P 9286/ES
`
`PHARMACEUTICAL DOSAGE FORMS
`
`[001] This application claims priority from U.S. Provisional Application Serial
`No. 60/840,244, filed August 25, 2006, the disclosure of which is hereby
`incorporated by reference.
`
`TECHNICAL FIELD OF THE INVENTION
`
`[002] The present invention relates to pharmaceutical dosage forms, for
`example to a tamper resistant dosage form including an opioid analgesic, and
`processes of manufacture, uses, and methods of treatment thereof.
`
`BACKGROUND OF THE INVENTION
`
`[003] Pharmaceuticul products are sometimes the subject of abuse. For
`example, a purticulur 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 tor illicit use. Controlled release opioid agonist
`formulations arc sometimes crushed. or subject to extraction with solvents
`(e.g., ethanol) by drug abusers to provide the opioid contained therein for
`immediate release upon ural ur parenteral administration.
`
`ro04l Controlled release opioid agonist dosage forms which can liberate a
`pmtion 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.
`
`[005] There continues to exist a need in the art for pharmaceutical oral dosage
`rorms comprisirlg arl opioid agtmisl wilhoul ~igni ricanlly changed opioitl
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`release properties when in contact with alcohol and/or with resistance to
`crushing.
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`OBJECTS AND SUMMARY OF THE INVENTION
`
`[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 tamper resistant.
`
`[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 crushing.
`
`[008]
`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 in contact with alcohol.
`
`[009]
`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 least flattened without
`breaking, characterized by a thickness of the tablet or of the individual multi
`particulate after the flattening which corresponds to no more than about 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 lOO rpm in 900 ml simulated gastric fluid without enzymes (SGF)
`at 37° C, characterized by the percent amount of active released at 0.5 hours
`of dissolution that deviates no more than about 20% points from the
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`corresponding in-vitro dissolution rate of a non-flattened reference tablet or
`reference multi particulates.
`
`[0010] In certain embodiments, the present invention is directC"£1 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 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 about 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 37o C,
`characterized by the percent amount of active released at 0.5 hours of
`dissolution that deviates no more than about 20% points from the
`corresponding in-vitro dissolution rate measured in a USP Apparatus 1
`(basket) at lOU rpm in 900 ml simulated gastric fluid without enzymes (SGF)
`at 3T C without ethanol, using a flattened and non flattened reference tablet
`or flattened and non flattened reference multi particulates, respectively.
`
`[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 alleasl:
`( 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
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`wherein the composition comprises at least about 80 % (by wt) polyethylene
`oxide.
`
`[0012] According to certain such embodiments the active agent is oxycodone
`hydrochloride and the composition comprises more than about 5% (by wt) of
`the oxycodone hydrochloride.
`
`[0013] 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 ofless than 1,000,000.
`
`[0014] In certain embodiments, the present invention is directed to a process of
`preparing a solid oral extended release pharmaceutical dosage for~
`comprising at least the steps of:
`combining at least
`(a)
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least
`1,000,000, and
`at least one active agent,
`(2)
`to form a composition;
`shaping the composition to form an extended release matrix
`formulation; and
`
`(b)
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`curing said extended release matrix formulation comprising at least a
`(c)
`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 about 1 minute.
`
`[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:
`(a)
`combining at least
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least
`1,000,000, and
`at least one active agent,
`(2)
`to form a composition;
`shaping the composition to form an extended release matrix
`formulation; and
`curing said extended release matrix formulation comprising at least a
`(c)
`curing step wherein said polyethylene oxide at least partially melts.
`
`(b)
`
`[0016] In certain embodiments, the present invention is directed to a solid oral
`extended release pharmacelltical dosage form comprising an extended release
`matrix formulation comprising an active agent 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 of the individual multi
`particulate after the flattening which corresponds to no more than about 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 37° C, characterized by the percent
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`amount of active agent released at 0.5 hours of dissolution that deviates no more than
`about 20% points from the corresponding in-vitro dissolution rate of a non-flattened
`reference tablet or reference multi particulates.
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`[0017] In certain embodiments, the present invention is directed to a solid oral
`extended release pharmaceutical dosage form comprising an extended release
`matrix formulation comprising an active agent in the form of a tablet or multi
`particulates,
`wherein the tablet or the individual multi particulates can at least be flattened
`10 without breaking, characterized by a thickness of the tablet or of the individual multi
`particulate after the flattening which corresponds to no more than about 60 % of the
`thickness of the tablet or the individual multi particulate before flattening, and
`wherein said flattened tablet or the flattened multi particulates and the non-flattened
`reference tablet or reference multi particulates provide an in-vitro dissolution rate,
`which when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated
`gastric fluid without enzymes (SGF) at 37o C, is between about 5 and about 40% (by
`wt) active agent released after 0.5 hours.
