Ciprofloxacin composition for inhalation as well as preparation method and application thereof

Abstract

The invention relates to a ciprofloxacin dry powder inhalation particle, the dry powder inhalation particle comprises 60-95% by weight of ciprofloxacin hydrochloride and a pharmaceutically acceptable carrier, the mass median aerodynamic diameter (MMAD) of the dry powder inhalation particle is 1-5 [mu] m, and the geometric particle size distribution is that D10 is less than or equal to 2.0 [mu] m, D50 is less than or equal to 4.5 [mu] m, and D90 is less than or equal to 8.0 [mu] m. The dry powder inhalation particle can target high-concentration deposition of a lung infection part, the bioavailability is remarkably improved, and risks of renal toxicity, ototoxicity, drug resistance and the like are reduced.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a ciprofloxacin dry powder inhalation granule, a preparation method thereof and application thereof. BACKGROUND

[0002] Ciprofloxacin (CIP) is a third-generation quinolone antibacterial drug with the chemical name of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid. The product has broad-spectrum antibacterial activity and has good inhibitory effect on various gram-positive bacteria (such as Staphylococcus, Streptococcus, Enterococcus, Bacillus, Mycobacterium, etc.) and gram-negative bacteria (such as Enterobacter, Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, Legionella, etc.). The product is widely used in the treatment of gastrointestinal infections, lower respiratory tract infections, anthrax, plague, salmonellosis, and skin, bone, joint infections, and can also be used for the treatment of prostatitis, typhoid fever and some sexually transmitted infections (such as gonorrhea, chancroid, etc.).

[0003] (Ciprofloxacin)

[0004] Ciprofloxacin has many stability problems such as photodegradation, pH sensitivity, metal chelation, thermal degradation, and strong hygroscopicity, which may affect its efficacy, safety and drug shelf life.

[0005] In the treatment of pulmonary infections, ciprofloxacin injection and oral preparations often require large doses of systemic administration, which can easily cause adverse reactions such as tendonopathy, muscle weakness, peripheral neuropathy, autonomic dysfunction, sleep disorders, cognitive and mental disorders, nephrotoxicity, ototoxicity, drug resistance, etc. Especially in the treatment of Pseudomonas aeruginosa infection, due to insufficient effective concentration of drugs in the lungs, it is easy to cause persistent infection and drug resistance problems.

[0006] Dry powder inhalation (DPI) is a kind of lung-targeted drug delivery method, which combines micronized drugs with carriers and makes the drugs deposit in the lung lesions through inhalation devices. The key to its efficacy is that the drug particles should have suitable powder characteristics to achieve efficient lung deposition.

[0007] The existing ciprofloxacin dry powder inhalation agent has the following defects: firstly, the preparation process is complex. The poorly soluble ciprofloxacin inner ammonium salt crystal is used as raw material, and the particle size needs to be reduced through micro-powdering process such as jet milling or high-pressure homogenization, and then the inhalation particles are prepared through emulsion spray drying, which has the risks of high energy consumption, low yield and degradation; secondly, the fine particle fraction (FPF) is low, and the distribution of aerodynamic diameter is uneven, which affects the lung deposition effect; thirdly, the existing preparation depends on the carrier material, which limits the drug delivery dose and makes it difficult to achieve ideal efficacy. Therefore, it is necessary to develop a safer and more efficient ciprofloxacin dry powder inhalation agent to improve the targeting and clinical effect of lung infection treatment. SUMMARY

[0008] The purpose of the present application is to provide a ciprofloxacin dry powder inhalation particle, which is composed of 60-95% ciprofloxacin hydrochloride and a pharmaceutically acceptable carrier, wherein the mass median aerodynamic diameter (MMAD) of the dry powder inhalation particle is 1-5 μm, and the geometric particle size distribution of the dry powder particle is D10≤2.0 μm, D50≤4.5 μm, and D90≤8.0 μm.

[0009] In the preferred technical scheme of the present application, the pharmaceutically acceptable carrier is any one or a combination of phospholipid, calcium chloride and perfluorooctyl bromide, wherein the phospholipid is any one or a combination of distearoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, hydrogenated soybean phospholipid, distearoyl phosphatidylglycerol and dipalmitoyl phosphatidylglycerol.

[0010] In the preferred technical scheme of the present application, the molar ratio of distearoyl phosphatidylcholine to calcium chloride in the dry powder inhalation particle is 1-5:1.

[0011] In the preferred technical scheme of the present application, the molar ratio of distearoyl phosphatidylcholine to calcium chloride in the dry powder inhalation particle is 1.2-4:1.

[0012] In the preferred technical scheme of the present application, the molar ratio of distearoyl phosphatidylcholine to calcium chloride in the dry powder inhalation particle is 1.3-3.5:1.

[0013] In the preferred technical scheme of the present application, the mass ratio of perfluorooctyl bromide to distearoyl phosphatidylcholine in the pharmaceutically acceptable carrier is 5-65:1, preferably 10-60:1.

