT and LPO extremely significantly reduces (p＜0.01).The result shows; N-acetylcystein, tiopronin, Guang sulfur compositions have protective effect to the mouse liver injury due to the acetaminophen; wherein Guang sulfur compositions curative effect is better than single N-acetylcystein and tiopronin used, and points out two medicines to share synergistic function.
The sweet compositions of experimental example 3 Guangs causes the protective effect of chmice acute hepatic injury to D-Gal
Test sample: 0.9% normal saline, self-control;
N-acetylcystein injection: 20ml:4g, self-control;
Monoammonium glycyrrhizinate injection: 10ml:40mg, self-control;
The sweet composite injection of Guang, 20ml contains N-acetylcystein 4g, monoammonium glycyrrhizinate 40mg.
Laboratory animal: ICR mice, body weight 20～25g, male and female half and half.
Experimental technique: get 70 of mices, be divided into 7 groups at random, be respectively blank group, model group, monoammonium glycyrrhizinate group, the basic, normal, high dosage group of the sweet compositions of Guang, 10 every group.Blank group and model group tail vein injection saline every day 20ml/kg Mus are heavy, every day 1 time, 10d continuously; The administration of administration group tail vein injection, every day 1 time, dosage sees the following form, continuously 10d.The blank group is tail vein injection 1h pneumoretroperitoneum injecting normal saline the last time, the D-Gal 500g/kg of the equal lumbar injection 100g/L of all the other each treated animals.Put to death animal behind the 24h and get blood, centrifugal, get serum, automatic clinical chemistry analyzer detects.The animal docking is got the blood slide method and is measured the animal clotting time before putting to death.The detection index is aspartate amino transferase (AST), serum albumin (ALB), clotting time (CT).The results are shown in Table 3.
The sweet compositions of table 3 Guang causes the influence of acute liver damage mice serum AST, ALB content and clotting time (CT) to D-Gal
| Group | Mice quantity | Dosage (mg/kg) | AST content (U/L) | ALB content (g/L) | CT (s) |
| The sweet composition low dose group of dosage group Guang in the sweet composition of blank group model group N-acetylcystein group ammonium glycyrrhizinate group Guang sweet composition high dose group Guang | 10 10 10 10 10 10 10 | - - 1600 24 2400 1600 800 | 269.2±26.5 456.8±45.4 △△△ 376.45±34.6 * 402.3±35.8 * 267.6±31.0 **bh 284.2±28.6 **bh 321.6±31.4 **ag | 27.91±2.46 19.26±1.23 △△ 22.86±1.79 * 21.59±2.08 26.14±1.65 **ag 25.41±1.98 **ag 23.48±2.15 * | 11.72±2.45 29.68±7.12 △△ 19.26±3.98 * 22.78±4.12 * 12.96±4.52 **bh 13.84±4.26 **bh 15.02±3.44 *ag |
Compare with the blank group
△ △P＜0.01; Compare with model group,
*P＜0.05,
*P＜0.01; Compare with the N-acetylcystein group
aP＜0.05,
bP＜0.01; Compare with the monoammonium glycyrrhizinate group,
gP＜0.05,
hP＜0.01
Conclusion: compare with the blank group, the activity of model group aspartate amino transferase (AST) extremely significantly raise (p＜0.001), serum albumin (ALB) numbers of poles significantly reduces (p＜0.01), and clotting time (CT) utmost point significant prolongation (p＜0.001) illustrates that modeling is reliable.Compare with model group, active (p＜0.05 that significantly reduces of N-acetylcystein group, monoammonium glycyrrhizinate group and each dosage group aspartate amino transferase (AST) of the sweet compositions of Guang, p＜0.01), serum albumin (ALB) quantity significantly increases (p＜0.05, p＜0.01), clotting time (CT) significantly shortens (p＜0.05, p＜0.01).Compare with the N-acetylcystein group, active significantly reduce (p＜0.05) of the sweet compositions low dose group of Guang aspartate amino transferase (AST), clotting time (CT) significantly shortens (p＜0.05); The activity of the middle and high dosage group of the sweet compositions of Guang aspartate amino transferase (AST) extremely significantly reduces (p＜0.01), and serum albumin (ALB) quantity significantly increases (p＜0.05), and clotting time (CT) extremely significantly shortens (p＜0.01).Compare with the monoammonium glycyrrhizinate group, active significantly reduce (p＜0.05) of the sweet compositions low dose group of Guang aspartate amino transferase (AST), clotting time (CT) significantly shortens (p＜0.05); The activity of the middle and high dosage group of the sweet compositions of Guang aspartate amino transferase (AST) extremely significantly reduces (p＜0.01), and serum albumin (ALB) quantity significantly increases (p＜0.05), and clotting time (CT) extremely significantly shortens (p＜0.01).The result shows that the sweet compositions of N-acetylcystein, monoammonium glycyrrhizinate and Guang is to hepatic injury all has protective effect to the D-Gal induced mice.The sweet compositions curative effect of Guang is better than single with N-acetylcystein and monoammonium glycyrrhizinate, shows that two medicines share and have synergistic function, wherein the middle and high dosage group of the sweet compositions of Guang better efficacy.
