(2) United States Patent a) we, @ oO ay @ (66) wy eo Jon 6) @) Villa et al. MESALAZINE CONTROLLED RELEASE ‘ORAL PHARMACEUTICAL COMPOSITIONS, Inventors: Roberto Villa, Panam (PA); Massimo Pedrani, Panama (PA); Mauro Ajani, Panama (PA); Lorenzo Fossati, Panama a) Assignee: Cosmo S.p.A., Milan (IT) Notice: Subject w any disclaimer, the term of this pateat is extended or adjusted under 35 USCC 1540) by 0 days 107009,491 Appl. No. PCT Filed: Jun, 8, 2000 PCT No. $371 (0X1). (2), Date: PCT Pub. No. PCT/EPOOs321 Dee. 13, 2001 WOWYT648L PCT Pub, Date: Dee 21, 2000 Foreign Application Priority Data 4,199 MIBeAL3I6 Int. C17 AGIK 9/127, AGIK 9/14; ‘AGIK 9/22; AOIK 926; AOIK 9/52 us.cl 424/480; 4241451; 4240452; 4241457; 424464; 424465; 424468; 424/469; ADAH; A2AUH85; 424488 US006773720B1 US 6,773,720 BL Aug. 10, 2004 (10) Patent No.: (45) Date of Patent: (58) Field of Search 4241451, 452, 24/457, 404, 465, 467, 408, 469, 484, 485, 488, 450, 489, 190, 66) References Cited US, PATENT DOCUMENTS 492,957 A * 5/1980: Wheatley a 5503/00 A 1/1997 Akiyama eta SASISS5 A 12/988 Sanghviel SISA A * 6/1999 Samour eta ay FOREIGN PATENT DOCUMENTS on wo 2245402 A wo 9825767 i062 61998 * cited by examinee Primary Examiner Thurman K. Page Assistant Examiner—8. Tran (74) Auormey, Agent, or Firm—Young & Thompson 6 ABSTRACT CContrlled-elease oral pharmaceutical compositions con ‘aining as active ingredient S-amino-salieylc aid, eompris- ing: a) an inner lipophilic matcix consisting of substances with a melting poiat below 90° C. ia which the active Ingredient is at leas pally inglobate; b) an outer hydo- philic matex in which the lipophilic matrix is dispersed) ‘optionally other excipients, 4 Claims, No DrawingsUS 6,773,720 B1 1 MESALAZINE CONTROLLED RELEASE, ‘ORAL PHARMACEUTICAL COMPOSITIONS ‘The present invention relates to conteolled release oral ‘pharmaceutical compositions containing ss active ingredient $ S.amino salicylic acid, also named mesalazine. BACKGROUND OF THE INVENTION Mesalazine i used in the treatment of Chron’s disease and ulcerative colitis thanks to its atinlammatocy activity fo the intestinal mucuses. Conteolled-elease formulations ‘of mesalazie are disclosed in WO 95/16451, EP 0453 001, EPO 377 477 ‘The preparation of a sustained, controlled, delayed or nyow modlied release fox can be cated out according to diferent 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 othe poor afnity towards aqueous fluids; such property being known 2 lipophila, 2. The use of hydrophilic matrices, in which the main ‘component of the matrix sucture opposes high resistance to the progress of the solvent, in that the presence of strongly hydrophilic groups in its chains, maialy branched, remarkably increases. viscosity inside the 2s baydrted layer 43. The use of bioerodible matrices, which ate capable of boeing degraded by the enaymes of some biological com- partmeat. Al the procedures listed above suffer, however, from eawhacks and imperfections Incet matrices, for example, generally entail non-linear, but esponential, release ofthe ative ingredient, ‘Hydrophilic matrices. have a linear behaviour until a cerain fraction of ative ingredient has heen released, then they significantly deviate from linear release Bioerodible matrices ae ideal o cary out the so-called “siteselease”, 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 toxicological inert ‘Annumber of formulations based on int ipopilic mati- ces have been described: Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses a process making use of vary- {ng amounts of colloidal silica as a poriation element for a lipophilic inert matrix in which the active ingredient is incorporated ‘The same notion of canalization of an inert matrix is described in US. Pat. No. 4,608,248 in which small amount of a hydrophilic polymer is mixed with the sab- sanees forming an inert matrix, in a non sequeatil com- pencteation of cllferent matsix materials, EP 375,063 discloses a technique forthe preparation of ‘multparicuate granules for the controlledtelease of the active ingredieat which comprises co-dissoluton of poly- ‘mers or Stable substances to form a inert matrix with the sctive ingredient and the subsequent deposition of said solution on an inet carrier which acts as the core of the evice. Altematively, the inert cartier is kneaded with the solution containing’ the inert polymer and the active ingredient, then the organic solvent used forthe their dis- solution is evaporated off to obtain a solid residue. The resulling structure is a “reservoit, ie, is nat macroscopi- cally homogeneous along all the symmetry axis of the final form, ‘The same “reservoir” structure is also