US 2004O224020A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224020 A1 Schoenhard (43) Pub. Date: Nov. 11, 2004

(54) ORAL DOSAGE FORMS WITH (22) Filed: Dec. 18, 2003 THERAPEUTICALLY ACTIVE AGENTS IN CONTROLLED RELEASE CORES AND Related U.S. Application Data IMMEDIATE RELEASE GELATIN CAPSULE COATS (60) Provisional application No. 60/434,839, filed on Dec. 18, 2002. (76) Inventor: Grant L. Schoenhard, San Carlos, CA (US) Publication Classification Correspondence Address: (51) Int. Cl...... A61K 9/24 Janet M. McNicholas (52) U.S. Cl...... 424/471 McAndrews, Held & Malloy, Ltd. 34th Floor (57) ABSTRACT 500 W. Madison Street Chicago, IL 60661 (US) The present invention relates to oral dosage form with active agents in controlled release cores and in immediate release (21) Appl. No.: 10/742,672 gelatin capsule coats. Patent Application Publication Nov. 11, 2004 Sheet 1 of 3 US 2004/0224020 A1

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ORAL DOSAGE FORMS WITH released formulations, a long t is particularly disadvan THERAPEUTICALLY ACTIVE AGENTS IN tageous to patients Seeking urgent treatment and to maintain CONTROLLED RELEASE CORES AND MEC levels. A second difference in the pharmacokinetic IMMEDIATE RELEASE GELATIN CAPSULE profiles of controlled release in comparison to immediate COATS release drug formulations is that the duration of Sustained plasma levels is longer in the controlled release formula CROSS REFERENCED APPLICATIONS tions. The longer duration of Such Sustained plasma levels facilitated by controlled release formulations are advanta 0001. None applicable. geous to all patients, prolonging the desired biological effect. Therefore, although the controlled release formula BACKGROUND OF THE INVENTION tion facilitates a Substantially longer period of time in 0002 The maximum time of effectiveness of many oral maintaining plasma levels of drug or active metabolite(s), it dosage forms is only a few hours. While it is often desirable Suffers from the drawback of requiring longer periods of to reach an effective dose quickly, in order to maximize time to achieve the C, when compared to immediate patient compliance, it is also considered desirable to reduce release formulations. Thus, there remains a long felt need for the frequency of dosing, thereby reducing the number of improved controlled release formulations, including dosage doses a patient must take in order to attain effective therapy. formulations that might have one or more desirable charac In the case of combination therapy where two drugs may be teristics of both immediate release and controlled release given in the same dosage form (e.g., tablets, capsules, etc.), formulations. the frequency of dosing is further reduced. SUMMARY OF THE INVENTION 0.003 For any given dosage form of an agent, such as a 0006 The present invention is directed to novel oral drug, the amount of the agent from the dosage form that is dosage forms with therapeutically active agents in both available to reach the circulation System depends first on the controlled release cores and immediate release gelatin cap rate and extent of release from the dosage form. Following Sule coats. The agents have different release profiles from oral administration, drug or prodrug is released from the the cores and gelatin capsule coats. The controlled release dosage form containing the drug or prodrug in the gas cores optionally comprise additional components for the trointestinal (GI) tract and free drug is absorbed. The extent immediate release of a portion of therapeutically active of release determines the amount of drug available for agent from the core. Such gelatin capsule encapsulated absorption. The rate of release gives the amount of drug controlled release oral dosage forms constitute improved available for absorption per unit time. Drug dosage forms controlled release dosage forms and achieve a rate of release that rapidly release the drug into the GI tract are termed and an extent of release not previously achieved by either immediate release or IR formulations. The time, t to immediate release or controlled release dosage forms of reach to maximum plasma concentrations (C) of the drug therapeutically active agent(s). Soft gelatin capsules, such as in the body ranges from a few minutes to two plus hours for Softgels, with at least one therapeutically active agent are Such immediate release formulations. During the absorption preferred for encapsulating the cores. The invention further phase, the drug is distributing throughout the body, and in relates to pharmaceutical formulations useful in the prepa most cases are beginning and/or simultaneously being elimi ration of Such dosage forms, as well as to methods of making nated from the body. Thus, the pharmacokinetic profile (the and administering Such dosage forms. Gelatin capsule graph of drug in blood or plasma concentration vs. time) for encapsulated controlled release cores of at least one thera repeated administration of immediate release formulations peutically active agent, including liquid, tablet, or Solid cycle from minimum or trough plasma concentrations C min cores, wherein the gelatin capsule encapsulating Such con to peak plasma concentrations, C, and back to minimum trolled release core comprises an immediate release formu or trough plasma concentrations, C. lation of at least one therapeutically active agent are 0004) To achieve Sustained concentration of circulating improved dosage forms with Surprising advantages. Such drug or active metabolite(s) or conjugate(s) of drug over a gelatin capsule encapsulating wherein the gelatin capsule longer period of time between doses, controlled release contains at least one therapeutically active agent, enables the (alternative constant release (SR) or extended release) drug increase of the rate of release of the therapeutically active formulations were developed. These controlled release (CR) agent(s) from oral dosage forms of the invention and/or formulations require approximately from 2 to 3 hours to increases the apparent extent of exposure to Sustained blood/ achieve C, and the minimum effective concentration plasma concentrations of the agent(s) and/or metabolites or (MEC) of drug in the circulation, and can maintain MEC conjugates of Such agent(s), as well as the related pharma levels from about 12 to about 22 hours before declining codynamic response, for example, when at least one of the exponentially because no more drug is being released from therapeutically active agents is the same in the gelatin the dosage form and Systematically absorbed. Thus, the capsule coating and in the core. pharmacokinetic profile of controlled release formulations 0007 Novel oral dosage forms according to the invention have a shape Similar to a hyperbole, with a slow and gradual comprise (i) an controlled release core, and (ii) an immediate increase in drug blood levels to a plateau, followed by a release gelatin capsule around the controlled release core, decline in plasma concentrations. wherein the controlled released core comprises at least one 0005. When comparing the pharmacokinetic profiles of therapeutically active agent and at least one controlled immediate release with controlled release drug formulations, release material, and wherein the immediate release gelatin there are two major differences. First, the time to achieve the capsule comprises at least one therapeutically active agent. C in the plasma is often longer in the controlled release Such oral dosage forms have at least one therapeutically Versus the immediate release formulation. In controlled active agent in the controlled release core that is the same as US 2004/0224020 A1 Nov. 11, 2004 or different from at least one therapeutically active agent in agonists, alone or in combination with opioid antagonists. the immediate release gelatin capsule. Preferred dosage The present invention thus provides controlled release phar forms according to the invention have the same therapeuti maceutical formulations in the form of a liquid, tablet, or cally active agent in both the core and the immediate release capsule as a controlled release core, wherein the core gelatin capsule and optionally may have other agents in comprises one or more therapeutically active agents and one either or both of the core and gelatin capsule. Such gelatin or more controlled release materials. Optionally, the core capsule encapsulated controlled release dosage forms as additionally comprises one or more therapeutically active described herein, achieve an increased rate of release of the agents and one or more immediate release components. therapeutically active agent via the immediate release gela Preferably, at least one active agent is in both a controlled tin capsule and an increased extent of duration of exposure release and an immediate release form in Such a core. A core to Stable blood/plasma concentration of the therapeutically is then encapsulated with an immediate release gelatin active agent(s) and/or active metabolite(s) or conjugate(s) capsule comprising immediate release pharmaceutical for via the combination of the release of active agents from the mulations of one or more therapeutically active agents. The immediate release gelatin capsule and the controlled release effect of Such novel dosage forms is to increase the rate of core, with initial and repeated administration of the dosage release of the therapeutically active agent(s) from the dosage form. Following repeated administration to a Subject, dosage form via the immediate release gelatin capsule coating forms according to the invention provide immediate and comprising the therapeutically active agent(s), and to continual release of active agent(s), Such as a drug, for increase the apparent extent of exposure to Sustained blood/ absorption by distribution of and elimination from the plasma concentration(s) of the therapeutically active Subject, and can maintain the desired pharmacokinetic and/ agent(s) or active metabolic or conjugate thereof, from the or pharmacodynamic profiles. Optionally, the controlled dosage form (via both the immediate release gelatin capsule release core with at least one therapeutically active agent coating and the controlled release core each comprising and at least one controlled release material, can further therapeutically active agent(s). The combination of gelatin comprise immediate release components having at least one capsule coating and controlled release core (with or without therapeutically active agent, wherein, for example, the com additional immediate release components in the core) ponents are in the form of a liquid, granulate, particulate, achieves the increased rate and extent/duration of release pellet, or bead. Preferably, at least one agent in the imme with initial and repeated administration of the dosage form diate release components of the core is the same as at least as well as the related pharmacodynamic response. Such one agent in the controlled release components of the core dosage forms according to the invention are administrable at and/or in the immediate release gelatin capsule coat. least every 8 hours and preferably administrable once-a-day 0008. The present invention provides novel oral dosage (every 24 hours) or twice daily (every 12 hours). A preferred forms with unexpectedly Superior results using a liquid dosage form according to the invention comprises (i) a (including, for example, a high Viscosity liquid) or Solid controlled release core that has an opioid agonist, Such as, (including, for example, a granulate, particulate, pellet or for example, oxycodone or morphine, as a therapeutically bead) controlled release formulation with at least one thera active agent, alone or in combination with an opioid antago peutically active agent and at least one controlled release nist, Such as, for example, naltrexone or nalmefene, and a material as a controlled release core. Thus, the core may be, controlled release material, Such as, for example, SAIB, and for example, a liquid, tablet or capsule. This core is coated (ii) an immediate release gelatin capsule, including a Soft by encapsulating Such core with angelatin capsule, prefer gelatin capsule, for example, Such as Softgels, enteric Soft ably a Soft gelatin capsule, that also contains at least one gels, or gelcaps, that has an opioid agonist, for example, therapeutically active agent as an immediate release formu Such as oxycodone or morphine, as a therapeutically active lation. Preferably, at least one therapeutically active agent agent, alone or in combination with an opioid antagonist, for that is in the core as a controlled release formulation is the example, Such as naltrexone or nalmefene. Preferred manu Same agent that is in the immediate release gelatin capsule facturers of gelatin capsules containing no active agent in coating as an immediate release formulation. A multiplicity the gelatin capsule are Banner Pharmacaps (see, e.g., their of controlled release materials are known and useful accord Softgel, Gelatin Binary SystemTM, and SofletTM Gelcap ing to the invention, including, for example, high Viscosity products) and Cardinal (see, e.g., their LIQUI-GELS(R), RP liquid carrier materials (HVLCM) as described herein and in SCHERERSOL(R), and PULSIN-CAP(R) technology and U.S. Pat. Nos. 5,747,058; 5,968,542; 6,413,536; and corre products). Novel gelatin capsules may be prepared accord sponding PCT publications WO 96/39995; WO 99/13913; ing to the invention by incorporating at least one therapeu WO 01/15734, such as, for example, sucrose acetate isobu tically active agent in a gelatin formulation that is used to tyrate (SAIB). encapsulate an core according to the invention. 0009. Therapeutically active agents suitable for dosage DESCRIPTION OF THE FIGURES forms of the invention include biologically active Substances that are useful for human therapy, veterinary therapy, or for 0010) The detailed description of the invention will be agricultural purposes. Therapeutically active agents include made with reference to the accompanying drawing, where organic molecules, for example, drugs. Drugs include Sub like numerals designate corresponding parts of the figures. stances used as medicines for the treatment (e.g., prophy The drawings are meant to be generally illustrative of lactic or therapeutic), cure or prevention of a disease, various examples of the present invention, but are merely condition or disorder. Drugs include prodrugs. Among the example and are not meant to be limiting the Scope of the preferred therapeutically active agents Suitable for dosage invention. forms according to the invention are analgesics, including 0011 FIG. 1 is a release profile of a traditional controlled opioids. Among the particularly preferred therapeutically release formulation or dosage form of therapeutically active active agents Suitable for Such dosage forms are opioid agent. US 2004/0224020 A1 Nov. 11, 2004

0012 FIG. 2 is a release profile of a formulation or Optionally, the core can additionally contain a portion of dosage form according to the present invention, illustrating immediate release components, in the form of, for example, an increased rate of release and an increased apparent extent liquids, granulates, pellets, or beads, each comprising at of exposure to Sustained blood/plasma concentrations of least one therapeutically active agent. Again, preferably the therapeutically active agent as compared with a traditional immediate release component of the controlled release core controlled formulation/dosage form. comprises at least one therapeutic agent that is the Same as 0013 FIG. 3 is the chemical structure of SAIB, sucrose the agent in the controlled release portion of the core and/or acetate isobutyrate. the same as the agent in one gelatin component. 0017. The invention provides liquids or liquid gels of DETAILED DESCRIPTION OF THE varying Viscosity, as well as tablets or capsules that comprise INVENTION an controlled release core with at least one controlled release material and at least one therapeutically active agent, 0.014. The present invention generally relates to an oral wherein the liquid, tablet, or capsule core is coated by an dosage form comprising (i) a controlled release core; and (ii) gelatin capsule. The gelatin capsule encapsulates the core. an immediate release gelatin capsule that encapsulates con Encapsulating includes coating, covering, encasing, enrob trolled release core, wherein the controlled released core ing, enveloping and capsuleing. This immediate release comprises at least one therapeutically active agent and at gelatin capsule comprises an immediate release formulation least one controlled release material, and wherein the imme of at least one therapeutically active agent, preferably the diate release gelatin capsule comprises at least one thera Same therapeutically active agent that is in the controlled peutically active agent. Such novel oral dosage forms rep release core. The invention thus provides an controlled resent improved controlled release dosage forms. The release core comprising a therapeutically active agent in the dosage forms and formulations presented herein achieve an form of a liquid, tablet, or capsule that is encapsulated with increased rate of release of the therapeutically active agent an immediate release gelatin capsule coating of the same and an increased apparent extent of exposure to Sustained therapeutically active agent, So as to provide an initial rapid blood/plasma concentrations of the therapeutically active increased rate of release of the agent. Dosage forms accord agent and/or its active metabolite(s) and/or conjugates via ing to the invention can be administered at least every 8 the combination of the immediate release gelatin capsule hours and preferably administered one-a day (every 24 and the controlled release core with initial and repeated hours) or twice daily (every 12 hours). administration of the dosage form. Optionally, the controlled release core can also contain an immediate release compo 0018 Gelatin capsules include soft gelatin capsules or nents in the form of, for example, liquids, granulates, hard gelatin capsules. A Soft gelatin capsule is often a one particulates, pellets, beads, etc.) also comprising a therapeu piece hermetically or Similarly effectively Sealed capsule tically active agent. Preferably, at least one therapeutically composed essentially of gelatin which may be plasticized or which may contain other gelatinous material that retains active agent is the same as in the controlled release core plasticity without becoming brittle. For example, a Soft and/or the immediate release gelatin capsule. gelatin capsule can be transparent and colorless or pale 0.015 The release profile of traditional controlled release yellow. Additionally or alternatively, for example, a Soft formulations or dosage forms, as shown in FIG. 1, generally gelatin capsule may have a colorant added. A hard gelatin have a shape Similar to a hyperbole, with a slow and gradual capsule is often a two piece (cap and body) capsule shell increase in blood/plasma levels of an active agent Such as a composed of gelatin or other gelatinous material with the drug, to a plateau, followed by a decline in blood/plasma appearance of having been or chemically plasticized to the concentrations. In contrast, FIG. 2 show the release profile extent of retaining in the unfilled or filled condition a of a formulation or dosage form according to the present Specified shape with a near brittle or brittle physical prop invention with active agent in both controlled release core erty. For example, a hard gelatin capsule can be opaque and immediate release gelatin capsule illustrating a rapid and/or a colorant can be added. A hard gelatin capsule is and increased rate of release of active agent, as well as an formed and filled in Separation operations. The gelatin increased apparent extent of exposure to Sustained blood/ capsule fill may be a liquid, Semisolid, or Solid. plasma concentrations of the active agent or active metabo lite(s) thereof from initial and repeated administration of the 0019 Controlled release or Sustained release refers to dosage form. Such increased rate and extent of release and formulation that provides a longer period of pharmacologi exposure results in an increase in the related pharmacody cal response after the administration of a therapeutically namic response. active agent that is ordinarily provided after the administra tion of the immediate release or rapid release formulation of 0016. The invention provides surprisingly and unexpect that agent. Controlled release or Sustained release formula edly Superior results using a liquid Semi-Solid or Solid tion which allow the release of a therapeutically active agent (including, without limitation, particulates, granules, or or agents in blood levels within a desired therapeutic range beads) controlled release formulation with at least one and maintains Such levels over an extended period of time, therapeutically active agent as an core that is coated with an Such as from at least about 8 hours, Such as from about 12 gelatin capsule by encapsulating wherein the gelatin capsule hours to about 24 hours. Controlled release formulations also contains at least one therapeutically active agent as an generally contain a controlled release material in order to immediate release formulation. Preferably, at least one achieve the controlled or Sustained release of the desired therapeutically active agent present in the core as a con agent. A controlled release material can include a continuous trolled release formulation is the same as at least one matrix, Such as an insoluble polymeric matrix or a high therapeutically active agent present in the immediate release Viscosity (e.g. non-polymeric) liquid material, wherein a gelatin capsule coating as an immediate release formulation. therapeutically active agent is dispersed within and is Sub US 2004/0224020 A1 Nov. 11, 2004

Sequently released typically by a diffusion-like process of tion) effects at these receptors, Such as opioid alkaloids, the liquid material, therapeutically active agent through the including the agonist morphine as well as morphine-6- continuous matrix. Controlled release formulations can also glucuronide, oxycodone as well as oxymorphone and refer to a dosage form comprising a therapeutically active noroxycodone, and the antagonist naltrexone and its agent that is coated with a controlled release material, So as metabolite, and Such as opioid peptides, including enkepha to permit release of the therapeutically active agent at a lins, dynorphins and endorphins. Opioid receptor agonists or Sustained rate in an aqueous medium. The controlled release opioid agonists are opioid compounds or compositions may be a Sustained release or delayed/modified release. A including any active metabolite as well as conjugates, Such controlled-release dosage form as defined in US Pharma as by glucoronidation, Sulfation, or acetylation of Such copeia XXII includes extended release dosage forms which compound or composition that binds to and activates opioid allow at least a twofold reduction in dosing frequency as receptors on nociceptive neurons which mediate pain. Such compared to the drug presented as a conventional dosage opioid agonists have analgesic activity (with measurable from and delayed release dosage forms which release the onset, peak, duration and/or total effect and can produce drug at a time other than promptly after administration. analgesia). Opioid antagonists refer to opioid compounds or 0020 Immediate release generally refers to formulations compositions including any active metabolite as well as that allow the release of a therapeutically active agent or conjugates, Such as by glucoronidation, Sulfation, or acety agents in blood levels within a desired therapeutic range in lation of Such compound or composition that in a Sufficient a rapid period of time, Such as, for example, from about 5 amount attenuates (e.g., antagonizes, blocks, inhibits, pre minutes to about 20 minutes. An immediate release formu vents or competes with) the action of an opioid agonist. lation can include Soluble components, for example, Sugars, 0023 The controlled release core of the present invention polymers, Surfactants, coatings and other components as is coated with an immediate release gelatin capsule coating described herein. using any of the many gelatin capsule coating processes, Such as spray coating, wet gelatin bath dipping, encapsulat 0021. Therapeutically active agent refers to a substance, ing, and Vacuum holding, for instance. The process of including a biologically active Substance that is useful for coating an core where the core is, for example, a liquid, human therapy, veterinary therapy, or for agricultural pur tablet, or capsule, with angelatin coating is also referred to poses. Therapy includes prophylactic and therapeutic treat as encasing, enrobing, or encapsulating. ment. Therapeutically active agents include organic mol ecules that are drugs, peptides, proteins, carbohydrates, 0024. The controlled release core can be in the form of a monosaccharides, oligosaccharides, polysaccharides, nucle tablet that is enrobed with the immediate release gelatin oprotein, mucoprotein, lipoprotein, Synthetic polypeptide or capsule coating, wherein the tablet core and the gelatin protein, Small molecules linked to a protein, glycoprotein, capsule coating each contain at least one therapeutically steroid, nucleic acid, DNA, cDNA, RNA, nucleotide, active agent, and wherein the immediate release gelatin nucleoside, oligonucleotides, antisense oligonucleotides, capsule coating is formed by application of respective layers gene, lipid, hormone, and Vitamin. Drugs include any Sub of elastic gelatin film with the agent to opposite Sides of the stance used as a medicine for the treatment, cure, or pre tablet. This enrobing process without the agent is described, vention of a disease, condition, or disorder. Non-limiting for example, in U.S. Pat. No. 5,146,730, the disclosure of examples of therapeutically active agents include antihista which is incorporated herein by reference. In this process, mines, analgesics, anti-inflammatory agents, gastro-intesti the applied gelatin layer conforms tightly to the table nals, anti-emetics, anti-epileptics, vasodilators, anti-tuSSive Surface, bonds Securely thereto, and the layers are Sealed agents, expectorants, anti-asthmatics, anti-Spasmodics, hor together edge-to-edge at a Seal line which extends around mones, diuretics, anti-hypertensives, bronchodilators, anti the tablet. inflammatory Steroids, antivirals, antibiotics, antihemor 0025 The controlled release core can be in the form of a rhoidals, hypnotics, psychotropics, antidiarrheals, tablet that is enrobed between two sealable gelatin films of mucolytics, Sedatives, decongestants, laxatives, antacids, the immediate release gelatin capsule coating with the agent Vitamins, Stimulants, and opioids. Among the preferred according to the invention. An enrobing process without the therapeutically active agents are analgesics, including opio agent is described, for example, in U.S. Pat. No. 6,482,516, ids. A therapeutically active agent includes a first agent that the disclosure of which is incorporated herein by reference. increases the effectiveness of a Second agent, for example, U.S. Pat. No. 6,482,516 describes an enrobement process by enhancing potency or reducing an adverse effect(s) of the which uses coacting die techniques wherein tablets or other Second agent. A therapeutically active agent includes an articles to be enrobed are introduced individually between agent that increases an effect of, acts Synergistically with, two Sealable gelatin films. and/or promotes, potentiates, or enhances an effect of another agent. Such therapeutically active agents are bio 0026. The controlled release core can be in the form of a logically active Substances in accordance with the invention. liquid comprising insoluble particles. This liquid core is The effect that is increased, promoted, potentiated or encapsulated within the immediate release gelatin capsule enhanced may be, for example, an analgesic effect and the with the agent that is in the form of a Soft gelatin capsule. therapeutically active agent may potentiate the analgesic An encapsulating process without the agent is described, for example, in U.S. Pat. No. 5,595,758, the disclosure of which effect of a different therapeutically active agent. is incorporated herein by reference. U.S. Pat. No. 5,595,758 0022. Opioids include compounds or compositions describes a capsule having a Soft, flexible gelatin skin and an including metabolites as well as conjugates, Such as by internal fill which comprises a pharmaceutically acceptable glucoronidation, Sulfation, or acetylation of Such com liquid carrier which is compatible with the gelatin coating pounds or compositions which bind to Specific opioid recep and which contains Small drug-bearing particles which do tors and have agonist (activation) or antagonist (inactiva not dissolve in the liquid. US 2004/0224020 A1 Nov. 11, 2004

