Exhibit 1010
`
`U.S. Patent No. 6,365,184 (“the ‘184 Patent”)
`
`

`
`(12) United States Patent
`Depui et al.
`
`US006365184B1
`US 6,365,184 B1
`(10) Patent N0.:
`Apr. 2, 2002
`(45) Date of Patent:
`
`EP
`EP
`EP
`EP
`EP
`
`(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, ?led as appli
`cation No. PCT/SE96/01735 on Dec. 20, 1996, now aban
`doned.
`Foreign Application Priority Data
`(30)
`Jan. 8, 1996
`(SE) ............................................ .. 9600070
`(51) Int. Cl.7 ........................... .. A61K 9/36; A61K 9/26
`(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
`References Cited
`US. PATENT DOCUMENTS
`4,786,505 A 11/1988 Lovgren et al. .......... .. 424/468
`5,417,980 A
`5/1995 Goldman et al. ......... .. 424/464
`5,753,265 A
`5/1998 Bergstrand et al. ....... .. 424/474
`5,763,422 A
`7/1998 Lichtenberger et al. ..... .. 514/78
`5,817,338 A 10/1998 Bergstrand et al. ....... .. 424/474
`5,955,451 A
`9/1999 Lichtenberger et al. ..... .. 514/78
`FOREIGN PATENT DOCUMENTS
`0008780
`8/1979
`
`(56)
`
`EP
`
`34 Claims, 2 Drawing Sheets
`
`8/1982
`0072021
`11/ 1982
`0080341
`10/1983
`0108295
`10/1983
`0108504
`10/1983
`0111103
`(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 Antiin?ammatory 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 “Con?dential inquiry into deaths
`from peptic ulcer .
`.
`. ” Health Trends 18:37—41.
`HaWkey C. “Non—steroidal anti—in?ammatory drugs and
`peptic ulcers .
`. .” (1990) 300:278—284.
`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 ?xed formulation, Wherein the proton pump inhibitor is
`protected by an enteric coating layer. The ?xed 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 ?xed formulation
`is especially useful in the treatment of gastrointestinal
`side-effects associated With NSAID treatment.
`
`.
`
`. ”
`
`

`
`US 6,365,184 B1
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`0170752
`12/1984
`0247983
`12/1987
`0013566
`1/1990
`0391518
`2/1990
`0365947
`5/1990
`0426479
`5/1990
`0541369
`11/1992
`0587220
`8/1993
`0648487
`10/1994
`2066070
`12/1980
`2091097
`11/1981
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`GB
`GB
`
`2132887
`GB
`2285989
`GB
`8501207
`W0
`8503436
`WO
`8702240
`WO
`9312772
`WO
`9403160
`WO
`9510264
`WO
`9725064
`W0
`9822117
`W0
`9822118
`W0
`* cited by examiner
`
`11/1983
`1/1995
`9/1984
`2/1985
`9/1986
`12/1992
`7/1993
`4/1995
`7/1997
`5/1998
`5/1998
`
`

`
`U.S. Patent
`
`Apr. 2, 2002
`
`Sheet 1 0f 2
`
`US 6,365,184 B1
`
`

`
`U.S. Patent
`
`Apr. 2, 2002
`
`Sheet 2 0f 2
`
`US 6,365,184 B1
`
`

`
`US 6,365,184 B1
`
`10
`
`15
`
`20
`
`25
`
`30
`
`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, ?led on Feb. 13, 1997 noW abandoned, Which is
`a 371 of PCT/SE96/01735, ?led 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 Antiin?ammatory Drugs (NSAIDs).
`The present preparations comprise an acid susceptible pro
`ton pump inhibitor in combination With one or more NSAID
`(s) in a neW ?xed 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 bene?ts 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 ?gure 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
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 con?rmed 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 ?nding, 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.
`Recent studies con?rm, that omepraZole signi?cantly
`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 speci?c 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
`?Xed 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 ?Xed 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 speci?c 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, ie the acid resistance of the
`enteric coating layer of the pellets Will not be suf?cient in the
`tablet after compression.
`SUMMARY OF THE INVENTION
`The present invention provides oral, ?Xed unit dosage
`forms, i.e. multiple unit tableted dosage forms, enteric
`
`

`
`10
`
`25
`
`US 6,365,184 B1
`3
`coating layered tablets, multilayered tablets or capsules
`?lled 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
`The tablet is covered by an ?lmcoating
`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
`The tablet is
`covered by a ?lmcoating 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 ?lmcoating 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
`The tablet is
`covered by a ?lmcoating 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
`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
`The tablet is covered by
`a pigmented ?lmcoating 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 signi?cantly 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
`
`4
`inhibitor in the form of compressed enteric coated layered
`units and another layer that comprises the NSAID(s).
`The neW ?xed 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 exempli?ed in FIG. 4.
`Further alternatives are exempli?ed 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 ?lmcoating 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 ?lled 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
`modi?ed 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.
`Alternatively, the components may be formulated in an
`effervescent formulation. Furthermore, as some NSAID(s)
`are light sensitive the formulation is preferably light pro
`tected by a pigmented tablet ?lmcoating layer, as exempli
`?ed 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 de?ned 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
`
`45
`
`55
`
`65
`
`

