EP2224806A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique

Info

Publication number
EP2224806A1
EP2224806A1 EP08862226A EP08862226A EP2224806A1 EP 2224806 A1 EP2224806 A1 EP 2224806A1 EP 08862226 A EP08862226 A EP 08862226A EP 08862226 A EP08862226 A EP 08862226A EP 2224806 A1 EP2224806 A1 EP 2224806A1
Authority
EP
European Patent Office
Prior art keywords
antagonist
release
naltrexone
opioid
sequestering
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08862226A
Other languages
German (de)
English (en)
Other versions
EP2224806A4 (fr
Inventor
Alfred Liang
Frank Matthews
Garth Boehm
Lijuan Tang
Frank Johnson
Joseph Stauffer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alpharma Pharmaceuticals LLC
Original Assignee
Alpharma Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alpharma Pharmaceuticals LLC filed Critical Alpharma Pharmaceuticals LLC
Publication of EP2224806A1 publication Critical patent/EP2224806A1/fr
Publication of EP2224806A4 publication Critical patent/EP2224806A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • This invention pertains Io composotions and methods useful for treating pain m human patients.
  • One such composition contains both an opioid antagonist and an opioid agonist formulated such that the agonist is released over time with minimal release of the antagonist.
  • OA osteoarthritis
  • OA is the most common form of arthritis in the United States (Hochberg et al., 1995a) ? affecting more than 21 million people. It is a disease of primarily middle-aged and older adults and is a leading cause of disability (American College of Rheumatology, 2000a).
  • OA results from degeneration of the joint cartilage, and usually involves the neck, low back, knees, hips, and fingers. The prevalence of OA of the hip and knee increases progressively with age (Peloso et al., 2000).
  • inflammation if present, is usually mild and localized to the joint.
  • the cause of OA is unknown, but biomechanicaJ stresses affecting the articular cartilage and subchondral bone, biochemical changes in the articular cartilage and synovial membrane, and genetic factors are significant in its pathogenesis (Hochberg et al., 1995b; American College of Rheumatology, 2000b).
  • OA is characterized by pain dial typically worsens with activity and weight bearing and improves with rest, as well as morning stiffness, and pain and stiffness that ease after a few minutes of movement
  • Clinical examination often reveals tenderness to palpation, bony enlargement, crepitus, and/or limited joint motion (American College of Rheumatology, 2000b).
  • OA patients experience increasing pain and loss of function, with pain intruding at periods of rest (Peloso et al., 2000). Since no
  • Nonpharmacologic and pharmacologic tteatme ⁇ for O ⁇ are used in conjunction to reduce pain and to improve functional status
  • Nonpharmacologic therapies include patient education, weight loss (if overweight), occupational therapy, physical therapy, and aerobic exercise psograrm to restore joint and increase strength and aerobic capacity ( American College of Rheumatology. 2000a)
  • the initial pharmacologic therapies for O ⁇ include nonopioid analgesics (e.g.. acetaminophen) and topical analgesics, folkmcd by treatment with nonsteroidal ami- inflammatory drugs (NSAf Ds) and judicious use of intra-articuiar steroid injections (JHoetrherg et al., 1995a).
  • naltrexone Although well absorbed orally, naltrexone is subject to significant first-pass metabolism, with oral bioavailability estimates ranging from 5Vo to 40°' « (Naltrexone H(I 1 ablets. I 1 SP Package Insert) The activity of naltrexone is believed to be due to both the parent compound and the o- ⁇ nalUexol metabolite.
  • ⁇ UC area under the concentration-time curve
  • C nm maximum plasma concentration
  • Kadi an contains polymer-coated extended-release pellets of morphine sulfate, to deliver up to 24 hours of continuous pain relief
  • This formulation lacks an immediate-release component, on Iv prov iding a slow release of the analgesic
  • This slow-release technology serves to mmirmzc plasma peaks and troughs, thereby providing a lelatnelv fiat pharmacokinetic U 3 K) curve upon multiple closing
  • Phis dehxeiy mechanism is ideally suited for chrome pain patients
  • Kadian capsules aie an extended-release oral formulation of morphine sulfate indicated foi the management of moderate to pam when a continuous, atou ⁇ d-the-clock opioid analgesic is needed for an extended pei iod of time
  • Kadian KT (morphine sulfate plus naltrexone hydiochloude extended-release capsules), is a product that is intended to be used as an opiate analgesic for raodeiate to sexeie pam Its abuse-detenence feature incoipoiat.es an immediate release of naltrexone upon illicit manipulation this is intended to neuUalue the euphoric potential of morphine and ui ⁇ ease safetv afici ingestion of the tamp ⁇ cd product If Kadian NT is used as duected.
  • a patient should receive a dose of morphine equivalent to the same n ⁇ dose of Kadi an if the drug pioduct is tampered w ith and ingested b ⁇ a patient who is opioio dependent, the patient may be exposed to a dose of naltiexone sufficient to produce w ithdiawai symptoms
  • Abusc-tesisstant, sustamed-release dosage fomis of products intended to treat pain !ki ⁇ e been described in the ait (see, for ex ⁇ mpfe. V S Application Mos 2003 0124185 and 200 > 0044458) that substantial amounts of the opioid antagonist oi othei antagonist found m these sequesteied f ⁇ ns ase released ume (usual Iv less than 24 hours) due to flic osmotic pressure that builds up m the core of the sequestered form as watei peuneates thiough the sequesieied foim mto the cot ⁇ I he high osmotic pi ⁇ ssute inside the coie of the sequesteied foini causes the opioid antagonist oi antagonist to be pushed out of the sequesteted form, theieby causing the opioid antagonist oi antagonist to be released fiom the sequesteied foim ⁇ s sliuwn below, certain embodiments described hcicin prov ide improved
  • Proxided herein is a pharmaceutical composition
  • a pharmaceutical composition comprising an antagonist, an agonist, a seal coat, and a sequestering polymer, wherein the antagonist, agonist, seal coat and at least one sequestering polymer are all components of a single unit and wherein the seal coat forms a layet physically separating the antagonist from the agonist from one another.
  • the methods described herein prov ide methods fot substantially ielicwng pain (e.g. puruduig an analgesic effect) for time pcuods of at least one week (e.g , two, four, eight, 12, 16. 20, 24, 2S, 32. 36, 40 and 100 weeks) with regular administration ⁇ e.g., once, twice, three or four times daily).
  • Pan ided heiehi are compositions and methods for adn ⁇ nisteting a multiple actne agents to a mammal in a form and manner that minimizes the effects of either acme ayeni upon the other hi vivo
  • at least two active agents are formulated as part of a pharmaceutical composition.
  • a first aclKe agent may pi oxide a therapeutic effect m vivo
  • the second active agent may be an antagonist of the first acme agent, and may be useful in preventing misuse of the composition.
  • the second aethe aj ⁇ etit may be an antagonist of the narcotic
  • the composition remains intact during normal usage patients and the antagonist is not released However, upon tampering with the composition, ⁇ he antagonist rnav be steleased theiet ⁇ presenting the naieotic from hav ing its intended effect.
  • the active agents arc both contained within a single unit, such as a bead, in the form of layers.
  • the acme agents may be formulated with a substantially impermeable barrier as. for example, a co ⁇ trolled-release composition, such that release of the antagonist from the composition is minimized.
  • the antagonist is released in //; assays but is substantially not released m vivo In v ⁇ fro and in vhv release of the active agent from the composition ma ⁇ be measured by any of ⁇ hv ielease may be determined by measuring the plasma levels of the active agent or metabolites thereof ( ⁇ .e, ⁇ U( ⁇ Cmaxl
  • one of the active agents is an opioid receptoi agonist.
  • opioid agonists are commercially available or in clinical ttials and be administered as described herein such that the alcohol effects arc minimized.
  • Opioid agonists include, foi example, alfenta ⁇ il, aily ⁇ piodme, alphapiodine, amie ⁇ dine, bcHzylnio ⁇ hine, bezitramidc. buprenorpliine.
  • butorphanol clonitazene, codeine, cvcla/ocine desomorphsne, dextroinoratnide, dezocine, dianipiomide, dthydrocodeme, ⁇ hydroetorpiurte dihydromorphine, dimenoxadol, dimepheptanoK dimetln ithiambutene, dioxaphetyl butjuue, dipipanone.
  • epta/ocine ethohepta/me, ethyl methylthiarnb ⁇ tene, ethylmo ⁇ hine, etonitazene, etorphine, fentanyi, heroin, hydiocodone, hydromoiphone, hydroxypethidine, isomethadonc kctobenudone, lcv allorphan, levorphanol, lofentani), mepeiidine, mepta/inol, raeta/ocine.
  • the opioid agonist is selected from the group consisting of hydrocodone, bydromorphone, oxycodone, dihydrocodeiue. codeine, dihydromoiphine, morphine, buprenorphme.
  • the opioid agonist is morphine, hydr ⁇ morphone, oxycodone or hydrocodone
  • Eqmanalgesic doses of these opioids, m comparison to a 15 mg dose of hydrocodonc, are as follows oxycodone ⁇ $ 5 mg ⁇ , codeine (90 0 mg ⁇ , hydiocodone ( 15 0 mg), hydromorpho ⁇ e (3,375 n ⁇ K (! 3 ragK meperidine ( 135.0 mg). methadone (90 rag), and morphine l2 7 0 rngh
  • a common dosage form of hydrocodone is in combination w ith acetaminophen and is commercially available, for example, as L ⁇ rtab ⁇ in the United States from UCB Pharara, ⁇ c Belgium! as 2.5 500 mg, 5 500 mg, 7.S/5OO mg and 10 500 rag hydrocodone/ ' acetammophen tablets. Tablets ate also available m the ratio of 7.5 rag hydrocodone bitartrate and 650 mg acetaminophen and a 7.5 mg hydrocodone bitanrate and 750 mg acetaminophen Hydrocodone, in combination with aspirin, is given in an oral dosage form io adults generally in 1 -2 tablets every 4-6 hours as needed to alicxiate pain.
  • Hie tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with 32 mg caffeine, or 5 mg hydrocodone bitartrate ami 500 mg aspirin.
  • Another formulation comprises hydrocodone bitartrate and ibuprofcn Vicopiofen®, cotnnicrc tally available in the U.S. from Knoll Laboratories ⁇ Mount Oine, N.J. ⁇ , is a tablet containing n 5 mg hydiocodone bitartrate and 200 nm ibuprofen lhe invention is contemplated to encompass all such formulations, with the inclusion of the opioid antagonist and or antagonist in sequestered form as part of a subunit comprising an opioid agonist.
  • Oxycodone chemically known as 45-epoxy-I4-hydro ⁇ y-3-methoxy-17- mcthylm ⁇ rphman- ⁇ -o ⁇ e. is an opioid agonist whose principal therapeutic action is analgesia
  • Other therapeutic effects of ONjcodone include anxiolysis, euphoria and feelings of relaxation
  • the precise mechanism of its analgesic action ⁇ s not known, but specific CNS opioid receptors for endogenous compounds with opioid-like aethil ⁇ been identified thioughout the biain and spinal cord and p!a> a role in the analgesic effects of this drug.
  • Oxycodone is commercial iy available in the United States, e.g., as Gxycctiivls horn Purdue Pharma L.P. ⁇ Stamford, Conn.), as control I ed ⁇ rel ease tablets for oral administration containing 10 mg, 20 ing, 40 mu. or 80 mg oxycodone hydrochloride, and as OxylRTM, also from Purdue Pharma L.F., as immediate-release capsules containing 5 mg oxycodone hydrochloride.
  • the invention is contemplated to encompass all such formulations, with the inclusion of an opioid antagonist and'Or antagonist in sequestered form as pan of a subimit comprising an opioid agonist
  • Oral bydroraorphone commercial! ⁇ available in the United States, e.g., as Dilaudid'D from Abbott Laboratories ⁇ Chicago, III), Oral morphine is commercially available in the United States, e.g., as Kadianl' from faulding Laboratories (Piscataway. NJ ⁇
  • the sustained-release oral dosage forms can include analgesic doses from about 8 rag to about 50 mg of hydrocodone per dosage unit.
  • sustained-release oiai dosage forms where iiydromo ⁇ boiie is the therapeutically active opioid it is included in an amount from about 2 mg to about 64 mg hydromorphone hydrochloride.
  • the opioid agonist comprises morphine
  • the sustained-release oral dosage forms of the imetition include from about 2.5 nig to about 800 ⁇ morphine, by weight.
  • the opioid agonist comprises oxycodone and the sustained-release oral dosage forms include from about 2.5 mg to about 800 mg oxycodone.
  • the sustained-release oral dosage forms include from about 20 mg to about 30 mg oxycodone.
  • Controlled release oxycodone formulations are known in the ait. The following documents des ⁇ ibe various control led ⁇ release oxycodone formulations suitable for use in the invention described herein, and processes for their manufacture; U.S. Pat. Nos. 5,266,331 ; 5,549,912; 5,508,042; and 5,656,295, which are incorporated herein by reference.
  • the opioid agonist cart comprise tramadol and the sustained-release oral dosage forms can include from about 25 mg to 800 mg tramadol per dosage unit.
