WO2020022546A1 - Préparation pharmaceutique contenant du bosentan - Google Patents

Préparation pharmaceutique contenant du bosentan Download PDF

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WO2020022546A1
WO2020022546A1 PCT/KR2018/009357 KR2018009357W WO2020022546A1 WO 2020022546 A1 WO2020022546 A1 WO 2020022546A1 KR 2018009357 W KR2018009357 W KR 2018009357W WO 2020022546 A1 WO2020022546 A1 WO 2020022546A1
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inhalation
mannitol
bosentan
carrier
microparticles
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PCT/KR2018/009357
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English (en)
Korean (ko)
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박천웅
김동욱
이효중
양민규
심희섭
김좌진
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주식회사 마더스제약
충북대학교 산학협력단
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Publication of WO2020022546A1 publication Critical patent/WO2020022546A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to pharmaceutical formulations containing bosentane, and more particularly to pharmaceutical formulations containing bosentane that can be administered to the lungs of an individual via inhalation.
  • the present invention relates to a composition for preventing or treating pulmonary arterial hypertension, including a pharmaceutical preparation containing bosentan.
  • Bosentane is represented by Formula 1, 4-tert-butyl-N- [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- (pyrimidine-2- Il) -pyrimidin-4-yl] -benzenesulfonamide is a compound with the chemical name of Endothelin Receptor antagonist (ERA) which prevents the decrease in motor performance due to pulmonary hypertension. It is known from 0526708 A1 and is a representative pulmonary hypertension therapeutic currently marketed under the product name Tracleer tablet (Accelion). It is primarily a therapeutic agent for patients with pulmonary hypertension functional class II, III, or IV, which is administered twice daily (morning and evening).
  • ERA Endothelin Receptor antagonist
  • bosentane liver cell damage caused by the induction of cytochrome P2C9 P450 enzymes. Hepatic dysfunction that should stop bosentan occurs in more than 1% of patients with an aminotransferase of more than five-fold increase and bilirubin more than two-fold increase. Other side effects include headaches, nasopharyngitis, flushing and lower extremity edema. Also, in combination with sildenafil, bosentan requires a 50% reduction in the concentration of sildenafil to increase the dose of sildenafil, and also requires dose control by increasing the metabolism of warfarin. These side effects are mainly due to interactions with other drugs, bypass and systemic circulation.
  • bosentane is taken twice a day because of its short half-life. This twice-daily administration is inconvenient to take the medication, not only reduce the patient's compliance with the medication, but also miss the appropriate time to increase the possibility of side effects is inevitably needs a solution.
  • bosentan is a drug having a large limit as an oral dosage form because it is difficult to achieve the convenience of taking it by improving the absorption or dispersibility by improving the solubility because it is very difficult to dissolve in water.
  • transpulmonary delivery efficiency the anatomical physiological characteristics of the lungs should be good in the lung area to which the inhaled drug is delivered, that is, transpulmonary delivery efficiency.
  • transpulmonary delivery efficiency is considered more important because pulmonary hypertension can be effective only when it is delivered and absorbed up to the alveolar level of respiratory bronchioles.
  • the transpulmonary delivery efficiency of the inhaled particles is determined by the physicochemical properties of the particle size distribution, surface energy, shape, surface shape, crystallinity, moisture content, and the like, but hardly any such studies have been conducted with respect to bosentane.
  • the present inventors have made intensive efforts to solve the drawbacks of the above bosentane drug, and thus completed the present invention by changing the formulation of bosentane into an inhalation formulation and formulating a suitable formulation.
  • An object of the present invention is a microparticle of bosentan hydrate; And inhalation comprising any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol It is to provide a pharmaceutical formulation.
  • An object of the present invention is a microparticle of bosentan hydrate; And any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol It is to provide a pharmaceutical aerosol composition for preventing or treating hypertension.
  • An object of the present invention is a microparticle of bosentan hydrate; And inhalation comprising any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol It is to provide a dry powder delivery device containing a pharmaceutical formulation.
  • Object of the present invention is bosentan hydrate; And / or micronize any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol It provides a method for the preparation of pharmaceutical formulation for inhalation comprising the step of.
  • the present invention is based on the development of a safe and effective pharmaceutical formulation of bosentan that can deliver an amount effective to exert potent biological activity in these target tissues while minimizing bosentan associated toxicity.
