WO2016041439A1 - 一种柚皮苷与盐酸左西替利嗪药物组合物及其制剂 - Google Patents

一种柚皮苷与盐酸左西替利嗪药物组合物及其制剂 Download PDF

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WO2016041439A1
WO2016041439A1 PCT/CN2015/088434 CN2015088434W WO2016041439A1 WO 2016041439 A1 WO2016041439 A1 WO 2016041439A1 CN 2015088434 W CN2015088434 W CN 2015088434W WO 2016041439 A1 WO2016041439 A1 WO 2016041439A1
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naringin
group
levocetirizine hydrochloride
pharmaceutical composition
hydrochloride
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PCT/CN2015/088434
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English (en)
French (fr)
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苏薇薇
焦豪妍
廖彦
李沛波
彭维
王永刚
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中山大学
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Priority to US15/100,992 priority Critical patent/US20160303156A1/en
Priority to EP15842769.0A priority patent/EP3069723B1/en
Publication of WO2016041439A1 publication Critical patent/WO2016041439A1/zh

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/10—Expectorants
    • 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
    • A61P11/14—Antitussive agents

Definitions

  • the present invention relates to a naringin pharmaceutical composition for use in relieving cough, phlegm and asthma, and a preparation thereof.
  • Cough and sputum are two common symptoms of respiratory diseases. They are closely related in pathology. Generally, coughing is more common, and phlegm is often coughing. Long-term unhealed may cause emphysema, bronchiectasis, and pulmonary heart disease. Cough variant asthma refers to a special type of asthma with chronic cough as the main or only clinical manifestation.
  • the most widely used antitussive drugs in pharmaceutical medicines include codeine phosphate and dextromethorphan hydrobromide.
  • Codeine phosphate is a central nervous system chemical widely used for coughing or catching cold.
  • Common adverse reactions are: psychopathy or fantasy; weak, slow or irregular breathing; heart rate is fast or slow, abnormal.
  • Uncommon adverse reactions convulsions, tinnitus, tremors, or uncontrolled muscle movements; urticaria; allergic reactions such as rash, rash, or swollen face; mental depression and muscle rigidity. Long-term applications can cause dependence. The tendency of the usual dose to cause dependence is weaker than other morphine drugs.
  • Typical symptoms are: goose bumps, loss of appetite, diarrhea, toothache, nausea and vomiting, runny nose, chills, sneezing, yawning, sleep disorders, stomach cramps, excessive sweating, weakness, heart rate, emotional agitation or unexplained causes Fever.
  • Dextromethorphan hydrobromide is also a commonly used central nervous chemical cough suppressant, which consumers can buy at pharmacies.
  • serious adverse reactions have occurred, especially the abuse.
  • the foreign patients have repeatedly reported that the capsules caused by excessive consumption of powdered dextromethorphan caused death.
  • the US Food and Drug Administration is always concerned about the abuse of dextromethorphan. And issued a warning not to abuse dextromethorphan.
  • the US Food and Drug Administration says that the correct use of dextromethorphan in small doses can safely and effectively suppress cold symptoms, but abuse can cause death and other serious adverse effects such as brain damage, seizures, loss of consciousness and irregular heartbeat.
  • Naringin has better antitussive, phlegm and asthma and has no drug dependence, and the side effects are minimal. Therefore, the development of a compound drug with better efficacy around naringin will have a good prospect of drug use.
  • the present invention provides a naringin pharmaceutical composition for cough, expectorant and asthma, and a preparation thereof.
  • the pharmaceutical composition consists of naringin and levocetirizine hydrochloride.
  • the preferred daily dosage of the composition is 27.5 to 275 mg of naringin and 1.25 to 12.5 mg of levocetirizine hydrochloride.
  • the pharmaceutical compositions can be formulated to be clinically acceptable, including dosage forms such as tablets, liquids, capsules, aerosols, and the like.
  • the adjuvant of the pharmaceutical composition preparation may be: starch, lactose, mannitol, calcium hydrogen phosphate, carboxymethyl starch or a salt thereof and a group substitute, dextrin, chitosan, polyvinylpyrrolidone, cellulose and derivatives thereof Or polyethylene glycol.
