CN113995721A - Ambroxol hydrochloride oral spray solution and preparation method thereof - Google Patents
Ambroxol hydrochloride oral spray solution and preparation method thereof Download PDFInfo
- Publication number
- CN113995721A CN113995721A CN202010731294.0A CN202010731294A CN113995721A CN 113995721 A CN113995721 A CN 113995721A CN 202010731294 A CN202010731294 A CN 202010731294A CN 113995721 A CN113995721 A CN 113995721A
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- CN
- China
- Prior art keywords
- ambroxol hydrochloride
- mixture
- spray solution
- mass ratio
- oral spray
- Prior art date
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- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 title claims abstract description 144
- 229960000985 ambroxol hydrochloride Drugs 0.000 title claims abstract description 142
- 229940041678 oral spray Drugs 0.000 title claims abstract description 44
- 239000000668 oral spray Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000008213 purified water Substances 0.000 claims abstract description 25
- 239000000463 material Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 97
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 93
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 63
- 238000003756 stirring Methods 0.000 claims description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- 239000002202 Polyethylene glycol Substances 0.000 claims description 33
- 229920001223 polyethylene glycol Polymers 0.000 claims description 33
- 229960005150 glycerol Drugs 0.000 claims description 32
- 238000002156 mixing Methods 0.000 claims description 30
- DYRITHBSVDXIQU-UHFFFAOYSA-N pentadecyl 2-hydroxyoctadecanoate Chemical compound OC(C(=O)OCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCC DYRITHBSVDXIQU-UHFFFAOYSA-N 0.000 claims description 29
- 238000011049 filling Methods 0.000 claims description 26
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 25
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 25
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 25
- 229960004998 acesulfame potassium Drugs 0.000 claims description 25
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 25
- 239000000619 acesulfame-K Substances 0.000 claims description 25
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 25
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 25
- 229960000281 trometamol Drugs 0.000 claims description 25
- 239000000811 xylitol Substances 0.000 claims description 25
- 235000010447 xylitol Nutrition 0.000 claims description 25
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 25
- 229960002675 xylitol Drugs 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 24
- 229960004873 levomenthol Drugs 0.000 claims description 24
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 24
- 235000010234 sodium benzoate Nutrition 0.000 claims description 24
- 239000004299 sodium benzoate Substances 0.000 claims description 24
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims description 22
- 238000001816 cooling Methods 0.000 claims description 13
- 239000003755 preservative agent Substances 0.000 claims description 12
- 239000000796 flavoring agent Substances 0.000 claims description 11
- 235000013355 food flavoring agent Nutrition 0.000 claims description 11
- 230000002335 preservative effect Effects 0.000 claims description 10
- 238000007789 sealing Methods 0.000 claims description 9
- 229960003885 sodium benzoate Drugs 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 16
- 239000007921 spray Substances 0.000 abstract description 14
- 210000000214 mouth Anatomy 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 7
- 206010006451 bronchitis Diseases 0.000 abstract description 6
- 239000007787 solid Substances 0.000 abstract description 6
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 206010006458 Bronchitis chronic Diseases 0.000 abstract description 2
- 208000007451 chronic bronchitis Diseases 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 208000023504 respiratory system disease Diseases 0.000 abstract 1
- 230000009747 swallowing Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 74
- 235000011187 glycerol Nutrition 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000008364 bulk solution Substances 0.000 description 14
- 239000012535 impurity Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 11
- 235000019640 taste Nutrition 0.000 description 11
- 238000009472 formulation Methods 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- 206010036790 Productive cough Diseases 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 5
- 229960005174 ambroxol Drugs 0.000 description 5
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 5
- 235000019658 bitter taste Nutrition 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 101100149471 Rattus norvegicus Sipa1l1 gene Proteins 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 208000024794 sputum Diseases 0.000 description 4
- 210000003802 sputum Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 208000019505 Deglutition disease Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005429 filling process Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229940100688 oral solution Drugs 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 208000030090 Acute Disease Diseases 0.000 description 2
- 208000014085 Chronic respiratory disease Diseases 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000032571 Infant acute respiratory distress syndrome Diseases 0.000 description 2
- 206010028974 Neonatal respiratory distress syndrome Diseases 0.000 description 2
- 208000024863 abnormal sputum Diseases 0.000 description 2
- 241001148470 aerobic bacillus Species 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 235000011194 food seasoning agent Nutrition 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 201000002652 newborn respiratory distress syndrome Diseases 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- -1 (2-amino-3, 5-dibromobenzyl) amino Chemical group 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000027775 Bronchopulmonary disease Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- 235000019687 Lamb Nutrition 0.000 description 1
- 101100533558 Mus musculus Sipa1 gene Proteins 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical class C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000010405 clearance mechanism Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- HFNCOTSLOKKPHU-UHFFFAOYSA-N cyclohexanol;hydrochloride Chemical compound Cl.OC1CCCCC1 HFNCOTSLOKKPHU-UHFFFAOYSA-N 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000012009 microbiological test Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000004313 potentiometry Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000002699 waste material Substances 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
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- 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
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dispersion Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an ambroxol hydrochloride oral spray solution and a preparation method thereof, wherein the ambroxol hydrochloride oral spray solution comprises 45-55mg/ml of ambroxol hydrochloride, pharmaceutically acceptable auxiliary materials and sufficient purified water. The ambroxol hydrochloride oral spray solution can be widely used for treating respiratory diseases such as acute bronchitis, chronic bronchitis and the like, is applied to patients needing treatment through an oral spray way, can enter gastrointestinal tracts through oral cavities, and has the advantages of quick absorption, quick response and high bioavailability. Meanwhile, the spray solution is convenient to use and high in drug compliance, and is particularly suitable for many patients who have difficulty in swallowing and cannot take the ambroxol hydrochloride oral solid preparation and solution.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an ambroxol hydrochloride oral spray solution and a preparation method thereof.
Background
Ambroxol is a metabolite of bromhexine, and ambroxol-containing drugs have been registered and marketed for many years. This material was used as the hydrochloride salt. Ambroxol has been shown to improve the mucus transport and clearance mechanisms at the airway epithelial surface and to stimulate surfactant synthesis and secretion by class II alveolar parietal cells. Ambroxol is used as an expectorant treatment for acute and chronic bronchopulmonary diseases characterized by abnormal sputum secretion or impaired expectoration function.