  • the present invention shows the surprising pharmacokinetic properties of the formulated bosentan.
  • bosentane delivered directly to the lung produces significantly higher drug concentrations in lung tissue and the amount of drug in lung tissue is higher than predictable from previous oral and intravenous studies. It can show good therapeutic effect without causing toxicity to tissue.
  • the organic binding of the carrier components can have a longer duration of action while reducing the number of administration of the drug can be useful in inhalation formulations.
  • fine particles of bosentan hydrate comprising any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol
  • any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol
  • Inhaled pharmaceutical formulations of the present invention deliver bosanthane hydrates directly to the lungs, but are non-toxic and provide longer duration of action at lower doses compared to other dosage forms of bosentan, such as oral or intravenous dosage forms. Indicates. Sedimentation occurs mainly when very small particles moving with the inhaled airflow face the physiological surface as a result of random diffusion inside the airflow.
  • the inhaled pharmaceutical formulations of the present invention are suitable for maximizing their deposition by sedimentation in the alveoli, in order to achieve the desired therapeutic efficacy.
  • Pharmaceutical inhalation refers to pharmaceutical inhalable through the respiratory tract, nasal cavity, or the like, including respirable particles or droplets containing bosentan.
  • Bosentan hydrate (hereinafter, bosentan) is represented by Formula 1, 4-tert-butyl-N- [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy)- 2- (pyrimidin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide.
  • Tracleer tablet (Acelion) and is used only as an oral dosage.
  • Bosentane microparticles in the present invention may be particles having an average median diameter in the range of 0.1 to 10 ⁇ m, preferably in the range of 1 to 5 ⁇ m.
  • the bosentane microparticles can be produced, for example, by spray drying or jet milling.
  • the carrier includes any one or more selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol.
  • microparticles prepared by spray drying, jet milling, sieving, or the like.
  • the carrier may be mannitol.
  • the mannitol has an advantage in that it is easy to adjust the stabilization of the crystal structure and the shape of the particle surface even in the manufacture according to the spray drying method, and also to remove the bronchial mucus.
  • the weight ratio of such bosentane and mannitol is 5: 1 to 1: 5, preferably 3: 1 to 1: 3, more preferably 2: 1 to 1: 2, most preferably 1: 1.
  • Zeta-potential has the largest absolute value and shows relatively stable surface energy, and most preferably shows the best and stable surface energy at a ratio of 1: 1, which is suitable for pharmaceutical preparations for inhalation.
  • the drug delivery to the pulmonary bronchiole is very good with the smallest mass median aerodynamic diameter (MMAD) and highest fine particle fraction (FPF%) values in the gastric ratio.
  • MMAD mass median aerodynamic diameter
  • FPF% fine particle fraction
  • each carrier consists of particles of a different size range, measured by average particle diameter.
  • the carrier consists of two different carriers, namely a first carrier and a second carrier (carrier).
  • the first carrier consists of particles having a diameter of 0.1 to 10 ⁇ m, preferably 0.5 to 5 ⁇ m
  • the second carrier consists of particles having a diameter in the range of about 5-300 ⁇ m, preferably 10-200 ⁇ m.
  • the weight ratio of the combined weight of the bosentane and the first carrier to the weight of the second carrier is 1:15 to 1:30, preferably 1:17 to 1:23, and more preferably 1:19.
  • the first carrier is mannitol and the second carrier is lactose.
  • mannitol has an advantage of easily stabilizing the crystal structure and controlling the surface shape of the particles and removing the bronchial mucus.
  • Lactose maintains homogeneity of the dispersion of bosentan microparticles to ensure homogeneity of capacity and improves flow characteristics, making it easy to handle and eject when used as an inhalation formulation. Furthermore, it can help the bosentane fine particles reach the lungs easily during inhalation.
  • the lactose is milled lactose, such as lactose sold under the granulac® 200 brand, or lactose sold under the trademarked lactose, such as the inhalac® 250 brand.
  • the amount of bosentane in the inhaled pharmaceutical formulation is about 0.01% to 20% (w / w) based on the total weight of the composition. In one embodiment, the amount is about 0.1% to 4% (w / w), and in other embodiments about 2.5%.
