Patent Description:
Mesalazine or <NUM>-aminosalicylic acid (<NUM>-ASA) is a medicament used in the acute and chronic treatment of inflammatory bowel disease (IBD), in particular in maintaining and/or inducing remission in patients suffering from mild/moderate active ulcerating colitis. Mesalazine derivatives or analogues comprise sulphasalazine, olsalazine, balsalazide and salazopyrin.

Mesalazine is available on the market in oral (coated tablets, slow-release tablets) or rectal pharmaceutical forms (suppositories, ready-to-use enemas, foam enemas, single-dose enemas, slow-release enemas). Slow-release oral and rectal technologies were devised to prolong the effect of the medicament and allow fewer daily administrations of tablets or enemas.

An ideal pharmaceutical form should release mesalazine into contact with the inflamed intestinal mucosa and limit its systemic bioavailability. In practice, mesalazine is absorbed by the intestinal mucosa, especially in the first part of the small intestine.

Mainly for this reason, the tablets are coated, so as to release the mesalazine into the last part of the small intestine and the colon. This result can be obtained by various technologies, for example by using pH-sensitive polymer matrices able to release mesalazine only in proximity to the colon.

In particular, some methacrylic acid copolymers (Eudragit), used as a coating in modern oral preparations, release the medicament when the pH of the external environment is between <NUM> and <NUM>-<NUM>, the pH values being measured in the intestinal lumen, in the part of the colon affected by ulcerating colitis.

Gastroenteric-release products release all of the product within an hour of solubilisation of the film-coating. Examples of said systems are described in <CIT>, <CIT> and <CIT>.

Multi-particulate systems, which are described, for example, in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> and <CIT>, are characterised by pH-dependent release or reservoir systems without a matrix.

Matrix systems for the release of medicaments with two or three ingredients were described in <CIT>, wherein mesalazine is incorporated in a lipophilic matrix dispersed in a hydrophilic matrix, or in three matrices (lipophilic, hydrophilic and amphiphilic), to delay and prolong the dissolution. A matrix system for the release of medicaments with two ingredients, wherein mesalazine is incorporated in a hydrophilic and amphiphilic matrix, has also been described (<CIT>). A gastroresistant polymer film gives rise to pH-dependent dissolution of the tablet at pH <NUM> in the terminal ileum. The monolithic matrix presents the drawback of possible irregular releases in the colonic tract, and the tablet is sometimes expelled before the medicament has been released. Other monolithic matrix systems are described in <CIT>, <CIT>, <CIT> and <CIT>.

The known formulations do not provide the ideal solution to the problem of gradual, constant colonic release of the medicament continuing for several hours so as to guarantee homogeneous distribution, a reproducible release profile, and a very low coefficient of relative standard deviation.

It has now been found that the drawbacks of the known formulations of mesalazine can be eliminated by using complex matrices, consisting of a combination of several polymers having different characteristics.

In particular, it has been found that by combining at least two types of hydroxypropyl methylcellulose having different viscosities with methacrylic acid copolymers soluble at pH ≥ <NUM>, formulations as claimed that overcome the limitations of the previously known formulations can be prepared. The formulations described in <CIT> possess a release profile characterised by a burst effect that is not found in the formulations according to the invention, which exhibit less variability of the dissolution profiles over time, with very low relative standard deviation (RSD) values, always under <NUM>.

The solid oral controlled-release pharmaceutical compositions according to the invention comprise a core containing mesalazine, the salts thereof or an analogue thereof selected from sulphasalazine, olsalazine, balsalazide and salazopyrin and an outer coating of said core, wherein:.

Mesalazine is the preferred active ingredient in all the different embodiments of the invention.

The coating consists of a layer comprising ethylcellulose or, in another embodiment of the invention, coating b) consists of a layer comprising ethylcellulose coated with gastroresistant polymers.

In yet another embodiment of the invention, the coating consists of a gastroresistant layer.

According to one embodiment of the invention, the methacrylic acid copolymer is associated with shellac.

The gastroresistant coating can be the conventional type, and typically comprises methacrylic acid copolymers soluble at pH ≥ <NUM>. Examples of said copolymers are available on the market (Eudragit). Preferably the combination of polymethacrylate L100 with polymethacrylate S100 at the ratio of <NUM>:<NUM> - <NUM>:<NUM> (preferably <NUM>:<NUM>); or L <NUM>/<NUM> soluble at pH ≥ <NUM>; or shellac; or cellulose acetate phthalates/succinates are used.

