PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6 :
`
`(11) International Publication Number:
`
`WO 97/25064
`
`A61K 45/06, 31144, 31/19, 31/54, 9/26,
`9/54
`
`(43) International Publication Date:
`
`17 July 1997 (17.07.97)
`
`(21) International Application Number:
`
`PCTlSE96/01735
`
`(22) International Filing Date:
`
`20 December 1996 (20.12.96)
`
`(30) Priority Data:
`9600070-8
`
`8 January 1996 (08.01.96)
`
`SE
`
`(for all designated States except US): ASTRA
`(71) Applicant
`AKTIEBOLAG [SE/SE]; S-151 85 deertalje (SE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): DEPUI, Helene [FR/SE];
`Wmngelsgatan 7B, 5-416 62 GOteborg (SE). LUNDBERG,
`Per. Johan [SE/SE]; Torsgatan 6, S-431 38 Molndal (SE).
`
`(74) Agent: ASTRA AKTIEBOLAG; Patent Dept., S-151 85
`Sodeniilje (SE).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GE, GE,
`HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS,
`LT, LU, LV, MD, MG, MK. MN, MW . MX, NO, NZ, PL,
`PT, RO, RU, SD, SE, 86, SI, SK, TJ, TM, TR, '1'1‘, UA,
`UG, US, UZ, VN, ARIPO patent (KE, LS, MW, SD, 82,
`UG), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European patent (AT. BE, CH, DE, DK. ES, FI, FR.
`GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF,
`BJ, CF, CG, CI, CM, GA, GN, ML. MR, NE. SN, TD, TG).
`
`Published
`With international search report.
`
`
`
`treatment.
`
`(54) Title: ORAL PHARMACEUTICAL DOSAGE FORMS COMPRISING A PROTON PUMP INHIBITOR AND A NSAID
`
`(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
`
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`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Viet Nam
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgyatan
`Democratic People‘s Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanlra
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`31
`BR
`BY
`CA
`CF
`CG
`CH
`C1
`CM
`CN
`CS
`CZ
`DE
`DK
`EE
`ES
`Fl
`FR
`GA
`
`Armenia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belams
`Canada
`Central African Republic
`Congo
`Switzerland
`Cue d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Dean
`Estonia
`Spain
`Finland
`France
`Gabon
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`
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`WO 97/25064
`
`PCT/SE96/01735
`
`ORAL PHARMACEUTICAL DOSAGE FORMS COMPRISING A PROTON PUMP
`
`INHIBITOR AND A NSAID
`
`Field of me inveng'on
`
`The present invention is related to new oral pharmaceutical preparations especially for use
`
`in the treatment and prophylaxis of gastrointestinal disorders associated with the use of Non
`
`Steroidal Antiinflarrunatory Drugs (NSAIDs). The present preparations comprise an acid
`
`susceptible proton 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.
`
`BA K ROUND OF
`
`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 (Mch DM. Gastroenterology 1989962662). 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 experienced in 30-60%
`
`of those on NSAID treatment (Larkai EN.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.
`
`IO
`
`15
`
`20
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`25
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`WO 97/25064
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`PCT/SE96/Ol 735
`
`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 problems 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
`
`gastrointestinal side-effects such as prostaglandin analogues, Hz—receptor antagonists or
`
`proton pump inhibitors.
`
`IO
`
`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 complication like bleeding or
`
`perforation badly, should receive prophylactic treatment in connection with their NSAID
`
`15
`
`treatment.
`
`NSAle 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 complication 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 (Catford:Health 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 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
`
`2O
`
`30
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`WO 97/25064
`
`PCT/SE96/01735
`
`ulcers as fast and effectively 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.
`
`Recent studies confirm, that omeprazole significantly reduces the risk of developing gastric
`
`ulcers, duodenal ulcers and also dyspeptic symptoms in patients on continuous NSAID
`
`UBaUnan
`
`m
`
`H
`
`20
`
`25
`
`30
`
`EP 0 426 479 describes tablet compositions comprising a NSAID such as ibuprofen and a
`
`gastric acid inhibiting drug, such as cirnetidin 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 substances 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/transfonnation 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 preparations of proton pump
`
`inhibitors described in the prior art, see for example US -A 4,786,505 (AB Hassle)
`
`comprising omeprazole.
