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US 2013 0195981A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0195981 A1 Pettersson (43) Pub. Date: Aug. 1, 2013

(54) NON-ABUSABLE PHARMACEUTICAL Publication Classification COMPOSITION COMPRISING OPODS (51) Int. Cl. (71) Applicant: Orexo AB, Uppsala (SE) A619/16 (2006.01) A613 L/4468 (2006.01) (72) Inventor: Anders Pettersson, Kode (SE) A613 L/485 (2006.01) (52) U.S. Cl. (73) Assignee: Orexo AB, Uppsala (SE) CPC ...... A61K 9/167 (2013.01); A61 K3I/485 (2013.01); A61 K3I/4468 (2013.01) USPC ...... 424/490; 514/282 (21) Appl. No.: 13/799,117 (57) ABSTRACT 1-1. There is provided pharmaceutical compositions for the treat (22) Filed: Mar 13, 2013 ment of pain comprising a pharmacologically-effective amount of an , or a pharmaceutically-accept Related U.S. Application Data able salt thereof, presented in particulate form upon the sur (63) Continuation of application No. 12/312.995, filed on faces of carrier particles comprising a pharmacologically OO4627Jan 2, On2010, Dec. ?ilication 3, 2007 No. PCT GE2007, pharmaceutically-acceptableelective amount of n Saltpioidantagonist thereof, which carrier or par a • - s 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 2013/0195981 A1 Aug. 1, 2013

NON-ABUSABLE PHARMACEUTICAL lar injection). However, injections are an unpopular mode of COMPOSITION COMPRISING OPODS administration, often being regarded as inconvenient and painful. RELATED APPLICATIONS 0013. In view of the above, there is a real and growing 0001. This application is a continuation of U.S. applica clinical need for fast-acting orally-delivered drug composi tion Ser. No. 12/312,995, filed Jan. 12, 2010, which is the tions comprising opioid . In particular, a need national stage of PCT/GB2007/0004627, filed Dec. 3, 2007, exists for further or better fast-acting formulations compris which claims priority to U.S. Provisional Application Ser. ing opioid analgesics, which may be administered by a con No. 60/872,496, filed Dec. 4, 2006, the disclosures of which Venient route, for example transmucosally, particularly, as is are each incorporated herein by reference in their entireties. usually the case, when such active ingredients are incapable 0002 This invention relates to new, fast acting, non-abus of being delivered perorally due to poor and/or variable able pharmaceutical compositions that are useful in the treat 0014. 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 0003) 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 0004. 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. 0005 (a) naturally-occurring alkaloids. These 0015 is a selective opioidantagonist that is used include and ; to reverse the pharmacological effects of opioids. Naloxone 0006 (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 bioavailability when administered by injection. diamorphine (), and ; 0016 A simple mixture combination of the opioid partial and agonist and naloxone for Sublingual adminis 0007 (c) truly synthetic compounds such as fentanyl tration is available under the trademark SuboxoneR). This and and . Such compounds may be completely other abuse-resistant opioid-containing formulations are different in terms of their chemical structures to the reviewed by Fudula and Johnson in Drug and Alcohol Depen naturally-occurring compounds. dence, 83S, S40 (2006). See also US patent applications US 0008 Of the three major classes of opioid receptors (u, K 2003/O124061 and US 2003/0191147. and Ö), opioids analgesic and sedative properties mainly (0017 International patent applications WO 00/16750, derives from agonism at the LL receptor. WO 2004/067004 and WO 2006/103418, all disclose drug 0009 Opioid analgesics are used to treat the severe, delivery systems for the treatment of e.g. acute pain by Sub chronic pain of terminal cancer, often in combination with lingual administration in which the active ingredient in non-steroid anti-inflammatory drugs (NSAIDs), as well as microparticulate form and is adhered to the Surface of larger acute pain (e.g. during recovery from Surgery). Further, their carrier particles in the presence of a bioadhesive and/or use is increasing in the management of chronic, non-malig mucoadhesive promoting agent. Specific combinations of nant pain. opioid analgesics and opioidantagonists are not mentioned or 0010 Opioid-requiring cancer patients are usually given Suggested anywhere in these