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CN1387431A - Combination comprising beta 2 adranoreceptor agonist and lenkotriene receptor antagonist - Google Patents

Combination comprising beta 2 adranoreceptor agonist and lenkotriene receptor antagonist Download PDF

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CN1387431A
CN1387431A CN00815363A CN00815363A CN1387431A CN 1387431 A CN1387431 A CN 1387431A CN 00815363 A CN00815363 A CN 00815363A CN 00815363 A CN00815363 A CN 00815363A CN 1387431 A CN1387431 A CN 1387431A
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zafirlukast
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J·特罗法斯特
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AstraZeneca AB
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Abstract

The invention provides a pharmaceutical composition, pharmaceutical product or kit comprising a first active ingredient which is a beta 2 adrenoreceptor agonist and a second active ingredient which is a leukotriene receptor antagonist, for use in the treatment of inflammatory disorders.

Description

新的包含β2肾上腺受体激动剂 和白三烯受体拮抗剂的组合物Novel compositions comprising beta2 adrenergic receptor agonists and leukotriene receptor antagonists

本发明涉及用于治疗炎性疾病/病症，特别是呼吸疾病的药用活性物质的组合物。The present invention relates to compositions of pharmaceutically active substances for use in the treatment of inflammatory diseases/disorders, especially respiratory diseases.

在呼吸疾病如气喘的发病机理中涉及很多不同的炎性介质。然而，用于治疗呼吸疾病的药物对这些疾病的病理特征不总是具有特定选择性的。因此，尽管已发现糖皮质类固醇控制气喘非常有效，但糖皮质类固醇具有较宽的和非特异性作用并且当口服时，可产生一系列副作用。另一方面，吸入糖皮质类固醇引起严重副作用的情况似乎少得多。Many different inflammatory mediators are involved in the pathogenesis of respiratory diseases such as asthma. However, drugs used to treat respiratory diseases are not always specifically selective for the pathological features of these diseases. Thus, although glucocorticosteroids have been found to be very effective in controlling asthma, glucocorticosteroids have broad and non-specific effects and when taken orally, can produce a range of side effects. On the other hand, inhaled corticosteroids seem to cause far fewer serious side effects.

由于呼吸疾病如气喘的复杂性，似乎没有任何一种介质可令人满意地单独治疗该疾病。Due to the complexity of respiratory diseases such as asthma, no single agent appears to be satisfactory for the treatment of the disease alone.

因此，需要开发新的可提供更有效治疗炎性疾病的药物。Therefore, there is a need to develop new drugs that can provide more effective treatments for inflammatory diseases.

因此，本发明提供一种药物组合物，它包含第一个活性组分，即选自福莫特罗及其可药用衍生物的β2肾上腺受体激动剂，和第二个活性组分，即选自zafirlukast、montelukast及其可药用衍生物的白三烯受体拮抗剂的混合物。Accordingly, the present invention provides a pharmaceutical composition comprising a first active ingredient, a beta2 adrenoreceptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof, and a second active ingredient, That is, a mixture of leukotriene receptor antagonists selected from zafirlukast, montelukast and pharmaceutically acceptable derivatives thereof.

在本说明书中，除非另外说明，福莫特罗(也称eformoterol)的可药用衍生物是指福莫特罗的可药用酯、盐或溶剂化物(例如富马酸福莫特罗)或所述酯或盐的可药用溶剂化物(例如富马酸福莫特罗二水合物)。应该同样地解释Zafirlukast或montelukast的可药用衍生物(例如momtelukast钠)。In this specification, unless otherwise stated, a pharmaceutically acceptable derivative of formoterol (also known as eformoterol) refers to a pharmaceutically acceptable ester, salt or solvate of formoterol (such as formoterol fumarate) Or a pharmaceutically acceptable solvate of said ester or salt (eg formoterol fumarate dihydrate). Pharmaceutically acceptable derivatives of Zafirlukast or montelukast (eg momtelukast sodium) should be interpreted similarly.

