WO1996031195A1 - Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation - Google Patents
Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation Download PDFInfo
- Publication number
- WO1996031195A1 WO1996031195A1 PCT/JP1996/000772 JP9600772W WO9631195A1 WO 1996031195 A1 WO1996031195 A1 WO 1996031195A1 JP 9600772 W JP9600772 W JP 9600772W WO 9631195 A1 WO9631195 A1 WO 9631195A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- aqueous solution
- procaterol hydrochloride
- water
- molecular
- Prior art date
Links
- LZULAZTXJLWELL-UHFFFAOYSA-N methyl hex-5-ynoate Chemical compound COC(=O)CCCC#C LZULAZTXJLWELL-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 229960002789 procaterol hydrochloride Drugs 0.000 title claims abstract description 91
- 239000007864 aqueous solution Substances 0.000 title claims abstract description 75
- 239000000203 mixture Substances 0.000 title description 136
- 238000009472 formulation Methods 0.000 title description 133
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 6
- 239000002997 ophthalmic solution Substances 0.000 claims description 34
- 230000004888 barrier function Effects 0.000 claims description 29
- 239000007789 gas Substances 0.000 claims description 29
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 229940054534 ophthalmic solution Drugs 0.000 claims description 25
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 claims description 22
- 150000002605 large molecules Chemical class 0.000 claims description 20
- 229920003023 plastic Polymers 0.000 claims description 18
- 239000004033 plastic Substances 0.000 claims description 18
- 229960000633 dextran sulfate Drugs 0.000 claims description 15
- 239000005022 packaging material Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 8
- 125000000129 anionic group Chemical group 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 229940005642 polystyrene sulfonic acid Drugs 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 6
- 229920000172 poly(styrenesulfonic acid) Polymers 0.000 claims description 6
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 229920001467 poly(styrenesulfonates) Polymers 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 4
- 239000001569 carbon dioxide Substances 0.000 claims description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 4
- 229940006186 sodium polystyrene sulfonate Drugs 0.000 claims description 4
- 239000006096 absorbing agent Substances 0.000 claims 1
- 230000000717 retained effect Effects 0.000 claims 1
- 238000003860 storage Methods 0.000 abstract description 11
- 230000007774 longterm Effects 0.000 abstract description 6
- -1 polyethylene Polymers 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000008215 water for injection Substances 0.000 description 32
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 23
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 22
- 230000001954 sterilising effect Effects 0.000 description 17
- 238000004659 sterilization and disinfection Methods 0.000 description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 16
- 239000004615 ingredient Substances 0.000 description 16
- 239000000123 paper Substances 0.000 description 16
- 239000004698 Polyethylene Substances 0.000 description 15
- 229920000573 polyethylene Polymers 0.000 description 15
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical class NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 229960004926 chlorobutanol Drugs 0.000 description 14
- 239000002250 absorbent Substances 0.000 description 12
- 230000002745 absorbent Effects 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 239000003002 pH adjusting agent Substances 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 235000011187 glycerol Nutrition 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 7
- 229910052782 aluminium Inorganic materials 0.000 description 7
- 229960000686 benzalkonium chloride Drugs 0.000 description 7
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 7
- 238000004806 packaging method and process Methods 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000004743 Polypropylene Substances 0.000 description 6
- 239000011888 foil Substances 0.000 description 6
- 229960001340 histamine Drugs 0.000 description 6
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 6
- 229920001155 polypropylene Polymers 0.000 description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000009517 secondary packaging Methods 0.000 description 5
- 241000700198 Cavia Species 0.000 description 4
- 206010010741 Conjunctivitis Diseases 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229960004106 citric acid Drugs 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000003204 osmotic effect Effects 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 3
- 229920001287 Chondroitin sulfate Polymers 0.000 description 3
- 239000004677 Nylon Substances 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940059329 chondroitin sulfate Drugs 0.000 description 3
- 229960003699 evans blue Drugs 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
- 229960002216 methylparaben Drugs 0.000 description 3
- 229920001778 nylon Polymers 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000139 polyethylene terephthalate Polymers 0.000 description 3
- 239000005020 polyethylene terephthalate Substances 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- 230000008728 vascular permeability Effects 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229960004543 anhydrous citric acid Drugs 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229940064004 antiseptic throat preparations Drugs 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000003359 percent control normalization Methods 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920002239 polyacrylonitrile Polymers 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000009461 vacuum packaging Methods 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- OBNWLFUZQQYJKA-UHFFFAOYSA-N 1h-quinolin-2-one;sulfuric acid Chemical compound OS(O)(=O)=O.C1=CC=CC2=NC(O)=CC=C21 OBNWLFUZQQYJKA-UHFFFAOYSA-N 0.000 description 1
- MUHFRORXWCGZGE-KTKRTIGZSA-N 2-hydroxyethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCO MUHFRORXWCGZGE-KTKRTIGZSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000720950 Gluta Species 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229920000288 Keratan sulfate Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229920002302 Nylon 6,6 Polymers 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229910001567 cementite Inorganic materials 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- LNGNZSMIUVQZOX-UHFFFAOYSA-L disodium;dioxido(sulfanylidene)-$l^{4}-sulfane Chemical compound [Na+].[Na+].[O-]S([O-])=S LNGNZSMIUVQZOX-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229940063583 high-density polyethylene Drugs 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 description 1
- 239000005001 laminate film Substances 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920006122 polyamide resin Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920005672 polyolefin resin Polymers 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229960002288 procaterol Drugs 0.000 description 1
- 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 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000007740 vapor deposition Methods 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
Definitions
- the present invention relates to a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride and a package which holds the pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride.
- Procaterol hydrochloride in a low concentration has drawbacks of being unstable in an aqueous solution and low in long-term storage stability.
- the procaterol hydrochloride in a low concentration has a further disadvantage that it readily flows away by dint of our tear or snivel after administration.
- An object of the present invention is to impart long-term storage stability to a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride (hereinafter referred to as "procaterol hydrochloride aqueous solution formulation") in a low concentration.
- Another object of the invention is to provide a procaterol hydrochloride aqueous solution capable of producing a prolonged effect after its application to the eye or the like.
- the present inventors conducted extensive research to impart long-term storage stability to a procaterol hydrochloride aqueous solution formulation in a low concentration and found that the procaterol hydrochloride in a low concentration is decomposed in the aqueous solution by the oxidation reaction of the procaterol hydrochloride in the solution and that the oxidation reaction is not allowed to proceed in the absence of oxygen.
- the present invention has been completed based on these novel findings.
- a package holding a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride such that the procaterol hydrochloride is kept from decomposing in the aqueous solution due to its oxidation reaction.
- the decomposition of procaterol hydrochloride in an aqueous solution due to its oxidation can be prevented, for example, by maintaining the procaterol hydrochloride aqueous solution formulation under an oxygen-free atmosphere.
- the oxygen-free atmosphere can be produced by replacing the air in a glass container with nitrogen gas and sealing the container.
- Plastics containers most widely used for ophthalmic solutions have too high a gas permeability to retain the oxygen-free atmosphere even after replacement with nitrogen gas.
- the procaterol hydrochloride aqueous solution formulation is filled in a plastics container, and the container is packaged in a gas barrier packaging material.
- the present inventors' research found the following. When a plastics ophthalmic container full of an aqueous solution of procaterol hydrochloride is accommodated and sealed, together with an oxygen absorbent, in a bottle or a bag made of a gas-impermeable film, there is obtained a procaterol hydrochloride aqueous solution formulation which is excellent in the long-term storage stability.
- a preferred embodiment of the package holding the procaterol hydrochloride aqueous solution formulation according to the invention is a package holding the procaterol hydrochloride aqueous solution formulation wherein the procaterol hydrochloride aqueous solution formulation is enclosed in a plastics container, and wherein the container is packaged, together with an oxygen absorbent, in a gas barrier packaging material .
- Another preferred embodiment of the package holding the procaterol hydrochloride aqueous solution formulation according to the invention is a package holding the procaterol hydrochloride aqueous solution formulation wherein the procaterol hydrochloride aqueous solution formulation is enclosed in a plastics container; wherein the container is packaged in a gas barrier packaging material; and wherein a nitrogen gas and/or carbon dioxide gas is sealed in a space between the container and the gas barrier packaging material.
