CN101856327A - Aerosol with quantitative inhalation of bencycloquidium bromide and preparation method thereof - Google Patents
Aerosol with quantitative inhalation of bencycloquidium bromide and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an aerosol with quantitative inhalation of bencycloquidium bromide and a preparation method thereof. The aerosol can be used for a non-freon (CFC) solution type formula which has high fine particle fraction (FPF). Shown by pharmacokinetic test results, the aerosol has fast effect, can be used for treating asthma and chronic obstructive pulmonary disease (COPD) and has good antiallergic function.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to aerosol with quantitative inhalation of bencycloquidium bromide and preparation method thereof.
Background technology
Charles Thiel invention pressure metered dose inhalation aerosol (pressurized metered dose inhaler since Riker Laboratories in 1956, pMDI) since, in five more than ten years in the past, owing to have quick-acting, locate and avoid gastrointestinal tract first pass effect and volume little, convenient drug administration, price is low, the patient is easy to use, need not be as Foradil Aerolizer formoterol fumarate drug loading or former thereby cause advantages such as the powder moisture absorption in the device before use because of environment etc., be treatment pulmonary disease such as asthma always, the main dosage form of chronic obstructive pulmonary disease has the irreplaceable advantage of other preparations.Enhancing along with people's environmental consciousness, 40 countries had signed Montreal Protocol on Substances that Deplete the Ozone Layer at Montreal, CAN in 1987, propellant-freon (Chlorofluorocarbon among the pMDI, CFC), because of it is a greenhouse gases, and the strong depletion of the ozone layer effect of tool, and face alternative.China has worked out " Chinese ODS is progressively eliminated national scheme " in January, 1993, and State Food and Drug Administration made an announcement in 2006, will stop to produce and using the pressure metered dose inhalation aerosol that contains freon in 2010 comprehensively.In alternative material, (hydrofluoroalkane is that HFA-134a (tetrafluoroethane) and HFA-227 (heptafluoro-propane) have got permission to be used for pMDI as medicinal propellant HFA) to two kinds of hydrofluoroalkanes.Nineteen ninety-five, European Union ratified the exploitation that HFA 134a and HFA 227 CFC alternative are used for medicinal aerosol, and U.S. FDA had also been ratified HFA 134a in the application that sucks preparation in 1996.
The alternative of CFC is not the simple replacement that a preparation prescription is formed in the medicinal aerosol.The physicochemical property of HFA has been compared than big-difference with CFC.Compare with CFC, HFA polarity is bigger, and dissolubility is bad.Kauri-Butanol Value (kauri-butanol value, K.B. value) is a kind of test value of reading that is used for representing organic liquid or organic solvent dissolution ability quality.Kauri is the title of a kind of natural gum (Gum), is soluble in butanols and is insoluble to other hydrocarbon cosolvent.Treat as a kind of standard test solution if will be dissolved with the butanols of examining upright glue, add, till becoming turbid (Yin Kaoli glue is insoluble to other solvent and muddiness), promptly get the KB value and the solvent that other is unknown is constantly a small amount of.20 ℃ CFC-12KB value is 18, and the KB value of HFA-134a only is 9.2.Other there are some researches show that in the presence that does not have cosolvent, originally span, oleic acid and phospholipid commonly used all was insoluble in HFA in the CFC-MDI prescription.Than CFC, HFA has better hydrophilic simultaneously, and this also just has higher requirement to the manufacturing process of aerosol mist production environment and tank body and valve.
Because of the special physiological structure of pulmonary, suck drug particle in the preparation and need the site of action of being allowed for access less than 5 μ m.Research worker is found, diameter of aspirin particle can change in suction process, should represent with dynamic particle diameter, its numerical value is different with initial size (being static particle diameter) in the prescription, this changes relevant with the character of other composition in suction air-flow, doser, suction, the preparation prescription, even diameter of aspirin particle 100% is less than 5 μ m, the dynamic particle diameter that 20-30% also may only be arranged is less than 5 μ m, and the amount that can arrive pulmonary may only have 5～30% (even lower).Therefore, (Fine ParticleFraction, FPF) mensuration is compared with other preparation the research of suction preparation and the foundation of quality control guarantee system, and is even more important and difficult to fine particle mark in the inhalant.
