`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`A61K 9/28, 9/50, 31/34, 31/485, 31/635,
`31/13
`
`Al
`
`(11) International Publication Number:
`
`WO 98/27967
`
`(43) International Publication Date:
`
`2 July 1998 (02.07 .98)
`
`(21) International Application Number:
`
`PCT/DK97/00582
`
`(22) International Filing Date:
`
`18 December 1997 (18.12.97)
`
`(30) Priority Data:
`1456/96
`
`20 December 1996 (20.12.96) DK
`
`(71) Applicant
`States
`designated
`all
`(for
`DUMEX-ALPHARMA A/S
`[DK/DK];
`11, DK-2300 Copenhagen S (DK).
`
`except US):
`Dalslandsgade
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only):
`ROMMELMA YER
`LARSEN, Annette [DK/DK]; Espegc'lrdsvej 26A, DK-2880
`Bagsvrerd (DK). PEDERSEN, Steen [DK/DK]; Gr0nnevej
`84, 2. tv., DK-2830 Virum (DK).
`
`(74) Agent: HOFMAN-BANG & BOUTARD, LEHMANN & REE
`A/S; Hans Bekkevolds Alie 7, DK-2900 Hellerup (DK).
`
`(81) Designated States: AL, AM, AT, AT (Utility model), AU, AZ,
`BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, CZ (Utility
`model), DE, DE (Utility model), DK, DK (Utility model),
`EE, EE (Utility model), ES, FI, FI (Utility model), GB, GE,
`GH, GM, GW, HU, ID, 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, SG, SI, SK, SK
`(Utility model), SL, TJ, TM, TR, TT, UA, UG, US, UZ,
`VN, YU, ZW, ARIPO patent (GH, GM, KE, LS, MW, SD,
`SZ, UG, ZW), 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), OAP!
`patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE,
`SN, TD, TG).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title: RELEASE-CONTROLLED COATED TABLETS
`
`(57) Abstract
`
`A tablet suitable for oral administration being formed from the following ingredients: a) an inner core containing a biologically active
`agent and conventional excipients (part B) and a pharmaceutically acceptable, water insoluble, non-swellable carrier (part A), wherein part
`A constitutes from 20 % to 70 % by weight of the core; b) an entering coating, which prevents gastric fluid to enter into the core thereby
`preventing drug release in the stomach, but being soluble in the intestinal fluid (pH> 5); and c) an outer coating consisting of one or more
`polymer(s), the permeability of which is independent of pH.
`
`KVK-TECH EXHIBIT 1035
`
`
`
`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.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Annenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`
`
`WO98/27967
`
`PCT/DK97/00582
`
`1
`
`Release-controlled coated tablets.
`
`5
`
`The present invention is concerned with a novel delivery
`system for targeting a wide variety of therapeutically
`active medicaments to the intestine and/or the colon. The
`delivery
`system
`is
`a
`tablet
`suitable
`for
`oral
`administration and comprising three parts:
`
`a biologically active
`inner core containing
`an
`a)
`ingredient and conventional excipients,
`
`10
`
`b) an enteric coating, which prevents gastric fluid to
`enter into the core thereby preventing drug release in
`the stomach, but being soluble in the intestinal fluid
`( pH > 5 ) , and
`
`of
`one or more
`an outer
`c)
`coating consisting
`polyrner(s). The
`permeability of
`the
`outer coating is
`independent of the pH value, therefore the release of the
`drug is largely unaffected by indi victual variations in
`the gastrointestinal fluids.
`
`agents which
`active
`biologically
`the
`Among
`can
`advantageously be formulated and orally administrated in
`form of the tablet of the present invention,
`there are
`considered
`in particular active agents
`for which
`a
`delayed effect and/or a local effect are desired.
`
`In a first aspect of the present invention the tablet can
`be used
`to provide controlled/delayed effect over
`a
`desired period of time.
`
`In a further aspect of the present invention the tablet
`is especially suitable for
`time-varying deli very of a
`drug,
`the s. c. chronobiologically mode of action. E.g.
`patients with elevated blood pressure experience
`that
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`WO 98/27967
`
`PCT/DK97/00582
`
`2
`
`their blood pressure has within-day rhytmicity and that
`high pressure values are often seen in the morning just
`after the patient has woken up. Treatment of the rise in
`blood pressure just after awakening requires a dosage
`form that is administrated at bed-time and delivers the
`drug after a predetermined drug free period. Examples of
`drugs which beneficially can be delivered in this way are
`calcium antagonists like e.g. verapamil.
