CN1075079A - Medicine - Google Patents
Medicine Download PDFInfo
- Publication number
- CN1075079A CN1075079A CN 93100477 CN93100477A CN1075079A CN 1075079 A CN1075079 A CN 1075079A CN 93100477 CN93100477 CN 93100477 CN 93100477 A CN93100477 A CN 93100477A CN 1075079 A CN1075079 A CN 1075079A
- Authority
- CN
- China
- Prior art keywords
- propellant
- preparation
- propionate
- medicine
- described preparation
- 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.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 74
- 229940079593 drug Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 60
- 239000003380 propellant Substances 0.000 claims abstract description 51
- 239000000443 aerosol Substances 0.000 claims abstract description 49
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 239000006184 cosolvent Substances 0.000 claims abstract description 18
- 239000004094 surface-active agent Substances 0.000 claims abstract description 18
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000009472 formulation Methods 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 208000023504 respiratory system disease Diseases 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 90
- GGJDOVFOVZIUPH-UHFFFAOYSA-N propanoic acid hydrofluoride Chemical compound F.CCC(O)=O.CCC(O)=O GGJDOVFOVZIUPH-UHFFFAOYSA-N 0.000 claims description 21
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 16
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 claims description 15
- 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 11
- 229960002052 salbutamol Drugs 0.000 claims description 11
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- 229940092705 beclomethasone Drugs 0.000 claims description 8
- CUUMRTMSOITJKD-UHFFFAOYSA-N [F].CCC Chemical class [F].CCC CUUMRTMSOITJKD-UHFFFAOYSA-N 0.000 claims description 7
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 claims description 7
- 229940124630 bronchodilator Drugs 0.000 claims description 7
- 238000012986 modification Methods 0.000 claims description 6
- 230000004048 modification Effects 0.000 claims description 6
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- 239000000043 antiallergic agent Substances 0.000 claims description 4
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- 239000012453 solvate Substances 0.000 claims description 3
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 230000000241 respiratory effect Effects 0.000 claims description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 claims 2
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- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 6
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- 239000004215 Carbon black (E152) Substances 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- 238000004519 manufacturing process Methods 0.000 description 3
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- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical group C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- HUYWAWARQUIQLE-UHFFFAOYSA-N Isoetharine Chemical compound CC(C)NC(CC)C(O)C1=CC=C(O)C(O)=C1 HUYWAWARQUIQLE-UHFFFAOYSA-N 0.000 description 2
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- PRPAGESBURMWTI-UHFFFAOYSA-N [C].[F] Chemical class [C].[F] PRPAGESBURMWTI-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
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- 150000002148 esters Chemical class 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
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- 210000004072 lung Anatomy 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000002048 anodisation reaction Methods 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- RZEVCBORQLBKTB-UHFFFAOYSA-N butan-1-ol 1H-pyrrole Chemical class CCCCO.c1cc[nH]c1 RZEVCBORQLBKTB-UHFFFAOYSA-N 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Natural products C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000013013 elastic material Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960001022 fenoterol Drugs 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003311 flocculating effect Effects 0.000 description 1
- 229960000785 fluocinonide Drugs 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- 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 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- HNJJXZKZRAWDPF-UHFFFAOYSA-N methapyrilene Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CS1 HNJJXZKZRAWDPF-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 229960004398 nedocromil Drugs 0.000 description 1
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- RLANKEDHRWMNRO-UHFFFAOYSA-M oxtriphylline Chemical compound C[N+](C)(C)CCO.O=C1N(C)C(=O)N(C)C2=C1[N-]C=N2 RLANKEDHRWMNRO-UHFFFAOYSA-M 0.000 description 1
- 229940100256 oxtriphylline Drugs 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- 239000008249 pharmaceutical aerosol Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N sec-butylidene Natural products CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- JGFYQVQAXANWJU-UHFFFAOYSA-M sodium fluoroacetate Chemical compound [Na+].[O-]C(=O)CF JGFYQVQAXANWJU-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to be used for the aerosol preparations of inhalation, relate in particular to medicinal aerosol formulations, it comprises granulated drug, fluorocarbon or hydrochlorofluorocarsolvent propellant and is no more than the polar co-solvent of propellant 5%, and said preparation is substantially free of surfactant.Also disclose the method for treatment respiratory disorder, it comprises and sucks the medicinal aerosol formulations as defined above of taking effective dose.
Description
The present invention relates to the aerosol preparations that the confession inhalation is used.
People have just known with the aerosol administration before the many decades.Aerosol comprises medicine, one or more Chlorofluorocarbons (CFCs) propellant and surfactant or solvent, for example ethanol usually.The most frequently used aerosol propellant is 11(CCl always in the medicine
3F) and/or propellant 114(CF
2ClCF
2Cl) with propellant 12(CCl
2F
2).But it is believed that now these propellant can cause the decomposition of stratospheric ozone, thereby the medicinal aerosol formulations of the propellant that uses so-called " to the ozone friendliness " need be provided.
