WO2012120337A1 - Aqueous paracetamol compositions and method of preparation - Google Patents

Aqueous paracetamol compositions and method of preparation Download PDF

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Publication number
WO2012120337A1
WO2012120337A1 PCT/IB2011/050994 IB2011050994W WO2012120337A1 WO 2012120337 A1 WO2012120337 A1 WO 2012120337A1 IB 2011050994 W IB2011050994 W IB 2011050994W WO 2012120337 A1 WO2012120337 A1 WO 2012120337A1
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Prior art keywords
composition according
paracetamol
water
composition
solution
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PCT/IB2011/050994
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French (fr)
Inventor
Yannis PSARRAKIS
Kosta LIOUMIS
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Emp Pharma Gmbh
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Priority to PCT/IB2011/050994 priority Critical patent/WO2012120337A1/en
Publication of WO2012120337A1 publication Critical patent/WO2012120337A1/en

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    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

  • the invention relates to ajiquid composition suitable for parenteral administration, comprising at least 1 mg/ml of acetaminophen.
  • the invention also relates to a method of preparation of such a composition.
  • Paracetamol also known as acetaminophen or its chemical name para-acetylaminophenol
  • Paracetamol is best known in solid administration forms, such as pressed tablets.
  • oral administration routes shows a relatively slow uptake of the effective component.
  • parenteral administration is preferred.
  • the achievable paracetamol dose and uptake rates by parenteral administration are limited by the poor water solubility of acetaminophen.
  • a known formulation for intravenous administration by infusion at a dose of 10 mg/ml is known under the trade name Perfalgan, marketed by Bristol-Myers Squibb. This is an aqueous solution of acetaminophen.
  • the invention provides a liquid composition suitable for parenteral administration, comprising at least 1 mg/ml of acetaminophen, preferably at least 10 mg/ml, most preferably at least 100 mg/ml, and at least one pharmaceutically acceptable excipient.
  • a liquid composition is suitable for parenteral administration, comprising at least 1 mg/ml of paracetamol or a derivative thereof, and at least one pharmaceutically acceptable chelating agent.
  • the composition comprises at least 10 mg/ml acetaminophen, more preferably 100 mg/ml, most preferably at least 150 mg/ml.
  • Chelating agents are chemical compounds that form stable soluble complexes (chelates) with traces of alkaline earth and heavy metal ions. It is postulated that chelation reduces or hampers catalytic processes that such ions may have in the degradation of acetaminophen. This significantly increases the shelf life of liquid formulations, i.e. the time a stored solution retains a certain percentage (for instance 90%) of the originally available active component.
  • a chelating agent ensures the desired concentration of active paracetamol species (as opposite to inactive degradation products) is preserved prior to administration, and is less susceptible to degradation by sources of potentially degrading metal surfaces, for instance the surface of metallic stirrer equipment or syringes.
  • the reduction in degradation rate was found in aqueous solutions of acetaminophen, but also in other solvents or mixtures of solvents.
  • the paracetamol concentration in the composition is at least 1 mg/ml, preferably at least 10 mg/ml, most preferably at least 100 mg/ml.
  • the achievable concentration is limited by the solubility of paracetamol in the chosen solvent.
  • the concentration may be in the range from 1-180 mg/ml.
  • Preparations comprising very high and stable doses of (higher than 100 mg/ml) may be achieved using solubilizer agents and stabilizing agents according to the invention.
  • the chelating agent comprises at least one water- soluble chelating agent selected from the group consisting of malic i o acid, fumaric acid, tartaric acid, edetic acid, dipotassium edetate; disodium edetate, calcium disodium, monosodium edetate; trisodium edetate, ethylenediamine tetraacetic acid (EDTA), citric acid, anhydrous citric acid, sodium citrate dihydrate, maltol and/or ethyl maltol, or pharmaceutically acceptable salt derivatives
  • water- soluble chelating agent selected from the group consisting of malic i o acid, fumaric acid, tartaric acid, edetic acid, dipotassium edetate; disodium edetate, calcium disodium, monosodium edetate; trisodium edetate, ethylenediamine tetraacetic acid (EDTA), citric acid, anhydrous citric acid, sodium citrate
  • salt derivatives typically include lithium, sodium, potassium, calcium and magnesium salts, including mixed salts.
  • the at least one water-soluble chelating agent comprises ethylenediamine tetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof.
  • EDTA ethylenediamine tetraacetic acid
  • EDTA was shown to be particularly effective in
  • Pharmaceutically acceptable salt derivatives typically include lithium, sodium, potassium, calcium and magnesium salts, including mixed salts of EDTA.
  • a commercially available mixed salt is the calcium disodium salt of EDTA (Na 2 Ca-EDTA).
  • Other popular mixed salt is the calcium disodium salt of EDTA (Na 2 Ca-EDTA).
