CN1425378A - Composition for curing branchial asthma - Google Patents
Composition for curing branchial asthma Download PDFInfo
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- CN1425378A CN1425378A CN 03100431 CN03100431A CN1425378A CN 1425378 A CN1425378 A CN 1425378A CN 03100431 CN03100431 CN 03100431 CN 03100431 A CN03100431 A CN 03100431A CN 1425378 A CN1425378 A CN 1425378A
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Abstract
The present invention relates to a kind of medicine composite for treating branchial asthma. The medicine composite consists of active component including salmeterol or its medicinal salt and budesonide in the molar ratio of 1 to 0.38-20, as well as non-active components including solvent, cosolvent, propellant, antioxidant, dilutent and lubricant. The present invention has large range of medicine dosage, long lasting period and high comprehensive effect, and may be prepared into various preparation forms.
Description
Technical field
The present invention relates to THE TREATMENT OF BRONCHIAL ASTHMA, a kind of compositions for the treatment of the salmaterol and the budesonide of bronchial asthma particularly is provided.The new salmaterol with pharmaceutically active substances and the compositions of budesonide can be made compound recipe inhalation aerosol and powder spray, non-inhalation aerosol and powder spray and compound spray, treat bronchial asthma effectively.
Background technology
Bronchial 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.
Salmaterol (Salmeterol) is a kind of beta 2-receptor analeptic of known potent, long-acting and high selectivity, and side effect is little, and cardiovascular system is not had influence, does not also influence skeletal muscle and trembles etc.Can be used for the reversibility airway obstruction in long-term treatment asthma (comprise night asthma and the asthma of exercise induced), chronic bronchitis and the emphysema.
Budesonide (Budesonide) is a kind of commercially available non-halo glucocorticoid, has very strong local anti-inflammatory effect; Can suppress early stage bronchospasm and late phase allergic responses; To the airway hyper-reaction patient, can reduce the airway hyperreactivity that histamine and acetylcholine cause; And because the structural characteristics of this product, after local medication absorbs, have 90% medicine to change into the non-activity metabolite rapidly through liver approximately, plasma drug level is lower, so the incidence rate of systemic side effects is much smaller than traditional glucocorticoid medicine.
The sufferer that above-mentioned two kinds of medicines are used for the treatment of respiratory system such as bronchial asthma has curative effect preferably, but general dosage is bigger, and curative effect is single, and is inconvenient again when using respectively.
Summary of the invention
The purpose of this invention is to provide a kind of treat bronchial asthma compositions, it is the compositions of salmaterol and budesonide, can overcome the shortcoming of prior art, can make compound recipe inhalation aerosol and powder spray, non-inhalation aerosol and powder spray and compound spray, the curative effect effect increases, and can treat bronchial asthma effectively.
The present invention includes:
(1) first active component, it is selected from salmaterol, or its pharmaceutically useful salt;
(2) second active component, it is a budesonide;
(3) one or more pharmaceutically useful non-active ingredients;
Wherein, the mol ratio of (1) and (2) is 1 in compositions: (0.38～20).Preferred mol ratio is 1: 3.
The salmaterol physiologically acceptable salt that is fit to comprises derived from the inorganic and organic acid-addition salts of acid, chloride for example, bromide, sulfate, phosphate, hydroxynaphthoate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoic acid salt, 2-or 4-hydroxy benzoate, the 4-chloro benzoate, tosilate, toluene fulfonate, Ascorbate, acetate, succinate, lactate, glutarate, tricarballylic acid salt, Hydroxynaphthoate or oleate or its solvate.First active component is salmaterol or salmaterol hydroxynaphthoate preferably.
When first active component is salmaterol, dosage every day of first active component is from 40 μ g to 200 μ g, when being the salmaterol hydroxynaphthoate, dosage every day of first active component is from 54 μ g to 290 μ g, and correspondingly dosage every day of second active component budesonide is from 80 μ g to 800 μ g.
Compositions of the present invention most preferably comprises the salmaterol of each using dosage 50 μ g and the budesonide of each using dosage 160 μ g, uses every day twice.
With the same or more pharmaceutically useful non-active ingredient of active component, as additive, diluent or carrier, propellant etc. use with form of mixtures, and preferably every dosage is from 20 μ g to 30mg.The example of the diluent or carrier that is fit in the powder spray comprises lactose, glucosan, arabic gum, mannose alcohol and glucose.Preferably use lactose.The solvent that is fit in aerosol and the spray is ethanol or oleic acid, preferably uses ethanol.The cosolvent 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 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 dichlorodifluoromethane (CCl
2F
2).
