WO2020201771A1 - New pharmaceutical compositions - Google Patents

Abstract

There are provided solid, pharmaceutically-acceptable compositions suitable for peroral administration to the gastrointestinal tract, in which (a) an opioid analgesic and (b) a sucrose ester with a hydrophilic-lipophilic balance value of between 6 and 20 are both dissolved and/or dispersed in a C12-22 fatty acid, which fatty acid is a solid at about 37°C, such as myristic acid, lauric acid, palmitic acid, stearic acid, arachidic acid and behenic 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 m-opioid receptor and an antagonist at the K- opioid receptor. It has high binding affinity at both receptors and competes with other agonists, such as methadone, heroin (diamorphine) and morphine, at the m-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 ai, 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 Alcohol Depend., 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 a/, Drug Alcohol Depend., 131, 119 (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 at, 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.

Furthermore, 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 at, Drug Alcohol Depend., 88, 75 (2007), Monte et at, J. Addict. Dis., 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, J. Control. 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 2007/110636);

(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 a/, J. Pharm. Pharmacol., 69, 23 (2017) and Maharao et at, Biopharm. Drug Dispos., 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 2010/104494.

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.

Sugar esters are a class of natural and biodegradable non-ionic surfactants consisting of a hydrophilic sugar 'head group' esterified with fatty acids. The properties of sugar esters depend on the nature of the sugar and fatty acids used, and the degree of esterification of the sugar. They are made from natural products, sugar and edible fats, are tasteless, odorless and biodegradable, and are relatively nontoxic with a recommended acceptable daily intake of up to 30 mg/kg (joint FAO/WHO Expert Committee on Food Additives (JECFA)). Sugar esters, and in particular sucrose esters, are widely used in the food and cosmetics industries but, thus far, are relatively underutilised in pharmaceutical formulations (see, for example, the recent review article by Szuts and Szabo-Revesz in Int. J. Pharm., 433, 1 (2012), as well as Ntawukulilyayo et al, ibid., 93, 209 (1993) and Hahn and Sucker, Pharm. Res., 6, 958 (1989)).

Sucrose esters are known to be excellent oil-in-water-type emulsifiers. For example, emulsion-based compositions comprising sucrose esters are described in WO 2005/065652, although NZ 521215 also described their use as a sole release controlling agent.

The use of sucrose and fatty acid esters to form multilamellar "onion-structured" vesicles to act as carriers for substances is discussed in US 5,908,697. This document focuses primarily on fragile and volatile compounds used in the food industry. The ability of sucrose esters to increase the release of flavour compounds in formulations such as chewing gum is also discussed in WO 00/25598.

Self-emulsifying drug delivery systems are described in WO 2015/103379, WO 2015/193380, WO 2016/022936, US 2016/0184258 and US 2019/0015346, although sucrose esters are not mentioned.

WO 2010/032140 and US 2017/0312226 describe particulate and/or multi-particulate pharmaceutical compositions, which are produced by lyophilization or by granulation, and comprise fatty acids to improve adsorption of the active ingredient in, for example, the gastrointestinal tract. Although US 2017/0312226 mentions sugar esters, the document describes self-emulsified abuse and tamper resistant liquid and solid dosages containing an active ingredient complexed within an ion-exchange resin.

Methods of improving the solubility of lipophilic drugs to allow them to be administered by non-invasive routes, such as orally, are disclosed in US 2009/0061011. The compositions disclosed describe particles of poorly soluble drugs, including several opioids, encapsulated by polymeric surfactant stabilisers.

Enhancing bioavailability of poorly absorbed therapeutic agents, to permit release at a preferred site in, for example, the gastrointestinal tract, via oral administration has been described using bioadhesive polymers and impermeable or semi-permeable layers (US 2011/0142889), using coating with redox-sensitive materials, such as azopolymers or disulphide polymers (WO 97/05903), using pH-dependent or anionic copolymer coatings (WO 2016/120378), and using acid labile and alka linizing coatings (US 2016/0022590).

Abuse-deterrent oral formulations for delivering drugs, such as opioids, to the gastrointestinal tract in the form of fatty acid salts in the presence of various carriers, such as waxes is described in inter alia WO 2005/123039 and WO 2017/222575. See also WO 2005/009409. The use of sucrose esters is not described in any of these documents.

Nanocarrier based controlled release drug delivery systems comprising buprenorphine are disclosed in US 2015/0024033. In such formulations, buprenorphine is entrapped in the lipid/phospholipid core of the nanocarriers, which are then coated with a polymer.

Abuse resistant capsules of abuse-susceptible APIs are disclosed in US 2014/0271835. These capsules contain a viscosity-enhancer, such as silica gel, to render them unsuitable for intravenous injection upon dissolution and heating in water.

See also US 2009/0047336, CN 102579340 and WO 95/27499.

There is little reported use of sucrose esters in self-emulsifying formulations (see by Szuts and Szabo-Revesz supra).

