for one aspect , the present invention relates to a process for preparing the granules according to the invention , said process comprising preparing the gelled composition by first dissolving polyvinylpyrrolidone in water and then , on dissolution , adding polysorbate to achieve the gelification . the gelled composition is indeed a dense composition with viscosity ranging between 4800 mp * s and 5200 mp * s . the process for preparing the granules also comprises that the above - mentioned gelled composition be added to and mixed with the mesalazine , preferably in a z - arm kneader ; the compound is at this point extruded , spheronized and dried . drying is preferably carried out in a fluid bed by means of the inlet of hot air at 80 ° c . until the product reaches 50 ° c . the result is a starting core containing mesalazine in a percentage greater than 97 %. extrusion preferably takes place with a net having mesh 400 - 600 μm mesh . the granules obtained according to the invention have an average size ranging between 0 . 4 mm and 2 mm in diameter , preferably 0 . 45 mm - 1 . 5 mm , more preferably 0 . 5 mm - 0 . 8 mm . the first protective membrane comprises a polymer , preferably ethyl cellulose having a viscosity of between 3 and 110 cps , and a solvent , preferably acetone , ethanol and mixtures thereof ; plasticisers , such as triethyl citrate , dibutyl sebacate or polyethylene glycol and anti - sticking agents , such as talc , magnesium stearate , colloidal anhydrous silica or sodium stearyl fumarate , can be optionally present . the viscosity of the ethyl cellulose was calculated on 5 % solutions in toluene / ethanol ( 80 %: 20 %) measured at 25 ° c . in a ubbelohde viscometer . the polymer is present in solution in a percentage ranging between 1 % and 10 %, preferably between 3 % and 8 %, more preferably still between 5 % and 6 %. the pellets are coated with the first membrane in a fluidized bed or in a coating pan until an increase in weight ranging between 0 . 2 % and 2 % of the dry weight is achieved with respect to the weight of the cores , preferably 0 . 5 %- 1 . 5 %, even more preferably 0 . 8 %- 1 . 2 %. the second outer , gastroprotective membrane therefore comprises a methacrylic acid derivative , and water ; plasticisers , such as triethyl citrate and polysorbate , and anti - sticking agents , such as talc and glyceryl monostearate , can be optionally present . the methacrylic acid derivative is selected from anionic polymers with methacrylic acid as functional group such as , for example , eudragit l100 - 55 , eudragit l 30 d - 55 , eudragit l100 , eudragit l12 . 5 , eudragit s100 , eudragit s12 . 5 , eudragit fs 30 or mixtures thereof ; they can sometimes also be mixed with eudragit ne30d and eudragit ne40d to adjust the gastro - resistance thereof . the methacrylic acid derivative is present in suspension in a percentage ranging between 12 % and 28 %, preferably between 15 % and 25 %, preferably between 16 % and 20 %. the pellets are coated with the second membrane in a fluidized bed or in a coating pan until an increase in weight ranging between 5 % and 15 % of the dry weight is achieved with respect to the weight of the cores , preferably 6 %- 12 %, even more preferably 7 %- 9 %. the pellets can at this point be sold in bags or , given the high percentage of active substance , even encapsulated or compressed . the present invention therefore relates to a pharmaceutical formulation comprising the above - mentioned multi - layer pellets , said formulation in the form of tablets or capsules . the pellets of the invention can safely be mixed with cellulose , and compressed with 400 mg - 500 mg - 800 mg dosages . particularly advantageous , however , is the possibility of encapsulating in a single dose an amount of mesalazine equal to 500 mg , which is the generally most common daily dose . unlike the other formulations present in literature , these pellets , having a medium to high titre (& gt ; 90 %) and a high density (& gt ; 0 . 89 g / ml or 900 mg / g ), have a very low specific weight per unit of active substance and can therefore can be inserted into a 500 mg size 0 capsule without any problems . this avoids the problem of multi - dose administrations , which would worsen patient compliance . a preferred embodiment of the invention provides for the encapsulation of 500 mg of pellets in a single capsule . the present invention will be better understood in the light of the following embodiments . the composition of salofalk ® granu - stix , also indicated in the patent under the name of classic formulation , is specified hereunder . component amount ( g ) polyvinylpyrrolidone 100 polysorbate 320 water 580 total 1000 dissolving polyvinylpyrrolidone in water , to then add polysorbate on dissolution . mesalazine raw material is mixed with the above - mentioned gelled composition to then extrude ( 500 μm net ) and spheronize the compound . immediately following spheronization , the granules obtained are dried in a fluid bed with inlet air at 80 ° c ., up to a product temperature of 50 ° c . cores having an average diameter of 480 μm - 520 μm are obtained with the following dry matter composition : the protective membrane is sprayed onto the previously obtained cores using a glatt fluid bed with wurster insert , up to a weight increase of 1 % with respect to the initial weight of the pellets , thus obtaining a compound with a mesalazine content of 97 . 