CN111110662A - Method for preparing solution preparation for inhalation - Google Patents
Method for preparing solution preparation for inhalation Download PDFInfo
- Publication number
- CN111110662A CN111110662A CN201811275570.6A CN201811275570A CN111110662A CN 111110662 A CN111110662 A CN 111110662A CN 201811275570 A CN201811275570 A CN 201811275570A CN 111110662 A CN111110662 A CN 111110662A
- Authority
- CN
- China
- Prior art keywords
- solution
- preparation
- acid
- packaging layer
- inhalation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 45
- 238000004806 packaging method and process Methods 0.000 claims abstract description 27
- 238000007789 sealing Methods 0.000 claims abstract description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 14
- 239000005022 packaging material Substances 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 230000003204 osmotic effect Effects 0.000 claims abstract description 11
- 239000000047 product Substances 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 239000011261 inert gas Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 239000012467 final product Substances 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 38
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 229910052782 aluminium Inorganic materials 0.000 claims description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical group [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 10
- 239000011888 foil Substances 0.000 claims description 10
- 229920001684 low density polyethylene Polymers 0.000 claims description 9
- 239000004702 low-density polyethylene Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 239000008215 water for injection Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- -1 and more preferably Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 5
- 229960000707 tobramycin Drugs 0.000 claims description 5
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 2
- FCSXYHUNDAXDRH-OKMNHOJOSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;n-[2-hydroxy-5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 FCSXYHUNDAXDRH-OKMNHOJOSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 claims description 2
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 claims description 2
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 claims description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 2
- 235000005807 Nelumbo Nutrition 0.000 claims description 2
- 240000002853 Nelumbo nucifera Species 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- 239000004743 Polypropylene Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 claims description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 229960004308 acetylcysteine Drugs 0.000 claims description 2
- 229960005012 aclidinium bromide Drugs 0.000 claims description 2
- XLAKJQPTOJHYDR-QTQXQZBYSA-M aclidinium bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 XLAKJQPTOJHYDR-QTQXQZBYSA-M 0.000 claims description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229960005174 ambroxol Drugs 0.000 claims description 2
- 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 claims description 2
- 229960000612 arformoterol tartrate Drugs 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 229960003644 aztreonam Drugs 0.000 claims description 2
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims description 2
- 229960002335 bromhexine hydrochloride Drugs 0.000 claims description 2
- 229960004399 carbocisteine Drugs 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 229960000265 cromoglicic acid Drugs 0.000 claims description 2
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 claims description 2
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 claims description 2
- 229960002848 formoterol Drugs 0.000 claims description 2
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 2
- 229960002462 glycopyrronium bromide Drugs 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- IREJFXIHXRZFER-PCBAQXHCSA-N indacaterol maleate Chemical compound OC(=O)\C=C/C(O)=O.N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 IREJFXIHXRZFER-PCBAQXHCSA-N 0.000 claims description 2
- 229960004735 indacaterol maleate Drugs 0.000 claims description 2
- 229960001361 ipratropium bromide Drugs 0.000 claims description 2
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229910052754 neon Inorganic materials 0.000 claims description 2
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 2
- 229960003073 pirfenidone Drugs 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 229920001155 polypropylene Polymers 0.000 claims description 2
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229960002288 procaterol Drugs 0.000 claims description 2
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 229960002052 salbutamol Drugs 0.000 claims description 2
- 229960005018 salmeterol xinafoate Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000008227 sterile water for injection Substances 0.000 claims description 2
- 229960000195 terbutaline Drugs 0.000 claims description 2
- 229960000257 tiotropium bromide Drugs 0.000 claims description 2
- 229960004541 umeclidinium bromide Drugs 0.000 claims description 2
- PEJHHXHHNGORMP-AVADPIKZSA-M umeclidinium bromide Chemical compound [Br-].C=1C=CC=CC=1C([C@@]12CC[N@@+](CCOCC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 PEJHHXHHNGORMP-AVADPIKZSA-M 0.000 claims description 2
- 229960004026 vilanterol Drugs 0.000 claims description 2
- DAFYYTQWSAWIGS-DEOSSOPVSA-N vilanterol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-DEOSSOPVSA-N 0.000 claims description 2
- 238000011049 filling Methods 0.000 abstract description 27
- 238000007664 blowing Methods 0.000 abstract description 18
- 230000000052 comparative effect Effects 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- 239000012528 membrane Substances 0.000 description 8