  • naringin and levocetirizine hydrochloride components in the pharmaceutical combination of the present invention have synergistic effects, and the efficacy of the composition is significantly better than that of naringin or levocetirizine hydrochloride alone.
  • the pharmaceutical composition of the present invention can treat wheezing caused by cough, expectoration and cough variant asthma, and
  • the pharmaceutical composition can be added to a conventional excipient, and can be prepared into a drug for relieving cough, phlegm and asthma, according to any conventional method, without causing side effects of lethargy, lethargy, nausea, and vomiting.
  • naringin is prepared according to daily dosage of 120mg
  • levocetirizine hydrochloride is prepared according to daily dosage of 6mg
  • composition (1) is based on daily dosage of naringin 27.5mg
  • hydrochloric acid Formulation (2) was prepared according to human daily dosage of naringin 27.5mg and levocetirizine hydrochloride 12.5mg
  • composition (3) group was based on human daily naringin 275mg, hydrochloric acid left Cetirizine 1.25mg was prepared
  • composition (4) group was prepared according to human daily naringin 275mg, levocetirizine hydrochloride 12.5mg
  • Instrument YLS-8A induces cough and asthma (Shandong Medical Science Equipment Station products).
  • naringin and levocetirizine hydrochloride were administered alone and had significant antitussive effects (P ⁇ 0.05 or 0.01 compared with the blank group); naringin and levocetirizine hydrochloride The drug combination also had a good antitussive effect, and the antitussive effect was significantly better than the naringin alone or the levocetirizine hydrochloride alone group, the difference was statistically significant (compared with the single administration group, P ⁇ 0.05 or 0.01).
  • the results demonstrate that the pharmaceutical composition has a good antitussive effect and is significantly superior to the respective individual administration groups.
  • mice Male and female, weighing 30-40g, were provided by Guangdong Medical Laboratory Animal Center.
  • naringin is prepared according to the daily dose of 120mg
  • levocetirizine hydrochloride is prepared according to the daily dose of 6mg
  • composition (1) group according to the daily dose of naringin 27.5mg, hydrochloric acid left West Formulation (2) was prepared according to human daily dosage of naringin 27.5mg and levocetirizine hydrochloride 12.5mg
  • composition (3) group was based on human daily naringin 275mg, hydrochloric acid left Cetirizine 1.25mg was prepared
  • composition (4) group was prepared according to human daily naringin 275mg, levocetirizine hydrochloride 12.5mg
  • Kunming mice male and female, were randomly divided into blank control group, ambroxol group, naringin group, levocetirizine hydrochloride, composition (1) ⁇ composition (5) group, 10 groups in each group. .
  • 0.2ml/10g was administered by continuous intragastric administration for 2 days, and 5% phenol red physiological saline 0.2ml/10g was intraperitoneally injected 30 minutes after the last administration. After 30 minutes, the mice were sacrificed and the trachea was separated, and a trachea from the thyroid cartilage to the tracheal branch was cut.
  • the test tube was placed in a test tube containing 3 ml of physiological saline, and 0.1 ml of a 15% sodium hydrogencarbonate solution was added.
  • the phenol red content was calculated from the phenol red standard curve. Standard curve: 0.1 ⁇ g/ml, 0.3 ⁇ g/ml, 0.5 ⁇ g/ml, 0.7 ⁇ g/ml, 1 ⁇ g/ml, 3 ⁇ g/ml, 5 ⁇ g/ml, and 10 ⁇ g/ml of phenol red standard solution were prepared. If the drug can increase the secretion function of the respiratory tract, it can increase the phenol red. The amount of excretion, so the measured phenol red content level, can compare the difference in drug drainage effect.
  • naringin and levocetirizine hydrochloride alone can significantly increase the phenol red excretion in mice (P ⁇ 0.05 or 0.01 compared with the blank group), with significant ⁇
  • the combination of naringin and levocetirizine hydrochloride also has a good effect on improving the phenol red excretion in mice, and the effect of increasing phenol red excretion in mice is significantly better than that in naringin alone.