In the compositions according to preferred embodiments of the invention, the hydroxypropyl methylcellulose having a viscosity ranging between <NUM> and <NUM> mPa. s <NUM>% in H<NUM>O at <NUM> constitutes <NUM> to <NUM>% of the weight of the core, the hydroxypropyl methylcellulose having a viscosity ranging between <NUM> and <NUM> mPa. s <NUM>% in H<NUM>O at <NUM> constitutes <NUM> to <NUM>% of weight of the matrix, and the methacrylic copolymer constitutes <NUM> to <NUM>% of the weight of the core.

Hydroxypropyl methylcellulose having a viscosity ranging between <NUM> and <NUM> mPa. s <NUM>% in H<NUM>O at <NUM> is available on the market under the names of Methocel K3LV, E <NUM> Premium, K100 LV and K4M.

Hydroxypropyl methylcellulose having a viscosity ranging between <NUM> and <NUM> mPa. s <NUM>% in H<NUM>O at <NUM> is available on the market under the names of Methocel K15M, K100 M and K200M.

Ethylcellulose is present in the core-coating layer in percentages ranging from <NUM>% to <NUM>% of the weight of the core, preferably <NUM>%.

The amounts of mesalazine in the compositions according to the invention can range from <NUM> to <NUM> per dosage unit.

The matrix core can comprise conventional excipients such as diluents (microcrystalline cellulose, starches, sugars, hydrated and anhydrous mono/dibasic phosphate/sodium phosphate salts), binders (PVP, starches, cellulose, dextrins, maltodextrins, low-viscosity cellulose), glidants (colloidal silicon dioxides), flow agents (talc), lubricants (Mg stearate, fumaryl stearate, stearic acid, glyceryl behenate), disintegrating agents (croscarmellose, sodium starch glycolate, crosslinked polyvinylpyrrolidone, starches) and other functional excipients (waxes, polycarbophil, carbomer, glycerides).

The matrix is prepared by processes of partition and direct compression, dry granulation, compacting, wet granulation, melting and extrusion.

Powders, granules, microgranules, pellets, mini-tablets, tablets, capsules, sachets and sticks can thus be obtained.

The resulting matrix/mini-matrix can then be coated with a gastroresistant film containing pH-dependent polymers that prevent release for at least <NUM> hours under pH conditions < <NUM>-<NUM>. The following can be used for this purpose: pH-dependent methacrylic acid copolymers soluble at pH ≥ <NUM> (L <NUM>-<NUM>/L <NUM> D-<NUM>); pH-dependent methacrylic acid copolymers soluble at pH <NUM>-<NUM> (L <NUM>/L <NUM>); pH-dependent methacrylic acid copolymers soluble at pH ≥ <NUM> (S <NUM>/S <NUM>/FS 30D); shellac; cellulose acetate phthalate; cellulose succinate.

At a third stage, a core coating can be applied which is alternative and/or additional to and beneath the gastroresistant coating with pH-independent polymers (ethylcellulose or hydroxypropyl methylcellulose with different viscosities), which act as membranes delaying the passage of the ingredient loaded into the matrix/mini-matrix core following contact with biological fluids.

The matrix is coated with a quantity of polymer sufficient to guarantee that it remains intact in gastric and enteric juices for at least <NUM>-<NUM> hours before the release of the active ingredient from the core (lag time). To reduce the impact of variable gastric voiding times, a further (pH-dependent) gastroresistant coating can be applied outside the (pH-independent) matrix core and outside the (pH-independent) cellulose film coating, to further delay contact between the biological fluids and the modified-release core (extended release).

In this way the system prevents early release during the stomach-jejunum transit time, initiating the modulated-release programme lasting up to <NUM> hours and ensuring homogeneous distribution of the active ingredient in the distal ileum and in the ascending, transverse and descending tracts of the large intestine.

The use of hydrophilic polymers with different rheological characteristics (viscosity/swelling properties) combined with pH-dependent and/or pH-independent polymers allows the release to be modulated for between <NUM> and <NUM> hours.

The system according to the invention offers the following advantages over the known monolithic and multiparticulate reservoir matrices:.

The invention is described in greater detail in the examples below.

<NUM> of mesalazine is loaded into a granulator with <NUM> of hydroxypropyl methylcellulose (HPMC K4M), <NUM> of hydroxypropyl methylcellulose (HPMC K100M), <NUM> of polymethacrylate L100 and <NUM> of polymethacrylate S100. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; <NUM> of magnesium stearate, <NUM> of talc and <NUM> of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. This mixture is then compressed to obtain a tablet weighing <NUM>. The resulting tablets are film-coated with a gastroresistant solution/suspension based on <NUM> of polymethacrylate L100, <NUM> of polymethacrylate S100, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate, to obtain a tablet with a mean weight of <NUM>.

