11111111111111111111111111f11111)!II11111111111111111111111111
`
`(12) United States Patent
`Villa et al.
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 8,784,888 B2
`*Jul. 22, 2014
`
`(54)
`
`(75)
`
`CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITION
`
`Inventors: Roberto Villa, Lecco (IT); Massimo
`Pedrani, Gignese (IT); Mauro Ajani,
`Milan (IT); Lorenzo Fossati, Milan (IT)
`
`(73)
`
`Assignee: (cid:9) 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.
`
`5,955,502 A (cid:9)
`5,965,167 A (cid:9)
`6,140,308 A (cid:9)
`6,190,692 B1 (cid:9)
`6,239,120 B1 (cid:9) * (cid:9)
`6,258,377 B1 (cid:9)
`6,363,635 B1 (cid:9)
`6,368,629 B1 (cid:9)
`6,562,363 B1 (cid:9)
`7,410,651 B2 (cid:9)
`7,410,652 B2 (cid:9)
`7,431,943 B1 (cid:9)
`8,029,823 B2 (cid:9)
`2006/0134208 Al (cid:9) * (cid:9)
`2012/0021052 Al (cid:9)
`2012/0021053 Al (cid:9)
`
`9/1999 (cid:9) Hansen et al.
`10/1999 (cid:9) Sanghvi
`10/2000 (cid:9) Brattsand
`2/2001 (cid:9) Busetti
`5/2001 (cid:9) Hallgren et al. (cid:9)
`7/2001 (cid:9) New
`4/2002 (cid:9) England
`4/2002 (cid:9) Watanabe et al.
`5/2003 (cid:9) Mantelle
`8/2008 (cid:9) Villa et al.
`8/2008 (cid:9) Villa et al.
`10/2008 (cid:9) Villa et al.
`10/2011 (cid:9) Villa et al.
`6/2006 (cid:9) Villa et al. (cid:9)
`1/2012 (cid:9) Villa et al.
`1/2012 (cid:9) Villa et al.
`
`FOREIGN PATENT DOCUMENTS
`
`
`
`514/174
`
`
`
`424/468
`
`(21) Appl. No.: 13/617,138
`
`(22) Filed: (cid:9)
`
`Sep. 14, 2012
`
`(65)
`
`Prior Publication Data
`
`US 2013/0022679 Al (cid:9)
`
`Jan. 24, 2013
`
`Related U.S. Application Data
`
`(63) 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, 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
`
`Jun. 14, 1999 (IT) (cid:9)
`Mar. 3, 2000 (IT) (cid:9)
`
` MI99A1317
` MI2000A0422
`
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A61K 9/28 (cid:9)
`A61K 9/20 (cid:9)
`(52) U.S. Cl.
` 424/474; 424/464; 424/465; 424/469
`USPC (cid:9)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,800,051
`4,608,248
`5,320,848
`5,342,625
`5,534,501
`5,597,844
`5,643,602
`5,681,584
`5,811,388
`5,840,332
`5,874,063
`5,908,833
`
`3/1974 Barnhart et al.
`8/1986 Knecht et al.
`6/1994 Geyer
`8/1994 Hauer
`7/1996 Samain
`1/1997 Chauhan
`7/1997 Ulmius
`* 10/1997 Savastano et al. (cid:9)
`* 9/1998 Friend et al. (cid:9)
`* 11/1998 Lerner et al. (cid:9)
`2/1999 Briggner et al.
`6/1999 Brattsand et al.
`
` 424/473
` 424/474
` 424/464
`
`CA
`EP
`EP
`EP
`EP
`EP
`EP
`GB
`WO
`WO
`WO
`WO
`WO
`
`2119253
`0 375 063 B1
`0 453 001 Al
`0482576
`0 514 008
`0 514 008 Al
`0514008
`935639
`93/00889 Al
`96/13273
`9800169
`WO 99/11245
`WO 99/17752
`
`11/1998
`6/1990
`10/1991
`4/1992
`11/1992
`11/1992
`11/1992
`9/1963
`1/1993
`5/1996
`1/1998
`3/1999
`4/1999
`
`OTHER PUBLICATIONS
`
`Travis, S. et al., Poster, "Induction of Clinical and Endo scopic Remis-
`sion with Budesonide MMX in Mild-to-Moderately Active Ulcer-
`ative Colitis, Magnitude of Response in Two Phase III Studies," Oct.
