(12) United States Patent
`US 6,365,184 B1
`(10) Patent N0.:
`(45) Date of Patent:
`Depui et al.
`Apr. 2, 2002
`
`USOO6365184B1
`
`(54) ORAL PHARMACEUTICAL DOSAGE
`FORMS COMPRISING A PROTON PUMP
`INHIBITOR AND A NSAID
`
`(75)
`
`Inventors: Helene Depui, Goteborg; Per
`Lundberg, Molndal, both of (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.: 09/471,958
`
`(22)
`
`Filed:
`
`Dec. 23, 1999
`
`Related US. Application Data
`
`(63) Continuation of application No. 08/793,078, filed as appli—
`cation No. PCT/SE96/01735 on Dec. 20, 1996, now aban—
`doned.
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 8, 1996
`
`(SE) .............................................. 9600070
`
`Int. Cl.7 ............................. A61K 9/36; A61K 9/26
`(51)
`(52) US. Cl.
`....................... 424/469; 424/469; 424/468;
`424/464; 424/465; 424/472; 424/473; 424/471;
`424/470; 424/490; 424/493; 424/494; 514/338
`(58) Field of Search ................................. 424/464, 465,
`424/472, 99, 473, 471, 468—469, 470, 474,
`493, 494, 490, 514/338
`
`(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
`7/1998 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
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`EP
`
`0072021
`0080341
`0108295
`0108504
`0111103
`
`8/1982
`11/1982
`10/1983
`10/1983
`10/1983
`
`(List continued on next page.)
`
`OTHER PUBLICATIONS
`
`Facts and Comparison’s 1994, pp. 1679—1684.*
`Remington, chapter 93, 1650—1656, 1995*
`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.
`
`. ’
`
`.
`
`Primary Examiner—Diana Dudash
`Assistant Examiner—Shahnam Sharareh
`
`(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.
`
`EP
`
`0008780
`
`8/1979
`
`34 Claims, 2 Drawing Sheets
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 1
`
`

`

`US 6,365,184 131
` Page 2
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`GB
`GB
`
`0170752
`0247983
`0013566
`0391518
`0365947
`0426479
`0541369
`0587220
`0648487
`2066070
`2091097
`
`12/1984
`12/1987
`1/1990
`2/1990
`5/1990
`5/1990
`11/1992
`8/1993
`10/1994
`12/1980
`11/1981
`
`GB
`GB
`WO
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`WO
`
`2132887
`2285989
`8501207
`8503436
`8702240
`9312772
`9403160
`9510264
`9725064
`9822117
`9822118
`
`11/1983
`1/1995
`9/1984
`2/1985
`9/1986
`12/1992
`7/1993
`4/1995
`7/1997
`5/1998
`5/1998
`
`* cited by examiner
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 2
`
`

`

`US. Patent
`
`Apr. 2, 2002
`
`Sheet 1 0f 2
`
`US 6,365,184 B1
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 3
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 3
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 3
`
`

`

`US. Patent
`
`Apr. 2, 2002
`
`Sheet 2 0f 2
`
`US 6,365,184 B1
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 4
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 4
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 4
`
`

`

`US 6,365,184 B1
`
`1
`ORAL PHARMACEUTICAL DOSAGE
`FORMS COMPRISING A PROTON PUMP
`INHIBITOR AND A NSAID
`
`This application is a continuation of application Ser. No.
`08/793,078, filed on Feb. 13, 1997 now abandoned, which is
`a 371 of 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 Antiinfiammatory 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
`
`NASAIDs including acetyl salicyclic 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 DM. 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
`En.AmJGas 1987;82:1153).
`In UK, NSAIDs account for 25% of all reports of adverse
`drug reactions received by the authorities, and the corre-
`sponding 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
`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 arthritis and osteoarthritis, which
`are most often seen in the elderly population. Compliance is
`especially important in elderly and fragile patients, who
`
`2
`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 Epide-
`miol 1988;41:35). The importance of compliance is further
`supported 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. 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.
`
`EPO 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 administred 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 (AB Hassle) compris-
`ing omeprazole.
`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
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 5
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 5
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 5
`
`

`

`US 6,365,184 B1
`
`3
`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.
`DESCRIPTION OF THE FIGURES
`
`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.
`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
`individual units of the acid susceptible proton pump inhibi-
`tor 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
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`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.
`
`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 layer 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
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 6
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`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 6
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`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 6
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`

