CN102008534A

CN102008534A - Antitubercular pharmaceutical composition containing balloonflower root extract

Info

Publication number: CN102008534A
Application number: CN 201010560916
Authority: CN
Inventors: 张瑶纾; 吴志丽; 周晶
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-11-26
Filing date: 2010-11-26
Publication date: 2011-04-13
Anticipated expiration: 2030-11-26
Also published as: CN102008534B

Abstract

The invention relates to an antitubercular pharmaceutical composition containing balloonflower root extract, which is prepared from the components of 0.1-100 parts of balloonflower root extract by weight and 1 part of antitubercular drug by weight through the steps as follows: extracting the balloonflower root extract for three times by water or extracting the balloonflower root extract for three times by 40-95% ethanol at the temperature of 90 DEG C, and concentrating, wherein the weight measurement ratio of the balloonflower root extract to the water is 1:(6-10), and the weight measurement ratio of the balloonflower root extract to the ethanol is 1:(5-15). The pharmaceutical composition in the invention has the functions of enriching the antitubercular drugs in lung tissues and improving the potency of the antitubercular drugs for curing phthisis as compared with single antitubercular drugs, and simultaneously has the positive effects such as reducing the liver injury caused by the antitubercular drugs and the like. By utilizing he pharmaceutical composition, the phthisis therapeutic window of the antitubercular drugs can be amplified, and the capability of effectively killing tubercle bacillus is enhanced, thereby increasing the potency, shortening the treatment cycle and lowering the possibility of tolerance of tubercle bacillus.

Description

A kind of antitubercular agent compositions that contains Radix Platycodonis extract

Technical field

The invention belongs to the Chinese medicine technical field of medicine, relate to the application that Chinese medicine Radix Platycodonis extract and antituberculotics are combined in field of medicaments.A kind of antitubercular agent compositions that contains Radix Platycodonis extract of saying so more specifically.

Background technology

Pulmonary tuberculosis is a kind of human infectious disease, and according to the statistics made by the departments concerned, China recent years has millions of human activity pulmonary tuberculosis patients.In a single day pulmonary tuberculosis is caught, some people is not healed all the life, and general state of an illness therapeutic process is wanted more than half a year at least.At present, still belonging to commonly encountered diseases, frequently-occurring disease in China's pulmonary tuberculosis, is one of ill crowd's ten big dead causes of disease of China.

The tuberculosis chemotherapy is to the control decisive role of tuberculosis, and reasonably chemotherapy can make focus all sterilize, fully recover.Antituberculotics commonly used has isoniazid, rifampicin, pyrazinamide, para-aminosalicylic acid etc.But, and limited their application because antitubercular agent all has stronger hepatotoxicity.Because can not kill tubercule bacillus effectively, use antituberculotics clinically and must continue 6-24 month treatment lungy, even the several years, its result causes the drug resistance of tulase.This is the reason why pulmonary tuberculosis is difficult to cure.

Radix Platycodonis is conventional Chinese medicine, derives from the dry root of campanulaceae Platycodon grandiflouorum (Platycodon grandif lorum Jacq.) A.DC..Traditional Chinese medicine theory is thought Radix Platycodonis nature and flavor hardship, suffering, flat, returns lung meridian, and lung qi dispersing gas is arranged out, and the effect of the evacuation of pus of eliminating the phlegm is used for the treatment of the exogenous cough, laryngopharynx swelling and pain, and lung abscess is spat, fullness in the chest costalgia, diseases such as dysentery stomachache.Modern pharmacology studies show that: Radix Platycodonis has antitussive, eliminates the phlegm, antiinflammatory, gastric acid inhibitory secretion and anti-gastric-ulcer, calmness, analgesic, analgesia, blood sugar lowering, blood fat reducing, cholesterol reducing, multiple efficacies such as antibiotic and anticancer.But itself and antituberculotics coupling are used for phthisical treatment yet there are no document record or report.

Summary of the invention

The object of the present invention is to provide the compositions of a kind of Radix Platycodonis extract and antituberculotics to be used for the treatment of pulmonary tuberculosis.

Technical scheme of the present invention is as follows:

A kind of antitubercular agent compositions that contains Radix Platycodonis extract is characterized in that it is made up of 0.1～100 part of Radix Platycodonis extract of parts by weight and 1 portion of antituberculotics.