`20-24, 2012, Amsterdam, UEG Week, 1 page.
`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 Use Study," May 2012, San Diego, CA, 1 page.
`
`(Continued)
`
`Primary Examiner — Susan Tran
`(74) Attorney, Agent, or Firm Rothwell, Figg, Ernst &
`Manbeck P.C.
`
`(57) (cid:9)
`
`ABSTRACT
`
`Controlled release and taste masking compositions contain-
`ing one or more active principles inglobated in a three-com-
`ponent matrix structure, i.e. a structure formed by successive
`amphiphilic, lipophilic or inert matrices and finally inglo-
`bated or dispersed in hydrophilic matrices. The use of a plu-
`rality of systems for the control of the dissolution of the active
`ingredient modulates the dissolution rate of the active ingre-
`dient in aqueous and/or biological fluids, thereby controlling
`the release kinetics in the gastrointestinal tract.
`
`9 Claims, No Drawings
`
`Exhibit 1002
`ARGENTUM
`IPR2018-00080
`
`000001
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`US 8,784,888 B2
`Page 2
`
`(56) (cid:9)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Sandborn, W.J. et al., "Once-Daily Budesonide MMX® Extended
`Release Tablets Induce Remission in Patients With Mild to Moderate
`Ulcerative Colitis: Results From the CORE I Study," Gastroenterol-
`ogy 2012, vol. 143, pp. 1218-1226.
`Jantzen, G.M. et al., "Sustained- and Controlled-Release Drug Deliv-
`ery Systems," Modern Pharmaceutics, 3rd Edition, Revised and
`Expanded, pp. 575-609, © 1996 by Marcel Dekker, Inc., 37 pages.
`Angelucci et al., "Budesonide for Inflammatory Bowel Disease
`Treatment," Current Medicinal Chemistry, 2008, vol. 15, No. 14, pp.
`2-9.
`D'Haens; G.R. et al., "Budesonide MMXTM Is Active and Safe in
`Patients With Active Left-Sided Ulcerative Colitis," Br J Clinic
`Pharmacol., 2005, vol. 61, 3 pages.
`Maejima, T., "Application of Tumbling Melt Granulation Method to
`Prepare Controlled-Release Beads by Coating with Mixture of Func-
`tional Non-Meltable and Meltable Materials," Chem. Pharm. Bull.,
`1998, Vol, 46, No. 3, pp. 531-533, © 1998 Pharmaceutical Society of
`Japan.
`Sandborn, W.J. et al., "Budesonide MXX® 9 mg for the Induction of
`Remission of Mild-to-Moderate Ulcerative Colitis (UC): Data From
`a Multicenter, Randomized, Double-Blind Placebo-Controlled Study
`in North America and India," Presentation at DDW 2011, Poster, 1
`page.
`D'Haens, G.R., et al., "Clinical Trial: Preliminary Efficacy and
`Safety Study of a New Budesonide-MMX® 9 mg Extended-Release
`Tablets in Patients With Active Left-Sided Ulcerative Colitis," Jour-
`nal of Crohn's and Colitis, 2010, vol. 4, pp. 153-160, © copyright
`2009 European Crohn's and Colitis Organisation.
`
`Flanders, P. et al., The Control of Drug Release From Conventional
`Melt Granulation Matrices, Drug Development and Industrial Phar-
`macy, 1987, vol. 13, No. 6, pp. 1001-1022, © 1987 Marcel Dekker,
`Inc.
`Ferraboschi, P. et al., "Estimation and Characterisation of
`Budesonide Tablets Impurities," Journal of Pharmaceutical and Bio-
`medical Analysis, 2008, vol. 47, pp. 636-640, © 2008 Elsevier B.V.
`Fiorino, G. et al., "New Drug Delivery Systems in Inflammatory
`Bowel Disease: MMXTM and Tailored Delivery to the Gut," Current
`Medicinal Chemistry, 2010, vol. 17, pp. 1851-1857, © 2010 Bentham
`Science Publlishers Ltd.
