CN106456534A - 液体药物组合物 - Google Patents
液体药物组合物 Download PDFInfo
- Publication number
- CN106456534A CN106456534A CN201480078319.4A CN201480078319A CN106456534A CN 106456534 A CN106456534 A CN 106456534A CN 201480078319 A CN201480078319 A CN 201480078319A CN 106456534 A CN106456534 A CN 106456534A
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- liquid composition
- pharmaceutical liquid
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- sodium
- acid
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- 239000007788 liquid Substances 0.000 title claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 title abstract 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 57
- GOZDTZWAMGHLDY-UHFFFAOYSA-L sodium picosulfate Chemical compound [Na+].[Na+].C1=CC(OS(=O)(=O)[O-])=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OS([O-])(=O)=O)C=C1 GOZDTZWAMGHLDY-UHFFFAOYSA-L 0.000 claims abstract description 23
- 239000000395 magnesium oxide Substances 0.000 claims abstract description 21
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims abstract description 21
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims abstract description 21
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 17
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000001630 malic acid Substances 0.000 claims abstract description 16
- 235000011090 malic acid Nutrition 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims description 60
- 229960005077 sodium picosulfate Drugs 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 235000003599 food sweetener Nutrition 0.000 claims description 7
- 239000003205 fragrance Substances 0.000 claims description 7
- 239000003002 pH adjusting agent Substances 0.000 claims description 7
- 239000003765 sweetening agent Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- 210000001072 colon Anatomy 0.000 claims description 5
- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 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 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims 1
- 235000013399 edible fruits Nutrition 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 229960000869 magnesium oxide Drugs 0.000 description 17
- 239000003814 drug Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 14
- 229940099690 malic acid Drugs 0.000 description 13
