WO2024001586A1 - Ciprofloxacin hydrochloride composition particles for lung delivery, method for preparing same, and use thereof - Google Patents

Ciprofloxacin hydrochloride composition particles for lung delivery, method for preparing same, and use thereof Download PDF

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Publication number
WO2024001586A1
WO2024001586A1 PCT/CN2023/094666 CN2023094666W WO2024001586A1 WO 2024001586 A1 WO2024001586 A1 WO 2024001586A1 CN 2023094666 W CN2023094666 W CN 2023094666W WO 2024001586 A1 WO2024001586 A1 WO 2024001586A1
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ciprofloxacin hydrochloride
preparation
freezing
particles
drug
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PCT/CN2023/094666
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French (fr)
Chinese (zh)
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吴铎
陈莹洁
张盛宇
严珅
尹全义
仇实
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苏州大学
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Publication of WO2024001586A1 publication Critical patent/WO2024001586A1/en

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the technical field of pharmaceutical preparations, and in particular to a ciprofloxacin hydrochloride composition microparticle for pulmonary delivery and its preparation method and application.
  • Bronchiectasis is divided into cystic fibrosis (CFBE) and non-cystic fibrosis bronchiectasis (NCFBE). It is caused by inflammation and expansion of the bronchial wall in the lungs, resulting in impaired mucociliary clearance and a change in the ability to clear respiratory secretions. Poor, leading to the accumulation of mucus, increasing bacterial infection and colonization, further damaging the bronchial wall, with chronic bacterial colonization as the main clinical feature, especially Pseudomonas aeruginosa.
  • CFBE cystic fibrosis transmembrane regulatory protein
  • abnormal transport of chloride ions through the lung epithelium resulting in abnormal viscosity of airway surface fluid.
  • the cause of NCFBE may be infection caused by external environmental stimulation.
  • Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). Mtb will be engulfed by macrophages, then proliferate and spread to nearby cells (such as epithelial cells), triggering the cellular immune system and forming granulomas to protect Mtb.
  • Mtb Mycobacterium tuberculosis
  • Antibiotics are used to treat a variety of bacterial respiratory infections. According to the different structures of antibiotics, they can be divided into lactams, fluoroquinolones, aminoglycosides and tricyclic glycopeptides, with different antibacterial and anti-inflammatory mechanisms.
  • the most common treatment method is to administer large doses of single or combined antibiotics orally or by injection; however, such administration routes have low targeting to the site of lung infection, low bioavailability, and may cause systemic adverse reactions.
  • aminoglycosides can cause ototoxicity and nephrotoxicity; colistin can cause nephrotoxicity and neurotoxicity. Therefore, the use of pulmonary drug delivery will have more advantages, as it can deliver targeted drugs, increase drug concentration at the infection site, and reduce systemic toxicity; at the same time, it can reduce the dose, reduce the frequency of drug administration, and improve compliance.
  • Ciprofloxacin is a third-generation fluoroquinolone broad-spectrum antibiotic. Its antibacterial mechanism is to inhibit bacterial DNA gyrase and DNA topoisomerase IV, thereby inhibiting cell division. It is effective against both Gram-positive and Gram-negative organisms. It has a wide range of therapeutic effects, has a good antibacterial activity spectrum and has high permeability in the lung epithelial intimal fluid. It is the most promising drug choice in the treatment of NCFBE.
  • Ciprofloxacin hydrochloride is the most common salt form of ciprofloxacin. Many antibiotics exist in the form of salts, whose chemical properties are stable and their efficacy is not affected; and because the solubility, purity and crystallinity of the salt form are better than those of the electrically neutral form, no toxic organic matter is needed during the granulation process. Solvents and complex methods. In addition, because ciprofloxacin hydrochloride has a certain degree of water solubility, the concentration of the drug in the lungs is rapidly increased after inhalation, reaching therapeutic levels.
  • the clinical phase III product Pulmaquin is an inhaled ciprofloxacin liposome suspension, in which free ciprofloxacin hydrochloride is added.
  • the purpose is to increase Cmax, reach the highest concentration in a short time, and rapidly increase the antibiotics in the lungs. concentration to achieve therapeutic levels.
  • the first thing is to improve the aerosol performance of the preparation and achieve high lung deposition rate, and the choice of granulation process is crucial.
  • ciprofloxacin powder aerosols due to the fast drying rate, the drug is usually amorphous.
  • particles of 1 to 5 ⁇ m have high surface energy and are easy to agglomerate.
  • most of the current spray freeze-drying technology uses liquid nitrogen as the refrigerant. Due to the large and uncontrollable supercooling, the freezing rate is high and the drugs are easy to exist in amorphous form. This results in poor physical stability of the powder, affecting the stability of the powder properties during storage and use.
  • the technical problem to be solved by the present invention is to provide a ciprofloxacin hydrochloride composition microparticle for pulmonary delivery.
  • the microparticles provided by the present invention have good dispersion and excellent aerosol performance and physical stability.
  • the invention provides a method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery, including:
  • the liquid droplets are frozen to obtain ice balls; the ice balls are vacuum freeze-dried to obtain microparticles; the median geometric diameter (D50) of the microparticles is greater than 25 ⁇ m.
  • the excipient in step A) is leucine.
  • the mass ratio of ciprofloxacin hydrochloride and excipients is 5:5 to 8:2; in the precursor liquid, the total mass ratio of ciprofloxacin hydrochloride and excipients is The mass concentration is 1% to 5%.
  • the atomizer in step B) can be a pressure atomizer, an air flow atomizer or an ultrasonic atomizer.
  • the atomizer in step B) is an ultrasonic atomizer, and the working parameters are:
  • the feed rate is 1 ⁇ 20mL/min, and the working frequency of the atomizer is 80 ⁇ 160kHz.
  • step C) freezing is specifically carried out in a spray freezing tower.
  • the freezing parameters are specifically: the tower wall temperature is -30°C ⁇ -50°C, and the temperature of the downstream cold air in the tower is -30°C ⁇ -50°C. °C, the cold air flow rate is 0 ⁇ 500L/min.
  • the vacuum freeze-drying time is 24 to 72 hours.
  • the drug loading capacity of the particles is greater than 60%
  • the median geometric particle diameter (D 50 ) is 25 ⁇ m ⁇ 50 ⁇ m
  • the tap density is 0.005g/cm 3 ⁇ 0.030g/cm 3
  • the mass median aerodynamic force is The chemical diameter is 3 to 5 ⁇ m
  • the basic flow energy (BFE) of the composition is 2 to 9 mJ.
  • the invention provides ciprofloxacin hydrochloride composition particles for pulmonary delivery, which are prepared by the preparation method described in any of the above technical solutions.
  • the present invention provides the use of ciprofloxacin hydrochloride composition particles prepared by any one of the above preparation methods in the preparation of pulmonary delivery products.
  • the present invention provides a pulmonary delivery product, including the ciprofloxacin hydrochloride composition particles described in the above technical solution.
  • the present invention provides a method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery, which includes: A) dissolving ciprofloxacin hydrochloride and excipients to obtain a precursor liquid; B) The precursor liquid is atomized and sprayed to obtain liquid droplets; C) The liquid droplets are frozen to obtain ice balls; the ice balls are vacuum freeze-dried to obtain microparticles; the median geometric diameter (D50) of the microparticles is greater than 25 ⁇ m.
  • the present invention adopts spray freezing combined with vacuum freeze-drying technology, and regulates the precursor liquid formula and process parameters to prepare an aerosol with excellent dispersion, excellent aerosol performance and physical stability.
  • Ciprofloxacin hydrochloride pharmaceutical composition particles Ciprofloxacin hydrochloride pharmaceutical composition particles.
  • the present invention provides ciprofloxacin hydrochloride pharmaceutical composition microparticles for pulmonary administration and a preparation method thereof.
  • the drug loading capacity of the microparticles is greater than 60%, the median geometric particle diameter (D50) is greater than 25 ⁇ m, and the tap density is less than 0.030g/cm 3 , the mass median aerodynamic diameter is 3 ⁇ 5 ⁇ m.
  • Figure 1 is a scanning electron microscope image of the raw material ciprofloxacin hydrochloride monohydrate
  • Figure 2 is the X-ray diffraction pattern of the raw materials ciprofloxacin hydrochloride monohydrate (a) and L-leucine (b);
  • Figure 3 is a scanning electron microscope image of a powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 5:5;
  • Figure 4 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 5:5;
  • Figure 5 is a scanning electron microscope image of a powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 7:3;
  • Figure 6 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 7:3;
  • Figure 7 is a scanning electron microscope image of a powder with a freezing temperature of -40°C, a solid content of 1wt%, and a drug-to-excipient ratio of 5:5;
  • Figure 8 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 1wt%, and a drug-to-adjuvant ratio of 5:5;
  • Figure 9 is a scanning electron microscope image of the powder with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-adjuvant ratio of 3:7.
  • Figure 10 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 3::7;
  • Figure 11 is a scanning electron microscope image of a powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 9:1;
  • Figure 12 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 9:1;
  • Figure 13 is a scan of the powder with a freezing temperature of -60°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5. trace electron micrograph;
  • Figure 14 is an X-ray diffraction pattern of powder with a freezing temperature of -60°C, a solid content of 2wt% and a drug-to-adjuvant ratio of 5:5;
  • Figure 15 is a scanning electron microscope image of a powder with a freezing temperature of -80°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 5:5;
  • Figure 16 is the X-ray diffraction pattern of the powder with a freezing temperature of -80°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5.
  • the present invention provides a ciprofloxacin hydrochloride composition microparticle for pulmonary delivery, its preparation method and application.
  • the present invention relates to compositions and methods of preparation, particularly for the treatment of acute exacerbations of cystic fibrosis (CF), non-CF bronchiectasis and tuberculosis.
  • CF cystic fibrosis
  • non-CF bronchiectasis tuberculosis
  • the invention provides a method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery, including:
  • the liquid droplets are frozen to obtain ice balls; the ice balls are vacuum freeze-dried to obtain microparticles; the median geometric diameter (D50) of the microparticles is greater than 25 ⁇ m.
  • the method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery provided by the present invention first dissolves ciprofloxacin hydrochloride and excipients to obtain a precursor liquid.
  • the excipient of the present invention is leucine.
  • the present invention does not limit the dissolution, as it is well known to those skilled in the art.
  • the mass ratio of ciprofloxacin hydrochloride and excipients is 5:5 to 8:2; including but not limited to 5:5, 7:3, 8:2, 6:4; and A point value between any two of the above.