documents. slow-release (slow-release morphine or ketobemi 0018. In endeavouring to solve the above-mentioned prob done, or transdermal fentanyl). A characteristic feature of lems, and to provide an improved, effective, fast-acting, non Such treatments is periods of inadequate analgesia (so-called abusable bioadhesive formulation comprising a potent opioid “breakthrough' pain). Such periods are thought to be due to analgesic, such as fentanyl, in combination with a sufficient increased physical activity of the patient. However, treatment dose of an opioidantagonist. Such as naloxone, we have found of breakthrough pain by administration of increased time that it is not possible to provide both active ingredients upon contingent doses of long-acting analgesic formulations is the surfaces of inert carrier particles as disclosed in the afore known to cause adverse side effects, including excess seda mentioned patent documents. We have therefore devised an tion, , and constipation. elegant Solution to this problem by providing particles of 0011 Presently-available oral, rectal and sublingual opioid analgesic drug upon the Surfaces of carrier particles opioid analgesic formulations have relatively lengthy onset comprising an , Such as naloxone. times and/or erratic absorption characteristics, which makes 0019. According to a first aspect of the invention there are then not entirely suitable for the control of acute and/or break provided particulate pharmaceutical compositions for the through pain. treatment of pain comprising a pharmacologically-effective 0012. In order to obtain rapid onset of analgesia in the amount of an opioid analgesic, or a pharmaceutically-accept treatment of other types of acute pain, including operative able salt thereof, presented in particulate form upon the sur pain, post-operative pain, traumatic pain, post-traumatic faces of carrier particles comprising a pharmacologically pain, and pain caused by severe diseases, such as myocardial effective amount of an opioid antagonist, or a infarction, nephrolithiasis, etc., opioid analgesics are often pharmaceutically-acceptable Salt thereof, which carrier par administered parenterally (e.g. by intravenous or intramuscu ticles are larger in size than the particles of the opioid anal US 2013/0195981 A1 Aug. 1, 2013

gesic, which compositions are referred to hereinafter as “the , opioid antagonist compounds having the same compositions of the invention”. pentacyclic nucleus as nalmefene, , methylmaltrex 0020 Compositions of the invention may further com one, , , , levallorphon, penta prise a bioadhesion and/or a mucoadhesion promoting agent, Zocine, oxymorphine, , bupremorphine, levor which agent is, at least in part, presented on the Surfaces of the phanol, , , or or their carrier particles. pharmacologically effective salts or esters such as, but not 0021. 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 nalmefene, pref by those skilled in the art to denote a mixture in which par erably methylmaltrexone, more preferably naltrexone and, ticles do not appear as single units, as in random mixtures, but particularly, naloxone. rather where Smaller particles (of for example, opioid anal 0025. 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 0026. 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 0022. 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 0027 Appropriate pharmacologically effective amounts properties and/or which binds to opioid receptors, particu of opioid analgesic compounds include those that are capable larly the 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 0023 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, thebaine 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 , pentazocine and 0028. 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 0029. 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 agonists/antagonists will depend upon the nature of the relevant active ingredient (such as buprenorphine, nalorphine and OXilorphan) and other that is employed, but may be in the range of about 0.0005%, opioids (such as , and dezocine). 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 0024. 