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WO2021068961A1 - Composition pharmaceutique de solution pour inhalation et son procédé de préparation - Google Patents

Composition pharmaceutique de solution pour inhalation et son procédé de préparation Download PDF

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Publication number
WO2021068961A1
WO2021068961A1 PCT/CN2020/120348 CN2020120348W WO2021068961A1 WO 2021068961 A1 WO2021068961 A1 WO 2021068961A1 CN 2020120348 W CN2020120348 W CN 2020120348W WO 2021068961 A1 WO2021068961 A1 WO 2021068961A1
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WIPO (PCT)
Prior art keywords
indacaterol
pharmaceutical composition
sodium
add
citric acid
Prior art date
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PCT/CN2020/120348
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English (en)
Chinese (zh)
Inventor
张轩邈
毛华
周洋
邹孟玮
杨必坤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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Application filed by Sichuan Haisco Pharmaceutical Co Ltd filed Critical Sichuan Haisco Pharmaceutical Co Ltd
Priority to CN202210912500.7A priority Critical patent/CN115998680A/zh
Priority to CN202080037401.8A priority patent/CN113853197B/zh
Priority to CN202210936672.8A priority patent/CN115337292A/zh
Publication of WO2021068961A1 publication Critical patent/WO2021068961A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/08—Solutions
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the invention relates to an inhalation solution pharmaceutical composition, in particular to an inhalation solution pharmaceutical composition containing indacaterol, and belongs to the field of pharmaceutical preparations.
  • COPD chronic obstructive pulmonary disease
  • Indacaterol is a new type of long-acting ⁇ 2-receptor agonist (LABA), produced by Novartis Pharmaceuticals, Switzerland. It has been marketed in more than 70 countries and regions around the world since 2009. It was approved by the Chinese National Drug Administration in June 2012. Approved by the Bureau for listing in China, it is China’s first single LABA formulation approved for the treatment of COPD.
  • the only single inhalation preparation of indacaterol currently on the market is Angrun (Indacaterol maleate inhalation powder mist) This kind of powder mist dosage form.
  • the dry powder inhalation method requires the patient to learn the method of inhalation and the patient needs to have good lung function to inhale the drug.
  • CN103860463A discloses a solution containing indacaterol maleate and its inhalation spray.
  • concentration of indacaterol maleate in the published prescription is very low, only 2.0 mcg/mL-15 mcg/mL.
  • the inhalation solution generally requires the atomization time to be controlled within 10 minutes. If the volume of the atomization solution is too large, the atomization time will increase significantly and cannot meet the clinical needs. Generally, the volume of the inhalation solution needs to be controlled within 3 mL.
  • indacaterol maleate inhalation solution drug concentration 15mcg/mL
  • drug concentration 15mcg/mL drug concentration 15mcg/mL
  • the specifications of (indacaterol maleate inhalation powder mist) (150mcg based on indacaterol) remain the same, so the volume of the atomized solution needs to be more than 10mL, which is much higher than the volume of the conventional atomized solution.
  • the concentration of the drug in the indacaterol maleate inhalation solution is too low, which causes the volume of the aerosol solution to be too large and the aerosol inhalation time is too long, which cannot meet the clinical needs.
  • Jerun (Indacaterol inhalation powder mist) is a new type of inhalation preparation for the treatment of COPD.
  • This product is a compound powder mist containing two bronchodilators, of which indacaterol is a long-acting ⁇ 2- Receptor agonist (LABA), glycopyrrolate is a long-acting anticholinergic (LAMA) drug.
  • LABA/LAMA drug As the world's first LABA/LAMA drug on the market, indacaterol glycopyrrolate can agonize ⁇ 2 receptors while blocking M3 receptors. It has a powerful synergistic effect and can significantly improve lung function compared with single-agent therapy. , Bringing better treatment methods for the treatment of COPD.
  • the product has only one dosage form of inhalation powder.
  • inhalation powder For some patients with severe COPD, due to their poor lung function, they may not be able to achieve the inhalation airflow required for inhalation of powder mist, and the drug cannot be effectively delivered to the lungs or delivered doses. Decrease, so that the efficacy of the drug decreases.
  • the use of aerosol inhalation to administer medicine does not require special training for patients, especially for severe COPD patients, who can inhale a sufficient dose of medicine by using normal breathing methods. Therefore, the development of a compound inhalation solution of indacaterol glycopyrronium bromide can well meet the clinical needs of such patients. However, so far there is no research report on indacaterol glycopyrrolate compound inhalation solution.
  • one object of the present invention is to provide a pharmaceutical composition of inhalation solution containing indacaterol or its salt.
  • concentration of the drug in the composition is high enough to meet the clinical requirements for the volume of the inhalation solution. It is required to use manual pump, ultrasonic spray, air compressor and other pressure to release the content in a mist form. It is a preparation for lung inhalation.
  • the high concentration of sodium chloride in the composition can help reduce respiratory tract irritation and keep the droplet size stable.
  • Another object of the present invention is to provide a stable indacaterol compound inhalation solution prescription and preparation method thereof.
  • the drug concentration in the preparation is high and the preparation has good chemical stability, which can meet the clinical requirements well. Demand.
  • a pharmaceutical composition for an inhalation solution which comprises an active ingredient indacaterol or a pharmaceutically acceptable salt thereof, a pH adjusting agent, and water, wherein the concentration of the active ingredient indacaterol or a pharmaceutically acceptable salt thereof is the same as the concentration of the active ingredient indacaterol or a pharmaceutically acceptable salt thereof. Daterol counts as 23.2mcg/mL ⁇ 231.5mcg/mL, and its pH is 2.0 ⁇ 5.5.
  • the pharmaceutically acceptable salt of the active ingredient indacaterol includes indacaterol maleate or indacaterol acetate.
