(12) United States Patent
`Us 6,613,354 B2
`(10) Patent N0.:
`(45) Date of Patent:
`Depui et al.
`Sep. 2, 2003
`
`US006613354B2
`
`(54) ORAL PHARMACEUTICAL DOSAGE
`FORMS COMPRISING A PROTON PUMP
`INHIBITOR AND A NSAID
`
`(75)
`
`Inventors: Helene Depui, Goteborg (SE); Per
`Lundberg, Molndal (SE)
`
`(73) Assignee: AstraZeneca AB, Sodertalje (SE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/090,882
`
`(22)
`
`Filed:
`
`Mar. 4, 2002
`
`(65)
`
`Prior Publication Data
`US 2002/0155153 A1 Oct. 24, 2002
`
`Related US. Application Data
`
`(63) Continuation of application No. 09/471,958, filed on Dec.
`23, 1999, now Pat. No. 6,365,184, which is a continuation
`of application No. 08/793,078, filed as application No.
`PCT/SE96/01735 on Dec. 20, 1996, now abandoned.
`
`(51)
`
`Int. Cl.7 ............................ A61K 9/48; A61K 9/52;
`A61K 9/54
`
`(52) US. Cl.
`
`....................... 424/458; 424/451; 424/452;
`424/457
`
`(58) Field of Search ................................. 424/468, 465,
`424/474, 489, 490, 469, 464, 470, 471,
`493, 494, 458, 457, 452, 451, 459, 461,
`462
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`............ 424/468
`11/1988 LOVgren et al.
`4,786,505 A
`........... 424/464
`5/1995 Goldman et al.
`5,417,980 A
`......... 424/474
`5/1998 Bergstrand et al.
`5,753,265 A
`6/1998 Lichtenberger et al.
`....... 514/78
`5,763,422 A
`10/1998 Bergstrand et al.
`......... 424/474
`5,817,338 A
`9/1999 Lichtenberger et al.
`....... 514/78
`5,955,451 A
`4/2002 Depui et al.
`................ 424/469
`6,365,184 B1 *
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`GB
`GB
`GB
`GB
`Page 1 of 19
`
`0008780
`0072021
`0080341
`0108295
`0108504
`0111103
`0170752
`0247983
`0013566
`0391518
`0365947
`0426479
`0541369
`0587220
`0648487
`2066070
`2091097
`2132887
`2285989
`
`8/1979
`8/1982
`11/1982
`10/1983
`10/1983
`10/1983
`12/1984
`12/1987
`1/1990
`2/1990
`5/1990
`5/1990
`11/1992
`8/1993
`10/1994
`12/1980
`11/1981
`11/1983
`1/1995
`
`JP
`WO
`WO
`WC
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`08—301763
`8501207
`8503436
`8702240
`9312772
`9403160
`9404484
`9412463
`9509831
`9510264
`9530641
`9725064
`9822117
`9822118
`0166087
`0222108
`
`11/1996
`9/1984
`2/1985
`9/1986
`12/1992
`7/1993
`3/1994
`6/1994
`4/1995
`4/1995
`11/1995
`7/1997
`5/1998
`5/1998
`9/2001
`3/2002
`
`OTHER PUBLICATIONS
`
`Chem. Pharm. Bull., 42(11), 2327—2331 (1994).
`Chem. Pharm. Bull., 44(7), 1361—1366 (1996).
`McCarthy, D.M. 1989 Gastroenterology 96:662—674, “Non-
`steroidal Antiinflammatory Drug—Induced Ulcers .
`.
`. ”
`Walan, A. Et al. 1989 “Effect of omeprazole and ranitine on
`ulcer healing .
`.
`. ” The N.E.J. Med 320:69.
`Guess, H.A. et al. 1988 “Fatal upper gastrointestinal hem-
`orrhage or perforation .
`.
`. ” J. Clin. Epidimol 41:35—45.
`Larkai, E.N. et al. 1987 “Gastroduodenal mucosa and dys-
`peptic symptoms .
`.
`. ”Am. J. Gastroenterology 82:1153.
`Catford, J.C. et al. 1986 “Confidential inquiry into deaths
`from peptic ulcer .
`.
`. ” Health Trends 18:37—41.
`Hawkey C. “Non—steroidal anti—inflammatory drugs and
`peptic ulcers .
`.
`. ” (1990) 300:278—284.
`a
`Scheiman, J.M. “Pathogenesis of gastroduodenal injury .
`(1982) Semin. Arthritis Reheum. 21(4):201—210.