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 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 0030 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 US 2013/0195981 A1 Aug. 1, 2013 range about 1%, such as about 2% (e.g. about 5%, such as complete adhesion of active ingredients to a biological Sur about 10%) to about 98%, such as about 99%, for example face, such as a mucosal membrane. about 99.9% (e.g. 99.9995%). The amount of this active 0038. The terms “mucoadhesive” and “mucoadhesion ingredient may also be expressed as the amount in a unit refer to adhesion or adherence of a substance to a mucous dosage form (e.g. a tablet). In such a case, the amount of membrane within the body, wherein mucous is present on the opioid antagonist active ingredient that may be present may surface of that membrane (e.g. the membrane is substantially 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 0031. 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 0032) 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 rnicropar 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 0.5um and about 15um, such as about 1 Jum capable of adhering to a biological surface when placed in and about 10 um. The term “weight based mean diameter” contact with that surface (in the presence of mucous or oth will be understood by the skilled person to include that the erwise) in order to enable compositions of the invention to average particle size is characterised and defined from a par adhere to that surface. Such materials are hereinafter referred ticle size distribution by weight, i.e. a distribution where the to together as “bio/mucoadhesives” or “bio/mucoadhesion existing fraction (relative amount) in each size class is defined promoting agents', and such properties together as “bio/mu as the weight fraction, as obtained e.g. by sieving. coadhesion' or “bio/mucoadhesive'. 0033 Microparticles of active ingredients may be pre 0039. A variety of polymers known in the art can be used pared by standard micronisation techniques, such as grinding, as bio/muco adhesion promoting agents, for example poly dry milling, wet milling, precipitation, etc. meric substances, preferably with an average (weight aver 0034 Preferably, opioid antagonist-containing carrier age) molecular weight above 5,000. It is preferred that such particles for use in compositions of the invention are of a size materials are capable of rapid swelling when placed in con that is between about 50 and about 1000 um (e.g. about 800 tact with water and/or, more preferably, mucous, and/or are um, such as about 750 um), and preferably between about 100 substantially insoluble in water at room temperature and and about 600 um. atmospheric pressure. 0035) It is possible for certain active ingredients that the 0040 Bio/mucoadhesive properties may be routinely relative sizes and amounts of the particles of opioid analgesic determined in a general sense in vitro, for example as active ingredient and the opioid antagonist-containing carrier described by G. Sala et al in Proceed. Int. Synzp. Contr. particles that are employed are sufficient to ensure that the Release. Bioact. Mat., 16, 420, 1989. Examples of suitable carrier particles may be at least about 90% covered by the bio/mucoadhesion promoting agents include cellulose opioid analgesic, for example at least about 100% and up to derivatives such as hydroxypropylmethyl cellulose (HPMC). about 200% (e.g. between about 130% and about 180%) hydroxyethyl cellulose (HEC), hydroxypropyl cellulose covered. The skilled person will appreciate in this context that (HPC), methyl cellulose, ethyl hydroxyethyl cellulose, car “100% coverage” of the carrier particles by the opioid anal boxymethyl cellulose, modified cellulose gum and sodium gesic means that the relative particle sizes and amounts of the carboxymethyl cellulose (NaCMC); starch derivatives such relevant particles that are employed are sufficient to ensure as moderately cross-linked starch, modified starch and that the entire surface area of each carrier particle could be sodium starch glycolate; acrylic polymers such as carbomer covered by particles of the opioid analgesic notwithstanding and its derivatives (Polycarbophyl, Carbopol R, etc.); polyvi that other ingredients (e.g. mucoadhesion promoting agent) nylpyrrolidone; polyethylene oxide (PEO); chitosan (poly may also be present in a composition. Obviously, if other such (D-glucosamine)); natural polymers such as gelatin, sodium ingredients are employed, then the actual degree of coverage alginate, pectin; scleroglucan: Xanthan gum; guar gum; poly of carrier particles by active ingredient may be less than the co-(methylvinyl ether/maleic anhydride); and crosscannel amounts specified above. 