Bencycloquidium bromide (bencycloquidium bromide) is a M cholinoceptor blocker, by Beijing JiaShiLianBo Pharmaceutical Technology Co., Ltd's research and development, is first cholinolytic one kind new medicine of domestic research and development, and it mainly acts on M
1And M
3Subtype acceptor is to M
2Receptor acting is very weak, and untoward reaction is few, and cholinolytic effect is strong.Its chemistry is by name: 3-{ (2-cyclopenta-2-hydroxyl-2-phenyl) ethyoxyl }-1-methyl-bromination-1-azabicyclo [2,2,2] octane.
Chinese patent [application number: 03150151.6 publication number: CN1568984A] " be used for the treatment of spray, aerosol of respiratory system disease and preparation method thereof " and disclose a kind of chemical compound general formula be figure below be the aerosol of propellant with hydrofluoroalkane hydro carbons (HFA) and Chlorofluorocarbons class (CFC) respectively, can use it for prevention and treatment mammal and people's all kinds of acute and chronic airway obstructive diseases, as chronic obstructive disease of lung, bronchial asthma etc.In its claims of announcing, connection hydrogen atom and R are hydrochloric acid on the nitrogen-atoms, phosphoric acid, hydrobromic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzenesulfonic acid, fumaric acid, maleic acid, malic acid, aminoacid, tartaric acid; Though and the bencycloquidium bromide parent nucleus is similar to it, on nitrogen-atoms, connects methyl, R and then be bromide ion.Except that principal agent is different with this patent structure cause physical and chemical properties of drugs different with pharmacological effect, aerosol is formed and to be comprised principal agent, propellant, cosolvent, organic or inorganic acid, surfactant in these patent disclosure claims; The solution-type prescription is added with and is no more than 5% water, and this patent is made up of principal agent, propellant, cosolvent, does not contain organic or mineral acid, does not contain water, can add surfactant.
Chinese patent [application number: 200510109292.3, publication number: CN1769286A] " a kind of treat nasal cavity secretion excessively and the chemical compound and the pharmaceutical composition of chronic obstructive pulmonary disease " medicine that a class is treated nasal cavity supersecretion and chronic obstructive pulmonary disease disclosed, comprising bencycloquidium bromide, relating to dosage form has aerosol, powder spray, nasal drop and nasal spray.But the aerosol in its claims of announcing, used propellant is one or more the mixing in isceon, dichlorodifluoromethane, Dichloromonofluoromethane, F-22, Dichlorotetrafluoromethane, a chlorine five fluoromethane, chlorodifluoroethane, Difluoroethane, the Perfluorocyclobutane, carry out alternate requirement and generally acknowledge that in the world adopting hydrofluoroalkane is under the situation of propellant at current freon, this patent has lost practicality gradually.
Chinese patent [the patent No.: ZL03121031.7, Granted publication number: CN1257903C] " a kind of quinine compounds and method for making and medicinal usage that contains quaternary ammonium group " disclose a kind of quinine compounds that contains quaternary ammonium group, be used for the treatment of chronic obstructive pulmonary disease, bronchial asthma, rhinitis and flu these mammal respiratory system disease and peptic ulcers, these mammal digestive system disease of dysentery, comprising bencycloquidium bromide, the related dosage form of this class pharmaceutical composition has tablet, capsule, aerosol, spray, injection, or slow releasing agent.But the type and the composition of aerosol are not described in its claims, used propellant is one or more the mixing in isceon, dichlorodifluoromethane, Dichloromonofluoromethane, F-22, Dichlorotetrafluoromethane, a chlorine five fluoromethane, chlorodifluoroethane, Difluoroethane, the Perfluorocyclobutane among the embodiment, carry out alternate requirement and generally acknowledge that in the world adopting hydrofluoroalkane is under the situation of propellant at current freon, this patent has lost practicality gradually.