03 %. homogenising polysorbate , triethyl citrate and glyceryl monostearate in water at 80 ° c ., then adding eudragit once the compound has cooled . the gastro resistant membrane is sprayed onto the previously obtained cores using a glatt fluid bed with wurster insert , up to a weight increase of 7 % with respect to the initial weight of the pellets , thus obtaining a compound with a mesalazine content of 90 . 68 %. the multilayer pellets thus obtained are analysed in - vitro in hcl 0 . 1n / 750 ml for 2 h , and then adjusted to ph 7 . 2 / 1000 ml ; the following dissolution profile is obtained : stability studies of the pellets according to the present invention are set up , in a climatic chamber with temperature of 25 ° c . and relative humidity of 60 %, to verify the development of impurities . after 3 to 6 months the following results are obtained and are compared with the stability results of a formulation obtained according to traditional composition and production methods : component amount ( g ) polyvinylpyrrolidone 80 polysorbate 300 water 620 total 1000 dissolving polyvinylpyrrolidone in water , to then add polysorbate on dissolution . mesalazine raw material is mixed with the above - mentioned - mentioned solution , to then extrude ( 400 μm net ) and spheronize the compound . immediately following spheronization , the granules obtained are dried in a fluid bed with inlet air at 80 ° c ., up to a product temperature of 50 ° c . cores having an average diameter of 380 μm - 430 μm are obtained with the following dry matter composition : the protective membrane is sprayed onto the previously obtained cores using a gs automatic coating pan , up to a 1 . 2 % increase in weight with respect to the initial weight of the pellets , thus obtaining a compound with a 97 . 83 % mesalazine content . homogenizing polysorbate , triethyl citrate and glyceryl monostearate in water at 80 ° c ., then adding eudragit once the compound has cooled . the gastro - resistant membrane is sprayed onto the previously obtained cores using a gs automatic coating pan , up to a 7 . 5 % increase in weight with respect to the initial weight of the pellets , thus obtaining a compound with a 91 . 00 % mesalazine content . the pellets are analysed in - vitro in hcl 0 . 1n / 750 ml for 2 h , and then adjusted to ph 7 . 2 / 1000 ml ; the following dissolution profile is obtained : stability studies of the pellets according to the present invention are set up , in a climatic chamber with temperature of 25 ° c . and relative humidity of 60 %, to verify the development of impurities . after 3 to 6 months the following results are obtained and are compared with the stability results of a formulation obtained according to traditional composition and production methods : component amount ( g ) polyvinylpyrrolidone 90 polysorbate 400 water 510 total 1000 dissolving polyvinylpyrrolidone in water , to then add polysorbate on dissolution . mesalazine raw material is mixed with the above - mentioned - mentioned solution , to then extrude ( 600 μm net ) and spheronize the compound . immediately following spheronization , the granules obtained are dried in a fluid bed with inlet air at 80 ° c ., up to a product temperature of 50 ° c . cores having an average diameter of 570 μm - 640 μm are obtained with the following dry matter composition : the protective membrane is sprayed onto the previously obtained cores using a glatt fluid bed with wurster insert , up to a weight increase of 0 . 8 % with respect to the initial weight of the pellets , thus obtaining a compound with a mesalazine content of 97 . 72 %. homogenising triethyl citrate and talc in water , then adding eudragit to the compound . the gastro resistant membrane is sprayed onto the previously obtained cores using a glatt fluid bed with wurster insert , up to a weight increase of 7 % with respect to the initial weight of the pellets , thus obtaining a compound with a mesalazine content of 91 . 33 %. the pellets are analysed in - vitro in hcl 0 . 1n / 750 ml for 2 h , and then adjusted to ph 7 . 2 / 1000 ml ; the following dissolution profile is obtained : stability studies of the pellets according to the present invention are set up , in a climatic chamber with temperature of 25 ° c . and relative humidity of 60 %, to verify the development of impurities . after 3 to 6 months the following results are obtained and are compared with the stability results of a formulation obtained according to traditional composition and production methods :
the present invention relates to a formulation containing mesalazine in a stable form , obtained by coating the starting core with a first membrane in non - aqueous solution ; said core containing mesalazine at a high concentration , greater than 90 %, obtained by producing starting cores with active substance content greater than 97 %. the formulation according to the present invention containing mesalazine with specific release in the colon ; in particular the capsule formulation containing 500 mg of mesalazine with specific release in the colon .