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US 20100129443A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0129443 A1 Pettersson (43) Pub. Date: May 27, 2010

(54) NON-ABUSABLE PHARMACEUTICAL Publication Classification COMPOSITION COMPRISING OPODS (51) Int. Cl. A69/20 (2006.01) (76) Inventor: Anders Pettersson, Uppsala (SE) A6IR 9/14 (2006.01) Correspondence Address: 3. ?t C RYAN KROMHOLZ & MANION, S.C. (2006.01) POST OFFICE BOX 266.18 A6IP 25/00 (2006.01) MILWAUKEE, WI 53226 (US) (52) U.S. Cl...... 424/465; 424/489: 514/329; 514/282: 424/464 (21) Appl. No.: 12/312,995 (57) ABSTRACT (22) PCT Filed: Dec. 3, 2007 There is provided pharmaceutical compositions for the treat ment of pain comprising a pharmacologically-effective (86). PCT No.: PCT/GB2OOTFOO4627 amount of an , or a pharmaceutically-accept S371 (c)(1) able salt thereof, presented in particulate form upon the sur (2), (4) Date: Jan. 12, 2010 faces of carrier particles comprising a pharmacologically s e -la?s effective amount of an , or a O O pharmaceutically-acceptable Salt thereof, which carrier par Related U.S. Application Data ticles are larger in size than the particles of the opioid anal (60) Provisional application No. 60/872,496, filed on Dec. gesic. The compositions are also useful in prevention of 4, 2006. opioid abuse by addicts. US 2010/0129443 A1 May 27, 2010

NON-ABUSABLE PHARMACEUTICAL ing opioid , which may be administered by a con COMPOSITION COMPRISING OPODS Venient route, for example transmucosally, particularly, as is usually the case, when such active ingredients are incapable of being delivered perorally due to poor and/or variable bio 0001. This invention relates to new, fast acting, non-abus availability. able pharmaceutical compositions that are useful in the treat 0013 However, a perennial problem with potent opioid ment of pain, which compositions may be administered trans analgesics such as is one of abuse by drug addicts. mucosally and in particular Sublingually. Addicts normally abuse pharmaceutical formulations by 0002 are widely used in medicine as analgesics. extracting a large quantity of active ingredient from that for Indeed, it is presently accepted that, in the palliation of more mulation into Solution, which is then injected intravenously. severe pain, no more effective therapeutic agents exist. With most commercially-available pharmaceutical formula 0003. The term “opioid' is typically used to describe a tions, this can be done relatively easily, which renders them drug that activates opioid receptors, which are found in the unsafe or “abusable'. Thus, there also is a need for a fast brain, the spinal cord and the gut. Three classes of opioids acting, non-abusable pharmaceutical formulation comprising exist: opioid analgesics. 0004 (a) naturally-occurring alkaloids. These 0014 is a selective opioidantagonist that is used include and ; to reverse the pharmacological effects of opioids. Naloxone 0005 (b) compounds that are similar in their chemical may therefore be used to treat drug overdose or to structure to the naturally-occurring opium alkaloids. diagnose Suspected opioid addiction. Naloxone has poor bio These so-called semi-synthetics are produced by chemi availability when administered transmucosally but has good cal modification of the latter and include the likes of diamorphine (), and ; bioavailability when administered by injection. and 0015. A simple mixture combination of the opioid partial 0006 (c) truly synthetic compounds such as fentanyl and naloxone for Sublingual adminis and . Such compounds may be completely tration is available under the trademark SuboxoneR). This and different in terms of their chemical structures to the other abuse-resistant opioid-containing formulations are naturally-occurring compounds. reviewed by Fudula and Johnson in Drug and Depen 0007 Of the three major classes of opioid receptors (u, K dence, 83S, S40 (2006). See also US patent applications US and Ö), opioids analgesic and sedative properties mainly 2003/O124061 and US 2003/0191147. derives from agonism at the LL receptor. (0016 International patent applications WO 00/16750, 0008 Opioid analgesics are used to treat the severe, WO 2004/067004 and WO 2006/103418, all disclose drug chronic pain of terminal cancer, often in combination with delivery systems for the treatment of e.g. acute pain by Sub non-steroid anti-inflammatory drugs (NSAIDs), as well as lingual administration in which the active ingredient in acute pain (e.g. during recovery from Surgery). Further, their microparticulate form and is adhered to the Surface of larger use is increasing in the management of chronic, non-malig carrier particles in the presence of a bioadhesive and/or nant pain. mucoadhesive promoting agent. Specific combinations of 0009 Opioid-requiring cancer patients are usually given opioid analgesics and opioidantagonists are not mentioned or slow-release (slow-release morphine or ketobemi Suggested anywhere in these documents. done, or transdermal fentanyl). A characteristic feature of 0017. In endeavouring to solve the above-mentioned prob Such treatments is periods of inadequate analgesia (so-called lems, and to provide an improved, effective, fast-acting, non “breakthrough' pain). Such periods are thought to be due to abusable bioadhesive formulation comprising a potent opioid increased physical activity of the patient. However, treatment analgesic, such as fentanyl, in combination with a sufficient of breakthrough pain by administration of increased time dose of an opioidantagonist. Such as naloxone, we have found contingent doses of long-acting analgesic formulations is that it is not possible to provide both active ingredients upon known to cause, adverse side effects, including excess seda the surfaces of inert carrier particles as disclosed in the afore tion, , and constipation. mentioned patent documents. We have therefore devised an 0010 Presently-available oral, rectal and sublingual elegant Solution to this problem by