a2) United States Patent
`US 8,293,273 B2
`(10) Patent No.:
`(45) Date of Patent:
`*Oct. 23, 2012
`Villa et al.
`
`
`US008293273B2
`
`(54) CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITION
`
`(75)
`
`Inventors: Roberto Villa, Lecco (IT); Massimo
`Pedrani, Gignese (IT); Mauro Ajani,
`Milan (IT); Lorenzo Fossati, Milan (IT)
`
`(73) Assignee: Cosmo Technologies Limited, Dublin
`(IE)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 13/462,409
`
`(22)
`
`Filed:
`
`May 2, 2012
`
`(65)
`
`Prior Publication Data
`
`US 2012/0213850 Al
`
`Aug. 23, 2012
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 13/249,839, filed on
`Sep. 30, 2011, which is a continuation of application
`No. 12/210,969,filed on Sep. 15, 2008, now Pat. No.
`8,029,823, which is
`a
` continuation-in-part of
`application No. 10/009,532, filed as application No.
`PCT/EP00/05356 on Jun. 9, 2000, now Pat. No.
`7,431,943.
`
`(30)
`
`Foreign Application Priority Data
`
`Jun. 14,1999
`Mar. 3, 2000
`
`IT) ce eecneeeeeee MI99A001317
`(IT) wo eeeeeeteeeseeeeneees MI00A000422
`
`(51)
`
`Int. Cl.
`(2006.01)
`AGIK 9/20
`(2006.01)
`AGIK 9/28
`(2006.01)
`AGIK 9/30
`(52) U.S.C occ 424/464; 424/474; 424/475
`(58) Field of Classification Search «0.0.0.0... None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,608,248 A
`5,320,848 A
`5,342,625 A
`5,534,501 A
`5,597,844 A
`5,643,602 A
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`5,840,332 A
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`7,410,651 B2*
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`7/2001 New
`4/2002 Akiyama
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`8/2008 Villaetal. wou... 424/468
`
`8/2008 Villa etal.
`7,410,652 B2
`7,431,943 B1* 10/2008 Villaetal. oe 424/468
`8,029,823 B2* 10/2011 Villaetal. we 424/464
`2012/0021052 Al
`1/2012 Villa etal.
`2012/0021053 Al
`1/2012 Villa etal.
`
`CA
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`FOREIGN PATENT DOCUMENTS
`2119253
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`0453001 Al
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`6510772
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`6511478
`12/1994
`8503482
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`2000510488
`8/2000
`2000515130
`11/2000
`93/00889 Al
`1/1993
`96/13273
`5/1996
`9800169
`1/1998
`WO 99/11245
`3/1999
`WO 99/17752
`4/1999
`
`OTHER PUBLICATIONS
`
`Jantzen, G.M.et al., “Sustained- and Controlled-Release Drug Deliv-
`ery Systems,” Modem Pharmaceutics, 3rd Edition, Revised and.
`Expanded, pp. 575-609, © 1996 by Marcel Dekker, Inc., 37 pages.
`Steward,P., “Review of Pharmaceutical Controlled Release Methods
`and Devices”, 1995, pp. 1-9.
`Jantzen,et al., “Sustained/Controlled-Release Drug Delivery”, Mod-
`ern Pharmaceutics, 3rd Edition, pp. 582-589.
`Physical Pharmacy, Chapter 19: Drug Product Design, Oct. 1993, pp.
`515-519.
`Moro, et al., “Drug Delivery Systems: Diffusion Controlled Sys-
`tems”, II Prodotto Chimico & Aerosol Selezione (The Chemical &
`Aerosol Selection), Apr. 1985, pp. 16-24.
`Brunner, M. et al., “Gastrointestinal Transit, Release and Plasma
`Pharmacokinetics of a New Oral Budesonide Formulation,” British
`Journal of Clinical Pharmacology, DOI:10.1111/).1365-2125.2005.
`02517.x, pp. 1-8, copyright 2005 Blackwell Publishing Ltd., 8 pages.
`Brunner, M. et al., “Gastrointestinal Transit and 5-ASA Release
`From a New Mesalazine Extended-Release Formulation,” Alimen-
`tary Pharmacology and Therapeutics, vol. 17, pp. 395-402, copyright
`2003 Blackwell Publishing Ltd., 8 pages.