When should be appreciated that the reference quantity when the amount of pointing out each active component, they are amounts of metering.When using active component, the amount of each composition that the patient sucks can be different from the amount of metering, for example because the retention of active component in suction apparatus.Therefore the applicating ratio of active component can be different from the ratio of metering.The ratio of preferably using is in above-mentioned 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.
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, for example the medicine of asthma.The present invention also provides according to the present invention and has used salmaterol or budesonide to make the disease that compositions is used for the treatment of respiratory system, for example 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 composition of compositions was suitable for inhaler administration from pressurization, they were preferably micronized form.Their are suspended or, preferably, be dissolved in the liquid propellant mixture.Spendable propellant comprises carbon dioxide, nitrous oxide, nitrogen, isceon (CCl
3F), dichlorodifluoromethane (CCl
2F
2), dichlorotetra-fluoroethane (CClF
2-CClF), propane (C
3H
8), iso-butane (iso-C
4H
10), normal butane (n-C
4H
10).Especially preferred propellant is dichlorodifluoromethane (CCl
2F
2), wherein each can use in compositions separately or with other propellant with mixing.They randomly with other excipient of one or more kinds, lubricant and/or antioxidant combination are used.
When the composition of compositions of the present invention or medicine-chest was adapted to pass through spray delivery, they can be with or without suitable pH or tonicity contributor with spray water suspension or solution form, can be used as unit dose or multiple dosage form.
Compositions can 1 to 4 administration every day, is preferably twice of every day.
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 that the compositions of salmaterol and budesonide has wide weight ratio scope, when being used for the treatment of the patient who suffers from asthma, compare during with first active component of independent application or second active component, composition of active components of the present invention provides surprisingly better effect.The optional scope of dosage of the present invention is bigger, and curative effect lasting time is long, and resultant effect is good, and is easy to use.
Description of drawings
Before and after Fig. 1 medication to Cavia porcellus draw breathe heavily preclinical influence (
*After the P＜0.01 expression medication with medication before draw and breathe heavily the difference that has significance incubation period;
+P＜0.05, budesonide/salmaterol is breathed heavily than drawing of budesonide, salmaterol significant difference is arranged incubation period after the expression medication).
The variation of lung resistance before and after Fig. 2 medicine sucks.
Fig. 3 sucks before and after budesonide/salmaterol, budesonide and the lactose, the variation of acetylcholine irritaiting concentration (mg/ml).
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, 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.Example 1
Salmaterol 2.5g
Budesonide 8.0g
Ethanol 750g
Propylene glycol 150g
Dichlorodifluoromethane 1500g
Vitamin C 7.5g
Preparation technology: the salmaterol and the budesonide of recipe quantity are added in vitamin C, ethanol and the 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 salmaterol 50 μ g, budesonide 160 μ g.Example 2
Salmaterol 2.5g
Budesonide 10.0g
Ethanol 750g
Propylene glycol 150g
Dichlorodifluoromethane 1500g
Vitamin C 7.5g
Preparation technology: the salmaterol and the budesonide of recipe quantity are added in vitamin C, ethanol and the 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 salmaterol 50 μ g, budesonide 200 μ g.Example 3
Hydroxyl naphthoic acid salmaterol 5.09g
Budesonide 10.0g
Ethanol 750g
Glycerol 150g
Isceon 1500g
Sodium pyrosulfite 7.5g
Preparation technology: the hydroxyl naphthoic acid salmaterol and the budesonide 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, isceon 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 salmaterol 70 μ g, budesonide 200 μ g.Example 4
Hydroxyl naphthoic acid salmaterol 3.5g
Budesonide 8.0g
Ethanol 750g
Glycerol 150g
Dichlorotetra-fluoroethane 1500g
Sodium pyrosulfite 7.5g
Preparation technology: the hydroxyl naphthoic acid salmaterol and the budesonide 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, dichlorotetra-fluoroethane 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 salmaterol 70 μ g, budesonide 160 μ g.Example 5
Salmaterol 50mg
Budesonide 160mg