providing particles of opioid analgesic formulations have relatively lengthy onset opioid analgesic drug upon the Surfaces of carrier particles times and/or erratic absorption characteristics, which makes comprising an opioid antagonist, Such as naloxone. then not entirely suitable for the control of acute and/or break 0018. According to a first aspect of the invention there are through pain. provided particulate pharmaceutical compositions for the 0011. In order to obtain rapid onset of analgesia in the treatment of pain comprising a pharmacologically-effective treatment of other types of acute pain, including operative amount of an opioid analgesic, or a pharmaceutically-accept pain, post-operative pain, traumatic pain, post-traumatic able salt thereof, presented in particulate form upon the sur pain, and pain caused by severe diseases, such as myocardial faces of carrier particles comprising a pharmacologically infarction, nephrolithiasis, etc., opioid analgesics are often effective amount of an opioid antagonist, or a administered parenterally (e.g. by intravenous or intramuscu pharmaceutically-acceptable Salt thereof, which carrier par lar injection). However, injections are an unpopular mode of ticles are larger in size than the particles of the opioid anal administration, often being regarded as inconvenient and gesic, which compositions are referred to hereinafter as “the painful. compositions of the invention. 0012. In view of the above, there is a real and growing 0019 Compositions of the invention may further com clinical need for fast-acting orally-delivered drug composi prise a bioadhesion and/or a mucoadhesion promoting agent, tions comprising opioid analgesics. In particular, a need which agent is, at least in part, presented on the Surfaces of the exists for further or better fast-acting formulations compris carrier particles. US 2010/0129443 A1 May 27, 2010

0020. The compositions of the invention are interactive limited to, their hydrochlorides, maleates, tartrates and lac mixtures. The term “interactive” mixture will be understood tates. Preferred opioid antagonists include , pref by those skilled in the art to denote a mixture in which par erably methylmaltrexone, more preferably and, ticles do not appear as single units, as in random mixtures, but particularly, naloxone. rather where Smaller particles (of for example, opioid anal 0024. Any of the active ingredients mentioned in the above gesic and/or bioadhesion and/or mucoadhesion promoting groupings may also be used in combination as required. agent) are attached to (i.e. adhered to or associated with) the Moreover, the above active ingredients may be used in free Surfaces of larger opioid antagonist-containing, or opioid form or, if capable of forming salts, in the form of a salt with antagonist-based, carrier particles. Such mixtures are charac a suitable acid or base. If the drugs have a carboxyl group, terised by interactive forces (for example van der Waals their esters may be employed. Active ingredients can be used forces, electrostatic or Coulombic forces, and/or hydrogen as racemic mixtures or as single enantiomers. bonding) between carrier and Surface-associated particles 0025. The term “pharmacologically effective amount (see, for example, Staniforth, Powder Technol., 45, 73 refers to an amount of an active ingredients, which is capable (1985)). In the final mixture, the interactive forces need to be of conferring a desired therapeutic effect on a treated patient, strong enough to keep the adherent particles at the carrier whether administered alone or in combination with another Surface, in order to create a homogeneous mixture. active ingredient. Such an effect may be objective (i.e. mea 0021. The term “opioid analgesic’ will be understood by Surable by some test or marker) or subjective (i.e. the subject the skilled person to include any Substance, whether natu gives an indication of, or feels, an effect). rally-occurring or synthetic, with opioid or morphine-like 0026 Appropriate pharmacologically effective amounts properties and/or which binds to opioid receptors, particu of opioid analgesic compounds include those that are capable larly the u-, having at least of producing (preferably rapid) relief of pain when adminis activity, thereby capable of producing an analgesic effect. tered transmucosally, whereas appropriate pharmacologi 0022. Opioid analgesics that may be mentioned include cally effective amounts of opioid antagonist compounds in opium derivatives and the opiates, including the naturally the carrier particles must be sufficient so as not to compete occurring phenanthrenes in opium (such as morphine, with the pain-relieving effect of the opioid analgesic present codeine, and Diels-Alder adducts thereof) and semi in the composition of the invention upon transmucosal synthetic derivatives of the opium compounds (such as administration, but to block the effect of the opioid analgesic diamorphine, , , hydrocodone, if an attempt is made by an opioid-addicted individual to oxycodone, , , hydrocodeine, dihy inject a composition of the invention. As stated above, we drocodeine, , and N-(2-phenylethyl) have found that this can be achieved elegantly by presenting normorphine). Other opioid analgesics that may be men Smaller microparticles of opioid analgesic on the Surfaces of tioned include fully synthetic compounds with opioid or larger carrier particles comprising opioid antagonist, and the morphine-like properties, including derivatives skilled person will appreciate that the relative sizes of the two (such as , , , leval active ingredients can be utilised to achieve the necessary lorphan, , butoiphanol and nalbufine); benzomor relevant doses in this respect. phan derivatives (such as , and 0027. The amounts of active ingredients that may be ); phenylpiperidines (such as (meperi employed in compositions of the invention may thus be deter dine), fentanyl, , , , ketobemi mined by the physician, or the skilled person, in