- (cid:9)
`
`%ICU Rec CT/PTO 1 2 ott 2001
`
`Riled 1=n:3.13w (cid:9) U.S. DEPARTMENT OF (cid:9) COME (cid:9) CE PATENT AND TRADEMARK OFFICE
`
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`CONCERNING A FILING UNDER 35 U.S.C. 371
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`Mir
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`ATTORNEY'S DOCKET NUMBER:
`9623 V/vmf/as
`
`U.S. APPII DV' "'°0' ti In 2
`
`INTERNATIONAL APPLICATION NO.:
`PCT/EP00/05356
`
`INTERNATIONAL FILING DATE:
`09 JUNE 2000 (09.06.00)
`
`PRIORITY DATE CLAIMED:
`14 JUNE 1999 (14.06.99)
`
`TITLE OF INVENTION: CONTROLLED RELEASE AND TASTE MASKING ORAL PHARMACEUTICAL COMPOSITIONS
`
`APPLICANT(S) FOR DO/EO/US: Roberto VILLA, Massimo PEDRANI, Mauro AJANI and Lorenzo FOSSATI
`
`
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items and other information:
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`of the applicable time limit set in 35 U.S.C. 371(b) and PCT Articles 22 and 39(1).
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`A translation
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`U.S. APPLICATION KICd IT n9 5 3 2
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`INTERNATIONAL APPLICATION NO.
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`$ (cid:9)
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`$ (cid:9)
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`890.00
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`890.00
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`445.00
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`By
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`Registration No. 35,041
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`Y&T 99 (cid:9)
`
`page 2 of 2 •
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`000002
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`(cid:9)
`(cid:9)
`

`

`WO 00/76478
`
`11)1 009532
`3Ree'd rum G 12 DEC 2001
`PCT/EP00/05356
`
`CONTROLLED RELEASE AND TASTE MASKING ORAL PHARMACEUTICAL
`
`COMPOSITIONS
`
`The present -invention. relates to : controlled release
`
`and taste-masking compositions containing one or more
`
`active principles incorporated in a three-component matrix
`
`structure, i.e. a structure formed by successive
`
`5 amphiphilic, lipophilic or inert matrices and finally
`
`incorporated or dispersed in hydrophilic matrices. The
`
`use
`
`of a plurality of systems
`
`for the' control- -(pf
`
`the
`
`dissolution of the active ingredient modulates
`
`the
`
`dissolution rate of the active -ingredient in aqueous and/or
`
`10 (cid:9)
`
`biological fluids, thereby controlling the release kinetics
`_ .
`in the gastrointestinal tract, and it also allows the oral
`
`administration of active principles having unfavourable
`
`taste characteristics or irritating action on the mucosae
`
`of the administration site, particularly in the buccal
`
`15 (cid:9)
`
`area.
`
`The compositions of the invention can-contain active
`
`principles belonging to the therapeutical classes of
`analgesics, (cid:9)
`tranquillizers, antihypertensives, disinfectants and
`
`ant iinflammatories, (cid:9)
`
`cardioactives,
`
`20 (cid:9)
`
`topical antimicrobials, antiparkinson drugs, antihistamines
`
`and are suitable to the oral administration or for acting
`
`topically at some areas of the gastrointestinal tract.
`
`TECHNOLOGICAL BACKGROUND
`
`The preparation of a sustained, controlled, delayed or
`
`25 (cid:9)
`
`anyhow modified release form can be carried out according
`
`to different known techniques:
`
`1. (cid:9)
`
`The use of inert matrices, in which the main component
`
`of the matrix structure opposes some resistance to the
`
`penetration of the solvent due to the poor affinity
`
`30 (cid:9)
`
`towards aqueous fluids; such property being known as
`
`lipophilia.
`
`:CONFIRMATION CON
`
`000003
`
`(cid:9)
`