`Koutroubakis, I., "Recent Advances in the Management of Distal
`Ulcerative Colitis," World Journal of Gastrointestinal Pharmacology
`and Therapeutics, 2010, vol. 1, No. 2, pp. 43-50, © 2010 Baishideng.
`Steward, P., "Review of Pharmaceutical Controlled Release Methods
`and Devices", 1995, pp. 1-9.
`Physical Pharmacy, Chapter 19: Drug Product Design, Oct. 1993, pp.
`515-519.
`Moro, et al., "Drug Delivery Systems: Diffusion Controlled Sys-
`tems", Il Prodotto Chimico & Aerosol Selezione (The Chemical &
`Aerosol Selection), Apr. 1985, pp. 16-24.
`Brunner, M. et al., "Gastrointestinal Transit, Release and Plasma
`Pharmacokinetics of a New Oral Budesonide Formulation," British
`Journal of Clinical Pharmacology, DOI:10.1111/j.1365-2125.2005.
`02517.x, pp. 1-8, copyright 2005 Blackwell Publishing Ltd., 8 pages.
`Brunner, M. et al., "Gastrointestinal Transit and 5-ASA Release
`From a New Mesalazine Extended-Release Formulation," Alimen-
`tary Pharmacology and Therapeutics, vol. 17, pp. 395-402, copyright
`2003 Blackwell Publishing Ltd., 8 pages.
`
`* cited by examiner
`
`000002
`
`

`

`US 8,784,888 B2
`
`1
`CONTROLLED RELEASE AND TASTE
`MASKING ORAL PHARMACEUTICAL
`COMPOSITION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of application Ser. No.
`13/462,409 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, 2011; which is a continuation of application Ser. No.
`12/210,969 filed on Sep. 15, 2008, which reissued as U.S. Pat.
`No. RE43,799 from U.S. Pat. No. 8,029,823; which 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 the
`35 U.S.C. 371 national stage of International application
`PCT/EP00/05356 filed on Jun. 9, 2000; which claimed prior-
`ity to Italian applications MI2000A000422 and
`MI99A001317 filed Mar. 3, 2000 and Jun. 14, 1999, respec-
`tively. The entire contents of each of the above-identified
`applications are hereby incorporated by reference.
`The present invention relates to controlled release and
`taste-masking compositions containing one or more active
`principles incorporated in a three-component matrix struc-
`ture, i.e. a structure formed by successive amphiphilic, lipo-
`philic or inert matrices and finally incorporated or dispersed
`in hydrophilic matrices. The use of a plurality of systems for
`the control of the dissolution of the active ingredient modu-
`lates the dissolution rate of the active ingredient in aqueous
`and/or biological fluids, thereby controlling the release kinet-
`ics 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 area.
`The compositions of the invention can contain active prin-
`ciples belonging to the therapeutical classes of analgesics,
`antiinflammatories, cardioactives, tranquillizers, antihyper-
`tensives, disinfectants and topical antimicrobials, antiparkin-
`son drugs, antihistamines and are suitable to the oral admin-
`istration or for acting topically at some areas of the
`gastrointestinal tract.
`
`TECHNOLOGICAL BACKGROUND
`
`The preparation of a sustained, controlled, delayed or any-
`how modified release form can be carried out according to
`different known 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 resis-
`tance to the progress of the solvent, in that the presence
`of strongly hydrophilic groups in its chains, mainly
`branched, remarkably increases viscosity inside the
`hydrated layer.
`3. The use of bioerodible matrices, which are capable of
`being degraded by the enzymes of some biological com-
`partment.
`All the procedures listed above suffer, however, from draw-
`backs and imperfections.
`Inert matrices, for example, generally entail non-linear, but
`exponential, release of the active ingredient.
`
`15 (cid:9)
`
`20 (cid:9)
`
`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
`toxicologically inert.
`A number of formulations based on inert lipophilic matri-
`10 ces 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 lipo-
`philic inert matrix in which the active ingredient is incorpo-
`rated.
