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WO2011071400A1 - Procédé et composition pour préparation de formulations liquides stables de paracétamol - Google Patents

Procédé et composition pour préparation de formulations liquides stables de paracétamol Download PDF

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Publication number
WO2011071400A1
WO2011071400A1 PCT/PT2009/000069 PT2009000069W WO2011071400A1 WO 2011071400 A1 WO2011071400 A1 WO 2011071400A1 PT 2009000069 W PT2009000069 W PT 2009000069W WO 2011071400 A1 WO2011071400 A1 WO 2011071400A1
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WO
WIPO (PCT)
Prior art keywords
formulation
aqueous solvent
paracetamol
liquid stable
solvent according
Prior art date
Application number
PCT/PT2009/000069
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English (en)
Inventor
Dina Stela Velez Ferreira
João Pedro SILVA SERRA
Nuno Miguel ARAÚJO QUINTAL
Original Assignee
Tecnimede - Sociedade Técnico-Medicinal, S.A.
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 Tecnimede - Sociedade Técnico-Medicinal, S.A. filed Critical Tecnimede - Sociedade Técnico-Medicinal, S.A.
Priority to PCT/PT2009/000069 priority Critical patent/WO2011071400A1/fr
Priority to CN200980163266.5A priority patent/CN102711726A/zh
Priority to US13/514,772 priority patent/US20120245230A1/en
Publication of WO2011071400A1 publication Critical patent/WO2011071400A1/fr
Priority to ZA2012/04009A priority patent/ZA201204009B/en