[0014] In the preferred technical scheme of the present application, the ciprofloxacin hydrochloride in the dry powder inhalation particle accounts for 60-95%, the distearoyl phosphatidylcholine accounts for 4.5-35%, and the calcium chloride accounts for 0.1-5% by weight percentage.

[0015] In the preferred technical scheme of the present application, the dry powder inhalation granule contains 65-90% of ciprofloxacin hydrochloride, 8-32% of distearoyl phosphatidylcholine and 0.5-3% of calcium chloride.

[0016] In the preferred technical scheme of the present application, the dry powder inhalation granule contains 70-88% of ciprofloxacin hydrochloride, 10-28% of distearoyl phosphatidylcholine and 0.8-2% of calcium chloride.

[0017] In the preferred technical scheme of the present application, the mass median aerodynamic diameter (MMAD) of the dry powder inhalation granule is 2-4.5 μm.

[0018] In the preferred technical scheme of the present application, the geometric particle size distribution of the dry powder inhalation granule is D10 of 0.5 μm -1.8 μm, D50 of 2 μm -4 μm and D90 of 5 μm -8 μm.

[0019] In the preferred technical scheme of the present application, the effective deposition rate (FPF) of the dry powder inhalation granule is ≥50%, preferably ≥55% and more preferably ≥60%.

[0020] In the preferred technical scheme of the present application, the emptying rate (ER) of the dry powder inhalation granule is ≥90%, preferably ≥95%.

[0021] In the preferred technical scheme of the present application, the bulk density of the dry powder inhalation granule is ≤0.4 g / cm 3 , preferably 0.05-0.1 g / cm 3 .

[0022] In the preferred technical scheme of the present application, the moisture content of the dry powder inhalation granule is ≤10%, preferably ≤7%.

[0023] In the preferred technical scheme of the present application, the dry powder inhalation granule has a porous surface structure.

[0024] In the preferred technical scheme of the present application, the dry powder inhalation granule can be prepared into any one of a powder mist agent and a capsule.

[0025] In the preferred technical scheme of the present application, the dry powder inhalation granule is administered by any one or a combination of pulmonary inhalation administration and respiratory tract atomization administration.

[0026] In the preferred technical scheme of the present application, the dry powder inhalation granule is prepared by the following steps:

[0027] (1) under stirring condition (3000rpm-10000rpm)*(1min-10min), a prescribed amount of calcium chloride and phospholipid is added into water at 70-90℃, after high-speed shearing (3000rpm-10000rpm)*(1min-10min), a required amount of perfluorooctyl bromide (PFOB) is added into the prepared water phase, after high-speed shearing (3000rpm-10000rpm)*(1min-10min), a prescribed amount of ciprofloxacin hydrochloride is added into the prepared primary emulsion, high-pressure homogenization (300-1000bar)*(1min-10min) is carried out, and a ciprofloxacin emulsion is prepared;

[0028] (2) the prepared ciprofloxacin emulsion is subjected to spray drying, and a ciprofloxacin dry powder inhalation particle is prepared.

[0029] In the preferred technical scheme of the present application, the stirring condition is (5000rpm-8000rpm)*(2min-5min).

[0030] In the preferred technical scheme of the present application, the high-speed shearing condition is (5000rpm-8000rpm)*(2min-5min).

[0031] In the preferred technical scheme of the present application, the high-pressure homogenization condition is (500-800bar)*(2min-6min).

[0032] In the preferred technical scheme of the present application, the Z-average particle size of the ciprofloxacin emulsion is 50nm-450nm, preferably 100nm-350nm.

[0033] In the preferred technical scheme of the present application, the solid content in the ciprofloxacin emulsion is 1%-8% by mass volume percentage, preferably 1.5%-3.5%.

[0034] In the preferred technical scheme of the present application, the inlet temperature of the spray drying is 100-180℃, preferably 120-160℃, more preferably 130-150℃.

[0035] In the preferred technical scheme of the present application, the outlet temperature of the spray drying is 55-85℃, preferably 60-80℃, more preferably 65-75℃.

[0036] Another object of the present application is to provide a preparation method of a ciprofloxacin dry powder inhalation particle, the dry powder inhalation particle is composed of 60-95% of ciprofloxacin hydrochloride and a pharmaceutically acceptable carrier by weight percentage, wherein the pharmaceutically acceptable carrier is a combination of phospholipid, calcium chloride and perfluorooctyl bromide, and the preparation steps of the dry powder inhalation particle are as follows:

[0037] (1) under stirring condition (3000rpm-10000rpm)*(1min-10min), a prescribed amount of calcium chloride and phospholipid is added into water at 70-90℃, after high-speed shearing (3000rpm-10000rpm)*(1min-10min), a required amount of perfluorooctyl bromide (PFOB) is added into the prepared water phase, after high-speed shearing (3000rpm-10000rpm)*(1min-10min), a prescribed amount of ciprofloxacin hydrochloride is added into the prepared primary emulsion, high-pressure homogenization (300-1000bar)*(1min-10min) is carried out, and a ciprofloxacin emulsion is prepared;

[0038] (2) the prepared ciprofloxacin emulsion is subjected to spray drying, and a ciprofloxacin dry powder inhalation particle is prepared.

