WO2024001586A1 - Particules de composition de chlorhydrate de ciprofloxacine pour administration pulmonaire, leur procédé de préparation, et leur utilisation - Google Patents

Particules de composition de chlorhydrate de ciprofloxacine pour administration pulmonaire, leur procédé de préparation, et leur utilisation Download PDF

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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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English (en)
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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    • 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 or sparfloxacin
    • 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%.

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Abstract

L'invention concerne un procédé de préparation de particules de composition de chlorhydrate de ciprofloxacine pour une administration pulmonaire, consistant : A) à dissoudre le chlorhydrate de ciprofloxacine et un excipient pour obtenir une solution de précurseur ; B) à atomiser et pulvériser la solution de précurseur pour obtenir des gouttes de liquide ; C) à congeler les gouttes de liquide pour obtenir des billes gelées ; et à effectuer une lyophilisation sous vide sur les billes gelées pour obtenir les particules, le diamètre géométrique médian (D50) des particules étant supérieur à 25 µm. Par combinaison d'une congélation par pulvérisation avec une technologie de lyophilisation sous vide, et au moyen de la régulation et du contrôle de la formule de la solution de précurseur et des paramètres de traitement, des particules de composition pharmaceutique de chlorhydrate de ciprofloxacine ayant une excellente dispersibilité, une excellente performance d'aérosol et une excellente stabilité physique sont préparées.
PCT/CN2023/094666 2022-06-30 2023-05-17 Particules de composition de chlorhydrate de ciprofloxacine pour administration pulmonaire, leur procédé de préparation, et leur utilisation WO2024001586A1 (fr)

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CN202210759590.0 2022-06-30
CN202210759590.0A CN114886861A (zh) 2022-06-30 2022-06-30 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

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CN109453145A (zh) * 2018-11-16 2019-03-12 苏州大学 一种可吸入性药物和/或药物载体颗粒的制备方法
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