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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention refers to stable liquid formulations of paracetamol for pharmaceutical use and to a method of preparation of stable paracetamol solutions.
  • Paracetamol is an active ingredient that has been widely used in a large number of pharmaceutical preparations over the last decades. It is commonly used as an analgesic and antipyretic. However, due to its lack of solubility in water and due to the fact that paracetamol in aqueous medium is unstable in the presence of oxygen and/or light, it is difficult to obtain a pharmaceutical ready-to-use solution for intravenous perfusion.
  • some of the resultant oxidation products may be hepatotoxic in humans, such as benzoquinoimines, and may additionally lead to the formation of coloured compounds, thus making the aqueous solution unsuitable for therapeutic applications.
  • Paracetamol can be decomposed through a plurality of degradation pathways.
  • Paracetamol pH-rate profile reveals a specific acid and specific base catalysis with maximum stability in the pH range of 5 to 7.(K. T. Koshy and J.L. Lach, J. Pharm. Sci., Philadelphia, 1975).
  • Oxygen elimination can be achieved by increasing the temperature of the aqueous solution.
  • Oxygen elimination can be achieved by submitting the aqueous solution to a vacuum.
  • Oxygen elimination can be achieved by bubbling an inert gas such as nitrogen or argon through the solution.
  • Neutralization of oxygen dissolved in the aqueous solution by addition of an antioxidant agent.
  • EP 858329 B1 the use of an antioxidant agent does not have a significant effect on paracetamol stability but it can prevent solution coloration.
  • the WO03/041687A2 application refers to a method for producing stabilized antioxidant-free solutions at low temperatures, which consists in deoxygenating the solutions by bubbling with an inert gas and in deoxygenating gas hold-ups of the vessels, of the manufacturing pipes and inerting of ampoules and flasks containing the solute with a dense inert gas.
  • the bubbling with an inert gas however only allows oxygen content to decrease to values of as low as 2 ppm maximum.
  • the aqueous formulations may contain an antioxidant agent and a hydroxypolycarboxylic acid or salt (for instance trisodium citrate or disodium tartrate).
  • an antioxidant agent completes the deoxygenation effect but it does not substitute the deoxygenation.
  • the addition of a hydroxypolycarboxylic acid decreases the antioxidant consumption and decreases the antioxidant concentration ranging from 0,1 mg to 1000 mg per one solution litre.
  • the vial filling is performed under an atmosphere of an inert gas and the stoppering is performed under depression in order to obtain a pressure of less than the atmospheric pressure, until a maximum of 65000 Pa.
  • the present invention now allows the preparation of stable pharmaceutical compositions containing paracetamol in an aqueous solvent, with an antioxidant, using a manufacturing process that does not require the use of bubbling devices, nor the increase of solution temperature to promote the solution deoxygenation.
  • the manufacturing process does not require the use of low working temperatures to assure solution stability.
  • the present invention also leads to an energetically more efficient manufacturing process (no need to use high or low working temperatures), and eliminates the need for bubbling devices, decreasing the number of devices that are in direct contact with the solution, and also decreasing possible contamination problems.
  • a deoxygenated paracetamol solution allows lower contents of antioxidant for paracetamol stabilization, rationalizing the use of antioxidants, and other stabilizing excipients present in the pharmaceutical formulation.
  • the present invention concerns a novel method for producing stabilized solutions based on paracetamol, consisting of protecting the solution against possible oxygen uptake by maintaining them under inert gas atmosphere during the manufacturing process and after the filling of the final containers, to obtain aqueous solutions having a residual oxygen concentration in the solution below 2 ppm, and preferably of the order of 1 ppm and even 0,5 ppm and an oxygen concentration in the final container headspace (gas phase) below 10 %, and preferably in the order of 3 % and even virtually oxygen free, after the filling process.
  • aqueous solutions having a residual oxygen concentration in the solution below 2 ppm, and preferably of the order of 1 ppm and even 0,5 ppm and an oxygen concentration in the final container headspace (gas phase) below 10 %, and preferably in the order of 3 % and even virtually oxygen free, after the filling process.
  • a liquid stable paracetamol formulation in an aqueous solvent comprising at least one of the following excipients: an antioxidant, a polyol, one or more buffering agent(s), a stabilizer, a base or an acid for adjustment of the pH of said formulation to 4 to 8 and, wherein the formulation in said solvent is deoxygenated by flushing an inert gas into the headspace of the tank and into the headspace of the final container.
  • antioxidant selected from the group consisting of ascorbic acid, sodium acetate, sodium metabisulphite, organic compounds which bear at least one thiol function, citrates, preferentially sodium citrate and citric acid, cysteine and/or acetylcysteine.
  • a liquid stable paracetamol formulation in an aqueous solvent according to any one of items 1 to 5 wherein the polyol is a polyhydroxylated alcohol or a sugar alcohol.
  • a liquid stable paracetamol formulation in an aqueous solvent wherein the formulation in said solvent is deoxygenated by decreasing the partial pressure of oxygen present in the headspace of a tank and the final container by flushing nitrogen, in which the pH is adjusted to 4 to 8 by the addition of a buffering agent and wherein the formulation comprises at least one of the following excipients: water, cysteine, sodium citrate, sodium phosphate, magnesium chloride, mannitol, and, a base or an acid for adjustment of the pH of said formulation to 4 to 8.
