EP2081574A1 - Composition de pulvérisation sans pressurisation contenant de la buprénorphine pour administration par voie transmuqueuse - Google Patents

Composition de pulvérisation sans pressurisation contenant de la buprénorphine pour administration par voie transmuqueuse

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Publication number
EP2081574A1
EP2081574A1 EP07824851A EP07824851A EP2081574A1 EP 2081574 A1 EP2081574 A1 EP 2081574A1 EP 07824851 A EP07824851 A EP 07824851A EP 07824851 A EP07824851 A EP 07824851A EP 2081574 A1 EP2081574 A1 EP 2081574A1
Authority
EP
European Patent Office
Prior art keywords
composition
composition according
buprenorphine
ethanol
solvent
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Withdrawn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
EP07824851A
Other languages
German (de)
English (en)
Inventor
Clive Booles
Padriac O'brien
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.)
Pharmasol Ltd
Original Assignee
Pharmasol 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 Pharmasol Ltd filed Critical Pharmasol Ltd
Publication of EP2081574A1 publication Critical patent/EP2081574A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy

Definitions

  • This invention relates to compositions of buprenorphine especially pump spray compositions suitable for transmucosal, particularly sublingual, delivery.
  • Buprenorphine is a partial agonist of opiate receptors which is widely used for the treatment of moderate to severe pain or in the treatment of opiate dependence.
  • Buprenorphine is often described as a partial agonist (receptor stimulator)/antagonist (prevents receptor stimulation). It has important actions on two types of opiate receptors in the brain. Many of the most common opioid effects, such as euphoria, respiratory effects and reduced pain sensation, are caused by stimulation of the mu receptor. Buprenorphine stimulates this receptor, albeit at lower intensity than other opiates such as heroin or methadone. This lower level of stimulation is of benefit clinically in people with respiratory compromise but require opioid medication, such as the elderly.
  • Buprenorphine is also an antagonist of the kappa opioid receptor, which is associated with some of the negative effects experienced in withdrawal, particularly depression. As buprenorphine inhibits stimulation of this receptor it may produce feelings of well-being. Finally, its disassociation from these receptors is slow, leading to a long duration of action, allowing once daily dosing and sometimes dosing every two days, making buprenorphine a versatile treatment option in treatment of drug addiction.
  • buprenorphine hydrochloride A number of presentations of buprenorphine are currently available. Low-dose sub-lingual tablets, containing 0.2-0.4 mg of the drug as hydrochloride, are sold under the brand name Temgesic and are normally used for analgesic purposes. Temgesic brand of buprenorphine hydrochloride is also available as ampoules for intramuscular or slow intravenous injection. The most common formulation of buprenorphine used for the treatment of opiate dependence is sublingual tablets containing 0.4, 2 and 8 mg buprenorphine hydrochloride and available under the brand name Subutex. Using a combination of tablets, doses of up to 32 mg may be administered.
  • These tablets are specifically intended for the treatment of problem drug use in patients who are being maintained in medically assisted treatment; in the case of patients undergoing withdrawal treatment, they are administered in a gradually reducing dose.
  • Low-dose sublingual tablets are sometimes used for the treatment of opiate dependence, in which case multiple tablets are prescribed in order to achieve the desired dose.
  • a liquid formulation for sub-lingual administration is described in GB2100985 (Todd). Specifically, this document describes formulations containing buprenorphine or a non-toxic salt thereof, but especially buprenorphine hydrochloride, dissolved in 20-30% v/v ethanol in water buffered to a pH of between 4.5-5.5 with 0.05-0.2 molar concentration of a buffering agent selected from citric acid/disodium hydrogen phosphate, sodium citrate/hydrochloric acid, lactic acid/disodium hydrogen phosphate, lactic acid/sodium lactate, sodium citrate/citric acid and sodium acetate/acetic acid, the concentration of buprenorphine being between 0.8 and 10 mg/ml (i.e.
  • compositions do not appear to be sprays as the document refers to the volume of liquid that a patient can hold sublingually for a reasonable amount of time.
  • mucosa for example the sublingual mucosa
  • mucosa for example the sublingual mucosa
  • Other mucosa to which medicaments may be administered include the nasal mucosa and buccal mucosa.
