AU2008338439A1 - Pharmaceutical composition - Google Patents

Description

WO 2009/079518 PCT/US2008/087030 PHARMACEUTICAL COMPOSITION RELATED APPLICATIONS This application claims priority to (ES. Ser. No. 60/007,882 filed December 17, 2007. FIELD OF STUDY This invention pertains to composotions and methods useful for treating pain in 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 10 anagonist, BACKGROUND Improved methods for treating pain are desired by those of skill in the art. A disease In which pain is a major symptom is osteoarthritis (OA), OA is the most 15 common form of arthritis in the United States (Hochber g 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). (A 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 p-rogrssively with 20 age (Peloso et at, 2000). Unlike rheumatoid arthritis and other inflammatory arthritides, inflammation, if present, is usually mild and localized to the joint. The cause of OA is unknown, but biomechanical 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 25 Rheumatology, 2000b). OA is characterized by pain that 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. Chuical examination often reveals tenderness to palpation. bony enlargement, crepitus, and/or limited joint motion (American College of 30 Rheumatology, 2000b). As the disease advances, OA patients experience increasing pain and loss of fimction, with pain intrding at periods of rest (Peloso et al, 2000), Since no WO 2009/079518 PCT/US2008/087030 cure for OA is available, the primary goal of OA treatment is to reduce pain while maintaining or improving joint mobility and limiting functional impairment. Nonphamiacologic and pharmacologic treatments for OA are used in conjunction to reduce pain and to improve functional status, Nonpharmacologic therapies include 5 patient education, weight loss (if overweight), occupational therapy, physical therapy, and aerobic exercise programs to restore joint movement and increase strength and aerobic capacity (American College of Rheumatology, 2000a). The initial pharnacologic therapies for OA include nonopioid analgesics (e.g, aetanunophen) and topical analgesics, followed by treatment with nonsteroidal. antiinflarnmatory drugs (NSA[ Ds) 10 and judicious use of intra-articular steroid injections (Hochberg et al, 1995a). Although these medications may provide temporary pain relief. the beneficial effect may be offset by other factors. Use of nonopioid analgesics to treat moderate to severe GA pain is limited by a ceiling effect for analgesia (Roth et aL. 2000). Additionally, NSAIDs can be toxic to the gastrointestnal tract, and NSAIDs and acetaminophen can produce renal 15 toxicity, especially in the elderly (Peloso et aL, 2000) Thus, a need exists for additional analgesic treatment options for pain associated with OA, Recent efforts have been made to liberalize the use of opioids for the treatment of chronic nonmalignant pain (Sullivan et a., 2005). Sullivan proposes subject-centered principles to guide efforts to relieve chronic nonmalignant pain, including the acceptance 20 of all subject pain reports as valid but negotiation of treatment goals early in care, avoidance of subject harm, and incorporation of chronic opioids as one part of the treatment plan if they improve the subject's overall health-related quality of life, Prescribing opiates in the treatment of chronic nonumlignant pain may pose a challenge to the primary care physician (Olsen et aL, 2004). 25 Although an outright ban on opioid use in chronic nonmaligniant pain is no longer ethically acceptable, ensuring that opioids provide overall benefit to subjects requires significant physician time and skill. Subjects with chronic nonmalignant pain should be assessed and treated for concurrent psychiatric disorders; those with disorders are entitled to equivalent efforts at pain relief, The essential question is not whether chronic 30 nonmalignant pain is real or proportional to objective disease severity, but how it should be managed so that the subject's overall quality of life is optimized. 1) WO 2009/079518 PCT/US2008/087030 As early as the mid 1990s, naltrexone has been shown to effectively block morphine effects in humans (Kaiko et al, 1995). Morphine effects in normal volunteers were blocked by three 100-mg doses of naltrexone. The first dose of naltrexone was given 24 hours before dosing with controlled release morphine sulfate (MS Contin), 5 followed by a second dose at the time of MS Contin dosing and a third dose 24 hours after MS Contin administration. Single 200 mg doses of MS Contin given with the naltrexone blockade were generally well tolerated, and adverse effects were similar to those reported for naltrexone alone and for lower doses of morphine without naltrexone. Naltrexone proved safe and effective in blocking the effects of controlled release 10 morphine, permitting bioequivalence studies of a high dose of morphine in normal volunteers. Although well absorbed orally, naltrexone is subject to significant first-pass metabolism, with oral bioavailability estimates ranging from 5% to 40% (Naltrexone HCI Tablets, USP Package Insert). The activity of naltrexone is believed to be due to both the 15 parent compound and the 6-f-naltrexol metabolite. Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose); however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The mean elimination terminal half-life (t) values for naltrexone and 6~ -naltrexol are 4 hours and 13 hours, respectively. Naltrexone and 20 6j-1naltrexol are dose-proportional in terms of area under the concentration-time curve (AUC) and maximum plasma concentration (C.W) over the range of 50 to 200 mg and do not accumulate after 100 mig daily doses. Various formulations of opioids are in development that have a reduced risk of diversion and non-medical use and can be used to treat patients with chronic, 25 nonmalignant conditions Kadian® (morphine sulfiate extended-release capsule) was developed for use in subjects with chronic pain who require repeated dosing with a potent opioid analgesic, and has been tested in subjects with pain due to malignant and nonmalignant conditions, Kadian contains polymer-coated extended-release pellets of morphine sulfate, to deliver up to 24 hours of continuous pain relief. This formulation 30 lacks an immediate-release component, only providing a slow release of the analgesic. This slow-release technology serves to minimize plasma peaks and troughs, thereby WO 2009/079518 PCT/US2008/087030 pro viding a relatively flat pharmacokinetic (PK) curve upon multiple dosing. This delivery mechanism is ideally suited for chronic pam patients. Kadian capsules are an extended-release oral formulation of morphine sulfate indicated foi the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed 5 for an extended period of time. However, persons abusing opioids are likely to tamper with controlled-release formulations in hopes of obtaining the entire dose to induce an inmediate euphoria. To further deter non-medical opioid use, formulations containing opioid antagonists are being developed. As described herein, Kadian NT (morphine sulfate plus naltrexone 10 hydrochloride extended-release capsules), is a product that is intended to be used as an opiate analgesic for moderate to severe pain, Its abuse-deterrence feature incorporates an inmediate release of naltrexone upon illicit maipulation; this is intended to neutralize the euphoric potential of morphine and increase safety after ingestion of the tampered product. If Kadian NT is used as directed., a patient should receive a dose of morphine 15 equivalent to the same mg dose of Kadian, However, if the drug product is tampered with and ingested by a patient who is opioid dependent, the patient may be exposed to a dose of naltrexone sufficient to produce withdrawal symptoms. Abuse-resistant, sustained-release dosage forms of products intended to treat pain have been described in the art (see, for example, L. S Application Nos. 2003/0124185 20 and 2003/0044458). However, it is believed that substantial amounts of the opioid antagonist or other antagonist found in these sequestered forms are released over time (usually less than 24 hours) due to the osmotic pressure that builds up in the core of the sequestered forrm, as water permeates through the sequestered form into the core. The high osmotic pressure inside the core of the sequestered form causes the opiold 25 antagonist or antagonist to be pushed out of the sequestered form., thereby causing the opioid antagonist or antagonist to be released from the sequestered form. As shown below, certain embodiments described herein provide improved forms of sequestered opioid antagonists and contro lied-release opioid agon ists. In view of the foregoing drawbacks of the sequestered forms of the prior art, there 30 exists a need in the art for methods of treating pain, a sequestered form of an opioid antagonist or other antagonist that is not substantially released from the sequestered form 4 WO 2009/079518 PCT/US2008/087030 due to osmotic pressure. The invention provides such a sequestering form of an opioid antagonist or antagonist. This and other objects and advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein, BRIEF DESCRIPTION OFTHE DRAWINGS Figure 1. Mean BPI Score Over Time by Treatment Group-Aorst Pain in Past 24 Hours. Figure 2, Mean DPI Score Over Time by Treatment Group-east Pain in Past 24 10 Hours. Figure 3. Mean BPI Score Over Time by Treatment Group-Average Pain in Past 24 Hours. Figure 4. Mean BPI Score Over Time by Treatment Group-Current Pain Level, 15 BRIEF SUMMARY Provided herein is a phannaceutical composion comprising an antagonist, an agonist, a seal coat, and a sequestering polynier, wherein the antagonist, agonist, seal coat ana st onStqetrig II. and at least one sequestering polymer are all components of a single unit, and wherein the seal coat forms a layer physically separating the antagonist from tie agonist from one 20 another. The methods described herein provide methods for substantially relieving pain (e.g, providing an analgesic effect) for time periods of at least one week (e g,, two, four, eight, 12, 16, 20, 24, 28, 321 36, 40 and 100 weeks) with regular administration (e.g, once, twice. three or four times daily). In certain embodiments, no substantial release of the antagonist from the intact form of the composition is observed. Methods for 25 manufacturing such a pharmaceutical composition are also provided. All references referred to or cited in this application are hereby incorporated by reference in their entirety. DETAIL ED DESCRIPTION 30 Provided herein are compositions and methods for administering a multiple active agents to a mammal in a form and manner that minimizes the effects of either active 5 WO 2009/079518 PCT/US2008/087030 agent upon die other in vivo. In certain embodiments, at least two active agents are formulated as part of a pharmaceutical composition. A first active agent may provide a therapeutic effect in vivo. The second active agent may be an antagonist of the first active agent, and may be useful in preventing misuse of the composition. 'For instance, 5 where the first active agent is a narcotic, the second active agent may be an antagonist of the narcotic. The composition remains intact during normal usage by patients and the antagonist is not released. However, upon tampering with the composition, the antagonist may be released thereby preventing the narcotic from having its intended effect. In certain embodiments, the active agents are both contained within a single unit, 10 such as a bead, in the foru of layers. The active agents may be formulated with a substantially impermeable barrier as, for example, a controlled-release composition, such that release of the antagonist front the composition is minimized. In certain embodiments, the antagonist is released in in vitro assays but is substantially not released in vivO, In vitro and in vivo release of the active agent from the coimposition may be 15 measured by any of several well-known techniques. For instance, in vivo release may be determined by measuring the plasma levels of the active agent or metabolites thereof (i.e, AUC, Cmax), In certain embodiments, one of the active agents is an opioid receptor agonist Several opioid agonists are commercially available or in clinical trials and may be 20 administered as described herein such that the alcohol effects are minimized, Opioid agonists inclde, for example, alfentanil, allylprodine, alphaprodine, anileridine benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dilhydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimediylthianbutene, 25 dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethyl methylthiambmtene, ethyhmorphine, etonitazene, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isometbadone, ketobemidone, levallorphan, levorphanol, levophenacyhnorphan, lofentanil, meperidine, meptazinol. metazocine, m ethadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, 30 normethadone, nalorphine, normorphi.ne, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, 6 WO 2009/079518 PCT/US2008/087030 piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tranadol, tilidine, derivatives or complexes thereof, pharmaceutical acceptable salts thereof, and combinations thereof Preferably, the opioid agonist is selected from the group consisting of hydrocodone, hydromorphone, oxycodone, 5 dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof Most preferably, the opioid agonist is morphine, hydromorphone, oxycodone or hydrocodone. Equianalgesic doses of these opioids, in comparison to a 15 mg dose of hydrocodone, are as follows: oxycodone (13,5 mig), codeine (90.0 nig), hydrocodone 10 (15.0 mng), hydromorphone (3.375 mg), levorphanol (1.8 mg), meperidine (135.0 mg), methadone (9.0 mg), and morphine (27.0 mg). A common dosage fonn of hydrocodone is in combination with acetaminophen and is commercially available, for example, as Lortab@ in the United States from UCB Pharma, Inc. (Brussels, Belgiumi), as 2.5/500 mg, 5/500 mg, 7,5/500 mg and 10/500 mg 15 hydrocodone/acetaiinophen tablets. Tablets are also available in the ratio of 7.5 tug hydrocodone bitartrate and 650 mg acetaminophen and a 7.5 mg hydrocodone bitartiate and 750 mg acetaminophen. Hydrocodone, in combination with aspirin, is given in an oral dosage form to adults generally in 1 -2 tablets every 4-6 hours as needed to alleviate pain. The tablet fbrm is 5 mug hydrocodone bitartrate and 224 mg aspirin with 32 mg 20 caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin, Another formulation comprises hydrocodone bitartrate and ibuprofen. Vicoprofen@, commercially available in the U.S. from Knoll Laboratories (Mount Olive, N.), is a tablet containing 7,5 mng hydrocodone bitartrate and 200 mng ibuprofen. The invention is contemplated to encompass all such formulations, with the inclusion of the opioid antagonist and/or 25 antagonist in sequestered form as pan of a subunit comprising an opioid agonist. Oxycodone, chemically known as 4,5-epoxy- 14-hydroxy-3-methoxy-l17 methylmorphinan-6-one, is an opioid agonist whose principal therapeutic action is analgesia. Other therapeutic effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. The precise mechanism of its analgesic action is not known, but 30 specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic 7 WO 2009/079518 PCT/US2008/087030 effects of this drag,. Oxycodone is commercially available in the United States, e.g., as Oxycotin@D from Purdue Pharia LP. (Stamford, Conn), as controllede-rlease tablets for oral administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodone hydrochloride, and as OxvIRTI-, also from Purdue Pharma LP., as immediate-release capsules 5 containing 5 mg oxycodone hydrochloride. The invention is contemplated to encompass all such fornulations, with the inclusion of an opioid antagonist and/or antagonist in sequestered form as part of a subunit comprising an opioid agonist. Oral hydromorphone is conmercially available in the United States, e.g., as Dilaudid@' from Abbott Laboratories (Chicago, III). Oral. morphine is commercially 10 available in the United States, e.g,. as Kadian@ from Faulding Laboratories (Piscataway, NJ In embodiments in which the opioid agonist comprises hydrocodone, the sustained-release oral dosage forms can include analgesic doses from about 8 mg to about 50 mg of hydrocodone per dosage unit. In sustained-release oral dosage forms where 15 hydromorphone is the therapeutically active opioid, it is included in an amount from about 2 mg to about 64 mg hydromorphone hydrochloride. In another embodiment, the opioid agonist comprises morphine, and the sustained-release oral dosage forms of the invention include from about 2.5 mg to about 800 mg morphine, by weight. In yet another embodiment, the opioid agonist comprises oxycodone and the sustained-release 20 oral dosage forms include from about 2.5 mug to about 800 mg oxycodone. In certain preferred embodiments, the sustained-release oral dosage forms include from about 20 mg to about 30 mg oxycodone. Controlled release oxycodone formulations are known in the art. Tite following documents describe various controlled-release oxycodone formulations suitable for use in the invention described herein, and processes for their 25 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 can comprise tramadol and the sustained-release oral dosage forms can include from about 25 mg to 800 mg tramadol per dosage unit. In certain embodiments, another active agent contained within the composition 30 may be an opioid receptor antagonist In certain embodiments, the agonist and antagonist are administered together, either separately or as part of a single pharmaceutical unit. In 8 WO 2009/079518 PCT/US2008/087030 the instance when the therapeutic agent is an opioid agonist, the antagonist preferably is an opioid antagonist, such as naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof More preferably, the opioid antagonist is naloxone or naltrexone. 5 By "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, stereoisoners 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 10 calcium salt, magnesium salt, and the like; organic amine salts, such as triethylaniine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, and the like; inoranic acid salts. such as hydrochloride, hydrobromide, sulfate, phosphate, and the like; organic acid salts, such as fonnate, acetate, trifluoroacetate,. maleate, tartrate, and the like; sulfonates, such as 15 methanesulfon'ate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts, such as arginate, asparginate, glutamate, and the like. In certain embodiments, the amount of the opioid antagonist can be about 10 ng to about 275 mg. In a preferred embodiment, when the antagonist is nalhrexone, it is preferable that the intact dosage forn releases less than 0.125 mg or less within 24 hours, with 0.25 mg or greater of naltrexone released 20 after I hour when the dosage forn is crushed or chewed. In a preferred embodiment, 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 discernable subjective effects, and 24 mg naloxone causes only slight drowsiness. Small doses (0.4-0.8 .mg) of n.aloxo.ne given 25 intramuscularly or intravenously in man prevent or promptly reverse the effects of morphine-like opioid agonist. One mg of naloxone intravenouslv has been reported to block completely the effect of 25 mg of heroin. The effect of naloxone are seen almost immediately after intravenous administration- The drug is absorbed after oral administration, but has been reported to be metabolized into an inactive form rapidly in 30 its first passage through the liver, such that it has been reported to have significantly lower potency than when parenterally administered. Oral dosages of more than 1 g have 9 WO 2009/079518 PCT/US2008/087030 been reported to be almost completely metabolized in less than 24 hours, It has been reported that 25% of naloxone administered sublingually is absorbed (Weinberg et al., (in. PharmauoL Pher. 44335-340 (1988)), In another preferred embodiment, the opioid antagonist comprises naltrexone, In 5 the treatment of patients previously addicted to opioids, naltrexone has been used in large oral doses (over 100 mg) to prevent euphorigenic effects of opioid agonists, Naltrexone has been reported to exert strong preferential blocking action against mu over delta sites. Nahrexone is known as a synthetic congener of oxymorpihone with no opioid agonist properties, and differs in structure from oxymorphone by the replacement of the methyl 10 group located on the nitrogen atom of oxymorphone with a cyclopropylmethyl group. The hydrochloride salt of naltrexone is soluble in water up to about 100 mg/cc. The pharmacological arid phaniacokinetic properties of nalrexone have been evaluated in multiple animal and clinical studies. See, e.g., Gonzalez et al .Drus 35:192-213 (1988), Following oral administration, natrexone is rapidly absorbed (within 1 hour) and has an 15 oral bioavailability ranging from 5-40%. Naltrexone's protein binding is approximately 21% and the volume of distribution following single-dose administration is 16.1 L/kg, Naltrexone is commercially available in tablet form (Revia, DuPont (Wilmington, Del.)) for the treatment of alcohol dependence and for the blockade of exogenously administered opioids. See, e.g, Revia (naltrexone hydrochloride tablets), 20 Physician's Desk Reference, Sl ed, Montvale, Nl; and Medical Economics 51:957-959 (1997). A dosage of 50 mg Revia@ blocks the pharmacoloucal effects of 25 mg N administered heroin for up to 24 hours, It is known that, when coadministered with morphine, heroin or other opioids on a chronic basis, naltrexone blocks the development of physical dependence to opioids, It is believed that the method by which naltrexone 25 blocks the effects of heroin is 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 with narcotic addicts having good prognosis, as part of a comprehensive occupational or rehabilitative program involving behavioral control or other compliance 30 enhancing methods. For treatment of narcotic dependence with nahirexone, it is desirable that the patient be opioid-free for at least 7-10 days, The initial dosage of naltrexone for 10 WO 2009/079518 PCT/US2008/087030 such purposes has typically been about 25 mg, and if no withdrawal signs occur, the dosage may be increased to 50 mg per day. A daily dosage of 50 mng is considered to produce adequate clinical blockade of the actions of parenterally administered opioids. Naltrexone also has been used for the treatment of alcoholism as an adjunct with social 5 and psychotherapeutic methods. Other preferred opioid antagonists include, for example, cyclazocine and naltrexone, both of which have cyclopropylmethyl substitutions on. the nitrogen, retain much of their efficacy by the oral route, and last longer, with durations approaching 24 hours after oral administration., 10 The antagonist may also be a bittering agent, The term "bittering agent" as used herein refers to any agent that provides an unpleasant taste to the host upon inhalation and/or swallowing of a tampered dosage form comprising the sequestering subunit. With the inclusion of a bittering agent, the intake of the tampered dosage form produces a bitter taste upon inhalation or oral administration, which, in certain embodiments, spoils 15 or hinders the pleasure of obtaining a high from the tampered dosage form, and preferably prevents the abuse of the dosage form, Various bittering agents can be employed including, for example, and without limitation, natural, artificial and synthetic flavor oils and flavoring aromatics and/or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, and so forth, and 20 combinations thereof Nonlimiting representative flavor oils include spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol and the like. Also useful bittering agents are artificial, natural and synthetic fruit flavors such as citrus oils, including lemon, orange, lime, and grapefruit, fruit essences, and so forth. Additional battering agents include sucrose derivatives (e.g, sucrose 25 octaacetate), chlorosucrose derivatives, quinine sulphate, and the like. A. preferred bittering agent for use in the invention is Denatonium Benzoate NF-Anhydrous, sold under the name BitrexTYI (Macfarlan