`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 form-
`ing 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 poly-
`mers or suitable substances to form a inert matrix with the
`active ingredient and the subsequent deposition of said solu-
`25 tion 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
`30 "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 poly-
`35 mer 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 hydrophilic matrix which comprises:
`dissolution of the active ingredient with gastro-resistant
`hydrophilic polymers in organic solvents;
`drying of said suspension;
`subsequent kneading and formulation of the pellets in 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 multi-
`particulate utilizes two coating membranes to decrease the
`release rate of the active ingredient, a pH-dependent mem-
`50 brave with the purpose of gastric protection and a pH-inde-
`pendent 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
`55 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
`60 matrices have the maximum release rate inside the logarith-
`mic 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
`65 polymer in a superficial hydrophilic matrix. The composi-
`tions of the invention are characterized by the absence of a
`first phase in which the medicament superficially present on
`
`40 (cid:9)
`
`45 (cid:9)
`
`000003
`
`

`

`US 8,784,888 B2
`
`DISCLOSURE OF THE INVENTION
`
`5 (cid:9)
`
`3
`the matrix is quickly solubilized, and by the fact the (cid:9)
`amphiphilic layer compensate the lack of affinity of the aque- (cid:9)
`ous solvent with the lipophilic compounds forming the inner (cid:9)
`inert matrix. (cid:9)
`
`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-
`The invention provides controlled release and taste mask- (cid:9)
`ethyl ether (Transcutol(R)).
`The lipophilic matrix consists of substances selected from
`ing oral pharmaceutical compositions containing an active
`10 unsaturated or hydrogenated alcohols or fatty acids, salts,
`ingredient, comprising:
`a) a matrix consisting of lipophilic compounds with melt- (cid:9)
`esters or amides thereof, fatty acids mono-, di- or triglycer-
`ides, the polyethoxylated derivatives thereof, waxes, ceram-
`ing point lower than 90° C. and optionally by amphiphilic
`ides, cholesterol derivatives or mixtures thereof having a
`compounds in which the active ingredient is at least partially
`incorporated; (cid:9)
`melting point within the range of 40 to 90° C., preferably from
`15 60 to 70° C.
`b) optionally an amphiphilic matrix;
`If desired, a fatty acid calcium salt may be incorporated in
`c) an outer hydrophilic matrix in which the lipophilic
`the lipophilic matrix which is subsequently dispersed in a
`matrix and the optional amphiphilic matrix are dispersed;
`d) optionally other excipients. (cid:9)
`hydrophilic matrix prepared with alginic acid, thus remark-
`ably increasing the hydrophilic matrix viscosity following
`A particular aspect of the invention consists of controlled
`release oral compositions containing one or more active 20 penetration of the solvent front until contact with the lipo-
`ingredients comprising: (cid:9)
`philic matrix granules dispersed inside.
`a) a matrix consisting of amphiphilic compounds and lipo- (cid:9)
`According to an embodiment of the invention, an
`amphiphilic matrix with high content in active ingredient,
`philic compounds with melting point below 90° C. in which
`typically from 5 to 95% w/w, is first prepared by dispersing
`the active ingredient is at least partially incorporated;
`b) an outer hydrophilic matrix in which the lipophilic/ 25 the active ingredient or the mixture of active ingredients in a
`amphiphilic matrix is dispersed; (cid:9)
`mixture of amphiphilic compounds, such as lecithin, other
`c) optional other excipients. (cid:9)
`type II polar lipids, surfactants, or in diethylene glycol mono-
`A further aspect of the invention provides taste masking (cid:9)
`ethyl ether; the resulting amphiphilic matrix is then mixed or
`kneaded, usually while hot, with lipophilic compounds suit-
`oral pharmaceutical compositions containing one or more
`30 able to form an inert matrix, such as saturated or unsaturated
`active ingredients comprising:
`fatty acids, such as palmitic, stearic, myristic, lauric, laurylic,
`an inert or lipophilic matrix consisting of C6-C20-alcohols
`or C8-C20 fatty acids or esters of fatty acids with glyc- (cid:9)
`or oleic acids or mixtures thereof with other fatty acids with
`erol or sorbitol or other polyalcohols with carbon atom (cid:9)
`shorter chain, or salts or alcohols or derivatives of the cited
`fatty acids, such as mono-, di-, or triglycerides or esters with
`chain not higher than six;
`an amphiphilic matrix consisting of polar lipids of type I or 35 polyethylene glycols, alone or in combination with waxes,
`II or glycols partially etherified with Cl -C4 alkyl chains; (cid:9)
`ceramides, cholesterol derivatives or other apolar lipids in
`an outer hydrophilic matrix containing the above matrices, (cid:9)
`various ratios so that the melting or softening points of the
`lipophilic compounds mixtures is within the range of 40 to
`mainly formed by saccharide, dextrin, polyalcohol or
`90° C., preferably from 60 to 70° C.
