WO2024051683A1 - 预防或治疗呼吸系统疾病的吸入用药物组合物 - Google Patents

预防或治疗呼吸系统疾病的吸入用药物组合物 Download PDF

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WO2024051683A1
WO2024051683A1 PCT/CN2023/116985 CN2023116985W WO2024051683A1 WO 2024051683 A1 WO2024051683 A1 WO 2024051683A1 CN 2023116985 W CN2023116985 W CN 2023116985W WO 2024051683 A1 WO2024051683 A1 WO 2024051683A1
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composition
optionally
long
acting
cyclodextrin
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PCT/CN2023/116985
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French (fr)
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李君宁
刘阳
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立生医药(苏州)有限公司
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/44—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
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • 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
    • 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
    • A61P11/08—Bronchodilators

Definitions

  • the present application relates to the field of drugs for preventing or treating diseases, and more specifically, to an inhaled pharmaceutical composition for preventing or treating respiratory diseases such as asthma and chronic obstructive pulmonary disease.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • airflow limitation that is not fully reversible. Airflow obstruction is often progressive and is associated with an abnormal inflammatory response of the lungs to toxic particles or gases, primarily caused by smoking.
  • COPD affects the lungs, it also has significant systemic effects. COPD is associated with excessive mucus secretion, emphysema, and bronchitis.
  • COPD treatment The main goals of COPD treatment include smoking cessation, relieving symptoms, improving physical function, and limiting complications such as ventilatory abnormalities and disease flare-ups.
  • maintenance health care such as smoking cessation, avoidance of indoor and outdoor pollutants and allergens and occupational exposure to allergens, and the gradual use of medications and complementary therapies as the disease progresses.
  • Current therapies to treat or prevent COPD and asthma include the use of long-acting bronchodilators or one or more inhaled corticosteroids (ICS).
  • ICS inhaled corticosteroids
  • Current therapies to treat or prevent COPD and asthma include one or more combinations of long-acting bronchodilators and inhaled corticosteroids.
  • Inhaled bronchodilators are the cornerstone of COPD therapy because of their ability to relieve symptoms, reduce flare-ups, and improve quality of life. These drugs also improve airflow limitation and hyperinflation, thereby reducing respiratory activity and improving exercise tolerance. Furthermore, bronchodilators reduce respiratory muscle fatigue and improve mucociliary clearance.
  • bronchodilator options include beta 2 agonists and anticholinergic drugs.
  • beta 2 agonists may be short-acting for immediate relief of asthma symptoms, or long-acting for long-term prevention of asthma symptoms.
  • LABA Long-acting beta - agonists
  • ULABA ultra-long-acting beta - agonists
  • LABA causes bronchiectasis by causing prolonged relaxation of airway smooth muscles.
  • LABA also exerts other effects, such as inhibition of airway smooth muscle cell proliferation and inflammatory mediator release, as well as non-smooth muscle effects, such as stimulation of mucociliary transport function, cytoprotection of the respiratory mucosa, and attenuation of neutrophils. Recruitment and activation.
  • LABA low-density polypeptide
  • ULABAs include indacaterol, vilanterol, and carmotrol. Rowe and Odatro.
  • Anticholinergic drugs are also used as bronchodilators and are potential alternatives to beta 2 agonists, especially LABA. However, anticholinergic drugs can also be taken with LABA to treat asthma. Anticholinergic drugs work by competing with acetylcholine for receptor sites on the vagus nerve or neuromuscular node. This prevents the transmission of reflexes induced by asthmatic irritants.
  • anticholinergic drugs offers advantages in elderly patients because responsiveness to beta 2 agonists decreases with age. Furthermore, the use of anticholinergic drugs would also be advantageous in patients who are intolerant to the use of beta 2 agonists.
  • beta -2 agonists and anticholinergic drugs provide symptomatic relief of bronchoconstriction
  • COPD as another element of inflammation requires separate treatment with steroids.
  • Most inhaled corticosteroids require multiple doses.
  • Corticosteroids show inhibitory effects on inflammatory cells and inflammatory mediators involved in the pathology of respiratory conditions such as COPD. Treatment with corticosteroids/glucocorticoids is considered to be one of the most promising and effective treatments for COPD currently available.
  • corticosteroid use has been limited due to possible side effects associated with their use, including suppression of the hypothalamic–pituitary–adrenal (HPA) axis, adverse effects on bone growth in children, and bone density in the elderly. , ophthalmic complications (cataract formation and glaucoma) and skin atrophy.
  • HPA hypothalamic–pituitary–adrenal
  • Treatment options for acute exacerbations of COPD remain limited, including bronchodilators, inhaled corticosteroids, and antibiotics, and new, effective anti-inflammatory drugs are needed.
  • Inhaled high molecular weight hyaluronic acid shortens the duration of respiratory failure and non-invasive ventilation in patients with acute exacerbations of COPD, according to preliminary findings published in Respiratory Research.
  • High molecular weight hyaluronic acid is a naturally occurring sugar that is abundant in the cell matrix, including in the lungs. Has multiple properties that make it an attractive candidate for treatment of acute exacerbations of COPD.
  • inhaled pharmaceutical compositions containing a combination of LABA and inhaled corticosteroids.
  • An example of this combination used to treat asthma and chronic obstructive pulmonary disease is salmeterol/fluticasone propionate ( diskus and HFA) and formoterol fumarate dihydrate/budesonide.
  • combination therapy with bronchodilators and ICS may improve lung efficiency, reduce inflammatory responses and provide symptom relief compared to high doses of ICS by itself.
  • the choice of specific bronchodilators and ICS plays a very important role in the formulation of fixed-dose combination therapy.
  • combination therapy reduces costs and provides control of respiratory conditions.
  • Minimizing dosing frequency is a major step in simplifying COPD treatment in order to improve patient compliance with therapy.
  • US 2009/0088408 A1 discloses a pharmaceutical composition of anticholinergic drugs, corticosteroids and P mimetic and its application in the treatment of respiratory diseases.
  • An example of this application is an inhalable powder or suspension aerosol composition containing tiotropium bromide or ipratropium bromide.
  • US 2005/0042174 A1 discloses the combined administration of beta 2 agonists, anticholinergic drugs and anti-inflammatory steroids.
  • WO 2006/105401 A1 discloses anticholinergic drugs in combination with corticosteroids and long-acting beta 2 agonists for simultaneous or sequential use in the prevention or treatment of respiratory, inflammatory or obstructive airway diseases.
  • US 2008/0279948 A1 discloses a medicament containing a beta 2 agonist, glycopyrrolate and mometasone furoate.
  • Examples of this application include the beta 2 agonist indacaterol maleate.
  • US 2008/0286363 A1 discloses a drug containing a beta 2 agonist (such as indacaterol maleate), glycopyrrolate and a corticosteroid.
  • a beta 2 agonist such as indacaterol maleate
  • glycopyrrolate such as glycopyrrolate
  • corticosteroid examples include corticosteroids: 3-methylthiophene-2-carboxylic acid-(6S,9R,10S,11S,13S,16R,17R)-9-chloro-6-fluoro-11-hydroxy-17-methyl Oxycarbonyl-10,13,16-trimethyl-3-oxyylidene-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- Cyclopent[a]phenanthrene-17-yl ester.
  • US 2010/0166671 A1 discloses a drug containing an antimuscarinic agent, a beta 2 agonist and a corticosteroid.
  • examples of this application include glycopyrrolate, formoterol fumarate and mometasone furoate.
  • US 7,439,393 B2 discloses certain phenylethanolamine derivatives for the treatment of respiratory diseases. The use of this compound in combination therapy with other therapeutic agents is also disclosed.
  • US 2008/0041369 A1 discloses a propellant-free aerosol formulation, which in particular contains olodaterol, a corticosteroid (such as budesonide, beclomethasone or fluticasone) and an anticholinergic drug (such as tiotropium bromide) , oxitropium bromide or ipratropium).
  • olodaterol such as budesonide, beclomethasone or fluticasone
  • an anticholinergic drug such as tiotropium bromide
  • oxitropium bromide oxitropium bromide or ipratropium
  • US 2005/0239778 A1 discloses a pharmaceutical combination comprising in particular olodaterol and at least one other active substance such as a steroid.
  • US 2008/0317862 A1 discloses medicines containing antimuscarinic agents and corticosteroids for the treatment of inflammatory or obstructive airway diseases.
  • this application discloses an aerosol composition comprising glycopyrrolate and mometasone furoate.
  • US 2006/0069073 A1 discloses a combination of glycopyrronium and one or more steroids as a second active substance.
  • CN 112804997 A discloses an inhalation solution of a combination of indacaterol maleate and glycopyrrolate.
  • TW 202012369 A1 discloses a propellant-free aerosol preparation, which particularly contains glycopyrrolate pharmaceutically acceptable salts, indacaterol pharmaceutically acceptable salts and water. It is also disclosed that the combination is particularly suitable for forming an aerosol of active drugs using a nebulizer for the treatment of asthma and COPD.
  • CN 109715160 A discloses an aerosol containing indacaterol or a derivative thereof.
  • the components additionally include at least one pharmaceutically acceptable salt of glycopyrrolate or at least one corticosteroid (such as budesonide, mometasone, beclomethasone, fluticasone and their pharmaceutically acceptable salts).
  • US 2021/0322311 A1 discloses a propellant-free liquid preparation, which specifically contains tiotropium bromide and olodaterol and physiologically acceptable salts thereof.
  • US 7,056,916 B2 discloses inhalation preparations containing olodaterol, including inhalation powder mist, aerosol containing booster or inhalation solution without booster.
  • US 2020/0368214 A1 discloses a booster-free inhalation spray, which specifically contains vilanterol or umeclidinium bromide or a drug combination of both vilanterol and umeclidinium bromide.
  • WO 2021/009573 A1 discloses a pressure vessel using a polymer or copolymer as an internal coating.
  • the pressure vessel specifically contains umeclidinium bromide or vilanterol or a pharmaceutical combination of the two.
  • WO 2020/100040 A1 discloses an inhaler containing a booster, which specifically contains a pharmaceutical combination and formula of umeclidinium bromide and vilanterol.
  • CN 112752572 A discloses a liquid, propellant-free pharmaceutical preparation and a method of using the medicine by atomizing the pharmaceutical preparation in an inhaler.
  • the liquid, propellant-free pharmaceutical preparation particularly contains an active substance selected from the group consisting of umeclidinium bromide, vilanterol triphenyl acetate and combinations thereof.
  • WO 2020/220855 A1 discloses a booster-free aerosol inhalation preparation and its preparation method.
  • the preparation particularly contains the active ingredients umeclidinium bromide and vilanterol.
  • the drug combination containing umeclidinium bromide and vilanterol has good stability, does not contain propellant, and the size of the atomized droplets is conducive to lung inhalation.
  • CN 113274596 A discloses a pressurized metering tank for treating respiratory diseases.
  • the tank contains at least a preparation of corticosteroid, LABA agent, LAMA agent and HFA152a or HFO propellant.
  • this application involves aerosols containing formoterol, beclomethasone, and glycopyrronium bromide.
  • CN 111150728 A discloses a stable pressurized aerosol solution composition of glycopyrrolate and formoterol.
  • WO 2020/229966 A1 discloses a stable suspension aerosol containing glycopyrrolate.
  • the aerosol formulation also contains one or more beta 2 agonists.
  • An example of this application is a combination aerosol containing glycopyrrolate and formoterol.
  • CN 112804991 A discloses a propellant-free liquid preparation and a method for atomizing it through an inhaler.
  • the formulation is a combination aerosol of umeclidinium bromide and formoterol.
  • WO 2020/084549 A1 discloses the composition and preparation method of an aerosol containing glycopyrrolate and formoterol, which is used for the treatment of pneumonia and obstructive airway diseases.
  • US 2018/0104184 A1 discloses the composition and preparation method of an aerosol containing tiotropium bromide and formoterol for the treatment of pneumonia and obstructive airway diseases.
  • US 6,433,027 B1 discloses a new pharmaceutical composition of anticholinergic compounds and its preparation process.
  • An example of this application is an inhalation spray containing cetiobromide and formoterol.
  • CN 111481550 A discloses a pharmaceutical combination containing tiotropium bromide and arformoterol. Examples of applications include aerosols and inhalation nebulizers containing both active ingredients.
  • WO 2010/048384 A1 discloses a composition and method for preventing and/or treating airway and/or respiratory diseases.
  • this application discloses an inhalation liquid formulation comprising arformoterol ((R,R)-formoterol) and tiotropium bromide.
  • CN 107233311 A discloses an atomizer with arformoterol and glycopyrrolate as active ingredients and a preparation method thereof.
  • US 2017/0027908 A1 or JP 2017-061456 A discloses an inhaled pharmaceutical composition for preventing and/or treating respiratory, inflammatory or obstructive airway diseases. It contains, inter alia, glycopyrronium bromide, beta 2 agonists and corticosteroids.
  • a pharmaceutical composition for inhalation including one or more bronchodilators, particularly long-acting beta 2 agonists and long-acting muscarinic antagonists.
  • one or more bronchodilators, particularly long-acting ⁇ 2 agonists and long-acting muscarinic antagonists are provided in the preparation of inhaled medicaments for the prevention and/or treatment of respiratory diseases.
  • Uses of the composition are also provided.
