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WO2010072398A2 - Formulations vétérinaires - Google Patents

Formulations vétérinaires Download PDF

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Publication number
WO2010072398A2
WO2010072398A2 PCT/EP2009/009196 EP2009009196W WO2010072398A2 WO 2010072398 A2 WO2010072398 A2 WO 2010072398A2 EP 2009009196 W EP2009009196 W EP 2009009196W WO 2010072398 A2 WO2010072398 A2 WO 2010072398A2
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
alcohol
buprenorphine
formulations
acid
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.)
Ceased
Application number
PCT/EP2009/009196
Other languages
English (en)
Other versions
WO2010072398A3 (fr
Inventor
Philip Watson
Claire Fowler
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.)
Boehringer Ingelheim Ltd
Original Assignee
Boehringer Ingelheim 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
Application filed by Boehringer Ingelheim Ltd filed Critical Boehringer Ingelheim Ltd
Publication of WO2010072398A2 publication Critical patent/WO2010072398A2/fr
Publication of WO2010072398A3 publication Critical patent/WO2010072398A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • 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

Definitions

  • Veterinary Formulations The present invention relates to pharmaceutical formulations and uses thereof, in particular to pharmaceutical formulations which contain buprenorphine or a salt thereof.
  • Buprenorphine and pharmaceutically acceptable salts thereof are used in veterinary practice as an analgesic, for example as a post-operative analgesic and as a sedative.
  • Buprenorphine acts on opiate receptors in the central nervous system.
  • Vetergesic® Rositt-Benckiser
  • this product may be misused, with the liquid remaining in the ampoule not discarded but retained for subsequent use, possibly in the next day's surgery.
  • the present inventors decided to investigate the possibility of a multi-dose formulation containing buprenorphine. As shown in the accompanying Examples, having decided to include a preservative in the formulation, selection of a suitable preservative was not straightforward. However, a suitable formulation was eventually made using an alcohol as preservative.
  • the present invention provides a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, said formulation containing ⁇ 1% w/v of buprenorphine or said salt thereof.
  • the invention provides a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, said formulation containing ⁇ 3% w/v of alcohol.
  • the alcohol is present in an amount effective to act as a preservative of said formulation, typically the formulation will contain at least 0.5% w/v of alcohol, more usually at least 1%, e.g. 1-2%, most preferably about 1.5%.
  • the formulation will typically contain 5 to 50 mg/ml of alcohol, preferably 10 to 25 mg/ml, most preferably about 15 mg/ml.
  • the preserving alcohol component may be made up of more than one type of alcohol, e.g. part benzyl alcohol and part ethanol , but preferably a single alcohol species will be used.
  • 'Alcohol' as used herein incorporates those molecules in which an OH group is covalently attached to a carbon atom which is itself not part of an aromatic group, thus phenols are excluded.
  • the alcohol may be polyhydric but is preferably monohydric. Suitable alcohols include benzyl alcohol, ethanol, isopropanol and phenoxy-ethanol .
  • the alcohol component preferably comprises, more preferably consists essentially of or consists of benzyl alcohol (i.e. the alcohol component is at least 90%, preferably at least 95%, more preferably at least 98 or 99% benzyl alcohol) .
  • the alcohol is not a glycol .
  • the formulations of the invention contain 1 to 3% w/v of benzyl alcohol. Most preferably they contain around 1.5% w/v benzyl alcohol.
  • Suitable pharmaceutically acceptable salts are well known in the art and may be formed with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, raaleic acid, hydroxyraaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzene ⁇ ulfonic acid and toluenesulfonic acid.
  • Buprenorphine hydrochloride is especially preferred and in the formulations of the present invention is preferred even to buprenorphine itself.
  • Formulations comprising buprenorphine hydrochloride and benzyl alcohol have been described in the art, in WO 2007/061739. These formulations are specifically for otic or transdermal use and are intended to be in single dosage form, in contrast to the present invention which is able to provide a multi-dose formulation, preferably for administration by injection.
  • the benzyl alcohol is not included to act as a preservative. Instead, the benzyl alcohol is included to act as a solubilizer and hence it is present at levels appropriate for that function, specifically at 5% or 10% w/w.
  • the level of buprenorphine present in the formulations of WO 2007/061739 reflects the specific route of administration. Otic (administered via the ear) or transdermal routes are less efficient methods of drug delivery than most other routes, e.g. via injection. Hence the buprenorphine is present at higher levels than those typically contemplated by the present invention. A reduction in the amount of buprenorphine or benzyl alcohol in these formulations is not compatible with the role these ingredients perform or the route of administration taught in WO 2007/061739.
  • the formulations of the present invention contain sufficient buprenorphine (unless otherwise clear from the context, reference herein to buprenorphine also encompasses pharmaceutically acceptable salts thereof) for the formulation to function as an analgesic or sedative
  • the formulations are preferably for administration to non-human animals and the appropriate dosage can be determined according to the animal species, the weight of the animal and other clinical factors.
  • the present multi-dose formulation is suitable for use in accordance with the guidelines proposed for the existing single dose Vetergesic® product, as exemplified below:
  • the formulations typically contain ⁇ 1% buprenorphme, e.g. 0.01 to 1%, preferably 0 02 to ⁇ 0 1%, more preferably 0.02 to 0.06%, still more preferably 0.03 to 0.04%, most preferably 0.03 to 0 035%. All percentages are given on a w/v basis.
  • formulations preferably contain 0.3 to 0.4 mg buprenorphme per ml of formulation, more preferably 0.30 to 0.35 mg/ml, e.g. about 0.32 mg/ml .
  • the formulations of the invention may be present in single-dosage form but are particularly suitable as multi-dose formulations.
  • the amount of the formulation present in a single packaged unit e.g m a glass vial, will typically be 5-50 ml, preferably 10-20 ml, most preferably about 10 ml, which is sufficient to supply an average veterinary surgery for about 3 days, although the formulations are usable after opening for longer than this.
  • the formulations of the invention should have a 'shelf life 1 of at least 5 days, preferably at least 7 days.