The ratio of preferred Radix Platycodonis extract and 1 part of antituberculotics isoniazid is 1-40: 1;

The ratio of preferred Radix Platycodonis extract and 1 part of antituberculotics rifampicin is 0.5-30: 1;

The ratio of preferred Radix Platycodonis extract and 1 part of antituberculotics pyrazinamide is 0.5-20: 1.

Preferred Radix Platycodonis extract and 1 part of para-aminosalicylic ratio of antituberculotics are: 0.2-5: 1

Pharmaceutical composition of the present invention, wherein the ratio of weight and number of Radix Platycodonis extract and antituberculotics is 0.2-50: 1

Pharmaceutical composition of the present invention, antituberculotics wherein are isoniazid, rifampicin, pyrazinamide or para-aminosalicylic acid.

Pharmaceutical composition of the present invention, wherein said Radix Platycodonis extract are to be 1 with w/v: 6-10 water is carried 3 times, or is 1 with w/v: 90 ℃ of the 40-95% ethanol of 5-15, extract 3 times, and concentrate and make.

Pharmaceutical composition of the present invention, compositions wherein are capsule, tablet, pill, granule, oral liquid, syrup, electuary, powder or injection.

Described raw material Radix Platycodonis of the present invention, derive from the raw material of any one plant of campanulaceae Platycodon grandiflouorum (Platycodon grandif lorum Jacq.) as extract, it can be commercially available Radix Platycodonis decoction pieces, also can be any part such as root, underground rhizome, stem, leaf, spica, fruit of these plants or whole plant, wherein preferred medical material position be the dry root of these plants.Above-mentioned described Radix Platycodonis comprises without crude drug in any process of preparing Chinese medicine place and decoction pieces, also comprises the various processed products through concocting.

The preparation technology of extract of the present invention can adopt following any one method, or the combination in any of these methods is prepared: adopt solvent extraction method, solvent extraction, macroporous adsorbent resin method, ultrasonic extraction, supercritical extraction, microwave extraction method, chromatography etc.

Use these methods to be prepared to be the combination in any that generally comprises following step or all:

Extract: solvent for use can be water or any one alcohols, ketone and esters solvent thereof, or the mixed solvent formed by a certain percentage of these solvents, or the acidity or the basic solvent that are made into by these solvents and acid, alkali, salt; Extracting method can be decoction, reflux, supersound extraction, microwave extraction, merceration, percolation, pressurised extraction etc.

Preferred technology is: the Radix Platycodonis medical material adds water or 40-95% ethanol, backflow or supersound extraction 3-4 time, and each 1-2 hour, the volume consumption was that 5-15 doubly measures (L/kg).

Filter: comprise centrifugal, sucking filtration, ultrafiltration, use or do not use clarifier: precipitate with ethanol, gelatin, Kaolin, chitosan, natural clarifying agent etc.

Concentrate: comprise thin film evaporation, rotary evaporation and decocting and concentrating etc. under normal pressure or the reduced pressure

Dry: as to comprise vacuum drying, spray drying, lyophilization etc.

Radix Platycodonis extract of the present invention is characterized in that in institute under the chromatographic condition, the main chromatographic peak number of HPLC is for (with the Platycodin D is object of reference, its t _RBeing 61 ± 0.69) table 3 gives 14 15%-100% in the chromatographic peak.Chromatographic condition is:

C18 post (250mm * 4.6mm 5 μ m), 30 ℃ of column temperatures; Mobile phase is (A) 0.05mol/L phosphate aqueous solution, (B) acetonitrile, gradient elution; Flow velocity 0.5ml/min detects wavelength 210nm, record 90min, and the gradient elution program sees Table 1, and equilibrium code sees Table 2.

Table 1 gradient elution program

Time (min)	Mobile phase (A)	Mobile phase (B)
			0	96	4
20	85	15
			35	77	23
40	72	28

55	72	28
			65	60	40
80	10	90

Table 2 equilibrium gradient elution program

Time (min)	Mobile phase (A)	Mobile phase (B)
			0	10	90
2	96	4
			22	96	4

Table 3HPLC chromatographic peak appearance time (t _R) comprising:

1	2	3	4	5	6	7
							5.43min	9.23min	18.87min	26.58min	33.82min	45.01min	50.91min
8	9	10	11	12	13	14
							52.11min	57.15min	60.12min	61.02min	61.72min	65.70min	69.0min

The present invention further discloses pharmaceutical composition and concentrate to lung tissue, improve the application of antituberculotics drug effect aspect at preparation treatment guiding antituberculotics.

