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WO2025155150A1 - Composition de rivaroxaban pour inhalation - Google Patents

Composition de rivaroxaban pour inhalation

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Publication number
WO2025155150A1
WO2025155150A1 PCT/KR2025/099008 KR2025099008W WO2025155150A1 WO 2025155150 A1 WO2025155150 A1 WO 2025155150A1 KR 2025099008 W KR2025099008 W KR 2025099008W WO 2025155150 A1 WO2025155150 A1 WO 2025155150A1
Authority
WO
WIPO (PCT)
Prior art keywords
rivaroxaban
dry powder
bead
inhalation composition
air jet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2025/099008
Other languages
English (en)
Korean (ko)
Inventor
김영진
최예린
남궁희
박윤상
김동욱
박천웅
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.)
P2kbio Inc
Original Assignee
P2kbio Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by P2kbio Inc filed Critical P2kbio Inc
Publication of WO2025155150A1 publication Critical patent/WO2025155150A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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

Definitions

  • the present invention relates to a composition for inhalation of rivaroxaban. Specifically, it relates to a method for producing fine particles including rivaroxaban for inhalation, which have the property of agglomerating nano-sized particles by a bead mill and the property of being dispersed by an air jet mill, by combining a bead mill and an air jet mill equipment, and a technology for producing dry powder fine particles for inhalation, which contain a high drug content, by a hollow bead mill or hollow air jet mill based on a small amount of a dispersion stabilizer.
  • Venous thromboembolism including pulmonary embolism and deep vein thrombosis
  • pulmonary embolism has the second highest mortality rate after cancer, with a mortality rate of up to 30% if left untreated.
  • the risk of developing the disease in cancer patients increases every year, and is 4-7 times higher than that of non-cancer patients, and the risk of pulmonary embolism has increased further due to recent complications caused by Covid-19.
  • the present invention can provide a method for manufacturing inhalable fine particles of several to several tens of micrometers in size by combining a bead mill device and an air jet mill device. It is expected that the combination of the two devices can reduce the particle size of a dry powder inhalant to an inhalable size and improve dispersibility, thereby increasing the inhalation efficiency of the drug.
  • the present invention is to manufacture a dry powder inhaler of rivaroxaban with excellent inhalation efficiency through a bead mill and an air jet mill and with a high content without a separate carrier, thereby enabling delivery of the drug to the deep lungs.
  • the present invention discloses a method for preparing a rivaroxaban dry powder inhalation composition, comprising the steps of (S1) placing rivaroxaban or a pharmaceutically acceptable salt thereof and beads in a ball mill and milling to obtain a bead-milled rivaroxaban dry powder; and (S2) placing the obtained bead-milled rivaroxaban dry powder in an air jet mill and grinding it.
  • the present invention discloses a rivaroxaban dry powder inhalation composition
  • a rivaroxaban dry powder inhalation composition comprising rivaroxaban dry powder having a Dv50 diameter of 5 ⁇ m or less.
  • the present invention demonstrates that it is possible to manufacture inhalable fine particles having a size of several to several tens of micrometers with superior suction efficiency by combining a bead mill and an air jet mill, rather than by using a bead mill alone or an air jet mill alone, and additionally confirms that the dispersibility of dry powder fine particles can be improved by adding a small amount of dispersion stabilizer, thereby achieving even superior aerodynamic characteristics and maximizing suction efficiency.
  • This is a method for manufacturing dry powder microparticles with a high drug content using a separate carrier, and is expected to be used in dry powder inhalers that require a high drug content.
  • Figure 1 shows a process diagram for manufacturing bead mill dried powder fine particles according to Comparative Example 1-1.
  • Figure 2 shows a process diagram for manufacturing air jet mill dried powder according to Comparative Example 1-2.