[0039] In the preferred technical scheme of the present application, the stirring condition is (5000rpm-8000rpm)*(2min-5min).

[0040] In the preferred technical scheme of the present application, the high-speed shearing condition is (5000rpm-8000rpm)*(2min-5min).

[0041] In the preferred technical scheme of the present application, the high-pressure homogenization condition is (500-800bar)*(2min-6min).

[0042] In the preferred technical scheme of the present application, the Z-average particle size of the ciprofloxacin emulsion is 50nm-450nm, preferably 100nm-350nm.

[0043] In the preferred technical scheme of the present application, the solid content in the ciprofloxacin emulsion is 1%-8% by mass volume percentage, preferably 1.5%-3.5%.

[0044] In the preferred technical scheme of the present application, the inlet temperature of the spray drying is 100-180℃, preferably 120-160℃, more preferably 130-150℃.

[0045] In the preferred technical scheme of the present application, the outlet temperature of the spray drying is 55-85℃, preferably 60-80℃, more preferably 65-75℃.

[0046] In the preferred technical scheme of the present application, the phospholipid is selected from any one or a combination of disteroyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, dilauroyl phosphatidyl choline, dimyristoyl phosphatidyl choline, hydrogenated soybean phospholipid, disteroyl phosphatidyl glycerol and dipalmitoyl phosphatidyl glycerol.

[0047] In the preferred technical scheme of the present application, the molar ratio of distearoyl phosphatidyl choline:calcium chloride in the dry powder inhalation particle is 1-5:1.

[0048] In the preferred technical scheme of the present application, the molar ratio of distearoyl phosphatidyl choline:calcium chloride in the dry powder inhalation particle is 1-5:1.

[0049] In the preferred technical scheme of the present application, the molar ratio of distearoyl phosphatidyl choline:calcium chloride in the dry powder inhalation particle is 1-5:1.

[0050] In the preferred technical scheme of the present application, the mass ratio of perfluorooctyl bromide:distearoyl phosphatidyl choline in the pharmaceutically acceptable carrier is 5-70:1, preferably 10-60:1.

[0051] In the preferred technical scheme of the present application, the dry powder inhalation particle contains 60-95% of ciprofloxacin hydrochloride, 4.5-35% of distearoyl phosphatidyl choline, and 0.1-5% of calcium chloride, in terms of weight percentage.

[0052] In the preferred technical scheme of the present application, the dry powder inhalation particle contains 65-90% of ciprofloxacin hydrochloride, 8-32% of distearoyl phosphatidyl choline, and 0.5-3% of calcium chloride.

[0053] In the preferred technical scheme of the present application, the dry powder inhalation particle contains 70-88% of ciprofloxacin hydrochloride, 10-28% of distearoyl phosphatidyl choline, and 0.8-2% of calcium chloride.

[0054] In the preferred technical scheme of the present application, the mass median aerodynamic diameter (MMAD) of the dry powder inhalation particle is 1-5 μm, and the geometric particle size distribution of the dry powder particle is D10≤2.0 μm, D50≤4.5 μm, and D90≤8.0 μm.

[0055] In the preferred technical scheme of the present application, the mass median aerodynamic diameter (MMAD) of the dry powder inhalation particle is 2-4.5 μm.

[0056] In the preferred technical scheme of the present application, the geometric particle size distribution of the dry powder inhalation particle is D10 is 0.5-1.8 μm, D50 is 2-4 μm, and D90 is 5-8 μm.

[0057] In the preferred technical scheme of the present application, the effective deposition rate (FPF) of the dry powder inhalation particle is ≥50%, preferably ≥55%, and more preferably ≥60%.

[0058] In the preferred technical scheme of the present application, the emptying rate (ER) of the dry powder inhalation particle is ≥90%, preferably ≥95%.

[0059] In a preferred technical solution of the present application, the bulk density of the dry powder inhalation particles is ≤ 0.4 g / cm 3 , preferably 0.05-0.1 g / cm 3 .

[0060] In a preferred technical solution of the present application, the moisture content of the dry powder inhalation particles is ≤ 10%, preferably ≤ 7%.

[0061] In a preferred technical solution of the present application, the dry powder inhalation particles have a surface porous structure.

[0062] In a preferred technical solution of the present application, the dry powder inhalation particles can be prepared into any one of a powder aerosol, a capsule.

[0063] In a preferred technical solution of the present application, the administration route of the dry powder inhalation particles is selected from any one or a combination of pulmonary inhalation administration, respiratory tract aerosol administration.

