FORMULATIONS IN MODIFIED-RELEASE TABLETS CONTAINING HIGH-DOSAGE MESALAZINE, PROCESS FOR THEIR PREPARATION AND THEIR USE

Field of the invention

The present invention relates to the field of formulations for the administration of Mesalazine in the form of modified-release tablets.

Prior art

Mesalazine, also known as 5-aminosalicylic acid, generally abbreviated as 5-ASA, is an active ingredient now widely known as the best medication in treating inflammation in the colon, and is the best adjuvant in ulcerative colitis and Crohn's disease maintenance and improvement therapies.

Mesalazine is a derivative of acetylsalicylic acid and has the anti-inflammatory characteristics thereof but has the advantage of acting only at a topical intestinal level, thus avoiding the systemic absorption; hence, the need arises to formulate preparations which have a specific release only at the level of the action zone, i.e. the colon.

Available on the market in different pharmaceutical forms, it is often employed with high dosages that very often worsen the patient compliance in taking the drug, since the amount of the medicine is either too large or should be split into multiple doses. For this reasons, studies have been directed to the production of formulations having such a concentration of Mesalazine that allows to reduce the total amount to be taken and improving the acceptability of the patient.

Patent EP1287822A2 relates to a dual-matrix formulation of Mesalazine: an inner inert matrix of a waxy nature, with melting point below 90°, is mixed with an outer matrix of hydrophilic nature. The active ingredient may be present only in the inner matrix or also partially in the outer one.

On the other hand, patent EP1 178781 B1 relates to a formulation containing Mesalazine which only releases in the colon.

This is a multilayer consisting of a core containing the active ingredient, a first inner layer containing a pH-independent retardant polymer and a second outer layer containing a pH-dependent polymer which only releases in the colon. Patent W098/26767 relates to a tablet, pellet, capsule, microtablet, granule or crystal formulation containing Mesalazine, formulated in such a way as to release only when it reaches the site of action, i.e. the colon.

Patent WO03/032952A1 describes a formulation containing delayed-release Mesalazine. Granules are produced by extrusion and are subsequently coated with retardant polymers and subsequently compressed.

Patent US2007/0043004 A1 describes a formulation in sachet containing delayed- release Mesalazine granules. The granules have the feature of having a high content of I PA (92-98%).

Patent WO92/1 6206 A1 describes formulations containing delayed-release Mesalazine to have an effect at a topical intestinal level. They are generally in the form of tablets and may be delayed-release or sustained-release. In the first case, the tablets are coated with enteric polymers that release the IPA only after passing through the stomach; in the second one, instead, the polymers placed inside the tablet to have a matrix effect are pH-independent and have a constant release over time.

Patent WO2010/077908 A1 describes formulations in pellets containing delayed- release Mesalazine to have an effect at a topical intestinal level.

Patent US2003/0152627 A1 describes a formulation in pellets (which are then compressed or encapsulated) containing Mesalazine with topical intestinal release. As can be seen, the prior art has tried to solve the efficacy/compliance problem essentially with formulations which, besides the obvious release of the active ingredient in the colon, tend to delay the therapeutic action thereof so as to prolong the effect thereof.

However, in this way there is the risk that the active ingredient may not be totally released and is thus eliminated before completely carrying out its therapeutic action on the patient as would be necessary.

Therefore, the importance of having a formulation which, in addition to the absorption of Mesalazine only in the colon, also allows to fully carry out the therapeutic action thereof, is clear. Summary of the invention

There are described tablets consisting of at least one gastro-resistant coating and a core containing Mesalazine in combination with a solubilizing, low viscosity hydrophilic excipient.

Detailed description of the invention

The present invention allows to overcome the above problems with a formulation in tablet form consisting of at least one gastro-resistant coating and a core containing Mesalazine and a solubilizing, low viscosity hydrophilic excipient.

