WO2023125472A1 - Ensemble de pulvérisation - Google Patents

Ensemble de pulvérisation Download PDF

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Publication number
WO2023125472A1
WO2023125472A1 PCT/CN2022/142152 CN2022142152W WO2023125472A1 WO 2023125472 A1 WO2023125472 A1 WO 2023125472A1 CN 2022142152 W CN2022142152 W CN 2022142152W WO 2023125472 A1 WO2023125472 A1 WO 2023125472A1
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Prior art keywords
spray
pharmaceutically acceptable
acceptable salt
spray assembly
solution
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PCT/CN2022/142152
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English (en)
Chinese (zh)
Inventor
牟丽秋
林旭其
贺素敏
何银燕
赵步文
宋学志
游劲松
黄芳芳
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广东东阳光药业有限公司
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Publication of WO2023125472A1 publication Critical patent/WO2023125472A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes

Definitions

  • the present invention relates to the field of pharmaceutical preparations, in particular to spray components that can be used for inhalation to treat COPD and/or asthma, more specifically, to ⁇ 2 receptor agonists, glucocorticoids, muscarinic receptor antagonists and phosphodiesterase 4 Novel spray, spray device for inhibitors.
  • the GOLD treatment guidelines (Global Initiative for Chronic Obstructive Lung Disease Treatment Guidelines) and the GINA Treatment Guidelines (Global Initiative for Asthma Management and Prevention Treatment Guidelines) respectively state that inhalation is the preferred treatment for COPD (chronic obstructive pulmonary disease) and asthma .
  • COPD chronic obstructive pulmonary disease
  • phosphodiesterase 4 inhibitors have also been used in the maintenance treatment of severe COPD; asthma
  • the main maintenance therapy is inhaled corticosteroids.
  • the efficacy of inhaled preparations is related to the dose of the drug deposited in the lung after inhalation and the specific deposition site of the drug in the lung.
  • the drug deposited in the oropharynx after inhalation is considered a waste of dose, and this part of the drug is swallowed and enters the gastrointestinal tract. Absorbed into the systemic circulation, it may cause systemic side effects; in addition, local side effects in the oropharynx are also related to the oropharyngeal deposition rate of inhaled drugs.
  • the lung and oropharyngeal deposition rates of inhaled formulations are related to the aerodynamic diameter of the inhaled particles and the nebulization velocity (i.e., the velocity at which the particles travel).
  • Inhaled particles are deposited in the oropharynx by an inertial impact mechanism that is mathematically described as X is the distance before the particle stops moving when the direction of the airflow in the airway changes, U represents the linear velocity of the particle running, d a is the aerodynamic particle size of the particle; when X is greater than or equal to the distance to the airway wall, Particles are deposited. It can be seen that the faster the particles run, the larger the aerodynamic particle size, and the easier the particles are deposited in the oropharynx.
  • the velocity of particle movement is also affected by the inspiratory flow rate of the patient. If the inspiratory flow rate of the patient is high, the velocity of the particles moving with the inhaled airflow is also high, which will increase the possibility of particle oropharyngeal deposition; when the patient uses inhalation products, every time The inspiratory flow rate is variable, resulting in large differences in the amount of drug deposited in the oropharynx and lungs with each inhalation. Therefore, in the development of inhalation products, the influence of inspiratory flow rate on lung and oropharyngeal deposition of inhaled drugs should be improved as much as possible.
  • Respimat soft mist is the inhalation preparation with the best performance among the portable multi-dose quantitative inhalation preparations on the market. It does not contain propellants, the droplet size produced is small, the percentage of respirable droplet is high, the droplet running speed is slow, and the spray is continuous A long time is beneficial for the patient to inhale the drug; the delivered dose is not affected by the patient's inspiratory flow rate. However, in vivo test results show that the oropharyngeal deposition rate of Respimat is still high, reaching about 40% of the delivered dose, and the simulated oropharyngeal deposition rate of Respimat reaches about 20%.
  • Particles with an aerodynamic particle size of 1 to 5 ⁇ m can be deposited in the lungs.
  • the dose of fine particles or the percentage of the dose of fine particles is used to characterize the amount of drug that can be deposited in the lungs.
  • Most of the currently available inhalation preparations on the market have a low dose of fine particles, resulting in a low lung deposition rate and a high oropharyngeal deposition rate of the inhaled drug.
  • the aerodynamic particle size distribution test in the study of the characteristics of inhalation preparations has a good in vivo and in vitro correlation.
  • the percentage of fine particle dose is positively correlated with the lung deposition rate of the drug in vivo;
  • the deposition rate of the artificial larynx is positively correlated with the oropharyngeal deposition rate of the drug in vivo; therefore, these two detection indicators can be used to predict the in vivo deposition of inhaled preparations feature.
  • the current inhalation preparations generally have the problem of low lung deposition rate and high oropharyngeal deposition rate.
  • the present invention aims to provide a spray assembly with high lung deposition rate and low oropharyngeal deposition rate, thereby improving the curative effect of inhalation preparations and reducing oropharyngeal side effects.
  • the high dose percentage of fine particles and slow spray speed can achieve high lung deposition rate and low oropharyngeal deposition rate.
  • the spray assembly provided by the invention has a high dose percentage of fine particles, which is beneficial for the deposition of the spray in the lungs; and a slow spray speed, which is beneficial for patients to inhale.
  • the present invention proposes a spray assembly, including a spray and a portable metered sprayer, wherein, the percentage of the spray with an aerodynamic particle size less than 5.8 ⁇ m in the total mass of the spray is 65% %above.
  • the droplet size of the spray according to the embodiment of the present invention has a more uniform particle size distribution and a narrower range, which is convenient for patients to absorb, so that most of the atomized active ingredients enter the lungs , reducing the deposition of drugs in the oral cavity and pharynx, greatly improving the bioavailability of drugs.
