PATENT
`Customer No. 6449
`Attorney Docket No. 3850-116
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application of:
`
`Roberto VILLA et al.
`
`Group Art Unit: TBD
`
`Application No.: TBD
`
`Examiner: TBD
`
`Filed: Herewith
`
`For: CONTROLLED RELEASE AND
`TASTE MASKING ORAL
`PHARMACEUTICAL COMPOSITION
`
`Confirmation No.: TBD
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`LETTER ACCOMPANYING CONTINUATION APPLICATION
`AND REQUEST FOR TELEPHONE INTERVIEW
`
`The present application is a continuation of application Serial No. 13/249,839 to pursue
`
`the claims as set forth in the present application.
`
`Claim Support
`
`Support for these claims can be found throughout the specification and claims of parent
`
`application Serial No. 13/249,839 as filed, for example, at least as follows, with reference to the
`
`parent patents:
`
`Claim recitation
`
`"A controlled release oral pharmaceutical
`composition"
`"a tablet core"
`
`1
`
`Support in Patent
`
`Support in Patent
`
`No. 8,029,823
`
`No. 7,431,943
`
`Title of application
`
`Title of application
`
`col. 4, lines 46-50;
`col. 3, lines 35-36;
`
`col. 4, lines 59-63;
`col. 3, lines 41-42;
`
`Exhibit 1056
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`Attorney Docket No. 3850-116
`Continuation of U.S. Application No. 13/249,839
`
`col. 7, lines 35-36
`
`col. 6, lines 49-50
`
`"budesonide in an amount effective for
`topically active treatment of
`inflammatory bowel disease in the
`gastrointestinal tract"
`"a lipophilic excipient"
`
`col. 5, lines 38-39;
`col. 1, lines 19-21;
`
`col. 5, lines 18-20,
`col. 1, lines 18-24;
`
`col. 2, lines 29-32
`
`col. 2, lines 34-37
`
`col. 3, line 28
`
`col. 3, line 33
`
`"an amphiphilic excipient"
`
`col. 3, line 22
`
`col. 3, lines 27-28
`
`"a hydrogel forming hydrophilic
`excipient"
`
`col. 3, line 34 to col.
`5, line 2
`
`col. 3, line 39 to
`col. 4, line 38
`
`"a coating on said tablet core, said coating
`comprising a gastro-resistant film"
`
`co1.4, lines 46-50
`
`co1.4, lines 49-53
`
`"wherein said lipophilic excipient is stearic
`sentence bridging
`col. 3 and 4
`acid"
`"wherein said amphiphilic excipient is lecithin" col. 3, lines 43-47
`
`"wherein said hydrophilic excipient is
`hydroxypropyl cellulose"
`
`col. 6, lines 1-3; col.
`4, lines 22-27
`
`2
`
`col. 4, lines 59-63
`
`col. 3, lines 50-51
`
`col. 4 lines 33-38
`[there is
`"hydroxyalkyl
`cellulose"; and Ex.
`2 uses
`hydroxypropyl
`methylcellulose]
`
`"wherein said gastro-resistant film comprises at
`least one methacrylic acid polymer"
`
`col. 4, lines 46-50
`
`col. 4, lines 59-63
`
`3 "wherein said tablet core further comprises
`microcrystalline cellulose, lactose, silica, and
`magnesium stearate"
`
`col. 7, lines 33-35
`
`col. 6, lines 46-49
`
`Therefore, no new matter is added by the claims of the present application. Applicants
`
`respectfully request that the examination of this application proceed with the present claims.
`
`-2-
`
`000002
`
`

`

`Attorney Docket No. 3850-116
`Continuation of U.S. Application No. 13/249,839
`
`Telephone Interview
`
`Applicants are filing concurrently herewith a Request for Prioritized Examination (Track
`
`1) for the present application. Applicants request that a telephone interview with the Examiner
`
`be scheduled before any office action on the merits.
`
`Authorization to Charge Deposit Account
`
`Please grant any extensions of time required to enter this paper and charge any additional
`
`required fees to Deposit Account No. 02-2135.
`
`Respectfully submitted,
`
`Dated: 2 May 2012 (cid:9)
`
`By (cid:9)
`
`/Jeffrey L. Ihnen/
`Jeffrey L. Ihnen
`Registration No. 28,957
`Attorney for Applicants
`607 14th Street, N.W., Suite 800
`Washington, D.C. 20005
`Phone: 202-783-6040
`Fax: 202-783-6031
`
`-3-
`
`000003
`
`