Lactose 25000mg
Sodium benzoate 125mg
Preparation technology: recipe quantity salmaterol, budesonide and lactose, sodium benzoate 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 salmaterol 50 μ g and budesonide 160 μ g, lactose 25mg, sodium benzoate 125 μ g.Example 6
Salmaterol 50mg
Budesonide 200mg
Mannitol 25000mg
Sodium benzoate 125mg
Preparation technology: recipe quantity salmaterol, budesonide and mannitol, sodium benzoate 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 salmaterol 50 μ g and budesonide 200 μ g, mannitol 25mg, sodium benzoate 125 μ g.Example 7
Salmaterol 70mg
Budesonide 160mg
Glucosan 25000mg
Magnesium stearate 125mg
Preparation technology: recipe quantity salmaterol, budesonide and glucosan, magnesium stearate 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 salmaterol 70 μ g and budesonide 160 μ g, glucosan 25mg, magnesium stearate 125 μ g.Example 8
Salmaterol 70mg
Budesonide 200mg
Xylitol 25000mg
Magnesium stearate 125mg
Preparation technology: recipe quantity salmaterol, budesonide and xylitol, magnesium stearate 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 salmaterol 70 μ g and budesonide 200 μ g, xylitol 25mg, magnesium stearate 125 μ g.Example 9:
Salmaterol 2.5g
Budesonide 8.0g
Ethanol 1000g
Propylene glycol 250g
Sodium pyrosulfite 25g
Preparation technology is as follows: the salmaterol and the budesonide of recipe quantity are added in the ethanol and propylene glycol that stirs, stir, in tepidarium, heat, make material dissolution, add sodium pyrosulfite, stirring makes the dissolving mix homogeneously, and sand core funnel filters, the divided dose fill, pour carbon dioxide, that is, 1000 bottles of theoretical fills, actual fill yield is more than 85%.Every bottle 50 spray of this product uses twice every day, and every spray contains salmaterol 50 μ g, budesonide 160 μ g.Example 10:
Salmaterol 2.5g
Budesonide 10.0g
Ethanol 1000g
Glycerol 250g
Sodium pyrosulfite 25g
Preparation technology is as follows: the salmaterol and the budesonide of recipe quantity are added in the ethanol and glycerol that stirs, stir, in tepidarium, heat, make material dissolution, add sodium pyrosulfite, stirring makes the dissolving mix homogeneously, and sand core funnel filters, the divided dose fill, pour nitrogen, that is, 1000 bottles of theoretical fills, actual fill yield is more than 85%.Every bottle 50 spray of this product uses twice every day, and every spray contains salmaterol 50 μ g, budesonide 200 μ g.Application example 1 relatively budesonide/salmaterol with take budesonide and salmaterol respectively, separately with budesonide, independent influence of histamine being induced the Cavia porcellus asthma attack with salmaterol
One, experiment purpose: the pharmaceutical dosage form of seeking a kind of more effective, simpler treatment asthma.
Two, experiment material
1 laboratory animal: choose Cavia porcellus childhood, body weight 150～200g is provided by Shandong Province's Experimental Animal Center;
2 experimental apparatus: the glass clock of air compressor, aerosol shower nozzle, hydrargyrum manometer, base, 4L is put;
3 experimental drugs: 2% acecoline, 0.1% histamine phosphate, budesonide/salmaterol aerosol: self-control (pressing the preparation of example 1 mol ratio).Budesonide: a day weighing apparatus institute of materia medica provides; Salmaterol: provide by the Drug Manufacturing Room of Medicine Industry Inst., Shandong Prov..
4 date processing: adopt the check of t in groups of SAS system.
Three, experimental technique
Choose Cavia porcellus childhood, male and female all can, body weight is 150～200g, 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 Cavia porcellus and breathe heavily incubation period (asthma promptly takes place, breathe and be the devil), draw and breathe heavily incubation period and will not select for use greater than 120 seconds Cavia porcellus until the time that tic is fallen.Learn from else's experience to measure to draw and breathe heavily 40 of qualified Cavia porcelluss incubation period, be divided into five groups incubation period at random, be i.e. budesonide/salmaterol high and low dose group, budesonide and salmaterol group, budesonide group, salmaterol group by drawing to breathe heavily.Be subjected to the reagent thing next day, dosage: budesonide/salmaterol 20ug/6ug/kg, 10ug/3ug/kg suction of spraying; Budesonide and salmaterol group are that the 20ug+6ug/kg spraying sucks; Budesonide group 20ug; Salmaterol group 6ug.Administration after 30 minutes the same spraying give 0.25% 2 hydrochloric acid histamine, observe to give to draw before and after the medicine 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 incubation period be to calculate in 360 seconds to draw).