`
`5
`
`are
`10 Other Examples of drugs, which
`advantageously
`delivered in a
`release-controlled manner, are organic
`nitrates
`like e.g. glyceryl
`trinitrate or
`isosorbide
`nitrates.
`Especially
`preferred
`is
`isosorbide-5-
`mononitrate,
`(l,4:3,6-dianhydro-D-glucitol-5-
`15 mononitrate).
`
`20
`
`Isosorbide-5-mononitrate (5-ISMN) is a vasodilator and an
`arterial dilator. 5-ISMN is an active metabolite of 2,5-
`isosorbide-dini tr ate, which have been used in treatment
`of angina pectoris for many years. Unlike
`the parent
`compound,
`5-ISMN does not undergo hepatic first-pass
`metabolism,
`thus providing
`for
`a greater
`systemic
`bioavailabili ty of the mononi trate dose. 5-ISMN is also
`completely absorbed from the gastrointestinal tract after
`25 oral administration and has a much longer half-life than
`isosorbide dinitrate. These factors make 5-ISMN a more
`attractive form of nitrate therapy for the management of
`angina and also for the development of long-acting oral
`nitrate forms.
`
`30
`
`35
`
`that once-a-day dosing of a drug has
`It is obvious,
`twice-
`or
`three
`times
`a day dosing
`advantages over
`regimens, both from a patient compliance point of view
`but also because it prevents unwanted side-effects like
`high peak/low
`through plasma profile. However,
`if a
`controlled release
`form of 5-ISMN gives a
`serum con-
`
`
`
`WO98/27967
`
`PCT/DK97/00582
`
`3
`
`than 100 ng/ml constantly during 24
`centration more
`hours, development of tolerance is likely to occur.
`
`Nitrate tolerance may be defined as that condition where
`the haemodynamic responsiveness of the target tissue is
`lost. Whilst the direct cause of nitrate tolerance is
`unknown, a possibility may be changes in pharmacokinetics
`or to alterations in the property of target tissues such
`as the arterial and venal smooth muscle, making them less
`sensitive to the nitrate effect.
`
`5
`
`10
`
`for
`regimen
`treatment
`the oldest
`is
`therapy
`Nitrate
`angina pectoris and the phenomenon of nitrate tolerance
`has been observed
`in humans with all commonly known
`15 nitrates, regardless of route of administration. 5-ISMN
`is no exception, and a need exists to design a form that
`overcomes this tolerance effect.
`
`20
`
`25
`
`30
`
`35
`
`Another well-known problem to those skilled in the art of
`treating angina is that many angina patients chronically
`experience discomfort during sleep, just before awakening
`and for the first hour or so upon awakening. A further
`need exists to a form which overcomes this problem.
`
`a nitrate drug for
`to Eastman Kodak,
`In US 4.956.181
`angina pectoris is disclosed, more specifically a method
`and a transdermal patch for treating angina pectoris and
`preventing tolerance to nitrate drugs which takes into
`account
`the frequent need to provide the patient with
`relief or prevention of pre-waking or early morning
`angina. The
`treatment comprises administrating a daily
`unit dose of the nitrate before bedtime in a transdermal
`dosage form that provides a washout period of 3-12 hours
`by sufficiently retarding deli very of the nitrate from
`the patch to the patient during the washout period so as
`to provide a rate of delivery of nitrate that is so low
`
`
`
`WO98/27967
`
`PCT/DK97/00582
`
`4
`
`as to be insufficient to cause tolerance to said nitrate
`in said patient.
`
`5
`
`Dutch patent No. NL 155
`SCHWARZ describes release
`of a granulate containing
`controlled, linear release.
`
`to SANOL-ARZNEIMITTEL DR
`452
`controlled tablets consisting
`talc and sugar with
`5-ISMN,
`
`3 M
`EP 163 000 B to ZERBE, H., KETTELHACK RIKER PH;
`10 MEDICA GMBH deals with controlled release pharmaceutical
`is coated
`with
`pellet,
`in which entero soluble core
`impermeable
`layer,
`5-ISMN-containing
`depot
`layer
`and
`release-controlling layer.
`
`JP 93087488 B to TOA EIYO KK concerns a sustained release
`preparation of hardly soluble medicine, e.g. 5-ISMN, - by
`pelletising mixture of
`5-ISMN with
`release control
`substance and swelling high molecular weight polymer.
