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WO2009127878A1 - Solution de spray liquide renfermant de la buprénorphine, de l’éthanol et un antioxydant - Google Patents

Solution de spray liquide renfermant de la buprénorphine, de l’éthanol et un antioxydant Download PDF

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Publication number
WO2009127878A1
WO2009127878A1 PCT/GB2009/050383 GB2009050383W WO2009127878A1 WO 2009127878 A1 WO2009127878 A1 WO 2009127878A1 GB 2009050383 W GB2009050383 W GB 2009050383W WO 2009127878 A1 WO2009127878 A1 WO 2009127878A1
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Prior art keywords
formulation
buprenorphine
formulation according
solvent
antioxidant
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English (en)
Inventor
David Antony Phillip Small
Matthew John Tyler
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Pharmasol Ltd
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Pharmasol Ltd
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    • 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
    • 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
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams

Definitions

  • This invention relates to formulations of buprenorphine especially pump spray formulations 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. 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.
  • the Examples relate to buprenorphine hydrochloride solutions containing various different concentrations of ethanol and a variety of buffers.
  • the formulations 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.
  • ways of administering formulations 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 formulation 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).
  • WO01 /97780 describes a pharmaceutical formulation comprising a solution of an opioid analgesic (especially fentanyl, although buprenorphine is referred to) and 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 discloses buffered compositions 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 formulation containing buprenorphine for transmucosal, particularly sublingual, administration. Further objects of the invention are to provide a spray formulation containing buprenorphine for transmucosal (eg sublingual) administration with good physical and chemical 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 formulation would mitigate many of the disadvantages of prior art formulations containing buprenorphine.
  • a non-pressurised pharmaceutical liquid solution spray formulation comprising:
  • antioxidants each of a molar ratio of antioxidant : buprenorphine between 0.2 : 1 and 25 : 1 .
  • FIG. 1 HPLC trace of comparator formulation A (Initial time point)
  • Figure 3 HPLC trace of comparator formulation A (6 months)
  • Figure 4 HPLC trace of comparator formulation B (Initial time point)
  • Figure 12 UV-vis scan 700nm-200nm of Example 1 c (Initial time point)
  • Figure 13 UV-vis scan 700nm-200nm of Example 1 c (6 weeks)
  • the formulation 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 PH 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 formulation is employed, suitably less than 2% eg less than 0.1 % w/w.
  • propellants are avoided altogether.
  • the w/v concentration of the buprenorphine in the formulation may typically vary between 0.05 and 12% w/v, more suitably 0.1-10% w/v, eg 0.1-6% w/v, particularly 0.1-4% w/v or especially 0.1-1 % w/v eg around 0.2% w/v (all figures being based on weight of buprenorphine base relative to total weight of formulation).
  • the molar concentration of the buprenorphine of the formulation may typically vary between 1 mM and 257mM, more suitably 2mM and 214mM mM, eg 2-86mM or especially 2- 21 mM eg around 4.3mM.
  • An advantage of the invention, and in particular of use of buprenorphine in a formulation which contains at one or more antioxidants, is improved stability over time (especially at higher temperatures) of buprenorphine formulations comprising one or more antioxidant over formulations that do not comprise antioxidant.
  • Antioxidants include, for example, alkyl gallates, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nordihydroguaiaretic acid, alpha-tocopherol, ascorbic acid and sodium metabisulfite (especially ascorbic acid).
  • the antioxidant is other than propyl gallate.
  • the antioxidant is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nordihydroguaiaretic acid, alpha-tocopherol, ascorbic acid and sodium metabisulfite (especially ascorbic acid).
  • Suitable antioxidants include butylated hydroxyanisole (BHA) butylated hydroxytoluene (BHT), alpha-tocopherol, and ascorbic acid, particularly alpha-tocopherol and ascorbic acid, particularly alpha-tocopherol and ascorbic acid, and most particularly ascorbic acid.
  • the antioxidant is butylated hydroxytoluene (BHT).
  • Formulations of the invention will contain one or more (e.g. one or two) antioxidants. Normally one antioxidant is suitable. In one embodiment, when the formulation contains one antioxidant, said antioxidant is other than propyl gallate.
  • the formulation suitably comprises two antioxidants selected from alkyl gallates, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), nordihydroguaiaretic acid, alpha-tocopherol, ascorbic acid and sodium metabisulfite.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • nordihydroguaiaretic acid alpha-tocopherol
  • the two antioxidants are alpha-tocopherol and ascorbic acid.
