WO2002026237A1 - Preparation liquide de prednisolone phosphate de sodium - Google Patents

Preparation liquide de prednisolone phosphate de sodium Download PDF

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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
Application number
PCT/JP2001/008304
Other languages
English (en)
Japanese (ja)
Inventor
Takanori Ijitsu
Original Assignee
Nisshin Pharma Inc.
Kyorin Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nisshin Pharma Inc., Kyorin Pharmaceutical Co., Ltd. filed Critical Nisshin Pharma Inc.
Priority to AU2001288120A priority Critical patent/AU2001288120A1/en
Priority to JP2002530067A priority patent/JP4860895B2/ja
Publication of WO2002026237A1 publication Critical patent/WO2002026237A1/fr

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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)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une préparation liquide de prednisolone phosphate de sodium contenant du prednisolone phosphate de sodium, un polymère de carboxyvinyle comme stabilisant du prednisolone phosphate de sodium, au moins un élément choisi parmi un régulateur de pH, un composé de phosphate de sodium, un chélateur et un antiseptique. Ladite préparation, très stable au stockage, s'avère extrêmement utile.
PCT/JP2001/008304 2000-09-26 2001-09-25 Preparation liquide de prednisolone phosphate de sodium WO2002026237A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001288120A AU2001288120A1 (en) 2000-09-26 2001-09-25 Liquid prednisolone sodium phosphate preparation
JP2002530067A JP4860895B2 (ja) 2000-09-26 2001-09-25 リン酸プレドニゾロンナトリウム液体製剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-292633 2000-09-26
JP2000292633 2000-09-26

Publications (1)

Publication Number Publication Date
WO2002026237A1 true WO2002026237A1 (fr) 2002-04-04

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PCT/JP2001/008304 WO2002026237A1 (fr) 2000-09-26 2001-09-25 Preparation liquide de prednisolone phosphate de sodium

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JP (1) JP4860895B2 (fr)
AU (1) AU2001288120A1 (fr)
WO (1) WO2002026237A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109125256A (zh) * 2018-10-18 2019-01-04 江西国药有限责任公司 一种氢化泼尼松注射液及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0338524A (ja) * 1989-06-21 1991-02-19 Ss Pharmaceut Co Ltd コルチコステロイド含有ローション剤
JPH04244016A (ja) * 1991-01-30 1992-09-01 Teikoku Seiyaku Co Ltd 注腸製剤
WO1994012217A1 (fr) * 1992-12-02 1994-06-09 Insite Vision Incorporated Cyclodextrine et systeme de liberation de medicament a base de polymere
JPH11279065A (ja) * 1998-03-25 1999-10-12 Shiseido Co Ltd 局所投与炎症治療剤

Family Cites Families (3)

* Cited by examiner, † Cited by third party
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 (ja) * 1996-07-19 1998-02-10 Showa Yakuhin Kako Kk 水性懸濁点眼剤
JPH11189546A (ja) * 1997-12-25 1999-07-13 Saitama Daiichi Seiyaku Kk 経皮吸収促進剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0338524A (ja) * 1989-06-21 1991-02-19 Ss Pharmaceut Co Ltd コルチコステロイド含有ローション剤
JPH04244016A (ja) * 1991-01-30 1992-09-01 Teikoku Seiyaku Co Ltd 注腸製剤
WO1994012217A1 (fr) * 1992-12-02 1994-06-09 Insite Vision Incorporated Cyclodextrine et systeme de liberation de medicament a base de polymere
JPH11279065A (ja) * 1998-03-25 1999-10-12 Shiseido Co Ltd 局所投与炎症治療剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109125256A (zh) * 2018-10-18 2019-01-04 江西国药有限责任公司 一种氢化泼尼松注射液及其制备方法

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AU2001288120A1 (en) 2002-04-08
JPWO2002026237A1 (ja) 2004-02-05

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