  • use of the pharmaceutical composition for preventing and/or treating respiratory diseases is also provided.
  • the pharmaceutical composition is used to prevent and/or treat respiratory diseases.
  • methods of preventing and/or treating respiratory diseases are provided, comprising administering the pharmaceutical composition.
  • respiratory disease includes respiratory, inflammatory or obstructive airway disease. In some embodiments, the respiratory disease includes asthma. In some embodiments, the respiratory disease includes chronic obstructive pulmonary disease.
  • the long-acting beta 2 agonist includes or consists of olodaterol.
  • the long-acting ⁇ 2 agonist includes or consists of Arformoterol, and the pH of the composition is 3.0-5.5, such as 3.5-5.5, such as 4.0-5.5, more such as 4.5–5.5.
  • the long-acting beta 2 agonist includes or consists of indacaterol, and the pH of the composition is 2.5-4.5, such as 3.0-4.5, or such as 2.5-4.0, or more For example, 3.0–4.0.
  • the long-acting muscarinic antagonist includes or consists of Revefenacin, and the pH of the composition is 3.5-5.5, such as 4.0-5.5, more such as 4.5-5.5. In some embodiments, the long-acting muscarinic antagonist includes or consists of Glycopyrronium bromide, and the pH value of the composition is 2.5-4.5, such as 2.5-4.0, more such as 2.5-3.5 . In some embodiments, the long-acting muscarinic antagonist includes or consists of Tiotropium, and the pH of the composition is 2.0-4.0, such as 2.5-4.0, more such as 2.5-3.5.
  • the long-acting beta 2 agonist includes indacaterol, formoterol, arformoterol, vilanterol, carmoterol, and at least one of the groups of which Odatro belongs, or consists of.
  • the long-acting muscarinic antagonist includes glycopyrronium bromide, Umeclidinium, Tiotropium, Aclidinium bromide, and At least one of the groups of which phenacin is composed, or consists of.
  • the long-acting beta 2 agonist includes indacaterol and the long-acting muscarinic antagonist includes glycopyrrolate. In some embodiments, the long-acting beta 2 agonist includes indacaterol and the long-acting muscarinic antagonist includes umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes indacaterol and the long-acting muscarinic antagonist includes tiotropium bromide. In some embodiments, the long-acting beta 2 agonist includes indacaterol and the long-acting muscarinic antagonist includes aclidinium bromide.
  • the long-acting beta 2 agonist includes indacaterol and the long-acting muscarinic antagonist includes raphenacin. In some embodiments, the long-acting beta 2 agonist includes formoterol and the long-acting muscarinic antagonist includes glycopyrrolate. exist In some embodiments, the long-acting beta 2 agonist includes formoterol and the long-acting muscarinic antagonist includes umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes formoterol and the long-acting muscarinic antagonist includes tiotropium bromide.
  • the long-acting beta 2 agonist includes formoterol and the long-acting muscarinic antagonist includes aclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes formoterol and the long-acting muscarinic antagonist includes raphenacin. In some embodiments, the long-acting beta 2 agonist includes arformoterol and the long-acting muscarinic antagonist includes glycopyrrolate. In some embodiments, the long-acting beta 2 agonist includes arformoterol and the long-acting muscarinic antagonist includes umeclidinium bromide.
  • the long-acting beta 2 agonist includes arformoterol and the long-acting muscarinic antagonist includes tiotropium bromide. In some embodiments, the long-acting beta 2 agonist includes arformoterol and the long-acting muscarinic antagonist includes aclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes arformoterol and the long-acting muscarinic antagonist includes raphenacin. In some embodiments, the long-acting beta 2 agonist includes vilanterol and the long-acting muscarinic antagonist includes glycopyrrolate.
  • the long-acting beta 2 agonist includes vilanterol and the long-acting muscarinic antagonist includes umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes vilanterol and the long-acting muscarinic antagonist includes tiotropium bromide. In some embodiments, the long-acting beta 2 agonist includes vilanterol and the long-acting muscarinic antagonist includes aclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes vilanterol and the long-acting muscarinic antagonist includes raphenacin.
  • the long-acting beta 2 agonist includes carmoterol and the long-acting muscarinic antagonist includes glycopyrrolate. In some embodiments, the long-acting beta 2 agonist includes carmoterol and the long-acting muscarinic antagonist includes umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes carmoterol and the long-acting muscarinic antagonist includes tiotropium bromide. In some embodiments, the long-acting beta 2 agonist includes carmoterol and the long-acting muscarinic antagonist includes aclidinium bromide.
  • the long-acting beta 2 agonist includes carmoterol and the long-acting muscarinic antagonist includes raphenacin. In some embodiments, the long-acting beta 2 agonist includes olodaterol and the long-acting muscarinic antagonist includes glycopyrrolate. In some embodiments, the long-acting beta 2 agonist includes olodaterol and the long-acting muscarinic antagonist includes umeclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes olodaterol and the long-acting muscarinic antagonist includes tiotropium bromide.
  • the long-acting beta 2 agonist includes olodaterol and the long-acting muscarinic antagonist includes aclidinium bromide. In some embodiments, the long-acting beta 2 agonist includes olodaterol and the long-acting muscarinic antagonist includes raphenacin.
  • the content of the long-acting ⁇ 2 agonist is 1-100 ⁇ g/mL, such as 5-100 ⁇ g/mL, such as 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9 ,9.5,10,10.5,11,11.5,12,12.5,13,14,15,16,17,18,19,20,22,24,25,26,28,30,35,40,45,50 , 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 ⁇ g/mL or a range between any two of them.
  • the content of the long-acting muscarinic antagonist is 1-100 ⁇ g/mL, such as 5-100 ⁇ g/mL, such as 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 25, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 ⁇ g/mL or a range between any two of them.
  • the weight ratio of the long-acting ⁇ 2 agonist and the long-acting muscarinic antagonist is 100:1-1:100, such as 1:80-80:1, more such as 1 :60–60:1, for example 1:50–50:1, for example 1:40–40:1, for example 1:30–30:1, for example 1:20–20:1 , for example 1:15–15:1.
  • the weight ratio of the long-acting ⁇ 2 agonist and the long-acting muscarinic antagonist is 100:1-1:1, such as 1:80-1:1, more such as 1 :60–1:1, for example 1:50–1:1, for example 1:40–1:1, for example 1:30–1:1, for example 1:20–1:1 , for example 1:15–1:1.
  • the weight ratio of the long-acting ⁇ 2 agonist and the long-acting muscarinic antagonist is 1:1-1:100, such as 1:1-80:1, more such as 1 :1–60:1, for example 1:1–50:1, for example 1:1–40:1, for example 1:1–30:1, for example 1:1–20:1 , for example 1:1–15:1.
  • the composition further includes hyaluronic acid.
  • the hyaluronic acid is high molecular weight hyaluronic acid (HMW-HA).
  • HMW-HA high molecular weight hyaluronic acid
  • the weight percent of hyaluronic acid is less than 0.500%.
  • the weight percentage of hyaluronic acid is 0.001%-0.500%, such as 0.010%-0.400%, such as 0.100%-0.300%, such as 0.300%.
  • high molecular weight hyaluronic acid has a molecular weight in the range of 1,000,000-10,000,000 daltons.
  • the pharmaceutical composition further includes sodium chloride, ethylenediaminetetraacetic acid (EDTA), and/or cyclodextrin. In some embodiments, the pharmaceutical composition further includes sodium chloride. In some embodiments, the pharmaceutical composition further includes EDTA, or cyclodextrin. In some embodiments, the pharmaceutical composition further includes EDTA. In some embodiments, the pharmaceutical composition further includes cyclodextrin. In some embodiments, the pharmaceutical composition further includes EDTA, and cyclodextrin. In some embodiments, the pharmaceutical composition further includes Tween, such as Tween 80. In some embodiments, the pharmaceutical composition further includes oleic acid. In some embodiments, the composition further includes a glucocorticoid.
  • the cyclodextrin includes alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin. In some embodiments, the cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, and gamma-cyclodextrin. In some embodiments, the cyclodextrin includes or consists of alpha-cyclodextrin. In some embodiments, the cyclodextrin includes or consists of beta-cyclodextrin. In some embodiments, the cyclodextrin includes or consists of gamma-cyclodextrin.
  • the cyclodextrin includes hydroxypropyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin.
  • the cyclodextrin is selected from the group consisting of hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin.
  • the cyclodextrin includes or consists of hydroxypropyl- ⁇ -cyclodextrin.
  • the cyclodextrin includes or consists of sulfobutyl- ⁇ -cyclodextrin.
  • the weight percentage of sodium chloride is less than 1.00%. In some embodiments, the weight percentage of sodium chloride is 0.01%-1.00%, such as 0.10%-1.00%, more such as 0.50%-1.00%, more such as 0.85%. In some embodiments, the weight percentage of EDTA is less than 0.100%. In some embodiments, the weight percentage of EDTA is 0.001%-0.100%, such as 0.010%-0.050%, such as 0.020%-0.040%, such as 0.030%. In some embodiments, the weight percentage of the cyclodextrin is less than 10%, such as 5.0% or less, such as 2.5% or less, such as 1.50% or less.
  • the weight percentage of the cyclodextrin is 0.01%-10%, such as 0.01%-5.0%, such as 0.01%-2.5%, such as 0.01%-1.50%, such as 0.01%- 1.00%, for example 0.10%–1.00%, for example 0.20%–0.80%, for example 0.25%–0.75%, for example 0.30%–0.70%, for example 0.40%–0.60%, for example 0.50%.
  • the weight percentage of Tween is less than 0.100%.
  • the weight percentage of Tween is 0.001%-0.100%, such as 0.010%-0.050%, such as 0.020%-0.040%, such as 0.030%.
  • the pharmaceutical composition further includes a buffer, such as a citric acid/citrate buffer, more such as a citric acid/sodium citrate buffer.
  • the pharmaceutical composition further includes a pH adjuster, such as hydrochloric acid, more such as dilute hydrochloric acid.
  • the long-acting beta 2 agonist includes olodaterol and the long-acting muscarinic antagonist includes raphenacin.
  • the long-acting beta 2 agonist includes olodaterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the pH of the composition is 4.0-5.5.
  • the long-acting beta 2 agonist includes olodaterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the composition further includes EDTA.
  • the long-acting beta 2 agonist includes arformoterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the pH of the composition is 4.0-5.5, for example, 4.5 –5.5, or for example 4.0–5.0.
  • the long-acting beta 2 agonist includes arformoterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the composition further includes EDTA.
  • the long-acting ⁇ 2 agonist includes arformoterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the composition further includes a buffer, such as citric acid/lemon A salt buffer, for example, is a citric acid/sodium citrate buffer.
  • the long-acting ⁇ 2 agonist includes arformoterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the composition further includes a buffer, such as citric acid/lemon
  • the acid salt buffer is, for example, a citric acid/sodium citrate buffer, and the concentration of the buffer is above 0.1mM, for example, 0.1mM to 20mM, for example, 0.1mM to 10mM, and for example, 1mM to 10mM.
  • the long-acting beta 2 agonist includes arformoterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the composition further includes sodium chloride, for example, in a weight percent of Sodium chloride below 1.00%, for example, sodium chloride in a weight percentage of 0.01%-1.00%.
  • the long-acting beta 2 agonist includes indacaterol
  • the long-acting muscarinic antagonist includes glycopyrrolate
  • the pH of the composition is 2.5-4.0, for example, 3.0–4.0, or for example 2.5–3.5, for example 3.0–3.5, for example 3.5.
  • the long-acting beta 2 agonist includes indacaterol
  • the long-acting muscarinic antagonist includes glycopyrrolate
  • the composition further includes EDTA and/or cyclodextrin, For example, it includes cyclodextrin, and for example, it includes EDTA and cyclodextrin.
  • the long-acting beta 2 agonist includes indacaterol, the long-acting muscarinic antagonist includes glycopyrrolate, and the composition further includes sodium hyaluronate.
  • the long-acting beta 2 agonist includes indacaterol, the long-acting muscarinic antagonist includes glycopyrrolate, and the composition further includes sodium hyaluronate, and a compound selected from the group consisting of At least one from the group consisting of EDTA and cyclodextrin.
  • the long-acting beta 2 agonist includes indacaterol, the long-acting muscarinic antagonist includes glycopyrrolate, and the composition further includes sodium hyaluronate and cyclodextrin .
  • the long-acting beta 2 agonist includes indacaterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the pH of the composition is 3.0-4.5, for example, 3.5–4.5, for example 3.5–4.0, or 4.0–4.5, for example 4.0.
  • the long-acting beta 2 agonist includes indacaterol
  • the long-acting muscarinic antagonist includes raphenacin
  • the composition further includes EDTA and/or cyclodextrin, For example, it includes cyclodextrin, and for example, it includes EDTA and cyclodextrin.
  • the long-acting beta 2 agonist includes indacaterol
  • the long-acting muscarinic antagonist includes tiotropium bromide
  • the pH of the composition is 2.0-4.0, for example, 2.5–4.0, for example 2.5–3.5, for example 2.5–3.0, for example 2.5.
  • the long-acting beta 2 agonist includes indacaterol
  • the long-acting muscarinic antagonist includes tiotropium bromide
  • the composition further includes a cyclodextrin.
  • the composition is a pharmaceutical composition for aerosol inhalation. In some embodiments, the composition is a pharmaceutical composition for aerosol inhalation administered via a vibrating screen, ultrasonic spray, or air compressor.
  • the pharmaceutical composition is an inhalation spray (Soft Mist), an aerosol (MDI) or a nebulizer (Nebulizer).
  • the pharmaceutical composition is administered via a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • the pharmaceutical composition further includes excipients, propellants, co-solvents, fillers, non-volatile components, buffers, pH adjustment One or more auxiliary materials such as regulators, surfactants, preservatives, complexing agents, antioxidants, or combinations thereof.
