WO2013131324A1 - 卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用 - Google Patents

卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用 Download PDF

Info

Publication number
WO2013131324A1
WO2013131324A1 PCT/CN2012/075729 CN2012075729W WO2013131324A1 WO 2013131324 A1 WO2013131324 A1 WO 2013131324A1 CN 2012075729 W CN2012075729 W CN 2012075729W WO 2013131324 A1 WO2013131324 A1 WO 2013131324A1
Authority
WO
WIPO (PCT)
Prior art keywords
rupatadine
pharmaceutical composition
chronic obstructive
copd
pulmonary disease
Prior art date
Application number
PCT/CN2012/075729
Other languages
English (en)
French (fr)
Inventor
胡卓伟
Original Assignee
北京伟峰益民科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京伟峰益民科技有限公司 filed Critical 北京伟峰益民科技有限公司
Priority to US14/383,459 priority Critical patent/US9241936B2/en
Priority to JP2014560212A priority patent/JP2015509509A/ja
Priority to EP12870905.2A priority patent/EP2823818B1/en
Publication of WO2013131324A1 publication Critical patent/WO2013131324A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the use of rupatadine for the preparation of a pharmaceutical composition for the treatment of chronic obstructive pulmonary disease. Background technique
  • COPD Chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • the airflow is reduced and the lungs are forced to empty slowly.
  • the clinical features of COPD include asthma, cough and cough, accompanied by chronic airway obstruction and excessive lung expansion, with chronic bronchitis and emphysema at the onset.
  • Airway remodeling in COPD can result in functional changes in the airways, including persistent irreversible airway narrowing and excessive secretion of mucus.
  • COPD is mainly caused by smoking, has a high morbidity and mortality, and the existing methods have very limited therapeutic effects. World Health Organization statistics show that COPD was the world's sixth leading cause of death in 1990 and is forecast to rise to third place by 2020.
  • COPD smokeless pulmonary disease
  • age is another factor in the pathogenesis of COPD.
  • the onset of COPD is long and the signs of the disease are not obvious.
  • the acute onset of bronchitis is usually not diagnosed as COPD, and clinical patients will show different disease characteristics. It is difficult to make accurate diagnosis in the early stage of the disease.
  • Most patients Until the obvious improvement in lung function or other symptoms such as difficulty breathing, persistent cough and cough, seek medical help, therefore, the diagnosis of general COPD is made in the moderate to severe stage. Because COPD is usually accompanied by emphysema and chronic bronchitis, the treatment is further made more difficult. At present, most of the clinical medications are conservative treatments, and the pathological changes cannot be fundamentally solved.
  • Rupatadine is a new, potent antiallergic drug developed by Uriach Pharmaceuticals of Spain. It was first launched in Spain on March 15, 2003 for the treatment of seasonal and perennial allergic rhinitis.
  • Rupatadine has a dual role of antihistamine and antagonistic platelet activating factor (PAF).
  • PAF platelet activating factor
  • PAF is another important inflammatory mediator in airway inflammation. Similar to histamine, PAF can also cause bronchial contraction and increased vascular permeability, leading to salivation and nasal congestion; at the same time, it can cause the main cause of asthma--the increase in bronchial sensitivity. Studies have shown that 66% of asthma is induced by rhinitis, and nasal diseases are the starting point of tracheal diseases such as asthma, chronic lung obstruction, and bronchiectasis. The new mechanism of action for PAF suggests that PAF acts indirectly on the airways, causing it to block and hypersensitivity, which in turn triggers the release of leukotrienes.
  • histamine is an early response medium released from the mast cell store, and PAF is synthesized de novo.
  • all anti-allergic drugs used in the clinic have anti-histamine activity and no PAF antagonism. It is clear that drugs that block both histamine and PAF will have a better clinical effect than blocking only one of them.
  • Rupatadine is currently the only anti-allergic drug with anti-histamine and antagonism of PAF activity, which has good clinical application prospects.
  • Rupatadine has a strong affinity for histamine HI receptors. Antagonizing histamine by rupatadine can induce The role of ileal contraction in isolated ham rats.
  • the prior art has experimental evidence comparing the antihistaminic activity of rupatadine with first and second generation antihistamines: rupatadine biteidine, chlorre Hedine, cetirizine, hydroxyzine and diphenhydramine have stronger antihistaminic activity. Of which, rupatadine
  • the anti-histamine activity of rupatadine and desloratadine is comparable in vitro.
  • in vitro experiments have also shown that certain metabolites of rupatadine also have antihistaminic activity, and the activity of individual metabolites is comparable to the loratadine metabolite desloratadine.
  • rupatadine 0.3-10 mg/kg, orally is effective in inhibiting vesicles, while loratadine and cetirizine only inhibit histamine induction. Blister.
  • Rupatadine also inhibits uveitis caused by histamine or PAF in guinea pigs, and loratadine does not inhibit conjunctivitis caused by PAF. Applying rupatadine to eye drops, the effect is loratadine 10 times.
  • rupatadine shows a broader spectrum of pharmacological activity on non-histamine-dependent pharmacological models compared to other antihistamines. It not only inhibits the degranulation of mast cells, but also inhibits the chemotaxis of eosinophils. It can be said that mast cell degranulation is a very important role in the process of allergic reactions, especially in the early stage, and eosinophils are the key effector cells in the late stage of allergic reaction.
  • the oral absorption rate of rupatadine is fast, and the peak plasma concentration can be reached 1 hour after the tablet is administered.
  • the peak plasma concentration is 1.5 hours after the capsule administration, and the half-life is 12 hours; it is mainly metabolized by hepatobiliary in the body. Certain metabolites also have antihistaminic effects, which may also be rupatadine The cause of anti-allergic effects and long-acting effects.
  • Phase II and III clinical trials of rupatadine were conducted in 10 clinical trial centers in Spain, France, South Africa and the United Kingdom. More than 2,900 patients participated in the trial, seasonal or long-term, aged 12-82 years. Patients with sexual allergic rhinitis. The safety and efficacy of the experimental rupatadine was affirmed.
  • One placebo-controlled, dose-ranging study evaluated lutastatin doses at 2.5, 5, 10, and 20 mg/day for efficacy and safety in 2 weeks, and the results showed: rupatadine compared to placebo
  • the group can more effectively alleviate the symptoms of the patients; among them, the 20mg/day dose has the highest symptom improvement score, while the lOmg/day dose group has the best comprehensive effect.
