WO2022122012A1 - 用于肺部递送的药物组合物 - Google Patents

用于肺部递送的药物组合物 Download PDF

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WO2022122012A1
WO2022122012A1 PCT/CN2021/137062 CN2021137062W WO2022122012A1 WO 2022122012 A1 WO2022122012 A1 WO 2022122012A1 CN 2021137062 W CN2021137062 W CN 2021137062W WO 2022122012 A1 WO2022122012 A1 WO 2022122012A1
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pharmaceutical composition
particles
salts
composition according
pharmaceutically acceptable
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PCT/CN2021/137062
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English (en)
French (fr)
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李金宇
吕扣
孙琼
柴夫娟
叶秀
卢韵
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江苏恒瑞医药股份有限公司
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Priority to CN202180083414.3A priority Critical patent/CN116546980A/zh
Publication of WO2022122012A1 publication Critical patent/WO2022122012A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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 for pulmonary delivery and a preparation method.
  • Active pharmaceutical ingredients (APIs) useful in the treatment of respiratory diseases are formulated for administration by inhalation, typically via a portable inhaler.
  • portable inhalers are pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs).
  • pMDIs pressurized metered dose inhalers
  • DPIs dry powder inhalers
  • inhalation preparations have the advantages of rapid onset of action, low dosage, and fewer side effects.
  • the dry powder inhaler it also has the characteristics of long-term stable preservation, and it is attracting more and more attention in the treatment of respiratory system diseases.
  • the deposition position of dry powder inhaler in the respiratory tract is closely related to its biological effect, and the deposition position is related to the particle size of drug particles.
  • Pulmonary fibrosis especially idiopathic pulmonary fibrosis (IPF) is a diffuse lung disease of unknown etiology. Mainly manifested as diffuse alveolitis, structural disorder of alveolar units and pulmonary fibrosis, which eventually led to severe damage to lung structure and function. As a result, it replaces the normal lung tissue structure, seriously affects the ventilation and ventilation function of the lung, and eventually leads to respiratory failure and death.
  • IPF idiopathic pulmonary fibrosis
  • Pirfenidone is an anti-fibrotic agent for idiopathic pulmonary fibrosis. Its mechanism of action is to regulate the production of various cytokines such as inflammatory cytokines and anti-inflammatory cytokines and proliferation factors involved in the formation of fibrosis. And showed anti-fibrotic effect.
  • WO2013039167 discloses a pirfenidone inhalation powder formulation, but the dosage of the carrier material is large, and the drug powder loading capacity is low;
  • WO2018012516 discloses another pirfenidone inhalation preparation, the drug loading is also low, and the preparation The fine particle fraction (FPF %) in the medium is less, which is not conducive to the pulmonary delivery of the drug.
  • US9155699 discloses a levodopa phospholipid drug-carrying particle. Although the drug-carrying amount and FPF are high, the particle shape is not good, and the requirements for equipment are high. However, there is no high drug-loaded inhalation particle for idiopathic pulmonary fibrosis in the prior art.
  • the present disclosure provides pharmaceutical compositions for pulmonary delivery.
  • the present disclosure provides a pharmaceutical composition for pulmonary delivery, the pharmaceutical composition comprising particles, the particles comprising an active agent, phospholipids and other pharmaceutically acceptable excipients, the mass of the particles
  • the median aerodynamic diameter is less than 5 microns
  • the volume median geometric diameter is less than 5 microns
  • the active agent mass accounts for more than 85% of the total particle mass.
  • the active agent mass accounts for more than 90% of the total mass of the particles.
  • the particles have a tap density of 0.01-0.6 g/cm 3 , preferably 0.1-0.5 g/cm 3 .
  • the phospholipids of the present disclosure include phospholipids having a gel to liquid crystal phase transition above about 40°C, eg, above 60°C or above about 80°C. Included phospholipids can be relatively long chain (eg, C16- C22 ) saturated phospholipids.
  • Exemplary phospholipids that can be used in the disclosed stable formulations include, but are not limited to, for example, dipalmitoyl phosphatidyl choline (DPPC), distearoyl phosphatidyl choline (DSPC), dipalmitoyl phosphatidyl glycerol (DPPG), Distearoylphosphatidylethanolamine (DSPE), hydrogenated egg or soybean phosphatidylcholine (eg, E-100-3, S-100-3, available from LipoidKG, Ludwigshafen, Germany) and combinations thereof.
  • the phospholipids can also be natural phospholipids, preferably hydrogenated, with a low iodine value ( ⁇ 10).
  • the phospholipid can be selected from distearoyl phosphatidyl choline (DSPC), dipalmitoyl phosphatidyl choline (DPPC), dipalmitoyl phosphatidyl glycerol (DPPG), or distearoyl phosphatidyl ethanolamine One or more of (DSPE); preferably selected from distearoyl phosphatidyl choline (DSPC), dipalmitoyl phosphatidyl choline (DPPC) or a combination thereof.
  • DSPC distearoyl phosphatidyl choline
  • DPPC dipalmitoyl phosphatidyl choline
  • DPPC dipalmitoyl phosphatidyl choline
  • the phospholipid is selected from distearoylphosphatidylcholine (DSPC); while in another embodiment, the phospholipid is selected from dipalmitoylphosphatidylcholine (DPPC).
  • DSPC distearoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • the mass of the phospholipid accounts for 1%-15% of the total mass of the particle; specifically, it can be selected from 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13% , 13.5%, 14%, 14.5% and 15%; in some embodiments, the mass of the phospholipid accounts for 3%-10% of the total mass of the particle; in some embodiments, the mass of the phospholipid accounts for the total mass of the particle is 5%-8%; in one embodiment, the phospholipid is 7% of the total mass of the particle.
  • the other pharmaceutically acceptable excipients include one or more monovalent cation-containing salts.
  • “Monovalent cations” include, but are not limited to, Li + , Na + , K + , Cs + , NH 4 + , and salts containing monocations refer to compounds formed by combining monovalent cations with acid ions, which may be composed of inorganic or organic acids. Acid ionization is produced.