  • the inhalation solution pharmaceutical composition of the present invention contains 30 mcg to 300 mcg of indacaterol maleate per 1 mL, and has a pH of 3.0 to 4.0.
  • the pH adjusting agent is selected from hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, disodium hydrogen phosphate
  • the pH of the pharmaceutical composition is 2.5-5.0.
  • the pharmaceutical composition further comprises other adjuvants, and the other adjuvants are selected from at least one of a solubilizer, an osmotic pressure regulator, and a buffer ion pair.
  • the solubilizer is selected from at least one of polysorbate, polyethylene glycol castor oil, polyoxyethylene castor oil, and lecithin.
  • the osmotic pressure regulator is selected from at least one of sodium chloride or mannitol.
  • the buffer ion pair is selected from the group consisting of citric acid-sodium citrate buffer pair, disodium hydrogen phosphate-sodium dihydrogen phosphate buffer pair, sodium bicarbonate-sodium carbonate buffer pair, acetic acid-sodium acetate buffer pair,
  • the tartaric acid-sodium tartrate buffer pair has a concentration of 1 mM-50 mM.
  • the concentration of the buffer ion pair mentioned here is calculated based on the total molar concentration of acid radicals that play a buffering role in the buffer ion pair.
  • a citric acid-sodium citrate buffer pair with a concentration of 6 mM is prepared. It means that the molar concentration of citrate is 6mM, which can be prepared by adding 4mmol of citric acid and 2mmol of sodium citrate to 1000mL of water.
  • the concentration of the buffer ion pair is 3 mM to 30 mM.
  • the citric acid-sodium citrate buffer pair can be prepared with citric acid and sodium hydroxide, and the citric acid used is selected from one or more of anhydrous citric acid and citric acid monohydrate The combination.
  • the citric acid-sodium citrate buffer pair can be prepared with citric acid and sodium citrate, and the citric acid used is selected from one or more of anhydrous citric acid and citric acid monohydrate
  • the sodium citrate used is selected from one or more combinations of anhydrous sodium citrate, sodium citrate dihydrate, and sodium citrate pentahydrate.
  • the pH 4.0 citric acid-sodium citrate buffer pair of the present invention can be prepared from citric acid and sodium citrate in an aqueous solution, wherein the molar ratio of the added amount of citric acid and sodium citrate The ratio is 2:1.
  • a pH 4.0 citric acid-sodium citrate buffer pair with a concentration of 5 mM it can be prepared by adding 3.34 mmol of citric acid and 1.67 mmol of sodium citrate to 1000 mL of water.
  • the pharmaceutical composition further comprises a short-chain alcohol selected from one or a combination of ethanol, propylene glycol, and glycerol.
  • the osmotic pressure regulator when the weight percentage of indacaterol or a pharmaceutically acceptable salt thereof is 23.2mcg/mL ⁇ 77.2mcg/mL based on indacaterol, the osmotic pressure regulator The content is 0.1% to 0.9%.
  • the osmotic pressure regulator when the weight percentage of indacaterol or a pharmaceutically acceptable salt thereof is 77.3mcg/mL ⁇ 231.5mcg/mL, the osmotic pressure regulator The content is 0.1% to 0.7%.
  • the content of the indacaterol maleate is 30 mcg/mL-100 mcg/mL, and the content of the osmotic pressure regulator is 0.3 g/mL- 0.9g/mL.
  • the content of the indacaterol maleate is 100 mcg/mL ⁇ 300 mcg/mL, and the content of the osmotic pressure regulator is 0.3g/mL ⁇ 0.7g/mL.
  • the short-chain alcohol when the short-chain alcohol is ethanol, its weight percentage is 0.02% to 0.08%.
  • the weight ratio of propylene glycol to water is 1:4-200.
  • the weight ratio of glycerol to water is 1:20-200.
  • the pharmaceutical composition further comprises the active ingredients glycopyrrolate, tiotropium bromide, ipratropium bromide, umetopium bromide, adesonium bromide, budesonide, ciclesonide , At least one of beclomethasone propionate, mometasone furoate, fluticasone propionate, fluticasone furoate, and the concentration of these active ingredients in the pharmaceutical composition is independently 20 mcg/mL to 500 mcg/mL.
  • the pharmaceutical composition further comprises glycopyrrolate, and each 1000 mL of the pharmaceutical composition contains the glycopyrrolate from 0.05 to 0.5 g.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, from 0.04 g to 0.23 g, glycopyrrolate from 0.02 g to 0.2 g, chlorine 3g ⁇ 7g of sodium, 0.6g ⁇ 2.8g of citric acid monohydrate, 0.4g ⁇ 2.0g of sodium citrate dihydrate, appropriate amount of pH regulator to adjust pH to 2.5 ⁇ 5.0, water to 1000mL.
