EP2170313A2 - Aqueous formulations of acetaminophen for injection - Google Patents

Aqueous formulations of acetaminophen for injection

Info

Publication number
EP2170313A2
EP2170313A2 EP08837144A EP08837144A EP2170313A2 EP 2170313 A2 EP2170313 A2 EP 2170313A2 EP 08837144 A EP08837144 A EP 08837144A EP 08837144 A EP08837144 A EP 08837144A EP 2170313 A2 EP2170313 A2 EP 2170313A2
Authority
EP
European Patent Office
Prior art keywords
approximately
acetaminophen
injection
aqueous formulation
aqueous
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP08837144A
Other languages
German (de)
French (fr)
Inventor
Sergio Lloret Perez
Agnès FERNANDEZ PEÑA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medichem SA
Original Assignee
Combino Pharm SL
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 Combino Pharm SL filed Critical Combino Pharm SL
Publication of EP2170313A2 publication Critical patent/EP2170313A2/en
Withdrawn legal-status Critical Current

Links

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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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 invention relates to novel stable aqueous formulations of acetaminophen for injection as well as processes for preparing and using the same.
  • Acetaminophen also known as paracetamol, is a common analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu medications and many prescription analgesics.
  • U.S. Pat. No. 6,028,222 describes aqueous formulations of acetaminophen containing a buffering agent and a free radical antagonist and/or a free radical scavenger which need to be bubbled with an inert gas through the aqueous solvent in order to remove oxygen from the medium and maintain the stability of acetaminophen.
  • U.S. Pat. No. 6,992,218 B2 relates to aqueous formulations with an active principle susceptible to oxidation, for example acetaminophen, wherein the essential means for stabilizing them is deoxygenating by bubbling with an inert gas and/or placing under vacuum until the oxygen content is below 2 ppm.
  • the invention relates to novel stable aqueous formulations of acetaminophen for injection as well as processes for preparing and using the same.
  • the invention provides new, stable, aqueous acetaminophen formulations.
  • the invention relates to a new stable, aqueous acetaminophen formulation that includes: a. approximately 200.0 mg to approximately 1,400.0 mg of acetaminophen; b. approximately 200.0 mg to approximately 10,000.0 mg of mannitol for injection; c. approximately 0.0 mg to approximately 30.0 mg of monobasic sodium phosphate; d. approximately 0.0 mg to approximately 300.0 mg of povidone; e. a sufficient amount of sodium hydroxide (as needed) is added to adjust the pH between approximately 4.0 and approximately 8.0; f. a sufficient amount of hydrochloric acid (as needed) is added to adjust the pH between approximately 4.0 and approximately 8.0; and g. an injection volume of water for injection up to a volume of approximately 100 mL.
  • the invention includes a new stable, aqueous composition that includes acetaminophen having the following composition: a. approximately 1,000.0 mg of acetaminophen; b. approximately 3,750.0 mg of mannitol for injection; c. approximately 13.0 mg of monobasic sodium phosphate; d. approximately 100.0 mg of povidone; e. a sufficient amount of sodium hydroxide is added to adjust the pH until approximately 5.5; f. a sufficient amount of hydrochloric acid is added to adjust the pH until approximately 5.5; and g. an injection volume of water for injection up to a volume of approximately 10O mL.
  • acetaminophen having the following composition: a. approximately 1,000.0 mg of acetaminophen; b. approximately 3,750.0 mg of mannitol for injection; c. approximately 13.0 mg of monobasic sodium phosphate; d. approximately 100.0 mg of povidone; e. a sufficient amount of sodium hydroxide is added to adjust the pH
  • Another embodiment of the invention provides a process for preparing the above- described aqueous composition that includes the following steps: a. adding monobasic sodium phosphate, povidone, mannitol for injection and acetaminophen in a volume of water for injection to form the aqueous formulation; b. if necessary, adding sodium hydroxide or hydrochloric acid to adjust the pH of the aqueous formulation between approximately 4.0 and approximately
  • bottles is meant to convey glass or plastic containers or any other materials suitable for containing the aqueous formulations of acetaminophen described herein.
  • the invention further includes the use of the aqueous pharmaceutical formulations of acetaminophen according to the invention for the treatment of pain.
  • the invention further includes the use of the aqueous pharmaceutical formulations of acetaminophen for the treatment of pain after surgery and treatment of short period of fever when intravenous administration is justified or when others routes of administration are not possible.
  • EXAMPLE 1 Aqueous solution of acetaminophen
  • Table 1 illustrates a formulation of an aqueous acetaminophen solution with the following constituents:
  • the aqueous acetaminophen formulation of Table 1 was prepared by dissolving 13.0 mg of monobasic sodium phosphate, 100.0 mg of povidone, 3,750.0 mg of mannitol for injection and 1,000.0 mg of acetaminophen in 80 mL of water for injection. Then, the pH is checked, and if necessary was adjusted until 5.5 by adding sodium hydroxide or hydrochloric acid. The solution was adjusted to 100 mL by the addition of water for injection. Next, he solution was filtered and filled into a 100 mL bottle. The bottle was then closed under a nitrogen atmosphere and sterilized.