  • the pharmaceutical composition is a spray
  • the preparation method of the spray includes mixing a bronchodilator and high molecular weight hyaluronic acid in a solvent, especially mixing a long-acting beta 2 agonist, a long-acting toxin muscarinic antagonists, and high molecular weight hyaluronic acid.
  • the pharmaceutical composition is an aerosol
  • the preparation method of the aerosol includes mixing a bronchodilator, high molecular weight hyaluronic acid, and a propellant in a solvent, especially mixing long-acting beta 2 Agonists, long-acting muscarinic antagonists, high molecular weight hyaluronic acid, and propellants.
  • the propellant is a hydrofluoroalkane.
  • the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane and/or 1,1,1,2,3,3,3-heptafluoropropane.
  • the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane. In some embodiments, the hydrofluoroalkane is 1,1,1,2,3,3,3-heptafluoropropane. In some embodiments, the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane.
  • the active substances of the pharmaceutical composition are present in fixed or free combination for simultaneous, sequential or separate administration with excipients in a pharmaceutical form suitable for inhalation application.
  • long-acting ⁇ 2 agonists long-acting muscarinic antagonists or other components
  • indacaterol formoterol, arformoterol, vilanterol , carmoterol, and olodaterol
  • glycopyrronium bromide umeclidinium bromide
  • tiotropium bromide tiotropium bromide
  • refenacin hyaluronic acids
  • EDTA high molecular weight hyaluronic acid
  • Oleic acid acetic acid, ...etc.
  • the pharmaceutical composition of the present application includes long-acting beta 2 agonists and long-acting muscarinic antagonists
  • the pharmaceutical composition of the application includes a long-acting beta 2 agonist or a pharmaceutically acceptable salt thereof, and a long-acting muscarinic antagonist or a pharmaceutically acceptable salt thereof
  • the embodiments of the application refer to References in these embodiments of the present application to pharmaceutical compositions including EDTA shall be deemed to refer to pharmaceutical compositions of the present application including EDTA and pharmaceutically acceptable salts thereof; and so on.
  • Figure 1 illustrates the changes in the content of raphenacin in the stability test of the arformoterol tartrate-refenacin composition with different buffer concentrations.
  • Figure 2 illustrates the changes in arformoterol content during the stability test of the arformoterol tartrate-refenacin composition with different buffer concentrations.
  • Figure 3 illustrates the change in pH value during the stability test of the arformoterol tartrate-refenacin composition with different buffer concentrations.
  • Figure 4 illustrates the changes in the content of raphenacin in the stability test of the arformoterol tartrate-refenacin composition with different types of excipients.
  • Figure 5 illustrates the changes in arformoterol content during the stability test of the arformoterol tartrate-refenacin composition with different types of excipients.
  • Figure 6 illustrates the changes in indacaterol content in the stability test of indacaterol maleate-glycopyrrolate compositions with different pH values.
  • Figure 7 illustrates the changes in glycopyrrolate content during the stability test of the indacaterol maleate-glycopyrrolate composition with different types of excipients.
  • Figure 8 illustrates the changes in total impurity content during the stability test of the indacaterol maleate-glycopyrrolate composition with different types of excipients.
  • Figure 9 illustrates the changes in indacaterol content and glycopyrrolate content in the stability test of the indacaterol maleate-glycopyrrolate composition with a pH value of 4 with different types of excipients.
  • Figure 10 illustrates the changes in the total impurity content in the stability test of the indacaterol maleate-glycopyrrolate composition with a pH value of 4 with different types of excipients.
  • Figure 11 illustrates the changes in indacaterol content and glycopyrrolate content in the stability test of the indacaterol maleate-glycopyrrolate composition with a pH value of 3 with different types of excipients.
  • Figure 12 illustrates the changes in the total impurity content in the stability test of the indacaterol maleate-glycopyrrolate composition with a pH value of 3 with different types of excipients.
  • Figure 13 shows the indacaterol content and glycopyrrolate content in the stability test of the indacaterol maleate-glycopyrrolate-sodium hyaluronate composition with a pH value of 4 with different types of excipients. The change.
  • Figure 14 illustrates the changes in the total impurity content in the stability test of the indacaterol maleate-glycopyrrolate-sodium hyaluronate composition with a pH value of 4 with different types of excipients.
  • Figure 15 shows the indacaterol content and glycopyrronium bromide content in the stability test of the indacaterol maleate-glycopyrrolate-sodium hyaluronate composition with a pH value of 3 with different types of excipients. The change.
  • Figure 16 illustrates the changes in the total impurity content in the stability test of the indacaterol maleate-glycopyrrolate-sodium hyaluronate composition with a pH value of 3 with different types of excipients.
  • Figure 17 illustrates the changes in indacaterol content in the stability test of indacaterol maleate-refenacin compositions with different pH values.
  • Figure 18 illustrates the changes in indacaterol content in the stability test of indacaterol maleate-refenacin compositions with different pH values.
  • Figure 19 illustrates changes in the total impurity content in the stability test of the indacaterol maleate-refenacin composition at different pH values.
  • Figure 20 illustrates the changes in the total impurity content in the stability test of the indacaterol maleate-refenacin composition with a pH value of 4 with different types of excipients.
  • Figure 21 illustrates the changes in the total impurity content of indacaterol maleate-tiotropium bromide compositions at different pH values during the stability test.
  • Figure 22 illustrates changes in the total impurity content of tiotropium bromide in the stability test of indacaterol maleate-tiotropium bromide compositions with different pH values.
  • Figure 23 illustrates the changes in the total impurity content during the stability test of the indacaterol maleate-tiotropium bromide composition with a pH value of 3 by adding different types of excipients.
  • Figure 24 illustrates the change in total impurity content in the stability test of the indacaterol maleate-tiotropium bromide composition with a pH value of 3, 4, or 5 with or without the addition of sodium hyaluronate.
  • the term “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items.
  • the term “and/or” (alternatively “and/or”, “and/or") means that any of the listed items may be used alone, or Any combination of two or more of the listed items may be used.
  • compositions or combination, construction, proposition, etc.
  • the composition can contain A alone, B alone, C alone, D alone, a combination of A and B, a combination of A and C, or a combination of A and Combination of D, Combination of B and C, Combination of B and D, Combination of C and D, Combination of A, B and C, Combination of A, B and D, Combination of A, C and D A combination containing B, C and D, or a combination containing A, B, C and D.
  • the numerical value may be ⁇ 0.1% of the stated value (or range of values), ⁇ 1% of the stated value (or range of values), ⁇ 2% of the stated value (or range of values), the stated value (or range of values) ⁇ 5% of the stated value (or range of values), ⁇ 10% of the stated value (or range of values), ⁇ 15% of the stated value (or range of values), ⁇ 20% of the stated value (or range of values), etc.
  • Any numerical range stated herein is intended to include all subranges or intervening values subsumed therein.
  • Example 1 Stability test of olodaterol hydrochloride-refenacin composition in the presence of different pH values and EDTA
  • arformoterol tartrate inhalation solution has a long-term storage condition of 2–8°C and an accelerated storage condition of 25 ⁇ 2°C. It can be stored for 3 months under accelerated conditions.
  • Example 3 Stability test of arformoterol tartrate-refenacin-hyaluronic acid composition at different pH values and different EDTA concentrations
  • Figure 1 shows the changes in the content of raphenacin in the stability test of the arformoterol-rafenacin composition with different buffer concentrations.
  • Figure 2 shows the changes in arformoterol content during the stability test of arformoterol-refenacin compositions with different buffer concentrations.
  • Figure 3 shows the change in pH value during the stability test of the arformoterol-refenacin composition with different buffer concentrations.
  • adding the pH buffer is beneficial to product stability; at the same time, as the concentration of the pH buffer increases, the stability of the active pharmaceutical ingredients raphenacin and arformoterol is significantly improved, and the pH also increases during the placement period. more stable.
  • the content of rafenacin in the arformoterol tartrate-rafenacin composition with a pH value in the range of 4.5–5.5 is reduced within 5%, and the medicinal solution Relatively stable; after being stored at 25°C and 60% RH for 2 months, the arformoterol content in the arformoterol-refenacin tartrate composition with a pH value in the range of 4.5–5.5 decreased within 5%.
  • Arformoterol solution is sensitive to temperature, and its commercially available single solution product can be stored for 6 weeks at 25°C and 60% RH. It is further stated that in some embodiments, the composition has a pH value in the range of 4.5-5.5 More stable.
  • Example 7 Stability test of indacaterol maleate-glycopyrrolate composition at different pH values
  • Figure 6 shows the changes in indacaterol content in the stability test of indacaterol maleate-glycopyrrolate compositions with different pH values.
  • Figure 7 shows the changes in glycopyrrolate content during the stability test of the indacaterol maleate-glycopyrrolate composition with different types of excipients.
  • Figure 8 shows the changes in total impurity content during the stability test of the indacaterol maleate-glycopyrrolate composition with different types of excipients.
  • indacaterol is more stable between pH 2.5-4, and is best at pH 3.5, while glycopyrrolate is more stable at pH 2.5-3.5, based on the contents of indacaterol and glycopyrrolate and total impurities Content changes determine that in some embodiments, the optimal pH of the indacaterol-glycopyrrolate composition is 3.5.
  • Figure 11 shows the changes in indacaterol content and glycopyrrolate content in the stability test of the indacaterol maleate-glycopyrrolate composition with a pH value of 3 with different types of excipients.
  • Figure 12 shows the changes in the total impurity content in the stability test of the indacaterol maleate-glycopyrrolate composition with a pH value of 3 with different types of excipients.
  • Example 9 Stability test of indacaterol maleate-glycopyrrolate-sodium hyaluronate composition with excipients added
  • Figure 14 shows the changes in total impurity content in the stability test of the indacaterol maleate-glycopyrrolate-sodium hyaluronate composition with a pH value of 4 with different types of excipients.
  • Figure 15 shows the changes in indacaterol content and glycopyrrolate content in the stability test of the indacaterol maleate-glycopyrrolate-sodium hyaluronate composition with a pH value of 3 with different types of excipients.
  • Figure 16 shows the changes in total impurity content in the stability test of the indacaterol maleate-glycopyrrolate-sodium hyaluronate composition with a pH value of 3 with different types of excipients.
  • Example 10 Stability test of indacaterol maleate-refenacin composition at different pH values
  • citric acid/sodium citrate buffers with pHs of 2.5, 3.0, 3.5, 4.0, and 5.5 at a concentration of 20mM.
  • indacaterol maleate according to the following recipe, and sonicate until completely dissolved.
  • sodium chloride and raphenacin and stir until completely dissolved.
  • the prepared experimental formula is shown in Table 19.
  • Figure 17 shows the changes in indacaterol content in the stability test of indacaterol maleate-refenacin compositions with different pH values.
  • Figure 18 shows the changes in indacaterol content in the stability test of indacaterol maleate-refenacin compositions with different pH values.
  • Figure 19 shows the changes in total impurity content in the stability test of indacaterol maleate-refenacin compositions with different pH values.
  • Example 10 In addition, the addition of EDTA (0.03% w/w) and cyclodextrin (0.05% w/w) to the indacaterol maleate-refenacin composition with a pH value of 4 in Example 10 was investigated. Effects of other excipients on the stability of medicinal solutions.
  • the experimental formula is shown in Table 21. Use citric acid and sodium citrate solutions to adjust the pH to the target pH, and put the prepared medicinal solution into a glass bottle and seal it.
  • Example 12 Stability test of indacaterol maleate-tiotropium bromide composition at different pH values
  • Example 12 In addition, the addition of EDTA (0.03% w/w) and cyclodextrin (0.05% w/w) to the indacaterol maleate-tiotropium bromide composition with a pH value of 3 in Example 12 was investigated. Effect of excipients on stability.
  • the experimental formula is shown in Table 25. Use citric acid and sodium citrate solutions to adjust the pH to the target pH, and put the prepared medicinal solution into a glass bottle and seal it.
  • Figure 23 shows the changes in total impurity content during the stability test of the indacaterol maleate-tiotropium bromide composition with a pH value of 3 by adding different types of excipients.
  • Example 12 the effect of adding sodium hyaluronate to the indacaterol maleate-tiotropium bromide composition with pH values of 3, 4, and 5 in Example 12 was investigated.
  • the experimental formula is shown in Table 27. Use citric acid and sodium citrate solutions to adjust the pH to the target pH, and put the prepared medicinal solution into a glass bottle and seal it.
  • Figure 24 shows the changes in the total impurity content in the stability test of the indacaterol maleate-tiotropium bromide composition with or without the addition of sodium hyaluronate with a pH value of 3, 4, or 5.
  • the terms “HA-free” and “HA-added” in Figure 24 mean “no sodium hyaluronate added” and “sodium hyaluronate added” respectively.
  • Table 33 Ingredient composition of olodaterol-refenacin-hyaluronic acid aerosol