  • another active agent contained within the composition may be an opioid receptor antagonist.
  • the agonist and antagonist are administered together, either separately or as part of a single pharmaceutical unit.
  • the antagonist preferably is an opioid antagonist, such as naltrexone, naloxone, ⁇ almeiene, cycliuaeine, levallorphan, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof.
  • opioid antagonist is naloxone or naltrexone
  • opioid antagonist is meant to include one or more opioid antagonists, either alone or in combination, and is further meant to include partial antagonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof.
  • the pharmaceutically acceptable salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like: alkaline earth metals, such as calcium salt, magnesium salt, and the like; organic amine salts, such as triethyiamine salt pyridine salt, picoline salt, ethanotamine salt, t ⁇ ethanolamine salt, dicyclohexylamine salt, N,N-dibenzyleihylenediarnine salt, and the like; inorganic acid sails, such as hydrochloride, hydrobromidc, sulfate, phosphate, and the like; organic acid salts, such as formate, acetate, trifluoroacelate.
  • alkaline earth metals such as calcium salt, magnesium salt, and the like
  • organic amine salts such as triethyiamine salt pyridine salt, picoline salt, ethanotamine salt, t ⁇ ethanolamine salt, dicyclohexylamine salt, N,N-dibenzyleihyl
  • the amount of the opioid antagonist can be about 10 ng to about 275 nig.
  • the antagonist when the antagonist is naltrexone, it is preferable that the intact dosage form releases less than 0.125 mg or less within 24 hours, with 0.25 mg or greater of naltrexone released after 1 hour when the dosage form is crushed or chewed,
  • the opioid antagonist comprises naloxone.
  • Naloxone is an opioid antagonist, which is almost void of agonist effects. Subcutaneous doses of up to 12 mg of naloxone produce no disce ⁇ iabie subjecihe effects, and 24 mg naloxone causes only slight drowsiness. Small doses (0.4-0.8 mg ⁇ of naloxone given intramuscularly or intravenously in man prevent or promptly reverse the effects of morphine-like opioid agonist. One mg of naloxone intravenously has been reported to block completely the effect: of 25 mg of heroin. The effects of naloxone are seen almost immediately after intravenous administration.
  • the dntg is absorbed after oral administration, but has been reported to be metabolized into an inactive form rapidly in its first passage through the such that it has been reported to have significantly lower potency than when parenteral Iy administered. Oral dosages of more than I g have been reported to be almost completely metabolized in less than 24 hours tt has been repotted that 25% of naloxone admin isteied sublingualis is absorbed (Weinberg ct al, Clin. Pharmacol, flier 44 335-340 U 988))
  • the opioid antagonist comprises naltrexone
  • naltrexone In the tieatmeut of patients iously addicted to opioids, naltrexone has been used in large oral doses (over 100 mg) to prevent eupho ⁇ aenic effects of opioid agonists Naltrexone has been reported to exert strong preferential blocking action against mu over delta sites Naltrexone is known as a synthetic congener of oxymorpho ⁇ e ⁇ Uh no opioid agonist properties, and differs in structure from oxymorprione by the replacement of the methyl group located on die nitrogen atom of oxymorphone w ith a cyciopropyimethyl group The hydrochloride salt of naltrexone is soluble in w afer up to about 100 mg,cc The pharmacological and pharmacokinetic properties of naltrexone have been evaluated m multiple animal and ciimcai studies.
  • naltrexone is rapidly absorbed (within 1 hour) and has an oral bioavailability ianging from 5-40% Naltrexone's protein binding is approximately 21% and the volume of distribution following single-dose administration is 16.1 L ⁇ g
  • Naltrexone is commercially available in tablet form ( Revia ⁇ DuPont (Wilmington, Del )) for the treatment of alcohol dependence and for the blockade of exogenous! ⁇ administered opioids. See, e.g.. ia (naltrexone hydrochioiide tablets), Physician's Desk Reference. 51 * ed . Montvale, N J., and Economic 51 957-059 (1997) A dosage of 50 mg blocks the pharmacological effccb of 25 rag IV administered heroin for up to 24 hours. It is known that, when coadministered with moiphine, heiom OJ other opioids on a chronic of physical dependence to opioids.
  • naltrexone blocki the effects of heroin h by competitively binding at the opioid receptors Naltrexone has been used to treat narcotic addiction by complete blockade of the effects of opioids. It has been found that the most successful use of naltrexone for a narcotic addiction is w ith narcotic addicts good prognosis, as part of a compreheashe occupational or rehabilitathe program involving behavioral control or other compliance- enhancing methods For treatment of naicotic dependence with naltrexone, n is desirable that the patient be opk ⁇ d-fiee foi at least 7-10 days.
  • naltrexone for such purposes lias typically been about 25 tng, and if no withd ⁇ awal signs occur the dosage may be ii ⁇ cascd to 50 mg pei day. A daily dosage of 50 mg is considered to produce adequate clinical blockade of the actions of parenteral ⁇ administered opioids.
  • Naltrexone also has been used for the treatment of alcoholism as an adjunct v, ith social and psychotherapeutic methods.
  • opioid antagonists include, for example, cydazocine and naltrexone, both of which rune cyclopropy t methyl substitutions on the nitrogen, retain ⁇ uich of the «' the ora! route, and last longer, with durations approaching 24 hours after oral administration
  • the antagonist may also be a bitter ⁇ g agent.
  • bittering agent refers to any agent that provides an unpleasant taste to the host upon inhalation and or swallowing ⁇ f a tampered dosage form comprising the sequestering subunit
  • the intake of the tampered dosage form produces a bitter taste upon inhalation or oral administiatio ⁇ , which, in certain embodiments, spoils or hinders the pleasure of obtaining a high from the tampered dosage form, and preferably presents the abuse of the dosage form
  • bittering agents can be employed, including, for example, and without limitation, riatmal, artificial and synthetic flavot oils and flavoring aromaticb and oi oik, oleoiesiiis and extracts derrved from plants, leases, flowers, fruits, and so forth, and combinations thereof.
  • Nonhmiting representative flavor oils include spearmint oil, peppeimint oil, eucalyptus oil, oil of nutmeg, auspice, mace, oil of bittei almonds, menthol and the like.
  • Also useful buttering agents are artificial natural and synthetic fruit flavors such as alms oils, including lemon, orange, lime, and gtapefr ⁇ it, fruit essences, and so forth Additional bitiering agents include sucrose demat ⁇ es (e.g., sucrose octaacetate), ehlorosucrose derh arrves., quinine sulphate, and the like
  • sucrose demat ⁇ es e.g., sucrose octaacetate
  • ehlorosucrose derh arrves. ehlorosucrose derh arrves.
  • quinine sulphate e.g., quinine sulphate
  • a preferred bitteri ⁇ g agent for use in the unention is Denatoninra Beozoate NF- Anhydrous, sold under the name BitrexTM ⁇ Macfarian Smith Limited, Edinburgh, I'Kj.
  • a brttermg agent can be added to the formulation in an amount of less than about 50 1 O by weight, preferably less than about 10% by weight, more preferably less than about 5% b> weight of die dosage form, and most pieferabiy in an amount ranging from about 0 I to LO peicent by weight of the dosage form, depending on the particular bitteiing agent(s) used.
  • the antagonist may be a dye
  • tefers to any agent ⁇ hat causes discoloration of the tissue in contact In this iegaui if (he sequestering subunit is tampered with and the contents are snorted, the dye w ill discolor the nasal tissues and surrounding tissues thereof.
  • Prefe ⁇ ed dyes are those that can bind strongly with subcutaneous tissue proteins and are well-known m the art.
  • D) es useful in applications ranging firom, for example, food coloring to tattooing, are exemplar) dyes suitable for the invention.
  • Food coloiing dyes include, but are not limited to FD&C G teen £ and FD&C Blue 41 , as well as any other F ⁇ ) &C os D&C color
  • Such food aie commercially available through companies, such as Yoigt Global Distribution (Kansas City. Mo.).
  • the antagonist may alternatively be an irritant.
  • the terra 'irritant' 1 as used herein includes a compound used to impart an irritating, e g , burning or uncomfortable, sensation to an abuser administering a tampered dosage form of the invention.
  • Use of an irritant will discourage an abuser from tasnpeitng with the dosage form and thereafter inhaling, injecting, oi swallowing the tampered dosage form
  • the irritant is released when the dosage form is tampered urth and provides a burning or irritating effect to the abuser upon inhalation, injection, and/or swallowing the tampeied dosage form
  • Various irritants can be employed including, for example, and without limitation, capsaicin, a capsaicin analog w ith similar type properties as capsaicin, and the IiIe.
  • capsaicin analogues or derivatives include, for example, and without limitation, lesiniferat ⁇ xm, tinvatoxin, bepianoylisobuty ⁇ araide, bcptanoyl jaiaiacylamkie, othet isobisty S amides or giiamcylamides.
  • Na 4,S l 2,446 describes capsaicin analogs and methods for their preparation Furthermore.
  • U S Pat. No 4,424205 cites Newman, 11 INaUa a! and Synthetic Pepper- Flavored Substances, " ' published m 1954 as listing pungency of capsaiein-l ⁇ ke analogs. Ton et al , Hrit&h J ⁇ untat o/ I'hatvnaa>hg ⁇ ⁇ 10 175-182 (1955), discusses pharmacological actions of capsaicin and its analogs.
  • Suitable capsaicin compositions include capsaicin (tians 8 ⁇ mel1iyl-N ⁇ vanill ⁇ l ⁇ 6-:i ⁇ iieamide) ot analogues thereof in a concentration between about 0 00125% and 50% b ⁇ weight, preferably between about 1% and about 7,5% by weight, and most preferably, between about !°b and about 5% by weight
  • the antagonist may also be a ueUina asent.
  • celling asenf as used herein refers to any agent that prov ides a gel-like quality to the tampered dosage form, which slows the absorption of the therapeutic agent, which is foimulaled with the sequestering subunit, such that a host is less likeh to obtain a rapid '"high "
  • the dosage form when the dosage form is tampeied with and exposed to a small amount (e.g., less than about 10 mt) of an aqueous liquid (e.g., water), the dosage form will be unsuitable for injection and oi inhalation Upon the addition of the aqueous liquid, the tampered dosage form preferably becomes thick and rendering it unsuitable for injection.
  • the term '"unsuitable for injection is defined foi purposes of the .mention to mean that one would have substantia! difficult ⁇ injecting the dosage form (e.g., due to pam upon administration or difficulty pushing the dosage form through a syringe) due to the uscosity imparted on the dosage form, thereby reducing the potential for abuse of the therapeutic agent in the dosage form
  • the gelling agent ss present in such an amount in the dosage form that attempts at evaporation (by the application of heat) to an aqueous mixture of the dosage form in an effort to produce a higher concentration of the therapeutic agent, pi educes a highly ⁇ beous substance unsuitable foi injection.
  • the gelling agent can become gei ⁇ hke upou administration to the nasal passages, due to the moisture of the mucous membranes.
  • This aiso makes such formulations to nasal administration, as the gel w ⁇ l stick to the nasal passage and minimize absorption of the abitsable substance
  • Various gelling agents may can be employed including, for example, and without limitation, sugars or sugar-derived alcohols, such as mam ⁇ tol, sorbitol, and the like, staich and starch deriv atives cellulose dematnes, such as im ⁇ ocrysialline cellulose, sodium caboxymethyl cellulose, methylceil ⁇ lose. ethyl cellulose, hydroxyethyl cellulose.
  • hydroxypiop cellulose
  • hyckoxv propyl metihylceilulose.
  • aitapulgties bentonites, dext ⁇ ns, alginates, catragee ⁇ ao, gum tragacant, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomers and caibopols.
  • the gelling agent is xauthan gum
  • the gelling agent of the invention is pectin, I he pectin or pectic substances useful for this invention include not only purified oi isolated pcctaics but also crude natural pectin sources, such as apple.
  • the pectins used in this invention are derived ftom citrus fruits, such as lime, lemon, grapefruit, and orange
  • the gelling agent preferably imparts a gel-hke quality to the dosage form upon tampering that spoils or hinders the pleasure of obtaining a rapid high from due to the gel-hke consistent; ⁇ of the tampered dosage form in contact with the mucous membrane, and in certain embodiments, prevents the abuse of the dosage form by minimizing absorption, e.g., in the nasal passages
  • ⁇ gelling agent can be added to the formulation m a ratio of gelling agent to opioid agonist of from about 1:40 to about 40' 1 by w eight, preferably from about i i to about 3Oi by weight, and more
  • the dosage fotm forms a gel haung a viscosity of at least about 10 cP after the dosage form is tampered uith by dissolution in an aqueous ⁇ quid (ftom about 0.5 to about 10 ml and pieferably from 1 to about 5 ml) Most preferably, the resulting mixture will ha ⁇ c a viscosity of at least about ⁇ O eP.
  • the antagonist can comprise a single type of antagonist (e g , a capsaicin), multiple forms of a single type of antagonist (e g, a capashi and an analogue thereof), or a combination of different types of antagonists (e g , one or more bittering agents and one or mojte gelling agents).
