1111111111111101111111111111111911,110111F11110111110101111111111111110111111
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2006/0134208 Al
`Jun. 22, 2006
`Villa et al. (cid:9)
`(43) Pub. Date: (cid:9)
`
`(54) CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITION (cid:9)
`
`(76) Inventors: Roberto Villa, Lecco (IT); Massimo
`Pedrani, Gignese (Verbanla) (IT);
`Mauro Ajani, Milano (IT); Lorenzo
`Fossati, Milano (IT)
`
`Correspondence Address:
`YOUNG & THOMPSON
`745 SOUTH 23RD STREET
`2ND FLOOR
`ARLINGTON, VA 22202 (US)
`
`(21) Appl. No.: (cid:9)
`
`11/268,500
`
`(22) Filed: (cid:9)
`
`Nov. 8, 2005
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 11/262,799,
`filed on Nov. 1, 2005, which is a continuation-in-part
`of application No. 10/009,532, filed on Dec. 12, 2001,
`filed as 371 of international application No. PCT/
`EP00/05356, filed on Jun. 9, 2000.
`
`(30) (cid:9)
`
`Foreign Application Priority Data
`
`Jun. 14, 1999 (IT) (cid:9)
`Mar. 3, 2000 (IT) (cid:9)
`
`MI99A001317
` MI2000A000422
`
`Publication Classification
`
`(51) Int. Cl.
`A61K 9/22 (cid:9)
`(52) U.S. Cl. (cid:9)
`
`(2006.01)
`
` 424/468; 514/179
`
`(57) (cid:9)
`
`ABSTRACT
`
`Controlled release and taste masking compositions contain-
`ing one or more active principles inglobated in a three-
`component matrix structure, i.e. a structure formed by
`successive amphiphilic, lipophilic or inert matrices and
`finally inglobated or dispersed in hydrophilic matrices. The
`use of a plurality of systems 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.
`
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`US 2006/0134208 Al (cid:9)
`
`Jun. 22, 2006
`
`1
`
`CONTROLLED RELEASE AND TASTE MASKING
`ORAL PHARMACEUTICAL COMPOSITION
`
`[0001] The present invention relates to controlled release
`and taste masking compositions containing budesonide as
`active ingredient incorporated in a three-component matrix
`structure, i.e. a structure formed by successive amphiphilic,
`lipophilic or inert matrices and finally incorporated or dis-
`persed in hydrophilic 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 con-
`trolling 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 or gastric area.
`
`[0002] The compositions of the invention are suitable to
`the oral administration or the efficaciously deliver the active
`ingredient acting topically at some areas of the gastrointes-
`tinal tract.
`
`TECHNOLOGICAL BACKGROUND
`
`[0003] The preparation of a sustained, controlled, delayed,
`extended or anyhow modified release form can be carried
`out according to different techniques:
`
`[0004] 1. The use of inert matrices, in which the main
`component of the matrix structure opposes some resis-
`tance to the penetration of the solvent due to the poor
`affinity towards aqueous fluids; such property being
`known as lipophilia.
`
`[0005] 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.
`
`[0006] 3. The use of bioerodible matrices, which are
`capable of being degraded by the anzimes of some
`biological compartment.
`
`[0007] All the procedures listed above suffer, however,
`from drawbacks and imperfections.
`
`[0008]
`Inert matrices, for example, generally entail non-
`linear, but exponential, release of the active ingredient.
`
`[0009] Hydrophilic matrices: have a linear behaviour until
`a certain fraction of active ingredient has been released, then
`significantly deviate from linear release.
`
`[0010] Bioerodible matrices are ideal to carry out the
`so-called "sire-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.
`
`[0011] 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 vary-
`ing amounts of colloidal silica as a porization element for a
`lipophilic inert matrix in which the active ingredient is
`incorporated
`
`[0012] 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 sub-
`stances forming an inert matrix, in a non sequential com-
`penetration of different matrix materials. EP 375,063 dis-
`closes a technique for the preparation of multiparticulate
`granules for the controlled-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 deposition 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
`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 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 tech-
`nique of the inert polymer layer which is deposited on the
`surface of the pellets.
