CN112569211A - Gatifloxacin solution for inhalation and preparation method thereof - Google Patents
Gatifloxacin solution for inhalation and preparation method thereof Download PDFInfo
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- CN112569211A CN112569211A CN201910923844.6A CN201910923844A CN112569211A CN 112569211 A CN112569211 A CN 112569211A CN 201910923844 A CN201910923844 A CN 201910923844A CN 112569211 A CN112569211 A CN 112569211A
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- gatifloxacin
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- inhalation
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- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 title claims abstract description 44
- 229960003923 gatifloxacin Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 52
- 229940041682 inhalant solution Drugs 0.000 claims abstract description 27
- 230000003204 osmotic effect Effects 0.000 claims abstract description 10
- 239000003381 stabilizer Substances 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 31
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 238000011049 filling Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 10
- 238000007789 sealing Methods 0.000 claims description 10
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 10
- 229960000281 trometamol Drugs 0.000 claims description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 8
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 8
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 239000001509 sodium citrate Substances 0.000 claims description 6
- 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 6
- 239000004310 lactic acid Substances 0.000 claims description 5
- 235000014655 lactic acid Nutrition 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 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
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 4
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 229940001607 sodium bisulfite Drugs 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- 239000008227 sterile water for injection Substances 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 9
- 239000003814 drug Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 9
- 238000007086 side reaction Methods 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 239000003380 propellant Substances 0.000 abstract description 3
- 230000002421 anti-septic effect Effects 0.000 abstract description 2
- 238000005259 measurement Methods 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 5
- 206010006451 bronchitis Diseases 0.000 description 4
- 206010006458 Bronchitis chronic Diseases 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 3
- 206010057190 Respiratory tract infections Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 208000007451 chronic bronchitis Diseases 0.000 description 3
- 229940124274 edetate disodium Drugs 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 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 3
- 108020000946 Bacterial DNA Proteins 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 241000606766 Haemophilus parainfluenzae Species 0.000 description 2
- 241000588655 Moraxella catarrhalis Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 229940047650 haemophilus influenzae Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- FGBGEKHVEJJJLT-LLVKDONJSA-N 1-cyclopropyl-7-[(3r)-3-ethylpyrrolidin-1-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1[C@H](CC)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1OC FGBGEKHVEJJJLT-LLVKDONJSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 201000006306 Cor pulmonale Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 108010041052 DNA Topoisomerase IV Proteins 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 208000004186 Pulmonary Heart Disease Diseases 0.000 description 1
- 206010037597 Pyelonephritis acute Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 201000001555 acute pyelonephritis Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- UNXNGGMLCSMSLH-UHFFFAOYSA-N dihydrogen phosphate;triethylazanium Chemical group OP(O)(O)=O.CCN(CC)CC UNXNGGMLCSMSLH-UHFFFAOYSA-N 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000001626 effect on respiratory system Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- XUBOMFCQGDBHNK-UHFFFAOYSA-N gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCNC(C)C1 XUBOMFCQGDBHNK-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
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
- A61K9/0078—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
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Otolaryngology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention relates to a gatifloxacin solution for inhalation and a preparation method thereof, wherein the inhalation solution comprises an active ingredient gatifloxacin, a solubilizer, a stabilizer, a pH regulator, an osmotic pressure regulator and a solvent; the gatifloxacin solution preparation for inhalation does not contain a propellant, and is an inhalation solution for releasing the medicament by means of an atomizing pump or compressed air pressure, wherein the dosage specification is 1ml-5 ml; has accurate measurement and good curative effect; no antiseptic, stable quality, less side reaction and the like.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a gatifloxacin solution for inhalation and a preparation method thereof.