relation to done, carfentanyl, anilleridine, , , what will be most suitable for an individual patient. This is alphaprodine, betaprodine, 1-methyl-4-phenyl-1,2,3,6-tet likely to vary with the route of administration, the type and rahydropyridine (MPTP), and ), severity of the condition that is to be treated, as well as the phenylheptamines or “open chain' compounds (such as age, weight, sex, renal function, hepatic function and methadone, , propoxyphene and levomethadyl response of the particular patient to be treated. acetate hydrochloride (LAAM)); diphenylpropylamine 0028. The total amount of opioid analgesic active ingredi derivatives (such as , , bezitra ent that may be employed in a composition of the invention mide and ); mixed /antagonists will depend upon the nature of the relevant active ingredient (such as buprenorphine, and ) and other that is employed, but may be in the range of about 0.0005%, opioids (such as , and ). More pre such as about 0.1% (e.g. about 1%, such as about 2%) to about ferred opioid analgesics include buprenorphine, alfentanil, 20%, such as about 10%, for example about 7%, by weight Sufentanil, remifentanil and, particularly, fentanyl. based upon the total weight of the composition. The amount 0023 The term “opioid antagonist will be understood by of this active ingredient may also be expressed as the amount the skilled person to include any Substance, whether natu in a unit dosage form (e.g. a tablet). In Such a case, the amount rally-occurring or synthetic, which binds to opioid receptors, of opioid analgesic active ingredient that may be present may particularly the u-opioid receptor, having at least partial be sufficient to provide a dose per unit dosage form that is in antagonist activity, thereby for example at least partially the range of between about 1 Lug (e.g. about 5ug) and about 20 reversing one or more of the pharmacological effects of an mg (e.g. about 15 mg. Such as about 10 mg). opioid analgesic mentioned hereinbefore. Opioid antagonists 0029. The total amount of opioid antagonist that may be that may be mentioned include naloxone, cyclazocine, employed in a composition of the invention may be in the nalmefene, opioid antagonist compounds having the same range about 1%, such as about 2% (e.g. about 5%, such as pentacyclic nucleus as nalmefene, naltrexone, methylmaltrex about 10%) to about 98%, such as about 99%, for example one, nalorphine, , thebaine, levallorphon, penta about 99.9% (e.g. 99.9995%). The amount of this active Zocine, oxymorphine, , bupremorphine, levor ingredient may also be expressed as the amount in a unit phanol, , dezocine, or pentazocine or their dosage form (e.g. a tablet). In Such a case, the amount of pharmacologically effective salts or esters such as, but not opioid antagonist active ingredient that may be present may US 2010/0129443 A1 May 27, 2010

be sufficient to provide a dose per unit dosage form that is in (e.g. >95%) covered by mucous). The terms “bioadhesive' the range of between about 0.1 mg and about 10 mg. Such as and “bioadhesion” refer to adhesion or adherence of a sub about 1 to about 5 mg (e.g. about 4 mg). stance to a biological Surface in a more general sense. Bio 0030 The above-mentioned dosages are exemplary of the logical Surfaces as Such may include mucous membranes average case; there can, of course, be individual instances wherein mucous is not present on that Surface, and/or Surfaces where higher or lower dosage ranges are merited, and Such are that are not substantially (e.g. <95%) covered by mucous. The within the scope of this invention. skilled person will appreciate that, for example, the expres 0031 Opioid analgesic active ingredients in the composi sions “mucoadhesion' and “bioadhesion' may often be used tions of the invention are preferably in the form of micropar interchangeably. In the context of the present invention, the ticles, preferably with a weight based mean diameter of relevant terms are intended to convey a material that is between about 0.5 um and about 15um, Such as about 1 um capable of adhering to a biological Surface when placed in and about 10 Lum. The term “weight based mean diameter' will be understood by the skilled person to include that the contact with that Surface (in the presence of mucous or oth average particle size is characterised and defined from a par erwise) in order to enable compositions of the invention to ticle size distribution by weight, i.e. a distribution where the adhere to that surface. Such materials are hereinafter referred existing fraction (relative amount) in each size class is defined to together as “bio/mucoadhesives” or “bio/mucoadhesion as the weight fraction, as obtained e.g. by sieving. promoting agents', and Such properties together as “bio/mu 0032 Microparticles of active ingredients may be pre coadhesion' or “bio/mucoadhesive'. pared by standard micronisation techniques, such as grinding, 0038 A variety of polymers known in the art can be used dry milling, wet milling, precipitation, etc. as bio/mucoadhesion promoting agents, for example poly 0033 Preferably, opioid antagonist-containing carrier meric Substances, preferably with an average (weight aver particles for use in compositions of the invention are of a size age) molecular weight above 5,000. It is preferred that such that is between about 50 and about 1000 um (e.g. about 800 materials are capable of rapid Swelling when placed in con um, such as about 750Lum), and preferably between about 100 tact with water and/or, more preferably, mucous, and/or are and about 600 um. Substantially insoluble in water at room temperature and 0034. It is possible for certain active ingredients that the atmospheric pressure. relative sizes and amounts of the particles of opioid analgesic active ingredient and the opioid antagonist-containing carrier 0039 Bio/mucoadhesive properties may be routinely particles that are employed are sufficient to ensure that the determined in a general sense in vitro, for example as carrier