Patent ID: 12201729

DETAILED DESCRIPTION

The present invention relates to a process for the preparation of a solid pharmaceutical formulation comprising 70-95%, preferably 80-90% of mesalazine and/or a salt thereof and/or a derivative thereof, preferably for oral use, said process comprising the steps of:(i) preparing a powder bed comprising mesalazine and/or a salt thereof and/or a derivative thereof and possibly also at least one pharmacologically acceptable excipient;(ii) adding to the powder according to step (i) an aqueous solution comprising 10-20% of a binding agent, preferably polyvinylpyrrolidone, so as to obtain a granulate, said granulate being characterised by a moisture content ranging from 20 to 40%;(iii) drying the granulate obtained from step (ii) until reaching a moisture content lower than or equal to 3.0%, preferably comprised between 2.5 and 3.0%;(iv) mixing the granulate dried according to step (iii) with at least one disintegrating agent;(v) adding water to the granulate obtained from step (iv) until reaching a moisture content ranging from 3.0 to 3.5%; and(vi) compacting the granulate, preferably after having added at least one lubricant agent.

Preferably in step (i) the excipients are at least one diluent agent and/or a disintegrating agent.

The diluent agents according to the present invention are preferably selected from among: cellulose, polyols, starch derivatives and mixtures thereof. More preferably, said diluents are selected from among: mannitol, starch, corn starch, microcrystalline cellulose, maltodextrin and mixtures thereof.

The disintegrating agents according to the present invention are preferably selected from among: starch derivatives, cellulose and polyvinylpyrrolidone derivatives, preferably sodium carboxymethyl starch, croscarmellose sodium, crospovidone, modified starch and pregelatinized starch.

The binding agents according to the present invention are preferably selected from among: polyvinylpyrrolidone, povidone, preferably PVP K30, and cellulose derivatives, preferably: hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose or a mixture thereof.

The aqueous solution of binding agent is preferably added through a nozzle, which may be pressurized or not, and is preferably supplied by a peristaltic pump. The solution is added to the powder bed and subsequently further water can be added until an effort of the mixer blade preferably ranging from 1000 to 1800 Nm and/or a water level in the powder mixture preferably ranging from 30% to 40% is reached.

The drying according to step (iii) is preferably carried out in a vacuum or ventilated static oven, or in a fluid bed.

The temperature of the drying step preferably ranges from 45 to 70° C. for the oven, whereas the incoming air in the case of the fluid bed has a temperature that preferably ranges from 65 to 85° C., more preferably from 70 to 80° C.

After drying a disintegrating agent is preferably added to the granulate.

The disintegrating agents are preferably those described above.

The compacting according to step (vi) preferably takes place by applying a force comprised between 30 and 50 KN.

The lubricant agents according to the present invention are preferably selected from among: anhydrous colloidal silica, talc, magnesium stearate, glyceryl behenate, sodium stearyl fumarate and mixtures thereof.

Following the compacting step, it is possible to calibrate the granulate, preferably using a metal mesh characterized by mesh sizes that preferably range from 0.85 to 1.5 mm. Finally, the granulate, preferably calibrated, is mixed with at least one lubricant and/or glidant agent.

Steps (i)-(iii) define a step of the process also known as wet granulation.

Steps (iv) and (v) define a step of the process also known as granulate rewetting step.

In the last step (vi) the granulate is compacted and this step is also known as dry granulation.

Preferably, the apparent density of the granulate obtained/obtainable with the process according to the invention ranges on average from 0.60 to 0.75 g/ml, more preferably from 0.65 to 0.75 g/ml.

Preferably, the packing density of the granulate obtained/obtainable with the process according to the invention ranges on average from 0.70 to 0.85 g/ml, more preferably from 0.75 to 0.85 g/ml.

Preferably the average size of the granulate obtained/obtainable with the process according to the invention is for 100% of the particles lower than or equal to 1.5 mm.

