CN102247336A - Bufothionine dry powder inhaler, and its preparation method and application - Google Patents
Bufothionine dry powder inhaler, and its preparation method and application Download PDFInfo
- Publication number
- CN102247336A CN102247336A CN 201110147782 CN201110147782A CN102247336A CN 102247336 A CN102247336 A CN 102247336A CN 201110147782 CN201110147782 CN 201110147782 CN 201110147782 A CN201110147782 A CN 201110147782A CN 102247336 A CN102247336 A CN 102247336A
- Authority
- CN
- China
- Prior art keywords
- thiophene
- bufo siccus
- repeated exhortations
- lactose
- powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Landscapes
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Abstract
The invention relates to a dry powder inhaler, more specifically to a dry powder inhaler prepared by bufothionine, and relates to a preparation method for the drypowder inhaler and application of the dry powder inhaler in preparing medicines for treating tumors of lung. The bufothionine dry powder inhaler is characterized by comprising bufothionine and medically acceptable accessories, wherein the mass ratio of bufothionine to the accessories is in a range of 1:0.01 to 1:100. The application of bufothionine dry powder inhaler is mainly directed at tumors of lung, can directly act on an affected part and is free of first pass effect of liver, thereby reducing adverse reactions and having a great prospect in developing new medicines.
Description
Technical field:
The present invention relates to Foradil Aerolizer formoterol fumarate, the Bufo siccus thiophene preparation method and the application in preparation treatment lung tumors medicine of the Foradil Aerolizer formoterol fumarate of making, described Foradil Aerolizer formoterol fumarate of giving repeated exhortations specifically.
Background technology:
Cutis Bufonis is the dry skin of Bufonidae animal Bufo siccus Bufobufo gargarizans Cantor, effect with heat-clearing and toxic substances removing, diuretic relieving distension, the Cutis Bufonis water soluble part contains mainly that the Bufo siccus thiophene is given repeated exhortations, N-phenyl-ethylnaphthalene amine, amino acids, and wherein to give repeated exhortations be one of its main component to the Bufo siccus thiophene.The Bufo siccus thiophene is given repeated exhortations and is colourless acicular crystal, and its molecular formula is C
12H
14N
2O
4S is water miscible indole alkaloids in the Cutis Bufonis, and antitumor activity in vitro shows that the Bufo siccus thiophene tumor control rate of giving repeated exhortations is 87.06%.With water soluble ingredient in the Cutis Bufonis is the existing a plurality of listings of medicine of main exploitation, and present cinobufacin injection, oral liquid, tablet have been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had effect preferably.HUACHANSU ZHUSHEYE, be from the water soluble preparation of Bufo siccus skin through being processed into, treatment primary hepatocarcinoma and medium and advanced lung cancer obtain 44% and 56% comprehensive effective percentage respectively, and tumor body minification is respectively 10% and 16%, and chemotherapy and radiation is had synergism.Though the clinical untoward reaction of HUACHANSU ZHUSHEYE is less, but still exist the intravenous drip meeting local vein reaction to occur, cause that the instillation vein shrinks spasm and causes pain, long-time stimulus causes the vein nonspecific inflammation; Dermoreaction mainly shows as the infringement of urticaria and skin blister sample; Secondly, cardiovascular system reactions such as premature beat, sinus bradycardia, sinus tachycardia, atrioventricular block appear in small part patient, and the reason of generation may be that the cardiac toxicity that a spot of bufotalin produced in the cinobufacin causes; In addition, injection need use in hospital, and patient compliance is poor.And the cinobufacin oral formulations need be through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.It is one of effective ingredient of cinobufacin injection and oral formulations that the Bufo siccus thiophene is given repeated exhortations, but the content in existing injection and oral formulations is lower, and above-mentioned preparation can not directly act on lesions position, and the inhibitory action that the Bufo siccus thiophene can not be given repeated exhortations to tumor performs to maximum.
