MXPA00001087A - Oral pharmaceutical preparation comprising an antiulcer activity compound, and process for its production - Google Patents

Abstract

It comprises an inert nucleus;and active layer which is soluble or which desintegrates in water and is obtained from a unique aqueous or hydro-alcoholic solution-suspension which comprises:an active principle having an antiulcer activity with formula (I, II or III) and at least one excipient;and a gastroresistant external coating layer obtained from a solution which comprises an enteric covering polymer and at least one excipient. The process is carried out by (1) covering the inert nucleus by nebulisation of the aqueous or hydroalcoholic suspension-solution;(2) drying the active layer formed during the nebulisation of the prior step;and (3) covering the nucleus charged through nebulisation with the solution comprising an enteric coating polymer with at least one excipient to obtain an external gastroresistant coating layer.

Description

ORAL PHARMACEUTICAL PREPARATION COMPRISING A COMPOSITE OF ANTIULCEROSA ACTIVITY AND PROCEDURE FOR YOUR OBTAINMENT FIELD OF THE INVENTION The present invention relates to new pharmaceutical formulations for oral administration comprising a compound of antiulcer activity as an active ingredient, and a process for obtaining them. BACKGROUND OF THE INVENTION In recent times, numerous techniques have been developed for the preparation of release systems in the form of my cryogram. In them, the mixture of active principle and excipients can be subjected to a process of kneading, extrusion, e s f e r oni z a tion, coating, etc. Each of these techniques requires a different technology, in such a way that there are numerous types of equipment, such as pails or drums, fluid bed equipment, extruders, and other equipment. - is fer oni z e s and centrifugal equipment among others. The final result seems to be the same although, nevertheless, there are really big differences between the pellets obtained by each technique. Various types of myroglobulin have been described for the formulation of certain benzimidazoles with antiulcer activity as those of European patents EP 247983, EP 244380, EP 237200 and EP 277741 and international patent WO 92/22284. This type of compound is generally acidic, and for this reason different procedures have been developed to protect it from the effect of the gastric acid medium. In European patents EP 247983 and EP 244380 the active principle is wet-mixed with a mixture of excipients which makes it possible to create an alkaline bi-metal. The mixture is extruded and then spheronized. The micro-inoculants are coated with one or more intermediate layers of water-soluble, alkaline, buffering, polymeric excipients, etc., and an external gastro-resistant layer is subsequently applied. Being an extrusion method-it is feronization, the total yield of the process will depend on numerous factors. On the one hand, during the extrusion stage it is essential to control dimensions such as the sectional cut and the length of the extrudate at the risk of having a large dispersion in the size and shape of the particles. Both facts justify that the posterior coating can be irregular and even the presence of pores is favored unless an excess quantity is triggered to ensure the complete coating of the cranium, but which, in turn, leads to problems when standardizing the cession of the active principle. On the other hand, the characteristics of cohesiveness, firmness and plasticity of the extrudate must be controlled at the risk of not guaranteeing its subsequent spheronization. These problems are added to the fact that on the basis of having to use various equipment such as: kneaders, extruders and spronisers, the losses by kneading, extrusion and spheronization may be greater than with other methods of pe e t i z ac ion. European patents EP 237200 and EP 277741, the latter published in Spain as ES 2.052.697, show an example of coating with powdered dust (powde r-1 a and e r ing) by r o t ogranuí a do r. Spherical granules are described which have a core coated with powdered powder containing a benzimidazole anti- ulcer compound and hydroxypropylcellulose of low degree of substitution. A process for producing the said spherical granules is also described, characterized in that the seed cores are wetted by nebulization with a binder solution and sprinkled with a powder containing the active ingredient and the low-substituted hydroxypropylcellulose. The technique of re-stretching using a rotogranulator is very abrasive; especially in the initial phase of the process. Apart from the friction of the particles against the walls of the machine due to the thrust of the air, normal circumstance in every fluid bed, there is a shear force exerted by the rotating disc of the rotogranulator. All this often leads to problems such as breakage and abrasion of granules. These problems not only make it more difficult to control the release of the active ingredient, but also considerably affect the yield of the production of the granules. For this reason and in order to reduce these problems, European patent EP 277741 proposes the use of extremely hard seeding cores as a solution. For the preparation of said spherical granules, the European patent 277741 describes the use of a rotogranulator of the centrifugal type, such as the CF360 granulator from Freund Co. In this process, two layers are added successively, but being perfectly separated. In the first, the active principle is added with excipients in powder form simultaneously with a solution of the aqueous binder. In the second, the excipients are simply added in powder form