WO2019064026A1 - New pharmaceutical compositions - Google Patents

Abstract

There are provided pharmaceutically-acceptable dosage forms suitable for peroral administration to the gastrointestinal tract, which dosage forms comprise pharmaceutically-acceptable compositions in the form of a liquid, in which an opioid analgesic, such as buprenorphine, is dissolved in a solvent system comprising a C8-20 fatty acid that is a liquid at about 40°C, such as caprylic acid, capric acid, lauric acid, oleic acid or linoleic acid. The dosage forms are abuse-resistant and are useful in the treatment of inter alia opioid dependency/addiction and/or pain.

Description

NEW PHARMACEUTICAL COMPOSITIONS

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.

Prior Art and Background

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.

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.

A perennial problem with potent opioid agonists however is one of abuse by drug addicts. Drug addiction is a worldwide problem of which opioid dependence, notably of heroin, is a major component. It was estimated in 2010 that there were 15.5 million opioid-dependent people globally. Prevalence in Australasia, Western Europe, and North America was higher than the global- pooled prevalence. According to the European Monitoring Centre for Drugs and Drug Addiction Report in 2017, there were an estimated 1.3 million high-risk opioid users in Europe in 2016. The opioid crisis has affected the US especially, and this has escalated during recent years. In 2015, drug overdoses accounted for 52,404 US deaths, of which 33,091 (63.1 %) involved an opioid (see e.g. Degenhardt et al, Addiction, 109, 1320 (2014)).

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. In addition, 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. In terms of its socio-economic impact, 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 On the street', typically in the form of opioid-based powders (such as heroin), but may also get hold of legally-marketed pharmaceutical formulations intended for the treatment of e.g. pain. 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'. Thus, there is a general need for less abusable pharmaceutical formulations comprising opioid agonists.

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. Further, 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. Additionally, 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. Complete opioid abstinence throughout pregnancy is ideal for both mother and fetus, but acute withdrawal during pregnancy is not recommended and relapse rates are high, prompting the need for substitution therapy in this group of patients (see, for example, Bart, J. Addict. Dis. , 31 , 207 (2012)) . Buprenorphine is a partial agonist at the μ-opioid receptor and an antagonist at the κ-opioid receptor. It has high binding affinity at both receptors and competes with other agonists, such as methadone, heroin (diamorphine) and morphine, at the μ-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. There is a reduced risk of overdose and reduced recreational value in opioid-tolerant subjects. 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.

Drawbacks of 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.

Nonetheless, diversion and illicit use of 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), Stimmel, 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. This formulation allows for approximately 30% lower doses for both active ingredients compared to an equivalent Suboxone formulation, and is now available under the trademark Zubsolv®. The reduced amount of buprenorphine in Zubsolv reduces the amount available for injection if diverted by way of intravenous abuse, decreasing its "street" value.

There is still nevertheless a need for effective, preferably abuse-resistant products for use in opioid addiction substitution and pain therapy. It would also be preferred if 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). In relation to the latter point, the reason why 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.

Numerous attempts have been made to enhance the oral bioavailability of buprenorphine with a view to developing a peroral product. For example:

(i) prodrugs of buprenorphine (e.g. a hemiadepate ester) have been made, which it was thought would be absorbed more readily and thereafter transformed to buprenorphine after absorption to produce higher blood concentrations after oral administration (see, for example, international patent application WO 2007/1 10636);

(ii) a pre-systemic inhibitors approach, in which 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));

(iii) delayed release formulations (see, for example, US 2016/0176890); and

(iv) a solid-dispersion, immediate-release approach, in which small particles comprising buprenorphine were dispersed in a polyethylene glycol matrix (see, for example, US 8,377,479).

See also WO 2015/103379, which relates to abuse-resistant drug formulations.

To the applicant's knowledge, despite several clinical pharmacokinetic studies having been undertaken in relation to at least some of the above approaches, none have been taken towards regulatory approval for commercial use. There is therefore a clear unmet medical need for effective peroral drug delivery systems comprising buprenorphine and other opioid analgesics that are, preferably, abuse resistant, by which we mean that the drug delivery system is physically resistant to abuse, and accordingly serves as an abuse- deterrent to an end user. We have now unexpectedly found that 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.