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 C12-22 fatty acids that are solid at body temperature (about 37°C), such as lauric acid, palmitic acid, stearic acid, arachidic acid, behenic acid and, in particular, myristic acid. Buprenorphine remains in a solubilised and/or molecularly dispersed form when the temperature is decreased to below the melting point of the C12-22 fatty acid, whereupon the fatty acid solidifies.

It has further been unexpectedly found that the additional presence of a sucrose ester in such compositions means they are readily capable of self-emulsification when placed in contact with an aqueous environment, and further that such compositions are capable of keeping the opioid analgesic in a dissolved state at levels far above the solubility of the opioid analgesic in the aqueous environment. Disclosure of the Invention

According to a first aspect of the invention, there is provided a solid, pharmaceutically- acceptable composition, in which (a) an opioid analgesic and (b) a sucrose ester with a hydrophilic-lipophilic balance value of between 6 and 20 are both dissolved and/or dispersed in a C12-22 fatty acid, which fatty acid is a solid at about 37°C, and which compositions are referred to hereinafter as "the compositions of the invention".

The term "solid" will be well understood by those skilled in the art as comprising matter (in this case, a composition of the invention and/or a C12-22 fatty acid) that retains its shape and density when not confined, in which molecules are generally compressed as tightly as the repulsive forces among them will allow.

Compositions of the invention are suitable for peroral administration and delivery to the gastrointestinal tract. This means that a composition of the invention, and/or dosage forms including them, should preferably be suitable for swallowing as a whole, complete composition/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.

Compositions of the invention may thus be suitable for direct administration to subjects, or may be contained within pharmaceutically-acceptable dosage forms. Dosage forms that comprise compositions of the invention should preferably be designed to deliver that composition to the gastrointestinal tract, such as the stomach, and/or 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. In this respect, suitable dosage forms may also comprise a pharmaceutically-acceptable carrier, which carrier is capable of releasing the composition of the invention within the gastrointestinal tract (such as within the stomach and/or small intestine and/or colon).

Appropriate pharmaceutically-acceptable carriers include appropriate dosing means known to the skilled person. For example, the aforementioned solid compositions of the invention may, along with further solid ingredients or excipients, be compressed into a tablet, granulated into a pellet or a pill, or, preferably, may be filled into a capsule, such as a soft-shell or a hard-shell capsule, which can be made from gelatin, cellulose polymers, e.g. hydroxypropyl methylcellulose (HPMC or hypromellose), hypromellose acetate succinate (HPMCAS), starch polymers, pullulan or other suitable materials, for example by way of standard capsule filling processes. 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, l-methyl-4-phenyl-l,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 compositions of the invention. By "pharmaceutically-acceptable salt" of opioid analgesics, we mean 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 C12-22 fatty acids that are employed as solvents for the opioid analgesic are solid at about 37°C. By "solid at about 37°C", we mean that the C12-22 fatty acid has a melting point that is above about 37°C i.e. it is solid at that temperature and below (and potentially at certain temperatures above that temperature) under normal atmospheric conditions, such as pressure and humidity.

It has further been unexpectedly found that the additional presence of a sugar ester in compositions of the invention means those compositions are readily capable of self emulsification when placed in contact with an aqueous environment.

Sugar esters that may be used in the compositions of the invention include monosaccharide and/or disaccharide esters, preferably disaccharide ester, and most preferably sucrose esters.

Sucrose esters that are employed in compositions of the invention have a hydrophilic- lipophilic balance value of between 6 and 20. The term "hydrophilic-lipophilic balance" (HLB) is a term of art that will be well understood by those skilled in the art (see, for example, "The HLB System: A Time-Saving Guide to Emulsifier Selection", published by ICI Americas Inc, 1976 (revised 1980), in which document, Chapter 7 (pages 20- 21) provides a method of how to determine HLB values). The longer the fatty acid chains in the sucrose esters and the higher the degree of esterification, the lower the HLB value. Preferred HLB values are between 10 and 20, more preferably between 12 and 20.

Sucrose esters thus include C8-22 saturated or unsaturated fatty acid esters, preferably saturated fatty acid esters and preferably a Cio-is fatty acid ester and most preferably a C12 fatty acid ester. Particularly suitable fatty acids from which such sucrose esters may be formed include erucic acid, behenic acid, oleic acid, stearic acid, palmitic acid, myristic acid and lauric acid. A particularly preferred such fatty acid is lauric acid. Commercially-available sucrose esters include those sold under the trademark Surfhope® and Ryoto® (Mitsubishi-Kagaku Foods Corporation, Japan).

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.

A particularly preferred sucrose ester is sucrose monolaurate.

Compositions of the invention may also exhibit surprisingly good bioavailability compared to corresponding compositions that do not include sucrose esters, and/or include different surfactants.

Suitable fatty acids for use in compositions of the invention 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 12 and 22, preferably between 14 and 18, in number. Hydrocarbon chains may be linear or branched, saturated, straight-chain, cyclic or part-cyclic. Preferred fatty acids include lauric acid, palmitic acid, stearic acid, arachidic acid and behenic acid. Particularly preferred fatty acids include myristic acid. The opioid analgesic is thus dissolved and/or dispersed in a solvent system comprising at least one or more such C12-22 fatty acids, which means that solvent system may comprise other components.