- the present inventors further found that the effect of the procaterol hydrochloride solution formulation can be prolonged by incorporating into the formulation a water-soluble high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000, preferably at least one water-soluble high-molecular-weight compound selected from the group consisting of acidic mucopolysaccharide and dextran sulfate containing a sulfuric acid group, and salts thereof.
- procaterol hydrochloride aqueous solution formulation incorporating therein at least one high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000.
- plastics containers can be used as the container for accommodating the procaterol hydrochloride aqueous solution formulation according to the invention.
- the materials useful for the plastics containers are not specifically limited and can be known plastics such as polyethylene, polypropylene and like polyolefins, copolymers thereof, polyvinyl chloride, ethylene-vinyl acetate copolymers, polyester, nylon, polycarbonate, polyethylene terephthalate, etc. A combination of at least two of these same or different polymers having a complex multilayered structure may also be used.
- the procaterol hydrochloride aqueous solution formulations of the present invention include various formulations such as ophthalmic solutions, insufflation- type solutions, rhinal solutions, etc. Among them, ophthalmic solutions are preferred.
- procaterol hydrochloride ophthalmic solutions are described below in detail.
- the ophthalmic solution can be prepared in the conventional manner. Stated more specifically, procaterol hydrochloride as an active ingredient is mixed with a suitable carrier and the mixture is treated for sterilization. Suitable carriers include, for example, sterilized and purified water. When required, such ophthalmic solutions may contain any of various conventional additives such as solubilizing agents, buffers, antioxidants, stabilizers, antiseptics, isotonizing agents, pH adjusters, thickeners, etc.
- useful solubilizing agents are sodium carboxymethyl cellulose, polyoxyethylene glycol ethers such as polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, etc., polyethylene glycol higher fatty acid esters such as polyethylene glycol monolaurate, polyethylene glycol monooleate, etc., polyoxyethylene sorbitan monolaurate, polyoxyethylene fatty acid ester, etc.
- useful buffers are sodium phosphate, sodium hydrogenphosphate, potassium hydrogenphosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, ⁇ -amino caproic acid, sodium gluta ate, etc.
- Useful antioxidants include, for example, sodium sulfite, sodium pyrosulfite, sodium bisulfite, sodium thiosulfite, ascorbic acid, etc.
- Useful stabilizers include, for example, ethylenediaminetetraacetic acid (EDTA), hydroxyquinolin sulfate, etc.
- Useful antiseptics are, for example, chlorobutanol, benzalkonium chloride, benzethonium chloride, mercuryphenyl salt, thi erosal, phenethyl alcohol, methylparaben, ethylparaben, propylparaben, butylparaben, etc.
- Useful isotonizing agents are sodium chloride, glucose, D-mannitol, glycerin, etc.
- Useful pH adjusters are sodium hydroxide, hydrochloric acid, etc.
- Useful thickeners are methyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and like cellulose derivatives, hydroxyethyl starch, methyl starch and like starch derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, etc.
- insufflation-type solutions and rhinal solutions are formulated in the same manner as said procaterol hydrochloride ophthalmic solutions.
- an isotonizing agent need not be incorporated.
- a wide variety of conventional compounds are usable as at least one water-soluble high-molecular-weight compound containing an anionic functional group which is used in the invention to prolong the effect of the procaterol hydrochloride.
- Such compounds include, for example, hyaluronic acid, chondroitin sulfate, carrageenan, chitin sulfate, ' chitosan sulfate, pullulan sulfate, alginic acid, carboxymethyl cellulose, carboxy- ethylcurdlan, carboxymethyldextran, carboxymethylpullu- lan, carboxymethylchitin, carboxymethylchitosan and like high-molecular-weight polysaccharides containing an anionic functional group and salts thereof, polystyrene- sulfonic acid, polyvinyl sulfate, polyacrylic acid, carboxyvinyl polymers, polymethacrylic acid and like synthetic high-molecular-weight compounds containing an ani
- suitable compounds are those having a sulfuric acid group such as acidic mucopolysaccharide, dextran sulfate, polystyrenesulfonic acid and salts thereof. More specific examples are chondroitin sulfate, heparin, heparan sulfate, keratan sulfate, dextran sulfate, polystyrenesulfonic acid and salts thereof (e.g., sodium salt, potassium salt or calcium salt), etc.
- a sulfuric acid group such as acidic mucopolysaccharide, dextran sulfate, polystyrenesulfonic acid and salts thereof. More specific examples are chondroitin sulfate, heparin, heparan sulfate, keratan sulfate, dextran sulfate, polystyrenesulfonic acid and salts thereof (e.g., sodium salt, potassium salt or calcium salt), etc.
- chondroitin sulfate preferred are chondroitin sulfate, dextran sulfate, polystyrenesulfonic acid and salts thereof, and more preferred are sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate. Of them, most preferred is sodium chondroitin sulfate.
- water-soluble high-molecular-weight compound having a molecular weight of at least 10,000, usually about 10,000 to about 3 millions. It is recommendable to use, in some cases, such compounds about 10,000 to about 100,000 in molecular weight and in other cases, those about 100,000 to about 1 million in molecular weight.
- the amount of such water-soluble high-molecular- weight compound to be used is at least 10 mg/ml, preferably 10 to 150 mg/ml, more preferably 15 to 100 mg/ml, most preferably 20 to 50 mg/ml, based on the amount of the procaterol hydrochloride aqueous solution formulation.
- the amount of the procaterol hydrochloride to be incorporated in the formulation is not critical but usually 0.1 to 10,000 ⁇ g/ml, preferably 1 to 1,000 ⁇ g/ml, more preferably 5 to 500 ⁇ g/ml. For use as an ophthalmic solution, the amount is 10 to 300 ⁇ g/ml.
- Oxygen absorbents useful in the invention include those heretofore known and comprising, e.g., iron hydroxide, iron oxide, iron carbide or like iron compounds as an active ingredient.
- Typical commercial products are, for example, those available under the tradenames
- the form of the oxygen absorbent is not specifically limited insofar as the absorbent can be placed in the space between the plastics container holding the procaterol hydrochloride aqueous solution formulation and the gas barrier packaging material as its external cover.
- the oxygen absorbent is in a powder form, preferably the required quantity of the powder is placed into a small-size air-permeable bag or the like, and the bag is laid in said space.
- gas barrier packaging material which encloses therewith the plastics container holding the procaterol hydrochloride aqueous solution formulation.
- these materials include glass containers, films or sheets and bottles made of various materials widely used, etc.
- gas barrier materials containing at least one species selected from olefin resins such as polypropylene, high- density polyethylene or like polyethylenes, etc., polyethylene terephthalate, ethylene-vinyl alcohol copolymer resins, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polycarbonate, polyamide resins such as nylon, etc., cellulose acetate, polyester, aluminum foil, glass and so on.
- Gas barrier materials for use herein include laminated films of the above-exemplified materials, for example, laminated films of nylon, ethylene-vinyl alcohol copolymer resin and polyethylene, etc.
- Gas barrier materials useful herein may be a laminate of aluminum foil and plastics such as polyethylene, a plastics film combined by vapor deposition with aluminum or silicic acid, etc.
- Preferred gas barrier materials have an oxygen permeability of not higher than 1.0 ml/m 2 'hr»atm at 25°C and 75% RH.
- the plastics container holding the procaterol hydrochloride aqueous solution formulation and the oxygen absorbent can be packaged (enclosed) in these packaging materials by conventional methods.
- the package holding the procaterol hydrochloride aqueous solution formulation according to the present invention may be one produced without using an oxygen absorbent and by degassing the space between the plastics container and the gas barrier packaging material and sealing a nitrogen gas and/or carbon dioxide gas into said space.
- the space can be degassed in the conventional manner using, e.g. a vacuum packaging machine.
- the procaterol hydrochloride aqueous solution formulation of the present invention can be used for the purposes which cover all known applications of procaterol hydrochloride.
- the formulation of the invention is suitable for use as a bronchodilator, peripheral vasodilators, antihypertensive, antiglaucoma, antiallergics, ophthalmic solutions for preventing and healing the inflammation and/or wound in eyes, etc.
