111111111111111111111111111Ms1011#11111111111111111111111111111
`
`(12) United States Patent (cid:9)
`Villa et al. (cid:9)
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 9,320,716 B2
`*Apr. 26, 2016
`
`(54) CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITIONS
`
`(71) Applicant: COSMO TECHNOLOGIES
`LIMITED, Dublin (IE)
`
`(72) Inventors: Roberto Villa, Lecco (IT); Massimo
`Pedrani, Gignese (IT); Mauro Ajani,
`Milan (IT); Lorenzo Fossati, Milan (IT)
`
`(73) Assignee: COSMO TECHNOLOGIES
`LIMITED, Dublin (IE)
`
`* )
`
`Notice: (cid:9)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 14/308,279
`
`(22) Filed: (cid:9)
`
`Jun. 18, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2014/0302139 Al (cid:9)
`
`Oct. 9, 2014
`
`(56) (cid:9)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
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`3,800,051 A
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`
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`Related U.S. Application Data
`
`FOREIGN PATENT DOCUMENTS
`
`(63) Continuation of application No. 13/617,138, filed on
`Sep. 14, 2012, now Pat. No. 8,784,888, which is a
`continuation of application No. 13/462,409, filed on
`May 2, 2012, now Pat. No. 8,293,273, which is a
`continuation of application No. 13/249,839, filed on
`Sep. 30, 2011, now abandoned, which is a continuation
`of application No. 12/210,969, filed on Sep. 15, 2008,
`now Pat. No. 8,029,823, which is a
`continuation-in-part of application No. 10/009,532,
`filed as application No. PCT/EP00/05356 on Jun. 9,
`2000, now Pat. No. 7,431,943.
`
`(30) (cid:9)
`
`Foreign Application Priority Data
`
`CA (cid:9)
`DE (cid:9)
`
`11/1998
`2119253 (cid:9)
`3/1993
`41 31 562 (cid:9)
`(Continued)
`
`OTHER PUBLICATIONS
`
`Jantzen, G.M. et al., "Sustained- and Controlled-Release Drug Deliv-
`ery Systems," Modern Pharmaceutics, 3rd Edition, Revised and
`Expanded, pp. 575-609, © 1996 Marcel Dekker, Inc., 37 pages.
`(Continued)
`
`Primary Examiner — Susan Tran
`
`Jun. 14, 1999 (IT) (cid:9)
`Mar. 3, 2000 (IT) (cid:9)
`
` MI99A1317
` MI2000A0422
`
`(74) Attorney, Agent, or Firm Rothwell, Figg, Ernst &
`Manbeck P.C.
`
`(51)
`
`Int. Cl.
`A 61K 9/20 (cid:9)
`A 61K 9/28 (cid:9)
`A 61K 9/16 (cid:9)
`A 61K 9/24 (cid:9)
`A 61K 31/58 (cid:9)
`(52) U.S. Cl.
`CPC (cid:9)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`A61K 9/2866 (2013.01); A61K 9/1617
`(2013.01); A61K 9/209 (2013.01); A61K
`9/2054 (2013.01); A61K 9/2077 (2013.01);
`A61K 9/2846 (2013.01); A 61K 31/58
`(2013.01); A61K 9/1652 (2013.01)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(57) (cid:9)
`
`ABSTRACT
`
`The invention relates to an oral pharmaceutical composition
`comprising an active agent, a macroscopically homogeneous
`structure and a gastro-resistant coating. The macroscopically
`homogeneous structure comprises at least one hydrophilic
`compound and at least one lipophilic compound and/or at
`least one amphiphilic compound. The macroscopically
`homogeneous structure controls the release of the active
`ingredient, and the gastro-resistant film prevents release of
`the active agent in the stomach.
`
`29 Claims, No Drawings
`
`MYLAN Ex 1001, Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`US 9,320,716 B2
`Page 2
`
`(56)
`
`References Cited
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`U.S. PATENT DOCUMENTS
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`4/2002 Akiyama
`6,368,635 B1 (cid:9)
`5/2003 Mantelle
`6,562,363 B1 (cid:9)
`8/2003 Odidi et al.
`6,607,751 B1 (cid:9)
`7,410,651 B2 (cid:9) * 8/2008 Villa et al. (cid:9)
`7,410,652 B2 (cid:9)
`8/2008 Villa et al.