The bitter compositions of test example 4 Guangs is to the protective effect of the chmice acute liver failure due to the acetaminophen
Test sample: 0.9% normal saline, self-control;
N-acetylcystein injection: 20ml:4g, self-control;
Matrine Injection: 2ml:0.2g, the Tianjin Biochemical Pharmaceutical Factory;
The bitter composite injection of Guang, 20ml contains N-acetylcystein 4g, kurarinone 400mg.
Animal subject: ICR kind, body weight 18～22g, male and female half and half.
Experimental technique: get 168 of mices, mice is divided into normal control group, negative control group, N-acetylcystein group, kurarinone group, the basic, normal, high dosage group of the bitter compositions of Guang, 24 every group, male and female half and half at random.Animal fasting 12h before the experiment, except that the normal control group, the equal lumbar injection acetaminophen of all the other animals 900mg/kg, the administration group is the lumbar injection relative medicine immediately, and dosage sees the following form.The negative control group intraperitoneal injection of saline.The back 7h that poisons gets 8 (male and female half and half) broken end for every group and gets blood, and separated plasma is measured main amino acid content, all the other animals death condition in the breeding observing 48h that does as usual.Calculate branched-chain amino acid/ArAA (BCAA/AAA) ratio.BCAA/AAA＝(Val+Ile+Leu)/(Phe+Tyr)。The results are shown in Table 4.
The bitter compositions of table 4 Guang is to acute hepatic failure mouse death rate and the amino acid whose influence of blood plasma due to the acetaminophen
| Group | Dosage mg/kg | Mortality rate (%) | Blood plasma amino acid content (μ mol/L) | BCAA /AAA | ||||
| Val | Ile | Leu | Phe | Tyr | ||||
| The bitter composition low dose group of dosage group Guang in the bitter composition of the bitter composition high dose group of negative control group Normal group N-acetylcystein group kushenin group Guang Guang | - - 2400 240 880 1760 2640 | 0 75.00 50.00 62.50 31.25 37.50 43.75 | 188±15 298±39 △△△ 225±19 * 245±23 175±10 **bd 198±12 **bd 216±27 **ac | 82±7 132±14 △△△ 102±9 * 115±10 90±8 **bd 94±8 **bd 98±12 **ac | 59±15 280±28 △△△ 202±19 * 236±24 * 146±12 **bd 154±16 **bd 171±23 **ac | 66±9 330±56 △△△ 212±35 * 254±49 * 82±11 **bd 95±12 **bd 126±16 **bd | 72±6 446±95 △△△ 312±54 * 376±76 * 118±12 **bd 154±19 **bd 206±34 **bd | 2.38 0.91 1.01 0.95 2.06 1.79 1.46 |
Compare with the normal control group
△ △ △P＜0.001; Compare with negative control group,
*P＜0.05,
*P＜0.01; Compare with the N-acetylcystein group
aP＜0.05,
bP＜0.01; Compare with the kurarinone group,
cP＜0.05,
dP＜0.01
Conclusion: compare with the normal control group, the negative control group mortality rate is up to 75.00%, and the blood plasma amino acid content extremely significantly raises (p＜0.001), and branched-chain amino acid/ArAA (BCAA/AAA) ratio significantly reduces, and illustrates that modeling is reliable.Compare with negative control group, each administration group mouse death rate obviously reduces, and the mortality rate of bitter each the dosage group of compositions of Guang reduces the most obvious; The various blood plasma amino acid contents of N-acetylcystein group significantly reduce (p＜0.05), and the various blood plasma amino acid contents of bitter each the dosage group of compositions of Guang extremely significantly reduce (p＜0.01).Compare with the N-acetylcystein group, the bitter compositions low dose group of Guang Val, Ile, Leu content significantly reduce (p＜0.05), Phe, Tyr content extremely significantly reduce (p＜0.01), and the various amino acid contents of the bitter middle and high dosage group of compositions of Guang all extremely significantly reduce (p＜0.01).Compare with the kurarinone group, the bitter compositions low dose group of Guang Val, Ile, Leu content significantly reduce (p＜0.05), Phe, Tyr content extremely significantly reduce (p＜0.01), and the various amino acid contents of the bitter middle and high dosage group of compositions of Guang all extremely significantly reduce (p＜0.01).
