WO2022148418A1 - Pharmaceutical composition capable of being delivered by metered dose inhaler - Google Patents

Pharmaceutical composition capable of being delivered by metered dose inhaler Download PDF

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Publication number
WO2022148418A1
WO2022148418A1 PCT/CN2022/070643 CN2022070643W WO2022148418A1 WO 2022148418 A1 WO2022148418 A1 WO 2022148418A1 CN 2022070643 W CN2022070643 W CN 2022070643W WO 2022148418 A1 WO2022148418 A1 WO 2022148418A1
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leu
composition
suspended particles
composition according
particles
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PCT/CN2022/070643
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French (fr)
Chinese (zh)
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仝新勇
邹爱峰
喻宙
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202280009160.5A priority Critical patent/CN116710104A/en
Publication of WO2022148418A1 publication Critical patent/WO2022148418A1/en

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a pharmaceutical composition that can be delivered by a metered dose inhaler and a preparation method.
  • Inhaled formulations have the advantages of rapid onset of action, low doses, and few systemic side effects.
  • An inhaler is a device known to deliver an active agent to a patient's respiratory tract.
  • Various inhaler systems are already commercially available. Obtained, three common inhalers are dry powder inhalers, nebulizers, and metered dose inhalers (MDIs).
  • MDIs metered dose inhalers
  • MDIs can be used to deliver drugs in dissolved or suspended form. When activated, MDIs can propel active agent-containing aerosol droplets into the respiratory tract through a relatively high vapor pressure propellant, whereas dry powder inhalers typically rely on the patient's Inspiratory action draws the drug in dry powder form into the respiratory tract. Active agents delivered by MDI are typically dispersed in the propellant in particulate form, and in order to form fine particles, the active agent is typically micronized. Active agent fine particles suspended in a propellant have a tendency to rapidly aggregate or flocculate, and aggregation or flocculation of these fine particles may result in a tendency to complicate the delivery of the active agent.
  • agglomeration or flocculation can lead to mechanical failures, such as may be caused by blockage of the valve opening of the inhaler container; agglomeration or flocculation of drug particles can also lead to rapid deposition or thickening of drug particles, which may lead to Dose delivery is inconsistent, which is especially troublesome for high potency, low dose drugs.
  • Another problem associated with such suspension MDI formulations is crystal growth during drug storage, which can lead to a decrease in inhaler performance and uniformity of MDI dose delivered over time.
  • WO2010138862 discloses a co-suspension that can be delivered by a metered dose inhaler, in which particulate phospholipid particles are used as a carrier to maintain the suspension
  • the dosage of its carrier particles is too high, resulting in a small amount of drug loading per unit dose, and multiple administrations are required per unit time to exert its efficacy.
  • compositions that can be delivered by a metered dose inhaler.
  • the present disclosure provides a pharmaceutical composition deliverable by a metered dose inhaler, comprising:
  • a first active agent in some embodiments, is selected from the group consisting of corticosteroids, long-acting beta agonists, long-acting anticholinergics, short-acting beta-agonists, short-acting anticholinergics one or more of alkaloids, phosphodiesterase inhibitors, anti-fibrotic drugs, and inhalable proteins, and
  • Inhalable suspended particles comprising hydrophobic amino acids or peptides containing hydrophobic amino acid residues.
  • Supended particles refers to those materials or combinations of materials that are suitable for respiratory delivery and can serve as carriers for active agent particles that interact with the active agent particles to repeatedly deliver the active agent to the respiratory tract.
  • the suspending particles described in this disclosure are dispersed in a suspending medium containing a propellant and have a shape, size or surface characteristics that can be formulated to achieve desired suspension stability or active agent delivery properties.
  • first active agent is meant that a second active agent may optionally be included in the composition.
  • hydrophobic amino acid refers to an amino acid with a hydrophobic side chain
  • exemplary hydrophobic amino acids include but are not limited to: leucine (leu), isoleucine (ile), phenylalanine (phe) , tryptophan (Trp), valine (val), methionine (met), cysteine (cys), tyrosine (tyr) and alanine (ala).
  • corticosteroids include, but are not limited to: budesonide, ciclesonide, fluticasone, mometasone, beclomethasone, flunisolide, and their pharmaceutically acceptable esters and hydrates;
  • optional "Long-acting beta agonists” include, but are not limited to: salmeterol, formoterol, indacaterol, milverterol, olodaterol, vilanterol, and their pharmaceutically acceptable Accepted salts;
  • optional "long-acting anticholinergics” (LAMAs) include, but are not limited to: aclidinium, glycopyrronium, tiotropium, umeclidinium, umeclidinium, and their pharmaceutically acceptable salts;
  • optional "short-acting beta agonists” include, but are not limited to: fenoterol, salbutamol, oxymethylene terbutaline, terbutaline, and their pharmaceutically acceptable salts ;
  • the first active agent is present in suspended particles.
  • "Presence in suspended particles” may include the following situations: a) participating in the formation of the walls of the suspended particles; b) embedded in the walls of the suspended particles in solid form; c) encased within them by the suspended particles; or d) a), A combination of any two or three of b) and c).
  • the first active agent is encapsulated within the suspended particles; in another embodiment, the first active agent participates in forming the walls of the suspended particles.
  • the first active agent and the suspending particles are present in a suspending medium to form a co-suspension.
  • co-suspension is meant a suspension of two or more types of particles of different composition in a suspending medium, wherein one type of particle is at least partially associated with one or more other types of particles .
  • the association can result in one or more specific changes in visibility of at least one type of particle suspended in the suspending medium; the specific changes caused by the association can include, for example, one or more of the following: Rate of aggregation or flocculation, rate of separation, settling or thickening behavior, density of paste or sediment, adhesion to vessel walls, adhesion to valve assemblies, and rate and extent of dispersion upon agitation.
  • Exemplary methods for determining the presence of a co-suspension include the following: If one particle type has a specific gravity density greater than the propellant and another particle type has a less specific gravity density than the propellant, visual observation of the coagulation or settling behavior can be used. A method to determine the presence of co-suspension.
  • the substance can be formulated in a form suitable for visual inspection, or the substance can be transferred to a glass vial for visual inspection. After initial agitation, allow the vial to stand long enough to form a settling or thick layer, typically 24 hours, if the observed settling or thick layer is a completely homogeneous or substantially homogeneous single layer, indicating the presence of a common coagulation Suspensions, i.e.
  • a "co-suspension” includes a partial co-suspension in which at least a majority of the different particle types are associated, however, some separation of the different particle types may also be observed.
  • association refers to the interaction or mutual relationship that occurs between different compounds when their surfaces are close to each other. Associations include, for example, adsorption, adhesion, covalent attachment, hydrogen bonding, ionic bonding, electrostatic attraction, Levan der Waals forces, and polar interactions.
  • the suspended particles have a corrugated surface.
  • wrinkleled is meant that the particle surface has a plurality of depressions and/or bulges.
  • the surface of the corrugated suspended particle is optionally continuous or discontinuous; where the suspended particle surface is discontinuous, the surrounding suspending medium can penetrate, pack or spread into the interior of the suspended particle.
  • the suspended particles comprise a hydrophobic amino acid selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, valine, methionine, cysteine, tyrosine and one or more of alanine; preferably one or more of leucine, isoleucine, valine, methionine and alanine; more preferably from leucine, isoleucine one or more of acid and alanine; even more preferably leucine.
  • a hydrophobic amino acid selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, valine, methionine, cysteine, tyrosine and one or more of alanine; preferably one or more of leucine, isoleucine, valine, methionine and alanine; more preferably from leucine, isoleucine one or more of acid and alanine; even more preferably leucine.
  • the suspended particles comprise a dipeptide or tripeptide containing a hydrophobic amino acid residue selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, valine One or more of acid, methionine, cysteine, tyrosine and alanine.
  • the suspended particles comprise a dipeptide containing at least one leucine residue.
  • the aforementioned dipeptide can be selected from: leu-leu, leu-gly, leu-ala, leu-val, leu-ile, leu-phe, leu-pro, leu-trp, leu-ser, leu- one or more of tyr, leu-cys, leu-met, leu-asp, leu-asn, leu-gln, leu-glu, leu-thr, leu-lys, leu-arg and leu-his; preferably One or more of leu-leu, leu-gly, leu-ala, leu-val, leu-ile, leu-phe, leu-trp, leu-tyr, leu-cys and leu-met; more preferred One or more of leu-leu, leu-ala, leu-val and leu-ile; even more preferably leu-leu.
  • the suspended particles comprise tripeptides containing at least 2 leucine residues.
  • the tripeptide consists of 2 leucine residues and 1 selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, valine, methionine, half Residue composition of cystine, tyrosine and alanine.
  • the tripeptide may be selected from the group consisting of: leu-leu-leu, leu-leu-ile, leu-ile-leu, leu-leu-phe, leu-phe-leu, leu-leu- trp, leu-trp-leu, leu-leu-val, leu-val-leu, leu-leu-met, leu-met-leu, leu-leu-cys, leu-cys-leu, leu-leu-tyr, one or more of leu-tyr-leu, leu-leu-ala and leu-ala-leu; preferably selected from leu-leu-leu, leu-leu-ile, leu-ile-leu, leu-leu-val one or more of , leu-val-leu, eu-leu-ala and leu-ala-leu; more preferably selected from among leu
  • the suspending particles further comprise a polymer that is substantially insoluble in the suspending medium.
  • substantially insoluble means that the substance is completely insoluble or poorly soluble in a particular solvent. In some embodiments, it is meant that a particular solute has a solubility of less than 1 part of solute per 100 parts of solvent.
  • the polymer comprises glucuronic acid units, and the polymer is preferably hyaluronic acid or a pharmaceutically acceptable salt thereof, including but not limited to sodium, potassium, ammonium, calcium, and magnesium salts , more preferably sodium hyaluronate.
  • the average molecular weight of the sodium hyaluronate is 1,000-1,000,000 Daltons, preferably 2,000-500,000 Daltons, more preferably 3,000-300,000 Daltons, even more preferably 10,000-100,000 Daltons.
  • the mass ratio of hydrophobic amino acids or peptides containing hydrophobic amino acid residues in the suspended particles to the polymer is 0.5 to 20, specifically 0.5, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.25, 5.5, 5.75, 6.0, 6.25, 6.5, 6.75, 7.0, 7.25, 7.5, 7.75, 8.0, 8.25, 8.5, 8.75, 9.0, 9.25, 9.5, 9.75, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20; preferably 1 to 10, 2-8 are more preferable,
  • the suspended particles of the present disclosure may further comprise one or more surfactants selected from the group consisting of Tween 20, Tween 40, Tween 60, Tween 65, Tween 80 , Tween 85, lauryl alcohol 400, Span 83, Span 85, Span 60, Span 80, magnesium lauryl sulfate, glycerol monooleate and lauric acid; preferably Tween 80.
  • one or more surfactants selected from the group consisting of Tween 20, Tween 40, Tween 60, Tween 65, Tween 80 , Tween 85, lauryl alcohol 400, Span 83, Span 85, Span 60, Span 80, magnesium lauryl sulfate, glycerol monooleate and lauric acid; preferably Tween 80.
  • the suspended particles of the present disclosure do not contain phospholipids, such as common distearoyl phosphatidyl choline (DSPC), dipalmitoyl phosphatidyl choline (DPPC), etc. Further, the suspended particles also do not contain phospholipids. Contains calcium salts, such as calcium chloride, etc.
  • the mass ratio of the inhalable suspended particles to the first active agent is 0.2 to 10, specifically 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0; preferably 0.5 to 5, more preferably 0.8 to 3, even more preferably 1.2 to 1.6.
  • the respirable suspended particles are contained in the suspension medium at a concentration of 1 mg/ml to 20 mg/ml, specifically 1 mg/ml, 1.5 mg/ml, 2 mg/ml ml, 2.5mg/ml, 3mg/ml, 3.5mg/ml, 4mg/ml, 4.5mg/ml, 5mg/ml, 5.5mg/ml, 6mg/ml, 6.5mg/ml, 7mg/ml, 7.5mg/ml ml, 8mg/ml, 8.5mg/ml, 9mg/ml, 9.5mg/ml, 10mg/ml, 10.5mg/ml, 11mg/ml, 11.5mg/ml, 12mg/ml, 12.5mg/ml, 13mg/ml , 13.5mg/ml, 14mg/ml, 14.5mg/ml, 15
  • the respirable suspended particles of the present disclosure have aerodynamic properties suitable for pulmonary delivery.
  • the respirable suspended particles have an MMAD of 0.5 to 10 ⁇ m, preferably 1 to 5 ⁇ m, and more preferably 2 to 2 ⁇ m. 4 ⁇ m, even more preferably 3 to 4 ⁇ m.
  • the respirable suspended particles have a volume median geometric diameter of 1 to 10 ⁇ m, preferably 2 to 8 ⁇ m, more preferably 3 to 6 ⁇ m, even more preferably 4 to 5 ⁇ m.
  • the first active agent comprises a long-acting beta agonist, which can be used as the active substance alone or in combination with other types of active substances Present in the suspending medium, the long-acting beta agonist is selected from one or more of salmeterol, formoterol, indacaterol, milverterol, olodaterol and vilanterol species, including any pharmaceutically acceptable salts thereof; pharmaceutically acceptable salts include inorganic salts such as hydrochloric acid, hydrobromic acid, sulfonic acid and phosphoric acid, and organic salts such as fumaric acid, maleic acid, acetic acid, lactic acid, citric acid, Tartaric acid, ascorbic acid, succinic acid, glutaric acid, gluconic acid, glyceric acid, oleic acid, benzoic acid, p-methoxybenzoic acid, salicylic acid, o- or p-hydroxybenzoic acid, p-chloro
  • the long-acting beta agonist is indacaterol or a pharmaceutically acceptable salt thereof, preferably indacaterol acetate or indacaterol maleate, more preferably indacaterol acetate Luo.
  • the present disclosure has no particular limitation on the form of the indacaterol or a pharmaceutically acceptable salt thereof, which may be crystalline or amorphous particles, preferably crystalline particles.
  • the particles of indacaterol or a pharmaceutically acceptable salt thereof of the present disclosure also possess aerodynamic properties suitable for pulmonary delivery.
  • the particles of indacaterol or a pharmaceutically acceptable salt thereof have an MMAD of 0.5 ⁇ 10 ⁇ m, preferably 1 to 6 ⁇ m, more preferably 2 to 5 ⁇ m, even more preferably 3 to 4 ⁇ m.
  • the volume median geometric diameter of the particles of indacaterol or a pharmaceutically acceptable salt thereof is 0.2-10 ⁇ m, preferably 0.5-5 ⁇ m, more preferably 1-4 ⁇ m, even more preferably 1.5-10 ⁇ m 3 ⁇ m.
  • the particles of indacaterol or a pharmaceutically acceptable salt thereof are present in the co-suspension at a certain concentration, and/or may be present at a certain concentration each time the metered dose inhaler is activated
  • the dose is delivered, and unless otherwise specified, the concentration or dose of indacaterol or a pharmaceutically acceptable salt thereof described in the present disclosure is calculated in equimolar conversion of indacaterol free base.
