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WO2019064026A1 - Nouvelles compositions pharmaceutiques - Google Patents

Nouvelles compositions pharmaceutiques Download PDF

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Publication number
WO2019064026A1
WO2019064026A1 PCT/GB2018/052792 GB2018052792W WO2019064026A1 WO 2019064026 A1 WO2019064026 A1 WO 2019064026A1 GB 2018052792 W GB2018052792 W GB 2018052792W WO 2019064026 A1 WO2019064026 A1 WO 2019064026A1
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WO
WIPO (PCT)
Prior art keywords
dosage form
buprenorphine
opioid
acid
treatment
Prior art date
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Ceased
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PCT/GB2018/052792
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English (en)
Inventor
Andreas Fischer
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Orexo AB
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Orexo AB
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Publication date
Priority claimed from GBGB1715881.7A external-priority patent/GB201715881D0/en
Priority claimed from GBGB1810265.7A external-priority patent/GB201810265D0/en
Application filed by Orexo AB filed Critical Orexo AB
Publication of WO2019064026A1 publication Critical patent/WO2019064026A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K9/08—Solutions
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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

Definitions

  • This invention relates to new pharmaceutical compositions containing opioids that are useful in the treatment of inter alia opioid/opiate dependency and/or pain, which compositions may be abuse-resistant.
  • Opioids are widely used in medicine as analgesics. Indeed, it is presently accepted that, in the palliation of more severe pain, no more effective therapeutic agents exist.
  • Opioid agonist analgesics are used to treat moderate to severe, chronic cancer pain, often in combination with non-steroidal anti-inflammatory drugs (NSAIDs), as well as acute pain (e.g. during recovery from surgery and breakthrough pain). Further, their use is increasing in the management of chronic, non-malignant pain.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Opioid dependence is a major health problem and long-term heroin use is connected to a substantially increased risk of premature death from drug overdoses, violence and suicide. Furthermore, sharing of needles among addicts contributes to the spreading of potentially fatal blood infections such as HIV, and hepatitis C.
  • opioid dependence often leads to difficulties with social relations, inability to manage a normal job and increased criminality to finance addiction, with severe implications for the opioid-dependent person and his/her family.
  • the US Center for Disease Control and Prevention estimates that the total economic burden of prescription opioid misuse alone in the US is $78.5 billion a year, which includes the cost of healthcare, lost productivity, addiction treatment, and involvement in criminal activity (see Florence et al, Med. Care., 54, 901 (2016)).
  • Opioid addicts not only feed their addiction by direct purchase of opioids
  • opioid-based powders such as heroin
  • opioid-based powders such as heroin
  • Such individuals then often apply innovative techniques in their abuse of such formulations, for example by extracting a large quantity of active ingredient from that formulation into solution, which is then injected intravenously. With most commercially-available pharmaceutical formulations, this can be done relatively easily, which renders them unsafe or 'abusable'.
  • Opioid addicts are often treated by way of 'substitution' therapy, in which mainly 'street' opioids of unknown strength and purity are replaced by pharmaceutical-grade opioids with a longer duration of action, such as buprenorphine.
  • a new cohort of opioid-dependent individuals has begun to emerge in the last decade, particularly in the US, namely so-called "white collar” addicts, who have become dependent upon prescription opioids, typically initiated for the treatment of pain. Substitution therapy is also required for this growing group of patients.
  • the incidence of prescription and illicit opioid use during pregnancy has increased in the US since 2000, paralleling a similar escalation in the general population.
  • Buprenorphine is a partial agonist at the ⁇ -opioid receptor and an antagonist at the ⁇ -opioid receptor. It has high binding affinity at both receptors and competes with other agonists, such as methadone, heroin (diamorphine) and morphine, at the ⁇ -opioid receptor.
  • Opioid agonist effects of buprenorphine are less than the maximal effects of other, "full" opioid agonists, such as morphine, and are limited by a “ceiling" effect.
  • the drug thus produces a lower degree of physical dependence than other opioid agonists, such as heroin, morphine or methadone and is therefore particularly useful in substitution therapy.
  • opioid agonists such as heroin, morphine or methadone
  • Buprenorphine has been listed on the WHO'S List of Essential Medicines for the treatment of opioid dependence (Degenhardt et al, supra).
  • Buprenorphine is also used for the treatment of moderate to severe pain and several buprenorphine-based products for the treatment of pain are currently available in the US and Europe. These products include an injectable solution under the trademark Buprenex®; a sublingual tablet, which is sold under the trademark Temgesic®; a buccal film sold under the trademark Belbuca®; and transdermal patches, which are available under the trademarks Norspan® and Butrans®.
  • Transdermal patch formulations are described in numerous prior art documents such as Canadian Patent CA 2670290, European Patent Applications EP 3 106 153 A, EP 171 742 A and EP 368 409 A, international patent applications WO 2013/088254, WO 2014/090921 , WO 2017/048595, WO 00/35456 and WO 2014/031958, Roy et al, J. Pharm. Sci., 83, 126 (1994) and Liao et al, J. Food Drug Anal., 16, 8 (2008).
  • a simple mixture combination tablet comprising the opioid partial agonist buprenorphine and the opioid antagonist, naloxone in a 4:1 ratio for sublingual administration is available under the trademark Suboxone® (and generic versions thereof).
  • Suboxone and other abuse-resistant opioid-containing formulations are reviewed by Fudula and Johnson in Drug and Alcohol Dependence, 83S, S40 (2006). If Suboxone is taken sublingually, as directed, the small amount of naloxone that is absorbed should not interfere with the desired effects of buprenorphine, due to the former's poor transmucosal bioavailability. On the other hand, if Suboxone is dissolved and injected parenterally, naloxone's increased bioavailability serves to antagonize the effects of buprenorphine and precipitates withdrawal symptoms in opioid-dependent subjects.
  • Suboxone tablets include a long sublingual dissolve time. A long sublingual residence time is not only coupled to poor patient acceptability, but also is time-consuming, and ultimately costly, in clinical settings with supervised administration. Furthermore, Suboxone tablets have repeatedly received low ratings for taste (see, for example, Lyseng- Williamson, Drugs Ther. Perspect, 29, 336 (2013) and Lintzeris et al, Drug Alcohol Depend, 131 , 1 19 (2013)). These drawbacks lead to poor acceptability and lower medication compliance.
