[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2020019952A1 - 一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用 - Google Patents

一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用 Download PDF

Info

Publication number
WO2020019952A1
WO2020019952A1 PCT/CN2019/094486 CN2019094486W WO2020019952A1 WO 2020019952 A1 WO2020019952 A1 WO 2020019952A1 CN 2019094486 W CN2019094486 W CN 2019094486W WO 2020019952 A1 WO2020019952 A1 WO 2020019952A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
acid
salt
indacaterol
composition according
Prior art date
Application number
PCT/CN2019/094486
Other languages
English (en)
French (fr)
Inventor
张春雨
秦践
李麒麟
Original Assignee
四川海思科制药有限公司
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 四川海思科制药有限公司 filed Critical 四川海思科制药有限公司
Priority to CN201980023670.6A priority Critical patent/CN111936124A/zh
Priority to CN202310107966.4A priority patent/CN116173025A/zh
Publication of WO2020019952A1 publication Critical patent/WO2020019952A1/zh

Links

Images

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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the invention relates to an aerosol pharmaceutical composition, in particular to an aerosol pharmaceutical composition containing a glycopyrrolium salt and an indacaterol salt and a preparation method thereof, and belongs to the field of pharmaceutical preparations.
  • Chronic obstructive pulmonary disease (Chronic, Obstructive, Disease, COPD), referred to as chronic obstructive pulmonary disease, is a feature of continuous airflow limitation, which develops progressively, and chronic inflammation caused by harmful gases and particles in the airway and lung tissue. Sexual response related to chronic respiratory diseases.
  • the morbidity and mortality of COPD are relatively high globally, and they are increasingly valued by various countries and organizations.
  • COPD ranks fourth in the world as the cause of death. According to the prediction of the World Health Organization (WHO), by 2020, the disease will become the third leading cause of human death worldwide.
  • WHO World Health Organization
  • the prevention and treatment of COPD is also very serious, and the morbidity and mortality have increased year by year with various factors such as aging, smoking population, and the environment.
  • bronchodilators are the core drugs for the management of COPD symptoms. They are applicable to the treatment of COPD at various stages. By adjusting the tension of airway smooth muscles, they relax the bronchi and improve the degree of airflow restriction. They play an important role in the treatment of COPD.
  • bronchodilators include three categories: anticholinergics, theophyllines, and ⁇ 2 receptor agonists.
  • Theophylline is generally not recommended for the treatment of COPD because of its low efficacy and high side effects.
  • Long-acting anticholinergic drugs (LAMA) and long-acting ⁇ 2 receptor agonists (LABA) are recommended as treatment by GOLD.
  • Glycommonium (glycopyrrolate) is a long-acting quaternary ammonium anticholinergic drug, which has a long-acting scopolamine receptor antagonist effect, usually in the form of its bromide salt (The structural formula is shown in the figure below) It is used in clinic.
  • Indacaterol is a bronchodilator that belongs to the class of long-acting inhaled beta 2 receptor agonists (LABA), usually in the form of its maleate (ie indacaterol maleate) (The structural formula is shown in the figure below) It is used in clinic.
  • LPA long-acting inhaled beta 2 receptor agonists
  • Glon bromide indacaterol maleate dry powder inhalation formulation was successfully developed by Novartis, Switzerland. It is administered through Breezhaler dry powder inhaler once a day for long-term relief of symptoms in adult patients with COPD.
  • Glymonium bromide indaterol dry powder inhalation formulations are mainly lactose and magnesium stearate. During the inhalation process, small particles in lactose and magnesium stearate may be inhaled into the lungs. , And its inhalation as a foreign body has the risk of adverse reactions; at the same time, due to the characteristics of the inhaled powder formulation itself, it can be inhaled into the lungs with a relatively low proportion of active ingredients, which makes glycopyrrolate and inda maleate Trow does not work well.
  • the present invention provides a propellant-free glycopyrrolate and indacaterol salt aerosol pharmaceutical composition and a preparation method thereof.
  • the pharmaceutical composition provided by the present invention uses glycopyrrolium ammonium salt and indacaterol salt as active substances. Based on glycopyrrolium ammonium, the concentration is between 0.045 ⁇ 0.001 g per 100 ml of the preparation and 0.090 ⁇ 0.001 g per 100 ml of the preparation. Based on indacaterol, its concentration is between 0.099 ⁇ 0.001 g per 100 ml of the preparation and 0.198 ⁇ 0.001 g per 100 ml of the preparation.
  • the glycopyrrolium salt and the indacaterol salt are Exists in completely dissolved form;
  • Chlorobenzyl ammonium as a pharmacologically acceptable preservative
  • Each 100 ml of the preparation contains 5 mg to 20 mg of ethylenediaminetetraacetic acid or a pharmacologically acceptable salt thereof as a pharmacologically acceptable complexing agent.
  • the glycopyrrolium salt is formed by glycopyrrolium and hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid or p-toluenesulfonic acid.
  • Salts; indacaterol salts are salts formed by indacaterol with benzoic acid, maleic acid, succinic acid, fumaric acid or tartaric acid.
  • composition of the present invention preferably, in addition to water, glycopyrrolium salt, indacaterol salt, ammonium chlorobenzylammonium, disodium ethylenediamine tetraacetate, hydrochloric acid, and optionally sodium chloride, Does not contain any other excipients and additives.
  • the present invention relates to liquid active substance preparation pharmaceutical compositions of these compounds which are generally administered by inhalation, wherein the liquid preparation pharmaceutical composition according to the present invention meets high quality standards.
  • a propellant-free liquid formulation pharmaceutical composition is administered using a suitable inhaler.
  • a particularly suitable inhaler is an aerosol pharmaceutical composition that is capable of nebulizing a small amount of a liquid formulation having a dose required for therapeutic purposes within a few seconds to form a therapeutic inhalation.
  • a preferred sprayer is an active substance liquid mist that is preferably capable of spraying in one or two shots, less than 100 microliters, preferably less than 50 microliters, and most preferably less than 20 microliters.
  • an aerosol having an average particle size of less than 20 microns, preferably less than 10 microns, such that the inhalable portion of the aerosol corresponds to a therapeutically effective amount.
  • any pharmaceutically acceptable glycopyrrolate, indacaterol salt can be used as a formulation.
  • glycopyrrolium and indacaterol are used within the scope of the present invention, they are used as references for glycopyrrolate and indacaterol.
  • the glycopyrrolate reference corresponds to the free ammonium cation.
