CN1568984A - Spray and aerosol for treating respiratory system disease and its preparing process - Google Patents
Spray and aerosol for treating respiratory system disease and its preparing process Download PDFInfo
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- CN1568984A CN1568984A CN 03150151 CN03150151A CN1568984A CN 1568984 A CN1568984 A CN 1568984A CN 03150151 CN03150151 CN 03150151 CN 03150151 A CN03150151 A CN 03150151A CN 1568984 A CN1568984 A CN 1568984A
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- acid
- aerosol
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- spray
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- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the spray and aerosol containing quinuclidine compounds having the general formula (I) disclosed in the specification, the medicament can be applied to the prevention and treatment for diseases of respiratory system.
Description
Technical fieldThe present invention relates to a kind of spray and aerosol of quinine compounds, be used for the prevention and the treatment of respiratory system disease.
Technical backgroundAcetylcholine (acetylcholine, ACh) be the neurotransmitter that cholinergic nerve tip (comprise Motor nerve fibre, vegetative nerve preganglionic fibre, parasympathetic ganglion after fiber and part sympathetic nerve postganglionic fibers) discharges, having very strong biological activity, is M-ChR (m receptor) and nicotine receptor (n receptor) performance effect by acting on cholinoceptor.The cholinoceptor blocking agent medicine that to be a class play a role by the blocking-up cholinoceptor is divided into M-cholinoceptor blocking agent and N-cholinoceptor blocking agent.Cholinoceptor on the effector of M-cholinoceptor blocking agent energy blocking-up maincenter and joint back cholinergic innervation, show as the plan mentation of nervus centralis and smooth muscle loosening, glandular secretion inhibition, platycoria, the rhythm of the heart speeds etc., has pharmacological action widely and clinical application.
The cholinoceptor blocking agent has critical role in the treatment of respiratory system disease, spray and aerosol are the more satisfactory dosage forms of treatment respiratory system disease, anticholinergic agent ipratropium bromide (the Ipratropium Bromide of Germany Boehringer Ingelheim (Boehringer) company, Atrovent) two kinds of dosage forms of spray and aerosol are arranged, spray is used for the treatment of various acute and chronic rhinitis, aerosol is used for the treatment of the acute and chronic obstructive pulmonary disease, and effect is remarkable.
The principle of cholinoceptor blocking agent treatment rhinitis mainly is: suppress glandular secretion, reduce nasal secretion; Shrink the nasal cavity blood vessel and reduce the nasal mucosa blood flow.Especially its spray nasal preparation can directly make medicine be deposited on the nasal cavity front portion, reaches nasopharynx part through the motion of cilium, and droplet is long in the nasal cavity time of staying, is evenly distributed, and can improve nasal airflow rapidly, removes the symptom of having a stuffy nose.Early stage in flu, this interaction energy stops virus to reflux and breeding, effectively shortens the flu cycle.
The used compound of Formula I of the present invention is a M-cholinoceptor blocking agent, and maincenter and peripheral nervous are all had stronger cholinolytic effect, and long half time, toxic and side effects a little less than, its hydrochlorate has been used for the first aid of animal and human's organophosphate poisoning.
The hydrochlorate of compound of Formula I is when being used for the first aid of animal and human's organophosphate poisoning, and used dosage form is an injection.And the medicine of many treatment respiratory system diseases, as the cholinoceptor blocking agent, its site of action is the respiratory tract surface, as the surface of nasal mucosa, trachea and bronchus, spray and aerosol can improve local drug concentration, increase curative effect; Reduce drug dose, reduce toxic and side effects.
In existing document, do not see spray and the aerosol that contains the quinine compounds of the present invention so far as yet, and be used for the report of the prevention and the treatment of respiratory system disease.
Summary of the inventionThe object of the present invention is to provide the spray that contains compound of Formula I and aerosol and preparation method thereof.
The present invention also aims to contain the various acute and chronic rhinitis that the spray of compound of Formula I is used to prevent and treat mammal and people.
The present invention also aims to contain the various acute and chronic airway obstructive diseases that the aerosol of compound of Formula I is used to prevent and treat mammal and people, as chronic obstructive pulmonary disease, bronchial asthma etc.
In order to realize the present invention's purpose, the present invention takes following technical scheme:
The present invention relates to contain the spray and the aerosol of the quinine compounds of general formula I:
In the formula: R is that organic and inorganic acid radical and other can be used as medicinal acid group.