described in Chem, Pharm. Bull 46 (3), 331-533, (1998) which improves the s 0 a 2 application through an annealing technique of the inert polymer layer which is deposited on the surface of the pelle To the “reservoir” structure also belong the products coblained according 10 the technique described in WO 93400889 which discloses a process for the preparation of pelleis in hydrophilic matrix which comprises: Aissolution of the active ingrediem with gasro-esstant hydrophilic polymers in organic solvents; drying of said suspension; subsequent kneading and formulation ofthe pellets ia a Laydropilic or lipophilic matrix without distinction of effectiveness between the two types of application, EPO 453001 discloses a mulipatculte with “reservoir” structure inserted in hydrophilic matrix. The basic muli- particulate tlizes ovo coating membranes to decrease the release rate ofthe active ingredient, a pH-dependent mem- borane with the purpose of gasiric protection and a pll-independlent methacrylie membrane with the purpose of slowing down the penetration ofthe agueous fui, WO 95)/16851 disceses a composition oly formed by a hydrophilic matrix coated with a gasto-esstant film for controlling the dissolution rate of mesalazine. ‘When preparing sisisined-, contolledtelease dosage forms of a medicament topically active in the gastointesti- nal trac, itis important to ensure a controlled release from the fst phases follaving administatioa, ie, when the inert ‘matrices have the maximum release rate inside the logarith- ‘mic phase, namely the higher deviation from linear release. Said object as been attained by the present inveation, whieh aso allows to prepare compositions characterized by ‘high conten inactive ingredient DISCLOSURE OF THE INVENTION ‘The invention provides controlled release oral pharma- ceutical compositions containing S-amino-saicylic acid as the active ingredient, comprising 8) an inner lipophilic matrix consisting of substances with melting poiat below 90°C. in which the active ingredient is at least panaly inglobated; ban outer hydrophilic matrix in which the lipophilic matrix is dispersed; ©) optionally otber excipients DETAILED DISCLOSE OF THE INVENTION ‘The compositions ofthe invention ean be obtained witha method comprising the following steps: 4) the active ingredion is ist inglobated in alow melting excipient or mixture of excipients, while beating to soften andor melt the excipient itself, which thereby incorporates the ative ingredient by simple dispersion, After evoling a oom temperature an inert matrix Forms, which can be reduced in size 10 obtain matrix granules containing the ative ingredient patcles ) the inert mateix granules are subsequently mixed together with one o¢ more hyerophiie water-svellable excipients. ‘This way, when the tablet is contacted with biological uid, 2 high viscosity swollen layer is fonmed, whit coordinates the solvent molecules and acts as a barrier to penetration of the aqueous fluid itself inside the new struc lure, Said bacriet antagonizes the starting “burst effet” ceased by the dissolution of the medicament inglobated inside the inert mattix, which is in its tm inside the hydrophilic matiUS 6,773,720 B1 3 ‘The lipophilic matrix consis of substances selected from unsaturated andor hydrogenated fatty acids, salts, esters oF amides thereof, fatty acids mono-, di- or uighyceids, waxes, ceramides, cholesterol derivatives or mixtures thereof hav ing melting point within the range of 40 10 90° C, Tf desize, fatty seid calcium salt may be incorporated. in the lipophilic matrix which i subsequently disperse in a Lbydrophlic matrix prepared with alginic acd, thus remask- ably increasing the hydrophilic matrix viscosity following penetration ofthe solvent front until contact with te lipo philic matrix granules dispersed inside The weight content of the active ingredient in the ipo- philic matrix usually ranges from 5 to 95%. ‘The inert lipophilic matrix is reduced into granules by an extrusion andior granulation process, or any other known, processes Which resin the homogeneous dispersion and ‘matrix structure of the starting mixture “The hydrophilic matrix consists of excipients knowa as hydrogel, ie. substances which pass from the dry state to the hydrated one, undergo the so-called “molecular relaxation", namely a remarkable increase in mass and ‘weight folowing the coordination of a lage number of water molecules by the polar groups present inthe poly- ‘meric chins ofthe excipients themselves Examples of hydrogels which can be used according to the invention are compounds selected from polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, earboxyalkyl