CN1075078A - Medicine - Google Patents
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- CN1075078A CN1075078A CN 93100476 CN93100476A CN1075078A CN 1075078 A CN1075078 A CN 1075078A CN 93100476 CN93100476 CN 93100476 CN 93100476 A CN93100476 A CN 93100476A CN 1075078 A CN1075078 A CN 1075078A
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- propionate
- salbutamol
- ermaite
- sha
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Abstract
The present invention relates to aerosol preparations for inhalation, relate in particular to a kind of medicinal aerosol formulations, it comprises the granulated drug that is selected from Sha Ermaite, salbutamol, propionate propionate fluoride and supplies physiologically acceptable salt and solvate, and fluorocarbon or hydrochlorofluorocarsolvent propellant, said preparation is substantially devoid of surfactant; Also relate to the method for the treatment of respiratory disorder, it comprises and sucks the medicinal aerosol formulations as defined above take effective dose.
Description
The present invention relates to the aerosol preparations that the confession inhalation is used.
People have just known with the aerosol administration before the many decades.Aerosol comprises medicine, one or more Chlorofluorocarbons (CFCs) propellant and surfactant or solvent, for example ethanol usually.The most frequently used aerosol propellant is 11(CCl always in the medicine
3F) and/or propellant 114(CF
2ClCF
2Cl) with propellant 12(CCl
2F
2).But it is believed that now these propellant can cause the decomposition of stratospheric ozone, thereby the medicinal aerosol formulations of the propellant that uses so-called " to the ozone friendliness " need be provided.
It is believed that a class propellant compares with the fluorochlorohydrocarbon of routine and have minimum ozone dilution effect (Ozone-depleting effects), this propellant comprises fluorocarbon and hydrogeneous fluorochlorohydrocarbon, adopt the multiple medications aerosol preparations of this propellant to be disclosed in for example EP0372777, WO091/04011, WO91/11173, WO91/11495 and WO91/14422.Above-mentioned application all is the preparation about the administrable pressurized aerosol, and tries hard to overcome the problem relevant with the use of new class propellant, specifically overcomes and the relevant problem of pharmaceutical formulation stability that makes.Above-mentioned application all proposes to add a small amount of one or more adjuvant even conventional Chlorofluorocarbons (CFCs) propellant, so that the potential destruction of ozone is reached minimum.Described examples of auxiliaries has: alcohols, alkane, dimethyl ether, surfactant (comprise and fluoridizing or surfactant, carboxylic acid, many b-oxides of nonfluorinated).
Thereby for example EP0372777 requires 1,1,1, the 2-tetrafluoroethane with have than 1,1,1, cosolvent of 2-tetrafluoroethane high polarity (for example: alcohol or lower paraffin hydrocarbon) and surfactant use together, to obtain stable medicated powder preparation.It is pointed out particularly at page 3 the 7th row: " have found that; use propellant 134a(1; 1; 1, the 2-tetrafluoroethane) and the binary mixture of medicine or unite use with conventional surfactants (for example sorbitan trioleate) and can not obtain the preparation that sacrificial vessel has the character that the inhaler that is fit to pressurize uses ".Those skilled in the art it is generally acknowledged: surfactant is the important component of aerosol preparations, not only needs it to reduce the coalescent of medicine but also needs it to lubricate used valve, thereby guarantee the constant repeatability of valve event and the accuracy of dosage.WO91/11173, WO91/11495 and WO91/14422 are about comprising the preparation of medicine and surfactant mixture, and WO91/04011 then discloses a kind of pharmaceutical aerosol preparation, granulated drug wherein is with 1,1,1, the 2-tetrafluoroethane is handled before just in advance coated with surfactant.
We find now uncannily, opposite with above-mentioned situation, in fact needn't lean against in the composition use surfactant or must be before handling with propellant pretreatment (for example: 1 just can access medicine at fluorocarbon or hydrochlorofluorocarsolvent propellant, 1,1,2-tetrafluoroethane) the satisfied dispersion in.Specifically, when employing is selected from the medicine of Sha Ermaite (Salmeterol), salbutamol, fluorine Kazon (fluficasone) propionic ester, Beclomethasone and physiologically acceptable salt and solvate, can form gratifying dispersion.
