• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    A composition for use in the treatment of chronic obstructive pulmonary diseases. The active ingredients of the composition are 0.1% to 99.9% of ambroxol hydrochloride and 99.9% to 0.1% of scopolamine. The composition has great synergistic effects.
    公开号:AU2012381574A1
    申请号:U2012381574
    申请日:2012-09-28
    公开日:2014-02-06
    发明作者:Jincan WANG；Liuyi WANG
    申请人:Hainan Weikang Pharmaceutical Qianshan Co Ltd；
    IPC主号:A61K31-137
    专利说明:
    COMPOUND AMBROXOL HYDROCHLORIDE COMPOSITION AND PREPARATION METHOD THEREFOR BACKGROUND OF THE INVENTION Field of Invention 5 The present invention relates to the field of medicine, and more particularly to a compound ambroxol hydrochloride composition and a preparation method therefor. Related Art Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease characteristic with airflow limitation, and the airflow limitation is not fully reversible and 10 shows progressive development. COPD mainly involves lungs, but can also cause systemic (or referred to as extrapulmonary) adverse effects. COPD is a common respiratory tract disease. The old are susceptible to COPD because they have an airway mucociliary clearance dysfunction and a lung oxidation dysfunction as they become aged. Tobacco smoke and other chronic irritants have effects on lungs to cause abnormal 15 inflammatory responses in the lungs. COPD may involve airways, lung parenchyma and pulmonary vessels, manifesting development of chronic inflammation characteristic with neutrophils, macrophages, and lymphocytes infiltration. The inflammatory mediators released by these cells interact with structure cells in airways and lung parenchyma, thereby promoting the accumulation of T lymphocytes (especially CD+8) and neutrophils and 20 eosinophils in the lung tissue, and the release of leukotriene B4 ( LTB4), interleukin8 (IL-8), tumor necrosis factor-a (TNF-a) and other mediators, causing lung structural damage. COPD lung inflammation may be aggravated further and airflow may be limited due to oxidation-oxidation imbalance, protease-anti-protease imbalance, autonomic nervous system dysfunction, and increased cholinergic tone. Genetic susceptibility plays a role in the 25 pathogenesis of COPD. 1 COPD is implicated with central airways, peripheral airways, lung parenchyma, and pulmonary vessels. Epithelial inflammatory cell infiltration occurs on central airways (trachea, bronchi, and bronchioles with diameter greater than 2-4 mm) surfaces, and the mucus secretion increases as the mucus gland enlarges and goblet cells increase. The 5 chronic inflammation in the peripheral airways (bronchi and bronchioles with diameter less than 2 mm) causes airway wall damage and repeated repair processes. Airway wall structural remodeling occurs during the repair processes, collagen content increases and scar tissue is formed, all of these changes cause the airways to narrow, resulting in fixed airway obstruction. 10 COPD lung parenchyma involvement manifests centrilobular emphysema, which involves respiratory bronchioles, and causes lumen expansion and destruction. When the disease is mild, lesions often occur in the upper area of the lungs, and when disease progresses, it may involve the entire lungs, accompanied by the destruction of the pulmonary capillary bed. 15 Changes in the COPD pulmonary vessels which are characteristic with thickness increase of the blood vessel wall can occur early, which manifest intimal thickening, smooth muscle proliferation and vascular wall inflammatory cell infiltration. When secondary pulmonary heart disease is developed in the late stages, there may be multiple in situ thrombosis in pulmonary arterioles. Acute exacerbation of COPD is often complicated 20 with deep vein thrombosis and pulmonary thromboembolism. SUMMARY OF THE INVENTION An objective of the present invention is to provide a compound ambroxol hydrochloride composition and a preparation method therefor. The compound preparation is used to treat chronic obstructive pulmonary disease, and has a strong synergy effect and 25 rapid effect. Technical solutions of the present invention are: 2 A compound ambroxol hydrochloride composition, characterized in that main ingredients of the composition are 0.1%-99.9% by mass of ambroxol hydrochloride and 99.9%-0.1% by mass of scopolamine. A method for preparing a compound preparation by using a compound ambroxol 5 hydrochloride composition, characterized