  • lutapstatin doses of 10 mg/day and 20 mg/day were evaluated for efficacy and safety in patients with seasonal rhinitis: patients were randomized into three groups, 10 mg, 20 mg. The placebo group was administered daily for 2 weeks. The results showed that: rupatadine 20 mg and 10 mg/day improved nasal and ocular symptoms in patients with seasonal allergic rhinitis much better than placebo; among them, lOmg and There was no significant difference between the 20 mg/day dose groups, but the first week after 20 mg/day administration showed a better tendency to slow the symptoms.
  • rupatadine is compared with other antihistamines: it shows that lOmg/day rupatadine is equivalent to the same dose of cetirizine, but the central nervous system side effects are small; at the same dose, lupa He is more likely to relieve seasonal allergic rhinitis than loratadine and ebastine.
  • rupatadine has a better therapeutic effect than ebastine, especially in terms of sneezing and tearing symptoms, the former is much better than the latter.
  • Rupatadine is highly selective for peripheral nerve HI receptors, with high intensity and long duration of action, low affinity for central nervous system HI receptors, low permeability of blood-brain barrier, and thus no sedation Side effects.
  • mice and macaque rupatadine 1000mg/kg and 10mg/kg, respectively will not prolong the QTC and QRS interval, nor will it cause arrhythmia in rats, guinea pigs and dogs;
  • the main metabolite of pitatidine, 3-hydroxydesloratadine does not affect cardiac activity.
  • the reason for this analysis is that the concentration of rupatadine in the heart is extremely low. Usually, it is difficult to detect it. It does not produce cardiotoxicity, it does not accumulate in continuous use, has no effect on alcohol, has a safe dose and is well tolerated.
  • rupatadine has a good anti-pulmonary fibrosis effect, can reverse the pulmonary fibrosis induced by bleomycin, reduce the mortality of bleomycin-induced pulmonary fibrosis, and reduce fibrosis.
  • Lung inflammation and tissue local EMT production, reducing collagen deposition effectively improve lung function.
  • COPD Unlike pulmonary fibrosis, COPD has its own specific pathogenesis and pathogenesis, so drugs for pulmonary fibrosis may not be effective in treating COPD.
  • smoking and aging are the most common causes of COPD, there are still instances in which non-smokers or non-middle-aged people can also develop disease. Therefore, the pathogenesis of COPD is very complicated and cannot be based on basic lung inflammation theory or other academics. Theory instead.
  • the technical problem to be solved by the present invention is to provide a new use of rupatadine for the lack of effective drugs for preventing or treating chronic obstructive pulmonary disease, and rupatadine can be used for effectively preventing or treating chronic obstruction. Bronchitis, obstructive emphysema or chronic obstructive pulmonary disease.
  • the technical solution adopted by the present invention to solve the above technical problems is: the use of rupatadine for the preparation of a pharmaceutical composition for preventing or treating chronic obstructive bronchitis, obstructive emphysema or chronic obstructive pulmonary disease.
  • the "chronic obstructive bronchitis” refers to chronic non-specific inflammation of the trachea, the bronchial mucosa and surrounding tissues thereof. It is clinically characterized by a cough, cough, or chronic process accompanied by wheezing and recurrent episodes.
  • the "obstructive emphysema” is caused by chronic bronchitis or other causes of bronchiole stenosis, and the terminal bronchiole is excessively inflated in the air chamber, and is accompanied by expansion and rupture of the air chamber wall. Clinically, it is a common complication of chronic bronchitis.
  • the "chronic obstructive pulmonary disease” refers to a disease characterized by airflow limitation, and clinical features include reduced expiratory flow, slow emptying of the lungs, asthma, cough and sputum, With chronic airway obstruction and excessive lung expansion, chronic obstructive bronchitis and obstructive emphysema occur simultaneously.
  • the chronic obstructive pulmonary disease refers to COPD of a human or an animal.
  • prevention refers to preventing or reducing chronic obstructive bronchitis, obstructive emphysema or the use in the presence of possible chronic obstructive bronchitis, obstructive emphysema or COPD factors.
  • the production of COPD is not limited to chronic obstructive bronchitis, obstructive emphysema or the use in the presence of possible chronic obstructive bronchitis, obstructive emphysema or COPD factors. The production of COPD.
  • the term "treatment” refers to reducing the degree of chronic obstructive bronchitis, obstructive emphysema or COPD, or curing chronic obstructive bronchitis, obstructive emphysema or COPD to normalize, Or slow the progression of chronic obstructive bronchitis, obstructive emphysema or COPD.
  • rupatadine can effectively improve lung function, restore the basic physiological structure of the lungs, reduce the infiltration and expression of various inflammatory cells, reduce the degree of inflammation and inflammatory cell infiltration, and regulate the body immunity in chronic inflammatory lung diseases.
  • the role of balance, balancing Th1 and Th2 immune responses, and reversing COPD against asthma can improve lung function and reverse emphysema.
  • the "rupatadine” means rupatadine or a pharmaceutically acceptable derivative thereof, and includes a pharmaceutically acceptable salt, ester or the like.
  • the pharmaceutical composition preferably includes rupatadine and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises 0.1% to 99% rupatadine and 0.1% to 99% of a pharmaceutical carrier, and the percentage is the mass percentage of each component to the total amount of the pharmaceutical composition.
  • the rupatadine may be used as an active ingredient alone or in combination with other compounds.
  • the "active ingredient” refers to an "active ingredient” having the function of treating chronic obstructive bronchitis, obstructive emphysema or chronic obstructive pulmonary disease.
  • the pharmaceutical composition preferably further comprises a histamine type 1 ⁇ 4 receptor inhibitor and/or a PAF Receptor inhibitor.
  • the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable excipient, a filler, a diluent, and the like.
  • the dosage form of the pharmaceutical composition is not particularly limited and may be in the form of a solid, a semi-solid or a liquid, and may be an aqueous solution, a non-aqueous solution or a suspension, or may be a tablet, a capsule, a granule, an injection or a loser. Injection, etc. It can be administered orally, or it can be administered by intravenous, intramuscular, intradermal or subcutaneous injection.
  • the dosage of the rupatadine-containing pharmaceutical composition of the present invention at the time of treatment depends on the age and condition of the patient, and the usual daily dose is about 0.0001 to 1000 mg, preferably 0.01 to 500 mg, more preferably 0.1 to 200 mg.
  • the number of administrations is one or more times per day.