`
`EP 219 161 to EURAND ITALIA describes a process for the
`preparation of stabilised 5-ISMN tablets, being also of
`sustained release, and form thus obtained. The tablets
`are containing PVP & hydroxypropyl methylcellulose.
`
`In JP 62126127 to KANEBO, production of long-releasing 5-
`ISMN preparation by spray coating with a solution of
`ethylcellulose and macrogol is disclosed.
`
`EP 240 351 to HANS LOWEY discloses a method of preparing
`controlled
`long acting pharmaceutical
`forms
`in unit
`dosage form having uniform and comparable bioavailability
`characteristics in which cellulose derivatives is mixed
`with 5-ISMN.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`WO98/27967
`
`PCT/DK97/00582
`
`5
`
`to ROBERTO VALDUCCI, pellets with a
`In EP 263 083 B
`medicament layer (e.g. 5-ISMN) applied thereon is coated
`with
`a membrane of steric acid & ethylcellulose.
`Sustained release from 4-22 h. is achieved.
`
`to ELAN CORP. discloses 5-ISMN oral and
`EP 325 843
`transdermal compositions, e.g. a once-a-day tablet. Onto
`non-parail seeds 5-ISMN, acid/diluent are applied and
`polymer blend is superimposed onto
`the core, which is
`then coated with a mix. of water-insoluble &
`and to a
`lesser degree) water-soluble polymer, e.g. Eudragi t RS®
`and RL®. The tablet insures a therapeutic level of ISMN
`in 14-18 h.
`followed by a wash-out period to prevent
`tolerance.
`
`EP 396 425 B to KV PHARM. CO. deals with extended release
`oral pharmaceutical compositions containing 5-ISMN,
`comprising a mixture of
`immediate release and coated
`particles for release of drug over 12-24 h. Membrane
`coating of the particles may be with Eudragit®.
`
`In EP 477061, PIERRE FABRE MEDICAMENT discloses prolonged
`release 5-ISMN
`tablets
`used for angina and cardiac
`insufficiency treatment.
`
`The granulate comprises 5-ISMN,
`hydrophilic polymer & diluent.
`
`swelling agent, e.g.
`
`an orally
`PHARMA describes
`SCHWARZ
`to
`92/05774
`WO
`administrated solvent
`free pharmaceutical preparation
`with delayed 5-ISMN release, in which 5-ISMN is dissolved
`in a matrix of polyvinylacrylate.
`
`INDUSTRIAL CO. LDT. discloses in EP 482 576 a
`FREUND
`prolonged release dosage form of 5-ISMN
`and method,
`in
`which 5-ISMN is microincapsulated with a water insoluble
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`
`
`WO98/27967
`
`PCT/DK97 /00582
`
`6
`
`material, e.g. hydrophobic
`are
`then granulated
`and
`methods.
`
`polymers. The microcapsules
`tabletted by
`conventional
`
`sustained-release
`concerns
`to YAMANOUCHI
`9406414
`WO
`preparation which releases 5-ISMN in the lower intestine
`for stable, sustained release,
`in the form of a matrix
`tablet consisting of 5-ISMN dissolved in hydrogel forming
`polymer, capable of swelling and releasing the active
`drug in the gastrointestinal tract.
`
`WO 94/25010 to BYK NEDERLAND discloses a solid form of
`administration of 5-ISMN. An
`inert core with a first
`layer of 5-ISMN, PEG, PVP & HPMC is coated with a mixture
`of ethylcellulose/Eudragi t 3: 1 - 3: 2.
`The release is pH
`independent.
`
`to
`WO 96/26722
`prevent
`stroke
`hypertension.
`
`to
`the use of 5-ISMN
`Astra discloses
`in patients with
`isolated
`systolic
`
`In the following 2 patents, 5-ISMN is not mentioned, but
`technologies of relevance is described.
`
`4.432.966
`in US
`describes
`ROUSSEL-UCLAF
`compressed
`the
`tablets coated with two layers,
`outer layer is an
`enterocoating persistent
`to acid
`in
`the stomach,
`the
`inner layer having C.R. properties.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`EURAND discloses in WO 91/ 16042 a targeted drug release
`form for the small intestine or colon consisting of a
`plurality of multidose units
`(< 5 mm), having a core of
`drug surrounded by two membranes, i.e. an inner membrane
`soluble at pH >5
`(e.g. Eudragi t® L30D)
`and an outer
`35 membrane, permeable to G.I. fluids (e.g. Eudragit RS/RL).