  • a number of ways of administering compositions sublingually are known. For example, tablets or liquids may be held under the tongue prior to swallowing. Another method is spray delivery.
  • spray delivery is preferred as it does not involve holding the composition under the tongue for an extended period of time as, for example, with a lozenge and it reduces the amount of material which is swallowed (and may enter the blood stream in a delayed manner via the gastrointestinal tract).
  • spray large volumes of liquid eg greater than around 500 uL
  • WO01/97780 describes a pharmaceutical composition comprising a solution of an opioid analgesic (especially fentanyl, although buprenorphine is referred to) and a propellant, for sublingual aerosol administration.
  • an opioid analgesic especially fentanyl, although buprenorphine is referred to
  • a propellant for sublingual aerosol administration.
  • the example formulations are pressurized and therefore require complex packaging and actuation technology. Also they employ halogenated propellants which may not be environmentally friendly.
  • WO01/89476 Patent et al discloses buffered compositons for transmucosal delivery. Buprenorphine is mentioned in a very long list of possible active agents and is not exemplified.
  • an object of the present invention is to provide a spray composition containing buprenorphine for transmucosal, particularly sublingual, administration. Further objects of the invention are to provide a spray composition containing buprenorphine for transmucosal (eg sublingual) administration with good physical properties, especially good stability and low environmental impact, and good biological properties, especially rapid onset of activity and efficacy at relatively low doses. Such a composition would mitigate many of the disadvantages of prior art compositions containing buprenorphine.
  • a non-pressurised pharmaceutical liquid solution spray composition comprising:
  • the composition is non-pressurised i.e. is substantially free of any propellant.
  • propellants to be substantially avoided include volatile substances which develop significant vapour pressure at ambient temperature and pressure such as lower alkanes (eg propane, butane and the like) and halogenated hydrocarbons such as CFCs (P12 etc) and hydrofluorocarbons (P134a, P227 etc) as well as other propellants commonly used in aerosol presentations.
  • Use of P1 1 is also preferably substantially avoided.
  • substantially free or “substantially avoided” is meant that an amount of less than 5% w/w based on weight of composition is employed, suitably less than 2% eg less than 0.1 % w/w.
  • propellants are avoided altogether.
  • the concentration of the buprenorphine in the composition may typically vary between 0.05 and 12% w/v, more suitably 0.1-10% w/v, eg 0.1-4% w/v or especially 2-8% w/v, for example 4-8% w/v eg 4% or 8% w/v (all figures being based on weight of buprenorphine base relative to total weight of composition).
  • substantially free of chloride is meant that the formulation has a substantial absence of chloride in ionised (i.e. such that Cl " is formed in solution) or unionised form.
  • the reason for the substantial absence of chloride is to avoid the precipitation of buprenorphine hydrochloride which is not highly soluble in aqueous or ethanolic solvents.
  • the amount of chloride in the composition is suitably less than 3% w/w based on weight of buprenorphine eg less than 1 % w/w, eg less than 0.5% w/w for example less than 0.1 % w/w, especially when the pH of the composition is less than 7.
  • the buprenorphine is employed as base or as citrate, particularly as base.
  • An advantage of the invention, and in particular of use of buprenorphine in a formulation which is substantially free of chloride, is that relatively concentrated compositions can be prepared which allows for administration of high doses of buprenorphine without using excessively large metering volumes.
  • concentration 4 and 8% w/v we have successfully prepared solutions of concentration 4 and 8% w/v, whereas buprenorphine hydrochloride has not proved soluble in water or ethanol at these concentrations.
  • These higher concentrations of buprenorphine are achieved by using a solvent containing a significant amount of ethanol and the highest concentrations are achieved by lowering the pH with citric acid.
  • WO02/094234 relates to an opioid-containing aerosol formulation for administration by inhalation.
  • the formulations are all aqueous solutions with no other solvent being suggested.
  • WO 03/080022 relates to aqueous solutions comprising an analgesic for intranasal administration.
  • the analgesic may be buprenorphine or a salt thereof but there is no teaching that the composition should not contain chloride and indeed the examples all relate to compositions comprising buprenorphine hydrochloride.