Organic and mineral acid is a hydrochloric acid, phosphoric acid, hydrobromic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzenesulfonic acid, fumaric acid, maleic acid, malic acid, aminoacid, tartaric acid etc.
The preparation technology of spray of the present invention is characterized in that the component and the weight proportion that constitute spray are:
1, compound of Formula I: 0.001～10.0%.
2, antibacterial: 0.0005%～10.0%.
3, inorganic or organic acid: regulate pH, pH3～9, commonly used is pH3～5, the best is pH4.
4, H
2O: an amount of.
With compound of Formula I and above-mentioned adjuvant one or more or all mix after, embedding is in the quantitative valve container.
Clearly,, change water into organic solvent and make solution, be applicable to the present invention too for those skilled in the art.The indication organic solvent can be an alcohols: as ethanol, and ethylene glycol, glycerol, propanol, isopropyl alcohol etc.; Ethers: as ether etc.; Esters: as ethyl acetate etc.; Saturated hydrocarbons: as cyclohexane extraction etc.The toxic and side effects of solvent for use should meet the requirements.
Used antibacterial can be: ethanol: 5%-20%; Glycerol: 20%-50%; Benzyl alcohol: 0.5%-1.0%; Chlorobutanol: 0.5%-5.0%.Nipalgin fat (first, second, third, fourth) or mixture: 0.01%-0.25%.Benzoic acid, sorbic acid, phenol, thymol, volatile oil: 0.01%-0.5%.Chlorine is pricked aniline, bromine is pricked aniline: 0.0005%-10.0%.And other pharmaceutically acceptable antibacterial.
Aerosol of the present invention can be stable suspension aerosol or solution aerosol.
The preparation technology of aerosol of the present invention is characterized in that the component and the weight proportion that constitute aerosol are:
1, compound of Formula I: 0.001%-10.0%.
2, propellant: 50.0%-99.0%.
3, cosolvent: 0%-50%.
4, organic acid: 0-50.0mg/ml.
With compound of Formula I and above-mentioned adjuvant one or more or all mix after, embedding is in the quantitative valve container.
Used propellant can be hydrogen fluorine carbon (HFC): appropriate H FC together solvent can form a kind of true solution system, and medicine can be dissolved in wherein fully.HFC answers avirulence and enough vapour pressures is arranged.In addition, HFC should not chemically react with device.Best HFC is 1,1,1,2-tetrafluoroethane (HFC-134 (a)) and 1,1,1,2,3,3,3-heptafluoro-propane (HFC-227).Other HFC is: difluoromethane (HFC-32), 1,1,1-HFC-143a (HFC-143 (a)), 1,1,2,2-tetrafluoroethane (HFC-134), 1, (HFC-152) such as 1-Difluoroethanes.
Clearly, for the personnel that are familiar with aerosol, non-fluorine hydrocarbon propellant also can be used for the present invention, for example saturated hydrocarbon propane, normal butane, iso-butane and ether etc.In addition, though HFC is single with best, several HFC mixture also can be used for the present invention.
Used propellant can also be Chlorofluorocarbons class (CFC): as the mixture of isceon, dichlorodifluoromethane, Dichloromonofluoromethane, F-22, Dichlorotetrafluoromethane, a chlorine five fluoromethane, chlorodifluoroethane, Difluoroethane or Perfluorocyclobutane etc. or above-claimed cpd.
The effect of cosolvent is to increase medicine and the dissolubility of other adjuvant in prescription.Cosolvent should be inoperative with medicine.Cosolvent can be an alcohols: as ethylene glycol, and glycerol, propanol, isopropyl alcohol etc., the best is an ethanol.Saturated hydrocarbons: as n-propane, normal butane, iso-butane, pentane, isopentane, neopentane, normal hexane.Ethers: as ether etc.; Esters: as ethyl acetate etc.; The toxic and side effects of used cosolvent should meet the requirements.
Used organic acid can be a citric acid: content is 0.0039-27.7mg/ml; Or ascorbic acid: content is 0.0045-5.0mg/ml.
In order to improve the serviceability of aerosol device valve system, can add some surfactants such as oleic acid, three oleic acid sorbitol esters, phosphides etc. increase lubricity.Other adjuvant has (a) antioxidant; (b) correctives, spice, sweeting agent, Herba Menthae etc.; (c) vapour pressure regulator such as pentane, isopentane, neopentane and normal hexane etc.