`7,431,943 B1 (cid:9) * 10/2008 Villa et al. (cid:9)
`8,029,823 B2 (cid:9) * 10/2011 Villa et al. (cid:9)
`8,787,888 B2 (cid:9) * 7/2014 Bridge et al. (cid:9)
`8,895,064 B2 (cid:9) * 11/2014 Villa et al. (cid:9)
`2006/0003006 Al (cid:9)
`1/2006 Remon et (cid:9) al.
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`2006/0134208 Al (cid:9)
`6/2006 Villa et al.
`2009/0011010 Al (cid:9)
`1/2009 Villa et al.
`2011/0123460 Al (cid:9)
`5/2011 Wilhelm et (cid:9) al.
`2012/0021052 Al (cid:9)
`1/2012 Villa et al.
`2012/0021053 Al (cid:9)
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`2012/0220559 Al (cid:9)
`8/2012 Villa et al.
`
`FOREIGN PATENT DOCUMENTS
`
` 424/468
`
` 424/468
` 424/464
` 455/415
` 424/464
`
`DE
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`EP
`EP
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`JP
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`
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`0482576 (cid:9)
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`
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`D'Haens, G.R. et al., "Budesonide MMXTM Is Active and Safe in
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`From Two Phase 3 Studies," poster, 1 page.
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`Fiorino, G. et al„ "New Drug Delivery Systems in inflammatory
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`Koutroubakis, I., "Recent Advances in the Management of Distal
`Ulcerative Colitis," World Journal of Gastrointestinal Pharmacology
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`and Devices", 1995, pp. 1-9.
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`JP Office Action dated May 6, 2010 from corresponding JP2001-
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`Lichtenstein, G. et al., Poster, "Effect of Budesonide MMX 6 mg on
`the Hypothalamic-Pituitary-Adrenal (HPA) Axis in Patients with
`Ulcerative Colitis: Results from Phase III, 12 Month Safety and
`Extended User Study," May 2012, San Diego, CA, 1 page.
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`Release Tablets Induce Remission in Patients With Mild to Moderate
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`sion with Budesonide MMX in Mild-to-Moderately Active Ulcer-
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`MYLAN Ex 1001, Page 2
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
`

`

`US 9,320,716 B2
`Page 3
`
`(56) (cid:9)
`
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`
`Travis et al., "Once-Daily Budesonide MMX in Active, Mild-to-
`Moderate Ulcerative Colitis: Results From the Randomised CORE II
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`
`* cited by examiner
`
`MYLAN Ex 1001, Page 3
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`

`

`US 9,320,716 B2
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`20 (cid:9)
`
`1
`CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITIONS
`
`2
`Hydrophilic matrices have a linear behaviour until a certain
`fraction of active ingredient has been released; then they
`significantly deviate from linear release.
`Bioerodible matrices are ideal to carry out the so-called
`5 "site-release", but they involve the problem of finding the
`suitable enzyme or reactive to degradation. Furthermore, they
`frequently release in situ metabolites that are not wholly
`This application is a continuation of application Ser. No. (cid:9)
`toxicologically inert.
`13/617,138 filed on Sep. 14, 2012, now U.S. Pat. No. 8,784, (cid:9)
`A number of formulations based on inert lipophilic matri-
`888; which is a continuation of application Ser. No. 13/462, 10 ces have been described: Drug Dev. Ind. Pharm. 13 (6), 1001-
`1022, (1987) discloses a process making use of varying
`409 filed on May 2, 2012, now U.S. Pat. No. 8,293,273; which
`is a continuation of Ser. No. 13/249,839 filed on Sep. 30, (cid:9)
`amounts of colloidal silica as a porization element for a lipo-
`2011, now abandoned; which is a continuation of application (cid:9)
`philic inert matrix in which the active ingredient is incorpo-
`Ser. No. 12/210,969 filed on Sep. 15, 2008, which reissued as (cid:9)
`rated.
`(cid:9) 15 (cid:9)
`The same notion of canalization of an inert matrix is
`U.S. Pat. No. RE43,799 from U.S. Pat. No. 8,029,823; which
`described in U.S. Pat. No. 4,608,248 in which a small amount
`is a continuation-in-part of application Ser. No. 10/009,532
`filed on Dec. 12, 2001, now U.S. Pat. No. 7,431,943; which is (cid:9)
`of a hydrophilic polymer is mixed with the substances form-
`ing an inert matrix, in a non sequential compenetration of
`the 35 U.S.C. 371 national stage of International application
`different matrix materials.