  • the spray provided by the invention does not use propellants, is environmentally friendly, and reduces discomfort and safety risks for patients during use.
  • the mist droplets with an aerodynamic particle size of less than 5.8 ⁇ m in the spray account for more than 70% of the total mass of the mist droplets. In some embodiments, the mist droplets with an aerodynamic particle size of less than 5.8 ⁇ m in the spray account for more than 75% of the total mass of the mist droplets. In some embodiments, the percentage of the droplets with an aerodynamic particle size smaller than 5.8 ⁇ m in the spray is more than 60% of the total mass of the droplets. In some embodiments, the percentage of the droplets with an aerodynamic particle size smaller than 5.8 ⁇ m in the spray is more than 65% of the total mass of the droplets. In some embodiments, the percentage of the droplets with an aerodynamic particle size of 1 ⁇ m-5 ⁇ m in the spray to the total mass of the droplets is more than 65%.
  • the spray speed of the spray at 1.5 cm from the nozzle of the nebulizer is not higher than 1.5 m/s. In some embodiments, the spray speed of the spray agent at 1.5 cm from the nozzle of the nebulizer is not higher than 1.2 m/s. In some embodiments, the spray speed of the spray agent at 1.5 cm from the nozzle of the nebulizer is not higher than 1 m/s. In some embodiments, the spray speed of the spray at 1.5 cm from the nozzle of the nebulizer is no higher than 0.8 m/s.
  • the in vitro simulated oropharyngeal deposition rate of the spray in the spray assembly is lower than 15%.
  • the spray has an in vitro simulated oropharyngeal deposition rate of less than 10%.
  • the spray has an in vitro simulated oropharyngeal deposition rate of less than 5%.
  • the spray has an in vitro simulated oropharyngeal deposition rate of less than 15%, 14%, 13%, 12%, 11%, 9%, 8%, 7%, 6%, or 4%.
  • the percentage of mist droplets with an aerodynamic particle size of less than 5.8 ⁇ m in the spray is more than 65% of the total mass of the mist, and the in vitro simulated oropharyngeal deposition rate of the spray is lower than 15%. %.
  • the percentage of fine particles in the spray is higher than 65%, and under different test flow rate conditions, the deposition rate at the artificial throat is lower than 15%; and after the percentage of fine particles is reduced, the deposition rate at the artificial throat significantly increased.
  • the percentage of mist droplets with an aerodynamic particle size of less than 5.8 ⁇ m in the spray is more than 65% of the total mass of the mist, and the in vitro simulated oropharyngeal deposition rate of the spray is lower than 15%. %, the spray velocity of the spray at 1.5cm from the sprayer nozzle is not higher than 1.5m/s.
  • the sprayer is a portable quantitative vibrating net sprayer.
  • the active ingredient in the spray is at least one of ⁇ 2 receptor agonists, glucocorticoids, muscarinic receptor antagonists and phosphodiesterase 4 inhibitors.
  • the spray kit comprises a ⁇ 2-receptor agonist single spray.
  • the spray kit comprises a glucocorticoid single spray.
  • the spray kit comprises a muscarinic receptor antagonist single spray.
  • the spray kit comprises a phosphodiesterase 4 inhibitor single spray.
  • the spray assembly comprises a combined spray of a ⁇ 2 receptor agonist and a glucocorticoid.
  • the spray component comprises a combination spray of a ⁇ 2 receptor agonist and a muscarinic receptor antagonist.
  • the spray kit comprises a combined spray of a muscarinic receptor antagonist and a glucocorticoid.
  • the spray kit comprises a tripartite spray of ⁇ 2 receptor agonist, muscarinic receptor antagonist and glucocorticoid.
  • the ⁇ 2 receptor agonists include albuterol or a pharmaceutically acceptable salt thereof, fenoterol or a pharmaceutically acceptable salt thereof, terbutaline or a pharmaceutically acceptable salt thereof, formoste rol or its pharmaceutically acceptable salt, olodaterol or its pharmaceutically acceptable salt, arformoterol or its pharmaceutically acceptable salt, indacaterol or its pharmaceutically acceptable salt, vilanterol or its at least one of the pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salt of salbutamol can be salbutamol sulfate and salbutamol hydrochloride.
  • the pharmaceutically acceptable salt of formoterol may be formoterol fumarate.
  • the pharmaceutically acceptable salt of olodaterol may be olodaterol hydrochloride.
  • the pharmaceutically acceptable salt of arformoterol may be arformoterol tartrate.
  • the pharmaceutically acceptable salt of indacaterol may be indacaterol maleate.
  • the pharmaceutically acceptable salt of vilanterol may be vilanterol triphenylacetate.
  • the glucocorticoids include fluticasone or a pharmaceutically acceptable salt or ester thereof, mometasone or a pharmaceutically acceptable salt or ester thereof, ciclesonide or a pharmaceutically acceptable salt or ester thereof, Clomethasone or a pharmaceutically acceptable salt or ester thereof, flunisolide or a pharmaceutically acceptable salt or ester thereof, budesonide or a pharmaceutically acceptable salt or ester thereof, triamcinolone acetonide or a pharmaceutically acceptable salt thereof or At least one of ester, dexamethasone, or a pharmaceutically acceptable salt or ester thereof.
  • the pharmaceutically acceptable salt of fluticasone may be fluticasone furoate and fluticasone propionate.
  • the pharmaceutically acceptable salt of mometasone may be mometasone furoate.
  • the pharmaceutically acceptable salt of beclomethasone can be beclomethasone dipropionate and beclomethasone dipropionate.
  • the pharmaceutically acceptable salt of dexamethasone can be dexamethasone sodium phosphate.