`
`(Continued)
`
`Primary Examiner — Susan Tran
`
`(74) Attorney, Agent, or Firm — Rothwell, Figg, Emst &
`Manbeck p.c.
`
`(57)
`
`ABSTRACT
`
`Controlled release and taste masking compositions contain-
`ing one or moreactive principles inglobated in a three-com-
`ponent matrix structure,i.e. a structure formed by successive
`amphiphilic, lipophilic or inert matrices and finally inglo-
`bated or dispersed in hydrophilic matrices. The use of a plu-
`rality of systems for the control ofthe dissolution ofthe active
`ingredient modulates the dissolution rate of the active ingre-
`dient in aqueous and/or biological fluids, thereby controlling
`the release kinetics in the gastrointestinaltract.
`
`4 Claims, No Drawings
`Cosmo Ex 2016-p. 1
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`IPR2017-01035
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`US 8,293,273 B2
`Page 2
`
`OTHER PUBLICATIONS
`Angelucci et al., “Budesonide for Inflammatory Bowel Disease
`Treatment,” Current Medicinal Chemistry, 2008, vol. 15, No. 14, pp.
`2-9.
`D’Haens, G.R.et al., “Budesonide MMX™Is Active and Safe in
`Patients With Active Left-Sided Ulcerative Colitis,” Br J Clinic
`Pharmacol., 2005, vol. 61, 3 pages.
`Sandborn, W.J., “Budesonide MMX®9 mg: Analysis ofPooled Data
`From Two Phase 3 Studies,” poster, 1 page.
`Maejima,T., “Application of Tumbling Melt Granulation Method to
`Prepare Controlled-Release Beads by Coating with Mixture of Func-
`tional Non-Meltable and Meltable Materials,” Chem. Pharm. Bull.,
`1998, vol. 46, No. 3, pp. 531-533, © 1998 Pharmaceutical Society of
`Japan.
`Sandborn, W.J.et al., “Budesonide MXX® 9 mgFor the Induction of
`Remission of Mild-to-Moderate Ulcerative Colitis (UC): Data From
`a Multicenter, Randomized, Double-Blind Placebo-Controlled Study
`in North America and India,” Presentation at DDW 2011, Poster, 1
`page.
`
`D’Haens, G.R., et al., “Clinical Trial: Preliminary Efficacy and.
`Safety Study of a New Budesonide-MMX® 9 mg Extended-Release
`Tablets in Patients With Active Left-Sided Ulcerative Colitis,” Jour-
`nal of Crohn’s and Colitis, 2010, vol. 4, pp. 153-160, © copyright
`2009 European Crohn’s and Colitis Organisation.
`Flanders, P. et al., The Control of Drug Release From Conventional
`Melt Granulation Matrices, Drug Development and Industrial Phar-
`macy, 1987, vol. 13, No. 6, pp. 1001-1022, © 1987 Marcel Dekker,
`Inc.
`“Estimation and Characterisation of
`al.,
`et
`P.
`Ferraboschi,
`Budesonide Tablets Impurities,” Journal of Pharmaceutical and Bio-
`medical Analysis, 2008, vol. 47, pp. 636-640, © 2008 Elsevier B.V.
`Fiorino, G. et al., “New Drug Delivery Systems in Inflammatory
`Bowel Disease: MMX™and Tailored Delivery to the Gut,” Current
`Medicinal Chemistry, 2010, vol. 17, pp. 1851-1857, © 2010 Bentham
`Science Publlishers Ltd.
`Koutroubakis, I., “Recent Advances in the Managementof Distal
`Ulcerative Colitis,’ World Journal of Gastrointestinal Pharmacology
`and Therapeutics, 2010, vol. 1, No. 2, pp. 43-50, © 2010 Baishideng.
`
`* cited by examiner
`
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`

`US 8,293,273 B2
`
`1
`CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of application Ser. No.
`13/249,839 filed on Sep. 30, 2011; which is a continuation of
`application Ser. No. 12/210,969 filed on Sep. 15, 2008, now
`USS. Pat. No. 8,029,823; which is a continuation-in-part of
`application Ser. No. 10/009,532 filed on Dec. 12, 2001, now
`US. Pat. No. 7,431,943; which is the 35 U.S.C. 371 national
`stage of International application PCT/EP00/05356 filed on
`Jun. 9, 2000; which claimedpriority to Italian applications
`MI20004000422 and MI99A001317 filed Mar. 3, 2000 and
`Jun. 14, 1999, respectively. The entire contents of each of the
`above-identified applications are hereby incorporated byref-
`erence.