  • WO 2004/071491 relates to liquid aerosol formulations in which the solvent may contain ethanol.
  • WO 2004/071491 relates to liquid aerosol formulations in which the solvent may contain ethanol.
  • it would be advantageous to provide a chloride-free composition and all of the examples relate to formulations containing buprenorphine hydrochloride.
  • the solvent is selected from ethanol and ethanol/water mixtures.
  • ethanol is substantially the only solvent.
  • concentration of ethanol in the solvent is greater than 90% w/w eg greater than 95% w/w particularly greater than 98% w/w, for example around 100% w/w (i.e. the solvent is ethanol, the presence of any water as contaminant from the atmosphere being ignored).
  • use of water as solvent is substantially avoided, for example the water concentration is less than 10% w/w eg less than 5% w/w particularly less than 98% w/w, for example around 0% w/w (i.e. the composition is substantially free of water).
  • avoidance of water can be advantageous especially in formulations of buprenorphine containing citrate since we have observed that such formulations have a tendency to turn pink on storage.
  • the solvent comprises water as well as ethanol.
  • the solvent consists of a water/ethanol mixture in which the concentration of ethanol is approximately 30-90% w/w (the balance being water) for example approximately 40-70% w/w eg around 50% w/w.
  • Preferably water when employed as solvent meets the USP (US Pharmacopoeia), EP (European Pharmacopoeia) "Purified Water” standards.
  • the pH of the solution may typically be between around 4 and 9.5 however will preferably be between around 4.5 and 9.
  • the pH is between 4 and 6 eg between around 4.5 and 6 eg around 5 or between around 4 and 5 eg around 4.5.
  • the pH is greater than 7 for instance between around 8 and 9.5 eg between around 8 and 9 eg around 8.5. It is envisaged that compositions at this higher pH will be more efficacious and/or have more rapid activity.
  • buprenorphine will be more rapidly or efficiently adsorbed through the mucosa, especially the sublingual mucosa, at a pH close to the pKa of buprenorphine, which is 8.5 (Pharmaceutical Codex).
  • Compositions of pH above 7 have not thus far been described in concrete terms, presumably due to the predominant use of buprenorphine hydrochloride and the problems of solubility of the active at higher pH. Such problems are substantially overcome by use of compositions of the invention.
  • pH is meant the pH reading that would be obtained using a conventional pH meter eg model pH 21 1 manufactured by Hanna Instruments Ltd and Orion 420A manufactured by Thermo Electron Corporation (i.e. in water free systems the word “pH” would be construed to mean “apparent pH”).
  • citrate/citric acid which does have adequate solubility in ethanolic solvents.
  • citrate/citric acid is itself problematic since we have found that compositions of the invention containing citrate/citric acid and water have a tendency to turn pink on storage especially at elevated temperature. Accordingly use of buffer salts and even citrate/citric acid is preferably avoided.
  • phosphate containing buffers eg phosphate and protonated derivatives such as hydrogen and dihydrogen phosphate
  • the amount of phosphate in the composition is suitably less than 3% w/w based on weight of buprenorphine eg less than 1 % w/w, eg less than 0.5% w/w for example less than 0.1 % w/w especially when the pH of the composition is less than 7.
  • citric acid is useful to enhance the solubility of buprenorphine base in ethanolic solvents (eg to concentrations of 4% w/v or higher eg 4-8% w/w (based on total weight of composition) particularly 5-8% w/w).
  • the solvent may (most suitably) be essentially ethanol (eg 100% ethanol) or may (alternatively) contain water (eg ethanol/water 1 :1 ).
  • citric acid may be employed at a concentration of around 0.1-10% w/w eg 0.2-5% w/v eg 0.2-2% w/w.
  • the pH of buprenorphine base in ethanol is not significantly affected by buprenorphine concentration.
  • saccharin may be effectively employed to lower the pH of buprenorphine base compositions, and is particularly useful in achieving a pH in the range 4-6, particularly 4.5-6 eg around 5.
  • the pH lowering effect of saccharin lessens with increased buprenorphine concentration.
  • Addition of menthol (eg L-menthol) or peppermint oil has relatively little impact on pH when in conjunction with saccharin.
  • saccharin sodium as well as menthol (eg L-menthol) and peppermint oil all have a modest but potentially useful effect on raising the pH of buprenorphine base compositions in ethanol, and is particularly useful in achieving a pH in the range between about 8 and 9.5 eg between around 8 and 9 eg around 8.5.
  • saccharin and saccharin sodium are useful as sweeteners which improve patient acceptability.
  • menthol eg L-menthol
