CN114515279A - Ambrisentan aerosol inhalation solution and preparation method thereof - Google Patents
Ambrisentan aerosol inhalation solution and preparation method thereof Download PDFInfo
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- CN114515279A CN114515279A CN202011305535.1A CN202011305535A CN114515279A CN 114515279 A CN114515279 A CN 114515279A CN 202011305535 A CN202011305535 A CN 202011305535A CN 114515279 A CN114515279 A CN 114515279A
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- ambrisentan
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- inhalation solution
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- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 title claims abstract description 82
- 229960002414 ambrisentan Drugs 0.000 title claims abstract description 81
- 229940041682 inhalant solution Drugs 0.000 title claims abstract description 53
- 239000000443 aerosol Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 239000006172 buffering agent Substances 0.000 claims abstract description 8
- 239000000872 buffer Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- 239000002245 particle Substances 0.000 claims description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000011049 filling Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 239000003708 ampul Substances 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000007789 sealing Methods 0.000 claims description 8
- 238000009688 liquid atomisation Methods 0.000 claims description 7
- 239000010419 fine particle Substances 0.000 claims description 5
- 239000003002 pH adjusting agent Substances 0.000 claims description 5
- 239000001509 sodium citrate Substances 0.000 claims description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- 238000009826 distribution Methods 0.000 claims description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 210000002345 respiratory system Anatomy 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000008227 sterile water for injection Substances 0.000 claims description 2
- 238000002663 nebulization Methods 0.000 claims 1
- 239000002552 dosage form Substances 0.000 abstract description 2
- 238000000889 atomisation Methods 0.000 description 25
- 239000000203 mixture Substances 0.000 description 15
- 239000003814 drug Substances 0.000 description 13
- 239000008215 water for injection Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 102000002045 Endothelin Human genes 0.000 description 7
- 108050009340 Endothelin Proteins 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 6
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000001502 supplementing effect Effects 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 230000007794 irritation Effects 0.000 description 4
- 230000002685 pulmonary effect Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 210000001147 pulmonary artery Anatomy 0.000 description 3
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010039163 Right ventricular failure Diseases 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000036593 pulmonary vascular resistance Effects 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 210000001533 respiratory mucosa Anatomy 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- BLUGYPPOFIHFJS-UUFHNPECSA-N (2s)-n-[(2s)-1-[[(3r,4s,5s)-3-methoxy-1-[(2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-[[(1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 BLUGYPPOFIHFJS-UUFHNPECSA-N 0.000 description 1
- 208000007934 ACTH-independent macronodular adrenal hyperplasia Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 208000032594 Vascular Remodeling Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000012387 aerosolization Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003434 inspiratory effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000007331 pathological accumulation Effects 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- DFIWJEVKLWMZBI-UHFFFAOYSA-M sodium;dihydrogen phosphate;phosphoric acid Chemical compound [Na+].OP(O)(O)=O.OP(O)([O-])=O DFIWJEVKLWMZBI-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- 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
- 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
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
- A61M11/02—Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Anesthesiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Dispersion Chemistry (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an ambrisentan aerosol inhalation solution, a preparation method and application. The single dose of the inhalation solution contains 0.1-20 mg of ambrisentan, a buffering agent, an isotonic regulator and a solvent, and can also comprise a pH regulator. The single dose specification of the inhalation solution is 1-5 ml. The dosage of the buffer is 0.01-0.5%; the isotonic regulator is added to enable the inhalation solution to have an osmolality of 200-400 mOsmol/kg; the addition amount of the pH regulator is such that the pH value of the inhalation solution is 6.5-10.0. The application discloses an ambrisentan aerosol inhalation solution combines liquid atomizing device can provide a convenient to use, and safe effective, and good ambrisentan aerosol inhalation solution's of stability pharmaceutical dosage form and delivery system.
Description
Technical Field
The invention belongs to the field of pharmaceutics, and particularly relates to an ambrisentan aerosol inhalation solution and a preparation method thereof.