0027. The immediate release gelatin capsule coating of Pat. Nos. 4,067,960, 4,198.391, 4,744,988, and 4,780,316, the present invention comprises at least one therapeutically the disclosures of all of which are incorporated herein by active agent. Processes of preparing gelatin capsules are reference. described herein. According to the present invention, pro 0030. After the rotary die process is used to thereby ceSSes are provided herein to incorporate therapeutically produce gelatin Shells having a medicament fill therein, the active agents, including drugs or other pharmaceutically resulting capsules are typically washed with an evaporatable acceptable agents, into immediate release gelatin formula Solvent. Thereafter, the capsules are typically dried a tem tions to encapsulate controlled release cores. Soft gelatin perature typically less than 35 C. After the drying process, capsules (e.g., gel caps) or hard gelatin capsules comprising a large proportion (50-60%) of the water from the gelatin at least one therapeutically active agent are used as the shell has been removed. Recent developments in drying immediate release gelatin capsule coat according to the include bypassing the drum drying Stage and having the invention. Soft gelatin capsules are preferred for incorpo capsules dried in a drying tunnel or room as discussed rating therapeutically active agent(s) according to the inven below. tion and preferred manufacturers include Banner Phar macaps see e.g., their Softgel, Gelatin Binary System", 0031. After the capsules exit the last drying drum, the and SofletTM Gelcap products and Cardinal see e.g., capsules are typically spread on drying trayS. The final LIQUI-GELS(R), RPSCHERERSOL(R), and PULSIN-CAP(R) drying phase for Softgels is typically accomplished by technology and products. passing the drying trays through drying tunnels or into drying rooms. Stacks of trays are inserted into drying tunnels 0028. The softgel (the currently accepted nomenclature or drying rooms, in which controlled temperature air (21-24 adopted by the SoftGel ASSociation) is a one-piece, hermeti C.) and low relative humidity (20%-30%) is continuously cally Sealed Soft gelatin Shell containing a liquid, a Suspen circulated. Although additional water may be removed from Sion, or a Semi-Solid. The most common modern manufac dry capsules by further heating, for example at 40 C., Such turing process involved in the preparation of Softgels is a a procedure has not been found to be practical or necessary. rotary die proceSS in which a molten mass of a gelatin See, e.g., Van Hostetler and J.Q; Bellard in The Theory and formulation is fed from a reservoir onto drums to form two Practice of Industrial Pharmacy, “Capsules”, (1970), Chap Spaced sheets or ribbons of gelatin in a Semi-molten State. ter 13 at pages 346-383, and in particular at page 380, the These ribbons are fed around rollers and brought together at disclosure of which is incorporated herein by reference. a convergent angle into the nip of a pair of roller dies that include opposed die cavities. A liquid or paste medicament 0032. The drying time, for most Softgels, is 16-24 hours, or other material to be encapsulated is fed into the wedge but may be slightly longer if the Softgels are over 20 minims shaped joiner of the ribbons. The gelatin ribbons are con in size or if the Softgels contain a non-oily type liquid base. tinuously conveyed between the dies, with portions of the Evaporation of liquids including ethanol or water can occur medicament being trapped between the sheets inside the die during the drying process. Softgels permitted to come to cavities. The sheets are then pressed together, and Severed water equilibrium in this controlled environment are con around each die So that opposed edges of the sheets flow sidered “dry”. The gelatin fill and shell of such “dry” together to form a continuous gelatin covering around the Softgels contain 6-10% water depending on the Specific entrapped medicament. The very Soft capsules are then dried gelatin and fill formula used. After drying, the capsules are to increase the integrity of the capsules, and packaged for typically inspected and finished using varied known tech later distribution and consumption. See P. Tyle, Specialized niques. Drug Delivery System, Marcel Dekker, Inc. (1990) for a 0033. The immediate release gelatin capsule can be general discussion of Softgel manufacturing and production coated with one or more layers of over-coating. Such technology, in particular, Chapter 10 by Paul K. Wilkinson overcoating can Seal and/or protect the gelatin capsule, and Foo Song Hom, the disclosures of which are incorpo including Sealing and/or protecting the therapeutically active rated herein by reference. agent(s) in the gelatin capsule and/or on its Surface. The agent(s) can migrate into the gelatin capsule layer or unto the 0029 Various gelatin shell masses may be prepared, gelatin capsule Surface during the drying process and would depending on the fill properties, climatic conditions, and end be protected by Such an overcoat. Such overcoating can also use. Typically gelatin formulations include the same basic improve the mechanical Strength of the gelatin capsule. Such ingredients, namely, gelatin, a plasticizer Such as glycerin, over-coating may, for example, comprise hydroxypropyl water, and optionally preservatives. Formulations of gelatins are well known. In most cases, the typical rotary die proceSS methylcellulose, as described, for instance, in U.S. Pat. No. requires a flowable liquid or fill. The fill may be a single 4,816,259, the disclosure of which is incorporated herein by phase liquid active, a mixture of miscible liquids, or a reference. U.S. Pat. No. 4,816,259 describes the application Solution or a Suspension of Solids and liquids. Generally the of a hydroxypropyl methylcellulose Subcoating to the Sur fill contains glycerin and a medicament. Liquids to be face of a Soft gel to improve mechanical Strength of the encapsulated in a gelatin Shell are also well known. Shell capsule and to better adhere enteric coating compositions. and fill formulations are discussed in Van Hostetler and J. Q. 0034. Where the controlled release core is in the form of Bellard noted below as well as in “Advances in Softgel a tablet, the immediate release gelatin capsule can comprise Formulation Technology”, M. S. Patel, F. S. S. Morton, and an overcoat of at least one adhesive gelatin film. This H. Seager, Manufacturing Chemists, July 1989; "Soft Elastic adhesive gelatin coating is advantageous in the gelatin Gelatin Capsules: A Unique Dosage Form”; William R. capsule drying process because it can become an integral Ebert, Pharmaceutical Technology, October 1977; “Soft part of the finished product dosage form and not be physi gelatin capsules: a Solution to many tableting problems, H. cally removed without damaging the finished product dos Seager, Pharmaceutical Technology, September 1985; U.S. age form or the controlled release core. This feature can be US 2004/0224020 A1 Nov. 11, 2004 particularly important where the product dosage form to be Sufficient to provide capsule integrity. The capsule formu produced is a tamper-evident medicine formulation. The use lation further comprises at least one therapeutically active of adhesive gelatin coating for tablets is described, for agent. example, in U.S. Pat. No. 5,459,983, the disclosure of which 0037. The immediate release gelatin capsule coating can is incorporated herein by reference. Compositions Suitable be in the form of a gum acacia Substituted Soft gelatin for use as an overcoat of an adhesive gelatin film comprise capsule. Gum acacia Substituted Soft gelatin capsules are a plasticizer in an optimal amount. Low ratioS of plasticizer composed from capsule formulations comprising gum aca to gelatin result in a brittle gelatin film coating whereas high cia as a gelatin extender. Gum acacia or gum arabic or acacia ratioS result in a gelatin coating that is flexible and can be is a plant exudates collected from the trees of Acacia Species. peeled from the product dosage form. An example of a Gum acacia is an arabino-galactan-protein complex com composition that is Satisfactory for use as an adhesive posed by weight of from about 17% to about 34% arabinose, gelatin coating comprises plasticizer and gelatin in a ratio of from about 32 to about 50% galactose, from about 11 to about 1:5, respectively. about 16% rhamnose, from about 13% to about 19% glcu 0035) Any gelatin formulation which can be used suc ronic acid and from about 1.8% to about 2.5% protein. cessfully in the manufacture of Soft or hard gelatin capsules Capsule formulations comprising gum acacia are described, containing flowable materials taking into account matters of for example, in U.S. Pat. No. 6,139,999, the disclosure of technical capability and/or capacity, where the materials which is incorporated herein by reference. Gum acacia can include, for example, powder, liquids, compressed Solids, or replace gelatin, in replacement amounts of from about 5% to pastes, along with any therapeutically active agent can be about 35% by total weight of gelatin in capsule forming used in the immediate release gelatin capsule coating of the compositions. These compositions may be used in thermally present invention. Any pharmaceutically acceptable gelatin Sealed, orally administered capsules manufactured by con Suitable for human administration can be employed in the ventional rotary dies encapsulation machines, without present invention. Gelatin is a coating material used in increasing the brittleness of the gelatin Shell. Other advan pharmaceutical formulation. Gelatin is commercially avail tages in formulating Softgels with gelatin compositions able in many forms, Such as acid bone gelatin or lime bone comprising gum acacia include, for example, shorter drying gelatin. Gelatin can be derived by at least partial acid or base periods because gum acacia is a film-former whereas gelatin hydrolysis of collagen of Skin, tendons, ligaments, or bones is not, shorter aging times of gel masses to allow for from a variety of animal Sources, Such as mammalian or fish, Shortening production cycles and increasing throughput, and resulting in gelatinous materials with varying bloom shorter opening and disintegration times for finished cap Strength and compatibility with the therapeutically active Sules due to the highly cold-water Soluble features of gum agent(s) Such as drug, mixed with the gelatin formulation. acacia. An example of a gum acacia Substituted Softgel Bloom refers to the cohesive Strength of a gelatinous mate composition comprises: (i) a film forming material in an rial. Bloom values are normally determined by measuring amount ranging from about 30% to about 60% by weight, the weight in grams required to move a plunger 0.5 inch in (ii) a water-dispersible or water-Soluble plasticizer in an diameter, 4 mm into a 6.67% gelatin gel that has been held amount ranging from about 5% to about 35% by weight, (iii) for 17 hours at 10 C. Conventional soft gelatin capsule have purified water in an amount ranging from about 25% to a bloom in the range of from about 150 to about 275. The about 65% by weight, wherein the film forming material gelatin in the gelatin capsule may be Type A or B gelatin or comprises gelatin and gum acacia, with gum acacia account a mixture thereof. Limed bone, acid bone, fish, and/or pig ing for from about 0.5% to about 50% by weight of the total skin gelatins may be used. amount of the film-forming material, a dried film having 0.036 The immediate release gelatin capsule coating with from 3% to about 12% by weight of water formed from the at least one therapeutically active agent can be in the form composition. The capsule formulation further comprises at of a chewable Soft gelatin capsule. Chewable Soft gelatin least one therapeutically active agent. capsules comprise a chewable gelatin encapsulating a liquid 0038. The immediate release gelatin capsule coating can fill which are designed to at least partially disperse or be in the form of a softgel that includes a filled portion and dissolve in the user's mouth within a brief period of time a non-filled portion wherein at least one of the filled and after the fill contents have been released, Such as within non-filled portions has an external Surfacing having defined about 60 seconds, so that it can be Swallowed. Chewable soft thereon an impressed graphical representation, Such as a gelatin capsules are described, for example, in U.S. Pat. No. letter, number, symbol, logo, or the like. Methods for 6,258,380, the disclosure of which is incorporated herein by making a Softgel that have a filled portion and a non-filled reference. Capsule formulations compatible for use in chew portion whereby upon Sealing, a graphical representation is able Soft gelatin capsules are formed of a mixture of a first gelatin having a bloom Substantially lower than the bloom of impressed as described, for example, in U.S. Pat. No. gelatins convention used to form capsules, in combination 5,827,535, the disclosure of which is incorporated herein by with a minor percentage of a Second gelatin having a bloom reference. within the range of conventional capsule-forming gelatin 0039 The immediate release gelatin capsule coating can blooms. A non-limiting example of a capsule formulation be in the form of a multiple layer softgel. Multiple layer comprises: (i) a first gelatin having a bloom of from about Softgels refer to Softgel capsules which comprise a first 80 to about 100 in an amount of from about 20% to about gelatin layer having a certain thickness and a Second layer 30% by weight, (ii) a second gelatin having a bloom of from having another certain thickneSS wherein the Second gelatin about 150 to about 275 in an amount of from about 5% to layer at least partially Surround the first gelatin layer. Such about 29% by weight, (iii) up to about 10% water, (iv) a multiple layer Softgels are described, for example, in U.S. plasticizer in an amount Sufficient to render the capsule Pat. No. 6,183,845, the disclosure of which is incorporated flexible, and (v) a moisture retention agent in an amount herein by reference. An example of a multiple layer Softgel US 2004/0224020 A1 Nov. 11, 2004 is a Softgel capsule with content, having opposing ends can be readily optimized to achieve the desired effect. comprising a first sheet that covers a first end, the first sheet Examples of plasticizers that can be used include, for comprising at least a first gelatin layer and a Second layer, instance, Sorbitol, Sorbitol with Sorbitan, (as described, for each layer having a uniform thickness, and a Second sheet example, in U.S. Pat. No. 4,744.988, the disclosure of which that covers a Second end, the Second sheet comprising at is incorporated herein by reference), malitol, (as described, least a third gelatin layer, the third layer having a uniform for example, in U.S. Pat. No. 5,569,461 the disclosure of thickneSS wherein the first and Second sheets meet at a Seam. which is incorporated herein by reference), glycerol, xylitol, At least one of the multiple gelatin layers comprise at least polyglycerol, glucose, fructose, or a mixture thereof. Also, one therapeutically active agent. Surfactants and drying agents may be added to the gelatin formulation of the present invention, Such as when the 0040. The immediate release gelatin capsule coating can gelatin formulation is to be used in a spray coating process be in the form of a one-piece gelatin capsule or shell that as described in U.S. Pat. No. 6,077.540, for example. includes a plasticizer to control the Softness and flexibility of Surfactants may act to complex gelatin proteins thereby the capsule, water, and optionally other additives, Such as restraining the adhesive character of gelatin. Non-limiting flavorants, colorants, opacifiers, etc. Such Soft or hard gela examples of Surfactants include Stearoyl lactylate, calcium tin compositions are described, for example, in U.S. Pat. No. Steroyl lactylate, and glyceryl monosterarate. Drying agents 6,251,426, the disclosure of which is incorporated herein by may act to desolvate gelatin and shorten the drying time of reference. The Softgel capsule may be produced in a known the gelatin coating. Non-limiting examples of drying agents manner with a rotary die process in which a molten mass of include magnesium aluminum Silicate and Sodium, magne a gelatin formulation is fed from a reservoir onto drums to sium and potassium Sulfate, and hydrophilic clayS. For form two spaced sheets or ribbons of gelatin in a Semi gelatinous compositions comprising hydrophilic clays and molten state. These ribbons are fed around rollers and magnesium aluminum Silicate, these two Substances have brought together at a convergent angle into the nip of a pair been described as Suspending agents and may play a dual of roller dies that include opposed die cavities. role in these compositions. Capsule formulations may also 0041 Additional examples of shell formulation that can contain taste modifiers, coloring agents, and moisture retain be used in Soft gelatin capsules are described, for example ing agent. Examples of taste modifiers include, for instance, in Van Hosteteler and J. Q. Bellard in “Advances in Softgel non-reducing Sugars, Such as xylitol, malitol, or Lycasin(D Formulation Technology”, M. S. Oatel F. S. S. Morton, and manufactured by Roquette America Inc. of Keokuk, Iowa H. Seager, Manufacturing Chemists, July 1989;"Soft Elastic and may comprise up to about 5% by weight of the gelatin Gelatin Capsules: A Unique Dosage Form”, William R. capsule composition. Examples of moisture retaining agents Ebert, Pharmaceutical Technology, October 1977; “Soft include, for instance, celluloses, cellulose derivatives, gelatin capsules: a Solution to many tableting problems, H. Starches, Starch derivatives, vegetable gums, non-hygro Seager, Pharmaceutical Technology, September 1985; U.S. Scopic mono- and di-oligosaccharides, Starch acetates, Pat. Nos. 3,959,540, 4,198.391, 4,744,988, 4,780,316, Starch derivatives, potato unbleached Starch acetate (as 5,200,191, 5,380,534, 5,422,160, 5,484,598, 5,505,961, described, for example, in U.S. Pat. No. 5,817,323, the 5,569,466, 5,595,758, 5,624,681, 5,682,733, 5,735,105, disclosure of which is incorporated herein by reference), and 5,750,145, 5,817,323, 5,827,535, 5,891,470, 5,985,321, Silicon dioxide. In determining the exact gelatinous compo 6,096,338, 6,120,806, 6,183,845, 6,193.999, 6,214,376, Sition to be used in formulating the immediate release 6,251,426, 6,285,380, 6,288,894, 6,387,400, the disclosures gelatin capsule coating, factorS Such as ease of handling, of all of which are incorporated herein by reference. Gelatin cost, and adaptability to Subsequent processes, for example, shell formulations in contrast to prior indices, comprise at are considered. least one therapeutically active agent. 0043. For consumer acceptability, immediate release 0.042 Various gelatin capsule formulations may be used gelatin capsules in the form of a Softgel capsule should be of to encapsulate the controlled released core. For example, size that is easily Swallowed. Generally, the fill size of the Suitable capsule formulation may include gelatin in an capsule can be leSS than 60 mg, Such as about 500 mg or less, amount of about 35% to about 50% by weight, a plasticizer for the capsule to be of an acceptably Small dimension, in an amount of from about 20% to about 40%, and water in although other sizes are possible. The controlled release core an amount of from about 25% to about 50%. The exact can comprise at least one Surfactant, Such as polyethylene weight percentage of gelatin to be used in the immediate glycol or polyvinylpyrrollidone, to accommodate a particular release gelatin capsule coating can be readily optimized by fill volume (as described, for example, in U.S. Pat. No. routine experimentation to achieve a gelatinous composition 6,387,400, the disclosure of which is incorporated herein by of desired bloom Strength. Since all forms of gelatin are reference). Also, the controlled release core may be free of water Soluble and comprise of hygroscopic protein, the water and other ingredients that increase fill Volume. The water content of gelatin formulations to be used in the controlled release core can also comprise ethanol and/or at immediate release immediate release gelatin capsule coating least one partial glyceride of fatty acids for Stable prepara can vary; however, the water content of the gelatinous tion. Such fill compositions comprise ethanol in an amount composition can also be readily optimized. In addition, of from about 5% to about 50% by weight and at least one plasticizers, additives, colorants, preservants, and pro partial glyceride of fatty acids having from about 6 to about tectants may be added to the gelatinous composition to 18 carbon atoms in an amount of from about 20% to about enhance the aesthetic and mechanical features (i.e. Softness 95% by weight. These ethanol containing fill compositions and flexibility) of the gelatin capsule. Again, the type and are described, for example, in U.S. Pat. No. 4,888,239, the amount of plasticizers, additives, colorants, preservants, and disclosure of which is incorporated herein by reference. protectants in Such gelatin formulations to be used in the 0044) The immediate release gelatin capsule coating immediate release immediate release gelatin capsule coating composition may be manufactured by an improved process US 2004/0224020 A1 Nov. 11, 2004

comprising Subjecting “dry” Softgels to a Subsequent StreSS BNTX, cyprodime, ICI-174,864, LY117413, MR2266, or an relieving Step Such that the Volume and number of defects opioid antagonist having the same pentacyclic nucleus as Such as dimples and bubbles existing in the Softgels prior to nalmefene, naltrexone, buprenorphine, levorphanol, the StreSS relieving Step can be Substantially reduced. In meptazinol, pentazocine, dezocine, or their pharmacologi addition, the StreSS-relieving Step reduces dimensional Stan cally effective esters or Salts. Commercial formulations, dard deviation thereby resulting in more dimensionally including commercial oral dose forms, currently used to uniform batches of Softgels. The StreSS relieving Step is administer an opioid agonist or opioid antagonist can be described, for example, in U.S. Pat. No. 5,200,191, the modified as described and used to provide oral dosage forms disclosure of which is incorporated herein by reference. The according to the present invention. In particular, commercial StreSS relieving Step comprises Subjecting the “dry” capsules controlled release oral dosage forms of opioid agonists, to a Subsequent heating Step at a heightened temperature, including, for example, Oxycodone, hydrocodone, or mor such as from about 32° C. to about 42 C., and relative humidity, such as from about 35% to about 60% relative phine that are tablets or capsules may be enrobed with an humidity. immediate release gelatin capsule coating comprising the opioid agonist alone or in combination with an opioid 004.5 The immediate release gelatin capsule coating of antagonist. Commercial oral dose forms of opioid agonists the present invention comprises at least one of any thera for human administration include: codeine, dihydrocodeine peutically active agent, including, for example, an opioid (e.g., SYNALGOS-DC(R) from Wyeth-Ayerst Pharmaceuti agonist and/or an opioid antagonist. In preferred embodi cals), fentanyl, hydrocodone (e.g., NORCET(R) from Abara; ments, the immediate release gelatin capsule coating of the DOLOREXFORTE(E) from A. G. Marin; VICODINTUSS(R) present invention comprises at least one opioid agonist from Allscripts; HY-PHENGR) from Ascher; HYCODANGR) and/or at least one opioid antagonist. Representative opioid and ZYDONE(E) from Endo Pharmaceuticals; BANCAP agonists include at least one of the following: alfentanil, HC(R), LORCET 10/650E, LORCET PLUS(R), and allylprodine, alphaprodine, anilleridine, apomorphine, apo LORCETHD(E) from Forest Pharm; VANACET(E) from GM codeine, benzylmorphine, beZitramide, buprenorphine, Pharm; VICODINGR), VICODIN ES(R), VICODIN HP(R), butorphanol, clonitaZene, codeine, cyclazocine, cyclorphen, VICODIN TUSS EXPECTORANT(R), and VICOPRO cyprenorphine, desomorphine, dextromoramide, dezocine, FENCE) from Knoll Pharma; ANEXSIA(E), HYDROCETE), diampromide, dihydrocodeine, dihydromorphine, and LORCET-HD(R) from Mallinckrodt, HYCOMED(E) from dimenoxadol, dimepheptanol, dimethylthiambutene, Med-Tek; CO-GESIC(R) from Schwarz Pharma; CETA dioxyaphetyl butyrate, dipipanone, eptazocine, ethohep PLUS(R) from Seatrace; LORTAB(R) and VICON FORTE(R) tazine, ethylmethylthiambutene, ethylmorphine, etonita from UCB Pharma; NORCO(E) from Watson Laboratories; Zene, fentanyl, heroin, hydrocodone, hydroxymethylmor ALLAYOR from Zenith Goldline), hydromorphone (e.g., phinan, hydromorphone, hydroxypethidine, isomethadone, DILAUDID(R) from Knoll), levorphanol (e.g., LEVO-DRO ketobemidone, levallorphan, levorphanol, levophenacyl MORANGE) from ICN Pharmaceuticals), meperidine (e.g., morphan, lofentanil, meperidine, meptazinol, metazocine, DEMEROL(R) from Sanofi Pharmaceuticals), methadone methadone, methylmorphine, metopon, morphine, myro (e.g., METHADOSE(R) from Mallinckrodt; and DOLO phine, nalbuphine, narceline, nicomorphine, norlevorphanol, PHINE(R) HCl from Roxane Laboratories), morphine (e.g., normethadone, nalorphine, normorphine, norpipanone, (R) from Allscripts; KADIANGR) from Faulding Laboratories; ohmefentanyl, opium, oxycodone, Oxymorphone, papavere AVINZATM from Elan/Ligand; MS CONTINGR) from Purdue tum, pentazocine, phenadoxone, phenomorphan, phenazo Frederick; ORAMORPHCR) SR from Roxane; RMS(R) from cine, phenoperidine, pholcodine, piminodine, piritramide, Upsher-Smith), nalbuphine (e.g., NUBAIN(R) from Endo propheptazine, promedol, profadol, properidine, propiram, Labs), oxycodone (e.g., PERCOCET(R), PERCODANCE), and propoxyphene, remifentanyl, Sufentanyl, tramadol, tilidine, PERCOLONECE) from Endo; OXYCET(R) from Mallinck Salts thereof, mixtures of any of the foregoing, mixed rodt; TYLOXE) from Ortho-McNeil Pharmaceutical; OXY mu-agonists/antagonists, mu-antagonist combinations, or CONTINGR and OXYFASTE) from Purdue Pharma; ROXI others known in the art. Some of the opioid agonists and/or CODONE(R) ROXILOX(R), ROXICODONE-INTENSOL(R), antagonists disclosed herein may contain one or more asym ROXANOLGR, ROXANOL-100CE), ROXANOL-TE), and metric centers and may thus give rise to enantiomers, ROXICET(R) from Roxane), oxymorphone (e.g., NUMOR diastereomer, and other Stereoisomeric forms. The present PHAN HCL(R) from Endo Labs), pentazocine (e.g., TAL invention is also meant to encompass all Such possible forms ACENGR) and TALWINGR) from Sanofi Pharmaceuticals), as well as their racemic and resolved forms and mixtures propoxyphene (e.g., PROPOXYPHENE HYDROCHLO thereof. When the compounds described herein contain RIDE(R) from Allscripts; PC-CAP(R) from Alra; PRONAP(R) olefinic double bond or other centers of geometric asymme from DHS Inc.; DARVOCET-NCR), DAVRONGR), DAVRON try, and unless Specified otherwise, it is intended to include N(R), DAVRON COMPOUND-65(R) from Eli Lilly & Co.; both E and Z geometric isomers. All tautomers are intended DOLENE(R) from Lederle; PROPOXYPHENE HCL COM to be encompassed by the present invention as well. POUND(R) from Major; PROPOXYPHENE COMPOUND 0.046 Representative opioid antagonists include at least 65(R) from Mylan; PROPOXYPHENE COMPOUND(R) from one of the following: naltrexone (marketed in 50 mg dosage PD-RX Pharm, Phys Total Care, and Southwood; PRO forms from Du Pont Pharma as ReVia(E) or Trexande), POXYPHENE COMPOUND-65CR) and PROPOXACET naloxone (marketed as Narcane(R), NALOXONE/PENTA N(R) from Quality Care; WYGESIC(R) from Wyeth-Ayerst), ZOCINE(R) from Pharma Pac), nalmefene, methylnaltrex and tramadol (e.g., ULTRAMCR from Ortho-McNeil Phar one, naloxone methiodide, nalorphine, naloxonazine, nalide, maceutical). Commercial liquid dose forms of opioid ago nalmeXOne, nalbuphine, nalorphine dinicotinate, naltrindole nists for human administration include: hydrocodone (e.g., (NTI), naltrindole isothiocyanate, (NTII), naltriben (NTB), HYDROPHANE(R) from Halsey), hydromorphone (e.g., nor-binal torphimine (nor-BNI), b-funaltrexamine (b-FNA), DILAUDID(R) from Knoll), meperidine (e.g., DEMEROL(R) US 2004/0224020 A1 Nov. 11, 2004 from Sanofi), methadone (e.g., DOLOPHINE(R) from Rox release gelatin capsule include, for example, distribution, ane), oxycodone (e.g., HYCOMINE(R) from Knoll; ROX absorption, and elimination rates of the therapeutically ILOXOR from Roxane), and propoxyphene (e.g., DARVON active agent. N(R) from Eli Lilly). Commercial parenteral dose forms for human administration include: alfentanil (e.g., ALFENTA(E) 0049 According to the invention, the therapeutically from Akom and Taylor Pharm), alfenantil hydrochloride active agent in the immediate release gelatin capsule is an from Abbott Hosp, buprenorphine and buprenorphine/halox opioid agonist that is present in a human Subject in an one (e.g., BUPRENEX(R) and SUBUTEX/SUBOXONE(R), analgesic or Subanalgesic amount, including, for example, a respectively from Reckitt & Colman Pharmaceuticals), non-analgesic amount. Alternatively or additionally, the buprenophine hydrochloride from A-A Spectrum, butorpha immediate release gelatin capsule includes an opioid antago nol (e.g., STADOLE) from Apothecon), codeine (e.g., nist. When the therapeutically active agent in the immediate DURAGANIDIN NR(R) from Duramed), dextrose morphine release gelatin capsule is a combination of an opioid agonist from Abbott Hosp, dezocine (e.g., DALGANCR) from Astra and an opioid antagonist, the opioid agonist can be present Zeneca), fentanyl (e.g., DURAGESIC(R) from Janssen), in a human Subject in an analgesic or Subanalgesic amount, hydrocodone (e.g., DURATUSS HD(R) from UGB Pharma, including, for example, a non-analgesic amount. HYDROCODONE ES(R) from Quality Care), hydromor 0050. An analgesic amount includes an amount of the phone (e.g. DILAUDID(R), DILAUDID COUGHB), opioid agonist which causes analgesia in Subject adminis DILAUDID-HP(R) from Knoll Pharma), levallorphan (e.g., tered the opioid agonist alone, and also includes Standard LORFANGR) from Roche), levorphanol (e.g., LEVO-DRO doses of the opioid agonist which are typically administered MORANGR) from ICN), meperidine (e.g., DEMEROL(R) from to cause analgesia (e.g. mg doses). A Subanalgesic amount Sanofi), methadone (e.g., DOLOPHINE(R) HCI and includes an amount which does not cause analgesia in a METHADONE HCL INTENSOLE) from Roxane, Subject administered with the opioid agonist alone, but when METHADOSE(R) from Mallinckrodt Pharma), morphine used in combination with the opioid antagonist, results in (e.g., ASTRAMORPHO from AstraZeneca; analgesia. A non-analgesic amount includes an amount DURAMORPHCR and INFUMORPHOE) from Elkins-Sinn; which does not cause analgesia when administered to a KADIANGR) from Faulding Labs, MS CONTINGR and Subject while an “anti-analgesic' amount is an amount MSIRCR) from Purdue Frederick), oxymorphone (e.g., which causes algesia (ie. pain) when administered to a NUMORPHANGR) from Endo), nalburphine (e.g., Subject. The amount of the opioid antagonist may be an NUBAIN(R) from Endo Pharmaceutical), and pentazocine amount effective to enhance analgesic potency of and/or (e.g., TALWINGR) from Abbott). Commercial suppository attenuate one or more adverse side effects of an opioid dose forms of opioid agonists for human administration agonist, including, for example, nausea, Vomiting, headache, include oxymorphone (e.g., NUMORPHANGR) from Endo). diZZiness, Somnolence, pruritus, tolerance, withdrawal, 0047 According to the invention, the therapeutically dependence, and/or addiction. Such adverse Side effects can active agent of the immediate release gelatin capsule coating include any known undesirable side effect of opioid ago can be an opioid agonist or metabolite, as well as conjugate nists. The amount of the opioid antagonist may be less than thereof, Such as morphine, tramadol, oxycodone, hydroc an effective antagonistic amount or an ineffective antago odone, Oxymorphone, or hydromorphone. The therapeuti nistic amount, yet still provide Some or all of the foregoing cally active agent of the immediate release gelatin capsule benefits. The optimum amounts of the opioid antagonist coating can be an opioid antagonist, Such as naltrexone or administered alone or in combination with an opioid agonist nalmefene. Finally, the therapeutically active agent of the or other therapeutic agent will, of course, depend upon the immediate release gelatin capsule coating can be a combi particular agonist and antagonist used, the excipients cho nation of an opioid agonist and an opioid antagonist, Such as Sen, the route of administration, and/or the pharmacokinetic naltrexone and oxycodone, respectively. properties of the patient being treated. 0.048. The amount of a therapeutically active agent 0051 Oral dosage forms comprising opioids, including included in the immediate release gelatin capsule of dosage an opioid agonist alone or in combination with an opioid forms according to the invention is any pharmaceutically antagonist are described, for example, in WO 01/852.57 A2, acceptable amount that is Sufficient to achieve an increase in WO 01/58447 A1, U.S. Pat. No. 6,475,494, U.S. Pat. No. the rate of release of the therapeutically active agent from 6,375,957, and U.S. patent application Publication 2002/ the oral dosage form via the immediate release gelatin 001012, the disclosures of which are incorporated herein by capsule comprising the therapeutically active agent, as com reference. These patents and patent publications do not pared to the rate of release from a controlled release core of disclose or Suggest the application of an immediate release the therapeutically active agent. The amount of the thera gelatin capsule coating comprising a therapeutically active peutically active agent in the immediate release gelatin agent as disclosed herein. Moreover, these patents and patent capsule of dosage form according to the invention can also publications do not disclose or Suggest the combination of a or alternatively be an amount Sufficient to achieve a rapid controlled release core encapsulated with an immediate release of the therapeutically active agent from the dosage release gelatin capsule each comprising at least one thera form in the GI tract (e.g., from about less than about 1 peutically active agent. minute to less than about 1.5 hours. The amount of the therapeutically active agent in the immediate release gelatin 0052. In one aspect of the invention, the therapeutically capsule of dosage forms according to the invention can also active agent of the immediate release gelatin capsule is an or alternatively depend upon the desired release profile and opioid antagonist, Such as naltrexone or nalmefene, and is the concentration required for a desired biological effect. provided in an amount of about 0.000001 to about 1.0 mg, Additional or alternative factors used to determine the alternatively less than about 1.0 mg, alternatively less than amount of the therapeutically active agent in the immediate about 0.5 mg. Preferred ranges of opioid antagonists also US 2004/0224020 A1 Nov. 11, 2004

