CN102895322B - Medicament composition for treating pulmonary interstitial fibrosis as well as preparation method and applications thereof - Google Patents
Medicament composition for treating pulmonary interstitial fibrosis as well as preparation method and applications thereof Download PDFInfo
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Abstract
The invention discloses a medicament composition for treating pulmonary interstitial fibrosis as well as a preparation method and applications thereof, wherein the medicament composition for treating pulmonary interstitial fibrosis is prepared from the raw materials of winged euonymus, rhodiola rosea, polygala fallax hemsl, herba epimedii and honey-fried licorice root, and the percentage by weight of any component does not exceed 30% of the total weight. The medicament composition for treating pulmonary interstitial fibrosis as well as the preparation method and applications thereof provided by the invention breaks through the research and development convention, and are not limited to the traditional theory of traditional Chinese medicine; the pathogenesis of pulmonary interstitial fibrosis patient is intermingled with deficiency and excess; the root is deficiency of yang and congealing cold, and the symptom is stagnant phlegm and blood stasis; prescriptions are screened bravely and are combined; and the animal experiment and clinical experiment show that the medicament composition has the characteristic of obvious effect, and has favorable clinical application prospect.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition for the treatment of interstitial pulmonary fibrosis.
Background technology
Interstitial lung disease is numerous have inflammation of lung and the general name of Fibrotic acute and chronic lung disease in various degree, and pulmonary fibrosis is its final pathological outcome.Idiopathic pulmonary fibrosis (IPF) is wherein the most representative one type, it is the mortality diffusivity interstitial diseases that a kind of etiology unknown, pathogenesis are unclear, lack treatment means, its pathological characters is damage and the fibroblast proliferation of alveolar epithelium, and is formed into the fibrocyte kitchen range.Previously the treatment of IPF be take glucocorticoid and cytotoxic drug as main, but curative effect is very micro-, and it is 2～4 years that IPF makes a definite diagnosis rear average survival time was, and within 5 years, survival rate is 30%～50%.(Idiopathic Pulmonary Fibrosis Clinical Research Network.A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.N Engl J Med; 2010,363:620-628; Raghu G, Collard HR, Egan JJ, et al.An Official ATS/ERS/JRS/ALAT Statement:Idiopathic pulmonary fibrosis:evidence-based guidelines for diagnosis and management.Am J Respir Crit Care Med, 2011,83:788-824) pulmonary fibrosis harm is serious, mortality rate is high, clinical treatment measure scarcity, therefore developing new anti-fibrosis drug seems extremely urgent, and Chinese medicine is the important sources of simple medicine.Pulmonary fibrosis belongs to Chinese medicine " consumptive lung disease " category, (chao enxiang, the difficulty of relaxing. consumptive lung disease is identification again. Beijing University of Chinese Medicine's journal, 1997,20 (5): 14-15; Open the difficulty of relaxing. try to make a comment the blood stasis consumptive lung disease. journal of shanghai Chinese medicine, 1994, (1): 7-9) nearly ten years, Chinese medicine makes some progress in the control pulmonary fibrosis, demonstrates good prospect.Aspect experiment, much research shows, no matter is the single medicinal materials such as Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis, or fixing square medicine all has and obviously alleviates effect alveolitis, the pulmonary fibrosis degree of pulmonary fibrosis model.(Zheng Lan, Zheng Jianping. nearly 10 years progress of Chinese medicine interstitial pulmonary fibrosis. the bright traditional Chinese medical science, 2011,26(1): 188-191) as number of patent application 200910083617.3, disclose a kind of Chinese medicine composition for the treatment of interstitial pulmonary fibrosis in this application, specifically comprised Bulbus Fritillariae Cirrhosae, Cordyceps mycelium, Radix Notoginseng, Radix Rhodiolae, Herba Erigerontis, Radix Salviae Miltiorrhizae, Folium Ginkgo, Hirudo, Pheretima, the Rhizoma Anemarrhenae.As number of patent application 200810103844.3, a kind of mongolian medicine for the treatment of interstitial pulmonary fibrosis is disclosed in this application, specifically comprise Folium Ilicis Purpureae, Radix Salviae Miltiorrhizae, Radix Glehniae, Fructus Hippophae, Semen Armeniacae Amarum, Radix Glycyrrhizae Preparata, Concretio Silicea Bambusae.As number of patent application 201010000734.1, this patent discloses a kind of breviscapine and Ginsenoside Rg1 compositions that is used for the treatment of interstitial pulmonary fibrosis, and its weight ratio is 2～5:1～2.As number of patent application 201010000735.6, this application provides the application of Ginsenoside Rg1 in preparation treatment interstitial pulmonary fibrosis medicine.
The treatment that above research is primary disease provides valuable experience.
But we are acutely aware also, the relevant traditional Chinese medical science research data of primary disease is less, has plenty of the case report, and difficulty has stronger cogency.In addition, Most scholars is held stasis of blood argument under the arm mainly with blood stasis or deficiency of qi and yin, in clinical practice, has some limitations.This seminar recognizes that by clinical practice the pulmonary fibrosis characteristic of disease is simulataneous insufficiency and excessive, and the yang deficiency cold coagulation is this, and the stagnant blood stasis of expectorant is mark.
Summary of the invention
The objective of the invention is, in order to overcome weak point of the prior art, provides a kind of pharmaceutical composition for the treatment of interstitial pulmonary fibrosis and its preparation method and application.
The pharmaceutical composition for the treatment of interstitial pulmonary fibrosis of the present invention, take winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water to fall lotus, Herba Epimedii and Radix Glycyrrhizae Preparata and prepare as raw material, and the quality percentage composition of arbitrary component all is no more than 30% of total amount;
Preferably, the pharmaceutical composition of described treatment interstitial pulmonary fibrosis is prepared by the raw material with following parts by weight:
1～30 part of winged euonymus, 1～30 part of Radix Rhodiolae, Hemerocallis citrina Baroni water fall 1～30 part of 1～30 part, lotus, 1～30 part of Herba Epimedii and Radix Glycyrrhizae Preparata;
Preferably, the pharmaceutical composition of described treatment interstitial pulmonary fibrosis is prepared by the raw material with following parts by weight:
2～25 parts of winged euonymus, 2～25 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 2～25 parts of 2～25 parts, lotus, 2～25 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
Further preferred, the pharmaceutical composition of described treatment interstitial pulmonary fibrosis is prepared by the raw material with following parts by weight:
6～12 parts of winged euonymus, 6～12 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 10～18 parts of 6～12 parts, lotus, 4～10 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
Most preferred, be prepared by the raw material with following parts by weight:
Winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water fall lotus, Herba Epimedii and Radix Glycyrrhizae Preparata each 10 parts;
Perhaps:
12 parts of winged euonymus, 6 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 14 parts of 6 parts, lotus, 8 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
Perhaps:
6 parts of winged euonymus, 6 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 18 parts of 6 parts, lotus, 10 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
Perhaps:
8 parts of winged euonymus, 12 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 12 parts of 12 parts, lotus, 8 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
Perhaps:
12 parts of winged euonymus, 8 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 16 parts of 8 parts, lotus, 4 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
The preparation method of the pharmaceutical composition of described treatment interstitial pulmonary fibrosis comprises the following steps:
(1) winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to lotus, Herba Epimedii and Radix Glycyrrhizae Preparata, at room temperature, with organic solvent or aqueous solutions of organic solvent, soak 20～28 hours, the weight consumption of organic solvent or aqueous solutions of organic solvent is that winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water fall lotus, Herba Epimedii and Radix Glycyrrhizae Preparata gross weight 3～5 times, then decompression is flung to organic solvent or aqueous solutions of organic solvent obtains extractum, described extractum, as for 100 ℃～105 ℃ drying 3～5h, is obtained to extractive with organic solvent;
Described organic solvent is selected from ethanol, methanol, acetone or ethyl acetate, and the volumetric concentration of aqueous solutions of organic solvent is 65～75%;
And then will extract later winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water through organic solvent or aqueous solutions of organic solvent and fall lotus, Herba Epimedii and Radix Glycyrrhizae Preparata (2), use again the water reflux, extract, 2～4 hours of 8～12 times of weight, then collect extracting solution, proportion while being concentrated into 25 ℃ is 1.05～1.10, the water extract of acquisition;
(3) winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to organic solvent or the aqueous solutions of organic solvent extract of lotus, Herba Epimedii and Radix Glycyrrhizae Preparata and mix with water extract, obtain the pharmaceutical composition of described treatment interstitial pulmonary fibrosis;
Animal experiment proves, the pharmaceutical composition of the treatment interstitial pulmonary fibrosis that the present invention obtains, can be used for the treatment of interstitial pulmonary fibrosis, can put on the patient who needs treatment by oral route, dosage is generally 0.5～4.0 gram crude drug amount/kg body weight/sky, specifically can, according to patient's age, the state of an illness, by the doctor, be determined;
The invention still further relates to a kind of pharmaceutical composition, comprise the pharmaceutical composition of the described treatment interstitial pulmonary fibrosis for the treatment of effective dose and pharmaceutically acceptable carrier;
Described carrier refers to the carrier of pharmaceutical field routine, such as: diluent, excipient are as water etc.; Binding agent is as cellulose derivative, gelatin, polyvinylpyrrolidone etc.; Filler is as starch etc.; Burst apart agent as calcium carbonate, sodium bicarbonate; In addition, can also in compositions, add other adjuvant as flavouring agent and sweeting agent.
Compositions of the present invention can be prepared into conventional solid preparation, as tablet, capsule etc., for oral.
The present invention is according to morbidity, pathology and the clinical characters of primary disease, and in conjunction with practice, the inventor thinks, pulmonary fibrosis its essence is a kind of " carbuncle of yin nature " that appears at lungs, academic viewpoint according to Hong Guangxiang professor " controlling the not far temperature of lung ", (Zhao Fengda, Cai Canlin. the utilization that Hong Guangxiang " controls the not far temperature of lung " in the chronic cough and asthma disease. the Jiangxi Chinese medicine, 1993,24 (2): 3-4) treatment must be take warming YANG to expel cold, the clots absorbing that reduces phlegm as main, therefore the applicant has carried out screening widely to the Chinese herbal medicine with the logical effect of temperature, and composition of prescription.
The present invention is according to tcm theory, from a large amount of Chinese medicine, selected winged euonymus to select branch or the aliform appurtenance of Celastraceae plant Euonymus alatus (Thunb.) Sieb. tool aliform thing, Radix Rhodiolae is selected dry root and the rhizome of crassulaceae plants Radix Rhodiolae Rhodiola crenulata (Hook.et Thoms.) H.Ohba, Hemerocallis citrina Baroni water falls lotus and selects milk wort Polygala fallax Hemsl.[P.aureocauda Dumn] root, Herba Epimedii selects Berberidaceae plant Herba Epimedii Epimedium brevicornu Maxim and Radix Glycyrrhizae Preparata to select the Preparation process product of glycyrrhizic legume Glycyrrhiza uralensis Fisch. dry root or rhizome, above-mentioned Chinese crude drug all is purchased from peaceful medical material market, Guangzhou, above-mentioned medical material identify through attached the second yellow will sea professor of pharmacy of hospital of Traditional Chinese Medicine University Of Guangzhou and meet " Chinese pharmacopoeia 2010 editions requires or local medical material standard), as raw material, prepared the pharmaceutical composition of described treatment interstitial pulmonary fibrosis, obtained beyond thought effect.
According to " Chinese pharmacopoeia and document record:
Branch or aliform appurtenance that winged euonymus is Celastraceae plant Euonymus alatus (Thunb.) Sieb. tool aliform thing, have another name called that Ramulus Euonymi, terrible arrow, June are insulted, four sides cutting edge of a knife or a sword, castor dustpan bavin, four rib trees, Gallus jabouillei strip, halberd, JIANZHONGXIAO, anaesthetic on four sides.In Compendium of Material Medica, put down in writing: " terrible arrow is given birth between the stone of mountain, little strain Cheng Cong, long epicormic branch of spring, on bar, there is plumage at four sides as fletching, if depending on three plumages thats.Folium Isatidis, shape is wild tea seemingly, to life, sour-puckery flavor.Three, open design of scattered small flowers and plants, yellow green April.Solid Fructus Ilicis Purpureae greatly ".Winged euonymus has that removing blood stasis stimulates the menstrual flow, the effect of removing toxic substances and promoting subsidence of swelling, parasite killing.Cure mainly that lump in the abdomen caking, trusted subordinate's pain, amenorrhea, dysmenorrhea, metrorrhagia and metrostaxis, the stagnant stomachache of the stasis of blood in puerperal, retention of lochia, hernia, severe and migratory arthralgia arthralgia pain, skin ulcer are swollen, traumatic pain, abdominal pain due to worm stagnation, burn and scald, venom.
Dry root and rhizome that Radix Rhodiolae is crassulaceae plants Radix Rhodiolae Rhodiola crenulata (Hook.et Thoms.) H.Ohba.Ancient Times in China First medical science ancient books and records Shennong's Herbal is just classified Radix Rhodiolae in medicine as top grade.Radix Rhodiolae nature and flavor sweetness and bitterness is flat, returns lung, heart channel, and the function benefiting QI for activating blood circulation, promote blood circulation and relieving asthma.Cure mainly blood stasis due to qi deficiency, obstruction of qi in the chest and cardialgia, apoplectic hemiplegia, asthenia asthma.The modern pharmacology experiment finds that Radix Rhodiolae has the multiple pharmacological effect such as two-ways regulation of anti-hypoxia, resisting fatigue, antibacterial action, analgesic activity, radiation resistance, delaying senility function and Endocrine system.
It is Polygalaceae polygala Polygala aureocauda Dunn. (PAD) that Hemerocallis citrina Baroni water falls lotus, has another name called Radix polygalae arillatae. be a kind of long traditional herbal medicine that uses.The provinces and regions such as main product Fujian, Jiangxi, Hunan, Guangxi and Yunnan, the mountain valley sylvan life of being born in height above sea level 1150～1650m, the other dark and damp place of water.The Hemerocallis citrina Baroni water sweet in the mouth of falling the lotus, micro-hardship, property is flat, tepor; The effects such as tool benefiting vital QI and blood, invigorating the spleen to clear away damp pathogen, blood circulation promoting and blood stasis dispelling, regulating menstruation, it is Guangxi ethnic groups common medicine among the people, its root can nourish, strong, wind-damp dispelling, the meridians that relax, and treats body void, lumbar muscle strain, rheumatic arthritis, traumatic injury, acute, chronic hepatitis, uterine prolapse and menoxenia after being ill.Modern study proves: its root contains saponin, polysaccharide, organic acid, aminoacid etc., has defying age, improves myocardial ischemia, the effect such as immunomodulating.Obtain good effect for regulating blood fat clinically, there is good DEVELOPMENT PROSPECT.
The dried leaves that Herba Epimedii is Berberidaceae plant Herba Epimedii Epimedium brevicornu Maxim, arrow leaf Herba Epimedii Epimedium sagittatum (Sieb.Et Zucc.) Maxim, pubescence Herba Epimedii Epimedium pubescens Maxim or Herba Epimedii Epimedium koreanum Nakai.Herba Epimedii is to use one of the longest Chinese medicine, is recorded in the earliest Shennong's Herbal; Herba Epimedii is one of Chinese medicine be most widely used now, and is subject to domestic and international extensive concern, and except its traditional usage kidney invigorating and YANG supporting wind-damp dispelling, Herba Epimedii still has the effects such as immunostimulant, defying age, antitumor, anti-AIDS.Clinically, Herba Epimedii is usually used in treating the diseases such as osteoporosis, climacteric syndrome, lump in breast, hypertension, coronary heart disease.
Radix Glycyrrhizae Preparata: dry root and rhizome that Radix Glycyrrhizae is leguminous plant Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. Glycyrrhiza inflate Bat. or Glycyrrhiza glabra L. Glycyrrhiza glabra L., Radix Glycyrrhizae Preparata is the Preparation process product of Radix Glycyrrhizae, sweet in the mouth is flat, GUIXIN, lung, spleen, stomach warp.Function spleen reinforcing stomach function regulating, Yiqi and vein recovery, cure mainly spleen and stomach function and go down, and large loose stool is thin, weak heating and cough, cardiopalmus etc.
In sum, beneficial effect of the present invention:
It is conventional that the present invention breaks through research and development, be not limited to the Traditional Chinese medical theory restriction, according to interstitial pulmonary fibrosis patient's pathogenesis, be simulataneous insufficiency and excessive, the yang deficiency cold coagulation is this, the stagnant blood stasis of expectorant is mark, bold screening of medicaments prescription, and zoopery and clinical test results show, this pharmaceutical composition has the effect outstanding feature, and good potential applicability in clinical practice is arranged.
The specific embodiment
Embodiment 1
At room temperature, get winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water and fall lotus, Herba Epimedii, Radix Glycyrrhizae Preparata each 10 kilograms (totally 50 kilograms), the soak with ethanol that is 95% by 500 kilograms of volumetric concentrations of concentration is extracted, soak time is 24 hours, decompression recycling ethanol obtains extractum, extractum, as for dry 5h in the baking oven of 100 ℃, is obtained to ethanol extraction;
The winged euonymus that to cross through ethanol extraction, Radix Rhodiolae, Hemerocallis citrina Baroni water fall lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and use 500 kg of water reflux, extract, 2 hours again, and proportion when extracting solution is concentrated into 25 ℃ is 1.05～1.10, and drying, obtain water extract;
Winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to the ethanol extraction of lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and water extract and mix, obtain the pharmaceutical composition of described treatment interstitial pulmonary fibrosis.
Pharmaceutical composition 100 grams of the treatment interstitial pulmonary fibrosis of acquisition and 100 gram soluble starches can be mixed, can adopt method preparation well known in the art to become film-making.
Embodiment 2
At room temperature, get 12 kilograms of winged euonymus, 6 kilograms of Radix Rhodiolaes, Hemerocallis citrina Baroni water and fall 6 kilograms, lotus, 8 kilograms of Herba Epimedii, 14 kilograms of Radix Glycyrrhizae Preparatas (totally 46 kilograms), 460 kilograms of methanol that are 70% by volumetric concentration soak and extract, soak time is 24 hours, reclaim under reduced pressure methanol obtains extractum, extractum, as for dry 5h in the baking oven of 100 ℃, is obtained to methanolic extract;
The winged euonymus that to cross through methanol extraction, Radix Rhodiolae, Hemerocallis citrina Baroni water fall lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and use 460 kilograms of reflux, extract, 4 hours again, and proportion when extracting solution is concentrated into 25 ℃ is 1.05～1.10, and drying, obtain water extract;
Winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to the methanolic extract of lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and water extract and mix, obtain the pharmaceutical composition of described treatment interstitial pulmonary fibrosis.
Pharmaceutical composition 100 grams of the treatment interstitial pulmonary fibrosis of acquisition and 150 gram soluble starches can be mixed, adopt method well known in the art, granulate, drying, then pack into granule with water soluble polysaccharide and be in the Capsules made of raw material, obtain capsule.
Embodiment 3
At room temperature, get 6 kilograms of winged euonymus, 6 kilograms of Radix Rhodiolaes, Hemerocallis citrina Baroni water and fall 6 kilograms, lotus, 10 kilograms of Herba Epimedii, 18 kilograms of Radix Glycyrrhizae Preparatas (totally 46 kilograms), soak and extract by 460 kilograms of ethyl acetate, soak time is 24 hours, the reclaim under reduced pressure ethyl acetate obtains extractum, extractum, as for dry 5h in the baking oven of 100 ℃, is obtained to ethyl acetate extract;
The winged euonymus that will extract through ethyl acetate, Radix Rhodiolae, Hemerocallis citrina Baroni water fall lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and use 460 kg of water reflux, extract, 3 times again, and proportion when extracting solution is concentrated into 25 ℃ is 1.05～1.10, and drying, obtain water extract;
Winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to the ethyl acetate extract of lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and water extract and mix, obtain the pharmaceutical composition of described treatment interstitial pulmonary fibrosis.
Pharmaceutical composition 100 grams of the treatment interstitial pulmonary fibrosis of acquisition and 100 gram soluble starches are mixed, adopt method well known in the art granule processed, drying, obtain granule.
Embodiment 4
At room temperature, get 8 kilograms of winged euonymus, 12 kilograms of Radix Rhodiolaes, Hemerocallis citrina Baroni water and fall 12 kilograms, lotus, 8 kilograms of Herba Epimedii, 12 kilograms of Radix Glycyrrhizae Preparatas (totally 52 kilograms), soak and extract with 520 kilograms of acetone, soak time is 24 hours, reclaim under reduced pressure acetone obtains extractum, extractum, as for dry 5h in the baking oven of 100 ℃, is obtained to acetone extract;
The winged euonymus that to cross through acetone extraction, Radix Rhodiolae, Hemerocallis citrina Baroni water fall lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and use 520 kg of water reflux, extract, 4 hours again, and proportion when extracting solution is concentrated into 25 ℃ is 1.05～1.10, and drying, obtain water extract;
Winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to the alcohol extract of lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and water extract and mix, obtain the pharmaceutical composition of described treatment interstitial pulmonary fibrosis.
Pharmaceutical composition 100 grams of the treatment interstitial pulmonary fibrosis of acquisition and 100 gram soluble starches can be mixed, adopt method preparation well known in the art to become tablet.
Embodiment 5
At room temperature, get 12 kilograms of winged euonymus, 8 kilograms of Radix Rhodiolaes, Hemerocallis citrina Baroni water and fall 8 kilograms, lotus, 4 kilograms of Herba Epimedii, 16 kilograms of Radix Glycyrrhizae Preparatas (totally 48 kilograms), 480 kilograms of alcohol solution dippings that are 70% by volumetric concentration extract, soak time is 24 hours, decompression recycling ethanol obtains extractum, extractum, as for dry 5h in the baking oven of 100 ℃, is obtained to ethanol extraction;
The winged euonymus that to cross through ethanol extraction, Radix Rhodiolae, Hemerocallis citrina Baroni water fall lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and use 480 kg of water reflux, extract, 2 hours again, and proportion when extracting solution is concentrated into 25 ℃ is 1.05～1.10, and drying, obtain water extract;
Winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to the ethanol extraction of lotus, Herba Epimedii, Radix Glycyrrhizae Preparata and water extract and mix, obtain the pharmaceutical composition of described treatment interstitial pulmonary fibrosis.
Can adopt method well known in the art, preparation becomes oral liquid formulations.
Embodiment 6
One, the treatment interstitial pulmonary fibrosis pharmaceutical composition that in following test, pharmaceutical composition used is embodiment 1 and embodiment 4;
Two, test is for observing effect and the Partial Mechanism of this medicine composite for curing interstitial pulmonary fibrosis.
1. materials and methods
1.1 the animal health male Wistar rat, weight 180～200g, be purchased from Guangdong Medical Lab Animal Center, laboratory animal licence numbering: 0086042, and the Experimental Establishment quality certification number: 0044963.
1.2 medicine Bleocin Hydrochloride (Haizheng Medicine Stock Co., Ltd., Zhejiang Prov).
1.3 instrument KMB biological tissue embedding machine (Jinhua, Zhejiang section enlightening instrument and equipment company limited); RM2126 paraffin slicing machine (Shanghai Lai Ka Instrument Ltd.); DH9l43B III electric heating constant-temperature blowing drying box (Shanghai new talent medical apparatus and instruments manufacturing company; Axiostar Plus biological microscope (German Carl Zeiss company).
1.4 animal grouping and 80 Wistar male rats of modeling are divided into 4 groups, 20 every group at random.Be respectively normal group, model group, positive drug group (prednisoni acetas) and pharmaceutical composition group, wherein normal group is normal the raising, other 3 treated animals are with after 10% chloral hydrate intraperitoneal injection of anesthesia, lie on the back and be fixed on the Mus platform, successively separate after the cervical region ethanol disinfection and expose trachea, syringe thrusts trachea through the tracheal cartilages czermak space, slowly Injecting Bleomycin after Retaining (5mg/kg), after notes, immediately by the upright also left rotation and right rotation of animal, medicinal liquid is uniformly distributed in lung.Postoperative the 2nd day starts gastric infusion, and positive drug group dosage is 1.5mgkgd
-1, pharmaceutical composition group dosage is 20mgkgd
-1.Model group gives isopyknic normal saline.Experimental session, rat freely drinks water and takes food, administration, after 14 days, is got 10 sacrifice of animal for every group at random, after weighing with 2% pentobarbital sodium intraperitoneal injection of anesthesia (2.5mL/kg)) after be fixed on operating board, by abdominal aortic blood, separation of serum.Separate again trachea and lungs, after the ligation trachea, take out lungs, then from tracheal intubation to left principal bronchus, carry out bronchoalveolar lavage, collect bronchoalveolar lavage fluid (overall recovery be greater than irrigating solution 90%).Get lung tissue, observe lung morphology and change, all the other animals are put to death in administration after 28 days, carry out same experimental implementation.
1.5 lung morphology is observed lung tissue disease's Neo-Confucianism and is checked that the pathology method is fixed routinely, dehydration, and embedding, section, according to the HE dyeing evaluation alveolar degree of inflammation for method of SZAPIEL, Masson dyeing evaluation pulmonary fibrosis degree.The ranked data of pulmonary fibrosis and alveolar degree of inflammation are converted into measurement data, and method is as follows: count 0 minute for 0 grade, count 1 minute for 1 grade, by that analogy.
2. result
2.1 respectively organize microscope under the observed result of H-E coloration result administration after 14 days found: normal group terminal bronchiole, respiratory bronchioles, alveolar duct and alveolar structure are normal.A large amount of fibroplasia kitchen ranges has appearred in the model group alveolar septum, i.e. the consolidation district.Positive drug group inflammation and fibrosis kitchen range are staggered, visible consolidation district around the part bronchia.The pharmaceutical composition group also shows inflammation and fibrosis kitchen range.Respectively organize microscope under the observed result of administration after 14 days found: the normal group structure is normal.Model group fibrosis rats degree is obvious, and large stretch of consolidation district is arranged, and around bronchus, fibrosis is higher.The part alveolar wall obviously thickens, and alveolar septum fibrosis focus is remarkable.The expansion of part alveolar space is cryptomere, the alveolar wall fracture, and alveolar space withers.Visible fiber focus still around positive drug group alveolar septum and bronchus, the inflammatory cell be dispersed in as seen in part alveolar and bronchioles.Pharmaceutical composition group alveolar septum fibroplasia kitchen range is less, has no obvious inflammatory cell in alveolar.
2.1 the Masson dyeing evaluation pulmonary fibrosis degree result of table 11 and table 12 as a result shows: administration is after 14 days and 28 days, the alveolar inflammation order of severity of model group is apparently higher than normal group (P<0.01), the alveolar inflammation order of severity of positive drug group and pharmaceutical composition group and model group are relatively, there is significance to reduce (P<0.01), pharmaceutical composition group and positive drug group are relatively, the alveolar inflammation order of severity of 2 groups was at the 14th day there was no significant difference (P>0.05), but the alveolar inflammation order of severity of the 28th day pharmaceutical composition group wants significance lower than positive drug group (P<0.05).
The result of table 21 and table 22 shows: administration is after 14 days and 28 days, the pulmonary fibrosis degree of model group is apparently higher than normal group (P<0.01), the pulmonary fibrosis degree of positive drug group and pharmaceutical composition group and model group are relatively, there is significance to reduce (P<0.01), pharmaceutical composition group and positive drug group are relatively, the pulmonary fibrosis degree of 2 groups was at the 14th day there was no significant difference (P>0.05), but the pulmonary fibrosis degree of the 28th day pharmaceutical composition group wants significance lower than positive drug group (P<0.05).
Table 11 is respectively organized the alveolar inflammation order of severity relatively
Minute
(with model group, compare ， ﹡ P<0.05 ， ﹡ ﹡ P<0.01; Compare △ P<0.05, △ △ P<0.01 with positive controls.）
Table 12 is respectively organized the alveolar inflammation order of severity relatively
Minute
(with model group, compare ， ﹡ P<0.05 ， ﹡ ﹡ P<0.01; Compare △ P<0.05, △ △ P<0.01 with positive controls.）
Table 21 is respectively organized the Pulmonary Fibrosis in Rats degree relatively
Minute
(with model group, compare ， ﹡ P<0.05 ， ﹡ ﹡ P<0.01; Compare △ P<0.05, △ △ P<0.01 with positive controls.）
Table 22 is respectively organized the Pulmonary Fibrosis in Rats degree relatively
Minute
(with model group, compare ， ﹡ P<0.05 ， ﹡ ﹡ P<0.01; Compare △ P<0.05, △ △ P<0.01 with positive controls.）
To sum up, this animal test results confirms to use pharmaceutical composition of the present invention can significantly reduce the Pulmonary Fibrosis in Rats with Bleomycin-induced alveolar inflammation order of severity and pulmonary fibrosis degree, and its curative effect was better than prednisolone acetate in the time of the 28th day.
Embodiment 7
One, the treatment interstitial pulmonary fibrosis pharmaceutical composition that in following test, pharmaceutical composition used is embodiment 1 and embodiment 4;
Two, test is for observing effect and the Partial Mechanism of this medicine composite for curing interstitial pulmonary fibrosis.
1. materials and methods
1.1 interstitial pulmonary fibrosis patient's case is selected
Include 60 interstitial pulmonary fibrosis patients in, test method according to randomized, double-blind, the experimenter is divided into to 2 groups, every group of 30 people, all cases all meets " diagnosis of idiopathic lung (interstitial) fibrosis and the treatment guide (draft) " that respirology branch of Chinese Medical Association works out.Exclusion standard: 1. suffer from severe cardiac Liver and kidney and other serious systemic disease persons; 2. the person that suffers from the psychosis; 3. complication with diabetes person; 4. merge pulmonary tuberculosis and other infectious disease person; 5. the person once used steroid hormone or other immunosuppressant in first 1 month; 6. be reluctant in the patient treatment way that continuation is treated by experimental program and compliance is poor or person lost to follow-up.Two groups of sex ratios, age, body weight, the course of disease, pulmonary function change and chest high resolution ct (HRCT) aspect differences are learned by statistics and are processed not statistically significant (P>0.05), have comparability.
1.2 the double spiral CT of detecting instrument Siemens; Germany Jaeger company lung function instrument.
1.3 curative effect observation efficacy determination, according to patient clinical remission degree, is judged to be improvement or invalid; Before and after treatment, relatively, the person of being improved, be judged to be improvement, without significant change, is invalid for lung CT, pulmonary diffusion function, serum fibrosis markers.
1.4 the Therapeutic Method all cases all on the basis of conventional therapy, the pharmaceutical composition of the present invention for the treatment of group (the Science and Technology Industrial Park Drug Manufacturing Room of Traditional Chinese Medicine University Of Guangzhou provide), each dosage is 3g crude drug kg
-1D
-1, every day 2 times; The oral prednisone acetate tablets of matched group (Tianjin Pacific Pharmaceutical Co., Ltd.), each dosage is 0.5mgkg
-1D
-1, every day 2 times.Be 8 weeks two groups of courses for the treatment of.