  • the particles of indacaterol or a pharmaceutically acceptable salt thereof coexist with the suspending particles in a suspension medium to form a co-suspension
  • concentration of indacaterol in the composition is 0.5 mg/ml to 10 mg/ml ml, specifically 0.5mg/ml, 1mg/ml, 1.5mg/ml, 2mg/ml, 2.5mg/ml, 3mg/ml, 3.5mg/ml, 4mg/ml, 4.5mg/ml, 5mg/ml, 5.5mg/ml, 6mg/ml, 6.5mg/ml, 7mg/ml, 7.5mg/ml, 8mg/ml, 8.5mg/ml, 9mg/ml, 9.5mg/ml, 10mg/ml; preferably 0.8mg/ml ml to 5 mg/ml, more preferably 1 mg/ml to 4 mg/ml
  • the indacaterol is included in the composition at a concentration sufficient to deliver a dose of indacaterol of 10-300 ⁇ g per actuation of the metered dose inhaler, specifically 10 ⁇ g, 20 ⁇ g, 30 ⁇ g , 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 105 ⁇ g, 110 ⁇ g, 115 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 150 ⁇ g, 160 ⁇ g, 170 ⁇ g, 180 ⁇ g, 190 ⁇ g, 180 ⁇ g, 190 ⁇ g, 180 ⁇ g, 190 ⁇ g , 220 ⁇ g, 230 ⁇ g, 240 ⁇ g, 250 ⁇ g, 260 ⁇ g, 270 ⁇ g, 280 ⁇ g, 290 ⁇ g, 300 ⁇ g; preferably 30-200 ⁇ g, more preferably 50-150 ⁇ g, even more preferably 80-120 ⁇ g.
  • the first active agent of the present disclosure comprises a corticosteroid, which may be present in the suspending medium as the active substance alone or in combination with other types of active substances, the corticosteroid being selected from the group consisting of budesonide One or more of acetonide, ciclesonide, fluticasone, mometasone, beclomethasone, and flunisolide, including any pharmaceutically acceptable esters and hydrates thereof.
  • the corticosteroid is fluticasone or a pharmaceutically acceptable ester and hydrate thereof, preferably fluticasone furoate or fluticasone propionate, more preferably fluticasone furoate.
  • the fluticasone including fluticasone furoate and fluticasone propionate, or pharmaceutically acceptable esters and hydrates thereof are crystalline or amorphous particles, preferably crystalline particles.
  • the fluticasone furoate particles of the present disclosure also have aerodynamic properties suitable for pulmonary delivery.
  • the MMAD of the fluticasone furoate particles is 0.5-10 ⁇ m, preferably 1-6 ⁇ m, more preferably 2- 5 ⁇ m, even more preferably 3 to 4 ⁇ m.
  • the fluticasone furoate particles have a volume median geometric diameter of 0.2 to 10 ⁇ m, preferably 0.5 to 5 ⁇ m, more preferably 1 to 4 ⁇ m, even more preferably 1.5 to 3 ⁇ m.
  • the fluticasone furoate particles and the suspending particles coexist in a suspension medium to form a co-suspension
  • concentration of fluticasone furoate in the composition is 0.2 mg/ml to 10 mg/ml, specifically 0.2 mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 1.0mg/ml, 1.5mg/ml, 2.0mg/ml, 2.5mg/ml, 3.0mg/ml, 3.5mg/ml, 4.0mg/ml, 4.5mg/ml, 5.0mg/ml, 5.5mg/ml, 6.0mg/ml, 6.5mg/ml, 7.0mg/ml, 7.5mg/ml, 8.0mg/ml, 8.5mg/ml, 9.0mg/ml, 9.5mg/ml, 10.0mg/ml, preferably 0.5mg/ml, preferably 0.5
  • the concentration of fluticasone furoate included in the composition is sufficient to deliver a dose of 10-300 ⁇ g of fluticasone furoate per actuation of the metered dose inhaler, specifically 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g , 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 105 ⁇ g, 110 ⁇ g, 115 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 150 ⁇ g, 160 ⁇ g, 170 ⁇ g, 180 ⁇ g, 222 ⁇ g, 190 ⁇ g, 200 ⁇ g, 190 ⁇ g , 230 ⁇ g, 240 ⁇ g, 250 ⁇ g, 260 ⁇ g, 270 ⁇ g, 280 ⁇ g, 290 ⁇ g, 300 ⁇ g; preferably 30-200 ⁇ g, more preferably 50-150 ⁇ g, even more preferably 80-120 ⁇ g.
  • compositions of the present disclosure further comprise a second active agent comprising a long-acting anticholinergic agent selected from the group consisting of aclidinium, One or more of glycopyrronium, tiotropium, umeclidinium, and umeclidinium, including any pharmaceutically acceptable salts thereof.
  • a second active agent comprising a long-acting anticholinergic agent selected from the group consisting of aclidinium, One or more of glycopyrronium, tiotropium, umeclidinium, and umeclidinium, including any pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts include inorganic salts such as fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate; and organic salts such as formate, acetate, trifluoroacetic acid Salt, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenylethyl Acid or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthyl-2-carboxylate, 3-hydroxynaphthyl-2-carboxylate, methanesulfonate acid and benzene sulfonate.
  • inorganic salts such as fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate
  • organic salts such as formate, acetate, trifluoroacetic acid Salt
  • the second active agent is glycopyrronium bromide, a bromide of glycopyrronium.
  • the glycopyrronium bromide is present in suspended particles.
  • the glycopyrronium bromide is crystalline or amorphous particles and coexists with the suspending particles in a suspending medium to form a co-suspension.
  • a portion of the glycopyrronium bromide is present in the suspended particles and the remainder is present in the suspension medium with the suspended particles to form a co-suspension.
  • the glycopyrronium bromide in the compositions of the present disclosure is present in a certain concentration and/or can be delivered in a certain dose per actuation of the metered dose inhaler , unless otherwise specified, the concentration or dosage of glycopyrronium bromide described in the present disclosure is calculated by equimolar conversion of glycopyrronium bromide without bromide ions.
  • the concentration of glycopyrronium bromide in the composition of the present disclosure is 0.1 mg/ml to 5 mg/ml, specifically 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1mg/ml, 1.1mg/ml, 1.2mg/ml, 1.3mg/ml, 1.4mg/ml, 1.5 mg/ml, 1.6mg/ml, 1.7mg/ml, 1.8mg/ml, 1.9mg/ml, 2mg/ml, 2.5mg/ml, 3mg/ml, 3.5mg/ml, 4mg/ml, 4.5mg/ml , 5mg/ml, preferably 0.2mg/ml to 4mg/ml, more preferably
  • the concentration of glycopyrronium bromide included in the composition is sufficient to deliver a dose of glycopyrronium bromide of 5 to 120 ⁇ g per actuation of the metered dose inhaler, specifically 5 ⁇ g, 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, 100 ⁇ g, 105 ⁇ g, 110 ⁇ g, 115 ⁇ g, 120 ⁇ g; preferably 10-100 ⁇ g, more preferably 20-80 ⁇ g, even more preferably 40-60 ⁇ g .
  • the glycopyrronium bromide in the composition of the present disclosure also has aerodynamic properties suitable for pulmonary delivery.
  • the MMAD of the glycopyrronium bromide is 0.5-10 ⁇ m, preferably 1-6 ⁇ m, more preferably 2 to 5 ⁇ m, even more preferably 3 to 4 ⁇ m.
  • Suitable propellants in the suspension medium of the present disclosure include hydrofluoroalkanes (HFA), perfluoroalkanes (PFC) and chlorofluoroalkanes (CFC).
  • Perfluoroalkanes preferably hydrofluoroalkanes, such as 1,1,1,2 - tetrafluoroethane ( CF3CH2F ) (HFA-134a), 1,1,1,2,3,3,3- Heptafluoro-n-propane (CF 3 CHFCF 3 ) (HFA-227), 1,1-difluoroethane (CF 2 HCH 3 ), and combinations thereof, more preferably HFA-134a.
  • composition of the present disclosure can effectively reduce the frequency of administration to patients and is convenient for patients to use.
  • the composition is suitable for administration once or twice a day; preferably, it is suitable for administration once a day.
  • each administration usually requires 1 to 2 swipes, preferably 1 swipe each time.
  • the present disclosure also provides a metered dose inhalation product comprising a container canister with an outlet valve with an actuator for delivering a metered volume, the container canister comprising the composition provided by the first aspect.
  • a metered dose inhaler comprising the composition of the first aspect has excellent delivery accuracy and uniformity, and in some embodiments, the metered dose inhaler of the present disclosure is delivered by ⁇ 30% or more throughout the entire process of emptying the container canister.
  • High delivered dose uniformity ie, DDU
  • composition and the inhaler of the present disclosure also have excellent pulmonary delivery efficiency, and the fine particle fraction (FPF ⁇ 5 ⁇ m ) of each active substance can reach more than 40%, preferably more than 50%, more preferably more than 60%; the composition During the emission process, the percentage of the propelled dose (ED) of each active substance to the nominal dose (ND) can reach more than 80%, preferably more than 85%, more preferably more than 90%.
  • the present disclosure also provides a method for preparing the composition of the first aspect, comprising the steps of:
  • the respirable suspended particles are prepared by spray-drying a carrier solution, and the components contained in the suspended particles are pre-dissolved in the carrier solution.
  • the first active agent is present in the suspended particles, and the method of preparation further comprises the step of dispersing the suspended particles loaded with the first active agent into a suspension medium.
  • the first active agent is co-suspended with the suspending particles
  • the method of preparation further comprises the step of mixing the first active agent and the suspending particles in a suspending medium to form a co-suspension.
  • the method further comprises the step of dissolving a second active agent in the carrier solution prior to spray drying, the second active agent comprising a long-acting anticholinergic, the long-acting anticholinergic Selected from aclidinium, glycopyrronium, tiotropium, umeclidinium, and umeclidinium, including any pharmaceutically acceptable salts thereof.
  • the second active agent is glycopyrronium bromide
  • the glycopyrronium bromide concentration is as described in the first aspect.
  • the solvent of the solution is selected from one or more of water, methanol, ethanol, n-propanol, isopropanol and n-butanol, preferably water, ethanol or a mixture thereof, more preferably water .
  • a porogen is further dissolved in the carrier solution, and the porogen is selected from one or more of ammonium bicarbonate, urea, polyvinylpyrrolidone, polyethylene glycol and polyvinyl alcohol, preferably carbonic acid Ammonium hydrogen.
  • the drying gas used in the spray drying step is nitrogen, and the nitrogen flow rate is 100L/h ⁇ 2000L/h, preferably 200L/h ⁇ 1500L/h, more preferably 300L/h ⁇ 1000L/h , even more preferably 400L/h ⁇ 800L/h.
  • the inlet temperature of the spray drying step is 50-200°C, preferably 75-150°C, more preferably 90-120°C, even more preferably 100°C.
  • the feed rate of the spray drying step is 1-30 ml/min, preferably 2-20 ml/min, more preferably 3-15 ml/min, even more preferably 4-10 ml/min.
  • the present disclosure also provides the use of the composition of the first aspect in the preparation of a medicament for the treatment of inflammatory or obstructive pulmonary diseases
  • the diseases can be selected from asthma, chronic obstructive pulmonary disease, secondary airway hyperresponsiveness Exacerbations, allergic rhinitis, sinusitis, pulmonary vasoconstriction, respiratory disorders, respiratory distress syndrome, pulmonary hypertension, and pulmonary inflammation and obstruction associated with cystic fibrosis.
  • the disease is chronic obstructive pulmonary disease (COPD), more preferably moderate to severe chronic obstructive pulmonary disease.
  • COPD chronic obstructive pulmonary disease
  • Active agent or “active substance” means the active ingredient of a drug, also known as an active pharmaceutical ingredient (API).
  • Volume median geometric diameter or " D50” refers to the median diameter of a plurality of particles under optical measurement, ie particles larger and smaller than this diameter each account for 50% of the total volume.
  • D90 means that 90% of the total volume of the particles is smaller than this diameter
  • D10 means that 10 % of the total volume of the particles is smaller than this diameter.
  • D 4,3 refers to the volume fourth moment mean diameter of the plurality of particles.
  • Mass Median Aerodynamic Diameter or “MMAD” means that particles larger and smaller than the aerodynamic diameter each account for 50% of the total mass.
  • a “fine particle dose” or “FPD” refers to a dose of active ingredient below a specified minimum aerodynamic particle size.
  • Fine Particulate Fraction or “FPF” refers to the proportion of active ingredient that is smaller than the specified minimum aerodynamic size relative to the propellant or nominal dose.
  • FPF ⁇ 5 ⁇ m refers to the proportion of particles having an aerodynamic diameter of less than 5 ⁇ m in the sprayed or nominal dose.
  • ED or "ejection dose” or “delivered dose” refers to the mass of drug that leaves the inhaler device when administered.
  • ND or “nominal dose” or “labeled dose” refers to the total mass of the labeled drug in a single dose of an inhaler.
  • FIG. 1 shows a scanning electron microscope (SEM) image of the carrier particles obtained by spray drying in Example 2.
  • SEM scanning electron microscope
  • FIG. 2 shows a scanning electron microscope (SEM) image of the carrier particles obtained by spray drying in Example 1.
  • SEM scanning electron microscope
  • FIG. 3 shows a scanning electron microscope (SEM) image of the carrier particles obtained by spray drying in Example 7.
  • SEM scanning electron microscope
  • sequence reagent source 1 fluticasone furoate Orient Pharmaceutical Co., Ltd. 2 Glycopyrrolate Jiangsu Hengrui Pharmaceutical Co., Ltd. 3 Indacaterol acetate Jiangsu Hengrui Pharmaceutical Co., Ltd. 4 Budesonide Minakem Dunkerque
  • the carrier particles were prepared by a method similar to that in Example 1, and filled to obtain an aerosol.
  • the main difference is that the carrier particles contain Tween 80, the dosage is 4.058mg/can, and does not contain glycopyrronium bromide and indacaterol acetate; budesonide (137 ⁇ g/press, 19.2mg/can) is mixed with the carrier during filling. Granular mix.
  • the carrier particles of Example 2 were observed with a scanning electron microscope (SEM, FEI Sirion 200), and the morphological results were shown in Figure 1. It can be seen that the carrier particles have a wrinkled shape.
  • Example 1 and Example 2 filled in the glass jar were mixed by vortex for 20 minutes, so that the carrier particles and the fluticasone furoate/indacaterol acetate particles were uniformly mixed. After inversion at room temperature for three days, the particles were shaken gently to disperse the particles evenly, and then left standing at room temperature to observe the suspension of the sample.
  • Example 1 and Example 2 can be stably suspended for more than 120 s without obvious sedimentation or suspension, which is beneficial to the accuracy and uniformity of the delivered dose during administration.
  • the sample continued to stand for 24 hours, the carrier particles and the active material particles settled into a uniform single layer, and no obvious separation phenomenon was observed.
  • budesonide inhalation aerosol (trade name BREZTRI AEROSPHERE; co-suspension of budesonide/glycopyrronium bromide/formoterol fumarate particles and DSPC carrier particles) was selected for stability evaluation using the same method. , the results show that it can be stably suspended for about 30s, indicating that the aerosol of the present disclosure has more excellent stability.
  • the carrier particles were prepared by a method similar to that in Example 1, and filled to obtain an aerosol.
  • the main difference is that the carrier particles contain trileucine and do not contain sodium hyaluronate, and also contain Tween 80 (the dosage is 4.058 mg/can).
  • the aerosol samples were tested for fine particle aerodynamic properties using the same method as in Example 5.
  • the measurement results are as follows.
  • the carrier particles were prepared by a method similar to that in Example 1, and filled to obtain an aerosol.
  • the main difference is that the carrier particles contain only sodium hyaluronate, not trileucine, and the active substance is replaced by budesonide (3.82 mg/can).
  • the electron microscope results are shown in Figure 3.
  • the aerosol samples were tested for fine particle aerodynamic properties using the same method as in Example 5.
  • the measurement results show that the MMAD of the particles in the prepared aerosol is between 4-5 ⁇ m, and the FPF% of budesonide is 28%.
  • the particle density is high and it is difficult to achieve co-suspension.

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Abstract

The present disclosure relates to a pharmaceutical composition capable of being delivered by a metered dose inhaler. Specifically, the pharmaceutical composition contains a suspension medium, a suspended particle, and an active agent. The pharmaceutical composition has excellent stability and delivery uniformity, and is applicable to inhalation therapy of pulmonary diseases.