  • compositions comprising EDTA could also comprise other chelating agents described herein.
  • EDTA calculated from the free acid, is added in amounts of at least 0.01 % w/v, preferably in the range of 0.01-0.1 w/v%.
  • the composition also comprises at least one tonicity agent selected from the group consisting of mannitol, sodium chloride and phosphate salts.
  • mannitol sodium chloride
  • phosphate salts Such an agent can be used to prevent or at least lower disadvantageous reactions such as irritations that a patient's body may show due to parenteral administration.
  • the concentration should have a tonicity compatible with human blood.
  • the composition comprises a combination of mannitol and disodium phosphate. This combination shows a slower development of degradation products of paracetamol than compositions of comparable tonicity using sodium chloride.
  • the composition also comprises at least one paracetamol solubilising agent. This allows for relatively high concentrations of paracetamol in solution, and at least partially prevents precipitation during processing and storage of the solution.
  • the minimum effective amount of solubilising agent depends on the amount of paracetamol to be dissolved in the composition.
  • the solubilising agent is selected from the group consisting of dimethylacetamide, glycerine, glycofurol, povidone, ethanol alcohol (95%) or admixtures thereof.
  • the solubilising agent combines an excellent solubility for paracetamol with a good acceptability for parenteral administration.
  • Each of these can be mixed with water, but solutions may also be prepared without water.
  • These excipients have very high solubility in water. The important is the ratio with between the excipient and acetaminophen. Also, I don't have figures for those excipients.
  • the solubilising agent comprises dimethylacetamide.
  • Paracetamol shows an excellent solubility in dimethylacetamide as well as dimethylacetamide/water mixtures.
  • the ratio of paracetamol and dimethylacetaminde is at least 1 : 1 by weight, preferably in the range from 1 : 1 to 3: 1.
  • a combination of dimethylacetamide and glycofurol also shows excellent properties.
  • the composition also comprises at least one 5 antioxidant.
  • the addition of antioxidants prevents or at least slows down the degradation of paracetamol in solution, and also allows for easier handling of the solution when exposed to air.
  • An antioxidant for the present invention is defined as an agent that is oxidised easier than acetaminophen.
  • the combination of at least i o one chelating agent and at least one antioxidant shows an even improved effect in preventing or at least slowing down the degradation of paracetamol in solution when compared to the same solution including only an antioxidant or only a chelating agent.
  • the antioxidant is water-soluble.
  • the at least one antioxidant is selected from the group of water-soluble antioxidants consisting of ascorbic acid, sodium bisulfite, erythorbic Acid, ascorbic acid, sodium erythorbate, ascorbyl palmitate; sodium ascorbate, ascorbyl palmitate, calcium
  • antioxidants having a low water-solubility may be used.
  • antioxidant 25 hydroxytoluene (BHT) and thymol are preferred.
  • a solubility enhancing agent preferably ethanol (alcohol 95%) would have to be used.
  • the at least one water-soluble antioxidant agent comprises sodium metabisulfite or a pharmaceutically acceptable salt thereof.
  • sodium metabisulfite achieved very good results in the stability studies. And works satisfactory way as antioxidant for the preservation of acetaminophen.
  • the at least one water-soluble antioxidant comprises thioglycol.
  • This compounds shows is highly soluble in water, chemically stable without Incompatibilities with acetaminophen, and proved to be a relatively nontoxic and nonirritant material for parenteral usage.
  • This antioxidant could be added in a concentration of at least 0.02% w/w.
  • composition is an aqueous solution having a pH between 5 and 6, preferably having a pH in the range of 5.4- 5.6. Within this pH range combined with chelating compounds yields the slowest degradation of paracetamol in solution.
  • the composition is suitable for intravenous injection.
  • a solution is typically also be suitable for intramuscular injection.
  • the composition is suitable for intramuscular injection.
  • Such a solution may be unsuitable for intravenous injection, due to the stricter requirements for intravenous injection, for instance regarding to tonicity and pH of the solution.
  • such limitations for the preventions of side effects are usually less strict.
  • the invention also provides a method for the preparation of a composition according to any of the preceding claims, comprising the steps of:
  • the solvent comprises dimethylacetamide or a mixture comprising dimethylacetamide and water.
  • the invention also provides a method for the preparation of a high dosage composition of paracetamol according to any of the preceding claims, comprising the steps of:
  • aqueous paracetamol solution dissolving at least 100 mg/ml, preferably at least 150 mg/ml of paracetamol or a derivative thereof in hot water heated at 60C, - the addition of a appropriate solubilising agent or solvent system, preferably dimethylacetamide, preferably in a ratio 1 : 1 , 2 : 1 or 3 : 1 with respect to the aqueous paracetamol solution.