It is believed that a class propellant compares with the fluorochlorohydrocarbon of routine and have minimum ozone dilution effect (Ozone-depleting effects), this propellant comprises fluorocarbon and hydrogeneous fluorochlorohydrocarbon, adopt the multiple medications aerosol preparations of this propellant to be disclosed in for example EP0372777, WO091/04011, WO91/11173, WO91/11495 and WO91/14422.Above-mentioned application all is the preparation about the administrable pressurized aerosol, and tries hard to overcome the problem relevant with the use of new class propellant, specifically overcomes and the relevant problem of pharmaceutical formulation stability that makes.Above-mentioned application all proposes to add a small amount of one or more adjuvant even conventional Chlorofluorocarbons (CFCs) propellant, so that the potential destruction of ozone is reached minimum.Described examples of auxiliaries has: alcohols, alkane, dimethyl ether, surfactant (comprise and fluoridizing or surfactant, carboxylic acid, many b-oxides of nonfluorinated).
Thereby for example EP0372777 requires 1,1,1, the 2-tetrafluoroethane with have than 1,1,1, cosolvent of 2-tetrafluoroethane high polarity (for example: alcohol or lower paraffin hydrocarbon) and surfactant use together, to obtain stable medicated powder preparation.It is pointed out particularly at page 3 the 7th row: " have found that; use propellant 134a(1; 1; 1, the 2-tetrafluoroethane) and the binary mixture of medicine or unite use with conventional surfactants (for example sorbitan trioleate) and can not obtain the preparation that sacrificial vessel has the character that the inhaler that is fit to pressurize uses ".Those skilled in the art it is generally acknowledged: surfactant is the important component of aerosol preparations, not only needs it to reduce the coalescent of medicine but also needs it to lubricate used valve, thereby guarantee the constant repeatability of valve event and the accuracy of dosage.WO91/11173, WO91/11495 and WO91/14422 are about comprising the preparation of medicine and surfactant mixture, and WO91/04011 then discloses a kind of pharmaceutical aerosol preparation, granulated drug wherein is with 1,1,1, the 2-tetrafluoroethane is handled before just in advance coated with surfactant.
We find now uncannily, opposite with above-mentioned situation, in fact needn't lean against in the composition use surfactant or must be before handling with propellant pretreatment (for example: 1 just can access medicine at fluorocarbon or hydrochlorofluorocarsolvent propellant, 1,1,2-tetrafluoroethane) the satisfied dispersion in.
Therefore, one aspect of the present invention provides a kind of medicinal aerosol formulations, and it comprises granulated drug, fluorocarbon or hydrochlorofluorocarsolvent propellant and is no more than 5 weight %(is benchmark with the propellant) polar co-solvent, said preparation is substantially free of surfactant.So-called " being substantially free of surfactant " is meant the preparation of the surfactant that does not contain obvious amount, and for example content is less than 0.0001 weight % of medicine.
The particle diameter of granular (for example micronized) medicine should allow basically all medicines to suck in lungs when taking this aerosol preparations, therefore, should be less than 100 microns, with less than 20 microns for well, the 1-10 micron is best, for example: the 1-5 micron.
Medicine that can the aerosol preparations form administration of the present invention comprises any medicine that can be used for sucking treatment, and the form that it can be insoluble to selected propellant basically exists.Therefore, suitable medicine can be selected from, analgesic for example, for example: codeine, paramorphane, Ergotamine, fentanyl or morphine; The persantin preparation, for example: ketone sulfur nitrogen); Anti-allergic drug, for example: cromoglycate, ketotifen or anti-many grammeters (nedocromil); Anti-infective, cephalosporin for example, penicillin, streptomycin, sulfonamides, tetracycline and pentamidine; Antihistaminic, for example, sleepwell; The antibiotic medicine, for example, beclomethasone, 9-remove fluorine fluocinonide, budesonide, general dawn of the base of a fruit (tipredane), the third scorching pine or fluorine Kazon (fluticasone); Cough medicine, for example: oscapine; Bronchodilator, for example: your (formoterol), isoprenaline, alotec, phenylephrine, phenylpropanolamine, pyrrole butanols, D-1959, asmaten, salbutamol, Sha Ermaite (salmeterol), terbutaline, Dilabron, C-78 of ephedrine, epinephrine, fenoterol, Ford, hydroxyl is breathed heavily or (-)-4-amino-3,5-two chloro-α-[[[the 6-[2-(2-pyridine radicals) ethyoxyl] hexyl] amino] methyl] benzyl alcohol; Diuretic, for example: amiloride; Anticholinergic agent, for example, Ipratropium Bromured, atropine or second scopolamine; Hormone, for example: cortisone, hydrocortisone or meticortelone; Xanthine, for example, aminophylline, Oxtriphylline, theophylline-lysine or theophylline or treatment protein and peptide, for example: insulin or glucagon.To those skilled in the art, obviously, in the time of suitably said medicine can with salt (for example: alkali metal salt or amine salt or acid-addition salts) or ester (for example: lower alkyl esters) or solvate (for example: form hydrate) is used, so that the active and/or stability of medicine reaches best and/or make the dissolubility of medicine in propellant reach minimum.