  • the total mass concentration of ciprofloxacin hydrochloride and excipients is preferably 1% to 5%; including but not limited to 1%, 2%, 3%, 4% or 5%; or A point value between any two of the above.
  • the precursor liquid is atomized and sprayed to obtain droplets.
  • the atomization of the present invention is preferably carried out in an atomizer.
  • the present invention does not limit the above-mentioned specific atomizer. It can be homemade in this laboratory or commercially available.
  • the atomizer of the present invention is selected from a pressure atomizer, an airflow atomizer or an ultrasonic atomizer.
  • the solution is preferably placed in a syringe and atomized with an ultrasonic atomizing nozzle; the parameters of the atomization are: the feed rate is preferably 1 to 20 mL/min, and more preferably 2 to 18 mL/min.
  • the operating frequency of the converter is preferably 80 to 160 kHz; more preferably, it is 85 to 150 kHz.
  • the size of the droplets of the present invention is preferably 2-50 ⁇ m.
  • the droplets are frozen to obtain ice balls.
  • the freezing of the present invention is specifically carried out in a spray freezing tower.
  • the preferred freezing parameters are: the tower wall temperature is -30°C to -50°C, the downstream cold air temperature in the tower is -30°C to -50°C, and the cold air temperature is -30°C to -50°C.
  • the flow rate is 0 to 500L/min; more preferably, the tower wall temperature is -35°C to -45°C, the downstream cold air temperature in the tower is -35°C to -45°C, and the cold air flow rate is 10 to 400L/min; the most preferred is
  • the tower wall temperature is -40°C, the downstream cold air temperature in the tower is -40°C, and the cold air flow rate is 50 ⁇ 300L/min.
  • the spray freezing device of the present invention can be commercially available or homemade, preferably the ones disclosed in 201610133187.1 and 201610202235.8 can be used.
  • the present invention can obtain products with different degrees of crystallinity.
  • a special tray for spray cooling is used to collect ice balls at the bottom of the tower.
  • the ice balls are vacuum freeze-dried to obtain microparticles; the vacuum freeze-drying time is preferably 24 to 72 hours; more preferably, it is 36 to 72 hours; most preferably, it is 40 to 72 hours.
  • the present invention interacts with each other through the above-mentioned freezing parameters, vacuum freeze-drying parameters, the total mass concentration range of ciprofloxacin hydrochloride and excipients, and drug-adjuvant ratios, and supports each other functionally, and there is mutual interaction. Only by the relevant technical features and the above overall solution can the particles with controllable size within a specific range be prepared and the technical effects of the present invention be achieved.
  • the present invention can create more unexpected aerosol properties compared to other temperature ranges.
  • the present invention combines spray freezing with vacuum freeze-drying technology, especially the freezing temperature control of the spray freezing process.
  • the traditional spray freezing process uses liquid nitrogen as the refrigerant to solidify the droplets (that is, the freezing temperature is a fixed freezing point of liquid nitrogen).
  • Temperature -196°C and in this patent, by controlling -30 to 50°C as the freezing temperature, on the one hand, it can break through the advantage of technically controllable temperature, and at the same time, it has excellent aerosol and other properties for prescription preparations in this temperature range.
  • the present invention uses a spray freezing tower combined with vacuum freeze-drying technology, uses ice crystals as pore-forming templates, avoids the use of traditional organic pore-forming agents, and controls the structural properties of particles by overall collaboratively regulating process parameters such as precursor liquid formula and freezing temperature. , optimized to obtain ciprofloxacin hydrochloride pharmaceutical composition particles with good dispersion, excellent aerosol performance and physical stability,
  • the drug loading capacity of the particles of the present invention is greater than 60%, the median geometric particle diameter (D 50 ) is greater than 25 ⁇ m; preferably 25 ⁇ m ⁇ 50 ⁇ m; and the tap density is 0.005g/cm3 ⁇ 0.030g/cm 3 , and the mass median
  • the aerodynamic diameter is 3 to 5 ⁇ m; the basic flow energy (BFE) of the composition is 2 to 9 mJ.
  • the invention provides ciprofloxacin hydrochloride composition particles for pulmonary delivery, which are prepared by the preparation method described in any of the above technical solutions.
  • composition of the present invention contains 50% to 80% ciprofloxacin hydrochloride drug.
  • the present invention has a clear description of the above preparation method, which will not be described in detail here.
  • the present invention provides the use of ciprofloxacin hydrochloride composition particles prepared by any one of the above preparation methods in the preparation of pulmonary delivery products.
  • microparticles prepared by the above method of the present invention can be used to prepare pulmonary delivery products, including but not limited to pulmonary delivery drugs. The inventor does not limit this.
  • the present invention provides a pulmonary delivery product, including the ciprofloxacin hydrochloride composition particles described in the above technical solution.
  • the above-mentioned pulmonary delivery product provided by the present invention includes the above-mentioned ciprofloxacin hydrochloride composition particles. It may also include pharmaceutically acceptable ingredients, which are not limited here.
  • the present invention provides a pharmaceutical preparation for pulmonary delivery, including the ciprofloxacin hydrochloride composition particles described in the above technical solution.
  • the present invention encompasses a pharmaceutical formulation for pulmonary delivery of ciprofloxacin hydrochloride in a form that can be effectively delivered to the lungs.
  • Compositions for pulmonary administration include a water-soluble salt of a fluoroquinolone, ciprofloxacin hydrochloride.
  • the ciprofloxacin hydrochloride composition microparticles for pulmonary delivery provided by the present invention, its preparation method and application are described in detail below in conjunction with the examples.
  • Powder X-ray diffraction is used to identify the crystal form of a substance. For example, crystalline substances often show sharp peaks, while amorphous drugs show diffuse peaks.
  • Sample measurement conditions accelerating voltage 30kV, current 10mA, diffraction angle range 2 ⁇ from 2° to 40°, step size 0.02°, time 0.3s.
  • Loss on drying refers to the weight of any volatile substance lost after the object to be tested is dried to constant weight under specified conditions. It is expressed as a percentage and is used to examine the moisture in the sample. The process is to take a glass container and weigh its weight m0, then accurately weigh a certain amount of the newly prepared sample in the glass container, shake the sample gently until it is evenly dispersed in the bottle, and record its total weight m1. A sample was prepared in triplicate. The samples were then dried in an oven at a temperature of 105°C for 3 h, and then cooled to room temperature in the drying oven. Accurately weigh the total weight m2 of the dried sample and glass container, and finally calculate its moisture content.
  • LOD Loss on drying
  • the hygroscopicity of a drug refers to the ability or degree of moisture absorption of a substance under certain temperature and humidity conditions.
  • the process is as follows: take the dried glass bottle and place it in a desiccator with a saturated ammonium sulfate solution (80 ⁇ 2%) at the bottom the day before the experiment, and then place it in an oven set at 25 ⁇ 1°C. Determine the weight of the glass bottle m1, take an appropriate amount of sample into the glass bottle, and accurately weigh the weight m2. Then, under the above constant temperature and humidity conditions for 24 hours, accurately weigh the weight m3. Finally, the weight gain rate due to moisture induction was calculated.
  • the moisture attraction weight gain rate is >15%, it is highly hygroscopic; if 2% ⁇ moisture attraction weight gain ⁇ 15%, it is hygroscopic; if 0.2% ⁇ moisture attraction weight gain ⁇ 2%, it is slightly hygroscopic; The moisture absorption weight gain rate is ⁇ 0.2%, indicating no or almost no moisture absorption.
  • a laser particle size analyzer measures particle size distribution based on the physical phenomenon that particles can diffract laser light.
  • Use dry powder mode use R3 lens, set the collection time and dispersion pressure, and control the measurement concentration.
  • Use The inhaler atomizes at a flow rate of 60L/min, and the inhalation time is 4 seconds.
  • Table 1 Physical properties of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5
  • the prepared CIP powder is filled into three inhalation-grade clean No. 3 hydroxypropyl methylcellulose (HPMC) capsules.
  • the total mass of the powder is about 4 ⁇ 0.5mg, and then delivered using a Breezhaler inhaler, using a new generation of cascade impaction.
  • the aerosol performance of the powder was measured using an NGI instrument.
  • the powder was atomized at a flow rate of 60L/min and the inhalation time was 4 seconds. Its atomization characteristics are shown in Table 2.
  • UV ultraviolet spectrophotometry
  • Effective drug deposition (%) is Refers to maintaining the same filling volume, based on the FPF value and drug loading capacity, the percentage of fine particle drugs (aerodynamic diameter ⁇ 5 ⁇ m) in the total drug volume.
  • Table 2 Atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5
  • This embodiment has excellent atomization performance and is within the preferred range of the present invention.
  • Table 3 Physical properties of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 7:3
  • Table 4 Atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 7:3
  • This embodiment has excellent atomization performance and is within the preferred range of the present invention.
  • Table 5 Physics of powders with a freezing temperature of -40°C, a solid content of 1wt% and a drug-to-excipient ratio of 5:5 nature
  • Table 6 Atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 1wt% and a drug-to-excipient ratio of 5:5
  • This embodiment has excellent atomization performance and is within the preferred range of the present invention.
  • Table 7 Physical properties of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 3:7 or 9:1
  • Table 8 Atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-excipient ratio of 3:7 or 9:1
  • the FPF is significantly reduced, and 10% LEU is not enough to improve the atomization properties of the powder; increasing the LEU content to 70% can significantly improve the aerosol performance of the particles, but its drug loading is low.
  • the effective drug deposition rate is far lower than that of the sample with a LEU content of 50%, so the powder with a drug-adjuvant ratio of (5:5)-(8:2) is within the preferred range of the present invention.
  • Freeze tower use special spray cooling tray to collect ice balls at the bottom of the tower. After atomization, it was transferred to a vacuum freeze-dryer and freeze-dried for 72 hours to obtain powder.
  • the overall phase diagram and crystal form diagram of the powder frozen at -60°C are shown in Figures 13 and 14 respectively; the overall phase diagram and crystal form diagram of the powder frozen at -80°C are shown in Figures 15 and 16 respectively; And compare it with Example 1.
  • Table 9 Physical properties of powders with freezing temperature of -60 or -80°C, solid content of 2wt% and drug-to-excipient ratio of 5:5
  • Table 10 Atomization characteristics of powders with freezing temperature of -60 or -80°C, solid content of 2wt% and drug-to-adjuvant ratio of 5:5
  • Freezing temperature has a significant impact on the FPF value.
  • the present invention uses ice crystals as pore-forming templates, avoids the use of traditional organic pore-forming agents, and directly prepares low-density porous particles with larger geometric particle sizes, reducing agglomeration, improving atomization efficiency, and achieving an FPF value of 50%.

