CN101628046B - Medicine combination and application thereof in preparing preparations for treating chronic hepatitis B - Google Patents
Medicine combination and application thereof in preparing preparations for treating chronic hepatitis B Download PDFInfo
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Abstract
The invention relates to a medicine combination and the application thereof in preparing preparations for treating chronic hepatitis B. The combination comprises a medicine combination with polysaccharide nucleic acid of bacillus calmette guerin as the active component and a Chinese traditional medicine combination, wherein the Chinese traditional medicine combination is prepared from astragalus, herba artemisiae scopariae, oldenlandia diffusa, herba lysimachiae, codonopsis pilosula, processed polygonum capitatum, salvia, radix paeoniae alba, chinaberry fruit, taraxacum, cortex moutan, poria and atractylodes; the polysaccharide nucleic acid of bacillus calmette Guerin is nonspecific immunity active reinforcer, and can effectively restrain the reproduction of hepatitis virus and promote the rapid negative turning of HBV-DNA and HbeAg; and the Chinese traditional medicine combination has the efficacy of invigorating qi and spleen, promoting blood circulation by removing blood stasis and clearing away heat and toxic material. The medicine combination can reduce the incidence rate of variation and drug resistance and effectively promote the improvement under the condition of improving the healing efficacy, and provides a novel, safe and effective drug choice for clinics.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and the application in preparation treatment chronic hepatitis B preparation thereof.
Background technology
It is a global health problem that chronic hepatitis B (HBV) infects, the whole world estimates have 3.5 hundred million people to infect hepatitis B virus approximately, wherein 75% live in the Asian-Pacific area, in China 1.2 hundred million people being arranged approximately is hepatitis B virus carrierss, hepatitis B patient is 2,800 ten thousand, prevalence is up to 27,70/,100,000, and wherein, 1/3rd hepatitis B patient will develop into chronic hepatitis, liver cirrhosis or hepatocarcinoma.The whole world had 2,000,000 people to die from the viral hepatocarcinoma that causes approximately in 1998, and the death toll of China is 300,000 people, and World Health Organization (WHO) classifies hepatitis B as the world the ninth-largest cause of the death.And in a single day people infect hepatitis virus, just must take medicine for a long time, and annual China is at about 300-500 hundred million RMB of the medical expense of various viral hepatitis.
At present still do not having specific drug aspect the treatment of hepatitis B, generally adopting interferon and antiviral drugs to treat.The effect of interferon is the immunologic function that improves patient, resist the ability of disease with enhancing, but side effect is big.Most popular in anti-hepatic-B virus medicine is lamivudine, and the inhibitory action that this medicine is stronger to duplicating of hepatitis B virus can reduce the content of HBV-DNA in the blood samples of patients rapidly, and evident in efficacy, and side effect is little, and human body has good toleration to it.Though lamivudine curative effect aspect the treatment chronic viral hepatitis B is better, the patient uses for a long time and can produce the HBV sudden change, and the course of treatment is long more, and the variation incidence rate is high more, thereby produces drug resistance, makes the state of an illness repeatedly.
Summary of the invention
The purpose of this invention is to provide a kind of pharmaceutical composition and the application in preparation treatment chronic hepatitis B preparation thereof.Said composition is combined by the pharmaceutical composition and a kind of Chinese medicine composition that with the bcg-polysaccharides nucleic acid are active component, wherein, described Chinese medicine composition is made by the Radix Astragali, Herba Artemisiae Scopariae, Herba Hedyotidis Diffusae, Herba Lysimachiae, Radix Codonopsis, Radix Polygoni Multiflori Preparata, Radix Salviae Miltiorrhizae, the Radix Paeoniae Alba, Fructus Toosendan, Herba Taraxaci, Cortex Moutan, Poria, the Rhizoma Atractylodis Macrocephalae.
Above-mentioned is in the pharmaceutical composition of active component with the bcg-polysaccharides nucleic acid, and the form that bcg-polysaccharides nucleic acid joins in the said composition comprises common lyophilized powder, micropowder, solid dispersion, clathrate, microsphere, liposome or microgranule.
Above-mentioned is that the pharmaceutical composition of active component is made injectable powder, injection, spray, oral administration mixed suspension with the bcg-polysaccharides nucleic acid.
In the preferred embodiments of the present invention, above-mentioned is that the dosage form dosage made of the pharmaceutical composition of active component is for containing 0.5 milligram of bcg-polysaccharides nucleic acid with the bcg-polysaccharides nucleic acid.