  • the combination of levocetirizine hydrochloride alone the difference was statistically significant (P ⁇ 0.05 or 0.01 compared with the single administration group).
  • naringin prepared according to daily dosage of 120mg; levocetirizine hydrochloride
  • the dosage of the composition (1) is 27.5 mg of naringin and 1.25 mg of levocetirizine hydrochloride; the composition (2) is 27.5 mg of naringin and hydrochloric acid.
  • Cetirizine 12.5mg was prepared; composition (3) group was prepared according to human daily naringin 275mg, levocetirizine hydrochloride 1.25mg; composition (4) group according to human daily naringin 275mg, hydrochloric acid left Cetirizine was prepared in 12.5 mg; composition (5) was prepared according to human daily dosage of naringin 120 mg and levocetirizine hydrochloride 6 mg.
  • the excitation concentration of methacholine (MeCh) was from low to high, 100 mg 100 mg/L, 200 mg/L, 400 mg/L, 800 mg/L, and 1600 mg/L, respectively, and the Penh average value under the excitation of each concentration grade MeCh was recorded.
  • the Penh value at each MeCh excitation concentration was converted to the percentage of the Penh value at the time of physiological saline (NS) challenge, expressed as Penh%, as an evaluation index of AR.
  • Bronchoalveolar lavage and bronchoalveolar lavage (BALF) white blood cell differential count: After the AR measurement, guinea pigs were anesthetized with sodium pentobarbital 30 mg/kg, then the neck skin was cut and cut in the middle of the trachea. Small mouth, insert the tracheal tube. Bronchoalveolar lavage was performed with 5 mL of normal saline, and washed back and forth 3 times, and bronchoalveolar lavage fluid was collected. All bronchoalveolar lavage fluid was centrifuged at 1500 rpm for 10 min at 4 ° C, and the supernatant was stored at -80 ° C until use.
  • 2.6 lung tissue section Take the frozen part of the right lung tissue, routine fixation, dehydration, HE staining, observe the pathological changes of airway and lung tissue.
  • the number of coughs was significantly increased in the model group compared with the normal control group (P ⁇ 0.01).
  • each of the administration groups was able to reduce the number of coughs, which was statistically different from the model control group.
  • the number of coughs was significantly lower in the naringin and levocetirizine hydrochloride combination groups than in the naringin-administered group or the levocetirizine hydrochloride alone group, and the difference was statistically significant (with administration alone).
  • Group comparison P ⁇ 0.05 or 0.01).
  • the above results demonstrate that the pharmaceutical composition has a good antitussive effect on ovalbumin-induced cough and is superior to the antitussive effect of each individual administration.
  • the total number of white blood cells, lymphocyte neutrophils and total eosinophils were significantly higher in the model control group than in the normal control group (P ⁇ 0.01 compared with the normal control group); naringin, hydrochloric acid
  • the administration of levocetirizine alone significantly reduced the total number of white blood cells, lymphocytes, neutrophils and total eosinophils (P ⁇ 0.05 or 0.01 compared with the model group); naringin and dextran hydrochloride
  • the telithizine composition significantly reduced the total number of white blood cells, lymphocytes, neutrophils, and total number of eosinophils (P ⁇ 0.05 or 0.01 compared with the model group), and with naringin alone or hydrochloric acid.
  • naringin and levocetirizine hydrochloride were significantly better than that of Otto group.
  • the naringin group and the levocetirizine hydrochloride group improved significantly.
  • naringin 40g levocetirizine hydrochloride 2g.
  • naringin 40g levocetirizine hydrochloride 2g.
  • 2 g of levocetirizine hydrochloride and 156 g of starch were mixed, and then mixed with naringin, wet granulation, granules were dried, 2 g of micro-silica gel was added, mixed, and pressed into 1000 tablets to obtain tablets.
  • naringin 40g levocetirizine hydrochloride 2g.