Disclosure of the Invention

According to a first aspect of the invention there is provided 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. In this respect, 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).

Appropriate pharmaceutically-acceptable carriers include appropriate dosing means known to the skilled person. For example, 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).

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 as pethidine (meperidine), fentanyl, alfentanil, sufentanil, remifentanil, ketobemidone, carfentanyl, anileridine, piminodine, ethoheptazine, alphaprodine, betaprodine, 1-methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP), diphenoxylate and loperamide), phenylheptamines or "open chain" compounds (such as methadone, isomethadone, propoxyphene and levomethadyl acetate hydrochloride (LAAM)); diphenylpropylamine derivatives (such as dextromoramide, piritramide, bezitramide and dextropropoxyphene); mixed agonists/antagonists (such as nalorphine and oxilorphan); and other opioids (such as tilidine, tramadol and dezocine). 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. By "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.

When the opioid analgesic that is employed is buprenorphine, we prefer that it is employed in the form of the free base. References made hereinafter to "opioid analgesics" (whether used in a general sense, or with reference to a specific opioid, such as buprenorphine) are to be taken to include such 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. By "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). To assist with processing and the creation of a composition of a dosage form of the invention, and in particular for Cs-2o fatty acids that have melting points that are above room temperature (e.g. above about 18°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. However, in such a situation, the primary solvent will still be the Cs-2o fatty acid.

Suitable fatty acids that may be mentioned 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. However, we prefer that 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. Preferably, 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. about 45%, such as about 50%) based on the total weight of the liquid composition. It is also preferred that 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. In this respect, 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. Spans™), polyethoxylated alcohols, polyvinyl alcohols, polyol esters (e.g. Cithrol™), polyoxyethylene alkyl ethers (e.g. Brij®, such as Brij 721), polyoxyethylene castor oil derivatives (e.g. Kolliphor®), ethoxylated fatty acid esters (e.g. Myrj™), 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.

Surfactants that may be mentioned include sugar esters. 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. The skilled person will appreciate that the term "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". Commercially-available 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. The skilled person will understand that any reference to a specific 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). As used herein, 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.

As demonstrated hereinafter, we have surprisingly found that 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.

Other surfactants that may be mentioned include polysorbates (Tweens™), 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).

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 (excipients) 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. 70% ethanol, 90% ethanol, 95% ethanol, 99.5% ethanol or absolute ethanol); benzyl benzoate, ethyl lactate, ethyl oleate, glycerol, propylene glycol, polyethylene glycols, dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide; 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. monoglycerides), such as glycerol monooleate (e.g. Cithrol™) and 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 (EDTA), 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®)); pH buffering agents (e.g. citric acid, maleic acid, malic acid, or glycine); colouring agents; penetration enhancers (e.g. myristic acid, palmitic acid, isopropyl myristate, isopropyl palmitate, pyrrolidone, or tricaprylin); and 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.). During self-emulsification, essentially no precipitation of opioid analgesic, such as buprenorphine, will take place in the aqueous environment (whether this aqueous environment is inside or outside of the body), despite the amount of opioid in the formulation being significantly above the maximum solubility in that specific aqueous phase environment.

As used herein, the term "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.

Hence, administration of dosage forms of the invention may lead to self-emulsification, wherein opioid analgesic, such as buprenorphine, is at least in part incorporated in lipid structures/phases (e.g. emulsion droplets, vesicles, micelles or the like). This feature has the potential to improve the bioavailability of the opioid (e.g. buprenorphine) as the latter will essentially be presented there in a solubilized state.

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. In this respect, 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).

Accordingly, 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. However, such 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.