  • the muscarinic receptor antagonists include tiotropium or a pharmaceutically acceptable salt thereof, glycopyrronium or a pharmaceutically acceptable salt thereof, umeclidinium or a pharmaceutically acceptable salt thereof, uridine At least one of benzinium or a pharmaceutically acceptable salt thereof, ipratropium or a pharmaceutically acceptable salt thereof, oxitropium or a pharmaceutically acceptable salt thereof, revefenacin or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of tiotropium can be tiotropium bromide.
  • the pharmaceutically acceptable salt of glycopyrronium may be glycopyrronium bromide.
  • the pharmaceutically acceptable salt of umeclidinium can be umeclidinium bromide.
  • the pharmaceutically acceptable salt of umeclidinium can be umeclidinium bromide.
  • the pharmaceutically acceptable salt of ipratropium ammonium can be ipratropium bromide.
  • the pharmaceutically acceptable salt of oxitropium can be oxitropium bromide.
  • the phosphodiesterase 4 inhibitor comprises at least one of roflumilast or a pharmaceutically acceptable derivative thereof, apremilast or a pharmaceutically acceptable derivative thereof.
  • the pharmaceutically acceptable derivative of roflumilast may be roflumilast N-oxide.
  • the active ingredient in the spray includes at least one of prostacyclin, treprostinil and iloprost.
  • the active ingredients in the spray include antibiotics or antiviral drugs.
  • the antibiotics include at least one of aztreonam, tobramycin, amikacin, and ciprofloxacin
  • the antiviral drugs include at least one of zanamivir, laninamivir, and ribavirin.
  • the active ingredient in the spray includes at least one of pirfenidone and nintedanib.
  • the active ingredients in the spray include small molecule cytotoxic drugs or biological agents.
  • the small molecule cytotoxic drugs include at least one of cisplatin, cyclophosphamide, etoposide, vinorelbine, and paclitaxel
  • the biological preparations include at least one of ipilimumab monoclonal antibody, nivolumab monoclonal antibody, and durvalumab monoclonal antibody. A sort of.
  • the spray includes at least one of a chelating agent, a preservative, a stabilizer, a pH regulator, a buffer and a thickener, thereby further improving the stability of the active ingredient in the spray .
  • the chelating agent includes ethylenediaminetetraacetic acid or a salt thereof, citric acid or a salt thereof.
  • the preservative includes benzalkonium chloride, benzalkonium bromide, parabens, benzyl alcohol, phenol, m-cresol, chlorobutanol, thimerosal, or phenylmercuric acetate, thereby ensuring The sterility during the storage or use period of the spray can improve the safety of the spray.
  • the stabilizer includes Tween, Span, polyethylene glycol, carboxymethylcellulose and its salts, hypromellose and its salts, poloxamer, lecithin, Tyrol Sapox, TPGS, Polyoxyethylene Castor Oil, Polyoxyethylene Hydrogenated Castor Oil, Solutol HS15, Glycerin, Polyvinylpyrrolidone PVP or Polyvinyl Alcohol PVA.
  • the pH adjuster includes hydrochloric acid, sodium hydroxide, sulfuric acid, nitric acid, or phosphoric acid.
  • the buffering agent comprises acetic acid and its salts, citric acid and its salts, tartaric acid and its salts, malic acid and its salts, succinic acid and its salts, phosphoric acid or phosphates.
  • the thickener includes polyethylene glycol, carboxymethylcellulose and its salts, hypromellose and its salts, polyvinylpyrrolidone PVP or polyvinyl alcohol PVA.
  • the concentration of the active ingredient in the spray is 0.001 mg/mL-50 mg/mL; preferably 0.01 mg/mL-30 mg/mL; more preferably 0.1 mg/mL-20 mg/mL. In some embodiments, the concentration of the active ingredient in the spray is 1 mg/mL-10 mg/mL. In some embodiments, the concentration of the active ingredient in the spray is 5 mg/mL-15 mg/mL.
  • the pH of the spray is 2.5-10. In some embodiments, the pH of the spray is 3-9. In some embodiments, the pH of the spray is 4-8. In some embodiments, the pH of the spray is 3-7. In some embodiments, the pH of the spray is 3-6.
  • the sprayer includes: an airflow guide on the atomization module, a sealing gasket, a pressing plate, a microporous membrane and a brake.
  • the nebulizer includes: an airflow guide on the atomization module, a sealing gasket, a pressure plate, a microporous membrane, a brake, a medicine bottle, and a driving device and a battery on the host module.
  • an airflow guide includes a first pipe body and a second pipe body, and the first pipe body is provided with a first inlet, a first outlet, and a first port communicating with the first inlet and the first outlet.
  • the second pipe body is provided with a second inlet, a second outlet, and a second guide passage communicating with the second inlet and second outlet; the end of the second pipe body is inserted into In the first pipe body (Fig. 1), the operating frequency output by the driving device is the natural frequency after the brake and the microporous sheet are bonded, so that the brake drives the microporous sheet to vibrate violently and atomize.
  • the present invention proposes the use of the aforementioned spray assembly in the preparation of a medicament for treating COPD and/or asthma.
  • the present invention proposes the use of the aforementioned spray assembly in the preparation of medicines for treating pulmonary hypertension.
  • the present invention proposes the use of the aforementioned spray assembly in the preparation of medicine for treating pulmonary infection.
  • the present invention proposes the use of the aforementioned spray assembly in the preparation of a drug for treating idiopathic pulmonary fibrosis.
  • the present invention proposes the use of the aforementioned spray assembly in the preparation of a drug for treating lung cancer.
  • the aforementioned spray assembly can be applied to the systemic administration of small molecule drugs such as levodopa and loxapine; it can also be used for the administration of biological agents such as insulin and insulin analogs, etc. Pulmonary systemic administration.
  • Salbutamol in the present invention includes levalbuterol, levalbuterol hydrochloride or salbutamol sulfate.