Thereby one aspect of the present invention provides a kind of medicinal aerosol formulations, it comprises the granulated drug that is selected from Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt thereof and solvate (for example hydrate), and fluorocarbon or hydrochlorofluorocarsolvent propellant, said preparation is substantially devoid of surfactant.So-called " being substantially free of surfactant " is meant the preparation of the surfactant that does not contain obvious amount, and for example content is less than 0.0001 weight % of medicine.
In another embodiment, the invention provides a kind of aerosol preparations defined above, but must work as the salbutamol and 1,1,1 that described preparation mainly comprises, the weight ratio of 2-tetrafluoroethane is 0.05: 18 o'clock, and described salbutamol exists with physiologically acceptable salt form.
The particle diameter of granular (for example micronized) medicine should allow basically all medicines to suck in lungs when taking this aerosol preparations, therefore, should be less than 100 microns, with less than 20 microns for well, the 1-10 micron is best, for example: the 1-5 micron.
The suitable pharmaceutically acceptable salt of used medicine comprises acid-addition salts in the preparation of the present invention, for example sulfate, hydrochlorate and Hydroxynaphthoate (1-hydroxyl-2-naphthoate), amine salt or alkali metal salt (for example sodium salt).Sha Ermaite is the form of its Hydroxynaphthoate preferably; Salbutamol is the form of its sulfate preferably.
Final aerosol preparations preferably contains 0.005-10%W/W, and 0.005-5%W/W is better, and particularly 0.01-1.0%W/W(is with respect to the gross weight of preparation) medicine.
The used propellant of the present invention can be any fluorocarbon or hydrochlorofluorocarsolvent or its mixture, and they should have enough vapour pressures so that as effective propellant.Propellant is the non-solvent of medicine preferably.For example: suitable propellant comprises: C
1-4Hydrochlorofluorocarsolvent, CH for example
2ClF, CClF
2CHClF, CF
3CHClF, CHF
2CClF
2, CHClFCHF
2, CF
3CH
2Cl and CClF
2CH
3, C
1-4The hydrogen-containing carbon fluorine compounds, CHF for example
2CHF
2, CF
3CH
2F, CHF
2CH
3And CF
3CHFCF
3; With perfluorocarbon CF for example
3CF
3And CF
3CF
2CF
3
When using the mixture of fluorocarbon or hydrochlorofluorocarsolvent, they can be above-claimed cpd or mixture (preferably binary mixture) and other fluorocarbon or hydrochlorofluorocarsolvent (CHClF for example
2, CH
2F
2And CF
3CH
3) mixture.Preferably adopt single fluorocarbon or hydrochlorofluorocarsolvent as propellant.Preferred especially is C as propellant
1-4The hydrogen-containing carbon fluorine compounds, for example 1,1,1,2-tetrafluoroethane (CF
3CH
2F) and 1,1,1,2,3,3,3-seven fluorine n-propane (CF
3CHFCF
3).
Preparation of the present invention does not preferably contain the component that can cause that stratospheric ozone decomposes.Especially preferably do not contain substantially in the preparation such as CCl
3F, CCl
2F
2And CF
3CCl
3And so on Chlorofluorocarbons (CFCs).
Propellant also can contain the volatility adjuvant, for example saturated hydrocarbons propane, normal butane, pentane and isopentane or dialkyl ether dimethyl ether for example for example.Usually, the propellant that is no more than 50%W/W can comprise for example volatile hydrocarbon of 1-30%W/W.But the preparation that is substantially free of the volatility adjuvant is preferred.
And preparation of the present invention preferably is substantially free of polarity and is higher than the polar liquid component of used propellant.Polarity can disclose No. 0327777 described method according to for example european patent application and measure.The preparation that is substantially free of alcohols (for example ethanol) is preferred especially." being substantially free of " used herein is meant the 1%W/W of content less than fluorocarbon or hydrochlorofluorocarsolvent, especially less than 0.5% for example 0.1% or littler.
A particularly preferred embodiment of the present invention provides a kind of medicinal aerosol formulations, and it mainly comprises one or more medicines that are selected from Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt and solvate and one or more fluorocarbons or hydrochlorofluorocarsolvent propellant.