  • peppermint oil are useful as flavourings and moisturing agents which may have penetration enhancing activity.
  • compositions may be further improved by including therein a number of additional formulation components.
  • - sweeteners such as saccharin, saccharin sodium, sucrose, flavouring or taste-masking agents
  • -moisturising agents to improve patient comfort and overcome the drying tendency of ethanol and other polar organic solvents
  • peppermint oil for example peppermint oil, menthol (eg L-menthol) pineapple extract, lanolin, polypropylene glycol, polyethylene glycol.
  • -mucoadherents for example carboxyvinyl polymers, chitosans, polyacrylic acid, gelatin, polyvinyl pyrrolidone.
  • -preservatives for example sodium metabisulphite, benzalkonium, Nipas.
  • alkyl gallates for example alkyl gallates, butylated hydroxyanisole butylated hydroxytoluene, nordihydroguaiaretic acid, tocopherols, Ascorbic acid, sodium metabisulphite
  • -anionic surfactants for example magnesium stearate, sodium cetostearyl sulphate, sodium lauryl sulphate, sodium oleate, sodium stearyl fumarate, sodium tetradecyl sulphate
  • -nonionic surfactants for example glyceryl monostearate, Macrogol cetostearyl ethers,
  • Poloxamers polyoxyl stearates, Polysorbates, sorbitan esters, sucrose esters, Tyloxapol, propylene glycol monostearate, Quillaia, polyoxyl, caster oils, nonoxinols, lecithins and derivatives, oleic acid and derivatives, oleyl alcohol and derivatives -foaming agents for example alginic acid and salts, propylene glycol alginate, sodium lauryl sulphate, sodium cetostearyl sulphate, carbomers, hydroxyethylcellulose
  • compositions according to the invention which are of higher strength (eg 4 % w/v or above), especially those containing saccharin, have a tendency to yellow on storage, especially at higher temperatures.
  • a stabiliser selected from anti-oxidants (eg ascorbic acid/ascorbate) and/or a chelating agent (eg EDTA/sodium edetate) may suitably be employed.
  • Suitable moisturising agents include, for example, the polar organic solvents such as glycols, especially propylene glycol, and the liquid polyethylene glycols, glycerol, methylcellulose, hypromellose, hydroxypropylcellulose, and many other substituted celluloses.
  • menthol especially L-menthol.
  • Menthol eg L-menthol
  • flavouring the composition has moisturising effect. It may also have effect as a penetration enhancer.
  • menthol eg L-menthol
  • menthol is employed in a concentration range of 0.1 % to 0.75% w/w eg around 0.2% w/w.
  • Peppermint oil is an alternative component which may be used in place of menthol. Peppermint is known to have incompatibilities with certain actives (eg fentanyl) however it appears to be compatible with buprenorphine. Suitably peppermint oil is employed in a concentration range of 0.1 % to 0.75% w/w eg around 0.5% w/w.
  • the composition contains a sweetener.
  • the sweetener is saccharin sodium.
  • the concentration of saccharin sodium is around 0.1-0.9% w/w eg around 0.45% w/w.
  • the composition contains saccharin.
  • the concentration of saccharin is around 0.025-0.75% w/w, for example around 0.05-0.4% w/w eg around 0.05-0.1 % w/w.
  • the concentration of saccharin may be varied depending on the eventual pH desired (see Figure 2).
  • compositions of the invention are considered to be especially suitable.
  • a suitable example composition comprises (or consists essentially of (eg consists of)):
  • composition is substantially free of chloride; and wherein the pH of the composition is greater than 7.
  • the pH of the composition may, for instance, be between around 8 and 9.5 eg between around
  • the solvent may suitably be ethanol.
  • compositions comprise saccharin sodium.
  • compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
  • compositions comprise a chelating agent (eg EDTA or sodium edetate).
  • a chelating agent eg EDTA or sodium edetate.
  • compositions comprise an anti-oxidant.
  • hydroxide eg NaOH, KOH
  • KOH potassium hydroxide
  • the concentration of buprenorphine base is 0.1-4% w/v.
  • Another suitable example composition comprises (or consist essentially of (eg consist of)):
  • -a solvent selected from ethanol and ethanol/water mixtures
  • composition is substantially free of chloride; and wherein the pH of the composition is between around 4 and 6 eg between around 4.5 and 6 eg around 5.
  • the solvent may suitably be ethanol.
  • compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
  • compositions comprise a chelating agent (eg EDTA or sodium edetate).
  • a chelating agent eg EDTA or sodium edetate.
  • compositions comprise an anti-oxidant.
  • the concentration of buprenorphine base is 0.1-4% w/v.
  • Another suitable example composition comprises (or consist essentially of (eg consist of)): -buprenorphine as base at a concentration of 4% w/v or more; -a solvent selected from ethanol and ethanol/water mixtures;