in that specific steps are: a. adding 0.1%-99.9% of ambroxol hydrochloride, 99.9%-0.1% of scopolamine and 5 to 10 times the main ingredients of mannitol to water for injection; b. stirring to dissolve, adjusting to pH 5.0 by adding an NaOH solution; c. adding 0.1% of activated carbon with stirring for 30 minutes; 10 d. filtering out the activated carbon, and then filtering the liquid with 0.45 [tm and 0.22 [tm microporous filter membranes; e. filling the filtered liquid to a large plate or vial; f. sending into a lyophilizer, cooling to -40'C, and holding the temperature for 2 hours; g. warming to -5 0 C to 0 0 C slowly to lyophilize the liquid, heating to 35'C, and holding 15 the temperature for 3 hours; h. taking out of the lyophilizer after lyophilizing to obtain a lyophilized powder injection containing ambroxol hydrochloride and scopolamine; i. crushing the lyophilized powder injection under a sterile condition, sieving with a 180- mesh sieve to obtain sterile lyophilized powder containing ambroxol hydrochloride 20 and scopolamine; and j. preparing various dosage forms by using the lyophilized powder as a raw material. The dosage forms include tablets, tinctures, suppositories, capsules, ointments, creams, 3 pastes, ophthalmic preparations, pills, implantations, syrups, aerosols, powder inhalations, sprays, films, granules, oral solutions, oral suspensions, oral emulsions, powders, and nasal preparations. Ambroxol hydrochloride mainly acts on respiratory secretory cells, regulates secretion 5 of mucinous and serous substances, thereby increasing serous secretion. It can also cleave polysaccharide fibers of acid glycoprotein in sputum, inhibit acidic protein synthesis in mucus glands and goblet cells, and decrease viscosity of sputum, so that mucus becomes thin and easy to discharge. It can also increase movement frequency and intensity of respiratory cilia, facilitate mucus discharge, and increase respiratory self-purification. 10 Further, ambroxol hydrochloride has significant antioxidant activities, and plays an important role in the pathogenesis of lung diseases caused by reactive free oxygen radicals. It can clear oxide H-, and Hoc reduces hyperreactivity to mucosal bronchial damage, thereby stimulating PS secretion in cells. In addition, ambroxol also activates intracellular glutathione system, and facilitates intracellular glutathione (GSH) synthesis, thereby 15 resisting the damage caused by oxygen free radicals. Scopolamine may have antagonism against oxygen free radicals produced by damaged cells, and have antioxidant activities and superoxide scavenging effects. In long-term studies on adult rat cardiac muscle exposure to pyrogallol, it is found that scopolamine can effectively inhibit superoxide generation and myocardial dysfunction caused by pyrogallol, 20 and has a certain effect on heart dysfunction caused by oxygen free radicals. Scopolamine can reduce LPO content in the kidney venous blood of a rabbit experiencing ischemia-reperfusion, reduce the lipid peroxidation caused by free radicals, and provide protection against rabbit renal ischemia-reperfusion injury; it can prevent thiol on erythrocyte membrane protein in rats from damages by exogenous H202; it have a 25 significant dose-dependent scavenging effect on superoxide anion radicals produced by a hypoxanthine-xanthine oxidase system, and the clearing effect is slightly lower than that on superoxide dismutase (SOD). 4 Scopolamine not only inhibits lipopolysaccharide (LPS)-induced endothelial cell expression of plasminogen activator inhibitor 1 (Pal-1) protein and mRNA expression, but also inhibits the basal level of Pal-1 expression, and thus plays a role in anti-thrombosis. Scopolamine may inhibit the increase of LPS-induced endothelial cell expression of Pal-1 5 through NF-KB pathway. Scopolamine can inhibit the synthesis of thromboxane B2, prevent platelet aggregation and release, prevent micro-thrombosis, and inhibit deposition of antigen-antibody complex. Scopolamine has the effect of relaxing smooth muscle, relieving blood vessel spasm, and improving microcirculation, and can inhibit glandular secretion. Scopolamine can act 10 on cholinergic receptors on the airway mucosa and the smooth muscle, effectively inhibit cholinergic nerve function of the airway, reduce vagal tone, and facilitate dilation of bronchi, capillary bronchi and the decrease of airway secretions, so as to relieve breath, reduce bell sound asthma, improve clinical