  • Figure 4 shows a process diagram for manufacturing a lysine-based hollow bead mill dry powder according to Comparative Example 2.
  • Figure 5 shows a process diagram for manufacturing a combined dry powder of a lysine-based hollow bead mill and an air jet mill according to Example 2.
  • Figure 6 shows a process diagram for manufacturing a simple mixed dry powder based on bead mill rivaroxaban and leucine according to Comparative Example 3.
  • Figure 7 shows a process diagram for manufacturing a combined dry powder using a bead mill rivaroxaban and a leucine-based co-air jet mill according to Example 3.
  • Figure 8 shows a process diagram for manufacturing a magnesium stearic acid-based bead mill dry powder according to Comparative Example 4.
  • Figure 9 shows a process diagram for manufacturing a combined dry powder of a magnesium stearate-based hollow bead mill and an air jet mill according to Example 4.
  • Figure 10 shows a process diagram for manufacturing a simple mixed dry powder based on bead mill rivaroxaban and magnesium stearic acid according to Comparative Example 5.
  • Figure 11 shows a process diagram for manufacturing a combined dry powder using a co-air jet mill based on bead mill rivaroxaban and magnesium stearate according to Example 5.
  • Figure 12 shows a SEM image of the particle morphology of a dry powder containing a drug.
  • Figure 13 shows the absorption efficiency of the combined dry powder of the bead mill and air jet mill according to Experimental Example 3.
  • Figure 14 shows the absorption efficiency of the combined dry powder of the lysine-based hollow bead mill and air jet mill according to Experimental Example 3.
  • Figure 15 shows the absorption efficiency of the combined dry powder of the bead mill rivaroxaban and leucine-based co-air jet mill according to Experimental Example 3.
  • Figure 16 shows the absorption efficiency of the combined dry powder of a magnesium stearate-based hollow bead mill and air jet mill according to Experimental Example 3.
  • Figure 17 shows the absorption efficiency of the combined dry powder of the bead mill rivaroxaban and leucine-based co-air jet mill according to Experimental Example 3.
  • rivaroxaban may include all of its crystalline modifications and amorphous forms, and its hydrates, solvates and cocrystals.
  • the pharmaceutically acceptable salt of rivaroxaban is an acid addition salt or a base addition salt.
  • the acid addition salt includes a salt with an inorganic acid or an organic acid.
  • the inorganic acid salt include a salt with hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid
  • the organic acid salt include, but are not limited to, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid), ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • the above-mentioned base addition salts include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), or ammonia salts or organic amine salts, for example, salts with diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, or dehydroabetylamine.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • ammonia salts or organic amine salts for example, salts with diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, or dehydroabetylamine.
  • the step (S1) may be a step of placing rivaroxaban or a pharmaceutically acceptable salt thereof and beads into a ball mill and milling under the condition of repeating 3 to 8 times for 5 to 20 minutes at a speed of 500 to 800 rpm to obtain a bead-milled dry powder of rivaroxaban, but is not limited thereto.
  • the step (S1) may further include a step of adding a dispersion stabilizer to obtain a bead-milled rivaroxaban dry powder based on a dispersion stabilizer, or, after the step (S1), a step (S1-1) of mixing the bead-milled rivaroxaban dry powder with a dispersion stabilizer may be further included, but is not limited thereto.
  • step (S1) rivaroxaban or a pharmaceutically acceptable salt thereof, beads, and a dispersion stabilizer are placed in a ball mill and milled to obtain a bead-milled rivaroxaban dry powder based on a dispersion stabilizer (obtaining a hollow bead-milled dry powder), and then step (S2) of air jet milling is performed, or step (S1-1) of mixing the bead-milled rivaroxaban dry powder (simple bead-milled dry powder) obtained by step (S1) with a dispersion stabilizer is additionally performed, and then step (S2) of air jet milling is performed.