适宜的酯的实例包括低级烷基(C1-C6烷基)酯。Examples of suitable esters include lower alkyl (C 1 -C 6 alkyl) esters.

如果应用，可药用盐包括由可药用无机和有机酸衍生的酸加成盐，如氯化物、溴化物、硫酸盐、磷酸盐、马来酸盐、富马酸盐、酒石酸盐、枸橼酸盐、苯甲酸盐、4-甲氧基苯甲酸盐、2-或4-羟基苯甲酸盐、4-氯苯甲酸盐、对甲苯磺酸盐、甲磺酸盐、抗坏血酸盐、乙酸盐、琥珀酸盐、乳酸盐、戊二酸盐、葡萄糖酸盐、丙三羧酸盐、羟基萘-羧酸盐或油酸盐；和由无机碱衍生的盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、三价锰、二价锰、钾、钠、锌和铋盐。特别优选的是铵、钙、镁、钾和钠盐。由可药用有机碱衍生的盐包括伯、仲和叔胺、环胺如精氨酸、甜菜碱、胆碱等的盐。Where applicable, pharmaceutically acceptable salts include acid addition salts derived from pharmaceutically acceptable inorganic and organic acids such as chlorides, bromides, sulfates, phosphates, maleates, fumarates, tartrates, citrates, Citrate, Benzoate, 4-Methoxybenzoate, 2- or 4-Hydroxybenzoate, 4-Chlorobenzoate, p-Toluenesulfonate, Methanesulfonate, Ascorbic Acid salt, acetate, succinate, lactate, glutarate, gluconate, tricarboxylate, hydroxynaphthalene-carboxylate, or oleate; and salts derived from inorganic bases including aluminum, Ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganic, potassium, sodium, zinc and bismuth salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include those of primary, secondary and tertiary amines, cyclic amines such as arginine, betaine, choline and the like.

可药用溶剂化物的实例包括水合物。Examples of pharmaceutically acceptable solvates include hydrates.

本发明所使用的某些活性组分能够以立体异构体形式存在。可以理解，本发明包括活性组分的所有几何和光学异构体及其混合物包括消旋体。互变异构体也组成本发明方面。Certain active ingredients employed in the present invention can exist in stereoisomeric forms. It is to be understood that the present invention includes all geometric and optical isomers of the active ingredients and mixtures thereof including racemates. Tautomers also form aspects of the invention.

本发明也提供一种药用产品，它包含在治疗中同时、顺序或分别联合使用的第一个活性组分，即选自福莫特罗及其可药用衍生物的β2肾上腺受体激动剂的制剂，和第二个活性组分，即选自zafirlukast、montelukast及其可药用衍生物的白三烯受体拮抗剂的制剂。The present invention also provides a pharmaceutical product comprising a first active ingredient selected from the group consisting of formoterol and pharmaceutically acceptable derivatives thereof for simultaneous, sequential or separate combination of a beta2 adrenoreceptor agonist A preparation of an agent, and a preparation of a second active ingredient, a leukotriene receptor antagonist selected from the group consisting of zafirlukast, montelukast and pharmaceutically acceptable derivatives thereof.

另一方面，本发明提供一种药盒，它包含第一个活性组分，即选自福莫特罗及其可药用衍生物的β2肾上腺受体激动剂的制剂，和第二个活性组分，即选自zafirlukast、montelukast及其可药用衍生物的白三烯受体拮抗剂的制剂，和同时、顺序或分别给予需要治疗的患者所述制剂的说明书。In another aspect, the present invention provides a kit comprising a first active ingredient, a preparation of a beta2 adrenoreceptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof, and a second active ingredient Components, namely a preparation of a leukotriene receptor antagonist selected from zafirlukast, montelukast, and pharmaceutically acceptable derivatives thereof, and instructions for simultaneous, sequential or separate administration of said preparation to a patient in need of treatment.