Pulmonary is the open organ of body, has great surface area, and alveolar wall is made up of cell monolayer, make drug molecule very easily enter blood, so the lung inhalation has plurality of advantages such as rapid-action, that untoward reaction is little.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation, DPIs) do not use propellant and solvent, the air-flow that produces by patient's autonomous respiration makes the medicine powder atomization, and then make drug powder be delivered to pulmonary, have use convenient, absorb rapidly, no liver first, rapid release and the localized characteristics of targeting, be a kind of novel drug-supplying system.
The sickness rate of pulmonary carcinoma rises rapidly in worldwide, and the andropathy philtrum pulmonary carcinoma of dying from carninomatosis ranks first.Current antitumor drug great majority all are drug administration by injection, and this whole body administering mode makes and the targeting reduction of medicine cause the curative effect of medicine to reduce that untoward reaction increases.
Adopt site-specific delivery of drugs antitumor drug to be transported to the tumor patient part of human body, medicine is improved in the concentration of patient part, can reduce the therapeutic effect of the dosage of medicine, the toxic and side effects that reduces medicine, raising medicine, have great clinical value.Employing can directly be transmitted medicine the focus of pulmonary carcinoma through the inhalant of lung administering mode, helps improving medicine to the curative effect of pulmonary carcinoma and reduce its toxic and side effects to normal structure.Through patent and non-patent literature retrieval both at home and abroad, do not see the report of relevant this project like product.
Summary of the invention:
Goal of the invention: an object of the present invention is to provide pulmonary's dry powder inhaler formulations that the Bufo siccus thiophene gives repeated exhortations and preparation method thereof.Another object of the present invention provides the application of Foradil Aerolizer formoterol fumarate of the present invention in preparation treatment lung tumors medicine.
At the foregoing invention purpose, the invention provides following technical scheme:
A kind of Bufo siccus thiophene Foradil Aerolizer formoterol fumarate of giving repeated exhortations is characterized in that it is given repeated exhortations by the Bufo siccus thiophene and medically acceptable adjuvant is formed, and the mass ratio that the Bufo siccus thiophene is given repeated exhortations with described adjuvant is 1: 0.01-1: 100.
The described Bufo siccus thiophene Foradil Aerolizer formoterol fumarate of giving repeated exhortations is characterized in that it is to be given repeated exhortations by the Bufo siccus thiophene to add the suction powder that adjuvant is made, and the particle diameter of powder is with D
50Meter is between the 0.1-1000 micron.
Described adjuvant is selected one or more mixture in sugar, alcohol, aminoacid, phospholipid, surfactant, cyclodextrin, biodegradable polymer substance, magnesium stearate, stearic acid, hard ester fumaric acid sodium, micropowder silica gel, the Pulvis Talci for use.
Described sugar can be selected one or more mixture in galactose, lactose, glucose, fructose, sucrose, trehalose, the Raffinose for use; Described alcohol can be selected one or more mixture in mannitol, xylitol, maltose alcohol, the sorbitol for use; Described aminoacid can be selected in glycine, Aspartic Acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, lysine, proline, the arginine one or more for use; Described phospholipid can be selected in soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, the synthetic phospholipid one or more for use; Described surfactant can be selected one or more mixture in pulmonary surfactant such as dipalmitoyl phosphatidyl choline, two Laurel phosphatidyl cholines, the cholesterol for use; Described polymer substance, can select the macromolecule that meets safety requirements for use, preferred biodegradable polymer substance is one or more mixture in albumin, starch, polylactic acid, polylactic acid-glycolic guanidine-acetic acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, the sodium alginate for example.
Preferred mode is that described adjuvant is the mixture of different-grain diameter lactose, preferred mode is that described adjuvant is for sucking the mixture with lactose granule and micronization lactose, wherein the lactose granule mean diameter is at the 30-250 micron, micronization lactose mean diameter is at the 1-10 micron, the mass ratio of lactose granule and micronization lactose is 1000: 1-1: 1, and most preferred mode is that the mass ratio of lactose granule and micronization lactose is 100: 1-5: 1.
