`
`27, 2011 at Reel 026656, Frame
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`Copy of IDS citations
`
`UTILITY PATENT APPLICATION TRANSMITTAL
`(Only for new nonprovisional applications under 37 CFR 1.53(b))
`To the Assistant Commissioner of Patents
`Transmitted herewith for filing is the patent application of:
`Inventors: (1) VILLA, ROBERTO (2) PEDRANI, MASSIMO (3) AJANI, MAURO (4) FOSSATI, LORENZO
`This application is a 0 continuation q division q continuation-in-part of co-pending Application No.
`are hereby incorporated by reference. 12/210,969, filed on September 15, 2008, the entire contents of which
`
`Title: CONTROLLED RELEASE AND TASTE-MASKING ORAL PHARMACEUTICAL COMPOSITION
`Enclosed are:
`Pages of Specification containing 15 claims
`15 (cid:9)
`0 (cid:9)
`0
`Sheets of Drawings (cid:9)
`Abstract of the Disclosure
`Submission of English translation of prior provisional application
`q
`under 37 CFR 1.78(a)(5)
`Newly executed Oath or Declaration/Power of Attorney
`Copy of Oath or Declaration/Power of Attorney from a prior
`(continuation/divisional)
`Q (cid:9)
`The entire disclosure of the prior application, from
`which a copy of the oath or declaration
`is supplied as indicated in the preceding box, is considered
`as being part of the disclosure
`
`by reference therein. of the accompanying application and is hereby incorporated
`deleting Deletion of inventor(s). A signed statement attached
`
`inventor(s) named in the prior application (see 37
`CFR 1.63 (d)(2) and 1.33(b)
`Applicant claims small entity status under 37 C.F.R. § 1.27
`Application Data Sheet under 37 C.F.R. § 1.76
`Assignment Papers (cover sheet & document(s))
`An assignment to COSMO TECHNOLOGIES LIMITED
`for parent application no. 12/210,969 was recorded on July
`0814
`Information Disclosure Statement (IDS) w/PTO-1449 - 0
`Preliminary Amendment
`Certified Copy of Priority Document(s)
`Priority of Italian applications M12000A000422 and MI99A001317
`filed March 3, 2000 and June
`le (cid:9)
`
`has been acknowledged by the 14, 1999 are claimed under 35 U.S.C. § 119. Claim to priority application
`Examiner in an Office Action dated November 15, 2010 in parent application
`12/210,969
`(Appendix)
`q
`CD-ROM or CD-R in duplicate, large table or Computer Program
`SEQUENCE INFORMATION
`LETTER REQUESTING TRANSFER OF PREVIOUSLY FILED
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`application
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`Other Attachment:
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`SEND ALL CORRESPONDENCE TO:
`
`YOUNG & THOMPSON (cid:9)
`209 Madison Street (cid:9)
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`Alexandria, VA 22314
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`/Benoit Castel/
`Signature
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`Benoit Castel, Reg. No. 35,041
`Name, Registration Number
`
`30 September 2011
`
`Y&T September 30, 2011
`
`Exhibit 1055
`ARGENTUM
`IPR2018-00080
`
`000001
`
`
`
`Docket No. 2551-1001-6
`
`Controlled Release and Taste-Masking Oral Pharmaceutical Composition
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation of copending application Serial number: 12/210,969
`
`filed on September 15, 2008; which is a continuatin in part of application Serial
`
`number: 10/009,532 filed on December 12, 2001; which is the 35 U.S.C. 371
`
`national stage of International application PCT/EP00/05356 filed on June 9, 2000;
`
`which claimed priority to Italian applications M12000A000422 and MI99A001317 filed
`
`March 3, 2000 and June 14, 1999, respectively. The entire contents of each of the
`
`above-identified applications are hereby incorporated by reference.
`
`BACKGROUND OF THE INVENTION
`
`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 dispersed 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 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 or gastric area.
`
`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
`
`gastrointestinal tract.
`
`The preparation of a sustained, controlled, delayed, extended or anyhow modified
`
`release form can be carried out according to different techniques:
`
`1. 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
`
`towards aqueous fluids; such property being known as lipophilia.
`
`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
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`000002
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`2
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`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
`
`anzimes of some biological compartment.
`
`All the procedures listed above suffer, however, from drawbacks 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 certain fraction of active
`
`ingredient has been released, then significantly 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 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 U.S. Pat. No.
`
`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 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
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`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
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`000003
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`3
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`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 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
`
`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 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 decrease the release rate of the active ingredient, a pH-dependent
`
`membrane with the purpose of gastric protection and a pH-independent methacrylic
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`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 administration, 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 hydrophilic matrix. The
`
`compositions of the invention are characterized 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 compensate the lack of affinity of the aqueous
`
`solvent with the lipophilic compounds forming the inner inert matrix.