together with the solution of the aqueous binder. The process of adding the active layer according to EP 277741 makes it quite porous and that it is distributed in a non-perfectly uniform manner along the surface of the initial inert particle. The obtained spherical granules are dried for sixteen hours and then pass through a cascade of sieves to select the appropriate size range. Finally, to carry out the enteric coating, the dry and sieved granules are introduced in a fluid bed type "urster". In summary, the spherical granules with a coating of s te r r e s t s described in the European patent EP 277741 have passed through four different equipments. Additional examples of coating pellets using the dry powder coating technique are described in EP 642 797 and WO 93 25204. European patent EP 642 797 describes lansoprazole pellets comprising an inert protective reaction layer. , from separation. To produce the pellets, several pieces of equipment are used for each stage of the process: a fluidized bed granulator for the active coating, a fluidized bed cover for the enteric coating and a vacuum for the drying stages. In patent WO 93 25204, omeprazole pellets carry an inert separation separation layer, they are produced using a process that also involves the use of several pieces of equipment. " DESCRIPTION OF THE INVENTION In the present invention a formulation and a working methodology have been developed in a fluid bed type "wurster" or similar. It eliminates the negative factors that affect the methods described so far and incorporates substantial differences compared to the methods of previous patents of pellets containing b in c imi da z or 1 e s. The object of the present invention is to find new pharmaceutical formulations for the oral administration of active ingredients of the type benzimidazole of formula I where: A can be: wherein: R and R are the same or different, being hydrogen, alkyl, alkoxy, or alkoxyalkoxy; and R 4 is hydrogen, alkyl, alkoxy which may be optionally fluorinated, alkoxyalkoxy, or 1 coxy or 1 qui 1, RJ is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, cobalt to 1 to 1, carbamoyl 1 to 1 qui 1, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carba- oyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl; R 2 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, 1 to 1 to 1 to 1 to 1, dialkyl to 1 to 1 to 1 to 1 carbonyl, alkoxycarbomethyl or alkylsulfonyl; and, m is an integer from 0 to 4; or of formula II or III: hereinafter referred to generically as antiulcer compounds. The new galenic formulations object of the present invention are characterized by being spherical granules with a homogeneous active loading layer and a very little porous surface, formed by the coating of an inert core by nebulization of a single aqueous or hydrous mixture. i ca containing the active substance (compound an t i ul ce r o s) together with the rest of the excipients. Then, in the same equipment and after a short drying step, the obtained granules are subjected to an enteric coating step. Optionally, if it is desired to obtain a lower moisture content, an additional drying can be used. Said formulations satisfactorily and innovatively solve the difficulties described in the prior art, while they have resistance to dissolution in acidic medium (gastrorresist in tees) and dissolve rapidly in alkaline environment presenting a disintegration of the granules and transfer of excellent active principle. In the present invention, the difficulty of coating the inert core with a water-based or water-borne coating containing an antipoint compound has generally been satisfactorily solved. , very labile in environment or acid medium and in aqueous solution, in the presence of excipients di s gregant is -infinite that cause an increase in viscosity that greatly impedes its nebulization on the inert nuclei. The fluid bed type "wurster" or similar in which the coating process is carried out minimizes the abrasion caused by the water jet. Therefore, the use of an especially hard inert core is not necessary. The microgranule is not subjected to any kneading or extrusion process, nor is it an inert core coated with powder dusted next to an aqueous binder. The microgranule used in the present invention consists of an inert core which is coated with a single active layer constituted by an aqueous or hydraulic cohesive system which comprises the antiulcer component and at least one excipient of the invention. s gregant e -hinchan te, a binder, an alkalizing medium, a surfactant and a diluent. By firing a single one of its s on s on or on the inert core, it is possible to obtain a less porous and more homogeneous product than in the procedures known up to now and a great simplification of all the subsequent manipulations is achieved. In turn, unlike what happens in the prior art (EP 244,380, EP 277,983, EP 237,200, EP 277,741, PCT W092 / 22289) in which the obtaining procedure is carried out in several different equipment, in the present invention, the whole process is carried out in a single fluid bed equipment so that the losses of time and product are minimized while they are more easily respected Rules of Proper Manufacture of medicines (GMP's). Even by avoiding manipulations and intermediate steps, the investment in machinery and installations is considerably reduced. The inert nuclei used are my neutral spherical molecules that can have two or more of the following substances: sorbitol, mannitol, sucrose, starch, microcrystalline cellulose, lactose, glucose, trehalose, maltitol and fructose. The initial size thereof can be between 200 and 1800 microns, preferably between 600-900 microns.