`Walan, A. Et al. 1989 “Effect of omeprazole and ranitine on
`ulcer healing .
`.
`. ” The N.E.J. Med 320:69.
`Drug Facts and Comparisons 1994, pp. 1679—1684.
`Remington: The Science and Practice of Pharmacy, chapter
`93, 1650—1656, 1995.
`
`. ’
`
`.
`
`Wan, L.S.C., “A Multiple—unit Tablet Formulation for Mul-
`ti—layer Drug—coated Granules”, S.T.P. Pharma Sciences,
`4(5)(1994), pp 336—342.
`
`* cited by examiner
`
`Primary Examiner—James M. Spear
`(74) Attorney, Agent, or Firm—White & Case LLP
`
`(57)
`
`ABSTRACT
`
`An oral pharmaceutical dosage form comprising an acid
`susceptible proton pump inhibitor and one or more NSAIDs
`in a fixed formulation, wherein the proton pump inhibitor is
`protected by an enteric coating layer. The fixed formulation
`is in the form of an enteric coating layered tablet, a capsule
`or a multiple unit tableted dosage form. The multiple unit
`dosage forms are most preferred. The new fixed formulation
`is especially useful
`in the treatment of gastrointestinal
`side-effects associated with NSAID treatment.
`
`24 Claims, 2 Drawing Sheets
`Patent Owner EX. 2013
`Lupin v. Pozen
`|PR2015—01775
`
`Page 1 of 19
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`Patent Owner Ex. 2013
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`US. Patent
`
`Sep. 2, 2003
`
`Sheet 1 0f 2
`
`US 6,613,354 B2
`
`
`
` 7
`
`5
`
`6
`
`0
`
`6'
`
`734
`
`F? 3
`'
`
`v
`43395::
`
`.
`
`”.0
`
`.
`
`mgéfigl‘fie‘
`
`
`
`Page 2 of 19
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`Patent Owner Ex. 2013
`Lupin v. Pozen
`IPR2015-01775
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`

`

`US. Patent
`
`Sep. 2, 2003
`
`Sheet 2 0f 2
`
`US 6,613,354 B2
`
`
`
`Page 3 of 19
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`Patent Owner EX. 2013
`Lupin v. Pozen
`|PR2015-01775
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`Page 3 of 19
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`Patent Owner Ex. 2013
`Lupin v. Pozen
`IPR2015-01775
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`

`

`US 6,613,354 B2
`
`1
`ORAL PHARMACEUTICAL DOSAGE
`FORMS COMPRISING A PROTON PUMP
`INHIBITOR AND A NSAID
`
`This is a continuation of US. patent application Ser. No.
`09/471,958, filed Dec. 23, 1999 US. Pat. No. 6,365,184,
`which is a continuation of US. patent application Ser. No.
`08/793,078, filed Feb. 13, 1997, abandoned, which was the
`National Stage of International Application No. PCT/SE96/
`01735, filed Dec. 20, 1996.
`
`FIELD OF THE INVENTION
`
`The present invention is related to new oral pharmaceu-
`tical preparations especially for use in the treatment and
`prophylaxis of gastrointestinal disorders associated with the
`use of Non Steroidal Antiinflanmmatory Drugs (NSAIDs).
`The present preparations comprise an acid susceptible pro-
`ton pump inhibitor in combination with one or more NSAID
`(s) in a new fixed unit dosage form, especially a tableted
`dosage form. Furthermore, the present invention refers to a
`method for the manufacture of such preparations and the use
`of such preparations in medicine.
`
`BACKGROUND OF THE INVENTION
`
`NSAIDs including acetyl salicylic acid are among the
`most commonly prescribed and used drugs world-wide.
`Despite the therapeutic benefits of NSAIDs, their use is
`frequently limited by an increased risk of gastrointestinal
`side-effects, mainly upper gastrointestinal side-effects like
`peptic ulceration and dyspeptic symptoms.
`The relative risk of developing a gastric ulcer during
`NSAID treatment is increased by a factor 40—50, and the
`relative risk of developing a duodenal ulcer is increased by
`a
`factor 8—10 (McCarty D M. Gastroenterology
`1989;96:662). The relative risk of developing an ulcer
`complication like bleeding and perforation of the stomach is
`increased by a
`factor 1.5—5 (Hawkey C. BMJ
`1990;300:278). Further, dyspeptic symptoms are experi-
`enced in 30—60% of those on NSAID treatment (Larkai E
`N.AmJGas 1987;82:1153).