  • the pharmaceutical composition per 1000 mL contains: 0.108 g indacaterol maleate, 0.058 g glycopyrrolate, 0.699 g citric acid monohydrate, 0.492 g sodium citrate dihydrate, sodium chloride 6g, adjust the pH to 4.0 with a proper amount of pH adjuster, and add water to 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, 0.04g ⁇ 0.23g, mometasone furoate 0.04g ⁇ 0.5g, chlorine 3g ⁇ 7g of sodium, 0.6g ⁇ 2.8g of citric acid monohydrate, 0.4g ⁇ 2.0g of sodium citrate dihydrate, appropriate amount of pH regulator to adjust pH to 2.5 ⁇ 5.0, water to 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, from 0.04 g to 0.23 g, glycopyrrolate from 0.02 g to 0.2 g, and bran Mometasone acid 0.04g ⁇ 0.5g, sodium chloride 3g ⁇ 7g, citric acid monohydrate 0.6g ⁇ 2.8g, sodium citrate dihydrate 0.4g ⁇ 2.0g, pH adjuster appropriate to adjust pH to 2.5 ⁇ 5.0, add water To 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, from 0.04 g to 0.23 g, glycopyrrolate from 0.02 g to 0.2 g, chlorine Sodium hydroxide 3g ⁇ 7g, citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g ⁇ 4g citric acid monohydrate and 0.1g ⁇ 0.8g sodium hydroxide, pH adjuster, adjust the pH to 2.5 ⁇ 5.0, add water to 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, 0.04g ⁇ 0.23g, mometasone furoate 0.04g ⁇ 0.5g, chlorine Sodium hydroxide 3g ⁇ 7g, citric acid-sodium citrate buffer pair obtained by the reaction of 0.5g ⁇ 4g citric acid monohydrate and 0.1g ⁇ 0.8g sodium hydroxide, pH adjuster, adjust the pH to 2.5 ⁇ 5.0, add water to 1000mL.
  • the pharmaceutical composition contains per 1000 mL: indacaterol or a pharmaceutically acceptable salt thereof, based on indacaterol, from 0.04 g to 0.23 g, glycopyrrolate from 0.02 g to 0.2 g, and bran Mometasone acid 0.04g ⁇ 0.5g, sodium chloride 3g ⁇ 7g, citric acid-sodium citrate buffer pair obtained by the reaction of citric acid monohydrate 0.5g ⁇ 4g and sodium hydroxide 0.1g ⁇ 0.8g, pH adjuster appropriate amount Adjust the pH to 2.5 ⁇ 5.0, and add water to 1000mL.
  • the aforementioned pH adjusting agent is selected from one of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, maleic acid, citric acid, lactic acid, amino acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate or disodium hydrogen phosphate Or multiple.
  • the citric acid-sodium citrate buffer pair of the present invention is prepared from citric acid and sodium citrate in an aqueous solution.
  • This buffer pair can also be prepared in other ways, such as using citric acid and sodium hydroxide in an aqueous solution, or using sodium citrate and hydrochloric acid in an aqueous solution.
  • the mcg is the mass unit microgram, that is, ⁇ g.
  • the citric acid used in the present invention is all citric acid monohydrate.
  • the use of anhydrous citric acid or other types of citric acid hydrates can also achieve the same technical effect as the use of citric acid monohydrate, which also belongs to the scope of the present invention.
  • the sodium citrate used in the present invention is all sodium citrate dihydrate.
  • the use of anhydrous sodium citrate or other types of sodium citrate hydrate such as sodium citrate pentahydrate can also achieve the same technical effect as the use of sodium citrate dihydrate, which also belongs to the scope of the present invention.
  • the present invention also provides a preparation method of indacaterol inhalation solution pharmaceutical composition, which comprises the following steps:
  • auxiliary materials are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols. Stir to disperse and dissolve the auxiliary materials and adjust the pH of the solution to Target value 2.0 ⁇ 5.5;
  • filter sterilization of the drug solution obtained in (b) above for example, filter sterilization with a filter membrane less than or equal to 0.22 ⁇ m to obtain a sterile drug solution.
  • sterile budesonide a compound selected from the group consisting of sterile budesonide, ciclesonide, beclomethasone propionate, mometasone furoate, fluticasone propionate, and fluticasone furoate to the sterile drug solution, and stir Disperse evenly.
  • the obtained sterile pharmaceutical solution is divided into a vial, a glass ampoule or a plastic ampoule, for example, to obtain the indacaterol inhalation solution pharmaceutical composition.
  • the present invention provides a preparation method of indacaterol inhalation solution pharmaceutical composition, the preparation method includes the following steps:
  • excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, use a pH regulator to adjust the pH of the solution. Adjust to the target value 2.0 ⁇ 5.5;
  • the present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution.
  • the preparation method includes the following steps:
  • excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, use a pH regulator to adjust the pH of the solution. Adjust to the target value 2.0 ⁇ 5.5;
  • the present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution.
  • the preparation method includes the following steps:
  • excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, use a pH regulator to adjust the pH of the solution. Adjust to the target value 2.0 ⁇ 5.5;
  • the present invention also provides another method for preparing the pharmaceutical composition of indacaterol inhalation solution.
  • the preparation method includes the following steps:
  • excipients are selected from at least one of solubilizers, osmotic pressure regulators, buffer ion pairs, and short-chain alcohols; after stirring uniformly to disperse and dissolve the excipients, use a pH regulator to adjust the pH of the solution. Adjust to the target value 2.0 ⁇ 5.5;
  • the pharmaceutical composition of indacaterol inhalation solution provided by the present invention overcomes the shortcomings of the existing indacaterol inhalation solution that the concentration is low and cannot be used clinically, and a higher concentration of sodium chloride can be added to the prescription while maintaining indacaterol.
  • the high concentration of indacaterol greatly increases the concentration of indacaterol in the inhalation solution preparation, and smoothly realizes the preparation of large-scale preparations of indacaterol inhalation solution preparations. This high-concentration indacaterol inhalation solution is better Meet the clinical needs.
  • the indacaterol glycopyrrolate compound inhalation solution composition provided by the present invention is the first report.
  • the drug concentration in the preparation is high and the preparation has good chemical stability, which can well meet the clinical needs; on the other hand,
  • the difference in FPF value of the inhalation solution of the present invention at different air flow rates is small (the dry powder inhalation preparation is larger), and it can be applied to patients with different inhalation capabilities (the dry powder inhalation preparation is not suitable for patients with weak inhalation ability), which improves The patient's medication compliance.