According to a further aspect of the invention, there is provided 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:

• derivatising active ingredient into a prodrug that is less degraded and/or absorbed in other parts of the gastrointestinal tract (compared to the active ingredient itself), for example by choosing a conjugate that may be removed by enzymes/microbiota in the colon;

• coating drug substances, units of dosage forms or the entire dosage form with a material (e.g. a polymer) that is degraded by the enzymes/microbiota in the colon;

• coating drug substances, units of dosage forms or the entire dosage form with a material (e.g. a polymer) that is insoluble in low pH (e.g. pH 1 to 6) but dissolves at higher pH (e.g. pH > 6), in a manner that targets the distal small intestine and/or the colon;

• coating drug substances, units of dosage forms or the entire dosage form with a material (e.g. a polymer) that is only sufficiently dissolved after a certain time whilst present in gastrointestinal fluids (e.g. a delayed release of several hours); and

• designing units of dosage forms or the entire dosage form to deliver the active ingredient based on luminal pressure.

(See, for example, the review article by Amidon et al, AAPS PharmSciTech, 16, 731 (2015).) Two or more of the above (or other known) techniques may be combined to achieve a more reliable targeting to the distal small intestine and/or colon (e.g. combinations of pH-release systems and colon-specific biodegradable systems, or pH- release systems and time release systems). In any event, when dosage forms of the invention reach the intended site of delivery they contact the aqueous environment there and may release their contents such that the opioid analgesic (e.g. buprenorphine) is presented in a form in which it may be absorbed through the gastrointestinal mucosa (e.g. the mucosa of the small and/or large intestine).

In this respect, when dosage forms of the invention are 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.

In addition, 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.

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.

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:

(i) a method of treatment of opioid dependency and/or addiction;

(ii) a method of treatment of pain; and

(iii) a method of treatment of both pain and opioid dependency and/or addiction, which methods comprise administration of a dosage form of the invention to patient suffering from, or susceptible to, the relevant conditions.

Pain includes mild, moderate and severe pain, acute pain and chronic pain. By "treatment" of pain, we include the therapeutic treatment, as well as the symptomatic and palliative treatment of the condition. As used herein, "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).

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.

According to a further aspect of the invention there is provided a method of treatment of opioid dependency and/or addiction, which method 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.

By "treatment" of opioid dependency and/or addiction, 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.

As used herein, 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). Thus, 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. In such a case, 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 μg (e.g. about 5 μg) 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 μg 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. Thus, preferred ranges for e.g. a capsule to be taken once daily for the treatment of pain are between about 1 μg 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 skilled person will appreciate that for opioid dependency and/or addiction treatment by substitution therapy 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.

According to a further aspect of the invention, there is provided 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).

According to a further aspect of the invention, there is provided the use of 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).

All of the factors discussed above also render the dosage forms of the invention less susceptible to diversion and/or abuse than other, currently available opioid analgesic (e.g. buprenorphine) containing pharmaceutical compositions. Upon dispersion or dissolution of a dosage form of the invention (or a liquid composition thereof), either during, or for the purposes of, parenteral abuse, opioid analgesic (e.g. buprenorphine) may be incorporated, integrated and/or entrapped in lipid structures which may be formed upon dispersion or dissolution of that composition (or are already present in that composition) in any aqueous environment.

It is expected to this end that less of a "high" will be experienced by the abuser when compared to injection of a simple opioid (e.g. buprenorphine) dispersion or solution. This is because such opioid (e.g. buprenorphine) entrapment is expected to significantly lower the plasma concentration of molecularly dissolved, "free", opioid (e.g. buprenorphine) that is available for opioid-receptor binding. This is to be contrasted to the use of dosage forms of the invention as intended where the lipid environment in, for example, the small and/or large intestine is expected to increase the amount of buprenorphine that is available for absorption within the intestinal tract for the reasons discussed hereinbefore.

In addition, the lipid structures incorporating opioid (e.g. buprenorphine) 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. This effect may act to further discourage the abuse of liquid compositions of the dosage forms of the invention by intravenous injection.

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.

