US20180015031A1 - Injectable buprenorphine formulation - Google Patents

Injectable buprenorphine formulation Download PDF

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US20180015031A1
US20180015031A1 US15/520,946 US201515520946A US2018015031A1 US 20180015031 A1 US20180015031 A1 US 20180015031A1 US 201515520946 A US201515520946 A US 201515520946A US 2018015031 A1 US2018015031 A1 US 2018015031A1
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buprenorphine
liquid formulation
injectable liquid
formulation
component
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Fredrik Tiberg
Markus Johnsson
Ian Harwigsson
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Camurus AB
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Camurus AB
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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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to injectable formulations of opioid agonists such as buprenorphine.
  • the invention relates to injectable lipid formulations having the ability to form controlled-release compositions upon injection.
  • Opioid agonists are a prime example of pharmaceutical agents for which adherence to an effective functional window, which may vary significantly between patients and over time, is of great importance.
  • Opioids are indicated in many conditions including treatment of pain and in various forms for treatment and maintenance in opioid dependence. Insufficient dose, especially in subject accustomed to opioids, can cause debilitating and unpleasant withdrawal symptoms while excessive dose cause euphoria, reinforcement of dependence and ultimately potentially fatal respiratory depression.
  • the present inventors have now established that certain opioids, particularly buprenorphine and its salts and derivatives, can be delivered as a sustained-release injection in simple lipid vehicles, providing a high concentration of the active agent is used.
  • Such formulations may be ineffective or inefficient at low concentrations of buprenorphine but provide a much more desirable release profile when the buprenorphine concentration is held above around 16% by weight.
  • the present invention therefore provides an injectable liquid formulation comprising:
  • lipid controlled-release matrix comprising at least 50% triacyl lipids
  • Preferred triacyl lipids in all aspects and embodiments of the present invention are triacyl glycerols (triglycerides).
  • Such injectable liquid formulations as described herein in all aspects and embodiments of the invention typically form a controlled-release composition upon administration to the body of a subject.
  • a subject may be a human or animal subject such as any of those described herein.
  • the injectable liquid formulations described herein in all aspects and embodiments of the invention typically have at least one active agent selected from buprenorphine and salts thereof present at a level of greater than 21% (e.g. greater than 30%, such as 31 to 50%) by weight buprenorphine.
  • active agent selected from buprenorphine and salts thereof present at a level of greater than 21% (e.g. greater than 30%, such as 31 to 50%) by weight buprenorphine.
  • all percentages of buprenorphine are calculated by weight as percentage of buprenorphine free base in the complete formulation, unless otherwise stated.
  • the injectable liquid formulations of the invention may be administered to a suitable subject, particularly a mammalian subject in thereby form a controlled-release formulation.
  • the present invention therefore provides a controlled-release composition formed by administration to a (preferably human) subject of an injectable liquid formulation as described in any of the aspects or embodiments disclosed herein.
  • preferred formulations of the invention will result in preferred controlled-release compositions.
  • the controlled-release compositions of the invention show advantageous release profiles, particularly with regard to maintaining plasma concentrations of buprenorphine within a functional window for an extended period.
  • Cmin and Cmax both fall with the range of between 0.2 ng/mL to 12 ng/mL, preferably 0.4 ng/mL and 15 ng/mL.
  • the invention also provides a method of sustained delivery of buprenorphine to a human or non-human animal body, said method comprising administering an injectable liquid formulation comprising:
  • compositions and compositions of the present invention can be used in the treatment of any indication for which the chronic administration of buprenorphine is suitable.
  • the invention thus provides a method of treatment or prophylaxis of a human or non-human animal subject comprising administration of an injectable liquid formulation as described in any aspect or embodiment of the invention.
  • Such a method may be for the treatment or prophylaxis of any suitable condition, including for the treatment of pain, for opioid maintenance therapy or for the treatment of opioid dependence by detoxification and/or maintenance or for the treatment or prophylaxis of the symptoms of opioid withdrawal and/or cocaine withdrawal.
  • the present invention provides an injectable liquid formulation or controlled-release composition as described herein for use in therapy.