The present invention also discloses the application of pharmaceutical composition aspect the caused liver injury medicament of preparation treatment reduction antituberculotics simultaneously.Wherein said Radix Platycodonis extract is to be 1 with w/v: 6-10 water is carried 3 times, or is 1 with w/v: 90 ℃ of the 40-95% ethanol of 5-15, extract 3 times, and concentrate and make.

Antitubercular agent compositions of the present invention has following function:

1, has the guiding antituberculotics and concentrate, improve the effect of antituberculotics drug effect to lung tissue.

2, reduce the caused hepatic injury of antituberculotics.

3, pharmaceutical composition of the present invention can make the tuberculosis treatment window of antituberculotics increase, and improves the ability of effectively killing tubercule bacillus, and then increases drug effect, shortening treatment cycle, reduces the generation of Mycobacterium tuberculosis drug-resistant.

4, the compositions of Radix Platycodonis extract of the present invention and antituberculotics, have and separately relatively make the effect of antituberculotics enrichment in lung tissue with antitubercular agent, take compositions and compare with independent use antituberculotics, the drug level in peak time point lung tissue can improve 5-90%.Simultaneously, it is little to hepar damnification with using the antitubercular agent comparison separately for the compositions of Radix Platycodonis extract of the present invention and antituberculotics.

The present invention makes above-mentioned dosage form respectively with Radix Platycodonis extract and antituberculotics, and administering drug combinations is used, or compositions is made above-mentioned dosage form use, or takes Radix Platycodonis extract separately after several days, again with the antituberculotics coupling.

Be pharmacological experiment of the present invention and data below,

1, experiment material

1.1 medicine and reagent

Isoniazid, rifampicin, pyrazinamide, para-aminosalicylic acid standard substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute)

Radix Platycodonis (available from Tianjin medical material company, by the teaching and research evaluation of this school Natural Medicine Chemistry) is the dry root decoction pieces of Radix Platycodonis.Getting Radix Platycodonis 10g, is solvent with water (or ethanol), solid-liquid ratio 1: 10,1: 8,1: 6, and water-bath reflux, extract, 3 times, each 1.0h, sucking filtration while hot after each the backflow, filtrate merges, and concentrated postlyophilization gets extract.Before the experiment medicine is made into the desired concn solution for standby with water dissolution.

Laboratory animal: wistar rat (200 ± 20) g; Kunming mouse (20 ± 2) g; Male and female half and half (available from Test Animal Centre, Academy of Military Medical Sciences, P.L.A, credit number: the 2007-004 of SCXK-army)

2. experimental technique and result

2.1 Radix Platycodonis and antituberculotics share the influence that tuberculosis medicine lung tissue of rats is distributed

Get the wistar rat and be divided into matched group and experimental group.Normal feed water inlet was raised 3 days before administration.Investigate Radix Platycodonis and antituberculotics isoniazid, rifampicin, pyrazinamide, para-aminosalicylic acid respectively and share the influence that it is distributed in lung tissue of rats.Matched group is irritated stomach respectively and is given isoniazid (50mgkg ^-1D ^-1), rifampicin (65mgkg ^-1D ^-1), pyrazinamide (165mgkg ^-1D ^-1), para-aminosalicylic acid (1.08gkg ^-1D ^-1).Experimental group is irritated stomach respectively and is given the aqueous solution of Radix Platycodonis extract and isoniazid, rifampicin, pyrazinamide, para-aminosalicylic acid, administration concentration 0.5,1.0,3.0g/kg in this experiment.Behind the continuous irrigation stomach 30 days, get after lung tissue of rats handles, measure peak time point lung tissue experimental group and matched group drug level, compare.

2.1.1. Radix Platycodonis water extract and isoniazid share: the peak time of isoniazid in lung tissue is 1.0h, relatively sees Table 4 at peak time point experimental group and matched group drug level

Chromatographic condition: chromatographic column: C18 mobile phase: potassium dihydrogen phosphate (0.05moL/L, pH6.5): methanol=65: 35; Flow velocity 1.0mLmin ^-1λ=340nm; Standard curve: A=63657C-12169

Table 4 Radix Platycodonis water extract and isoniazid share lung tissue Chinese medicine concentration ratio

(n=10)

* represent p＜0.01 experimental group and matched group comparison and statistical significance

As shown in Table 4, compare with matched group, isoniazid concentration is higher than matched group in the experimental group lung tissue.Show that Radix Platycodonis can guide antituberculotics to concentrate to lung tissue.

