Europäisches Patentamt *EP001183014B1* (19) European Patent Office Office européen des brevets (11) EP 1 183 014 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61K 9/16, A61K 9/20 of the grant of the patent: 08.10.2003 Bulletin 2003/41 (86) International application number: PCT/EP00/05356 (21) Application number: 00942044.9 (87) International publication number: (22) Date of filing: 09.06.2000 WO 00/076478 (21.12.2000 Gazette 2000/51) (54) CONTROLLED RELEASE AND TASTE MASKING ORAL PHARMACEUTICAL COMPOSITIONS GESCHMACKSMASKIERTE ORALE PHARMAZEUTISCHE ZUSAMMENSETZUNGEN MIT KONTROLLIERTER ABGABE COMPOSITIONS PHARMACEUTIQUES ADMINISTRABLES PAR VOIE ORALE A LIBERATION CONTROLEE ET GOUT MASQUE (84) Designated Contracting States: • AJANI, Mauro AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Panama City (PA) MC NL PT SE • FOSSATI, Lorenzo Panama City (PA) (30) Priority: 14.06.1999 IT MI991317 03.03.2000 IT MI200042 (74) Representative: Minoja, Fabrizio, Dr. Bianchetti Bracco Minoja S.r.l. (43) Date of publication of application: Via Rossini, 8 06.03.2002 Bulletin 2002/10 20122 Milano (IT) (73) Proprietor: Cosmo S.p.A. (56) References cited: 20121 Milano (IT) EP-A- 0 514 008 WO-A-99/11245 WO-A-99/17752 DE-A- 4 131 562 (72) Inventors: GB-A- 935 639 US-A- 5 597 844 • VILLA, Roberto Panama City (PA) Remarks: • PEDRANI, Massimo The file contains technical information submitted Panama City (PA) after the application was filed and not included in this specification Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 183 014 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 183 014 B1 2 Description that are not wholly toxicologically inert. [0008] A number of formulations based on inert li- [0001] The present invention relates to controlled re- pophilic matrices have been described: Drug Dev. Ind. lease and taste-masking compositions containing one Pharm. 13 (6), 1001-1022, (1987) discloses a process or more active principles incorporated in a three-com- 5 making use of varying amounts of colloidal silica as a ponent matrix structure, i.e. a structure formed by suc- porization element for a lipophilic inert matrix in which cessive amphiphilic, lipophilic or inert matrices and fi- the active ingredient is incorporated. nally incorporated or dispersed in hydrophilic matrices. [0009] The same notion of canalization of an inert ma- The use of a plurality of systems for the control of the trix is described in US 4,608,248 in which a small dissolution of the active ingredient modulates the disso- 10 amount of a hydrophilic polymer is mixed with the sub- lution rate of the active ingredient in aqueous and/or bi- stances forming an inert matrix, in a non sequential com- ological fluids, thereby controlling the release kinetics in penetration of different matrix materials. the gastrointestinal tract, and it also allows the oral ad- [0010] EP 375,063 discloses a technique for the prep- ministration of active principles having unfavourable aration of multiparticulate granules for the controlled-re- taste characteristics or irritating action on the mucosae 15 lease of the active ingredient which comprises co-dis- of the administration site, particularly in the buccal area. solution of polymers or suitable substances to form a [0002] The compositions of the invention can contain inert matrix with the active ingredient and the subse- active principles belonging to the therapeutical classes quent deposition of said solution on an inert carrier of analgesics, antiinflammatories, cardioactives, tran- which acts. as the core of the device. Alternatively, the quillizers, antihypertensives, disinfectants and topical 20 inert carrier is kneaded with the solution containing the antimicrobials, antiparkinson drugs, antihistamines and inert polymer and the active ingredient, then the organic are suitable to the oral administration or for acting topi- solvent used for the their dissolution is evaporated off cally at some areas of the gastrointestinal tract. to obtain a solid residue. The resulting structure is a "reservoir", i.e. is not macroscopically homogeneous TECHNOLOGICAL BACKGROUND 25 along all the symmetry axis of the final form. [0011] The same "reservoir" structure is also de- [0003] The preparation of a sustained, controlled, de- scribed in Chem. Pharm. Bull. 46 (3), 531-533, , (1998) layed or anyhow modified release form can be carried which improves the application through an annealing out according to different known techniques: technique of the inert polymer layer which is deposited 30 on the surface of the pellets. 1. The use of inert matrices, in which the main com- [0012] DE 4131562 discloses pharmaceutical com- ponent of the matrix structure opposes some resist- positions comprising a solid core consisting of lipophilic ance to the penetration of the solvent due to the compounds in which the active agent is inglobated; a poor affinity towards aqueous fluids; such property stabilising agent such as lecithin; and an aqueous me- being known as lipophilia. 