Smith Limited, Edinburgh, UK). A bittering agent can be added to the formulation in an amount of less than about 50% by weight, preferably less than about 10% by weight, more preferably less than about 5% by weight 30 of the dosage form, and most preferably in an amount ranging from about 0.1 to 1.0 percent by weight of the dosage form, depending on the particular bittering agents) used. 1 1 WO 2009/079518 PCT/US2008/087030 Alternatively, the antagonist may be a dye. The term "dye" as used herein refers to any agent that causes discoloration of the tissue in contact. In this regard, if the sequestering subunit is tampered with and the contents are snorted, the dye will discolor the nasal tissues and surrounding tissues thereof Preferred dyes are those that can bind 5 strongly with subcutaneous tissue proteins and are well-known in the art. Dyes useful in applications ranging from, for example, food coloring to tattooing, are exemplary dyes suitable for the invention. Food coloring dyes include, but are not limited to FD&C Green #3 and FD&C Blue 41, as well as any other FD&C or D&C color. Such food dyes are commercially available through companies, such as Voigt Global Distribution (Kansas 10 City, Mo.). The antagonist may alternatively be an irritant. The term "irritant" 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 tampering with the dosage form and thereafter 15 inhaling, injecting, or swallowing the tampered dosage form. Preferably, the irritant is released when the dosage form is tampered with and provides a burning or irritating effect to the abuser upon inhalation, injection, and/or swallowing the tampered dosage form. Various irritants can be employed including, for example, and without limitation, capsalen, a capsaicin analog with similar type properties as capsaicin, and the like. Some 20 capsaicin analogues or derivatives include, for example, and without limitation, resiniferatoxin, tinyatoxmn, hptanoyisobutylam ie heptanoyl guaiacylamide, other isobutyl aides or guaiacylamides, dihydrocapsaicin, homovan illyI octylester, nonanoyl vanillylarnide, or other compounds of the class known as vanilloids. Resiniferatoxin is described, for example, in U.S. Pat, No. 5,290,816. U.S. Pat, No. 4,8 12,446 describes 25 capsaicin analogs and methods for their preparation. Furthermore. U.S. Pat. No. 4,424,205 cites Newman, "Natural and Synthetic Pepper- Flavored Substances," published in 1954 as listing pungency of capsaicin-like analogs. Ton et at, Briish Journal of Phanacology 10:175-1.82 (1955), discusses pharmacological actions of capsaicin and its analogs, With the inclusion of an irritant (eg, capsaicin) in the dosage 30 form, the irritant imparts a burning or discomforting quality to the abuser to discourage the inhalation, injection, or oral administration of the tampered dosage form, and 12 WO 2009/079518 PCT/US2008/087030 preferably to prevent the abuse of the dosage form. Suitable capsaicin compositions include capsaicin (trans 8-methyl-N-vanillyl-6-noneamide) or analogues thereof in a concentration between about 0,00125% and 50% by weight, preferably between about 1% and about 7.5% by weight, and most preferably, between about 1% and about 5% by 5 weight. The antagonist may also be a gelling agent. The term "geling agent" as used herein refers to any agent that provides a gel-like quality to the tampered dosage form, which slows the absorption of the therapeutic agent, which is formulated with the sequestering subunit, such that a host is less likely to obtain a rapid "high," In certain 10 preferred embodiments, when the dosage form is tampered with and exposed to a small amount (e~g, less than about 10 ni) of an aqueous liquid (e.g., water), the dosage form will be unsuitable for injection and/or inhalation, Upon the addition of the aqueous liquid, the tampered dosage form preferably becomes thick and viscous, rendering it unsuitable 'for injection. The term "unsuitable for section" is defined for purposes of the invention 15 to mean that one would have substantial difficulty injecting the dosage form (e,g., due to pain upon administration or difficulty pushing the dosage form through a syringe) due to the viscosity imparted on the dosage form, thereby reducing the potential for abuse of the therapeutic agent in the dosage form. In certain embodiments, the gelling agent is present in such an amount in the dosage form that attempts at evaporation (by the application of 20 heat) to an aqueous mixture of the dosage form in an effort to produce a higher concentration of the therapeutic agent, produces a highly viscous substance unsuitable for injection. When nasally inhaling the tampered dosage form, the geling agent can become ge- Hike upon administration to the nasal passages, due to the moisture of the mucous membranes. This also makes such formulations aversive to nasal administration, as the 25 gel will stick to the nasal passage and minimize absorption of the abusable substance. Various gelling agents may can be employed including, for example, and without limitation, sugars or sugar-derived alcohols, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives, such as rnicrocrvstalline cellulose, sodium caboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, 30 hydroxypropyl celhdlose, and hydroxypropyl methylcellulose, attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacant, gum acacia, guar gum, xanthan gum, 13 WO 2009/079518 PCT/US2008/087030 pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomers and carbopols, polyvinylpyrrol done, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant/wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof; etc. In certain preferred embodiments, 5 the gelling agent is xanthan gum. In other preferred embodiments, the gelling agent of the invention is pectin. The pectin or pectic substances useful for this invention include not only purified or isolated pectates but also crude natural pectin sources, such as apple, citrus or sugar beet residues, which have been subjected, when necessary, to esterification or de-esterification, e.g., by alkali or enzymes. Preferably, the pectius used in this 10 invention are derived from citrus fruits, such as lime, lemon, grapefruit, and orange. With the inclusion of a gelling agent in the dosage form, the gelling agent preferably imparts a gel-like quality to the dosage form upon tampering that spoils or hinders the pleasure of obtaining a rapid high from due to the gel-like consistency of the tampered dosage form in contact with the mucous membrane, and in certain embodiments., prevents 15 the abuse of the dosage form by minimizing absorption, e.g., in the nasal passages. A gelling agent can be added to the formulation in a ratio of gelling agent to opioid agonist of from about 1:40 to about 40:1 by weight, preferably from about 1:1 to about 30:1 by weight, and more preferably from about 2:1 to about 10:1. by weight of the opioid agonist. In certain other embodiments, the dosage formi forms a viscous gel having a 20 viscosity of at least about 10 cP after the dosage form is tampered with by dissolution in an aqueous liquid (from about 0.5 to about 10 ml and preferably from I to about 5 ml), Most preferably, the resulting mixture will have a viscosity of at least about 60 cP. The antagonist can comprise a single type of antagonist (eg, a capsaicin), multiple forms of a single type of antagonist (e.g, a capasin and an analogue thereof, or 25 a combination of different types of antagonists (e., one or more bittering agents and one or more gelling agents), Desirably, the amount of antagonist in a unit of the invention is not toxic to the host, In one embodiment, the invention provides a sequestering subunit comprising an opioid antagonist and a blocking agent, wherein the blocking agent substantially prevents 30 release of the opioid antagonist from the sequestering subumt in the gastrointestinal tract for a time period that is greater than 24 hours. This sequestering subunit is incorporated 14 WO 2009/079518 PCT/US2008/087030 into a single pharmaceutical unit that also includes an opioid agonist. The pharmaceutical unit thus includes a core portion to which the opioid antagonist is applied. A seal coat is then optionally applied upon the antagonist. Upon the seal coat is then applied a composition comprising the pharmaceutically active agent. An additional layer 5 containing the same or a different blocking agent may then be applied such that the opioid agonist is released in the digestive tract over time (i.e., controlled release), Thus, the opioid antagonist and the opioid agonist are both contained within a single pharmaceutical unit, which is typically in the form of a bead. The term "sequestering subunit" as used herein refers to any means for containing 10 an antagonist and preventing or substantially preventing the release thereof in the gastrointestinal tract when intact, i.e., when not tampered with. The term "blocking agent" as used herein refers to the means by which the sCquCstering subunit is able to prevent substantially the antagonist from being released, The blocking agent may be a sequestering polymer, for instance, as described in greater detail below. 15 The terms "substantially prevents," "prevents," or any words stemmrin therefrom, as used herein, means that the antagonist is substantially not released from the sequestering subunit in the gastrointestinal tract, By "substantially not released" is meant that the antagonist may be released in a small amount, but the amount released does not affect or does not significantly affect the analgesic efficacy when the dosage form is 20 orally administered to a host, e,g., a mammal (e.g. a human), as intended, The terms "substantially prevents," "prevents," or any words stemming therefrori, as used herein., does not necessarily imply a complete or 100% prevention, Rather, there are varying degrees of prevention of which one of ordinary skill in the art recognizes as having a potential benefit. In this regard, the blocking agent substantially prevents or prevents the 25 release of the antagonist to the extent that at least about 80% of the antagonist is prevented from being released from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours. Preferably, the blocking agent 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 30 blocking agent prevents release of at least about 95% of the antagonist from the sequestering subunit. Most preferably, the blocking agent prevents release of at least 15 WO 2009/079518 PCT/US2008/087030 about 99% of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours. For purposes of this invention, the amount of the antagonist released after oral administration can be measured in-vitro by dissolution testing as described in the United 5 States Phannacopeia (USP26) in chapter <71 1> Dissolution. For example, using 900 mL of 0. 1 N HC, Apparatus 2 (Paddle), 75 rpm, at 374 C to measure release at various times from the dosage unit. Other methods of measuring the release of an antagonist from a sequestering subunit over a given period of time are known in the art (see, e.g., USP26). Without being bound to any particular theory, it is believed that the sequesterng 10 subunit of the invention overcomes the limitations of the sequestered forms of an antagonist known in the art in that the sequestering subunit of the invention reduces osrnoticalv-driven release of the antagonist frn t sequestering subunit Furthermore, it is believed that the present inventive sequestering subunit reduces the release of the antagonist for a longer period of time (e.g, greater than 24 hours) in comparison to the 15 sequestered forms of antagonists known in the art. The fact that the sequestered subunit of the invention provides a longer prevention 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 that the gastrointestinal tract transit time for individuals varies greatly within the population. Hence, the residue of the 20 dosage form may be retained in the tract for longer than 24 hours, and in some cases for longer than 48 hours. It is further well known that opioid analgesics cause decreased bowel motility, further prolonging gastrointestinal tract transit time. Currently, sustained release forms having an effect over a 24 hour time period have been approved by the Food and Drug Administration .in this regard, the present inventive sequestering subunit 25 provides prevention of release of the antagonist for a time period that is greater than 24 hours when the sequestering subunit has not been tampered. The sequestering subunit of the invention is designed to prevent substantially the release of the antagonist when intact By "intact" is meant that a dosage form has not undergone tampering. The term "tampering" is meant to include any manipulation by 30 mechanical, thermal and/or chemical means, which changes the physical properties of the dosage form. The tampering can be, for example, crushing, shearing, grinding, chewing. 16 WO 2009/079518 PCT/US2008/087030 dissolution in a solvent, heating (for example, greater than about 45' C.), or any combination thereof When the sequestering subunit of the invention has been tampered with, the antagonist is immediately released from the sequestering subunit By "subunit" is meant to include a composition, mixture, particle; etc., that can 5 provide a dosage form (e.g an oral dosage form) when combined with another subunit. The subunit can be in the form of a bead, pellet, granule, spheroid, or the like, and can be combined with additional same or different subunits, in the form of a capsule, tablet or the like, to provide a dosage form, e.g,, an oral dosage form. The subunit may also be part of a larger, single unit, forming part of that unit, such as a layer. For instance, the 10 subunit may be a core coated with an antagonist and a seal coat; this subunit may then be coated with additional compositions including a pharmaceutically active agent such as an opioid agonist. For purposes of the invention, the antagonist can be any agent that negates the effect of the therapeutic agent or produces an unpleasant or punishing stimulus or effect, 15 which will deter or cause avoidance of tampering with the sequestering subunit or compositions comprising the same. Desirably, the antagonist does not harm a host by its administration or consumption but has properties that deter its administration or consumpon, e.g., by chewig and swallowing or by crushing and snorting, for example. The antagonist can have a strong or foul taste or smell, provide a buying or tingling 20 sensation, cause a lachrymation response, nausea, vomiting, or any other unpleasant or repugnant sinsation, or color tissue, for example. Preferably., 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. 25 By "antagonist of a therapeutic agent" is meant any drug or molecule, naturally occurring or syuthetic, 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. In this regard, 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 30 preventing the achievement of a "high" in the host 17 WO 2009/079518 PCT/US2008/087030 In the instance when the therapeutic agent is an opioid agonist, the antagonist preferably is an opioid antagonist, such as naltrexone, naloxone, nalnefene, cyclazacine, levallorphan, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof. More preferably, the opioid antagonist is naloxone or 5 naltrexone. By "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, 10 such as calcium salt, magnesiuni salt, and the like; organic amine salts., such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexyl amine salt, N,N-dibenzylethylenediain e salt, and the like; inorganic acid salts, such as hydrochloride, hydrobromide, sulfate, phosphate, and the like; organic acid salts, such as fbrmate, acetate, trifluoroacetate, maleate, tartrate, and the like; sulfonates, 15 such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts, such as arginate, asparginate, glutamate, and the like., In certain embodiments, the amount of the opioid antagonist, present in sequestered form, can be about 10 ng to about 275 ng. In a preferred embodiment, when the antagonist is naltrexone, it is preferable that the intact dosage form releases less than 0. 125 mug or less within 24 hours, with 0.25 20 ng or greater of naltrexone released after 1 hour when the dosage form is crushed 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 capasin and an analogue thereof), or a combination of different types of antagonists (e.g, one or more bittering agents and one 25 or more gelling agents). Desirable, the amount of antagonist in the sequestering subunit of the invention is not toxic to the host. The blocking agent prevents or substantially prevents the release of the antagonist in the gastrointestinal tract for a time period that is greater than 24 hours, e.g., between 24 and 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 48 hours, 50 hours, 55 hours, 60 30 hours, 65 hours, 70 hours, 72 hours, 75 hours, 80 hours, 85 hours, 90 hours, 95 hours, or 100 hours; etc. Preferably, the time period for which the release of the antagonist is 18 WO 2009/079518 PCT/US2008/087030 prevented or substantially prevented in the gastrointestinal tract is at least about 48 hours. More preferably, the blocking agent prevents or substantially prevents the release for a time period of at least about 72 hours. The blocking agent of the present inventive sequestering subunit can be a system 5 comprising a first antagonist-impermeable material and a core. By "antagonist impermeable material" is meant any material that is substantially impermeable to the antagonist, such that the antagomst is substantially not released from the sequestering subunit. The term "substantially impermeable" as used herein does not necessarily imply complete or 100% impermeability. Rather, there are varying degrees of impermeability of 10 which one of ordinary skill in the art recognizes as having a potential benefit. in this regard, the antagonist-impermeable material substantially prevents or prevents the release of the antagonist to an exteit that at least about 80% of the antagonist is prevented from being released from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 2.4 hours. Preferably, tie antauonis-impermeable material prevents 15 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 release of at least about 95% of the antagonist from the sequestering subunit. Most preferably, the antagonist-i mperneable material prevents release of at least about 99% of the antagonist from the sequestering subunit in 20 the gastrointestinal tract for a time period that is greater than 24 hours. The antagonist impermeable material prevents or substantially prevents the release of the antagoist in the gastrointestinal tract for a timie period that is greater than 24 hours, and desirably, at least about 48 hours. More desirably, the antagonist-impermeable material prevents or substantially prevents the release of the adversive agent from the sequestering subunit for 25 a time period of at least about 72 hours. Preferably, the first antagonist-impermeable material comprises a hydrophobic material, such that the antagonist is not released or substantially not released during its transit through the gastrointestinal tract when administered orally as intended, without having been tampered with, Suitable hydrophobic materials for use in the invention are 30 described herein and set forth below. The hydrophobic material is preferably a 19 WO 2009/079518 PCT/US2008/087030 pharmaceutically acceptable hydrophobic material Preferably, the pharmaceutically acceptable hydrophobic material comprises a cellulose polymer. It is preferred that the first antagonist-impermeable material comprises a polymer insoluble in the gastrointestinal tract. One of ordinary skill in tie art appreciates that a 5 polymer that is insolible in the gastrointestinal tract will prevent the release of the antagonist upon ingestion of the sequestering subunit. The polymer can be a cellulose or an acrylic polyner. Desirably, the cellulose is selected from the group consisting of ethyleellulose, cellulose acetate, cellulose propionate, celulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, and 10 combinations thereof Ethylcellulose includes, for example, one that has an ethoxy content of about 44 to about 55%, Ethylcellulose can be used in the form of an aqueous dispersion, an alcoholic solution, or a solution in other suitable solvents. The cellulose can have a degree of substitution (D.S.) on the anhydroglucose unit, from greater than zero and up to 3 inclusive. By "degree of substitution" is mcant the average number of 15 hydroxyl groups on the anhydroglucose 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 triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, monocellulose alkanylate, dicell lose alkanylate, tricellulose alkanvlate, monocellulose alkenylates, dicellulose alkenylates, tricellulose 20 alkenylates, monocellulose aroylates, dicellulose aroylates, and tricellulose aroylates, More specific celluloses include cellulose propionate having a DS of 18 and a propyl content of 39.2 to 45 and a hydroxy content of 2.8 to 5.4%; cellulose acetate butyrate having a DS. of 1L8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%, a butyryl content 25 of 17 to 53% and a hydroxy content of 0.5 to 47%; cellulose triacylate having a D.S. of 2.9 to 3., such as cellulose triacetate., cellulose trivalerate, cellulose trilaurate, cellulose tripatmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to 2.6. such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose, such as cellulose acetate 30 butyrate, cellulose acetate octanoate butyrate, and cellulose acetate propionate. 