- 229910001873 dinitrogen Inorganic materials 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011146 sterile filtration Methods 0.000 description 4
- 238000009924 canning Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229940041682 inhalant solution Drugs 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- OWNWYCOLFIFTLK-YDALLXLXSA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;hydron;chloride Chemical compound Cl.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 OWNWYCOLFIFTLK-YDALLXLXSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940087642 levalbuterol hydrochloride Drugs 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 238000012371 Aseptic Filling Methods 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- NWKHIZXZESQPSP-UHFFFAOYSA-N acetonitrile;phosphoric acid;hydrate Chemical compound O.CC#N.OP(O)(O)=O NWKHIZXZESQPSP-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000000071 blow moulding Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005261 decarburization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
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
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutics, and particularly relates to a preparation method of a solution preparation for inhalation. The preparation method is realized by the following technical scheme that (1) active ingredients are added into a solvent to be dissolved to obtain a solution A; (2) adding an osmotic pressure regulator and a pH regulator into the solution A, and preparing a solution B; (3) filtering the solution B and encapsulating the solution B into an inner packaging layer made of a semi-permeable medicine packaging material to obtain a finished product; the preparation method further comprises sealing the final product into an outer packaging layer made of impermeable medicinal packaging material, wherein inert gas or nitrogen is filled between the inner packaging layer and the outer packaging layer. The preparation method can completely replace the prior art, simultaneously avoids adding nitrogen equipment in a blowing, filling and sealing integrated filling machine, and reduces equipment requirements and cost.
Description
Technical Field
The invention belongs to the field of pharmaceutics, and particularly relates to a preparation method of a solution preparation for inhalation.
Background
The aerosol inhalation solution preparation is taken as a respiratory tract or lung administration preparation, can directly act on the affected part, can improve the administration concentration of the respiratory tract or the lung, has quick response, avoids the first pass effect of the liver, reduces the administration dosage of the medicine, improves the bioavailability of the medicine, reduces the distribution of the medicine in other tissues, reduces the side effect, has the advantages of small inhalation administration stimulation, convenient use, good patient compliance, small toxic and side effect, suitability for long-term treatment and the like, and has been recommended by the world health organization to be the first-choice therapy of respiratory tract diseases such as asthma, phlegm, tracheitis, bronchitis, pneumonia, slow obstructive lung and the like.
The solution for inhalation is usually stored in an inner packaging layer of low density polyethylene filled with nitrogen because of its instability, and then the inner packaging layer is placed in an outer air-tight packaging layer (US patent US5508269A), but this process is not only cumbersome, but also has certain requirements for the performance of the production equipment; or stabilizing agents such as antioxidants, preservatives, metal ion complexes and the like are added into the inhalation solution to improve the stability of the preparation in the using process (Chinese patent applications CN108159026A and CN108014099A), but the addition of the preservatives can increase the risk of adverse reactions such as bronchospasm and the like, and the addition of pharmaceutical excipients such as the stabilizing agents can bring safety risk and increase process steps, thereby increasing the cost; or filtering with an activated carbon filter element in the preparation of the solution for inhalation to achieve the aim of solution oxidation resistance (chinese patent application CN106692046A), but this method may introduce impurities into the solution and is fresh in the field.
Disclosure of Invention
In order to solve the above technical problems, the present invention provides a method for preparing a solution preparation for inhalation, which can maintain the stability of a solution for inhalation to solve the problems of short storage period of the solution for inhalation and safety caused by the addition of a stabilizer with the lapse of time, and can reduce the requirements of production equipment, reduce the production cost and improve the production efficiency.
The invention is realized by the following technical scheme:
a method of preparing a solution formulation for inhalation comprising the steps of:
(1) adding the active ingredients into a solvent for dissolving to obtain a solution A;
(2) adding an osmotic pressure regulator and a pH regulator into the solution A, and preparing a solution B;
(3) filtering the solution B and encapsulating the solution B into an inner packaging layer made of a semi-permeable medicine packaging material to obtain a finished product;
the method is characterized in that: the preparation method further comprises sealing the final product into an outer packaging layer made of impermeable medicinal packaging material, wherein inert gas or nitrogen is filled between the inner packaging layer and the outer packaging layer.