Comprise by sucking used anti-allergic drug, bronchodilator and anti-inflammatory type sterol compound in the therapy treatment respiratory disorder (for example asthma), for example with the preferred medicine of aerosol preparations administration of the present invention: cromoglycate (for example sodium salt), salbutamol (for example: the form of free alkali or sulfate), Sha Ermaite (for example: the form of Hydroxynaphthoate), uncle's fourth breathe heavily you (for example: sulphate form), D-1959 (for example: hydrochloride form), Beclomethasone.Propionate propionate fluoride or (-)-4-amino-3,5-dihydro-α-[[[the 6-[2-(2-pyridine radicals)-ethyoxyl] hexyl] amino] methyl] benzyl alcohol.Sha Ermaite, uncle's fourth breathe heavily that, propionate propionate fluoride, Beclomethasone and physiologically acceptable salt thereof and solvate preferred especially.
This area professional is apparent, and aerosol preparations of the present invention in case of necessity can comprise the combination of two or more active component.For example, the aerosol composition that contains two kinds of active component (in conventional propellant system) has been used to the treatment of respiratory disorder (for example asthma).Therefore, the present invention further provides the aerosol preparations of the present invention that contains two or more granulated drug.Medicine can be selected from the appropriate combination of said medicine.Thereby the appropriate combination of bronchiectasis medicine comprises that ephedrine and the thiophene film (thiophylline), fragrant third breathe heavily peace Ipratropium Bromured, Dilabron and phenylephrine aerosol preparations.
The preferred aerosol preparations of the present invention comprises (a) effective amount of particulate bronchodilator, (b) effective amount of particulate antibiotic medicine, steroid antibiotic medicine preferably, (c) fluorocarbon or hydrochlorofluorocarsolvent propellant, (d) being no more than 5%(W/W, is benchmark in the propellant) cosolvent.Particularly preferred aerosol preparations contains bronchodilator, salbutamol (for example: free alkali or sulphate form), Sha Ermaite (for example hydroxynaphthoic acid salt form or isoprenaline for example, be mixed with the disappearance steroid simultaneously, as beclomethasone ester (for example dipropionate) or fluorine Kazon ester (for example propionic ester).Perhaps, aerosol preparations can comprise bronchodilator and anti-allergic drug, as cromoglycate (for example: sodium salt).Isoprenaline and sodium cromoglicate; Sand Mai Te and propionate propionate fluoride; Or salbutamol, the loose dipropionate in chlorine ground is preferred especially.
Final aerosol preparations preferably contains 0.005-10%, and 0.005-5%W/W is better, and particularly 0.01-1.0%W/W(is with respect to the gross weight of preparation) medicine.
The used propellant of the present invention can be any fluorocarbon or hydrochlorofluorocarsolvent or its mixture, and they should have enough vapour pressures so that as effective propellant.Propellant is the non-solvent of medicine preferably.For example: suitable propellant comprises: C
1-4Hydrochlorofluorocarsolvent, CH for example
2ClF, CClF
2CHClF, CF
3CHClF, CHF
2CClF
2, CHClFCHF
2, CF
3CH
2Cl and CClF
2CH
3, the hydrogen-containing carbon fluorine compounds of C1-4, for example CHF
2CHF
2, CF
3CH
2F, CHF
2CH
3And CF
3CHFCF
3; With perfluorocarbon CF for example
3CF
3And CF
3CF
2CF
3
When using the mixture of fluorocarbon or hydrochlorofluorocarsolvent, they can be above-claimed cpd or mixture (preferably binary mixture) and other fluorocarbon or hydrochlorofluorocarsolvent (CHClF for example
2, CH
2F
2And CF
3CH
3) mixture.Preferably adopt single fluorocarbon or hydrochlorofluorocarsolvent as propellant.Preferred especially is C as propellant
1-4The hydrogen-containing carbon fluorine compounds, for example 1,1,1,2-tetrafluoroethane (CF
3CH
2F) and 1,1,1,2,3,3,3-seven fluorine n-propane (CF
3CHFCF
3).