[0064] Another object of the present application is to provide the use of the ciprofloxacin inhalation dry powder particles and the preparation thereof in the preparation of a medicament for treating respiratory tract infection.

[0065] In a preferred technical solution of the present application, the microorganism causing respiratory tract infection is selected from any one or a combination of bacteria, chlamydia, mycoplasma, ureaplasma urealyticum.

[0066] In a preferred technical solution of the present application, the bacteria is selected from any one or a combination of enterobacteriaceae, klebsiella pneumoniae, enterobacter cloacae, escherichia coli, haemophilus, haemophilus influenzae, haemophilus parainfluenzae, proteus, pasteuria, acinetobacter, neisseria, vibrio, pseudomonas, pseudomonas aeruginosa, yersinia pestis, moraxella catarrhalis, legionella, staphylococcus, pneumococcus, streptococcus, streptococcus pneumoniae, streptococcus haemolyticus, enterococcus faecalis, mycobacterium tuberculosis, atypical mycobacterium, bacillus anthracis.

[0067] Unless otherwise specified, the detection method and terms of the present application are defined as follows:

[0068] 1. Solid: refers to the solid substance remaining after the liquid mixture is dried or volatilized at a temperature not exceeding 200℃.

[0069] 2. Geometric particle size: refers to the one-dimensional diameter defined based on the geometric size of the particle, which only reflects its geometric size. Particles usually exist in a polydisperse system, and the particle size distribution can be characterized by D10, D50, D90 (corresponding to 10%, 50%, and 90% cumulative percentage, respectively) in the cumulative distribution curve.

[0070] Detection instrument: laser diffraction particle size analyzer (new patrick HELOS-RODOS, Germany).

[0071] 3. Mass Median Aerodynamic Diameter (MMAD): refers to the mass median aerodynamic diameter of particles in a polydisperse particle population.

[0072] Detection instrument: next generation impactor (NGI).

[0073] 4. Fine Particle Fraction (FPF, also known as fine particle fraction): the mass percentage of particles with an aerodynamic diameter less than 5 μm in the total particles in the inhaled preparation, reflecting the deposition capacity of the drug in the lung.

[0074] Detection instrument: next generation impactor (NGI).

[0075] 5. Geometric Standard Deviation (GSD) of dry powder inhalation particles: an important parameter for quantifying the width of the aerodynamic diameter distribution of the particle population.

[0076] GSD is the ratio of D84% to D50% in the aerodynamic diameter distribution of particles, or the ratio of D50% to D16% (both are equal under ideal logarithmic normal distribution):

[0077] ;

[0078] Where, D 84% : the aerodynamic diameter corresponding to 84% of the cumulative distribution (i.e. the 84% percentile of the cumulative distribution); D 16% : the aerodynamic diameter corresponding to 16% of the cumulative distribution (i.e. the 16% percentile of the cumulative distribution); D 50% : mass median aerodynamic diameter (MMAD).

[0079] GSD≈1: indicates that the particle size is highly uniform (monodisperse system);

[0080] GSD>1: indicates that the particle size distribution is wide, and the larger the value, the more dispersed the distribution;

[0081] The GSD of inhalants is generally 1.5-3.0 to ensure the uniformity and repeatability of particle deposition in the lung.

[0082] 6. Emulsion Z-average: the particle diameter obtained by harmonic intensity averaging in dynamic light scattering technology.

[0083] Detection instrument: nanoparticle size potential instrument (Malvern Zetasizer Nano-ZS90, UK).

[0084] 7. Bulk density detection: weigh the 10 mL graduated cylinder mass (m1), slowly and evenly add dry powder to near full scale with a spoon, record the volume V, weigh the total mass (m2), calculate the bulk density:

[0085]

[0086] 8. The Karl Fischer method is used to detect moisture by using a Karl Fischer moisture meter (Metrohm 870 KF Titrinoplus, Switzerland).

[0087] 9. Emptying rate (ER) is used to evaluate the flowability and atomization performance of the capsule, and the calculation formula is:

[0088]

[0089] Wherein, W1 is the weight of the capsule shell, W2 is the weight of the capsule before administration, and W3 is the weight of the capsule after administration by the inhalation device and NGI.

[0090] 10. The present application adopts liquid chromatography-tandem mass spectrometry (LC-MS / MS) to detect the blood drug concentration of ciprofloxacin.

[0091] Ultra-high performance liquid chromatograph (LC-30 AD, Shimadzu, Japan) and triple quadrupole mass spectrometer (AB SCIEX Qtrap 5500, equipped with electrospray ion source).