Description

可通过定量吸入器递送的药物组合物Pharmaceutical compositions deliverable by metered dose inhalers
本申请要求申请日为2021/1/8的中国专利申请202110023409.5和2021/01/18的中国专利申请202110061936.5的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 202110023409.5 with filing date of 2021/1/8 and Chinese patent application 202110061936.5 of 2021/01/18. This application cites the full text of the above Chinese patent application.
技术领域technical field
本公开属于医药领域，涉及一种可通过定量吸入器递送的药物组合物以及制备方法。The present disclosure belongs to the field of medicine, and relates to a pharmaceutical composition that can be delivered by a metered dose inhaler and a preparation method.
背景技术Background technique
吸入制剂具有起效迅速、用药量低、全身副作用小等优势，吸入器是一种已知可以将活性剂递送到患者呼吸道的装置，已有多种不同的吸入器***已经可以通过商业渠道购买获得，三种常见的吸入器为干粉吸入器、喷雾器以及定量吸入器(MDI)。Inhaled formulations have the advantages of rapid onset of action, low doses, and few systemic side effects. An inhaler is a device known to deliver an active agent to a patient's respiratory tract. Various inhaler systems are already commercially available. Obtained, three common inhalers are dry powder inhalers, nebulizers, and metered dose inhalers (MDIs).
MDI可用于递送溶解或悬浮形式的药物，当被启动时，MDI可以通过相对较高蒸汽压的推进剂将含有活性剂的气溶胶液滴推送到呼吸道，而干粉吸入器则通常依赖于患者的吸气作用将干粉形式的药物吸入到呼吸道。通过MDI递送的活性剂通常以微粒形式分散在推进剂中，为了形成微细粒子，通常将活性剂进行微粒化处理。悬浮在推进剂中的活性剂微细粒子具有快速聚集或絮凝的趋势，这些微细粒子的聚集或絮凝可能导致活性剂的递送趋向复杂化。例如，聚集或絮凝可导致机械故障，比如可能会因为吸入器容器的阀口堵塞而引起各种故障；药物颗粒的聚集或絮凝也可以导致药物颗粒的快速沉积或凝稠，这些行为可能会导致剂量递送不一致，这对于高效力的低剂量药物而言尤其麻烦。跟此类悬浮MDI制剂相关的另一问题是，药物贮存期间的晶体生长，这会导致吸入器性能以及MDI递送剂量的均匀性随着时间 而下降。MDIs can be used to deliver drugs in dissolved or suspended form. When activated, MDIs can propel active agent-containing aerosol droplets into the respiratory tract through a relatively high vapor pressure propellant, whereas dry powder inhalers typically rely on the patient's Inspiratory action draws the drug in dry powder form into the respiratory tract. Active agents delivered by MDI are typically dispersed in the propellant in particulate form, and in order to form fine particles, the active agent is typically micronized. Active agent fine particles suspended in a propellant have a tendency to rapidly aggregate or flocculate, and aggregation or flocculation of these fine particles may result in a tendency to complicate the delivery of the active agent. For example, agglomeration or flocculation can lead to mechanical failures, such as may be caused by blockage of the valve opening of the inhaler container; agglomeration or flocculation of drug particles can also lead to rapid deposition or thickening of drug particles, which may lead to Dose delivery is inconsistent, which is especially troublesome for high potency, low dose drugs. Another problem associated with such suspension MDI formulations is crystal growth during drug storage, which can lead to a decrease in inhaler performance and uniformity of MDI dose delivered over time.
一种改善MDI稳定性及递送性能的方式是引入载体颗粒，例如，WO2010138862公开了一种可通过定量吸入器递送的共悬浮液，其中使用了微粒状的磷脂颗粒作为载体，以维持混悬液的稳定性；但其载体颗粒的用量过高，致使单位剂量的载药量较小，单位时间内需要多次给药才可发挥药效。One way to improve the stability and delivery performance of MDI is to introduce carrier particles, for example, WO2010138862 discloses a co-suspension that can be delivered by a metered dose inhaler, in which particulate phospholipid particles are used as a carrier to maintain the suspension However, the dosage of its carrier particles is too high, resulting in a small amount of drug loading per unit dose, and multiple administrations are required per unit time to exert its efficacy.
发明内容SUMMARY OF THE INVENTION
为了克服现有技术的不足，本公开提供了可通过定量吸入器递送的药物组合物。To overcome the deficiencies of the prior art, the present disclosure provides pharmaceutical compositions that can be delivered by a metered dose inhaler.
第一方面，本公开提供一种可通过定量吸入器递送的药物组合物，包括：In a first aspect, the present disclosure provides a pharmaceutical composition deliverable by a metered dose inhaler, comprising:
含有可药用的推进剂的悬浮介质；A suspension medium containing a pharmaceutically acceptable propellant;
第一活性剂，在一些实施方案中，所述第一活性剂选自皮质类固醇、长效β受体激动剂、长效抗胆碱能药、短效β受体激动剂、短效抗胆碱能药、磷酸二酯酶抑制剂、抗纤维化药和可吸入蛋白质中的一种或多种，以及A first active agent, in some embodiments, the first active agent is selected from the group consisting of corticosteroids, long-acting beta agonists, long-acting anticholinergics, short-acting beta-agonists, short-acting anticholinergics one or more of alkaloids, phosphodiesterase inhibitors, anti-fibrotic drugs, and inhalable proteins, and
可吸入的悬浮颗粒，所述悬浮颗粒包含疏水性氨基酸或含有疏水性氨基酸残基的肽。Inhalable suspended particles comprising hydrophobic amino acids or peptides containing hydrophobic amino acid residues.
本公开所述“悬浮颗粒”是指那些适用于呼吸递送并可以作为活性剂颗粒之载体的材料或者材料组合，悬浮颗粒与活性剂颗粒相互作用从而可以重复地将活性剂递送至呼吸道。本公开所述的悬浮颗粒分散在包含推进剂的悬浮介质中，并且具有可以配制成适于达到所需的悬浮稳定性或活性剂递送性能的形状、尺寸或表面特性。"Suspended particles" as used in the present disclosure refers to those materials or combinations of materials that are suitable for respiratory delivery and can serve as carriers for active agent particles that interact with the active agent particles to repeatedly deliver the active agent to the respiratory tract. The suspending particles described in this disclosure are dispersed in a suspending medium containing a propellant and have a shape, size or surface characteristics that can be formulated to achieve desired suspension stability or active agent delivery properties.
所述“第一活性剂”，意指所述组合物中可任选地包含第二活性剂。By "first active agent" is meant that a second active agent may optionally be included in the composition.
所述“疏水性氨基酸”是指具有疏水性侧链的氨基酸，示例性的疏水性氨基酸包括但不限于：亮氨酸(leu)、异亮氨酸(ile)、苯丙氨酸(phe)、色氨酸(Trp)、缬氨酸(val)、蛋氨酸(met)、半胱氨酸(cys)、酪氨酸(tyr)和丙氨酸(ala)。The "hydrophobic amino acid" refers to an amino acid with a hydrophobic side chain, and exemplary hydrophobic amino acids include but are not limited to: leucine (leu), isoleucine (ile), phenylalanine (phe) , tryptophan (Trp), valine (val), methionine (met), cysteine (cys), tyrosine (tyr) and alanine (ala).
可选的“皮质类固醇”包括但不限于：布***、环索奈德、氟替卡松、莫米松、倍氯米松、氟尼缩松，以及它们药学上可接受的酯及水合物；可选的“长效β受体激动剂”(LABA)包括但不限于：沙美特罗、福莫特罗、茚达特罗、米维特罗、奥达特罗、维兰特罗，以及它们药学上可接受的盐；可选的“长效抗胆碱能药”(LAMA)包括但不限于：阿地铵、格隆铵、噻托铵、乌美铵、芜地铵，以及它们药学上可接受的盐；可选的“短效β受体激动剂”(SABA)包括但不限于：非诺特罗、沙丁胺醇、羟甲叔丁肾上腺素、特布他林，以及它们药学上可接受的盐；可选的“短效抗胆碱能药”(SAMA)包括但不限于：异丙托铵、氧托铵，以及它们药学上可接受的盐；可选的“磷酸二酯酶抑制剂”包括针对PDE1、PDE2、PDE3、PDE4和PDE5中一个或多个亚型的抑制剂，具体可以包括但不限于：非明司特、吡拉米司特、罗氟司特、托波力农、米贝拉地尔、莫他匹酮、匹克苯丹、扎达维林、氰胍佐旦、伊马唑旦、沙特力农、洛普力农、阿比茶碱、托巴茶碱、多索茶碱、胆茶碱、南力农、西洛他唑、环己喹酰胺、匹罗昔酮、米利酮、氨吡酮、托拉芬群、帕帕非林，以及它们药学上可接受的盐；可选的“抗纤维化药”包括但不限于：吡非尼酮、尼达尼布、法米替尼、伊马替尼、N-乙酰半胱氨酸，以及它们药学上可接受的盐；可选的“可吸入蛋白质”包括但不限于：胰岛素、α1-抗胰蛋白酶、CSJ117、Pulmozyme、莫拉司丁、阿地白介素、阿替普酶、SNG001、DAS181，以及它们的生物类似物。Alternative "corticosteroids" include, but are not limited to: budesonide, ciclesonide, fluticasone, mometasone, beclomethasone, flunisolide, and their pharmaceutically acceptable esters and hydrates; optional "Long-acting beta agonists" (LABA) include, but are not limited to: salmeterol, formoterol, indacaterol, milverterol, olodaterol, vilanterol, and their pharmaceutically acceptable Accepted salts; optional "long-acting anticholinergics" (LAMAs) include, but are not limited to: aclidinium, glycopyrronium, tiotropium, umeclidinium, umeclidinium, and their pharmaceutically acceptable salts; optional "short-acting beta agonists" (SABAs) include, but are not limited to: fenoterol, salbutamol, oxymethylene terbutaline, terbutaline, and their pharmaceutically acceptable salts ; Optional "short-acting anticholinergic drugs" (SAMAs) include, but are not limited to: ipratropium, oxytropium, and their pharmaceutically acceptable salts; optional "phosphodiesterase inhibitors" Including inhibitors against one or more subtypes of PDE1, PDE2, PDE3, PDE4 and PDE5, specifically including but not limited to: filminlast, piramilast, roflumilast, topollinone, Mibelapadil, Motapidone, Picklebendan, Zadaverine, Cyguanazodane, Imazodane, Satrinone, Loprinone, Abiphylline, Tobaphylline, Dole Sophylline, chophylline, nanlinone, cilostazol, cycloheximide, piloxidone, milidone, ampicillin, torafentran, papafilin, and their pharmaceutically acceptable salt; optional "antifibrotic drugs" include, but are not limited to: pirfenidone, nintedanib, famitinib, imatinib, N-acetylcysteine, and their pharmaceutically acceptable Accepted salts; optional "inhalable proteins" include, but are not limited to: insulin, alpha 1-antitrypsin, CSJ117, Pulmozyme, molastin, aldesleukin, alteplase, SNG001, DAS181, and their biosimilars.
在一些实施方案中，第一活性剂存在于悬浮颗粒中。“存在于悬浮颗粒中”可以包括如下情形：a)参与形成悬浮颗粒的壁；b)以固体形式嵌入到悬浮颗粒的壁中；c)被悬浮颗粒包裹在其内部；或d)a)、b)和c)中任意两者或三者的组合。In some embodiments, the first active agent is present in suspended particles. "Presence in suspended particles" may include the following situations: a) participating in the formation of the walls of the suspended particles; b) embedded in the walls of the suspended particles in solid form; c) encased within them by the suspended particles; or d) a), A combination of any two or three of b) and c).
在一个实施方案中，第一活性剂被悬浮颗粒包裹在其内部；在另一个实施方案中，第一活性剂参与形成悬浮颗粒的壁。In one embodiment, the first active agent is encapsulated within the suspended particles; in another embodiment, the first active agent participates in forming the walls of the suspended particles.
在另一些实施方案中，第一活性剂与悬浮颗粒共存于悬浮介质中以形成 共悬浮液。In other embodiments, the first active agent and the suspending particles are present in a suspending medium to form a co-suspension.
所述“共悬浮液”是指在悬浮介质中具有不同组成的两种或多种类型的颗粒的悬浮液，其中一种类型的颗粒与一种或多种其他类型的颗粒至少发生部分缔合。缔合作用可以导致悬浮在悬浮介质中的至少一种类型的颗粒出现一种或多种特定的可视性变化；缔合作用所引起的特定变化可以包括例如以下的一种或多种变化：聚集或絮凝的速率、分离速率、沉降或凝稠行为、膏状物或沉降物的密度、与容器壁的黏附性、与阀组件的黏附性、以及在搅动时的分散速率和程度。By "co-suspension" is meant a suspension of two or more types of particles of different composition in a suspending medium, wherein one type of particle is at least partially associated with one or more other types of particles . The association can result in one or more specific changes in visibility of at least one type of particle suspended in the suspending medium; the specific changes caused by the association can include, for example, one or more of the following: Rate of aggregation or flocculation, rate of separation, settling or thickening behavior, density of paste or sediment, adhesion to vessel walls, adhesion to valve assemblies, and rate and extent of dispersion upon agitation.
用于判断是否存在共悬浮液的示例性方法包括如下：如果一种颗粒的比重密度大于推进剂而另一种颗粒类型的比重密度小于推进剂，则可以采用可视观察凝稠或沉降行为这一方法来确定共悬浮液是否存在。可以将物质配制成适于目视观察的形式，或者也可以将物质转移到玻璃小瓶中目视观察。在初始搅动后，将小瓶静置足够长的时间以形成沉降或凝稠层，通常为24小时，如果观察到的沉降或凝稠层是完全均匀或基本上均匀的单一层，则表明存在共悬浮液，即基本上无法观察到那些因为它们在推进剂中的浮力差异而引起的分离现象。“共悬浮液”包括部分共悬浮液，其中至少大多数的不同颗粒类型之间发生了缔合，然而，也可以观察到不同颗粒类型的少许分离。Exemplary methods for determining the presence of a co-suspension include the following: If one particle type has a specific gravity density greater than the propellant and another particle type has a less specific gravity density than the propellant, visual observation of the coagulation or settling behavior can be used. A method to determine the presence of co-suspension. The substance can be formulated in a form suitable for visual inspection, or the substance can be transferred to a glass vial for visual inspection. After initial agitation, allow the vial to stand long enough to form a settling or thick layer, typically 24 hours, if the observed settling or thick layer is a completely homogeneous or substantially homogeneous single layer, indicating the presence of a common coagulation Suspensions, i.e. those separations due to their differences in buoyancy in the propellant are essentially unobservable. A "co-suspension" includes a partial co-suspension in which at least a majority of the different particle types are associated, however, some separation of the different particle types may also be observed.
前述“缔合”是指不同化合物个体表面接近时，在它们之间所发生的相互作用或相互关系。缔合包括例如吸附、黏附、共价连接、氢键、离子键、静电吸引、利范德华力以及极性作用。The aforementioned "association" refers to the interaction or mutual relationship that occurs between different compounds when their surfaces are close to each other. Associations include, for example, adsorption, adhesion, covalent attachment, hydrogen bonding, ionic bonding, electrostatic attraction, Levan der Waals forces, and polar interactions.
在一些实施方案中，悬浮颗粒具有褶皱的表面。所述“褶皱”意指颗粒表面具有复数个塌陷和/或***部位。褶皱的悬浮颗粒的表面任选为连续或不连续的；在悬浮颗粒表面为不连续的情况下，周围的悬浮介质可以渗透、填装或蔓延至悬浮颗粒的内部。In some embodiments, the suspended particles have a corrugated surface. By "wrinkled" is meant that the particle surface has a plurality of depressions and/or bulges. The surface of the corrugated suspended particle is optionally continuous or discontinuous; where the suspended particle surface is discontinuous, the surrounding suspending medium can penetrate, pack or spread into the interior of the suspended particle.