Of course, the core may then contain other excipients normally used in pharmacopeia in the composition of tablets of this type, such as: lubricants (such as: magnesium stearate, glycerol dibehenate, stearic acid, sodium stearyl fumarate), glidants (such as: colloidal anhydrous silica), binders (such as polyvinylpyrrolidone, sucrose, hydroxypropylcellulose).

The amount of Mesalazine in the tablets according to the invention is normally in the range from 500 mg to 2000 mg, an amount corresponding to 70%-95% calculated by weight on the total weight of the tablet.

For example, the core of a tablet according to the invention may have the following composition:

Mesalazine 75%-96% calculated by weight on the weight of the core;

solubilizing hydrophilic excipient 2%-20%;

binders 1 %-5%,

lubricants 0.005%-0.5%

glidants 0.005%-0.5%

According to the invention, solubilizing hydrophilic excipient means a product capable of modifying the release of Mesalazine, such as any polymer having hydrophilic features which can act as a modifier of the release by solubilization with subsequent erosion of the core.

The preferred solubilizing agents are low molecular weight cellulose derivatives, such as: hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose having viscosity lower than 100 cps, preferably lower than 70 cps, more preferably lower than 40 cps; hydroxypropylmethylcellulose having the indicated viscosities is particularly preferred.

The gastro-resistant coating is of a known type and consists of polymers which, having pH-dependent features, lead to have a release of the active ingredient only when the tablet reaches high pH values, i.e. in the colon.

This behavior is due to the presence of carboxylic groups which, in acidic environment, are hydrogenated and devoid of charge, thus insoluble, but which become soluble when they lose the hydrogen in basic environment, due to the appearance of a negative charge.

The coating may consist of only one of the polymers listed above or of an association thereof in ratios in the range from 95:5 to 5:95.

Preferred for this purpose are methacrylic acid derivatives, preferably methacrylic acid anionic polymers, even more preferably methacrylic acid anionic copolymers and methyl acrylates (also known as type A and type B Copolymers, such as Eudragit S and Eudragit L).

If preferred, the coating may also be formed by two or more superimposed coatings containing different polymers or in different ratios, with the purpose of adjusting the release to the desired pH.

The coating may then comprise any plasticizers (such as: triethyl citrate, dibutyl phthalate, triacetin, castor oil, medium chain triglycerides, polyethylene glycol), opacifiers (such as: titanium dioxide, talc), dyes (such as: iron oxides, indigotine, erythrosine), antisticking agents (such as: talc, colloidal anhydrous silica, magnesium stearate), etc.

Normally, the coating is 5%-15% with respect to the total weight of the tablet.

It is noted that unlike the prior art formulation, in which the modification of the core release is carried out by a retardant agent, sometimes of a waxy lipophilic nature, sometimes of a high viscosity hydrophilic polymer nature, the core of the tablet according to the present invention does not require retardants, since the compressed active ingredient surprisingly creates a kind of matrix that is sufficient per se to delay the release, to the extent that it is necessary to use the solubilizing hydrophilic excipient which speeds up the release so as to obtain a tablet that, after the dissolution of the gastro-resistant coating, leads to the total release of the active ingredient in the site of action, thus ensuring full bioavailability and therapeutic efficacy, with the advantage of sill maintaining a sustained release profile over time. In the absence of the solubilizing hydrophilic excipient, there would be only a partial release of active ingredient, since the delaying effect given by the matrix formed by the compression of Mesalazine alone would be too strong; a reduction of this delaying effect is achieved by introducing a solubilizer.

As the amount of solubilizing agent increases, the speed at which the core is eroded increases and as a result, there will be a more sudden release of Mesalazine.

The tablet according to the invention is produced using the normal processes used in the pharmacopoeia for the production of this type of tablets.

The core is first formed, which is produced by compression using a conventional rotary tablet press.

Such a compression may occur either by direct compression of the mixture consisting of Mesalazine and excipients, or by compression of a granulate produced in advance, which ensures a better flowing in the tablet press.

