TAMPER RESISTANT DOSAGE FORMS
`
`TECHNICAL FIELD OF THE INVENTION
`
`[001] The present invention relates to a tamper resistant dosage form, in
`particular to a tamper resistant dosage form including an opioid analgesic,
`and the corresponding process of manufacture and use thereof in a method of
`treatment.
`
`BACKGROUND OF THE INVENTION
`
`[002] Pharmaceutical products are sometimes the subject of abuse. For
`example, a particular dose of opioid agonist may be more potent when
`administered parenterally as compared to the same dose administered orally.
`Some formulations can be tampered with to provide the opioid agonist
`contained therein for illicit use. Controlled release opioid agonist
`formulations are sometimes crushed, or subject to extraction with solvents
`(e.g., ethanol) by drug abusers to provide the opioid contained therein for
`immediate release upon oral or parenteral administration.
`
`[003] Controlled release opioid agonist dosage forms which can liberate a
`portion of the opioid upon exposure to ethanol, can also result in a patient
`receiving the dose more rapidly than intended if a patient disregards
`instructions for use and concomitantly uses alcohol with the dosage form.
`
`[004] There continues to exist a need in the art for an oral dosage form
`comprising an opioid agonist without significantly changed opioid release
`upon exposure to alcohol and/or with resistance to crushing.
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`OBJECTS AND SUMMARY OF THE INVENTION
`
`[005]
`It is an object of certain embodiments of the present invention to provide
`an oral extended release dosage form comprising an active agent such as an
`opioid analgesic which is tamper resistant.
`
`[006]
`It is an object of certain embodiments of the present invention to provide
`an oral extended release dosage form comprising an active agent such as an
`opioid analgesic which is resistant to crushing.
`
`[007]
`It is an object of certain embodiments of the present invention to provide
`an oral extended release dosage form comprising an active agent such as an
`opioid analgesic which is resistant to alcohol extraction and dose dumping
`when concomitantly used with or exposed to alcohol.
`
`[008]
`In certain embodiments, the present invention is directed to a solid oral
`extended release pharmaceutical dosage form comprising an extended release
`matrix formulation in the form of a tablet or multi particulates, wherein the
`tablet or the individual multi particulates can be at lt,;ast flattened without
`breaking, characterized by a thickness of the tablet or ofthe individual multi
`particulate after the flattening which corresponds to no more than 60 % of the
`thickness of the tablet or the individual multi particulate before flattening,
`and wherein said flattened tablet or the flattened multi particulates provide an
`in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at 100
`rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 3 7° C,
`characterized by the percent amount of active released at 0.5 hours of
`dissolution that deviates no more than 20 % points from the corresponding in-
`vitro dissolution rate of a non-flattened reference tablet or reference multi
`particulates.
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`(009]
`In certain embodiments, the present invention is directed to a solid oral
`extended release pharmaceutical dosage form comprising a extended release
`matrix formulation in the form of a tablet or multi particulates, wherein the
`tablet or the individual multi particulates can at least be flattened without
`breaking, characterized by a thickness of the tablet or the individual multi
`particulate after the flattening which corresponds to no more than 60% of the
`thickness of the tablet or the individual multi particulate before flattening,
`and wherein the flattened or non flattened tablet or the flattened or non
`flattened multi particulates provide an in-vitro dissolution rate, when
`measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated
`gastric fluid without enzymes (SGF) comprising 40% ethanol at 37° C,
`characterized by the percent amount of active released at 0.5 hours of
`dissolution that deviates no more than 20 % points from the corresponding in-
`vitro dissolution rate measured in a USP Apparatus 1 (basket) at 100 rpm in
`900 ml simulated gastric fluid withol;lt enzymes (SGF) at 37° C without
`ethanol, using a flattened and non flattened reference tablet or flattened and
`non flattened reference multi particulates, respectively.