2.1.2 Radix Platycodonis water extract and rifampicin share: the peak time of rifampicin in lung tissue is 2.0h, sees Table 5 at peak time point experimental group and matched group drug level comparative result.

Chromatographic condition: mobile phase: methanol: acetonitrile: potassium dihydrogen phosphate (0.05moL/L)=50: 20: 30; Flow velocity 1.0mLmin-1; λ=254nm; Standard curve: A=673500C-99450

Table 5 Radix Platycodonis water extract and rifampicin share lung tissue Chinese medicine concentration ratio

(n=10)

As shown in Table 5, with matched group relatively, rifampicin concentration is higher than matched group guiding antituberculotics and concentrates to lung tissue in Radix Platycodonis concentration 2.5, the 4.0g/kg experimental group lung tissue.

2.1.3. Radix Platycodonis 95% ethanol extract and pyrazinamide share: the peak time 3.0h of pyrazinamide in the lung tissue sees Table 6 at peak time point experimental group and matched group drug level comparative result.

Chromatographic condition: acetonitrile: 0.02moL/L Ammonium biphosphate=2: 98, λ=263nm standard curve: A=78302C+55044

Table 6 Radix Platycodonis ethanol extract and pyrazinamide share lung tissue Chinese medicine concentration ratio

(n=10)

As shown in Table 6, with matched group relatively, rifampicin concentration is higher than matched group guiding antituberculotics and concentrates to lung tissue in the experimental group lung tissue.

2.1.4. Radix Platycodonis 40% ethanol extract and para-aminosalicylic acid share: para-aminosalicylic peak time 2.0h in the lung tissue sees Table 7 at peak time point experimental group and matched group drug level comparative result.

Chromatographic condition: mobile phase: 0.01moL/L phosphoric acid: methanol=78: 22, λ=279nm standard curve: A=18997C+3754

Table 7 Radix Platycodonis 40% ethanol extract and para-aminosalicylic acid share lung tissue Chinese medicine concentration ratio

(n=10)

As shown in Table 7, with matched group relatively, rifampicin concentration is higher than matched group guiding antituberculotics and concentrates to lung tissue in the experimental group lung tissue.

2.2 pharmacodynamics test

The water extract of Radix Platycodonis and the chromatographic peak of ethanol extract are not more found significantly different, therefore, below the water extract of Radix Platycodonis is all adopted in experiment.

Radix Platycodonis is tested the treatment of mouse experiment tuberculosis:

1. animal and grouping: use Kunming mouse, body weight 18g-20g, male and female half and half, random packet, 20 every group.

2. infect: be taken at the culture of the mycobacterium hominis H37RV in two weeks of growth on the modified Russell medium, wear into the even bacteria suspension (the sterile saline solution that contains 0.05% Tween 80) of 5mg/ml, in every mouse tail vein, inject 0.2ml with agate mortar.

3. administration: rifampicin is made suspension with 0.5%CMC, the isoniazid dissolved in distilled water, and Radix Platycodonis extract+rifampicin is made suspension with 0.5%CMC, Radix Platycodonis extract+isoniazid dissolved in distilled water, all gastric infusion.Each administration group (feedwater of blank group) is in the 2nd day beginning gastric infusion every day that infects 1 time, till the dead half of blank group.

4. observation index: in time write down each treated animal death toll, treat that animal finishes experiment when all dead, try to achieve the half animals survived time (ST50) of each group, and carry out statistical procedures and the results are shown in Table 8

Table 8 pharmacodynamic experiment result

# represents P＜0.01

Annotate: molecule and branch alphameric are respectively the dosage of isoniazid and rifampicin in the compound recipe in the bracket

On behalf of P＞0.05#, "-" represent P＜0.01

1. 0.02 group of isoniazid+Radix Platycodonis (0.02+20) group and isoniazid are than P＜0.01

2. 0.02 group of isoniazid+Radix Platycodonis (0.02+30) group and isoniazid are than P＜0.01