  • Inhalable pharmaceutical formulations of the present invention may further comprise additional pharmaceutically acceptable excipients.
  • it may further include a material such as a diluent, stabilizer, adjuvant, antioxidant, adjuvant, propellant, or vehicle.
  • Dry powders such as, but not limited to, hydrocarbons and fluorocarbon propellants, compressed gases, sterile liquids, water, buffered saline, ethanol, suspending agents, antioxidants (eg, ascorbic acid or glutathione), chelating agents, low molecular weight proteins , Or suitable mixtures thereof.
  • Inhaled pharmaceutical formulations of the present invention are suitable for use in either dry powder inhaler devices (DPIs) or compressed metered dose inhalers (pMDIs), preferably in dry powder inhaler devices.
  • Drug particles are lightly compressed into a frangible matrix contained within a delivery device (dry powder inhaler).
  • the delivery device abolishes some of the drug particles from the matrix and disperses them into the inhaled breath that delivers the drug particles to the airways.
  • the drug particles may be free flowing powders contained within a reservoir in a delivery device (dry powder inhaler).
  • the reservoir can be an integral chamber inside the device, or a capsule, blister or similar capacity reservoir inserted into the device prior to operation.
  • the device disperses some of the drug particles from the reservoir and disperses them into inhaled breath that delivers the drug particles to the airways.
  • An object of the present invention is a microparticle of bosentan hydrate; And any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol It is to provide a pharmaceutical aerosol composition for preventing or treating hypertension.
  • Aerosol composition means an aerosolizable composition suitable for producing respirable particles or droplets containing bosentane. It is preferably a dry powder suitable for administration via a dry powder inhalation device.
  • the present invention provides methods and compositions for the treatment and prophylaxis in a subject in need thereof for pulmonary hypertension, comprising administering a pharmaceutical aerosol composition.
  • the present invention may be administered in an effective amount of about 0.125 mg to 125 mg, preferably 1.25 mg to 62.5 mg, but is not limited to once per week, twice a week, three times a week, four times a week, Pulmonary hypertension can be treated by administering five times a week, six times a week, and seven times a week. This minimizes the side effects of drug administration by reducing the frequency of administration compared to the conventional oral administration method.
  • the aerosol composition of the present invention can be administered in combination with one or more additional therapeutic agents. That is, the aerosol formulations of the invention may be administered alone or in combination with one or more additional therapies, each of which may be administered by the same or different routes, such as orally, intravenously, and the like.
  • the target tissue of the aerosol composition of the invention is the lung and the therapeutic level lasts at least 12 hours, 24 hours, 2 days, 3 days, 4 days or more after delivery.
  • the amount of bosentane composition in the aerosol composition is 20, 40, 50, 100, 125, or 250 ⁇ g.
  • An effective amount of the composition of the present invention reduces or ameliorates the progression, severity, and / or duration of pulmonary hypertension (PAH) or one or more symptoms of pulmonary hypertension, prevents the development of pulmonary hypertension, resulting in the regression of pulmonary hypertension, To prevent the onset or onset of one or more symptoms associated with pulmonary hypertension, to prevent the severity or onset of one or more symptoms of pulmonary hypertension, or to develop or progress pulmonary hypertension, or to prevent other therapies (eg, prophylactic or therapeutic agents), or May enhance or improve the therapeutic effect. Also in connection with the treatment of pulmonary arterial hypertension, a therapeutically effective amount can inhibit or reduce the proliferation of vascular cells, inhibit or reduce smooth muscle cell proliferation, reduce hypertrophy of the pulmonary canal or improve FVC or FEV1. .
  • Treatment refers to the severity, duration, or progression of pulmonary arterial hypertension, or the reduction of one or more symptoms associated with pulmonary arterial hypertension.
  • Prevention means the prevention of recurrence, development, progression or onset of one or more symptoms of pulmonary hypertension resulting from the administration of a composition identified in accordance with the methods of the present invention or the combination of a known therapy for a disease or disorder with such a compound. Refers to.
  • An object of the present invention is a microparticle of bosentan hydrate; And inhalation comprising any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol It is to provide a dry powder delivery device containing a pharmaceutical formulation.
