CN103127208A - Medicinal composition for treating chronic hepatopathy, and its application - Google Patents

Abstract

The invention discloses a medicinal composition for treating chronic hepatopathy. The medicinal composition is composed of astragaloside and glycyrrhizic acid, and the weight ratio of astragaloside to glycyrrhizic acid is 3-6:1. Results of tests and verification through adopting a classic animal model show that the medicinal composition can substantially reduce the collagen content of the hepatic tissue of a model rat, mitigate the hepatic fibrosis degree and the hepatic damage degree, improve the hepatic fibrosis resistance, effectively prevent the development of the hepatic fibrosis and promote the reversion of the hepatic fibrosis, the above effects are better than effects realized through singly using the above components, and the medicinal composition can be used for treating and preventing various diseases comprising chronic hepatitis, hepatic fibrosis, hepatic cirrhosis and the like. The medicinal composition can be processed to prepare oral solid preparations comprising a tablet, a granule, a capsule and the like.

Description

Pharmaceutical composition and the application thereof for the treatment of chronic hepatopathy

The application is Chinese patent CN201010263205.0(original application) divide an application, the applying date of original application is on 08 26th, 2010, invention and created name for the treatment chronic hepatopathy pharmaceutical composition and application thereof.

Technical field

The present invention relates to a kind of pharmaceutical composition and application thereof for the treatment of chronic hepatopathy; Be specifically related to a kind of pharmaceutical composition and application thereof with anti-hepatic fibrosis, anti-liver injury effect.

Background technology

Liver cirrhosis is the end stage eventually of multiple chronic hepatic diseases, forms its morphological feature with diffusivity hepatic fibrosis companion abnormal nodule.Liver cirrhosis is one of China's common disease and main Death causes, and China is the hepatitis B hotspot, and only chronic hepatitis B patient reaches 3,000 ten thousand, wherein approximately 30% develops into liver cirrhosis.Existing positive evidence show hepatic fibrosis even liver cirrhosis be reversible, blocking-up, suppress or reverse the important goal that hepatic fibrosis is the treatment chronic hepatopathy, but the anti-hepatic fibrosis chemistry or the biological preparation that there is no at present the FDA approval enter clinical practice.

The progress of external hepatic fibrosis is mainly reflected in pathogenetic further investigation.Authoritative professor Friedman of U.S. hepatic fibrosis research once pointed out: " constantly the illustrating of hepatic fibrosis mechanism makes effectively, and Strategies of Anti-fibrosis Therapy becomes possibility; yet; Strategies of Anti-fibrosis Therapy remains the challenge of a rich challenge; there is no clinically so far effective anti-hepatic fibrosis medicines, and its useful effect is in liver and without the medicine development of the obvious toxic-side effects long-term endeavour of still needing.”

Chinese patent CN1539483A discloses a kind of Chinese medicine for the treatment of chronic hepatopathy and anti-hepatic fibrosis on October 27th, 2004, belong to the Chinese medicine technical field, it is comprised of Stigma Croci 3-9 part, Gecko 3-9 part, Radix Salviae Miltiorrhizae 4-18 part, Carapax Trionycis 9-24 part, Radix Astragali 9-30 part, Radix Ginseng Rubra 3-9 part, Radix Angelicae Sinensis 1-6 part, Rhizoma Chuanxiong 1-6 part, Fructus Amomi 1-6 part, Bombyx Batryticatus 1-6 part, Radix Notoginseng 3-9 part, Fructus Lycii 1-9 part, Radix Aucklandiae 1-6 part, through screening cleaning, be ground into fine powder, sieve, mixing, every 100 gram powder add honey refining 100 grams, make honeyed pill, sterilize with Co 60; The present invention can treat chronic hepatitis and hepatic fibrosis effectively through clinical proof, and total effective rate can reach 94%.

Chinese patent CN1985902A discloses a kind of Chinese medicine for the treatment of chronic hepatopathy on 06 27th, 2007, and according to " monarch " formulation principle compatibility, monarch drug is Rhizoma Atractylodis Macrocephalae; Ministerial drug comprises Radix Panacis Quinquefolii, Polyporus, Poria, Radix Astragali; Adjuvant drug comprises Herba Sedi, Herba Hedyotidis Diffusae, Herba Artemisiae Scopariae; Make medicated bag draw together Grilled chicken Endothelium corneum, Radix Salviae Miltiorrhizae, Radix Paeoniae Rubra, the Radix Paeoniae Alba; The percentage by weight of each component is: Rhizoma Atractylodis Macrocephalae 5%～18%, Radix Panacis Quinquefolii 1%～10%, Polyporus 1%～15%, Poria 0%～15%, Radix Astragali 5%～20%, Herba Sedi 10%～50%, Herba Hedyotidis Diffusae 5%～30%, Herba Artemisiae Scopariae 1%～15%, Grilled chicken Endothelium corneum 1%～10%, Radix Salviae Miltiorrhizae 0%～15%, Radix Paeoniae Rubra 1%～10%, the Radix Paeoniae Alba 1%～10%, each component summation is 100%.

Chinese patent CN101361782A discloses a kind of medicine for the treatment of chronic hepatopathy on 02 11st, 2009, adopt Cordyceps polysaccharide, amygdalin, Herb Gynostemmae Pentaphylli total glycosides Chinese medicine active component or the one-tenth of specific proportioning to be grouped into the anti-hepatic fibrosis of desirable curative effect, the pharmaceutical composition of anti-liver injury effect.

In recent years, disease combination under Chinese medicine organic conception (system approach) instructs, determination for the treatment of based on pathogenesis obtained through differentiation of symptoms and signs show out theory characteristic and clinical advantage gradually to solving this difficult problem, not only can improve clinical symptoms and liver function, significantly improve Quality of Life, and suppressing inflammation reaction and proliferation of fibrous tissue, promote the aspects such as reverse of hepatic fibrosis to demonstrate advantage.China nearly two Liver Fibrosis with Traditional Chinese Medicine research has during the last ten years obtained remarkable break-throughs.From 2000, successively there is the national new Chinese medicine of the anti-hepatic fibrosis such as FUFANG BIEJIA RUANGAN PIAN, FUZHENG HUAYU JIAONANG (sheet) to be applied to clinical, Fuzhenghuayu tablet is carried out anti-hepatitis C hepatic fibrosis II clinical trial phase by drugs approved by FDA in the U.S..The Chinese medicine compound effect of anti hepatic fibrosis is realized by multipath, multi-level effect, presents comprehensive effect, adapts with the complicated pathomechanism of hepatic fibrosis genesis, and this is the advantage place of Chinese medicine organic conception just also.

Nearly two during the last ten years, also carried out the research of some anti-hepatic fibrosis Chinese medicine active components or composition both at home and abroad, and found Chinese medicine active component or the composition that some have the anti-hepatic fibrosis effect.Yet no matter Chinese medicine compound recipe or single effective ingredient, all have its weak point.The Chinese medicine compound recipe is due to complicated component, and Quality Control is difficult, less stable, and this is also one of difficult problem of internationalization of tcm; And one-component or composition often are difficult to obtain good effect or obvious side effect will appear in effective dose.Therefore how traditional compound recipe " being discarded the dross and selected the essential " and keeps the compound Chinese prescription compatibility to treat the advantage of complex disease, is a great problem, is also one of important development direction of Liver Fibrosis with Traditional Chinese Medicine drug research.

Summary of the invention

Technical problem to be solved by this invention is to provide and a kind ofly can improves anti-hepatic fibrosis, anti-liver injury effect, can effectively treat the pharmaceutical composition of chronic hepatopathy, and propose the purposes of this pharmaceutical composition.

In order to solve the problems of the technologies described above, the present invention uses mathematical model " uniform Design " and orthogonal design analytical technology, on the prior art basis, carry out the research of active component/components compatibility anti-hepatic fibrosis, adopted the pharmaceutical composition of Radix Astragali total glycosides (Astragalus Astragalosides) and glycyrrhizic acid (Glycyrrhiza Acid) Chinese medicine active component or the anti-hepatic fibrosis that becomes to be grouped into, anti-liver injury effect to screen.

Pharmaceutical composition of the present invention is by two kinds of components of Radix Astragali total glycosides and glycyrrhizic acid or become to be grouped into, and the weight ratio of Radix Astragali total glycosides and glycyrrhizic acid is 3～6:1, and wherein Radix Astragali total glycosides derives from the Radix Astragali; Glycyrrhizic acid derives from glycyrrhiza uralensis fisch.

Method and the conventional method of the prior art extracting Radix Astragali total glycosides and extract glycyrrhizic acid from the Radix Astragali from Radix Glycyrrhizae are as good as.The preparation method of pharmaceutical composition of the present invention there is no special feature, takes by weight Radix Astragali total glycosides and glycyrrhizic acid, makes according to a conventional method clinical common dosage forms, and the dosage form of described preparation comprises the oral solid formulations such as tablet, granule, capsule.

Pharmaceutical composition of the present invention is through N-nitrosodimethylamine (Dimethylnitrosamine, the hepatic injury of the classics of DMN) inducing, Hepatic Fibrosis of Animal model test (get involved in the model evolution and intervene), and use " uniform Design " and " orthogonal design " screening and checking repeatedly.The result confirmation, medicine of the present invention can significantly reduce rat model hepatic tissue collagen content, alleviates degree of hepatic fibrosis regulating liver-QI degree of injury, and above-mentioned effect is better than the alone effect of each component.The effect that the medicine of described 2 kinds of components or components compatibility combination can improve anti-hepatic fibrosis can effectively stop the development of hepatic fibrosis and the reverse of promotion hepatic fibrosis, can be used for treatment and prevents the diseases such as various chronic hepatitiss, hepatic fibrosis, liver cirrhosis.

Description of drawings

Fig. 1 be embodiment 1 respectively organize liver tissues of rats Picro-Sirius red collagen staining photo (* 100).

The specific embodiment

Below in conjunction with the drawings and specific embodiments, further set forth the present invention.These embodiment are interpreted as only being used for explanation the present invention and are not used in restriction protection scope of the present invention.After the content of having read the present invention's record, those skilled in the art can make various changes or modifications the present invention, and these equivalences change and modification falls into claim limited range of the present invention equally.

Pharmaceutical composition beneficial effect of the present invention passes through following experiment confirm:

Embodiment 1

The Rat Liver Fibrosis Model that utilization DMN induces and orthogonal design analysis obtain the optimal proportion of the compositions of reduction Liver Collagen content effect.

One, materials and methods:

1. animal

160 of Wistar male rats (40 of normal group, 120 of modeling groups), the cleaning level, body weight (150 ± 10) g is provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center.Shanghai Univ. of Traditional Chinese Medicine's Experimental Animal Center cleaning level Animal House raising, modeling and observation are freely drunk water.

2. main agents and equipment

N-nitrosodimethylamine (Dimethylnitrosamine, DMN) and hydroxyproline (hydroxyproline, Hyp) standard substance, Tokyo HuaCheng Industry Co., Ltd's product; Hepatest box used is all available from build up biological reagent company in Nanjing; Image-Pro Plus6.1 specialty image analysis software is available from Media Cybernetics company; Olympus IX70 optical microscope is available from Olympus company.

3. medicine

Radix Astragali total glycosides (Astragalus Astragalosides, A): derive from the Radix Astragali, Xi'an Honson Biotechnology Co., Ltd.'s product, specification 90%; Glycyrrhizic acid (Glycyrrhiza Acid, B): derive from Radix Glycyrrhizae, Nanjing Zelang Pharmaceutical Technology Inc.'s product, specification 98%.

Radix Astragali total glycosides and glycyrrhizic acid according to weight ratio 3:1,4:1,5:1 and 6:1 mix homogeneously, are chosen the pharmaceutical composition A+B that is mixed to get by different proportion at random, be used for experimental program subsequently.

