CN101347621A - Medicament composition for treating respiratory disease - Google Patents
Medicament composition for treating respiratory disease Download PDFInfo
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- CN101347621A CN101347621A CNA2007100583503A CN200710058350A CN101347621A CN 101347621 A CN101347621 A CN 101347621A CN A2007100583503 A CNA2007100583503 A CN A2007100583503A CN 200710058350 A CN200710058350 A CN 200710058350A CN 101347621 A CN101347621 A CN 101347621A
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- ciclesonide
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Abstract
The invention provides a pharmaceutical composition for the treatment of respiratory diseases, in particular asthma, rhinitis or COPD and especially asthma. Particularly, the composition contains glucocorticoid and leukotriene antagonist, especially Ciclesonide, Montelukast and salts usable for treatment. The pharmaceutical composition can be prepared to compound respirable powder and aerosol, irrespirable powder and aerosol and pressurized spray.
Description
Technical field
The invention provides a kind of treatment respiratory tract disease particularly asthma, rhinitis or chronic obstructive pulmonary disease (COPD), especially the pharmaceutical composition of asthma, particularly contain glucocorticoid and leukotriene antagonist, especially contain ciclesonide and montelukast and the compositions of the salt that can be used for treating.
Background technology
Asthma is a kind of chronic airway inflammation, it is characterized by reversibility airway obstruction and airway reactivity and 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 have only 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 pulmonary disease such as asthma at present mainly contains following several:
(1) broxaterol
(2) xanthine drug
(3) anticholinergic agent
(4) glucocorticoid
(5) antiallergic agent
By the treatment practice, people find that gradually simple a kind of medicine can not better controlled and treatment asthma, so engendered various antasthmatic compound preparations, wherein general with the use of inhaled glucocorticoid/long-acting beta 2 receptor stimulating agents again, present existing inhaled glucocorticoid/long-acting beta 2 receptor stimulating agents mainly contain the fluticasone and salmeterol of Britain GlaxoSmithKline PLC company, and (trade name: Shu Li repeatedly, Advair), U.S.'s Aunar is received budesonide/formoterol of company (Altana) etc., yet U.S. FDA clearly proposes to limit the scope of application of antasthmatic Advair in its official website.FDA thinks, Advair should only not be applied to the out of contior asthma of other drug as the first-line treatment medicine.Because a clinical studies show, contain the medicine of long-acting beta 2 receptor stimulating agents (LABAs), as Advair, can trigger serious asthma attack and death sometimes.
Ciclesonide is a kind of novel suction parahormone (ICS), receive company (Altana) exploitation and went on the market in Europe by German Aunar in 2005, commodity Alverso, be mainly used in treatment respiratory tract disease especially san bronchial asthma etc., rhinitis, chronic obstructive pulmonary disease (COPD) etc., particularly treat asthma, have that antiphlogistic effects is good, systemic side effects is little, effectively the little advantage of using dosage.
Leukotriene antagonist belongs to a kind of of antiallergic class medicine, comprise zafirlukast (Zafirlukast), montelukast (Montelukast) etc., and pharmaceutically useful salt, its energy competitive antagonism leukotriene D combining and using as a kind of novel nonsteroidal antasthmatic with the Cys-LT1 receptor.The domestic preparation that has gone on the market is peroral dosage form at present.
According to epidemiology statistics, allergic rhinitis and asthma are united morbidity, and about 80% asthma merges allergic rhinitis, and 40% allergic rhinitis merge asthma.In addition, a lot of allergic rhinitis patients are often with the high reaction of specific bronchus.And prior art studies show that.Both often have identical virulence factor, have common immunopathogenesis approach.The two pathogenetic contact extensively confirms after deliberation.Chronic obstructive pulmonary disease (COPD) can be caused by multiple reason, and the long-term asthma that continues to exist, show effect repeatedly is the major reason that causes COPD, the LTRA that is used for the treatment of asthma in treatment also can be used for the treatment of the chronic obstructive pulmonary disease that causes because of the asthma of showing effect repeatedly, and the imbedibility glucocorticoid also is used for the treatment of COPD acute attack.