在一些实施方案中，悬浮颗粒包含疏水性氨基酸，疏水性氨基酸选自亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、缬氨酸、蛋氨酸、半胱氨酸、酪氨酸 和丙氨酸中的一种或多种；优选自亮氨酸、异亮氨酸、缬氨酸、蛋氨酸和丙氨酸中的一种或多种；更优选自亮氨酸、异亮氨酸和丙氨酸中的一种或多种；甚至更优选为亮氨酸。In some embodiments, the suspended particles comprise a hydrophobic amino acid selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, valine, methionine, cysteine, tyrosine and one or more of alanine; preferably one or more of leucine, isoleucine, valine, methionine and alanine; more preferably from leucine, isoleucine one or more of acid and alanine; even more preferably leucine.
在另一些实施方案中，悬浮颗粒包含含有疏水性氨基酸残基的二肽或三肽，所述疏水性氨基酸选自亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、缬氨酸、蛋氨酸、半胱氨酸、酪氨酸和丙氨酸中的一种或多种。In other embodiments, the suspended particles comprise a dipeptide or tripeptide containing a hydrophobic amino acid residue selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, valine One or more of acid, methionine, cysteine, tyrosine and alanine.
在一些实施方案中，所述悬浮颗粒包含至少含有1个亮氨酸残基的二肽。In some embodiments, the suspended particles comprise a dipeptide containing at least one leucine residue.
具体来说，前述的二肽可以选自：leu-leu、leu-gly、leu-ala、leu-val、leu-ile、leu-phe、leu-pro、leu-trp、leu-ser、leu-tyr、leu-cys、leu-met、leu-asp、leu-asn、leu-gln、leu-glu、leu-thr、leu-lys、leu-arg和leu-his中的一种或多种；优选自leu-leu、leu-gly、leu-ala、leu-val、leu-ile、leu-phe、leu-trp、leu-tyr、leu-cys和leu-met中的一种或多种；更优选自leu-leu、leu-ala、leu-val和leu-ile中的一种或多种；甚至更优选为leu-leu。Specifically, the aforementioned dipeptide can be selected from: leu-leu, leu-gly, leu-ala, leu-val, leu-ile, leu-phe, leu-pro, leu-trp, leu-ser, leu- one or more of tyr, leu-cys, leu-met, leu-asp, leu-asn, leu-gln, leu-glu, leu-thr, leu-lys, leu-arg and leu-his; preferably One or more of leu-leu, leu-gly, leu-ala, leu-val, leu-ile, leu-phe, leu-trp, leu-tyr, leu-cys and leu-met; more preferred One or more of leu-leu, leu-ala, leu-val and leu-ile; even more preferably leu-leu.
而在另一些实施方案中，所述悬浮颗粒包含至少含有2个亮氨酸残基的三肽。In yet other embodiments, the suspended particles comprise tripeptides containing at least 2 leucine residues.
在一些实施方案中，其中，所述三肽由2个亮氨酸残基和1个选自亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、缬氨酸、蛋氨酸、半胱氨酸、酪氨酸和丙氨酸的残基组成。In some embodiments, wherein the tripeptide consists of 2 leucine residues and 1 selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, valine, methionine, half Residue composition of cystine, tyrosine and alanine.
在一些具体的实施方案中，所述三肽可以选自：leu-leu-leu、leu-leu-ile、leu-ile-leu、leu-leu-phe、leu-phe-leu、leu-leu-trp、leu-trp-leu、leu-leu-val、leu-val-leu、leu-leu-met、leu-met-leu、leu-leu-cys、leu-cys-leu、leu-leu-tyr、leu-tyr-leu、leu-leu-ala和leu-ala-leu中的一种或多种；优选自leu-leu-leu、leu-leu-ile、leu-ile-leu、leu-leu-val、leu-val-leu、eu-leu-ala和leu-ala-leu中的一种或多种；更优选自优选自leu-leu-leu、leu-leu-ile、leu-ile-leu中的一种或多种；甚至更优选为leu-leu-leu，即三亮氨酸。In some specific embodiments, the tripeptide may be selected from the group consisting of: leu-leu-leu, leu-leu-ile, leu-ile-leu, leu-leu-phe, leu-phe-leu, leu-leu- trp, leu-trp-leu, leu-leu-val, leu-val-leu, leu-leu-met, leu-met-leu, leu-leu-cys, leu-cys-leu, leu-leu-tyr, one or more of leu-tyr-leu, leu-leu-ala and leu-ala-leu; preferably selected from leu-leu-leu, leu-leu-ile, leu-ile-leu, leu-leu-val one or more of , leu-val-leu, eu-leu-ala and leu-ala-leu; more preferably selected from among leu-leu-leu, leu-leu-ile, leu-ile-leu one or more; even more preferably leu-leu-leu, ie trileucine.
在一些具体的实施方案中，所述悬浮颗粒还包含基本不溶于悬浮介质的 聚合物。“基本不溶”是指物质完全不溶于特定溶剂或难溶于该特定溶剂。在一些实施方案中，是指特定的溶质在每100份溶剂中的溶解度低于1份溶质。In some specific embodiments, the suspending particles further comprise a polymer that is substantially insoluble in the suspending medium. "Substantially insoluble" means that the substance is completely insoluble or poorly soluble in a particular solvent. In some embodiments, it is meant that a particular solute has a solubility of less than 1 part of solute per 100 parts of solvent.
在一些实施方案中，所述聚合物包含葡萄糖醛酸单元，所述聚合物优选为透明质酸或其可药用盐，包括但不限于钠盐、钾盐、铵盐、钙盐和镁盐，更优选为透明质酸钠。In some embodiments, the polymer comprises glucuronic acid units, and the polymer is preferably hyaluronic acid or a pharmaceutically acceptable salt thereof, including but not limited to sodium, potassium, ammonium, calcium, and magnesium salts , more preferably sodium hyaluronate.
所述透明质酸钠的平均分子量为1000～1000000道尔顿，优选为2000～500000道尔顿，更优选3000～300000道尔顿，甚至更优选10000～100000道尔顿。The average molecular weight of the sodium hyaluronate is 1,000-1,000,000 Daltons, preferably 2,000-500,000 Daltons, more preferably 3,000-300,000 Daltons, even more preferably 10,000-100,000 Daltons.
在一些实施方案中，所述悬浮颗粒中疏水性氨基酸或含有疏水性氨基酸残基的肽，与聚合物的质量比值为0.5～20，具体可以是0.5、0.6、0.65、0.7、0.75、0.8、0.85、0.9、0.95、1.0、1.25、1.5、1.75、2.0、2.25、2.5、2.75、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9、5.0、5.25、5.5、5.75、6.0、6.25、6.5、6.75、7.0、7.25、7.5、7.75、8.0、8.25、8.5、8.75、9.0、9.25、9.5、9.75、10、10.5、11、11.5、12、12.5、13、13.5、14、14.5、15、15.5、16、16.5、17、17.5、18、18.5、19、19.5、20；优选为1～10，更优选为2～8，甚至更优选为3～5。In some embodiments, the mass ratio of hydrophobic amino acids or peptides containing hydrophobic amino acid residues in the suspended particles to the polymer is 0.5 to 20, specifically 0.5, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.25, 5.5, 5.75, 6.0, 6.25, 6.5, 6.75, 7.0, 7.25, 7.5, 7.75, 8.0, 8.25, 8.5, 8.75, 9.0, 9.25, 9.5, 9.75, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20; preferably 1 to 10, 2-8 are more preferable, and 3-5 are even more preferable.
在一些实施方案中，本公开的悬浮颗粒中还可包含一种或多种表面活性剂，所述表面活性剂选自吐温20、吐温40、吐温60、吐温65、吐温80、吐温85、聚桂醇400、司盘83、司盘85、司盘60、司盘80、月桂硫酸镁、单油酸甘油酯和月桂酸；优选为吐温80。In some embodiments, the suspended particles of the present disclosure may further comprise one or more surfactants selected from the group consisting of Tween 20, Tween 40, Tween 60, Tween 65, Tween 80 , Tween 85, lauryl alcohol 400, Span 83, Span 85, Span 60, Span 80, magnesium lauryl sulfate, glycerol monooleate and lauric acid; preferably Tween 80.
本公开的悬浮颗粒中不含有磷脂类物质，例如常见的二硬脂酰基磷脂酰胆碱(DSPC)、二棕榈酰基磷脂酰胆碱(DPPC)等，进一步地，所述悬浮颗粒中同时还不含有钙盐，例如氯化钙等。The suspended particles of the present disclosure do not contain phospholipids, such as common distearoyl phosphatidyl choline (DSPC), dipalmitoyl phosphatidyl choline (DPPC), etc. Further, the suspended particles also do not contain phospholipids. Contains calcium salts, such as calcium chloride, etc.
在一些实施方案中，本公开的组合物中，所述可吸入的悬浮颗粒与第一活性剂的质量比值为0.2～10，具体可以是0.2、0.25、0.3、0.4、0.5、0.6、0.7、 0.75、0.8、0.9、1.0、1.05、1.1、1.15、1.2、1.25、1.3、1.35、1.4、1.45、1.5、1.55、1.6、1.65、1.7、1.75、1.8、1.85、1.9、1.95、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10.0；优选为0.5～5，更优选为0.8～3，甚至更优选为1.2～1.6。In some embodiments, in the composition of the present disclosure, the mass ratio of the inhalable suspended particles to the first active agent is 0.2 to 10, specifically 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0; preferably 0.5 to 5, more preferably 0.8 to 3, even more preferably 1.2 to 1.6.
在一些实施方案中，本公开的组合物中，所述可吸入的悬浮颗粒以1mg/ml至20mg/ml的浓度包含在悬浮介质中，具体可以是1mg/ml、1.5mg/ml、2mg/ml、2.5mg/ml、3mg/ml、3.5mg/ml、4mg/ml、4.5mg/ml、5mg/ml、5.5mg/ml、6mg/ml、6.5mg/ml、7mg/ml、7.5mg/ml、8mg/ml、8.5mg/ml、9mg/ml、9.5mg/ml、10mg/ml、10.5mg/ml、11mg/ml、11.5mg/ml、12mg/ml、12.5mg/ml、13mg/ml、13.5mg/ml、14mg/ml、14.5mg/ml、15mg/ml、15.5mg/ml、16mg/ml、16.5mg/ml、17mg/ml、17.5mg/ml、18mg/ml、18.5mg/ml、19mg/ml、19.5mg/ml、20mg/ml；优选以2mg/ml至15mg/ml的浓度，更优选以3mg/ml至10mg/ml的浓度，更优选以4mg/ml至8mg/ml的浓度。In some embodiments, in the composition of the present disclosure, the respirable suspended particles are contained in the suspension medium at a concentration of 1 mg/ml to 20 mg/ml, specifically 1 mg/ml, 1.5 mg/ml, 2 mg/ml ml, 2.5mg/ml, 3mg/ml, 3.5mg/ml, 4mg/ml, 4.5mg/ml, 5mg/ml, 5.5mg/ml, 6mg/ml, 6.5mg/ml, 7mg/ml, 7.5mg/ml ml, 8mg/ml, 8.5mg/ml, 9mg/ml, 9.5mg/ml, 10mg/ml, 10.5mg/ml, 11mg/ml, 11.5mg/ml, 12mg/ml, 12.5mg/ml, 13mg/ml , 13.5mg/ml, 14mg/ml, 14.5mg/ml, 15mg/ml, 15.5mg/ml, 16mg/ml, 16.5mg/ml, 17mg/ml, 17.5mg/ml, 18mg/ml, 18.5mg/ml , 19mg/ml, 19.5mg/ml, 20mg/ml; preferably at a concentration of 2mg/ml to 15mg/ml, more preferably at a concentration of 3mg/ml to 10mg/ml, more preferably at a concentration of 4mg/ml to 8mg/ml concentration.
本公开的可吸入悬浮颗粒具备适于肺部递送的空气动力学性质，在一些实施方案中，所述可吸入的悬浮颗粒的MMAD为0.5～10μm，优选为1～5μm，更优选为2～4μm，甚至更优选为3～4μm。The respirable suspended particles of the present disclosure have aerodynamic properties suitable for pulmonary delivery. In some embodiments, the respirable suspended particles have an MMAD of 0.5 to 10 μm, preferably 1 to 5 μm, and more preferably 2 to 2 μm. 4 μm, even more preferably 3 to 4 μm.
在一些实施方案中，所述可吸入的悬浮颗粒的体积中值几何直径为1～10μm，优选为2～8μm，更优选为3～6μm，甚至更优选为4～5μm。In some embodiments, the respirable suspended particles have a volume median geometric diameter of 1 to 10 μm, preferably 2 to 8 μm, more preferably 3 to 6 μm, even more preferably 4 to 5 μm.
在一些实施方案中，本公开的组合物中，所述第一活性剂包含长效β受体激动剂，所述长效β受体激动剂可作为活性物质单独或与其他类型的活性物质一同存在于悬浮介质中，所述长效β受体激动剂选自沙美特罗、福莫特罗、茚达特罗、米维特罗、奥达特罗和维兰特罗中的一种或多种，包括任何其可药用的盐；可药用的盐包括无机盐比如盐酸、氢溴酸、磺酸及磷酸，以及有机盐比如富马酸、马来酸、乙酸、乳酸、柠檬酸、酒石酸、抗坏血酸、琥珀酸、戊二酸、葡萄糖酸、丙三羧酸、油酸、苯甲酸、对甲氧基苯甲酸、 水杨酸、邻或对羟基苯甲酸、对氯苯甲酸、甲烷磺酸、对甲苯磺酸及3-羟基-2-萘羧酸。In some embodiments, in the compositions of the present disclosure, the first active agent comprises a long-acting beta agonist, which can be used as the active substance alone or in combination with other types of active substances Present in the suspending medium, the long-acting beta agonist is selected from one or more of salmeterol, formoterol, indacaterol, milverterol, olodaterol and vilanterol species, including any pharmaceutically acceptable salts thereof; pharmaceutically acceptable salts include inorganic salts such as hydrochloric acid, hydrobromic acid, sulfonic acid and phosphoric acid, and organic salts such as fumaric acid, maleic acid, acetic acid, lactic acid, citric acid, Tartaric acid, ascorbic acid, succinic acid, glutaric acid, gluconic acid, glyceric acid, oleic acid, benzoic acid, p-methoxybenzoic acid, salicylic acid, o- or p-hydroxybenzoic acid, p-chlorobenzoic acid, methanesulfonic acid acid, p-toluenesulfonic acid and 3-hydroxy-2-naphthalenecarboxylic acid.
在一些实施方案，所述长效β受体激动剂为茚达特罗或其可药用的盐，优选为乙酸茚达特罗或马来酸茚达特罗，更优选为乙酸茚达特罗。In some embodiments, the long-acting beta agonist is indacaterol or a pharmaceutically acceptable salt thereof, preferably indacaterol acetate or indacaterol maleate, more preferably indacaterol acetate Luo.
本公开对于所述茚达特罗或其可药用盐的形态无特殊限制，可以为晶体状或无定形的颗粒，优选为晶体状颗粒。The present disclosure has no particular limitation on the form of the indacaterol or a pharmaceutically acceptable salt thereof, which may be crystalline or amorphous particles, preferably crystalline particles.
本公开的茚达特罗或其可药用盐颗粒同样具备适于肺部递送的空气动力学性质，在一些实施方案中，所述茚达特罗或其可药用盐颗粒的MMAD为0.5～10μm，优选为1～6μm，更优选为2～5μm，甚至更优选为3～4μm。The particles of indacaterol or a pharmaceutically acceptable salt thereof of the present disclosure also possess aerodynamic properties suitable for pulmonary delivery. In some embodiments, the particles of indacaterol or a pharmaceutically acceptable salt thereof have an MMAD of 0.5 ~10 μm, preferably 1 to 6 μm, more preferably 2 to 5 μm, even more preferably 3 to 4 μm.