[0092] Chromatographic column: Agilent Poroshell 120 EC-C18 (150 mm × 3.0 mm, 2.7 μm);

[0093] Mobile phase A: 5 mM ammonium acetate aqueous solution (containing 0.1% formic acid);

[0094] Mobile phase B: acetonitrile (containing 0.1% formic acid);

[0095] Diluent: 5 mM ammonium acetate aqueous solution (containing 0.1% formic acid);

[0096] Column temperature: 40℃; injector temperature: 10℃;

[0097] Injection volume: 5 μL; flow rate: 0.5 mL / min;

[0098] Gradient elution:

[0099] Time / min Mobile phase A (%) Mobile phase B (%) 0 86 14 5 70 30 6 86 14 9 86 14

[0100] The present application adopts positive ion electrospray ion source (ESI +), and detected in multiple reaction monitoring (MRM) mode. The mass spectrometry parameters of ciprofloxacin and the internal standard (levofloxacin) are as follows: declustering potential (DP) is 80 V and 162 V, respectively; collision energy (CE) is 46 eV and 40 eV, respectively. The ion source parameters are set as follows: curtain gas 20 psi, nebulizer gas 15 psi, auxiliary heater gas 60 psi, ion source temperature 500 DEG C, ion source voltage 5500 V, and collision activated dissociation setting is "Medium". The detection ion pair of ciprofloxacin is m / z 332.2→230.9, and that of levofloxacin (internal standard) is m / z 362.2→261.0.

[0101] Take 50 μL of plasma sample, standard curve working solution or quality control solution, add 50 μL of internal standard working solution (levofloxacin, 1000 ng / mL), then add 300 μL of methanol, vortex and mix, and centrifuge at 13000 r / min for 5 min. Take 5 μL of supernatant for LC-MS / MS analysis.

[0102] Unless otherwise specified, when the present application relates to the percentage between liquids, the percentage is volume / volume percentage; when the present application relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present application relates to the percentage between solids and liquids, the percentage is weight / volume percentage; and the rest is weight / weight percentage.

[0103] Compared with the prior art, the present application has the following beneficial effects:

[0104] 1. The ciprofloxacin inhalation dry powder particles of the present application are scientifically selected from ciprofloxacin hydrochloride, phospholipid, calcium chloride, perfluorooctyl bromide and their ratio, and the key quality attributes of the dry powder inhalation particles are accurately controlled, so that the mass median aerodynamic diameter (MMAD) is 1-5 μm, the geometric particle size distribution is D 10 ≤2.0 μm, D 50 ≤4.5 μm, D 90The particle size of the ciprofloxacin inhalation dry powder granules is less than 8.0 microns, and the ciprofloxacin inhalation dry powder granules are deposited in the lower respiratory tract and lung infection sites with high efficiency, so that the local targeted delivery effect and targeted drug delivery are achieved, high drug concentration is formed in the lesion area, and the action time is prolonged, the pathogen is directly killed, the lung deposition rate, drug delivery accuracy and bioavailability are significantly improved, and the systemic drug dose is effectively reduced, which is beneficial to reduce the adverse reactions such as nephrotoxicity and ototoxicity and the risk of drug resistance. The ciprofloxacin inhalation dry powder granules have excellent stability and bioavailability, significantly improve the efficacy and safety, and improve the drug compliance of patients, thereby providing an important local treatment option for lower respiratory tract chronic infections (such as cystic fibrosis combined with bronchopulmonary infection, acute exacerbation of chronic obstructive pulmonary disease, etc.) caused by pathogens such as pseudomonas aeruginosa.

[0105] 2、The preparation method of the ciprofloxacin dry powder inhalation granules of the present application omits the complex micronization treatment step, significantly improves the process reliability and yield, has the advantages of simple operation, more cost-advantageous, good industrial application prospect and the like. BRIEF DESCRIPTION OF DRAWINGS

[0106] Figure 1 The electron microscope observation result of the ciprofloxacin dry powder inhalation granules of the present application. DETAILED DESCRIPTION

[0107] The present application is described in detail by the following examples and test examples, but is only for illustrative purposes and not for limiting the scope of the present application.

[0108] Example 1 Preparation of the ciprofloxacin dry powder inhalation granules of the present application

[0109] Composition of the ciprofloxacin dry powder inhalation granules:

[0110] Component Amount (g) Cycloxydne hydrochloride 42.424 Distearoyl phosphatidylcholine 7.161 Calcium chloride 0.840

[0111] The preparation steps of the ciprofloxacin dry powder inhalation granules are as follows:

[0112] (1) Emulsion preparation: under stirring (8000 rpm) conditions, a specified amount of calcium chloride and distearoyl phosphatidylcholine were added into 70 DEG C 1.5 L pure water, after high-speed shearing for 10 minutes at 12000 rpm, 286.52 g perfluorooctyl bromide was added dropwise, and then shearing was continued at 12000 rpm for 10 minutes, a specified amount of ciprofloxacin hydrochloride was added, shearing was continued at 12000 rpm for 10 minutes again, and then high-pressure homogenization was carried out at 800 bar pressure for 6 minutes, so that an emulsion with a Z-average particle size of 140.4 ± 1.5 nm and a solid content of 3.4% (m / v) was prepared;

[0113] (2) Spray drying: the prepared emulsion is spray dried, the inlet temperature is set to 135°C, and the outlet temperature is 72°C-74°C, to prepare ciprofloxacin dry powder inhalation particles.