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Abstract

公开了一种吸入用药物组合物，包括长效β2激动剂和长效毒蕈碱拮抗药。长效β2激动剂可包括奥达特罗；或长效β2激动剂可包括阿福特罗，且组合物的pH值可为3.5–5.5；或长效β2激动剂可包括茚达特罗，且组合物的pH值可为2.5–4.5；或长效毒蕈碱拮抗药可包括雷芬那辛，且组合物的pH值可为3.5–5.5；或长效毒蕈碱拮抗药可包括格隆溴铵，且组合物的pH值可为2.5–4.5；或长效毒蕈碱拮抗药包括噻托溴铵，且所述组合物的pH值为2.0–4.0。公开了所述药物组合物在制备预防或治疗哮喘、慢性阻塞性肺病等呼吸系统疾病的吸入用药物组合物的用途。

Description

预防或治疗呼吸系统疾病的吸入用药物组合物 技术领域
本申请涉及预防或治疗疾病的药物的领域，更具体涉及一种预防或治疗哮喘、慢性阻塞性肺病等呼吸系统疾病的吸入用药物组合物。
背景技术
慢性阻塞性肺病(COPD)是在世界上患病率不断增加的严重呼吸性病症。在中国预计患病率约1亿多，它目前是英国和美国的第四大死亡原因，2020年在全球疾病影响排到第三。
COPD是可预防和治疗的疾病，其特征在于非完全可逆的气流限制。气流阻塞通常是渐进的，与主要由抽烟引起的肺对有毒颗粒或气体的异常炎性响应有关。虽然COPD影响肺部，其也产生显著的全身性影响。COPD与粘液过度分泌、肺气肿、支气管炎有关。
COPD治疗的主要目标包括戒烟、缓解症状、改善生理机能和限制并发症，如换气异常和疾病的发作。不过，COPD治疗的整个手段涉及维持卫生保健的组合，如戒烟、避免室内室外污染物和过敏原以及避免职业性接触过敏原、随着疾病的进展逐步使用药物和补充治疗。
目前，治疗或预防COPD和哮喘的疗法包括使用长效支气管扩张剂或一种或多种吸入皮质类固醇(ICS)。
目前，治疗或预防COPD和哮喘的疗法包括使用长效支气管扩张剂和吸入皮质类固醇中的一种或多种联合用药。
吸入支气管扩张剂是COPD疗法的基础，因为其能够缓解症状、减少疾病发作和改善生活质量。这些药物还改善了气流限制和充气过度，从而减少呼吸活动并改善运动耐量。而且，支气管扩张剂可以减少呼吸肌疲劳和改善粘液纤毛清除功能。
更具体而言，支气管扩张剂的选择包括β2激动剂和抗胆碱能药物。而且β2激动剂可以是短效的以用于立即减轻哮喘症状，或者长效的以用于长期预防哮喘症状。
长效β2激动剂(LABA)或超长效β2激动剂(ULABA)在患有哮喘和COPD的患者中有改善肺功能、减少症状并防范运动诱发的呼吸困难的作用。LABA通过引起气道平滑肌的延长松弛而引起支气管扩张。除了延长的支气管扩张之外，LABA也发挥其他作用，如抑制气道平滑肌细胞增殖和炎性介质释放，以及非平滑肌作用，如刺激粘膜纤毛转运功能、呼吸道粘膜的细胞保护以及弱化中性粒细胞募集和活化。
另外，使用LABA减少了药物服用的频率。市售每日两次的LABA包括沙美特罗、福莫特罗、阿福特罗，市售每日一次的超长效β2激动剂ULABA包括茚达特罗、维兰特罗、卡莫特罗和奥达特罗。
抗胆碱能药物也用于支气管扩张剂，是β2激动剂、特别是LABA潜在的替代物。不过，抗胆碱能药物也可以与LABA一起服用来治疗哮喘。抗胆碱能药物通过与乙酰胆碱竞争迷走神经或神经肌肉结处的受体位点来发挥作用。这可防止由哮喘刺激物诱导的反射的传递。
使用抗胆碱能药物在老年患者中提供了有利之处，因为β2激动剂的响应性随着年龄增大而下降。而且在不耐受β2激动剂的使用的患者中使用抗胆碱能药物也将是有利的。
尽管β2激动剂和抗胆碱能药物提供了支气管收缩的症状缓解，但是COPD作为炎症的另一要素需要用类固醇进行单独治疗。大多数吸入皮质类固醇需要多次给药。
皮质类固醇显示出对如COPD等呼吸性病症的病理中涉及的炎性细胞和炎性介质的抑制作用。利用皮质类固醇/糖皮质激素进行治疗被认为是对于COPD目前已有的最有潜力和有效的疗法的一种。
不过，皮质类固醇使用一直受到限制，这是由于与其使用有关的可能的副作用，包括对下丘脑–脑垂体–肾上腺(HPA)轴的抑制、对儿童骨骼生长和对老年人的骨密度的不利影响、眼科并发症(白内障形成和青光眼)和皮肤萎缩。
COPD急性加重的治疗药物仍然有限，包括支气管扩张剂、吸入皮质类固醇和抗生素，并且需要新型、有效的抗炎药。根据发表在《呼吸研究》上的一项初步研究结果，吸入高分子量透明质酸可缩短COPD急性加重患者的呼吸衰竭持续时间和无创通气。高分子透明质酸是一种天然存在的糖，在细胞基质中含量丰富，包括在肺中。具有多种特性，使其成为急性加重COPD治疗剂的有吸引力的候选者。
目前存在若干市售的包含LABA和吸入皮质类固醇的组合的吸入用药物组合物。该组合用于治疗哮喘和慢性阻塞性肺病的实例为沙美特罗/丙酸氟替卡松(diskus与HFA)和富马酸福莫特罗二水合物/布地奈德。
因此，在受到如COPD等呼吸病症的影响的患者中，与高剂量的ICS本身相比，支气管扩张剂与ICS的联合疗法可改善肺效率、减少炎性反应和提供症状缓解。选择特定支气管扩张剂和ICS在固定剂量联合疗法的制剂中起到非常重要的作用。
而且，联合疗法降低了费用，还提供了对于呼吸性病症的控制。将剂量频率降至最低是为了改善患者对疗法的依从性而简化COPD治疗的主要步骤。
US 2009/0088408 A1公开了抗胆碱能药物、皮质类固醇和P模拟物的药物组合物及其在呼吸疾病的治疗中的应用。该应用的实例为含有噻托溴铵或异丙托溴铵的可吸入粉末或悬浮气雾剂组合物。
US 2005/0042174 A1公开了β2激动剂、抗胆碱能药物和抗炎性类固醇的联合给药。
WO 2006/105401 A1公开了抗胆碱能药物与皮质类固醇和长效β2激动剂组合，其用于同时或依次使用，来预防或治疗呼吸性、炎性或阻塞性气道疾病。
US 2008/0279948 A1公开了包含β2激动剂、格隆溴铵和糠酸莫米松的药物。该应用的实例包含β2激动剂马来酸茚达特罗。
US 2008/0286363 A1公开了包含β2激动剂(如马来酸茚达特罗)、格隆溴铵和皮质类固醇的药物。该应用的实例包含皮质类固醇：3-甲基噻吩-2-羧酸-(6S,9R,10S,11S,13S,16R,17R)-9-氯-6-氟-11-羟基-17-甲氧基羰基-10,13,16-三甲基-3-氧亚基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊[a]菲-17-基酯。
US 2010/0166671 A1公开了包含抗毒覃碱剂、β2激动剂和皮质类固醇的药物。该应用的实例包括格隆溴铵、富马酸福莫特罗和糠酸莫米松。
US 7,439,393 B2公开了用于治疗呼吸疾病的某些苯乙醇胺衍生物。还公开了该化合物与其他治疗剂在联合疗法中的应用。
US 2008/0041369 A1公开了无推进剂的气雾剂制剂，其特别包含奥达特罗、皮质类固醇(如布地奈德、倍氯米松或氟替卡松)和抗胆碱能药物(如噻托溴铵、氧托溴铵或异丙托铵)。
US 2005/0239778 A1公开了特别包含奥达特罗和至少一种其他活性物(如类固醇)的药物组合。
US 2008/0317862 A1公开了用于治疗炎性或阻塞性气道疾病的包含抗毒覃碱剂和皮质类固醇的药物。特别是，该应用公开了包含格隆溴铵和糠酸莫米松的气雾剂组合物。
US 2006/0069073 A1公开了格隆铵与作为第二活性物的一种或多种类固醇的组合。
CN 112804997 A公开了马来酸茚达特罗和格隆溴铵的组合的吸入溶液。
TW 202012369 A1、CN 111936124 A公开了无助推剂的气雾剂制剂，其特别包含格隆铵可药用的盐、茚达特罗可药用的盐和水。还公开了该组合特别适合借助雾化器将活性药物形成气雾用于哮喘及COPD的治疗应用。
CN 109715160 A公开了含有茚达特罗或其衍生物的气雾剂，组分中额外包括格隆溴铵的至少一种药学上可接受的盐或至少一种皮质类固醇(如布地奈德、莫米松、倍氯米松、氟替卡松和其药学上可接受的盐)。
US 2021/0322311 A1公开了一种无助推剂的液体制剂，其特别含有噻托溴铵和奥达特罗及其生理上可接受的盐。
US 7,056,916 B2公开了含有奥达特罗的吸入制剂，包括吸入粉雾剂、含助推剂的气雾剂或不含助推剂的吸入溶液。
US 2020/0368214 A1公开了一种不含助推剂的吸入喷雾剂，其特别包含维兰特罗或乌美溴铵或维兰特罗和乌美溴铵两者的药物组合。
WO 2021/009573 A1公开了一种用聚合物或共聚物作为内部涂层的压力容器，该压力容器中特别包含了乌美溴铵或维兰特罗或两者的药物组合。
WO 2020/100040 A1公开了一种含助推剂的吸入器，其特别包含乌美溴铵和维兰特罗的药物组合及配方。
CN 112752572 A公开了一种液态、无助推剂的药物制剂以及通过将药物制剂于吸入器雾化来使用药物的方法。该液态、无推进剂的药物制剂，特别包含了选自芜地溴铵、三苯乙酸维兰特罗及其组合中的活性物质。
WO 2020/220855 A1公开了一种不含助推剂的雾化吸入制剂及其制备方法，该制剂特别包含活性成分芜地溴铵和维兰特罗。含芜地溴铵和维兰特罗的药物组合稳定性好，不含抛射剂，雾化出来的雾滴粒径有利于肺部吸入。
CN 113274596 A公开了用于治疗呼吸系统疾病的加压定量罐，罐内至少包含皮质类固醇、LABA药剂、LAMA药剂和HFA152a或HFO推进剂的制剂。特别是，该应用涉及含有福莫特罗、倍氯米松和格隆溴铵的气雾剂。
CN 111150728 A公开了一种格隆溴铵和福莫特罗组合的稳定的加压气雾剂溶液组合物。
WO 2020/229966 A1公开了一种含有格隆溴铵的稳定的混悬型气雾剂。该气雾剂的处方组成还包含一种或更多种β2激动剂。该应用的实例为含有格隆溴铵和福莫特罗的复方气雾剂。
CN 112804991 A公开了一种无助推剂的液体制剂以及经吸入器雾化使用的方法。特别是，该制剂为芜地溴铵和福莫特罗的组合气雾剂。
WO 2020/084549 A1公开了一种含格隆溴铵和福莫特罗的雾化剂组成及制备方法，用于肺炎和阻塞性气管疾病的治疗。
US 2018/0104184 A1公开了一种含噻托溴铵和福莫特罗的雾化剂组成和制备方法，用于肺炎和阻塞性气管疾病的治疗。
US 6,433,027 B1公开了一种关于抗胆碱能化合物的新型药物组合物及其制备过程。该应用的实例为包含塞托溴铵和福莫特罗的吸入喷雾剂。
CN 111481550 A公开了一种包含噻托溴铵和阿福特罗的药物组合。其应用实例包括含有这两种活性成分的气雾剂和吸入雾化剂。
WO 2010/048384 A1公开了一种用于预防和/或治疗气道和/或呼吸到疾病的组合物和方法。特别是，该应用公开了包含阿福特罗((R,R)-福莫特罗)和噻托溴铵的吸入液体制剂。
CN 107233311 A公开了一种以阿福特罗和格隆溴铵为活性成分的雾化剂及其制备方法。
US 2017/0027908 A1或JP 2017-061456 A公开了一种吸入药物组合物，用于预防和/或治疗呼吸道、炎症或阻塞性气道疾病。其特别包含格隆溴铵、β2激动剂和皮质类固醇。
发明内容
提供了一种吸入用药物组合物，包括一种或多种支气管扩张剂，特别是包括长效β2激动剂和长效毒蕈碱拮抗药。在一些实施方式中，提供了一种或多种支气管扩张剂，特别是长效β2激动剂和长效毒蕈碱拮抗药，在制备用于预防和/或治疗呼吸系统疾病的吸入用药物组合物的用途。在一些实施方式中，还提供了所述药物组合物的制备方法。在一些实施方式中，还提供了所述药物组合物在用于预防和/或治疗呼吸系统疾病的用途。在一些实施方式中，所述药物组合物是用于预防和/或治疗呼吸系统疾病。在一些实施方式中，提供了预防和/或治疗呼吸系统疾病的方法，包括施用所述药物组合物。
在一些实施方式中，呼吸系统疾病包括呼吸性、炎性或阻塞性气道疾病。在一些实施方式中，呼吸系统疾病包括哮喘。在一些实施方式中，呼吸系统疾病包括慢性阻塞性肺病。
在一些实施方式中，长效β2激动剂包括奥达特罗(Olodaterol)或由其组成。在一些实施方式中，长效β2激动剂包括阿福特罗(Arformoterol)或由其组成，且组合物的pH值为3.0–5.5，例如为3.5–5.5，例如为4.0–5.5，更例如为4.5–5.5。在一些实施方式中，长效β2激动剂包括茚达特罗(Indacaterol)或由其组成，且组合物的pH值为2.5–4.5，例如为3.0–4.5，或例如为2.5–4.0，更例如为3.0–4.0。在一些实施方式中，长效毒蕈碱拮抗药包括雷芬那辛(Revefenacin)或由其组成，且组合物的pH值为3.5–5.5，例如为4.0–5.5，更例如为4.5–5.5。在一些实施方式中，长效毒蕈碱拮抗药包括格隆溴铵(Glycopyrronium bromide)或由其组成，且组合物的pH值为2.5–4.5，例如为2.5–4.0，更例如为2.5–3.5。在一些实施方式中，长效毒蕈碱拮抗药包括噻托溴铵(Tiotropium)或由其组成，且组合物的pH值为2.0–4.0，例如为2.5–4.0，更例如为2.5–3.5。
在一些实施方式中，所述长效β2激动剂包括选自由茚达特罗、福莫特罗(Formoterol)、阿福特罗、维兰特罗(Vilanterol)、卡莫特罗(Carmoterol)、以及奥达特罗所组成的组中的至少一个，或由其组成。在一些实施方式中，所述长效毒蕈碱拮抗药包括选自格隆溴铵、乌美溴铵(Umeclidinium)、噻托溴铵(Tiotropium)、阿地溴铵(Aclidinium bromide)、以及雷芬那辛所组成的组中的至少一个，或由其组成。
在一些实施方式中，所述长效β2激动剂包括茚达特罗，且所述长效毒蕈碱拮抗药包括格隆溴铵。在一些实施方式中，所述长效β2激动剂包括茚达特罗，且所述长效毒蕈碱拮抗药包括乌美溴铵。在一些实施方式中，所述长效β2激动剂包括茚达特罗，且所述长效毒蕈碱拮抗药包括噻托溴铵。在一些实施方式中，所述长效β2激动剂包括茚达特罗，且所述长效毒蕈碱拮抗药包括阿地溴铵。在一些实施方式中，所述长效β2激动剂包括茚达特罗，且所述长效毒蕈碱拮抗药包括雷芬那辛。在一些实施方式中，所述长效β2激动剂包括福莫特罗，且所述长效毒蕈碱拮抗药包括格隆溴铵。在 一些实施方式中，所述长效β2激动剂包括福莫特罗，且所述长效毒蕈碱拮抗药包括乌美溴铵。在一些实施方式中，所述长效β2激动剂包括福莫特罗，且所述长效毒蕈碱拮抗药包括噻托溴铵。在一些实施方式中，所述长效β2激动剂包括福莫特罗，且所述长效毒蕈碱拮抗药包括阿地溴铵。在一些实施方式中，所述长效β2激动剂包括福莫特罗，且所述长效毒蕈碱拮抗药包括雷芬那辛。在一些实施方式中，所述长效β2激动剂包括阿福特罗，且所述长效毒蕈碱拮抗药包括格隆溴铵。在一些实施方式中，所述长效β2激动剂包括阿福特罗，且所述长效毒蕈碱拮抗药包括乌美溴铵。在一些实施方式中，所述长效β2激动剂包括阿福特罗，且所述长效毒蕈碱拮抗药包括噻托溴铵。在一些实施方式中，所述长效β2激动剂包括阿福特罗，且所述长效毒蕈碱拮抗药包括阿地溴铵。在一些实施方式中，所述长效β2激动剂包括阿福特罗，且所述长效毒蕈碱拮抗药包括雷芬那辛。在一些实施方式中，所述长效β2激动剂包括维兰特罗，且所述长效毒蕈碱拮抗药包括格隆溴铵。在一些实施方式中，所述长效β2激动剂包括维兰特罗，且所述长效毒蕈碱拮抗药包括乌美溴铵。在一些实施方式中，所述长效β2激动剂包括维兰特罗，且所述长效毒蕈碱拮抗药包括噻托溴铵。在一些实施方式中，所述长效β2激动剂包括维兰特罗，且所述长效毒蕈碱拮抗药包括阿地溴铵。在一些实施方式中，所述长效β2激动剂包括维兰特罗，且所述长效毒蕈碱拮抗药包括雷芬那辛。在一些实施方式中，所述长效β2激动剂包括卡莫特罗，且所述长效毒蕈碱拮抗药包括格隆溴铵。在一些实施方式中，所述长效β2激动剂包括卡莫特罗，且所述长效毒蕈碱拮抗药包括乌美溴铵。在一些实施方式中，所述长效β2激动剂包括卡莫特罗，且所述长效毒蕈碱拮抗药包括噻托溴铵。在一些实施方式中，所述长效β2激动剂包括卡莫特罗，且所述长效毒蕈碱拮抗药包括阿地溴铵。在一些实施方式中，所述长效β2激动剂包括卡莫特罗，且所述长效毒蕈碱拮抗药包括雷芬那辛。在一些实施方式中，所述长效β2激动剂包括奥达特罗，且所述长效毒蕈碱拮抗药包括格隆溴铵。在一些实施方式中，所述长效β2激动剂包括奥达特罗，且所述长效毒蕈碱拮抗药包括乌美溴铵。在一些实施方式中，所述长效β2激动剂包括奥达特罗，且所述长效毒蕈碱拮抗药包括噻托溴铵。在一些实施方式中，所述长效β2激动剂包括奥达特罗，且所述长效毒蕈碱拮抗药包括阿地溴铵。在一些实施方式中，所述长效β2激动剂包括奥达特罗，且所述长效毒蕈碱拮抗药包括雷芬那辛。