China's document " foreign medical science pharmacy fascicle " the 30th the 5th phase of volume of October in 2003,284～287 disclose, leukotriene antagonist montelukast and glucocorticoid are to the control effect of symptoms of asthma and similar to the inhibitory action of airway inflammation, and both have collaborative and vicarious function.Accept to suck the asthmatic patient of glucocorticoid treatment, adding the consumption that can reduce glucocorticoid with montelukast gradually.And 2006 the 10th the 6th phases of volume of Chinese document " practical clinical medical magazine ", the research of the drug combination treatment asthma of montelukast and imbedibility glucocorticoid is provided in 47～49, result of study shows that montelukast is united and inhales people's glucocorticoid and can improve severe asthma patient's lung function index effectively, relieving asthma symptoms, treatment asthma.But at employed montelukast in the document is oral medication.Dosage is bigger, uses inconvenient.And a spot of general action is arranged, gastrointestinal tract is had zest." adverse effect magazine " 2005 7 volumes 2 phase 116-117 disclose in clinical research, and using montelukast has 1% left and right sides patient headache, dizziness, the stomachache relevant with medication to occur.
Summary of the invention
For solving the problems of the technologies described above, reduce dosage, the invention provides a kind of treat respiratory tract disease compositions, it is the compositions of leukotriene antagonist and glucocorticoid, said composition is by directly acting on respiratory tract, needn't be oral, reduce dosage, corresponding untoward reaction can reduce relatively, can overcome the shortcoming of prior art, potential danger when avoiding inhaled glucocorticoid/long-acting beta 2 receptor stimulating agents in the prior art to use, have simultaneously easy to use, the advantage that dosage is few.This pharmaceutical composition can be made compound recipe and suck powder spray and aerosol, non-suction powder spray and aerosol and spray.
The invention provides the particularly pharmaceutical composition of rhinitis, asthma, chronic obstructive pulmonary disease (COPD) of a kind of treatment respiratory tract disease, it is characterized in that
(1) first active component, it is one or more glucocorticoids.
(2) second active component, it is one or more leukotriene antagonists.
(3) one or more pharmaceutically useful non-active ingredients: wherein, (1) is 1 with the mass ratio of (2) in compositions: (0.01-100).Preferred mass ratio is 1: (0.1-50).Preferred mass ratio is 1: (0.5-20).
Described first active component dosage every day is from 0.4 μ g/kg to 40 μ g/kg.
Described second active component dosage every day is from 0.4 μ g/kg to 40 μ g/kg.
Described first active component dosage every day is during from 0.4 μ g/kg to 40 μ g/kg, and described second active component dosage every day is from 4 μ g/kg to 40 μ g/kg.
Described first active component can be selected from one or more of ciclesonide, budesonide, fluticasone, momestasone furoate, beclomethasone, flunisolide, triamcinolone acetonide and its pharmaceutically useful salt or carboxylate.Preferred one or more in ciclesonide, budesonide, fluticasone and its pharmaceutically useful salt or carboxylate.Preferred especially ciclesonide.
Described second active component can be selected from ONO-1078, zafirlukast, montelukast, or in its pharmaceutically acceptable salt one or more.Preferred montelukast, or in its pharmaceutically acceptable salt one or more.Preferred especially Menglusitena
Described pharmaceutical composition, when first active component was preferably ciclesonide especially, second active component was preferably Menglusitena.Dosage every day of preferred ciclesonide is from 1 μ g/kg to 10 μ g/kg, and dosage every day of Menglusitena is from 8 μ g/kg to 20 μ g/kg.
The pharmaceutically useful non-active ingredient of one or more in the described pharmaceutical composition comprises the pharmaceutically useful adjuvant that can be suitable for aerosol or powder spray.Contain lactose, arabic gum, glucose, mannitol or can be used for as in the aminoacid of powder spray carrier one or more.
The pharmaceutically useful non-active ingredient of one or more in the described pharmaceutical composition also contains the pharmaceutically useful propellant that is suitable for aerosol.
Described propellant is one or more in dichlorodifluoromethan hydrocarbon, fluorohydrocarbon class, Compressed Gas, the ethers.Be preferably in the fluorohydrocarbon compounds one or more.Be preferably a kind of or its combination among HFA134a and the HFA227 especially.
Described pharmaceutical composition can be made aerosol, the powder spray that can suck, the aerosol of non-suction, dust cloud and spray.