  • the antioxidants are in a ratio of between 1 :10 and 10:1 , more suitably between 1 :5 and 5:1 , more suitably 1 :2 and 2:1 , most suitably 1 :1.
  • the ratio of molar concentration of each antioxidant : molar concentration of buprenorphine is in the range 0.2 : 1 to 25 : 1 , e.g. between 1 : 1 and 10 : 1 e.g. 2 : 1 and 8 : 1 , e.g. around 4.65:1
  • the ratio of total molar concentration of antioxidant: buprenorphine is in the range 0.2 : 1 to 25 : 1 , e.g. between 1 : 1 and 10 : 1 , e.g. 2 : 1 and 8 : 1 , e.g. around 4.65:1
  • Suitable concentrations of each antioxidant range from 0.01 mM to 25OmM, e.g. 1 mM to 10OmM, e.g. 1 mM to 5OmM e.g. 1 mM to 25mM e.g. 5mM to 25mM. such as 5mM, 1 OmM and 2OmM, e.g. 1OmM and 2OmM, particularly 2OmM.
  • the concentration of each antioxidant ranges from 0.01 mM to 10mM, such as 1 mM to 5mM (e.g. 2.8mM).
  • the concentration of each antioxidant ranges from 5OmM to 25OmM, such as 8OmM to 23OmM (e.g. 90.8mM or 226.9mM).
  • Suitable total concentration for antioxidant(s) range from 1 mM to 10OmM, e.g. 1 mM to 5OmM e.g. 1 mM to 25mM e.g. 5mM to 25mM. such as 5mM, 1 OmM and 2OmM, e.g. 1 OmM and 2OmM, particularly 2OmM.
  • the concentration of total antioxidant ranges from 0.01 mM to 1 OmM, such as 1 mM to 5mM (e.g. 2.8mM).
  • the concentration of total antioxidant ranges from 5OmM to 25OmM, such as 8OmM to 23OmM (e.g. 90.8mM or 226.9mM).
  • a chelating agent such as EDTA may optionally be employed in the formulation.
  • the formulation is suitably free of EDTA.
  • the formulation is characterised in that the formulation is substantially free of chloride.
  • 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 in this embodiment is to avoid the precipitation of buprenorphine hydrochloride which is not highly soluble in aqueous or ethanolic solvents.
  • the amount of chloride in the formulation of this embodiment 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 formulation is less than 7.
  • the buprenorphine is employed in the form of its free base or as citrate, particularly as free base.
  • a further advantage of the invention, and in particular of use of buprenorphine in an embodiment which is a formulation which is substantially free of chloride, is that relatively concentrated formulations can be prepared which allows for administration of high doses of buprenorphine without using excessively large metering volumes. For example, as will be explained below, 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.
  • 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 formulation should not contain chloride and indeed the examples all relate to formulations 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.
  • None of the above documents suggests that buprenorphine suffers any problems with degradation in solution and specifically formation of a dimer. None of the above documents suggests that inclusion of an antioxidant would provide any specific advantage.
  • 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 85% w/w, such as 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 formulation 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 4.5 and 7 e.g. between around 4.5 and
  • the pH is between 7 and 9 e.g. between 7 and 8.5.
  • pH is meant the pH reading that would be obtained using a conventional pH meter eg model pH 211 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”).
  • pH buffer salts In order to adjust the pH buffer salts can be employed, however we have found that careful attention must be paid to the concentration of these due to the insolubility of many organic and inorganic salts in substantially ethanolic solvents. If a buffer system is to be employed we have found that citrate/citric acid is preferably avoided since we have found that formulations of the invention containing citrate/citric acid and water have a tendency to turn pink on storage especially at elevated temperature.
  • phosphate containing buffers eg phosphate and protonated derivatives such as hydrogen and dihydrogen phosphate
  • the amount of phosphate in the formulation 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 formulation is less than 7.
  • buffers In general it should not be necessary to add buffers to formulations of the invention and therefore adding buffers is preferably avoided (ascorbic acid, sodium saccharin and saccharin are not considered to be added buffers for the purpose of this statement).
  • saccharin may be effectively employed to lower the pH of buprenorphine base formulations, 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 formulations 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 in the presence of antioxidants which are not acids (e.g. not ascorbic acid).
  • menthol eg L-menthol
  • peppermint oil all have a modest but potentially useful effect on raising the pH of buprenorphine base formulations 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 in the presence of antioxidants which are not acids (e.g. not ascorbic acid).
  • 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.
  • pH can be adjusted by adding a strong acid (e.g. HCI) or strong base (e.g. NaOH).
  • a strong acid e.g. HCI
  • strong base e.g. NaOH
  • the properties of the claimed formulations 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 to improve long term resistance to microbial contamination for example sodium metabisulfite, benzalkonium, Nipas.
  • -anionic surfactants for example magnesium stearate, sodium cetostearyl sulfate, sodium lauryl sulfate, sodium oleate, sodium stearyl fumarate, sodium tetradecyl sulfate -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 sulfate, sodium cetostearyl sulfate, carbomers, hydroxyethylcellulose