In some preferred embodiments of the invention, the granulate obtained/obtainable from the process described above is further processed for the purpose of obtaining a further solid pharmaceutical form, preferably tablets, also characterised by 70-95%, preferably 80-90%, of mesalazine and/or a salt thereof and/or a derivative thereof. Therefore, in the tablets the quantity of mesalazine (active ingredient) preferably ranges from 1000 to 1600 mg.

Preferably, the tablets according to the present invention while having a high concentration of mesalazine (active ingredient) are characterized by physical parameters, in particular friability, hardness, disintegration and weight uniformity, which are suitable and optimal for allowing a subsequent coating step to enable the controlled release of this drug.

With the formulation processes currently available, it is not possible to obtain the same result, maintaining a release of the drug that is simultaneously complete and immediate so that it can perform its topical action.

Preferably the tablets obtained with the process according to the present invention are characterized by friability ranging from 0.000% to 1.000%, more preferably ranging from 0.000% to 0.250%.

Preferably the tablets obtained with the process according to the present invention are characterized by hardness preferably higher than 6 Kp, more preferably comprised between 10Kp and 30Kp.

Preferably the tablets obtained with the process according to the present invention are characterised by disintegration in less than 15 minutes.

Preferably the tablets obtained with the process according to the present invention comprise at least one coating (coat, layer, film) for the controlled release of the drug.

The methods and substances used to coat the tablets are those known in the prior art. Preferably the coating is a pH-dependent coating that preferably comprises at least one of the following compounds: polymers and copolymers of methacrylic acid, plasticizing agents, pigments and glidant agents. In a preferred embodiment of the invention the mesalazine used has the following characteristics:apparent density ranging from 0.15 to 0.35 g/ml, preferably from 0.20 to 0.30 g/ml, where apparent density means the density of a powder as poured, measured in g/ml; and/orpacking density ≥0.4 g/ml, where packing density means the density of a powder subjected to packing through a specific test and is measured in g/ml; and/orparticle size distribution (PSD) for 100% of the particles ≤90 μm, preferably ≤70 μm; of which:D90 comprised between 30 and 45 μm, preferably between 35 and 40 μm; and/orD50 comprised between 5 and 20 μm, preferably between 10 and 15 μm.

Where particle size distribution means the distribution on a statistical basis of the size of a powder/granulate measured in μm; D90 means the dimensional value below which 90% of the population is found; D50 means the dimensional value below which 50% of the population is found.

A further aspect of the present invention relates to a granulate obtained/obtainable with the process described above. Said granulate is preferably characterized by a quantity of mesalazine and/or a salt thereof and/or a derivative thereof ranging from 70 to 95%, preferably from 80 to 90%, and/or an average density ranging from 0.65 to 0.85 g/ml, of which preferably the apparent density ranges from 0.60 to 0.75 and/or more preferably from 0.65 to 0.75 g/ml and the packing density ranges on average from 0.70 to 0.85 g/ml, more preferably 0.75 to 0.85 g/ml and/or with an average size for 100% lower than or equal to 1.5 mm.

A further aspect of the present invention relates to the tablets obtained/obtainable through the process described above characterized by a quantity of mesalazine and/or a salt thereof and/or a derivative thereof ranging from 70 to 95%, preferably from 80 to 90% i.e. from 1000 to 1600 mg and preferably by at least one of the following physical parameters:friability preferably ranging from 0.000% to 1.000%, more preferably ranging from 0.000% to 0.250%; and/orhardness preferably higher than 6 Kp, more preferably comprised from 10 Kp to 30 Kp; and/ordisintegration preferably less than 15 minutes.

Preferably the tablets are gastro-resistant and/or modified release tablets.

A further aspect of the invention relates to the granulate and/or the tablets described above or a process for producing a medicament, preferably for use in the treatment of an inflammation-based pathology, more preferably of the chronic type.

The chronic inflammatory pathologies to which the present invention refers are preferably those affecting the intestinal tract, more preferably ulcerous colitis and Crohn's disease.

Treatment is preferably by topical use. Administration is preferably oral.

EXAMPLE

The process according to the present invention was used by way of example for the preparation of solid pharmaceutical formulations with a high content of mesalazine as the active ingredient, in particular in quantities of 1200 mg/tablet.

The first step involves the dry mixing of a composition comprising the ingredients in Table I:

TABLE I%Mesalazine83.33Microcrystalline cellulose2.85Sodium starch glycolate2.50Corn starch2.08Mannitol1.56

In particular, in this embodiment the quantities specified in Table Il were mixed.

TABLE IIAmountKgMESALAZINE200.00MICROCRYSTALLINE CELLULOSE6.85MANNITOL3.75SODIUM STARCH GLYCOLATE6.00STARCH5.00

Then, the process involves a wet granulation step. In this specific case, a High Shear Mixer was used.

Wet granulation consists in wetting the mixture of Table Il in the form of a powder bed with an 11% polyvinylpyrrolidone K30 (PVPK30) aqueous solution supplied by a peristaltic pump which, in particular, works at the flow rate of 4 L/min.

In order to reach the granulation end point, more water is generally added.

Usually, the wet granulation end point is reached when the measured effort of the mixer blade is between 1000-1800 Nm and the water content is 30-40%.

This is followed by a drying step which takes place in a static oven, which may be ventilated or vacuum, at a temperature comprised between 55-60° C. This step may also be performed in a fluid bed.

The granulate is considered dry when the LOD—loss on drying—is less than or equal to 2.5-3.0%.

At this point of the process, the residual water content in the product is fundamental. In fact, it has been demonstrated that a relative humidity degree comprised between 2.5-3.5% allows performing the subsequent steps until compression, thus obtaining the desired characteristics of the cores.

Since it is difficult to control such parameter during drying, it is necessary to rewet the granulate for the purpose of complying with the limits specified above. Therefore, once the drying step has finished, a rewetting step is carried out.

In the case of the fluid bed, such step may take place in a continuous equipment, following the drying step.

A compacting step of the granulate previously mixed with a disintegrating agent and magnesium stearate is then performed, through a roller compactor by applying a pressure comprised between 35 and 45 kN.

Subsequently, downstream of this system there is an oscillating granulator that has the aim of calibrating the belt coming out from the rollers thus producing a granulate with dimensions of less than 1.5 mm.

A further mixing step with only magnesium stearate follows.

Finally, a rotary tablet press allows tablets of active ingredient to be obtained that may be coated so as to be gastro-resistant. Table III below shows the composition of the gastro-resistant mesalazine tablets obtained with the process according to the present invention.

TABLE IIICORE COMPONENTSmg/tabletMESALAZINE1200.00MICROCRYSTALLINE CELLULOSE 10241.10CORN STARCH30.00MANNITOL22.50POLYVINYLPYRROLIDONE K3045.00SODIUM CARBOXYMETHYL STARCH75.00MAGNESIUM STEARATE26.40FILM COMPONENTSmg/tabletMETHACRYLIC ACID COPOLYMERS35.72TRIETHYL CITRATE17.89RED IRON OXIDE2.55TITANIUM DIOXIDE5.95TALC17.89

For the purpose of obtaining cores with a high drug load, the inventors have found the technical characteristics of the active ingredient used to be critical, in particular the following physical characteristics of mesalazine: PSD-particle size distribution, apparent and packing density were critical, in particular, for obtaining maximum reliability and repeatability of the process.

Preferably, the active ingredient, in the case of mesalazine, must have the characteristics summarized in Table IV.

TABLE IVPARAMETERSPECIFICATIONSAPPARENT DENSITY-g/ml0.2-0.3PACKING DENSITY-g/ml≥0.4PSD-μm100% < 70D90-μm35-40D50-μm10-15