WO2022127092A1 - 一种川丁特罗吸入粉雾剂及其制备方法和应用 - Google Patents

一种川丁特罗吸入粉雾剂及其制备方法和应用 Download PDF

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WO2022127092A1
WO2022127092A1 PCT/CN2021/106225 CN2021106225W WO2022127092A1 WO 2022127092 A1 WO2022127092 A1 WO 2022127092A1 CN 2021106225 W CN2021106225 W CN 2021106225W WO 2022127092 A1 WO2022127092 A1 WO 2022127092A1
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micropowder
lactose
carrier
hydrochloride
tetrabuterol
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PCT/CN2021/106225
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English (en)
French (fr)
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寸冬梅
程卯生
刘婷婷
潘莉
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沈阳药科大学
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and relates to a powder aerosol of a novel ⁇ 2-adrenoceptor agonist tetrabuterol and its hydrochloride and a preparation method thereof, and also relates to the preparation of the powder aerosol for treating asthma and chronic obstruction.
  • ⁇ 2-receptor agonists produce bronchodilation by activating ⁇ 2-receptors on airway smooth muscle, and are currently the first-line drugs for the clinical treatment of asthma, chronic obstructive pulmonary disease and other pulmonary diseases. It can quickly improve symptoms such as dyspnea and cough during acute asthma attacks.
  • Chubuterol hydrochloride is a new type of highly selective ⁇ 2-receptor agonist, which can significantly expand airway smooth muscle, stabilize mast cells, and enhance the ability of airway cilia to play an anti-asthma effect.
  • the drug has a strong anti-asthmatic effect, and its effect is much stronger than that of salbutamol sulfate, and the effect lasts for a longer time. In addition, compared with other similar drugs, it has fewer adverse reactions and high safety.
  • pulmonary inhalation is the preferred route of administration.
  • pulmonary inhalation formulations can deliver the drug rapidly to the lungs, directly to the site of action, with high drug concentrations at the site of action, and lower systemic exposure to the drug, so it can be Effectively reduce the toxic and side effects of drugs.
  • Pulmonary inhalation formulations include aerosol, powder and water aerosol forms. Jinzhou Jiutai Pharmaceutical Co., Ltd. published a patent for aerosol hydrochloride (CN100431535C) in January 2008. The aerosol is composed of 0.005-0.01 part of tetrabuterol hydrochloride, 5-10 parts of solvent and 90-95 parts of propellant.
  • the drug in the aerosol is dispersed in the propellant in a dissolved or suspended state, which is unfavorable for drug stability.
  • aerosols require patients to coordinate spraying and deep inhalation during use, which has high technical requirements, which is difficult for elderly and young patients, and the destruction of the ozone layer in the atmosphere by propellants also makes aerosols The development of agents has been limited.
  • Powder aerosol also known as dry powder inhalation (DPI) is a preparation in which a dry powder of a drug or a mixed dry powder of a drug and excipients is actively inhaled into the lungs by a patient orally through a specific drug delivery device.
  • the drug powder is dispersed by the airflow generated by the patient's active inhalation to form an aerosol, which is inhaled into the respiratory system with the airflow to produce curative effects.
  • Powder aerosol has the advantages of good patient compliance, simple prescription, low cost, stable drug, environmental friendliness, and no preservatives that irritate mucous membranes.
  • the conventional technological process of powder aerosol includes crushing, mixing, filling and so on of APIs. Because the dosage of tetrabuterol hydrochloride is extremely small (microgram level), it is easy to cause uneven drug content in the powder.
  • the fluidity of the powder aerosol is also an important performance for evaluating the powder aerosol. How to avoid the uneven content of powder aerosols, low FPF and poor powder fluidity are the problems that need to be solved in the process of powder aerosol development.
  • the object of the present invention is to overcome the defect of the existing Tributerol hydrochloride preparation, and a kind of Tributerol hydrochloride (or Tributerol hydrochloride) inhalation powder spray and preparation method thereof are provided.
  • the tetrabuterol (or tetrabuterol hydrochloride) inhalation powder aerosol provided by the invention has uniform drug content, good powder fluidity, easy dispersion, high FPF value, is suitable for pulmonary inhalation administration, and can obtain Higher pulmonary deposition rates.
  • the invention provides a new option with better patient compliance for the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease.
  • the tranbuterol inhalation powder aerosol comprises an active ingredient and a surface-modified carrier.
  • the weight percent composition of each component is: 0.05%-0.25% active ingredient, 99.75%-99.95% surface-modified carrier.
  • the active ingredient described in the present invention is Tributerol or Tributerol hydrochloride micropowder.
  • Described tributerol or tributerol hydrochloride micropowder is characterized in that: its median diameter (D 50 ) is less than 2 ⁇ m, and the particle size (D 90 ) of 90% of the tributerol (or tetrabuterol hydrochloride) micropowder is less than 3 ⁇ m.
  • the surface-modified carrier is a carrier whose surface has been modified by a surface modifier.
  • the surface modifier includes one or more mixtures of micropowders such as magnesium stearate, lactose or leucine.
  • the characteristics of the surface modifier are: after the micronization treatment, the median diameter (D 50 ) of the surface modifier micro powder is less than 5 ⁇ m, and the particle size (D 90 ) of 90% of the carrier surface modifier micro powder is less than 10 ⁇ m.
  • the surface modifier is preferably a combination of lactose micropowder and magnesium stearate micropowder, and the weight ratio of the magnesium stearate micropowder to the lactose micropowder is 1:20--1:10.
  • the carrier is one or more of physiologically friendly sugars, polyols and amino acids, selected from lactose, sucrose, glucose, fructose, maltose, trehalose, mannitol, xylitol, sorbitol, leucine , Alanine, Tryptophan, Valine, Isoleucine, Glycine, Phenylalanine, Proline, Serine, Tyrosine, Cysteine, Methionine, Glutamic Acid, Threonine, One or more mixtures of aspartic acid, glutamine, lysine, arginine, histidine and asparagine.
  • the carrier is preferably one or more mixtures of lactose, mannitol or leucine.
  • the carrier material is characterized by a D 10 greater than 10 ⁇ m, a D 50 less than 100 ⁇ m, and a D 90 less than 200 ⁇ m.
  • the surface-modified carrier can be obtained commercially, such as lactose containing 10% micronized lactose;
  • the surface-modified carrier can also be obtained by performing high shear mixing treatment with the surface modifier and the carrier.
  • the preferred surface-modified carrier of the present invention is: with magnesium stearate, one or more mixtures in the micropowder such as lactose or leucine as the surface modifier, with lactose, mannitol or leucine
  • the carrier is preferably a lactose carrier containing micronized lactose, a lactose carrier containing micronized magnesium stearate, a mannitol carrier containing micronized magnesium stearate, a lactose carrier containing micronized lactose, micronized magnesium stearate, and the like.
  • the weight ratio of the carrier surface modifier to the carrier in the present invention is: 1:399--25:75, preferably: 1:199--11:39.
  • the present invention is preferably the following tetrabuterol inhalation powder aerosol, comprising tetrabuterol or tetrabuterol hydrochloride micropowder, 10% lactose of micropowder lactose, and the weight percent composition of each component is 1:750--1:500.
  • the powder aerosol fine particle percentage (FPF) ranges from 25% to 35%.