在一些实施方式中，所述长效β2激动剂的含量为1–100μg/mL，例如为5–100μg/mL，例如为5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、11.5、12、12.5、13、14、15、16、17、18、19、20、22、24、25、26、28、30、35、40、45、50、55、60、65、70、75、80、85、90、95、或100μg/mL或其中任意二个数值之间的范围。在一些实施方式中，所述长效毒蕈碱拮抗药的含量为1–100μg/mL，例如为5–100μg/mL，例如为5、5.5、6、6.5、7、7.5、8、8.5、9、9.5、10、10.5、11、11.5、12、12.5、13、14、15、16、17、18、19、20、22、24、25、26、28、30、35、40、45、50、55、60、65、70、75、80、85、90、95、或100μg/mL或其中任意二个数值之间的范围。在一些实施方式中，所述长效β2激动剂和所述长效毒蕈碱拮抗药的重量比例为100:1–1:100，例如为1:80–80:1，更例如为1:60–60:1，更例如为1:50–50:1，更例如为1:40–40:1，更例如为1:30–30:1，更例如为1:20–20:1，更例如为1:15–15:1。在一些实施方式中，所述长效β2激动剂和所述长效毒蕈碱拮抗药的重量比例为100:1–1:1，例如为1:80–1:1，更例如为1:60–1:1，更例如为1:50–1:1，更例如为1:40–1:1，更例如为1:30–1:1，更例如为1:20–1:1，更例如为1:15–1:1。在一些实施方式中，所述长效β2激动剂和所述长效毒蕈碱拮抗药的重量比例为1:1–1:100，例如为1:1–80:1，更例如为1:1–60:1，更例如为1:1–50:1，更例如为1:1–40:1，更例如为1:1–30:1，更例如为1:1–20:1，更例如为1:1–15:1。
在一些实施方式中，所述组合物还包括透明质酸。在一些实施方式中，所述透明质酸是高分子量透明质酸(high molecular weight hyaluronic acid，HMW-HA)。在一些实施方式中，所述透明质酸的重量百分比为0.500％以下。在一些实施方式中，所述透明质酸的重量百分比为0.001％–0.500％，例如为0.010％–0.400％，例如为0.100％–0.300％，例如为0.300％。在一些实施方式中，高分子量透明质酸的分子量范围为1,000,000–10,000,000道尔顿。
在一些实施方式中，所述药物组合物还包括氯化钠、乙二胺四乙酸(EDTA)、和/或环糊精。在一些实施方式中，所述药物组合物还包括氯化钠。在一些实施方式中，所述药物组合物还包括EDTA、或环糊精。在一些实施方式中，所述药物组合物还包括EDTA。在一些实施方式中，所述药物组合物还包括环糊精。在一些实施方式中，所述药物组合物还包括EDTA、和环糊精。在一些实施方式中，所述药物组合物还包括吐温，例如是吐温80。在一些实施方式中，所述药物组合物还包括油酸乙酸。在一些实施方式中，所述组合物还包括糖皮质激素。在一些实施方式中，环糊精包括α-环糊精、β-环糊精或γ-环糊精。在一些实施方式中，环糊精选自由α-环糊精、β-环糊精和γ-环糊精所组成的组。在一些实施方式中，环糊精包括α-环糊精或由其组成。在一些实施方式中，环糊精包括β-环糊精或由其组成。在一些实施方式中，环糊精包括γ-环糊精或由其组成。在一些实施方式中，环糊精包括羟丙基-β-环糊精或磺丁基-β-环糊精。在 一些实施方式中，环糊精选自由羟丙基-β-环糊精和磺丁基-β-环糊精所组成的组。在一些实施方式中，环糊精包括羟丙基-β-环糊精或由其组成。在一些实施方式中，环糊精包括磺丁基-β-环糊精或由其组成。
在一些实施方式中，所述氯化钠的重量百分比为1.00％以下。在一些实施方式中，所述氯化钠的重量百分比为0.01％–1.00％，例如为0.10％–1.00％，更例如为0.50％–1.00％，更例如为0.85％。在一些实施方式中，所述EDTA的重量百分比为0.100％以下。在一些实施方式中，所述EDTA的重量百分比为0.001％–0.100％，例如为0.010％–0.050％，例如为0.020％–0.040％，例如为0.030％。在一些实施方式中，所述环糊精的重量百分比为10％以下，例如为5.0％以下，例如为2.5％以下，例如为1.50％以下。在一些实施方式中，所述环糊精的重量百分比为0.01％–10％，例如为0.01％–5.0％，例如为0.01％–2.5％，例如为0.01％–1.50％，例如为0.01％–1.00％，例如为0.10％–1.00％，更例如为0.20％–0.80％，更例如为0.25％–0.75％，更例如为0.30％–0.70％，更例如为0.40％–0.60％，更例如为0.50％。在一些实施方式中，所述吐温的重量百分比为0.100％以下。在一些实施方式中，所述吐温的重量百分比为0.001％–0.100％，例如为0.010％–0.050％，例如为0.020％–0.040％，例如为0.030％。
在一些实施方式中，所述药物组合物还包括缓冲液，例如是柠檬酸/柠檬酸盐缓冲液，更例如是柠檬酸/柠檬酸钠缓冲液。在一些实施方式中，所述药物组合物还包括pH调节剂，例如是盐酸、更例如是稀盐酸。
在一些实施方式中，所述长效β2激动剂包括奥达特罗，所述长效毒蕈碱拮抗药包括雷芬那辛。在一些实施方式中，所述长效β2激动剂包括奥达特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物的pH值为4.0–5.5。在一些实施方式中，所述长效β2激动剂包括奥达特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物还包括EDTA。
在一些实施方式中，所述长效β2激动剂包括阿福特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物的pH值为4.0–5.5，例如为4.5–5.5，或例如为4.0–5.0。在一些实施方式中，所述长效β2激动剂包括阿福特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物还包括EDTA。在一些实施方式中，所述长效β2激动剂包括阿福特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物还包括缓冲液，例如是柠檬酸/柠檬酸盐缓冲液，更例如是柠檬酸/柠檬酸钠缓冲液。在一些实施方式中，所述长效β2激动剂包括阿福特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物还包括缓冲液，例如是柠檬酸/柠檬酸盐缓冲液，更例如是柠檬酸/柠檬酸钠缓冲液，且所述缓冲液的浓度为0.1mM以上，例如是0.1mM至20mM，例如是0.1mM至10mM，更例如是1mM至10mM。在一些实施方式中，所述长效β2激动剂包括阿福特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物还包括氯化钠，例如是重量百分比为1.00％以下的氯化钠，更例如是重量百分比为0.01％–1.00％的氯化钠。
在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括格隆溴铵，且所述组合物的pH值为2.5–4.0，例如为3.0–4.0，或例如为2.5–3.5，更例如为3.0–3.5，更例如为3.5。在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括格隆溴铵，且所述组合物还包括EDTA和/或环糊精，例如是包括环糊精，更例如是包括EDTA和环糊精。在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括格隆溴铵，且所述组合物还包括透明质酸钠。在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括格隆溴铵，且所述组合物还包括透明质酸钠，以及选自由EDTA和环糊精所组成的组中的至少一个。在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括格隆溴铵，且所述组合物还包括透明质酸钠和环糊精。
在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物的pH值为3.0–4.5，例如为3.5–4.5，更例如为3.5–4.0，或例如为4.0–4.5，更例如为4.0。在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物还包括EDTA和/或环糊精，例如是包括环糊精，更例如是包括EDTA和环糊精。
在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括噻托溴铵，且所述组合物的pH值为2.0–4.0，例如为2.5–4.0，例如为2.5–3.5，例如为2.5–3.0，更例如为2.5。在一些实施方式中，所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括噻托溴铵，且所述组合物还包括环糊精。
在一些实施方式中，所述组合物是雾化吸入用药物组合物。在一些实施方式中，所述组合物是通过震动筛、超声喷雾或空气压缩机给药的雾化吸入用药物组合物。
在一些实施方式中，所述药物组合物是吸入喷雾剂(Soft Mist)、气雾剂(MDI)或雾化吸入剂(Nebulizer)。
在一些实施方式中，所述药物组合物通过定量吸入器(MDI)的形式使用。
在一些实施方式中，所述药物组合物还包括，赋形剂、抛射剂、共溶剂、填充剂、非挥发性组分、缓冲液、pH调 节剂、表面活性剂、防腐剂、络合剂、抗氧化剂、或其组合，的一种或多种辅料。
在一些实施方式中，所述药物组合物为喷雾剂，所述喷雾剂的制备方法包括在溶剂中混合支气管扩张剂和高分子量透明质酸，特别是混合长效β2激动剂、长效毒蕈碱拮抗药、和高分子量透明质酸。
在一些实施方式中，所述药物组合物为气雾剂，所述气雾剂的制备方法包括在溶剂中混合支气管扩张剂、高分子量透明质酸、和抛射剂，特别是混合长效β2激动剂、长效毒蕈碱拮抗药、高分子量透明质酸、和抛射剂。在一些实施方式中，所述抛射剂为氢氟烷烃。在一些实施方式中，所述氢氟烷烃为1,1,1,2-四氟乙烷和/或1,1,1,2,3,3,3-七氟丙烷。在一些实施方式中，所述氢氟烷烃为1,1,1,2-四氟乙烷。在一些实施方式中，所述氢氟烷烃为1,1,1,2,3,3,3-七氟丙烷。在一些实施方式中，所述氢氟烷烃为1,1,1,2-四氟乙烷和1,1,1,2,3,3,3-七氟丙烷。
在一些实施方式中，所述药物组合物的活性物质存在于固定或自由组合中，用于与赋形剂一起，适于吸入应用的药物形式中同时、顺次或分开给药。
在本申请的实施方案中，提及到长效β2激动剂、长效毒蕈碱拮抗药或其他组分，例如是茚达特罗、福莫特罗、阿福特罗、维兰特罗、卡莫特罗、以及奥达特罗，格隆溴铵、乌美溴铵、噻托溴铵、阿地溴铵、以及雷芬那辛，透明质酸例如高分子量透明质酸、EDTA、油酸乙酸……等等，都包括提及到这些组分或其药学上可接受的盐，除非另有具体说明。举例来说：本申请的实施方案中提及到本申请的药物组合物包括长效β2激动剂和长效毒蕈碱拮抗药，即应当视为本申请的这些实施方案中提及到本申请的药物组合物包括长效β2激动剂或其药学上可接受的盐、和长效毒蕈碱拮抗药或其药学上可接受的盐；本申请的实施方案中提及到本申请的药物组合物包括EDTA即应当视为本申请的这些实施方案中提及到本申请的药物组合物包括EDTA及其药学上可接受的盐；依此类推。
附图说明
图1绘示了不同缓冲液浓度的酒石酸阿福特罗–雷芬那辛组合物的稳定性测试中，雷芬那辛含量的变化。
图2绘示了不同缓冲液浓度的酒石酸阿福特罗–雷芬那辛组合物的稳定性测试中，阿福特罗含量的变化。
图3绘示了不同缓冲液浓度的酒石酸阿福特罗–雷芬那辛组合物的稳定性测试中，pH值的变化。
图4绘示了不同种类辅料的酒石酸阿福特罗–雷芬那辛组合物的稳定性测试中，雷芬那辛含量的变化。
图5绘示了不同种类辅料的酒石酸阿福特罗–雷芬那辛组合物的稳定性测试中，阿福特罗含量的变化。
图6绘示了不同pH值的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，茚达特罗含量的变化。
图7绘示了不同种类辅料的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，格隆溴铵含量的变化。
图8绘示了不同种类辅料的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，总杂质含量的变化。
图9绘示了不同种类辅料的pH值为4的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，茚达特罗含量和格隆溴铵含量的变化。
图10绘示了不同种类辅料的pH值为4的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，总杂质含量的变化。
图11绘示了不同种类辅料的pH值为3的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，茚达特罗含量和格隆溴铵含量的变化。
图12绘示了不同种类辅料的pH值为3的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，总杂质含量的变化。
图13绘示了不同种类辅料的pH值为4的马来酸茚达特罗–格隆溴铵–透明质酸钠组合物的稳定性测试中，茚达特罗含量和格隆溴铵含量的变化。
图14绘示了不同种类辅料的pH值为4的马来酸茚达特罗–格隆溴铵–透明质酸钠组合物的稳定性测试中，总杂质含量的变化。
图15绘示了不同种类辅料的pH值为3的马来酸茚达特罗–格隆溴铵–透明质酸钠组合物的稳定性测试中，茚达特罗含量和格隆溴铵含量的变化。
图16绘示了不同种类辅料的pH值为3的马来酸茚达特罗–格隆溴铵–透明质酸钠组合物的稳定性测试中，总杂质含量的变化。
图17绘示了不同pH值的马来酸茚达特罗–雷芬那辛组合物的稳定性测试中，茚达特罗含量的变化。
图18绘示了不同pH值的马来酸茚达特罗–雷芬那辛组合物的稳定性测试中，茚达特罗含量的变化。
图19绘示了不同pH值的马来酸茚达特罗–雷芬那辛组合物的稳定性测试中，总杂质含量的变化。
图20绘示了不同种类辅料的pH值为4的马来酸茚达特罗–雷芬那辛组合物的稳定性测试中，总杂质含量的变化。
图21绘示了不同pH值的马来酸茚达特罗–噻托溴铵组合物的稳定性测试中，茚达特罗总杂质含量的变化。
图22绘示了不同pH值的马来酸茚达特罗–噻托溴铵组合物的稳定性测试中，噻托溴铵总杂质含量的变化。
图23绘示了加入不同种类辅料的pH值为3的马来酸茚达特罗–噻托溴铵组合物的稳定性测试中，总杂质含量的变化。
图24绘示了加入或未加入玻璃酸钠的pH值为3、4、或5的马来酸茚达特罗–噻托溴铵组合物的稳定性测试中，总杂质含量的变化。
具体实施方式
为更进一步阐述本申请为了达成预定目的所采取的技术手段及功效，以下结合附图及较佳实施例，对依据本申请的具体实施方式、结构、特征及其功效，详细说明如下。
如本申请中所使用的术语“和/或”(或者是“且/或”、“及/或”)是指并且涵盖一个或多个相关联的所列项目的任何和所有可能的组合。当在两个或多个项目的列表中使用时，术语“和/或”(或者是“且/或”、“及/或”)表示所列出的项目中的任何一个可以单独使用，或者可以使用两个或多个所列出的项目的任何组合。例如，如果组合物(或组合、构造、命题等)被描述为包括(或包含)组分(或条件)A、B、C和/或(或者是“且/或”、“及/或”)D，则该组合物(或组合、构造、命题等)可以单独包含A，单独包含B，单独包含C，单独包含D，包含A和B的组合，包含A和C的组合，包含A和D的组合，包含B和C的组合，包含B和D的组合，包含C和D的组合，包含A、B和C的组合，包含A、B和D的组合，包含A、C和D的组合，包含B、C和D的组合，或包含A、B、C和D的组合。
如本申请中所使用的，包括如实施例中所使用的且除非另有明确规定，所有数字都可以看成如同以“基本上”、“大约”或“约”措辞开头一样，即使该术语并未明确出现。当描述幅度和/或位置以表明所描述的数值和/或位置在合理的预期值和/或位置范围内时，可以使用短语“大约”或“约”。例如，数值可以是所述数值(或数值范围)的±0.1％、所述数值(或数值范围)的±1％、所述数值(或数值范围)的±2％、所述数值(或数值范围)的±5％、所述数值(或数值范围)的±10％、所述数值(或数值范围)的±15％、所述数值(或数值范围)的±20％等。本申请所述的任何数值范围旨在包括其中所含的所有子范围或中间值。
对具体参数的数值和数值范围的公开不排除对本申请有用的其他数值和数值范围。可以预想的是，给定参数的两个或更多个具体示例数值可以确定参数可要求的数值范围的端点。例如，如果参数X在本申请中举例为具有数值A且还举例为具有数值Z，则可以预期参数X可以具有从大约A到大约Z的数值范围。类似地，可以预期公开参数的两个或者更多个数值范围(无论这些范围是嵌套的、有重叠的还是截然不同的)就包括了使用所公开范围的端点可以要求的数值范围的所有可能组合。例如，如果参数X在本申请中示例为具有1–10范围内的值，则它还描述了参数X的子范围，包括仅作为例子的，如：1–9、1–8、1–7、2–9、2–8、2–7、3–9、3–8、3–7、2–8、3–7、4–6或7–10、8–10或9–10。范围包括其端点以及端点内的值，例如范围0–5包括0、>0、1、2、3、4、<5和5。
实施例1盐酸奥达特罗–雷芬那辛组合物在不同pH值与EDTA存在下的稳定性测试
用5mM(mmol/L)的柠檬酸溶液和柠檬酸钠溶液分别配制pH为4.0、4.5、5.0、5.5(pH为5.0的溶液两份，其余溶液各1份)的缓冲液。称取处方量的氯化钠，用200mL的pH缓冲液溶解，精密加入处方量的盐酸奥达特罗与雷芬那辛，混合均匀，用pH缓冲液定容各溶液至250mL。然后，向其中1份pH 5.0的药液中，加入EDTA，搅拌至完全溶解。将所得药液以每支2mL灌装至低密度聚乙烯塑料瓶中。实验配方见表1。
表1盐酸奥达特罗与雷芬那辛组合物实验配方