celluloses, polysaccharide, dextrin, pectns, starches and derivatives, Datura or synthetic gums, alginic aid “The lipophilic matrix granules containing the ative ingre- dient ae mixed the with hydrophilic compounds cited above in a weight ratio typically canging from 100.5 to 100.20, (ipophilic masx: hydrophilic matrix). Part of mesalazine can optionally be mixed with hydrophilic substances to ‘provide compositions in which the active ingredient is ispersed both inthe lipophilic andthe hydrophilic mati, said comoositions being preferably in the form of tablets, capsules andior mintablets. “The compression of the mixture of lipophilic mati, bydrogel-forming compounds and, optionally, ative ingre+ ieot non inglobated in the lipophilic matrix, yields a macroscopically homogeneous sirucure in all is volume, ‘pamely a matrix containing a dispersion of the lipophilic granules in a hydrophilic matex. The tablets, capsules andlor minitablets obtainable according to the invention can optionally be subjected to ‘known costing processes with gasto-resisan film, con- sisting of for example polymers of methacrylic acids (Eudragit®) or cellulose derivatives, such as cxlulose s acetophthalate ‘The compositions of the invention can contain high percentage of active ingredient compared with the total ‘composition weight up 0 95% an advantageous character- istic inthe ease of mesalazine which requires rather high unitary doses In terms of dissolution characteristics, the compositions of the invention provide a release profile of the active ingredient more homogeneous than the traditional systems. In fat, the immediate peneeation of water inside the super- ficial layer of the hydrophilic mattix and the coasequeat ‘swelling due tthe distension of the polymeric chains of the hydrogels, gives rise to high viscosity hydrated front which prevents the further penetation of wate, linearly slowing Gown the dissoltion process to a well determined point ‘which can be loated at about half the thickness unt the further penecation of Water would cause the disintegration ™ s 4 of the hydeophilic layer and therefore the release of the content which, consisting of lipophilic granules, however induces the difasional mechanism typical ofthese structures and therefore further slows down the dissolution profile of the active ingredient, The following examples illustrate the invention in greater eu EXAMPLE 1 ‘770g of -aminosaicylic acid are added inakneader with 20 g of carnauba wax and 50 g of stearic aid with heating ‘until bomogeneous dispersion, then extruded into small ‘granules while cold. ‘The inert matix granules are loaded into & mixer in which 30g of Carbopol 971P and 65 g of hydroxypropyl methylcelulose are sequentially added. ‘Aller fist mixing step for homogeneously dispersing the powders, 60 g of microcrystalline cellulose and Sg of ‘magnesium stearate ae added. After mixing, the final mix- ture is tabletted to unitary weight of 649 mgtablet or $10 _mgtablet to obtain S00 and 400 mg desages, respectively The resulting tablets are flm-coated with cellulose scetopithalate or polymethacrylates and a plasticizer to provide gastic resistance and prevent the eatly release of Product inthe stomach ‘The dissolution profle of these tablets shows the release of am ative ingredient amount lower than 30% within the fist hour of permanence in simulated enteric juice, an amount lower than 60% atthe fourth houe and an smeuat Tower than 90% atthe eighth hour, thus proving thatthe double matrix effectively controls dssoltion EXAMPLE 2 1000 g of S-aminosalicylie acid are ale in a kneader with 10°g of carnauba wax and 20 g of stearic acid with ‘ating until homogeneous dispersion, then extruded into small granules while cold or divelly granulated in a igh rate miser. ‘The resulting granules are loaded into a mixer in which 80 of bydoxypropy! methylelilose and 12 g of sodium Starch glycolate are sequentially added. After a fist mixing step, 1 g of silica colloidal and 11 gof magnesium stearate are added, The final mixture is homogenized, hen tabletted {oa unitary weight of 1144 mtable The resulting tablets are then film coated with poly- smethacrylates or cellulose acetophthalte and plasticizers to provide gastric resistance. ‘The dissolution profile ofthese tables after lag time of permanence in the stomach and partly in the intestine provides the release of no more than 30% within the firs. ‘hour, no more than 55% within two hours, no more than 70% ‘within four hous, no more than 90% within eight hous. EXAMPLE 3 850 g of S-aminoslicyic acid are added in granulatoe/ neader with 9g of beesvax and 22g of palmitic acid with beating, until homogeneous