在一些实施方案中，所述茚达特罗或其可药用的盐颗粒的体积中值几何直径为0.2～10μm，优选为0.5～5μm，更优选为1～4μm，甚至更优选为1.5～3μm。In some embodiments, the volume median geometric diameter of the particles of indacaterol or a pharmaceutically acceptable salt thereof is 0.2-10 μm, preferably 0.5-5 μm, more preferably 1-4 μm, even more preferably 1.5-10 μm 3μm.
在一些实施方案中，本公开的组合物中，茚达特罗或其可药用盐颗粒以一定的浓度存在于共悬浮液中，和/或在定量吸入器每次启动时可以以一定的剂量被递送，如无特殊说明，本公开所述茚达特罗或其可药用盐的浓度或剂量，均以等摩尔换算后的茚达特罗游离碱进行计算。In some embodiments, in the compositions of the present disclosure, the particles of indacaterol or a pharmaceutically acceptable salt thereof are present in the co-suspension at a certain concentration, and/or may be present at a certain concentration each time the metered dose inhaler is activated The dose is delivered, and unless otherwise specified, the concentration or dose of indacaterol or a pharmaceutically acceptable salt thereof described in the present disclosure is calculated in equimolar conversion of indacaterol free base.
在一些实施方案中，所述茚达特罗或其可药用盐颗粒与悬浮颗粒共存于悬浮介质中以形成共悬浮液，组合物中茚达特罗的浓度为0.5mg/ml～10mg/ml，具体可以为0.5mg/ml、1mg/ml、1.5mg/ml、2mg/ml、2.5mg/ml、3mg/ml、3.5mg/ml、4mg/ml、4.5mg/ml、5mg/ml、5.5mg/ml、6mg/ml、6.5mg/ml、7mg/ml、7.5mg/ml、8mg/ml、8.5mg/ml、9mg/ml、9.5mg/ml、10mg/ml；优选为0.8mg/ml～5mg/ml，更优选为1mg/ml～4mg/ml，甚至更优选为2mg/ml～3mg/ml。In some embodiments, the particles of indacaterol or a pharmaceutically acceptable salt thereof coexist with the suspending particles in a suspension medium to form a co-suspension, and the concentration of indacaterol in the composition is 0.5 mg/ml to 10 mg/ml ml, specifically 0.5mg/ml, 1mg/ml, 1.5mg/ml, 2mg/ml, 2.5mg/ml, 3mg/ml, 3.5mg/ml, 4mg/ml, 4.5mg/ml, 5mg/ml, 5.5mg/ml, 6mg/ml, 6.5mg/ml, 7mg/ml, 7.5mg/ml, 8mg/ml, 8.5mg/ml, 9mg/ml, 9.5mg/ml, 10mg/ml; preferably 0.8mg/ml ml to 5 mg/ml, more preferably 1 mg/ml to 4 mg/ml, even more preferably 2 mg/ml to 3 mg/ml.
在另一些实施方案中，包含在组合物中的茚达特罗的浓度足以使定量吸入器的每次启动作用产生的茚达特罗递送剂量为10～300μg，具体可以为10μg、20μg、30μg、40μg、50μg、60μg、70μg、75μg、80μg、85μg、90μg、95μg、100μg、105μg、110μg、115μg、120μg、125μg、130μg、135μg、140μg、150μg、160μg、170μg、180μg、190μg、200μg、210μg、220μg、230μg、240μg、 250μg、260μg、270μg、280μg、290μg、300μg；优选为30-200μg，更优选为50～150μg，甚至更优选为80～120μg。In other embodiments, the indacaterol is included in the composition at a concentration sufficient to deliver a dose of indacaterol of 10-300 μg per actuation of the metered dose inhaler, specifically 10 μg, 20 μg, 30 μg , 40μg, 50μg, 60μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 150μg, 160μg, 170μg, 180μg, 190μg, 180μg, 190μg , 220μg, 230μg, 240μg, 250μg, 260μg, 270μg, 280μg, 290μg, 300μg; preferably 30-200μg, more preferably 50-150μg, even more preferably 80-120μg.
而在另一些实施方案中，本公开所述第一活性剂包含皮质类固醇，所述皮质类固醇可作为活性物质单独或与其他类型的活性物质一同存在于悬浮介质中，所述皮质类固醇选自布***、环索奈德、氟替卡松、莫米松、倍氯米松和氟尼缩松中的一种或多种，包括任何其可药用的酯及水合物。In yet other embodiments, the first active agent of the present disclosure comprises a corticosteroid, which may be present in the suspending medium as the active substance alone or in combination with other types of active substances, the corticosteroid being selected from the group consisting of budesonide One or more of acetonide, ciclesonide, fluticasone, mometasone, beclomethasone, and flunisolide, including any pharmaceutically acceptable esters and hydrates thereof.
在一些实施方案中，所述皮质类固醇为氟替卡松或其可药用的酯及水合物，优选为糠酸氟替卡松或丙酸氟替卡松，更优选为糠酸氟替卡松。In some embodiments, the corticosteroid is fluticasone or a pharmaceutically acceptable ester and hydrate thereof, preferably fluticasone furoate or fluticasone propionate, more preferably fluticasone furoate.
在一些实施方案中，所述包含糠酸氟替卡松及丙酸氟替卡松在内的氟替卡松或其可药用的酯及水合物为晶体状或无定形的颗粒，优选为晶体状颗粒。In some embodiments, the fluticasone including fluticasone furoate and fluticasone propionate, or pharmaceutically acceptable esters and hydrates thereof, are crystalline or amorphous particles, preferably crystalline particles.
本公开的糠酸氟替卡松颗粒同样具备适于肺部递送的空气动力学性质，在一些实施方案中，所述糠酸氟替卡松颗粒的MMAD为0.5～10μm，优选为1～6μm，更优选为2～5μm，甚至更优选为3～4μm。The fluticasone furoate particles of the present disclosure also have aerodynamic properties suitable for pulmonary delivery. In some embodiments, the MMAD of the fluticasone furoate particles is 0.5-10 μm, preferably 1-6 μm, more preferably 2- 5 μm, even more preferably 3 to 4 μm.
在一些实施方案中，糠酸氟替卡松颗粒的体积中值几何直径为0.2～10μm，优选为0.5～5μm，更优选为1～4μm，甚至更优选为1.5～3μm。In some embodiments, the fluticasone furoate particles have a volume median geometric diameter of 0.2 to 10 μm, preferably 0.5 to 5 μm, more preferably 1 to 4 μm, even more preferably 1.5 to 3 μm.
在一些实施方案中，糠酸氟替卡松颗粒与悬浮颗粒共存于悬浮介质中以形成共悬浮液，组合物中糠酸氟替卡松的浓度为0.2mg/ml～10mg/ml，具体可以为0.2mg/ml、0.3mg/ml、0.4mg/ml、0.5mg/ml、1.0mg/ml、1.5mg/ml、2.0mg/ml、2.5mg/ml、3.0mg/ml、3.5mg/ml、4.0mg/ml、4.5mg/ml、5.0mg/ml、5.5mg/ml、6.0mg/ml、6.5mg/ml、7.0mg/ml、7.5mg/ml、8.0mg/ml、8.5mg/ml、9.0mg/ml、9.5mg/ml、10.0mg/ml，优选为0.5mg/ml～5mg/ml，更优选为1mg/ml～3mg/ml，甚至更优选为1.5mg/ml～2.5mg/ml。In some embodiments, the fluticasone furoate particles and the suspending particles coexist in a suspension medium to form a co-suspension, and the concentration of fluticasone furoate in the composition is 0.2 mg/ml to 10 mg/ml, specifically 0.2 mg/ml, 0.3mg/ml, 0.4mg/ml, 0.5mg/ml, 1.0mg/ml, 1.5mg/ml, 2.0mg/ml, 2.5mg/ml, 3.0mg/ml, 3.5mg/ml, 4.0mg/ml, 4.5mg/ml, 5.0mg/ml, 5.5mg/ml, 6.0mg/ml, 6.5mg/ml, 7.0mg/ml, 7.5mg/ml, 8.0mg/ml, 8.5mg/ml, 9.0mg/ml, 9.5mg/ml, 10.0mg/ml, preferably 0.5mg/ml to 5mg/ml, more preferably 1mg/ml to 3mg/ml, even more preferably 1.5mg/ml to 2.5mg/ml.
在另一些实施方案中，包含在组合物中的糠酸氟替卡松的浓度足以使定量吸入器的每次启动作用产生的糠酸氟替卡松递送剂量为10～300μg，具体可以为10μg、20μg、30μg、40μg、50μg、60μg、70μg、75μg、80μg、85μg、90μg、95μg、100μg、105μg、110μg、115μg、120μg、125μg、130μg、135μg、 140μg、150μg、160μg、170μg、180μg、190μg、200μg、210μg、220μg、230μg、240μg、250μg、260μg、270μg、280μg、290μg、300μg；优选为30-200μg，更优选为50～150μg，甚至更优选为80～120μg。In other embodiments, the concentration of fluticasone furoate included in the composition is sufficient to deliver a dose of 10-300 μg of fluticasone furoate per actuation of the metered dose inhaler, specifically 10 μg, 20 μg, 30 μg, 40 μg , 50μg, 60μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 150μg, 160μg, 170μg, 180μg, 222μg, 190μg, 200μg, 190μg , 230μg, 240μg, 250μg, 260μg, 270μg, 280μg, 290μg, 300μg; preferably 30-200μg, more preferably 50-150μg, even more preferably 80-120μg.
在另一些实施方案中，本公开所述组合物还包括第二活性剂，所述第二活性剂包含长效抗胆碱能药，所述长效抗胆碱能药选自阿地铵、格隆铵、噻托铵、乌美铵和芜地铵中的一种或多种，包括任何其可药用的盐。所述可药用的盐包括无机盐，例如氟化物、氯化物、溴化物、碘化物、硝酸盐、硫酸盐、磷酸盐；以及有机盐，例如甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丁酸盐、乳酸盐、柠檬酸盐、酒石酸盐、苹果酸盐、马来酸盐、琥珀酸盐、苯甲酸盐、对氯苯甲酸盐、二苯基乙酸盐或三苯基乙酸盐、邻羟基苯甲酸盐、对羟基苯甲酸盐、1-羟基萘基-2-羧酸盐、3-羟基萘基-2-羧酸盐、甲磺酸盐及苯磺酸盐。In other embodiments, the compositions of the present disclosure further comprise a second active agent comprising a long-acting anticholinergic agent selected from the group consisting of aclidinium, One or more of glycopyrronium, tiotropium, umeclidinium, and umeclidinium, including any pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salts include inorganic salts such as fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate; and organic salts such as formate, acetate, trifluoroacetic acid Salt, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenylethyl Acid or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1-hydroxynaphthyl-2-carboxylate, 3-hydroxynaphthyl-2-carboxylate, methanesulfonate acid and benzene sulfonate.
在一些实施方案中，所述第二活性剂为格隆溴铵，即格隆铵的溴化物。In some embodiments, the second active agent is glycopyrronium bromide, a bromide of glycopyrronium.
在一些实施方案中，所述格隆溴铵存在于悬浮颗粒中。In some embodiments, the glycopyrronium bromide is present in suspended particles.
在另一些实施方案中，格隆溴铵为晶体状或无定形的颗粒，并与悬浮颗粒共存于悬浮介质中以形成共悬浮液。In other embodiments, the glycopyrronium bromide is crystalline or amorphous particles and coexists with the suspending particles in a suspending medium to form a co-suspension.
而在另一些实施方案中，部分格隆溴铵存在于悬浮颗粒中，而其余部分与悬浮颗粒共存于悬浮介质中以形成共悬浮液。In yet other embodiments, a portion of the glycopyrronium bromide is present in the suspended particles and the remainder is present in the suspension medium with the suspended particles to form a co-suspension.
无论格隆溴铵以上述的何种形式存在，整体上，本公开组合物中的格隆溴铵以一定的浓度存在，和/或在定量吸入器每次启动时可以以一定的剂量被递送，如无特殊说明，本公开所述格隆溴铵的浓度或剂量，均以等摩尔换算后的不含溴离子的格隆铵进行计算。Regardless of the form in which the glycopyrronium bromide is present, as a whole, the glycopyrronium bromide in the compositions of the present disclosure is present in a certain concentration and/or can be delivered in a certain dose per actuation of the metered dose inhaler , unless otherwise specified, the concentration or dosage of glycopyrronium bromide described in the present disclosure is calculated by equimolar conversion of glycopyrronium bromide without bromide ions.
在一些实施方案中，本公开组合物中格隆溴铵的浓度为0.1mg/ml～5mg/ml，具体可以为0.1mg/ml、0.2mg/ml、0.3mg/ml、0.4mg/ml、0.5mg/ml、0.6mg/ml、0.7mg/ml、0.8mg/ml、0.9mg/ml、1mg/ml、1.1mg/ml、1.2mg/ml、1.3mg/ml、1.4mg/ml、1.5mg/ml、1.6mg/ml、1.7mg/ml、1.8mg/ml、 1.9mg/ml、2mg/ml、2.5mg/ml、3mg/ml、3.5mg/ml、4mg/ml、4.5mg/ml、5mg/ml，优选为0.2mg/ml～4mg/ml，更优选为0.5mg/ml～2mg/ml，甚至更优选为0.8mg/ml～1.5mg/ml。In some embodiments, the concentration of glycopyrronium bromide in the composition of the present disclosure is 0.1 mg/ml to 5 mg/ml, specifically 0.1 mg/ml, 0.2 mg/ml, 0.3 mg/ml, 0.4 mg/ml, 0.5mg/ml, 0.6mg/ml, 0.7mg/ml, 0.8mg/ml, 0.9mg/ml, 1mg/ml, 1.1mg/ml, 1.2mg/ml, 1.3mg/ml, 1.4mg/ml, 1.5 mg/ml, 1.6mg/ml, 1.7mg/ml, 1.8mg/ml, 1.9mg/ml, 2mg/ml, 2.5mg/ml, 3mg/ml, 3.5mg/ml, 4mg/ml, 4.5mg/ml , 5mg/ml, preferably 0.2mg/ml to 4mg/ml, more preferably 0.5mg/ml to 2mg/ml, even more preferably 0.8mg/ml to 1.5mg/ml.
在一些实施方案中，包含在组合物中的格隆溴铵的浓度足以使定量吸入器的每次启动作用产生的格隆溴铵递送剂量为5～120μg，具体可以为5μg、10μg、20μg、30μg、40μg、50μg、60μg、70μg、75μg、80μg、85μg、90μg、95μg、100μg、105μg、110μg、115μg、120μg；优选为10-100μg，更优选为20～80μg，甚至更优选为40～60μg。In some embodiments, the concentration of glycopyrronium bromide included in the composition is sufficient to deliver a dose of glycopyrronium bromide of 5 to 120 μg per actuation of the metered dose inhaler, specifically 5 μg, 10 μg, 20 μg, 30μg, 40μg, 50μg, 60μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, 100μg, 105μg, 110μg, 115μg, 120μg; preferably 10-100μg, more preferably 20-80μg, even more preferably 40-60μg .
本公开组合物中的格隆溴铵同样具备适于肺部递送的空气动力学性质，在一些实施方案中，所述格隆溴铵的MMAD为0.5～10μm，优选为1～6μm，更优选为2～5μm，甚至更优选为3～4μm。The glycopyrronium bromide in the composition of the present disclosure also has aerodynamic properties suitable for pulmonary delivery. In some embodiments, the MMAD of the glycopyrronium bromide is 0.5-10 μm, preferably 1-6 μm, more preferably 2 to 5 μm, even more preferably 3 to 4 μm.