Abstract

Provided is a method for preparing ciprofloxacin hydrochloride composition particles for lung delivery, comprising: A) dissolving ciprofloxacin hydrochloride and an excipient to obtain a precursor solution; B) atomizing and spraying the precursor solution to obtain liquid drops; C) freezing the liquid drops to obtain ice balls; and carrying out vacuum freeze-drying on the ice balls to obtain the particles, the median geometric diameter (D50) of the particles being greater than 25 μm. By combining spray freezing with vacuum freeze-drying technology, and by means of regulating and controlling the formula of the precursor solution and process parameters, the ciprofloxacin hydrochloride pharmaceutical composition particles with excellent dispersity, aerosol performance and physical stability are prepared.

Description

一种用于肺部递送的盐酸环丙沙星组合物微粒及其制备方法和应用Ciprofloxacin hydrochloride composition microparticles for pulmonary delivery and preparation method and application thereof
本申请要求于2022年06月30日提交中国专利局、申请号为202210759590.0、发明名称为“一种用于肺部递送的盐酸环丙沙星组合物微粒及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application is required to be submitted to the China Patent Office on June 30, 2022, with the application number 202210759590.0 and the Chinese patent title "A Ciprofloxacin Hydrochloride Composition Particle for Pulmonary Delivery and its Preparation Method and Application" claim of priority, the entire contents of which are incorporated herein by reference.
技术领域Technical field
本发明涉及药物制剂技术领域，尤其是涉及一种用于肺部递送的盐酸环丙沙星组合物微粒及其制备方法和应用。The present invention relates to the technical field of pharmaceutical preparations, and in particular to a ciprofloxacin hydrochloride composition microparticle for pulmonary delivery and its preparation method and application.
背景技术Background technique
目前，由于肺部感染引起的疾病致死率高。其中，由细菌引起的感染疾病有支气管扩张症和结核病等。支气管扩张症分为囊性纤维化(CFBE)和非囊性纤维化支气管扩张症(NCFBE)，起因是支气管壁在肺内发炎和扩张，导致粘液纤毛清除受损，清除呼吸道分泌物的能力变差，导致粘液的积累，增加细菌感染与定植，进一步破坏支气管壁，以慢性细菌定植为主要临床特性，尤其是铜绿假单胞菌。其中，CFBE是由于囊性纤维化跨膜调节蛋白功能缺失(氯离子通过肺上皮的异常运输)而导致气道表面液体黏度异常。NCFBE起因可能是外界环境刺激引起的感染。结核病(TB)是由结核分枝杆菌(Mtb)引起的一种传染性疾病。Mtb会被巨噬细胞吞噬，然后增殖，扩散到附近细胞(如上皮细胞)，引发细胞免疫系统，形成肉芽肿，使Mtb受到保护。这些菌株具有许多毒性因子和一套免疫逃避特性，导致反复感染，难以根除。Currently, the mortality rate from diseases caused by lung infections is high. Among them, infectious diseases caused by bacteria include bronchiectasis and tuberculosis. Bronchiectasis is divided into cystic fibrosis (CFBE) and non-cystic fibrosis bronchiectasis (NCFBE). It is caused by inflammation and expansion of the bronchial wall in the lungs, resulting in impaired mucociliary clearance and a change in the ability to clear respiratory secretions. Poor, leading to the accumulation of mucus, increasing bacterial infection and colonization, further damaging the bronchial wall, with chronic bacterial colonization as the main clinical feature, especially Pseudomonas aeruginosa. Among them, CFBE is due to the loss of function of the cystic fibrosis transmembrane regulatory protein (abnormal transport of chloride ions through the lung epithelium), resulting in abnormal viscosity of airway surface fluid. The cause of NCFBE may be infection caused by external environmental stimulation. Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). Mtb will be engulfed by macrophages, then proliferate and spread to nearby cells (such as epithelial cells), triggering the cellular immune system and forming granulomas to protect Mtb. These strains possess numerous virulence factors and a set of immune evasion properties that lead to recurrent infections that are difficult to eradicate.
抗生素可用于治疗多种呼吸道细菌感染。根据抗生素结构不同，可分为内酰胺类、氟喹诺酮类、氨基糖甙类和三环糖肽类，其抑菌抗炎作用机制各有不同。目前，最常见的治疗方法是口服或注射给予大剂量的单一或联合抗生素；但这样的给药途径对肺部感染部位的靶向性低，生物利用率低，并且可能造成全身性的不良反应，比如氨基糖苷类药物会造成耳毒性和肾毒性；粘菌素引起肾毒性和神经毒性。因此，采用肺部给药将更有优势，可靶向性递送，提高感染部位的药物浓度，减少全身毒性；同时降低剂量，减少给药频率，提高依从性。 Antibiotics are used to treat a variety of bacterial respiratory infections. According to the different structures of antibiotics, they can be divided into lactams, fluoroquinolones, aminoglycosides and tricyclic glycopeptides, with different antibacterial and anti-inflammatory mechanisms. Currently, the most common treatment method is to administer large doses of single or combined antibiotics orally or by injection; however, such administration routes have low targeting to the site of lung infection, low bioavailability, and may cause systemic adverse reactions. , for example, aminoglycosides can cause ototoxicity and nephrotoxicity; colistin can cause nephrotoxicity and neurotoxicity. Therefore, the use of pulmonary drug delivery will have more advantages, as it can deliver targeted drugs, increase drug concentration at the infection site, and reduce systemic toxicity; at the same time, it can reduce the dose, reduce the frequency of drug administration, and improve compliance.
环丙沙星是第三代氟喹诺酮类广谱抗生素，其抑菌机制是抑制细菌DNA旋转酶、DNA拓扑异构酶Ⅳ，从而抑制细胞分裂，对革兰氏阳性和革兰氏阴性生物均有广泛的治疗作用，并且有着良好的抗菌活性谱和在肺上皮内膜液中的渗透性较高，在治疗NCFBE中是最有希望的药物选择。Ciprofloxacin is a third-generation fluoroquinolone broad-spectrum antibiotic. Its antibacterial mechanism is to inhibit bacterial DNA gyrase and DNA topoisomerase IV, thereby inhibiting cell division. It is effective against both Gram-positive and Gram-negative organisms. It has a wide range of therapeutic effects, has a good antibacterial activity spectrum and has high permeability in the lung epithelial intimal fluid. It is the most promising drug choice in the treatment of NCFBE.
盐酸环丙沙星是环丙沙星最常见的盐形。很多抗生素是以盐的形式存在，其化学性质稳定，药效不受影响；并且由于盐形的溶解度、纯度和结晶度都比电中性形式好，所以在制粒过程中，无需有毒的有机溶剂和复杂的方法。另外，由于盐酸环丙沙星具有一定的水溶性，吸入后迅速增加药物在肺部浓度，达到治疗水平。如临床三期Pulmaquin产品为吸入环丙沙星脂质体悬浮液，其中就加入了游离的盐酸环丙沙星，目的是提高Cmax、在较短时间达到最高浓度，迅速增加抗生素在肺部的浓度，以达到治疗水平。Ciprofloxacin hydrochloride is the most common salt form of ciprofloxacin. Many antibiotics exist in the form of salts, whose chemical properties are stable and their efficacy is not affected; and because the solubility, purity and crystallinity of the salt form are better than those of the electrically neutral form, no toxic organic matter is needed during the granulation process. Solvents and complex methods. In addition, because ciprofloxacin hydrochloride has a certain degree of water solubility, the concentration of the drug in the lungs is rapidly increased after inhalation, reaching therapeutic levels. For example, the clinical phase III product Pulmaquin is an inhaled ciprofloxacin liposome suspension, in which free ciprofloxacin hydrochloride is added. The purpose is to increase Cmax, reach the highest concentration in a short time, and rapidly increase the antibiotics in the lungs. concentration to achieve therapeutic levels.
为实现高疗效，首要是要提高制剂的气溶胶性能，实现高肺沉积率，制粒工艺的选择至关重要。目前学术界和产业界是采用喷雾干燥技术制备环丙沙星粉雾剂，但由于干燥速率较快，药物通常为无定型。同时，1～5μm的颗粒具有高表面能，易团聚。但目前的喷雾冷冻干燥技术多数是以液氮作为冷媒，由于过冷度大且无法控制，导致冷冻速率高，药物也易以无定型存在。造成粉末的物理稳定性较差，影响在储存和使用过程中粉末性能的稳定性。In order to achieve high efficacy, the first thing is to improve the aerosol performance of the preparation and achieve high lung deposition rate, and the choice of granulation process is crucial. At present, academia and industry use spray drying technology to prepare ciprofloxacin powder aerosols. However, due to the fast drying rate, the drug is usually amorphous. At the same time, particles of 1 to 5 μm have high surface energy and are easy to agglomerate. However, most of the current spray freeze-drying technology uses liquid nitrogen as the refrigerant. Due to the large and uncontrollable supercooling, the freezing rate is high and the drugs are easy to exist in amorphous form. This results in poor physical stability of the powder, affecting the stability of the powder properties during storage and use.
因此，提供一种良好分散性和稳定性的肺部递送的盐酸环丙沙星组合物微粒是非常必要的。Therefore, it is very necessary to provide a ciprofloxacin hydrochloride composition microparticle with good dispersion and stability for pulmonary delivery.
发明内容Contents of the invention
有鉴于此，本发明要解决的技术问题在于提供一种用于肺部递送的盐酸环丙沙星组合物微粒，本发明提供的微粒具有良好分散性和优良的气溶胶性能和物理稳定性。In view of this, the technical problem to be solved by the present invention is to provide a ciprofloxacin hydrochloride composition microparticle for pulmonary delivery. The microparticles provided by the present invention have good dispersion and excellent aerosol performance and physical stability.
本发明提供了一种用于肺部递送的盐酸环丙沙星组合物微粒的制备方法，包括：The invention provides a method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery, including:
A)盐酸环丙沙星和赋形剂溶解，得到前驱液；A) Dissolve ciprofloxacin hydrochloride and excipients to obtain a precursor solution;
B)前驱液经雾化喷雾，得到液滴； B) The precursor liquid is atomized and sprayed to obtain droplets;
