111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20040224020Al
`
`(19) United States
`(12) Patent Application Publication
`Schoenhard
`
`(10) Pub. No.: US 2004/0224020 A1
`Nov. 11, 2004
`(43) Pub. Date:
`
`(54) ORAL DOSAGE FORMS WITH
`THERAPEUTICALLY ACTIVE AGENTS IN
`CONTROLLED RELEASE CORES AND
`IMMEDIATE RELEASE GELATIN CAPSULE
`COATS
`
`(76)
`
`Inventor: Grant L. Schoenhard, San Carlos, CA
`(US)
`
`Correspondence Address:
`Janet M. McNicholas
`McAndrews, Held & Malloy, Ltd.
`34th Floor
`500 W. Madison Street
`Chicago, IL 60661 (US)
`
`(21)
`
`Appl. No.:
`
`10/742,672
`
`(22)
`
`Filed:
`
`Dec. 18, 2003
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 60/434,839, filed on Dec.
`18, 2002.
`
`Publication Classification
`
`Int. Cl? ....................................................... A61K 9/24
`(51)
`(52) U.S. Cl. .............................................................. 424/471
`
`(57)
`
`ABSTRACT
`
`The present invention relates to oral dosage form with active
`agents in controlled release cores and in immediate release
`gelatin capsule coats.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1011, Pg. 1 of 38
`
`

`

`Patent Application Publication Nov. 11, 2004 Sheet 1 of 3
`
`US 2004/0224020 Al
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`Petitioner - Catalent Pharma Solutions
`Ex. 1011, Pg. 2 of 38
`
`

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`Patent Application Publication Nov. 11, 2004 Sheet 2 of 3
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`Petitioner - Catalent Pharma Solutions
`Ex. 1011, Pg. 3 of 38
`
`

`

`Patent Application Publication Nov. 11, 2004 Sheet 3 of 3
`
`US 2004/0224020 Al
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`Petitioner - Catalent Pharma Solutions
`Ex. 1011, Pg. 4 of 38
`
`