Term of the present invention
Term " suspension aerosol " is meant that contained drug is scattered in other adjuvant of aerosol with fines.
Term " solution aerosol " is meant that contained drug and adjuvant are miscible mutually, forms a kind of true solution.
Term " stable suspension type or solution aerosol " is meant in suspension type or solution aerosol prescription and adds a kind of stabilizing agent in addition that for example organic or inorganic acid makes aerosol more stable.
The specific embodimentBelow with reference to embodiment invention is described further, but does not limit the scope of the invention.
The preparation of spray of the present invention:
Embodiment 1
The hydrochlorate of compound of Formula I: 0.05%.
Chlorine is pricked aniline: 0.05%.
1M hydrochloric acid: regulate pH to pH4.
H
2O：99.9％。
Embedding is in the quantitative valve container.
Embodiment 2
The mesylate of compound of Formula I: 0.05%.
Bromine is pricked aniline: 0.05%.
1M hydrochloric acid: regulate pH to pH4.
H
2O：99.9％。
Embedding is in the quantitative valve container.
The preparation of aerosol of the present invention:
Embodiment 3
The hydrochlorate 0.00505g of compound of Formula I
Dehydrated alcohol 2.025g
HFC-134(a) 11.40209g
Nitric acid 0.00036g
Water 0.06750g
Total amount 13.5g
Embedding is in the quantitative valve container.
Embodiment 4
The hydrochlorate 0.00505g of compound of Formula I
Dehydrated alcohol 2.025g
HFC-134(a) 11.267g
Ascorbic acid 0.135g
Water 0.0675g
Total amount 13.5g
Embedding is in the quantitative valve container.
Embodiment 5
The hydrochlorate of compound of Formula I: 0.05%.
Glycerol: 5.0%.
Ethanol: 30.0%.
Dichlorodifluoromethane 30.0%
Dichlorotetra-fluoroethane 40.0%.
Embedding is in the quantitative valve container.
Embodiment 6
The mesylate of compound of Formula I: 0.05%.
Glycerol: 5.0%.
Ethanol: 30.0%.
Dichlorodifluoromethane 30.0%
Dichlorotetra-fluoroethane 40.0%.
Embedding is in the quantitative valve container.
Embodiment 7
The hydrochlorate 0.28g of compound of Formula I
Propylene glycol 42g
Dehydrated alcohol 210g
Dichlorodifluoromethane 231g
Dichlorotetra-fluoroethane 971g
Embedding is in the quantitative valve container.
Embodiment 8
The hydrochlorate 0.03% of compound of Formula I
Dichlorodifluoromethane 45%
Dichlorotetra-fluoroethane 50%
Lecithin 5%
Embedding is in the quantitative valve container.
Embodiment 9
The hydrochlorate 0.00505g of compound of Formula I
HFC-134(a) 13.427g
Citric acid 0.135g
Total amount 13.5g
Embedding is in the quantitative valve container.
Embodiment 10 sprays of the present invention are to the therapeutical effect of rat nasal mucosa inflammation
This test adopts method well known to those skilled in the art to carry out.Get 65 body weight 200-220g SD rat, male and female half and half, tell 13 at random as the blank group, all the other rat nasal cavities splash into 1% 2.4 dinitro-chloro-benzene acetone soln 0.1ml, in kind splashed in the 7th day and the 14th day, after last sensitization, 1% 2.4 dinitro-chloro-benzene acetone soln 0.1ml were splashed into the rat nasal cavity in the 14th day, anatomic part rat after 24 hours, as seen rat nasal mucosa redness, congested, inflammatory reaction appears in the visible rat nasal mucosa of pathologic finding, the nasal vestibule squamous epithelial cancer thickens, columnar epithelium increases, thicken, the inflammatory cell disperse distributes, and is remarkable with blank group comparing difference.The rhinitis rat is divided into 4 groups at random, every group of male and female half and half, i.e. model group, positive controls (hydrochloric acid levocabastine nasal spray, 10ml/ bottle, 30 μ g/ spray.Manufacturer: Belgian Janssen Pharmaceutica.Import drugs registration certificate number: BX20010160.Product batch number: 011211104.Date of manufacture: 2001/12/11.Valid until: 2004/11), the embodiment of the invention 1 spray group, the embodiment of the invention 2 spray groups, 10 every group.Medication: the each spray in every nostril twice, twice of every day.Successive administration 6 days, after the last administration 24 hours with sacrifice of animal, do the pathology inspection, carry out curative effect by table 1 standard and judge, the results are shown in Table 2.