This area specially comes personnel apparent, and in case of necessity, aerosol preparations of the present invention can comprise two or more active component simultaneously.The aerosol composition (in conventional propellant system) that comprises two kinds of active component has been used for the treatment of respiratory disorder (for example asthma).Therefore, the present invention further provides the aerosol preparations of the present invention that contains two or more granulated drug.Medicine can be selected from the appropriate combination of above-mentioned each medicine or can be selected from any other and be used for the suitable medicine of anapnotherapy, and the form that in fact it can be insoluble to selected propellant exists.Therefore, suitable medicine can be selected from, analgesic for example, for example: codeine, paramorphane, Ergotamine, fentanyl or morphine; The persantin preparation, for example: sulfur nitrogen
Ketone; Anti-allergic drug, for example: cromoglycate, ketotifen or anti-many grammeters (nedocromil); Anti-infective, cephalosporin for example, penicillin, streptomycin, sulfonamides, tetracycline and pentamidine; Antihistaminic, for example, sleepwell; The antibiotic medicine, for example, 9-goes fluorine fluocinonide, budesonide, general dawn of the base of a fruit (tipredane), the third scorching pine; Cough medicine, for example: oscapine; Bronchodilator, for example: your (formoterol), isoprenaline, alotec, phenylephrine, phenylpropanolamine, pyrrole butanols, D-1959, asmaten, terbutaline, Dilabron, C-78 of ephedrine, epinephrine, fenoterol, Ford, hydroxyl is breathed heavily or (-)-4-amino-3,5-two chloro-α-[[[the 6-[2-(2-pyridine radicals) ethyoxyl] hexyl] amino] methyl] benzyl alcohol; Diuretic, for example: amiloride; Anticholinergic agent, for example, Ipratropium Bromured, atropine or second scopolamine; Hormone, for example: cortisone.Hydrocortisone or meticortelone; Xanthine, for example, aminophylline, Oxtriphylline, theophylline-lysine or theophylline and treatment protein and peptide, for example: insulin or glucagon.To those skilled in the art, obviously, in the time of suitably said medicine can with salt (for example: alkali metal salt or amine salt or acid-addition salts) or ester (for example: lower alkyl esters) or solvate (for example: form hydrate) is used, so that the active and/or stability of medicine reaches best and/or make the dissolubility of medicine in propellant reach minimum.
Particularly preferred aerosol preparations contains salbutamol (for example free alkali or sulphate form) or Sha Ermaite (for example hydroxynaphthoic acid salt form), be mixed with the anti-inflammatory type sterol simultaneously, for example the beclomethasone ester (for example: dipropionate) or fluorine Kazon ester (for example propionic ester) or anti-allergic drug as cromoglycate (for example sodium salt).The combination of Sha Ermaite and propionate propionate fluoride or Beclomethasone, or the combination of salbutamol and propionate propionate fluoride or Beclomethasone is preferred.
Preparation of the present invention can sonication makes by medicine being scattered in selected impelling in appropriate containers and for example carrying out.This process is preferably under the anhydrous condition carries out, in order to avoid dampness is to any adverse effect of suspension stability.
Form flocculating suspension slightly after preparation of the present invention leaves standstill, amazing is that even find through long-term storage, suspension obtains being applicable to that through slowly stirring very easily redispersion the pressurization inhaler has fabulous suspension for property of medicine energy.Make formulation excipients in the aerosol preparations of the present invention (for example surfactant) minimum, preferably need not, also be favourable, because the tasteless basically nothing of preparation is smelt, than less dose of sharp property of conventional formulation and toxicity.
The technology that the pharmacy of aerosol preparations of the present invention mensuration acceptable and physics and chemical stability can adopt this area professional to know is carried out.Therefore, for example, the chemical stability of each component can be passed through the HPLC assay determination at for example product after long-term storage.The physical stability data can obtain by other conventional analysis technology, for example, by leak test, by valve for medicine evaluation (each open the average weight that penetrates), by dosage repeatability evaluation (each active principle that penetrates of opening) with spray the medicine distributional analysis.
