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CN-117064869-B - Capsule type inhalation powder spray and preparation method thereof

CN117064869BCN 117064869 BCN117064869 BCN 117064869BCN-117064869-B

Abstract

The invention belongs to the technical field of biological medicines, relates to a medicinal preparation, and in particular relates to a capsule type inhalation powder spray and a preparation method thereof. The active ingredient of the capsule type inhalation powder spray is glycopyrrolate, the content of glycopyrrolate in each capsule is not higher than 20.0 mug calculated by glycopyrrolate, and the FPF in aerodynamic characteristics is 50.0-75.0%. The capsule type inhalation powder spray provided by the invention can obviously improve the medication safety on the premise of ensuring the drug effect.

Inventors

  • SUN YINGJI
  • XU JIHANG
  • YANG HAOWEI
  • LI TIEJUN
  • LU HUI
  • An Fanrong
  • XU YUWEN

Assignees

  • 山东京卫制药有限公司

Dates

Publication Date
20260512
Application Date
20230927

Claims (20)

  1. 1. The capsule type inhalation powder spray is characterized by comprising an active ingredient, a dispersing auxiliary and a carrier, wherein the active ingredient is glycopyrronium bromide, the content of glycopyrronium bromide in each capsule is 11.0-20.0 mug calculated by glycopyrronium, and the FPF in aerodynamic characteristics is 50.0-75.0%; In the APSD, the level deposition amount of 5-MOC is 1.3-4.1 mug, and the content uniformity is RSD less than or equal to 5%; the preparation method of the capsule type inhalation powder spray comprises the following steps: Providing an active ingredient, a dispersing aid and a carrier according to a prescription, wherein the carrier is divided into a large-particle-size carrier and a small-particle-size carrier; Mixing part of the dispersing auxiliary with part of the small-particle-size carrier to obtain a carrier compound; Mixing the carrier compound with the active ingredient, and carrying out micronization treatment to obtain an active ingredient intermediate I; uniformly mixing the active ingredient intermediate I with part of large-particle-size carriers to obtain an active ingredient intermediate II, and uniformly mixing the active ingredient intermediate II with the rest prescription components; Mixing part of the dispersing auxiliary and part of the small-particle-size carrier according to the weight ratio of 1:5-20; The particle size distribution range of the large-particle-size carrier is that D 10 is 4-10 mu m, D 50 is 30-60 mu m, and D 90 is 80-150 mu m; The particle size distribution range of the small particle size carrier is that D 10 is 0.4-1.2 mu m, D 50 is 1.5-4.7 mu m, and D 90 is 5.0-20.0 mu m; The particle size distribution range of the dispersing auxiliary is that D 10 is 2.2-4.2 mu m, D 50 is 7.2-11.5 mu m, and D 90 is 16-30 mu m; The content of the small-particle-size carrier is 2.0-6.0% of the total weight of the powder fog formulation; The carrier is one or more of lactose, dextran, mannitol, xylitol, phosphatidylcholine and cholesterol; The dispersing auxiliary is one or more of sodium stearate, magnesium stearate, calcium stearate and colloidal silicon dioxide; the content of the dispersing auxiliary is 0.1-0.5% of the total weight of the powder fog formulation.
  2. 2. The capsule-type inhalation powder spray of claim 1, wherein the content of glycopyrrolate in each capsule is 13.0-18.0 μg in terms of glycopyrrolate.
  3. 3. The encapsulated inhalation powder formulation of claim 1, wherein the aerodynamic profile is an FPF of 55.0-72.0%.
  4. 4. A capsule-type inhalation according to claim 3, wherein the FPF in aerodynamic characteristics is 59.0-69.0%.
  5. 5. The encapsulated inhalation powder aerosol formulation of claim 4, wherein the deposition level of 5 to moc in APSD is 2.0 μg to 3.5 μg.
  6. 6. The encapsulated inhalation powder formulation of claim 5, wherein the deposition level of 5-moc in APSD is 2.0 μg to 3.0 μg.
  7. 7. The encapsulated inhalation powder of claim 6 wherein the content uniformity is RSD < 3%.
  8. 8. The encapsulated inhalation powder of claim 7 wherein the content uniformity is RSD less than or equal to 2%.
  9. 9. The capsule-type inhalation powder spray of claim 1, wherein the glycopyrrolate content is 0.05-0.20% of the total weight of the powder spray formulation.
