CN102847151B - Inhalant preparation containing sodium 2-mercaptoethanesulfonate and glucocorticoid - Google Patents
Inhalant preparation containing sodium 2-mercaptoethanesulfonate and glucocorticoid Download PDFInfo
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- CN102847151B CN102847151B CN201110184122.7A CN201110184122A CN102847151B CN 102847151 B CN102847151 B CN 102847151B CN 201110184122 A CN201110184122 A CN 201110184122A CN 102847151 B CN102847151 B CN 102847151B
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Abstract
An inhalant preparation containing sodium 2-mercaptoethanesulfonate and glucocorticoid, comprising glucocorticoid and sodium 2-mercaptoethanesulfonate as active ingredients and one or more pharmaceutical adjuvants for inhalation administration.
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 bronchial mucosa inflammation, myxedema and two kinds of factors of inflammatory stimulus smooth muscle spasm cause; And airway reactivity to increase be also the result of the bronchial epithelial cell damage that causes due to airway inflammation.People recognize to only have the inflammation of controlling air flue mucosa, just can reach the object 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 4th the 1st phase of volume of January in 2007,16-18) point out, sucking parahormone (ICS) has become the first-line drug of asthma long-term treatment, 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 compared with general hormone in existing huge progress aspect the safety for the treatment of, still can not meet well the needs of clinical treatment.Long-term, high-dose is used ICS still to there will be the untoward reaction such as adrenal cortex function inhibition, and uses separately the ICS (inferior heavy dose) of so-called safe dose can't effectively control severe asthma in majority.
Mercapto ethylsulfonic acid sodium (CAS, 19767-45-4; Molecular formula, C
2h
5naO
3s
2; Trade name Mesna) be a kind of expectorant, be used for the treatment of the dyspnea that a large amount of sticky stagnation of phlegm plugs cause, the thick sputum that difficult, the acute and chronic bronchitis of coughing up phlegm as postoperative, bronchiectasis, pulmonary tuberculosis, pneumonia, emphysema etc. cause, the difficulty of coughing up phlegm, stagnation of phlegm trachea etc.While treating mercapto ethylsulfonic acid sodium for eliminating the phlegm in prior art, adopt atomization suction or trachea to splash into, 20% solution 1～2ml, yet the zest of existence, easily causes and local irritant effect can cause the untoward reaction such as cough, bronchospasm while adopting the treatment of mercapto ethylsulfonic acid sodium.
Summary of the invention:
The discovery that we are surprised, when micro-mercapto ethylsulfonic acid sodium and glucocorticoid are made compound recipe and sucked preparation, has produced significant synergism, the therapeutic effect while having improved treatment asthma.
The invention provides a kind of Inhaled pharmaceutical composition, the pharmaceutic adjuvant that is applicable to inhalation by the glucocorticoid as active component and mercapto ethylsulfonic acid sodium and one or more forms.
Described glucocorticoid is selected from one or more in ciclesonide, fluticasone propionate, momestasone furoate, budesonide.
Described Inhaled pharmaceutical composition, is characterized in that the mass ratio of described glucocorticoid and mercapto ethylsulfonic acid sodium is 1: 1-15.Be preferably 1: 5-12, more preferably 1: 8-10.
Described Inhaled pharmaceutical composition, preferably makes micropowder as glucocorticoid and the mercapto ethylsulfonic acid sodium of active component, and the particle diameter of described micropowder is 0.5～10 μ m, and preferably 1～8 μ m, is particularly preferably 2～5 μ m.
Described Inhaled pharmaceutical composition, preferably makes powder spray or aerosol.
Described Inhaled pharmaceutical composition, makes powder spray, and preferably 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 particle diameter 5-15 μ m and the micropowder of particle diameter 20-60 μ m.
Described carrier is one or more in saccharide carrier, aminoacid, and described aminoacid includes but are not limited to glycine, valine.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 20 carbon atoms at the most of at least one hydroxyl on glycan molecule replaces, include but are not limited to eight acetate fiber 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, in derived carbohydrate, as carrier, be preferably eight acetic acid-D-cellobiose ester, in above-mentioned various carriers, most preferably carrier is lactose.Described lactose is alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose, particularly preferably crystallizing and drying lactose.
