`Substitute Specification (Clean Copy)
`
`Controlled Release and Taste Masking Oral Pharmaceutical Compositions
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`CROSS REFERENCE TO RELATED APPLICATIONS
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`[0001] (cid:9)
`
`This application is a continuation of application Serial No. 13/462,409 filed on May 2,
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`2012, now U.S. Patent No. 8,293,273; which is a continuation of 13/249,839 filed on September
`
`30, 2011; which is a continuation of application Serial No. 12/210,969 filed on September 15,
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`2008, which reissued as U.S. Patent No. RE43,799 from U.S. Patent No. 8,029,823; which is a
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`continuation-in-part of application Serial No. 10/009,532 filed on December 12, 2001, now U.S.
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`Patent No. 7,431,943; which is the 35 U.S.C. 371 national stage of International application
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`PCT/EP00/05356 filed on June 9, 2000; which claimed priority to Italian applications
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`MI2000A000422 and MI99A001317 filed March 3, 2000 and June 14, 1999, respectively. The
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`entire contents of each of the above-identified applications are hereby incorporated by reference.
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`[0002] (cid:9)
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`The present invention relates to controlled release and taste-masking compositions
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`containing one or more active principles incorporated in a three-component matrix structure, i.e.
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`a structure formed by successive amphiphilic, lipophilic or inert matrices and finally
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`incorporated or dispersed in hydrophilic matrices. The use of a plurality of systems for the
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`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
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`gastrointestinal tract, and it also allows the oral administration of active principles having
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`unfavourable taste characteristics or irritating action on the mucosae of the administration site,
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`particularly in the buccal area.
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`[0003] (cid:9)
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`The compositions of the invention can contain active principles belonging to the
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`therapeutical classes of analgesics, antiinflammatories, cardioactives, tranquillizers,
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`antihypertensives, disinfectants and topical antimicrobials, antiparkinson drugs, antihistamines
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`and are suitable to the oral administration or for acting topically at some areas of the
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`gastrointestinal tract.
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`TECHNOLOGICAL BACKGROUND
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`[0004] (cid:9)
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`The preparation of a sustained, controlled, delayed or anyhow modified release form
`
`can be carried out according to different known techniques:
`
`Exhibit 1014
`ARGENTUM
`IPR2018-00080
`
`000001
`
`
`
`2
`
`[0005] (cid:9)
`
`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.
`
`[0006] (cid:9)
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`2. The use of hydrophilic matrices, in which the main component of the matrix
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`structure opposes high resistance to the progress of the solvent, in that the
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`presence of strongly hydrophilic groups in its chains, mainly branched,
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`remarkably increases viscosity inside the hydrated layer.
`
`[0007] (cid:9)
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`3. The use of bioerodible matrices, which are capable of being degraded by the
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`enzymes of some biological compartment.
`
`[0008] (cid:9)
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`All the procedures listed above suffer, however, from drawbacks and imperfections.
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`[0009] (cid:9)
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`Inert matrices, for example, generally entail non-linear, but exponential, release of the
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`active ingredient.
`
`[0010] (cid:9)
`
`Hydrophilic matrices have a linear behaviour until a certain fraction of active
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`ingredient has been released; then they significantly deviate from linear release.
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`[0011] (cid:9)
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`Bioerodible matrices are ideal to carry out the so-called "site-release", but they involve
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`the problem of finding the suitable enzyme or reactive to degradation. Furthermore, they
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`frequently release in situ metabolites that are not wholly toxicologically inert.
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`[0012] (cid:9)
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`A number of formulations based on inert lipophilic matrices have been described:
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`Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses a process making use of varying
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`amounts of colloidal silica as a porization element for a lipophilic inert matrix in which the
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`active ingredient is incorporated.
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`[0013] (cid:9)
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`The same notion of canalization of an inert matrix is described in U.S. Pat. No.
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`4,608,248 in which a small amount of a hydrophilic polymer is mixed with the substances
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`forming an inert matrix, in a non sequential compenetration of different matrix materials.