  • the dispersion stabilizer is used to control the dispersibility of the bead-milled dry powder of rivaroxaban.
  • the dispersion stabilizer may be included in an amount of 3 wt% or more based on the total weight of rivaroxaban, specifically, 5 wt% or more and less than 10 wt% based on the total weight of rivaroxaban, but is not limited thereto.
  • the amino acids may be at least one selected from the group consisting of leucine, trileucine, glycine, histidine, methionine, phenylalanine, valine, aspartame, arginine, and threonine, but are not limited thereto.
  • the lipids may be at least one selected from the group consisting of magnesium stearic acid, calcium stearic acid, sodium stearic acid, zinc stearic acid, and stearic acid, but are not limited thereto.
  • the step (S2) is a step of grinding using an air jet mill device, and the grinding step may be performed two or more times, but is not limited thereto.
  • the step (S1) may be a step of placing 1000 mg or more of rivaroxaban and beads into a ball mill and milling to obtain a bead-milled dry powder of rivaroxaban, specifically, it may be a step of adding 1000 mg or more and less than 4000 mg, and more specifically, 2500 to 3000 mg of rivaroxaban, but is not limited thereto.
  • the method for manufacturing a rivaroxaban dry powder inhalation composition according to the present invention has an advantage in that it can include a high content of rivaroxaban or a pharmaceutically acceptable salt thereof without a separate carrier, and thus can be applied to a dry powder inhaler that must have a high drug content.
  • the present invention provides a rivaroxaban dry powder inhalation composition.
  • the present invention provides a rivaroxaban dry powder inhalation composition
  • a rivaroxaban dry powder inhalation composition comprising rivaroxaban dry powder having a Dv50 diameter of 5 ⁇ m or less.
  • the Dv50 diameter refers to the particle diameter corresponding to the cumulative particle size distribution percentage reaching 50%. Its physical meaning is that particles with a particle diameter larger than this account for 50%, and particles smaller than this account for 50%, and Dv50 is also called the median diameter or median particle size. At this time, if the Dv50 diameter of the rivaroxaban dry powder exceeds 5 ⁇ m, it becomes difficult to inhale through an inhaler.
  • the dry powder inhalation composition may further include a dispersion stabilizer, but is not limited thereto.
  • the dispersion stabilizer may be included in an amount of 3 wt% or more based on the total weight of rivaroxaban or a pharmaceutically acceptable salt thereof, and specifically, may be included in an amount of 5 wt% or more and less than 10 wt% based on the total weight of rivaroxaban, but is not limited thereto.
  • the dispersion stabilizer may be at least one of amino acids or lipids, but is not limited thereto.
  • the amino acids may be at least one selected from the group consisting of leucine, trileucine, glycine, histidine, methionine, phenylalanine, valine, aspartame, arginine, and threonine, but are not limited thereto.
  • the lipids may be at least one selected from the group consisting of magnesium stearic acid, calcium stearic acid, sodium stearic acid, zinc stearic acid, and stearic acid, but are not limited thereto.
  • the above-described method for preparing a rivaroxaban dry powder inhalation composition can be applied to all of the above rivaroxaban dry powder inhalation compositions, as long as they are not contradictory to each other.
  • the present invention provides a dry powder inhaler comprising the above rivaroxaban dry powder inhalation composition.
  • the method for preparing a rivaroxaban dry powder inhalation composition and the description of the rivaroxaban dry powder inhalation composition described above can be applied to both of the above dry powder inhalers, as long as they are not contradictory to each other.