In a preferred embodiment of the invention, above-mentioned Chinese medicine composition is made by the raw material of following weight portion: Radix Astragali 500-650 part, Herba Artemisiae Scopariae 500-650 part, Herba Hedyotidis Diffusae 350-450 part, Herba Lysimachiae 350-450 part, Radix Codonopsis 450-550 part, Radix Polygoni Multiflori Preparata 450-550g part, Radix Salviae Miltiorrhizae 450-550 part, Radix Paeoniae Alba 350-450 part, Fructus Toosendan 350-450 part, Herba Taraxaci 350-450 part, Cortex Moutan 350-450 part, Poria 350-450 part, Rhizoma Atractylodis Macrocephalae 350-450 part.
Chinese medicine composition of the present invention is an oral formulations.
Above-mentioned oral formulations is a granule.
In the preferred embodiments of the present invention, above-mentioned granule is a sugar-free granule, and its dosage is 3 grams.
In the preferred embodiments of the present invention, above-mentioned granule is the sugar-containing type granule, and its dosage is 17 grams.
The purposes of pharmaceutical composition of the present invention in the medicine of preparation treatment chronic hepatitis B.
Bcg-polysaccharides nucleic acid of the present invention is the polyoses nucleic acid preparation that extracts through hot phenol method from bacill calmette-guerin, contain that polyoses nucleic acid etc. is multiple to have an immunocompetent material, can strengthen the natural killer cell function and come the enhancing body resistance against diseases by the intravital cellular immunization of adjusting machine, humoral immunization, stimulation reticuloendothelial system, activated mononuclear-macrophage function; Stablize mast cell membrane, suppress mast cell degranulation and release medium; Stimulate body to produce IgG class blocking antibody, stop allergen to combine with specific IgE on the sensitization mast cell membrane, the performance antiallergic is renderd a service; Strengthen macrophage and NK cytoactive in the body, inducing interferon forms, so the effect that strengthens infection and antitumor cell growth is arranged.
Select for use QI invigorating such as the Radix Astragali to set upright in the Chinese medicine composition of the present invention, can regulate immunologic function, prevent that liver glycogen from reducing, and reduces the vigor of sero-enzyme, the liver protecting.Dampness removing jaundice eliminatings such as Herba Artemisiae Scopariae can suppress hepatitis B virus duplication, promote bile secretion and cholic acid, bilirubinic drainage, also can make gallbladder lipid content reduction in the bile; Blood circulation promoting and blood stasis dispelling such as Radix Salviae Miltiorrhizae can improve liver microcirculation, quicken the pathological changes reparation, and the protection hepatocyte promotes liver cell regeneration, and the while is function of gallbladder promoting again; Radix Paeoniae Alba nourishing blood to suppress the hyperactive liver, the soft liver spleen that contracts, Radix Paeoniae Alba glycosides can antiinflammatories, protect the liver, fall enzyme, can promote spleen lymphocyte proliferation simultaneously.Medicine-feeding becomes the rule of regulating QI spleen invigorating, nourishing the liver and kidney, function of gallbladder promoting heat clearing away, blood circulation promoting and blood stasis dispelling altogether.
Compositions of the present invention has regulates immunologic function, strengthens immunity to hepatitis B virus, suppresses hepatitis B virus duplication and prevent the liver injury effect, develops into the certain curative effect of having of liver cirrhosis, hepatocarcinoma to preventing chronic hepatitis B.
The specific embodiment
Below further specify the present invention by specific embodiment, embodiment only be used for the explanation, can not limit the scope of the invention.
Embodiment 1
Bcg-polysaccharides nucleic acid required for the present invention can obtain by the following method, but it will be appreciated by those skilled in the art that the preparation of bcg-polysaccharides nucleic acid includes, but are not limited to this method:
1) cultivation of bacill calmette-guerin and results
1. yeast culture: with dissolving under the strain of liquid sub preservation (Chinese bacillus calmette-guerin vaccine preparation with bacill calmette-guerin strain D2PB302, the Nat'l Pharmaceutical ﹠ Biological Products Control Institute) room temperature, be inoculated in the logical culture medium of Rhizoma Solani tuber osi Soviet Union, 37 ℃ continuous culture 14-20 days; Or 37 ℃ of continuous culture after 15 days transferred species in the logical culture medium of the liquid Soviet Union of improvement, 37 ℃ continuous culture 14-20 days.
2. microorganism collection: when treating thalli growth, after culture bottle checked by bottle, collect Mycoderma, add an amount of deionized-distilled water washing, weigh after pressing dry to logarithmic (log) phase.