Preferably in described carrier micropowder, add additives, 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, as disclosed in " pharmaceutics " (Cui Fude etc., August in 2003 the 5th edition, People's Health Publisher).
The preferred poloxamer of described surfactant.The summation of active component: 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, 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: 10～100.
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 subpackage of capsule, and each capsule contains the above-mentioned powder spray of 5-40mg.Preferably each capsule contains the above-mentioned powder spray of 10-30mg.
Preferably each capsule contains 50-250 μ g glucocorticoid, 50-2500 μ g mercapto ethylsulfonic acid sodium.
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 active component micronization is become to particle diameter is the micropowder of 0.5-10 μ m, again carrier being become to particle diameter with additives micronization is the micropowder of 20～60 μ m, or part carrier micronization is become to 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, carrier micropowder is mixed with active component micropowder after 200 mesh sieve mixes for 3 times and is contained in capsule.
Particle diameter of the present invention is mass median diameter (mass mean diameter).
Described composition for inhalation, can also prepare and become 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 fluorohydrocarbon compounds.Be preferably a kind of or its combination in HFA 134a (HFA134a) and HFC-227ea (HFA227).Preferably adopt HFA134a.
In described additives, comprise solvent, 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, as decanol (decyl alcohol), the sugar alcohol that comprises Sorbitol, mannitol, lactose, maltose alcohol, glycofural (tetrahydrofuran base methanol) and dipropylene glycol.Comprise that vegetable oil, organic acid are as comprised 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 is as dodecane and octadecane; Terpenes is as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide is as ethyl cellulose, dextran; Antioxidant is as Yoshinox BHT, ascorbic acid, sodium pyrosulfite, butylated hydroxyanisol; Polymer is as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone; Amine is as ethanolamine, diethanolamine, triethanolamine; Steroid class is as cholesterol, cholesteryl ester.Can not add other low volatile components.
Described composition for inhalation, while making aerosol, optimization formula is: active component summation content is 1-30mg/ml, is preferably 1-5mg/ml; Ethanol weight percent content as solvent is 5-20%, and the propellant of surplus.
The preparation method of described aerosol is: to the active component micropowder that adds recipe quantity in aerosol bottle, open the valve on bottle, the mixture of premixed propellant and optional additives is imported by valve, valve-off, obtains required aerosol.Optional aerosol bottle is carried out to ultra sonic bath with solubilising
Or can adopt following preparation method: micronized active component is distributed in additives, then adds in the propellant after pre-cooling and mix, then divide and install in 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, as the retention of active component in suction apparatus, the amount of every kind of active component that patient sucks can be different from the amount of metering.Therefore the applicating ratio between active component can be different from the ratio of metering.The ratio of preferably using is in the described metered proportions indicating.
Preferably aerosol is often pressed and is contained 50-250 μ g glucocorticoid, 50-2500 μ g mercapto ethylsulfonic acid sodium,
Described aerosol bottle and valve system adopt known aerosol bottle and valve system, can select disclosed aerosol bottle and valve system in Chinese patent CN98805261.X.
Inhaled pharmaceutical composition provided by the invention, the compound preparation of a kind of glucocorticoid and mercapto ethylsulfonic acid sodium is provided, the experimental group that sucks two kinds of active component with independent glucocorticoid administration and priority is compared, pharmacology embodiment shows, compound recipe Inhaled pharmaceutical composition provided by the invention can significantly reduce Brown-Norway rats with asthma SERUM IgE, IL-4 and IL-5 content, significantly improve the airway remodeling causing because of asthma, thereby realize better therapeutic effect, and suck separately the therapeutic effect of mercapto ethylsulfonic acid sodium animal pattern asthma of same dose 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 be used known mechanical crushing method or spray drying method.Mechanical crushing method refers to and utilizes the method for fluid energy mill respectively active component and carrier powder to be broken into needed particle diameter.Spray drying method refers to ciclesonide or carrier is dissolved in to organic solvent entirely as in ethanol, through spray dryer, solid material is made to needed particle diameter.While using spray drying method, can also add surfactant as poloxamer etc.