When subjected to disintegration and dissolution tests at pH <NUM>, the tablets remain intact for at least <NUM> hours, with release below <NUM>%; when subjected to the dissolution test at pH ≥ <NUM> they exhibit the following release profile: not more than <NUM>% after <NUM> hour, at pH <NUM> not more than <NUM>% after <NUM> hour, and not more than <NUM>% after <NUM> hours; the value must be > <NUM>% after <NUM> hours; and <NUM>% after <NUM> hours.

<NUM> of mesalazine is loaded into a granulator, and wet-granulated with an aqueous solution containing <NUM> of PVP. The resulting granulate is dried, and then placed in a mixer with <NUM> of hydroxypropyl methylcellulose (HPMC K4M), <NUM> of hydroxypropyl methylcellulose (HPMC K100M) and <NUM> of polymethacrylate L100-<NUM>. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; <NUM> of magnesium stearate, <NUM> of talc and <NUM> of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. This mixture is then compressed to obtain a tablet weighing <NUM>. The resulting tablets are film-coated with a solution/suspension of <NUM> of ethylcellulose, <NUM> of talc and <NUM> of triethyl citrate. This is followed by a gastroresistant coating containing <NUM> of polymethacrylate L100-<NUM>, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate, to obtain a tablet with a mean weight of <NUM>.

When subjected to disintegration and dissolution tests at pH <NUM>, the tablets remain intact for at least <NUM> hours, with release below <NUM>%; when subjected to the dissolution test at pH ≥ <NUM> they exhibit the following release profile: not more than <NUM>% after <NUM> hour, at pH <NUM> not more than <NUM>% after <NUM> hour, and not more than <NUM>% after <NUM> hours; not more than <NUM>% after <NUM> hours; less than <NUM>% after <NUM> hours; less than <NUM>% after <NUM> hours; and <NUM>% after <NUM> hours.

<NUM> of mesalazine is loaded into a granulator with <NUM> of hydroxypropyl methylcellulose (HPMC K 100lv), <NUM> of hydroxypropyl methylcellulose (HPMC K100M), <NUM> of polymethacrylate L100, <NUM> of polymethacrylate S100 and <NUM> of shellac. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; <NUM> of magnesium stearate, <NUM> of talc and <NUM> of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. This mixture is then compressed to obtain a tablet weighing <NUM>. The resulting tablets are then film-coated with a solution/suspension of <NUM> of ethylcellulose, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate, to obtain a tablet with a mean weight of <NUM>.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. The resulting granulate is dried, and then placed in a mixer with <NUM> of hydroxypropyl methylcellulose (HPMC K4M), <NUM> of hydroxypropyl methylcellulose (HPMC K100M) and <NUM> of polymethacrylate L100-<NUM>. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; <NUM> of magnesium stearate, <NUM> of talc and <NUM> of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. This mixture is then compressed to obtain a tablet weighing <NUM>. The resulting tablets are then film-coated with a solution/suspension of <NUM> of ethylcellulose, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate, to obtain a tablet with a mean weight of <NUM>.

<NUM> of mesalazine is loaded into a granulator with <NUM> of lactose monohydrate, <NUM> of mannitol, <NUM> of hydroxypropyl methylcellulose (HPMC K 100lv), <NUM> of hydroxypropyl methylcellulose (HPMC K100M), <NUM> of polymethacrylate RL100, <NUM> of polymethacrylate RS100 and <NUM> of shellac. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; <NUM> of magnesium stearate, <NUM> of talc and <NUM> of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. This mixture is then compressed to obtain a tablet weighing <NUM>. The resulting tablets are then film-coated with a solution/suspension of <NUM> of ethylcellulose, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate, to obtain a tablet with a mean weight of <NUM>.

<NUM> of mesalazine is loaded into a granulator with <NUM> of lactose and <NUM> of microcrystalline cellulose, and wet-granulated with an aqueous solution containing <NUM> of PVP. <NUM> of hydroxypropyl methylcellulose (HPMC K 100lv), <NUM> of hydroxypropyl methylcellulose (HPMC K15M), <NUM> of polymethacrylate RL <NUM> and <NUM> of polymethacrylate RS <NUM> are added in sequence to the resulting granulate after drying. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. This mixture will form part of the first, controlled-release layer of the tablet.