`
`[0010] In certain embodiments, the present invention is directed to a solid oral
`extended release pharmaceutical dosage form comprising an extended release
`matrix formulation, the extended release matrix formulation comprising
`a composition comprising at least:
`(1) at least one polyethylene oxide having, based on rheological
`measurements, an approximate molecular weight of at least 1 ,000,000;
`and
`(2) at least one active agent; and
`wherein the composition comprises at least 80% (by wt) polyethylene oxide.
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`[0011] In certain embodiments, the present invention is directed to a solid oral
`extended release pharmaceutical dosage form comprising an extended release
`matrix formulation, the extended release matrix formulation comprising
`a composition comprising at least:
`(1) at least one active agent;
`(2) at least one polyethylene oxide having, based on rheological
`measurements, an approximate molecular weight of at least 1 ,000,000;
`and
`(3) at least one polyethylene oxide having, based on rheological
`measurements, a molecular weight of less than 1 ,000,000.
`
`[0012] In certain embodiments, the present invention is directed to a method of
`treatment wherein a dosage form according to the invention comprising an
`opioid analgesic is administered for treatment of pain to a patient in need
`thereof.
`
`[0013] In certain embodiments, the present invention is directed to the use of a
`dosage form according to the invention comprising an opioid analgesic for
`the treatment of pain.
`
`[0014] In certain embodiments, the present invention is directed to the use of
`high molecular weight polyethylene oxide that has, based on rheological
`measurements, a molecular weight of at least 1 ,000,000, as matrix forming
`material in the manufacture of a solid extended release oral dosage form
`comprising an active selected from opioids for imparting to the solid
`extended release oral dosage form resistance to alcohol extraction.
`
`[0015] In certain embodiments, the present invention is directed to a process of
`preparing a solid oral extended release pharmaceutical dosage form,
`comprising at least the steps of:
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`(a) combining at least
`(1)
`at least one polyethylene oxide having, based on rheological
`measurements, a molecular weight of at least 1 ,000,000, and
`at least one active agent,
`(2)
`to form a composition;
`(b) shaping the composition to form the extended release matrix
`formulation; and
`(c) curing said extended release matrix formulation comprising at least a
`curing step of subjecting the extended release matrix formulation to a
`temperature which is at least the softening temperature of said
`polyethylene oxide for a time period of at least 5 minutes.
`
`[0016] The term "extended release" is defined for purposes of the present
`invention as to refer to products which are formulated to make the drug
`available over an extended period after ingestion thereby allowing a reduction
`in dosing frequency compared to a drug presented as a conventional dosage
`form (e.g. as a solution or an immediate release dosage form).
`
`[0017] The term "immediate release" is defined for the purposes of the present
`invention as to refer to products which are formulated to allow the drug to
`dissolve in the gastrointestinal contents with no intention of delaying or
`prolonging the dissolution of absorption of the drug.
`
`[0018] The term "solid oral extended release pharmaceutical dosage form" refers
`to the administration form comprising a unit dose of active agent in extended
`release form such as in form of a "extended release matrix formulation" and
`optionally other adjuvants and additives conventional in the art, such as a
`protective coating or a capsule and the like, and optionally any other
`additional features or components that are used in the dosage form. Unless
`specifically indicated the term "solid oral extended release pharmaceutical
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`dosage form" refers to said dosage form in intact form i.e. prior to any
`tampering. The extended release pharmaceutical dosage form can e.g. be a
`tablet comprising the extended release matrix formulation or a capsule
`comprising the extended release matrix formulation in the form of multi
`particulates.
`
`[0019] The term "extended release matrix formulation" is defined for purposes of
`the present invention as shaped solid form of a composition comprising at
`least one active agent and at least one extended release feature such as an
`extended release matrix material such as e.g. high molecular weight
`polyethylene oxide. The composition can optionally comprise more than
`these two compounds namely further active agents and high molecular weight
`polyethylene oxides and/or other materials, including but not limited to low
`molecular weight polyethylene oxides and other adjuvants and additives
`conventional in the art.