Other components of the fatty acid-containing solvent system in which opioid analgesic is included include triglycerides and/or, preferably, monoacyl glycerols.

Triglycerides that may be mentioned include any ester that is derived from glycerol and three fatty acids, for example C8-22 saturated or unsaturated fatty acids, at least two of which may be the same or different. Triglycerides may be derived from animal or vegetable fats. Preferred triglycerides include vegetable oils and fractions thereof, such as castor oil, peanut oil, corn oil, safflower oil, sesame oil, soybean oil, coconut oil, palm oils, medium chain triglyceride oils and, especially, olive oil.

Monoacyl glycerols (also known as "monoglycerides") that may be employed in compositions of the invention are composed of glycerol linked to a fatty acid, for example a C8-22 saturated or unsaturated fatty acid, through an ester bond, and includes 1-monoacyl- and 2-monoacylglycerols. Monoacyl glycerols may be produced by a variety of techniques including enzymatic hydrolysis of triglycerides or diglycerides, by alkanoylation of glycerol, or glycerolysis reaction between triglycerides and glycerol, and/or are commercially-available. Suitable monoacyl glycerols include 2-oleoylglycerol, 2-arachidonoylglycerol, monolaurin, glycerol monomyristate, glycerol monopalmitate, glyceryl hydroxystearate and, preferably, glycerol monostearate, glycerol monooleate (e.g. Cithrol®) and glycerol monocaprylate (e.g. Capmul®).

It is preferred that compositions of the invention comprise one or more non-volatile monoacyl glycerol.

In this respect, we have found that the solubility of sucrose esters in fatty acids can be improved by the further inclusion of one or more such monoacyl glycerols, such as glycerol monostearate, glycerol monooleate (e.g. Cithrol™) and glycerol monocaprylate (e.g. Capmul®). Such monoacyl glycerols are good co-solvents for sucrose esters and are, at the same time, soluble and/or miscible with fatty acids, and are not detrimental to capsule shells.

In compositions of the invention, it is preferred that at least about 50% (such as at least about 70%) of the molecules of the opioid analgesic that are within a composition of the invention are present in a dissolved form, a molecularly dispersed form, and/or are arranged in an amorphous form, such as in the form of small particles. The term "dissolved" and/or "molecularly dispersed" form(s) may include that the molecules of the opioid analgesic are dissolved in a colloidal structure (e.g. micellar, hexagonal and bilayer phases, which can be normal or reverse).

Preferred optional additional excipients include one or more surfactants. Surfactants that may be mentioned include polyoxyethylene esters (e.g. Myrj™), including polyoxyl 8 stearate (Myrj™ S8), polyoxyl 32 stearate (Gelucire® 48/16), polyoxyl 40 stearate (Myrj™ S40), polyoxyl 100 stearate (Myrj™ S100), and polyoxyl 15 hydroxystearate (Kolliphor® HS 15), polyoxyethylene alkyl ethers (e.g. Brij™), including polyoxyl cetostearyl ether (e.g. Brij™ CS12, CS20 and CS25), polyoxyl lauryl ether (e.g. Brij™ L9 and L23), and polyoxyl stearyl ether (e.g. Brij™ S10 and S20), and polyoxylglycerides (e.g. Gelucire®), including lauroyl polyoxylglycerides (Gelucire® 44/14) and stearoyl polyoxylglycerides (Gelucire® 50/13), sorbitan esters (e.g. Span™), including sorbitan monopalmitate (Span™ 40) and sorbitan monostearate (Span™ 60), polysorbates (Tweens™), including polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) andpolysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), and sodium lauryl sulfate.

Not including sucrose ester(s) that is/are present in compositions of the invention, surfactants may be present in a total amount of up to about 30%, such as up to about 15%, by weight, based on the total weight of the composition.

Additional ingredients (excipients) may include solvents or co-solvents, such as water; alcohols, including lower alkyl (e.g. Ci-6 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, and dimethyl sulfoxide; oils, such as vegetable oils (e.g. castor, peanut, corn, safflower, sesame, soybean, coconut, palm oils and, especially, olive oil); di- and triglycerides of fatty acids (e.g. medium chain monoglycerides); fatty alcohols (or long chain alcohols) (e.g. cetyl alcohol, cetostearyl alcohol and stearyl alcohol (e.g. Crodacol™ C70, C90, C95, CS50, CS90 and S95); sterols (or steroid alcohols) such as cholesterol and phytosterols (e.g. campesterol, sitosterol, and stigmasterol); 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. 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. isopropyl myristate, isopropyl palmitate, pyrrolidone, or tricaprylin); and other lipids (neutral and polar).

The compositions of the invention may include an aromatic carboxylic acid as an additional component. Suitable aromatic acids include benzoic acid optionally substituted with one or more groups selected from methyl, hydroxyl, amino, and/or nitro, for instance, toluic acid or salicylic acid. Benzoic acid is particularly preferred.

Aromatic acids such as benzoic acid have been found to increase the solubility of the opioid in the fatty acid, particularly in solid formulations. Suitably, the aromatic acid (e.g. benzoic acid) is present in an amount of up to 35 weight percent, preferably from 1 to 20 wt%.