<NUM> of mesalazine is loaded into a second granulator. <NUM> of microcrystalline cellulose, <NUM> of lactose monohydrate, <NUM> of crospovidone, <NUM> of croscarmellose, <NUM> of magnesium stearate and <NUM> of talc are added and homogeneously mixed. The mixture is then homogenised for at least <NUM> minutes. This mixture will form part of the second, immediate-release layer of the tablet. The two separate mixtures are then compressed to obtain a double-layer tablet weighing <NUM>. The resulting tablets are then film-coated with a solution/suspension of <NUM> of ethylcellulose, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate, to obtain a tablet with a mean weight of <NUM>.

<NUM> of mesalazine is loaded into a granulator with <NUM> of hydroxypropyl methylcellulose (HPMC K4M), <NUM> of hydroxypropyl methylcellulose (HPMC K100M), <NUM> of polymethacrylate L <NUM>, <NUM> of polymethacrylate S <NUM> and <NUM> of shellac. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained; <NUM> of magnesium stearate, <NUM> of talc and <NUM> of colloidal silicon dioxide are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. This mixture is then compressed to obtain a tablet weighing <NUM>. The resulting tablets are then film-coated with a gastroresistant solution/suspension based on <NUM> of shellac, <NUM> of hydroxypropyl methylcellulose E <NUM> Premium, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate to obtain a mini-tablet with a mean weight of <NUM>.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. After drying, <NUM> of hydroxypropyl methylcellulose (HPMC K4M), <NUM> of hydroxypropyl methylcellulose (HPMC K100M), <NUM> of polymethacrylate L <NUM> and <NUM> of polymethacrylate S <NUM> are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. The mixture is then compressed to obtain a mini-tablet weighing <NUM>. The resulting mini-tablets are then film-coated with a gastroresistant solution of <NUM> of polymethacrylate L <NUM>, <NUM> of polymethacrylate S <NUM>, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate, to obtain a mini-tablet with a mean weight of <NUM>. When subjected to disintegration and dissolution tests at pH <NUM>, the tablets remain intact for at least <NUM> hours, with release ≤ <NUM>%; when subjected to the dissolution test at pH ≥ <NUM>, the tablets exhibit a release not exceeding <NUM>% after <NUM> minutes; when subjected to the dissolution test at pH ≥ <NUM> they exhibit the following release profile: not more than <NUM>% after <NUM> minutes; not more than <NUM>% after <NUM> minutes, not less than <NUM>% after <NUM> minutes; the value must be <NUM>% after <NUM> hours.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. After drying, <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>) and <NUM> of polymethacrylate L <NUM>-<NUM> are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. The mixture is then compressed to obtain a mini-tablet weighing <NUM>. The mini-tablets thus obtained are then film-coated with a solution/suspension of <NUM> of ethylcellulose and <NUM> of triethyl citrate; then further film-coated with a gastroresistant solution of <NUM> of polymethacrylate L <NUM>-<NUM>, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate to obtain a mini-tablet with a mean weight of <NUM>.

When subjected to disintegration and dissolution tests at pH <NUM>, the tablets remain intact for at least <NUM> hours, with release ≤ <NUM>%; when subjected to the dissolution test at pH ≥ <NUM>, the tablets exhibit a release not exceeding <NUM>% after <NUM> minutes; when subjected to the dissolution test at pH ≥ <NUM> they exhibit the following release profile: not more than <NUM>% after <NUM> minutes; not more than <NUM>% after <NUM> minutes, and not less than <NUM>% after <NUM> minutes; the value must be <NUM>% after <NUM> hours.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. After drying, <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of polymethacrylate L <NUM> and <NUM> of polymethacrylate S <NUM> are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. The mixture is then compressed to obtain a mini-tablet weighing <NUM>. The resulting mini-tablets are film-coated with a solution/suspension of <NUM> of ethylcellulose, <NUM> of triethyl citrate, <NUM> of talc and <NUM> of titanium dioxide to obtain a mini-tablet with a mean weight of <NUM>.

When subjected to disintegration and dissolution tests at pH <NUM>, the tablets remain intact for at least <NUM> hours, with release ≤ <NUM>%; when subjected to the dissolution test at pH ≥ <NUM>, the tablets exhibit a release not exceeding <NUM>% after <NUM> hour; when subjected to the dissolution test at pH ≥ <NUM> they exhibit the following release profile: not more than <NUM>% after <NUM> hour; not more than <NUM>% after <NUM> hours, not more than <NUM>% after <NUM> hours; the value must be ≥ <NUM>% after <NUM> hours; and must reach <NUM>% after <NUM> hours.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. After drying, <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>) and <NUM> of polymethacrylate L <NUM>-<NUM> are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. The mixture is then compressed to obtain a mini-tablet weighing <NUM>. The resulting mini-tablets are film-coated with a solution/suspension of <NUM> of ethylcellulose, <NUM> of triethyl citrate, <NUM> of talc and <NUM> of titanium dioxide to obtain a mini-tablet with a mean weight of <NUM>.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. After drying, <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of polymethacrylate L <NUM> and <NUM> of polymethacrylate S <NUM> are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. The mixture is then compressed to obtain a mini-tablet weighing <NUM>. The resulting mini-tablets are film-coated with a gastroresistant solution/suspension of <NUM> of polymethacrylate L <NUM>, <NUM> of polymethacrylate S <NUM>, <NUM> of triethyl citrate, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of iron oxide to obtain a mini-tablet with a mean weight of <NUM>.