`
`[0020] The term "polyethylene oxide" is defined for purposes of the present
`invention as having a molecular weight of at least 25,000, measured as is
`conventional in the art, and preferably having a molecular weight of at least
`100,000. Compositions with lower molecular weight are usually referred to as
`polyethylene glycols.
`
`[0021] The term "high molecular weight polyethylene oxide" is defined for
`proposes of the present invention as having an approximate molecular weight
`of at least 1 ,000,000. For the purpose of this invention the approximate
`molecular weight is based on rheological measurements. Polyethylene oxide
`is considered to have an approximate molecular weight of 1,000,000 when a
`2% (by wt) aqueous solution of said polyethylene oxide using a Brookfield
`viscometer Model RVF, spindle No. 1, at 10 rpm, at 25°C shows a viscosity
`range of 400 to 800 mPa s (cP). Polyethylene oxide is considered to have an
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`approximate molecular weight of2,000,000 when a 2% (by wt) aqueous
`solution of said polyethylene oxide using a Brookfield viscometer Model
`RVF, spindle No.3, at 10 rpm, at 25°C shows a viscosity range of2000 to
`4000 mPa s ( cP). Polyethylene oxide is considered to have an approximate
`molecular weight of 4,000,000 when a 1% (by wt) aqueous solution of said
`polyethylene oxide using a Brookfield viscometer Model RVF, spindle No.2,
`at 2 rpm, at 25°C shows a viscosity range of 1650 to 5500 mPa s (cP).
`Polyethylene oxide is considered to have an approximate molecular weight of
`5,000,000 when a 1% (by wt) aqueous solution of said polyethylene oxide
`using a Brookfield viscometer Model RVF, spindle No.2, at 2 rpm, at 25°C
`shows a viscosity range of5500 to 7500 mPa s (cP). Polyethylene oxide is
`considered to have an approximate molecular weight of 7,000,000 when a 1%
`(by wt) aqueous solution of said polyethylene oxide using a Brookfield
`viscometer Model RVF, spindle No.2, at 2 rpm, at 25°C shows a viscosity
`range of7500 to 10,000 mPa s (cP). Polyethylene oxide is considered to have
`an approximate molecular weight of 8,000,000 when a 1% (by wt) aqueous
`solution of said polyethylene oxide using a Brookfield viscometer Model
`RVF, spindle No.2, at 2 rpm, at 25°C shows a viscosity range of 10,000 to
`15,000 mPa s ( cP). Regarding the lower molecular weight polyethylene
`oxides; Polyethylene oxide is considered to have an approximate molecular
`weight of 100,000 when a 5% (by wt) aqueous solution of said polyethylene
`oxide using a Brookfield viscometer Model RVT, spindle No. 1, at 50 rpm, at
`25°C shows a viscosity range of 30 to 50 mPa s ( cP) and polyethylene oxide
`is considered to have an approximate molecular weight of 900,000 when a
`5% (by wt) aqueous solution of said polyethylene oxide using a Brookfield
`viscometer Model RVF, spindle No.2, at 2 rpm, at 25°C shows a viscosity
`range of 8800 to 17,600 mPa s (cP).
`
`[0022] The term "low molecular weight polyethylene oxide" is defined for
`proposes of the present invention as having, based on the rheological
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`measurements outlined above, an approximate molecular weight of less than
`1,000,000.
`
`[0023] The term "direct compression" is defined for purposes of the present
`invention as referring to a tableting process wherein the tablet or any other
`compressed dosage form is made by a process comprising the steps of dry
`blending the compounds and compressing the dry blend to form the dosage
`form, e.g. by using a diffusion blend and/or convection mixing process (e.g.
`Guidance for Industry, SUPAC-IR/MR: Immediate Release and Modified
`Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum).
`
`[0024] The term "bed of free flowing tablets" is defined for the purposes of the
`present invention as referring to a batch of tablets that are kept in motion with
`respect to each other as e.g. in a coating pan set at a suitable rotation speed or
`in a fluidized bed of tablets. The bed of free flowing tablets prevents the
`tablets substantially from potential sticking to each other.