现已发现，选择本发明活性组分是有利的，因为它产生有益的抗炎和支气管扩张药作用并因此可用于治疗各种急性和慢性炎性疾病/病症如慢性阻塞性肺病(COPD)；气喘如支气管性气喘、变应性气喘、内因性气喘、外因性气喘和尘埃性气喘，特别是慢性或慢性顽固性气喘(例如晚期气喘和气道高反应性)；鼻炎和风湿性关节炎。It has now been found that the choice of the active ingredient according to the invention is advantageous as it produces beneficial anti-inflammatory and bronchodilatory effects and is therefore useful in the treatment of various acute and chronic inflammatory diseases/disorders such as chronic obstructive pulmonary disease (COPD); Asthma such as bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma and dust asthma, especially chronic or chronic refractory asthma (eg, advanced asthma and airway hyperresponsiveness); rhinitis and rheumatoid arthritis.

本发明药物组合物可通过将第一个活性组分与第二个活性组分混合来制备。因此，本发明另一方面提供制备药物组合物的方法，它包括将第一个活性组分，即选自福莫特罗及其可药用衍生物的β2肾上腺受体激动剂，和第二个活性组分，即选自zafirlukast、montelukast及其可药用衍生物的白三烯受体拮抗剂混合。The pharmaceutical compositions of this invention can be prepared by admixing a first active ingredient with a second active ingredient. Therefore, another aspect of the present invention provides a method for the preparation of a pharmaceutical composition, which comprises combining a first active ingredient, a beta2 adrenoreceptor agonist selected from formoterol and pharmaceutically acceptable derivatives thereof, and a second The active ingredient is a mixture of leukotriene receptor antagonists selected from zafirlukast, montelukast and pharmaceutically acceptable derivatives thereof.

可以选择性地同时、顺序或分别给予第一个和第二个活性组分(而不是上述混合物)来治疗炎性疾病。顺序给予是指在给予第一个和第二个活性组分中的一个后立即给予另一个。如果分别给予它们，但间隔时间小于大约4小时，优选小于大约2小时，更优选小于大约30分钟，那么它们仍具有预期的作用。Inflammatory diseases may optionally be administered simultaneously, sequentially or separately (rather than the mixtures described above) with the first and second active ingredients. Sequential administration means administration of one of the first and second active ingredients immediately after the other. If they are administered separately but less than about 4 hours apart, preferably less than about 2 hours, more preferably less than about 30 minutes apart, they still have the intended effect.

活性组分可以并且的确通常在与一种或多种可选自，例如助剂、载体、粘合剂、润滑剂、稀释剂、稳定剂、缓冲剂、乳化剂、粘度调节剂、表面活性剂、防腐剂、调味剂和着色剂的可药用组分的混合物中使用。The active ingredient can be, and does usually be, in combination with one or more of, for example, adjuvants, carriers, binders, lubricants, diluents, stabilizers, buffers, emulsifiers, viscosity regulators, surfactants , preservatives, flavoring and coloring agents in a mixture of pharmaceutically acceptable components.

在上述治疗应用中，所给予的剂量当然将依据所使用的第一个或第二个活性组分，给药方式，所需要的治疗和适应症改变。然而通常，当第一个活性组分采取口服吸入时的每日总剂量在1-50μg范围，特别是在1，2，3，4或5至48，优选至40，更优选至24μg范围时，并且当第二个活性组分采取口服吸入时的每日总剂量在1-800μg范围，特别是在1，2，5，10或20至400，优选至200μg范围时，将获得令人满意的结果。In the above therapeutic applications the dosage administered will of course vary depending upon whether the first or second active ingredient is employed, the mode of administration, the treatment desired and the indication. Usually, however, the total daily dose when the first active ingredient is taken by oral inhalation is in the range of 1-50 μg, especially in the range of 1, 2, 3, 4 or 5 to 48, preferably to 40, more preferably to 24 μg , and when the second active ingredient is taken orally inhaled in a total daily dose in the range of 1-800 μg, especially in the range of 1, 2, 5, 10 or 20 to 400, preferably to 200 μg, satisfactory the result of.