The example of the diluent or carrier that is fit in the powder spray comprises lactose, glucosan, arabic gum, the manna alcohol and glucose or can be used for as the powder spray carrier amino acid whose one or more.The preferred glycine of described aminoacid, described carrier or diluent preferably use lactose.Preferably when utilizing spray drying method to reach mean diameter, add non-ionic surface active agent in the carrier.
Can also contain suitable cosolvent in aerosol and the spray is ethanol or oleic acid, preferably uses ethanol.The solvent that is fit to is a glycerol, and propylene glycol or Polyethylene Glycol preferably use glycerol.Solvent and cosolvent also can be referred to as diluent herein.The propellant that is fit to is a hydrofluoroalkane, and is preferred 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1.2,3,3,3-heptafluoro-propane (HFA227), isceon (CCl
3F), dichlorodifluoromethane (CCl
2F
2), dichlorotetra-fluoroethane (CClF
2-CClF
2), propane (C
3H
8), iso-butane (iso-C
4H
10), normal butane (n-C
4H
10), carbon dioxide, nitrous oxide, nitrogen.Be preferably HFA227 and/or HFA134a.
Also imagine various other materials and can be suitable for use as aerosol and the low volatility component of spraying in being, comprise other pure and mild glycol, alkanol for example is 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 comprising dodecylic acid and tetradecanoic acid and stearic saturated carboxylic acid; Comprise sorbic acid, particularly oleic unsaturated carboxylic acid, the known aerosol that is applied to, to improve the physical stability of drug suspension, it is used to keep 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 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.
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 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 described indicated metered proportions.
The active component that uses among the present invention can be made powder spray, with the form of dried powder, is preferably in small, broken bits; for example micronized dried powder, for example, the mid diameter of the powdered rubber that contains is less than 10 μ m; for example from 1 to 5 μ m more preferably is accumulative micronized dried powder.As a kind of replacement of aggregation, active component in small, broken bits can with one or more pharmaceutically useful non-active ingredients, as additive, diluent or carrier etc. form specified form of mixtures.The composition that uses among the present invention can obtain these preferred forms by method known to those skilled in the art.Add non-ionic surface active agent in the carrier to increase flowability when utilizing spray drying method to reach mean diameter, preferred nonionic is a poloxamer.Glucocorticoid: the poloxamer weight ratio is 1: (0.01～5).The composition that uses among the present invention can obtain these preferred forms by method known to those skilled in the art.
The present invention further provides and utilized described compositions manufacturing to be used for the treatment of respiratory system disease, particularly asthma, rhinitis, chronic obstructive pulmonary disease are especially treated the medicine of asthma.
Compositions of the present invention can through port or intranasal inhalation.Composition is suitable for from dry powder inhaler, and a kind of metered dose inhaler of pressurization or aerosol apparatus administration also are suitable for carrying out aerosol delivery.When the active component of compositions was suitable for inhaler administration from pressurization, they were preferably mid diameter less than 10 μ m, for example the micronized form of from 1 to 5 μ m.Their are suspended or, preferably, be dissolved in the liquid propellant mixture.Spendable propellant comprises or hydrofluoroalkane (preferred HFA227 and/or HFA134a), carbon dioxide, nitrous oxide, nitrogen, isceon (CCl
3F), dichlorodifluoromethane (CCl
2F
2), dichlorotetra-fluoroethane (CClF
2-CClF
2), propane (C
3H
8), iso-butane (iso-C
4H
10), normal butane (n-C
4H10).Especially preferred propellant be HFA143a and/HFA227, wherein every kind of propellant can use in compositions separately or with other propellant with mixing, especially the mixture of preferred HFA143a and HFA227, preferably particles suspended density is identical or close in the density of HFA143a and HFA227 mixture and the compositions.
When the active component of compositions uses as powder spray, randomly use with other excipient, lubricant and/or antioxidant combination of one or more kinds.
When the active component of compositions of the present invention was adapted to pass through spray delivery, they can be with spray water suspension or solution form, available units dosage or multiple dosage form administration.
Compositions can 1 to 4 administration every day, is preferably every day one to twice.Comprise the research that the pharmacology aspect of first active component and second active component is carried out repeatedly among the present invention, its result shows glucocorticoid particularly ciclesonide and leukotriene antagonist when especially the compositions of montelukast is used for the treatment of the patient who suffers from asthma, compares during with first active component of independent application or second active component to have better effect.Compare the more oral obvious minimizing of montelukast use amount of the present invention, and therapeutic equivalence with oral montelukast coupling ciclesonide inhalant.