  • the pharmaceutical composition of rupatadine may be used alone or in combination with other drugs.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progress of the present invention is as follows:
  • the present invention provides a new prophylactic or therapeutic drug, rupatadine, which is effective in treating chronic obstructive bronchitis, obstructive emphysema or chronic obstructive pulmonary disease. Less toxic side effects and safe to use.
  • Fig. 1 is a graph showing the comparison of the number of various inflammatory cells in the alveolar lavage fluid of the sham operation group, the model group and the rupatadine treatment group of COPD mice induced by smoking in Example 1.
  • Fig. 2 is a graph showing the comparison of various inflammatory cytokines in the alveolar lavage fluid of the sham operation group, the model group and the rupatadine treatment group of the smoking-induced COPD mice in Example 1.
  • Fig. 3 is a photograph showing the pathological examination of lung tissue of the sham operation group, the model group, and the rupatadine treatment group of COPD mice caused by smoking in Example 1.
  • Fig. 4 is a photograph showing the pathological examination of lung tissue of the sham operation group, the model group, the positive drug control group, and the rupatadine treatment group of the TLR4-deficient mouse emphysema in Example 2. detailed description
  • ⁇ Standard error indicates that after parameter or nonparametric variance test, a significant difference was considered by comparison p ⁇ 0.05, and ⁇ .01 considered to be extremely significant.
  • the statistics of pathological grading data were analyzed by chi-square test. After comparison, p ⁇ 0.05 was considered to have significant difference, and p ⁇ 0.01 was considered to have extremely significant difference.
  • PBS i.e., phosphate buffer
  • Example 1 phosphate buffer
  • Cigarettes used in the experiment were purchased from the University of Kentucky Tobacco Research Center, Model 3R4F; SPF-class C57BL/6 mice (male, 6-8 weeks old, 16-18 g) used in the experiments were purchased from Chinese medicine. Institute of Zoology, Academy of Sciences.
  • COPD animal model preparation C57BL/6 mice were smoked in a cigarette case, inhaling 5 filterless cigarettes each time, the ratio of smoke to air was 1:6, and the total gas flow was 150 ml/min. 4 smoking tests per day, 30 minutes each time, for a total of 24 weeks.
  • rupatadine manufactured by Zhejiang Cifu Pharmaceutical Co., Ltd., is a raw drug for lupastatin fumarate, with a rupatadine content >99%.
  • Group A is the sham operation group (Sham);
  • Group B is the model group (Model);
  • Group C is the rupatadine treatment group (Rupa) 3. Detection of the number of various inflammatory cells in alveolar lavage fluid of COPD mice
  • mice were dissected in the neck, and the trachea was intubated, and the PBS lavage volume was 0.8 ml, and the number of lavage was 3-5 times.
  • the recovered lavage fluid was centrifuged at 1500 rpm for 10 minutes at 4 ° C, and the recovered supernatant was placed at -20 ° C for cytokine detection.
  • the cell pellet was reselected with 1 ml of PBS containing 1% BSA, and the ⁇ resuspension was used for cell counting, and analyzed by a blood cell analyzer.
  • the results are shown in Fig. 1.
  • the specific data are shown in Table 2.
  • Figure 1A the total number of white blood cells in the alveolar lavage fluid of smoked COPD mice compared with the sham operation group (Fig. 1A), the number of monocytes (Fig. 1B), the number of neutrophils (Fig. 1C), lymph
  • the number of cells Fig. 1D
  • the number of basophils Fig. 1E
  • the number of eosinophils Fig. 1F
  • mice were dissected in the neck, and the trachea was intubated, and the PBS lavage volume was 0.8 ml, and the number of lavage was 3-5 times.
  • the recovered lavage fluid was centrifuged at 1500 rpm for 10 minutes at 4 ° C, and the recovered supernatant was placed at -20 ° C for testing.
  • HE staining also known as hematoxylin-eosin staining
  • hematoxylin dyeing solution is alkaline, mainly to make the chromatin in the nucleus and the ribosome in the inclusions purple blue
  • eosin is an acid dye, mainly cytoplasm And coloring the components in the extracellular matrix.
  • Fig. 3 The right lower lobe lung tissue of the animal was taken, 4 wt% paraformaldehyde was fixed and embedded in paraffin, and the largest cross section of the wax block embedded in the lung tissue was observed.
  • the HE staining results are shown in Fig. 3.
  • the alveolar area of the lungs of COPD mice (Fig. 3B) increased significantly, the distal air chamber of the bronchioles expanded, the normal lung tissue was destroyed, and emphysema appeared, while rupatadine (Fig. 3C) Effectively restore the normal structure of the alveolar part, reduce the distal air chamber of the terminal bronchus.
  • mice SPF wild type C3H/HeN mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • TLR4 mutant C3H/HeJ mice were purchased from the Institute of Model Animals of Nanjing University.
  • mice and TLR4 mutant mice were housed in the Experimental Animal Center of the Institute of Drug Research, Chinese Academy of Medical Sciences, constant temperature and humidity, and free diet. Animals were sacrificed to the third month of age.
  • Lupatatadine manufactured by Zhejiang Cifu Pharmaceutical Co., Ltd., is a raw drug for rupatadine fumarate with a rupatadine content >99%.
  • Positive control drug recombinant IL-17A was purchased from R&D.
  • Group A was the sham operation group (Sham); Group B was the model group; Group C was the IL-17A treatment group (IL-17A); Group D was the rupatadine treatment group (Rupa).
  • HE staining also known as hematoxylin-eosin staining
  • hematoxylin dyeing solution is alkaline, mainly to make the chromatin in the nucleus and the ribosome in the inclusions purple blue
  • eosin is an acid dye, mainly cytoplasm And coloring the components in the extracellular matrix.
  • Fig. 4 The lung tissue of the right lower lobe of the animal was taken, 4% paraformaldehyde was fixed and embedded in paraffin, and the largest cross section of the wax block embedded in the lung tissue was observed.
  • the results of HE staining are shown in Fig. 4.
  • the lung alveolar area of the emphysema mice (Fig. 4B) increased significantly, the distal air chamber of the terminal bronchioles expanded, and the normal lung tissue was destroyed.
  • the positive control drug IL-17A Fig. 4C
  • Fig. 4D The development of emphysema; and rupatadine (Fig. 4D) can effectively restore the normal structure of the alveolar region and reduce the distal air chamber of the terminal bronchus.
  • Rupatadine can effectively improve lung function in COPD mice, restore the basic physiological structure of lungs in COPD mice, reduce multiple inflammatory cell infiltration and expression, in chronic inflammatory lung diseases It plays a role in regulating the body's immune balance and balances the Th1 and Th2 type immune responses.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明公开了卢帕他定在制备预防或治疗慢性阻塞性支气管炎、阻塞性肺气肿或慢性阻塞性肺病的药物组合物中的应用。本发明新的治疗慢性阻塞性肺病的药物————卢帕他定，在治疗慢性阻塞性支气管炎、阻塞性肺气肿或慢性阻塞性肺病方面，疗效显著，毒副作用少，使用安全。

