Process for mesalazine solid formulations

Abstract

The present invention relates to a process to prepare solid pharmaceutical forms comprising a quantity of mesalazine comprised between 75 and 95%, i.e. between 1000 and 1600 mg of drug per dosage unit. Furthermore, the present invention relates to a granulate and/or tablets obtained/obtainable with the process according to the invention, preferably coated to allow the controlled release of the drug. Finally, the present invention relates to the use of the granulate and/or the tablets as a medicament, preferably for the treatment of chronic inflammatory pathologies that preferably affect the intestinal tract.

Claims

1. A process for preparing a solid pharmaceutical formulation comprising based on a total weight of said solid pharmaceutical formulation from 70% to 95% by weight of mesalazine and/or a salt thereof and/or a derivative thereof, said process comprising the steps of: (i) preparing a powder bed comprising mesalazine and/or a salt thereof and/or a derivative thereof and optionally also at least one pharmacologically acceptable excipient; (ii) adding to the powder according to step (i) an aqueous solution comprising from 10% to 20% of a binding agent so as to obtain a granulate of the mixture characterized 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%; (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 obtained from step (v).

2. The process according to claim 1, wherein said excipient according to step (i) is a diluent agent and/or a disintegrating agent, where said diluent agent is selected from the group consisting of cellulose, polyols, starch derivates and mixtures thereof; and/or said disintegrating agent is selected from the group consisting of starch, cellulose and polyvinylpyrrolidone derivatives.

3. The process according to claim 1, wherein said binding agent according to step (ii) is selected from the group consisting of polyvinylpyrrolidone, povidone, and cellulose derivatives.

4. The process according to claim 1, wherein the drying according to step (iii) is carried out in a vacuum or ventilated static oven at a temperature ranging from 45° C. to 70° C., or in a fluid bed with incoming air ranging from 65° C. to 85° C.

5. The process according to claim 1, further comprising, prior to the compacting step, the step of adding at least one lubricating agent to the granulate.

6. The process according to claim 5, wherein said lubricating agent is selected from the group consisting of anhydrous colloidal silica, talc, magnesium stearate, glyceryl behenate, sodium stearyl fumarate and mixtures thereof.

7. The process according to claim 1, further comprising a step of calibrating the granulate obtained from step (vi) with a metal mesh characterized by mesh sizes that range from 0.85 mm to 1.5 mm.

8. The process according to claim 1, further comprising a step of mixing the granulate obtained from step (vi) with at least one lubricant and/or glidant agent.

9. The process according to claim 1, further comprising a step of compressing the granulate obtained from step (vi) in order to obtain tablets.

10. The process according to claim 9, wherein the tablets comprise at least one coating for gastro-resistance and/or controlled release of the drug.

11. The process according to claim 1, wherein the mesalazine has at least one of the following characteristics: an apparent density ranging from 0.15 ci/ml to 0.35 g/ml, where the apparent density is the density of a powder as poured; and/or a packing density 0.4 g/ml, where the packing density is the density of a powder subjected to packing; and/or a Particle Size Distribution (PSD) for 100% of the particles 90 prn, where the PSD is a distribution, on a statistical basis, of the particle size of a powder/granulate; and/or a D90 value, the size below which 90% of the particles are found, of between 30 μm and 45 urn; and/or a D50 value, the size below which 50% of the particles are found, of between 5.sub.n and 20 μm.

12. The process according to claim 1, wherein the solid pharmaceutical formulation comprises based on the total weight of said solid pharmaceutical formulation 80% to 90% by weight of masalazine and/or a salt thereof and/or a derivative thereof.

13. The process according to claim 1, wherein, in step (iii), the granulate obtained from step (ii) is dried until reaching a moisture content, in tho drying step, ic; lower than or equal to 2.5.

14. The process according to claim 1, wherein said binding agent according to step (ii) is PVP K30.

15. The process according to claim 1, wherein the weight of mesalazine ranges from 1000 to 1600 mg per dosage unit.

Description

DETAILED DESCRIPTION

(1) 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.

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

(3) 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.

(4) 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.

(5) 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.

(6) 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.

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

(8) 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.

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

(10) The disintegrating agents are preferably those described above.

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

(12) 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.

(13) 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.

(14) 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.

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

(16) 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.

(17) 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.

(18) 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.

(19) 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.

(20) 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.

(21) 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.

(22) 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%.

(23) 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 10 Kp and 30 Kp.

(24) 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.

(25) 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/or packing 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/or particle 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/or D50 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.

(26) 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/or hardness preferably higher than 6 Kp, more preferably comprised from 10 Kp to 30 Kp; and/or disintegration preferably less than 15 minutes.

(27) 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.

(28) 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.

(29) Treatment is preferably by topical use. Administration is preferably oral.

Example

(30) 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.

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

(32) TABLE-US-00001 TABLE I % Mesalazine 83.33 Microcrystalline cellulose 2.85 Sodium starch glycolate 2.50 Corn starch 2.08 Mannitol 1.56

(33) In particular, in this embodiment the quantities specified in Table II were mixed.

(34) TABLE-US-00002 TABLE II Amount Kg MESALAZINE 200.00 MICROCRYSTALLINE CELLULOSE 6.85 MANNITOL 3.75 SODIUM STARCH GLYCOLATE 6.00 STARCH 5.00

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

(36) Wet granulation consists in wetting the mixture of Table II 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.

(37) 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%.

(38) 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.

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

(40) 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.

(41) 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.

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

(43) 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.

(44) A further mixing step with only magnesium stearate follows.

(45) 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.

(46) TABLE-US-00003 TABLE III mg/tablet CORE COMPONENTS MESALAZINE 1200.00 MICROCRYSTALLINE CELLULOSE 102 41.10 CORN STARCH 30.00 MANNITOL 22.50 POLYVINYLPYRROLIDONE K30 45.00 SODIUM CARBOXYMETHYL STARCH 75.00 MAGNESIUM STEARATE 26.40 FILM COMPONENTS METHACRYLIC ACID COPOLYMERS 35.72 TRIETHYL CITRATE 17.89 RED IRON OXIDE 2.55 TITANIUM DIOXIDE 5.95 TALC 17.89

(47) 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.

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

(49) TABLE-US-00004 TABLE IV PARAMETER SPECIFICATIONS APPARENT DENSITY -g/ml 0.2-0.3 PACKING DENSITY -g/ml ≥0.4 PSD - μm 100% < 70 D90 - μm 35-40 D50 - μm 10-15