`
`[0025] The term "flattening" and related terms as used in the context of
`flattening tablets or other dosage forms in accordance with the present
`invention means that a tablet is subjected to force applied from a direction
`substantially perpendicular to the diameter and substantially inline with the
`thickness of e.g. a tablet. The force is applied with a carver style bench press
`(unless expressly mentioned otherwise) to the extent necessary to achieve the
`target flatness/reduced thickness. According to the invention the flattening
`does not result in breaking the tablet in pieces. However, edge spits and
`cracks are allowed. The flatness is described in terms of the thickness of the
`flattened tablet compared to the non-flattened tablet expressed in% thickness,
`based on the thickness (mm) of the non flattened tablet. Apart from tablets,
`the flattening can be applied to any shape of a dosage form, wherein the force
`is applied from a direction substantially in line with the smallest diameter (i.e.
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`the thickness) of the shape when the shape is other than spherical and from
`any direction when the shape is spherical. The flatness is then described in
`terms of the thickness/smallest diameter of the flattened shape compared to
`the thickness/smallest diameter of the non-flattened shape expressed in%
`thickness, based on the thickness/smallest diameter in mm of the non
`flattened shape, when the initial shape is non spherical, or the % thickness,
`based on the non flattened diameter when the initial shape is spherical. The
`thickness is measured using a thickness gauge (e.g., digital thickness gauge or
`digital caliper) In Figures 4 to 6 tablets are shown that where flattened using a
`carver bench press. The initial shape of the tablets is shown in Figures 1 to 3
`on the left hand side of the photograph.
`
`[0026] Apart from using a bench press a hammer can be used for flattening
`tablets/dosage forms. In such a flattening process hammer strikes are
`manually applied from a direction substantially inline with the thickness of
`e.g. the tablet. The flatness is then also described in terms of the
`thickness/smallest diameter of the flattened shape compared to the non-
`flattened shape expressed in % thickness, based on the thickness/smallest
`diameter in mm of the non-flattened shape when the initial shape is non
`spherical, or the % thickness, based on the non flattened diameter when the
`initial shape is spherical. The thickness is measured using a thickness gauge
`(e.g., digital thickness gauge or digital caliper).
`
`[0027] By contrast, when conducting the breaking strength test using the
`Schleuniger Apparatus the force is applied substantially perpendicular to the
`thickness and substantially in line with the diameter of the tablet, thereby
`reducing the diameter in that direction. This reduced diameter is described in
`terms of% diameter, based on the diameter in mm of the tablet before
`conducting the breaking strength test.
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`[0028] The term "resistant to crushing" is defined for the purposes of the present
`invention as referring to dosage forms that can at least be flattened with a
`bench press as described above without breaking to no more than 60%
`thickness, preferably no more than 50% thickness, more preferred no more
`than 40% thickness, even more preferred no more than 30% thickness and
`most preferred no more than 20% thickness.
`
`[0029] For the purpose of the present invention dosage forms are regarded as
`"resistance to alcohol extraction" when the respective dosage form provides
`an in-vitro dissolution rate, when measured in a USP Apparatus 1 (basket) at
`100 rpm in 900 ml simulated gastric fluid without enzymes (SGF)
`comprising 40% ethanol at 37° C, characterized by the percent amount of
`active released at 0.5 hours, preferably at 0.5 and 0.75 hours, more preferred
`at 0.5, 0. 75 and 1 hour, even more preferred at 0.5, 0. 75, 1 and 1.5 hours and
`most preferred at 0.75, 1, 1.5 and 2 hours of dissolution that deviates no more
`than 20 % points or preferably no more than 15 % points at each of said time
`point from the corresponding in-vitro dissolution rate measured in a USP
`Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without
`enzymes (SGF) at 37° C without ethanol.
`
`[0030] The term "tamper resistant" for the purposes of the present invention
`refers to dosage forms that at least provide resistance to crushing or resistance
`to alcohol extraction, preferably both, as defined above.