Description

卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用 技术领域
本发明涉及卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用。 背景技术
慢性阻塞性肺病 （COPD) 是一种以气流受限为特征的疾病， 通常呈进 行性发展， 不完全可逆， 多与肺部对有害颗粒物或有害气体的异常炎症反应 有关， 表现特征为呼气气流减少和肺用力排空缓慢。 COPD的临床特征包括 气喘， 咳嗽和咳痰， 并伴有慢性气道阻塞及肺部过度膨胀， 发病时同时出现 慢性支气管炎、 肺气肿。 COPD中的气道重塑可导致气道的功能性改变， 包 括持续不可逆的气道变窄及粘液的过度分泌。 COPD主要由吸烟所致， 具有 较高的发病率和死亡率， 现有方法治疗效果十分有限。 世界卫生组织统计显 示， COPD在 1990年是世界性第六位的致死疾病， 并预测到 2020年将上升 为第三位。
吸烟是导致 COPD的首要因素， 绝大多数 CODP患者均有长期的吸烟 史， 而年龄是 COPD发病的另一要素。 COPD的发病时期长， 发病征兆并不 明显， 支气管炎的急性发作通常不会被诊断为 COPD, 并且临床患者会显示 出不同的疾病特征， 在疾病的早期一般难以作出精确的诊断， 大多数患者直 到有明显肺功能降低或其他症状如呼吸困难、持续咳嗽咳痰才去寻求医疗求 助， 因此， 一般 COPD的诊断都在中度至重度阶段作出。 由于 COPD通常 伴随肺气肿和慢性支气管炎， 进一步使得治疗更为困难， 目前临床用药大多 属于保守治疗， 并不能从根本解决其病理改变。
卢帕他定， CAS号 158876-82-5 ; 分子式 C26H26C1N3; 分子量 415.958; 蛋白结合率 98%-99%； 半衰期 5.9小时。 化学结构式如式 I所示。
Figure imgf000003_0001
I
卢帕他定是由西班牙 Uriach制药公司研制的新型、强效抗过敏药，于 2003 年 3月 15 日首次在西班牙上市， 用于治疗季节性和常年性过敏性鼻炎。 商 品名 Rupafm和 Dupafm, 剂量为 10mg， 一日一次。
卢帕他定具有抗组胺和拮抗血小板活化因子（PAF)双重作用。研究表明， 过敏和炎症性疾病是由多种不同介质的生成和释放产生的多因素复杂过程。 组胺即是在变态反应早期和这类疾病症状出现时含有的最多炎性介质，存在 于肥大细胞和嗜碱性粒细胞颗粒中，被过敏原激活的肥大细胞和嗜碱细胞会 释放而产生， 可发挥促平滑肌收缩、 血管扩张、 增强毛细血管通透性和黏膜 腺体分泌等效应， 介导 I型超敏反应发生。 其中， 这类疾病症状如打喷嚏、 鼻痒、 含泪和流涕大多数都是由组胺 HI受体所导致的。 而 PAF则是气道炎 症中又一重要炎性介质。 与组胺类似， PAF也可以引起支气管的收缩和血管 通透性的增强， 从而导致流涕和鼻充血； 同时， 它还能引起诱发哮喘的主要 原因一一支气管敏感度的上升。有研究表明 66%的哮喘因鼻炎诱发，而鼻部 疾病是哮喘、 慢性肺阻塞、 支气管扩张等气管疾病的起始点。 新的有关 PAF 的作用机制认为， PAF间接作用于气道， 使之阻塞以及高敏亢进， 继而引发 白三烯释放。通常 PAF和组胺的作用是互补的，组胺是从肥大细胞贮藏器中 释放出的早期应答介质， 而 PAF则是从头合成的。但是目前， 临床上使用的 抗过敏药均只有抗组胺活性， 而没有 PAF拮抗作用。很显然， 同时阻断组胺 和 PAF的药物将会比仅阻断其中一种具有更好的临床效果。卢帕他定是目前 唯一上市的既具有抗组胺作用又拮抗 PAF活性的抗过敏药，具有较好的临床 应用前景。
卢帕他定对组胺 HI受体有很强的亲和性。通过卢帕他定拮抗组胺能够诱 发的离体臀鼠回肠收缩的作用， 现有技术有比较卢帕他定与第一、 二代抗组 胺药物的抗组胺活性的实验证明： 卢帕他定比特非那定、 氯雷他定、 西替利 嗪、 羟嗪以及苯海拉明具有更强的抗组胺活性。 其中， 卢帕他定
(ΙΟ50=0.0035μηι) 比氯雷他定 （IC50=0.29 m) 抗组胺活性强 80倍； 比其 它的抗组胺药抗组胺活性强 100倍以上。卢帕他定和地氯雷他定体外抗组胺 活性相当。另外，体外实验也显示卢帕他定的某些代谢物也具有抗组胺活性， 个别代谢物的活性与氯雷他定的代谢物地氯雷他定 （desloratadine) 相当。
现有技术中， 卢帕他定的 PAF拮抗活性评价研究是在几个种属动物如小 鼠、 家兔、 豚鼠和犬等体内和体外模型上进行的。 在家兔的富血小板血桨、 血清、及犬的全血中进行的拮抗 PAF诱导的血小板聚集实验中，卢帕他定的 IC50分别是 2.9， 0.2， 和 0.29μηι。 这一实验说明卢帕他定具有很好的 PAF 拮抗作用。而已知第二代抗组胺药在富血小板的家兔血桨中拮抗 PAF诱导的 血小板聚集实验中， 氯雷他定、 西替利嗪、 咪唑斯汀和非索非那定 IC50值 分别是 7142、 7200、 7200和 7200μηι， 可以说几乎没有或仅有微弱的 PAF 拮抗作用。 在犬皮下给药组胺或 PAF 诱导的水疱模型中， 卢帕他定 (0.3-10mg/kg, 口服）能有效抑制水疱， 而氯雷他定和西替利嗪仅能抑制组 胺诱导的水疱。 卢帕他定单剂量给药的最佳药效在给药后 4小时， 有效性可 持续 24小时，提示该药为一长效药物。卢帕他定也能抑制豚鼠由组胺或 PAF 导致的结子膜炎，氯雷他定则不能抑制 PAF所致的结膜炎，将卢帕他定应用 于滴眼液， 疗效是氯雷他定的 10倍。
另外， 卢帕他定与其它抗组胺药相比， 在非组胺依赖性药理模型上， 显 示具有更广谱的药理活性。 它既具有抑制肥大细胞的脱粒作用， 又具有抑制 嗜曙红细胞的趋化作用。 可以说， 肥大细胞脱粒是过敏反应过程中， 特别是 早期起着非常重要的作用， 而嗜曙红细胞是变态反应后期关键性的效应细 胞。 卢帕他定口服吸收速度快， 一般片剂给药后 1小时可达血药浓度峰值， 胶囊给药后 1.5小时达血药浓度峰值，半衰期为 12小时；其在体内主要通过 肝胆代谢， 其某些代谢物亦具有抗组胺作用， 这也可能是卢帕他定具有全身 抗过敏作用和长效作用的原因。
卢帕他定的 II期和 III期临床试验是在西班牙、 法国、 南非和英国 10个 临床试验中心进行的， 参加试验的患者超过了 2900人， 年龄范围 12-82岁 的季节性或长年性过敏性鼻炎患者。实验卢帕他定的安全性和有效性得到了 肯定。 一项与安慰剂对照， 剂量范围研究评估卢帕他定剂量 2.5， 5， 10 和 20mg/天给药， 在 2周内的有效性和安全性实验， 结果表明： 卢帕他定较安 慰剂组能更有效的减轻患者症状； 其中， 20mg/天的剂量症状改善得分最高， 而 lOmg/天剂量组综合疗效效果最好。 在另一项与安慰剂组对照剂量范围研 究评估卢帕他定剂量 lOmg/天和 20mg/天， 对于季节性鼻炎患者的有效性和 安全性实验： 患者被随机分为三组即 10mg、 20mg和安慰剂组， 每天给药， 连续 2周， 结果显示： 卢帕他定 20mg和 lOmg/天对季节性过敏性鼻炎患者 鼻和眼部症状改善较安慰剂组要好得多； 其中， lOmg和 20mg/天剂量组之 间没有显著性差异，但 20mg/天给药第一周后都显示有较好的减缓症状趋势。