20 WO 2009/079518 PCT/US2008/087030 Additional cellulose polymers useful for preparing a sequestering subunit of the invention includes acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methycarbamate., and cellulose acetate dimethylaminocellulose acetate. The acrylic polymer preferably is selected from the group consisting of methacrylic polymers, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl mehieacrylates, cyanoethyl methacrylate, poly(acrylic acid), po ly(methacrylic acid), methacrylic acid alkylamide copolymrer, poly(methyl methacrylate), polyniethacrylate, poly(methyl methacrylate) copolymer, 10 polyacrylamide, aminoalkyl metbacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers, and combinations thereof. An acrylic polymer useful for preparation of a sequestering subunit of the invention includes acrylic resist comprising copolymers synthesized from acrylic and inethacylic acid esters (eg, the copolymer of acrylic acid lower alkyl estr and niethacrylic acid lower alkyl ester) 15 containing about 0.02 to about 0.03 mole of a tri (lower alkyl) amnonium group per mole of the acrylic and methacrylic monomer used. An example of a suitable acrylic resin is amnionio nethacrylate copolvmer NF21, a polymer manufactured by Rohm Pharma GmbH, Darmstadt, Germany, and sold under the Eudragit@ trademark. Eudragit RS30D is preferred. Eudragit@ is a water-insoluble copolymer of ethyl acrylate (EA), methyl 20 methacrylate (NIM) and trimethy] ammonimethyl methacrylate chloride (TAM) in which the molar ratio of TAM to the remaining components (EA and MM) is A:40 Acrylic resins, such as Eudragit@, can be used in the form of an aqueous dispersion or as a soltion in suitable solvents. i another preferred embodiment, the antaonisis selected 25 from the group consisting of polylactic acid, polyglycolic acid, a co-polymer of polylactic acid and polyglycolic acid, and combinations thereof In certain other embodiments, the hydrophobic material includes a biodegradable polymer comprising a poly(lactic/glycolic acid) ("PLGA"), a polylactide, a polyglycolide, a polyanhydri de, a polyorthoester, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers., 30 polyesters, polydioxanone, polygluconate, polylactic-acid-polvethvlene oxide copolymers, poly~hydroxybutyrate), polyphosphoester or combinations thereof, 21, WO 2009/079518 PCT/US2008/087030 Preferably, the biodegradable polymer comprises a poly(lactic/glycolic acid), a copolymer of lactic and glycolic acid, having a molecular weight of about 2,000 to about 500,000 daltons. The ratio of lactic acid to glycolic acid is preferably from about 100:1 to about 25:75, with the ratio of lactic acid to glycolic acid of about 65:35 being more 5 preferred. Poly(lactic/glycolic acid) can be prepared by the procedures set forth in US. Pat. No. 4,293,539 (Ludwig et al), which is incorporated herein by reference, h1 brief, Ludwig prepares the copolymer by condensation of lactic acid and glycolic acid in the presence of a readily removable polymerization catalyst (e.g a strong ion-exchange resin 10 such as Dowex HCR-W2-H). The amount of catalyst is not critical to the polymerization., but typically is from about 0,01 to about 20 parts by weight relative to the total weight of combined lactic acid and glycolic acid. The polImerization reaction can be conducted without solvents at a temperature from about 100* C. to about 2504 C. for about 48 to about 96 hours, preferably under a reduced pressure to ffacilitate removal of water and by 15 products. Poly(lactic/glycolic acid) is then recovered by filtering the molten reaction mixture in an organic solvent, such as dichloromethane or acetone, and then filtering to remove the catalyst. Suitable plasticizers, for example, acetyl triethyl. citrate, acetyl tributyl citrate, triethyl citrate, diethyl phthalate, dibutyI phthalate, or dibutyl sebacate, also can. be 20 admixed with the polymer used to make the sequestering subunit- Additives, such as coloring agents, talc and/or magnesiun stearate, and other additives also can be used in making the present inventive sequestering subunit. In certain embodinents, additives may be inchided in the compositions to improve the sequestering characteristics of the sequestering subunit. As described below, 25 the ratio of additives or components with respect to other additives or components may be modified to enhance or delay improve sequestration of the agent contained within the subunit. Various amounts of a functional additive (. a charge-neutralizing additive) may be included to vary the release of an antagonist, particularly where a water-soluble core (i.e, a sugar sphere) is utilized. For instance, it has been determined that the 30 inclusion of a low amount of charge-neutralizing additive relative to sequestering polymer on a weight-by-weight basis may cause decreased release of the antagonist, 22 WO 2009/079518 PCT/US2008/087030 In certain embodiments, a surfactant may serve as a charge-neutralizing additive. Such neutralization may in certain embodiments reduce the swelling of the sequestering polymer by hydration of positively charged groups contained therein. Surfactants (ionic or non-ionic) may also be used in preparing the sequestering subunit, It is preferred that 5 the surfactant be ionic. Suitable exemplary agents include, for example, alkylaryl sulphonates, alcohol sulphates., sulphosuccinates, sulphosuccinamates. sarcosinates or taurates and others. Additional examples mclude but are not limited to ethoxylated castor oil, benzalkonium chloride, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene fatty acid esters, polyoxyethylene 10 derivatives, nonoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium lauryl sulfate, dioctyl sodium sulphosuccinate, sodiumn auryl sarcosinate and sodium methyl cocoyl taurate, magnesium lauryl sufiate, triethanolamine., cetrimide, sucrose laurate and other sucrose esters, glucose (dextrose) esters, simethicone, ocoxyniol, dioctyl sodiumsulfosuceinate, 15 polyglycolyzed glycerides, sodiumdodecylbenzene sulfonate. dialkyl sodiumsulfosuccinate, fatty alcohols such as lauryl, cetyl, and steryl,glycerylesters, cholic acid or derivatives thereof, lecithins, and phospholipids. These agents are typically characterized as ionic (ie, anionic or cationic) or nonionic. In certain embodiments described herein, an anionic surfactant such as sodium lauryl sulfate (SLS) is preferably 20 used (U.S. Pat. No. 5,725,883; U.S. Pat, No. 7,201,920; EP 502642A1; Shokri, et al. Pharn Sci. 2003I. The e t f sodium lawyl sulphate on the release ofadiazepain fom solid dispersions prepared by corbndln technique, Wells, et at, Lject of Anionic Suracmnts on the Release of Chlorpheniramine aleate From an Inert, Heierogeneous Matrix, Drug Development and Industrial Pharmacy 18(2) (1992): 175-186, Rao, et al 25 "Fffect of Sodium Laurvl Sulfate on the Release of Rifampicin from Guar Gum Matrix." idian Jourmal of Pharmaceutical Science (2000) 404-406; Knop, et al Influence of surfactan of diterent charge and concentration on drIg release from pellets coated with an aqueous dispersion of quternary cnyic polymers. ST P Phanna Sciences. Vol 7, No, 6, (1997) 507-512). Other suitable agents are known in the art, 30 As shown herein, SLS is particularly useful in combination with Eudragit RS when the sequestering subunit is built upon a sugar sphere substrate. The inclusion of 23 WO 2009/079518 PCT/US2008/087030 SLS at less than approximately 6.3% on a weight-to-weight basis relative to the sequestering polymer (i.e., Eudragit RS) may provide a charge neutralizing ftuction (theoretically 20% and 41% neutralization, respectfully), and thereby significantly slow the release of the active agent encapsulated thereby (i.e, the antagonist naltrexone) 5 Inclusion of more than approximately 6.3% SLS relative to the sequestering polymer appears to increase release of the antagonist from the sequestering subunit. With respect to SLS used in coiunction with Eudragit( RS, it is preferred that the SLS is present at approximately 1%, 2%, 3%,4% or 5%, and typically less than 6% on a w/w basis relative to the sequestering polymer (i.e., Eudragi' RS). In preferred embodiments, SLS may be 10 present at approximately 1.6% or approximately 3.3% relative to the sequestering polymer, As discussed above, many agents (ie., surfactants) may substitute for SLS in the compositions disclosed herein. Additionally useful agents include those that may physically block migration of the antagonist from the subunit and ! or enhance the hydrophobicity of the barrier. One 15 exemplary agent is talc, which is commonly used in pharmaceutical compositions (Pavar et al. Agglomerafion iof bprofen With Tal/c b Novel Crysta!/o-Co Agglomeation Technique, AAPS PharmSeiTech. 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. Any form of talc may be used, so long as it does not detrimentally 20 affect the function of the composition. Most talc results from the alteration of dolomite (CaM g(CO)2 or magnesite (MgO) in the presence of excess dissolved silica (SiO2) or by altering serpentine or quarzite. Talc may be include minerals such as tremolite (CaM g(SiO,)4), serpentine (3MgO-2SiO 2 2lH2z0), anthophyllite (Mgr(OH 0)1(SiaQ )2), magnesite, mica, chlorite, dolomite, the calcite form of calcium carbonate (CaCO3), iron 25 oxide, carbon, quartz, and / or manganese oxide. The presence of such impurities may be acceptable in. the compositions described herein provided the function of the talc is maintained. It is preferred that that talc be USP grade, As mentioned above, the function of talc as described herein is to enhance the hydrophobicity and therefore the functionality of the sequestering polymer. Many substitutes for talc may be utilized in 30 the compositions described herein as may be determined by one of skill in the art. 24 WO 2009/079518 PCT/US2008/087030 It has been determined that the ratio of talc to sequestering polymer may make a dramatic difference in the functionality of the compositions described herein. For instance, the Examples described below demonstrate that the talc to sequestering polymer ratio (w/w) is important with respect to compositions designed to prevent the release of 5 naltrexone therefrom. It is shown therein that inclusion of an approximately equivalent amount (on a weight-by-weight basis) of talc and Eudragit* RS results in a very low naltrexone release profile. In contrast, significantly lower or higher both a lower (69% wfw) and a higher (151% w/w) talc E udragt R.S ratios result in increased release of naltrexone release. Thus. where talc and Eudragit* RS are utilized, it is preferred that 10 talc is present at approximately 75%, 80%,. 85%, 90%, 95%, 100%, 105%:, 110%., 15%., 120% or 1 25% w/w relative to Eudragit RS. As described above, the most beneficial ratio for other additives or components will vary awd may be determined using standard experimental procedures, In certain embodiments, such as where a water-soluble core is utilized, it is useful 15 to include agents that may affect the osmotic pressure of the composition (i,, an osmotic pressure regulating agent) (see, in general, WO 2005/046561 A2 and WO 2005/046649 A2 relating to Eudramode"). This agent is preferably applied to the Eudragit* RS / talc laver described above. In a pharmaceutical uit comprising a sequestering subunit overlayed by an active agent (i.e., a controlled-release agonist preparation), the osmotic 20 pressure regulating agent is preferably positioned immediately beneath the active agent layer. Suitable osmotic pressure regulating agents may include, for instance, hydroxypropylmethyl cellulose (HPMC) or chloride ions (i.e., from NaCl), or a combination of IPMJC and chloride ions (i.e., from NaCI). Other ions that may be useful include bromide or iodide. The combination of sodium chloride and HPMC may be 25 prepared in water or in a mixture of ethanol and water, for instance. H PMC is commonly utilized in phannaceutical compositions (see, for example, US, Pat. Nos. 7,226,620 and 7,229,982). In certain embodiments, H PMC may have a molecular weight ranging from about 10,000 to about 1,500,000. and typically from about 5000 to about 10,000 (low molecular weight HPMC). The specific gravity of HJPMC is typically from about 1,19 to 30 about L31, with an average specific gravity of about 1.26 and a viscosity of about 3600 to 5600. HPMC may be a water-soluble synthetic polymer. Examples of suitable, 25 WO 2009/079518 PCT/US2008/087030 commercially available hydroxypropyl methylcellulose polymers include Methocel K100 LV and Methocel K4M (Dow). Other HPMC additives are known in the art and may be suitable in preparing the compositions described herein. As shown in the Examples, the inclusion of NaCl (with HPMC) was found to have positively affect sequestration of 5 naltrexone by Eludragit RS. In certain embodimnents, it is preferred that the charge neutralizing additive (i.e. NaCl) is included at less than approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% of the composition on a weight-by-weitght basis. In other preferred embodiments, the charge-neutralizing additive is presei at approximately 4% of the composition on a weight-by-weight basis, 10 Thus, in one embodiment, a sequestering subunit built upon a sugar sphere substrate is provide d comprising a sequestering polymer (i.e., Eudragit* RS) in combination with several opimizming agents, including sodimn lauri sulfate (SLS) as a charge-neutralizing agent to reduce swelling of the film by hydration of the positively charged groups on the polymer; tale to create a solid imperneable obstacle to naltrexone 15 transport through the film and as a hydrophobicity-enhacing agent; and a chloride ion (i.e,, as NaCI) as an osmotic pressure reducing agent. The ratio of each of the additional ingredients relative to the sequestering polymer was surprisingly found to be important to the Function of the sequestering subunit. For instance, the Examples provide a sequestering subunit including a sequestering polymer and the optimizing agents SLS at 20 less than 6%, preferably 1-4%, and even more preferably 1 6% or 3.3% on a w/w basis relative to Eudragit RS: talc in an amount approximately equal, to Eudragi" KS (on a ww basis): and, NaCI present at approximately 4% on a w/w basis relative to Eudragit* RS_ The therapeutic agent applied upon the sequestering subunit may be any 25 medicament. The therapeutic agent of the present inventive compositions can be any medicinal agent used for the treatment of a condition or disease, a pharmaceutically 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, non steroidal anti-inflammatory drugs ("NSAIDS"), N-methyl-D-aspartate ("NMDA") 30 receptor antagonists, cycooxygenase-II inhibitors ("COX-l inhibitors"), and glycine receptor antagonists), an antibacterial agent, an anti-viral agent, an anti-microbial agent, 26 WO 2009/079518 PCT/US2008/087030 anti-infective agent., a chemotherapeutic, an immunosuppressant agent, an annitussive, an expectorant, a decongestant, an antihistamine drugs, a decongestant, antihistamine drugs, and the like. Preferably, the therapeutic agent is one that is addictive (physically and/or psychologically) upon repeated use and typically leads to abuse of the therapeutic agent. 5 in this regard, the therapeutic agent can be any opioid agonist as discussed herein. The therapeutic agent can be an opioid agonist, By "opioid" is meant to include a drug, hormone., or other chemical or biological substance, natural or synthetic, having a sedative, narcotic, or otherwise similar effect(s) to those containing opium. or its natural or synthetic derivatives. By "opioid agonist," sometimes used herein interchangeably 10 with terms "opioid" and "opioid analgesic," is meant to include one or more opioid agonists, either alone or in combination, and is further meant to include the base of the opioid, mixed or combined agonist-antagonists, partial agonists, pharmaceutically acceptable salts thereof, stereoisomers thereof, ethers thereof, esters thereof, and combinations thereof. 15 Opioid agonists include, for example, alfentanil, allyiprodine,. alphaprodine., anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diamnpromide, di hydrocodeine, dihydroetorphine, dihvdromorphine, dimienoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine., ethoheptazine, 20 ethylmethylthianibutene, ethyliorphine, etonitazene, etorphine, fentany, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemi done, levallorphan, levorphanol, levophenacylnorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine., nalbtphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, 25 opium, oxycodone, oxyniorphone, papaveretu, pentazocine, ph enadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, piritramide, propheptazine, proniedol, properidine, propiram, propoxyphene, sufentanil, tramadol. tilidine, derivatives or complexes thereof, pharmaceutically acceptable salts thereof, and combinations thereof Preferably, the opioid agonist is selected from the group consisting 30 of hydrocodone, hydronmorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, derivatives or complexes thereof, 27 WO 2009/079518 PCT/US2008/087030 pharmaceutically acceptable salts thereof, and combinations thereof. Most preferably, the opioid agonist is morphine, hydromorphone, oxycodone or hydrocodone. In a preferred embodiment, the opioid agonist comprises oxycodone or hydrocodone and is present in the dosage form in an amount of about 15 to about 45 mg, and the opioid antagonist 5 comprises nalirexone and is present in the dosage form in an amount of about 0.5 to about 5 mg. Equianalgesic doses of these opioids, M comparison to a .15 rmg dose of hydrocodone, are set forth in Table 1 below: 10 Table I Equianalgesic Doses of Opioids Opioid Calculated Dose (mg) Oxycodone 13.5 Codeine 90,0 Hydrocodone 15,0 Hydromorphone 3_375 Levorphanol 1.8 Meperidine 135.0 Methadone 9.0 Morphine 27.0 Hydrocodone is a semisynthetic narcotic analgesic and antitussive with multiple nervous system and gastrointestinal actions. Chemically, hydrocodone is 4,5-epoxy-3 15 methoxy- I 7-metylrorphina-6-one, and is also known as dihydrocodeinone. Like other opioids, hydrocodone can be habit-forining and can produce drug dependence of the morphine type, Like other opium derivatives, excess doses of hydrocodone will depress respiration. Oral hydrocodone is also available in Europe (e.g,, Belgium, Germany, Greece, 20 Italy, Luxembourg, Norway and Switzerland) as an antitussive agent. A parenteral formulation is also available in Germany as an antitssive agent. For use as an analgesic, 28 WO 2009/079518 PCT/US2008/087030 hydrocodone bitartrate is commonly available in the United States only as a fixed combination with non-opiate drugs (e.g, ibuprofen, acetaminopb.en, aspirin; etc.) for relief of moderate to moderately severe pain. A common dosage form of hydrocodone is in combination with acetaminophen 5 and is commercially available, for example, as Lortab@ in the United States from U(CB Pharma, Inc. (Brussels, Belgium), as 2.5/500 mg., 5/500 mg, 7,5/500 mg and 10/500 mg hydrocodonefacetamiinophen tablets. Tablets are also available in the ratio of 7.5 mg hydrocodone bitart-rate and 650 mg acetaminophen and a 7.5 mg hydrocodone bitartrate and 750 mg ace taminophen. Iydrocodone, in combination with aspirin, is given in an 10 oral dosage form to adults generally in 1-2 tablets every 4-6 hours as needed to alleviate pain, The tablet form is 5 mg hydrocodone bitartrate and 224 mg aspirin with 32 mg caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin. Another formulation comprises hydrocodone bitartrate and ibuprofen. Vicoprofen@, commercially available in the U.S. from Knoll Laboraories (Mount Olive, N.J.), is a tablet containing 7.5 mg 15 hydrocodone bitartrate and 200 mg ibuprofen. The 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. Oxvcodone, chemically known as 4,5-epoxy -14~ihydroxv-3-methoxyt-l7 nmethyhorphinan-6-one, is an opioid agonist whose principal therapeutic action is 20 analgesia. Other therapeutic effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. The precise mechanism of its analgesic action, is not known. but specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. 25 Oxycodone is commercially available in the United States, e.g, as Oxycotin@ from Purdue Pharma L.P. (Staniford, Conn., as controlled-release tablets for oral administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodone hydrochloride, and as OxylRTM, also from Purdue Pharma LP., as immediate-release capsules containing 5 mg oxycodone hydrochloride. The invention is contemplated to encompass all such 30 forrnuIlations, with the inclusion of an opioid antagonist and/or antagonist in sequestered form as part of a subunit comprising an opioid agonist. 29 WO 2009/079518 PCT/US2008/087030 Oral hydromorphone is comnmercially available in the United States, e.g, as DilaudidC from Abbott Laboratories (Chicago, ll). Oral morphine is commercially available in the United States, e g, as Kadiatn@ from Faulding Laboratories (Piscataway, N.J) 5Exemplary NSAIDS include ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen., flubu fen, ketoprofen, indoprofen, piroprofen, carprofen. oxaprozin, pramoprofen, muroprofen, trioxaprofen, suproten, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, topinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic 10 acid, flufenamic acid, niflumic acid, tolfenamic acid., ditlurisal, flufenisal, piroxicam., sudoxicam or isoxicam, and the like. Usefil dosages of these drugs are well-known, Exemplary NMDA receptor medicaments Include norphinans, such as dexotromethorphan or dextrophan, ketamiin, d-methadone, and pharmaceutically acceptable salts thereof, and encompass drugs that block a major intracellular 15 consequence of NM DA-receptor activation, e.g., a ganglioside, such as (6-aminothexyl) 5-chloro-1 -naphthalenesnlfonamide. These drugs are stated to inhibit the development of tolerance to and/or dependence on addictive drugs, e.g., narcotic analgesics, such as morphine, codeine; etc., in U.S. Pat. Nos. 5,321,012 and 5,556;838 (both to Mayer al ), both of which are incorporated herein by reference, and to treat chronic pain in U.S. Pat. 20 No. 5,502,058 (Mayer et al,), incorporated herein by reference. The NMDA agonist can be included alone or in combination with a local anesthetic, such as lidocaine, as described in these patents by Mayer et al. COX-2 inhibitors have been reported in the art, and many chemical compounds are known to produce inhibition of cyclooxygenase-2, COX-2 inhibitors are described, 25 for example, in U.S. Pat. Nos. 5,616,601: 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436265; 5,409,944 and 5,130,311, all of which are incorporated herein by reference. Certain preferred COX 2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2-naphtbylacetic acid (6-NMA), MK-966 (also known as Vioxx), 30 nabumetone (prodrug for 6~MNA), niiesulide, NS-398, SC-5766, SC-58215, T-614. or combinations thereof Dosage levels of COX-2 inhibitor on the order of from about 0,005 30 WO 2009/079518 PCT/US2008/087030 mg to about 140 mg per kilogram of body weight per day have been shown to be therapeutically effective in combination with an opioid analgesic, Altematively, 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 chronic pain via the use of glycine receptor antagonists and the identification of such drugs is described in U.S. Pat. No. 5,514,680 (Weber et al), which is incorporated herein by reference. Pharmaceutically acceptable salts of the antagonist or agonist agents discussed herein include metal salts, such as sodium sal, potassium salt, cesium salt, and the like; 10 alkaline earth metals, such as calcium salt, magnesium saft, and the like or ganic amine salts, such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolanmine salt, dicyclohexylamine salt, N,Ndtibenzvletiylenediamne sail, and the like; inorganic acid salts, such as hydrochloride, hydrobromide, sulfate, phosphate, and the like: organic acid salts, such as format. acetate, trifluoroacetate, maleue, tartrate, and 15 the like; sulfonates, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid sals, such as arginate, asparginate, glutamate, and the like, In embodiments in which the opioid agonist comprises hydrocodone, the sustained-release oral dosage forns can include analgesic doses from about 8 rug to about 50 m, of hydrocodone per dosage unit, In sustained-release oral dosage forms where 20 hydromorphone is the therapeutically active opioid, it is included in an amount from about 2 mg to about 64 ng hydromorphone hydrochloride, In another embodiment, the opioid agonist comprises morphine, and the sustained-release oral dosage forms of the invention include from about 2.5 mg to about 800 mg morphine, by weight, In yet another embodiment, the opioid agonist comprises oxycodone and the sustained-release 25 oral dosage forms include from about 2.5 mg to about 800 mg oxycodone. In certain preferred embodiments, the sustained-release oral dosage forms include from about 20 mg to about 30 mg oxvcodone. Controlled release oxycodone forniulations are known in the art. The following documents describe various controlled-release oxycodone fornulations suitable for use in the invention described herein, and processes for their 30 manufacture: 11S. Pat. Nos. 5,266,331; 5,549,912; 5,508,042; and 5,656,295, which are incorporated herein by reference. The opioid agonist can comprise tramadol and the 31 WO 2009/079518 PCT/US2008/087030 sustained-release oral dosage forms can include from about 25 img to 800 mg tramadol per dosage unit. Methods of making any of the sequestering subunits of the invention are known in the art. See, for example, Remington: The Science and Pie/ice ofPha'nrmacy, Alfonso R. 5 Genaro (ed), 201 edition, and Example 2 set forth below. The sequestering subunits can be prepared by any suitable method to provide, for example, beads, pellets, granules, spheroids., and the like. Spheroids or beads, coated with an active ingredient can be prepared, for example, by dissolving the active ingredient in water and then spraying the solution onto a substrate, for example, nu pariel 18/20 beads, using a Wurster insert. 