include: from about 0.000001 mg to less than 1.0 mg; from tions, a drug-containing particle is coated with or is dis about 0.00001 mg to less than 1.0 mg, from about 0.0001 mg persed within a controlled release material that is a continu to less than 1.0 mg; from about 0.001 mg to less than 1.0 mg; ous matrix, Such as a polymeric matrix. The coating layer or from about 0.01 mg to less than 1.0 mg; or from about 0.1 matrix can comprise insoluble materials and upon diffusion mg to less than 1.0 mg. Additional preferred ranges of opioid of the Soluble drug through the coating layer or matrix by antagonists include: from about 0.000001 mg to less than 1.0 means of resistance, the drug is released in a controlled mg; from about 0.00001 mg to less than 1.0 mg, from about fashion. Various formulations of controlled release materi 0.0001 mg to about 0.1 mg; from about 0.001 mg to about al(s) and soluble drug(s) have been described. Controlled 0.1 mg; from about 0.01 mg. to about 0.1 mg; from about release materials are described, for example, in U.S. Pat. No. 0.001 mg to about 0.1 mg; from about 0.001 mg to about 6,387.404, U.S. Patent No. 5,747,058, U.S. Pat. No. 6,413, 0.01 mg; or from about 0.01 mg to about 0.1 mg. Further 536, U.S. Pat. No. 5,968,542, WO 01/58447, U.S. Publica preferred ranges of opioid antagonists include: from about tion No. US 2002/0010127A1, the disclosures of all of 0.000001 mg to less than 1.0 mg; from about 0.00001 mg to which are incorporated herein by reference. less than 1.0 mg, from at least about 0.0001 to less than 0057 Controlled release materials useful in dosage forms about 0.5 mg; from at least about 0.01 to less than about 0.5 and formulations according to the invention can include at mg, or from at least about 0.1 to less than about 0.5 mg. least one hydrophobic and/or at least one hydrophilic mate Alternatively, the maximum amount of opioid antagonist in rial. Hydrophobic materials that are useful include water the immediate release gelatin capsule is 1 mg. Alternatively, insoluble materials with more or leSS pronounced hydro the maximum amount of opioid antagonist in the immediate philic and/or hydrophobic trends. Any pharmaceutically release gelatin capsule is less than 0.5 mg. The minimum acceptable hydrophobic material or hydrophilic material amount of opioid antagonist in the immediate release gelatin which is capable of imparting controlled release of a thera capsule is 0.000001 mg. Any minimum amount and any peutically active agent, including, for example, an opioid maximum amount of antagonist in the immediate release agonist alone or in combination with an opioid antagonist gelatin capsule, as Specified above, may be combined to may be used in accordance with the present invention. define a range of amounts in increments of 0.000001 or Hydrophobic materials that may be used include those 0.00001 or 0.0001 or 0.001 or 0.01 or 0.1, providing that the having a melting point from about 30° C. to about 200 C., minimum Selected is equal to or less than the maximum Such as from about 45° C. to about 90° C. Selected. In an embodiment of the invention, the amount of antagonist in the immediate release gelatin capsule is leSS 0058. The controlled release material can be at least one than an effective amount to antagonize an exogenous or type of hydrophilic alkylcellulosic material Such as hydroxy endogenous opioid agonist, but Such an amount may include alkylcellulose or hydroxypropylmethylcellulose. an amount that enhances the potency and/or attenuates an 0059. The controlled release material can be at least one adverse effect of the agonist, including, for example, nausea, acrylic polymer. The acrylic polymer may be cationic, Vomiting, headache, dizziness, Somnolence, pruritus, toler anionic, or non-ionic polymers and may be acrylates an/or ance, withdrawal, dependence, and/or addiction. methacrylates, formed of methacrylic acid or methacrylic 0053. In another aspect of the invention, the therapeuti acid esters. Examples of Suitable acrylic polymer include, cally active agent of the immediate release gelatin capsule is but are not limited to, acrylic acid and methacrylic acid an opioid agonist alone, Such as Oxycodone, and is provided copolymers, methyl methacrylate copolymers, ethoxyethyl in an amount from about 0.0025 mg to about 60 mg. methacrylates, cyanoethyl methacrylate, methyacryacylic 0054. In yet another aspect of the invention, the thera acid copolymers, and aminoalkyl methacrylate copolymers. peutically active agent in the immediate release gelatin The acrylic polymer can be one or more ammonio meth capsule is a combination of an opioid agonist, Such as acrylate copolymers. Ammonio methacrylate copolymers Oxycodone, Oxymorphone, hydrocodone, hydromorphone, are and can be described as fully polymerized copolymers of morphine, or tramadol and an opioid antagonist, Such as acrylic and methacrylic acid esters with a low content of naltrexone or nalmefene. Preferably, the opioid antagonist is quaternary ammonium groups. Additional examples include, but are not limited to, acrylic acid and methacrylic acid present in an amount of about 0.000001 to about 1.0 mg, copolymers, methyl methacrylate copolymers, ethoxyethyl alternatively less than about 1.0 mg, alternatively less than methacrylates, cyanoethyl methacrylate, poly(acrylic acid), about 0.5 mg, and the opioid agonist is present in an amount poly(methacrylic acid), methacrylic acid alkylamide copoly from about 0.0025 to about 60 mg. Optionally, the opioid mer, poly(methyl methacrylate), polymethacrylate, poly(m- agonist and opioid antagonist are released concurrently over ethyl methacrylate) copolymer, polyacrylamide, aminoalkyl a period of less than about 1.5 hours, including for example, methacrylate copolymer, poly(methacrylic acid anhydride), over a period of about 5 minutes to about 20 minutes. and glycidyl methacrylate copolymers. 0.055 The controlled release core of the present invention comprises at least one therapeutically active agent and at 0060. In order to obtain a desirable dissolution profile, it least one controlled release material. Any controlled release may be necessary to incorporate two or more ammonio material that does not substantially interfere with the solu methacrylate copolymers having differing physical proper bility of the therapeutically active agent can be used in the ties, Such as different molar ratioS of the quaternary ammo controlled release core of the present invention. The con nium groups to the neutral (meth)acrylic esters. trolled release core of the present invention may be in any 0061 The controlled release material can be a mixture of pharmaceutically acceptable dosage form, preferably cap two acrylic resin lacquerS. Compositions comprising a mix Sules, tablets, or caplets. ture of two acrylic resin lacquers can be used as controlled 0056 Controlled release materials can be at least partially release coatings. Some commercially available acrylic resin hydrophobic in nature. In Some controlled release formula lacquers are from Rohm Pharma under the Tradenames US 2004/0224020 A1 Nov. 11, 2004

EudragitE RL30D and Eudragit(R) RS30D, respectively. coating Solution is based on the concentration of the film EudragitERL30D and Eudragit(R) RS30D are copolymers of former, e.g., most often from about 1 to about 50 percent by acrylic and methacrylic esters with a low content of quater weight of the film-former. The concentration of the plasti nary ammonium groups, the molar ratio of ammonium cizer, however, can only be properly determined after rou groups to the remaining neutral (meth)acrylic esters being tine experimentation with the particular coating Solution and 1:20 in Eudragit(R) RL30D and 1:40 in Eudragit(R) RS30D. its intended method of application. Examples of Suitable The mean molecular weight is about 150,000. The code plasticizers for ethylcellulose include, but are not limited to, designations RL (high permeability) and RS (low perme water insoluble plasticizerS Such as dibutyl Sebacate, diethyl ability) refer to the permeability properties of these agents. phthalate, triethyl citrate, tributyl citrate, and triacetin, 0.062 Eudragit R. RL/RS dispersions may be mixed although it is possible that other water-insoluble plasticizers together in any desired ratio in order to ultimately obtain a (Such as acetylated monoglycerides, phthalate esters, castor controlled release formulation having a desirable dissolution oil, etc.) may be used. Triethyl citrate can be used as a profile. Desirable controlled release formulations may be plasticizer for the aqueous dispersions of ethyl cellulose of obtained, for instance, from a retardant coating derived from the present invention. Examples of Suitable plasticizers for 100% Eudragit(R) RL, 50% Eudragit(R) RL and 50% the acrylic polymers include, but are not limited to, citric Eudragit(R) RS, and 10% Eudragit(R) RL: 90% Eudragit(R) RS. acid esters such as triethyl citrate NF XVI, tributyl citrate, Other acrylic polymerS may also be used, Such as, for dibutyl phthalate, and possibly 1,2-propylene glycol. Other example, EudragitE L. plasticizers which have proved to be Suitable for enhancing the elasticity of the films formed from acrylic films, such as 0.063. The controlled release core according to the present Eudragit(R) RL/RS lacquer Solutions, include polyethylene invention can be formulated So as to not exhibit a significant glycols, propylene glycol, diethyl phthalate, castor oil, and fed/fast effect. No fed/fast effect refers to pharmacokinetic triacetin. Triethylcitrate can be used as a plasticizer for the parameters, Such as blood plasma concentration of drug, that aqueous dispersions of ethyl cellulose of the present inven exhibit less than a 20% difference in formulations that are tion. The addition of a small amount of talc reduces the administered to patients on an empty Stomach verSuS admin tendency of aqueous dispersions to Stick during processing, istration to patients who have ingested a high-fat meal, as and may act as a polishing agent. defined by the U.S.F.D.A. Sustained release formulations 0065. The release profile of the controlled release core that do not exhibit a food effect are described, for example, can be altered, for example, by altering the manner in which in U.S. application Ser. Nos. 2001/0031278 A1 and 2002/ the plasticizer is added to the hydrophobic material, by 0102303 and in WO 97/45091, the disclosures of which are varying the amount of plasticizer relative to hydrophobic incorporated herein by reference. U.S. application Ser. NoS. material, by the inclusion of additional ingredients or excipi 2001/0031278 A1 and 2002/0102303 and WO 97/45091 ents, and/or by altering the method of manufacture. Further describe the preparation of Sustained release oxycodone modifications to the release profile may also be imple formulation which do not exhibit a significant fed/fast effect mented, for example, by increasing or decreasing the thick by utilizing a carrier which preferentially causes the formu lation to release the Oxycodone in fluids having a relatively neSS of the retardant coating. lower (acidic) pH. Non-limiting examples of a controlled 0066. The controlled release core can further include a release formulation that does not exhibit a significant fed/ colorant to provide elegance and product distinction. Color fast effect include a composition comprising Eudragit RSPO may be added to the Solution of the therapeutically active in an amount of approximately 48.75% by weight, Eudragit agent instead. Any Suitable method of providing color to L-100 in an amount of approximately 3.75% by weight, and controlled release formulations may be used. Suitable ingre Stearic acid in an amount of approximately 22.5% by weight. dients for providing color to the formulation when an Additional non-limiting examples of a controlled release aqueous dispersion of an acrylic polymer is used include formulation that does not exhibit a significant fed/fast effect titanium dioxide and color pigments, Such as iron oxide include a composition comprising Eudragit R30SD (solid) pigments. The incorporation of pigments, may, however, in an amount of approximately 10.8% by weight, Spray dried increase the retard effect of the coating. lactose in an amount of approximately 27.1% by weight, 0067. The release of the therapeutically active agent from PVP in an amount of approximately 3.9% by weight, tri the controlled release formulation according to the present acetin in an amount of approximately 1.5% by weight, invention can be further influenced, i.e., adjusted to a desired Stearyl alcohol in an amount of approximately 19.2% by release rate, by the addition of at least one release-modifying weight, talc in an amount of approximately 1.9% by weight, agents, or by providing one or more passageways through and magnesium Stearate in an amount of approximately the coating. The release-modifying agents which function as 0.9% by weight. pore-formerS may be organic or inorganic, and include 0064. The core can be coated with at least one controlled materials that can be dissolved, extracted, or leached from release material in an aqueous dispersion comprising at least the coating in the environment of use. The pore-formerS may one hydrophobic material and further comprising an effec comprise one or more hydrophilic materials Such as hydrox tive amount of at least one plasticizer to improve the ypropylmethylcellulose. The release-modifying agent may physical properties of the controlled release coating. For also comprise a Semi-permeable polymer. The release-modi example, because ethylcellulose has a relatively high glass fying agent can be selected from hydroxypropylmethylcel transition temperature and does not form flexible films under lulose, lactose, or metal Stearates. The controlled release normal coating conditions, it is preferable to incorporate a coatings can also include erosion-promoting agents Such as plasticizer into an ethylcellulose coating containing SuS Starch and gums. tained release coating before using the same as a coating 0068 The controlled release material can be at least one material. Generally, the amount of plasticizer included in a material useful for making microporous lamina in the envi US 2004/0224020 A1 Nov. 11, 2004 ronment of use, Such as polycarbonates comprised of linear lacrylate, methyl methacrylate), poly(ethyl acrylate, methyl polyesters of carbonic acid in which carbonate groups methacrylate, trimethylamminoethyl methacrylate chloride), reoccur in the polymer chain. polymethyl methacrylate-methacrylic acid copolymers, cel 0069. The controlled release material comprises at least lulose acetate, ethylcellulose, cellulose acetate phthalate, one passageway, orifice, or the like. The passageway may be and hydroxypropyl methylcellulose phthalate. formed by such methods as those disclosed in U.S. Pat. Nos. 0076. The controlled release material can be at least one 3,845,770, 3,916,889, 4,063,064, and 4,088,864, the disclo of the following: polyamides, polycarbonates polyalkylenes, Sures of all of which are hereby incorporated by reference. polymers of acrylic and methacrylic esters, polyvinyl poly The passageway can have any shape Such as round, trian mers, polyglycolides, polysiloxanes, polyurethanes and co gular, Square, elliptical, irregular, etc. polymers thereof, celluloses, polypropylene, polyethylenes, 0070 The controlled release material can be at least one polystyrene, polymers of lactic acid and glycolic acid, natural or Synthetic wax, fatty alcohol (Such as lauryl, polyanhydride, poly(ortho)esters, poly(butic acid), poly(va myristyl, Stearyl, cetyl or preferably cetostearyl alcohol), leric acid), poly (lacfide-co-caprolactone), polysaccharides, fatty acid, including but not limited to fatty acid ester, fatty proteins, polyhyaluronic acids, polycyanoacrylates, and acid glyceride (mono-, di-, and tri-glycerides), hydrogenated blends, mixtures, or copolymers thereof. fat, hydrocarbon, normal wax, Stearic aid, Stearyl alcohol, or 0077. The controlled release material can be at least one hydrophobic and/or hydrophilic material having hydrocar type of alkylcellulosic polymer, Such as ethylcellulose, bon backbones. Suitable waxes include, for example, bees although the artisan will appreciate combination, as all or wax, glycowax, castor wax and carnauba wax. A wax-like part of the controlled release materials presented herein. One Substance includes any material which is normally Solid at commercially available aqueous dispersion of ethylcellulose room temperature and has a melting point of from about 30 is Aquacoat(R) (FMC Corp., Philadelphia, Pa., U.S.A.). C. to about 100° C. Aquacoat(R) is prepared by dissolving the ethylcellulose in a 0071. The controlled release material can be at least one that other cellulose and/or alkylcellulose polymerS may be water-insoluble wax-like thermoplastic Substance that is readily employed, Singly or in any water-immiscible organic optionally mixed with at least one less hydrophobic wax-like Solvent and then emulsifying the same in water in the thermoplastic Substance. In order to achieve Sustained presence of a Surfactant and a Stabilizer. Another aqueous release, the individual wax-like Substances in the controlled dispersion of ethylcellulose is commercially available as release material should be substantially non-degradable and Surelease(R) (Colorcon, Inc., West Point, Pa., U.S.A.). Sure insoluble in gastrointestinal fluids during the initial release lease(R) is prepared by incorporating plasticizer into the phases. Useful water-insoluble wax-like Substances may be aqueous dispersion during the manufacturing process. A hot those with a water-solubility that is lower than about 1:5,000 melt of a polymer, plasticizer (dibutyl sebacate), and Stabi (w/w). lizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline Solution to obtain an 0.072 The controlled release material can be at least one aqueous dispersion, which can be directly applied. digestible, long chain (Cs-Cso, Such as C-Clio), Substituted or unsubstituted hydrocarbon, Such as a fatty acid, fatty 0078. The core of dosage forms according to the inven alcohol, glyceryl ester of at least one fatty acid, mineral oil, tion comprises a therapeutically active agent that is dis or vegetable oil. Hydrocarbons having a melting point of persed within at least one controlled release material. The from about 25° C. to about 90° C. may be used in the core of dosage forms according to the invention comprises invention. Fatty (aliphatic) alcohols may be used as a long a therapeutically active agent that is dispersed within a chain hydrocarbon material. matrix comprising at least one controlled release material. The core of dosage forms according to the invention com 0073. The controlled release material can be at least one prises a therapeutically active agent that is dispersed within hydroxyalkyl cellulose or acrylic resin and at least one a matrix that is coated with at least one controlled release aliphatic alcohol or polyalkylene glycol in a ratio of from material. The controlled core of dosage forms according to about 1:2 to about 1:4, respectively, Such as a ratio of from the invention comprises the opioid agonist and optionally, about 1:3 2 to about 1:4, respectively. The at least one opioid antagonist, which is coated additionally or alterna polyalkylene glycol may be, for example, polypropylene tively with a controlled release material. The controlled glycol or polyethylene glycol. The number average molecu release coating or controlled release matrix of the core lar weight of the at least one polyalkylene glycol can range comprises at least one controlled release material that facili from about 1,000 to about 15,000, Such as from about 1,500 tates in Vitro dissolution rates of at least one therapeutically to about 12,000. active agent within the preferred ranges disclosed herein. 0.074 The controlled release material can be at least one of the following: Stearate esters, Such as those of propylene 0079. Materials suitable for inclusion in a controlled glycol, glyceryl, diethylaminoethyl, and glycol, Stearate release matrix will depend on the particular method used to form the matrix. For example, the controlled release matrix amides and other long-chain fatty acid amides, Such as may comprise at least one hydrophilic and/or hydrophobic N,N'-ethylene disteramide, steramide MEA and DEA, eth material, Such as gum, cellulose ether, acrylic resin, and ylene bisteramide, cocoamine oxide, long chain fatty alco protein derived material. The controlled release matrix may hols, Such as cetyl alcohol and steryl alcohol, long chain comprise of a combination of two or more hydrophobic esterS Such as myristyl myristate, beheny erucate, glyceryl controlled release materials. Controlled release matrices phosphates, and acetylated Sucrose distearate. may also comprise at least one digestible, long chain (Cs 0075. The controlled release material can be at least one Cso, Such as C-Clio), Substituted or unsubstituted hydro of the following: methacrylic ester copolmers, poly(ethy carbon, Such as fatty acid, fatty alcohol, glyceryl ester of US 2004/0224020 A1 Nov. 11, 2004