The only aqueous or hydrolytic liquid ion that is nebulized on the inert nucleus is formed by the active principle with antiulcer activity and the rest of the excipients. The hydrous or coho 1 medium is formed by mixtures of water: ethanol in proportions less than or equal to 50% v / v, preferably between 25% -45% v / v. The oral pharmaceutical preparation of the present invention comprises a compound of antiulcer activity as an active ingredient and is characterized in that it further comprises: a) an inert nucleus; b) a soluble active layer or rapid disintegration in water obtained from a single aqueous suspension or aqueous solution comprising: an active principle of antiulcer activity of general formula I (R ') where: A can be wherein: R3 and R5 are the same or different, being hydrogen, alkyl, alkoxy, or alkoxyalkoxy; and R 4 is hydrogen, alkyl, alkoxy which may be optionally fluorinated, alkoxyalkoxy, or alkoxycycloalkyl, R 1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, ca rb or 1 coxi to 1 qu i 1, carbamoyl, camoba 1, hydroxy, alkoxy, hydroxy alkyl, trifluoromethyl, acyl, camobamoyl, oxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl; R2 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, at 1 qui 1 ca rbamoi 1, di al qui 1 carba -moyl, at 1 qu i 1 ca rbon i lme ti 1, at 1 coxi carboni lme ti 1 or alkylsulfonyl; and, m is an integer from 0 to 4; or of formula II or III - at least one pharmaceutically acceptable excipient selected from the group comprising: a binder, an alkaline reaction compound, a surfactant, a filler and a disintegrating-swelling excipient; and c) an external coating layer of gas obtained in a solution comprising: - an enteric coating polymer; and at least one excipient selected from the group comprising: a plasticizer, a surfactant, a pigment and a lubricant. Among the excipients present in the specification of the active compound of formula I, II or III which is refluxed on the inert nuclei are: a) a binder or mixture of binders: sucrose, starch, methylcellulose, carboxymethyl cellulose (CMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinyl pyrrolidone (PVP), dextrin or gum arabic, dissolved in water, ethanol, or a mixture of both (50% .v / v or less). - b) an alkaline reaction compound, such as trisodium and disodium phosphate, magnesium oxide, hydroxide or carbonate, aluminum hydroxide, carbonate, phosphate or citrate of aluminum, calcium, sodium or potassium, mixed aluminum compounds / magnesium 'A1203.6MgO. C02.12 H20 or MgO. A1203.2 S i02 • nH20 or similar compounds and alkaline-reactive amino acids. c) a surfactant, such as sodium, sodium, polysorbate, poloxamer and other ionic and nonionic surfactants. d) a filler material such as lactose, starch, sucrose or microcrystalline cellulose; e) a di-gregant compound, such as starch, calcium carboxymethylcellulose (CMCCa), sodium starch glycolate or hydroxypropylcellulose (L-HPC). Once the microgranules have been shaped by nebulization of the suspensions or aqueous or hydrochloric light containing the active principle, dried and coated with an enteric coating layer. Enteric-coating polymers can be used: methylcellulose, hydroxyethylcellulose (HEC), hydroxybutylcellulose (HBC), HPMC, ethylcellulose, i-dr or 1-l-1-amine (HMC), HPC, pol i oxy ethyl glycol, oil of castor, cellulose acetate phthalate, HPMC phthalate, HMC acetate succinate, ca rb ox ime ti 1 ami 1 sodiumpeptide, chitosan, alginic acid, genus trapping, ga actoman, tragacanth, shellac, agar-agar, gum arabic, guar gum and xanthan gum, polyacrylic, methacrylic acids and their salts, polyvinyl alcohol (PVA), polyethylene and polypropylene oxides and their mixtures. The polymer may be accompanied by: plasticizers such as T r i e t i 1 (TCE), polyethylene glycol (PEG), cetyl and stearyl alcohol; surfactants such as sodium lauryl sulfate, polysorbate and polaxamer, pigments such as titanium dioxide, iron sesquoxide; lubricants such as talc, magnesium stearate or glyceryl monostearate, as well as a mixture of the same. Another object of the present invention is a method of manufacturing said galenic formulations. The process for obtaining the oral pharmaceutical