The possible granulations are of various types, such as melt extrusion, granulation by compaction, wet granulation, etc.

Particularly in the case of wet granulation, the mixture of Mesalazine and the solubilizing hydrophilic excipient, after mixing, is wetted with water or with a solution containing water and a binding agent, such as polyvinylpyrrolidone; then, the granules are formed by passing the wet compound in a vibrating screen and forcing it through the mesh of a dome extruder.

After drying the previously obtained granulate, the addition of excipients useful for the compression may be optionally provided, such as lubricants (e.g. Magnesium stearate) and glidants (e.g. colloidal anhydrous silica) to improve the flowability of the granulate and prevent the attachment to the punches.

The cores containing Mesalazine thus obtained are then coated with a gastro- resistant coating as described above.

The application of the coating to the core is also carried out according to the standard techniques used in the pharmacopoeia for this purpose: the polymers dissolved in organic solution (such as acetone, ethanol, isopropanol) or suspended in an aqueous suspension are applied to the core, for example by means of coating pans, preferably automated coating pans.

The tablet, once taken, will remain completely intact both in the stomach and in the first part of the intestine, then beginning to melt once it reaches the colon.

Here, the slow dissolution of the membrane, associated with the solubilizing action of the solubilizing hydrophilic excipient, will lead to a gradual and prolonged release of Mesalazine.

If only the gastro-resistant membrane effect was used, there would not be a full dissolution of Mesalazine since the core would remain partially intact while if only the modified-release effect of the core was used, the formulation would have an inappropriate behavior since there would not be a specificity of dissolution in the colon.

The amount of solubilizing polymer, the ratio between enteric polymers as well as the amount of coating allows to obtain the desired release profiles.

In particular, the amount of solubilizing agent should be properly dosed, since an excessive amount would result in a too sudden release of IPA which would be poorly absorbed and partially eliminated prior to the absorption, since the maximum absorption concentration would be reached in too short a period.

A prolonged release is also needed to ensure the action specificity of the drug: in fact, under altered intestinal pH conditions, the gastro-resistant membrane may dissolve in unsuitable areas, even far from the colon. In this way, the drug would be totally wasted, as it would not act in its site of action; a prolonged release of the drug instead bypasses this problem because, even if the membrane would dissolve too soon, a part of the active ingredient could still reach the site of action.

By way of clarification, below are some examples of formulations according to the invention which describe the production methods in detail. EXAMPLE 1

Tablets are prepared, containing Mesalazine at the dose of 1200 mg/TBL, having the following composition:

The tablets have an amount of solubilizing agent equal to 8.6% with respect to the total weight of the core and a total amount of gastro-resistant coating of 138.7 mg, divided into two separate membranes that differ in the ratio of methacrylic acid copolymers (1 st coating - ratio Type B/Type A 30:70 / 2nd coating - ratio Type B/Type A 10:90).

The tablets are produced according to the following method:

Mesalazine and HPMC are mixed and then wetted in cutter with PVP dissolved in water; this mixture is then extruded in a dome extruder and then sieved by a vibrating screen. After drying in F.V. cabinet, the granulate is mixed with the compression excipients.

The mixture is processed in a 20-punch rotary tablet press, obtaining 21 mm x 10 mm size tablets.

The tablets are placed in an automated coating pan and coated sequentially with the two gastro-resistant coatings. The preparation of the membrane for coating is made by dissolving the gastro-resistant polymers in Acetone:Ethanol:Water at a concentration of 6.67%, then incorporating the remaining components under homogenization.