fatty acids, mineral and vegetable oil, and wax, Stearyl wet granulation Step can be between 1.5 and 5 times, Such alcohol, and polyalkylene glycol. Of these polymers, acrylic as between 1.75 and 3.5 times, the dry weight of the opioid. polymers, especially Eudragit(R) RSPO-the cellulose 0083 Controlled release matrices can also be prepared ethers, especially hydroxyalkylcelluloses and carboxyalky via melt-granulation or melt-extrusion techniques. Gener lcelluloses, can be used. The controlled release matrix may ally, melt-granulation techniques involve melting a normally comprise at least one hydrophilic or hydrophobic material in Solid hydrophobic material, e.g. a wax, and incorporating a an amount ranging from about 1% to about 80% (by weight). powdered drug therein. To obtain a controlled release dosage In an embodiment where the controlled release matrix form, it may be necessary to incorporate an additional comprises at least one hydrocarbon, Such as a long chain hydrophobic Substance, e.g. ethylcellulose or a water-in hydrocarbon or fatty (aliphatic) alcohol, the hydrocarbon Soluble acrylic polymer, into the molten wax hydrophobic can have a melting point of from about 25 C. to about 90 material. Examples of controlled release formulations pre C. and can be present in an amount up to 60% (by weight). pared via melt-granulation techniques are found in U.S. Pat. In certain embodiments, the controlled release matrix com No. 4,861,598, the disclosure of which is hereby incorpo prises at least one polyalkylene glycol in an amount up to rated by reference. 60% (by weight). 0084. An example of a method of preparing a suitable 0080. An example of a suitable matrix comprises at least melt-extruded matrix is described, for example, in U.S. Pat. one water-Soluble hydroxyalkyl cellulose, at least one C2 No. 6,288,398, the disclosure of which is incorporated C. Such as C-C, aliphatic alcohol and, optionally, at herein by reference. The method is multi-step which first least one polyalkylene glycol. The at least one hydroxyalkyl involves blending a therapeutically active agent, Such as an cellulose can be a hydroxy (C. to C) alkyl cellulose, Such opioid agonist, and optionally an opioid antagonist, together as hydroxypropylcellulose, hydroxypropylmethylcellulose, with at least one hydrophobic controlled release material to or hydroxyethylcellulose. The amount of the at least one obtain a homogeneous mixture. The homogeneous mixture hydroxyalkylcellulose in the invention can be determined, is then heated to a temperature Sufficient to at least Soften the inter alia, by the precise rate of release required for a mixture Sufficiently to extrude the same. The resulting therapeutically active agent, Such as an opioid. The at least homogeneous mixture is then extruded to form Strands. The one aliphatic alcohol can be, for example, lauryl alcohol, cooled, hardened Strand may be comminuted to produce a myristyl alcohol, or Stearyl alcohol. The at least one aliphatic multiparticulate intermediate with the desired pellet Size, alcohol can be cetyl alcohol or cetostearyl alcohol. The shape and size distribution. Common types of comminutors amount of the at least one aliphatic alcohol can be deter that may be employed include cutters, choppers, grinders, mined, inter alia, by the precise rate of release required for mills, etc. The resulting pellets additionally may be shaped a therapeutically active agent, Such as an opioid, and into Spheres by a spheronization proceSS. Changing the whether or not at least one polyalkylene glycol is present. In diameter of the die modifies the aspect ratio of the pellets or the absence of at least one polyalkylene glycol, the amount diameter of the resulting spheres. The extrudate preferably of the at least one aliphatic alcohol can range from about has a diameter of from about 0.1 to about 5 mm. Multipar 20% to about 50% (by wt). When at least one polyalkylene ticulates comprising the therapeutically active agents and the glycol is present, the combined weight of the at least one hydrophobic controlled release material provide Sustained aliphatic alcohol and the at least one polyalkylene glycol can release for a time period of from about 8 to about 24 hours. range from about 20% to about 50% (by wt) of the total weight of the core. 0085. The controlled release core of dosage forms according to the invention can be in the form of liquids, 0081. Another example of a suitable controlled release tablets, or capsules comprising at least one multiparticulate matrix comprises an alkylcellulose, Such as ethyl cellulose, which comprises at least one controlled release material and a C2 to Caliphatic alcohol, and optionally a polyalkylene at least one therapeutically active agent. glycol. 0086 Dosage forms comprising multiparticulate formu 0082 In order to facilitate the preparation of a controlled lations have been described, for example, in U.S. Pat. No. release oral dosage form according to the invention, any 6,066,339 and U.S. Pat. No. 5,681.584, the disclosures of method of preparing a matrix formulation known in the which are incorporated herein by reference. U.S. Pat. No. formulation art may be used. In one aspect of the invention, 6,066,339 describes an oral multiparticulate formulation the controlled release core is in the form of a tablet com comprising Sustained release particle, wherein each particle posed of particles comprising at least one opioid agonist, and has a core containing water Soluble morphine and an optionally at least one opioid antagonist, dispersed within a oSmotic agent, and wherein the core is coated with a controlled release matrix. For example, incorporation of at rate-controlled polymer comprised of ammonia methacry least one opioid agonist, and optionally at least one opioid late polymers. U.S. Pat. No. 5,681,584 describes a delay antagonist, in a controlled release matrix is accomplished by jacket coating over a core, which comprises a therapeutically (a) forming granules comprising at least one water-soluble active agent, with an OSmotic agent. Osmotic agents refer to hydroxyalkyl cellulose and at least one opioid agonist, and a pharmaceutically acceptable material that enhances the optionally at least one opioid antagonist, (b) mixing the passage of the water Soluble therapeutically active agent, hydroxyalkyl cellulose containing granules with at least one Such as morphine, through the rate-controlling polymer coat C-C aliphatic alcohol, and (c) optionally, compressing or through the tissue in the gastrointestinal tract. Osmotic and Shaping the granules. The granules can be formed by wet agents may act to enhance the absorption of a water Soluble granulating the hydroxyalkylcellulose/opioid agonist or therapeutically active agent, Such as morphine, by creating hydroxyalkylcellulose/opioid agonist/opioid antagonist with a local pH and/or chemical potential environment. Osmotic water. In this process, the amount of water added during the agents can comprise of at least one of the following: an US 2004/0224020 A1 Nov. 11, 2004 organic acid, a pharmaceutically acceptable Salt, or a gas multiparticulates within a capsule. For example, a plurality trointestinal absorption enhancer. Suitable OSmotic agents of the melt-extruded multiparticulates may be placed in a include, but are not limited to, adipic acid, ascorbic acid, gelatin capsule in an amount Sufficient to provide an effec citric acid, fumaric acid, malic acid, Succinic acid, tartaric tive controlled release dose when ingested and contacted by acid, lactic acid, monopotassium citrate, potassium acid gastric fluid. tartrate, Sodium fumarate, Sodium dihydrogen phosphate, Sodium bisulfate, Sodium metabisulfate, or combinations 0091. The controlled release core can be prepared in an thereof. Rate-controlled polymers compatible for use in the oral dosage form of an effective amount of melt-extruded multiparticulate formulation disclosed in U.S. Pat. No. multiparticulates that are compressed into an oral tablet 6,066,339 include, for example, ammonia methacrylate using conventional tableting equipment using Standard tech copolymer type A and ammonia methacrylate copolymer niques. Techniques and compositions for making tablets type B as described in USP/NF in a ratio of from about 15:85 (compressed and molded), capsules (hard and Soft gelatin) to about 1:99, respectively, such as a ratio of 5:95. Addi and pills are also described in Remington's Pharmaceutical tional rate-controlled polymers compatible for use in the Sciences, (Arthur Osol, editor), 1553-1593 (1980), incorpo multiparticulate formulation disclosed in U.S. Pat. No. rated by reference herein. 6,066,339 include, for example, Eudragit RL and Eudragit 0092. The controlled release core can be prepared in an RS in a ratio of about 5:95, respectively, such as a ratio of oral dosage form of an effective amount of melt-extruded 12.5:12.5. multiparticulates that are compressed into an oral tablet as set forth in U.S. Pat. No. 4,957,681, the disclosure of which 0087. The controlled release core of dosage forms is hereby incorporated by reference. according to the invention can be in the form of liquids, tablets, or capsules comprising at least one multiparticulate 0093. The controlled release melt-extruded multiparticu which comprises (i) at least one controlled release material, lates can be further coated with at least one hydrophobic (ii) at least one therapeutically active agent, and (iii) at least controlled release material. The amount of the hydrophobic one OSmotic agent. controlled release material in the additional coating can be Sufficient to obtain a weight gain ranging from about 2% to 0088 Another example of a method of preparing a suit about 30% (by weight), although the exact amount in the able melt-extruded matrix includes the steps of (i) directly additional coat may be greater depending upon the physical metering into an extruder a homogeneous mixture compris properties of the particular therapeutically active agent uti ing at least one hydrophobic controlled release material, at lized in the controlled release core and the desired release least one therapeutically active agent Such as an opioid rate of the therapeutically active agent, for instance. agonist, and optionally at least one therapeutically active agent, Such as at least one opioid antagonist, and optionally 0094. The controlled release core is in the dosage form of at least one binder, (ii) heating the homogenous mixture, (iii) a capsule comprising a first melt-extruded multiparticulate extruding the homogenous mixture to form Strands, (iv) and a Second melt-extruded multiparticulate which com cooling the Strands, and (V) cutting the Strands into particles prises at least one therapeutically active agent different from having a size from about 0.1 mm to about 12 mm. A the therapeutically active agent of the first melt-extruded relatively continuous manufacturing procedure is described, multiparticulate. The controlled release core can be in a for example, in WO 01/58447 A1, the disclosure of which is dosage form comprising an amount of an immediate release incorporated herein by reference. The diameter of the therapeutically active agent, including, for example, an extruder aperture or exit port can be adjusted to vary the opioid agonist, and optionally opioid antagonist, for prompt thickness of the extruded Strands and the exit part of the therapeutic effect. The controlled release core can be in a extruder can be any shape, Such as round, oblong, or dosage form comprising a combination of beads comprising rectangular, for example. The exiting Strands can be reduced controlled release materials and matrix multiparticulates. to particles using a hot wire cutter, guillotine, etc. 0.095 The release profile of the melt-extruded formula 0089. The melt extruded multiparticulate system can be, tions can be altered, for example, by varying the amount of for example, in the form of granules, spheroids or pellets retardant, i.e., hydrophobic material, by varying the amount depending upon the extruder exit orifice. Melt-extruded of plasticizer relative to hydrophobic material, by the inclu multiparticulate(s) and melt-extruded multiparticulate Sys Sion of additional ingredients or excipients, by altering the tem(s) and melt-extruded particles can refer to a plurality of method of manufacture, etc. units, including within a range of Similar size and/or shape 0096. The melt-extruded material can be prepared with and containing one or more active agents and one or more out the inclusion of particles comprising a therapeutically excipients, and/or including a hydrophobic material as active agent, which is added thereafter to the extrudate. Such described herein. In this regard, the melt-extruded multipar formulations typically will have the therapeutically active ticulates can be of a range of from about 0.1 to about 12 mm agent blended together with the extruded matrix material, in length and have diameter of from about 0.1 to about 5 and then the mixture could be tableted in order to provide a mm. In addition, it is to be understood that the melt-extruded Slow release of the therapeutically active agent. Such for multiparticulates can be any geometrical shape within this mulations may be advantageous, for example, when the Size range. Alternatively, the extrudate may simply be cut therapeutically active agent included in the formulation is into desired lengths and divided into unit doses of the Sensitive to temperatures needed for Softening the controlled therapeutically active agent without the need of a spheroni release material and/ or the retardant material. Zation Step. 0097. The core can be in the form of granulates or 0090 The controlled release core can be prepared in an particulates comprising different therapeutically active oral dosage form of an effective amount of melt-extruded agents including, for example, an opioid agonist dispersed in US 2004/0224020 A1 Nov. 11, 2004 a first controlled release matrix and an opioid antagonist resultant Spheroids or beads can thereafter be placed in a dispersed in a Second controlled-release matrix, wherein the gelatin capsule optionally with at least one therapeutically controlled release matrix may be the same or different, and active agent, Such as an opioid antagonist in a Substantially wherein the first and Second matrices release different thera non-releasable form. This dosage form provides an effective peutically active agents including, for example, the opioid controlled release dose of the therapeutically active agent, agonist and the opioid antagonist, respectively, at Substan Such as an opioid agonist, when ingested and contacted by tially the same rate. The core can be in the form of granulates an environmental fluid, e.g., gastric fluid or dissolution comprising different therapeutically active agents including, media. for example, an opioid agonist, and optionally an opioid 0101 Preferred controlled release materials useful antagonist, dispersed in a controlled-release matrix and according to the invention include non-polymeric, non further comprising an additional controlled release material. water Soluble high-Viscosity liquid carrier materials 0.098 Where the core comprises at least one therapeuti (HVLCM) of viscosity of at least 5,000 cp at 37° C. which cally active agent that is coated with at least one controlled do not crystallize neat under ambient or physiological con release material, the controlled release material coating can ditions. HVLCMs are described, for example, in U.S. Pat. be chosen So as to achieve, in combination with the other No. 5,747,058, the disclosure of which is incorporated by Stated properties, desired in Vitro dissolution rates of the reference herein. This HVLCM release material and at least therapeutically active agent, including within the preferred one therapeutically active agent comprise a controlled ranges disclosed herein. The controlled release coating released core according to a preferred aspect of the inven should be capable of producing a strong, continuous film tion. A particularly preferred HVLCM is sucrose acetate that is Smooth and elegant, capable of Supporting pigments isobutyrate (SAIB). SAIB is a modified sucrose molecule and other coating additives, non-toxic, inert, and tack-free. containing two acetic acid and Six isobutyric moieties. The The controlled release coating can be at least one hydro structure of SAIB is shown as FIG. 3. Thus, in a preferred phobic material Selected from (i) an alkylcellulose; (ii) an aspect, the controlled release core comprises a controlled acrylic polymer; or (iii) mixtures thereof. The coating can be release material that is an HVLCM according to U.S. Pat. applied in the form of an organic or aqueous Solution or No. 5,747,058 and a Substance to be delivered, wherein the dispersion. The coating can be applied to obtain a weight HVLCM is SAIB. In other embodiments, the controlled gain from about 2% to about 25% of the controlled release release core comprises a HVLCM that is a stearate ester such dosage form in order to obtain a desired Sustained release as those of propylene glycol, glyceryl, diethylaminoethyl, profile. Coatings derived from aqueous dispersions are glycol, Stearate amides and other long-chain fatty acid described, for example, in U.S. Pat. Nos. 5,273,760 and amide, Such as N,N'-ethylene distearamide, Stearamide 5,286,493, the disclosure of which are hereby incorporated MEA and DEA, ethylene bistearamide, cocoamine oxide, by reference. Other examples of controlled release formu long chain t?atty alcohols, Such as cetyl alcohol and Stearyl lations and coatings which may be used in accordance with alcohol, long-chain esterS Such as myristyl myristate, beheny the present invention include U.S. Pat. Nos. 5,324,351, erucate, and glyceryl phosphate. In an embodiment, the 5,356,467, and 5,472,712, the disclosures of all of which are HVLCM is acetylated sucrose distearate (Crodesta A-10). incorporated by reference in their entirety. 0102 SAIB is orally non-toxic and has been used to 0099 Many methods, such as spray coating, for example, Stabilize emulsions in the food industry. It is a very Viscous can be employed to coat the core with controlled release liquid and has an unusual property that there is a dramatic materials. In one possible method, a Wurster fluidized-bed change in Viscosity with Small additions of heat or with the System is used in which an air jet, injected from underneath, addition of solvents. It is soluble in a large number of fluidizes the core material and effects drying while the biocompatible solvents. When in solution or in an emulsion, controlled release material coating, Such as acrylic polymer, SAIB can be applied via injection or an aerosol spray. SAIB is sprayed on with a Sufficient amount of the controlled is compatible with cellulose esters and other polymers that release material, So as to obtain a predetermined controlled can affect the rate of delivery of the Substance. release of the therapeutically active agent when the coated 0.103 Biocompatible solvents to be used with an core is exposed to acqueous Solutions, for example, a gastric HVLCM such as SAIB include ethanol, dimethysulfoxide, millieux, Such as gastric fluid. In determining the Sufficient ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, N-me amount of coating, factorS Such as the physical characteris thylpyrrollidone, propylene carbonate, glycofurol, freons tics of the therapeutically active agent, the manner of Such as trichlorofuloromethan and dichloromethane, dim incorporation of the plasticizer, etc. are taken into account. ethyl ether, propane, butane, dimethyl formamide, dimethyl After coating with the controlled release material, an addi acetamide, diethylene carbonate, butylenes glycol, N-(beta tional overcoat of a film-former, Such as Opadryo can be hydromethyl)lactamide, dioxolanes, and other amides, optionally applied to the beads. This overcoat can be pro esters, ethers, alcohols, to form a lower Viscosity liquid Vided, if at all, to Substantially reduce agglomeration of the carrier material (LVLCM) which is mixed with the Sub beads. stance (e.g. therapeutically active agent) to be delivered. In 0100. The controlled release core can be in the form of an embodiment, the LVLCM has a viscosity less than 1000 Spheroids or beads for encapsulation. Such beads comprise cP. On administration the controlled release core comprising at least one therapeutically active agent, including for the LVLCM is encapsulated with an immediate release example, at least one opioid agonist and optionally, at least gelatin capsule and is placed into the body, and the Solvent one opioid antagonist, which are then Subsequently coated dissipates or diffuses away from the LVLCM, forming with a hydrophobic controlled release material. Such hydro in-Situ a highly viscous composition that release the Sub phobic materials include, for example, cellulosic materials stance over time. By appropriate Selection of the Solvent and and polymers, Such as alkylcelluloses. A plurality of Such the HVLCM, a wide variety of pre- and post-administration US 2004/0224020 A1 Nov. 11, 2004 composition Viscosities can be achieved. In a preferred to produce a resultant liquid mixture of (i) SAIB, (ii) aspect, the HVLCM is biodegradable. Biocompatible sol biocompatible Solvent(s), and (iii) oxycodone alone or, vents can be added to SAIB to obtain a resultant product optionally, with naltrexone, is pharmaceutically acceptable with a desired viscosity. Biocompatible solvents can be for encapsulation and/or tabulation. added in an amount ranging from about 5% to about 55% by weight, relative to the total weight of the composition, Such 0.107) A variety of additives can optionally be added to as from about 10% to about 50%, further Such as from about the HVLCM or LVLCM to modify the properties of the 10% to about 30%. The amount of SAIB in the controlled therapeutically active agent as desired. The additives can be release core of the invention is determined by the effect present in any amount which is Sufficient to impart the desired. The amount of SAIB in the controlled release core desired properties to the composition. The amount of addi can range from 99.5% to 0.01% by weight (relative to the tive used will in general be a function of the nature of the additive and the effect to be achieved, and can be readily total weight of the controlled release core), Such as from determined by routine experimentation. Non-limiting 99.5% to 10%, and such as from 95% to 25%, and Such as examples of additive include, for instance, biodegradable from 85% to 45%, and further such as from 10% to 0.01%, polymers and oligomers that can be used to alter the release and further Such as from 2% to about 0.1%. profile of the therapeutically active agent, non-biodegrad 0104. The controlled release core comprises SAIB and at able polymers, natural and Synthetic oils and fats, and least one biocompatible Solvent, preferably ethanol, and at carbohydrate and carbohydrate derivatives. For example, at least one therapeutically agent. The amount of SAIB and the least one additive may be included in the oxycodone/SAIB biocompatible Solvent, preferably ethanol, is optimized by or oxycodone/naltrexone/SAIB. Such additives include, for routine experimentation to achieve a particular desired vis example, cellulose acetate butyrate (CAB), cellulose acetate cosity. For example, a low Viscosity Solution that can be propionate (CAP), PVP, PVP-25, PEG-10K, PEG-1K, and expelled from a glass pipet is obtained with a mixture Sucrose. Again, the amount and type of additive(s) should be containing 9 g of SAIB combined with 1 g of ethanol optimized. In a preferred aspect, the amount and type of whereas, a thin film that can retain its shape for more than additive(s) used with oxycodone alone or optionally, with one week is obtained with a mixture containing 8 g of SAIB naltrexone is optimized to produce a resultant liquid mixture combined with 1 g of ethanol. The amount and type of the of (i) SAIB, (ii) at least one biocompatible solvent, and (iii) Solvent used with SAIB display varying Viscosities, as can oxycodone alone or, optionally, with naltrexone, and (iv) be measured using a Cannon-Fenske Viscometer of Size 200 additive, wherein the mixture is pharmaceutically acceptable at 30° C. For example, compositions comprising SAIB with for encapsulation and/or tabulation. ethanol in a ratio of 60:40, 70:30, and 90:10 exhibit centi poises values of 7.7, 17.0, and 494.8, respectively. In com 0108. The controlled release core can comprise SAIB that parison, ethanol only exhibits a centopoise value of 1.3. is loaded into an aerosol container and Sprayed onto agar Also, compositions comprising SAIB, ethanol, and cellulose plates to form an adhesive continuous film. In another acetate butyrate (CAB) in a ratio of 55:40:5 respectively aspect, the controlled release core comprising SAIB is exhibits a centopoise value of 68.9. Sprayed onto gelatin. In yet another aspect, the controlled release core comprising SAIB is loaded into a Syringe 0105. Where the controlled release core is in the form of equipped with a gauged needle and extruded. a liquid, the amount and type of solvent used with SAIB should be optimized So as to obtain a liquid wherein the at 0109 The controlled release core of the invention com least one therapeutically active agent is acceptably Soluble. prises at least one of any therapeutically active agent. The at For example, formulations comprising Small organic mol least one therapeutically active agent in the controlled ecules, Such as ibuprofen, require approximately 15% (by release core can be the same or different from the at least one weight) of ethanol in order to achieve solubility with SAIB therapeutically active agent in the immediate release gelatin whereas, formulations comprising large peptidic molecules capsule coating. In an aspect of the invention, the therapeu Such as bovine serum albumin, do not solubilize with about tically active agent of the controlled release comprises at 40% ethanol, even with the addition of co-solvents, such as least one opioid agonist. In a preferred aspect of the inven glycerol and/or DMSO. Another example is a composition tion, the therapeutically active agent of the controlled release comprising SAIB and naproxen (Sodium salt), which is oxycodone. In another aspect of the invention, the thera requires glycolfurol as a Solvent So as to achieve Solubility peutically active agent of the controlled release is a combi because naproxen is not Soluble in ethanol and ethylacetate. nation of at least one opioid agonist and at least one opioid antagonist. In another preferred aspect of the invention, the 0106 In a preferred aspect, the amounts of (i) SAIB, (ii) therapeutically active agent of the controlled release is a at least one biocompatible Solvent and (iii) oxycodone alone combination of oxycodone and naltrexone. or optionally, with naltrexone are optimized to achieve a desired viscosity. Preferred solvents for SAIB formulations 0110. When the core comprises a hydrophobic therapeu with Small organic molecules include, but are not limited to, tically active agent, the controlled release core can comprise ethanol, glycofurol, ethylactate, ethylacetate, N-methyl a carrier System to aid in formulation. Such carrier Systems pyrrollidone, and propylene carbonate. Optionally, cosol are described, for example, in U.S. Pat. No. 6,096,338, the vents, Such as dimethylsulfoxide, or glycerS may be added to disclosure of which is incorporated herein by reference. The enhance the Solubility. However, the amount and type of carrier System can comprise, for example, at least one solvent(s) with SAIB formulations are optimized with the digestible oil and at least one pharmaceutical acceptable Oxycodone alone and optionally, naltrexone that is to be Surfactant, wherein the Surfactant comprises at least one formulated. In this example, the amount of SAIB and the hydrophilic component that substantially inhibits in vivo amount and type of biocompatible Solvent(s) used with lipolysis of the digestible oil, and wherein the Surfactant Oxycodone alone or optionally, with naltrexone is optimized comprises at least one lipophilic component that Substan US 2004/0224020 A1 Nov. 11, 2004

tially reduces the inhibitory effect of the hydrophilic surfac from about 0.0001 mg to less than 1.0 mg; from about 0.001 tant component. Non-limiting examples of Surfactants mg to less than 1.0 mg; from about 0.01 mg to less than 1.0 include fatty acids, Such as oleic acid, mono- and/or di mg, or from about 0.1 mg to less than 1.0 mg. Additional glycerides of fatty acids, Such as capric/caprylic acid, acetic, preferred ranges of opioid antagonists include: from about Succinic, lactic, citricic, and/or tartaric esters, propylene 0.000001 mg to less than 1.0 mg; from about 0.00001 mg to glycol, castor oil ethoxylates, and Sorbitan esters of fatty less than 1.0 mg, from about 0.0001 mg to about 0.1 mg; acids. from about 0.001 mg to about 0.1 mg; from about 0.01 mg. to about 0.1 mg; from about 0.001 mg to about 0.1 mg; from 0111. The amount of the therapeutically active agent in about 0.001 mg to about 0.01 mg; or from about 0.01 mg to asSociation with a controlled release material in the core is about 0.1 mg. Further preferred ranges of opioid antagonists Sufficient to facilitate a Sustained, desired biological effect include: from about 0.000001 mg to less than 1.0 mg; from for a prolonged period of time, Such as from about 2 hours about 0.00001 mg to less than 1.0 mg, from at least about to about 24 hours, and Such as from about 8 hours to about 0.0001 to less than about 0.5 mg; from at least about 0.01 to 24 hours. The amount of the therapeutically active agent in less than about 0.5 mg; or from at least about 0.1 to less than the controlled release core can also depend upon the desired about 0.5 mg. Alternatively, the maximum amount of opioid release profile and the concentration of drug required for a antagonist in the immediate release gelatin capsule is 1 mg. desired biological effect. Additional factors used to deter Alternatively, the maximum amount of opioid antagonist in mine the amount of the therapeutically active agent in the the immediate release gelatin capsule is less than 0.5 mg. controlled release core include absorption, inactivation, and The minimum amount of opioid antagonist in the immediate excretion rates of the therapeutically active agent, as well as release gelatin capsule is 0.000001 mg. Any minimum other factors known to those of ordinary skill in the art. amount and any maximum amount of antagonist in the 0112 The controlled release core is formulated in a immediate release gelatin capsule, as Specified above, may pharmaceutically acceptable oral dosage form, Such as a be combined to define a range of amounts in increments of liquid, capsule, or tablet. Exact dimensions and size of the 0.000001 or 0.00001 or 0.0001 or 0.001 or 0.01 or 0.1, controlled release core of the present invention can be providing that the minimum Selected is equal to or less than optimized within the Scope of routine experimentation. the maximum Selected. In an embodiment of the invention, 0113. The therapeutically active agent in the controlled the amount of antagonist in the immediate release gelatin release core is an opioid agonist alone, Such as Oxycodone, capsule is less than an effective amount to antagonize an present in an analgesic or Subanalgesic (e.g. non-analgesic) exogenous or endogenous opioid agonist, but Such an amount in a human Subject. The agonist may also be present amount may include an amount that enhances the potency in an amount that is anti-analgesic in the human Subject. In and/or attenuates an adverse effect of the agonist, including, a preferred aspect, the amount of the opioid agonist, alone, for example, nausea, vomiting, headache, dizziness, Som in the controlled release core is from about 0.1 to about 300 nolence, pruritus, tolerance, withdrawal, dependence, and/or addiction. mg. 0116. In a preferred aspect of the invention, the controlled 0114. The therapeutically active agent in the controlled release core is optionally further coated with an enteric release core is a combination of an opioid antagonist and an coating that is affixed between the controlled release core opioid agonist, which is present in a Subanalgesic amount. In and the immediate release gelatin capsule coating. In this a preferred aspect, the controlled-release oral dosage form embodiment, the therapeutically active agent in the imme provides a controlled release of an opioid agonist and a diate release gelatin capsule coating is immediately released controlled-release of an opioid antagonist, Such that when into the gastric juices of the Stomach and the enteric coating the dosage form is administered to a human, the blood levels protects the controlled release core allowing passage of the of the agonist is maintained throughout the dosing period at controlled release core through the Stomach and into the an analgesically effective level, and the antagonist at a level basic environment of the duodenum. Upon dissolution of the Sufficient to decrease the Side effects associated with the enteric coat in the duodenum, the therapeutically active opioid agonist but not Sufficient to negate the analgesic effect agent of the controlled release core is released. This embodi of the opioid agonist. ment provides a significantly Stable drug concentration 0115 The therapeutically active agent of the controlled profile in the plasma, and is especially beneficial for thera release core is a combination of oxycodone and naltrexone, peutically active agents that have narrow therapeutic win wherein oxycodone is present in an amount of about 0.1 to dows and require multiple daily dosings. Moreover, in this about 300 mg, and wherein the naltrexone is provided in an embodiment, the therapeutically active agent of the con amount of about 0.000001 to about 1.0 mg, alternatively less trolled release core exhibits an absorption profile wherein than about 1.0 mg, alternatively less than about 0.5 mg. the period of time in which MEC levels are maintained When the opioid antagonist is used in combination with the ranges from at least about eight hours, Such as from at least opioid agonist, the amount of the opioid agonist adminis about twelve hours, to up to about twenty-four hours in a tered can be an analgesic or Sub-analgesic amount (e.g., human Subject. non-analgesic) in the human Subject. Alternatively, the 0117 Enteric coating includes any coating or layering opioid agonist can be present in an amount that is anti which Serves to resist disintegration in the Stomach and analgesic in the human Subject. The opioid antagonist in the permits the component to pass intact into the duodenum or controlled release core is present in an amount of about to be delayed in release. Enteric gelatin capsules with at least 0.000001 to about 1.0 mg, alternatively less than about 1.0 one therapeutically active agent are useful in dosage forms mg, alternatively less than about 0.5 mg. Preferred ranges of of the invention. Such encapsulation materials and methods opioid antagonists also include: from about 0.000001 mg to without an active agent are available from Banner Phar less than 1.0 mg; from about 0.00001 mg to less than 1.0 mg, macaps as their Gelatin Binary SystemTM. US 2004/0224020 A1 Nov. 11, 2004