  • the monovalent cation-containing salt is selected from sodium, potassium or ammonium salts; preferably from sodium chloride, potassium chloride, ammonium chloride or sodium citrate. In one embodiment, the monovalent cation-containing salt is selected from sodium chloride; while in another embodiment, the monovalent cation-containing salt is selected from sodium citrate.
  • the above-mentioned salt containing monovalent cations accounts for 0.2-20% of the total mass of the particles; specifically, it can be selected from 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% %, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13% , 14%, 15%, 16%, 17%, 18%, 19% and 20%, in some embodiments, the above-mentioned monovalent cation-containing salt is 0.5% to 15% by mass of the total particle mass; in some In embodiments, the above-mentioned salt containing monovalent cations accounts for 1% to 10% of the total mass of the particles; in some embodiment
  • other pharmaceutically acceptable excipients in the particles include one or more salts comprising multivalent cations.
  • Multivalent cation includes but is not limited to all divalent cations, trivalent cations, and tetravalent cations, and salts containing multivalent cations refer to compounds formed by combining multivalent cations with acid ions, which can be composed of inorganic acids or organic acids. Acid ionization is produced.
  • the salt comprising a multivalent cation is selected from a divalent cation salt; the divalent cation salt may be a calcium, magnesium, barium, zinc, copper or ferrous salt. In some embodiments, the salt comprising a multivalent cation is selected from calcium salts, preferably calcium chloride.
  • the above-mentioned salts containing multivalent cations account for 0.1-10% of the total mass of the particles, and can be specifically selected from 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5% , 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%; in some embodiments, the above The salt containing multivalent cations, the mass of which accounts for 0.2% to 5% of the total mass of the particles; in some embodiments, the above-mentioned salts containing polyvalent cations, the mass of which accounts for 0.5% to 2% of the total mass of the particles; in some implementations In the solution, the above-mentioned salt containing polyvalent cations
  • the other pharmaceutically acceptable adjuvants include both monovalent cation-containing salts and multivalent cation-containing salts, such as both sodium salts and calcium salts, preferably both sodium chloride and calcium chloride.
  • the masses of the sodium and calcium salts are as defined above.
  • the active agent is selected from pulmonary fibrosis therapeutic agents, including but not limited to pirfenidone or a pharmaceutically acceptable salt thereof, nintedanib or a pharmaceutically acceptable salt thereof, N-acetylcysteine acid, imatinib or a pharmaceutically acceptable salt thereof, famitinib or a pharmaceutically acceptable salt thereof.
  • the pulmonary fibrosis therapeutic agent is selected from pirfenidone or a pharmaceutically acceptable salt thereof; in one embodiment, the pulmonary fibrosis therapeutic agent is selected from famitinib or a pharmaceutically acceptable salt thereof salt; in another embodiment, the pulmonary fibrosis therapeutic agent is selected from nintedanib or a pharmaceutically acceptable salt thereof.
  • the particles have a hollow and/or corrugated morphology.
  • "Hollow and/or corrugated” means that the particle has a hollow irregular morphology, and/or that the particle surface has at least one depression and/or bulge.
  • hollow and/or corrugated particles are shown in Figures 2-4.
  • the particles have a porous morphology.
  • Porous means that a plurality of grooves are distributed on the surface and/or inside the particle, the grooves optionally connecting the inside and outside of the particle.
  • the particles of the present disclosure have both "hollow and/or corrugated” and “porous” morphologies, ie, the particles have a hollow, irregular morphology with a plurality of depressions and/or ridges (ie, corrugations) on the surface of the particles , and in the above-mentioned collapsed and/or raised parts, as well as other positions on the particle surface, there are also a plurality of grooves (ie, pores) distributed, forming a "secondary wrinkle” as a whole.
  • the hollow pleated porous particle is shown in FIG. 2 .
  • the present disclosure provides an inhalation unit formulation comprising a container, and a pharmaceutical composition of the present disclosure contained within the container.
  • containers include, but are not limited to, capsules, blisters, or container closure systems made of metals, polymers (eg, plastics, elastomers), glass, and the like.
  • the present disclosure also provides a method for preparing the pharmaceutical composition of the first aspect, comprising the step of spray drying after mixing an organic phase and an aqueous phase.
  • the preparation method of the pharmaceutical composition comprises the steps of:
  • step iii) dissolving the active agent and phospholipid in an organic solvent to obtain an organic phase; ii) dissolving other pharmaceutically acceptable excipients in water to obtain an aqueous phase; iii) slowly adding the aqueous phase to the organic phase, stirring and mixing; iv ) spray-drying the material obtained in step iii) to obtain granules.
  • the solvent of the organic phase is ethanol.
  • the volume ratio of ethanol to water is 0.2-5:1; specifically, it can be selected from 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1 , 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.1 : 1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, and 5:1; in some embodiments, the volume of ethanol to water The ratio is from 0.5 to 3:1; in some embodiments, the volume ratio of ethanol to water is from 1.0 to 2.5:1. In one embodiment, the volume ratio of ethanol to water is 1.5:1. In yet another implementation, the volume ratio of ethanol to water is 1:1.
  • the total amount of active agent, phospholipids and other pharmaceutically acceptable auxiliary materials is below 5g/L; specifically, it can be selected from 5g/L, 4.5g/L, 4g/L L, 3.5g/L, 3g/L, 2.75g/L, 2.5g/L, 2.25g/L, 2g/L, 1.75g/L, 1.5g/L, 1.25g/L, 1g/L, 0.75 g/L, 0.5g/L and 0.25g/L; in some embodiments, after the organic phase and the aqueous phase are mixed, the total amount of active agent, phospholipids and other pharmaceutically acceptable excipients is below 4.5g/L; In some embodiments, after the organic phase and the water phase are mixed, the total amount of the active agent, phospholipids and other pharmaceutically acceptable excipients is below 4 g/L; in some embodiments, after the organic phase and the water phase are mixed, the active agent The total amount of
  • the drug-loaded inhalation particles of the present disclosure can be obtained by spray drying at relatively low gas flow rates and feed rates.