`
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`WO 97/25064
`
`PCT/SE96/Ol 735
`
`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 tablets. 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 compound. The active compounds are preferably an
`
`acid susceptible proton pump inhibitor in combination with one or more NSAIDs and
`
`wherein at least the proton pump inhibitor is protected by an enteric coated layer. These
`
`new dosage forms will simplify the regimen and improve the patient compliance.
`
`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 comprising 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 cyclodexlrin complex (3) included in a fast disintegrating granulate
`
`(4). The tablet is covered by a filmcoating layer (13).
`
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`10
`
`[5
`
`20
`
`25
`
`30
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`WO 97/25064
`
`PCT/SE96/01735
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`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 (l) in
`
`admixture with excipients (5) and the other layer comprises a N8 AID (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 ( l) 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 (1 l) 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 desa’ipg'gn Qf 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 NSAle and
`
`tablet excipients compressed into a tablet The enteric coating layer(s) covering the
`
`individual 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
`
`IO
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`15
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`20
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`25
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`30
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`WO 97/25064
`
`PCT/SE96/01735
`
`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 coating layered units of the acid susceptible substance and the other
`
`active substance(s) in the granulated material constituting the rest of the compressed tablet,
`
`as shown in Fig. 1.
`
`Alternatively, the different active substances may be intimately mixed with each other and
`
`compressed into a conventional 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 dosage 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 preparation the acid susceptible proton pump inhibitor is in the form of
`
`10
`
`[5
`
`20
`
`25
`
`30
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`WO 97/25064
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`PCT/SE96/01735
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`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. Alternatively, the components may be formulated in an effervescent
`
`formulation. Furthermore, as some NSAID(s) are light sensitive the formulation is
`
`preferably light protected by a pigmented tablet filmcoating layer, as exemplified in Fig. 6,
`
`or by including a pigment in one of the coating layers to be applied on the tableted dosage
`
`IO
`
`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.
`
`Ativ
`
`b
`
`n
`
`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
`
`0u
`
`Hetl- X—S -Het.l
`
`1
`
`wherein
`
`15
`
`20
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`25
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`WO 97/25064
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`PCT/SE96/01735
`
`8
`
`or
`
`/
`
`Alf/S
`or AN
`.
`H
`
`__
`
`R2
`I \ R3
`
`/
`N
`
`R]
`
`R5
`
`I
`
`“H
`H
`
`R
`
`7
`R8
`
`R9
`
`—C'H—
`R10
`
`0’
`
`Hetl is
`
`Hetz 15
`
`X =
`
`wherein
`
`3
`a ‘Rs
`
`r
`R5
`
`/N
`
`:N]
`
`N
`/
`
`or
`
`R's
`
`R11
`
`R12
`
`10
`
`15
`
`20
`
`N in the benzimidazole moiety means that one of the carbon atoms substituted by R5-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;
`
`R5’ is hydrogen, halogen, u'ifluoromethyl, alkyl and alkoxy;
`
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`W0 97/2 5064
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`PCT/SE96/Ol 735
`
`Ré-Rg are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo-
`
`alkoxy, alkylcarbonyl, alkoxycarbony], 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
`
`R“ 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
`
`N
`
`CH2_SHa?_“\N—/©/OCH3
`
`Omeprazole
`
`H
`
`10
`
`15
`
`OCH3O
`/’
`
`\N’
`
`o
`COCH
`
`l:::-s-—k;:]:::I:CH
`
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`WO 97/25064
`
`PCT/SE96/01735
`
`10
`
`/ \
`
`N $4.17ng
`
`H
`
`Lansoprazole
`
`m
`
`Pantoprazole
`
`N
`
`[I N
`
`H
`
`|
`
`N
`
`H
`