  • 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 formulation 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 formulation 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 formulation 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).
  • a suitable example formulation comprises (or consists essentially of (eg consists of)): -buprenorphine in the form of its base; -a solvent selected from ethanol and ethanol/water mixtures;
  • antioxidants each of a molar ratio of antioxidant:buprenorphine between 0.2 : 1 and 25 : 1 and wherein the pH of the formulation is between 7 and 9.
  • the pH of the formulation may, for instance, be between around 7 and 8.5 eg around 8 or around 8.5.
  • none of the antioxidants is an acid (e.g. ascorbic acid).
  • the solvent may suitably be ethanol.
  • such formulations are substantially free of chloride.
  • such formulations comprise saccharin sodium.
  • such formulations comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
  • such formulations comprise a chelating agent (eg EDTA or sodium edetate).
  • EDTA EDTA
  • hydroxide eg NaOH, KOH
  • the concentration of buprenorphine base is 0.1-4% w/v eg 0.1-1 % w/v.
  • a suitable example formulation comprises (or consists essentially of (eg consists of)): -buprenorphine in the form of its base;
  • -a solvent selected from ethanol and ethanol/water mixtures
  • antioxidants one or more of which is an acid (e.g. ascorbic acid), each of a molar ratio of antioxidant:buprenorphine between
  • pH of the formulation is between around 4.5 and 7 eg between around 4.5 and 7 e.g. between around 5 and 7, e.g. around 5.
  • the solvent may suitably be ethanol.
  • such formulations are substantially free of chloride.
  • such formulations comprise saccharin sodium.
  • such formulations comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
  • such formulations comprise a chelating agent (eg EDTA or sodium edetate).
  • a chelating agent eg EDTA or sodium edetate.
  • hydroxide eg NaOH, KOH
  • KOH potassium hydroxide
  • the concentration of buprenorphine base is 0.1-4% w/v eg 0.1-1 % w/v.
  • Another suitable example formulation comprises (or consists essentially of (eg consists of)): -buprenorphine in the form of its base; -a solvent selected from ethanol and ethanol/water mixtures;
  • antioxidants each of a molar ratio of antioxidant:buprenorphine between 0.2 : 1 and 25 : 1 ; -saccharin; wherein the pH of the formulation is between around 4.5 and 7 eg between around 4.5 and 7 e.g. between around 5 and 7, e.g. around 5.
  • the solvent may suitably be ethanol.
  • such formulations are substantially free of chloride.
  • such formulations comprise a flavouring agent selected from menthol (eg L-menthol), peppermint oil and mixtures thereof.
  • such formulations comprise a chelating agent (eg EDTA or sodium edetate).
  • a chelating agent eg EDTA or sodium edetate.
  • concentration of buprenorphine base is 0.1-4% w/v eg 0.1-1 % w/v.
  • a process for preparation of formulations of the invention comprises:
  • buprenorphine in the form of its base and antioxidant and a solvent comprising ethanol optionally containing the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc) and dissolving the buprenorphine and antioxidant in the solvent; or
  • buprenorphine in the form of its base and antioxidant and a solvent comprising ethanol and dissolving the buprenorphine and antioxidant in the solvent, then adding the other formulation ingredients (eg saccharin, saccharin sodium, menthol, peppermint oil etc); or
  • the solution formulations of the invention are homogenous and have limited or no susceptibility to dose-to-dose variation. Furthermore formulations of the present invention are characterised by good long-term physical and chemical stability.
  • the formulations of the invention are preferably administered transmucosally (particularly sublingually) as a spray.
  • the formulations 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 formulation 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 formulation 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 formulation 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 formulation 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 formulation 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 formulation 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.
  • 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 formulation.
  • Suitable metering volumes are 10-1000 ⁇ l_, more suitably 50-250 ⁇ l_, eg 100 ⁇ l_ or 200 ⁇ l_, particularly 200 ⁇ l_.
  • 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
  • Formulations 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 formulation of the invention.
  • a formulation according to the invention in the manufacture of a medicament for the treatment or prevention of opiate dependency and abuse or pain.
  • a formulation 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.
  • Example formulation 1 (Ascorbic acid, pH 5.0) a)
  • Example formulation 2 (Alpha-tocopherol, pH 5.0)
  • Example formulation 5 (Ascorbic acid) a) pH 6.2 b) pH 5.9 c) pH 5.7
  • Example formulation 8 (Butylated hydroxyanisole, pH 8.5)
  • Example formulation 9 (Butylated hydroxyanisole, pH 6.5)
  • compositions were prepared as follows:
  • a single dose of buprenorphine was administered sublingually to each volunteer.
  • 14 blood collections were made over 10 hours, at the following times: immediately before administration of the study drug (0.0 hours) and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0 and 10.0 hours after administration.