  • the spray drying uses nitrogen as the spray gas
  • the spray gas flow rate of the spray drying is lower than 50kg/h, preferably lower than 20kg/h, specifically lower than 19kg/h, 18kg/h, 17kg/h, 16kg/h, 15kg/h h, 14kg/h, 13kg/h, 12kg/h, 11kg/h, 10kg/h, 9.5kg/h, 9kg/h, 8.5kg/h, 8kg/h, 7.5kg/h, 7kg/h, 6.5 kg/h, 6kg/h, 5.5kg/h, 5kg/h, 4.5kg/h, 4kg/h, 3.5kg/h, 3kg/h, 2.9kg/h, 2.8kg/h, 2.7kg/h, 2.6kg/h, 2.5kg/h, 2.4kg/h, 2.3kg/h, 2.2kg/h, 2.1kg/h, 2kg/h, 1.9kg/h, 1.8kg/h, 1.7kg/h, 1.6 kg/h or 1.5kg/h; in other embodiments,
  • the feed rate of the spray drying is lower than 50ml/min, preferably lower than 30ml/min, specifically lower than 29ml/min, 28ml/min, 27ml/min, 26ml/min, 25ml/min , 24ml/min, 23ml/min, 22ml/min, 21ml/min, 20ml/min, 19ml/min, 18ml/min, 17ml/min, 16ml/min, 15ml/min, 14ml/min, 13ml/min, 12ml /min, 11ml/min, 10ml/min, 9ml/min, 8ml/min, 7ml/min, 6ml/min or 5ml/min, in some embodiments, the feed rate of the spray drying is less than 15ml/min , in some embodiments, the feed rate of the spray drying is 10 ml/min.
  • the present disclosure also provides a mixture comprising ethanol and water, wherein the mixture is spray-dried to obtain the pharmaceutical composition according to the first aspect.
  • the mixture comprising ethanol and water may be a clear solution, emulsion or suspension; preferably a clear solution.
  • the volume ratio of ethanol to water is 0.2-5:1; specifically, it can be selected from 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7 :1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 , 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, and 5:1; in some embodiments , in the composition, the volume ratio of ethanol to water is 0.5-3:1; in some embodiments, in the composition, the volume ratio of ethanol to water is 1-2.5:1. In one embodiment, the volume ratio of ethanol to water is 1.5:1. In yet another implementation, the volume ratio of ethanol to water is 1:1.
  • the mass of A accounts for x% of the total mass of the particles means that the total mass of substance A in the pharmaceutical composition accounts for x% of the total mass of the particles in the pharmaceutical composition; those skilled in the art should understand that the mass of A in a single particle under the microscopic level accounts for x% of the total mass of the particles in the pharmaceutical composition.
  • the ratio is allowed to deviate from the above ratio, as long as it is consistent with the overall ratio.
  • Active agent or “drug” means the active ingredient of a drug, also known as an active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • Volume median geometric diameter or "X 50 " or refers to the median diameter of a plurality of particles, ie particles larger and smaller than this diameter each account for 50% of the total volume. "X90” means that 90 % of the particles by volume are smaller than this diameter.
  • 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 “Jet Dose” refers to the mass of drug that leaves the inhaler device when administered.
  • GSD or “Geometric Standard Deviation” refers to the parameter describing the width of the aerodynamic particle size distribution, Among them, D84.1 and D15.9 are the aerodynamic diameters of particles whose cumulative distribution is lower than 84.1% and 15.9%, respectively.
  • Figure 1 shows the comparison of the X-ray powder diffraction patterns of pirfenidone before and after the formulation;
  • A the raw drug pirfenidone before the formulation,
  • B the pirfenidone in the inhaled dry powder a of Example 1.
  • Figure 2 shows a scanning electron microscope (SEM) image of Example 1 inhaled dry powder a.
  • Figure 3 shows a scanning electron microscope (SEM) image of Example 2 inhaled dry powder b.
  • Figure 4 shows a scanning electron microscope (SEM) image of Example 3 inhaled dry powder e.
  • serial number reagent source 1 Pirfenidone Beijing Lairison Pharmaceutical Technology Co., Ltd. 2 Distearoylphosphatidylcholine Lipoid GmbH 3 dipalmitoylphosphatidylcholine Lipoid GmbH 4 Sodium chloride Jiangsu Qinfen Pharmaceutical Co., Ltd. 5 calcium chloride Hebei Huachen Pharmaceutical Co., Ltd. 6 Ethanol Nanjing Chemical Reagent Co., Ltd. 7 No. 3 HPMC transparent capsule Suzhou Capsule Co., Ltd.
  • Organic phase 0.07g of distearoyl phosphatidylcholine (DSPC) was added to 480ml of absolute ethanol, magnetic stirring at room temperature was used to dissolve it completely, and then 0.9g of pirfenidone bulk drug was added to it with magnetic stirring at room temperature. Completely dissolved.
  • DSPC distearoyl phosphatidylcholine
  • Aqueous phase add 0.02 g of sodium chloride and 0.01 g of calcium chloride to 320 ml of deionized water, and stir to dissolve completely.
  • Example 1 A preparation method similar to that of Example 1 was adopted, except that the amounts of ethanol and water were adjusted, as shown in Table 1.
  • Example 2 A method similar to Example 1 was adopted, except that the shell-forming material distearoyl phosphatidyl choline (DSPC) was replaced with dipalmitoyl phosphatidyl choline (DPPC), and the amounts of ethanol and water were adjusted.
  • DSPC distearoyl phosphatidyl choline
  • DPPC dipalmitoyl phosphatidyl choline
  • Aqueous phase add 0.02 g of sodium chloride and 0.01 g of calcium chloride to 400 ml of deionized water, and stir to dissolve completely.
  • Example 1 A method similar to that of Example 1 was adopted, except that the ratio of alcohol to water and the solid content of the solution preparation process were adjusted, and the parameters in the spraying process were adjusted.
  • Aqueous phase add 0.07g of sodium chloride and 0.035g of calcium chloride to 300ml of deionized water, stir to dissolve completely.