  • Suboxone is now marketed in some countries as a sublingual film-based product, but the film formulation is also reported to have an unpleasant taste (see Lintzeris et al, supra). Furthermore, a maximum of only two films (with doses of 2 mg, 4 mg, 8 mg or 12 mg of buprenorphine) may be administered simultaneously.
  • Suboxone has frequently been reported, especially in hidden populations such as incarcerated and active drug abusers (see, for example, Alho et al. , Drug and Alcohol Dependence, 88, 75 (2007), Monte et al. , Journal of Addictive Diseases, 28, 226 (2009),skyl, ibid., 26, 1 (2007) and Smith et al., ibid., 26, 107 (2007)).
  • Another film-based product based on a combination of buprenorphine and naloxone is available in the US to treat opioid dependence (Bunavail®).
  • the film is buccally administered by pressing against the inside of the cheek until it sticks to the mucosa.
  • the film delivers the buprenorphine to the buccal mucosa and eventually dissolves.
  • Patients taking Bunavail must avoid touching the buccal film with their tongue or fingers, and avoid drinking or eating, until after the film has completely dissolved.
  • a sublingual tablet formulation with a significantly improved buprenorphine and naloxone bioavailability compared to Suboxone is reported in international patent application WO 2013/041851.
  • opioid addiction products did not require the presence of an opioid antagonist, such as naloxone, and/or were capable of being administered perorally (i.e. to be swallowed and ingested within the gastrointestinal tract).
  • opioid antagonist such as naloxone
  • buprenorphine has not been previously formulated commercially for peroral delivery is due to its poor bioavailability when administered via the gastrointestinal route.
  • Buprenorphine undergoes significant first pass metabolism in the gastrointestinal tract and liver (see, for example, Cassidy et al, Journal of Controlled Release, 25, 21 (1993)). Buprenorphine is understood to be metabolized primarily to its N-dealkylated metabolite norbuprenorphine.
  • prodrugs of buprenorphine e.g. a hemiadepate ester
  • buprenorphine e.g. a hemiadepate ester
  • compositions comprising e.g. buprenorphine and one or more inhibitors of uridine diphosphate glucuronosyl transferases (UGTs) were co-administered with a view to decreasing the pre- systemic metabolism of the one or more opioids (see, for example, international patent application WO 2014/168925, Joshi et al, Journal of Pharmacy and Pharmacology, 69, 23 (2017) and Maharao et al, Biopharmaceutics & Drug Disposition, 38, 139 (2017));
  • UDTs uridine diphosphate glucuronosyl transferases
  • opioid analgesics and in particular buprenorphine in the form of its free base, can be solubilised at very high concentrations in Cs-2o fatty acids that are liquid at a slightly higher temperature than body temperature, such as caprylic acid, capric acid, lauric acid, linoleic acid and, in particular, oleic acid.
  • a pharmaceutically-acceptable dosage form which dosage form is suitable for peroral administration to the gastrointestinal tract and comprises a pharmaceutically-acceptable composition in the form of a liquid, in which liquid an opioid analgesic is dissolved in a solvent system comprising at least one Cs-2o fatty acid that is a liquid at about 40°C, which dosage forms are referred to hereinafter as "the dosage forms of the invention".
  • Dosage forms of the invention are suitable for peroral administration and delivery, as a complete dosage form, to the gastrointestinal tract. This means that a dosage form of the invention must be suitable for swallowing as a whole, complete dosage form for subsequent consumption and/or ingestion within the gastrointestinal tract, and, in use, is swallowed and then consumed and/or ingested within that tract.
  • Dosage forms of the invention are in particular designed to deliver to the gastrointestinal tract (such as any part of the small intestine (including the duodenum, the jejunum and the ileum, including the terminal ileum), and/or the large intestine or colon) the liquid pharmaceutically-acceptable composition in which opioid analgesic is dissolved in a solvent system comprising a Cs-2o fatty acid, which liquid composition is an essential feature of the dosage form of the invention.
  • dosage forms of the invention may also comprise a pharmaceutically-acceptable carrier, which carrier is capable of releasing that liquid composition within the gastrointestinal tract (such as within the small intestine and/or colon).
  • the aforementioned liquid compositions may be filled into a capsule, such as a soft-shell or a hard-shell capsule, which can be made from gelatin, cellulose polymers or starch polymers, for example by way of standard capsule filling processes.
  • the liquid compositions may also be formulated with adsorbant materials (e.g. colloidal silicon dioxide, cellulose, and aluminium metasilicate) into a powder, which can be filled into capsules or further processed into tablets (in which case the adsorbant material is a carrier as hereinbefore defined).
  • adsorbant materials e.g. colloidal silicon dioxide, cellulose, and aluminium metasilicate
  • Opioid analgesic compounds that may be employed in dosage forms of the invention include opium derivatives and the opiates, including the naturally-occurring phenanthrenes in opium (such as morphine, codeine, thebaine) and semisynthetic derivatives of the opium compounds (such as diamorphine, hydromorphone, oxymorphone, hydrocodone, oxycodone, etorphine, nicomorphine, hydrocodeine, dihydrocodeine, metopon, normorphine, nalbuphine and N-(2-phenylethyl)normorphine); fully synthetic compounds with opioid or morphine-like properties, including morphinan derivatives (such as racemorphan, levorphanol, dextromethorphan, levallorphan, cyclorphan, butorphanol and oliceridine); benzomorphan derivatives (such as cyclazocine, pentazocine and phenazocine); phenylpiperidines (such
  • Preferred opioid analgesics include morphine, codeine, hydrocodone, oxycodone, methadone, tramadol, fentanyl, hydromorphone, oxymorphone and, particularly, buprenorphine.
  • Pharmaceutically-acceptable salts of opioid analgesics may also be employed in dosage forms of the invention.
  • pharmaceutically-acceptable salt of opioid analgesics, we mean an acid addition, or base addition, salts that may be used as pharmaceuticals.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of an active ingredient with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a delivery agent in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • opioid analgesic When the opioid analgesic that is employed is buprenorphine, we prefer that it is employed in the form of the free base.
  • opioid analgesics whether used in a general sense, or with reference to a specific opioid, such as buprenorphine
  • opioid ingredients in the form of either the free acid or free base (as appropriate), and/or in the form of a pharmaceutically-acceptable salt, unless otherwise specified, and/or if the context dictates otherwise.
