WO2014083071A1 - Préparation liquide injectable consistant en une combinaison de tramadol et de paracétamol - Google Patents

Préparation liquide injectable consistant en une combinaison de tramadol et de paracétamol Download PDF

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Publication number
WO2014083071A1
WO2014083071A1 PCT/EP2013/074896 EP2013074896W WO2014083071A1 WO 2014083071 A1 WO2014083071 A1 WO 2014083071A1 EP 2013074896 W EP2013074896 W EP 2013074896W WO 2014083071 A1 WO2014083071 A1 WO 2014083071A1
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WO
WIPO (PCT)
Prior art keywords
liquid formulation
paracetamol
formulation according
tramadol
autoclaving
Prior art date
Application number
PCT/EP2013/074896
Other languages
English (en)
Inventor
Mario Ortuzar Gutierrez
Ignacio Ortuzar Andechaga
Original Assignee
Genfarma Laboratorio, S.L.
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 Genfarma Laboratorio, S.L. filed Critical Genfarma Laboratorio, S.L.
Publication of WO2014083071A1 publication Critical patent/WO2014083071A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K47/16—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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic 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
    • A61K47/26—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
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the treatment of pain is an essential role of the doctors due to the fact that pain is one of the main symptoms of the patients, more particularly in patients after surgery.
  • pain is one of the main symptoms of the patients, more particularly in patients after surgery.
  • analgesics there is a wide range of analgesics to choose, and the final analgesic elected is normally chosen taking into account its efficacy as well as all the aspects related to its safety and adverse effects.
  • the treatment is in monotherapy, although in many cases the combination of different drugs that act in different targets facilitates the treatment.
  • Paracetamol also known as acetaminophen or N-acetyl-p-aminophenol, is an active ingredient that has been widely used in the last decades in pharmaceutical preparations due to its activity as an analgesic and an antipyretic, which was introduced by Von Mering in 1893. It is further well tolerated by human beings and does not alter the acid-base equilibrium, therefore it is widely used to relive mild to moderate pain both in adults and in children and in the elderly. However, it is poorly soluble in water, and for this reason a number of prior art liquid paracetamol solutions need an additional solubilizing adjuvant such as an alcohol like ethanol. Paracetamol does not become habit-forming when taken for a long time, but may cause other unwanted effects with taken in large doses, including liver damage.
  • Tramadol ((1 R,2R) or (1 S, 2S) (dimethylamino)methyl-1 -(3-methoxyphenyl) cyclohexanol) belongs to the group of medicines called opioid analgesics (narcotics), acting in the central nervous system to relieve pain. Tramadol is used in the treatment of modere to severe pain. When tramadol is used for a long time, it may become habit-forming, causing mental or physical dependence.
  • the solutions disclosed in this document lack of any of the stabilizing compounds used in the present invention; the only additive used there is Tween 80, a pharmacological dispersant.
  • Tween 80 a pharmacological dispersant
  • document FR 2 751 875 and its several patent family members such as AU 199739451 , disclose methods for obtaining aqueous formulations for paracetamol, optionally including a central nervous system analgesic.
  • the aqueous solvent used in these formulations needs to be bubbled into an inert gas (or, in the case of AU2006203741 B2, the solution is alternatively placed under vacuum) in order to substantially eliminate any dissolved oxygen from the solvent.
  • the formulations disclosed therein require additional components such as anti-radical agents or free radical scavengers.
  • no experimental examples of solutions comprising both paracetamol and tramadol were included in these documents, and consequently it is not clear how solutions comprising paracetamol and tramadol prepared according to these disclosures could react upon autoclaving.
  • document CN101 147731 discloses formulations containing paracetamol and tramadol.
  • all the examples refer to either small-capacity vials (3 mL) or to a freeze-dried (lyophilized) powder, which should be dissolved before administration. Therefore, these compositions are not suitable for infusion but, probably, just for intravenous injection as bolus, because intravenous solution in bolus should have a volume lower than 10 mL to allow the drug to act quickly; therefore these solutions should be administered in 1 -2 minutes.
  • intravenous infusion is used when the drug is to be administered in more than 10 min, the volume of these solutions being usually higher than 50 mL (intravenous infusion is the usual administration method for pain control).
  • the present invention is thus directed to combinations of tramadol and paracetamol in different proportions, combinations that are suitable to be administered by intravenous infusion and that are stable upon autoclaving, i.e, they can be successfully sterilised by autoclaving with a minimal loss of active principle and development of undesirable impurities.
  • the problem to be solved by the present invention is to provide an stable liquid formulation based on the combination of tramadol and paracetamol in a aqueous solvent that is suitable to be administered by infusion in the treatment of moderate to acute pain, that allows thermal sterilization by autoclaving with minimal loss of content of the active ingredients and minimal production of impurities.
  • aqueous solution depends of the choice of the different components of the formulation, such as the pH and the sterilization process, among others variables.
  • the following formulations were prepared. In each case, the osmolality was adjusted to 300 mOsmol/kg with an isotonizing agent, if required.
  • Formulation B containing tramadol and paracetamol using manitol and cysteine as stabilizing agent To a 65 mL aqueous solution containing paracetamol (650 mg, 10 mg/mL paracetamol), cysteine HCI 16.2 mg, and manitol 2.5 g (or q.s. for isotonicity) buffered with phosphate buffer, 75 mg of tramadol hydrochloride were added and the volume was completed to 100 mL using water for injection, the final pH being adjusted to a value between 4.90-5.30 using hydrochloric acid or sodium hydroxide as required.
  • the composition of formula B is described in the table below:
  • Formulation F containing tramadol and paracetamol using manitol and hvdroxyethylstarch as stabilizing agent To a 65 mL aqueous solution containing paracetamol (650 mg, 10 mg/mL paracetamol), hydroxyethylstarch 325 mg and manitol 2.0 g or q.s. for isotonicity buffered with citrate-acetate buffer, 75 mg of tramadol hydrochloride were added and the volume was completed to 100 mL using water for injection, the final pH being adjusted to a value between 5.30 - 5.80 using acetic acid as required.
  • the composition of formula F is described in the table below:
  • the content of active substances after autoclaving is an essential parameter.
  • the minimum acceptable content of tramadol and paracetamol after autoclaving has been considered to be at least 95% of the initial active substance content added to the solution.

Abstract

L'invention concerne une préparation liquide pour perfusion intraveineuse comprenant du tramadol et du paracétamol dans un solvant aqueux non désoxygéné. La préparation est adaptée à la perfusion intraveineuse, elle est stable après autoclavage avec un minimum de perte en principes actifs et un minimum de développement d'impuretés indésirables.
PCT/EP2013/074896 2012-11-27 2013-11-27 Préparation liquide injectable consistant en une combinaison de tramadol et de paracétamol WO2014083071A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12382465 2012-11-27
EP12382465.8 2012-11-27

Publications (1)

Publication Number Publication Date
WO2014083071A1 true WO2014083071A1 (fr) 2014-06-05

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PCT/EP2013/074896 WO2014083071A1 (fr) 2012-11-27 2013-11-27 Préparation liquide injectable consistant en une combinaison de tramadol et de paracétamol

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WO (1) WO2014083071A1 (fr)
ZA (1) ZA201300398B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017134540A1 (fr) * 2016-02-05 2017-08-10 Innopharma, Inc. Procédé de fabrication d'une poche pour perfusion intraveineuse stable et prête à l'emploi pour une formulation sensible à l'oxydation
WO2019161938A1 (fr) * 2018-02-20 2019-08-29 Laboserve Pharmaceutical Company S.A. Solutions orales comprenant du tramadol

Citations (12)

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Publication number Priority date Publication date Assignee Title
WO1993004675A1 (fr) 1991-09-06 1993-03-18 Mcneilab, Inc. Composition renfermant une matiere a base de tramadol et de l'acetaminophene, et son utilisation
FR2751875A1 (fr) 1996-08-05 1998-02-06 Scr Newpharm Nouvelles formulations liquides stables a base de paracetamol et leur mode de preparation
CN101147731A (zh) 2006-11-22 2008-03-26 陈旭良 盐酸曲马多与对乙酰氨基酚组合的注射剂
WO2009047634A2 (fr) * 2007-06-18 2009-04-16 Combino Pharm, S.L. Préparations aqueuses d'acétaminophène pour injection
EP2100596A2 (fr) * 2006-07-18 2009-09-16 Genfarma Laboratorio S.L. Formule du paracetamol liquide injectable
AU2006203741B2 (en) 2000-06-06 2009-11-05 Scr Pharmatop Method for obtaining aqueous formulations with active principles susceptible to oxidation and the aqueous solutions thus obtained
EP2277546A1 (fr) * 2009-07-23 2011-01-26 Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. Formule de paracétamol injectable, stable et prête à utiliser
WO2011071400A1 (fr) * 2009-12-10 2011-06-16 Tecnimede - Sociedade Técnico-Medicinal, S.A. Procédé et composition pour préparation de formulations liquides stables de paracétamol
EP2377514A2 (fr) 2010-04-19 2011-10-19 Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. Formulation parentérale liquide comportant un matériau de tramadol et paracétamol
WO2011128364A1 (fr) * 2010-04-14 2011-10-20 B. Braun Melsungen Ag Composition d'acétaminophène
WO2011144335A1 (fr) * 2010-05-19 2011-11-24 Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. Préparation de paracétamol injectable stable, prête à l'emploi
WO2012107093A1 (fr) * 2011-02-10 2012-08-16 Neogen N.V. Formulation de paracétamol en solution aqueuse stable au stockage

