WO2009070829A1 - Compositions de fentanyle à base d'huile, non aqueuses, pour une administration par voie transmucosale - Google Patents

Compositions de fentanyle à base d'huile, non aqueuses, pour une administration par voie transmucosale Download PDF

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Publication number
WO2009070829A1
WO2009070829A1 PCT/AU2008/001779 AU2008001779W WO2009070829A1 WO 2009070829 A1 WO2009070829 A1 WO 2009070829A1 AU 2008001779 W AU2008001779 W AU 2008001779W WO 2009070829 A1 WO2009070829 A1 WO 2009070829A1
Authority
WO
WIPO (PCT)
Prior art keywords
oil
fentanyl
composition
active agent
solvent
Prior art date
Application number
PCT/AU2008/001779
Other languages
English (en)
Inventor
Alexander James Kelly
Original Assignee
Krius Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2007906641A external-priority patent/AU2007906641A0/en
Application filed by Krius Pty Ltd filed Critical Krius Pty Ltd
Publication of WO2009070829A1 publication Critical patent/WO2009070829A1/fr

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0043—Nose
    • 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 invention described herein relates generally to anesthesia and analgesia.
  • the invention is directed to transmucosal administration of a non-aqueous composition containing fentanyl or its derivatives, including nasal administration, although the scope of the invention is not necessarily limited thereto.
  • Fentanyls are extensively used for anesthesia and analgesia, most often in the operating room and intensive care unit.
  • Fentanyl transdermal patch is used in chronic pain management.
  • Fentanyl patches work by releasing fentanyl into body fats, which then slowly release the drug into the blood stream over 72 hours, allowing for long lasting relief from pain.
  • Fentanyl lozenges are a solid formulation of fentanyl citrate on a stick in the form of a lollipop that dissolves slowly in the mouth for transmucosal absorption. These lozenges are intended for opioid-tolerant individuals and are effective in treating breakthrough cancer pain.
  • Small fentanyl buccal pellets have also been developed. These are effervescent tablets placed in the cheek and is absorbed through the buccal mucosa. One advantage of such tablets is claimed to be quicker absorption into the bloodstream at lower dosage levels.
  • Fentanyl is frequently given intrathecally as part of spinal anesthesia or epidurally for epidural anesthesia and analgesia. It is also used as a sedative.
  • fentanyl administered transmucosally or intranasally is effective in the relief of postoperative pain and cancer pain.
  • Transmucosal and intranasal delivery of low concentrations and low doses of fentanyl have been performed.
  • Transmucosal and nasal routes would therefore be suitable for use in patients requiring rapid relief from severe pain.
  • General advantages of transmucosal and nasal application aiming at systemic effect are ease of self-administration, supporting a health- economic argument and the self-care concept. In addition, first pass liver metabolism and gastro-intestinal metabolism are avoided.
  • WO2002/009707 describes intranasal delivery of fentanyl in aqueous solutions. Although effective, fentanyl and derivatives are not particularly soluble in water. In addition, absorption of the active agent from an aqueous solution is not optimal.
  • the invention provides compositions of fentanyl and derivatives in non-aqueous formulation with unexpected advantages over the compositions disclosed in the prior art.
  • the invention provides a composition for transmucosal administration, the composition comprising a solution of at least one active agent selected from the group consisting of fentanyl, a derivative of fentanyl and an analogue of fentanyl in at least one non-aqueous oil-based solvent.
  • the invention provides a method of treating pain in a subject, the method comprising transmucosal administration of a composition comprising at least one active agent selected from the group consisting of fentanyl, a derivative of fentanyl and an analogue of fentanyl, in a non-aqueous oil-based solvent.
  • the composition comprises fentanyl or a derivative thereof, such as alfentanyl, sulfentanyl, remifentanyl, carfentanyl and ohmefentanyl, or the salts of fentanyl and the derivatives.
  • the composition comprises a mixture of fentanyl and one or more fentanyl derivative.
  • the concentration of active agent in the composition can be any practicable concentration but is preferably from l ⁇ g/ml to 100mg/ml.
  • the solvent of the invention can be any practicable non-aqueous oil-based solvent, such as vegetable oils, for example olive oil, almond oil, peppermint oil, macadamia oil, eucalyptus oil, canola oil, cottonseed oil, peanut oil and soybean oil; or other equivalents of a pharmacopoeial nature, for example paraffin liquid, glycerine, polyethylene glycol, polypropylene glycol.