`[0013] To the "reservoir" structure also belong the prod-
`ucts obtained according to the technique described in WO
`93/00889 which discloses a process for the preparation of
`pellets in bydrophilic matrix which comprises: -dissolution
`of the active ingredient with gastro resistant hydrophilic
`polymers in organic solvents; -diying of said suspension;
`-subsequent kneading and formulation of the pellets in a
`hydrophilic or lipophilic matrix without distinction of effec-
`tiveness 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 decrease the release rate
`of the active ingredient, a pH-dependent membrane with the
`purpose of gastric protection and a pH-independent meth-
`acrylic membrane with the purpose of slowing down the
`penetration of the aqueous fluid. WO 95/16451 discloses a
`composition only formed by a 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 gastrointestinal tract, it is important to ensure
`a controlled release from the first phases following admin-
`istration, i.e. when the inert matrices have the maximum
`release rate inside the logarithmic phase, namely the higher
`deviation from linear release. 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 lipophilic polymer in a superficial hydro-
`philic matrix. The compositions of the invention are char-
`acterized by the absence of a first phase in which the
`medicament superficially present on the matrix is quickly
`solubilized, and by the fact the amphiphilic layer compen-
`sate the lack of affinity of the aqueous solvent with the
`lipophilic compounds forming the inner inert matrix.
`
`DISCLOSURE OF THE INVENTION
`[0014] The invention provides controlled release and taste
`masking oral pharmaceutical compositions containing as
`active ingredient budesonide comprising:
`[0015] a) a matrix consisting of lipophilic compounds
`with melting point lower than 90° C. and optionally by
`amphiphilic compounds in which the active ingredient is at
`least partially incorporated;
`
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`US 2006/0134208 Al (cid:9)
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`Jun. 22, 2006
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`2
`
`[0016] b) an amphiphilic matrix;
`
`[0017] c) an outer hydrophilic matrix in which the lipo-
`philic matrix and the amphiphilic matrix are dispersed;
`
`[0018] d) optionally other excipients.
`
`[0019] A particular aspect of the invention consists of
`controlled release oral compositions containing as active
`ingredient budesonide comprising:
`
`[0020] a) 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;
`
`[0021] b) an outer hydrophilic matrix in which the
`lipophilic/amphiphilic matrix is dispersed, preferably
`by mixing;
`
`[0022] c) optionally other excipients.
`
`[0023] A further aspect of the invention provides taste
`masking oral pharmaceutical compositions budesonide con-
`taining comprising:
`
`[0024] an inert or lipophilic matrix consisting of
`C6-C20 alcohols or C8-C20 fatty acids or esters of fatty
`acids with glycerol or sorbitol or other polyalcohols
`with carbon atom chain not higher than six:
`
`[0025] an amphiphilic matrix consisting of polar lipids
`of type I or II or glycols partially etherified with Cl-C4
`alkyl chains;
`
`[0026] an outer hydrophilic matrix containing the above
`matrices, mainly formed by saccharide, dextrin, poly-
`alcohol or cellulose compounds or by hydrogels or their
`mixtures;
`
`[0027] optional excipients to give stability to the phar-
`maceutical formulation.
`
`DETAILED DISCLOSURE OF THE INVENTION
`
`[0028] The compositions of the invention can be prepared
`by a method comprising the following steps:
`
`[0029] a) the active ingredient, represented by budes-
`onide, 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 ingredient can be mixed with the
`amphiphilic compounds without the aid of solvents or
`with small amounts of water-alcoholic solvents.
`
`[0030] b) the matrix obtained as specified under a) is
`incorporated in a low melting lipophilic excipient or
`mixture of excipients, if necessary while heating to
`soften and/or melt the excipient 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 ingre-
`dient particles.