symptoms, and promote recovery from the disease. In addition, scopolamine has many good effects, including sedation of the cerebral 15 cortex, reduction of oxygen consumption, relief from small artery spasm, improvement in brain tissue hypoxia, blockage of multiorgan dysfunction and so on. The preparation method provided by the present invention is scientific and reasonable, and is convenient for preparing various dosage forms. The compound preparation prepared with the method can: 1) reduce the viscosity of sputum so as to make sputum thin and 20 promote mucus discharge, thereby improving respiratory self-purification; 2) increase the anti-oxidation effect of the human body, and help COPD patients to enhance their immune systems; 3) excite respiratory center, relieve bronchial and vascular smooth muscle spasm, decrease preload and post load of heart, promote recovery of the cardiac function, relieve small artery spasm of heart , brain, lungs, kidneys and other tissues, improve 25 microcirculation and tissue hypoxia status, and improve clearance of airway epithelial surface, thereby preventing and treating COPD. 5 DETAILED DESCRIPTION OF THE INVENTION The present invention will be illustrated further with reference to specific embodiments, in order to make technical means, creative features, purposes and effects achieved by the present invention easy to understand. 5 Embodiment 1: Preparation of a lyophilized powder injection containing ambroxol hydrochloride and scopolamine, based on 1000 injections 1. Prescription Ambroxol hydrochloride 15 g Scopolamine 0.02 g 10 Mannitol 100 g Water for injection 2000 ml 2. Preparation process The prescribed amounts of ambroxol hydrochloride, scopolamine and mannitol were added to water for injection, dissolved with stirring, and then adjusted to pH 5.0 by adding 15 an NaOH solution. 0.1% of activated carbon was added with stirring for 30 minutes, and then was filtered out. The liquid was filtered with 0.45 [tm and 0. 22 [tm mircroporous filter membranes, filled into a container, sent into a lyophilizer, and cooled to -40'C; the temperature was held for 2 hours, and the liquid was warmed to -5 0 C-0 0 C slowly to lyophilize, and heated to 35'C; the temperature was held for 3 hours, and the product was 20 taken out of the container after lyophilizing. Embodiment 2: Preparation of a tablet containing ambroxol hydrochloride and scopolamine, based on 1000 tablets 1. Prescription 6 Name Dosage Ambroxol hydrochloride log Scopolamine 0.02g Microcrystalline cellulose 30 g 5 Crosslinked povidone log Hydroxypropyl cellulose log Mannitol 30 g Sucralose 1 g Menthol 1 g 10 Lactose 50 g Magnesium stearate 5 g Silica 1 g 2. Preparation process The prescribed amounts of ambroxol hydrochloride, scopolamine and mannitol were 15 added to water for injection, stirred to dissolve, and then adjusted to pH 5.0 by adding an NaOH solution. 0.1% of activated carbon was added with stirring for 30 minutes, and then filtered out. The liquid was filtered with 0.45 [tm and 0. 22 [tm mircroporous filter membranes, filled to a large plate, sent into a lyophilizer, and cooled to -40'C; the temperature was held for 2 hours, and the liquid was warmed to -5 0 C-0 0 C slowly to 20 lyophilize, and heated to 35'C; the temperature was held for 3 hours, and the product was taken out of the lyophilizer after lyophilizing. The lyophilized preparation in the large plate was crushed under a sterile condition, and sieved with a 180-mesh sieve to obtain sterile 7 lyophilized powder containing ambroxol hydrochloride and scopolamine. The prescribed amounts of sucralose and menthol were mixed, the lyophilized powder containing ambroxol hydrochloride and scopolamine was added and mixed well, and then microcrystalline cellulose, lactose crosslinked povidone, hydroxypropyl cellulose were 5 added and mixed well, finally magnesium stearate, silica were added and mixed well. The tablets were prepared by using a direct compression method, during which the humidity is controlled below 50% . Embodiment 3: Preparation of an injection containing ambroxol hydrochloride and scopolamine, based on 1000 injections 10 1. Prescription Ambroxol hydrochloride 15 g Scopolamine 0.02 g Sodium chloride 16 g Water for injection 2000 ml 15 2. Preparation process The prescribed amounts of ambroxol hydrochloride, scopolamine and mannitol were added to water for injection, stirred to dissolve, and then adjusted to pH 5.0 by adding an NaOH solution. 