  • Example 1-4 The drug-containing inhalation dry powder a-f prepared in Example 1-4 was filled into transparent HPMC capsules (No. 3), 25 mg, and the NGI impactor of the COPLEY company was used for the capsule samples according to the Chinese Pharmacopoeia 2015 Edition Four General Rules 0951 [Inhalation Preparations. Determination of Aerodynamic Characteristics of Fine Particles] specifies the APSD test.
  • the MMAD of inhaled dry powder a-f is not higher than 5 ⁇ m, indicating that it can be deposited in the lungs, and each embodiment has higher FPF and ED values, indicating that its pulmonary delivery efficiency is high.
  • the FPD and ED ratios of each embodiment under the conditions of 60L/min and 30L/min flow rates are close to 1, which proves that the aerodynamic characteristics of the inhaled dry powder particles of the present disclosure do not depend on the gas flow rate, and the particles as a whole have excellent dispersibility and mobility, lower tendency to aggregate, especially suitable for patients with impaired lung function.
  • Embodiment 6 Determination of geometric particle size of inhaled dry powder
  • the particle size was measured using a SYMPATEC particle size analyzer with a dispersion pressure of 4 bar.
  • the particle size results are shown in Table 3.
  • Embodiment 7 Inhalation dry powder density measurement
  • Embodiment 9 Inhalation dry powder form observation
  • inhalation dry powder a of Example 1 was observed with a scanning electron microscope (SEM), and the morphological results are shown in FIG. 2 .
  • SEM scanning electron microscope
  • FIG. 2 It can be seen from Fig. 2 that the inhaled dry powder a has the form of hollow folds. Studies have shown that the form of folds can improve the dispersibility and stability of the particles by reducing the contact area between the particles. This is consistent with the test in Example 5. The results are consistent.
  • inhaled dry powder a also has a porous "secondary fold" shape, which further reduces the contact area between particles, suggesting that it has better dispersion and fluidity.

Abstract

一种用于肺部递送的干粉颗粒，包含活性剂、磷脂及其它药学上可接受的辅料，其质量中值空气动力学直径小于5微米，体积中值几何直径小于5微米，并且活性剂质量占颗粒总质量的85％以上。该颗粒的载药量高，并拥有较高的肺部递送效率，可用于肺部疾病的吸入治疗。

Description

用于肺部递送的药物组合物
本申请要求申请日为2020/12/11的中国专利申请202011459388.3的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于医药领域，涉及一种用于肺部递送的药物组合物以及制备方法。
背景技术
可用于治疗呼吸疾病的活性药物成分(API)经配制通常通过便携式吸入剂吸入来施用。两类最普遍的便携式吸入剂是加压式计量吸入剂(pMDI)及干粉吸入剂(DPI)。相较于其他常规的给药方法，吸入制剂具有起效迅速、用药量低、副作用小等优势。而对于干粉吸入剂，其还具有可长期稳定保存的特点，在呼吸系统疾病的治疗中，正日渐受到关注。干粉吸入剂在呼吸道的沉降位置与其发挥生物性效应有着密切的关系，而沉降位置又与药物颗粒的粒径相关，本领域通常认为，空气动力学粒径大于5μm的颗粒将主要在咽喉部沉积，无法达到支气管或肺部，并可能会诱发副作用；而空气动力学粒径小于1μm的颗粒容易随呼吸被排除体外，不利于药效的发挥；因此，一般认为空气动力学粒径1-5μm的颗粒是较为理想的。