2) preparation of bcg-polysaccharides nucleic acid mixture
1. bacterial cell disruption and hot phenol are handled: with the thalline the collected ratio adding purified water by 10: 1, smash the broken thalline of refiner (12000rpm/min) to pieces with tissue, 3min * 3 time, thalline is smashed to pieces, and then adding the hot phenol (30～100 ℃) of broken bacteria suspension 0.5-2.0 times volume, insulation is 30 minutes～1 hour in stirring at low speed.
2. the extraction of bcg-polysaccharides nucleic acid mixture: the mixed liquor natural sedimentation that hot phenol is good 1～10 day, draw supernatant, behind the tube centrifuge high speed centrifugation, supernatant filters through 0.45 μ m sterile filters, is the bcg-polysaccharides nucleic acid mixture.
3) preparation of refining BCG polysaccharide nucleic acid extractive
Can prepare BCG polysaccharide nucleic acid extractive by following two kinds of methods:
1. dialysis is made with extra care BCG polysaccharide nucleic acid extractive
The bcg-polysaccharides nucleic acid mixture manually packed into dialysed in the purified water of 100 times of volumes 7～10 days in the bag filter (molecular weight that dams＞5000 dalton), change purified water in the dialysis pond every day, every day is sampling Detection phenol residual quantity from bag filter.Add an amount of ethanol in the bcg-polysaccharides nucleic acid mixture that dialysis is good and make the alcohol amount 60～85% that contains, natural sedimentation is after 1～10 day, precipitate with dehydrated alcohol stir, centrifuge washing 3 times.After washing centrifugal 3 times with ether then, put to the exsiccator drying, drying was refining BCG polysaccharide nucleic acid extractive in 2～5 days.
2. the gel filtration chromatography method is made with extra care BCG polysaccharide nucleic acid extractive
The K-PRIME 40II gel chromatography filtration system that adopts U.S. Mi Libo (MILLIPORE) company to make carries out with the GH-25 gel media that bcg-polysaccharides nucleic acid, phenol and bacill calmette-guerin are proteic to be separated.Concrete preparation process is as follows:
(1) open main frame and monitoring computer, with system warm-up 20 to 30 minutes, and check pipeline, whether cylinder is unimpeded intact, whether has bubble.
(2) balance: with 0.9% normal saline with 1000mL/ minute through the post forward flow, finish equilibrium process when electric conductance, pH are consistent behind the post front pillar.
(3) go up sample: the bcg-polysaccharides nucleic acid mixture is gone up sample through last sample system, and last sample speed is 600mL/ minute.
(4) eluting: behind the end of the sample, carry out eluting with 0.9% normal saline with 800mL/ minute speed, adopt ultraviolet spectrometer (wavelength adopts 260nm or 280nm) to detect effluent, collect the purpose peak, the purpose peak of collecting is filtered by 0.45 μ m sterile filters, be refining bcg-polysaccharides nucleic acid extracting solution.
(5) clean: behind the eluting with water for injection to system clean before post, when electric connection is bordering on zero behind the post till.
Collected refining bcg-polysaccharides nucleic acid extracting solution is carried out precipitate with ethanol, in refining bcg-polysaccharides nucleic acid extracting solution, add medicinal alcohol and carry out precipitate with ethanol, contain the alcohol amount and be 70-75%.After the natural sedimentation 4 days, the collecting precipitation thing.Precipitate by dehydrated alcohol stir, centrifuge washing 3 times, wash centrifugal 3 times with ether then after, put to the exsiccator drying, dry thing is refining BCG polysaccharide nucleic acid extractive.
Embodiment 2
With the bcg-polysaccharides nucleic acid is the production method of the pharmaceutical composition injectable powder of active component, and writing out a prescription is:
Card Jie polyoses nucleic acid: 0.3g
Physiological sodium chloride solution (0.9%): 100ml
Get the common lyophilized powder D BCG vaccine polysaccharide nucleic acid and an amount of water for injection mix homogeneously of recipe quantity, those skilled in the art also is appreciated that and obtains, this bcg-polysaccharides nucleic acid can be with micropowder, solid dispersion, clathrate, microsphere, the form of liposome or microgranule adds, fully the dissolving back is 4000 rev/mins of rotating speeds, under 3 ℃ of environment centrifugal 15 minutes, get supernatant, carry out polysaccharide, the content detection of nucleic acid, to be detected qualified after, supernatant carries out essence by 0.22 μ m filter and filters, and is sub-packed in the cillin bottle behind the filtrate high pressure steam sterilization, lyophilization, tamponade, gland promptly gets injectable powder.