  • the Cs-20 fatty acids that are employed as solvents for the opioid analgesic are liquid at about 40°C.
  • liquid at about 40°C we mean that the Cs-2o fatty acid has a melting point that is below about 40°C, such as below about body temperature (i.e. 37°C).
  • a small amount e.g. up to about 10%, such as up to about 7.5%) of another solvent, including one or more of the optional additional excipients that are described hereinafter (e.g. ethanol, isopropyl alcohol, and/or a liquid lipid material) may be included in order to lower the melting point of that acid.
  • the primary solvent will still be the Cs-2o fatty acid.
  • Suitable fatty acids include those that contain one or more carboxylic acid (-CO2H) groups, and one or more aliphatic hydrocarbon chains, in which the total number of carbon atoms in the fatty acid molecule is between 8 and 20, preferably between 12 and 18, in number. Hydrocarbon chains may be linear or branched, saturated or unsaturated, straight-chain, cyclic or part-cyclic.
  • Preferred fatty acids include caprylic acid, capric acid, lauric acid, oleic acid and linoleic acid. Particularly preferred fatty acids include oleic acid.
  • the solvent system in which an opioid analgesic is dissolved comprises one or more such Cs-20 fatty acids, which means it may comprise other components.
  • one or more fatty acids is/are the main component of the liquid composition of the dosage form of the invention, which means that the total amount of fatty acid(s) that is/are present in the liquid composition (by weight) is greater than the individual amounts (by weight) of the opioid analgesic and any other optional, additional components that may be present in that liquid composition of the dosage form of the invention.
  • the amount of fatty acid(s) that are present in the liquid compositions of the dosage forms of the invention is at least about 30% by weight, such as at least about 40% (e.g.
  • liquid compositions of dosage forms of the invention are in the main part presented in the form of solutions. That is, by weight, at least about 50% (such as at least about 70%) of the opioid analgesic and, if present, other optional additional solid components in such a liquid composition are dissolved in the fatty acid(s) and/or any other optional additional liquid components that may be present.
  • the liquid compositions may be in the form of part-solutions/part-suspensions, in which at least part (e.g. at least about 30%, such as at least about 45%, e.g. about 50%, by weight) of the opioid analgesic is so dissolved. It is further preferred that the liquid compositions of dosage forms of the invention are not presented in the form of a water-in-oil, or an oil-in-water, emulsion prior to administration.
  • Preferred optional additional excipients include one or more surfactants.
  • Surfactants that may be mentioned include sodium dodecyl sulfate (sodium lauryl sulfate), sorbitan esters (e.g. SpansTM), polyethoxylated alcohols, polyvinyl alcohols, polyol esters (e.g. CithrolTM), polyoxyethylene alkyl ethers (e.g. Brij®, such as Brij 721), polyoxyethylene castor oil derivatives (e.g. Kolliphor®), ethoxylated fatty acid esters (e.g. MyrjTM), polyoxylglycerides (e.g.
  • Gelucire® lauryl dimethyl amine oxide, bile salts (e.g. sodium deoxycholate, sodium cholate), phospholipids (e.g. Phospholipon®), N,N-dimethyldodecylamine-N-oxide (DDAO), hexadecyltrimethylammonium bromide (CTAB), poloxamers (e.g. Pluronic®), lecithin (e.g. Lipoid), sterols (e.g. cholesterol) and the like.
  • bile salts e.g. sodium deoxycholate, sodium cholate
  • phospholipids e.g. Phospholipon®
  • DDAO N,N-dimethyldodecylamine-N-oxide
  • CTAB hexadecyltrimethylammonium bromide
  • Pluronic® poloxamers
  • lecithin e.g. Lipoid
  • sterols e.g
  • sugar esters are a class of natural and biodegradeable non-ionic surfactants consisting of a hydrophilic sugar 'head group' esterified with fatty acids.
  • Sugar esters that may be employed include sucrose esters and maltose esters.
  • Sucrose esters that may be employed include Cs-22 saturated or unsaturated fatty acid esters, preferably saturated fatty acid esters and preferably a C10-18 fatty acid ester and most preferably a C12 fatty acid ester.
  • Particularly suitable fatty acids from which such sugar/sucrose esters may be formed include erucic acid, behenic acid, oleic acid, stearic acid, palmitic acid, myristiric acid and lauric acid.
  • a particularly preferred such fatty acid is lauric acid.
  • Sucrose esters may be diesters or monoesters of fatty acids, preferably monoesters, such as sucrose monolaurate.
  • sucrose monolaurate refers to a mono-ester of lauric acid, and that the terms “lauric acid ester” and “laurate” have the same meaning and can therefore be used interchangeably.
  • Commercially available sucrose monolaurate products are also sometimes referred to as “sucrose laurate”.
  • sucrose monolaurate (or sucrose laurate) products such as Surfhope ® D-1216 (Mitsubishi-Kagaku Foods Corporation (Japan)), which may contain small amounts of diesters and/or higher sucrose esters, and minor amounts of other sucrose esters and free sucrose, are suitable for use in the invention.
  • sucrose ester herein includes commercially available products comprising that sucrose ester as a principle component.
  • Preferred sucrose esters contain only one sucrose ester, which means that a single sucrose ester (e.g. a commercially-available sucrose ester product) contains a single sucrose ester as the/a principle component (commercially available products may contain impurities, for example a monoester product may contain small amounts of diesters and/or higher esters, such products may be considered to "contain only one sucrose ester" in the context of the present invention).
  • the term "principle component” will be understood to refer to the major component (e.g. greater than about 50%, such as about 70% weight/weight or volume/volume) in a mixture of sucrose esters, such as commonly commercially available surfactant products, which are typically sold with a certain range of ester compositions.
  • liquid compositions that may be employed in dosage forms of the invention that include a sucrose ester as a surfactant may exhibit surprisingly good bioavailability compared to corresponding liquid compositions that do not include sucrose esters, and/or include different surfactants.
  • surfactants that may be mentioned include polysorbates (TweensTM), including polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) and, preferably, polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate) and/or polysorbate 80 ((polyoxyethylene (20) sorbitan monooleate).