肺纤维化尤其是特发性肺纤维化(idiopathic pulmonary fibrosis，IPF)是一种原因不明的弥漫性肺疾病。主要表现为弥漫性肺泡炎、肺泡单位结构紊乱和肺纤维化，最终导致肺脏结构和功能的严重破坏，其病理主要表现为早期弥漫性肺泡炎及后期大量间质细胞增生、基质胶原进行性聚集以致取代正常的肺组织结构，严重影响肺的通气和换气功能，最终导致呼吸功能衰竭而死亡。
吡非尼酮(Pirfenidone)是一种针对特发性肺纤维症的抗纤维化剂。其作用机制为对炎症性细胞因子、抗炎症性细胞因子等各种细胞因子和参与纤维化形成的增殖因子的产生具有调节作用，基于纤维母细胞增殖抑制作用、胶原产生抑制作用等复合的作用而显示出抗纤维化作用。WO2013039167公开了一种吡非尼酮吸入粉末制剂，但其载体材料用量较大，药粉载药量较低；WO2018012516公开了另一种吡非尼酮吸入制剂，载药量同样较低，同时制剂中的细颗粒部分(FPF％)较少，不利于药物的肺部递送。
US9155699公开了一种左旋多巴磷脂载药颗粒，虽然载药量及FPF较高，但颗粒形态不佳，并且对设备的要求较高。而现有技术中尚无针对特发性肺纤维化的高载药吸入 颗粒。
发明内容
为了克服现有技术的不足，本公开提供了用于肺部递送的药物组合物。
第一方面，本公开提供了一种用于肺部递送的药物组合物，所述药物组合物包含颗粒，所述颗粒包含活性剂、磷脂及其他药学上可接受的辅料，所述颗粒的质量中值空气动力学直径小于5微米，体积中值几何直径小于5微米，并且活性剂质量占颗粒总质量的85％以上。
在一些实施方案中，所述颗粒中，活性剂质量占颗粒总质量的90％以上。
在一些实施方案中，所述颗粒的振实密度为0.01-0.6g/cm 3，优选0.1-0.5g/cm 3。
本公开所述磷脂包含具有高于约40℃、例如高于60℃或高于约80℃的凝胶至液晶相转变的磷脂。所纳入的磷脂可为相对长链(例如，C 16-C 22)饱和磷脂。可用于所公开的稳定制剂中的示例性磷脂包括但不限于例如二棕榈酰基磷脂酰胆碱(DPPC)、二硬脂酰基磷脂酰胆碱(DSPC)、二棕榈酰基磷脂酰甘油(DPPG)、二硬脂酰基磷脂酰乙醇胺(DSPE)、氢化卵或大豆磷脂酰胆碱(例如，E-100-3、S-100-3，可自LipoidKG，Ludwigshafen，Germany购得)以及它们的组合物。所述磷脂还可以为天然磷脂，优选氢化、碘值较低(<10)的。
在一些实施方案中，磷脂可以选自二硬脂酰基磷脂酰胆碱(DSPC)、二棕榈酰基磷脂酰胆碱(DPPC)、二棕榈酰基磷脂酰甘油(DPPG)或二硬脂酰基磷脂酰乙醇胺(DSPE)中的一种或几种；优选自二硬脂酰基磷脂酰胆碱(DSPC)、二棕榈酰基磷脂酰胆碱(DPPC)或其组合。
在一个实施方案中，所述磷脂选自二硬脂酰基磷脂酰胆碱(DSPC)；而在另一个实施方案中，磷脂选自二棕榈酰基磷脂酰胆碱(DPPC)。
在一些实施方案中，所述磷脂的质量占颗粒总质量的1％-15％；具体可以选自1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％、5％、5.5％、6％、6.5％、7％、7.5％、8％、8.5％、9％、9.5％、10％、10.5％、11％、11.5％、12％、12.5％、13％、13.5％、14％、14.5％和15％；在一些实施方案中，所述磷脂的质量占颗粒总质量为3％-10％；在一些实施方案中，所述磷脂的质量占颗粒总质量为5％-8％；在一个实施方案中，磷脂占颗粒总质量的7％。
在一些实施方案中，所述其他药学上可接受的辅料包括一种或多种包含单价阳离子的盐。“单价阳离子”包括但不限于Li +、Na +、K +、Cs +、NH 4 +，包含单阳离子的盐指单价 阳离子与酸根离子结合形成的化合物，所述酸根离子可以由无机酸或有机酸电离产生。
在一些实施方案中，所述包含单价阳离子的盐选自钠盐、钾盐或铵盐；优选自氯化钠、氯化钾、氯化铵或柠檬酸钠。在一个实施方案中，所述包含单价阳离子的盐选自氯化钠；而在另一个实施方案中，所述包含单价阳离子的盐选自柠檬酸钠。
在一些实施方案中，上述包含单价阳离子的盐，其质量占颗粒总质量0.2～20％；具体可以选自0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％、1.5％、1.6％、1.7％、1.8％、1.9％、2.0％、2.1％、2.2％、2.3％、2.4％、2.5％、2.6％、2.7％、2.8％、2.9％、3.0％、3.5％、4％、4.5％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％和20％，在一些实施方案中，上述包含单价阳离子的盐，其质量占颗粒总质量为0.5％～15％；在一些实施方案中，上述包含单价阳离子的盐，其质量占颗粒总质量为1％～10％；在一些实施方案中，上述包含单价阳离子的盐，其质量占颗粒总质量为1.5％～5％；在一些实施方案中，上述包含单价阳离子的盐，其质量占颗粒总质量1.5％～3％；在一个实施方案中，包含单价阳离子的盐占颗粒总质量的2％。
在另一些实施方案中，所述颗粒中，其他药学上可接受的辅料包括一种或多种包含多价阳离子的盐。“多价阳离子”包括但不限于所有2价阳离子、3价阳离子、4价阳离子，包含多价阳离子的盐指多价阳离子与酸根离子结合形成的化合物，所述酸根离子可以由无机酸或有机酸电离产生。
在一些实施方案中，所述包含多价阳离子的盐选自2价阳离子盐；所述2价阳离子盐可以为钙盐、镁盐、钡盐、锌盐、铜盐或亚铁盐。在一些实施方案中，包含多价阳离子的盐选自钙盐，优选为氯化钙。
在一些实施方案中，上述包含多价阳离子的盐，其质量占颗粒总质量0.1～10％，具体可以选自0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％、1.5％、1.6％、1.7％、1.8％、1.9％、2.0％、2.1％、2.2％、2.3％、2.4％、2.5％、2.6％、2.7％、2.8％、2.9％、3.0％、3.5％、4％、4.5％、5％、6％、7％、8％、9％、10％；在一些实施方案中，上述包含多价阳离子的盐，其质量占颗粒总质量为0.2％～5％；在一些实施方案中，上述包含多价阳离子的盐，其质量占颗粒总质量为0.5％～2％；在一些实施方案中，上述包含多价阳离子的盐，其质量占颗粒总质量为0.8％～1.5％；在一个实施方案中，包含多价阳离子的盐占颗粒总质量的1％。