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`[0014] (cid:9)
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`EP 375,063 discloses a technique for the preparation of multiparticulate granules for
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`the controlled-release of the active ingredient which comprises co-dissolution of polymers or
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`suitable substances to form a inert matrix with the active ingredient and the subsequent
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`deposition of said solution on an inert carrier which acts as the core of the device. Alternatively,
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`the inert carrier is kneaded with the solution containing the inert polymer and the active
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`ingredient, then the organic solvent used for the their dissolution is evaporated off to obtain a
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`000002
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`
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`3
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`solid residue. The resulting structure is a "reservoir", i.e. is not macroscopically homogeneous
`
`along all the symmetry axis of the final form.
`
`(cid:9) (cid:9)
`
`[0015] (cid:9)
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`The same "reservoir" structure is also described in Chem. Pharm. Bull. 46 (3), 531-
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`533, (1998) which improves the application through an annealing technique of the inert polymer
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`layer which is deposited on the surface of the pellets.
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`[0016] (cid:9)
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`To the "reservoir" structure also belong the products obtained according to the
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`technique described in WO 93/00889 which discloses a process for the preparation of pellets in
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`hydrophilic matrix which comprises:
`
`[0017]
`
`[0018] (cid:9)
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`[0019] (cid:9)
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`dissolution of the active ingredient with gastro-resistant hydrophilic polymers in
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`organic solvents;
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`drying of said suspension;
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`subsequent kneading and formulation of the pellets in a hydrophilic or lipophilic
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`matrix without distinction of effectiveness between the two types of application.
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`[0020] (cid:9)
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`EP 0 453 001 discloses a multiparticulate with "reservoir" structure inserted in a
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`hydrophilic matrix. The basic multiparticulate utilizes two coating membranes to decrease the
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`release rate of the active ingredient, a pH-dependent membrane with the purpose of gastric
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`protection and a pH-independent methacrylic membrane with the purpose of slowing down the
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`penetration of the aqueous fluid.
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`[0021] (cid:9) WO 95/16451 discloses a composition only formed by a hydrophilic matrix coated
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`with a gastro-resistant film for controlling the dissolution rate of the active ingredient.
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`[0022] (cid:9) When preparing sustained-, controlled-release dosage forms of a medicament topically
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`active in the gastrointestinal tract, it is important to ensure a controlled release from the first
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`phases following administration, i.e. when the inert matrices have the maximum release rate
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`inside the logarithmic phase, namely the higher deviation from linear release.
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`[0023] (cid:9)
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`Said object has been attained according to the present invention, through the
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`combination of an amphiphilic matrix inside an inert matrix, the latter formulated with a
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`lipophilic polymer in a superficial hydrophilic matrix. The compositions of the invention are
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`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
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`affinity of the aqueous solvent with the lipophilic compounds forming the inner inert matrix.
`
`000003
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`4
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`DISCLOSURE OF THE INVENTION
`
`[0024] (cid:9)
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`The invention provides controlled release and taste masking oral pharmaceutical
`
`compositions containing an active ingredient, comprising:
`
`[0025] a) a matrix consisting of lipophilic compounds with melting point lower than
`
`90°C and optionally by amphiphilic compounds in which the active ingredient is at least partially
`
`incorporated;
`
`[0026] b) optionally an amphiphilic matrix;
`
`[0027]
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`c) (cid:9)
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`an outer hydrophilic matrix in which the lipophilic matrix and the optional
`
`amphiphilic matrix are dispersed;
`
`[0028] d) (cid:9)
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`optionally other excipients.
`
`[0029] (cid:9)
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`A particular aspect of the invention consists of controlled release oral compositions
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`containing one or more active ingredients comprising:
`
`[0030] 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;
`
`[0031] b) an outer hydrophilic matrix in which the lipophilic/amphiphilic matrix is
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`dispersed;
`
`[0032]
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`c) (cid:9)
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`optional other excipients.
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`[0033] (cid:9) A further aspect of the invention provides taste masking oral pharmaceutical
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`compositions containing one or more active ingredients comprising:
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`[0034] - (cid:9)
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`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
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`atom chain not higher than six;
`
`[0035] - (cid:9)
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`an amphiphilic matrix consisting of polar lipids of type I or II or glycols
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`partially etherified with Cl-C4 alkyl chains;
`
`[0036] - (cid:9)
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`an outer hydrophilic matrix containing the above matrices, mainly formed
`
`by saccharide, dextrin, polyalcohol or cellulose compounds or by hydrogels;
`
`[0037] - (cid:9)
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`optional excipients to give stability to the pharmaceutical formulation.