  • the present invention is preferably the following tetrabuterol inhalation powder aerosol, comprising tetrabuterol or tetrabuterol hydrochloride micropowder, lactose micropowder, lactose, and the weight percent composition of each component is: 1:75:675--1:150: 600.
  • the powder aerosol FPF range is: 23%-38%.
  • the present invention is preferably the following tetrabuterol inhalation powder aerosol, comprising tetrabuterol or tetrabuterol hydrochloride micropowder, magnesium stearate micropowder, lactose, and the weight percent composition of each component is: 4:15:2985--4 :45:2955.
  • the powder aerosol FPF range is 32%-43%.
  • the present invention is preferably the following tetrabuterol inhalation powder aerosol, comprising tetrabuterol or tetrabuterol hydrochloride micropowder, leucine micropowder, lactose, and the weight percent composition of each component is: 4:15:2985--4: 45:2955.
  • the powder aerosol FPF range is 25%-32%.
  • the present invention is preferably the following tetrabuterol inhalation powder aerosol, comprising tetrabuterol or tetrabuterol hydrochloride micropowder, magnesium stearate micropowder, lactose micropowder, lactose, and the weight percent composition of each component is: 1:5:100 :1894--1:10:100:289.
  • the powder aerosol FPF range is 40%-51%.
  • the preparation method of tetrabuterol inhalation powder mist described in the present invention or tetrabuterol hydrochloride comprises the steps:
  • the tributerol or tributerol hydrochloride micropowder described in the step (1) is prepared by adopting the jet pulverization method.
  • the preparation of the surface-modified carrier in the step (2) is that the carrier and the carrier surface modifier or the micropowder of the surface modifier are subjected to high-shear mixing treatment using a mixing granulator.
  • the high shear mixing speed is 100-300 rpm.
  • the surface modifier micropowder is prepared by using a commercially available micropowder with a median diameter (D 50 ) of less than 5 ⁇ m and a D 90 of less than 10 ⁇ m, or by using an air jet pulverization method.
  • step (1) prepares tributerol and the surface modifier to co-pulverize micropowder, and roughly mixes tetrabuterol or tetrabuterol hydrochloride and the surface modification carrier in proportion, and adopts the co-jet pulverization method to prepare .
  • the final powder mist described in the present invention is obtained by mixing tetrabuterol or tetrabuterol hydrochloride micropowder and a surface modified carrier. Described tetrabuterol or tetrabuterol hydrochloride micropowder and the surface modification carrier are mixed and processed, first adopt the method of equal dilution to carry out rough mixing to the tetrabuterol or tetrabuterol hydrochloride micropowder and the surface modified carrier, It is then further mixed using a high shear mixer. The high shear mixing speed is 100-250rpm. The mixing time is 10-60min.
  • the inhalation powder of tetrabuterol or tetrabuterol hydrochloride described in the present invention adopts #3HPMC capsule to be filled.
  • the capsule filling amount is 15 mg/capsule.
  • the inhalation powder spray of Tributerol or Tributerol hydrochloride in the present invention has good content uniformity, and in the most preferred formulations, tetrabuterol hydrochloride micropowder, magnesium stearate micropowder, lactose micropowder and lactose are prepared,
  • the weight percent composition of each component is: 1:5:50:445--1:5:100:395, and the FPF value is more than 45%.
  • the FPF value of the inhalation powder aerosol of Tributerol or Tributerol hydrochloride according to the present invention is stable after storage.
  • the FPF change value after storage is less than 3%.
  • the inhalation powder aerosol of Tributerol or Tributerol hydrochloride described in the present invention is a solid dry powder preparation that utilizes the airflow generated by the patient's active inhalation to inhale the drug powder into the lungs, and exerts a curative effect in the lungs.
  • the powder aerosol is obtained by optimizing the particle size distribution, the mixing ratio and the mixing process of the active drug, the carrier and the carrier surface modifier in the prescription, and obtains uniform drug content, low hygroscopicity, good storage stability,
  • the inhalation powder spray of tranbuterol or tranbuterol hydrochloride with excellent aerodynamic properties and high FPF value, suitable for pulmonary inhalation administration.
  • the powder aerosol can be applied to capsule, blister or reservoir-type inhalation devices.
  • the preparation effectively overcomes many shortcomings such as poor drug stability in aerosols, environmental damage caused by propellants, low deposition rate of drugs in the lungs, and the need to train users to coordinate spraying and deep inhalation.
  • the clinical treatment of COPD patients provides a new option.
  • the addition of the carrier in the inhalation powder aerosol described in the present invention increases the volume and weight of the extremely small amount of tetrabuterol or tetrabuterol hydrochloride used in the process of use, making the medicine easy to fill and use.
  • the addition of the surface modifier exerts its effect on the surface modification of the carrier, improves the aerodynamic properties of the final powder aerosol, and is conducive to better deposition of drug particles in the lungs.
  • the fluidity of the powder aerosol is improved, the filling is facilitated, the hygroscopicity of the medicine is reduced, and the storage of the medicine is facilitated.
  • Fig. 1 Example 1 of 100 rpm mixing speed to prepare the aerodynamic measurement results of tetrabuterol powder aerosol.
  • Fig. 2 In Example 2, 250rpm mixing rotational speed prepares the aerodynamic measurement result of tetrabuterol powder aerosol.
  • Fig. 3 results of measurement of aerodynamics of tetrabuterol powder aerosol in the embodiment.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill.
  • the feed pressure is 7.0 bar
  • the pulverization pressure is 6.0 bar
  • pulverized collected to obtain tetrabuterol hydrochloride micropowder, and dried and stored.
  • Precisely weigh the prescription amount of tetrabuterol hydrochloride micropowder and commercially available lactose carrier containing 10% micropowder lactose pass through a 60-mesh sieve and mix, put into a wet granulator, adjust the rotational speed to 100 ⁇ 10rpm, and mix for 10min/time, Mix 6 times.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill. Feed pressure 7.0 bar, pulverization pressure 6.0 bar, pulverize, collect tetrabuterol hydrochloride micropowder, and store it under dry conditions. Precisely weigh the prescription amount of tetrabuterol hydrochloride micropowder and commercially available lactose carrier containing 10% micropowder lactose, pass through a 60-mesh sieve and mix, put into a wet granulator, adjust the rotational speed to 250 ⁇ 10rpm, and mix for 10min/time. Mix 6 times.
  • the product is collected and stored in drying.
  • the content uniformity results are shown in Table 3. The content uniformity of different mixing times is slightly different.
  • the aerodynamic measurement results show that the FPF value is 29.6%.
  • the fluidity test results show that the contact angle is 29°, and the fluidity is very good.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill. Feed pressure 7.0 bar, pulverization pressure 6.0 bar, pulverize, collect tetrabuterol hydrochloride micropowder, and store it under dry conditions. Precisely weigh the recipe amount of lactose micropowder and the commercially available lactose carrier without micropowder lactose, pass through a 60 mesh sieve and mix, put into a wet granulator, adjust the rotational speed to 300 ⁇ 10rpm, mix 3 times for 10min/time.