  • the term 'simple' means that no dispersion stabilizer is added during bead milling or air jet milling (for example, it means that no dispersion stabilizer is added during bead milling or air jet milling), 'co-milling' means that a dispersion stabilizer, leucine or magnesium stearate, is added together during bead milling or air jet milling (for example, a process in which a dispersion stabilizer is added together during bead milling or air jet milling means a co-bead mill or co-air jet mill), and 'combination' means that an air jet mill (simple air jet mill or co-air jet mill) is performed after a bead mill (simple bead mill or co-bead mill) (for example, a combination of bead milled rivaroxaban and leucine-based co-air jet mill means that bead-milled rivaroxaban and a dispersion stabilizer, leu
  • Comparative Example 1-1 Manufacturing of fine particle powder by bead mill drying (simple bead mill)
  • Example 1 Production of dry powder by combination of bead mill and air jet mill (simple bead mill followed by simple air jet mill)
  • rivaroxaban As shown in Table 1 above, 3 g of rivaroxaban is weighed and placed into a ball mill device (PM-100, Retsch GmbH, Germany) together with 750 g of 1 mm beads and 20 mL of distilled water, and milled five times at a speed of 650 rpm for 12 minutes (interval 3 minutes) (see Table 2). Thereafter, the drug rivaroxaban and the beads are separated and dried in an oven at 60°C to obtain bead-milled rivaroxaban (hereinafter referred to as 'WB rivaroxaban') dry powder.
  • 'WB rivaroxaban' bead-milled rivaroxaban
  • the obtained WB rivaroxaban dry powder is placed in small amounts into the inlet of an air jet mill device (A-O JET MILL; JS Tech Co. Ltd., South Korea).
  • the grinding pressure of the air jet mill is 0.45 MPa
  • the pushing pressure is 0.5 MPa
  • compressed air is supplied to grind it.
  • the crushed result is obtained and fed back into the inlet of the air jet mill equipment in small amounts for secondary crushing to obtain a combined dry powder of the bead mill and air jet mill (see Table 3).
  • the manufacturing process sequence for Example 1 is shown in Fig. 3.
  • Comparative Example 2 Production of dry powder using a hollow bead mill based on leucine (a hollow bead mill based on leucine)
  • Example 2 Production of dry powder by combination of hollow bead mill and air jet mill based on lysine (combination of hollow bead mill followed by simple air jet mill)
  • the grinding pressure of the air jet mill is 0.45 MPa
  • the pushing pressure is 0.5 MPa
  • compressed air is supplied to grind it.
  • the crushed product is obtained and fed back into the inlet of the air jet mill equipment in small amounts for secondary crushing to obtain a combined dry powder of a lysine-based hollow bead mill and air jet mill (see Table 3).
  • the manufacturing process sequence for Example 2 is shown in Fig. 5.
  • Example Example 2-1 Example 2-2 Example 2-3 note Rivaroxaban (mg) 3000 3000 3000 Leucine (mg) 30 150 300
  • Example 3 Production of dry powder by combination of bead mill rivaroxaban and leucine-based co-air jet mill (combination of simple bead mill followed by co-air jet mill)
  • the obtained pulverized products are put in small amounts into the inlet of the air jet mill equipment to perform secondary pulverization to obtain a combination of bead-milled rivaroxaban and leucine-based co-air jet mill (WB/co-AJ) dry powder.
  • the manufacturing process sequence for Example 3 is shown in Fig. 7.
  • Example Example 3-1 Example 3-2
  • Example 3-3 note Bidmil Rivaroxaban (mg) 3000 3000 3000 Leucine (mg) 30 150 300
  • Comparative example Comparative Example 4-1 note Rivaroxaban (mg) 3000 Magnesium Stearate (mg) 150
  • Example 4 Preparation of dry powder using a combination of a hollow bead mill and an air jet mill based on magnesium stearate (combination of a hollow bead mill followed by a simple air jet mill)
  • Comparative example Comparative Example 5-1 note Bidmil Rivaroxaban (mg) 3000 Magnesium Stearate (mg) 150
  • Example 5 The manufacturing process sequence for Example 5 is shown in Fig. 11.
  • Example Example 5-1 Example 5-2
  • Example 5-3 note Bidmil Rivaroxaban (mg) 3000 3000 3000 Magnesium Stearate (mg) 30 150 300
  • the particles of the dry powders manufactured according to Comparative Example 1-1, Comparative Example 1-2, and Example 1 are placed on a carbon tape and then coated with platinum using a coater. Thereafter, the particle morphology is observed using an electron scanning microscope (ZEISS-GEMINI LEO 1530, Zeiss, Germany) (observation is performed at magnifications of 1k and 10k).