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`DETAILED DISCLOSURE OF THE INVENTION
`
`[0038] (cid:9)
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`The compositions of the invention can be prepared by a method comprising the
`
`following steps:
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`000004
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`5
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`[0039] (cid:9)
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`a) the active ingredient 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 principle(s) can be mixed with the amphiphilic compounds without
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`the aid of solvents or with small amounts of water-alcoholic solvents.
`
`[0040] (cid:9)
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`b) The matrix obtained in a) is incorporated in a low melting lipophilic excipient or
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`mixture of excipients, while heating to soften and/or melt the excipient itself, which thereby
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`incorporates the active ingredient by simple dispersion. After cooling at room temperature an
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`inert matrix forms, which can be reduced in size to obtain inert matrix granules containing the
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`active ingredient particles.
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`[0041] (cid:9)
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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 swollen
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`layer is formed, which coordinates the solvent molecules and acts as a barrier to penetration of
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`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
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`in its turn inside the hydrophilic matrix.
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`[0042] (cid:9)
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`The amphiphilic compounds which can be used according to the invention comprise
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`polar lipids of type I or II (lecithin, phosphatidylcholine, phosphatidylethanolamine), ceramides,
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`glycol alkyl ethers such as diethylene glycol monomethyl ether (Transcutol(R)).
`
`[0043] (cid:9)
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`The lipophilic matrix consists of substances selected from unsaturated or
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`hydrogenated alcohols or fatty acids, salts, esters or amides thereof, fatty acids mono-, di- or
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`triglycerides, the polyethoxylated derivatives thereof, waxes, ceramides, cholesterol derivatives
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`or mixtures thereof having a melting point within the range of 40 to 90°C, preferably from 60 to
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`70°C.
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`[0044] (cid:9)
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`If desired, a fatty acid calcium salt may be incorporated in the lipophilic matrix which
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`is subsequently dispersed in a hydrophilic matrix prepared with alginic acid, thus remarkably
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`increasing the hydrophilic matrix viscosity following penetration of the solvent front until
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`contact with the lipophilic matrix granules dispersed inside.
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`[0045] (cid:9)
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`According to an embodiment of the invention, an amphiphilic matrix with high
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`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,
`
`000005
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`
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`6
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`such as lecithin, other type II polar lipids, surfactants, or in diethylene glycol monoethyl ether;
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`the resulting amphiphilic matrix is then mixed or kneaded, usually while hot, with lipophilic
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`compounds suitable to form an inert matrix, such as saturated or unsaturated fatty acids, such as
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`palmitic, stearic, myristic, lauric, laurylic, or oleic acids or mixtures thereof with other fatty acids
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`with shorter chain, or salts or alcohols or derivatives of the cited fatty acids, such as mono-, di-,
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`or triglycerides or esters with polyethylene glycols, alone or in combination with waxes,
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`ceramides, cholesterol derivatives or other apolar lipids in various ratios so that the melting or
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`softening points of the lipophilic compounds mixtures is within the range of 40 to 90°C,
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`preferably from 60 to 70°C.
`
`[0046] (cid:9)
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`Alternatively, the order of formation of the inert and amphiphilic matrices can be
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`reversed, incorporating the inert matrix inside the amphiphilic compounds.
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`[0047] (cid:9)
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`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
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`matrix structure of the starting mixture.
`
`[0048] (cid:9)
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`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
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`relaxation", namely a remarkable increase in mass and weight following the coordination of a
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`large number of water molecules by the polar groups present in the polymeric chains of the
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`excipients themselves.
`
`[0049] (cid:9)
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`Examples of hydrogels which can be used according to the invention are compounds
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`selected from acrylic or methacrylic acid polymers or copolymers, alkylvinyl polymers,
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`hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and
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`derivatives, natural or synthetic gums, alginic acid.
`
`[0050] (cid:9)
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`In case of taste-masking formulations, the use of polyalcohols such as xylitol, maltitol
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`and mannitol as hydrophilic compounds can also be advantageous.
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`[0051] (cid:9)
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`The lipophilic matrix granules containing the active ingredient are mixed with the
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`hydrophilic compounds cited above in a weight ratio typically ranging from 100:0.5 to 100:50
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`(lipophilic matrix: hydrophilic matrix). Part of the active ingredient can optionally be mixed with
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`hydrophilic substances to provide compositions in which the active ingredient is dispersed both
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`in the lipophilic and the hydrophilic matrix, said compositions being preferably in the form of
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`tablets, capsules and/or minitablets.