The active component that uses among the present invention also can be made into aerosol and spray, and with active component and one or more pharmaceutically useful non-active ingredient, as additive, diluent, propellant or antioxidant mix the specified form of mixtures of formation.Specified form of mixtures is aerosol or spray.The composition that uses among the present invention can obtain these preferred forms by method known to those skilled in the art.According to the present invention, further provide the medicine that is used for the treatment of the disease of respiratory system by compositions manufacturing of the present invention here.
The specific embodiment
By the furthermore bright the present invention of following example, but it has no intent in the scope of restriction application.Micronize is carried out in a usual manner in example, as mechanical milling method or spray drying method, so that the granular size scope of each component is suitable for inhalation; Or the solution form, also prepare in a usual manner, make into regular solution type or suspension type, so that make aerosol or spray.
Embodiment 1
Montelukast 20g
Budesonide 10g
Ethanol 750g
Propylene glycol 150g
Dichlorodifluoromethane 1500g
Preparation technology: the montelukast and the budesonide of recipe quantity are added in the ethanol and propylene glycol that stirs, stir, heat in tepidarium, make material dissolution, sand core funnel filters, the divided dose fill, sealing-in dosage valve system, dichlorodifluoromethane is injected in pressurization more respectively, promptly, 1000 bottles of theoretical fills, the fill yield is more than 85%.Through 45-50 ℃ of water-bath leak detection 30 minutes, do not have and leak.Press for every bottle 50, whenever press and contain montelukast 400 μ g, budesonide 200 μ g.
Embodiment 2
Menglusitena 12.5g
Ciclesonide 3.5g
Ethanol 200g
Glycerol 19.5g
HFA227 750g
HFA134a 750g
Vitamin C 7.5g
Preparation technology: the montelukast and the ciclesonide of recipe quantity are added in vitamin C, ethanol and the glycerol that stirs, stir, heat in tepidarium, make material dissolution, sand core funnel filters, the divided dose fill, sealing-in dosage valve system, pressurize again respectively HFA134a and HFA227, promptly, theoretical canned 1000 bottles, the fill yield is more than 85%.Through 45-50 ℃ of water-bath leak detection 30 minutes, do not have and leak.Press for every bottle 50, whenever press and contain Menglusitena 250 μ g, ciclesonide 70 μ g.
Embodiment 3
Montelukast 5g
FLUTICASONE PROPIONATE 10g
Ethanol 750g
Glycerol 150g
Dichlorotetra-fluoroethane 1500g
Sodium pyrosulfite 7.5g
Preparation technology: the montelukast and the FLUTICASONE PROPIONATE of recipe quantity are added in sodium pyrosulfite, ethanol and the glycerol that stirs, stir, heat in tepidarium, make material dissolution, sand core funnel filters, the divided dose fill, sealing-in dosage valve system, the dichlorotetra-fluoroethane that pressurizes again respectively, promptly, theoretical canned 1000 bottles, the fill yield is more than 85%.Through 45-50 ℃ of water-bath leak detection 30 minutes, do not have and leak.Press for every bottle 50, whenever press and contain montelukast 100 μ g, FLUTICASONE PROPIONATE 200 μ g.
Embodiment 4
Zafirlukast 12.5g
Ciclesonide 1.75g
Ethanol 200g
Glycerol 25g
Dichlorotetra-fluoroethane 1500g
Preparation technology: the zafirlukast and the ciclesonide of recipe quantity are added in vitamin C, ethanol and the glycerol that stirs, stir, heat in tepidarium, make material dissolution, sand core funnel filters, the divided dose fill, sealing-in dosage valve system, the dichlorotetra-fluoroethane that pressurizes again, promptly, theoretical canned 1000 bottles, the fill yield is more than 85%.Through 45-50 ℃ of water-bath leak detection 30 minutes, do not have and leak.Press for every bottle 50, whenever press and contain zafirlukast 250 μ g, ciclesonide 35 μ g.