  • therapy may be for the treatment or prophylaxis of any suitable condition, including for the treatment of pain, for opioid maintenance therapy or for the treatment of opioid dependence by detoxification and/or maintenance or for the treatment or prophylaxis of the symptoms of opioid withdrawal and/or cocaine withdrawal.
  • lipid-based controlled-release formulations have been disclosed over the last few years, including formulations such as those of WO2005/117830 which comprise diacyl lipids and phospholipids in appropriate mixtures so as to generate formulations which change phase upon administration. This allows a low-viscosity formulation to be injected and to generate a higher viscosity depot composition in vivo which traps the active agent and provides a slow-release effect. Such compositions are effective for a broad range of active agents and rely primarily on the lipid matrix to control the active agent release.
  • lipid-based controlled-release formulations have typically found that a lipid mixture and a phase-change upon injection as described above is generally necessary for controlled-release of most active agents.
  • bioactive agents that, depending on the therapeutic window (i.e. plasma concentration window where treatment effects are realized and side effects are acceptable), may be amenable to the use of simpler lipid formulations.
  • the use of simpler systems is always an advantage in medicine because this reduces the number of components for which stringent sourcing and quality-control procedures must be established. Simpler systems also make the toxicological assessment and processes of regulatory approval less complex, particularly where the remaining excipients are generally regarded as safe (GRAS) or have an established record of pharmaceutical use, e.g., previous use in registered injection products.
  • GRAS toxicological assessment and processes of regulatory approval less complex, particularly where the remaining excipients are generally regarded as safe (GRAS) or have an established record of pharmaceutical use, e.g., previous use in registered injection products.
  • buprenorphine and related compounds can be released in a controlled fashion from triacyl-lipid containing formulations providing that the concentration of buprenorphine compound (“buprenorphine” being used herein to include all appropriate salts and structural analogues where context allows) is above a certain threshold level.
  • buprenorphine to be at a high concentration is in itself unexpected because drug release in controlled-release formulations is generally controlled by the carrier matrix.
  • the active agent will have the active role in the biological effect but typically exhibits a passive role in the controlled-release.
  • high concentrations of active agent will generally interfere with the function of the controlled-release matrix and thus the concentration of active agent will often be limited by the disruptive effect that such an agent has upon the controlled-release.
  • the present case is quite the reverse of the established norm and formulations having at least 16% buprenorphine are found to provide more effective release than similar formulations with a lower active-agent content.
  • the invention provides an injectable liquid formulation comprising:
  • lipid controlled-release matrix comprising at least 50% triacyl lipids
  • the active agent (generally selected from buprenorphine, its structural analogues and salts thereof) is present at a level of greater than 16% in all aspects and embodiments of the invention. This will preferably be greater than 21% (e.g. greater than 30%, such as 31 to 50%) by weight buprenorphine (all calculated as buprenorphine free base). Concentrations of up to 60% buprenorphine may be used but preferably up to 50%, e.g. up to 45% will be used.
  • FIG. 1 The advantage of high buprenorphine concentrations is illustrated in the attached FIG. 1 .
  • the Figure shows dose normalized plasma concentrations of buprenorphine after administration of a 33.8% formulation (A1) and a 1.06% formulation (C1) to rats. It is evident from FIG. 1 that formulation A 1 provides a much more sustained and stable release of buprenorphine into blood plasma and has the potential to provide a much greater duration of release, since the level does not change significantly over the 14 day period of the experiment.
  • component a Another critical component in the liquid formulations and controlled-release compositions of the invention is the lipid matrix component a).
  • component a) typically forms 10% to 70% of the total precursor formulation. This may be 15% to 64% or 20 to 50% by weight.
  • lipid component a at least 50% of the lipids are formed of triacyl lipids.
  • generally 50% to 100% (such as at least 80%), preferably 60 to 90% or 60% to 95%, more preferably 70 to 90% of said lipid controlled release matrix (component b)) is formed of triacyl lipids.
  • Component a) may consist essentially of triacyl lipids (e.g. be 95% or more triacyl lipids).