`
`DISCLOSURE OF THE INVENTION
`
`The invention provides controlled release and taste masking oral pharmaceutical
`
`compositions containing as active ingredient budesonide comprising:
`
`a) a matrix consisting of lipophilic compounds with melting point lower than 90[deg.]
`
`000004
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`4
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`C. and optionally by amphiphilic compounds in which the active ingredient is at least
`partially incorporated;
`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 lipophilic compounds with
`melting point below 900 C. in which the active ingredient is at least partially
`incorporated;
`b) an outer hydrophilic matrix in which the lipophilic/amphiphilic 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 acids or
`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 type I or II or glycols partially
`etherified with Cl -C4 alkyl chains;
`
`an outer hydrophilic matrix containing the above matrices, mainly formed by
`saccharide, dextrin, polyalcohol or cellulose compounds or 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:
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`000005
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`5
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`a) the active ingredient, represented by budesonide, 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.
`
`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 ingredient particles.
`
`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 swollen 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,
`
`phosphatidylethanolainine), ceramides, glycol alkyl ethers such as diethylene glycol
`
`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, 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 ingredient, typically from 5 to 95% w/w, in particular
`
`000006
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`6
`
`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
`
`lcneaded, 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, 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 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 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 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 compositions 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 inglobated in the lipophilic matrix, yields a
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`000007
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`7
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`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
`
`coating. The tablets obtainable according to the invention are 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 composition of the invention can further contain
`
`conventional 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 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 penetration of water would 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
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`typical of these structures and therefore further slows down the dissolution profile of
`
`the active ingredient. The presence of the amphiphilic matrix inside the lipophilic
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`matrix inert allows to prevent any unevenness of the release profile of the active
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`ingredient. The surfactants present in the amphiphilic portion promote wettability of
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`the porous canaliculuses which cross the inert matrix preventing or reducing
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`resistance to penetration of the solvent inside the inert matrix. To obtain taste
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`masking tablets, the components of the hydrophilic matrix are carefully selected to
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`minimize the active substance release time through penetration accelerated by the
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`canalization induced by the hydrophilic compound.
`
`EXPERIMENTAL PART
`
`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
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`dissolution test is taken as monitoring and discriminating tool. Dissolution Test
`
`Method.
`
`Tablets according to the present invention undergo to dissolution test to verify the
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`formulation capacity in modulating and controlling the rate by which the active
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`ingredient is leaked by the device or dosage form in the environmental medium,
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`generally a buffered solution simulating gastric or intestinal juices.
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`The dissolution test is performed by introducing individual tablets in a glace vessel
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`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
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`that the whole digestive tract pH conditions, from stomach to large intestine, should
`
`be reproduced. To simulate the human body conditions, the test is carried out at a
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`temperature of 37° C.-E-<=2° C. and at predetermined time periods samples of the
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`dissolution medium are withdrawn to detect the percentage of 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 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
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`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
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`short exposition time and only mediums at pH 7.2 have been able to determine an
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`active ingredient dissolution at a progressive and quite constant rate during a
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`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
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`greater than 80% was achieved at 8th 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 of inert, functional excipients
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`000009
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`
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`9
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`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%.
`
`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 functional excipients (in particular, microcrystalline cellulose, lactose and silicon
`dioxide)
`and, after 15 minutes of mixing, 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(TM) (methacrylate copolymers),
`0.6 kg of triethylcitrate and 3.0 kg of dyes and talc, using alcohol as solvent.
`
`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.
`
`EXAMPLE 2
`Component mg/tablet
`Tablet
`Budesonide
`Stearic Acid
`Lecithin
`
`Microcristalline cellulose
`Hydroxypropylcellulose
`Lactose monohydrate
`Silicon dioxide
`
`9.0
`10.0
`
`156.0
`
`10.0
`
`60.0
`50.0
`2.0
`
`000010
`
`
`
`Magnesium stearate
`Coating materials
`Eudragit L100
`Eudragit S100
`Talc
`Titanium dioxiede
`Triethylcitrate
`Alcohol
`
`10
`
`3.0
`
`14.0
`12.0
`
`1.6
`q.s.
`
`7.9
`4.5
`
`According to the present invention, coated tablets individually weighing about 220
`mg are obtained.
`
`The above described dissolution test is performed on the tablets of Example 2.
`
`The results are the following (indicated as average value):
`after 2 hours at pH 1 (cid:9)
`resistant (<5%)
`after 1 hour at pH 6.4 resistant (<5%)
`after 2 hours at pH 7.2 15%
`after 4 hours at pH 7.2 37%
`after 8 hours at pH 7.2 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 solution obtained by dissolving
`medium viscosity polyvinylpirrolidone 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 rotating tabletting machine and
`the tablets so obtained are coated in a pan coat with a gastroresistant composition
`
`000011
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`
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`containing Eudragit(TM), plasticizers, dyes and pigments.
`
`11
`
`According to the present example, coated tablets individually weighing around 105
`
`mg are obtained.
`
`The results of the above described dissolution test are the following (indicated as
`
`average value of at least six tablets):
`
`after 2 hours at pH 1 resistant (<5%)
`
`after 1 hour at pH 6.4 resistant (<5%)
`
`after 2 hours at pH 7.2 9%
`
`after 4 hours at pH 7.2 28%
`
`after 8 hours at pH 7.2 86%
`
`EXAMPLE 4
`
`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[deg.] 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
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`hydrophilic excipients: 1500 g of hydroxypropyl methylcellulose and 500 g of
`
`Policarbophil(TM) are added. 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 and 50 g of magnesium stearate. After further 5
`
`minute mixing, the mix is 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 resistant (<5%)
`
`000012
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`12
`
`after 1 hour at pH 6.4 resistant (<5%)
`
`after 2 hours at pH 7.2 11%
`
`after 4 hours at pH 7.2 32%
`
`after 8 hours at pH 7.2 (cid:9)
`
`76%
`
`000013
`
`
`
`13
`
`CLAIMS
`
`1. A controlled release and taste-masking oral pharmaceutical composition
`
`comprising:
`
`budesonide as an active ingredient incorporated into a matrix structure
`
`consisting essentially of:
`
`a) a lipophilic matrix consisting of lipophilic compounds with a melting
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`point lower than 90° C in which the active ingredient is at least partially inglobated;
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`b) an amphiphilic matrix;
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`c) an outer hydrophilic matrix in which the lipophilic matrix and the amphiphilic
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`matrix are dispersed;
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`d) a gastro-resistant coating.
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`2. The composition according to claim 1, wherein the active ingredient is mixed and
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`at least partially inglobated in the amphiphilic matrix.
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`3. The composition according to claim 1, wherein the active ingredient is at least
`
`partially inglobated and a hydrophilic matrix.
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`4. The composition according to claim 1, wherein the active ingredient is mixed and
`
`at least partially inglobated and a hydrophilic matrix containing the previous matrix.
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`5. The composition according to claim 1, wherein 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. The composition according to claim 1, wherein the amphiphilic matrix comprises
`
`amphiphilic compounds selected from the group consisting ofpolar lipids of type I or
`
`II (lecithin, phosphatidylcholine, phosphatidylethanolamine), ceramides, glycol alkyl
`
`ethers, esters of fatty acids with polyethylene glycols, and diethylene glycols.
`
`7. The composition according to claim 1, wherein the lipophilic matrix consists of a
`
`compound selected from unsaturated or hydrogenated alcohols or fatty acids, salts,
`
`esters or amides thereof, mono-, di-or triglycerides of fatty acids, the polyethoxylated
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`000014
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`derivatives thereof, waxes, and cholesterol derivatives.
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`14
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`8. The composition according to claim 1, wherein the hydrophilic matrix consists of
`hydrogel-forming compounds.
`
`9. The composition according to claim 8, wherein the hydrophilic matrix consists of
`compounds selected from acrylic or methacrylic acid polymers or copolymers,
`allcylvinyl polymers, hydroxyallcylcellulose, carboxyallcylcellulose, polysaccharides,
`dextrins, pectins, starches and derivatives, alginic acid, natural or synthetic gums,
`polyalcohols.
`
`10. The composition according to claim 1, wherein the gastro-resistant coating
`consists of acrylic and methacrylic acid polymers or copolymer or cellulose
`derivatives.
`
`11. The composition according to claim 1, wherein the active ingredient is wholly
`contained in the lipophilic/amphiphilic matrix, and the composition is in the form of
`tablets, capsules or minitablets.
`
`12. The composition according to claim 1, wherein the active ingredient is dispersed
`both in the hydrophilic matrix and in the lipophilic/amphiphilic matrix, and the
`composition is in the form of tablets, capsules or minitablets.
`
`13. The composition according to claim 1, further comprising bioadhesive
`substances.
`
`14. The composition according to claim 1, wherein the composition is in tablet form,
`and said tablet form is chewable or edible in the buccal cavity or in the first portion of
`the gastrointestinal tract.
`
`15. A method for the treatment a subject suffering from Inflammatory Bowel Disease
`and Irritable Bowel Syndrome, comprising administering an effective amount of the
`pharmaceutical compositions according to claim 1 to a subject in need of such a
`treatment.
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`15
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`ABSTRACT
`
`Controlled release and taste masking compositions containing one or more active
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`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
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`ingredient in aqueous and/or biological fluids, thereby controlling the release kinetics
`
`in the gastrointestinal tract.
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