3. 0.03 group of rifampicin+Radix Platycodonis (0.03+20) group and rifampicin are than P＜0.01

4. 0.03 group of rifampicin+Radix Platycodonis (0.03+30) group and rifampicin are than P＜0.01

The result shows: 1. under this experiment condition, single with isoniazid (INH) 0.02mg/ only and single during with 0.03mg/ of rifampicin, all do not show the tuberculosis activity.2. when Radix Platycodonis water extract dosage be 20mg/ only, during 30mg/, all do not show the tuberculosis activity.2. the RFP of INH of ineffective dose (0.02mg/ only) and ineffective dose (0.03mg/ only) respectively with Radix Platycodonis decoction liquor 20mg/, when 30mg/ only makes up, can prolong the half animals survived time significantly (P＜0.01).And increase half animals survived time lengthening with the Radix Platycodonis amount

2.3 liver protection experiment

2.3.1 Radix Platycodonis causes the protective effect experiment of Mouse Liver infringement to isoniazid

Heavy (18 ± 2) g of Kunming mouse, every group of 10 mices.According to isoniazid (INH) 0.1gkg ^-1d ^-1Radix Platycodonis group (quite medical material) 2.0gkg ^-1Gastric infusion is grouped as follows:

1. blank group

2. the isoniazid administration was placed 7 days (modeling group) after 7 days

3. the isoniazid administration was given Radix Platycodonis 7 days (treatment group) after 7 days

4. the administration simultaneously of isoniazid and Radix Platycodonis was placed 7 days (prevention group) after 7 days

Mouse orbit is got blood and is surveyed ALT in the blood, the activity of AST, gets hepatic tissue, measures the content of SOD, GSH and MDA in the liver homogenate, and observes the hepatopathy reason.

2.3.1.1 Radix Platycodonis causes the influence of ALT, AST in the hepatic injury mice serum to isoniazid, the results are shown in Table 9,10

Table 9 Radix Platycodonis causes the influence of ALT in the hepatic injury mice serum to isoniazid

Table 10 Radix Platycodonis causes the influence of AST in the hepatic injury mice serum to isoniazid

* represent that modeling group and blank group compare p＜0.05 # and represent to compare p＜0.05 with the modeling group

ALT: prevention group and treatment group be p＞0.05 AST relatively: prevention group and treatment group be p＞0.05 relatively

By table 9,10 as can be known isoniazid under finite concentration, can cause ALT, AST in the mice serum obviously to increase.Can play the effect that prevention the isoniazid ALT, the AST that cause increase after Radix Platycodonis and isoniazid share, reduce the hepatic injury that isoniazid causes.

2.3.1.2 Radix Platycodonis causes the influence of GSH, MDA, SOD in the hepatic injury murine liver tissue to isoniazid, the results are shown in Table 11,12

Table 11 Radix Platycodonis causes the influence of GSH in the hepatic injury murine liver tissue to isoniazid

Table 12 Radix Platycodonis causes the influence of MDA in the hepatic injury murine liver tissue to isoniazid

Table 13 Radix Platycodonis causes the influence of SOD in the hepatic injury murine liver tissue to isoniazid

* expression is compared with the normal control group, and there is statistical significance P＜0.05

# represents to compare with model control group, and there is statistical significance P＜0.05

By table 11,12,13 as can be known isoniazid under finite concentration, can reduce GSH, the SOD in the murine liver tissue, the MDA in the rising murine liver tissue.Can play GSH, the SOD reduction that the prevention isoniazid causes after Radix Platycodonis and isoniazid share, the effect that MDA raises reduces the hepatic injury that isoniazid causes.

2.3.2 Radix Platycodonis causes the protective effect experiment of Mouse Liver infringement to rifampicin

Heavy (18 ± 2) g of Kunming mouse, every group of 10 mices.According to rifampicin 0.1gkg ^-1d ^-1Radix Platycodonis group 2.0gkg ^-1Irritate stomach, be grouped as follows:

1. blank group

2. the rifampicin administration was placed 7 days (modeling group) after 7 days

3. the rifampicin administration was given Radix Platycodonis 7 days (treatment group) after 7 days

4. the administration simultaneously of rifampicin and Radix Platycodonis was placed 7 days (prevention group) after 7 days

2.3.2.1 Radix Platycodonis causes the influence of ALT, AST in the hepatic injury mice serum to rifampicin, the results are shown in Table 14,15

Table 14 Radix Platycodonis causes the influence of ALT in the hepatic injury mice serum to rifampicin

Table 15 Radix Platycodonis causes the influence of AST in the hepatic injury mice serum to rifampicin

* represent that modeling group and blank group compare P＜0.05

By table 14,15 as can be known rifampicin under finite concentration, can cause ALT, AST in the mice serum obviously to increase.Can play the effect that prevention the rifampicin ALT, the AST that cause increase after Radix Platycodonis and rifampicin share, reduce the hepatic injury that rifampicin causes.