  • a modified lactose carrier containing 10% lactose micropowder was obtained, which was stored under dry conditions. Precisely weigh the prescription amount of tributanterol hydrochloride micropowder and 150g of modified lactose containing 10% lactose micropowder, pass through a 60-mesh sieve, put it into a wet granulator, adjust the rotational speed to 250 ⁇ 10rpm, mix for 10min/time, and mix 3 times. After the mixing is completed, the product is collected and stored in drying. The aerodynamic measurement results show that the FPF value is 25.1%, and the fluidity test results show that the contact angle is 28.1°, and the fluidity is very good.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill. Feed pressure 7.0 bar, pulverization pressure 6.0 bar, pulverize, collect tetrabuterol hydrochloride micropowder, and store it under dry conditions. Precisely weigh the formula amount of lactose micropowder and commercially available lactose carrier without micropowder lactose, pass through a 60-mesh sieve, mix, put into a wet granulator, adjust the rotational speed to 300 ⁇ 10rpm, mix 3 times, 10min each time, to obtain Modified lactose containing 20% lactose micropowder, stored dry.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill. Feed pressure 7.0 bar, pulverization pressure 6.0 bar, pulverize, collect tetrabuterol hydrochloride micropowder, and store it under dry conditions. The magnesium stearate was crushed by the same method, and dried and stored to obtain the magnesium stearate micropowder.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill. Feed pressure 7.0 bar, pulverization pressure 6.0 bar, pulverize, collect tetrabuterol hydrochloride micropowder, and store it under dry conditions. The magnesium stearate was crushed by the same method, and dried and stored to obtain the magnesium stearate micropowder.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill.
  • the feeding pressure was 7.0 bar
  • the pulverizing pressure was 6.0 bar
  • pulverized and the micropowder of tetrabuterol hydrochloride was collected and stored under dry conditions.
  • the magnesium stearate was crushed by the same method, and dried and stored to obtain the magnesium stearate micropowder.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill.
  • the feeding pressure was 7.0 bar
  • the pulverizing pressure was 6.0 bar
  • pulverized and the micropowder of tetrabuterol hydrochloride was collected and stored under dry conditions.
  • the magnesium stearate was crushed by the same method, and dried and stored to obtain the magnesium stearate micropowder.
  • Preparation method take tetrabuterol and magnesium stearate, mix them roughly according to the prescription ratio, and use compressed nitrogen as a gas source to pulverize by a jet mill.
  • the feed pressure is 7.0 bar
  • the crushing pressure is 6.0 bar.
  • the collected product is a co-pulverized micropowder of tetrabuterol and magnesium stearate, the particle size is measured, and it is dried and stored.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill.
  • the feed pressure is 7.0 bar
  • the pulverization pressure is 6.0 bar
  • pulverized collected to obtain tetrabuterol hydrochloride micropowder, and dried and stored.
  • Precisely weigh the prescription amount of tetrabuterol hydrochloride micropowder and commercially available lactose carrier containing 10% micropowder lactose pass through a 60-mesh sieve and mix, put into a wet granulator, adjust the rotational speed to 250 ⁇ 10rpm, and mix for 10min/time. Mix 3 times. After the mixing is completed, the product is collected and stored in drying.
  • the aerodynamic measurement results show that the FPF value is 29.3%
  • the fluidity test results show that the contact angle is 28.6°, and the fluidity is very good.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize by a jet mill. Feed pressure 7.0 bar, pulverization pressure 6.0 bar, pulverize, collect tetrabuterol hydrochloride micropowder, and store it dry. Precisely weigh the prescription amount of tetrabuterol hydrochloride micropowder and commercially available lactose carrier containing 10% micropowder lactose, pass through a 60-mesh sieve and mix, load into a wet granulator, adjust the rotational speed to 250 ⁇ 10rpm, and mix for 10min/time. Mix 3 times. After mixing, the product was collected and stored in dry form. The aerodynamic measurement results show that the FPF value is 32.6%, and the fluidity test results show that the contact angle is 28.2°, and the fluidity is very good.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill.
  • the feed pressure is 7.0 bar
  • the crushing pressure is 6.0 bar.
  • the collected product was tetrabuterol hydrochloride micropowder, the particle size was determined, and the product was dried and stored.
  • the leucine was pulverized in the same way and stored in a dry state. Precisely weigh the leucine micropowder and the commercially available lactose carrier without micropowder lactose, pass through a 60-mesh sieve, and put them into a wet granulator, adjust the rotation speed to 300 ⁇ 10rpm, and mix 3 times for 10min/time.
  • the collected product was modified lactose containing 1% leucine micropowder, and stored in a dry state. Precisely weigh the prescription amounts of tributronate hydrochloride micropowder and 150.00g of modified lactose containing 1% leucine micropowder, pass through a 60-mesh sieve, put them into a wet granulator, adjust the rotation speed to 250 ⁇ 10rpm, and mix the time 10min/ times, mix 3 times. After the mixing is completed, the product is collected and stored in drying. The aerodynamic measurement results show that the FPF value is 29.1%, and the fluidity test results show that the contact angle is 27.9°, and the fluidity is very good.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill. Feed pressure 7.0 bar, pulverization pressure 6.0 bar, pulverize, collect tetrabuterol hydrochloride micropowder, and store it under dry conditions. Precisely weigh the recipe quantity of magnesium stearate and lactose carrier, pass through a 60-mesh sieve and mix, put into a wet granulator, adjust the rotational speed to 300 ⁇ 10rpm, mix 3 times, 10min each time, to prepare a 1% stearic acid Magnesium-modified lactose, stored dry.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill.
  • the feeding pressure was 7.0 bar
  • the pulverizing pressure was 6.0 bar
  • pulverized and the micropowder of tetrabuterol hydrochloride was collected and stored under dry conditions.
  • the magnesium stearate was crushed by the same method, and dried and stored to obtain the magnesium stearate micropowder.
  • Preparation method take tetrabuterol hydrochloride, use compressed nitrogen as a gas source, and pulverize it with a jet mill. Feed pressure 7.0 bar, pulverization pressure 6.0 bar, pulverize, collect tetrabuterol hydrochloride micropowder, and store it under dry conditions. Precisely weigh the prescription amounts of tributanterol hydrochloride micropowder and lactose, pass through a 60-mesh sieve, and put them into a wet granulator, adjust the rotational speed to 250 ⁇ 10 rpm, and mix 3 times for 10 min/time. After the mixing is completed, the product is collected and stored in drying. The aerodynamic measurement results show that the FPF value is 17.5%, and the fluidity test results show that the contact angle is 35.3°.
  • the particle size of each component in a dry powder inhalation preparation has a significant impact on the properties of the preparation.
  • the particle size of each composition was determined by a dry laser diffraction method (New Patek laser particle sizer, Germany). Adopt ROLOS module, R1/R3 lens, operation mode ref 5s start 1% stop 5s tb 1.
  • Table 1 shows the particle size measurement results of the raw and auxiliary materials, namely the intermediates.
  • the content uniformity of powder aerosol was determined by high performance liquid phase method. After the powder aerosol was mixed, six sampling locations were selected in the wet granulator, and about 100 mg of the sample was removed from each. method for sample concentration analysis.
  • Tables 2 and 3 are respectively the content determination results of the powder aerosols in Examples 1 and 2 at each time point, and there is no significant difference in the content uniformity at different mixing times at the respective mixing speeds.
  • NGI next generation impactor
  • Fig. 1 is the aerodynamic measurement result of drug and lactose carrier in 100rpm rotating speed of tetrabuterol hydrochloride powder aerosol with different mixing time. With the prolongation of mixing time, the aerodynamic properties of the drug in the powder aerosol improved.