Total amounts of such "additional" excipients are no more than about 40%, such as 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 composition of the invention.

It is preferred that compositions of the invention in the main part comprise components that are solid at about 37°C below. That is, by weight, at least about 50% (such as at least about 70%) of the components in such a solid composition are solid at about 37°C or below.

When other excipients, such as those mentioned above, are employed, which happen to be substances that are liquid at about 37°C, it is preferred that no more than about 10%, such as about 5% by weight, based on the total weight of a composition of the invention comprises such excipients.

It is further preferred that the compositions of the invention are not presented in the form of a water-in-oil, or an oil-in-water, emulsion prior to administration. Compositions 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 solid compositions 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 compositions 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.

Compositions of the invention may be prepared by standard techniques, and using standard equipment, known to the skilled person. In this respect, the compositions 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, compositions of the invention may be prepared by stirring together opioid analgesic (or salt thereof), along with the other ingredients including the sucrose ester and the C12-22 fatty acid (and, if present, monoacyl glycerol) as hereinbefore defined, along with any other ingredients as mentioned hereinbefore at elevated temperature (e.g. about 60°C) until a solution is formed. Such a solution may be later cooled to a lower temperature (e.g. about 20°C) whereupon the composition solidifies.

Compositions of the invention may be prepared as described hereinafter. Alternative and/or additional process steps may also be employed to make compositions of the invention, such as spray cooling, spray congealing, extrusion cooling and/or freeze casting, to promote solidification. Also, process media such as cooled air, dry ice and liquid nitrogen may be employed to the cooling step.

Such processes may also comprise other process steps, such as high shear mixing and/or sonication at the elevated temperature to promote solubilisation and/or a uniform distribution of ingredients within the composition.

According to one aspect of the invention, the compositions of the invention may be solidified to uniform and spherical particles appropriate for a finished dosage form using spray congealing or prilling. The solidified particles are formed in a manner in which, preferably, a water-soluble excipient, more preferably a saccharide ester or a sucrose ester, is suspended in a mixture of low melting point ingredients and is congealed. After spray congealing, the resulting composition is allowed to cool and solidify.

In a preferred embodiment, the composition of the inventions may be made by feeding the precursor through a nozzle, producing a stable beam of solution which is broken up into sub-millimeter sized round droplets. The droplets may then be solidified by cooling as they fall through the rising cold nitrogen flow forming uniform and spherical particles.

According to a further aspect of the invention, there is provided a process for the manufacturing of a composition of the invention, wherein said process comprises the steps of:

i) stirring together the opioid analgesic (or salt thereof), along with the other ingredients including the sucrose ester and the C12-22 fatty acid (and, if present, monoacyl glycerol) as hereinbefore defined, along with any other ingredients as mentioned hereinbefore at elevated temperature (e.g. about 60°C) until a solution is formed; ii) cooling the solution of step i) to a lower temperature (e.g. about 20°C) allowing the composition to solidify, optionally in the form of multiparticulates; and

iii) optionally, further processing of the invention after step ii) by means of e.g. milling, screening, sieving, blending, coating, compression, and filling.

Step i) may also comprise other process steps, such as high shear mixing and/or sonication to promote solubilisation and/or uniform distribution of ingredients within the formulation.

Process media such as cooled air and other gases, dry ice and liquid nitrogen may be employed to the cooling step ii).

Compositions of the invention may be solidified in any size and shape appropriate for a finished dosage form, and/or may be further processed after solidification by means of e.g. milling, screening, sieving, blending, coating, compression, and filling.

Preferred particle sizes include a weight- or volume-based average particle size of less than about 2 mm, such as less than about 1 mm, including less that about 0.75 mm in (e.g. the particles' largest) diameter.

Preferred particle shapes include spherical or substantially spherical, by which we mean that the particles possess an aspect ratio smaller than about 20, more preferably less than about 10, such as less than about 4, and especially less than about 2, and/or may possess a variation in radii (measured from the centre of gravity to the particle surface) in at least about 90% of the particles that is no more than about 50% of the average value, such as no more than about 30% of that value, for example no more than about 20% of that value.

Nevertheless, particles may be any shape, including irregular shaped (e.g. "raisin"- shaped), needle-shaped, disc-shaped or cuboid-shaped, particles. For a non-spherical particle, the size may be indicated as the size of a corresponding spherical particle of e.g. the same weight, volume or surface area.

According to a further aspect of the invention, there is provided the compositions of the invention for use in medicine (human and veterinary). The compositions 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, compositions 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.

Compositions of the invention may be provided with such a protective coating as a single-unit dosage form (e.g. a composition of the invention may be filled into a dosage form, such as a capsule, which may be coated with a controlled and/or delayed release coating), and/or multiple-units comprising compositions of the invention (e.g. multiple pellets) may first be individually coated for controlled and/or delayed release and thereafter filled into a capsule that may be an immediate release capsule.