2.3.2.3 Radix Platycodonis causes the influence of GSH, MDA, SOD in the hepatic injury murine liver tissue to rifampicin, the results are shown in Table 16,17,18

Table 16 Radix Platycodonis causes the influence of GSH in the hepatic injury murine liver tissue to rifampicin

Table 17 Radix Platycodonis causes the influence of MDA in the hepatic injury murine liver tissue to rifampicin

Table 18 Radix Platycodonis causes the influence of SOD in the hepatic injury murine liver tissue to rifampicin

* represent that modeling group and blank group compare P＜0.05

# represents with the modeling group statistical significance P＜0.05 is arranged relatively

By table 16,17,18 as can be known rifampicin under finite concentration, can reduce GSH, the SOD in the murine liver tissue, the MDA in the rising murine liver tissue.Can play GSH, the SOD reduction that the prevention rifampicin causes after Radix Platycodonis and rifampicin share, the effect that MDA raises reduces the hepatic injury that rifampicin causes.

2.3.3 Radix Platycodonis causes the protective effect experiment of mouse liver injury to isoniazid, rifampicin

Heavy (18 ± 2) g of Kunming mouse, every group of 10 mices.According to isoniazid (INH)+each 0.1gkg of rifampicin (RFP) ^-1d ^-1, Radix Platycodonis low dose group 1.5gkg ^-1d ^-1, dosage group 2.0gkg in the Radix Platycodonis ^-1Radix Platycodonis high dose group 2.5gkg ^-1d ^-1Irritate stomach, mouse orbit is got blood and is surveyed ALT in the blood, the activity of AST, gets the content that hepatic tissue is measured SOD, GSH and MDA in liver index and the liver tissue homogenate, and observes the hepatopathy reason.

2.3.3.1 Radix Platycodonis the results are shown in Table 19 to the exponential influence of hepatic injury Mouse Liver due to isoniazid+rifampicin

Table 19 Radix Platycodonis is to the exponential influence of hepatic injury Mouse Liver due to isoniazid+rifampicin

* expression is compared with the normal control group, and there is statistical significance P＜0.05;

# represents to compare with model control group, and there is statistical significance P＜0.05.

2.3.3.2 Radix Platycodonis the results are shown in Table 20,21 to the influence of ALT, AST in the hepatic injury mice serum due to isoniazid+rifampicin

Table 20 Radix Platycodonis is to the influence of hepatic injury mice ALT due to isoniazid+rifampicin

Table 21 Radix Platycodonis is to the influence of hepatic injury mice AST due to isoniazid+rifampicin

Isoniazid, rifampicin share ALT, the AST that can cause in the mice serum and obviously increase under finite concentration as can be known by table 20,21.Can play the effect that ALT, AST that prevention isoniazid, rifampicin cause increase after Radix Platycodonis and isoniazid, rifampicin share, reduce the hepatic injury that isoniazid, rifampicin cause.

2.3.3.3 Radix Platycodonis share the influence that causes GSH, MDA, SOD in the hepatic injury murine liver tissue to isoniazid, rifampicin, the results are shown in Table 22,23,24

Table 22 Radix Platycodonis is to the influence of hepatic injury mice MDA due to isoniazid+rifampicin

Table 23 Radix Platycodonis is to the influence of hepatic injury SOD in Mice due to isoniazid+rifampicin

Table 24 Radix Platycodonis is to the influence of hepatic injury mice GSH due to isoniazid+rifampicin

Annotate: * represents to compare with the normal control group, and there is statistical significance P＜0.05;

Isoniazid, rifampicin share GSH, the SOD that can reduce in the murine liver tissue, the MDA in the rising murine liver tissue under finite concentration as can be known by table 22,23,24.Can play the GSH, the SOD that prevent isoniazid, rifampicin to cause after Radix Platycodonis and isoniazid, rifampicin share and reduce, the effect that MDA raises, the hepatic injury that reduction isoniazid, rifampicin cause.