  • the glycopyrrolium salt therefore contains an anion as a counterion.
  • the glycopyrrolium salt that can be used within the scope of the present invention preferably contains, in addition to glycopyrrolium, as a counter ion (anion), chloride ion, bromide ion, iodide ion, methanesulfonate ion, p-toluenesulfonate ion and / Or methyl sulfate ion compounds.
  • Indacaterol that can be used within the scope of the present invention is preferably a compound of benzoic acid, maleic acid, succinic acid, fumaric acid, and tartrate ions.
  • glycopyrronium bromide is preferred.
  • References to glycopyrronium bromide within the scope of the present invention are generally understood as references to all possible amorphous and crystalline modified glycopyrronium bromides; preferred Malay Indacaterol maleate, references to indacaterol maleate within the scope of the present invention are generally understood as references to all possible amorphous and crystalline modified indacaterol maleates.
  • the pharmaceutical composition of the formulation of the present invention is preferably an active substance that does not contain any other active substance not containing glycopyrrolium, indacaterol, or a pharmaceutically acceptable salt thereof.
  • glycopyrrolate and indacaterol salts in the pharmaceutical composition of the formulation according to the present invention are dissolved in water. No other solvents are used. In particular, this formulation has no propellant gas.
  • the pharmaceutical composition of the preparation according to the present invention preferably contains a glycopyrrolate salt, an indacaterol salt, and preferably a glycopyrrolate bromide and an indacaterol maleate.
  • the pharmaceutical composition of this formulation may also contain a mixture of different glycopyrrolium salts, indacaterol salts, and solvates.
  • the concentration of glycopyrrolate and indacaterol depends on the therapeutic effect to be achieved.
  • the concentration of glycopyrronium is between 0.03 g per 100 g of preparation and 0.10 g per 100 g of preparation
  • the concentration of indaterol is 0.033 g per 100 g of preparation
  • the density of the formulation is 1 g / cm 3
  • a 100 gram formulation corresponds to a volume of 100 ml.
  • the expression "per 100 mL" or "/ 100 mL” is, unless stated differently, a preparation per 100 ml in each case. It is preferably contained in an amount of 0.035 g / 100 mL to 0.095 g / 100 mL of glycopyrronium ammonium, 0.077 g / 100 mL to 0.209 g / 100 mL of indaterol, and more preferably 0.04 g / 100 mL to 0.09 g / 100 mL of indoletron. Datrol in an amount from 0.088 g / 100 mL to 0.198 g / 100 mL.
  • the optimal amount is 0.045 ⁇ 0.001 g per 100 ml of preparation, 0.090 ⁇ 0.001 g per 100 ml of preparation, 0.099 ⁇ 0.001 g of indacaterol, and 0.198 ⁇ 0.001 g per 100 ml of preparation.
  • the aerosol pharmaceutical composition of the present invention has a pH between 2.7 and 3.1, preferably between 2.8 and 3.05, more preferably between 2.80 and 3.0, and most preferably 2.9.
  • the pH is adjusted by adding a pharmacologically acceptable acid.
  • Examples of preferred inorganic acids for this purpose also include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • Examples of particularly suitable organic acids are ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid, and the like.
  • Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which form acid addition salts with the active substances.
  • ascorbic acid, fumaric acid and citric acid are preferred, and citric acid is most preferred.
  • mixtures of the aforementioned acids can also be used, especially in the case of acids having other properties in addition to acidifying properties, such as acids used as flavoring agents or antioxidants, such as citric acid and ascorbic acid.
  • hydrochloric acid and citric acid are particularly preferred.
  • pharmacologically acceptable bases can be used to accurately titrate the pH.
  • Suitable bases include, for example, alkali metal hydroxides and alkali metal carbonates.
  • a preferred alkali metal ion is sodium. If such a base is used, care must be taken to ensure that the final salt contained in the final pharmaceutical formulation is pharmacologically compatible with the aforementioned acids.
  • the aerosol pharmaceutical composition comprises ethylenediaminetetraacetic acid (EDTA) or one of its known salts, such as sodium ethylenediaminetetraacetate or disodium ethylenediaminetetraacetate dihydrate, as Stabilizer or complex forming agent.
  • EDTA ethylenediaminetetraacetic acid
  • the use of disodium ethylenediamine tetraacetate is preferred.
  • disodium ethylenediamine tetraacetate it is between 5 mg per 100 ml of the preparation and 20 mg per 100 ml of the preparation, preferably between 5 mg per 100 ml of the preparation and 15 mg per 100 ml of the preparation, more It is preferably between 8 mg per 100 ml of the preparation and 12 mg per 100 ml of the preparation, and most preferably 10 mg per 100 ml of the preparation.
  • disodium ethylenediaminetetraacetate can be used similarly.
  • Other additives although not preferred compared to ethylenediaminetetraacetic acid or its salts, have complexing properties and can be used instead, such as nitrogen Acetic acid and its salts.
  • the complexing agent preferably refers to a molecule capable of entering a coordination bond.
  • the cations are complexed by metal cations.
  • the aerosol pharmaceutical composition may also be added with other pharmacologically acceptable auxiliaries.
  • auxiliaries and additives refer to any pharmacologically acceptable and therapeutically useful substance, which is not an active substance, but can be formulated with the active substance in a pharmacologically suitable solvent to improve the preparation of the active substance. quality. Preferably, these substances have no pharmacological effect or do not have a comparable or at least no pharmacological effect in the desired therapeutic condition.
  • auxiliaries and additives include, for example, other stabilizers, complexing agents, antioxidants, and / or preservatives, flavoring agents, vitamins, and / or other additives known in the art that can extend the shelf life of the final pharmaceutical formulation. This additive also contains pharmaceutically acceptable salts, such as sodium chloride.
  • Preferred auxiliaries include antioxidants, such as ascorbic acid, provided that they are not used to adjust pH, vitamin A, vitamin E, tocopherols and similar vitamins or vitamin precursors present in the human body.
  • Preservatives can be added to protect the formulation from contamination by pathogenic bacteria. Suitable preservatives are known in the prior art, in particular ammonium chlorobenzyl, or benzoic acid, or a benzoate, such as sodium benzoate, the concentration of which is known in the prior art. Preferably, according to the present invention, the benzalkonium chloride is mixed in the preparation.
  • the amount of chlorobenzyl ammonium is between 5 mg per 100 ml of the preparation and 20 mg per 100 ml of the preparation, preferably between 5 mg per 100 ml of the preparation and 15 mg per 100 ml of the preparation, more preferably between Between 8 mg per 100 ml of preparation and 12 mg per 100 ml of preparation, most preferably 10 mg per 100 ml of preparation.