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`000006
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`7
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`[0052] (cid:9)
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`The compression of the mixture of lipophilic and/or amphiphilic matrix, hydrogel-
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`forming compound and, optionally, active ingredient not inglobated in the lipophilic matrix,
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`yields a macroscopically homogeneous structure in all its volume, namely a matrix containing a
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`dispersion of the lipophilic granules in a hydrophilic matrix. A similar result can also be obtained
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`by coating the lipophilic matrix granules with a hydrophilic polymer coating.
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`[0053] (cid:9)
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`The tablets obtainable according to the invention can optionally be subjected to known
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`coating processes with a gastro-resistant film, consisting of, for example, methacrylic acids
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`polymers (Eudragit(R)) or cellulose derivatives, such as cellulose acetophthalate.
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`[0054] (cid:9)
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`Active ingredients which can conveniently be formulated according to the invention
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`comprise:
`
`[0055] (cid:9)
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`analgesics, such as acetaminophen, phenacetin, sodium salicylate; antitussives, such as
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`dextromethorphan, codeine phosphate;
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`bronchodilators, such as albuterol, procaterol;
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`antipsychotics, such as haloperidol, chlorpromazine;
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`antihypertensives and coronary-dilators, such as isosorbide mono- and dinitrate,
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`[0056] (cid:9)
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`[0057] (cid:9)
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`[0058] (cid:9)
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`captopril;
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`[0059] (cid:9)
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`selective 0 2 antagonists such as salbutamol, terbutaline, ephedrine, orciprenaline
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`sulfate;
`
`[0060] (cid:9)
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`[0061] (cid:9)
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`[0062] (cid:9)
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`calcium antagonists, such as nifedipine, nicardipine, diltiazem, verapamil;
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`antiparkinson drugs, such as pergolide, carpidopa, levodopa;
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`non steroid anti-inflammatory drugs, such as ketoprofen, ibuprofen, diclofenac,
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`diflunisal, piroxicam, naproxen, ketorolac, nimesulide, thiaprophenic acid, mesalazine (5-
`
`aminosalicylic acid); antihistamines, such as terfenedine, loratadine;
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`[0063] (cid:9)
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`antidiarrheals and intestinal antiinflammatories, such as loperamide, 5-aminosalicylic,
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`olsalazine, sulfasalazine, budenoside;
`
`[0064] (cid:9)
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`[0065] (cid:9)
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`spasmolytics such as octylonium bromide;
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`anxiolytics, such as chlordiazepoxide, oxazep am, medazep am, alprazo lam,
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`donaz ep am, lorazep an;
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`[0066] (cid:9)
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`[0067] (cid:9)
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`[0068] (cid:9)
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`oral antidiabetics, such as glipizide, metformin, phenformin, gilclazide, glibenclamide;
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`cathartics, such as bisacodil, sodium picosulfate;
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`antiepileptics, such as valproate, carbamazepine, phenyloin, gabapentin;
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`000007
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`8
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`[0069] (cid:9)
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`[0070]
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`antitumorals, such as flutamide, etoposide;
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`oral cavity disinfectants or antimicrobials, such as benzalkonium chloride,
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`cetylpyridinium chloride or tibezonium iodide, and some amino derivatives such as benzydamine
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`and chlorhexidine as well as the salts and derivatives thereof;
`
`[0071] (cid:9)
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`sodium fluoride.
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`[0072] (cid:9)
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`The compositions of the invention can further contain conventional excipients, for
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`example bioadhesive excipients such as chitosans, polyacrylamides, natural or synthetic gums,
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`acrylic acid polymers.
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`[0073] (cid:9)
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`The compositions of the invention can contain more than one active ingredient, each
`
`of them being optionally contained in the hydrophilic matrix or in the inert amphiphilic matrix,
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`and are preferably in the form of tablets, capsules or minitablets.