- the package holding the procaterol hydrochloride aqueous solution formulation according to the invention enhances the long-term storage stability of the formulation. Further the procaterol hydrochloride aqueous solution formulation containing the foregoing specific water-soluble high-molecular-weight compound can produce markedly prolonged effects. Examples
- Methylparaben 0.5 mg pH adjuster q.s.
- Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.
- Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.
- Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.
- Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.
- An aqueous solution formulation was prepared in the same manner as in Formulation Example 16 with the exception of using sodium chondroitin sulfate in an amount of 10 mg.
- An aqueous solution formulation was prepared in the same manner as in Formulation Example 17 with the exception of using sodium chondroitin sulfate in an amount of 10 mg.
- An aqueous solution formulation was prepared in the same manner as in Formulation Example 18 with the exception of using sodium chondroitin sulfate in an amount of 10 mg.
- a 5 ml portion of each ophthalmic solution prepared in Formulation Example 1 or 2 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by
- the container, together with an oxygen absorbent (AGELESS) and an oxygen detecting composition (AGELESS EYE) was packaged in a gas barrier film to accomplish secondary packaging, whereby a package according to the present invention was obtained.
- AGELESS oxygen absorbent
- AGELESS EYE oxygen detecting composition
- An oxygen barrier laminated film comprising 15 ⁇ -thick stretched nylon 66 film, 15 ⁇ -thick nylon- ethylene vinyl alcohol copolymer film and 15 ⁇ -thick polyethylene film, the film having an oxygen permeability of 0.8 ml/m 2 -24 hrs at 20 ⁇ C and 65% RH or 1.2 ml/m 2 »24 hrs at 25°C and 65% RH.
- a vapor/oxygen barrier laminated film comprising 12 ⁇ -thick polyethylene terephthalate film, 12 ⁇ -thick film made of silicon oxide deposited on polyvinyl alcohol, and 50 ⁇ -thick straight-chain low-density polyethylene film, the film having an oxygen permeability of 0.1 ml/m 2 .24 hrs at 20 ⁇ C and 65% RH or 0.1 ml/m 2 .24 hrs at 25°C and 65% RH.
- the secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 1 using an oxygen barrier laminated film as a gas barrier film is hereinafter referred to as "present product A” .
- the secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 1 using the vapor/oxygen barrier laminated film as a gas barrier film is hereinafter referred to as "present product B” .
- the secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 2 using the oxygen barrier laminated film as a gas barrier film is hereinafter referred to as "present product C".
- the secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 2 using the vapor/oxygen barrier laminate film as a gas barrier film is hereinafter referred to as "present product D".
- the oxygen concentration in the secondary package was detected by AGELESS EYE.
- AGELESS EYE is adapted to turn pink in an oxygen concentration of up to 0.1% and adapted to turn blue in an oxygen concentration of not lower than 0.5%. All of "AGELESS EYE" compositions placed in the present products A to D became pink within 3 days.
- each ophthalmic solution prepared in Formulation Example 1 or 2 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.).
- the container was packaged in an aluminum foil or aluminum-deposited film. Then the space between the ophthalmic container and the secondary package was deaerated by a vacuum packaging machine and nitrogen gas was introduced into the space, whereby present product E (packaged in aluminum foil) and present product F (packaged in an aluminum-deposited film) were obtained.
- present product G accommodating the aqueous solution formulation of Formulation Example 3
- present product H accommodating the aqueous solution formulation of Formulation Example 4
- present product I accommodating the aqueous solution formulation of Formulation Example 5.
- Preparation Example 4 The aqueous solution formulations prepared in
- Formulation Examples 6-8 were filled into polyvinyl chloride containers and the containers were packaged, together with an oxygen absorbent (MODULAN) , in a packaging material comprising a laminate of aluminum foil and polyethylene to accomplish secondary packaging, whereby the present product was obtained.
- MODULAN oxygen absorbent
- the aqueous solution formulations prepared in Formulation Examples 9-11 were filled into polyester containers and the containers were packaged, together with an oxygen absorbent (SEQUL), in a gas barrier film comprising an ethylene-vinyl alcohol copolymer resin to accomplish secondary packaging, whereby the present product was obtained.
- SEQUL oxygen absorbent
- Preparation Example 6 The aqueous solution formulations prepared in Formulation Examples 12-14 were filled into containers of ethylene-vinyl acetate copolymer and secondary packaging was accomplished using a gas barrier film containing polyacrylonitrile. Thereafter carbon dioxide gas was sealed into the deaerated space, whereby the present product was obtained.
- a 5 ml portion of each ophthalmic solution prepared in Formulation Examples 15, 16 and 17 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.).
- the container, together with an oxygen absorbent ("AGELESS”), was packaged in a packaging material comprising a laminate of aluminum foil and polyethylene to accomplish secondary packaging, whereby the present product was obtained.
- the secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 15 is hereinafter referred to as "present product J".
- the secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 16 is hereinafter referred to as "present product K”.
- the secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 17 is hereinafter referred to as "present product L”.
- Tables 1 and 2 show the following.
- the comparative product 1 showed about 10% decrease in the ratio of residual procaterol hydrochloride after 24-week storage at 40°C and 75% RH, whereas the present products A and B showed less than 5% decrease in the ratio of residual procaterol hydrochloride.
- the comparative product 2 showed about 2% decrease in the ratio of residual procaterol hydrochloride after 12-week storage at 25°C and 75% RH, whereas the present products C and D had no decrease in the ratio of residual procaterol hydrochloride even after 24-week storage.
- the comparative product 2 decreased by about 6% in the ratio of residual procaterol hydrochloride after 12-week storage at 40°C and 75% RH, whereas the present products C and D decreased by less than 5% in the ratio of residual procaterol hydrochloride even after 24-week storage. It has been be confirmed from these results that the removal of oxygen pronouncedly contributes to stabilization of procaterol hydrochloride.
- Test Example 2
- Hartley-strain male guinea pigs were used as model animals. The test was carried out using the animal in a pentobarbital-anesthetized (30 mg/kg, i.p.) state. Test formulations (aqueous solution formulations of Formulation Examples 6-8) were applied by an eyedropper to the animal's right eye and 10 ⁇ l of ophthalmic buffer or physiological salt solution to the animal's left eye. One hour, 2 hours or 3 hours after application, 10 ⁇ l of 2 mg/ml histamine/physiological salt solution was applied to both eyes of the animals to induce conjunctivitis. To the non-treatment group was applied a physiological salt solution in place of histamine. Evans blue was intravenously administered at a dose of 10 mg/ml/kg immediately before application of histamine.
- Blood was collected from vena cava inferior 30 minutes after application of histamine to determine the absorbance (A g2n ) of blood plasma at 620 nm. Animals' eyelids and conjunctiva were removed. Evans blue was extracted for 2 days using 1.5 ml of acetone-0.5% sodium sulfate (7 : 3, v/v) after which the absorbance of blood plasma at 620 nm was measured. The leakage of blood plasma was calculated by the following equation. Blood plasma leakage ( ⁇ l/tissue)- A620 of tissue extract/A620 of blood plasma X 1500
- the potency of the drug was expressed in terms of percent control of rise of vascular permeability of the right eye (drug- treated eye) against the left eye (control eye) .
- the percent control was calculated by the following equation.
- Test for effect on guinea pigs with histamine- induced conjunctivitis Hartley-strain male guinea pigs were used as model animals. The test was carried out using the animal in a pentobarbital-anesthetized (30 mg/kg, i.p.) state. A test formulation (aqueous solution formulation of Formulation Example 17) was applied by an eyedropper to the animal's right eye and 10 ⁇ l of ophthalmic buffer or physiological salt solution to the animal's left eye. Five minutes or 3 hours after application, 10 ⁇ l of 2 mg/ml histamine/physiological salt solution was applied to both eyes of the animals to induce conjunctivitis.
- comparative product 5 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 15
- comparative product 6 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 16
- comparative product 7 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 17.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
An object of the present invention is to impart long-term storage stability to a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride. This invention is directed to an aqueous solution of procaterol hydrochloride which assures that the procaterol hydrochloride is kept from decomposing in the aqueous solution due to its oxidation reaction.