  • a solubilising agent or solvent system preferably dimethylacetamide
  • the solvent preferably water
  • the solvent is heated to at least 60 °C, preferably approximately 70 °C. This allows for a relatively fast dissolution of acetaminophen.
  • the manufacturing process for the examples 1 - 16_ is: A. Dissolve paracetamol (acetaminophen) using the solvent system, in water (in some cases use of hot water 70°C_or 60°C)
  • Solvent systems used in the examples are glycofurol,
  • DMAC dimethylacetamide
  • glycerine glycerine
  • povidone 95% ethanol alcohol and mixtures thereof, typically used as a mix with water.
  • Chromatographic parameters Mobile phase: 0.01M sodium butanesulphonate in a mixture of 0.4 volume of formic acid, 15 volumes of methanol and 85 volumes of water; Injection volume: 20 ⁇ ; Flow rate: 2.0 ml_ min-1; Column temperature: ambient; Run time(Assay) : 10 min; Run time(Related substances) : 45 min; Quantification wavelength : (a) assay 243 nm; (b) 4-aminophenol// unspecified impurities 272 nm.
  • Table 1 impurities in sulotion after 1 month. For examples 1-41.
  • Table 2 pH as measured in solution after 1 month for examples 1- 17.5.
  • Table 3 pH and osmolarity after 1 month for examples 18-41. All solutions were clear.
  • Table 7 pH and osmolarity of formulations 34-41 after 2 months of storage. All formulations were clear solutions.
  • Table 8 impurities in formulations 34-41 after 2 months of storage.
  • Table 9 impurities, pH and osmolality of Perfalgan after 1 month of storage under controlled conditions.
  • Table 9 impurities, pH and osmolarity of Perfalgan after 2 months of storage under controlled conditions.

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Abstract

The invention relates to a liquid composition suitable for parenteral administration, comprising at least 1 mg/ml of acetaminophen. The invention also relates to a method of preparation of such a composition. The liquid composition may comprise at least one pharmaceutically acceptable chelating agent and/or a tonicity agent and/or an antioxidant and/or a solubilising agent, and is suitable for intravenous injection and/or intramuscular injection.

Description

Aqueous paracetamol compositions and method of
preparation
FIELD OF THE INVENTION
The invention relates to ajiquid composition suitable for parenteral administration, comprising at least 1 mg/ml of acetaminophen. The invention also relates to a method of preparation of such a composition.
BACKGROUND OF THE INVENTION
Paracetamol, also known as acetaminophen or its chemical name para-acetylaminophenol, is a well known pain killer. Paracetamol is best known in solid administration forms, such as pressed tablets. However, oral administration routes shows a relatively slow uptake of the effective component. For some applications, parenteral administration is preferred. The achievable paracetamol dose and uptake rates by parenteral administration are limited by the poor water solubility of acetaminophen.
A known formulation for intravenous administration by infusion at a dose of 10 mg/ml is known under the trade name Perfalgan, marketed by Bristol-Myers Squibb. This is an aqueous solution of acetaminophen.
OBJECT AND SUMMARY OF THE INVENTION
It is an object of the invention to provide an improved paracetamol liquid formulation suitable for parenteral administration. It is an object to provide liquid paracetamol solutions having sufficient paracetamol stability. Another object of this invention is to enable high dosage paracetamol formulations suitable for intramuscular administration. Liquid formulations comprising more than lOmg/ml are considered to be high dosage formulations The invention provides a liquid composition suitable for parenteral administration, comprising at least 1 mg/ml of acetaminophen, preferably at least 10 mg/ml, most preferably at least 100 mg/ml, and at least one pharmaceutically acceptable excipient. In a preferred embodiment, a liquid composition is suitable for parenteral administration, comprising at least 1 mg/ml of paracetamol or a derivative thereof, and at least one pharmaceutically acceptable chelating agent. Preferably, the composition comprises at least 10 mg/ml acetaminophen, more preferably 100 mg/ml, most preferably at least 150 mg/ml.
The addition of a chelating agent was shown to slow down the rate of paracetamol degradation in solutionsT Paracetamol degrades in liquid formulations over time at a significantly faster rate than in solid formulations such as tablets, and the invention aims to at least slow down the degradation rate in liquid aqueous formulations.
Chelating agents are chemical compounds that form stable soluble complexes (chelates) with traces of alkaline earth and heavy metal ions. It is postulated that chelation reduces or hampers catalytic processes that such ions may have in the degradation of acetaminophen. This significantly increases the shelf life of liquid formulations, i.e. the time a stored solution retains a certain percentage (for instance 90%) of the originally available active component. Also for freshly prepared formulations of acetaminophen, the addition of a chelating agent ensures the desired concentration of active paracetamol species (as opposite to inactive degradation products) is preserved prior to administration, and is less susceptible to degradation by sources of potentially degrading metal surfaces, for instance the surface of metallic stirrer equipment or syringes. The reduction in degradation rate was found in aqueous solutions of acetaminophen, but also in other solvents or mixtures of solvents.