  • API refers to active ingredient
  • COPD chronic obstructive pulmonary disease
  • “Aerodynamic particle size” means a particle of a certain type, regardless of its shape, size and density, if its settling velocity in air is consistent with the settling velocity of a spherical particle with a density of 1.
  • the diameter of a particle is the aerodynamic size of that particle.
  • Dose percentage of fine particles refers to the percentage of the mass of particles with an aerodynamic particle diameter smaller than 5.8um in a given dose.
  • Spray velocity refers to the velocity at which the spray front travels.
  • the spray speed at 1.5cm from the nozzle refers to the instantaneous speed of the spray front when the spray front runs to 1.5cm from the edge of the nozzle.
  • ⁇ m means micron
  • mg means milligram
  • mL means milliliter
  • EDTA edetic acid (ethylenediaminetetraacetic acid)
  • min means minute
  • g means gram
  • mm means millimeter
  • nm means nanometer
  • cm means centimeter
  • ⁇ l means microliter
  • °C means degrees Celsius
  • MeOH means methanol.
  • Figure 1 is a cross-sectional view of the self-developed atomizer (atomizer 1-atomizer 9 in the embodiment is common), and the corresponding parts of the serial numbers in the figure are as follows:
  • Embodiment 1 the aerodynamic particle size distribution determination of tiotropium bromide
  • tiotropium bromide preparation weigh auxiliary materials and bulk drug in a 500ml beaker according to the prescription table, add water for injection with 95% of dosing weight, magnetic stirring makes the raw and auxiliary materials dissolve completely; adjust pH to 2.8 with 3.7% hydrochloric acid solution; add Make up to full volume with purified water. Dispense the liquid medicine into the vials matched with the nebulizer and store it for later use.
  • Reagents phosphoric acid (AR), sodium heptanesulfonate monohydrate (AR), acetonitrile (HPLC), hydrochloric acid (AR), disodium edetate (AR).
  • Reference substance tiotropium bromide monohydrate working reference substance.
  • Mobile phase 0.18% sodium heptanesulfonate solution: take 1.79g of sodium heptanesulfonate monohydrate, add 1000ml of ultrapure water to dissolve, adjust the pH value to 3.2 with phosphoric acid, and use a water-based microporous filter membrane (0.45 ⁇ m, ⁇ 50mm ) suction filtration, that is. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Mobile phase Measure 2800ml of the above-mentioned 0.18% sodium heptanesulfonate solution, mix with 1200ml of acetonitrile, and degas it by ultrasonic for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Diluent 1mol/L hydrochloric acid solution: Measure 9mL of concentrated hydrochloric acid, add ultrapure water to 100ml, stir well, and obtain. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Hydrochloric acid solution of disodium edetate Weigh 25 mg of disodium edetate, add 950 ml of ultrapure water to dissolve, add 10 ml of 1 mol/L hydrochloric acid solution, dilute to 1000 ml with ultrapure water, shake well, have to. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Reference substance solution reference substance stock solution a: Take about 31mg of the working reference substance of tiotropium bromide monohydrate, accurately weigh it, put it into a 200ml measuring bottle, add about 50ml of diluent, shake for 10min to dissolve, and use diluent Dilute to the mark and shake well to obtain a reference substance stock solution with a tiotropium concentration of about 0.125 mg/ml, and prepare 2 parts in parallel.
  • Reference substance stock solution b Accurately pipette 2ml of the above reference substance stock solution a into a 200ml measuring bottle, dilute to the mark with a diluent, and shake well to obtain a reference substance stock solution b with a tiotropium concentration of about 1.25 ⁇ g/ml , prepare 2 copies in parallel.
  • Reference substance solution Accurately pipette 5ml of the above-mentioned reference substance stock solution b into a 50ml measuring bottle, dilute to the mark with a diluent, shake up to obtain a reference substance solution with a tiotropium concentration of about 0.125 ⁇ g/ml, prepare 2 in parallel share.
  • Quantitation limit solution accurately pipette 1.0mL of the reference substance stock solution b into a 500mL measuring bottle, dilute to the mark with diluent, shake well, and obtain. (Tiotropium concentration is about 0.0025 ⁇ g/ml)
  • Test solution After the last layer of filter paper is put into the Anderson cascade impactor, install the Anderson cascade impactor step by step. After the airtightness is confirmed, put it in a refrigerator at 5 ⁇ 3°C for at least 90 minutes and then take it out (it takes about 5 minutes to complete the test after taking it out of the refrigerator, the test environment temperature and humidity are 20 ⁇ 5°C, 40%RH ⁇ 75%RH). Connect the outlet of the impactor to the vacuum pump, connect the flow meter to the end of the L-shaped connecting pipe, turn on the vacuum pump, and adjust the flow rate to 28.3L/min ( ⁇ 5%) and 40L/min ( ⁇ 5%).
  • the sum of drug deposition at each site should be 75% to 125% of the delivered dose, otherwise another sample should be taken for testing.
  • WS the weight of the reference substance, mg
  • PS the content of the reference substance, %
  • AA the main peak area of the adapter test solution
  • DA the dilution volume of the adapter test solution
  • AL L-shaped connecting tube, tapered mouth The peak area of the main peak of the two parts of the test solution
  • DL the diluted volume of the two parts of the L-shaped connecting tube and the tapered mouth
  • A0 ⁇ 7 the main peak area of the test solution of grade 0 ⁇ 7
  • D0 ⁇ 7 the dilution volume of the need testing solution of grade 0-7
  • AF the main peak peak area of the need testing solution of the F grade
  • DF the dilution volume of the need testing solution of the F grade
  • DS the dilution volume of the reference solution, that is, 200,000ml
  • F the conversion factor between the salt/ester form of the raw drug and the active form of the raw drug
  • L the administered dose
  • N the number of sprays
  • Embodiment 2 Tiotropium Bromide Delivery Dose Uniformity Test
  • the sample preparation method is the same as in Example 1.