  • composition is substantially free of chloride; and wherein the pH of the composition is between around 4 and 6 eg between around 4 and 5 eg around 4.5.
  • the solvent may suitably be ethanol.
  • compositions comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
  • compositions comprise saccharin.
  • compositions comprise a chelating agent (eg EDTA or sodium edetate).
  • a chelating agent eg EDTA or sodium edetate.
  • compositions comprise an anti-oxidant.
  • the concentration of buprenorphine base is 4-8% w/v.
  • a process for preparation of compositions of the invention comprises:
  • buprenorphine as base and a solvent comprising ethanol optionally containing the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc) and dissolving the buprenorphine in the solvent; or
  • buprenorphine as base and a solvent comprising ethanol and dissolving the buprenorphine in the solvent, then adding the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc); or
  • compositions of the invention are homogenous and have limited or no susceptibility to dose-to-dose variation. Furthermore compositions of the present invention are characterised by good long-term physical and chemical stability.
  • compositions of the invention are preferably administered transmucosally (particularly sublingually) as a spray.
  • the compositions are expected to be well tolerated when administered to the sensitive sublingual mucosa and the sublingual spray administration will result in rapid onset of the therapeutic effect of the buprenorphine.
  • a metered dose dispensing system comprising a sealed container containing a composition of the invention fitted with a metering pump, an actuator and a channelling device.
  • the metered dose dispensing system is preferably adapted for transmucosal (particularly sublingual) administration.
  • the container for the pharmaceutical liquid composition may contain a single dose of buprenorphine (which may, nevertheless be a divided dose), preferably the container will contain a plurality of doses (eg 20 to 200 doses) of buprenorphine.
  • the composition could be packaged in a suitable pharmaceutical grade, plastics container, such a container would be relatively easy to open for abuse of the product. Therefore a glass container would be more suitable. Glass would shatter if attempts were made to open the pack, rendering the contents either lost or unusable due to glass fragments.
  • the glass container will be coated on the exterior with a suitable moulded film of plastic to protect against shattering.
  • the film may be of polypropylene.
  • the material may be coloured and contain a UV absorber.
  • the container glass may be colourless or more suitably may be provided with a UV protective colouring, for example amber colouring.
  • the interior of the container can be coated to enhance stability of the product. Coatings include polymers and lacquers but also silicone dioxide as an unreactive coating can be used to line the inside of the container.
  • the composition is non-pressurised, it is suitably administered to the patient by pump action.
  • the metering dose dispensing system suitably contains a metering pump permitting a metered dose of the composition to be administered as a spray.
  • Suitable metering pumps include those adapted for dispensation with the container in the upright or inverted orientation.
  • the metering chamber is adapted for dispensation with the container in the upright orientation since this facilitates administration under the tongue. Accordingly the metering chamber will be in communication with the composition by means of a dip-tube.
  • the metering pump is suitably a non-venting type. Suitable materials of construction include polypropylene and polyethylene.
  • Example metering pumps are those manufactured by Valois (eg VP3, VP6, VP7 and VP7D) and for example those illustrated in International Patent Application No. WO01 /66089.
  • Other conventional pumps include those from Rexam (eg SP270) and Calmar (eg Accupump or Mistette Mk II).
  • the actuator will be designed to deliver a transmucosally (particularly a sublingually) effective dose.
  • the pump may suitably be manually actuated, although assisted actuation using stored energy (eg spring or gas) may be contemplated.
  • stored energy eg spring or gas
  • the pump is suitably crimped onto the container neck.
  • Suitable sealing materials eg thermo plastic crimp gaskets suitable for the purpose will be employed.
  • a suitable aluminium ferrule purposely designed for crimping on to glass containers may suitably be employed.
  • Suitable grade stainless steel springs will preferably be adopted.
  • the metering pump will administer a metered volume of composition.