  • the particle shapes of the dry powders containing drugs manufactured according to Comparative Example 1-1, Comparative Example 1-2, and Example 1 were evaluated and are shown in FIG. 12.
  • the bead mill dried powder according to Comparative Example 1-1 showed a shape in which nano-sized crystalline particles were aggregated
  • the air jet mill dried powder according to Comparative Example 1-2 showed a shape in which the particles were separated to form a single unit.
  • the inhalation efficiency of the dry powders according to Comparative Example 2-1, Example 2-1, Example 2-2, and Example 2-3 was evaluated in-vitro .
  • the dry powder according to Example 2-2 was evaluated to have higher inhalation efficiency than the dry powder of Comparative Example 2-1 (see FIG. 14 and Table 18).
  • a statistically more significant difference was shown in the FPF and FPD values, which confirmed that the combination process of the leucine-based hollow bead mill-air jet mill can actually work more advantageously in the deep lung than when the leucine-based hollow bead mill is performed alone.
  • Example 2-1 Example 2-2
  • Example 2-3 ED (%) 51.43 ⁇ 3.46 67.77 ⁇ 1.62 ** 74.57 ⁇ 3.12 **/$ FPF ( ⁇ 4.46 ⁇ m) 46.89 ⁇ 12.25 72.10 ⁇ 2.46 * 69.22 ⁇ 7.93 * FPD ( ⁇ g) 4831.10 ⁇ 1617.41 9306.22 ⁇ 315.75 ** 9366.71 ⁇ 898.04 ** MMAD ( ⁇ m) 4.91 ⁇ 2.36 3.80 ⁇ 0.13 3.13 ⁇ 0.39 GSD 3.02 ⁇ 0.82 2.00 ⁇ 0.06 2.13 ⁇ 0.30
  • the FPD value which is the amount of drug released from the capsule.
  • the FPD value was lower in the case of 1% leucine (Example 3-1) compared to Example 1 without leucine, it was confirmed that the ratio of leucine should be 5% or more (see Table 21).
  • Example 3-1 Example 3-2
  • FPD ( ⁇ g) 7845.94 ⁇ 1601.86 8560.54 ⁇ 42.77 6359.76 ⁇ 451.01
  • MMAD ( ⁇ m) 4.41 ⁇ 0.07 3.43 ⁇ 0.11 4.02 ⁇ 0.40
  • Example 4-1 The inhalation efficiency of the dry powders according to Comparative Example 4, Example 4-1, Example 4-2, and Example 4-3 was evaluated in-vitro .
  • the dry powder according to Example 4-2 was evaluated to have higher inhalation efficiency than the dry powder according to Comparative Example 4 (see FIG. 16 and Table 22).
  • a statistically more significant difference was shown in the FPF and FPD values, which confirmed that the combination process of the magnesium stearate-based hollow bead mill-air jet mill can actually work more advantageously in the deep lung than when the magnesium stearate-based hollow bead mill is performed alone.
  • Example 5-3 The inhalation efficiency of the dry powders according to Comparative Example 5, Example 5-1, Example 5-2, and Example 5-3 was evaluated in-vitro .
  • the dry powder according to Example 5-2 was evaluated to have higher inhalation efficiency than the dry powder according to Comparative Example 5 (see FIG. 17 and Table 24).
  • a statistically more significant difference was shown in the FPF and FPD values, which confirmed that the hollow air jet mill process can actually work more advantageously in the deep lung than simply mixing magnesium stearate into the bidimilled rivaroxaban.

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Abstract

Est divulgué un procédé de préparation d'une composition de poudre sèche de rivaroxaban pour inhalation, le procédé comprenant les étapes consistant à : (S1) placer du rivaroxaban ou un sel pharmaceutiquement acceptable de celui-ci et des billes dans un dispositif de broyeur à billes et broyer celui-ci pour obtenir une poudre sèche de rivaroxaban broyée par billes ; et (S2) placer la poudre sèche de rivaroxaban broyée obtenue dans un dispositif de broyeur à jet d'air et pulvériser celle-ci. Sont divulgués en outre : une composition de poudre sèche de rivaroxaban pour inhalation comprenant de la poudre sèche de rivaroxaban ayant un diamètre Dv50 inférieur ou égal à 5 µm ; et un inhalateur de poudre sèche comprenant la composition.
PCT/KR2025/099008 2024-01-16 2025-01-15 Composition de rivaroxaban pour inhalation Pending WO2025155150A1 (fr)

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KR1020240006867A KR20250112022A (ko) 2024-01-16 2024-01-16 리바록사반 흡입용 조성물
KR10-2024-0006867 2024-01-16

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WO2025155150A1 true WO2025155150A1 (fr) 2025-07-24

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