  • Test Examples 1-8 Study the solubility of indacaterol maleate in different pH solutions
  • Preparation method Measure 1000mL of water, add appropriate amount of hydrochloric acid to adjust the pH to the pH value stated in the prescription, the error range does not exceed ⁇ 0.05, then add 0.5g of indacaterol maleate raw material, stir at 25°C for 24 hours, and filter After testing the sample concentration.
  • test results show that in a solution with a pH of 2.0 to 5.5, about 100 to 300 mcg of indacaterol maleate can be dissolved per 1 ml, and the solubility of indacaterol maleate is higher in a low pH solution.
  • Test Examples 9-14 To study the stability of indacaterol solution under different pH conditions.
  • Test Example 9 Test Example 10 Test Example 11 Test Example 12 Test Example 13 Test Example 14 Indacaterol maleate 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g pH 3.0 3.5 4.0 4.5 5.0 5.5 Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water separately, adjust the pH of the solution to the pH value stated in the prescription with an appropriate amount of hydrochloric acid, and the error range does not exceed ⁇ 0.05, and then add 0.15g of indacaterol maleate raw material, stir overnight, and filter Fill them in ampoules and place them at 4°C and 25°C, and check the relevant substances in the samples in January, 2 and March.
  • test results show that under the condition of 4° C., the impurity amount of Test Example 9-14 has no obvious change compared with that of 0 days, and at the same time, the impurity amount of Test Example 9-14 has increased with the increase of temperature.
  • the inventor also found that in a solution with a pH of 5.0 to 5.5, the amount of impurities exceeded 1% for 3 months at 25°C. Therefore, in a pH 3.0-4.5 solution, indacaterol maleate is more stable at 25°C.
  • Test Examples 15-18 To investigate the solubility of indacaterol maleate in different pH solutions when stored at low temperature
  • Test Example 15 Test Example 16 Test Example 17 Test Example 18 Indacaterol maleate 0.3g 0.3g 0.3g 0.3g hydrochloric acid Right amount / / / Citric acid-sodium citrate buffer pair / 5mM 5mM 5mM pH 3.0 4.0 4.5 5.0 Add water to 1000mL 1000mL 1000mL 1000mL
  • Test Example 16-18 add 0.699g of citric acid and 0.492g of sodium citrate, stir and dissolve, adjust the pH to the prescribed pH, the error range is not If it exceeds ⁇ 0.05, add 0.3g of indacaterol maleate, stir overnight, filter and dispense into ampoules, store in a refrigerator at 2-8°C, test the concentration and pH of the sample at 0 time and 72 hours respectively . Before the concentration test, the sample in the ampoule needs to be filtered to remove undissolved drug particles. The test results are:
  • an osmotic pressure regulator needs to be added, and sodium chloride is commonly used to adjust the osmotic pressure of the solution.
  • sodium chloride is commonly used to adjust the osmotic pressure of the solution.
  • the present invention found in the research that sodium chloride will affect the solubility of indacaterol maleate, so it is necessary to investigate the effect of different concentrations of sodium chloride on the solubility of indacaterol maleate.
  • Test Examples 19-27 Investigate the influence of sodium chloride concentration on the solubility of indacaterol maleate
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in test examples 19-21; add 1.398 g of citric acid and 0.984 g of sodium citrate in test examples 22-24; add citric acid in test examples 25-27 2.796g, 1.968g sodium citrate, stir until completely dissolved, then add the corresponding sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add 0.3g of indacaterol maleate raw material , Stir overnight, filter and dispense into ampoules. Test the concentration and pH of the chemical solution. At the same time, they were placed in a refrigerator at 2-8°C for 3 days and 7 days respectively to determine the concentration and pH of the sample. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • test results are:
  • the present invention finds that the citric acid-sodium citrate buffer pair can improve the solubility of indacaterol maleate in a solution containing sodium chloride, and reduce the risk of drug precipitation during storage.
  • citric acid-sodium citrate buffer In order to clarify the concentration of citric acid-sodium citrate buffer in the solution, it is necessary to study the influence of different concentrations of citric acid-sodium citrate buffer on the solubility of indacaterol maleate in sodium chloride solution.
  • Test Examples 28-32 Investigate the effect of citric acid-sodium citrate buffer on the solubility of indacaterol maleate in sodium chloride solution
  • Test Example 32 Indacaterol maleate 0.2g 0.2g 0.2g 0.2g 0.2g 0.2g Citric acid-sodium citrate buffer pair - 5mM 20mM 30mM 50mM Sodium chloride 6g 6g 6g 6g 6g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add citric acid 0.699 g, 1.398 g, 4.194 g, 6.990 g, and sodium citrate 0.492 g, 1.968 g, 2.952 g, 4.920 g, respectively, in Test Examples 29-32, and stir until completely dissolved.
  • Test examples 28 to 32 were then added 6g of sodium chloride and stirred until completely dissolved; added appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, and then added 0.2g of indacaterol maleate raw material, stirred overnight, filtered and then packed Test the concentration and pH of the sample in an ampoule. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles. At the same time, they were placed in a refrigerator at 2-8°C for 7 days and then tested again. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • test results are:
  • the citric acid-sodium citrate buffer pair can increase the solubility of indacaterol maleate in sodium chloride solution, and can reduce the indacaterol maleate during storage. The risk of precipitation.
  • Test Example 33 To investigate whether a high-concentration and stable indacaterol maleate solution can be prepared according to the prescription of Example 1 in patent CN103860463A.