`In the UK, NSAIDs account for 25% of all reports of
`adverse drug reactions received by the authorities, and the
`corresponding figure is 21% in USA. Therefore, therapies
`which avoid gastrointestinal side-effect caused by NSAIDs
`is requested.
`Attempts to modify the NSAID structure in order to
`prevent such side-effects have so far been less successful.
`The most promising solution to the problem of healing and
`preventing NSAID associated upper gastrointestinal prob-
`lems like ulcers and dyspeptic symptoms in patients with a
`need for continuous NSAID treatment is to combine the
`
`NSAID treatment with an anti-ulcer drug approved for the
`healing and/or prophylaxis of NSAID associated gas-
`trointestinal side-effects such as prostaglandin analogues,
`H2-receptor antagonists or proton pump inhibitors.
`Established risk factors for developing NSAID associated
`upper gastrointestinal side-effects and complications are for
`instance high age, previous peptic ulcer and/or bleeding,
`high dose of NSAID, co-therapy with steroids, and
`co-therapy with anticoagulants. This means,
`that
`for
`Page 4 of 19
`
`2
`example fragile and elderly patients tolerating a complica-
`tion like bleeding or perforation badly, should receive pro-
`phylactic treatment in connection with their NSAID treat-
`ment.
`
`NSAIDs are mainly used for the treatment of chronic
`diseases like rheumatoid arthtritis and osteoarthritis, which
`are most often seen in the elderly-population. Compliance is
`especially important in elderly and fragile patients, who
`have the highest risk of developing a life-threatening com-
`plication to NSAID treatment like bleeding or perforation. It
`is known that 50% of all peptic ulcer deaths occur in NSAID
`users and that 68% of these are >75 years old
`(CatfordzHealth Trends 1986;18:38). This is confirmed in
`another study concluding, that NSAID-related deaths occur
`primarily in those >75 years of age (Guess. J Clin Epidemiol
`1988;41:35). The importance of compliance is further sup-
`ported by the finding,
`that a majority of peptic ulcers
`associated with NSAID treatment are asymptomatic until the
`event.
`
`Omeprazole being a well known proton pump inhibitor
`has been shown to be able to prevent gastric and duodenal
`erosions in healthy volunteers during treatment with acetyl
`salicylic acid. Clinical studies have shown, that omeprazole
`heals gastric as well as duodenal ulcers as fast and effec-
`tively in patients on continuous NSAID treatment as in
`non-NSAID users (Walan A. N Engl J Med 1989;320:69).
`These results have been the basis for an amendment to the
`
`dose recommendation for the use of omeprazole in healing
`of gastric and duodenal ulcers during continuous NSAID
`treatment approved by regulatory authorities in UK and
`Sweden.
`
`that omeprazole significantly
`Recent studies confirm,
`reduces the risk of developing gastric ulcers, duodenal ulcers
`and also dyspeptic symptoms in patients on continuous
`NSAID treatment.
`
`EP 0 426 479 describes tablet compositions comprising a
`NSAID such as ibuprofen and a gastric acid inhibiting drug,
`such as cimetidin etc. No specific arrangement is taken to
`avoid degradation if the gastric acid inhibitor is an acid
`susceptible compound, such as a proton pump inhibitor.
`In proposed therapies comprising NSAID(s) and an acid
`susceptible proton pump inhibitor the different active sub-
`stances are administered separately. It is well known that
`patient compliance is a main factor in receiving a good result
`in medical treatments. Therefore, administration of two or
`even more different tablets to the patient is not convenient or
`satisfactory to achieve the most optimal results. The present
`invention now provides new oral dosage forms comprising
`two or more different active substances combined in one
`
`fixed unit dosage form, preferably a tablet.
`Some anti-ulcer drugs such as proton pump inhibitors are
`susceptible to degradation/transformation in acid reacting
`and neutral media as mentioned above. In respect of the
`stability properties, it is obvious that the one of the active
`substances being a proton pump inhibitor must be protected
`from contact with acidic gastric juice by an enteric coating
`layer. There are different enteric coating layered prepara-
`tions of proton pump inhibitors described in the prior art, see
`for example US. Pat. No. 4,786,505 (A B Hassle) compris-
`ing omeprazole.