`
`BACKGROUND OF THE INVENTION
`
`Thepresent inventionrelates to controlled release andtaste
`masking compositions containing budesonide as active ingre-
`dient incorporated in a three-component matrix structure,i.e.
`a structure formed by successive amphiphilic, lipophilic or
`inert matrices andfinally incorporatedor dispersed in hydro-
`philic matrices. The use of a plurality of systems mechanism
`for the control of the dissolution of the active ingredient
`modulates the dissolution rate of the active ingredient in
`aqueous and/or biological fluids,
`thereby controlling the
`release kinetics in the gastrointestinal tract, and it also allows
`the oral administration of active principles having unfavour-
`able taste characteristics orirritating action on the mucosae of
`the administration site, particularly in the buccal or gastric
`area.
`
`The compositions of the invention are suitable to the oral
`administration or the efficaciously deliver the active ingredi-
`ent acting topically at some areas ofthe gastrointestinaltract.
`The preparation of a sustained, controlled, delayed,
`extended or anyhow modified release form can be carried out
`according to different techniques:
`1. The use ofinert matrices, in which the main componentof
`the matrix structure opposes someresistance to the pen-
`etration of the solvent due to the poor affinity towards
`aqueousfluids; such property being knownaslipophilia.
`2. The use of hydrophilic matrices, in which the main com-
`ponent of the matrix structure opposes high resistance to
`the progressof the solvent, in that the presence of strongly
`hydrophilic groups in its chains, mainly branched, remark-
`ably increases viscosity inside the hydrated layer.
`3. The use ofbioerodible matrices, which are capable ofbeing
`degraded by the anzimes of some biological compartment.
`All the procedures listed above suffer, however, from draw-
`backs and imperfections.
`Inert matrices, for example, generally entail non-linear, but
`exponential, release of the active ingredient.
`Hydrophilic matrices: have a linear behaviour until a cer-
`tain fraction of active ingredient has been released, then sig-
`nificantly deviate from linear release.
`Bioerodible matrices are ideal to carry out the so-called
`“sire-release”, but they involve the problem of finding the
`suitable enzymeor reactive to degradation. Furthermore, they
`frequently release in situ metabolites that are not wholly
`toxicologically inert.
`A numberof formulations based oninert lipophilic matri-
`ces have been described: Drug Dev. Ind. Pharm.13 (6), 1001-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`aan
`
`2
`1022, (1987) discloses a process making use of varying
`amounts of colloidal silica as a porization elementfor a lipo-
`philic inert matrix in which the active ingredient is incorpo-
`rated
`The same notion of canalization of an inert matrix is
`described in U.S. Pat. No. 4,608,248 in which a small amount
`of a hydrophilic polymer is mixed with the substances form-
`ing an inert matrix, in a non sequential compenetration of
`different matrix materials. EP 375,063 discloses a technique
`for the preparation of multiparticulate granules for the con-
`trolled-release of the active ingredient which comprises co-
`dissolution of polymers or suitable substances to form a inert
`matrix with the active ingredient and the subsequent deposi-
`tion of said solution on an inert carrier which acts as the core
`
`of the device. Alternatively, the inert carrier is kneaded with
`the solution containing the inert polymerandtheactive ingre-
`dient, then the organic solvent usedforthetheir dissolution is
`evaporated off to obtain a solid residue. The resulting struc-
`ture is a “reservoir”, i.e. is not macroscopically homogeneous
`along all the symmetry axis of the final form. The same
`“reservoir”structure is also described in Chem. Pharm.Bull.
`
`46 (3), 531-533, (1998) which improves the application
`through an annealing technique of the inert polymer layer
`which is deposited on the surface ofthe pellets.