2.3.3.4 Radix Platycodonis the results are shown in Table 25 to the influence of hepatic injury mice pathology due to isoniazid+rifampicin

Table 25 Radix Platycodonis is to the influence of hepatic injury mice pathology due to isoniazid+rifampicin

+ represent slight cloudy swelling; ++ represent that the degeneration of most of cell cloudy swelling increases the weight of; +++expression has the point-like necrotic lesion and sees inflammatory cell infiltration

Experimental result:

Compare with the normal control group, the activity of model group Mouse Liver index, Serum ALT and AST, the content of MDA all significantly increases (P＜0.05) in the liver homogenate, and the content of GSH and SOD all significantly reduces (P＜0.05) in the liver homogenate, and the hepatic pathology degree of injury increases the weight of that statistical significance is arranged (P＜0.05).

Compare with model group, the content that the middle and high dosage group of Radix Platycodonis mouse liver index significantly reduces MDA in the activity, liver homogenate of (P＜0.05), the high, medium and low dosage group of Radix Platycodonis mice serum ALT, AST reduces significantly that the content of SOD and GSH significantly increases (P＜0.05) in (P＜0.05), the middle and high dosage group of the Radix Platycodonis mouse liver even slurry, and the alleviating of pathology damage degree of mouse liver has statistical significance (P＜0.05) simultaneously.

The murine liver tissue pathological section

More blank group, matched group, experimental mice hepatic tissue pathology section (seeing Fig. 2-4)

By the disorder of pathological section modeling group as can be known hepatic cords, swelling of liver cell, accidental vacuolar degeneration of hepatic cell.The experimental group hepatocyte is arranged more neat, and swelling is not obvious, but indivedual hepatocyte still sees vacuolar degeneration.

2.4 median lethal dose(LD 50) experiment

Get 140 of Kunming mouses, be divided into 10 every group of experimental and control groups.Experimental group gastric infusion Radix Platycodonis (quite medical material 2.0g/kg), matched group feedwater, gastric infusion pneumoretroperitoneum injection in 7 days INH.

Get matched group according to preliminary experiment: LD ₀=130mg/kg, LD ₁₀₀=355mg/kg

Experimental group: LD ₀=150mg/kg, LD ₁₀₀=355mg/kg

Matched group:

According to D _n=D _N-1* 1.182, the dosage that obtains 1,2,3,4,5,6,7 group INH is 130,153.66,181.63,214.68,253.75,299.94 respectively, 354.53mg/kg.

Experimental group:

According to D _n=D _N-1* 1.154, the dosage that obtains 1,2,3,4,5,6,7 group INH is 150,173.1,199.76,230.52,266.02,306.99 respectively, 354.26mg/kg.The results are shown in Table 26

Table 26 median lethal dose(LD 50) experimental result

As shown in Table 26, the dead number of elements of experimental mice is less than matched group, and Radix Platycodonis can make the median lethal dose(LD 50) value of isoniazid raise, and increases the scope of medication of isoniazid.

Description of drawings:

Fig. 1 is a Radix Platycodonis D infared spectrum;

Fig. 2 is blank group (normally) murine liver tissue pathological section;

Fig. 3 is model control group (isoniazid+rifampicin) murine liver tissue pathological section;

Fig. 4 is experimental group (Radix Platycodonis adds an isoniazid+rifampicin) murine liver tissue pathological section.

The specific embodiment

Below, foregoing of the present invention is elaborated, should not be construed as the above-mentioned subject area of the present invention and only limit to following example by the specific embodiment of embodiment form.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.

Embodiment 1:

Radix Platycodonis medical material 200g is a solvent with 80% ethanol, solid-liquid ratio 1: 10,1: 8,1: 6,90 ℃ of water-bath reflux, extract, 3 times, each 1.0h, sucking filtration while hot after each the backflow, filtrate merges, concentrate extractum 82.2g.

Embodiment 2:

Precision takes by weighing Radix Platycodonis medical material 200g, adds 50% ethanol solid-liquid ratio 1: 8, and supersound extraction 30min extracts 3 times, and merging filtrate concentrates, and lyophilization gets extract 61.8g.