  • the triacyl lipids forming part or all of component a) may be any suitable triacyl lipid and will generally have a polar “head” group and three non-polar “tail” groups. Typically these will be joined by an ester moiety, although carbon-carbon bonds, ethers, amides etc. may be used.
  • Suitable polar head groups will generally be non-ionic and include polyols such as glycerol, diglycerol (and oligo/ploy glycerol such as 2 to 10 glycerols) and sugar or carbohydrate moieties (such as mono-, di-, and tri-saccharides including sorbitan, sorbitol, trehalose, inositol, glucose, maltose and sucrose moieties and derivatives thereof) and esters of polyols, such as acetate or succinate esters.
  • Preferred polar groups are glycerol and diglycerol, especially glycerol.
  • Suitable non-polar “tail” groups are typically C8 to C20 acyl groups which may have one or more unsaturations in the carbon chain.
  • component a) may comprise lipids (particularly triacyl lipids) with “medium chain” fatty acyl components, such as C8 to C12 acyl chains (especially with zero, one or two unsaturations).
  • Such components may comprise some or all of the triacyl lipid component, such as 1 to 100% of the triacyl lipid component (e.g. 1 to 70% or 10 to 50%). Preferably such components will comprise less than 50% of the triacyl lipids.
  • the triacyl lipid and any other lipids present will comprise fatty acyl chains having 12 to 22 carbons, particularly C16 to C20 fatty acyl chains, especially with zero, one or two unsaturations.
  • component a) comprises at least 50% by weight of triacyl lipids with such triacyl lipids comprising C16 to C20 acyl groups having zero, one or two unsaturations.
  • especially preferred groups include C16:0, C16:1, C18:0, C18:1, C18:2, C18:3 and/or 020:1 acyl groups.
  • the triacyl lipids of component a) of the present invention will comprise not more than 25% of acyl groups shorter than C12. That is to say, at least 75% of the acyl groups of the triacyl components will be C12 or longer (typically having zero, one or two unsaturations or a mixture thereof). This may be at least 85% acyl groups of C12 or longer or at least 90% acyl groups of C12 or longer.
  • the triacyl lipids of component a) may comprise acyl groups wherein at least 25% of such acyl groups are unsaturated (e.g. having 1, 2 or 3 unsaturations, preferably 1 or 2 unsaturations in the acyl chain). This will preferably be at least 50% (e.g. 50 to 100% or 50 to 95%) unsaturated acyl moieties and more preferably at least 75% unsaturated moieties in the triacyl component (e.g. triacyl glycerol or others described herein).
  • at least 50% by weight of triacyl lipids in component a) may comprise at least 1 unsaturated acyl moiety (e.g. at least one acyl moiety having 12 or more carbons in the acyl chain and 1 or 2 unsaturations in that chain).
  • non-polar groups suitable for use in various embodiments of the present invention include caproyl (C6:0), capryloyl (C8:0), capryl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoly (C16:0), palmitoleoyl (C16:1), stearoyl (C18:0), oleoyl (C18:1), elaidoyl (C18:1), ricinoleoyl (C18:1), linoleoyl (C18:2), linolenoyl (C18:3), arachidonoyl (C20:4), behenoyl (C22:0) and lignoceroyl (C24:9) groups.
  • typical non-polar chains are based on the fatty acids of natural ester lipids, including caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, ricinoleic, linoleic, linolenic, arachidonic, behenic or lignoceric acids, or the corresponding alcohols.
  • Preferable non-polar chains include palmitic, stearic, ricinoleic, oleic and linoleic acids, particularly oleic acid.
  • the injectable liquid formulation of any aspect of the present invention may comprise at least 60% of triacyl lipids having C16 to C18 acyl groups with zero, one or two unsaturations. That is to say, of the triacyl lipids present, at least 60% of the non-polar groups will be C16 to C18, preferably, with zero, one or two unsaturations.
  • the total triacyl lipid (e.g. triacyl glycerol) component present will be as indicated in any embodiment herein.