`

`
`
`10.
`
`15
`
`20
`
`25
`
`30
`
`(cid:9) (cid:9)(cid:9) (cid:9)(cid:9) (cid:9)(cid:9) (cid:9)(cid:9) (cid:9)(cid:9) (cid:9)
`
`
`
`5
`
`
`
`
`
`
`
`WO 00/76478
`
`PCT/EPO0/05356
`
`2
`2. The use of hydrophilic matrices, in which the main
`
`component of the matrix structure opposes high
`
`resistance to the progress of the solvent, in that. the
`
`presence of strongly. hydrophilic groups in its chains,
`
`mainly branched, remarkably increases viscosity inside
`
`the hydrated layer.
`
`3. The. use of bioerodible matrices, which are capable of
`
`being degraded by the enzymes of some biological
`
`compartment.
`
`All the procedures listed above suffer, however, from
`
`drawbacks and imperfections.
`
`_ Inert matrices, for example, generally entail non-
`
`linear, but esponential, release of the active ingredient-.-
`
`_Hydrophilic matrices have a linear behaviour until a
`
`certain fraction of active ingredient has been released-,
`
`then they significantly deviate from linear release.
`
`Bioerodible matrices are ideal to carry out the - so-
`
`called "site-release", but they involve the problem of
`
`-finding- the suitable enzyme or reactive to degradation:-:
`
`Furthermore, they frequently release in situ metabolites
`
`that are not wholly toxicologically inert.
`
`A number of formulations based on inert lipophilic
`
`matrices have been described: Drug Dev. Ind. Pharm. 13 (6),
`
`1001-1022, (1987) discloses a process making use of varying
`
`amounts of colloidal silica as a porization element for a
`
`lipophilic inert matrix in which the active ingredient is
`
`incorporated.
`
`The same notion of canalization of an inert matrix is
`
`described in US 4,608,248 in which a small amount of a
`
`hydrophilic polymer is mixed with the substances forming 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 controlled-release of
`
`000004
`
`(cid:9)
`

`

`WO 00/76478
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`PCT/EP00/05356
`
`3
`the active ingredient which comprises co-dissolution of
`
`polymers or suitable substances to form a inert matrix with
`
`the active ingredient and the subsequent deposition of said
`
`solution on an inert carrier which acts -as the core of the-
`
`5 - -.device. Alternatively, .the inert carrier-is kneaded- With
`
`the solution containing the inert polymer and the active
`
`ingredient, then the organic solvent used for the their
`
`dissolution is evaporated off to obtain a solid residue.
`
`The resulting structure is a "reservoir", i.e. is not
`
`10 (cid:9)
`
`macroscopically homogeneous along all the symmetry axis of
`
`the final form.
`The _same-_ "reservoir" structure - is also described in
`Chem. Pharm. Bull. 46 (I), 531-533„ (-1998) which improves
`
`the application through an annealing technique of the inert
`
`15 (cid:9)
`
`polymer layer which is deposited on the surface of the
`
`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
`
`20 (cid:9)
`
`pellets in hydrophilic matrix which comprises:
`
`- dissolution of the active ingredient with gastro-
`
`resistant hydrophilic polymers in organic. solvents;
`
`- drying of said suspension;
`
`- subsequent kneading and formulation of the pellets in
`
`25 (cid:9)
`
`a hydrophilic 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 membranes to
`
`30 (cid:9)
`
`decrease the release rate of the active ingredient, a pH-
`
`dependent membrane with the purpose of gastric protection
`
`and a pH-independent methacrylic membrane with the purpose
`
`of slowing down the penetration of the aqueous fluid.
`
`WO 95/16451 discloses a composition only formed by a
`
`000005
`
`(cid:9)
`