进一步地， 卢帕他定与其它抗组胺药相比： 显示 lOmg/天卢帕他定与相 同剂量的西替利嗪疗效相当， 但前者的中枢神经系统副作用小； 在相同剂量 下卢帕他定比氯雷他定和依巴斯汀更能缓解季节性过敏性鼻炎症状。
在一项随机、 双盲、 安慰剂对照、 多中心平行给药研究中， 比较了卢帕 他定 lOmg或 20mg/天、 氯雷他定 lOmg/天或安慰剂， 治疗季节性过敏性鼻 炎患者， 连续 2周的实验， 结果显示， 卢帕他定 lOmg或 20mg/天比氯雷他 定 lOmg/天具有更好的治疗效果， 尤其是在打喷嚏和鼻痒症状改善方面前者 比后者要好。
另一随机、 双盲、 安慰剂对照、 多中心平行给药研究中， 250 名季节性 过敏性鼻炎患者， 每天服用卢帕他定 10mg， 依巴斯汀 lOmg或者安慰剂， 连续 2周的实验， 结果显示， 卢帕他定比依巴斯汀有更好的治疗效果， 尤其 是在打喷嚏和流泪症状改善方面， 前者要比后者效果好得多。
卢帕他定对外周神经 HI受体具有高度选择性，作用强度大，作用时间长， 而对中枢神经系统 HI受体的亲和性低， 血脑屏障通透性小， 因而没有镇静 副作用。实验表明，即使分别给小鼠和猕猴卢帕他定 1000mg/kg和 10mg/kg， 也不会延长 QTC和 QRS间期， 也不会导致大鼠、 豚鼠和犬产生心律不齐； 另外， 卢帕他定在体内主要代谢物 3-羟基地氯雷他定也不影响心脏活动， 分 析原因是由于卢帕他定在心脏中的浓度极低， 通常情况下， 很难检出， 故使 用卢帕他定不会产生心脏毒性， 连续服用没有蓄积反应， 对酒精无作用， 安 全剂量较广， 耐受性好。
最新研究发现， 卢帕他定具有良好的抗肺纤维化作用， 能够很好的逆转 博来霉素所诱导肺纤维化， 降低博莱霉素所致肺纤维化哺乳动物死亡率， 降 低纤维化肺部炎症和组织局部 EMT的产生，减少胶原沉积有效改善肺功能。
与肺纤维化不同， COPD有着自己特殊的发病原因和发病过程， 因此应 用于肺纤维化的药物并不一定能有效治疗 COPD。 尽管吸烟和老化是 COPD 发病的最常见原因， 但仍有实例证明非吸烟人群或非中老年人群也可患病， 因此 COPD的发病机制十分复杂，并不能用基本的肺部炎症理论或其他学术 理论代替。
然而， 目前对于慢性阻塞性肺病还缺乏有效的治疗方法， 因此， 本领域 迫切需要开发新的疗效好的药物， 用于减轻或者治疗慢性阻塞性肺病。 发明内容
本发明要解决的技术问题就是针对的缺乏有效的预防或治疗慢性阻塞 性肺病的药物的不足， 提供一种卢帕他定的新用途， 卢帕他定可以用于有效 的预防或治疗慢性阻塞性支气管炎、 阻塞性肺气肿或慢性阻塞性肺病。
本发明解决上述技术问题所采用的技术方案是：卢帕他定在制备预防或 治疗慢性阻塞性支气管炎、阻塞性肺气肿或慢性阻塞性肺病的药物组合物中 的应用。
本发明中， 所述的 "慢性阻塞性支气管炎"是指气管、 支气管粘膜及其 周围组织的慢性非特异炎症。 临床上以咳嗽、 咳痰或伴有喘息及反复发作的 慢性过程为特征。 本发明中， 所述的 "阻塞性肺气肿" 由慢性支气管炎或其他原因逐渐引 起的细支气管狭窄， 终末细支气管远端气腔过度充气， 并伴有气腔壁膨胀、 破裂而产生， 临床上多为慢性支气管炎的常见并发症。
本发明中， 所述的 "慢性阻塞性肺病"（COPD)是指一种以气流受限为 特征的疾病， 临床特征包括呼气气流减少、 肺用力排空缓慢， 气喘， 咳嗽和 咯痰， 并伴有慢性气道阻塞及肺部过度膨胀， 发病时同时出现慢性阻塞性支 气管炎和阻塞性肺气肿。
本发明中， 所述的慢性阻塞性肺病， 是指人或动物的 COPD。
本发明中， 所述的 "预防"是指在可能的慢性阻塞性支气管炎、 阻塞性 肺气肿或 COPD因素的存在下， 使用后防止或降低慢性阻塞性支气管炎、 阻 塞性肺气肿或 COPD的产生。
本发明中， 所述的 "治疗" ， 是指减轻慢性阻塞性支气管炎、 阻塞性肺 气肿或 COPD的程度，或者治愈慢性阻塞性支气管炎、阻塞性肺气肿或 COPD 使之正常化， 或减缓慢性阻塞性支气管炎、 阻塞性肺气肿或 COPD的进程。 具体为卢帕他定能有效改善肺功能， 恢复肺部基本生理结构， 减少多种炎性 细胞浸润和表达， 减少炎症程度和炎性细胞浸润， 在慢性炎性肺疾病中起到 调节机体免疫平衡的作用， 平衡 Thl 和 Th2 型免疫反应， 对抗哮喘逆转 COPD, 可以改善肺功能， 逆转肺气肿。
本发明中， 所述的 "卢帕他定"， 是指卢帕他定或其药用衍生物， 包括 药学上可接受的盐、 酯等形式。
本发明中， 所述的药物组合物较佳的包括卢帕他定和药用载体。
其中，所述的药物组合物更佳的包括 0.1%-99%卢帕他定和 0.1%-99%药 用载体， 百分比为各成分占药物组合物总量的质量百分比。
其中， 所述的卢帕他定可以单独或和其他化合物一起作为活性成分。 所 述的 "活性成分"是指具有治疗慢性阻塞性支气管炎、 阻塞性肺气肿或慢性 阻塞性肺病功能的 "活性成分"。
其中，所述的药物组合物较佳的还包括组胺 1~4型受体抑制剂和 /或 PAF 受体抑制剂。
其中， 所述的药用载体包括药学上可接受的赋形剂、填充剂、稀释剂等。 其中， 所述的药物组合物的剂型没有特别限制， 可以是固体、 半固体或 液体的形式， 可以是水溶液、 非水溶液或混悬液， 也可以是片剂、 胶囊、 颗 粒剂、 注射剂或输注剂等。 可以经口服途径应用， 也可以经静脉、 肌肉、 皮 内或皮下注射途径给药。
本发明的含卢帕他定的药物组合物在治疗时的使用剂量根据患者的年龄 和病情而定， 常用每日剂量约为 0.0001~1000mg， 优选 0.01~500mg， 更优选 0.1~200mg。 给药次数为每天一次或多次。
在预防或治疗 COPD时，所述的卢帕他定的药物组合物可以单独使用或 者和其他药物联合使用。
本发明所用试剂和原料均市售可得。
在符合本领域常识的基础上， 本发明中上述的各技术特征的优选条件可 以任意组合得到本发明较佳实例。
本发明的积极进步效果在于： 本发明提供了一种新的预防或治疗药物一 一卢帕他定， 在治疗慢性阻塞性支气管炎、 阻塞性肺气肿或慢性阻塞性肺病 方面， 疗效显著， 毒副作用少， 使用安全。 附图说明
图 1为实施例 1对吸烟所致 COPD小鼠的假手术组、模型组、卢帕他定 治疗组的肺泡灌洗液内各种炎性细胞数量对比图。
图 2为实施例 1对吸烟所致 COPD小鼠的假手术组、模型组、卢帕他定 治疗组的肺泡灌洗液内各种炎性细胞因子含量对比图。
图 3为实施例 1对吸烟所致 COPD小鼠的假手术组、模型组、卢帕他定 治疗组的肺组织病理检查照片。
图 4为实施例 2对 TLR4缺失小鼠肺气肿的假手术组、 模型组、 阳性药 对照组、 卢帕他定治疗组的肺组织病理检查照片。 具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在 所述的实施例范围之中。
下述实施例中， 所述溶液涉及％均为质量体积百分比。实验结果用均值
±标准误差 （X±SE) 表示， 经参数或者非参数方差检验， 经比较 p<0.05 认 为有显著性差异， ρθ.01认为有极其显著性差异。病理学分级资料的统计使 用卡方检验， 经比较 p<0.05认为有显著性差异， p<0.01认为有极其显著性 差异。 实施例中， 所用的 PBS, 即磷酸缓冲液， 浓度为 0.1M, pH值为 7.2。 实施例 1
1、 制备 COPD动物模型
主要试剂及实验动物： 实验所用香烟购自美国肯塔基大学烟草研究中 心，型号 3R4F;实验所用的 SPF级 C57BL/6小鼠（雄性， 6-8周龄， 16~18g)， 均购自中国医学科学院动物所。
COPD动物模型制备： C57BL/6小鼠至于烟箱中， 每次吸入 5支无过滤 嘴香烟， 烟气与空气比例为 1:6， 气体总流量为 150ml/min。每天 4次吸烟实 验， 每次 30分钟， 共 24周时间。
2、 卢帕他定治疗吸烟小鼠 COPD
主要试剂： 卢帕他定， 生产厂商为浙江赐富医药有限公司， 为富马酸卢 帕他定原料药， 卢帕他定含量 >99%。
治疗方法： 将动物模型进行分组给药， 实验分组如下表 1所示。
表 1
Figure imgf000009_0001
注： A组为假手术组 （Sham) ; B组为模型组 （Model) ; C组为卢帕他定治疗组 （Rupa) 3、 检测 COPD小鼠肺泡灌洗液中多种炎性细胞数量
小鼠进行颈部解剖， 暴露气管进行插管， PBS灌洗量 0.8ml， 灌洗次数 3-5次。 回收的灌洗液 4°C 1500r离心 10分钟， 回收上清置于 -20°C待进行细 胞因子检测。
用 1ml含有 1%BSA的 PBS重选细胞沉淀， 取 ΙΟμΙ重悬液进行细胞计 数， 应用血细胞分析仪进行分析， 结果见图 1， 具体数据如表 2所示。 从图 1可见， 与假手术组相比， 烟熏 COPD小鼠肺泡灌洗液中总白细胞数量 （图 1A)、 单核细胞数量（图 1B)、 中性粒细胞数量（图 1C)、 淋巴细胞数量（图 1D)、 嗜碱性粒细胞数量 （图 1E)、 嗜酸性粒细胞数量 （图 1F) 极其显著升 高， 由此表明， 卢帕他定 6mg/kg组与模型组相比可以显著减少 COPD小鼠 肺泡灌洗液内各种炎性细胞数量。
表 2
Figure imgf000010_0001
4、 检测 COPD小鼠肺泡灌洗液内炎性细胞因子含量
小鼠进行颈部解剖， 暴露气管进行插管， PBS灌洗量 0.8ml， 灌洗次数 3-5次。 回收的灌洗液 4°C 1500r离心 10分钟， 回收上清置于 -20°C待检。
取上清 ΙΟΟμΙ进行 ELISA检测， 使用商业化 ELISA试剂盒进行炎性细 胞因子含量检测， 结果见图 2， 具体数据如表 3所示。 从图 2可见， 与假手 术组相比， COPD小鼠肺部 IL-2 (图 2A)、 IL-4 (图 2C)、 IL-17 (图 2D) 含量均明显增加， 由此表明， 卢帕他定 6mg/kg组可以降低 COPD小鼠肺部 炎性细胞因子含量， 与此同时， 卢帕他定并不影响在组织修复中起重要作用 的 IFN-γ (图 2B) 的含量， 证明卢帕他定可以方向性调节机体免疫反应。 表 3
Figure imgf000011_0002
Figure imgf000011_0001
HE染色法， 又称苏木精-伊红染色法， 苏木素染液为碱性， 主要使细胞 核内的染色质与包质内的核糖体着紫蓝色； 伊红为酸性染料， 主要使细胞质 和细胞外基质中的成分着色。
取动物右侧下叶肺组织， 4wt%多聚甲醛固定后石蜡包埋， 在包埋肺组 织的蜡块最大横截面切片， HE染色结果见图 3。如图显示， COPD小鼠肺部 (图 3B ) 肺泡面积显著增加， 终末细支气管远端气腔扩大， 正常肺组织破 坏， 同时有肺气肿出现， 而卢帕他定 （图 3C) 能有效恢复肺泡部分正常结 构， 减小终末支气管远端气腔。
实施例 2
1、 TLR4突变所致肺气肿模型制备
实验动物： SPF级野生型 C3H/HeN小鼠购自北京维通利华实验动物技 术有限公司， TLR4突变 C3H/HeJ小鼠购自南京大学模式动物研究所。
方法：取 SPF小鼠和 TLR4突变小鼠饲养于中国国医学科学院药物研究 所实验动物中心，恒温恒湿， 自由饮食。饲养至年龄为第 3个月时处死动物。
2、 卢帕他定治疗 TLR4突变小鼠肺气肿
主要试剂及实验动物： 卢帕他定， 生产厂商为浙江赐富医药有限公司， 为富马酸卢帕他定原料药， 卢帕他定含量 >99%。 阳性对照药重组 IL-17A购 自 R&D公司。
治疗方法： 将动物模型进行分组给药， 实验分组如下表 4所示： 表 4
Figure imgf000012_0001
注： A组为假手术组 （Sham) ; B组为模型组 （Model) ; C组为 IL-17A治疗组 （IL-17A) ; D组为卢 帕他定治疗组 （Rupa)。
3、 TLR4缺失小鼠肺气肿病理评价
HE染色法， 又称苏木精-伊红染色法， 苏木素染液为碱性， 主要使细胞 核内的染色质与包质内的核糖体着紫蓝色； 伊红为酸性染料， 主要使细胞质 和细胞外基质中的成分着色。
取动物右侧下叶肺组织， 4%多聚甲醛固定后石蜡包埋， 在包埋肺组织 的蜡块最大横截面切片， HE染色结果见图 4。 如图显示， 肺气肿小鼠 （图 4B)肺部肺泡面积显著增加，终末细支气管远端气腔扩大，正常肺组织破坏; 阳性对照药 IL-17A (图 4C) 能有效阻止小鼠肺气肿的发生发展； 而卢帕他 定 （图 4D) 能有效恢复肺泡部分正常结构， 减小终末支气管远端气腔。 根据实施例 1-2分析得到的结论： 卢帕他定能有效改善 COPD小鼠肺功 能， 恢复 COPD小鼠肺部基本生理结构， 减少多种炎性细胞浸润和表达， 在 慢性炎性肺疾病中起到调节机体免疫平衡的作用，平衡 Thl和 Th2型免疫反 应。
一般说来， 稳定期 COPD患者存在 Thl淋巴细胞功能亢进， 而急性加重 期 Thl/Th2平衡有向 Th2漂移的特点， 根据上述实验结果， 可以合理判断卢 帕他定能抗炎、 调节免疫平衡， 对抗哮喘逆转 COPD, 因此， 利用卢帕他定 治疗 COPD可以改善肺功能， 逆转肺气肿， 减少炎症程度和炎性细胞浸润。