0.1% of activated carbon was added with stirring for 30 minutes, and then filtered out. The liquid was filtered with 0.45 [tm and 0.22 [tm mircroporous filter 20 membranes, filled to a large plate, sent into a lyophilizer, and cooled to -40'C; the temperature was held for 2 hours, and the liquid was warmed to -5 0 C-0 0 C slowly to lyophilize, and heated to 35'C; the temperature was held for 3 hours, and the product was taken out of the lyophilizer after lyophilizing. The lyophilized preparation in the large plate was crushed under a sterile condition, sieved with a 180-mesh sieve to obtain sterile 8 lyophilized powder containing ambroxol hydrochloride and scopolamine. The lyophilized powder and sodium chloride were added to water for injection to 80%, and stirred to dissolve. 0.05% activated carbon was added and stirred to adsorb for 15 minutes, and filtered out coarsely. The liquid was adjusted to pH 4.5-5.5 by using citric 5 acid-disodium hydrogen phosphate buffer solution (pH 4.0), and water for injection was added to the full amount. The liquid was filtered with a 0.22 [tm fine filter membrane. The filtrate was determined to be qualified with respect to pH, osmotic pressure and content, filled in a 2 ml ampoule and sealed, and sterilized at 121'C for 15 minutes. The basic principles, main features and advantages of the present invention are shown 10 and described above. Persons skilled in the art should understand that the present invention is not limited by the above embodiments. The embodiments described above and the specification only describes the principles of the present invention. Various modifications and improvements can be made to the present invention without departing from the spirit and scope of the present invention, and these modifications and improvements shall fall 15 within the protection scope of the present invention. The protection scope of the present invention is defined by the appended claims and their equivalents. 9
    权利要求:
    Claims (3)
    [1] 1. A compound ambroxol hydrochloride composition, characterized in that main ingredients of the composition are 0.1%-99.9% by mass of ambroxol hydrochloride and 5 99.9%-0.1% by mass of scopolamine.
    [2] 2. A method for preparing a compound preparation by using the composition according to claim 1, characterized in the specific steps are: a. adding 0.1%-99.9% of ambroxol hydrochloride, 99.9%-0.1% of scopolamine and 5 to 10 times the main ingredients of mannitol to water for injection; 10 b. stirring to dissolve, adjusting to pH 5.0 by adding an NaOH solution; c. adding 0.1% of activated carbon with stirring for 30 minutes; d. filtering out the activated carbon, and then filtering the liquid with 0.45 [tm and 0.22 [tm microporous filter membranes; e. filling the filtered liquid into a large plate or vial; 15 f. sending into a lyophilizer, cooling to -40'C, and holding the temperature for 2 hours; g. warming to -5 0 C to 0 0 C slowly to lyophilize the liquid, heating to 35'C, and holding the temperature for 3 hours; h. taking out of the lyophilizer after lyophilizing to obtain a lyophilized powder injection containing ambroxol hydrochloride and scopolamine; 20 i. crushing the lyophilized powder injection under a sterile condition, sieving with a
    [3] 180-mesh sieve to obtain sterile lyophilized powder containing ambroxol hydrochloride and scopolamine; and 10 j. preparing various dosage forms by using the lyophilized powder as a raw material. 3. The method for preparing a compound preparation according to claim 2, characterized in that the dosage forms comprise tablets, tinctures, suppositories, capsules, ointments, creams, pastes, ophthalmic preparations, pills, implantations, syrups, aerosols, 5 powder inhalations, sprays, films, granules, oral solutions, oral suspensions, oral emulsions, powders, and nasal preparations. 11
    类似技术:
    公开号 | 公开日 | 专利标题
    AU2012381574B2|2015-04-30|Compound ambroxol hydrochloride composition and preparation method therefor
    JP4097044B2|2008-06-04|How to treat asthma with O-desulfated heparin
    Guo et al.2016|Early blood purification therapy of severe acute pancreatitis complicated by acute lung injury
    CA2871815C|2019-12-24|Tritoqualine for use in the treatment of cystic fibrosis
    KR20080113409A|2008-12-30|Thioredoxin production promoting agent
    US20130172414A1|2013-07-04|Pharmaceutical composition comprising levocarnitine and dobesilate