本发明药物组合物、药用产品或药盒可以以每日1-4次并且特别优选每日1或2次的分剂量给予。The pharmaceutical composition, pharmaceutical product or kit according to the invention can be administered in divided doses of 1 to 4 times a day and particularly preferably 1 or 2 times a day.

第一个和第二个活性组分典型地以溶液剂、悬浮液、气雾剂和干粉制剂的形式方便地给予(到肺和/或气道)。The first and second active ingredients are typically conveniently administered (to the lungs and/or airways) in the form of solutions, suspensions, aerosols and dry powder formulations.

例如，计量剂量的吸入器装置可用于给予分散在适宜的推进剂中并且含有或不含其它赋形剂如乙醇、表面活性剂或稳定剂的活性组分。For example, metered dose inhaler devices may be used to administer the active ingredient dispersed in a suitable propellant with or without other excipients such as alcohols, surfactants or stabilizers.

适宜的推进剂包括烃、氯氟烃和氢氟烷烃(例如七氟烷烃)推进剂或任何所述推进剂的混合物。特别优选的推进剂是P134a和P227，其中任一推进剂都可以单独或与其它推进剂和/或表面活性剂和/或其它赋形剂联合使用。Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (eg heptafluoroalkane) propellants or mixtures of any of said propellants. Particularly preferred propellants are P134a and P227, either of which may be used alone or in combination with other propellants and/or surfactants and/or other excipients.

也可以使用经过或未经过适宜的pH和/或张力调节的、以单位剂量或多剂量制剂存在的雾化水悬浮液，或者优选水溶液。Nebulizable aqueous suspensions, or preferably aqueous solutions, in unit-dose or multi-dose formulations, with or without suitable pH and/or tonicity adjustment, may also be used.

干粉吸入器也可以用于单独或与可药用载体联合给予活性组分，在后一情况下，可给予磨碎的粉剂或有序混合物。干粉吸入器可以是单剂量的或多剂量的并且可使用干粉或含干粉的胶囊。Dry powder inhalers may also be used to administer the active ingredient alone or in combination with a pharmaceutically acceptable carrier, in which case a finely divided powder or an ordered mixture may be administered. Dry powder inhalers may be single-dose or multi-dose and may use dry powder or capsules containing dry powder.

计量剂量的吸入器、雾化和干粉吸入器装置是公知的并且各种所述装置都可获得。Metered dose inhaler, nebulizer and dry powder inhaler devices are well known and a variety of such devices are available.

本发明进一步提供本发明药物组合物、药用产品或药盒在生产用于治疗炎性疾病的药物中的应用。The present invention further provides the use of the pharmaceutical composition, pharmaceutical product or kit of the present invention in the manufacture of a medicament for the treatment of inflammatory diseases.

本发明也提供治疗炎性病症的方法，它包括给予需要治疗的患者治疗有效量本发明药物组合物。The invention also provides a method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention.

本发明进一步还提供治疗炎性病症的方法，它包括同时、顺序或分别给予需要治疗的患者：The present invention further provides a method of treating inflammatory disorders, which comprises simultaneously, sequentially or separately administering to a patient in need of treatment:

(a)、一定(治疗有效)剂量的第一个活性组分，即选自福莫特罗及其可药用衍生物的β2肾上腺受体激动剂；和(a), a certain (therapeutically effective) dose of the first active ingredient, namely a beta2 adrenoreceptor agonist selected from formoterol and its pharmaceutically acceptable derivatives; and

(b)、一定(治疗有效)剂量的第二个活性组分，即选自zafirlukast、montelukast及其可药用衍生物的白三烯受体拮抗剂。(b) A certain (therapeutically effective) dose of the second active ingredient, a leukotriene receptor antagonist selected from zafirlukast, montelukast and pharmaceutically acceptable derivatives thereof.