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 compositions of the invention or entire dosage forms comprising compositions of the invention with a material (e.g. a polymer) that is degraded by the enzymes/microbiota in the colon;

• coating drug substances, units of compositions of the invention or entire dosage forms comprising compositions of the invention 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, compositions of the invention or entire dosage forms comprising compositions of the invention 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 compositions of the invention or entire dosage forms comprising compositions of the invention to deliver the active ingredient based on luminal pressure.

(See, for example, the review article by Amidon et at, 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 compositions of the invention (e.g. in appropriate dosage forms) 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 compositions of the invention are administered to a patient and reach 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 compositions 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 compositions 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 compositions of the invention may enhance intestinal lymphatic delivery, and thereby avoid to a great extent pre-systemic (first-pass) metabolism.

Compositions 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 compositions of the invention are particularly useful in the treatment of pain and/or when, in particular, the composition comprises buprenorphine or a salt thereof, in the treatment of opioid dependency and/or addiction. Compositions 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 composition 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/definitionl, 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).

Compositions 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 composition 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 compositions 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 composition 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 composition 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 composition.

The amount of the active ingredient may also be expressed as the amount in a unit dosage form comprising a composition of the invention. 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 pg (e.g. about 5 pg) 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 pg 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 pg to about 10 mg, depending on the opioid analgesic that is employed.

Preferred ranges for e.g. a capsule (or other peroral dosage form, such as a tablet) comprising a composition 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 compositions 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 compositions 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 compositions 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 composition of the invention (or a dosage form containing one), 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 compositions 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 compositions of the invention (and dosage forms containing them) 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 composition 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 compositions 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. All of these factors render compositions 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 compositions 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 compositions of the invention or dosage forms including them. Upon dissolution, or other interference and/or manipulation of the composition/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 composition 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 composition of the invention or a dosage form including one.

Thus, the amounts of opioid antagonist (or salt thereof) if employed in compositions 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 composition 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 compositions of the invention comprise both buprenorphine and naloxone, it is preferred that the dose ratio of buprenorphine aloxone 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. Compositions of the invention may be formulated with additional active ingredients, including (as appropriate) other pain-relieving agents, such as non-steroidal anti inflammatory agents, as well as cannabinoids.

The term 'cannabinoid' will be understood to include any compound that acts on cannabinoid receptors in cells that alter neurotransmitter release in the brain, such as phytocannabinoids (e.g., CBG, CBC, CBD, THC, CBN, CBE, iso-THC, CBL, and CBT), endocannabinoids (e.g., AEA, 2-AG, noladin ether, NAD A, OAE, and LPI), plant cannabinoids (e.g., cannabigerol-type (CBG-type), cannabichromene-type (CBC-type), cannabidiol-type (CBD-type), cannabinodiol-type (CBND-type), D⁹- tetrahydrocannabinol-type (A⁹-THC-type), A⁸-tetrahydrocannabinol-type (A⁸-THC- type), cannabinol-type (CBN-type), cannabitriol-type (CBT-type), cannabielsoin-type (CBE-type), isocannabinoids, cannabicyclol-type (CBL-type), cannabitriol-type (CBT- type), or cannabichromanone-type (CBCN-type)), dehydrocannabifuran, cannabifuran, cannabichromanon, 10- oxo-5-6a-tetrahydrocannabinol or cannabiripsol, or synthetic cannabinoids (e.g., nabilone, rimonabant, JWH-018, JWH- 073, CP-55940, Dimethylheptylpyran, HU-210, HU-331, SR144528, WIN 55,212-2, JWH- 133, Levonantradol (Nantrodolum), or AM-2201) and mimics thereof.

The cannabinoid may include at least one of THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), CBT (cannabicitran), Nabilone, Rimonabant, JWH-018, JWH- 073, CP-55940, Dimethylheptylpyran, HU-210, HU-331, SR144528, WIN 55,212- 2, JWH- 133, Levonantradol (Nantrodolum), or AM-2201.

Preferred endocannabinoids are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors such as CBi, CB2, or CB3 (GPR55) and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system (including the brain) and peripheral nervous system.

Preferred cannabinoids include THC (tetrahydrocannabinol, e.g. dronabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran).

A particularly preferred cannabinoid is cannabidiol.

Compositions 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: Figures 1 and 2 are microscope pictures showing the self-emulsification of solid compositions that may be included in compositions of the invention; Figures 3 and 6 to 8 show the results of comparative in vitro dissolution experiments for different solid compositions, with Figures 4 and 5 relating to correlations between observed and predicted values for a composition of the invention, Figure 9 showing the dissolution of buprenorphine base after addition of hydrochloric acid, and Figure 10 being a photographic representation of the dissolution behaviour of the respective compositions.