  • a liquid stable paracetamol formulation in an aqueous solvent wherein the formulation in said solvent is deoxygenated by decreasing the partial pressure of oxygen present in the headspace of a tank and the final container by flushing argon, in which the pH of the aqueous solution is adjusted to 4 to 8 by the addition of a buffering agent and wherein the formulation comprises at least one of the following excipients: water, cystein, sodium citrate, sodium phosphate, magnesium chloride, mannitol and, a base or an acid for adjustment of the pH to 4 to 8.
  • a liquid stable paracetamol formulation in an aqueous solvent according to any one of the items 1 to 8 wherein the buffering agent is selected from the group consisting of phosphates and/or citrates.
  • a process for producing a liquid stable paracetamol formulation in an aqueous solvent wherein the formulation in said solvent is deoxygenated by decreasing the partial pressure of oxygen present in the headspace of the tank and in the headspace of the final container by flushing nitrogen, in which the pH of the formulation in said solvent is adjusted to 4 to 8 by the addition of a buffering agent and the formulation comprises at least one of the following excipients. water, cysteine, sodium citrate, sodium phosphate, magnesium chloride, mannitol, and, a base or an acid for adjustment of the pH to 4 to 8.
  • the aqueous solvent is preferably water. It is known that paracetamol is very slightly soluble in water ("The Merck Index", 12 th edition, page 9, n° 45, 1996).
  • the liquid pharmaceutical compositions according to the present invention are preferentially injectable compositions.
  • the paracetamol concentration in solution is preferably comprised between 2 mg/ml and 50 mg/ml.
  • the present inventive manufacturing process does not involve bubbling the aqueous solution or solvent with an inert gas.
  • the compositions according to the invention are prepared with water for injections with a dissolved oxygen content of lower then 8,8 mg l.
  • An antioxidant in the present context is a molecule capable of slowing or preventing the oxidation of other molecules.
  • the aqueous solution stability is influenced by the presence of an antioxidant such as cysteine, acetylcysteine, dithiothreitol, thiomalic acid, thioglycerol or methionine, sodium metabisulphite, ascorbic acid, sodium acetate, citric acid or sodium citrate.
  • the antioxidant completes the deoxygenation of the solution. Without an antioxidant, an essentially deoxygenated solution becomes pink in colour after a certain time at ambient temperature, for the reasons as explained above.
  • a thiol in the present context is a compound that contains a functional group composed of a sulphur-hydrogen (-SH). Being the sulphur analogue of an alcohol group (-OH), this functional group is referred to either as a thiol group or a sulphydryl group.
  • -SH sulphur-hydrogen
  • -OH sulphur analogue of an alcohol group
  • cysteine and glutathione are examples of thiols.
  • a stabilizer in the present context is a chemical substance which tends to inhibit the reaction between two or more other chemicals. Surprisingly, an increase in solution stability occurs, when a stabilizer, like e.g. magnesium chloride is added to the present paracetamol solution. Magnesium is also available in other forms such as oxide, gluconate, malate, citrate, sulphate, etc.
  • a buffering agent adjusts the pH of the solution. These agents are added to substances that are to be placed into acidic or basic conditions in order to stabilize the substance.
  • the presently employed buffer is compatible with human injectable administration, in order to establish the pH between 4 and 8, or preferably 5 to 7, even more preferably close to 6, the optimal pH for paracetamol aqueous solution stability.
  • An appropriate buffer will be, for example, a sodium hydrogenphosphate, disodic phosphate, sodium acetate, sodium citrate or trisodic citrate buffer.
  • the buffer concentration may be comprised between 0,1 and 10 mg/ml.
  • a base in the present context is any chemical compound that, when dissolved in water, results in a solution with a hydrogen ion activity which is lower than that of pure water.
  • the employed base is compatible with human injectable administration, in order to establish the pH between 4 and 8, preferably 5 to 7, even more preferably close to 6, the optimal pH for paracetamol aqueous solution stability.
  • An appropriate base will be for example, sodium hydroxide.
  • An acid in the present context is any chemical compound that, when dissolved in water, results in a solution with a hydrogen ion activity which is higher than that of pure water.
  • the employed acid is compatible with human injectable administration, in order to establish the pH between 4 and 8, preferably 5 to 7, even more preferably close to 6, the optimal pH for paracetamol aqueous solution stability.
  • An appropriate acid will be for example, hydrochloric acid.
  • a polyol in the present context is a compound containing more than one hydroxyl group (OH). Each hydroxyl group is attached to an aliphatic skeleton.
  • the presently employed polyol is compatible with human injectable administration. Mannitol, sorbitol, and/or xylitol are examples of polyols.
  • the tanks used in the manufacturing process are preferably standard stainless steel tanks, typically used by the current art of manufacturing pharmaceutical compositions.
  • the final containers used in the manufacturing process are standard containers of glass or plastic, typically used by the current art of manufacturing pharmaceutical compositions.
  • the head space of the final container is the volume left at the top of an almost filled final container such as ampoules, injection bottles, infusion bottles, etc.
  • all references to 'containers' in the present application refer to those containers as defined above, used during manufacture and/or (final) storage of the paracetamol formulation.
  • Inert gas is a non-reactive gas used during preservation of reactive materials. Nitrogen and argon are the most common inert gases for use in chemistry. According to the present invention a stable liquid paracetamol formulation can be achieved using an inert gas or a mixture of inert gases in the manufacturing process.
  • manufacturing pipes used in the present invention are standard pipes typically used by the current art of manufacturing pharmaceutical compositions.