  • levocetirizine hydrochloride 2g Take naringin 40g, levocetirizine hydrochloride 2g. First, levocetirizine hydrochloride 2g plus lactose 38g mixed, then add naringin, 118g starch mixed, wet granulation, granules dry, add 2g of micro-silica gel, mix, press into 1000 tablets, that is, tablets.

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Abstract

一种柚皮苷组合物及其制剂，其特征在于：该药物组合物由柚皮苷和盐酸左西替利嗪组成。优选配比为柚皮苷27.5～275mg，盐酸左西替利嗪为1.25～12.5mg。优选质量比为柚皮苷∶盐酸左西替利嗪为20∶1。该药物组合物对各种原因引起的咳嗽和痰多，以及治疗咳嗽变异性哮喘具有良好疗效，该药物组合物的药效明显优于柚皮苷或盐酸左西替利嗪单独应用时的药效。

Description

一种柚皮苷与盐酸左西替利嗪药物组合物及其制剂 技术领域
本发明涉及一种用于止咳、化痰和平喘的柚皮苷药物组合物及其制剂。
背景技术
咳嗽、咯痰是呼吸系统疾病常见的两大症状，在病理上密切相关，一般咳嗽多夹痰，而痰多也常致咳嗽，长期不愈可能引发肺气肿、支气管扩张、肺心病等。咳嗽变异性哮喘，是指以慢性咳嗽为主要或唯一临床表现的一种特殊类型哮喘。
目前，药学药物中应用最广泛的止咳药物有磷酸可待因和氢溴酸右美沙芬等。
磷酸可待因是广泛用于止咳或感冒的中枢神经类化学药品，但近几年由于其严重不良反应一再被国家食品药品监督管理提高其管理级别。常见的不良反应有：心理变态或幻想；呼吸微弱、缓慢或不规则；心率或快或慢、异常。少见的不良反应：惊厥、耳鸣、震颤或不能自控的肌肉运动等；荨麻疹；疹痒、皮疹或脸肿等过敏反应；精神抑郁和肌肉强直等。长期应用可引起依赖性。常用量引起依赖性的倾向较其他吗啡类药为弱。典型的症状为：鸡皮疙瘩、食欲减退、腹泻、牙痛、恶心呕吐、流涕、寒颤、打喷嚏、打呵欠、睡眠障碍、胃痉挛、多汗、衰弱无力、心率增速、情绪激动或原因不明的发热。
氢溴酸右美沙芬也是常用的中枢神经类化学止咳药，消费者在药店可以买到。但随着其用量的增大，也出现了严重不良反应，特别是滥用情况，国外多次报道患者因过量服用粉状右美沙芬包装成的胶囊造成死亡。美国食品药品监督管理局时刻关注右美沙芬的滥用情况， 并发出不要滥用右美沙芬的警告。美国食品药品监督管理局表示，右美沙芬小剂量正确使用，可以安全有效地抑制感冒症状，但滥用可造成死亡和其他严重的不良反应，如脑损伤、癫痫发作、意识丧失和心跳不规则。
柚皮苷具有较好止咳、化痰和平喘作用且没有药物依赖性，副作用极小。因此，围绕柚皮苷开发疗效更好的复方药物将具备良好的用药前景。
发明内容
本发明提供了一种用于止咳、祛痰和平喘的柚皮苷药物组合物及其制剂。
所述的药物组合物由柚皮苷和盐酸左西替利嗪组成。
组合物的优选日用量配比是柚皮苷27.5～275mg，盐酸左西替利嗪1.25～12.5mg。
所述药物组合物的优选质量配比为建议为柚皮苷:盐酸左西替利嗪＝20:1，其优选剂量为每一日用量配比单位制剂含柚皮苷40mg及盐酸左西替利嗪2mg。