0118 Enteric layers or coatings are described, for included in the dosage form, in addition to the opioid example, in U.S. Pat. No. 5,968,554, the disclosure of which antagonist. For example, the dosage form may include two is incorporated herein by reference. Enteric layerS or coat opioid agonists having different properties, Such as half-life, ings do not dissolve in the acidic environment of the Solubility, potency, and a combination of any of the forego stomach, but do dissolve at a pH of 5.0 or higher. A variety ing. Alternatively, one or more opioid agonists are included of materials can be used for Such enteric layerS or coatings, and a non-opioid drug is also included, alternatively or in as long as they do not readily dissolve or disperse in the addition to an opioid antagonist. However, non-opioid drugs gastric juices of the Stomach and do dissolve or disperse in can provide additional analgesia, and include, for example, the intestinal fluid. aspirin, acetaminophen; non-Steroidal anti-inflammatory 0119) Non-limiting examples of materials that can be drugs (“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.; N-me used for enteric layerS or coating include, for example, thyl-D-aspartate (NMDA) receptor antagonists, e.g., a mor polymeric acids and mixtures of polymeric acids, shellac, phinan Such as dextromethorphan or dextrorphan, or ket cetyl alcohol, and cellulose acetate. Other representative amine; cycboxygenase-II inhibitors (“COX II inhibitors”); enteric layers or coating include, for example, polymers of cyclooxygenase-III inhibitors (“COX-III inhibitors”) and/or ethylcellulose, hydroxypropy cellulose, and carbomethylcel glycine receptor antagonists. lulose. Additional representative enteric layerS or coating 0.122 For example, lower doses of the opioid analgesic include, for example, shellac, cellulose acetate phthalate can be used by virtue of the inclusion of an additional (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropy non-opioid agonist, such as an NSAID or a COX-2 inhibitor. lmethylcellulose phthalate, and methacrylic acid ester By using lower amounts of either or both drugs, the Side copolymers, Zein, and the like. Blends of various enteric effects associated with effective pain management in polymers can also be used. Other non-limiting examples of humans can be reduced. materials useful in enteric layerS or coatings include, for example, acrylic resins, wax, or other film forming materials 0123 Suitable non-steroidal anti-inflammatory agents, that will dissolve or disperse in the intestine but remain including ibuprofen, diclofenac, naproxen, benoxaprofen, intact in the Stomach. An enteric polymer coating may be flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, applied with or without solvent to the substrate that contains piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, the agent, for example a drug. The pharmaceutic proceSS trioxaprofen, Suprofen, aminoprofen, tiaprofenic acid, flu may include Spray coating, Spray drying and preSS coating. profen, bucloxic acid, indomethacin, Sulindac, tolmetin, An enteric coating comprising a water-based emulsion poly ZOmepirac, tiopinac, Zidometacin, acemetacin, fentiazac, mers can also be used. An enteric coating that can be used clidanac, Oxpinac, mefenamic acid, meclofenamic acid, in the present invention can be ethylacrylate methacrylic flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, acid copolymerS Sold under the trademark Eudragit(R) by flufenisal, piroXicam, Sudoxicam or isoxicam, and the like. Rhom GmbH of Domstadt, Germany. One type of enteric Useful dosages of these drugs are well known in the art. coating is EudragitEL30D, which has a molecular weight of 0124 N-methyl-D-aspartate (NMDA) receptor antago about 250,000 and is generally applied as a 25-75% aqueous nists are well known in the art, and encompass, for example, Solution. Another type of enteric coating is Eudragit(R) morphinans Such as dextromethorphan or dextrorphan, ket L30D-55 and is applied as a 45-55% weight acqueous solu amine, d-methadone or pharmaceutically acceptable Salts tion. Other types of Eudragits(R that may be used for enteric thereof. NMDA antagonist encompasses drugs that block a layers or coating include HP50, HP55, L100, and S100. major intracellular consequence of NMDA-receptor activa 0120 Certain methacrylic acid ester-type polymers are tion, e.g. a ganglioside Such as GM.Sub.1 or GTSub.1b a useful for preparing enteric coating. For example, there are phenothiazine Such as trifluoperazine or a naphthalene a family of copolymerS Synthesized from diethylaminoethyl sulfonamide such as N-(6-aminotbexyl)-5-chloro-1-naph methacrylate and other neutral methacrylic esters, also thalene-Sulfonamide. These drugs are Stated to inhibit the known as methacrylic acid copolymer or polymeric meth development of tolerance to and/or dependence on addictive acrylates, commercially available as Eudragit(R) from Rohm drugs, e.g., narcotic analgesics Such as morphine, codeine, Tech, Inc. There are several different types of Eudragit(R) that etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to are Suitable for use as enteric coatings. For example, Mayer, et al.), and to treat chronic pain in U.S. Pat. No. Eudragit(B E is an example of a methacrylic acid copolymer 5,502,058 (Mayer, et al.), all of which are hereby incorpo which SWells and dissolves in acidic media. EudragitE L is rated by reference. In addition, antagonist(s), of other glu a methacrylic acid copolymer which does not Swell at about tomate receptor Subtypes, e.g., AMPA, kainite or metabo pH-5.7 and is soluble at about pH>6. Eudragit(R) S does not tropic glutamate receptors, or of glutamate receptor Subunits Swell at about pH-6.5 and is soluble at about pH>7. for the treatment of pain, tolerance or action. The NMDA or EudragitE RL and Eudragit(R) RS are water Swellable, and other glutomate receptor Subtypes antagonist may be the amount of water absorbed by these polymers is pH included alone, or in combination with a local anesthetic dependent, however, dosage forms coated with Eudragit(R) Such as lidocaine, as described in these Mayer, et. al. patents. RL and RS are pH-independent. Analgesic immediate and controlled release pharmaceutical compositions of NMDA receptor antagonists and methods 0121 An oral dosage form according to the invention of for treating pain with Such compositions are described in the controlled release core and/or immediate release gelatin U.S. Pat. No. 6,194,000, which is hereby incorporated by capsule may further include, in addition to a therapeutically active agent, including, for example, an opioid agonist and reference. optionally an opioid antagonist, one or more drugs that may 0.125 The NMDA receptor antagonist may be selected or may not act Synergistically with Such agent(s). For from a morphinan Such as destromethorphan and dextror example, a combination of two opioid agonists may be phan, ketamine, amantadine, memantine, eliprodil, ifen US 2004/0224020 A1 Nov. 11, 2004