10 Optionally, additional ingredients are also added prior to coating the beads in order to assist the active ingredient in binding to the substrates, and/or to color the solution; etc. The resultng substrate-active material optionally can be overcoated with a barrier material to separate the therapeutically active agent from the next coat of material, e.g, release-retarding material. Preferably, the barrier material is a material comprising 15 hydroxypropyl methylcellalose. However, any fIm-former known in the art can be used. Preferably, the barrier material does not affect the dissolution rate of the final product. Pellets comprising an active ingredient can be prepared, for example, by a melt pelletization technique. Typical of such techniques is when. the active ingredient in finely divided form is combined with a binder (also in particulate form) and other optional inert 20 ingredients, and thereafter the mixture is pelletized, e.g,, by mechanically working the mixture ini a high shear mixer to form the pellets (erg, pellets, granules, spheres, beads; etc, collectively referred to herein as "pellets"). Thereafter, the pellets can be sieved in order to obtain pellets of the requisite size. The binder material is preferably in particulate form and has a melting point above about 40' C. Suitable binder substances include, for 25 example, hydrogenated castor oil, hydrogenated vegetable oil, other hydrogenated fats, fatty alcohols, fatty acid esters, fatty acid glycerides, and the like, The diameter of the extruder aperture or exit port also can be adjusted to vary the thickness of the extruded strands. Furthermore, the exit part of the extruder need not be round; it can be oblong, rectangular; etc. The exiting strands can be reduced to particles 30 using a hot wire cutter, guillotine; etc. 32 WO 2009/079518 PCT/US2008/087030 The nelt-extruded multiparticrdate system can be, for example, in the form of granules, spheroids, pellets, or the like, depending upon the extruder exit orifice. The terms "melt-extruded multiparticulate(s)" and "melt-extruded multiparticulate systemss" and "melt-extruded particles" are used interchangeably herein and include a plurality of 5 subunits, preferably within a range of similar size and/or shape. The melt-extruded multiparticulates are preferably in a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 nm. In addition, the melt-extruded nultiparticulates can be any geometrical shape within this size range. Alternatively, the extrudate can simply be cut into desired lengths and divided into unit doses of the 10 therapeutically active agent without the need of a spheronization step. The substrate also can be prepared via a granulation technique, Generally, melt granulation techniques involve melting a normally solid hydrophobic material, e.g., a wax, and incorporating an active ingredient therein. To obtain a sustained-release dosage fon, it can be necessary to incorporate an additional hydrophobic material.. 15 A coating composition can be applied onto a substrate by spraying it onto the substrate using any suitable spray equipment. For example, a Wurster fluidized-bed system can be used in which an air flow from underneath,. fluidizes the coated material and effects drying, while the insoluble polynier coating is sprayed on. The thickness of the coating will depend on the characteristics of the particular coating composition, and 20 can be determined by using routine experimentation. Any maIner of preparing a subunit can be employed. By way of example, a subunit in the form of a pellet or the like can be prepared by co-extruding a material comprising the opioid agonist and a material comprising the opioid antagonist and/or antagonist in sequestered form. Optionally, the opioid agonist composition can. cover, 25 e.g., overcoat, the material comprising the antagonist and/or antagonist in sequestered form. A 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 agonist. The sequestering subunits of the invention are particularly well-suited for use in 30 compositions compnsing the sequestering subunit and a therapeutic agent in releasable form. In this regard, the invention also provides a composition comprising any of the 33 WO 2009/079518 PCT/US2008/087030 sequestering subunits of the invention and a therapeutic agent in releasable form. By releasablee 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 5 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 10 chosen so as to achieve, in combination with the other stated properties, a desired in vitro release rate. In a preferred embodiment, the oral dosage form, of the invention can be formulated to provide for an increased duration of therapeutic action allowing once-daily dosing In general, a release-retarding material is used to provide the increased duration 15 of therapeutic action. Preferably, the once-daily dosing is provided by the dosage forms and methods described in U.S. Patent Application Pub. 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, al-kylcelluloses, 20 shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and combinations thereof. In certain preferred embodiments, the release-retarding material is a pharmaceutically acceptable acrylic polymer, including acrylic acid. and methacrylic acid copolyners, meth acrylate copolymers, ethoxyethyl nethacriltes, cynaoethyl methacry late, aminoalkyl rmiethacrvlate copolymer, poly(acrylic acid), poly(methacrylic 25 acid), methacrylic acid alkylamide copolymer, poly(nmethyl methacrylate), poly(methacrylic acid anhydride), methyl methacrylate, polymetnehacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, arminoalkyl methacrylate copolymer, and glycidyl methacrylate copolyiners. In certain preferred embodiments, the acrylic polymer comprises one or more ammonio methacrylate copolymers, Ammonio methacrylate 30 copolymers are well-known in the art, and are described in NF2 1, the 21'edition of the National Formulary, published by the United States Pharmacopeial Convention Inc. 34 WO 2009/079518 PCT/US2008/087030 (Rockville, Md. ) as fully polymerized copolymers of acrylic and methacryic acid esters with a low content of quaternary ammonium groups. In other preferred embodiments, the release-retarding material Is an alkyl cellulosic material, such as ethyleellulose. Those skilled in the art will appreciate that other cellulosic polymers, including other alkyl 5 cellulosic polymers, can be substituted for part or all of the ethylcellulose. Release-modifying agents, which affect the release properties of the release retarding material, also can be used. In a preferred embodiment, the release-modifying agent functions as a pore-former. The pore-former can be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the 10 environment of use, The pore-former can comprise one or more hydrophilic polymers., such as hydroxyproplmruethylcelulose. in certain preferred embodiments, the release modifving agent is selected from hy droxypropylImethIlcellulose, lactose ,.metal stearates, and combinations thereof The release-retarding material can also include an erosion-promoting agent, such 15 as starch and gums; a release-niodifying 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 semi permeable polyner. The release-retarding material can also include an exit means comprising at least 20 one passageway, orifice, or the like. The passageway can be formed by such methods as those disclosed in US, Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864, which are incorporated herein by reference. The passageway can have any shape, such as round, triangular, square, elliptical, irregular; etc. In certain embodiments, the therapeutic agent in sustained-release form can 25 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 heads, ion-exchange resin beads, spheroids, microspheres, seeds, pellets, granules, and other multiparticulate systems in order to 30 obtain a desired sustained-release of the therapeutic agent. The multiparticulate system can be presented in a capsule or in anly other suitable unit dosage form. 35 WO 2009/079518 PCT/US2008/087030 In certain preferred embodiments, niore than one multiparticulate system can be used, each exhibiting different characteristics, such as pH dependence of release, tine for release in various media (e. acid, base, simulated intestinal fluid), release in vivo, size and composition. To obtain a sustamed-release of the therapeutic agent in a manner sufficient to provide a therapeutic effect for the sustained durations, the therapeutic agent can be coated with an amount of release-retarding material sufficient to obtain a weight gain level from about 2 to about 30%, although the coat can be greater or lesser depending upon the physical properties of the particular therapeutic agent utilized and the desired 10 release rate, among other things, Moreover, there can be more than one release-retarding material used in the coat, as well as various other pharmaceutical excipients, Solvents typically used for the release-retarding material include pharmaceutically acceptable solvents, such as water, methanol, ethanol, methylene chloride and comniUOnS thereof. 15 in certain embodiments of the invention, the release-retarding material is in the form of a coating comprising an aqueous dispersion of a hydrophobic polymer. The inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic polymer will further improve the physical properties of the filn. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible 20 films under normal coating conditions, it is necessary to plasticize the ethyleellulose before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, eg., most often from about I to about 50 percent by weight of the fihn-former. Concentirations of the plasticizer, however, can be determined by routine experimentation. 25 Examples of plasticizers for ethylcellulose and other celluloses include dibutyl sebacate, diethyl phthailate, triethyI citrate, tributyl citrate, and triacetin, although it is possible that other plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil; etc.) can be used. Examples of plasticizers for the acrylic polymers include citric acid esters, such as 30 tiethyl citrate NF21, tributyl citrate, dibutyl plithalate, and possibly 1,2-propylene glycol, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin, 36 WO 2009/079518 PCT/US2008/087030 although it is possible that other plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil; etc.) can be used. The sustained-release profile of drug release in the formulations of the invention (either in vivo or in vitro) can be altered, for example, by using more than one release 5 retarding material, varying the thickness of the release-retarding material, changing the particular release-retarding, material used, altering the relative amounts of release retarding material, altering the manner in which the plasticizer is added (e.g, when the sustained-release coating is derived from an aqueous dispersion of hydrophobic polymer), by varying the amount of plasticizer relative to retardant material, by the 10 inclusion of additional ingredients or excipients, by altering the method of manufacture: etc. In certain other enbodiments, the oral dosage form can utilize a muiltiparticulate sustained-re lease matrix. In certain embodiments, the sustained-release matrix comprises a hydrophilic and/or hydrophobic polymer, such as gums, cellulose ethers, acrylic resins 15 and protein-derived materials. Of these polymers, the cellulose ethers, specifically hydroxvalkylcelluloses and carboxyalkylcelluloses, are preferred. The oral dosage form can contain between about 1% and about 80% (by weight) of at least one hydrophilic or hydrophobic polymer. The hydrophobic material is preferably selected from the group consisting of 20 alkylcellulose, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof Preferably, the hydrophobic material is a pharmaceutical acceptable acrylic polymer, including acrylic acid and inethacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxvethyl rethacrylates, cyanoethyl methacrylate, aminoalkyl 25 methacrylate copolymer, poly(acrylicacid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl i methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylainude, poly(nethacrylic acid anhydride) and glycidyl methacrylate copolymers. In other embodniments, the hydrophobic material can also include hydrooxyalkylcelluloses such as hydroxypropylmethylcellulose and mixtures of 30 the foregoing. 37 WO 2009/079518 PCT/US2008/087030 Preferred hyldrophobic materials are water-insoluble with more or less pronounced hydrophobic trends. Preferably, the hydrophobic material has a melting point from about 30* C. to about 200* C., more preferably from about 45*' C. to about 90* C. The hydrophobic material can include neutral or synthetic waxes. fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats., hydrocarbons, normal waxes, stearic acid, stearyl. alcohol. and hydrophobic and hydrophilic materials having hydrocarbon backbones. Suitable waxes include beeswax, glycowax, castor wax, carnauba wax and wax-like substances, e.g., material normally 10 solid at room temperature and having a melting point of from about 30 C. to about I O0 C. Preferably, a combination of two or more hydrophobic materials are included in the matrix formlations. If an additional hydrophobic material is included, it is preferably a natural or synthetic wax, a fatty acid, a fatty alcohol, or mixtures thereof. Examples 15 include beeswax, carnauba wax, stearic acid and stearyl alcohol. In other embodiments, the sustained-release matrix comprises digestible, long-chain (e.g., (X-C,, preferably CI 4), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Hydrocarbons having a melting point of between about 25* C. and about 90" C. are 20 preferred. Of these long-chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form can contain up to about 60% (by weight) of at least one digestible, long-chain hydrocarbon, Further, the sustained-release matrix can contain up to 60% (by weight) of at least one polyalkylene glycol. 25 In a preferred embodiment, the matrix comprises at least one water-soluble hydroxyakyl cellulose, at least one Cu-C, preferably Cw 14

-C

22 , aliphatic alcohol and, optionally, at least one polyalkylene glycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy (C-C 6 ) alkyl cellulose, such as hydroxypropylcellulose. hydroxypropylmethylcellulose and, preferably, hydroxyethyl cellulose. The amount of 30 the at least one hydroxyalkyl cellulose in the oral dosage form will be determined, amongst other things, by the precise rate of opioid release required. The amount of the at 38 WO 2009/079518 PCT/US2008/087030 least one aliphatic alcohol in the present oral dosage form will be determined by the precise rate of opioid release required. However, it will also depend on whether the at least one polyalkylene glycol is absent from the oral dosage form. In certain embodiments, a spheronizing agent, together with the active ingredient, 5 can be spheronized to form spheroids. Microcrystalline cellulose and hydrous lactose impalpable are examples of such agents. Additionally (or alternatively), the spheroids can contain a water-insoluble polymer, preferably an acrylic polymer, an acrylic copolymer, such as a methacrvlic acid-ethyl acrylate copolymer, or ethyl cellulose. In such embodiments, the sustained-release coating will generally include a water-insoluble 10 material such as (a) a wax, either alone or in admixture with a fatty alcohol, or (b) shellac or zein. Preferably, the sequestering subunit comprises the therapeutic agent in sustained release form. The sustained-release subunit can be prepared by any suitable method. For example, a plasticized aqueous dispersion of the release-retarding material can be applied 15 onto the subunit comprising the opioid agonist. A sufficient amount of the aqueous dispersion of release-retarding material to obtain 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 physical characteristics of the opioid agonist, the manner of incorporation of the plasticizer; etc. Optionally, a further overcoat 20 of a film-former, such as Opadry (Colorcon, West Point, Va,), can be applied after coating with the release-retarding material The subunit can be cured in order to obtain a stabilized release rate of the therapeutic agent. In embodiments employing an acrylic coating, a stabilized product can be preferably obtained by subjecting the subunit to oven curing at a telmiperature above 25 the glass transition temperature of the plasticized acrylic polymer for the required time period. The optimum temperature and time for the particular formulation can be determined by routine experimentation. Once prepared, the subunit can be combined with at least one additional subunit and, optionally, other excipients or drugs to provide an oral dosage form. 39 WO 2009/079518 PCT/US2008/087030 in addition to the above ingredients, a sustained-release matrix also can contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. Optionally and preferably, the mechanical fragility of any of the sequestering 5 subunits described herein is the same as the mechanical fragility of the therapeutic agent in releasable form. In this regard, tampering with the composition of the invention in a manner to obtain the therapeutic agent will result in. the desiuction 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 10 therapeutic agent cannot be administered in the absence of the antagonist. Methods of assaying the mechanical fragility of the sequestering subunit and of a therapeutic agent are known in the art. The composition of the invention can be in any suitable dosage form or formulation, (see, e.g., Pharmaceutics aud Pharmacy Prctice, I B. Lippincott 15 Company, Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982)). Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of th.e inhibitor dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) 20 suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, ben zyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant. Capsule forms can be of the ordinary hard- or sof-shelled gelatin type contaning, for example, surfactants, lubricants, and inert fillers, such as lactose, 25 sucrose, calcium phosphate, and com starch. Tablet forms can include one or more of lactose, sucrose, mannitol, com starch, potato starch, alginic acid, nicrocrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarnellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, 30 preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or 40 WO 2009/079518 PCT/US2008/087030 tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia., emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the at. One of ordinary skill in. the art will readily appreciate that the compositions of the 5 invention can be modified in any number of ways, such that the therapeutic efficacy of the composition is increased through the modification. For instance, the therapeutic agent or sequestering subunit could be con ugated either directly or indirectly through a linker to a targeting moiety. The practice of conjugating therapeutic agents or sequestering subunits to targetmg 'moieties is known in the an. See, for instance, Wadwa et al, J Drng 10 Tageing 3: 111 (1995), and US, Pat, No. 5,087,616. The term "targeting moiety" as used herein. refers to any molecule or agent that specifically recognizes and binds to a cell-surface receptor, such that the targeting moiety directs the delivery of the therapeutic agent or sequestering subunit to a population of cells on which the receptor is expressed, Targeting moieties include, but are not limited to, antibodies, or fragments thereof, 15 peptides, hormones, growth factors, cytokines, and any other naturally- or non-naturally existing ligands, which bind to cell-surface receptors. The term "linker" as used herein, refers to any agent or molecule that bridges the therapeutic agent or sequestering subunit to the targeting moiety- One of ordinary skill in the art recognizes that sites on the therapeutic agent or sequestering submit, which are not necessary for the function of the 20 agent or sequestering subunit, are ideal sites for attaching a linker and/or a targeting moiety, provided that the linker and/or targetog moety, once attached to the agent or sequestering subunit, do(es) not interfere with the function of the therapeutic agent or sequestering subunitL With respect to the present inventive compositions, the composition is preferably 25 an oral dosage fom. By "oral dosage form" is meant to include a. unit dosage form prescribed or intended for oral administration comprising subunits. Desirably, the composition comprises the sequestering subunit coated with the therapeutic agent in releasable form. thereby forming a composite subunit comprising the sequestering subunit and the therapeutic agent, Accordingly, the invention further provides a capsule 30 suitable for oral administration comprising a plurality of such composite subunits. 41, WO 2009/079518 PCT/US2008/087030 Alternatively, the oral dosage form can comprise any of the sequestering subunits of the invention in combina tion with a therapeutic agent subunit, wherein the therapeutic agent subunit comprises the therapeutic agent in releasable form. In this respect, the invention provides a capsule suitable for oral administration comprising a plurality of 5 sequestering subunits of the invention and a plurality of therapeutic subunits, each of which comprises a therapeutic agent in releasable form. The invention further provides tablets comprising a sequestering subunit of the invention and a therapeutic agent in releasable forn. For instance, the invention provides a tablet suitable for oral administration comprisig a first layer comprising any of the 10 sequestering subunits of the invention and a second layer comprising therapeutic agent in releasable form, wherein the first layer is coated with the second layer. The first layer can comprise a plurality of sequestering subunits. Alternatively, the first layer can be or can consist of a single sequestering subunit. The therapeutic agent in releasable form can be in the form of a therapeutic agent subunit and the second laver can comprise a plurality of 15 therapeutic subunits, Alternatively, the second layer can comprise a single substantially homogeneous layer comprising the therapeutic agent in releasable form, When the blocking agent is a system comprising a first antagonist-impermeable material and a core, the sequestering subunit can be in one of several different forms. For example, the system can further comprise a second antagonist-impermeable material, in 20 which case the sequestering unit comprises an antagonist, a first antagonist-impermeable material, a second antagonist-impermeable material, and a core. In, this instance, the core is coated with the first antagonist-impermeable material, which, in turn, is coated with the antagonist., which, in turn, is coated with the second antagonst-impermeable material The first antagonist-inpermeable material and second antagonist-impermeable material 25 substantially prevent release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours In some instances. it is preferable that the first antagonist-impermeable material is the same as the second anta ist-impermeable material. I other instances, the first tagonist-meeb material is different from the second antagonist-impermeable material, It is within the 30 skill of the ordinary artisan to determine whether or not the first and second antagonist impermeable materials should be the same or different, Factors that influence the 42 WO 2009/079518 PCT/US2008/087030 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 part or all of the antagonist-impermeable laver when applying the next layer or properties to promote 5 adhesion of a layer to be applied over the antagonist-impermeable layer. Alternatively, the antagonist can be incorporated into the core, and the core is coated with the first antagonist-impermeable material i this case, 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 10 coated with the first antagonist-impermeable material, and wherein the first antagonist impermeable material substantially prevents release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period that is greater than 24 hours. By "incorporate" and words stemming therefrom, as used herein is meant to include any means of corporation e.g., homogeneous dispersion of the antagonist 15 throughout the core, a single layer of the antagonist coated on top of a core, or a multi layer system of the antagonist, which comprises the core. In another alternative embodiment, the core comprises a water-insoluble material, and the core is coated with the antagonist, which, in turn, is coated with the first antagonist-impermeable material. In this case, the invention further provides a 20 sequestering subunit comprising an antagonist, a first antagonist-impermeable material, and a core, which comprises a water-isoluble material, where. the core is coated with the antagonist, which, in turn, is coated with the first antagonist-impermeable