`0CH2CF3
`
`CH3
`
`OH
`
`CH2— 8
`
`0
`N
`
`OCH3
`
`o
`N
`
`OCH3
`
`0
`H
`CH2— S
`
`C
`
`/ Hz\CH2/
`
`CH —OCH
`
`0
`N
`
`H3
`
`0
`H
`CH2_ S
`
`N“
`
`N
`
`H
`
`Pariprazolc
`
`10
`
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`WO 97/25064
`
`PCT/SE96/01735
`
`ll
`
`CHr" S
`
`[I
`
`Lcminoprazolc
`
`CH3-—-N
`
`CH
`
`|
`
`2
`
`CH
`/ \
`CH3
`CH3
`
`T
`H
`
`OCH3
`
`O
`N
`
`O
`
`" vsS
`CHz ”" S —J\N \
`
`H
`
`/ N
`
`
`
`10
`
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`WO 97/25064
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`PCT/SE96/0l 735
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`12
`
`OCH3
`
`H30
`
`\ CH3
`
`/
`
`N
`
`N
`
`0
`II
`/_<
`CH —s
`
`I
`H
`
`/
`
`\ I
`N
`
`OCH3
`
`00:43
`
`H30
`
`CH3
`
`\
`
`N
`
`CHz—s_</ :O/(N
`
`i
`
`\
`
`0
`n
`
`N
`
`H“
`H
`
`The acid susceptible proton pump inhibitors used in the dosage forms of
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`the invention may be used in their neutral form or in the form of an alkaline salt, such as for
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`instance the Mgz“,Ca2+,Na+ , K+ or Li+salts, preferably the Mg2+ salts. Further where
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`applicable, the compounds listed above may be used in racemic form or in the form of the
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`substantially pure enantiomer thereof, or alkaline salts of the single enantiomers.
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`Suitable proton pump inhibitors are for example disclosed in EP-A1-0005129,
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`EP-A1-174 726. EP-Al-l66 287, GB 2 163 747 and WO90/06925,
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`WO91/197] l, W091/19712, and further especially suitable compounds are
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`described in W095/Ol977 and WO94/27988.
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`A wide variety of NSAle may be used in combination with a suitable proton pump
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`inhibitor and optional pharmaceutically acceptable excipients in the fixed unit dosage form
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`according to the present invention. Such NSAIDs include for example propionic acid
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`‘derivatives, oxicams, acetic acid and acetamide derivatives, salicylic acid derivatives and
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`pyrazolidine derivatives.
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`lo
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`15
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`20
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`WO 97/25064
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`PCT/SE96/01735
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`13
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`Also future NSAIDs like cyclooxygenase (COX) 2 selective NS AIDS and NO-releasing
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`NSAIDs (dc Soldato P, NO-releasing NSAlDzs, A new class of safer anti-inflammatory
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`analgesic and anti-pyrretic agents; The IV International meeting on side-effects of anti-
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`inflammatory drugs August 7 — 9, 1995) may be included.
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`In the following examples of some suitable NSAIDs are listed: Acetyl salicylic acid,
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`indometacin, diclofenac, piroxicam, tenoxicam, ibuprofen, naproxen, ketoprofen,
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`nabumetone, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, sulindac, diflunisal,
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`tiaprofenic acid, podophyllotoxin derivatives, acemetacin, aceclofenac, droxicam,
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`oxaprozin, floctafenine, phenylbutazone, proglumetacin, flurbiprofen, tolrnetin and fenbufen.
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`The active NSAIDs could be in standard forms or used as salts, hydrates, esters etc. A
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`combination of two or more of the above listed drugs may be used. Preferable NSAIDs for
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`the new fixed dosage form are diclofenac, ibuprofen, naproxen and piroxicam.