Abstract

The invention relates to novel stable aqueous formulations of acetaminophen for injection as well as processes for preparing and using the same.

Description

AQUEOUS FORMULATIONS OF ACETAMINOPHEN FOR INJECTION CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to United States Provisional Application
No. 60/929, 192, filed June 18, 2007, which application is expressly incorporated herein by reference in its entirety.
BACKGROUNP OF THE INVENTION
1. Field of the Invention
[0002] The invention relates to novel stable aqueous formulations of acetaminophen for injection as well as processes for preparing and using the same.
2. Discussion of the Related Art
[0003] Acetaminophen, also known as paracetamol, is a common analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu medications and many prescription analgesics.
[0004] It has been known for many years the poor stability of acetaminophen in aqueous solutions and its inadequate solubility. Acetaminophen forms undesired degradation products by reaction with the oxygen in the air or with the oxygen dissolved in the aqueous solution. The rate of decomposition is accelerated as the temperature is increased and upon exposure to light. The stability is also a function of the solution's pH.
[0005] The instability of acetaminophen in aqueous solutions and the specific regulatory requirements to assure the safety, efficacy and quality of pharmaceutical drugs have prevented the development of intravenous dosage forms in comparison with tablet and suppository forms.
[0006] U.S. Pat. No. 6,028,222 describes aqueous formulations of acetaminophen containing a buffering agent and a free radical antagonist and/or a free radical scavenger which need to be bubbled with an inert gas through the aqueous solvent in order to remove oxygen from the medium and maintain the stability of acetaminophen. [0007J U.S. Pat. No. 6,992,218 B2 relates to aqueous formulations with an active principle susceptible to oxidation, for example acetaminophen, wherein the essential means for stabilizing them is deoxygenating by bubbling with an inert gas and/or placing under vacuum until the oxygen content is below 2 ppm.
[0008] Thus, there is thus still a need for acetaminophen aqueous formulations, free of any organic solvent, which are stable at ambient and room temperature and avoids removing the dissolved oxygen by bubbling an inert gas and/or placing under vacuum. The fact of not having to bubble an inert gas and/or to applying vacuum is traduced to an improved manufacturing process that requires less steps and therefore less cost.
SUMMARY OF THE INVENTION
[0009] The invention relates to novel stable aqueous formulations of acetaminophen for injection as well as processes for preparing and using the same.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0010] Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.
[0011] The invention provides new, stable, aqueous acetaminophen formulations.
[0012] In one aspect, the invention relates to a new stable, aqueous acetaminophen formulation that includes: a. approximately 200.0 mg to approximately 1,400.0 mg of acetaminophen; b. approximately 200.0 mg to approximately 10,000.0 mg of mannitol for injection; c. approximately 0.0 mg to approximately 30.0 mg of monobasic sodium phosphate; d. approximately 0.0 mg to approximately 300.0 mg of povidone; e. a sufficient amount of sodium hydroxide (as needed) is added to adjust the pH between approximately 4.0 and approximately 8.0; f. a sufficient amount of hydrochloric acid (as needed) is added to adjust the pH between approximately 4.0 and approximately 8.0; and g. an injection volume of water for injection up to a volume of approximately 100 mL.