Description
DESCRIPTION
PACKAGE HOLDING A PROCATEROL HYDROCHLORIDE AQUEOUS SOLUTION FORMULATION, AND A PROCATEROL HYDROCHLORIDE AQUEOUS SOLUTION FORMULATION
Technical Field The present invention relates to a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride and a package which holds the pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride. Bac ground Ajt;
Various procaterol preparations have been known. Procaterol hydrochloride in a low concentration has drawbacks of being unstable in an aqueous solution and low in long-term storage stability. The procaterol hydrochloride in a low concentration has a further disadvantage that it readily flows away by dint of our tear or snivel after administration.
Disclosure of the Invention An object of the present invention is to impart long-term storage stability to a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride (hereinafter referred to as "procaterol hydrochloride aqueous solution formulation") in a low concentration. Another object of the invention is to provide a
procaterol hydrochloride aqueous solution capable of producing a prolonged effect after its application to the eye or the like.
The present inventors conducted extensive research to impart long-term storage stability to a procaterol hydrochloride aqueous solution formulation in a low concentration and found that the procaterol hydrochloride in a low concentration is decomposed in the aqueous solution by the oxidation reaction of the procaterol hydrochloride in the solution and that the oxidation reaction is not allowed to proceed in the absence of oxygen. The present invention has been completed based on these novel findings.
According to the present invention, there is provided a package holding a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride such that the procaterol hydrochloride is kept from decomposing in the aqueous solution due to its oxidation reaction. The decomposition of procaterol hydrochloride in an aqueous solution due to its oxidation can be prevented, for example, by maintaining the procaterol hydrochloride aqueous solution formulation under an oxygen-free atmosphere. The oxygen-free atmosphere can be produced by
replacing the air in a glass container with nitrogen gas and sealing the container. Plastics containers most widely used for ophthalmic solutions have too high a gas permeability to retain the oxygen-free atmosphere even after replacement with nitrogen gas. Thus, according to the invention, the procaterol hydrochloride aqueous solution formulation is filled in a plastics container, and the container is packaged in a gas barrier packaging material. The present inventors' research found the following. When a plastics ophthalmic container full of an aqueous solution of procaterol hydrochloride is accommodated and sealed, together with an oxygen absorbent, in a bottle or a bag made of a gas-impermeable film, there is obtained a procaterol hydrochloride aqueous solution formulation which is excellent in the long-term storage stability.
Consequently a preferred embodiment of the package holding the procaterol hydrochloride aqueous solution formulation according to the invention is a package holding the procaterol hydrochloride aqueous solution formulation wherein the procaterol hydrochloride aqueous solution formulation is enclosed in a plastics container, and wherein the container is packaged, together with an oxygen absorbent, in a gas barrier packaging
material .
Another preferred embodiment of the package holding the procaterol hydrochloride aqueous solution formulation according to the invention is a package holding the procaterol hydrochloride aqueous solution formulation wherein the procaterol hydrochloride aqueous solution formulation is enclosed in a plastics container; wherein the container is packaged in a gas barrier packaging material; and wherein a nitrogen gas and/or carbon dioxide gas is sealed in a space between the container and the gas barrier packaging material.
The present inventors further found that the effect of the procaterol hydrochloride solution formulation can be prolonged by incorporating into the formulation a water-soluble high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000, preferably at least one water-soluble high-molecular-weight compound selected from the group consisting of acidic mucopolysaccharide and dextran sulfate containing a sulfuric acid group, and salts thereof.
Consequently, according to the present invention, there is also provided a procaterol hydrochloride aqueous solution formulation incorporating therein at least one high-molecular-weight compound
containing an anionic functional group and having a molecular weight of at least 10,000.
Conventional plastics containers can be used as the container for accommodating the procaterol hydrochloride aqueous solution formulation according to the invention. The materials useful for the plastics containers are not specifically limited and can be known plastics such as polyethylene, polypropylene and like polyolefins, copolymers thereof, polyvinyl chloride, ethylene-vinyl acetate copolymers, polyester, nylon, polycarbonate, polyethylene terephthalate, etc. A combination of at least two of these same or different polymers having a complex multilayered structure may also be used. There is no specific limitation on the shape and size of the container insofar as the container can hold a usual procaterol hydrochloride aqueous solution formulation. Bag-like and bottle-like shapes are generally recommendable.
The procaterol hydrochloride aqueous solution formulations of the present invention include various formulations such as ophthalmic solutions, insufflation- type solutions, rhinal solutions, etc. Among them, ophthalmic solutions are preferred.
For example, procaterol hydrochloride ophthalmic solutions are described below in detail. The ophthalmic
solution can be prepared in the conventional manner. Stated more specifically, procaterol hydrochloride as an active ingredient is mixed with a suitable carrier and the mixture is treated for sterilization. Suitable carriers include, for example, sterilized and purified water. When required, such ophthalmic solutions may contain any of various conventional additives such as solubilizing agents, buffers, antioxidants, stabilizers, antiseptics, isotonizing agents, pH adjusters, thickeners, etc. Examples of useful solubilizing agents are sodium carboxymethyl cellulose, polyoxyethylene glycol ethers such as polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, etc., polyethylene glycol higher fatty acid esters such as polyethylene glycol monolaurate, polyethylene glycol monooleate, etc., polyoxyethylene sorbitan monolaurate, polyoxyethylene fatty acid ester, etc. Examples of useful buffers are sodium phosphate, sodium hydrogenphosphate, potassium hydrogenphosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, ε-amino caproic acid, sodium gluta ate, etc. Useful antioxidants include, for example, sodium sulfite, sodium pyrosulfite, sodium bisulfite, sodium thiosulfite, ascorbic acid, etc. Useful stabilizers include, for example, ethylenediaminetetraacetic acid (EDTA),
hydroxyquinolin sulfate, etc. Useful antiseptics are, for example, chlorobutanol, benzalkonium chloride, benzethonium chloride, mercuryphenyl salt, thi erosal, phenethyl alcohol, methylparaben, ethylparaben, propylparaben, butylparaben, etc. Useful isotonizing agents are sodium chloride, glucose, D-mannitol, glycerin, etc. Useful pH adjusters are sodium hydroxide, hydrochloric acid, etc. Useful thickeners are methyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and like cellulose derivatives, hydroxyethyl starch, methyl starch and like starch derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, etc.
The insufflation-type solutions and rhinal solutions are formulated in the same manner as said procaterol hydrochloride ophthalmic solutions. In the case of the insufflation-type solutions, an isotonizing agent need not be incorporated.
A wide variety of conventional compounds are usable as at least one water-soluble high-molecular-weight compound containing an anionic functional group which is used in the invention to prolong the effect of the procaterol hydrochloride. Such compounds include, for example, hyaluronic acid, chondroitin sulfate, carrageenan, chitin sulfate, 'chitosan sulfate, pullulan
sulfate, alginic acid, carboxymethyl cellulose, carboxy- ethylcurdlan, carboxymethyldextran, carboxymethylpullu- lan, carboxymethylchitin, carboxymethylchitosan and like high-molecular-weight polysaccharides containing an anionic functional group and salts thereof, polystyrene- sulfonic acid, polyvinyl sulfate, polyacrylic acid, carboxyvinyl polymers, polymethacrylic acid and like synthetic high-molecular-weight compounds containing an anionic functional group and salts thereof. Among these water-soluble high-molecular-weight compounds, suitable compounds are those having a sulfuric acid group such as acidic mucopolysaccharide, dextran sulfate, polystyrenesulfonic acid and salts thereof. More specific examples are chondroitin sulfate, heparin, heparan sulfate, keratan sulfate, dextran sulfate, polystyrenesulfonic acid and salts thereof (e.g., sodium salt, potassium salt or calcium salt), etc. Among them, preferred are chondroitin sulfate, dextran sulfate, polystyrenesulfonic acid and salts thereof, and more preferred are sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate. Of them, most preferred is sodium chondroitin sulfate. In the practice of the invention, it is suitable to use said water-soluble high-molecular-weight compound having a molecular weight of at least 10,000, usually about 10,000 to about 3
millions. It is recommendable to use, in some cases, such compounds about 10,000 to about 100,000 in molecular weight and in other cases, those about 100,000 to about 1 million in molecular weight. The amount of such water-soluble high-molecular- weight compound to be used is at least 10 mg/ml, preferably 10 to 150 mg/ml, more preferably 15 to 100 mg/ml, most preferably 20 to 50 mg/ml, based on the amount of the procaterol hydrochloride aqueous solution formulation.