  • a single type of antagonist e g , a capsaicin
  • multiple forms of a single type of antagonist e g, a capashi and an analogue thereof
  • a combination of different types of antagonists e g , one or more bittering agents and one or mojte gelling agents.
  • the amount of antagonist in a unit of the ⁇ nentkm is not toxic to die host
  • the invention proudes a sequestering subimit comprising an opioid antagonist and a blocking agent, wherein the blocking agent substantially prevents telease of the opioid antagonist ftom the sequestering subumt in the gastioimesiinai tract for a time peiiod that is gieatei than 24 hours.
  • This sequestering subimit is mcoiporated into a single pharmaceutical unit that also includes an opioid agonist lhe pharmaceutical unit thus includes a core portion to which the opioid antagonist is applied.
  • ⁇ seal coat is then optionally applied upon the antagonist Upon the seal coat is then applied a composition comprising the pharmaceutically acthe agent.
  • the term "sequestering subunif as used herein refers to any means for containing an antagonist and presenting or substantially preventing the release thereof in the gastrointestinal tract when intact, i e.. when not tampered with.
  • blocking agent refers to the means by which the sequestering subumt k able to prevent substantially the antagonist from being released
  • the blocking agent may be a sequestering polymet, for instance, as described in greater detail below .
  • the dosage form is orally administered to a host e.g , a mammal (e.g., a human), as Intended.
  • a mammal e.g., a human
  • the blocking agent substantially prevents or pr ⁇ enfs the release of the antagonist to the extent that at least about 80% of the antagonist is prevented from being released from the sequestering subu ⁇ it in the gastrointestinal tract for a time period that is greater than 24 hours.
  • the blocking &gcnt prevents i ⁇ iea& ⁇ of at ieast about 90" n of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours.
  • the blocking agent prevents release of at least about 95" o of the antagonist ftom the seqtiesteting subumt. Most pteferab!> ⁇ the blocking agent pt events ielease of at least about 99% of the antagonist fiom the sequestering subunit in the gastrointestinal tract for a time period ⁇ bat is greater than 24 hours.
  • the amount of the antagonist released after oral administration can be measured in-vjtro by dissolution testing as described in the United States Pharmacopeia (USP26) in chapter ⁇ 7 ⁇ 1 ⁇ Dissolution i-or example, using Q OO mL of 0.1 N HCi, Apparatus 2 ⁇ Paddle ⁇ , 7 5 ⁇ m, at 3? '" C to measure release at times fiom the dosage unit.
  • Other methods of measuring the release of an antagonist from a sequeste ⁇ ng subunit o ⁇ er a given period of time are known m the ait (see e g., USP26).
  • the sequestering subun.it of the invention overcomes the limitation 1 ; of the sequestered forms of an antagonist known in the art in that the sequestering subunit of the invention reduces osm ⁇ tically-d ⁇ ven release of the antagonist from the sequestering subunit. Furthermore, it is believed that the present inventive sequestering subunit reduces the release of the antagonist fur a longer period of time (e.g.. greatci than 24 horns) in companson to the sequestered forms of antagonists known in the art.
  • the sequestered subunit of the invention provides a longer pre ⁇ ention of release of the antagonist is particularly relevant, since precipitated withdrawal could occur after the time for which the therapeutic agent is released and acts It is well known thai the gastrointestinal tract tia ⁇ sit time for indiv iduals ⁇ aries great! within the population, Hence, the residue of the dosage form may be retained in the tract for longer than 24 hours, and in some cases for longer than 48 hours.
  • Ii is further well known that opioid analgesics cause decreased bowel motility, further prolonging gastrointestinal tract transit time
  • the sequestering subunit of the invention is designed to prevent substantially the ieiease of the antagonist when imacl
  • 'imacf is meant that a dosage form has not undergone tampering.
  • tampering is meant to include am manipulation by mechanical, thermal and or chemical means, which changes the physical properties of ⁇ he dosage form.
  • the tampeiing can be, for example, crushing, shearing, g ⁇ nding. chewing, dissolution in a solvent, heating (for example, greater than about 45 a C), or any combination thereof
  • the antagonist is immediately released from the sequestering subimlt.
  • s ⁇ bunit is meant to include a composition, mixture, particle; etc., that can provide a dosage form (e.g., an. orai dosage form) when combined with another sulnmit.
  • the subimit can be in the form of a bead, pellet, granule, spheroid, or the like, and can be combined with additional same or different sub ⁇ nits, in the form of a capsule, tablet or the like, to provide a dosage form, e.g., an oral dosage form.
  • the subun.it may also be part of a larger, single unit, forming part of that unit, such as a layer.
  • the subun.it may be a core coated with an antagonist and a seai coat; this summit may then be coated with additional compositions including a pharmaceutically active agent such as an opioid agonist.
  • the antagonist can be any agent that negates the effect of the therapeutic agent or produces an unpleasant or punishing stimulus or effect, which will deter or cause avoidance of tampering with the sequestering subuntt or compositions comprising the same.
  • the antagonist does not harm a host by its administration or consumption but has properties that deter its administration or consumption, e.g., by chewing and swallowing or by crushing and snorting, for example.
  • the antagonist can have a strong or foul taste or smell provide a burning or tingling sensation, cause a fachrymation response, nausea, vomiting, or any other unpleasant or repugnant sensation, or color tissue, for example.
  • the antagonist is selected from the group consisting of an antagonist of a therapeutic agent, a bittering agent, a dye, a gelling agent, and an irritant.
  • exemplary antagonists include capsaicin, dye, bittering agents and emetics.
  • antagonist of a therapeutic agent is meant any drug or molecule, naturally- occurring or synthetic, that binds to the same target molecule (e.g., a receptor) of the therapeutic agent, yet does not produce a therapeutic, intracellular, or in vivo response
  • the antagonist of a therapeutic agent binds to the receptor of the therapeutic agent, thereby preventing the therapeutic agent from acting on the receptor, thereby preventing the achievement of a "high" in the host hi the instance when the therapeutic agent is an opioid agonist
  • the antagonist whilrat% is an opioid antagonist, such as naluexone, naloxone, naimciene, cyclazacine, dernatnes or complexes thereof pharmaceutically acceptable salts thereof, and combinations thereof.
  • opioid antagonist is naloxone 01
  • opioid antagonist ' ts meant to include one or mote opioid antagonists, either alone oi in combination and is further meant to include partial antagonists, pharmaceutically acceptable salts thereof, steteots ⁇ mors tbeieof etheis thcieof, esters thereof, and combinations thereof
  • pharmaceutically acceptable sails include metal salts, such as sodium salt, potassium salt cesium salt, and the like, alkaline earth metals, such as calcium sait. magnesium salt, and the iike.
  • organic amine salts such as trieth ⁇ lar ⁇ ne !>att, pyiidioe salt, picoline salt, cthanolaminc salt, metlianoiamine salt, dic>clohexylai ⁇ une salt, K N-dsben/ylethyle ⁇ edtarai ⁇ c bah and the like, inorganic acid salts, such as hvdiochioride. hydrobromide.
  • sulfate phosphate, and the like
  • oiganic acid salts such as fo ⁇ nate, acetate, tiifiuoioacetate, maleate, taitiate, and the like
  • sulfonates such as methanesuifbnate.
  • the amount of the opioid antagonist present m sequestered fotm can be about 10 ng to about 275 nig
  • the antagonist is naltrexone, it is ptefeiahle that the intact dosage fomi ieleases less than 0, 125 mg or less vnthm 24 houis, with 0 25 mg or greatci of naltrexone icleased after 1 hour when the dosage form is ciushed or chewed
  • the antagonist can comprise a single type of antagonist (e.g , a capsaicin), multiple forms of a single type of antagonist (e g , a capasm and an analogue theteof), oi a combmatiofl of diffeient types of antagonists (e g , one oi moie hiUe ⁇ ng agents and one oi more gelling agents)
  • a single type of antagonist e.g , a capsaicin
  • multiple forms of a single type of antagonist e.g , a capasm and an analogue theteof
  • oi a combmatiofl of diffeient types of antagonists e g , one oi moie hiUe ⁇ ng agents and one oi more gelling agents
  • the amount of antagonist in the sequestering sobunit of the invention is not toxic to the host
  • the blocking agent cuts or substantially cuts the release of the antagonist in the gastiouHestinal tract foj a time peu ⁇ d that is gteatet than 24 houis, e g , between 24 and 25 hours. 30 hours. 35 hours. 40 hours 45 hours, 48 hours, 50 hours 55 houis. 60 hours, 65 kouis. 70 hoius, 72 houis, 75 htiuTs. 80 houis, 85 houis, 90 hours. 95 hours o? 100 hours, etc.
  • the time pe ⁇ od for which the release of the antagonist is prevented 01 substantially presented in the gastrointestinal tract is at least about 48 hours More preferably, the blocking agent prevents or substantially prev ents the release for a time period of at least about 72 hours
  • the blocking agent of the present sequestering siibunit can be a system comprising a first antagonisi-rmpe ⁇ neabfe material and a core "'antagotnst- impermeable material " ' is meant any materia! that is substantially impermeable to the antagonist, such that the antagonist is substantially not released from the sequestering subunit I he term ''substantially rmpenn ⁇ able " as used herein does not necessa ⁇ l ⁇ imply complete or 100% impermeability.
  • the antagonist- impermeable material substantially presents or pme ⁇ ts the release of the antagonist to an extent that at least about 80% of the antagonist ts prevented ftom being released from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours.
  • the a ⁇ tagonist-impeimeable material prevents release of at least about 90% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours More preferably, the antagonist-impermeable material prevents ieiease of at least about 95° « of the antagonist from the sequestering subunit Most pieferably, the antagonist-impermeable material release of at least about 99% of the antagonist from the sequesteung subunil m the gastrointestinal tract for a time period that is greater than 24 hours.
  • tiie autagonisi-mipeimeabie material prevents ⁇ r substantialii the release of the ad ⁇ ersne agent ftom the sequestennit subunit for a time period of at least about 72 hours
  • the first antagonist-impermeable material comprises a hydrophobic material, such that the antagonist is not released or substantially not released during its ttansit tbough the gasfiointestinai tiact when ad ⁇ iinisieied orally as intended, without having been tampered with Suitable hydrophobic materials for use in the invention are described herein and sd forth below
  • the hydrophobic material is prefeiably a pharmaceutical!) acceptable hydiophobic material P ⁇ eferahk, the pharmaceutically acceptable hydrophobic material comprises a celiutose poh mer.
  • the first antagonist-impermeable material comprises a polymei insoluble in the gastrointestinal tract.
  • a polymer that is insoluble m the gastrointestinal tract will prevent the release of the antagonist upon ingestion of the sequestering s ⁇ bunit I foe polymer can be a cellulose or an acrylic polymer
  • the cellulose is selected from the group consisting of ethyfcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, and combinations thereof
  • btln lcelhilose includes, for example, one that has an ethoxy content of about 44 to about 55 0 O.
  • Ethylcelluiose can be used in the form of an aqueous dispersion, an alcoholic solution, or a solution in other suitable sohents.
  • the cellulose can ha ⁇ c a degree of substitution I D. S ⁇ on the anhydroglucose unit, from greater than £ ⁇ iio and up to 3 inclusive.
  • degree of substitution is meant the aveiage number of hydroxy! groups on the anhydro. glucose unit of the cellulose polymer that are replaced by a substituting group.
  • Representative materials include a polymer selected from the group consisting of cellulose acylate. cellulose diacylate.
  • cellulose vriaevSate cellulose acetate, cellulose diacetate, cellulose triacetate, monocelhii ⁇ se alkanylate, diceSlulosc alkanylate, tucelSulose alkaaj late, monocellulose alk ⁇ n lates, dicellulose adenylates, t ⁇ eellulose alkcnylates, monocellulose aro ⁇ latcs, dicellulose aroylates, and tricellulose ar ⁇ ylatcs
  • More specific celluloses include cellulose propionate having a D S of 1 S and a propyl content of 39.2 to 45 and a hydroxy content of 2,8 to 5.4%; cellulose acetate butyrate ha ⁇ iug a D.S of LS 1 an acetyl content of 13 to 15° a and a butuyl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content of 17 to 53% and a hydroxy content of 0 5 to 47%, cellulose triacj late hav ing a D S of 2$ to 3, such as cellulose triacetate, cellulose tmalerate, cellulose trilaurate.
  • cellulose tripatmitatc, cellulose trisuccioate, and cellulose trioctan ⁇ ate cellulose diacylatcs having a D.S of 2.2 to 2 6.
  • cellulose disuccioate, cellulose dipalmitate cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose such as cellulose acetate but ⁇ rate, cellulose acetate octanoate vafytate, and cellulose acetate p ⁇ op ⁇ nate.
  • Additional cellulose polymers useful for pieparing a sequestering suhur ⁇ t of the invention includes aeetaldehyde dimethyl cellulose acetate, cellulose acetate ethyfcarbamate, cellulose acetate methycarbamate and cellulose acetate dimethylaminocei lulose acetate
  • the acrylic polymer preferably ts selected from the group consisting of r ⁇ ethacryhc polymers, acry lic acid and mefhacrylic acid copolymers, methyi metrsaciylate copolymers, ethoxyethyl mothacryiates, cya ⁇ oetliyi methacrylate.