2. result
The compositions that table 31 is embodiment 1, the compositions that table 32 is embodiment 4, result from table 31 and table 32, the interstitial pulmonary fibrosis patient uses pharmaceutical composition of the present invention after 8 weeks, its dyspnea, zest dry cough, mobility and pulmonary diffusion function all have improvement in various degree, and effect is better than prednisone acetate tablets (P<0.05), the breast CT result shows 2 groups of curative effect there was no significant differences (P>0.05).
Cardinal symptom, breast CT and lung disperse situation comparative example (%) after table 31 liang group treatment
Cardinal symptom, breast CT and lung disperse situation comparative example (%) after table 32 liang group treatment
To sum up, this clinical test results shows, pharmaceutical composition of the present invention improves interstitial pulmonary fibrosis patient respiratory difficulty, zest dry cough, mobility, pulmonary diffusion function etc. and has good therapeutic effect, and effect significantly is better than prednisone acetate tablets, the result that breast CT is improved with the prednisone acetate tablets there was no significant difference.
Claims (6)
1. treat the pharmaceutical composition of interstitial pulmonary fibrosis, it is characterized in that, the pharmaceutical composition of described treatment interstitial pulmonary fibrosis is prepared by the raw material with following parts by weight: 6～12 parts of winged euonymus, 6～12 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 10～18 parts of 6～12 parts, lotus, 4～10 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas.
2. the pharmaceutical composition for the treatment of interstitial pulmonary fibrosis according to claim 1, is characterized in that, is prepared by the raw material with following parts by weight: winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water fall each 10 parts of lotus, Herba Epimedii and Radix Glycyrrhizae Preparatas;
Perhaps:
12 parts of winged euonymus, 6 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 14 parts of 6 parts, lotus, 8 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
Perhaps:
6 parts of winged euonymus, 6 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 18 parts of 6 parts, lotus, 10 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
Perhaps:
8 parts of winged euonymus, 12 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 12 parts of 12 parts, lotus, 8 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas;
Perhaps:
12 parts of winged euonymus, 8 parts of Radix Rhodiolaes, Hemerocallis citrina Baroni water fall 16 parts of 8 parts, lotus, 4 parts of Herba Epimedii and Radix Glycyrrhizae Preparatas.
3. the method for the pharmaceutical composition of the described treatment interstitial pulmonary fibrosis of preparation claim 1～2 any one, is characterized in that, comprises the following steps:
(1) winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to lotus, Herba Epimedii and Radix Glycyrrhizae Preparata, at room temperature, with organic solvent or aqueous solutions of organic solvent, soak 20～28 hours, the weight consumption of organic solvent or aqueous solutions of organic solvent is that winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water fall lotus, Herba Epimedii and Radix Glycyrrhizae Preparata gross weight 3～5 times, then decompression is flung to organic solvent or aqueous solutions of organic solvent obtains extractum, described extractum is placed in to 100 ℃～105 ℃ drying 3～5h, obtains extractive with organic solvent;
Described organic solvent is selected from ethanol, methanol, acetone or ethyl acetate, and the volumetric concentration of aqueous solutions of organic solvent is 65～75%;
(2) and then by extract winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water later through organic solvent or aqueous solutions of organic solvent fall lotus, Herba Epimedii and Radix Glycyrrhizae Preparata, use again the water reflux, extract, 2～4 hours of 8～12 times of weight, then collect extracting solution, proportion while being concentrated into 25 ℃ is 1.05～1.10, the water extract of acquisition;
(3) winged euonymus, Radix Rhodiolae, Hemerocallis citrina Baroni water are fallen to the extractive with organic solvent of lotus, Herba Epimedii and Radix Glycyrrhizae Preparata and mix with described water extract, obtain the pharmaceutical composition of described treatment interstitial pulmonary fibrosis.
4. a medicine for the treatment of interstitial pulmonary fibrosis, be comprised of the pharmaceutical composition of the described treatment interstitial pulmonary fibrosis of claim 1～2 any one for the treatment of effective dose and pharmaceutically acceptable carrier.
5. medicine according to claim 4, is characterized in that, is tablet or capsule.
6. the application of the pharmaceutical composition of the described treatment interstitial pulmonary fibrosis of claim 1～2 any one in the medicine of preparation treatment interstitial pulmonary fibrosis.
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Inventor after: Liu Liangji Inventor after: Zhang Yuanbing Inventor after: Lan Zhihui Inventor after: Fu Xiangchun Inventor before: Liu Liangji Inventor before: Zhang Yunbing Inventor before: Lan Zhihui Inventor before: Fu Xiangchun |
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