When subjected to disintegration and dissolution tests at pH <NUM>, the tablets remain intact for at least <NUM> hours, with release ≤ <NUM>%; when subjected to the dissolution test at pH ≥ <NUM>, the tablets exhibit a release not exceeding <NUM>% after <NUM> hour; when subjected to the dissolution test at pH ≥ <NUM> they exhibit the following release profile: not more than <NUM>% after <NUM> hour; not more than <NUM>% after <NUM> hours, and not less than <NUM>% after <NUM> hours; the value must be ≥ <NUM>% after <NUM> hours; and must reach <NUM>% after <NUM> hours.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. After drying, <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of polymethacrylate L <NUM> and <NUM> of polymethacrylate S <NUM> are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. The mixture is then compressed to obtain a mini-tablet weighing <NUM>. The resulting mini-tablets are film-coated with a solution/suspension of <NUM> of ethylcellulose, <NUM> of triethyl citrate, <NUM> of titanium dioxide and <NUM> of iron oxide to obtain a mini-tablet with a mean weight of <NUM>.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. After drying, <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of polymethacrylate RL <NUM>, <NUM> of polymethacrylate RS <NUM> and <NUM> of shellac are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. The mixture is then compressed to obtain a mini-tablet weighing <NUM>. The resulting mini-tablets are then film-coated with a gastroresistant solution/suspension of <NUM> of shellac, <NUM> of hydroxypropyl methylcellulose E <NUM> Premium, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate to obtain a mini-tablet with a mean weight of <NUM>.

When subjected to disintegration and dissolution tests at pH <NUM>, the tablets remain intact for at least <NUM> hours, with release ≤ <NUM>%; when subjected to the dissolution test at pH ≥ <NUM>, the tablets exhibit a release not exceeding <NUM>% after <NUM> minutes; when subjected to the dissolution test at pH ≥ <NUM> they exhibit the following release profile: not more than <NUM>% after <NUM> minutes; not more than <NUM>% after <NUM> minutes, not less than <NUM>% after <NUM> minutes; the value must be <NUM>% after <NUM> hours.

<NUM> of mesalazine is loaded into a granulator and wet-granulated with an aqueous solution containing <NUM> of PVP. After drying, <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM> lv), <NUM> of hydroxypropyl methylcellulose (HPMC K <NUM>), <NUM> of polymethacrylate L <NUM> and <NUM> of polymethacrylate S <NUM> are added to the resulting granulate. The ingredients are mixed until a homogeneous dispersion of active ingredient in the matrices is obtained. <NUM> of talc, <NUM> of colloidal silicon dioxide and <NUM> of magnesium stearate are then added in sequence. The mixture is then homogenised for at least <NUM> minutes. The mixture is then compressed to obtain a mini-tablet weighing <NUM>. The resulting mini-tablets are then film-coated with a gastroresistant solution of <NUM> of polymethacrylate L <NUM>, <NUM> of polymethacrylate S <NUM>, <NUM> of talc, <NUM> of titanium dioxide and <NUM> of triethyl citrate, to obtain a mini-tablet with a mean weight of <NUM>.

Table <NUM> below summarises the qualitative and quantitative compositions of Examples <NUM>-<NUM>.

Claim 1:
A controlled-release solid oral pharmaceutical composition comprising a core containing mesalazine, the salts thereof or an analogue thereof selected from sulphasalazine, olsalazine, balsalazide and salazopyrin, and an outer coating of said core, characterised in that:
a) the core consists of:
a monolithic matrix containing mesalazine, the salts or an analogue thereof, at least one hydroxypropyl methylcellulose having a viscosity ranging between <NUM> and <NUM> mPa.s <NUM>% in H<NUM>O at <NUM>, at least one hydroxypropyl methylcellulose having a viscosity ranging between <NUM> and <NUM> mPa.s <NUM>% in H<NUM>O at <NUM>, at least one or more methacrylic acid copolymers soluble at pH ≥ <NUM>,
b) the coating consists of a layer comprising ethylcellulose or of a gastroresistant layer.