所述药物组合物可制成临床可接受的，包括片剂、水剂、胶囊剂、气雾剂等剂型。本药物组合物制剂的辅料可以是：淀粉、乳糖、甘露醇、磷酸氢钙、羧甲基淀粉或其盐及基团取代物、糊精、壳聚糖、聚乙烯吡咯烷酮、纤维素及其衍生物或聚乙二醇。
试验证明，本发明药物组合中的柚皮苷和盐酸左西替利嗪成分具有协同作用，组合物的药效明显优于柚皮苷或盐酸左西替利嗪单独应用时的药效，体现了良好的止咳、化痰和平喘作用。采用本发明所及的药物组合物能治疗咳嗽、咯痰和咳嗽变异性哮喘引起的喘息，且 在服用时不会引起嗜睡、嗜睡、恶心、呕吐的副作用，该药物组合物可加入常规辅料，根据任何常规方法制备成止咳、祛痰和平喘的药物。
研究中，发明人还对柚皮苷和其他药物的组合作用进行了研究，结果表量柚皮苷分别与盐酸茶海拉明、盐酸茶苯海明马来酸氯苯那敏、氯雷他定、地氯雷他定、盐酸氮卓斯汀、咪唑斯汀、盐酸依匹斯汀联合应用时，之间均无协同。
具体实施方式
下面结合实施例对本发明做进一步的说明。
实施例1：
对枸橼酸所致豚鼠咳嗽的抑制
1.材料
1.1实验动物合格Hartley豚鼠，体重250～300g，雌雄各半，由广东省医学实验动物中心提供。
1.2药物及试剂惠菲宁；柚皮苷按人日用量120mg配制；盐酸左西替利嗪按人日用量6mg配制；组合物(1)组按人日用量柚皮苷27.5mg、盐酸左西替利嗪1.25mg配制；组合物(2)组按人日用量柚皮苷27.5mg、盐酸左西替利嗪12.5mg配制；组合物(3)组按人日用量柚皮苷275mg、盐酸左西替利嗪1.25mg配制；组合物(4)组按人日用量柚皮苷275mg、盐酸左西替利嗪12.5mg配制；组合物(5)组按人日用量柚皮苷120mg、盐酸左西替利嗪6mg配制。
1.3仪器YLS-8A诱咳引喘仪(山东省医学科学设备站产品)。
2.方法
取合格Hartley豚鼠72只，体重250～300g，随机分为空白对照组、柚皮苷组、惠菲宁组、盐酸左西替利嗪、组合物(1)～组合物(5)组，共9组，每组8只。各组豚鼠按0.5ml/100g体重灌胃给 药，其中空白对照组给等体积生理盐水，灌胃给药1h后，开始接受枸橼酸喷雾7min，喷雾结束，观察并记录从喷雾开始时十分钟内咳嗽次数(典型咳嗽为咳嗽声音清脆响亮，常有前扑动作)。
3.结果
由表1可见，柚皮苷和盐酸左西替利嗪药物单独给药，均具有显著镇咳作用(与空白组比较，P<0.05或0.01)；各柚皮苷和盐酸左西替利嗪药物组合也均有良好的镇咳效果，且镇咳效果显著优于柚皮苷单独给药组或盐酸左西替利嗪单独给药组，差异具有统计学意义(与单独给药组比较，P<0.05或0.01)。结果证明：该药物组合物具有良好的镇咳效果，且显著优于各自的单独给药组。
表1受试药物对枸橼酸诱导的咳嗽的抑制情况(n＝8)
Figure PCTCN2015088434-appb-000001
注：
1.与空白对照组比较，*P＜0.05，**P＜0.01；
2.与柚皮苷组比较，※P＜0.05,※※P＜0.01；
3.与盐酸左西替利嗪组比较，□P＜0.05,□□P＜0.01。
实施例2：
对小鼠酚红排泌实验的影响
1.材料
1.1实验动物昆明小鼠，雌雄各半，体重30～40g，由广东省医学实验动物中心提供。
1.2药物及试剂氨溴索；柚皮苷按人日用量120mg配制；盐酸左西替利嗪按人日用量6mg配制；组合物(1)组按人日用量柚皮苷27.5mg、盐酸左西替利嗪1.25mg配制；组合物(2)组按人日用量柚皮苷27.5mg、盐酸左西替利嗪12.5mg配制；组合物(3)组按人日用量柚皮苷275mg、盐酸左西替利嗪1.25mg配制；组合物(4)组按人日用量柚皮苷275mg、盐酸左西替利嗪12.5mg配制；组合物(5)组按人日用量柚皮苷120mg、盐酸左西替利嗪6mg配制。