Embodiment 3
With the bcg-polysaccharides nucleic acid is the preparation method of the medicine composition injection of active component, and writing out a prescription is:
Card Jie polyoses nucleic acid: 0.3g
Physiological sodium chloride solution (0.9%) or water for injection: 100ml
Get bcg-polysaccharides nucleic acid and an amount of physiological sodium chloride solution (0.9%) or the water for injection mix homogeneously of recipe quantity, fully the dissolving back is 4000 rev/mins of rotating speeds, under 3 ℃ of environment centrifugal 15 minutes, get supernatant, carry out the content detection of polysaccharide, nucleic acid, to be detected qualified after, supernatant carries out essence by 0.22 μ m filter and filters, embedding is in ampoule then, and high pressure steam sterilization promptly is able to the medicine composition injection that bcg-polysaccharides nucleic acid is an active component.The next day give patient's intramuscular injection 1 time, each 1ml.
Embodiment 4
With the bcg-polysaccharides nucleic acid is the preparation method of active component micropowder injection, and writing out a prescription is:
Card Jie polyoses nucleic acid: 0.3g
Physiological sodium chloride solution (0.9%) or water for injection: 100ml
The former powder 0.3g of bcg-polysaccharides nucleic acid adopts the air-flow vortex pulverizing mill to pulverize, and gets the bcg-polysaccharides nucleic acid of 5-8 micron.In Agitation Tank, add an amount of physiological sodium chloride solution (0.9%) or water for injection, fully the dissolving back is 4000 rev/mins of rotating speeds, under 3 ℃ of environment centrifugal 15 minutes, get supernatant, supernatant carries out essence by 0.22 μ m filter and filters, embedding is in ampoule then, and it is active component micropowder injection that high pressure steam sterilization promptly is able to bcg-polysaccharides nucleic acid.The next day give patient's intramuscular injection 1 time, each 1ml.
Embodiment 5
With the bcg-polysaccharides nucleic acid is the production method of the microsphere suspensoid of active component, and writing out a prescription is:
Bcg-polysaccharides nucleic acid 0.25g
Poly (lactic acid-glycolic acid) 0.7g
Poloxamer 188 0.01g
Polyvinyl alcohol 200mL
Phosphate buffer 50mL
Dichloromethane 6mL
Sodium carboxymethyl cellulose 0.5g
Glycerol 10g
Distilled water adds in right amount
An amount of bcg-polysaccharides nucleic acid is dissolved in a certain amount of phosphate buffer that contains poloxamer 188 (interior water), and poly (lactic acid-glycolic acid) is dissolved in (oil phase) in the dichloromethane, and interior water is added in the oil phase, stirs 1min in the ice-water bath high speed and carries out emulsifying just.Then colostrum is changed in the polyvinyl alcohol (PVA) (, outer water), in ice-water bath, continue to stir 10min with the rotating speed of 1900rmin, form emulsion.Emulsion is changed among the 700mL 0.25%PVA, the control temperature is about 0 ℃ again, and stirring at low speed 3h is cured and solvent evaporates.Centrifugal collection microsphere is used distilled water wash 3 times, and lyophilization promptly gets the pastille microsphere, and the pastille microsphere is put in the mortar, glycerol adding grinds to form thin pasty state, in addition the sodium carboxymethyl cellulose water is made rubber cement, under agitation slowly adds in the mortar, moves in the measuring device, adding distil water stirs evenly to full dose, promptly.
Embodiment 6
With the bcg-polysaccharides nucleic acid is the production method of the clathrate injection of active component, and writing out a prescription is:
Bcg-polysaccharides nucleic acid 0.1g
Hydroxypropyl 10g
Carbomer 1.2g
Glycerol 5g
Ethyl hydroxybenzoate 1g
Propylene glycol 15ml
Sodium sulfite 0.3g
Distilled water adds to 100g
Comprise the steps:
Getting hydroxypropyl puts in the conical flask, add water 90mL dissolving, 45 ℃ of enclose temperature, fixed rotating speed 500r/min, bcg-polysaccharides nucleic acid dropwise adds in the hydroxypropyl solution after with anhydrous alcohol solution, and constant temperature stirs 4h recession baths of anhydrating, and continues stirring and is cooled to room temperature and gets inclusion complex in solution, porphyrize after the solution for vacuum lyophilization is crossed 80 mesh sieves and is promptly got clathrate.Clathrate dissolves with propylene glycol, the sodium sulfite dissolving, and the physiological sodium chloride solution (0.9%) that adds 100ml promptly gets bcg-polysaccharides nucleic acid clathrate injection.The next day give patient's intramuscular injection 1 time, each 1ml.
