CN101081212B - Protease inhibitors liposomes aerosol - Google Patents
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- CN101081212B CN101081212B CN2007101226503A CN200710122650A CN101081212B CN 101081212 B CN101081212 B CN 101081212B CN 2007101226503 A CN2007101226503 A CN 2007101226503A CN 200710122650 A CN200710122650 A CN 200710122650A CN 101081212 B CN101081212 B CN 101081212B
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Abstract
The present invention discloses one kind of liposome aerosol with protease inhibitor for preventing and treating alveolitis and pulmonary interstitial fibrosis. The liposome aerosol of the present invention is prepared with protease inhibitor, lecithin, cholesterol, vitamin E, ether and other ingredients, and through rotary evaporation, ultrasonic crushing, vibrating stirring, compression atomizing and other steps.
Description
Patent application of the present invention is for dividing an application, and the original bill application number is 03156753.3, and the applying date is JIUYUE in 2003 9 days, and denomination of invention is the new medicine use of protease inhibitor prevention and treatment pulmonary disease.
Technical field
The present invention relates to a kind of new purposes of medicine, particularly the new purposes of protease inhibitor.
Background technology
Protease inhibitor is prevention and the active drug for the treatment of various thrombosiss, disseminated inravascular coagulation, inflammatory diseases (pancreatitis, anaphylaxis conjunctivitis, rhinitis, rheumatoid arthritis, nephritis etc.), inhibition growth of tumour cell and infiltration, autoimmune (asthma) and relevant disease.But protease inhibitor also of no use at present and be made into the report of pulmonary disease such as liposome aerosols dosage form treatment acute lung injury, the poverty-stricken disease of acute respiratory failure and pulmonary fibrosis.
Summary of the invention
The object of the invention is that open protease inhibitor is in the application that prevents and treat pulmonary disease such as alveolitis, acute lung failure, pulmonary fibrosis.
The mentioned protease inhibitor of the present invention not only comprises the generalized protease inhibitor of chemosynthesis, but also comprises the protease inhibitor of extraction from natural plants and Chinese medicine, separation, purification.
The present invention is with several protease inhibitor (PIs), as big steamed buns stuffed with sweetened bean paste Man-Bai Ke trypsin inhibitor (BBI), peas protein inhibitor Benzylsulfonyl chloride (PMSF), aprotinin protease inhibitor such as (AP), with oral, liposome aerosols atomizing suction is route of administration, the injury of lung that causes with bleomycin and Bleomycin A5 is an animal model, and the therapeutical effect of protease inhibitor to acute lung injury, chronic pulmonary damage and pulmonary fibrosis is described.
The present invention has not only comprised alveolitis and pulmonary fibrosis in many pulmonary disease of being prevented and treated, and be extended to other pulmonary disease with identical pathological change, as diseases such as asthma, chronic bronchitiss, enlarged the scope that the protease inhibitors for treating pulmonary disease is used.
Press practice of pharmacy, protease inhibitor can be added adjuvant and be prepared into the various clinical pharmaceutical dosage form, comprise the dosage form of oral formulations or parenterai administration.Said oral formulations is selected from any in tablet, capsule, pill, granule, suspensoid, drop pill, the oral liquid; Said parenterai administration dosage form is selected from a kind of in the middle of injection, aerosol, suppository or the subcutaneous administration dosage form.The preferred liposome aerosol.
Described adjuvant is meant conventional excipient, as solvent, disintegrating agent, correctives, antiseptic, coloring agent, binding agent etc.
The preparation method of described liposome aerosols is as follows:
Protease inhibitor 200-300 weight portion, lecithin 450-550 weight portion, cholesterol 200-300 weight portion, vitamin E 40-60 weight portion, propellant
12The 10-15 weight portion, phosphate buffered solution (Ph7.0～7.5) 40-60 parts by volume, ether 10-25 parts by volume; Take by weighing protease inhibitor, lecithin, cholesterol, vitamin E respectively by recipe quantity, be dissolved in fully in the diethyl ether solution; Pump remaining diethyl ether solution with rotary evaporator, and make solute form one deck homogeneous thin film at container inner wall; Slowly phosphate buffered solution is poured in the container that adheres to the solute thin film, and fully shake agitating solution, until the suspension of solute and phosphate buffered solution formation homogeneous with the ultrasonic grinding instrument; Press recipe quantity and add propellant, mixing; Solution is added the atomizing of compression atomizing inhalation machine, get final product.
The preparation method of described liposome aerosols is preferably as follows:
Protease inhibitor 250 weight portions, lecithin 500 weight portions, cholesterol 250 weight portions, vitamin E 50 weight portions, propellant 1212.5 weight portions, Ph 7.2 phosphate buffered solution 50 parts by volume, ether 15 parts by volume, take by weighing protease inhibitor, lecithin, cholesterol, vitamin E respectively by recipe quantity, be dissolved in fully in the 15ml diethyl ether solution; Pump remaining diethyl ether solution with rotary evaporator, and make solute form one deck homogeneous thin film at container inner wall; Slowly phosphate buffered solution is poured in the container that adheres to the solute thin film, and fully shake agitating solution, until the suspension of solute and phosphate buffered solution formation homogeneous with the ultrasonic grinding instrument; Press recipe quantity and add propellant, mixing; Solution is added the atomizing of compression atomizing inhalation machine, get final product; Described protease inhibitor is big steamed buns stuffed with sweetened bean paste Man-Bai Ke trypsin inhibitor or peas protein inhibitor Benzylsulfonyl chloride.
Described protease inhibitor is the various Pis that mention in the patent; Weight portion/parts by volume of the present invention is corresponding with mg/ml.
The new purposes of protease inhibitor of the present invention and pharmaceutical preparation thereof is illustrated by following experimental example.
Experimental example
Experiment purpose: observe PMSF, BBI and AP therapeutical effect to Acute Lung Injury due to the hydrochloric acid bleomycin and pulmonary fibrosis.Method: the treatment group takes that BBI is oral, atomizing sucks two kinds of different administering modes, PMSF and AP liposome aerosols atomizing inhalation, and set up model group, normal group and sham operated rats, treat after 7,28 days, get each treated animal right upper lobe specimen and carry out HE dyeing, Masson dyeing, the method that provides according to Szapiel etc., determine alveolitis (HE dyeing) and pulmonary fibrosis degree, carry out the pathology variance analysis; Observe its influence to lung tissue structure.Measure the lung tissue hydroxyproline content, and calculate the content of lung tissue collagen protein.The result: protease inhibitor (PIs) comprises that acute pulmonary alveolitis (after 7 days) and interstitial fibrosis (after 28 days) that BBI, PMSF, AP all cause the tracheal instillation bleomycin have prevention and therapeutical effect.Pathological section shows that the alveolitis degree alleviates, alveolar interstitial edema and alveolar epithelial cells desquamation alleviate.It also can slow down lung collagen protein hypertrophy and the interstitial pulmonary fibrosis that bleomycin causes simultaneously.
1. materials and methods
1.1 main medicine and reagent
BBI: this laboratory is purified; PMSF and AP are available from SIGMA company; Three kinds of albumen enzyme inhibitors become liposome aerosols by this making in laboratory respectively; Prednisoni acetas (in this experiment as positive drug): Guangdong Huanan Pharmaceutical Factory production, lot number 011201; The hydrochloride for injection bleomycin: Nippon Kayaku K. K makes, lot number X12100.
1.2 laboratory animal:
160 of healthy SD male rats, body weight 200 ± 12g is available from Beijing Wei Tongliization laboratory animal technology company limited, secondary animal.Animal feeding is at the secondary Animal House, and room temperature maintains 25 ± 2 ℃.
1.3 grouping of animal and modeling method:
During experiment rat is divided at random normal group (A group), sham operated rats (B group), model group (C group), positive drug group (D group), BBI oral group of (E group), BBI atomizing group (F group), PMSF atomizing group (G group), AP atomizing group 8 groups such as (H groups), 10 every group.With behind the 1.5% pentobarbital sodium intraperitoneal injection of anesthesia rat being fixed, the cervical region sterilization, cut skin of neck, successively peel off, expose trachea, in trachea, inject 0.3ml bleomycin normal saline solution (7.5mg/kg) then, immediately with the upright also left rotation and right rotation of animal, make medicinal liquid uniform distribution in lung after the injection.Wherein isopyknic normal saline injects in B group rat pulmonary, and A group rat is left intact.More than each treated animal sub-cage rearing, give the plain particles feedstuff, the experimental session animal freely drinks water.In strict accordance with pharmacological experiment method raising rat.
1.4 experimental drug:
Used protease inhibitor comprises PMSF and AP, BBI, and route of administration is oral and atomizing sucks.
Oral administration route: with physiological saline solution or add 0.5%CMC solution with medicine dissolution, per os is irritated and is fed 100mg/kg, once a day.
Atomizing inhalation approach: protease inhibitors liposomes aerosol, per nasal and oral cavity suck 100mg/kg, and suck every day at twice.
Concrete administrated method sees Table one:
Grouping of table 1 laboratory animal and medication
1.5 inspection item
1.5.1 the ordinary circumstance experimental session is observed rat mental status, mobility, fur color and luster, food ration and body weight etc.
1.5.2 lungs are observed quality, color, outward appearance, size etc.
1.5.3 lung tissue om observation HE, Masson dyeing.
1.5.4Szapissel alveolitis classification and interstitial pulmonary fibrosis classification
1.5.5 lung tissue homogenate collagen content is measured
1.5.6 bronchioles and bronchoalveolar lavage fluid cell counting and classification and determining the protein quantity,
2 experimental results:
2.1 ordinary circumstance
Experimental session, the normal group animal breath is normal, and reaction is quick, and the fur densification is neat and glossy, the equal Non Apparent Abnormality of growth, feed and active situation, body weight increases gradually.The modeling treated animal after the 3rd day obviously rapid breathing, can hear directly that pulmonary sends the gong sound when breathing, malnutrition, listlessness is slow in action, inappetence, fur is fluffy, withered tarnish.Wherein obvious with model group, positive drug group (D group), BBI oral group of (E group), BBI atomizing group (F group), PMSF atomizing group (G group), AP atomizing group (H group) all are better than model group in various degree.
2.2 learning, the lungs general form checks
Normal group (A group) and the two lung color and lusters of sham operated rats (B group) are normal, the smooth surface good springiness; Model group (C group) lung color is dark red, shows coarse injustice, and quality is harder, and that touches has a rubber sense, carefully watches two lungs can find somewhat block pathological changes kitchen range, and color fawn focus size is 0.3 * 0.3mm
2, every nearly 5～6 places of rat pulmonary.5 groups such as positive drug group (D group), BBI oral group of (E group), BBI atomizing group (F group), PMSF atomizing group (G group), AP atomizing group (H group) lung surface color is slightly dark, degree of roughness is starkly lower than model group, the quantity of speckle shape focus obviously reduces, every rarely seen 1～2 place of rat pulmonary, the elastance of lung of touching approaches normal group (A group).Show the function that the lungs organizational structure that has clear improvement the PIs treated animal bleomycin caused changes.
2.3 lung tissue light microscopy checking
As seen microscopically is observed: the pulmonary branches trachea of normal rat, whole end property bronchioles structure are normal.Whole end property bronchioles epithelium is a simple columnar epithelium, and the visible cilium of most of epithelium, lamina propria have complete annular smooth muscle outward.Visible monolayer column of respiratory bronchioles or cubic epithelium, visible a little the alveolar opening of tube wall, the terminal globulate of alveolar septum expands, and I, II type i alveolar cell quantity and structure are normal on the alveolar wall.
Model group in the time of 7 days (C group) rat lungs can obviously be seen: diffuse alveolitis district is arranged around lobi inferior and the bronchial tree, and a large amount of inflammatory exudations and cellular infiltration (as many types of karyosome cell and macrophage etc.) arranged, the remarkable edema of alveolar wall thickens, the alveolar structure disorder, the expansion of part alveolar space is cryptomere, the alveolar wall fracture, the part alveolar space withers, visible exudate of intracavity and cell alluvial.Masson dyeing shows that the interstitial lung collagen fiber increase.Lesion degree such as group such as 5 of positive drug group (D group), BBI oral group of (E group), BBI atomizing group (F group), PMSF atomizing group (G group), AP atomizing groups (H group) etc. is light or approach normal group (A group), sham operated rats (B group) and normal group (A group) no significant difference show the function of the lungs acute pulmonary alveolitis disease pathological change that the hydrochloric acid bleomycin caused that has clear improvement PIs.
Model group in the time of 28 days (C group) rat lungs still have the inflammatory cell infiltration (as macrophage, lymphocyte etc.) of some, alveolar wall significantly thickens, lung II type epithelial hyperplasia, the alveolar structure disorder, the expansion of part alveolar space is cryptomere, the alveolar wall fracture, and the part alveolar space withers, the still visible unabsorbed exudate alluvial of intracavity, and can see a large amount of alveolar cell desquamations. between the part alveolar matter with along whole end property bronchioles, the visible a large amount of fibroplasias of bronchioles periphery.Masson dyeing shows that collagen fiber increase, and tangible interstitial pulmonary fibrosis is arranged.5 groups such as positive drug group (D group), BBI oral group of (E group), BBI atomizing group (F group), PMSF atomizing group (G group), AP atomizing group (H group) lesion degree gentlier approaches normal group (A group), sham operated rats (B group) and normal group (A group) no significant difference, showing that PIs has obviously weakens the lung chronic inflammatory disease that the hydrochloric acid bleomycin is caused, strengthen the absorption of exudate in the alveolar, alleviate the alveolar epithelial cells desquamation and the alveolar septum fiber gathers, anti-interstitial pulmonary fibrosis effect.
2.4 alveolitis classification and interstitial pulmonary fibrosis classification pathology semi-quantitative results (seeing Table 2)
Classification of table 2 alveolitis and interstitial pulmonary fibrosis classification pathology semi-quantitative results
2.5 bronchioles and bronchoalveolar lavage fluid cell counting and determining the protein quantity
7 days, 28 days model group (C group) rat lungs can obviously be observed has a large amount of inflammatory exudations and cellular infiltration (seeing Table 2) and protein content obviously to increase (table 3) in the bronchoalveolar lavage fluid.Positive drug group (D group), BBI oral group of (E group), BBI atomizing group (F group), PMSF atomizing group (G group), AP atomizing group 5 treatment group lesion degrees such as (H groups) more almost approach normal group (A group), sham operated rats (B group) and normal group (A group) there was no significant difference, the result shows the function of pathological changes such as the lungs acute pulmonary alveolitis disease that has clear improvement PIs the hydrochloric acid bleomycin caused and periapical fibroma.
7,28 days each treated animal bronchoalveolar lavage fluid cell counting comparative results of table 3 bleomycin tracheal instillation
☆ represents to compare P＜0.05 with sham operated rats, and ★ represents to compare P＜0.01 with sham operated rats
△ represents to compare P＜0.05 with model group, and ▲ expression is compared P＜0.01 with model group
The measurement result of 7,28 days each treated animal bronchoalveolar lavage fluid protein contents of table 4 bleomycin tracheal instillation
△ represents to compare P＜0.05 with model group, and ▲ expression is compared P＜0.01 with model group
☆ represents to compare P＜0.05 with sham operated rats, and ★ represents to compare P＜0.01 with model group
2.6 lung tissue homogenate collagen content is measured
Model group (C group) rat lungs homogenate collagen content all obviously increased (table 4) in 7 days, 28 days, showed that the tracheal instillation bleomycin can cause that Pulmonary Fibrosis in Rats changes.Lesion degree such as group such as 5 of positive drug group (D group), BBI oral group of (E group), BBI atomizing group (F group), PMSF atomizing group (G group), AP atomizing groups (H group) etc. obviously alleviates, and shows the function of the pathological change of the lungs periapical fibroma that the hydrochloric acid bleomycin caused that has clear improvement PIs.
The measurement result of 7,28 days each treated animal lung homogenate collagen contents of table 5 bleomycin tracheal instillation
△ represents to compare P＜0.05 with model group, and ▲ expression is compared P＜0.01 with model group
☆ represents to compare P＜0.05 with sham operated rats, and ★ represents to compare P＜0.01 with model group
Can reach a conclusion through above experimental result, PIs treatment acute lung injury and pulmonary fibrosis have curative effect preferably.Simultaneously, the result shows that atomizing sucks liposome aerosols and aspect prevention and the treatment pulmonary fibrosis better therapeutic arranged.
3, conclusion:
3.1PIs influence to acute lung injury
The present invention's prompting, PIs has the acute pulmonary alveolitis of alleviating, slows down the inflammatory cell gathering, reduces inflammatory exudation, the antiinflammatory actions such as asking the matter edema that disappears, and the generation that can alleviate the lung collagen fiber.Can find that equally PIs has the effect that delays the pulmonary fibrosis process.Delay the mechanism of action of lung diffusivity alveolitis process, the ill effect that mainly is to alleviate the inflammatory cell infiltration of interstitial lung and reduces cytokine, improve the gas exchange function of lungs, thereby reach the pathological process of treatment lung acute inflammation and acute lung failure.
3.2PIs influence to Pulmonary Fibrosis in Rats lungs pathological change
Rat through tracheal instillation hydrochloric acid bleomycin can cause the lungs respiratory function change, cause the change of indexs such as vital capacity reduces, carbon dioxide diffusion volume, intra-arterial oxygen partial pressure, finally can cause pulmonary fibrosis and sclerosis.The inventor finds in experiment, and the lungs respiratory function of PIs group rat is comparatively normal, and the lungs of experimental model group rat obviously harden.The lesion degree of pathological section HE dyeing proof PIs group rat lungs is lower than model control group, above results suggest, PIs has the pathological change that alleviates lung tissue, weakens the acute pulmonary alveolitis and the fibrosis of lungs, thereby has reached the effect of prevention and treatment acute lung injury and pulmonary fibrosis.Clinical use can effectively improve acute lung failure and pulmonary fibrosis patient's respiratory function, reduces the fibrosis and the hardenability of lungs.
Protease inhibitor kind commonly used is more, comprising bacitracin, aprotinin, trypsin inhibitor, 1, and 10-adjacent two assorted nitrogen phenanthrene, to hydroxyurea yl benzoic acid, organic phosphorus compound (DFP) and puromycin etc.Wherein most widely used, effect is preferably aprotinin.But aprotinin is higher because of its cost, so its application is subjected to certain restriction.Bibliographical information: also have a large amount of multiple protein enzyme inhibitors in natural plants and the Chinese medicine, its wide material sources, with low cost utilize DEVELOPMENT PROSPECT widely so have.
The natural plant protein enzyme inhibitor is the protease inhibitor that a class derives from plant, comprises BBI, Semen phaseoli radiati albumen enzyme inhibitor, corn thiol protease inhibitor (CPIs), Semen Tritici aestivi thiol protease inhibitor, aprotinin (AP), Radix Et Rhizoma Fagopyri Tatarici protease inhibitor etc.They and this are tested used BBI many something in common.Therefore this experimental result can be expanded and be above-mentioned natural plant protein application of enzyme inhibitors.
Further specify the present invention by the following examples, should be noted that, these embodiment only are used for illustrative purposes, do not constitute the restriction to scope of the present invention.It will be apparent to those skilled in that under situation without departing from the spirit and scope of the present invention, can make some variations and improvement, these include in category of the present invention.
The specific embodiment
Embodiment 1:BBI liposome aerosols treatment alveolitis
[prescription] BBI250mg, lecithin 500mg, cholesterol 250mg, vitamin E 50mg, propellant
1212.5mg, phosphate buffered solution (Ph 7.2) 50ml, ether 15ml.
[method for making] takes by weighing BBI, lecithin, cholesterol, vitamin E respectively by recipe quantity, is dissolved in fully in the 15ml diethyl ether solution.Pump remaining diethyl ether solution with rotary evaporator, and make solute form one deck homogeneous thin film at container inner wall.Slowly phosphate buffered solution (pH 7.2) is poured in the container that adheres to the solute thin film, and fully shaken agitating solution, until the suspension of solute and phosphate buffered solution formation homogeneous with the ultrasonic grinding instrument.Press recipe quantity and add propellant, mixing.Solution is added the atomizing of compression atomizing inhalation machine, get final product 200mg～500mg/ day.
Embodiment 2:PMSF liposome aerosols is treated acute lung failure
[prescription] PMSF250mg, lecithin 500mg, cholesterol 250mg, vitamin E 50mg, propellant
1212.5mg, phosphate buffered solution (Ph 7.2) 50ml, ether 15ml.