Preparation of the present invention does not preferably contain the component that can cause that stratospheric ozone decomposes.Especially preferably do not contain substantially in the preparation such as CCl
3F, CCl
2F
2And CF
3CCl
3And so on Chlorofluorocarbons (CFCs).
Propellant also can contain the volatility adjuvant, for example saturated hydrocarbons propane, normal butane, pentane and isopentane or dialkyl ether dimethyl ether for example for example.Usually, the propellant that is no more than 50%W/W can comprise for example volatile hydrocarbon of 1-30%W/W.But the preparation that is substantially free of the volatility adjuvant is preferred.
The polar co-solvent that can sneak into preparation of the present invention (for example: C comprises
2-6) aliphatic alcohol and polyhydric alcohol, for example ethanol, isopropyl alcohol and propylene glycol and composition thereof.Preferably use ethanol.Usually only need a small amount of (for example 0.05-3.0%W/W) polar co-solvent to promote to disperse, when consumption surpasses 5%W/W, may cause the light molten unfavorable result of medicine.Preparation preferably contains and is less than 1%W/W, for example the polar co-solvent of about 0.1%W/W.Polar mensuration can disclose the 0327777th described method by for example european patent application and carry out.
Particularly preferred embodiment of the present invention provides a kind of medicinal aerosol formulations, and it mainly comprises one or more granulated drug, one or more fluorocarbons or hydrochlorofluorocarsolvent propellant and 0.01-5%W/W(is benchmark with the propellant) polar co-solvent.
In proper container, for example,, medicine is scattered in the selected propellant can makes preparation of the present invention by means of sonication.
May be preferably with medicine with adding cosolvent again after propellant mixes, because can make any solvation effect of cosolvent reach minimum like this, thereby has strengthened dispersion.This process is preferably under the anhydrous condition carries out, in order to avoid dampness is to any adverse effect of suspension stability.
Form flocculating suspension slightly after preparation of the present invention leaves standstill, amazing is that even find through long-term storage, suspension obtains being applicable to that through slowly stirring very easily redispersion the pressurization inhaler has fabulous suspension for property of medicine energy.Make formulation excipients in the aerosol preparations of the present invention (for example surfactant) minimum, preferably need not, also be favourable, because the tasteless basically nothing of preparation is smelt, than less dose of sharp property of conventional formulation and toxicity.
The technology that the pharmacy of aerosol preparations of the present invention mensuration acceptable and physics and chemical stability can adopt this area professional to know is carried out.Therefore, for example, the chemical stability of each component can be passed through the HPLC assay determination at for example product after long-term storage.The physical stability data can obtain by other conventional analysis technology, for example, by leak test, by valve for medicine evaluation (each open the average weight that penetrates), by dosage repeatability evaluation (each active principle that penetrates of opening) with spray the medicine distributional analysis.
The particle size distribution of aerosol preparations of the present invention is given deep especially seal and is thought, can measure by routine techniques, for example: measure by collision (cascade impaction) or " binary collision " (Twin Impinger) analytical method step by step.Alleged herein " binary collision " calibrating is meant " deposition of measuring the ejection medicament with device A in adding the pressure solution device ", and British Pharmacopoeia 1988, the A204-207 pages or leaves are seen in this definition, symbol record XVIIC.This technology can calculate " can breathe part " of aerosol preparations.Alleged herein " can breathe part " is meant the method that adopts above-mentioned " binary collision ", opens the amount of the active component of collecting from the collision cell bottom at every turn, is expressed as the percent of the active component total amount of each unlatching ejection.We find that but the respiratory region of preparation of the present invention is divided into drug weight 20% or higher, preferably 25-70%, for example 30-60%.
Medicine also can carry out surface modification before disperseing with propellant, that is, and and with the non-solvent of medicine, nonpolar liquid medium processing basically.Thereby, the present invention further provides a kind of aerosol preparations, it comprises granulated drug, fluorocarbon or the hydrochlorofluorocarsolvent propellant of surface modification as defined above and is no more than the polar co-solvent of propellant 5%W/W, and said preparation is substantially free of surfactant.So-called " medicine of surface modification " be meant and nonpolar non-solvent liquid mixing basically, removes liquid again and by the drug particles of surface modification.(for example: lower paraffin hydrocarbon) be advisable, after medicine slurrying, it has enough volatility to this nonpolar basically non-solvent liquid medium under for example room temperature and normal pressure with it, very easily evaporation with aliphatic hydrocarbon.In this respect, adopt different propane as the liquid medium advantageous particularly.
Be preferably under the anhydrous condition medicine with liquid medium slurrying, in order to avoid dampness has a negative impact to suspension stability.Serosity is preferably through acoustical treatment, to reach the best surface modified effect.Can adopt any method easily to remove liquid, for example evaporation or filtration, evaporation supposes that subsequent treatment is anhydrous basically subsequently.Preparation of the present invention is substantially free of the non-solvent nonpolar liquid.
Preparation of the present invention can be packed into and is suitable for emitting in the tube of medicinal aerosol formulations.Described tube generally includes a container that can bear used propellant vapour pressure, plastics or the vial that is coated with plastics canister preferably for example, aluminium pot for example, it can be apply through anodization, varnish and/or plastic coat, this container seals with a metering valve.The metering valve amount is used for providing the preparation of metered amount when each the unlatching, and a liner is housed leaks from valve to prevent propellant.Liner can comprise any suitable elastic material, for example: low density polyethylene (LDPE), chlorobutyl, black or white acrylonitrile-butadiene rubber, butyl rubber and neoprene.Suitable valve can be buied from the manufacturer that aerosol industry is known, for example from Valois, France (DF10 for example, DF30, DF60), Bespak plc, Britain (BK300 for example, BK356) and 3M-Neotechnic Ltd, Britain (Spraymiser for example
TM) buy.
The conventional batch manufacturing method and the equipment that can use medical aerosol manufacturing field professional to know carry out the large-scale production of fitted tube medicine.Therefore, for example, in a kind of batch manufacturing method, metering valve is crimped on the empty tube of formation on the aluminium pot.Granulated drug is packed in the filling containers, and the propellant of polar solvent and liquefaction charged into by the filling containers pressurization make in the container.Before entering the filling machine circulation, drug suspension is mixed, aliquot drug suspension is charged in the tube by metering valve.Perhaps, when medicine is soluble in polar co-solvent, can before adding cosolvent, granulated drug be suspended in the propellant of 50-90%W/W, before pressurization charges in the tube, mix then and weigh with propellant.Usually in the producing by batch of medicine, with the tube check of each filling, weigh, stamp lot number, deposit in the dish of before release test, packing into.
Each tube of filling can make it to be suitable for a suitable channel unit before use, forming metered dose inhaler, so that to patient's lung or nasal-cavity administration.Suitable channel unit comprises for example opening of valves device and column or conial channel, and medicine can be sent in patient's the nose or mouth, for example by metering valve by the tube of filling through this passage: the ozzle actuator.Metered dose inhaler is used for providing fixed unit dose when each unlatching or injection, for example: spray 10-5000 μ g medicine at every turn.
Administration is suitable for treating gentle, moderate or serious acute or cherish symptom slowly, or prophylactic treatment.Self-evident, accurate dosage will depend on patient's the year order and the state of an illness, employed concrete granulated drug and administration frequency, and finally determine by the clinicist.During drug combination, the dosage the when dosage of each component is generally its independent medication.In general, can be administered once every day or repeatedly, for example 1-9 time, spray medicine for example 1,2,3 or 4 times at every turn.
Thereby, for example, drive valve at every turn 25 μ g Sha Ermaite can be provided, 100 μ g salbutamols, 25,50,125 or 50 μ g propionate propionate fluorides or 50,100,200 or 250 μ g Beclomethasones.Each used filling tube comprises the medicine of 100,160 or 240 dosings or injecting times in the general metered dose inhaler.
The tube and the metered dose inhaler of filling as herein described have constituted another aspect of the present invention.
The method that comprises on the one hand treatment respiratory disorder (for example asthma) more of the present invention, it comprises and sucks the preparation as herein described of taking effective dose.
Following non-limiting example is used for illustrating the present invention.
Embodiment 1
Micronized Sha Ermaite Hydroxynaphthoate (9.57mg) is directly weighed in the opening aluminium pot.With 1,1,1,2-tetrafluoroethane (18.2g) adds from vacuum flask with ethanol (182mg), and the metering valve crimping is good.The gained aerosol contains 9.57mg Sha Ermaite Hydroxynaphthoate (1.0%W/W ethanol), each ejection 25 μ g Sha Ermaite that open.
Embodiment 2
Micronized Sha Ermaite Hydroxynaphthoate (9.57mg) is directly weighed in the opening aluminium pot.With 1,1,1,2-tetrafluoroethane (455mg) adds from vacuum flask with ethanol (182mg), and the metering valve crimping is good.Contain 9.57mg Sha Ermaite Hydroxynaphthoate (2.5%W/W ethanol) in the gained inhaler, each ejection 50 μ g Sha Ermaite that open.