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`[0074] (cid:9)
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`In terms of dissolution characteristics, contact with water or aqueous fluids causes the
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`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
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`hydrogels, giving rise to a high viscosity hydrated front which prevents the further penetration of
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`the solvent itself linearly slowing down the dissolution process to a well determined point which
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`can be located at about half the thickness, until the further penetration of water would cause the
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`disintegration of the hydrophilic layer and therefore the release of the content which, consisting
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`of inert matrix granules, however induces the diffusion mechanism typical of these structures and
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`therefore further slows down the dissolution profile of the active ingredient.
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`[0075] (cid:9)
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`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
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`the amphiphilic portion promote wettability of the porous canaliculuses which cross the inert
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`matrix preventing or reducing resistance to penetration of the solvent inside the inert matrix.
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`[0076] (cid:9)
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`To obtain taste masking tablets, the components of the hydrophilic matrix are carefully
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`selected to minimize the active substance release time through penetration accelerated by the
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`canalization induced by the hydrophilic compound.
`
`[0077] (cid:9)
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`The following Examples illustrate the invention in greater detail.
`
`000008
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`9
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`EXAMPLE 1
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`[0078] (cid:9)
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`500 g of 5-aminosalicylic-acid and 20 g of octylonium bromide are mixed with 10 g of
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`soy lecithin dissolved in 50 g of a water:ethyl alcohol 1:3 mixture at about 50°C. After
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`homogenization and drying, the granules of the resulting matrix are treated in a kneader with 20
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`g of carnauba wax and 50 g of stearic acid, heating until homogeneous dispersion, then cold-
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`extruded into small granules. The inert matrix granules are loaded into a mixer in which 30 g of
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`carbopol 971 P and 65 g of hydroxypropyl methylcellulose are sequentially added. After a first
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`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 is tabletted to unitary weight
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`of 760 mg/tablet. The resulting tablets are film-coated with cellulose acetophthalate or
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`polymethacrylates and a plasticizer to provide gastric resistance and prevent the early release of
`
`product in the stomach.
`
`[0079] (cid:9)
`
`The resulting tablets, when subjected to dissolution test in simulated enteric juice,
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`have shown a release of the active principles having the following profile: after 60 minutes no
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`more than 30%, after 180 minutes no more than 60%, after 5 hours no more than 80%.
`
`EXAMPLE 2
`
`[0080] (cid:9)
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`50 g of diethylene glycol monoethyl ether are homogeneously distributed on 500 g of
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`microcrystalline cellulose; then 100 g of Budesonide are added, mixing to complete
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`homogenization. This mix is further added with 400 g of Budesonide, then dispersed in a blender
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`containing 100 g of carnauba wax and 100 g of stearic acid preheated at a temperature of 60°C.
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`After kneading for 5 minutes, the mixture is cooled to room temperature and extruded in
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`granules of size below 1 mm.
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`[0081] (cid:9)
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`A suitable mixer is loaded with the matrix granules prepared as above and the
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`following amounts of hydrophilic excipients: 1500 g of hydroxypropyl methylcellulose and 500
`
`g of policarbophil.
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`[0082] (cid:9)
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`The components are mixed until homogeneous dispersion of the matrices, then added
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`with 2450 g of microcrystalline cellulose, 400 g of lactose, 100 g of colloidal silica and 50 g of
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`magnesium stearate. After further 5 minute mixing, the mix is tabletted to unitary weight of 250
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`mg/tablet.
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`000009
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`10
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`EXAMPLE 3
`
`[0083] (cid:9)
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`850 g of metformin are dispersed in a granulator/kneader with 35 g of diethylene
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`glycol monoethyl ether previously melted with 100 g of stearic acid and 55 g of carnauba wax.
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`The system is heated to carry out the granulation of the active ingredient in the inert matrix. The
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`resulting 1040 g of formulation are added with 110 g of hydroxypropyl methylcellulose and 20 g
`
`of magnesium stearate.
`
`[0084] (cid:9)
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`The final mixture is tabletted to unitary weight of 1170 mg/tablet equivalent to 850 mg
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`of active ingredient.
`
`[0085] (cid:9)
`
`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
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`more than 35%, after 180 minutes no more than 60%, after 5 hours no more than 80%.
`
`EXAMPLE 4
`
`[0086] (cid:9)
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`120 g of octylonium bromide are dispersed in a granulator/kneader with 30 g of stearic
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`acid and 15 g of beeswax in which 10 g of diethylene glycol monoethylene had previously been
`
`melted.