The amount of the procaterol hydrochloride to be incorporated in the formulation is not critical but usually 0.1 to 10,000 μg/ml, preferably 1 to 1,000 μg/ml, more preferably 5 to 500 μg/ml. For use as an ophthalmic solution, the amount is 10 to 300 μg/ml.
Oxygen absorbents useful in the invention include those heretofore known and comprising, e.g., iron hydroxide, iron oxide, iron carbide or like iron compounds as an active ingredient. Typical commercial products are, for example, those available under the tradenames
"AGELESS" (product of Mitsubishi Gas Chemical Co., Ltd.), "MODULAN" (product of Nippon Kayaku Co., Ltd.), "SEQUL" (product of Nippon Soda Co., Ltd.), "VITALON" (product of Toa Gosei Co., Ltd.), "TAMOTSU" (product of Oji Kako Co., Ltd.), etc. The form of the oxygen absorbent is not
specifically limited insofar as the absorbent can be placed in the space between the plastics container holding the procaterol hydrochloride aqueous solution formulation and the gas barrier packaging material as its external cover. For example, if the oxygen absorbent is in a powder form, preferably the required quantity of the powder is placed into a small-size air-permeable bag or the like, and the bag is laid in said space.
Various materials can be used as the gas barrier packaging material which encloses therewith the plastics container holding the procaterol hydrochloride aqueous solution formulation. Examples of these materials include glass containers, films or sheets and bottles made of various materials widely used, etc. Specific examples are gas barrier materials containing at least one species selected from olefin resins such as polypropylene, high- density polyethylene or like polyethylenes, etc., polyethylene terephthalate, ethylene-vinyl alcohol copolymer resins, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polycarbonate, polyamide resins such as nylon, etc., cellulose acetate, polyester, aluminum foil, glass and so on. Gas barrier materials for use herein include laminated films of the above-exemplified materials, for example, laminated films of nylon, ethylene-vinyl alcohol copolymer resin and
polyethylene, etc. Gas barrier materials useful herein may be a laminate of aluminum foil and plastics such as polyethylene, a plastics film combined by vapor deposition with aluminum or silicic acid, etc. Preferred gas barrier materials have an oxygen permeability of not higher than 1.0 ml/m2'hr»atm at 25°C and 75% RH. The plastics container holding the procaterol hydrochloride aqueous solution formulation and the oxygen absorbent can be packaged (enclosed) in these packaging materials by conventional methods.
The package holding the procaterol hydrochloride aqueous solution formulation according to the present invention may be one produced without using an oxygen absorbent and by degassing the space between the plastics container and the gas barrier packaging material and sealing a nitrogen gas and/or carbon dioxide gas into said space. The space can be degassed in the conventional manner using, e.g. a vacuum packaging machine.
The procaterol hydrochloride aqueous solution formulation of the present invention can be used for the purposes which cover all known applications of procaterol hydrochloride. The formulation of the invention is suitable for use as a bronchodilator, peripheral vasodilators, antihypertensive, antiglaucoma, antiallergics, ophthalmic solutions for preventing and
healing the inflammation and/or wound in eyes, etc.
Effects of the Invention The package holding the procaterol hydrochloride aqueous solution formulation according to the invention enhances the long-term storage stability of the formulation. Further the procaterol hydrochloride aqueous solution formulation containing the foregoing specific water-soluble high-molecular-weight compound can produce markedly prolonged effects. Examples
The following examples are given to illustrate the invention. However, the present invention is not limited to the examples. Formulation Example 1 Per milliliter,
Procaterol hydrochloride 0 . 003 mg Glycerin 24 . 8 mg
Anhydrous citric acid 0 . 422 mg Sodium citrate 0 . 824 mg Sodium ethylenediamine tetraacetate
0 . 1 mg
10% Benzalkonium chloride 1 μl Sodium hydroxide q . s Water for injection q . s In water for injection were dissolved the above-
mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an ophthalmic solution was produced. The pH of the ophthalmic solution was 5.0. Formulation Example 2
Per milliliter,
Procaterol hydrochloride 0.001 mg
Glycerin 24.8 mg
Anhydrous citric acid 0.422 mg Sodium citrate 0.824 mg
Sodium ethylenediamine tetraacetate
0.1 mg 10% Benzalkonium chloride 1 μl
Sodium hydroxide q.s. Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an ophthalmic solution was produced. The pH of the ophthalmic solution was 5.0. Formulation Example 3
An aqueous solution formulation was prepared in the same manner as in Formulation Example 1 with the exception of using procaterol hydrochloride in an amount of 0.01 mg.
Formulation Example 4
Per milliliter,
Procaterol hydrochloride 0.01 mg
Glycerin 25 mg Sodium chondroitin sulfate 10 mg
Methylparaben 0.5 mg pH adjuster q.s.
Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The pH of the formulation was 5.0. Formulation Example 5 An aqueous solution formulation was prepared in the same manner as in Formulation Example 1 with the exception of altering the amount of procaterol hydrochloride to 0.01 mg and using 0.5 mg of methylparaben in place of benzalkonium chloride. Formulation Example 6
Per milliliter,
Procaterol hydrochloride 0.01 mg
Sodium chondroitin sulfate 10 mg
Sodium chloride 5.5 mg Chlorobutanol 3.5 mg
Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 7
Per milliliter,
Procaterol hydrochloride 0.1 mg
Sodium chondroitin sulfate 10 mg Sodium chloride 5.5 mg
Chlorobutanol 3.5 mg
Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 8
Per milliliter,
Procaterol hydrochloride 0.1 mg Sodium dextran sulfate 50 mg
Glycerin 18 mg
Chlorobutanol 3 mg pH adjuster q.s.
Water for injection q.s. In water for injection were dissolved the above-
mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 9 Per milliliter,
Procaterol hydrochloride 0.001 mg
Sodium chondroitin sulfate 30 mg
Glycerin 18 mg
Chlorobutanol 3.5 mg pH adjuster q.s.
Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 10
Per milliliter,
Procaterol hydrochloride 0.01 mg
Sodium chondroitin sulfate 50 mg Glycerin 14 mg
Chlorobutanol 3.5 mg pH adjuster q.s.
Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was
filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 11
Per milliliter, Procaterol hydrochloride 0.1 mg
Sodium chondroitin sulfate 100 mg
Glycerin 4 mg
Chlorobutanol 3.5 mg pH adjuster q.s. Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 12
Per milliliter,
Procaterol hydrochloride 0.001 mg
Sodium dextran sulfate 30 mg
Glycerin 20 mg Citric acid 0.4 mg
Trisodium dihydrate citrate 0.26 mg
Chlorobutanol 3.5 mg pH adjuster q.s.
Water for injection q.s. In water for injection were dissolved the above-
mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 13 Per milliliter,
Procaterol hydrochloride 0.01 mg
Sodium dextran sulfate 50 mg
Glycerin 18 mg
Citric acid 0.4 mg Trisodium dihydrate citrate 0.26 mg
Chlorobutanol 3.5 mg pH adjuster q.s.
Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 14
Per milliliter, Procaterol hydrochloride 0.1 mg
Sodium dextran sulfate 100 mg
Glycerin 13 mg
Citric acid 0.4 mg
Trisodium dihydrate citrate 0.26 mg Chlorobutanol 3.5 mg
pH adjuster q.s.
Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 15
Per milliliter,
Procaterol hydrochloride 0.01 mg Sodium chondroitin sulfate 30 mg
Chlorobutanol 2 mg
Benzalkonium chloride 0.023 mg
Sodium chloride 6 mg
Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The formulation had a pH of 4.7-5.0 and an osmotic pressure ratio of 1.0. Formulation Example 16
Per milliliter,
Procaterol hydrochloride 0.03 mg Sodium chondroitin sulfate 30 mg
Chlorobutanol 2 mg
Benzalkoniu chloride 0.023 mg
Sodium chloride 6 mg
Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The formulation had a pH of 4.7-5.0 and an osmotic pressure ratio of 1.0. Formulation Example 17
Per milliliter,
Procaterol hydrochloride 0.1 mg Sodium chondroitin sulfate 30 mg
Chlorobutanol 2 mg
Benzalkonium chloride 0.023 mg
Sodium chloride 6 mg
Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The formulation had a pH of 4.7-5.0 and an osmotic pressure
ratio of 1.0. Formulation Example 18
Per milliliter,
Procaterol hydrochloride 0.3 mg Sodium chondroitin sulfate 30 mg
Chlorobutanol 2 mg
Benzalkonium chloride 0.023 mg
Sodium chloride 6 mg
Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.
In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The formulation had a pH of 4.7-5.0 and an osmotic pressure ratio of 1.0. Formulation Example 19
An aqueous solution formulation was prepared in the same manner as in Formulation Example 15 with the exception of using sodium chondroitin sulfate in an amount of 10 mg. Formulation Example 20
An aqueous solution formulation was prepared in the same manner as in Formulation Example 16 with the exception of using sodium chondroitin sulfate in an amount
of 10 mg.
Formulation Example 21
An aqueous solution formulation was prepared in the same manner as in Formulation Example 17 with the exception of using sodium chondroitin sulfate in an amount of 10 mg.
Formulation Example 22
An aqueous solution formulation was prepared in the same manner as in Formulation Example 18 with the exception of using sodium chondroitin sulfate in an amount of 10 mg.
Preparation Example 1
A 5 ml portion of each ophthalmic solution prepared in Formulation Example 1 or 2 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by
Taisei Kako Co., Ltd.). The container, together with an oxygen absorbent (AGELESS) and an oxygen detecting composition (AGELESS EYE) was packaged in a gas barrier film to accomplish secondary packaging, whereby a package according to the present invention was obtained.
The following two types of gas barrier films were used. (i) An oxygen barrier laminated film comprising
15 μ-thick stretched nylon 66 film, 15 μ-thick nylon- ethylene vinyl alcohol copolymer film and 15 μ-thick polyethylene film, the film having an oxygen permeability of 0.8 ml/m2-24 hrs at 20βC and 65% RH or 1.2 ml/m2»24 hrs at 25°C and 65% RH.
(ii) A vapor/oxygen barrier laminated film comprising 12 μ-thick polyethylene terephthalate film, 12 μ-thick film made of silicon oxide deposited on polyvinyl alcohol, and 50 μ-thick straight-chain low-density polyethylene film, the film having an oxygen permeability of 0.1 ml/m2.24 hrs at 20βC and 65% RH or 0.1 ml/m2.24 hrs at 25°C and 65% RH.
The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 1 using an oxygen barrier laminated film as a gas barrier film is hereinafter referred to as "present product A" . The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 1 using the vapor/oxygen barrier laminated film as a gas barrier film is hereinafter referred to as "present product B" . The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 2 using the oxygen barrier laminated film as a gas barrier film is hereinafter referred to as
"present product C". The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 2 using the vapor/oxygen barrier laminate film as a gas barrier film is hereinafter referred to as "present product D". The oxygen concentration in the secondary package was detected by AGELESS EYE. AGELESS EYE is adapted to turn pink in an oxygen concentration of up to 0.1% and adapted to turn blue in an oxygen concentration of not lower than 0.5%. All of "AGELESS EYE" compositions placed in the present products A to D became pink within 3 days. Preparation Example 2
A 5 ml portion of each ophthalmic solution prepared in Formulation Example 1 or 2 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.). The container was packaged in an aluminum foil or aluminum-deposited film. Then the space between the ophthalmic container and the secondary package was deaerated by a vacuum packaging machine and nitrogen gas was introduced into the space, whereby present product E (packaged in aluminum foil) and present product F (packaged in an aluminum-deposited film) were obtained
Preparation Example 3
In the same manner as the production of present product B in Preparation Example 1, there were obtained present product G accommodating the aqueous solution formulation of Formulation Example 3, present product H accommodating the aqueous solution formulation of Formulation Example 4, and present product I accommodating the aqueous solution formulation of Formulation Example 5. Preparation Example 4 The aqueous solution formulations prepared in
Formulation Examples 6-8 were filled into polyvinyl chloride containers and the containers were packaged, together with an oxygen absorbent (MODULAN) , in a packaging material comprising a laminate of aluminum foil and polyethylene to accomplish secondary packaging, whereby the present product was obtained. Preparation Example 5
The aqueous solution formulations prepared in Formulation Examples 9-11 were filled into polyester containers and the containers were packaged, together with an oxygen absorbent (SEQUL), in a gas barrier film comprising an ethylene-vinyl alcohol copolymer resin to accomplish secondary packaging, whereby the present product was obtained. Preparation Example 6
The aqueous solution formulations prepared in Formulation Examples 12-14 were filled into containers of ethylene-vinyl acetate copolymer and secondary packaging was accomplished using a gas barrier film containing polyacrylonitrile. Thereafter carbon dioxide gas was sealed into the deaerated space, whereby the present product was obtained. Preparation Example 7
A 5 ml portion of each ophthalmic solution prepared in Formulation Examples 15, 16 and 17 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.). The container, together with an oxygen absorbent ("AGELESS"), was packaged in a packaging material comprising a laminate of aluminum foil and polyethylene to accomplish secondary packaging, whereby the present product was obtained.
The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 15 is hereinafter referred to as "present product J". The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 16 is hereinafter referred to as "present product K". The
secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 17 is hereinafter referred to as "present product L". Test Example 1
Present products A to D were placed into a box of cardboard, and the box was left to stand in a chamber at 25°C and 75% RH or at 40°C, 75% RH. In 4 weeks, 7 weeks, 12 weeks, 18 weeks and 24 weeks, the amount of the procaterol hydrochloride in the ophthalmic solution was measured to calculate the ratio of remaining procaterol hydrochloride in the conventional manner. For comparison, a box of cardboard containing the ophthalmic containers filled with the ophthalmic solutions of Formulation Examples 1 and 2 (comparative products 1 and 2, respectively) were provided to calculate the ratio of remaining procaterol hydrochloride. The results are shown in Tables 1 and 2.
Table 1
Ratio of residual procaterol hydrochloride (%) |
4 weeks 7 weeks 12 weeks 18 weeks 24 weeks
Present product A 100.24 98.47 97.41 93.80 95.21
40°C, Present product B 99.11 98.17 98.55 94.89 96.29 75% RH Comparative product 1 98.65 96.82 95.95 91.11 90.20
Table 2
Tables 1 and 2 show the following. In Table 1, the comparative product 1 showed about 10% decrease in the ratio of residual procaterol hydrochloride after 24-week storage at 40°C and 75% RH, whereas the present products A and B showed less than 5% decrease in the ratio of residual procaterol hydrochloride. In Table 2, the comparative product 2 showed about 2% decrease in the ratio of residual procaterol hydrochloride after 12-week storage at 25°C and 75% RH, whereas the present products C and D had no decrease in the ratio of residual procaterol hydrochloride even after 24-week storage. Further, the comparative product 2 decreased by about 6% in the ratio of residual procaterol hydrochloride after 12-week storage at 40°C and 75% RH, whereas the present products C and D decreased by less than 5% in the ratio of residual procaterol hydrochloride even after 24-week storage. It has been be confirmed from these results that the removal of oxygen pronouncedly contributes to stabilization of procaterol hydrochloride. Test Example 2
Present products G to I were placed into a box of cardboard, and the box was left to stand in a chamber at 40°C and 75% RH. In 2 weeks, 4 weeks and 8 weeks, the amount of the procaterol hydrochloride in the aqueous solution formulation was measured to calculate the ratio
of remaining procaterol hydrochloride in the conventional manner. For comparison, a box of cardboard containing the plastics containers filled with the aqueous solution formulations of Formulation Examples 3 to 5 was used to calculate the ratio of remaining procaterol hydrochloride in the same manner as above. The results are shown in Table 3.