  • the dry powder delivery device for example Accuhaler®, Conix TM, Rotahaler®, TwinCaps®, XCaps®, FlowCaps®, Turbuhaler®, NextHaler®, CycloHaler®, Revolizer TM, Diskhaler®, Diskus®, Spinhaler, Handihaler®, Microdose inhaler, It is contained in a dry powder inhaler (DPI) device selected from GyroHaler®, OmniHaler®, Clickhaler®, Duohaler® (Vectura), and ARCUS® Inhaler (Civitas Therapeutics).
  • DPI dry powder inhaler
  • the present invention provides a DPI device containing the dry powder composition described herein.
  • the device is for example selected from the group consisting of XCaps, FlowCaps, Handihaler, TwinCaps, Aerolizer®, Plastiape® RS01 Model 7, and Plastiape® RS00 Model 8.
  • Pulmonary delivery is preferably achieved by inhalation of the aerosol through the mouth and throat into the lungs.
  • the aerosol is delivered to the airways via the oral cavity.
  • the present invention also provides fine particles of bosentan hydrate; And inhalation comprising any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol
  • a method of treating pulmonary hypertension by administering a pharmaceutical formulation inhaled to a patient in a pharmaceutically effective amount.
  • the present invention also provides microparticles of the bosentane hydrate in the manufacture of a medicament for the treatment of pulmonary hypertension; And inhalation comprising any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol Provides the use of pharmaceutical preparations.
  • the invention also relates to microparticles of the bosentane hydrate for use in the treatment of pulmonary hypertension; And inhalation comprising any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol It provides a composition comprising a pharmaceutical formulation.
  • Object of the present invention is bosentan hydrate; And / or micronize any one or more carriers selected from arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, maltose, starch, dextran, lactose and mannitol It provides a method for the preparation of pharmaceutical formulation for inhalation comprising the step of.
  • Particle sizes can be obtained from conventional polishing methods, such as by grinding in air-jet mills, ball mills or vibratory mills, from wet polishing, microprecipitation, spray drying, lyophilization or subcritical or supercritical solutions. Recrystallization can be reduced to the desired microparticulates. Jet milling or grinding in this context refers to the micronization of dry drug particles by mechanical means. In certain embodiments, it is desirable to include a carrier material that will be co-micronized with bosentan.
  • bosentan fine particles in the size range of 0.1 to 10 or 1 to 5 ⁇ m are produced by a jet milling method.
  • the carrier may also be prepared together or separately prepared through spray drying, jet milling, sieving, or the like, followed by mixing.
  • Spray drying generally involves preparing a solution, slurry, or suspension of a drug, atomizing the solution, slurry, or suspension to form particles, and then evaporating the solution, slurry, or suspension medium to form the particles.
  • Solutions, slurries or suspensions may be formed in subcritical or supercritical conditions.
  • the evaporation step can be accomplished by raising the temperature of the atmosphere in which spraying occurs therein, by reducing the pressure, or by a combination of both.
  • a powder formulation comprising bosentane spray-drys an aqueous dispersion of bosentane and mannitol to form a dry powder consisting of agglomerated particles of bosentane having a size suitable for pulmonary delivery, as described above.
  • Aggregated particle size may be adjusted (increased or reduced) to target either the deep lung or the upper respiratory area, such as the upper bronchial region or the nasal mucosa. This can be achieved, for example, by increasing the concentration of bosentane in the spray-dried dispersion or by increasing the droplet size produced by the spray dryer.
  • Bosentane and mannitol microparticles can then be prepared by mixing with lactose microparticles.
  • the method for preparing the inhaled pharmaceutical formulation may preferably include the following steps.
  • step (b) mixing the bosentan hydrate and mannitol microparticles prepared by micronization in step (a) with lactose microparticles.
  • the micronization step may be a spray drying method, and the weight ratio of bosentane hydrate and mannitol is 5: 1 to 1: 5, preferably 3: 1 to 1: 3, more preferably 2: 1 to 1: 2, most preferably 1: 1.
  • the weight ratio of bosentan hydrate and mannitol microparticles to lactose microparticles is 1:15 to 1:30, preferably 1:17 to 1:23, and more preferably 1:19. .
  • the pharmaceutical composition containing bosentan according to the present invention has excellent drug delivery characteristics to target the lungs while minimizing drug toxicity of bosentan by organic bonding of bosentan and formulation components, and has a longer action while reducing the frequency of drug administration. It can have a duration and can be usefully used as an inhalation formulation.