`PCT/EP00/05356 filed on Jun. 9, 2000; which claimed prior-
`EP 375,063 discloses a technique for the preparation of
`ity (cid:9)
`to Italian applications MI2000A000422 and
`MI99A001317 filed Mar. 3, 2000 and Jun. 14, 1999, respec- (cid:9)
`multiparticulate granules for the controlled-release of the
`active ingredient which comprises co-dissolution of poly-
`tively. The entire contents of each of the above-identified
`applications are hereby incorporated by reference. (cid:9)
`mers or suitable substances to form a inert matrix with the
`active ingredient and the subsequent deposition of said solu-
`The present invention relates to controlled release and
`taste-masking compositions containing one or more active 25 tion on an inert carrier which acts as the core of the device.
`principles incorporated in a three-component matrix struc- (cid:9)
`Alternatively, the inert carrier is kneaded with the solution
`ture, i.e. a structure formed by successive amphiphilic, lipo- (cid:9)
`containing the inert polymer and the active ingredient, then
`the organic solvent used for the their dissolution is evaporated
`philic or inert matrices and finally incorporated or dispersed
`in hydrophilic matrices. The use of a plurality of systems for (cid:9)
`off to obtain a solid residue. The resulting structure is a
`the control of the dissolution of the active ingredient modu- 30 "reservoir", i.e. is not macroscopically homogeneous along
`lates the dissolution rate of the active ingredient in aqueous (cid:9)
`all the symmetry axis of the final form.
`and/or biological fluids, thereby controlling the release kinet- (cid:9)
`The same "reservoir" structure is also described in Chem.
`Pharm. Bull. 46 (3), 531-533, (1998) which improves the
`ics in the gastrointestinal tract, and it also allows the oral
`administration of active principles having unfavourable taste (cid:9)
`application through an annealing technique of the inert poly-
`characteristics or irritating action on the mucosae of the 35 mer layer which is deposited on the surface of the pellets.
`administration site, particularly in the buccal area. (cid:9)
`To the "reservoir" structure also belong the products
`The compositions of the invention can contain active prin- (cid:9)
`obtained according to the technique described in WO
`ciples belonging to the therapeutical classes of analgesics, (cid:9)
`93/00889 which discloses a process for the preparation of
`antiinflammatories, cardioactives, tranquillizers, antihyper- (cid:9)
`pellets in hydrophilic matrix which comprises:
`tensives, disinfectants and topical antimicrobials, antiparkin- (cid:9) 40 (cid:9)
`dissolution of the active ingredient with gastro-resistant
`hydrophilic polymers in organic solvents;
`son drugs, antihistamines and are suitable to the oral admin-
`drying of said suspension;
`istration or for acting topically at some areas of the
`gastrointestinal tract. (cid:9)
`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"
`The preparation of a sustained, controlled, delayed or any- (cid:9)
`structure inserted in a hydrophilic matrix. The basic multi-
`how modified release form can be carried out according to (cid:9)
`particulate utilizes two coating membranes to decrease the
`different known techniques: (cid:9)
`release rate of the active ingredient, a pH-dependent mem-
`1. The use of inert matrices, in which the main component 50 brave with the purpose of gastric protection and a pH-inde-
`of the matrix structure opposes some resistance to the (cid:9)
`pendent methacrylic membrane with the purpose of slowing
`penetration of the solvent due to the poor affinity
`down the penetration of the aqueous fluid.
`towards aqueous fluids; such property being known as
`WO 95/16451 discloses a composition only formed by a
`lipophilia. (cid:9)
`hydrophilic matrix coated with a gastro-resistant film for
`2. The use of hydrophilic matrices, in which the main 55 controlling the dissolution rate of the active ingredient.
`component of the matrix structure opposes high resis- (cid:9)
`When preparing sustained-, controlled-release dosage
`tance to the progress of the solvent, in that the presence
`forms of a medicament topically active in the gastrointestinal
`of strongly hydrophilic groups in its chains, mainly (cid:9)
`tract, it is important to ensure a controlled release from the
`branched, remarkably increases viscosity inside the
`first phases following administration, i.e. when the inert
`hydrated layer. (cid:9)
`60 matrices have the maximum release rate inside the logarith-
`3. The use of bioerodible matrices, which are capable of
`mic phase, namely the higher deviation from linear release.
`being degraded by the enzymes of some biological com- (cid:9)
`Said object has been attained according to the present
`partment. (cid:9)
`invention, through the combination of an amphiphilic matrix
`All the procedures listed above suffer, however, from draw- (cid:9)
`inside an inert matrix, the latter formulated with a lipophilic
`backs and imperfections. (cid:9)
`65 polymer in a superficial hydrophilic matrix. The composi-
`Inert matrices, for example, generally entail non-linear, but
`tions of the invention are characterized by the absence of a
`exponential, release of the active ingredient. (cid:9)
`first phase in which the medicament superficially present on
`
`TECHNOLOGICAL BACKGROUND
`
`45 (cid:9)
`
`MYLAN Ex 1001, Page 4
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`US 9,320,716 B2
`
`3
`the matrix is quickly solubilized, and by the fact the
`amphiphilic layer compensate the lack of affinity of the aque-
`ous solvent with the lipophilic compounds forming the inner
`inert matrix.