`

`US 2004/0224020 Al
`
`Nov. 11, 2004
`
`1
`
`ORAL DOSAGE FORMS WITH
`THERAPEUTICALLY ACTIVE AGENTS IN
`CONTROLLED RELEASE CORES AND
`IMMEDIATE RELEASE GELATIN CAPSULE
`COATS
`
`CROSS REFERENCED APPLICATIONS
`
`[0001] None applicable.
`
`BACKGROUND OF THE INVENTION
`
`[0002] The maximum time of effectiveness of many oral
`dosage forms is only a few hours. While it is often desirable
`to reach an effective dose quickly, in order to maximize
`patient compliance, it is also considered desirable to reduce
`the frequency of dosing, thereby reducing the number of
`doses a patient must take in order to attain effective therapy.
`In the case of combination therapy where two drugs may be
`given in the same dosage form (e.g., tablets, capsules, etc.),
`the frequency of dosing is further reduced.
`
`[0003] For any given dosage form of an agent, such as a
`drug, the amount of the agent from the dosage form that is
`available to reach the circulation system depends first on the
`rate and extent of release from the dosage form. Following
`oral administration, drug or prodrug is released from the
`dosage form containing the drug or prodrug in the gas(cid:173)
`trointestinal ( GI) tract and free drug is absorbed. The extent
`of release determines the amount of drug available for
`absorption. The rate of release gives the amount of drug
`available for absorption per unit time. Drug dosage forms
`that rapidly release the drug into the GI tract are termed
`immediate release or IR formulations. The time, tmax to
`reach to maximum plasma concentrations (CmaJ of the drug
`in the body ranges from a few minutes to two plus hours for
`such immediate release formulations. During the absorption
`phase, the drug is distributing throughout the body, and in
`most cases are beginning and/or simultaneously being elimi(cid:173)
`nated from the body. Thus, the pharmacokinetic profile (the
`graph of drug in blood or plasma concentration vs. time) for
`repeated administration of immediate release formulations
`cycle from minimum or trough plasma concentrations cmin
`to peak plasma concentrations, cmax and back to minimum
`or trough plasma concentrations, C~in·
`[0004] To achieve sustained concentration of circulating
`drug or active metabolite(s) or conjugate(s) of drug over a
`longer period of time between doses, controlled release
`(alternative constant release (SR) or extended release) drug
`formulations were developed. These controlled release (CR)
`formulations require approximately from 2 to 3 hours to
`achieve cmax and the minimum effective concentration
`(MEC) of drug in the circulation, and can maintain MEC
`levels from about 12 to about 22 hours before declining
`exponentially because no more drug is being released from
`the dosage form and systematically absorbed. Thus, the
`pharmacokinetic profile of controlled release formulations
`have a shape similar to a hyperbole, with a slow and gradual
`increase in drug blood levels to a plateau, followed by a
`decline in plasma concentrations.
`
`[0005] When comparing the pharmacokinetic profiles of
`immediate release with controlled release drug formulations,
`there are two major differences. First, the time to achieve the
`cmax in the plasma is often longer in the controlled release
`versus the immediate release formulation. In controlled
`
`released formulations, a long tmax is particularly disadvan(cid:173)
`tageous to patients seeking urgent treatment and to maintain
`MEC levels. A second difference in the pharmacokinetic
`profiles of controlled release in comparison to immediate
`release drug formulations is that the duration of sustained
`plasma levels is longer in the controlled release formula(cid:173)
`tions. The longer duration of such sustained plasma levels
`facilitated by controlled release formulations are advanta(cid:173)
`geous to all patients, prolonging the desired biological
`effect. Therefore, although the controlled release formula(cid:173)
`tion facilitates a substantially longer period of time in
`maintaining plasma levels of drug or active metabolite(s), it
`suffers from the drawback of requiring longer periods of
`time to achieve the cmax• when compared to immediate
`release formulations. Thus, there remains a long felt need for
`improved controlled release formulations, including dosage
`formulations that might have one or more desirable charac(cid:173)
`teristics of both immediate release and controlled release
`formulations.
`
`SUMMARY OF THE INVENTION
`[0006] The present invention is directed to novel oral
`dosage forms with therapeutically active agents in both
`controlled release cores and immediate release gelatin cap(cid:173)
`sule coats. The agents have different release profiles from
`the cores and gelatin capsule coats. The controlled release
`cores optionally comprise additional components for the
`immediate release of a portion of therapeutically active
`agent from the core. Such gelatin capsule encapsulated
`controlled release oral dosage forms constitute improved
`controlled release dosage forms and achieve a rate of release
`and an extent of release not previously achieved by either
`immediate release or controlled release dosage forms of
`therapeutically active agent(s). Soft gelatin capsules, such as
`softgels, with at least one therapeutically active agent are
`preferred for encapsulating the cores. The invention further
`relates to pharmaceutical formulations useful in the prep a(cid:173)
`ration of such dosage forms, as well as to methods of making
`and administering such dosage forms. Gelatin capsule
`encapsulated controlled release cores of at least one thera(cid:173)
`peutically active agent, including liquid, tablet, or solid
`cores, wherein the gelatin capsule encapsulating such con(cid:173)
`trolled release core comprises an immediate release formu(cid:173)
`lation of at least one therapeutically active agent are
`improved dosage forms with surprising advantages. Such
`gelatin capsule encapsulating wherein the gelatin capsule
`contains at least one therapeutically active agent, enables the
`increase of the rate of release of the therapeutically active
`agent(s) from oral dosage forms of the invention and/or
`increases the apparent extent of exposure to sustained blood/
`plasma concentrations of the agent(s) and/or metabolites or
`conjugates of such agent(s), as well as the related pharma(cid:173)
`codynamic response, for example, when at least one of the
`therapeutically active agents is the same in the gelatin
`capsule coating and in the core.
`
`[0007] Novel oral dosage forms according to the invention
`comprise (i) an controlled release core, and (ii) an immediate
`release gelatin capsule around the controlled release core,
`wherein the controlled released core comprises at least one
`therapeutically active agent and at least one controlled
`release material, and wherein the immediate release gelatin
`capsule comprises at least one therapeutically active agent.
`Such oral dosage forms have at least one therapeutically
`active agent in the controlled release core that is the same as
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1011, Pg. 5 of 38
`
`