Ambroxol Hydrochloride, is white or yellowish crystalline powder, has unique bitter taste, and has paralysis after being taken. This material was slightly soluble in water, soluble in methanol, and almost insoluble in dichloromethane. Substances are stable in aqueous suspension when exposed to heat, acidic and basic conditions, but are sensitive to oxides, such as hydrogen peroxide, chemical name: trans-4- [ (2-amino-3, 5-dibromobenzyl) amino group]Cyclohexanol hydrochloride, molecular formula: c13H18Br2N2O · HCl, molecular weight: 414.57, structural formula:
there is Mucosolvan (Mucosolvan) which has been marketed abroad, developed and marketed by Boringer Invitrogen, Germany in 1979, and successively in nearly twenty countries, Italy, Switzerland, Argentina, Japan, and the like. The sputum Baker (Transbroncho), produced by the pharmaceutical factory of California, USA; FU LE SHU TANG (Losolvan), produced by Taiwan FU Fu Chemicals GmbH; lanbo sustained release capsule (75 mg/day) (lamb roxol) is produced by the famous hair of the law, and is imported and subpackaged by the fourth pharmaceutical factory in Changzhou China.
The original formulation on the market is injection, tablet, syrup, oral liquid and sustained-release capsule, China is approved to import from 1991, the trade name is 'Musultan', and the specification of ambroxol hydrochloride injection is 2 ml: 15mg, the ambroxol hydrochloride injection is suitable for acute and chronic respiratory diseases with abnormal sputum secretion and bad sputum excretion function, such as the sputum excretion treatment of acute exacerbation of chronic bronchitis, asthmatic bronchitis and bronchial asthma, the prevention treatment of postoperative pulmonary complications and the treatment of Infant Respiratory Distress Syndrome (IRDS) of premature infants and newborns.
For the research of ambroxol hydrochloride, the research of preparation formulations and the development of new clinical indications are mostly focused at home and abroad, and currently, the ambroxol hydrochloride has various preparation types in China, such as ambroxol hydrochloride tablets, ambroxol hydrochloride capsules, ambroxol hydrochloride oral solutions, ambroxol hydrochloride sustained-release capsules and the like. Solid preparations such as oral controlled release tablets or capsules are often difficult to swallow and dose, thereby causing inconvenience in taking the patients, affecting the completion of the normal treatment scheme and the exertion of the drug effect, if the common tablet is taken 3 times a day, 1 tablet (30 mg/tablet) is taken each time, the patient can change the dosage scheme accidentally due to pain, trouble and the like, the administration is missed once or twice, the concentration of the drug level in blood plasma and tissues fluctuates greatly, even if the medicine is continuously taken, the treatment concentration can not be reached in a short time, and the treatment level can be rebuilt only by repeated medication, thereby wasting the medicine and delaying the treatment, and furthermore, if children take the medicine, one tablet or one granule of the medicine needs to be divided into a plurality of parts for taking, the dosage is difficult to accurately control, moreover, the solid preparation can be absorbed by human body only by dissolving and then dissolving, and the absorption speed and the effect are slow. The liquid preparation has the characteristics of quick absorption, capability of being taken in divided doses and easy acceptance by old people and children, so that the research and development of the liquid sustained-release preparation with good taste and stable drug effect are highly regarded by pharmaceuticists and clinicians.
In addition, the ambroxol hydrochloride oral solution consists of ambroxol hydrochloride, water, ethanol and other flavoring agents, and is widely applied clinically due to convenient administration. However, the product has unpleasant tastes such as bitter, astringent and numb, is tolerable to adults and is difficult to accept by children, and the oral solution is widely known to be mainly used for children and patients with dysphagia. At present, no better solution exists for the clinical application of the contradiction, which greatly reduces the compliance of the product, namely, some patients do not want to take the medicine and can not take the medicine regularly according to the regulation, so that the treatment effect of the medicine can not reach the expected effect.
Therefore, the ambroxol hydrochloride preparation with good treatment effect, good taste, stable quality and strong drug compliance is urgently needed in the technical field.
The present invention has been made in view of this situation.
Disclosure of Invention
The invention aims to solve the technical problem of poor clinical requirement/compliance in the prior art, and provides an ambroxol hydrochloride oral spray solution which can enable the administration dosage to be more accurate and effective, greatly improves the stability through the prescription and the adjustment of the pH value, has better taste and effectively improves the compliance of patients.
In order to solve the technical problems, the invention adopts the technical scheme that:
the invention discloses an ambroxol hydrochloride oral spray solution which comprises the following components in 1 ml: 45-55mg of ambroxol hydrochloride, and further comprises pharmaceutically acceptable auxiliary materials and sufficient purified water.
The ambroxol hydrochloride oral spray solution greatly increases the convenience of taking medicine for patients suffering from acute attack of chronic bronchitis, asthmatic bronchitis and bronchial asthma. In clinical application, many patients with dysphagia cannot take oral solid preparations and solutions of ambroxol hydrochloride, and the oral solid preparations and solutions are sprayed to the oral cavity every time and easily enter the gastrointestinal tract, so that the oral solid preparations and solutions can be used for many patients with dysphagia.
The ambroxol hydrochloride oral spray solution is a new prescription, the concentration of the ambroxol hydrochloride in the prescription is 45-55mg/ml, preferably 50mg/ml, the ambroxol hydrochloride oral spray solution has two packaging specifications of 1250mg/25ml and 650mg/13ml respectively, and the oral spray solution can ensure that the administration dosage is more accurate and effectively improve the compliance of patients.
In addition, compared with the prior art, the spraying solution has the advantages of convenience, flexibility, no need of special environment and portability.
Further, the pharmaceutically acceptable auxiliary materials comprise one or more of a solvent, a surfactant, a preservative, a flavoring agent and a pH regulator.
Further, the auxiliary materials comprise a solvent, a surfactant, a preservative, a flavoring agent and a pH regulator.
By adding the active ingredients and pharmaceutically acceptable auxiliary materials, the clear liquid preparation with good taste can be prepared, and the preparation has stable quality, no visible foreign matter precipitation and safe medication.