`

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`Application Data Sheet 37 CFR 1.76
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`Attorney Docket Number
`
`3850-116
`
`Application Number
`
`Title of Invention
`
`Controlled Release and Taste Masking Oral Pharmaceutical Composition
`
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`VILLA
`Roberto
`Residence Information (Select One) (cid:9) 0 US Residency (cid:9) 0 (cid:9) Non US Residency (cid:9)
`City
`Country Of Residencei
`IT
`Lecco
`
`0 Active US Military Service
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`Via Col Di Lana 26
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`IT
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`Lecco
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`23900
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`Massimo
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`IT
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`Salita Rognoni 18
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`
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`Gignese
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`
`28836
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`IT
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`Mauro
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`City Milano
`Country Of Residencei
`IT
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`EFS Web 2.2.2
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`PTO/SB/14 (11-08)
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`Application Data Sheet 37 CFR 1.76
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`3850-116
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`Title of Invention
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`Controlled Release and Taste Masking Oral Pharmaceutical Composition
`
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`IT
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`20121-20162
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`IT
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`Via Creta 6
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`IT
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`Milano
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`Controlled Release and Taste Masking Oral Pharmaceutical Composition
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`Controlled Release and Taste Masking Oral Pharmaceutical Composition
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`/Jeffrey L. Ihnen/
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`Date (YYYY-MM-DD) 2012-05-02
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`First Name
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`Jeffrey L.
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`Ihnen
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`PTO/SB/14 (11-08)
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`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
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`Application Data Sheet 37 CFR 1.76
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`Attorney Docket Number
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`3850-116
`
`Application Number
`
`Title of Invention
`
`Controlled Release and Taste Masking Oral Pharmaceutical Composition
`
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`Controlled Release and Taste-Masking Oral Pharmaceutical Composition
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation of application Serial No. 13/249,839 filed on
`
`[0001] (cid:9)
`September 30, 2011; which is a continuation of application Serial No. 12/210,969 filed
`
`on September 15, 2008, now U.S. Patent No. 8,029,823; which is a continuation-in-part
`
`of application Serial No. 10/009,532 filed on December 12, 2001, now U.S. Patent No.
`
`7,431,943; 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 M199A001317 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
`[0002] 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.
`[0003] 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.
`
`[0004] 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 of strongly
`
`000009
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`

`

`2
`
`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.
`
`[0005] All the procedures listed above suffer, however, from drawbacks and
`imperfections.
`
`[0006] (cid:9)
`
`Inert matrices, for example, generally entail non-linear, but exponential,
`
`release of the active ingredient.
`[0007] (cid:9) 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
`
`[0008] (cid:9)
`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.
`
`[0009] 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
`
`[0010] (cid:9)
`
`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 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 technique of the inert polymer layer which is deposited on the surface of the
`
`pellets.
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`000010
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`

`3
`
`[0011] (cid:9)
`
`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 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
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`according to the present invention, through the combination of an amphiphilic matrix
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`inside an inert matrix, the latter formulated with a lipophilic polymer in a superficial
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`hydrophilic matrix. The compositions of the invention are characterized by the absence
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`of a first phase in which the medicament superficially present on the matrix is quickly
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`solubilized, and by the fact the amphiphilic layer compensate the lack of affinity of the
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`aqueous solvent with the lipophilic compounds forming the inner inert matrix.
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`DISCLOSURE OF THE INVENTION
`
`[0012] (cid:9)
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`The invention provides controlled release and taste masking oral
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`pharmaceutical compositions containing as active ingredient budesonide comprising:
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`a) a matrix consisting of lipophilic compounds with melting point lower than 90[deg.] C.
`
`and optionally by amphiphilic compounds in which the active ingredient is at least
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`partially incorporated;
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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 matrix
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`are dispersed;
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`000011
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`d) optionally other excipients.
`
`4
`
`[0013] (cid:9)
`
`A particular aspect of the invention consists of controlled release oral
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`compositions containing as active ingredient budesonide comprising:
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`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;
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`b) an outer hydrophilic matrix in which the lipophilic/amphiphilic matrix is dispersed,
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`preferably by mixing;
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`c) optionally other excipients.
`
`[0014] (cid:9)
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`A further aspect of the invention provides taste masking oral pharmaceutical
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`compositions budesonide containing comprising:
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`an inert or lipophilic matrix consisting of C6-C20 alcohols or C8-C20 fatty acids or
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`esters of fatty acids with glycerol or sorbitol or other polyalcohols with carbon atom
`
`chain not higher than six:
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`an amphiphilic matrix consisting of polar lipids of type I or II or glycols partially etherified
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`with C1-C4 alkyl chains;
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`an outer hydrophilic matrix containing the above matrices, mainly formed by
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`saccharide, dextrin, polyalcohol or cellulose compounds or by hydrogels or their
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`mixtures;
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`optional excipients to give stability to the pharmaceutical formulation.
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`DETAILED DISCLOSURE OF THE INVENTION
`
`[0015] (cid:9)
`
`The compositions of the invention can be prepared by a method comprising
`
`the following steps:
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`a) the active ingredient, represented by budesonide, is first inglobated by simple
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`kneading or mixing in a matrix or coating consisting of compounds having amphiphilic
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`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
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`water-alcoholic solvents.
`
`b) the matrix obtained as specified under a) is incorporated in a low melting lipophilic
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`excipient or mixture of excipients, if necessary while heating to soften and/or melt the
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`excipient itself, which thereby incorporates the active ingredient by simple dispersion
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`forming an inert matrix which can be reduced in size to obtain inert matrix granules
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`containing the active ingredient particles.
`
`000012
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`5
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`c) the inert matrix granules are subsequently mixed together with one or more
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`hydrophilic water-swellable excipients. The mixture is then subjected to compression or
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`tabletting. This way, when the tablet is contacted with biological fluids, a high viscosity
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`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
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`amphiphilic compounds which can be used according to the invention comprise polar
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`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
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`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,
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`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 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
`
`000013
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`6
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`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 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.
`
`[0016] (cid:9)
`
`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
`
`000014
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`7
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`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 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 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 accelerated by the canalization induced by
`
`the hydrophilic compound.
`
`EXPERIMENTAL PART
`
`[0017] (cid:9)
`
`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 monitoring and discriminating tool. Dissolution Test Method.
`
`[0018] (cid:9)
`
`Tablets according to the present invention undergo to dissolution test to verify
`
`the formulation capacity in modulating and