ITFI20100175A1 - NEW PHARMACEUTICAL FORMULATIONS SUITABLE FOR ORAL ADMINISTRATION OF DIHYDRATE ESOMEPRAZOLE MAGNESIUM, IN THE FORM OF MUPS TABLETS (MULTI UNIT PELLETS SYSTEM). - Google Patents

Description

TITLE

New pharmaceutical formulations suitable for oral administration of Esomeprazole Magnesium Dihydrate, in the form of MUPS (Multi Unit Pellets System) tablets.

Field of the invention

The present invention relates to the field of formulations of pharmaceutical compositions; in particular it relates to MUPS-type tablets for oral administration of esomeprazole, and their method of preparation.

State of the art

Esomeprazole belongs to the family of proton pump inhibitors (PPIs): drugs containing relatively recently discovered active ingredients which have proven to be very effective in fighting various gastroenterological diseases thanks to the reduction of stomach acid secretion.

They are drugs normally well tolerated, with a relatively short plasma half-life but long duration of action thanks to the irreversible inhibition of the enzyme H <+> / K <+> ATPase which supervises the production of hydrochloric acid by the parietal cells gastric.

In the preparation of formulations suitable for oral administration of Esomeprazole there is the problem of the stabilization of the active principle, absorbed in the intestine but susceptible to degradation in an acid environment. The addition of alkaline substances and / or layers of â € œinertâ € coating, applied to the pellets, in addition to the creation of one or more gastro-resistant layers, are repeatedly reported in the literature to avoid the inactivation of the drug in the gastric environment and ensure stable formulations.

The tablets made gastro-resistant obtained with the conventional technique have long periods of stay in the stomach, sometimes unpredictable: the risk of degradation of the active ingredient is high, mediated by the gastric dwell time and by micro-infiltrations in the gastro-resistant layer.

In the MUPS (Multi Unit Pellet System) type tablets or capsules, however, the residence time in the stomach is short as the tablets or capsules disintegrate, releasing gastro-resistant pellets with a diameter between 0.5-2.0 mm and then pass the stomach without stopping.

For tablets in the compression phase, in order to obtain an adequate hardness to be able to handle the tablets, it is generally necessary to use forces normally greater than 10-12 KN; however, even these minimal forces can damage the gastro-resistant coating of the pellets by about 10%, consequently causing the degradation of a similar percentage of product.

The need to carry out the above therefore imposes to resort to particular formulations of pellets or to a minimum compression force, with the risk of not obtaining them with sufficient hardness, in order not to damage the gastro-resistant layer of the pellets during compression.

WO96 / 01623 describes tablets of the MUPS type, containing esomeprazole, in which, to overcome the aforementioned compression problems, the pellets have been coated with a gastro-resistant coating that contains a plasticizer in quantities ranging from 20 to 50% by weight, with respect to weight. of the gastro-resistant lining. Such a high quantity of plasticizer gives the pellets a mechanical resistance to the pressure applied during compression, such as to preserve the gastro-resistant characteristics of the pellets.

There are many patents on the preparation of pharmaceutical formulations of the MUPS type containing Esomeprazole Magnesium Dihydrate which can be substantially divided according to the method of preparation of the pellets: some patents provide for the preparation of an initial core by stratification of the active ingredient, others by extrusion and spheronization. The prepared nuclei are isolated with neutral polymers for the protection of the active principle and made gastro-resistant through the use of different types of membranes. Among the various patents, the following can be mentioned: WO 2006/002077 A2 and WO 2005/034924 A1 which, however, describe capsules and not tablets. In the aforementioned patents, the active principle is preferably mixed with alkaline substances in order to protect the active principle from acidic materials and environments. The nuclei are isolated by applying neutral polymers characterized by low solubility due to their high degree of viscosity: therefore dilute solutions must be used which lead to lengthening of the covering times, aggravated by the adhesiveness of the membrane itself. The usable concentrations must be between 2 and 5% otherwise the viscosity becomes so high as to make the solutions non-spraying.

Despite the numerous studies in the sector to try to overcome the aforementioned problem, none of the proposed solutions has proved to be completely satisfactory at the moment and it is therefore evident the interest in being able to have pharmaceutical formulations and methods for obtaining them capable of solving this problem.

Summary of the invention

It was surprisingly discovered that by compressing gastro-resistant microgranules containing esomeprazole with a wet granulate of compression excipients at a much lower pressure than that generally applied for the preparation of tablets, it is possible to obtain MUPS-type tablets of suitable hardness and friability. to the subsequent filming and packaging processes.

The present invention, therefore, solves the aforementioned problem by means of a method for the preparation of MUPS (Multi Unit Pellet System) type tablets comprising esomeprazole, said method comprising the following steps:

(i) preparation of gastro-resistant microgranules (pellets) containing esomeprazole; (ii) granulation of inert compression excipients with water to obtain a wet granulate whose water content is 6-15% by weight with respect to said excipients; wherein said excipients include cellulose;

(iii) preparation of a mixture comprising the gastro-resistant microgranules obtained from step (i) and the wet granulate obtained from step (ii);

(iv) compression of the mixture obtained from step (iii) with a compression force equal to 1.8-2.5 kN with lubricated punches.