This patent is on these patent bases, and adopting the environmental protection gas hydrofluoroalkane that does not have the effect of destruction atmospheric ozone layer is propellant, invents a kind of new metered dose inhalation aerosol.
Summary of the invention
The object of the invention provides a kind of bencycloquidium bromide inhalation aerosol and preparation method, is used for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
The invention provides aerosol with quantitative inhalation of bencycloquidium bromide.This metered dose inhalation aerosol is made up of principal agent, cosolvent, surfactant, propellant.
Described aerosol, its principal agent is a bencycloquidium bromide, its structural formula is.
Described aerosol, its drug content are 0.001-3% by weight percentage.
Described aerosol, its cosolvent are one or more in dehydrated alcohol, the Polyethylene Glycol.
Described aerosol, its cosolvent content are 0.001-40% by weight percentage.
Described aerosol, its surfactant is an oleic acid; Lactic acid oligomer (OLA); The anhydro sorbitol class is as span20, span60, span65, span80, span85; The polyethenoxy sorbitan class is as tween20, tween80; The polyoxyethylene aliphatic alcohol ether class is as Brij30, Brij35, Cremophor EL; Poloxalkol is as Pluronic F-68; The polyglycol distearate class is as Solutol HS15; Phospholipid is as in soybean phospholipid, egg yolk lecithin, the lecithin one or more.
Described aerosol, its surface-active contents are 0-3% by weight percentage.
Described aerosol, its propellant are a kind of in tetrafluoroethane (HFA-134a), seven fluoroethanes (HFA-227ea) or the mixture of the two.
Described aerosol, its propellant content are 54-99.998% by weight percentage.
Described aerosol is a solution aerosol.
Another object of the present invention has provided the preparation method of aerosol with quantitative inhalation of bencycloquidium bromide, specifically is with after bencycloquidium bromide, cosolvent and/or the surfactant dissolves, goes on foot fill methods or a step fill method or cold pot process through two and is prepared from.
Description of drawings
Fig. 1 is beagle dog bencycloquidium bromide 100 μ g air flues curve charts when splashing into the medicine of administration
Fig. 2 is beagle dog bencycloquidium bromide 200 μ g air flues curve charts when splashing into the medicine of administration
Fig. 3 is beagle dog bencycloquidium bromide 400 μ g air flues curve charts when splashing into the medicine of administration
Curve chart when Fig. 4 is the medicine of beagle dog bencycloquidium bromide 2mg air flue spray delivery
Curve chart when Fig. 5 is the medicine of beagle dog bencycloquidium bromide 4mg air flue spray delivery
The specific embodiment
Composition weight (%)
Bencycloquidium bromide 40mg 0.26
Ethanol 3g 19.95
HFA-134a 12g 79.79
Behind bencycloquidium bromide and dissolve with ethanol, the two-step method fill charges into HFA-134a promptly.
Composition weight: (%)
Bencycloquidium bromide 20mg 0.13
Ethanol 1g 6.65
Oleic acid 6mg 0.04
HFA-134a 14g 93.18
Behind bencycloquidium bromide and oleic acid and dissolve with ethanol, the two-step method fill charges into HFA-134a promptly.
Embodiment 3
Composition weight (%)
Bencycloquidium bromide 200mg 1.33
PEG1000 800mg 5.32
Ethanol 1g 6.65
Soybean phospholipid 40mg 0.26
HFA-134a 13g 86.44
Behind bencycloquidium bromide, PEG1000, soybean phospholipid and dissolve with ethanol, the one-step method fill charges into HFA-134a promptly.