`
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`Patent Owner EX. 2013
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`US 6,613,354 B2
`
`3
`There are problems to produce a fixed unit dosage form
`comprising a rather high amount of active substance. Active
`substances with different physical properties combined in
`the same preparation give further problems. Preparation of
`a multiple unit tableted dosage form arises specific problems
`when enteric coating layered pellets containing the acid
`susceptible proton pump inhibitor are compressed into tab-
`lets. If the enteric coating layer does not withstand the
`compression of the pellets into a tablet,
`the susceptible
`active substance will be destroyed upon administration by
`penetrating acidic gastric juice, i.e. the acid resistance of the
`enteric coating layer of the pellets will not be sufficient in the
`tablet after compression.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides oral, fixed unit dosage
`forms,
`i.e. multiple unit
`tableted dosage forms, enteric
`coating layered tablets, multilayered tablets or capsules
`filled with more than one pharmaceutically active com-
`pound. The active compounds are preferably an acid sus-
`ceptible proton pump inhibitor in combination with one or
`more NSAIDs and wherein at least the proton pump inhibi-
`tor is protected by an enteric coated layer. These new dosage
`forms will simplify the regimen and improve the patient
`compliance.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 illustrates a cross-section of a multiple unit
`tableted dosage form comprising an acid susceptible proton
`pump inhibitor in the form of enteric coating layered pellets
`(1) in admixture with a fast disintegrating granulate com-
`prising a NSAID (2). The tablet is covered by an filmcoating
`layer (13).
`FIG. 2 illustrates a cross-section of a multiple unit
`tableted dosage form comprising an acid susceptible proton
`pump inhibitor in the form of enteric coating layered pellets
`(1) and a NSAID in the form of cyclodextrin complex (3)
`included in a fast disintegrating granulate (4). The tablet is
`covered by a filmcoating layer (13).
`FIG. 3 illustrates a cross-section of a tablet with two
`
`separate layers, one layer comprises an acid susceptible
`proton pump inhibitor in the form of enteric coating layered
`pellets (1) in admixture with excipients (5) and the other
`layer comprises a NSAID (6) included in a gelling matrix
`giving extended release. The separate layers are optionally
`separated by a separating layer (12) and the tablet is covered
`by a filmcoating layer (13).
`FIG. 4 illustrates a cross-section of a multiple unit
`tableted dosage form comprising an acid susceptible proton
`pump inhibitor in the form of enteric coating layered pellets
`(1) and a NSAID in the form of enteric coating layered
`pellets (7) in admixture with excipients (5). The tablet is
`covered by a filmcoating layer (13).
`FIG. 5 illustrates a cross-section of an enteric coating
`layered tablet comprising an acid susceptible proton pump
`inhibitor (8) in admixture with one or more NSAID(s) (9)
`and excipients (5). The tablet
`is covered by an enteric
`coating layer (11) and optionally a separating layer (10) is
`layered in between the tablet core and the enteric coating
`layer.
`Page 5 of 19
`
`4
`FIG. 6 illustrates a tablet comprising an acid susceptible
`proton pump inhibitor in the form of enteric coating layered
`pellets (1) in admixture with a fast disintegrating granulate
`(4) in a tablet core, surrounded by a coating layer comprising
`a NSAID substance/granulation (2). The tablet is covered by
`a pigmented filmcoating layer (13).
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`One object of the invention is to provide an oral, multiple
`unit tableted dosage form comprising an anti-ulcer drug,
`preferably an acid susceptible proton pump inhibitor in the
`form of individually enteric coating layered units, together
`with one or more NSAIDs and tablet excipients compressed
`into a tablet The enteric coating layer(s) covering the indi-
`vidual units of the acid susceptible proton pump inhibitor
`has properties such that the compression of the units into a
`tablet does not significantly affect the acid resistance of the
`individually enteric coating layered units. Furthermore, the
`multiple unit tableted dosage form provides a good stability
`to the active substances during long-term storage.
`Alternatively, the prepared tablet has separate layers, one
`layer that comprises the acid susceptible proton pump
`inhibitor in the form of compressed enteric coated layered
`units and another layer that comprises the NSAID(s).
`The new fixed dosage form is preferably in the form of a
`multiple unit tableted dosage form comprising enteric coat-
`ing layered units of the acid susceptible substance and the
`other active substance(s) in the granulated material consti-
`tuting the rest of the compressed tablet, as shown in FIG. 1.
`Alternatively, the different active substances may be inti-
`mately mixed with each other and compressed into a con-
`ventional tablet, which is enteric coating layered, see FIG. 5,
`or both active substances are in the form of enteric coating
`layered pellets compressed into a multiple unit
`tableted
`formulation together with preferably fast disintegrating
`granules of inactive excipients, as exemplified in FIG. 4.