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`The preferred multiple unit tableted dosage form comprising a proton pump inhibitor (in the
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`form of a racemat, an alkaline salt or one of its single enantiomers) and one or more
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`NSAIDS, is characterized in the following way. Individually enteric coating layered units
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`(small beads, granules or pellets) containing the proton pump inhibitor and optionally
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`containing alkaline reacting substances, are mixed with the NSAID(s) and conventional
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`tablet excipients. Preferably, the NS AID(s) and tablet excipients are in the form of a
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`granulation. The dry mixture of enteric coating layered units, NSAlD granules and optional
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`excipients are compressed into multiple unit tableted dosage forms. With the expression
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`“individual units” is meant small beads, granules or pellets, in the following referred to as
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`pellets of the acid susceptible proton pump inhibitor.
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`The compaction process (compression) for formulating the multiple unit tableted dosage
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`form must not significantly affect the acid resistance of the enteric coating layered pellets
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`comprising the acid susceptible proton pump inhibitor. In other words the mechanical
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`properties, such as the flexibility and hardness as well as the thickness of the enteric coating
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`IO
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`15
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`20
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`25
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`30
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`WO 97/25064
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`PCT/SE96/01735
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`14
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`layer(s), must secure that the requirements on enteric coated articles in the United States
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`Pharmacopeia are accomplished in that the acid resistance does not decrease more than
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`10% during the compression of the pellets into tablets.
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`The acid resistance is defined as the amount of proton pump inhibitor in the tablets or
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`pellets after being exposed to simulated gastric fluid USP, or to 0,1 M HCl (aq) relative to
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`that of unexposed tablets and pellets, respectively. The test is accomplished in the following
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`way. Individual tablets or pellets are exposed to simulated gastric fluid of a temperature of
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`37°C. The tablets disintegrate rapidly and release the enteric coating layered pellets to the
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`medium. After two hours the enteric coating layered pellets are removed and analyzed for
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`content of the proton pump inhibitor using High Performance Liquid Chromatography
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`(HPLC).
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`Further specific components which may be used in the fixed unit dosage forms of the
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`present invention are defined below.
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`rematrial-f
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`te‘cc tinl
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`r
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`eet
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`The core material for the individually enteric coating layered pellets can be constituted
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`according to different principles. Seeds layered with the proton pump inhibitor, optionally
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`mixed with alkaline substances, can be used as the core material for the further processing.
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`The seeds which are to be layered with the proton pump inhibitor can be water insoluble
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`seeds comprising different oxides, celluloses, organic polymers and other materials, alone or
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`in mixtures or water-soluble seeds comprising different inorganic salts, sugars, non-pareils
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`and other materials, alone or in mixtures. Further, the seeds may comprise the proton pump
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`inhibitor in the form of crystals, agglomerates, compacts etc. The size of the seeds is not
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`essential for the present invention but may vary between approximately 0.1 and 2 mm. The
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`seeds layered with the proton pump inhibitor are produced either by powder or
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`10
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`15
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`20
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`25
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`WO 97/25064
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`PCT/SE96/0] 735
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`15
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`solution/suspension layering using for instance granulation or spray coating layering
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`equipment
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`Before the seeds are layered, the proton pump inhibitor may be mixed with further
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`components. Such components can be binders, surfactants fillers, disintegrating agents,
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`alkaline additives or other and/or phannaceutically acceptable ingredients alone or in
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`mixtures. The binders are for example polymers such as hydroxypropyl methylcellulose
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`(HPMC), hydroxypropyl-cellulose (HPC), carboxymethylcellulose sodium, polyvinyl
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`pyrrolidone (PVP), or sugars, starches or other pharmaceutically acceptable substances with
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`cohesive properties. Suitable surfactants are found in the groups of pharmaceutically
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`acceptable non-ionic or ionic surfactants such as for instance sodium lauryl sulfate.
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`Alternatively, the proton pump inhibitor optionally mixed with alkaline substances and
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`further mixed with suitable constituents can be formulated into a core material. Said core
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`material may be produced by extrusion/spheronization, balling or compression utilizing
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`conventional process equipment. The size of the formulated core material is approximately
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`between 0.1 and 4 mm and preferably between 0.1 and 2 mm. The manufactured core
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`material can further be layered with additional ingredients comprising the proton pump
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`inhibitor and/or be used for further processing.