C)液滴经冷冻，得到冰球；将所述冰球真空冷冻干燥，即得微粒；所述微粒的中值几何粒径(D50)大于25μm。C) The liquid droplets are frozen to obtain ice balls; the ice balls are vacuum freeze-dried to obtain microparticles; the median geometric diameter (D50) of the microparticles is greater than 25 μm.
优选的，步骤A)所述赋形剂为亮氨酸。Preferably, the excipient in step A) is leucine.
优选的，步骤A)所述前驱液中，盐酸环丙沙星和赋形剂的质量比为5:5～8:2；所述前驱液中，盐酸环丙沙星和赋形剂的总质量浓度为1％～5％。Preferably, in the precursor liquid of step A), the mass ratio of ciprofloxacin hydrochloride and excipients is 5:5 to 8:2; in the precursor liquid, the total mass ratio of ciprofloxacin hydrochloride and excipients is The mass concentration is 1% to 5%.
优选的，步骤B)所述雾化器可选用压力式雾化器、气流式雾化器或超声雾化器。Preferably, the atomizer in step B) can be a pressure atomizer, an air flow atomizer or an ultrasonic atomizer.
优选的，步骤B)所述雾化器选择超声雾化器，工作参数为：Preferably, the atomizer in step B) is an ultrasonic atomizer, and the working parameters are:
进料速率为1～20mL/min，雾化器工作频率为80～160kHz。The feed rate is 1~20mL/min, and the working frequency of the atomizer is 80~160kHz.
优选的，步骤C)冷冻具体为在喷雾冷冻塔中进行冷冻，所述冷冻的参数具体为：塔壁面温度为-30℃～-50℃，塔内顺流冷风温度为-30℃～-50℃，冷风流量为0～500L/min。Preferably, step C) freezing is specifically carried out in a spray freezing tower. The freezing parameters are specifically: the tower wall temperature is -30°C ~ -50°C, and the temperature of the downstream cold air in the tower is -30°C ~ -50°C. ℃, the cold air flow rate is 0~500L/min.
优选的，所述真空冷冻干燥的时间为24～72h。Preferably, the vacuum freeze-drying time is 24 to 72 hours.
优选的，所述颗粒的载药量大于60％、中值几何粒径(D50)为25μm～50μm；且振实密度为0.005g/cm3～0.030g/cm3，质量中值空气动力学直径为3～5μm；组合物的基本流动能(BFE)为2～9mJ。Preferably, the drug loading capacity of the particles is greater than 60%, the median geometric particle diameter (D 50 ) is 25 μm ~ 50 μm; the tap density is 0.005g/cm 3 ~ 0.030g/cm 3 , and the mass median aerodynamic force is The chemical diameter is 3 to 5 μm; the basic flow energy (BFE) of the composition is 2 to 9 mJ.
本发明提供了一种用于肺部递送的盐酸环丙沙星组合物微粒，由上述技术方案任意一项所述的制备方法制备得到。The invention provides ciprofloxacin hydrochloride composition particles for pulmonary delivery, which are prepared by the preparation method described in any of the above technical solutions.
本发明提供了上述任意一项所述的制备方法制备得到的盐酸环丙沙星组合物微粒在制备肺部递送产品中的应用。The present invention provides the use of ciprofloxacin hydrochloride composition particles prepared by any one of the above preparation methods in the preparation of pulmonary delivery products.
本发明提供了一种肺部递送产品，包括上述技术方案所述的盐酸环丙沙星组合物微粒。The present invention provides a pulmonary delivery product, including the ciprofloxacin hydrochloride composition particles described in the above technical solution.
与现有技术相比，本发明提供了一种用于肺部递送的盐酸环丙沙星组合物微粒的制备方法，包括：A)盐酸环丙沙星和赋形剂溶解，得到前驱液；B)前驱液经雾化喷雾，得到液滴；C)液滴经冷冻，得到冰球；将所述冰球真空冷冻干燥，即得微粒；所述微粒的中值几何粒径(D50)大于25μm。本发明采用喷雾冷冻结合真空冷冻干燥技术，通过调控前驱液配方及工艺参数，制备具有优良分散性、优良的气溶胶性能和物理稳定性 的盐酸环丙沙星药物组合物微粒。本发明提供用于肺部给药的盐酸环丙沙星药物组合物微粒及其制备方法，所述微粒的载药量大于60％、中值几何粒径(D50)大于25μm且振实密度小于0.030g/cm3，质量中值空气动力学直径为3～5μm。Compared with the prior art, the present invention provides a method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery, which includes: A) dissolving ciprofloxacin hydrochloride and excipients to obtain a precursor liquid; B) The precursor liquid is atomized and sprayed to obtain liquid droplets; C) The liquid droplets are frozen to obtain ice balls; the ice balls are vacuum freeze-dried to obtain microparticles; the median geometric diameter (D50) of the microparticles is greater than 25 μm. The present invention adopts spray freezing combined with vacuum freeze-drying technology, and regulates the precursor liquid formula and process parameters to prepare an aerosol with excellent dispersion, excellent aerosol performance and physical stability. Ciprofloxacin hydrochloride pharmaceutical composition particles. The present invention provides ciprofloxacin hydrochloride pharmaceutical composition microparticles for pulmonary administration and a preparation method thereof. The drug loading capacity of the microparticles is greater than 60%, the median geometric particle diameter (D50) is greater than 25 μm, and the tap density is less than 0.030g/cm 3 , the mass median aerodynamic diameter is 3~5μm.
附图说明Description of drawings
图1是原材料盐酸环丙沙星一水合物的扫描电子显微镜图；Figure 1 is a scanning electron microscope image of the raw material ciprofloxacin hydrochloride monohydrate;
图2是原材料盐酸环丙沙星一水合物(a)和L-亮氨酸(b)的X-射线衍射图；Figure 2 is the X-ray diffraction pattern of the raw materials ciprofloxacin hydrochloride monohydrate (a) and L-leucine (b);
图3是冷冻温度为-40℃、固含量为2wt％和药辅比为5:5粉末的扫描电子显微镜图；Figure 3 is a scanning electron microscope image of a powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 5:5;
图4是冷冻温度为-40℃、固含量为2wt％和药辅比为5:5粉末的X-射线衍射图；Figure 4 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 5:5;
图5是冷冻温度为-40℃、固含量为2wt％和药辅比为7:3粉末的扫描电子显微镜图；Figure 5 is a scanning electron microscope image of a powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 7:3;
图6是冷冻温度为-40℃、固含量为2wt％和药辅比为7:3粉末的X-射线衍射图；Figure 6 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 7:3;
图7是冷冻温度为-40℃、固含量为1wt％和药辅比为5:5粉末的扫描电子显微镜图；Figure 7 is a scanning electron microscope image of a powder with a freezing temperature of -40°C, a solid content of 1wt%, and a drug-to-excipient ratio of 5:5;
图8是冷冻温度为-40℃、固含量为1wt％和药辅比为5:5粉末的X-射线衍射图；Figure 8 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 1wt%, and a drug-to-adjuvant ratio of 5:5;
图9是冷冻温度为-40℃、固含量为2wt％和药辅比为3:7粉末的扫描电子显微镜图。Figure 9 is a scanning electron microscope image of the powder with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-adjuvant ratio of 3:7.
图10是冷冻温度为-40℃、固含量为2wt％和药辅比为3::7粉末的X-射线衍射图；Figure 10 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 3::7;
图11是冷冻温度为-40℃、固含量为2wt％和药辅比为9:1粉末的扫描电子显微镜图；Figure 11 is a scanning electron microscope image of a powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 9:1;
图12是冷冻温度为-40℃、固含量为2wt％和药辅比为9:1粉末的X-射线衍射图；Figure 12 is an X-ray diffraction pattern of powder with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 9:1;
图13是冷冻温度为-60℃、固含量为2wt％和药辅比为5:5粉末的扫 描电子显微镜图；Figure 13 is a scan of the powder with a freezing temperature of -60°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5. trace electron micrograph;
图14是冷冻温度为-60℃、固含量为2wt％和药辅比为5:5粉末的X-射线衍射图；Figure 14 is an X-ray diffraction pattern of powder with a freezing temperature of -60°C, a solid content of 2wt% and a drug-to-adjuvant ratio of 5:5;
图15是冷冻温度为-80℃、固含量为2wt％和药辅比为5:5粉末的扫描电子显微镜图；Figure 15 is a scanning electron microscope image of a powder with a freezing temperature of -80°C, a solid content of 2wt%, and a drug-to-adjuvant ratio of 5:5;
图16是冷冻温度为-80℃、固含量为2wt％和药辅比为5:5粉末的X-射线衍射图。Figure 16 is the X-ray diffraction pattern of the powder with a freezing temperature of -80°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5.
具体实施方式Detailed ways
本发明提供了一种用于肺部递送的盐酸环丙沙星组合物微粒、其制备方法和应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都属于本发明保护的范围。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。The present invention provides a ciprofloxacin hydrochloride composition microparticle for pulmonary delivery, its preparation method and application. Those skilled in the art can learn from the content of this article and appropriately improve the process parameters for implementation. It should be pointed out in particular that all similar substitutions and modifications are obvious to those skilled in the art, and they all fall within the protection scope of the present invention. The methods and applications of the present invention have been described through preferred embodiments. Relevant persons can obviously modify or appropriately change and combine the methods and applications herein without departing from the content, spirit and scope of the present invention to implement and apply the present invention. Invent technology.
本发明涉及组合物以及制备方法，特别用于囊性纤维化(CF)、非-CF支气管扩张和结核病急性恶化的治疗。The present invention relates to compositions and methods of preparation, particularly for the treatment of acute exacerbations of cystic fibrosis (CF), non-CF bronchiectasis and tuberculosis.
本发明提供了一种用于肺部递送的盐酸环丙沙星组合物微粒的制备方法，包括：The invention provides a method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery, including:
A)盐酸环丙沙星和赋形剂溶解，得到前驱液；A) Dissolve ciprofloxacin hydrochloride and excipients to obtain a precursor solution;
B)前驱液经雾化喷雾，得到液滴；B) The precursor liquid is atomized and sprayed to obtain droplets;
C)液滴经冷冻，得到冰球；将所述冰球真空冷冻干燥，即得微粒；所述微粒的中值几何粒径(D50)大于25μm。C) The liquid droplets are frozen to obtain ice balls; the ice balls are vacuum freeze-dried to obtain microparticles; the median geometric diameter (D50) of the microparticles is greater than 25 μm.