The particle size distribution of aerosol preparations of the present invention is given deep especially seal and is thought, can measure by routine techniques, for example: measure by collision (cascade impaction) or " binary collision " (Twin Impinger) analytical method step by step.Alleged herein " binary collision " calibrating is meant " deposition of measuring the ejection medicament with device A in adding the pressure solution device ", and British Pharmacopoeia 1988, the A204-207 pages or leaves are seen in this definition, symbol record XVIIC.This technology can calculate " can breathe part " of aerosol preparations.Alleged herein " can breathe part " is meant the method that adopts above-mentioned " binary collision ", opens the amount of the active component of collecting from the collision cell bottom at every turn, is expressed as the percent of the active component total amount of each unlatching ejection.We find that but the respiratory region of preparation of the present invention is divided into drug weight 20% or higher, preferably 25-70%, for example 30-60%.
Medicine also can carry out surface modification before disperseing with propellant, that is, and and with the non-solvent of medicine, nonpolar liquid medium processing basically.Thereby, the present invention further provides a kind of aerosol preparations, it comprises granulated drug, fluorocarbon or the hydrochlorofluorocarsolvent propellant of surface modification as defined above and is no more than the polar co-solvent of propellant 5%W/W, and said preparation is substantially free of surfactant.So-called " medicine of surface modification " be meant and nonpolar non-solvent liquid mixing basically, removes liquid again and by the drug particles of surface modification.(for example: lower paraffin hydrocarbon) be advisable, after medicine slurrying, it has enough volatility to this nonpolar basically non-solvent liquid medium under for example room temperature and normal pressure with it, very easily evaporation with aliphatic hydrocarbon.In this respect, adopt different propane as the liquid medium advantageous particularly.
Be preferably under the anhydrous condition medicine with liquid medium slurrying, in order to avoid dampness has a negative impact to suspension stability.Serosity is preferably through acoustical treatment, to reach the best surface modified effect.Can adopt any method easily to remove liquid, for example evaporation or filtration, evaporation supposes that subsequent treatment is anhydrous basically subsequently.Preparation of the present invention is substantially free of the non-solvent nonpolar liquid.The surface modification medicine that makes with said method has constituted another aspect of the present invention.
Preparation of the present invention can be packed into and is suitable for emitting in the tube of medicinal aerosol formulations.Described tube generally includes a container that can bear used propellant vapour pressure, plastics or the vial that is coated with plastics canister preferably for example, aluminium pot for example, it can be apply through anodization, varnish and/or plastic coat, this container seals with a metering valve.The metering valve amount is used for providing the preparation of metered amount when each the unlatching, and a liner is housed to prevent that propellant is from valve processing leakage.Liner can comprise any suitable elastic material, for example: low density polyethylene (LDPE), chlorobutyl, black or white acrylonitrile-butadiene rubber, butyl rubber and neoprene.Suitable valve can be buied from the manufacturer that aerosol industry is known, for example from Valois, France (DF10 for example, DF30, DF60), Bespak plc, Britain (BK300 for example, BK356) and 3M-Neotechnic Ltd, Britain (Spraymiser for example
TM) buy.
The conventional batch manufacturing method and the equipment that can use medical aerosol manufacturing field professional to know carry out the large-scale production of fitted tube medicine.Therefore, for example, in a kind of batch manufacturing method, metering valve is crimped on the empty tube of formation on the aluminium pot.Granulated drug is packed in the filling containers, and the propellant of polar solvent and liquefaction charged into by the filling containers pressurization make in the container.Before entering the filling machine circulation, drug suspension is mixed, aliquot drug suspension is charged in the tube by metering valve.Perhaps, when medicine is soluble in polar co-solvent, can before adding cosolvent, granulated drug be suspended in the propellant of 50-90%W/W, before pressurization charges in the tube, mix then and weigh with propellant.Usually in the producing by batch of medicine, with the tube check of each filling, weigh, stamp lot number, deposit in the dish of before release test, packing into.
Each tube of filling can make it to be suitable for a suitable channel unit before use, forming metered dose inhaler, so that to patient's lung or nasal-cavity administration.Suitable channel unit comprises for example opening of valves device and column or conial channel, and medicine can be sent in patient's the nose or mouth, for example by metering valve by the tube of filling through this passage: the ozzle actuator.Metered dose inhaler is used for providing fixed unit dose when each unlatching or injection, for example: spray 10-5000 μ g medicine at every turn.