  • TeweensTM polysorbates
  • polysorbate 40 polyoxyethylene (20) sorbitan monopalmitate
  • polysorbate 60 polyoxyethylene (20) sorbitan monostearate
  • polysorbate 20 polyoxyethylene (20) sorbitan monolaurate
  • polysorbate 80 polyoxyethylene (20) sorbitan monooleate
  • Dosage forms of the invention that include a polysorbate as a surfactant may exhibit improved bioavailability and/or may be more abuse resistant compared to other liquid compositions that may be employed in dosage forms of the invention and/or compositions of the prior art.
  • Surfactants may be present in a total amount of between about 5% and about 50%, such as between about 10% and about 45%, by weight, based on the total weight of the liquid composition.
  • Additional ingredients may include solvents or co-solvents, such as water; alcohols, including lower alkyl (e.g. Ci-e alkyl) alcohols, such as isopropyl alcohol and, particularly, ethanol (e.g.
  • oils such as vegetable oils (e.g. castor, peanut, corn, safflower, sesame, soybean, coconut, palm oils and, especially, olive oil); mono-, di and triglycerides of fatty acids (e.g. medium chain monoglycerides, and, in particular, monoacyl glycerols (i.e.
  • glycerol monooleate e.g. CithrolTM
  • glycerol monocaprylate e.g. Capmul®
  • antioxidants e.g. a-tocopherol, ascorbic acid, potassium ascorbate, sodium ascorbate, ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, dodecyl gallate, octyl gallate, propyl gallate, ethyl oleate, monothioglycerol, vitamin E polyethylene glycol succinate, or thymol
  • chelating (complexing) agents e.g.
  • edetic acid citric acid, tartaric acid, malic acid, cyclodextrins, maltol and galactose
  • preservatives e.g. benzoic acid, benzyl alcohol, boric acid, parabens, propionic acid, phenol, cresol, or xylitol
  • viscosity modifying agents or gelling agents such as cellulose derivatives, including hydroxypropylcellulose, methylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, etc. , starches and modified starches, colloidal silicon dioxide, aluminium metasilicate, polycarbophils (e.g. Noveon®), carbomers (e.g.
  • Carbopol® Carbopol®
  • pH buffering agents e.g. citric acid, maleic acid, malic acid, or glycine
  • colouring agents e.g. citric acid, maleic acid, malic acid, or glycine
  • penetration enhancers e.g. myristic acid, palmitic acid, isopropyl myristate, isopropyl palmitate, pyrrolidone, or tricaprylin
  • other lipids neutral and polar
  • Total amounts of other excipients are no more than about 35% (e.g. about 25%), for example no more than about 30% (e.g. about 20%), such as about 25% (e.g. about 15%) by weight, based on the total weight of a liquid composition of a dosage form of the invention.
  • compositions that are included in dosage forms of the invention may be/are capable of self-emulsification when placed in contact with an aqueous environment, for example as described hereinafter.
  • Self-emulsification means that the liquid compositions of the dosage forms of the invention are capable of dispersing into various lipid structures and/or phases (e.g. emulsion droplets, liposomes, vesicles, bilayer sheets, micelles etc.) when placed in contact with an aqueous environment, with simple agitation and/or stirring, and without the need of high energy input (such as sonication, high shear mixing, homogenization, extrusion etc.).
  • lipid structures and/or phases e.g. emulsion droplets, liposomes, vesicles, bilayer sheets, micelles etc.
  • opioid analgesic such as buprenorphine
  • aqueous environment may be understood to mean water or any medium that comprises water. Amounts of water that may be employed in aqueous environments include those necessary to induce the formation of a dispersion and/or an emulsion comprising opioid.
  • opioid analgesic such as buprenorphine
  • lipid structures/phases e.g. emulsion droplets, vesicles, micelles or the like.
  • Dosage forms of the invention, and liquid compositions that may be included therein, may be prepared by standard techniques, and using standard equipment, known to the skilled person.
  • the liquid compositions (and other components) of dosage forms of the invention may be combined with conventional pharmaceutical additives and/or excipients used in the art for relevant preparations, and incorporated into various kinds of pharmaceutical preparations using standard techniques (see, for example, Lachman et al, "The Theory and Practice of Industrial Pharmacy", Lea & Febiger, 3 rd edition (1986); “Remington: The Science and Practice of Pharmacy", Troy (ed.), University of the Sciences in Philadelphia, 21 st edition (2006); and/or “Aulton's Pharmaceutics: The Design and Manufacture of Medicines", Aulton and Taylor (eds.), Elsevier, 4 th edition, 2013).
  • liquid compositions of the dosage forms of the invention may be prepared by stirring together opioid analgesic or salt thereof, along with the solvent system comprising a Cs-20 fatty acid as hereinbefore defined, and any other ingredients as mentioned hereinbefore at ambient (e.g. room) temperature until a solution is formed.
  • a process may also comprise other process steps, such as heating, high shear mixing and/or sonication to promote solubilisation and/or a uniform distribution of ingredients within the formulation.
  • the dosage forms of the invention for use in medicine (human and veterinary).
  • the dosage forms of the invention may be designed for immediate release (e.g. release in the stomach after swallowing), and/or may be targeted for delivery at the small intestine and/or the colon. Accordingly, dosage forms of the invention may be administered perorally to the gastrointestinal tract and protected by an appropriate extended/sustained release, controlled or delayed release (e.g. enteric) coating.
  • Targeted delivery that may be mentioned includes targeting release of the active ingredient to the distal parts of the small intestine (e.g. the ileum, including the terminal ileum) and/or the colon.
  • Various methods may be employed to do this, including:
  • dosage forms of the invention when administered to a patient and liquid compositions released at the relevant site, they may provide a higher intestinal absorption of an opioid analgesic (e.g. buprenorphine) than is presently possible with existing pharmaceutical compositions, such as those described hereinbefore.
  • an opioid analgesic e.g. buprenorphine
  • the dosage forms of the invention may increase the bioavailability of opioid analgesic (e.g. morphine, codeine, hydrocodone, oxycodone, methadone, tramadol, fentanyl, hydromorphone, oxymorphone and, in particular, buprenorphine), by decreasing its pre-systemic metabolism and/or or first-pass metabolism.