Embodiment 5
Menglusitena 10g
Ciclesonide 8g
Ethanol 750g
Glycerol 150g
Isceon 1500g
Sodium pyrosulfite 7.5g
Preparation technology: the Menglusitena and the ciclesonide of recipe quantity are added in sodium pyrosulfite, ethanol and the glycerol that stirs, stir, heat in tepidarium, make material dissolution, sand core funnel filters, the divided dose fill, sealing-in dosage valve system, the isceon that pressurizes again respectively, promptly, theoretical canned 1000 bottles, the fill yield is more than 85%.Through 45-50 ℃ of water-bath leak detection 30 minutes, do not have and leak.Press for every bottle 50, whenever press and contain Menglusitena 200 μ g, ciclesonide 160 μ g.
Embodiment 6
Menglusitena 500mg
Ciclesonide 140mg
Lactose 25000mg
Preparation technology: recipe quantity Menglusitena, ciclesonide and lactose are mixed, with fluid energy mill medicine is carried out abundant micronization processes after, the fill of medicine carrying powder to capsule, is got final product theoretical fill 1000 capsules.Every capsules includes micronized Menglusitena 500 μ g and ciclesonide 140 μ g, lactose 25mg.
Embodiment 7
Pranlukast 800mg
Ciclesonide 160mg
Mannitol 25000mg
Preparation technology: recipe quantity pranlukast, ciclesonide and lactose are mixed, with fluid energy mill medicine is carried out abundant micronization processes after, the fill of medicine carrying powder to capsule, is got final product theoretical fill 1000 capsules.Every capsules includes micronized pranlukast 800 μ g and ciclesonide 160 μ g, mannitol 25mg.
Embodiment 8
Menglusitena 1g
Ciclesonide 1.6g
Lactose 18.8g,
Poloxamer 0.2g
Preparation technology: after the above-mentioned material of recipe quantity is mixed with the medicine alcoholic solution of solid content 3%, after the filtration, the filtrate spray drying, micronization makes it mean diameter and reaches 5 μ m, crosses to incapsulate behind 3 mixings of 200 mesh sieves.Theoretical several 1000 of the capsule of irritating, every capsules includes micronized Menglusitena 1000 μ g and ciclesonide 1600 μ g, lactose 18.8mg.
Embodiment 9
Menglusitena 500mg
Ciclesonide 50mg
Mannitol 25000mg
Preparation technology: recipe quantity Menglusitena, ciclesonide and mannitol are mixed, with fluid energy mill medicine is carried out abundant micronization processes after, the fill of medicine carrying powder to capsule, is got final product, theoretical fill 1000 capsules, yield rate is more than 85%.Every capsules includes micronized Menglusitena 500 μ g and ciclesonide 50 μ g, mannitol 25mg.
Application Example 1
Relatively ciclesonide/Menglusitena with take ciclesonide and Menglusitena respectively, separately with ciclesonide, independent influence of histamine being induced the rat asthma attack with Menglusitena
One, experiment purpose: the pharmaceutical dosage form of seeking a kind of more effective, simpler treatment asthma.
Two, experiment material
1 laboratory animal: choose rat childhood, body weight 180～200g.
2 experimental apparatus: the glass bell jar of air compressor, aerosol shower nozzle, hydrargyrum manometer, base, 4L
3 experimental drugs: 2% acecoline, 0.1% histamine phosphate, ciclesonide/Menglusitena aerosol: self-control (pressing the preparation of example 2 mass ratioes).Ciclesonide is pressed embodiment 2 disclosed methods, makes compositions, promptly uses
Ciclesonide 3.5g
Ethanol 200g
Glycerol 19.5g
HFA227?750g
HFA134a?750g
Ascorbic acid 7.5g
Method according to embodiment 2 is mixed with spray
4 date processing: adopt the check of t in groups of SAS system.
