CN102846634A - Inhalant containing N-acetyl-L-cysteine and budesonide and preparation method thereof - Google Patents
Inhalant containing N-acetyl-L-cysteine and budesonide and preparation method thereof Download PDFInfo
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- CN102846634A CN102846634A CN2011101841655A CN201110184165A CN102846634A CN 102846634 A CN102846634 A CN 102846634A CN 2011101841655 A CN2011101841655 A CN 2011101841655A CN 201110184165 A CN201110184165 A CN 201110184165A CN 102846634 A CN102846634 A CN 102846634A
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Abstract
The invention relates to an inhalant containing N-acetyl-L-cysteine and budesonide and preparation method thereof. The inhalant is composed of budesonide and N-acetyl-L-cysteine as the active ingredients, and one or more pharmaceutical adjuvants suitable for inhalation drug delivery.
Description
Technical field:
The present invention relates to treat the respiratory tract disease especially medicine of asthma, particularly inhalation powder spray and preparation method thereof.
Background technology:
Asthma is a kind of chronic airway inflammation, it is characterized by Reversible airway obstruction and airway reactivity increases, and the secretions increase that airway obstruction is caused by the bronchial mucosa inflammation, myxedema and two kinds of factors of inflammatory stimulus smooth muscle spasm cause; And airway reactivity to increase also be because the result of the bronchial epithelial cell damage that airway inflammation causes.People recognize to only have the inflammation of control air flue mucosa, just can reach the purpose of final reduction airway hyperreactivity, relieving asthma symptoms.The medicine for the treatment of at present the pulmonary disease such as asthma mainly contains following several: (1) broxaterol, (2) xanthine drug, (3) anticholinergic agent, (4) glucocorticoid, (5) antiallergic agent.China's document " inhaled corticosteroids is for learning and pharmacodynamics " (Wang Changzheng, practical hospital clinical magazine, the 1st phase of the 4th volume January in 2007,16-18) point out, sucking parahormone (ICS) has become the first-line drug of asthma long-term treatment, such as ciclesonide, fluticasone propionate, momestasone furoate, budesonide etc.The document also points out, desirable ICS should be the perfect adaptation of effectiveness and safety, although ICS than the general hormone in existing huge progress aspect the safety for the treatment of, still can not satisfy well the needs of clinical treatment.Long-term, high-dose uses ICS the untoward reaction such as adrenal cortex function inhibition still can occur, and uses separately the ICS (inferior heavy dose) of so-called safe dose can't effectively control severe asthma in the majority.
N-acetyl-L-cysteine (CAS, 616-91-1; Molecular formula, C
5H
9NO
3S; N-Acetyl-L-Cysteine, be called for short NAC) be a kind of expectorant, Guo Shu very waits (the efficacy and safety evaluation of N-acetylcystein injection atomizing suction in the molten expectorant treatment of acute and chronic respiratory tract infection, Medical University Of Chongqing's journal the 3rd phase of the 30th volume in 2005,444-446) application as the atomization inspiration treatment that eliminates the phlegm with NAC is disclosed.(anti-oxidation characteristics of N-acetylcystein reaches the therapeutical effect to chronic obstructive pulmonary disease to Lei Ling etc., the international breathing magazine the 5th phase of the 26th volume in 2006; 388-391) disclose NAC and can produce antioxidation when oral, thereby chronic obstructive pulmonary disease is produced certain therapeutic effect, yet in above-mentioned two documents, the consumption of NAC is all larger, daily dose reaches more than the 300mg.
Summary of the invention:
The discovery that we are surprised when the N-acetyl-L-cysteine of trace and budesonide are made compound recipe and sucked preparation, has produced significant synergism, the therapeutic effect when having improved treatment asthma,
The invention provides a kind of Inhaled pharmaceutical composition, consisted of with the pharmaceutic adjuvant that one or more are applicable to inhalation by budesonide and N-acetyl-L-cysteine (NAC) as active component.