200% coverage means that there is lose (e.g. crosscarmellose sodium). Such polymers may be sufficient particles of opioid analgesic to cover the surfaces of crosslinked. Combinations of two or more bio/mucoadhesive the carrier particles twice over, notwithstanding the presence polymers can also be used. of other ingredients. 0041) Suitable commercial sources for representative bio/ 0036. It is surprising that compositions with greater than mucoadhesive polymers include: Carbopol Racrylic copoly 90% theoretical coverage are effective. Based on current mer (BF Goodrich Chemical Co. Cleveland, 08, USA); knowledge, the skilled person would understand that, in order HPMC (Dow Chemical Co., Midland, Mich., USA); NEC to ensure rapid dissolution, it would be important to ensure (Natrosol; Hercules Inc., Wilmington, Del. USA); HPC that the relative sizes/amounts of opioid analgesic/carrier par (Klucel(R: Dow Chemical Co., Midland, Mich., USA); ticles are sufficient to ensure that 70% or less of the surfaces NaCMC (Hercules Inc. Wilmington, Del. USA); PEO (Ald of the latter could be covered by the former. rich Chemicals, USA); sodium alginate (Edward Mandell 0037. As mentioned hereinbefore, compositions of the Co., Inc., Carmel, N.Y., USA); pectin (BF Goodrich Chemi invention may comprise one or more bioadhesion and/or cal Co., Cleveland, Ohio, USA); crosslinked polyvinylpyr mucoadhesion promoting agent at least in part presented on, rolidone (Kollidon CLR, BASF, Germany, Polyplasdone and/or adhered to, the surface of an opioid antagonist-con XL(R), Polyplasdone XL-10R and Polyplasdone INF-100, taining carrier particle, and may thus facilitate the partial or ISP Corp., US); Ac-Di-Sol(R) (modified cellulose gum with a US 2013/0195981 A1 Aug. 1, 2013

high swellability: FMC Corp., USA); Actigum (Mero-Rous also well known to those skilled in the art and include any selot-Satia, Baupte, France); Satiaxana (Sanofi Biolndustries, technique in which primary powder particles are aggregated Paris, France); Gantrez(R) (ISP. Milan, Italy); chitosan under high pressure, including slugging and roller compac (Sigma, St Louis, Mo., USA); and Sodium starch glycolate tion, for example as described hereinafter. (Primojel R, DMV International By, Netherlands, Vivastar R, 0049. Primary particles of ingredients (e.g. opioid antago J. Rettenmaier & Sohne 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 0042 Preferred bio/mucoadhesion promoting agents that cipitation, etc., prior to granulation. may be employed in compositions of the invention include 0050 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 0043. 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 0044 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. 0051 Compositions of the invention, once prepared, are 0045. 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 0052 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 disinteg, Such an antagonist. These percentages exclude the presence ration/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 the material 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. 0053. If present, disintegrating agent is preferably 0046 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, 0054. 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. 0047. When carrier particles do not consist essentially of 0055 When the “same material is employed as a bio/ opioid antagonist, additional materials may be admixed mucoadhesive and as a disintegrant, the material can be said together with opioid antagonist by a variety of techniques, to be in two separate fractions (a bio/mucoadhesive fraction Such as dry mixing, extrusion and/or spheronisation, or a and a disintegrant fraction). In Such instances, it is preferred process of granulation, which may comprise wet and/or dry that the particles within the disintegrant fraction are coarser granulation. (i.e. are, relatively speaking, of a larger particle size) than 0048 Wet granulation techniques are well known to those those in the bioadhesive fraction (vide infra). skilled in the art and include any technique involving the 0056. 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 US 2013/0195981 A1 Aug. 1, 2013