Table 3
Ratio of residual procaterol hydrochloride (%)
2 weeks 4 weeks 8 weeks
Present product G 99.6 99.2 98.5
Present product H 98.5 98.8 97.3
Present product I 98.8 98.0
Formulation Ex. 3 98.7 98.4 97.5
Formulation Ex. 4 97.6 97.0 93.8
Formulation Ex. 5 96.1 97.3 94.7
Test Example 3
Test for effect on guinea pigs with histamine- induced conjunctivitis
Hartley-strain male guinea pigs (weight 440-570 g) were used as model animals. The test was carried out using the animal in a pentobarbital-anesthetized (30 mg/kg, i.p.) state. Test formulations (aqueous solution formulations of Formulation Examples 6-8) were applied by an eyedropper to the animal's right eye and 10 μl of ophthalmic buffer or physiological salt solution to the animal's left eye. One hour, 2 hours or 3 hours after application, 10 μl of 2 mg/ml histamine/physiological salt solution was applied to both eyes of the animals to induce conjunctivitis. To the non-treatment group was applied a physiological salt solution in place of histamine. Evans blue was intravenously administered at a dose of 10 mg/ml/kg immediately before application of histamine.
Blood was collected from vena cava inferior 30 minutes after application of histamine to determine the absorbance (Ag2n) of blood plasma at 620 nm. Animals' eyelids and conjunctiva were removed. Evans blue was extracted for 2 days using 1.5 ml of acetone-0.5% sodium sulfate (7 : 3, v/v) after which the absorbance of blood plasma at 620 nm was measured. The leakage of blood plasma was calculated by the following equation.
Blood plasma leakage (μl/tissue)- A620 of tissue extract/A620 of blood plasma X 1500
The rise of vascular permeability due to histamine was expressed in terms of an increase with respect to the leakage of blood plasma of non-treatment group, i.e. 2.6 + 0.2 μl (mean ± S.E., n=7). The potency of the drug was expressed in terms of percent control of rise of vascular permeability of the right eye (drug- treated eye) against the left eye (control eye) . The percent control was calculated by the following equation.
% Control=(l- Blood plasma leakage of right eye-2.6lχ 1Q Q Blood plasma leakage of left eye-2.6 The results are shown in Table 4.
Table 4
Administra¬ % Control of blood tion time plasma leakage (mean ± S.E. )
1 hour
Formulation before 53.0 + 5.5 Example 6
2 hours before 27.3 ± 5.4
Formulation 2 hours Example 7 before 33.3 ± 5.2
Formulation 3 hours Example 8 before 35.3 ± 6.2 Test Example 4
Test for effect on guinea pigs with histamine- induced conjunctivitis
Hartley-strain male guinea pigs (weight 440-570 g) were used as model animals. The test was carried out using the animal in a pentobarbital-anesthetized (30 mg/kg, i.p.) state. A test formulation (aqueous solution formulation of Formulation Example 17) was applied by an eyedropper to the animal's right eye and 10 μl of ophthalmic buffer or physiological salt solution to the animal's left eye. Five minutes or 3 hours after application, 10 μl of 2 mg/ml histamine/physiological salt solution was applied to both eyes of the animals to induce conjunctivitis. To the non-treatment group was applied a physiological salt solution in place of histamine. Evans blue was intravenously administered at a dose of 10 mg/ml/kg immediately before application of histamine. The leakage of blood plasma was calculated in the same manner as in Test Example 3 to determine the percent control of rise of vascular permeability. The results are shown in Table 5. For comparison. Table 5 also shows the results obtained when use was made of an aqueous solution formulation
(comparative product 4) prepared in the same manner as in Formulation Example 1 with the exception of using procaterol hydrochloride in an amount of 0.1 mg in Formulation Example 1 in place of the aqueous solution formulation of Formulation Example 17, and the results
obtained when a physiological salt solution (control) was used.
Table 5
Test Example 5
Present products J to L were placed into a box of cardboard, and the box was left to stand in a chamber at 40°C and 75% RH. In 2 weeks, 4 weeks, 6 weeks, 8 weeks and 12 weeks, the amount of the procaterol hydrochloride in the ophthalmic solution was measured to calculate the ratio of remaining procaterol hydrochloride in the conventional manner. For comparison, a box of cardboard holding ophthalmic containers (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.) full of ophthalmic solutions of
Formulation Examples 15, 16 an 17. The results are shown in Table 6. In Table 6, comparative product 5 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 15, comparative product 6 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 16, and comparative product 7 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 17.
Table 6
Ratio of residual procaterol hydrochloride (%) |
2 weeks 4 weeks 6 weeks 8 weeks 12 weeks
Present product J 98.3 98.3 98.4 98.3 98.1
Comparative product 5 94.7 90.4 86.8 83.4 75.0
Present product K 98.9 98.4 98.4 98.2 95.9
Comparative I product 6 96.9 93.5 91.0 88.2 80.9 ■
I
Present product L 99.0 98.0 98.4 97.1 96.2
Comparative product 7 97.2 93.8 92.0 88.6 83.7 |
Claims
1. A package holding a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride such that the procaterol hydrochloride is kept from decomposing in the aqueous solution due to its oxidation reaction.
2. The package according to claim 1 wherein an oxygen-free atmosphere is retained.
3. The package according to claim 1 wherein the pharmaceutical composition is filled in the plastics container and the container is packaged in a gas barrier packaging material.
4. The package according to claim 3 wherein the pharmaceutical composition is filled in the plastics container and the container is packaged, together with an oxygen absorber, in a gas barrier packaging material.
5. The package according to claim 4 wherein the pharmaceutical composition is an ophthalmic solution.
6. The package according to claim 3 wherein the the pharmaceutical composition is filled in a plastics container; wherein the container is packaged in a gas barrier packaging material; and wherein a nitrogen gas and/or carbon dioxide gas is sealed in a space between the container and the gas barrier packaging material. 7 . The package according to claim 6 wherein the
pharmaceutical composition is an ophthalmic solution.
8. The package according to claim 1 wherein the pharmaceutical composition contains a water-soluble high- molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000. . The package according to claim 8 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of acidic mucopolysaccharide, dextran sulfate and polystyrenesulfonic acid containing a sulfuric acid group, and salts thereof.
10. The package according to claim 8 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate.
11. The package according to claim 4 or 6 wherein the pharmaceutical composition contains a water- soluble high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000.
12. The package according to claim 11 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of acidic mucopolysaccharide, dextran sulfate and
polystyrenesulfonic acid containing a sulfuric acid group, and salts thereof.
13. The package according to claim 11 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate.
14. The package according to claim 11 wherein the water-soluble high-molecular-weight compound is sodium chondroitin sulfate.
15. The package according to claim 14 wherein the pharmaceutical composition is an ophthalmic solution.
16. The package according to claim 15 wherein the pharmaceutical composition contains 1 to 1,000 μg/ml of procaterol hydrochloride and 10 to 150 mg/ml of sodium chondroitin sulfate.
17. A pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride which contains a water-soluble high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000.
18. The pharmaceutical composition according to claim 17 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of acidic mucopolysaccharide, dextran sulfate
and polystyrenesulfonic acid containing a sulfuric acid group, and salts thereof.
19. The pharmaceutical composition according to claim 17 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate.
20. The pharmaceutical composition according to claim 17 wherein the water-soluble high-molecular-weight compound is sodium chondroitin sulfate.