Table 1 rat rhinitis model grade scale
Qualitative changeization between the classification mucous epithelium changes
-nasal vestibule squamous epithelial cancer is complete, and thick about 6-10 layer is breathed blood vessel and slightly expanded hyperemia.
Portion's columnar epithelium is complete, sees a small amount of goblet cell therebetween.
+ nasal vestibule squamous epithelial cancer slightly thickens, about 10-15 layer, and the expansion of column blood vessel moderate is hemorrhage, a matter
Epithelial cell increases, and small quantities of leukocytes is swum out of.Body of gland has squamous metaplasia to become
Gesture, a small amount of inflammatory cell distributes.
++ the nasal vestibule squamous epithelial cancer thickens, about 15-20 layer, and interstitial gland body squamous metaplasia on the column,
Skin thickens, and increases, and goblet cell increases, and the inflammatory cell disperse of mucosa top layer distributes.
Hemorrhage, leukocyte is swum out of, the sub-district mucosal necrosis.
Table 2. spray of the present invention is to the influence of rat rhinitis
Group n dosage changes in microstructure
Matter between (mg/ only) mucous epithelium
Blank group 10---
Model group 10-++ ++
Positive controls 10 0.72++
Embodiment 1 spray group 10 0.48++
Embodiment 2 spray groups 10 0.48++
Through above-mentioned result of the test, those skilled in the art know, and spray of the present invention comprises that to mammal people's rhinitis has the good curing effect.
Embodiment 11 aerosols of the present invention are to the therapeutical effect of Cavia porcellus specificity allergic asthma
This test adopts method well known to those skilled in the art to carry out.Select the healthy guinea pig of 52 body weight for use, male and female half and half at 200-220g.Give the oralbumin normal saline solution 1.0ml (oralbumin 100mg) of every guinea pig intraperitoneal injection 10%, be divided into blank group, positive controls [love complete happy (ipratropium bromide aerosol) at random, the 10ml/ bottle, 20 μ g/ spray, vigorous woods Green lattice writing brush (Boehringer lngelheim) company of Germany produces lot number: 202329, and the date of manufacture: 200202, valid until: 02 2005], the embodiment of the invention 3 aerosol groups, the embodiment of the invention 4 aerosol groups, 10 every group.Began every day once on the 6th day in the injection back through the respiratory tract spray delivery, behind the successive administration 5 days, animal is put separately in the airtight bell jar, with ultrasound atomizer 0.5% oralbumin normal saline solution is sprayed into 30s in the bell jar equably, observe record also from spraying into the oralbumin normal saline solution, be asthma incubation period to producing the time of abdominal muscle between shrinking.The data of surveying through t check comparable group differences.
Result: when giving the guinea pig intraperitoneal injection oralbumin after 10 days, when contacting same antigen once more, antigen antibody reaction just occurred, be referred to as the specificity allergic asthma based on the edema and the spasm of respiratory tract.Evidence, aerosol of the present invention has the obvious suppression effect to this specific reaction, and asthma incubation period is than blank group significant prolongation, P＜0.01.The results are shown in Table 3.
Table 3. aerosol of the present invention is to the influence of Cavia porcellus allergic asthma (s X ± SD)
Group n dosage incubation period (s)
μg·kg
-1
Blank group 10-117.82 ± 25.33
Positive controls 10 100 228.15 ± 32.42
Embodiment 3 aerosol groups 10 100 231.74 ± 28.36
Embodiment 4 aerosol groups 10 100 235.11 ± 31.24
Through above-mentioned result of the test, those skilled in the art know, and aerosol of the present invention comprises that to mammal people's respiratory system disease, especially airway obstructive disease have the good curing effect.
Claims (10)
1, the spray and the aerosol that contain compound of Formula I is characterized in that with the compound of Formula I being primary raw material.
In the formula: R is that organic and inorganic acid radical and other can be used as medicinal acid group.
2, according to claim 1, organic and mineral acid is a hydrochloric acid, phosphoric acid, hydrobromic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzenesulfonic acid, fumaric acid, maleic acid, malic acid, aminoacid, tartaric acid etc.