Embodiment 3 and 4
(66mg or 6.6mg) directly weighs in 100 opening aluminium pots separately with micronized propionate propionate fluoride, then metering valve is crimped on each jar.Add and depress, in each, add ethanol (0.182g) and 1,1,1 by valve, 2-tetrafluoroethane (18.2g), with the tube vibration of each filling with dispersion medicine.Contain 66 or 6.6mg propionate propionate fluoride (1%W/W ethanol) in the gained insufflator, each ejection 250 or 25 μ g propionate propionate fluorides (corresponding respectively to embodiment 3 and 4) of opening.
Embodiment 5 and 6
(24mg or 48mg) directly weighs respectively in three opening aluminium pots with micronized salbutamol.With 1,1,12-sym-tetrachloroethane (18.2g) adds each jar from vacuum flask with ethanol (0.364g), and the metering valve crimping is good.Tube with each filling vibrated 8 minutes in ultrasonic bath then.Contain 24mg or 48mg salbutamol (2%W/W ethanol) in the gained inhaler, each ejection 100 or 200 μ g salbutamols (corresponding respectively to embodiment 5 and 6) of opening.
Embodiment 7
Micronized salbutamol sulfate (15mg) is directly weighed in the opening aluminium pot.With 1,1,1,2-tetrafluoroethane (18.2g) and ethanol (0.182g) add from vacuum flask together, and the metering valve crimping is good.The tube that to fill then vibrated 5 minutes in ultrasound wave is molten.Contain 15 μ g salbutamol sulfate (1%W/W ethanol) in the gained inhaler.
Embodiment 8
Isopentane (20ml) is added in the micronized Sha Ermaite Hydroxynaphthoate (0.5g), forms serosity, sonication 3 minutes.The gained suspension is evaporated isopentane to dry in room temperature, get the Sha Ermaite Hydroxynaphthoate of surface modification.Pack into after this product sample (9.57mg) weighed in the aerosol can, add 1,1,1,2-tetrafluoroethane (18.2g-99.95%W/W, total loading is a benchmark), the suitable metering valve of crimping on jar.The tube of filling is distinguished sonication 5 minutes.Sha Ermaite content is equivalent to spray 25 μ g at every turn in the gained aerosol, can spray 240 times amount (0.5%W/W ethanol).
Embodiment 9
Pack into after a micronized hydration Beclomethasone (68mg) weighed in the vial of drying, cleaning, plastic coat, add 1,1,1 from vacuum flask, 2-tetrafluoroethane and ethanol (≤0.182g), rapidly bottle is sealed with metering valve.The gained aerosol dispersion has 250mg Beclomethasone (as monohydrate), each ejection 75.8 μ g(1%W/W ethanol of opening).
Embodiment 10
(1.2g) directly weighs in aluminium pot with micronized sodium cromoglicate, with 1,1,1, the 2-tetrafluoroethane (≤18.2g) add from vacuum flask with ethanol (455mg).The crimping metering valve was with the tube sonication of filling 5 minutes.This aerosol is opened ejection 5 μ g sodium cromoglicate (2.5%W/W ethanol) at every turn.
Embodiment 11
Micronized uncle's fourth is breathed heavily your sulfate (60mg) in aluminium pot, directly weighs, add 1,1,1 from Dewar bottle, the 2-tetrafluoroethane (≤18.2g) with ethanol (91mg).The metering valve crimping is good, with the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 250 μ uncle g fourths to breathe heavily your sulfate (0.5W/W ethanol).
Embodiment 12
(120mg) directly weighs in aluminium pot with micronized W-2946M, with 1,1,1, the 2-tetrafluoroethane (≤18.2g) add from vacuum flask with ethanol (364mg).The crimping metering valve was with the tube sonication of filling 5 minutes.This aerosol is opened ejection 500 μ g W-2946Ms (2%W/W ethanol) at every turn
Embodiment 13
Micronized uncle's fourth is breathed heavily your sulfate (60mg) in aluminium pot, directly weighs, add 1,1,1,2,3,3 from vacuum flask, 3-seven fluorine n-propanes (≤21.4g) with ethanol (214mg).The metering valve crimping is good, with the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 250 μ uncle g fourths to breathe heavily your sulfate (1%W/W ethanol).
Embodiment 14
Micronized Sha Ermaite Hydroxynaphthoate (9.57mg) is directly weighed in aluminium pot, add 1 from vacuum flask, 1,1,2,3,3,3-seven fluorine n-propanes (≤21.4g) with ethanol (428mg), the metering valve crimping is good, with the tube sonication of filling 5 minutes, the each unlatching of this aerosol provided 25 μ g Sha Ermaite Hydroxynaphthoates (2%W/W ethanol).
Embodiment 15
(13.3mg) directly weighs in aluminium pot with micronized propionate propionate fluoride, adds 1,1,1,2,3,3 from vacuum flask, 3-seven fluorine n-propanes (≤21.4g) and ethanol (107mg).The metering valve crimping is good, with the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 50 μ g propionate propionate fluorides (0.5%W/W ethanol).