  • the formulations of the invention will preferably have a pH between 4 and 7, more preferably between 4.5 and 5.5, most preferably between 4.8 and 5.2, e.g. around 5.0.
  • the formulations of the invention will contain other solvents, buffers, pH adjustor ⁇ and/or diluents.
  • Preferred buffers include acetic acid and citric acid and phosphate buffers.
  • Various physiologically acceptable inorganic acids and ackalis which may be used to adjust pH are known in the art and include hydrochloric acid and sodium hydroxide.
  • Agents such as glucose monohydrate have electrolytic properties to aid isotonicity of the injection solution.
  • Other tonicity adjusters include sodium chloride and mannitol. Water is the preferred diluent, acting as solvent and vehicle allowing the concentration of active to be optimised.
  • the formulations of the invention may optionally contain additional active agents or be combined with other active agents in a therapeutic regime where the other active or actives is not coformulated with buprenorphine.
  • the additional ingredient is preferably a non-opioid analgesic.
  • Suitable additional active agents include acepromazine, alphaxalone/alphadalone, atropine, halothane, isoflurane, ketamine, medetomidine, propofol, sevoflurane, thiopentone and xylazine.
  • the formulations of the invention are preferably administered by injection. Most preferably the formulations are administered by intramuscular or intravenous injection. Administration should be in accordance with guidelines and standard practice for the Vetergesic ® single-dose ampoule. Thus, sedative affects should be present by 15 minutes after administration and analgesic activity after about 30 minutes.
  • the present invention is not proposing a new use of buprenorphine, rather a new way of formulating it to facilitate safe and convenient use thereof .
  • the formulations may be used over several days and the preservative itself may interact with the container, it is advised that the formulation is stored in a glass vial, preferably Type 1 glass.
  • the stopper will preferably be suitable for multiple needle insertions, e.g. at least 10 needle insertions, more preferably at least 20 needle insertions, and also resistant to release of extractables and/or reaction with the active agents.
  • the stopper will be a composite of synthetic rubber, such as blends of chlorobutyl and synthetic isoprene, e.g. 4588/40 grey (supplied by West Pharma) and preferably this will have an inert coating such as FluroTec or B2-40 (West Pharma) . Most preferably the stopper has a B2-40 coat and a FluroTec film. Other coatings and films may be used which minimise the transfer of silicone oil or other extractables into the formulation and preferably improve lubricity which enhances machinability. Suitable coatings are cross-linkable polydimethylsiloxane-silicone based organic polymers and suitable films are fluorocarbon films, e.g.
  • the present invention provides a product comprising a vessel with a re-sealable closure containing 5 to 50 ml, preferably 10 to 20 ml, of a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, preferably benzyl alcohol.
  • the formulations of the present invention are preferably manufactured using coated tubing, i.e. an inert coating should be applied to any standard rubber or rubber-like tubing.
  • Teflon® is a suitable coating material .
  • the present invention provides a method of making a pharmaceutical formulation as defined herein which comprises bringing into admixture buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, preferably benzyl alcohol, at the amounts indicated above.
  • the present formulations are suitable for use as a sedative or analgesic for many animals, including domestic and livestock animals, the formulations are particularly suitable for use with domestic animals such as cats, dogs, rabbits and guinea pigs and other rodents.
  • the present invention provides a formulation as defined herein for use as an analgesic or sedative.
  • Such formulations are preferably for use as an injectable analgesic or sedative.
  • the present invention provides a formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol for use as an injectable analgesic or sedative.
  • the invention provides a formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and benzyl alcohol for use as an injectable analgesic or sedative.
  • the present invention provides a method for inducing analgesia in an animal or sedating an animal which comprises injecting said animal with a formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol.
  • a formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol.
  • the formulation comprises benzyl alcohol as said alcohol .
  • the formulations of the invention may also be used for the treatment of chronic pain, e.g. pain associated with neoplasia, osteoarthritis or pruritis.
  • Methyl parabens and propyl parabens Ascorbic acid Methyl parabens and propyl parabens Ascorbic acid
  • the candidate formulation chosen to move to pilot batch manufacture was methyl parabens 0.21 mg/ml with propyl parabens 0.02 mg/ml .
  • a manufacturing site was identified and the manufacturing process was determined - aseptic filling and mixing with no terminal sterilisation.
  • Bulk solutions were prepared by dissolving the buprenorphine hydrochloride and dextrose 5% in water for irrigation, using a magnetic stirrer. Additional excipients were added as listed in Table 3. The pH of the solutions were measured and adjusted as appropriate with dilute sodium hydroxide and dilute hydrochloric acid solutions if required. The solutions were made to volume with further water for irrigation and the pH adjusted if necessary. For the solutions containing parabens the water for irrigation was heated before adding the parabens. This solution was allowed to cool before the dextrose was added. For the parabens solution containing propylene glycol, the parabens was dissolved in propylene glycol before adding to the water.
  • the buprenorphine hydrochloride (0.3 mg/ml as buprenorphine) was added and mixed until dissoved. Aliquots of 10 ml were filtered through 0.22 ⁇ m filters into 10 ml clear Type 1 glass vials and sealed with stoppers and aluminium crimps and stored at 2.8°C and 5O 0 C. Table 3
  • Formulations SP05059/7-SP05059/14 all contain 5% dextrose monohydrate.
  • Formulation SP05059/15 an ampoule formulation which contains 54.25 mg/ml dextrose monohydrate .
  • Crystalline material was observed in all candidate formulations using preservative systems with the exception of benzyl alcohol (m-Cresol was rejected at an early stage as particulate matter was found at four weeks) .
  • Initial preservative efficacy results indicate that the level of benzyl alcohol would have to be raised to 15 - 20 mg/ml (levels of 0.72 mg/ml and 0.9 mg/ml failed the test) .
  • a preferred formulation according to the invention is