  • the preparation is subjected to sterilization by filtration under inert gas before this solution is introduced into the container.
  • the solution is introduced into the container under aseptic conditions, under a sterile inert gas.
  • the paracetamol aqueous solution is introduced into the final container, the latter is cleared of the air contained therein, for example by the insufflation of an inert gas.
  • the containers are stoppered under an inert gas atmosphere, preferably nitrogen at a pressure of preferably 1 atm.
  • an inert gas atmosphere preferably nitrogen at a pressure of preferably 1 atm.
  • the deoxygenation process used is performed without any bubbling of the aqueous solution with an inert gas. Regardless of this fact, the deoxygenation process is still efficient and adequate in order to assure sufficient deoxygenation of the paracetamol aqueous solution.
  • the paracetamol aqueous solution's stability is significantly increased, by maintaining the solution under an inert gas atmosphere during the manufacturing process and after the filling of the final containers.
  • the headspace of the tank(s) and of the container(s) is almost completely deoxygenated. In an even more preferred embodiment, the headspace of the tank(s) and the container(s) is completely deoxygenated, i.e. all possible headspace involved in manufacture and storage are deoxygenated.
  • the final liquid paracetamol formulation will be isotonized.
  • Solution A Weigh 17,9 g of disodium hydrogen phosphate (Na 2 HP0 4 ) and dilute in 1000 mL of water.
  • Solution B Weigh 7,8g of sodium di- hydrogen phosphate monohydrate
  • Solution C Dissolve 4g of tetrabutylammonium hydroxide in 10 mL of water. Sonicate for 5 minutes. Weigh 4,6g of this solution and dilute in 1000 mL of methanol.
  • Standard solution Dissolve 25 mg of a paracetamol chemical reference substance (European Pharmacopeia) to a 50 mL volumetric flask and complete the volume with mobile phase (500 ⁇ g/mL). Sonicate for 5 minutes. Transfer 3 mL of this solution to a 50 mL volumetric flask and complete the volume with mobile phase.
  • a paracetamol chemical reference substance European Pharmacopeia
  • Sample solution Take 5 mL of a paracetamol test solution (See Table 1)[3] to a 10 mL volumetric flask and complete the volume with mobile phase. Pipette 0,300 mL of this solution to a 50 mL volumetric flask and complete the volume with mobile phase.
  • the paracetamol assay is expressed in percentage of paracetamol theoretical concentration in the test solution to be analized.
  • Solution A Weigh 17,9 g of disodium hydrogen phosphate (Na 2 HP0 4 ) and dilute in 1000 mL of water.
  • Solution B Weigh 7,8 g of sodium di- hydrogen phosphate monohydrate
  • Solution C Dissolve 4 g of tetrabutylammonium hydroxide in 10 mL of water. Sonicate for 5 minutes. Weight 4,6g of this solution and dilute in 1000 mL of methanol.
  • System suitability Solution Dissolve 5,0 mg of 4-aminophenol, 5 mg of standard paracetamol and 5,0 mg of chloroacetanilide in methanol and dilute in a 20 ml volumetric flask with the same solvent. Dilute 0,5 ml in a 250,0 ml volumetric flask with mobile phase.
  • Sample solution Transfer 5 mL of paracetamol test solution (See Table 1) to a 10 mL volumetric flask and complete the volume with mobile phase.
  • Paracetamol-related substances are expressed in percentage of paracetamol theoretical concentration in the test solution to be analized.
  • the reference Y7 being the least intense degree of coloration and the Y1 being the most intense degree of coloration.
  • test solutions were submitted to photostability tests in an Atlas Suntest device working at 500W/m 2 .
  • test solution's composition is described in Table 1
  • cysteine has a stabilizing effect on paracetamol, decreasing its degradation rate in aqueous solutions.
  • the stability was evaluated in terms of percentage of impurities formed in the solution and colour of the solution.
  • the colour of the solution is related to the presence of p-aminophenol, benzoquinoneimines, polymerization products and other impurities related to the synthesis and degradation of paracetamol.
  • cysteine used as antioxidant improves paracetamol stability, preventing the formation of impurities, i.e. degradation products of paracetamol.
  • paracetamol aqueous solutions are unstable in the presence of oxygen. Therefore, decreasing the dissolved oxygen content in paracetamol solution prevents the degradation of paracetamol.
  • end solution A was deoxygenated by flushing nitrogen into the head- space of the tank.
  • the pH of paracetamol solution was adjusted to 5.8.
  • the paracetamol solution was filled in glass bottles under nitrogen atmosphere.
  • Solution C was prepared and the pH of the paracetamol solution was adjusted to 5.8.
  • the paracetamol solution was filled in glass bottles.
  • the stability was evaluated under photostability stress conditions over 48 hours at 40°C.
  • the colour of solution is related to the presence of p-aminophenol, benzoquinoneimines, polymerization products and other impurities related to the synthesis and degradation of paracetamol.
  • the stability was evaluated in terms of colour of solution.
  • the colour of solution is related to the presence of p-aminophenol, benzoquinoneimines, polymerization products and other impurities related to the synthesis and degradation of paracetamol.
  • sodium metabisulphite used as antioxidant improves paracetamol stability.
  • the stability was evaluated in terms of colour of solution.
  • the colour of solution is related to the presence of p-aminophenol, benzoquinoneimines, polymerization products and other impurities related to the synthesis and degradation of paracetamol.
  • sodium citrate used as antioxidant improves paracetamol stability.
  • magnesium chloride has a stabilizing effect on paracetamol, decreasing its degradation rate in aqueous solutions.
  • the stability was evaluated in terms of percentage of colour of solution.
  • the colour of solution is related to the presence of p-aminophenol, benzoquinoneimines, polymerization products and other impurities related to the synthesis and degradation of paracetamol.
  • magnesium chloride used as antioxidant improves paracetamol stability.