Embodiment 16
Micronized salbutamol sulfate (31.7mg) is directly weighed in aluminium pot, add 1,1,1,2,3,3 from vacuum flask, 3-seven fluorine n-propanes (≤21.4g) and ethanol (535mg).The metering valve crimping is good, with the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 100 μ g salbutamol sulfate (2.5%W/W ethanol).
Embodiment 17
(13.6mg) directly weighs in aluminium pot with micronized Beclomethasone, directly adds 1,1,1,2,3,3 from vacuum flask, 3-seven fluorine n-propanes (≤21.4g) and ethanol (107mg).The metering valve crimping is good, with the tube sonication of filling 5 minutes.The each unlatching of this aerosol provides 50 μ g Beclomethasones (0.5%W/W ethanol).
Embodiment 18
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 microgram
Propionate propionate fluoride 0.132 100 microgram
Ethanol 1.0 0.76mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 19
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 microgram
Propionate propionate fluoride 0.330 250 microgram
Ethanol 2.5 1.9mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 20
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 microgram
Propionate propionate fluoride 0.066 50 microgram
Ethanol 0.5 0.38mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 21
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 microgram
Propionate propionate fluoride 0.165 125 microgram
Ethanol 1.0 0.76mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 22
Each inhaler %W/W opens at every turn
Salbutamol
*0.132 100 μ g
Propionate propionate fluoride 0.132 100 μ g
Ethanol 1.0 0.76mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
* as free alkali or equivalent salt, for example sulfate.
Embodiment 23
Each inhaler %W/W opens at every turn
Salbutamol
*0.264 200 μ g
Propionate propionate fluoride 0.330 250 μ g
Ethanol 2.0 1.52mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
* as free alkali or equivalent salt, for example sulfate.
Embodiment 24
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 μ g
Propionate propionate fluoride 0.066 50 μ g
Ethanol 0.5 0.38mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 25
Each inhaler %W/W opens at every turn
Sha Ermaite Hydroxynaphthoate 0.048 36.25 μ g
Propionate propionate fluoride 0.264 200 μ g
Ethanol 0.5 0.38mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
Embodiment 26
Each inhaler %W/W opens at every turn
Salbutamol
*0.132 100 μ g
Propionate propionate fluoride 0.066 50 μ g
Ethanol 2.0 1.52mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
* as free alkali or equivalent salt, for example sulfate.
Embodiment 27
Each inhaler %W/W opens at every turn
Salbutamol
*0.264 200 μ g
Propionate propionate fluoride 0.264 200 μ g
Ethanol 2.5 1.9mg
1,1,1,2-tetrafluoroethane to 100≤75.8mg
* as free alkali or equivalent salt, for example sulfate.
In embodiment 18-27, micronized medicine is weighed and is packed into behind the aluminium pot, adds 1,1,1 from vacuum flask, and 2-tetrafluoroethane and ethanol are good with the metering valve crimping again.
Claims (16)
1, a kind of medicinal aerosol formulations, it comprises granulated drug, fluorocarbon or hydrogeneous fluorochlorohydrocarbon propellant and the polar co-solvent that is no more than propellant 5%W/W, said preparation is substantially free of surfactant.
2, a kind of medicinal aerosol formulations, it mainly comprises one or more granulated drug, one or more fluorocarbons or hydrogeneous fluorochlorohydrocarbon propellant and consumption is the polar co-solvent of the 0.01-5%W/W of propellant.
3, preparation as claimed in claim 1 or 2, wherein said medicine are anti-allergic drug, bronchodilator or anti-inflammatory type phytosterin compound.
4, as each described preparation of claim 1 to 3, its Chinese medicine is selected from Sha Ermaite, salbutamol, propionate propionate fluoride, Beclomethasone and physiology thereof and goes up acceptable salt or solvate.
5, as the described preparation of claim 1 to 4, include two or more granulated drug.
6, as each described preparation of claim 1 to 5, it comprises granular bronchodilator and granular antibiotic medicine.
7, as each described preparation of claim 1 to 6, it comprises Sha Ermaite or its physiology goes up acceptable salt and propionate propionate fluoride.
8, as each described preparation of claim 1 to 7, it comprises Sha Ermaite Hydroxynaphthoate and propionate propionate fluoride.
9, as each described preparation of claim 1 to 8, wherein, propellant comprises 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-seven fluorine n-propanes.
10, as each described preparation of claim 1 to 9, wherein, polar co-solvent is an ethanol.
11, as each described preparation of claim 1 to 10, wherein, content of medicines is the 0.005-10%W/W of total formulation weight.