Further, the buffering agent comprises tromethamine and/or sodium hydroxide, preferably, the buffering agent comprises tromethamine and sodium hydroxide; the mass ratio of the tromethamine to the ambroxol hydrochloride is 0.06-0.08: 1, preferably, the mass ratio of the tromethamine to the ambroxol hydrochloride is 0.072: 1; the mass ratio of the 0.01N sodium hydroxide to the ambroxol hydrochloride is 0.12-0.14: 1, more preferably, the mass ratio of the 0.01N sodium hydroxide to the ambroxol hydrochloride is 0.125: 1.
repeated experiments show that a certain amount of tromethamine is added into the ambroxol hydrochloride serving as an active ingredient, so that the stability of a solution system can be greatly improved, and when the mass ratio of the tromethamine to the ambroxol hydrochloride is 0.06-0.08: 1, the stability of the product is increased along with the increase of the using amount of the tromethamine, but the product is hardly changed after the using amount is increased to a certain amount, but the total impurity is increased, when the mass ratio of the tromethamine to the ambroxol hydrochloride is 0.072: 1, the stability effect is best.
Further, the solvent comprises glycerol and/or ethanol; the solvent comprises glycerol and 96% ethanol, and the mass ratio of the glycerol to the ambroxol hydrochloride is (0.54-0.6): 1, preferably, the mass ratio of the glycerol to the ambroxol hydrochloride is 0.58: 1; the mass ratio of the 96% ethanol to the ambroxol hydrochloride is 0.08-0.14: 1, preferably, the mass ratio of the 96% ethanol to the ambroxol hydrochloride is 0.1: 1.
further, the surfactant comprises polyethylene glycol pentadecyl hydroxystearate; the mass ratio of the polyethylene glycol pentadecyl hydroxystearate to the ambroxol hydrochloride is 1.8-2.2: preferably, the mass ratio of the polyethylene glycol pentadecyl hydroxystearate to the ambroxol hydrochloride is 2: 1.
according to research, the surfactant polyethylene glycol pentadecyl hydroxystearate can react with ambroxol to generate impurity B indicated in European pharmacopoeia if trace formaldehyde is contained in the polyethylene glycol pentadecyl hydroxystearate, so that the content of the formaldehyde in the polyethylene glycol pentadecyl hydroxystearate is less than or equal to 5ppm so as to avoid the generation of the impurity B.
The invention adopts glycerin and polyethylene glycol pentadecyl hydroxystearate to dissolve the active ingredient ambroxol hydrochloride, and after repeated tests, the mass ratio of the glycerin to the polyethylene glycol pentadecyl hydroxystearate to the ambroxol hydrochloride is found to be 0.54-0.6: 1-3: 1, the solubility of the ambroxol hydrochloride is increased along with the increase of the dosage of the glycerol and the polyethylene glycol pentadecyl hydroxystearate, but impurities are generated when the dosage is increased beyond a certain amount, and when the mass ratio of the glycerol to the polyethylene glycol pentadecyl hydroxystearate to the ambroxol hydrochloride is 0.58: 2: 1, the ambroxol hydrochloride is completely dissolved.
Further, the preservative comprises sodium benzoate, and the mass ratio of the sodium benzoate to the ambroxol hydrochloride is (0.08-0.12): 1, more preferably, the mass ratio of the sodium benzoate to the ambroxol hydrochloride is 0.1: 1.
the oral spray solution of the present invention contains 5mg/ml preservative sodium benzoate, which is preferred over benzoic acid because of its better solubility in water, and over paraben preservatives because the latter typically require a combination of two preservatives (e.g., methyl and propyl parabens) to achieve bacterial and fungal resistance.
In view of the high concentration of active ingredient contained in the formulation, and the supply in multi-dose containers equipped with metering pumps, sodium benzoate was chosen at a concentration of 5 mg/ml. The concentration of preservative is higher than that of comparable products, e.g.
Syrup, but the amount of preservative administered is likewise lower due to the small dosage of the formulation. In fact, the amount of preservative administered is about 3-6 times lower for ambroxol hydrochloride daily doses of 90mg compared to other products.
Further, the flavoring agent is one or more of levomenthol, ammonium glycyrrhetate, acesulfame potassium and xylitol; the flavoring agent comprises L-menthol, ammonium glycyrrhizinate, acesulfame potassium and xylitol; preferably, the mass ratio of the levomenthol, the ammonium glycyrrhizinate, the acesulfame potassium, the xylitol and the ambroxol hydrochloride is 0.08-0.15: 0.01-0.05: 0.2-0.6: 3.82-4.12: 1; more preferably, the weight ratio of the levomenthol, the ammonium glycyrrhizinate, the acesulfame potassium, the xylitol and the ambroxol hydrochloride is 0.1: 0.0128: 0.3: 4: 1.
repeated experiments show that the mass ratio of the levomenthol, the ammonium glycyrrhizinate, the acesulfame potassium, the xylitol and the ambroxol hydrochloride is 0.08-0.15: 0.01-0.05: 0.2-0.6: 3.82-4.12: 1, the bitter taste of the ambroxol hydrochloride can be effectively covered, and when the weight ratio of the levomenthol, the ammonium glycyrrhizinate, the acesulfame potassium, the xylitol and the ambroxol hydrochloride is 0.1: 0.0128: 0.3: 4: 1, the bitter taste of the ambroxol hydrochloride can be effectively covered, so that the taste of the spray solution is fresh.
The spray solution has fresh taste, acceptable mouthfeel is obtained by adding acesulfame potassium, xylitol, levomenthol and ammonium glycyrrhetate, the bitter taste of ambroxol hydrochloride can be effectively covered by the combination of the flavoring agents, and the oral spray solution with excellent mouthfeel and acceptable taste is obtained.
Further, the ambroxol hydrochloride oral spray solution comprises the following components in parts by weight based on 1 ml: 50mg of ambroxol hydrochloride, 3.6mg of tromethamine, 100mg of polyethylene glycol pentadecahydroxy stearate, 29mg of glycerol, 15mg of acesulfame potassium, 200mg of xylitol, 5mg of sodium benzoate, 5mg of levomenthol, 0.64mg of ammonium glycyrrhizinate, 5mg of 96% ethanol, 6.25mg of 0.01N sodium hydroxide and the balance of purified water.