  • Triacyl lipids such as triacyl glycerols, may be synthetic but will typically be derived from natural sources. Many oils of natural products are high in triacyl lipids and these may be used either in their extracted form or in partially or fully purified forms. Animal or preferably vegetable oils are highly suitable sources of triacyl lipids (especially triacyl glycerols) and may include olive oil, corn oil, sunflower oil, rapeseed (canola) oil, palm oil, soybean oil, sesame oil, castor oil and mixtures thereof. Sesame oil, soybean oil, castor oil and mixtures thereof are preferred.
  • the lipid matrix component a) contains up to 50% of lipids that are not triacyl lipids.
  • lipids may be any appropriate component including mono-, and di-glycerides, phospholipids (diacyl and/or “lyso” monoacyl), cholesterol, tocopherol etc.
  • the non-triacyl lipid may comprise:
  • Lipids that are not triacyl lipids will evidently comprise that part of component a) which is not accounted for by triacyl lipids, thus, the amount on non-triacyl lipids may be, for example 0 to 49%, such as 1 to 40% or 3 to 30%. In one embodiment less than 10% of component a) (e.g. 0.5 to 10%) is a non-triacyl lipid, such as i) to iii) above or mixtures thereof.
  • Component i) above may be any neutral diacyl lipid and will typically comprise a non-ionic polar “head” group as described above, linked (e.g. by and ester, ether, C—C bond or amide) to two non-polar “tail” groups such as the acyl groups described herein.
  • Preferred polar head groups and non-polar tail groups described herein above apply to the diacyl lipid component (and equally to any mono-acyl lipid that may be present).
  • composition ii) above is “tocopherols”, which are a class of compounds which may be used as part of component a) in any compatible aspect or embodiment herein.
  • a tocopherol is used to indicate the non-ionic lipid tocopherol, often known as vitamin E, and/or any suitable salts and/or structural analogues thereof.
  • Suitable analogues will be those providing the physical properties, lack of toxicity, and structure which is equivalent or highly similar to tocopherol itself. Such analogues will generally not form liquid crystalline phase structures as a pure compound in water.
  • the most preferred of the tocopherols is tocopherol itself, having the structure below.
  • a tocopherol will contain no more than 10% of non-tocopherol-analogue compounds, preferably no more than 5% and most preferably no more than 2% by weight.
  • Component iii) above is at least one phospholipid.
  • this component comprises a polar head group non-polar tail group(s).
  • the key feature of the phospholipid lies principally in the polar group.
  • the non-polar portions may thus suitably be derived from the fatty acids or corresponding alcohols considered above for triacyl lipids (e.g. independently chosen from C16 to C22 acyl groups with zero to two unsaturations). It will typically be the case that the phospholipid will contain two non-polar groups, although one or more constituents of this component may have one non-polar moiety. Where more than one non-polar group is present these may be the same or different.
  • Preferred phospholipid polar “head” groups include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol.
  • Preferred phospholipids are phosphatidylcholine (PC), phosphatidylethanolamine (PE). Most preferred is phosphatidylcholine (PC).
  • the phospholipid portion may be derived from a natural source.
  • Suitable sources of phospholipids include egg, heart (e.g. bovine), brain, liver (e.g. bovine) and plant sources including soybean, castor bean and sesame seed.
  • Such sources may provide one or more constituents of component iii), which may comprise any mixture of phospholipids.
  • the ratio of triacyl lipid(s):phospholipid(s) (w/w) in the lipid controlled-release matrix a) is in the range of 50:50 to 100:0, preferably 80:20 to 100:0, especially 90:10 to 100:0, such as 93:7 to 100:0, 95:5 to 100:0 or 97:3 to 100:0.
  • the combined amount of phospholipid(s) present in the injectable formulation may be less than 8 wt % of the formulation, 6 wt % or less, 4 wt % or less, or 2 wt % or less.
  • the amount of phospholipid in the formulation may be less than 5% by weight, such as less than 4.5% by weight (e.g. 0% to 4.4%), or less than 4.2% by weight of the total formulation (e.g. of the total of components a) to c)).
  • the amount of triacyl lipid in component a) of the formulation may be at least 90% by weight. This may be at least 95% (e.g. 96 to 100%) or at least 95.5%.
  • Preferred triacyl lipids include those described herein, including triacylglycerols and triacyldiglycerols.