  • Test Example 34 To investigate whether a high-concentration and stable indacaterol maleate solution can be prepared according to the prescription of Example 3 in patent CN103860463A
  • Indacaterol maleate 0.02g Disodium phosphate 2g Dipotassium phosphate 7.5g Sodium chloride 0.5g Sodium formaldehyde sulfoxylate 22.5mg Ethylenediaminetetraacetic acid monocalcium disodium 50mg water 1000mL
  • Preparation method Measure 1000mL of water and add 0.1g of polysorbate-80 to dissolve it, adjust the pH to the prescribed pH with hydrochloric acid, and the error range does not exceed ⁇ 0.05, and then add the corresponding amount of indacaterol maleate. Stir and dissolve at room temperature, filter and fill in an ampoule to detect the sample concentration and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • Example 1 77.41 0.133
  • Example 2 229.76 0.138
  • Example 3 76.64 0.129
  • Example 4 231.07 0.117
  • Example 5 78.87 0.122
  • Example 6 230.23 0.123
  • Example 7 76.95 0.163
  • Example 8 228.98 0.149
  • Example 10 Indacaterol maleate 0.2g 0.2g 0.2g Polyethylene Glycol Castor Oil / / 1g Lecithin / 1g / Polyoxyethylene castor oil 0.4g / / pH 4.0 4.0 4.0 Add water to 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add corresponding amounts of polyethylene glycol castor oil, lecithin, and polyoxyethylene castor oil according to the above-mentioned examples. After it is completely dissolved, adjust the pH to 4.0 ⁇ 0.05 with hydrochloric acid, and then add Malay 0.2g of indacaterol acid was stirred and dissolved at room temperature, filtered and filled in an ampoule to detect the concentration of the sample and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • Example 9 154.20 0.132
  • Example 10 159.29 0.121
  • Example 11 155.59 0.133
  • Example 13 Indacaterol maleate 0.05g 0.05g sulfuric acid Right amount / Lysine / Right amount pH 4.0 4.0 Add water to 1000mL 1000mL
  • Preparation method Measure 1000mL of water, adjust the pH to 4.0 ⁇ 0.05 with sulfuric acid or lysine respectively, add 0.05g of indacaterol maleate drug, stir and dissolve at room temperature, filter and fill in an ampoule. Detect sample concentration and related substances. Before the concentration test, the sample in the ampoule needs to be filtered to remove possible precipitated drug particles.
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid, 0.492g of sodium citrate, stir until completely dissolved, then add 6g of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add the corresponding Ethanol, propylene glycol, and glycerol, stir to make the mixture uniform. Measure 1000 mL of the corresponding solution, add 0.15 g of indacaterol maleate, stir overnight, filter, and divide the solution to test the content and pH value. Test the concentration and pH value after 3 days and 7 days in the refrigerator at 2-8°C. Before the concentration test, the sample needs to be filtered to remove possible precipitated drug particles.
  • Example 21 Example 22
  • Example 23 Example 24 Indacaterol maleate 0.05g 0.1g 0.1g 0.25g 0.15g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 20mM 20mM Sodium chloride 3g 6g 9g 3g 6g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid and 0.492g of sodium citrate in Examples 20-22; add 2.796g of citric acid and 1.968g of sodium citrate in Examples 23-24, stir until completely dissolved, add the corresponding After the amount of sodium chloride is completely dissolved, adjust the pH to 4.00 ⁇ 0.05 with hydrochloric acid, and then add the corresponding amount of indacaterol maleate drug, stir overnight, filter, and distribute, and test the concentration and related substances. Before the concentration test, the sample needs to be filtered to remove possible precipitated drug particles.
  • Example 20 38.94 0.127
  • Example 21 80.03 0.132
  • Example 22 78.18 0.137
  • Example 23 193.33 0.112
  • Example 24 115.42 0.125
  • Example 25 Example 26
  • Example 27 Example 28 Indacaterol maleate 0.15g 0.15g 0.15g 0.15g 0.15g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 5mM Sodium chloride 3g 4g 5g 6g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid, 0.492g of sodium citrate, dissolve, add the prescribed amount of sodium chloride, stir to dissolve, adjust the pH to 4.00 ⁇ 0.05 with appropriate amount of hydrochloric acid, and finally add inda maleate Terol drug is 0.15g, stirred overnight, filtered and then divided into aliquots to test the concentration and related substances. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 25 116.00 0.142
  • Example 26 119.35 0.133
  • Example 27 114.84 0.152
  • Example 28 115.53 0.139
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid and 0.492g of sodium citrate in Examples 29 to 31; add 4.194g of citric acid and 2.952g of sodium citrate in Examples 32 to 34, stir until completely dissolved, add 6g respectively Sodium chloride, after it is completely dissolved, adjust the pH to 4.00 ⁇ 0.05 with hydrochloric acid, then add the corresponding amount of indacaterol maleate and glycopyrrolate, stir overnight, filter and dispense, test the concentration, related substances and pH value. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 36 Indacaterol maleate 0.15g 0.15g 0.15g Glycopyrrolate 0.1g 0.2g 0.2g Polysorbate-80 / / 0.05g Citric acid-sodium citrate buffer pair 20mM 20mM 20mM Sodium chloride 3g 3g 3g hydrochloric acid Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL
  • Preparation method Measure 1000mL of water, add 2.796g of citric acid and 1.968g of sodium citrate, stir until completely dissolved, then add sodium chloride and polysorbate-80, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add 0.15g of indacaterol maleate and glycopyrrolate, stir to dissolve, filter and dispense into ampoules to test the concentration of the two drugs and related substances. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 24 and Examples 35 to 37 were placed in a thermostat at 5 ⁇ 2° C. to investigate the changes in related substances and pH values of the samples during the placement process.