The granulate of the excipients is mixed, moist as it is, as obtained without carrying out prior drying, with the gastro-resistant pellets previously produced. What distinguishes the present invention from other pharmaceutical formulations of the MUPS type containing Esomeprazole Magnesium Dihydrate already on the market is the use of a considerably lower compression force and therefore such as not to damage the gastro-resistant layer of the pellets during compression. In fact, the tablets obtained in contact with liquids disintegrate and release the protected granules contained in them. By subjecting the tablets obtained by the above method to release experiments in aqueous solutions of 0.1M HCl it was observed that, in a preferred embodiment, less than 0.3% by weight of the esomeprazole contained therein is released in two hours; this confirms that the gastro-resistant microgranules preserve their characteristics and are not damaged during compression.

The presence of a water content equal to about 10% in the wet granulate of the compression excipients surprisingly allows to obtain tablets with high hardness and low friability while applying a minimum compression force equal to about 2kN. The tablets obtained by the above method have a hardness (greater than 15kp) and friability suitable for supporting the usual subsequent film-forming and packaging phases.

The tablets can subsequently be coated with normal film-forming excipients in aqueous medium. During filming, the tablets lose the water added during the granulation phase of the compression excipients. The finished tablets thus produced surprisingly show a further increase in hardness at the end of the film-forming cycle.

In one aspect, the present invention also relates to gastro-resistant microgranules containing esomeprazole which are particularly simple and convenient to prepare and which, although not having particular mechanical resistance as they do not have to be subjected to strong pressures during the compression phase, can be used in a particularly advantageous manner in the above method; said microgranules each comprising:

(a) an inert core;

(b) an esomeprazole-containing layer applied to said inert core;

(c) an insulating layer consisting of mannitol, said insulating layer applied to layer (b);

(d) an outer covering consisting of a gastro-resistant membrane; said microgranules preferably having an average diameter comprised between 500 and 800 µm;

said layer (b) containing esomeprazole does not contain alkaline substances; said coating layer (d) may also contain plasticizing substances but in quantities such as not to give said coating sufficient mechanical strength to preserve the gastroresistance during dry compression. The insulating layer (c) consisting of mannitol, simply applied in aqueous solution, allows to obtain the pellets with very rapid production times and with excellent results. With the same operating conditions compared to the neutral polymers used in the aforementioned patents, production times decrease by about 5 times.

Said microgranules can be used, besides for the preparation of tablets of the MUPS type according to the method of the present invention, for the preparation of capsules filled with said microgranules.

Detailed description of the invention

By compression excipients we mean those inert additives, known and referred to in the various pharmacopoeias that are generally added to the active ingredients, or to the granules that contain them, to facilitate their compression into tablets; in particular for the preparation of tablets of the MUPS type, disintegrating compression excipients are needed such as for example microcrystalline cellulose, carboxymethyl starch, croscarmellose, crospovidone, pregelatinized starch and others.

Preferably for the purposes of the present invention, esomeprazole is esomeprazole magnesium dihydrate.

Preferably the pellets object of the present invention have an average diameter comprised between 500 and 800 µm.

In the pellets according to the invention they are prepared by fluid bed technology. Preferably the layer containing the active principle further comprises usual excipients, preferably polysorbate, povidone or PEG and their mixtures. The active ingredient layer does not include basifying substances.

The layer containing the active principle is applied on the inert (neutral) cores using an aqueous suspension of the components of the layer in which the active principle is contained at 15-25% by weight, more preferably at about 20%. In said aqueous suspension the active principle is contained in higher quantities than what is known in the state of the art in which 6-10% by weight suspensions of active principle are used. It has now been discovered that it is possible to work even with higher concentrations (at 15-25% by weight) when said aqueous suspension is prepared and maintained at a temperature not exceeding 20 ° C, preferably between 10 and 20 ° C; in fact, by homogenizing the suspension at this temperature, it is possible to prevent its gelation and allow the spraying operation.

The mannitol insulating layer is preferably applied by fluid bed technology using a solution of mannitol in water preferably at a weight concentration of less than 50%, more preferably 10-30%. Said mannitol solution is preferably at pH 9-10, said pH preferably obtained by adding a 1N NaOH solution.

The pellets according to the invention are made gastro-resistant using membranes suitable for this purpose, known and referred to in the various pharmacopoeias; among these it is preferable to use Eudragit L100-55, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulose succinate, polyvinyl acetate. The gastro-resistant coating may further comprise other usual excipients such as glyceryl monostearate, triethyl citrate, talc, paraffin and mixtures thereof. However, any plasticizing substances present are less than 25% by weight with respect to the gastro-resistant polymers. The aforementioned quantity of plasticizers is not sufficient to give the pellets the necessary mechanical resistance to dry compression. However, the pellets are preserved when compressed with wet granulate of compression excipients according to the method of the present invention.

The pellets according to the invention or others selected for example from those known in the state of the art are mixed with the compression excipients and subsequently compressed. Conveniently, for the purposes of the present method, the microgranules object of the present invention are used because they are easier to prepare while maintaining the desired gastroresistance and release characteristics at neutral or slightly alkaline pH.

Preferably the granulate of the compression excipients comprises cellulose and preferably also comprises an alditol of general formula H [CH (OH)] nH where n is between 5 and 12. Conveniently said compression excipients consist of cellulose or cellulose mixtures and an alditol of general formula H [CH (OH)] nH where n is between 5 and 12, preferably selected from mannitol, lactitol, isomalt, maltitol, sorbitol or xylitol. The above mixture of cellulose + alditol preferably comprises 70-90% by weight of cellulose and the remaining 10-30% of alditol. The aforementioned cellulose + alditol mixture is preferably obtained by co-spray drying.