sive (or bio/mucoadhesive fraction) is always largely associ 0067 Standard mixing equipment may be used in this ated (i.e. is at least about 60%, such as about 70%, e.g. about regard. The mixing time period is likely to vary according to 80% and, more particularly, about 90% by weight associated) the equipment used, and the skilled person will have no dif with the carrier particles, that is to say presented on (i.e. ficulty in determining by routine experimentation a Suitable 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. 0068. Similarly, bio/mucoadhesion promoting agent (if 0057 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 0069. 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). 0058 Compositions of the invention may comprise a phar 0070 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 0071. 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 0072 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. 0059 Suitable further additives and/or excipients that may 0073. 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, 0060 (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)). 0061 (b) flavourings (e.g. lemon, or, prefer 0074 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 0062 (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 at 0063 (d) other ingredients, such as carrier agents, pre (eds.), Marcel Dekker, New York and Basel (1989) p. 354-356 servatives and gliding agents. and the documents cited therein.) Suitable compacting equip 0064 Compositions of the invention may be prepared by ment includes standard tabletting machines, such as the Kil standard techniques, and using standard equipment, known to ian SP300 or the Korsch EKO. the skilled person. 0075 Suitable final sublingual tablet weights are in the 0065. In one embodiment, particles of opioid analgesic range of about 30 to about 400 mg, such as about 40 (e.g. may be thy 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. 0066. The skilled person will appreciate that, in order to 0076 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. US 2013/0195981 A1 Aug. 1, 2013

0077. Wherever the word “about” is employed herein in water-soluble carrier particles, consisting of a dry granulate the context of dimensions (e.g. tablet sizes and weights, par of a water-soluble excipient and naloxone hydrochloride is ticle sizes etc.), Surface coverage (e.g. of opioid antagonist prepared as follows. containing carrier particles by particles of opioid analgesic), I0088 Active ingredients are accurately weighed out, amounts (e.g. relative amounts of individual constituents in a along with the other excipients (see below), in appropriate composition or a component of a composition and absolute proportions that enable the production of tablets with the doses of active ingredients), it will be appreciated that Such absolute amounts of various ingredients mentioned below. variables are approximate and as such may vary by it 10%, for I0089 Naloxone hydrochloride (Mallinckrodt, USA) and example+5% and preferably +2% (e.g. +1%) from the num mannitol (Roquette, France) are mixed in a tumbling mixer (2 bers specified herein. L Turbula W. A. Bachofen AG, Basel, Switzerland) for 60 0078 Compositions of the invention may be administered minutes at 32 rpm. by way of appropriate dosing means known to the skilled 0090 The resultant mixture is then processed in a roller person. For example, a Sublingual tablet may be placed under compaction into compacts which are reduced in size by a the tongue, and the active ingredients absorbed through the rotor sieving mill. The particle size of the resultant particles, Surrounding mucous membrane. which are used as carrier particles in the formulation, is larger 007.9 The compositions of the invention are useful in the than 90 Lum. treatment of pain for example the symptomatic treatment of 0091. The carrier particles are then mixed with fentanyl pain, particularly severe, acute and/or breakthrough pain. citrate (Diosynth, Netherlands) in a tumbling mixer for 72 According to a further aspect of the invention there is pro hours (laboratory scale) at 32 rpm. vided a method of treatment of pain which method comprises 0092 Croscarmellose sodium (Ac-Di-SolR; FMC, USA) administration of a composition of the invention to a person and silicified microcrystalline cellulose (ProSolv; Penwest Suffering from, or Susceptible to, such a condition. pharmaceuticals Co., USA) are added to the resultant mixture 0080. For the avoidance of doubt, by “treatment” we and the mixing is continued for another 30 minutes. include the therapeutic treatment, as well as the symptomatic 0093. Finally, magnesium stearate (Peter Greven, Nether treatment, the prophylaxis, or the diagnosis, of the condition. lands) is added to the mixture and the mixing is continued for 0081. The compositions of the invention enable the pro another 2 minutes. duction of unit dosage forms that are easy and inexpensive to manufacture, and which enable the rapid release and/or a 0094. 