WO2002026237A1 - Liquid prednisolone sodium phosphate preparation - Google Patents
Liquid prednisolone sodium phosphate preparation Download PDFInfo
- Publication number
- WO2002026237A1 WO2002026237A1 PCT/JP2001/008304 JP0108304W WO0226237A1 WO 2002026237 A1 WO2002026237 A1 WO 2002026237A1 JP 0108304 W JP0108304 W JP 0108304W WO 0226237 A1 WO0226237 A1 WO 0226237A1
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- WO
- WIPO (PCT)
- Prior art keywords
- sodium phosphate
- liquid preparation
- phosphate
- prednisolone sodium
- liquid
- Prior art date
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- 229960002943 prednisolone sodium phosphate Drugs 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 239000007788 liquid Substances 0.000 title claims abstract description 36
- JDOZJEUDSLGTLU-VWUMJDOOSA-N prednisolone phosphate Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 JDOZJEUDSLGTLU-VWUMJDOOSA-N 0.000 title claims abstract 7
- -1 sodium phosphate compound Chemical class 0.000 claims abstract description 26
- 239000001488 sodium phosphate Substances 0.000 claims abstract description 11
- 229910000162 sodium phosphate Inorganic materials 0.000 claims abstract description 8
- 239000002738 chelating agent Substances 0.000 claims abstract description 7
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 11
- 229920000642 polymer Polymers 0.000 claims description 9
- 241000792859 Enema Species 0.000 claims description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 8
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 8
- 235000019800 disodium phosphate Nutrition 0.000 claims description 8
- 239000007920 enema Substances 0.000 claims description 8
- 229940095399 enema Drugs 0.000 claims description 8
- 235000011008 sodium phosphates Nutrition 0.000 claims description 8
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 7
- 239000012669 liquid formulation Substances 0.000 claims description 6
- 239000003755 preservative agent Substances 0.000 claims description 5
- 229940037001 sodium edetate Drugs 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- 230000000087 stabilizing effect Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 claims description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 2
- 235000019801 trisodium phosphate Nutrition 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 abstract description 6
- 229920002125 Sokalan® Polymers 0.000 abstract 1
- 230000002421 anti-septic effect Effects 0.000 abstract 1
- VJZLQIPZNBPASX-OJJGEMKLSA-L prednisolone sodium phosphate Chemical compound [Na+].[Na+].O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 VJZLQIPZNBPASX-OJJGEMKLSA-L 0.000 description 46
- 239000000243 solution Substances 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 6
- 229920000573 polyethylene Polymers 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 208000025865 Ulcer Diseases 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 206010009900 Colitis ulcerative Diseases 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 3
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 229960005205 prednisolone Drugs 0.000 description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 206010002091 Anaesthesia Diseases 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 229920001328 Polyvinylidene chloride 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
- 229920000122 acrylonitrile butadiene styrene Polymers 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- IMBXRZKCLVBLBH-OGYJWPHRSA-N cvp protocol Chemical compound ClCCN(CCCl)P1(=O)NCCCO1.O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1.C([C@H](C[C@]1(C(=O)OC)C=2C(=C3C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)=CC=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 IMBXRZKCLVBLBH-OGYJWPHRSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000003750 lower gastrointestinal tract Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000000689 upper leg Anatomy 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Definitions
- the present invention relates to a liquid preparation containing prednisolone sodium phosphate. More specifically, the present invention relates to a liquid preparation containing prednisolone sodium phosphate and a carboxybutyl polymer as a stabilizer, wherein the stability of prednisolone sodium phosphate is improved.
- Prednisolone a synthetic corticosteroid, is used as the most effective drug for the treatment of active ulcerative colitis and is usually administered locally to the affected lower GI tract as an enema. Since prednisolone is hardly soluble in water, prednisolone sodium phosphate, which is obtained by esterifying prednisolone with phosphoric acid and converting the obtained phosphate ester to sodium salt, is used. Usually, this is dissolved in water or the like and diluted and administered.
- sodium prednisolone phosphate is very unstable because ester hydrolysis tends to occur in a low concentration aqueous solution. For this reason, it is necessary to dissolve it immediately before use, and there is a problem that the preparation takes time.
- Japanese Patent Laying-Open No. 4-244016 discloses that as one means for solving the above-mentioned problem, a base solution containing prednisolone sodium phosphate and a diluent thereof are separately isolated in one container. It discloses an enema formulation that is contained and mixed at the point of use. However, since this enema preparation mixes the two solutions at the time of use, there may be a problem in the uniformity of the mixed solution, and it is not advantageous in terms of convenience and economy. No. In addition, Japanese Patent Application Laid-Open No. 4-244016 does not mention anything about the stability of prednisolone sodium phosphate aqueous solution.
- An object of the present invention is to provide a liquid preparation containing prednisolone sodium phosphate excellent in storage stability and a method for stabilizing the preparation.
- the inventor of the present invention has found that by adding a propyloxyvir polymer (abbreviation: CVP) as a stabilizer to prednisolone sodium phosphate, the decomposition of prednisolone sodium phosphate is suppressed, and an extremely stable liquid preparation can be obtained.
- CVP propyloxyvir polymer
- the present invention relates to a liquid formulation containing prednisolone sodium phosphate and a lipoxyvul polymer as stabilizer.
- the liquid preparation containing prednisolone sodium phosphate of the present invention is used for treatment of active ulcerative colitis, it is directly administered to the site of inflammation as an enema.
- the preparation is very preferable as an enema because it is made viscous by the addition of carboxybutyl polymer.
- the stabilizing effect of carboxybutyl polymer (CVP) on prednisolone sodium phosphate is based on the fact that the prednisolone sodium phosphate molecule is trapped in the network structure in the gel by CVP, and as a result, This is probably because the molecular motion is suppressed and the decomposition reaction is reduced.
- the concentration of prednisolone sodium phosphate as the main agent is usually in the range of 0.001 to 1.Ow / v%, preferably in the range of 0.01 to 0.2 w / v%. is there.
- Solvents used for dissolving or diluting prednisolone sodium phosphate include sterilized purified water and physiological saline, and preferably, distilled water for injection.