3, as described in the claim 2, mineral acid is a hydrochloric acid, and organic acid is a methanesulfonic acid.
4, the preparation technology of spray according to claim 1 is characterized in that the component and the weight proportion that constitute spray are:
(1) compound of Formula I: 0.001%-10.0%.
(2) antibacterial: 0.0005%～10.0%.
(3) inorganic or organic acid: regulate pH, pH3～9, commonly used is pH3～5, the best is pH4.
(4) H
2O: an amount of.
With compound of Formula I and above-mentioned adjuvant one or more or all mix after, embedding is in the quantitative valve container.
5,, can be: ethanol: 5%-20% as antibacterial as described in the claim 4; Glycerol: 20%-50%; Benzyl alcohol: 0.5%-1.0%; Chlorobutanol: 0.5%-5.0%.Nipalgin fat (first, second, third, fourth) or mixture: 0.01%-0.25%.Benzoic acid, sorbic acid, benzoic acid, thymol, volatile oil: 0.01%-0.5%.Chlorine is pricked aniline, bromine is pricked aniline: 0.0005%-10.0%.And other pharmaceutically acceptable antibacterial.
6, aerosol according to claim 1 can be stable suspension aerosol or solution aerosol.It is characterized in that the component and the weight proportion that constitute aerosol are:
(1) compound of Formula I: 0.001%-10.0%.
(2) propellant: 50.0%-99%.
(3) cosolvent: 0%-50%.
(4) organic or inorganic acid: 0-50.0mg/ml.
(5) surfactant: an amount of.
With compound of Formula I and above-mentioned adjuvant one or more or all mix after, embedding is in the quantitative valve container.
7, as solution aerosol as described in the claim 6, be a kind of stable solution aerosol, wherein contain compound of Formula I, a kind of HFC, a kind of cosolvent and a kind of organic or inorganic acid have a spot of water (maximum 5%) in addition.
8, as aerosol as described in the claim 6, used propellant can be: (1) hydrogen fluorine carbon (HFC): 1,1,1,2-tetrafluoroethane (HFC-134 (a)), 1,1,1,2,3,3,3-heptafluoro-propane (HFC-227), difluoromethane (HFC-32), 1,1,1-HFC-143a (HFC-143 (a)), 1,1,2,2-tetrafluoroethane (HFC-134), 1, (HFC-152) such as 1-Difluoroethanes.(2) mixture of Chlorofluorocarbons class (CFC) isceon, dichlorodifluoromethane, Dichloromonofluoromethane, F-22, Dichlorotetrafluoromethane, a chlorine five fluoromethane, chlorodifluoroethane, Difluoroethane or Perfluorocyclobutane etc. or above-claimed cpd.Used cosolvent can be an alcohols: as ethanol (best), ethylene glycol, glycerol, propanol, isopropyl alcohol etc.; Ethers: as ether etc.; Esters: as ethyl acetate etc.; Saturated hydrocarbons: as cyclohexane extraction etc.The toxic and side effects of used cosolvent should meet the requirements.Organic acid can be citric acid or ascorbic acid.Surfactant can be oleic acid, three oleic acid sorbitol esters, phosphide etc.
9, the application of spray according to claim 1, the various acute and chronic rhinitis that it is characterized in that using it for prevention and treat mammal and people.
10, the application of aerosol according to claim 1, the various acute and chronic airway obstructive diseases that it is characterized in that using it for prevention and treat mammal and people are as chronic obstructive pulmonary disease, bronchial asthma etc.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011160252A1 (en) * | 2010-06-21 | 2011-12-29 | 中国人民解放军军事医学科学院毒物药物研究所 | Organic acid salts of penehyclidine optical isomer |
| CN101830896B (en) * | 2009-03-12 | 2013-05-15 | 中国人民解放军军事医学科学院毒物药物研究所 | Organic acid salt of optical isomer of penehyclidine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830896B (en) * | 2009-03-12 | 2013-05-15 | 中国人民解放军军事医学科学院毒物药物研究所 | Organic acid salt of optical isomer of penehyclidine |
| WO2011160252A1 (en) * | 2010-06-21 | 2011-12-29 | 中国人民解放军军事医学科学院毒物药物研究所 | Organic acid salts of penehyclidine optical isomer |
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