  • Instruments, reagents and reference substances Instruments: Dosage Unit Sampling Apparatus (DUSA), filter paper (glass fiber, ⁇ 25mm, Copley, product number 8316 (need to be cut) or glass fiber, ⁇ 25mm, Beijing Huironghe Technology Co., Ltd., item number 1238 or other inspected brands), high performance liquid chromatography, electronic balance, pH meter, shaker (Burrell, 75CC or other inspected brands), without rubber stopper Syringe (DISPOSABLE or Jiangnan or other brands that have been tested), filter membranes (polyethersulfone, 0.22 ⁇ m, ⁇ 13mm, Jinteng or other brands that have been tested).
  • Dosage Unit Sampling Apparatus DUSA
  • filter paper glass fiber, ⁇ 25mm, Copley, product number 8316 (need to be cut) or glass fiber, ⁇ 25mm, Beijing Huironghe Technology Co., Ltd., item number 1238 or other inspected brands
  • high performance liquid chromatography electronic balance
  • Reagents phosphoric acid (AR), sodium heptanesulfonate monohydrate (HPLC), acetonitrile (HPLC), hydrochloric acid (AR), disodium edetate (AR).
  • Reference substance tiotropium bromide monohydrate reference substance.
  • Mobile phase 0.18% sodium heptanesulfonate solution: take 1.79g of sodium heptanesulfonate monohydrate, add 1000ml of ultrapure water to dissolve, adjust the pH value to 3.2 with phosphoric acid, and use a water-based microporous filter membrane (0.45 ⁇ m, ⁇ 50mm ) suction filtration, that is. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Mobile phase Measure 2800ml of the above-mentioned 0.18% sodium heptanesulfonate solution, mix with 1200ml of acetonitrile, and degas it by ultrasonic for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Diluent 1mol/L hydrochloric acid solution: Measure 9mL of concentrated hydrochloric acid, add ultrapure water to 100ml, stir well, and obtain. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Hydrochloric acid solution of disodium edetate Weigh 25 mg of disodium edetate, add 950 ml of ultrapure water to dissolve, add 10 ml of 1 mol/L hydrochloric acid solution, dilute to 1000 ml with ultrapure water, shake well, have to.
  • Reference substance solution reference substance stock solution: take about 31 mg of tiotropium bromide monohydrate reference substance (equivalent to 25 mg of tiotropium), accurately weighed, put in a 200ml measuring bottle, add about 50ml of diluent, shake for 10min to make Dissolve, dilute to the mark with a diluent, shake well to obtain a reference substance stock solution with a tiotropium concentration of about 0.125 mg/ml, and prepare 2 parts in parallel.
  • Reference substance solution accurately pipette 2ml of the above-mentioned reference substance stock solution into a 500ml measuring bottle, dilute to the mark with a diluent, and shake well to obtain a reference substance solution with a tiotropium concentration of about 0.5 ⁇ g/ml, and prepare 2 copies in parallel .
  • Solution to Test Use the appropriate tip adapter to ensure that the spray tip port is flush with the sample collection tube orifice.
  • the base port is connected to a vacuum pump, and the other end of the sample collection tube is connected to a flowmeter. Adjust the vacuum pump to draw air from the sample collection tube (including filter paper) at a flow rate of 28.3 L/min ( ⁇ 5%).
  • the air should be continuously pumped out from the device to avoid loss of active substances into the air.
  • the connection between the various parts of the device shall be airtight, and all the air drawn from the sample collection tube shall only pass through the inhalation spray to be tested.
  • Determination of the uniformity of delivered dose in the tank Take 1 bottle of the test product, and use the above-mentioned measuring device to measure the marked spray times before (initial 3 doses), during (n/2) 4 doses are sucked up, that is, the 30th and 31st sprays ; the 32nd, 33rd spray; the 34th, 35th spray; the 36th, 37th spray;), after (the last 3 doses), n is the indicated total spraying times, a total of 10 delivered doses.
  • Measurement of delivery dose uniformity between tanks Take 1 bottle of the test product, use the above-mentioned measuring device to collect the clinical minimum recommended dose in the product manual, and repeatedly measure 10 bottles of the test product. Among them, 3 bottles measure the first dose specified in the instruction manual, 4 bottles measure the middle (n/2 sucks the first dose, ie the 30th, 31st spray) dose, and 3 bottles measure the last dose.
  • WS the weighing amount of the reference substance, mg
  • PS the content of the reference substance (purity is calculated as anhydrous matter), %
  • a Ti the main peak area of the test solution
  • D T the test solution Dilution volume, specifications: 1.25 ⁇ g/spray and 2.5 ⁇ g/spray, dilution volume 10ml; 5 ⁇ g/spray, dilution volume 20ml
  • a S average peak area of the main peak of the reference solution
  • D S dilution volume of the reference solution, that is, 50000ml
  • F Conversion factor between tiotropium bromide anhydrate and tiotropium bromide, 1.2036 (relative molecular mass of tiotropium bromide anhydrous: 472.42, relative molecular mass of tiotropium bromide: 392.51)
  • L tiotropium bromide inhalation spray Indicated dosage of the agent, specifications: 1.25 ⁇ g
  • the uniformity of the delivered dose in the can and between the cans all meet the requirements of the Chinese Pharmacopoeia, that is, the average delivered dose is 80% to 120% of the labeled amount.
  • the spray assembly of the present invention can well realize quantitative administration.
  • Embodiment 3 Aerodynamic particle size distribution test of commercially available soft mist Tiotropium bromide spray (Silihua Respimat)
  • Test method is the same as embodiment 1
  • Example 4 Determination of the percentage of droplets less than 5.8 ⁇ m in atomizers with different micropore diameters
  • Electron microscope parameter settings accelerating voltage: elemental analysis (15KV), velocity current intensity: low velocity flow or standard velocity flow, probe mode: backscattering.
  • Test process put the cleaned atomized sheet on the sample stage, insert the sample stage into the sample cup completely, set the electron microscope parameters, select 25000 times magnification for imaging, adjust the image brightness and contrast before taking pictures; use Image-Pro The Plus image processing software performs image processing on the photos obtained above, and sets the software calculation parameters to measure the size of the holes in the image.
  • Spray particle size analyzer (Malvern SPRAYTEC, model STP5311)
  • test parameters first measure the background, after the background measurement is completed, click the sample test start button, and start the atomizer to spray at the same time; after the test is over, select the spectrum with a light transmittance of ⁇ 90% for ⁇ 5.8 ⁇ m fog Calculate the drop percentage, and export the result after the calculation is completed.
  • Test process The commercially available nebulizer Raffles portable ultrasonic nebulizer (model Air Pro 3S) and the self-developed nebulizer were selected to test the spray velocity at the nozzle, the percentage of fine particles and the deposition rate at the artificial throat. Refer to Example 2 for the results of the spray velocity at the nozzle of the commercially available soft mist agent Silihua Respira, the percentage of the dose of fine particles and the deposition rate of the artificial throat according to literature reports.
  • test methods for the percentage of fine particle dose and artificial throat deposition rate of the self-developed atomizer are the same as in Example 1.
  • Measuring instruments laser source, mobile phone with specific functions (the camera can be set to slow motion 32 times + automatic recognition of motion trajectory, such as Huawei P40pro, mate30), software Motion Studio auxiliary equipment: iron stand, stable bracket (triangular bracket + optical Platform, used for stabilizing mobile phones), measuring ruler (1*1 cell in computer Word or other inspection available), tape measure.
  • Computer WORD design form 1cm*1cm square, 100% scaling as a measuring ruler for subsequent calculations.
  • the horizontal distance between the mobile phone and the measuring ruler is fixed at 30cm.
  • the left and right shooting positions of the mobile phone and the measuring ruler can be adjusted at the same time. Observe from the camera recording that the shell of the spray device is tangent to 0cm to facilitate subsequent data collection.
  • Time (ms) (the moment when the spray front reaches a certain distance of the measuring ruler - the moment when the distance from the initial end of the spray trigger is 0cm) ⁇ 32*1000
  • tiotropium bromide olodaterol preparation Weigh benzalkonium chloride, edetate disodium, tiotropium bromide, and olodaterol in sequence according to the prescription table into a 250ml beaker, add about 95% of the total amount of preparation Put purified water into the beaker, and magnetically stir to completely dissolve the raw and auxiliary materials; adjust the pH to 2.8 with 3.7% hydrochloric acid solution; adjust the volume to the full amount; fill the liquid medicine in a vial matching the nebulizer, and conduct aerodynamic particle size distribution test.
  • Reference substance tiotropium bromide monohydrate working reference substance; the same batch of olodaterol raw material used for preparation preparation.
  • Diluent 1mol/L hydrochloric acid solution: Measure 9mL of concentrated hydrochloric acid, add ultrapure water to 100ml, stir well, and obtain. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Hydrochloric acid solution of disodium edetate Weigh 25 mg of disodium edetate, add 950 ml of ultrapure water to dissolve, add 10 ml of 1 mol/L hydrochloric acid solution, dilute to 1000 ml with ultrapure water, shake well, have to.
  • Mobile phase pH3.0: Weigh 2.5g of potassium dihydrogen phosphate, add it to 1L of ultrapure water, stir to dissolve, adjust the pH to 3.0 with phosphoric acid, filter with water membrane (PES, 0.45um), and ultrasonic for 15min, that is have to. Measure 700ml of the above pH3.0 solution, mix it with 300ml of methanol, and degas it by ultrasonic for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • PES water membrane
  • Odaterol reference substance solution Take about 22 mg of olodaterol raw material (hydrochloride of olodaterol, the conversion factor of the two is 0.9138), accurately weigh it, put it into a 200mL measuring bottle, and add an appropriate amount of diluent Make it dissolve, dilute to the mark with a diluent, and shake well to obtain the reference substance stock solution a. Precisely pipette 2ml of the reference substance stock solution a into a 200ml measuring bottle, dilute to the mark with a diluent, and shake well to obtain the reference substance stock solution b.
  • Tiotropium bromide reference substance solution the preparation process is the same as in Example 1.
  • Need testing solution the preparation process of need testing solution is the same as embodiment 1.
  • the calculation method is the same as in Example 1.
  • Table 6-2 Test results of tiotropium bromide fine particle dose percentage and artificial throat deposition rate:
  • Table 6-3 Test results of olodaterol fine particle dose percentage and artificial throat deposition rate:
  • the artificial throat deposition rate of tiotropium bromide olodaterol compound preparation is related to the percentage of fine particle dose, and the higher the percentage of fine particle dose, the lower the deposition rate of artificial throat at different flow rates. Low; and when the percentage of fine particle dose is low, the deposition rate at the artificial throat is high at different flow rates.
  • fluticasone furoate preparation take Tween 80 and sodium carboxymethylcellulose according to the prescription table, add the prescribed amount of purified water, and magnetically stir to completely dissolve the Tween 80 and sodium carboxymethylcellulose; add the prescribed amount of fluticasone furoate , stirring to disperse fluticasone furoate evenly; grinding (equipment: Nanjing Chishun planetary ball mill, grinding frequency 10Hz, ball milling bead size 0.3mm, ball milling bead consumption 300g) for 16 hours; after grinding, take out the suspension and add the prescribed amount of benzene ammonium chloride, magnetically stirred for half an hour.