12, as each described preparation of claim 1 to 11, but its respiratory region be divided into drug weight 20% or higher.
13, as each described preparation of claim 1 to 12, wherein said granulated drug is through surface modification.
14, a kind of tube that medicinal aerosol formulations is provided that is applicable to, it comprises a container that can bear used propellant vapour pressure, this container seals with a metering valve, and aerosol preparations is housed, described aerosol preparations comprises granulated drug, fluorocarbon or hydrochlorofluorocarsolvent propellant and is no more than the polar co-solvent of propellant 5%W/W, and said preparation is substantially free of surfactant.
15, a kind of metered dose inhaler upon actuation, it comprises the tube as claimed in claim 14 that is suitable for a suitable lane device.
16, a kind of method for the treatment of respiratory disorder, it comprises and sucks the medicinal aerosol formulations take effective dose.Said preparation comprises granulated drug, fluorocarbon or hydrochlorofluorocarsolvent propellant and is no more than the polar co-solvent of propellant 5%W/W, and said preparation is substantially free of surfactant.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929202522A GB9202522D0 (en) | 1992-02-06 | 1992-02-06 | Medicaments |
| GB9202522.0 | 1992-02-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1075079A true CN1075079A (en) | 1993-08-11 |
| CN1048627C CN1048627C (en) | 2000-01-26 |
Family
ID=10709932
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93100477A Expired - Lifetime CN1048627C (en) | 1992-02-06 | 1993-01-02 | Medicaments |
| CN93100476A Expired - Lifetime CN1063321C (en) | 1992-02-06 | 1993-01-02 | Medicaments |
| CNB001200720A Expired - Lifetime CN1152669C (en) | 1992-02-06 | 2000-06-30 | Medicinal aerosol preparation, its preparing method and release |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93100476A Expired - Lifetime CN1063321C (en) | 1992-02-06 | 1993-01-02 | Medicaments |
| CNB001200720A Expired - Lifetime CN1152669C (en) | 1992-02-06 | 2000-06-30 | Medicinal aerosol preparation, its preparing method and release |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN1048627C (en) |
| GB (1) | GB9202522D0 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100337614C (en) * | 1998-09-22 | 2007-09-19 | 气体药品技术公司 | Medicinal aerosol formulation |
| CN103709109A (en) * | 2013-12-24 | 2014-04-09 | 福建省福抗药业股份有限公司 | Preparation method of sulfadimidine hydrosulfate |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102379846B (en) * | 2011-10-21 | 2014-07-02 | 江苏长风药业有限公司 | Fluticasone propionate aerosol preparation with hydrofluoroalkane and polyethylene glycol as auxiliary materials |
| CN102366405A (en) * | 2011-10-21 | 2012-03-07 | 江阴长风医药科技有限公司 | Fluticasone propionate aerosol preparation with hydrofluoroalkane as propellant |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8828477D0 (en) * | 1988-12-06 | 1989-01-05 | Riker Laboratories Inc | Medical aerosol formulations |
| GB8921222D0 (en) * | 1989-09-20 | 1989-11-08 | Riker Laboratories Inc | Medicinal aerosol formulations |
| IE67185B1 (en) * | 1990-02-02 | 1996-03-06 | Fisons Plc | Propellant compositions |
| IL98639A0 (en) * | 1990-06-28 | 1992-07-15 | Glaxo Inc | Aerosol drug formulations |
| US5290539A (en) * | 1990-12-21 | 1994-03-01 | Minnesota Mining And Manufacturing Company | Device for delivering an aerosol |
-
1992
- 1992-02-06 GB GB929202522A patent/GB9202522D0/en active Pending
-
1993
- 1993-01-02 CN CN93100477A patent/CN1048627C/en not_active Expired - Lifetime
- 1993-01-02 CN CN93100476A patent/CN1063321C/en not_active Expired - Lifetime
-
2000
- 2000-06-30 CN CNB001200720A patent/CN1152669C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100337614C (en) * | 1998-09-22 | 2007-09-19 | 气体药品技术公司 | Medicinal aerosol formulation |
| CN103709109A (en) * | 2013-12-24 | 2014-04-09 | 福建省福抗药业股份有限公司 | Preparation method of sulfadimidine hydrosulfate |
| CN103709109B (en) * | 2013-12-24 | 2016-08-17 | 福建省福抗药业股份有限公司 | A kind of preparation method of sulfadimidine hydrosulfate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1284330A (en) | 2001-02-21 |
| CN1152669C (en) | 2004-06-09 |
| CN1063321C (en) | 2001-03-21 |
| CN1075078A (en) | 1993-08-11 |
| CN1048627C (en) | 2000-01-26 |
| GB9202522D0 (en) | 1992-03-25 |
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