dispersion; then worked to a sranulate ina high shear granulating device. The resulting ‘granules are then loaded into a mixer which i added ia succession with 45.5 g of hydroxypropyl methykelulose, 455 g of microcrystalline cellulose, 20 g of sodium starch alycolate, 22 g of colloidal silica and 23 g of magnesium Searae, Ater homogenization, te final mixture is tableted {0 a unitary weight of 975 mgtablet ‘The resulting tablets are then film coated with poly- smethacrylaes or actophthalteof cellulose and plasticizers, to provide gastie resistanceUS 6,773,720 B1 5 ‘The dissolution profile ofthese tables after a lag time of permanence in the stomach and partly in the intestine provides the celease of no more than 30% within the fst Four, no more than 50% within two hours, no more than 70% ‘within four hous, no more than 90% within eight hous, EXAMPLE 4 1100 g of 5-aminosalicyic acid are added in granulator/ Jkncader with 10 g of wax carnauba and 20 gof stearic acd 10 gf polyacrylamide, 39.5 of microcrystalline cellulose and 2 g of colloidal silica are separately loaded into the Domogenizeriganulator to obtain a homogeneous solid mixture, which is placed in the mixer where the active ingredient has been granulated and homogenized, 49.5 g of hydroxypropyl methyloelulose and 12 g of sodium alginate ‘are thocoughly mixed, thon added with $ g of ealeium carbonate, 345 g of microcrystalline cellulose and 11 g of ‘magnesium stearate. The mixture is homogenized, then tableted to final unitary weight of 1194 mgtablet. The resulting tablets are thea fl coated with polymethacrylates, orcxllulose acetophibalate and plasticizers to provide gastric resistance. ‘The dissolution profile ofthese tables after lag time of permanence ia the stomach and partly in the intestine provides the release of no more than 356% within the firs. Four, 09 more than 50% within two hours, no more thaa 70% within four hous, no more than 904% within eight hous, EXAMPLE 5 1200 g of S-aminosalicyic acid are added in mixer with 10 g of caroauba wax and 20 g of steavi acid, with beating ‘until homogeneous dispersion, then cold extruded into small. aranules or directly granulated inthe high ate mixer. The resulting granules are loaded ito a mixer, then 70 g of * hydroxypropyl methylellulexe and 20 g of sodium sarch alycolate are sequentially added. ‘Afra frst mixing step, 80 g of sodium carbonate and 5 1g of magnesium stearate ae added. The final mixtuce is Domogenized, then tubletied to unitary weight of 1375, mgtablet ‘The resulting tablets are then flm-coated with poly- methacrylate or cellulose aevtophthalate and plasticizers to provide gasrie resistance. 6 ‘The dissolution profile ofthese tablets after a lag time of permanence in the stomach and partly in the intestine provides the celease of no more than 30% within the fis. Four, no more than 504% within swo hours, no more than 70% within four hours, no more than 90% within eight hous, ‘What is claimed is 1. Contoled-elease oral pharmaceutical compositions containing as an active ingredient S-amino-salcylie acid, ‘comprising: 8) an inner lipophilic matrix consisting of substances selected from the goup consisting of unsaturated andl or hydrogenated faty acid, sills, esters or amides thereof, faty acid mono, di- or triglyeerid, wanes, coramides, and cholesterol derivatives. with melting points below 90° C., and where the active ingredient {sdlispersed both in said the lipophilic matrix apd in the hydrophilic matrix; ) an outer hydzophilic matrix wherein the lipophilic tmatrix is dispersed, and sad outer hydrophilic matrix 2 consiss of compauinds selected from the group con- ‘Sistng of polymers or copolymers of acrylic of meth- serylic acid, alkylvinyl polymers, hydeoxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, extrns, pectin, sarches and derivatives alginic acid, and natural of synthetie gums; ©) optionally other excipients; ‘wherein the ative ingredient is present a an amount of 80 {0 95% by weight ofthe total composition, and wherein the active ingredient is dispersed both inthe lipophilic ‘matrix and in the hydrophilic matrix. 2. Compositions as claimed in 1, wherein Seaminosaliylic acid is dispersed in « molten lipophilic ‘matrix by kneading extrusion andor granulation, as 3. Compositions a6 claimed in claim 1, inthe form of tables, capsules, mintabets. 4.4 process for the preparation of the compositions of claim 1, which comprises: 8) melt granulation of at last one portion ofthe active ingredient withthe lipophilic excipients with melting point lower than 90° C; 1b) mixing the granules fzom step a) with the hydophilc excipients and subsequent ableting or compression. 0 2