Preferably, the paracetamol concentration in the composition is at least 1 mg/ml, preferably at least 10 mg/ml, most preferably at least 100 mg/ml. The achievable concentration is limited by the solubility of paracetamol in the chosen solvent. The concentration may be in the range from 1-180 mg/ml. Preparations comprising very high and stable doses of (higher than 100 mg/ml) may be achieved using solubilizer agents and stabilizing agents according to the invention. Aqueous compositions based on dimethylacetamide , prepared using hot water, yield clear and 5 stable formulations of acetaminophen, which may be further stabilized using suitable chelating agents, pH and/or antioxidants.
Preferably,_the chelating agent comprises at least one water- soluble chelating agent selected from the group consisting of malic i o acid, fumaric acid, tartaric acid, edetic acid, dipotassium edetate; disodium edetate, calcium disodium, monosodium edetate; trisodium edetate, ethylenediamine tetraacetic acid (EDTA), citric acid, anhydrous citric acid, sodium citrate dihydrate, maltol and/or ethyl maltol, or pharmaceutically acceptable salt derivatives
15 thereof. These compounds have shown to be effective in slowing down the degradation rates of paracetamol in liquid compositions. Pharmaceutically acceptable salt derivatives typically include lithium, sodium, potassium, calcium and magnesium salts, including mixed salts.
20
In a preferred embodiment, the at least one water-soluble chelating agent comprises ethylenediamine tetraacetic acid (EDTA) or a pharmaceutically acceptable salt thereof. Ethylenediamine tetraacetic acid (EDTA) was shown to be particularly effective in
25 slowing down degradation rates of acetaminophen.
Pharmaceutically acceptable salt derivatives typically include lithium, sodium, potassium, calcium and magnesium salts, including mixed salts of EDTA. A commercially available mixed salt is the calcium disodium salt of EDTA (Na2Ca-EDTA). Other popular
30 forms are the disodium salt and the tetrasodium salt. The composition comprising EDTA could also comprise other chelating agents described herein. Preferably, EDTA, calculated from the free acid, is added in amounts of at least 0.01 % w/v, preferably in the range of 0.01-0.1 w/v%.
35
It is preferred if the composition also comprises at least one tonicity agent selected from the group consisting of mannitol, sodium chloride and phosphate salts. Such an agent can be used to prevent or at least lower disadvantageous reactions such as irritations that a patient's body may show due to parenteral administration. For intravenous administration, the concentration should have a tonicity compatible with human blood.
In a preferred embodiment the composition comprises a combination of mannitol and disodium phosphate. This combination shows a slower development of degradation products of paracetamol than compositions of comparable tonicity using sodium chloride.
It is preferred if the composition also comprises at least one paracetamol solubilising agent. This allows for relatively high concentrations of paracetamol in solution, and at least partially prevents precipitation during processing and storage of the solution. The minimum effective amount of solubilising agent depends on the amount of paracetamol to be dissolved in the composition.
In a preferred embodiment, the solubilising agent is selected from the group consisting of dimethylacetamide, glycerine, glycofurol, povidone, ethanol alcohol (95%) or admixtures thereof. Each of these solvents combines an excellent solubility for paracetamol with a good acceptability for parenteral administration. Each of these can be mixed with water, but solutions may also be prepared without water. These excipients have very high solubility in water. The important is the ratio with between the excipient and acetaminophen. Also, I don't have figures for those excipients.
It is preferred if the solubilising agent comprises dimethylacetamide. Paracetamol shows an excellent solubility in dimethylacetamide as well as dimethylacetamide/water mixtures. Preferably, the ratio of paracetamol and dimethylacetaminde is at least 1 : 1 by weight, preferably in the range from 1 : 1 to 3: 1. A combination of dimethylacetamide and glycofurol also shows excellent properties.
It is preferred if the composition also comprises at least one 5 antioxidant. The addition of antioxidants prevents or at least slows down the degradation of paracetamol in solution, and also allows for easier handling of the solution when exposed to air. An antioxidant for the present invention is defined as an agent that is oxidised easier than acetaminophen. The combination of at least i o one chelating agent and at least one antioxidant shows an even improved effect in preventing or at least slowing down the degradation of paracetamol in solution when compared to the same solution including only an antioxidant or only a chelating agent. Preferably, the antioxidant is water-soluble.
15
Preferably, the at least one antioxidant is selected from the group of water-soluble antioxidants consisting of ascorbic acid, sodium bisulfite, erythorbic Acid, ascorbic acid, sodium erythorbate, ascorbyl palmitate; sodium ascorbate, ascorbyl palmitate, calcium
20 ascorbate. sodium sulfite, sodium sulfite heptahydrate, sodium metabisulfite, Potassium metabisulfite, sodium bisulfite, propionic acid, sodium propionate, malic Acid, d-Malic acid, and l-Malic acid. Also, antioxidants having a low water-solubility may be used. Butylated hydroxyanisole (BHA), propyl gallate, butylated
25 hydroxytoluene (BHT) and thymol are preferred. In order to achieve an effective amount of antioxidant having a low water- solubility, a solubility enhancing agent, preferably ethanol (alcohol 95%) would have to be used.
30 In a preferred embodiment, the at least one water-soluble antioxidant agent comprises sodium metabisulfite or a pharmaceutically acceptable salt thereof. Sodium metabisulfite achieved very good results in the stability studies. And works satisfactory way as antioxidant for the preservation of acetaminophen.
In another preferred embodiment the at least one water-soluble antioxidant comprises thioglycol. This compounds shows is highly soluble in water, chemically stable without Incompatibilities with acetaminophen, and proved to be a relatively nontoxic and nonirritant material for parenteral usage. This antioxidant could be added in a concentration of at least 0.02% w/w.
It is preferred if the composition is an aqueous solution having a pH between 5 and 6, preferably having a pH in the range of 5.4- 5.6. Within this pH range combined with chelating compounds yields the slowest degradation of paracetamol in solution.
In a preferred embodiment, the composition is suitable for intravenous injection. Such a solution is typically also be suitable for intramuscular injection. In another preferred embodiment, the composition is suitable for intramuscular injection. Such a solution may be unsuitable for intravenous injection, due to the stricter requirements for intravenous injection, for instance regarding to tonicity and pH of the solution. For intramuscular injections, such limitations for the preventions of side effects are usually less strict.
The invention also provides a method for the preparation of a composition according to any of the preceding claims, comprising the steps of:
- dissolving at least 1 mg/ml of paracetamol or a derivative thereof in a solvent, preferably water,
- and dissolving at least one pharmaceutically acceptable chelating agent in the solvent. Other components of the composition may be dissolved in the solution before, after or simultaneously during these steps. Preferably, the solvent comprises dimethylacetamide or a mixture comprising dimethylacetamide and water.
The invention also provides a method for the preparation of a high dosage composition of paracetamol according to any of the preceding claims, comprising the steps of:
-.dissolving at least 100 mg/ml, preferably at least 150 mg/ml of paracetamol or a derivative thereof in hot water heated at 60C, - the addition of a appropriate solubilising agent or solvent system, preferably dimethylacetamide, preferably in a ratio 1 : 1 , 2 : 1 or 3 : 1 with respect to the aqueous paracetamol solution. This yields a stable, clear solution at room temperature with a very high concentration. This aqueous solution may optionally be further stabilized by adjusting the pH, adding at least one pharmaceutically acceptable chelating agent in the solvent and/ or adding an antioxidant
It is advantageous if at least during the dissolving step the solvent, preferably water, is heated to at least 60 °C, preferably approximately 70 °C. This allows for a relatively fast dissolution of acetaminophen.
BRIEF DESCRIPTION OF THE DRAWINGS
DESCRIPTION OF PREFERRED EMBODIMENTS
The following examples 1-16 are suitable for both intramuscular and intravenous application.
Aqueous solutions with an additional solvent
The manufacturing process for the examples 1 - 16_is: A. Dissolve paracetamol (acetaminophen) using the solvent system, in water (in some cases use of hot water 70°C_or 60°C)
B. Add the rest of water
C. Add the rest of excipients
D. Adjust the pH value using HCL or NaOH IN, if needed.
E. Fill the solution into suitable containers, which are sealed airtight for testing.
This method yields clear solutions of acetaminophen.
Solvent systems used in the examples are glycofurol,
dimethylacetamide (DMAC), glycerine, povidone, 95% ethanol alcohol and mixtures thereof, typically used as a mix with water.
EXAMPLE 1
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol 15 gr
Glycofurol 45 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 2
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 15 gr
Glycofurol 75 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 3
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol 1 gr
Glycofurol 3 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 4
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 1 gr
DM AC 1 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 5
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol 1 gr
DM AC 5 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 6
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 1 gr
DM AC 1.6 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 7
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 1 gr
DM AC 0.5 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 8
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 15 gr
DM AC 15 gr
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 8.1
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 15 gr
DM AC 30 gr
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 8.2
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol 15 gr
DM AC 35 gr
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 8.3
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 15 gr
DM AC 50 gr
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 8.4
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 18 gr
DM AC 50 gr
Purified water qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 8.5
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 18 gr
DM AC 20 gr
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 9
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol 15 gr
DM AC 15 gr
Hydrochloric acid qs to pH 4
Sodium hydroxide qs to pH 4
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 9.1
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol 15 gr
DM AC 30 gr
Hydrochloric acid qs to pH 4
Sodium hydroxide qs to pH 4
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 10
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol 1 gr
DM AC 0.5 gr
Alcohol_95° 2 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 11
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol ~ 1 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
water 0.9%* qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 12
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol ~ 1 gr
Glycerine 3 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 13
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol ~ 1 gr
Glycerine 1 gr
Alcohol 95° 1 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 14
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol ~ 1 gr
Glycerine 1 gr
Dimethylacetamide (DMAC) 1 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 15
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol ~ 1 gr
Povidone 1 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 16
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol ~ 1 gr
Povidone 2 gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Purified water qs to 100 ml
TOTAL VOLUME 100 ml Aqueous solutions: Examples 17-33
The manufacturing process for the examples 17 - 33_is:
A. Dissolve Paracetamol using the solvent system, in water (in some cases the water is heated to_70°C_or 60°C to speed up the dissolving proces)
B. Add the rest of water
C. Add the rest of excipients_(chelating agents or /and
antioxidants)
D. Adjust the pH value using HCL or/and_NaOH IN
E. Fill the solution into suitable containers
In case of alcohol usage of an excipient insoluble or poorly soluble in water the excipient is first dissolved in ethanol alcohol 95% before adding the excipient to the solution in Step C.
EXAMPLE 17
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol
Malic acid 0.02gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 17.1
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Fumaric.acid 0.02gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 17.2
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Tartaric acid 0.02gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 17.3
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol lgr
Citric acid 0.05gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 17.4
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -lgr
Ascorbyl palmitate 0.03gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 17.5
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol gr
Maltol 0.0 lgr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 18
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol gr
Metabisulphite sodium 0.07gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 18.1
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol .lgr
Sulfite sodium 0.05gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 18.2
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Ascorbic acid 0.5gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 18.3
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Sodium propionate 0.5gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 18.4
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Erythorbic acid 0.5gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 18.5
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Sodium erythorbate 0.5gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
Final pH ~5.5
EXAMPLE 19
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Edetate sodium 0.07gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 20
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol lgr
Monothioglycerol 0.3gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 21
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol lgr
Monothioglycerol lgr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 22
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -lgr
Dimethylacetamide (DMAC) 0.5gr
Malic acid 0.03gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 23
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol gr
Dimethylacetamide (DMAC) 0.5gr
Metabisulphite Sodium 0.08gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 24
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol -lgr
Dimethylacetamide (DMAC) 0.5gr
Edetate sodium 0.08gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 25
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Alcohol 95° 5gr
Malic acid 0.08gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 26
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol
Alcohol 95° 5gr
Metabisulphite sodium 0.07gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 27
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol -igr
Alcohol 95° 5gr
Edetate sodium 0.07gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 28
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Alcohol 95° 5gr
BHA 0.002gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 29
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Alcohol 95° 5gr
BHA 0.002gr
Malic acid 0.04gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 30
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Dimethylacetamide (DMAC) 0.5gr
Alcohol 95° 2gr
Malic acid 0.02gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 31
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol -igr
Dimethylacetamide (DMAC) 0.5gr
Alcohol 95° 2gr
Metabisulphite sodium 0.08gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 32
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Dimethylacetamide (DMAC) 0.5gr
Alcohol 95° 2gr
BHA 0.002gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
Figure imgf000020_0001
Method Examples 34-41 The manufacturing process used for the examples 34 - 41_is:
A. Dissolve Paracetamol using the solvent system, in hot water (70-75°C) or dissolve paracetamol in DMAC using also hot water (60°C)
B. Add the rest of water and cool the solution to room temperature (25° C)
C. Add the rest of excipients (antioxidant, tonicity agents)
D. Adjust the pH value by titration with HCL and/or NaOH IN
E. Fill the solution into suitable containers
EXAMPLE 34
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol
Edetate sodium 0.05gr
Sodium chloride 0.66gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 35
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol
Edetate sodium O. lgr
Sodium chloride 0.66gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml EXAMPLE 36
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Dimethylacetamide (DMAC) 0.5gr
Edetate sodium 0.05gr
Sodium chloride 0.49gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 37
INGREDIENTS Quantity for 100 ml of_solution
Paracetamol -igr
Dimethylacetamide (DMAC) 0.5gr
Edetate sodium O. lgr
Sodium chloride 0.49gr
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 38
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol -igr
Edetate sodium 0.05gr
Mannitol 0.85gr
sodium dihydrogen phosphate
1.20gr
di hydrate
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
EXAMPLE 39
INGREDIENTS Quantity for 100 ml of.solution
Paracetamol -igr
Dimethylacetamide (DMAC) 0.5g
Edetate sodium 0.05gr
Mannitol l . l Ogr
sodium dihydrogen phosphate
0.70gr
di hydrate
Hydrochloric acid qs to pH 5.50
Sodium hydroxide qs to pH 5.50
Water for injection qs to 100 ml
TOTAL VOLUME 100 ml
Figure imgf000022_0001
PRE-STABILITY STUDIES
The preparations were subjected to stability studies. These studies indicate the relative stability of paracetamol in the various formulations. In the result tables, NP indicates the test was not yet performed, and ND indicates the species were not detected. Experimental
Analytical column Thermo Hypersil BDS C18, 250 x 4.6 mm, 5 pm Part No. 28105-254630 or equivalent. References: Paracetamol (paracetamol) reference material and 4-aminophenol reference material_of analytical quality were used as references. Reagents: HPLC-grade water, Methanol (MeOH), (HPLC grade), Sodium butanesulfonate, Formic acid, all of analytical quality.
Chromatographic parameters: Mobile phase: 0.01M sodium butanesulphonate in a mixture of 0.4 volume of formic acid, 15 volumes of methanol and 85 volumes of water; Injection volume: 20 μΙ; Flow rate: 2.0 ml_ min-1; Column temperature: ambient; Run time(Assay) : 10 min; Run time(Related substances) : 45 min; Quantification wavelength : (a) assay 243 nm; (b) 4-aminophenol// unspecified impurities 272 nm.
IDENTIFICATION OF IMPURITIES.
The identity of each impurity was determined by HPLC by the comparison of its Relative Retention Time (RRT) against the
Retention Time of the main peak, which corresponds to the active material Paracetamol (acetaminophen). The main degradation product of paracetamol is 4-aminophenol. NP: Not Performed, ND : Not Detected (below detection limit). All formulations yielded clear solutions during these studies
The following tables show the results after one month of storage at controlled temperature of normal (25 °C), 40 °C or 70 °C.
Table 1 : impurities in sulotion after 1 month. For examples 1-41.
Figure imgf000023_0001
Figure imgf000024_0001
Table 2 : pH as measured in solution after 1 month for examples 1- 17.5.
Figure imgf000025_0002
Table 3 : pH and osmolarity after 1 month for examples 18-41. All solutions were clear.
Figure imgf000025_0001
Figure imgf000026_0001
Table 4 : impu rities in examples 1- 17.5.
total other related any other
4-aminophenol% substances% impurities% conditions conditions conditions exa
mpl norm norm norm
e al 40C 70C al 40C 70C al 40C 70C
1 NP NP NP NP NP NP NP NP NP
2 NP NP NP NP NP NP NP NP NP
3 NP NP NP NP NP NP NP NP NP
4 ND ND NP NP NP NP NP NP NP
0,02
5 0,031 3 NP NP NP NP NP NP NP
6 ND ND ND NP NP NP NP NP NP
7 NP NP NP NP NP NP NP NP NP
8 ND ND NP NP NP NP NP NP NP
8.1 ND ND NP NP NP NP NP NP NP
8.2 ND ND NP NP NP NP NP NP NP
8.3 ND ND NP NP NP NP NP NP NP
8.4 ND ND NP NP NP NP NP NP NP
8.5 NP NP NP NP NP NP NP NP NP
9 NP NP NP NP NP NP NP NP NP
9.1 NP NP NP NP NP NP NP NP NP
10 NP NP NP NP NP NP NP NP NP
11 NP NP NP NP NP NP NP NP NP
12 NP NP NP NP NP NP NP NP NP
13 NP NP NP NP NP NP NP NP NP
14 NP NP NP NP NP NP NP NP NP
15 NP NP NP NP NP NP NP NP NP 16 NP NP NP NP NP NP NP NP NP
17 NP NP NP NP NP NP NP NP NP
17.1 NP NP NP NP NP NP NP NP NP
17.2 NP NP NP NP NP NP NP NP NP
17.3 NP NP NP NP NP NP NP NP NP
17.4 NP NP NP NP NP NP NP NP NP
17.5 NP NP NP NP NP NP NP NP NP
Table 5 : Impu rities after 1 month in examples 18-41.
Figure imgf000027_0001
The following tables show impurities and pH in the examples after 2 months of storages under controlled conditions. All formulations were clear solutions. Table 6: impurities after 2 months of storage for formulations 34-41.
Figure imgf000028_0002
Table 7: pH and osmolarity of formulations 34-41 after 2 months of storage. All formulations were clear solutions.
Table 8: impurities in formulations 34-41 after 2 months of storage.
Figure imgf000028_0001
Perfalqan
For comparison, the stability tests were also performed on the commercially available PERFALGAN® 10 MG/ML formulation, comprising 10 mg/ml of acetaminophen. NP: Not Performed, ND: Not Detected (below detection limit)
Table 9 : impurities, pH and osmolality of Perfalgan after 1 month of storage under controlled conditions.
Figure imgf000029_0001
Table 9 : impurities, pH and osmolarity of Perfalgan after 2 months of storage under controlled conditions.
conditions conditions
density (g/ml)
normal 40C 70C normal 40C 70C
97 96,6 0,08 0,33 NP
appearance PH
conditions conditions
normal 40C 70C normal 40C 70C osmolarity (mOsm/kg) clear solution 5,7 5,5 5,4 296
total ot her re ated
4-aminophenol% subst ances % any other impurities% conditions conditions conditions normal 40C 70C normal 40C 70C normal 40C 70C
0,03 0,36 NP NP 0,04 0,31

Claims

1. Liquid composition suitable for parenteral administration, comprising at least 1 mg/ml of acetaminophen, preferably at least 10 mg/ml, most preferably at least 100 mg/ml, and dimethylacetamide as a solubilising agent, and optionally at least one pharmaceutically acceptable excipient.
2. Composition according to claim 1, wherein the solubilising agent comprises dimethylacetamide in quantity of at least 5 mg/ml of the total solution, preferably at least 10 mg/ml .
3. Composition according to claim 1 or 2, wherein the solubilising agent comprises dimethylacetamide in a ratio of at least 1 : 1 w/w with respect to acetaminophen, preferably in the range of 1 : 1 - 1 : 3.
4. Liquid composition according to any of the preceding claims, comprising at least one pharmaceutically acceptable chelating agent.
5. Composition according to claim 4, wherein the
chelating agent comprises at least one water-soluble chelating agent selected from the group consisting of malic acid, fumaric acid, tartaric acid, edetic acid, dipotassium edetate; disodium edetate, calcium disodium, monosodium edetate; trisodium edetate, ethylenediamine tetraacetic acid (EDTA), citric acid, anhydrous citric acid, sodium citrate dihydrate, maltol and/or ethyl maltol, and/or pharmaceutically acceptable derivatives thereof.
6. Composition according to claim 3, wherein the at least one water-soluble chelating agent comprises ethylenediamine tetraacetic acid or a pharmaceutically acceptable salt thereof.
7. Composition according to any of the preceding claims, wherein the composition also comprises at least one tonicity agent selected from the group consisting of mannitol, sodium chloride and phosphate salts.
8. Composition according to claim 7, wherein the composition comprises a combination of mannitol and disodium phosphate.
9. Composition according to any of the preceding claims, wherein the composition also comprises at least one additional paracetamol solubilising agent.
10. Composition according to claim 9, wherein the additional solubilising agent is selected from the group consisting of glycerine, glycofurol, povidone, ethanol alcohol (95%) or admixtures thereof.
11. Composition according to any of the preceding claims, wherein the composition also comprises at least one antioxidant.
12. Composition according to any of the preceding claims, wherein the composition is an aqueous solution having a pH between 5 and 6, preferably having a pH in the range of 5.4-5.6.
13. Composition according to any of the preceding claims, wherein the composition is suitable for intravenous injection and/or intramuscular injection.
14. Method for the preparation of a composition according to any of the preceding claims, comprising the steps of:
- dissolving at least 1 mg/ml of acetaminophen, preferably at least 10 mg/ml, most preferably at least 100 mg/ml or a derivative thereof in a solvent, preferably water,
- and dissolving at least one pharmaceutically acceptable excipient in the solvent.
PCT/IB2011/050994 2011-03-10 2011-03-10 Aqueous paracetamol compositions and method of preparation WO2012120337A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102973500A (en) * 2012-12-25 2013-03-20 江苏吴中苏药医药开发有限责任公司 Linezolid liquid preparation and preparation method thereof
CN108379222A (en) * 2018-04-03 2018-08-10 彭进洪 A kind of paracetamol injection determined and its manufacturing process
US11891588B2 (en) 2019-07-31 2024-02-06 Ecolab Usa Inc. Personal protective equipment free delimer compositions o

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MXPA04003136A (en) * 2004-04-02 2005-10-06 Leopoldo Espinosa Abdala Solid pharmaceutical formulations in aqueous solution, suspension and emulsion, which contain paracetamol, ascorbic acid and loratadine.

Patent Citations (1)

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MXPA04003136A (en) * 2004-04-02 2005-10-06 Leopoldo Espinosa Abdala Solid pharmaceutical formulations in aqueous solution, suspension and emulsion, which contain paracetamol, ascorbic acid and loratadine.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102973500A (en) * 2012-12-25 2013-03-20 江苏吴中苏药医药开发有限责任公司 Linezolid liquid preparation and preparation method thereof
CN108379222A (en) * 2018-04-03 2018-08-10 彭进洪 A kind of paracetamol injection determined and its manufacturing process
US11891588B2 (en) 2019-07-31 2024-02-06 Ecolab Usa Inc. Personal protective equipment free delimer compositions o

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