`
`[0031] For the purpose of the present invention the term "active agent" is defined
`as a pharmaceutically active substance which includes without limitation
`opioid analgesics.
`
`[0032] For purposes of the present invention, the term "opioid analgesic"
`includes single compounds and compositions of compounds selected from the
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`group of opioids and which provide an analgesic effect such as one single
`opioid agonist or a combination of opioid agonists, one single mixed opioid
`agonist-antagonist or a combination of mixed opioid agonist-antagonists, or
`one single partial opioid agonist or a combination of partial opioid agonists
`and combinations of an opioid agonists, mixed opioid agonist-antagonists and
`partial opioid agonists with one ore more opioid antagonists, stereoisomers,
`ether or ester, salts, hydrates and solvates thereof, compositions of any of the
`foregoing, and the like.
`
`[0033] The present invention disclosed herein is specifically meant to encompass
`the use of the opioid analgesic in form of any pharmaceutically acceptable
`salt thereof.
`
`[0034] Pharmaceutically acceptable salts include, but are not limited to,
`inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate
`and the like; organic acid salts such as formate, acetate, trifluoroacetate,
`maleate, tartrate and the like; sulfonates such as methanesulfonate,
`benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as
`arginate, asparginate, glutamate and the like, and metal salts such as sodium
`salt, potassium salt, cesium salt and the like; alkaline earth metals such as
`calcium salt, magnesium salt and the like; organic amine salts such as
`triethylamine salt, pyridine salt, picoline salt, ethanolamine salt,
`triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine
`salt and the like.
`
`[0035] The opioids used according to the present invention may contain one or
`more asymmetric centers and may give rise to enantiomers, diastereomers, or
`other stereoisomeric forms. The present invention is also meant to
`encompass the use of all such possible forms as well as their racemic and
`resolved forms and compositions thereof. When the compounds described
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`herein contain olefinic double bonds or other centers of geometric
`asymmetry, it is intended to include both E and Z geometric isomers. All
`tautomers are intended to be encompassed by the present invention as well.
`
`[0036] As used herein, the term "stereoisomers" is a general term for all isomers
`of individual molecules that differ only in the orientation of their atoms is
`space. It includes enantiomers and isomers of compounds with more than
`one chiral center that are not mirror images of one another (diastereomers).
`
`[0037] The term "chiral center" refers to a carbon atom to which four different
`groups are attached.
`
`[0038] The term "enantiomer" or "enantiomeric" refers to a molecule that is
`nonsuperimposeable on its mirror image and hence optically active wherein
`the enantiomer rotates the plane of polarized light in one direction and its
`mirror image rotates the plane of polarized light in the opposite direction.
`
`[0039] The term "racemic" refers to a mixture of equal parts of enantiomers and
`which is optically inactive.
`
`[0040] The term "resolution" refers to the separation or concentration or
`depletion of one of the two enantiomeric forms of a molecule.
`
`[0041] Opioid agonists useful in the present invention include, but are not limited
`to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,
`bezitramide, buprenorphine, butorphanol, clonitazene, codeine,
`desomorphine, dextromoramide, dezocine, diampromide, diamorphone,
`dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
`dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,
`ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,
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`etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone,
`hydromorphone, hydroxypethidine, isomethadone, ketobemidone,
`levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,
`metazocine, methadone, metopon, morphine, myrophine, narceine,
`nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene,
`normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,
`pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,
`piminodine, piritramide, propheptazine, promedol, properidine,
`propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable
`salts, hydrates and solvates thereof, mixtures of any of the foregoing, and the
`like.
`
`[0042] Opioid antagonist useful in combination with opioid agonists as described
`above are e.g. naloxone and naltrexone or pharmaceutically acceptable salts,
`hydrates and solvates thereof, mixtures of any of the foregoing, and the like.
`
`[0043] In certain embodiments e.g. a combination of oxycodone HCl and
`naloxone HCl in a ratio of 2: 1 is used.