`cellulose compounds or by hydrogels;
`Alternatively, the order of formation of the inert and
`optional excipients to give stability to the pharmaceutical 40 (cid:9)
`formulation. (cid:9)
`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
`The compositions of the invention can be prepared by a 45 known processes which retain the homogeneous dispersion
`method comprising the following steps: (cid:9)
`and matrix structure of the starting mixture.
`a) the active ingredient is first inglobated by simple knead- (cid:9)
`The hydrophilic matrix consists of excipients known as
`ing or mixing in a matrix or coating consisting of compounds
`hydrogels, i.e. substances which when passing from the dry
`having amphiphilic properties, which will be further specified
`state to the hydrated one, undergo the so-called "molecular
`below. The active principle(s) can be mixed with the so relaxation", namely a remarkable increase in mass and weight
`amphiphilic compounds without the aid of solvents or with
`following the coordination of a large number of water mol-
`small amounts of water-alcoholic solvents. (cid:9)
`ecules by the polar groups present in the polymeric chains of
`b) The matrix obtained in a) is incorporated in a low melt- (cid:9)
`the excipients themselves.
`ing lipophilic excipient or mixture of excipients, while heat- (cid:9)
`Examples of hydrogels which can be used according to the
`ing to soften and/or melt the excipient itself, which thereby 55 invention are compounds selected from acrylic or meth-
`incorporates the active ingredient by simple dispersion. After (cid:9)
`acrylic acid polymers or copolymers, alkylvinyl polymers,
`cooling at room temperature an inert matrix forms, which can
`hydroxyalkyl celluloses, carboxyalkyl celluloses, polysac-
`be reduced in size to obtain inert matrix granules containing (cid:9)
`charides, dextrins, pectins, starches and derivatives, natural or
`the active ingredient particles. (cid:9)
`synthetic gums, alginic acid.
`c) The inert matrix granules are subsequently mixed 60 (cid:9)
`In case of taste-masking formulations, the use of polyal-
`together with one or more hydrophilic water-swellable (cid:9)
`cohols such as xylitol, maltitol and mannitol as hydrophilic
`excipients. The mixture is then subjected to compression or (cid:9)
`compounds can also be advantageous.
`tabletting. This way, when the tablet is contacted with bio- (cid:9)
`The lipophilic matrix granules containing the active ingre-
`logical fluids, a high viscosity swollen layer is formed, which
`dient are mixed with the hydrophilic compounds cited above
`coordinates the solvent molecules and acts as a barrier to 65 in a weight ratio typically ranging from 100:0.5 to 100:50
`penetration of the aqueous fluid itself inside the new struc- (cid:9)
`(lipophilic matrix: hydrophilic matrix). Part of the active
`ture. Said barrier antagonizes the starting "burst effect"
`ingredient can optionally be mixed with hydrophilic sub-
`
`DETAILED DISCLOSURE OF THE INVENTION
`
`000004
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`US 8,784,888 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(R)) 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 13 2 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 inert amphiphilic
`matrix, and 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
`
`500 g of 5-aminosalicylic-acid and 20 g of octylonium
`bromide are mixed with 10 g of soy lecithin dissolved in 50 g
`30 of a water:ethyl alcohol 1:3 mixture at about 50° C. After
`homogenization and drying, the granules of the resulting
`matrix are treated in a kneader with 20 g of carnauba wax and
`50 g of stearic acid, heating until homogeneous dispersion,
`then cold-extruded into small granules. The inert matrix gran-
`35 ules are loaded into a mixer in which 30 g of carbopol 971 P
`and 65 g of hydroxypropyl methylcellulose are sequentially
`added. After a first mixing step for homogeneously dispersing
`the powders, 60 g of microcrystalline cellulose and 5 g of
`magnesium stearate are added. After mixing, the final mixture
`40 is tabletted to unitary weight of 760 mg/tablet. The resulting
`tablets are film-coated with cellulose acetophthalate or poly-
`methacrylates and a plasticizer to provide gastric resistance
`and prevent the early release of product in the stomach.