`

`WO 00/76478 (cid:9)
`
`PCIYEP00/05356
`
`4
`hydrophilic matrix coated with a gastro-resistant film for
`
`controlling the dissolution rate of the active ingredient.
`
`When preparing sustained-, controlled- release dosage
`
`forms of a medicament topically active in the
`
`*5 (cid:9)
`
`gastrointestinal tract it it is dmPortant to ensure' a
`
`controlled release from the first phases following
`
`administration, i.e. when the inert matrices have the
`
`maximum release rate inside the logarithmic phase, namely
`
`the higher deviation from linear release.
`
`10 (cid:9)
`
`Said object has been attained according to the present
`
`invention, through the combination of an amphiphilic matrix
`
`inside- an inert matrix, the latter formulated __with -a.1--
`
`lipophilic polymer in a superficial hydrophilic matrix. The
`
`compositions of the invention are characterized by the--
`
`Fi
`
`I^
`
`0 3
`
`9 :9
`
`15 absence of a first phase in which. the medicament
`
`superficially present on the matrix-.is quickly solubilized,
`
`and by the fact the the amphiphilic layer compensate the
`
`lack of affinity of the aqueous solvent with the lipophilic
`
`compounds-forming the inner.inert_matrix. .
`
`20 (cid:9)
`
`DISCLOSURE OF THE INVENTION
`
`The invention provides controlled release and taste
`
`masking oral pharmaCeutical compositions containing an
`
`active ingredient, comprising:
`
`a) a matrix consisting of lipophilic compounds with
`
`25 (cid:9)
`
`melting point lower than 90°C and optionally by amphiphilic
`
`compounds in which the active ingredient is at least
`
`partially incorporated;
`
`b) optionally an amphiphilic matrix;
`
`c) an outer hydrophilic matrix in which the
`
`30 (cid:9)
`
`lipophilic matrix and the optional amphiphilic matrix are
`
`dispersed;
`
`d) optionally other excipients.
`
`A particular aspect of the invention consists of
`
`controlled release oral compositions containing one or more
`
`000006
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 00/76478 (cid:9)
`
`5
`active ingredients comprising:
`
`PCT/EP00/05356
`
`a) (cid:9)
`
`a matrix consisting of amphiphilic compounds and
`
`lipophilic compounds with melting point below 90°C in which
`
`the active ingredient is at least partially incorporated;
`
`5
`
`b) (cid:9)
`
`an outer hydrophilic matrix_ in _which the
`
`lipophilic/amphiphilic matrix is dispersed;
`
`c) (cid:9)
`
`optional other excipients.
`
`A further aspect of the invention provides taste
`
`masking oral pharmaceutical compositions containing one or
`
`10 (cid:9)
`
`more active ingredients comprising:
`
`- an inert or lipophilic matrix consisting of C6-
`
`C20-alcohols or C8-C20 tatty acids—or esters of fatty-,acids
`
`with. glycerol or _sorbitol or other polyalcohols with carbon
`
`atom chain not higher than six;
`
`15
`
`- an amphiphilic matrix consisting of polar lipids
`
`. of type .1 or II or glycols partially etherified with C1-C4.
`
`.alkyl chains;
`
`- an outer hydrophilic matrix containing the above
`
`matrices,--mainly formed by saccharide, dextrin, polyalcohol
`
`20 (cid:9)
`
`or cellulose compounds or by hydrogels;
`
`- optional excipients to_ give stability to the
`
`pharmaceutical formulation.
`
`DETAILED DISCLOSURE OF THE INVENTION
`
`The compositions of the invention can be prepared by a
`
`25 (cid:9)
`
`method comprising the following steps:
`
`a) the active ingredient is first inglobated by
`
`simple kneading or mixing in a matrix or coating consisting
`
`of compounds having amphiphilic properties, which will be
`
`further specified below. The active principle(s) can be
`
`30 (cid:9)
`
`mixed with the amphiphilic compounds without the aid of
`
`..solvents or with small amounts of water-alcoholic solvents.
`
`b) The matrix obtained in a) is incorporated in a
`
`low melting lipophilic excipient or mixture of excipients,
`
`while heating to soften and/or melt the excipient itself,
`
`000007
`
`(cid:9)
`(cid:9)
`