  10. 10. The capsule-type inhalation powder spray of claim 1, further comprising polyglycolic acid or polycaprolactone, wherein the content of the polyglycolic acid is 0.08-0.12% of the total weight of the powder spray prescription, and the content of the polycaprolactone is 0.08-0.15% of the total weight of the powder spray prescription.
  11. 11. The capsule-type inhalation powder of claim 10, wherein the particle size distribution of the polyglycolic acid is in the range of 0.5 to 0.7. Mu.m, D 50 is in the range of 1.2 to 2.0. Mu.m, D 90 is in the range of 3.0 to 5.0. Mu.m, and the particle size distribution of the polycaprolactone is in the range of 1.0 to 1.5. Mu.m, D 50 is in the range of 2.5 to 3.5. Mu.m, and D 90 is in the range of 5.0 to 7.0. Mu.m.
  12. 12. The capsule-type inhalation powder spray of claim 1, wherein the active ingredient further comprises one or more of formoterol, indacaterol, salmeterol and vilan Luo Zhong, and the mass ratio of the active ingredient in the prescription is 0.06% -0.15%.
  13. 13. The encapsulated inhalation powder aerosol formulation of claim 12, wherein the active ingredient further comprises at least one or more of budesonide, ciclesonide, triamcinolone acetonide, wherein the mass ratio of the budesonide, ciclesonide, triamcinolone acetonide in the formulation is 1.0% -5.0%.
  14. 14. A method for preparing the capsule type inhalation powder spray of claim 1, which is characterized by comprising the following steps: Providing an active ingredient, a dispersing aid and a carrier according to a prescription, wherein the carrier is divided into a large-particle-size carrier and a small-particle-size carrier; Mixing part of the dispersing auxiliary with part of the small-particle-size carrier to obtain a carrier compound; Mixing the carrier compound with the active ingredient, and carrying out micronization treatment to obtain an active ingredient intermediate I; uniformly mixing the active ingredient intermediate I with part of large-particle-size carriers to obtain an active ingredient intermediate II, and uniformly mixing the active ingredient intermediate II with the rest prescription components; Mixing part of the dispersing auxiliary and part of the small-particle-size carrier according to the weight ratio of 1:5-20; The particle size distribution range of the large-particle-size carrier is that D 10 is 4-10 mu m, D 50 is 30-60 mu m, and D 90 is 80-150 mu m; The particle size distribution range of the small particle size carrier is that D 10 is 0.4-1.2 mu m, D 50 is 1.5-4.7 mu m, and D 90 is 5.0-20.0 mu m; The particle size distribution range of the dispersing auxiliary is that D 10 is 2.2-4.2 mu m, D 50 is 7.2-11.5 mu m, and D 90 is 16-30 mu m; The content of the small-particle-size carrier is 2.0-6.0% of the total weight of the powder fog formulation; the content of the dispersing auxiliary is 0.1-0.5% of the total weight of the powder fog formulation.
  15. 15. The method for preparing a capsule type inhalation powder spray of claim 14, wherein the weight ratio of the partial dispersing auxiliary to the partial small particle size carrier is 1:5-10.
  16. 16. The method for preparing a capsule type inhalation powder spray of claim 14, wherein the weight ratio of the partial dispersing auxiliary to the partial small particle size carrier is 1:10-15.
  17. 17. The method for preparing a capsule type inhalation powder spray of claim 14, wherein the weight ratio of the partial dispersing auxiliary to the partial small particle size carrier is 1:15-20.
  18. 18. The method for preparing a capsule type inhalation powder spray of claim 14, wherein the addition amount of the partial dispersion auxiliary agent is 1/8~3/5 of the total dispersion auxiliary agent weight in the process of mixing the partial dispersion auxiliary agent with the partial small particle size carrier to obtain the carrier composite.
  19. 19. The method of claim 18, wherein the partial dispersing aid is added in an amount of 1/4~3/5 by weight of the total dispersing aid.
  20. 20. The method for preparing a capsule type inhalation powder spray of claim 19, wherein the addition amount of the partial dispersing aid is 1/2 to 3/5 of the total dispersing aid weight.