  • opioid analgesic e.g. morphine, codeine, hydrocodone, oxycodone, methadone, tramadol, fentanyl, hydromorphone, oxymorphone and, in particular, buprenorphine
  • the dosage forms of the invention may have the potential to keep more opioid analgesic (e.g. opioids with a high pre-systemic metabolism, such as morphine, codeine, hydrocodone, oxycodone, methadone, tramadol, fentanyl, hydromorphone, oxymorphone and, in particular, buprenorphine) solubilized in gastrointestinal fluids, and thereby expose the intestinal enterocytes to high concentrations of opioid analgesic, so that the intestinal metabolic system is saturated and a relatively smaller portion of opioid analgesic is metabolized. In this way, it is expected that more non-metabolized opioid analgesic (e.g. buprenorphine) will traverse the intestinal cells and enter circulation.
  • opioid analgesic e.g. opioids with a high pre-systemic metabolism, such as morphine, codeine, hydrocodone, oxycodone, methadone, tramadol, fentanyl, hydromorphone, oxymorphone
  • the dosage forms of the invention may enhance intestinal lymphatic delivery, and thereby avoid to a great extent pre-systemic (first-pass) metabolism.
  • Dosage forms of the invention thus provide for improved peroral bioavailability as determined by an improved plasma concentration versus time profile (which can in turn be represented by a greater AUC and/or a more extended plasma concentration-time profile).
  • the dosage forms of the invention are particularly useful in the treatment of pain and/or when, in particular, the dosage form comprises buprenorphine or a salt thereof, in the treatment of opioid dependency and/or addiction. Dosage forms of the invention may also be used in the treatment of clinical depression, cough, diarrhoea and/or restless legs. According to three further aspects of the invention there are provided:
  • Pain includes mild, moderate and severe pain, acute pain and chronic pain.
  • treatment we include the therapeutic treatment, as well as the symptomatic and palliative treatment of the condition.
  • patients includes animals, including mammalian (particularly human) patients.
  • Opioid dependency and/or addiction may be defined in numerous ways (see, for example, www.who.int/substance_abuse/terminology/definition1 , and/or the standard Diagnostic and Statistical Manual of Mental Disorders, 5 th edition (DSM-5; publ. American Psychiatric Association (APA)) classification of mental disorders), but may be characterized for example by physiological, behavioural, and cognitive phenomena wherein the use of a substance or a class of substances takes on a much higher priority for a given individual than other behaviours that once had greater value, and/or characterised by a desire (often strong, and sometimes overpowering) to take opioids and/or opiates (which may or may not have been medically prescribed).
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders
  • APA publ. American Psychiatric Association
  • Dosage forms of the invention may also be administered in the induction phase (i.e. the start-up) of therapy, wherein the active ingredient (e.g. buprenorphine) is administered once an opioid-addicted individual has abstained from using opioids for about 12-24 hours and is in the early stages of opioid withdrawal.
  • the active ingredient e.g. buprenorphine
  • a method of treatment of opioid dependency and/or addiction comprises administration of a dosage form of the invention, and in particular one that comprises buprenorphine, to an individual that has abstained from using opioids for at least about 12 hours and/or is in the early stages of opioid withdrawal.
  • treatment we further include the prophylaxis, or the diagnosis of the relevant condition in addition to therapeutic, symptomatic and palliative treatment. This is because, by employing dosage forms of the invention in the treatment of pain, they may abrogate or prevent the development of opioid dependency and/or addiction.
  • the term "therapeutically effective amount” refers to an amount of active ingredient that is capable of conferring a desired therapeutic effect on a treated patient, whether administered alone or in combination with another active ingredient. Such an effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of, or feels, an effect).
  • appropriate pharmacologically effective amounts of opioid analgesic (or salt thereof) include those that are capable of producing, and/or contributing to the production of, the desired therapeutic effect, namely decreased opioid and/or opiate craving and/or decreased illicit drug use, or treating pain, as appropriate, irrespective of the mode of administration that is employed.
  • the amount of active ingredient that may be employed in a dosage form of the invention may thus be determined by the skilled person, in relation to the condition, and what will be most suitable for an individual patient. This is also likely to vary with the nature of the formulation, or the aspect of the invention, as well as the route of administration, the type and severity of the condition that is to be treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.
  • the total amount of opioid analgesic that may be employed in a dosage form of the invention may be in the range of about 0.0005%, such as about 0.1 % (e.g. about 1 %, such as about 2%) to about 30%, such as about 20%, for example about 15%, by weight based upon the total weight of the liquid formulation.
  • the amount of the active ingredient may also be expressed as the amount in a unit dosage form.
  • the amount of opioid analgesic that may be present may be sufficient to provide a dose of opioid (calculated as the free acid/base) per unit dosage form that is in the range of between about 1 ⁇ g (e.g. about 5 ⁇ g) and about 100 mg, for example up to about 50 mg, including about 30 mg, such as about 20 mg (e.g. about 15 mg, such as about 10 mg).
  • Preferred ranges of opioid analgesic (calculated as the free acid/base) per unit dosage form for the treatment of pain are between about 1 ⁇ g to about 15 mg, depending on the active ingredient that is employed, as well as the specific dosage form and the dosage regime that is employed.
  • preferred ranges for e.g. a capsule to be taken once daily for the treatment of pain are between about 1 ⁇ g to about 10 mg, depending on the opioid analgesic that is employed.
  • Preferred ranges for e.g. a capsule comprising a dosage form comprising e.g. buprenorphine to be taken once daily for the treatment of opioid dependency and/or addiction are between about 0.1 mg to about 100 mg, more preferably about 1 mg to about 50 mg, calculated as the free base.
  • the appropriate amount of e.g. buprenorphine loading may depend on the stage of treatment, with progressively lower amounts typically being used as treatment progresses.
  • the dosage forms of the invention for use in the treatment of opioid dependency and/or addiction, and/or pain (as well as clinical depression, cough, diarrhoea and/or restless legs).
  • the dosage forms of the invention for the manufacture of a medicament for the treatment of opioid dependency and/or opioid addiction, and/or pain (as well as clinical depression, cough, diarrhoea and/or restless legs).
  • opioid analgesic e.g. buprenorphine
  • opioid analgesic e.g. buprenorphine
  • lipid structures which may be formed upon dispersion or dissolution of that composition (or are already present in that composition) in any aqueous environment.
  • the lipid structures incorporating opioid may be cleared from the circulation (i.e. the blood stream) by cells of the mononuclear phagocyte system (MPS), which also would lower the plasma concentration of such molecularly dissolved, "free", opioid (e.g. buprenorphine) available for opioid-receptor binding.