[0114] The scanning electron microscope results (see Figure 1 ) show that the prepared ciprofloxacin dry powder inhalation particles have uniform morphology. The prepared ciprofloxacin dry powder inhalation particles have a geometric particle size distribution of D 10 0.91 μm, D 50 2.51 μm, D 90 5.48 μm; a bulk density of 0.158 g·cm -3 ; a moisture content of 4.68%; a fine particle fraction (FPF) of 64.68%; a mass median aerodynamic diameter (MMAD) of 3.075 μm, and a geometric standard deviation (GSD) of 1.664.

[0115] Example 2 The present application also provides a preparation method of the ciprofloxacin dry powder inhalation particle capsule.

[0116] The ciprofloxacin dry powder inhalation particles prepared in Example 1 are loaded into #2 hydroxypropyl methyl cellulose capsules to prepare ciprofloxacin dry powder inhalation particle capsules.

[0117] The capsule has an emptying rate (ER) of 91.82% after testing.

[0118] Example 3 The present application also provides a preparation method of the ciprofloxacin dry powder inhalation particle.

[0119] The composition of the ciprofloxacin dry powder inhalation particles comprises:

[0120] Component Amount (mg) Cycloxydne hydrochloride 1478.66 Distearoyl phosphatidylcholine 493.56 Calcium chloride 28.90

[0121] The preparation of the ciprofloxacin dry powder inhalation particles comprises the following steps:

[0122] (1) Emulsion preparation: under stirring (8000 rpm) conditions, a specified amount of calcium chloride and distearoyl phosphatidylcholine are added to 75°C 60 mL of pure water, after high-speed shearing at 8000 rpm for 5 minutes, 5.73 g of perfluorooctyl bromide is added dropwise, and after high-speed shearing at 8000 rpm for 5 minutes, a specified amount of ciprofloxacin hydrochloride is added, and after high-speed shearing at 8000 rpm for 5 minutes, high-pressure homogenization is performed at a pressure of 800 bar for 6 minutes to prepare an emulsion with a Z-average particle size of 104.1±2.7 nm and a solid content of 3.3% (m / v);

[0123] (2) Spray drying: the prepared emulsion is spray dried, the inlet temperature is set to 135°C, and the outlet temperature is 68°C-70°C, to prepare ciprofloxacin dry powder inhalation particles.

[0124] The geometric particle size distribution of the ciprofloxacin dry powder inhalation particles prepared was detected, D10 was 0.49 μm, D50 was 2.45 μm, and D90 was 5.92 μm; the bulk density was 0.089 (g·cm -3 ); the moisture was 5.95%; the effective deposition rate FPF was 64.49%; the mass median aerodynamic diameter MMAD was 3.382 μm, and the geometric deviation GSD was 1.609.

[0125] Example 4 Preparation of ciprofloxacin dry powder inhalation particle capsules

[0126] The ciprofloxacin dry powder inhalation particles prepared in Example 3 were loaded into #2 hydroxypropyl methyl cellulose capsules to prepare ciprofloxacin dry powder inhalation particle capsules.

[0127] The emptying rate (ER) of the capsules was detected to be 95.31%.

[0128] Example 5 Preparation of ciprofloxacin dry powder inhalation particles

[0129] The composition of the ciprofloxacin dry powder inhalation particles:

[0130] Component Amount (mg) Cycloxydne hydrochloride 1676.83 Distearoyl phosphatidylcholine 283.72 Calcium chloride 39.80

[0131] The preparation steps of the ciprofloxacin dry powder inhalation particles are as follows:

[0132] (1) Emulsion preparation: under stirring (8000 rpm) conditions, a specified amount of calcium chloride and distearoyl phosphatidylcholine were added into 60 mL of pure water at 70°C, after high-speed shearing at 8000 rpm for 5 minutes, 5.73 g of perfluorooctyl bromide was added dropwise, after high-speed shearing at 8000 rpm for 5 minutes, a specified amount of ciprofloxacin hydrochloride was added, and after high-speed shearing at 8000 rpm for 5 minutes again, high-pressure homogenization was carried out at 800 bar pressure for 6 minutes, to prepare an emulsion with a Z-average particle size of 103.0±0.3 nm and a solid content of 3.3% (m / v);

[0133] (2) Spray drying: the prepared emulsion was subjected to spray drying, the inlet temperature was set to 135°C, and the outlet temperature was 68-71°C, to prepare ciprofloxacin dry powder inhalation particles.

[0134] According to the method of the present application, the geometric particle size distribution of the ciprofloxacin dry powder inhalation particles prepared was detected, D10 was 0.66 μm, D50 was 2.54 μm, and D90 was 6.04 μm; the bulk density was 0.086 (g·cm -3); moisture content: 6.35%; fine particle fraction (FPF) of effective deposition rate: 61.57%; mass median aerodynamic diameter (MMAD): 3.341 μm; geometric standard deviation (GSD): 1.652.