Described Inhaled pharmaceutical composition, the mass ratio that it is characterized in that described budesonide and NAC is 1: 1-15.Be preferably 1: 5-12 more preferably is 1: 8-10.
Described Inhaled pharmaceutical composition is preferably made micropowder as budesonide and the NAC of active component, and the particle diameter of described micropowder is 0.5～10 μ m, and preferred 1～8 μ m is particularly preferably 2～5 μ m.
Described Inhaled pharmaceutical composition is preferably made powder spray or aerosol.
Described Inhaled pharmaceutical composition is made powder spray, and preferred described pharmaceutic adjuvant comprises carrier and additives, and the particle diameter of described carrier micropowder is 20～60 μ m.The particle diameter of preferred vector is 30～60 μ m.
Described carrier micropowder also can mixing for the micropowder of the micropowder of particle diameter 5-15 μ m and particle diameter 20-60 μ m.
Described carrier is one or more in saccharide carrier, the aminoacid, and described aminoacid includes but are not limited to glycine, valine, leucine.Described saccharide comprises monosaccharide, disaccharide and/or its derived carbohydrate, described monosaccharide includes but are not limited to mannitol, fructose, glucose, described disaccharide includes but are not limited to maltose, trehalose, cellobiose, lactose, sucrose, described derived carbohydrate refers to that the straight or branched hydrocarbon chain of involved at the most 20 carbon atoms of at least one hydroxyl on the glycan molecule replaces, include but are not limited to eight acetate fibers, two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid Sargassum sugar esters, described derived carbohydrate can also the description with reference to international monopoly WO99/33853 in disclosed derived carbohydrate example, preferred in derived carbohydrate is eight acetic acid-D-cellobiose ester as carrier; In above-mentioned various carriers, most preferably carrier is lactose.Described lactose is the alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, the crystallizing and drying lactose, particularly preferably crystallizing and drying lactose.
Preferably add additives in described carrier micropowder, described additives include but are not limited to surfactant, lubricant, antistatic additive.The consumption of described additives and kind can be with reference to any known prior art and documents, and (Cui Fude etc., August in 2003 the 5th edition, People's Health Publisher) is disclosed such as " pharmaceutics ".
The preferred poloxamer of described surfactant.The summation of active component: the poloxamer weight ratio is 1: 0.01～5.Poloxamer is also as antistatic additive.Described lubricant can also include but are not limited to one or more in magnesium stearate, micropowder silica gel, the Pulvis Talci, and consumption is 0.01%～1% of carrier micropowder weight.
The summation of described active component and the weight ratio of carrier are 1: 5～100.
The method of micronization of described active component can adopt spray drying method, fluid bed supersonic jet mill method, and speed lapping method, ball-milling method, fluid energy mill method, solvent method etc. preferably adopt spray drying method.
Described composition for inhalation, packaged that can single or multiple dosage when being prepared into powder spray preferably adopts the mode packing of capsule, and each capsule contains the above-mentioned powder spray of 5-40mg.Preferred each capsule contains the above-mentioned powder spray of 10-30mg.
Preferred each capsule contains 50-250 μ g budesonide, 50-2500 μ gNAC.
The described capsule that contains powder spray can adopt known powder spray capsule inhaler to suck.Described inhaler for example WO94/28958 is disclosed.
Described composition for inhalation, preparation method when being prepared into powder spray is that the active component micronization is become particle diameter is the micropowder of 0.5-10 μ m, again carrier being become particle diameter with the additives micronization is the micropowder of 20～60 μ m, or part carrier micronization is become particle diameter is the micropowder of 5-15 μ m, it is the micropowder of 20～60 μ m that all the other carrier micronizations become particle diameter, is contained in the capsule carrier micropowder was mixed 3 mixings of 200 mesh sieves with the active component micropowder after.
Particle diameter of the present invention is mass median diameter (mass mean diameter).
Described composition for inhalation, can also prepare becomes aerosol, and described pharmaceutic adjuvant comprises pharmaceutically useful propellant and other the optional additives that are applicable to aerosol.