  • the amount of phospholipid in component a) may be less than 5% by weight, such as less than 4.5% by weight (e.g. 0 to 4.4% by weight), or less than 4.2% by weight of component a).
  • components b) and c) will generally not contain any phospholipid components.
  • the components a and b including components i) to iii) if present, are biocompatible.
  • diacyl phospholipids rather than mono-acyl (lyso) compounds.
  • tocopherol as described above. Although having only one alkyl chain, this is not a “lyso” lipid in the convention sense. The nature of tocopherol as a well tolerated essential vitamin evidently makes it highly biocompatible.
  • the formulations of the present invention comprise only a single extract or component as component a). That is to say, component a) may be a single naturally occurring mixture or a single mixture separated from a single natural product. Thus, component a) may consist of or consist essentially of a single vegetable oil. Suitable examples include castor oil or sesame oil.
  • the compositions are comparatively simple to prepare and validate for tasks such as quality control and regulatory approval. This potentially makes them simpler and/or more economical to manufacture than comparable compositions containing mixtures of lipid components.
  • Component b) of the various aspects of the present invention is at least one oxygen-containing organic solvent.
  • Organic solvents comprise at least one carbon and generally at least one carbon-hydrogen bond and in the case of component b) will contain at least one oxygen in their structure.
  • Such solvents may also contain at least one other “heteroatom” such as nitrogen, sulphur or a halide (chloride, fluoride, bromide, iodide). It is preferred that component b) consists of at least 80% by weight solvents not containing any halogen, more preferably at least 95%.
  • component b) comprises at least 50% solvents having at least one nitrogen and/or sulphur atom in their structure. Preferred component b) will comprise at least 75% and preferably at least 90% of such solvents.
  • Preferred solvents will typically be around 45 to 500 g/mol in molar mass, more typically around 50 to 200 g/mol.
  • Preferred solvents include alcohols, amides, including lactams, and sulphoxides.
  • component b) may comprise, consist essentially of, or consist of amides, sulphoxides or mixtures thereof.
  • component b) Two highly preferred solvents which may be included (individually or as a mixture) in component b) are N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO).
  • NMP N-methyl-2-pyrrolidone
  • DMSO dimethyl sulfoxide
  • component b) will comprise at least 50% of NMP and/or DMSO.
  • component b) will comprise at least 70% of NMP, DMSO or mixtures thereof, more preferably at least 80% and most preferably at least 90%.
  • component b) consists of NMP, DMSO or mixtures thereof or consists essentially of such components.
  • the term “substantially” is used to indicate that an aspect or component is, in substance, defined by the indicated limitation but allows for insubstantial variation not having any material effect upon the nature or behaviour. Such variation might be by, for example 10% or preferably 5% from the indicated amount, state or behaviour.
  • a component that “consists essentially of” some stated component will, in essence, consist of that component but may contain small, trivial or unavoidable other components such as deliberate additives (e.g. flavourings, preservatives, tracers etc) or components that are not easily or economically separable (such as lipids with a distribution of chain lengths etc) including contaminants and/or impurities which do not change the essential behaviour of the stated component.
  • a component “consisting essentially” of a stated compound or mixture may include such compound(s) in any amount that controls the essential behaviour but typically at greater than 90% (e.g. 90% to 100%), more preferably greater than 95% and most preferably greater than 98%.
  • Terms “about” and “around” carry meanings equivalent to “substantially” or “essentially”.
  • Component b) may be present at any amount that provides a formulation suitable for injection (e.g. subcutaneous injection).
  • a formulation suitable for injection e.g. subcutaneous injection.
  • Such a formulation will have the sterility, biocompatibility etc. required of an injectable formulation but will additionally have a viscosity suitable for injection.
  • viscosities are discussed herein and the solvent may be chosen and used at a level to provide any such viscosities.
  • the solvent will also be required in order to help dissolve the active agent and provide suitable controlled release. Such properties may be optimised from the Examples and discussion herein.
  • the formulations of the present invention in all aspects will comprise component b) present at 10 to 60%, especially 15 to 50% by weight of the precursor formulation. This will preferably be 20 to 45%, most preferably 25 to 40% by weight.