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, and (n=10, the group dosage/kg of mean ± SD) draw and breathe heavily incubation period (second) tic incidence rate
Bud/sal 20/6ug 87.8 behind the medicine prodrug ± 10.2 350 ± 70.5 behind the medicine prodrug
+ * *100 30bud/sal 10/3ug 88.3 ± 11.6 289 ± 68
*100 40bud+sal 20ug+6ug 89.3 ± 14.8 349 ± 85.6
+ * *100 30bud 20ug 90.4 ± 12.5 250 ± 69.3
*100 50sal 6ug 89.4 ± 11.3 278.6 ± 84.5
*100 40
*After the P＜0.01 expression medication with medication before draw and breathe heavily the difference that has significance incubation period;
+P＜0.05, budesonide/salmaterol and budesonide, salmaterol draws to breathe heavily significant difference is relatively arranged incubation period after the expression medication.
By table 1 and Fig. 1 as seen, budesonide/salmaterol 20/6,10/3ug/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, to take budesonide close with the salmaterol effect with separating, with take budesonide and separately suctions/salmaterol comparison separately, act on stronger.
Five, conclusion: as the unitary agent therapy, budesonide/salmaterol is compared with salmaterol with taking budesonide simultaneously, is respectively 350 ± 70.5,349 ± 85.6, there was no significant difference, curative effect is constant, but uses conveniently, has improved compliance of patients; With take budesonide separately, salmaterol is compared, effect has significant difference, is embodied as to draw to breathe heavily incubation period (second) and be respectively 350 ± 70.5,250 ± 69.3,278.6 ± 84.5, and obviously prolongation is drawn and breathed heavily incubation period, determined curative effect has clinical use value very much.
Application example 2: the influence that sucks the airway hyperreactivity that budesonide/salmaterol brings out Canis familiaris L. air flue oxyphil cell and anaphylactogen
One, experiment purpose: the main pharmacodynamics effect of research budesonide/salmaterol
Two, experiment material:
1 animal: kind, strain: mongrel; Body weight: 20～35kg; Selected condition: intradermal injection A.suum extract is positive, and has to suck airway hyperreactivity history behind the A.suum.
2 reagent: budesonide/salmaterol: self-control (pressing the prescription of example 1)
Budesonide aerosol: day weighing apparatus institute of materia medica; Salmaterol aerosol: day weighing apparatus institute of materia medica
Ascaris suum (A.suum) extract (anaphylactogen), 0.4% phenol (anaphylactogen diluent)
Three, experimental technique
Get mongrel, carry out following experiment:
Suck the A.suum diluent behind the 1 suction lactose
Suck the A.suum anaphylactogen behind the 2 suction lactose
Suck the A.suum diluent behind 3 suction budesonide/salmaterol
Suck the A.suum anaphylactogen behind 4 suction budesonide/salmaterol
Suck the A.suum diluent behind the 5 suction budesonides
Suck the A.suum anaphylactogen behind the 6 suction budesonides
Each experiment needed at least at interval for 4 weeks or more than 4 weeks.
During each the experiment, Canis familiaris L. sucks twice budesonide/salmaterol or budesonide, salmaterol or lactose aerosol (morning and afternoon each once) every day, continuous 7 days, in the 8th day the morning, behind the last inhalation, Canis familiaris L. intravenous injection 30mg/kg pentobarbital sodium is anaesthetized, the circulation of qi promoting cannula, connect the respirator of a constant volume on the intubate, the setting tidal volume is 10ml/kg, and breathing rate is 30 times/minute.A balloon shape esophagus intubate is linked to each other with the pressure reduction pressure transducer, measure the airway hyperreactivity that lung resistance value and acetylcholine are brought out, carried out bronchovesicular perfusion (BAL) after 15 minutes, measure the number of oxyphil cell in the perfusate.
(1) anaphylaxis is attacked
Press decimal dilution method, with the stock solution (10 of normal saline with the A.suum extract
-1W/v) be diluted to the solution (10 of a series of concentration
-610
-510
-410
-3With 10
-2W/v).Behind the Fundamentals of Measurement lung resistance, every Canis familiaris L. sucks the certain density A.suum that can cause airway hyperreactivity, and each concentration sucked at least at interval in 10 minutes.The diluent of A.suum (0.4% phenol) also sucks with method, and every Canis familiaris L. all sucks A.suum or its diluent of same concentrations in all experiments.