`

`US 2004/0224020 Al
`
`Nov. 11, 2004
`
`2
`
`or different from at least one therapeutically active agent in
`the immediate release gelatin capsule. Preferred dosage
`forms according to the invention have the same therapeuti(cid:173)
`cally active agent in both the core and the immediate release
`gelatin capsule and optionally may have other agents in
`either or both of the core and gelatin capsule. Such gelatin
`capsule encapsulated controlled release dosage forms as
`described herein, achieve an increased rate of release of the
`therapeutically active agent via the immediate release gela(cid:173)
`tin capsule and an increased extent of duration of exposure
`to stable blood/plasma concentration of the therapeutically
`active agent(s) and/or active metabolite(s) or conjugate(s)
`via the combination of the release of active agents from the
`immediate release gelatin capsule and the controlled release
`core, with initial and repeated administration of the dosage
`form. Following repeated administration to a subject, dosage
`forms according to the invention provide immediate and
`continual release of active agent(s), such as a drug, for
`absorption by distribution of and elimination from the
`subject, and can maintain the desired pharmacokinetic and/
`or pharmacodynamic profiles. Optionally, the controlled
`release core with at least one therapeutically active agent
`and at least one controlled release material, can further
`comprise immediate release components having at least one
`therapeutically active agent, wherein, for example, the com(cid:173)
`ponents are in the form of a liquid, granulate, particulate,
`pellet, or bead. Preferably, at least one agent in the imme(cid:173)
`diate release components of the core is the same as at least
`one agent in the controlled release components of the core
`and/or in the immediate release gelatin capsule coat.
`[0008] The present invention provides novel oral dosage
`forms with unexpectedly superior results using a liquid
`(including, for example, a high viscosity liquid) or solid
`(including, for example, a granulate, particulate, pellet or
`bead) controlled release formulation with at least one thera(cid:173)
`peutically active agent and at least one controlled release
`material as a controlled release core. Thus, the core may be,
`for example, a liquid, tablet or capsule. This core is coated
`by encapsulating such core with an gelatin capsule, prefer(cid:173)
`ably a soft gelatin capsule, that also contains at least one
`therapeutically active agent as an immediate release formu(cid:173)
`lation. Preferably, at least one therapeutically active agent
`that is in the core as a controlled release formulation is the
`same agent that is in the immediate release gelatin capsule
`coating as an immediate release formulation. A multiplicity
`of controlled release materials are known and useful accord(cid:173)
`ing to the invention, including, for example, high viscosity
`liquid carrier materials (HVLCM) as described herein and in
`U.S. Pat. Nos. 5,747,058; 5,968,542; 6,413,536; and corre(cid:173)
`sponding PCT publications WO 96/39995; WO 99/13913;
`WO 01!15734, such as, for example, sucrose acetate isobu(cid:173)
`tyrate (SAlE).
`[0009] Therapeutically active agents suitable for dosage
`forms of the invention include biologically active substances
`that are useful for human therapy, veterinary therapy, or for
`agricultural purposes. Therapeutically active agents include
`organic molecules, for example, drugs. Drugs include sub(cid:173)
`stances used as medicines for the treatment (e.g., prophy(cid:173)
`lactic or therapeutic), cure or prevention of a disease,
`condition or disorder. Drugs include prodrugs. Among the
`preferred therapeutically active agents suitable for dosage
`forms according to the invention are analgesics, including