Embodiment 7
With the bcg-polysaccharides nucleic acid is the medicine compound liposome spray preparing process of active component, and writing out a prescription is:
Bcg-polysaccharides nucleic acid 0.25g
Hetastarch 0.5g
Mannitol 0.5g
Hydroxypropyl beta cyclodextrin 10g
Citrate buffer solution adds to 100ml
Comprise the steps:
Hetastarch, mannitol, hydroxypropyl beta cyclodextrin are dissolved in an amount of citrate buffer solution, form homogeneous solution, after the sterilization, the sterile working adds an amount of bcg-polysaccharides nucleic acid, add the sterilization citrate buffer solution to full dose, mix homogeneously divides to be filled in the spray device, promptly gets the agent of polysaccharide nucleic acid fraction of bacillus calmette guerin lipid spray body.Nasal cavity sprays into, and press in each every nostril 2, each 1 time sooner or later.
Embodiment 8
The proportioning of Chinese medicine composition is formed: Radix Astragali 500g, Herba Hedyotidis Diffusae 400g, Herba Artemisiae Scopariae 550g, Herba Lysimachiae 400g, Radix Codonopsis 550g, Cortex Moutan 350g, Radix Polygoni Multiflori Preparata 500g, Radix Salviae Miltiorrhizae 450g, Poria 400g, Radix Paeoniae Alba 450g, Rhizoma Atractylodis Macrocephalae 350g, Fructus Toosendan 350g, Herba Taraxaci 400g.
More than 13 flavors, get the Radix Astragali and decoct with water twice, each 2 hours, collecting decoction filtered, filtrate is concentrated into the extractum that relative density is 1.25 (20 ℃), Herba Artemisiae Scopariae is extracted volatile oil, 290g comprises with beta cyclodextrin, and is standby; Medicinal residues and all the other ten decoct with water twice simply, each 2 hours, collecting decoction, filter, filtrate is concentrated into the extractum that relative density is about 1.25 (20 ℃), put cold, add ethanol and make that to contain alcohol amount be 55%, left standstill 24 hours, supernatant reclaims ethanol to there not being the alcohol flavor, add above-mentioned Radix Astragali extractum, being concentrated into relative density is the extractum of 1.26 (20 ℃), adds gelatin 145g, steviosin 1.2g, lactose 1.62g and above-mentioned volatile oil clathrate compound, makes granule, dry below 60 ℃, make the 1000g sugar-free granule.Select for use boiled water to take after mixing it with water, a 3g, 3 times on the one.
Embodiment 9
The proportioning of Chinese medicine composition is formed: Radix Astragali 600g, Herba Hedyotidis Diffusae 350g, Herba Artemisiae Scopariae 650g, Herba Lysimachiae 350g, Radix Codonopsis 500g, Cortex Moutan 400g, Radix Polygoni Multiflori Preparata 450g, Radix Salviae Miltiorrhizae 550g, Poria 350g, Radix Paeoniae Alba 400g, Rhizoma Atractylodis Macrocephalae 400g, Fructus Toosendan 450g, Herba Taraxaci 350g.
More than 13 flavors, get the Radix Astragali and decoct with water twice, each 2 hours, collecting decoction filtered, filtrate is concentrated into the extractum that relative density is 1.25 (20 ℃), Herba Artemisiae Scopariae is extracted volatile oil, 290g comprises with beta cyclodextrin, and is standby; Medicinal residues and all the other ten decoct with water twice simply, each 2 hours, collecting decoction, filter, filtrate is concentrated into the extractum that relative density is about 1.25 (20 ℃), put coldly, add ethanol and make that to contain alcohol amount be 55%, left standstill 24 hours, supernatant reclaims ethanol to there not being the alcohol flavor, add above-mentioned Radix Astragali extractum, being concentrated into relative density is the extractum of 1.26 (20 ℃), and extractum is concentrated into the thick paste that relative density is 1.26 (20 ℃), add above-mentioned volatile oil clathrate compound and sucrose 5270g, make granule, dry below 60 ℃, make 5670g sugar-containing type granule.Select for use boiled water to take after mixing it with water, a 17g, 3 times on the one.