本发明提供的用于肺部递送的盐酸环丙沙星组合物微粒的制备方法首先将盐酸环丙沙星和赋形剂溶解，得到前驱液。The method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery provided by the present invention first dissolves ciprofloxacin hydrochloride and excipients to obtain a precursor liquid.
本发明所述赋形剂为亮氨酸。本发明对于所述溶解不进行限定，本领域技术人员熟知的即可。The excipient of the present invention is leucine. The present invention does not limit the dissolution, as it is well known to those skilled in the art.
本发明所述前驱液中，盐酸环丙沙星和赋形剂的质量比为5:5～8:2；包括但不限于5:5、7:3、8:2、6:4；以及上述任意二者之间的点值。 In the precursor solution of the present invention, the mass ratio of ciprofloxacin hydrochloride and excipients is 5:5 to 8:2; including but not limited to 5:5, 7:3, 8:2, 6:4; and A point value between any two of the above.
具体的，所述前驱液中，盐酸环丙沙星和赋形剂的总质量浓度优选为1％～5％；包括但不限于1％、2％、3％、4％或5％；或者上述任意二者之间的点值。Specifically, in the precursor solution, the total mass concentration of ciprofloxacin hydrochloride and excipients is preferably 1% to 5%; including but not limited to 1%, 2%, 3%, 4% or 5%; or A point value between any two of the above.
前驱液经雾化喷雾，得到液滴。The precursor liquid is atomized and sprayed to obtain droplets.
本发明所述雾化优选在雾化器中进行，本发明对上述具体的雾化器不进行限定，可以是本实验室自制的，；可以是是市售的均可。The atomization of the present invention is preferably carried out in an atomizer. The present invention does not limit the above-mentioned specific atomizer. It can be homemade in this laboratory or commercially available.
本发明所述雾化器选自压力式雾化器、气流式雾化器或超声雾化器。The atomizer of the present invention is selected from a pressure atomizer, an airflow atomizer or an ultrasonic atomizer.
本发明优选将溶液置于注射器中，用超声雾化喷嘴将其雾化；所述雾化的参数为：进料速率优选为1～20mL/min，更优选为2～18mL/min，超声雾化器工作频率优选为80～160kHz；更优选为85～150kHz。In the present invention, the solution is preferably placed in a syringe and atomized with an ultrasonic atomizing nozzle; the parameters of the atomization are: the feed rate is preferably 1 to 20 mL/min, and more preferably 2 to 18 mL/min. The operating frequency of the converter is preferably 80 to 160 kHz; more preferably, it is 85 to 150 kHz.
本发明所述液滴的尺寸优选为2-50μm。The size of the droplets of the present invention is preferably 2-50 μm.
液滴经冷冻，得到冰球。The droplets are frozen to obtain ice balls.
本发明冷冻具体为在喷雾冷冻塔中进行冷冻，所述冷冻的参数优选具体为：塔壁面温度为-30℃～-50℃，塔内顺流冷风温度为-30℃～-50℃，冷风流量为0～500L/min；更优选为塔壁面温度为-35℃～-45℃，塔内顺流冷风温度为-35℃～-45℃，冷风流量为10～400L/min；最优选为塔壁面温度为-40℃，塔内顺流冷风温度为-40℃，冷风流量为50～300L/min。The freezing of the present invention is specifically carried out in a spray freezing tower. The preferred freezing parameters are: the tower wall temperature is -30°C to -50°C, the downstream cold air temperature in the tower is -30°C to -50°C, and the cold air temperature is -30°C to -50°C. The flow rate is 0 to 500L/min; more preferably, the tower wall temperature is -35°C to -45°C, the downstream cold air temperature in the tower is -35°C to -45°C, and the cold air flow rate is 10 to 400L/min; the most preferred is The tower wall temperature is -40℃, the downstream cold air temperature in the tower is -40℃, and the cold air flow rate is 50~300L/min.
本发明的喷雾冷冻装置可以为市售或者自制，优选可以采用201610133187.1和201610202235.8公开的。The spray freezing device of the present invention can be commercially available or homemade, preferably the ones disclosed in 201610133187.1 and 201610202235.8 can be used.
本发明通过上述冷冻条件的控制，可以得到不同结晶度的产品。By controlling the above-mentioned freezing conditions, the present invention can obtain products with different degrees of crystallinity.
塔底用喷冷专用盘收集冰球。A special tray for spray cooling is used to collect ice balls at the bottom of the tower.
将所述冰球真空冷冻干燥，即得微粒；所述真空冷冻干燥的时间优选为24～72h；更优选为36～72h；最优选为40～72h。The ice balls are vacuum freeze-dried to obtain microparticles; the vacuum freeze-drying time is preferably 24 to 72 hours; more preferably, it is 36 to 72 hours; most preferably, it is 40 to 72 hours.
本发明通过上述冷冻的参数、真空冷冻干燥的参数、盐酸环丙沙星和赋形剂的总质量浓度范围，以及药辅比等参数上述组分上相互作用，功能上彼此相互支持，存在相互关系的技术特征，上述整体的方案才能使得制备得到特定范围内，尺寸可控的微粒，才能达到本发明的技术效果。The present invention interacts with each other through the above-mentioned freezing parameters, vacuum freeze-drying parameters, the total mass concentration range of ciprofloxacin hydrochloride and excipients, and drug-adjuvant ratios, and supports each other functionally, and there is mutual interaction. Only by the relevant technical features and the above overall solution can the particles with controllable size within a specific range be prepared and the technical effects of the present invention be achieved.
本发明通过上述冷冻的温度区间(-30到-50℃)结合相对常规的组合物，相比于其他的温度区间，能创造出更意想不到的气溶胶性能。 By combining the above-mentioned frozen temperature range (-30 to -50°C) with relatively conventional compositions, the present invention can create more unexpected aerosol properties compared to other temperature ranges.
进一步的，本发明通过喷雾冷冻结合真空冷冻干燥技术，尤其是喷雾冷冻过程的冷冻温度控制，传统的喷雾冷冻过程是使用液氮作为致冷剂固化液滴(即冷冻温度为固定的液氮冰点温度-196℃)，而本专利中通过控制-30～50℃作为冷冻温度，一方面能够突破技术上温度可控的优势，同时在该温度区间对处方制剂具有优良的气溶胶等性能。Further, the present invention combines spray freezing with vacuum freeze-drying technology, especially the freezing temperature control of the spray freezing process. The traditional spray freezing process uses liquid nitrogen as the refrigerant to solidify the droplets (that is, the freezing temperature is a fixed freezing point of liquid nitrogen). Temperature -196°C), and in this patent, by controlling -30 to 50°C as the freezing temperature, on the one hand, it can break through the advantage of technically controllable temperature, and at the same time, it has excellent aerosol and other properties for prescription preparations in this temperature range.
本发明采用喷雾冷冻塔结合真空冷冻干燥技术，利用冰晶作为致孔模板，避免了传统有机造孔剂的使用，通过整体上协同调控前驱液配方以及冷冻温度等工艺参数，从而控制颗粒的结构属性，优化得到具有良好分散性，优良的气溶胶性能和物理稳定性的盐酸环丙沙星药物组合物微粒，The present invention uses a spray freezing tower combined with vacuum freeze-drying technology, uses ice crystals as pore-forming templates, avoids the use of traditional organic pore-forming agents, and controls the structural properties of particles by overall collaboratively regulating process parameters such as precursor liquid formula and freezing temperature. , optimized to obtain ciprofloxacin hydrochloride pharmaceutical composition particles with good dispersion, excellent aerosol performance and physical stability,
本发明所述颗粒的载药量大于60％、中值几何粒径(D50)大于25μm；优选为25μm～50μm；且振实密度为0.005g/cm3～0.030g/cm3，质量中值空气动力学直径为3～5μm；组合物的基本流动能(BFE)为2～9mJ。The drug loading capacity of the particles of the present invention is greater than 60%, the median geometric particle diameter (D 50 ) is greater than 25 μm; preferably 25 μm ~ 50 μm; and the tap density is 0.005g/cm3 ~ 0.030g/cm 3 , and the mass median The aerodynamic diameter is 3 to 5 μm; the basic flow energy (BFE) of the composition is 2 to 9 mJ.
本发明提供了一种用于肺部递送的盐酸环丙沙星组合物微粒，由上述技术方案任意一项所述的制备方法制备得到。The invention provides ciprofloxacin hydrochloride composition particles for pulmonary delivery, which are prepared by the preparation method described in any of the above technical solutions.
本发明所述组合物包含50％～80％盐酸环丙沙星药物。The composition of the present invention contains 50% to 80% ciprofloxacin hydrochloride drug.
本发明对于上述制备方法有了清楚的描述，在此不再赘述。The present invention has a clear description of the above preparation method, which will not be described in detail here.
本发明提供了上述任意一项所述的制备方法制备得到的盐酸环丙沙星组合物微粒在制备肺部递送产品中的应用。The present invention provides the use of ciprofloxacin hydrochloride composition particles prepared by any one of the above preparation methods in the preparation of pulmonary delivery products.
本发明上述方法制备得到的微粒可以用于制备肺部递送产品，包括但不限于肺部递送药物。本发明人对此不进行限定。The microparticles prepared by the above method of the present invention can be used to prepare pulmonary delivery products, including but not limited to pulmonary delivery drugs. The inventor does not limit this.
本发明提供了一种肺部递送产品，包括上述技术方案所述的盐酸环丙沙星组合物微粒。The present invention provides a pulmonary delivery product, including the ciprofloxacin hydrochloride composition particles described in the above technical solution.
本发明提供的上述肺部递送产品包括上述盐酸环丙沙星组合物微粒。还可以包括药学上可以接受的配料，在此不进行限定。The above-mentioned pulmonary delivery product provided by the present invention includes the above-mentioned ciprofloxacin hydrochloride composition particles. It may also include pharmaceutically acceptable ingredients, which are not limited here.
本发明提供了一种肺部递送药物制剂，包括上述技术方案所述的盐酸环丙沙星组合物微粒。The present invention provides a pharmaceutical preparation for pulmonary delivery, including the ciprofloxacin hydrochloride composition particles described in the above technical solution.
