MXPA00008985A - Solid oral pharmaceutical formulation of modified release that contains an acid labile benzimidazole compound - Google Patents

Abstract

The pharmaceutical formulation consists of a number of pellets that comprise an inert nucleus, a layer with the active ingredient, one or more intermediate layers that comprise at least a system of modified release, and an external layer of enteric coating. These pellets can be obtained applying the different layers by means of fluid bed coaling techniques using aqueous solutions or suspensions of the componentsof such layers. The pharmaceutical formulations can be hard gelatin capsules or tablets and are suitable for use in the prevention and treatment of disorders related to abnormal gastric acid secretion.

Description

PHARMACEUTICAL SOLID ORAL MODIFIED LIBERATION CONTAINING A COMPOUND OF LOW-WEIGHT BENZYMIDAZOLE IN MEDIUM ACID FIELD OF THE INVENTION The invention relates to new modified release dosage forms containing an acid labile benzimidazole compound, suitable for oral administration, consisting of a plurality of pellets comprising the active ingredient, one or more intermediate layers comprising at least one modified release system, and an outer layer of enteric coating. The invention also relates to the process for the preparation of said pellets and pharmaceutical forms and to the use thereof in Medicine.

BACKGROUND OF THE INVENTION Omeprazole, 5-methoxy-2 [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, is a benzimidazole compound suitable for inhibiting gastric secretion in mammals, in particular, suitable for the prevention and treatment of disorders related to the secretion of gastric acid, for example, gastric ulcer, duodenal ulcer, reflux esophagitis, Zolliger-Ellison syndrome, etc. Other benzimidazole compounds with antiulcer activity are pantoprazole, lansoprazole and rabeprazole. Omeprazole, like other benzimidazole compounds with ^^ ¡^^ (^ ^^ b- -árt therapeutic interest, is a labile compound in acid medium, which causes numerous problems when developing a pharmaceutical form intended for oral administration because when said compound it comes into contact with the content of the stomach, which is a strongly acidic medium, its rupture occurs.This lability may be responsible for the variability in the intra- and inter-individual therapeutic response of omeprazole.To avoid contact between the compounds labile in acid medium and gastric juice after oral administration of said compounds, solid pharmaceutical forms have been developed comprising a core containing the labile compound in acid medium and an outer layer that constitutes a gastroresistant coating that could be separated by one or In some cases, conventional enteric coatings of an acidic nature can not be used because The active compound would decompose due to direct or indirect contact with such a coating, which is evidenced by a color alteration and by a decrease in the active compound over time. There are several ways to solve the problem related to the stability of the active compound. One of them consists in the creation of an alkaline environment around the labile benzimidazole compound in an acidic medium, which is achieved by using alkaline salts of the benzimidazole compound and / or by incorporating an alkaline reaction compound in the gastroresistant pharmaceutical preparation [see, for example, example, European patent application EP 0 244 380 and US patent 4,786,505]. Other • - - - - - - - - - •• «- - - i? ? MM ^ ^ ^^ ai way to solve the problem of the stability of the active compound is based on the creation of a physical barrier that achieves a complete separation between the active compound and the enteric layer, thus avoiding any degradation of the active compound, and comprises the use of pharmaceutically acceptable excipients except those that give an alkaline reaction [see, for example, European patent EP 0 773 025]. European patent application EP 0 244 380 describes pharmaceutical formulations suitable for the oral administration of labile substances in acid medium comprising (a) a core containing the active substance together with an alkaline reaction compound, (b) one or more intermediate inert layers containing the excipients for the tablets which are water soluble and rapidly disintegrate in water, a water soluble film forming polymer optionally together with alkaline reaction compounds that act as pH regulators between the core and the layer external, and (c) an outer layer constituted by an enteric coating. U.S. Patent No. 4,786,505 describes pharmaceutical formulations suitable for the oral administration of omeprazole comprising (a) a core comprising omeprazole and an alkaline reaction compound, an alkaline salt of omeprazole and a reaction compound alkaline, or just one alkaline salt of omeprazole, (b) one or more intermediate inert layers soluble in water or rapidly disintegrating in water, and (c) an outer layer constituted by an enteric coating. U.S. Patent No. 5,626,875 describes formulations Pharmaceutical agents suitable for the oral administration of acid-labile benzimidazole compounds comprising (a) a core consisting of inert granules, the active compound, an inert polymer soluble in water and non-alkaline reaction excipients, ( b) an inert coating disposed on said core, formed by a polymer soluble in water and non-alkaline excipients, and (c) an outer layer constituted by an enteric coating. Other pharmaceutical formulations of benzimidazole compounds are described in the PCT patent applications: WO 96/01623, which describes a multiple unit compressed dosage form containing omeprazole or an alkaline salt thereof, and is composed of units arranged in a form of layers, individually coated with an enteric coating, containing the active compound. These units arranged in the form of enteric coated layers are mixed with excipients for tablets and compressed together; and - WO 96/01624, which describes a multiple unit compressed dosage form similar to that described in PCT application WO 96/01623 which contains as an active compound an inhibitor of H + K + -ATPase [proton pump], labile in acid medium, for example, omeprazole, lansoprazole or pantoprazole. A problem that some pharmaceutical forms of oral administration of labile benzimidazole compounds present in acid medium, is related to the plasma half-life of the active principle. In general, the plasma concentration of omeprazole administered by hard gelatine capsules containing omeprazole pellets with enteric coating, shows a maximum at 2 hours of its administration that gradually decreases with time, which causes large fluctuations in the concentration of the active principle in blood and tissues that cause the need to carry out frequent administrations thereof in order to maintain an adequate effective concentration. As it is known, for a certain active principle to be able to exercise its action efficiently it is necessary that it reach a concentration in blood comprised within the range of the so-called effective concentration. The blood concentration of the active ingredient at levels higher than those of the effective concentration tends to increase the incidence of side effects, while at levels lower than those of the effective concentration would result in a weak or no pharmacological response. In order to get In a blood level of the active principle comprised in the effective concentration range, various oral solid forms of modified release have been developed that allow to adjust the release and absorption of the active principle to the process that follows in terms of its biotransformation and elimination in the body , thus allowing to reduce the effects secondary and prolong the action of the active principle. Despite the numerous advantages that solid oral forms of modified release have a priori, many pharmaceutical forms of this type have not been described for the administration of omeprazole - ^ - ».. ^. < »* *«. .. ...... ..Y . -. * ..... - -? m - ,. ? _ ^ _ um_? __? _? __ Lim or other benzimidazole compounds labile in acid medium. The PCT patent application WO 98/52547 describes a pharmaceutical formulation of an active principle, for example, a proton pump inhibitor such as omeprazole, suitable for oral administration comprising a composition for the controlled release of an active ingredient in the gastric environment for a prolonged period of time constituted by microspheres comprising a active ingredient in the inner core of the microsphere, a layer controlling the rate of release of the active principle constituted by a water insoluble polymer, and an outer layer of a bioadhesive agent in the form of a cationic polymer. In general, these formulations act by releasing the active ingredient in the gastric environment for a prolonged period of time and an adhesion thereof on the mucous membranes. It would be convenient, therefore, to develop new oral solid dosage forms of modified release that increase the arsenal of means for effectively administering labile benzimidazole compounds in acidic medium. However, due to the characteristics of this type of active principles, compounds of an acidic nature can not be used, since they could lead to the decomposition of the active principle.