Example 1

Buprenorphine Solubility in Myristic Acid and Stearic Acid

Buprenorphine free base (508 mg; Siegfried AG, Switzerland) and myristic acid (995 mg; Sigma-Aldrich Sweden AB) were added to a 4 mL glass vial. Buprenorphine free base (506 mg) and stearic acid (999 mg; IMCD Nordic, Sweden) were added to another 4 mL glass vial. The samples were heated to about 65°C and stirred by magnet for 6 hours, followed by centrifugation (4000 rpm) at about 60°C, which resulted in a sedimentation of undissolved buprenorphine particles and a clear supernatant. The samples were left at room temperature overnight, whereupon they solidified. The following day the samples were re-heated to about 65°C without stirring, whereupon the fatty acids melted, and again a clear supernatant was formed with undissolved buprenorphine particles on the bottom in both samples. The samples were allowed to equilibrate at about 65°C for 4 hours.

After equilibration, a clear excess of undissolved buprenorphine was still visually observed, and the assay of the dissolved buprenorphine was chemically analysed from the clear supernatants.

The supernatants 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 myristic acid and stearic acid was found to be 282 mg/g and 224 mg/g, respectively. The high solubility of buprenorphine in myristic acid and stearic acid was unexpected.

Example 2

Buprenorphine/Naloxone Formulation

Buprenorphine base (0.400 g), naloxone base (0.100 g; converted from naloxone HCI by Latvian Institute of Organic Synthesis), myristic acid (2.008 g), sucrose laurate (1.003 g; IMCD Nordic AB), glycerol monostearate (1.003 g; IOI Oleo GmbH, Germany), cholesterol (0.200 g; Merck Chemical 8i Lifescience AB, Sweden) and propyl gallate (0.050 g; Sigma-Aldrich Sweden AB) were weighed into a 20 mL glass vial with a screw-cap. The sample was stirred by magnet at 60°C, and sonicated in a sonication bath at 50°C until a visually isotropic clear lipid solution resulted at 50°C.

A minor part of the lipid solution at 50°C was withdrawn into a heated Pasteur pipette and immediately emptied dropwise on a flat stainless steel lid cooled on ice, resulting in the formation of drop sized solid lipid pellets. Example 3

Spontaneous Surface Self-Emulsification Experiment

The solid composition from Example 2 was subjected to spontaneous surface self dispersion/emulsification. A thin flake of solid lipid pellet was added to a microscope slide. Beside this flake, but not in contact with it, one drop of pH 6.8 phosphate buffer (50 mM) was added to the slide. The microscope slide was mounted in a light microscope equipped with a lOx magnifying lens and a digital camera. With the flake and the drop of pH 6.8 phosphate buffer in focus, a cover glass was gently applied over which then, by capillary forces, brought the pH 6.8 phosphate buffer in contact with the flake.

Upon contact, the solid composition slowly self-emulsified at the interface, resulting in a multitude of various lipid structures/phases protruding into the aqueous phase. In Figure 1, the spontaneous self-dispersion/emulsification process is shown, with the solid composition to the bottom left in the picture and the aqueous phase to the top right.

Example 4

Self-Emulsification Experiment

The solid composition from Example 2 was subjected to dispersion/emulsification by adding one solid lipid pellet to a 4 mL glass vial containing 2 mL of pH 6.8 phosphate buffer (50 mM), and stirring by magnet at approximately 400 rpm, at 37°C.

The solid composition of Example 2 slowly diminished and dispersed/emulsified resulting in a milky white macroscopically homogeneous dispersions/emulsions. After 10 minutes a sample was withdrawn from the dispersions/emulsions and examined under a light microscope, as showed in Figure 2. A multitude of lipid structures, such as vesicles, was observed. No solid crystals were observed, specifically no crystals of buprenorphine.

Example 5

Multiparticulate Composition I

Buprenorphine base (1.000 g), myristic acid (4.875 g), glycerol monostearate (3.125 g) and sucrose laurate (2.750 g) were weighed into a 20 mL glass vial with a screw- cap. The sample was stirred by magnet at 65°C until a visually isotropic clear lipid solution resulted at 65°C. The lipid solution at 65°C was poured onto a flat stainless steel lid cooled on ice, resulting in the immediate formation of a solid lipid thin sheet. The solid lipid thin sheet was put in a polyethylene bag and held in a freezer at -20°C overnight. The frozen composition was then crushed into a coarse powder, once again held in a freezer at -20°C overnight, and finally screened through frozen sieves of 1.00 mm and 0.71 mm, and sieved on 0.25 mm. The final multiparticulate solid lipid composition thus had a particle size distribution from about 0.25 mm to about 0.71 mm.

Example 6 (Comparative)

Multiparticulate Composition II

Buprenorphine base (1.000 g) and myristic acid (5.000 g) were weighed into a 20 mL glass vial with a screw-cap. The sample was stirred by magnet at 65°C until a visually isotropic clear lipid solution resulted at 65°C.

The final multiparticulate solid lipid composition with a particle size distribution from about 0.25 mm to about 0.71 mm was produced as described in Example 5.

Example 7 (Comparative)

Multiparticulate Composition III

Buprenorphine base (1.003 g), myristic acid (5.004 g) and beeswax (2.001 g; Croda Nordica AB, Sweden) were weighed into a 20 mL glass vial with a screw-cap. The sample was stirred by magnet at 65°C until a visually isotropic clear lipid solution resulted at 65°C.

The final multiparticulate solid lipid composition with a particle size distribution from about 0.25 mm to about 0.71 mm was produced as described in Example 5.