  • Component c) of the formulations and compositions of all aspects and embodiments of the present invention is at least one active agent selected from buprenorphine and salts thereof, calculated as buprenorphine free base.
  • This may be any suitably active and biotolerable form of any buprenorphine compound having an effect (e.g. agonism and/or antagonism) at one or more opioid receptors.
  • Buprenorphine free base is the most preferred buprenorphine active agent and where weight percentages are specified herein, these are in terms of the equivalent amount of buprenorphine free base unless otherwise specified.
  • Suitable salts, including mixtures thereof, may be used and these salts may be any biocompatible salt.
  • Suitable salts include acetate, citrate, pamoate or halide (e.g. chloride or bromide) salts, or any of the many biocompatible salts which are known in the art.
  • halide e.g. chloride or bromide
  • Buprenorphine is an opioid with mixed agonist-antagonist properties (also known as a partial agonist) that has been used in the treatment of opioid dependence in a number of countries. It is approved by the Food and Drug Administration (FDA) for the treatment of opioid dependence in the United States and clinical studies have shown buprenorphine to be effective in reducing opioid-positive urines and retaining patients in outpatient maintenance treatment of opioid dependence, as well as in the detoxification of opioid abusers.
  • FDA Food and Drug Administration
  • Buprenorphine has a unique pharmacological profile with several potential strengths over other opioid treatments:
  • a ceiling on its agonist activity that may reduce its abuse liability and contribute to a superior safety profile.
  • buprenorphine treatment is associated with a relatively low-intensity withdrawal syndrome upon discontinuation, making it particularly promising for detoxification treatments.
  • Buprenorphine is currently available commercially in sublingual dosing forms, which require dosing every 1-2 days either at a clinic, or with “take-home” medication. Because of the potential for abuse of opioids, however, “take-home” of any opioid poses potential logistic and legislative problems. This is made more problematic by the low bioavailability of existing sublingual formulations meaning that the dose being “taken home” is potentially quite a significant one.
  • a controlled-release formulation of the present invention offers several advantages in use for treating opioid dependence, including fast onset and relatively stable levels of buprenorphine over time, thereby suppressing withdrawal symptoms and blocking the effects of exogenously-administered opioids for several weeks.
  • the slow decay and elimination of the depot buprenorphine could also provide a gradual opioid detoxification with minimal withdrawal syndrome.
  • a controlled-release buprenorphine injection may offer a promising approach for delivering effective opioid maintenance or detoxification treatment.
  • a controlled-release formulation administrable at intervals of at least 1 month should minimize the burdens of patient compliance as it would require a less frequent dosing regimen, thereby also reducing the frequency of clinic visits and the amount of clinical support needed.
  • a periodic buprenorphine injection in controlled-release form should reduce the risks of misuse and drug diversion of the medication by eliminating or reducing the need for take-home medication.
  • the amount of buprenorphine required in the treatment of any particular subject will depend greatly upon the indication and upon the tolerance of the specific subject, as well as the frequency of administration and the rate of release following administration. In general, pain treatment will require lower doses than opioid dependence related therapies.
  • Buprenorphine will be present in the formulations of the present invention at 16% by weight or more as discussed herein.
  • the injectable liquid formulations in any aspects and embodiments of the present invention will generally have a dose of buprenorphine in the range 20 to 240 mg buprenorphine (calculated as free base) per month of release duration.
  • release duration will be the period (typically the average or recommended period) between injections for a fully compliant subject. Suitable periods are discussed herein below.
  • the buprenorphine content will thus depend upon the frequency of administration and may be, for example, 20 to 200 mg per month, preferably 20 to 1140 mg per month of buprenorphine (based upon equivalent amount of free base).
  • formulations in any aspect or embodiment of the present invention will have a dose in the range 20 to 800 mg, such as 50 to 600 mg buprenorphine per dose (calculated as free base) particularly 60 to 300 mg, more preferably 90 to 200 mg.