particles may be at least about 90% covered by the described by G. Sala et al in Proceed. Int. Symp. Contr. opioid analgesic, for example at least about 100% and up to Release. Bioact. Mat., 16, 420, 1989. Examples of suitable about 200% (e.g. between about 130% and about 18.0%) bio/mucoadhesion promoting agents include cellulose covered. The skilled person will appreciate in this context that derivatives such as hydroxypropylmethyl cellulose (HPMC), “100% coverage' of the carrier particles by the opioid anal hydroxyethyl cellulose (HEC), hydroxypropyl cellulose gesic means that the relative particle sizes and amounts of the (HPC), methyl cellulose, ethyl hydroxyethyl cellulose, car relevant particles that are employed are sufficient to ensure boxymethyl cellulose, modified cellulose gum and Sodium that the entire surface area of each carrier particle could be carboxymethyl cellulose (NaCMC); starch derivatives such covered by particles of the opioid analgesic notwithstanding as moderately cross-linked Starch, modified Starch and that other ingredients (e.g. mucoadhesion promoting agent) Sodium starch glycolate; acrylic polymers such as carbomer may also be present in a composition. Obviously, if other Such and its derivatives (Polycarbophyl, Carbopol R, etc.); polyvi ingredients are employed, then the actual degree of coverage nylpyrrolidone; polyethylene oxide (PEO); chitosan (poly of carrier particles by active ingredient may be less than the (D-glucosamine)); natural polymers such as gelatin, sodium amounts specified above. 200% coverage means that there is alginate, pectin; Scleroglucan: Xanthan gum, guar gum, poly Sufficient particles of opioid analgesic to cover the Surfaces of co-(methylvinyl /maleic anhydride); and crosscarmel the carrier particles twice over, notwithstanding the presence lose (e.g. crosscarmellose Sodium). Such polymers may be of other ingredients. crosslinked. Combinations of two or more biof mucoadhesive 0035. It is surprising that compositions with greater than polymers can also be used. 90% theoretical coverage are effective. Based on current 0040 Suitable commercial sources for representative bio/ knowledge, the skilled person would understand that, in order mucoadhesive polymers include: Carbopol Racrylic copoly to ensure rapid dissolution, it would be important to ensure mer (BF Goodrich Chemical Co., Cleveland, 08, USA); that the relative sizes/amounts of opioid analgesic/carrier par HPMC (Dow Chemical Co., Midland, Mich., USA); NEC ticles are sufficient to ensure that 70% or less of the surfaces (Natrosol. Hercules Inc., Wilmington, Del. USA); HPC of the latter could be covered by the former. (Klucel(R: Dow Chemical Co., Midland, Mich., USA); 0036. As mentioned hereinbefore, compositions of the NaCMC (Hercules Inc. Wilmington, Del. USA); PEO (Ald invention may comprise one or more bioadhesion and/or rich Chemicals, USA); sodium alginate (Edward Mandell mucoadhesion promoting agent at least in part presented on, Co., Inc., Carmel, N.Y., USA); pectin (BF Goodrich Chemi and/or adhered to, the Surface of an opioid antagonist-con cal Co., Cleveland, Ohio, USA); crosslinked polyvinylpyr taining carrier particle, and may thus facilitate the partial or rolidone (Kollidon CLR, BASF, Germany, Polyplasdone complete adhesion of active ingredients to a biological Sur XL(R), Polyplasdone XL-10R and Polyplasdone INF-10R, face. Such as a mucosal membrane. ISP Corp., US); Ac-Di-SolR) (modified cellulose gum with a 0037. The terms “mucoadhesive' and “mucoadhesion high swellability: FMC Corp., USA); Actigum (Mero-Rous refer to adhesion or adherence of a Substance to a mucous selot-Satia, Baupte, France); Satiaxana (Sanofi Biolndustries, membrane within the body, wherein mucous is present on the Paris, France); Gantrez(R) (ISP. Milan, Italy); chitosan Surface of that membrane (e.g. the membrane is Substantially (Sigma, St Louis, Miss., USA); and Sodium starch glycolate US 2010/0129443 A1 May 27, 2010

(Primojel R, DMV International BV. Netherlands, Vivastar R, 0048 Primary particles of ingredients (e.g. opioidantago J. Rettenmaier & Söhne GmbH & Co., Germany, Explotab(R), nist and other carrier particle materials) may be processed by Roquette America, US). techniques, such as grinding, dry milling, wet milling, pre 0041 Preferred bio/mucoadhesion promoting agents that cipitation, etc., prior to granulation. may be employed in compositions of the invention include 0049 Granulates comprising opioid antagonist may be internally crosslinked sodium carboxymethylcellulose. Such further processed following their formation and prior to as croscarmellose sodium NF (e.g. Ac-Di-SolR (FMC Corp., admixing with other ingredients to produce a composition of USA)) and crosslinked polyvinylpyrollodine (e.g. Kollidon the invention. For example, a dry granulate may be ground or CL(R), BASF, Germany). milled using a suitable milling technique to produce particu 0042. Depending on the type of the bio/mucoadhesion late material of a smaller size, which may also be sieved to promoting agent used, the rate and intensity of bio/mucoad separate the desired size fraction. Wet granulate may be hesion may be varied. screened to break up agglomerates of granules and remove 0043 Suitably, the amount of bio/mucoadhesion promot fine material. In either case, the unused fine material may be ing agent that is presentina composition of the invention may reworked to avoid waste. Suitable granulate particle sizes are be in the range of about 0.1 to about 25% by weight based in the range of about 0.05 mm to about 1.2 mm (e.g. about 1 upon the total weight of the composition. A preferred range is mm), such as about 0.1 mm to about 1.0 mm (e.g. about 0.8 from about 0.5 to about 15% by weight, such as about 1 to mm), for example about 0.2 to about 0.6 mm. about 10% (e.g. about 2 to about 8%) by weight. 