preparation according to the invention is characterized in that it is carried out: 1) a coating of the inert nuclei by the nebulization of a single suspension-aqueous solution or 1-coho 1 i ca, described above, comprising: the active ingredient of antiulcer activity of formula I, II "or III, and at least one pharmaceutically acceptable excipient selected from the group comprising: binders, alkaline reaction compounds, surfactants, filler material and disintegrating-blowing excipients; 2) a drying of the active layer formed during the nebulization of the previous stage; and 3) coating the charged cores by nebulizing a solution comprising an enteric coating polymer with at least one pharmaceutically acceptable excipient selected from the group comprising: a plasticizer, a surfactant, a pigment and a lubricant, to obtain an outer coating layer ga st ro rr es is ten te. Optionally, after step 3) of coating the charged cores an additional drying is carried out. Next, the method of the invention will be described with special reference to the methodology and percentages used for each of its components. In a tank of suitable dimensions, an aqueous or alkaline hydrochloric acid solution is prepared by incorporating the alkaline reaction compound in a percentage between 0.1% and 5% into the aqueous vehicle or to the coholic (p / p). By continuous stirring, the compound b is incorporated into an antiulcerous agent or another compound with antiulcer activity (6% -25% w / w) and the filler material (3-15% w / w). The surfactant (0.01% -3% w / w), a binder and a di-gregant agent are added to the resulting solution in percentages between 2% ~ 10% re pectively, taking into account the times of use of the prepared solution. The homogenization of the mixture is carried out with continuous stirring and at room temperature (23 + 2 ° C). The stirring is maintained during the nebulization phase of the active layer on the inert pellets; process that is carried out in a "wurstert" type fluid bed equipment or similar in which the inert nuclei with a size of 850μm are poured. The fogging conditions are as follows: Nebulization pressure: 2-3bar. Product temperature: 35-45 ° C. Volume of a i r e: 700-120 Om3 / h at 80-90 ° C. Nozzle diameter: 1, 2 mm). Once the loading phase is finished, the cores coated with the active ingredient are dried in the same equipment. The air flow is 600-800 m3 / h at a temperature of 35-45 ° C for 45 minutes. The next step is the enteric coating of the active pellets that is carried out in the same equipment. An aqueous or organic dispersion of the strresistant ga polymer is prepared (10-40% w / w). In turn, the plasticizer (0.2-10% w / w) is dissolved in water and the agent is added with constant agitation. surfactant (up to 3% w / w) and, if necessary, pigments (0-5% w / w) and lubricants (0.5-16% w / w). Once the mixture has been homogenized, the dispersion of the polymer is added to the mixture (25-45% w / w) maintaining the agitation. To obtain a lower moisture content, an additional drying can be carried out by means of a dryer with encional. More than 90% of the resulting grains must have a diameter between 0.4 and 1.95 mm and more specifically between 0.5 and 1.8 mm The cores of the present invention are resistant to the dissolution in an acidic medium, they dissolve rapidly in an alkaline environment, they are eatable during long periods of storage, they present excellent disintegration characteristics and the active layer is more homogeneous and less porous than the granules described in the previous patents. They solve satisfactorily the drawbacks derived from the prior art since a single one is prepared with its stencil 1 with which the inert nuclei are loaded.For this phase a fluid bed equipment type wurster or similar, much less abrasive, is used. that the rotogranulator that has to be used when coating a seeding core with an active powder and a solution of a binder. the loading of the inert nuclei until the enteric coating is completed, the whole procedure has been carried out in a single "wurster" type fluid bed equipment or similar, unlike other procedures that take place in different equipment.