prodil, dizocilpine, remacemide, iamotrigine, riluzole, apti Thus, it is possible that controlled release formulations ganel, phencyclidine, flupirtine, celfotel, felbamate, prepared in accordance with the present invention include a Spermine, Spermidine, levemopamil, a pharmaceutically greater total acetominophen dose than the 325-650 mg dose, acceptable Salt or ester thereof, or a metabolic precursor of but that dose will be released in a controlled-release manner any of the foreoing. over a longer dosing interval (e.g., over 8 hours or more). 0126 The formulation may include sufficient NMDA 0.130. It is contemplated that the dosage of acetami receptor antagonist to provide from about 1-5000 mg/day, nophen and opioid agonist in the formulations and method typically 1-1000 mg/day and preferably about 100-800 of the present invention may be Similar or the same as mg/day of the active ingredient. The composition includes dosages which are already commercially available and an NMDA receptor antagonist in an immediate release form accepted by clinicians. Acetaminophen is commercially in association with a NMDA receptor antagonist in a con available in the United States in fixed combination with trolled release form. The composition may include an opioid agonists, namely, codeine, oxycodone and hydroc amount of NMDA receptor antagonist in the immediate odone. Typical oral capsule dosages of acetaminophen/ release form of approximately 5% to 90% of the total codeine combinations include 325 mg acetaminophen and NMDA receptor antagonist, preferably 10% to 60%. An 15 mg codeine phosphate, 325 mg acetaminophen and 30 immediate release NMDA receptor antagonist content of mg codeine phosphate and 325 mg acetaminophen and 60 about 15% to 50% is particularly preferred. The controlled mg codeine phosphate. Tablets typically include 300 mg release form of the NMDA receptor antagonist may consti acetaminophen and 7.5 mg codeine phosphate, 300 mg tute the remainder of the active ingredients. acetaminophen and 15 mg codeine phosphate, 300 mg acetaminophen and 30 mg codeine phosphate, and 300 mg 0127. The treatment of chronic pain via the use of glycine acetaminophen and 60 mg codeine phosphate. receptor antagonists and the identification of Such drugs is described in U.S. Pat. No. 5,514,680 (Weber, et al.), hereby 0131 Hydrocodone/acetaminophen products are typi incorporated by reference. cally available in fixed combinations of 5 mg hydrocodone (as the bitartrate salt) and 500 mg acetaminophen. Hydro 0128 COX-2 inhibitors have been reported in the art and codone/acetaminophen tablets are typically available in many chemical Structures are known to produce inhibition of fixed combinations of 500 mg acetaminophen and 2.5 mg cyclooxygenase-2. COX-2 inhibitors are described, for hydrocodone bitartrate, 500 mg acetaminophen and 5 mg example, in U.S. Pat. Nos. 5,616,601; 5,604.260; 5,593,994; hydrocodone bitartrate, 500 mg acetaminophen and 7.5 mg 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; hydrocodone, 7.5 mg hydrocodone bit artrate and 650 or 750 5,604,253; 5,552,422, 5,510,368; 5,436,265; 5,409,944; and mg acetaminophen, and 10 mg hydrocodone bit artrate and 5,130,311, all of which are hereby incorporated by refer 500, 650, 660 mg acetaminophen. Oxycodone/acetami ence. Certain preferred COX-2 inhibitors include valdecoxib nophen capsules and caplets are available in fixed combi (also known as Bextra), celecoxib (SC-58635, also known as nation of 5 mg oxycodone (as the hydrochloride Salt) and Celebrex), DUP-697, flosulide (CGP-28238), meloxicam, 500 mg acetaminophen, and in tablets as 5 mg oxycodone 6-methoxy-2 naphthylacetic acid (6-MNA), MK-966 (also hydrochloride and 325 mg acetaminophen. known as Vioxx), nabumetone (prodrug for 6-MNA), nime Sulide, NS-398, SC-5766, SC-58215, T-614; or combina 0132 Fixed combination tablets may be useful as a tions thereof. Dosage levels of COX-2 inhibitor on the order Source of therapeutically active agent(s) for formulation into of from about 0.005 mg to about 140 mg per kilogram of dosage forms with controlled release cores that are enrobed body weight per day can be therapeutically effective in with a gelatin capsule comprising therapeutically active combination with an opioid analgesic. Alternatively, about agent(s). 0.25 mg to about 7 g per patient per day of a COX-2 0133. The fixed combinations described above are for inhibitor can be administered in combination with an opioid information purposes only and are not meant to limit the analgesic. COX-3 inhibitors have also been reported in the possible relative amounts of opioid and acetaminophen art and are useful in dosage forms according to the invention contained in the formulations encompassed within the (Chandrasekhara, et al., 2002, Proc. Medl. Acad. Sci. USA present invention. AS disclosed herein and in accordance 99: 13926-31). with the present invention, it is contemplated that in certain 0129. Additionally or alternatively, a non-opioid drug can embodiments, the opioid agonist/opioid antagonist/acetami be included which provides a desired effect other than nophen combinations encompassed herein will have greater analgesia, e.g., antituSSive, expectorant, decongestant, anti or lesser dosages of either the opioid agonist or acetami histamine drugs, local anesthetics, and the like. Improved nophen, and that the ratio of opioid agonist to acetami controlled release oral dosage forms according to the inven nophen will vary based on the particular opioid agonist and tion comprise an opioid agonist and an opioid antagonist in opioid antagonist chosen for a formulation and the amount combination with a non-opiod drug, for example, acetomi of opioid antagonist included therein, among other things. nophen. Acetaminophen is an analgesic/antipyretic drug that 0134). An oral dosage form can comprise an opioid ago has been utilized for treating mild to moderate pain Such as nist (hydrocodone or oxycodone) and opioid antagonist headache, neuralgia, and musculoskeletal pain. The recom (naltrexone or nalmefene) and acetaminophen. A non-opioid mended daily adult dose is about 325 to about 650 mg every drug also can be included which provides a desired effect 4 hours, not to exceed a total dose of 4 g in 24 hours. The other than analgesia, e.g., antituSSive, expectorant, decon maximum dose of immediate release acetaminophen is generally considered to be about 1000 mg. Combination gestant, antihistamine drugs, local anesthetics, and the like. formulations can include Such acetaminophen doses as those 0.135 At least one therapeutically active agent in the Set forth above, or lower doses per 4 hour dosing interval. immediate release gelatin capsule coating and/or at least one US 2004/0224020 A1 Nov. 11, 2004 2O therapeutically active agent in the controlled release core of for use in contact with the tissueS of human beings and the present invention may be provided in the form of free animals without excessive toxicity, irritation, allergic bases or pharmaceutically acceptable acid addition Salts. response, or other problem or complication, commensurate Pharmaceutically acceptable Salts refer to derivatives of a with a reasonable benefit/risk ratio. therapeutically active agent, wherein the therapeutically active agent is modified by making an acid or base Salts 0.137 The dosage form of the present invention including thereof. The pharmaceutically acceptable Salt embraces an the immediate release gelatin capsule coating and/or the inorganic or an organic Salt. Examples of pharmaceutically controlled release core may be compounded with at least one acceptable Salts include, but are not limited to, mineral or of the usual non-toxic, pharmaceutically acceptable excipi organic acid Salts of the therapeutically active agent. Non ents, carriers, diluents or other adjuvants. The choice of limiting examples of pharmaceutically acceptable Salts adjuvants will depend upon the active ingredients employed, include, but are not limited to, metal Salts Such as Sodium, the physical form of the composition, the route of admin potassium Salt, Secium Salt and the like; alkaline earth metals istration, and other factors. Such as calcium Salt, magnesium Salt and the like, organic 0.138. The excipients, binders, carriers, and diluents amine Salts. Such as triethylamine Salt, pyridine Salt, picoline which can be used include water, glucose, lactose, natural Salt, ethanolamine Salt, triethanolamine Salt, dicyclohexy SugarS Such as Sucrose, glucose, or corn Sweeteners, Sorbitol, lamine salt, N,N'-dibenzylethylenediame salt and the like; natural and Synthetic gums. Such as gum acacia, tragacanth, inorganic acid Salts. Such as hydrochloride, hydrobromide, Sodium alginate, and gum arabic, gelatin, mannitol, Starches Sulfate, phosphate and the like, organic acid Salts. Such as Such as Starch paste, corn Starch, or potato Starch, magne formate, acetate, trifluoroacetate, maleatem tartarate and the sium trisilicate, talc, keratin, colloidal Silica, urea, Stearic like, Sulfonates Such as methaneSulfonate, benzeneSulfonate, acid, magnesium Stearate, dibasic calcium phosphate, crys p-tolueneSulfonate, and the like; amino acid Salts. Such as talline cellulose, methyl cellulose, carboxymethyl cellulose, arginate, asparginate, glutamate and the like. The pharma polyethylene glycol, waxes, glycerin, and Saline Solution, ceutically acceptable Salts include the conventional non among others. toxic Salts made, for example, from non-toxic inorganic or organic acids. For example, Such conventional non-toxic 0.139 Suitable dispersing or Suspending agents for aque Salts include those derived from inorganic acids Such as ouS Suspensions include Synthetic and natural gums Such as hydrochloric, hydrobromic, Sulfuric, Sulfonic, Sulfamic, tragacanth, acacia, alginate, dextran, Sodium carboxymeth phosphoric, nitric and others known to those skilled in the ylcellulose, methylcellulose, polyvinylpyrrollidone or gela art; and the Salts prepared from organic acids Such as amino tin. acids, acetic, propionic, Succinic, glycolic, Stearic, lactic, 0140. The dosage form of the immediate release gelatin malic, malonic, tartaric, citric, ascorbic, pamoic, maleic, capsule coating and/or the controlled release core can also hydroxymaleic, phenylacetic, glutamic, benzoic, Salicylic, comprise at least one acidifying agent, adsorbent, alkalizing Sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, agent, antiadherent, antioxidant, binder, buffering agent, methaneSulfonic, ethane disulfonic, oxalic, isethionic, glu colorant, complexing agent, diluent, filler, direct compres curonic, and other acids. Other pharmaceutically acceptable Sion excipient, disintegrant, flavorant, fragrance, glidant, Salts and variants include mucates, phosphate (dibasic), lubricant, opaquant, plasticizer, polishing agent, preserva phosphate (monobasic), acetate trihydrate, bi(heptafluo tive, Sweetening agent, or other ingredients known for use in robutyrate), bi(methylcarbamate), bi(pentafluoropropi pharmaceutical preparations. onate), meSylate, bi(pyridine-3-carboxylate), bictrifluoroac etate), bit artrate, chlorhydrate, and Sulfate pentahydrate. An 0141 Acidifying agents include compounds used to pro oxide, though not usually referred to by chemists as a Salt, vide an acidic medium for product Stability. Such com is also a “pharmaceutically acceptable Salt' for the present pounds include, by way of example and without limitation, purpose. For acidic compounds, the Salt may include an acetic acid, amino acid, citric acid, fumaric acid and other amine-based (primary, Secondary, tertiary or quaternary alpha hydroxy acids, hydrochloric acid, ascorbic acid, nitric amine) counterion, an alkali metal cation, or a metal cation. acid, phosphoric acid, and others known in the art. Lists of Suitable Salts are found in texts. Such as Remington's Pharmaceutical Sciences, 18" Ed. (Alfonso R. Gennaro, 0142. Adsorbents include agents capable of holding other ed., Mack Publishing Company, Easton, Pa., 1990); Rem molecules onto their Surface by physical or chemical ington: the Science and Practice of Pharmacy 19" Ed. (Lip (chemisorption) means. Such compounds include, by way of pincott, Williams & Wilkins, 1995); Handbook of Pharma example and without limitation, powdered and activated ceutical Excipients, (Arthur H. Kibbe, ed.; Amer. charcoal, Zeolites, and other materials known in the art. Pharmaceutical Assoc., 2002); the Pharmaceutical Codex: 0.143 Alkalizing agents include compounds used to pro Principles and Practice of Pharmaceutics 12" Ed. (Walter vide an alkaline medium for product Stability. Such com Lund ed., Pharmaceutical Press, London, 1994); The United pounds include, by way of example and without limitation, States Pharmacopeia: The National Formulary (United ammonia Solution, ammonium carbonate, diethanolamine, States Pharmacopeial Convention); and Goodman and Gil monoethanolamine, potassium hydroxide, Sodium borate, man's. The Pharmacological Basis of Therapeutics 10" Ed. Sodium carbonate, Sodium bicarbonate, Sodium hydroxide, (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, triethanolamine, and trolamine and others known in the art. 2002), the disclosures of which are hereby incorporated by 0144 Antiadherents include agents that prevent the stick reference. ing of Solid dosage formulation ingredients to punches and 0.136 Pharmaceutically acceptable refers to those com dies in a tableting machine during production. Such com pounds, materials, compositions, and/or dosage forms which pounds include, by way of example and without limitation, are, within the Scope of Sound medical judgment, Suitable magnesium Stearate, talc, calcium Stearate, glyceryl behen US 2004/0224020 A1 Nov. 11, 2004 ate, PEG, hydrogenated vegetable oil, mineral oil, Stearic 0152 Disintegrants include compounds used in solid acid and other materials known in the art. dosage forms to promote the disruption of the Solid mass into Smaller particles that are more readily dispersed or 0145 Antioxidants include agents which inhibit oxida dissolved. Exemplary disintegrants include, by way of tion and thus is used to prevent the deterioration of prepa example and without limitation, Starches Such as corn Starch, rations by the oxidative process. Such compounds include, potato Starch, pre-gelatinized and modified Starches thereof, by way of example and without limitation, ascorbic acid, Sweeteners, clayS Such as bentonite, microcrystalline cellu ascorbyl palmitate, butylated hydroxyanisole, butylated lose (e.g., Avicel), methyl cellulose, carboxymethylcellulose hydroxytoluene, hypophophorous acid, monothioglycerol, calcium, Sodium carboxymethylcellulose, hydroxy propyl propyl gallate, Sodium ascorbate, Sodium bisulfite, Sodium cellulose-low Substituted, colloidal Silicon dioxide, alginic formaldehyde sulfoxylate and sodium metabisulfite and acid, Sodium alginate, cellulose polyacrilin potassium (e.g., other materials known in the art. Amberlite), alginates, Sodium Starch glycolate, gums, agar, 0146 Binders include substances used to cause adhesion guar, locust bean, karaya, Xanthan, pectin, tragacanth, agar, of powder particles in Solid dosage formulations. Such bentonite, polyvinylpyrrollidone and other materials known compounds include, by way of example and without limi in the art. tation, acacia, alginic acid, carboxymethylcellulose Sodium, poly(Vinylpyrrolidone), compressible Sugar (e.g., NuTab), 0153. Glidants are agents used in Solid dosage formula ethylcellulose, gelatin, liquid glucose, methylcellulose, tions to promote flowability of the solid mass. Such com poVidone and pregelatinized Starch and other materials pounds include, by way of example and without limitation, known in the art. colloidal Silica, cornstarch, talc, calcium Silicate, magne sium Silicate, colloidal Silicon, tribasic calcium phosphate, 0147 When needed, binders may also be included in the Silicon hydrogel and other materials known in the art. dosage forms of the immediate release gelatin capsule coating and/or the controlled release core of the present 0154) Lubricants include substances used in solid dosage invention. Exemplary binders include acacia, tragacanth, formulations to reduce friction during compression. Such gelatin, Starch, cellulose materials. Such as methyl cellulose, compounds include, by way of example and without limi HPMC, HPC, HEC and sodium carboxy methyl cellulose, tation, Sodium oleate, Sodium Stearate, calcium Stearate, Zinc alginic acids and Salts thereof, polyethylene glycol, guar Stearate, magnesium Stearate, polyethylene glycol, talc, min gum, polysaccharide, bentonites, Sugars, invert Sugars, eral oil, Stearic acid, Sodium benzoate, Sodium acetate, poloxamers (PLURONICTM F68, PLURONICTM F127), col Sodium chloride, and other materials known in the art. lagen, albumin, gelatin, cellulosics in nonaqueous Solvents, O155 Opaquants include compounds used to render a combinations thereof and others known to those skilled in coating opaque. An opaquant may be used alone or in the art. Other binders include, for example, polypropylene combination with a colorant. Such compounds include, by glycol, polyoxyethylene-polypropylene copolymer, polyeth way of example and without limitation, titanium dioxide, ylene ester, polyethylene Sorbitan ester, polyethylene oxide, talc and other materials known in the art. combinations thereof and other materials known in the art. 0148 Buffering agents include compounds used to resist 0156 Polishing agents include compounds used to impart changes in pH upon dilution or addition of acid or alkali. an attractive Sheen to Solid dosage forms. Such compounds Such compounds include, by way of example and without include, by way of example and without limitation, camauba limitation, potassium metaphosphate, potassium phosphate, wax, white wax and other materials known in the art. monobasic Sodium acetate and Sodium citrate anhydrous and O157 Colorants include compounds used to impart color dihydrate and other materials known in the art. to Solid (e.g., tablets) pharmaceutical preparations. Such compounds include, by way of example and without limi 0149 Sweetening agents include compounds used to tation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow impart Sweetness to a preparation. Such compounds include, No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange by way of example and without limitation, aspartame, No. 5, D&C Red No. 8, caramel, ferric oxide, other FD&C (EQUAL(R), sucralose (SPLENDATM) acesulfame K dyes and natural coloring agents Such as grape skin extract, (Sunette(R) or Sweet One(E), dextrose, glycerin, mannitol, beet red powder, beta-carotene, annato, carmine, turmeric, Saccharin Sodium, Sorbitol, Sucrose, and other materials paprika, and other materials known in the art. The amount of known in the art. coloring agent used will vary as desired. 0150 Diluents or fillers include inert Substances used to create the desired bulk, flow properties, and compression 0158 Flavorants include compounds used to impart a characteristics in the preparation of Solid dosage forms. pleasant flavor and often odor to a pharmaceutical prepara Such compounds include, by way of example and without tion. Exemplary flavoring agents or flavorants include Syn limitation, dibasic calcium phosphate, kaolin, lactose, dex thetic flavor oils and flavoring aromatics and/or natural oils, trose, magnesium carbonate, Sucrose, mannitol, microcryS extracts from plants, leaves, flowers, fruits and So forth and talline cellulose, powdered cellulose, precipitated calcium combinations thereof. These may also include cinnamon oil, carbonate, calcium Sulfate, Sorbitol, and Starch and other oil of wintergreen, peppermint oils, clove oil, bay oil, anise materials known in the art. oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of Sage, oil of bitter almonds and cassia oil. Other useful 0151. Direct compression excipients include compounds flavors include Vanilla, citrus oil, including lemon, orange, used in compressed Solid dosage forms. Such compounds grape, lime and grapefruit, and fruit essences, including include, by way of example and without limitation, dibasic apple, pear, peach, Strawberry, raspberry, cherry, plum, pine calcium phosphate (e.g., Ditab) and other materials known apple, apricot and So forth. Flavors which have been found in the art. to be particularly useful include commercially available US 2004/0224020 A1 Nov. 11, 2004 22 orange, grape, cherry and bubble gum flavors and mixtures tions (J. M. Harris, Ed., Plenum Press, NY) the disclosure of thereof. The amount of flavoring may depend on a number which is hereby incorporated by reference. of factors, including the organoleptic effect desired. Flavors 0.165. The controlled release core and/or immediate will be present in any amount as desired by those skilled in release gelatin capsule coating of the present invention can the art. Particularly contemplated flavors are the grape and also include oils, for example, fixed oils, Such as peanut oil, cherry flavors and citrus flavorS Such as orange. Sesame oil, cottonseed oil, corn oil and olive oil; fatty acids, 0159 Complexing agents include, for example, EDTA Such as oleic acid, Stearic acid and isoStearic acid; and fatty disodium or its other Salts and other agents known in the art. acid esters, Such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. It can 01.60 Exemplary fragrances include those generally also be mixed with alcohols, Such as ethanol, isopropanol, accepted as FD&C grade. hexadecyl alcohol, glycerol and propylene glycol, with 0.161 Exemplary preservatives include materials that glycerol ketals, Such as 2,2-dimethyl-1,3-dioxolane4-metha inhibit bacterial growth, Such as Nipagin, Nipasol, alcohol, nol; with ethers, such as poly(ethyleneglycol) 450, with antimicrobial agents, benzoic acid, Sodium benzoate, benzyl petroleum hydrocarbons, Such as mineral oil and petrolatum; alcohol, Sorbic acid, parabens, isopropyl alcohol and others with water, or with mixtures thereof; with or without the known in the art. addition of a pharmaceutically Suitable Surfactant, Suspend ing agent or emulsifying agent. Soaps and Synthetic deter 0162 For example, where the controlled release core is in gents may be employed as Surfactants and as vehicles for the a Solid dosage form, at least one Surface active agents or dosage form. Suitable Soaps include fatty acid alkali metal, coSolvents that improve wetting or disintegration of the core ammonium, and triethanolamine Salts. Suitable detergents and/or layer and/or coating of the Solid dosage form can be include cationic detergents, for example, dimethyl dialkyl included. ammonium halides, alkyl pyridinium halides, and alky lamine acetates, anionic detergents, for example, alkyl, aryl 0163 The controlled release core and/or immediate and olefin Sulfonates, alkyl, olefin, ether and monoglyceride release gelatin capsule coating can include plasticizers Sulfates, and SulfoSuccinates, nonionic detergents, for where plasticizers can be included to modify the physical, example, fatty amine oxides, fatty acid alkanolamides, and mechanical, and aesthetic properties of the polymers used in poly(oxyethylene)-block-poly(oxypropylene) copolymers; the coats or the dosage form. Plasticizers include com pounds capable of plasticizing or Softening a polymer or and amphoteric detergents, for example, alkyl -aminopropi binder used. The plasticizer should be able to lower the onates and 2-alkylimidazoline quaternary ammonium Salts, melting temperature or glass transition temperature (Soften and others known in the art, and mixtures thereof. ing point temperature) of the polymer or binder. Plasticizers, 0166 A water soluble coat or layer can be formed to Such as low molecular weight PEG, generally broaden the Surround a Solid dosage form or a portion thereof. The water average molecular weight of a polymer in which they are Soluble coat or layer can either be inert or drug-containing. included thereby lowering its glass transition temperature or Such a coat or layer will generally comprise an inert and Softening point. Plasticizers also generally reduce the vis non-toxic material which is at least partially, and optionally cosity of a polymer. It is possible the plasticizer will impart Substantially completely, Soluble or erodible in an environ Some particularly advantageous physical properties to the ment of use. Selection of Suitable materials will depend upon dosage form of the invention. the desired behavior of the dosage form. A rapidly dissolving 0164 Plasticizers useful in dosage forms according to the coat or layer will be Soluble in the buccal cavity and/or upper invention can include, by way of example and without GI tract, Such as the Stomach, duodenum, jejunum or upper limitation, low molecular weight polymers, oligomers, Small intestines. Exemplary materials are disclosed in U.S. copolymers, oils, Small organic molecules, low molecular Pat. No. 4,576,604 to Guittard et al. and U.S. Pat. No. weight polyols having aliphatic hydroxyls, ester-type plas 4,673,405 to Guittard et al., and U.S. Pat. No. 6,004,582 to ticizers, glycol ethers, poly(propylene glycol), multi-block Faour et al. and the text Pharmaceutical DOSage Forms. polymers, Single block polymers, low molecular weight Tablets Volume I, 2" Edition. (A. Lieberman. ed. 1989, poly(ethylene glycol), citrate ester-type plasticizers, triace Marcel Dekker, Inc.), the disclosures of which are hereby tin, propylene glycol and glycerin. Such plasticizers can also incorporated by reference. In Some embodiments, the rap include ethylene glycol, 1,2-butylene glycol, 2,3-butylene idly dissolving coat or layer will be soluble in saliva, in the glycol, Styrene glycol, diethylene glycol, triethylene glycol, gastric millieux, gastric juices, or acidic fluids. tetraethylene glycol and other poly(ethylene glycol) com 0.167 Materials which are suitable for making the water pounds, monopropylene glycol monoisopropyl ether, pro Soluble coat or layer include, by way of example and without pylene glycol monoethyl ether, ethylene glycol monoethyl limitation, water Soluble polysaccharide gums Such as car ether, diethylene glycol monoethyl ether, Sorbitol lactate, rageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, pectin, and Xanthan, water-Soluble Salts of polysaccharide acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, gums Such as Sodium alginate, Sodium tragacanthin, and tributyl citrate and allyl glycolate. All Such plasticizers are Sodium gum ghattate; water-Soluble hydroxyalkylcellulose commercially available from Sources Such as Aldrich or wherein the alkyl member is straight or branched of 1 to 7 Sigma Chemical Co. It is also contemplated and within the carbons Such as hydroxymethylcellulose, hydroxyethylcel Scope of the invention, that a combination of plasticizers lulose, and hydroxypropylcellulose, Synthetic water-Soluble may be used in the present formulation. The PEG based cellulose-based lamina formerS Such as methyl cellulose and plasticizers are available commercially or can be made by a its hydroxyalkyl methylcellulose cellulose derivatives such variety of methods, such as disclosed in Poly(ethylene as a member Selected from the group consisting of hydroxy glycol) Chemistry: Biotechnical and Biomedical Applica ethyl methylcellulose, hydroxypropyl methylcellulose, and US 2004/0224020 A1 Nov. 11, 2004 23 hydroxybutyl methylcellulose, croScarmellose Sodium; 0173 For immediate release formulations, concurrent other cellulose polymerS Such as Sodium carboxymethylcel release and released concurrently refer to release in in Vitro lulose, and other materials known in the art. Other lamina dissolution assays in an overlapping manner of more than forming materials that can be used for this purpose include one therapeutically active agent. The respective beginnings poly(Vinyl alcohol), poly(ethylene oxide), gelatin, glucose of release of each agent can but need not necessarily be and Saccharides. The water Soluble coating can comprise Simultaneous. Concurrent release will occur when the other pharmaceutical excipients that may or may not alter majority of the release of the first agent overlap a majority the way in which the water soluble coating behaves. The of release of the Second agent. According to one exemplary above-noted materials include film-forming polymers. embodiment, release of the agonist and antagonist begins and ends at approximately the same time. In Some embodi 0168 A water soluble coat or layer can also comprise ments of formulations comprising an opioid antagonist and hydroxypropyl methylcellulose, which is supplied by Dow an opioid agonist, the dissolution rates of the antagonist and under its Methocel E-15 trademark. The materials can be the agonist are Substantially the Same. A desired portion of prepared in Solutions having different concentrations of each active pharmaceutical ingredient may be released polymer according to the desired Solution Viscosity. For within a desired time. The desired portions may be, for example, a 2% WNv aqueous solution of MethocelTM E-15 example, 5%, 50% or 90%, or some other percentage. The has a viscosity of about 13-18 cps at 20° C. desired time may be, for example, 10 minutes, 20 minutes, 0169. A solid dosage form of the invention can be coated 30 minutes or 45 minutes. Generally, the entire charge of with a finish coat as is commonly done in the art to provide each therapeutically active agent is released in less than 120 the desired Shine, color, taste or other aesthetic characteris min, less than 90 min, less than 60 min, less than 45 min, less tics. Materials Suitable for preparing the finish coat are well than 30 min, less than 20 minor less than 10 min. Preferably, known in the art and found in the disclosures of many of the the entire charge of each active pharmaceutical ingredient is references cited and incorporated by reference herein. released in less than 45 minutes. 0170 Various other components, in some cases not oth 0.174 Dosage forms of the present invention can be erwise listed above, can be added to drug- or agent-contain presented in any type of container-closure System or holding ing formulations for optimization of a desired active agent vessel of any type for packaging one or more gelatin release profile including, by way of example and without capsules, including enrobed cores that are liquids, tablets or limitation, glycerylmonoStearate, nylon, cellulose acetate capsules. For example, a bottle, envelope, Sachet, Vial, tube, butyrate, d.l-poly(lactic acid), 1,6-hexanediamine, diethyl blister pack, bag, or pouch comprising eSSentially of the enetriamine, Starches, derivatized Starches, acetylated dosage forms presented herein are included. Various types of monoglycerides, gelatin coacervates, poly (styrene-maleic blister packs are described, for example, in U.S. Pat. No. acid) copolymer, glycowax, castor wax, Stearyl alcohol, 5,624,036, the disclosure of which is incorporated herein by glycerol palmitostearate, poly(ethylene), poly(Vinyl reference. A non-limiting example of a blister pack includes acetate), poly(Vinyl chloride), 1,3-butylene-glycold push-through packs which are made with an aluminum foil imethacrylate, ethyleneglycol-dimethacrylate and methacry or aluminum foil laminate lid. Blister packs can optionally late hydrogels. contain materials of construction or design which may affect the Stability, impart tamper evidency, or evidence of expo 0171 It should be understood that compounds used in the Sure to resist children's acceSS or aid dispensation of the formulation arts, including the art of pharmaceutical formu product from its primary container. For instance, they may lation, generally Serve a variety of functions or purposes. protect dosage forms of the invention, including enrobed Thus, whether a compound named herein is mentioned only tablets and capsules from extraneous influences Such as once or is used to define more than one term herein, its moisture, light, oxygen and dirt. The container-closure Sys purpose or function should not be construed as being limited tem may preserve a desired environment for the product Solely to the named purpose(s) or function(s). within the package by its design or by inclusion of an 0172 For preparing liquid or solid compositions such as additional component Separate from the product Such as a tablets, the therapeutically active agent, including, for desiccant or humectant. example, an opioid agonist, alone or in conjunction with an 0.175. The container-closure system by its design or opioid antagonist, is mixed with a pharmaceutical carrier or through incorporation of a component within may indicate excipient, Such as conventional tableting ingredients and or record exposure to certain conditions including tempera other pharmaceutical diluents, Such as water, to form a Solid ture, humidity or vibration. Different container closure Sys intermediate composition containing a homogeneous mix tems (bottles, blisters, pouches) are constructed of different ture of a compound or a non-toxic pharmaceutically accept materials and with various physical design that imparts able salt thereof. When referring to these intermediate function. For example, bottles may be glass (most protec compositions as homogeneous, it is meant that the thera tive) or plastic. There are several different plastics polymers peutically active agent(s), including, for example, an opioid that are commonly used including, for example polyethylene antagonist, alone or in conjunction with an opioid agonist, is (low and high density), polypropylene, polyvinylidene fluo dispersed evenly throughout the composition So that the ride (PVDF). Advantages of glass include its impervious composition may be readily Subdivided into equally effec ness to moisture and oxygen transmission. Bottles (glass and tive unit dosage forms Such as capsules, tablets, caplets, or plastic) may incorporate colorants. Light blocking coatings, pills. This Solid preformulation composition is then Subdi or pacifiers are useful in packaging to block transmission of Vided into unit dosage forms of the type described above light, moisture and/or oxygen. Bottles may include Special containing the above-Stated dose of the therapeutically ized Seals, including foam, paper and foil Seals within the active agent(s), including, for example, an opioid antagonist, closure that improve barrier to the above elements and are alone or in combination with opioid agonist. tamper evident. Foil Seals (single or laminates, Sealed by US 2004/0224020 A1 Nov. 11, 2004 24 magnetic induction rather than adhesive) may be used for 0181. The dosage amounts of oxycodone alone or option moisture barrier and tamper-evidence. Plastic bottles may ally, with naltrexone are described herein. also include additives to the polymer that opacifies the 0182 To achieve a particular desired viscosity in the plastic (e.g., titanium dioxide) that, at certain levels, effec resulting SAIB composition, the amount of SAIB and at tively minimize light transmission, and may also include a least one biocompatible Solvent, preferably ethanol, is opti light blocking coating for the same reason. Bottles may mized. For example, a low Viscosity Solution that can be incorporate a desiccant or humectant (packets or cartridges) expelled from a glass pipet is obtained with a mixture within for humidity control. containing 9 g of SAIB combined with 1 g of ethanol whereas, a thin film that can retain its shape for more than 0176 Blisters may be constructed completely from foil, one week is obtained with a mixture containing 8 g of SAIB or from a plastic film closed with a foil lidding. Each of these combined with 1 g of ethanol. materials may be included within a laminate Structure, and may include polyester, polyethylene or polypropylene to 0183 In order to obtain a soluble liquid fill, the amounts prevent "push-through', to impart child-resistance and a of (i) SAIB, (ii) at least one biocompatible solvent, and (iii) paper layer externally. All pharmaceutical packaging is at least one therapeutically active agent is optimized. For example, in formulations comprising Small organic mol child-resistant, but blisters may have additional design fea ecules Such as ibuprofen, approximately 15% (by weight) of tures that make them easy to open thus facilitating removal ethanol is added to achieve solubility with SAIB whereas, of medication by the elderly or physically challenged. Typi formulations comprising large peptidic molecules Such as cal plastic films include those made from polyvinyl chloride bovine serum albumin, do not solubilize with about 40% (PVC), polyvinylidene chloride (PVdC) coated PVC, and ethanol, even with the addition of co-Solvents, Such as polypropylene, Vinyl/polyethylene/Aclaro laminate. Such glycerol and/or DMSO. Also, in Some organic molecules films have different moisture and oxygen transmission char formulations Such as naproxen (Sodium salt) another type of acteristics. In addition to the type of plastic, film thickneSS Solvent, glycolfurol, is required to achieve Solubility since influences transmissibility also. Certain of these films may naproxen is not Soluble in ethanol and ethylacetate. be opacified as well. A desiccant can be contained within the 0184. In a preferred aspect, the amounts of (i) SAIB, (ii) blister package design, or within a pouch that contains the at least one biocompatible Solvent and (iii) oxycodone alone blister package. The foil blister may also incorporate a or optionally, with naltrexone are optimized to achieve a desiccant into its design for dehumidification. Accordingly, desired viscosity. Preferred solvents for SAIB formulations dosage forms of the invention are conveniently packaged for with Small organic molecules include, but are not limited to, Safety, Stability and ease of use as described above. ethanol, glycofurol, ethylactate, ethylacetate, N-methyl pyrrollidone, and propylene carbonate. Optionally, cosol EXAMPLES vents, Such as dimethylsulfoxide, or glycers may be added to enhance the Solubility. However, the amount and type of 0177. The following examples are provided for illustra solvent(s) with SAIB formulations is optimized with the tive purposes and are not to be construed to limit the Scope Oxycodone alone and optionally, naltrexone that is to be of the claims in any manner whatsoever. formulated. In this example, the amount of SAIB and the amount and type of biocompatible Solvent(s) used with Example 1 Oxycodone alone or optionally, with naltrexone is optimized to produce a resultant liquid mixture of (i) SAIB, (ii) Controlled Release Core Dosage Formulations biocompatible Solvent(s), and (iii) oxycodone alone or, optionally, with naltrexone, is pharmaceutically acceptable 0.178 The controlled release core of dosage forms for encapsulation and/or tabulation. according to the present invention can be in any type of pharmaceutically acceptable dosage form comprising at 0185. In addition, at least one additive may be included least one therapeutically active agent and at least one in the oxycodone/SAIB or oxycodone/naltrexone/SAIB controlled release material. For example, the controlled mixture to increase solubility. Such additives include, for release core can be in the forms of liquids, Semi-Solids and example, cellulose acetate butyrate (CAB), cellulose acetate Solids, including, pills, tablets, capsules and caplets. Pre propionate (CAP), PVP, PVP-25, PEG-10K, PEG-1K, and ferred dosage forms for the controlled release core of the Sucrose. Again, the amount and type of additive(s) should be present invention are tablets and capsules. Preferred opioid optimized with the particular type of therapeutic agent that agonists and, optionally, opioid antagonists of the controlled is to be formulated. In a preferred aspect, the amount and release core of the present invention include Oxycodone, type of additive(s) used with oxycodone alone or optionally, morphine, hydrocodone, tramadol, oxymorphone, hydro with naltrexone is optimized to produce a resultant liquid morphone, naltrexone, and nalmefene. For the purpose of mixture of (i) SAIB, (ii) at least one biocompatible solvent, illustration only, the following examples describe controlled and (iii) oxycodone alone or, optionally, with naltrexone, release tablets and capsules comprising either oxycodone and (iv) additive, wherein the mixture is pharmaceutically alone or in combination with naltrexone. acceptable for encapsulation and/or tabulation. 0179 Capsules: SAIB Liquids and SAIB Films 0186. In another preferred aspect, the resultant liquid mixture of (i) SAIB, (ii) at least one biocompatible solvent, 0180. In an preferred aspect of the invention, an encap (iii) oxycodone alone or optionally, with naltrexone, and (iv) Sulated liquid fill comprising Oxycodone alone or optionally optionally, at least one additive is loaded into an aeroSol with naltrexone is mixed with SAIB, a high viscosity liquid container and Sprayed onto agar plates to form an adhesive controlled release material. continuous film. In yet another embodiment, the resultant US 2004/0224020 A1 Nov. 11, 2004 25 liquid mixture of (i) SAIB, (ii) at least one biocompatible 0.195 Lastly, cured controlled release beads are encap Solvent, (iii) oxycodone alone or optionally, with naltrexone, Sulated into Suitably sized capsules. In an embodiment, and (iv) optionally, at least one additive is sprayed onto Oxycodone controlled release beads alone or, optionally, gelatin. In yet a further embodiment, the resultant liquid with naltrexone controlled release beads are encapsulated mixture of (i) SAIB, (ii) at least one biocompatible solvent, into hard gelatin capsules. In another embodiment, oxyc (iii) oxycodone alone or optionally, with naltrexone, and (iv) odone/naltrexone controlled release beads are encapsulated optionally, at least one additive is loaded into a Syringe into hard gelatin capsules. equipped with a gauged needle and extruded. 0.196 Dissolution studies may be conducted on the result 0187 Capsules: Coated Beads ant cured beads. Samples can be measured for the rate of dissolution using any spectroscopic measurement. For 0188 In an embodiment of the invention, oxycodone example, HPLC analysis of the dissolved beads monitoring controlled release beads are incorporated into hard gelatin the UV/vis characteristics of oxycodone or oxycodone/ capsules which can then be encapsulated alone or optionally, naltrexone can be measured over Set increments of time to with naltrexone controlled release beads. For instance, oxy determine the rate of dissolution. codone controlled release beads are formulated and com bined with naltrexone controlled release beads in a gelatin 0197) Tablet: Dispersed Granulates capsule. 0198 In an embodiment of the invention, controlled release granulates are combined with melted wax, Such as 0189 In another embodiment of the invention, beads cetoStearyl alcohol, to produce waxed granulates that are containing both oxycodone and naltrexone are incorporated Subsequently milled and mixed with other excipients before into hard gelatin capsules which are then encapsulated. finally being compressed into tablets. The controlled release Thus, in this embodiment, encapsulation of one bead granulates comprise an opioid agonist and optionally, opioid releases both oxycodone and naltrexone simultaneously. antagonist dispersed in a controlled-release matrix. 0190. The dosage amounts of oxycodone alone or option 0199. In a preferred aspect of the invention, the con ally, with naltrexone are described in the Specification. trolled release tablet comprises controlled release granulates 0191 In this non-limiting example, the controlled release which comprise oxycodone and optionally, naltrexone dis beads are generated in a multi-step proceSS wherein the persed in a controlled-release matrix. controlled release materials are spray dried onto beads 0200. The dosage amounts of oxycodone alone or, containing oxycodone and/or naltrexone. First, inert non optionally, with naltrexone are described in the Specification. pareil beads (i.e. 30/35 mesh) are layered with oxycodone and/or naltrexone, by Spray drying the beads with an aque 0201 In this non-limiting example, the controlled release ous Solution of oxycodone and/or naltrexone in a fluid bed granulates are generated in a multi-step proceSS. First, the coater with Wurster insert. The non-pareil beads and/or the opioid agonist and optionally, opioid antagonist is dissolved aqueous Solution of Oxycodone and/or naltrexone may con in an aqueous Solution before being granulated with a tain excipients, Such as Plasdone C30 and talc, binders, Such Solution of Spray dried lactose, hydroxyethyl cellulose, and as povidone and Eudragit RS30D, and fillers, such as optionally, either an opioid agonist or opioid agonist/antago lactose. Thus, the non-pareil beads can be spray dried, for nist. instance, with a blend of (i) a binder solution of povidone 0202 Next, the resultant granulations are dried in a fluid and Eudragit RS30D and (ii) an aqueous solution of oxyc bed dryer. The dried granulations are then passed through a odone and/or naltrexone. mill and can be further dried before proceeding to the next Step, waxing. The dried granulations can be waxed by 0.192 Second, the oxycodone, naltrexone, or oxycodone/ adding melted cetoStearyl alcohol to the granulations during naltrexone beads are optionally Sealed with an inert Sealing the mixing Step. Before passing onto a mill, the waxed solution, such as Opadry Clear (HPMC) Solution. granulates are cooled on a fluid bed dryer. The milled, waxed 0193 Next, an aqueous sustained release solution is granulates can then be added with excipients, Such as talc Spray dried onto the Sealed oxycodone, naltrexone, or oxy and magnesium Stearate, before compression with a tablet codone/naltrexone beads to produce the corresponding preSS. resultant controlled release beads. An example of an aque ous sustained release solution contains Eudragit R30SD, Example 2 tributyl citrate, Tween 80, and talc. Another example of an aqueous Sustained release Solution contains Eudragit Immediate Release Gelatin Capsule for Oral R30SD, Eudragit RL30D, triethyl citrate, talc, and triehtyl Dosage Form citrate. Spray drying StepS can be performed in a fluid bed coater with Wurster insert. 0203 Gelatin capsules comprising at least one therapeu tically active agent are used to encase, enrobe, or encapsu 0194 These beads can be optionally coated with addi late controlled release cores prepared, for example, accord tional Opadry Clear (HPMC) for further sealing and/or spray ing to Example 1. Hard or Soft gelatin capsules can be used dried with an enteric coating composition. Both the Opadry as the immediate release gelatin capsule. Soft gelatin cap Clear (HPMC) Solution and an enteric coating composition Sules are preferred for the preparation of oral dosage forms are dissolved in aqueous Solution before being used in the according to the invention. Numerous methods for encap Spray drying apparatus. Beads are then cured at elevated Sulating the controlled release core are described, for temperature for a period of time, So as to ensure complete example, in U.S. Pat. Nos. 5,146,730, 5,595,758, 6,482.516. drying of the beads. A variety of methods and materials related to the preparation US 2004/0224020 A1 Nov. 11, 2004 26 and use of gelatin formulations, coatings and capsules are produce tablets or capsules having Soft elastic gelatin film described, for example, in U.S. Pat. Nos.: 3,959,540; 4,744, Sealed to opposite Side of the tablet or core in an essentially 988; 4,780,316; 5,200,191; 5,380,534, 5,422,160; 5,484, edge-to-edge manner along a Seal line. 598; 5,505,961; 5,569.466; 5,595,758; 5,624,681; 5,682, 0210 Gelatin composition comprises gelatin of varying 733; 5,735,105; 5,750,145; 5,817,323; 5,827,535; 5,891, bloom Strength and optionally further comprises at least one 470; 5,985,321; 6,096,338; 6,120,806; 6,183,845; 6,193, plasticizer, at least one gelatin extender, at least one additive, 999; 6,214,376; 6,251,426; 6,258,380; 6,285,380; 6,288, at least one colorant, at least one preservant, at least one 894; 6,387,400;. Surfactant, at least one drying agent, at least one taste 0204 Liquid Controlled Release Core modifier, at least one moisture retaining agent, and/or at least one opacifier. At least one therapeutically active agent is 0205 Where the controlled release core is in liquid form, mixed in the gelatin capsule composition to be used in the immediate release gelatin capsule can be a Soft or hard formulating the immediate release gelatin capsule. The at gelatin capsule. Preferred Soft gelatin capsules Suitable for least one therapeutically active agent in the gelatin capsule use in the immediate release gelatin capsule include Soft composition is (i) an opioid agonist alone, Such as oxyc letOR and Gelatin Binary System(R) from Banner Pharmacap odone, (ii) an opioid antagonist, Such as naltrexone, or (iii) and Liquid-Gels(R), RP Scherersol(R), and Puslin-Cap(R) from combination of an opioid agonist and opioid antagonist, Cardinal/RP Scherer Corp. Methods for encapsulating a Such as Oxycodone and naltrexone. liquid fill formulant are well known and are described, for example, in U.S. Pat. No. 6,251,426. 0211 Gelatin capsule compositions comprising at least one therapeutically active agent is heated into a liquid. 0206 Gelatin capsules compositions comprise gelatin of Liquid gelatin capsule compositions are poured into a dis varying bloom Strength and optionally further comprise at pensing device and kept at an elevated temperature by an least one plasticizer, at least one gelatin extender, at least one electric heater. The liquid gelatin is introduced to a moving additive, at least one colorant, at least one preservant, at least casting Surface as a layer of gelatin of predetermined thick one Surfactant, at least one drying agent, at least one taste neSS and Solidifies on a drum casting Surface Sufficiently to modifier, at least one moisture retaining agent, and/or at least form films. The gelatin film passes from individual tractor one opacifier. At least one therapeutically active agent is rolls and is wrapped around an adjacent die roll core tablets included in the composition of the formulation for the or capsules are processed into a feed horn and placed immediate release gelatin capsule. The at least one thera Symmetrically around the die roll. Heater blocks are placed peutically active agent in the composition of the gelatin as close as possible to the point at which the tablet or capsule capsule formulation is (i) an opioid agonist alone, Such as core emerges from the wedge-shaped lower portion of the oxycodone, (ii) an opioid antagonist, Such as naltrexone, or feed horn at the nip. The die nip is the place where films are (iii) combination of an opioid agonist and opioid antagonist, brought into contact with each other So as to Seal the film Such as Oxycodone and naltrexone. together around the tablet or capsule and cut the enrobed 0207 Gelatin capsule compositions comprising at least tablet or capsule from the film. Enrobed tablets or capsules one therapeutically active agent is heated into a molten mass are open air or tumble-dried in a series of hollow drums with and is fed onto drums to form two Spaced sheets or ribbons. perforated walls that continuously pump heated dry air. The ribbons are fed around rollers and brought together at a Drying times Span approximately 16-24 hours. After the convergent angle into the nip of a pair of roller dies. The enrobed tablets or capsules exit the last drying drum, the liquid controlled release core is fed into the wedge-shaped capsules are typically spread on drying trays are cooled. joiner of the ribbons. The gelatin ribbons are continuously Cooled enrobed tablets or capsules are packaged in alumi conveyed between the dies, with portion of the liquid numblistered foil packS. controlled release core being trapped between the sheets Example 3 inside the die cavities. The sheets are then pressed together to form a continuous gelatin covering around the entrapped Dosage Formulations with Commercially Available liquid controlled release core to form resultant capsules. Controlled Release Therapeutically Active Agents Capsules are open air or tumble-dried in a Series of hollow 0212. A variety of commercially available dosage form drums with perforated walls that continuously pump heated and controlled release formulations of therapeutically active dry air. Drying times Span approximately 16-24 hours. After agents, including opioid agonists, Such as Oxycodone, the capsules exit the last drying drum, the capsules are hydrocodone, and morphine, are useful as controlled release typically spread on drying trays are cooled. Cooled capsules cores for the preparation of oral dosage forms according to are packaged in aluminum blistered foil packs. the invention. Preferred commercial dosage forms and for mulations of opioid agonists include, for example, OXY 0208 Tablet or Capsule Controlled Release Core CONTINGR) from Purdue Pharma, MS-CONTINGR) from Pur 0209 Where the controlled release core is a tablet or due Frederick and AVINZATM from Elan. Additional non capsule, the immediate release gelatin capsule is enrobed limiting examples of commercial controlled release over the tablet or capsule and can be in the form of a hard formulations comprising opioid agonists include Ovamorph or Soft gelatin capsule. Preferred Soft gelatin capsules Suit SR from Boehringer Ingelheim and Roxanol-SR and Kadian able for use in the immediate release gelatin capsule include from Faulding. However, any commercial or non-commer Softlet(R) and Gelatin Binary System(R) from Banner Phar cial controlled release formulation of any therapeutically macap and Liquid-Gels(R), RP Scherersole, and Puslin active agent, including any opioid agonist, can be used in the Cap(R) from Cardinal/RP Scherer Corp. Methods for enrob controlled release core according to the invention. ing a tablet or capsule are well known and are described, for 0213 For example, OXYCONTING) from Purdue example, in U.S. Pat. No. 6,482.516. Enrobing methods Pharma is a controlled release tablet formulation comprising US 2004/0224020 A1 Nov. 11, 2004 27