  • the solvent of the invention is preferably glycerine (glycerol), paraffin liquid, olive oil or almond oil.
  • the composition can further comprise a fragrance component, such as an ester, scented oil, or artificial scent.
  • a fragrance component such as an ester, scented oil, or artificial scent.
  • the composition can also further comprise a preservative such as benzyl alcohol, LiquaPar® Oil (ISP Corporation), benzalkonium chloride, EDTA, benzethonium chloride, chlorobutanol, parabens and phenoxyethanol, to allow for inclusion of the composition in a device for multi-dose administration.
  • a preservative such as benzyl alcohol, LiquaPar® Oil (ISP Corporation), benzalkonium chloride, EDTA, benzethonium chloride, chlorobutanol, parabens and phenoxyethanol.
  • the preservative is LiquaPar® Oil, parabens, benzyl alcohol or benzalkonium chloride.
  • Transmucosal administration can be effected by any practicable manner, but is preferable effected by nasal administration.
  • the nasal administration of the composition can be effected in any practicable manner, including by swab, droplets, or spray.
  • the composition is preferably administered by spray, from a suitable spray device.
  • the device can be of any appropriate configuration, and is preferably a device which delivers a spray volume of between 1 ⁇ l and 1 ml per actuation of the device.
  • An example of such a device is a Valois® VP7 pump, or the Valois FreepodTM system.
  • the invention therefore provides a composition of fentanyl or derivatives thereof with enhanced solubility, drug delivery and drug uptake, which necessitates lower doses of the active and consequent lower incidence of side effects.
  • the non-aqueous oil-based solvent also increases the stability of the active in solution, ensuring a longer shelf-life and preservation of activity of the composition.
  • fragrance acts as an identifier for both healthcare workers and patients to increase safety of administration and patient compliance.
  • composition is packaged in a glass vial of Type 1 clear or amber glass of volume from 0.1 milliliter up to 100 milliliters of the type typically used for an injection pharmaceutical.
  • composition may also be packaged in a single use device of the type manufactured by Valois or equivalent such as the Valois MonodoseTM or DolphinTM.
  • a single use device of the type manufactured by Valois or equivalent such as the Valois MonodoseTM or DolphinTM.
  • volume of a single-use container is between 0.1 and 2 milliliters
  • Fentanyl is highly lipid soluble and stable in such a non-aqueous liquid phase. It has an octanol-water partition coefficient (drug lipid-solubility study method) several thousand times higher than morphine, a readily water soluble opiate drug.
  • Fentanyl's high solubility in non-aqueous solutions can improve the uptake of the drug via the transmucosal and particularly the nasal route.
  • fentanyl citrate Using a non-aqueous system allows the form ⁇ lator to use the exact quantity of fentanyl base for formulation, thereby reducing errors and reducing salts of addition for some water- soluble versions of fentanyl, for example fentanyl citrate.
  • a non-aqueous formulation is retained for a prolonged period on the mucosa, particularly the nasal mucosa, when compared to an aqueous formulation.
  • a non-aqueous formulation can mask the unpleasant taste experienced at the back of the throat upon application of an opioid-containing nasal spray.
  • a non-aqueous formulation ensures the drug cannot be easily misused by mixing with other solutions, for example a non-aqueous solution of fentanyl would not be miscible with an alcoholic drink and therefore a potential 'date-rape' victim would be alerted to the presence of that formulation in such a drink.
  • Non-aqueous based transmucosal and nasal sprays have more comfortable feel on administration, avoiding the "cold" feeling of an aqueous system.
  • Non-aqueous formulations can assist with inclusion of a fragrance to improve drug safety and compliance. It is clear from the foregoing that the invention provides an improved composition of fentanyl and/or its derivatives for transmucosal administration.
  • the invention provides a composition of fentanyl or derivatives thereof with enhanced solubility, drug delivery and drug uptake, which necessitates lower doses of the active and consequent lower incidence of side effects. Stability of the active in solution is also increased.
  • optional inclusion of a fragrance acts as an identifier for both healthcare workers and patients to increase safety of administration and patient compliance.
  • optimal inclusion of a preservative allows for provision of a multi-dose formulation.

Abstract

L'invention porte sur une composition et sur un procédé de traitement de la douleur à l'aide de la composition, la composition comprenant une solution d'au moins un agent actif choisi dans le groupe constitué par le fentanyle, un dérivé de fentanyle et un analogue du fentanyle dans au moins un solvant à base d'huile, non aqueux, pour une administration par voie transmucosale.
PCT/AU2008/001779 2007-12-05 2008-12-02 Compositions de fentanyle à base d'huile, non aqueuses, pour une administration par voie transmucosale WO2009070829A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2007906641A AU2007906641A0 (en) 2007-12-05 Novel Compositions
AU2007906641 2007-12-05

Publications (1)

Publication Number Publication Date
WO2009070829A1 true WO2009070829A1 (fr) 2009-06-11

Family

ID=40717187

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2008/001779 WO2009070829A1 (fr) 2007-12-05 2008-12-02 Compositions de fentanyle à base d'huile, non aqueuses, pour une administration par voie transmucosale

Country Status (1)

Country Link
WO (1) WO2009070829A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8017627B2 (en) 2000-07-31 2011-09-13 Nycomed Danmark Aps Fentanyl composition for nasal administration
GB2481728A (en) * 2010-06-30 2012-01-04 Londonpharma Ltd Formulations and delivery devices for the sublingual administration of opioids
GB2534624A (en) * 2014-08-21 2016-08-03 Simon Corbitt Terence Formulations for transmucosal delivery

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009707A1 (fr) * 2000-07-31 2002-02-07 Nycomed Danmark A/S Composition a base de fentanyl destinee a l'administration nasale
US20040115133A1 (en) * 2000-05-10 2004-06-17 Wermeling Daniel P. Intranasal opioid compositions
WO2005117830A1 (fr) * 2004-06-04 2005-12-15 Camurus Ab Formulations de depot lipidique
US20070225379A1 (en) * 2001-08-03 2007-09-27 Carrara Dario Norberto R Transdermal delivery of systemically active central nervous system drugs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040115133A1 (en) * 2000-05-10 2004-06-17 Wermeling Daniel P. Intranasal opioid compositions
WO2002009707A1 (fr) * 2000-07-31 2002-02-07 Nycomed Danmark A/S Composition a base de fentanyl destinee a l'administration nasale
US20070225379A1 (en) * 2001-08-03 2007-09-27 Carrara Dario Norberto R Transdermal delivery of systemically active central nervous system drugs
WO2005117830A1 (fr) * 2004-06-04 2005-12-15 Camurus Ab Formulations de depot lipidique

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8017627B2 (en) 2000-07-31 2011-09-13 Nycomed Danmark Aps Fentanyl composition for nasal administration
US8158651B2 (en) 2000-07-31 2012-04-17 Nycomed Danmark Aps Fentanyl composition for nasal administration
US8653107B2 (en) 2000-07-31 2014-02-18 Takeda Pharma A/S Fentanyl composition for nasal administration
GB2481728A (en) * 2010-06-30 2012-01-04 Londonpharma Ltd Formulations and delivery devices for the sublingual administration of opioids
WO2012001411A3 (fr) * 2010-06-30 2012-03-29 Londonpharma Ltd Formulations et administration
GB2481728B (en) * 2010-06-30 2012-05-23 Londonpharma Ltd Formulations and delivery devices for the sublingual administration of opioids
EP2653152A1 (fr) * 2010-06-30 2013-10-23 Londonpharma Ltd. Compositions pharmaceutiques pour l'administration par voie sublinguale d'opioïdes
GB2534624A (en) * 2014-08-21 2016-08-03 Simon Corbitt Terence Formulations for transmucosal delivery

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