Embodiment 10
Below prove beneficial effect of the present invention by pharmacodynamics test:
Infect the cherry valley duck of 1 age in days with the DHBV positive serum, preparation duck hepatitis-B model.60 ducklings that infect successfully are divided into 5 groups at random: bcg-polysaccharides nucleic acid group 60mg/kg, the Chinese medicine composition group, bcg-polysaccharides nucleic acid adds the Chinese medicine composition group, normal saline model group and acyclovir (ACV) matched group, 12 every group.Bcg-polysaccharides nucleic acid group every other day intramuscular injection 4 weeks of bcg-polysaccharides nucleic acid; The Chinese medicine composition group gives Chinese medicine composition 8.42g/kg and irritates stomach, 1 time/day; Bcg-polysaccharides nucleic acid adds Chinese medicine composition group every other day intramuscular injection 4 weeks of bcg-polysaccharides nucleic acid, gives Chinese medicine composition 8.42g/kg simultaneously and irritates stomach, and 1 time/day, model group gives the equivalent normal saline enema; The medicine matched group gives ACV 100mg/kg and irritates stomach; Equal 1 time/d, successive administration 28 days.And, get blood from the lower limb vein respectively at the 8th day (for T0 before the administration), administration (T14), administration (T28) and drug withdrawal 7 days (P7) in 28 days in 14 days after infecting, and 0.5ml/, separation of serum ,-70 ℃ of preservations are to be checked.Detect the situation of change of the clear middle DHBV DNA copy number of Sanguis Anas domestica with real-time PCR method.
Experimental result: (1) respectively organizes duckling different time serum DHBV dna level and situation of change sees Table 1.Table 1 shows: 1. compare with (T0) before the administration: the bcg-polysaccharides nucleic acid small dose group descends in the logarithm value of 28 days (T28) DHBV of administration DNA copy number, and difference has statistical significance.The logarithm value of dosage group administration 14 days (T14), 28 (T28) DHBV DNA copy number all reduces in the bcg-polysaccharides nucleic acid, and difference has statistical significance.Bcg-polysaccharides nucleic acid adds that the logarithm value of different time (T14, T28) and 7 days (P7) DHBV of drug withdrawal DNA copy number all reduces after the administration of Chinese medicine composition group, and difference has statistical significance.2. compare with (T0) before the administration: the logarithm value of ACV matched group administration 14 days (T14), 28 days (T28) DHBV DNA copy numbers reduces, and difference has statistical significance.The result: 1. bcg-polysaccharides nucleic acid group, Chinese medicine composition group and bcg-polysaccharides nucleic acid add the Chinese medicine composition group all the effect that suppresses DHBV DNA in various degree, especially it is obvious to add the Chinese medicine composition group with bcg-polysaccharides nucleic acid, and prompting bcg-polysaccharides nucleic acid and Chinese medicine composition are united use and had the significance effect for the effect that inhibition DHBVDNA duplicates.2. the ACV inhibitory action certain to duplicating of DHBV DNA.
The logarithm value that table 1 is respectively organized duckling different time DHBV DNA copy number changes relatively (x ± s)
| Group | n | T0 | T14 | T28 | P7 |
| Model group | 12 | 9.699±0.935 | 8.627±0.711 | 9.711±0.678 | 10.043±0.686 |
| The ACV matched group | 12 | 9.349±0.372 | 8.091±0.486 * | 7.571 *0.781 * | 8.628±0.467 |
| The Chinese medicine composition group | 12 | 9.654±0.925 | 8.302±0.442 | 7.89±0.752 | 8.895±0.718 |
| The bcg-polysaccharides nucleic acid group | 12 | 9.661±0.592 | 7.952±0.893 ** | 7.524±0.536 * | 8.220±0.576 |
| Bcg-polysaccharides nucleic acid adds the Chinese medicine composition group | 12 | 9.785±0.585 | 7.945±0.323 ** | 6.768±0.586 ** | 7.384±0.565 ** |
With (T0) before the administration on the same group relatively,
*P＜0.05;
*P＜0.01
(2) respectively organizing duckling different time DHBV DNA is suppressed situation and sees Table 2.The result shows: 1. little, the middle dosage group of bcg-polysaccharides nucleic acid has similar inhibition DHBV DNA effect to ACV.2. the effect that suppresses DHBV DNA after the drug withdrawal of the heavy dose of group of bcg-polysaccharides nucleic acid is strong than ACV.