material, and wherein the first aniagonist-impermeaible material substantially prevents release of the antagonist from the sequestering subunit in the gastrointestinal tract for a time period 25 that is greater than 24 hours, The term "water-insoluble material" as used herein means any material that is substanually water-insoluble. The term "substantially water insoluble" does not necessarily refer to complete or 100% water-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 30 example, microcrystalline cellulose, a calcium salt, and a wax. Calcium salts include, but are not limited to, a calcium phosphate (e.g., hydroxyapatite, apatite; etc.), calcium 43 WO 2009/079518 PCT/US2008/087030 carbonate, calcium sulfate, calcium stearate, and the like. Waxes include, for example, carnuba wax, beeswax, petroleum wax, candelilla wax. and the like. In one embodiment, the sequestering subunit includes an antagonist and a seal coat where the seal coat forms a layer physically separating the antagonist within the 5 sequestering subunit from the agonist which is layered upon the sequestering subunit. In one embodiment, the seal coat comprises one or more of an osmotic pressure regulating agent, a charge-neutralzing additive, a sequestering polymer hydrophobicity-enhancing additive, and a first sequestering polymer (each having been described above). In such embodiments,. it is preferred that the osmotic pressure regulating agent, charge 10 neutralizing additive, and / or sequestering polymer hvdrophobicity-enhancing additive, respectively where present, are present in proportion to the first sequestering polymer such that no more than 10% of the antagonist is released from the intact dosage form. Where an opioid antagonist is used in the sequestering subunit and the intact dosage form includes an opioid agontst, it is preferred that ratio of the osmotic pressure regulating 15 agent., charge-neutralizing additive, and / or sequestering polymer hydrophobicity enhancing additive, respectively where present, in relation to the first sequestering polymer is such that the physiological effect of the opioid agonist is not diminished when the composition is in its intact dosage form or during the normal course digestion in the patient. Release may be determined as described above using the USP paddle method 20 (optionally using a buffer containing a surfactant such as Triton X-100) or measured from plasma after administration to a patient in the fed or non-fed state. In one embodinient, plasma naltrexone levels are determined; in others, plasma 6-beta naltrexol levels are determined. Standard tests may be utilized to ascertain the antagonist's effect on agonist function (i.e., reduction of pain), 25 The sequestering subunit of the invention can have a blocking agent that is a tether to which the antagonist is attached. The term "tether" as used herein refers to any means by which the antagonist is tethered or attached to the interior of the sequestering subunit, such that the antagonist is not released, unless the sequestering subunit is tampered with. In this instance, a tether-antagonist complex is formed. The complex is 30 coated with a tether-impermeable material, thereby substantially preventing release of the antagonist froni the subunit, The term "tether-impermeable material" as used herein 44 WO 2009/079518 PCT/US2008/087030 refers to any material that substantially prevents or prevents the tether from permeating through the material. The tether preferably is an ion exchange resin bead. The invention further provides a tablet suitable for oral administration comprising a single layer comprising a therapeutic agent in releasable form and a plurality of any of 5 the sequesterin.g subunits of the invention dispersed throughout the layer of the therapeutic agent in releasable form The invention also provides a tablet in which the therapeutic agent in releasable form is in the ornm. of a therapeutic agent subunit and the tablet comprises an at least substantially homogeneous mixture of a plurality of sequestering subunits and a plurality of subunits comprising the therapeutic agent, 10 In preferred embodiments, oral dosage forms are prepared to include an effective amount of melt-extruded subunits in the forn of multiparticles within a capsule. For example, a plurality of the melt-extruded muliparticulates can be placed in a gelatin capsule in an amount sufficient to provide an effective release dose when ingested and contacted by gastric fluid. 15 In another preferred embodiment, the subunits, e.g., in the form of multiparticulates, can be compressed into an oral tablet using conventional tableting equipment using standard techniques, T'echniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Ren/on's Pharmaceutical Sciences, (Aurther Osol, editor), 1553-1593 (1980), which 20 is incorporated herein by reference. Excipients in tablet fomulation can include, for example, an inert diluent such as lactose, granulating and disintegrating agents, such as cornstarch, binding agents, such as starch, and lubricating agents, such as magnesium stearate. In yet another preferred embodiment, the subunits are added during the extrusion 25 process and the extrudate can be shaped into tablets as set forth in US, Pat. No. 4,957,681 (Klimesch et al.), which is incorporated herein by reference. Optionally, the sustained-release, melt-extrded, multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a sustained release coating, such as the sustained-release coatings described herein, Stich coatings are 30 particularly useful when the subunit comprises an opioid agonist in releasable form, but not in sustained-release form. The coatings preferably include a sufficient amount of a 45 WO 2009/079518 PCT/US2008/087030 hydrophobic material to obtain a weight gain level form about 2 to about 30 percent, although the overcoat can be greater, depending upon the physical properties of the particular opiold analgesic utilized and the desired release rate, among other thin> The melt-extruded dosage forms can further include combinations of melt 5 extruded multiparticulates containing one or more of the therapeutically active agents before being encapsulated. Furthermore, the dosage forms can also include an amount of an immediate release therapeutic agent for Prompt therapeutic effect. The immediate release therapeutic agent can be incorporated or coated on the surface of the subunits after preparation of the dosage forms (e, controlled-release coating or matrix-based). 10 The dosage forns can also contain a combination of controlled-release beads and matrix nmiultiparticulates to achieve a desired effect. The sustained-release formulations preferably slowly release the therapeutic agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. The sustained-release profile of the melt-extruded formulations can be altered, for example, 15 by varying the amount of retardant, e.g, hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture; etc. In other embodiments, the relt-extruded material is prepared without the inclusion of the subunits, which are added thereafter to the extrudate. Such formulations 20 can have the subunits and other drugs blended together with the extruded matrix material, and then the mixture is tableted in order to provide a slow release of the therapeutic agent or other drugs. Such formulations can be particularly advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures needed for softening the hydropliobic material and/or the retardant material, 25 In certain embodiments, the release of the antagonist of the sequestering subunit or composition is expressed in terms of a ratio of the release achieved after tampering, e. by crushing or chewing, relative to the amount released from the intact formulation The ratio is, therefore, expressed as [Crushed]:[Whole], and it is desired that this ratio have a numerical range of at least about 4:1 or greater (e.g, crushed release within I 30 hour/intact release in 24 hours). In certain embodiments, the ratio of the therapeutic agent and the antagonist, present in the sequestering subunit, is about 1:1, about 50:1, 46 WO 2009/079518 PCT/US2008/087030 about 75:1, about 100:1, about 150:1, or about 200:1, for example, by weight, preferably aboutI 1:1 to about 20:1 by weight or 15:1 to about 30:1 by weight. The weight ratio of the therapeutic agent to antagonist refers to the weight of the active ingredients. Thus, for example, the weight of the therapeutic agent excludes the weight of the coating, matrix, 5 or other component that renders the antagonist sequestered, or other possible excipients associated with the antagonist particles, In certain preferred embodiments, the ratio is about 1:1 to about 10:1 by weight. Because in certain embodiments the antagonist is in a sequestered from, the amount of such antagonist within the dosage form can be varied more widely than the therapeutic agentantagonist combination dosage forms, where both 10 are available for release upon administration, as the formulation does not depend on differential metabolism or hepatic clearance for proper functioning. For safety reasons, the amount of the antagonist present In a substantiallyi non-releasable form is selected as not to be harmful to humans, even if fully released under conditions of tampering, The compositions of the invention are particularly well-suited for use i.n 15 preventing abuse of a therapeutic agent. In this regard, the invention also provides a method of preventing abuse of a therapeutic agent by a human being. The method comprises incorporating the therapeutic agent into any of the compositions of the invention. Upon administration of the composition of the invention to the person, the antagonist is substantially prevented from being released in the gastrointestinal tract for a 20 time period that is greater than 24 hours, However, if a person tampers with the compositions, the sequestering subunit, which is mechanically fragile, will 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 25 components is virtually impossible. The effectiveness of treatment of chronic moderate to severe pain (focusing on osteoarthritis of the hip or knee) is typically measured by mean change in diary Brief Pain Inventory (B:PI) score of average pain (daily scores of average pain averaged over 7 days; in-clinic BPI and/or daily diary :BPI (worst, least, and current pain)), WOMAC 30 Osteoarthritis Index, Medical Outcomes Study (MOS) Sleep Scale, Beck Depression Inventory, and Patient Global h[mpression of Change (PGIC). The safety and tolerability 47 WO 2009/079518 PCT/US2008/087030 of opioid medications such as Kadian NT are compared to placebo using Adverse Events (AE), clinical laboratory data, vital signs, and two measures of opioid withdrawal: Subjective Opiate Withdrawal Scale (SOWS) and Clinical Opiate Withdrawal Scale (COWS), SBPI is typically measured using I I-point BPI system as follows: 1. Please rate your pain by circling the one number that best describes your pain at its worst in the last 24 hours. o 1 2 3 4 5 6 7 8 9 10 No pain Pain as bad as you Can Imagie 10 2. Please rate your pain by circling the one number that best describes your pain at its least in the last 24 hours. o 1 2 3 4 5 6 7 8 9 10 No pain Pain as had as you Can aame 3. Please rate your pain by circling the one number that best describes your 15 pain on the average in the last 24 hours. 0 i 2 3 4 5 6 7 8 9 10 No pain Pain as had as you can image~ 4. Please rate your pain by circling the one number that tells how much pain you have right now. 0 1 2 3 4 5 6 7 8 9 10 No pain Pain as bad as you ca imagime 20 The MOS Sleep Scale is a self-administered, subject-rated questionnaire consisting of 12 items that assess key components of sleep (R. D, & Stewart, A, L (10992)- Sleep measures. In A. L Stewart & J. E. Ware (eds.), Measuring functioning and 48 WO 2009/079518 PCT/US2008/087030 wel-being: The Medical Outcomes Study approach (pp. 235-259), Durham, NC: Duke University Press). When scored, the instrument provides seven subscale scores (sleep disturbance, snoring, awaken short of breath or with a headache, quantity of sleep, optimal sleep, sleep adequacy, and somnolence) as well as a nine-item overall sleep 5 problems index. Higher scores reflect more impairment in all subscales except for sleep adequacy, where a higher score reflects less impairment. A typical representation of the MOS Sleep Scale is shown below: 1, How long did it usually take for you to fall asleep during the past four weeks? 10 (Circle One) 0 15 minutes 1 16 - 30 minutes 31 - 45 minutes 46 - 60 minutes 4 More than 60 minutes 5 2. On the average, how many hours did you sleep each nihht during the past four weeks? Write in the number of hours per night:L 15 How often during the past four weeks did you... (Circle One Number On Each Line) All of Most A Good Sonic A Little None the of the Bit of of the of the of the Time Time the Time Time Time Time V V V V V V 3, feel that your sleep was not 1 2 3 4 5 6 quiet (moving restlessly, feeling tense, speaking. etc., while sleeping)? 4. get enough sleep to feel rested I 2 3 4 5 6 upon waking in the morning? 49 WO 2009/079518 PCT/US2008/087030 5. awaken short of breath or with 1 2 3 4 5 6 a headache? 6. feel drowsy or sleepy during 1 2 3 4 5 6 the day? 7. have trouble falling asleep? 1 2 3 4 5 6 8. awaken during your sleep 1 2 3 4 5 6 time and have trouble falling asleep again? 9. have trouble staying awake 1 2 3 4 5 6 during the day? 10. snore during your sleep? I2 3 4 5 6 11, take naps (5 minutes or 1 2 3 4 5 6 longer) during the day 12. get the amount of sleep you 1 2 3 4 5 6 needed? The Beck Depression Inventory is a self-administered, 21-iten test in nmultiple-choice format that measures the presence and degree of depression (Beck et al An inventory for measuring depression; Arch Gen Psych- 1961;4:561-571). Each of the inventory 5 questions corresponds to a specific category of depressive symptom and/or attitude. Answers are scored on a 0 to 3 scale, where "0" is minimal and "3" is severe. A score of < 15 indicates mild depression, a score of 15-30 indicates moderate depression, and a score >30 indicates severe depression. The WOMAC Osteoarthris Index consists of questions on three subscales: Pain, 10 Stiffness, and Physical Function (Bellamy et al, Validation study of WOMAC: a health stams instrument for measunug chnically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol, 1988;15:1833-1840; Bellamy N. Pain assessment in osteoarthrits: experience with the WOMAC osteoarthritis index. Semin Arthritis Rheum. 1989;,18:14-17; Bellamy et al 15 Double blind randomized controlled trial of sodiurim meclofenamate (Meclomen) and 50 WO 2009/079518 PCT/US2008/087030 diclofenac sodium (Voltaren): post validation reapplication of the WOMA.C Osteoarthritis index. J Rheumatol. [992;19:153-159). Questions are typically completed by the subject before any other efficacy assessments are performed. A typical WOMAC survey is reproduced below The PGIC is a self-administered instrument that measures change in patient's overall status on a scale ranging from 1 (very much improved) to 7 (very much worse). The PGIC is based on the Clinical Global Impression of Change (CGIC) (Guy W. ECDEU assessment manual for psychopharmacology. Washington. DC: Department of Health, Education and Welfare, 1976;217-222. Publication Number (ADM) 76-338), 10 which is a validated scale, A typical form of the PGIC survey is shown below: 1ow would you rate your overall status since your last visit? (Please circle one) Very Much Improved I Much Improved 2 Minimally Improved 3 No Change 4 Minimally Worse 5 Much Worse 6 Very Much Worse 7 15 Any or all of these measures of effectiveness may be used alone or in combination to determine the efficacy of various formulations or treatment regimens, Proviced 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 in the patient. By "substantially relieved" is meant that the person reports a decrease in pain 20 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 hut not limited to another composition, either one described herein or otherwise available to one of skill in the art. Typically but not necessarily, pain is considered substantially relieved where the decrease 25 is significant (e.g., p<0.05). The methods described herein provide methods for substantially relieving pain (eg, providing an analgesic effect) for time periods of at least one week (e.g,, two, four, eight, 12, 16, 20, 24, 28, 32, 36, 40 and 100 weeks) by 51, WO 2009/079518 PCT/US2008/087030 administering a multi-layer pharmaceutical composition as described herein. In one embodiment, the method includes regularly administering (e.g, at least once. twice, three, or four times daily) a multi-layer pharmaceutical composition comprising an agoist and an atagonist as described herein for at least one week (e g one, two, four, 5 eight, 12, 16, 20, 24, 28, 32, 36, 40 and 100 weeks) wherein no substantial release (e.g., zero, or less than about 10%., 20%, or 30% release) of the antagonist is observed. In some embodiments, administration of the composition to a population once daily for a time period of at least one week results in no suIbstantial release in. at least about 90%, 80%, 70%, 60%. or 50% of the individuals making up the population. Release may be 10 measured by detecting naltrexone or 0-naltrexol in plasma. A better understanding of the present invention and of its many advantages will be had from the -following examples, given by way of illustration. 52 WO 2009/079518 PCT/US2008/087030 EXAMPLES Exemplary KadianNT formulations and methods described below in Examples 1~ 4 may also be found in PCTUS2007/tf014282 (WO 2007/149438 A2), PCT/US2007/021627 (WO 2008/063301 A2), and PCT;US08/10357. Example 1 Optimization Study #4, KadianNT, Mrphine sulf ae and Naltrexone 11C 60mg/I4.8mg (20- 780-) N) 1P1-1495 P1-1496 mg/unit Percent mg unit Percent ealed-coated sugar spheres sugar spheres (#25-30 mesh) 37-2 117 7 Uhvlcellulose N50 62 1.9 2 '2. 0 Mag Stearate 2 5 1,8 5 8 BS 0.6 o.2 6 0,2 alc 15,5 4.9 550 Subow 62 0 19.4 61 9 19.9 Naltrexone cores ealed sugar spheres (62.0) (9A 461 9) 19.9) Ialtrexone HCI 4,8 1.50 48 L54 HPC (Klucel LF) 0,9 03 09 3, Ascorbic acid 405 02 0.5 FaIe 2.27 0,7 2.24 7 Subtotal 70. 2 1 702 Naltrexone pellets Nahrexone cores (70 5) (22]) ( 0 3) 22.6) Eudiagit RS PO 53.3 16,7 15 3 171 SLS 1.8 0,6 18 06 DBS 5.36 1,7 5.36 L7 alc 52.1 163 52,1 16,8 53 WO 2009/079518 PCT/US2008/087030 Subtotal 183,0 74 182.9 8.8 Nattrexone-morphine cores atrexone pellet (183.0) (7.4) 182.9) 58]8) Morphine sulfate 59.9 18.8 59-7 19.2 Sodium cloride I .2 3.5 HPC (Klucel LF) 7.3 2376 L.5 IPMC, 3 eps 7 6 24 Subtotal 261,4 0 255.0 20 6 lrxnemrhn pellets l/rexone-morphine cores (261.4) (82 0) (255.0) f8 0) Ethylcellulose N50 19,81 6 2 19,16 2 PEG 6000 9.16 289 89 29 EudragitL100-55 43 1.3 4 2 1.4 DEP 1-.12 1.3 4 1.3 Talc 20,13 63 1962 6 3 otal 319.0 I00O iL 100.0 A. Method of preparation 1 Dissolve Ethylcellulose and dibutyl sebacate into ethanol, then disperse talc and magnesium stearate into the solution. 5 2. Spray the dispersion from 1 onto sugar spheres in a Wurster to form seal-coated sugar spheres (50tn seal coat). 3, Dissolve Klucel LF and ascorbic acid into 20:80 mixture of water and ethanol, Disperse naltrexone [WC and talc into the solution. 4. Spray the naltrexone dispersion from 3 onto seal-coated sugar spheres from 2 in a 10 Wurster to form nal trexone cores. 5. Dissolve Eudragit RS., sodium laurvi sulfate and dibutyl debacate into ethanol. Disperse talc into the solution. 6. Spray the dispersion from 5 onto naltrexone cores from 4 in a Wurster to form naltrexone pellets. 15 7, The Naltrexone pellets are dried at 50 CI for 48 hours. 54 WO 2009/079518 PCT/US2008/087030 8. Resulting pellets have a Etidragit RS coat thickness of 150pm for both PI-1495 PI-1496. 9. (Only for P1-1495) Dissolve sodium chloride and hypromellose into water. 10. Dissolve lpromellose into 10:90 mixture of water and ethanol. Disperse morphine sufthie into the solIion. 11. (Only for P1-1495) Spray the solution from 9 followed by the dispersion from 10 onto naltrexone pellets in 7 in a rotor to form ialtrexone-morphine cores, 12. (Only for P1-1496) Spray the dispersion from 10 onto naltrexone pellets in 7 in a rotor to form naltrexone-miorphine cores, 10 13 Dissolve ethyicellulose, PEG 6000, Eudragit L100-55 and diethyl phthalate into ethanol. Disperse tal into the solution. 14. Spray the dispersion from 12 onto naltrexone-morphine cores in 11 or 12 to form naltrexone-mor-phine pellets. 15. The pellets are filled into capsules. 15 B. In-vitro dug release 1. Method - USP paddle method at 37C and 100rpm - I hour in 0.IN HC-, then 72 hours in 0.05M pH 7.5 phosphate buffer 20 Results - Percent of NT released at 73 hours for PI~1495 = 0% - Percent of NT released at 73 hours for P- 1496= 0% 2. Method - USP paddle method at 37"C and 100ipm - 72 hrs in 0-2% Triton X-100/0.2% sodium acetate/0,002N HC, pH 25 5,5 Results - Percent of NT released at 73 hours for PI-1495 = 0% - Percent of NT released at 73 hours for P1-1496= 0% 30 55 WO 2009/079518 PCT/US2008/087030 C. In-vivo study This is a single-dose, open-label, two period study in which two groups of eight subjects received one dose of either PI-1495 or P1-1496. Each subject received an assigned treatment sequence based on a randomization schedule under fasting and non 5 fasting conditions. Blood samples were drawn prior to dose administration and at 0 5 to 168 hours post-dose. Limits of quantitation are 4.00 pglmL for naltrexone and 0.250 pg/mL for 6-beta-naltrexol. A summary of the pharmacokinetic results is shown in the following tables. Natrexone PI-1495 PI-I 496 Fast Fed Fast Fed Tmax (hr) 54.00 (N=2) 14.34 (N=3) 55.20 (N=5) 41,60 (N=5) Cmax (pg/mL) 8.53 632 (N=7) 24.23 (N=7) 45.67 (N= ) AUQ (pghmL) 100.8 75.9 (N=7) 500.6 (N=7) 1265 (N=7) AUCo (pg*himL) 2 1053 (N=2) 3737 (N=2 T1/2 (h) 44.56 (N=2) 33,17 (N=2) Relative Bioavailability to an oral solution (Dose-adjusted) (max Ratio (TestiSolution) 0.29% 0.2 1% 0.82% 1 5 5 % A UCa Ratio (Test/Solution) I 13% 0.85% 5-61% 1417% AUC% Ratio (Test Solution) 22,0% 39,1% 10 N:=8, unless specified otherwise 6-beta-Naltrexol PI1495 PI-1496 Fast Fed Fast Fed Tmax (hr) 69,00 41.44 (N=7) 70,51 67.63 Cmax (pg/mL) 116.3 151 7 (N=..7) 303.3 656,7

AUTC

1 (pg~h/mL) 5043 7332 (N-7) 14653 27503 AU&4 (pg*himL) 5607 8449 (N::::6) 14930 27827 56 WO 2009/079518 PCT/US2008/087030 T1/2 (hr) 0.97 16.69 (N:::7) 16.29 22.59 Relative Bioavailability to an oral solution (Dose-adjusted) Cmax Ratio (Test/Solution) 0,47% 0.62% 123% 2.67% AUQt Ratio (Test/Solution) 2.45% 3,45% 7,12% 1.3,36% AUC( Ratio (est/Solution) 2,64% 3.97% 7.02%4, 13.08%__ _ _ N=8, unless specified otherwise Kadian NT pellets with naltirexone pellet coat thickness of 150pum had comparable naltrexone release as NT pellets with 90Om coat thickness. This comparable NT release 5 may also be attributed from the presence of 50pn seal coat on the sugar spheres used in Kadian NT pellets. Significant NT sequestering was observed, both at fasting (>97%) and fed states (>96%). Kadian NT pellets containing sodium chloride immediately above the naltrexone pellet coat (P-I 1495) had half the release of nalrexone compared to Kadian NT pellet without sodium chloride (PI-1496), consistent with in vitro results 10 There is again ifod effect observed. Lag time was significantly reduced. 57 WO 2009/079518 PCT/US2008/087030 Example 2 Optimization Study #5, KadianNT, Morphine sulfite and Naltrexone H C 60mg/2.4mg (20-903-AU) P1-1510 _____ Mg/unit Percent Sealed suear spheres Sugar spheres (25-30 mesh) 3919 2.2 Ethylcelhilose N50 6.5 2,0 Mag Stearate 2.6 0.8 DBS U3 0,2) Talc 16,7 5.1 Suboal 66.4 20.3 Naltrexone cores Sealed sugar spheres (66 4) (20,3) Nahtrexone ICI 2.4 0.73 HPY Klycel U 0.5 0. Ascorbic acid U12 0. Talc 1 OA Subiota 70.6 21.6 Naltrexone pellets A.litrexoane Cores (70,6) 21.6) Eudrazit RS PO 53.0 16.2 SLS LS 0.6 DBS 5.3 1.6 Talc 53.0 16,2 Subtotal 183. 7 56.2 Naltrexone-norphine cores |alxnepelles (183. 7) 562) Morphine sulfate 60.1 18.4 Sodium chloride 12.5 3,.8 HPC (Kiucel LF) 6.2 1.9 Suboail 262.4 80.2 Naltrexone-morphine peets Nahtrexn~mrphine cores (262 4) (80.2) EthyIcellu lose N50 22.9 7O PEG 6000 10.6 3. 2 Eudragit L 100-55 5.0 1,5 DEP 47 15 Talc 21-5 6,6 Total 3271 100A 58 WO 2009/079518 PCT/US2008/087030 B. Method of preparation.