`

`WO 00/76478
`
`PCT/EP00/05356
`
`6
`which thereby incorporates the active ingredient by simple
`
`dispersion. After cooling at room temperature an inert
`
`matrix forms, which can be reduced in size to obtain inert
`
`matrix granules containing the active ingredient particles.
`
`.c) (cid:9)
`
`The inert matrix granules are subsequently mixed
`
`together with one or more hydrophilic water-swellable
`
`excipients. The mixture is then subjected to compression or
`
`tabletting. This way, when the tablet is contacted with
`
`biological fluids, a high viscosity swollen layer is
`
`10 (cid:9)
`
`formed, which coordinates the solvent molecules and acts as
`
`a barrier to penetration of the aqueous fluid itself inside
`
`D
`
`the new., structure. Said_jbarrier antagonizes_the starting
`
`"burst effect" caused by the dissolution of the medicament
`
`inglobated inside the inert matrix, which is in its- Turn
`
`15 (cid:9)
`
`inside the hydrophilic matrix.
`
`The. amphiphilic compounds. which can be used according.
`to the invention comprise polar lipids of type I or II
`
`(lecithin, phosphatidylcholine, phosphatidylethanolamine),
`
`ceramides, glycol alkyl ethers such as diethylene glycol
`
`20 (cid:9)
`
`monomethyl ether (Transcutol(R)).
`
`The_lipophilic matrix consists of substances selected
`
`from unsaturated or hydrogenated alcohols or fatty acids,
`
`salts, esters or amides thereof, fatty acids mono-, di- or
`
`triglycerids, the polyethoxylated derivatives thereof,
`
`25 waxes, ceramides, cholesterol derivatives or mixtures
`
`thereof having melting point within the range of 40 to
`
`90°C, preferably from 60 to 70°C.
`
`If desired, a fatty acid calcium salt may be
`
`incorporated in the lipophilic matrix which is subsequently
`
`30 (cid:9)
`
`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.
`
`000008
`
`(cid:9)
`