The described Bufo siccus thiophene Foradil Aerolizer formoterol fumarate of giving repeated exhortations, its preparation process is as follows:
The Bufo siccus thiophene is given repeated exhortations by pulverizing or spray drying is made powder, and powder and adjuvant mix homogeneously are made suction and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps the Bufo siccus thiophene is given repeated exhortations and the adjuvant mix homogeneously, make to suck by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus; Partial supplementary material mix homogeneously in perhaps the Bufo siccus thiophene being given repeated exhortations and write out a prescription is made powder by pulverizing or spray drying, and residue adjuvant mix homogeneously is made to suck and used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
The preferred Bufo siccus thiophene Foradil Aerolizer formoterol fumarate of giving repeated exhortations, its preparation process is as follows:
The Bufo siccus thiophene is given repeated exhortations by pulverizing or spray drying is made powder, make suction with the mixture mix homogeneously of the lactose of different-grain diameter or lactose granule and micronization lactose and use powder, be packaged in capsule or bubble-cap or the Diskus.
The application of Foradil Aerolizer formoterol fumarate in preparation lung tumors medicine of giving repeated exhortations of described Bufo siccus thiophene.
Beneficial effect:
1, pulmonary is the open organ of body, has great surface area, and alveolar wall is made up of cell monolayer, make drug molecule very easily enter blood, so the lung inhalation has plurality of advantages such as rapid-action, that untoward reaction is little.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation, DPIs) do not use propellant and solvent, the air-flow that produces by patient's autonomous respiration makes the medicine powder atomization, and then make drug powder be delivered to pulmonary, have use convenient, absorb rapidly, no liver first, rapid release and the localized characteristics of targeting, be a kind of novel drug-supplying system.At present relevant Foradil Aerolizer formoterol fumarate is used for the treatment of the infection of respiratory tract and pulmonary more, does not appear in the newspapers but be used for the Foradil Aerolizer formoterol fumarate that lung tumors treats.Simultaneously, through patent and non-patent literature retrieval both at home and abroad, do not see the report of relevant this project like product.Present Cutis Bufonis extract injection, oral liquid, tablet have been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had effect preferably.Especially HUACHANSU ZHUSHEYE, be from the water soluble preparation of Bufo siccus skin through being processed into, treatment primary hepatocarcinoma and medium and advanced lung cancer obtain 44% and 56% comprehensive effective percentage respectively, and tumor body minification is respectively 10% and 16%, and chemotherapy and radiation is had synergism.Though the clinical untoward reaction of HUACHANSU ZHUSHEYE is less, but still exist the intravenous drip meeting local vein reaction to occur, cause that the instillation vein shrinks spasm and causes pain, long-time stimulus causes the vein nonspecific inflammation; Dermoreaction mainly shows as the infringement of urticaria and skin blister sample; Secondly, cardiovascular system reactions such as premature beat, sinus bradycardia, sinus tachycardia, atrioventricular block appear in small part patient, and the possible cause of generation is that the cardiac toxicity that a spot of bufotalin produced in the cinobufacin causes.In addition, injection need use in hospital, and patient compliance is poor.And oral formulations need be through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.It is one of effective ingredient of cinobufacin injection and oral formulations that the Bufo siccus thiophene is given repeated exhortations, but the content in injection and oral formulations is lower, and above-mentioned preparation can not directly act on lesions position, and the inhibitory action that the Bufo siccus thiophene can not be given repeated exhortations to tumor performs to maximum.And the dry powder inhaler formulations that the Bufo siccus thiophene is given repeated exhortations can directly act on affected part at lung tumors, and does not have the first pass effect of liver, does not have above-mentioned untoward reaction, so its new drug development has very big prospect.