Patent Citations (13)

* Cited by examiner, † Cited by third party
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WO1993004675A1 (fr) 1991-09-06 1993-03-18 Mcneilab, Inc. Composition renfermant une matiere a base de tramadol et de l'acetaminophene, et son utilisation
FR2751875A1 (fr) 1996-08-05 1998-02-06 Scr Newpharm Nouvelles formulations liquides stables a base de paracetamol et leur mode de preparation
AU3945197A (en) 1996-08-05 1998-02-25 Scr Pharmatop Novel stable liquid paracetamol compositions, and method for preparing same
AU2006203741B2 (en) 2000-06-06 2009-11-05 Scr Pharmatop Method for obtaining aqueous formulations with active principles susceptible to oxidation and the aqueous solutions thus obtained
EP2100596A2 (fr) * 2006-07-18 2009-09-16 Genfarma Laboratorio S.L. Formule du paracetamol liquide injectable
CN101147731A (zh) 2006-11-22 2008-03-26 陈旭良 盐酸曲马多与对乙酰氨基酚组合的注射剂
WO2009047634A2 (fr) * 2007-06-18 2009-04-16 Combino Pharm, S.L. Préparations aqueuses d'acétaminophène pour injection
EP2277546A1 (fr) * 2009-07-23 2011-01-26 Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. Formule de paracétamol injectable, stable et prête à utiliser
WO2011071400A1 (fr) * 2009-12-10 2011-06-16 Tecnimede - Sociedade Técnico-Medicinal, S.A. Procédé et composition pour préparation de formulations liquides stables de paracétamol
WO2011128364A1 (fr) * 2010-04-14 2011-10-20 B. Braun Melsungen Ag Composition d'acétaminophène
EP2377514A2 (fr) 2010-04-19 2011-10-19 Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. Formulation parentérale liquide comportant un matériau de tramadol et paracétamol
WO2011144335A1 (fr) * 2010-05-19 2011-11-24 Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. Préparation de paracétamol injectable stable, prête à l'emploi
WO2012107093A1 (fr) * 2011-02-10 2012-08-16 Neogen N.V. Formulation de paracétamol en solution aqueuse stable au stockage

Non-Patent Citations (2)

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Title
EMIR E ET AL: "Tramadol Versus Low Dose Tramadol-paracetamol for Patient Controlled Analgesia During Spinal Vertebral Surgery", KAOHSIUNG JOURNAL OF MEDICAL SCIENCES, KAOHSIUNG MEDICAL COLLEGE, KAOHSIUNG, TW, vol. 26, no. 6, 9 June 2010 (2010-06-09), pages 308 - 315, XP027081216, ISSN: 1607-551X, [retrieved on 20100601], DOI: 10.1016/S1607-551X(10)70044-9 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017134540A1 (fr) * 2016-02-05 2017-08-10 Innopharma, Inc. Procédé de fabrication d'une poche pour perfusion intraveineuse stable et prête à l'emploi pour une formulation sensible à l'oxydation
CN108601704A (zh) * 2016-02-05 2018-09-28 因诺制药有限公司 制造用于氧化敏感制剂的稳定的、即用型输液袋的方法
JP2019506407A (ja) * 2016-02-05 2019-03-07 イノファーマ インク 酸化感受性製剤のための安定なすぐ使用できる注入バッグを製造するプロセス
AU2017215419B2 (en) * 2016-02-05 2019-11-21 Innopharma, Inc. Process of manufacturing a stable, ready to use infusion bag for an oxidation sensitive formulation
RU2729528C2 (ru) * 2016-02-05 2020-08-07 ИННОФАРМА, Инк. Способ изготовления стабильного, готового к применению инфузионного мешка для чувствительной к окислению композиции
AU2019257508B2 (en) * 2016-02-05 2020-12-24 Innopharma, Inc. Process of manufacturing a stable, ready to use infusion bag for an oxidation sensitive formulation
WO2019161938A1 (fr) * 2018-02-20 2019-08-29 Laboserve Pharmaceutical Company S.A. Solutions orales comprenant du tramadol

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