The suppression ratio that table 2 is respectively organized duckling different time DHBV DNA compares (%)
| Group | n | T14 | T28 | P7 |
| Model group | 12 | 11 | 0 | -4 |
| The ACV matched group | 12 | 13 | 19 ** | 8 |
| The Chinese medicine composition group | 12 | 7 | 10 * | 5 |
| The bcg-polysaccharides nucleic acid group | 12 | 19 | 21 ** | 16 * |
| Bcg-polysaccharides nucleic acid adds the Chinese medicine composition group | 12 | 20 | 29 ** | 25 **# |
With the model group comparison same period,
*P＜0.05,
*P＜0.01; With the ACV matched group comparison same period, #
*P＜0.05
Conclusion
Cherry valley duck is a kind of of Beijing duck, and the natural infection rate of DHBV is extremely low, is particularly suitable for studying hepatitis B virus infection.ACV is a kind of antiviral drugs, and HBV is had certain antivirus action, and lot of domestic and international scholar uses the control drug of ACV as the anti-hepatic-B virus medicine screening experiment.Result of study shows, each dosage group duckling of bcg-polysaccharides nucleic acid, and all than descending (＞2 logarithm level) before the administration, difference has statistical significance (P＜0.01) to different times serum DHBV dna level after administration.Showing that bacill calmette-guerin nucleic acid can suppress duplicating of the interior DHBV of duck body effectively, serves as significantly with the heavy dose group especially, presents the effect dose-dependent effect.
Embodiment 11
For the further clinical efficacy of checking the present invention in the treatment chronic hepatitis B, the patient of chronic hepatitis B is adopted the present invention program to treat to carry out in 6 months clinical supervisory.The patient did not use immunomodulator or antiviral agents before selected, and totally 58 examples are divided into treatment at random and organize 30 examples, matched group 28 examples.Male's 43 examples, women's 15 examples, age 18-63 year, average 32.4 years old, course of disease 1-15, average 3.2 years.Whole case HBsAg positives.The HBsAg positive: 27 examples are organized in treatment, matched group 25 examples.The HBV-DNA positive: 27 examples are organized in treatment, matched group 26 examples.Between two groups of sexes, age, the state of an illness comparability is arranged.Two groups of case Primary Cares are identical, oral oral administered compound silybin, vitamin C and vitamin E etc., treatment group add with bcg-polysaccharides nucleic acid (Si Qikang injection, every 1ml, 0.5mg/ml), the next day 1 time, each 0.5mg, intramuscular injection, continuous use 6 months, two groups of patients of viewing duration are without other immunomodulator or antiviral agents.
Ordinary circumstance: comprise weak, appetite, abdominal distention, pain in the hepatic region etc.Treatment beginning looked in 3 months every month liver function (comprise ALT, AST, ALP, r-GT, TB, DB, TP, ALB), five indexes of hepatitis b (HBsAg, anti--HBs, HBeAg, anti--HBe, anti--HBc).
(1) variation of main liver function project sees Table 3.
The different therapies of table 3 to patient's liver function project normalization rate and multiple often between the (d of x ± s)
Compare with matched group:
*P＜0.05
As can be seen from Table 3 on main liver function project, bcg-polysaccharides nucleic acid add Chinese medicine composition group normalization rate be higher than single with Chinese medicine composition group or single with bacill calmette-guerin ribonucleic acid group, and on pair is long-time also than these two groups weak points.
(2) variation of hepatitis b virus marker:
The differentiation of hepatitis b virus marker before and after the different treatment group of table 4 patient
Compare with matched group:
*P＜0.05,
*P＜0.01
As can be seen from Table 4 in serum on the negative conversion rate of HbeAg and HBV-DNA, bcg-polysaccharides nucleic acid add Chinese medicine composition group effect apparently higher than single with Chinese medicine composition group or single with bacill calmette-guerin ribonucleic acid group.
Conclusion
The major reason that chronic hepatitis B forms is an immunity of organism defective or low, the hepatocyte that can not thoroughly remove hepatitis B virus and viral infection.Be a kind of nonspecific immunity active reinforcing agent, knowing of activating macrophage bitten function and offered antigenic ability effectively, and inducer T lymphocyte produces immune factors such as IL-2, r-IFN, strengthens cellular immune function and regulates humoral immunity level.
In the bcg-polysaccharides nucleic acid treatment chronic hepatitis B process, comparing there was no significant difference with matched group aspect the recovery of liver function (ALT), but at HBeAg, the moon commentaries on classics aspect of virus replication indexs such as HBV DNA all significantly is better than matched group, the duplicated inhibitory action of bcg-polysaccharides nucleic acid to hepatitis B virus is described, can be used for the clinical treatment of chronic hepatitis B.The immunological enhancement of bcg-polysaccharides nucleic acid is sure, is used for the treatment safety of chronic hepatitis B, effective, convenience, inexpensive, and untoward reaction is few, and better tolerance is worth clinical practice.All medicines share in the Chinese medicine composition, can set upright society's heresy. giving consideration to both the incidental and fundamental, the merit of playing regulating QI spleen invigorating, nourishing the kidney and liver, function of gallbladder promoting heat clearing away, blood circulation promoting and blood stasis dispelling altogether.Being just accord with the chronic hepatitis pathogenesis that " damp and hot surplus heresy is residual comes to the greatest extent stagnation of liver-QI spleen kidney qi blood deficiency " wait manages.Modern pharmacological research confirms, square Chinese medicine has in various degree adjusting immunity, improves organism metabolism, strengthens liver detoxification, suppresses virus replication, the anti-inflammatory and choleretic jaundice eliminating, recovers effects such as liver function, anti-hepatic fibrosis.