1L Dissolve Ethyleellulose and dibutyl sebacate into ethanol, then disperse tale and magnesium stearate into the solution, 2. Spray the dispersion from I onto sugar spheres in a Wurster to form seal, coated sugar spheres (50tm seal coat). 3. Dissolve Khicel LI and ascorbic acid into 20:80 mixture of water and ethanol. Disperse naltrexone H C. and tale into the solution. 4. Spray the naltrexone dispersion from 3 onto seal-coated sugar spheres from 2 10 in a Wurster to form naltrexone cores, 5, Dissolve Eudragit RS, sodium lauryl sulfate and dibutyl sebacate into ethanol. Disperse talc into the solution. 6. Spray the dispersion from 5 onto naltrexone cores from 4 in a Wurster to form naltrexone pellets. 15 7. The Naltrexone pellets are dried at 50*T for 48 hours. 8. Resulting pellets have a Eudragit RS coat thickness of I 50tm. 9. Dissolve sodium chloride and hypromeliose into water. 10. Dissolve hypronellose into 10:90 mixture of water and ethanol. Disperse morphine sulfate into the solution, 20 11, Spray the solution from 9 followed by the dispersion from 10 onto naltrexone pellets in 7 in a rotor to form naltrexone-morphine cores. 12. Dissolve ethylcellulose, PEG 6000, Eudragit L100-55 and diethyl phthalate into ethanol. Disperse talc into the solution. 13. Spray the dispersion from 12 onto naltrexone-iorphine cores in 11 or 12 to 25 form naltrexone-morphine pellets, 14. The pellets are filled into capsules. B. In-vitro drug release 1, Method - USP paddle method at 37*C and 100rpm 30 - I hour in 0. 1 N HCA, then 72 hours in 0.05MN pH1 7.5 phosphate buffer Results - Percent of NT released at 73 hours for = 0% 59 WO 2009/079518 PCT/US2008/087030 2. Method - USP paddle method at 37*C and 1 00rpm - 72 hrs in 10.2% Triton X- 00/0.2% sodium acetate/0.002N HC, pH 5,5 Results -Percent of:NT released at 73 hours = 0% C. In-vivo sud This is a single-dose, opendabel, two period study in which eight subjects were randomized to receive one dose of P1- 1510 under either fIasted or fed state during Study 10 Period I and atenate fasted or fed state for Study Period 2. Blood samples were drawn prior to dose administration and at 0.5 to 168 hours post-dose. Limits of quantitation are 4.00 pgr/nL for naltrexone and 0.250 pg/mL for 6-beta-nahrexol A sununarv of the pharmacokinetic measurements is provided in the following tables. 6-beta-Nal trexol levels PI-1510 Fast Fed Tmax (hr) 45.00 (N=6) 57.29 (N=7) Cmax (pg/mL) 161 25A0 AUat (pgh/mL) 609.2 1057 AUCr (pg*h/mL) 1233 1431 (N=6) T1/2 (hr) 17.36 17.48 (N=6) Relative Bioavailability to an oral solution (Dose adjusted) Cmax Ratio (Tes0/Solutio) 0.44% J0 68% AIUC. Ratio (Test/Solution) 1.97% 3142% AUCo Ratio (Test/Solution) 386% 14 49% 15 N=8, unless specified otherwise It was concluded that P1-1510 and PI-1495 are comparable. The reduction in naltrexone loading in the pellets (kom I 1.5% in Pf-1495 to 0,7% in PI-1510) does not seem to affect NT release. Significant NT sequestering was observed., both at fasting (>96%) and fed states (>95%). The food effect observed was modest in terms of total NT 20 release. I1owever, the lag time was slTiificatIv reduced in the presence of food. There were subjects with multiple peaks of release, 60 WO 2009/079518 PCT/US2008/087030 Summary of NT release from all in-vivo studies BA (Cmax) = Relative bioavailability based on Cmax = Dose-adjusted ratio of Cmax (NT/KN'T pellet) to Cmax (NT so[n) BA (AUC last) = Relative bioavailability based on AUC last Dose-adjusted ratio of 5 AUC last (NT/KNT pellet) to AU BA (AUC inf) = Relative bioavailability based on AUC inf Dose-adjusted ratio of AUC inf (NTKNT pellet) Total in-vivo cumulative NT release can be extrapolated from BA (AUC inf) calculations from 6-beta-Nalrexol plasma levels 10 BA (AUC last) BA (Cmax) (%) (%) BA (AUC inf) (% OPT] . #4 P1-1495 Fast Avg±SD 05 O5 25 23 + Range 01 459 -0 5.7 Fed Avg SD *0 6.7 02 19.4 Range 0.1 - 194 02-57.0 Fed (-Subject ) Avg ±SD 0,6i09 36 ±49 Range 0,1 - 2,5 0.2 - 13,8 PI-4496 Fast Avg ±SD 12i09 71+6±E4.6 Ra nge 0,1-2,7 0 6- 14.2 Fed Avg ±SD 2,7 2.9 13.4 12.6 Range 0.1 - 7.6 0.1 - 31. 6 OPTIM.#5 PI-1510 Fast _ _ _ _ _ _ _ _ _ _ _ _ _ Avg 0.4 12-0 61, WO 2009/079518 PCT/US2008/087030 Fed Avg 0,7 34 Example3 Kodian NT Fornuation #6 (IL-41) 15'TPCW Final fonmulation AL-01 Seal-coated Sugar Spheres ......... Sugar Spheres (425-30 mesh) 11 99 t194 Ethyleellulose NF 50 cps 2,00 1,99 Magnesium Stearate NF 0.80 0.80 Dibutyl Sebacate NF 0,20 0,20 Talc USiP (Suzorite 1656) 5,00 498 Naltrexone Clt Core Seal-coated Sugar Spheres (79 90) Naltrexone Hydrochloride USP 0.73 0,72 Hydroxypropyl Cellulose NF 0,14 0,14 Ascorbic Acid USP 0017 0.07 Tale USP (Suzorite 1656) 0-34 0,34 Naltrexone HCI Intermediate Pellet Naltrexone HCI Core (2/ 17) Animni Methacrylate Copolymer Type B NTF 626 6,23 Sodium Lauryl Sulfate NF 0.22 0.22 Dibutyl Sebacate NF 0. 63 0.62 Talc USP (Suzoite 1656) 6,08 6,05 Valtrexone liC Finisiei Pellet Naltrexone HCI litetmediate Pellet (34 29) .nig thacadate Copolymer Type B NF 9.89 .......... 9985 Sodium Lauryl Sulfate NF M134 0,34 Dibutyl Sebacate NF 099 0.98 Talc lSp (Suzorite 1656) 9.71 9.67 NaCt Overcoated Naltrexone HU Pellet Naltrexone HCI Finished Pellet (55.13) Sodium Chlorde USP 3.75 3.73 Hydroxypropyl Cellulose N 1 0.42 0,41 M.S Cores with Sequestered Naltrexone ICI NaCl Overcoated Naltrexone HCI Pellet (59.28) 62 WO 2009/079518 PCT/US2008/087030 Morphine Sulfate USP 1811 18,03 Hydroxypropyl Cellulose NF 1,42 L42 MS Extended-release with Sequestered Naltrexone Ht Pellet MS Cores with Sequestered Naltrexone HC 78 73) Component (a): ethyIcellulose N F (50 eps) 7.40 7. 36 Component (c): polethylene glycol NF(6000) 342 3,40 componentt (b) methacrylic acid copolymer N F 1.60 1.60 (Type C, Powder) Diethyl Phthalate NF (plasticizer) ,53 153 Talc USP (Suzorite 1656) (filler) 698 7,38 Total 100) 100.0 In certain embodiments, components (a) (b) and / or (c) may be included as described below: (a) preferably a matrix polymer insoluble at pH1 of about 1 to about 7.5: preferably ethylcellulose; preferably at least 35 % by weight of ab-c; (b) preferably an enteric polymer insoluble at pH of about I to about 4 but soluble at pH of about 6 to about 7,5; preferably methacrylic acid-ethyl acrylate copolymer (nethacrylic acid copolymer type C) preferably about I to about 30% of a+b+c; and, 10 (c) compound soluble at a pH from about I to about 4; preferably polyethylene glycol with a molecular weight from about 1700 to about 20,000; preferably from about 1% to about 60% by weight of abtc. C. Method of preparation 15 1. EthyIcellulose and Dibutyl Sebacate were dissolved into Alcohol SDA3A. Talc and Magnesium Stearate were then dispersed into the solution. The percent solid of the dispersion was 20%. 2. The dispersion from I was sprayed onto Sugar Spheres in a Wurster to form Seal-coated Sugar Spheres (approx. 5OP.m seal coat). 20 3. Hydroxypropyl Cellulose and Ascorbic Acid were dissolved into a 20:80 mixture of Water and Alcohol SDA3A. Naltrexone ICL and Tale were then dispersed into the solution. The percent solid of the dispersion is 20.4%. 63 WO 2009/079518 PCT/US2008/087030 4, The Naltrexone HC dispersion from 3 was sprayed onto Seakcoated Sugar Spheres from 2 in a Wurster to form Naltrexone HCI cores. 5. Ammonlo Methacrylate Copolymer, Sodium Lauryl Sulfate and Dibutyl Sebacate were dissolved into a 22:78 mixture of Water and Alcohol SDA3A. Tale was dispersed into the soluton The percent solid of the dispersion was 20%, 6. The dispersion from 5 was sprayed onto Naltrexone HCI cores from 4 in a Wurster to form Naltrexone HOl Intermediate Pellets. 7. The Naltrexone 1HCI Intermediate Pellets were dried in an oven at 50C for 24 10 hours. 8. Ammonio Methacrylate Copolymer, Sodium Lauryi Sulfate and Dibutyl Sebacate were dissolved into a 22:78 mixture of Water and Alcohol SDA3A. Talc was dispersed into the solution. The percent solid of the dispersion was 15 9. The dispersion from 8 was sprayed onto Naltrexone HCI Intermediate Pellets from 7 in a Wurster to form Naltrexone HCI Finished Pellets. 10. The Naltrexone 1-CI Finished Pellets were dried in an oven at 50'C for 24 hours. 11, The resulting pellets had a pellet coat thickness of approximately 150pm. 20 12, Sodium Chloride (NaCl) and Hydroxypropyl Cellulose were dissolved into Water, The percent solid in the solution was 6%. 13. The Sodium Chloride solution from 12 was sprayed onto Naltrexone HCI Finished Pellets froni 10 in a Wurster to frn Sodium Chloride (NaCI) Overcoated Naltrexone H11 Pellets. 25 14. H ydroxypropyl Cellulose was dissolved into Alcohol SDA3A, and Morphine Sulfate dispersed into the solution. The percent solid in the dispersion was 24.4%. 15. The Morphine Sulfate dispersion from 14 was sprayed onto NaCl Overcoated Naltrexone HC Pellets in 13 in a rotor to forn Morphine Sulfate Cores with 30 Sequestered Nahrexone HC. 64 WO 2009/079518 PCT/US2008/087030 16. Ethyl cellulose, Polyethylene Glycol, Methacrylic Acid Copolymer and Diethyl Phthalate were dissolved into Alcohol SDA3A, Talc was dispersed into the solution. The percent solid in the dispersion was 14.3%. 17, The Dispersion from 16 was sprayed onto Morphine Sulfate Cores with Seqestered Naltrexone FCI in 15 to form Morphine Sulfate Ixtended-release with Sequestered Naltrexone HCO Pellets 18. The pellets were filled into capsules. Example 4 10 Methods foi Treating Pain (202) As an example, Kadian NT (60mg morphine sulfate, 2.4mg naltrexone JICI) was administered to humans and compared to the previTusly described product Kadian. Each Kadian sustained release capsule contains either 20, 30, 50, 60, or 100 mg of NMorphine Sulfate USP and the following inactive ingredients common to all strengths: 15 hydroxypropyl methylcelllose, ethycellulose, methacrylic acid copolymer, polyethylene glycol, diethyl phthalate, tale, corn starch, and sucrose, In these studies, the effects of Kadian were compared to those of Kadian NT, Patients already being treated with Kadian were subjected to a "washout" period of approximately 14 days during which Kadian was not administered. Immediately 2 following this washout period, the trial was begun. Patients were either adrmnstered Kadian or Kadian NT at day 0. After a period of up to 28 days treatment with Kadian@, patients were then "crossed-over" to Kadian NT or continued taking Kadian@. The amount of Kadian NT was ind ividually adjusted such that each patient was receiving approximately the same amount of morphine they had previously been receiving while 25 taking Kadian. This cross-over was then repeated after 14 days. Various physiological responses were measured at different timepoints, as discussed below, These responses included morphine blood levels, nalirexone blood levels, 6-p-natrexol blood levels and pam scores. Mean morphine concentrations were measured and determined to be 30 approximately the same for Kadian® and Kadian NT. This observation confirms that the 65 WO 2009/079518 PCT/US2008/087030 new formulation effectively releases morphine into the blood of patients. This is shown in the table below: Ciax Cmin Cavg Tnmax FH tuation AUC(TA U) (pg/mL)(pg/mL)(pg/nL) (br) (%) (hr*pgjmL) Kadian N 68 68 68 68 68 68 Mean 12443 6-50 9 17 490 66 3 111,806 SD 7OO 4,544 6,019 3.36 28.8 72,223 Min 2,630 1,000 1,758 0,00 214 21,100 Median 9 870 5,285 7A26 5 00 63.5 89,110 Max 35,600 21,600 28,908 12,0 213 346,900 CV% 617 68.3 64.6 68.5 43 4 646 Kadian NT N 68 68 68 68 68 68 Mean 13997 6,869 10,120 4.29 7149 12 1438 SD 10,949 5-377 7 316 3.05 38.59 87,794 Min 2 420 0,00 1-815 0.00 21,04 21 775 Median 10,200 5,805 71496 4,00 65 .S9 89,948 Max 57,600 29,000 35,046 12.0 265 420,550 CV% 782 783 72.3 71,0 54.0 72.3 5 It is important that the Kadian NT formulation not release significant amounts of antagonist (i.e., naltrexone or derivatives thereof) into the bloodstream such that the activity of morphine is diminished. Only 14 of 69 patients had quantifiable (> 4.0 pg/mL) naltrexone concentrations. The range of quantifiable concentrations was 4.4-25.5 pg/mL. However, the release of some naltrexone into the bloodstream did not 10 significantly affect the pain scores (see below). 66 WO 2009/079518 PCT/US2008/087030 Subject Naltrexone Pain Score* (pg/mL) 49411 25.5 2 49408 16.8 3 59510 15.9 2 29218 13,5 0 39308 774 0 39306 898 1 49422 8 12 4 79709 7,15 2 89817 6,82 3 59509 6. 29 2 49409 6.58 2 49431 4 81 1 49430 4.58 59530 4.4 3 *A pain score of 0-3 is considered "mild" and 4-7 is considered "moderate". When provided in an immediate formulation, naltrexone (parent) is rapidly absorbed and converted to the 6-P-naltrexol metabolite. 6-0-naltrexol is a weaker opioid 5 antagonist than naltrexone, having only 2 to 4% the antagonist potency, Most patients had quantifiable levels (> 0.25 pg/mL) of 6-p-naltrexol. The incidental presence of 6-p naltrexol in the plasma had no effect on pain scores. It was also important to confirm that Kadian NT did not result in a significantly different type, number or severity of common adverse events. This was confirmed, as 10 shown below: Open-label Double-blind Event Kadian Kadian Kadian NT 67 WO 2009/079518 PCT/US2008/087030 (N=7 1) (N7=71) Any event 83.8% 45.1% 46.5% Constipation 46.8% 12.7% 15.5% Nausea 41,5% 8.5% 9.9% Somnolence 28.8% 8.5% 9.9% Vomiting 24.3% 4.2% 8.5% Dizziness 20.7% 7.0% 1.4% Headache 16.2% 8.5% 4.2% In addition, it was important to note Whether Kadian NT functioned similady to Kadian with respect to adverse events typically associated with withdrawal symptoms. 5 This was confirmed as shown below: Open-label Double-blind Event Kadian Kadian Kadian NT (N-l 11 1) (N=71) (N=71) Tremor 3.6% 0.0% 0.0% Anxiety 2,7% 2.8% 14% r itability 1.8% 0.0% 0.0% Restlessness 0.9% 0.0% 0.0% Muscle Twitch 0.9% 0.0% 0.0% Cold Sweat 0.9% 0.1% .4% Piloerection 00% 0.0% 0.0'% Rhinitis 0.0% 0.0% 0.0% Tachycardia 0.0% 0.0% 0.0% 68 WO 2009/079518 PCT/US2008/087030 Other measurements, including InI-Cinic Pain, WOMAC Pain, WOMAC Stiflhess, WOMAC Daily Activities, and BPI Pain were also made. It was determined that the differences in these measurements in those taking Kadian and those taking Kadian NT was not significant, as shown below. In-Clinic Pain (ITT Population, Conpleters) Mean Treatment 95% CI for Day Kadian }Kadia P-value Difference NT I Baseline 2.13 CThange Day 7 N=::68 N=:69 09773 -0.2, .3 0.18 +0 16 Change Day 14 N=69 N=69 O.2176 -. 3,,5 ±028 +0106 WOMAC Pain (IT T Population, Completers) Mean Tretment 95% CI for Day Kdan Kadian NT P-value Difference Baseline 98.1 a nan Change Day N=69 N=::69 0.0928 ~ 2.0. 26.0 14 +08 t 5.9 10 WOMAC Stiffness (ITT PopnUation, Compieters) Meani Treatment 95% CI for Baseline 51.1 ............. .. ............