  • the preferred formulation in addition to the water solvent and the glycopyrrolium salt, contains only ammonium chlorobenzyl alkane, disodium ethylenediamine tetraacetate and the acid required to adjust the pH, preferably hydrochloric acid.
  • glycopyrrolate and indacaterol salt aerosol pharmaceutical compositions of the present invention can be prepared by mixing the individual components.
  • glycopyrrolate aerosol pharmaceutical composition of the present invention can be used with the Respimat aerosol inhalation device, and can also be used with the aerosol inhalation device shown in FIG. 1 or 2.
  • the aerosol inhalation device shown in FIG. 1 is a piezoelectrically actuated droplet delivery device for delivering a medicinal solution as a jet of droplets to a patient's lung system.
  • the device includes:
  • a liquid storage tank which is arranged in the housing or communicates with a liquid passage in the housing, and is used for storing a certain volume of medicinal liquid
  • the ejection mechanism which is in communication with the liquid in the liquid storage tank includes a piezoelectric actuator and an orifice plate, the orifice plate has a plurality of openings, and the piezoelectric actuator can oscillate the orifice plate with a certain frequency to generate ejected liquid droplets. flow;
  • At least one pressure difference sensor disposed in the housing
  • the differential pressure sensor activates the ejection mechanism when it senses a predetermined pressure change in the housing, thereby generating a stream of ejected droplets
  • the spraying mechanism can generate a sprayed droplet flow, wherein at least about 70% of the droplets have an average sprayed droplet diameter of less than about 5 micrometers, so that at least about 70% of the sprayed droplet flow is delivered to the lungs of the patient.
  • Figure 1 provides a detailed view of an exemplary injector closing mechanism. Removing the housing top cover 152 exposes the ejector closing actuation mechanism 506, which includes a closing guide 508, a sliding seal plate 510, and a motor mechanism 512. When the motor mechanism 512 is activated, the motor mechanism 512 can open and close the sliding seal plate 510 . Any suitable micromotor mechanism can be used.
  • the aerosol inhalation device shown in FIG. 2 includes a base unit 100, an interface tube 200, a spray head 300, and a screw cap 304.
  • the base unit includes an air inlet 101, an air outlet 102, a groove 103 for receiving an interface pipe, and a key lock member 104;
  • the interface pipe includes a first section 200a and a second section 200b, and the first section 200a includes an air inlet 201 and a side opening 202 for accommodating the spray generator, the first segment can be inserted into the groove of the base unit, and the second segment 200b includes a spray outlet 203;
  • the spray head includes a spray generator 301, a liquid container 302, and a base unit
  • the key lock member 303 is complementary to the key lock member 303; the base unit, the interface pipe, and the spray head can be connected to each other, so that when the key lock member is joined with the complementary member, the spray generator is inserted into the side opening of the interface pipe.
  • the glycopyrrolium indacaterol salt aerosol pharmaceutical composition provided by the invention does not contain the side effects of the existing glycopyrrolate indacaterol salt aerosol auxiliary material being inhaled into the lungs.
  • the problem also solves the problem that the active ingredient of the glycopyrrolium indacaterol salt powder can reach the lungs in a small amount, which can reduce the product specifications and reduce the raw materials of the glycopyrrolate and indacaterol salt.
  • the dosage reduces the cost of medicines and reduces the burden on patients.
  • most existing aerosols for chronic obstructive pulmonary disease contain propellants. On the one hand, propellants will destroy the ozone layer in the atmosphere and are not good for the environment.
  • the aerosol has a short fogging time, which reduces the effectiveness of the drug.
  • the glycopyrrolium indaterol salt aerosol provided by the present invention does not contain a propellant, and there is no problem that has an impact on environmental protection. Due to the long fogging time during use, the efficiency of the drug's functioning is greatly improved.
  • the present invention also provides a pharmaceutical combination system comprising an aerosol pharmaceutical composition and an aerosolized inhalation device for treating COPD, the aerosol pharmaceutical composition is selected from the foregoing glycopyrrolate-containing salt and indate Aerosol formulations of rosidium, or selected from the group consisting of ipratropium bromide, fenoterol hydrobromide, salbutamol sulfate, tiotropium bromide, ordaterol hydrochloride, adibromide, and humidinium bromide One or more aerosol formulations.
  • the drug combination system processes the aerosol pharmaceutical composition through the atomizing inhalation device to make it atomize, and the unit dose volume processed by the atomizing inhalation device is 10 to 50 microliters .
  • the aerosol inhalation device in the drug combination system is shown in FIG. 1 or shown in FIG. 2.
  • Figure 1 is a schematic diagram of aerosol inhalation devices related to patents such as WO2017192767A1, US20170319796A1, WO2017192773A1, WO2017192774A1, WO2017192778A1, WO2017192782A1, CN109475707A, CN109414178A, CN109475709A and other patents.
  • Figure 2 is a schematic diagram of an aerosol inhalation device involved in patents such as CN103785086A, CN104010685A, CN104271187A, CN107929894A and the like.
  • glycopyrrolate and indacaterol salt aerosol pharmaceutical composition contains:
  • the remaining components are purified water, or water for injection at a temperature of 15-31 ° C and a density of 1.00g / cm 3 , which are prepared by mixing individual components. After filtering and sterilizing, they are canned in a pill box of an atomizing device. .
  • the lung deposition rate (FPF value) of the product of the present invention and a commercially available product of glycopyrrolate bromide indacaterol powder was measured by a new generation impactor (NGI). The results are as follows:
  • the above FPF value is the FPF value of the two active ingredients in the powder or aerosol generated after the inhalation preparation product passes through the corresponding inhalation device, which are measured by the new generation impactor (NGI).
  • the inhalation device is Breezhaler (that is, a commercially available device of this product).
  • the inhalation device used in the product of Example 1 of the present invention is the inhalation device shown in FIG. 1, and the inhalation device used in the product of Example 6 of the present invention is the inhalation device shown in FIG. 2. .
  • the lung deposition rate of the glycopyrrolate maleate indacaterol of the present invention is much higher than that of the glycopyrrolate maleate indacaterol commercially available from Novartis Inhalation of the powder mist significantly improved the utilization efficiency of glycopyrrolate and indacaterol.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