  • pol ⁇ (acrylic a ⁇ d ⁇ poh(raethacryi?c acid), methacryiic acid a ⁇ kylarmde copolymer, poly ⁇ mcthyl methacryiateK polymethacryiatc, poly(methyl methacrylatei copoly mer, polya ⁇ ylamsde, a ⁇ unoalkyi methac ⁇ ylate copolymer, po!y ⁇ methacryiic acid anhydride), glycidyi methacrylate copolymers, and combinations thereof.
  • An aenlie polymer useful for preparation of a sequestering sub ⁇ r ⁇ f of the imention includes awjlic resins comprising copolymers synthesized from acrylic and methacryiic acid esters ⁇ c g , the copoKnici of aery Hc acid lower aikyi ester and raeihacryhc acid lower alky! ester) containing about 0,02 to about 0 03 mole of a rri (Sower alkyl) ammonium group per mole of the acrylic and methacryhc monomer used.
  • a suitable acrylic resin is amnionic methacrvlate copolymer NF2L a polymer manufactured by Rohm Pharma GmbH, Darmstadt, Germany, and sold under the Eudnigik ⁇ trademark Tudragit RS30D is prefeired hudrauitO ⁇ is a water-insoluble copolymer of ethyl acrylaie (HA), methyl methaciylatc (MM) and tnmethylaimnonimnetiiyl methacrvlate chloride (TAM) in which the molar ratio of TAM to the remaining components (FA and MM) ⁇ s I 40
  • Acrylic resins such as Eudi'agitl-, can be used in the form of an aqueous dispersion or as a solution in suitable solvents
  • the antagonist-impermeable material is selected from the group consisting of polylactic acid, poiygiycolic acid, a co ⁇ polj mer of poiylactic acid a «d poiygiycolic acid, and combinations thereof,
  • the hydrophobic material includes a biodegradable polymer comprising a polytlactic glycolic aeid) ⁇ '"P ⁇ .GA"'), a polylactide, a polyglycokle, a polyanhydtide. a poiycaprolac tones, polypbosphazenes. polysaccharides, proteinaceous polymers.
  • the biodegradable polymer comprises a poly (lactic glycolic acid), a copolymer of lactic and glycolic acid, having ft molecular weight of about 2,000 to about
  • the ratio of lactic acid to giycoiie acid is preferably from about 10Oi to about 25:75, with the ratio of lactic acid to glycolic acid of about 65,35 being more prefer ⁇ ed
  • Poly(lactic glycolic acid) can be prepared by the procedures set forth in I 5 S Pat No 4,293,539 ⁇ Ludvv ig ct al ). which is incorporated herein by reference
  • I udwig prepares the copolymer by condensation of lactic acid and glycolic acid in ⁇ be presence of a readily removable polymerization catalyst (e.g . a strong ion-exchange resin such as Dowex HCR- W2-H)
  • a readily removable polymerization catalyst e.g a strong ion-exchange resin such as Dowex HCR- W2-H
  • the amount of catalyst is not critical to the polymerization, but typically is from about 0.0] to about 20 part?, by weight re lathe to the total weight of combined lactic acid and giyc ⁇ lic acid.
  • the polymerization reaction can be conducted without solvents at a temperature from about 10CP C.
  • Suitable plastickers for example, acetyl triethyi citrate, acetyl triburvl citrate, triethyl curate, diethyl phthalate, dibutv l phthalate. or ⁇ biitvl sebacate, also can be admixed with the polymer u ⁇ ed to make the sequestering subunit.
  • Addit ⁇ es. such as coloring agents, talc and/ ⁇ r magnesium stearate, and othei additives also can be i ⁇ ;>ed in making the present inventive sequestering subunit
  • additiv es may be included m the compositions to imprm e the sequestering characteristics of the sequestering subunit ⁇ s deset ibed below , the ratio of additives or components with respect to other additiv es or components may be modified to enhance or delay improve sequestration of the agent contained within the subunit
  • a functional additiv e i.e.. a charge-neutralizing additive
  • a water-soluble core i.e.. a sugar sphere
  • a swfactant may serve as a charge-neutralizing Such neutralization may in certain embodiments i educe the swelling of the sequestering poKmer by hydration of positively charged groups contained therein.
  • Surfactants s ionic or non-ionic) oiay also be used in preparing the sequestering subunit It is preferred that the surfactant he ionic Suitable exemplary agents include, for example, alkylary! sulphonates, alcohol sulphates, sulphosuccmates, sulphosuccinamates. sarcosi ⁇ ates or taurates and others.
  • Additional examples include but are not limited to ethoxylated castor oil, ben/aikonmni chloride, poSyglycoiyzed glyce ⁇ des acerylated rnonoglyce ⁇ des, sorbitasi fatty acid esters, poloxamers, polyc ⁇ yethylene fatty acid esters, polyox ⁇ ethylene derivatives, moaoglycerides or ethoxylated derivatives thereof, dighce ⁇ des or poK'oxycthylene derivatives thereof, sodium docusate, sodium lauryl sulfate, dioct ⁇ ⁇ sodium sulphosuccinate, sodium lauryl sarcosinate and sodium methyl cocoyl taurate, magnesium lauryl sulfate, t ⁇ ethanolarnine.
  • cetrimide sucrose laurate and other sucrose esters, glucose (devtiose) estei.s, .simethicone, ocoxv ⁇ ol, di ⁇ ctyl sodiumsiilfosuceinate, poiyglycolyzed giycerides, sodiumdodecylbenzene sulfonate. dialkyl sodmr ⁇ siilfosuccmatc, fatty alcohols such as lauryl. cetyl, and ster ⁇ Lglyceryl esters, cholic acid or derivatives thereof, lecithins, and phospholipids. These agents are Upicaily ehatacten/ed as ionic (i e .
  • anionic or catio ⁇ ic) oi nonionic In ccttain einbodiinenls described herein, ant anionic surfactant such as sodium iaurxl sulfate (SLS) is preferably used (U S. Pat. No. 5,725,883; U.S. Pat Ko. 7,201,920, EP 502642A1; Shokri et al. Pharra Sci. 2003. The effect of sodium loury!
  • SLS sodium iaurxl sulfate
  • Sl. S is particularly useful in combination with Fudragit RS when the sequestering subunit is built upon a sugar spheie substrate.
  • SI S at iess than approximately 6 3% on a basis ieiatKe to the sequestering poly met may provide a chaige neuUaSi-dng function (theoretically 20% and 41% neutralization, respectfulh), and thereby significantly slow the release of the acme agent encapsulated thereby (i.e.. the antagonist naltrexone), Inclusion of more than approximately 6 3% SLS relativ e to the sequestering polymer appears to increase release of the antagonist from the sequestering subimit.
  • SLS used m conjunction w ith Kudragit x RS, it is piefe ⁇ ed that die SLS is present at approximates) 1 %, 2V 3%, 4 c !o ot 5 0 O. and typically less than 6% on a w w basis ieiatne to the sequestering polymer ⁇ i e.. Eudragit' RS).
  • SLS may be present at approximately Lt% or approximately 3 3*?O ielame to the sequestering polymer
  • agents i e., soifactants
  • u&cful agents include those that may physically block migration of the antagonist from the subun.it and / or enhance the hydrephohiciiy of the barrier.
  • One exemplary agent is talc, which is commonly used in pharmaceutical compositions (Pawar et al Agglomeration of Jbf ⁇ rqfen With Talc by Xovel ( rystallo-Co- ⁇ ggbwcnrtion fevln ⁇ que ⁇ AFS PharmSci Tech. 2004; 5(4)- article 55). As shown in the Examples, talc is especially useful where the sequestering subunit is built upon a sugar sphere core.
  • talc ⁇ n> form of talc be used, so long as it does not detrimentally affect the function of the composition
  • Most talc results from the alteration of dolomite (CaMg(CO ⁇ h or magnesite (MgO) in the presence of excess dissolved silica (SiO;) oi by altering serpentine or quartzite Tale may be include minerals such as trcmolite ( CaMgI(SiOOO, seipenline J 3MgO 2S?0; 2 ⁇ R ) )_ anthophylhie ( Mg- (OHb ( SMOH):), magoesite.
  • talc mica, chlorite, dolomite, the caicite form of calcium carbonate (CaCOO- iron oxide, carbon, quart/, and - or manganese oxide.
  • the presence of such impurities may be acceptable m the compositions described herein provided the function of the talc is maintained, ⁇ t is preferred that that talc be USP grade.
  • the function of talc as described herein is to enhance the hydrophobic ⁇ and therefore the functionality of the sequestering polymer.
  • Mam substitutes for talc may be utilized in die compositions described herein as may be determined b ⁇ one of skill in die art It has been determined thai the ratio of taic to sequestering polymer may make a diamatic diiVeience m the functionality of the compositions described hoi em.
  • the Fxamples described below demonstrate that the taic to sequestering polymei ratio ( ⁇ i ⁇ ) is important with respect to compositions designed to present the release of naltrexone therefrom, it is shown therein that inclusion of at) equiv alent amount (on a weight-In -weight basis) of talc and E ⁇ tdragit ⁇ RS results m a very low naltrexone release profile in contrast, significantly km ei oi higher both a lower ⁇ 69 IS ⁇ Wu) and a lnghei ( 151% w w) RS ratios result in increased release of naltrexone ielcase Thus, where talc and Eudragit* RS are utilized, it is preferred that talc is present at approximately 75%.
  • the most beneficial ratio for other additives or components will vary and may be determined using sHindaul experimental procedures in certain embodiments, such as where a watet-soiuble coie is utilised, ii is useful to include agents that may affect the osmotic pressure of the composition (i.e , an osmotic pressure regulating agent) (see, m general WO 2005 046561 A2 and WO 2005/046649 ⁇ 2 relating to fcudfamode*).
  • osmotic pi cssiit e iegiilatitig agent is pieferabl) positioned immcdiatclj beneath the actne agent layci.
  • Suitable osmotic press ⁇ ie regulating agents may include, foi instance, hydrox>piOpy!mcthyi cellulose ⁇ HPMC) or chloride ions (i.e . from NaCl), or a combination of !
  • HPMC may have a molecular weight ranguig from about 10,000 to about L500.000. and typicalh from about 5000 to about ⁇ 0,000 (low molecular weight HPMC).
  • the specific of HPMC is typically from about I ! *? to about 1 31, with an .specific giaw.y of about 1 26 and a v iscositv of about 3600 to 5600.
  • HPMC may be a water-soluble synthetic polymei. Examples of suitable.
  • lcelluiose polymers include Methocel R lOO LV ami Mclhocel K4M (Dow).
  • Othci IiPMC addithes arc known in the art and may be suitable ui preparing the compositions described herein ⁇ $ shown in the Examples, the inclusion of NaCl (w ith HPMC) was found to have posifrveh affect sequestration of RS in certam embodiments, it is preferred ihai the charge- neutraliziog addstne ⁇ i e.. KaC i) is included at less than approximately I 2, 3. 4, 5. 6, 7.
  • a sequestering subunit buiit upon a sugar sphere substrate is prov ide d comprising a sequestering polymei ⁇ ?
  • the therapeutic agent of the present inventive compositions can be any medicinal agent used for the treatment of a condition or disease, a pha maceutically acceptable salt thereof, or an analogue of either of the foregoing
  • the therapeutic agent can be, for example, an analgesic (e g , an opioid agonist, aspirin, acetaminophen, nonsteroidal aoti-mflarar ⁇ aton drags ("NSAIDS”), N-meth>l-D-aspartate (“"NMDA”) receptor antagonists eycooxjgenase-II inhibitois pCO ⁇ -H inhibitors”), and gi) curse ieceptor antagonists), an antibaeteiial agent an agent, an anti-microbial agent,
  • an analgesic e g , an opioid agonist, aspirin, acetaminophen, nonsteroidal aoti-mfl
  • the therapeutic agent is one that is addicth e (physically and/or psychologically) upon repeated use and typically leads to abuse of the thesapeutic agent, In ibis regard, the therapeutic agent can he M ⁇ y opioid agonist as discussed herein
  • the therapeutic agent can be an opioid agonist.
  • 'Opioid ' ' is meant to include a diug. hormone. 01 other chemical ot biological substance, natural or synthetic, having a sedat ⁇ e, narcotic, or otherwise simiiai effect(s) to those containing opium or its natural or synthetic derivatives
  • opioid agonist,' sometimes used herein interchangeabi ⁇ with terms “opioid 1” and ' " opioid analgesic, " is meant to include one or more opioid agonists, either alone or in combination, and is tbrther meant to include the base of the opioid, mixed or combined agomsi-amag ⁇ nists, partial ago ⁇ isb, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof.
  • Opioid agonists include, for example, alfentantl, alls Iprodi ⁇ e. alphapiodine. anileridine, henzylmurphme, bezitramide, buprenorphine, butorphanol, domtazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromtde, dihvdrocodeiiie dilrydroetorphinc, dihydinmorphine, dimcnoxadol, dimcphcptanol, dimethylthiambutene, dioxaphetv! butyrate.
  • the opioid agonist is selected from the group consisting of hydrocodone, hydromoi phone, oxycodone, di ⁇ n drocodeme, codeine, dih> dromo ⁇ hine, morphine, buprenorphine, or complexes thereof, pharmaceutical!) acceptable salts thereof, and combinations theieof Most prefejabh, the opioid agonist is morphine, hydtoniorphone, oxycodone or hydrocodone. in a ptei ' e ⁇ ed embodiment, the opioid agonist compiles oxycodone or hydrocodcme and is present in the dosage form in an araoimt of about ! 5 to about 45 mg, and the opioid antagonist compnses naltrexone and is present in the dosage form in an amount of about 0.5 to about 5 mg
  • Hydtocodoiie is a semisynthetic narcotic analgesic and antitussive with multiple nervous system and gastrointestinal action?. Chemically, hydrocodone is 4.5 ⁇ e ⁇ oxy-3- r»etlioxy-17 ⁇ tnethyhnorphinan-A-one, and is also known as dihydrocodeiiione ⁇ ike other opioids, hydrocodone am be habit-forming and can produce drug dependence of the morphine type. Like other opmm h ⁇ drocodone will depress i aspiration.
  • Oral tndfocodone is also available in Europe (e.g , Belgium, Germany, Greece. KaI) , Luxembourg, Norway and Swit/edaud) as an antitusshe agent
  • a pendederal formulation is also av ailable in Germany as an antitussive agent For use as an analgesic,
  • ⁇ common dosage form of h ⁇ d ⁇ ocodone is m combination with acetaminophen and is commeieially a ⁇ atlable, foi example, as I onab4* m the. United Slates from LUB Phaima, inc (Btussels, Belgium), as 2 5/500 mg ?
  • Owcodono chemicalh known as 7 - is an opioid agonist whose p ⁇ nc ⁇ al therapeutic action is analgesia
  • Othei therapeutic effects of oxycodone include anxiohsis euphoria and feelings of iciavatson.
  • the piecibo mechanism of us analgesic action is> not known but specific CNS opioid receptors for endogenous compounds with opioid-hke acttsity been identified throughout the biain and spmai cotd and pla) a ⁇ ole ⁇ n the analgesic effects of this di ug Oxycodone ss eommcicuilh a% as!
  • Oxx lRTM 40 nig or 80 nig oxycodone hydrochloride, and as Oxx lRTM, also from Puidue Phaima L P as tminediate-telease capsules containing 5 mg oxycodone indrochJorsde f lie un entjon is contemplated to encompass all such fotmulatious with the inclusion of an opioid antagonist and ot antagonist m sequesteied form as pan of a subunit composing an opioid agonist Oral hydiomoiphone is commercially in the United States, e g,, as Dilaiidid-I; from Abbott Laboratories ⁇ Chicago, III ⁇ . Ota!
  • morphine is conimeiciaily in the United States, e g , as Kadiaiv ⁇ from Fauldmg Laboratories ( Pbcataway, NJ.), hxemplary NS ⁇ iDS Include ibuprofen, diclofenac, naproxen, flurbiprofen, fenoprofen. flubufen, ketoprofen, indoprofen, piroprofen, carprofen. oxapio/in, pramoprofcn, nu ⁇ oprofe ⁇ , trioxaprofen, stiproten. aminoprofcn, tiaprofemc acid, fiuprafen. bucloxic acid, indomettaaem.
  • Exemplary NMDA receptor medicaments include moiphmans, such as dcxotronicthorphan or dextrophan, ketaminc, d-methadone, and pharmaceutically acceptable baits tbe.eof, and encompass dmgs that block a major intfaccilukr consequence of NMD ⁇ -receptor actuation, e.g though a gaiiglioside, such as (6-ammothexyU- 5-chloro-l -naphtbaienesuifbnamide.
  • moiphmans such as dcxotronicthorphan or dextrophan, ketaminc, d-methadone, and pharmaceutically acceptable baits tbe.eof, and encompass dmgs that block a major intfaccilukr consequence of NMD ⁇ -receptor actuation, e.g though a gaiiglioside, such as (6-ammothexyU- 5-chloro-l -n
  • narcotic analgesics such as moiphinc, codeine, etc in U S Pat Nos 5,321 012 and 5,556,838 (both to Mayer cl al ), both of which are incorporated herein by leference. and to tieat chronic pain in U S Pat. No. 5.502,05 S (Mayer et a!.), incorporated herein bv reference.
  • the N MDA agonist can be included alone or in. combination with a ⁇ oca! anesthetic, t>uch as lidocame, as described m these patents by Ma ⁇ er et al.
  • COX- 2 inhibitor include celeco. ⁇ b (SC-58o35X DL'P-697, OosuHde (C ⁇ iP-28238), meloxicam, 6-methoxy-2-naphth ⁇ lacetic acid (6-NMA), V ⁇ K-966 (also known as Vioxx). nabumetone ⁇ pjodrug fo ⁇ 6-MNA), nimesuhde, NS-398. SC-5766. SC-5S215. " 1-614. o» combinations thereof.
  • COX-2 inhibitoi on the oidei of tiorn about 0.005 iiig to about 140 rag per kilogram of body weight per day been shown to be therapeutically effective in combination with an opioid analgesic.
  • about 0 25 mg to about 7 g per patient per day of a COX-2 inhibitor can be administered in combination with an opioid analgesic.
  • the treatment of chrome pain ⁇ ia the use of glycine receptor antagonists and the identification of such drugs is described in ILS. Pat. No. 5,5 S 4,6BO (Weber et al ). which is incorporated herein by reference.
  • K acceptable salts of the antagonist or agonist agents discussed hciein include metal salts, such as sodium salt, potassium salt, cesium salt, and the like, alkaline earth metals, such as calcium salt, magnesium salt, and the like; organic amine salts, such as t ⁇ ethviamine salt, pyridine salt, picolme salt ethanolamine salt, methanoiamine salt, ⁇ cyclohexUaramc salt, N,N' ⁇ diben/ylcthylenedtam ⁇ ne sail, and the like; inorganic acid salts, such as hydrochloride, hvdrobromide, sulfate, phosphate, and the like: organic acsd salts, such as foimate.
  • metal salts such as sodium salt, potassium salt, cesium salt, and the like, alkaline earth metals, such as calcium salt, magnesium salt, and the like
  • organic amine salts such as t ⁇ ethviamine salt, pyridine salt, picolme salt ethanolamine salt
  • acetaie trifluot ⁇ aeetate, maieaie, taruatc, and the like
  • sulfonates such as methanes ⁇ lfonate, benzenesitlfonate, p-tolueaesulfonate, and the like
  • amino acid salts such as argmate. asparginate, glutarnate, and the like
  • the sustained-relcavc oial dosage forms car? include analgesic doses from about 8 mg to about 50 mg of hydiocodone pet dosage unit, In sustained-release oial dosage foims where hydromorphone is the therapeutically active opioid, it is included m an amount from about 2 mg to about 64 mg bydromorphonc hydrochloride
  • the opioid agonist comprises morphine
  • the sustained-release oral dosage forms of the invention include from about 2.5 mg to about SOO mg morphme. by weight
  • the opioid agonist comprises oxycodone and the sustained-release oral dosage forms include from about 2 5 nig to about HOO mg oxycodone.
  • die sustained-release oral dosage forms include fioni about 20 mg to about 30 mg oxycodone
  • Controlled release oxycodone formulations are known in the ait
  • the following documents describe various conti oiled-release oxy codone formulations suitable for use in the invention described herein, and processes for their manufacture.
  • the opioid agonist can comprise uamadol and the sustained-ie ⁇ ease oral dosage foims can include fiom about 25 nig to 800 mg uamadol par dosage unit.
  • Spheroids oi beads, coated ⁇ ⁇ h an active ingredient can be piepaied for example, by dissoh mg the acme ingiedient in water and then spra>mg the solution onto a sohstsate, for example, n ⁇ pane! 18 20 beads, lining a Wurster insert.
  • the resulting substtate-activc material optionally can he ovcicoated with a bamei material to separate the therapeutical Iv actne agent from the next coat of material e.g , ⁇ e-!eas>e- ⁇ eta ⁇ d» ⁇ g material Pieteiably, the batriei mateiial ib a matetial comptisi ⁇ g methj lcef ttilose
  • the barrier material does not affect the dissolution rate of the final product
  • Pellets comprising an actne ingredient can be prepared, for example, by a melt pclleti/ation technique Typical of such techniques is when the actne mgiedierst in finely divided foira Ls combined with a bmdei (also m paniculate foim) and olbei optional inert ingredients, and thereafter the mixture is pcllchzed. e.g . by mechanically the mixture in a high shear mixei io form the pellet (e g.. pellet, gia ⁇ ule&, spheres, heacta. etc .
  • a melt pclleti/ation technique Typical of such techniques is when the actne mgiedierst in finely divided foira Ls combined with a bmdei (also m paniculate foim) and olbei optional inert ingredients, and thereafter the mixture is pcllchzed. e.g . by mechanically the mixture in a high shear mixei io form
  • Suitable binder substances include for example, h) dr ⁇ genated castoi oil, hydrogemited vegetable oil, other hjdrogenated fats, fatty alcohols. fatt> acid esters, fatty acid glycetides, and the like.
  • the diameter of the extruder aperture or exit port also can be adjusted to vary the thickness of the extruded stiands Fiirtheunoie, the exit part of the extruder need not be round; it can be oblong, rectangular; etc fhe exiting strands can be reduced to particles using a hot ⁇ ire Bingoi , guillotine, etc
  • the melt-extruded multiparticulate system can be, fot example in the form of gianules. spheroids, pellets, 01 the like, depending upon the extruder exit orifice.
  • melt-extruded and " 'melt-extruded multiparticulate system(s) "1 and melt-extruded particles” are used interchangeably herein and include a plurality of subunits. preferably within a range of similar si/e and'or shape
  • the melt-extruded multiparticulates are preferably in a range of from about 0.1 to about 12 mm in length and c a diameter of from about O. I to about 5 mm in addition, the melt-extruded multiparticulates can be any geometrical shape within this ssze range. Alternately the extredate can simply be cut into desired lengths and div ided into unit doses of the therapeutically active agent without the need of a spheronization step.
  • the substrate also can be prepared via a granulation technique
  • rnelt- granulation techniques invoke melting a normally solid hydrophobic material, e g , a wax, and incorporating an acm e ingredient therein.
  • a coatmg composition can be applied onto a substrate by spraying it onto the substrate using any suitable spraj equipment.
  • a W ⁇ rstcr fiuidized-bed system can be used m which an air flow from underneath. fjuidizes the coated material and effects drying, while the insoluble poiymci coating is sprayed on
  • the thickness of the coating will depend on the characteristics of the particular coating composition, and can be determined by using routine experimentation
  • a su bun it in the form of a pellet or the like can be prepared by co-extruding a material c ⁇ mp ⁇ siug the opioid agoinst and a material comprising the opioid antagonist and/or antagonist in sequestered form.
  • the opioid agonist composition can cover, e.g , ov ercoat, the material comprising the antagonist and or antagonist in sequestered form.
  • ⁇ bead for example, can be prepared by coating a substrate comprising an opioid antagonist and ' Or an antagonist in sequestered form with a solution comprising an opioid agimist.
  • the sequestering subunits of the are particularly well-suited for use in compositions comprising the sequestering suhunit and a theiapeutic agent in re ⁇ easable form.
  • the invention also prov tdes a composition comprising any of the sequestering subunits of the invention and a therapeutic agent in releasabie form.
  • Yeleasable form is meant to include immediate release, intermediate release, and sustained-release forms.
  • the therapeutic agent can be formulated to provide immediate release of the therapeutic agent, in preferred embodiments, the composition provides sustained-release of the therapeutic agent
  • the therapeutic agent in sustained-release form is preferably a particle of therapeutic agent that is combined with a release-retarding material.
  • the release-retarding material is preferably a material that permits release of the therapeutic agent at a sustained rate in an aqueous medium.
  • the release-retarding material can be selectively chosen so as to achieve, in combination with the other stated properties, a desired in vitro release rate.
  • the oral dosage form of the invention can be formulated to provide for an increased duration of therapeutic action allowing once-daily dosing.
  • a release-retarding material is used to provide the increased duration of therapeutic action.
  • the once-daily dosing is provided by the dosage forms and methods described in U.S. Patent Application Pob. No. 20050020613 to Boehm, entitled “Sustained-Release Opioid Formulations and Method of Use. " filed on Sep. 22, 2003, and incorporated herein by reference.
  • Preferred release-retarding materials include acrylic polymers, alkylceJluloses, shellac, zein. hydrogenated vegetable oil, hydrogenated castor oil, and combinations thereof.