The tablets are analyzed with 100 rpm paddle, initially for 2 h in HCI 0.1 N/1000 ml_, then the tablets are transferred in Na3P0 ₄ 0.2 M pH 7.5/1000 ml_, obtaining the following release profile:

EXAMPLE 2

Tablets are prepared, containing Mesalazine at the dose of 1200 mg/TBL, having the following composition:

The tablets have an amount of solubilizing agent equal to 6.2% with respect to the total weight of the core and a total amount of gastro-resistant coating of 141 mg, divided into two separate membranes that differ in the ratio of methacrylic acid copolymers (1 st coating - ratio Type B/Type A 40:60 / 2nd coating - ratio Type B/Type A 20:80).

The tablets are produced according to the following method:

Mesalazine and HPMC are mixed and then wetted in cutter with PVP dissolved in water; this mixture is then sieved by vibrating screen. After drying in F.V. cabinet, the granulate is mixed with the compression excipients.

The mixture is processed in a 20-punch rotary tablet press, obtaining 21 mm x 10 mm size tablets.

The tablets are placed in an automated coating pan and coated sequentially with the two gastro-resistant coatings. The preparation of the membrane for coating is made by dissolving the gastro-resistant polymers in Acetone:Ethanol:Water at a concentration of 7.3%, then incorporating the remaining components under homogenization.

The tablets are analyzed with 100 rpm paddle, initially for 2h in HCI 0.1 N/1000 ml_, then the tablets are transferred in Na ₃ P0 ₄ , 0.2 M pH 7.5/1000 imL, obtaining the following release profile:

EXAMPLE 3

Tablets are prepared, containing Mesalazine at the dose of 1200 mg/TBL, having the following composition:

The tablets have an amount of solubilizing agent equal to 10.6% with respect to the total weight of the core and a total amount of gastro-resistant coating of 162 mg, divided into two separate membranes that differ in the ratio of methacrylic acid copolymers (1 st coating - ratio Type B/Type A 25:75 / 2nd coating - ratio Type B/Type A 15:85).

The tablets are produced according to the following method:

Mesalazine and HPMC are mixed and then wetted in cutter with PVP dissolved in water; this mixture is then sieved by a vibrating screen. After drying in F.V. cabinet, the granulate is mixed with the compression excipients.

The mixture is processed in a 20-punch rotary tablet press, obtaining 21 mm x 10 mm size tablets.

The tablets are placed in an automated coating pan and coated sequentially with the two gastro-resistant coatings. The preparation of the membrane for coating is made by dissolving the gastro-resistant polymers in Acetone:Ethanol:Water at a concentration of 6.9%, then incorporating the remaining components under homogenization.

The tablets are analyzed with 100 rpm paddle, initially for 2 h in HCI 0.1 N/1000 ml_, then the tablets are transferred in Na ₃ P0 ₄ 0.2 M pH 7.5/1000 imL, obtaining the following release profile:

Tablets are prepared, containing Mesalazine at the dose of 1200 mg/TBL, having the following composition:

The tablets have an amount of solubilizing agent equal to 9.9% with respect to the total weight of the core and an amount of gastro-resistant coating of 144.2 mg, applied in a single step and containing 2 types of methacrylic acid copolymer in different amounts (Type B / Type A ratio 1 5:85).

The tablets are produced according to the following method:

Mesalazine and HPMC are mixed and then wetted in cutter with PVP dissolved in water; this mixture is then extruded in a dome extruder and then sieved by a vibrating screen. After drying in F.V. cabinet, the granulate is mixed with the compression excipient.

The mixture is processed in a 20-punch rotary tablet press, obtaining 21 mm x 10 mm size tablets. The tablets are placed in an automated coating pan and coated with the gastro- resistant coating. The preparation of the membrane for coating is made by dissolving the gastro-resistant polymers in Acetone:Ethanol:Water at a concentration of 6.7%, then incorporating the remaining components under homogenization.

The tablets are analyzed with 100 rpm paddle, initially for 2 h in HCI 0.1 N/1000 ml_, then the tablets are transferred in Na3P0 ₄ 0.2 M pH 7.5/1000 ml_, obtaining the following release profile: