CN102058566A - Dry powder inhaler with constituent rubescensin A as well as preparation method and application thereof - Google Patents
Dry powder inhaler with constituent rubescensin A as well as preparation method and application thereof Download PDFInfo
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- CN102058566A CN102058566A CN 201010604247 CN201010604247A CN102058566A CN 102058566 A CN102058566 A CN 102058566A CN 201010604247 CN201010604247 CN 201010604247 CN 201010604247 A CN201010604247 A CN 201010604247A CN 102058566 A CN102058566 A CN 102058566A
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- rubescensine
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- formoterol fumarate
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Abstract
The invention relates to a dry powder inhaler with a constituent rubescensin A as well as a preparation method and application thereof. The dry powder inhaler is a medicinal composition formed by mixing the constituent rubescensin A as an active constituent with pharmaceutically acceptable excipients. Compared with orally administrated medicines, the dry powder inhaler developed by using the technical scheme provided by the invention greatly improves the effect of the constituent rubescensin A on treating esophagus cancers, lung tumors and leukemia.
Description
Technical field
The present invention relates to a kind of rubescensine A constituents Foradil Aerolizer formoterol fumarate and its production and use, belong to medical technical field.
Background technology
Rabdosia rubescens has another name called Rabdosia rubescens (Rabdosia rubescens (Hamst)), is Labiatae Rabdosia plant, sweet-bitter flavor, cold nature.Herb is a medical herbs commonly used among the people, has heat-clearing and toxic substances removing, anti-inflammatory analgetic, effect such as invigorate blood circulation is good for the stomach.Modern pharmacology, toxicologic study show that this plant antitumor action is good, and toxicity is not obvious, are described as " paclitaxel second ".Isolate five kinds of diterpene-kind compounds from the extract of Rabdosia rubescens leaf, promptly Rabdosia rubescens first, second, third, fourth and penta element for its main anticancer active constituent, have good therapeutic effect to the esophageal carcinoma, pulmonary carcinoma, leukemia etc.Clinical application at present mainly contains conventional dosage forms such as Rabdosia rubescens tablet, capsule, syrup, injection and injectable powder, and deficiency has limited its application in clinical but anticancer components such as rubescensine A dissolubility in water is very little and biological half-life is short etc.
Inhalant through the oral cavity administration has many good qualities: medicine through suck can rapid subsidence in esophagus, trachea and pulmonary, can avoid or reduce the toxic and side effects at other positions of health, pulmonary's absorption area is big, the membrane permeability height, blood flow is abundant, and drug absorption is rapid, no liver first-pass effect, help improving bioavailability of medicament and at the drug level of pulmonary, and pulmonary administration can be used for the treatment of pulmonary disease, the inhalant listing of a lot of pulmonarys medicine has been arranged at present.Foradil Aerolizer formoterol fumarate (drypowderinhalers, DPIs) do not use propellant and solvent, rely on air-flow to make the medicine powder atomization, and then make drug powder be delivered to pulmonary, having the convenience of application, absorb rapid, the localized characteristics of targeting, is a kind of novel drug-supplying system.The research of rubescensine A constituents Foradil Aerolizer formoterol fumarate does not at present appear in the newspapers.
The Foradil Aerolizer formoterol fumarate that has gone on the market at present is the adjuvant carrier with the lactose generally in addition, yet the foreign protein in the lactose might cause severe anaphylactic reaction, therefore needs the dry powder inhaler formulations of the non-lactose carrier of exploitation badly.
Summary of the invention
The purpose of this invention is to provide a kind of rubescensine A constituents Foradil Aerolizer formoterol fumarate and preparation method thereof.Another object of the present invention provides the application of Foradil Aerolizer formoterol fumarate of the present invention in preparation the treatment esophageal carcinoma, lung tumors and leukemia medicament.
At the foregoing invention purpose, the invention provides following technical scheme:
A kind of Foradil Aerolizer formoterol fumarate of rubescensine A constituents is characterized in that the pharmaceutical composition that it is made up of rubescensine A constituents and acceptable accessories, by the oral cavity inhalation.
Described rubescensine A constituents is made up of in rubescensine A, rubescensine B, rubescensine C, rubescensine D, the rubescensine E one or more.
The mass ratio of rubescensine A constituents and described adjuvant is 1: 0.01-1: 100, be preferably 1: 0.1-1: 50.
Described Foradil Aerolizer formoterol fumarate, the particle diameter that it is characterized in that powder is (with D
50Meter) between the 0.1-1000 micron, the particle diameter that is preferably powder is (with D
50Meter) between the 1-500 micron
Described Foradil Aerolizer formoterol fumarate is characterized in that described adjuvant selects one or more in saccharide, alcohols, amino acids, phospholipid, pulmonary surfactant, cyclodextrin, polymer substance, fluidizer, antioxidant, citric acid and salt thereof, the phosphate for use.
Described saccharide is selected from lactose, galactose, glucose, fructose, sucrose, trehalose, the Raffinose one or more; Described alcohols is selected from mannitol, xylitol, maltose alcohol, the sorbitol one or more; Described amino acids is selected from glycine, Aspartic Acid, alanine, tryptophan, threonine, glutamic acid, phenylalanine, leucine, isoleucine, cystine, lysine, proline, the arginine one or more; Described phospholipid is selected from soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, the synthetic phospholipid one or more; Described pulmonary surfactant is selected from dipalmitoyl phosphatidyl choline, two Laurel phosphatidyl cholines, the cholesterol one or more; Described cyclodextrin, be selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, large cyclodextrin, the alpha-cyclodextrin derivant of various substitution values, the beta-cyclodextrin derivative of various substitution values, the gamma-cyclodextrin derivant of various substitution values, HP-, sulfobutyl ether-beta-cyclodextrin, branched cyclodextrin, methylated cyclodextrin, dimethyl-, hydroxyethyl cyclodextrin, low-molecular-weight beta cyclo dextrin polymer (molecular weight is 3000～6000), the ethyl cyclodextrin, the acetyl group cyclodextrin, ionic cyclodextrin derivative, carboxymethyl cyclodextrin, in the sulfuric ester cyclodextrin one or more; Described polymer substance is selected from for example one or more among albumin, dextrin, polyvinylpyrrolidone, cellulose derivative, starch derivatives, polylactic acid, polylactic acid-glycolic guanidine-acetic acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, sodium alginate, the Solutol HS 15 of biodegradable polymer substance; Described fluidizer is selected from micropowder silica gel, Pulvis Talci, magnesium stearate, stearic acid, the hard ester fumaric acid sodium one or more; Described antioxidant is selected from vitamin C, sodium L-ascorbate-2-phosphate, each analog derivative of vitamin C, coenzyme Q10, vitamin E, polyethylene glycol 1000 vitamin E succinic acid ester, each analog derivative of vitamin E one or more.
The preferred mode of adjuvant of described rubescensine A constituents Foradil Aerolizer formoterol fumarate is a lactose, or leucine and phenylalanine, and the weight ratio of leucine and phenylalanine is 1: 50-50: 1.
The preparation method of described rubescensine A constituents Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
The rubescensine A constituents is made powder by pulverizing or spray drying, and powder and adjuvant mix homogeneously are made to suck and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps, make suction by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus rubescensine A constituents and adjuvant mix homogeneously; Perhaps with partial supplementary material mix homogeneously in rubescensine A constituents and the prescription, make powder by pulverizing or spray drying, residue adjuvant mix homogeneously is made to suck and is used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
The application of described rubescensine A constituents Foradil Aerolizer formoterol fumarate in preparation the treatment esophageal carcinoma, lung tumors and leukemia medicament.
D described in the present invention
50The cumulative particle sizes percentile that is a sample reaches 50% o'clock pairing particle diameter.To be particle diameter account for 50% greater than its powder particle to its physical significance, also accounts for 50% less than its powder particle, is used for representing the particle mean size of powder body.
D described in the present invention
90The cumulative particle sizes distribution number that is a sample reaches 90% o'clock pairing particle diameter.To be particle diameter account for 90% less than its powder particle to its physical significance, is used for representing the size indicator of powder body butt end.
Beneficial effect of the present invention mainly is:
1, rapid, no liver first-pass effect are used conveniently, absorbed to described rubescensine A constituents Foradil Aerolizer formoterol fumarate, pulmonary drug concentration height is compared with oral administration and have been improved the Oridonin component for treating esophageal carcinoma, lung tumors and leukemic effect greatly.
2, rubescensine A constituents and adjuvant are mixed into Foradil Aerolizer formoterol fumarate, in practical study, find, medicine is easy to caking, therefore need carry out proportioning with adjuvant, overcome the easily difficult problem of caking of extract, the applicant is known through a large amount of experiments, medicine and ratio of adjuvant is controlled in the particular range, particularly adjuvant is selected leucine and the phenylalanine or the lactose of different-grain diameter for use, can make the good Foradil Aerolizer formoterol fumarate of intake performance.
3, by research of the present invention, it is adjuvant that rubescensine A constituents Foradil Aerolizer formoterol fumarate can adopt leucine and phenylalanine, and not using lactose, the severe allergic reaction of having avoided the foreign protein in the lactose to cause, leucine and phenylalanine are united use, can avoid rubescensine A constituents caking preferably, and powder density is little, and good fluidity is non-hygroscopic, have good powder dispersibility and pulmonary deposition, the pulmonary deposition rate has reached more than 30%.
The specific embodiment
Below in conjunction with example the present invention is described in further detail, but scope of the present invention is not subjected to any restriction of these examples.
Embodiment 1
Adopt comminution by gas stream to D rubescensine A
90=2.6 microns, with D
50=120 microns lactose mixes by mass ratio at 1: 9, and behind the mix homogeneously, powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Embodiment 2
Rubescensine B, micropowder silica gel are mixed by mass ratio at 1: 1, adopt comminution by gas stream to D
90=3.5 microns, powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Embodiment 3
Adopt comminution by gas stream to D rubescensine C
90=3.3 microns, with D
90=4.2 microns lactose, D
50=150 microns lactose is to mix at 1: 1: 7 by mass ratio, and behind the mix homogeneously, powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Foradil Aerolizer formoterol fumarate pulmonary deposition rate is investigated
Investigate according to People's Republic of China (PRC) version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of preparation reaches 25.62%, be placed into 24 months under the room temperature condition after, the pulmonary deposition rate of preparation does not have significant change.
Embodiment 4
The prescription mass ratio of rubescensine D, leucine, mannitol is 1: 1: 8, adopts comminution by gas stream to D rubescensine D and leucine
90=3.2 microns, again with D
50=130 microns mannitol mixes, and behind the mix homogeneously, powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Foradil Aerolizer formoterol fumarate pulmonary deposition rate is investigated
Investigate according to People's Republic of China (PRC) version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of preparation reaches 22.83%, be placed into 24 months under the room temperature condition after, the pulmonary deposition rate of preparation does not have significant change.
Embodiment 5
The prescription mass ratio of rubescensine E, leucine, phenylalanine is 1: 4: 5, adopts comminution by gas stream to D rubescensine E and leucine
90=4.1 microns, again with D
50=130 microns phenylalanine mixes, mix homogeneously, and powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Embodiment 6
Rubescensine A, rubescensine B, leucic prescription mass ratio are 1: 1: 1, are dissolved in 95% the ethanol, and spray drying obtains D
90=3.6 microns powder is again with the D of 8 times of amounts of powder
50=130 microns phenylalanine mixes, mix homogeneously, and powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Embodiment 7
The prescription mass ratio of rubescensine A, trehalose, glycine, soybean phospholipid, dipalmitoyl phosphatidyl choline, poloxamer 188, hard ester fumaric acid sodium, polyethylene glycol 1000 vitamin E succinic acid ester, sodium L-ascorbate-2-phosphate is 10: 1: 1: 1: 1: 1: 1: 1: 1, be scattered in 95% the ethanol, spray drying obtains particle diameter D
90=4.3 microns powder, happy with the German U.S. agent of 8 times of amounts of powder again
120 lactose mix, mix homogeneously, and under the condition of logical nitrogen protection, powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Embodiment 8
The prescription mass ratio of rubescensine A, lactose, trisodium citrate, sodium dihydrogen phosphate is 10: 10: 1: 1, and grind and obtain D
90=4.5 microns powder, happy with the German U.S. agent of 8 times of amounts of powder again
70 lactose mix, mix homogeneously, and under the condition of logical nitrogen protection, powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Embodiment 9
Rubescensine A is adopted the HP-enclose, and spray drying is to D
90=3.9 microns, powder and D
50=130 microns mannitol, D
50=60 microns leucine mixes in 1: 5: 2 ratio of mass ratio, is packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 10
Rubescensine B is adopted the HP-enclose, and spray drying is to D
90=3.5 microns, with the U.S. agent pleasure of Germany
230 lactose mix in 1: 9 ratio of mass ratio, are packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 11
Rubescensine A is adopted the sulfobutyl ether-beta-cyclodextrin enclose, and spray drying is to D
90=3.9 microns, with the U.S. agent pleasure of Germany
70 lactose mix in 1: 9 ratio of mass ratio, are packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 12
The prescription mass ratio of rubescensine A, galactose, sorbitol, proline, albumin, polyethylene glycol 6000, Pulvis Talci, coenzyme Q10 is 10: 1: 1: 1: 1: 1: 1: 1, under the condition of logical nitrogen protection, grind and obtain D
90=4.7 microns powder is again with the D of 8 times of amounts of powder
50=130 microns lactose mixes, mix homogeneously, and powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
Embodiment 13
Adopt comminution by gas stream to D rubescensine A
90=3.5 microns, with D
90=4.7 microns leucine, D
50=130 microns phenylalanine is to mix at 1: 2: 6 by mass ratio, and behind the mix homogeneously, powder packets is packed in capsule or bubble-cap or the Diskus, obtains Foradil Aerolizer formoterol fumarate.
The micromeritis character of Foradil Aerolizer formoterol fumarate is investigated
According to the bulk density algoscopy, recording bulk density is 0.26g/ml.
Foradil Aerolizer formoterol fumarate pulmonary deposition rate is investigated
Investigate according to People's Republic of China (PRC) version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate of preparation reaches 33.95%, be placed into 24 months under the room temperature condition after, the pulmonary deposition rate of preparation does not have significant change.
Embodiment 14
The resisting tumor of lung effect experiment
Method: the method for benzopyrene percutaneous puncture pulmonary injection is set up the induced lung animal model for tumour, gets 150 of modeling rats, is divided into 15 groups at random, 10 every group.Every day 1 time, medication 7 days.Administering mode: 1-13 group is the inhalant inhalation, obtains inhalant according to embodiment 1-13 respectively, and dosage is 10mg rubescensine A constituents/kg; The 14th group of oral rubescensine A, dosage: 10mg rubescensine A/kg; The 15th group is physiology saline control group.Next day is put to death rat in drug withdrawal, dissects the rat lungs, observes the lung lesion situation.
Experimental result: it is 10% that the pulmonary of rat of each group of inhalant administration the incidence rate of lump or tuberosity pathological changes occurs minimum, be up to 30%, the incidence rate that lump or tuberosity pathological changes appear in the pulmonary of rubescensine A oral administration group rat is 90%, the normal saline group is 100%, each group of inhalant administration has significant difference (P＜0.05) with rubescensine A oral administration group, dirt reason saline group, and what therapeutic effect was best is the inhalant of pressing embodiment 13 preparations.
Embodiment 15
The anti esophageal cancer effect experiment
Method: the Wistar rat with 6 ages in week is raised with the precursor hydrochloric acid sarcosine ethyl and the sodium nitrite of nitrososarcosine-ethyl-ester and brings out the esophageal squamous cell carcinoma animal model, gets 150 of modeling rats, is divided into 15 groups at random, 10 every group.Every day 1 time, medication 7 days.Administering mode: 1-13 group is the inhalant inhalation, obtains inhalant according to embodiment 1-13 respectively, and dosage is 10mg rubescensine A constituents/kg; The 14th group of oral rubescensine A, dosage: 10mg rubescensine A/kg; The 15th group is physiology saline control group.Next day is put to death rat in drug withdrawal, dissects rat, observes the pathological changes situation.
Experimental result: the cancer suppression ratio of the rat of each group of inhalant administration is minimum to be 53%, be up to 86%, the cancer suppression ratio of rubescensine A oral administration group rat is 13%, the normal saline group is 0, each group of inhalant administration has significant difference (P＜0.05) with rubescensine A oral administration group, normal saline group, and what therapeutic effect was best is the inhalant of pressing embodiment 13 preparations.
Embodiment 16
The experiment of leukemia drug effect
Method: with mice grain list leukaemia is that WEHI-3 tail intravenous inoculation is set up animal model in BALB/c mouse.Get 150 of modeling mices, be divided into 15 groups at random, 10 every group.Every day 1 time, medication 7 days.Administering mode: 1-13 group is the inhalant inhalation, obtains inhalant according to embodiment 1-13 respectively, and dosage is 10mg rubescensine A constituents/kg; The 14th group of oral rubescensine A, dosage: 10mg rubescensine A/kg; The 15th group is physiology saline control group.Next day is put to death mice in drug withdrawal, by light microscopic, fluorescence microscope, electron microscopy observation bone marrow many index.
Experimental result: the inhalant administration organizes respectively that the bone marrow leukemia cells apoptosis rate of mice significantly raises after the administration, and the bone marrow leukemia cells apoptosis rate of rubescensine A oral administration group and normal saline group mice does not have significant change.
Claims (10)
1. the Foradil Aerolizer formoterol fumarate of a rubescensine A constituents is characterized in that the pharmaceutical composition that it is made up of rubescensine A constituents and acceptable accessories, by the oral cavity inhalation.
2. Foradil Aerolizer formoterol fumarate according to claim 1 is characterized in that described rubescensine A constituents is made up of in rubescensine A, rubescensine B, rubescensine C, rubescensine D, the rubescensine E one or more.
3. Foradil Aerolizer formoterol fumarate according to claim 1, the mass ratio that it is characterized in that rubescensine A constituents and described adjuvant is 1: 0.01-1: 100, be preferably 1: 0.1-1: 50.