Composition weight (%)
Bencycloquidium bromide 4mg 0.025
Span85 4mg 0.025
Tween20 200mg 1.25
Ethanol 800mg 5.0
HFA-134a 15g 93.7
Behind bencycloquidium bromide, Span85, Tween20 and dissolve with ethanol, the one-step method fill charges into HFA-134a promptly.
Composition weight (%)
Bencycloquidium bromide 40mg 0.24
Ethanol 4g 24.2
SolutolHS15 500mg 3.0
HFA-227 12g 72.56
Behind bencycloquidium bromide, Solutol HS15 and dissolve with ethanol, the cold filling fill charges into HFA-227 promptly.
Composition weight (%)
Bencycloquidium bromide 200mg 1.27
Ethanol 2g 12.7
Soybean phospholipid 40mg 0.25
Lactic acid oligomer (OLA) 500mg 3.18
HFA-227 13 82.6
Behind bencycloquidium bromide, soybean phospholipid and dissolve with ethanol, the cold filling fill charges into HFA-227 promptly.
Composition weight (%)
Bencycloquidium bromide 4mg 0.025
PEG400 800g 5.05
Cremophor?EL 40mg 0.25
HFA-227 12g 75.75
HFA-134a 3g 18.93
After bencycloquidium bromide, PEG400, Cremophor EL dissolving, the two-step method fill charges into HFA-134a and HFA-227 promptly.
Composition weight (%)
Bencycloquidium bromide 500mg 3.3
Ethanol 6g 40.0
Brij30 300m 2.0
Fluronic?F-68 200mg 1.3
HFA-227 1g 6.7
HFA-134a 7g 46.7
Behind bencycloquidium bromide, Brij30, Fluronic F-68 and dissolve with ethanol, the one-step method fill charges into HFA-134a and HFA-227 promptly.。
Composition weight (%)
Bencycloquidium bromide 200mg 1.06
Ethanol 4g 21.28
Oleic acid 100mg 0.53
Lecithin 500mg 2.66
HFA-227 8g 42.5
HFA-134a 6g 31.97
Behind bencycloquidium bromide, oleic acid, lecithin and dissolve with ethanol, cold filling charges into HFA-134a and HFA-227 promptly.The mensuration of embodiment 10TI particle size distribution
(Fine Particle Fraction FPF) as weigh sucking important parameters in the quality of the pharmaceutical preparations control, has very big dependency with the curative effect of preparation to fine particle dosage.After embodiment sample 1～9 preparation is finished, select 10～20 bottles of samples respectively, with reference to Chinese Pharmacopoeia 2005 editions, inhalation aerosol droplet (grain) the measure of spread method and the instrument that record among two appendix X H carry out.
With following chromatographic condition, the bencycloquidium bromide content in the working sample.
Mobile phase: acetonitrile-0.02mol/L potassium dihydrogen phosphate (35: 65), wavelength: 210nm, flow velocity: 1ml/min, sample size: 20 μ l;
The reference substance solution preparation: it is an amount of that precision takes by weighing the bencycloquidium bromide reference substance, is dissolved in water, and makes every 1mL and contain 20ug bencycloquidium bromide solution, product solution in contrast approximately.