In the method according to the invention, the compression excipients are granulated with the addition of water, to obtain a wet granulate whose water content is preferably 7-13%, more preferably 9-11% (referring to weight of excipients). This water content was evaluated by weight loss tests by drying. The water used for the preparation of the granules of the compression excipients is preferably previously acidified to pH 3-5, preferably using hydrochloric acid.

The wet granulate is mixed with the gastro-resistant pellets previously produced without drying. The mixture thus obtained is compressed using conventional tablet presses, equipped to obtain tablets of the desired form and dosage. The punches at the moment of compression must be lubricated. A tablet press equipped with automatic distribution of a lubricant is therefore preferably used. The lubricant is preferably selected from sodium stearyl fumarate, stearic acid, magnesium stearate, talc, purified silica, kaolin. The quantity of lubricant to be used to lubricate the punches is preferably 0.2-3.0% by weight with respect to the total mixture to be compressed.

Preferably, the gastro-resistant pellets are mixed with the wet granulate of compression excipients in the presence of a lubricant, which is preferably the same used to lubricate the punches. Therefore the lubricant is preferably partly directly applied to the punches and partly mixed with the pellets and the compression excipients.

Preferably the mixture to be compressed, on lubricated punches, has the following percentage composition by weight:

gastro-resistant pellets 20-40%

wet granulate of excipients 60-80%

lubricant 0-3%

Most preferably the blend comprises:

gastro-resistant pellets 25-35%

wet granulate of excipients 65-75%

lubricant 0.2-3%

For completeness and for a better understanding of the invention, some examples of formulations according to the invention and their preparation are given below.

Dosage: 43.38 mg of Esomeprazole Magnesium Dihydrate (equal to 40 mg of Esomeprazole base) per tablet

Example 1

The neutrals are introduced into the fluid bed with wurster insert and the suspension (prepared and kept at 20 ° C) containing esomeprazole, polysorbate 80, povidone PEG and purified water is started to be sprained in these quantities:

Esomeprazole magnesium dihydrate 2800 g. 20.32%

Polysorbate 80 160 g. 1.16%

Povidone 320 g. 2.32%

PEG 20 g. 0.14%

Purified water 10480 g. 76.06%

Neutral 60 1600 g.

Operating conditions:

Inlet air temperature: 90 ° C

Outlet air temperature: 40-50 ° C

Core temperature: 40-50 ° C

We discovered that the suspension described above containing the active principle must be kept at a temperature not exceeding 20 ° C, otherwise, by heating up during homogenization, it gels and makes the spraying operation impossible.

After having sprinkled all the suspension described above, we proceed with the drying of the pellets inside the same fluid bed.

At the end of drying, the pellets thus obtained are forced through a vibrating screen equipped with a mesh having holes with a diameter of 650 microns.

Below these pellets are always coated in a fluidized bed equipped with a wurster insert, with an aqueous solution based on mannitol in these quantities:

Mannitol 480 g. 20%

Purified water 1920 g. 80%

Sodium hydroxide 1N enough to bring the pH of the solution to 9-10 Pellets 4800 g.

Operating conditions:

Inlet air temperature: 70 ° C

Outlet air temperature: 40-45 ° C

Core temperature: 40-45 ° C

Subsequently, these pellets are further coated in a fluidized bed equipped with a wurster insert with an aqueous solution based on Eudragit L100-55 as follows:

Eudragit L100-55 6114 g. 19.86%

Glyceryl monostearate 105 g. 0.34%

Triethyl citrate 1420 g. 4.61%

Talc 276 g. 0.90%

Paraffin 86.4 g. 0.28%

Polysorbate 80 34.5 g. 0.11%

Water 22757 g 73.9%

Pellets 5000 g.

Operating conditions:

Inlet air temperature: 45 ° C

Outlet air temperature: 25-30 ° C

Core temperature: 25-30 ° C

The analysis of these gastro-resistant pellets gave the following results:

Title in esomeprazole magnesium dihydrate 204.9 mg / g

Release of the first 2 hours in HCl 0.1 0.5%

Transfer of the next 45â € ™ in pH 6.8 101.1%

Example 2

A part of the pellets of example 1 is mixed with cellulose + mannitol (marketed by Avicel under the name of HFE-102 it is a dryed co-spray mixture containing microcrystalline cellulose and mannitol at 83% and 17% by weight respectively) in the following quantities:

Gastro-resistant pellets 4234 g. 30.25%

Cellulose + mannitol 9696 g. 69.25%

Sodium stearyl fumarate 70 g. 0.5%

With an adequately equipped compressing machine, tablets with a dosage of 43.38 mg of esomeprazole magnesium dihydrate are formed, having an average weight of 700 mg / tablet and hardness 11 kp obtained with an applied compression force equal to 4.5 kN.

The aforementioned tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 13.3%

Transfer of the next 45â € ™ in pH 6.8 not performed

Example 3

A part of cellulose + mannitol (Avicel HFE-102) is granulated in an automatic pan by wetting the powder with acidified water at pH 4 using hydrochloric acid, in these quantities:

Cellulose + mannitol 10000 g.