  • Figure 2 is the aerodynamic measurement results of the drug and the lactose carrier in the tetrabuterol hydrochloride powder spray at 250 rpm rotating speed and different mixing times. The deposition of drug particles at different levels of NGI varies with different mixing times. Aerodynamic behavior is best when mixing for more than 30 minutes.
  • the aerodynamic performance of powder aerosol is improved by adding surface modifier to the carrier.
  • unmodified lactose was used as a carrier to prepare a powder aerosol, and its aerodynamic properties were measured to compare the use of the modifier.
  • Figure 3 and Table 4 compare the aerodynamic performance of the powder aerosols in each example.
  • lactose micropowder 10% lactose micropowder, 1% magnesium stearate micropowder and 20% lactose micropowder and 2% magnesium stearate micropowder were used to modify the lactose carrier at the same time.
  • weight ratio of lactose micropowder is 1:20-1:10, its aerodynamic behavior is better, which is more conducive to the deposition of drugs in the lungs.
  • the co-pulverizing micropowder of tetrabuterol and magnesium stearate is prepared by the method of co-pulverizing, and its aerodynamic behavior is improved to some extent.
  • the energy of the carrier exposure, the drug particles are more likely to fall off the lactose surface.
  • Example 12 1% leucine was used to modify lactose to prepare a powder aerosol, which improved the aerodynamic performance of the powder aerosol.
  • Example 13 1% magnesium stearate was used to modify and prepare a powder aerosol, which improved the aerodynamic performance of the powder aerosol, but its modification effect was weaker than that in Example 6, and 1% magnesium stearate was added. Micronized powder aerosol. It shows that the micronization treatment of magnesium stearate is beneficial to its modification effect of lactose carrier.
  • the angle of repose of the powder is measured by the fixed funnel method.
  • the funnel is fixed at a certain height above the coordinate paper (the paper is placed on the water platform), and the material is added from the funnel until the top of the formed stacking cone is just in contact with the bottom of the funnel, and the diameter of the cone is measured.
  • the ratio of the base height to the cone radius is used as the tangent to calculate the angle of repose.
  • Table 4 shows the flowability results of the comparative example and each example.
  • the raw materials and intermediates are stored in a dry state, and the powders to be dried and stored are placed in an aluminum foil bag, and the color-changing silica gel is added to the aluminum foil bag as a desiccant, sealed, and stored in a desiccator containing the color-changing silica gel at room temperature.
  • the powder aerosol was subjected to accelerated experiments, and the storage conditions were as follows: temperature 40°C, humidity 75% for 7 days; temperature 40°C, humidity 75% for 14 days; temperature 40°C, humidity 75% for 30 days; temperature 40°C, humidity 75 % storage for 60 days; temperature 40 °C, humidity 75% storage for 90 days.
  • Fig. 4 and table 5 are the powder aerosol acceleration experiment measurement result that mixing time is 30min in embodiment 2.
  • the results showed that the FPF value of tetrabuterol hydrochloride in the powder aerosol did not drop significantly, indicating that the powder aerosol was relatively stable at a temperature of 40°C and a humidity of 75%.