4. model preparation

With reference to Ala-Kokko method modeling (Ala-Kokko L, Pihlajaniemi T, Myers JC et al.Gene expression of type I, III and IV collagens in hepatic fibrosis induced by dimethylnitrosamine in the rat.Biochem J 1987; 244:75 – 9.).Be 0.5% solution with DMN dilution with normal saline, 120 rats of modeling group are with 2ml/g body weight dosage, lumbar injection every day 1 time, front 3 days continuous lumbar injections, totally 4 weeks weekly.40 lumbar injection equivalent normal saline of rats in normal control group.

5. grouping and administration

4 weekends are got 10 normal rats in 3 weekends of 2 weekends of 3 days ends of modeling, modeling, modeling, modeling, 10 rat models are dynamically observed as model, from 2 weekends of modeling, modeling type rat is divided into orthogonal design 1-6 group and model group at random, every group each 10, when continuing modeling, the orthogonal design group becomes 8 times of amounts of the body weight such as body weight for humans quantity to carry out pharmaceutical intervention by 65kg, respectively according to the design administration.The 10mL distilled water diluting is used in medicine-feeding before use, presses the dosage of 10ml/kg rat body weight with the relative medicine gavage, every day 1 time, and totally 2 weeks, and be provided with normal control rat (10) and model control group (10); Normal rat and model control group are with volume distilled water gavage.

6. experimental program

As investigating the factor, each factor is got respectively 2 levels (1 level=medication, 2 levels=need not), obtains the orthogonal design scheme with Radix Astragali total glycosides A, glycyrrhizic acid B and pharmaceutical composition A+B.Separately establish model group and intact animal group.

7. statistical method

Measurement data is used SAS9.1.2 is adopted in expression, and DAS2.1.1 and SPSS16.0 statistical software deal with data adopt one factor analysis of variance to carry out between many groups relatively.

Two, result shows

Normal liver tissue is only seen a small amount of collagen fiber in portal area and central vein wall.The collagen fiber of DMN modeling hypertrophy during 4 week are cut apart lobules of liver and are formed thicker, fine and close complete interval, and the normal hepatocytes leaflet structure disappears, and forms individually imperfect pseudolobuli, and 89% rat model has formed the hepatic fibrosis of III phase.Medication group rat collagen fiber hypertrophy situation has in various degree and alleviates, and the fibrous septum is narrower, loose and discontinuous, sees accompanying drawing 1.

The hydroxyproline content measurement result shows, compares with model group, and A+B group liver tissues of rats hydroxyproline content significantly reduces (P ﹤ 0.01) than 4 all model control group, sees Table 1.

Table 1. is respectively organized rat liver Collagen Proliferation degree by stages

Annotate: with the Normal group comparison same period, * *, P＜0.01; With the model group comparison same period, ##, P＜0.01

With normal group relatively, modeling is rat model Serum ALT, AST, ALP activity and TBil content significantly raise (P＜0.01) during 4 week.Compare the active significantly reduction (P＜0.01) of A+B group rat blood serum ALT with 4 all model group; A+B and A group serum AST activity also significantly reduce (P ﹤ 0.05); A+B and B group rat blood serum ALP activity are significantly lower than 4 all model control group (P＜0.01); B group rat blood serum TBiL activity is also significantly lower than 4 all model control group (P＜0.05).The results are shown in Table 2.

Table 2. serum liver changes of function (

)

Annotate: with the Normal group comparison same period, *, P＜0.05, * *, P＜0.01.With the model group comparison same period, #, P＜0.05, ##, P＜0.01.

The ceiling effect that reduces hepatic tissue Hyp content and serum ALT activities is combined as A+B; Reducing the AST ceiling effect is A and A+B.Improving Alb content ceiling effect is A and A+B.Reduce the ALP ceiling effect and be combined as B and A+B.To sum up, A and B have the collaborative effect that reduces serum ALT activities and hepatic tissue hydroxyproline content and significantly improve Liver Fibrosis Stages; B is the main component that reduces TBil content, and the A medical instrument has the effect of remarkable reduction AST.

Claims (3)

1. the application of Radix Astragali total glycosides in preparation treatment chronic hepatitis medicine.

2. the application of Radix Astragali total glycosides in preparation control hepatic fibrosis medicines.

3. the application of Radix Astragali total glycosides in preparation control liver cirrhosis medicine.

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