`
`DISCLOSURE OF THE INVENTION
`
`5
`
`4
`caused by the dissolution of the medicament inglobated
`inside the inert matrix, which is in its turn inside the hydro-
`philic matrix.
`The amphiphilic compounds which can be used according
`to the invention comprise polar lipids of type I or II (lecithin,
`phosphatidylcholine, phosphatidylethanolamine), ceram-
`ides, glycol alkyl ethers such as diethylene glycol monom-
`ethyl ether (Transcutol®).
`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 triglycer-
`ides, the polyethoxylated derivatives thereof, waxes, ceram-
`ides, cholesterol derivatives or mixtures thereof having a
`melting point within the range of 40 to 90° C., preferably from
`60 to 70° C.
`If desired, a fatty acid calcium salt may be incorporated in
`the lipophilic matrix which is subsequently dispersed in a
`hydrophilic matrix prepared with alginic acid, thus remark-
`ably increasing the hydrophilic matrix viscosity following
`penetration of the solvent front until contact with the lipo-
`philic matrix granules dispersed inside.
`According to an embodiment of the invention, an
`amphiphilic matrix with high content in active ingredient,
`typically from 5 to 95% w/w, is first prepared by dispersing
`the active ingredient or the mixture of active ingredients in a
`mixture of amphiphilic compounds, such as lecithin, other
`type II polar lipids, surfactants, or in diethylene glycol mono-
`ethyl ether; the resulting amphiphilic matrix is then mixed or
`kneaded, usually while hot, with lipophilic compounds suit-
`able 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 triglycerides 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 gran-
`ules 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 mol-
`ecules 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 meth-
`acrylic acid polymers or copolymers, alkylvinyl polymers,
`hydroxyalkyl celluloses, carboxyalkyl celluloses, polysac-
`charides, 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 hydrophilic
`compounds can also be advantageous.
`The lipophilic matrix granules containing the active ingre-
`dient 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 sub-
`
`10
`
`15
`
`The invention provides controlled release and taste mask-
`ing oral pharmaceutical compositions containing an active
`ingredient, comprising:
`a) a matrix consisting of lipophilic compounds with melt-
`ing point lower than 90° C. and optionally by amphiphilic
`compounds in which the active ingredient is at least partially
`incorporated;
`b) optionally an amphiphilic matrix;
`c) an outer hydrophilic matrix in which the lipophilic
`matrix and the optional amphiphilic matrix are dispersed;
`d) optionally other excipients.
`A particular aspect of the invention consists of controlled
`release oral compositions containing one or more active 20
`ingredients comprising:
`a) a matrix consisting of amphiphilic compounds and lipo-
`philic compounds with melting point below 90° C. in which
`the active ingredient is at least partially incorporated;
`b) an outer hydrophilic matrix in which the lipophilic/ 25
`amphiphilic matrix is dispersed;
`c) optional other excipients.
`A further aspect of the invention provides taste masking
`oral pharmaceutical compositions containing one or more
`active ingredients 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 35
`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 cellu-
`lose compounds or by hydrogels;
`optional excipients to give stability to the pharmaceutical 40
`formulation.
`
`30
`
`DETAILED DISCLOSURE OF THE INVENTION
`
`The compositions of the invention can be prepared by a 45
`method comprising the following steps:
`a) the active ingredient is first inglobated by simple knead-
`ing or mixing in a matrix or coating consisting of compounds
`having amphiphilic properties, which will be further specified
`below. The active principle(s) can be mixed with the 50
`amphiphilic compounds without the aid of solvents or with
`small amounts of water-alcoholic solvents.
`b) The matrix obtained in a) is incorporated in a low melt-
`ing lipophilic excipient or mixture of excipients, while heat-
`ing to soften and/or melt the excipient itself, which thereby 55
`incorporates the active ingredient by simple dispersion. After
`cooling at room temperature an inert matrix forms, which can
`be reduced in size to obtain inert matrix granules containing
`the active ingredient particles.