Powder spray adopts No. 3 plant capsules, and (sino-america joint-venture Suzhou Capsule Co., Ltd produces, trade name: Vcaps), each embodiment feeds intake according to 1000 capsules.It is aluminum-plastic packaged that the capsule of powder spray packs bubble-cap type into, during use, takes out, and packs powder spray inhaler (Shanghai balance pharmaceutical factory) into and use.
Embodiment 1
By ciclesonide 80mg, mercapto ethylsulfonic acid sodium 1g, is dissolved in ethanol, after filtration, filtrate spraying is dry, and micronization makes it mean diameter and reaches 2 μ m, lactose 10g is micronized to mean diameter 20 μ m with fluid energy mill, after mixing, crosses after 200 mesh sieve mixes for 3 times and is divided in No. 3 capsules.Every capsules has ciclesonide 80 μ g, mercapto ethylsulfonic acid sodium 1mg
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h
Embodiment 2-1
By budesonide 250mg, mercapto ethylsulfonic acid sodium 2500mg is dissolved in ethanol, after filtration, filtrate spraying is dry, and micronization makes it mean diameter and reaches 4 μ m, lactose 40g, with fluid energy mill, be micronized to mean diameter 30 μ m, mix, after mixing for 3 times with 200 mesh sieve, divide and install in No. 3 capsules.Every capsules has budesonide 80 μ g, mercapto ethylsulfonic acid sodium 2.5mg
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 2-2
According to the formula of embodiment 2-1, carrier is changed into eight acetic acid-D-cellobiose ester of mean diameter 35 μ m, according to the technique of embodiment 2-1, prepare powder spray.
Embodiment 3
By momestasone furoate 110mg, mercapto ethylsulfonic acid sodium 500mg is dissolved in ethanol, after filtration, filtrate spraying is dry, makes it mean diameter and reaches 5 μ m, lactose 5g, with fluid energy mill, be micronized to mean diameter 40 μ m, mix, cross after 200 mesh sieve mixes for 3 times and divide and install in No. 3 capsules.Every capsules has momestasone furoate 110 μ g, mercapto ethylsulfonic acid sodium 500 μ g
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 4
Get fluticasone propionate 50mg, mercapto ethylsulfonic acid sodium 50mg is dissolved in ethanol, filters rear filtrate spraying and is dried, and 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 after 150 mesh sieve mixes for 3 times and divides and install in No. 3 capsules.Every capsules has fluticasone propionate 50 μ g, mercapto ethylsulfonic acid sodium 50 μ g
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
The preparation of aerosol, ethanol used is dehydrated alcohol, active component used is 0.5-10 μ m for being micronized to particle diameter.Adopt aerosol that the dosage valve system of different size makes to make can reach the required dosage of often pressing.
Embodiment 5
Ciclesonide 1000mg mercapto ethylsulfonic acid sodium 1000mg
Ethanol 67.8g
HFA227 1287.g
Preparation technology: the ciclesonide of recipe quantity and mercapto ethylsulfonic acid sodium are added to ethanol, stir, make material dissolution, divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, obtains.Dosage is often pressed ciclesonide 50 μ g, mercapto ethylsulfonic acid sodium 50 μ g.
Embodiment 5-1
Ciclesonide 1000mg
Ethanol 67.8g
HFA227 1287.g
Preparation technology: the ciclesonide of recipe quantity is added to ethanol, stir, make material dissolution, divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, obtains.Dosage is often pressed ciclesonide 5 μ g.
Embodiment 6
Budesonide 2500mg mercapto ethylsulfonic acid sodium 25000mg
Ethanol 220g
HFA227 970g
Preparation technology: the ciclesonide of recipe quantity and mercapto ethylsulfonic acid sodium are added to ethanol, stir, make material dissolution, divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, obtains.Often press budesonide 250 μ g, mercapto ethylsulfonic acid sodium 2500 μ g.
Embodiment 6-1
Budesonide 2500mg
Ethanol 220g
HFA227 970g
Preparation technology: the budesonide of recipe quantity is added to ethanol, stir, make material dissolution, divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, obtains.Often press budesonide 25 μ g.