在本发明说明书中，除非有相反的特定说明，术语“治疗”也包括“预防”。也应该相应地解释术语“治疗的”和“治疗上”。In the specification of the present invention, the term "treatment" also includes "prevention" unless there is a specific statement to the contrary. The terms "therapeutic" and "therapeutically" should also be interpreted accordingly.

预期，对于以前患有过所述疾病或病症，或者被认为具有增加的患所述疾病或病症危险的人来说，预防和治疗是特别相关的。处于患特定疾病或病症危险的患者通常包括有该疾病或病症家族史的，或者通过基因试验或筛选已被鉴定为特别容易患所述疾病或病症的那些人。Prevention and treatment are expected to be of particular relevance to persons who have previously suffered from, or are considered to be at increased risk of, the disease or condition. Patients at risk for a particular disease or condition generally include those who have a family history of the disease or condition, or who have been identified by genetic testing or screening as being particularly susceptible to the disease or condition.

现通过下列例举的实施例来进一步理解本发明。这些实施例描述特定的可以被制备成口腔吸入的干粉制剂的药物组合物。The present invention will now be further understood by the following illustrative examples. These examples describe specific pharmaceutical compositions that can be formulated as dry powder formulations for oral inhalation.

实施例1富马酸福莫特罗二水合物       4.5μgZafirlukast                  100μg乳糖一水合物                 200-2000μgExample 1 Formoterol fumarate dihydrate 4.5 μg Zafirlukast 100 μg lactose monohydrate 200-2000 μg

实施例2富马酸福莫特罗二水合物       9.0μgZafirlukast                  100μg乳糖一水合物                 200-2000μgExample 2 Formoterol fumarate dihydrate 9.0 μg Zafirlukast 100 μg lactose monohydrate 200-2000 μg

实施例3富马酸福莫特罗二水合物       4.5μgZafirlukast                  200μg乳糖一水合物                 300-2000μg实施例4富马酸福莫特罗二水合物      9.0μgZafirlukast                 200μg乳糖一水合物                300-2000μgExample 3 Ful-Pharotico Moto Erwater 4.5 μgzafirukast 200 μg of lactose, a water compound 300-2000 μg Example 4 Fate-Macoloolo Moto Erzhong 9.0 μgzafirukast 200 μg Lact sugar 300-2000 μg 300-2000 μg

实施例5富马酸福莫特罗二水合物      4.5μgZafirlukast                 50μg乳糖一水合物                200-2000μgExample 5 Formoterol fumarate dihydrate 4.5 μg Zafirlukast 50 μg lactose monohydrate 200-2000 μg

实施例6富马酸福莫特罗二水合物      4.5μgZafirlukast                 100μg乳糖一水合物                200-2000μgExample 6 Formoterol fumarate dihydrate 4.5 μg Zafirlukast 100 μg lactose monohydrate 200-2000 μg

Claims (23)

1. pharmaceutical composition, it comprises with form of mixtures: first active component of β 2 adrenoreceptor agonists β 2 adrenoreceptor agonists promptly are selected from formoterol and pharmaceutically acceptable derivant thereof; With second active component LTRA, be selected from zafirlukast, montelukast and pharmaceutically acceptable derivant thereof.
2. the compositions of claim 1, wherein first and second active component exist with the solvate forms of its officinal salt, ester or solvate or ester or salt.
3. claim 1 or 2 compositions, wherein first active component is a formoterol fumarate dihydrate.
4. the compositions of claim 1, wherein second active component is Zafirlukast.
5. the compositions of claim 1, wherein second active component is montelukast sodium.
6. arbitrary compositions of claim 1-5, described preparation of compositions is the preparation by the oral cavity inhalation.
7. the compositions of claim 1 is used for the treatment of application in the medicine of inflammatory disease in preparation.
8. method for preparing the pharmaceutical composition of claim 1, this method comprise mixes first active component and second active component.
9. method for the treatment of inflammatory disease, this method comprise the pharmaceutical composition that needs claim 1 treatment or the treatment effective dose.
10. the method for claim 9, wherein inflammatory disease is asthma or chronic obstructive pulmonary disease.
11. medicinal product, this product is included in while in the treatment, order or unites first active component of use respectively, promptly be selected from the preparation of β 2 adrenoreceptor agonists of formoterol and pharmaceutically acceptable derivant thereof, with second active component, promptly be selected from the preparation of the LTRA of zafirlukast, montelukast and pharmaceutically acceptable derivant thereof.
12. the product of claim 11, wherein first exists with the solvate forms of second active component with its officinal salt, ester or solvate or ester or salt.
13. the product of claim 11 or 12, wherein first active component is a formoterol fumarate dihydrate.
14. the product of claim 11, wherein second active component is Zafirlukast.
15. the product of claim 11, wherein second active component is montelukast sodium.
16. the product of claim 11 is used for the treatment of application in the medicine of inflammatory disease in preparation.
17. medicine box, this medicine box comprises first active component, promptly be selected from the preparation of β 2 adrenoreceptor agonists of formoterol and pharmaceutically acceptable derivant thereof, with second active component, promptly be selected from zafirlukast, montelukast and pharmaceutically acceptable derivant thereof LTRA preparation and simultaneously, the description of order or needs the respectively described preparation of patient for the treatment of.
18. the medicine box of claim 17, wherein first exists with the solvate forms of second active component with its officinal salt, ester or solvate or ester or salt.
19. the medicine box of claim 17 or 18, wherein first active component is a formoterol fumarate dihydrate.
20. the medicine box of claim 17, wherein second active component is Zafirlukast.
21. the medicine box of claim 17, wherein second active component is montelukast sodium.
22. the medicine box of claim 17 is used for the treatment of application in the medicine of inflammatory disease in preparation.
23. a method for the treatment of inflammatory disease, this method comprise while, order or need the patient of treatment respectively:
(a), first active component of doses, promptly be selected from β 2 adrenoreceptor agonists of formoterol and pharmaceutically acceptable derivant thereof; With
(b), second active component of doses, promptly be selected from the LTRA of zafirlukast, montelukast and pharmaceutically acceptable derivant thereof.
CN00815363A 1999-11-03 2000-10-27 Combination comprising beta 2 adranoreceptor agonist and lenkotriene receptor antagonist Pending CN1387431A (en)

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US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
PE20050130A1 (en) * 2002-08-09 2005-03-29 Novartis Ag ORGANIC COMPOUNDS
GB0312148D0 (en) 2003-05-28 2003-07-02 Aventis Pharma Ltd Stabilized pharmaceutical products
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TWI359675B (en) 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
CA2562009A1 (en) * 2004-04-05 2005-10-20 Sepracor Inc. (r,r)-formoterol in combination with other pharmacological agents
ES2245612B1 (en) * 2004-06-29 2007-08-16 Universidad De Barcelona NEW THERAPEUTIC USE OF FORMOTEROL.
AU2006224842B2 (en) * 2005-03-16 2011-09-29 Meda Pharma Gmbh & Co Kg The combination of anticholinergics and leukotriene receptor antagonists for the treatment of respiratory diseases
CN103562185A (en) * 2011-06-06 2014-02-05 奇斯药制品公司 Derivatives of 1-phenyl-2-pyridylalkyl alcohols as phosphodiesterase inhibitors
ES2716142T3 (en) * 2012-12-05 2019-06-10 Chiesi Farm Spa 1-Phenyl-2-pyridinyl alkyl alcohol derivatives as phosphodiesterase inhibitors
JP5846185B2 (en) 2013-11-21 2016-01-20 大日本印刷株式会社 Through electrode substrate and semiconductor device using the through electrode substrate
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CA2388657A1 (en) 2001-05-10

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