[method for making] takes by weighing PMSF, lecithin, cholesterol, vitamin E respectively by recipe quantity, is dissolved in fully in the 15ml diethyl ether solution.Pump remaining diethyl ether solution with rotary evaporator, and make solute form one deck homogeneous thin film at container inner wall.Slowly phosphate buffered solution (pH 7.2) is poured in the container that adheres to the solute thin film, and fully shaken agitating solution, until the suspension of solute and phosphate buffered solution formation homogeneous with the ultrasonic grinding instrument.Press recipe quantity and add propellant, mixing.Solution is added the atomizing of compression atomizing inhalation machine, get final product 200mg～500mg/ day.
Embodiment 3:AP liposome aerosols treatment pulmonary fibrosis
[prescription] AP250mg, lecithin 500mg, cholesterol 250mg, vitamin E 50mg, propellant
1212.5mg, phosphate buffered solution (Ph 7.2) 50ml, ether 15ml.
[method for making] takes by weighing AP, lecithin, cholesterol, vitamin E respectively by recipe quantity, is dissolved in fully in the 15ml diethyl ether solution.Pump remaining diethyl ether solution with rotary evaporator, and make solute form one deck homogeneous thin film at container inner wall.Slowly phosphate buffered solution (pH 7.2) is poured in the container that adheres to the solute thin film, and fully shaken agitating solution, until the suspension of solute and phosphate buffered solution formation homogeneous with the ultrasonic grinding instrument.Press recipe quantity and add propellant, mixing.Solution is added the atomizing of compression atomizing inhalation machine, get final product.
Lecithin among the above embodiment, cholesterol, vitamin E is available from China Drug Co.; Propellant
12Available from SIGMA company.
The compression atomizing inhalation machine is hundred auspicious compression atomizing inhalation machines, and Paul Ritzau Pari-Werk Gmbh makes.
Claims (1)
1. one kind has the protease inhibitors liposomes aerosol that prevents or treat alveolitis and/or interstitial pulmonary fibrosis, it is characterized in that by following method preparation: protease inhibitor 250 weight portions, lecithin 500 weight portions, cholesterol 250 weight portions, vitamin E 50 weight portions, propellant 12 12.5 weight portions, pH7.2 phosphate buffered solution 50 parts by volume, ether 15 parts by volume, take by weighing protease inhibitor, lecithin, cholesterol, vitamin E respectively by recipe quantity, be dissolved in fully in the 15ml diethyl ether solution; Pump remaining diethyl ether solution with rotary evaporator, and make solute form one deck homogeneous thin film at container inner wall; Slowly phosphate buffered solution is poured in the container that adheres to the solute thin film, and fully shake agitating solution, until the suspension of solute and phosphate buffered solution formation homogeneous with the ultrasonic grinding instrument; Press recipe quantity and add propellant, mixing; Solution is added the atomizing of compression atomizing inhalation machine, get final product; Described protease inhibitor is big steamed buns stuffed with sweetened bean paste Man-Bai Ke trypsin inhibitor or peas protein inhibitor Benzylsulfonyl chloride, and described weight portion/parts by volume is corresponding with mg/ml.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101226503A CN101081212B (en) | 2003-09-09 | 2003-09-09 | Protease inhibitors liposomes aerosol |
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| CN2007101226503A CN101081212B (en) | 2003-09-09 | 2003-09-09 | Protease inhibitors liposomes aerosol |
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| CNB031567533A Division CN1332715C (en) | 2003-09-09 | 2003-09-09 | Novel medicinal use of proteinase inhibior for preventing and curing lang disease |
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| CN101081212B true CN101081212B (en) | 2011-03-16 |
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| EP2371857A1 (en) * | 2010-04-01 | 2011-10-05 | CSL Behring GmbH | Factor XII inhibitors for treating interstitial lung disease |
| CN115414473A (en) * | 2022-08-25 | 2022-12-02 | 中国人民解放军军事科学院军事医学研究院 | Collagenase liposome inhalant and application thereof in treating pulmonary fibrosis |
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Non-Patent Citations (2)
| Title |
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| 毕殿洲.药剂学 第四版.人民卫生出版社,2002,392-395，453-454. |
| 毕殿洲.药剂学 第四版.人民卫生出版社,2002,392-395,453-454. * |
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