`
`US 6,365,184 B1
`
`6
`Examples of proton pump inhibitors according to formula
`I are
`
`OCH3
`Omeprazole
`
`CoCH3
`
`CH3
`
`F
`
`OCH3
`
`CH3
`
`CH3
`
`N
`
`oCH3
`
`O N
`
`II
`
`I
`
`CH;— —k N | H
`
`CH
`/ 3
`I
`\
`N
`
`O N
`II
`|
`CH2—S
`
`0/»
`
`/
`I
`\
`N
`
`O N
`||
`|
`CH;—
`
`I|\I
`
`H
`
`N l H
`
`OCH2CF3
`CH3
`
`0 I
`
`O N
`
`N
`
`CH2—S
`
`OCH3
`
`oCH3 0
`
`O N
`
`I
`
`II
`CH2—S
`
`N
`
`N | H
`
`Lansoprazole
`
`OCHFZ
`
`Pantoprazole
`
`I
`
`wherein
`
`Hetl is
`
`R2
`R
`R
`1 \ 3
`/ N
`
`or
`
`I'M
`N
`\ \R5
`I
`/ /
`R's
`
`Het; is
`
`R6
`
`R7
`
`N
`X R8
`N I
`R9
`
`H
`
`N / s
`or X or
`I
`H
`
`N] N %N
`
`R's/l /
`
`X =
`
`—CH— or
`R10
`
`R11
`\
`\
`—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 ?uorine,
`alkylthio, alkoXyalkoXy, dialkylamino, piperidino,
`morpholino, halogen, phenyl and phenylalkoXy;
`R4 and R5 are the same or different and selected from
`hydrogen, alkyl and aralkyl;
`R6v is hydrogen, halogen, tri?uoromethyl, alkyl and
`alkoXy;
`R6—R9 are the same or different and selected from
`hydrogen, alkyl, alkoXy, halogen, halo-alkoXy,
`alkylcarbonyl, alkoXycarbonyl, oXaZolyl, tri?uoroalkyl, 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.
`
`1O
`
`25
`
`55
`
`N | H
`CH
`CH —OCH
`0/ 2\CH2/ 2
`3
`CH3
`C)
`
`O N
`
`I
`
`N
`
`CH2—S
`
`II
`O N
`CH2—
`
`I
`
`CH —N
`3
`\CH2
`CH
`CH: \CH3
`
`65
`
`Pariprazole
`
`Leminoprazole
`
`N | H
`
`T
`
`H
`
`

`
`US 6,365,184 B1
`
`7
`-continued
`
`OCH3
`
`o N /
`II
`|
`5
`CH2_
`\
`
`N
`/ N I
`
`CH3O
`
`T
`
`H
`
`if
`
`N
`
`5—</ N / H
`
`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, di?unisal, tiaprofenic acid, podo
`phyllotoxin derivatives, acemetacin, aceclofenac, droxicam,
`oxaproZin, ?octafenine, phenylbutaZone, proglumetacin,
`?urbiprofen, 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 ?xed 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 signi?cantly
`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
`?exibility 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 de?ned as the amount of proton
`pump inhibitor in the tablets or pellets after being exposed
`to simulated gastric ?uid 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 ?uid 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 speci?c components Which may be used in the
`?xed unit dosage forms of the present invention are de?ned
`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,
`
`10
`
`15
`
`25
`
`45
`
`55
`
`65
`
`cH3
`N
`
`</ N
`
`/
`H
`
`i
`
`O
`
`CH3
`
`o
`N
`CH;— —<
`T
`H
`
`I
`
`\
`N
`
`ocH3
`
`H3C
`
`\
`
`N
`
`OCH3
`H3C / CH3
`
`|
`
`\
`N
`
`0
`
`\ >
`
`N
`
`N
`W
`CH;— —</
`N | H
`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 ?xed 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
`in?ammatory analgesic and anti-pyrretic agents; The IV
`International meeting on side-effects of anti-in?ammatory
`drugs Aug. 7—9, 1995) may be included.
`
`

`
`US 6,365,184 B1
`
`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 ?llers, 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 ?nal preparation. Pharmaceutical constitu
`ents such as ?llers, 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 Al2O30.6MgO.CO20.12H2O, (MgGAl2
`(OH)16CO30.4H2),MgO.Al2O30.2SiO2.nH2O 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
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`10
`such as coating pan, coating granulator or in a ?uidized 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, ?llers 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
`Al2O30.6MgO.CO20.12H2O, (Mg6Al2(OH)16CO30.4H2O),
`MgO.Al2O30.2SiO2.nH2O, 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, eg 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
`enteric coating polymer(s).
`The enteric coating layers contain pharmaceutically
`acceptable plasticiZers to obtain the desired mechanical
`properties, such as ?exibility and hardness of the enteric
`coating layers. Such plasticiZers are for instan