`

`WO 00/76478
`
`PCT/EP00/05356
`
`7
`According to an embodiment of the invention, an
`
`amphiphilic matrix with high content in active ingredient,
`
`typically from 5 to 95% w/w, is first prepared by
`
`dispersing the active ingredient or the mixture of active.
`
`5 (cid:9)
`
`ingredients in a_ Mixture_ Of amphiphilic Compounds; such as
`
`lecithin, other type II polar lipids, surfactants, or in
`
`diethylene glycol monoethyl ether; the resulting
`
`amphiphilic matrix is then mixed or kneaded, usually while
`
`hot, with lipophilic compounds suitable to form an inert
`
`10 (cid:9)
`
`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, or salts or alcohols or derivatives of the
`
`cited fatty acids, such as mono-, di-, or -triglycerids or
`
`15 (cid:9)
`
`esters with polyethylene glycols, alone or in combination
`
`with waxes, ce-ramides, cholesterol. deriVatives or - other
`apolar lipids in various ratios so that. the 'melting or
`
`softening points of the lipophilic compounds mixtures is
`
`within the range of 40° to - 90°C-, prefei-dEly from 60 to-
`70°C.
`
`20 (cid:9)
`
`Alternatively, the order -cif 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
`
`25 (cid:9)
`
`granules by an extrusion and/or granulation process, or any
`
`other known processes which retain the homogeneous
`
`dispersion and matrix structure of the starting mixture.
`
`The hydrophilic matrix consists of excipients known as
`
`hydrogels, i.e. substances which when passing from the dry
`
`30 (cid:9)
`
`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 themselves.
`
`000009
`
`(cid:9)
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`(cid:9) (cid:9)
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`10
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`WO 00/76478 (cid:9)
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`PCT/EP00/05356
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`8
`Examples of hydrogels which can be used according to
`
`the invention are compounds selected from acrylic _or
`
`methacrylic. acid polymers or copolymers, alkylvinyl
`polymers, hydroxyalkyl cellulbses, carboxyalkyl •celluloses,
`
`polysaccharides,- deXtrins, pectins, starches and
`
`derivatives, 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 hydrophilic compounds cited
`
`above_ in a_weight ratio typically ranging _from 100:0.5
`
`(cid:9) (cid:9)
`
`100:50 (lipophilic matrix: hydrophilic matrix). Part of the
`.. (cid:9)
`•
`active ingredient can optionally be mixed with_hydrophilic.
`15 -- - substances to provide compositions - in which the active-
`ingredient is dispersed both..in the lipophilic :And-. the
`
`hydrophilic matrix; said coMpositions being preferably in
`
`the form of-tablets, capsules and/or minitablets.
`.The7cOMpression of the- mixture of lipophilic and/or-
`20 amphiphilic matrix, hydrogel-forming compound and,
`
`-optionally,- active -ingredient not -inglobated in the-
`
`lipophilic matrix, yields a macroscopiCally homogeneous
`
`structure in all its volume, namely a matrix containing a
`
`dispersion of the lipophilic granules in a hydrophilic-
`
`matrix. A similar result can also be obtained by coating
`
`the lipophilic matrix granules with a hydrophilic polymer
`
`25
`
`coating.
`
`The tablets obtainable according to the invention can
`
`optionally be subjected to known coating processes with a
`
`30 gastro-resistant film, consisting of, for example,
`methacrylic acids polymers (Eudragit(R)) or cellulose
`
`derivatives, such as cellulose acetophthalate.
`
`Active ingredients which can conveniently be
`
`formulated according to the invention comprise:
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`W000/76478 (cid:9)
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`PCT/EP00/05356
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`9
`- analgesics, such as acetaminophen, phenacetin,
`
`sodium salicylate;
`
`- antitussives, such as dextromethorphan, codeine
`
`phosphate;
`
`5 (cid:9)
`
`- (cid:9)
`
`bronchodilators, such as albuterol, procaterol;
`
`- antipsychotics, (cid:9)
`
`such (cid:9)
`
`as (cid:9)
`
`haloperidol,
`
`chlorpromazine;
`
`- antihyDertensives and coronary-dilators, such as
`
`isosorbide mono- and dinitrate, captopril;
`
`10 (cid:9)
`
`selective S -2 antagonists such as salbutamol,
`
`terbutaline, ephedrine, orciprenaline sulfate;
`
`calcium - antagonists,- such---as- —nifedipine,
`
`nicardipine, diltiazem, verapamil;
`
`_antiparkinson drugs, such as pergolide,
`
`15 (cid:9)
`
`carpidopai levodopa;
`
`.non steroid .anti-inflammatory drugs, .such-as
`
`ketop±Ofen,- ibuprofen, diclofenac, diflunisal, piroxicam,
`
`naproxen, (cid:9)
`
`ketorolac, . nimesulide, (cid:9)
`
`thiaprophenic acid,
`
`mesalazine:(5-a-thiribsalicylic acid);
`
`▪
`
`20 (cid:9)
`
`- (cid:9)
`
`antihistamines, such as terfenedine, loratadine;
`
`-antidiarrheals and intestinal antiinflammatories,
`
`such as loperamide, 5-aminosalicylic, olsalazine,
`
`sulfasalazine, budenoside;
`
`- spasmolytics such as octylonium bromide;
`
`25 (cid:9)
`
`- (cid:9)
`
`anxiolytics, such as chlordiazepoxide, oxazepam,
`
`medazepam, alprazolam, donazepam, lorazepan;
`
`- oral antidiabetics, such as glipizide, metformin,
`
`phenformin, gilclazide, glibenclamide;
`
`- cathartics, (cid:9)
`
`such (cid:9)
`
`as (cid:9)
`
`bisacodil, (cid:9)
`
`sodium
`
`30 (cid:9)
`
`picosulfate;
`
`- antiepileptics, such as valproate, carbamazepine,
`
`phenytoin, gabapentin;
`
`antitumorals, such as flutamide, etoposide;
`
`- oral cavity disinfectants or antimicrobials, such
`
`000011
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`(cid:9)
`(cid:9)
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`.WO 00/76478 (cid:9)
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`PCT/EP00/05.356
`
`10
`as benzalkonium chloride, cetylpyridinium chloride or
`
`tibezonium iodide, and some amino derivatives such as
`
`benzydamine. and chlorhexidine as well as the - salts and
`
`derivatives thereof;
`
`5 (cid:9)
`
`sodium fluoride:
`
`The compositions of the invention can further contain
`
`conventional excipients, for example bioadhesive excipients
`
`such as chitosans, polyacrylamides, natural or synthetic
`
`gums, acrylic acid polymers.
`
`10 (cid:9)
`
`The compositions of the invention can contain more
`
`than one active ingredient, each of them being optionally
`
`contained in the hydrophilic matrix or in the inert
`- _
`amphiphilic matrix, and are preferably in the form of
`
`tablets, capsules or minitablets..
`
`15 _ (cid:9)
`
`In terms of dissolution characteristica,_contact.with__
`
`water or. aqueous fluids causes the immediate penetration of.
`
`.water inside the more superficial layer of the matrix
`
`which, thanks to the presence of the aqueous solvent,
`
`..swells due to the distension of the polymeric_ chains of the-
`
`20 (cid:9)
`
`hydrogels, giving rise to a high viscosity hydrated front
`
`which prevents the further penetration of the _solvent_