Described propellant is for being one or more in the fluorohydrocarbon compounds.Be preferably a kind of or its combination in HFA 134a (HFA134a) and the HFC-227ea (HFA 227).The preferred HFA134a that adopts.
Comprise solvent in the described additives, be selected from glycerol, propylene glycol, Polyethylene Glycol, ethanol or oleic acid, preferably use ethanol.
Described additives can also comprise other low volatility component, comprise other alcohol, glycol, alkanol for example is such as decanol (decyl alcohol), comprise sugar alcohol, glycofural (tetrahydrofuran base methanol) and the dipropylene glycol of Sorbitol, mannitol, lactose, maltose alcohol.Comprise that vegetable oil, organic acid are as comprising dodecylic acid and tetradecanoic acid and stearic saturated carboxylic acid; Comprise sorbic acid, the unsaturated carboxylic acid of oleic acid particularly, the known aerosol that is applied to, to improve the physical stability of drug suspension, it is used for keeping the na non agglomerating composition of particle to have as dispersant: glucide, ascorbic acid, cyclamic acid, aminoacid or aspartame; Alkane such as dodecane and octadecane; Terpenes such as menthol, eucalyptol, limonene; Sugar is such as lactose, glucose, sucrose; Polysaccharide such as ethyl cellulose, dextran; Antioxidant such as Yoshinox BHT, ascorbic acid, sodium pyrosulfite, butylated hydroxyanisol; Polymer such as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone; Amine such as ethanolamine, diethanolamine, triethanolamine; Steroid class such as cholesterol, cholesteryl ester.Can not add other low volatile components.
The preparation method of described aerosol is: add the active component micropowder of recipe quantity in the aerosol bottle, open the valve on the bottle, the mixture of premixed propellant and optional additives is imported by valve, valve-off obtains required aerosol.Optional the aerosol bottle is carried out ultra sonic bath with solubilising
Perhaps can adopt following preparation method: micronized active component is distributed in the additives, adds again mixing in the propellant after the pre-cooling, divide again to install in the aerosol bottle.
Required active component is crushed into the micropowder that particle diameter is 0.5-10 μ m.
Should be appreciated that because of known reason, such as the retention of active component in suction apparatus, the amount of every kind of active component that the patient sucks can be different from the amount of metering.Therefore the applicating ratio between the active component can be different from the ratio of metering.The ratio of preferably using is in the described metered proportions that indicates.
Preferred aerosol is whenever pressed and is contained 50-250 μ g budesonide, 50-2500 μ gN-acetyl-Cys.
Described aerosol bottle and valve system adopt known aerosol bottle and valve system, can select disclosed aerosol bottle and valve system among the Chinese patent CN98805261.X.
Inhaled pharmaceutical composition provided by the invention, the compound preparation of a kind of budesonide and N-acetyl-L-cysteine is provided, the experimental group that sucks two kinds of active component with independent budesonide administration and priority is compared, pharmacology embodiment shows, compound recipe Inhaled pharmaceutical composition provided by the invention can significantly reduce the Brown-Norway rats with asthma SERUM IgE, IL-4 and IL-5 content, significantly improve the airway remodeling that causes because of asthma, thereby realize better therapeutic effect, and suck separately the therapeutic effect of NAC animal pattern asthma of same dose and not obvious, illustrate and only have the suction preparation that adopts active component proportioning provided by the invention, when treatment asthma, could produce synergism.
The specific embodiment
Micronization of the present invention can use known mechanical crushing method or spray drying method.Mechanical crushing method refers to utilize the method for fluid energy mill respectively budesonide and carrier powder to be broken into needed particle diameter.Spray drying method refers to budesonide or carrier are dissolved in organic solvent such as the ethanol entirely, through spray dryer, solid material is made needed particle diameter.Can also add surfactant such as poloxamer etc. when using spray drying method.