`opioids. Among the particularly preferred therapeutically
`active agents suitable for such dosage forms are opioid
`
`agonists, alone or in combination with opioid antagonists.
`The present invention thus provides controlled release phar(cid:173)
`maceutical formulations in the form of a liquid, tablet, or
`capsule as a controlled release core, wherein the core
`comprises one or more therapeutically active agents and one
`or more controlled release materials. Optionally, the core
`additionally comprises one or more therapeutically active
`agents and one or more immediate release components.
`Preferably, at least one active agent is in both a controlled
`release and an immediate release form in such a core. A core
`is then encapsulated with an immediate release gelatin
`capsule comprising immediate release pharmaceutical for(cid:173)
`mulations of one or more therapeutically active agents. The
`effect of such novel dosage forms is to increase the rate of
`release of the therapeutically active agent(s) from the dosage
`form via the immediate release gelatin capsule coating
`comprising the
`therapeutically active agent(s), and to
`increase the apparent extent of exposure to sustained blood/
`the
`therapeutically active
`plasma concentration(s) of
`agent(s) or active metabolic or conjugate thereof, from the
`dosage form (via both the immediate release gelatin capsule
`coating and the controlled release core each comprising
`therapeutically active agent(s). The combination of gelatin
`capsule coating and controlled release core (with or without
`additional immediate release components in the core)
`achieves the increased rate and extent/duration of release
`with initial and repeated administration of the dosage form
`as well as the related pharmacodynamic response. Such
`dosage forms according to the invention are administrable at
`least every 8 hours and preferably administrable once-a-day
`(every 24 hours) or twice daily (every 12 hours). A preferred
`dosage form according to the invention comprises (i) a
`controlled release core that has an opioid agonist, such as,
`for example, oxycodone or morphine, as a therapeutically
`active agent, alone or in combination with an opioid antago(cid:173)
`nist, such as, for example, naltrexone or nalmefene, and a
`controlled release material, such as, for example, SAlE, and
`(ii) an immediate release gelatin capsule, including a soft
`gelatin capsule, for example, such as softgels, enteric soft(cid:173)
`gels, or gelcaps, that has an opioid agonist, for example,
`such as oxycodone or morphine, as a therapeutically active
`agent, alone or in combination with an opioid antagonist, for
`example, such as naltrexone or nalmefene. Preferred manu(cid:173)
`facturers of gelatin capsules containing no active agent in
`the gelatin capsule are Banner Pharmacaps (see, e.g., their
`Softgel, Gelatin Binary System ™, and Sofiet™ Gelcap
`products) and Cardinal (see, e.g., their LIQUI-GELS®, RP
`SCHERERSOL®, and PULSIN-CAP® technology and
`products). Novel gelatin capsules may be prepared accord(cid:173)
`ing to the invention by incorporating at least one therapeu(cid:173)
`tically active agent in a gelatin formulation that is used to
`encapsulate an core according to the invention.
`
`DESCRIPTION OF THE FIGURES
`[0010] The detailed description of the invention will be
`made with reference to the accompanying drawing, where
`like numerals designate corresponding parts of the figures.
`The drawings are meant to be generally illustrative of
`various examples of the present invention, but are merely
`example and are not meant to be limiting the scope of the
`invention.
`[0011] FIG. 1 is a release profile of a traditional controlled
`release formulation or dosage form of therapeutically active
`agent.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1011, Pg. 6 of 38
`
`