  • Figure 1 shows a scanning electron micrograph of the bosentan and mannitol-containing microparticles.
  • Figure 2 shows a scanning electron micrograph of the microparticles mixed with bosentan and mannitol-containing microparticles and lactose microparticles (carrier).
  • Figure 3 shows the results of differential scanning calorimetry of bosentan-mannitol fine particles.
  • Figure 5 shows the results of confirming the aerosol performance of the microparticles mixed with bosentan and mannitol-containing microparticles and lactose microparticles (carrier).
  • Figure 6 shows the dissolution rate test results of bosentan-mannitol fine particles.
  • Figure 7 shows an in vivo experimental schedule for confirming the effect of the treatment of pulmonary hypertension of bosentan-mannitol microparticles.
  • Figure 8 shows a parasternal short axis image of the ventricles confirmed in vivo experiments to confirm the effect of pulmonary hypertension treatment.
  • Figure 9 shows the results of confirming the change in morphology and vascular wall thickness ratio of the pulmonary artery in an in vivo experiment to confirm the effect of pulmonary hypertension treatment.
  • Example 1-1 Micronized Bosentane Preparation by Spray Drying
  • Bosentan hydrate (Hanmi Pharm Co. Ltd., Seoul, Korea) was ground by ultrasonication for 20 minutes, dissolved in ethanol and sprayed with 1%, 3%, and 5% drug concentration solutions (SD 1%, respectively). SD 3% and SD 5%) were obtained.
  • Borsentan was spray dried using EYELA SD-1000 (Rikakikai Co., Ltd., Japan) under the following conditions: inlet temperature 110 ° C .; outlet temperature 65-75 ° C .; nozzle size 0.4 mm; feeding rate 10 mL / min; atomization air pressure 200 kPa; And blower rate 0.30 m 3 / min.
  • the spray dried bosentane microparticles prepared were stored in glass vials containing silica gel at ⁇ 20 ° C. until use.
  • the bosentane microparticles produced are round smooth amorphous particles.
  • Jet-mill bosentan hydrate microparticles were prepared using A-O JET MILL (J S Tech Co., Ltd., Korea). Prepared according to 0.2, 0.3 and 0.4 MPa air pressure (JM 0.2, JM 0.3 and JM 0.4) and other parameters were performed identically under the following conditions: feeding rate 250%; feeding vibration 40 Hz; And pushing air pressure of 0.5 MPa.
  • the prepared jet-mill bosentan microparticles were stored in glass vials containing silica gel at ⁇ 20 ° C. until use.
  • the prepared bosentane microparticles have a smaller particle size compared to ordinary bosentane.
  • bosentane hydrate and D-mannitol were dissolved in 70% ethanol at a ratio of 3: 1, 1: 1, 1: 3 (w / w), respectively, and the total powder concentration was 1% ( w / v) was obtained (referred to as SDBM 3: 1, SDBM 1: 1, SDBM 1: 3 after preparation, respectively). Then, bosentane and mannitol-containing microparticles were prepared and stored by spray drying under the same conditions as in Example 1-1.
  • Milled lactose granulac® 200
  • filled lactose inhalac® 250
  • M-SDBM milled lactose
  • S-SDBM filled lactose
  • the starting materials of lactose were separated using 75 ⁇ m and 150 ⁇ m sieves and only particles were left between the two.
  • microparticles prepared in Example 2 in the ratio of 1: 1 and each lactose in a ratio of 1:19 were mixed with a Turbula mixer (Impandex Inc., Maywood, NJ, USA) at 72 rpm for 15 minutes in a glass vial. Stored.
  • Turbula mixer Impandex Inc., Maywood, NJ, USA
  • Example 4-1 Scanning electron microscope (SEM) analysis
  • Bosentane samples were placed on carbon tape and platinum coated using a Hummer VI sputtering device. Then, it was observed using a scanning electron microscope (ZEISS-GEMINI LEO 1530, Zeiss, Germany).
  • FIG. 1 shows the results of scanning electron microscopy analysis of bosentan and mannitol-containing microparticles prepared in Example 2.