- 238000000034 method Methods 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000012530 fluid Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- -1 hydrogen Potassium oxide Chemical class 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 235000011083 sodium citrates Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- LTTKIXMKQRJPFP-UHFFFAOYSA-N S(=O)(=O)(O)O.C1(=CC=CC=C1)[Na] Chemical compound S(=O)(=O)(O)O.C1(=CC=CC=C1)[Na] LTTKIXMKQRJPFP-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000004376 Sucralose Substances 0.000 description 2
- 235000010358 acesulfame potassium Nutrition 0.000 description 2
- 229960004998 acesulfame potassium Drugs 0.000 description 2
- 239000000619 acesulfame-K Substances 0.000 description 2
- 238000002052 colonoscopy Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000004337 magnesium citrate Substances 0.000 description 2
- 229960005336 magnesium citrate Drugs 0.000 description 2
- 235000002538 magnesium citrate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 235000019408 sucralose Nutrition 0.000 description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 2
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 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
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229960005164 acesulfame Drugs 0.000 description 1
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940057277 disodium edetate hydrate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/08—Oxides; Hydroxides
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
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- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
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- Health & Medical Sciences (AREA)
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了包含匹可硫酸钠、氧化镁、柠檬酸和苹果酸的物理和化学稳定的药物液体组合物。
Description
技术领域
本发明涉及药物液体组合物，并且更具体涉及包含匹可硫酸钠(sodiumpicosulfate)、氧化镁、柠檬酸和苹果酸的物理和化学稳定的药物液体组合物。
背景技术
包含柠檬酸、氧化镁和匹可硫酸钠的药物在外科手术、结肠镜检查或结肠X射线检查时用作用于预处理的泻药，并且目前可以以Picolight粉的名称商购获得。这种药物是当口服时通过溶解在水中使用的白色粉末。
粉末剂型的药物应当通过将一个包装溶解在适量的水中而服用。然而，当将药物溶解在水中时，一些患者会觉得不方便，并且一些不能识别如何恰当使用的患者可能会在将粉末放入口中之后喝水。在这种情况下，当粉末溶解在水中时发生的放热反应可能会烧伤病人的嘴。
因此，可以将粉末形式的药物事先溶解在水中并且在服用之前储存在冰箱或另一种储存空间中。然而，在这种情况下，作为主要成分的柠檬酸和氧化镁可能会彼此反应而成为柠檬酸镁，并且在反应之后剩余的氧化镁可能会加速柠檬酸镁随时间的沉淀而下沉至底部。因此，如果当服用时未用水将药物充分稀释，则不能获得适当的效果，因为沉淀的量不能被服用。由于将药物的pH保持得低，所以沉淀的量倾向于被减少。然而，在这种情况下，出现了使得匹可硫酸钠变得不稳定的问题。
因此，为了解决上述问题，对于物理和化学稳定的药物液体组合物存在需求。
发明内容
[技术问题]
鉴于上述，本发明提供了包含匹可硫酸钠、氧化镁和柠檬酸的物理和化学稳定的药物液体组合物。
然而，本发明的目的不限于在本文中所给出的。通过参考以下给出的本发明的详细描述，本发明的以上和其他目的对本发明所属领域的普通技术人员来说将会变得明显。
[技术方案]
根据本发明的一个方面，提供了一种包含匹可硫酸钠、氧化镁、柠檬酸和苹果酸的药物液体组合物。
所述药物液体组合物可以在外科手术、结肠镜检查或结肠X射线检查时作为用于预处理的泻药而用于结肠清洁。
液体组合物的一次剂量(one-time dose)可以根据有效成分的含量而不同，但作为非限制性实例，可以在50ml至500ml的范围内。在一个示例性实施方案中，其可以在100ml至300ml的范围内或者可以在150ml至200ml的范围内，但是其不限于此。
为了消除当通过将粉末溶解在水中来服用粉末形式的药物时的不便，意图将剂型由粉末改变为液体。然而，本发明提供了在储存时是物理和化学稳定的药物液体组合物。