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid, 0.492 g of sodium citrate, and 5 g of sodium chloride in Examples 41 to 43, stir until completely dissolved, adjust the pH to the corresponding pH with hydrochloric acid, and the error range does not exceed ⁇ 0.05; For Examples 38-40, add 5g of sodium chloride, stir and dissolve, adjust the pH to the corresponding pH with hydrochloric acid, and the error range does not exceed ⁇ 0.05. Finally, each example is added with the prescribed amount of medicine, stirred and dissolved, filtered, and packed into ampoules. In, test the concentration separately. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 38 116.23 100.32
  • Example 39 115.53 100.74
  • Example 40 115.19 202.42
  • Example 41 117.15 99.81
  • Example 42 116.11 204.20
  • Example 43 115.53 100.84
  • test results show that in a solution containing 0.5% sodium chloride and a pH of 2 to 5, an inhalation solution with a suitable concentration can be prepared.
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid and 0.492g of sodium citrate, stir until completely dissolved, then add the prescribed amount of sodium chloride, and stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then Add 0.15 g of indacaterol acetate or indacaterol and the prescription amount of glycopyrrolate crude drug, stir until completely dissolved, and test the concentration after filtration. Before the concentration test, the undissolved drug needs to be filtered out.
  • test results show that both indacaterol acetate or indacaterol can be combined with glycopyrrolate to prepare a compound inhalation solution.
  • Example 51 Example 52
  • Example 53 Indacaterol 0.15g 0.15g 0.15g 0.15g 0.15g Glycopyrrolate 0.1g / / / Tiotropium Bromide / 0.1g / / Ipratropium bromide / / 0.1g / Umetium Bromide / / / 0.1g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 5mM Sodium chloride 3g 3g 3g 3g 3g 3g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000mL of water, add 0.699g of citric acid and 0.492g of sodium citrate, stir until completely dissolved, then add 3g of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add The prescription amount of the medicine as shown in the above table is stirred until it is completely dissolved, filtered and then divided into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Examples 54 to 57, stir until completely dissolved, then add the prescribed amount of sodium chloride, stir until completely dissolved, add an appropriate amount of hydrochloric acid to adjust the pH To 4.00 ⁇ 0.05;
  • Examples 58-59 add the prescription amount of sodium chloride, stir to dissolve, add appropriate amount of hydrochloric acid to adjust the pH to 3.00 ⁇ 0.05; All the examples add indacaterol maleate and glycopyrrolate according to the prescriptions , After stirring overnight for the drug to dissolve, add mometasone furoate or fluticasone propionate, stir evenly, and dispense into ampoules to test the concentration.
  • the test results are as follows:
  • Preparation method Measure 1000mL of water, add prescription amount of citric acid and sodium citrate, stir until completely dissolved, then add prescription amount of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add to the table
  • the prescription amount of indacaterol acetate and glycopyrronium bromide shown in stir overnight until the raw material is completely dissolved, then add the prescription amount of mometasone furoate or fluticasone propionate or fluticasone furoate, stir well, and dispense into ampoules In the bottle, test the concentration separately.
  • the test results are as follows:
  • test results show that indacaterol acetate and glycopyrrolate can be combined with different steroid hormones to prepare a ternary compound inhalation solution.
  • Preparation method Measure 1000mL of water, add the prescribed amount of buffer salt, stir until completely dissolved, then add 3g of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to the pH set in the table, and then add the prescription
  • the amount of medicine is stirred until it is completely dissolved, filtered and divided into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 66 115.53 100.42
  • Example 67 114.38 102.73
  • Example 68 116.11 202.22
  • Example 69 77.72 299.10
  • Example 70 45.80 399.69
  • Example 71 45.94 51.17
  • Example 76 Indacaterol maleate 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g Glycopyrrolate 0.1g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair - 5mM 20mM 5mM 5mM Mannitol 50g 50g 50g 25g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Example 73 and Examples 75 to 76, and add 2.796 g of citric acid and 1.968 g of sodium citrate in Example 74. After stirring and dissolving, each Example Add mannitol according to the prescription, stir to dissolve, adjust the pH to 4.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount of indacaterol maleate and glycopyrrolate, stir to dissolve, filter and dispense into ampoules , Respectively test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 72 116.11 100.20
  • Example 73 117.73 100.52
  • Example 74 115.42 103.17
  • Example 75 114.84 99.42
  • Example 76 118.31 100.71
  • test results show that mannitol, as an osmotic pressure regulator, can prepare a compound inhalation solution with a content that meets the requirements.
  • Example 81 Indacaterol maleate 0.15g 0.15g 0.15g 0.15g 0.15g 0.15g Glycopyrrolate 0.1g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 10mM 20mM Sodium chloride 3g 4g 5g 5g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add 0.699 g of citric acid and 0.492 g of sodium citrate in Examples 77 to 79; add 1.398 g of citric acid and 0.984 g of sodium citrate in Example 80; add 2.796 g of citric acid in Example 81 Sodium citrate 1.968g, after stirring and dissolving, in each example, add sodium chloride according to the prescription, stir and dissolve, adjust the pH to 3.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount of indacaterol maleate and glycopyrrolate. Stir to dissolve, filter and dispense into ampoules to test the concentration. Before the concentration test, the undissolved drug needs to be filtered out.
  • Example 77 116.23 100.23
  • Example 78 117.15 99.83
  • Example 79 115.19 102.90
  • Example 80 115.53 101.45
  • Example 81 116.11 101.27
  • test results show that the pH3.0 solution contains different concentrations of citrate buffer salt, and a binary compound inhalation solution with a content that meets the requirements can be prepared.
  • Example 82 Example 83
  • Example 84 Example 85
  • Example 86 Indacaterol maleate 0.25g 0.05g 0.15g 0.15g 0.15g Glycopyrrolate 0.1g 0.3g 0.1g 0.1g 0.1g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 10mM 40mM Sodium chloride 3g 4g 5g 5g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Preparation method Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 82 to 84; add 2.102 g of citric acid and 0.456 g of sodium hydroxide in Example 85; add 8.408 g of citric acid in Example 86.