本公开悬浮介质中适宜的推进剂包括氢氟烷烃(HFA)、全氟烷烃(PFC)及氯氟烷烃(CFC)，从对环境友好的角度出发，本公开的推进剂可以为氢氟烷烃或全氟烷烃，优选为氢氟烷烃，例如1,1,1,2-四氟乙烷(CF 3CH 2F)(HFA-134a)、1,1,1,2,3,3,3-七氟正丙烷(CF 3CHFCF 3)(HFA-227)、1,1-二氟乙烷(CF 2HCH 3)以及它们的组合，更优选为HFA-134a。 Suitable propellants in the suspension medium of the present disclosure include hydrofluoroalkanes (HFA), perfluoroalkanes (PFC) and chlorofluoroalkanes (CFC). Perfluoroalkanes, preferably hydrofluoroalkanes, such as 1,1,1,2 - tetrafluoroethane ( CF3CH2F ) (HFA-134a), 1,1,1,2,3,3,3- Heptafluoro-n-propane (CF 3 CHFCF 3 ) (HFA-227), 1,1-difluoroethane (CF 2 HCH 3 ), and combinations thereof, more preferably HFA-134a.
本公开的组合物可有效降低患者给药频次，方便患者使用，具体地，所述组合物适用于每天给药1次或2次；优选适用于每天给药1次。The composition of the present disclosure can effectively reduce the frequency of administration to patients and is convenient for patients to use. Specifically, the composition is suitable for administration once or twice a day; preferably, it is suitable for administration once a day.
其中，每次给药通常需1～2揿，优选每次1揿。Among them, each administration usually requires 1 to 2 swipes, preferably 1 swipe each time.
第二方面，本公开还提供一种定量吸入产品，包括带有出口阀的容器罐，该出口阀带有用于递送定量体积的启动器，所述容器罐包含第一方面所提供的组合物。In a second aspect, the present disclosure also provides a metered dose inhalation product comprising a container canister with an outlet valve with an actuator for delivering a metered volume, the container canister comprising the composition provided by the first aspect.
包含第一方面所述组合物的定量吸入器具有优异的递送准确性和均一性，在一些实施方案中，本公开的定量吸入器在排空容器罐的全过程中，以±30％或更高的递送剂量均匀性(即DDU)递送活性剂；优选以±25％或更高的递送剂量均匀性递送活性剂；更优选以±25％或更高的递送剂量均匀性递送 活性剂。A metered dose inhaler comprising the composition of the first aspect has excellent delivery accuracy and uniformity, and in some embodiments, the metered dose inhaler of the present disclosure is delivered by ±30% or more throughout the entire process of emptying the container canister. High delivered dose uniformity (ie, DDU) delivers the active agent; preferably, the active agent is delivered with a delivered dose uniformity of ±25% or more; more preferably, the active agent is delivered with a delivered dose uniformity of ±25% or more.
本公开的组合物及吸入器还具有优异的肺部递送效率，各活性物质的细颗粒部分(FPF ＜5μm)可达到40％以上，优选达到50％以上，更优选达到60％以上；组合物发射过程中，各活性物质的喷射剂量(ED)占名义剂量(ND)的百分比均可达80％以上，优选达85％以上，更优选达90％以上。 The composition and the inhaler of the present disclosure also have excellent pulmonary delivery efficiency, and the fine particle fraction (FPF <5 μm ) of each active substance can reach more than 40%, preferably more than 50%, more preferably more than 60%; the composition During the emission process, the percentage of the propelled dose (ED) of each active substance to the nominal dose (ND) can reach more than 80%, preferably more than 85%, more preferably more than 90%.
第三方面，本公开还提供制备第一方面所述组合物的方法，其包括如下步骤：In a third aspect, the present disclosure also provides a method for preparing the composition of the first aspect, comprising the steps of:
提供含有可药用的推进剂的悬浮介质；providing a suspension medium containing a pharmaceutically acceptable propellant;
提供第一活性剂；providing a first active agent;
通过喷雾干燥载体溶液制备得到可吸入的悬浮颗粒，悬浮颗粒所包含的成分预先溶解于载体溶液中。The respirable suspended particles are prepared by spray-drying a carrier solution, and the components contained in the suspended particles are pre-dissolved in the carrier solution.
在一些实施方案中，第一活性剂存在于悬浮颗粒中，所述制备方法还包括将载有第一活性剂的悬浮颗粒分散至悬浮介质的步骤。In some embodiments, the first active agent is present in the suspended particles, and the method of preparation further comprises the step of dispersing the suspended particles loaded with the first active agent into a suspension medium.
在另一些实施方案中，第一活性剂与悬浮颗粒共悬浮，所述制备方法还包括将第一活性剂与悬浮颗粒在悬浮介质中混合以形成共悬浮液的步骤。In other embodiments, the first active agent is co-suspended with the suspending particles, and the method of preparation further comprises the step of mixing the first active agent and the suspending particles in a suspending medium to form a co-suspension.
在一些实施方案中，所述方法还包括在喷雾干燥前将第二活性剂溶解于载体溶液中的步骤，第二活性剂包含长效抗胆碱能药，所述长效抗胆碱能药选自阿地铵、格隆铵、噻托铵、乌美铵和芜地铵，包括任何其可药用的盐。In some embodiments, the method further comprises the step of dissolving a second active agent in the carrier solution prior to spray drying, the second active agent comprising a long-acting anticholinergic, the long-acting anticholinergic Selected from aclidinium, glycopyrronium, tiotropium, umeclidinium, and umeclidinium, including any pharmaceutically acceptable salts thereof.
在一些实施方案中，第二活性剂为格隆溴铵，格隆溴铵浓度如第一方面所述。In some embodiments, the second active agent is glycopyrronium bromide, and the glycopyrronium bromide concentration is as described in the first aspect.
在一些实施方案中，所述溶液的溶剂选自水、甲醇、乙醇、正丙醇、异丙醇和正丁醇中的一种或多种，优选自水、乙醇或其混合物，更优选为水。In some embodiments, the solvent of the solution is selected from one or more of water, methanol, ethanol, n-propanol, isopropanol and n-butanol, preferably water, ethanol or a mixture thereof, more preferably water .
在一些实施方案中，载体溶液中还溶解有致孔剂，所述致孔剂选自碳酸氢铵、尿素、聚乙烯吡咯烷酮、聚乙二醇和聚乙烯醇中的一种或多种，优选为碳酸氢铵。In some embodiments, a porogen is further dissolved in the carrier solution, and the porogen is selected from one or more of ammonium bicarbonate, urea, polyvinylpyrrolidone, polyethylene glycol and polyvinyl alcohol, preferably carbonic acid Ammonium hydrogen.
在一些实施方案中，所述喷雾干燥步骤所使用的干燥气体为氮气，氮气 流速为100L/h～2000L/h，优选为200L/h～1500L/h，更优选为300L/h～1000L/h，甚至更优选为400L/h～800L/h。In some embodiments, the drying gas used in the spray drying step is nitrogen, and the nitrogen flow rate is 100L/h～2000L/h, preferably 200L/h～1500L/h, more preferably 300L/h～1000L/h , even more preferably 400L/h～800L/h.
在一些实施方案中，所述喷雾干燥步骤的入口温度为50～200℃，优选为75～150℃，更优选为90～120℃，甚至更优选为100℃。In some embodiments, the inlet temperature of the spray drying step is 50-200°C, preferably 75-150°C, more preferably 90-120°C, even more preferably 100°C.
在一些实施方案中，所述喷雾干燥步骤的进料速率为1～30ml/min，优选为2～20ml/min，更优选为3～15ml/min，甚至更优选为4～10ml/min。In some embodiments, the feed rate of the spray drying step is 1-30 ml/min, preferably 2-20 ml/min, more preferably 3-15 ml/min, even more preferably 4-10 ml/min.
第四方面，本公开还提供第一方面组合物在制备治疗炎性或阻塞性肺部疾病药物中的用途，所述疾病可以选自哮喘、慢性阻塞性肺病、继发性气道高反应性恶化、过敏性鼻炎、鼻窦炎、肺血管收缩、呼吸障碍、呼吸窘迫综合征、肺动脉高压、以及与囊性纤维化相关的肺部炎症及阻塞。In the fourth aspect, the present disclosure also provides the use of the composition of the first aspect in the preparation of a medicament for the treatment of inflammatory or obstructive pulmonary diseases, the diseases can be selected from asthma, chronic obstructive pulmonary disease, secondary airway hyperresponsiveness Exacerbations, allergic rhinitis, sinusitis, pulmonary vasoconstriction, respiratory disorders, respiratory distress syndrome, pulmonary hypertension, and pulmonary inflammation and obstruction associated with cystic fibrosis.
在一些实施方案中，所述疾病为慢性阻塞性肺病(COPD)，更优选中度至重度的慢性阻塞性肺病。In some embodiments, the disease is chronic obstructive pulmonary disease (COPD), more preferably moderate to severe chronic obstructive pulmonary disease.
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。"Optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
“活性剂”或“活性物质”意指药物的活性成分，也称为活性药物成分(API)。"Active agent" or "active substance" means the active ingredient of a drug, also known as an active pharmaceutical ingredient (API).
“体积中值几何直径”或“D 50”指光学测量下多个颗粒的中值直径，即大于及小于该直径的颗粒均占总体积的50％。“D 90”指占总体积90％的颗粒小于该直径，“D 10”指占总体积10％的颗粒小于该直径。“D 4,3”指多个颗粒的体积四次矩平均径。 "Volume median geometric diameter" or " D50 " refers to the median diameter of a plurality of particles under optical measurement, ie particles larger and smaller than this diameter each account for 50% of the total volume. " D90 " means that 90% of the total volume of the particles is smaller than this diameter, and "D10" means that 10 % of the total volume of the particles is smaller than this diameter. "D 4,3 " refers to the volume fourth moment mean diameter of the plurality of particles.
“质量中值空气动力学直径”或“MMAD”是指大于和小于该空气动力学直径的粒子质量各占总质量的50％。"Mass Median Aerodynamic Diameter" or "MMAD" means that particles larger and smaller than the aerodynamic diameter each account for 50% of the total mass.
“细颗粒剂量”或“FPD”指低于指定最小空气动力学粒径的活性成分剂量。A "fine particle dose" or "FPD" refers to a dose of active ingredient below a specified minimum aerodynamic particle size.
“细颗粒部分”或“FPF”指相对于喷射剂量或名义剂量，小于指定的最小空气动力学尺寸的活性成分的比例。例如“FPF<5μm”指具有小于5μm空气动力学直径的颗粒占喷射剂量或名义剂量的比例。"Fine Particulate Fraction" or "FPF" refers to the proportion of active ingredient that is smaller than the specified minimum aerodynamic size relative to the propellant or nominal dose. For example "FPF < 5 μm" refers to the proportion of particles having an aerodynamic diameter of less than 5 μm in the sprayed or nominal dose.
“ED”或“喷射剂量”或“递送剂量”指给药时离开吸入器装置的药物质量。"ED" or "ejection dose" or "delivered dose" refers to the mass of drug that leaves the inhaler device when administered.
“ND”或“名义剂量”或“标示剂量”指吸入剂单剂量标示药物总质量。"ND" or "nominal dose" or "labeled dose" refers to the total mass of the labeled drug in a single dose of an inhaler.
此外，用以界定本公开的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。因此，除非另有明确的说明，应当理解本公开所用的所有范围、数量、数值与百分比均经过“约”的修饰。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。Furthermore, the numerical ranges and parameters used to define the present disclosure are approximations, and the numerical values in the specific embodiments have been presented as precisely as possible. Any numerical value, however, inherently contains the standard deviation resulting from individual testing methods. Therefore, unless expressly stated otherwise, it should be understood that all ranges, amounts, values and percentages used in this disclosure are modified by "about". As used herein, "about" generally means within plus or minus 10%, 5%, 1%, or 0.5% of the actual value of a particular value or range.
附图说明Description of drawings
图1表示实施例2喷雾干燥所得载体颗粒的扫描电子显微镜(SEM)图像。FIG. 1 shows a scanning electron microscope (SEM) image of the carrier particles obtained by spray drying in Example 2. FIG.
图2表示实施例1喷雾干燥所得载体颗粒的扫描电子显微镜(SEM)图像。FIG. 2 shows a scanning electron microscope (SEM) image of the carrier particles obtained by spray drying in Example 1. FIG.
图3表示实施例7喷雾干燥所得载体颗粒的扫描电子显微镜(SEM)图像。FIG. 3 shows a scanning electron microscope (SEM) image of the carrier particles obtained by spray drying in Example 7. FIG.
具体实施方式Detailed ways
以下将结合具体实例详细地解释本发明，使得本专业技术人员更全面地理解本发明。具体实例仅用于说明本发明的技术方案，并不以任何方式限定本发明。The present invention will be explained in detail below with reference to specific examples, so that those skilled in the art can more fully understand the present invention. The specific examples are only used to illustrate the technical solutions of the present invention, and do not limit the present invention in any way.
实验试剂Experimental reagents
序sequence 试剂reagent 来源source
11 糠酸氟替卡松fluticasone furoate 奥锐特药业股份有限公司Orient Pharmaceutical Co., Ltd.
22 格隆溴铵Glycopyrrolate 江苏恒瑞医药股份有限公司Jiangsu Hengrui Pharmaceutical Co., Ltd.
33 乙酸茚达特罗Indacaterol acetate 江苏恒瑞医药股份有限公司Jiangsu Hengrui Pharmaceutical Co., Ltd.
44 布***Budesonide Minakem DunkerqueMinakem Dunkerque
55 透明质酸钠Sodium hyaluronate 华熙福瑞达生物医药有限公Bloomage Freda Biomedical Co., Ltd.
66 三亮氨酸Trileucine 江苏恒瑞医药股份有限公司Jiangsu Hengrui Pharmaceutical Co., Ltd.
77 HFA-134aHFA-134a Mexichem FluorMexichem Fluor
实施例1制备含有糠酸氟替卡松/格隆溴铵/乙酸茚达特罗的定量吸入气雾剂Example 1 Preparation of metered dose inhalation aerosols containing fluticasone furoate/glycopyrronium bromide/indacaterol acetate
1)配制溶液：称取一定量纯化水，称取透明质酸钠，缓慢加入水中，先室温静置溶胀，后室温磁力搅拌至溶解。再称取三亮氨酸，于室温磁力搅拌下缓慢加入水中，用稀盐酸调节pH至3.5，后加热搅拌至溶解。冷却至室温后，加入碳酸氢铵和格隆溴铵，室温磁力搅拌至溶解。1) Preparation of solution: Weigh a certain amount of purified water, weigh sodium hyaluronate, slowly add it to the water, let it stand at room temperature to swell, and then magnetically stir at room temperature until dissolved. Then, trileucine was weighed, slowly added to water under magnetic stirring at room temperature, pH was adjusted to 3.5 with dilute hydrochloric acid, and then heated and stirred until dissolved. After cooling to room temperature, ammonium bicarbonate and glycopyrronium bromide were added and magnetically stirred at room temperature until dissolved.
2)喷雾干燥：使用Büchi B-290设备对溶液进行喷雾干燥，制备载有格隆溴铵的载体颗粒。工艺参数设定值如下：入口温度100℃，进料泵速率为20％(约6.25ml/min)，氮气流量为40(约666.93L/h)。收集产品取出容器中的载体颗粒。采用扫描电子显微镜(SEM，FEI Sirion 200)对载体颗粒进行观察，形态结果如图2所示，载体颗粒呈现出褶皱的形态。2) Spray drying: The solution was spray-dried using Büchi B-290 equipment to prepare glycopyrronium bromide-loaded carrier particles. The process parameters were set as follows: the inlet temperature was 100° C., the feed pump rate was 20% (about 6.25 ml/min), and the nitrogen flow rate was 40 (about 666.93 L/h). Collect the carrier particles in the product removal container. The carrier particles were observed with a scanning electron microscope (SEM, FEI Sirion 200).