Embodiment 7
Momestasone furoate 2000mg mercapto ethylsulfonic acid sodium 5000mg
Ethanol 82.7g
HFA134a 1098g
Preparation technology: the ciclesonide of recipe quantity and mercapto ethylsulfonic acid sodium are added to ethanol, stir, make material dissolution, divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, obtains.Often press momestasone furoate 100 μ g, mercapto ethylsulfonic acid sodium 250 μ g.
Embodiment 7-1
Momestasone furoate 2000mg
Ethanol 82.7g
HFA134a 1098g
Preparation technology: the momestasone furoate of recipe quantity is added to ethanol, stir, make material dissolution, divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, obtains.Often press momestasone furoate 20 μ g.
Embodiment 8
Fluticasone propionate 2000mg mercapto ethylsulfonic acid sodium 10000mg
Ethanol 94.7g
HFA134a 1098g
Preparation technology: the ciclesonide of recipe quantity and mercapto ethylsulfonic acid sodium are added to ethanol, stir, make material dissolution, divided dose fill, sealing-in dosage valve system, HFA134a is injected in pressurization more respectively, obtains.Often press fluticasone propionate 100 μ g, mercapto ethylsulfonic acid sodium 500 μ g.
Embodiment 8-1
Fluticasone propionate 1000mg
Ethanol 94.7g
HFA134a 1098g
Preparation technology: the fluticasone propionate of recipe quantity and N-acetyl-L-cysteine are added to ethanol, stir, make material dissolution, divided dose fill, sealing-in dosage valve system, HFA134a is injected in pressurization more respectively, obtains.Often press fluticasone propionate 10 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 in this pharmacology embodiment, the serum content with above-mentioned three kinds of factors changes to characterize the therapeutic effect of medicine to Brown-Norway rats with asthma.
1, laboratory animal, male wistar rat, age in 6-8 week, body weight 180 ± 20g, 10 every group.Grouping with administration situation as following table:
1, experimental group 1-4 adopts respectively the aerosol combination that embodiment 5-8 makes, 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, first use experimental group 9 pharmaceutical composition administration used, after 15min, use again experimental group 6-1 pharmaceutical composition administration used, not administration of model group.According to the quantitative valve system of dosage sealing-in different size.
2, Experimental agents, chicken egg protein (OVA) ((U.S. SIGMA company), deactivation pertussis vaccine (5 * 10
9/ ml)
3, modeling and administration, according to Chinese document " impact of dexamethasone on Airway in Asthmatic Guinea Pigs wall thickness " (Wang Luning etc., Chinese Journal of Pathophysiology, 2002,18 (5); 564-565), disclosed method is carried out modeling, 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 was placed in atomization inlet box (60cm * 40cm * 40cm) with each treated animal of experiment on 1, and every order once sucks to excite with 1%OVA solution atomization with ultrasound atomizer, puts into 10 rats at every turn, sucks 20min, sucks continuously eight weeks.Matched group adopts same amount physiologic saline for substitute modeling medicine to inject and atomization sucks.Testing each group excites front 30min to adopt aerosol inhalation every day, matched group and model group adopt blank HFA134a to replace, aerosol drug delivery method is: animal is fixed on and on operating-table, becomes 60-70 ° of placement with level, by adhesive tape, seal nostril, make animal can only per os air-breathing, aerosol nozzle place connects a plastic tube (3cm), animal tongue is pulled out and plastic tube is extended to throat position, treats that animal is air-breathing to complete administration.
4, after exciting, gets last in 24h with opening breast under 1% pentobarbital intraperitoneal anesthesia (40mg/kg), through right ventricle intubate to pulmonary artery, after getting express developed with normal saline, get middle lobe of right lung, be placed in 10% formaldehyde fixing, carry out HE dyeing and at light Microscopic observation Asthmatic Rat Lung pathology.Before facing anesthesia, get blood survey blood calcium value.