`

`US 2004/0224020 Al
`
`Nov. 11, 2004
`
`3
`
`[0012] FIG. 2 is a release profile of a formulation or
`dosage form according to the present invention, illustrating
`an increased rate of release and an increased apparent extent
`of exposure to sustained blood/plasma concentrations of
`therapeutically active agent as compared with a traditional
`controlled formulation/dosage form.
`
`[0013] FIG. 3 is the chemical structure of SAIB, sucrose
`acetate isobutyrate.
`
`DETAILED DESCRIPTION OF 1HE
`INVENTION
`
`[0014] The present invention generally relates to an oral
`dosage form comprising (i) a controlled release core; and (ii)
`an immediate release gelatin capsule that encapsulates con(cid:173)
`trolled release core, wherein the controlled released core
`comprises at least one therapeutically active agent and at
`least one controlled release material, and wherein the imme(cid:173)
`diate release gelatin capsule comprises at least one thera(cid:173)
`peutically active agent. Such novel oral dosage forms rep(cid:173)
`resent improved controlled release dosage forms. The
`dosage forms and formulations presented herein achieve an
`increased rate of release of the therapeutically active agent
`and an increased apparent extent of exposure to sustained
`blood/plasma concentrations of the therapeutically active
`agent and/or its active metabolite(s) and/or conjugates via
`the combination of the immediate release gelatin capsule
`and the controlled release core with initial and repeated
`administration of the dosage form. Optionally, the controlled
`release core can also contain an immediate release compo(cid:173)
`nents in the form of, for example, liquids, granulates,
`particulates, pellets, beads, etc.) also comprising a therapeu(cid:173)
`tically active agent. Preferably, at least one therapeutically
`active agent is the same as in the controlled release core
`and/or the immediate release gelatin capsule.
`
`[0015] The release profile of traditional controlled release
`formulations or dosage forms, as shown in FIG. 1, generally
`have a shape similar to a hyperbole, with a slow and gradual
`increase in blood/plasma levels of an active agent such as a
`drug, to a plateau, followed by a decline in blood/plasma
`concentrations. In contrast, FIG. 2 show the release profile
`of a formulation or dosage form according to the present
`invention with active agent in both controlled release core
`and immediate release gelatin capsule illustrating a rapid
`and increased rate of release of active agent, as well as an
`increased apparent extent of exposure to sustained blood/
`plasma concentrations of the active agent or active metabo(cid:173)
`lite(s) thereof from initial and repeated administration of the
`dosage form. Such increased rate and extent of release and
`exposure results in an increase in the related pharmacody(cid:173)
`namic response.
`
`[0016] The invention provides surprisingly and unexpect(cid:173)
`edly superior results using a liquid semi-solid or solid
`(including, without limitation, particulates, granules, or
`beads) controlled release formulation with at least one
`therapeutically active agent as an core that is coated with an
`gelatin capsule by encapsulating wherein the gelatin capsule
`also contains at least one therapeutically active agent as an
`immediate release formulation. Preferably, at least one
`therapeutically active agent present in the core as a con(cid:173)
`trolled release formulation is the same as at least one
`therapeutically active agent present in the immediate release
`gelatin capsule coating as an immediate release formulation.
`
`Optionally, the core can additionally contain a portion of
`immediate release components, in the form of, for example,
`liquids, granulates, pellets, or beads, each comprising at
`least one therapeutically active agent. Again, preferably the
`immediate release component of the controlled release core
`comprises at least one therapeutic agent that is the same as
`the agent in the controlled release portion of the core and/or
`the same as the agent in one gelatin component.
`[0017] The invention provides liquids or liquid gels of
`varying viscosity, as well as tablets or capsules that comprise
`an controlled release core with at least one controlled release
`material and at least one therapeutically active agent,
`wherein the liquid, tablet, or capsule core is coated by an
`gelatin capsule. The gelatin capsule encapsulates the core.
`Encapsulating includes coating, covering, encasing, enrob(cid:173)
`ing, enveloping and capsuleing. This immediate release
`gelatin capsule comprises an immediate release formulation
`of at least one therapeutically active agent, preferably the
`same therapeutically active agent that is in the controlled
`release core. The invention thus provides an controlled
`release core comprising a therapeutically active agent in the
`form of a liquid, tablet, or capsule that is encapsulated with
`an immediate release gelatin capsule coating of the same
`therapeutically active agent, so as to provide an initial rapid
`increased rate of release of the agent. Dosage forms accord(cid:173)
`ing to the invention can be administered at least every 8
`hours and preferably administered one-a day (every 24
`hours) or twice daily (every 12 hours).
`[0018] Gelatin capsules include soft gelatin capsules or
`hard gelatin capsules. A soft gelatin capsule is often a one
`piece hermetically or similarly effectively sealed capsule
`composed essentially of gelatin which may be plasticized or
`which may contain other gelatinous material that retains
`plasticity without becoming brittle. For example, a soft
`gelatin capsule can be transparent and colorless or pale
`yellow. Additionally or alternatively, for example, a soft
`gelatin capsule may have a colorant added. A hard gelatin
`capsule is often a two piece (cap and body) capsule shell
`composed of gelatin or other gelatinous material with the
`appearance of having been or chemically plasticized to the
`extent of retaining in the unfilled or filled condition a
`specified shape with a near brittle or brittle physical prop(cid:173)
`erty. For example, a hard gelatin capsule can be opaque
`and/or a colorant can be added. A hard gelatin capsule is
`formed and filled in separation operations. The gelatin
`capsule fill may be a liquid, semisolid, or solid.
`
`[0019] Controlled release or sustained release refers to
`formulation that provides a longer period of pharmacologi(cid:173)
`cal response after the administration of a therapeutically
`active agent that is ordinarily provided after the administra(cid:173)
`tion of the immediate release or rapid release formulation of
`that agent. Controlled release or sustained release formula(cid:173)
`tion which allow the release of a therapeutically active agent
`or agents in blood levels within a desired therapeutic range
`and maintains such levels over an extended period of time,
`such as from at least about 8 hours, such as from about 12
`hours to about 24 hours. Controlled release formulations
`generally contain a controlled release material in order to
`achieve the controlled or sustained release of the desired
`agent. A controlled release material can include a continuous
`matrix, such as an insoluble polymeric matrix or a high
`viscosity (e.g. non-polymeric) liquid material, wherein a
`therapeutically active agent is dispersed within and is sub-
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1011, Pg. 7 of 38
`
`