2, the Bufo siccus thiophene is given repeated exhortations to be needed to be mixed into Foradil Aerolizer formoterol fumarate with adjuvant, find in the practical operation, because it is water soluble ingredient that the Bufo siccus thiophene is given repeated exhortations, easily moisture absorption, the Bufo siccus thiophene is given repeated exhortations when being crushed to certain particle size because of electrostatic interaction between the powder, cohesivenesss etc. influence medicine and are easy to reunite, and because surface area increases, hygroscopicity strengthens, therefore need carry out proportioning with adjuvant, overcome the problem of moisture absorption caking, the applicant knows through a large amount of experiments, the Bufo siccus thiophene given repeated exhortations and ratio of adjuvant is controlled in the particular range, and particularly adjuvant selects for use the mixture of lactose granule and micronization lactose can make the good Foradil Aerolizer formoterol fumarate of intake performance.
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
The preparation of inhalant: the Bufo siccus thiophene is given repeated exhortations the employing comminution by gas stream to D
90=5 microns, mix at 1: 8 by mass ratio with the lactose of particle diameter at the 45-100 micron, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 2
The preparation of inhalant: the Bufo siccus thiophene is given repeated exhortations the employing comminution by gas stream to D
90=5 microns, mix in 10: 80: 1 ratio at the leucine of 30-55 micron with lactose, the particle diameter of particle diameter at the 45-110 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 3
The preparation of inhalant: the Bufo siccus thiophene is given repeated exhortations the employing comminution by gas stream to D
90=7 microns, mix in 1: 8 ratio with the leucine of particle diameter 50-165 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 4
The preparation of inhalant: the Bufo siccus thiophene is given repeated exhortations powder, lactose, mannitol, glycine, two Laurel phosphatidyl cholines, lecithin, magnesium stearate in 1: 5: 5: 3: 0.5: 0.5: 0.1 ratio was mixed, and comminution by gas stream is to powder D
50=8 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 5
The preparation of inhalant: with the Bufo siccus thiophene give repeated exhortations, lactose, cholesterol mix in 1: 10: 1 ratio, comminution by gas stream is to powder D
50=7 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 6
The preparation of inhalant: in the Bufo siccus thiophene is given repeated exhortations, add lactose, polyethylene glycol 6000, the albumin of 4 times, 2 times, 3 times of quality respectively, spray drying, powder D
50=8 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 7
The preparation of inhalant: mean diameter is mixed in 10: 85: 5 ratio at mannitol, the micronization silica gel of 5-100 micron at give repeated exhortations drug powder, particle diameter of the Bufo siccus thiophene of 5-10 micron, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 8
The preparation of inhalant: give repeated exhortations drug powder, mannitol, leucine of Bufo siccus thiophene mixed in 10: 90: 3 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 4.5 microns powder, with mean diameter be the lactose granule mixing of 125-150 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 9
The preparation of inhalant: give repeated exhortations powder, mannitol, glycine of Bufo siccus thiophene mixed in 10: 100: 3 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 6.8 microns powder, with mean diameter be the lactose granule mixing of 75-125 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 10
1, the preparation of inhalant: with the Bufo siccus thiophene powder (D that gives repeated exhortations
90=6.7 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.1 microns) mix in 6: 90: 5 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate that the Bufo siccus thiophene is given repeated exhortations reaches 31.4%, and room temperature condition is placed after 18 months down, and the pulmonary deposition rate that the Bufo siccus thiophene is given repeated exhortations does not have significant change.
Embodiment 11
1, the preparation of inhalant: with the Bufo siccus thiophene powder (D that gives repeated exhortations
90=6.2 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.8 microns) mix in 3: 72: 1 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate that the Bufo siccus thiophene is given repeated exhortations reaches 28.5%, and room temperature condition is placed after 18 months down, and the pulmonary deposition rate that the Bufo siccus thiophene is given repeated exhortations does not have significant change.
Embodiment 12
1, the preparation of inhalant: with the Bufo siccus thiophene powder (D that gives repeated exhortations
90=6.5 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.4 microns) mix in 1: 65: 13 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, inhalant pulmonary deposition rate is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition rate that the Bufo siccus thiophene is given repeated exhortations reaches 29.4%, and room temperature condition is placed after 18 months down, and the pulmonary deposition rate that the Bufo siccus thiophene is given repeated exhortations does not have significant change.