  • the release-retarding material is a pharmaceutically acceptable acrylic polymer, including acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl rnethacryiates, cynao ⁇ thyi methacryiate, aminoaikyi methacrylate copolymer, polytacrylic acid), poly(methacryi ⁇ c acid), methacrylic acid aikylamide copolymer, poly ⁇ methyl methacrylate), poiyjmethacrylic acid anhydride), methyl metha ⁇ ylate, polymemacryiate, poly(methyi methacrylate) copolymer, poiyacrylamide, aminoaikyi merhacrylate copolymer, and j
  • die acrylic polymer comprises one or more ammonio r ⁇ ethacryiate copolymers.
  • Ammonio methacrylate copolymers are well-known in the art, and are described in NRUl 1 the 21"' edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. (Rockvili ⁇ , Md.), as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary aoimonium groups.
  • the release-retarding materia! is an alkyl celSul ⁇ sic material, such as ethyicelhilose.
  • cellulosie polymers including other alky! cellulosic polymers, can be substituted for part or all of the ethylcellulose.
  • the release-modifying agent functions as a pore-former.
  • the pore-fcrmer can be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
  • the pore-former can comprise one or more hydrophilic polymers, such as hydroxypropylmethylcelluiose.
  • the release- modifying agent is selected from hydroxypropylmethylcellulose, lactose, .metal stearates, and combinations thereof.
  • the release-retarding material can also include an. erosion-promoting agent, such as starch and gums; a release-modifying agent useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain; and/or a semipermeable polymer.
  • an erosion-promoting agent such as starch and gums
  • a release-modifying agent useful for making microporous lamina in the environment of use such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain
  • a semipermeable polymer such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain.
  • the release-retarding material can also include an exit means comprising at least one passageway, orifice, or the like.
  • the passageway can be formed, by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; »044,088,864, which are incorporated herein by reference.
  • the passageway can have any shape, such as round, triangular, square, elliptical, irregular; etc,
  • Ae therapeutic agent in sustained-release form can include a plurality of substrates comprising the active ingredient, which substrates are coated with a sustained-release coating comprising a release-retarding material
  • the sustained-release preparations of the invention can be made in conjunction with any multiparticulate system, such as beads, ion-exchange resin beads, spheroids, microspheres, seeds, pellets,, granules, and other multiparticulate systems in order to obtain a desired sustained-release of die therapeutic agent.
  • the multiparticulate system can be presented i ⁇ a capsule or in any other suitable unit dosage form, hi eeitam pr ⁇ fe ⁇ ed embodiments, moie than one multiparticulate system can be used, each exhibiting different characteristics, such a:> pl f dependence of release, time for release in in ⁇ ho size and composition.
  • the therapeutic agent can be coated "w nh an amount of release-retarding material sufficient to obtain a weight gain from about 2 to about 30V although the coat can be greater or lesser depending upon the physical properties of the particular therapeutic agent utilized and the desired release rate, among other things.
  • the coat can be greater or lesser depending upon the physical properties of the particular therapeutic agent utilized and the desired release rate, among other things.
  • Solvents typically used for the release-retarding material include pharmaceutically acceptable solvents, such as water, methanol, ethanol, methylene chloride and combinations thereof !n certain embodiments of the invention, the release-retarding material is m the form of a coating comprising an aqueous dispersion of a hydrophobic polymer
  • a plasticizer in the aqueous dispersion of hydrophobic polvmcr will further improve the physical properties of the Him foi example, because ethylcelkilose has a relatively high glass transition tempeiature and does not form flexible films under norma!
  • the amount of plasticizer included in a coating solution is based on the concentration of the fi!m- former, e g., most often from about 1 to about 50 peicenl by weight of the film-former Concentrations of the plastict/er. howeser, can be determined by routine experimentation, Examples of plastici/ers for ethj leellolo ⁇ e and other celluloses include dibutj l sebacate, diethyl pbiiiaiate, triethyl citrate, tributy!
  • plasticizers such as acetylated monoglycc ⁇ des, phthalatc esters, castor oil, etc
  • plasticizers for the acrvUc polymers include citric acid esters, such as trieth)! citrate NI-21, tiihuiv! citrate, dibufyl phthalate, and possibly 1,2-p ⁇ opylene glycol, po! ⁇ eth ⁇ iene gKcols, piopv!ene glycol, diethyl phthalate, castor oil.
  • the formulations of the invention can be atteied for example, by using more than one release - retarding material, varying the thickness of the release-retarding maLenal chaa ⁇ ia ⁇ the particular release- retarding material used, altering the relative amounts of release- tetardi ⁇ g material, altoting the manner in which the plastiei/ei is added ⁇ e g , when ⁇ he sustained-release coating is demed from an aqueous dispersion of hydrophobic polymer), by relative to retardant material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture: etc
  • the oral dosage form can utilize a multiparticulate sustained-release matrix
  • the sustained-release matrix comprises a hulropMlie and'or hydrophobic polymer, such as gums, cellulose ethers, acrylic renins and protein-derh ed materials Of these pohmeis, the cellulose ethers, specifically hydroxyalkylcelluioses and carboxyaikyleel.uloses, are preferred
  • the oral dosage form can contain between about 1% and about 80% ⁇ by weight) of at least one hvdrophilic or hydrophobic polymer
  • the hydrophobic materia! is preferably selected fiom the group consisting of alkylcellulose, acrylic and methaeiylic acid polymers and copolymers, shellac, zein. hydrogenated cantor oil, oil, ur mixtures theieof
  • the hydrophobic mate ⁇ al is a pharmaceuticalh acceptable acrylic polymer, including acn lic acid and methacrylic acid copolymers * , methyl meihaciyiate, methj l m ⁇ thaciylaie copoKmers, ethoxyeihyl raetliacrvlate, animoalkyl methacrylatc copolymer, poly(aciy licacid).
  • poiyt methacrylic acid methacrylic acid alkylamine copoi ⁇ nier. poiy(methy! methactylate), poly (methacrv tic acid ) ⁇ anhydride), polymcthacryiate, polyacrylainide, poiyfmethacA'hc acid anhydride), and glycidyi metha ⁇ ylate copolymers.
  • the hydrophobic material can also include hydroox ⁇ aik ⁇ lce!luloses such as hydroxypropyJmethykeUiilose and mixtures of the foregoing Piefeired lndiophobic mateiials ate watei-insoluble uith mote or less pio ⁇ ouneed heliophobic fiends Picfciabls, the hydrophobic materia! ha:> a melting point fi ⁇ rn about K ) ' C to about 200° C , more prefeiahiv fiom about 4 ⁇ ° C to about 90° C I he h ⁇ dtoph ⁇ bie material can include neima!
  • oi svnthetsc waxes fatty alcohols (such as Luu)i, tnyusty!, steaiyi, cet>) ot piefetably cetosieat) ! alcohol), fatty acids, mchtdnig fattv a ⁇ d esteis, fattv acid ghceudes (mono-, di-, and tn-giyceudes), hydiogenated fats, hydiocaiboiis normal waxes, stearic acid, stearyl alcohol and hvdiophobic and h ⁇ diophihc raate ⁇ ah mg hydrocaibon backbones
  • Suitable waxes include beeswax, ghcowax, castor wax, carnauha wax and wax-tike substances, e g , material normally solid at room tempeiature and ing a melting point of from about 3O 1- C to about 100
  • Ptcf ⁇ iabiv a combination of oi ntoie hydtophobic mate ⁇ als are included m the matrix formulation_. It an additional matcnal is included, it is prefeiabK a ⁇ atmai or svnthctic wax, a fatty acid, a tatty alcohol oi mixtures theieof. Examples include beeswax, carnauba stearic acid and steai ⁇ -1 alcohol
  • the sustained-release matrix comprises digestible, iong-cham
  • the sustaiued-ielease malax can contain up t ⁇ 60° a f bv weight) of at least one polvalkylene ghcol ⁇ n a prefers ed embodiment, the mat ⁇ x comprises at least one water-soluble hydtowalkvl cellulose, at least one i ⁇ :-( ⁇ ., ptefeiabh Cu-( ⁇ , aliphatic alcohol and, optionally at least one polyaikylenc glycol
  • the at least one hydio ⁇ yalk ⁇ l cellulose is prefeiably a hvdtoxv (C ⁇ -C f) ) alkvl cellulose such as and, preferabh .
  • cellobse T he amount of die at least one l cellulose m the oial dosage f ⁇ u will be determined, amongst other tluogs. by the precise iate of opioid jelease required
  • the amount of the at lea.st one aliphatic aicoho! in the present oral dosage form will be determined by the piocise iate of opioid release required. However, if will also depend on whether ⁇ lie at least one polyalkylene glycol is absent from the oral dosage fomi.
  • a spheromzing agent together with the active ingredient, can be &pheroni/ed to form spheroids
  • Microcrysiailme cellulose and hydrous lactose impalpable are examples of such agents.
  • the spheroids cart contain a watei-insoluble poly mer, preferab ' ⁇ an acrylic polymer, an acrylic copolymer, such as a methacrylic a ⁇ d-ethx- i acrylate copolymer or eth> !
  • the sustained-release coating will generally include a water-in soluble materia! such as (a) a wax, either alone or in admixture with a fatty alcohol or O)) shellac or zein
  • the sequestering subunit compiles the therapeutic agent in sustained- release form.
  • the sustained-release subunit can be prepared by any suitable method.
  • a plasticized aqueous dispe.si ⁇ i. of the iulease-tetaulmg materia! can be applied onto the subunit comprising the opioid agonist.
  • a sufficient amount of the aqueous dispersion of release-retarding material to obtain a predetermined sustained -release of the opioid agonist when the coated substrate is exposed to aqueous solutions, e g , gastric fluid, is preferably applied, taking into account the phvsical characteristics of the opioid agonist, the manner of incorporation of the plastici/er, etc.
  • a fuither cn ercoat of a f ⁇ iffl-formcr. such as Opadry (Colorcon, West Point, VaJ, can be applied after coating ⁇ * ith the release-retarding material
  • the subunit can be cured m order to obtain a stabilized release rate of the therapeutic agent
  • a stabilized product can be pieierably obtained by subjecting the subunit to ox en curing at a temperature abo ⁇ e the glass transition temperature of the plast ⁇ ci?ed acrylic poij mer for the required time period.
  • the optimum temperature and time for the particular formulation can be determined by routine experimentation.
  • a sustamed-relea.se matrix also can contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, fkvorants and glidants that are comentionai ni the pharmaceutical art.
  • the mechanical fragility of of the sequestering siibunits described herein is the same as the mechanical fragility of the therapeutic agent in reieasable tbroi.
  • tampering with the composition of the im ention in a manner to obtain the therapeutic agent will result m the destruction of the sequestering subunit such that the antagonist is released and mixed in with the therapeutic agent Consequently, the antagonist cannot be separated from the therapeutic agent, and the therapeutic agent cannot be administered in the absence of the antagonist.
  • Methods of assaying the mechanical fragilit ⁇ of the sequestering subunit and of a therapeutic agent are known in the art.
  • composition of the invention can be in any suitable dosage form or formulation, (see, e.g.. Pharmaceutic* and Pharmacy Practice, J. B. Lippincoit Company, Philadelphia, Pa., Banker and Chalmers, eds , pages 238-250 ( 19S2)).
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the inhibitor dissohed in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lo/enges. and troches, each containing a predetermined amount of the acthe ingredient as solids ot giamiles.
  • Liquid formulations may include diluents, such as water and alcohols, for example, cthano ⁇ , ben/yi alcohol and the polyethylene alcohols, either with or w ithout the addition of a pharmaceutically acceptable suifactant
  • Capsule forms can he of the oidinaiy hard- or soft-shelled gelatin type contaminu, for example, surfactants, lubricants, and ineit fillers, such as lactose, sucrose, calcium phosphate, and corn starch Tablet forms can include one or more of lactose, sucrose, ma ⁇ mtoL corn starch, potato starch, algink acid, microcrystalline cellulose, acacia, gelatin, g ⁇ ar gum, colloidal silicon dioxide, croscarrneibse sodium, talc, magnesium stearate, calcium sleaiate, /inc
  • Lozenge forms can comprise the active ingredient in a flavor, usualh sucrose and acacia or tiagacanth, as well as pastilles comprising the acthe ingredient in an ineit base, such as gelatin and giyeeiin, 01 sucrose and acacia, emulsions, gels, and the like containing, in addition to the acthe ingtedient such excipients as are known in the an
  • compositions of the invention can be modified in any number of ways, such that the therapeutic efficacy of the composition is increased through the modification.
  • the therapeutic agent oi sequestering subunu could be conjugated either directly oi indirectly through a linker to a targeting moiety
  • the therapeutic agent oi sequestering subunu could be conjugated either directly oi indirectly through a linker to a targeting moiety
  • targeting moiety refers to a ⁇ v molecule or agent that specifically recognizes and binds to a cell-surface receptor. such that the targeting moiety directs the deliv ery of the tlie ⁇ tpeutie agent or sequestering subumt to a population of cells on which the receptor is expressed
  • Taigeiing moieties include, but are not limited to. antibodies, or fragments theieof, peptides, hormones, growth factors, cytokines, and am other naturallv- or non- ⁇ atuialiy- hgarsds, which bind to cell-surface receptors.
  • linker ' refers to any agent or molecule that bridges the therapeutic agent or sequestering subumt to the targeting moiety
  • sites on the theiapeutk agent or sequestering subunil which are not necessary foi the function of the agent or sequestering subunit are ideal sites for attaching a linker and or a targeting moiety, provided that the linker and oi targeting moiety, once attached to the agent or sequestering subunit, do(es) not interfere w ith the function of the therapeutic agent or sequestering s ⁇ hunn
  • the composition is preferably an oral dosage form
  • oral dosage form' is meant to include a unit dosage form prescribed oi intended for oral adr ⁇ imsrjation comprising subu ⁇ its Desiiably.
  • the composition comprises the sequestering subunit coated with the therapeutic agent in ⁇ deasable form, thereby founing a composite subunit comprising the sequestering subunit and the therapeutic agent,
  • the invention further pros ides a capsule suitable for otal administration comprising a plurality of such composite subimits. Akematheiy.
  • the oral dosage form can comprise any of the sequestering subumts of the im ention in combination with a therapeutic agent subun ⁇ t the lheiapeutic agent subunit comprises the therapeutic agent in releasahle form
  • the ⁇ mention provides a capsule suitable for oral adramisttaticm comprising a plurality of sequestering subunits of the imentson and a pluraht) of therapeuuc subumts, each of which comprises a therapeutic agent in reieasable form
  • the invention furthei provides tablets comprising a sequestering subunit of (he invention and a therapeutic agent m ieleasable foim
  • the invention provides a tablet suitable for oral administration comprising a first layer comprising any of the sequestering subumts of the invention and a second layer comprising therapeutic agent m re leasable form, wherein tlie first layer is coated with the second layer
  • the first layer can comprise a plurality of sequestering subunits
  • the frtsi layer can be or can consist of a single sequestering subunit.
  • the therapeutic agent in releasable form can be in the f ⁇ rni of a therapeutic agent subun.it and the second layer can comprise a plurality of therapeuuc subunits. Alternately, the second layer can comprise a single substantially homogeneous layer comprising the therapeutic agent in releasable form.
  • the sequestering s ⁇ bumi ⁇ in be in one of several different foims
  • the system can further comprise a second antagonsst-mipetmeable materia ⁇ , m which case tlie sequestering unit comprises an antagonist, a first antagonist-impermeable matetiai, a sec ⁇ nd antagonisHrnpeimeabie material and a coie.
  • the core is coated with the first antagonist-impermeable material which, in turn, is coated with the antagonist, which, in u»n, ts coated wiih the second antagonist-impermeable material Hie first antagonist-impermeable material and second antagonist-impermeable material substantially prevent release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours.
  • the first antagonist-impermeable material is the same as the second antagonist-impermeable materia! In otiiei instances, the fust antagonist-impermeable materia!
  • the second antagonist-impermeable material is different from the second antagonist-impermeable material It is within the skill of the oidinary artisan to deteimine whether oi not the Hist and second antagonist- impermeable materials should be the same cu diffeient. Factors that influence the decision as to whether the first and second antagonist-impermeable materials should be the same or different can include whether a layer to be placed over the antagonist- impermeable material requires certain properties to prevent dissolving pait or all of the antagonist-impermeable layer when applyiug the next layer or properties to promote adhesion of a layer to be applied over the antagonist- impermeable layer.
  • the antagonist can he incorporated into the core, and the core is coated with the first antagonist-impermeable material.
  • the invention provides a sequestering subunit comprising an antagonist, a core and a first antagonist- impermeable material wherein the antagonist is incorporated into the core and the core is coated with the first antagonist-impermeable material and wherein the first antagonist- impermeable material substantially prevents release of the antagonist from the sequestering subunii in the gastrointestinal tract for a time period that is greater than 24 hours.
  • 'incorporate' ' and words stemming therefrom is meant to include any means of incorporation, e.g.. homogeneous dispersion of the antagonist throughout the core, a single layer of the antagonist coated on top of a core, or a multilayer system of the antagonist, which comprises the core.
  • the core comprises a water-insoluble material and the core is coated with the antagonist, which, in lorn, is coated with the first antagonist-impermeable material.
  • the indention further provides a sequestering subunit comprising art antagonist, a first antagonist-impermeable materia!, and a core, which comprises a water-insoluble material, wherein the core is coated with the antagonist, which, in turn, is coated with the first antagonist-impermeable material and wherein the first antagonist-impermeable materia! substantially presents release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours.
  • water-insoluble material as used herein means any material mat is substantially water-insoluble.
  • substantially water- insoluble does not necessarily refer to complete or 100% wafer-insolubility. Rather, there are varying degrees of water insolubility of which one of ordinary skill in the art recognizes as having a potential benefit.
  • Preferred water-insoluble materials include, for example, microcrystalline cellulose, a calcium salt, and a -wax.
  • Calcium salts include, but are not limited to. a calcium phosphate (e.g., hvdroxyapatite, apatite: etc), calcium carbonate, calcium sulfate, calcium stearate, and the like.
  • Waxes include, for example, cauiuba wax, beeswax, petioleum wax, canddilSa wax. and the like.
  • the sequestering subunit includes an antagonist and a sea! coat where the sea! coat forms a layer physically separating the antagonist within the sequestering suhunu from the agonist which is layered upon the sequestering subunit.
  • the seal coat comprises one or more of an osmotic pressure regulating agent, a chaige-noutiaii/iitg additive, a sequestering polymer hydrophohicHy-enhaneing additn e, and a first sequestering polymei (each haung been desciibed abo ⁇ e). in such embodiments, it is preferred that the osmotic pressure regulating agent, charge- neutralizing addime.
  • Standaul tests may be utilized io ascettam the antagonist's effect on agonist function (i e., reduction of pain ⁇ .
  • the sequestering subunit of the can hav e a blocking agent that is a tether to which the antagonist is attached.
  • the teim "tether" as used herein iefers to am means by which the antagonist is tethered or attached to the interior of the sequestering subimit, such that the antagonist is not released, unless the sequestering subunii is tampered with. Ui this instance, a tether-antagonist complex is formed.
  • the complex is coated with a tether-irnpeimeable mateiiah thereby substantially pies en ting release of the antagonist furni the subunit.
  • the terra "tethei-impeimeable material" as ms ⁇ herein refers to any material that substantially presents or the teihef from petmeating through the mate ⁇ al.
  • the tether pieferably is an too exchange resin bead.
  • l he imenuoti further provides a tablet suitable for oral administration composing a single la ⁇ er comprising a therapeutic agent in releasable form and a plurality of any of the sequestering suhunils of the im enium dispersed throughout the layer of the therapeutic agent in releasabie form.
  • Hie im ention also ⁇ ro ⁇ ides a tablet in which the therapeutic agent in releasable form is in the form of a therapeutic agent subitnit and the tablet comprises an at least substantially homogeneous mi ⁇ tuie of a plurality of sequestering subunits and a plurality of subunits comprising the therapeutic agent !
  • oral dosage forms ate prepared to include an effective amount of melt-extruded sub ⁇ mts in the form of raultipartic ⁇ es % ithin a capsule
  • a plurality ⁇ f the melt-extruded muliparticulates can be placed m a gelatin capsule in an amount sufficient to provide an effects e release dose when ingested and contacted by gastric fluid.
  • the subunits e.g , in the form of multiparticulates
  • Exciptents in tablet formulation can include, for example, an inert diluem such as lactose, granulating and disintegrating agents, such as cornstarch, binding agents, such as starch, and lubricating agents, such as magnesium stearate.
  • the subunits are added during the extrusion process and the ettrudate can be shaped into tablets as set forth in U. S Pat. No 4, ⁇ 57,681 (Klimesch et al. ⁇ , which is incorporated herein by reference.
  • the sustamed-reicasc. melt-extruded, multiparticulate systems or tablets can be coated, or the geJatm capsule can be fuithei coated, uuh a sits ⁇ anied- reiease coating, such as the sustained-release coatings described herein
  • Such coatings are panicdaily useful when the subunil comprises an opioid agonist in ieleasabie fo ⁇ n, but ⁇ c*t ia sustained-release form.
  • the coatings preferably include a sufficient amount of a hydrophobic materia! to obtain a weight gam foira about 2 to about 30 percent, although the overcoat can be greater, depending upon the physical properties of the particular opioid analgesic utilized and the desired release rate, among other things
  • the raelt-extruded dosage forms can further include combinations of melt- extruded multiparticulates containing one o ⁇ more of the therapeutically active agents before being encapsulated Furthermore, the dosage forms can also include an amount of an immediate ieleasc ⁇ hetape ⁇ tic agent for prompt tbeiapemie effect
  • the immediate release therapeutic agent can be incorporated oi coated on the surface of the subunits after preparation of the dosage forms (e.g . control led -release coating or matrix-based). Tiie dosage forms cast also contain a combination of control led-release beads and matrix multiparticulates to a desired effect.
  • the sustained-release formulations preferably slowly release the the ⁇ eittie agent, e g.. when ingested and exposed to gastric fluids, and then to intestinal fluids
  • the sustained-release profile of the niek-ex.ruded formulations can be altered, for example, by the amount of retardatrt, e.g.. hydrophobic material by the amount of plastiC ⁇ zer relative to hydrophobic material, by the inclusion of additional ingredients or e ⁇ cipients. by altering the method of manufacture; etc.
  • the melt-extruded material is prepared without the inclusion of the subunits, which are added thereafter to the extrudate
  • Such formulations can ha ⁇ e the subunits and other drugs blended together with the extruded matrix material, and then the miviuie is tabieted in order to ide a slow ielease of the therapeutic agent or other drugs.
  • Such formulations can be particularly advantageous, for example, when the therapeutically active agent included m the formulation is sensitne to temperatures needed for softening the hydrophobic materia!
  • the release of the antagonist of the sequestering sobunit or composition is expiessed in terms of a ratio of the release achieved after tampering, eg , by crushing or chew ing, relative to the amount released from the intact formulation
  • the iatio is, thetefoie, expiessed a& [Cr ⁇ nhedj.[Wholej, and it is desired that tins ratio have a numerical range of at least about 4 1 or greater [e.u. , crushed release within I hour/intact release iu 24 hours).
  • the iatio of the therapeutic agent and the antagonist present ⁇ n the sequesteiing subunit, is about I J, about 50.1, about 75 1, about 100 1 , about 150 I , or about 200" I, foi example, b> weight, preferably about 1 .1 to about 20.1 by weight oi !5 ! to about 30.1 by weight.
  • the weight tatio of the therapeutic agent to antagonist refers to the weight of the active ingredients HUB, for example, the w eight of the therapeutic agent excludes the weight of the coating, matrix, or other component that renders the antagonist sequestered, or other possible exc ⁇ ients associated with the antagonist particles, in certain preferred embodiments, the ratio is about 1.1 to about 10 1 by weight.
  • the amount of such antagonist wnhm the dosage form can be more w idely than the therapeutic agent antagonist combination dosage forms, where both are available for release upon administration, as tlte formulation does not depend on differential metabolism or hepatic clearance for proper functioning.
  • the amount of the antagonist present in a substantially n ⁇ n-releasabie form is selected as not to be harmful to humans, even if fully released under conditions of tampering
  • the composition;? of the [mention are particularly well-suited foi use in presenting abuse of a therapeutic agent, hi this regard, the (m ention also presides a method of preventing abuse of a therapeutic agent by a human benig.
  • the method comprises incorporating the therapeutic agent into any of the compositions of the imeniion Upon administration of the composition of the invention to the person, the antagonist is substantial!) from being released in the gastrointestinal tract for a time period that is grcatei than 24 hours.
  • the sequestering subunit which is mechanically fragile, v ⁇ ili break and thereby allow the antagonist to be released. Since the mechanical fragility of the sequestering subunit is the same as the therapeutic agent in releasable form, the antagonist will be mixed with the therapeutic agent such that separation between the two components is virtually impossible
  • the effectiveness of treatment of chronic moderate to severe pain is typically measured by mean change in diary Brief Pain Inventory (BPl) seoie of av erage pain (daily scores of average pain averaged over 7 days, in-clinic BP! and/or dailv diary BPI ⁇ worst, least, and current pain)), WOMAC Osteoarthritis Index, Medical Outcomes Study (MOS) Sleep Scale, Beck Depression Inventory, and Patient Global impression of Change (PGlC).
  • BPl diary Brief Pain Inventory
  • MOS Medical Outcomes Study
  • PHS Patient Global impression of Change
  • BPi is typically measured using 11 -point BPl system as follows L Ptease pain circling the one number that best describes your pain at its worst in the last 24 hours.
  • the Reek Depression inventory is a self-admin&tered, 2 i -item test in multiple-choice format that measures the presence and degree of depression (Beck et al. An im entory for measuring depression ⁇ teh (Jen Psych 1%1 :4 561 -571 ).