3)灌装：玻璃罐(圣戈班)或铝罐(Presspart 19mL等离子涂层)中加入糠酸氟替卡松、乙酸茚达特罗及载体颗粒，安装计量阀(Aptar DF316-50)，并灌装HFA 134a，加装驱动器(华瑞Ab23/02/03，0.30*0.65mm)，得成品气雾剂，气雾剂成品中的各组分的含量如表1所示。3) Filling: Add fluticasone furoate, indacaterol acetate and carrier particles to glass jars (Saint-Gobain) or aluminum cans (Presspart 19mL plasma coating), install metering valve (Aptar DF316-50), and fill with HFA 134a , install the driver (Huarui Ab23/02/03, 0.30*0.65mm), obtain the finished aerosol, the content of each component in the finished aerosol is shown in Table 1.
表1实施例1气雾剂中各组分的含量The content of each component in the aerosol of table 1 embodiment 1
Figure PCTCN2022070643-appb-000001
Figure PCTCN2022070643-appb-000001
Figure PCTCN2022070643-appb-000002
Figure PCTCN2022070643-appb-000002
实施例2制备含有布***的定量吸入气雾剂Example 2 Preparation of metered dose inhalation aerosols containing budesonide
采用与实施例1类似的方法制备得到载体颗粒，并灌装得到气雾剂。主要区别在于载体颗粒中含有吐温80，用量4.058mg/罐，并且不含格隆溴铵和乙酸茚达特罗；灌装时将布***(137μg/揿，19.2mg/罐)与载体颗粒混合。采用扫描电子显微镜(SEM，FEI Sirion 200)对实施例2的载体颗粒进行观察，形态结果如图1所示。可见，载体颗粒呈现出褶皱的形态。The carrier particles were prepared by a method similar to that in Example 1, and filled to obtain an aerosol. The main difference is that the carrier particles contain Tween 80, the dosage is 4.058mg/can, and does not contain glycopyrronium bromide and indacaterol acetate; budesonide (137μg/press, 19.2mg/can) is mixed with the carrier during filling. Granular mix. The carrier particles of Example 2 were observed with a scanning electron microscope (SEM, FEI Sirion 200), and the morphological results were shown in Figure 1. It can be seen that the carrier particles have a wrinkled shape.
实施例3载体颗粒几何粒径测定Example 3 Determination of Geometric Particle Size of Carrier Particles
采用马尔文2000激光粒度仪和干法进样器，测定压力设定为1bar，进料速率设定为50％、遮光度范围设定为0.5-6、样品测定时间和背景时间分别为10、12s、清洗时间60s进样适量实施例1的载体颗粒，测定三次并计算平均值，几何粒径如表2所示。Malvern 2000 laser particle size analyzer and dry sampler were used, the measurement pressure was set to 1 bar, the feed rate was set to 50%, the shading range was set to 0.5-6, the sample measurement time and background time were set to 10, 12s, cleaning time 60s, inject an appropriate amount of the carrier particles of Example 1, measure three times and calculate the average value. The geometric particle size is shown in Table 2.
表2实施例1载体颗粒的几何粒径Table 2 Geometric particle size of carrier particles in Example 1
D 10(μm) D 10 (μm) D 50(μm) D 50 (μm) D 90(μm) D 90 (μm) D 4,3(μm) D 4,3 (μm)
1.6651.665 4.2044.204 8.6788.678 5.775.77
实施例4悬浮液的稳定性评价Example 4 Stability Evaluation of Suspension
将玻璃罐中灌装的实施例1及实施例2成品涡旋混合20min，使载体颗粒和糠酸氟替卡松/乙酸茚达特罗颗粒均匀混合。室温下倒置三天后轻摇使得颗粒均匀分散，并于室温下静置，观察样品悬浮情况。The finished products of Example 1 and Example 2 filled in the glass jar were mixed by vortex for 20 minutes, so that the carrier particles and the fluticasone furoate/indacaterol acetate particles were uniformly mixed. After inversion at room temperature for three days, the particles were shaken gently to disperse the particles evenly, and then left standing at room temperature to observe the suspension of the sample.
观察结果表明，实施例1及实施例2样品能够稳定悬浮120s以上而不发生明显沉降或悬浮，有利于给药时递送剂量的准确和均一性。将样品继续静置至24小时，载体颗粒与活性物质颗粒的沉降呈均匀的单一层，未观察到明显的分离现象。The observation results show that the samples of Example 1 and Example 2 can be stably suspended for more than 120 s without obvious sedimentation or suspension, which is beneficial to the accuracy and uniformity of the delivered dose during administration. The sample continued to stand for 24 hours, the carrier particles and the active material particles settled into a uniform single layer, and no obvious separation phenomenon was observed.
作为对比，选取布地格福吸入气雾剂(商品名BREZTRI AEROSPHERE；布***/格隆溴铵/富马酸福莫特罗颗粒与DSPC载体颗粒的共悬浮液)采 用相同方法进行稳定性评价，结果表明其能够稳定悬浮30s左右，说明本公开的气雾剂具有更为优异的稳定性。As a comparison, budesonide inhalation aerosol (trade name BREZTRI AEROSPHERE; co-suspension of budesonide/glycopyrronium bromide/formoterol fumarate particles and DSPC carrier particles) was selected for stability evaluation using the same method. , the results show that it can be stably suspended for about 30s, indicating that the aerosol of the present disclosure has more excellent stability.
实施例5空气动力学性质评价Example 5 Evaluation of Aerodynamic Properties
使用COPLEY公司的NGI撞击器按照中国药典2015版四部通则0951【吸入制剂微细粒子空气动力学特性测定法】规定对实施例1和2的成品进行测试。统计每揿主药含量，并将APSD各级分布结果输入CITDAS version 3.10软件(COPLEY)得出FPF(＜5μm)、MMAD等值，测试结果如表3所示。The finished products of Examples 1 and 2 were tested using the NGI impactor of COPLEY Company in accordance with the provisions of the Chinese Pharmacopoeia 2015 Edition Four General Chapter 0951 [Determination of Aerodynamic Characteristics of Inhaled Preparations of Fine Particles]. The content of each main drug was counted, and the distribution results of APSD at all levels were input into CITDAS version 3.10 software (COPLEY) to obtain FPF (<5μm), MMAD and other values. The test results are shown in Table 3.
表3实施例1和2气雾剂的空气动力学测试结果Table 3 Aerodynamic test results of the aerosols of Examples 1 and 2
Figure PCTCN2022070643-appb-000003
Figure PCTCN2022070643-appb-000003
实施例6制备含有糠酸氟替卡松/格隆溴铵/乙酸茚达特罗的定量吸入气雾剂Example 6 Preparation of metered dose inhalation aerosols containing fluticasone furoate/glycopyrronium bromide/indacaterol acetate
采用与实施例1类似的方法制备得到载体颗粒，并灌装得到气雾剂。主要区别在于载体颗粒中含有三亮氨酸且不包含透明质酸钠，还含有吐温80(用量4.058mg/罐)。The carrier particles were prepared by a method similar to that in Example 1, and filled to obtain an aerosol. The main difference is that the carrier particles contain trileucine and do not contain sodium hyaluronate, and also contain Tween 80 (the dosage is 4.058 mg/can).
采用与实施例4的方法测试气雾剂样品的悬浮液的稳定性。测定结果表明，制备的气雾剂样品同样能够稳定悬浮120s以上而不发生明显沉降或悬浮。Suspensions of aerosol samples were tested for stability as in Example 4. The measurement results show that the prepared aerosol samples can also be stably suspended for more than 120s without obvious sedimentation or suspension.
采用与实施例5的方法测试气雾剂样品的微细粒子空气动力学特性。测定结果如下表。The aerosol samples were tested for fine particle aerodynamic properties using the same method as in Example 5. The measurement results are as follows.
表4空气动力学测试结果Table 4 Aerodynamic test results
Figure PCTCN2022070643-appb-000004
Figure PCTCN2022070643-appb-000004
实施例7制备含有布***的定量吸入气雾剂Example 7 Preparation of metered dose inhalation aerosols containing budesonide
采用与实施例1类似的方法制备得到载体颗粒，并灌装得到气雾剂。主要区别在于载体颗粒中仅包含透明质酸钠，不包含三亮氨酸，且活性物质替换为布***(3.82mg/罐)。电镜结果如图3所示。The carrier particles were prepared by a method similar to that in Example 1, and filled to obtain an aerosol. The main difference is that the carrier particles contain only sodium hyaluronate, not trileucine, and the active substance is replaced by budesonide (3.82 mg/can). The electron microscope results are shown in Figure 3.
采用与实施例5的方法测试气雾剂样品的微细粒子空气动力学特性。测定结果表明，制备的气雾剂中颗粒的MMAD在4-5μm之间，布***FPF％为28％。颗粒密度大，难以实现共悬浮。The aerosol samples were tested for fine particle aerodynamic properties using the same method as in Example 5. The measurement results show that the MMAD of the particles in the prepared aerosol is between 4-5 μm, and the FPF% of budesonide is 28%. The particle density is high and it is difficult to achieve co-suspension.

Claims (48)

  1. 一种可通过定量吸入器递送的药物组合物，包括：A pharmaceutical composition deliverable by a metered dose inhaler comprising:
    含有可药用的推进剂的悬浮介质；A suspension medium containing a pharmaceutically acceptable propellant;
    第一活性剂，优选所述第一活性剂选自皮质类固醇、长效β受体激动剂、长效抗胆碱能药、短效β受体激动剂、短效抗胆碱能药、磷酸二酯酶抑制剂、抗纤维化药和可吸入蛋白质中的一种或多种，以及The first active agent, preferably the first active agent is selected from corticosteroids, long-acting beta agonists, long-acting anticholinergics, short-acting beta-agonists, short-acting anticholinergics, phosphoric acid one or more of a diesterase inhibitor, an antifibrotic drug, and an inhalable protein, and
    可吸入的悬浮颗粒，所述悬浮颗粒包含疏水性氨基酸或含有疏水性氨基酸残基的肽。Inhalable suspended particles comprising hydrophobic amino acids or peptides containing hydrophobic amino acid residues.
  2. 根据权利要求1所述组合物，其中，所述第一活性剂存在于悬浮颗粒中。6. The composition of claim 1, wherein the first active agent is present in suspended particles.
  3. 根据权利要求1所述组合物，其中，所述第一活性剂与悬浮颗粒共存于悬浮介质中以形成共悬浮液。6. The composition of claim 1, wherein the first active agent and the suspending particles are present in a suspending medium to form a co-suspension.
  4. 根据权利要求1-3任一所述组合物，其中，所述悬浮颗粒具有褶皱的表面。4. The composition of any of claims 1-3, wherein the suspended particles have a corrugated surface.
  5. 根据权利要求1-4任一所述组合物，其中，所述悬浮颗粒包含疏水性氨基酸，疏水性氨基酸选自亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、缬氨酸、蛋氨酸、半胱氨酸、酪氨酸和丙氨酸中的一种或多种；优选自亮氨酸、异亮氨酸、缬氨酸、蛋氨酸和丙氨酸中的一种或多种；更优选自亮氨酸、异亮氨酸和丙氨酸中的一种或多种；甚至更优选为亮氨酸。The composition according to any one of claims 1-4, wherein the suspended particles comprise hydrophobic amino acids, and the hydrophobic amino acids are selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, and valine , one or more of methionine, cysteine, tyrosine and alanine; preferably one or more of leucine, isoleucine, valine, methionine and alanine ; more preferably selected from one or more of leucine, isoleucine and alanine; even more preferably leucine.
  6. 根据权利要求1-4任一所述组合物，其中，所述悬浮颗粒包含含有疏水性氨基酸残基的二肽或三肽，所述疏水性氨基酸选自亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、缬氨酸、蛋氨酸、半胱氨酸、酪氨酸和丙氨酸中的一种或多种。The composition according to any one of claims 1-4, wherein the suspended particles comprise a dipeptide or tripeptide containing a hydrophobic amino acid residue selected from the group consisting of leucine, isoleucine, benzene One or more of alanine, tryptophan, valine, methionine, cysteine, tyrosine, and alanine.
  7. 根据权利要求6所述组合物，其中，所述悬浮颗粒包含至少含有1个亮氨酸残基的二肽。7. The composition of claim 6, wherein the suspended particles comprise a dipeptide containing at least one leucine residue.
  8. 根据权利要求7所述组合物，其中，所述二肽选自：leu-leu、leu-gly、 leu-ala、leu-val、leu-ile、leu-phe、leu-pro、leu-trp、leu-ser、leu-tyr、leu-cys、leu-met、leu-asp、leu-asn、leu-gln、leu-glu、leu-thr、leu-lys、leu-arg和leu-his中的一种或多种；优选自leu-leu、leu-gly、leu-ala、leu-val、leu-ile、leu-phe、leu-trp、leu-tyr、leu-cys和leu-met中的一种或多种；更优选自leu-leu、leu-ala、leu-val和leu-ile中的一种或多种；甚至更优选为leu-leu。The composition of claim 7, wherein the dipeptide is selected from the group consisting of: leu-leu, leu-gly, leu-ala, leu-val, leu-ile, leu-phe, leu-pro, leu-trp, One of leu-ser, leu-tyr, leu-cys, leu-met, leu-asp, leu-asn, leu-gln, leu-glu, leu-thr, leu-lys, leu-arg, and leu-his one or more; preferably one of leu-leu, leu-gly, leu-ala, leu-val, leu-ile, leu-phe, leu-trp, leu-tyr, leu-cys and leu-met or more; more preferably one or more of leu-leu, leu-ala, leu-val and leu-ile; even more preferably leu-leu.
  9. 根据权利要求6所述组合物，其中，所述悬浮颗粒包含至少含有2个亮氨酸残基的三肽。7. The composition of claim 6, wherein the suspended particles comprise a tripeptide containing at least 2 leucine residues.
  10. 根据权利要求9所述组合物，其中，所述三肽由2个亮氨酸残基和1个选自亮氨酸、异亮氨酸、苯丙氨酸、色氨酸、缬氨酸、蛋氨酸、半胱氨酸、酪氨酸和丙氨酸的残基组成。The composition according to claim 9, wherein the tripeptide consists of two leucine residues and one selected from the group consisting of leucine, isoleucine, phenylalanine, tryptophan, valine, Residue composition of methionine, cysteine, tyrosine and alanine.
  11. 根据权利要求9或10所述组合物，其中，所述三肽选自：leu-leu-leu、leu-leu-ile、leu-ile-leu、leu-leu-phe、leu-phe-leu、leu-leu-trp、leu-trp-leu、leu-leu-val、leu-val-leu、leu-leu-met、leu-met-leu、leu-leu-cys、leu-cys-leu、leu-leu-tyr、leu-tyr-leu、leu-leu-ala和leu-ala-leu中的一种或多种；优选自leu-leu-leu、leu-leu-ile、leu-ile-leu、leu-leu-val、leu-val-leu、eu-leu-ala和leu-ala-leu中的一种或多种；更优选自优选自leu-leu-leu、leu-leu-ile、leu-ile-leu中的一种或多种；甚至更优选为leu-leu-leu。The composition according to claim 9 or 10, wherein the tripeptide is selected from the group consisting of: leu-leu-leu, leu-leu-ile, leu-ile-leu, leu-leu-phe, leu-phe-leu, leu-leu-trp, leu-trp-leu, leu-leu-val, leu-val-leu, leu-leu-met, leu-met-leu, leu-leu-cys, leu-cys-leu, leu- one or more of leu-tyr, leu-tyr-leu, leu-leu-ala and leu-ala-leu; preferably selected from leu-leu-leu, leu-leu-ile, leu-ile-leu, leu - one or more of leu-val, leu-val-leu, eu-leu-ala and leu-ala-leu; more preferably from leu-leu-leu, leu-leu-ile, leu-ile - one or more of leu; even more preferably leu-leu-leu.
  12. 根据权利要求1-11任一所述组合物，其中，所述悬浮颗粒还包含基本不溶于悬浮介质的聚合物。11. The composition of any of claims 1-11, wherein the suspended particles further comprise a polymer that is substantially insoluble in the suspending medium.