[0135] Example 6 Preparation of ciprofloxacin dry powder inhalation granule capsule

[0136] The ciprofloxacin dry powder inhalation granule prepared in Example 5 was filled into a #2 hydroxypropyl methyl cellulose capsule to prepare a ciprofloxacin dry powder inhalation granule capsule.

[0137] It was detected that the emptying rate (ER) of the capsule was 93.19%.

[0138] Example 7 Preparation of ciprofloxacin dry powder inhalation granule

[0139] The composition of the ciprofloxacin dry powder inhalation granule is as follows:

[0140] Component Amount (mg) Cycloxydne hydrochloride 1696.50 Distearoyl phosphatidylcholine 286.56 Calcium chloride 16.86

[0141] The preparation steps of the ciprofloxacin dry powder inhalation granule are as follows:

[0142] (1) Emulsion preparation: under stirring (8000 rpm) conditions, a specified amount of calcium chloride and distearoyl phosphatidylcholine were added into 75℃ 60 mL pure water, after high-speed shearing at 8000 rpm for 5 minutes, 17.19 g perfluorooctyl bromide was added dropwise, after high-speed shearing at 8000 rpm for 5 minutes, a specified amount of ciprofloxacin hydrochloride was added, after high-speed shearing at 8000 rpm for 5 minutes again, high-pressure homogenization was carried out at 800 bar pressure for 6 minutes, to prepare an emulsion with a Z-average particle size of 119.9 ± 1.3 nm and a solid content of 3.3% (m / v);

[0143] (2) Spray drying: the prepared emulsion was subjected to spray drying, the inlet temperature was set to 135℃, and the outlet temperature was 69-70℃, to prepare the ciprofloxacin dry powder inhalation granule.

[0144] According to the method of the present application, it was detected that the geometric particle size distribution of the prepared ciprofloxacin dry powder inhalation granule was: D 10 = 1.67 μm, D 50 = 3.96 μm, D 90 = 7.45 μm; bulk density: 0.064 g·cm -3 ; moisture content: 6.35%; fine particle fraction (FPF): 60.74%; mass median aerodynamic diameter (MMAD): 2.345 μm; geometric standard deviation (GSD): 1.653.

[0145] Example 8 Preparation of ciprofloxacin dry powder inhalation granule capsule

[0146] The ciprofloxacin dry powder inhalation granule prepared in Example 7 is filled into a #2 hydroxypropyl methyl cellulose capsule to prepare a ciprofloxacin dry powder inhalation granule capsule.

[0147] Example 9 Preparation of ciprofloxacin dry powder inhalation granule

[0148] Composition of ciprofloxacin dry powder inhalation granule:

[0149] Component Amount (mg) Cycloxydne hydrochloride 1696.38 Distearoyl phosphatidylcholine 248.80 Calcium chloride 16.80

[0150] The preparation steps of the ciprofloxacin dry powder inhalation granule are as follows:

[0151] (1) Emulsion preparation: Under stirring (8000 rpm) conditions, a specified amount of calcium chloride and distearoyl phosphatidylcholine is added to 127 mL of pure water at 70°C, and after high-speed shearing at 8000 rpm for 5 minutes, 11.52 g of perfluorooctyl bromide is added dropwise, and after high-speed shearing at 8000 rpm for 5 minutes, a specified amount of ciprofloxacin hydrochloride is added, and after high-speed shearing at 8000 rpm for 2 minutes again, high-pressure homogenization is carried out at a pressure of 800 bar for 6 minutes to prepare an emulsion with a Z-average particle size of 118.7±1.8 nm and a solid content of 1.6% (m / v);

[0152] (2) Spray drying: The prepared emulsion is spray dried, with the inlet temperature set to 135°C and the outlet temperature set to 67-69°C to prepare ciprofloxacin dry powder inhalation granules.

[0153] According to the method of the present application, the geometric particle size distribution of the prepared ciprofloxacin dry powder inhalation granule is detected, with D10 being 0.76 μm, D50 being 2.30 μm, and D90 being 5.00 μm; the bulk density is 0.144 (g·cm -3 ); the moisture content is 4.58%; the effective deposition rate FPF is 59.23%; the mass median aerodynamic diameter MMAD is 2.904 μm, and the geometric deviation GSD is 1.701.

[0154] Example 10 Preparation of ciprofloxacin dry powder inhalation granule capsule

[0155] The ciprofloxacin dry powder inhalation granule prepared in Example 9 is filled into a #2 hydroxypropyl methyl cellulose capsule to prepare a ciprofloxacin dry powder inhalation granule capsule.

[0156] Test Example 1 Pharmacokinetic study of ciprofloxacin dry powder inhalation granule

[0157] Select 12 male SD rats (purchased from Spafas (Beijing) Biotechnology Co., Ltd.) with a body weight of 330-360 g, and randomly divide them into two groups (intravenous administration group and inhalation administration group), 6 rats in each group.