`To the “reservoir” structure also belong the products
`obtained according to the technique described in WO
`93/00889 which discloses a process for the preparation of
`pellets in hydrophilic matrix which comprises: —dissolution
`ofthe active ingredient with gastro resistant hydrophilic poly-
`mers in organic solvents; —dryingofsaid suspension; —sub-
`sequent kneading and formulation ofthe pellets in a hydro-
`philic or lipophilic matrix without distinction of effectiveness
`between the two types of application. EP 0 453 001 discloses
`a multiparticulate with “reservoir” structure inserted in a
`hydrophilic matrix. The basic multiparticulate utilizes two
`coating membranesto decrease the release rate of the active
`ingredient, a pH-dependent membrane with the purpose of
`gastric protection and a pH-independent methacrylic mem-
`brane with the purpose of slowing downthe penetration ofthe
`aqueous fluid. WO 95/16451 discloses a composition only
`formed by a hydrophilic matrix coated with a gastro-resistant
`film for controlling the dissolutionrate ofthe active ingredi-
`ent. When preparing sustained-, controlled-release dosage
`forms of a medicamenttopically active in the gastrointestinal
`tract, it is important to ensure a controlled release from the
`first phases following administration,
`i.e. when the inert
`matrices have the maximum release rate inside the logarith-
`mic phase, namely the higher deviation from linearrelease.
`Said object has been attained according to the present inven-
`tion, through the combination of an amphiphilic matrix inside
`an inert matrix, the latter formulated with a lipophilic poly-
`merin a superficial hydrophilic matrix. The compositions of
`the invention are characterized by the absenceofa first phase
`in which the medicamentsuperficially present on the matrix
`is quickly solubilized, and by the fact the amphiphilic layer
`compensatethe lack ofaffinity ofthe aqueous solvent with the
`lipophilic compounds forming the inner inert matrix.
`
`DISCLOSURE OF THE INVENTION
`
`The invention provides controlled release and taste mask-
`ing oral pharmaceutical compositions containing as active
`ingredient budesonide comprising:
`a) a matrix consisting of lipophilic compounds with melting
`point lower than 90° C. and optionally by amphiphilic
`compounds in which the active ingredientis at least par-
`tially incorporated;
`
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`US 8,293,273 B2
`
`3
`
`b) an amphiphilic matrix;
`c) an outer hydrophilic matrix in which the lipophilic matrix
`and the amphiphilic matrix are dispersed;
`d) optionally other excipients.
`A particular aspect of the invention consists of controlled
`release oral compositions containing as active ingredient
`budesonide comprising:
`a) a matrix consisting of amphiphilic compounds and lipo-
`philic compounds with melting point below 90° C.
`in
`which the active ingredient is at least partially incorpo-
`rated;
`b) an outer hydrophilic matrix in which the lipophilic/am-
`phiphilic matrix is dispersed, preferably by mixing;
`c) optionally other excipients.
`A further aspect of the invention provides taste masking
`oral pharmaceutical compositions budesonide containing
`comprising:
`an inert or lipophilic matrix consisting of C6-C20 alcohols or
`C8-C20 fatty acidsor esters of fatty acids with glycerol or
`sorbitol or other polyalcohols with carbon atom chain not
`higher than six:
`an amphiphilic matrix consisting of polar lipids of typeI or II
`or glycols partially etherified with C1-C4 alkyl chains;
`an outer hydrophilic matrix containing the above matrices,
`mainly formed by saccharide, dextrin, polyalcoholor cel-
`lulose compoundsor by hydrogels or their mixtures;
`optional excipients to give stability to the pharmaceutical
`formulation.
`
`DETAILED DISCLOSURE OF THE INVENTION
`
`The compositions of the invention can be prepared by a
`method comprising the following steps:
`a) the active ingredient, represented by budesonide, is first
`inglobated by simple kneading or mixing in a matrix or
`coating consisting ofcompoundshaving amphiphilic prop-
`erties, which will be further specified below. The active
`ingredient can be mixed with the amphiphilic compounds
`withoutthe aid of solvents or with small amounts of water-
`alcoholic solvents.
`
`b) the matrix obtained as specified under a) is incorporated in
`alow melting lipophilic excipient or mixture of excipients,
`if necessary while heating to soften and/or melt the excipi-
`ent itself, which thereby incorporates the active ingredient
`by simple dispersion forming an inert matrix which can be
`reduced in size to obtain inert matrix granules containing
`the active ingredientparticles.
`c) the inert matrix granules are subsequently mixed together
`with one or more hydrophilic water-swellable excipients.
`The mixtureis then subjected to compressionor tabletting.
`This way, when the tablet is contacted with biological
`fluids, a high viscosity swollen layer is formed, which
`coordinates the solvent molecules and acts as a barrier to
`penetration of the aqueousfluid itself inside the new struc-
`ture. Said barrier antagonizes the starting “burst effect”
`caused by the dissolution of the medicament inglobated
`insidethe inert matrix, whichis in its turn inside the hydro-
`philic matrix. The amphiphilic compounds which can be
`used according to the invention comprise polar lipids of
`type I or II (lecithin, phosphatidylcholine, phosphatidyle-
`thanolainine), ceramides, glycol alkyl] ethers such as dieth-
`ylene glycol monomethy] ether (Transcutol®). The lipo-
`philic matrix consists of substances
`selected from
`unsaturated or hydrogenated alcohols or fatty acids,salts,
`esters or amides thereof, fatty acids mono-, di- ortriglyc-
`erides,
`the polyethoxylated derivatives thereof, waxes,
`ceramides, cholesterol derivatives or mixtures thereof hav-
`
`20
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`ing melting point within the range of 40 to 90° C., prefer-
`ably from 60 to 70 C. If desired, a fatty acid calcium salt
`maybe incorporatedin the lipophilic matrix which is sub-
`sequently dispersed in a hydrophilic matrix prepared with
`alginic acid, thus remarkably increasing the hydrophilic
`matrix viscosity following penetration of the solvent front
`until contact with the lipophilic matrix granules dispersed
`inside. An amphiphilic matrix with high content in active
`ingredient, typically from 5 to 95% w/w,in particular from
`20 to 70%,is first prepared by dispersing the active ingre-
`dient in a mixture of amphiphilic compounds, such as
`lecithin, other type II polar lipids, surfactants, or in dieth-
`ylene glycol monoethyl ether; the resulting amphiphilic
`matrix is then mixed or kneaded, usually while hot, with
`lipophilic compoundssuitable to form an inert matrix, such
`as saturated or unsaturated fatty acids, such as palmitic,
`stearic, myristic, lauric, laurylic, or oleic acids or mixtures
`thereof with other fatty acids with shorter chain,orsalts or
`alcohols or derivatives of the cited fatty acids, such as
`mono-, di-, or triglyceride or esters with polyethylene gly-
`cols, alone or in combination with waxes, ceramides, cho-
`lesterol derivatives or other apolar lipids in variousratios
`so that the melting or softening points of the lipophilic
`compounds mixtures is within the range of 40 to 90 C,
`preferably from 60 to 70 C. Alternatively, the order of
`formation of the inert and amphiphilic matrices can be
`reversed,
`incorporating the inert matrix inside the
`amphiphilic compounds. The resulting inert
`lipophilic
`matrix is reduced into granules by an extrusion and/or
`granulation process, or any other known processes which
`retain the homogeneousdispersion and matrix structure of
`the starting mixture. The hydrophilic matrix consists of
`excipients knownas hydrogels,i.e. substances which when
`passing from thedry state to the hydrated one, undergo the
`so-called “molecular relaxation”, namely a remarkable
`increase in mass and weight following the coordination of
`a large number of water molecules by the polar groups
`present in the polymeric chains of the excipients them-
`selves. Examples of hydrogels which can be used accord-
`ing to the invention are compoundsselected from acrylic or
`methacrylic acid polymers or copolymers, alkylvinyl poly-
`mers, hydroxyalkyl celluloses, carboxyalkyl celluloses,
`polysaccharides, dextrins, pectins, starches and deriva-
`tives, natural or synthetic gums, alginic acid. In case of
`taste-masking formulations, the use of polyalcohols such
`as xylitol, maltitol and mannitol as hydrophilic compounds
`can also be advantageous. The lipophilic matrix granules
`containing the active ingredient are mixed with the hydro-
`philic compounds cited above in a weight ratio typically
`ranging from 100:0.5 to 100:50 (lipophilic matrix: hydro-
`philic matrix). Part of the active ingredient can optionally
`be mixed with hydrophilic substances to provide compo-
`sitions in which the active ingredient is dispersed both in
`the lipophilic and the hydrophilic matrix, said composi-
`tions being preferably in the form of tablets, capsules and/
`or minitablets. The compression of the mixture of lipo-
`philic
`and/or amphiphilic matrix, hydrogel-forming
`compound and,optionally, active ingredient not inglobated
`in the lipophilic matrix, yields a macroscopically homoge-
`neousstructure in all its volume, namely a matrix contain-
`ing a dispersion ofthe lipophilic granules in a hydrophilic
`matrix. A similar result can also be obtained by coating the
`lipophilic matrix granules with a hydrophilic polymer
`coating. The tablets obtainable according to the invention
`are subjected to known coating processes with a gastro-
`resistantfilm, consisting of, for example, acrylic and meth-
`acrylic acids polymers (Eudragit®) or copolymeror cellu-
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`US 8,293,273 B2
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`5
`lose derivatives, such as cellulose acetophthalate. The
`composition of the invention can further contain conven-
`tional excipients, for example bioadhesive excipients such
`as chitosans, polyacrylamides, natural or synthetic gums,
`acrylic acid polymers.
`The compositions of the invention are preferably in the
`form oftablets, capsules or minitablets. In terms of dissolu-
`tion characteristics, contact with water or aqueous fluids
`causes the immediate penetration of water inside the more
`superficial layer ofthe matrix which,thanksto the presence of
`the aqueoussolvent, swells due to the distension of the poly-
`meric chains of the hydrogels, givingrise to a high viscosity
`hydrated front which prevents the further penetration of the
`solventitself linearly slowing downthe dissolution process to
`a well determined point which can be located at about halfthe
`thickness, until the further penetration of water would cause
`the disintegration of the hydrophilic layer and therefore the
`release of the content which, consisting of inert matrix gran-
`ules, however induces the diffusion mechanism typical of
`these structures and therefore further slows downthe disso-
`lution profile of the active ingredient. The presence of the
`amphiphilic matrix inside the lipophilic matrix inert allows to
`prevent any unevennessofthe release profile of the active
`ingredient. The surfactants presentin the amphiphilic portion
`promote wettability of the porous canaliculuses which cross
`the inert matrix preventing or reducing resistance to penetra-
`tion of the solvent inside the inert matrix. To obtain taste
`maskingtablets, the components ofthe hydrophilic matrix are
`carefully selected to minimize the active substance release
`time through penetration accelerated by the canalization
`induced by the hydrophilic compound.
`
`EXPERIMENTAL PART
`
`To test the effective ability ofthe formulationsofthe inven-
`tion to modify the release rate and extent of the active ingre-
`dient from the dosage form suitable for the drug administra-
`tion, before any pharmacokinetic study on patients or
`volunteers, the dissolution test is taken as monitoring and
`discriminating tool. Dissolution Test Method.
`Tablets according to the present invention undergoto dis-
`solution test to verify the formulation capacity in modulating
`and controlling the rate by which the active ingredient is
`leaked by the device or dosage form in the environmental
`medium, generally a buffered solution simulating gastric or
`intestinal juices.
`Thedissolutiontest is performedby introducing individual
`tablets in a glace vessel containing from 500 to 1000 ml of a
`buffered solution set to different pH conditions (pH 1, 6.4 and
`7.2 are the pH condition generally used in this test applica-
`tions), so that the whole digestive tract pH conditions, from
`stomachto large intestine, should be reproduced. To simulate
`the human body conditions, the test is carried out at a tem-
`perature of 37° C.+-<=2° C. and at predetermined timeperi-
`ods samples of the dissolution medium are withdrawn to
`detect the percentageof active ingredient dissolved over time.
`The tablets according to the present
`invention, when
`designed to be used to treat inflammatory bowel disease, in
`principle have to show a goodresistance, thanks to the poly-
`meric film resistant to the low pH conditions (intended as <5
`to simulate the gastric environment) applied to cover the
`tablet surface, resistance whichlast at least for two hours; to
`target the large intestinal sectors, also the pH condition of 6.4
`shown unsuitability to determine a drug leakage from the
`administration device for a short exposition time and only
`mediums at pH 7.2 have been able to determine an active
`ingredient dissolution at a progressive and quite constantrate
`
`6
`during a timeframe from 6 to 12 hours; the dissolution per-
`centage obtained with this tablet formulation were below
`15% at first hour sampling, below 25% at second hour sam-
`pling, then values were in the range 25% to 55% at fourth hour
`and a dissolution greater than 80% was achieved at 8” hour
`sampling.
`
`Example 1
`
`2.7 kg of budesonide, 3.0 kg of lecithin (amphiphilic
`matrix forming material) and 3.0 kg of stearic acid (lipophilic
`matrix forming material) are mixing after sieving till an
`homogeneous mixture is obtained; then add 39.0 kg ofinert,
`functional excipients and 9.0 kg of low viscosity hydroxypro-
`pylcellulose (binder) and mix for 10 minutes before adding
`purified water and kneading to a suitable consistence. Then
`pass the granulate through a rotating granulator equipped
`with the suitable screen andtransfer the granulate to the fluid
`bed drier to lower the residual moisture content under 3%.
`
`After a new sieving on thedry, the granulate is added of 9.0
`kg of hydroxypropylcellulose (hydrophilic matrix forming
`material) and the suitable amountof functional excipients (in
`particular, microcrystalline cellulose,
`lactose and silicon
`dioxide) and, after 15 minutes ofmixing, magnesium stearate
`in a suitable quantity to act as lubricant is added.
`After a final blending,tablets of around 300 mg of unitary
`weight are generated.
`The core are then subjected to be coated with a suspension
`obtained introducing into a stainless steel container 5.8 kg of
`Eudragit™ (methacrylate copolymers), 0.6 kg of triethylci-
`trate and 3.0 kg of dyes andtalc, using alcoholas solvent.
`The meandissolution percentage (as average of six or more
`tablets) obtained with this tablet formulation were around
`10-20% at second hour sampling, in the range 25% to 65% at
`fourth hour anda dissolution greater than 80% was achieved
`at 8” hour sampling.
`
`Example 2
`
`40
`
`45
`
`Component
`Tablet
`
`Budesonide
`Stearic Acid
`Lecithin
`Microcristalline cellulose
`Hydroxypropylcellulose
`Lactose monohydrate
`Silicon dioxide
`Magnesium stearate
`Coating materials
`
`Eudragit L100
`Eudragit $100
`Tale
`Titanium dioxiede
`Triethylcitrate
`Alcohol
`
`me/tablet
`
`9.0
`10.0
`10.0
`156.0
`60.0
`50.0
`2.0
`3.0
`
`14.0
`12.0
`79
`45
`1.6
`q.s.
`
`65
`
`Accordingto the presentinvention, coated tablets individu-
`ally weighing about 220 mgare obtained.
`The above described dissolution test is performed on the
`tablets of Example 2.
`
`Cosmo Ex 2016-p. 5
`Mylan v Cosmo
`IPR2017-01035
`
`Cosmo Ex 2016-p. 5
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`Theresults are the following (indicated as average value):
`
`US 8,293,273 B2
`
`5
`
`10
`
`30
`
`35
`
`40
`
`45
`
`60
`
`after 2 hours at pH 1
`after 1 hour at pH 6.4
`after 2 hours at pH 7.2
`after 4 hours at pH 7.2
`after 8 hours at pH 7.2
`
`resistant (<5%)
`resistant (<5%)
`15%
`37%
`91%
`
`Example 3
`
`Budesonide (3.0 kg) is mixed with soybean Lecithin (5.0
`kg) till an homogeneous mixture is obtained. Then carnauba
`wax (2.0 kg) and stearic acid (2.0 kg) sieved through a fine
`screen are added. After mixing, the powders are added with
`other functional excipients and kneaded with a binder solu-
`tion obtained by dissolving medium viscosity polyvinylpir-
`rolidone in water. After drying in a fluid bed and milling
`throughout a suitable screen, hydroxypropylmethylcellulose
`(35.0 kg) and other excipients, including magnesium stearate
`as lubricant, in a suitable quantity are added and the mixture
`is blended till an homogeneous powder dispersion is
`obtained.
`The powder mixture is subjected to compression in a rotat-
`ing tabletting machine andthe tablets so obtained are coated
`in a pan coat with a gastroresistant composition containing
`Eudragit™, plasticizers, dyes and pigments.
`Accordingto the present example, coated tablets individu-
`ally weighing around 105 mgare obtained.
`Theresults of the above described dissolution test are the
`following (indicated as average value ofat least six tablets):
`
`after 2 hours at pH 1
`after 1 hour at pH 6.4
`after 2 hours at pH 7.2
`after 4 hours at pH 7.2
`after 8 hours at pH 7.2
`
`resistant (<5%)
`resistant (<5%)
`9%
`28%
`86%
`
`Example 4
`
`50 g of diethylene glycol monoethyl ether are homoge-
`neously distributed on 500 g of microcrystalline cellulose;
`then 100 g of Budesonide are added, mixing to complete
`homogenization. This mix is further added with 400 g of
`Budesonide, then dispersed in a blender containing 100 g of
`carnauba wax and 100 g of stearic acid preheated at a tem-
`perature of 60 [deg.] C. After kneading for 5 minutes, the
`mixture is cooled to room temperature and extruded in gran-
`ules of size below 1 mm. A suitable mixeris loaded with the
`
`matrix granules prepared as above andthe following amounts
`of hydrophilic excipients: 1500 g of hydroxypropyl methyl-
`cellulose and 500 g of Policarbophil™ are added. The com-
`ponents are mixed until homogeneous dispersion of the
`matrices, then added with 2450 g of microcrystalline cellu-
`lose, 400 g of lactose, 100 g of colloidal silica and 50 g of
`magnesiumstearate. After further 5 minute mixing, the mixis
`tabletted to unitary weight of 250 mg/tablet.
`Tablets are then subjected to coating using a suspension n
`containing polyacrylate and poly methacrilate copolymers in
`addition to other dyes, plasticizers and colouring agents in
`solvent (ethylic alcohol).
`The results of the dissolution test performed on these
`coated tablets are the following (indicated as average value of
`at least six tablets):
`
`after 2 hours at pH 1
`after 1 hour at pH 6.4
`after 2 hours at pH 7.2
`after 4 hours at pH 7.2
`after 8 hours at pH 7.2
`
`resistant (<5%)
`resistant (<5%)
`1%
`32%
`76%
`
`Example A
`
`500 g of 5-aminosalicylic-acid and 20 g of octylonium
`bromide are mixed with 10 g of soy lecithin dissolved in 50 g
`of a water:ethyl alcohol 1:3 mixture at about 50° C. After
`homogenization and drying, the granules of the resulting
`matrix are treated in a kneader with 20 g of carnauba wax and
`50 g of stearic acid, heating until homogeneous dispersion,
`then cold-extrudedinto small granules. The inert matrix gran-
`ules are loaded into a mixer in which 30 g of carbopol 971 P
`and 65 g of hydroxypropyl methylcellulose “are sequentially
`added.”Aftera first mixing step for homogeneously dispers-
`ing the powders, 60 g of microcrystalline cellulose and 5 g of
`magnesium stearate are added. After mixing,the final mixture
`is tabletted to unitary weight of 760 mg/tablet. The resulting
`tablets are film-coated with cellulose acetophthalate or poly-
`methacrylates and a plasticizer to provide gastric resistance
`and preventthe early release of product in the stomach.
`Theresulting tablets, when subjected to dissolution test in
`simulated enteric juice, have showna release of the active
`principles having the following profile: after 60 minutes no
`more than 30%, after 180 minutes no more than 60%,after 5
`hours no more than 80%.
`
`Example B
`
`50 g of diethylene glycol monoethyl ether are homoge-
`neously distributed on 500 g of microcrystalline cellulose;
`then 100 g of Budesonide are added, mixing to complete
`homogenization. This mix is further added with 400 g of
`Budesonide, then dispersed in a blender containing 100 g of
`carnauba wax and 100 g of stearic acid preheated at a tem-
`perature of 60° C. After kneading for 5 minutes, the mixture
`is cooled to room temperature and extruded in granules of size
`below 1 mm.
`A suitable mixer is loaded with the matrix granules pre-
`pared as above and the following amounts of hydrophilic
`excipients: 1500 g ofhydroxypropyl methylcellulose and 500
`g of policarbophil.
`The components are mixed until homogeneous dispersion
`of the matrices, then added with 2450 g of microcrystalline
`cellulose, 400 g of lactose, 100 g of colloidal silica