5, SERUM IgE, IL-4 and IL5 assay, according to experimental rat model of asthma abdominal aortic blood after anesthesia, after 4 ℃ of standing 30min, with the centrifugal 15min of 1500r/min, collect upper serum, adopt ELISA method to measure SERUM IgE, the content of IL-4 and IL-5), ELISA test kit (Wuhan doctor's moral biological company limited), result 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 are all 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 are also decreased significantly (P < 0.05), illustrate that glucocorticoid and mercapto ethylsulfonic acid sodium makes the more alone Donisolone of compound preparation and can produce significant effect to Brown-Norway rats with asthma.And the experimental group of alone mercapto ethylsulfonic acid sodium is compared with model group, therapeutic effect is also not obvious.Adopt the experimental group 10 of successively administration to compare with adopting the experimental group 2 of 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 treatment.
6, Asthmatic Rat Lung pathological change, light Microscopic observation, compares with matched group, and model group rat airway wall and smooth muscle obviously thicken, epithelial cell shedding, luminal stenosis, inflammatory cell infiltration in tube wall and around, 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 adopt the effect of the experimental group 10 of two kinds of active component of inhalation successively between experimental group 1-4 and experimental group 9, experimental group 1-4 demonstrates and glucocorticoid and mercapto ethylsulfonic acid sodium is made to compound preparation Inhalation in Treating the airway remodeling of inhibition Brown-Norway rats with asthma has been produced to significant synergistic therapeutic effect.
Claims (42)
1. an Inhaled pharmaceutical composition, the pharmaceutic adjuvant that is applicable to inhalation by the inhaled glucocorticoids as active component and mercapto ethylsulfonic acid sodium and one or more forms, and the mass ratio of inhaled glucocorticoids and mercapto ethylsulfonic acid sodium is 1:1-15.
2. pharmaceutical composition as claimed in claim 1, is characterized in that described inhaled glucocorticoids is selected from one or more in ciclesonide, fluticasone propionate, momestasone furoate, budesonide.
3. pharmaceutical composition as claimed in claim 1, is characterized in that the inhaled glucocorticoids of described active component and mercapto ethylsulfonic acid sodium 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 described carrier is mixing of the micropowder of particle diameter 5-15 μ m and the micropowder of particle diameter 20-60 μ m.
8. pharmaceutical composition as claimed in claim 5, is characterized in that described carrier is one or more in saccharide carrier, aminoacid.
9. pharmaceutical composition as claimed in claim 5, described aminoacid is glycine, valine, leucine.
10. pharmaceutical composition as claimed in claim 8, it is characterized in that described saccharide is one or more of monosaccharide, disaccharide or its derived carbohydrate, derived carbohydrate is eight acetate fiber 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.
11. pharmaceutical compositions as claimed in claim 10, is characterized in that described monosaccharide is mannitol, fructose, glucose.
12. pharmaceutical compositions as claimed in claim 10, is characterized in that described disaccharide is maltose, trehalose, cellobiose, lactose, sucrose.
13. pharmaceutical compositions as claimed in claim 8, is characterized in that carrier is lactose.
14. pharmaceutical compositions as claimed in claim 13, is characterized in that described lactose is alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose.
15. pharmaceutical compositions as claimed in claim 13, is characterized in that described lactose is crystallizing and drying lactose.
16. pharmaceutical compositions as claimed in claim 5, is characterized in that additives are one or more in surfactant, lubricant, antistatic additive.
17. pharmaceutical compositions as claimed in claim 16, is characterized in that surfactant is poloxamer.
18. pharmaceutical compositions as claimed in claim 16, is characterized in that described lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci.
19. pharmaceutical compositions as claimed in claim 5, is characterized in that the described summation of active component and the weight ratio of carrier are 1:10～100.
20. pharmaceutical compositions as claimed in claim 3, the method for micronization of described active component adopts spray drying method, fluid bed supersonic jet mill method, speed lapping method, ball-milling method, fluid energy mill method or solvent method.
21. pharmaceutical compositions as claimed in claim 3, is characterized in that the method for micronization of described active component is spray drying method.
22. pharmaceutical compositions as claimed in claim 4, the preparation method that it is characterized in that described powder spray is by active component micronization, again by carrier and additives micronization, then by carrier micropowder, mixed with active component micropowder after 200 mesh sieve mixes for 3 times and be contained in capsule.
23. pharmaceutical compositions as claimed in claim 22, is characterized in that, each capsule contains 5-40mg powder spray.