- the amount of CVP added in the liquid preparation of the present invention is usually in the range of 0.001 to 5.
- Ow / v ° / 0 preferably 0.01 to: L.
- Ow / v% based on the total amount of the preparation. It is.
- prednisolone sodium phosphate is stabilized by adding additives such as preservatives, pH adjusters, sodium phosphates and chelating agents to the liquid preparation containing prednisolone sodium phosphate in addition to CVP. 1 ⁇ Life can be further improved. Therefore, the present invention further provides a preservative, a pH adjuster, and sodium phosphate.
- the present invention relates to a liquid formulation containing prednisolone sodium phosphate containing at least one member selected from the group consisting of chelating agents.
- preservatives examples include paraoxybenzoic acid esters such as methyl paraoxybenzoate, paraethyl benzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl parahydroxybenzoate and isoptyl paraoxybenzoate.
- paraoxybenzoic acid esters such as methyl paraoxybenzoate, paraethyl benzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl parahydroxybenzoate and isoptyl paraoxybenzoate.
- ethyl para-hydroxybenzoate and butyl para-oxybenzoate preferred are ethyl para-hydroxybenzoate and butyl para-oxybenzoate.
- the amount of the paraoxybenzoic acid ester to be added is in the range of 0.001 to 1.0 Ow / v% with respect to the liquid preparation, preferably 0.0005 to 0.1 lw /. v%.
- the pH of the liquid formulation must be adjusted with a pH adjuster.
- the prednisolone sodium phosphate solution is adjusted to a pH in the range of 6 to 10, preferably pH 7 to 9.
- pH adjusters include hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
- sodium phosphate salts and the like which can be added to the liquid preparation of the present invention include, for example, trisodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate and the like. However, it is preferably sodium hydrogen phosphate.
- the amount of sodium phosphate added is in the range of 0.01 to 1.0 w / v% based on the liquid preparation.
- chelating agents examples include sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, preferably sodium edetate.
- the added amount of the chelating agent is 0.001 to 1.0 w / v% based on the liquid preparation.
- the stability of prednisolone sodium phosphate in the liquid formulation over a wide temperature range can be further improved by combining CVP and one or more of the above-mentioned additives.
- liquid preparation of prednisolone sodium phosphate of the present invention When used as an enema, it can be filled in a commonly used container, for example, a plastic container or a glass container.
- a plastic container or a glass container Polyethylene, PVC, etc. Benzyl, polyvinylidene chloride, ABS resin, polystyrene, polycarbonate, polyester, polyurethane, silicone, polypropylene and the like, but polyethylene is preferred.
- Prednisolone sodium phosphate and carboxybutyl polymer (CVP) were dissolved in sterile purified water to give final concentrations of 0.02 w / v% and 0.025 w / v%, respectively. Then, the pH was adjusted to 7 to 8 by neutralization to prepare a liquid preparation containing prednisolone sodium phosphate.
- prednisolone sodium phosphate diluted with sterilized purified water so as to have a drug solution concentration of about 0.02 w / v% was used.
- the obtained solution was stored at a temperature of 25 ° C, 40 ° C, or 60 ° C for one month or three months. After storage, prednisolone sodium phosphate was measured by high performance liquid chromatography, and the residual ratio was calculated with the amount of prednisolone sodium phosphate immediately after preparation as 100%. The results obtained are shown in Table 1 below.
- the obtained solution was used as a basic formulation. To this was added sodium hydrogen phosphate or sodium edetate, and the solution was filled into a 1 OmL polyethylene container (Nunc Misorp TM tube). The obtained liquid was stored at 25 ° C. (at a temperature of 40 ° C. for 1 month or 6 months. After storage, the prednisolone sodium phosphate residual ratio in the container was determined in the same manner as in Example 1 (%). Was measured by the high performance liquid chromatography method, and the results are shown in Table 2.
- Preduzolone sodium phosphate and CVP were added to sterilized purified water to give final concentrations of 0.033 w / v% and 0.1 w / v%, respectively, and the pH was adjusted to 8 with sodium hydroxide.
- the obtained solution was used as a basic formulation.
- a mixture of ethyl ethyl paraoxybenzoate and butyl ethyl paraoxybenzoate was added thereto, and the resulting solution was filled into a 1 OmL polyethylene container (Nunc Mini Soap TM tube).
- the obtained solution was stored at a temperature of 25 ° C. and 40 ° C., and the residual ratio (%) of prednisolone sodium phosphate in the container was measured by a high-performance liquid chromatography in the same manner as in Example 1.
- Table 3 shows the results. Table 3
- Prednisolone sodium phosphate (0.037 w / v o / o ), CVP (0.08 w / v%), sodium hydrogen phosphate (0.05 w / v%), ethyl ethyl paraoxybenzoate (0.006 w / v%) and butyl para-hydroxybenzoate (0.00067 w / v%) was adjusted to H8 by adding sodium hydroxide.
- This solution was filled in a polyethylene container.
- the obtained liquid preparation was stored at a temperature of 25 ° C. and 40 ° C., and the residual ratio (%) of prednisolone sodium phosphate in the container was determined by the high-speed liquid mouth matodaraf method as in Example 1. Was measured by Table 4 shows the results.
- Table 4 Table 4
- prednisolone sodium phosphate Using a commercially available injection solution of prednisolone sodium phosphate, the drug concentration was 0.03 7 It was diluted with physiological saline and distilled water so as to be w / v%. The dilutions of these commercially available injections were filled in polyethylene containers. The container was stored at 25 ° C and 40 ° C for a fixed period of time. The residual ratio of prednisolone sodium phosphate in the container was measured by high performance liquid chromatography, and the experimental results were stored in each condition under the condition that the main drug content immediately after preparation was 100% and stored. Table 5
- Negative control solution solution prepared in the same manner as in Example 4 except that prednisolone sodium phosphate was not added
- Positive control solution solution containing sodium prednisolone phosphate 0.037 w / v o / o in physiological saline
- Example 4 12.9 + 4.5 From Table 6, the liquid preparation of Example 4 showed the same efficacy as the positive control. From these results, it was confirmed that the addition of CVP, sodium phosphate and ester of paraoxybenzoate did not affect the efficacy of prednisolone sodium phosphate. Industrial applicability
- liquid preparation containing prednisolone sodium phosphate excellent in storage stability is provided.
