CN105497003B - Application of the epimedium aglucone in preparation prevention or treatment pulmonary fibrosis medicine - Google Patents
Application of the epimedium aglucone in preparation prevention or treatment pulmonary fibrosis medicine Download PDFInfo
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- CN105497003B CN105497003B CN201410505292.4A CN201410505292A CN105497003B CN 105497003 B CN105497003 B CN 105497003B CN 201410505292 A CN201410505292 A CN 201410505292A CN 105497003 B CN105497003 B CN 105497003B
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Abstract
The present invention is claimed epimedium aglucone and is used to prepare prevention or treats the purposes of pulmonary fibrosis medicine, belongs to field of medicaments.Epimedium aglucone of the present invention is the traditional Chinese medicine monomer extracted from traditional Chinese medicine Herba Epimedii, and animal experiment is shown, has significant preventive and therapeutic effect for pulmonary fibrosis.The effect of epimedium aglucone pulmonary fibrosis resistant is curative for effect, side effect is low, there is wide medical applications prospect.
Description
Technical field
The invention belongs to field of medicaments, are related to a kind of medical usage of epimedium aglucone, and in particular to epimedium aglucone exists
Medical usage in preparation prevention or treatment pulmonary fibrosis medicine.
Background technique
Pulmonary fibrosis is the final pathological change of a variety of interstitial lung diseases, it is characterized in that long-term Diffuse alveolar is scorching, at
It is excessive then to there is extrtacellular matrix deposition, and gradually replaces normal lung tissue for fibrocyte hyper-proliferative, ultimately causes lung function
Energy obstacle, patient may be dead due to respiratory failure.Pulmonary fibrosis can substantially be divided into reason bright (such as radioactive ray, drug, silicosis
Deng) and unknown (such as idiopathic pulmonary fibrosis) two major classes of reason.Pathogenic microorganism, dust, drug, chemicals etc. are thought in research
Many factors can induce the generation of pulmonary fibrosis, but its detailed mechanism is unclear.Pulmonary fibrosis can betide any age,
Global incidence is 7-10/10 ten thousand, and patient's mean survival time is 3-4, and with advancing age, disease incidence gradually increases
And the mean survival time is gradually shortened.It can be seen that pulmonary fibrosis seriously endangers human health and survives, pulmonary fibrosis resistant medicine
The research and development of object seem particularly significant.
The drug of pulmonary fibrosis resistant mainly has at present: 1) glucocorticoid, is the main selection of current clinical treatment, but this
A possibility that class Drug side reaction is big, seriously affects body's immunity, increases secondary infection；2) interferon gamma (IFN-γ),
Adverse reaction is more, easy induction tolerance；3) cytotoxic drug (imuran, cyclophosphamide etc.), therapeutic agent poor selectivity,
Adverse reaction is more；4) antioxidant (N-acetylcystein etc.), curative effect is not ideal enough；5) other drugs, colchicin, pyrrole coffee
Ketone etc..In consideration of it, it is necessary to the drugs of efficient, the safe treatment pulmonary fibrosis of development of new.
Herba Epimedii is Berberidaceae plant Herba Epimedii, Epimedium sagittatum, Epimedium acuminatium, E. wushanense T. S. Ying or korean epimedium herb
Dry aerial parts.Herba Epimedii contains a variety of flavones ingredients, such as icariin, icariside, epimedium aglucone
(Icaritin, ICT) etc..Chinese medicine thinks its acrid flavour, sweet, warm-natured, returns liver and kidney channel, cures mainly function: kidney-replenishing, strengthening the bones and muscles, wind-dispelling
It is wet.Epimedium aglucone category flavonoid drugs, are present in epimedium herb, chemical structural formula is as follows on a small quantity:
Epimedium aglucone can isolated from the cylinder metabolism-ure of epimedium herb or icariin (Sun Pengyue, Xu
Grain husk, text is bright etc., the chemical component of korean epimedium herb, Chinese Plants The Chemicals, 1998,8 (2): 122-125；Liu strong determined person, king
It is firm, Wu Lijun etc., metabolic conversion of the intestines bacterium metabolism research I. intestinal bacterium of icariin to icariin, 2000,31 (11):
834-837), or by icariin through digest it is isolated (Ye Haiyong, Liu Jian, Lou Yijia, the preparation of two derivatives from icariin and investigation and
Its estrogen-like effects, journal of Zhejiang university, 2005,34 (2): 131-136).
There is document report epimedium aglucone and causes rat primary cultured nerve cell apoptosis (Zhang Xiang with anti-A β peptide
South, Wang Huanhuan, Wang Zhiqiang etc., the anti-A β peptide of epimedium aglucone cause the effect of rat primary cultured nerve cell apoptosis, Zhejiang University
Journal, 2007,36 (3): 224-226).It is raw with antineoplastic vascular that Chinese patent CN101836976A discloses epimedium aglucone
At effect.Chinese patent CN101428015A, which discloses epimedium aglucone, has the function for the treatment of endotoxemia.Chinese patent
CN101284000A, which discloses epimedium aglucone, to be had the function of preventing and treating obesity or fatty liver.Chinese patent CN1869204A is public
Purposes of the epimedium aglucone in terms of inducing stem cell in vitro directed differentiation is opened.Chinese patent CN1194701C discloses excessive sheep
Leaves of pulse plants aglycon or demethyl epimedium aglucone, which have, is preparing the application in estrogenic agents.
But the research in terms of so far, having no in relation to epimedium aglucone pulmonary fibrosis resistant bioactivity or clinical application.
Summary of the invention
The present invention provides the drugs of a kind of new prevention or treatment pulmonary fibrosis, and the drug is using epimedium aglucone as drug
Active constituent.Epimedium aglucone is a kind of traditional Chinese medicine monomer extracted from Herba Epimedii, the prior art indicate that it is with a variety of
Therapeutic activity, therefore the present invention relates to the new medical usage of one kind of epimedium aglucone, i.e. epimedium aglucone in preparation prevention or
Treat the purposes in pulmonary fibrosis medicine.
In medical usage described above, epimedium aglucone can be prepared into suitable pharmaceutical dosage form oral administration or injection
Administration, applicable object can be people or other homeothermal animals.When applicable object is people, the dosage of epimedium aglucone is preferably
0.001mg/kgd~50mg/kgd, further preferably 0.01mg/kgd~10mg/kgd.The present invention is prevented
Or the administration time and administration number of times of the drug for the treatment of pulmonary fibrosis need depending on the specific diagnostic result of the state of an illness, this is at this
Within the technical scope that field technical staff grasps.For example, the therapeutic scheme application that will prevent mouse or treat pulmonary fibrosis
In on the person, drug used can convert to the effective dose of people by effective dose of the drug to mouse, this for
It is obvious for those skilled in the art.
In medical usage described above, epimedium aglucone can be prepared into according to the animal state of an illness and agents area by conjunction
Suitable pharmaceutical preparation is to facilitate medication, as epimedium aglucone can develop into oral preparation, sublingual administration preparation or ejection preparation
Facilitate the use of patient, wherein the oral preparation can be tablet, capsule or microemulsion formulation, preferably tablet；The tongue
Under containing formulation be containing epimedium aglucone and to be applicable in the pharmaceutical preparation of sublingual administration, preferably its sublingual tablet；The injection system
Agent can be its injection, injection micro emulsion etc., preferably injection.When epimedium aglucone is prepared into injection, drug can be connect
The carrier received can be water for injection, sodium chloride, sodium citrate, citric acid, glycerol, ethyl alcohol, propylene glycol etc..Excessive sheep described above
Suitable additives can also be added in leaves of pulse plants aglycon injection according to the property of drug, such as osmotic pressure regulator, pH adjusting agent, increasing
Solvent, treatment oxygen agent, bacteriostatic agent, emulsifier, suspending agent etc., wherein the solubilizer is polyethylene glycol 400, in Tween-80
Any one or two kinds.
The preparation method of said medicine preparation can be used those skilled in the art and prepare this kind of dosage form routinely using preparation
Method is made.In said medicine preparation, the content in each preparation unit containing epimedium aglucone is 0.001mg~50mg.
Compared with prior art, present invention has an advantage that
1, epimedium aglucone of the present invention has the function of significantly preventing or treating pulmonary fibrosis.The present invention is implemented
Example 10 shows that epimedium aglucone of the invention can significantly improve the survival rate of pulmonary fibrosis mice, improves pulmonary fibrosis mice
Index and spleen index and thymus index, the Lung Exponent for reducing pulmonary fibrosis mice, mitigate the pulmonary fibrosis degree of pulmonary fibrosis mice, right
There is significant therapeutic effect in pulmonary fibrosis.
2, epimedium aglucone of the present invention is the natural traditional Chinese medicine monomer extracted from traditional Chinese medicine Herba Epimedii, right
Human body toxic side effect is low, can significantly improve the drug safety and compliance of patient, and then significantly improves lung fibre
The therapeutic effect and quality of life of dimensionization patient.
Specific embodiment
In order to make those skilled in the art fully understand the present invention, this hair is further illustrated below by way of specific embodiment
It is bright, but those skilled in the art should know that the embodiment of the present invention is not limit the invention in any way.
1 epimedium aglucone injection of embodiment
Preparation process: the propylene glycol of recipe quantity and ethyl alcohol are uniformly mixed, and epimedium aglucone is added, and stirring and dissolving is added
0.9% sodium chloride solution of recipe quantity, stirs evenly, be added 0.5% needle-use activated carbon, stirring, take off charcoal to get.
2 epimedium aglucone injection of embodiment
Preparation process: epimedium aglucone is added to the PEG-400 of recipe quantity, 0.9% sodium chloride solution is added in stirring and dissolving
To 10L, stir evenly, be added 0.5% needle-use activated carbon, stirring, take off charcoal to get.
3 epimedium aglucone injection of embodiment
Preparation process: the ethyl alcohol of recipe quantity and Tween-80 are uniformly mixed, and epimedium aglucone is added, and stirring and dissolving is added
Water for injection is stirred evenly to 10L, is added 0.5% needle-use activated carbon, stirring, take off charcoal to get.
4 epimedium aglucone injection of embodiment
Epimedium aglucone 0.01g
Ethyl alcohol 3.3L
Water for injection adds to 10L
Preparation process: epimedium aglucone is added in the ethyl alcohol of recipe quantity, water for injection is added to 10L, stirring in stirring and dissolving
Uniformly, be added 0.5% needle-use activated carbon, stirring, take off charcoal to get.
The preparation of 5 tablet of embodiment
Preparation process: epimedium aglucone and microcrystalline cellulose excipients, sodium carboxymethyl starch are uniformly mixed, and are added suitable
Then starch slurry softwood crosses the granulation of 16 meshes.Wet granular is crossed 20 mesh sieves, is sifted out in dry granular in 60 DEG C of dryings, dry particl
Fine powder, with magnesium stearate mix, then again with dry particl mix, tabletting, every agreement that contracts a film or TV play to an actor or actress 200mg to get.
6 epimedium aglucone sublingual tablet of embodiment
Preparation process: said components drying, pulverize and sieve pretreatment after mix direct tablet compressing be made.
7 epimedium aglucone sublingual tablet of embodiment
Preparation process: by main ingredient and the drying of each adjunct ingredient, the pretreatment that pulverizes and sieves, by main ingredient and sugar, lactose, carboxylic first
Base sodium cellulosate mixes, and the material of mixing is prepared softwood using pure water as adhesive, crosses the granulation of 20 meshes and does at 60 DEG C
Magnesium stearate is added to above-mentioned dry particl total mix by dry preparation dry particl, and tabletting to obtain the final product.
8 micro emulsion concentrate of embodiment
Preparation process: recipe quantity medium-chain fatty glyceride, Polyoxyethylene castor oil EL-40,1,2-PD, nothing are weighed
Water-ethanol stirs evenly after mixing, and epimedium aglucone dissolution is then added, can also obtain clear with ultrasonication to accelerate to dissolve
Clear concentrate, as epimedium aglucone micro emulsion concentrate.Above-mentioned micro emulsion concentrate can further be diluted for injecting or taking orally.
9 micro emulsion concentrate of embodiment
Preparation process: it is stirred after weighing recipe quantity PEG-2- stearate, Tween-20,1- hexanol, PEG3350 mixing
It is even, epimedium aglucone dissolution is then added, clarification concentrate, as Herba Epimedii can also be obtained with ultrasonication to accelerate to dissolve
Aglycon micro emulsion concentrate.Above-mentioned micro emulsion concentrate can be needed to carry out according to medication further dilution for patient's drug administration by injection or
Oral administration.
Effect study of 10 epimedium aglucone of embodiment to mouse pulmonary fibrosis
1. animal packet and administration
Healthy ICR mouse, SPF grades, male, 105, mouse is randomly divided into 7 groups by weight, often by weight (20 ± 2) g
Group 15, respectively Normal group, model control group, epimedium aglucone low dosage injection group, epimedium aglucone middle dosage note
Penetrate group, epimedium aglucone high dose injection group, epimedium aglucone stomach-filling group, Dexamethasone group.Chloraldurate is injected intraperitoneally
350mg/kg anesthetized mice, Normal group tracheal instillation physiological saline, remaining 6 groups of tracheal instillation bleomycin (5mg/kg),
It is uniformly distributed medical fluid in intrapulmonary mouse vertical rotary 2min immediately after instillation, puts back in cage and normally raise.
Epimedium aglucone and dexamethasone are suspended with 0.5% sodium carboxymethylcellulose, from after modeling the 2nd day, are continuously given
Medicine, once a day, normal group and model group give 0.5% sodium carboxymethylcellulose of equal capacity.
Each group gives following drugs respectively:
Normal group: isometric sodium carboxymethylcellulose, intraperitoneal injection
Model control group: isometric sodium carboxymethylcellulose, intraperitoneal injection
Epimedium aglucone low dosage injection group: 1mg/kg epimedium aglucone, intraperitoneal injection
Epimedium aglucone middle dosage injection group: 3mg/kg epimedium aglucone, intraperitoneal injection
Epimedium aglucone high dose injection group: 9mg/kg epimedium aglucone, intraperitoneal injection
Epimedium aglucone stomach-filling group: 15mg/kg epimedium aglucone, gastric infusion
Dexamethasone group: 5mg/kg dexamethasone sodium phosphate injection, intraperitoneal injection
2. experimental method and data processing
Daily measurement mouse weight, records mouse diing time.The 30th day after modeling, chloraldurate is injected intraperitoneally
350mg/kg anesthetized mice, abdominal aorta sacrificed by exsanguination take mouse spleen, thymus gland and lung, weigh.Take the left lung of each group mouse
Inferior lobe is placed in 4% formaldehyde and fixes, remaining lung tissue is placed in -70 DEG C of freezen protectives.
2.1 the statistics of mouse survival rate
30th day survival rate after statistics mouse modeling.
The calculating of 2.2 mouse spleens, thymus gland, Lung Exponent
Spleen, thymus gland, the Lung Exponent of each group mouse are calculated as follows.
The calculating of 2.3 mouse pulmonary fibrosis degree
After lung tissue fixes 1 week, conventional dehydration, embedding, slice, referring to (Szapiel S V, Elson N such as Szapiel
A,Fulmer J D.Bleomycin-induced interstitial pulmonary disease in the nude,
Athymic mouse [J] .Am Rev Respir Dis, 1979,120:893.) degree of method evaluation pulmonary fibrosis, and
Measurement data is converted by ranked data.Without pulmonary alveolitis or pulmonary fibrosis (-, 1 point)；Slight pulmonary alveolitis or pulmonary fibrosis (+, 2
Point)；Moderate pulmonary alveolitis or pulmonary fibrosis (++, 3 points)；Severe pulmonary alveolitis or pulmonary fibrosis (+++, 4 points).