The medicine packaging material refers to a packaging material and a container which are used by medicines produced by medicine production enterprises and preparations prepared by medical institutions and are in direct contact with the medicines; the semi-permeability refers to certain water permeability and air permeability; the impermeability refers to the absence of water, air and light permeability;
further, the active ingredient is one or a combination of several of ambroxol, tobramycin, terbutaline, salbutamol, acetylcysteine, aztreonam, bromhexine hydrochloride, cromolyn sodium, ipratropium bromide, arformoterol tartrate, procaterol, carbocisteine, pirfenidone, formoterol, indacaterol maleate, tiotropium bromide, vilanterol, salmeterol xinafoate, umeclidinium bromide, aclidinium bromide, nelumbo, potassium sodium dehydroandroandrographolide, potassium dehydroandroan drographolide, sodium dehydroandroan drographolide, aldterol hydrochloride, glycopyrronium bromide, and salts and/or hydrates thereof;
further, the solvent is purified water, water for injection or sterile water for injection;
further, the osmotic pressure regulator is one or a combination of several of inorganic salt osmotic pressure regulators and sugar osmotic pressure regulators, and further, the inorganic salt osmotic pressure regulators are sodium chloride;
further, the pH regulator is acid or alkali, further, the acid is one or a combination of more of hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, phosphoric acid and citric acid, and further, the acid is hydrochloric acid or sulfuric acid; the alkali is one or a combination of more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate;
further, the pH value of the preparation is 4.5-7.0, preferably 4.5-6.5;
further, the sterile filtration is primary filtration by using a 0.45 mu m filter membrane, and fine filtration by using a 0.22 mu m filter membrane;
further, the filling and sealing process uses a blowing and sealing integrated machine;
further, the semipermeable medicine packaging material is low-density polyethylene, polyethylene or polypropylene;
further, the impermeable medicine packaging material is an aluminum foil;
further, the inert gas refers to helium, neon or argon;
further, an opening part is arranged on the inner packaging layer; further, the opening part is a disposable opening part; still further, the opening means may be closed by any conventional means, but is not limited to, screw cap, heat seal, flip cap, twist off cap, peel top, etc.;
further, the unit dose of the inner packaging layer is 2-5 ml;
furthermore, one end of the outer packaging layer also comprises an easy-tearing opening;
further, the sterilization time is 30 min.
Blowing, filling and sealing (BFS) are three-in-one aseptic filling technology of blowing, filling and sealing, wherein the blowing process comprises the steps of conveying a mold to the lower part of an extrusion pipe through a conveying device, extruding raw materials in a hopper into the mold through the extrusion pipe, conveying the mold filled with the raw materials to the lower part of a blowing suction pipe through the conveying device, and blowing sterile gas into the raw materials by the blowing suction pipe to mold plastics. In the prior art, the solution for inhalation is filled into the unit dose inner packaging layer by using a blowing, filling and sealing integrated filling machine in a million-level environment and is filled with nitrogen. The invention does not need to add nitrogen equipment in the blowing, filling and sealing integrated filling machine, but independently fills nitrogen into the outer packaging layer, and the process is simple and has low requirement on equipment. The differences between the blowing, filling and sealing integrated machine used in the invention and the prior art are shown in table 1.
Table 1 difference of the blowing, filling and sealing integrated machine used in the present invention from the prior art
| Blowing encapsulation process flow | The invention | Prior Art |
| Nitrogen blow molding equipment | × | √ |
| Filling | √ | √ |
| Sealing closure | √ | √ |
Compared with the prior art, the invention has the following obvious advantages and positive progress:
(1) the invention does not need to add a stabilizer in the prescription of the inhalation solution except for conventional auxiliary materials, and has good safety and little side effect; active carbon does not need to be added in the preparation process, so that the risk of introducing new impurities and insoluble particles into the active carbon is reduced; in the product filling process, nitrogen generation equipment is not required to be added to the blowing, filling and sealing equipment, the process is simple, the production efficiency is high, the requirements on production equipment are reduced, and the production cost is reduced.