`
`[0031] c) 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 swol-
`len layer is formed, which coordinates the solvent
`molecules and acts as a barrier to penetration of the
`
`aqueous fluid itself inside the new structure. Said
`barrier antagonizes the starting "burst effect" caused by
`the dissolution of the medicament inglobated inside the
`inert matrix, which is in its turn 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, phosphatidyletha-
`nolainine), ceramides, glycol alkyl ethers such as dieth-
`ylene glycol monomethyl ether (Transcuto1R) 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-or
`triglycerids, the polyethoxylated derivatives thereof,
`waxes, ceramides, cholesterol derivatives or mixtures
`thereof having melting point within the range of 40
`to90 C, preferably from 60 to 70 C. If desired, a fatty
`acid calcium salt may be incorporated in the lipophilic
`matrix which is subsequently 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 ingre-
`dient, typically from 5 to 95% w/w, in particular from
`20 to 70%, is first prepared by dispersing the active
`ingredient 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 Icneaded, usually
`while hot, with lipophilic compounds suitable to form
`an inert matrix, such as saturated or unsaturated fatty
`acids, such as palmitic, stearic, myristic, lauric, lau-
`rylic, or oleic acids or mixtures thereof with other fatty
`acids with shorter chain, or salts or alcohols or deriva-
`tives of the cited fatty acids, such as mono-, di-, or
`triglycerids or esters with polyethylene glycols, alone
`or in combination with waxes, ceramides, 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,
`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 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 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.
`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 celluloses, carboxyalkyl cellu-
`loses, polysaccharides, dextrins, pectins, starches and
`derivatives, natural or synthetic gums, alginic acid. In
`case of taste-masking formulations, the use of polyal-
`cohols such as xylitol, maltitol and mannitol as hydro-
`philic compounds can also be advantageous. The lipo-
`
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`US 2006/0134208 Al (cid:9)
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`Jun. 22, 2006
`
`3
`
`philic matrix granules containing the active ingredient
`are mixed with the hydrophilic compounds cited above
`in a weight ratio typically ranging from 100:0.5 to
`100:50 (lipophilic matrix: hydrophilic matrix). Part of
`the active ingredient can optionally be mixed with
`hydrophilic substances to provide compositions 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
`lipophilic and/or amphiphilic matrix, hydrogel-forming
`compound and, optionally, active ingredient not inglo-
`bated in the lipophilic matrix, yields a macroscopically
`homogeneous structure in all its volume, namely a
`matrix containing a dispersion of the lipophilic gran-
`ules 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 can optionally be subjected
`to known coating processes with a gastro-resistant film,
`consisting of, for example, acrylic and methacrylic
`acids polymers(Eudragit (R)) or copolymer or cellulose
`derivatives, such as cellulose acetophthalate. The com-
`position of the invention can further contain conven-
`tional excipients, for example bioadhesive excipients
`such as chitosans, polyacrylamides, natural or synthetic
`gums, acrylic acid polymers.
`
`[0032] The compositions of the invention are preferably in
`the form of tablets, capsules or minitablets. In terms of
`dissolution characteristics, 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 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 penetra-
`tion of water would cause the disintegration of the hydro-
`philic layer and therefore the release of the content which,
`consisting of inert matrix granules, however induces the
`diffusion mechanism typical of these structures and there-
`fore further slows down the dissolution profile of the active
`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 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 hydrophilic matrix are carefully selected to minimize
`the active substance release time through penetration accel-
`erated by the canalization induced by the hydrophilic com-
`pound.
`
`EXPERIMENTAL PART
`
`[0033] To test the effective ability of the formulations of
`the invention to modify the release rate and extent of the
`active ingredient from the dosage form suitable for the drug
`administration, before any pharmacokinetic study on
`patients or volunteers, the dissolution test is taken as moni-
`toring and discriminating tool.
`
`Dissolution Test Method
`
`[0034] Tablets according to the present invention undergo
`to dissolution 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 simu-
`lating gastric or intestinal juices.
`
`[0035] The dissolution test is performed by 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 applications), so that the whole digestive tract pH
`conditions, from stomach to large intestine, should be repro-
`duced. To simulate the human body conditions, the test is
`carried out at a temperature of 37° C.± 2° C. and at
`predetermined time periods samples of the dissolution
`medium are withdrawn to detect the percentage of active
`ingredient dissolved over time.