  • administration takes place on a periodic basis. Such administration will be less frequent than the dosing every 1-2 days used with current sublingual products. Generally the administration will be no more frequently than once every 28 days. An administration about once every 1 to 4 months may be desirable, such as every 28 to 136 or 28 to 96 days. This may be at periods of around 1 month, around 2 months or around 3 months. Thus, administration may be once every 28 to 32 days, once every 56 to 62 days, or once every 82 to 95 days. Such periods may be the recommended periods for administration and may be the periods between administration (generally the average periods) for a fully compliant subject.
  • formulations in all aspects and embodiments of the invention are “injectable”. Such formulations thus have the properties of sterility and biocompatibility required of a formulation for injection.
  • Administration by injection is used herein to indicate any method in which the formulation is passed through the skin or other body surface, such as by needle, catheter or needle-less injector.
  • Subcutaneous, intracavitary, intravitreal or intramuscular injection by any suitable method will thus be appropriate with subcutaneous or intramuscular, particularly subcutaneous injection being preferred.
  • formulations must be capable of injection, preferably manually using convention equipment such as a disposable syringe and hypodermic needle of conventional gauge (e.g. 18 to 28 gauge). This requires that the formulations be of low viscosity.
  • the formulations are preferably low viscosity mixtures.
  • the term “low viscosity mixture” is used to indicate a mixture which may be readily administered to a subject. This may be indicated, for example, by the ability to be dispensed from a 1 ml disposable syringe through a 22 gauge needle by manual pressure, preferably within a period of less than 1 minute.
  • the low viscosity mixture should be a mixture capable of passing through a standard sterile filtration membrane such as a 0.22 ⁇ m syringe filter.
  • a typical range of suitable viscosities would be, for example, 20 to 600 mPas at 20° C., preferably 50 to 400 mPas at 20° C., most preferably 80 to 300 mPas at 20° C.
  • the formulations of the present invention are advantageous in that they may be provided in a form that does not require mixing or lengthy preparation before administration.
  • the formulations of the invention may be in ready-to-administer form.
  • Such a form may be in a sealed vial or similar vessel, or in a pre-filled administration device, such as a pre-filled syringe or cartridge.
  • a pre-filled administration device such as a pre-filled syringe or cartridge.
  • Such a device will contain a single dose and optionally the means to vary the administered dose according to the needs of the subject (such as volume markings).
  • Such pre-filled devices evidently form a further aspect of the invention.
  • the injectable formulations of the invention can be provided in ready-to-administer for because, in one embodiment, they can be stable to storage in such ready-to-administer form.
  • Stability to storage will typically mean that a formulation of the invention will lose less than 20%, preferably less than 10%, more preferably less than 5% of its buprenorphine content after storage for at least 1 month, preferably at least 6 months, more preferably at least 12 months.
  • Such storage will preferably be at 2-8° C., more preferably at 25° C.
  • the formulations of the present invention When administered to a subject, the formulations of the present invention will preferably form the controlled-release compositions of the invention. This is typically upon contact with body fluid. Such subjects will be animal subjects, typically mammalian and most preferably human subjects.
  • the controlled-release compositions of the invention release buprenorphine in a very controlled fashion, providing that at least 16% of buprenorphine is present. Illustration of this is provided in FIG. 1 below.
  • the average (mean) Cmin and Cmax (preferably in a population of at least 10 subjects) at a steady-state both fall with the range of between 0.3 ng/mL to 12 ng/mL, preferably 0.4 ng/mL and 5 ng/mL. This allows for the therapeutic window of buprenorphine to be maintained very effectively and gives a significantly improved experience for the subject.
  • compositions of the invention will lose solvent component b) upon administration and my take up at least a little water.
  • compositions after injection may thus comprise:
  • Aqueous component d) will typically be an aqueous body fluid.
  • All of the injectable formulations described herein may be used in therapy.
  • Such therapy will be for any condition for which buprenorphine is indicated, particularly over an extended period.
  • Such indications include pain, particularly chronic pain including post-operative pain, cancer pain, and pain due to degenerative diseases such as arthritis.
  • Most importantly, such indications will include treatment or maintenance in opioid dependence or withdrawal.