进行稳定性测试，测定初始状态和在60℃放置2周后的样品中，奥达特罗与雷芬那辛的含量。结果如表2。
表2盐酸奥达特罗与雷芬那辛组合物稳定性测试实验结果
可以看到，所有样品经60℃放置2周处理后，奥达特罗含量的变化在2％内，雷芬那辛含量几乎无变化，稳定性较好。
实施例2酒石酸阿福特罗–雷芬那辛组合物在不同pH值的稳定性测试
分别用适量5mM的柠檬酸溶液和柠檬酸钠溶液混合，配制成pH为4.0、4.5和5.0的3份缓冲液。各取其中450mL pH缓冲液，精密加入处方量的氯化钠、酒石酸阿福特罗与雷芬那辛，混合均匀，缓冲液定容至500mL，将所得药液以2mL每支的量灌装至低密度聚乙烯塑料瓶中，所配制的实验配方见表3。
表3酒石酸阿福特罗–雷芬那辛组合物实验配方
进行稳定性测试，测定初始状态和在25±2℃放置4周后的样品中，阿福特罗与雷芬那辛的含量。结果如表4。
表4酒石酸阿福特罗–雷芬那辛组合物稳定性测试实验结果
可以看到，所有样品经25±2℃放置4周处理后，阿福特罗含量的变化在3％范围内，雷芬那辛含量几乎无变化，稳定性较好。市售酒石酸阿福特罗吸入溶液的长期存储条件为2–8℃，加速条件为25±2℃，在加速条件可储存3个月。
实施例3酒石酸阿福特罗–雷芬那辛–透明质酸组合物在不同pH值以及不同EDTA浓度下的稳定性测试
向450mL体积的5mM的柠檬酸/柠檬酸钠缓冲液(pH分别为4.5、5.5、5.0、4.5和5.5)中，依次加入处方量的氯化钠，搅拌溶解后，再加入精密称量的处方量的酒石酸阿福特罗、雷芬那辛和透明质酸，混合均匀，用pH缓冲液定容至500mL，将所得药液以2mL每支的量灌装至低密度聚乙烯塑料瓶中，所配制的实验配方见表5。
表5酒石酸阿福特罗–雷芬那辛–透明质酸组合物实验配方

进行稳定性测试，测定初始状态和在25±2℃放置4周后的样品中，阿福特罗与雷芬那辛的含量。结果如表6。
表6阿福特罗–雷芬那辛–透明质酸组合物稳定性测试结果
可以看到，所有样品经25±2℃放置4周处理后，阿福特罗含量的变化在5％范围内，雷芬那辛含量几乎无变化。
实施例4酒石酸阿福特罗–雷芬那辛组合物在不同缓冲液浓度的稳定性测试
准备不同浓度的pH为5的柠檬酸/柠檬酸钠缓冲液各1L(其中未加缓冲液的用稀盐酸调节pH)。向缓冲液中加入处方量的氯化钠，搅拌溶解后，加入雷芬那辛和酒石酸阿福特罗，搅拌至全部溶解。将所得药液以2mL每支的量灌装至低密度聚乙烯塑料瓶中，再用铝箔袋密封，所配制的实验配方见表7。
表7酒石酸阿福特罗–雷芬那辛组合物实验配方
进行稳定性测试，测定初始状态和在25℃，60％RH(相对湿度，Relative Humidity)条件下放置3个月后的样品中，阿福特罗与雷芬那辛的含量与样品pH值，结果如表8和图1–3。图1为不同缓冲液浓度的阿福特罗–雷芬那辛组合物的稳定性测试中，雷芬那辛含量的变化。图2为不同缓冲液浓度的阿福特罗–雷芬那辛组合物的稳定性测试中，阿福特罗含量的变化。图3为不同缓冲液浓度的阿福特罗–雷芬那辛组合物的稳定性测试中，pH值的变化。
表8阿福特罗–雷芬那辛组合物稳定性测试结果
可以看到，加入pH缓冲液后，有利于产品稳定；同时，随着pH缓冲液浓度升高，活性药物成分雷芬那辛和阿福特罗的稳定性均显著提高，且在放置期间pH也更加稳定。
实施例5酒石酸阿福特罗–雷芬那辛组合物在不同pH值的稳定性测试
配制1mM的pH分别为4.5、4.75、5.25、5.5的柠檬酸/柠檬酸钠缓冲液，加入处方量的氯化钠，搅拌至全部溶解，再加入处方量的雷芬那辛和酒石酸阿福特罗，搅拌至全部溶解。将所得药液以2mL每支的量灌装至低密度聚乙烯塑料瓶中，再用铝箔袋密封，所配制的实验配方见表9。
表9酒石酸阿福特罗–雷芬那辛组合物实验配方
进行稳定性测试，测定初始状态和在40℃，75％RH或25℃，60％RH条件下放置3个月后的样品中，阿福特罗与雷芬那辛的含量与样品pH值。结果如表10。
表10酒石酸阿福特罗–雷芬那辛组合物稳定性测试结果
可以看到，在40℃，75％RH放置3个月后，pH值为4.5–5.5范围的酒石酸阿福特罗–雷芬那辛组合物中雷芬那辛含量降低在5％以内，药液较稳定；在25℃、60％RH条件下存放2个月后，pH值为4.5–5.5范围的酒石酸阿福特罗–雷芬那辛组合物中阿福特罗含量降低在5％以内，相较于阿福特罗溶液对温度较敏感，其市售的单方溶液产品在25℃、60％RH条件下可存储6周，进一步说明在一些实施方式中，该组合物在pH值4.5–5.5范围内较稳定。
实施例6酒石酸阿福特罗–雷芬那辛组合物加入辅料的稳定性测试
另外，考察了酒石酸阿福特罗–雷芬那辛组合物(以pH为5的10mM的柠檬酸-柠檬酸钠缓冲液为溶媒)中加入氯化钠、EDTA和吐温等辅料对产品稳定性的影响。实验配方如表11。将配制完的药液装入低密度聚乙烯瓶内，再用铝箔袋密封。
表11酒石酸阿福特罗–雷芬那辛组合物实验配方
进行稳定性测试，测定初始状态和在加速45℃，75％RH条件下放置3个月后的样品中，阿福特罗与雷芬那辛的含量与样品pH值。结果如表12和图4、5。图4为不同种类辅料的酒石酸阿福特罗–雷芬那辛组合物的稳定性测试中，雷芬那辛含量的变化。图5为不同种类辅料的酒石酸阿福特罗–雷芬那辛组合物的稳定性测试中，阿福特罗含量的变化。
表12酒石酸阿福特罗–雷芬那辛组合物稳定性测试结果

可以看到，相较于未加入辅料或是加入EDTA和吐温，加入辅料氯化钠显著有利于雷芬那辛的稳定性。而氯化钠、EDTA和吐温的加入对提高阿福特罗溶液的稳定性无显著影响。
实施例7马来酸茚达特罗–格隆溴铵组合物在不同pH值的稳定性测试
按如下配方配制不同pH的马来酸茚达特罗和格隆溴铵的软雾溶液。准备6份浓度为0.02mM柠檬酸溶液各500mL。用1M(mol/L)的氢氧化钠溶液调节pH至2.5、3.0、3.5、4.0、4.5和5.0。向其中加入马来酸茚达特罗、格隆溴铵，配液过程中，为提高茚达特罗的溶解，将药液统一在30℃的水浴中超声20min至无可见颗粒物。实验配方如表13。
表13马来酸茚达特罗–格隆溴铵组合物实验配方
将药液装于玻璃瓶内，进行稳定性测试，测定初始状态和在60℃下放置4周后的样品中，茚达特罗与格隆溴铵的含量与总杂质含量，结果如表14和图6–8。图6为不同pH值的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，茚达特罗含量的变化。图7为不同种类辅料的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，格隆溴铵含量的变化。图8为不同种类辅料的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，总杂质含量的变化。
表14马来酸茚达特罗–格隆溴铵组合物稳定性测试结果
可以看到，分析不同pH的药液在稳定性期间的变化可知，茚达特罗和格隆溴铵在pH＝5和pH＝4.5的稳定性均较差。茚达特罗在pH 2.5–4之间较稳定，在pH 3.5时最好，而格隆溴铵在pH2.5–3.5较稳定，综合茚达特罗和格隆溴铵的含量以及总杂质含量的变化，确定在一些实施方式中，茚达特罗–格隆溴铵组合物的最佳pH为3.5。
实施例8马来酸茚达特罗–格隆溴铵组合物加入辅料的稳定性测试
另外，考察了马来酸茚达特罗–格隆溴铵组合物中加入EDTA和环糊精等辅料对稳定性的影响。实验配方如表15。使用柠檬酸、柠檬酸钠溶液调节pH至目标pH，将制备好的药液装入玻璃瓶内密封。
表15马来酸茚达特罗–格隆溴铵组合物实验配方

将药液装于玻璃瓶内，进行稳定性测试，测定初始状态和在60℃下放置4周后的样品中，茚达特罗含量、格隆溴铵含量、及总杂质含量，结果如表16和图9–12。图9为不同种类辅料的pH值为4的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，茚达特罗含量和格隆溴铵含量的变化。图10为不同种类辅料的pH值为4的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，总杂质含量的变化。图11为不同种类辅料的pH值为3的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，茚达特罗含量和格隆溴铵含量的变化。图12为不同种类辅料的pH值为3的马来酸茚达特罗–格隆溴铵组合物的稳定性测试中，总杂质含量的变化。
表16马来酸茚达特罗–格隆溴铵组合物稳定性测试结果
可以看到，在pH为4的组合物中，加入环糊精或同时加入环糊精和EDTA后，组合物中茚达特罗含量和格隆溴铵含量降低更少，总杂质含量增加得更少，说明加入环糊精、或环糊精和EDTA，能显著提高药液的稳定性。而在pH为3的组合物中，考察了加入EDTA及同时加入EDTA和环糊精的作用，稳定性趋势说明，加入EDTA能提高组合物的稳定性，但是同时加入了EDTA和环糊精，相较于仅加入EDTA能更显著提高组合物的稳定性。
实施例9马来酸茚达特罗–格隆溴铵–透明质酸钠组合物加入辅料的稳定性测试
按如下配方配制不同pH的马来酸茚达特罗、格隆溴铵和透明质酸钠的溶液。先准备8份20mM的柠檬酸溶液各8份，用1M的氢氧化钠调节pH至2.5、3.0、3.5、4.0、4.5和5.0，加入格隆溴铵和马来酸茚达特罗，使其溶解。考察加入EDTA和环糊精等辅料对药液稳定性的影响。具体配方如表17。
表17马来酸茚达特罗–格隆溴铵–透明质酸钠组合物实验配方
将药液装于玻璃瓶内，进行稳定性测试，测定初始状态和在60℃下放置4周后的样品中，茚达特罗含量、格隆溴铵含量、及总杂质含量，结果如表18和图13–16。图13为不同种类辅料的pH值为4的马来酸茚达特罗–格隆溴铵–透明质酸钠组合物的稳定性测试中，茚达特罗含量和格隆溴铵含量的变化。图14为不同种类辅料的pH值为4的马来酸茚达特罗–格隆溴铵–透明质酸钠组合物的稳定性测试中，总杂质含量的变化。图15为不同种类辅料的pH值为3的马来酸茚达特罗–格隆溴铵–透明质酸钠组合物的稳定性测试中，茚达特罗含量和格隆溴铵含量的变化。图16为不同种类辅料的pH值为3的马来酸茚达特罗–格隆溴铵–透明质酸钠组合物的稳定性测试中，总杂质含量的变化。
表18马来酸茚达特罗–格隆溴铵–透明质酸钠组合物稳定性测试结果

可以看到，向pH为3.0和4.0的茚达特罗–格隆溴铵–透明质酸钠组合物中，加入辅料EDTA、环糊精对药液稳定性均有提高。对比加入环糊精和同时加入环糊精和EDTA的结果可知，环糊精对药液稳定性的提高作用最好。
实施例10马来酸茚达特罗–雷芬那辛组合物在不同pH值的稳定性测试
配制浓度20mM的pH分别为2.5、3.0、3.5、4.0、5.5的柠檬酸/柠檬酸钠缓冲液。按如下处方配比加入马来酸茚达特罗，超声至完全溶解。再加入氯化钠、雷芬那辛，搅拌至全部溶解。将制备好的药液装入玻璃瓶内密封，所配制的实验配方见表19。
表19马来酸茚达特罗–雷芬那辛组合物实验配方
将样品放入高温60℃放置4周，进行稳定性测试，测定样品中茚达特罗含量、雷芬那辛含量、及总杂质含量的变化(总杂使用面积归一化法)，如表20和图17–19。图17为不同pH值的马来酸茚达特罗–雷芬那辛组合物的稳定性测试中，茚达特罗含量的变化。图18为不同pH值的马来酸茚达特罗–雷芬那辛组合物的稳定性测试中，茚达特罗含量的变化。图19为不同pH值的马来酸茚达特罗–雷芬那辛组合物的稳定性测试中，总杂质含量的变化。
表20马来酸茚达特罗–雷芬那辛组合物稳定性测试结果
上述结果表明，马来酸茚达特罗–雷芬那辛的复方溶液，在高温条件下放置4周，药液pH值在3.5至4.5之间较pH值2.5和5.0更稳定。
实施例11马来酸茚达特罗–雷芬那辛组合物加入辅料的稳定性测试
另外，考察了在实施例10中的pH值为4的马来酸茚达特罗–雷芬那辛组合物中加入EDTA(0.03％w/w)和环糊精(0.05％w/w)等辅料对药液稳定性的影响。实验配方如表21。使用柠檬酸、柠檬酸钠溶液调节pH至目标pH，将制备好的药液装入玻璃瓶内密封。
表21马来酸茚达特罗–雷芬那辛组合物中加入辅料助剂的配方
将样品放入60℃高温环境中放置4周，进行稳定性测试，测定样品中总杂质含量的变化结果见表22和图20。图20为加入不同种类辅料的pH值为4的马来酸茚达特罗–雷芬那辛组合物的稳定性测试中，总杂质含量的变化。
表22马来酸茚达特罗–雷芬那辛组合物中加入辅料助剂的总杂质含量变化结果
结果表明，加入环糊精对药液稳定性的改善更显著，若同时向药液中加入环糊精和EDTA，能显著提高药液的稳定性。
实施例12马来酸茚达特罗–噻托溴铵组合物在不同pH值的稳定性测试
配制20mM的pH分别为2.5、3.0、3.5、4.0、5.5的柠檬酸/柠檬酸钠缓冲液，按表23处方配比加入马来酸茚达特罗，超声至完全溶解。再加入氯化钠、噻托溴铵，搅拌至全部溶解。将制备好的药液装入玻璃瓶内密封，所配制的实验配方见表23。
表23马来酸茚达特罗–噻托溴铵组合物实验配方
将样品放入高温60℃放置4周，进行稳定性测试，测定样品中茚达特罗与噻托溴铵的含量及总杂质含量的变化如表24和图21–22。图21为不同pH值的马来酸茚达特罗–噻托溴铵组合物的稳定性测试中，茚达特罗总杂质含量的变化。图22为不同pH值的马来酸茚达特罗–噻托溴铵组合物的稳定性测试中，噻托溴铵总杂质含量的变化。
表24马来酸茚达特罗–噻托溴铵组合物稳定性测试结果
结果表明，样品pH在2.5至4.5时，茚达特罗的含量降低少于5％；对于噻托溴铵，在pH在2.5至3.5时，噻托 溴铵含量的变化低于5％。同时，再结合茚达特罗和噻托溴铵的总杂结果分析，选择马来酸茚达特罗–噻托溴铵组合物合适的pH介于2.5至3.5之间更好。
实施例13茚达特罗–噻托溴铵组合物加入辅料的稳定性测试
另外，考察了在实施例12的pH值为3的马来酸茚达特罗–噻托溴铵组合物中加入EDTA(0.03％w/w)和环糊精(0.05％w/w)等辅料对稳定性的影响。实验配方如表25。使用柠檬酸、柠檬酸钠溶液调节pH至目标pH，将制备好的药液装入玻璃瓶内密封。
表25茚达特罗–噻托溴铵组合物中加入辅料助剂的配方
将样品放入60℃高温环境中放置4周，进行稳定性测试，测定样品中总杂质含量的变化如表26和图23。图23为加入不同种类辅料的pH值为3的马来酸茚达特罗–噻托溴铵组合物的稳定性测试中，总杂质含量的变化。
表26茚达特罗–噻托溴铵组合物中加入辅料助剂的总杂质含量变化结果
根据表26和图23的总杂质含量变化结果可知，相较于未加入辅料或是加入EDTA加入环糊精能显著提高药液稳定性。
实施例14马来酸茚达特罗–噻托溴铵组合物加入辅料的稳定性测试
另外，考察了在实施例12中pH值分别为3、4、5的马来酸茚达特罗–噻托溴铵组合物中加入玻璃酸钠的影响。实验配方如表27。使用柠檬酸、柠檬酸钠溶液调节pH至目标pH，将制备好的药液装入玻璃瓶内密封。
表27马来酸茚达特罗–噻托溴铵组合物中加入辅料助剂的配方
放入60℃高温环境中放置4周，进行稳定性测试，测定样品中总杂质含量的变化如表28和图24。图24为加入或未加入玻璃酸钠的pH值为3、4、或5的马来酸茚达特罗–噻托溴铵组合物的稳定性测试中，总杂质含量的变化。图24中的术语“无HA”、“加HA”分别意指“无添加透明质酸钠”以及“添加透明质酸钠”。
表28马来酸茚达特罗–噻托溴铵组合物中加入透明质酸钠对总杂质变化的影响

根据表28和图24的总杂质变化结果可知，加入透明质酸钠后，药液的稳定性无明显变化，且稳定性变化趋势与未加入透明质酸钠之前保持一致。
实施例15长效β2激动剂–长效毒蕈碱拮抗药–透明质酸药物组合物的制备
盐酸奥达特罗–雷芬那辛–透明质酸喷雾剂的制备
精密称取处方量的盐酸奥达特罗、雷芬那辛、高分子量透明质酸、依地酸钙钠，加入处方量的乙醇搅拌均匀，加入适量注射用水以及适量苯扎氯铵，用柠檬酸/柠檬酸钠缓冲液调节pH至4.5至5.5，灌装制成喷雾剂。所制备的喷雾剂其具体的成分组成，如表29所示。
表29奥达特罗–雷芬那辛–透明质酸气雾剂的成分组成
盐酸奥达特罗–格隆溴铵–透明质酸气雾剂的制备
称取处方量的油酸乙酯与吐温80，混合均匀，精密加入处方量的盐酸奥达特罗与格隆溴铵和高分子量透明质酸，混合均匀，将所得药液转移至添加了氢氟烷烃(HFA)抛射剂的混合容器中。所制备的气雾剂其具体的成分组成，如表30所示。
表30盐酸奥达特罗–格隆溴铵–透明质酸气雾剂的成分组成
盐酸奥达特罗–格隆溴铵–透明质酸吸入喷雾剂的制备
称取处方量的甘油与乙醇，混合均匀，精密加入处方量的盐酸奥达特罗与格隆溴铵和高分子量透明质酸，混合均匀，用稀盐酸调节pH至4.5至5.5，将所得药液转移至添加了HFA(氢氟烷烃)的混合容器中。所制备的吸入喷雾剂其具体的成分组成，如表31所示。
表31奥达特罗–格隆溴铵–透明质酸吸入喷雾剂的成分组成

盐酸奥达特罗–雷芬那辛–透明质酸吸入喷雾剂的制备
称取处方量的依地酸二钠，混合均匀，精密加入处方量的盐酸奥达特罗与雷芬那辛和高分子量透明质酸，混合均匀，用柠檬酸调节pH至4.5至5.5，灌装制成吸入喷雾剂。所制备的吸入喷雾剂其具体的成分组成，如表32所示。
表32奥达特罗–雷芬那辛–透明质酸吸入喷雾剂的成分组成
盐酸奥达特罗–雷芬那辛–透明质酸气雾剂的制备
称取处方量的丙二醇和乙醇，混合均匀，精密加入处方量的盐酸奥达特罗与雷芬那辛和高分子量透明质酸，混合均匀，将所得药液转移至添加了HFA的混合容器中，混合、再循环并装填入特制容器中。所制备的气雾剂其具体的成分组成，如表33所示。
表33奥达特罗–雷芬那辛–透明质酸气雾剂的成分组成
盐酸奥达特罗–格隆溴铵–透明质酸气雾剂的制备
称取处方量的油酸乙酸与吐温80,混合均匀，精密加入处方量的维兰特罗、格隆溴铵和高分子量透明质酸，混合均匀，将所得药液转移至添加了HFA的混合容器中。具体配方见表34。
表34格隆溴铵–维兰特罗–透明质酸气雾剂配方

盐酸奥达特罗–格隆溴铵–透明质酸气雾剂的制备
称取处方量的氯化钠、EDTA用注射用水溶解，混合均匀，精密加入处方量的维兰特罗与格隆溴铵和高分子量透明质酸，混合均匀，用柠檬酸、柠檬酸钠缓冲液调节pH。将所得药液转移低密度聚乙烯小瓶内，并用铝箔密封，具体配方见表35。
表35格隆溴铵–维兰特罗–透明质酸气雾剂配方
盐酸奥达特罗–格隆溴铵–透明质酸气雾剂的制备
称取处方量的氯化钠、EDTA用注射用水溶解，混合均匀，精密加入处方量的奥达特罗与格隆溴铵和高分子量透明质酸，混合均匀，用柠檬酸、柠檬酸钠缓冲液调节pH。将所得药液转移低密度聚乙烯小瓶内，并用铝箔密封，具体配方见表36。
表36格隆溴铵–奥达特罗–透明质酸气雾剂配方
上述实施方式仅为本申请的优选实施方式，不能以此来限定本申请保护的范围，本领域的技术人员在本申请的基础上所做的任何非实质性的变化及替换均属于本申请所要求保护的范围。

Claims (15)

  1. 一种吸入用药物组合物，包括：
    长效β2激动剂或其药学上可接受的盐；和
    长效毒蕈碱拮抗药或其药学上可接受的盐，
    其中
    所述长效β2激动剂包括奥达特罗；或
    所述长效β2激动剂包括阿福特罗，且所述组合物的pH值为3.5–5.5；或
    所述长效β2激动剂包括茚达特罗，且所述组合物的pH值为2.5–4.5；或
    所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物的pH值为3.5–5.5；或
    所述长效毒蕈碱拮抗药包括格隆溴铵，且所述组合物的pH值为2.5–4.5；或
    所述长效毒蕈碱拮抗药包括噻托溴铵，且所述组合物的pH值为2.0–4.0。
  2. 如权利要求1所述的组合物，其中所述长效β2激动剂选自茚达特罗、福莫特罗、阿福特罗、维兰特罗、卡莫特罗、以及奥达特罗所组成的组中的至少一个。
  3. 如权利要求1或2所述的组合物，其中所述长效毒蕈碱拮抗药选自格隆溴铵、乌美溴铵、噻托溴铵、阿地溴铵、以及雷芬那辛所组成的组中的至少一个。
  4. 如权利要求1至3任一所述的组合物，其中所述长效β2激动剂或其药学上可接受的盐的含量为1–100μg/mL，可选地5–100μg/mL。
  5. 如权利要求1至4任一所述的组合物，其中所述长效毒蕈碱拮抗药或其药学上可接受的盐的含量为1–100μg/mL，可选地5–100μg/mL。
  6. 如权利要求1至5任一所述的组合物，其中所述长效β2激动剂或其药学上可接受的盐和所述长效毒蕈碱拮抗药或其药学上可接受的盐的重量比例为100:1–1:100，可选地为1:80–80:1，可选地为1:60–60:1，可选地为1:50–50:1，可选地为1:40–40:1，可选地为1:30–30:1，可选地为1:20–20:1，可选地为1:15–15:1。
  7. 如权利要求1至6任一所述的组合物，其中所述长效β2激动剂包括奥达特罗，且所述长效毒蕈碱拮抗药包括雷芬那辛；
    可选地，所述组合物的pH值为4.0–5.5；
    可选地，所述组合物还包括EDTA。
  8. 如权利要求1至6任一所述的组合物，其中所述长效β2激动剂包括阿福特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物的pH值为4.0–5.5；
    可选地，所述组合物的pH值为4.5–5.5；
    可选地，所述组合物的pH值为4.0–5.0；
    可选地，所述组合物还包括EDTA；
    可选地，所述组合物还包括缓冲液，
    可选地，所述缓冲液为柠檬酸/柠檬酸盐缓冲液；
    可选地，所述缓冲液为柠檬酸/柠檬酸钠缓冲液；
    可选地，所述缓冲液的浓度为0.1mM至20mM；
    可选地，所述组合物还包括氯化钠；
    可选地，在所述组合物中，所述氯化钠的重量百分比为0.01％–1.00％。
  9. 如权利要求1至6任一所述的组合物，其中所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括格隆溴铵，且所述组合物的pH值为2.5–4.0；
    可选地，所述组合物的pH值为3.0–4.0；
    可选地，所述组合物的pH值为2.5–3.5；
    可选地，所述组合物的pH值为3.0–3.5；
    可选地，所述组合物还包括EDTA和/或环糊精；
    可选地，所述组合物还包括环糊精；
    可选地，所述组合物还包括EDTA和环糊精；
    可选地，所述组合物还包括透明质酸钠；
    可选地，所述组合物还包括透明质酸钠，以及选自由EDTA和环糊精所组成的组中的至少一个；
    可选地，所述组合物还包括透明质酸钠和环糊精。
  10. 如权利要求1至6任一所述的组合物，其中所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括雷芬那辛，且所述组合物的pH值为3.0–4.5；
    可选地，所述组合物的pH值为3.5–4.5；
    可选地，所述组合物的pH值为3.5–4.0；
    可选地，所述组合物的pH值为4.0–4.5；
    可选地，所述组合物还包括EDTA和/或环糊精；
    可选地，所述组合物还包括环糊精；
    可选地，所述组合物还包括EDTA和环糊精。
  11. 如权利要求1至6任一所述的组合物，其中所述长效β2激动剂包括茚达特罗，所述长效毒蕈碱拮抗药包括噻托溴铵，且所述组合物的pH值为2.0–4.0；
    可选地，所述组合物的pH值为2.5–4.0；
    可选地，所述组合物的pH值为2.5–3.5；
    可选地，所述组合物的pH值为2.5–3.0；
    可选地，所述组合物还包括环糊精。
  12. 如权利要求1至11任一所述的组合物，还包括透明质酸或其药学上可接受的盐；
    可选地，所述透明质酸是高分子量透明质酸；
    可选地，所述透明质酸的重量百分比为0.01％–0.50％。
  13. 如权利要求1至12任一所述的组合物，还包括氯化钠、EDTA或其药学上可接受的盐类、和/或环糊精或其衍生物类或其药学上可接受的盐类；
    可选地，所述环糊精包括α-环糊精、β-环糊精或γ-环糊精；
    可选地，所述环糊精包括羟丙基-β-环糊精或磺丁基-β-环糊精；
    可选地，所述氯化钠的重量百分比为0.01％–1.00％；
    可选地，所述EDTA或其药学上可接受的盐类的重量百分比为0.001％–0.100％；
    可选地，所述环糊精的重量百分比为0.01％–10％，可选地为0.01％–1.00％。
  14. 如权利要求1至13任一所述的组合物，用于预防或治疗呼吸系统疾病，特别是用于作为预防或治疗呼吸系统疾病的吸入用药物组合物。
  15. 如权利要求14所述的组合物，其中所述呼吸系统疾病包括哮喘或慢性阻塞性肺病。
PCT/CN2023/116985 2022-09-05 2023-09-05 预防或治疗呼吸系统疾病的吸入用药物组合物 WO2024051683A1 (zh)

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