一种不含推进剂的气雾剂药物组合物，其包含格隆铵可药用的盐、茚达特罗可药用的盐和水，所述药物组合物每100mL含格隆铵0.045±0.001g至0.090±0.001g、茚达特罗0.099±0.001g至0.198±0.001g；该药物组合物特别适合于借助于雾化器而将活性物质形成气雾以在气喘及COPD症状中以吸入方式施用活性剂。

Description

一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用 技术领域
本发明涉及一种气雾剂药物组合物，具体涉及一种含格隆铵盐、茚达特罗盐的气雾剂药物组合物及其制备方法，属于药物制剂领域。
背景技术
慢性阻塞性肺病(Chronic Obstructive Pulmonary Disease,COPD)，简称慢阻肺，是一种以持续气流受限为特征，多呈进行性发展，与气道及肺组织因有害气体及颗粒所致慢性炎性反应有关的慢性呼吸系统疾病。COPD的发病率和死亡率在全球范围内均较高，越来越多的受到各个国家和组织的高度重视。目前，COPD居全球死亡原因第四位，据世界卫生组织(WHO)预测，到2020年，该病将成为全球导致人类死亡的第三大疾患。在中国，COPD的防治状况也十分严峻，且发病率和死亡率随老龄化、吸烟人群、环境等多种因素逐年攀升。该疾病不仅严重威胁着人们的身心健康，而且对整个社会也造成了严重的经济负担。据Globe Burden of Disease Study预测，到2020年COPD的经济负担将跃居世界疾病经济负担的第五位，而中国COPD疾病经济负担将跃升第一位。
由于COPD的发病机制复杂，目前临床上还没有可逆转该疾病进程或显著改变肺功能下降的特效治疗方法，多为对症治疗。临床上用于治疗COPD的药物很多，如支气管扩张药、抗炎药、祛痰药等。其中支气管舒张药是COPD症状管理的核心药物，适用于各个阶段的COPD治疗，通过调节气道平滑肌的张力，舒张支气管，改善气流受限程度，在COPD的药物治疗中发挥重要作用。常用的支气管舒张药包括三类：抗胆碱能类、茶碱类、β2受体激动剂类。基于茶碱疗效低和副作用较高的特点，一般不推荐茶碱治疗COPD，而长效的抗胆碱能药物(LAMA)和长效的β2受体激动剂(LABA)则被GOLD推荐为治疗稳定期慢阻肺的一线支气管舒张剂。
格隆铵(glycopyrrolate)是一种长效季铵类抗胆碱能药物，具有长效毒醰碱受体拮抗剂作用，通常取其溴化物盐(即格隆溴铵，glycopyrronium bromide)的形式(结构式如下图所示)用于临床。
Figure PCTCN2019094486-appb-000001
茚达特罗(indacaterol)是一种支气管舒张剂，属于长效吸入β2受体激动剂(LABA)类，通常取其马来酸盐(即马来酸茚达特罗，indacaterol maleate)的形式(结构式如下图所示)用于临床。
Figure PCTCN2019094486-appb-000002
格隆溴铵马来酸茚达特罗复方干粉吸入制剂，由瑞士诺华公司开发成功，每日1次通过Breezhaler干粉吸入器用药，用于长期缓解成人COPD患者的症状。
现有格隆溴铵马来酸茚达特罗干粉吸入制剂，其辅料主要为乳糖及硬脂酸镁，在吸入过程中，乳糖及硬脂酸镁中的小颗粒有被吸入肺部的可能，而其作为异物被吸入有产生不良反应的风险；同时因吸入粉雾剂剂型本身的特点，其能被吸入肺部的有效成分占比较低，从而使格隆溴铵、马来酸茚达特罗不能很好地发挥药效。
发明内容
为了解决现有技术的不足，本发明提供一种不含推进剂的格隆铵盐、茚达特罗盐气雾剂药物组合物及其制备方法。
本发明的技术方案如下：
本发明提供的药物组合物，以格隆铵盐、茚达特罗盐作为活性物质，基于格隆铵，其浓度为介于每100毫升制剂0.045±0.001克与每100毫升制剂0.090±0.001克之间，基于茚达特罗，其浓度为介于每100毫升制剂0.099±0.001克与每100毫升制剂0.198±0.001克之间，其中在该药物制剂中的格隆铵盐、茚达特罗盐是以完全溶解的形式存在；
水为唯一的溶剂；
以酸调整pH值使之介于2.8和3.05之间；
氯苄烷铵作为药理上可接受的防腐剂；
每100毫升制剂含5毫克至20毫克的乙二胺四乙酸或其药理上可接受的盐作为药理上可接受的络合剂。
根据本发明的上述药物组合物，优选地，该格隆铵盐为格隆铵和氢溴酸、氢氯酸、氢碘酸、单甲基硫酸酯、甲磺酸或对甲苯磺酸所形成的盐类；茚达特罗盐为茚达特罗与苯甲酸、马来酸、琥珀酸、富马酸或酒石酸所形成的盐类。
根据本发明的上述药物组合物，优选地，除了水、格隆铵盐、茚达特罗盐、氯苄烷铵、乙二胺四乙酸二钠、盐酸和任选的氯化钠之外，不包含任何其它赋形剂与添加剂。
本发明是关于通常吸入给药的这些化合物的液体活性物质制剂药物组合物，其中根据本发明的液体制剂药物组合物合乎高品质标准。
为达到活性物质在肺部的最佳活性物质分布，使用合适的吸入器投药无推进气体的液体制剂药物组合物。特别适合的吸入器为能够在几秒钟内将具有治疗目的所需的剂量的少量液体制剂雾化以形成适合治疗性吸入的气雾剂药物组合物。在本发明范围内，优选的喷雾器为优选地能够在一或两次喷出中，将少于100微升，优选是少于50微升，最佳是少于20微升的活性物质液体雾化，以形成平均颗粒大小小于20微米，优选小于10微米的气雾剂，使得该气雾剂的可吸入部分相当于治疗上有效的量。