Brief description of the figures Figure 1 is a photograph obtained by scanning electron microscopy showing a section of the lansoprazole pellet of example 1. Figures 2 and 3 are photographs also obtained by electron microscopy showing more details of the layers present. Figure 4 is a photograph showing the porosity of the cover.

Figures 5, 6 and 7 are photographs showing a section of the pellet of omeprazole of Example 2 with a gauge coating in the form of f or rm I. Figure 8 is a photograph showing the homogeneity of the cover and the shortage of pores. EXAMPLES For a better understanding of what has been explained, some examples are attached in which, schematically and only by way of non-limiting example, a practical case of carrying out the invention is represented.

EXAMPLE 1 In a stainless steel vessel of sufficient capacity, an aqueous alkalizing solution of trisodium phosphate is prepared to which lansoprazole, lactose and 1 to 1% sodium are incorporated by continuous stirring. When the mixture is homogeneous, the aqueous colloidal solution of hydroxypropylmethylcellulose (13.50 'w / w) is incorporated maintaining the agitation in order to guarantee the homogeneity of the product. On said solution-suspension, li-HPC is incorporated. The agitation is maintained until the moment of spraying on the neutral pellets.

Lansoprazole 1.29 Kg La u r i 1 eul f a t sodium. 5.28 10-3 Kg Crystallized disodium phosphate. 0.052 Kg Hydroxypropylmethylcellulose 0.68 Kg Lactose 0.51, Kg Hydroxypropylcellulose 0.39 Kg Water 14.28 Kg kg of inert nuclei composed of sucrose (62.5-91.5%) and starch (37.5-8.5%) of 800 microns of medium size are introduced in a NIRO fluid bed type "wurster" and covered with the oligos. uspension previously prepared under the following conditions: air flow: 250m3 / hour. Nozzle diameter: 1.2 mm. Spray pressure: 2.5 bar. Product fogging: 100 g / min. Air temperature: 85 ° C. Product temperature: 38 ° C. The loaded cores are then dried in the same bed for 45 minutes with air at a temperature of 35 ° C with an air flow of 250m3 / h to obtain the appropriate degree of humidity.

The dried granules are subjected to an enteric restimulation by nebulizing the solution or suspension according to the following detailed description and which is prepared from the aqueous solution of polyethylene glycol to which the rest of the excipients are incorporated by means of continuous agitation. Talc 0 , 57 Kg Titanium dioxide ... 0.18 Kg - Polyethylene glycol 6000 ... 0.18 Kg Polysorbate 0.08 Kg Eudragit L30D55 5.78 Kg Water 12.14 Kg The working conditions are as follows: air flow: 250 m3 / hour. Nozzle diameter: 1.2 mm. Spray pressure: 2.5 bar. Product mist: lOOg / min. Air temperature: 70 ° C. Product temperature: 36 ° C The optional drying of the coated pellets is carried out for 45 minutes with air at a temperature of 35 ° C with an air flow of 250m3 / h. The results of the stability studies carried out on a batch of Lansoprazole pellets under different storage conditions are described below: ambient temperature, and 40 ° C and 75% relative humidity.

Storage conditions: Ambient temperature Packaging: Topaz glass bottle with silica gel bag inside, provided with a metal screw cap that includes a zelelastic plastic seal Time Color Gastrorre- Transfer Active P. Moisture Transmittance of resistance at 440nm test hour white 98.8% 82.8% 33.0mg / 370mg 1.62% 97% zero cream 1 month white 98.6% 82.0% 33 , 0mg / 370mg 1.50% 97% cream 3 white 97.0% 80.9% 32.8mg / 370mg 1.48% 97% cream months 6 white 97.4% 79.8% 32.0mg / 370mg 1.47% 96% cream months 18 white 97.4% 78.9% 31, 9mg / 370mg 1.46% 95 * cream months ro 03 No differences detected i i gn f i I t s in the values of gas t r or re s i s t ction and cession of active principle with respect to the initial values independently of the storage conditions. Both tests are carried out according to the USP XXIII Pharmacopoeia. The active principle potency is determined by high performance liquid chromatography. The degradation products are evaluated on the basis of the results of mitigation detected at 44 Onm. From the results obtained, it can be deduced that there are no great differences with respect to the initial values. A slight loss of activity can be detected after six months of storage at a temperature of 40 ° C, which justifies the decrease in transmittance values at 44 Onm. From the results obtained, the chemical stability of the active principle is verified under the storage conditions tested. On the other hand, there is no appreciable variation in the moisture of the pellets during storage, thus ensuring the physical stability of the f ormulation. All these results demonstrate the stability of the formulations object of the present invention, which differ in addition to those described in the prior art because they do not have an intermediate layer of separation between the active layer and the ga r t ror r es i s t in t e. The scanning electron microscopy study is carried out in a Jeol JSM6400 scanning microscope. Photograph No. 1 shows a section of the lansoprazole pellet of example 1 in which the presence of the inert core, the active layer, intimately attached to the nucleus, and the gas-tight cover in t e can be clearly observed. Photographs 2 and 3 show more details of both layers with greater clarity showing the absence of intermediate layer of separation "between the two Photo 4 shows the low porosity of the cover.The shortage of surface pores justifies the physiological stability chemistry of the pellet.