`Further alternatives are exemplified as multiple unit dos-
`age forms wherein the proton pump inhibitor is in the form
`of individually enteric coating layered units and the NSAID
`(s)
`in the form of a) a complex to obtain improved
`bioavailability, see FIG. 2, or b) in the form of a gelling
`matrix resulting in a preparation with extended release of the
`NSAID(s), see FIG. 3. A further alternative is a multiple
`dosage form with the proton pump inhibitor in the form of
`individually enteric coating layered units compressed into a
`tablet and thereupon a separate layer of the NSAID(s) is
`applied by spray layering on the tablet. The tablet is covered
`by a pigmented filmcoating layer to protect the NSAID(s),
`see FIG. 6, because some NSAID(s) are light sensitive and
`require a light protecting layer.
`In still another alternative, the different active substances
`are dry mixed and filled into a capsule. In the latter prepa-
`ration the acid susceptible proton pump inhibitor is in the
`form of enteric coating layered units and the NSAID(s)
`is/are in the form of granules or alternatively in the form of
`modified release formulated units such as enteric coating
`layered units or units layered with a controlled release layer.
`The NSAID(s) may be formulated in instant release,
`sustained release or extended release formulations.
`
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`US 6,613,354 B2
`
`5
`the components may be formulated in an
`Alternatively,
`effervescent formulation. Furthermore, as some NSAID(s)
`are light sensitive the formulation is preferably light pro-
`tected by a pigmented tablet filmcoating layer, as exempli-
`fied in FIG. 6, or by including a pigment in one of the
`coating layers to be applied on the tableted dosage form.
`A further object of the invention is to provide a dosage
`form which is divisible, such as divisible tablets.
`Still a further object of the invention is to provide a
`multiple unit tableted dosage form, which is divisible and
`easy to handle. Some of the multiple unit tableted dosage
`forms may be dispersed in a slightly acidic aqueous liquid
`and can be given to patients with swallowing disorders and
`in pediatrics. Such a suspension of dispersed units/pellets of
`appropriate size can be used for oral administration and also
`for feeding through a naso-gastric tube.
`The different active components used in the present
`dosage forms are defined below.
`Active Substances
`
`The anti-ulcer drug is preferably an acid susceptible
`proton pump inhibitor. Such proton pump inhibitors are for
`example compounds of the general formula I
`
`O
`
`Hetl—X—S—Hetz
`
`R7
`
`R8
`
`R9
`
`N
`X
`
`N
`
`I
`H
`
`N / s
`or X _ or
`N
`I
`H
`
`N
`
`4 jN
`H\N
`
`R's/I
`
`/
`
`—CH—
`R10
`
`or
`
`\/\Rjn
`—R12
`/
`
`I
`
`X :
`
`wherein
`
`N in the benzimidazole moiety means that one of the
`carbon atoms substituted by R6—R9 optionally may be
`exchanged for a nitrogen atom without any substituents;
`Page 6 of 19
`
`6
`R1, R2 and R3 are the same or different and selected from
`hydrogen, alkyl, alkoxy optionally substituted by fluorine,
`alkylthio, alkoxyalkoxy, dialkylamino, piperidino,
`morpholino, halogen, phenyl and phenylalkoxy;
`
`R4 and R5 are the same or different and selected from
`hydrogen, alkyl and aralkyl;
`
`v
`R6 is hydrogen, halogen,
`alkoxy;
`
`trifluoromethyl, alkyl and
`
`RG—R9 are the same or different and selected from
`hydrogen, alkyl, alkoxy, halogen, halo-alkoxy,
`alkylcarbonyl, alkoxycarbonyl, oxazolyl,
`trifluoroalkyl, or adjacent groups R6—R9 form ring
`structures which may be further substituted;
`
`R10 is hydrogen or forms an alkylene chain together with
`R3 and
`
`R11 and R12 are the same or different and selected from
`hydrogen, halogen or alkyl, alkyl groups, alkoxy
`groups and moities thereof, they may be branched or
`straight C1—C9-chains or comprise cyclic alkyl groups,
`such as cycloalkyl-alkyl.
`Examples of proton pump inhibitors according to formula
`I are
`
`OCH3
`
`O
`||COCH3
`
`CH3
`
`F
`
`OCH3
`
`CH3
`
`CH3
`
`N H
`
`O
`
`H
`
`N
`
`|
`
`N
`
`CH2—
`
`OCH3
`
`Omeprazole
`
`OCH3
`
`_||
`
`N |
`
`0%:
`
`/
`
`\
`
`N
`
`l
`
`O
`||
`CHZ—S
`
`N
`|
`
`OCHZCF3
`
`fi:<:|H
`
`H
`
`Lansoprazole
`
`Patent Owner EX. 2013
`Lupin v. Pozen
`|PR2015—01775
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`wherein
`
`Hetl is
`
`R
`
`Hetz is
`
`R2
`
`R
`
`1\fi\/Vk3
`
`/
`
`N
`
`T4
`N
`
`6k\R5
`
`I
`/ /R’s
`
`or
`
`Page 6 of 19
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`Patent Owner Ex. 2013
`Lupin v. Pozen
`IPR2015-01775
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`

`

`US 6,613,354 B2
`
`8
`-continued
`
`OCHFZ
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`The acid susceptible proton pump inhibitors used in the
`dosage forms of the invention may be used in their neutral
`form or in the form of an alkaline salt, such as for instance
`the Mg2+, Ca2+, Na+, K+ or Li+ salts, preferably the Mg2+
`salts. Further where applicable, the compounds listed above
`may be used in racemic form or in the form of the substan-
`tially pure enantiomer thereof, or alkaline salts of the single
`enantiomers.
`
`Suitable proton pump inhibitors are for example disclosed
`in EP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2
`163 747 and WO90/06925, WO91/19711, WO91/19712,
`and further especially suitable compounds are described in
`WO95/01977 and WO94/27988.
`
`A wide variety of NSAIDs may be used in combination
`with a suitable proton pump inhibitor and optional pharma-
`ceutically acceptable excipients in the fixed unit dosage
`form according to the present
`invention. Such NSAIDs
`include for example propionic acid derivatives, oxicams,
`acetic acid and acetamide derivatives, salicylic acid deriva-
`tives and pyrazolidine derivatives.
`Also future NSAIDs like cyclooxygenase (COX) 2 selec-
`tive NSAIDs and NO-releasing NSAIDs (de Soldato P,
`NO-releasing NSAIDzs, A new class of safer anti-
`inflammatory analgesic and anti-pyrretic agents; The IV
`International meeting on side-effects of anti-inflammatory
`drugs Aug. 7—9, 1995) may be included.
`In the following examples of some suitable NSAIDs are
`listed: Acetyl salicylic acid,
`indometacin, diclofenac,
`piroxicam,
`tenoxicam,
`ibuprofen, naproxen, ketoprofen,
`nabumetone, ketorolac, azapropazone, mefenamic acid,
`tolfenamic acid, sulindac, diflunisal, tiaprofenic acid, podo-
`phyllotoxin derivatives, acemetacin, aceclofenac, droxicam,
`oxaprozin,
`floctafenine, phenylbutazone, proglumetacin,
`flurbiprofen, tolmetin and fenbufen.
`The active NSAIDs could be in standard forms or used as
`
`salts, hydrates, esters etc. A combination of two or more of
`the above listed drugs may be used. Preferable NSAIDs for
`the new fixed dosage form are diclofenac,
`ibuprofen,
`naproxen and piroxicam.
`The preferred multiple unit tableted dosage form com-
`prising a proton pump inhibitor (in the form of a racemat, an
`alkaline salt or one of its single enantiomers) and one or
`more NSAIDs, is characterized in the following way. Indi-
`vidually enteric coating layered units (small beads, granules
`or pellets) containing the proton pump inhibitor and option-
`ally containing alkaline reacting substances, are mixed with
`the NSAID(s) and conventional
`tablet excipients.
`Preferably, the NSAID(s) and tablet excipients are in the
`form of a granulation. The dry mixture of enteric coating
`layered units, NSAID granules and optional excipients are
`Patent Owner EX. 2013
`Lupin v. Pozen
`|PR2015—01775
`
`7
`-continued
`
`N |
`
`H
`
`OCH3
`
`o
`
`H
`
`N
`
`|
`
`CH2—
`
`Pantoprazole
`
`QO
`
`CH3
`
`N
`
`N |H
`
`N
`
`I
`H
`
`CH3
`
`0
`
`C
`
`H2—
`
`||
`
`N
`
`||
`
`O
`
`N
`
`Pariprazole
`
`O
`
`H
`
`N
`
`|
`
`CH2—
`
`CH3—N
`
`\
`
`CH2
`
`/CH\
`CH3
`
`CH3
`
`Leminoprazole
`
`OCH3
`
`CH3O
`
`H
`
`N
`(ll
`s—</N
`/H
`
`
`
`H3C
`
`OCH3
`
`65
`
`Page 7 of 19
`
`Page 7 of 19
`
`Patent Owner Ex. 2013
`Lupin v. Pozen
`IPR2015-01775
`
`

`

`US 6,613,354 B2
`
`9
`compressed into multiple unit tableted dosage forms. With
`the expression “individual units” is meant small beads,
`granules or pellets, in the following referred to as pellets of
`the acid susceptible proton pump inhibitor.
`The compaction process (compression) for formulating
`the multiple unit tableted dosage form must not significantly
`affect
`the acid resistance of the enteric coating layered
`pellets comprising the acid susceptible proton pump inhibi-
`tor. In other words the mechanical properties, such as the
`flexibility and hardness as well as the thickness of the enteric
`coating layer(s), must secure that the requirements on enteric
`coated articles in the United States Pharmacopeia are
`accomplished in that the acid resistance does not decrease
`more than 10% during the compression of the pellets into
`tablets.
`
`The acid resistance is defined as the amount of proton
`pump inhibitor in the tablets or pellets after being exposed
`to simulated gastric fluid USP, or to 0,1 M HCl (aq) relative
`to that of unexposed tablets and pellets, respectively. The
`test is accomplished in the following way. Individual tablets
`or pellets are exposed to simulated gastric fluid of a tem-
`perature of 37° C. The tablets disintegrate rapidly and
`release the enteric coating layered pellets to the medium.
`After two hours the enteric coating layered pellets are
`removed and analyzed for content of the proton pump
`inhibitor using High Performance Liquid Chromatography
`(HPLC).
`Further specific components which may be used in the
`fixed unit dosage forms of the present invention are defined
`below.
`
`Core Material—For Enteric Coating Layered
`Pellets/Units
`
`The core material for the individually enteric coating
`layered pellets can be constituted according to different
`principles. Seeds layered with the proton pump inhibitor,
`optionally mixed with alkaline substances, can be used as
`the core material for the further processing.
`The seeds which are to be layered with the proton pump
`inhibitor can be water insoluble seeds comprising different
`oxides, celluloses, organic polymers and other materials,
`alone or in mixtures or water-soluble seeds comprising
`different
`inorganic salts, sugars, non-pareils and other
`materials, alone or in mixtures. Further,
`the seeds may
`comprise the proton pump inhibitor in the form of crystals,
`agglomerates, compacts etc. The size of the seeds is not
`essential for the present invention but may vary between
`approximately 0.1 and 2 mm. The seeds layered with the
`proton pump inhibitor are produced either by powder or
`solution/suspension layering using for instance granulation
`or spray coating layering equipment.
`Before the seeds are layered, the proton pump inhibitor
`may be mixed with further components. Such components
`can be binders, surfactants fillers, disintegrating agents,
`alkaline additives or other and/or pharmaceutically accept-
`able ingredients alone or in mixtures. The binders are for
`example polymers such as hydroxypropyl methylcellulose
`(HPMC), hydroxypropyl-cellulose (HPC), carboxymethyl-
`cellulose sodium, polyvinyl pyrrolidone (PVP), or sugars,
`starches or other pharmaceutically acceptable substances
`with cohesive properties. Suitable surfactants are found in
`Page 8 of 19
`
`10
`the groups of pharmaceutically acceptable non-ionic or ionic
`surfactants such as for instance sodium lauryl sulfate.
`Alternatively, the proton pump inhibitor optionally mixed
`with alkaline substances and further mixed with suitable
`constituents can be formulated into a core material. Said
`
`core material may be produced by extrusion/spheronization,
`balling or compression utilizing conventional process equip-
`ment. The size of the formulated core material is approxi-
`mately between 0.1 and 4 mm and preferably between 0.1
`and 2 mm. The manufactured core material can further be
`
`layered with additional ingredients comprising the proton
`pump inhibitor and/or be used for further processing.
`The proton pump inhibitor is mixed with pharmaceutical
`constituents to obtain preferred handling and processing
`properties and a suitable concentration of the proton pump
`inhibitor in the final preparation. Pharmaceutical constitu-
`ents such as fillers, binders, lubricants, disintegrating agents,
`surfactants and other pharmaceutically acceptable additives
`may be used.
`Further, the proton pump inhibitor may also be mixed
`with an alkaline, pharmaceutically acceptable substance (or
`substances). Such substances can be chosen among, but are
`not restricted to substances such as the sodium, potassium,
`calcium, magnesium and aluminium salts of phosphoric
`acid, carbonic acid, citric acid or other suitable weak inor-
`ganic or organic acids; aluminium hydroxide/sodium bicar-
`bonate coprecipitate; substances normally used in antacid
`preparations such as aluminium, calcium and magnesium
`hydroxides; magnesium oxide or composite substances,
`such as A1203.6MgO.C02.12H20,
`(Mg6A12(OH)16
`CO3.4H20), MgO.Ale3.2Si02.nH20 or similar com-
`pounds; organic pH-buffering substances such as
`trihydroxymethylaminomethane, basic amino acids and
`their salts or other similar, pharmaceutically acceptable
`pH-buffering substances.
`Alternatively,
`the aforementioned core material can be
`prepared by using spray drying or spray congealing tech-
`nique.
`
`Enteric Coating Layer(s)
`
`Before applying the enteric coating layer(s) onto the core
`material in the form of individual pellets, the pellets may
`optionally be covered with one or more separating layer(s)
`comprising pharmaceutical excipients optionally including
`alkaline compounds such as pH-buffering compounds. This/
`these separating layer(s), separate(s) the core material from
`the outer layers being enteric coating layer(s). This/these
`separating layer(s) protecting the core material of proton
`pump inhibitor should be water soluble or rapidly disinte-
`grating in water.
`The separating layer(s) can be applied to the core material
`by coating or layering procedures in suitable equipments
`such as coating pan, coating granulator or in a fluidized bed
`apparatus using water and/or organic solvents for the coating
`process. As an alternative the separating layer(s) can be
`applied to the core material by using powder coating tech-
`nique. The materials for the separating layers are pharma-
`ceutically acceptable compounds such as, for instance,
`sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl
`alcohol, polyvinyl acetate, hydroxypropyl cellulose,
`Patent Owner EX. 2013
`Lupin v. Pozen
`|PR2015—01775
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 8 of 19
`
`Patent Owner Ex. 2013
`Lupin v. Pozen
`IPR2015-01775
`
`

`

`US 6,613,354 B2
`
`11
`methylcellulose, ethylcellulose, hydroxypropyl methyl
`cellulose, carboxymethylcellulose sodium, water soluble
`salts of enteric coating polymers and others, used alone or in
`mixtures. Additives such as plasticizers, colorants,
`pigments, fillers anti-tacking and anti-static agents, such as
`for instance magnesium stearate, titanium dioxide, talc and
`other additives may also be included into the separating
`layer(s).
`When the optional separating layer, is applied to the core
`material it ay constitute a variable thickness. The maximum
`thickness of the separating layer(s) is normally only limited
`by processing conditions. The separating layer may serve as
`a diffusion barrier and may act as a pH-buffering zone. The
`pH-buffering properties of the separating layer(s) can be
`further strengthened by introducing into the layer(s) sub-
`stances chosen from a group of compounds usually used in
`antacid formulations such as,
`for
`instance, magnesium
`oxide, hydroxide or carbonate, aluminium or calcium
`hydroxide, carbonate or silicate; composite aluminium/
`magnesium compounds such as,
`for
`instance
`A1203.6MgO.C02.12H20,
`(Mg6A12(OH)16CO3.4H20),
`MgO.AlZO3.ZSi02.nH20, aluminium hydroxide/sodium
`bicarbonate coprecipitate or similar compounds; or other
`pharmaceutically acceptable pH-buffering compounds such
`as, for instance the sodium, potassium, calcium, magnesium
`and aluminium salts of phosphoric, carbonic, citric or other
`suitable, weak,
`inorganic or organic acids; or suitable
`organic bases, including basic amino acids and salts thereof.
`Talc or other compounds may be added to increase the
`thickness of the layer(s) and thereby strengthen the diffusion
`barrier. The optionally applied separating layer(s) is not
`essential for the invention. However, the separating layer(s)
`may improve the chemical stability of the active substance
`and/or the physical properties of the novel multiple unit
`tableted dosage form.
`Alternatively, the separating layer may be formed in situ
`by a reaction between an enteric coating polymer layer
`applied on the core material and an alkaline reacting com-
`pound in the core material. Thus, the separating layer formed
`comprises a water soluble salt formed between the enteric
`coating layer polymer(s) and an alkaline reacting compound
`which is in the position to form a salt
`One or more enteric coating