Claims

权利要求
1、 卢帕他定在制备预防或治疗慢性阻塞性支气管炎、 阻塞性肺气肿或 慢性阻塞性肺病的药物组合物中的应用。
2、 如权利要求 1所述的应用， 其特征在于， 所述的卢帕他定为卢帕他 定或其药用衍生物。
3、 如权利要求 2所述的应用， 其特征在于， 所述的卢帕他定药用衍生 物为卢帕他定的药用盐或酯。
4、 如权利要求 1所述的应用， 其特征在于， 所述的药物组合物包括卢 帕他定和药用载体。
5、 如权利要求 4 所述的应用， 其特征在于， 所述的药物组合物包括 0.1%-99%卢帕他定和 0.1%-99%药用载体， 百分比为各成分占药物组合物总 量的质量百分比。
6、 如权利要求 4所述的应用， 其特征在于， 所述的药物组合物还包括 组胺 1~4型受体抑制剂和 /或 PAF受体抑制剂。
7、 如权利要求 1所述的应用， 其特征在于， 所述的药物组合物适于口 服给药、 经静脉、 肌肉、 皮内或皮下给药。
8、 如权利要求 1所述的应用， 其特征在于， 所述的药物组合物是水溶 液、 非水溶液或混悬液。
PCT/CN2012/075729 2012-03-06 2012-05-18 卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用 WO2013131324A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US14/383,459 US9241936B2 (en) 2012-03-06 2012-05-18 Use of rupatadine in the manufacture of pharmaceutical composition for treating chronic obstructive pulmonary disease
JP2014560212A JP2015509509A (ja) 2012-03-06 2012-05-18 慢性閉塞性疾患を治療するための医薬品組成物の製造のための、ルパタジンの使用
EP12870905.2A EP2823818B1 (en) 2012-03-06 2012-05-18 Use of rupatadine in the manufacture of pharmaceutical composition for treating chronic obstructive pulmonary disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210058649.X 2012-03-06
CN201210058649.XA CN102614177B (zh) 2012-03-06 2012-03-06 卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用