1.3仪器日立3010紫外可见分光光度计。
2.方法
取昆明小鼠，雌雄各半，随机分为空白对照组、氨溴索组、柚皮苷组、盐酸左西替利嗪、组合物(1)～组合物(5)组，每组10只。0.2ml/10g连续灌胃给药2d，末次给药后30min腹腔注射5％酚红生理盐水0.2ml/10g，30min后处死小鼠并分离气管，剪下自甲状软骨至气管分支处的一段气管，放入盛有3ml生理盐水的试管中，再加入0.1ml15％的碳酸氢钠溶液.离心后取上清液，于546nln处测OD值。根据酚红标准曲线折算出酚红含量。标准曲线：分别配制0.1μg/ml、0.3μg/ml、0.5μg/ml、0.7μg/ml、lμg/ml、3μg/ml、5μg/ml、10μg/ml的酚红标准液。药物若能增加呼吸道的分泌功能，则能增加酚红 的排泌量，所以测得酚红含量的高低，可以比较出药物排痰效果的差异。
3.结果
由表2可见，柚皮苷和盐酸左西替利嗪药物单独给药，均能显著提高小鼠酚红排泌量(与空白组比较，P<0.05或0.01)的作用，具有显著祛痰作用；各柚皮苷和盐酸左西替利嗪药物组合也均有良好的提高小鼠酚红排泌量效果，且提高小鼠酚红排泌量效果显著优于柚皮苷单独给药组或盐酸左西替利嗪单独给药组，差异具有统计学意义(与单独给药组比较，P<0.05或0.01)。结果证明：柚皮苷和盐酸左西替利嗪药物组合有良好的祛痰效果，且祛痰效果优于柚皮苷单独给药组和盐酸左西替利嗪单独给药组。
表2受试药物对小鼠酚红排泌实验的影响(n＝10)
Figure PCTCN2015088434-appb-000002
注：
1.与空白对照组比较，*P＜0.05，**P＜0.01；
2.与柚皮苷组比较，※P＜0.05,※※P＜0.01；
3.与盐酸左西替利嗪组比较，□P＜0.05,□□P＜0.01。
实施例3：
对卵清蛋白诱导所致过敏性咳嗽(咳嗽变异哮喘)的影响
1.材料
1.1实验动物：Hartley豚鼠，雄性，体重250～300g，SPF级，由广东省医学实验动物中心提供。
1.2药物及试剂环磷酰胺；卵清蛋白；辣椒素；乙酰甲胆碱；奥亭止咳露(复方磷酸可待因溶液)；柚皮苷按人日用量120mg配制；盐酸左西替利嗪按人日用量6mg配制；组合物(1)组按人日用量柚皮苷27.5mg、盐酸左西替利嗪1.25mg配制；组合物(2)组按人日用量柚皮苷27.5mg、盐酸左西替利嗪12.5mg配制；组合物(3)组按人日用量柚皮苷275mg、盐酸左西替利嗪1.25mg配制；组合物(4)组按人日用量柚皮苷275mg、盐酸左西替利嗪12.5mg配制；组合物(5)组按人日用量柚皮苷120mg、盐酸左西替利嗪6mg配制。
1.3仪器设备：BUXCO咳嗽系统和全身体积描记系统(美国BUXCO公司)。
2.方法
2.1分组：雄性Hartley豚鼠，体重250～300g，随机分为正常对照组、模型对照组、奥亭组、柚皮苷组、盐酸左西替利嗪组、组合物(1)～组合物(5)组，每组10只。
2.2造模：除正常对照组外，其余各组豚鼠按如下方法致敏：即第1d以30mg/kg剂量腹腔注射环磷酰胺；第3d腹腔注射含卵蛋白2mg和氢氧化铝100mg的混悬液1mL；3周后再次注入含卵蛋0.01mg 和氢氧化铝100mg的混悬液1mL，正常组豚鼠腹腔注射生理盐水1mL；3周后所有造模动物雾化吸入1％卵蛋白溶液90s激发，正常对照组雾化吸入生理盐水90s。