WO 2009/079518 PCT/US2008/087030 Change Day N=69 N=69 0.0200 17, 18,5 14 J12.3 +2-1 WOMAC Daily Activities (iTT' Population. Coileters} Mean Treatment 95% C for Day Kadian [ Kadian NT P-value Difference Baseline 396.6 Change Day N::69 f N=:69 0.12'06 -1 0 93 6 14 +T7 [ +28,9 5 In conclusion, plasma morphiine levels for Kadian and Kadian NT are ioequivalent It was observed that 55 of 69 (80%) patients had no measurable levels of naltrexone. Of the 14 patients with measurable levels of naltrexone, there was n negative effect on pain scores, Seven of these 14 patients had a measurable level at only one time point. Most patients had some leveI of 6naltrexol. however there was no 10 negative e effect on pain scores. In addition, there was no difference in pain scores in individuals taking Kadian or Kadian NT. 70 WO 2009/079518 PCT/US2008/087030 Example 5 Long-Term Sqfey Study of Kadian NT (302) A. METHODS The primary objective of this study was to evaluate the long-tern safety of Kadian 5 NT administered for up to 12 months. The secondary objectives of this study were to: " evaluate the long-term efficacy of Kadian NT during a 12-month period by assessig pain intensity (P.) in the past 24 hours using the Brief Pain inventoryy (BPI) Short Fomi and the Global Assessment of Study Drug; " evaluate opioid withdrawal symptoms in subjects who receive Kadian NT upon 10 completion of I 2-months exposure or early termination from the study using the Clinical Opiate Withdrawal Scale (COWS); and, " evaluate plasma naltrexone, 61-naltrexot, and morphine concentrations at Visits 2 through 15 in selected male and female subjects for pharnacokinetic study 15 This long-term, open-label study evaluated the safety of Kadian NT administered once or twice daily (QD or BID) over a 12-month period. Kadian NT was used in dosage strengths of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg and 100 mg. There was no maximum allowable daily dose set for this study. Subjects were titrated upward as needed in a manner consistent with the current Kadian" labeling and in accordance with 20 the invesdgator's best medical judgment for the most effective pam management. Multiples of the available dosage strengths were combined as needed to achieve the intended necessary daily dose. Subjects with chronic moderate to severe nonmalignant pain who meet all inclusion/exclsion critera were enrolled into the long-term study. Each subject was 25 provided with Kadian NT at each clinic visit in the form of capsules to be administered BID approximately 12 hours apart or QD at 24-hour intervals. Oploid-naive subjects began at a total daily dose of 40 mg Kadian NT administered as 20 mg BID. Opioid naive subjects who fully qualify for study and have documented normal labs within the previous three months were enrolled and dosed on the BaseliTie Visit day. All other 30 subjects were to return within seven days for enrollment and dosing. 71 WO 2009/079518 PCT/US2008/087030 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 5 Dispensing clinic visit It was recommended that subjects who are already taking opioid medication be started on a Kadian NT dose equivalent to 50% to 75% of the current daily opioid dose rounded to the lowest available Kadian 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 10 opioid conversion schedule 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. All subjects were to return to the clinic one week after the Drug Dispensing Visit and then monthly for the remainder of the study. Pain Intensity and Global Assessment 15 of Study Drug were collected at each scheduled visit. Urine drug screens, adverse events (AEs), concomitant medications, and vital signs were collected at all clinic visits. Urine pregnancy tests will be performed monthly on females of child-bearing potential Drug accountability was conducted at all clinic. visits- The occurrence of withdrawal symptoms for subjects taking Kadian NT was assessed utilizing the Clinical Opiate 20 Withdrawal Scale (COWS). The COWS was administered at every visit from Visit 3 through 16, or at early ternmation (whichever comes first). Dose titration was allowed throughout the duration of the study. At each clinic visit,. the dose of Kadian NT was increased where all of the following criteria were met: * Subject was tolerating study medication (no unacceptable A.Es); 25 * Pain Intensity (PI) within the past 24 hours is > 3; and, * Both investigator and subject agreed that the dose should be increased. Even if a subject is experiencing a PI > 3, the subject was free to 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 30 reported unacceptable AEs or an opioid-experienced subject was converted to a dose that results in unacceptable AEs. the dose was decreased. 72 WO 2009/079518 PCT/US2008/087030 If a subject experiences inadequate pain relief and desired to have his 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 level The subject was then to retum to the site for an unscheduled clinic visit to return study 5 medication and to receive new study medication at the increased dose. Opioid toxicity assessments and drug accountability were conducted, but a complete battery of efficacy assessments was not necessary for these unscheduled visits. Investigators provided a stimulating bowel regimen for prophylactic treatment of constipation, the most common opioid side effect. (American Pain Society, 2003) If 10 unacceptable opioid-related AEs were experienced prior to a scheduled clinic visit, subjects were allowed to return to the clinic between scheduled visits for a dose reduction and to obtain treatment for opioid-related A.Es. Subjects were required to return for a post-treatment follow-up visit approximately 28 to 32 days after the final dose of study medication to record AEs and 15 concomitant medications and to assure that appropriate tapering 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 period. The suggested mechanism for tapering was for the subject to take half of his or her last effective dose of study medication in divided doses of Kadian (BID) for three days, and 2(0 then to take half of that reduced dose in divided doses (BID) for the next three days; on the seventh day, all dosing will discontinue Subjects were also allowed to convert to currently-approved extended release opioid per investigator discretion, Safety was evaluated by vital signs (heart rate, respiratory rate, blood pTessure after sitting for three minutes, and oral temperature), physical examinations., 25 electrocardiograms (ECGs), clinical laboratory tests and Adverse Events. Clinical laboratory tests were performed at Base ine and at the end of months 3, 6, 9, and .12 or at early termination. Qualitative urine drug screens were performed months and included reflex testing to identify specific opiates taken by subjects during study participation. Urine pregnancy tests were performed monthly for female subjects of child-bearing 30 potential. EC.G was performed at Baseline, at the end of months 6 and 12 or early termiation. 73 WO 2009/079518 PCT/US2008/087030 Population pharmacokinetic (PK) sanpling was also performed in this stidy monthly after the Baseline Visit. The Interactive Voice Response System ([VRS) was used to identify up to 20 subjects in each of the following daily dosin.g categories to undergo PK sample collection at their scheduled visits: 40 mg to 60 mg, 80 mg to 5 120 ng, and > 120 mg. Up to 20 subjects aged 65 years and above were also identified to participate in the PK sample collection. The primary focus of this PK sampling was to quantify naltrexone, 6-beta naltrexol and morphine concentrations. Study medications were in the form of orally administered capsules. Study medications were: 1) Kadian NT 20, 30, 40, 50, 60, 80 and 100 mg capsules; or, 2) acetaminophen up to two 10 (2) grams per day (500 mg every 6 hours as needed) as rescue medication. 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. 15 2. The subject agreed to refrain from taking any opioid medications other than study medication during the study period, and agreed to report all non-opicid analgesic medications taken; 3. Sujbect had a history of chronic moderate to severe pain caused by a nonmalignant condition for at least three months prior to Baseline Visit. Conditions may include, 20 but are not limited to, osteoarthritis of any joint, chronic low back pain with or without radiculopathy, diabetic peripheral neuropathy, and post-herpetic neuralgia. Subject was directed to choose the most painful joint or body area to serve as the target joint area for this study. A target joint was not to contain any type of orthopedic and/or prosthetic device. 25 4. If female. subject was either not of childbearing potential (defined as postmuenopausal for at least one year or surgically sterile (bilateral tubal ligation, bilateral oophorectony or hysterectomy)) childbearing potential iand practicing one of the following methods of birth control: * total abstinence from sexual intercourse (minimum one complete menstrual cycle 30 before study entry), * a vasectomized partner., 74 WO 2009/079518 PCT/US2008/087030 " contraceptives (oral, parenteral, or transdernal) for three consecutive months prior to investigational product administration, " intrauterine device (IUD), or * double-barrier method (condoms, sponge, diaphragm or vaginal ring with jellies or cream). 5. If female of childbearing potential, subject had a negative urine pregnancy test at screening (urine specimen must be obtained within 14 days prior to randomization) and monthly throughout study participation, 6- Subject was able to understand and cooperate with study procedures. was to be easily 10 reached by telephone, and signed a written informed consent prior to entering the study. A subject will be excluded from the study if he/she meets any of the following Criteria: 1. Subject had a documented history of an allergic reaction (hives, rash, etc.) or a 15 clinically significant intolerance to morphine or other opioids, such that treatment with morphine is contraindicated. 2. Subject was pregnant or breast-feeding, 3. Subject was receiving systemic chemotherapy or has an active malignancy of any type, or has been diagnosed with cancer within the past three years excludingg 20 squamous or basal cell carcinoma of the skin). 4. Subject had a documented history of drug abuse/dependence/misuse or narcotic analgesic abuse/dependence/mnisuse within five years prior to the Baseline Visit. 5 Subject had a documented history of alcohol abuse (>2 glasses/day) and/or dependence within five years prior to the Baseline Visit, which, in the opinion of the investigator, may have influenced subject compliance with the study. 6. Subject had a positive urine drug screen at the Baseline Visit NOT caused by any therapeutic concomitant medication reported by the subject. 7, Subject was considered by the investigator, for any reason, to be an unsuitable candidate to receive extended-release morphine sulfate with naltrexone, including 30 (but not limited to) the risk(s) in terms of precautions, wamings, and contraindications in the Investigator's Brochure for Kadian NT. 75 WO 2009/079518 PCT/US2008/087030 8. Subject had a Body Mass Index (13MI)> 45 kg/m. 9. Subject had a psychiatric illness or medical illness/condition, and/or abnormal diagnostic finding, that, in the opinion of the investigator, would interfere with the completion of the study, confound the results of the study, or pose risk to the subject 10. Subject had abnormalities on physical examination, or abormal vital signs or ECG findings that judged to be clinically significant by the investigator. 11. Subject had clinically significant abnormalities in clinical chemistry, hematology or -rinalysis, including serum gItamic-oxaloacetc transaminase/aspartate 10 aminotransferase (AST) or serun glutamic-pyruviC transaminase/alanine aminotransferase (ALT) 3.10 times the upper limit of the reference range or a serum creatinine > 3,0 mg/dL at the Baseline Visit. 12. Subject had pain in the target area due to conditions such as malignancy, fibromyalgia, migraine, recent trauma or fracture, or infection. 15 13. Subject was involved in an unsettled claim such as automobile accident, civil lawsuit, or worker's compensation pertaining to a specific injury. Subjects with settled claims were allowed to participate, 14. Subject received intraspinal infusion of any medication within one month of the Baseline Visit, had an implanted spinal cord stimulator, or had plans for such 20 treatment during the proposed study period. 15. Subject received epidural or local corticosteroid injections -in target joint within two months of the Baseline Visit, or target joint viscosupplementaon within the past three months, 16. Subject received oral or intramuscular corticosteroids within the past 90 days. (Topical, nasal and inhaled corticosteroids were permitted and low, stable doses e.g. t10 mg prednisone, provided were no changes in dosing within the previous four weeks.) 17. Subject had surgical itervention to the back within six months of study entryn or plans for surgical intervention, while in the study. 76 WO 2009/079518 PCT/US2008/087030 8. Subject underwent an elective surgical procedure wihin eight weeks prior to the Baseline Visit, or was scheduled for an elective surgical procedure during the course of the study. 19. Subject had a history of severe impairment of pulmonary function, hypercarbia, hypoxia, chronic obstructive puhmonary disease, cor pulmonale. uncontrolled asthma, sleep apnea syndrome, or respiratory depression. 20. Subject had a history of gastric or small intestine surgery leading to clinical nalabsorption (e.g., gastric bypass), or any other disease that causes clinical malabsorptio. 10 21. Subject had active cardiac disease or other health conditions) that pose a significant health risk in the event of opioid withdrawal. 22. Subject was taking phenothiazines or high doses of sedatives, hypnotics, or tranquilizers. Chronic low dose sleep aids or anxiolvtics were allowed with Medical Monitor approval. 15 23. Subject was historically non-responsive (no therapeutic response) to morphine. 24. Subject had received treatment with an investigational product in the 30 days prior to Baseline Visit, Safety endpoints were the incidence of treatment-emergent AEs; changes from 20 pre-treatment to post-treatment for vital signs, ECGs, physical examination findings, and clinical laboratory test results; and opioid toxicity assessments. The efficacy endpoints were Pain Intensity (PI) within the past 24 hours: and, Global Assessment of Study Drug. Three subject analysis populations were defined as follows: 1) the "safety population" consisting of all subjects who take study medication, used for safety 25 analyses: 2) the "intent-to-treat" (ITT) population consisting of all subjects who take study medication and have at least one post-Baseline Brief Pain iventory, or Global Assessment of Study Drug observation: the ITT population will be used for efficacy analyses: 3) the pharmacokinetic (PK) population will consist of all subjects with PK samples and will be used for PK analyses, 30 Safety was assessed based on the incidence of treatment-emergent Ails, changes from pre-treatmuent to post-treatment for vital signs, ECGs, physical examination findings 77 WO 2009/079518 PCT/US2008/087030 and clinical laboratory test results. Changes on a Physical Exam were captured as Adverse Events. The number and percentage of subjects with AEs will be displayed by System Organ Class and preferred term using the Medical Dictionary for Regulatory Activities" 5(MedDRA*). Summaries in terms of severity and relationship to study medication were also provided. SAEs and AEs causing discontinuation of study medication were summarized separately in a similar manner. Subject listings of AEs causing discontinuation of study medication and SAEs was produced. The incidence and severity of selected opioid-associated AEs, including dry mouth, constipation, dizziness, 10 somnolence, pruritus, nausea, and vomiting were also be tabulated. Vital signs were summarized at each visit in terms of descriptive statistics including the mean, median, standard deviation, minimum, maxintunm, and quartiles. Actual values and change from Baseline were summarized. ECGs were performed at Baseline, Visit 8 (end of month 6) and Visit 15 (end of month 12) or Early Termination. Changes from Baseline were 15 summarized. Quantitative laboratory test results were summarized at each visit in terms of descriptive statistics, Actual values and change from Ba seline were summarized. For qualitative laboratory tests, the number and percentage of subjects in each category were produced at each visit. For all laboratory tests, a shift table was produced summarizing changes from normal (at Baseline) to abnormal and vice-versa. The number and 20 percentage of subjects with normal and abnormal findings in the physical examination at each visit were displayed, A shift table was produced sumnimarzing changes front normal (at Baseline) to abnormal and vice-versa. COWS were summarized at each visit beginning with Visit 3 in terms of descriptive statistics. Actual values and change through study period were summarized. Selected analyses were repeated by subgroups 25 based on age, sex, and race. Efficacy was assessed based on the BPI Short Form, and subject's Global Assessment of Study Drug. All efficacy analyses were descriptive, with no formal testing of statistical hypotheses, although p-v- alues or confidence intervals were presented to aid in interpretation. Each of the four items of the BPI Short Font were analyzed at 30 each visit in tents of the values themselves as well as in terms of change and percent change from Baseline. Descriptive statistics were calculated, and pairwise t-test p-values 78 WO 2009/079518 PCT/US2008/087030 used to summarize the difference between each postfBaseline time point and Baseline. Global Assessment of Study Drug was sunmarized descriptively. Rescue medication (additional analgesic medication) was summarized. All efficacy analyses are considered secondary. Sparse blood samples (one trough blood sample taken from each subject 5 participating in the P:K study, total 1.4 blood samples) were taken at selected visits for morphine, naltrexone, and 64-pnaltrexol determinations. 