  • Sodium hydroxide 1.824g after stirring and dissolving, sodium chloride was added in each example according to the prescription, stirring and dissolving, adjusting the pH to 3.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally adding the prescription amount of indacaterol maleate and glycopyrrolate.
  • Example 82 190.13 101.23
  • Example 83 38.90 299.72
  • Example 84 116.00 100.23
  • Example 85 115.49 99.74
  • Example 86 114.43 100.29
  • test results show that in a pH 3.0 solution, a citric acid buffer solution prepared with citric acid and sodium hydroxide can prepare a binary compound inhalation solution with a content that meets the requirements.
  • Example 87 Example 88
  • Example 89 Example 90
  • Example 91 Indacaterol maleate 0.12g 0.12g 0.12g 0.12g 0.12g Glycopyrrolate 0.06g 0.06g 0.06g 0.06g Mometasone furoate / / / 0.15g 0.15g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 5mM 50mM Sodium chloride 4g 5g 6g 4g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Example 91 Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 87 to 90; add 10.51 g of citric acid and 2.28 g of sodium hydroxide in Example 91.
  • sodium chloride was added in each example according to the prescription, stirred and dissolved, adjusted to pH 4.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally added the prescription amount of indacaterol maleate and Glycopyrrolate, stir to dissolve.
  • Examples 87-89 were filtered and divided into ampoules, and the concentrations were tested respectively.
  • a prescription amount of mometasone furoate was added after filtration, and mometasone furoate was dispersed by high-speed shearing, and then divided into ampoules to test the concentration.
  • test results show that: in a pH 4.0 solution, a citric acid buffer solution prepared with citric acid and sodium hydroxide can prepare a binary compound inhalation solution and a ternary compound inhalation preparation that meet the requirements.
  • Example 92 Example 93
  • Example 94 Example 95
  • Example 96 Indacaterol maleate 0.12g 0.12g 0.12g 0.12g 0.12g Mometasone furoate 0.5g 0.3g 0.4g 0.15g 0.05g Citric acid-sodium citrate buffer pair 5mM 5mM 5mM 5mM 50mM Sodium chloride 4g 5g 6g 4g 5g hydrochloric acid Right amount Right amount Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Example 96 Measure 1000 mL of water, add 1.051 g of citric acid and 0.228 g of sodium hydroxide in Examples 92 to 95; add 10.51 g of citric acid and 2.28 g of sodium hydroxide in Example 96.
  • sodium chloride was added in each example according to the prescription, stirred and dissolved, adjusted to pH 4.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally added the prescription amount of indacaterol maleate.
  • Stir to dissolve add the prescribed amount of mometasone furoate after filtering, disperse mometasone furoate at high speed, and then divide them into ampoules to test the concentration.
  • Example 92 91.72 507.63
  • Example 93 90.56 294.31
  • Example 94 91.16 405.66
  • Example 95 93.25 147.58
  • Example 96 94.67 53.12
  • test results show that in a pH 4.0 solution, a citric acid buffer pair solution prepared by citric acid and sodium hydroxide can prepare indacaterol mometasone furoate binary compound inhalation solution with a content that meets the requirements.
  • Example 97 Example 98 Example 99 Indacaterol maleate 0.005g 0.005 0.12 Disodium phosphate 2g / / Dipotassium phosphate 7.5g / / Sodium chloride 0.5g 4g 4g Sodium formaldehyde sulfoxylate 0.0225g / / Ethylenediaminetetraacetic acid-calcium disodium 0.05g / / Citric acid-sodium citrate buffer pair / 5mM 5mM hydrochloric acid / Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL
  • Example 97 was prepared with reference to the formulation of Example 3 in patent CN103860463A.
  • Example 98 and Example 99 respectively measure 1000mL of water, add 1.051g of citric acid, 0.228g of sodium hydroxide, stir to dissolve, add 4g of sodium chloride, stir to dissolve, adjust the pH to 4.00 ⁇ 0.05 with a proper amount of hydrochloric acid, and finally add The prescription amount of indacaterol maleate is stirred and dissolved in ampoules.
  • Example 97 Measure 1000 mL of water, add 2 g of disodium hydrogen phosphate, 7.5 g of dipotassium hydrogen phosphate, 0.5 g of sodium chloride, 0.0225 g of sodium formaldehyde sulfoxylate, and 0.05 g of ethylenediaminetetraacetic acid-calcium disodium.
  • Example 97 prepared by the example prescription in the patent CN103860463A
  • the impurities in Example 97 increase significantly during the room temperature storage process, and the amount of impurities has exceeded 1% after being placed for 3 months.
  • the impurity increased slightly after being left for 3 months, and there was no significant difference in impurity growth between the two examples.
  • indacaterol maleate and glycopyrrolate are pulverized and pretreated with a jet mill to make the particle size D 90 ⁇ 5 ⁇ m, and then indacaterol maleate, glycopyrrolate and magnesium stearate are mixed uniformly , And then gradually mixed with lactose according to the same amount of stepwise addition, and the total mixed powder obtained is filled in the capsule.
  • the fine particle fraction (Fine Particle Fraction, FPF) reflects the proportion of the amount of medicine that the inhalation preparation can enter the lungs.
  • FPF Fraction
  • Example 34 Example 68, Example 79, Example 82, Example 87, and Example 100
  • the FPF value of the preparation was determined by using a next generation pharmaceutical impactor (NGI). Using different flow rates to simulate changes in FPF values in different embodiments under different breathing modes.
  • NTI next generation pharmaceutical impactor
  • Example 34 The test results show that the FPF values of the inhaled solutions of Example 34, Example 68, Example 79, Example 82, and Example 87 are not significantly different at different flow rates, and the proportion of fine particles reaching the lungs in the preparation will not vary depending on the person.