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique comprenant de la buprénorphine ou l'un de ses sels pharmaceutiquement acceptables et un alcool, ladite formulation contenant une concentration ≤ 1 % p/v de buprénorphine ou de son sel ; et une formulation pharmaceutique comprenant de la buprénorphine ou l'un de ses sels pharmaceutiquement acceptables et un alcool, ladite formulation contenant une concentration ≤ 3 % p/v d'alcool. L'invention concerne également l'utilisation desdites préparations en tant qu'antalgiques ou sédatifs. L'invention concerne en outre un produit comprenant un récipient doté d'une ouverture refermable contenant de 5 à 50 ml, de préférence de 10 à 20 ml, d'une formulation pharmaceutique comprenant de la buprénorphine ou l'un de ses sels acceptables pharmaceutiquement et un alcool, de préférence l'alcool benzylique.
PCT/EP2009/009196 2008-12-22 2009-12-21 Formulations vétérinaires Ceased WO2010072398A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08254107 2008-12-22
EP08254107.9 2008-12-22

Publications (2)

Publication Number Publication Date
WO2010072398A2 true WO2010072398A2 (fr) 2010-07-01
WO2010072398A3 WO2010072398A3 (fr) 2010-11-25

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/009196 Ceased WO2010072398A2 (fr) 2008-12-22 2009-12-21 Formulations vétérinaires

Country Status (1)

Country Link
WO (1) WO2010072398A2 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007061739A2 (fr) 2005-11-21 2007-05-31 Schering-Plough Ltd. Compositions pharmaceutiques

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU8533582A (en) * 1981-07-10 1984-01-12 Reckitt & Colman Products Limited Stable solutions of buprenorphine
US7666876B2 (en) * 2002-03-19 2010-02-23 Vernalis (R&D) Limited Buprenorphine formulations for intranasal delivery
GB0620661D0 (en) * 2006-10-18 2006-11-29 Pharmasol Ltd Novel compounds
US20080227805A1 (en) * 2007-02-28 2008-09-18 Abbott Laboratories Sustained release parenteral formulations of buprenorphine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007061739A2 (fr) 2005-11-21 2007-05-31 Schering-Plough Ltd. Compositions pharmaceutiques

Also Published As

Publication number Publication date
WO2010072398A3 (fr) 2010-11-25

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