EXAMPLE 2 In a stainless steel vessel, the alkalizing aqueous solution of disodium phosphate is prepared, on which omeprazole, lactose and 1-urinary acid are added. The agitation is maintained until total homogeneity and the colloidal solution of hydroxypropylmethylcellulose (12.55% w / w) and hydroxypropylcellulose (L-HPC) is added. The pulverization on the neutral pellets, the composition of which 1 is the size of this system, is as follows: Omeprazole 1, 38 Kg Sodium lauryl sulfate 5, 28 10-3 Kg Disodium phosphate crystallized 0, 052 Kg Hydroxypropylmethylcellulose 0.68 Kg Lactose 0.51 Kg Hydroxypropylcellulose 0.39 Kg Water 14.28 Kg Kg of inert nuclei composed of sucrose (62.5-91.5%) and starch (37.5-8.5%) of 850 microns of average size are introduced in a fluid bed NIRO type "wurster" and covered with so lu ci ón - susp in yes above, working under the following conditions: air flow: 250 m3 / hour. Diameter of boqui 1 s: 1, 2 mm. Spray pressure: 2.5 bar. Product fogging: 100 g / min. Air temperature: 75 ° C. Product temperature: 35 ° C. The loaded cores are then dried to obtain the appropriate humidity level in the same bed for 30 minutes with air at a temperature of 30 ° C with an air flow of 250 m3 / h. The dried granules are enteric coated by nebulizing any of the gas-resisting formulas shown below and which are prepared from the aqueous polyethylene glycol solution to which the rest of the excipients are incorporated by continuous stirring (Formula I) ) or from the organic solution of acetone and ethyl alcohol to which the rest of the excipients are incorporated with continuous agitation (formula II). Fórmu la I Talco 0,57 Kg Titanium dioxide .... 0,18 Kg Polyethylene glycol 6000 ... 0,18 Kg Polysorbate 0,08 Kg Eudragit L30D55 5,78 Kg Water 12,14 K Formula II Acetone 20, 86 Kg Hydroxypropylmethylcellulose phthalate ... 2,35 Kg Diethyl phthalate: 0.011 Kg Alconol ethylic 8.93 Kg To this end, work is carried out under the following conditions: air flow: 250 m3 / hour Nozzle diameter: 1.2 mm. Spray pressure: 2.5 bar. Product fogging: 100 g / min. Air temperature: 70 ° C. Product temperature: 36 ° C. The drying of the coated pellets is carried out for 45 minutes with air at a temperature of 35 ° C and with a flow rate of 250m3 / h. The results of the stability studies carried out with a batch of Omeprazole under different storage conditions are shown below: room temperature, and 30 ° C and 65% relative humidity.

Storage conditions: Temperature: 30 ° C. Moisture: 65% Packaging: Topaz glass bottle with silicagel bag inside with metal screw cap that includes a zelelastic plastic seal Color Time Gastrorre- Transfer Active P. Moisture Transmittance test at 44Onm hour zero white 99.0% 94.0% 20.4mg / 233mg 1.12% 98% cream 1 month white 98.0% 93.8% 20 , 0mg / 233mg 1.16% 97% cream cp 3 months white 97.8% 93.1% 20.5mg / 233mg 1.26% 96% cream 6 months white 97.0% 92.6% 20.3mg / 233mg 1.37% 95% cream The values of gas, moisture, and transfer justify the physical stability of the pellet under the storage conditions tested. In turn, the potency of the active principle as well as the transmittance values at 440nm guarantee the chemical stability of the formulation. All these results demonstrate the stability of the formulations object of the present invention, which differ in addition to those described in the prior art because they do not have an intermediate layer of separation between the active layer and the ga s t r or r e s i s t in t e. The scanning electron microscopy study is carried out in a Jeol JSM6400 scanning microscope. Photographs 5, 6 and 7 show a section of the pellet of omeprazole of Example 2 coated with gas in formula I, in which the presence of the inert nucleus, the active layer, intimately bound, can be clearly observed. to the nucleus, and the 'cover ga str or r is ist en te. The photograph number 8 reveals the homogeneity of the cover and the shortage of pores, factors that favor the physical stability of the pellet.