(2) oxyphil cell's mensuration in the BAL perfusion
After the processing of BAL perfusate, measure total cellular score and macrophage, neutrophil(e) cell, oxyphil cell, lymphocyte and metachromasy cell number.
To test (1) and experiment in (3) (5) in the measured BAL liquid oxyphil cell's number respectively as suck lactose or suck budesonide/salmaterol, budesonide to anaphylactogen attack before air flue oxyphil cell's basic value.
(3) mensuration of total pulmonary resistance
Measure transpulmonary pressure (being the pressure differential between oral cavity and the esophagus), flow velocity (measuring),, connect the mensuration total pulmonary resistance with breath analyzer according to the transpulmonary pressure flow velocity with respiration rate measurement device, pressure reduction pressure transducer and pressure amplifier.
(4) measurement of bronchial responsiveness
Determine airway reactivity according to the amount effect curve between lung resistance and the acetylcholine concentration (0.7-80.0ng/ml).After measuring basic lung resistance, Canis familiaris L. sucked normal saline, sucked an acetylcholine (increasing concentration gradually) then every 5 minutes, and suction is inferior altogether, in each 3 seconds, increases 5cm H until lung resistance at least than basic value
2O L
-1The concentration of the required acetylcholine of s (being the acetylcholine irritaiting concentration) represents that this value reduces representative and shows that airway reactivity increases.
Four, experimental result
(1) oxyphil cell's mensuration in the BAL perfusion
Suck behind budesonide/salmaterol, budesonide and salmaterol, budesonide or the lactose attack to the anaphylactogen diluent before, the equal number in oxyphil cell Deping is respectively 0.2 ± 0.18 * 10 in the BAL perfusate
4/ ml, 0.3 ± 0.22 * 10
4/ ml, but budesonide/salmaterol, budesonide significance reduce the number (P＜0.05) that the anaphylactogen diluent is attacked oxyphil cell in the BAL perfusate, but the number of not obvious other cell of minimizing (seeing Table 2).
After sucking budesonide/salmaterol, budesonide or lactose, anaphylactogen attack group is compared with the diluent group, can significantly increase neutrophil's number (P＜0.05, see Table 2), and the lactose group is compared with budesonide/salmaterol, budesonide group, neutrophil's number there was no significant difference P＞0.05.In addition, the yield of BAL perfusate, the equal no significant difference of number (seeing Table 2) of total cell number, macrophage, lymphocyte and metachromasy cell.
Table 2: budesonide/salmaterol, budesonide or lactose suck the influence (* 10 of cell number in the BAL liquid of front and back to anaphylactogen and diluent thereof
4/ ml) (the cell type lactose lactose budesonide/salmaterol budesonide/salmaterol budesonide budesonide of means ± SE)
+ diluent+anaphylactogen+diluent+anaphylactogen+diluent+anaphylactogen macrophage 24.5 ± 4.18 24.7 ± 5.68 31.0 ± 5.23 25.3 ± 4.32 28.9 ± 4.23 23.5 ± 3.52 neutrophilic granulocyte 1.7 ± 0.56 13.0 ± 3.56
+0.4 ± 0.12 17.4 ± 10.2
+0.5 ± 0.13 16.6 ± 11.4
+Lymphocyte 1.8 ± 0.59 1.5 ± 0.25 1.0 ± 0.22 0.7 ± 0.23 1.1 ± 0.33 1.0 ± 0.25 oxyphil cell 3.6 ± 2.32 5.7 ± 3.69 0.2 ± 0.18
*0.6 ± 0.45 0.3 ± 0.22
*0.7 ± 0.48 metachromasy cell 0.2 ± 0.02 0.2 ± 0.04 0.2 ± 0.03 0.1 ± 0.02 0.2 ± 0.03 0.1 ± 0.03 amounts to 31.8 ± 7.67 45.1 ± 13.2 32.8 ± 5.78 44.1 ± 15.2 31 ± 4.94 41.9 ± 15.68
*P＜0.05, after expression sucked budesonide/salmaterol, budesonide or lactose, anaphylactogen attack group was compared with the dilution group, can significantly reduce oxyphil cell's number.