It is envisaged that, upon dispersion or dissolution of a liquid composition of the dosage form of the invention for the purpose of parenteral abuse, opioid analgesic (e.g. buprenorphine) will be incorporated, or entrapped, in the aforementioned lipid structures, 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. Even if the structures pass through the filter, or the solution/dispersion of the formulation in water is not filtered, the ability of the lipid structures to entrap opioid (e.g. buprenorphine) should still reduce the amount of free-opioid available for receptor binding.

Also, 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. Furthermore, 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. In particular, because of the high solubility of opioid analgesic (such as buprenorphine) in the fatty acid solvent, 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. All of these factors render dosage forms of the invention less susceptible to diversion and/or abuse than other, currently available pharmaceutical compositions containing opioids, such as buprenorphine. This notwithstanding, in order to further enhance the abuse resistance of dosage forms of the invention, 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. Upon dissolution, or other interference and/or manipulation of the dosage form by an abuser and subsequent illicit intravenous injection (abuse), the opioid antagonist may antagonize the opioid analgesic, such as buprenorphine, to abrogate the abuser's "high".

In this respect, 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.

Thus, 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. We prefer that naloxone is employed in the form of the free base, although, if employed, preferred pharmaceutically acceptable salts of naloxone (and buprenorphine) include hydrochloride salts.

If 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). There can, of course, be individual instances where higher or lower dosage ranges and/or ratios are merited, and such are within the scope of this invention. 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). 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.

Wherever the word "about" is employed herein in the context of amounts, for example absolute amounts, such as doses, weights, volumes, etc., or relative amounts of individual constituents in a composition or a component of a composition (including concentrations and ratios), timeframes, etc., it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1 %) from the actual numbers specified herein.

The invention is illustrated but in no way limited by way of the following examples, with reference to the attached figures, in which 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; and Figures 3 to 7 are microscope picture showing the self-emulsification of compositions that may be included in dosage forms of the invention.

Example 1

Buprenorphine solubility in olive oil and oleic acid

Buprenorphine free base (40 mg; Siegfried AG, Switzerland) and olive oil (3056 mg; Croda Nordica AB, Sweden) were added to a 4 ml_ glass vial. 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.

After equilibration, a clear excess of undissolved buprenorphine was still visually observed, and the assay of the dissolved buprenorphine was chemically analysed. Oleic acid (2010 mg; Croda Nordica AB) was added to a 4 mL glass vial. Buprenorphine base was added portion-wise to the oleic acid and allowed to dissolve at room temperature with magnetic stirring.

The results are tabulated in Table 1 below (in which BUP is buprenorphine base).

Table 1

After 870 mg of buprenorphine had been added in total to the 2010 mg oleic acid, a clear excess of undissolved buprenorphine was visually observed, and the assay of dissolved buprenorphine was chemically analysed.

The samples with buprenorphine saturated in olive oil and oleic acid were re-suspended at room temperature by magnetic stirring for a few minutes. Sample aliquots of about 1 mL were transferred into centrifuge tubes which were placed in a minicentrifuge (Eppendorf Centrifuge 5415 D) and spun at 16,000 rpm at room temperature for 30 minutes. Approximately 60 mg of the clear supernatant was accurately weighed into 200 mL volumetric flasks, dissolved in 40 mL of isopropanol and diluted to volume with phosphate buffer pH 2.5. Then further diluted five times with phosphate buffer pH 2.5 before HPLC analysis on a reversed phase column with UV detection. The determined solubility of buprenorphine in olive oil and oleic acid were found to be 8 mg/g and 299 mg/g, respectively. The high solubility of buprenorphine in oleic acid was unexpected. Example 2

Buprenorphine solubility in caprylic acid, oleic acid and linoleic acid Caprylic acid

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.

The results are tabulated in Table 2 below (in which BUP is buprenorphine base).

After a clear excess of undissolved buprenorphine was visually observed, the assay of the dissolved buprenorphine was chemically analysed.

Table 2

Oleic acid

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. Linoleic acid

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.