Powder spray adopts No. 3 plant capsules, and (sino-america joint-venture Suzhou Capsule Co., Ltd produces, and trade name: Vcaps), each embodiment feeds intake according to 1000 capsules.The capsule of the powder spray bubble-cap type of packing into is aluminum-plastic packaged, takes out during use, and the powder spray inhaler of packing into (Shanghai balance pharmaceutical factory) uses.
Embodiment 1
With budesonide 80mg, N-acetyl-L-cysteine 1g is dissolved in ethanol, after the filtration, filtrate spray drying, micronization make it mean diameter and reach 2 μ m, and lactose 10g is micronized to mean diameter 20 μ m with fluid energy mill, after the mixing, cross and to be divided in behind 3 mixings of 200 mesh sieves in No. 3 capsules.Every capsules has budesonide 80 μ g, N-acetyl-L-cysteine 1mg
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h
Embodiment 2-1
With budesonide 250mg, N-acetyl-L-cysteine 2500mg is dissolved in ethanol, after the filtration, filtrate spray drying, micronization make it mean diameter and reach 4 μ m, lactose 40g, be micronized to mean diameter 30 μ m with fluid energy mill, mixing is with minute installing to behind 3 mixings of 200 mesh sieves in No. 3 capsules.Every capsules has budesonide 250 μ g, N-acetyl-L-cysteine 2500 μ g.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 2-2
According to the prescription of embodiment 2-1, carrier is changed into eight acetic acid of mean diameter 35 μ m-D-cellobiose ester, prepare powder spray according to the technique of embodiment 2-1.
Embodiment 3
With budesonide 110mg, N-acetyl-L-cysteine 500mg is dissolved in ethanol, after the filtration, the filtrate spray drying makes it mean diameter and reaches 5 μ m, lactose 5g, be micronized to mean diameter 40 μ m with fluid energy mill, mix, cross behind 3 mixings of 200 mesh sieves and minute to install in No. 3 capsules.Every capsules has budesonide 110 μ g, N-acetyl-L-cysteine 500 μ g
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 4
Get budesonide 50mg, N-acetyl-L-cysteine 50mg is dissolved in ethanol, filters the rear filtrate spray drying, makes it mean diameter and reaches 7 μ m, and lactose 40g is micronized to mean diameter 60 μ m with fluid energy mill, crosses behind 3 mixings of 150 mesh sieves minute to install in No. 3 capsules.Every capsules has budesonide 50 μ g, N-acetyl-L-cysteine 50 μ g
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
The preparation of aerosol, used ethanol are dehydrated alcohol, and used active component is 0.5-10 μ m for being micronized to particle diameter.The aerosol that makes adopts the dosage valve system of different size so that can reach the required dosage of whenever pressing.
Embodiment 5
Budesonide 1000mg N-acetyl-L-cysteine 1000mg
Ethanol 67.8g
HFA227 1287.g
Preparation technology: budesonide and the N-acetyl-L-cysteine of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, and get final product.Dosage is whenever pressed budesonide 50 μ g, NAC50 μ g.
Embodiment 5-1
Budesonide 1000mg
Ethanol 67.8g
HFA227 1287.g
Preparation technology: the budesonide of recipe quantity is added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, and get final product.Dosage is whenever pressed budesonide 5 μ g.
Embodiment 6
Budesonide 2500mg N-acetyl-L-cysteine 25000mg
Ethanol 220g
HFA227 970g
Preparation technology: budesonide and the N-acetyl-L-cysteine of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, and get final product.Whenever press budesonide 25 μ g, NAC250 μ g.
Embodiment 6-1
Budesonide 2500mg
Ethanol 220g
HFA227 970g
Preparation technology: the budesonide of recipe quantity is added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, and get final product.Whenever press budesonide 25 μ g.
Embodiment 7
Budesonide 2000mg N-acetyl-L-cysteine 5000mg
Ethanol 82.7g
HFA134a 1098g
Preparation technology: budesonide and the N-acetyl-L-cysteine of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, and get final product.Whenever press budesonide 100 μ g, NAC250 μ g.