+P＜0.05, after expression sucked budesonide/salmaterol, budesonide or lactose, anaphylactogen attack group was compared with the dilution group, can significantly increase neutrophil's number
(2) mensuration of lung resistance
Through budesonide/salmaterol, suck anaphylactogen and can obviously improve lung resistance, and compare significant difference (P＜0.01) before the treatment; After budesonide treatment, suck anaphylactogen and can obviously improve lung resistance, and compare significant difference (P＜0.01) before the treatment; After the lactose treatment, with compare before the treatment, difference is highly significant also, but the increase there was no significant difference that anaphylactogen brings out lung resistance between budesonide/salmaterol, budesonide and lactose three treatment groups (is seen Fig. 2, Fig. 2 is the variation diagram of lung resistance before and after medicine sucks), but increase trend is arranged.
Lung resistance before and after table 3 medicine sucks changes (cm H
2O/s, the inhibitor lactose lactose budesonide/salmaterol budesonide/salmaterol budesonide budesonide of means ± SD)
Preceding 1.20 ± 0.18 0.80 ± 0.08 0.93 ± 0.13 0.81 ± 0.17 0.75 ± 0.18 0.87 ± 0.17 backs 1.05 ± 0.08 8.68 ± 2.15 of+diluent+anaphylactogen+diluent+anaphylactogen+diluent+anaphylactogen
*0.92 ± 0.15 7.92 ± 3.19
*0.90 ± 0.12 6.90 ± 0.16
*
*P＜0.01, expression sucks before and after budesonide/salmaterol, budesonide and the lactose, and lung resistance has significant difference.
(2) measurement of bronchial responsiveness
Suck budesonide/salmaterol and do not change basic airway reactivity, yet it can be significantly but can not weaken the airway reactivity that the suction anaphylactogen brings out fully and increase.After sucking budesonide/salmaterol, 3.62 ± 1.09mg/ml before the meansigma methods of acetylcholine irritaiting concentration sucks from anaphylactogen reduces to 1.48 ± 1.23mg/.ml after the suction, the two have significant difference (
*P＜0.01); After sucking budesonide, 3.60 ± 1.19mg/ml before the meansigma methods of acetylcholine irritaiting concentration sucks from anaphylactogen reduces to 1.56 ± 1.48mg/.ml after the suction, the two have significant difference (
*P＜0.05); The average logarithm difference of lactose group acetylcholine irritaiting concentration is 0.78 ± 0.13, is significantly higher than budesonide/salmaterol group 0.38 ± 0.13, the two significant difference (
*P＜0.05).(see Table 4 and Fig. 3) table 4: suck before and after budesonide/salmaterol, budesonide and the lactose variation of acetylcholine irritaiting concentration (mg/ml) inhibitor lactose lactose budesonide/salmaterol budesonide/salmaterol budesonide budesonide
Preceding 3.55 ± 1.35 3.65 ± 1.23 3.60 ± 1.05 3.62 ± 1.09 3.60 ± 1.14 3.63 ± 1.19 backs 3.57 ± 1.54 0.78 ± 1.12 of+diluent+anaphylactogen+diluent+anaphylactogen+diluent+anaphylactogen
*3.60 ± 1.14 1.48 ± 1.23
*3.58 ± 1.24 1.56 ± 1.48
*
*P＜0.01,
*P＜0.05, the expression airway reactivity has significance to change.
Five, conclusion:
The distinctive air flue allergy of asthma is that the various chemical mediator by releases such as acidophil and mastocytes is caused.The inflammatory cells such as Monocytes, mastocyte that are present in airway tissue stimulate the back to activate at specific antigen, all can discharge IL-8, but IL-8 chemotactic, activation neutrophilic granulocyte are gathered in bronchial tissue, the air flue nonspecific inflammation is formed produce material impact.IL-8 can be as the marker of these inflammatory cells.
The imbedibility budesonide can suppress the cell-mediated inflammatory reaction of T in the organ walls, reduce mastocyte and lymphocytic number in epithelium oxyphil cell and lymphocyte and the lamina propria, reduce the release and the seepage of blood plasma in bronchus of oxyphil cell's cationic protein in the bronchoalveolar lavage fluid.Lung biopsy result showed that the inflammatory cell number reduces after asthmatic patient sucked budesonide for a long time.Can reduce the organ high response behind the conventional suction budesonide, improve clinical symptoms, after the drug withdrawal, budesonide reduces the time and the dosage of holding time and depending on medication of airway hyperreactivity effect.
The suction of budesonide/salmaterol does not change the antiinflammatory action of budesonide, and the influence of the influence of lung resistance and air flue inflammatory reaction is more helped the treatment of symptoms of asthma, and effect increases, and determined curative effect.
Suck budesonide/salmaterol and can significantly reduce the air flue oxyphil cell, significantly increase the neutrophil(e) cell, do not bring out the increase of lung resistance simultaneously.Suck budesonide/salmaterol and do not change basic airway reactivity, yet it can be significantly but can not weaken the airway reactivity that the suction anaphylactogen brings out fully and increase.The curative effect of budesonide/salmaterol obtains definite proof, effect obviously is better than taking separately budesonide, salmaterol, and the identical special Luo Xiaoguo with the salmaterol effect of budesonide is identical with taking simultaneously, but it takes more convenient, is a kind of compound preparation that clinical use value is arranged very much of treatment asthma.Application example 3: toxicologic study
One, acute toxicity test
The minimal lethal dose that kunming mice sucks budesonide is 80mg/kg (is about maximum recommended human inhalation dose every day 250 times).The Wistar rat once sucks budesonide 68mg/kg (be about maximum recommended human inhalation dose every day 345 times), occurs dead.The minimal lethal dose of mice and the oral this product of rat is respectively 200mg/kg and less than 100mg/kg (be about maximum recommended human inhalation dose every day 500 times).
The LD of salmaterol mouse peritoneal drug administration by injection
50=269.55mg/kg; The LD of mouse stomach administration
50=1024.61mg/kg; 833.34 times of rat spray delivery dosage intelligent consumption, animal does not see toxic reaction; Above result shows that the clinical practice of this medicine is safe.
Two, local toxicity research
Adopt white big ear rabbit, the local excitation toxicity of research budesonide/salmaterol aerosol.The result shows that the rabbit aerosol sucked budesonide/salmaterol 160/50 μ g/ days, a continuous week, no local irritant effect.
Three, specific toxicity research
(1) carcinogenesis
Oral budesonide/salmaterol 100/25 μ the g/kg/ of kunming mice days (being about 1/2 maximum recommended human inhalation dose every day) in continuous 91 weeks, does not see carcinogenesis.In the carcinogenic research in 104 weeks of Sprague-Dawley rat, the gliomatous incidence rate of male rat of (being about 1/4 maximum recommended human inhalation dose every day) obviously increases to accept oral dose 50/10 μ g/kg/ days, and statistical significance is arranged; The male rat of (be about respectively maximum recommended human inhalation dose every day 1/20 and 1/8) and the female rats that oral dose is 25/10 μ g/kg/ days (being about 1/4 maximum recommended human inhalation dose every day) all do not have carcinogenesis and to accepting oral dose 10/5,15/10 μ g/kg/ days.
(2) mutagenic action
Repair experimentation through Ames experiment, micronuclei in mice experiment, mouse lymph lymphoma experiment, the experiment of human lymphocyte chromosomal aberration, the experiment of Drosophila melanogaster recessive lethal and rat hepatocytes culture DNA and confirm that budesonide/salmaterol does not have mutagenic action and clastogenic effect.
(3) genotoxicity research
The subcutaneous Wistar of giving rat budesonide/salmaterol 10/5 μ g/kg/ days (be about maximum recommended human inhalation dose every day 1/10), parent weightening finish, antenatal survival rate, when producing and age of sucking young baby's survival rate descend, in 5/2 μ g/kg (be about maximum recommended human inhalation dose every day 1/40) dosage this effect of nothing down.
Rabbit and rat be subcutaneous respectively to give budesonide/salmaterol 15/10,400/100 μ g/kg/ days (be about respectively maximum recommended human inhalation dose every day the 1/4 and 2 times) tire that can cause death, young baby's weight loss, skeleton deformity.
Do not see teratogenesis and deadly tire effect during rat sucked budesonide/salmaterol 100～250/20～50 μ g/kg/ days (be about maximum recommended human inhalation dose every day 1/2～1/4) dosage.
Conclusion: acute, local, the specific toxicity result of study of mice, rat, rabbit show that budesonide/salmaterol is not because of drug combination, and toxicity increases to some extent.