2.3给药：激发后24h，各组按照表1所示剂量给药，连续给药7天。豚鼠咳嗽次数的测定：末次给药1h后，将豚鼠置于Buxco咳嗽记录仪中，采用50μmol/L的辣椒素引咳，总量1ml，记录10min(含雾化时间)内的咳嗽次数。
2.4豚鼠气道反应性(AR)的测定：咳嗽测定后24h，用Buxco全身体积描记系统中检测豚鼠的增强呼气间歇(Enhanced Pause,Penh)。测定乙酰甲胆碱(MeCh)雾化激发后Penh的变化。
乙酰甲胆碱(MeCh)的激发浓度由低到高，依次为100mg100mg/L,200mg/L,400mg/L,800mg/L,1600mg/L，记录各浓度级MeCh激发下的Penh平均值。将每个MeCh激发浓度下的Penh值转换为与生理盐水(NS)激发时Penh值的百分比，以Penh％表示，作为AR的评价指标。
2.5支气管肺泡灌洗及支气管肺泡灌洗液(BALF)白细胞分类计数：AR测定结束后，豚鼠采用戊巴比妥钠30mg/kg进行麻醉，然后剪开颈部皮肤，并于气管正中处剪开小口，插入气管套管。以生理盐水5mL行支气管肺泡灌洗，来回冲洗3次，收集支气管肺泡灌洗液。全部的支气管肺泡灌洗液4℃离心1500rpm×10min，上清液－80℃保存备用。
2.6肺组织切片：取右肺部分组织行冰冻切片，常规固定，脱水，行HE染色，观察气道及肺组织病理学改变。
3.结果
3.1咳嗽次数
由表3可见，模型组与正常对照组比较，咳嗽次数显著增多(P<0.01)。给药后，各个给药组均能降低咳嗽次数，与模型对照组比较，在统计学上有差异。各柚皮苷和盐酸左西替利嗪组合物组与柚皮苷单独给药组或盐酸左西替利嗪独给药组比较，咳嗽次数显著降低，差异具有统计学意义(与单独给药组比较，P<0.05或0.01)。以上结果证明，药物组合物对于卵清蛋白诱导的咳嗽有良好的镇咳效果，且均优于各自单独给药的镇咳效果。
表3受试药物对豚鼠辣椒素引咳的抑制(n＝10)
Figure PCTCN2015088434-appb-000003
注：
1.与正常对照组比较，##P＜0.01；
2.与模型对照组比较，*P＜0.05，**P＜0.01；
3.与柚皮苷组比较，※P＜0.05,※※P＜0.01；
4.与盐酸左西替利嗪组比较，□P＜0.05,□□P＜0.01。
3.2气道反应性
由表4可见，与正常对照组比较，模型组气道反应性明显提高(与正常对照组比较,P<0.01)；给药后，各组药物均能降低气道反应性；其中，各柚皮苷和盐酸左西替利嗪组合物，降低乙酰甲胆碱(MeCh)所致气道高反应的作用优于柚皮苷单独给药组或盐酸左西替利嗪单独给药组(与单独给药组比较，P<0.05或0.01)。结果表明，柚皮苷和盐酸左西替利嗪药物组合物对卵清蛋白诱导的咳嗽变异性哮喘有显著的平喘作用，且均优于各自的单独给药组。
表4受试药物对豚鼠气道反应性的影响(n＝10)
Figure PCTCN2015088434-appb-000004
注：
1.与正常对照组比较，#P＜0.01，##P＜0.01；
2.与模型对照组比较，*P＜0.05，**P＜0.01；
3.与柚皮苷组比较，※P＜0.05,※※P＜0.01；
4.与盐酸左西替利嗪组比较，□P＜0.05,□□P＜0.01。
3.3肺泡灌洗液白细胞分类计数结果。