4. Foradil Aerolizer formoterol fumarate according to claim 1, the particle diameter that it is characterized in that powder is (with D
50Meter) between the 0.1-1000 micron, the particle diameter that is preferably powder is (with D
50Meter) between the 1-500 micron.
5. Foradil Aerolizer formoterol fumarate according to claim 1 is characterized in that described adjuvant selects one or more in saccharide, alcohols, amino acids, phospholipid, pulmonary surfactant, cyclodextrin, polymer substance, fluidizer, antioxidant, citric acid and salt thereof, the phosphate for use.
6. adjuvant according to claim 5 is characterized in that described saccharide, is selected from lactose, galactose, glucose, fructose, sucrose, trehalose, the Raffinose one or more; Described alcohols is selected from mannitol, xylitol, maltose alcohol, the sorbitol one or more; Described amino acids is selected from glycine, Aspartic Acid, alanine, tryptophan, threonine, glutamic acid, phenylalanine, leucine, isoleucine, cystine, lysine, proline, the arginine one or more; Described phospholipid is selected from soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, the synthetic phospholipid one or more; Described pulmonary surfactant is selected from dipalmitoyl phosphatidyl choline, two Laurel phosphatidyl cholines, the cholesterol one or more; Described cyclodextrin, be selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, large cyclodextrin, the alpha-cyclodextrin derivant of various substitution values, the beta-cyclodextrin derivative of various substitution values, the gamma-cyclodextrin derivant of various substitution values, HP-, sulfobutyl ether-beta-cyclodextrin, branched cyclodextrin, methylated cyclodextrin, dimethyl-, hydroxyethyl cyclodextrin, low-molecular-weight beta cyclo dextrin polymer (molecular weight is 3000～6000), the ethyl cyclodextrin, the acetyl group cyclodextrin, ionic cyclodextrin derivative, carboxymethyl cyclodextrin, in the sulfuric ester cyclodextrin one or more; Described polymer substance is selected from for example one or more among albumin, dextrin, polyvinylpyrrolidone, cellulose derivative, starch derivatives, polylactic acid, polylactic acid-glycolic guanidine-acetic acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, sodium alginate, the Solutol HS 15 of biodegradable polymer substance; Described fluidizer is selected from micropowder silica gel, Pulvis Talci, magnesium stearate, stearic acid, the hard ester fumaric acid sodium one or more; Described antioxidant is selected from vitamin C, sodium L-ascorbate-2-phosphate, each analog derivative of vitamin C, coenzyme Q10, vitamin E, polyethylene glycol 1000 vitamin E succinic acid ester, each analog derivative of vitamin E one or more.
7. Foradil Aerolizer formoterol fumarate according to claim 5 is characterized in that described adjuvant is a lactose.
8. Foradil Aerolizer formoterol fumarate according to claim 5 is characterized in that described adjuvant is leucine and phenylalanine, and the weight ratio of leucine and phenylalanine is 1: 50-50: 1.
9. method for preparing the described Foradil Aerolizer formoterol fumarate of claim 1, its preparation process is as follows:
The rubescensine A constituents is made powder by pulverizing or spray drying, and powder and adjuvant mix homogeneously are made to suck and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps, make suction by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus rubescensine A constituents and adjuvant mix homogeneously; Perhaps with partial supplementary material mix homogeneously in rubescensine A constituents and the prescription, make powder by pulverizing or spray drying, residue adjuvant mix homogeneously is made to suck and is used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
10. the application of the Foradil Aerolizer formoterol fumarate of claim 1 in preparation the treatment esophageal carcinoma, lung tumors and leukemia medicament.
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| CN104224717A (en) * | 2014-04-25 | 2014-12-24 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Application of oridonin powder aerosol in treatment of acute lung injury |
| CN105636964A (en) * | 2014-05-30 | 2016-06-01 | 江苏恒瑞医药股份有限公司 | I-type crystal of l-alanine-(14-oridonin) ester trifluoroacetate and preparation method therefor |
| CN105636964B (en) * | 2014-05-30 | 2017-04-12 | 江苏恒瑞医药股份有限公司 | I-type crystal of l-alanine-(14-oridonin) ester trifluoroacetate and preparation method therefor |
| CN106692116A (en) * | 2015-11-15 | 2017-05-24 | 复旦大学 | Capsule-type inhalation aerosol powder containing isoforskolin |
| CN105919984A (en) * | 2016-04-15 | 2016-09-07 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Oridonin porous particle inhalant and application thereof on treating primary lung cancer |
| CN107773730A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of medicine for treating insomnia and preparation method thereof |
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