Embodiment 13
The preparation of inhalant: with the Bufo siccus thiophene powder (D that gives repeated exhortations
50=5.5 microns), leucine (D
50=215 microns) mix in 1: 8 ratio, mix the particulate D in back
50Be 225 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 14
The preparation of inhalant: the Bufo siccus thiophene given repeated exhortations mix comminution by gas stream, powder D with leucine in 1: 1 ratio
90Below 5 microns, this powder is mixed with the mannitol of 8 times of amounts again, mix the particulate D in back
50Be 279 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 15
The preparation of inhalant: the Bufo siccus thiophene given repeated exhortations mix comminution by gas stream, powder D with poloxamer in 8: 1 ratio
90Below 8 microns, this powder is mixed with the lactose granule of 10 times of amounts, the magnesium stearate of 1 times of amount again, mix the particulate D in back
50Be 301 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 16
The preparation of inhalant: with the Bufo siccus thiophene comminution by gas stream of giving repeated exhortations, powder D
90=6 microns, this powder is mixed with the lactose granule of 15 times of amounts again, mix the particulate D in back
50Be 75 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 17
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment.
Effect experiment:
The method of benzopyrene percutaneous puncture pulmonary injection is set up the induced lung animal model for tumour, gets 190 of modeling rats, is divided into 19 groups at random, 10 every group.Every day 1 time, medication 7 days.The inhalant inhalation that administering mode: 1-16 group obtains for embodiment 1-16, dosage is that 1mg Bufo siccus thiophene is given repeated exhortations/kg; The 17th group of lumbar injection Bufo siccus thiophene given repeated exhortations, and dosage is that 1mg Bufo siccus thiophene is given repeated exhortations/kg; The 18th group of filling stomach gives the Bufo siccus thiophene and gives repeated exhortations, and dosage is that 1mg Bufo siccus thiophene is given repeated exhortations/kg; The 19th group is physiology saline control group, lumbar injection 10mL/kg.Next day is put to death rat in drug withdrawal, dissects the rat lungs, observes the lung lesion situation.
Experimental result: it is 15% that the pulmonary of rat of each group of inhalant administration the incidence rate of lump or tuberosity pathological changes occurs minimum, is up to 35%; The Bufo siccus thiophene injection group of giving repeated exhortations is 55%, the Bufo siccus thiophene is given repeated exhortations and irritated the stomach group is 65%, the normal saline group is 100%, and injection group that the inhalant administration is respectively organized and the Bufo siccus thiophene is given repeated exhortations, Bufo siccus thiophene are given repeated exhortations and irritated the stomach group, the normal saline group has significant difference (P＜0.05) on the pulmonary lesion incidence rate.
Embodiment 18
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment.
1, the foundation of rabbit VX2 original position lung cancer model
1) the freezing cell suspension of the conventional recovery VX2 tumor of the making of lotus tumor kind rabbit makes 10
6The living cells suspension of/mL is got 1mL and is inoculated in 1 rabbit right rear leg outside intramuscular, 3 week the back can lay one's hand on and the lump of the about 30cm of a diameter in inoculation position, promptly make lotus tumor kind rabbit.
2) cut the intramuscular tumor in the lotus tumor kind rabbit leg outside under the preparation aseptic condition of piece of tissue suspension, get to be and oppress the eugonic tumor tissues of sample, be cut into the mud shape.30 mesh sieves were descended in the flushing of RPMI RPMI-1640, removed individual cells and too small piece of tissue, and 20 mesh sieves were descended in the flushing of RPMI RPMI-1640 in sieve top, removed excessive piece of tissue.Get the lower part of screen branch, after the centrifugation, taking precipitate 2mL adds the RPMI RPMI-1640 and is mixed with piece of tissue suspension 20mL.