本发明包含盐酸环丙沙星的肺部递送的药物制剂，它是可以有效递送到肺部的形式。肺部给药的组合物包含含有氟喹诺酮水溶性盐类，为盐酸环丙沙星。 The present invention encompasses a pharmaceutical formulation for pulmonary delivery of ciprofloxacin hydrochloride in a form that can be effectively delivered to the lungs. Compositions for pulmonary administration include a water-soluble salt of a fluoroquinolone, ciprofloxacin hydrochloride.
为了进一步说明本发明，以下结合实施例对本发明提供的一种用于肺部递送的盐酸环丙沙星组合物微粒、其制备方法和应用进行详细描述。In order to further illustrate the present invention, the ciprofloxacin hydrochloride composition microparticles for pulmonary delivery provided by the present invention, its preparation method and application are described in detail below in conjunction with the examples.
实施例1Example 1
精密称取适量的CIP和L-亮氨酸(LEU)以一定的比例(质量比为5:5)混合，溶于一定体积的去离子水中(总固含量为2wt％)，将溶液置于注射器中，用超声雾化喷嘴将其雾化到冷冻温度为-40℃的喷雾冷冻塔，塔底用喷冷专用盘收集冰球。雾化完后将其转移到真空冻干机中冷冻干燥72h，得到粉末。Precisely weigh an appropriate amount of CIP and L-leucine (LEU) and mix them in a certain ratio (mass ratio 5:5), dissolve in a certain volume of deionized water (total solid content 2wt%), and place the solution in In the syringe, use an ultrasonic atomization nozzle to atomize it into a spray freezing tower with a freezing temperature of -40°C. A special spray cooling plate is used to collect the ice balls at the bottom of the tower. After atomization, it was transferred to a vacuum freeze-dryer and freeze-dried for 72 hours to obtain powder.
用扫描电子显微镜(SEM)来定性评估喷雾冷冻干燥颗粒的形态。将适量样品附着在贴有双面导电胶的样品底座上，注意不按压样品，尽量保持制剂形态原始且完整。用离子溅射锻膜法以Pt/Pd为靶材样品表面镀膜。然后将样品放入扫描电子显微镜真空仓中观察，EHT电压为15kV。原材料盐酸环丙沙星特点是长块状的，表面较光滑晶体(图1)；并且原材料盐酸环丙沙星(水合结晶形态，图2a)和亮氨酸为高度结晶(图2b)。而喷雾冷冻干燥的CIP颗粒为球形，多孔(图3)并且药物为水合晶型形态(图4)。Scanning electron microscopy (SEM) was used to qualitatively evaluate the morphology of spray freeze-dried particles. Attach an appropriate amount of sample to the sample base with double-sided conductive adhesive. Be careful not to press the sample and try to keep the preparation form original and complete. The surface of the sample was coated using the ion sputtering film forging method with Pt/Pd as the target material. The sample was then placed into a scanning electron microscope vacuum chamber for observation, and the EHT voltage was 15kV. The raw material ciprofloxacin hydrochloride is characterized by long block crystals with a smooth surface (Figure 1); and the raw materials ciprofloxacin hydrochloride (hydrated crystal form, Figure 2a) and leucine are highly crystalline (Figure 2b). The spray freeze-dried CIP particles are spherical and porous (Figure 3) and the drug is in the hydrated crystalline form (Figure 4).
粉末X-射线衍射(XRPD)用来鉴定物质的晶型，如晶体物质常呈现出锐锋，而非晶形药物则表现出弥散峰。样品测定条件：加速电压为30kV，电流为10mA，衍射角范围2θ为2°至40°，步长为0.02°，时间为0.3s。Powder X-ray diffraction (XRPD) is used to identify the crystal form of a substance. For example, crystalline substances often show sharp peaks, while amorphous drugs show diffuse peaks. Sample measurement conditions: accelerating voltage 30kV, current 10mA, diffraction angle range 2θ from 2° to 40°, step size 0.02°, time 0.3s.
干燥损失化(LOD)是指待测物在规定条件下，经干燥至恒重后所损失的任何易挥发物质的重量，以百分率表示，用于考察样品中的水分。其过程为，取玻璃容器并称量其重量m0，再精密称取一定量的新制备的样品于玻璃容器中，轻摇样品至均分分散在瓶中，记录其总重量m1。一个样品平行做三份。然后将样品放入温度为105℃的烘箱中干燥3h，然后在干燥箱中冷却至室温。精密称定干燥后样品与玻璃容器总重量m2，最后进行计算其含水量。Loss on drying (LOD) refers to the weight of any volatile substance lost after the object to be tested is dried to constant weight under specified conditions. It is expressed as a percentage and is used to examine the moisture in the sample. The process is to take a glass container and weigh its weight m0, then accurately weigh a certain amount of the newly prepared sample in the glass container, shake the sample gently until it is evenly dispersed in the bottle, and record its total weight m1. A sample was prepared in triplicate. The samples were then dried in an oven at a temperature of 105°C for 3 h, and then cooled to room temperature in the drying oven. Accurately weigh the total weight m2 of the dried sample and glass container, and finally calculate its moisture content.
药物的引湿性是指在一定温度及湿度条件下该物质吸收水分能力或程度的特性。其过程为，取干燥的玻璃瓶于实验前一天置于底部放饱和硫酸铵饱和溶液(80±2％)的干燥器，再置于设定为25±1℃的烘箱，精密 称定玻璃瓶重量m1，取适量样品于玻璃瓶，精密称定重量m2。接着，于上述恒温恒湿条件下24h，精密称定重量m3。最后计算得到引湿增重率。引湿增重率>15％，为极具引湿性；2％≤引湿增重率≤15％，为有引湿性；0.2％≤引湿增重率≤2％，为略有引湿性；引湿增重率<0.2％，为无或几乎无引湿性。The hygroscopicity of a drug refers to the ability or degree of moisture absorption of a substance under certain temperature and humidity conditions. The process is as follows: take the dried glass bottle and place it in a desiccator with a saturated ammonium sulfate solution (80±2%) at the bottom the day before the experiment, and then place it in an oven set at 25±1°C. Determine the weight of the glass bottle m1, take an appropriate amount of sample into the glass bottle, and accurately weigh the weight m2. Then, under the above constant temperature and humidity conditions for 24 hours, accurately weigh the weight m3. Finally, the weight gain rate due to moisture induction was calculated. If the moisture attraction weight gain rate is >15%, it is highly hygroscopic; if 2% ≤ moisture attraction weight gain ≤ 15%, it is hygroscopic; if 0.2% ≤ moisture attraction weight gain ≤ 2%, it is slightly hygroscopic; The moisture absorption weight gain rate is <0.2%, indicating no or almost no moisture absorption.
激光粒度仪(Sympatec，Germany)是根据颗粒能使激光产生衍射这一物理现象测试粒度分布的。采用干粉模式，选用R3镜头，设置好采集时间和分散压力，控制测量浓度。采用吸入器在60L/min流速下进行雾化，吸入时间为4s。A laser particle size analyzer (Sympatec, Germany) measures particle size distribution based on the physical phenomenon that particles can diffract laser light. Use dry powder mode, use R3 lens, set the collection time and dispersion pressure, and control the measurement concentration. use The inhaler atomizes at a flow rate of 60L/min, and the inhalation time is 4 seconds.
冷冻温度为-40℃、固含量为2wt％和药辅比为5:5粉末的物理性质列于表1。The physical properties of the powder with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5 are listed in Table 1.
表1：冷冻温度为-40℃、固含量为2wt％和药辅比为5:5粉末的物理性质
Table 1: Physical properties of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5
制备的CIP粉末，填装到3个吸入级干净3号羟丙基甲基纤维素(HPMC)胶囊中，药粉总质量约4±0.5mg，再用Breezhaler吸入器递送，采用新一代级联撞击器(NGI)来测定粉末的气溶胶性能，在60L/min流速下进行雾化，吸入时间为4s。其雾化特性如表2所示。最后，采用紫外分光光度法(UV)测定盐酸环丙沙星的含量。有效药物沉积(％)是 指保持相同的灌装量，根据FPF值和载药量，细颗粒药物(空气动力学直径<5μm)占总药物量的百分比。The prepared CIP powder is filled into three inhalation-grade clean No. 3 hydroxypropyl methylcellulose (HPMC) capsules. The total mass of the powder is about 4±0.5mg, and then delivered using a Breezhaler inhaler, using a new generation of cascade impaction. The aerosol performance of the powder was measured using an NGI instrument. The powder was atomized at a flow rate of 60L/min and the inhalation time was 4 seconds. Its atomization characteristics are shown in Table 2. Finally, ultraviolet spectrophotometry (UV) was used to determine the content of ciprofloxacin hydrochloride. Effective drug deposition (%) is Refers to maintaining the same filling volume, based on the FPF value and drug loading capacity, the percentage of fine particle drugs (aerodynamic diameter <5 μm) in the total drug volume.
表2：冷冻温度为-40℃、固含量为2wt％和药辅比为5:5粉末的雾化特性
Table 2: Atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 5:5
该实施例有着优良的雾化性能，在本发明的优选范围内。This embodiment has excellent atomization performance and is within the preferred range of the present invention.
实施例2Example 2
精密称取适量的CIP和LEU以一定的比例(质量比为7:3)混合，溶于一定体积的去离子水中(总固含量为2wt％)，将溶液置于注射器中，用超声雾化喷嘴将其雾化到冷冻温度为-40℃的喷雾冷冻塔，塔底用喷冷专用盘收集冰球。雾化完后将其转移到真空冻干机中冷冻干燥72h，得到粉末。粉末的整体相貌图和晶型图分别如图5和图6所示。Precisely weigh an appropriate amount of CIP and LEU and mix them in a certain ratio (mass ratio 7:3), dissolve in a certain volume of deionized water (total solid content 2wt%), place the solution in a syringe, and use ultrasonic atomization The nozzle atomizes it to the spray freezing tower with a freezing temperature of -40°C, and a special spray cooling plate is used to collect the ice balls at the bottom of the tower. After atomization, it was transferred to a vacuum freeze-dryer and freeze-dried for 72 hours to obtain powder. The overall phase diagram and crystal form diagram of the powder are shown in Figure 5 and Figure 6 respectively.
冷冻温度为-40℃、固含量为2wt％和药辅比为7:3粉末的物理性质和雾化特性分别列于表3和表4。The physical properties and atomization characteristics of the powder with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 7:3 are listed in Table 3 and Table 4 respectively.
表3：冷冻温度为-40℃、固含量为2wt％和药辅比为7:3粉末的物理性质
Table 3: Physical properties of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 7:3
表4：冷冻温度为-40℃、固含量为2wt％和药辅比为7:3粉末的雾化特性