Claims (11)
1, a kind of compositions for the treatment of bronchial asthma is characterized in that described compositions comprises:
(1) first active component, it is selected from salmaterol or its pharmaceutically useful salt;
(2) second active component, it is a budesonide;
(3) one or more pharmaceutically useful non-active ingredients; Wherein, the mol ratio of (1) and (2) is 1 in compositions: (0.38～20).
2, compositions according to the described treatment bronchial asthma of claim 1, it is characterized in that described salmaterol officinal salt is suitable salmaterol physiologically acceptable salt, comprise derived from inorganic and organically sour acid-addition salts, comprise chloride, bromide, sulfate, phosphate, hydroxynaphthoate, maleate, fumarate, tartrate, citrate, benzoate, 4-methoxybenzoic acid salt, 2-or 4-hydroxy benzoate, the 4-chloro benzoate, tosilate, toluene fulfonate, Ascorbate, acetate, succinate, lactate, glutarate, tricarballylic acid salt, Hydroxynaphthoate or oleate.
3,, it is characterized in that described first active component is salmaterol or salmaterol hydroxynaphthoate according to the compositions of the described treatment bronchial asthma of claim 1-2.
4,, it is characterized in that described non-active ingredient comprises any one or more the compositions in solvent, cosolvent, propellant, antioxidant, diluent or the lubricant according to the compositions of the described treatment bronchial asthma of claim 1.
5, according to the compositions of the described treatment bronchial asthma of claim 1, it is characterized in that it is an aerosol, its non-active ingredient is solvent, cosolvent, antioxidant and propellant.
6, according to the compositions of the described treatment bronchial asthma of claim 5, it is characterized in that described solvent is ethanol or oleic acid, cosolvent is glycerol, propylene glycol or Polyethylene Glycol, antioxidant is vitamin C or sodium pyrosulfite, and propellant is isceon, dichlorodifluoromethane, dichlorotetra-fluoroethane, propane, iso-butane or normal butane.
7, according to the compositions of the described treatment bronchial asthma of claim 1, it is characterized in that it is a powder spray, its non-active ingredient is diluent and lubricant.
8, according to the compositions of the described treatment bronchial asthma of claim 7, its feature is lactose, arabic gum, glucosan, mannitol or glucose at described diluent, and described lubricant is sodium benzoate or magnesium stearate.
9, according to the compositions of the described treatment bronchial asthma of claim 1, it is characterized in that it is a spray, its non-active ingredient is solvent, cosolvent, propellant and antioxidant.
10, according to the compositions of the described treatment bronchial asthma of claim 9, it is characterized in that described solvent is ethanol or oleic acid, cosolvent is glycerol, propylene glycol or Polyethylene Glycol, and propellant is carbon dioxide, nitrous oxide or nitrogen, and antioxidant is vitamin C or sodium pyrosulfite.
11, according to the compositions of claim 5,7 or 9 described treatment bronchial asthmas, the mol ratio of described first active component and described second active component is 1: 3.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012041031A1 (en) * | 2010-09-28 | 2012-04-05 | 健乔信元医药生技股份有限公司 | Compound composition for inhalation used for treating asthma |
| CN107320464A (en) * | 2017-04-28 | 2017-11-07 | 北京北朋科技有限公司 | The preparation method of the budesonide suspension of high pH value |
| CN114522143A (en) * | 2022-02-22 | 2022-05-24 | 暨南大学 | Low-refrigeration-effect composite propellant for inhalation aerosol and preparation method and application thereof |
-
2003
- 2003-01-14 CN CN 03100431 patent/CN1197579C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012041031A1 (en) * | 2010-09-28 | 2012-04-05 | 健乔信元医药生技股份有限公司 | Compound composition for inhalation used for treating asthma |
| US8877740B2 (en) | 2010-09-28 | 2014-11-04 | Intech Biopharm Ltd. | Compound composition for inhalation used for treating asthma |
| AU2011307899B2 (en) * | 2010-09-28 | 2015-03-12 | Intech Biopharm Ltd. | Compound composition for inhalation used for treating asthma |
| CN107320464A (en) * | 2017-04-28 | 2017-11-07 | 北京北朋科技有限公司 | The preparation method of the budesonide suspension of high pH value |
| CN114522143A (en) * | 2022-02-22 | 2022-05-24 | 暨南大学 | Low-refrigeration-effect composite propellant for inhalation aerosol and preparation method and application thereof |
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