Tests show that the ambroxol hydrochloride spray solution has no obvious change in index properties, pH value, content and related substances in comparison with 0 month surprisingly under specific proportion and composition, and the ambroxol hydrochloride spray solution has good stability.
Further, the pH value of the ambroxol hydrochloride oral spray solution is 6.1-6.6, and preferably, the pH value of the ambroxol hydrochloride oral spray solution is 6.5.
The invention ensures that the pH value of the oral cavity spray solution is between 6.1 and 6.6, preferably 6.5, so that the stability of the ambroxol hydrochloride is good, and the pH value of the oral cavity spray solution is more suitable for oral cavity spray administration, namely the ambroxol hydrochloride oral cavity spray solution has high stability of active ingredients and is more suitable for oral cavity administration.
The invention also discloses a preparation method of the ambroxol hydrochloride oral spray solution, which comprises the following steps:
(1) mixing ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, tromethamine and levomenthol according to the formula amount, stirring and heating to obtain a mixture A;
(2) mixing and stirring purified water, sodium benzoate, acesulfame potassium and xylitol according to the prescription amount, and heating to obtain a mixture B;
(3) mixing and stirring ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide according to the prescription amount to obtain a mixture C, slowly adding the mixture B obtained in the step (2) into the mixture A obtained in the step (1), continuously stirring and cooling, then adding the mixture C, continuously adding purified water to the full amount, and then filtering and filling and sealing to obtain the product.
Further, in the step (1), heating to 60-70 ℃, and maintaining the temperature for about 30-45 minutes to obtain a mixture A;
further, in the step (2), heating to 60-70 ℃, and maintaining the temperature for about 10-20 minutes to obtain a mixture B;
further, in the step (3), stirring for 5-15 minutes at 60-70 ℃, continuously stirring and cooling to 20-30 ℃, and then adding the mixture C under stirring;
further, in the step (3), a 10-micron box type filter is adopted for filtering, and the relative density of the ambroxol hydrochloride solution is 1.098-1.117.
The preparation method of the ambroxol hydrochloride oral spray solution comprises the following steps:
(1) mixing and stirring ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, tromethamine and levomenthol according to the formula amount, heating to 60-70 ℃, and maintaining the temperature for about 30-45 minutes to obtain a mixture A;
(2) mixing and stirring purified water, sodium benzoate, acesulfame potassium and xylitol according to the prescription amount, heating to 60-70 ℃, and maintaining the temperature for about 10-20 minutes to obtain a mixture B, thus obtaining a mixture B;
(3) taking ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide according to the formula amount, mixing and stirring to obtain a mixture C, slowly adding the mixture B obtained in the step (2) into the mixture A obtained in the step (1), stirring for 5-15 minutes at 60-70 ℃ to obtain a milky mixture, continuously stirring and cooling to 20-30 ℃ to obtain a clear and colorless solution, then adding the mixture C, continuously adding purified water to full amount, filtering by using a 10-micron box filter, and then encapsulating to obtain the water-based paint.
In the preparation method, firstly, a certain amount of tromethamine is added into the ambroxol hydrochloride serving as an active ingredient to improve the stability of a solution system, then polyethylene glycol 15 hydroxystearate and glycerol are added to completely dissolve the active ingredient, and levomenthol is added to mask the taste to obtain a uniform mixture A;
adding a mixture B prepared from sodium benzoate, acesulfame potassium and xylitol into the mixture A, performing antiseptic and seasoning treatment, adding a mixture C prepared from ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide for seasoning and pH correction, filtering, bottling to obtain ambroxol hydrochloride oral cavity spray solution, and filling into a spray bottle with a quantitative valve, wherein the volume of each spray is 0.2ml (equivalent to 10mg of ambroxol hydrochloride).
In addition, in the preparation process, the obtained product is further found to be more stable when the stirring temperature in the step (1) is 60-70 ℃, preferably 65 ℃ or the cooling temperature in the step (3) is 20-30 ℃, preferably 25 ℃.
After adopting the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the ambroxol hydrochloride oral spray solution can be widely used for treating thick sputum, difficult expectoration and the like caused by various acute and chronic respiratory diseases, can be applied to patients needing treatment through an oral spray way, has the dosage of 10 mg/time generally, and can be determined by doctors according to the illness state, age and the like of the patients.
After the ambroxol hydrochloride oral spray solution is sprayed and administrated through the oral cavity, the medicine can enter the gastrointestinal tract through the oral cavity, and the ambroxol hydrochloride oral spray solution is quick to absorb, quick in effect taking and high in bioavailability. Meanwhile, the spray solution is convenient to use, does not need to be taken with water during administration, and has good compliance.
Compared with the existing ambroxol hydrochloride dosage forms (such as tablets, capsules and the like), the ambroxol hydrochloride oral spray solution prepared by the method has the advantages of more convenient and flexible usability, no need of special environment and auxiliary equipment, wide application range, unified dosage standard, less dosage and less waste.
According to the invention, all components are completely dissolved by improving the components of the prescription, the stability is good, a liquid preparation with higher concentration than that of the current commercially available oral solution is obtained, through content detection of 3 batches of ambroxol hydrochloride, all values meet the requirement of 95.0-105.0% of the labeled amount of 5.00g/ml, the packaging size is smaller due to the high-concentration prescription, the sizes of 25ml and 13ml are smaller, and the carrying and the use are convenient.
The solution of the invention has fresh taste, acceptable mouthfeel is obtained by adding acesulfame potassium, xylitol, levomenthol and ammonium glycyrrhetate, the combination of the sweetening agent and the flavoring agent can effectively cover the bitter taste of ambroxol hydrochloride, and a liquid preparation with excellent mouthfeel and acceptable taste is obtained.
In the invention, the detection of formaldehyde is added on the basis of the quality standard of European pharmacopoeia for the surfactant polyethylene glycol pentadecahydroxy stearate, the limit is not more than 5ppm, and the generation of impurity B is avoided.
The solution prepared by the invention can be well stored and meets the microbial limit requirements of oral medicinal preparations in European pharmacopoeia.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments will be clearly and completely described below, and the following embodiments are used for illustrating the present invention and are not used for limiting the scope of the present invention.
Experimental example 1
Using the formulation as in table 1, an ambroxol hydrochloride oral spray solution was prepared as follows:
step 1: mixing and stirring ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, tromethamine and levomenthol according to the prescription amount, heating to 60 ℃, and maintaining the temperature for about 30 minutes to obtain a mixture A;
step 2: mixing and stirring purified water, sodium benzoate, acesulfame potassium and xylitol according to the prescription amount, heating to 65 ℃, and maintaining the temperature for about 10 minutes to obtain a mixture B and obtain a mixture B;
and step 3: mixing and stirring ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide according to the prescription amount to obtain a mixture C, slowly adding the mixture B obtained in the step (2) into the mixture A obtained in the step (1), stirring for 5 minutes at 65 ℃ to obtain a milky mixture, continuously stirring and cooling to 25 ℃ to obtain a clear and colorless solution, then adding the mixture C, and continuously adding purified water to full amount to obtain a bulk solution.
And 4, step 4: the bulk solution was filtered through a 10 micron box filter and the filtrate was collected in a storage vessel and continued for processing in step 5.
And 5: filling the solution into a type III amber glass bottle through a filling station connected with a nitrogen line, and sealing by using a metering pump; the filling volume and the integrity of the seal are checked.
Example 2
Using the formulation as in table 1, an ambroxol hydrochloride oral spray solution was prepared as follows:
step 1: mixing and stirring ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, tromethamine and levomenthol according to the prescription amount, heating to 65 ℃, and maintaining the temperature for about 40 minutes to obtain a mixture A;
step 2: mixing and stirring purified water, sodium benzoate, acesulfame potassium and xylitol according to the prescription amount, heating to 65 ℃, and maintaining the temperature for about 15 minutes to obtain a mixture B and obtain a mixture B;
and step 3: mixing and stirring ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide according to the prescription amount to obtain a mixture C, slowly adding the mixture B obtained in the step (2) into the mixture A obtained in the step (1), stirring for 10 minutes at 65 ℃ to obtain a milky mixture, continuously stirring and cooling to 25 ℃ to obtain a clear and colorless solution, then adding the mixture C, and continuously adding purified water to full amount to obtain a bulk solution.
And 4, step 4: the bulk solution was filtered through a 10 micron box filter and the filtrate was collected in a storage vessel and continued for processing in step 5.
And 5: filling the solution into a type III amber glass bottle through a filling station connected with a nitrogen line, and sealing by using a metering pump; the filling volume and the integrity of the seal are checked.
Example 3
Using the formulation as in table 1, an ambroxol hydrochloride oral spray solution was prepared as follows:
step 1: mixing and stirring ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, tromethamine and levomenthol according to the prescription amount, heating to 70 ℃, and maintaining the temperature for about 32 minutes to obtain a mixture A;
step 2: mixing and stirring purified water, sodium benzoate, acesulfame potassium and xylitol according to the prescription amount, heating to 70 ℃, and maintaining the temperature for about 10 minutes to obtain a mixture B and obtain a mixture B;
and step 3: mixing and stirring ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide according to the prescription amount to obtain a mixture C, slowly adding the mixture B obtained in the step (2) into the mixture A obtained in the step (1), stirring for 8 minutes at 70 ℃ to obtain a milky mixture, continuously stirring and cooling to 30 ℃ to obtain a clear and colorless solution, then adding the mixture C, and continuously adding purified water to full amount to obtain a bulk solution.
And 4, step 4: the bulk solution was filtered through a 10 micron box filter and the filtrate was collected in a storage vessel and continued for processing in step 5.
And 5: filling the solution into a type III amber glass bottle through a filling station connected with a nitrogen line, and sealing by using a metering pump; the filling volume and the integrity of the seal are checked.
Example 4
Using the formulation as in table 1, an ambroxol hydrochloride oral spray solution was prepared as follows:
step 1: mixing and stirring ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, tromethamine and levomenthol according to the prescription amount, heating to 68 ℃, and maintaining the temperature for about 36 minutes to obtain a mixture A;
step 2: mixing and stirring purified water, sodium benzoate, acesulfame potassium and xylitol according to the prescription amount, heating to 67 ℃, and maintaining the temperature for about 12 minutes to obtain a mixture B and obtain a mixture B;
and step 3: mixing and stirring ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide according to the prescription amount to obtain a mixture C, slowly adding the mixture B obtained in the step (2) into the mixture A obtained in the step (1), stirring for 15 minutes at 67 ℃ to obtain a milky mixture, continuously stirring and cooling to 28 ℃ to obtain a clear and colorless solution, then adding the mixture C, and continuously adding purified water to full amount to obtain a bulk solution.
And 4, step 4: the bulk solution was filtered through a 10 micron box filter and the filtrate was collected in a storage vessel and continued for processing in step 5.
And 5: filling the solution into a type III amber glass bottle through a filling station connected with a nitrogen line, and sealing by using a metering pump; the filling volume and the integrity of the seal are checked.
Example 5
Using the formulation as in table 1, an ambroxol hydrochloride oral spray solution was prepared as follows:
step 1: mixing and stirring ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, tromethamine and levomenthol according to the prescription amount, heating to 63 ℃, and maintaining the temperature for about 42 minutes to obtain a mixture A;
step 2: mixing and stirring purified water, sodium benzoate, acesulfame potassium and xylitol according to the prescription amount, heating to 63 ℃, and maintaining the temperature for about 18 minutes to obtain a mixture B and obtain a mixture B;
and step 3: mixing and stirring ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide according to the prescription amount to obtain a mixture C, slowly adding the mixture B obtained in the step (2) into the mixture A obtained in the step (1), stirring for 15 minutes at 63 ℃ to obtain a milky mixture, continuously stirring and cooling to 26 ℃ to obtain a clear and colorless solution, then adding the mixture C, and continuously adding purified water to full amount to obtain a bulk solution.
And 4, step 4: the bulk solution was filtered through a 10 micron box filter and the filtrate was collected in a storage vessel and continued for processing in step 5.
And 5: filling the solution into a type III amber glass bottle through a filling station connected with a nitrogen line, and sealing by using a metering pump; the filling volume and the integrity of the seal are checked.
Examples 1 to 5
Prescription:
TABLE 1 formulations of examples 1-5
Comparative examples 1 to 4
Adding different pH regulators to the prescription experiment (specification 3.6mg, pH regulator see Table 2)
Step 1: mixing 50mg of ambroxol hydrochloride, 100mg of polyethylene glycol pentadecyl hydroxystearate, 29mg of glycerol, a pH regulator in a prescription amount and 5mg of levomenthol, stirring, heating to 65 ℃, and maintaining the temperature for about 40 minutes to obtain a mixture A;
step 2: mixing purified water, 5mg of sodium benzoate, 15mg of acesulfame potassium and 200mg of xylitol, stirring, heating to 65 ℃, and maintaining the temperature for about 15 minutes to obtain a mixture B, thus obtaining a mixture B;
and step 3: mixing ammonium glycyrrhizinate 0.64mg, 96% ethanol 5mg and 0.001N sodium hydroxide 6.25mg, stirring to obtain mixture C, slowly adding mixture B obtained in step (2) into mixture A obtained in step (1), stirring at 65 deg.C for 10 min to obtain milky mixture, continuously stirring and cooling to 25 deg.C to obtain clear and colorless solution, adding mixture C, and continuously adding purified water to full volume to obtain bulk solution.
And 4, step 4: the bulk solution was filtered through a 10 micron box filter and the filtrate was collected in a storage vessel and continued for processing in step 5.
And 5: filling the solution into a type III amber glass bottle through a filling station connected with a nitrogen line, and sealing by using a metering pump; the filling volume and the integrity of the seal are checked.
Table 2 formula of each pair of proportional pH regulators
Stability studies were performed on the above examples and comparative examples: after each sample was left for 5 days and 10 days, it was examined and the results are shown in Table 3.
TABLE 3 stability test results
Note: the content is calculated by ambroxol hydrochloride.
The experimental results show that compared with the sample added with other pH regulators in the comparative example, the ambroxol hydrochloride oral spray solution prepared by the embodiment of the invention has the advantages that after the tromethamine is added, the total impurity content is obviously reduced, the solution is clear, no visible foreign matters exist, and the product content is improved, which indicates that the ambroxol hydrochloride oral spray solution prepared by the invention has good stability and high quality.
Test examples 1 to 5
Influence of the amount of glycerol and polyethylene glycol pentadecahydroxy stearate on the active ingredient ambroxol hydrochloride
TABLE 4 Glycerol (mg), Macrogol pentadecyl hydroxystearate (mg) and ambroxol hydrochloride (mg) amounts
Note: mass ratio glycerin (mg): polyethylene glycol pentadecyl hydroxystearate (mg): ambroxol hydrochloride (mg)
Step 1: mixing ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, 3.6g of tromethamine and 5mg of levomenthol according to the prescription amount, stirring, heating to 65 ℃, and maintaining the temperature for about 40 minutes to obtain a mixture A;
step 2: mixing purified water, 5mg of sodium benzoate, 15mg of acesulfame potassium and 200mg of xylitol, stirring, heating to 65 ℃, and maintaining the temperature for about 15 minutes to obtain a mixture B, thus obtaining a mixture B;
and step 3: mixing ammonium glycyrrhizinate 0.64mg, 96% ethanol 5mg and 0.001N sodium hydroxide 6.25mg, stirring to obtain mixture C, slowly adding mixture B obtained in step (2) into mixture A obtained in step (1), stirring at 65 deg.C for 10 min to obtain milky mixture, continuously stirring and cooling to 25 deg.C to obtain clear and colorless solution, adding mixture C, and continuously adding purified water to full volume to obtain bulk solution.
And 4, step 4: the bulk solution was filtered through a 10 micron box filter and the filtrate was collected in a storage vessel and continued for processing in step 5.
And 5: filling the solution into a type III amber glass bottle through a filling station connected with a nitrogen line, and sealing by using a metering pump; the filling volume and the integrity of the seal are checked.
And (3) carrying out stability investigation on the obtained finished product: the samples were left for 5 days, 10 days, and then examined, the results are shown in Table 5.
TABLE 5 stability test results
Note: the content is calculated by ambroxol hydrochloride.
From the above table, when the mass ratio of the glycerol, the polyethylene glycol pentadecyl hydroxystearate and the ambroxol hydrochloride is 0.54-0.6: 1-3: 1, along with the increase of the using amount of the glycerol and the polyethylene glycol pentadecyl hydroxystearate, the solubility of the ambroxol hydrochloride is increased, the product stability is increased, foreign matters are reduced, when the amount of the glycerol and the polyethylene glycol pentadecyl hydroxystearate is increased to exceed a certain amount, the ambroxol hydrochloride begins to be separated out, the foreign matters are increased, and the total impurities are increased, when the mass ratio of the glycerol to the polyethylene glycol pentadecyl hydroxystearate to the ambroxol hydrochloride is 0.58: 2: 1, the ambroxol hydrochloride is completely dissolved, and the stability is best.
Test example 6 quality test results
The invention also samples and detects 3 batches of ambroxol hydrochloride spray solution in the embodiment 2:
A. detection standard:
B. description of a process control method
(1) Appearance of the solution: visual inspection of the solution samples was performed in colorless, transparent, neutral glass test tubes.
(2) pH: the pH of the solution was measured according to the European pharmacopoeia 2.3.3 "potentiometry pH".
(3) Relative density: the relative density of the solution was determined by densitometry according to the european pharmacopoeia 2.2.5 "relative density".
1) Sampling plan
A homogeneous sample was taken at about the middle layer of the solution. The content of ambroxol hydrochloride must be within + -5% of the theoretical value.
The time points indicated are the filling operations, i.e. 3 samples each were taken at the beginning, in the middle and at the end of the filling process.
2) Results
The results of the validation study are listed below in tabular form.
a) Appearance of solution
| Sample (I) | Batch SPa1 | Batch SPa2 | Batch SPa3 |
| PH3 | Conform to | Conform to | Conform to |
| PH4bot | Conform to | Conform to | Conform to |
| PH4top | Conform to | Conform to | Conform to |
| PH5start | Conform to | Conform to | Conform to |
| PH5mid | Conform to | Conform to | Conform to |
| PH5end | Conform to | Conform to | Conform to |
The appearance of the solution was checked for each batch in each process step. The results meet the acceptance criteria.
b) pH and relative Density
The mean, standard deviation and relative standard deviation RSD (PH5start, PH5 midle and PH5end) of the samples taken during filling were calculated. These values show that the production process is robust and reproducible with small batch-to-batch variation.
C) Ambroxol hydrochloride content
The table below shows the content of ambroxol hydrochloride in the samples taken in step 3 and step 4 of the production process.
Step 3
Step 4
The results of the ambroxol hydrochloride content in each batch of step 5 are reported in the table below.
Step 5-batch Spa1
| Sample (I) | Indicating amount [ g/100ml] | Found [ g/100ml ]] | Measured value (indicated quantity%) |
| PH5start/1 | 5.00 | 4.89 | 97.8 |
| PH5start/2 | 5.00 | 5.07 | 101.4 |
| PH5start/3 | 5.00 | 5.02 | 100.4 |
| PH5mid/1 | 5.00 | 4.95 | 99.0 |
| PH5mid/2 | 5.00 | 5.01 | 100.2 |
| PH5mid/3 | 5.00 | 5.08 | 101.6 |
| PH5end/1 | 5.00 | 5.05 | 101.0 |
| PH5end/2 | 5.00 | 4.88 | 97.6 |
| PH5end/3 | 5.00 | 5.02 | 100.4 |
| Mean value | ～～～ | 5.00 | 99.93 |
| Standard deviation of | ～～～ | 0.07 | 1.39 |
| RSD[％] | ～～～ | 1.39 | 1.39 |
Step 5-batch Spa2
Step 5-batch Spa3
For the content of the ambroxol hydrochloride, all the values meet the requirement that the labeled amount is 5.00g/100ml and is 95.0-105.0%. Furthermore, the RSD value confirms the homogeneity of the solution during the filling process.
D) Degradation products
In the table below, the results of impurity testing of representative samples of step 5 from each batch are reported.
Step 5-batch Spa1
| Sample (I) | Impurity A [% (w/w)] | Impurity B [% (w/w)] | Impurity E [% (w/w)] | Unspecified impurities [% (w/w)] | Total impurities [% (w/w)] |
| PH5start/1 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5start/2 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5start/3 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5mid/1 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5mid/2 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5mid/3 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5end/1 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5end/2 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5end/3 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
n.d. -, not detected
Step 5-batch Spa2
n.d. -, not detected
Step 5-batch Spa3
| Sample (I) | Impurity A [% (w/w)] | Impurity B [% (w/w)] | Impurity E [% (w/w)] | Unspecified impurities [% (w/w)] | Total impurities [% (w/w)] |
| PH5start/1 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5start/2 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5start/3 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5mid/1 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5mid/2 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5mid/3 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5end/1 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5end/2 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
| PH5end/3 | n.d. | n.d. | n.d. | n.d. | <0.5％ |
n.d. -, not detected
For each batch, the impurity test results met the acceptance criteria.
E) Determination of sodium benzoate content
In the table below, the results of the sodium benzoate content determination of a representative sample of step 5 from each batch are reported.
Step 5-batch Spa1
Step 5-batch Spa2
Step 5-batch Spa3
For the determination of the content of sodium benzoate, all the values meet the marking amount of 95.0-105.0%. I.e., 0.50g/100 ml. In addition, the RSD value confirms the homogeneity of the solution during the filling process.
F) Microorganisms
In the table below, the results of the microbiological tests carried out on representative samples of step 5 in each batch are reported.
Step 5-batch Spa1
| Sample (I) | Aerobic bacteria [ cfu/ml] | Aerobic fungus [ cfu/ml] | Escherichia coli |
| PH5start/1 | ＜10 | ＜10 | Is absent from |
| PH5start/2 | ＜10 | ＜10 | Is absent from |
| PH5start/3 | ＜10 | ＜10 | Is absent from |
| PH5mid/1 | ＜10 | ＜10 | Is absent from |
| PH5mid/2 | ＜10 | ＜10 | Is absent from |
| PH5mid/3 | ＜10 | ＜10 | Is absent from |
| PH5end/1 | ＜10 | ＜10 | Is absent from |
| PH5end/2 | ＜10 | ＜10 | Is absent from |
| PH5end/3 | ＜10 | ＜10 | Is absent from |
Step 5-batch Spa2
Step 5-batch Spa3
| Sample (I) | Aerobic bacteria [ cfu/ml] | Aerobic fungus [ cfu/ml] | Escherichia coli |
| PH5start/1 | ＜10 | ＜10 | Is absent from |
| PH5start/2 | ＜10 | ＜10 | Is absent from |
| PH5start/3 | ＜10 | ＜10 | Is absent from |
| PH5mid/1 | ＜10 | ＜10 | Is absent from |
| PH5mid/2 | ＜10 | ＜10 | Is absent from |
| PH5mid/3 | ＜10 | ＜10 | Is absent from |
| PH5end/1 | ＜10 | ＜10 | Is absent from |
| PH5end/2 | ＜10 | ＜10 | Is absent from |
| PH5end/3 | ＜10 | ＜10 | Is absent from |
The results met the acceptance limit of each sample in each batch.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. An ambroxol hydrochloride oral spray solution is characterized in that: the ambroxol hydrochloride oral spray solution comprises the following components in 1 ml: 45-55mg of ambroxol hydrochloride, and also comprises pharmaceutically acceptable auxiliary materials and sufficient purified water.
2. The ambroxol hydrochloride oral spray solution of claim 1, characterized in that: the content of the ambroxol hydrochloride is 50mg calculated by 1 ml.
3. The ambroxol hydrochloride oral spray solution of claim 1 or 2, characterized in that: the pharmaceutically acceptable auxiliary materials comprise one or more of a solvent, a surfactant, a preservative, a flavoring agent and a pH regulator;
preferably, the adjuvants include a solvent, a surfactant, a preservative, a flavoring agent and a pH adjuster.
4. The ambroxol hydrochloride oral spray solution of claim 3, characterized in that:
the solvent comprises glycerol and/or ethanol, preferably, the solvent comprises glycerol and 96% ethanol;
the pH regulator comprises tromethamine and/or sodium hydroxide, and preferably, the pH regulator comprises tromethamine and sodium hydroxide;
the surfactant comprises polyethylene glycol pentadecyl hydroxystearate;
the preservative comprises sodium benzoate;
the flavoring agent is one or more of levomenthol, ammonium glycyrrhizinate, acesulfame potassium and xylitol, preferably, the flavoring agent comprises levomenthol, ammonium glycyrrhizinate, acesulfame potassium and xylitol.