  • Example 2 250rpm mixing speed in Example 2 prepares the content (%) of each sampling point of tetrabuterol hydrochloride powder aerosol.
  • Table 5 250rpm mixing rotational speed 30min acceleration experiment aerodynamics measurement result of tetrabuterol hydrochloride powder aerosol in the embodiment 2.
  • the results show that by modifying the lactose carrier, the aerodynamic behavior of the drugs in each example is improved compared with the comparative example.
  • the FPF value of tetrabuterol hydrochloride powder spray is improved, preferably the following ratio, the weight ratio of lactose micropowder and lactose is: 1:4--1:9; magnesium stearate micropowder

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Abstract

一种β2-肾上腺素受体激动剂川丁特罗及其盐酸盐的粉雾剂及其制备方法，粉雾剂在制备治疗哮喘和慢性阻塞性肺病药物中的应用。所述药物包括川丁特罗作为吸入粉雾剂的活性成分和经过表面改性的载体。其中各组分重量百分组成为：0.05％-0.25％活性成分，99.75％-99.95％经过表面改性的载体。所述的表面改性的载体为：以硬脂酸镁，乳糖或亮氨酸等的微粉中一种或多种混合物作为表面改性剂，以乳糖、甘露醇或亮氨酸中一种或多种混合物作为载体。所述表面改性剂的加入，发挥了其对载体的表面改性的作用，改善了最终粉雾剂空气动力学性质，有利于药物颗粒更好的沉积在肺部。改善了粉雾剂的流动性，便于填充，降低药物的引湿性，便于储藏。

Description

一种川丁特罗吸入粉雾剂及其制备方法和应用 技术领域：
本发明属于医药制剂领域，涉及一种新型β2-肾上腺素受体激动剂川丁特罗及其盐酸盐的粉雾剂及其制备方法，还涉及该粉雾剂在制备治疗哮喘和慢性阻塞性肺病药物中的应用。
背景技术：
选择性β2受体激动剂通过激动气道平滑肌上的β2受体产生支气管扩张作用，是目前临床治疗哮喘、慢性阻塞性肺病等肺部疾病的一线药物。它能迅速改善哮喘急性发作时的呼吸困难、咳嗽等症状。盐酸川丁特罗是一个新型的高选择性的β2受体激动剂，它能显著扩张气道平滑肌，稳定肥大细胞，增强气道纤毛运动能力，从而发挥抗哮喘作用。该药具有很强的平喘作用，其作用强度远大于硫酸沙丁胺醇、且作用时间更长。另外，与其它同类药相比，不良反应少，安全性高。
对于哮喘等肺部疾病的治疗，肺部吸入是首选的给药途径。与口服片剂等全身性给药的制剂相比，肺部吸入制剂可将药物迅速送达至肺部，直接到达作用部位，作用部位药物浓度高，而药物的全身暴露量较低，因此可有效减轻药物的毒副作用。肺部吸入制剂包括气雾剂、粉雾剂和水雾剂三种形式。锦州九泰药业有限责任公司曾于2008年1月公开了一种盐酸川丁特罗气雾剂(CN100431535C)的专利。该气雾剂由盐酸川丁特罗0.005-0.01份、溶剂5-10份和抛射剂90-95份组成。该气雾剂中药物以溶解或混悬状态分散在抛射剂中，对药物稳定性不利。另外，气雾剂在使用过程中要求患者协调喷药和深吸气动作，具有较高技术要求，这对于老年以及年幼的患者较困难，而且抛射剂对大气中臭氧层的破坏也使气雾剂的开发受到了限制。粉雾剂，也称为干粉吸入剂(Dry Powder Inhalation，DPI)，是将药物干粉或药物和辅料的混合干粉通过特定给药装置由患者经口主动吸入至肺部的制剂。通过患者主动吸入产生的气流将药物粉末分散，形成气溶胶，随气流吸入呼吸系统产生疗效。粉雾剂具有患者依从性好、处方简单、成本低、药物稳定、环境友好、不含刺激黏膜的防腐剂等优点。
粉雾剂的常规工艺流程包括原料药的粉碎、混合、灌装等。由于盐酸川丁特罗给药剂量极其微小(微克级别)，从而易导致粉体中药物含量不均匀。粉雾剂的空气动力学性能，包括细粒子分数(fine particle fraction，FPF)等，影响药物的肺部沉积效率。同时，粉雾剂的流动性，也是评价粉雾剂的重要性能。如何避免粉雾剂含量不均匀，FPF低及粉体流动性差等问题是粉雾剂开发过程中需要解决的难题。
发明内容：
本发明的目的在于克服现有盐酸川丁特罗制剂的缺陷，提供一种川丁特罗(或盐酸川丁特罗)吸入粉雾剂及其制备方法。本发明提供的川丁特罗(或盐酸川丁特罗)吸入粉雾剂药物含量均匀，粉体流动性好，易于分散，具有很高的FPF值，适合于肺部吸入给药，可获得较高的肺部沉积率。该发明为哮喘、慢阻肺等肺部疾病的治疗提供了一种新的、患者顺应性更好的选择。
本发明通过以下技术方案实现：所述川丁特罗吸入粉雾剂包含活性成分、经过表面改性的载体。其中各组分重量百分组成为：0.05％-0.25％活性成分，99.75％-99.95％经过表面改性的载体。
本发明中所述的活性成分为川丁特罗或盐酸川丁特罗微粉。所述川丁特罗或盐酸川丁特罗微粉特征为：其中位径(D 50)小于2μm，90％的川丁特罗(或盐酸川丁特罗)微粉的粒径(D 90)小于3μm。
所述的经过表面改性的载体是经过表面改性剂进行表面改进的载体。
所述的表面改性剂，包含硬脂酸镁，乳糖或亮氨酸等的微粉中一种或多种混合物。所述表面改性剂特征为：微粉化处理后，表面改性剂微粉的中位径(D 50)小于5μm，90％的载体表面改性剂微粉的粒径(D 90)小于10μm。
所述的表面改性剂，优选乳糖微粉与硬脂酸镁微粉的组合，所述的硬脂酸镁微粉与乳糖微粉的重量比为1：20--1：10。
所述的载体为生理友好的糖、多元醇、氨基酸中的一种或几种，选自乳糖、蔗糖、葡萄糖、果糖、麦芽糖、海藻糖、甘露醇、木糖醇、山梨醇、亮氨酸、丙氨酸、色氨酸、缬氨酸、异亮氨酸，甘氨酸，苯丙氨酸，脯氨酸，丝氨酸，酪氨酸，半胱氨酸，蛋氨酸，谷氨酸，苏氨酸，天冬氨酸，谷氨酰胺，赖氨酸，精氨酸，组氨酸和天冬酰胺中的一种或多种混合物。所述载体优选为乳糖、甘露醇或亮氨酸中一种或多种混合物。载体材料的特征为：D 10大于10μm，D 50小于100μm，D 90小于200μm。
所述经过表面改性的载体可以通过商购获得，如含10％微粉乳糖的乳糖；
所述经过表面改性的载体也可以通过表面改性剂与载体进行高剪切混合处理获得。
进一步地，本发明优选的表面改性的载体为：以硬脂酸镁，乳糖或亮氨酸等的微粉中一种或多种混合物作为表面改性剂，以乳糖、甘露醇或亮氨酸中一种或多种混合物作为载体。优选为含有微 粉乳糖的乳糖载体，含有微粉硬脂酸镁的乳糖载体，含有微粉硬脂酸镁的甘露醇载体，含有微粉乳糖、微粉硬脂酸镁的乳糖载体等。
本发明中所述载体表面改性剂与载体的重量比为：1：399--25：75，优选为：1：199--11：39。
本发明优选如下川丁特罗吸入粉雾剂，包含川丁特罗或盐酸川丁特罗微粉、10％微粉乳糖的乳糖，各成分的重量百分组成为1：750--1：500。粉雾剂细粒子百分数(FPF)范围为：25％--35％。
本发明优选如下川丁特罗吸入粉雾剂，包含川丁特罗或盐酸川丁特罗微粉、乳糖微粉、乳糖，各成分的重量百分组成为：1：75：675--1：150：600。粉雾剂FPF范围为：23％-38％。
本发明优选如下川丁特罗吸入粉雾剂，包含川丁特罗或盐酸川丁特罗微粉、硬脂酸镁微粉、乳糖，各成分的重量百分组成为：4：15：2985--4：45：2955。粉雾剂FPF范围为32％-43％。
本发明优选如下川丁特罗吸入粉雾剂，包含川丁特罗或盐酸川丁特罗微粉、亮氨酸微粉、乳糖，各成分的重量百分组成为：4：15：2985--4：45：2955。粉雾剂FPF范围为25％-32％。
本发明优选如下川丁特罗吸入粉雾剂，包含川丁特罗或盐酸川丁特罗微粉、硬脂酸镁微粉、乳糖微粉、乳糖，各成分的重量百分组成为：1：5：100：1894--1：10：100：289。粉雾剂FPF范围为40％-51％。