The samples were centrifuged to give clear supernatants, which were accurately weighed into 200 ml_ volumetric flasks, dissolved in 40 ml_ of isopropanol and diluted to volume with phosphate buffer (pH 2.5). Five further dilutions with phosphate buffer (pH 2.5) were carried out prior to HPLC analysis on a reversed phase column with UV detection.

The determined solubility of buprenorphine in the three fatty acids was as follows:

caprylic acid: 508 mg/g (mean of three analyses)

oleic acid: 318 mg/g

linoleic acid: 325 mg/g

Unexpectedly the results show that buprenorphine has a high solubility in all fatty acids tested.

Example 3

Pharmacokinetic study in rats after intraduodenal or intragastric administration of buprenorphine formulations Three different formulations were administered intraduodenally to male Sprague Dawley rats.

Formulation A, Buprenorphine/Oleic acid/Sucrose ester formulation (8 mg/mL)

Oleic acid (20.992 g), sucrose ester, Surfhope™ 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. The mixture was stirred at room temperature using 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_. Formulation B, Buprenorphine/Oleic acid/Polvsorbate formulation (8 mg/mL)

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.

Formulation C, Buprenorphine aqueous solution (8 mg/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. To facilitate dissolution of the last few particles, 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 μηι Acrodisc filter. A clear solution without any particles was then obtained.

Formulation D, Buprenorphine agueous solution (2 mg/mL)

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).

Table 3

7.8 mg/mL 0.14% impurity A

The in vivo part of the investigation was made in compliance with the OECD Principle of Good Laboratory Practice, ENV/MC/CHEM (98) 17, 1997. Male Sprague Dawley rats were anaesthetized with use of isoflurane, after which a small incision was made into the abdominal cavity to localize duodenum. A single injection was made directly into the duodenum after which the abdominal wall was closed using Ethilon sutures 4-0. Animals receiving Formulation D had a single dose of the test item administered per orally. All animals were administered a dose of 0.8 mg buprenorphine.

Blood samples were collected from the tail vein 30 min, 1 , 2, 4, 6, 8, 10, 24 and 30 h after administration. Approximately 250 μΙ_ 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.

Bioanalvsis

Blood 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).

All samples were analysed by first separating them by reversed-phase gradient LC and subsequently detecting them using positive electrospray ionization and multiple reaction monitoring (MRM). Quantification was performed in the range 0.2 to 200 ng/mL. Results

Table 4

AUCIast (h*uq/L) for the four test formulations:

¹One animal less compared to the other groups due to that one rat was found dead in the morning at the day of administration, i.e. before administration. The 1 hour sampling point value for one subject in this group was identified as an outlier value, and this single time point was excluded in the AUC generation.

The relative bioavailability of Formulation A was found to be approximately 200% of that of Formulations B and C. A graph showing the mean buprenorphine plasma concentration vs. time profiles for the four formulations is shown in Figure 1.

Example 4

In vitro test showing formulation slowly releasing buprenorphine

Preparation of formulations

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, Surfhope™ SE D-1216 (2.995 g) and ethanol (1.001 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 lipid solution comprising 6.8% w/w of buprenorphine. 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, Surfhope™ SE D-1216 (3.015 g), glycerol monooleate (1.005 g) and ethanol (0.503 g) were weighed into a 20 mL glass vial with a screw-cap and were stirred at first about 40°C until all glycerol monooleate was dissolved and finally at room temperature using a magnetic stirring bar to give a clear lipid solution comprising 6.5% w/w of buprenorphine. 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. Reference Formulation, Buprenorphine HCI in MQ-water

Buprenorphine hydrochloride (93 mg) was dissolved in MQ-water (107.7 g) to a final concentration of 0.80 mg of buprenorphine per mL.

In vitro release

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..