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  • Pain & Pain Management (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

La présente invention porte sur des formulations liquides stables de paracétamol pour utilisation pharmaceutique et sur un procédé de préparation de solutions stables de paracétamol.
PCT/PT2009/000069 2009-12-10 2009-12-10 Procédé et composition pour préparation de formulations liquides stables de paracétamol WO2011071400A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/PT2009/000069 WO2011071400A1 (fr) 2009-12-10 2009-12-10 Procédé et composition pour préparation de formulations liquides stables de paracétamol
CN200980163266.5A CN102711726A (zh) 2009-12-10 2009-12-10 用于制备扑热息痛稳定液体制剂的方法和组合物
US13/514,772 US20120245230A1 (en) 2009-12-10 2009-12-10 Method and composition for preparing stable liquid formulations of paracetamol
ZA2012/04009A ZA201204009B (en) 2009-12-10 2012-06-01 Method and composition for preparing stable liquid formulations of paracetamol

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/PT2009/000069 WO2011071400A1 (fr) 2009-12-10 2009-12-10 Procédé et composition pour préparation de formulations liquides stables de paracétamol

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WO2011071400A1 true WO2011071400A1 (fr) 2011-06-16

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CN (1) CN102711726A (fr)
WO (1) WO2011071400A1 (fr)
ZA (1) ZA201204009B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
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WO2012107093A1 (fr) * 2011-02-10 2012-08-16 Neogen N.V. Formulation de paracétamol en solution aqueuse stable au stockage
WO2013108180A1 (fr) * 2012-01-16 2013-07-25 Novocat Farma, S. A. Composition aqueuse de paracétamol pour injection
WO2014083071A1 (fr) * 2012-11-27 2014-06-05 Genfarma Laboratorio, S.L. Préparation liquide injectable consistant en une combinaison de tramadol et de paracétamol
US20150105471A1 (en) * 2009-04-22 2015-04-16 Fresenius Kabi Deutschland Gmbh Paracetamol for parenteral administration
WO2016156147A1 (fr) 2015-03-27 2016-10-06 Grünenthal GmbH Formulation stable pour l'administration parentérale de tapentadol
WO2018055070A1 (fr) 2016-09-23 2018-03-29 Grünenthal GmbH Formulation stable pour l'administration parentérale de tapentadol
US11547678B2 (en) 2011-03-04 2023-01-10 Gruenenthal Gmbh Aqueous pharmaceutical formulation of tapentadol for oral administration

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WO2017177160A1 (fr) 2016-04-07 2017-10-12 Nevakar Llc Formulation destinée à être utilisée dans une méthode de traitement de la douleur
CN106619593A (zh) * 2016-12-09 2017-05-10 南京理工大学 一种提高含对乙酰氨基酚药物稳定性的方法
JP7249670B2 (ja) * 2017-10-03 2023-03-31 ネヴァカー インジェクテーブルズ インコーポレイテッド アセトアミノフェン－プレガバリン組み合わせ及び疼痛を処置する方法
CN108379222A (zh) * 2018-04-03 2018-08-10 彭进洪 一种对乙酰氨基酚注射液及其制造工艺
CN111170880A (zh) * 2020-01-06 2020-05-19 河北冀衡（集团）药业有限公司 一种对乙酰氨基酚的生产系统和方法
CN116158429B (zh) * 2021-11-25 2024-06-18 沈阳中化农药化工研发有限公司 一种含有联苯类化合物稳定的液体制剂

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WO2001093830A1 (fr) 2000-06-06 2001-12-13 Pharmatop Scr Procede d'obtention de formulations aqueuses de principes actifs sensibles a l'oxydation
WO2002072080A2 (fr) * 2001-03-13 2002-09-19 Fresenius Kabi De Gmbh Solutions de paracetamol stables au stockage et pretes a la perfusion
WO2003041687A2 (fr) 2001-11-15 2003-05-22 Laboratoire Aguettant Procede de production de solutions stables de substances phenoliques et les solutions en resultant
EP1752139A1 (fr) * 2005-08-05 2007-02-14 TheraSelect GmbH Formulation stable et liquide de la paracétamol
EP1992334A1 (fr) * 2007-05-08 2008-11-19 Docpharma NV/SA Formule stable pour le stockage de médicament phénolique sensible à l'oxydation, spécialement le paracétamol, et qui comprend une solution de médicament aqueuse désoxygénée par le processus de fabrication à température contrôlée de la formule
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WO2009098716A2 (fr) * 2008-01-17 2009-08-13 Aptuit Laurus Private Limited Compositions pharmaceutiques aqueuses stables

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EP0858329B1 (fr) 1996-08-05 2003-06-04 SCR Pharmatop Nouvelles formulations liquides stables a base de paracetamol et leur mode de preparation
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EP1752139A1 (fr) * 2005-08-05 2007-02-14 TheraSelect GmbH Formulation stable et liquide de la paracétamol
US20090044700A1 (en) * 2005-12-06 2009-02-19 Francois Dietlin Process for Producing Injectable Solutions by Degassing Liquids and the Use Thereof for Stabilizing Oxidation-Sensitive Substances
EP1992334A1 (fr) * 2007-05-08 2008-11-19 Docpharma NV/SA Formule stable pour le stockage de médicament phénolique sensible à l'oxydation, spécialement le paracétamol, et qui comprend une solution de médicament aqueuse désoxygénée par le processus de fabrication à température contrôlée de la formule
WO2009047634A2 (fr) * 2007-06-18 2009-04-16 Combino Pharm, S.L. Préparations aqueuses d'acétaminophène pour injection
WO2009098716A2 (fr) * 2008-01-17 2009-08-13 Aptuit Laurus Private Limited Compositions pharmaceutiques aqueuses stables

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FAIRBROTHER J.E., ACETOMINOPHEN, IN ANALYTICAL PROFILES OF DRUG SUBSTANCES, vol. 3, 1974, pages 1 - 109
K. T. KOSHY; J.L. LACH, J. PHARM. SCI., 1975

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150105471A1 (en) * 2009-04-22 2015-04-16 Fresenius Kabi Deutschland Gmbh Paracetamol for parenteral administration
WO2012107093A1 (fr) * 2011-02-10 2012-08-16 Neogen N.V. Formulation de paracétamol en solution aqueuse stable au stockage
US9089477B2 (en) 2011-02-10 2015-07-28 Neogen N.V. Storage-stable formulation of paracetamol in aqueous solution
US11547678B2 (en) 2011-03-04 2023-01-10 Gruenenthal Gmbh Aqueous pharmaceutical formulation of tapentadol for oral administration
WO2013108180A1 (fr) * 2012-01-16 2013-07-25 Novocat Farma, S. A. Composition aqueuse de paracétamol pour injection
WO2014083071A1 (fr) * 2012-11-27 2014-06-05 Genfarma Laboratorio, S.L. Préparation liquide injectable consistant en une combinaison de tramadol et de paracétamol
EA036258B1 (ru) * 2015-03-27 2020-10-20 Грюненталь Гмбх Стабильный препарат для парентерального введения тапентадола
JP2018509462A (ja) * 2015-03-27 2018-04-05 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング タペンタドールの非経口投与のための安定な製剤
EP3479823A1 (fr) 2015-03-27 2019-05-08 Grünenthal GmbH Formulation stable pour l'administration parenterale de tapentadol
US11013701B2 (en) 2015-03-27 2021-05-25 Grünenthal GmbH Stable formulation for parenteral administration of tapentadol
WO2016156147A1 (fr) 2015-03-27 2016-10-06 Grünenthal GmbH Formulation stable pour l'administration parentérale de tapentadol
WO2018055070A1 (fr) 2016-09-23 2018-03-29 Grünenthal GmbH Formulation stable pour l'administration parentérale de tapentadol
US10898452B2 (en) 2016-09-23 2021-01-26 Gruenenthal Gmbh Stable formulation for parenteral administration of Tapentadol

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