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`[0018] In certain embodiments, the present invention is directed to a solid oral
`extended release pharmaceutical dosage form comprising an extended release
`matrix formulation comprising an active agent in the form of a tablet or m11lti
`particulates,
`wherein the tablet or the individual multi particulates can at least be ilatlened
`without breaking, characterized by a thickness of the tablet or the individual multi
`particulate after the ilallening which corresponds lo no more lhan aboul 60% of lhe
`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
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`agent released at 0.5 hours of dissolution that deviates no more than about 20%
`points from the corresponding in-vitro dissolution rate measured in a USP Apparatus
`1 (basket) at 100 rpm in 900 m1 simulated gastric fluid without enzymes (SGF) at
`37° C without ethanol, using a flattened and non flattened reference tablet or
`flattened and non flattened reference multi particulates, respectively.
`
`[0019] In certain embodiments, the present invention is directed to a solid oral
`extended release pharmaceutical dosage form comprising an extended release
`matrix formulation comprising an active agent 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 about 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, which when measured in a USP
`Apparatus 1 (basket) at 100 rpm in 900 m1 simulated gastric fluid without enzymes
`(SGF) comprising 40% or 0% ethanol at 37u C, is between about 5 and about 40%
`(by wt) active agent released after 0.5 hours.
`
`[0020] 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 ntatrix formulation comprising
`a composition comprising at least:
`alleasl one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least 1,000,000;
`and
`at least one active agent selected from opioid analgesics; and
`(2)
`wherein the composition comprises at least about SO% (by wt) polyethylene
`oxide.
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`[0021] ln 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 1natrix formulation comprising
`a campo sition comprising at least:
`at least one polyethylene oxide having, based on rheological
`( 1)
`measurements, an approximate molecular weight of at least 1,000,000;
`and
`10 mg oxycodone hydrochloride; and
`(2)
`wherein the composition comprises at least about 85 % (by wt) polyethylene
`oxide.
`
`[0022] 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 campo sition comprising at least:
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least 1,000,000;
`and
`(2)
`15 mg or 20 mg oxycodone hydrochloride; and
`wherein the composition comprises at least about 80% (by wt) polyethylene
`oxide.
`
`[0023] In certain embodiments, the present invention is directed to a solid oral
`exlended release pharmaceutical dosage form comprising an extended release
`matrix formulation, the extended release matrix formulation comprising
`a composition comprising at least:
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least 1,000,000;
`and
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`40 mg oxycodone hydrochloride; and
`(2)
`wherein the composition comprises at least about 65% (by wt) polyethylene
`oxide.
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`[0024] 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:
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least 1,000,000;
`and
`60 mg or 80 mg oxycodone hydrochloride; and
`(2)
`wherein the composition comprises at least about 60% (by wt) polyethylene
`oxide.
`
`[0025] 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:
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at lea 'it 1 ,000,000;
`and
`8 mg hydromorphone hydrochloride; and
`(2)
`wherein the composition comprises at least about 94% (by wt) polyethylene
`oxide.
`
`[0026] 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 campo sition comprising at least:
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`(l)
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`at least one polyethylene oxide having, based on rheological
`measurements, an approximate molecular weight of at least 1,000,000;
`and
`12 mg hydromorphone hydrochloride; and
`(2)
`wherein the composition comprises at least about 92 % (by wt) polyethylene
`oxide.
`
`[0027] 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:
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least 1,000,000;
`and
`32 mg hydromorphone hydrochloride: and
`(2)
`wherein the composition comprises at least about 90% (by wt) polyethylene
`oxide.
`
`[0028] 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 form11lation comprising a
`composition comprising at least:
`at least one active agent selected from opioid analgesics;
`(1)
`(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,
`an approximate molecular weight of less than 1,000,000.
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`[0029] ln 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:
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, a molecular weight of at least 800,000; and
`at least one active agent selected from opioid analgesics; and
`(2)
`wherein the composition comprises at least about 80% (by wt) polyethylene
`oxide.
`
`[0030] ln 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 campo sition comprising at least:
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least 1,000,000;
`and
`at least one active agent; and
`(2)
`wherein the extended release matrix formulation when subjected to an
`indentation test has a cracking force of at least about 110 N.
`
`[0031] 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 alleasl:
`at least one polyethylene oxide having, based on rheological
`(1)
`measurements, an approximate molecular weight of at least 1,000.000;
`and
`at least one active agent; and
`
`(2)
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`wherein the extended release matrix formulation when subjected to an
`indentation test has a "penetration depth to crack distance" of at least about 1.0 mm.
`
`[0032] In certain embodiments, the present invention is directe-£1 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.
`
`[0033] 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 manufacture of a medicament for the treatment of pain.
`
`[0034] In certain embodiments, the present invention is directed to the use of
`high molecular weight polyethylene oxide that has, based on rheological
`measurements, an approximate 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.
`
`(1)
`
`[0035] In certain embodiments, the present invention is directed to a process of
`preparing a solid oral extended release pharmace11tical dosage form,
`comprising at least the steps of:
`(a) combining alleasl
`at least one polyethylene oxide having, based on rheological
`measurements, a molecular weighl of alleasl 1 ,000,000, and
`(2)
`at least one active agent,
`to form a composition;
`(b) shaping the composition to form an extended release matrix
`formulation; and
`(c) curing said extended release matrix formulation comprising at least a
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`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.
`
`[0036] According to certain embodiments of the invention the solid extended
`release pharmaceutical dosage form is for use as a suppository.
`
`[0037] 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).
`
`[0038] 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 or absorption of the drug.
`
`[0039] 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 an "extended release matrix formulation" and optionally
`other adjuvants and additives conventional in the art, such as a protective
`coaling 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 lenn "solid oral extended release pharmaceutical dosage forn1" 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. The "extended
`release pharmaceutical dosage form" may comprise a portion of active agent
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`in extended release form and another portion of active agent in immediate
`release form, e.g. as an immediate release layer of active agent surrounding
`the dosage form or an immediate release component included within the
`dosage form.
`
`[0040] 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 additional retardants
`anc\Jor other materials, including but not limited to low molecular weight
`polyethylene oxides and other adjuvants and additives conventional in the art.
`
`[0041] The term "bioequivalent/bioequivalence" is defined for the purposes of
`the present invention to refer to a dosage form that provides geometric mean
`values of Cmax. AU Ct. and AUCnt for an active agent, wherein the 90%
`confidence intervals estimated tor the ratio (test/reference) fall within the
`range of 80.00% to 125.00%. Preferably, the mean values Cmax, AUC1, and
`AUCnr fall within the range of 80.00% to 125.00% as determined in both the
`fed and the fasting states.
`
`[0042] 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 Lhe art, and preferably having a molecular weight of alleasl
`100,000. Compositions with lower molecular weight are usually referred to as
`polyethylene glycols.
`
`[0043] The term "high molecular weight polyethylene oxide" is defined for
`proposes of the present invention as having an approximate molecular weight
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`of at least 1,000,000. For the purpose ofthis 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
`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 of 2000 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 moleculm· 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 of 5500 to 7500 mPa s (cP). Polyethylene oxide is
`considered to have an approximate molecular weight of7,UOU,UOU 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 7500 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 rnPa s (cP). RegmTling 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 moleculm· weight of 900,000 when a
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`5o/c (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).
`
`[0044] The term "low molecular weight polyethylene oxide" is defined for
`purposes of the present invention as having, based on the rheological
`measurements outlined above, an approximate molecular weight of less than
`1,000,000.
`
`[0045] 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, SUP AC-IR/MR: Immediate Release and Modified
`Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum).
`
`L 0046 J The term "bed of free flowing tablets" is defined for the purposes of the
`present in vent ion 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 preferably
`reduces or prevents the sticking of tablets to one another.
`
`[0047] The term "flattening" and related terms as used in the context of
`ilallening 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 may be applied with a carver style bench
`press (unless expressly mentioned otherwise) to the extent necessary to
`achieve the target flatness/reduced thickness. According to certain
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`embodiments of the invention the flattening does not result in breaking the
`tablet in pieces, however, edge spits and cracks may occur. The flatness is
`described in terms of the thickness of the flattened tablet compared to the
`thickness of the non-flattened tablet expressed in % thickness, based on the
`thickness 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. 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 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.
`
`[0048] In certain embodiments of the invention, apart from using a bench press a
`hammer can be used for flattening tablets/dosage forms. In s11ch 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 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).
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`[0049] By contrast, when conducting the breaking strength or tablet hardness test
`as described in Remington's Pharmaceutical Sciences, 18th edition, 1990,
`Chapter 89 "Oral Solid Dosage Forms", pages 1633-1665, which is
`incorporated herein by reference, using the Schleuniger Apparatus the
`tablet/dosage form is put between a pair of flat plates arranged in parallel, and
`pressed by means of the flat plates, such that 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 of the
`tablet before conducting the breaking strength test. The breaking strength or
`tablet hardness is defined as the force at which the tested tablet/dosage form
`breaks. Tablets/dosage forms that do not break, but which are deformed due
`to the force applied are considered to be break-resistant at that patiicular
`force.
`
`[0050] A further test to quantify the strength of tablets/dosage forms is the
`indentation test using a Texture Analyzer, such as the TA-XT2 Texture
`Analyzer (Texture Technologies Corp., 18 Fairview Road, Scarsdale, NY
`10583). In this method, the tablets/dosage forms are placed on top of a
`stainless stand with slightly concaved surface and subsequently penetrated by
`the descending probe of the Textl1re Analyzer, s11ch as a TA-8A 118 inch
`diameter stainless steel ball probe. Before stmting the measurement, the
`tablets are aligned directly under