The sample solution preparation steps is as follows: be acceptable solution with water, get 1 jar of aerosol, placed 1 hour shake well in test temperature at least, after discarding the number spray, driver is inserted in the rubber interface, opened vacuum pump, 5 seconds of jolting aluminium pot, aluminium pot is inserted on the driver, spray immediately 1 time, timing waited for for 10 seconds; After taking off aluminium pot, insert driver again in 5 seconds of jolting aluminium pot, spray the 2nd time; Repeat this process, until finishing 10 or 20 times.After spraying the last time, take off driver and aluminium pot, timing waited for for 5 seconds, detaching device.Wash driver with water; Rubber running-on and throat; Trunnion and one-level distribution bottle; The conduit inside and outside wall of filter, F interface and importing lower taper bottle and the surface and the second level distribution bottle (conical flask) of pad ridge, the each several part washing liquid is settled to scale, shake up, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram, with calculated by peak area, the conduit inside and outside wall of filter, F interface and importing lower taper bottle and the surface of pad ridge and the collected medication amount of second level distribution bottle promptly get the FPF value of sample divided by the summation of each several part collection medicine by external standard method.Gained data result table 1:
Table 1
Embodiment 11
After 1～9 preparation of embodiment sample is finished, select 10～20 bottles of samples respectively, with reference to the fine particle mark (Fine Particle Fraction) of the U.S. and British Pharmacopoeia employing Andersen Cascade Impactor working sample
With following chromatographic condition, the bencycloquidium bromide content in the working sample.
Mobile phase: acetonitrile-0.02mol/L potassium dihydrogen phosphate (35: 65), wavelength: 210nm, flow velocity: 1ml/min, sample size: 20 μ l;
The reference substance solution preparation: it is an amount of that precision takes by weighing the bencycloquidium bromide reference substance, is dissolved in water, and makes every 1mL and contain 20ug bencycloquidium bromide solution, product solution in contrast approximately.
The experimental enviroment relative humidity should be 45% to 55%.Regulate flow velocity to 28 liter/minute.Get 2 bottles of this product respectively, placed at least 1 hour at 22 ± 2 ℃; Behind the shake well, discard 4 sprays, water flushing valve and driver are dried, discard 2 sprays again, open vacuum pump, 5 seconds of jolting, this product is inserted the special (purpose) rubber interface, sprays immediately 1 time, take off aluminium pot and driver after, 5 seconds of jolting, insert the rubber interface again, spray the 2nd time, repeat this process, until finishing 5 times, after spraying for the last time, wait for 1 minute, take off aluminium pot, powered-down.Wash rubber interface and conduit, each layer of ram, filter paper with water, the each several part washing liquid is settled to scale, shake up, precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram, with calculated by peak area,, promptly get the FPF value of sample by external standard method from the 3rd layer of summation of collecting medicine divided by each several part of ram to the collected medication amount of filter paper.Gained data result table 2:
Table 2
Embodiment 12
After embodiment sample 1～9 preparation is finished, select 10～20 bottles of samples respectively, adopt the fine particle mark (Fine Particle Fraction) of the working sample of NewGeneration Impactor working sample with reference to the U.S. and British Pharmacopoeia.
With following chromatographic condition, the bencycloquidium bromide content in the working sample.
Mobile phase: acetonitrile-0.02mol/L potassium dihydrogen phosphate (35: 65), wavelength: 210nm, flow velocity: 1ml/min, sample size: 20 μ l;
The reference substance solution preparation: it is an amount of that precision takes by weighing the bencycloquidium bromide reference substance, is dissolved in water, and makes every 1mL and contain 20ug bencycloquidium bromide solution, product solution in contrast approximately.
The experimental enviroment relative humidity should be 45% to 55%.Regulate flow velocity to 30 liter/minute.Get 2 bottles of this product respectively, placed at least 1 hour at 22 ± 2 ℃; Behind the shake well, discard 4 sprays, water flushing valve and driver are dried, discard 2 sprays again, open vacuum pump, 5 seconds of jolting, this product is inserted the special (purpose) rubber interface, sprays immediately 1 time, take off aluminium pot and driver after, 5 seconds of jolting, insert the rubber interface again, spray the 2nd time, repeat this process, until finishing 5 times, after spraying for the last time, wait for 1 minute, take off aluminium pot, powered-down.Wash rubber interface and conduit with water; Each sedimentation glass of ram; Filter paper, the each several part washing liquid is settled to scale, shakes up, precision is measured 20 μ l and is injected chromatograph of liquid, and the record chromatogram is pressed external standard method with calculated by peak area, collect the summation of medicine from ram the 4th sedimentation glass to the collected medication amount of filter paper divided by each several part, promptly get the FPF value of sample.Gained data result table 3:
Table 3
The test of embodiment 13 pharmacokineticss
Get embodiment 2 samples, adopt the beagte dog to carry out following test
(1) with the sodium intravenous anesthesia of 30mg/kg pentobarbital beagle dog.Operation separates the exposure trachea, puts tracheal intubation.