Three, experimental technique
Choose rat childhood, male and female all can, body weight is 180-200g, puts into the bell glass about 5 liters, sprays into 2% acecoline and 15 seconds of 0.1% histamine phosphate's volume mixed liquor with the pressure of 400mmHg.After spraying stops, observing drawing of rat and breathe heavily incubation period (asthma promptly takes place, breathe and be the devil), draw and breathe heavily the phase of diving and to select for use greater than 120 seconds rat until the time that tic is fallen.Learn from else's experience to measure to draw and breathe heavily 50 of qualified rats incubation period, be divided into five groups incubation period at random by drawing to breathe heavily, be ciclesonide (CIC)/Menglusitena (MON) compound recipe high and low dose group, the common use group of ciclesonide (CIC) and Menglusitena (MON), ciclesonide (CIC) group, Menglusitena (MON) group.Be subjected to the reagent thing next day, dosage: CIC/MON14 μ g/50 μ g/kg, the 7 μ g/25 μ g/kg suction of spraying; CIC and MON group are that 7 μ g/kg spraying suction+200 μ g/kg are oral; CIC organizes 7 μ g/kg; MON organizes 25 μ g/kg.Administration gave 0.25% 2 hydrochloric acid histamine according to the aforementioned spray method that draws the mode of breathing heavily after 30 minutes, observe to give and to draw the variation of breathing heavily incubation period and tic incidence rate (draw when breathing heavily animal do not occur the person of falling in 6 minutes to breathe heavily the volt phase be to calculate in 360 seconds to draw) before and after the medicine.
Four, experimental result: a few treated animal generation asthma, difference is all arranged, see Table 1 until the time that tic is fallen:
The spraying of table 1 pair histamine phosphate sucks the influence of inducing asthma attack (n=10, mean ± SD)
By table 1 as seen, CIC/MON 14/50 μ g/kg, 7/25 μ g/kg spraying sucks and can obviously prolong the inductive Cavia porcellus asthma attack of histamine phosphate incubation period, reduce its tic incidence rate, remarkable with comparing difference before the medicine, (with low dosage ratio) close with MON group effect even better (with the high dose ratio) with common use CIC, compare with independent suction CIC and independent oral MON, act on stronger.
Five, conclusion: as the unitary agent therapy, CIC/MON low dose group and common use CIC compare with the MON group, draw after the medication to breathe heavily incubation period (second) and be respectively 295 ± 60.5,300 ± 66.1 seconds, there was no significant difference, curative effect is constant, but use conveniently, improved compliance of patients; Compare with independent use CIC, MON, effect has significant difference, is embodied as to draw to breathe heavily incubation period (second) and be respectively 295 ± 60.5,260 ± 58.7,211 ± 29.5, and obviously prolongation is drawn and breathed heavily incubation period, and determined curative effect has clinical use value very much.
Application Example 2: suck of the influence of ciclesonide/Menglusitena to the airway of mice inflammation
One, experiment purpose: the main pharmacodynamics effect of research ciclesonide/Menglusitena inhalant
Two, experiment material:
1. animal: 40 of male C57BL/6 mices, 6～8 weeks of monthly age, average weight 18～22g, 8 every group
2. reagent: ciclesonide/Menglusitena atomized liquid (0.35mgCIC+1.25mgMON/ml), Menglusitena atomized liquid (1.25mgMON/ml).Ciclesonide atomized liquid (0.35mgCIC/ml), chicken ovalbumin (0VA, Grade V, U.S. Sigma company), adjuvant liquid aluminium { Imject Alum[Al (OH)
3/ Mg (OH)
2], Alum, U.S. PIERCE company }.
Three, experimental technique
1. experimental design and grouping, experiment mice is with being divided into 5 groups at random, 8 every group:
A group, i.e. positive controls, OVA sensitization/excite group,
B group, i.e. negative control group
The C group, i.e. CIC treatment group
The D group, i.e. CIC/MON treatment group
The E group, i.e. MON treatment group
2. experimental technique
OVA sensitization/exciting method is as follows: A, C, D, E group, every mouse peritoneal injection 0.2ml sensitization liquid [containing OVA80 μ g, adjuvant liquid aluminium (Alum) 0.1ml] is in injection in the 0th, 14 day 2 times.(2) excite: after the 1st sensitization the 24th day, people 2.5% OVA 45min was inhaled in atomizing, every day 1 time, continues 18d.
The A group, 2h sucks normal saline before each atomizing, and every day 1 time, 45min continues to last OVA atomizing altogether.
B group, mice with continuous normal saline atomizing 18d, are total to 45min once a day after the injection of physiologic saline for substitute sensitizing agent.
C group, sensitization and OVA atomizing program are organized with A, and the 1d beginning before the OVA atomizing, the 2h spraying sucked the CIC atomized liquid 10ml of 0.35mg/ml before each OVA excited, and was total to 45min 1 time every day.
D group, sensitization and OVA atomizing program are organized with A, and the 1d beginning before the OVA atomizing, the 2h spraying sucked the ciclesonide/Menglusitena atomized liquid 10ml of (0.35mgCIC+1.25mgMON/ml) before each OVA excited, and was total to 45min 1 time every day.