`This form may be characterised by the release of no more
`
`
`
`WO 98/27967
`
`PCT/DK97/00582
`
`7
`
`(stomach)
`than 5
`lower
`than 10% drug at pH
`release at pH 6-8 in 1-1½ h. (small intestine).
`
`and 90%
`
`Summary of the invention.
`
`5
`
`10
`
`to provide a
`invention is
`the
`The general object of
`controlled release tablet, wherein
`the release of
`the
`biologically active agent is controlled in such a manner
`that the release is low, e.g. less than 10 %,
`in a first
`period of e.g. 1-6 hours and that the release is high,
`e.g. more than 80 %, and continuous in a second period of
`e.g. 3-12 hours.
`
`This object is obtained with the tablet of the invention,
`the tablet being formed from the following ingredients:
`
`15
`
`a) an inner core containing a biologically active agent
`and
`conventional
`excipients
`(part
`B)
`and
`a
`pharmaceutically
`acceptable, water
`insoluble,
`non-
`swellable carrier (part A) , wherein part A constitutes
`from 20 % to 70 % by weight of the core,
`
`b) an enteric coating, which prevents gastric fluid to
`enter into the core thereby preventing drug release in
`the stomach, but being soluble in the intestinale fluid
`(pH > 5), and
`
`c) an outer coating consisting of one or more polymer(s),
`the permeability of which is independent of pH.
`
`the
`The above-discussed release profile obtained with
`two
`tablet of the invention is believed to result from
`novel factors, viz. 1)
`the presence of the carrier (part
`A)
`in the core and 2)
`the sequence of the two coatings,
`according to which the enteric coating constitutes the
`inner coating.
`
`2 0
`
`25
`
`30
`
`35
`
`
`
`WO 98/27967
`
`PCT/DK97/00582
`
`8
`
`In one of the preferred objects of the present invention
`the aim is to provide angina pectoris patients with a
`controlled release tablet, which should be administrated
`at bedtime, and which tablet has a nitrate-free lag time
`of 1-6 hours,
`followed by
`release of 5-ISMN
`in
`a
`controlled manner. More particularly,
`the preferred
`object of the present invention can be described in the
`following way:
`
`1) At bedtime, a tablet is administrated to a patient in
`need thereof, which tablet contains a premeasured amount
`of 5-ISMN that is effective to treat angina pectoris,
`which tablet has controlled release properties. During
`the best part of the night, no 5-ISMN is released from
`the tablet.
`
`2) At a pre-determined time before awakening, release of
`5-ISMN starts to prevent pre-wakening or early morning
`angina episodes. The release of 5-ISMN continues steadily
`for 3-12 hours.
`
`3) A 5-ISMN free period follows to prevent development of
`tolerance.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`4) At bedtime, the cycle restarts.
`
`Detailed description of the invention.
`
`30 Accordingly, the invention provides a controlled release
`drug containing
`tablet for oral administration,
`said
`tablet comprising:
`
`a) an inner core containing a biologically active agent
`and a pharmaceutically acceptable carrier, which carrier
`
`35
`
`
`
`W098/27967
`
`PCT/DK97 /00582
`
`9
`
`is modified
`controlled,
`
`in such
`
`a way
`
`that
`
`the dissolution
`
`is
`
`5
`
`b) an enteric coating, which prevents gastric fluid to
`enter into the core thereby preventing drug release in
`the stomach, but being soluble in the intestinal fluid
`(pH > 5 ) ,
`
`c) an outer coating consisting of a mixture of one or
`10 more polymer(s). The permeability of the outer coating is
`independent of the pH value, therefore the release of the
`drug is largely unaffected by individual variations in
`the gastrointestinal fluids.
`
`15
`
`The core.
`
`2 0
`
`To our surprise we have found that the composition of the
`core is a critical factor. It has become apparent that if
`the core dissolutes too fast it will be
`impossible to
`produce a coated tablet with a reproducible dissolution
`profile. On
`the other hand if a core
`with delayed
`dissolution
`is produced,
`it has
`unexpectedly been
`possible
`to create a coated tablet with a
`retarded
`dissolution profile. This can be obtained if the carrier
`25 materials consist of two parts, A and B:
`
`30
`
`compounds
`inorganic
`Preferably part A consists of
`consisting of alkaline-, alkaline earth- or aluminium
`salts which
`are
`non-toxic
`and
`pharmaceutically
`acceptable,
`e.g.