  • FIG. 1 shows the results of scanning electron microscopy analysis of bosentan and mannitol-containing microparticles prepared in Example 2.
  • FIG. 1 shows the results of scanning electron microscopy analysis of bosentan and mannitol-containing microparticles prepared in Example 2.
  • FIG. 1 shows the results of scanning electron microscopy analysis of bosentan and mannitol-containing microparticles prepared in Example 2.
  • FIG. 2 shows a scanning electron micrograph of lactose carrier-based bosentan microparticles prepared in Example 3.
  • FIG. 2 shows a scanning electron micrograph of lactose carrier-based bosentan microparticles prepared in Example 3.
  • FIG. 2 shows a scanning electron micrograph of lactose carrier-based bosentan microparticles prepared in Example 3.
  • FIG. 2 shows a scanning electron micrograph of lactose carrier-based bosentan microparticles prepared in Example 3.
  • FIG. 2 shows a scanning electron micrograph of lactose carrier-based bosentan microparticles prepared in Example 3.
  • Example 4- Particle size and particle distribution, surface charge, water content, true density, surface area, differential scanning calorimetry (DSC)
  • Particle size, distribution and surface charge were determined using a dynamic light scattering technique (Zetasizer Nano ZS, Malvern Instruments, UK, measurement range of 0.3 nm-10.0 ⁇ m). After adding 3 mg of sample to 10 mg distilled water, the suspension was vortexed for 20 seconds and left for 1 hour. The average particle size and particle distribution were then expressed as Z-means, polydispersity index.
  • Water content was quantified using Karl Fischer titration (736 GP Titrino, Metrohm, Switzerland). The sample was dissolved in methanol, and the sample solution was filled with Hydranal ® Composite and injected into the titration cell. Residual water in the sample was checked through the above instrument.
  • True density was determined using a pycnometer under helium gas, and the temperature was repeated 10 times at 27 ° C.
  • Differential scanning calorimetry was measured using a differential scanning calorimeter (DSC 2910, TA Instruments, DE, USA). Samples were placed in a DSC aluminum pan and scanned at 30 ° C. to 180 ° C. at 10 ° C./min after sealing.
  • DSC 2910 differential scanning calorimeter
  • thermogram of bosentan-mannitol fine particles showed a melting peak of mannitol while no melting peak of bosentan was found. This shows that amorphous bosentane and crystalline mannitol form a particle together, indicating that the formulation is suitable for delivery to the lungs.
  • lactose carrier-based bosentan microparticles were dispersed using a sample in isopropyl alcohol and then laser diffraction particle sizing by wet dispersion method (Mastersizer 2000, Malvern Instruments, Worcestershire, UK).
  • the aerosol performance of the fine particles prepared in Examples 2 or 3 was determined by 8-stage non-viable Andersen Cascade Impactor (ACI) (TE-20-800, TISCH Environmental, Inc.). , OH, USA) and Handihaler® (Boehringer Ingelheim, Germany) DPI devices. 60 L / min was operated and measured before using a flow meter (DFM 2000, COPLEY scientific, Nottingham, UK). ACI stage collection plates were precoated with silicone oil to prevent particle bounce and re-entrainment. At 20 mg the powder equivalent was loaded into a hydroxypropyl methylcellulose hard capsule.
  • ACI 8-stage non-viable Andersen Cascade Impactor
  • the capsule was placed in the Handihaler® and firmly inserted into the mouthpiece suitable for the induction port.
  • the particles were aerosolized at 60 L / min for 4 seconds and the amount of drug deposited in each stage was quantified using HPLC analysis.
  • the cut-off diameters represented by -1, 0, 1, 2, 3, 4, 5 and 6 stages at 60 L / min were 8.6, 6.5, 4.4, 3.3, 2.0, 1.1, 0.54, and 0.25 ⁇ m, respectively. .
  • Mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were calculated using a web-based tool (www.mmadcalculator.com/andersen-impactor-mmad.html) and all the above experiments were repeated three times.
  • the mixing of bosentane and mannitol significantly improved the MMAD and FPF%.
  • the smallest MMAD and the highest FPF% values were found in the microparticles of bosentan and mannitol in a 1: 1 ratio.
  • the medium of the receptor phase was used at 37 ° C PBS pH 7.4 (tween # 80 5% w / w; 12 mL; 37 ° C), and a cellulose filter (pore size: 0.45 ⁇ m; Advantec) was used as the membrane. It was.