  • MPS mononuclear phagocyte system
  • the abuser In order to abuse opioid-containing compositions, the abuser typically dissolves/disperses the commercial (e.g. sublingual, transdermal or oral) formulation in water, then filters the solution/dispersion to remove excipients such as cellulose and silica particles before injecting the filtrate.
  • the commercial (e.g. sublingual, transdermal or oral) formulation in water, then filters the solution/dispersion to remove excipients such as cellulose and silica particles before injecting the filtrate.
  • opioid analgesic e.g. buprenorphine
  • the size of which will likely not pass through many readily-available filters such as disposable syringe filters and cigarette filters. This will reduce the concentration of opioid analgesic in the filtrate.
  • filters such as disposable syringe filters and cigarette filters.
  • the ability of the lipid structures to entrap opioid should still reduce the amount of free-opioid available for receptor binding.
  • the filtrate is likely to be cloudy (and therefore not something an abuser would want to inject), and, if injected, physiological aversions to excipients, such as surfactants, that are present can be expected.
  • opioid e.g. buprenorphine
  • the separation of opioid from the other components of the liquid compositions of the dosage forms of the invention, and subsequent ex vivo extraction and purification of opioid (e.g. buprenorphine) is likely to be extremely challenging to the opioid abuser using standard techniques such as solvent extraction.
  • opioid analgesic such as buprenorphine
  • a small volume of liquid may be employed in a dosage form of the invention, making it extremely difficult to obtain a decent recovery of active ingredient using normal chemical extraction procedures.
  • opioids such as buprenorphine.
  • they may be formulated together with an opioid antagonist (or a pharmaceutically-acceptable salt thereof), such as naloxone, nalmefene and/or naltrexone or salts thereof, which will reverse the pharmacological effects of opioids, and thus further reduce the abuse potential of dosage forms of the invention.
  • the opioid antagonist may antagonize the opioid analgesic, such as buprenorphine, to abrogate the abuser's "high".
  • opioid antagonist if employed, appropriate pharmacologically effective amounts of opioid antagonist must be sufficient so as not to compete with the above-mentioned pharmacological effect of the opioid analgesic present in the dosage form of the invention upon administration, but to antagonize the effect of the opioid analgesic and precipitate withdrawal symptoms if an attempt is made by an opioid-addicted individual to inject a dosage form of the invention.
  • the amounts of opioid antagonist (or salt thereof) if employed in dosage forms of the invention may be determined by the skilled person in relation to what will be most suitable balance between deterring abuse (illicit use) of the dosage form and maintaining sufficient pharmacological effect of the opioid analgesic. This is likely to vary with the route of administration, and the type and severity of the condition that is to be treated.
  • Preferred opioid antagonists include naloxone and pharmaceutically-acceptable salts thereof.
  • naloxone is employed in the form of the free base, although, if employed, preferred pharmaceutically acceptable salts of naloxone (and buprenorphine) include hydrochloride salts.
  • dosage forms of the invention comprise both buprenorphine and naloxone, it is preferred that the dose ratio of buprenorphine: naloxone is about 4: 1 (calculated as the respective free bases).
  • dose ratio of buprenorphine: naloxone is about 4: 1 (calculated as the respective free bases).
  • Dosage forms of the invention may be formulated with additional active ingredients, including (as appropriate) other pain relieving agents, such as non-steroidal antiinflammatory agents.
  • Dosage forms of the invention may also be formulated together with components which are known to enhance the uptake of lipid structures incorporating opioids, e.g.
  • buprenorphine by cells of the mononuclear phagocyte system (MPS), for example cetylmannoside (or any other fatty acid mannoside).
  • MPS mononuclear phagocyte system
  • Such a component may bind to the mannose receptors of the macrophage cells of the MPS and so enhance the ingestion of lipid structures incorporating opioid analgesic, such as buprenorphine, by the macrophage and thereby the clearance of the lipid structures, and ultimately buprenorphine, from circulation.
  • opioid analgesic such as buprenorphine
  • Figure 1 shows mean buprenorphine plasma concentration versus time profiles for four different formulations administered to rats in an in vivo test
  • Figure 2 shows the concentrations of molecularly-free buprenorphine over time for different test formulations in an in vitro test
  • Figures 3 to 7 are microscope picture showing the self-emulsification of compositions that may be included in dosage forms of the invention.
  • Buprenorphine free base 40 mg; Siegfried AG, Switzerland
  • olive oil 3056 mg; Croda Nordica AB, Sweden
  • the sample was vortexed a few times, stirred by magnet for 6 hours, and allowed to equilibrate at room temperature for at least 60 hours.
  • Oleic acid 2010 mg; Croda Nordica AB
  • Buprenorphine base was added portion-wise to the oleic acid and allowed to dissolve at room temperature with magnetic stirring.
  • Buprenorphine base (826 mg) and caprylic acid (1204 mg; Sigma-Aldrich Sweden AB) were added into a 4 ml_ glass vial. The sample was stirred by magnet for 11 days at room temperature, whereafter it was visually observed that all of the buprenorphine had dissolved. More buprenorphine base was added portion-wise to the caprylic acid and allowed to dissolve at room temperature with stirring using a magnet and a spatula.
  • Buprenorphine base (820 mg) and oleic acid (1 197 mg) were added into a 4 ml_ glass vial.
  • the sample was stirred by magnet for 11 days at room temperature, and allowed to equilibrate at room temperature, without stirring, for at least 60 hours. After equilibration, a clear excess of undissolved buprenorphine was still visually observed, and the assay of the dissolved buprenorphine was chemically analysed.
  • Buprenorphine base (813 mg) and linoleic acid (1203 mg; Sigma-Aldrich Sweden AB) were added into a 4 ml_ glass vial.
  • the sample was stirred by magnet for 11 days at room temperature, and allowed to equilibrate at room temperature, without stirring, for at least 60 hours. After equilibration, a clear excess of undissolved buprenorphine was still visually observed, and the assay of the dissolved buprenorphine was chemically analysed.
  • caprylic acid 508 mg/g (mean of three analyses)
  • oleic acid 318 mg/g
  • Oleic acid (20.992 g), sucrose ester, SurfhopeTM SE D-1216 (8.999 g; Harke Pharma GmbH, Germany), ascorbyl palmitate (0.300 g; Merck Chemical & Lifescience AB, Sweden) and ethanol 99.5% (2.999 g) were weighed into a 20 ml_ glass vial with a screw- cap and were stirred at room temperature with a magnetic stirring bar to give a clear lipid solution.