Publications (1)

Publication Number Publication Date
WO2013131324A1 true WO2013131324A1 (zh) 2013-09-12

Family

ID=46554630

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2012/075729 WO2013131324A1 (zh) 2012-03-06 2012-05-18 卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用

Country Status (5)

Country Link
US (1) US9241936B2 (zh)
EP (1) EP2823818B1 (zh)
JP (1) JP2015509509A (zh)
CN (1) CN102614177B (zh)
WO (1) WO2013131324A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102614177B (zh) 2012-03-06 2014-08-06 北京伟峰益民科技有限公司 卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用
US10463656B2 (en) 2017-01-05 2019-11-05 Iowa State University Research Foundation, Inc. Methods and compositions for prevention of feedlot bovine respiratory disease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101257891A (zh) * 2005-09-01 2008-09-03 比奥里波克斯公司 包含抗组胺剂以及皮质类固醇的脂质体组合物及其在制备治疗鼻炎以及相关疾病的药物中的用途
WO2010054158A2 (en) * 2008-11-07 2010-05-14 Auspex Pharmaceuticals, Inc. Steroid modulators of glucocorticoid receptor
WO2010075090A2 (en) * 2008-12-15 2010-07-01 Auspex Pharmaceuticals, Inc. Scopine modulators of muscarinic acetylcholine receptor

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7135575B2 (en) * 2003-03-03 2006-11-14 Array Biopharma, Inc. P38 inhibitors and methods of use thereof
WO2005089748A1 (en) * 2004-03-17 2005-09-29 Pfizer Limited Combination for treating inflammatory diseases
SE531698C2 (sv) * 2007-07-12 2009-07-07 Respiratorius Ab Nya bronkdilaterande a,b-omättade amider
GEP20125635B (en) * 2007-11-13 2012-09-10 Icos Corp Inhibitors of human phosphatidyl-inositol 3-kinase delta
CN101669926B (zh) 2008-09-11 2011-07-06 广州达信生物技术有限公司 用于鼻腔给药的液体制剂及其制备方法
US8088936B2 (en) * 2009-03-23 2012-01-03 Hoffman-La Roche Inc. Leukotriene B4 inhibitors
CN102145002B (zh) * 2010-02-05 2012-12-05 北京伟峰益民科技有限公司 卢帕他定在预防或治疗肺纤维化方面的用途
CN102614177B (zh) 2012-03-06 2014-08-06 北京伟峰益民科技有限公司 卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101257891A (zh) * 2005-09-01 2008-09-03 比奥里波克斯公司 包含抗组胺剂以及皮质类固醇的脂质体组合物及其在制备治疗鼻炎以及相关疾病的药物中的用途
WO2010054158A2 (en) * 2008-11-07 2010-05-14 Auspex Pharmaceuticals, Inc. Steroid modulators of glucocorticoid receptor
WO2010075090A2 (en) * 2008-12-15 2010-07-01 Auspex Pharmaceuticals, Inc. Scopine modulators of muscarinic acetylcholine receptor

Also Published As

Publication number Publication date
JP2015509509A (ja) 2015-03-30
EP2823818A4 (en) 2015-08-26
EP2823818A1 (en) 2015-01-14
US20150018382A1 (en) 2015-01-15
CN102614177B (zh) 2014-08-06
CN102614177A (zh) 2012-08-01
EP2823818B1 (en) 2018-12-26
US9241936B2 (en) 2016-01-26

Similar Documents

Publication Publication Date Title
US8182837B2 (en) Methods and compositions for reducing the risk associated with the administration of opioid analgesics in patients with diagnosed or undiagnosed respiratory illness
ES2775425T3 (es) Procedimiento de tratamiento del síndrome de Prader-Willi
JP5208473B2 (ja) アゼラスチンと抗コリン薬を含有する医薬組成物
Catania et al. Pharmacological and clinical overview of cloperastine in treatment of cough
JP2008517938A (ja) 呼吸器障害を処置するために他の活性剤と組み合わせたｍ１レセプターアンタゴニストおよび／またはｍ３レセプターアンタゴニスト
JP2007314517A (ja) ロキソプロフェンを含有する鎮咳又は去痰のための医薬組成物
BR112014023795B1 (pt) Uso de inibidores de ccr3
JP2010540607A (ja) セチリジンと、非β２−アドレナリン受容体作動薬、β２−アドレナリン受容体作動薬、又は抗炎症薬とを含む組成物及びそれらの呼吸器疾患治療への使用法
JP5091474B2 (ja) フドステインと抗コリン薬を含有する医薬組成物
WO2013131324A1 (zh) 卢帕他定在制备治疗慢性阻塞性肺病药物组合物中的应用
CA2623184A1 (en) Combination s-nitrosothiol-based pharmaceutical products for restoring normal breathing rhythm
WO2022117004A1 (zh) 间质性肺炎的治疗方法
JP6178058B2 (ja) 抗炎症及び／又は抗ヒスタミン剤組成物
US20100105685A1 (en) S-Nitrosothiol Compounds and Related Derivatives
JP5364330B2 (ja) アゼラスチンとアンブロキソールとを含有する医薬組成物
JP7433331B2 (ja) 特発性肺線維症を治療するための組成物及び方法
JP2010111667A (ja) フェキソフェナジン又はエバスチンを含有する鎮咳及び／又は去痰のための医薬組成物
JP2012516306A (ja) 気道疾患、特に喘息の処置のための５−ｈｔ４阻害剤
WO2024041633A1 (zh) 一种稠环嘧啶类化合物的用途
JP2009007332A (ja) アゼラスチン類とエフェドリン類を含有する医薬組成物
JP5463019B2 (ja) エピナスチン類とエフェドリン類とを含有する気道杯細胞過形成を抑制するための医薬組成物
JP2010150242A (ja) アンレキサノクスとエフェドリン類を含有する経口用医薬組成物
JP2010111666A (ja) セチリジンを含有する鎮咳及び／又は去痰のための医薬組成物
MX2008003935A (en) Combination s-nitrosothiol-based pharmaceutical products for restoring normal breathing rhythm
WO2003101437A2 (en) Method of treating asthma using fexofenadine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12870905

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2014560212

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14383459

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2012870905

Country of ref document: EP