在一个实施方案中，所述其他药学上可接受的辅料同时包括含有单价阳离子的盐以及含有多价阳离子的盐，例如同时包括钠盐与钙盐，优选同时包括氯化钠与氯化钙。所述钠盐与钙盐的质量如前述所定义。
在一些实施方案中，所述活性剂选自肺纤维化治疗剂，包括但不限于吡非尼酮或其可药用盐、尼达尼布或其可药用盐、N-乙酰半胱氨酸、伊马替尼或其可药用盐、法米替尼或其可药用盐。在一个实施方案中，所述肺纤维化治疗剂选自吡非尼酮或其可药用盐；在一个实施方案中，所述肺纤维化治疗剂选自法米替尼或其可药用盐；在另一个实施方案中，所述肺纤维化治疗剂选自尼达尼布或其可药用盐。
在一些实施方案中，所述颗粒具有中空和/或褶皱的形态。“中空和/或褶皱”意指颗粒具有中空的不规则形态，和/或颗粒表面具有至少一个塌陷和/或隆起部位。作为示范性的实例，中空和/或褶皱的颗粒如图2-图4所示。
在一些实施方案中，所述颗粒具有多孔的形态。“多孔”意指在颗粒表面和/或内部分布有复数个凹槽，所述凹槽任选地连通颗粒的内外部。
在一个实施方案中，本公开的颗粒同时具有“中空和/或褶皱”和“多孔”的形态，即颗粒具有中空的不规则形态，颗粒表面具有复数个塌陷和/或隆起部位(即褶皱)，并且在上述塌陷和/或隆起部位，以及颗粒表面的其他位置，还分布有复数个凹槽(即多孔)，整体形成“二级褶皱”的形态。作为示范性的实例，中空褶皱多孔的颗粒如图2。第二方面，本公开提供了一种吸入单位制剂，所述制剂包括容器，以及所述容器内包含的本公开所述药物组合物。容器的实例包括但不限于胶囊、泡罩或由金属、聚合物(例如塑料、弹性体)、玻璃等制成的容器封闭系统。
第二方面，本公开还提供了一种制备第一方面所述药物组合物的方法，包括将有机相和水相混合后喷雾干燥的步骤。
在一个实施方案中，所述药物组合物的制备方法包括如下步骤：
i)将活性剂和磷脂溶解于有机溶剂，得到有机相；ii)将其他药学上可接受的辅料溶解于水中，得到水相；iii)将水相缓慢加入到有机相中，搅拌混合；iv)对步骤iii)所得物质进行喷雾干燥，得到颗粒。
在一些实施方案中，所述有机相的溶剂为乙醇。
在一些实施方案中，乙醇与水的体积比为0.2～5：1；具体可以选自0.2:1、0.3:1、0.4:1、0.5:1、0.6:1、0.7:1、0.8:1、0.9:1、1:1、1.1:1、1.2:1、1.3:1、1.4:1、1.5:1、1.6:1、1.7:1、1.8:1、1.9:1、2.0:1、2.1:1、2.2:1、2.3:1、2.4:1、2.5:1、3:1、3.5:1、4:1、4.5:1和5:1；在一些实施方案中，乙醇与水的体积比为0.5～3:1；在一些实施方案中，乙醇与水的体积比为1.0～2.5:1。在一个实施方案中，乙醇与水的体积比为1.5:1。而在另一个实施中，乙醇与水的体积比为1:1。
在一些实施方案中，有机相和水相混合后，活性剂、磷脂以及其他药学上可接受的辅料的总量在5g/L以下；具体可以选自5g/L、4.5g/L、4g/L、3.5g/L、3g/L、2.75g/L、2.5g/L、2.25g/L、2g/L、1.75g/L、1.5g/L、1.25g/L、1g/L、0.75g/L、0.5g/L和0.25g/L；在一些实施方案中，有机相和水相混合后，活性剂、磷脂以及其他药学上可接受的辅料的总量在4.5g/L以下；在一些实施方案中，有机相和水相混合后，活性剂、磷脂以及其他药学上可接受的辅料的总量在4g/L以下；在一些实施方案中，有机相和水相混合后，活性剂、磷脂以及其他药学上可接受的辅料的总量为3.5g/L。
本公开的载药吸入颗粒可以在较低的气流流速与进料速度下通过喷雾干燥得到。
在一些实施方案中，所述喷雾干燥以氮气为喷雾气体；
在另一些实施方案中，所述喷雾干燥的喷雾气体流量低于50kg/h，优选低于20kg/h，具体可以低于19kg/h、18kg/h、17kg/h、16kg/h、15kg/h、14kg/h、13kg/h、12kg/h、11kg/h、10kg/h、9.5kg/h、9kg/h、8.5kg/h、8kg/h、7.5kg/h、7kg/h、6.5kg/h、6kg/h、5.5kg/h、5kg/h、4.5kg/h、4kg/h、3.5kg/h、3kg/h、2.9kg/h、2.8kg/h、2.7kg/h、2.6kg/h、2.5kg/h、2.4kg/h、2.3kg/h、2.2kg/h、2.1kg/h、2kg/h、1.9kg/h、1.8kg/h、1.7kg/h、1.6kg/h或1.5kg/h；在另一些实施方案中，所述喷雾干燥的喷雾气体流量低于10kg/h；在另一些实施方案中，所述喷雾干燥的喷雾气体流量低于5kg/h；在另一些实施方案中，所述喷雾干燥的喷雾气体流量低于3kg/h。
在一些实施方案中，所述喷雾干燥的进料速度低于50ml/min，优选低于30ml/min，具体可以低于29ml/min、28ml/min、27ml/min、26ml/min、25ml/min、24ml/min、23ml/min、22ml/min、21ml/min、20ml/min、19ml/min、18ml/min、17ml/min、16ml/min、15ml/min、14ml/min、13ml/min、12ml/min、11ml/min、10ml/min、9ml/min、8ml/min、7ml/min、6ml/min或5ml/min，在一些实施方案中，所述喷雾干燥的进料速度低于15ml/min，在一些实施方案中，所述喷雾干燥的进料速度为10ml/min。
第三方面，本公开还提供一种包含乙醇和水的混合物，其特征在于，该混合物经过喷雾干燥后得到如第一方面所述的药物组合物。
所述包含乙醇和水的混合物可以为澄清溶液、乳浊液或混悬液；优选为澄清溶液。
在一些实施方案中，所述组合物中，乙醇与水的体积比为0.2～5：1；具体可以选自0.2:1、0.3:1、0.4:1、0.5:1、0.6:1、0.7:1、0.8:1、0.9:1、1:1、1.1:1、1.2:1、1.3:1、1.4:1、1.5:1、1.6:1、1.7:1、1.8:1、1.9:1、2.0:1、2.1:1、2.2:1、2.3:1、2.4:1、2.5:1、3:1、3.5:1、4:1、4.5:1和5:1；在一些实施方案中，所述组合物中，乙醇与水的体积比为0.5～3:1；在一些实施方案中，所述组合物中，乙醇与水的体积比为1～2.5:1。在一个实施方案中，乙醇与水的体积比为1.5:1。而在另一个实施中，乙醇与水的体积比为1:1。