Embodiment 7-1
Momestasone furoate 2000mg
Ethanol 82.7g
HFA134a 1098g
Preparation technology: the momestasone furoate of recipe quantity is added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, and get final product.Whenever press momestasone furoate 20 μ g.
Embodiment 8
Budesonide 1000mg N-acetyl-L-cysteine 5000mg
Ethanol 94.8g
HFA134a 1098g
Preparation technology: budesonide and the N-acetyl-L-cysteine of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA134a is injected in pressurization more respectively, and get final product.Whenever press budesonide 100 μ g, NAC500 μ g.
Embodiment 8-1
Budesonide 1000mg
Ethanol 94.7g
HFA134a 1098g
Preparation technology: budesonide and the N-acetyl-L-cysteine of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA134a is injected in pressurization more respectively, and get final product.Whenever press budesonide 10 μ g.
Embodiment 9
N-acetyl-L-cysteine 25000mg
Ethanol 94.7g
HFA134a 1098g
Preparation technology: the N-acetyl-L-cysteine of recipe quantity is added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA134a is injected in pressurization more respectively, and get final product.Whenever press N-acetyl-L-cysteine 250 μ g.
Pharmacology embodiment 1
According to Chinese document " airway inflammation disease " (Liu Chuntao, People's Health Publisher, 2004; 506-507) open, SERUM IgE, IL-4, IL-5 occupies critical role in the pathogenesis of asthma, so the serum content with above-mentioned three kinds of factors changes to characterize medicine to the therapeutic effect of Brown-Norway rats with asthma among this pharmacology embodiment.
1, laboratory animal, male wistar rat, age in 6-8 week, body weight 180 ± 20g, 10 every group.Grouping and administration situation such as following table:
The aerosol combination that experimental group 1-4 adopts respectively embodiment 5-8 to make, the aerosol combination that experimental group 5-8 adopts respectively embodiment 5-1 to 8-1 to make, what experimental group 9 adopted is the aerosol combination that embodiment 9 makes, during experimental group 10 administration, use first the used pharmaceutical composition administration of experimental group 9, use again the used pharmaceutical composition administration of experimental group 6-1 behind the 15min, not administration of model group.Adopt different quantitative valve systems according to dosage
2, Experimental agents, chicken egg protein (OVA) ((U.S. SIGMA company), deactivation pertussis vaccine (5 * 10
9/ ml)
3, modeling and administration are according to Chinese document " dexamethasone is on the impact of Airway in Asthmatic Guinea Pigs wall thickness " (Wang Luning etc., Chinese Journal of Pathophysiology, 2002,18 (5); Disclosed method is carried out modeling 564-565), and the 1st, model group and each treated animal of experiment (contained OVA10mg, deactivation pertussis vaccine 5 * 10 with 1ml sensitization liquid
9Individual, gel aluminum hydroxide 100mg) lumbar injection sensitization; The 8th repeats sensitization once; Pattern drawing group on the 15th places the atomizing inlet box with each treated animal of experiment, and (60cm * 40cm * 40cm), suck to excite with the 1%OVA solution atomization with ultrasound atomizer once a day puts into 10 rats at every turn, sucks 20min, sucks continuously for eight weeks.Matched group adopts the suction of injecting and atomize of same amount physiologic saline for substitute modeling medicine.Experiment is respectively organized every day and is excited front 30min to adopt the aerosol inhalation, matched group and model group adopt blank HFA134a to replace, the aerosol drug delivery method is: animal is fixed on the operating-table becomes 60-70 ° of placement with level, seal the nostril with adhesive tape, make animal can only per os air-breathing, aerosol nozzle place connects a plastic tube (3cm), the animal tongue is pulled out and plastic tube is extended the throat position, treats that animal is air-breathing to finish administration.