Trans-membrane flow filtration

Equipment: KrosFlo Research lii TFF System, Spectrum Laboratories Inc. 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)

Test set-up

Reservoir: 500 mL PBS, pH 7.4

Feed: 200 mL/min

Stirring of reservoir: 200 rpm

Temperature: room temperature Test formulation

For each test, at time 0, 0.20 mg of buprenorphine was added to the reservoir (500 mL PBS, pH 7.4) by adding 0.244 mL of Test Formulation A (0.82 mg buprenorphine per mL), 0.247 mL of Test Formulation B (0.81 mg/mL), and 0.235 mL of Test Formulation C (0.85 mg/mL), to the reservoir. Before addition, the reservoir had been circulated through the hollow fibre filter with a feed rate of 200 mL/min for a couple of minutes to equilibrate. Sampling of permeate into glass vials was at 2, 4, 7, 10, 15, 20, 25, 30, 40, 50, 70 and 90 minutes. The concentration of buprenorphine in the permeate samples was determined by HPLC analysis on a reversed phase column with UV detection.

Reference formulation

At time 0, 0.20 mg of buprenorphine was added to the reservoir (500 mL PBS, pH 7.4) by adding 0.250 mL of reference formulation (0.80 mg buprenorphine per mL) to the reservoir. Before addition, the reservoir had been circulated through the hollow fibre filter with a feed rate of 200 mL/min for a couple of minutes to equilibrate. Sampling of permeate into glass vials was at 2, 4, 7, 10, 15, 20, 25, 30, 40, 50, 70 and 90 minutes. The concentration of buprenorphine in the permeate samples was determined by HPLC analysis on a reversed phase column with UV detection.

Results

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.

The results show that the test formulation may provide for increased abuse deterrence for the reasons described hereinbefore. Example 5

Self-emulsification experiment

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. Then, the sucrose esters Surfhope™ SE D-1216 (3.030 g) and Surfhope™ 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.

One drop of this composition was added to a microscope slide. Beside this drop, but not in contact with it, one drop of fasted state simulated intestinal fluid (FaSSIF, Biorelevant.com; UK) was added to the slide. The microscope slide was mounted in a light microscope equipped with a 10x magnifying lens and a digital camera. With the two drops in focus, a cover glass was gently applied over the drops which then became in contact by capillary forces. Upon contact, the composition self-emulsified resulting in a multitude of various lipid structures/phases protruding into the aqueous phase. In Figure 3, the self-emulsification process is shown, with the composition to the right in the picture and the aqueous phase to the left.

Example 6

Buprenorphine/Naloxone Formulation I

Buprenorphine base (0.162 g), naloxone base (0.040 g; converted from naloxone HCI by Latvian 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.

Example 7

Buprenorphine/Naloxone Formulation II

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.

Example 8

Buprenorphine/Naloxone Formulation III

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.

Example 9

Buprenorphine/Naloxone Formulation IV

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

Stability Experiment

Samples from Example 6, 7, 8 and 9 above were stored at room temperature. After one month, all samples were still, visually, isotropic clear lipid solutions with no sign of precipitation of any material in any of the samples.

Example 11

Self-Emulsification Experiment

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. After 10 minutes of stirring, 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).

Example 12

Animal Study

6 male Gottingen minipigs, 5-6 months of age, are split into 2 groups of 3. During a period of acclimatization to the testing facility of 21 days, and one week prior to the start of dosing, a fistula is created in the terminal ileum of the pigs, and a cannula fitted for the purpose of direct administration of test formulation, which is a lipid solution of the invention (see e.g. Example 9). In the first group of animals 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. Following administration, 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.

In this group, seven complete days after the first administration of test formulation (i.e. Day 8), 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)) is administered to the first group by oral gavage. A blood sample is taken no more than 5 minutes prior to dosing and thereafter at the same time intervals following administration as above.

In the second group of animals 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.

In this group, at Day 8, 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.

Withdrawn blood samples are tested and plasma concentrations of buprenorphine, norbuprenorphine and naloxone are measured.

During the course of the study, clinical observations are made daily at appropriate intervals. Body weights are measured weekly and food consumption (unconsumed diet) measured. One faecal sample from each animal following dosing on Day 1 and 8 (in total 12 samples) are taken for analysis.

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.