  • Buprenorphine base (0.160 g) was weighed into a 20 ml_ glass vial with a screw- cap and 20.0 ml_ of the clear lipid solution above was added.
  • Oleic acid (21.008 g), polysorbate 20 (16.817 g; Croda Nordica AB), ascorbyl palmitate (0.301 g) and ethanol 99.5% (3.001 g) were weighed into a 20 mL glass vial with a screw- cap and stirred at room temperature using a magnetic stirring bar to give a clear lipid solution.
  • Buprenorphine base (0.160 g) was weighed into a 20 mL glass vial with a screw- cap and 20.0 mL of the clear lipid solution above was added. The mixture was stirred at room temperature using by a magnetic stirring bar until all of the buprenorphine was dissolved to give a clear buprenorphine-lipid solution of a concentration of 8 mg buprenorphine per mL.
  • Buprenorphine hydrochloride (0.173 g; Siegfried AG) and milli-Q (MQ) water (19.997 g) were weighed into a 20 mL glass vial with a screw-cap and were stirred at room temperature using a magnetic stirring bar to give a clear aqueous solution, with a few particles of possibly undissolved buprenorphine.
  • citric acid anhydrous (0.030 g; Brenntag Nordic AB, Sweden) was added and the aqueous solution, which was stirred again, but still a few undissolved particles was observed visually. The mass of these particles was assessed as insignificant and the solution was filtered through a 0.22 ⁇ Acrodisc filter. A clear solution without any particles was then obtained.
  • the buprenorphine aqueous solution of 8 mg/mL (5.0 mL; Formulation C above) was diluted with MQ water (15.0 mL) to give a clear buprenorphine aqueous solution of 2 mg/mL.
  • Formulations A to C were analysed for buprenorphine assay and related substances by means of HPLC/UV.
  • the results in Table 2 below showed that the formulations were of correct assay and had low levels of related substances (impurities).
  • Blood samples were collected from the tail vein 30 min, 1 , 2, 4, 6, 8, 10, 24 and 30 h after administration. Approximately 250 ⁇ _ of blood was withdrawn into Li Hep plasma tubes (BD Microguard, OneMed Sverige AB, Sweden). The blood samples were kept on wet ice before being centrifuged at 2000 x g, for 10 minutes at +4°C. Plasma was extracted and transferred to pre-labelled Eppendorf tubes and frozen at -20°C before transportation for bioanalysis.
  • Li Hep plasma tubes BD Microguard, OneMed Sverige AB, Sweden
  • Plasma samples (0.25 mL) were collected in lithium heparin Vacutainer® tubes. The samples were kept on ice and then centrifuged at 4°C for 10 minutes at 2000 x g. The plasma was transferred into pre-labelled plastic tubes and stored at -20°C prior to analysis. The frozen plasma samples were transported to Recipharm OTC, Uppsala, Sweden, where the buprenorphine concentration in the samples was measured. Plasma concentrations of buprenorphine were determined by using H PLC- MS- MS. This analytical procedure is capable of measuring concentrations of buprenorphine in rat plasma within the range of 0.2 to 200 ng/mL.
  • Buprenorphine and the deuterated internal standard buprenorphine-D4 were extracted from the sample plasma using liquid-liquid extraction (LLE). After removal and evaporation of the organic phase, the samples were re-constituted in acetonitrile:0.1 % formic acid (1 : 1).
  • Test Formulation A Buprenorphine/Oleic acid/Polvsorbate
  • Oleic acid (7.011 g), polysorbate 20 (4.012 g) and buprenorphine base (0.800 g) were weighed into a 20 mL glass flask with a screw-cap and were stirred at room temperature using a magnetic stirring bar to give a clear lipid solution comprising 6.8% w/w of buprenorphine.
  • the lipid solution (6.8% w/w; 121 mg) was emulsified in the presence of 10 mL of MQ-water to a final concentration of 0.82 mg of buprenorphine per mL.
  • Test Formulation B Buprenorphine/Oleic acid/Sucrose ester
  • Oleic acid 7.014 g
  • buprenorphine base 0.801 g
  • sucrose ester 0.801 g
  • SurfhopeTM SE D-1216 2.995 g
  • ethanol 1.001 g
  • the lipid solution (6.8% w/w; 120 mg) was emulsified in the presence of 10 mL of MQ-water to a final concentration of 0.81 mg of buprenorphine per mL.
  • Test Formulation C Buprenorphine/Oleic acid/Sucrose ester/Glvcerol monooleate
  • Oleic acid 7.003 g
  • buprenorphine base 0.802 g
  • sucrose ester 0.802 g
  • SurfhopeTM SE D-1216 3.015 g
  • glycerol monooleate 1.005 g
  • ethanol 0.503 g
  • the lipid solution (6.5% w/w; 131 mg) was emulsified in the presence of 10 mL of MQ-water to a final concentration of 0.85 mg of buprenorphine per mL.
  • Buprenorphine hydrochloride (93 mg) was dissolved in MQ-water (107.7 g) to a final concentration of 0.80 mg of buprenorphine per mL.
  • the release of molecularly-free buprenorphine following addition to 500 mL of phosphate buffer saline (PBS) pH 7.4 was measured by analyzing the buprenorphine assay in permeate samples collected after circulation of the buprenorphine in 500 mL PBS solution through a hollow fibre with a 50 kDa molecular weight cut-off (trans-membrane flow filtration).
  • the 50 kDa cut-off separates the molecularly-free buprenorphine from buprenorphine bound into lipid structures too large to permeate through the 50 kDa filter..
  • Hollow fiber filter Product No. D02-E050-05-N (Module: MidiKros, Length: 20 cm, Membrane type: Modified Polyethersulfone, MWCO rating: 50 kDa, Fiber Inner Lumen: 0.50 mm, Packaging: Normal)
  • the concentration of molecularly free buprenorphine (permeate) over time for the test formulations and the reference formulation is presented in Figure 2.
  • the test formulations are representative of a liquid composition of a dosage form of the invention that has been dispersed and/or dissolved in water for intravenous injection and abuse.