Table 4: Atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 7:3

该实施例有着优良的雾化性能，在本发明的优选范围内。This embodiment has excellent atomization performance and is within the preferred range of the present invention.
实施例3Example 3
精密称取适量的CIP和LEU以一定的比例(质量比为5:5)混合，溶于一定体积的去离子水中(总固含量为1wt％)，将溶液置于注射器中，用超声雾化喷嘴将其雾化到冷冻温度为-40℃的喷雾冷冻塔，塔底用喷冷专用盘收集冰球。雾化完后将其转移到真空冻干机中冷冻干燥72h，得到粉末。粉末的整体相貌图和晶型图分别如图7和图8所示。Precisely weigh an appropriate amount of CIP and LEU and mix them in a certain ratio (mass ratio 5:5), dissolve in a certain volume of deionized water (total solid content 1wt%), place the solution in a syringe, and use ultrasonic atomization The nozzle atomizes it to the spray freezing tower with a freezing temperature of -40°C, and a special spray cooling plate is used to collect the ice balls at the bottom of the tower. After atomization, it was transferred to a vacuum freeze-dryer and freeze-dried for 72 hours to obtain powder. The overall phase diagram and crystal form diagram of the powder are shown in Figures 7 and 8 respectively.
冷冻温度为-40℃、固含量为1wt％和药辅比为5:5粉末的物理性质和雾化特性分别列于表5和表6。The physical properties and atomization characteristics of the powder with a freezing temperature of -40°C, a solid content of 1wt% and a drug-to-excipient ratio of 5:5 are listed in Table 5 and Table 6 respectively.
表5：冷冻温度为-40℃、固含量为1wt％和药辅比为5:5粉末的物理 性质
Table 5: Physics of powders with a freezing temperature of -40°C, a solid content of 1wt% and a drug-to-excipient ratio of 5:5 nature
表6：冷冻温度为-40℃，固含量为1wt％和药辅比为5:5粉末的雾化特性

Table 6: Atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 1wt% and a drug-to-excipient ratio of 5:5

该实施例有着优良的雾化性能，在本发明的优选范围内。This embodiment has excellent atomization performance and is within the preferred range of the present invention.
对比例1Comparative example 1
精密称取适量的CIP和LEU以一定的比例(质量比为3:7或9:1)混合，溶于一定体积的去离子水中(总固含量为2wt％)，将溶液置于注射器中，用超声雾化喷嘴将其雾化到冷冻温度为-40℃的喷雾冷冻塔，塔底用喷冷专用盘收集冰球。雾化完后将其转移到真空冻干机中冷冻干燥72h，得到粉末。药辅比为3:7的粉末整体相貌图和晶型图分别如图9和图10所示；药辅比为9:1的粉末整体相貌图和晶型图分别如图11和图12所示；并将其与实施例1和实施2进行对比。Precisely weigh an appropriate amount of CIP and LEU and mix them in a certain ratio (mass ratio is 3:7 or 9:1), dissolve in a certain volume of deionized water (total solid content is 2wt%), and place the solution in a syringe. Use an ultrasonic atomization nozzle to atomize it into a spray freezing tower with a freezing temperature of -40°C. A special spray cooling plate is used to collect the ice balls at the bottom of the tower. After atomization, it was transferred to a vacuum freeze-dryer and freeze-dried for 72 hours to obtain powder. The overall phase diagram and crystal form diagram of the powder with a drug-to-adjuvant ratio of 3:7 are shown in Figures 9 and 10 respectively; the overall phase diagram and crystal form diagram of the powder with a drug-to-adjuvant ratio of 9:1 are shown in Figures 11 and 12 respectively. shown; and compare it with Example 1 and Implementation 2.
冷冻温度为-40℃、固含量为2wt％和药辅比为3:7或9:1粉末的物理性质和雾化特性分别列于表7和表8。The physical properties and atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-excipient ratio of 3:7 or 9:1 are listed in Table 7 and Table 8, respectively.
表7：冷冻温度为-40℃、固含量为2wt％和药辅比为3:7或9:1粉末的物理性质