0050 Compositions of the invention, once prepared, are 0044) The carrier particles that are employed in composi preferably directly compressed/compacted into unit dosage tions of the invention comprise opioid antagonist as defined forms (e.g. tablets) for administration to mammalian (e.g. herein. Carrier particles may or may not consistessentially of human) patients, for example as described hereinafter. opioid antagonist. By "consisting essentially of opioid 0051. A disintegrating agent, or “disintegrant may also antagonist, we mean that the carrierparticles comprise at least be included in the composition the invention, particularly about 95%, such as at least about 98%, more preferably those that are in the form of tablets for e.g. Sublingual admin greater than about 99%, and particularly at least about 99.5% istration. Such an agent may be defined as any material that is by weight (based on the total weight of the carrier particle) of capable of accelerating to a measurable degree the disinte Such an antagonist. These percentages exclude the presence gration/dispersion of a composition of the invention, and in of trace amounts of water and/or any impurities that may be particular carrier particles, as defined herein. This may be present in such materials, which impurities may arise follow achieved, for example, by thematerial being capable of swell ing the production of Such materials, either by a commercial ing and/or expanding when placed in contact with water or non-commercial third party Supplier, or by a skilled person and/or mucous (e.g. saliva), thus causing tablet formulations/ making a composition of the invention. In any event, the carrier particles to disintegrate when so wetted. Suitable dis possibility of particles of opioid antagonist also being pre integrants include cross-linked polyvinylpyrrolidone, car sented, at least in part, upon the Surfaces of, and/or between, boxymethyl starch and natural starch and mixtures thereof. Such carrier particles is not excluded. 0052. If present, disintegrating agent is preferably 0045. When the carrier particles do not consist essentially employed in an amount of between 0.5 and 10% by weight of opioid antagonist, additional materials that may also form based upon the total weight of the composition. A preferred part of the carrier particles include pharmaceutically-accept range is from 1 to 8%, such as from about 2 to about 7% (e.g. able Substances, such as carbohydrates, e.g. Sugar, mannitol about 5%, such as about 4%) by weight. and lactose; pharmaceutically-acceptable inorganic salts, 0053. It will be evident from the list of possible disinte Such as sodium chloride, calcium phosphate, dicalcium phos grants provided above that certain materials may function in phate hydrate, dicalcium phosphate dehydrate, tricalcium compositions of the invention in the form of tablets both as phosphate, calcium carbonate, and barium sulfate; polymers, bio/mucoadhesion promoting agents and as disintegrating Such as microcrystalline cellulose, cellulose and crosslinked agents. Thus, these functions may both be provided by dif polyvinylpyrrolidone; or mixtures thereof. ferent Substances or may be provided by the same Substance. 0046 When carrier particles do not consist essentially of 0054 When the “same material is employed as a bio/ opioid antagonist, additional materials may be admixed mucoadhesive and as a disintegrant, ant, the material can be together with opioid antagonist by a variety of techniques, said to be in two separate fractions (a bio/mucoadhesive frac Such as dry mixing, extrusion and/or spheronisation, or a tion and a disintegrant fraction). In Such instances, it is pre process of granulation, which may comprise wet and/or dry ferred that the particles within the disintegrant fraction are granulation. coarser (i.e. are, relatively speaking, of a larger particle size) 0047 Wet granulation techniques are well known to those than those in the bioadhesive fraction (vide infra). skilled in the art and include any technique involving the 0055. In any event, the skilled person will appreciate that, massing of a mix of dry primary powder particles using a in compositions of the invention in the form of tablets, any granulating fluid, which fluid comprises a volatile, inert Sol disintegrant (or disintegrant fraction) will be largely not pre vent, such as water, ethanol or isopropanol, either alone or in sented on (i.e. attached to, adhered to and/or associated with) combination, and optionally in the presence of a binder or the surfaces of the carrier particles, but rather will be largely binding agent. The technique may involve forcing a wet mass presented (i.e. at least about 60%, such as about 70%, e.g. through a sieve to produce pellets by spheronisation or wet about 80% and, more particularly, about 90% by weight pre granules which are then dried. Dry granulation techniques are sented) between such particles. Conversely, bio/mucoadhe also well known to those skilled in the art and include any sive (or bio/mucoadhesive fraction) is always largely associ technique in which primary powder particles are aggregated ated (i.e. is at least about 60%, such as about 70%, e.g. about under high pressure, including slugging and roller compac 80% and, more particularly, about 90% by weight associated) tion, for example as described hereinafter. with the carrier particles, that is to say presented on (i.e. US 2010/0129443 A1 May 27, 2010