  • Suitable metering volumes are 10-1000 uL, more suitably 50-250 uL, eg 10OuL or 200 uL, particularly 200 uL.
  • a channelling device is provided to direct the liquid sprayed from the metered dose dispensing area to the appropriate part of the mouth e.g. to the sublingual cavity or if desired to the nose.
  • Channelling devices are suitably fabricated from moulded plastics.
  • a number of channelling devices adapted to administer sprays to the mouth or nose are known to persons skilled in the art eg
  • compositions of the invention are useful in treatment or prevention of opiate dependency and abuse, particularly in the treatment or prevention of dependency on opiates such as heroin and for analgesic purposes eg for the treatment of moderate to severe pain.
  • a method of treatment or prevention of opiate dependency and abuse or pain which comprises administering to a subject in need thereof an effective amount of a composition of the invention.
  • a composition according to the invention in the manufacture of a medicament for the treatment or prevention of opiate dependency and abuse or pain.
  • a composition of the invention for use in the treatment or prevention of opiate dependency and abuse or pain.
  • the container or the dispensing system may be provided with features to prevent tampering.
  • the container or the dispensing system may suitably be provided with features to prevent or discourage access to the reservoir and/or to prevent administration of more than one dose of buprenorphine at one time.
  • the dispensing system in particular the actuator, may, for example, be provided with a lock-out feature to prevent administration of a second dose within a specified time interval of the first.
  • Lock-out features are, for example, described in US2006191532, WO03097141 and WO0232487.
  • a patient is treated by administration transmucosally (eg sublingually) of 1 to 4 actuations eg 1 or 2 actuations from the spray pump.
  • transmucosal spray delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single actuation. This is not the case with other forms of drug delivery (patches, lozenges, tablets, suppositories).
  • compositions of the invention are useful in the treatment of animals, particularly non-human mammals (for example domestic or livestock animals) as well as humans. Accordingly pharmaceutical uses, for example uses in the treatment of pain, may be extended to veterinary uses. Dosages and methods of administration (eg the spray actuator design) will be adapted for the intended recipient as would be known to a skilled person. Examples
  • compositions formed a clear colourless solution at 4, 25 and 40 0 C and remained so after 1 month storage at these temperatures.
  • compositions were prepared as follows:
  • compositions formed a clear colourless solution at 4, 25 and 40 0 C and remained so after 2 weeks storage (Example 8) or 1 month storage (Examples 5-7) at these temperatures.
  • compositions were prepared as follows:
  • compositions formed a clear colourless solution at 4, 25 and 40 0 C and remained so after 1 month storage at these temperatures.
  • compositions were prepared as follows:
  • Example 13 the composition formed a clear colourless solution at 4, 25 and 40 0 C. and remained so after 2 months storage at these temperatures.
  • Example 14 the composition formed a clear colourless solution at 4 and 25 0 C and a clear very light yellow solution at 4O 0 C after 2 months storage at these temperatures.
  • Examples 15, 16 the compositions formed a clear colourless solution at 4 and 25 0 C and a clear light yellow solution at 4O 0 C after 3.5 months storage at these temperatures.
  • compositions were prepared as follows:
  • Examples 17 and 18 the compositions formed a clear colourless solution at 4 and 25 0 C and a dark yellow solution at 4O 0 C after 3.5 months storage at these temperatures.
  • Example 19 the composition formed a clear light yellow solution at 4 0 C, a clear yellow solution at 25 0 C and a clear dark yellow solution at 4O 0 C after 3.5 months storage at these temperatures.
  • Example 20 the composition formed a clear colourless solution at 4 0 C, a clear light yellow solution at 25 0 C and a clear yellow solution at 4O 0 C after 2 months storage at these temperatures.
  • compositions were prepared as follows:
  • Examples 21 and 22 the compositions formed a clear colourless solution at 4, a light yellow solution at 25 0 C and a yellow solution at 4O 0 C after 3 months storage at these temperatures.
  • Example 23 the composition formed a clear colourless solution at 4 0 C and 25 0 C and a clear pink solution at 4O 0 C after 3 months storage at these temperatures.
  • Example 24 the composition formed a clear colourless solution at 4 0 C and 25 0 C and a clear light pink solution at 4O 0 C after 3 months storage at these temperatures.