(1) The inner packing layer material is the semi-permeable material, has certain ventilative ability of permeating water. According to the invention, nitrogen is filled between the outer packaging layer and the inner packaging layer, and air in the inner packaging layer and nitrogen in the outer packaging layer are mutually permeated, so that the solution for inhalation in the inner packaging layer can not contact air for a long time in the process of placing, thereby reducing the oxidation degree of the solution for inhalation and improving the long-term stability.
The invention is further described with reference to the following figures and detailed description.
Drawings
FIG. 1 is a schematic structural diagram of the present invention.
The reference numerals in the figures are explained below:
1-outer packaging layer, 2-inner packaging layer, 3-inert gas or nitrogen, 4-solution for inhalation, and 5-easy-to-tear opening.
Detailed Description
The preparation process and the materials used in the preparation or the dosage of the materials used in the preparation in the following examples of the pharmaceutical preparation are not limited to the words, and all methods containing the pharmaceutical preparation provided by the present invention are within the protection scope of the present invention.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The solution preparation for inhalation of the present invention is packaged with a single dose of medicine. A single dose refers to a dose of the pharmaceutically active ingredient used in a single inhalation. In the examples of the present specification, a single dose means 5 mL. The single dose provided by the invention is convenient to use, does not need to be diluted and prepared, can greatly reduce microbial pollution and waste in the using process, and avoids the defects that multiple doses and large package solution cause repeated taking and repeated dilution and preparation and are easy to breed microbes due to the adoption of the dose for single administration.
Examples 1 to 5
(1) Adding 70% of water for injection, slowly adding 80% of sulfuric acid, stirring, and cooling; adding tobramycin according to the prescription amount, and stirring until the tobramycin is completely dissolved;
(2) adding sodium chloride, and stirring until the sodium chloride is completely dissolved;
(3) adding sulfuric acid to adjust pH to 6.0, adding water for injection to full volume of 100L, and stirring to mix well;
(4) performing primary filtration by using a 0.45 mu m filter membrane, and performing fine filtration by using a 0.22 mu m filter membrane, wherein sterile filtration is performed; filling the sterile filtrate into a low-density polyethylene bottle with an inner packaging material of 5ml by using a filling machine integrating blowing, canning and sealing in a million-level environment;
(5) and filling the finished product into an aluminum foil bag, filling nitrogen into the bag and sealing.
See table 2 for experimental parameters for examples 1-5.
Table 2 examples 1-5 experimental parameters
Comparative examples 1 and 2: a process for preparing a solution preparation for inhalation, wherein comparative example 1 is the same as example 3 and comparative example 2 is the same as example 4 except that in step (4) nitrogen gas is additionally introduced into low density polyethylene as an inner wrapper and nitrogen gas is not introduced into an aluminum foil bag as an outer wrapper in step (5).
Comparative examples 3 and 4: a process for preparing a solution preparation for inhalation, wherein the preparation method of comparative example 3 is the same as that of example 3, and the preparation method of comparative example 4 is the same as that of example 4, except that the solution is filtered through an activated carbon filter element before step (4), and nitrogen is not filled in an aluminum foil bag as an outer wrapping material in step (5).
Comparative examples 5 and 6: a process for producing a solution preparation for inhalation, comparative example 5 being the same as example 3 and comparative example 6 being the same as example 4 except that no nitrogen gas was filled in the aluminum foil pouch as the outer wrapper in step (5).
Example 7
(1) Adding 70% of water for injection, adding 186mg of levalbuterol hydrochloride, and stirring to dissolve completely;
(2) adding 7.2g of sodium chloride, and stirring until the sodium chloride is completely dissolved;
(3) adding sulfuric acid to adjust pH to 4.7, adding water for injection to 900ml, and stirring to mix well;
(4) performing primary filtration by using a 0.45 mu m filter membrane, and performing fine filtration by using a 0.22 mu m filter membrane, wherein sterile filtration is performed; filling the sterile filtrate into a low-density polyethylene bottle with an inner packaging material of 5ml by using a filling machine integrating blowing, canning and sealing in a million-level environment;
(5) and filling the finished product into an aluminum foil bag, filling nitrogen into the bag and sealing.