`water
`insoluble
`non-swellable
`ingredients which can be calcium phosphate,
`calcium
`hydrogen phosphate, calcium hydrogen phosphate dihydrate,
`calcium carbonate, calcium sulphate, calcium silicate,
`calcium magnesium silicate, kaolin, magnesium oxide,
`35 magnesium carbonate, aluminium silicate, silicium dioxide
`or titanium dioxide. Most preferred is anhydrous calcium
`
`
`
`WO 98/27967
`
`PCT/DK97/00582
`
`10
`
`hydrogen phosphate(also referred to as e.g. anhydrous
`dicalcium phosphate, which can be purchased from Mendell
`under
`the
`trade name Anhydrous Emcompress®. Anhydrous
`Emcompress® is a white, odourless and tasteless granular
`solid. It complies with the specifications of the United
`States Pharmacopeia (U.S.P.) and the Food Chemicals Codex
`(F.C.C.). Preferably, part A constitutes from 20% to 70%,
`preferably 40 % to 55 % by weight of the core.
`
`5
`
`10 Part B consists of a biologically active compound and
`conventional tabulating excipients,
`like e.g. diluents,
`binders
`and
`lubricants.
`Any
`conventional
`tablet
`formulating materials may be used to produce the core.
`The core may be prepared by any conventional means in the
`tablet-forming art, e.g. by direct compression or wet
`granulation method using a suitable tablet compression
`machine. Preferably,
`the granules are compressed into a
`tablet having a weight of 30-800 mg, preferably 200-800
`mg and a hardness of 40-120 N.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`In a preferred form, part A is anhydrous calcium hydrogen
`phosphate, part Bis: diluent= a mixture of lactose and
`microcrystalline cellulose ( e.g. AvicelR) ), the binder=
`a
`mixture
`of
`polyethyleneglycol
`6000
`and
`polyvinylpyrrolidone (e.g. Kollidon 30), the lubricant=
`a mixture of talc and magnesium stearate.
`
`The preferred dissolution profile of the core is 30-60%
`dissolved drug after 1 hour, 60-90% after 2 hours and >
`90% after 5 hours, (according to U.S.P. ~' p. 1795-96.)
`
`The inner coating.
`
`The inner coating is an
`penetration of gastric
`preventing
`any
`drug
`
`enteric coating which prevents
`fluid
`into
`the core,
`thereby
`release
`in
`the
`stomach. Any
`
`
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`WO98/27967
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`PCT/DK97/00582
`
`11
`
`conventional enteric coating materials may be used in the
`delivery system of the invention.
`
`Examples of enteric coating materials are hydroxypropyl
`5 methylcellulose phthalate, polyvinyl acetate phthalate or
`acid/ester
`acrylic-
`and/or methacrylic
`copolymers.
`Preferred is such a copolymer which dissolves in media at
`and above pH 5. Most preferred is Eudragit®L30D, which
`is anionic in character and soluble in the intestine. The
`ratio of free carboxyl groups to ester groups is 1:1 and
`it is supplied as an aqueous dispersion containing 30%
`w/w dry polymer substance. Optionally, plastisizers can
`be
`added
`to
`the
`polymer
`film
`to
`enhance
`its
`characteristics.
`
`10
`
`15
`
`The outer coating.
`
`independent erodible
`The outer coating consists of a pH
`film, which is penetrated and partly solubilized in the
`20 gastrointestinal tract. This coating preferably consists
`of
`one
`or more
`polymer ( s) ,
`e.g.,
`ethylcellulose,
`polysiloxan or polyethylen or copolymers of acrylic(cid:173)
`and/or methacrylic acids/esters like e.g those compounds
`sold under the trade name Eudragit®. Most preferred is
`25 Eudragi t®RL or a mixture of Eudragi t®RL and Eudragi t®
`RS. Eudragit®RS is slightly permeable to gastric fluid,
`RL freely permeable. The difference between the two types
`is the ratio of quaternary ammonium groups
`to neutral
`acid esters, which is 1:40 for RS, 1:20 for RL. The ratio
`of RS
`to RL
`is the release determining factor of the
`outer coating, and this ratio can be from 0:100 to 100:0.