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. 0.095 In-process controls, such as tablet weight, crushing 0082. 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. 0083. 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) Mannitol 49.49 0084 Compositions of the invention may also have the 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 0085 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 Sublingual Tablets (Incorporating a other useful pharmacological, physical, or chemical proper Dry Granulation Process Step) ties over, pharmaceutical compositions known in the prior art, whether for use in the treatment of pain or otherwise. 0096. Sublingual tablets were made using the same mate I0086. The invention is illustrated by way of the following rials, in the same proportions, as those specified in Example 1 examples. above. 0097 Carrier particles were manufactured by mixing EXAMPLE1 mannitol and naloxone HCl in the tumbling mixer at 32 rpm for 60 minutes. Dry granulation was performed by compac Naloxone/Fentanyl Sublingual Tablets tion of the mixture in a single punch press (Korsch EKO. Germany) using 20 mm flat-faced punches. The compacts 0087 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. US 2013/0195981 A1 Aug. 1, 2013

0098 Fentanyl citrate was added to the carrier material in dine, diphenoxylate, loperamide, methadone, isometha amounts corresponding to a batch size of 300 tablets. Mixing done, propoxyphene, levomethadyl acetate hydrochlo was carried out under the same conditions as those described ride, dextromoramide, piritramide, , in Example 1. CroScarmellose Sodium and silicified microc dextropropoxyphene, buprenorphine, nalorphine, rystalline cellulose, and then magnesium Stearate, were added OXilorphan, tilidine, tramadol and dezocine. and admixed under the same conditions as those described in 0.108 5. A composition as recited in embodiment 4, Example 1. wherein the opioid analgesic is selected from buprenor 0099. The mixture was compressed into tablets in the phine, alfentanil, Sufentanil, remifentanil and fentanyl. single punch press using 6 mm flat faced bevel edged 0.109 6. A composition as recited in embodiment 5, punches. wherein the opioid analgesic is fentanyl. 0110. 7. A composition as recited in in any one of the EXAMPLE 3 preceding embodiments, wherein the opioid analgesic is in the form of microparticles. Naloxone/Fentanyl Sublingual Tablets (Incorporating a 0.111 8. A composition as recited in embodiment 7. Wet Granulation Process Step) wherein the microparticles have a weight based mean 0100 Sublingual tablets were made using the same mate diameter of less than about 15um. rials, in the same proportions, as those specified in Example 1 0112 9. A composition as recited in any one of the above. preceding embodiments wherein the total amount of 0101 To make carrier particles, mannitol and naloxone opioid analgesic that is employed is in the range of about HC1 were firstly mixed as described in Example 2 above. 0.0005% to about 20% by weight based upon the total 18.5 mL of ethanol was then added to the mixture, the wet weight of the composition. mass was sieved (1.0 mm) and the granulate was dried at room 0113 10. A composition as recited in embodiment 9 temperature for 18 hours. The granulate was then sieved to wherein the range is about 2% to about 7%. obtain particles with a fraction of 90-800 um particles. 0114 11. A composition as recited in any one of the 0102 Fentanyl citrate, croscarmellose sodium and silici preceding embodiments wherein the amount of opioid fied microcrystalline cellulose, and then magnesium Stearate, analgesic that is presentis Sufficient to provide a dose per were all added and admixed under the same conditions as unit dosage form of between about 1 mg and about 20 those described in Examples 1 and 2 above. The mixture was ng. compressed as described in Example 2. 0115 12. A composition as recited in embodiment 11 0103 Embodiments of the invention include, but are not wherein the amount is between about 5 mg and about 10 limited to, the following: ng. 0.104) 1. A particulate pharmaceutical composition for 0116 13. A composition as recited in any one of the the treatment of pain comprising a pharmacologically preceding embodiments wherein the opioid antagonist effective amount of an opioid analgesic, or a pharma is selected from nalmefene, methylmaltrexone, naltrex ceutically-acceptable salt thereof, presented in particu one and naloxone. late form upon the Surfaces of carrier particles comprising a pharmacologically-effective amount of an 0.117 14. A composition as recited in embodiment 13, opioidantagonist, or a pharmaceutically-acceptable salt wherein the opioid antagonist is naloxone. thereof, which carrier particles are larger in size than the 0118 15. A composition as recited in any one of the particles of the opioid analgesic. preceding embodiments wherein the total amount of 0105 2. A composition as recited in embodiment 1, opioid antagonist that is employed is in the range of wherein the opioid analgesic is a naturally-occurring about 1% to about 99.9995% by weight based upon the opium-derived compound, a semisynthetic derivative of total weight of the composition. an opium compound, or a synthetic compound with 0119) 16. A composition as claimed in embodiment 15, opioid or morphine-like properties. wherein the range is about 10% to about 98%. 0106 3. A composition as recited in embodiment 2, 0120 17. A composition as recited in any one of the wherein the synthetic compound is a morphinan deriva preceding embodiments wherein the amount of opioid tive, a benzomorphan derivative, a phenylpiperidine, a antagonist that is present is sufficient to provide a dose phenylheptamine, an open chain compound, a diphenyl per unit dosage form of between about 0.1 mg and about propylamine derivative, a mixed agonist/antagonist or 10 mg. another synthetic opioid. 0121 18. A composition as recited in embodiment 17, 0107 4. A composition as recited in embodiments 2 or wherein the amount is between about 1 and about 5 mg. 3, wherein the opioid analgesic is selected from mor 0.122 19. A composition as recited in any one of the phine, codeine, thebaine or a Diels-Alder adduct preceding embodiments, wherein the carrier particles thereof, diamorphine, hydromorphone, oxymorphone, are of a size that is between about 50 and about 1,000 hydrocodone, oxycodone, etorphine, nicomorphine, lm. hydrocodeine, , metopon, normorphine, 0123. 20. A composition as recited in embodiment 19, N-(2-phenylethyl)normorphine, racemorphan, levor wherein the size range is between about 100 and about phanol, dextromethorphan, , cyclorphan, 800 um. butorphanol, nalbufine, cyclazocine, pentazocine, 0.124. 21. A composition as recited in any one of the phenazocine, pethidine (meperidine), fentanyl, alfenta preceding embodiments, which further comprises a bio nil, Sufentanil, remifentanil, , carfentanyl, adhesion and/or a mucoadhesion promoting agent, , piminodine, ethoheptazine, alphaprodine, which agent is, at least in part, presented on the Surfaces betaprodine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri of the carrier particles. US 2013/0195981 A1 Aug. 1, 2013

0.125 22. A composition as recited in embodiment 21, ensure that the carrier particles may be at least about wherein the bioadhesion and/or mucoadhesion promot 90% covered by the opioid analgesic particles. ing agent is a polymeric Substance with a weight average 0.136. 33. A composition as recited in any one of the molecular weight above 5,000. preceding embodiments which is in the form of a tablet I0126. 23. A composition as recited in embodiment 22, Suitable for Sublingual administration. wherein the bioadhesion and/or mucoadhesion promot 0.137 34. A composition as recited in embodiment 33, ing agent is selected from a cellulose derivative, a starch wherein the composition further comprises a disinte derivative, an acrylic polymer, polyvinylpyrrolidone, grating agent. polyethylene oxide, chitosan, a natural polymer, Sclero 0.138 35. A composition as recited in embodiment 34. glucan, Xanthan gum, guar gum, poly co-(methylvinyl wherein the disintegrating agent is selected from ether/maleic anhydride) and crosscarmellose, or a mix crosslinked polyvinylpyrrolidone, carboxymethyl ture thereof starch, natural starch and mixtures thereof. I0127 24. A composition as recited in embodiment 23, 0.139 36. A composition as recited in embodiment 34 or wherein the bioadhesion and/or mucoadhesion promot embodiment 35, wherein the amount of disintegrating ing agent is selected from hydroxypropylmethyl cellu agent is between about 2 and about 7% by weight based lose, hydroxyethyl cellulose, hydroxypropyl cellulose, upon the total weight of the composition. methyl cellulose, ethyl hydroxyethyl cellulose, car 0140. 37. A process for the preparation of a composition boxymethyl cellulose, modified cellulose gum, sodium as defined in any one of embodiments 1 to 36, which carboxymethyl cellulose, moderately cross-linked comprises dry mixing the carrier particles with the starch, modified Starch, Sodium starch glycolate, car opioid analgesic. bomer or a derivative thereof, crosslinked polyvinylpyr 0.141. 38. A process for the preparation of a sublingual rolidone, polyethylene oxide, chitosan, gelatin, sodium tablet as defined in any one of embodiments 33 to 36, alginate, pectin, Scleroglucan, Xanthan gum, guar gum, which comprises directly compressing or compacting a poly co-(methylvinyl ether/maleic anhydride) and composition as defined in any one of embodiments 1 to crosscarmellose sodium, or a mixture thereof. 32. I0128 25. A composition as recited in embodiment 24, 0.142 39. A process as recited in embodiment 38 or wherein the bioadhesion and/or mucoadhesion promot embodiment 39 which further comprises a process step ing agent is crosscarmellose Sodium or crosslinked poly in which the carrierparticles are prepared by a process of vinylpyrrolidone. dry or wet granulation. I0129. 26. A composition as recited in any one of 0.143 40. The use of a composition as defined in any one embodiments 21 to 25 wherein the amount of bioadhe of embodiments 1 to 36 for the manufacture of a medi sion and/or mucoadhesion promoting agent present is in cament for the treatment of pain. the range of about 0.1 to about 25% by weight based 0144. 41. A method of treatment of pain which method upon the total weight of the composition. comprises administration of a composition as defined in 0.130) 27. A composition as recited in embodiment 26, any one of embodiments 1 to 36 to a patient suffering wherein the range is about 1 to about 15% by weight. from, or Susceptible to, such a condition. I0131) 28. A composition as recited in any one of 0145 42. A use as recited in embodiment 40, or a embodiments 21 to 27, wherein the bioadhesion and/or method as recited in embodiment 41, wherein the pain is mucoadhesion promoting agent has a particle size in the severe, acute and/or breakthrough pain. range of about 1 to about 100 um. 0146 43. A use or method as recited in embodiment 42, 0.132. 29. A composition as recited in any one of the wherein the medicament and/or composition is resistant preceding embodiments, wherein the carrier particles to abuse by an opioid addict. further comprise a carbohydrate, a pharmaceutically What is claimed is: acceptable inorganic salt or a polymer. 1. A particulate transmucosal pharmaceutical composition 0.133 30. A composition as recited in embodiment 29, comprising a pharmacologically-effective amount of an wherein the particles comprise Sugar, mannitol, lactose, opioid analgesic, or a pharmaceutically-acceptable salt Sodium chloride, calcium phosphate, dicalcium phos thereof, presented in particulate form upon the Surfaces of phate hydrate, dicalcium phosphate dehydrate, trical carrier particles comprising a pharmacologically-effective cium phosphate, calcium carbonate, barium Sulfate, amount of an opioid antagonist, or a pharmaceutically-ac microcrystalline cellulose, cellulose, crosslinked poly ceptable salt thereof, which carrier particles are larger in size vinylpyrrolidone or a mixture thereof. than the particles of the opioid analgesic, wherein both of said 0.134 31. A composition as recited in embodiment 30, opioid analgesic and said opioid antagonist are delivered wherein the particles comprise mannitol and/or lactose. transmucosally, wherein the opioid analgesic is selected from 0.135 32. A composition as recited in any one of the fentanyl, alfentanil, Sufentanil, remifentanil and buprenor preceding embodiments, wherein the relative sizes and phine, and the opioid antagonist is selected from nalmefene, amounts of the particles of opioid analgesic and the methylmaltrexone, naltrexone and naloxone. carrier particles that are employed are Sufficient to k . . . .