Water 250 g

By carrying out the test of the loss in weight by drying on this compound, the result obtained is about 5%, as on the cellulose + mannitol as it is, the test of the loss in weight by drying gives as a result about 2, 6%. At this point a part of the pellets of example 1 is mixed with granulated mannitol cellulose in the following quantities:

Gastro-resistant pellets 4234 g. 29.24% Cellulose + granulated mannitol at p.p.5% 10,180 g. 70.28%

Sodium stearyl fumarate 70 g. 0.48%

With a compressing machine equipped with automatic distribution of the lubricant on the punches, tablets are formed with a dosage of 43.38 mg of esomeprazole magnesium dihydrate having a weight

average of 724 mg / tablet and 16 kp hardness obtained with a compression force of 3.5 kN.

The aforesaid tablets are dried in an automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 12.3%

Transfer of the next 45â € ™ in pH 6.8 not performed

Example 4

A part of cellulose + mannitol (Avicel HFE-102) is granulated in an automatic pan by wetting the powder with acidified water at pH 4 using hydrochloric acid, in these quantities:

Cellulose + mannitol 10000 g.

Purified water 800 g

By performing the weight loss test for drying on this compound, the result obtained is about 10%.

At this point a part of the pellets of example 1 is mixed with granulated mannitol cellulose in the following quantities:

Gastro-resistant pellets 4234 g. 28.28%

Cellulose + granulated mannitol at p.p 10% 10665 g. 71.26%

Sodium stearyl fumarate 70 g. 0.46%

With an adequately equipped compressing machine as described in example n ° 3, tablets with a dosage of 43.38 mg of esomeprazole magnesium dihydrate having a weight of

average of 748 mg / tablet and 20 kp hardness obtained by applying a compression force of 2.0 kN.

The aforementioned tablets are dried in an automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 0.3%

Sale of the next 45â € ™ in pH 6.8 102.1%

Example 5

The tablets produced in example 4 are placed in an automatic pan and coated with a coloring suspension with the following composition:

Hpmc 5cps 202.3 g. 5%

Peg 4000 26.3 g. 0.65%

Talc 177.8 g. 4.39%

Titanium dioxide 101.2 g. 2.5%

Red iron oxide 5.14 g. 0.13%

Iron oxide yellow 1.3 g. 0.03%

Purified water 202.3 g. 5%

Ethanol 3330 g. 82.3%

Tablets 12000 g.

Operating conditions:

Inlet air temperature: 50 ° C

Outlet air temperature: 25-30 ° C

Core temperature: 25-30 ° C

Spray this suspension on the tablets until a weight gain of 25 mg / tablet is obtained. Once the pre-set average weight has been reached, dry the tablets in the automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 1.4%

Transfer of the next 45â € ™ in pH 6.8 100.5%

Example 6

The neutrals are introduced into the fluidized bed with wurster insert and the suspension (prepared and kept at 20 ° C) containing esomeprazole, polysorbate 80, povidone, PEG and purified water in these quantities is begun:

Esomeprazole magnesium dihydrate 2800 g. 20.32%

Polysorbate 80 160 g. 1.16%

Povidone 320 g. 2.32%

PEG 20 g. 0.14%

Water 10480 g. 76.06%

Neutral 60 1600 g.

Operating conditions:

Inlet air temperature: 90 ° C

Outlet air temperature: 40-50 ° C

Core temperature: 40-50 ° C

After having sprinkled all the suspension described above, we proceed with the drying of the pellets inside the same fluid bed. At the end of drying, the pellets thus obtained are forced through a vibrating screen equipped with a mesh having holes with a diameter of 650 microns.

Below these pellets are always coated in a fluidized bed equipped with a wurster insert, with an aqueous solution based on mannitol in these quantities:

Mannitol 480 g. 20%

Purified water 1920 g. 80%

1N sodium hydroxide enough to bring the pH of the solution to 9-10

Pellets 4800 g.

Operating conditions:

Inlet air temperature: 70 ° C

Outlet air temperature: 40-45 ° C

Core temperature: 40-45 ° C

Subsequently these pellets are further coated in a fluidized bed equipped with a wurster insert with an aqueous solution based on Eudragit L100-55 as follows:

Eudragit L100-55 6114 g. 19.86%

Glyceryl monostearate 105 g. 0.34%

Triethyl citrate 1420 g. 4.61%

Talc 276 g. 0.90%

Paraffin 86.4 g. 0.28%

Polysorbate 80 34.5 g. 0.11%

Purified water 22757 g 73.90%

Pellets 5000 g.

Operating conditions:

Inlet air temperature: 45 ° C

Outlet air temperature: 25-30 ° C

Core temperature: 25-30 ° C

The analysis of these gastro-resistant pellets gave the following results:

Title in esomeprazole magnesium dihydrate 202.1 mg / g

Release of the first 2 hours in HCl 0.1 0.3%

Transfer of the next 45â € ™ in pH 6.8 102.7%

Example 7

A part of the pellets of example 6 is mixed with microcrystalline cellulose in the following quantities:

Gastro-resistant pellets 4293 g. 30.66%

Cellulose microcrist. 9637 g. 68.84%

Sodium stearyl fumarate 70 g. 0.5%

With an adequately equipped compressing machine, tablets with a dosage of 43.38 mg of esomeprazole magnesium dihydrate having an average weight of 700 mg / tablet and hardness 10 kp obtained with a compression force equal to 5.0 kN are formed.