Claims (25)

1. Oral pharmaceutical preparation comprising a compound with an active activity as an active ingredient, characterized in that the preparation consists of: a) an inert nucleus; b) a soluble or rapidly disintegrating active layer in water obtained from a single solvent, its aqueous or hydrophilic pendant comprising: an active principle of antiulcer activity of general formula I in where : A can be where R 'and R- are the same different it being hydrogen, alkyl, alkoxy, or alkoxyalkoxy; and R4. is hydrogen, alkyl, alkoxy which may be optionally fluorinated, alkoxyalkoxy, or 1 coxy or 1 qui 1, R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carb.amoi lalki, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyl, oxy, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl; R 2 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, di to 1 quib i amoe 1, 1 to 1 carbonyl 111, 1 to 1 oxocarbonyl or alkylsulfonyl; and, m is an integer from 0 to 4; Or of formula II or III, - at least one pharmaceutically acceptable excipient selected from the group comprising: a binder, an alkaline reaction compound, a surfactant, a filler and a disintegrating-swelling excipient; and c) a coating layer external to a solution obtained from a solution comprising: an enteric coating polymer; and - at least one excipient selected from the group comprising: a plasticizer, a surfactant, a pigment and a lubricant.

2. Pharmaceutical preparation according to claim 1, characterized in that said inert core is a neutral spherical microgranule comprising in its composition two or more of the following substances: sorbitol, mannitol, sucrose, starch, microcrystalline cellulose, lactose, glucose, trehalose , maltitol or fructose.

3. Pharmaceutical preparation according to the rei indication 1 or 2, characterized in that said inert core has an initial size comprised between 200 and 1800 microns, preferably between 60-0 -900 microns.

4. Pharmaceutical preparation according to claim 1, characterized in that said binder present in said aqueous solution or hydrochloric suspension is selected from the group comprising sucrose, starch, methylcellulose, CMC, HPC, HPMC, poly inylpyrrolidone ( P VP), dex tri na or gum arabic, either alone or mixed, dissolved in water, ethanol or a mixture of both at 50% (v / v).

5. Pharmaceutical preparation according to claim 1, characterized in that said alkaline reaction compound present in said aqueous or hydrophobic suspension solution is selected from the group comprising trisodium phosphate, disodium phosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, carbonate, phosphate, or aluminum, calcium, sodium or potassium citrate, and the mixed compounds of a1 or ini o / ma gn esio A1203.6MgO. C02.12H20 or MgO. l 2032 S i 02. nH20, and alkaline reaction amino acids.

6. Pharmaceutical preparation according to claim 1, characterized in that said surfactant present in said aqueous or cobalt hydrochloric solution-suspension is selected from the group consisting of sodium aurite, polysorbate, poloxamer or other ionic surfactants and non-ionic

7. Pharmaceutical preparation according to claim 1, characterized in that said filler material present in said aqueous solution or suspension or at 1 coh or 1 i ca is selected from the group comprising lactose, starch, sucrose and microcrystalline cellulose.

8. Pharmaceutical preparation according to claim 1, characterized in that said disintegrating-swelling excipient is present in said solution- its aqueous or hydrocarbon solvent is selected from the group comprising starch, CMCCa, starch sodium glycolate and L-HPC.

9. Pharmaceutical preparation according to rei indication 1, characterized in that said enteric coating polymer present in said external coating layer ga st or resist in te is selected from the group comprising methyl cellulose, HEC, HBC, HPMC, ethyl cellulose, HMC, HPC, po 1 i oxyeti 1 eng 1 i co 1, castor oil, cellulose acetate phthalate, HPMC phthalate, HMC acetate succinate, sodium carboxymethyl-aminopectin, chitosan, alginic acid, catarrhine, ga 1 act Omanans, tragacanth, shellac, agar-agar, gum arabic, guar gum, xanthan gum, polyacrylic acids, methacrylics and their salts, PVA, polyethylene and polypropylene oxides and their mixtures.

10. Pharmaceutical preparation according to claim 1, characterized in that said plasticizer present in said external coating layer is selected from the group comprising TEC, PEG, cetyl and stearyl alcohol.

11. Pharmaceutical preparation according to the rei indication 1, characterized in that said surfactant present in said external coating layer ga s t r or is i s t in t e is selected from the group comprising sodium lauryl, polysorbate and poloxamer.

12. The pharmaceutical preparation according to claim 1, characterized in that said pigment present in said external coating layer is selected from the group comprising titanium dioxide and iron sesquioxide.

13. Pharmaceutical preparation according to claim 1, characterized in that said lubricant present in said external coating layer is selected from the group comprising talc, magnesium stearate and glyceryl monostearate.

14. Process for obtaining an oral pharmaceutical preparation according to any of the previous claims, characterized in that it is carried out: 1) a coating of the inert nuclei by means of the nebulization of a single spense on 1 uci ón Aqueous or hi dr or 1 cohó 1 i ca ac comprende: - an active principle of antiulcer activity of general formula I where: A can be: wherein: R3 and R5 are the same or different, being hydrogen, alkyl, alkoxy, or alkoxyalkoxy; and R 4 is hydrogen, alkyl, alkoxy which may be optionally fluorinated, alkoxyalkoxy, or alkoxycycloalkyl, R 1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, ca rb oa 1 cox ia 1 qu i 1, carbamoyl, ca rbamoi 1 a 1 q i 1, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl, acyl, ca rbamoi 1 oi, nitro, acyloxy, aryl, aryloxy, alkylthio or alkylsulfinyl; R2 is hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, at 1 qui 1 carbamoi 1, di at qu i 1 ca rbamoi 1, at 1 qui 1 ca rboni lme ti 1, at 1 cox ica rb on i lme ti 1 o alkylsulfonyl; and, m is an integer from 0 to 4; or of formula II or III, and - at least one pharmaceutically acceptable excipient selected from the group comprising: binders, alkaline reaction compounds, surfactants, filler and disintegrant-swelling excipients; 2) a drying of the active layer formed during nebulization of the previous stage; and 3) coating the charged cores by nebulizing a solution comprising an enteric coating polymer with at least one pharmaceutically acceptable excipient selected from the group comprising: a plasticizer, a surfactant, a pigment and a lubricant , to obtain an external coating layer ga str or re sis t being all the stages carried out in a fluidized bed coater.

15. Process according to claim 14, characterized in that after the step 3) of coating the charged cores an additional drying is carried out.

16. Procedure according to the claim 14, characterized in that said pre-binder in said aqueous solution or suspension is selected from the group comprising sucrose., starch, methylcellulose, CMC, HPC, HPMC, polyvinylpyrrolidone (PVP), dextrin or gum arabic, either alone or mixed, dissolved in water, ethanol or a mixture of both at 50% (v / v).

17. Process according to claim 14, characterized in that said alkaline reaction compound present in said aqueous or hydrophobic suspension to the coholate is selected from the group comprising trisodium phosphate, disodium phosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, carbonate, phosphate, or aluminum citrate, calcium, sodium or potassium, and the mixed compounds of a luminium / magnesium A1203.6MgO. C02.12H20 or MgO. At 2032 S i 02. nH20, and alkaline reaction amino acids.

18. Process according to claim 14, characterized in that said surfactant present in said solution - its aqueous or hydrophilic spen sone is selected from the group comprising sodium sulfate, polysorbate, polaxamer or other ionic and nonionic surfactants.

19. A process according to claim 14, characterized in that said filler material present in said solution-its aqueous or hydrocarbon-is selected from the group comprising lactose, starch, sucrose and cellulose mi c ro crystalline

20. A process according to claim 14, characterized in that said disintegrating-swelling excipient present in said aqueous or hydrolytic hydrocarbon solvent is selected from the group comprising starch, CMCCa, sodium starch glycolate and L-HPC.

21. Process according to claim 14, characterized in that said enteric coating polymer present in said external coating layer ga str orr is selected from the group comprising methylcellulose, HEC, HBC, HPMC, ethylcellulose, HMC, HPC, pol i oxi eti 1 engl i col, castor oil, cellulose acetate phthalate, HPMC phthalate, HMC acetate succinate, sodium carboxymethyl laminepe, chitosan, alginic acid, ca rr age age, ga 1 act man s, tragacanth, shellac, agar-agar, gum arabic, guar gum, xanthan gum, polyacrylic acids, methacrylics and their salts, PVA, polyethylene and polypropylene oxides and their mixtures.

22. Process according to claim 14, characterized in that said plasticizer present in said external coating layer is selected from the group comprising TEC, PEG, cetyl and stearyl alcohol.

23. Procedure according to the claim 14, characterized in that said surfactant is present in said external coating layer if it is selected from the group comprising 1 gold, sodium, polysorbate and poloxamer.

24. A process according to claim 14, characterized in that said pigment present in said external coating layer is selected from the group comprising titanium dioxide and iron sesquioxide.

25. Process according to claim 14, characterized in that said lubricant present in said external coating layer is selected from the group comprising talc, magnesium stearate and glyceryl monostearate.