根据本发明，可使用任何药物上可接受的格隆铵盐、茚达特罗盐作为制剂。当格隆铵、茚达特罗使用于本发明的范围内时，是作为格隆铵类、茚达特罗类的参照。格隆铵的参照相当于游离的铵的阳离子。格隆铵盐因此包含一阴离子作为相反离子。可用于本发明范围内的格隆铵盐优选为包含除了格隆铵外作为相反离子(阴离子)的，还有氯离子，溴离子，碘离子，甲磺酸根离子，对甲苯磺酸根离子及/或甲基硫酸根离子的化合物。可用于本发明范围内的茚达特罗优选为苯甲酸、马来酸、琥珀酸、富马酸、酒石酸根离子的化合物。
在本发明范围内优选是格隆溴铵，在本发明范围内格隆溴铵的参照通常理解为所有可能的非晶态及晶态的改性的格隆溴铵的参照；优选的马来酸茚达特罗，在在本发明范围内马来酸茚达特罗的参照通常理解为所有可能的非晶态及晶态的改性的马来酸茚达特罗的参照。
本发明的制剂药物组合物优选为不含有任何其他的不含格隆铵、茚达特罗的活性物质或其药物上可接受的盐的活性物质。
根据本发明制剂药物组合物中的一种或多种的格隆铵盐、茚达特罗盐类溶解于水中。不使用其他溶剂。特别的是，这种制剂没有推进气体。
根据本发明的制剂药物组合物优选含有格隆铵盐、茚达特罗盐，优选为格隆溴铵与马来酸茚达特罗。然而，这种制剂药物组合物也可能含有不同格隆铵盐、茚达特罗盐类与溶剂合物的混合物。
依据最终的药物制剂的格隆铵、茚达特罗比例，格隆铵盐、茚达特罗盐的浓度决定于所要达到的治疗效果。大部分对格隆铵、茚达特罗响应的病症，格隆铵的浓度介于每100克制剂0.03克和每100克制剂0.10克之间，茚达特罗浓度介于每100克制剂0.033克和每100克制剂0.22克之间。因为制剂的密度为1g/cm 3，100克的制剂相当于100ml的体积。在本说明书范围内，“每100mL”或“/100mL”的表达方式，除非不同的陈述，在每种状况下的为每100毫升的制剂。优选为含格隆铵0.035g/100mL至0.095g/100mL、茚达特罗0.077g/100mL至0.209g/100mL的量，更优选为含格隆铵0.04g/100mL至0.09g/100mL、茚达特罗0.088g/100mL至0.198g/100mL的量。最佳的量为每100毫升制剂含格隆铵0.045±0.001克至每100毫升制剂0.090±0.001克、茚达特罗0.099±0.001克至每100毫升制剂0.198±0.001克。
本发明气雾剂药物组合物的pH值为介于2.7和3.1之间，优选为介于2.8和3.05之间，更佳为介于2.80和3.0之间，最佳为2.9。
通过添加药理上可接受的酸调整pH值。
合乎此目的优选的无机酸实例也包括：盐酸、氢溴酸、硝酸、硫酸及/或磷酸。特别适合的有机酸实例为抗坏血酸、柠檬酸、苹果酸、酒石酸、马来酸、琥珀酸、富马酸、醋酸、甲酸及/或丙酸等。优选的无机酸为盐酸和硫酸。也可能使用与活性物质形成酸加成盐的酸。在有机酸中抗坏血酸，富马酸和柠檬酸为优选的，最佳为柠檬酸。必要时，也可使用上述酸的混合物，特别在除了具有酸化性质外还具有其他性质的酸的情况下，例如作为调味剂或抗氧化剂的酸，如柠檬酸与抗坏血酸。
在上述所提及的酸中，清楚指明盐酸和柠檬酸为特别优选。
必要时，药理上可接受的碱可用于精确地滴定pH值。适合的碱包括例如碱金属氢氧化物和碱金属碳酸盐。优选的碱金属离子为钠。如果使用这类的碱，必须注意确保包含在最终药物制剂的最终盐与上述酸在药理上是相容的。
根据本发明，所述气雾剂药物组合物包含乙二胺四乙酸(EDTA)或其一种已知盐类，例如乙二胺四乙酸钠或乙二胺四乙酸二钠二水合物，作为稳定剂或络合物成形 剂。使用乙二胺四乙酸二钠为优选。
根据乙二胺四乙酸二钠的含量为介于每100毫升制剂5毫克与每100毫升制剂20毫克之间，优选为介于每100毫升制剂5毫克和每100毫升制剂15毫克之间，更佳的为介于每100毫升制剂8毫克和每100毫升制剂12毫克之间，最佳的为每100毫升制剂10毫克。
若使用一种不同的乙二胺四乙酸的盐或其酸，则使用类似量的络合剂。
注意到涉及乙二胺四乙酸二钠，也可以类似地使用其他的虽然与乙二胺四乙酸或其盐相比并不优选的添加物，但其具有络合性质可取代使用，例如氮三乙酸及其盐类。
在本发明范围内，络合剂优选是指能够进入配位键合的分子。优选的，通过这些化合物阳离子最佳是金属阳离子进行络合。
根据本发明，所述气雾剂药物组合物也可添加其他药理上可接受的助剂。
在本文中助剂和添加剂是指任何药理上可接受，治疗上有用的物质，其不是一种活性物质，但可在药理上适合的溶剂中与活性物质一起进行调配，以改善活性物质制剂的质量。优选的，这些物质无药理作用或在所要的治疗状况下没有相当的或至少没有所要的药理作用。这些助剂和添加剂包括例如其他的稳定剂、络合剂、抗氧化剂、和/或可延长最终药物制剂保存期限的防腐剂、调味剂、维生素和/或其他本技术中已知的添加剂。这种添加剂也包含药理上可接受的盐类，例如氯化钠。
优选的助剂包括抗氧化剂，例如抗坏血酸，但其前提为其没有用于调整pH值，维生素A、维生素E、生育酚和类似的在人体中存在的维生素或维生素前体。
可添加防腐剂以保护制剂免于病源菌的污染。适合的防腐剂为现有技术中所已知，特别是氯苄烷铵，或苯甲酸，或苯甲酸盐，例如苯甲酸钠，其浓度为现有技术所已知。优选的，根据本发明，制剂中混合有氯苄烷铵。氯苄烷铵的量介于每100毫升制剂5毫克和每100毫升制剂20毫克之间，优选为介于每100毫升制剂5毫克和每100毫升制剂15毫克之间，更佳的为介于每100毫升制剂8毫克和每100毫升制剂12毫克之间，最佳的是每100毫升制剂10毫克。
优选的制剂除了水溶剂和格隆铵盐之外，只包含氯苄烷铵，乙二胺四乙酸二钠和调整pH值所需的酸，优选为盐酸。
本发明的格隆铵盐和茚达特罗盐气雾剂药物组合物可以通过混合单个组成而进行制备。