3) all rabbit right thoracic wall depilations of inoculation in the lung, intramuscular injection speed is slept and is fixed after new mixture 0.8mL/kg anaesthetizes, routine disinfection, get aseptic three way cock, connecing No. 12 injection needles, suctions respectively has the 1mL syringe of rabbit self blood clot and the syringe that suction has VX2 tumor tissue suspension or cell suspension 1mL.Under X line perspective, No. 12 syringe needles are thrust in the rabbit inferior lobe of right lung, behind the resorption depletion of blood, inject 0.4mL piece of tissue suspension or cell suspension, inject 0.2mL rabbit self blood clot then, extract syringe needle, inoculation finishes.
4) the whole rabbit of the observation of growth of xenografted situation are from inoculating back the 3rd day, and carry out layer wide, bed thickness be 5mm CT scan to chest every day, observes transfer case in tumor growth, the thoracic cavity.
5) rabbit VX2 original position lung cancer model is set up as a result rabbit all tumor growth in the lung, success ratio of inoculation 100%.
2, pharmacodynamic experiment
Get successfully 190 of modeling rabbit, be divided into 19 groups at random, 10 every group.Every day 1 time, medication 12 days.The inhalant inhalation that administering mode: 1-16 group obtains for embodiment 1-16, dosage is that 1mg Bufo siccus thiophene is given repeated exhortations/kg; The 17th group of lumbar injection Bufo siccus thiophene given repeated exhortations, and dosage is that 1mg Bufo siccus thiophene is given repeated exhortations/kg; The 18th group of filling stomach gives the Bufo siccus thiophene and gives repeated exhortations, and dosage is that 1mg Bufo siccus thiophene is given repeated exhortations/kg; The 19th group is physiology saline control group, lumbar injection 10mL/kg.Next day is put to death rabbit in drug withdrawal, dissects the rabbit lungs, peels off tumor tissues, weighs, and calculates tumour inhibiting rate.
Experimental result: the tumour inhibiting rate minimum of each group of inhalant administration is 55.9%, is up to 65.9%; The give repeated exhortations tumour inhibiting rate of injection group of Bufo siccus thiophene is 48.7%, the Bufo siccus thiophene tumour inhibiting rate of irritating the stomach group of giving repeated exhortations is 28.6%, the normal saline group does not have obvious inhibition to tumor, and each group of inhalant administration and Bufo siccus thiophene injection group, the Bufo siccus thiophene tumour inhibiting rate of irritating stomach group, normal saline group of giving repeated exhortations of giving repeated exhortations has significant difference (P＜0.05).
Claims (10)
1. Bufo siccus thiophene Foradil Aerolizer formoterol fumarate of giving repeated exhortations is characterized in that it is given repeated exhortations by the Bufo siccus thiophene and medically acceptable adjuvant is formed, and the mass ratio that the Bufo siccus thiophene is given repeated exhortations with described adjuvant is 1: 0.01-1: 100.
2. a kind of Bufo siccus thiophene according to claim 1 Foradil Aerolizer formoterol fumarate of giving repeated exhortations is characterized in that it is to be given repeated exhortations by the Bufo siccus thiophene to add the suction powder that adjuvant is made, and the particle diameter of powder is with D
50Meter is between the 0.1-1000 micron.
3. a kind of Bufo siccus thiophene according to claim 1 Foradil Aerolizer formoterol fumarate of giving repeated exhortations is characterized in that described adjuvant selects one or more mixture in sugar, alcohol, aminoacid, phospholipid, surfactant, cyclodextrin, biodegradable polymer substance, magnesium stearate, stearic acid, hard ester fumaric acid sodium, micropowder silica gel, the Pulvis Talci for use.