The aforementioned tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 15.6%

Transfer of the next 45â € ™ in pH 6.8 not performed

Example 8

A part of microcrystalline cellulose is granulated in an automatic pan by wetting the powder with acidified water at pH 4 using hydrochloric acid, in these quantities:

Cellulose microcrist. 10000 g.

Purified water 150 g

By carrying out the weight loss test by drying on this compound, the result obtained is about 5%, as on the microcrystalline cellulose as it is, the weight loss by drying test gives as a result about 3.4 %. At this point a part of the pellets of example 6 is mixed with granulated microcrystalline cellulose in the following quantities:

Gastro-resistant pellets 4293 g. 29.64% Cellulose microcrist. granulated at 5% p.p.10120 g. 69.88% Sodium stearyl fumarate 70 g. 0.48%

With a suitable compressing machine equipped with automatic distribution of the lubricant on the punches, tablets are formed with a dosage of 43.38 mg of esomeprazole magnesium dihydrate having an average weight of 724 mg / tablet and hardness 14 kp obtained with a compression force equal to 3.5 kN .

The aforementioned tablets are dried in an automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 14.6%

Transfer of the next 45â € ™ in pH 6.8 not performed

Example 9

A part of microcrystalline cellulose is granulated in an automatic pan by wetting the powder with acidified water at pH 4, preferably using hydrochloric acid, in these quantities:

Microcrystalline cellulose 10000 g.

Purified water 650 g

By performing the weight loss test by drying on this compound, the result obtained is about 10%.

At this point a part of the pellets of example 6 is mixed with granulated microcrystalline cellulose in the following quantities:

Gastro-resistant pellets 4293 g. 28.69%

Cellulose microcrist. granulated at 10% p.p.10,600 g. 70.84%

Sodium stearyl fumarate 70 g. 0.47%

With a compressing machine equipped with automatic distribution of the lubricant on the punches, tablets with a dosage of 43.38 mg of esomeprazole magnesium dihydrate with an average weight of 748 mg / tablet and hardness 16 kp obtained with a compression force equal to 2.0 kN are formed.

The aforementioned tablets are dried in an automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 2.4%

Sale of the next 45â € ™ in pH 6.8 96.1%

Example 10

The tablets produced in example 9 are placed in an automatic pan and coated with a coloring suspension with the following composition:

Hpmc 5cps 202.3 g. 5%

Peg 4000 26.3 g. 0.65%

Talc 177.8 g. 4.39%

Titanium dioxide 101.2 g. 2.50%

Red iron oxide 5.14 g. 0.13%

Iron oxide yellow 1.3 g. 0.03%

Purified water 202.3 g. 5%

Ethanol 3330 g. 82.30%

Tablets 12000 g.

Operating conditions:

Inlet air temperature: 50 ° C

Outlet air temperature: 25-30 ° C

Core temperature: 25-30 ° C

Spray this suspension on the tablets until a weight gain of 25 mg / tablet is obtained. Once the pre-set average weight has been reached, dry the tablets in the automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 2.5%

Transfer of the next 45â € ™ in pH 6.8 98.4%

Dosage: 21.69 mg of Esomeprazole Magnesium Dihydrate (equal to 20 mg of Esomeprazole base) per tablet

Example 11

The neutrals are introduced into the fluid bed with wurster insert and the suspension (prepared and kept at 20 ° C) containing esomeprazole, polysorbate 80, povidone, PEG and purified water in these quantities is started to be spraied. :

Esomeprazole magnesium dihydrate 2800 g. 20.32%

Polysorbate 80 160 g. 1.16%

Povidone 320 g. 2.32%

PEG 20 g. 0.14%

Purified water 10480 g. 76.06%

Neutral 60 1600 g.

Operating conditions:

Inlet air temperature: 90 ° C

Outlet air temperature: 40-50 ° C

Core temperature: 40-50 ° C

After having sprinkled all the suspension described above, we proceed with the drying of the pellets inside the same fluid bed.

At the end of drying, the pellets thus obtained are forced through a vibrating screen equipped with a mesh having holes with a diameter of 650 microns.

Below these pellets are always coated in a fluidized bed equipped with a wurster insert, with an aqueous solution based on mannitol in these quantities:

Mannitol 480 g. 20%

Purified water 1920 g. 80%

1N sodium hydroxide enough to bring the pH of the solution to 9-10

Pellets 4800 g.

Operating conditions:

Inlet air temperature: 70 ° C

Outlet air temperature: 40-45 ° C

Core temperature: 40-45 ° C

Subsequently, these pellets are further coated in a fluidized bed equipped with a wurster insert with an aqueous solution based on Eudragit L100-55 as follows:

Eudragit L100-55 6114 g. 19.86%

Glyceryl monostearate 105 g. 0.34%

Triethyl citrate 1420 g. 4.61%

Talc 276 g. 0.90%

Paraffin 86.4 g. 0.28%

Polysorbate 80 34.5 g. 0.11%

Water 22757 g 73.9%

Pellets 5000 g.

Operating conditions:

Inlet air temperature: 45 ° C

Outlet air temperature: 25-30 ° C

Core temperature: 25-30 ° C

The analysis of these gastro-resistant pellets gave the following results:

Title in esomeprazole magnesium dihydrate 199.6 mg / g

Release of the first 2 hours in HCl 0.1 0.2%

Transfer of the next 45â € ™ in pH 6.8 99.8%

Example 12

A part of the pellets of example 11 is mixed with cellulose + mannitol (Avicel HFE-102) in the following quantities:

Gastro-resistant pellets 4346 g. 31.04%

Cellulose + mannitol 9584 g. 68.46%

Sodium stearyl fumarate 70 g. 0.5%

With an adequately equipped compressing machine, tablets are formed at a dosage of 21.69 mg of esomeprazole magnesium dihydrate having an average weight of 350 mg / tablet and hardness of 7 kp obtained with a compression force of 5.0 kN.

The aforementioned tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 11.6%

Transfer of the next 45â € ™ in pH 6.8 not performed

Example 13

A part of cellulose + mannitol (Avicel HFE-102) is granulated in an automatic pan by wetting the powder with acidified water at pH 4 using hydrochloric acid, in these quantities:

Cellulose + mannitol 10000 g.

Water 250 g.

By carrying out the test of the loss in weight by drying on this compound, the result obtained is about 5%, as on the cellulose + mannitol as it is, the test of the loss in weight by drying gives as a result about 2, 6%. At this point a part of the pellets of example 11 is mixed with granulated mannitol cellulose in the following quantities:

Gastro-resistant pellets 4346 g. 30.02% Cellulose + granulated mannitol at p.p 5% 10062 g. 69.50%

Sodium stearyl fumarate 70 g. 0.48%

With a suitable tablet press, tablets with a dosage of 21.69 mg of esomeprazole magnesium dihydrate are formed having an average weight of 362 mg / tablet and hardness 15 kp obtained with a compression force equal to 3.0 kN. The aforementioned tablets are dried in an automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 7.6%

Transfer of the next 45â € ™ in pH 6.8 not performed

Example 14

A part of cellulose + mannitol (Avicel HFE-102) is granulated in an automatic pan by wetting the powder with acidified water at pH 4 using hydrochloric acid, in these quantities:

Cellulose + mannitol 10000 g.

Purified water 800 g

By performing the weight loss test by drying on this compound, the result obtained is about 10%.

At this point a part of the pellets of example 11 is mixed with granulated mannitol cellulose in the following quantities:

Gastro-resistant pellets 4346 g. 29.05% Cellulose + granulated mannitol at p.p 10% 10542 g. 70.48%

Sodium stearyl fumarate 70 g. 0.47%

With a compressing machine equipped with automatic distribution of the lubricant on the punches, tablets are formed with a dosage of 43.38 mg of esomeprazole magnesium dihydrate having an average weight of 374 mg / tablet and 25 kp hardness obtained by applying a compression force equal to 2.3 kN .

The aforementioned tablets are dried in an automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 0.4%

Transfer of the next 45â € ™ in pH 6.8 100.7%

Example 15

The tablets produced in example 14 are placed in an automatic pan and coated with a coloring suspension with the following composition:

Hpmc 5cps 202.3 g. 5%

Peg 4000 26.3 g. 0.65%

Talc 177.8 g. 4.39%

Titanium dioxide 101.2 g. 2.50%

Red iron oxide 5.14 g. 0.13%

Iron oxide yellow 1.3 g. 0.03%

Purified water 202.3 g. 5%

Ethanol 3330 g. 82.30%

Tablets 12000 g.

Operating conditions:

Inlet air temperature: 50 ° C

Outlet air temperature: 25-30 ° C

Core temperature: 25-30 ° C

Spray this suspension on the tablets until a weight gain of 12.5 mg / tablet is obtained. Once the pre-set average weight has been reached, dry the tablets in the automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 0.6%

Sale of the next 45â € ™ in pH 6.8 100.1%

Example 16

The neutrals are introduced into the fluidized bed with wurster insert and the suspension (prepared and kept at 20 ° C) containing esomeprazole, polysorbate 80, povidone, PEG and purified water in these quantities is begun:

Esomeprazole magnesium dihydrate 2800 g. 20.32%

Polysorbate 80 160 g. 1.16%

Povidone 320 g. 2.32%

PEG 20 g. 0.14%

Water 10480 g. 76.06%

Neutral 60 1600 g.

Operating conditions:

Inlet air temperature: 90 ° C

Outlet air temperature: 40-50 ° C

Core temperature: 40-50 ° C

After having sprinkled all the suspension described above, we proceed with the drying of the pellets inside the same fluid bed. At the end of drying, the pellets thus obtained are forced through a vibrating screen equipped with a mesh having holes with a diameter of 650 microns.

Below these pellets are always coated in a fluidized bed equipped with a wurster insert, with an aqueous solution based on mannitol in these quantities:

Mannitol 480 g. 20%

Purified water 1920 g. 80%

1N sodium hydroxide enough to bring the pH of the solution to 9-10

Pellets 4800 g.

Operating conditions:

Inlet air temperature: 70 ° C

Outlet air temperature: 40-45 ° C

Core temperature: 40-45 ° C

Subsequently, these pellets are further coated in a fluidized bed equipped with a wurster insert with an aqueous solution based on Eudragit L100-55 as follows:

Eudragit L100-55 6114 g. 19.86%

Glyceryl monostearate 105 g. 0.34%

Triethyl citrate 1420 g. 4.61%

Talc 276 g. 0.90%

Paraffin 86.4 g. 0.28%

Polysorbate 80 34.5 g. 0.11%

Purified water 22757 g 73.9%

Pellets 5000 g.