本发明格隆铵盐气雾剂药物组合物可配合Respimat气雾剂吸入装置使用，也可配合图1或图2所示的气雾剂吸入装置使用。
图1所示气雾剂吸入装置为一种压电致动液滴输送装置，其用于将药液作为喷射的液滴流输送到患者的肺部系统，该装置包括：
壳体；
储液仓，设置在壳体内或与壳体内液体通路连通，用于储存一定体积的药液；
与储液仓药液连通的喷射机构，其包括压电致动器和孔板，该孔板具有多个开孔，该压电致动器可以一定频率振荡孔板，从而产生喷射的液滴流；
至少一个压差传感器，设置在壳体内；
压差传感器在感测到壳体内的预定压力变化时便启动喷射机构，从而产生喷射的液滴流；
该喷射机构可产生喷射的液滴流，其中至少约70％的液滴具有小于约5微米的平均喷射液滴直径，使喷射的液滴流至少约70％传送至患者肺部。
图1所示的气雾剂吸入装置的详细结构和功能可参见WO2017192767A1、US20170319796A1、WO2017192773A1、WO2017192774A1、WO2017192778A1、WO2017192782A1、CN109475707A、CN109414178A、CN109475709A等专利，这里将其全部引入。图1提供了示例性喷射器封闭机构的详细视图。移除壳体顶盖152暴露喷射器封闭致动机构506，其包括封闭引导件508、滑动密封板510和马达机构512，当马达机构512启动时，马达机构512可打开和关闭滑动密封板510。可以使用任何合适的微型马达机构。
图2所示气雾剂吸入装置包括基体单元100、接口管200、喷雾头300以及螺旋盖304。基体单元包括进气口101、出气口102、用于容纳接口管的槽103以及键锁构件104；接口管包括第一节段200a和第二节段200b，第一节段200a包括进气口201和用于容纳喷雾发生器的侧开口202，第一节段可插入基体单元的槽中，第二节段200b包括喷雾出口203；喷雾头包括喷雾发生器301、液体容器302以及与基体单元的键锁构件互补的键锁构件303；基体单元、接口管以及喷雾头能够彼此连接，使得当将键锁构件与互补构件接合时，喷雾发生器插入到接口管的侧开口内。
图2所示的气雾剂吸入装置的详细结构和功能可参见CN103785086A、CN104010685A、CN104271187A、CN107929894A等专利，这里将其全部引入。
本发明提供的不含有推进剂的格隆铵盐茚达特罗盐气雾剂药物组合物，既解决了现 有格隆铵盐茚达特罗盐粉雾剂辅料被吸入肺部产生副作用的问题，又解决了格隆铵盐茚达特罗盐粉雾剂活性成分实际能到达肺部的量偏少的问题，从而可缩小产品规格，减少格隆铵盐、茚达特罗盐原料的用量，降低了药品成本，减轻了患者负担；同时，因现有治疗慢性阻塞性肺疾病的气雾剂大多数都含有推进剂，一方面推进剂会破坏大气中臭氧层不利于环保，另一方面这种气雾剂由于呈雾时间短，降低了药物发挥作用的效率，而本发明提供的格隆铵盐茚达特罗盐气雾剂不含推进剂不存在对环保有影响的问题，同时由于其使用时呈雾时间长，大大提高了药物发挥作用的效率。
本发明还提供一种药物组合系统，包含气雾剂药物组合物和一种用于治疗COPD的雾化吸入装置，所述气雾剂药物组合物选自上述含格隆铵盐和茚达特罗盐的气雾制剂，或选自含异丙托溴铵、非诺特罗氢溴化物、硫酸沙丁胺醇、噻托溴铵、盐酸奥达特罗、阿地溴铵、芜地溴铵中的一种或多种的气雾制剂。
在一实施方案中，所述药物组合系统通过所述雾化吸入装置处理所述气雾剂药物组合物，使其雾化，所述雾化吸入装置处理的单位剂量体积为10至50微升。
在一实施方案中，所述药物组合系统中所述雾化吸入装置如图1所示或者如图2所示。
附图说明
图1为WO2017192767A1、US20170319796A1、WO2017192773A1、WO2017192774A1、WO2017192778A1、WO2017192782A1、CN109475707A、CN109414178A、CN109475709A等专利涉及的气雾剂吸入装置示意图。
图2为CN103785086A、CN104010685A、CN104271187A、CN107929894A等专利涉及的气雾剂吸入装置示意图。
具体实施方式
下面结合实施例对本发明作进一步说明，可使本领域专业技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1-6：
每100毫升格隆铵盐和茚达特罗盐气雾剂药物组合物包含：
Figure PCTCN2019094486-appb-000003
Figure PCTCN2019094486-appb-000004
其剩余成分为纯化水，或温度15-31℃、密度1.00g/cm 3的注射用水，均采用通过混合单个组成而进行制备，通过过滤除菌后，罐装于雾化装置的药盒中。
对比例
通过新一代撞击器(NGI)测定本发明产品与格隆溴铵马来酸茚达特罗粉雾剂市售品的肺部沉积率(FPF值)，结果如下：
Figure PCTCN2019094486-appb-000005
上述FPF值为吸入制剂产品通过相应吸入装置后产生的粉雾或气雾中二活性成分的FPF值，均通过新一代撞击器(NGI)测得，诺华公司格隆溴铵吸入粉雾剂对应的吸入装置为Breezhaler(即该产品的市售装置)，对本发明实施例1产品采用的吸入装置为图1所示吸入装置，对本发明实施例6产品采用的吸入装置为图2所示吸入装置。
比较上表中的结果可以看出，本发明格隆溴铵马来酸茚达特罗气雾剂的肺部沉积率大大高于诺华公司市售的格隆溴铵马来酸茚达特罗吸入粉雾剂，显著地提高了格隆溴铵和茚达特罗的利用效率。

Claims (21)

  1. 一种不含推进剂的气雾剂药物组合物，其特征在于，所述药物组合物包括格隆铵盐、茚达特罗盐、防腐剂氯苄烷铵、络合剂乙二胺四乙酸或其药学上可接受的盐、水，所述药物组合物中水为唯一的溶剂，其中格隆铵盐、茚达特罗盐以完全溶解的形式存在；以格隆铵、茚达特罗和乙二胺四乙酸计，每100mL所述药物组合物含格隆铵0.045±0.001g至0.090±0.001g、茚达特罗0.099±0.001g至0.198±0.001g、乙二胺四乙酸5mg至20mg；所述药物组合物的pH值介于2.8和3.05之间。
  2. 根据权利要求1的药物组合物，其特征在于所述格隆铵盐为格隆铵和氢溴酸、氢氯酸、氢碘酸、单甲基硫酸酯、甲磺酸或对甲苯磺酸所形成的盐类。
  3. 根据权利要求2的药物组合物，其特征在于所述格隆铵盐为格隆溴铵。
  4. 根据权利要求1所述的药物组合物，其特征在于所述茚达特罗盐为茚达特罗与苯甲酸、马来酸、琥珀酸、富马酸、酒石酸所形成的盐类。
  5. 根据权利要求4所述的药物组合物，其特征在于茚达特罗盐为马来酸茚达特罗。
  6. 根据权利要求1-5中任一项所述的药物组合物，其特征在于所述络合剂为乙二胺四乙酸二钠，以乙二胺四乙酸计，每100mL所述药物组合物含乙二胺四乙酸8-12mg。
  7. 根据权利要求1-6中任一项所述的药物组合物，其特征在于每100mL所述药物组合物含所述防腐剂氯苄烷铵5mg至20mg。
  8. 根据权利要求1-7中任一项所述的药物组合物，其特征在于所述pH值介于2.8和3.0之间。
  9. 根据权利要求8所述的药物组合物，其特征在于所述pH值为2.9。
  10. 根据权利要求1-9中任一项所述的药物组合物，其特征在于以无机酸调整pH值。
  11. 根据权利要求10所述的药物组合物，其特征在于所述无机酸为盐酸。
  12. 根据权利要求1-11中任一项所述的药物组合物，其特征在于除了水、格隆铵盐、茚达特罗盐、氯苄烷铵、乙二胺四乙酸二钠、盐酸和氯化钠之外，不包含任何其它赋形剂与添加剂。
  13. 权利要求1-12中任一项所述的药物组合物的用途，其特征在于所述药物组合物用于在吸入器中的雾化。
  14. 根据权利要求13的用途，其特征在于单位剂量的体积为10至50微升。
  15. 权利要求1-12中任一项所述的药物组合物在制备用于治疗气喘及/或COPD的 药物中的用途。
  16. 一种制备权利要求1-12中任一项所述的药物组合物的方法，其特征在于，它是通过混合单个组成而进行。
  17. 权利要求1-12中任一项所述的药物组合物在图1所示气雾剂装置中的应用。
  18. 权利要求1-12中任一项所述的药物组合物在图2所示气雾剂装置中的应用。
  19. 一种药物组合系统，包含气雾剂药物组合物和一种用于治疗COPD的雾化吸入装置，所述气雾剂药物组合物选自权利要求1-12中任一项所述的药物组合物，或选自含异丙托溴铵、非诺特罗氢溴化物、硫酸沙丁胺醇、噻托溴铵、盐酸奥达特罗、阿地溴铵、芜地溴铵中的一种或多种的气雾制剂。
  20. 根据权利要求19所述的药物组合系统，其特征在于通过所述雾化吸入装置处理所述气雾剂药物组合物，使其雾化，所述雾化吸入装置处理的单位剂量体积为10至50微升。
  21. 根据权利要求20所述的药物组合系统，其特征在于所述雾化吸入装置如图1所示或者如图2所示。
PCT/CN2019/094486 2018-07-26 2019-07-03 一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用 WO2020019952A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201980023670.6A CN111936124A (zh) 2018-07-26 2019-07-03 一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用
CN202310107966.4A CN116173025A (zh) 2018-07-26 2019-07-03 一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810820450.3 2018-07-26
CN201810820450 2018-07-26

Publications (1)

Publication Number Publication Date
WO2020019952A1 true WO2020019952A1 (zh) 2020-01-30

Family

ID=69182038

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/094486 WO2020019952A1 (zh) 2018-07-26 2019-07-03 一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用

Country Status (3)

Country Link
CN (2) CN111936124A (zh)
TW (1) TWI758617B (zh)
WO (1) WO2020019952A1 (zh)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111349036A (zh) * 2020-03-13 2020-06-30 安徽省逸欣铭医药科技有限公司 一种格隆溴铵的替代物及其制备方法和医药用途
WO2021068961A1 (zh) * 2019-10-11 2021-04-15 四川海思科制药有限公司 一种吸入溶液药物组合物及其制备方法
WO2021252586A1 (en) * 2020-06-09 2021-12-16 Anovent Pharmaceutical (U.S.), Llc Pharmaceutical formulation containing glycopyrrolate and indacaterol maleate
WO2022073009A1 (en) * 2020-09-29 2022-04-07 iPharma Labs, Inc. Liquid formulations of indacaterol
CN115209884A (zh) * 2020-01-20 2022-10-18 广州谷森制药有限公司 含有格隆溴铵和盐酸奥达特罗的可吸入制剂
WO2023192445A1 (en) * 2022-03-30 2023-10-05 Aerorx Therapeutics Llc Liquid formulations of indacaterol and glycopyrronium