  • Reference substance fluticasone furoate reference substance
  • Mobile phase A Measure 970ml of ultrapure water and 30ml of methanol, add 0.5ml of phosphoric acid, mix well, and ultrasonically degas for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Mobile phase B Measure 970ml of acetonitrile and 30ml of methanol respectively, add 0.5ml of phosphoric acid, mix well, and degas by ultrasonic for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Diluent/blank solution Measure 70ml of mobile phase A and 30ml of mobile phase B respectively, mix well, and get ready. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Reference substance stock solution take 10mg of fluticasone furoate reference substance, accurately weighed, put in a 250ml measuring bottle, add 10ml of acetonitrile, shake for 10min to dissolve, dilute to the scale with the diluent, shake well, and prepare 2 parts in parallel ( 0.04mg/ml).
  • Reference substance solution Precisely pipette 2.5ml of reference substance stock solution, put it in a 200ml measuring bottle, dilute with diluent to the mark, shake well, and prepare 2 parts in parallel (0.5ug/ml)
  • Test solution After the last layer of filter paper is put into the Anderson cascade impactor, install the Anderson cascade impactor step by step. After the airtightness is confirmed, place it in a refrigerator at 5 ⁇ 3°C for at least 90 minutes and then take it out to room temperature. Connect the outlet of the impactor to the vacuum pump, connect a flowmeter to the end of the L-shaped connecting pipe, turn on the vacuum pump, and adjust the flow rate to 28.3/40L/min. Take 1 bottle of the test product, insert this product into the special adapter, pump for about 6 seconds every time you spray, and collect the 1st to 8th sprays (collect the sprayed weight and total sprayed away amount).
  • the deposition rate of fluticasone furoate suspension in the artificial throat is related to the percentage of the dose of fine particles, the dose of fine particles is high, and the deposition rate of the artificial throat is lower at different test flow rates; The deposition rate at the artificial larynx was significantly higher at lower dose percentages.
  • fluticasone furoate olodaterol preparation Weigh Tween 80 and sodium carboxymethylcellulose according to the prescription table, add the prescribed amount of purified water, and magnetically stir to completely dissolve the Tween 80 and sodium carboxymethylcellulose; Measure fluticasone furoate, stir to disperse fluticasone furoate evenly; grind (equipment: Nanjing Chishun planetary ball mill, grinding frequency 30Hz, ball milling bead size 0.3mm, ball milling bead consumption 300g) for 5 hours; take out the suspension after grinding, Add the prescribed amount of benzalkonium chloride and olodaterol, and stir magnetically for half an hour.
  • Reference substance fluticasone furoate reference substance, and the same batch of olodaterol raw material used for preparation.
  • Fluticasone furoate mobile phase A Measure 970ml of ultrapure water, 30ml of methanol, add 0.5ml of phosphoric acid, mix well, and degas it by ultrasonic for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Fluticasone furoate mobile phase B Measure 970ml of acetonitrile and 30ml of methanol respectively, add 0.5ml of phosphoric acid, mix well, and degas by ultrasonic for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Diluent/blank solution Measure 70ml of fluticasone furoate mobile phase A and 30ml of fluticasone furoate mobile phase B respectively, and mix well to obtain. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Odaterol mobile phase Weigh 2.5g of potassium dihydrogen phosphate, add it to 1L of ultrapure water, stir to dissolve, adjust the pH to 3.0 with phosphoric acid, filter with water membrane (PES, 0.45um), ultrasonic for 15min, that is have to. Measure 700ml of the above pH3.0 solution, mix it with 300ml of methanol, and degas it by ultrasonic for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • PES water membrane
  • Reference substance solution the preparation of fluticasone furoate reference solution is the same as in Example 5, and the preparation of olodaterol reference solution is the same as in Example 2.
  • Need testing solution is prepared with embodiment 5.
  • Odaterol Chromatographic column: Agilent, ZORBAX SB-C18 150 ⁇ 4.6mm, 5 ⁇ m; detection wavelength: 225nm; column temperature: 38°C; flow rate: 1.5mL/min; injection volume: 25 ⁇ L; running time: 15min; Needle washing solution: diluent.
  • Table 8-2 Fluticasone furoate fine particle dose percentage and artificial larynx deposition rate test results:
  • Table 8-3 Test results of olodaterol fine particle dose percentage and artificial throat deposition rate:
  • dexamethasone sodium phosphate preparation weigh benzalkonium chloride, edetate disodium, sodium citrate, and dexamethasone sodium phosphate into a 250ml beaker in sequence according to the prescription table; add purified water accounting for about 95% of the total preparation , magnetic stirring to completely dissolve the raw materials; 2% sodium hydroxide solution to adjust the pH to 7.8; constant volume.
  • Dexamethasone sodium phosphate reference substance stock solution 1 Take about 20 mg of dexamethasone sodium phosphate reference substance, weigh it accurately, put it in a 20ml measuring bottle, dissolve it with diluent and dilute to the mark, shake well, and get it.
  • Dexamethasone Sodium Phosphate Reference Substance Stock Solution 2 Precisely pipette 2mL of Control Stock Solution 1 into a 50mL measuring bottle, dilute to the mark with diluent, shake well, and the concentration of dexamethasone sodium phosphate is about 0.04mg/mL . ;
  • Dexamethasone Sodium Phosphate ACI Reference Substance Solution Precisely pipette 2.5mL of the control stock solution 2 into a 100mL measuring bottle, dilute to the mark with diluent, shake well, and obtain.
  • concentration of dexamethasone sodium phosphate is about 0.001mg/mL.