21. The pharmaceutical composition according to claim 20 which is an ophthalmic solution.
22. The pharmaceutical composition according to claim 21 which contains 1 to 1,000 μg/ml of procaterol hydrochloride and 10 to 150 mg/ml of sodium chontroitin sulfate.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU50152/96A AU5015296A (en) | 1995-04-04 | 1996-03-25 | Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation |
| MX9707695A MX9707695A (en) | 1995-04-04 | 1996-03-25 | Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation. |
| EP96906940A EP0820274A1 (en) | 1995-04-04 | 1996-03-25 | Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7/78564 | 1995-04-04 | ||
| JP7856495 | 1995-04-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996031195A1 true WO1996031195A1 (en) | 1996-10-10 |
Family
ID=13665401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1996/000772 WO1996031195A1 (en) | 1995-04-04 | 1996-03-25 | Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0820274A1 (en) |
| KR (1) | KR19980703582A (en) |
| AR (1) | AR002981A1 (en) |
| AU (1) | AU5015296A (en) |
| CA (1) | CA2217360A1 (en) |
| MX (1) | MX9707695A (en) |
| WO (1) | WO1996031195A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002058668A3 (en) * | 2000-12-21 | 2002-12-27 | Alcon Inc | Artificial tear composition adapted to be used with contact lenses |
| WO2013043832A1 (en) * | 2011-09-22 | 2013-03-28 | Theo Holdings, Llc | Hypertonic dextran solution and methods of treating and preventing recurrent corneal erosion |
| WO2017082771A1 (en) * | 2015-11-10 | 2017-05-18 | Общество с ограниченной ответственностью "ДИАМЕД-фарма" | Pharmaceutical preparation for treating arthrological diseases |
| RU2688935C2 (en) * | 2014-05-07 | 2019-05-23 | Крома-Фарма Гезелльшафт М.Б.Х. | Aqueous ophthalmic solution and method of treating dry eye syndrome |
| CN114159398A (en) * | 2021-03-22 | 2022-03-11 | 南京艾德加生物制药科技有限公司 | Procaterol hydrochloride oral solid composition and preparation method thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6996713B2 (en) * | 2015-10-06 | 2022-02-04 | エイチエルビー・セラピューティクス・カンパニー・リミテッド | Method for manufacturing ophthalmic preparation containing thymosin beta 4 |
| RU2612019C1 (en) * | 2015-12-11 | 2017-03-01 | Общество с ограниченной ответственностью "ДИАМЕД-фарма" | Production method of preparation injectable form based on sulfate chondroitin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0443027A1 (en) * | 1988-11-11 | 1991-08-28 | Kurita Water Industries Ltd. | Drug composition |
| EP0609042A1 (en) * | 1993-01-25 | 1994-08-03 | Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation) | Drug composition and process for preparing the same |
-
1996
- 1996-03-25 WO PCT/JP1996/000772 patent/WO1996031195A1/en not_active Application Discontinuation
- 1996-03-25 EP EP96906940A patent/EP0820274A1/en not_active Withdrawn
- 1996-03-25 AU AU50152/96A patent/AU5015296A/en not_active Abandoned
- 1996-03-25 MX MX9707695A patent/MX9707695A/en unknown
- 1996-03-25 KR KR1019970706987A patent/KR19980703582A/en not_active Withdrawn
- 1996-03-25 CA CA002217360A patent/CA2217360A1/en not_active Abandoned
- 1996-04-03 AR ARP960102037A patent/AR002981A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0443027A1 (en) * | 1988-11-11 | 1991-08-28 | Kurita Water Industries Ltd. | Drug composition |
| EP0609042A1 (en) * | 1993-01-25 | 1994-08-03 | Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation) | Drug composition and process for preparing the same |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002058668A3 (en) * | 2000-12-21 | 2002-12-27 | Alcon Inc | Artificial tear composition adapted to be used with contact lenses |
| WO2013043832A1 (en) * | 2011-09-22 | 2013-03-28 | Theo Holdings, Llc | Hypertonic dextran solution and methods of treating and preventing recurrent corneal erosion |
| US9351991B2 (en) | 2011-09-22 | 2016-05-31 | Theo Holdings, Llc | Hypertonic dextran solution and methods of treating and preventing recurrent corneal erosion |
| US9351990B2 (en) | 2011-09-22 | 2016-05-31 | Theo Holdings, Llc | Hypertonic dextran solution and methods of treating and preventing recurrent corneal erosion |
| US9636355B2 (en) | 2011-09-22 | 2017-05-02 | Theo Holdings, Llc | Hypertonic dextran solution and methods of treating and preventing recurrent corneal erosion |
| RU2688935C2 (en) * | 2014-05-07 | 2019-05-23 | Крома-Фарма Гезелльшафт М.Б.Х. | Aqueous ophthalmic solution and method of treating dry eye syndrome |
| WO2017082771A1 (en) * | 2015-11-10 | 2017-05-18 | Общество с ограниченной ответственностью "ДИАМЕД-фарма" | Pharmaceutical preparation for treating arthrological diseases |
| CN114159398A (en) * | 2021-03-22 | 2022-03-11 | 南京艾德加生物制药科技有限公司 | Procaterol hydrochloride oral solid composition and preparation method thereof |
| CN114159398B (en) * | 2021-03-22 | 2023-05-23 | 南京艾德加生物制药科技有限公司 | Procaterol hydrochloride oral solid composition and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR19980703582A (en) | 1998-11-05 |
| MX9707695A (en) | 1997-12-31 |
| EP0820274A1 (en) | 1998-01-28 |
| AR002981A1 (en) | 1998-05-27 |
| AU5015296A (en) | 1996-10-23 |
| CA2217360A1 (en) | 1996-10-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2002310461B2 (en) | Olopatadine formulations for topical administation | |
| RU2106138C1 (en) | Improved lyophilized and phosphamide compositions | |
| US5460834A (en) | Combinations of polymers for use in physiological tear compositions | |
| ZA200509440B (en) | Ophthalmic compositions containing a synergistic combination of two polymers | |
| AU2002310461A1 (en) | Olopatadine formulations for topical administation | |
| CA2726616A1 (en) | Pharmaceutical compositions containing a fluoroquinolone antibiotic drug | |
| WO1996031195A1 (en) | Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation | |
| CN1186019C (en) | Method to increase retinal blood flow | |
| HUP0204520A2 (en) | Pharmaceutical composition containing esmolol and process for its preparation | |
| KR100307846B1 (en) | Polymer Compositions Used in Physiological Tear Compositions | |
| EP1825855A1 (en) | Product containing prostaglandin having fluorine atom in molecule | |
| MXPA06007208A (en) | Pharmaceutical composition of vinflunine which is intended for parenteral administration preparation method thereof and use of same. | |
| JPH08333257A (en) | Product holding pharmaceutical preparation of procaterol hydrochloride aqueous solution and pharmaceutical preparation of aqueous solution of procaterol hydrochloride | |
| CA1111348A (en) | Solution containing a hydrogenated ergopeptide alkaloid | |
| KR100760326B1 (en) | Parenteral formulations comprising carbamasepine or derivatives thereof | |
| US20220000776A1 (en) | Parenteral dosage form of amiodarone | |
| DK175270B1 (en) | Pharmaceutical Composition for Ophthalmic Use About a Water-Soluble Acid Addition Salt of ibopamine | |
| CA2293008A1 (en) | Premixed alatrofloxacin injectable compositions | |
| JP2002528230A (en) | Plastic container containing stabilized drug preparation | |
| WO2004112778A1 (en) | Cisplatin preparation and process for producing the same | |
| IE44167B1 (en) | Ophthalmic compositions | |
| FI111334B (en) | Eye drop formulation contg. pilocarpine - and further agent for treating ocular hypertension, having regulated PH and viscosity | |
| WO2025015011A1 (en) | Bupivacaine compositions and methods | |
| WO2024008293A1 (en) | Injectable phenylephrine compositions | |
| WO2007069070A2 (en) | Aseptically filled multidose injectable dosage forms of granisetron |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase |
Ref document number: 96193067.5 Country of ref document: CN |
|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA CN KR MX US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 1996906940 Country of ref document: EP |
|
| ENP | Entry into the national phase |
Ref document number: 2217360 Country of ref document: CA Ref document number: 2217360 Country of ref document: CA Kind code of ref document: A |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1019970706987 Country of ref document: KR |
|
| WWE | Wipo information: entry into national phase |
Ref document number: PA/a/1997/007695 Country of ref document: MX |
|
| ENP | Entry into the national phase |
Ref document number: 1998 930496 Country of ref document: US Date of ref document: 19980102 Kind code of ref document: A |
|
| WWP | Wipo information: published in national office |
Ref document number: 1996906940 Country of ref document: EP |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 1996906940 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: 1019970706987 Country of ref document: KR |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 1019970706987 Country of ref document: KR |