  • the breathing capacity of the powder is different; and the FPF value of the powder aerosol of Example 100 at different flow rates is quite different.
  • the FPF value at low flow rates is significantly lower, and the glycopyrrolate is more significantly lower, so the powder aerosol It has certain limitations for patients with weak breathing ability, and the inhalation solution of the present invention overcomes this shortcoming.
  • Preparation method Measure 1000mL of water, add prescription amount of citric acid and sodium citrate, stir until completely dissolved, then add prescription amount of sodium chloride, stir until completely dissolved; add appropriate amount of hydrochloric acid to adjust the pH to 4.00 ⁇ 0.05, then add to the table
  • the prescription amount of indacaterol maleate and aclidinium bromide shown in the formula stir overnight until the raw material is completely dissolved, then add the prescription amount of budesonide or ciclesonide or beclomethasone dipropionate and mix well. Dispense them into ampoules and test the concentration. The test results are as follows:
  • test results show that indacaterol maleate and aclidinium bromide can be combined with different steroid hormone drugs to prepare a ternary compound inhalation solution.
  • Example 109 Example 110
  • Example 111 Example 112 Indacaterol maleate 0.108g 0.108g 0.08g 0.13g Glycopyrrolate / 0.058g 0.046g 0.07g Sodium acetate / / / / ascorbic acid / / / / Citric acid 0.699g 0.699g 0.699g 0.699g Sodium citrate 0.492g 0.492g 0.492g 0.492g 0.492g 0.492g 0.492g 0.492g 0.492g Sodium chloride 6g 6g 6g 6g hydrochloric acid Right amount Right amount Right amount Right amount Add water to 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL 1000mL
  • Example 107 and Example 108 are samples prepared according to the recipe process of Example 1 and Example 2 in patent CN103860463A, respectively.
  • Example 109 Measure the prescription amount of water, add the prescription amount of citric acid and sodium citrate, stir to dissolve, add the prescription amount of sodium chloride, stir to dissolve, adjust the pH to 4.00 ⁇ 0.05 with an appropriate amount of hydrochloric acid, and finally add the prescription amount Indacaterol maleate, stir to dissolve and filter, and dispense into ampoules.
  • Example 107 to Example 110 were placed in a thermostat at 25 ⁇ 2° C. to investigate the changes of related substances during the placement of the samples.
  • Example 107 and Example 108 prepared with reference to the formulations of Example 1 and Example 2 in the patent CN103860463A, the content of related substances of indacaterol increased significantly during storage at room temperature, and it exceeded that after 3 months of storage. Increased by 0.8% to 1.0%.
  • the samples of Example 109 and Implementation 110 prepared according to the technical scheme of the present invention only slightly increased the content of indacaterol related substances after being placed at room temperature for 3 months, and the stability of indacaterol maleate was significantly better than that in CN103860463A.
  • Example 1 The samples of Example 1 and Example 2; and there was no significant difference in the growth of related substances of indacaterol between the samples of Example 109 and Example 110, indicating that the addition of glycopyrrolate in the composition of the present invention will not Affecting the stability of indacaterol maleate, there is no compatibility problem between indacaterol maleate and glycopyrrolate.

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Abstract

Composition pharmaceutique de solution pour inhalation et son procédé de préparation. La composition comprend de l'indacatérol ou des sels de ce dernier, un régulateur de pH et de l'eau, et un régulateur de pression osmotique facultatif et une paire d'ions tampon, et est préparée par dissolution des ingrédients dans de l'eau. La composition pharmaceutique est appropriée pour former une brume à partir d'une substance active à l'aide d'un nébuliseur pour une administration à des patients présentant de l'asthme et des symptômes de la BPCO au moyen d'une inhalation.
PCT/CN2020/120348 2019-10-11 2020-10-12 Composition pharmaceutique de solution pour inhalation et son procédé de préparation Ceased WO2021068961A1 (fr)

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WO2019142214A1 (fr) * 2018-01-19 2019-07-25 Cipla Limited Composition pharmaceutique comprenant du tiotropium destinée à être inhalée
WO2020019952A1 (fr) * 2018-07-26 2020-01-30 四川海思科制药有限公司 Composition pharmaceutique aérosol renfermant un glycopyrrolate et un sel d'indacatérol, son procédé de préparation et ses applications
WO2020105012A1 (fr) * 2018-11-22 2020-05-28 Glenmark Specialty S.A. Compositions stériles d'indacatérol appropriées pour la nébulisation
WO2020141472A1 (fr) * 2019-01-03 2020-07-09 Glenmark Specialty S.A. Composition de nébulisation comprenant du tiotropium et de l'indacatérol

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CN116963715A (zh) * 2020-09-29 2023-10-27 艾罗克斯医疗有限责任公司 茚达特罗的液体配制品
US12419883B2 (en) 2020-09-29 2025-09-23 Aerorx Therapeutics, Inc. Liquid formulations of indacaterol
WO2023139381A1 (fr) * 2022-01-21 2023-07-27 Nanopharm Limited Formulations inhalables
CN117679423A (zh) * 2022-09-05 2024-03-12 立生医药(苏州)有限公司 预防或治疗呼吸系统疾病的吸入用药物组合物
WO2024051683A1 (fr) * 2022-09-05 2024-03-14 立生医药(苏州)有限公司 Composition pharmaceutique pour inhalation destinée à prévenir ou à traiter une maladie respiratoire
CN115531359A (zh) * 2022-09-30 2022-12-30 郑州深蓝海生物医药科技有限公司 一种异烟肼吸入溶液剂及其制备方法和应用

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