Among the embodiment of the invention 10, the embodiment 11, the result shows, the compositions curative effect that two kinds of combination of compositions form obviously is better than single with bcg-polysaccharides nucleic acid or Chinese medicine composition, this shows, aspect promoting that liver function is normal again and improving symptom, the therapy of combining Chinese and Western medicine chronic viral hepatitis B obviously is better than simple doctor trained in Western medicine or Chinese traditional treatment.Because doctor trained in Western medicine in the high antiviral drugs that both had been of no curative effect aspect the treatment chronic viral hepatitis B, does not have definite stable liver plasma membrane yet, prevents the medicine of hepatocyte injury, so still do not have breakthrough in treatment; And on the basis of western medical treatment according to theory of Chinese medical science, determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs is set upright by getting rid of evils, regulating functional activities of qi, can help hepatocellular reparation and regeneration, so the new purposes of the present composition is selected for the chronic viral hepatitis B patient provides important treatment.
Claims (5)
1. pharmaceutical composition for the treatment of chronic hepatitis B, it is characterized in that, this pharmaceutical composition is combined by the pharmaceutical composition and a kind of Chinese medicine composition that with the bcg-polysaccharides nucleic acid are active component, wherein said Chinese medicine composition is made by the raw material of following weight portion: Radix Astragali 500-650 part, Herba Artemisiae Scopariae 500-650 part, Herba Hedyotidis Diffusae 350-450 part, Herba Lysimachiae 350-450 part, Radix Codonopsis 450-550 part, Radix Polygoni Multiflori Preparata 450-550 part, Radix Salviae Miltiorrhizae 450-550 part, Radix Paeoniae Alba 350-450 part, Fructus Toosendan 350-450 part, Herba Taraxaci 350-450 part, Cortex Moutan 350-450 part, Poria 350-450 part, Rhizoma Atractylodis Macrocephalae 350-450 part, described Chinese medicine composition is an oral granular formulation, the dosage of sugar-free granule is 3 grams, and the dosage of sugar-containing type granule is 17 grams; Described is that the dosage form dosage made of the pharmaceutical composition of active component is for containing 0.5 milligram of bcg-polysaccharides nucleic acid with the bcg-polysaccharides nucleic acid.
2. pharmaceutical composition according to claim 1, it is characterized in that, described is in the pharmaceutical composition of active component with the bcg-polysaccharides nucleic acid, and the form that bcg-polysaccharides nucleic acid joins in the said composition is common lyophilized powder, micropowder, solid dispersion, clathrate, microgranule.
3. pharmaceutical composition according to claim 2 is characterized in that described microgranule is microsphere, liposome.
4. pharmaceutical composition according to claim 2 is characterized in that, described is that the pharmaceutical composition of active component is made injectable powder, injection, spray or oral administration mixed suspension dosage form with the bcg-polysaccharides nucleic acid.
5. the purposes of the described pharmaceutical composition of claim 1 in the medicine of preparation treatment chronic hepatitis B.
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| CN103948763A (en) * | 2014-05-21 | 2014-07-30 | 李玮 | Traditional Chinese medicinal composition for treating hepatosis |
| CN105982984B (en) * | 2015-02-28 | 2019-09-27 | 九芝堂股份有限公司 | A kind of pharmaceutical composition and preparation method thereof for treating hepatopathy |
| CN106902223A (en) * | 2017-03-15 | 2017-06-30 | 王海燕 | A kind of pharmaceutical composition for treating hepatitis B, liver fibrosis and preparation method thereof |
| CN109364155A (en) * | 2018-12-18 | 2019-02-22 | 丹东瑞丰动物药业有限责任公司 | A kind of Chinese medicine and preparation method thereof for treating duck virus hepatitis |
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Assignee: Hunan Siqi Biopharmaceutical Co., Ltd. Assignor: Limited by Share Ltd of the nine world Contract record no.: 2011430000292 Denomination of invention: Medicine combination and application thereof in preparing preparations for treating chronic hepatitis B License type: Exclusive License Open date: 20100120 Record date: 20111229 |