  • the amount of drug transferred to medium by loading and eluting the bosentane-mannitol microparticles prepared in Example 2 corresponding to about 5 mg was analyzed by HPLC.
  • HPLC analysis was performed using HPLC (Ultimate 300 series HPLC, Thermo Fisher Scientific), and the analysis conditions were column: Luna L11 250X4.60mm, 5 ⁇ m, mobile phase: acetonitrile and buffer (0.1% triethylamine solution, pH 2.5) at a ratio of 45:55 (v / v), flow rate: 1.5 mL / min, injection volume: 10 ⁇ L, detector: UV 220 nm.
  • microparticles produced as a result of the co-spray drying of bosentan and mannitol exhibited significantly enhanced aerosol performance and dissolution rate. These microparticles were rapidly eluted after being delivered deeply to the pulmonary bronchiole as a dry powder inhalant. It can be seen to show effectively enhanced bioavailability.
  • Example 7-1 Preparation of pulmonary hypertension (PAH) -induced animal model and drug administration
  • Pulmonary hypertension was induced by 8-week-old male SD-rats fed free diet at 50 ⁇ 10% relative humidity and room temperature for 12 h night / day cycle and intraperitoneal injection of monocrotaline at 50 mg / kg.
  • the experimental group was set up as shown in Table 5 below to perform the experiment.
  • NC negative control group
  • PC positive control group
  • IR normal bosentane inhalation administration group
  • IR pulmonary hypertension uninduced general bosentan inhalation administration group
  • the bosentan-mannitol inhalation group showed an AUC value about 10 times higher than oral administration. Compared to oral administration, inhalation can avoid the hepatic bypass of the drug, and has the advantage of increasing the bioavailability due to the advantages of the large surface area of the lung, large blood flow, and thin epithelial cells. Among them, the bosentan-mannitol inhalation group, which had very high aerosol performance and dissolution rate, showed the highest effect.
  • Example 7-4 Long-term weighing to determine treatment effectiveness
  • Pulmonary hypertension is due to the constant blood flow resistance of the pulmonary artery and the myocardium has to exercise excessively to maintain cardiac output. appear.
  • the positive control group showed a significantly larger value than the negative control group, and the bosentan- according to the present invention.
  • the experimental group administered with mannitol inhalation group (ISD, 1: 1 SDBM) showed the best improvement of right ventricular hypertrophy.
  • the cardiac morphology was observed through echocardiography immediately before the end of the experiment, and the ventricular morphology parameters were measured and shown in FIGS. 8 and 8.
  • Eccentricity is an indicator of the deformation of the circular left ventricular axial phase into elliptical shape due to the increase in the right ventricular pressure. It is expressed as the ratio of the long axis and the short axis of the left ventricular lumen during contraction.
  • RVIDd right ventricular internal diameter
  • RVPWd right ventricular posterior wall end diastole
  • the experimental group administered the bosentan-mannitol inhalation administration group (ISD, 1: 1 SDBM) according to the present invention reduced the right ventricular internal diameter (RVIDd) and the right ventricular posterior wall end diastole (RVPWd) close to the negative control group. Showed.
  • the positive control group induced pulmonary hypertension was confirmed that the muscle layer (pink area) present in the vascular muscle was significantly enlarged compared to the negative control group.
  • the thinnest vessel wall thickness ratio could be confirmed when the experimental group administered the bosentan-mannitol inhalation administration group (ISD, 1: 1 SDBM) according to the present invention.

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Abstract

L'invention concerne une composition pharmaceutique contenant du bosentan. Selon l'invention, une composition pharmaceutique contenant du bosentan présente une excellente propriété de libération de médicament ciblant le poumon, tout en réduisant au minimum la toxicité médicamenteuse du bosentan en raison de la combinaison organique de bosentan et de composants de préparation, et présentant une durée d'action médicamenteuse plus longue tout en réduisant la fréquence d'administration de médicament, ce qui permet d'utiliser efficacement ladite composition en tant que formulation pour inhalation.
PCT/KR2018/009357 2018-07-24 2018-08-14 Préparation pharmaceutique contenant du bosentan WO2020022546A1 (fr)

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