4. a kind of Bufo siccus thiophene according to claim 3 Foradil Aerolizer formoterol fumarate of giving repeated exhortations is characterized in that described sugar, selects one or more mixture in galactose, lactose, glucose, fructose, sucrose, trehalose, the Raffinose for use; Described alcohol is selected one or more mixture in mannitol, xylitol, maltose alcohol, the sorbitol for use; Described aminoacid is selected in glycine, Aspartic Acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, lysine, proline, arginine, the methionine one or more for use; Described phospholipid can be selected in soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, the synthetic phospholipid one or more for use; Described surfactant is selected one or more mixture in pulmonary surfactant such as dipalmitoyl phosphatidyl choline, two Laurel phosphatidyl cholines, the cholesterol for use; Biodegradable polymer substance is one or more mixture in albumin, starch, polylactic acid, polylactic acid-glycolic guanidine-acetic acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, the sodium alginate.
5. a kind of Bufo siccus thiophene according to claim 3 Foradil Aerolizer formoterol fumarate of giving repeated exhortations is characterized in that described adjuvant is the mixture of different-grain diameter lactose or lactose and micronization lactose.
6. a kind of Bufo siccus thiophene according to claim 5 Foradil Aerolizer formoterol fumarate of giving repeated exhortations, it is characterized in that described adjuvant is for sucking the mixture with lactose granule and micronization lactose, wherein the lactose granule mean diameter is at the 30-250 micron, micronization lactose mean diameter is at the 1-10 micron, and the mass ratio of lactose granule and micronization lactose is 1000: 1-1: 1.
7. adjuvant according to claim 6, the mass ratio that it is characterized in that lactose granule and micronization lactose is 100: 1-5: 1.
8. one kind prepares the give repeated exhortations method of Foradil Aerolizer formoterol fumarate of the described a kind of Bufo siccus thiophene of claim 1, and its preparation process is as follows:
The Bufo siccus thiophene is given repeated exhortations by pulverizing or spray drying is made powder, and powder and adjuvant mix homogeneously are made suction and are used powder, are packaged in capsule or bubble-cap or the Diskus; Perhaps the Bufo siccus thiophene is given repeated exhortations and the adjuvant mix homogeneously, make to suck by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus; Partial supplementary material mix homogeneously in perhaps the Bufo siccus thiophene being given repeated exhortations and write out a prescription is made powder by pulverizing or spray drying, and residue adjuvant mix homogeneously is made to suck and used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
9. one kind prepares the give repeated exhortations method of Foradil Aerolizer formoterol fumarate of the described Bufo siccus thiophene of claim 1, and its preparation process is as follows:
The Bufo siccus thiophene is given repeated exhortations by pulverizing or spray drying is made powder, make suction with the mixture mix homogeneously of the lactose of different-grain diameter or lactose granule and micronization lactose and use powder, be packaged in capsule or bubble-cap or the Diskus.
10. a kind of Bufo siccus thiophene of claim 1 application of Foradil Aerolizer formoterol fumarate in preparation treatment lung tumors medicine of giving repeated exhortations.
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| CN1068043A (en) * | 1991-06-22 | 1993-01-20 | 吴玉琢 | A kind of method and special implement thereof that extracts Venenum Bufonis |
| CN101176739A (en) * | 2006-11-08 | 2008-05-14 | 山东绿叶制药有限公司 | Toadpoison ligand extract as well as preparation method and application thereof |
| CN101822693A (en) * | 2010-04-29 | 2010-09-08 | 周莹 | Medicine treating tympanitis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068043A (en) * | 1991-06-22 | 1993-01-20 | 吴玉琢 | A kind of method and special implement thereof that extracts Venenum Bufonis |
| CN101176739A (en) * | 2006-11-08 | 2008-05-14 | 山东绿叶制药有限公司 | Toadpoison ligand extract as well as preparation method and application thereof |
| CN101822693A (en) * | 2010-04-29 | 2010-09-08 | 周莹 | Medicine treating tympanitis |
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| Title |
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| 《中国新药杂志》 20070623 史宁等 干粉吸入剂的研究进展 , 第12期 * |
| 《医药导报》 20070325 王振旺等 从上市产品分析干粉吸入剂的研究进展 , 第03期 * |
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