79 WO 2009/0795 18 PPCT/US2008/087030 X:> ,xxX _____ - - - - - - -- - - - - - -, -1* 'R <I Ell. V t 7. '1<:< tp~ Ca U8 WO 2009/079518 PCT/US2008/087030 81 WO 2009/079518 PCT/US2008/087030 B. RESULTS 1. Adverse Events Treatment-Emergent AEs (TEAEs) occurring in more than 5% of patients included constipation, nausea, vomiting, headache, somunolence, diarrhea, prtritis and fatigue. These are all typical opioid-related AEs. A summary of the number of Treatmentergent Adverse Events, Seflous Adverse Events and Deaths (none) resultinIg from treatment with Kadian NT is shown below. TEAEs resulting in discontinuation of treatment was observed in approximately 10 30% of patients administered 1ess than 80 nig Kadian NT per day; approximately 10% of patients administered between 80 and 120 mg Kadian NT per day; and, approximately 9% of patients administered more than -120 mig Kadian NT per day, Overall, TE AEs were observed in approximately 24% of patients. Serious AEs (SEAEs) resulting in discontinuation of Kadian NT treatment were 15 observed in approximately 2% of patients administered less than 80 mg Kadian NT per day; approximately 8% of patients administered between 80 and 120 mg Kadian NT per day; and, approximately 2% of patients administered more than 120 mg Kadian NT per day. Overall, SE AEs were observed in approximately 3% of patients. 20 Summary of Treahnent-Emergent Adverse Events, Serious Adverse Events and Death - Safetv Population Average Daily Dose of Kadian NT <80 mg 80-120 mg >120 mg Overall N::::307 N:67 N='56 N;439 Any Treatrnent-Emengent Adverse 246 56 340 Event (80.1%) (83.6%) (66,1%) (77.4%) Treatment-Emergent Adverse Events 210 31 22 264 which are Possibly, Probably, or 684% Definitely related to Kadian NT TreatmetEmerget Adverse Events 92 7 - 105 which led to discontinuation of (30.0'%) (10.4%) (8.9%) (239"X Kadian NT Severe Treatment-Energent Adverse 39 II 6 56 Events (12.7%) (16.4%) (107%) (128%) Serious Adverse Events 1 6 2 19 (3.6%) (3.6%) (4 82 WO 2009/079518 PCT/US2008/087030 (9.0%) Serious Adverse Events which led to 6 5 1 12 discontinuation of Kadian NT (2,0%) (7.5%) (1,8%) 22%) Deaths 0 0 0 0 2. Efficacy As shown in Figs, 1-4, daily administration of Kadian NT to patients included in this trial results in lower mean BPI scores for up to six months. The data indicates that 5 the affects of morphine in this population is ntot negatively affected by the concomitant administration of both morphine and naltrexone in an intact dosage form (Kadian NT). Thus, Kadian NT may be used to effectively treat pain in human patients for long periods of time (i.e, greater than two weeks). Previously, Kadian NT was only shown to be effective for periods tp to two weeks. It was not known, whether the cumulative effect of 10 repeatedly administering a composition containing a morphine antagonist over a period of greater than two weeks would eventually nfegatively affect the actions of morphine in the patient, Surprisingly, the data indicates that Kadian NT may be used to alleviate pain for long periods of time (i.e, greater than two weeks). The data. also indicates that Kadian NT may be most effective at the lowest dose tested (i.e., less than 80 mg per day). 15 Pharmacokinetic (PK) data was also analyzed as shown below, The results demonstrate that nahrexone was indeed sequestered over the course of the trial. While there were a couple of outliers, the data indicates sequestration is possible over long periods of time (i.e, greater than two weeks and out to 100 weeks). ALO-KNT-302 PK Data Morphine Conc Naltrexone 6B-Naltrexol Week Subject Conc (pq/mL) Conc (pg/mL) 201 1 2005 4,16 0 0 201 2006 3.28 Missing Missing 201 2013 2 0 3,24 202 2001 US Mssing Mssing 203~ 2004 0 0 0 83 WO 2009/079518 PCT/US2008/087030 204 2003 4.04 0 10.3 204 2006 5.11 0 BLQ<10 0 204 2008 9 27 0 26.3 205 2001 5,18 0 0 205 2002 18.9 0 3.31 205 2007 4 17 4,33 63,3 209~ 2012 3 28 0 Missing 211 __2001 395 0 BLQ<100 211 2003 2,98 0 ALQ>10.0 211 2005 743 0 146 212 ____ 2001 4,23 0 BLQcI.00 2002 5,31 0 10.3 212 2005 Missing 0 584 212 2006 3,7 4,68 12.8 213 2002 0 0 21,9 213 2003 3 86 4.03 43.7 213 2004 36.2 0 69.5 213 2005 2.45 0 BLQ<5.00 213 2007 7,35 0 BLQ<2,50 214 2002 5.77 0 33.2 217 2010 423 0 13.4 217 2014 35.3 0 280 222 2001 1 99 0 25,3 222 2002 2.81 0 0.532 222 2003 2.66 0 Missing 222 2008 24.4 0 13.4 222 2009 4,01 0 4.31 84 WO 2009/079518 PCT/US2008/087030 222 2016 6 1 0 2.04 229 2005 912 0 1.1 229 2006 5,94 0 36.7 229 2008 4 32 0 9.86 235 2001 5.85 0 14.5 235 2008 601 0 0 239~ 2002 1 76 0 Missing 240 .... __ 2003 22.7 0 9.33 241 2001 0 0 0 241 2007 321 0 BLQ<2,50 252 2001 24,9 0 128 252 2002 5,04 0 0 255 2001 0,608 0 BLQ<10.0 255 2003 101 0 28,4 257 2005 7,74 0 10 257 2010 7,85 0 6.75 257 2011 7.57 0 121 259 2002 15.5 0 24.6 N T 46 48 37 Mean: 9.44 0,272 30.3 SD 15.8 1.07 53,6 Min 0 0 0 Median 4.68 0 12, Max 101 4,68 280 CV% 167.7 392.2 176,6 Morphine Conc Naltrexone GB-Naltrexol Week Subect ( ng/mL-) C (pg--mL} Con (p/mL) 201 4 2005 206 0 1.01 201~ 2006 3.45 0 0 201 2013 3.29 0 58,3 204- PC 0 BLQ<200 85 WO 2009/079518 PCT/US2008/087030 2006 204 2008 9.95 0 T16 205 2001 3,3 0 3,12 205 2002 28,9 0 1.27 205 2007 4,58 6.76 172 209 2012 14.2 0 Missin9 212 2001 10.8 0 51.1 212~ 2002 5,88 0 Missing 212 2005 Missing 17.7 763 212 2006 2.7 0 Missing 213 2002 0 0 3.58 213~ 2003 9.63 0 22,3 213 2004 Missing 0 107 213 2007 8.52 0 BLQ<1.00 214 2010 4.28 0 1.26 217 2014 24.2 BLQ<8.00 293 222 2002 0.693 0 0 222 2003 0 0 0 222 t0:6 574 0 0_ 229 2005 14.9 0 0.813 229~ 2008 4.51 0 24.3 229 2009 6.34 0 1,29 235 2001 12.6 0 10.9 241 2001 11,6 0 4,1 241~ 2004 30.6 0 16,3 241 2007 0 0 BLQ<0.500 243 2005 Missing Missing 252- 21.7 0 16.9 86 WO 2009/079518 PCT/US2008/087030 2001| 252 2002 1.25 0 0 257 2005 7,77 BLO<40.0 BLQ<5.00 257 2010 15 0 1.53 259 2002 Missing 0 32.2 N 30 32 27 Mean 8.95 0.764 59 SD 8,35 3,31 155 Min 0 0 0 I Median 611 0 41 Max 30,6 17,7 763 CV% 93.4 433.4 262, Morphine Conc Naltrexone 6B-Naltrexol Week Subject (ng/mL) Conc (pg/mL) Conc (pg/mL) 201 8 2005 6 74 4.83 58,8 201 2006 5.93 0 7,12 204 2008 939 0 28 205~ 2002 21.6 0 1.68 205 2007 6.93 0 25,7 209 2013 16.4 0 Missing 212 2001 15,2 0 14,7 212 2002 10.3 US 49,9 212 2005 Missing 12.8 330 212 2006 3 2 0 Missing 213 2002 28.8 0 35.4 213 2003 17.6 0 43,5 213~ 2004 80.5 0 85 213 2006 186 0 9.07 213 2007 12.9 0 6.35 214 2002 19 0 18,5 217~ 2010 6,47 0 0.866 87 WO 2009/079518 PCT/US2008/087030 217 2014 24.4 0 31 222 2002 0 0 BLQ<0,500 228 2011 139 0 229 2005 9,48 0 BLQO.500 229 2008 8 3 0 25.1 229 2009 4 76 0 0.527 235~ 2001 935 0 13.1 241 _2004 379 0 BLQ<1,25 252 2001 66.3 0 37.3 252 2005 5,33 0 40,6 257~ 2005 6 88 0 14,6 257 2010 7,17 0 7.81 N 28 28 23 Mean 16.9 0,63 38,5 SD 18.1 2,55 66,9 MinM 0 0 0.527 Median 989 0 25,1 Max 80.5 12.8 330 CV% 107.1 405.6 173,9 Morphine Conc Naltrexone 6B-Naltrexol Week Subject (ng/mL) Conc (pg/mL) Conc (pg/mL) 201 12 2005 13.8 0 20.2 201 2006 4.63 0 10.7 204 2008 7,35 0 Missing 205~ 2002 26,2 0 209 2013 20.7 0 11.9 212 2002 921 0 0.722 212 2005 Missing 24,5 681 212~ 2006 3.47 0 2.48 213 2004 73.7 0 30.9 213- 17.6 0 17.5 88 WO 2009/079518 PCT/US2008/087030 2006 213 2007 7.2 0 46.2 214 2002 11 0 72.5 217 2010 4,33 0 0 217 2014 384 0 92.3 222 2002 2,9 0 189 228 2006 8,37 0 Missing 229~ 2005 2.7 0 0 229 2006 6.56 0 BLQ<1.00 229 2008 6.07 0 21.3 233 2006 23,3 0 Missing 235~ 2001 19.4 0 19,1 241 2004 30 0 28.3 252 2001 32.4 0 62,3 252 2002 0 0 Missing N 23 24 18 Mean 161 1.02 72.6 SD 16,6 5 159 Min 0 0 0 I Median 9.21 0 20;8 Max 73.7 24.5 681 CV% 102.8 489.9 218.6 Morphine Cone Naltrexone 6B-Naltrexol Week Subject (ng/mLL Conc (pglmL} Conc (pg/mL) 201 16 12005 1.23 0 0 201 2006 511 0 7,25 204~ 2008 107 18.3 153 205 2002 435 0 10.3 209 201 3 26.5 Missing Missing 212 2005 ALQ>60,0 Missing Missing 212~ 2006 8,99 0 10.8 89 WO 2009/079518 PCT/US2008/087030 213 2004 Missing 0 39.9 213 2006 226 0 1,71 213 2007 27 4.15 69.6 214 2002 27.2 0 25.8 217 2010 2.27 0 Missing 217 2014 15.9 LS 35.9 222 2002 27.7 23.5 477 228 ... __ 2006 9,49 0 21,2 229 2005 3 93 0 Missing 229 2006 10.8 0 Missing 229 2008 13.9 0 86.3 232 2001 6 23 US Missing 235 2001 12.3 7.89 201 241 2004 28.8 0 13.4 252 2002 4,12 0 Missing 257 2005 7,73 9.88 1.46 257 2010 9.37 0 BLQ<10.0 N 22 20 16 Mean 14.8 3.19 72.2 SD 11.1 6,73 122 Min 1.23 0 0 Median 10,8 0 23,5 Max 435 23.5 477 CV% 754 211.3 169.6 Morphine Conc Naltrexone $B-Naltrexol Week Subject (ng/mL) Conc (pg/mL) Conc (pg/mL) 201 20 2005 6.22 0 Missing 201 2006 7 51 0 Missing 204~ 2008 10.7 0 31,4 212 2005 Missing 0 371 ...... 213- 43.9 0 40 90 WO 2009/079518 PCT/US2008/087030 2004 213 2006 25.2 0 Missing 213 2007 17.9 0 Missing 214 2002 26 US 149 217 2010 7,47 0 12.1 217 2014 26.7 PC 21,6 222 2002 22.1 145 1680 228~ 2006 15.9 0 32 229 2005 10 0 Missing 229 2006 7 55 0 Missing 229 2008 5.09 0 29,1 235~ 2001 19.4 9.27 163 241 2004 31.6 0 18,7 252 2001 24.8 0 32,2 252 :2002 0 0 Missing 257 2005 4 5 0 Missing N 19 18 12 Mean 16.4 8.57 215 SD 11.4 34.1 473 Min 0 0 12.1 Median 15.9 0 32.1 Max 43.9 145 1680 CV% 69.2 398.1 220 Morphine Conc Naltrexone B-Nalrexoi Week Subject ( Conc (pgmL) ffi cpgfmL 201 24 2005 366 0 Missing 201~ 2006 5,04 0 missing 203 2002 78 0 11.1 204 2008 9.95 Missing Missinjg 205 2002 Missing 0 26,2 213~ 2004 49 0 112 9.

WO 2009/079518 PCT/US2008/087030 213 2007 17.1 0 17.9 214 2001 19.8 Missing Missing 214 2002 21.9 US 21.4 214 2010 105 0 17,7 217 2010 4.26 0 22 2 222 2002 0,684 0 257 229~ 2005 6,95 0 18.7 229 .... __ 2006 4 54 0 Missing 229 2008 13 0 86.9 235~ 2001 38,8 12,7 95,1 240~ 2005 19 Missing Missing 241 2004 44,9 0 Missing 252 2001 28.7 4.99 121 N 18 15 12 Mean 17 1,18 67,3 SD 14.7 344 72 8 Min 0,684 0 11A Median 11,s 0 24 2 Max 49 12,7 257 CV% 86.3 291.A 108,2 Morphine Conc Naltrexone GB-Naltrexol Week Subject (nglmL) Conc (pg/mL) Conc (pg/mL) 201 28 2005 8.63 0 Missing 201 2006 8.22 0 Missing 203~ 2002 9,94 Missing Missing 203 2003 3.05 Missing Missing 204 2008 17.5 Missing Missin 213 2004 38 0 Missing 213~ 2007 23.4 Missing Missing 214 2002 37 0 142 217- LIS Missing Missing 92 WO 2009/079518 PCT/US2008/087030 2010 222 2002 10.1 38.6 1440 226 2002 0Mssing Missing 229 2005 3.5 0 Missing 229 2006 9,69 0 Missing 229 2008 9.11 0 24,9 235 2001 30.6 10,1 132 241~ 2004 39,5 0 Missing 251 2001 34.1 0 13.5 251 2002 391 missing Missing 252 2001 54,3 Missing Missing 252~ 2002 0 Missing Missing N 19 11 5 Mean 19,8 4.43 350 SD 16.5 11.7 612 Min 0 0 13.5 Median 10.1 0 132 Max 54X3 38I6 1440 CV% 83.6 265 174.6 Morphine Conc Naltrexone 6B-Naltrexol Week . Subject (ng/mL) Conc (pglmL) Conc (pg/mL) 201 32 2005 8.4 Missing 201 2006 2,35 Missin Missing 203 2002 9 58 Missing Missing 204 2008 19.1 Missing ssing 213 2004 29.8 Missing Missing 213~ 2007 21 4 Missing missing 214 2002 23.4 Missing Missing 226 200 2 1.98 Missing Missing 229 2005 5 74 Missing Missing 229~ 2006 8,95 Missing Missing 93 WO 2009/079518 PCT/US2008/087030 229 2008 15 Missing Missn 235 2001 24.7 0 16 241 2004 24.5 missing M -sing 251 2001 35.5 Missing Missing 251 2002 33,5 Missing Mssing 252 2001 43.8 Missing Missing 252~ 2002 0 Missing Missing N 17 1 1 Mean 18.1 0 16 SD 13 Missing M ssing Min 0 0 16 Median 191 0 16 Max 43.8 0 16 CV% 719 Missing Missing Morphine Conc Naltrexone 6B-Naltrexol Week Subject (ng/mL) Conc (pg/mL) Conc (pg/mL) 201 36 2005 3.62 Missin 201 2006 5.77 Missing Missing 213 2004 45.2 Missing Missing 213 2007 Mfissing Missing Missing 214~ 2002 27,9 Missing Missing 216 2001 7,86 Missing Missing 217 2010 missing Missin missing 226 2002 missing Missing Missing 229~ 2005 US missing Missing 229 2006 11.8 Missing Missing 229 2008 7 82 Missin Missing 235 2001 30.9 Missing Missing 241~ 2004 43.5 Missing Missing 251 2001 35.2 Missing Missing ...... 251- 371 Missing Missing 94 WO 2009/079518 PCT/US2008/087030 2002 252 2001 14.8 Missing Missing 252 2002 0 Missing Missing N 13 0 0 Mean 20.9 Missing Missing SD 16.2 Missing Missing Min 1 0 Missing Missing Median 14.8 Missing Max 45.2 Missing Missing CV% 77.5 Missing Missing Morphine Conc Naltrexone SB-Naltrexol Week Subject (ng/mL) Conc (pg/mL) Conc (pg/mL) 201 40 2005 4 74 Missing Missing 201~ ------ 2006 missing Missing Missing 209 _______ 2013 Missing mission 213 M2004 29 issing Missing 214 2002 Missing Missing Missing 226 2002 Missing Missing Missing 229 2005 Missing Missing Missing 229 2006 Missing Missing Missing 229 2008 Missing Missing Missing 235~ 2001 29 Missing Missing 236 2002 Missing Missing Missing 241 2004 ALQ>60,0 Missing Missing 251 2001 MsigMissing Missing 251 2002 Missi n Missing Missing 252~ 2002 0 Missing missing N 4 0 0 Mean 157 Missing Missing SD 15,5 Missing Missing Mil 0 Missing Missing Median 16.9 Missing Missing Max 29 Missing Missing CV% 98.8 Missing Missing 95 WO 2009/079518 PCT/US2008/087030 Morphine Conc Naltrexone 6B-Naitrexol Week Subject (ng/mL. Conc (pg/mL) Conc (pg/mL) 201 44 2005 gMissing 201 2006 Missing Missing Missing 235 2001 f fMissi Missing Missing 241 2004 Missing Missing Missing 252~ 2001 14.2 Missing Missing 252 2002 0 Missing Missing N 2 0 0 Mean 7.1 Missing Missing SD 10 Missing Missing min 0 Missing Missing Median 7,1 Missing Missing __ Max 14,2 Missing Missing CV% 141.4 Missin Morphine Conc Naltrexone SB-Nahtrexol Week Subject (ng/mL) C gmL Conc (pg/mL) 100 201 ET) 2013 0 0 0 202 2004 0 missing MIssingq 205 2001 0 0 BLQ<2.50 205~ 2003 0 778 0 5.36 205 2006 0 0 0 208 2001 0 0 0.533 211 2010 0 Missing Missing 212 2001 1.02 0 BLQCD 500 212 2002 1.78 0 0 212 2006 8.8 0 12.6 213 2002 BLQ<1.00 0 BLQ<100 213 2003 18,7 0 1.17 213 2005 5.27 0 BLQ<100 213 2006 24.2 0 35.8 96 WO 2009/079518 PCT/US2008/087030 214 2003 34.4 0 3.21 216 2009 33 Missing Missing 217 2014 3,81 US 21.9 222 2002 40.9 118 2860 222 2011 0.214 0 137 229 2001 0 0 14,7 229~ 2007 0 0 ALQ>10-0 241 ... __ 2001 0 0 0 241 2007 8.64 0 BLQ<0,500 241 2019 0 0 BLQ<0500 255 ____ 2001 Mi 0 Misig~ 2003 204 16.8 192 257 2001 7.75 0 12 257 2010 15.6 0 54 259 2002 1 88 0 5.91 N 27 25 18 Mean 15.2 5.39 180 ____ SD 39A6 217 £70 Min 0 0 0 Median 1.78 0 8.96 Max 204 118 2860 CV% 260.3 439.5 373,3 While the present invention has been described in terms of the preferred embodiments, it is understood that variations and modifications will occur to those skilled in the art Therefore, it is intended that the appended claims cover all such equivalent variations that come within the scope of the invention as claimed. 97

Claims (8)

1. 2. The method of claim I wherein administration of the intact form of the composition 10 to the host once daily for at least a time period selected from the group consisting of four, eight, 12, 16, 20, 24, 28, 32, 36, 40 and 100 weeks results in zero release of antagonist.
2. 3. The method of either claim I or 2 wherein the antagonist is naltrexone,
3. 4. The method of either claim 3 wherein release of naltrexone is determined by 15 measuring plasma levels of 9-naltrexol.
4. 5. A method of treating a condition in a host that is responsive to an agonist, the method compnsmng administering a nulti-layer pharmaceutical composition comprising an agonist and an antagonist thereof that are not in direct contact with one another in the intact form of the composition, wherein administration of the intact form of the 20 composition to a population once daily for a time period of at least one week results in zero release of the antagonist in about 90% of the population.
5. 6. The method of claim I wherein the time period is selected from the group consisting of four, eight, 12, 16, 20, 24, 28, 32, 36, 40 and 100 weeks results in zero release of antagonist. 25 7. The method of either claim 1 or 2 wherein the antagonist is naltrexone.
6. 8. The method of either claim 3 wherein release of naltrexone is determined by measuring plasma levels of S-naltrexol
7. 9. A method of treating a condition in a host that is responsive to an agonist, the method comprising administering a multi-layer pharmaceutical composition comprising an 30 agonist and an antagonist thereof that are not in direct contact with one another in the intact form of the composition, wherein administration of the intact form of the 98 WO 2009/079518 PCT/US2008/087030 composition to the host once or twice daily for a time period of at least two weeks provides an analgesic effect.
8. 10. The method of claim 9 wherein the time period is selected from the gmup consisting offour, eight, 12, 16, 20, 24. 28, 32, 36,40 and 100 weeks. 99