24. pharmaceutical compositions as claimed in claim 23, is characterized in that each capsule contains the above-mentioned powder spray of 10-30mg.
25. as described in claim 22 or 23 pharmaceutical composition, it is characterized in that each capsule contains 50-250 μ g inhaled glucocorticoids, 50-2500 μ g mercapto ethylsulfonic acid sodium.
26. pharmaceutical compositions as claimed in claim 4, is characterized in that the pharmaceutic adjuvant of described aerosol comprises pharmaceutically useful propellant and other additives that are applicable to aerosol.
27. pharmaceutical compositions as claimed in claim 26, it is characterized in that described propellant for in fluorohydrocarbon compounds one or more.
28. pharmaceutical compositions as claimed in claim 26, is characterized in that described propellant is a kind of or its combination in HFA 134a, HFC-227ea.
29. pharmaceutical compositions as claimed in claim 26, is characterized in that described propellant is HFA 134a.
30. pharmaceutical compositions as claimed in claim 26, is characterized in that comprising solvent in described additives.
31. pharmaceutical compositions as claimed in claim 30, is characterized in that described solvent is selected from one or more in glycerol, propylene glycol, Polyethylene Glycol, ethanol or oleic acid.
32. pharmaceutical compositions as claimed in claim 30, is characterized in that described solvent is selected from ethanol.
33. pharmaceutical compositions as claimed in claim 26, is characterized in that described additives also comprise other low volatility component.
34. pharmaceutical compositions as claimed in claim 33, is characterized in that described other low volatility component is alcohol, glycol, one or more in vegetable oil, organic acid.
35. pharmaceutical compositions as claimed in claim 26, is characterized in that described additives also comprise one or more of dispersant, alkane, terpenes, sugar, polysaccharide, antioxidant, polymer, amine, steroid apoplexy due to endogenous wind.
36. pharmaceutical compositions as claimed in claim 4, is characterized in that active component is crushed into the micropowder that particle diameter is 0.5-10 μ m.
37. pharmaceutical compositions as claimed in claim 4, it is characterized in that described production of aerosol is: to the active component micropowder that adds recipe quantity in aerosol bottle, open the valve on bottle, the mixture of premixed propellant and additives is imported by valve, valve-off, obtains required aerosol.
38. pharmaceutical compositions as claimed in claim 4, is characterized in that described production of aerosol is: micronized active component is distributed in additives, then adds in the propellant after pre-cooling and mix, then divide and install in aerosol bottle.
39. pharmaceutical compositions as claimed in claim 4, it is characterized in that described aerosol is often pressed contains 50-250 μ g inhaled glucocorticoids, 50-2500 μ g mercapto ethylsulfonic acid sodium.
40. pharmaceutical compositions as claimed in claim 5, the particle diameter that it is characterized in that described carrier is 30～60 μ m.
41. pharmaceutical compositions as claimed in claim 1, the mass ratio of inhaled glucocorticoids and mercapto ethylsulfonic acid sodium is 1:5-12.
42. pharmaceutical compositions as claimed in claim 1, the mass ratio of inhaled glucocorticoids and mercapto ethylsulfonic acid sodium is 1:8-10.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1327382A (en) * | 1998-12-23 | 2001-12-19 | 伊迪亚股份公司 | Improved formulation for topical non-invasive application in vivo |
| CN1965234A (en) * | 2004-03-31 | 2007-05-16 | 特罗弗根公司 | Human glycoprotein hormone superagonists and uses thereof |
| CN101754747A (en) * | 2007-06-05 | 2010-06-23 | Paka肺部医药公司 | Methods and compositions for delivering drugs to the lungs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1327382A (en) * | 1998-12-23 | 2001-12-19 | 伊迪亚股份公司 | Improved formulation for topical non-invasive application in vivo |
| CN1965234A (en) * | 2004-03-31 | 2007-05-16 | 特罗弗根公司 | Human glycoprotein hormone superagonists and uses thereof |
| CN101754747A (en) * | 2007-06-05 | 2010-06-23 | Paka肺部医药公司 | Methods and compositions for delivering drugs to the lungs |
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