Background
Gatifloxacin, which is a fourth-generation fluoroquinolone antibacterial drug, belongs to 8-methoxyfluoroquinolone racemic compounds, has broad-spectrum gram-negative and gram-positive microorganism resistance and activity, is developed successfully for the first time by Kyorin Pharmaceutical (japan apricot forest Pharmaceutical corporation), has the same antibacterial activity of R-and S-enantiomers, acts by inhibiting bacterial DNA gyrase and topoisomerase IV, thereby inhibiting bacterial DNA replication, transcription and repair processes, has strong antibacterial action on various bacteria, has better curative effect on respiratory system infection and reproductive system infection, and is one of the representatives of the 'respiratory fluoroquinolone' drugs which grow rapidly in recent years. The clinical application is mainly used for treating various light and medium infectious diseases caused by sensitive pathogens, including: respiratory tract infection diseases, simple urinary tract infection and complicated urinary tract infection, cystitis, acute pyelonephritis, and urinary tract, cervical and rectal infection caused by Neisseria gonorrhoeae. Can be used for treating respiratory diseases such as acute episode of chronic bronchitis, acute bronchitis, community-acquired pneumonia and the like, and has obvious curative effect on respiratory infectious diseases.
Gatifloxacin is used for treating infectious diseases caused by sensitive strains above a moderate level. The chemical name is as follows: (±) -1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid; the chemical formula is as follows: c19H22FN3O4Molecular weight: 375.40, structural formula:
the gatifloxacin dosage forms sold in the markets at home and abroad at present are tablets, capsules, powder injections, eye drops, injection, dispersible tablets and ophthalmic gels, but no inhalation preparation is available, and the dosage forms sold in the markets can not directly reach diseased parts for treating respiratory tract infection diseases.
The invention overcomes the defects and provides the medicine with quick response and wider application range. The inhalation solution preparation can disperse the medicine and the solvent into fog drops or particles or aerosol through a special device, so that the medicine is inhaled by a patient and is deposited in the nose, throat, bronchi and alveoli at all levels, thereby achieving the local or systemic treatment effect. The inhalation therapy is especially suitable for treating respiratory system diseases such as asthma, COPD, respiratory tract infection, cystic fibrosis, pulmonary heart disease, pulmonary hypertension and the like, and is convenient for special people such as children, old people, serious patients and the like to take. The liquid preparation of the invention meets the high quality standard, has the characteristics of quick absorption, high curative effect, high bioavailability, no gastrointestinal toxic or side effect and irritation, can directly act the medicine on the pathological change part, has quick effect after atomization inhalation of the solution, and is more suitable for children of low age, postoperative patients and old people.
Disclosure of Invention
The invention aims to provide an inhalation solution which does not contain a propellant and releases a medicament by means of an atomizing pump or compressed air pressure, and the dosage specification is 1ml-5 ml. Has accurate measurement and good curative effect; no antiseptic, stable quality, less side reaction and the like.
The invention aims to provide an inhalation solution for treating acute attack of chronic bronchitis and community-acquired pneumonia caused by streptococcus pneumoniae, haemophilus influenzae, haemophilus parainfluenzae, moraxella catarrhalis or staphylococcus aureus.
In the above inhalation solution, characterized in that the inhalation solution is a gatifloxacin solution for inhalation.
Among the above inhalation solutions, characterized in that the inhalation solution comprises gatifloxacin as an active ingredient, a solubilizer, a stabilizer, a pH adjuster, an osmotic pressure adjuster and a solvent.
In the inhalation solution, the concentration of the active ingredient gatifloxacin in the inhalation solution is 20-100 mg/ml.
In the inhalation solution, the solubilizer is selected from one or two of ethanol and tromethamine, and the dosage of the solubilizer is 0.001-25% w/v.
In the inhalation solution, the stabilizing agent is one or a combination of propylene glycol, edetate disodium, sodium metabisulfite and sodium bisulfite, and the dosage of the stabilizing agent is 0.003-25% w/v.
In the above inhalation solution, the pH regulator is pharmaceutically acceptable acid or alkali, specifically one or more selected from citric acid, sodium citrate, lactic acid, hydrochloric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, glycine, and sodium hydroxide.