attached to, adhered to and/or associated with) the surfaces of mixing time for a given combination of opioid analgesic the carrier particles, or presented within such particles (vide active ingredient and carrier particle material(s). infra), or both. 0067 Similarly, bio/mucoadhesion promoting agent (if 0056 Compositions of the invention in the form of tablets present) may be admixed with opioid antagonist-containing for e.g. Sublingual administration may also comprise a binder. carrier particles may be mixed together with opioid antago A binder may be defined as a material that is capable of acting nist-containing carrier particles for a Sufficient time in order as a bond formation enhancer, facilitating the compression of to produce an ordered or interactive mixture. This results in the powder mass into coherent compacts. Suitable binders discrete particles of bio/mucoadhesion promoting agent include cellulose gum and microcrystalline cellulose. If being presented on and/or adhered to the surfaces of the present, binder is preferably employed in an amount of carrier particles. between 0.5 and 20% by weight based upon the total weight 0068. The bio/mucoadhesion promoting agent suitably of the tablet formulation. A preferred range is from 1 to 15%, has a particle size with a weight based mean diameter of such as from about 2.0 to about 12% (e.g. about 10%) by between about 0.1 and about 100 um (e.g. about 1 and about weight. 50 um). 0057 Compositions of the invention may comprise a phar 0069 Ordered, or interactive, mixtures may also be pro maceutically acceptable Surfactant or wetting agent, which vided using techniques other than dry mixing, which tech may enhance the hydration of active ingredients and carrier niques will be well known to those skilled in the art. particles, resulting in faster initiation of both bio/mucoadhe 0070. Other ingredients (e.g. disintegrants and surfac sion and dissolution. If present, the Surfactant should be pro tants) may be incorporated by standard mixing as described vided in finely dispersed form and mixed intimately with the above for the inclusion of active ingredients. active ingredients. Examples of Suitable Surfactants include 0071. The compositions of the invention may be adminis Sodium lauryl Sulphate, lecithin, polysorbates, bile acid salts tered transmucosally, such as buccally, rectally, nasally or and mixtures thereof. If present, the Surfactant may comprise preferably Sublingually by way of appropriate dosing means between about 0.1% (e.g. about 0.3%) and about 5% by known to the skilled person. A sublingual tablet may be weight based upon the total weight of the composition, and placed under tongue, and the active ingredients absorbed preferably between about 0.5 and about 3% by weight. through the Surrounding mucous membranes. 0058 Suitable further additives and/or excipients that may 0072. In this respect, the compositions of the invention be employed in compositions of the invention, in particular may be incorporated into various kinds of pharmaceutical those in the form of tablets for e.g. Sublingual administration preparations intended for transmucosal (e.g. Sublingual) may comprise: administration using standard techniques (see, for example, 0059 (a) lubricants (such as sodium stearyl fumarate or, Lachman et al., “The Theory and Practice of Industrial Phar preferably, magnesium Stearate). When a lubricant is macy”. Lea & Febiger, 3" edition (1986) and “Remington: employed it should be used in very Small amounts (e.g. The Science and Practice of Pharmacy”. Gennaro (ed.), up to about 3%, and preferably up to 2%, by weight Philadelphia College of Pharmacy & Sciences, 19" edition based upon the total weight of the tablet formulation); (1995)). 0060 (b) flavourings (e.g. lemon, or, prefer 0073 Pharmaceutical preparations for sublingual admin ably, peppermint powder), Sweeteners (e.g. neohesperi istration may be obtained by combining compositions of the din) and dyestuffs; invention with conventional pharmaceutical additives and/or 0061 (c) antioxidants, which may be naturally occur excipients used in the art for Such preparations, and thereafter ring or otherwise (e.g. vitamin C, vitamin E, B-carotene, preferably directly compressed/compacted into unit dosage uric acid, uniquion, SOD, glutathione peroxidase or per forms (e.g. tablets). (See, for example, Pharmaceutical Dos oxidase catalase); and/or age Forms: Tablets. Volume 1, 2" Edition, Lieberman et al 0062 (d) other ingredients, such as carrier agents, pre (eds.), Marcel Dekker, New York and Base1 (1989) p. 354 servatives and gliding agents. 356 and the documents cited therein.) Suitable compacting 0063 Compositions of the invention may be prepared by equipment includes standard tabletting machines, such as the standard techniques, and using standard equipment, known to Kilian SP300 or the Korsch EKO. the skilled person. 0074 Suitable final sublingual tablet weights are in the 0064. In one embodiment, particles of opioid analgesic range of about 30 to about 400 mg, such as about 40 (e.g. may be dry mixed with opioid antagonist-containing carrier about 50) to about 200 mg, for example about 50 (e.g. about particles over a period of time that is sufficiently long to 60) to 180 mg, more preferably between about 60 (e.g. about enable appropriate amounts of active ingredients to adhere to 70) and about 160 mg. Suitable final tablet diameters are in the surface of the carrier particles (with or without the pres the range 4 to 10 mm, for example 5 to 9 mm, and more ence of bio/mucoadhesion promoting agent). preferably about 6 to about 8 mm. 0065. The skilled person will appreciate that, in order to 0075 Irrespective of the foregoing, compositions of the obtain a dry powder formulation in the form of an interactive invention should be essentially free (e.g. less than about 20% mixture, larger carrier particles must be able to exert enough by weight based on the total weight of the formulation) of force to break up agglomerates of Smaller particles. This water. It will be evident to the skilled person that “premature' ability will primarily be determined by particle density, Sur hydration will dramatically decrease the mucoadhesion pro face roughness, shape, flowability and, particularly, relative moting properties of a tablet formulation and may result in particle sizes. premature dissolution of active ingredients. 0066 Standard mixing equipment may be used in this (0076. Wherever the word “about” is employed herein in regard. The mixing time period is likely to vary according to the context of dimensions (e.g. tablet sizes and weights, par the equipment used, and the skilled person will have no dif ticle sizes etc.), Surface coverage (e.g. of opioid antagonist ficulty in determining by routine experimentation a Suitable containing carrier particles by particles of opioid analgesic), US 2010/0129443 A1 May 27, 2010