Table 7: Physical properties of powders with a freezing temperature of -40°C, a solid content of 2wt% and a drug-to-excipient ratio of 3:7 or 9:1

表8：冷冻温度为-40℃、固含量为2wt％和药辅比为3:7或9:1粉末的雾化特性

Table 8: Atomization characteristics of powders with a freezing temperature of -40°C, a solid content of 2wt%, and a drug-to-excipient ratio of 3:7 or 9:1

CIP含量越多，FPF显著降低，而10％LEU不足以提高粉末的雾化性质；提高LEU含量至70％可显著提高微粒的气溶胶性能，然而其载药量低，在发射相同质量粉体的情况下，有效药物沉积率远不及LEU含量为50％的样品，因此药辅比为(5:5)-(8:2)粉末在本发明的优选范围内。The higher the CIP content, the FPF is significantly reduced, and 10% LEU is not enough to improve the atomization properties of the powder; increasing the LEU content to 70% can significantly improve the aerosol performance of the particles, but its drug loading is low. In the case of , the effective drug deposition rate is far lower than that of the sample with a LEU content of 50%, so the powder with a drug-adjuvant ratio of (5:5)-(8:2) is within the preferred range of the present invention.
对比例2Comparative example 2
精密称取适量的CIP和LEU以一定的比例(质量比为5:5)混合，溶于一定体积的去离子水中(总固含量为2wt％)，将溶液置于注射器中，用超声雾化喷嘴将其雾化到冷冻温度为-60或-80℃的喷雾冷Precisely weigh an appropriate amount of CIP and LEU and mix them in a certain ratio (mass ratio 5:5), dissolve in a certain volume of deionized water (total solid content 2wt%), place the solution in a syringe, and use ultrasonic atomization The nozzle atomizes it to a spray cooling temperature of -60 or -80°C.
冻塔，塔底用喷冷专用盘收集冰球。雾化完后将其转移到真空冻干机中冷冻干燥72h，得到粉末。冷冻温度为-60℃的粉末整体相貌图和晶型图分别如图13和图14所示；冷冻温度为-80℃的粉末整体相貌图和晶型图分别如图15和图16所示；并将其与实施例1进行对比。Freeze tower, use special spray cooling tray to collect ice balls at the bottom of the tower. After atomization, it was transferred to a vacuum freeze-dryer and freeze-dried for 72 hours to obtain powder. The overall phase diagram and crystal form diagram of the powder frozen at -60°C are shown in Figures 13 and 14 respectively; the overall phase diagram and crystal form diagram of the powder frozen at -80°C are shown in Figures 15 and 16 respectively; And compare it with Example 1.
冷冻温度为-60或-80℃、固含量为2wt％和药辅比为5:5粉末的物理性质和雾化特性分别列于表9和表10。The physical properties and atomization characteristics of powders with a freezing temperature of -60 or -80°C, a solid content of 2wt%, and a drug-to-excipient ratio of 5:5 are listed in Table 9 and Table 10, respectively.
表9：冷冻温度为-60或-80℃、固含量为2wt％和药辅比为5:5粉末的物理性质

Table 9: Physical properties of powders with freezing temperature of -60 or -80°C, solid content of 2wt% and drug-to-excipient ratio of 5:5

表10：冷冻温度为-60或-80℃、固含量为2wt％和药辅比为5:5粉末的雾化特性

Table 10: Atomization characteristics of powders with freezing temperature of -60 or -80°C, solid content of 2wt% and drug-to-adjuvant ratio of 5:5

冷冻温度对FPF值有着显著的影响，冷冻温度越低，FPF值越低。所以冷冻温度为-30～-50℃粉末在本发明的优选范围内。Freezing temperature has a significant impact on the FPF value. The lower the freezing temperature, the lower the FPF value. Therefore, the powder with a freezing temperature of -30 to -50°C is within the preferred range of the present invention.
本发明利用冰晶作为致孔模板，避免了传统有机造孔剂的使用，直接制备出几何粒径较大的低密度多孔颗粒，降低团聚，提高雾化效率，FPF值达50％。The present invention uses ice crystals as pore-forming templates, avoids the use of traditional organic pore-forming agents, and directly prepares low-density porous particles with larger geometric particle sizes, reducing agglomeration, improving atomization efficiency, and achieving an FPF value of 50%.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。 The above are only preferred embodiments of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principles of the present invention. These improvements and modifications can also be made. should be regarded as the protection scope of the present invention.

Claims (10)

  1. 一种用于肺部递送的盐酸环丙沙星组合物微粒的制备方法，其特征在于，包括：A method for preparing ciprofloxacin hydrochloride composition particles for pulmonary delivery, which is characterized by including:
    A)盐酸环丙沙星和赋形剂溶解，得到前驱液；A) Dissolve ciprofloxacin hydrochloride and excipients to obtain a precursor solution;
    B)前驱液经雾化喷雾，得到液滴；B) The precursor liquid is atomized and sprayed to obtain droplets;
    C)液滴经冷冻，得到冰球；将所述冰球真空冷冻干燥，即得微粒；所述微粒的中值几何粒径(D50)大于25μm。C) The liquid droplets are frozen to obtain ice balls; the ice balls are vacuum freeze-dried to obtain microparticles; the median geometric diameter (D50) of the microparticles is greater than 25 μm.
  2. 根据权利要求1所述的制备方法，其特征在于，步骤A)所述赋形剂为亮氨酸。The preparation method according to claim 1, characterized in that the excipient in step A) is leucine.
  3. 根据权利要求1所述的制备方法，其特征在于，步骤A)所述前驱液中，盐酸环丙沙星和赋形剂的质量比为5:5～8:2；所述前驱液中，盐酸环丙沙星和赋形剂的总质量浓度为1％～5％。The preparation method according to claim 1, characterized in that, in the precursor liquid of step A), the mass ratio of ciprofloxacin hydrochloride and excipient is 5:5~8:2; in the precursor liquid, The total mass concentration of ciprofloxacin hydrochloride and excipients is 1% to 5%.
  4. 根据权利要求1所述的制备方法，其特征在于，步骤B)所述雾化采用压力式雾化器、气流式雾化器或超声雾化器中的一种；所述雾化的参数为：The preparation method according to claim 1, characterized in that the atomization in step B) adopts one of a pressure atomizer, an airflow atomizer or an ultrasonic atomizer; the parameters of the atomization are: :
    进料速率为1～20mL/min，雾化器工作频率为80～160kHz。The feed rate is 1~20mL/min, and the working frequency of the atomizer is 80~160kHz.
  5. 根据权利要求1所述的制备方法，其特征在于，步骤C)冷冻具体为在喷雾冷冻塔中进行冷冻，所述冷冻的参数具体为：塔壁面温度为-30℃～-50℃，塔内顺流冷风温度为-30℃～-50℃，冷风流量为0～500L/min。The preparation method according to claim 1, characterized in that step C) freezing is specifically freezing in a spray freezing tower, and the freezing parameters are specifically: the tower wall surface temperature is -30°C ~ -50°C, and the temperature in the tower is The downstream cold air temperature is -30℃~-50℃, and the cold air flow rate is 0~500L/min.
  6. 根据权利要求1所述的制备方法，其特征在于，所述真空冷冻干燥的时间为24～72h。The preparation method according to claim 1, characterized in that the vacuum freeze-drying time is 24 to 72 hours.
  7. 根据权利要求1所述的制备方法，其特征在于，所述颗粒的载药量大于60％、中值几何粒径(D50)为25μm～50μm；且振实密度为0.005g/cm3～0.030g/cm3，质量中值空气动力学直径为3～5μm；组合物的基本流动能(BFE)为2～9mJ。The preparation method according to claim 1, characterized in that the drug loading capacity of the particles is greater than 60%, the median geometric particle diameter (D 50 ) is 25 μm ~ 50 μm; and the tap density is 0.005g/cm 3 ~ 0.030g/cm 3 , the mass median aerodynamic diameter is 3 to 5 μm; the basic flow energy (BFE) of the composition is 2 to 9 mJ.
  8. 一种用于肺部递送的盐酸环丙沙星组合物微粒，其特征在于，由权利要求1～7任意一项所述的制备方法制备得到。 A ciprofloxacin hydrochloride composition microparticle for pulmonary delivery, characterized in that it is prepared by the preparation method described in any one of claims 1 to 7.
  9. 权利要求1～8任意一项所述的制备方法制备得到的盐酸环丙沙星组合物微粒在制备肺部递送产品中的应用。Application of ciprofloxacin hydrochloride composition particles prepared by the preparation method according to any one of claims 1 to 8 in the preparation of pulmonary delivery products.
  10. 一种肺部递送产品，其特征在于，包括权利要求8所述的盐酸环丙沙星组合物微粒。 A pulmonary delivery product, characterized by comprising the ciprofloxacin hydrochloride composition particles according to claim 8.
PCT/CN2023/094666 2022-06-30 2023-05-17 Ciprofloxacin hydrochloride composition particles for lung delivery, method for preparing same, and use thereof WO2024001586A1 (en)

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