`
`[0087] (cid:9)
`
`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 methylcellulose
`
`and 5 g of policarbophyl, 2 g of magnesium stearate and 3 g of microcrystalline cellulose.
`
`[0088] (cid:9)
`
`The final mixture is tabletted to unitary weight of 200 mg/tablet equivalent to 120 mg
`
`of active ingredient.
`
`[0089] (cid:9)
`
`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
`
`[0090] (cid:9)
`
`12 g of diethylene glycol monoethyl ether are loaded on 6 g of microcrystalline
`
`cellulose and 6 grams of calcium carbonate, 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
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`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
`
`000010
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`
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`11
`
`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
`
`[0091] (cid:9)
`
`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.
`
`[0092] (cid:9)
`
`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 (2 g) of
`
`magnesium stearate.
`
`[0093] (cid:9)
`
`The final mixture is tabletted to unitary weight of 400 (200) mg/tablet equivalent to 50
`
`(25) mg of carbidopa and 200 (100) mg di levodopa.
`
`EXAMPLE 7
`
`[0094] (cid:9)
`
`4 g of Nimesulide are solubilised in 50 g of diethylene glycol monoethyl ether, then
`
`100 g of microcrystalline cellulose are added to obtain a homogeneous mixture.
`
`[0095] (cid:9)
`
`The resulting mixture is added in a granulator/kneader with 196 g of Nimesulide, 50 g
`
`of stearic acid and 25 g of carnauba wax. The system is heated to carry out the granulation of the
`
`active ingredient in the inert and amphiphilic matrix system.
`
`[0096] (cid:9)
`
`425 g of the resulting granulate are added with 60 g of hydroxypropyl methylcellulose,
`
`5 g of policarbophil and 10 g of magnesium stearate.
`
`[0097] (cid:9)
`
`The final mixture is tabletted to unitary weight of 500 mg/tablet equivalent to 200 mg
`
`of active ingredient.
`
`[0098] (cid:9)
`
`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 1 hour no more
`
`than 25%, after 2 hours no more than 40%, after 4 hours no more than 60%, after 8 hours no
`
`more than 90%.
`
`EXAMPLE 8
`
`000011
`
`
`
`12
`
`[0099] (cid:9)
`
`500 g of propionyl carnitine are dispersed in a granulator/kneader with 90 g of stearic
`
`acid and 40 g of carnauba wax, in which 20 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/amphiphilic matrix. The resulting 650 g of formulation are added with 60 g of
`
`hydroxypropyl methylcellulose and 10 g of magnesium stearate.
`
`[0100] (cid:9)
`
`The final mixture is tabletted to unitary weight of 720 mg/tablet equivalent to 500 mg
`
`of active ingredient.
`
`[0101] (cid:9)
`
`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 40%, after 180 minutes no more than 60%, after 4 hours no more than 80%, after 8
`
`hours no more than 90%.
`
`EXAMPLE 9
`
`[0102] (cid:9)
`
`One kg of Nimesulide is placed in a high rate granulator, pre-heated to about 70°,
`
`together with 200 g of cetyl alcohol and 25 g of glycerol palmitostearate the mixture is kneaded
`
`for about 15 minutes and stirred while decreasing temperature to about 30°C. The resulting inert
`
`matrix is added, keeping stirring and kneading during cooling, with 50 g of soy lecithin and 50 g
`
`of ethylene glycol monoethyl ether. The granulate is extruded through a metallic screen of
`
`suitable size and mixed with 50 g of hydroxypropyl methylcellulose, 1320 kg of maltodextrins, 2
`
`kg of lactose-cellulose mixture, 50 g of colloidal silica, 40 g of aspartame, 150 g of citric acid, 75
`
`g of flavour and 65 g of magnesium stearate. The final mixture is tabletted to unitary weight of
`
`about 500 mg, having hardness suitable for being dissolved in the mouth and a pleasant taste.
`
`EXAMPLE 10
`
`[0103] (cid:9)
`
`Operating as in the preceding example, chewable tablets are prepared replacing
`
`dextrin with mannitol and the lactose-cellulose mixture with xylitol. The resulting tablets have
`
`pleasant taste and give upon chewing a sensation of freshness enhancing the flavour.