`

`US 2004/0224020 Al
`
`Nov. 11, 2004
`
`4
`
`sequently released typically by a diffusion-like process of
`the liquid material, therapeutically active agent through the
`continuous matrix. Controlled release formulations can also
`refer to a dosage form comprising a therapeutically active
`agent that is coated with a controlled release material, so as
`to permit release of the therapeutically active agent at a
`sustained rate in an aqueous medium. The controlled release
`may be a sustained release or delayed/modified release. A
`controlled-release dosage form as defined in US Pharma(cid:173)
`copeia XXII includes extended release dosage forms which
`allow at least a twofold reduction in dosing frequency as
`compared to the drug presented as a conventional dosage
`from and delayed release dosage forms which release the
`drug at a time other than promptly after administration.
`
`[0020]
`Immediate release generally refers to formulations
`that allow the release of a therapeutically active agent or
`agents in blood levels within a desired therapeutic range in
`a rapid period of time, such as, for example, from about 5
`minutes to about 20 minutes. An immediate release formu(cid:173)
`lation can include soluble components, for example, sugars,
`polymers, surfactants, coatings and other components as
`described herein.
`
`[0021] Therapeutically active agent refers to a substance,
`including a biologically active substance that is useful for
`human therapy, veterinary therapy, or for agricultural pur(cid:173)
`poses. Therapy includes prophylactic and therapeutic treat(cid:173)
`ment. Therapeutically active agents include organic mol(cid:173)
`ecules that are drugs, peptides, proteins, carbohydrates,
`monosaccharides, oligosaccharides, polysaccharides, nucle(cid:173)
`oprotein, mucoprotein, lipoprotein, synthetic polypeptide or
`protein, small molecules linked to a protein, glycoprotein,
`steroid, nucleic acid, DNA, eDNA, RNA, nucleotide,
`nucleoside, oligonucleotides, antisense oligonucleotides,
`gene, lipid, hormone, and vitamin. Drugs include any sub(cid:173)
`stance used as a medicine for the treatment, cure, or pre(cid:173)
`vention of a disease, condition, or disorder. Non-limiting
`examples of therapeutically active agents include antihista(cid:173)
`mines, analgesics, anti-inflammatory agents, gastro-intesti(cid:173)
`nals, anti-emetics, anti-epileptics, vasodilators, anti-tussive
`agents, expectorants, anti-asthmatics, anti-spasmodics, hor(cid:173)
`mones, diuretics, anti-hypertensives, bronchodilators, anti(cid:173)
`inflammatory steroids, antivirals, antibiotics, antihemor(cid:173)
`rhoidals,
`hypnotics,
`psychotropics,
`antidiarrheals,
`mucolytics, sedatives, decongestants, laxatives, antacids,
`vitamins, stimulants, and opioids. Among the preferred
`therapeutically active agents are analgesics, including apia(cid:173)
`ids. A therapeutically active agent includes a first agent that
`increases the effectiveness of a second agent, for example,
`by enhancing potency or reducing an adverse effect(s) of the
`second agent. A therapeutically active agent includes an
`agent that increases an effect of, acts synergistically with,
`and/or promotes, potentiates, or enhances an effect of
`another agent. Such therapeutically active agents are bio(cid:173)
`logically active substances in accordance with the invention.
`The effect that is increased, promoted, potentiated or
`enhanced may be, for example, an analgesic effect and the
`therapeutically active agent may potentiate the analgesic
`effect of a different therapeutically active agent.
`
`[0022] Opioids
`include compounds or compositions
`including metabolites as well as conjugates, such as by
`glucoronidation, sulfation, or acetylation of such com(cid:173)
`pounds or compositions which bind to specific opioid recep(cid:173)
`tors and have agonist (activation) or antagonist (inactiva-
`
`tion) effects at these receptors, such as opioid alkaloids,
`including the agonist morphine as well as morphine-6-
`glucuronide, oxycodone as well as oxymorphone and
`noroxycodone, and
`the antagonist naltrexone and
`its
`metabolite, and such as opioid peptides, including enkepha(cid:173)
`lins, dynorphins and endorphins. Opioid receptor agonists or
`opioid agonists are opioid compounds or compositions
`including any active metabolite as well as conjugates, such