In the above inhalation solution, the osmotic pressure regulator is selected from inorganic salt osmotic pressure regulators, specifically one or more selected from sodium chloride, potassium chloride, magnesium chloride and calcium chloride, preferably sodium chloride, and the dosage thereof is 0.60-0.85% w/v.
In the above inhalation solution, characterized in that the solvent is selected from purified water, water for injection or sterile water for injection.
In the above inhalation solution, it is characterized in that the pH value of the inhalation solution is 3.0 to 10.0, more preferably 3.0 to 6.0;
another object of the present invention is to provide a method for preparing gatifloxacin inhalation solution. The preparation process is simple, good in reproducibility and product stability, and is easy for large-scale industrial production.
The method specifically comprises the following steps:
the method comprises the following steps: adding a solvent with the total volume of 50-80% into a liquid preparation device, and controlling the water temperature to be 20-60 ℃;
step two: adding a solubilizer, a stabilizer and an osmotic pressure regulator in the formula amount into the solvent in the step one, and stirring to dissolve;
step three: adding a pH regulator into the solution obtained in the second step, and stirring to dissolve the pH regulator to enable the pH value to be 3.0-10.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
1. the invention provides an inhalation solution for treating acute attack of chronic bronchitis and community-acquired pneumonia caused by streptococcus pneumoniae, haemophilus influenzae, haemophilus parainfluenzae, moraxella catarrhalis or staphylococcus aureus.
2. The invention provides a gatifloxacin inhalation solution which does not contain a propellant and releases medicaments by means of an atomizing pump or compressed air pressure, and the gatifloxacin inhalation solution has the dosage specification of 1ml-5ml, accurate metering and good curative effect.
3. The present invention provides a method for improving solubility of gatifloxacin by adding a solubilizing agent and controlling the pH range.
4. The invention provides an inhalation solution which does not contain preservative, has stable quality and less side reaction.
5. The inhalation solution of the invention has simple preparation process, good reproducibility and good product stability, and is easy for large-scale industrial production.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The experimental methods in the examples are conventional methods unless otherwise specified; the raw materials, reagent materials and the like used are all commercially available products unless otherwise specified.
Example 1
Prescription composition
The preparation method comprises the following steps:
the method comprises the following steps: adding 500ml of solvent into a liquid dispenser, and controlling the water temperature at 25 ℃;
step two: adding the tromethamine, sodium metabisulfite and sodium chloride in the formula amount into the solvent in the step one, and stirring to dissolve;
step three: adding citric acid and sodium citrate into the solution obtained in the second step, and stirring to dissolve until the pH value is 3.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Example 2
Prescription composition
| Name (R) | Composition of |
| Gatifloxacin | 50g |
| Ethanol | 100g |
| Citric acid | 0.25g |
| Citric acid sodium salt | 0.20g |
| Sodium metabisulfite | 5g |
| Sodium chloride | 8.2g |
| Adding a solvent to | 1000ml |
The preparation method comprises the following steps:
the method comprises the following steps: adding 800ml of solvent into a liquid preparation device, and controlling the water temperature at 30 ℃;
step two: adding ethanol, sodium metabisulfite and sodium chloride in the formula amount into the solvent in the first step, and stirring to dissolve;
step three: adding citric acid and sodium citrate into the solution obtained in the second step, and stirring to dissolve until the pH value is 4.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Example 3
Prescription composition
| Name (R) | Composition of |
| Gatifloxacin | 100g |
| Ethanol | 100g |
| Tromethamine | 0.10g |
| Citric acid | 0.30g |
| Citric acid sodium salt | 0.25g |
| Sodium bisulfite | 10g |
| Sodium chloride | 7.0g |
| Adding a solvent to | 1000ml |
The preparation method comprises the following steps:
the method comprises the following steps: adding 600ml of solvent into a liquid dispenser, and controlling the water temperature at 60 ℃;
step two: adding ethanol, tromethamine, sodium bisulfite and sodium chloride with the prescription amount into the solvent in the step one, and stirring to dissolve;
step three: adding citric acid and sodium citrate into the solution obtained in the second step, and stirring to dissolve until the pH value is 4.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Example 4
Prescription composition
| Name (R) | Composition of |
| Gatifloxacin | 50g |
| Tromethamine | 0.01g |
| Citric acid | 0.17g |
| Citric acid sodium salt | 0.35g |
| Edetate disodium | 0.03g |
| Sodium chloride | 8.0g |
| Adding a solvent to | 1000ml |
The preparation method comprises the following steps:
the method comprises the following steps: adding 800ml of solvent into a liquid preparation device, and controlling the water temperature at 20 ℃;
step two: adding the tromethamine, the edetate disodium and the sodium chloride in the formula amount into the solvent in the step one, and stirring to dissolve;
step three: adding citric acid and sodium citrate into the solution obtained in the second step, and stirring to dissolve until the pH value is 6.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Example 5
Prescription composition
| Name (R) | Composition of |
| Gatifloxacin | 50g |
| Ethanol | 50g |
| Disodium hydrogen phosphate | 1.7g |
| Sodium dihydrogen phosphate | 0.04g |
| Propylene glycol | 50g |
| Calcium chloride | 6.5g |
| Adding a solvent to | 1000ml |
The preparation method comprises the following steps:
the method comprises the following steps: adding 800ml of solvent into a liquid preparation device, and controlling the water temperature at 30 ℃;
step two: adding ethanol, propylene glycol and calcium chloride in the formula amount into the solvent in the step one, and stirring to dissolve;
step three: adding disodium hydrogen phosphate and sodium dihydrogen phosphate into the solution obtained in the second step, and stirring to dissolve until the pH value is 8.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Example 6
Prescription composition
| Name (R) | Composition of |
| Gatifloxacin | 50g |
| Tromethamine | 0.01g |
| Glycine | 0.75g |
| Sodium hydroxide | 0.07g |
| Sodium metabisulfite | 5.0g |
| Sodium chloride | 6.5g |
| Adding a solvent to | 1000ml |
The preparation method comprises the following steps:
the method comprises the following steps: adding 700ml of solvent into a liquid dispenser, and controlling the water temperature at 30 ℃;
step two: adding the tromethamine, sodium metabisulfite and sodium chloride in the formula amount into the solvent in the step one, and stirring to dissolve;
step three: adding glycine and sodium hydroxide into the solution obtained in the second step, and stirring to dissolve until the pH value is 10.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Example 7
Prescription composition
| Name (R) | Composition of |
| Gatifloxacin | 80g |
| Ethanol | 150g |
| Lactic acid | Proper amount of |
| Propylene glycol | 80g |
| Magnesium chloride | 8.5g |
| Adding a solvent to | 1000ml |
The preparation method comprises the following steps:
the method comprises the following steps: adding 800ml of solvent into a liquid preparation device, and controlling the water temperature at 30 ℃;
step two: adding ethanol, propylene glycol and magnesium chloride in the formula amount into the solvent in the step one, and stirring to dissolve;
step three: adding lactic acid into the solution obtained in the second step, and stirring to dissolve the lactic acid until the pH value is 4.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Example 8
Prescription composition
The preparation method comprises the following steps:
the method comprises the following steps: adding 800ml of solvent into a liquid preparation device, and controlling the water temperature at 30 ℃;
step two: adding the tromethamine, sodium metabisulfite and potassium chloride in the formula amount into the solvent in the step one, and stirring to dissolve;
step three: adding dilute hydrochloric acid into the solution obtained in the second step, and stirring to dissolve the dilute hydrochloric acid to ensure that the pH value is 4.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
Test examples stability test
The gatifloxacin inhalation solution prepared in the embodiment 1 to 8 is taken and placed at the temperature of 60 ℃ for 10 days; testing the content of gatifloxacin on day 0 in the gatifloxacin inhalation solutions prepared in examples 1 to 8 by using HPLC, and the content of gatifloxacin in the gatifloxacin inhalation solutions of examples 1 to 8 after the accelerated test; detection conditions are as follows: HPLC method is adopted, and the chromatographic column is Agilent HC-C18(250mm multiplied by 4.6mm, 5 μm); the mobile phase is triethylamine phosphate solution [ triethylamine solution (1 → 100), pH value is adjusted to 4.3] -acetonitrile (87: 13) by phosphoric acid, and gradient elution is carried out; the detection wavelength is 325nm, the column temperature is 30 DEG C
The results are shown in Table 1.
TABLE 1 Gatifloxacin content variation in gatifloxacin inhalation solutions before and after accelerated testing
As can be seen from table 1, the gatifloxacin inhalation solution within the scope of the present invention has an impurity content of less than 1.2% after accelerated testing. In step three, the pharmaceutically acceptable base is too basic to destroy gatifloxacin; in addition, the inhalation solution of the invention has stable quality and less side reaction.
Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these embodiments are merely illustrative and various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.
Claims (9)
1. A gatifloxacin solution formulation for inhalation characterized by: comprises gatifloxacin, a solubilizer, a stabilizer, a pH regulator, an osmotic pressure regulator and a solvent.
2. The formulation of claim 1, wherein: the content of the gatifloxacin is 20-100 mg/ml.
3. The formulation of claim 1, wherein: the solubilizer is one or two of ethanol and tromethamine, and the dosage of the solubilizer is 0.001-25% w/v.
4. The formulation of claim 1, wherein: the stabilizer is one or a combination of more of propylene glycol, disodium edetate, sodium metabisulfite and sodium bisulfite, and the dosage of the stabilizer is 0.003-25% w/v.
5. The formulation of claim 1, wherein: the pH regulator is pharmaceutically acceptable acid or alkali, and is one or more of citric acid, sodium citrate, lactic acid, hydrochloric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, glycine, and sodium hydroxide.
6. The formulation of claim 1, wherein: the osmotic pressure regulator is selected from inorganic salt osmotic pressure regulators, specifically one or more of sodium chloride, potassium chloride, magnesium chloride and calcium chloride, preferably sodium chloride, and the dosage of the osmotic pressure regulator is 0.60-0.85% w/v.
7. The formulation of claim 1, wherein: the solvent is selected from purified water, water for injection or sterile water for injection.
8. The formulation of claim 1, wherein: the pH value of the inhalation solution is 3.0-10.0, more preferably 3.0-6.0.
9. A process for the preparation of a formulation according to any one of claims 1 to 8: the method is characterized by comprising the following steps:
the method comprises the following steps: adding a solvent with the total volume of 50-80% into a liquid preparation device, and controlling the water temperature to be 25-60 ℃;
step two: adding a solubilizer, a stabilizer and an osmotic pressure regulator in the formula amount into the solvent in the step one, and stirring to dissolve;
step three: adding a pH regulator into the solution obtained in the second step, and stirring to dissolve the pH regulator to enable the pH value to be 3.0-10.0;
step four: adding the prescription amount of gatifloxacin into the solution obtained in the third step, and stirring to dissolve;
step five: adding solvent to full volume, stirring, and filtering with 0.22 μm filter membrane or filter core;
step six: and (6) filling and sealing.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114652704A (en) * | 2022-04-29 | 2022-06-24 | 兆科药业（广州）有限公司 | Tryprostinil soft mist inhalant |
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| CN1813744A (en) * | 2005-02-03 | 2006-08-09 | 南京圣和药业有限公司 | Method for preparing levogatifloxacin formulation for intravenous injection and formulation using same |
| CN101222927A (en) * | 2005-05-18 | 2008-07-16 | Mpex医药有限公司 | Aerosolized fluoroquinolones and uses thereof |
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