由表5可见，模型对照组与正常对照组比较，白细胞总数、淋巴细胞中性粒细胞和嗜酸性粒细胞总数均明显升高(与正常对照组比较,P<0.01)；柚皮苷、盐酸左西替利嗪单独给药，也能显著降低白细胞总数、淋巴细胞、中性粒细胞和嗜酸性粒细胞总数(与模型组比较，P<0.05或0.01)；各柚皮苷和盐酸左西替利嗪组合物，均能显著降低白细胞总数、淋巴细胞、中性粒细胞和嗜酸性粒细胞总数(与模型组比较，P<0.05或0.01)，且与柚皮苷单独给药组或盐酸左西替利嗪单独给药组相比，其降低白细胞总数、中性粒细胞数、淋巴细胞数和嗜酸性粒细胞数的作用更显著(与单独给药组比较，P<0.05或0.01)。结果证明药物组合物在抑制炎症细胞方面均优于各自的单独给药组。
表5受试药物对豚鼠肺泡灌洗液白细胞分类计数的结果
Figure PCTCN2015088434-appb-000005
注：
1.与正常对照组比较，#P＜0.01，##P＜0.01；
2.与模型对照组比较，*P＜0.05，**P＜0.01；
3.与柚皮苷组比较，※P＜0.05,※※P＜0.01；
4.与盐酸左西替利嗪组比较，□P＜0.05,□□P＜0.01。
3.4肺组织切片结果
给药后，从炎症细胞浸润程度，肺泡壁水肿和充血程度，肺泡腔结构和支气管腔完整程度等方面综合评价，柚皮苷与盐酸左西替利嗪药物各组合物组明显比奥亭组、柚皮苷组、盐酸左西替利嗪组改善明显。
实施例4：
取柚皮苷40g，盐酸左西替利嗪2g。先将盐酸左西替利嗪2g加淀粉76g混匀，再与柚皮苷混匀，再加入微粉硅胶2g，混匀，装入1000粒胶囊中，即得胶囊剂。
实施例5：
取柚皮苷40g，盐酸左西替利嗪2g，再加淀粉76g混匀，再加入微粉硅胶2g，混匀，装入1000粒胶囊中，即得胶囊剂。
实施例6：
取柚皮苷40g，盐酸左西替利嗪2g。先将盐酸左西替利嗪2g加淀粉156g混匀，再与柚皮苷混匀，湿法制粒，颗粒干燥，加入微粉硅胶2g，混匀，压成1000片，即得片剂。
实施例7：
取柚皮苷40g，盐酸左西替利嗪2g。先将盐酸左西替利嗪2g加糊精28g混匀，再与柚皮苷混匀，再加入48克糊精混匀，再加入微粉硅胶2g，混匀，装入1000粒胶囊中，即得胶囊剂。
实施例8：
取柚皮苷40g，盐酸左西替利嗪2g。先将盐酸左西替利嗪2g加乳糖 38g混匀，再加入柚皮苷、118克淀粉混匀，湿法制粒，颗粒干燥，加入微粉硅胶2g，混匀，压成1000片，即得片剂。

Claims (6)

  1. 一种柚皮苷药物组合物，其特征在于：所述的药物组合物由柚皮苷27.5～275mg，盐酸左西替利嗪1.25～12.5mg组成。
  2. 根据权利要求1所述的药物组合物，其特征在于：柚皮苷与盐酸左西替利嗪的质量配比为20:1。
  3. 根据权利要求1或2所述的药物组合物，其特征在于：所述的药物组合物由柚皮苷40mg，盐酸左西替利嗪2mg组成。
  4. 根据权利要求1至3所述药物组合物所制成的临床可接受的制剂。
  5. 根据权利要求4所述的制剂，其特征在于：所述制剂为片剂、胶囊剂、水剂或气雾剂。
  6. 根据权利要求5所述的制剂，其特征在于：所述的制剂辅料为淀粉、乳糖、甘露醇、磷酸氢钙、羧甲基淀粉或其盐及基团取代物、糊精、壳聚糖、聚乙烯吡咯烷酮、纤维素及其衍生物或聚乙二醇。
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CN104224819A (zh) 2014-12-24
US20160303156A1 (en) 2016-10-20

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