Oxycodone hydrochloride in doses of 10 mg, 20 mg, 40 mg, trolled release core is MS-CONTINGR) or AVINZATM, the 80 mg, and formerly 160 mg. OXYCONTINGR) tablets are immediate release gelatin capsule coating comprises naltr designed to provide controlled delivery of oxycodone over eXOne or nalmefene. 12 hours in a pH independent manner. Oral bioavailability of 0219. Additionally, where the controlled release core is a oxycodone ranges from about 60% to about 87%. OXY commercial or non-commercial controlled release formula CONTINGR) tablets exhibit a biphasic absorption pattern with tion comprising an opioid agonist, the therapeutically active two apparent absorption half-times, t, of 0.6 and 6.9 agent of the immediate release gelatin capsule can be at least hours, which described the initial release of oxycodone from one opioid agonist and at least one opioid antagonist present the tablet followed by a prolonged release. in amounts within preferred ranges disclosed herein. Where 0214) Additionally, for example, MS-CONTINGR) from the controlled release core is OXYCONTIN(E), the immedi Purdue Frederick is a controlled release formulation com ate release gelatin capsule coating comprises oxycodone in prising morphine sulfate in doses of 15, 30, 60, 100, and an amount ranging from about 0.025 to about 60 mg and 200mg. MS-CONTINGR) tablets are designed to provide naltrexone or nalmefene in an amount ranging from about controlled delivery of morphine over 12 hours. Average t 0.000001 to about 0.5 mg. Where the controlled release core for MS-CONTINGR) tablets is approximately 2.06 hours and is MS-CONTINGR) or AVINZATM, the immediate release average half-life of absorption, t , is 0.87 hours. gelatin capsule coating comprises oxycodone in an amount ranging from about 0.025 to about 60 mg and naltrexone or 0215. Additionally, for example, AVINZATM from Elan is nalmefene in an amount ranging from about 0.000001 to an extended release capsule formulation comprising mor about 0.5 mg. phine sulfate in doses of 30, 60,90, and 120 mg. AVINZATM capsules contain both immediate release and extended Example 4 release beads of morphine to achieve plateau morphine plasma concentrations throughout a 24-hour dosing interval. In vivo Testing of Oral Dosage Formulations in Following a single-dose of 60 mg of AVINZATM under Dog Models fasting conditions, morphine concentration of approxi mately 3 to 6 ng/mL were achieved within 30 minutes and 0220. In vivo testing in dog models is performed to maintained for 24 hours. determine the relative bioavailability of various oral dosage formulations presented herein. Studies using common mam 0216 Commercial formulations of controlled release malian laboratory animals, Such as dogs, are essential and opioid agonists, preferably OXYCONTINGR), MS-CON are routinely used for the evaluation of absorption, distri TINGR), and AVINZATM can be enrobed, encased, or encap bution, metabolism, and excretion (ADME) properties, of Sulated according to Example 2 with an immediate release chemical entities. The dog is Selected for this study based on gelatin capsule comprising at least one therapeutically active anatomical, physiological, and biochemical Similarities to agent, preferably an opioid agonist, an opioid antagonist, or human, which may facilitate extrapolation of observed a combination of an opioid agonist and antagonist present in ADME properties to man. preferred amounts disclosed herein. 0221) This study uses the minimum number of animals 0217 Where the controlled release core is a commercial required for complete collection of the desired biological or non-commercial controlled release dosage form or for Samples and to obtain Scientifically valid results. This Study mulation comprising an opioid agonist, the therapeutically is conducted in accordance with applicable Standard Oper active agent of the immediate release gelatin capsule can be ating Procedures and generally recognized good laboratory at least one opioid agonist present in amounts within pre practice. All procedures in the protocol of this study are in ferred ranges disclosed herein, including, for example, from compliance with the Animal Welfare Act Regulations as Set about 0.025 mg to about 60 mg. Where the controlled release forth in 9 C.F.R. 3. All personnel involved in this study will core is OXYCONTINE), the immediate release gelatin cap follow all Safety precautions as required by Testing Labo Sule comprises oxycodone. Where the core is 10 mg. OXY ratory's Policies and Procedures in consideration of the CONTINGR) tablet, the amount of oxycodone in the gelatin Material Safety Data Sheet or other relevant safety infor capsule enrobing the tablet is from about 0.25 mg to about mation. Animals are maintained and monitored for good 2.0 mg. Where the controlled release core is MS-CONTINGR) health in accordance with laboratory Standard Operating or AVINZATM (as a hydrochloride or free base), the imme Procedures and at the discretion of a laboratory animal diate release gelatin capsule coating comprises morphine Veterinarian. sulfate. Where the core is a 30 mg MS-CONTINGR) tablet or a 30 mg. AVINZATM capsule, the amount of morphine sulfate 0222 Six healthy female purebred beagles from a stock in the gelatin capsule enrobing the tablet or capsule is from colony weighing approximately 5 kg to 7 kg and approxi about 0.75 mg to about 60 mg. mately 4 months to 18 months in age are entered into a 4-phase Study. Each phase is followed by a 14-day washout 0218. Additionally, where the controlled release core is a period thus Phase 1 is administered on Day 1, phase 2 is commercial or non-commercial controlled release formula administered on Day 14, phase 3 is administered on Day 28, tion comprising an opioid agonist, the therapeutically active and phase 4 is administered on Day 42. As outlined in Table agent of the immediate release gelatin capsule can be at least 1, formulations A, B, C, and D will be administered as oral one opioid antagonist present in amounts within preferred capsule doses to each dog, followed by administration of a ranges disclosed herein, including, for example, from about placebo capsule. Animals are fasted overnight prior to 0.000001 to about 0.5 mg. Where the controlled release core dosing through approximately 4 hours post-dose for each is OXYCONTINE), the immediate release gelatin capsule phase of the Study. Individual doses for each dog are coating comprises naltrexone or nalmefene. Where the con calculated based on body weight taken on each day of US 2004/0224020 A1 Nov. 11, 2004 28 dosing. Prior to and after oral dose administration of various 6. The oral dosage form of claim 1, wherein at least one oral dosage forms according to the invention (post dose therapeutically active agent in the controlled release core samples withdrawn at 0.167, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, comprises an opioid agonist. 12, 24, 48, 72, and 96 hours after administration), approxi 7. The oral dosage form of claim 6, wherein the opioid mately 1 mL of blood from each dog is collected into tubes agonist in the controlled release core comprises at least one containing heparin anticoagulant. Blood Samples are Stored of the following: alfentanil, allylprodine, alphaprodine, on wet ice, in chilled Kryorack, or at approximately 5 C. anilleridine, apomorphine, apocodeine, benzylmorphine, prior to centrifugation to obtain plasma. Resultant plasma bezitramide, buprenorphine, butorphanol, clonitaZene, Samples are tested for the presence of the administered codeine, cyclazocine, cyclorphen, cyprenorphine, desomor therapeutically active agent(s) using analytical procedures phine, dextromoramide, dezocine, diampromide, dihydroco known in the art. deine, dihydromorphine, dimenoxadol, dimepheptanol, dim 0223) Each dog is uniquely marked with a numbered ear ethylthiambutene, dioxyaphetyl butyrate, dipipanone, tattoo for proper identification. The dogs are acclimated in eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl an environment-controlled study room (temperature of 18 morphine, etonitaZene, fentanyl, heroin, hydrocodone, C.-29 C., 12-hour light/12-hour dark cycle) for at least 4 hydroxymethylmorphinan, hydromorphone, hydroxypethi days prior to the initial dose administration. During accli dine, isomethadone, ketobemidone, levallorphan, levorpha mation and the test period, the dogs are housed in individual nol, levophenacylmorphan, lofentanil, meperidine, meptazi cages and are not commingled in order to minimize the nol, metazocine, methadone, methylmorphine, metopon, possibility of injury. The dogs are fed non-certified canine morphine, myrophine, nalbuphine, narceline, nicomorphine, diet #5L03 (PMI Feeds, Inc.) ad libitum, except as specified norlevorphanol, normethadone, nalorphine, normorphine, under Dosing Procedures, and may be provided with certi norpipanone, ohmefentanyl, opium, oxycodone, oxymor fied canine treats, as appropriate, during non-fasted periods. phone, papaveretum, pentazocine, phenadoxone, phenom The dogs are provided ad libitum with tap water from a well orphan, phenazocine, phenoperidine, pholcodine, piminod Supply that is tested quarterly and annually for total ine, piritramide, propheptazine, promedol, profadol, coliforms and for the presence of pesticides, trace metals, properidine, propiram, propoxyphene, remifentanyl, Sufen and heavy metals to ensure Safe drinking Status. Both the tanyl, tramadol, tilidine, or Salts thereof. food and water given to the dogs do not contain any known 8. The oral dosage form of claim 7, wherein the opioid contaminants that would interfere with the conducted Study. agonist in the controlled release core comprises oxycodone. 9. The oral dosage form of claim 6, wherein at least one 0224 Mortality and moribundity checks are performed therapeutically active agent in the controlled release core twice daily, in the morning and evening. CageSide observa further comprises an opioid antagonist. tion for general health and appearance is done once daily. 10. The oral dosage form of claim 9, wherein the opioid Any unusual observations noted during dose administration antagonist in the controlled release core comprises at least and Sample collection are recorded in the raw data. Body one of the following: maltrexone, naloxone, nalmefene, weights are taken on each day of dose administration. methylmaltrexone, naloxone methiodide, nalorphine, nalox 0225. The invention now being fully described, it will be onazine, nalide, nalmexone, nalbuphine, nalorphine dinico apparent to one of ordinary skill in the art that many changes tinate, naltrindole, naltrindole isothiocyanate, naltriben, nor and modifications can be made thereto without departing binaltorphimine, b-funaltrexamine, BNTX., cyprodime, ICI from the Spirit or Scope of the appended claims. 174-864, LY117413, MR2266, or an opioid antagonist having the same pentacyclic nucleus as nalmefene, naltrex one, buprenorphine, levorphanol, meptaZinol, pentazocine, or dezocine. What is claimed is: 11. The oral dosage form of claim 9, wherein the opioid 1. An oral dosage form comprising (i) an controlled antagonist in the controlled release core comprises naltrex release core; and (ii) an immediate release gelatin capsule OC. around the controlled release core, wherein the controlled 12. The oral dosage form of claim 1, wherein the at least released core comprises at least one therapeutically active one therapeutically active agent in the immediate release agent and at least one controlled release material; and gelatin capsule is a drug. wherein the immediate release gelatin capsule comprises at 13. The oral dosage form of claim 1, wherein at least one least one therapeutically active agent. therapeutically active agent in the immediate release gelatin 2. The oral dosage form of claim 1, wherein at least one capsule is an analgesic. therapeutically active agent in the controlled release core is 14. The oral dosage form of claim 1, wherein at least one the same as at least one therapeutically active agent in the therapeutically active agent in the immediate release gelatin immediate release gelatin capsule. capsule comprises an opioid agonist. 3. The oral dosage form of claim 1, wherein at least one 15. The oral dosage form of claim 14, wherein the opioid therapeutically active agent in the controlled released core is agonist in the immediate release gelatin capsule comprises at different from at least one therapeutically active agent in the least one of the following: alfentanil, allylprodine, alphapro immediate release gelatin capsule. dine, anilleridine, apomorphine, apocodeine, benzylmor 4. The oral dosage form of claim 1, wherein at least one phine, beZitramide, buprenorphine, butorphanol, clonita therapeutically active agent in the controlled release core is Zene, codeine, cyclazocine, cyclorphen, cyprenorphine, a drug. deSomorphine, dextromoramide, dezocine, diampromide, 5. The oral dosage form of claim 1, wherein at least one dihydrocodeine, dihydromorphine, dimenoxadol, dime therapeutically active agent in the controlled release core is pheptanol, dimethylthiambutene, dioxyaphetyl butyrate, an analgesic. dipipanone, eptazocine, ethoheptazine, ethylmethylthiam US 2004/0224020 A1 Nov. 11, 2004 29 butene, ethylmorphine, etonitaZene, fentanyl, heroin, hydro comprises an opioid agonist; and wherein at least one codone, hydroxymethylmorphinan, hydromorphone, therapeutically active agent in the immediate release gelatin hydroxypethidine, isomethadone, ketobemidone, levallor capsule comprises an opioid antagonist. phan, levorphanol, levophenacylmorphan, lofentanil, mep 24. The oral dosage form of claim 23, wherein the opioid eridine, meptazinol, metazocine, methadone, methylmor agonist in the controlled released core comprises at least one phine, metopon, morphine, myrophine, nalbuphine, of the following: alfentanil, allylprodine, alphaprodine, narceline, nicomorphine, norlevorphanol, normethadone, anilleridine, apomorphine, apocodeine, benzylmorphine, nalorphine, normorphine, norpipanone, ohmefentanyl, bezitramide, buprenorphine, butorphanol, clonitaZene, opium, oxycodone, oxymorphone, papaveretum, pentazo codeine, cyclazocine, cyclorphen, cyprenorphine, desomor cine, phenadoxone, phenomorphan, phenazocine, phenope phine, dextromoramide, dezocine, diampromide, dihydroco ridine, pholcodine, piminodine, piritramide, propheptazine, deine, dihydromorphine, dimenoxadol, dimepheptanol, dim promedol, profadol, properidine, propiram, propoxyphene, ethylthiambutene, dioxyaphetyl butyrate, dipipanone, remifentanyl, Sufentanyl, tramadol, tilidine, or Salts thereof. eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl 16. The oral dosage form of claim 14, wherein the opioid morphine, etonitaZene, fentanyl, heroin, hydrocodone, agonist in the immediate release gelatin capsule comprises hydroxymethylmorphinan, hydromorphone, hydroxypethi Oxycodone. dine, isomethadone, ketobemidone, levallorphan, levorpha 17. The oral dosage form of claim 1, wherein at least one nol, levophenacylmorphan, lofentanil, meperidine, meptazi therapeutically active agent in the immediate release gelatin nol, metazocine, methadone, methylmorphine, metopon, capsule comprises an opioid antagonist. morphine, myrophine, nalbuphine, narceline, nicomorphine, 18. The oral dosage form of claim 17, wherein the opioid norlevorphanol, normethadone, nalorphine, normorphine, antagonist in the immediate release gelatin capsule com norpipanone, ohmefentanyl, opium, oxycodone, oxymor prises at least one of the following: naltrexone, naloxone, phone, papaveretum, pentazocine, phenadoxone, phenom nalmefene, methylnaltrexone, naloxone methiodide, nalor orphan, phenazocine, phenoperidine, pholcodine, piminod phine, naloxonazine, nalide, nalmexone, nalbuphine, nalor ine, piritramide, propheptazine, promedol, profadol, phine dinicotinate, naltrindole, naltrindole isothiocyanate, properidine, propiram, propoxyphene, remifentanyl, Sufen maltriben, nor-binaltorphimine, b-funaltrexamine, BNTX, tanyl, tramadol, tilidine, or Salts thereof, and wherein the cyprodime, ICI-174-864, LY117413, MR2266, or an opioid opioid antagonist in the immediate release gelatin capsule antagonist having the same pentacyclic nucleus as comprises at least one of the following: maltrexone, nalox nalmefene, naltrexone, buprenorphine, levorphanol, one, nalmefene, methylnaltrexone, naloxone methiodide, meptazinol, pentazocine, or dezocine. nalorphine, naloxonazine, nalide, nalmeXOne, nalbuphine, 19. The oral dosage form of claim 17, wherein the opioid nalorphine dinicotinate, naltrindole, naltrindole isothiocyan antagonist in the immediate release gelatin capsule com ate, naltriben, nor-binal torphimine, b-funaltrexamine, prises naltrexone. BNTX, cyprodime, ICI-174-864, LY117413, MR2266, oran 20. The oral dosage form of claim 17, wherein at least one opioid antagonist having the same pentacyclic nucleus as therapeutically active agent in the immediate release gelatin nalmefene, naltrexone, buprenorphine, levorphanol, capsule further comprises an opioid agonist. meptazinol, pentazocine, or dezocine. 21. The oral dosage form of claim 20, wherein the opioid 25. The oral dosage form of claim 23, wherein at least one agonist in the immediate release gelatin capsule comprises at therapeutically active agent in the controlled released core least one of the following: alfentanil, allylprodine, alphapro comprises oxycodone, and wherein at least one therapeuti dine, anilleridine, apomorphine, apocodeine, benzylmor cally active agent in the immediate release gelatin capsule phine, beZitramide, buprenorphine, butorphanol, clonita comprises naltrexone. Zene, codeine, cyclazocine, cyclorphen, cyprenorphine, 26. The oral dosage form of claim 1, wherein at least one deSomorphine, dextromoramide, dezocine, diampromide, therapeutically active agent in the controlled released core dihydrocodeine, dihydromorphine, dimenoxadol, dime comprises an opioid agonist; and wherein at least one pheptanol, dimethylthiambutene, dioxyaphetyl butyrate, therapeutically active agent in the immediate release gelatin dipipanone, eptazocine, ethoheptazine, ethylmethylthiam capsule comprises an opioid antagonist and an opioid ago butene, ethylmorphine, etonitaZene, fentanyl, heroin, hydro nist. codone, hydroxymethylmorphinan, hydromorphone, 27. The oral dosage form of claim 26, wherein the opioid hydroxypethidine, isomethadone, ketobemidone, levallor agonist in the controlled released core and in the immediate phan, levorphanol, levophenacylmorphan, lofentanil, mep release gelatin capsule comprises at least one of the follow eridine, meptazinol, metazocine, methadone, methylmor ing: alfentanil, allylprodine, alphaprodine, anilleridine, apo phine, metopon, morphine, myrophine, nalbuphine, morphine, apocodeine, benzylmorphine, beZitramide, narceline, nicomorphine, norlevorphanol, normethadone, buprenorphine, butorphanol, clonitaZene, codeine, cyclazo nalorphine, normorphine, norpipanone, ohmefentanyl, cine, cyclorphen, cyprenorphine, desomorphine, dextro opium, oxycodone, oxymorphone, papaveretum, pentazo moramide, dezocine, diampromide, dihydrocodeine, dihy cine, phenadoxone, phenomorphan, phenazocine, phenope dromorphine, dimenoxadol, dimepheptanol, ridine, pholcodine, piminodine, piritramide, propheptazine, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, promedol, profadol, properidine, propiram, propoxyphene, eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl remifentanyl, Sufentanyl, tramadol, tilidine, or Salts thereof. morphine, etonitaZene, fentanyl, heroin, hydrocodone, 22. The oral dosage form of claim 20, wherein the opioid hydroxymethylmorphinan, hydromorphone, hydroxypethi agonist in the immediate release gelatin capsule comprises dine, isomethadone, ketobemidone, levallorphan, levorpha Oxycodone. nol, levophenacylmorphan, lofentanil, meperidine, meptazi 23. The oral dosage form of claim 1, wherein at least one nol, metazocine, methadone, methylmorphine, metopon, therapeutically active agent in the controlled released core morphine, myrophine, nalbuphine, narceline, nicomorphine, US 2004/0224020 A1 Nov. 11, 2004 30 norlevorphanol, normethadone, nalorphine, normorphine, comprises oxycodone and naltrexone, and wherein at least norpipanone, ohmefentanyl, opium, Oxycodone, oxymor one therapeutically active agent in the immediate release phone, papaveretum, pentazocine, phenadoxone, phenom gelatin capsule comprises naltrexone. orphan, phenazocine, phenoperidine, pholcodine, piminod 32. The oral dosage form of claim 1, wherein at least one ine, piritramide, propheptazine, promedol, profadol, therapeutically active agent in the controlled released core properidine, propiram, propoxyphene, remifentanyl, Sufen comprises an opioid agonist and an opioid antagonist; and tanyl, tramadol, tilidine, or Salts thereof, and wherein the wherein at least one therapeutically active agent in the opioid antagonist in the immediate release gelatin capsule immediate release gelatin capsule comprises an opioid ago comprises at least one of the following: naltrexone, nalox nist and an opioid antagonist. one, nalmefene, methylmaltrexone, naloxone methiodide, 33. The oral dosage form of claim 32, wherein the opioid nalorphine, naloxonazine, nalide, nalmeXOne, nalbuphine, agonist in the controlled released core and in the immediate nalorphine dinicotinate, naltrindole, naltrindole isothiocyan release gelatin capsule comprises at least one of the follow ate, naltriben, nor-binal torphimine, b-funaltrexamine, ing: alfentanil, allylprodine, alphaprodine, anilleridine, apo BNTX, cyprodime, ICI-174-864, LY117413, MR2266, oran morphine, apocodeine, benzylmorphine, beZitramide, opioid antagonist having the same pentacyclic nucleus as buprenorphine, butorphanol, clonitaZene, codeine, cyclazo nalmefene, naltrexone, buprenorphine, levorphanol, cine, cyclorphen, cyprenorphine, desomorphine, dextro meptazinol, pentazocine, or dezocine. moramide, dezocine, diampromide, dihydrocodeine, dihy 28. The oral dosage form of claim 26, wherein at least one dromorphine, dimenoxadol, dimepheptanol, therapeutically active agent in the controlled released core dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, comprises oxycodone; and wherein at least one therapeuti eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl cally active agent in the immediate release gelatin capsule morphine, etonitaZene, fentanyl, heroin, hydrocodone, comprises naltrexone and oxycodone. hydroxymethylmorphinan, hydromorphone, hydroxypethi 29. The oral dosage form of claim 1, wherein at least one dine, isomethadone, ketobemidone, levallorphan, levorpha therapeutically active agent in the controlled released core nol, levophenacylmorphan, lofentanil, meperidine, meptazi comprises an opioid agonist and an opioid antagonist; and nol, metazocine, methadone, methylmorphine, metopon, wherein at least one therapeutically active agent in the morphine, myrophine, nalbuphine, narceline, nicomorphine, immediate release gelatin capsule comprises an opioid norlevorphanol, normethadone, nalorphine, normorphine, antagonist. norpipanone, ohmefentanyl, opium, oxycodone, oxymor 30. The oral dosage form of claim 29, wherein the opioid phone, papaveretum, pentazocine, phenadoxone, phenom agonist in the controlled released core comprises at least one orphan, phenazocine, phenoperidine, pholcodine, piminod of the following: alfentanil, allylprodine, alphaprodine, ine, piritramide, propheptazine, promedol, profadol, anilleridine, apomorphine, apocodeine, benzylmorphine, properidine, propiram, propoxyphene, remifentanyl, Sufen bezitramide, buprenorphine, butorphanol, clonitaZene, tanyl, tramadol, tilidine, or Salts thereof, and wherein the codeine, cyclazocine, cyclorphen, cyprenorphine, desomor opioid antagonist in the controlled released core and in the phine, dextromoramide, dezocine, diampromide, dihydroco immediate release gelatin capsule comprises at least one of deine, dihydromorphine, dimenoxadol, dimepheptanol, dim the following: maltrexone, naloxone, nalmefene, methylnal ethylthiambutene, dioxyaphetyl butyrate, dipipanone, trexone, naloxone methiodide, nalorphine, naloxonazine, eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl nalide, nalmexone, nalbuphine, nalorphine dinicotinate, nal morphine, etonitaZene, fentanyl, heroin, hydrocodone, trindole, naltrindole isothiocyanate, naltriben, nor-binaltor hydroxymethylmorphinan, hydromorphone, hydroxypethi phimine, b-funaltrexamine, BNTX., cyprodime, ICI-174 dine, isomethadone, ketobemidone, levallorphan, levorpha 864, LY117413, MR2266, or an opioid antagonist having the nol, levophenacylmorphan, lofentanil, meperidine, meptazi Same pentacyclic nucleus as nalmefene, naltrexone, nol, metazocine, methadone, methylmorphine, metopon, buprenorphine, levorphanol, meptazinol, pentazocine, or morphine, myrophine, nalbuphine, narceline, nicomorphine, dezocine. norlevorphanol, normethadone, nalorphine, normorphine, 34. The oral dosage form of claim 32, wherein at least one norpipanone, ohmefentanyl, opium, Oxycodone, oxymor therapeutically active agent in the controlled released core phone, papaveretum, pentazocine, phenadoxone, phenom comprises oxycodone and naltrexone, and wherein at least orphan, phenazocine, phenoperidine, pholcodine, piminod one therapeutically active agent in the immediate release ine, piritramide, propheptazine, promedol, profadol, gelatin capsule comprises oxycodone and naltrexone. properidine, propiram, propoxyphene, remifentanyl, Sufen 35. The oral dosage form of claim 1, wherein at least one tanyl, tramadol, tilidine, or Salts thereof, and wherein the therapeutically active agent in the controlled released core opioid antagonist in the controlled released core and in the comprises an opioid agonist; and wherein at least one immediate release gelatin capsule comprises at least one of therapeutically active agent in the immediate release gelatin the following: maltrexone, naloxone, nalmefene, methylnal capsule comprises an opioid agonist. trexone, naloxone methiodide, nalorphine, naloxonazine, 36. The oral dosage form of claim 35, wherein the opioid nalide, nalmexone, nalbuphine, nalorphine dinicotinate, nal agonist in the controlled released core and in the immediate trindole, naltrindole isothiocyanate, naltriben, nor-binaltor release gelatin capsule comprises at least one of the follow phimine, b-funaltrexamine, BNTX., cyprodime, ICI-174 ing: alfentanil, allylprodine, alphaprodine, anilleridine, apo 864, LY117413, MR2266, or an opioid antagonist having the morphine, apocodeine, benzylmorphine, beZitramide, Same pentacyclic nucleus as nalmefene, naltrexone, buprenorphine, butorphanol, clonitaZene, codeine, cyclazo buprenorphine, leVorphanol, meptazinol, pentazocine, or cine, cyclorphen, cyprenorphine, desomorphine, dextro dezocine. moramide, dezocine, diampromide, dihydrocodeine, dihy 31. The oral dosage form of claim 29, wherein at least one dromorphine, dimenoxadol, dimepheptanol, therapeutically active agent in the controlled released core dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, US 2004/0224020 A1 Nov. 11, 2004

eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl the immediate release gelatin capsule is in an amount morphine, etonitaZene, fentanyl, heroin, hydrocodone, ranging from about 0.1 mg to about 300 mg. hydroxymethylmorphinan, hydromorphone, hydroxypethi 47. The oral dosage form of claims 29, 30, or 31, wherein dine, isomethadone, ketobemidone, levallorphan, levorpha the opioid agonist in the controlled release core is in an nol, levophenacylmorphan, lofentanil, meperidine, meptazi Subanalgesic amount; wherein the opioid antagonist in the nol, metazocine, methadone, methylmorphine, metopon, controlled release core is in an amount ranging from about morphine, myrophine, nalbuphine, narceline, nicomorphine, 0.001 mg to less than about 0.5 mg; and wherein the opioid norlevorphanol, normethadone, nalorphine, normorphine, antagonist in the immediate release gelatin capsule is in an norpipanone, ohmefentanyl, opium, Oxycodone, oxymor amount ranging from about 0.001 mg to less than about 0.5 phone, papaveretum, pentazocine, phenadoxone, phenom mg. orphan, phenazocine, phenoperidine, pholcodine, piminod 48. The oral dosage form of claims 29, 30, or 31, wherein ine, piritramide, propheptazine, promedol, profadol, the opioid agonist in the controlled release core is in an properidine, propiram, propoxyphene, remifentanyl, Sufen amount ranging from about 0.1 mg to about 300 mg, tanyl, tramadol, tilidine, or Salts thereof. wherein the opioid antagonist in the controlled release core 37. The oral dosage form of claim 35, wherein at least one is in an amount ranging from about 0.001 mg to less than therapeutically active agent in the controlled released core about 0.5 mg, and wherein the opioid antagonist in the comprises oxycodone; and wherein at least one therapeuti immediate release gelatin capsule is in an amount ranging cally active agent in the immediate release gelatin capsule from about 0.001 mg to less than about 0.5 mg. comprises oxycodone. 49. The oral dosage form of claims 32, 33, or 34, wherein 38. The oral dosage form of claims 6-8 and 23-37, the opioid agonist in the controlled release core is in an wherein the opioid agonist in the controlled release core is Subanalgesic amount; wherein the opioid antagonist in the in a Subanalgesic amount. controlled release core is in an amount ranging from about 39. The oral dosage form of claims 6-8 and 23-37, 0.001 mg to less than about 0.5 mg; wherein the opioid wherein the opioid agonist in the controlled release core is agonist in the immediate release gelatin capsule is in an in an amount ranging from about 0.1 mg to about 300 mg. Subanalgesic amount, and wherein the opioid antagonist in 40. The oral dosage form of claims 17-34 wherein the S the immediate release gelatin capsule is in an amount opioid antagonist in the immediate release gelatin capsule is ranging from about 0.001 mg to less than about 0.5 mg. in an amount ranging from about 0.001 mg to less than about 50. The oral dosage form of claims 32, 33, or 34, wherein 0.5 mg. the opioid agonist in the controlled release core is in an 41. The oral dosage of claims 17-36 wherein the opioid amount ranging from about 0.1 mg to about 300 mg, antagonist in the immediate release gelatin capsule is in an wherein the opioid antagonist in the controlled release core amount ranging from about 0.001 mg to less than about 0.5 is in an amount ranging from about 0.001 mg to less than mg and wherein the opioid agonist in the immediate release about 0.5 mg, wherein the opioid agonist in the immediate gelatin capsule is in an Subanalgesic amount. release gelatin capsule is in an amount ranging from about 42. The oral dosage of claims 17-36 wherein the opioid 0.1 mg to about 300 mg, and wherein the opioid antagonist antagonist in the immediate release gelatin capsule is in an in the immediate release gelatin capsule is in an amount amount ranging from about 0.001 mg to less than about 0.5 ranging from about 0.001 mg to less than about 0.5 mg. mg and wherein the opioid agonist in the immediate release 51. The oral dosage form of claims 35, 36, or 37, wherein gelatin capsule is in an amount ranging from about 0.1 mg the opioid agonist in the controlled release core is in an to about 300 mg. analgesic or Subanalgesic amount; and wherein the opioid 43. The oral dosage form of claims 23, 24, or 25, wherein agonist in the immediate release gelatin capsule is in an the opioid agonist in the controlled release core is in an analgesic or Subanalgesic amount. Subanalgesic amount, and wherein the opioid antagonist in 52. The oral dosage form of claims 35, 36, or 37, wherein the immediate release gelatin capsule is in an amount the opioid agonist in the controlled release core is in an ranging from about 0.001 mg to less than about 0.5 mg. amount ranging from about 0.1 mg to about 300 mg, and 44. The oral dosage form of claims 23, 24, or 25, wherein wherein the opioid agonist in the immediate release gelatin the opioid agonist in the controlled release core is in an capsule is in an amount ranging from about 0.1 mg to about amount ranging from about 0.1 mg to about 300 mg, and 300 mg. wherein the opioid antagonist in the immediate release 53. The oral dosage form of claim 1, wherein the con gelatin capsule is in an amount ranging from about 0.001 mg trolled release core comprises at least one therapeutically to less than about 0.5 mg. active agent and at least one controlled release material, 45. The oral dosage form of claims 26, 27, or 28, wherein wherein the agent or the material are formulated as a liquid, the opioid agonist in the controlled release core is in an granulate, particulate, pellet, or bead. analgesic or Subanalgesic amount; wherein the opioid 54. The oral dosage form of claim 1, wherein the con antagonist in the immediate release gelatin capsule is in an trolled release material comprises at least one hydrophobic amount ranging from about 0.001 mg to less than about 0.5 or hydrophilic polymer. mg, and wherein the opioid agonist in the immediate release 55. The oral dosage form of claim 1, wherein the con gelatin capsule is in an Subanalgesic amount. trolled release material comprises at least one acrylate or at 46. The oral dosage forms of claims 26, 27, or 28, wherein least one methacrylate polymer. the opioid agonist in the controlled release core is in an 56. The oral dosage form of claim 54, wherein the amount ranging from about 0.1 mg to about 300 mg, controlled release material comprises at least one acrylic wherein the opioid antagonist in the immediate release polymer. gelatin capsule is in an amount ranging from about 0.001 mg 57. The oral dosage form of claim 56, wherein at least one to less than about 0.5 mg, and wherein the opioid agonist in acrylic polymer is cationic, anionic, or non-ionic. US 2004/0224020 A1 Nov. 11, 2004 32

58. The oral dosage form of claim 57, wherein at least one wherein n is between 1 and 20; acrylic polymer is an acrylic acid copolymer, a methacrylic acid copolymer, a methyl methacrylate copolymer, an R-O-(CH)-O-R- (Figure III) ethoxyethyl methacrylate copolymer, a cyanoethyl meth wherein n is an integer between 4 and 8, and acrylate copolymer, a methyacryacylic acid copolymer, or an aminoalkyl methacrylate copolymer. wherein R and R are independently selected from the 59. The oral dosage form of claim 1, wherein the con group consisting of hydrogen, alkanoyl, hydroxy-Sub trolled release material comprises at least one propylene Stituted alkanoyl, and acyloxy-Substituted alkanoyl; glycol, glyceryl, diethylaminoethyl, glycol, amide, long chain fatty acid amide, long chain fatty alcohol, or long chain ester. FIG. IV 60. The oral dosage form of claim 59, wherein the long O O-Rs chain fatty acid amide comprises at least one of the follow R-O ing: N,N'-ethylene disteramide, Steramide monoethanola mine (MEA), steramide diethanolamine (DEA), ethylene CH-O-R bisteramide, or cocoamine oxide. O O 61. The oral dosage form of claim 59, wherein the long R1 NR, chain fatty alcohol comprises at least one cetyl alcohol or Steryl alcohol. 62. The oral dosage form of claim 59, wherein the long wherein R, R2, R., R., and Rs are independently Selected chain ester comprises at least one of the following: myristyl from the group consisting of hydrogen, alkanoyl, myristate, beheny erucate, glyceryl phosphates, or acety hydroxy-Substituted alkanoyl, and acyloxy-Substituted lated Sucrose distearate. alkanoyl; 63. The oral dosage form of claim 1, wherein the con trolled release material comprises at least one of the follow Ing: FIG. V O-Rs O FIG. I R-O CH-O-R O-R O O CH2 R1 YR, CH2 O O -O- R4 R-O C 5 H wherein R, R2, R, R, and Rs are independently Selected O from the group consisting of hydrogen, alkanoyl, hydroxy-Substituted alkanoyl, and acyloxy-Substituted R-O O OR O-Rs alkanoyl;

FIG. VI wherein R, R2, R., R., RS, R, R-7, and Rs are indepen OR OR | H H 6 dently Selected from the group consisting of hydrogen, R-O-C-C-C-C-C-C-O-R alkanoyl, hydroxy-Substituted alkanoyl, and acyloxy H2 H H H2 5 Substituted alkanoyl, OR O wherein at least three of R, R2, R., R., Rs, R, R-7, and Rs are not hydrogen, and wherein R, R2, R., R., Rs, and R are independently wherein when R, R2, R., R., Rs, R, R-7, and Rs are Selected from the group consisting of hydrogen, Selected from the group consisting of acetyl and isobu alkanoyl, hydroxy-Substituted alkanoyl, and acyloxy tyryl, at least three of R, R2, R., R., Rs, R, R-7, and Substituted alkanoyl; Rs are acetyl,

FIG. VII FIG. II OR OR3 OR | H H 6 R-O-C-C-C-C-C-C-O-R H., H H H. OR O

wherein R, R2, and R are independently Selected from wherein R, R2, R., R., Rs, and R are independently the group consisting of hydrogen, alkanoyl, hydroxy Selected from the group consisting of hydrogen, Substituted alkanoyl, and acyloxy-Substituted alkanoyl, alkanoyl, hydroxy-Substituted alkanoyl, and acyloxy and Substituted alkanoyl; US 2004/0224020 A1 Nov. 11, 2004 33

77. The oral dosage form of claim 3, wherein at least one controlled release material comprises Sucrose acetate isobu FIG. VIII tyrate (SAIB). HC- OR2 78. The oral dosage form of claims 1, 2, or 3, wherein the R-O-C-C-C-O-R immediate release gelatin capsule is the in the form of a Soft H2 H2 gelatin capsule or a hard gelatin capsule. HC- OR 79. The oral dosage form of claim 78, wherein the controlled release core is in the form of a liquid, capsule, tablet, or caplet. wherein R, R2, R, and R are independently Selected 80. The oral dosage form of claim 1, wherein the imme from the group consisting of hydrogen, alkanoyl, diate release gelatin capsule is the in the form of a Soft hydroxy-Substituted alkanoyl, and acyloxy-Substituted gelatin capsule, and wherein the controlled release core is in alkanoyl. the form of a tablet. 64. The oral dosage form of claim 63, wherein at least one of the alkanoyl, hydroxy-Substituted alkanoyl, or acyloxy 81. The oral dosage form of claim 1, wherein the imme substituted alkanoyl groups in compounds I, II, III, IV, V, VI, diate release gelatin capsule is in the form of a Soft gelatin VII, or VIII, further comprises at least one alkanoyl moiety capsule, and wherein the controlled release core is in the comprising from about 2 to about 6 carbon atoms. form of a tablet. 65. The oral dosage form of claim 63, wherein at least one 82. The oral dosage form of claim 1, wherein the imme of compounds I, II, III, IV, V, VI, VII, or VIII comprises at diate release gelatin capsule is the in the form of a Soft least one hydroxy-Substituted alkanoyl moiety or acyloxy gelatin capsule, and wherein the controlled release core is in Substituted alkanoyl moiety. the form of a capsule. 66. The oral dosage form of claim 65, wherein the at least 83. The oral dosage form of claims 1, 2, or 3, further one hydroxy-Substituted alkanoyl moiety or acyloxy-Substi comprising at least one enteric coating. tuted alkanoyl moiety further comprises at least one 84. The oral dosage form of claim 83, wherein at least one alkanoyl moieties comprising from about 2 to about 6 enteric coating is affixed over the controlled release core and carbon atoms. under the immediate release gelatin capsule. 67. The oral dosage form of claim 62, wherein at least one 85. The oral dosage form of claim 83, wherein the acyl group of the acyloxy-Substituted alkanoyl moiety is of immediate release gelatin capsule coating is an enteric the form RoCO-, and wherein Ro comprises at least one coating. oxy-Substituted alkyl group comprising from about 2 to 86. The oral dosage form of claim 83, wherein the about 6 carbon atoms. immediate release gelatin capsule is in the form of a Soft 68. The oral dosage form of claim 67, wherein the gelatin capsule, and wherein the controlled release core is in oxy-Substituted alkyl group of Ro is a hydroxy Substitution the form of a liquid, tablet, or capsule. or a Substitution comprising at least one acyl moiety. 87. The oral dosage form of claim 1, further comprising 69. The oral dosage form of claim 68, wherein Ro at least one of the following: pharmaceutically acceptable comprises at least one oligomer of oxy-Substituted carboxy Salt, excipient, carrier, diluent, adjuvant, dispersing agent, lic acids, wherein the oxy-Substituted carboxylic acids are Suspending agent, acidifying agent, adsorbent, alkalizing linked by an ester bond between (i) the hydroxy group of at agent, anti-adherent, antioxidant, binder, buffering agent, least one acid monomer, and (ii) the carboxy group of colorant, complexing agent, filler, direct compression another acid monomer. excipient, disintegrant, flavorant, fragrance, glidant, lubri 70. The oral dosage form of claim 69, wherein Ro cant, opaquant, plasticizer, polishing agent, preservative, or comprises from about 1 to about 5 lactide or glycolide units. Sweetening agent. 71. The oral dosage form of claim 70, wherein Ro 88. The oral dosage form of claim 87, wherein the comprises a mixture comprising at least one lactide unit and excipient is Explotab(R). at least one glycolide unit. 89. The oral dosage form of claim 83, further comprising 72. The oral dosage form of claim 69, wherein Ro Explotab(R). comprises a mixture comprising at least one lactic acid unit and at least one glycolic acid unit, and wherein the mixture 90. The oral dosage form of claim 84, further comprising does not comprise lactide units or glycolide units. Explotab(R). 73. The oral dosage of claim 63, wherein R, R2, and R. 91. The oral dosage form of claim 85, further comprising of compound II is lactoyl, polylactoyl, e-caproyl, hydroxy Explotab(R). acetyl, polyhydroxyacetyl, polylactoyl, or polyhydroxy 92. The oral dosage form of claim 86, further comprising acetyl. Explotab(R). 74. The oral dosage of claim 63, wherein R, R, and R. 93. A method of making an oral dosage form comprising: of compound III is lactoyl, polylactoyl, e-caproyl, hydroxy acetyl, polyhydroxyacetyl, polylactoyl, or polyhydroxy (i) preparing a controlled release core, wherein the con acetyl. trolled released core comprises at least one therapeu 75. The oral dosage form of claim 1, wherein at least one tically active agent and at least one controlled release controlled release material comprises Sucrose acetate isobu material; and tyrate (SAIB). (ii) an immediate release gelatin capsule around the 76. The oral dosage form of claim 2, wherein at least one controlled release core, wherein the immediate release controlled release material comprises Sucrose acetate isobu gelatin capsule coating comprises at least one thera tyrate (SAIB). peutically active agent. US 2004/0224020 A1 Nov. 11, 2004 34

94. The method of claim 93, wherein the oral dosage form (a) a controlled release core; and comprises the same therapeutically active agent in both the controlled release core and the immediate release gelatin (b) an immediate release gelatin capsule coating around capsule. the controlled release core; 95. A method of Selectively enhancing analgesic potency wherein the controlled released core comprises at least of an opioid agonist or attenuating an adverse side effect of one opioid agonist, at least one opioid antagonist, and the opioid agonist in a human Subject comprising: at least one controlled release material; (i) administering to the human Subject an oral dosage wherein the immediate release gelatin capsule comprises form comprising: at least one opioid agonist, and wherein the antagonist (a) a controlled release core; and enhances the analgesic potency of the opioid agonist or attenuates an adverse side effect of the agonist in the (b) an immediate release gelatin capsule around the human Subject. controlled release core; 100. The method of claim 99, wherein the opioid agonist wherein the controlled released core comprises at least in the controlled release core comprises oxycodone, wherein one opioid agonist and at least one controlled release the opioid antagonist in the controlled release core com material; prises naltrexone, and wherein the opioid agonist in the immediate release gelatin capsule comprises oxycodone. wherein the immediate release gelatin capsule coating comprises at least one opioid antagonist, and wherein 101. A method of Selectively enhancing analgesic potency the antagonist enhances the analgesic potency of the of an opioid agonist or attenuating an adverse side effect of opioid agonist or attenuates an adverse side effect of the the opioid agonist in a human Subject comprising: agonist in the human Subject. (i) administering to the human Subject an oral dosage 96. The method of claim 95, wherein the opioid agonist form comprising: comprises oxycodone and the antagonist comprises naltrex Oc. (a) a controlled release core; and 97. A method of Selectively enhancing analgesic potency (b) an immediate release gelatin capsule around the of an opioid agonist or attenuating an adverse side effect of the opioid agonist in a human Subject comprising: controlled release core; wherein the controlled released core comprises at least (i) administering to the human Subject an oral dosage one opioid agonist, at least one opioid antagonist, and form comprising: at least one controlled release material; (a) a controlled release core; and wherein the immediate release gelatin capsule comprises (b) an immediate release gelatin capsule around the at least one opioid agonist and at least one opioid controlled release core; antagonist, and wherein the antagonist enhances the analgesic potency of the opioid agonist or attenuates an wherein the controlled released core comprises at least adverse side effect of the agonist in the human Subject. one opioid agonist and at least one controlled release 102. The method of claim 101, wherein the opioid agonist material; in the controlled release core comprises oxycodone, wherein wherein the immediate release gelatin capsule comprises the opioid antagonist in the controlled release core com at least one opioid agonist and at least one opioid prises naltrexone, wherein the opioid agonist in the imme antagonist, and wherein the antagonist enhances the diate release gelatin capsule comprises oxycodone, and analgesic potency of the opioid agonist or attenuates an wherein the opioid antagonist in the immediate release adverse side effect of the agonist in the human Subject. gelatin capsule comprises naltrexone. 98. The method of claim 97, wherein the opioid agonist in 103. The oral dosage form of any of the claims 1-92, the controlled release core comprises oxycodone, wherein wherein the controlled release core further comprises at least the opioid agonist in the immediate release gelatin capsule one immediate release component comprising at least one comprises oxycodone, and wherein the opioid antagonist in therapeutically active agent. the immediate release gelatin capsule comprises naltrexone. 104. The oral dose form of any of claims 1-92 and 103 99. A method of Selectively enhancing analgesic potency wherein the controlled released core is an inner controlled of an opioid agonist or attenuating an adverse side effect of released core, and wherein the immediate release gelatin the opioid agonist in a human Subject comprising: capsule is an Outer immediate release gelatin capsule. (i) administering to the human Subject an oral dosage form comprising: