CN100342879C - Liver fibrosis treating prepn and its process - Google Patents

Abstract

The present invention relates to a preparation for treating hepatic fibrosis, and a preparation method thereof. The preparation for treating hepatic fibrosis comprises the following raw medicinal materials: 15 to 150 parts by weight of astragalus root, 15 to 150 parts by weight of coastal glehnia root, 15 to 150 parts by weight of rehmannia root and 3 to 30 parts by weight of panax notoginseng. The medicine prescription is developed by combining Chinese medicine theories with modern medicine and pharmacy methods. The medicine of the present invention promotes blood circulation for removing blood stasis without warm dampness, and supplements qi and nourishes yin without obstructing stomach fluid production. Multiple medicines are combined for use. The preparation has the functions of promoting blood circulation for removing blood stasis, supplementing qi, nourishing yin and tonifying the liver and the kidney, and treats both manifestations and the root causes of diseases according to the pathogenesis of the stagnation of QI and blood and the deficiency of liver yin and kidney yin in the process of hepatic fibrosis. The medicine of the present invention can improve hepatitis clinical symptoms, can improve serum albumin, can reduce globulin, can retract splenomegaly, and can reduce blood serum hepatic fibrosis indexes. The prepatation also has the advantages of convenient administration, safety and low price. Because China is a country with a great population with hepatitis B and the incidence rates of chronic hepatitis and hepatic cirrhosis are high, the medicine has wide application prospect.

Description

Preparation of treatment hepatic fibrosis and preparation method thereof

Technical field:

The present invention relates to a kind of medicine, relate in particular to a kind of medicine for the treatment of hepatic fibrosis.

Background technology:

Hepatic fibrosis be development of chronic hepatitis be liver cirrhosis total pathological change and must be through approach, hepatic fibrosis is reversible, liver cirrhosis then is irreversible.Stop the formation of hepatic fibrosis, significant to preventing to develop into liver cirrhosis.The Chinese medicine anti-hepatic fibrosis has certain advantage, but treats adopt many based on drug for invigorating blood circulation and eliminating stasis at present, is aided with replenishing QI to invigorate the spleen, softening the hard mass merit knot, nourishing the liver and kidney, does not see the reported in literature of blood circulation promoting and blood stasis dispelling and supplementing QI and nourishing YIN medicine compatibility treatment hepatic fibrosis.

Summary of the invention:

The object of the present invention is to provide the preparation and preparation method thereof of the treatment hepatic fibrosis of a kind of activating blood circulation to dissipate blood stasis, liver and kidney tonifying, treating both the principal and secondary aspects of a disease

Technical scheme of the present invention is as follows:

1, the preparation of treatment hepatic fibrosis: it comprises the crude drug of following ratio of weight and number, Radix Astragali 15-150 part, Radix Glehniae 15-150 part, Radix Rehmanniae 15-150 part, Radix Notoginseng 3-30 part.

2, the preparation method of treatment hepatic fibrosis preparation:

(1) Radix Salviae Miltiorrhizae, Radix Notoginseng, the Radix Astragali three flavor Chinese medicines are directly pulverized, it is standby to get fine powder;

(2) with the remaining coarse powder of step (1) with other crude drug, adopt that the preparation method of existing Chinese patent medicine is carried out infusion, filtration, concentrated, ethanol precipitation, filtration, recovery ethanol, concentrate and put cold;

(3) with the fine powder of step (1) and step (2) concentrate and with put cold thing mix homogeneously, make medicament.

This medicine prescription is developed in conjunction with modern medicine, method of pharmacy according to theory of Chinese medical science.The present invention mainly is the anti-hepatic fibrosis pathological changes, clinically is used for the treatment of chronic hepatitis, early stage liver cirrhosis.But this medicine is blood circulation promoting and blood stasis dispelling both, again supplementing QI and nourishing YIN.So this medicine blood circulation promoting and blood stasis dispelling is not too crossed warm-dryness syndrome again; Supplementing QI and nourishing YIN and do not hinder stomach and give birth to wet.All medicines share, at the pathogenesis of the stagnation of QI and blood hepatic and renal YIN deficiency in the liver fibrosis process, and blood circulation promoting and blood stasis dispelling, supplementing QI and nourishing YIN, liver and kidney tonifying, treating both the principal and secondary aspects of a disease.No matter zoopery of medicine of the present invention, or clinical experiment all demonstrates good result.Can improve the hepatitis clinical symptoms, improve serum albumin, reduce globulin, the splenomegaly retraction reduces the serum hepatic fibrosis index, and taking convenience, safety, and cheap.Because China is hepatitis B big country, the incidence rate height of chronic hepatitis, liver cirrhosis.Therefore this medical instrument has broad application prospects.

The specific embodiment:

1, the preparation of treatment hepatic fibrosis: it comprises the crude drug of following ratio of weight and number, Radix Astragali 15-150 part, Radix Glehniae 15-150 part, Radix Rehmanniae 15-150 part, Radix Notoginseng 3-30 part, Semen Persicae 10-100 part, Rhizoma Chuanxiong 9-90 part, Fructus Crataegi 15-150 part, Poria 10-100 part, Radix Angelicae Sinensis 9-90 part, Radix Salviae Miltiorrhizae 15=150 part, Radix Paeoniae Rubra 15-150 part.

2, the preparation method of treatment hepatic fibrosis preparation:

(1) Radix Salviae Miltiorrhizae, Radix Notoginseng, the Radix Astragali three flavor Chinese medicines is directly pulverized, got 80 mesh sieves or 80 orders are standby with the top sieve fine powder;

(2) the remaining coarse powder of step (1) adds the water infusion 2 times with other crude drug, boils 1 hour at every turn, merges to boil liquid, filters, filtrate concentrates, and puts coldly, adds 95% ethanol and reaches 70% to containing the alcohol amount, leaves standstill 24 hours, filters, and gets filtrate for later use;

(3), and be concentrated into the thick paste shape with above-mentioned decompression filtrate recycling ethanol, put cold, add above-mentioned fine powder, make granule, drying, compacting is in flakes or incapsulate.

One, the acute toxicity test of medicament of the present invention:

1 material

1.1 30 of laboratory animal KM kind mices, cleaning level, body weight 19.84 ± 1.42g, male and female half and half, raising in 19～30 ℃, humidity is 55%～60%, throws mice standard particle material.Provide by Colleges Of Traditional Chinese Medicine Of Fujian's Experimental Animal Center.The animal quality certification number: No. the 003rd, Chinese Academy of Medical Sciences's the care of animal.

1.2 being subjected to the reagent thing is medicament of the present invention, is provided by Fuzhou City Infectious Disease Hospital, gets this medicine 7g and is made into 10ml solution with distilled water, every mice gavages the 0.4ml/10g body weight 1 time.

2 test methods

2.1 10 of mices are got in trial test, water is can't help in the 12h fasting before the experiment.Make Cmax (just by irritating the stomach syringe needle with medicament of the present invention, do not cause the concentration 700mg/ml that former pharmacology, voltinism shape change), maximal dose (0.4ml/10g body weight, every≤1ml) irritate stomach 1 time, observe dead mouse number and general situation in 7 days, if do not have death, then ask 1 maximum tolerated dose (MTD); If death toll 〉=30%, then use " karber's method " ask median lethal dose(LD 50) (LD50).

2.2 1 week of test mice adaptability sub-cage rearing is made 1 mtd test for 400 times with human oral dosage behind the 12h on an empty stomach, free diet after the administration, and every day at the upper and lower noon respectively observes 1 time, observes continuously 7 days.

3 observation index

3.1 1. behavior and reaction of nervous system (comprise undesired cry, agitation, uneasiness, irritability, hyperesthesia, few moving, drowsiness or stupor etc.); 2. motion (comprising muscle twitches, stiff, forced movement, lax, paralysis etc.); 3. pupil and secretions (pupil have do not dwindle or amplify, sialorrhea is shed tears etc.).

3.2 breathe and the cardiovascular-respiratory state, pareordia heart rate speed etc. is touched in the nose secretion.

3.3 gastrointestinal abdominal part flatulence or contraction, stool character and color and luster.

3.4 genitourinary system labia, mammary gland swelling, perineal position dirt.

3.5 skin and hair color, integrity has or not hyperemia, and cyanosis is pale, dermexanthesis, and fur is loose etc.

3.6 eye has or not blepharoptosis, exophthalmos trembles etc.

3.7 other appetite and body weight change, measure every day.

4 results

4.1 trial test animal does not as a result have death, so ask MTD.

4.2 state all observation index during experimental observation are no abnormal before and after the filling stomach.

4.3 body weight and feed consumption see Table 1 before and after the filling stomach.

Table 1 is irritated the (x ± s) of mice body weight and every day food consumption thing before and after the stomach

D number after the administration	The example number	Body weight	Only consume feedstuff g/
				0 1 2 3 4 5 6	20 20 20 20 20 20 20	19.84±1.42 20.51±1.42 21.18±1.68 22.13±1.97 23.08±2.05 23.88±2.17 24.63±2.30	4.78±0.34 5.05±0.12 5.15±0.12 5.27±0.25 5.35±0.30 5.40±0.38 5.40±0.42

Table 1 shows the mice body weight still by the physiological conditions normal growth, and every day, feed consumption did not have significant change.

5 conclusions

Medicament of the present invention has replenishing QI to invigorate the spleen, the blood circulation promoting and blood stasis dispelling effect of nourishing the liver and kidney of holding concurrently.Carry out mtd test with the KM mice.The present invention is with 1 tolerance test the most much of 400 times of works of population dosing, and observed every index is all normal, does not see 1 animal dead.Result of the test proof medicament of the present invention does not have obvious acute toxicity effect.

Two, the clinical trial visual report of medicament anti-hepatic fibrosis of the present invention is as follows

1 materials and methods

1.1 testing of materials object is chronic hepatitis patient 200 examples of coming institute's diagnosis and treatment, wherein male 170 examples, women 30 examples; 11～55 years old age is by nineteen ninety-five whole nation infectious disease parasite requirement meeting revision diagnostic criteria.

1.2 adding, method (1) uses medicament of the present invention on the basis of the liver protecting and ALT lowering treatment; Each 4, every day 3 times, 3 months be 1 course of treatment, continuous 2 courses of treatment of having.(2) observe the symptoms respectively before and after the treatment sign, liver function wadding turbidity, serum albumin, globulin, hepatic fibrosis III procollagen type peptide (PIVP), IV Collagen Type VI (IV-C), monoamine oxidase, MAO (MAO), hyaluronic acid four indices such as (HA).(3) partly case hepatic tissue specimen is worn acquisition for the percutaneous liver.

1.3 statistical procedures adopts significant t-test

2 results

2.1 after 1～2 course of treatment, its clinical manifestation and laboratory result all show satisfied curative effect, see Table 1～3 through pharmaceutical treatment of the present invention:

The variation of table 1 200 routine hepatitis clinical manifestations after Drug therapy of the present invention

Clinical manifestation	Treatment precedent number	Routine number is recovered in the treatment back		Effective percentage %
					Treated back 3 months	Treated back 6 months
		Weak pain in the hepatic region or uncomfortable dim complexion body of the tongue blood stasis	138 120 133 106				125 96 90 81	128 03 111 95	92.75 85.83 83.46 89.62

Table 2 200 routine hepatitis are biochemistry and the inspection of B ultrasonic spleen after Drug therapy of the present invention

Project	Treatment precedent number	Routine number is improved in the treatment back		Effective percentage %
					Routine number takes a turn for the better	Positive common practice number
		Wadding turbidity raising albumin (＜35g/L) globulin (＞35g/L) splenomegaly	142 73 108 155Δ				70 31 36 85	49 24 55 35	83.8 75.64 84.26 86.96

Δ is checked 145 examples, wherein 7 routine no changes

Table 3 200 routine hepatitis are through the variation of 4 indexs of Drug therapy heptic fibrosis of the present invention (x ± S)

Project	Before the treatment	After the treatment	P
				HA(ng/ml) MAO(u/L) PIIIP(ug/L)	366.20±277.41 44.15±12.37 1.297±1.039	144.00±138.20 40.39±2.41 0.972±1.534	＜0.001 ＜0.001 ＜0.05

IV-C(ng/L)

204.82±186.4

95.67±52.36

＜0.001

2.2 it is 1.23 ± 0.12cm that Dsv, inner diameter of portal vein change the preceding inner diameter of portal vein of treatment, is 1.18 ± 0.09cm after the treatment, P＜0.001 is respectively 0.72 ± 0.13cm and 0.66 ± 0.1cm, P＜0.001 before and after the Dsv treatment.

2.3 liver makes hepatic tissue puncture pathologic finding to 15 gently routine～moderate chronic hepatitis patients during wearing treatment.4 examples after 6 months for the second time liver wear, as a result 3 routine hepatic tissues all have in various degree improve, show as inflammation in the hepatic tissue, necrosis alleviates, outgrowth fibrosis disappears, effective percentage is 75% (3/4), wherein 2 example check heptic fibrosis are 0 grade, effective percentage 50% (2/4).

3 discuss

Hepatitis B is the commonly encountered diseases frequently-occurring disease in China, wherein 1/3 can develop into chronic hepatopathy.The hepatic fibrosis incidence rate of chronic hepatitis can reach 85.15%.For this reason, slowly, the generation of blocking-up or reverse hepatic fibrosis team's minimizing liver cirrhosis or hepatocarcinoma is significant.The late world well-known scholar professor POPPer once pointed out emphatically: " who can stop or delay the generation of hepatic fibrosis, and who just will cure most of chronic hepatopathys.

The traditional Chinese medical science is thought the clinical syndrome complexity of chronic hepatitis, liver cirrhosis, but basic lesion mechanism is evil Sheng of just declining, and damp and hot blood stasis, stagnation of liver-QI spleen kidney qi blood deficiency, the stagnation of QI due to depression of the liver of holding concurrently to the greatest extent causes blood stasis.Meridian and vessels obstruction, not nourishing the liver of blood, crux are blood stasis.Blood stasis shows that the pathological change of chronic hepatitis, liver cirrhosis is the formation and the microcirculation disturbance of hepatic fibrosis.Recently research thinks that the Chinese medicine of hard masses softening and resolving, blood circulation promoting and blood stasis dispelling has the proliferation of fibrous tissue of inhibition liver, makes the fibrous tissue dissolving absorb, expand the liver vessel microcirculation improvement, helps the improvement and adjusting immunologic function of hepatocellular reparation and liver function.Drug therapy chronic hepatopathy 200 examples of the present invention.The result shows, clinical symptom remission, blood stasis doing well,improving after treating, and serum albumin increases, globulin descends, the spleen retraction of enlargement, and the every index of hepatic fibrosis all is significantly improved.Simultaneously B ultrasonic shows that inner diameter of portal vein, Dsv have and dwindles after treatment.Show that Drug therapy fibrosis in chronic liver disease patient of the present invention has good result at the aspects such as retraction of improving tcm symptom, hepatic tissue pathology change and serology hepatic fibrosis index, enlargement spleen.Except that individual patient has slight xerostomia and " hotness ", there are not other side reactions during the medication.Other relevant observations are still underway.

Three, pharmaceutical treatment chronic hepatitis fibrosis 200 routine results of the present invention report as follows.

1 clinical data

All cases are that be in hospital in the court or the chronic hepatitis patients with liver fibrosis of outpatient service.Be divided into treatment at random and organize 200 examples, male 170 examples, women 30 examples, 11～15 years old age.Matched group 100 examples, male 89 examples.Woman's 11 examples, 15～60 years old.Diagnosis meets the standard of nineteen ninety-five whole nation infectious disease parasitic disease academic conference revision.

2 Therapeutic Method

Treatment group medicine of the present invention under the identical condition of Primary Care, 3 times on the 1st, each 4,3 months is 1 course of treatment, takes 1～2 course of treatment.The matched group FUFANG DANSHEN PIAN, 3 times on the 1st, 1 time 4, oral, the course of treatment is the same.

Observe two groups of symptoms, sign before and after the treatment, serum wadding turbidity, albumin, globulin, 4 indexs of hepatic fibrosis [III] precollagen peptides (PIIIP), IV Collagen Type VI (IV-C) monoamine oxidase, MAO (MAO), hyaluronic acid (HA)], B ultrasonic looks into that hepatosplenomegaly is little, the splenic vein and inner diameter of portal vein etc.Full automatic biochemical apparatus and reagent that biochemistry detection is produced with U.S. Beckman company.The reagent that PIIIP produces with capital lion biological medicine company limited.The reagent that the reagent MAO that IV-C produces with the biological company limited of the gloomy hero in Shanghai produces with the biological company limited of Erie's health.The reagent that HA produces with Shanghai naval institute.Part hepatic tissue specimen percutaneous liver is worn acquisition.

3 therapeutic outcomes

3.1 after 1～2 course of treatment, clinical manifestation and lab testing result all have satisfied the improvement through Drug therapy of the present invention for symptom and lab index before and after two groups of treatments.The effective percentage of treatment group and matched group symptom, weakly be respectively 92.75%, 93.78%; Hepatalgia or discomfort are respectively 85.83%, 84.60%; Dim complexion is respectively 83.46%, 80.38%; The tongue ecchymosis is respectively 89.62%, 87.20%.

3.2 the splenic vein, inner diameter of portal vein change the preceding portal vein of treatment of control group, Dsv is respectively (1.223 ± 0.111) cm, (0.73 ± 0.143) cm; Be respectively (1.224 ± 0.102) cm, (0.170 ± 0.138) cm after the treatment, both compare P＜0.01.Portal vein, Dsv are respectively (1.232 ± 0.118) cm, (0.723 ± 0.125) cm before the treatment of treatment group, are respectively (1.18 ± 0.09) cm, (0.665 ± 0.101) cm after the treatment, and both compare P＜0.01.Compare for two groups the treatment back, is respectively P＜0.01, P＜0.05.

The effective percentage of treatment group and matched group biochemical analysis and ultrasound diagnosis, the wadding turbidity is respectively 83.80%, 82.30%; Albumin (＜35g/L) be respectively 75.34%, 78.30%; Globulin (＞35g/L) being respectively 84.26%, 90.97%, splenomegaly is respectively 86.96%, 31.50%.Wherein two groups of effective percentage of splenomegaly compare, and difference has highly significant, P＜0.01.Index determinings such as hepatic fibrosis see Table 1.

3.3 that liver is worn is light to 15 examples during the treatment, the moderate chronic hepatitis is carried out liver puncture and done the pathology inspection.Drug induced hepatitis 1 example wherein, chronic hepatitis B 14 examples.4 customary the 2nd livers are worn after 6 months, and 3 routine hepatic tissues all have improvement in various degree as a result, see that inflammation, necrosis alleviate in the hepatic tissue, and outgrowth fiber disappears, and wherein 2 routine hepatic fibrosis are 0 grade.

After individual patient is taken medicine, feel slight xerostomia and the hotness in the course of treatment, do not find other side effect.

3 discuss

Hepatic fibrosis be chronic hepatitis progress for liver cirrhosis must be through approach, and primary hepatocarcinoma has substantial connection with liver cirrhosis.According to my institute's statistics, local 265 routine primary hepatocarcinoma confirm to merge the liver cirrhosis person through B ultrasonic and account for 76.19%.Show that blocking-up or reverse hepatic fibrosis are significant to the generation that reduces liver cirrhosis or primary hepatocarcinoma.Medicine of the present invention have invigorate blood circulation, thereby circulation of qi promoting, promotion hepatocyte restitution make clinical symptom remission, the blood stasis doing well,improving, serum albumin increases, globulin descends, enlargement spleen retraction, the every index of hepatic fibrosis is improved, and reaches desirable therapeutic.Data shows, Drug therapy chronic hepatopathy of the present invention all has effect preferably at the aspects such as spleen of improving patient's clinical symptoms, hepatic tissue pathology variation, serology liver fiber index and retraction enlargement, compare with the square medicine that with the blood circulation promoting and blood stasis dispelling is purpose merely, its mechanism of action and approach may show on the pharmacological characteristic of polytropism, stage construction, many target spots.

Hepatic fibrosis index before and after the table 1 liang group treatment (x ± s)

Group	The n/ example	HA/(ng/ml)	PIIIP/(μg/L)	IV-/(μg/L)	MAO/(U/L)
						The treatment of control group group	After treating before the preceding treatment of 100 treatments back 200 treatments	396.16±306.75* 296.09±279.49** 366.0±277.41 144.0±138.2**ΔΔ	1.394±0.212* 1.429±0.249 1.297±1.039 0.972±1.534*	227.78±19.91 169.87±15.28** 204.82±186.4 95.67±52.36**ΔΔ	47.25±1.29 47.83±1.71** 44.15±12.37 40.39±2.41**ΔΔ

Relatively preceding with treatment, * P＜0.05, * * P＜0.01; Compare Δ Δ P＜0.01 with matched group

Claims (8)

1, a kind of preparation for the treatment of hepatic fibrosis, it is characterized in that: make the raw materials of effective components medicine and consist of by weight, Radix Astragali 15-150 part, Radix Glehniae 15-150 part, Radix Rehmanniae 15-150 part, Radix Notoginseng 3-30 part, Fructus Crataegi 15-150 part, Semen Persicae 10-100 part, Rhizoma Chuanxiong 9-90 part, Poria 10-100 part, Radix Angelicae Sinensis 9-90 part, Radix Salviae Miltiorrhizae 15-150 part, Radix Paeoniae Rubra 15-150 part.

2, the preparation of treatment hepatic fibrosis according to claim 1 is characterized in that: described preparation is a said peroral dosage form on the pharmaceutics.

3. the preparation of treatment hepatic fibrosis according to claim 2 is characterized in that: described preparation is tablet or capsule.

4, according to the preparation method of claim 1 or 2 or 3 described treatment hepatic fibrosis preparations: it is characterized in that: its processing step is as follows:

(1) Radix Salviae Miltiorrhizae, Radix Notoginseng, the Radix Astragali three flavor Chinese medicines are directly pulverized, it is standby to get fine powder;

(2) with the remaining coarse powder of step (1) with other crude drug, adopt that the preparation method of existing Chinese patent medicine is carried out infusion, filtration, concentrated, ethanol precipitation, filtration, recovery ethanol, concentrate and put cold;

(3) with the fine powder of step (1) and step (2) to concentrate and put cold mixing of materials even, make medicament.

7, the preparation method of treatment hepatic fibrosis preparation according to claim 6: it is characterized in that: the fine powder described in the step (1) was that 80 mesh sieves or 80 orders are with top sieve.

8, the preparation method of treatment hepatic fibrosis preparation according to claim 6: it is characterized in that: the infusion technology described in the step (2) is, adds the water infusion 2 times, each infusion 1 hour, and merge and endure liquid.

9, the preparation method of treatment hepatic fibrosis preparation according to claim 6: it is characterized in that: the ethanol extraction technology described in the step (2) is, adds 95% ethanol and reaches 70% to containing the alcohol amount, leaves standstill 24 hours.

10, the preparation method of treatment hepatic fibrosis preparation according to claim 6: it is characterized in that: the filtrate behind the recovery ethanol described in the step (2) is concentrated into the thick paste shape.