`
`[0044] In certain embodiments, the opioid analgesic is selected from codeine,
`morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone or
`pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of
`any of the foregoing, and the like.
`
`[0045] In certain embodiments, the opioid analgesic is oxycodone or a salt
`thereof such as e.g. the hydrochloride. The dosage form comprises from 5 mg
`to 500 mg oxycodone hydrochloride, 1 mg to 100 mg hydromorphone
`hydrochloride or 5 mg to 500 mg oxycodone hydrochloride. If other salts,
`derivatives or forms are used, equimolar amounts of any other
`pharmaceutically acceptable salt or derivative or form including but not
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`limited to hydrates and so1vates or the free base may be used. The dosage
`form comprises e.g. 5 mg, 10 mg, 15 mg, 20 mg, 30, mg, 40 mg, 45 mg, 60
`mg, or 80 mg, 90 mg, 120 mg or 160 mg oxycodone hydrochloride or
`equimolar amounts of any other pharmaceutically acceptable salt, derivative
`or form including but not limited to hydrates and solvates or of the free base.
`The dosage form comprises e.g. 5 mg, 10 mg, 15 mg, 20 mg, 30, mg, 40 mg,
`45 mg, 60 mg, or 80 mg, 90 mg, 120 mg or 160 mg oxymorphone
`hydrochloride or equimolar amounts of any other pharmaceutically
`acceptable salt, derivative or form including but not limited to hydrates and
`solvates or of the free base. The dosage form comprises e.g. 2 mg, 4 mg, 8
`mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg or 64 mg hydromorphone
`hydrochloride or equimolar amounts of any other pharmaceutically
`acceptable salt, derivative or form including but not limited to hydrates and
`solvates or of the free base.
`
`[0046] In certain other embodiments other therapeutically active agents may be
`used in accordance with the present invention, either in combination with
`opioids or instead of opioids. Examples of such therapeutically active agents
`include antihistamines (e.g., dimenhydrinate, diphenhydramine,
`chlorpheniramine and dexchlorpheniramine maleate), non -steroidal anti-
`inflammatory agents (e.g., naproxen, diclofenc, indomethacin, ibuprofen,
`sulindac) and acetaminophen, anti-emetics (e.g., metoclopramide,
`methylnaltrexone), anti-epileptics (e.g., phenytoin, meprobmate and
`nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and
`nicardipine), anti-tussive agents and expectorants (e.g. codeine phosphate),
`anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g. atropine,
`scopolamine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic acid,
`bendrofluthiazide ), anti-hypotensives (e.g., propranolol, clonidine ),
`antihypertensives (e.g., clonidine, methyldopa), bronchodilatiors (e.g.,
`albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisone),
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`antibiotics (e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics,
`antidiarrheals, mucolytics, sedatives, decongestants (e.g. pseudoephedrine ),
`laxatives, vitamins, stimulants (including appetite suppressants such as
`phenylpropanolamine), as well as pharmaceutically acceptable salts, hydrates,
`and solvates of the same.
`
`[0047] The present invention is also directed to the dosage forms utilizing active
`agents such as for example, benzodiazepines, barbiturates or amphetamines.
`These may be combined with the respective antagonists.
`
`[0048] The term "benzodiazepines" refers to benzodiazepines and drugs that are
`derivatives ofbenzodiazepine that are able to depress the central nervous
`system. Benzodiazepines include, but are not limited to, alprazolam,
`bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam,
`flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam,
`prazepam, quazepam, temazepam, triazolam, methylphenidate as well as
`pharmaceutically acceptable salts, hydrates, and solvates and mixtures
`thereof. Benzodiazepine antagonists that can be used in the present invention
`include, but are not limited to, flumazenil as well as pharmaceutically
`acceptable salts, hydrates, and solvates.
`
`[0049] Barbiturates refer to sedative-hypnotic drugs derived from barbituric acid
`(2, 4, 6,-trioxohexahydropyrimidine). Barbiturates include, but are not
`limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital,
`mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital and as
`well as pharmaceutically acceptable salts, hydrates, and solvates mixtures
`thereof. Barbiturate antagonists that can be used in the present invention
`include, but are not limited to, amphetamines as well as pharmaceutically
`acceptable salts, hydrates, and solvates.
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`[0050] Stimulants refer to drugs that stimulate the central nervous system.
`Stimulants include, but are not limited to, amphetamines, such as
`amphetamine, dextroamphetamine resin complex, dextroamphetamine,
`methamphetamine, methylphenidate as well as pharmaceutically acceptable
`salts, hydrates, and solvates and mixtures thereof. Stimulant antagonists that
`can be used in the present invention include, but are not limited to,
`benzodiazepines, as well as pharmaceutically acceptable salts, hydrates, and
`solvates as described herein.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0051] Fig. 1 is a photograph that depicts a top view (view is in line with the
`thickness of the tablet) of tablets of Example 7.1 before (left side) and after
`(right side) the breaking strength test using the Schleuniger Model 6D
`apparatus.
`
`[0052] Fig. 2 is a photograph that depicts a top view (view is in line with the
`thickness of the tablet) of tablets of Example 7.2 before (left side) and after
`(right side) the breaking stren~h test using the Schleuniger Model6D
`apparatus.
`
`[0053] Fig. 3 is a photograph that depicts a top view (view is in line with the
`thickness of the tablet) of tablets of Example 7.3 before (left side) and after
`(right side) the breaking strength test using the Schleuniger Model 6D
`apparatus.
`
`[0054] Fig. 4 is a photograph that depicts a top view (view is in line with the
`thickness of the tablet) of a tablet of Example 7.1 after flattening with a
`Carver manual bench press (hydraulic unit model #3912).
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`[0055] Fig. 5 is a photograph that depicts a top view (view is in line with the
`thickness of the tablet) of a tablet of Example 7.2 after flattening with a
`Carver manual bench press (hydraulic unit model #3912).
`
`[0056] Fig. 6 is a photograph that depicts a top view (view is in line with the
`thickness of the tablet) of a tablet of Example 7.3 after flattening with a
`Carver manual bench press (hydraulic unit model #3912).
`
`[0057] Fig. 7 is a photograph that depicts a top view (view is in line with the
`thickness ofthe tablet) of a tablet ofExample 7.1 after 10 manually
`conducted hammer strikes.
`
`[0058] Fig. 8 is a photograph that depicts a top view (view is in line with the
`thickness of the tablet) of a tablet of Example 7.2 after 10 manually
`conducted hammer strikes.
`
`[0059] Fig. 9 is a photograph that depicts a top view (view is in line with the
`thickness ofthe tablet) of a tablet ofExample 7.3 after 10 manually
`conducted hammer strikes.
`
`DETAILED DESCRIPTION
`
`[0060] In a certain embodiment the present invention concerns a process of
`preparing a solid oral extended release pharmaceutical dosage form,
`comprising at least the steps of:
`(a) combining at least
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, a molecular weight of at least 1 ,000,000; and
`at least one active agent,
`(2)
`to form a composition;
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`(b) shaping the composition to form the extended release matrix
`formulation; and
`(c) curing said extended release matrix formulation comprising at least a
`curing step of subjecting the extended release matrix formulation to a
`temperature which is at least the softening temperature of said
`polyethylene oxide for a time period of at least 5 minutes.
`
`[0061) In certain embodiments the composition is shaped to form an extended
`release matrix formulation in the form of tablet. For shaping the extended
`release matrix formulation in the form of tablet a direct compression process
`can be used. Direct compression is an efficient and simple process for
`shaping tablets by avoiding process steps like wet granulation. However, any
`other process for manufacturing tablets as known in the art may be used, such
`as wet granulation and subsequent compression of the granules to form
`tablets.
`
`[0062] The temperature employed in step c), i.e. the curing temperature, is at
`least as high as