本发明中所述的川丁特罗或盐酸川丁特罗吸入粉雾的制备方法包括如下步骤：
(1)川丁特罗或盐酸川丁特罗微粉的制备；
(2)表面改性载体的制备；
(3)川丁特罗或盐酸川丁特罗微粉与表面改性载体混合。
步骤(1)中所述川丁特罗或盐酸川丁特罗微粉，采用气流粉碎方法制备得到。
步骤(2)中所述表面改性载体的制备，是将载体与载体表面改性剂或表面改性剂微粉采用混合制粒机进行高剪切混合处理。所述高剪切混合转速为100-300rpm。
所述表面改性剂微粉，采用中位径(D 50)小于5μm，D 90小于10μm的市售微粉，或采用气流粉碎方法制备得到。
步骤(1)所述过程制备川丁特罗与表面改性剂共粉碎微粉，将川丁特罗或盐酸川丁特罗与表面改性载体按比例进行粗混合，采用共气流粉碎方法制备得到。
本发明中所述最终粉雾剂，为川丁特罗或盐酸川丁特罗微粉与表面改性载体混合得到。所述的川丁特罗或盐酸川丁特罗微粉与表面改性载体混合处理，先采用等量稀释的方法对川丁特罗或盐酸川丁特罗微粉和表面改性载体进行粗混合，然后再采用高剪切混合器进一步混合。所述的高剪切混合转速为100-250rpm。所述的混合时间为10-60min。
本发明中所述川丁特罗或盐酸川丁特罗微粉与表面改性载体混合处理过程中，先进行等量稀释后进行混合，有助于提高混合物的均匀度。
本发明中所述川丁特罗或盐酸川丁特罗吸入粉雾剂采用#3HPMC胶囊进行填装。所述的胶囊填装量为15mg/颗。
本发明中所述川丁特罗或盐酸川丁特罗吸入粉雾剂，含量均匀度好，且制得最优选处方中盐酸川丁特罗微粉、硬脂酸镁微粉、乳糖微粉、乳糖，各成分的重量百分组成为：1：5：50：445--1：5：100：395，FPF值为45％以上。
本发明所述川丁特罗或盐酸川丁特罗吸入粉雾剂经储存后，其FPF值稳定。所述储藏后FPF变化数值小于3％。
本发明中所述的川丁特罗或盐酸川丁特罗吸入粉雾剂是利用患者主动吸入产生的气流将药物粉末吸入至肺部，在肺部发挥疗效的一种固体干粉制剂。所述的粉雾剂通过对处方中活性药物、载体以及载体表面改性剂三者的粒径分布、混合比例和混合工艺的优化，得到了药物含量均匀、引湿性低、储存稳定性良好、空气动力学性质优良、FPF值较高、适合肺部吸入给药的川丁特罗或盐酸川丁特罗吸入粉雾剂。所述的粉雾剂可适用于胶囊型、泡罩型或者储库型的吸入装置。该制剂有效克服了气雾剂中药物稳定性差、抛射剂对环境有破坏、药物在肺部沉积率低、需要对使用者进行培训以协调喷药和深吸气动作等诸多缺点，为哮喘、慢阻肺患者的临床治疗提供了一种新的选择。
本发明中所述的吸入粉雾剂中载体的加入，增加了极其微量使用的川丁特罗或盐酸川丁特罗在使用过程中的体积和重量，使药物便于填充和使用。所述的表面改性剂的加入，发挥了其对载体的表面改性的作用，改善了最终粉雾剂空气动力学性质，有利于药物颗粒更好的沉积在肺部。同时，改善了粉雾剂的流动性，便于填充的进行，降低药物的引湿性，便于药物的储藏。
附图说明：
图1实施例1中100rpm混合转速制备川丁特罗粉雾剂空气动力学测定结果。
图2实施例2中250rpm混合转速制备川丁特罗粉雾剂空气动力学测定结果。
图3实施例中川丁特罗粉雾剂空气动力学测定结果。
图4实施例2中250rpm混合转速30min川丁特罗粉雾剂加速实验空气动力学测定结果。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。
实施例1
处方：
盐酸川丁特罗           200mg
含10％微粉乳糖的乳糖   150g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥保存。精密称取处方量的盐酸川丁特罗微粉和市售含10％微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速100±10rpm，混合时间10min/次，混合6次。混合结束后，收集产物，干燥保存。含量均匀度结果如表2显示不同混合时间含量均匀度略有差异，其空气动力学测定结果显示，FPF值为31.2％，流动性测试结果显示，接触角为28.9°，流动性很好。
实施例2
处方：
盐酸川丁特罗           200mg
含10％微粉乳糖的乳糖   150g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥条件下保存。精密称取处方量的盐酸川丁特罗微粉和市售含10％微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速250±10rpm，混合时间10min/次，混合6次。混合结束后，收集产物，干燥保存。含量均匀度结果如表3显示不同混合时间含量均匀度略有差异，其空气动力学测定结果显示，FPF值为29.6％，流动性测试结果显示，接触角为29°，流动性很好。
实施例3
处方：
盐酸川丁特罗        200mg
乳糖微粉            15g
乳糖                135g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥条件下保存。精密称取处方量乳糖微粉和市售不含微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速300±10rpm，混合时间10min/次，混合3次。混合结束后，得到含10％乳糖微粉的改性乳糖载体，干燥条件下保存。精密称量处方量盐酸川丁特罗微粉和150g含10％乳糖微粉的改性乳糖，过60目筛后，装入湿法制粒机中，调节转速250±10rpm，混合时间10min/次，混合3次。混合结束后，收集产物，干燥保存。其空气动力学测定结果显示，FPF值为25.1％，流动性测试结果显示，接触角为28.1°，流动性很好。
实施例4
处方：
盐酸川丁特罗        200mg
乳糖微粉            30g
乳糖                120g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥条件下保存。精密称取处方量乳糖微粉和市售不含微粉乳糖的乳糖载体，过60目筛后混合，装入湿法制粒机中，调节转速为300±10rpm，混合3次，每次10min，制得含20％乳糖微粉的改性乳糖，干燥保存。精密称量处方量盐酸川丁特罗微粉和150.00g含20％乳糖微粉的改性乳糖，过60目筛混合，装入湿法制粒机中，调节转速250±10rpm，混合3次，每次10min，收集，干燥保存。其空气动力学测定结果显示，FPF值为29.1％，流动性测试结果显示，接触角为27.8°，流动性很好。
实施例5
处方：
盐酸川丁特罗        200mg
硬脂酸镁微粉        0.75g
乳糖                149.25g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥条件下保存。相同方法粉碎硬脂酸镁，干燥保存，得到硬脂酸镁微粉。精密称量处方量硬脂酸镁微粉和市售不含微粉乳糖的乳糖载体，过 60目筛混合，装入湿法制粒机中，调节转速为300±10rpm，混合3次，每次10min，制备得到含0.5％硬脂酸镁微粉的改性乳糖，干燥保存。精密称取处方量盐酸川丁特罗微粉和150g含0.5％硬脂酸镁微粉的改性乳糖，过60目筛混合，装入湿法制粒机中，调节转速为250±10rpm，混合3次，每次10min，收集，干燥保存。其空气动力学测定结果显示，FPF值为38.6％，流动性测试结果显示，接触角为26.4°，流动性很好。
实施例6
处方：
盐酸川丁特罗        200mg
硬脂酸镁微粉        1.5g
乳糖                148.5g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥条件下保存。相同方法粉碎硬脂酸镁，干燥保存，得到硬脂酸镁微粉。精密称取处方量硬脂酸镁微粉和市售不含微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速为300±10rpm，混合3次，每次10min，制备得到含1％硬脂酸镁微粉的改性乳糖，干燥保存。精密称取处方量盐酸川丁特罗微粉和150g含1％硬脂酸镁微粉的改性乳糖，过60目筛混合，装入湿法制粒机中，调节转速为250±10rpm，混合3次，每次10min，收集，干燥保存。其空气动力学测定结果显示，FPF值为41.4％，流动性测试结果显示，接触角为25.2°，流动性很好。