[0013] In another aspect, the invention includes a new stable, aqueous composition that includes acetaminophen having the following composition: a. approximately 1,000.0 mg of acetaminophen; b. approximately 3,750.0 mg of mannitol for injection; c. approximately 13.0 mg of monobasic sodium phosphate; d. approximately 100.0 mg of povidone; e. a sufficient amount of sodium hydroxide is added to adjust the pH until approximately 5.5; f. a sufficient amount of hydrochloric acid is added to adjust the pH until approximately 5.5; and g. an injection volume of water for injection up to a volume of approximately 10O mL.
[0014] Another embodiment of the invention provides a process for preparing the above- described aqueous composition that includes the following steps: a. adding monobasic sodium phosphate, povidone, mannitol for injection and acetaminophen in a volume of water for injection to form the aqueous formulation; b. if necessary, adding sodium hydroxide or hydrochloric acid to adjust the pH of the aqueous formulation between approximately 4.0 and approximately
8.0; c. adjusting the final volume of he aqueous formulation by adding additional water for injection; d. filtering the aqueous formulation; e. filling the aqueous formulation into bottles; f. closing the bottles containing the aqueous formulation under an inert (e.g., nitrogen) atmosphere; and g. sterilizing the bottle containing the aqueous formulation.
[0015] It should be understood that the word "bottles" is meant to convey glass or plastic containers or any other materials suitable for containing the aqueous formulations of acetaminophen described herein.
[0016] The invention further includes the use of the aqueous pharmaceutical formulations of acetaminophen according to the invention for the treatment of pain. In particular, the invention further includes the use of the aqueous pharmaceutical formulations of acetaminophen for the treatment of pain after surgery and treatment of short period of fever when intravenous administration is justified or when others routes of administration are not possible.
[0017] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
[0018] The following example is for illustrative purposes only and is not intended, nor should it be interpreted, to limit the scope of the invention.
[0019] EXAMPLE 1: Aqueous solution of acetaminophen
[0020] Table 1 illustrates a formulation of an aqueous acetaminophen solution with the following constituents:
Table 1
[0021] The aqueous acetaminophen formulation of Table 1 was prepared by dissolving 13.0 mg of monobasic sodium phosphate, 100.0 mg of povidone, 3,750.0 mg of mannitol for injection and 1,000.0 mg of acetaminophen in 80 mL of water for injection. Then, the pH is checked, and if necessary was adjusted until 5.5 by adding sodium hydroxide or hydrochloric acid. The solution was adjusted to 100 mL by the addition of water for injection. Next, he solution was filtered and filled into a 100 mL bottle. The bottle was then closed under a nitrogen atmosphere and sterilized.
[0022] The stability of acetaminophen solution was evaluated until 6 weeks. The solution was stored at 25° C/60% HR and 40° C/75% HR. During the stability period time, relative substances, color and pH were studied and we can conclude that acetaminophen solution is stable and no acetaminophen degradation occurred and none of its physicochemical characteristics has changed significantly.
[0023] Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the disclosure has been made only by way of example, and that numerous changes in the conditions and order of steps can be resorted to by those skilled in the art without departing from the spirit and scope of the invention.