Description

Capsule type inhalation powder spray and preparation method thereof Technical Field The invention belongs to the technical field of biological medicines, relates to a medicinal preparation, and in particular relates to a capsule type inhalation powder spray and a preparation method thereof. Background The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art. Glycopyrrolate is a quaternary ammonium long-acting anticholinergic agent, can specifically bind to and inhibit M3 type acetylcholine receptors distributed in bronchus smooth muscle, and has pharmacological action of dilating bronchus. The current commercial glycopyrrolate-containing inhalation powder aerosol products mainly comprise single glycopyrrolate inhalation powder aerosol (Xilun ®), compound indacaterol bromide inhalation powder aerosol (Jie Run ®) and three-party indacaterol inhalation powder aerosol (En Zhuo Run ®) produced by Nohua, switzerland. In the three products, the content of glycopyrrolate in each capsule is 63 mug (50 mug calculated by glycopyrrolate), and the dosage of the product is 1 inhalation each time and 1 time a day. The inhaled powder spray has the advantages of quick response, high local medicine concentration, relatively small systemic side effect and the like when being used for treating COPD. However, inhalation of higher doses of glycopyrrolate also increases the probability and risk of clinical adverse effects such as dry mouth, urinary retention and adverse effects associated with local tolerability including pharyngeal irritation, nasopharyngitis etc. According to reports in the product specification, even if the product is used at recommended doses, quite common (more than or equal to 1/10) upper respiratory tract infection symptoms and common (more than or equal to 1/100 to < 1/10) nasopharyngitis, sinusitis, urinary tract infection and other adverse reactions can be brought. In addition, some neurological diseases such as dizziness, headache, ocular diseases such as glaucoma, gastrointestinal diseases such as dyspepsia, dry mouth, kidney and urinary system diseases such as bladder obstruction and urinary retention are common or occasional (> 1/1000 to < 1/100) adverse reactions listed in the product specification. Inhalation powder aerosols are very prone to diffusion of drug powder into the peripheral areas of the lungs due to their efficient aerosolization, resulting in rapid dissolution and absorption of drug powder into the blood, particularly in the case of ultrafine powders in micronized drugs, which are very prone to deposit at the bronchi and alveoli of the fine powders, where the drug tends to exhibit very high Cmax and systemic exposure in pharmacokinetic parameters in the body. This pharmacokinetic behavior tends to give rise to an increased probability of systemic adverse events. In addition, inhalation of the powder spray may cause a large amount of active ingredient to be trapped in the throat and other parts due to insufficient dissociation, causing symptoms such as throat irritation and inflammation, which are the main cause of adverse reactions related to local tolerability. Disclosure of Invention The inhalation powder aerosol refers to a preparation which is prepared by inhaling atomized medicines to the lung by a patient in a form of capsules, vesicles or a multi-dose storage after solid micronized raw medicines are singly or mixed with a proper carrier by adopting a special dry powder inhalation device. The medicine curative effect and the occurrence rate of adverse reaction of the medicine of the inhalation powder spray are closely related to the medicine dosage and the deposition position of the medicine in the respiratory tract. Generally, drug particles with the aerodynamic particle size of more than 5 μm are mainly deposited on the throat part through inertial impact and can be absorbed into the systemic circulation along with swallowing to reach the gastrointestinal tract, and particles with the particle size of 0.5-5 μm are deposited into the lung along with gravity, wherein the particles with the particle size of 3-5 μm are mainly distributed in the central region of the lung (such as the trachea, the bronchi and the like), and the particles with the particle size of less than 3 μm can be deeply delivered to the peripheral region of the lung (such as the respiratory bronchi, the alveolar tube, the lung vesicles and the like). Drugs with particle sizes less than 5 μm are considered inhalable doses and can bind to receptors in the lungs to produce therapeutic effects. In the in vitro research process of inhalation powder aerosol, drug particles with aerodynamic particle size smaller than 5 μm are generally defined as Fine Particle Dose (FPD)