amounts (e.g. relative amounts of individual constituents in a I0087 Active ingredients are accurately weighed out, composition or a component of a composition and absolute along with the other excipients (see below), in appropriate doses of active ingredients), it will be appreciated that Such proportions that enable the production of tablets with the variables are approximate and as such may vary by it 10%, for absolute amounts of various ingredients mentioned below. example+5% and preferably +2% (e.g. +1%) from the num I0088 Naloxone hydrochloride (Mallinckrodt, USA) and bers specified herein. mannitol (Roquette, France) are mixed in a tumbling mixer (2 0077 Compositions of the invention may be administered L Turbula W. A. Bachofen AG, Basel, Switzerland) for 60 by way of appropriate dosing means known to the skilled minutes at 32 rpm. person. For example, a Sublingual tablet may be placed under I0089. The resultant mixture is then processed in a roller the tongue, and the active ingredients absorbed through the compaction into compacts which are reduced in size by a Surrounding mucous membrane. rotor sieving mill. The particle size of the resultant particles, 0078. The compositions of the invention are useful in the which are used as carrier particles in the formulation, is larger treatment of pain for example the symptomatic treatment of than 90 Lum. pain, particularly severe; acute and/or breakthrough pain. 0090 The carrier particles are then mixed with fentanyl According to a further aspect of the invention there is pro citrate (Diosynth, Netherlands) in a tumbling mixer for 72 vided a method of treatment of pain which method comprises hours (laboratory scale) at 32 rpm. administration of a composition of the invention to a person (0091 Croscarmellose sodium (Ac-Di-SolR; FMC, USA) Suffering from, or Susceptible to, such a condition. and silicified microcrystalline cellulose (ProSolv; Penwest 0079. For the avoidance of doubt, by “treatment” we pharmaceuticals Co., USA) are added to the resultant mixture include the therapeutic treatment, as well as the symptomatic and the mixing is continued for another 30 minutes. treatment, the prophylaxis, or the diagnosis, of the condition. 0092 Finally, magnesium stearate (Peter Greven, Nether 0080. The compositions of the invention enable the pro lands) is added to the mixture and the mixing is continued for duction of unit dosage forms that are easy and inexpensive to another 2 minutes. manufacture, and which enable the rapid release and/or a 0093. The powder mixture is then compacted in a single rapid uptake of the active ingredients employed through the punch press with 6 mm flat bevel edged punches, to give a mucosa, Such as the oral mucosa, thus enabling rapid relief of tablet weight of 70 mg. pain symptoms, such as those described hereinbefore. 0094. In-process controls, such as tablet weight, crushing 0081. The compositions of the invention also have the strength and disintegration time, are employed, with test advantage that, if injected by an opioid addict, they do not samples being withdrawn throughout the tabletting process. produce the euphoric effects that such an addict seeks and Tablets are packaged and labelled. indeed induce opioid withdrawal syndrome. 0082. The compositions of the invention may also have the advantage that they Substantially reduce the degree of absorp One tablet contains - Amount tion of active ingredients via Swallowed saliva, as well as Ingredient (mg) enabling the administration of “reduced amounts of the Fentanyl citrate O314 opioid analgesic active ingredient that is employed, so Sub (corresponding to fentanyl base 200 g) stantially reducing the risk of side effects, as well as intra- and Naloxone hydrochloride 9.77 interpatient variability of therapeutic response. (corresponding to naloxone base 8 mg) 0083 Compositions of the invention may also have the Mannitol 49.49 Silicified microcrystalline cellulose 9.35 advantage that they may be prepared using established phar croscarmellose sodium 0.73 maceutical processing methods and employ materials that are magnesium Stearate O3S approved for use in foods or pharmaceuticals or of like regu latory status. Total tablet weight 7O.OO 0084 Compositions of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, pro EXAMPLE 2 duce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile than, and/or have Naloxone/Fentanyl other useful pharmacological, physical, or chemical proper Sublingual Tablets (Incorporating a Dry Granulation ties over, pharmaceutical compositions known in the prior art, Process Step) whether for use in the treatment of pain or otherwise. 0085. The invention is illustrated by way of the following 0.095 Sublingual tablets were made using the same mate examples. rials, in the same proportions, as those specified in Example 1 above. EXAMPLE1 0096 Carrier particles were manufactured by mixing mannitol and naloxone HCl in the tumbling mixer at 32 rpm Naloxone/Fentanyl for 60 minutes. Dry granulation was performed by compac tion of the mixture in a single punch press (Korsch EKO, Sublingual Tablets Germany) using 20 mm flat-faced punches. The compacts I0086. An ordered mixture of micronised fentanyl citrate were then crushed by sieving (1.4, 1.0 and 0.8 mm) and a final and a mucoadhesive component adhered to the Surface of fraction of 90-800 um particles was obtained by sieving. water-soluble carrier particles, consisting of a dry granulate 0097. Fentanyl citrate was added to the carrier material in of a water-soluble excipient and naloxone hydrochloride is amounts corresponding to a batch size of 300 tablets. Mixing prepared as follows. was carried out under the same conditions as those described US 2010/0129443 A1 May 27, 2010