  • Table 9-2 Test results of fine particle dose percentage and artificial throat deposition rate:
  • Preparation of ipratropium bromide albuterol preparation Weigh benzalkonium chloride, edetate disodium, ipratropium bromide, and salbutamol sulfate into a 250ml beaker in sequence according to the prescription table; add purified water accounting for about 95% of the total preparation , magnetic stirring to completely dissolve the raw and auxiliary materials; 3.7% hydrochloric acid solution to adjust the pH of the solution to 3.5; add purified water to make up to the full volume.
  • Reference substance use the same batch of raw material drug as the preparation preparation as the reference substance.
  • Solution A Weigh 2.7g of potassium dihydrogen phosphate into 1L of ultrapure water, stir to dissolve, and filter with suction to obtain. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Mobile phase A Measure 200ml of acetonitrile and 3800ml of solution A, mix evenly, and sonicate for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Mobile phase B Measure 1600ml of acetonitrile and 2400ml of solution A, mix evenly, and sonicate for 15min. The volume of the prepared solution can be adjusted proportionally according to the actual situation.
  • Ipratropium bromide reference substance solution Accurately weigh about 22 mg of Ipratropium bromide monohydrate bulk drug (Ipratropium bromide and Ipratropium bromide monohydrate, the conversion factor of the two is 0.95815), accurately Weigh it, put it into a 500mL measuring bottle, add an appropriate amount of diluent to dissolve it, dilute to the mark with diluent, and shake well to obtain the reference substance stock solution a. Precisely pipette 4ml of the reference substance stock solution a into a 250ml measuring bottle, dilute to the mark with a diluent, and shake well to obtain the reference substance solution. 2 copies in parallel. (Concentration is about 0.67 ⁇ g/mL).
  • Salbutamol sulfate reference substance solution Accurately weigh about 22 mg of the salbutamol sulfate crude drug (the sulfate salt of salbutamol, the conversion factor of the two is 0.41496), accurately weigh it, and put it into a 200mL measuring bottle, add an appropriate amount of diluent to dissolve it, and dilute it with Dilute the solution to the mark, and shake well to obtain the reference substance stock solution a. Precisely pipette 8ml of the reference substance stock solution a into a 200ml measuring bottle, dilute to the mark with a diluent, and shake well to obtain the reference substance solution. 2 copies in parallel. (Concentration is about 1.83 ⁇ g/mL).
  • Need testing solution preparation method is the same as embodiment 1.
  • Table 10-2 Test results of ipratropium bromide fine particle dose percentage and artificial throat deposition rate:
  • the artificial throat deposition rate of the ipratropium bromide salbutamol compound preparation is related to the percentage of fine particle dose. Both were low; when the percentage of fine particle dose was lower than 60%, at the flow rate of 40L/min, the deposition rate of the artificial throat was significantly increased to more than 20%.
  • Preparation of formoterol fumarate preparation Weigh benzalkonium chloride, citric acid, and formoterol fumarate in turn according to the prescription table into a beaker, add purified water accounting for 95% of the total amount prepared into the beaker, and magnetically Stir to completely dissolve the raw and auxiliary materials, adjust the pH to 5.0 with 2% sodium hydroxide solution, and add purified water to make up to full volume.
  • Reference substance the same batch of raw materials used for preparation preparation.
  • Mobile phase A Weigh 3.7g of sodium dihydrogen phosphate monohydrate and 0.35g of phosphoric acid, add water to dissolve and dilute to 1L, and adjust the pH to 3.1.
  • Reference substance solution Accurately weigh about 22 mg of formoterol fumarate raw material, accurately weigh it, put it into a 200mL measuring bottle, add an appropriate amount of diluent and ultrasonically dissolve it for about 10 minutes, dilute to the mark with diluent, shake well, That is, the reference substance stock solution a. Precisely pipette 2ml of the reference substance stock solution a into a 200ml measuring bottle, dilute to the mark with a diluent, and shake well to obtain the reference substance stock solution b.
  • Need testing solution preparation method is the same as embodiment 1.
  • Table 11-2 Formoterol fumarate dose percentage of fine particles and test results of artificial throat deposition rate:
  • the aerodynamic particle size of the particles when the aerodynamic particle size of the particles is less than 10 microns, it can be deposited in the lungs, but only when the aerodynamic particle size of the particles is less than 5 microns, can the ideal lung deposition effect be obtained.
  • the proportion of the aerodynamic particle size within 5.8 microns of the spray of the present invention is about 75.3%-80.5%, which is higher than the proportion of the particle size distribution range of the aerosol (about 29.5%). Therefore, most of the atomized active ingredients of the present invention enter the lungs, reducing the deposition of drugs in the oral cavity and pharynx, improving the bioavailability of drugs, and reducing local side effects in the oropharynx.

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Abstract

L'invention concerne un ensemble de pulvérisation, comprenant un agent de pulvérisation et un pulvérisateur quantitatif portatif, le pourcentage de gouttes de brouillard dont la taille aérodynamique est inférieure à 5,8 μm dans l'agent de pulvérisation représentant 65 % ou plus de la masse totale des gouttes de brouillard. Le pourcentage de dosage des microparticules de l'ensemble de pulvérisation est élevé et la vitesse de pulvérisation est faible, ce qui permet d'obtenir un taux de dépôt pulmonaire élevé et un taux de dépôt oropharyngé faible.
PCT/CN2022/142152 2021-12-28 2022-12-27 Ensemble de pulvérisation WO2023125472A1 (fr)

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CN117224482A (zh) * 2023-09-07 2023-12-15 苏州易合医药有限公司 一种用于治疗ipf疾病的吸入制剂及其制备方法

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WO2017011729A1 (fr) * 2015-07-16 2017-01-19 Patara Pharma, LLC Polythérapies pour le traitement de maladies pulmonaires
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CN117224482A (zh) * 2023-09-07 2023-12-15 苏州易合医药有限公司 一种用于治疗ipf疾病的吸入制剂及其制备方法

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