实施例7
处方：
盐酸川丁特罗        200mg
硬脂酸镁微粉        2.25g
乳糖                147.75g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集盐酸川丁特罗微粉，干燥条件下保存。相同方法粉碎硬脂酸镁，干燥保存，得到硬脂酸镁微粉。精密称取处方量硬脂酸镁微粉和市售不含微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速为300±10rpm，混合3次，每次10min，制备得到含1.5％硬脂酸镁微粉的改性乳糖，干燥保存。精密称取处方量盐酸川丁特罗微粉和150g含1.5％硬脂酸镁微粉的改性乳糖，过60目筛混合，装入湿法制粒机中，调节转速为250±10rpm，混合3次，每次 10min，收集，干燥保存。其空气动力学测定结果显示，FPF值为40.7％，流动性测试结果显示，接触角为24.8°，流动性很好。
实施例8
处方：
Figure PCTCN2021106225-appb-000001
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集盐酸川丁特罗微粉，干燥条件下保存。相同方法粉碎硬脂酸镁，干燥保存，得到硬脂酸镁微粉。精密称取处方量硬脂酸镁微粉、乳糖微粉和市售不含微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速300±10rpm，混合3次，每次10min，制备得到含1％硬脂酸镁微粉和10％乳糖微粉的改性乳糖，干燥保存。精密称量处方量盐酸川丁特罗微粉和150.00g改性乳糖，过60目筛混合，装入湿法制粒机中，调节转速250±10rpm，混合3次，每次10min，收集产物，干燥保存。其空气动力学测定结果显示，FPF值为47.8％，流动性测试结果显示，接触角为26.2°，流动性很好。
实施例9
处方：
川丁特罗            200mg
硬脂酸镁微粉        1.50g
乳糖                148.50g
制备方法：取川丁特罗和硬脂酸镁，按照处方比例进行粗混合，并以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar。收集产物为川丁特罗与硬脂酸镁共粉碎微粉，测定粒径，干燥保存。精密称量处方量川丁特罗与硬脂酸镁共粉碎微粉和市售不含微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速250±10rpm，混合3次，每次10min，混合结束后，收集产物，干燥保存。其空气动力学测定结果显示，FPF值为30.5％，流动性测试结果显示，接触角为27.5°，流动性很好。
实施例10
处方：
盐酸川丁特罗            100mg
10％微粉乳糖的乳糖      150.00g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥保存。精密称取处方量的盐酸川丁特罗微粉和市售含10％微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速250±10rpm，混合时间10min/次，混合3次。混合结束后，收集产物，干燥保存。其空气动力学测定结果显示，FPF值为29.3％，流动性测试结果显示，接触角为28.6°，流动性很好。
实施例11
处方：
盐酸川丁特罗            300mg
10％微粉乳糖的乳糖      150.00g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥保存。精密称取处方量的盐酸川丁特罗微粉和市售含10％微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速250±10rpm，混合时间10min/次，混合3次。混合结束后，收集产物，干燥保存。其空气动力学测定结果显示，FPF值为32.6％，流动性测试结果显示，接触角为28.2°，流动性很好。
实施例12
处方：
盐酸川丁特罗        200mg
亮氨酸微粉          1.50g
乳糖                148.50g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar。收集产物为盐酸川丁特罗微粉，测定粒径，干燥保存。相同方法粉碎亮氨酸，干燥保存。精密称量处方量亮氨酸微粉和市售不含微粉乳糖的乳糖载体，过60目筛后，装入湿法制粒机中，调节转速300±10rpm，混合时间10min/次，混合3次。混合结束后，收集产物为含1％亮氨酸微粉的改性乳糖，干燥保存。精密称量处方量盐酸川丁特罗微粉和150.00g含1％亮氨酸微粉的改性乳糖，过60目筛后，装入湿法制粒机中，调节转速250±10rpm，混合时间10min/次，混合3次。混合结束后，收集产物，干燥保存。其空气动力学测定结果显示，FPF值为29.1％，流动性测试结果显示，接触角为27.9°，流动性很好。
实施例13
处方：
盐酸川丁特罗        200mg
硬脂酸镁微粉        1.5g
乳糖                148.5g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥条件下保存。精密称取处方量硬脂酸镁和乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速为300±10rpm，混合3次，每次10min，制备得到含1％硬脂酸镁的改性乳糖，干燥保存。精密称取处方量盐酸川丁特罗微粉和150g含1％硬脂酸镁的改性乳糖，过60目筛混合，装入湿法制粒机中，调节转速为250±10rpm，混合3次，每次10min，收集，干燥保存。其空气动力学测定结果显示，FPF值为29.6％，流动性测试结果显示，接触角为25.9°，流动性很好。
实施例14
处方：
Figure PCTCN2021106225-appb-000002
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集盐酸川丁特罗微粉，干燥条件下保存。相同方法粉碎硬脂酸镁，干燥保存，得到硬脂酸镁微粉。精密称取处方量硬脂酸镁微粉、乳糖微粉和市售不含微粉乳糖的乳糖载体，过60目筛混合，装入湿法制粒机中，调节转速300±10rpm，混合3次，每次10min，制备得到含1％硬脂酸镁微粉和10％乳糖微粉的改性乳糖，干燥保存。精密称量处方量盐酸川丁特罗微粉和150.00g改性乳糖，过60目筛混合，装入湿法制粒机中，调节转速250±10rpm，混合3次，每次10min，收集产物，干燥保存。其空气动力学测定结果显示，FPF值为45.9％，流动性测试结果显示，接触角为25.4°，流动性很好。
对比例
处方：
盐酸川丁特罗        200mg
乳糖                150.00g
制备方法：取盐酸川丁特罗，以压缩氮气作为气源，采用气流粉碎机粉碎。进料压力7.0bar，粉碎压力6.0bar，粉碎，收集得到盐酸川丁特罗微粉，干燥条件下保存。精密称量处方量盐酸川丁特罗微粉和乳糖，过60目筛后，装入湿法制粒机中，调节转速250±10rpm，混合时间10min/次，混合3次。混合结束后，收集产物，干燥保存。其空气动力学测定结果显示，FPF值为17.5％，流动性测试结果显示，接触角为35.3°。
试验例1
干粉吸入制剂中各组成部分的粒径，对制剂性质有显著影响。采用干法激光衍射法(新帕泰克激光粒度仪，德国)测定各组成的粒径。采用ROLOS模块，R1/R3镜头，操作模式ref 5s start 1％stop 5s tb 1.
表1为原辅料即中间体的粒径测定结果，其中气流粉碎后，川丁特罗或与表面改性剂一起经过气流粉碎，喷雾干燥或超临界流体技术处理后，均形成适合肺部吸入给药粒径大小的微粒，使其可用于进一步的干粉吸入制剂的制备。各种表面改性剂微粉，粒径与川丁特罗微粉粒径相当，有利于发挥其对乳糖载体的表面改性作用。
试验例2
采用高效液相法测定粉雾剂含量均匀度。粉雾剂混合结束后，在湿法制粒机中选取六个取样位置，各去约100mg样品，精密称定后，装入25mL容量瓶中，加水溶解，定容摇匀，并采用高效液相法进行样品浓度分析。
表2和3分别为实施例1和2中粉雾剂在各时间点的含量测定结果，各自混合速度下不同混合时间，含量均匀度无显著差异。
试验例3
由于肺部生理结构，以及肺部给药的特殊性，药物粉末需要有特定的空气动力学性质，才能有效沉积于肺部。药物粉末在肺部的沉积量，直接影响了药物的疗效。根据2015年《中国药典》规定，利用有效部位的雾滴(粒)分布作为筛选的指标，用以评价工艺参数的合理性。本发明利用新一代药用撞击器(next generation impactor，NGI)测定制剂的空气动力学行为。并以其结果作为处方筛选的依据。
图1为盐酸川丁特罗粉雾剂中药物与乳糖载体在100rpm转速下，不同混合时间的空气动力学测定结果。随混合时间延长，粉雾剂中药物空气动力学性能有所提高。
图2为盐酸川丁特罗粉雾剂中药物与乳糖载体在250rpm转速下，不同混合时间的空气动力学测定结果。不同混合时间，药物颗粒在NGI各层级的沉积有所不同。混合30min以上时，空气动力学行为最佳。
通过在载体中加入表面改性剂提升粉雾剂空气动力学性能。对比例中，采用未经改性处理的乳糖作为载体进行粉雾剂制备，测定其空气动力学性质，为改性剂的使用做对比。
图3和表4对比各实施例中粉雾剂的空气动力学性能。
实施例3和4，通过在乳糖载体中加入10％和20％的乳糖微粉，提高了粉雾剂空气动力学性能，并且乳糖微粉含量为20％的粉雾剂具有更高的FPF值。但是由于乳糖细粉具有较高的表面能，容易聚集成团，在实际生产过程中20％细粉含量，会带来含量不均匀和药物与载体离析的问题。
实施例5，6和7，通过在乳糖载体中加入0.5％，1％和1.5％的硬脂酸镁微粉，提高了粉雾剂空气动力学性能，并且硬脂酸镁含量为1％的粉雾剂具有更高的FPF值。
实施例8，14中采用10％的乳糖微粉，1％的硬脂酸镁微粉和20％乳糖微粉，2％硬脂酸镁微粉同时对乳糖载体进行改性处理，当硬脂酸镁微粉与乳糖微粉的重量比为：1：20-1：10时，其空气动力学行为更优，更有利于药物在肺部的沉积。
实施例9中采用共粉碎的方法制备川丁特罗与硬脂酸镁的共粉碎微粉，其空气动力学行为有所改善，可能的原因是药物与硬脂酸镁共粉碎，改变药物与乳糖载体接触的能量，药物颗粒更容易从乳糖表面脱落。
实施例10和11中，制剂中加入不同量盐酸川丁特罗，其FPF值随盐酸川丁特罗的加入量增加而增加。
实施例12中，采用1％亮氨酸对乳糖进行改性并制备粉雾剂，提高了粉雾剂空气动力学性能。
实施例13中，采用1％硬脂酸镁进行改性并制备粉雾剂，提高了粉雾剂空气动力学性能，但其改性作用弱于实施例6中，加入1％硬脂酸镁微粉的粉雾剂。说明对硬脂酸镁的微粉化处理，有利于其发挥乳糖载体的改性作用。
试验例4
采用固定漏斗法测定粉体休止角，将漏斗固定于坐标纸(纸放置于水平台上)上方一定高度,从漏斗加入物料直到形成的堆积圆锥顶部与漏斗底部刚好接触,测定圆锥直径,以漏斗底高度与圆锥半径比作为正切值计算休止角。
表4为对比例和各实施例的流动性结果。通过加入乳糖微粉，硬脂酸镁微粉和亮氨酸微粉，粉雾剂流动性提高，并且随加入量增加，流动性越来越好。
试验例5
原料药及中间体干燥保存，将需干燥保存粉体装入铝箔袋，铝箔袋中加入变色硅胶作为干燥剂，封口，置于含变色硅胶的干燥器中室温保存。
试验例6
粉雾剂进行加速实验，储存条件为：温度40℃，湿度75％储存7天；温度40℃，湿度75％储存14天；温度40℃，湿度75％储存30天；温度40℃，湿度75％储存60天；温度40℃，湿度75％储存90天。
图4和表5为实施例2中混合时间为30min的粉雾剂加速实验测定结果。结果显示，粉雾剂中盐酸川丁特罗FPF值未出现明显下降，表明粉雾剂在温度40℃，湿度75％的条件下相对稳定。
表1 原辅料及中间体粒径
Figure PCTCN2021106225-appb-000003
表2 实施例1中100rpm混合转速制备盐酸川丁特罗粉雾剂各取样点含量(％)
Figure PCTCN2021106225-appb-000004
Figure PCTCN2021106225-appb-000005
表3 实施例2中250rpm混合转速制备盐酸川丁特罗粉雾剂各取样点含量(％)。
Figure PCTCN2021106225-appb-000006
表4 空气动力学与流动性对比
Figure PCTCN2021106225-appb-000007
表5 实施例2中250rpm混合转速30min盐酸川丁特罗粉雾剂加速实验空气动力学测定结果。
Figure PCTCN2021106225-appb-000008
Figure PCTCN2021106225-appb-000009
结果表明，通过对乳糖载体的改性处理，与对比例相比，各实施例中的药物的空气动力学行为均有改善。加入不同表面改性剂后盐酸川丁特罗粉雾剂的FPF值均有提高，优选为以下比例，乳糖微粉与乳糖的重量比为：1：4--1：9；硬脂酸镁微粉与乳糖的重量比为：1：199--3：197；亮氨酸与乳糖的重量比为：1：199--3：197；硬脂酸镁微粉、乳糖微粉与乳糖的重量比为：1：20：378.8-1：10：28.9，更优选为1：10：89—1：20：79。

Claims (10)

  1. 一种川丁特罗吸入粉雾剂，其特征在于，包含活性成分、经过表面改性的载体，其中各组分重量百分组成为：0.05％-0.25％活性成分，99.75％-99.95％经过表面改性的载体，所述的活性成分为川丁特罗，经过表面改性的载体为经过表面改性剂进行表面改进的载体，所述的载体表面改性剂与载体的重量比为：1：399--25：75，优选为：1：199--11：39。
  2. 如权利要求1所述的川丁特罗吸入粉雾剂，其特征在于，所述的川丁特罗为盐酸川丁特罗。
  3. 如权利要求1所述的川丁特罗吸入粉雾剂，其特征在于，所述的表面改性剂包含硬脂酸镁，乳糖或亮氨酸等的微粉中一种或多种混合物。
  4. 如权利要求1所述的川丁特罗吸入粉雾剂，其特征在于，所述的载体为生理友好的糖、多元醇、氨基酸中的一种或几种，选自乳糖、蔗糖、葡萄糖、果糖、麦芽糖、海藻糖、甘露醇、木糖醇、山梨醇、亮氨酸、丙氨酸、色氨酸、缬氨酸、异亮氨酸，甘氨酸，苯丙氨酸，脯氨酸，丝氨酸，酪氨酸，半胱氨酸，蛋氨酸，谷氨酸，苏氨酸，天冬氨酸，谷氨酰胺，赖氨酸，精氨酸。
  5. 如权利要求1所述的川丁特罗吸入粉雾剂，其特征在于，所述的表面改性的载体以硬脂酸镁，乳糖或亮氨酸的微粉中一种或多种混合物作为表面改性剂，以乳糖、甘露醇或亮氨酸中一种或多种混合物作为载体。
  6. 如权利要求5所述的川丁特罗吸入粉雾剂，其特征在于，所述的表面改性剂为乳糖微粉改性的乳糖、硬脂酸微粉改性的乳糖、硬脂酸镁微粉和乳糖微粉改性的乳糖，其中，所述的乳糖微粉与乳糖的重量比为：1：4--1：9；硬脂酸镁微粉与乳糖的重量比为1：199--3：197；亮氨酸微粉与乳糖的重量比为1：199--3：197；硬脂酸镁微粉、乳糖微粉与乳糖的重量比为：1：10：89-1：20：79。
  7. 如权利要求1-6任何一项所述的川丁特罗吸入粉雾剂，其特征在于，所述的表面改性剂微粉的中位径小于5μm，90％的载体表面改性剂微粉的粒径小于10μm。
  8. 如权利要求1所述的川丁特罗吸入粉雾剂的制备方法，其特征在于，川丁特罗或盐酸川丁特罗微粉的制备；
    (1)川丁特罗或盐酸川丁特罗微粉的制备；
    (2)表面改性载体的制备；
    (3)川丁特罗或盐酸川丁特罗微粉与表面改性载体混合。
  9. 如权利要求8所述的川丁特罗吸入粉雾剂的制备方法，其特征在于，所述步骤(2)中，载体与载体表面改性剂或表面改性剂微粉采用混合制粒机进行高剪切混合处理。
  10. 权利要求1-7任何一项所述的的川丁特罗吸入粉雾剂在制备治疗哮喘或慢性阻塞性肺病药物中的应用。
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