(2) medication and dosage:
1. in trachea, splash into the bencycloquidium bromide of each dosage with the 1ml syringe; 100 μ g/dog, 200 μ g/dog, 400 μ g/dog.
2. when complete lattice dog is air-breathing, spray into aerosol with quantitative inhalation of bencycloquidium bromide, 2mg/dog, 4mg/dog.
(3) get blood: beagle dog hind leg small saphenous vein is placed remaining needle.Respectively at 0min, 2min, 5min, 10min, 15min, 20min, 30min, 45min, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h get blood 0.5ml and place anticoagulant tube, and the centrifugal 10min of 3000rpm/min gets upper plasma.
(4) beagle dog lung tissue:
The anesthesia of beagle dog, 15min after the administration puts to death the beagle dog, gets trachea, hilus pulumonis, and lobi inferior.Carry out homogenate by adding 1ml methanol in the 100mg tissue, the centrifuging and taking supernatant is to be measured.
The concentration that splashes into air pipe behind the bencycloquidium bromide 400 μ g/ 15min, hilus pulumonis position and lobi inferior tissue in the canine trachea is respectively 52.71 ± 14.40,25.68 ± 22.94 and 14.96 ± 9.63 (C μ g/L), is equivalent to plasma C respectively
Max12.0,5.9 and 3.4 times.
Dog MDI aerosol only sucks bencycloquidium bromide 4mg/, and the concentration of air pipe, hilus pulumonis position and lobi inferior tissue is respectively 25.7 ± 10.87,20.4 ± 8.86 and 19.1 ± 16.47 (C μ g/L) behind the 15min, is equivalent to plasma C respectively
Max5.8,4.6 and 4.3 times.
Dog pMDI aerosol sucks in bencycloquidium bromide and the trachea and splashes into bencycloquidium bromide relatively, and aerosol suction blood drug level is about and splashes into 10% of blood drug level in the trachea; The drug level of lung tissue also is about 10%.
Trachea splashes into the height that sucks the drug level of two kinds of administering mode lung tissues with aerosol and is air pipe＞hilus pulumonis position＞lobi inferior successively.
Dog pMDI aerosol sucks and splashes into bencycloquidium bromide in bencycloquidium bromide and the trachea relatively, T
MaxFaster (seeing Fig. 1, Fig. 2, Fig. 3, Fig. 4 and Fig. 5).
The test of embodiment 14 antiallergic
One, bencycloquidium bromide is attacked the effect that the back pulmonary function changes to sensitized guinea pig antigen
1. sensitized guinea pig: ovalbumin (grade II, sigma Co.USA) 10mg is dissolved in 1% normal saline-gel aluminum hydroxide every each 0.25ml of Cavia porcellus two back legs (i.m), 0.5ml (i.p).Be used for experiment after 21 days.
2. grouping: divide 5 groups, several 10 of every treated animal.Be the normal saline matched group, each 1 group of bencycloquidium bromide 5,10,20,40nmol concentration.
3. administration time and antigen are attacked: put into Cavia porcellus and trace base curve after the lung function tests case is stablized, atomizing earlier sucks and respectively organizes medicine, comprises the normal saline matched group, and the time is 30s, trace the pulmonary function curve, carry out antigen with ovalbumin 10mg/ml then and attack 30s.
4. trace the pulmonary function variation that antigen is attacked: antigen is attacked back 1,2,3,4,5,10,15,20,25,30min respectively traces the pulmonary function curve one time, calculates airway resistance and pulmonary dynamic compliance parameter.
Result: cause behind the sensitized guinea pig antigen that tangible airway resistance increase and pulmonary dynamic compliance descend.Bencycloquidium bromide 5,10,20,40nmol concentration aerosol suck and are dosage and rely on inhibitory action, and 20 or 40nmol aerosol suction group and model group comparison, statistics has evident difference (P＜0.05-0.01).
Two, bencycloquidium bromide is attacked the effect that the back pneumonia changes to sensitized mice antigen
1. sensitized mice: ovalbumin (grade V, sigma Co.USA) 1mg is dissolved in 0.5ml in 1% normal saline-gel aluminum hydroxide, every mice two back each 0.025ml of the sole of the foot (s.c), groin, cervical region, each 0.05ml of back bilateral (s.c), 0.25ml (i.p).The pneumoretroperitoneum same amount was strengthened sensitization once in 10～14 days, and antigen is attacked the preparation inflammatory model after 21 days.
2. grouping: divide 5 groups, every treated animal is only counted 6-10.Be blank (sensitization is not attacked), normal saline matched group (model group), each 1 group of bencycloquidium bromide 10,20,40nmol concentration.
3. administration time and antigen are attacked: put into the 4L bell jar in mice group, atomizing sucks and respectively organizes medicine, comprises the normal saline matched group, and the time is 10min, and 10-30min behind the suction medicine carries out antigen with ovalbumin (grade V) 10mg/ml and attacks 20min.Once a day, amount to 7 days.
4. sampling: ether is slightly anaesthetized, and plucks eyeball and gets blood.The thoracic cavity is opened in dislocation, ligation left pulmonary (take off and do histopathologic slide or molecular biology test), and tracheal intubation right side bronchial lavage, each 0.5ml 3 times, amounts to 1.5ml.
5. testing index:
A. separation of serum is put-80 ℃ of refrigerators and is preserved (OVA-specific IgE, OVAspecific IgG1and IgG2a) to be measured;
B.BALF:WBC counts (Total cells), differential counting (Macrophages, Eosinophils, Lymphocytes, Neutrophils);
The centrifugal back of C.BALF supernatant is kept somewhere biochemical indicators such as cytokine to be measured; IL-4, IL-5, IL-13, pro-MMP-9, TIMP-1, TGF-β 1.
D. lung tissue is done histopathologic slide; H-E dyeing (observation inflammatory cell), periodic acid-Schiff dyeing (PAS observes goblet cell), Masson ' s trichrome dyeing (observe airway tissue and reinvent fibrosis)
E. mRNA such as lung tissue IL-13, MMP-9, TI MP-1, TGF-β 1, eotaxin express.
Result: induce tangible airway inflammation reaction after sensitized mice antigen is attacked, be dosage from total cellular score, eosinophilic granulocyte's number than the obvious rising of matched group, bencycloquidium bromide 10,20,40nmol concentration in the bronchial perfusate and rely on inhibitory action, 20 or 40nmol aerosol suction group and model group relatively, statistics has evident difference (P＜0.05～0.01).In addition, bencycloquidium bromide 20,40nmol concentration can obviously suppress cytokine expression such as IL-4, IL-5 in the bronchial perfusate.Lung tissue section is observed, and bencycloquidium bromide 20,40nmol concentration can obviously suppress sensitized mice antigen and attack the lung tissue eosinophilic granulocyte's who causes the infiltration (H-E dyeing) and the propagation (periodic acid-Schi ff dyeing) of goblet epithelium cell.
Claims (12)
1. bencycloquidium bromide pressure metered dose inhalation aerosol is characterized in that this aerosol is made up of principal agent, cosolvent, surfactant, propellant.
2. according to the described aerosol of claim 1, its principal agent is a bencycloquidium bromide, and its structural formula is
3. according to claim 2, its drug content is 0.001-3% by weight percentage.
4. according to the described aerosol of claim 1, its cosolvent is one or more in dehydrated alcohol, the Polyethylene Glycol.
5. according to the described aerosol of claim 4, its cosolvent content is 0.001-40% by weight percentage.
6. according to the described aerosol of claim 1, its surfactant is an oleic acid; Lactic acid oligomer (0LA); The anhydro sorbitol class is as span20, span60, span65, span80, span85; The polyethenoxy sorbitan class is as tween20, tween80; The polyoxyethylene aliphatic alcohol ether class is as Brij30, Brij35, Cremophor EL; Poloxalkol is as Pluronic F-68; The polyglycol distearate class is as Solutol HS15; Phospholipid, as in soybean phospholipid, the lecithin one or more.
7. according to the described aerosol of claim 6, its surface-active contents is 0-3% by weight percentage.
8. according to the described aerosol of claim 1, its propellant is a kind of in tetrafluoroethane (HFA-134a), seven fluoroethanes (HFA-227ea) or the mixture of the two.
9. described according to Claim 8 aerosol, its propellant content are 54-99.998% by weight percentage.
10. according to the described aerosol of claim 1, be solution aerosol.
11. the preparation technology of described aerosol with quantitative inhalation of bencycloquidium bromide is with after bencycloquidium bromide, cosolvent and/or the surfactant dissolves, goes on foot fill methods or a step fill method or cold pot process through two and is prepared from.
12. the described aerosol of claim 1 can be used for treating asthma and chronic obstructive pulmonary disease, and has good anti-allergic effects.
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| CN103784401A (en) * | 2012-10-29 | 2014-05-14 | 北京市丰硕维康技术开发有限责任公司 | Solution-type metered dose inhalation aerosol for treating respiratory diseases and preparation method thereof |
| CN107304207A (en) * | 2016-04-18 | 2017-10-31 | 银谷制药有限责任公司 | The crystal formation I of compound and the mixing crystal formation of crystal formation II and its production and use |
| CN107304209A (en) * | 2016-04-18 | 2017-10-31 | 银谷制药有限责任公司 | Compound it is unformed and preparation method thereof |
| CN107304208A (en) * | 2016-04-18 | 2017-10-31 | 银谷制药有限责任公司 | Crystal formation II of compound and its production and use |
| CN107304206A (en) * | 2016-04-18 | 2017-10-31 | 银谷制药有限责任公司 | Crystal formation I of compound and its production and use |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1257903C (en) * | 2003-03-21 | 2006-05-31 | 嘉事堂药业股份有限公司 | Quinic compound containing quaternary ammonium group and its preparation and medicina use |
| CN1769286B (en) * | 2005-10-20 | 2010-10-06 | 嘉事堂药业股份有限公司 | Compound and pharmaceutical composition for treating nasal oversecreation and chronic obstructive pulmonary disease |
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2009
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103784401A (en) * | 2012-10-29 | 2014-05-14 | 北京市丰硕维康技术开发有限责任公司 | Solution-type metered dose inhalation aerosol for treating respiratory diseases and preparation method thereof |
| CN107304207A (en) * | 2016-04-18 | 2017-10-31 | 银谷制药有限责任公司 | The crystal formation I of compound and the mixing crystal formation of crystal formation II and its production and use |
| CN107304209A (en) * | 2016-04-18 | 2017-10-31 | 银谷制药有限责任公司 | Compound it is unformed and preparation method thereof |
| CN107304208A (en) * | 2016-04-18 | 2017-10-31 | 银谷制药有限责任公司 | Crystal formation II of compound and its production and use |
| CN107304206A (en) * | 2016-04-18 | 2017-10-31 | 银谷制药有限责任公司 | Crystal formation I of compound and its production and use |
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|---|---|
| CN101856327B (en) | 2012-02-22 |
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