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  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

La présente invention concerne la composition d'une solution liquide pharmaceutique par pulvérisation qui comprend : (i) de la buprénorphine et 5 (ii) un solvant comprenant de l'éthanol dont la composition est sensiblement dépourvue de chlorure.
EP07824851A 2006-10-18 2007-10-17 Composition de pulvérisation sans pressurisation contenant de la buprénorphine pour administration par voie transmuqueuse Withdrawn EP2081574A1 (fr)

Applications Claiming Priority (2)

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GBGB0620661.9A GB0620661D0 (en) 2006-10-18 2006-10-18 Novel compounds
PCT/GB2007/050639 WO2008047163A1 (fr) 2006-10-18 2007-10-17 Composition de pulvérisation sans pressurisation contenant de la buprénorphine pour administration par voie transmuqueuse

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EP2081574A1 true EP2081574A1 (fr) 2009-07-29

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EP (1) EP2081574A1 (fr)
CN (1) CN101573116A (fr)
AU (1) AU2007311621A1 (fr)
CA (1) CA2666581A1 (fr)
GB (2) GB0620661D0 (fr)
IL (1) IL197908A0 (fr)
WO (1) WO2008047163A1 (fr)
ZA (1) ZA200902123B (fr)

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US10010612B2 (en) 2007-05-25 2018-07-03 Indivior Uk Limited Sustained delivery formulations of risperidone compounds
US10022367B2 (en) 2014-03-10 2018-07-17 Indivior Uk Limited Sustained-release buprenorphine solutions
US10058554B2 (en) 2005-09-30 2018-08-28 Indivior Uk Limited Sustained release small molecule drug formulation
US10172849B2 (en) 2010-06-08 2019-01-08 Indivior Uk Limited Compositions comprising buprenorphine
US10198218B2 (en) 2010-06-08 2019-02-05 Indivior Uk Limited Injectable flowable composition comprising buprenorphine

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GB2481619B (en) * 2010-06-30 2012-06-20 Londonpharma Ltd Formulations and delivery devices for the sublingual administration of opioids
SG10202012743WA (en) * 2011-12-21 2021-01-28 Biodelivery Sciences Int Inc Transmucosal drug delivery devices for use in chronic pain relief
US9901539B2 (en) 2011-12-21 2018-02-27 Biodelivery Sciences International, Inc. Transmucosal drug delivery devices for use in chronic pain relief
CN108463214A (zh) 2015-10-27 2018-08-28 因塞斯发展股份有限公司 液体丁丙诺啡制剂

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Cited By (12)

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US10058554B2 (en) 2005-09-30 2018-08-28 Indivior Uk Limited Sustained release small molecule drug formulation
US11110093B2 (en) 2005-09-30 2021-09-07 Indivior Uk Limited Sustained release small molecule drug formulation
US10010612B2 (en) 2007-05-25 2018-07-03 Indivior Uk Limited Sustained delivery formulations of risperidone compounds
US10376590B2 (en) 2007-05-25 2019-08-13 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US11013809B2 (en) 2007-05-25 2021-05-25 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US11712475B2 (en) 2007-05-25 2023-08-01 Indivior Uk Limited Sustained delivery formulations of risperidone compound
US10172849B2 (en) 2010-06-08 2019-01-08 Indivior Uk Limited Compositions comprising buprenorphine
US10198218B2 (en) 2010-06-08 2019-02-05 Indivior Uk Limited Injectable flowable composition comprising buprenorphine
US10558394B2 (en) 2010-06-08 2020-02-11 Indivior Uk Limited Injectable flowable composition comprising buprenorphine
US10592168B1 (en) 2010-06-08 2020-03-17 Indivior Uk Limited Injectable flowable composition comprising buprenorphine
US10022367B2 (en) 2014-03-10 2018-07-17 Indivior Uk Limited Sustained-release buprenorphine solutions
US10517864B2 (en) 2014-03-10 2019-12-31 Indivior Uk Limited Sustained-release buprenorphine solutions

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AU2007311621A1 (en) 2008-04-24
WO2008047163A1 (fr) 2008-04-24
ZA200902123B (en) 2010-04-28
IL197908A0 (en) 2009-12-24
GB2456434A (en) 2009-07-22
CA2666581A1 (fr) 2008-04-24
CN101573116A (zh) 2009-11-04
GB0905120D0 (en) 2009-05-06
GB0620661D0 (en) 2006-11-29

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