  • Lach of the inx entoiy questions corresponds to a specific category of depressive symptom and or attitude. Answers are scored on a 0 to 3 scale, where " v 0 " ' is minimal and u ⁇ i6 severe A scote of -- 15 indicates raild depression, a score of 15-30 indicates moderate depression, and a score >30 indicates depression
  • the WOMAC Osteoarthritis index consists of questions on three subscaies' Pain, Stiffness, and Physical Function (Bellamy et al. Validation stixis of WOMAC : a health status instrument for measuring clinically important patient ant outcomes to antirheumatic drug tlierap ⁇ in patients with osteoarthritis of the hip or knee, J Rheumatol 1988; 15 1833-1840; Bellamy K Pain assessment in osteoarthritis: experience with the WOM ⁇ C osteoarthritis index Semin Arthritis Rheum.
  • the PGIC is based on the Clinical Global Impression of Change (CGIC) (Guy W. M. ' DL-li assessment manual for psychopharmacology. Washington. DC: Department of Health, Education and Welfare, 197 ⁇ ;217-222, Publication Number (ADM) 76-338), which is a validated scale.
  • CGIC Clinical Global Impression of Change
  • ADM Publication Number
  • Prcn iced herein are methods for treating pain in a person comprising administering thereto a multilayer pharmaceutical composition as described herein such that pain is substantially relieved m the patient.
  • substantially relieved is meant that the person reports a decrease in pain as measured by any of several known methods (including but not limited to those described herein) for determining pain. This decrease may be in comparison to no treatment, a placebo, or another form of treatment Including but not limited to another composition, either one described herein or otherwise available to one of skill in the art.
  • pain is considered substantially relieved where the decrease is significant (e.g., ⁇ 0.05).
  • the methods described herein provide methods for substantially relieving pain (e.g, providing an analgesic effect ⁇ for time periods of at least one week ⁇ eg , two, four, eight, 52, 16, 20, 24, 28, 32, 36, 40 and 100 weeks) by admimsteiing a multi-lavei pharmaceutical composition as descnbed liejein in one ei ⁇ bodiiuciit.
  • the method includes icguiativ adnimistcting (e g , at least once, twice, three, or four times ) & multi-k> ⁇ pharmaceutical composition comprising an agonist and an atagooist as descnbed herein for at least one week le g., one, two, four, eight 12, 16, 20, 24, 28, 32, 36. 40 and 100 week** ⁇ wherein no substantial release (e g , zero, or less than about 10% 20V or 30° o release) of the antagonist is observ ed, in some embodiments, administration of the composition to a population once daily for a tune pe ⁇ od of at least one week results m no substantial ⁇ e ⁇ ease in at least about Wo, 80% v 70 0 O, ft ⁇ %. or 5Q% of the making up the population Release ma> be measured by detecting naltrexone or (1-naltrexoi in plasma.
  • Exemplary KadianNT formulations and methods described below in Examples 1 - 4 may also be found in PCT/US2OO7/014282 (WO 2007/149438 A2), PCT/US2007/021627 (WO 2008/063301 A2), and PCT/US08/ 10357.
  • Kadian NI pellets with naltrexone pellet coat thickness of I5 ⁇ m had comparable naltrexone release as KT pellets with 90 um coat thickness
  • This comparable NT ielease may also be attributed ftom the presence of 50 ⁇ m seal coat on the sugar spheres used in Kadian NT pellets
  • Significant NT sequestering was observ ed, both at fasting (>97%) and fed states ( ⁇ "-%%)
  • Kadian NT pellets conia ⁇ nng sodium chloiide above the naltrexone pellet coat (Fi-H 1 J?) had half the release of naltrexone compared to Kadian NT pellet without sodium chloride (PI- 1496), consistent with in vitro results There is again food effect observed. Lag time was significantly reduced.
  • C max Relative bioavailability based on Cmax ::: Dose-adjusted ratio of Cmax (NT/KNT pellet) to Cmax (NT soin)
  • BA (AUC inf) ⁇ Relative bioavailability based on AUC inf ⁇ Dose-adjusted ratio of AUC iuf (NT/KNT pellet)
  • components (a), (b) and / or (c) may be included as described below;
  • Kadian KT ⁇ 60mg morphine sulfate.
  • 2.4i ⁇ g naltrexone H(T) was administered io humane and compared to the piewously described product Kadian
  • Each Kadian sustained release capsule contains either 20. 30, 50. 60. or 100 mg of Morphine Sulfate USP and the following inactive ingtcdients common io ail strengths.
  • naltrexone (parent ⁇ is iapidly absoibcd and coin cited to the metabolite is a opioid antagonist than naltrexone. ing onl> 2 to 4°o the antagonist potencv Most patients had quantifiable levels ⁇ > U 25 pg/mL) of 6- ⁇ -naitrexol The incidental piescnce of 6- ⁇ - ⁇ aitrexol m the plasma had no effect on pain scores
  • Oth ⁇ measuteraents including hi-Chmc Pain, WOM ⁇ C Pam, WOM ⁇ C Stiffness, WOM ⁇ C Daily Activ ities, and BP! Pain w cie albo made. It was ⁇ etct mined that the diffeiences in these measuiements in those taking Kadmn and those taking Kadian .N I ' was not significant as shown belcnv .
  • COWS Oimcal Opsale Wuhdiawal Scale
  • This long-term, open-label study evaluated the safety of Kadian NT administered once or twice daily (QD oi BID) o ⁇ ei a 12-month period Kadian ⁇ S T was used in dosage strengths of 20 rag, 30 mg, 40 nig, 50 mg, 60 mg, 80 mg and 100 mg. There no maximum allowable daily dose set for this study Subjects wete titrated upward as needed in a manner consistent with the current Kadian" labeling and in accordance with the investigator's best medical judgment for the most effective pain management Multiples of the a ⁇ aiiable dosage strengths were combined as needed to achiev e the intended necessity daily dose.
  • Subjects currently taking opioids who will have their opioid dose converted to a Kadian NT dose should be scheduled for a morning clinic appointment (before noon) for the Drug Dispensing Visit. Additionally, subjects were instructed to refrain from taking the morning dose of their current opioid pain medication on the day of their Drug Dispensing clinic visit. It was recommended that subjects who are already taking opioid medication be started on a Kadi an NT dose equivalent to 50% to 75% of the current daily opioid dose rounded to the lowest available Kadi an NT dosage strength due to potential for incomplete cross tolerance. The dose was determined utilizing the conversion table provided in Appendix V of this protocol; investigators were free to choose an alternate opioid conversion seiieduie at their own discretion. Opioid dose requirements were based on the subject ' s average combined daily opioid consumption for chronic and rescue dosing over the week prior to study entry.
  • a subject Even if a subject is experiencing a Pl " ⁇ 3, the subject was free io choose not to have the dose increased. For example, a subject may have been satisfied with having his or her pain level reduced to a PI level of 4, If a subject's dose was increased and the subject repotted unacceptable AEs or an opioid-expe ⁇ eticed subject was convened to a dose that results in unacceptable AEs, the dose was decreased. If a subject expediences inadequate pain relief and desired to have bis or her dose increased prior to a scheduled clinic visit, the subject was allowed to telephone the site and request a dose increase after a minimum of three days at the previous dosage !e ⁇ e!
  • Subjects were required to return for a post-treatment follow-up appioximately 28 to 32 days aftet the final dose of sluch medication to record AEs and concomitant medications and to assure that appropriate taperuig from study medication and transition to standard of care has been accomplished
  • Subjects wishing to discontinue opioid medication were converted to Kadian ⁇ for the taper penod, fhe suggested mechanism for tapering was for the subject to take half of hib oi bet last effective dose of stud> medication in divided doses of Kadian (BID) for three days, and then to take half of that i educed dose in divided doses ⁇ BID ⁇ for the next three days, on the sev enth day, all dosing will discontinue.
  • Subjects weie also allowed to convert to c ⁇ rrently-approv ed extended release opioid per investigator discretion
  • the Interactive Voice Response S stem (iVRS) was used to identify up to 20 subjects in each of the follow ing daily dosing categories to undergo PK sample collection at their scheduled visits. 40 mg to 60 ing, 80 rag to 120 ma, and y 120 nig, I p to 20 subjects aged 65 years atid above v>e ⁇ e also identified to participate in the PK sample collection. I be primary focus of this PK sampling was to quantify naltrexone, 6-beia naltrcxol and rr ⁇ rpbine concentrations. Study medications were in the form of orally administered capsules Study medications were. I )
  • a subject was eligible for study participation if he she meets the following criteria: 1. The subject was I S to 70 years of age and exhibited sufficient literary skills to complete study assessments. 2 The subject agreed to refrain from taking am opioid medications other than study medication during the study period, and agreed to report all non-opioiti analgesic medications taken;
  • Sujbect had a histoiy of chronic moderate to seven c pain caused by a notimalignam condition for ai least thiee months prior to Baseline Visit Conditions include. but are not limited to. osteoarthritis of any joint, chronic km back pain ⁇ ith or without radiculopathy, diabetic peripheral neuropathy, and post-he ⁇ etic neutalgia. Subject was directed to choose the most painful joint or body area to serve as the target joint atea for this stud) ⁇ target joint. ⁇ *as not to contain any type of orthopedic sod oi prosthetic device.
  • a subject v iil be excluded from the s ⁇ xh if he she meets any of the following critciia:
  • Subject had a documented histoty of an allergic reaction (hives, rash, etc ⁇ or a clinically significant intolerance to morphine ot other opioids, such that treatment with morphine is coiuxanidicaied. 2. Subject was pregnant or breast-feeding,
  • Subject had a documented histoiy of ⁇ iusf abuse dependence misuse or naieotic analgesic abuse/dcpciidcnce.'misusc within live years ptioi to the Baseline Visit.
  • Subject had a documented histoiy of alcohol abuse ( ⁇ 2 glasses/day) and'or dependence within fix e years prior to the Baseline Visit, which, in the opinion of the investigator, may ha ⁇ e influenced subject compliance w ith the study
  • Subject was considered b> the im estigator. for any reason, to be an unsuitable candidate to receive extended-release morphine sulfate with naltrexone, including ( but not limited to) the risk(s) in terms of precautions, warnings, and contraindications in the Investigator's Brochure for Kadian KT. 8. Subject had a Bod ⁇ Mass Index (BMf) -- 45 kg m : .
  • Subject had a psyehiatiie illness or medical iiinoss'condition, and or abnormal diagnostic finding, that, m the opinion of the hn estimator, would interfere with the completion of the study, confound the results of the studs, or pose risk to the subject
  • Subjects with settled claims were allowed to participate,
  • Subject had a histor> of impairment of pislmo ⁇ an fimction, hypercarbia, b) chronic obstructive pulmonary disease, cor pulmonale, uncontrolled asthma, sleep apnea s ⁇ ndrome, or respiratory deptession.
  • Subject had a history of gastiie or small intestine surgery leading to din seal malabsorption (e g , gastric tnpassL oi ain othet disease that causes chnical malabsorption, 2 !
  • Subject had active cardiac disease or other health conditions s) that pose a significant health risk m the event of opioid withdrawal 22 Subject was taking phcnothia/incs oi high doses of sedatives, hypnotics, oi tranquilizers. Chronic low dose sleep aids or anxiolvtks were allowed with
  • Safety endpoims wei ⁇ the incidence of treatment-emergent AI j .s, changes from pre-treatment to post-treatment tor s ital signs, ECGs. physical examination findings, and clinical laboratory test results, and opioid tovicity assessments.
  • the efficacy endpoints were Pain Intensity (PI) within trie past 24 hours, and. Global Assessment of Study Drug.
  • Three subject analysis populations * were defined as follows 1 ) the "safety population” " consisting of ail subjects who take study medication, used for safety analyses. 2) the “mtem-to-treaf " (ITT) population consisting of all subjects who take study medication and Io ⁇ emon , or Global Assessment of Study Drug observation: the !TT population will be used for efficacy analyses; 3 ⁇ the pharmacokinetic ⁇ PK) population will consist of ail subjects w ith PK samples ami will be used for PK, analyses.
  • TFAEs resulting in discontinuation of treatment was observed in approximate! 30" ⁇ of patients admmtsteied less than 80 ma Kadian Nl pet day: approximately 10% of patients administered between 80 and 120 mg Kadian NT per and, approximate! ⁇ - 9 0 O of patients administered more than 120 mg Kadian NT pet day Oveiall, TB AEb were obseived m approximately 24° ⁇ of patients
  • Seuoifo AEs resulting in djsconiimiation of Kadian KT tteamicnt were m approximately 2% of patients admmisteied less than 80 mg Kadsao Kl per dav, approximately 8° ⁇ of patients administered between 80 and 120 mg Kadian KT per day, and approximately 2% of patients administered more than 120 n ⁇ kadian K F per da) Overall SF AFs vu'ie obseived in approximate!) ⁇ 0 O of patients

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Abstract

La présente invention concerne une composition pharmaceutique constituée d'un antagoniste, d'un agoniste, d'un enrobage étanche et d'un polymère séquestrant, composition pharmaceutique dans laquelle l'antagoniste, l'agoniste, l'enrobage étanche et au moins un polymère séquestrant sont tous des composants d'une seule unité, et dans laquelle l'enrobage étanche forme une couche séparant physiquement l'antagoniste de l'agoniste. L'invention concerne également des procédés de fabrication de ladite composition pharmaceutique. L'invention concerne, en outre, des procédés de prise en charge de la douleur au moyen desdites compositions.
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