[0158] Intravenous administration group: the test animals are injected with ciprofloxacin hydrochloride solution through the tail vein (40 mg of ciprofloxacin hydrochloride is dissolved in 10 mL of water to prepare a ciprofloxacin hydrochloride solution with a concentration of 4 mg / mL, and the ciprofloxacin concentration is 3.35 mg / mL), and the administration dose is 3.35 mg·kg -1 ;

[0159] Inhalation administration group: a lung dry powder administration device is used, and the test animals are given the ciprofloxacin dry powder inhalation particles of Example 1 through intratracheal administration, and the administration dose is 3.35 mg·kg -1 .

[0160] After the test animals are administered, blood is collected from the orbit at 2 min, 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, and 48 h, about 0.5 mL each time. Within 1 hour after blood collection, the blood samples are centrifuged in a low-temperature centrifuge at 4°C and 5000 rpm for 10 min, the supernatant is stored in a-20°C refrigerator, the blood drug concentration of ciprofloxacin is detected by the method of the application, and the pharmacokinetic parameters are calculated by non-compartment model analysis using Phoenix WinNonlin software (version 8.1, Certara Corporation, USA). The results are shown in Table 1.

[0161] Table 1

[0162]

[0163] After the dry powder inhalation particles of the application are administered to the lung, the lung deposition rate of the drug is targeted to be increased, the effective drug concentration and bioavailability in the lung are improved, the lung retention time and half-life are prolonged, and the incidence of adverse reactions is reduced.

[0164] The above description of the specific embodiments of the application does not limit the application, and those skilled in the art can make various changes or modifications to the application without departing from the spirit of the application, and all such changes or modifications shall fall within the scope of protection of the claims of the application.

Claims

1. A ciprofloxacin dry powder inhalation granule, wherein, by weight percentage, the dry powder inhalation granule comprises 60-95% ciprofloxacin hydrochloride and a pharmaceutically acceptable carrier, wherein, The mass median aerodynamic diameter (MMAD) of the dry powder inhaled particles is 1μm-5μm, and the geometric particle size distribution of the dry powder particles is D10≤2.0μm, D50≤4.5μm, and D90≤8.0μm.

2. The dry powder inhalation granules as described in claim 1, wherein the pharmaceutically acceptable carrier is any one or a combination of phospholipids, calcium chloride, and perfluorooctane, wherein, The phospholipid is selected from any one or a combination of distearyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, hydrogenated soybean phospholipid, distearyl phosphatidylglycerol, and dipalmitoyl phosphatidylglycerol.

3. The dry powder inhalation granules according to any one of claims 1-2, wherein the molar ratio of distearate phosphatidylcholine to calcium chloride in the dry powder inhalation granules is 1-5:1, preferably 1.2-4:1, and more preferably 1.3-3.5:

1.

4. The dry powder inhalation granules according to any one of claims 1-3, wherein, by weight percentage, the dry powder inhalation granules contain 60-95% ciprofloxacin hydrochloride, 4.5-35% distearate phosphatidylcholine, and 0.1-5% calcium chloride.

5. The dry powder inhalation particles according to any one of claims 1-4, wherein the effective deposition rate (FPF) of the dry powder inhalation particles is ≥50%, preferably ≥55%, more preferably ≥60%.

6. The dry powder inhalation particles according to any one of claims 1-5, wherein the emptying rate (ER) of the dry powder inhalation particles is ≥85%, preferably ≥90%, more preferably ≥95%.

7. The dry powder inhalation particles according to any one of claims 1-6, wherein the bulk density of the dry powder inhalation particles is ≤0.4 g / cm³. 3 Preferably, it is 0.05-0.1 g / cm³. 3 .

8. The dry powder inhalation particles according to any one of claims 1-7, wherein the moisture content of the dry powder inhalation particles is ≤10%, preferably ≤7%.

9. A method for preparing dry powder inhalation granules as described in any one of claims 1-8, comprising the following steps: (1) Under stirring conditions (3000rpm-10000rpm)*(1min-10min), add the specified amount of calcium chloride and phospholipid to water at 70-90℃, and after high-speed shearing (3000rpm-10000rpm)*(1min-10min), add the required amount of perfluorobromooctane (PFOB) to the aqueous phase, and after high-speed shearing (3000rpm-10000rpm)*(1min-10min), add the specified amount of ciprofloxacin hydrochloride to the primary emulsion, and homogenize under high pressure (300-1000bar)*(1min-10min) to obtain ciprofloxacin emulsion; (2) The prepared ciprofloxacin emulsion was spray-dried to obtain ciprofloxacin dry powder inhalation particles.

10. The use of ciprofloxacin dry powder inhalation granules as described in any one of claims 1-8, or ciprofloxacin inhalation dry powder granules and their formulations prepared by the method described in any one of claims 9, in the preparation of anti-respiratory tract infection drugs.

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