`
`itself linearly slowing down the dissolution process to a
`
`well determined point which can be located at about half
`
`the thickness, until the further penetration of water would
`
`25 cause the disintegration of the hydrophilic layer and
`
`therefore the release of the content which, consisting of
`
`inert matrix granules, however induces the diffusion
`
`mechanism typical of these structures and therefore further
`
`slows down the dissolution profile of the active
`
`30 (cid:9)
`
`ingredient.
`
`The presence of the amphiphilic matrix inside the
`
`lipophilic matrix inert allows to prevent any unevenness of
`
`the release profile of the active ingredient. The
`
`surfactants present in the amphiphilic portion promote
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`WO 00/76478 (cid:9)
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`PCI7EP00/05356
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`11
`wettability of the porous canaliculuses which cross the
`
`inert matrix preventing or reducing resistance to
`
`penetration of the solvent inside the inert matrix.
`
`To obtain. taste masking tablets, the components of the
`
`5 (cid:9)
`
`hydrophilic matrix are carefully selected -to- minimize the
`
`active (cid:9)
`
`substance (cid:9)
`
`release (cid:9)
`
`time . through penetration
`
`accelerated by the canalization induced by the hydrophilic
`
`compound.
`
`The following ExaMples illustrate the invention in
`
`10 (cid:9)
`
`greater detail.
`
`EXAMPLE 1
`
`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.
`
`15 After homogenization and drying, the grantaeb---6-f -the
`
`resulting matrix are treated- in (cid:9)
`
`kneader with 20.. g of
`
`carnauba wax and 50 g of stearic acid, heating until
`
`homogeneous dispersion, then cold-extruded into small
`
`grandle. The inert matrix granules are loaded into a mixer
`
`20 (cid:9)
`
`in which 30 g of carbopol 971 P and 65 g of hydroxypropyl
`
`methylcellulose are sequentially added. After a first
`
`mixing step for homogeneously dispersing the powders, 60 g
`
`of microcrystalline cellulose and 5 g of magnesium stearate
`
`are added. After mixing, the final mixture is tabletted to
`
`25 (cid:9)
`
`unitary weight of 760 mg/tablet. The resulting tablets are
`
`film-coated (cid:9)
`
`with (cid:9)
`
`cellulose (cid:9)
`
`acetophthalate (cid:9)
`
`or
`
`polymethacrylates and a plasticizer to provide gastric
`
`resistance and prevent the early release of product in the
`
`stomach.
`
`:0 (cid:9)
`
`The resulting tablets, when subjected to dissolution
`
`test in simulated enteric juice, have shown a 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%.
`
`000013
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`Ls.
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`WO 00/76478
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`EXAMPLE 2
`
`12
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`PCT/EP00/05356
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`50 g of diethylene glycol monoethyl ether are
`
`homogeneously distributed on 500 g of microcrystalline
`
`cellulose; then 100 g of Budesonide are. added, mixing to
`
`5 (cid:9)
`
`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
`
`temperature of 60°C. (cid:9)
`
`After kneading for 5 minutes, the
`
`mixture is cooled to room temperature and extruded in
`
`10 (cid:9)
`
`granules of size below i mm.
`
`A suitable mixer is loaded with the matrix granules
`
`__prepared as above and_the_ following amounts of hydrophilic -
`
`excipients: 1500.g of hydroxypropyl methylcellulose and 500
`. _
`g of policarbophil.
`
`15 (cid:9)
`
`The components-- a-re--mixed until homogeneous dispersion
`
`of the matrices, then added with' 2450 g of microcrystalline
`
`cellulose, 400 g of lactose, 100 - g - of colloidal silica and
`
`50 g of magnesium stearate. After further 5 minute mixing,
`
`the mix-is tabletted to unitary weight of 250 mg/tablet
`
`20 (cid:9)
`
`EXAMPLE 3
`
`850 --g of -metformin are dispersed in
`
`granulator/kneader with 35 g of diethylene glycol monoethyl
`
`ether previously melted with 100 g of stearic acid and 55 g
`
`of carnauba wax. The system is heated to carry out the
`
`25 (cid:9)
`
`granulation of the active ingredient in the inert matrix.
`
`The resulting 1040 g of formulation are added with 110 g of
`
`hydroxypropyl methylcellulose and 20 g of magnesium
`
`stearate.
`
`The final mixture is tabletted to unitary weight of
`
`30 (cid:9)
`
`1170 mg/tablet equivalent to 850 mg of active ingredient.
`
`The resulting tablets, when subjected to dissolution
`
`test in simulated enteric juice, have shown a release of
`
`the active principles having the following profile: after
`
`60 minutes no more than 35%, after 180 minutes no more than
`
`000014
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`(cid:9)
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`WO 00/76478
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`13
`60%, after 5 hours no more than 80%.
`
`EXAMPLE 4
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`PCT/EP00/05356
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`120 g of octylonium bromide are dispersed in a
`
`granulator/kneader-with 30 2 of stearic acid and -15 g of
`
`5 f beeswax in which - 10 g of diethylene glycol mohoethylene had
`
`(cid:9) (cid:9)
`
`previously been melted.
`
`The system is heated to carry out the granulation of
`
`the active ingredient in the inert matrix. The resulting 10
`
`g of formulation are added with 5 g of hydroxypropyl
`
`methylcellulose and - 5`g of policarbophyl, 2 g of magnesium
`
`stearate and 3 g of microcrystalline cellulose.
`
`The final mixture is tabletted to- unitary weight' of
`
`200 mg/tablet equivalent to 120 mg_of active ingredient,
`
`10
`
`The resulting tablets-, when subjected to dissolution
`
`teSt in simulated- enteric juice, have shown a release of
`
`15
`
`.the active principleS having the- following profile :• after.
`
`60 minutes no more than 25%; after 180 minutes no more than
`
`50%; after 5 hours no more than 70%.
`
`EXAMPLE .5
`
`20 (cid:9)
`
`12 g of diethylene glycol monoethyl ether are loaded
`
`on 6 g-of microcryStalline cellulose and 6 grams—of calcium
`
`carbonate, then 100 g of Gabapentin are added and the
`
`mixture is homogenized. After that, 800 g of Gabapentin are
`
`added which are dispersed in a granulator/kneader with 4.5
`
`25 (cid:9)
`
`g of white wax and 5 g of stearic acid. The system is
`
`heated to carry out the granulation of the active
`
`ingredient in the inert matrix. The resulting 916.5 g of
`
`formulation are added with 39.5 g of hydroxypropyl
`
`methylcellulose, 10 g of alginic acid, 11 g of magnesium
`
`30 (cid:9)
`
`stearate and 6 g of syloid. The final mixture is-tabletted
`
`to unitary weight of 1000 mg/tablet equivalent to 900 mg of
`
`active ingredient.
`
`EXAMPLE 6
`
`50 g (25 g) of carbidopa and 200 g (100 g) of levodopa
`
`000015
`
`(cid:9)
`