Example 8 (Comparative)

Multiparticulate Composition IV

Buprenorphine base (1.003 g), myristic acid (5.010 g) and glycerol monostearate (2.005 g) were weighed into a 20 mL glass vial with a screw-cap. The sample was stirred by magnet at 65°C until a visually isotropic clear lipid solution resulted at 65°C.

The final multiparticulate solid lipid composition with a particle size distribution from about 0.25 mm to about 0.71 mm was produced as described in Example 5. Example 9

In Vitro Dissolution Experiments

In vitro dissolution of buprenorphine from the compositions of Examples 5 to 8 was analysed by UV-VIS spectroscopy (Agilent Cary 60 UV-Vis, Agilent Technologies).

Centrifuge tubes, 50 mL (Fisherbrand®), were filled with 20 mL of pH 7 phosphate buffer 0.1 M, and kept at 37°C in a water bath. A stirring magnet of 20 x 6 mm was placed in the tube, and the dissolution medium was stirred at 300 rpm. At time zero, one unit dose of test formulation, each corresponding to 8 mg of buprenorphine, was added, and immediately afterwards, a fibreoptic dip probe with a path-length of 2 mm was inserted to a depth so that the entire probe-house was submerged.

Absorbance was measured at 265 nm, 288 nm and 311 nm, and the absorbance of dissolved buprenorphine was determined as the difference between the value of Abs(288 nm) and the mean value of Abs(265 nm) plus Abs(311 nm) (averaged two- point baseline correction). Measurements were made every 6 seconds up to 20 minutes and every 12 seconds from 20 minutes onwards.

To account for measurement variability, dissolution data (absorbance) was fitted to the Weibull dissolution model by minimizing the sum of squared difference between observed and model predicted values.

The Weibull dissolution model used :

M = M₀ (1 - _e- ^fc(t-^;r)) where M is released amount (absorbance) as a function of time (t), Mo is the total amount being released (maximum absorbance), T is the lag time of the dissolution system and k is the release rate constant (see Dash et at, Acta Pol. Pharm. - Drug Research, 67, 3 (2010)).

Observed values and Weibull fit was plotted over time from 0 to 60 minutes for the compositions of Examples 5 to 8, see Figures 3, 6, 7 and 8, respectively.

A diagnostic of the Weibull model fit was done for Example 5. The observed versus predicted absorbance was plotted, and a linear trendline was fitted with an R² (coefficient of determination - a statistical measure of how well the model approximates to the real data points) value of 0.8863, which indicates a good correlation between observed and predicted over the entire range (see Figure 4). The observed absorbance minus predicted absorbance was plotted over time, and a linear trendline was fitted with an R² value of 0.0002, which indicates no correlation (e.g. drift) of observed absorbance minus predicted absorbance over time (see Figure 5).

The in vitro dissolution of buprenorphine base (8.0 mg) was also analysed according to the method described above with the amendments that the test was run for 120 minutes and that, at minute 110, an aliquot of 125 pL of concentrated hydrochloric acid was added to adjust the pH to about 2.5 where buprenorphine has a solubility of about 15 mg/ml_.

After 110 minutes at pH 7.0, the absorbance value of 0.003 indicated that only about 2% of the buprenorphine was dissolved. These values correspond to a solubility of about 8 pg/mL at pH 7.0, which falls within the literature values of 13 pg/mL and 3 pg/mL reported for buprenorphine solubility in 0.1 M phosphate buffer at pH 6.8 and 7.4, respectively (see Liao et ai, J. Food Drug Anal., 16, 8 (2008)).

Upon addition of hydrochloric acid to a pH of about 2.5, all the buprenorphine dissolved within 10 minutes and a maximum absorbance of 0.17 was obtained for 100% dissolved of 8.0 mg buprenorphine in 20 mL 0.1 M phosphate buffer (see Figure 9).

After 60 minutes the absorbance for the composition of Example 5 was about 0.13, which indicates that about 75% (0.13/0.17) of the buprenorphine was dissolved. For the compositions of Examples 6, 7 and 8, the absorbance after 60 minutes indicates the about 10%, 5% and 5%, respectively, of the buprenorphine was dissolved.

During the in vitro dissolution experiments carried out on Examples 5 to 8 the dispersion/emulsification was observed and captured photographically after 10 minutes (see Figure 10).

The results of the in vitro dissolution experiments unexpectedly show that only compositions of the invention are readily capable of self-emulsification, and are also capable of dissolving and keeping the opioid analgesic in a dissolved state at levels far above the solubility of the opioid analgesic in the aqueous environment. Example 10

Buprenorphine Formulation Made by Prilling

Buprenorphine base (5.000 g), myristic acid (24.375 g), glycerol monostearate (16.625 g), sucrose laurate (13.750 g) and propyl gallate (0.250 g) are weighed into a 100 mL glass flask with a screw-cap. The sample is stirred with a magnet at 65°C until a visually isotropic clear lipid solution results at 65°C.