The bitter compositions of N-acetylcystein and Guang has protective effect to the chmice acute liver failure due to the acetaminophen; wherein the bitter compositions curative effect of Guang is more obvious; it can significantly reduce mouse death rate; reduce various amino acid contents in the hepatic injury mice plasma, improve branched-chain amino acid/ArAA (BCAA/AAA) ratio.
The 4 injected in mice administration acute toxicity tests of test example
(1) test method
Test sample: the bitter composite injection of Guang, dosage form: liquid drugs injection, specification: 20ml derives from embodiment 1;
Guang sulfur composite injection, dosage form: liquid drugs injection, specification: 20ml derives from embodiment 1;
The sweet composite injection of Guang, dosage form: liquid drugs injection, specification: 20ml derives from embodiment 1.
Animal subject: mice, each 5 of every group of male and female, male body weight 24～29g, female body weight 20～25g.
Route of administration: intravenous injection, lumbar injection.
Observation index: death toll, general state, body weight, cut open inspection, half lethal dose.
(2) result of the test
Require to carry out prerun according to acute toxicity test, lumbar injection and intravenous injection two route of administration all can't be measured the median lethal dose(LD 50) of medicine, also do not see tangible toxic reaction, so carry out a day maximum dosage-feeding test.Dosage: tail vein injection 0.4ml/10g, lumbar injection 0.4ml/10g, 2 times on the one.
Death toll: do not occur dead.
General state: no abnormality seen changes.
Body weight: in administration preceding 1 day, administration day, measured in 2,4,6,8,10,12,14 days after the administration; No abnormality seen changes.
Cut open inspection: the heart, liver, lung, kidney etc. organize no abnormality seen to change.
(3) conclusion
Do not occur dead in this experiment, the bitter composite injection of Guang, Guang sulfur composite injection and the sweet composite injection of Guang are 0.8ml/10g to the maximum tolerated dose of male and female mouse vein and intraperitoneal injection, are equivalent to 120 times of maximum consumption 40ml of the 60kg body weight day for human beings.Show this product low toxicity, safe.
Experimental example 5 KLH composite injection stability experiments
Test sample: the bitter composite injection of Guang, dosage form: liquid drugs injection, specification: 20ml derives from embodiment 1;
Guang sulfur composite injection, dosage form: liquid drugs injection, specification: 20ml derives from embodiment 1;
The sweet composite injection of Guang, dosage form: liquid drugs injection, specification: 20ml derives from embodiment 1.
Investigation project: character, pH value, clarity.
Long-time stability experimental technique and result: each compositions of this product is put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 6 months, 12 months, every index has no significant change, and experimental result shows that the long-term placement of each composite injection of this product is basicly stable.
[specific embodiment]
Come by the following examples further to set forth preparation of drug combination method of the present invention, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The adjuvant of each dosage form can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
The preparation of embodiment 1 pharmaceutical composition aqueous injection of the present invention
The bitter composition prescription of Guang:
N-acetylcystein 4000g
Kurarinone 400g
Polyoxyethylene sorbitan monoleate 20g
Water for injection adds to 20000ml
Prepare 1000 altogether
Guang sulfur composition prescription:
N-acetylcystein 4000g
Tiopronin 10g
Polyoxyethylene sorbitan monoleate 20g
Water for injection adds to 20000ml
Prepare 1000 altogether
The sweet composition prescription of Guang:
N-acetylcystein 4000g
Monoammonium glycyrrhizinate 40g
Polyoxyethylene sorbitan monoleate 20g
Water for injection adds to 20000ml
Prepare 1000 altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) N-acetylcystein is added in the water for injection of dosing amount 50% the heated and stirred dissolving fully.Kurarinone (or tiopronin or monoammonium glycyrrhizinate) is added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) with the solution sealing by fusing in glass ampule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.01% methylene blue solution hunts leak.
11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 2 pharmaceutical composition injectable powder of the present invention
The bitter composition prescription of Guang:
N-acetylcystein 4000g
Kurarinone 400g
Polyoxyethylene sorbitan monoleate 20g
Mannitol 400g
Sterile water for injection adds to 5000ml
Prepare 1000 altogether
Guang sulfur composition prescription:
N-acetylcystein 4000g
Tiopronin 10g
Polyoxyethylene sorbitan monoleate 20g
Mannitol 400g
Sterile water for injection adds to 5000ml
Prepare 1000 altogether
The sweet composition prescription of Guang:
N-acetylcystein 4000g
Monoammonium glycyrrhizinate 40g
Polyoxyethylene sorbitan monoleate 20g
Mannitol 400g
Sterile water for injection adds to 5000ml
Prepare 1000 altogether
Preparation technology:
1) vessel of at first dosing being used and antibiotic glass bottle, plug etc. carry out aseptic process.
2) take by weighing supplementary material according to recipe quantity.
3) N-acetylcystein is added in the water for injection of dosing amount 50% the heated and stirred dissolving fully.Kurarinone (or tiopronin or monoammonium glycyrrhizinate) is added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, add sterile water for injection to full dose.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.22um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then.
9) lyophilizing finishes, and lid is rolled in tamponade.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 3 pharmaceutical composition glucose infusion liquids of the present invention
The bitter composition prescription of Guang:
N-acetylcystein 4000g
Kurarinone 400g
Glucose 12500g
Water for injection adds to 250000ml
Prepare 1000 bottles altogether
Guang sulfur composition prescription:
N-acetylcystein 4000g
Tiopronin 10g
Glucose 12500g
Water for injection adds to 250000ml
Prepare 1000 bottles altogether
The sweet composition prescription of Guang:
N-acetylcystein 4000g
Monoammonium glycyrrhizinate 40g
Glucose 12500g
Water for injection adds to 250000ml
Prepare 1000 bottles altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) N-acetylcystein is added in the water for injection of dosing amount 50% the heated and stirred dissolving fully.Kurarinone (or tiopronin or monoammonium glycyrrhizinate) is added a small amount of water for injection heated and stirred dissolving.Merge above-mentioned solution, benefit adds to the full amount of water for injection.Glucose is complete with the water for injection dissolving of dosing amount 40%, heated and boiled 15 minutes.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 250ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 4 drug composition oral liquid agent of the present invention
The bitter composition prescription of Guang:
N-acetylcystein 4000g
Kurarinone 400g
Polyoxyethylene sorbitan monoleate 100g
Sodium benzoate 15g
Stevioside 20g
Essence 15g
Purified water adds to 20000ml
Prepare 2000 altogether
Guang sulfur composition prescription:
N-acetylcystein 4000g
Tiopronin 10g
Polyoxyethylene sorbitan monoleate 50g
Sodium benzoate 10g
Stevioside 20g
Essence 15g
Purified water adds to 20000ml
Prepare 2000 altogether
The sweet composition prescription of Guang:
N-acetylcystein 4000g
Monoammonium glycyrrhizinate 40g
Polyoxyethylene sorbitan monoleate 80g
Sodium benzoate 8g
Stevioside 4g
Essence 15g
Purified water adds to 20000ml
Prepare 2000 altogether
Preparation technology:
1) polyoxyethylene sorbitan monoleate is added dosing amount 50% purified water dissolving fully, add N-acetylcystein again, kurarinone (or tiopronin or monoammonium glycyrrhizinate) heating for dissolving is complete.
2) sodium benzoate, essence and stevioside is complete with the water dissolution of dosing amount 20%.
3) merge above-mentioned solution, add purified water water to full dose.
4) filtering with microporous membrane of mistake 0.8um.
5) semi-finished product chemical examination.
6) fill.Finished product is examined entirely, the packing warehouse-in.
Claims (10)
1. pharmaceutical composition is characterized in that said composition contains the medicine of acceptable salt and at least a treatment hepatopathy on the acetylcysteine of effective dose or its materia medica.
2. pharmaceutical composition as claimed in claim 1 is characterized in that the medicine of wherein treating hepatopathy is selected from: kurarinone, tiopronin or glycyrrhizic acid monoammonium.
3. pharmaceutical composition as claimed in claim 1, it is characterized in that said composition comprises the crude drug of following parts by weight: acceptable salt is 400～40000 parts on acetylcysteine or its materia medica, the medicine of treatment hepatopathy is different and different according to medicine, for kurarinone is 40～4000 parts, for tiopronin is 1～100 part, is 4～400 parts for glycyrrhizic acid monoammonium.
4. pharmaceutical composition as claimed in claim 3, it is characterized in that said composition comprises the crude drug of following parts by weight: acceptable salt is 1000～8000 parts on acetylcysteine or its materia medica, the medicine of treatment hepatopathy is different and different according to medicine, for kurarinone is 80～2000 parts, for tiopronin is 2～50 parts, is 8～200 parts for glycyrrhizic acid monoammonium.
5. pharmaceutical composition as claimed in claim 4, it is characterized in that said composition comprises the crude drug of following parts by weight: acceptable salt is 4000 parts on acetylcysteine or its materia medica, the medicine of treatment hepatopathy is different and different according to medicine, for kurarinone is 400 parts, for tiopronin is 10 parts, is 40 parts for glycyrrhizic acid monoammonium.
6. pharmaceutical composition as claimed in claim 4 is characterized in that said composition comprises the crude drug of following parts by weight: acceptable salt is 4000 parts on acetylcysteine or its materia medica, 400 parts of kurarinones.
7. pharmaceutical composition as claimed in claim 4 is characterized in that said composition comprises the crude drug of following parts by weight: acceptable salt is 4000 parts on acetylcysteine or its materia medica, 10 parts of tiopronins.
8. pharmaceutical composition as claimed in claim 4 is characterized in that said composition comprises the crude drug of following parts by weight: acceptable salt is 4000 parts on acetylcysteine or its materia medica, 40 parts of glycyrrhizic acid monoammoniums.
9. as the described arbitrary pharmaceutical composition of claim 1～8, it is characterized in that acceptable salt is machine nitrogen salt, hydrochlorate, sulfate, acetate, mesylate, tartrate, maleate, fumarate, hydrobromate, aspartate on described acetylcysteine or its materia medica.
10. as the described arbitrary pharmaceutical composition of claim 1～8, it is characterized in that this pharmaceutical composition can be made clinically any or pharmaceutically acceptable dosage form with mixing acceptable accessories.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610043505A CN100584327C (en) | 2006-04-07 | 2006-04-07 | Medication composition in use for treating liver disease |
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| CN200610043505A CN100584327C (en) | 2006-04-07 | 2006-04-07 | Medication composition in use for treating liver disease |
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| CN200610043505A Expired - Fee Related CN100584327C (en) | 2006-04-07 | 2006-04-07 | Medication composition in use for treating liver disease |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822686B (en) * | 2010-02-02 | 2012-04-18 | 邓学峰 | Cefpirome sulfate combined drug |
| CN104524546A (en) * | 2014-12-18 | 2015-04-22 | 中国科学院广州生物医药与健康研究院 | Pharmaceutical composition for treating Alpers-Huttenlocher syndrome |
-
2006
- 2006-04-07 CN CN200610043505A patent/CN100584327C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101822686B (en) * | 2010-02-02 | 2012-04-18 | 邓学峰 | Cefpirome sulfate combined drug |
| CN104524546A (en) * | 2014-12-18 | 2015-04-22 | 中国科学院广州生物医药与健康研究院 | Pharmaceutical composition for treating Alpers-Huttenlocher syndrome |
| CN104524546B (en) * | 2014-12-18 | 2019-06-21 | 中国科学院广州生物医药与健康研究院 | For treating the pharmaceutical composition of Alpers-Huttenlocher syndrome |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100584327C (en) | 2010-01-27 |
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