`
`[0036] The tablets according to the present invention,
`when designed to be used to treat inflammatory bowel
`disease, in principle have to show a good resistance, thanks
`to the polymeric film resistant to the low pH conditions
`(intended as <5 to simulate the gastric environment) applied
`to cover the tablet surface, resistance which last 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 constant rate during a timeframe from 6 to 12
`hours; the dissolution percentage obtained with this tablet
`formulation were below 15% at first hour sampling, below
`25% at second hour sampling, then values were in the range
`25% to 55% at fourth hour and a dissolution greater than
`80% was achieved at 8th hour sampling.
`
`EXAMPLE 1
`
`[0037] 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 of inert, functional excipients and 9.0 kg of low
`viscosity hydroxypropylcellulose (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 and
`transfer the granulate to the fluid bed drier to lower the
`residual moisture content under 3%.
`
`[0038] After a new sieving on the dry, the granulate is
`added of 9.0 kg of hydroxypropylcellulose (hydrophilic
`matrix forming material) and the suitable amount of func-
`tional excipients (in particular, microcrystalline cellulose,
`lactose and silicon dioxide)
`
`[0039] and, after 15 minutes of mixing, magnesium stear-
`ate in a suitable quantity to act as lubricant is added.
`
`[0040] After a final blending, tablets of around 300 mg of
`unitary weight are generated.
`
`[0041] The core are then subjected to be coated with a
`suspension obtained introducing into a stainless steel con-
`
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`US 2006/0134208 Al (cid:9)
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`Jun. 22, 2006
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`4
`
`tainer 5.8 kg of EudragitTM (methacrylate copolymers), 0.6
`kg of triethylcitrate and 3.0 kg of dyes and talc, using
`alcohol as solvent.
`
`[0042] The mean dissolution 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 and a dissolution greater than 80% was
`achieved at 8th hour sampling.
`
`coated in a pan coat with a gastroresistant composition
`containing EudragitTM, plasticizers, dyes and pigments.
`
`[0049] According to the present example, coated tablets
`individually weighing around 105 mg are obtained.
`
`[0050] The results of the above described dissolution test
`are the following (indicated as average value of at least six
`tablets):
`
`EXAMPLE 2
`
`[0043]
`
`Component
`
`mg/tab let
`
`Tablet
`
`Budesonide
`Stearic Acid
`Lecithin
`Microcristalline cellulose
`Hydroxypropylcellulose
`Lactose monohydrate
`Silicon dioxide
`Magnesium stearate
`Coating materials
`
`Eudragit L100
`Eudragit 5100
`Talc
`Titanium dioxiede
`Triethylcitrate
`Alcohol
`
`9.0
`10.0
`10.0
`156.0
`60.0
`50.0
`2.0
`3.0
`
`14.0
`12.0
`7.9
`4.5
`1.6
`q. s.
`
`[0044] According to the present invention, coated tablets
`individually weighing about 220 mg are obtained.
`
`[0045] The above described dissolution test is performed
`on the tablets of Example 2.
`
`[0046] The results are the following (indicated as average
`value):
`
`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
`[0047] Budesonide (3.0 kg) is mixed with soybean Leci-
`thin (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 solution obtained by dissolving medium viscosity
`polyvinylpirrolidone in water. After drying in a fluid bed and
`milling throughout a suitable screen, hydroxypropylmethyl-
`cellulose (35.0 kg) and other excipients, including magne-
`sium stearate as lubricant, in a suitable quantity are added
`and the mixture is blended till an homogeneous powder
`dispersion is obtained.
`
`[0048] The powder mixture is subjected to compression in
`a rotating tabletting machine and the tablets so obtained are
`
`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
`
`[0051] 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
`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. 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 prepared as above and the following
`amounts of hydrophilic excipients: 1500 g of hydroxypropyl
`methylcellulose and 500 g of PolicarbophilTM are added. The
`components 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
`magnesium stearate. After further 5 minute mixing, the mix
`is tabletted to unitary weight of 250 mg/tablet.
`
`[0052] Tablets are then subjected to coating using a sus-
`pension n containing polyacrylate and poly methacrilate
`copolymers in addition to other dyes, plasticizers and
`colouring agents in solvent (ethylic alcohol).