`as by glucoronidation, sulfation, or acetylation of such
`compound or composition that binds to and activates opioid
`receptors on nociceptive neurons which mediate pain. Such
`opioid agonists have analgesic activity (with measurable
`onset, peak, duration and/or total effect and can produce
`analgesia). Opioid antagonists refer to opioid compounds or
`compositions including any active metabolite as well as
`conjugates, such as by glucoronidation, sulfation, or acety(cid:173)
`lation of such compound or composition that in a sufficient
`amount attenuates (e.g., antagonizes, blocks, inhibits, pre(cid:173)
`vents or competes with) the action of an opioid agonist.
`[0023] The controlled release core of the present invention
`is coated with an immediate release gelatin capsule coating
`using any of the many gelatin capsule coating processes,
`such as spray coating, wet gelatin bath dipping, encapsulat(cid:173)
`ing, and vacuum holding, for instance. The process of
`coating an core where the core is, for example, a liquid,
`tablet, or capsule, with an gelatin coating is also referred to
`as encasing, enrobing, or encapsulating.
`[0024] The controlled release core can be in the form of a
`tablet that is enrobed with the immediate release gelatin
`capsule coating, wherein the tablet core and the gelatin
`capsule coating each contain at least one therapeutically
`active agent, and wherein the immediate release gelatin
`capsule coating is formed by application of respective layers
`of elastic gelatin film with the agent to opposite sides of the
`tablet. This enrobing process without the agent is described,
`for example, in U.S. Pat. No. 5,146,730, the disclosure of
`which is incorporated herein by reference. In this process,
`the applied gelatin layer conforms tightly to the table
`surface, bonds securely thereto, and the layers are sealed
`together edge-to-edge at a seal line which extends around
`the tablet.
`[0025] The controlled release core can be in the form of a
`tablet that is enrobed between two sealable gelatin films of
`the immediate release gelatin capsule coating with the agent
`according to the invention. An enrobing process without the
`agent is described, for example, in U.S. Pat. No. 6,482,516,
`the disclosure of which is incorporated herein by reference.
`U.S. Pat. No. 6,482,516 describes an enrobement process
`which uses coacting die techniques wherein tablets or other
`articles to be enrobed are introduced individually between
`two sealable gelatin films.
`[0026] The controlled release core can be in the form of a
`liquid comprising insoluble particles. This liquid core is
`encapsulated within the immediate release gelatin capsule
`with the agent that is in the form of a soft gelatin capsule.
`An encapsulating process without the agent is described, for
`example, in U.S. Pat. No. 5,595,758, the disclosure of which
`is incorporated herein by reference. U.S. Pat. No. 5,595,758
`describes a capsule having a soft, flexible gelatin skin and an
`internal fill which comprises a pharmaceutically acceptable
`liquid carrier which is compatible with the gelatin coating
`and which contains small drug-bearing particles which do
`not dissolve in the liquid.
`
`Petitioner - Catalent Pharma Solutions
`Ex. 1011, Pg. 8 of 38
`
`

`

`US 2004/0224020 Al
`
`Nov. 11, 2004
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`5
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`[0027] The immediate release gelatin capsule coating of
`the present invention comprises at least one therapeutically
`active agent. Processes of preparing gelatin capsules are
`described herein. According to the present invention, pro(cid:173)
`cesses are provided herein to incorporate therapeutically
`active agents, including drugs or other pharmaceutically
`acceptable agents, into immediate release gelatin formula(cid:173)
`tions to encapsulate controlled release cores. Soft gelatin
`capsules (e.g., gel caps) or hard gelatin capsules comprising
`at least one therapeutically active agent are used as the
`immediate release gelatin capsule coat according to the
`invention. Soft gelatin capsules are preferred for incorpo(cid:173)
`rating therapeutically active agent(s) according to the inven(cid:173)
`tion and preferred manufacturers include Banner Phar(cid:173)
`macaps [