Comparative example 7
Comparative example 7 is the same as example 7 except that in step (4), nitrogen gas was additionally charged into the inner wrapper low density polyethylene and in step (5), nitrogen gas was not charged into the outer wrapper aluminum foil pouch.
Example 8
(1) Adding 70% of water for injection, adding 93mg of levalbuterol hydrochloride, and stirring to dissolve completely;
(2) adding 7.2g of sodium chloride, and stirring until the sodium chloride is completely dissolved;
(3) adding sulfuric acid to adjust pH to 5.0, adding water for injection to 900ml, and stirring to mix well;
(4) performing primary filtration by using a 0.45 mu m filter membrane, and performing fine filtration by using a 0.22 mu m filter membrane, wherein sterile filtration is performed; filling the sterile filtrate into a low-density polyethylene bottle with an inner packaging material of 5ml by using a filling machine integrating blowing, canning and sealing in a million-level environment;
(5) and filling the finished product into an aluminum foil bag, filling nitrogen into the bag and sealing.
Comparative example 8
Comparative example 8 is the same as example 8 except that in step (4), nitrogen gas was added to the inner wrapper low density polyethylene and in step (5), nitrogen gas was not added to the outer wrapper aluminum foil pouch.
Stability test
The stability test aims to investigate the influence of different prescriptions and preparation processes on the stability of the solution preparation by comparing detection results of appearance, absorbance, related substances and the like, and the results are shown in table 3.
The method for measuring absorbance comprises the following steps: the absorbance was measured at a wavelength of 410nm by ultraviolet-visible spectrophotometry (2015 edition, Chinese pharmacopoeia).
The contents of the effective components of the inhalation solutions in the examples and comparative examples were measured by HPLC high performance liquid chromatography (chinese pharmacopoeia 2015 edition of the four-part general regulation 0512); detection conditions are as follows: a chromatographic column: bonded phenyl porous silica gel microspheres are used as filler (GRACEAlltima phenyl 4.6 × 250mm, 5 μm); mobile phase A: water-acetonitrile-phosphoric acid (95:5: 0.08); mobile phase B: acetonitrile-water-phosphoric acid (75:25: 0.08); flow rate: 1.2 ml/min; column temperature: 30 ℃; detection wavelength: 365 nm; sample introduction volume: 45 mu l of the solution; the detection results are shown in table 2, and the experimental stability investigation results are accelerated.
TABLE 3 accelerated test stability investigation results
As can be seen from Table 3, the tobramycin solution for inhalation and the L-salbutamol hydrochloride solution can ensure good stability of the product and reduce the requirements of production equipment under the conditions that no stabilizer is added in the prescription, no decarburization is caused in the preparation process, and no nitrogen is filled in the packing materials for sample subpackaging.
For the different inhalation solutions, comparative examples 1 to 8 were of the prior art and examples 1 to 8 were of the method of preparation of inhalation solutions according to the invention. As can be seen from the stability investigation result of the accelerated experiment in Table 3, the appearance, absorbance, content, pH value, total impurities and other data are basically the same, i.e., the preparation method of the invention can completely replace the prior art, and simultaneously avoids adding nitrogen equipment in a blowing, filling and sealing integrated filling machine, and reduces the equipment requirement and cost.
Claims (9)
1. A method of preparing a solution formulation for inhalation comprising the steps of:
(1) adding the active ingredients into a solvent for dissolving to obtain a solution A;
(2) adding an osmotic pressure regulator and a pH regulator into the solution A, and preparing a solution B;
(3) filtering the solution B and encapsulating the solution B into an inner packaging layer made of a semi-permeable medicine packaging material to obtain a finished product;
the method is characterized in that: the preparation method further comprises sealing the final product into an outer packaging layer made of impermeable medicinal packaging material, wherein inert gas or nitrogen is filled between the inner packaging layer and the outer packaging layer.