作为一个实例，在所述药物液体组合物中，在24个月内(或长达24个月的时间)，每种成分的含量变化相对于每种成分的重量可以在±5.0重量％内，并且可以产生2.0重量％以下的匹可硫酸钠的杂质A(4-[(吡啶-2-基)(4-羟基苯基)甲基]苯基硫酸钠)。此外，可以不发生沉淀，或者可以以5.0体积％以下发生沉淀。
根据本发明的发明人的实验，在使用除苹果酸外的有机酸或无机酸的情况下，难以预期如上所述的稳定性。所述苹果酸可以包括l-苹果酸和d-苹果酸二者。
为了具有上述稳定性，在一个优选的实例中，药物液体制剂的pH可以在4.1至5.4的范围内。
根据本发明的发明人的实验，已经确认在该pH范围内表现出优异的稳定性。如果药物液体组合物的pH小于4.1，则匹可硫酸钠的杂质A增加，并且其不是优选的，因为当服用药物时患者会感觉不舒服连同强烈的酸味。另一方面，如果药物液体组合物的pH大于5.4，则其不是优选的，因为难以溶解氧化镁，这导致沉淀。
本发明的药物液体组合物可以包含各种各样的赋形剂和净化水。使用净化水以制备液体形式的药物，并且赋形剂可以用于非常好的味道从而增加服药依从性以及药物液体组合物的稳定性。
例如，赋形剂可以包括，但不限于，pH调节剂、稳定剂、防腐剂、增甜剂和香料成分(fragrance ingredient)。
pH调节剂可以是碱化剂(alkalizing agent)。在碱化剂的情况下，可以调节由于苹果酸所致的pH的降低。
作为碱化剂，例如，可以使用氢氧化钠、氢氧化钾、碳酸氢钠、氨溶液、柠檬酸钾、三乙醇胺和柠檬酸钠等，但是其不限于此。在一个示例性实施方案中，可以使用氢氧化钠、氢氧化钾、柠檬酸钠等，但是其不限于此。
匹可硫酸钠、氧化镁、柠檬酸和苹果酸可以具有0.003～0.009∶1～3∶3.5～10.5∶0.01～13(匹可硫酸钠∶氧化镁∶柠檬酸∶苹果酸)的重量比。
以下将描述制备本发明的药物液体组合物的一种示例性方法。
所述方法可以包括下列步骤：称重柠檬酸和氧化镁以制备混合物，将苹果酸和pH调节剂与所制备的混合物混合，将匹可硫酸钠与该混合物混合，和将净化水加入至混合物中。
所述称重还可以包括称重并且单独制备(准备，prepare)要使用的成分中的每一个的步骤。
在一个实例中，在加入净化水之前，可以将增甜剂、香料成分或它们的混合物加入至混合物或灭菌的混合物中。增甜剂和/或香料成分可以用于非常好的味道从而增加服药依从性。
[有益效果]
本发明的实施方案至少提供以下效果。
通过提供包含匹可硫酸钠、氧化镁、柠檬酸和苹果酸的药物液体组合物，可以增加服药依从性和便利性以及储存和运输的容易性。
本发明的效果不限于上述效果，并且根据以下描述，未在本文中描述的其他效果对本领域技术人员来说将会变得明显。
附图说明
图1是图示制造根据本发明的一个实施方案的药物液体组合物的方法的工艺流程图。
具体实施方式
尽管本发明可以各种各样地变化并且包括多个实施方案，但在详细描述中将详细地描述附图中所示的具体实施方案。然而，应该理解的是，本发明不限于该具体实施方案，并且在不背离本发明的范围和精神的情况下，可以做出各种变化、等同替换和替代。
<实施方案1>
通过在重量比为75的净化水中溶解重量比为0.005∶1.75∶6∶4.19的匹可硫酸钠∶氧化镁∶柠檬酸∶dl-苹果酸、重量比为0.043的作为防腐剂的苯甲酸钠，重量比为0.035的作为稳定剂的乙二胺四乙酸二钠水合物、重量比为2.1的作为pH调节剂的氢氧化钠、重量比为0.1的丁磺氨钾(acesulfame postassium)和重量比为0.1的作为增甜剂的三氯半乳蔗糖(sucralose)以及重量比为0.043的橙子味道的香料成分来制备药物液体组合物。
<比较例1>
通过包含重量比为0.005∶1.75∶6∶4.19的匹可硫酸钠∶氧化镁∶柠檬酸、重量比为0.21的作为赋形剂的碳酸氢钠、作为增甜剂的丁磺氨钾qs(适量(quantum satis))和具有橙子味道的香料成分qs(适量)来制备粉末组合物。
<实验例1>
对作为通过将实施方案1的液体组合物溶解在150ml水中获得的溶液的主要组分的匹可硫酸钠、氧化镁和柠檬酸的含量与通过将比较例1的粉末组合物溶解在150ml水中获得的溶液的那些含量进行比较。含量比较方法是根据英国药典2004用于口服溶液的化合物匹可硫酸钠粉末(British Pharmacopoeia 2004 Compound sodium Picosulfate Powderfor Oral Soluion)的实验方法并且通过高效液相色谱法进行测量。结果在以下表1中示出。
[表1]
作为实验的结果，可以从表1中看到，在实施方案1和比较例1的主要组分的含量之间没有显著(或实质性，subtantial)差异。因此，认为该粉末组合物和液体组合物二者作为结肠清洁剂具有相同的效果。
<实验例2>
通过在重量比为75的净化水中溶解重量比为0.005∶1.75∶6∶4.19的匹可硫酸钠∶氧化镁∶柠檬酸并且相对于总液体重量以5.0重量％加入作为增溶剂的聚氧乙烯氢化蓖麻油、聚乙烯脱水山梨糖醇单油酸酯、聚氧乙烯辛基十二烷基醚、聚山梨醇酯20、聚山梨醇酯60和聚山梨醇酯80中的每一种来制备液体组合物。将该液体组合物在室温条件(25℃、60％)下留置以检查是否发生沉淀，并且测量在样品容器的底部上以5.0体积％发生沉淀时的时间点(天数)。结果在以下表2中示出。
[表2]
| 原料名称 | 室温条件(当沉淀发生时：天数) |
| 聚氧乙烯氢化蓖麻油 | 20 |
| 聚乙烯脱水山梨糖醇单油酸酯 | 17 |
| 聚氧乙烯辛基十二烷基醚 | 17 |
| 聚山梨醇酯20 | 23 |
| 聚山梨醇酯60 | 22 |
| 聚山梨醇酯80 | 20 |
如可以在表2中看到的，可以确认，作为应用增溶剂的结果形成了5.0体积％以上的沉淀，并且该增溶剂并不有助于防止沉淀。
<实验例3>