  • the total volume of blood taken from each volunteer was approximately 300 ml. Plasma concentration of buprenorphine was measured.
  • Treatment A Buprenorphine 0.4mg spray Formulation A (pH 8.5), 1 *0.4 mg spray,
  • Treatment A Buprenorphine spray 0.4 mg Formulation A (pH 8.5)
  • Treatment B Buprenorphine spray 0.4 mg Formulation B (pH 5.0), Pharmasol Ltd., UK) have a similar rate and extent of absorption.
  • Treatment A and Treatment B were suprabioavailable compared to the tablet formulation (Treatment C, Temgesic® SL tablets 0.4 mg, Schering Plough, UK).
  • FIG. 2 and 4 show the HPLC trace of comparator formulations A and B at the initial time point. As can clearly be seen from Figures 2 and 4, there an HPLC peak corresponding to buprenorphine at the initial time point.
  • peaks at 2.64 and 3.05mins are injection peaks and the peak at 12.26mins is the buprenorphine peak.
  • peaks at 2.64 and 3.05mins are injection peaks and the peak at 12.31 mins is the buprenorphine peak.
  • Figures 3 and 5 show the HPLC trace of comparator formulations A and B, 6 months after the initial time point, after degradation has occurred. As can clearly be seen from Figures 3 and 5, a number of new peaks corresponding to degradation products, which were not present at the initial time point, have developed.
  • LCMS Figures 6 and 8 show the LCMS trace of comparator formulations A and B at the initial time point. As can clearly be seen from Figures 6 and 8, there is no LCMS m/z peak corresponding to the dimer or a UV-vis absorption corresponding to the dimer at the initial time point.
  • Figures 7 and 9 show the LCMS trace of comparator formulations A and B, 12 months after the initial time point, after degradation has occurred. As can clearly be seen from Figures 7 and 9, an m/z peak corresponding to the dimer (at m/z 941.6) and a UV-vis absorption (at 458nm) corresponding to the dimer, which were not present at the initial time point, have developed.
  • the UV-vis scan was performed at 458nm, as this is the optimum wavelength to detect the buprenorphine dimerisation. For the time points at 3, 4 and 6 weeks, a scan between 700-200nm was performed on the same sample in addition to the scan at 458nm.
  • Figures 10 and 12 show that at the initial time point there was no UV-vis absorption between 400nm and 500nm.
  • Figure 1 1 shows that for formulation B after 6 weeks, a peak between 400nm and 500nm is clearly visible. This peak corresponds to the dimerisation product.
  • Figure 13 shows that for Example 1 c after 6 weeks, the presence of 2OmM ascorbic acid has prevented the development of a peak between 400nm and 500nm i.e. the presence of antioxidant in Example 1 c has inhibited the dimerisation process of buprenorphine.
  • FIG 14 clearly shows that ascorbic acid and alpha-tocopherol significantly enhance stability of the buprenorphine.
  • Figure 15 clearly shows that BHT and BHA make a significantly positive difference on the stability of the buprenorphine.
  • the degradation and assay for buprenorphine tests were carried out as per methods used for standard productions to see if the antioxidants had any effect on the buprenorphine formulation.
  • the data for the following tables was generated from spectroscopic data.
  • Figure 16 clearly shows that ascorbic acid and alpha-tocopherol control the level of degradation compared to the comparator formulation of buprenorphine.
  • the Comparator Formulation A used in this stability trial over 1 month at 3O 0 C and 4O 0 C was taken from a 3 litre manufactured batch of said formulation.
  • Comparator Formulation B used in this stability trial over 1 month at 3O 0 C and 4O 0 C was taken from a 3 litre manufactured batch of said formulation
  • Figure 17 clearly shows that the formulations containing BHT and BHA keep the level of degradation at a better level compared to the comparator formulation of buprenorphine.
  • the data for the following tables was generated from spectroscopic data.
  • Buprenorphine Formulations + ascorbic acid / alpha-tocopherol Below is a table summarising the results for the assay for buprenorphine for the formulations containing ascorbic acid and alpha-tocopherol.
  • test formulations were measured for appearance of colour and a UV scan (to detect possible dimerisation), buprenorphine assay, pH and the presence of related substances.
  • the tables show that the antioxidants BHT and BHA have a positive effect upon the stability of buprenorphine when compared with the results obtained in the absence of antioxidant.
  • BHT appeared to confer optimal stability upon buprenorphine.
  • propyl gallate provides a negative effect upon the stability of buprenorphine when compared with the results obtained in section 6 in the absence of antioxidant.
  • Antioxidants have generally been shown to have a beneficial effect on the stability of buprenorphine formulations.
  • Alpha-tocopherol Inclusion of alpha-tocopherol in example formulations prevented the yellow colour from forming over three weeks, which is better than the comparator formulation but not as good as the ascorbic acid formulations. Reduction in degradation products as determined by HPLC appears to be better in the alpha-tocopherol formulations than in the ascorbic acid formulations.
  • propyl gallate provides a negative effect upon the stability of buprenorphine when present as a sole antioxidant. For example, dimerisation occurred after just 2 weeks when compared with 1 month in the absence of antioxidant.