  • the reference formulation is representative of a composition of a buprenorphine sublingual tablet formulation that has been dispersed and/or dissolved in water for intravenous injection and abuse.
  • Buprenorphine base (0.801 g) and oleic acid (6.998 g) were first dispensed into a 20 mL glass vial and were stirred using a magnet at room temperature, until all of the buprenorphine had been dissolved, resulting in a clear isotropic solution.
  • sucrose esters SurfhopeTM SE D-1216 (3.030 g) and SurfhopeTM SE D-1816 (0.993 g; Harke Pharma GmbH, Germany), and also ethanol 99.5% (1.200 g) were weighed into the 20 mL glass vial with a screw-cap and were stirred at room temperature with a magnetic stirring bar to give a clear isotropic solution of a concentration of 6.15% w/w buprenorphine.
  • Buprenorphine base (0.162 g), naloxone base (0.040 g; converted from naloxone HCI by Lithuanian Institute of Organic Synthesis), oleic acid (1.406 g), sucrose laurate (0.602 g), ethanol 96% (0.202 g) and ascorbyl palmitate (0.022 g; Merck Chemical & Lifescience AB, Sweden) were weighed into a 4 mL glass vial with a screw-cap. The sample was stirred by magnet and initially sonicated in a sonication bath at room temperature until a visually isotropic clear lipid solution resulted, with a concentration of 8% w/w ethanol.
  • Buprenorphine base (0.161 g), naloxone base (0.040 g), oleic acid (1.398 g), sucrose laurate (0.605 g), glycerol monocaprylate (0.301 g), ethanol 90% (0.065 g) and ascorbyl palmitate (0.020 g) were weighed into a 4 mL glass vial with a screw-cap. The sample was stirred by magnet and initially sonicated in a sonication bath at room temperature until a visually isotropic clear lipid solution resulted, with a concentration of 2% w/w ethanol and 12% w/w monoacyl glycerol.
  • Buprenorphine base (0.160 g), naloxone base (0.040 g), oleic acid (1.405 g), sucrose laurate (0.600 g), glycerol monocaprylate (0.300 g) and ascorbyl palmitate (0.019 g) were weighed into a 4 mL glass vial with a screw-cap. The sample was stirred by magnet and initially sonicated in a sonication bath at room temperature until a visually isotropic clear lipid solution resulted, with a concentration of 12% w/w monoacyl glycerol.
  • Oleic acid (6.0 g), polysorbate 20 (3.0 g), polysorbate 80 (1.0 g), glycerol monocaprylate (3.0 g) and glycerol monooleate (1.0 g) were weighed into a 20 mL glass vial with a screw- cap. The sample was stirred by magnet at room temperature, and for a short time at 35°C to facilitate dissolution of the monoglycerides, until a visually isotropic clear lipid solution resulted. Buprenorphine base (0.187 g), naloxone base (0.0465 g) and the lipid solution above (3.25 g) were weighed into a 4 mL glass vial with a screw-cap. The sample was stirred by magnet and initially sonicated in a sonication bath at room temperature until a visually isotropic clear lipid solution resulted.
  • Example 10 Example 10
  • Example 6 Samples from Example 6, 7, 8 and 9 above were subjected to emulsification by adding approximately 130 of each to a 20 mL glass vial containing 10 mL of pH 6.8 phosphate buffer (50 rtiM), with stirring by magnet at approximately 400 rpm, at 37°C.
  • the samples showed identically good emulsification properties; instantly milky white macroscopically homogeneous dispersions/emulsions were formed upon addition of the lipid solutions.
  • a sample was withdrawn from the dispersions/emulsions and examined under a light microscope, as showed in Figures 4 (Example 6), 5 (Example 7), 6 (Example 8) and 7 (Example 9).
  • test formulation which is a lipid solution of the invention (see e.g. Example 9).
  • a single 160 mg dose (which comprises 8 mg of buprenorphine and 2 mg of naloxone) of the test formulation is administered through the cannula into the terminal ileum.
  • plasma samples are taken at the following time intervals: 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours.
  • a reference formulation an 8 ml_ aqueous solution comprising buprenophine hydrochloride and naloxone hydrochloride (corresponding to 8 mg of buprenorphine and 2 mg of naloxone free bases)
  • a blood sample is taken no more than 5 minutes prior to dosing and thereafter at the same time intervals following administration as above.
  • the same single dose of the reference formulation is first administered by oral gavage, with plasma samples being taken at the same time intervals after administration as above.
  • 160 mg of the test formulation is administered through the cannula into the terminal ileum. Blood samples are taken no more than 5 minutes prior to dosing and thereafter at the following time intervals after dosing: 15 minutes, 30 minutes, 45 minutes, 1 hour 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours and 12 hours.
  • a further 160 mg dose of test formulation is administered through the cannula into the colon 24 hours after the first dose the previous day, with plasma samples being taken as indicated above. This procedure is repeat twice further, on separate days.
  • Animals in the first group are terminated upon completion of sampling on Day 10, and no further examinations are performed. Animals in the second group are terminated upon completion of sampling on Day 13. Inspections of the implantation sites, as well as sampling and histopathology of selected organs (ileum and colon), are carried out.

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Abstract

L'invention concerne des formes galéniques pharmaceutiquement acceptables appropriées pour une administration perorale dans le tractus gastro-intestinal, lesdites formes galéniques comprenant des compositions pharmaceutiquement acceptables sous la forme d'un liquide, dans lesquelles un analgésique opioïde, tel que de la buprénorphine, est dissous dans un système de solvant comprenant un acide gras en C8-20 qui est un liquide à environ 40 °C, tel que l'acide caprylique, l'acide caprique, l'acide laurique, l'acide oléique ou l'acide linoléique. Les formes galéniques empêchent un usage abusif et sont utiles dans le traitement, entre autres, de la dépendance/accoutumance aux opioïdes et/ou de la douleur.<i />
PCT/GB2018/052792 2017-09-29 2018-09-28 Nouvelles compositions pharmaceutiques Ceased WO2019064026A1 (fr)

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WO2020201771A1 (fr) * 2019-04-04 2020-10-08 Orexo Ab Nouvelles compositions pharmaceutiques
CN114681457A (zh) * 2022-06-01 2022-07-01 济南广盛源生物科技有限公司 丁丙诺啡透皮溶液及其制备方法和应用

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