液体组合物通过以下方式制备：在重量比为75的净化水中溶解重量比为0.005∶1.75∶6∶4.19的匹可硫酸钠∶氧化镁∶柠檬酸，作为有机酸使用重量比为4.19的柠檬酸、dl-苹果酸、马来酸、酒石酸盐、富马酸、乳酸、柠檬酸钠、天冬氨酸、琥珀酸、谷氨酸、盐酸、磷酸、硫酸和乙酸中的每一种，并且作为pH调节剂，对于每个pH加入重量比为2.1的氢氧化钠。将该液体组合物在室温条件(25℃、60％)下留置24个月以检查是否发生沉淀。测量在样品的容器底部上以5.0体积％发生沉淀时的时间点(天数)并且在以下表3中示出。测量在24个月之后产生的匹可硫酸钠的杂质的含量并且在以下表4中示出。
[表3]
如可以在表3中看到的，可以确认在除苹果酸外的有机酸的所有情况中均在24个月内发生沉淀。
[表4]杂质(在24个月之后)
如可以在表4中看到的，确认了在包含苹果酸的情况下，在上述pH范围内产生了2.0重量％以下的匹可硫酸钠的杂质A(4-[(吡啶-2-基)(4-羟基苯基)甲基]苯基硫酸钠)。
在下文中，将参照附图描述本发明的实施方案。
图1是举例说明制备根据本发明的一个实施方案的药物液体组合物的方法的工艺流程图。
制备药物液体组合物的方法可以包括下列步骤：称重柠檬酸和氧化镁以制备混合物(S110)，将苹果酸和氢氧化钠与在步骤S110中制备的混合物混合(S120)，将匹可硫酸钠与在步骤S120中制备的混合物混合(S130)，和将净化水加入至在步骤S130中的混合物(S140)。
在步骤S110中，可以将pH调节剂、稳定剂、增甜剂等加入至混合物中。
在一些情况下，步骤S110和步骤S120可以同时进行，并且步骤S110、S120和S130可以同时进行。此外，尽管已经以所提及的顺序举例说明了步骤S110、S120和S130，但顺序不限于此。
尽管已经出于举例说明的目的公开了本发明的实施方案，但本领域技术人员将会理解，在不背离如在所附权利要求中公开的本发明的范围和精神的情况下，各种修改、增加和替换是可能的。
Claims (10)
1.一种药物液体组合物，其是物理和化学稳定的，所述药物液体组合物包含匹可硫酸钠、氧化镁、柠檬酸和苹果酸。
2.根据权利要求1所述的药物液体组合物，其中所述药物液体组合物用于结肠清洁。
3.根据权利要求1所述的药物液体组合物，其中所述药物液体组合物的一次剂量在50ml至500ml的范围内。
4.根据权利要求1所述的药物液体组合物，其中所述药物液体组合物的pH在4.1至5.4的范围内。
5.根据权利要求1所述的药物液体组合物，其中所述药物液体组合物包含赋形剂和净化水。
6.根据权利要求5所述的药物液体组合物，其中所述赋形剂是选自由下列各项组成的组中的至少一种：pH调节剂、稳定剂、防腐剂、增甜剂和香料成分。
7.根据权利要求6所述的药物液体组合物，其中所述pH调节剂是碱化剂。
8.根据权利要求7所述的药物液体组合物，其中所述碱化剂是选自由下列各项组成的组中的至少一种：氢氧化钠、氢氧化钾、碳酸氢钠、氨溶液、柠檬酸钾、三乙醇胺和柠檬酸钠。
9.根据权利要求1所述的药物液体组合物，其中所述匹可硫酸钠、氧化镁、柠檬酸和苹果酸具有的重量比为0.003～0.009∶1～3∶3.5～10.5∶0.01～13(匹可硫酸钠：氧化镁：柠檬酸：苹果酸)。
10.根据权利要求1所述的药物液体组合物，其中所述物理和化学稳定性是指在24个月内，产生的杂质为2.0重量％以下并且不发生沉淀或沉淀以5.0体积％以下发生。
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| JP2019507121A (ja) * | 2016-01-28 | 2019-03-14 | シーティーシー バイオ，インコーポレイテッド | 下剤組成物 |
| AR108992A1 (es) * | 2016-07-08 | 2018-10-17 | Ferring Bv | Formulaciones líquidas estabilizadas que contienen picosulfato |
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| US20200345708A1 (en) | 2020-11-05 |
| US10624879B2 (en) | 2020-04-21 |
| US11191753B2 (en) | 2021-12-07 |
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| CA2942878A1 (en) | 2015-09-24 |
| EP3120835A4 (en) | 2017-10-18 |
| EP3120835A1 (en) | 2017-01-25 |
| WO2015141897A1 (ko) | 2015-09-24 |
| JP2017508815A (ja) | 2017-03-30 |
| US9827231B2 (en) | 2017-11-28 |
| US20160324837A1 (en) | 2016-11-10 |
| AU2014386903B2 (en) | 2020-01-30 |
| US20220193052A1 (en) | 2022-06-23 |
| US20180235947A1 (en) | 2018-08-23 |
| MX366499B (es) | 2019-07-11 |
| RU2016138577A (ru) | 2018-04-20 |
| CA2942878C (en) | 2021-08-24 |
| AU2014386903A1 (en) | 2016-11-03 |
| RU2668882C2 (ru) | 2018-10-04 |
| KR101420315B1 (ko) | 2014-07-17 |
| ES2907324T3 (es) | 2022-04-22 |
| CN106456534B (zh) | 2019-05-14 |
| MX2016011938A (es) | 2017-05-30 |
| EP3120835B1 (en) | 2021-12-08 |
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