`c) The inert matrix granules are subsequently mixed 60
`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 bio-
`logical fluids, a high viscosity swollen layer is formed, which
`coordinates the solvent molecules and acts as a barrier to 65
`penetration of the aqueous fluid itself inside the new struc-
`ture. Said barrier antagonizes the starting "burst effect"
`
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`US 9,320,716 B2
`
`EXAMPLE 1
`
`5
`6
`stances to provide compositions in which the active ingredi-
`distension of the polymeric chains of the hydrogels, giving
`ent is dispersed both in the lipophilic and the hydrophilic
`rise to a high viscosity hydrated front which prevents the
`matrix, said compositions being preferably in the form of
`further penetration of the solvent itself linearly slowing down
`tablets, capsules and/or minitablets.
`the dissolution process to a well determined point which can
`The compression of the mixture of lipophilic and/or 5
`be located at about half the thickness, until the further pen-
`amphiphilic matrix, hydrogel-forming compound and,
`etration of water would cause the disintegration of the hydro-
`optionally, active ingredient not inglobated in the lipophilic
`philic layer and therefore the release of the content which,
`matrix, yields a macroscopically homogeneous structure in
`consisting of inert matrix granules, however induces the dif-
`all its volume, namely a matrix containing a dispersion of the
`fusion mechanism typical of these structures and therefore
`lipophilic granules in a hydrophilic matrix. A similar result 1
`o further slows down the dissolution profile of the active ingre-
`can also be obtained by coating the lipophilic matrix granules
`dient.
`with a hydrophilic polymer coating.
`The presence of the amphiphilic matrix inside the lipo-
`The tablets obtainable according to the invention can
`philic matrix inert allows to prevent any unevenness of the
`optionally be subjected to known coating processes with a
`release profile of the active ingredient. The surfactants
`gastro-resistant film, consisting of, for example, methacrylic 1
`5 present in the amphiphilic portion promote wettability of the
`acids polymers (Eudragit®) or cellulose derivatives, such as
`porous canaliculuses which cross the inert matrix preventing
`cellulose acetophthalate.
`or reducing resistance to penetration of the solvent inside the
`Active ingredients which can conveniently be formulated
`inert matrix.
`according to the invention comprise:
`To obtain taste masking tablets, the components of the
`analgesics, such as acetaminophen, phenacetin, sodium 2
`o hydrophilic matrix are carefully selected to minimize the
`salicylate; antitussives, such as dextromethorphan, codeine
`active substance release time through penetration accelerated
`phosphate;
`by the canalization induced by the hydrophilic compound.
`bronchodilators, such as albuterol, procaterol;
`The following Examples illustrate the invention in greater
`antipsychotics, such as haloperidol, chlorpromazine;
`detail.
`antihypertensives and coronary-dilators, such as isosor- 25
`bide mono- and dinitrate, captopril;
`selective P2 antagonists such as salbutamol, terbutaline,
`ephedrine, orciprenaline sulfate;
`calcium antagonists, such as nifedipine, nicardipine, dilt-
`iazem, verapamil;
`antiparkinson drugs, such as pergolide, carpidopa,
`levodopa;
`non steroid anti-inflammatory drugs, such as ketoprofen,
`ibuprofen, diclofenac, diflunisal, piroxicam, naproxen,
`ketorolac, nimesulide, thiaprophenic acid, mesalazine
`(5-aminosalicylic acid); antihistamines, such as terfenedine,
`loratadine;
`antidiarrheals and intestinal antiinflammatories, such as
`loperamide, 5-aminosalicylic, olsalazine, sulfasalazine,
`budeno side ;
`spasmolytics such as octylonium bromide;
`anxiolytics, such as chlordiazepoxide, oxazepam,
`medazepam, alprazolam, donazepam, lorazepan;
`oral antidiabetics, such as glipizide, metformin, phen-
`formin, gilclazide, glibenclamide;
`cathartics, such as bisacodil, sodium picosulfate;
`antiepileptics, such as valproate, carbamazepine, pheny-
`loin, gabapentin;
`antitumorals, such as flutamide, etoposide;
`oral cavity disinfectants or antimicrobials, such as benza- so
`lkonium chloride, cetylpyridinium chloride or tibezonium
`iodide, and some amino derivatives such as benzydamine and
`chlorhexidine as well as the salts and derivatives thereof;
`sodium fluoride.
`The compositions of the invention can further contain con-
`ventional excipients, for example bioadhesive excipients
`such as chitosans, polyacrylamides, natural or synthetic
`gums, acrylic acid polymers.
`The compositions of the invention can contain more than
`one active ingredient, each of them being optionally con-
`tained in the hydrophilic matrix or in the