- the liquid preparation of the present invention is very useful because the storage stability of predazolone sodium phosphate, particularly at low concentrations used in clinical practice, is significantly improved. Further, the liquid preparation of the present invention comprises a carboxybutyl polymer
- (CVP) imparts a viscous property to the liquid preparation, and is therefore extremely preferable as an enema for treating active ulcerative colitis.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
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- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A liquid prednisolone sodium phosphate preparation. It is characterized by containing prednisolone sodium phosphate and a carboxyvinyl polymer as a stabilizer with which the prednisolone sodium phosphate is stabilized. The liquid preparation further contains at least one member selected from the group consisting of a pH regulator, sodium phosphate compound, chelating agent, and antiseptic. It has excellent storage stability and is hence extremely useful.
Description
明 細 書 Specification
リン酸プレドニゾロンナトリゥム液体製剤 技術分野 Prednisolone sodium phosphate liquid formulation
本発明は、 リン酸プレドニゾロンナトリウム含有液体製剤に関する。 より詳細 には、 リン酸プレドニゾロンナトリゥムおよび安定化剤としてカルボキシビュル ポリマーを含有する、 リン酸プレドニゾロンナトリゥムの安定 1"生が改善された液 体製剤に関する。 背景技術 The present invention relates to a liquid preparation containing prednisolone sodium phosphate. More specifically, the present invention relates to a liquid preparation containing prednisolone sodium phosphate and a carboxybutyl polymer as a stabilizer, wherein the stability of prednisolone sodium phosphate is improved.
合成副腎皮質ホルモンであるプレドニゾロンは活動性潰瘍性大腸炎の治療に最 も有効な薬剤として用いられ、 通常は患部である下部消化管に注腸剤として局部 投与される。 プレドニゾロンは水に溶け難いため、 プレドニゾロンをリン酸でェ ステル化し、 得られたリン酸エステルをナトリゥム塩に転換したリン酸プレドニ ゾロンナトリウムが用いられている。 通常、 これを水などに溶解'希釈して投与 して ヽる。 Prednisolone, a synthetic corticosteroid, is used as the most effective drug for the treatment of active ulcerative colitis and is usually administered locally to the affected lower GI tract as an enema. Since prednisolone is hardly soluble in water, prednisolone sodium phosphate, which is obtained by esterifying prednisolone with phosphoric acid and converting the obtained phosphate ester to sodium salt, is used. Usually, this is dissolved in water or the like and diluted and administered.
しかしながら、 リン酸プレドニゾロンナトリゥムは、 低濃度の水溶液ではエス テルの加水分解が起こり易く、 極めて不安定である。 このため、 使用直前に溶解 する必要があり、 調剤に手間がかかるという問題がある。 However, sodium prednisolone phosphate is very unstable because ester hydrolysis tends to occur in a low concentration aqueous solution. For this reason, it is necessary to dissolve it immediately before use, and there is a problem that the preparation takes time.
特開平 4— 2 4 4 0 1 6号公報は、 前記問題を解決する一つの手段として、 リ ン酸プレドニゾロンナトリゥムを含む基剤液とその希釈液を一つの容器に別々に 隔離して収容し、 使用時に混合する注腸製剤を開示している。 しかしながら、 こ の注腸製剤は使用時に二液を混合するために、 その混合溶液の均一性において問 題が生じる可能性があり、 そして利便性、 経済性の面から有利なものとはいえな い。 また、 特開平 4— 2 4 4 0 1 6号公報は、 リン酸プレドニゾロンナトリウム 水溶液の安定ィ匕について何ら言及していない。 Japanese Patent Laying-Open No. 4-244016 discloses that as one means for solving the above-mentioned problem, a base solution containing prednisolone sodium phosphate and a diluent thereof are separately isolated in one container. It discloses an enema formulation that is contained and mixed at the point of use. However, since this enema preparation mixes the two solutions at the time of use, there may be a problem in the uniformity of the mixed solution, and it is not advantageous in terms of convenience and economy. No. In addition, Japanese Patent Application Laid-Open No. 4-244016 does not mention anything about the stability of prednisolone sodium phosphate aqueous solution.
このため、 使用時にリン酸プレドニゾロンナトリゥムを溶解または混合する必 要がなく、 その保存安定性が改善されたリン酸プレドニゾロンナトリゥム含有液
体製剤の開発が求められている。 発明の開示 Therefore, it is not necessary to dissolve or mix prednisolone sodium phosphate at the time of use, and a solution containing prednisolone sodium phosphate with improved storage stability is used. There is a need for the development of body preparations. Disclosure of the invention
本発明の課題は、 保存安定性に優れたリン酸プレドニゾロンナトリゥム含有液 体製剤およぴ当該製剤の安定化方法を提供することである。 An object of the present invention is to provide a liquid preparation containing prednisolone sodium phosphate excellent in storage stability and a method for stabilizing the preparation.
本発明者は、 リン酸プレドニゾロンナトリゥムに安定化剤として力ルポキシビ -ルポリマー （略称： CVP) を添加することにより、 リン酸プレドュゾロンナ トリゥムの分解が抑制され、 極めて安定な液体製剤が得られることを見出した。 従って、 本発明は、 リン酸プレドニゾロンナトリウムおよび安定化剤として力 ルポキシビュルポリマーを含有する液体製剤に関する。 本発明のリン酸プレドニ ゾロンナトリウム含有液体製剤は、 活動性潰瘍性大腸炎の治療に用いる場合、 注 腸剤として炎症部位に直接投与される。 当該製剤は、 カルボキシビュルポリマー の添加により粘稠性が付与されるため、 注腸剤として極めて好ましいものである。 本発明において、 リン酸プレドニゾロンナトリゥムに対するカルボキシビュル ポリマ一 （C VP) の安定化作用は、 C VPによるゲル中の網目構造にリン酸プ レドニゾロンナトリゥム分子が捕捉され、 結果として分子運動が抑制されて分解 反応が低下することがーつの理由と考えられる。 The inventor of the present invention has found that by adding a propyloxyvir polymer (abbreviation: CVP) as a stabilizer to prednisolone sodium phosphate, the decomposition of prednisolone sodium phosphate is suppressed, and an extremely stable liquid preparation can be obtained. Was found. Accordingly, the present invention relates to a liquid formulation containing prednisolone sodium phosphate and a lipoxyvul polymer as stabilizer. When the liquid preparation containing prednisolone sodium phosphate of the present invention is used for treatment of active ulcerative colitis, it is directly administered to the site of inflammation as an enema. The preparation is very preferable as an enema because it is made viscous by the addition of carboxybutyl polymer. In the present invention, the stabilizing effect of carboxybutyl polymer (CVP) on prednisolone sodium phosphate is based on the fact that the prednisolone sodium phosphate molecule is trapped in the network structure in the gel by CVP, and as a result, This is probably because the molecular motion is suppressed and the decomposition reaction is reduced.