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。
“A质量占颗粒总质量的x％”指药物组合物中物质A的总质量占药物组合物中颗粒总质量的x％；本领域技术人员应当能够理解，微观下单一颗粒中A的质量占比允许与上述占比存在偏差，只需在整体上符合即可。
“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。
“活性剂”或“药物”意指药物的活性成分，也称为活性药物成分(API)。
“体积中值几何直径”或“X 50”或指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％。“X 90”指占总体积90％的颗粒小于该直径。
“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％。
“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。
“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。
“ED”或“喷射剂量”指给药时离开吸入器装置的药物质量。
“GSD”或“几何标准偏差”指描述空气动力学粒径分布宽度的参数，
Figure PCTCN2021137062-appb-000001
其中D84.1和D15.9分别为累积分布低于84.1％和15.9％的粒子空气动力学直径。
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。
附图说明
图1表示制剂前后吡非尼酮的X-射线粉末衍射图谱对比；A：制剂前的原料药吡非尼酮，B：实施例1吸入干粉a中的吡非尼酮。
图2表示实施例1吸入干粉a的扫描电子显微镜(SEM)图像。
图3表示实施例2吸入干粉b的扫描电子显微镜(SEM)图像。
图4表示实施例3吸入干粉e的扫描电子显微镜(SEM)图像。
具体实施方式
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。
实验试剂
序号 试剂 来源
1 吡非尼酮 北京莱瑞森医药科技有限公司
2 二硬脂酰基磷脂酰胆碱 Lipoid GmbH
3 二棕榈酰磷脂酰胆碱 Lipoid GmbH
4 氯化钠 江苏省勤奋药业有限公司
5 氯化钙 河北华晨药业有限公司
6 乙醇 南京化学试剂有限公司
7 3号HPMC透明胶囊 苏州胶囊有限公司
实验仪器
序号 仪器 来源
1 BüCHI B-290微型喷雾干燥仪 瑞士步琦有限公司
2 SYMPATEC粒径测定仪 德国新帕泰克有限公司
3 X射线衍射仪 布鲁克公司(BRUKER)
4 Ultra 55扫描电子显微镜 德国蔡司公司
5 集热式恒温磁力搅拌水浴锅 巩义市予华仪器有限责任公司
实施例1 吸入干粉a的制备
有机相：将0.07g二硬脂酰基磷脂酰胆碱(DSPC)加入至480ml的无水乙醇中，室温下磁力搅拌使其溶解完全，然后将0.9g吡非尼酮原料药加入其中室温磁力搅拌溶解完全。
水相：将0.02g的氯化钠和0.01g的氯化钙加入到320ml的去离子水中，搅拌溶解完全。
混合：有机相在室温下磁力搅拌过程中，将320ml水相缓慢滴加入有机相中，混合后溶液为白色浑浊状，将白色浑浊溶液50℃磁力搅拌加热，一段时间后变为澄清溶液。
喷雾干燥：将所得的澄清溶液持续50℃磁力搅拌加热条件下在BüCHI B-290微型喷雾干燥器上喷雾干燥，喷干参数：入口温度＝120℃，进料速度＝10mL/min，风机频率：100％，喷雾气体流量＝60mm(转子流量计)(2.37kg/h)，氮气露点值：-69℃，得到载药颗粒干粉。
实施例2 吸入干粉b、c、d的制备
采用与实施例1类似的制备方法，区别在于对乙醇和水的用量进行调整，如表1所示。
表1 制备吸入干粉b、c、d时水与乙醇的用量
编号 乙醇用量 水用量
b 680ml 120ml
c 560ml 240ml
d 400ml 400ml
实施例3 吸入干粉e的制备
采用与实施例1类似的方法，区别在于将成壳材料二硬脂酰基磷脂酰胆碱(DSPC)替换成二棕榈酰磷脂酰胆碱(DPPC)，并调整乙醇和水的用量。
有机相：将0.07g二棕榈酰磷脂酰胆碱(DPPC)加入至400ml的无水乙醇中，室温 下磁力搅拌使其溶解完全，然后将0.9g吡非尼酮原料药加入其中室温磁力搅拌溶解完全。
水相：将0.02g的氯化钠和0.01g的氯化钙加入到400ml的去离子水中，搅拌溶解完全。
混合：有机相在室温下磁力搅拌过程中，将400ml水相缓慢滴加入有机相中，混合后溶液为白色浑浊状，将白色浑浊溶液50℃磁力搅拌加热，一段时间后变为澄清溶液。
喷雾干燥：将所得的澄清溶液持续50℃磁力搅拌加热条件下在BüCHI B-290微型喷雾干燥器上喷雾干燥，喷干参数：入口温度＝120℃，进料速度＝10mL/min，风机频率：100％，喷雾气体流量＝60mm(转子流量计)(2.37kg/h)，氮气露点值：-69℃，得到载药颗粒干粉。
实施例4 吸入干粉f的制备
采用与实施例1类似的方法，区别在于调整溶液配制过程的醇水比和固含量，并且调整喷雾过程中参数。
有机相：将0.245g二硬脂酰基磷脂酰胆碱(DSPC)加入至700ml的无水乙醇中，室温下磁力搅拌使其溶解完全，然后将3.15g吡非尼酮原料药加入其中室温磁力搅拌溶解完全。
水相：将0.07g的氯化钠和0.035g的氯化钙加入到300ml的去离子水中，搅拌溶解完全。
混合：有机相在室温下磁力搅拌过程中，将300ml水相缓慢滴加入有机相中，混合后溶液为白色浑浊状，将白色浑浊溶液50℃磁力搅拌加热，一段时间后变为澄清溶液。
喷雾干燥：将所得的澄清溶液持续50℃磁力搅拌加热条件下在BüCHI B-290微型喷雾干燥器上喷雾干燥，喷干参数：入口温度＝124℃，进料速度＝10mL/min，风机频率：100％，喷雾气体流量＝60mm(转子流量计)(2.37kg/h)，氮气露点值：-69℃，得到载药颗粒干粉。