Administration is suitable for treating gentle, moderate or serious acute or cherish symptom slowly, or prophylactic treatment.Self-evident, accurate dosage will depend on patient's the year order and the state of an illness, employed concrete granulated drug and administration frequency, and finally by clinical doctor teacher of topic decision.During drug combination, the dosage the when dosage of each component is generally its independent medication.In general, can be administered once every day or repeatedly, for example 1-9 time, spray medicine for example 1,2,3 or 4 times at every turn.
Suitable daily dose can be, 50-200 μ g Sha Ermaite for example, and 100-1000 μ g salbutamol, 50-2000 μ g propionate propionate fluoride or 100-2000 μ g Beclomethasone, this depends on the state of an illness.
Thereby, for example, drive valve at every turn 25 μ g Sha Ermaite can be provided, 100 μ g salbutamols, 25,50,125 or 50 μ g propionate propionate fluorides or 50,100,200 or 250 μ g Beclomethasones.Each used filling tube comprises the medicine of 100,160 or 240 dosings or injecting times in the general metered dose inhaler.
The tube and the metered dose inhaler of filling as herein described have constituted another aspect of the present invention.
The method that comprises on the one hand treatment respiratory disorder (for example asthma) more of the present invention, it comprises and sucks the preparation as herein described of taking effective dose.
Following non-limiting example is used for illustrating the present invention.
Embodiment 1
Micronized Sha Ermaite Hydroxynaphthoate (24mg) is weighed, insert in the vial of plastic coat of clean dried, add 1,1,1 from vacuum flask, 2-tetrafluoroethane (18.2g).Seal bottle rapidly with blind aluminum sleeve.The gained aerosol contains the Sha Ermaite Hydroxynaphthoate of 0.132%W/W.
Embodiment 2
With micronized Sha Ermaite Hydroxynaphthoate (38.28g) and 1,1,1,2-tetrafluoroethane (36.36Kg) adds in the pressure vessel, mixes 20 minutes with high-shear mixer.Each five equilibrium of suspension (18.2g) is packed in the aluminium pot, seal, load by the valve pressurization with conventional stuffing apparatus with metering valve.The gained inhaler contains 9.57mg Sha Ermaite Hydroxynaphthoate, and each the unlatching provides 25 μ g Sha Ermaite (39.9 μ g salt).
Embodiment 3
(24mg) weighs with micronized propionate propionate fluoride, in the vial of the plastic coat of the clean dried of packing into, adds 1,1,1 from vacuum flask, 2-tetrafluoroethane (18.2g).Seal bottle rapidly with blind aluminum sleeve.The gained aerosol contains the propionate propionate fluoride of 0.132%W/W.
Embodiment 4 and 5
(66mg or 6.6mg) directly weighs in 100 opening aluminium pots separately with micronized propionate propionate fluoride, then metering valve is crimped on each jar.Add and depress, in each, add 1,1,1 by valve, 2-tetrafluoroethane (18.2g), with the tube vibration of each filling with dispersion medicine.Contain 66 or the 6.6mg propionate propionate fluoride in the gained insufflator, each ejection 250 or 25 μ g propionate propionate fluorides (corresponding respectively to embodiment 3 and 4) of opening.
Embodiment 6
(24mg) weighs with micronized salbutamol, in the vial of the plastic coat of the clean dried of packing into, adds 1,1,1 from vacuum flask, 2-tetrafluoroethane (18.2g).Rapidly bottle is sealed with blind aluminum sleeve.The gained aerosol contains the 0.132%W/W salbutamol.
Embodiment 7 and 8
(24mg or 48mg) directly weighs respectively in three opening aluminium pots with micronized salbutamol.With 1,1,1,2-tetrafluoroethane (18.2g) adds each jar from vacuum flask, and the metering valve crimping is good.Tube with each filling vibrated 8 minutes in ultrasonic bath then.Contain 24mg or 48mg salbutamol in the gained inhaler, each ejection 100 or 200 μ g salbutamols (corresponding respectively to embodiment 7 and 8) of opening.
Embodiment 9
Micronized salbutamol sulfate is weighed, in the vial of the cleaning of packing into, drying, plastic coat, add 1,1,1 from vacuum flask, 2-tetrafluoroethane (18.2g).Rapidly bottle is sealed with blind aluminum sleeve.The gained aerosol contains 0.174%W/W salbutamol sulfate.
Embodiment 10
Micronized salbutamol sulfate (31.7mg) is directly weighed in 4 opening aluminium pots.With 1,1,1,2-tetrafluoroethane (18.2g) adds in each jar from vacuum flask.Each tube of filling vibrated 5 minutes in ultrasonic bath.The gained inhaler contains 31.7mg salbutamol sulfate, and each the unlatching provides 100 μ g salbutamols.
Embodiment 11
Isopentane (25ml) is added in the micronized Sha Ermaite Hydroxynaphthoate (0.5g), forms serosity, sonication 3 minutes.The gained suspension is evaporated isopentane to dry in room temperature, get the Sha Ermaite Hydroxynaphthoate of surface modification.Pack into after this product sample (11.6mg) weighed in the aerosol can, add 1,1,1,2-tetrafluoroethane (18.2g-99.95%W/W, total loading is a benchmark), the suitable metering valve of crimping on jar.The tube of filling is distinguished sonication 5 minutes.Sha Ermaite content is equivalent to spray 25 μ g at every turn in the gained aerosol, can spray 240 times amount.
Embodiment 12
Pack into after a micronized hydration Beclomethasone (68mg) weighed in the vial of drying, cleaning, plastic coat, add 1,1,1 from vacuum flask, the 2-tetrafluoroethane (≤0.182g), rapidly bottle is sealed with metering valve.The gained aerosol dispersion has 250 μ g Beclomethasones (as monohydrate), each ejection 75.8 μ g that open.
Embodiment 13
Micronized Sha Ermaite hydroxynaphthoic acid ester (9.57mg) is directly weighed in aluminium pot, add 1,1,1,2,3,3 from vacuum flask, the own propane of 3-seven fluorine (≤21.4g).The metering valve crimping is good, the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 25 μ g Sha Ermaite Hydroxynaphthoates.
Embodiment 14
(13.3mg) directly weighs in aluminium pot with micronized propionate propionate fluoride, adds 1,1,1,2,3,3 from vacuum flask, 3-seven fluorine n-propanes (≤21.4g).The metering valve crimping is good, with the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 50 μ g propionate propionate fluorides.
Embodiment 15
Micronized salbutamol sulfate (29mg) is directly weighed in aluminium pot, add 1,1,1,2,3,3 from vacuum flask, 3-seven fluorine n-propanes (≤21.4g).The metering valve crimping is good, with the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 100 μ g salbutamols.
Embodiment 16
(62mg) directly weighs in aluminium pot with micronized Beclomethasone, adds 1,1,1,2,3,3 from vacuum flask, 3-seven fluorine n-propanes (≤21.4g).The metering valve crimping is good, with the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 250 μ g chlorine ground last loose dipropionate.
Embodiment 17
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 microgram
Propionate propionate fluoride 0.066 50 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Micronized medicine is weighed, in the aluminium pot of packing into, add 1,1,1 from vacuum flask, 2-tetrafluoroethane (18.2g) is also good with the metering valve crimping.
Embodiment 18
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 microgram
Propionate propionate fluoride 0.165 125 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Micronized medicine is weighed, in the aluminium pot of packing into, add 1,1,1 from vacuum flask, 2-tetrafluoroethane (18.2g) is also good with the metering valve crimping.
Embodiment 19
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 microgram
Propionate propionate fluoride 0.132 100 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Micronized medicine is weighed, in the aluminium pot of packing into, add 1,1,1 from vacuum flask, 2-tetrafluoroethane (18.2g) is also good with the metering valve crimping.
Embodiment 20
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 microgram
Propionate propionate fluoride 0.330 250 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 21
Each inhaler %W/W opens at every turn
Salbutamol
*0.132 100 μ g
Propionate propionate fluoride 0.132 100 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
* free alkali or equivalent salt, for example sulfate.
Embodiment 22
Each inhaler %W/W opens at every turn
Salbutamol
*0.264 200 μ g
Propionate propionate fluoride 0.330 250 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
* free alkali or equivalent salt, for example sulfate.
Embodiment 23
Each inhaler %W/W opens at every turn
Salbutamol 0.048 36.25 μ g
Fluorine ground betamethasone dipropionate 0.066 50 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 24
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 35.25 μ g
Propionate propionate fluoride 0.264 200 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 25
Each inhaler %W/W opens at every turn
Salbutamol
*0.132 100 μ g
Beclomethasone dipropionate 0.066 50 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
* free alkali or equivalent salt, for example sulfate.
Embodiment 26
Each inhaler %W/W opens at every turn
Salbutamol
*0.264 200 μ g
Beclomethasone dipropionic acid fat 0.264 200 μ g
1,1,1,2-tetrafluoroethane to 100≤75.8mg
* free alkali or equivalent salt, for example sulfate.
In embodiment 19-26, micronized medicine is weighed and is packed into behind the aluminium pot, adds 1,1 from vacuum flask, and 12-tetrafluoroethane (18.2g) is good with the metering valve crimping again.
Claims (22)
1, a kind of medicinal gasoloid preparation, it comprises the granulated drug that is selected from Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt and solvate, and fluorocarbon or hydrochlorofluorocarsolvent propellant, said preparation is substantially devoid of surfactant.
2, a kind of medicinal gasoloid preparation, it comprises the granulated drug that is selected from Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt and solvate, and fluorocarbon or hydrochlorofluorocarsolvent propellant, said preparation is substantially devoid of surfactant, but must work as the salbutamol and 1,1 that described preparation mainly comprises, 1, the weight ratio of 2-tetrafluoroethane is 0.05: 18 o'clock, and described salbutamol exists with physiologically acceptable salt form.
3, a kind of medicinal aerosol formulations, it mainly comprises one or more medicines that are selected from Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt and solvate and one or more fluorocarbons or hydrochlorofluorocarsolvent propellant.
4, as each described preparation of claim 1-3, its Chinese medicine is the Sha Ermaite Hydroxynaphthoate.
5, as each described preparation of claim 1-3, its Chinese medicine is a salbutamol sulfate.
6, as each described preparation of claim 1-3, its Chinese medicine is a fluorine Kazon propionate.
7, as each described preparation of claim 1-3, its Chinese medicine is beclomethasone dipropionate or its physiologically acceptable solvate.
8, as each described preparation of claim 1-7, wherein propellant comprises 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-seven fluorine n-propanes.
9, as each described preparation of claim 1-8, wherein propellant comprises 1,1,1, the 2-tetrafluoroethane.
10, as each described preparation of claim 1-9, wherein medicament contg is the 0.005-10%W/W of preparation total amount.
11, as each described preparation of claim 1-10, it contains two or more granulated drug.
12, preparation as claimed in claim 11, it contains the combination of the physiologically acceptable salt of salbutamol or Sha Ermaite or its and anti-inflammatory type sterol or anti-allergic drug.
13, preparation as claimed in claim 12, it contains Sha Ermaite or the physiologically acceptable salt of salbutamol its its and propionate propionate fluoride or Beclomethasone or its physiologically acceptable solvate.
14, preparation as claimed in claim 13, it contains Sha Ermaite Hydroxynaphthoate and chlorine Kazon propionic ester.
15, preparation as claimed in claim 13, it contains salbutamol and Beclomethasone.
16, as each described preparation of claim 1-15, it can breathe part is the 20%(weight of medicine) or higher.
17, as each described preparation of claim 1-16, wherein said granular medicine shape is a surface modification.
18, a kind of surface modification medicine, its preparation method is to be selected from the drug particles of Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt and solvate and nonpolar, non-solvent liquid mixing basically, to remove this liquid subsequently.
19, a kind of tube that is suitable for providing medicinal aerosol formulations, it comprises a container that can bear used propellant vapour pressure, this container seals with a metering valve, and medicinal aerosol formulations is housed, said preparation comprises the granulated drug that is selected from Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt and solvate, and fluorocarbon or hydrochlorofluorocarsolvent propellant, said preparation is substantially devoid of surfactant.
20, a kind of tube as claimed in claim 19, wherein container is a canister.
21, a kind of metered dose inhaler, it comprises as claim 19 or 20 described tubes and is suitable for suitable lane device.
22, a kind of method for the treatment of respiratory disorder, it comprises and sucks the medicinal gasoloid preparation take effective dose, it comprises the granulated drug that is selected from Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt and solvate, and fluorocarbon or hydrochlorofluorocarsolvent propellant, said preparation is substantially devoid of surfactant.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9202522.0 | 1992-02-06 | ||
| GB929202522A GB9202522D0 (en) | 1992-02-06 | 1992-02-06 | Medicaments |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB001200720A Division CN1152669C (en) | 1992-02-06 | 2000-06-30 | Medicinal aerosol preparation, its preparing method and release |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1075078A true CN1075078A (en) | 1993-08-11 |
| CN1063321C CN1063321C (en) | 2001-03-21 |
Family
ID=10709932
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93100476A Expired - Lifetime CN1063321C (en) | 1992-02-06 | 1993-01-02 | Medicaments |
| CN93100477A Expired - Lifetime CN1048627C (en) | 1992-02-06 | 1993-01-02 | Medicaments |
| CNB001200720A Expired - Lifetime CN1152669C (en) | 1992-02-06 | 2000-06-30 | Medicinal aerosol preparation, its preparing method and release |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93100477A Expired - Lifetime CN1048627C (en) | 1992-02-06 | 1993-01-02 | Medicaments |
| CNB001200720A Expired - Lifetime CN1152669C (en) | 1992-02-06 | 2000-06-30 | Medicinal aerosol preparation, its preparing method and release |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN1063321C (en) |
| GB (1) | GB9202522D0 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100337614C (en) * | 1998-09-22 | 2007-09-19 | 气体药品技术公司 | Medicinal aerosol formulation |
| CN102366405A (en) * | 2011-10-21 | 2012-03-07 | 江阴长风医药科技有限公司 | Fluticasone propionate aerosol preparation with hydrofluoroalkane as propellant |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102379846B (en) * | 2011-10-21 | 2014-07-02 | 江苏长风药业有限公司 | Fluticasone propionate aerosol preparation with hydrofluoroalkane and polyethylene glycol as auxiliary materials |
| CN103709109B (en) * | 2013-12-24 | 2016-08-17 | 福建省福抗药业股份有限公司 | A kind of preparation method of sulfadimidine hydrosulfate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8828477D0 (en) * | 1988-12-06 | 1989-01-05 | Riker Laboratories Inc | Medical aerosol formulations |
| GB8921222D0 (en) * | 1989-09-20 | 1989-11-08 | Riker Laboratories Inc | Medicinal aerosol formulations |
| IL97065A (en) * | 1990-02-02 | 1994-01-25 | Fisons Plc | Aerosol propellant compositions |
| IE912246A1 (en) * | 1990-06-28 | 1992-01-01 | Glaxo Inc | Aerosol drug formulations |
| US5290539A (en) * | 1990-12-21 | 1994-03-01 | Minnesota Mining And Manufacturing Company | Device for delivering an aerosol |
-
1992
- 1992-02-06 GB GB929202522A patent/GB9202522D0/en active Pending
-
1993
- 1993-01-02 CN CN93100476A patent/CN1063321C/en not_active Expired - Lifetime
- 1993-01-02 CN CN93100477A patent/CN1048627C/en not_active Expired - Lifetime
-
2000
- 2000-06-30 CN CNB001200720A patent/CN1152669C/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100337614C (en) * | 1998-09-22 | 2007-09-19 | 气体药品技术公司 | Medicinal aerosol formulation |
| CN102366405A (en) * | 2011-10-21 | 2012-03-07 | 江阴长风医药科技有限公司 | Fluticasone propionate aerosol preparation with hydrofluoroalkane as propellant |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1284330A (en) | 2001-02-21 |
| CN1048627C (en) | 2000-01-26 |
| GB9202522D0 (en) | 1992-03-25 |
| CN1075079A (en) | 1993-08-11 |
| CN1152669C (en) | 2004-06-09 |
| CN1063321C (en) | 2001-03-21 |
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| PB01 | Publication | ||
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| SE01 | Entry into force of request for substantive examination | ||
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Expiration termination date: 20130104 Granted publication date: 20010321 |