35 dium in which the lipophilic phase is dispersed. 2. The use of hydrophilic matrices, in which the main [0013] To the "reservoir" structure also belong the component of the matrix structure opposes high re- products obtained according to the technique described sistance to the progress of the solvent, in that the in WO 93/00889 which discloses a process for the prep- presence of strongly hydrophilic groups in its aration of pellets in hydrophilic matrix which comprises: chains, mainly branched, remarkably increases vis- 40 cosity inside the hydrated layer. - dissolution of the active ingredient with gastro-re- 3. The use of bioerodible matrices, which are capa- sistant hydrophilic polymers in organic.solvents; ble of being degraded by the enzymes of some bi- - drying of said suspension; ological compartment. - subsequent kneading and formulation of the pellets 45 in a hydrophilic or lipophilic matrix- without distinc- [0004] All the procedures listed above suffer, howev- tion of effectiveness between the two types of ap- er, from drawbacks and imperfections. plication. [0005] Inert matrices, for example, generally entail nonlinear, but esponential, release of the active ingredi- [0014] EP 0 453 001 discloses a multiparticulate with ent. 50 "reservoir" structure inserted in a hydrophilic matrix. The [0006] Hydrophilic matrices have a linear behaviour basic multiparticulate utilizes two coating membranes to until a certain fraction of active ingredient has been re- decrease the release rate of the active ingredient, a pH- leased, then they significantly deviate from linear re- dependent membrane with the purpose of gastric pro- lease. tection and a pH-independent methacrylic membrane [0007] Bioerodible matrices are ideal to carry out the 55 with the purpose of slowing down the penetration of the so-called "site-release", but they involve the problem of aqueous fluid. finding the suitable enzyme or reactive to degradation. [0015] WO 95/16451 discloses a composition only Furthermore, the frequently release in situ metabolites formed by a hydrophilic matrix coated with a gastro-re- 2 3 EP 1 183 014 B1 4 sistant film for controlling the dissolution rate of the ac- a) the active ingredient is first inglobated by simple tive ingredient. kneading or mixing in a matrix or coating consisting [0016] When preparing sustained-, controlled- re- of compounds having amphiphilic properties, which lease dosage forms of a medicament topically active in will be further specified below. The active principle the gastrointestinal tract, it is important to ensure a con- 5 (s) can be mixed with the amphiphilic compounds trolled release from the first phases following adminis- without the aid of solvents or with small amounts of tration, i.e. when the inert matrices have the maximum water-alcoholic solvents. release rate inside the logarithmic phase, namely the b) The matrix obtained in a) is incorporated in a low higher deviation from linear release. melting lipophilic excipient or mixture of excipients, [0017] Said object has been attained according to the 10 while heating to soften and/or melt the excipient it- present invention, through the combination of an am- self, which thereby incorporates the active ingredi- phiphilic matrix inside an inert matrix, the latter formu- ent by simple dispersion. After cooling at room tem- lated with a lipophilic polymer in a superficial hydrophilic perature an inert matrix forms, which can be re- matrix. The compositions of the invention are character- duced in size to obtain inert matrix granules con- ized by the absence of a first phase in which the medi- 15 taining the active ingredient particles. cament superficially present on the matrix is quickly sol- c) The inert matrix granules are subsequently mixed ubilized, and by the fact the the amphiphilic layer com- together with one or more hydrophilic water-swella- pensate the lack of affinity of the aqueous solvent with ble excipients. The mixture is then subjected to the lipophilic compounds forming the inner inert matrix. compression or tabletting. This way, when the tablet 20 is contacted with biological fluids, a high viscosity DISCLOSURE OF THE INVENTION swollen layer is formed, which coordinates the sol- vent molecules and acts as a barrier to penetration [0018] The invention provides controlled release and of the aqueous fluid itself inside the new structure. taste masking oral pharmaceutical compositions con- Said barrier antagonizes the starting "burst effect" taining an active ingredient, comprising: 25 caused by the dissolution of the medicament inglo- bated inside the inert matrix, which is in its turn in- a) a matrix consisting of lipophilic compounds with side the hydrophilic matrix.