in Example 1. CroScarmellose Sodium and silicified microc 7. A composition as claimed in claim 1, wherein the opioid rystalline cellulose, and then magnesium Stearate, were added analgesic is in the form of microparticles. and admixed under the same conditions as those described in 8. (canceled) Example 1. 9. A composition as claimed in claim 1, wherein the total 0098. The mixture was compressed into tablets in the amount of opioid analgesic that is employed is in the range of single punch press using 6 mm flat faced bevel edged about 0.0005% to about 20% by weight based upon the total punches. weight of the composition. 10-18. (canceled) EXAMPLE 3 19. A composition as claimed in claim 1, wherein the carrier particles are of a size that is between about 50 and Naloxone/Fentanyl about 1,000 um. 20. (canceled) Sublingual Tablets (Incorporating a Wet Granulation 21. A composition as claimed in any claim 1, which further Process Step) comprises a bioadhesion and/or a mucoadhesion promoting 0099 Sublingual tablets were made using the same mate agent, which agent is, at least in part, presented on the Sur rials, in the same proportions, as those specified in Example 1 faces of the carrier particles. above. 22-25. (canceled) 0100. To make carrier particles, mannitol and naloxone 26. A composition as claimed in claim 21, wherein the HCl were firstly mixed as described in Example 2 above. 18.5 amount of bioadhesion and/or mucoadhesion promoting mL of ethanol was then added to the mixture, the wet mass agent present is in the range of about 0.1 to about 25% by was sieved (1.0 mm) and the granulate was dried at room weight based upon the total weight of the composition. temperature for 18 hours. The granulate was then sieved to 27. (canceled) obtain particles with a fraction of 90-800 um particles. 28. A composition as claimed in claim 21, wherein the 0101 Fentanyl citrate, croscarmellose sodium and silici bioadhesion and/or mucoadhesion promoting agent has a par fied microcrystalline cellulose, and then magnesium Stearate, ticle size in the range of about 1 to about 100 um. were all added and admixed under the same conditions as 29. A composition as claimed in claim 1, wherein the those described in Examples 1 and 2 above. The mixture was carrier particles further comprise a carbohydrate, a pharma compressed as described in Example 2. ceutically-acceptable inorganic salt or a polymer. 30-31. (canceled) 1. A particulate pharmaceutical composition for the treat 32. A composition as claimed in claim 1, wherein the ment of pain comprising a pharmacologically-effective relative sizes and amounts of the particles of opioid analgesic amount of an opioid analgesic, or a pharmaceutically-accept and the carrier particles that are employed are sufficient to able salt thereof, presented in particulate form upon the sur ensure that the carrier particles may be at least about 90% faces of carrier particles comprising a pharmacologically covered by the opioid analgesic particles. effective amount of an opioid antagonist, or a 33. A composition as claimed in claim 1, which is in the pharmaceutically-acceptable salt thereof, which carrier par form of a tablet suitable for sublingual administration. ticles are larger in size than the particles of the opioid anal 34. A composition as claimed in claim 33, wherein the gesic. composition further comprises a disintegrating agent. 2. A composition as claimed in claim 1, wherein the opioid 35. (canceled) analgesic is a naturally-occurring opium-derived compound, 36. A composition as claimed in claim 34, wherein the a semisynthetic derivative of an opium compound, or a syn disintegrating agent is selected from crosslinked polyvi thetic compound with opioid or morphine-like properties. nylpyrrolidone, carboxymethyl starch, natural starch and 3. A composition as claimed in claim 2, wherein the syn mixtures thereof, wherein the amount of disintegrating agent thetic compound is a morphinan derivative, a benzomorphan is between about 2 and about 7% by weight based upon the derivative, a phenylpiperidine, a phenylheptamine, an open total weight of the composition. chain compound, a diphenylpropylamine derivative, a mixed 37. A process for the preparation of a composition as agonist/antagonist or another synthetic opioid. defined in claim 1, which comprises dry mixing the carrier 4. A composition as claimed in claim 2, wherein the opioid particles with the opioid analgesic. analgesic is selected from morphine, codeine, thebaine or a 38. A process according to claim 37 further comprising Diels-Alder adduct thereof, diamorphine, hydromorphone, directly compressing or compacting the composition as oxymorphone, hydrocodone, oxycodone, etorphine, nico defined to formatablet suitable for sublingual administration. morphine, hydrocodeine, , metopon, normor 39. A process as claimed in claim 37 which further com phine, N-(2-phenylethyl)normorphine, racemorphan, levor prises a process step in which the carrier particles are pre phanol, dextromethorphan, , cyclorphan, pared by a process of dry or wet granulation. butorphanol, nalbufine, cyclazocine, pentazocine, phenazo 40. (canceled) cine, pethidine (meperidine), fentanyl, alfentanil, Sufentanil, 41. A method of treatment of pain which method comprises remifentanil, , carfentanyl, anilleridine, pimi administration of a composition as defined in claim 1 to a nodine, ethoheptazine, alphaprodine, betaprodine, 1-methyl patient Suffering from, or Susceptible to. Such a condition. 4-phenyl-1,2,3,6-tetrahydropyridine, diphenoxylate, lopera 42. The method as claimed in claim 41, wherein the pain is mide, methadone, isomethadone, propoxyphene, severe, acute and/or breakthrough pain, wherein the medica levomethadyl acetate hydrochloride, dextromoramide, pirit ment and/or composition is resistant to abuse by an opioid ramide, , dextropropoxyphene, buprenorphine, addict. nalorphine, oxilorphan, tilidine, tramadol and dezocine, 43. (canceled) nalmefene, methylmaltrexone, naltrexone and naloxone. 5-6. (canceled)