`
`[0053] 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%)
`11%
`32%
`76%
`
`1. Controlled release and taste-masking oral pharmaceu-
`tical compositions containing budesonide as active ingredi-
`ent comprising:
`
`a) a matrix consisting of lipophilic compounds with
`melting point lower than 90 C in which the active
`ingredient is at least partially inglobated;
`
`b) an amphiphilic matrix;
`
`c) an outer hydrophilic matrix in which the lipophilic
`matrix and the amphiphilic matrix are dispersed;
`
`d) optionally other excipients.
`
`MYLAN Ex 1011, Page 5
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`5
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`2. Controlled release and taste-masldng oral pharmaceu-
`tical compositions according to claim 1 in which the active
`ginredient is mixed and at least partially inglobated in the
`amphiphilic matrix of point b).
`3. Controlled release pharmaceutical compositions
`according to claim 1 comprising a lipophilic or inert matrix
`consisting of lipophilic compounds with melting point
`below 90° C. in which the active ingredient is at least
`partially inglobated and a hydrophilic matrix.
`4. Controlled release pharmaceutical compositions
`according to claim 1 comprising a lipophilic or inert matrix
`consisting of lipophilic compounds with melting point
`below 90° C. in which the active ingredient is mixed and at
`least partially inglobated and a hydrophilic matrix contain-
`ing the previous matrix.
`5. Taste-masking formulations according to claim 1 com-
`prising a lipophilic matrix, an amphiphilic matrix and a
`hydrophilic matrix, in which the lipophilic matrix consists of
`C6-C20 alcohols or C8-C20 fatty acids or esters of fatty
`acids with glycerol or sorbitol or other polyalcohols with
`carbon atom chain not higher than six.
`6. Compositions according to claim 1 in which the
`amphiphilic compounds are polar lipids of type I or II
`(lecithin, phosphatidylcholine, phosphatidylethanolamine),
`ceramides, glycol alkyl ethers, esters of fatty acids with
`polyethylene glycols, diethylene glycols.
`7. Compositions according to claim 1, in which the
`lipophilic matrix consists of compound selected from unsat-
`urated or hydrogenated alcohols or fatty acids, salts, esters
`or amides thereof, mono-, di-or triglycerides of fatty acids,
`the polyethoxylated derivatives thereof, waxes, cholesterol
`derivatives.
`8. Compositions according to claim 1, in which the
`hydrophilic matrix consists of hydrogel-forming com-
`pounds.
`
`9. Compositions according to claim 8 in which the hydro-
`philic matrix consists of compounds selected from acrylic or
`methacrylic acid polymers or copolymers, allcylvinyl poly-
`mers, (cid:9)
`hydroxyallcylcellulo se, (cid:9)
`carboxyallcylcellulo se,
`polysaccharides, dextrins, pectins, starches and derivatives,
`alginic acid, natural or synthetic gums, polyalcohols.
`10. Compositions according to claim 1, comprising a
`gastro-resistant coating.
`11. Compositions according to claim 10, in which the
`gastro-resistant coating consists of acrylic and methacrylic
`acid polymers or copolymer or cellulose derivatives.
`12. Compositions according to claim 1, in which the
`active ingredient is wholly contained in the inert/am-
`phiphilic matrix, in the form of tablets, capsules or minit-
`ablets.
`13. Compositions according to claims 1, in which the
`active ingredient is dispersed both in the hydrophilic matrix
`and in the lipophilic/amphiphilic matrix, in the form of
`tablets, capsules or minitablets.
`14. Compositions according to claim 1, containing bio-
`adhesive substances.
`15. Compositions according to claim 1, in the form of
`tablets chewable or erodible in the buccal cavity or in the
`first portion of the gastrointestinal tract.
`16. Method for the treatment of Inflammatory Bowel
`Disease and Irritable Bowel Syndrome which comprises the
`administration of the pharmaceutical compositions accord-
`ing to claim 1 to a patient in need of such a treatment.
`
`MYLAN Ex 1011, Page 6
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