`
`EXAMPLE 11
`
`[0104] (cid:9)
`
`- (cid:9)
`
`Operating as described in example 9, but with the following components:
`active ingredient: ibuprofen (cid:9)
`
`mg 100
`
`000012
`
`
`
`13
`
`lipophilic/inert matrix component:
`
`cetyl alcohol
`
`amphiphilic matrix component: soy lecithin
`
`
`
`hydrophilic matrix components: mannitol
`
`
`
`maltodextrins
`
`methylhydroxypropylcellulose
`
`adjuvants: aspartame
`
`flavour
`
`colloidal silica
`
`magnesium stearate
`
`mg 15
`
`mg
`
`8
`
`mg 167
`
`mg
`
`150
`
`mg 30
`
`mg
`
`mg
`
`mg
`
`mg
`
`15
`
`5
`
`5
`
`5
`
`[0105] (cid:9)
`
`500 mg unitary weight tablets are obtained, which undergo progressive erosion upon
`
`buccal administration, and effectively mask the bitter, irritating taste of the active ingredient.
`
`EXAMPLE 12
`
`[0106] (cid:9)
`
`Operating as described in example 9, but with the following components:
`
`-
`
`-
`
`-
`
`-
`
`-
`
`- (cid:9)
`
`- (cid:9)
`
`-
`
`-
`
`-
`
`-
`
`-
`
`active ingredient: diclofenac sodium (cid:9)
`
`lipophilic/inert matrix component:
`
`cetyl alcohol
`
`glycerol palmitostearate
`
`amphiphilic matrix component:
`
`soy lecithin
`
`
`
`hydrophilic matrix components: xylitol
`
`
`
`maltodextrins
`
`hydroxypropylmethylcellulose
`
`adjuvants: aspartame
`
`flavour
`
`colloidal silica
`
`magnesium stearate
`
`mg 25
`
`mg
`
`mg
`
`5
`
`5
`
`mg
`
`7
`
`mg 168
`
`mg 150
`
`mg 20
`
`mg
`
`mg
`
`mg
`
`mg
`
`5
`
`5
`
`5
`
`5
`
`[0107] (cid:9)
`
`400 mg unitary weight tablets are obtained, which undergo progressive erosion upon
`
`buccal administration, and effectively mask the irritating taste of the active ingredient.
`
`000013
`
`
`
`14
`
`EXAMPLE 13
`
`[0108] (cid:9)
`
`Operating as described in example 9, but with the following components:
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`active ingredient: chlorhexidine (cid:9)
`
`lipophilic/inert matrix component:
`
`cetyl alcohol (cid:9)
`
`glycerol palmitostearate (cid:9)
`
`amphiphilic matrix component:
`
`diethylene glycol monoethyl ether (cid:9)
`
`hydrophilic matrix components: xylitol (cid:9)
`
`maltodextrins (cid:9)
`
`hydroxypropyl methylcellulose (cid:9)
`
`adjuvants: aspartame (cid:9)
`
`flavour (cid:9)
`
`colloidal silica (cid:9)
`
`magnesium stearate (cid:9)
`
`mg 2.5
`
`mg 0.5
`
`mg 0.5
`
`mg 0.3
`
`mg 38
`
`mg 96
`
`mg 10
`
`mg (cid:9)
`
`3
`
`mg 5
`
`mg (cid:9)
`
`mg (cid:9)
`
`2
`
`2
`
`[0109] (cid:9)
`
`150 mg unitary weight tablets are obtained, which undergo progressive erosion upon
`
`buccal administration, and effectively mask the irritating taste of the active ingredient.
`
`EXAMPLE 14
`
`[0110] (cid:9)
`
`One Kg of Nimesulide is placed in a high rate granulator, pre-heated to about 70°,
`
`together with g 125 of cetyl alcohol: the mixture is kneaded for about 15 minutes and stirred
`
`while decreasing temperature to about 30°C, then added with g 30 of lecithin. The resulting
`
`matrix is then extruded through a metallic screen of suitable size and mixed with 2.415 kg of
`
`lactose, 1.0 kg of maltodextrins, 50 g of hydroxypropyl methylcellulose, 50 g of colloidal silica,
`
`40 g of aspartame, 150 g of citric acid, 75 g of flavour and 65 g of magnesium stearate. The final
`
`mixture is tabletted to about 500 mg tablets, having hardness suitable for being dissolved in the
`
`mouth and pleasant taste.
`
`000014
`
`