`

`
`
`20
`
`25
`
`30
`
`(cid:9) (cid:9)(cid:9) (cid:9)(cid:9) (cid:9)
`
`(cid:9) (cid:9)
`
`5
`
`10 (cid:9)
`
`15- (cid:9)
`
`
`
`WO 00/76478
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`PCT/EP00/05356
`
`14
`are dispersed in a granulator/kneader with 60 g (30 g) of
`
`stearic acid and 30 g (15 g) of yellow wax, in which 10 (5)
`
`g of diethylene glycol monoethyl ether had previously been
`
`melted.
`
`The system is heated to carry out the granulation. of
`
`the active ingredient in the inert matrix. The. resulting
`
`340 g (170 g) of formulation are added with 20 g (10 g) of
`
`hydroxypropyl methylcellulose, 10 g (5 g) of xantangum, 16
`
`g (8 g) of microcrystalline cellulose, 4 g (2 g) of
`
`magnesium stearate.
`
`The final mixture is tabletted to unitary weight of
`
`400_ (200), mg/tablet equivalent to 50(25) _mg_ of carbidopa,-
`
`and 200 (100) mg di levodopa.
`
`EXAMPLE 7
`
`4 g of Nimesulide—are solubilised- in -50 g of
`diethylene - (cid:9)
`monoethyl ether,