2.4 data statistics and analysis
Data withIt indicates, variance analysis is carried out using SPSS15.0 software.
3. results and discussion
Influence of 3.1 epimedium aglucones to pulmonary fibrosis mice survival rate
1 epimedium aglucone of table causes the influence of pulmonary fibrosis mice survival rate to bleomycin
Table 1 the result shows that: the 30th day after modeling, model group mouse survival rate be 53.3%；Dexamethasone group survival rate with
Model group is close；The basic, normal, high dosage injection group mouse survival rate of epimedium aglucone is 60.0%, 93.3%, 73.3%；Excessive sheep
Leaves of pulse plants aglycon stomach-filling group mouse survival rate is 66.7%.Show that epimedium aglucone can significantly improve the survival rate of pulmonary fibrosis mice.
Influence of the 3.2 excessive leaves of pulse plants aglycons to pulmonary fibrosis mice spleen, thymus gland, Lung Exponent
2 epimedium aglucone of table causes the influence of pulmonary fibrosis mice spleen, thymus gland, Lung Exponent to bleomycin
Compared with Normal group,$P < 0.05,$$P<0.01；
Compared with model control group,#P < 0.05,##P<0.01；
Table 2 the result shows that, epimedium aglucone can be improved the index and spleen index and thymus index of pulmonary fibrosis mice, reduce lung
The Lung Exponent of fibrosis mouse.
Influence of 3.3 epimedium aglucones to pulmonary fibrosis mice various pulmonary lesions
3 epimedium aglucone of table causes the influence of pulmonary fibrosis mice pulmonary fibrosis degree to bleomycin
Compared with Normal group,$P < 0.05,$$P<0.01；
Compared with model control group,#P < 0.05,##P<0.01；
As shown in table 3, the 30th day after modeling, model group lung fibrosis degree is very serious, epimedium aglucone each group
Pulmonary fibrosis degree can significantly be lowered with Dexamethasone group, wherein epimedium aglucone middle dosage injection group reduces pulmonary fibrosis journey
The effect of degree is best.
In conclusion epimedium aglucone has effects that prevent and/or treat pulmonary fibrosis disease.
Claims (7)
1. purposes of the epimedium aglucone in preparation prevention or treatment pulmonary fibrosis medicine.
2. purposes as described in claim 1, it is characterised in that the people of the epimedium aglucone is 0.001mg/ with dosage
Kgd~50mg/kgd.
3. purposes as claimed in claim 2, it is characterised in that the people of the epimedium aglucone is 0.01mg/kg with dosage
D~10mg/kgd.
4. purposes as described in claim 1, it is characterised in that the epimedium aglucone be oral preparation, sublingual administration preparation or
Ejection preparation.
5. purposes as claimed in claim 4, it is characterised in that the oral preparation is its tablet, capsule or microemulsion formulation.
6. purposes as claimed in claim 4, it is characterised in that the ejection preparation is its injection or injection micro emulsion.
7. purposes as claimed in claim 4, it is characterised in that the content in each preparation unit containing epimedium aglucone is
0.001mg~50mg.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101284002A (en) * | 2008-02-29 | 2008-10-15 | 中国人民解放军第二军医大学 | Medicine for preventing and curing liver injury |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101284002A (en) * | 2008-02-29 | 2008-10-15 | 中国人民解放军第二军医大学 | Medicine for preventing and curing liver injury |
Non-Patent Citations (2)
| Title |
|---|
| "中药对组织器官纤维化防治机制研究";吴红媛，等;《中国实验方剂学杂志》;20131130;第19卷(第21期);第331页右栏 |
| "淫羊藿苷对卵蛋白和内毒素诱导炎症反应的影响及机制研究";徐长青;《中国博士学位论文全文数据库》;20101215;中文摘要,正文第28页 |
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