5. The ambroxol hydrochloride oral spray solution of claim 4, characterized in that:
the mass ratio of the glycerol to the ambroxol hydrochloride is 0.54-0.6: 1, preferably, the mass ratio of the glycerol to the ambroxol hydrochloride is 0.58: 1, the mass ratio of the 96% ethanol to the ambroxol hydrochloride is 0.08-0.14, preferably, the mass ratio of the 96% ethanol to the ambroxol hydrochloride is 0.1: 1;
the mass ratio of the tromethamine to the ambroxol hydrochloride is 0.06-0.08: 1, preferably, the mass ratio of the tromethamine to the ambroxol hydrochloride is 0.072: 1; the mass ratio of the 0.01N sodium hydroxide to the ambroxol hydrochloride is 0.12-0.14: 1, preferably, the mass ratio of the 0.01N sodium hydroxide to the ambroxol hydrochloride is 0.125: 1;
the mass ratio of the polyethylene glycol pentadecyl hydroxystearate to the ambroxol hydrochloride is 1.8-2.2: preferably, the mass ratio of the polyethylene glycol pentadecyl hydroxystearate to the ambroxol hydrochloride is 2: 1;
the mass ratio of the sodium benzoate to the ambroxol hydrochloride is 0.08-0.12: 1, preferably, the mass ratio of the sodium benzoate to the ambroxol hydrochloride is 0.1: 1;
the mass ratio of the levomenthol, the ammonium glycyrrhizinate, the acesulfame potassium, the xylitol and the ambroxol hydrochloride is 0.08-0.15: 0.01-0.05: 0.2-0.6: 3.82-4.12: 1, preferably, the mass ratio of the levomenthol, the ammonium glycyrrhizinate, the acesulfame potassium, the xylitol and the ambroxol hydrochloride is 0.1: 0.0128: 0.3: 4: 1.
6. the ambroxol hydrochloride oral spray solution of any one of claims 1 to 5, characterized in that: the ambroxol hydrochloride oral spray solution comprises the following components in parts by weight based on 1 ml: 50mg of ambroxol hydrochloride, 3.6mg of tromethamine, 100mg of polyethylene glycol pentadecahydroxy stearate, 29mg of glycerol, 15mg of acesulfame potassium, 200mg of xylitol, 5mg of sodium benzoate, 5mg of levomenthol, 0.64mg of ammonium glycyrrhizinate, 5mg of 96% ethanol, 6.25mg of 0.01N sodium hydroxide and the balance of purified water.
7. The ambroxol hydrochloride oral spray solution of any one of claims 1 to 6, which is characterized in that: the pH value of the ambroxol hydrochloride oral spray solution is 6.1-6.6, and preferably, the pH value of the ambroxol hydrochloride oral spray solution is 6.5.
8. A process for the preparation of an ambroxol hydrochloride oral spray solution as claimed in any one of claims 1 to 7, characterized in that: the method comprises the following steps:
(1) mixing ambroxol hydrochloride, polyethylene glycol pentadecyl hydroxystearate, glycerol, tromethamine and levomenthol according to the formula amount, stirring and heating to obtain a mixture A;
(2) mixing and stirring purified water, sodium benzoate, acesulfame potassium and xylitol according to the prescription amount, and heating to obtain a mixture B;
(3) mixing and stirring ammonium glycyrrhizinate, 96% ethanol and 0.001N sodium hydroxide according to the prescription amount to obtain a mixture C, slowly adding the mixture B obtained in the step (2) into the mixture A obtained in the step (1), continuously stirring and cooling, then adding the mixture C, adding purified water to the full amount, and then filtering and filling and sealing to obtain the product.
9. The method for preparing ambroxol hydrochloride solution according to claim 8, characterized in that:
in the step (1), heating to 60-70 ℃, and maintaining the temperature for about 30-45 minutes to obtain a mixture A;
in the step (2), heating to 60-70 ℃, and maintaining the temperature for about 10-20 minutes to obtain a mixture B.
10. The method for preparing ambroxol hydrochloride solution according to claim 8 or 9, characterized in that: in the step (3), stirring for 5-15 minutes at 60-70 ℃, continuously stirring and cooling to 20-30 ℃, and then adding the mixture C under stirring;
preferably, in the step (3), a 10-micron box filter is adopted for filtering, and the relative density of the ambroxol hydrochloride solution is 1.098-1.117.
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| CN202010731294.0A CN113995721A (en) | 2020-07-27 | 2020-07-27 | Ambroxol hydrochloride oral spray solution and preparation method thereof |
| PCT/CN2020/138891 WO2022021769A1 (en) | 2020-07-27 | 2020-12-24 | Ambroxol hydrochloride oral spray solution and preparation method therefor |
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| US20050075403A1 (en) * | 2003-10-02 | 2005-04-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ambroxol for the treatment of inflammation in the pharynx |
| EP1543826A1 (en) * | 2003-12-16 | 2005-06-22 | Advance Holdings Limited | Concentrated aqueous solution of ambroxol |
| US20050266058A1 (en) * | 2004-05-03 | 2005-12-01 | Boehringer Ingelheim International Gmbh | Topical preparations containing ambroxol |
| WO2012085185A1 (en) * | 2010-12-23 | 2012-06-28 | Advance Holdings Limited | Aqueous solution of ambroxol |
| TW201249427A (en) * | 2011-03-14 | 2012-12-16 | Boehringer Ingelheim Int | Use of sprayable composition containing ambroxol |
| CN107669636A (en) * | 2016-09-30 | 2018-02-09 | 青岛大学 | A kind of ambroxol spray |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2453770A (en) * | 2007-10-19 | 2009-04-22 | Reckitt Benckiser Healthcare | Oral composition comprising a cooling agent |
| JP6472722B2 (en) * | 2015-06-30 | 2019-02-20 | サンスター株式会社 | Salivary secretagogue for oral administration |
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| US20050075403A1 (en) * | 2003-10-02 | 2005-04-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ambroxol for the treatment of inflammation in the pharynx |
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