Background
Pulmonary Arterial Hypertension (PAH) is a malignant cardiovascular disease in which the blood flow of the pulmonary artery is restricted due to pathological accumulation of pulmonary artery endothelial cells, muscle layers and adventitia, leading to increased pulmonary vascular resistance, progressive increase of pulmonary arterial pressure, and finally right heart failure and even death, and is mainly characterized in that pulmonary artery obstruction causes Pulmonary Vascular Resistance (PVR) and progressive increase of Pulmonary Arterial Pressure (PAP), and along with irreversible pulmonary vascular remodeling, the patient symptoms are severe to cause right heart failure and death, and the prognosis is poor, and the death rate is high. Meanwhile, with the aggravation of the aging of the population in China, the total number of PAH patients rises year by year in recent years, and the physical and mental health of the patients is seriously harmed.
Ambrisentan, also known as ambrisentan, chemical name: (+) - (2S)2- (4, 6-dimethylpyrimidin-2-yl) oxy-3-methoxy-3, 3-diphenylpropanoic acid; the chemical formula is as follows: c22H22N2O4Molecular weight: 378.42, the structural formula is as follows:
ambrisentan as an oral selective endothelin receptor antagonist has the effects of reducing endogenous vasoconstriction, resisting hyperplasia, resisting fibrosis, resisting inflammation and the like, and is approved by FDA in 2007 to be orally taken for treating patients with pulmonary hypertension.
The pulmonary vascular Endothelin (ET) system has become a new target for the treatment of PAH, with ET receptor antagonists becoming the first-line drugs for the oral treatment of severe PAH. Ambrisentan as ET receptor antagonist plays a role after being combined with ET receptor, reduces the combination of ET and endothelin receptor, reduces the action of endothelin, improves the fibrosis of lesion tissues and improves the vasodilatation capability of blood vessels. In clinical experiments, the motor ability of patients can be improved, the worsening of symptoms can be relieved, and the medicine is taken only once a day, so that the medicine is more convenient.
The ambrisentan dosage forms sold in the markets at home and abroad are all tablets, but the tablets are not suitable for being swallowed by infants and coma patients, have complex preparation process and high technical requirement, have slow effect when being used for treating PAH, and cannot directly reach lesion parts.
Chinese patent CN103860525A discloses an ambrisentan capsule type inhalation powder cloud agent, wherein the ambrisentan capsule type inhalation powder cloud agent is described to comprise a capsule shell and capsule contents, and the weight of the capsule contents is 5-300 mg; the weight ratio of the ambrisentan to the excipient lactose is 1: 0.5-50; the average particle size of ambrisentan is less than 10 mu m, wherein 80% of the particles are less than 5 mu m; the particle size range of the excipient lactose is 30-200 mu m. However, the aerosol powder requires a large inspiratory flow rate to activate the aerosolization, and the patient cannot achieve drug delivery under normal breathing conditions, and therefore is not suitable for children, the elderly, and other patients with difficult active breathing.
In view of the above, the ambrisentan preparation disclosed in the prior art has limitations in terms of the population to be used, and therefore it is an urgent problem to those skilled in the art to develop an ambrisentan preparation which is suitable for infants and children and patients with active dyspnea who do not have the ability of autonomous inhalation, can directly act on the diseased region, and has low irritation, simple preparation process and good stability.
Disclosure of Invention
In order to solve the technical problems, the invention provides an ambrisentan aerosol inhalation solution preparation, a preparation method and application thereof.
The invention aims to solve the defects in the prior art to a certain extent, and provides the following technical scheme:
on one hand, the invention provides an ambrisentan aerosol inhalation solution which comprises ambrisentan, a solvent and auxiliary materials,
the inhalation solution with single dose specification contains 0.1-20 mg of ambrisentan, preferably 2.5-15 mg of ambrisentan.
The single dose specification of the inhalation solution is 1-5 ml, preferably, the single dose specification is 2-5 ml;
the solvent is sterile water for injection;
the auxiliary materials comprise a buffering agent and an isoosmotic adjusting agent;
the dosage of the buffer is 0.01-1.0% (w/v);
the addition of the isoosmotic adjusting agent is to enable the inhalation solution to have the osmolality of 200-400 mOsmol/kg;
the buffer can be one or more of sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate;
the isotonic regulator can be one or more selected from glucose, sodium chloride, glycerol and propylene glycol, preferably sodium chloride;
the auxiliary material can also comprise a pH regulator;
the addition amount of the pH regulator is that the pH value of the inhalation solution is 6.5-10.0, and preferably, the pH value is 8.0-10.0;
the pH regulator can be one or more of pharmaceutically acceptable sodium bicarbonate, sodium carbonate and sodium hydroxide.
In another aspect, the present invention provides a method for preparing an ambrisentan aerosol inhalation solution, comprising the steps of:
(1) measuring a solvent with the total amount of the required preparation solution of 60-80% (v/v) to obtain a first solution;
(2) under the condition that the temperature of the first solution is controlled to be 50-90 ℃, sequentially adding an isotonic regulator and a buffering agent into the first solution one by one, and uniformly stirring to obtain a second solution;
(3) adding ambrisentan into the second solution, and uniformly stirring to obtain a third solution;
(4) when the temperature of the third solution is reduced to below 30 ℃, adding a pH regulator, uniformly stirring, and regulating the pH of the solution to 6.5-10.0 to obtain a fourth solution;
(5) adding a solvent into the fourth solution, fixing the volume to the total amount of the solution to be prepared, uniformly stirring to obtain a fifth solution, and filtering by using a 0.22 mu m filter membrane or filter core;
(6) filling into an ampoule bottle with the specification of 1-5 ml, and sealing.
In another aspect: the invention provides an inhalation system for atomizing an ambrisentan inhalation solution to a human respiratory tract, which comprises 1ml-5ml of ambrisentan inhalation solution and a liquid atomization device, wherein the ambrisentan inhalation solution is atomized into aerosol by the liquid atomization device,
the gas flow pressure of the liquid atomization device is 5bar,
the flow rate of the liquid atomization device is (15 +/-0.75) L/min,
the delivery rate of the active ingredient in the aerosol is >1.5mg/min,
the aerosol delivery rate is > 60%,
the aerosol NGI has a Fine Particle Fraction (FPF) > 60%,
the particle size distribution of the aerosol droplets is 1-6 μm.
The beneficial effects of the invention are:
1. the stable ambrisentan aerosol inhalation solution is prepared, a surfactant and a stabilizer are not required to be added, and a proper amount of buffering agent and a proper amount of pH regulator are added, so that the solubility and the pH value of the ambrisentan solution meet the requirements of a pharmaceutical inhalation solution, and the solution has good stability; by adding the isoosmotic adjusting agent, the irritation to respiratory mucosa is reduced, the compliance is increased, and the preparation is safer.
2. The invention provides a preparation process of an ambrisentan aerosol inhalation solution, which is characterized in that the proper solution preparation temperature is controlled to ensure that the active ingredient has proper dissolution speed in a solvent; the filtration sterilization process is adopted, the stability of the preparation is further improved while the sterility level of the product is ensured, the quality is reliable, the process operation is simple, the control is easy, and the method is suitable for large-scale production.
3. The invention provides a novel safe and effective ambrisentan medicinal preparation for infants and children without self-inhalation capacity and patients with active dyspnea.
4. The invention provides an ambrisentan aerosol inhalation solution atomization drug delivery system, which can accurately control the particle size of aerosol droplets formed by accurately controlling the particle size to be uniformly distributed in 1-6 mu m most suitable for lung inhalation by controlling the airflow pressure and the flow rate of a liquid atomization device and the delivery rate, the delivery total amount and the particle size distribution of active ingredients in aerosol after atomization, so that enough liquid medicine can be absorbed in the lung, and the corresponding drug effect can be exerted, and the ambrisentan aerosol inhalation solution can accurately adjust the drug delivery dosage.
Detailed Description
In the following detailed description, numerous specific details are set forth in order to provide a better understanding of the invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Any equivalent replacement in the field, which is made in accordance with the teachings of the present invention, is within the scope of the present invention.
The components making up the ambrisentan aerosol inhalation solution of the present invention are described below.
Test example 1 examination of the influence of different auxiliary materials on the dissolution of ambrisentan
Different auxiliary materials are added into a solvent (25 ℃), and the influence on the dissolving condition of ambrisentan is observed:
as can be seen from the above table, the solubility of ambrisentan in test group 1 could not reach the pharmaceutically effective concentration; in the test group 2, ambrisentan can be dissolved, but the pH value of the dissolved liquid medicine exceeds the pH value range (3-10) required by the inhalation solution, and the irritation of the liquid medicine on the respiratory tract is enhanced due to overhigh pH value; the solubility of ambrisentan in the test groups 3, 4 and 5 can reach the pharmaceutically effective concentration, the pH value of the dissolved liquid medicine is within the pH value range (3-10) required by the inhalation solution, and the isotonic regulator is added, so that the compliance of the solution is improved, and the irritation to respiratory mucosa is reduced. In summary, the composition of the adjuvants in the ambrisentan inhalation solution formulation was determined to be: buffer and isoosmotic adjusting agent, and pH regulator can be added in proper amount.
In addition, the experimental results show that the solubility of ambrisentan can be increased by adding proper auxiliary materials when the pH value of the liquid medicine is more than 6.5, but the dissolution speed of ambrisentan cannot be increased by different pH values and different auxiliary materials.
Test example 2 examination of different liquid preparation temperatures
The dissolving conditions of the ambrisentan solution at different solution preparation temperatures are considered:
from the above table, it can be seen that: along with the increase of the temperature of the prepared solution, the dissolving rate of ambrisentan becomes fast, the dissolving time is too long when the temperature of the prepared solution is 25 ℃, the dissolving rate is fast when the temperature is 50-90 ℃, and the production requirement can be met.
Test example 3 investigation of different pH values of solutions
Under the condition of the same prescription, the influence of different solution pH value systems on the quality of a sample is examined:
the prescription composition is as follows:
| name(s) | Make up of |
| Ambrisentan | 2.0g |
| Sodium chloride | 7.5g |
| Citric acid sodium salt | 3.0g |
| Sodium hydroxide | Proper amount of the mixture is adjusted to pH values of 6.0, 6.5, 7.5, 8.0 and 10.0 |
| Adding water for injection to | 1000ml |
The preparation method comprises the following steps:
weighing 700ml (70% of the prescription amount) of water for injection, heating to 80 ℃, preserving heat, sequentially adding the prescription amount of sodium chloride and sodium citrate, stirring to dissolve, adding ambrisentan, continuously stirring, simultaneously adding a proper amount of sodium hydroxide solution, adjusting until the pH value of the liquid medicine is 6.0, 6.5, 7.5, 8.0 and 10.0, uniformly stirring, supplementing the liquid medicine to the full amount with a solvent, filtering with a 0.22 mu m filter membrane or a filter element, filling into a 2ml ampoule bottle, and sealing to obtain the composition.
And (3) measuring related substances of samples adjusted to different pH values by adopting an HPLC method, wherein the detection conditions are as follows: a chromatographic column: waters symmetry Shield RP18(3.9 × 150mm, 5 μm); mobile phase: mobile phase A: potassium dihydrogen phosphate buffer-acetonitrile (62:38), mobile phase B: acetonitrile, gradient elution; flow rate: 1.2 ml/min; column temperature: 30 ℃; detection wavelength: 220 nm; the results of the assay are shown in the following table:
as can be seen from the above table: when the pH value of the sample is 6.0 (lower than 6.5), the sample is separated out after being prepared and placed for the next day, the pH value of the sample is 6.5-10.0, and the sample is not separated out after being placed for 2 days at room temperature and 10 days at 60 ℃, so that the requirement of atomizing inhalation solution can be met; when the pH value of the sample is between 8.0 and 10.0, the total amount of related substances is lower, and the increase is slower after the sample is placed at 60 ℃ for 10 days, namely the stability is better.
When the results of test example 1 and test example 3 are considered together, it is found that: when the auxiliary materials in the ambrisentan inhalation solution preparation comprise a buffering agent and an isotonic regulator, the solubility of ambrisentan can reach the pharmaceutically effective concentration, and the pH value of the dissolved liquid medicine is 6.5-7.5, so that the pH value range (3-10) required by an inhalation solution agent can be met; by combining the investigation on the pH value of the solution, when the pH value of the solution is between 8.0 and 10.0, the total amount of related substances is lower, and the substances grow more slowly after being placed at 60 ℃ for 10 days, namely, the stability is better, and because the pH value of the solution can be adjusted to be between 8.0 and 10.0 by adding the pH adjusting agent, the auxiliary materials absorbed into the solution preparation preferably comprise a buffering agent, an isotonic adjusting agent and a pH adjusting agent.
The present invention will be described in detail below with reference to examples, but the scope of the present invention is not limited thereto.
Example 1
Prescription composition
| Name (R) | Composition of |
| Ambrisentan | 2.0g |
| Sodium chloride | 7.5g |
| Citric acid sodium salt | 3.0g |
| Sodium hydroxide | Adjusting the pH to 8.0 |
| Adding water for injection to | 1000ml |
The preparation method comprises the following steps:
weighing 800ml of water for injection (80% of the prescription amount), heating to 70 ℃, keeping the temperature, sequentially adding the prescription amount of sodium chloride and sodium citrate, stirring to dissolve, adding ambrisentan, continuously stirring to dissolve, adding sodium hydroxide solution to adjust the pH value to 8.0, uniformly stirring, supplementing the solution to the full amount with a solvent, filtering with a 0.22 mu m filter membrane or filter element, filling into a 5ml ampoule bottle, and sealing to obtain the compound injection.
Example 2
Prescription composition
The preparation method comprises the following steps:
weighing 700ml (70% of the prescription amount) of water for injection, heating to 50 ℃, keeping the temperature, sequentially adding the prescription amount of sodium chloride and sodium citrate, stirring to dissolve, adding ambrisentan, continuously stirring to dissolve, uniformly stirring (the pH value is 6.5), supplementing the solvent to the full amount, filtering with a 0.22 mu m filter membrane or filter core, filling into a 1ml ampoule bottle, and sealing to obtain the injection.
Example 3
Prescription composition
| Name (R) | Composition of |
| Ambrisentan | 2.0g |
| Glucose | 40g |
| Sodium bicarbonate | 10g |
| Sodium hydroxide | Adjusting the pH to 10.0 |
| Adding water for injection to | 1000ml |
The preparation method comprises the following steps:
weighing 600ml (60% of the prescription amount) of water for injection, heating to 60 ℃, keeping the temperature, sequentially adding glucose and sodium bicarbonate with the prescription amount, stirring to dissolve, adding ambrisentan, continuing to stir to dissolve, adding sodium hydroxide solution to adjust the pH value to 10.0, uniformly stirring, supplementing the solution to the full amount with a solvent, filtering with a 0.22 mu m filter membrane or filter element, filling into a 2ml ampoule bottle, and sealing to obtain the compound injection.
Example 4
Prescription composition
The preparation method comprises the following steps:
weighing 800ml of water for injection (80% of the prescription), heating to 90 ℃, keeping the temperature, sequentially adding the prescription amount of glycerol and dipotassium phosphate, stirring to dissolve, adding ambrisentan, adding sodium hydroxide solution to adjust the pH value to 9.0, stirring uniformly, compensating to the full amount with a solvent, filtering with a 0.22 mu m filter membrane or filter core, filling into a 3ml ampoule bottle, and sealing to obtain the injection.