The lipid solution, kept at 70°C, is fed to the nozzle of prilling equipment. The nozzle has an orifice of 345 pm and vibrates at an amplitude of 3.70 kHz, producing a stable beam of lipid solution which is broken up into sub-millimeter sized round droplets. The droplets are then solidified by cooling as they fall through the rising cold nitrogen flow. The inlet temperature at the bottom of the column is below -20°C, and the outlet temperature at the top of the column is below -10°C. The solidified particles are uniform and spherical.

Claims

Claims

1. A solid, pharmaceutically-acceptable composition suitable for peroral administration to the gastrointestinal tract, in which (a) an opioid analgesic and (b) a sucrose ester with a hydrophilic-lipophilic balance value of between 6 and 20 are both dissolved and/or dispersed in a C12-22 fatty acid, which fatty acid is a solid at about 37°C.

2. The composition as claimed in Claim 1, wherein the C12-22 fatty acid is selected from the group consisting of myristic acid, lauric acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and combinations thereof.

3. The composition as claimed in Claim 2, wherein the fatty acid is myristic acid.

4. The composition as claimed in any one of the preceding claims wherein the sucrose ester is sucrose monolaurate or sucrose laurate.

5. The composition as claimed in any one of the preceding claims wherein the composition further comprises one or more monoacyl glycerol.

6. The composition as claimed in Claim 5 wherein the monoacyl glycerol is selected from the group consisting of 2-oleoylglycerol, 2-arachidonoylglycerol, monolaurin, glycerol monomyristate, glycerol monopalmitate, glycerol monostearate, glyceryl hydroxystearate and mixtures thereof.

7. The composition as claimed in Claim 5 wherein the monoacyl glycerol is selected from the group consisting of glycerol monostearate, glycerol monooleate and glycerol monocaprylate.

8. The composition as claimed in Claim 6 or Claim 7 wherein the monoacyl glycerol is glycerol monostearate.

9. The composition as claimed in any one of the preceding claims wherein the composition includes one or more additional ingredients.

10. The composition as claimed in Claim 9, wherein the total amount of the one or more additional ingredient is no more than about 30% by weight, based on the total weight of a composition of the invention.

11. The composition as claimed in Claim 9 or Claim 10, wherein the one or more additional ingredient is a solvent or co-solvent or a surfactant or a mixture thereof.

12. The composition as claimed in Claim 9 or Claim 10, wherein the one or more additional ingredient is an aromatic carboxylic acid.

13. The composition as claimed in Claim 12, wherein the aromatic carboxylic acid is benzoic acid.

14. The composition as claimed in any one of the preceding claims, wherein the opioid analgesic is buprenorphine or a pharmaceutically-acceptable salt thereof.

15. The composition as claimed in Claim 14, wherein the buprenorphine is in the form of the free base.

16. The composition as claimed in any one of the preceding claims, wherein the composition form further comprises an opioid antagonist.

17. The composition as claimed in Claim 16, wherein the opioid antagonist is naloxone or a pharmaceutically acceptable salt thereof.

18. The composition as claim in Claim 17, as dependent on any one of Claims 14 to 16, wherein the dose ratio of buprenorphine to naloxone (calculated as the free bases) is 4: 1.

19. The composition as claimed in any one of the preceding claims, which is suitable for consumption and/or ingestion within the gastrointestinal tract.

20. A dosage form comprising a composition as defined in any one of the preceding claims and a pharmaceutically-acceptable carrier that is capable of releasing the composition within the gastrointestinal tract.

21. The dosage form as claimed in Claim 20, wherein the carrier is capable of releasing the composition within the small intestine.

22. The dosage form as claimed in Claim 20 or Claim 21, wherein the carrier is capable of releasing the composition within the terminal ileum and/or colon.

23. The dosage form as claimed in any one of Claims 20 to 22, wherein the carrier is an optionally-coated capsule.

24. A composition as defined in any one of Claims 1 to 19, or the dosage form as defined in any one of Claims 20 to 23, for use in human and/or veterinary medicine.

25. A composition as defined in any one of Claims 1 to 19, or the dosage form as defined in any one of Claims 20 to 23, for use in a method of treatment of opioid dependency, and/or a method of treatment of pain.

26. A method of treatment of opioid dependency, and/or a method of treatment of pain, which method comprises administration of a composition as defined in any one of Claims 1 to 19, or a dosage form as defined in any one of Claims 20 to 23, to a person suffering from, or susceptible to, the relevant condition.

27. The use of a composition as defined in any one of Claims 1 to 19, or a dosage form as defined in any one of Claims 20 to 23, for the manufacture of a medicament for a method of treatment of opioid dependency, and/or a method of treatment of pain.

28. A process for the preparation of a composition as defined in any one of Claims 1 to 19, which comprises the step of dissolving and/or dispersing the opioid analgesic or salt thereof and the sucrose ester in the one or more fatty acids.

29. A process for the preparation of a dosage form as defined in any one of Claims 20 to 23, which comprises the step of loading a composition as defined in any one of Claims 1 to 19 into a carrier as defined in any one of Claims 20 to 23.

30. A process as claimed in Claim 29, which further comprises a process step as claimed in Claim 28.