`

`US 6,365,184 B1
`
`6
`Examples of proton pump inhibitors according to formula
`I are
`
`OCH3
`
`Omeprazole
`
`if
`COCH3
`
`CH3
`
`F
`
`CH3
`
`OCH3
`
`CH3
`
`O
`
`N
`
`CH2—
`
`II
`
`OCH3
`
`/
`
`\
`
`N
`
`I
`
`CH
`
`3
`
`O
`||
`CHZ—S
`
`N
`
`I
`
`N
`|
`
`TH
`
`III
`H
`
`N H
`
`0/»
`
`/
`
`\
`
`N
`
`I
`
`O
`||
`CH2—
`
`N
`|
`
`10
`
`15
`
`20
`
`25
`
`0
`
`Hetl—X—S—Hetz
`
`wherein
`
`Hetl is
`
`R
`
`1
`
`Hetz is
`
`R2
`R
`\ 3
`/
`N
`
`T4
`N
`\ \ R5
`
`|
`y /R 6
`
`Of
`
`R6
`
`R7
`
`N
`X
`
`N
`
`I
`H
`
`N / s
`or X
`
`N
`
`or
`
`R8
`
`R9
`
`I
`H
`
`Lansoprazole
`
`OCHFZ
`
`Pantoprazole
`
`Pariprazole
`
`Leminoprazole
`
`N |H
`
`N
`
`I
`
`N |H
`
`N]N
`H\N
`R’s/I /
`
`30
`
`35
`
`OCHZCF3
`
`CH3
`
`0
`
`0 II
`
`N
`
`CH2—
`
`40
`
`OCH3
`
`45
`
`N
`
`OCH3
`
`O
`
`CH2—
`
`II
`
`N
`
`I
`
`CH
`
`0/
`
`2\CH2/
`CH3
`
`CH —OCH
`2
`
`3
`
`N |H
`
`T
`H
`
`N
`
`I
`
`N
`
`I
`
`0
`
`0 II
`
`N
`
`CH2—
`
`O
`
`CH2—
`
`II
`
`CH —N
`3
`
`\CH2
`CH
`\CH3
`
`CH:
`
`50
`
`55
`
`60
`
`65
`
`X =
`
`—CH—
`R10
`
`or
`
`R11
`\/\j
`—R12
`/
`
`I
`
`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;
`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;
`R6'
`is hydrogen, halogen,
`alkoxy;
`R6—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.
`
`trifluoromethyl, alkyl and
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 7
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 7
`
`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 7
`
`

`

`US 6,365,184 B1
`
`7
`-continued
`
`o
`
`CH2—
`
`||
`
`N
`
`|
`
`/
`
`\
`
`5
`
`OCH3
`
`N
`
`/ N
`\ I
`
`CH3O
`
`(ll
`S
`
`TH
`
`/N
`N
`/H
`
`
`
`OCH3
`
`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-Al-0005129, EP-Al-174 726, EP-Al-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 NASAIDs
`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.
`
`8
`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
`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 layers(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,
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`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 8
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`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 8
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`MYLAN PHARMS. INC. EXHIBIT 1084 PAGE 8
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`

`

`US 6,365,184 B1
`
`9
`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
`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 be 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 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 or 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 A12030.6MgO.C020.12H20,
`(MgGAl2
`(OH)16CO30.4H2),MgO.A12030.ZSi02.nH20 or similar
`compounds; 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 suing 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 layers(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
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`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,
`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 may constitute a variable thickness. The maxi-
`mum 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)
`substances 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
`A12030.6MgO.C020.12H20, (Mg6A12(OH)16CO30.4H20),
`MgO.Ale30.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 strenghten 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 layers are applied onto the
`core material or onto the core material covered with sepa-
`rating layer(s) by using a suitable coating technique. The
`enteric coating layer material may be dispersed or dissolved
`in either water or in suitable organic solvents. As enteric
`coating layer polymers one or more, separately or
`in
`combination, of the following can be used, e.g. solutions or
`dispersions of methacrylic acid copolymers, cellulose
`acetate phthalate, hydroxypropyl methylcellulose phthalate,
`hydroxypropyl methylcellulose acetate succinate, polyvinyl
`acetate phthalate, cellulose acetate trimellitate,
`carboxymethylethylcellulose, shellac or other suitable
`ent