Operating conditions:

Inlet air temperature: 45 ° C

Outlet air temperature: 25-30 ° C

Core temperature: 25-30 ° C

The analysis of these gastro-resistant pellets gave the following results:

Titre in esomeprazole magnesium dihydrate 201.7 mg / g

Transfer of the first 2 hours in HCl 0.1 0.3%

Sale of the next 45â € ™ in pH 6.8 101.7%

Example 17

A part of the pellets of example 16 is mixed with microcrystalline cellulose in the following quantities:

Gastro-resistant pellets 4301 g. 30.72%

Cellulose microcrist. 9629 g. 68.78%

Sodium stearyl fumarate 70 g. 0.5%

With an adequately equipped compressing machine, tablets with a dosage of 21.69 mg of esomeprazole magnesium dihydrate having an average weight of 350 mg / tablet and hardness of 5 kp obtained with a compression force of 5.0 kN are formed.

The aforementioned tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 12.6%

Transfer of the next 45â € ™ in pH 6.8 not performed

Example 18

A part of microcrystalline cellulose is granulated in an automatic pan by wetting the powder with acidified water at pH 4 using hydrochloric acid, in these quantities:

Cellulose microcrist. 10000 g.

Purified water 150 g

By carrying out the weight loss test by drying on this compound, the result obtained is about 5%, as on the microcrystalline cellulose as it is, the weight loss by drying test gives as a result about 3.4 %. At this point a part of the pellets of example 16 is mixed with granulated microcrystalline cellulose in the following quantities:

Gastro-resistant pellets 4301 g. 29.7%

Cellulose microcr. granulated at 5% p.p.10110 g. 69.82%

Sodium stearyl fumarate 70 g. 0.48%

With a suitable compressing machine equipped with automatic distribution of the lubricant on the punches, tablets are formed with a dosage of 21.69 mg of esomeprazole magnesium dihydrate having an average weight of 362 mg / tablet and hardness 13 kp obtained with a compression force equal to 3.5 kN .

The aforementioned tablets are dried in an automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 10.6%

Transfer of the next 45â € ™ in pH 6.8 not performed

Example 19

A part of microcrystalline cellulose is granulated in an automatic pan by wetting the powder with acidified water at pH 4 using hydrochloric acid, in these quantities:

Microcrystalline cellulose 10000 g.

Purified water 650 g

By performing the weight loss test by drying on this compound, the result obtained is about 10%.

At this point a part of the pellets of example 16 is mixed with granulated microcrystalline cellulose in the following quantities:

Gastro-resistant pellets 4301 g. 28.74%

Cellulose + microcrist. granulated at 10% p.p. 10592 g. 70.79%

Sodium stearyl fumarate 70 g. 0.47%

With a compressing machine equipped with automatic distribution of the lubricant on the punches, tablets are formed with a dosage of 21.69 mg of esomeprazole magnesium dihydrate having an average weight of 748 mg / tablet and 20 kp hardness obtained with a compression force of 2.3 kN.

The aforementioned tablets are dried in an automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 2.5%

Transfer of the next 45â € ™ in pH 6.8 97.1%

Example 20

The tablets produced in example 19 are placed in an automatic pan and coated with a coloring suspension with the following composition:

Hpmc 5cps 202.3 g. 5%

Peg 4000 26.3 g. 0.65%

Talc 177.8 g. 4.39%

Titanium dioxide 101.2 g. 2.50%

Red iron oxide 5.14 g. 0.13%

Iron oxide yellow 1.3 g. 0.03%

Purified water 202.3 g. 5%

Ethanol 3330 g. 82.30%

Tablets 12000 g.

Operating conditions:

Inlet air temperature: 50 ° C

Outlet air temperature: 25-30 ° C

Core temperature: 25-30 ° C

Spray this suspension on the tablets until a weight gain of 12.5 mg / tablet is obtained. Once the pre-set average weight has been reached, dry the tablets in the automatic pan.

These tablets have the following supplies:

Release of the first 2 hours in HCl 0.1 2.6%

Sale of the next 45â € ™ in pH 6.8 97.9%

43.38 mg Esomeprazole Magnesium Dihydrate

(equal to 40 mg of Esomeprazole base)

Example 2

Active pellets Cellulose mannitol and Strength of Hardness Release in Release in per tablet SSF per tablet compression tablet HCl 0.1 pH 6.8

211.71 mg 488.29 mg 4.5 kN 11 kp 13.3% / Example 3

Cellulose active pellets

per tablet mannitol / water and SSF Strength of Hardness Release on Release in per tablet compression tablet HCl 0.1 pH 6.8 211.71 mg 512.52 mg 3.5 kN 16 kp 12.3% / Example 4

Cellulose active pellets

per tablet mannitol / water and SSF Strength of Hardness Release on Release in per tablet compression tablet HCl 0.1 pH 6.8 211.71 mg 536.77 mg 2.0 kN 20 kp 0.3% 102.1

Example 7

Active pellets Cellulose micr. and SSF Strength of Hardness Release in Release in per tablet per tablet compression tablet HCl 0.1 pH 6.8

214.64 mg 485.36 mg 5.0 kN 10 kp 15.6% / Example 8

Active pellets Cellulose micr. / Water and Strength of Hardness Release in Release in per tablet SSF per tablet compression tablet HCl 0.1 pH 6.8

214.64 mg 509.45 mg 3.5 kN 14 kp 14.6% / Example 9

Active pellets Cellulose micr. / Water and Strength of Hardness Release in Release in per tablet SSF per tablet compression tablet HCl 0.1 pH 6.8

214.64 mg 533.54 mg 2.0 kN 16 kp 2.4% 96.1

Note:

SSF = sodium stearyl fumarate

Cellulose + mannitol / water = mannitol cellulose granulated with water

Microcrystalline cellulose / water = microcrystalline cellulose granulated with water

21.69 mg Esomeprazole Magnesium Dihydrate

(equal to 20 mg of Esomeprazole base)

Example 12

Active pellets Cellulose mannitol and Strength of Hardness Release in Release in per tablet SSF per tablet compression tablet HCl 0.1 pH 6.8

108.66 mg 241.34 5.0 kN 7 kp 11.6% / Example 13

Active pellets Cellulose n per tablet mannitol / water and SSF Strength of Hardness Release in Release i per tablet compression tablet HCl 0.1 pH 6.8 108.66 mg 253.31 mg 3.0 kN 15 kp 7.6% / Example 14

Cellulose active pellets

per tablet mannitol / water and SSF Strength of Hardness Release in Release in per tablet compression tablet HCl 0.1 pH 6.8 108.66 mg 265.30 mg 2.3 kN 25 kp 0.4% 100.7

Example 17

Active pellets Cellulose micr. and SSF Strength of Hardness Release in Release in per tablet per tablet compression tablet HCl 0.1 pH 6.8

107.53 mg 242.47 mg 5.0 kN 5 kp 12.6% / Example 18

Active pellets Cellulose micr. / Water and Strength of Hardness Release in Release in per tablet SSF per tablet compression tablet HCl 0.1 pH 6.8

107.53 mg 254.50 mg 3.5 kN 13 kp 10.6% / Example 19

Active pellets Cellulose micr. / Water and Strength of Hardness Release in Release in per tablet SSF per tablet compression tablet HCl 0.1 pH 6.8

107.53 mg 266.54 mg 2.3 kN 20 kp 2.5% 97.1

Note:

SSF = sodium stearyl fumarate

Cellulose + mannitol / water = mannitol cellulose granulated with water

Microcrystalline cellulose / water = microcrystalline cellulose granulated with water

The hardness of the tablets was evaluated using Erweka model TBH 225 TD hardness tester.

Considerations

From the examples it can be deduced that by compressing the gastro-resistant esomeprazole pellets with microcrystalline cellulose as it is (whether it is cellulose + mannitol or whether it is simple microcrystalline cellulose) the gastro-resistant pellets partially shatter during compression, primarily damaging the gastro-resistant coating

Also from the examples it can be seen that by compressing esomeprazole pellets with granulated cellulose with water, the percentage of pellets that break during compression is reduced to almost zero when cellulose + mannitol wetted with water is used (with weight loss due to drying equal to about 10%). This is true for the tablets of both strengths.

Claims (10)

CLAIMS 1. A method for preparing MUPS-type tablets comprising esomeprazole, said method comprising the following steps: (i) preparation of gastro-resistant microgranules (pellets) containing esomeprazole; (ii) granulation of compression excipients with water to obtain a wet granulate whose water content is 6-15% by weight with respect to said excipients; wherein said excipients include cellulose; (iii) preparation of a mixture comprising the gastro-resistant microgranules obtained from step (i) and the wet granulate obtained from step (ii); (iv) compression of the mixture obtained from step (iii) with a compression force equal to 1.8-2.5 kN with lubricated punches. 2. Method according to claim 1 wherein said excipients further include an alditol of general formula H [CH (OH)] nH where n is comprised between 5 and 12. 3. Method according to claim 2 wherein said excipients consist of cellulose; or said excipients consist of a mixture of cellulose and an alditol of general formula H [CH (OH)] nH where n is between 5 and 12 .. Method according to any one of claims 1-3 wherein the mixture obtained from step (iii) has the following weight percentage composition: ∠’20-40% gastro-resistant pellets ∠’wet granules of excipients 60-80% ∠’lubricant 0.2-3% Method according to any one of claims 1-4 wherein said microgranules each comprise: (a) an inert core; (b) an esomeprazole-containing layer applied to said inert core; (c) an insulating layer consisting of mannitol, said insulating layer applied to layer (b); (d) an outer covering consisting of a gastro-resistant membrane; wherein said esomeprazole-containing layer (b) does not contain alkaline substances. Method according to any one of claims 1-5, wherein after compression the tablets are filmed. 7. Gastro-resistant microgranules containing esomeprazole, called microgranules each comprising: (a) an inert core; (b) an esomeprazole-containing layer applied to said inert core; (c) an insulating layer consisting of mannitol, said insulating layer applied to layer (b); (d) an outer covering consisting of a gastro-resistant membrane; wherein said esomeprazole-containing layer (b) does not contain alkaline substances. 8. Pharmaceutical formulations of the MUPS type comprising the microgranules according to claim 7. 9. MUPS-type tablets for oral administration of esomeprazole, said tablets obtainable with the method according to any one of claims 1-6, said tablets having a hardness higher than 15 kp and having a release degree of esomeprazole in HCl 0.1 M in 2 hours less than 3% by weight with respect to the total esomeprazole contained in them. 10. MUPS-type tablets for oral administration of esomeprazole, said tablets comprising as excipients for compression cellulose or a mixture of cellulose and an alditol of general formula H [CH (OH)] nH where n is between 5 and 12.