E group, sensitization and OVA atomizing program are organized with A, and the 1d beginning before the OVA atomizing, the 2h spraying sucked the MON atomized liquid 10ml of 1.25mg/ml before each OVA excited, and was total to 45min 1 time every day.
All mices are all put to death behind last atomizing 48h.And carry out bronchoalveolar lavage collection irrigating solution (BALF) and carry out differential counting statistical result seeing Table 2.
Table 2 different pharmaceutical and pharmaceutical composition are to influence (X ± s, * 10 of the numeration of mice BALF cell divide
4Ml)
Four conclusions
From the data of table 2 as can be seen, when sucking ciclesonide, Menglusitena and ciclesonide/Menglusitena respectively, the eosinophilic granulocyte among the BALF, lymphocyte, neutrophilic granulocyte number and A group (positive controls) more all have significance.Eosinophilic granulocyte, lymphocyte, macrophage, neutrophilic granulocyte number among the BALF of C, E group and D group more all have significance (P＜0.05) respectively, have shown that ciclesonide and Menglusitena have synergism when uniting suction.Especially, when list is used Menglusitena, the macrophage number organizes with A that the macrophage number does not more have significance (P＞0.05) among the BALF among the E group BALF, and coupling ciclesonide/Menglusitena is when sucking, macrophage counts that the macrophage number among the BALF had significance (P＜0.05) when comparison C group is single to suck with ciclesonide among the mice BALF, explanation, when ciclesonide/Menglusitena sucks, except working in coordination with the eosinophilic granulocyte who reduces among the mice BALF, lymphocyte, outside the neutrophilic granulocyte number, more can beat all generation better reduce the effect of BALF macrophage number.Thereby might when treatment asthma, reach better therapeutic effect.
Claims (10)
1, a kind of compositions that is used to prepare the medicine for the treatment of respiratory tract disease is characterized in that being made up of following material,
(1) first active component, it is one or more glucocorticoids.
(2) second active component, it is one or more leukotriene antagonists.
(3) one or more pharmaceutically useful non-active ingredients
2, pharmaceutical composition as claimed in claim 1 is characterized in that, the mass ratio of described first active component and second active component is 1: (0.01-100).
3, pharmaceutical composition as claimed in claim 1 is characterized in that, described first active component dosage every day is from 0.4 μ g/kg to 40 μ g/kg.
4, pharmaceutical composition as claimed in claim 1 is characterized in that, described second active component dosage every day is from 4 μ g/kg to 40 μ g/kg.
5, pharmaceutical composition as claimed in claim 1 is characterized in that, described first active component can be selected from one or more in ciclesonide, budesonide, fluticasone, momestasone furoate, beclomethasone, flunisolide, the triamcinolone acetonide.
6, pharmaceutical composition as claimed in claim 1 is characterized in that, described first active component is a ciclesonide.
7, pharmaceutical composition as claimed in claim 1 is characterized in that, described second active component can be selected from ONO-1078, zafirlukast, montelukast, pranlukast, or in its pharmaceutically acceptable salt one or more.
8, pharmaceutical composition as claimed in claim 1 is characterized in that, described one or more pharmaceutically useful non-active ingredient comprises that all can be suitable for the pharmaceutically useful non-active ingredient of spray, powder spray.
9, pharmaceutical composition as claimed in claim 1 is characterized in that, aerosol, the powder spray of described compositions for sucking, the aerosol of non-suction, spray, powder spray.
10, pharmaceutical composition as claimed in claim 1 is characterized in that, described respiratory tract disease is pipe asthma, chronic obstructive pneumonia, rhinitis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100583503A CN101347621A (en) | 2007-07-20 | 2007-07-20 | Medicament composition for treating respiratory disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100583503A CN101347621A (en) | 2007-07-20 | 2007-07-20 | Medicament composition for treating respiratory disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101347621A true CN101347621A (en) | 2009-01-21 |
Family
ID=40266702
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100583503A Pending CN101347621A (en) | 2007-07-20 | 2007-07-20 | Medicament composition for treating respiratory disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101347621A (en) |
-
2007
- 2007-07-20 CN CNA2007100583503A patent/CN101347621A/en active Pending
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Open date: 20090121 |