本発明の液体製剤において、 主剤であるリン酸プレドニゾロンナトリゥムの濃 度は、 通常は 0.001〜1. Ow/v%の範囲であり、 好ましくは 0.01〜0. 2 w/v%の範囲である。 リン酸プレドニゾロンナトリゥムの溶解または希釈に使用さ れる溶媒としては、 滅菌精製水および生理食塩水が挙げられるが、 好ましくは注 射用蒸留水である。 In the liquid preparation of the present invention, the concentration of prednisolone sodium phosphate as the main agent is usually in the range of 0.001 to 1.Ow / v%, preferably in the range of 0.01 to 0.2 w / v%. is there. Solvents used for dissolving or diluting prednisolone sodium phosphate include sterilized purified water and physiological saline, and preferably, distilled water for injection.
本発明の液体製剤中の C VPの添加量は、 通常は製剤の全量に対して 0, 001 〜5. Ow/v°/0の範囲であり、 好ましくは 0.01〜： L. Ow/v%である。 The amount of CVP added in the liquid preparation of the present invention is usually in the range of 0.001 to 5. Ow / v ° / 0 , preferably 0.01 to: L. Ow / v% based on the total amount of the preparation. It is.
本発明において、 CVPに加えて防腐剤、 pH調整剤、 リン酸ナトリウム塩類 およびキレート剤等の添加剤をリン酸プレドニゾロンナトリゥム含有液体製剤に 添加することにより、 リン酸プレドニゾロンナトリゥムの安定 1·生をさらに改善す ることができる。 故に、 本発明は、 さらに防腐剤、 pH調整剤、 リン酸ナトリウ
ム塩類おょぴキレート剤からなる群から選択される 1種以上を含有するリン酸プ レドニゾロンナトリゥム含有液体製剤に関する。 In the present invention, prednisolone sodium phosphate is stabilized by adding additives such as preservatives, pH adjusters, sodium phosphates and chelating agents to the liquid preparation containing prednisolone sodium phosphate in addition to CVP. 1 ・ Life can be further improved. Therefore, the present invention further provides a preservative, a pH adjuster, and sodium phosphate. The present invention relates to a liquid formulation containing prednisolone sodium phosphate containing at least one member selected from the group consisting of chelating agents.
本発明において使用しうる防腐剤の例には、 パラォキシ安息香酸メチル、 パラ ォキシ安息香酸ェチル、 パラォキシ安息香酸プロピル、 パラォキシ安息香酸イソ プロピル、 パラォキシ安息香酸プチルおよびパラォキシ安息香酸イソプチルなど のパラォキシ安息香酸エステルが包含されるが、 好ましくはパラォキシ安息香酸 ェチルおよびパラォキシ安息香酸プチルである。 パラォキシ安息香酸エステル類 の添加量は、 該液体製剤に対して 0 . 0 0 0 1〜 1 . O w/v%の範囲であり、 好まし くは 0 . 0 0 0 5〜0. l w/v%である。 Examples of preservatives that can be used in the present invention include paraoxybenzoic acid esters such as methyl paraoxybenzoate, paraethyl benzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl parahydroxybenzoate and isoptyl paraoxybenzoate. However, preferred are ethyl para-hydroxybenzoate and butyl para-oxybenzoate. The amount of the paraoxybenzoic acid ester to be added is in the range of 0.001 to 1.0 Ow / v% with respect to the liquid preparation, preferably 0.0005 to 0.1 lw /. v%.
安定化剤として C V Pを使用する場合、 液体製剤の： p Hを pH調整剤により調 整する必要がある。 この場合、 リン酸プレドニゾロンナトリウム溶液を p H 6〜 1 0の範囲、 好ましくは p H 7〜9に調整する。 p H調整剤の例には、 塩酸、 ク ェン酸、 リン酸、 酢酸、 酒石酸、 水酸化ナトリウム、 炭酸ナトリウム、 炭酸水素 ナトリゥム等が包含される。 When using CVP as a stabilizer, the pH of the liquid formulation must be adjusted with a pH adjuster. In this case, the prednisolone sodium phosphate solution is adjusted to a pH in the range of 6 to 10, preferably pH 7 to 9. Examples of pH adjusters include hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
また、 本発明の液体製剤に添加しうるリン酸ナトリゥム塩類等には、 例えばリ ン酸三ナトリウム、 リン酸水素ナトリウム、 リン酸二水素ナトリウム、 リン酸二 水素ナトリゥム一水和物等が包含されるが、 好ましくはリン酸水素ナトリウムで ある。 リン酸ナトリウム塩類の添加量は該液体製剤に対して、 0 . 0 1〜1 . 0 w/v%の範囲である。 Further, sodium phosphate salts and the like which can be added to the liquid preparation of the present invention include, for example, trisodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate and the like. However, it is preferably sodium hydrogen phosphate. The amount of sodium phosphate added is in the range of 0.01 to 1.0 w / v% based on the liquid preparation.
使用しうるキレート剤の例には、 ェデト酸ナトリウム、 ェデト酸四ナトリウム、 ェデト酸四ナトリゥム四水塩が包含されるが、 好ましくはェデト酸ナトリゥムで ある。 キレート剤の添加量は該液体製剤に対して 0. 0 0 0 1〜 1 . O w/v%である。 リン酸プレドニゾロンナトリゥム液体製剤において、 C V Pと前記添加剤の 1 種以上を組み合わせることにより、 広範な温度範囲において液体製剤中のリン酸 プレドニゾロンナトリゥムの安定性をより改善することができる。 Examples of chelating agents that can be used include sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, preferably sodium edetate. The added amount of the chelating agent is 0.001 to 1.0 w / v% based on the liquid preparation. In liquid prednisolone sodium phosphate formulations, the stability of prednisolone sodium phosphate in the liquid formulation over a wide temperature range can be further improved by combining CVP and one or more of the above-mentioned additives.
本発明のリン酸プレドニゾロンナトリゥム液体製剤を注腸剤として使用する場 合、 通常使用されている容器、 例えばプラスチック容器またはガラス容器に充填 することができる。 プラスチック容器の素材として、 ポリエチレン、 ポリ塩化ビ
ニル、 ポリ塩化ビユリデン、 AB S樹脂、 ポリスチレン、 ポリカーボネート、 ポ リエステル、 ポリウレタン、 シリコーン、 ポリプロピレン等があるが、 好ましく はポリエチレンである。 発明を実施するための最良の形態 When the liquid preparation of prednisolone sodium phosphate of the present invention is used as an enema, it can be filled in a commonly used container, for example, a plastic container or a glass container. Polyethylene, PVC, etc. Benzyl, polyvinylidene chloride, ABS resin, polystyrene, polycarbonate, polyester, polyurethane, silicone, polypropylene and the like, but polyethylene is preferred. BEST MODE FOR CARRYING OUT THE INVENTION
次に、 本発明を下記の実施例により具体的に説明するが、 これにより本発明の 範囲が限定されるものではない。 Next, the present invention will be specifically described with reference to the following examples, but the scope of the present invention is not limited thereto.
実施例 1 Example 1
リン酸プレドニゾロンナトリウム、 カルボキシビュルポリマー （CVP) (カー ポポール (R), BF Goodrich社製） を滅菌精製水にそれぞれ最終濃度 0.02w/v%, 0.025 w/v%になるように溶解して、 次いで中和して p H 7〜 8に調整し、 リ ン酸プレドニゾロンナトリウム含有液剤を調製した。 対照としては、 リン酸プレ ドニゾロンナトリゥムを薬液濃度が約 0.02w/v%になるように滅菌精製水で希 釈したものを用いた。 得られた液剤を 25°C、 40°C、 60°Cの温度にて、 1ケ 月または 3ヶ月保存した。 保存後、 リン酸プレドニゾロンナトリウムを高速液体 クロマトグラフ法により測定し、 調製直後のリン酸プレドニゾロンナトリゥム量 を 100 %として残存率を算出した。 得られた結果を下記の表 1に示す。 Prednisolone sodium phosphate and carboxybutyl polymer (CVP) (Carpopol (R) , manufactured by BF Goodrich) were dissolved in sterile purified water to give final concentrations of 0.02 w / v% and 0.025 w / v%, respectively. Then, the pH was adjusted to 7 to 8 by neutralization to prepare a liquid preparation containing prednisolone sodium phosphate. As a control, prednisolone sodium phosphate diluted with sterilized purified water so as to have a drug solution concentration of about 0.02 w / v% was used. The obtained solution was stored at a temperature of 25 ° C, 40 ° C, or 60 ° C for one month or three months. After storage, prednisolone sodium phosphate was measured by high performance liquid chromatography, and the residual ratio was calculated with the amount of prednisolone sodium phosphate immediately after preparation as 100%. The results obtained are shown in Table 1 below.
1 1
25°C 40°C 60°C 添加量 1ヶ月 3ヶ月 1ヶ月 3ヶ月 1ヶ月 25 ° C 40 ° C 60 ° C Addition amount 1 month 3 months 1 month 3 months 1 month
CVP 0.025w/v% 94.8 91.7 98.1 93.7 94.4 対照 79.7 61.6 81.5 66.8 35.5 表 1に示した結果から、 安定化剤として C VPを添加することにより、 リン酸 プレドニゾロンナトリゥムの分解が抑制されることがわかる。 CVP 0.025w / v% 94.8 91.7 98.1 93.7 94.4 Control 79.7 61.6 81.5 66.8 35.5 From the results shown in Table 1, the addition of CVP as a stabilizer suppresses the degradation of prednisolone sodium phosphate. I understand.
実施例 2 Example 2
リン酸プレドニゾロンナトリウム、 C VPを滅菌精製水にそれぞれ最終濃度
0. 033w/v%、 0. 033w/v%になるように添加し、 水酸化ナトリウムを添加して： H 8に調整した。 得られた溶液を基本処方とした。 これにリン酸水素ナトリウムま たはェデト酸ナトリウムを添加し、 この液を 1 O mL のポリエチレン製容器 （N unc ミ ソープ™チューブ） に充填した。 得られた液剤を 2 5 ° (、 4 0 °Cの温度 にて、 1ヶ月または 6ヶ月保存した。 保存後、 実施例 1と同様に容器中のリン酸 プレドニゾロンナトリゥム残存率 (%)を高速液体クロマトダラフ法により測定した。 結果を表 2に示す。 Prednisolone sodium phosphate and CVP in sterile purified water at final concentrations 0.033w / v%, 0.033w / v%, and adjusted to H8 by adding sodium hydroxide. The obtained solution was used as a basic formulation. To this was added sodium hydrogen phosphate or sodium edetate, and the solution was filled into a 1 OmL polyethylene container (Nunc Misorp ™ tube). The obtained liquid was stored at 25 ° C. (at a temperature of 40 ° C. for 1 month or 6 months. After storage, the prednisolone sodium phosphate residual ratio in the container was determined in the same manner as in Example 1 (%). Was measured by the high performance liquid chromatography method, and the results are shown in Table 2.