  • Therapy for opioid dependence typically includes several phases of treatment including “induction”, “stabilisation” and “maintenance”.
  • Formulations of the present invention may be used in any such phase, and/or in gradual dose reduction if desirable. Due to the long duration of the controlled-release effect, the formulations and compositions of the invention are very suitable for the maintenance phase.
  • a subject who is receiving frequent injections (e.g. daily injections) or sublingual buprenorphine for opioid dependence may transition onto formulations of the present invention for stabilisation and/or maintenance phases of treatment.
  • buprenorphine formulations of the present invention may be used in therapy relating to dependence on other substances including cocaine.
  • the present invention further provides methods of treatment of a human or animal subject (such as one described herein) comprising administering any of the formulations described herein.
  • a human or animal subject such as one described herein
  • Such a method will typically be for the treatment of any conditions for which buprenorphine is indicated.
  • These include all the conditions and therapies discussed herein in any aspect or embodiment of the invention.
  • FIG. 1 Shows dose normalized plasma buprenorphine (BUP) concentrations after subcutaneous administration of Formulations A1 and C1 (from Examples 1 and 3 respectively) to rats.
  • BUP normalized plasma buprenorphine
  • composition Comprising Buprenorphine Base, Sesame Oil and N-Methyl Pyrrolidone (NMP)
  • composition according to Table 1 was prepared by weighing 2.03 g buprenorphine base, 1.80 g NMP and 2.17 g of Sesame oil in a 10 mL injection glass vial.
  • the vial was closed with Flurotec®-coated rubber stopper and aluminum crimp cap followed by end-over-end rotation mixing at ambient room temperature until a liquid, transparent and homogenous formulation was obtained.
  • the formulation was finally subjected to filtration through a sterile 0.22 ⁇ m Millex®-GV membrane (Millipore) under nitrogen pressure.
  • compositions Comprising Buprenorphine Base, Triglycerides and Solvents
  • compositions according to Table 2 are prepared by weighing the required amounts of buprenorphine base, triglyceride and solvent in 4 mL injection glass vials.
  • the vials are closed with Flurotec®-coated rubber stoppers and aluminum crimp caps followed by end-over-end rotation mixing at ambient room temperature.
  • Composition Comprising Low Drug Load Buprenorphine Base, Triglyceride and Solvent
  • composition according to Table 3 was prepared by weighing 0.0424 g buprenorphine base, 0.400 g Ethanol and 3.558 g of Castor oil in a 10 mL injection glass vial.
  • the vial was closed with Flurotec®-coated rubber stopper and aluminum crimp cap followed by end-over-end rotation mixing at ambient room temperature until a liquid, transparent and homogenous formulation was obtained.
  • the formulation was finally subjected to filtration through a sterile 0.22 ⁇ m Millex-GP membrane (Millipore) under nitrogen pressure.
  • Formulation A1 provides a rapid onset of buprenorphine release and stable buprenorphine plasma levels thereafter.
  • the plasma buprenorphine levels decline more rapidly after the initial peak for the low buprenorphine loading Formulation C1.
  • Formulation A1 is seen to provide stable plasma levels over the entire study period whereas the buprenorphine levels for Formulation C1 decline about one order of magnitude during the same period.
  • Formulations A1 and C1 were administered subcutaneously to rats (male MPF Sprague-Dawley rats) in doses of 30 and 2 mg/kg, respectively, and blood samples were collected pre-dose, and at 1 hour, 6 hours, 1 day, 2 days, 5 days, 8 days, 14 days after dosing.
  • a blood volume of 0.25 mL was collected into EDTA-treated test tubes (Capiject®3T-MQK, Terumo Medical Corporation) by sub-lingual bleeding.
  • the blood samples were placed on ice immediately after collection and centrifuged (approximately 1500 ⁇ g, at 5° C. for 10 min) within 30 to 60 minutes.
  • the plasma was transferred into 0.5 mL propylene test tubes (Eppendorf Safe lock tubes, Fisher Scientific) and stored below ⁇ 70° C. until bioanalysis.
  • the plasma concentrations were determined with the aid of a commercial ELISA kit adapted for analysis of buprenorphine in rat plasma.

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