Claims

Claims

1. A pharmaceutically-acceptable dosage form suitable for peroral administration to the gastrointestinal tract, which dosage form comprises a pharmaceutically-acceptable composition in the form of a liquid, in which an opioid analgesic, or a pharmaceutically- acceptable salt thereof, is dissolved in a solvent system comprising at least one Cs-2o fatty acid that is a liquid at about 40°C.

2. A dosage form as claimed in Claim 1 , which is suitable for consumption and/or ingestion within the gastrointestinal tract.

3. A dosage form as claimed in Claim 1 or Claim 2, which further comprises a pharmaceutically-acceptable carrier that is capable of releasing a liquid composition as defined in Claim 1 within the gastrointestinal tract.

4. A dosage form as claimed in Claim 3, wherein the carrier is capable of releasing the liquid composition within the small intestine.

5. A dosage form as claimed in Claim 3, wherein the carrier is capable of releasing the liquid composition within the terminal ileum and/or the colon.

6. A dosage form as claimed in any one of Claims 3 to 5, wherein the carrier is an optionally-coated capsule.

7. A dosage form as claimed in any one of the preceding claims, wherein the opioid analgesic is buprenorphine or a pharmaceutically-acceptable salt thereof.

8. A dosage form as claimed in Claim 7, wherein the buprenorphine is in the form of the free base.

9. A dosage form as claimed in any one of the preceding claims, wherein the at least one Cs-20 fatty acid is selected from caprylic acid, capric acid, lauric acid, oleic acid and linoleic acid.

10. A dosage form as claimed in Claim 9, wherein the fatty acid is oleic acid.

1 1. A dosage form as claimed in any one of the preceding claims, wherein the at least one Cs-20 fatty acid is the main component of the liquid composition.

12. A dosage form as claimed in any one of the preceding claims, which further comprises one or more surfactants.

13. A dosage form as claimed in Claim 12, wherein the one or more surfactants comprise a sugar ester.

14. A dosage form as claimed in Claim 13, wherein the sugar ester is sucrose monolaurate.

15. A dosage form as claimed in Claim 12, wherein the one or more surfactants comprise a polysorbate.

16. A dosage form as claimed in Claim 15, wherein the polysorbate comprises polyoxyethylene (20) sorbitan monolaurate and/or polyoxyethylene (20) sorbitan monooleate.

17. A dosage form as claimed in any one of Claims 13 to Claim 16, wherein the dosage form further comprises a monoacyl glycerol.

18. A dosage form as claimed in Claim 17, wherein the monoacyl glycerol is glycerol monooleate or glycerol monocaprylate.

19. A dosage form as claimed in any one of the preceding claims, wherein the dosage form further comprises an opioid antagonist.

20. A dosage form as claimed in Claim 19 wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

21. A dosage form as claim in Claim 20 as dependent on any one of Claims 7 to 19, wherein the dose ratio of buprenorphine to naloxone (calculated as the free bases) is 4: 1.

22. A dosage form as defined in any one of the preceding claims for use in human and/or veterinary medicine.

23. A dosage form as defined in any one of Claims 1 to 21 for use in a method of treatment of opioid dependency, and/or a method of treatment of pain.

24. A method of treatment of opioid dependency, and/or a method of treatment of pain, which method comprises administration of a dosage form as defined in any one of Claims 1 to 21 to a person suffering from, or susceptible to, the relevant condition.

25. The use of a dosage form as defined in any one of Claims 1 to 21 for the manufacture of a medicament for a method of treatment of opioid dependency, and/or a method of treatment of pain.

26. A process for the preparation of a liquid composition as defined in any one of Claims 1 to 21 , which comprises the step of dissolving the opioid analgesic or salt thereof in the one or more fatty acids.

27. A process for the preparation of a dosage form as defined in any one of Claims 3 to 21 , which comprises the step of loading a liquid composition as defined in any one of Claims 1 , 2 or 7 to 21 into a carrier as defined in any one of Claims 3 to 6.

28. A process as claimed in Claim 27, which further comprises a process step as claimed in Claim 26.