表 2 Table 2
添加量 25°C 40で At 40 ° C at 25 ° C
W/V 1ヶ月 6ヶ月 1ヶ月 6ヶ月 基本処方 100 87. 5 100 93. 6 リン酸水素ナトリウム添加 0. 1 100 94. 7 100 96. 6 ェテ、、ト酸ナトリウム添加 0. 00067 100 99. 2 100 99. 1 表 2の結果から、 さらにリン酸水素ナトリウムまたはェデト酸ナトリゥムを添 加することにより、 リン酸プレドニゾロンナトリゥムの分解がより抑制されるこ とがわかる。 W / V 1 month 6 months 1 month 6 monthsBasic prescription 100 87.5 100 93.6 Sodium hydrogen phosphate added 0.1 1 100 94.7 100 96.6 . 2 100 99.1 From the results in Table 2, it can be seen that the addition of sodium hydrogen phosphate or sodium edetate further suppresses the decomposition of sodium prednisolone phosphate.
実施例 3 Example 3
リン酸プレドュゾロンナトリゥム、 C V Pを滅菌精製水にそれぞれ最終濃度 0. 033w/v%、 0. lw/v%になるように添加し、 水酸化ナトリウムにより p H 8に調 整した。 得られた溶液を基本処方とした。 これにパラォキシ安息香酸ェチルとパ ラオキシ安息香酸プチルの混合物を添加し、 この液を 1 O mL のポリエチレン製容 器 （Nunc ミニソープ™チューブ） に充填した。 得られた液剤を 2 5 °C、 4 0 °C の温度にて保存し、 実施例 1と同様に容器中のリン酸プレドニゾロンナトリウム 残存率 (%)を高速液体ク口マトグラフ法により測定した。 結果を表 3に示す。
表 3 Preduzolone sodium phosphate and CVP were added to sterilized purified water to give final concentrations of 0.033 w / v% and 0.1 w / v%, respectively, and the pH was adjusted to 8 with sodium hydroxide. The obtained solution was used as a basic formulation. A mixture of ethyl ethyl paraoxybenzoate and butyl ethyl paraoxybenzoate was added thereto, and the resulting solution was filled into a 1 OmL polyethylene container (Nunc Mini Soap ™ tube). The obtained solution was stored at a temperature of 25 ° C. and 40 ° C., and the residual ratio (%) of prednisolone sodium phosphate in the container was measured by a high-performance liquid chromatography in the same manner as in Example 1. Table 3 shows the results. Table 3
添加邐 25°C 40。C w/v°/o 1ヶ月 3ヶ月 1ヶ月 3ヶ月 基本処方 96. 2 95. 9 96. 1 94. 0 °ラオキシ安息香酸ェチル 0. 006 Addition 25 ° C 40. C w / v ° / o 1 month 3 months 1 month 3 months Basic prescription 96.2 95.9 96.1 94.0 ° Ethyl laoxybenzoate 0.006
+ 98. 5 98. 2 99. 4 96. 7 ハ°ラオキシ安息香酸フ、'チル 0. 00067 表 3の結果から、 パラォキシ安息香酸ェチルとパラォキシ安息香酸プチルの混 合物を添加することにより、 基本処方に比較して更にリン酸プレドニゾロンナト リゥムの分 が抑制されることがわかる。 + 98.5 98.2 99.4 96.7 H-Oxybenzoic acid, 'Chill 0.0000067 From the results in Table 3, by adding a mixture of ethyl para-hydroxybenzoate and butyl ethyl para-hydroxybenzoate, It can be seen that the content of prednisolone sodium phosphate is further suppressed as compared with the basic prescription.
実施例 4 Example 4
滅菌精製水中においてリン酸プレドニゾロンナトリウム （0. 037w/vo/o)、 C V P (0. 08w/v%) リン酸水素ナトリウム （0. 05w/v%)、 パラォキシ安息香酸ェチル (0. 006w/v%)およびパラォキシ安息香酸プチル （0. 00067w/v%)を含有する溶液 に水酸化ナトリゥムを添加して; H 8に調整した。 この溶液をポリエチレン製容 器に充填した。 得られた液剤を 2 5 °C、 4 0 °Cの温度にて保存し、 実施例 1と同 様に容器中のリン酸プレドニゾロンナトリゥム残存率 (%)を高速液体ク口マトダラ フ法により測定した。 結果を表 4に示す。 表 4 Prednisolone sodium phosphate (0.037 w / v o / o ), CVP (0.08 w / v%), sodium hydrogen phosphate (0.05 w / v%), ethyl ethyl paraoxybenzoate (0.006 w / v%) and butyl para-hydroxybenzoate (0.00067 w / v%) was adjusted to H8 by adding sodium hydroxide. This solution was filled in a polyethylene container. The obtained liquid preparation was stored at a temperature of 25 ° C. and 40 ° C., and the residual ratio (%) of prednisolone sodium phosphate in the container was determined by the high-speed liquid mouth matodaraf method as in Example 1. Was measured by Table 4 shows the results. Table 4
25°C 40°C 25 ° C 40 ° C
ヶ月 3ヶ月 6ヶ月 1ヶ月 3ヶ月 6ヶ月 Months 3 months 6 months 1 month 3 months 6 months
99. 7 99. 1 100 99. 6 98. 4 97. 6 表 4の結果から、 添加した C V P、 水酸化ナトリウム （適量)、 リン酸水素ナト リゥム、 パラォキシ安息香酸ェチルおよびパラォキシ安息香酸ブチルにより更に リン酸プレドュゾ口ンナトリゥムの分解を抑制できることがわかる。 99.7 99.1 100 99.6 98.4 97.6 From the results in Table 4, the added CVP, sodium hydroxide (appropriate amount), sodium hydrogen phosphate, ethyl ethyl paraoxybenzoate and butyl paraoxybenzoate further increase It can be seen that the decomposition of preduzophosphate phosphate can be suppressed.
比較例 Comparative example
リン酸プレドニゾロンナトリゥムの市販注射液を用い、 薬液濃度が 0. 0 3 7
w/v%になるように、 生理食塩水及び蒸留水で希釈した。 これらの市販注射剤の希 釈液をポリエチレン製容器に充填した。 当該容器を、 2 5 °C、 4 0 °Cの条件下、 —定期間保存した。 容器中のリン酸プレドニゾロンナトリウム残存率を高速液体 クロマトグラフ法により測定し、 調製直後の主薬含量を 1 0 0 %として各条件で 保存した実験結果を表 5に示す。 表 5 Using a commercially available injection solution of prednisolone sodium phosphate, the drug concentration was 0.03 7 It was diluted with physiological saline and distilled water so as to be w / v%. The dilutions of these commercially available injections were filled in polyethylene containers. The container was stored at 25 ° C and 40 ° C for a fixed period of time. The residual ratio of prednisolone sodium phosphate in the container was measured by high performance liquid chromatography, and the experimental results were stored in each condition under the condition that the main drug content immediately after preparation was 100% and stored. Table 5
25。C 40。C twenty five. C 40. C
1ヶ月 3ヶ月 1ヶ月 3ヶ月 1 month 3 months 1 month 3 months
生理食塩水希釈液剤 94. 0 86. 0 72. 6 50. 1 Physiological saline dilution 94.0 86.0 72.6 50.1
蒸留水希釈液剤 99. 1 68. 0 95. 8 89. 7 表 5の結果から、 リン酸プレドニゾロンナトリゥムを生理食塩水または蒸留水 で希釈した場合、 常温で長期間の保存に耐えられないことがわかる。 本発明のリン酸プレドュゾ口ンナトリゥム含有液剤の薬理効果を試験した。Diluent in distilled water 99.1 68.0 95.8 89.7 From the results in Table 5, when prednisolone sodium phosphate is diluted with physiological saline or distilled water, it cannot withstand long-term storage at room temperature. You can see that. The pharmacological effect of the liquid preparation containing preduzo oral phosphate of the present invention was tested.
( 1 ) 試験試料 (1) Test sample
•実施例 4の薬剤 • Example 4 drug
■ネガティブコントロールの液剤 (リン酸プレドニゾロンナトリゥムを添加しな いことを除いて、 実施例 4と同様に調製した液剤） ■ Negative control solution (solution prepared in the same manner as in Example 4 except that prednisolone sodium phosphate was not added)
•ポジティブコントロールの液剤 （生理食塩水中においてリン酸プレドニゾロン ナトリウム 0. 037w/vo/oを含有する液剤） • Positive control solution (solution containing sodium prednisolone phosphate 0.037 w / v o / o in physiological saline)
•生理食塩水 • saline
なお、 本試験において、 各液剤は使用直前に調製した。 In this test, each liquid preparation was prepared immediately before use.
( 2 ) 試験方法 (2) Test method
8週齢のラット （Wistar、 雄性、 各群 5例） をエーテル麻酔下に開腹し、 盲腸 から下方約 5 cm の粘膜下に 2 0 %酢酸 2 0 μ L を注入し、 酢酸誘発潰瘍性大腸炎 モデルを作製した。 モデル作製日より 5日間、 1日 2回、 試験試料をモデルの体 重 1 k gあたり 2 m Lの投与量にて大腸内投与した。 投与期間終了の翌日、 潰瘍
を含む大腸を摘出し、 潰瘍患部の面積 （腿2) を測定した。 各群について得られた 結果を表 6に示す。 An 8-week-old rat (Wistar, male, 5 subjects in each group) was laparotomized under ether anesthesia, and 20% acetic acid (20 μL) was injected submucosally about 5 cm below the cecum to produce acetic acid-induced ulcerative colon. A flame model was created. The test sample was administered into the large intestine twice a day for 5 days from the date of model preparation at a dose of 2 mL per 1 kg body weight of the model. The day after the end of the administration period, ulcer The large intestine containing the ulcer was removed and the area of the ulcer affected area (thigh 2 ) was measured. Table 6 shows the results obtained for each group.
( 3 ) 結果 表 6 (3) Results Table 6
試験試料 患部面積の平均値 （mm2) Test sample Average value of affected area (mm 2 )
生理食塩水 72. 0+6. 0 Saline 72.0 + 6.0
ネガテイブコント口一ノレ 71. 5+7. 5 Negative control mouth mouth 71.5 + 7.5
ポジテイブコント口一ノレ 11. 7+2. 2 Positive control opening 11.7 + 2.2
実施例 4 12. 9+4. 5 表 6から、 実施例 4の液剤はポジティブコントロールと同等の薬効を示した。 この結果から、 C V P、 リン酸ナトリウム塩類およびパラォキシ安息香酸エステ ルの添加が、 リン酸プレドニゾロンナトリゥムの薬効に影響を与えないことが確 認された。 産業上の利用可能性 Example 4 12.9 + 4.5 From Table 6, the liquid preparation of Example 4 showed the same efficacy as the positive control. From these results, it was confirmed that the addition of CVP, sodium phosphate and ester of paraoxybenzoate did not affect the efficacy of prednisolone sodium phosphate. Industrial applicability
本発明によれば、 保存安定性に優れたリン酸プレドニゾロンナトリゥム含有液 体製剤が提供される。 本発明の液体製剤は、 特に臨床において使用される低濃度 におけるリン酸プレドュゾロンナトリゥムの保存安定性が顕著に改善されている ため非常に有用である。 また、 本発明の液体製剤は、 カルボキシビュルポリマー According to the present invention, a liquid preparation containing prednisolone sodium phosphate excellent in storage stability is provided. The liquid preparation of the present invention is very useful because the storage stability of predazolone sodium phosphate, particularly at low concentrations used in clinical practice, is significantly improved. Further, the liquid preparation of the present invention comprises a carboxybutyl polymer
( C V P ) の添加により液体製剤に粘稠性が付与されるため、 活動性潰瘍性大腸 炎治療のための注腸剤として極めて好ましいものである。
The addition of (CVP) imparts a viscous property to the liquid preparation, and is therefore extremely preferable as an enema for treating active ulcerative colitis.
Claims
1 . リン酸プレドニゾロンナトリゥムおよびカルボキシビュルポリマーを含有 する液体製剤。 1. Liquid preparation containing prednisolone sodium phosphate and carboxybutyl polymer.