Embodiment 3:

Precision takes by weighing Radix Platycodonis medical material 20g, adds 95% ethanol solid-liquid ratio 1: 10, and supersound extraction 30min extracts 3 times, and merging filtrate concentrates, and lyophilization gets extract 66.9g.

Embodiment 4:

Precision takes by weighing Radix Platycodonis medical material 200g, and in 100 ℃ of water boiling and extraction medical materials 3 times, medicinal liquid extracted 1h than 1: 6 for the first time, and medicinal liquid is than 1: 8 dose of extraction 1h for the second time, and medicinal liquid was than 1: 10 for the third time.Each extracts the 1h merging filtrate, concentrates, and lyophilization gets extract 84.48g.

Embodiment 5

With the extractum 50g that embodiment 1 method prepares, isoniazid 10g, sorbic acid 5g, sodium citrate 5g, essence 1mL, the suitable quantity of water mixing is made oral liquid, encapsulation.

Embodiment 6

Dry extract 50g with the preparation of embodiment 2 methods is attained the Way adds isoniazid 5g (or rifampicin 10g or pyrazinamide 18g or para-aminosalicylic acid 50g), HPMC39g, and lactose 70g, magnesium stearate 1g mixes the back tabletting.

Embodiment 7

Dry extract 50g with the preparation of embodiment 3 methods is attained the Way adds isoniazid 2.5 (or rifampicin 5g or pyrazinamide 9g or para-aminosalicylic acid 25g), starch 100g, and Pulvis Talci 5g, mixing incapsulates.

Embodiment 8

Dry extract 50g with the preparation of embodiment 2 methods is attained the Way is ground into fine powder and crosses 120 mesh sieves, adds isoniazid 5g (or rifampicin 10g or pyrazinamide 18g or para-aminosalicylic acid 50g), add the starch mixing, make pill, ventilation is dried in the shade, the bottling sealing.

Embodiment 9

Dry extract 50g with the preparation of embodiment 3 methods is attained the Way adds isoniazid 10g (or rifampicin 20g or pyrazinamide 36g or para-aminosalicylic acid 50g), cane sugar powder 680g, and dextrin 80g mixing is made granule, the sealing bottling.

Embodiment 10

Dry extract 50g with the preparation of embodiment 2 methods is attained the Way adds isoniazid 5g, rifampicin 10g, HPMC39g, and lactose 70g, magnesium stearate 1g mixes the back tabletting, gets the antituberculotics complex.

Obviously; according to foregoing of the present invention, according to the ordinary skill knowledge and the customary means of this area, under the prerequisite that does not break away from the above-mentioned basic fundamental thought of the present invention; can also make modification, replacement or the change of other various ways, the interest field that these also all belong to the present invention is protected.

Claims

1. antitubercular agent compositions that contains Radix Platycodonis extract is characterized in that it is made up of 0.1～100 part of Radix Platycodonis extract of parts by weight and 1 portion of antituberculotics.

2. right 1 described pharmaceutical composition, wherein the ratio of weight and number of Radix Platycodonis extract and antituberculotics is 1-50: 1.

3. right 1 described pharmaceutical composition, antituberculotics wherein is isoniazid, rifampicin, pyrazinamide or para-aminosalicylic acid.

4. right 1 described pharmaceutical composition, wherein said Radix Platycodonis extract are to be 1 with w/v: 6-10 water is carried 3 times, or is 1 with w/v: the 40-95% ethanol of 5-15,90 ℃ are extracted 3 times, concentrate to make.

5. right 1 described pharmaceutical composition, compositions wherein is capsule, tablet, pill, granule, oral liquid, syrup, electuary, powder or injection.

6. the described compositions of claim 1 concentrates to lung tissue at preparation treatment guiding antituberculotics, improves the application of antituberculotics drug effect aspect, and wherein 1-50 part Radix Platycodonis extract and 1 portion of antituberculotics are formed.

7. the application of the described compositions of claim 1 aspect the caused liver injury medicament of preparation treatment reduction antituberculotics, wherein 1-50 part Radix Platycodonis extract and 1 portion of antituberculotics are formed.

8. the application aspect the liver injury medicament that causes at preparation prevention antituberculotics of the described compositions of claim 1, wherein 1-50 part Radix Platycodonis extract and 1 part of antituberculotics composition.