Example 5
Prescription composition
| Name (R) | Composition of |
| Ambrisentan | 2.5g |
| Propylene glycol | 15g |
| Disodium hydrogen phosphate | 9.0g |
| Sodium dihydrogen phosphate (dihydrogen phosphate) | 1.25g |
| Adding water for injection to | 1000ml |
The preparation method comprises the following steps:
weighing 800ml of water for injection (80% of the prescription amount), heating to 70 ℃, keeping the temperature, sequentially adding the prescribed amount of propylene glycol, disodium hydrogen phosphate and sodium dihydrogen phosphate, stirring for dissolving, adding ambrisentan, continuously stirring for dissolving, stirring uniformly (the pH value is 7.5), supplementing the solvent to the full amount, filtering by using a 0.22 mu m filter membrane or a filter element, filling into a 2ml ampoule bottle, and sealing to obtain the injection.
Example 6 aerodynamic atomization particle size determination
The particle size of the aerosol inhalation solution samples of ambrisentan in the examples 1-5 is measured by a starpadaik particle size tester, and the measurement results are as follows:
from the above table, it can be seen that: atomized particle size of examplesX50All are between 2 and 4 mu m, X84<6 μm, in accordance with the aerodynamic parameters of the atomized formulation.
Example 7 comparison of different atomization devices
The samples of example 1 were taken and atomized using different brand atomizers, the atomization being shown in the following table:
| atomizer brand | 3min atomization Rate% | 5min atomization Rate% | Atomization rate at 8 min% |
| Bairui (Bairui) | 40.25±1.08 | 64.33±0.79 | 78.20±1.66 |
| Ohm dragon | 39.47±1.22 | 65.35±0.94 | 76.92±2.03 |
Note: each brand of nebulizer was serially examined in parallel for 3 sets of data.
From the above table, it can be seen that: by adopting two atomizer devices of different brands of Bairui and ohm dragon, after 8min of atomization is accumulated, the atomization rates of the Bairui atomizer and the ohm dragon atomizer to the sample are not obviously different.
Example 8 determination of atomization Performance-delivery Rate and Total amount delivered
An NEU22 type ohm dragon atomizer (compressed air atomization) is adopted, the ambrisentan atomization inhalation solution (the atomization volume is the specification of a sample) of the embodiment 1-5 is respectively taken and placed in a weighed atomizer, atomization is started until no fog is released after precise weighing, the atomization is carried out again, and the delivery rate, the total delivery amount, the aerosol loss, the atomizing cup residue, the balance recovery rate and the output drug amount are calculated. The results are as follows:
note: each set of example samples was subjected to 10 replicates.
The above table shows; 1) the atomization type is fixed, the atomization pressure and the flow rate controlled by the method are adopted, the samples in the examples have good atomization performance and high durability, and the delivery rate and the total delivery amount of the samples in the examples are not obviously different; 2) different embodiments have different sample filling specifications, different demisting time and no difference in atomization performance; 3) the ambrisentan aerosol inhalation solution protected in the application has a high total delivery amount and a low residual amount of the aerosol cup under the condition of the aerosol parameters.
EXAMPLE 9 determination of atomization Performance-Fine particle dose
The method comprises the following steps of (1) respectively taking an ambrisentan atomized inhalation solution (the atomized volume is a sample specification) of the above examples 1-5 by using an NEU22 type ohm dragon atomizer (compressed air atomization), placing the ambrisentan atomized inhalation solution into the atomizer, and measuring the FPF% and MMAD values of the examples by using NGI by using a set airflow pressure (5bar) and a set flow rate (15 +/-0.75L/min), wherein the measurement results are shown in the following table:
note: each set of example samples was subjected to 3 replicates.
From the above table, it can be seen that: the prepared sample atomizes the fine particle according to the set parameters, wherein the FPF% of the fine particle dose is more than 60%, and the particle size is distributed between 1 and 6 mu m.
EXAMPLE 10 stability Studies
An ambrisentan aerosol inhalation solution sample is prepared according to the application examples 1-5, and simultaneously lofting is carried out, and the determination result of the stability influence factor determination is shown in the following table:
stability determination data for samples of each example
As can be seen from the results of the stability and the aerosol output drug (%) measurement of each example, the ambrisentan aerosol inhalation solution prepared under the prescription composition and the preparation process condition protected by the patent has stable quality, the total amount of related substances of each example sample is less than 0.3% after being placed at 25 ℃ for 6 months, and the total amount of related substances is less than 0.1% after being placed at 4 ℃ for 6 months; the atomization parameters protected by the patent and the atomization output dose of the ambrisentan atomization inhalation solution with specific equipment are more than 60%.
The present invention has been described in detail, and the principle and embodiments of the present invention are explained herein by using specific examples, which are only used to help understand the method and the core idea of the present invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the principle of the present invention, and these changes and modifications also fall into the protection scope of the appended claims.
Claims (10)
1. An ambrisentan aerosol inhalation solution is characterized by comprising ambrisentan, auxiliary materials and a solvent, wherein the auxiliary materials comprise a buffering agent and an isotonic regulator.
2. An ambrisentan nebulized inhalation solution according to claim 1, characterized in that said single dose inhalation solution comprises 0.1-20 mg ambrisentan, preferably comprises 2.5-15 mg ambrisentan.
3. An ambrisentan nebulized inhalation solution according to claim 1, characterized in that the inhalation solution has a single dose size of 1-5 ml, preferably the single dose size is 2-5 ml.
4. An ambrisentan nebulized inhalation solution according to claim 1, characterized in that the solvent is sterile water for injection.
5. An ambrisentan aerosol inhalation solution according to claim 1, wherein the buffer can be selected from one or more of sodium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate, and is used in an amount of 0.01% to 0.5% (w/v).
6. An ambrisentan aerosol inhalation solution according to claim 1, characterized in that the isotonicity adjusting agent can be selected from one or more of glucose, sodium chloride, glycerol, propylene glycol, preferably sodium chloride, and is added to give the inhalation solution an osmolality of 200-400 mOsmol/kg.
7. An ambrisentan nebulized inhalation solution according to claim 1, characterized in that said excipients can also comprise a pH adjusting agent.
8. An ambrisentan aerosol inhalation solution according to claim 7, characterized in that the pH adjusting agent can be selected from one or more of pharmaceutically acceptable sodium bicarbonate, sodium carbonate, sodium hydroxide, and the amount of the pH adjusting agent added is such that the pH value of the inhalation solution is 6.5-10.0, preferably 8.0-10.0.
9. A method of preparing an ambrisentan nebulized inhalation solution according to any one of claims 1-8, characterized in that it comprises the steps of:
(1) measuring a solvent with the total amount of the required preparation solution of 60-80% (v/v) to obtain a first solution;
(2) under the condition that the temperature of the first solution is controlled to be 50-90 ℃, sequentially adding an isotonic regulator and a buffering agent into the first solution one by one, and uniformly stirring to obtain a second solution;
(3) adding ambrisentan into the second solution, and uniformly stirring to obtain a third solution;
(4) when the temperature of the third solution is reduced to below 30 ℃, adding a pH regulator, uniformly stirring, and regulating the pH of the solution to 6.5-10.0 to obtain a fourth solution;
(5) adding a solvent into the fourth solution, fixing the volume to the total amount of the required prepared solution, uniformly stirring to obtain a fifth solution, and filtering by using a 0.22-micron filter membrane or filter core;
(6) filling into an ampoule bottle with the specification of 1-5 ml, and sealing.
10. An inhalation system for the nebulization of inhaled solutions of ambrisentan to the human respiratory tract, characterized in that: comprising 1ml to 5ml of an inhaled ambrisentan solution according to any one of claims 1 to 8 and a liquid nebulizing means, said inhaled ambrisentan solution being nebulized into an aerosol using the liquid nebulizing means, wherein:
the gas flow pressure of the liquid atomization device is 5bar,
the flow rate of the liquid atomization device is (15 +/-0.75) L/min,
the delivery rate of the active ingredient in the aerosol is >1.5mg/min,
the aerosol delivery rate is > 60%,
the aerosol NGI has a Fine Particle Fraction (FPF) > 60%,
the particle size distribution of the aerosol droplets is 1-6 μm.
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