2 . 防腐剤、 p H調整剤、 リン酸ナトリウム塩類おょぴキレート剤からなる群 から選択される 1種以上を含有する請求項 1記載の液体製剤。 2. The liquid preparation according to claim 1, further comprising at least one selected from the group consisting of a preservative, a pH adjuster, and a sodium phosphate chelating agent.
3 . p H調整剤により p H 6〜l 0の範囲に調整されている、 請求項 2に記載 の液体製剤。 3. The liquid preparation according to claim 2, wherein the pH is adjusted to a range of 6 to 10 with a pH adjuster.
4 . 防腐剤がパラォキシ安息香酸エステルである請求項 2記載の液体製剤。 4. The liquid preparation according to claim 2, wherein the preservative is a paraoxybenzoate.
5 . パラォキシ安息香酸エステルが、 パラォキシ安息香酸メチル、 パラォキシ 安息香酸ェチル、 パラォキシ安息香酸プロピル、 パラォキシ安息香酸ィソプロピ ル、 パラォキシ安息香酸プチルおよびパラォキシ安息香酸ィソプチルからなる群 から選択される 1種以上である請求項 4記載の液体製剤。 5. The paraoxybenzoate is at least one member selected from the group consisting of methyl paraoxybenzoate, ethyl parabenzoyl benzoate, propyl parahydroxybenzoate, isopropyl isopropyl parabenzoate, butyl propoxy parabutyl benzoate, and isoptyl paraoxybenzoate. The liquid preparation according to claim 4.
6 . リン酸ナトリウム塩類が、 リン酸三ナトリウム、 リン酸水素ナトリウムお ょぴリン酸二水素ナトリゥム一水和物からなる群から選択される 1種以上である 請求項 2記載の液体製剤。 6. The liquid preparation according to claim 2, wherein the sodium phosphate is at least one selected from the group consisting of trisodium phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate monohydrate.
7 . キレート剤が、 ェデト酸ナトリウム、 ェデト酸四ナトリウムおよびェデト 酸四ナトリゥム四水塩からなる群から選択される 1種以上である請求項 2記載の 液体製剤。 7. The liquid preparation according to claim 2, wherein the chelating agent is at least one selected from the group consisting of sodium edetate, tetrasodium edetate and tetrasodium edetate tetrahydrate.
8 . 注腸剤である請求項 1〜 7のいずれか 1項に記載の液体製剤。 8. The liquid preparation according to any one of claims 1 to 7, which is an enema preparation.
9 . リン酸プレドニゾロンナトリゥムにカルポキシビュルポリマーを配合する ことを特徴とするリン酸プレドニゾロンナトリゥム含有液体製剤の安定化方法。
9. A method for stabilizing a liquid formulation containing prednisolone sodium phosphate, which comprises mixing a carboxyl polymer with prednisolone sodium phosphate.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002530067A JP4860895B2 (en) | 2000-09-26 | 2001-09-25 | Prednisolone sodium phosphate liquid formulation |
| AU2001288120A AU2001288120A1 (en) | 2000-09-26 | 2001-09-25 | Liquid prednisolone sodium phosphate preparation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000292633 | 2000-09-26 | ||
| JP2000-292633 | 2000-09-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002026237A1 true WO2002026237A1 (en) | 2002-04-04 |
Family
ID=18775547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2001/008304 WO2002026237A1 (en) | 2000-09-26 | 2001-09-25 | Liquid prednisolone sodium phosphate preparation |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP4860895B2 (en) |
| AU (1) | AU2001288120A1 (en) |
| WO (1) | WO2002026237A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109125256A (en) * | 2018-10-18 | 2019-01-04 | 江西国药有限责任公司 | A kind of prednisolone injection and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0338524A (en) * | 1989-06-21 | 1991-02-19 | Ss Pharmaceut Co Ltd | Corticosteroid-containing lotions |
| JPH04244016A (en) * | 1991-01-30 | 1992-09-01 | Teikoku Seiyaku Co Ltd | Enema pharmaceutical preparation |
| WO1994012217A1 (en) * | 1992-12-02 | 1994-06-09 | Insite Vision Incorporated | Cyclodextrin and polymer based drug delivery system |
| JPH11279065A (en) * | 1998-03-25 | 1999-10-12 | Shiseido Co Ltd | Inflammation treating agent for local administration |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW389694B (en) * | 1995-08-17 | 2000-05-11 | Novartis Ag | Compositions including o-carboxyalkyl chitosan and methods of use in ophthalmics |
| JPH1036253A (en) * | 1996-07-19 | 1998-02-10 | Showa Yakuhin Kako Kk | Aqueous suspended collyria |
| JPH11189546A (en) * | 1997-12-25 | 1999-07-13 | Saitama Daiichi Seiyaku Kk | Percutaneous absorption promoter |
-
2001
- 2001-09-25 WO PCT/JP2001/008304 patent/WO2002026237A1/en active Application Filing
- 2001-09-25 JP JP2002530067A patent/JP4860895B2/en not_active Expired - Lifetime
- 2001-09-25 AU AU2001288120A patent/AU2001288120A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0338524A (en) * | 1989-06-21 | 1991-02-19 | Ss Pharmaceut Co Ltd | Corticosteroid-containing lotions |
| JPH04244016A (en) * | 1991-01-30 | 1992-09-01 | Teikoku Seiyaku Co Ltd | Enema pharmaceutical preparation |
| WO1994012217A1 (en) * | 1992-12-02 | 1994-06-09 | Insite Vision Incorporated | Cyclodextrin and polymer based drug delivery system |
| JPH11279065A (en) * | 1998-03-25 | 1999-10-12 | Shiseido Co Ltd | Inflammation treating agent for local administration |
Non-Patent Citations (1)
| Title |
|---|
| CHRISTEN P. ET AL.: "Stability of prednisolone and prednisolone acetate in various vehicles used in semi- solid topical preparation", JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS, vol. 15, no. 5, 1990, pages 325 - 329, XP002907895 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109125256A (en) * | 2018-10-18 | 2019-01-04 | 江西国药有限责任公司 | A kind of prednisolone injection and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4860895B2 (en) | 2012-01-25 |
| JPWO2002026237A1 (en) | 2004-02-05 |
| AU2001288120A1 (en) | 2002-04-08 |
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