2. The process according to claim 1, wherein the active ingredient is one or more of ambroxol, tobramycin, terbutaline, salbutamol, acetylcysteine, aztreonam, bromhexine hydrochloride, cromolyn sodium, ipratropium bromide, arformoterol tartrate, procaterol, carbocisteine, pirfenidone, formoterol, indacaterol maleate, tiotropium bromide, vilanterol, salmeterol xinafoate, umeclidinium bromide, aclidinium bromide, nelumbo, potassium sodium dehydrosuccinate, potassium dehydrosuccinate, alduterol hydrochloride, glycopyrronium bromide, and salts and/or hydrates thereof.
3. The method of claim 1 or 2, wherein the solvent is purified water, water for injection, or sterile water for injection.
4. The preparation method according to any one of claims 1 to 3, wherein the osmotic pressure regulator is one or a combination of inorganic salt osmotic pressure regulators and sugar osmotic pressure regulators, and preferably, the inorganic salt osmotic pressure regulators are sodium chloride.
5. The preparation method according to any one of claims 1 to 4, wherein the pH regulator is an acid or an alkali, preferably, the acid is one or a combination of hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, phosphoric acid and citric acid, and more preferably, the acid is hydrochloric acid or sulfuric acid; the alkali is one or a combination of more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
6. The method of any one of claims 1 to 5, wherein the formulation has a pH of from 4.5 to 7.0, preferably from 4.5 to 6.5.
7. The process according to any one of claims 1 to 6, wherein the semipermeable drug-containing material is low-density polyethylene, polyethylene or polypropylene.
8. The method of any one of claims 1-7, wherein the impermeable wrapper is aluminum foil.
9. The method of any one of claims 1-8, wherein the inert gas is helium, neon, or argon.
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| CN110251491A (en) * | 2019-06-21 | 2019-09-20 | 上海禾丰制药有限公司 | A kind of sucking bromhexine hydrochloride solution and preparation method thereof |
| CN111481550A (en) * | 2020-05-14 | 2020-08-04 | 王兆霖 | Pharmaceutical formulation containing tiotropium bromide and arformoterol |
| CN114028330A (en) * | 2021-03-22 | 2022-02-11 | 南京艾德加生物制药科技有限公司 | Procaterol hydrochloride oral solution |
| CN114099425A (en) * | 2020-08-28 | 2022-03-01 | 成都倍特药业股份有限公司 | Preparation method of salbutamol sulfate solution |
| WO2022073459A1 (en) * | 2020-10-09 | 2022-04-14 | 刘志 | Inhalation formulation, and preparation method therefor and application thereof |
| WO2022166724A1 (en) * | 2021-02-04 | 2022-08-11 | 扬子江药业集团有限公司 | Fudosteine solution preparation for inhalation, preparation method therefor and use thereof |
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| CN101659336A (en) * | 2009-08-07 | 2010-03-03 | 昆山维信诺显示技术有限公司 | Product packaging and packaging method thereof |
| CN106692046A (en) * | 2016-12-30 | 2017-05-24 | 珠海亿胜生物制药有限公司 | Preparation method of inhalation tobramycin solution |
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| CN101606903A (en) * | 2008-06-19 | 2009-12-23 | 北京韩美药品有限公司 | A kind of atomizing of ambroxol sucks with solution and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110251491A (en) * | 2019-06-21 | 2019-09-20 | 上海禾丰制药有限公司 | A kind of sucking bromhexine hydrochloride solution and preparation method thereof |
| CN111481550A (en) * | 2020-05-14 | 2020-08-04 | 王兆霖 | Pharmaceutical formulation containing tiotropium bromide and arformoterol |
| CN114099425A (en) * | 2020-08-28 | 2022-03-01 | 成都倍特药业股份有限公司 | Preparation method of salbutamol sulfate solution |
| WO2022073459A1 (en) * | 2020-10-09 | 2022-04-14 | 刘志 | Inhalation formulation, and preparation method therefor and application thereof |
| WO2022166724A1 (en) * | 2021-02-04 | 2022-08-11 | 扬子江药业集团有限公司 | Fudosteine solution preparation for inhalation, preparation method therefor and use thereof |
| CN114028330A (en) * | 2021-03-22 | 2022-02-11 | 南京艾德加生物制药科技有限公司 | Procaterol hydrochloride oral solution |
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