    JP2020521002A|2020-07-16|Application of tetramethylpyrazine nitrone derivative in prevention and treatment of diabetic complications
    Dehua et al.2006|Sequential hemoperfusion and continuous venovenous hemofiltration in treatment of severe tetramine poisoning
    Lan et al.2015|Effects of different tidal volume ventilation on paraquat-induced acute lung injury in piglets
    EP2606883B1|2017-08-09|Uses of n-Butylidenephthalide in Treating a Liver Injury and Improving Liver Function
    US20080249144A1|2008-10-09|Preventive or Therapeutic Agent for Chronic Inflammatory Lung Disease
    WO2019096144A1|2019-05-23|Use of pientzhuang and preparation thereof in treatment of cerebral stroke sequelae
    Saetta et al.1995|Fatal asthma attack during an inhalation challenge with ultrasonically nebulized distilled water
    CN112076247A|2020-12-15|Application of perilla leaf extract in preparation of medicine for treating chronic obstructive pulmonary disease
    Liu et al.2017|Acute lung injury mechanism and therapy induced by paraquat poisoning
    KR102144083B1|2020-08-13|Application of Cucurbitan Tetracyclic Triterpenoid Compounds to Antipulmonary Fibrosis
    CN106729661A|2017-05-31|The new application of human urokinase-type peptidase and the pharmaceutical composition containing human urokinase-type peptidase
    EP3072521A1|2016-09-28|Use of recombined ganoderma lucidum immunoregulation protein | in preparing drugs for treating tissue fibrosis
    TW201717925A|2017-06-01|Agent for improving dry eye
    CN110946947B|2021-11-23|Application of Miao medicine fruit upper leaves in preparation of medicine for preventing and treating chronic obstructive pulmonary disease
    WO2021223894A1|2021-11-11|Peptide for prevention or treatment of covid-19
    CN102670609A|2012-09-19|Compound preparation for treating chronic obstructive pulmonary disease
    WO2020073275A1|2020-04-16|Application of oligomannuronic acid in inhibiting total tau expression, phosphorylation and aggregation
    CN113274389A|2021-08-20|Application of flufenidone in preparation of medicine for treating acute lung injury
    RU2497523C1|2013-11-10|Method for improving therapeutic effectiveness in lung tissue disorders after action of cytostatics
    同族专利:
    公开号 | 公开日
    BR112014004737A2|2017-06-13|
    CN102670607A|2012-09-19|
    EP2857012A1|2015-04-08|
    RU2014102274A|2016-07-20|
    US20140206710A1|2014-07-24|
    AU2012381574B2|2015-04-30|
    EP2857012A4|2015-11-25|
    US9000004B2|2015-04-07|
    WO2013177880A1|2013-12-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE10110772A1|2001-03-07|2002-09-12|Boehringer Ingelheim Pharma|New drug compositions based on anticholinergics and PDE-IV inhibitors|
    EP1417961A1|2002-11-08|2004-05-12|Boehringer Ingelheim International GmbH|New pharmaceutical compositions containing a combination of ambroxol or bromhexine and isopropamide iodide|
    CN1843372A|2006-05-11|2006-10-11|陈旭良|Pharmaceutical compositions separately constituted by ambroxol and two other antibacterials|
    CN100506217C|2007-08-14|2009-07-01|山东罗欣药业股份有限公司|Ambroxol hydrochloride freeze-dried powder injection and preparing method thereof|
    CN102018694A|2010-06-30|2011-04-20|吴光彦|Tablet capsule loaded with salbutamol sulfate tablet and ambroxol hydrochloride tablet|
    CN102670608A|2012-05-28|2012-09-19|海南卫康制药有限公司|Ambroxol hydrochloride freeze-dried powder composite used for injection and preparation method thereof|
    CN102670609A|2012-05-29|2012-09-19|海南卫康制药有限公司|Compound preparation for treating chronic obstructive pulmonary disease|CN104771358A|2014-01-14|2015-07-15|江苏柯菲平医药股份有限公司|Acebrophylline injection and preparation method thereof|
    WO2018089797A1|2016-11-14|2018-05-17|Mingwu Wang|Formulations for the treatment of ocular surface diseases and related methods|
    IT201800006909A1|2018-07-04|2020-01-04||DRY POWDER OF AMBROXOL FOR INHALATION USE WITH BRONCHIAL TARGET|
    CN110237030A|2019-06-04|2019-09-17|华润双鹤利民药业（济南）有限公司|A kind of production technology of ambroxol hydrochloride injection|
    法律状态:
    2015-08-27| FGA| Letters patent sealed or granted (standard patent)|
    2021-04-22| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|
    优先权:
    申请号 | 申请日 | 专利标题
    CN2012101692797A|CN102670607A|2012-05-28|2012-05-28|Compound ambroxol hydrochloride composition and preparation method thereof|
    CN201210169279.7||2012-05-28||
    PCT/CN2012/082337|WO2013177880A1|2012-05-28|2012-09-28|Compound ambroxol hydrochloride composition and preparation method therefor|
    [返回顶部]