Claims

1. A stable aqueous formulation of acetaminophen for injection comprising: a. approximately 200.0 mg to approximately 1,400.0 mg of acetaminophen; b. approximately 200.0 mg to approximately 10,000.0 mg of mannitol for injection; c. approximately 0.0 mg to approximately 30.0 mg of monobasic sodium phosphate; d. approximately 0.0 mg to approximately 300.0 mg of povidone; e. a sufficient amount of sodium hydroxide and hydrochloric acid as needed in order to adjust the pH to between approximately 4.0 and approximately 8.0; and f. a volume of water for injection up to a volume of approximately 100 mL.
2. The aqueous formulation of acetaminophen of claim 1 comprising approximately 1,000.0 mg of said acetaminophen; approximately 3,750.0 mg of said mannitol for injection; approximately 13.0 mg of said monobasic sodium phosphate; and approximately 100.0 mg of said povidone.
3. A process for preparing the aqueous formulation of acetaminophen of any of claims 1 and 2 comprising: a. adding said monobasic sodium phosphate, said povidone, said mannitol for injection and said acetaminophen in a volume of water for injection to form the aqueous formulation; b. if necessary, adding sodium hydroxide or hydrochloric acid to adjust the pH of the aqueous formulation to between approximately 4.0 and approximately 8.0; and c. adjusting the final volume of the aqueous formulation by adding additional water for injection.
4. The process of claim 3, further comprising at least one of: a. filtering the aqueous formulation; b. filling the aqueous formulation into a bottle; c. closing a bottle containing the aqueous formulation under an inert atmosphere; and d. sterilizing a bottle containing the aqueous formulation.
5. Use of the aqueous formulation of acetaminophen according to any of claims 1 and 2 or made by any of the methods of claims 3 and 4 comprising administering a sufficient amount of the aqueous formulation of acetaminophen to a patient in need thereof to eliminate pain.
6. The use of claim 5, wherein the pain occurs following surgery.
EP08837144A 2007-06-18 2008-06-18 Aqueous formulations of acetaminophen for injection Withdrawn EP2170313A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US92919207P 2007-06-18 2007-06-18
PCT/IB2008/003217 WO2009047634A2 (en) 2007-06-18 2008-06-18 Aqueous formulations of acetaminophen for injection

Publications (1)

Publication Number Publication Date
EP2170313A2 true EP2170313A2 (en) 2010-04-07

Family

ID=40429866

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08837144A Withdrawn EP2170313A2 (en) 2007-06-18 2008-06-18 Aqueous formulations of acetaminophen for injection

Country Status (3)

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EP (1) EP2170313A2 (en)
AR (1) AR067048A1 (en)
WO (1) WO2009047634A2 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2243477A1 (en) * 2009-04-22 2010-10-27 Fresenius Kabi Deutschland GmbH Paracetamol for parenteral application
US20120245230A1 (en) * 2009-12-10 2012-09-27 Tecnimede-Sociedade Tecnico- Medicinal, S.A. Method and composition for preparing stable liquid formulations of paracetamol
PT2377516E (en) 2010-04-14 2012-07-02 Braun Melsungen Ag Acetaminophen composition
ES2866636T3 (en) * 2010-06-30 2021-10-19 Troikaa Pharmaceuticals Ltd Pharmaceutical compositions comprising paracetamol and process for preparing the same
ZA201300398B (en) * 2012-11-27 2013-09-25 Genfarma Laboratories S L Injectable liquid formulation of the combination of tramadol and paracetamol
AU2015365533A1 (en) 2014-12-20 2017-07-06 Troikaa Pharmaceuticals Limited Injectable formulations of paracetamol

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2751875B1 (en) * 1996-08-05 1998-12-24 Scr Newpharm NOVEL STABLE LIQUID FORMULATIONS BASED ON PARACETAMOL AND THEIR METHOD OF PREPARATION
FR2809619B1 (en) * 2000-06-06 2004-09-24 Pharmatop NOVEL AQUEOUS FORMULATIONS OF OXIDATION-SENSITIVE ACTIVE INGREDIENTS AND PROCESS FOR OBTAINING THEM
FR2851164B1 (en) * 2003-02-14 2005-04-22 Xuan Tho Nguyen INFLATABLE LIQUID FORMULATION OF PARACETAMOL
GB0613925D0 (en) * 2006-07-13 2006-08-23 Unilever Plc Improvements relating to nanodispersions
EP1992334A1 (en) * 2007-05-08 2008-11-19 Docpharma NV/SA Storage-stable formulation of oxidation-sensitive phenolic drug, especially paracetamol, comprises aqueous drug solution deoxygenated by a temperature-controlled manufacturing process of the formulation

Non-Patent Citations (1)

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Title
See references of WO2009047634A3 *

Also Published As

Publication number Publication date
AR067048A1 (en) 2009-09-30
WO2009047634A2 (en) 2009-04-16
WO2009047634A3 (en) 2009-06-04

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