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`The proton pump inhibitor is mixed with pharmaceutical constituents to obtain preferred
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`handling and processing properties and a suitable concentration of the proton pump
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`inhibitor in the final preparation. Pharmaceutical constituents such as fillers, binders,
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`lubricants, disintegrating agents, surfactants and other pharmaceutically acceptable additives
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`may be used.
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`10
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`15
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`20
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`Further, the proton pump inhibitor may also be mixed with an alkaline, pharmaceutically
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`acceptable substance (or substances). Such substances can be chosen among, but are not
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`restricted to substances such as the sodium, potassium, calcium, magnesium and aluminium
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`30
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`salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or
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`WO 97/25064
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`PCT/SE96/01735
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`16
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`organic acids; aluminium hydroxide/sodium bicarbonate coprecipitate; substances normally
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`used in antacid preparations such as aluminium, calcium and magnesium hydroxides;
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`magnesium oxide or composite substances, such as A1203.6MgO.C02.12H20,
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`(Mg5A12(OH)mC03.4H20), MgO.A1203. ZSiOZ.nH20 or similar compounds; organic pH-
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`buffering substances such as trihydroxymethylaminomethane, basic amino acids and their
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`salts or other similar, pharmaceutically acceptable pH-buffering substances.
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`Alternatively, the aforementioned core material can be prepared by using spray drying or
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`spray congealing technique.
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`Enteric coating layer; 51
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`Before applying the enteric coating layer(s) onto the core material in the form of individual
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`pellets, the pellets may optionally be covered with one or more separating layer(s)
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`comprising pharmaceutical excipients optionally including alkaline compounds such as pH-
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`buffering compounds. This/these separating layer(s), separate(s) the core material from the
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`outer layers being enten’c coating layer(s). This/these separating layer(s) protecting the core
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`material of proton pump inhibitor should be water soluble or rapidly disintegrating in water.
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`10
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`15
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`The separating layer(s) can be applied to the core material by coating or layering procedures
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`in suitable equipments such as coating pan, coating granulator or in a fluidized bed
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`apparatus using water and/or organic solvents for the coating process. As an alternative the
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`separating layer(s) can be applied to the core material by using powder coating technique.
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`The materials for the separating layers are pharmaceutically acceptable compounds such as,
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`for instance, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl
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`acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulosc, hydroxypropyl methyl
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`cellulose, carboxymethylcellulose sodium, water soluble salts of enteric coating polymers
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`and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments,
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`fillers anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium
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`30
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`dioxide, talc and other additives may also be included into the separating layer(s).
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`WO 97/25064
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`PCT/SE96/01735
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`17
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`When the optional separating layer, is applied to the core material it may constitute a
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`variable thickness. The maximum thickness of the separating layer(s) is normally only
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`limited by processing conditions. The separating layer may serve as a diffusion barrier and
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`may act as a pH-buffering zone. The pI-I-buffering properties of the separating layer(s) can
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`be further strengthened by introducing into the layer(s) substances chosen from a group of
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`compounds usually used in antacid formulations such as, for instance, magnesium oxide,
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`hydroxide or carbonate, aluminium or calcium hydroxide, carbonate or silicate; composite
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`aluminium/magnesium compounds such as, for instance A1203.6Mg0.C02.12H20,
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`(Mg6A12(OH)16C03.4H20), MgO.A1203_25i02.nH20, aluminium hydroxide/sodium
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`bicarbonate coprecipitate or similar compounds; or other pharrnaceutically acceptable pH-
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`buffering compounds such as, for instance the sodium, potassium, calcium, magnesium and
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`aluminium salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic
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`acids; or suitable organic bases, including basic amino acids and salts thereof. Talc or other
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`compounds may be added to increase the thickness of the layer(s) and thereby strenghten
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`the diffusion barrier. The optionally applied separating layer(s) is not essential for the
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`invention. However, the separating layer(s) may improve the chemical stability of the active
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`substance and/or the physical properties of the novel multiple unit tableted dosage form.
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`Alternatively, the separating layer may be formed in situ by a reaction between an enteric
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`coating polymer layer applied on the core material an