`The resulting tablets, when subjected to dissolution test in
`45 simulated enteric juice, have shown a release of the active
`principles having the following profile: after 60 minutes no
`more than 30%, after 180 minutes no more than 60%, after 5
`hours no more than 80%.
`
`EXAMPLE 2
`
`50 g of diethylene glycol monoethyl ether are homoge-
`neously distributed on 500 g of microcrystalline cellulose;
`then 100 g of Budesonide are added, mixing to complete
`55 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 tem-
`perature of 60° C. After kneading for 5 minutes, the mixture
`is cooled to room temperature and extruded in granules of size
`60 below 1 mm.
`A suitable mixer is loaded with the matrix granules pre-
`pared as above and the following amounts of hydrophilic
`excipients: 1500 g of hydroxypropyl methylcellulose and 500
`g of policarbophil.
`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
`
`65 (cid:9)
`
`000005
`
`

`

`US 8,784,888 B2
`
`7
`of magnesium stearate. After further 5 minute mixing, the
`mix is tabletted to unitary weight of 250 mg/tablet.
`
`EXAMPLE 3
`
`850 g of metformin are dispersed in a granulator/kneader
`with 35 g of diethylene glycol monoethyl ether previously
`melted with 100 g of stearic acid and 55 g of carnauba wax.
`The system is heated to carry out the granulation of the active
`ingredient in the inert matrix. The resulting 1040 g of formu-
`lation are added with 110 g of hydroxypropyl methylcellulose
`and 20 g of magnesium stearate.
`The final mixture is tabletted to unitary weight of 1170
`mg/tablet equivalent to 850 mg of active ingredient.
`The resulting tablets, when subjected to dissolution test in
`simulated enteric juice, have shown a release of the active
`principles having the following profile: after 60 minutes no
`more than 35%, after 180 minutes no more than 60%, after 5
`hours no more than 80%.
`
`EXAMPLE 4
`
`120 g of octylonium bromide are dispersed in a granulator/
`kneader with 30 g of stearic acid and 15 g of beeswax in which
`10 g of diethylene glycol monoethylene had previously been
`melted.
`The system is heated to carry out the granulation of the
`active ingredient in the inert matrix. The resulting 10 g of
`formulation are added with 5 g of hydroxypropyl methylcel-
`lulose and 5 g of policarbophyl, 2 g of magnesium stearate
`and 3 g of microcrystalline cellulose.
`The final mixture is tabletted to unitary weight of 200
`mg/tablet equivalent to 120 mg of active ingredient.
`The resulting tablets, when subjected to dissolution test in
`simulated enteric juice, have shown a release of the active
`principles having the following profile: after 60 minutes no
`more than 25%; after 180 minutes no more than 50%; after 5
`hours no more than 70%.
`
`EXAMPLE 5
`
`12 g of diethylene glycol monoethyl ether are loaded on 6
`g of microcrystalline cellulose and 6 grams of calcium car-
`bonate, then 100 g of Gabapentin are added and the mixture is
`homogenized. After that, 800 g of Gabapentin are added
`which are dispersed in a granulator/kneader with 4.5 g of
`white wax and 5 g of stearic acid. The system is heated to
`carry out the granulation of the active ingredient in the inert
`matrix. The resulting 916.5 g of formulation are added with
`39.5 g of hydroxypropyl methylcellulose, 10 g of alginic acid,
`11 g of magnesium stearate and 6 g of syloid. The final
`mixture is tabletted to unitary weight of 1000 mg/tablet
`equivalent to 900 mg of active ingredient.
`
`EXAMPLE 6
`
`50 g (25 g) of carbidopa and 200 g (100 g) of levodopa are
`dispersed in a granulator/kneader with 60 g (30 g) of stearic
`acid and 30 g (15 g) of yellow wax, in which 10 (5) g of
`diethylene glycol monoethyl ether had previously been
`melted.
`The system is heated to carry out the granulation of the
`active ingredient in the inert matrix. The resulting 340 g (170
`g) of formulation are added with 20 g (10 g) of hydroxypropyl
`methylcellulose, 10 g (5 g) of xantangum, 16 g (8 g) of
`microcrystalline cellulose, 4 g (