4, SERUM IgE, IL-4 and IL5 assay, according to experimental rat model of asthma abdominal aortic blood after anesthesia, in 4 ℃ leave standstill 30min after, with the centrifugal 15min of 1500r/min, collect upper serum, adopt the ELISA method to measure SERUM IgE, the content of IL-4 and IL-5, ELISA test kit (the biological company limited of Wuhan doctor's moral), result such as following table (
N=10)
SERUM IgE, IL-4 and IL-5 content detection result show, compare experimental group 1-4 SERUM IgE with model group, IL-4 and IL-5 content all are decreased significantly (P＜0.01), and compare with the experimental group 5-8 of alone hormone, experimental group 1-4 SERUM IgE, IL-4 and IL-5 content also are decreased significantly (P＜0.05), illustrate that budesonide and N-acetyl-L-cysteine make the more alone budesonide formulation of compound preparation and can produce significant effect to Brown-Norway rats with asthma.And the experimental group of alone NAC is compared with model group, and therapeutic effect is also not obvious.Adopt the experimental group 10 of successively administration to compare with the experimental group 2 that adopts the compound recipe administration, also there were significant differences for therapeutic effect, and experimental group 10 is compared with the experimental group 6 of identical hormone dosage, curative effect is basic identical, and it is relevant that this may be that two kinds of active component are made the synergism that compound preparation produces in the treatment.
5, Asthmatic Rat Lung pathological change is observed under the light microscopic, compares with matched group, and model group rat airway wall and smooth muscle obviously thicken, epithelial cell shedding, and inflammatory cell infiltration around reaching in the luminal stenosis, tube wall, collagen deposition increases.The above-mentioned change of experimental group 1-4 obviously alleviates.Experimental group 9 is compared no significant difference with model group, and experimental group 5-8 and the effect that adopts the experimental group 10 of two kinds of active component of inhalation successively be between experimental group 1-4 and experimental group 9, and experimental group 1-4 demonstrates and budesonide and N-acetyl-L-cysteine made the compound preparation Inhalation in Treating airway remodeling of inhibition Brown-Norway rats with asthma has been produced significant synergistic therapeutic effect.
Claims (10)
1. Inhaled pharmaceutical composition is made of the pharmaceutic adjuvant that is applicable to inhalation as the budesonide of active component and N-acetyl-L-cysteine and one or more.
2. pharmaceutical composition as claimed in claim 1, the mass ratio that it is characterized in that described budesonide and N-acetyl-L-cysteine is 1: 1-15.
3. pharmaceutical composition as claimed in claim 1 is characterized in that the budesonide of described active component and N-acetyl-L-cysteine are micropowder, and the particle diameter of micropowder is 0.5～10 μ m.
4. pharmaceutical composition as claimed in claim 1 is characterized in that described Inhaled pharmaceutical composition is powder spray or aerosol.
5. pharmaceutical composition as claimed in claim 4 is characterized in that the pharmaceutic adjuvant of described powder spray comprises carrier and additives.
6. pharmaceutical composition as claimed in claim 5, the particle diameter that it is characterized in that described carrier is 20～60 μ m.
7. pharmaceutical composition as claimed in claim 5 is characterized in that the summation of described active component and the weight ratio of carrier are 1: 5～100.
8. pharmaceutical composition as claimed in claim 4, preparation method when it is characterized in that described powder spray is with the active component micronization, again with carrier and additives micronization, be contained in the capsule after again the carrier micropowder being mixed 3 mixings of 200 mesh sieves with the active component micropowder.
9. pharmaceutical composition as claimed in claim 8 is characterized in that each capsule contains 50-250 μ g budesonide, 50-2500 μ gN-acetyl-Cys.
10. pharmaceutical composition as claimed in claim 4, it is characterized in that described aerosol is whenever pressed contains 50-250 μ g budesonide, 50-2500 μ gN-acetyl-Cys.
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| CN2011101841655A CN102846634A (en) | 2011-07-01 | 2011-07-01 | Inhalant containing N-acetyl-L-cysteine and budesonide and preparation method thereof |
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Non-Patent Citations (1)
| Title |
|---|
| 黄振杰等: "布地奈德吸入联合N-乙酰半胱氨酸治疗特发性肺纤维化", 《临床肺科杂志》 * |
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Application publication date: 20130102 |