`Optionally, plastisizers can be added to the polymer film
`to
`enhance
`its
`characteristics. Also,
`dissolution
`modifiers can be added to the outer coating to enhance
`the
`dissolution,
`which
`excipients
`can
`be
`e.g.
`polyethylene glycol, mono-, di-, or polysaccharides like
`
`30
`
`35
`
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`WO 98/27967
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`
`12
`
`carboxy-
`hydroxypropylmethylcellulose,
`e.g.
`methylcellulose, xanthan gum, lactose or sucrose.
`
`third coating can be applied to the
`a
`Advantageously,
`a s.c. "sealcoat" which e.g. can be
`coated
`tablet,
`composed of
`a mixture of methylcellulose, propylene
`glycol and silicone liquid. The sole purpose of this
`sealcoat is
`to
`improve
`the shelf-life of
`the coated
`tablets of the invention.
`
`5
`
`10
`
`If desired, a multiple unit dosage form can be prepared
`by filling two or more tablets according to the invention
`into a hard gelatine capsule.
`
`15 Biologically active agents
`
`The biologically active agents which can be incorporated
`into
`the
`release-controlled coated
`tablets are
`any
`substance which posses
`a
`therapeutic or
`any other
`20 beneficial action, e.g. steroids
`like hydrocortisone,
`budesonide, triamcinolone or prednisone; NSAIDS like e.g.
`diclofenac
`sodium, piroxicam, aspirin or ketoprofen;
`analgetic agents like e.g. codein, morphine, oxycodone or
`dihydromorhpone;
`antibiotics
`like
`e.g.
`amoxycillin,
`clavulanic acid or erythromycin, antimicrobic agents for
`the urogenital tract like e.g. nitrofurantoin, nalidixic
`acid
`or
`pipemidic
`acid,
`antihistamines
`and/or
`antiasthamatics
`like
`e.g.
`ephedrine,
`terfenadine,
`theophyllin or methylprednisolone; broncodilators
`like
`e.g. albuterol, salbutamol or
`terfenadine; antiemitics
`like e.g. metoclopramide; antiviral drugs
`like e.g.
`acyclovir, ribavirin or AZT; anti ulcer drugs like e.g.
`ranitidine or cimetidine; Anti-parkinson drugs
`like
`levodopa, carbidopa or benserazide; diuretics like e.g.
`furosemide or thiazides; calcium antagonists like e.g.
`diltiazem, nifedipine or verapamil; drugs for treatment
`
`35
`
`25
`
`30
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`
`13
`
`(ramipril,
`ace-inhibitores
`eg.
`like
`of hypertension
`captopril) beta-blockers (pindolol, metoprolol, sotalol)
`or other drugs for treatment of cardiovascular diseases
`like organic nitrates, e.g. nitroglycerin,
`isosorbide
`5 mono- or dinitrate. The active agents can be in the form
`of salts or derivatives, and can be administrated as a
`single drug or combinations of two or more drugs.
`
`10
`
`15
`
`the active
`In a preferred embodiment of the invention,
`substances are drugs for treatment of various diseases
`associated with pain, inflammation, hypertension and/or
`heart conditions
`
`embodiment
`another preferred
`In still
`ketoprofen,
`is
`selected
`from
`substance
`metoprolol and isosorbide-5-mononitrate.
`
`the
`active
`morphine,
`
`Mode of action.
`
`25
`
`30
`
`20 When a dual-coated tablet of the present invention is
`ingested by a patient, the tablet normally resides in the
`stomach for 1-2 hours. The outer coating posses
`the
`ability to swell and thereby becomes permeable for water
`and dissolved drugs. The permeability of
`the outer
`coating is determined by the thickness of the coating
`and, when
`the outer coating consists of a mixture of
`Eudragit®RS and Eudragit®RL, by the ratio of Eudragit®RS
`to Eudragi t®RL. The
`outer
`coating begins
`to
`swell
`immediately after contact with liquid. When the swelling
`of
`the outer coating starts,
`in acidic medium,
`the
`enteric
`coating will
`prevent
`the
`core
`from
`disintegrating. After 1-6 hours,
`the
`inner coating is
`dissolved, and the biologically active agent will diffuse
`into the intestine. The prolonged release is dependent of
`the permeability and degradation of the coating material.
`
`35
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`
`14
`
`The present invention further relates to a process for
`preparing a tablet as defined in claim 1 comprising the
`steps of 1) mixing and compressing ingredients a) to form
`a core, 2) applying a solution/dispersion of the enteric
`coating b)
`in a first solvent onto the core and drying
`the coated core
`to
`remove
`the first solvent and 3)
`applying a solution/dispersion of the outer coating c) in
`a second solvent onto
`the coated core and drying the
`double-coated core to remove the second solvent.
`
`5
`
`10
`
`the
`the process of
`embodiment of
`a preferred
`In
`invention, the biologically active agent is isosorbide-5-
`mononitrate,
`the core materials are anhydrous calcium
`hydrogen phosphate, lactose, microcrystalline cellulose,
`15 polyvinylpyrrolidone,
`talc and magnesium stearate,
`the
`inner coating is Eudragi t®L 30 D and the outer coating
`is Eudragi t®RL
`or
`a mixture of Eudragi t®RS
`and
`Eudragi t®RL.
`
`20
`
`to a
`invention also relates
`The
`claim 1 for use as a medicament.
`
`tablet as defined in
`
`25
`
`30
`
`Furthermore, the invention relates to the use of a tablet
`as defined in claim 1 in the manufacture of a medicament
`for
`the
`treatment of angina pectoris or other heart
`diseases.
`
`the invention relates to a method of treating
`Finally,
`angina pectoris or other heart diseases, wherein a tablet
`as defined in claim 14 is administrated to a patient in
`need thereof. Preferably, the tablet is administrated to
`the patient at bedtime to prevent pre-wakening or early
`morning angina pectoris.
`
`
`
`WO 98/27967
`
`PCT/DK97/00582
`
`15
`
`Description of the drawings
`
`Figures 1-5 each demonstrate the dissolution profiles of
`6 tablets as a function of time. Each tablet has been
`5 measured
`individually.
`Figure
`6
`and
`7
`show
`the
`dissolution profiles of the coated tablet as a mean value
`of 6 tablets.
`
`Figure 1 and Figure 3 show the dissolution of a coated
`tablet, in which part A of the core is absent.
`
`10
`
`the dissolution of a coated tablet,
`Figure 2 shows
`which core a too large excess of part A has been used.
`
`in
`
`15
`
`The results clearly demonstrate that the ratio between
`the excipients in the core of the coated tablet is a
`critical factor.
`
`Figure 4 shows the dissolution of a first coated tablet
`according to the invention.
`
`20
`
`Figure 5 shows the dissolution of a second coated tablet
`according to the invention.
`
`tablets
`the dissolution of coated
`shows
`6
`Figure
`invention. Example 5
`include 5-ISMN,
`to
`the
`according
`include metoprolol succinate and
`Example 7
`Example 6
`include morphine hydrochloride. The results show that the
`diffusion rate of the drugs through the films depends on
`the physical and chemical properties of the drugs.
`
`Figure 7 shows dissolution of coated tablets according to
`the
`invention. Example 8
`include 5-ISMN, Example 9
`include metoprolol succinate, Example 10 include morphine
`hydrochloride and Example 11 include ketoprofen.
`
`25
`
`30
`
`35
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`W098/27967
`
`PCTIDK97 /00582
`
`16
`
`following,
`The
`preparation of
`
`the
`illustrate
`non-limiting Examples
`the controlled release tablet for oral
`
`administration.
`
`5
`
`EXAMPLE 1
`
`The core
`
`Materials
`10 Each tablet contains:
`Isosorbide-5-mononitrate
`
`15
`
`20
`
`25
`
`30
`
`Lactose
`Microcrystalline Cellulose (Avicel pH 101)
`
`Carboxymethylcellulose sodium (Ac-Di-sol)
`Polyvinylpyrrolidon (Kollidon 30)
`Magnesium Stearate
`Talc
`
`Methods
`
`60 mg
`189 mg
`
`30 mg
`
`12 mg
`3 mg
`3 mg
`3 mg
`
`The cores are being produced by wet granulation in a
`
`blade mixer. The binder solution contains 8% Kollidon 30
`
`in ethanol/ purified water 50:50. The tablets are pressed
`in any tablet compression machine. The average weight of
`the core is 300 mg.
`
`The inner coating
`
`Materials
`
`The spray suspension contains:
`Methacrylic Acid copolymer (Eudragit L30D)
`Triethylcitrate (Eudraflex)
`
`Talc
`
`Antifoam emulsion
`35 Purified water
`
`513.0 g
`15.4 g
`93.6 g
`2. 0 g
`500.0 g
`
`
`
`WO98/27967
`
`PCT/DK97/00582
`
`17
`
`Methods
`
`2200 g cores are being introduced into the fluidized-bed
`machine Glatt GPCG with the Wurster insert. The inlet-air
`is 34-37°C. The nozzle is placed as a bottom spray system
`and with
`a nozzle pressure of 2
`atm. The product
`temperature is 34-35 °C. The spraying rate is about 15
`g/ml. The fluidized air velocity is 180-181 m3 /hour. The
`cores are sprayed for a period of about 60 minutes. The
`tablets are finally removed from the coating machine and
`spread out on trays and dried at 40°C for 4 hours.
`
`5
`
`10
`
`The outer coating
`
`15 Materials:
`The spray suspension contains:
`Amrnoniomethacrylate copolymer
`Amrnoniomethacrylate copolymer
`Triethylcitrate (Eudraflex)
`20 Talc
`Antifoam emulsion
`Purified water
`
`Methods
`
`(Eudragit
`(Eudragi t
`
`RL30D)
`RS30D)
`
`167.0 g
`167.0 g
`20.0 g
`50.0 g
`0.6
`g
`366.0
`g
`
`25
`
`30
`
`35
`
`The tablets are coated in the fluidized-bed machine Glatt
`GPCG with the Wurster insert. The inlet-air is 34-41°C.
`The nozzle is placed as a bottom spray system and with a
`nozzle pressure of 2 atm. The product
`temperature 33-
`35°C. The spraying rate is about 15 g/ml. The fluidized
`air velocity is 180-181 m3/hour. The cores are sprayed
`for a period of about 60 minutes. The tablets are finally
`removed from the coating machine and spread out on trays
`and dried at 40°C for 10 hours.
`
`
`
`WO98/27967
`
`PCT/DK97/00582
`
`18
`
`EXAMPLE 2.
`
`The core
`
`5 Materials
`Each tablet contains:
`Isosorbide-5-mononitrate
`Lactose
`Microcrystalline Cellulose (Avicel pH 101)
`Dibasic calciumphosphate (Emcompresss)
`Polyvinylpyrrolidon (Kollidon 30)
`Magnesium stearate
`Talc
`
`10
`
`60 mg
`15 mg
`
`30 mg
`186 mg
`3 mg
`3 mg
`3 mg
`
`15
`
`The cores are compressed
`Example 1.
`
`and
`
`coated
`
`analogous
`
`with
`
`EXAMPLE 3.
`
`20
`
`The core
`
`Materials
`Each tablet contains:
`Isosorbide-5-mononitrate
`Lactose
`(Avicel
`Microcrystal line Cellulose
`Polyvinylpyrrolidon (Kollidon 30)
`Magnesium stearate
`Talc
`
`pH 101)
`
`60 mg
`201 mg
`30 mg
`3 mg
`3 mg
`3 mg
`
`25
`
`30
`
`The cores are compressed and
`Example 1.
`
`coated
`
`analogous
`
`with
`
`
`
`WO98/27967
`
`PCT/DK97/00582
`
`19
`
`EXAMPLE 4.
`
`The core.
`
`5 Materials
`Each tablet contains:
`Isosorbide-5-mononitrate
`Lactose
`Microcrystalline Cellulose (Avicel pH 101)
`10 Polyethylene glycol 6000
`Calcium hydrogen phosphate
`dihydrate (Calstar)
`Polyvinylpyrrolidon (Kollidon 30)
`Magnesium stearate
`15 Talc
`
`60 mg
`15 mg
`75 mg
`6 mg
`
`135 mg
`3 mg
`3 mg
`3 mg
`
`The cores are compressed and coated analogous with
`Example 1.
`
`20
`
`EXAMPLE 5
`
`The core composition and the inner coating are analogous
`with Example 4.
`
`25
`
`The outer coating
`
`Materials:
`The spray suspension contains:
`Arnrnoniomethacrylate copolymer (Eudragit RL30D)
`30 Arnrnoniomethacrylate copolymer (Eudragit RS30D)
`Triethylcitrate (Eudraflex)
`Talc
`Antifoam emulsion
`Purified water
`
`251.00 g
`84.00 g
`20.00 g
`50.00 g
`0.55 g
`403.00 g
`
`35
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`WO98/279