实施例5 吸入干粉空气动力学粒径(APSD)测试
将实施例1-4制备得到的含药吸入干粉a-f填充至透明HPMC胶囊(3号)中，25mg 装量，将胶囊样品使用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】规定进行APSD测试。
将APSD各级分布结果输入CITDAS version 3.10软件(COPLEY)得出FPF(＜5μm)、MMAD、GSD等值。测试结果见表2
表2 吸入干粉a-f的APSD结果
Figure PCTCN2021137062-appb-000002
由表2可以看出，吸入干粉a-f的MMAD均不高于5μm，说明其能够在肺部沉积，并且各实施例均拥有较高的FPF和ED数值，说明其肺部递送效率较高。同时，各实施例在60L/min和30L/min流速条件下的FPD、ED比值接近于1，证明本公开吸入干粉颗粒的空气动力学特性并不依赖于气体流速，颗粒整体具有优良的分散性和流动性，聚集倾向较低，特别适合肺部功能受损的患者。
实施例6 吸入干粉几何粒径测定
粒径测定采用SYMPATEC粒径测定仪，采用4bar分散压力，粒径结果见表3。
表3 吸入干粉a-f的几何粒径测定结果
编号 a b c d e f
X50(μm) 3.06 3.11 3.18 2.90 2.09 2.49
X90(μm) 6.29 5.97 10.06 5.13 3.86 4.43
实施例7 吸入干粉密度测定
称取一定量(重量为m)的吸入粉末缓慢倒入量筒中，反复振实至粉末体积无变化(最终量筒刻度为v)，通过ρ＝m/v计算粉末密度，结果见表4。
表4 吸入干粉a、c、e、f的振实密度测定结果
编号 a c e f
密度(g/cm 3) 0.38 0.33 0.41 0.42
实施例8 吸入干粉晶型测定
晶型测定采用X射线衍射仪(XRD)，对原料药和实施例1晶型进行测定，结果见图1。从图1可以看出，吸入干粉a中药物晶型未发生改变。
实施例9 吸入干粉形态观察
形态观察采用扫描电子显微镜(SEM)对实施例1的吸入干粉a进行观察，形态结果见图2。由图2可以看出吸入干粉a具有中空褶皱的形态，已有研究表明，褶皱的形态可以通过减小颗粒之间的接触面积而提高颗粒的分散性和稳定性，这与实施例5的测试结果相一致。吸入干粉a在表面褶皱的基础上，还具有多孔的“二级褶皱”形态，进一步降低了颗粒之间的接触面积，暗示其拥有更佳的分散性和流动性，实施例2的吸入干粉b形态结果见图3，颗粒表面具褶皱，图4是实施例3的吸入干粉e，形态为球形褶皱颗粒，表面黏附药物晶体。

Claims (21)

  1. 一种用于肺部递送的药物组合物，所述药物组合物包含颗粒，所述颗粒包含活性剂、磷脂及其他药学上可接受的辅料，其特征在于：所述颗粒的质量中值空气动力学直径小于5微米，体积中值几何直径小于5微米，并且活性剂质量占颗粒总质量的85％以上。
  2. 根据权利要求1所述的药物组合物，其中所述颗粒的振实密度为0.01-0.6g/cm 3，优选0.1-0.5g/cm 3。
  3. 根据权利要求1或2所述的药物组合物，其中，所述磷脂选自二硬脂酰基磷脂酰胆碱(DSPC)、二棕榈酰基磷脂酰胆碱(DPPC)、二棕榈酰基磷脂酰甘油(DPPG)或二硬脂酰基磷脂酰乙醇胺(DSPE)中的一种或几种；优选自二硬脂酰基磷脂酰胆碱(DSPC)、二棕榈酰基磷脂酰胆碱(DPPC)或其组合；更优选为二硬脂酰基磷脂酰胆碱(DSPC)。
  4. 根据权利要求1-3任一所述的药物组合物，其中，所述磷脂的质量占颗粒总质量的1％-15％；优选3％-10％；更优选5％-8％；甚至更优选7％。
  5. 根据权利要求1-4任一所述的药物组合物，其中，所述其他药学上可接受的辅料包括一种或多种包含单价阳离子的盐。
  6. 根据权利要求5所述的药物组合物，其中，所述包含单价阳离子的盐选自钠盐、钾盐或铵盐；优选自氯化钠、氯化钾、氯化铵或柠檬酸钠；更优选自氯化钠或柠檬酸钠；甚至更优选为氯化钠。
  7. 根据权利要求1-6任一所述的药物组合物，其中，所述其他药学上可接受的辅料包括一种或多种包含多价阳离子的盐。
  8. 根据权利要求7所述的药物组合物，其中，所述包含多价阳离子的盐选自二价阳离子盐；优选自钙盐、镁盐、钡盐、锌盐、铜盐或亚铁盐；更优选自钙盐；甚至更优选为氯化钙。
  9. 根据权利要求1-8任一所述的药物组合物，其中，所述活性剂选自肺纤维化治疗剂；优选为吡非尼酮或其可药用盐。
  10. 根据权利要求1-9任一所述的药物组合物，其中，所述颗粒具有中空和/或褶皱的形态。
  11. 根据权利要求1-10任一所述的药物组合物，其中，所述颗粒具有多孔的形态。
  12. 一种吸入单位制剂，所述制剂包括容器，以及所述容器内包含的权利要求1-10所述的药物组合物。
  13. 一种制备权利要求1-11任一所述药物组合物的方法，其特征在于，包括将有机相 和水相混合后喷雾干燥的步骤。
  14. 根据权利要求13所述的方法，其中，所述有机相的溶剂为乙醇。
  15. 根据权利要求14所述的方法，其中，乙醇与水的体积比为0.2～5：1；优选为0.5～3:1；更优选为1.0～2.5:1。
  16. 根据权利要求13-15任一所述的方法，其中，有机相和水相混合后，活性剂、磷脂以及其他药学上可接受的辅料的总量在5g/L以下；优选在4.5g/L以下；更优选在4g/L以下；甚至更优选为3.5g/L。
  17. 根据权利要求13-16任一所述的方法，其中，所述喷雾干燥以氮气为喷雾气体。
  18. 根据权利要求13-17任一所述的方法，其中，所述喷雾干燥的喷雾气体流量低于50kg/h，优选低于20kg/h，更优选低于10kg/h，甚至更优选低于5kg/h。
  19. 根据权利要求13-18任一所述的方法，其中，所述喷雾干燥的进料速度低于50ml/min，优选低于30ml/min，更优选低于15ml/min，甚至更优选为10ml/min。
  20. 一种包含乙醇和水的混合物，其特征在于，该混合物经过喷雾干燥后得到权利要求1-11任一所述的药物组合物。
  21. 根据权利要求20所述的组合物，其中，乙醇与水的体积比为0.2～5:1；优选为0.5～3:1；更优选为1.0～2.5:1。
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