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021143785A1 (zh) * 2020-01-15 2021-07-22 四川海思科制药有限公司 一种含茚达特罗的吸入气雾剂药物组合物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1333682A (zh) * 1998-10-17 2002-01-30 贝林格尔英格海姆法玛公司 可储存的含福莫特罗的活性物质浓缩液
CN1473044A (zh) * 2000-10-31 2004-02-04 ���ָ��Ӣ��ķ�������Ϲ�˾ 含提欧川平盐的溶液的可吸入制剂
CN101484134A (zh) * 2006-06-30 2009-07-15 诺瓦提斯公司 用于吸入的格隆铵盐组合物
WO2017192767A1 (en) * 2016-05-03 2017-11-09 Pneuma Respiratory, Inc. Droplet delivery device for delivery of fluids to the pulmonary system and methods of use

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10056104A1 (de) * 2000-11-13 2002-05-23 Boehringer Ingelheim Pharma Neue Arzneimittelkompositionen auf der Basis von Tiotropiumsalzen und Salzen des Salmeterols
DK2724741T3 (en) * 2012-10-26 2017-09-18 Vectura Gmbh Inhalation device for use in aerosol treatment
CN105793250A (zh) * 2013-12-05 2016-07-20 奇斯药制品公司 用于治疗呼吸病的杂芳基衍生物
CN105982880A (zh) * 2015-03-16 2016-10-05 四川海思科制药有限公司 一种干粉吸入剂药物组合物及其制备方法
CN106943350A (zh) * 2017-03-14 2017-07-14 上海现代药物制剂工程研究中心有限公司 含毒蕈碱受体拮抗剂和β2受体激动剂的气雾剂及制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1333682A (zh) * 1998-10-17 2002-01-30 贝林格尔英格海姆法玛公司 可储存的含福莫特罗的活性物质浓缩液
CN1473044A (zh) * 2000-10-31 2004-02-04 ���ָ��Ӣ��ķ�������Ϲ�˾ 含提欧川平盐的溶液的可吸入制剂
CN101484134A (zh) * 2006-06-30 2009-07-15 诺瓦提斯公司 用于吸入的格隆铵盐组合物
WO2017192767A1 (en) * 2016-05-03 2017-11-09 Pneuma Respiratory, Inc. Droplet delivery device for delivery of fluids to the pulmonary system and methods of use

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021068961A1 (zh) * 2019-10-11 2021-04-15 四川海思科制药有限公司 一种吸入溶液药物组合物及其制备方法
CN115209884A (zh) * 2020-01-20 2022-10-18 广州谷森制药有限公司 含有格隆溴铵和盐酸奥达特罗的可吸入制剂
CN115209884B (zh) * 2020-01-20 2024-05-28 广州谷森制药有限公司 含有格隆溴铵和盐酸奥达特罗的可吸入制剂
CN111349036A (zh) * 2020-03-13 2020-06-30 安徽省逸欣铭医药科技有限公司 一种格隆溴铵的替代物及其制备方法和医药用途
WO2021252586A1 (en) * 2020-06-09 2021-12-16 Anovent Pharmaceutical (U.S.), Llc Pharmaceutical formulation containing glycopyrrolate and indacaterol maleate
CN115884756A (zh) * 2020-06-09 2023-03-31 广州谷森制药有限公司 含有格隆溴铵和马来酸茚达特罗的药物制剂
WO2022073009A1 (en) * 2020-09-29 2022-04-07 iPharma Labs, Inc. Liquid formulations of indacaterol
US11844793B2 (en) 2020-09-29 2023-12-19 Aerorx Therapeutics Llc Liquid formulations of indacaterol
WO2023192445A1 (en) * 2022-03-30 2023-10-05 Aerorx Therapeutics Llc Liquid formulations of indacaterol and glycopyrronium

Also Published As

Publication number Publication date
TWI758617B (zh) 2022-03-21
CN111936124A (zh) 2020-11-13
TW202012369A (zh) 2020-04-01
CN116173025A (zh) 2023-05-30

Similar Documents

Publication Publication Date Title
WO2020019952A1 (zh) 一种含格隆铵盐及茚达特罗盐的气雾剂药物组合物及其制备方法与应用
US7579358B2 (en) Aerosol formulation for inhalation comprising an anticholinergic
US20060222598A1 (en) Aerosol formulation for inhalation comprising an anticholinergic
CA2495275C (en) Aerosol formulation for inhalation comprising an anticholinergic agent
US20090075990A1 (en) Aerosol Formulation for Inhalation Containing an Anticholinergic Agent
US20090170839A1 (en) Aerosol formulation for inhalation containing an anticholinergic agent
US20060205758A1 (en) Method for reducing the mortality rate
US20090306065A1 (en) Aerosol formulation for inhalation containing an anticholinergic agent
US20090317337A1 (en) Aerosol formulation for inhalation containing an anticholinergic agent
US20090221626A1 (en) Aerosol formulation for inhalation containing an anticholinergic agent
MXPA03004164A (es) Nuevas composiciones de medicamentos a base de sales de tiotropio y sales del salmeterol.
US20040192675A1 (en) Pharmaceutical compositions containing tiotropium salts and antihistamines and their use
CA2575385A1 (en) Aerosol formulation for inhalation, containing an anticholinergenic agent
CA2552939A1 (en) New pharmaceutical compositions based on benzilic acid esters and soluble tnf receptor fusion proteins
WO2020019953A1 (zh) 一种含格隆铵盐的气雾剂药物组合物及其制备方法与应用
US20210220367A1 (en) Inhalable formulation of a solution containing glycopyrrolate and olodaterol hydrochloride
US20050186145A1 (en) Pharmaceutical compositions based on fluorenecarboxylic acid esters and soluble TNF receptor fusion proteins
US20210205223A1 (en) Propellant-free formulation for inhalation
US20060251656A1 (en) New pharmaceutical compositions based on anticholinergics and anti-tnf antibodies
WO2021178232A1 (en) Inhalable formulation of a solution containing glycopyrronium bromide
US20070021333A1 (en) Pharmaceutical compositions based on anticholinergics and soluble tnf receptor fusion proteins
US20050187157A1 (en) Pharmaceutical compositions based on anticholinergics and pegsunercept
CA2553369A1 (en) Pharmaceutical compositions based on anticholinergics and pegsunercept
CA2515534A1 (en) New pharmaceutical compositions based on anticholinergics and tace-inhibitors
CA2515530A1 (en) New pharmaceutical compositions based on anticholinergics and inhibitors of tnf alpha synthesis or action

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: 19840553

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19840553

Country of ref document: EP

Kind code of ref document: A1