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

Abstract

La présente invention concerne une formulation de spray sous forme de solution liquide pharmaceutique non pressurisée renfermant : (i) de la buprénorphine ; (ii) un solvant comprenant de l’éthanol ; et (iii) un ou plusieurs antioxydants, chacun dans un rapport molaire d’antioxydant/buprénorphine situé entre 0,2/1 et 25/1.
PCT/GB2009/050383 2008-04-17 2009-04-17 Solution de spray liquide renfermant de la buprénorphine, de l’éthanol et un antioxydant Ceased WO2009127878A1 (fr)

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GB0806978A GB2461681A (en) 2008-04-17 2008-04-17 Buprenorphine liquid spray formulation with solvent and antioxidant
GB0806978.3 2008-04-17

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JP2016529328A (ja) * 2013-09-10 2016-09-23 インシス・ファーマ・インコーポレーテッド 舌下ブプレノルフィンスプレー
CN106232104A (zh) * 2014-03-10 2016-12-14 英立维尔英国有限公司 持续释放的丁丙诺啡溶液
WO2017075256A1 (fr) 2015-10-27 2017-05-04 Insys Development Company, Inc. Formulations liquides de buprénorphine
CN111246841A (zh) * 2017-10-20 2020-06-05 奇斯药制品公司 包含阿片样物质受体激动剂作为活性成分的药物制剂、其制备方法和治疗用途

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US9918981B2 (en) 2013-09-10 2018-03-20 Insys Development Company, Inc. Liquid buprenorphine formulations
US9867818B2 (en) 2013-09-10 2018-01-16 Insys Development Company, Inc. Sublingual buprenorphine spray
US9839611B2 (en) 2013-09-10 2017-12-12 Insys Development Company, Inc. Sublingual buprenorphine spray
US10085971B2 (en) 2016-08-22 2018-10-02 Navinta Iii Inc Pharmaceutical solution of asenapine for sublingual or buccal use

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WO2004071491A1 (fr) * 2003-02-04 2004-08-26 Chrysalis Technologies Incorporated Formulations d'aerosols et distribution par aerosols de buspirone, buprenorphine, triazolam, cyclobenzaprine et zolpidem
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EP1868569B8 (fr) * 2005-03-24 2012-08-15 Globopharm Pharmazeutische Produktions- und Handelsgesellschaft m.b.H. Forme galenique aqueuse liquide pour applications sublinguales ou nasales de principes actifs presentant des groupes amino
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US20070117828A1 (en) * 2005-11-21 2007-05-24 Schering-Plough Animal Health Corp. Pharmaceutical compositions

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016529328A (ja) * 2013-09-10 2016-09-23 インシス・ファーマ・インコーポレーテッド 舌下ブプレノルフィンスプレー
CN106232104A (zh) * 2014-03-10 2016-12-14 英立维尔英国有限公司 持续释放的丁丙诺啡溶液
US10517864B2 (en) 2014-03-10 2019-12-31 Indivior Uk Limited Sustained-release buprenorphine solutions
WO2017075256A1 (fr) 2015-10-27 2017-05-04 Insys Development Company, Inc. Formulations liquides de buprénorphine
EP3368013A4 (fr) * 2015-10-27 2019-05-22 Insys Development Company, Inc. Formulations liquides de buprénorphine
CN111246841A (zh) * 2017-10-20 2020-06-05 奇斯药制品公司 包含阿片样物质受体激动剂作为活性成分的药物制剂、其制备方法和治疗用途

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