  13. 根据权利要求12所述组合物，其中，所述聚合物包含葡萄糖醛酸单元，所述聚合物优选为透明质酸或其可药用盐，更优选为透明质酸钠。The composition of claim 12, wherein the polymer comprises glucuronic acid units, preferably hyaluronic acid or a pharmaceutically acceptable salt thereof, more preferably sodium hyaluronate.
  14. 根据权利要求12或13所述组合物，悬浮颗粒中疏水性氨基酸或含有疏水性氨基酸残基的肽，与聚合物的质量比值为0.5～20，优选为1～10，更优选为2～8，甚至更优选为3～5。According to the composition of claim 12 or 13, the mass ratio of the hydrophobic amino acid or the peptide containing the hydrophobic amino acid residue in the suspended particles to the polymer is 0.5-20, preferably 1-10, more preferably 2-8 , even more preferably 3-5.
  15. 根据权利要求1-14任一所述组合物，其中，可吸入的悬浮颗粒与第一活性剂的质量比值为0.2～10，优选为0.5～5，更优选为0.8～3，甚至更优选 为1.2～1.6。The composition according to any one of claims 1-14, wherein the mass ratio of the respirable suspended particles to the first active agent is 0.2-10, preferably 0.5-5, more preferably 0.8-3, even more preferably 1.2 to 1.6.
  16. 根据权利要求1-15任一所述组合物，其中，可吸入的悬浮颗粒以1mg/ml至20mg/ml的浓度包含在悬浮介质中，优选以2mg/ml至15mg/ml的浓度，更优选以3mg/ml至10mg/ml的浓度，更优选以4mg/ml至8mg/ml的浓度。A composition according to any one of claims 1 to 15, wherein the respirable suspended particles are contained in the suspending medium at a concentration of 1 mg/ml to 20 mg/ml, preferably at a concentration of 2 mg/ml to 15 mg/ml, more preferably At a concentration of 3 mg/ml to 10 mg/ml, more preferably at a concentration of 4 mg/ml to 8 mg/ml.
  17. 根据权利要求1-16任一所述组合物，其中，可吸入的悬浮颗粒的MMAD为0.5～10μm，优选为1～5μm，更优选为2～4μm，甚至更优选为3～4μm。The composition according to any one of claims 1-16, wherein the respirable suspended particles have an MMAD of 0.5-10 μm, preferably 1-5 μm, more preferably 2-4 μm, even more preferably 3-4 μm.
  18. 根据权利要求1-17任一所述组合物，其中，可吸入的悬浮颗粒的体积中值几何直径为1～10μm，优选为2～8μm，更优选为3～6μm，甚至更优选为4～5μm。The composition according to any one of claims 1-17, wherein the volume median geometric diameter of the respirable suspended particles is 1-10 μm, preferably 2-8 μm, more preferably 3-6 μm, even more preferably 4- 5μm.
  19. 根据权利要求1-18任一所述组合物，其中，所述第一活性剂包含长效β受体激动剂，所述长效β受体激动剂选自沙美特罗、福莫特罗、茚达特罗、米维特罗、奥达特罗和维兰特罗中的一种或多种，包括任何其可药用的盐。The composition according to any one of claims 1-18, wherein the first active agent comprises a long-acting beta-receptor agonist selected from the group consisting of salmeterol, formoterol, One or more of indacaterol, milverterol, odaterol and vilanterol, including any pharmaceutically acceptable salts thereof.
  20. 根据权利要求19所述组合物，其中，所述长效β受体激动剂为茚达特罗或其可药用的盐，优选为乙酸茚达特罗或马来酸茚达特罗，更优选为乙酸茚达特罗。The composition according to claim 19, wherein the long-acting beta receptor agonist is indacaterol or a pharmaceutically acceptable salt thereof, preferably indacaterol acetate or indacaterol maleate, more Preferred is indacaterol acetate.
  21. 根据权利要求20所述组合物，其中，所述茚达特罗或其可药用的盐为晶体状或无定形的颗粒，优选为晶体状颗粒。The composition according to claim 20, wherein the indacaterol or a pharmaceutically acceptable salt thereof is a crystalline or amorphous particle, preferably a crystalline particle.
  22. 根据权利要求21所述组合物，其中，茚达特罗或其可药用盐颗粒的体积中值几何直径为0.2～10μm，优选为0.5～5μm，更优选为1～4μm，甚至更优选为1.5～3μm。The composition according to claim 21, wherein the volume median geometric diameter of the particles of indacaterol or a pharmaceutically acceptable salt thereof is 0.2-10 μm, preferably 0.5-5 μm, more preferably 1-4 μm, even more preferably 1.5～3μm.
  23. 根据权利要求21或22所述组合物，其中，所述茚达特罗或其可药用盐颗粒与悬浮颗粒共存于悬浮介质中以形成共悬浮液，组合物中茚达特罗的浓度为0.5mg/ml～10mg/ml，优选为0.8mg/ml～5mg/ml，更优选为1mg/ml～4mg/ml，甚至更优选为2mg/ml～3mg/ml。The composition according to claim 21 or 22, wherein the particles of indacaterol or a pharmaceutically acceptable salt thereof and the suspended particles coexist in a suspension medium to form a co-suspension, and the concentration of indacaterol in the composition is 0.5 mg/ml to 10 mg/ml, preferably 0.8 mg/ml to 5 mg/ml, more preferably 1 mg/ml to 4 mg/ml, even more preferably 2 mg/ml to 3 mg/ml.
  24. 根据权利要求20所述组合物，其中，包含在组合物中的茚达特罗的浓度足以使定量吸入器的每次启动作用产生的茚达特罗递送剂量为10～300μg，优选为30-200μg，更优选为50～150μg，甚至更优选为80～120μg。The composition of claim 20, wherein the indacaterol is included in the composition at a concentration sufficient to deliver a dose of indacaterol of 10-300 μg, preferably 30-30 μg per actuation of the metered dose inhaler 200 μg, more preferably 50 to 150 μg, even more preferably 80 to 120 μg.
  25. 根据权利要求1-24任一所述组合物，其中，第一活性剂包含皮质类固醇，所述皮质类固醇选自布***、环索奈德、氟替卡松、莫米松、倍氯米松和氟尼缩松中的一种或多种，包括任何其可药用的酯及水合物。24. The composition of any one of claims 1-24, wherein the first active agent comprises a corticosteroid selected from the group consisting of budesonide, ciclesonide, fluticasone, mometasone, beclomethasone, and flunisolide One or more of pine, including any pharmaceutically acceptable esters and hydrates thereof.
  26. 根据权利要求25所述组合物，其中，所述皮质类固醇为氟替卡松或其可药用的酯及水合物，优选为糠酸氟替卡松或丙酸氟替卡松，更优选为糠酸氟替卡松。The composition according to claim 25, wherein the corticosteroid is fluticasone or a pharmaceutically acceptable ester and hydrate thereof, preferably fluticasone furoate or fluticasone propionate, more preferably fluticasone furoate.
  27. 根据权利要求26所述组合物，其中，所述糠酸氟替卡松为晶体状或无定形的颗粒，优选为晶体状颗粒。The composition according to claim 26, wherein the fluticasone furoate is a crystalline or amorphous particle, preferably a crystalline particle.
  28. 根据权利要求27所述组合物，其中，糠酸氟替卡松颗粒的体积中值几何直径为0.2～10μm，优选为0.5～5μm，更优选为1～4μm，甚至更优选为1.5～3μm。The composition according to claim 27, wherein the volume median geometric diameter of the fluticasone furoate particles is 0.2-10 μm, preferably 0.5-5 μm, more preferably 1-4 μm, even more preferably 1.5-3 μm.
  29. 根据权利要求27所述组合物，其中，糠酸氟替卡松颗粒与悬浮颗粒共存于悬浮介质中以形成共悬浮液，组合物中糠酸氟替卡松的浓度为0.2mg/ml～10mg/ml，优选为0.5mg/ml～5mg/ml，更优选为1mg/ml～3mg/ml，甚至更优选为1.5mg/ml～2.5mg/ml。The composition according to claim 27, wherein the fluticasone furoate particles and the suspended particles coexist in a suspension medium to form a co-suspension, and the concentration of the fluticasone furoate in the composition is 0.2 mg/ml to 10 mg/ml, preferably 0.5 mg/ml mg/ml to 5 mg/ml, more preferably 1 mg/ml to 3 mg/ml, even more preferably 1.5 mg/ml to 2.5 mg/ml.
  30. 根据权利要求26所述组合物，其中，包含在组合物中的糠酸氟替卡松的浓度足以使定量吸入器的每次启动作用产生的糠酸氟替卡松递送剂量为10～300μg，优选为30-200μg，更优选为50～150μg，甚至更优选为80～120μg。The composition of claim 26, wherein the concentration of fluticasone furoate included in the composition is sufficient to deliver a dose of fluticasone furoate of 10-300 μg, preferably 30-200 μg, per actuation of the metered dose inhaler, More preferably, it is 50 to 150 μg, and even more preferably, it is 80 to 120 μg.
  31. 根据权利要求1-30任一所述组合物，其中，组合物还包括第二活性剂，所述第二活性剂包含长效抗胆碱能药，所述长效抗胆碱能药选自阿地铵、格隆铵、噻托铵、乌美铵和芜地铵中的一种或多种，包括任何其可药用的盐。The composition according to any one of claims 1-30, wherein the composition further comprises a second active agent comprising a long-acting anticholinergic agent selected from the group consisting of One or more of aclidinium, glycopyrronium, tiotropium, umeclidinium, and umeclidinium, including any pharmaceutically acceptable salts thereof.
  32. 根据权利要求31所述组合物，其中，所述第二活性剂为格隆溴铵。The composition of claim 31, wherein the second active agent is glycopyrronium bromide.
  33. 根据权利要求32所述组合物，其中，所述格隆溴铵存在于悬浮颗粒中。33. The composition of claim 32, wherein the glycopyrronium bromide is present in suspended particles.
  34. 根据权利要求32所述组合物，其中，格隆溴铵为晶体状或无定形的颗粒，并与悬浮颗粒共存于悬浮介质中以形成共悬浮液。The composition of claim 32, wherein the glycopyrronium bromide is in the form of crystalline or amorphous particles and coexists with the suspended particles in a suspension medium to form a co-suspension.
  35. 根据权利要求32-34任一所述组合物，其中，组合物中格隆溴铵的浓度为0.1mg/ml～5mg/ml，优选为0.2mg/ml～4mg/ml，更优选为0.5mg/ml～2mg/ml，甚至更优选为0.8mg/ml～1.5mg/ml。The composition according to any one of claims 32-34, wherein the concentration of glycopyrronium bromide in the composition is 0.1 mg/ml to 5 mg/ml, preferably 0.2 mg/ml to 4 mg/ml, more preferably 0.5 mg /ml to 2 mg/ml, even more preferably 0.8 mg/ml to 1.5 mg/ml.
  36. 根据权利要求32-34任一所述组合物，其中，包含在组合物中的格隆溴铵的浓度足以使定量吸入器的每次启动作用产生的格隆溴铵递送剂量为5～120μg，优选为10-100μg，更优选为20～80μg，甚至更优选为40～60μg。34. The composition of any one of claims 32-34, wherein glycopyrronium bromide is included in the composition at a concentration sufficient to deliver a dose of glycopyrronium bromide of 5 to 120 μg per actuation of the metered dose inhaler, It is preferably 10-100 μg, more preferably 20-80 μg, even more preferably 40-60 μg.
  37. 根据权利要求1-36任一所述组合物，其中，所述推进剂为氢氟烷烃或全氟烷烃，优选为氢氟烷烃，更优选为HFA-134a。The composition according to any one of claims 1-36, wherein the propellant is a hydrofluoroalkane or a perfluoroalkane, preferably a hydrofluoroalkane, more preferably HFA-134a.
  38. 根据权利要求1-37任一所述组合物，其中，所述组合物适用于每天给药1次或2次；优选适用于每天给药1次。The composition according to any one of claims 1-37, wherein the composition is suitable for administration once or twice a day; preferably it is suitable for administration once a day.
  39. 根据权利要求38所述的组合物，其中每次给药1～2揿，优选每次1揿。38. The composition of claim 38, wherein 1 to 2 swipes are administered per administration, preferably 1 swipe per administration.
  40. 一种定量吸入产品，包括带有出口阀的容器罐，该出口阀带有用于递送定量体积的启动器，所述容器罐包含如权利要求1-39任一项所述的组合物。A metered dose inhalation product comprising a container canister with an outlet valve with an actuator for delivering a metered volume, the container canister comprising the composition of any one of claims 1-39.
  41. 一种制备权利要求1-30任一所述组合物的方法，其包括如下步骤：A method of preparing the composition of any one of claims 1-30, comprising the steps of:
    提供含有可药用的推进剂的悬浮介质；providing a suspension medium containing a pharmaceutically acceptable propellant;
    提供第一活性剂；providing a first active agent;
    通过喷雾干燥载体溶液制备得到可吸入的悬浮颗粒，悬浮颗粒所包含的成分预先溶解于载体溶液中。The respirable suspended particles are prepared by spray-drying a carrier solution, and the components contained in the suspended particles are pre-dissolved in the carrier solution.
  42. 根据权利要求41所述的方法，其还包括在喷雾干燥前将第二活性剂溶解于载体溶液中的步骤，第二活性剂包含长效抗胆碱能药，所述长效抗 胆碱能药选自阿地铵、格隆铵、噻托铵、乌美铵和芜地铵，包括任何其可药用的盐。The method of claim 41, further comprising the step of dissolving a second active agent in the carrier solution prior to spray drying, the second active agent comprising a long-acting anticholinergic, the long-acting anticholinergic The drug is selected from the group consisting of aclidinium, glycopyrronium, tiotropium, umeclidinium, and umeclidinium, including any pharmaceutically acceptable salts thereof.
  43. 根据权利要求42所述的方法，其中，第二活性剂为格隆溴铵。The method of claim 42, wherein the second active agent is glycopyrronium bromide.
  44. 根据权利要求41-43任一所述的方法，其中，所述溶液的溶剂选自水、甲醇、乙醇、正丙醇、异丙醇和正丁醇中的一种或多种，优选自水、乙醇或其混合物，更优选为水。The method according to any one of claims 41-43, wherein the solvent of the solution is selected from one or more of water, methanol, ethanol, n-propanol, isopropanol and n-butanol, preferably from water, Ethanol or a mixture thereof, more preferably water.
  45. 根据权利要求41-44任一所述的方法，其中，载体溶液中还溶解有致孔剂，所述致孔剂选自碳酸氢铵、尿素、聚乙烯吡咯烷酮、聚乙二醇和聚乙烯醇中的一种或多种，优选为碳酸氢铵。The method according to any one of claims 41-44, wherein a porogen is further dissolved in the carrier solution, and the porogen is selected from the group consisting of ammonium bicarbonate, urea, polyvinylpyrrolidone, polyethylene glycol and polyvinyl alcohol One or more, preferably ammonium bicarbonate.
  46. 权利要求1-39任一所述组合物在制备治疗炎性或阻塞性肺部疾病药物中的用途。Use of the composition of any one of claims 1-39 in the preparation of a medicament for treating inflammatory or obstructive pulmonary diseases.
  47. 根据权利要求46所述用途，所述疾病选自哮喘、慢性阻塞性肺病、继发性气道高反应性恶化、过敏性鼻炎、鼻窦炎、肺血管收缩、呼吸障碍、呼吸窘迫综合征、肺动脉高压、以及与囊性纤维化相关的肺部炎症及阻塞。The use according to claim 46, wherein the disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease, exacerbation of secondary airway hyperresponsiveness, allergic rhinitis, sinusitis, pulmonary vasoconstriction, respiratory disorder, respiratory distress syndrome, pulmonary artery High blood pressure, and lung inflammation and obstruction associated with cystic fibrosis.
  48. 根据权利要求47所述用途，所述疾病为慢性阻塞性肺病。The use according to claim 47, wherein the disease is chronic obstructive pulmonary disease.
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