DETAILED DESCRIPTION OF THE INVENTION The invention provides a solid pharmaceutical form of modified release containing as active ingredient a benzimidazole compound labile in acidic medium, suitable for oral administration, hereinafter, pharmaceutical form of the invention, comprising a plurality of pellets containing the active ingredient, one or more intermediate layers comprising, at least, a sustained release system, and an external enteric coating. In the sense used in this description, the term benzimidazole compound labile in acid medium includes the benzimidazole compounds with therapeutic interest whose half-life (i) is less than 10 minutes in an aqueous solution having a pH below 4, and / or (ii) is comprised between 10 minutes and 65 hours in an aqueous solution having a pH of 7, for example, omeprazole, lansoprazole, pantoprazole, rabeprazole as well as the compounds referred to in the PCT patent application WO 97 / 12581. In a particular embodiment, said labile benzimidazole compound in acidic medium is a compound of 2 - [(2-pyridyl) methylsulfinyl] benzimidazole of formula (I) wherein R1 is hydrogen, methoxy or difluoromethoxy, R is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy, and R4 is hydrogen or methyl.

Active, modified-release and gastro-resistant pellets containing an acid-labile benzimidazole compound as an active ingredient, provided by this invention, hereinafter pellets of the invention, comprise: (a) an inert core; (b) an active layer, deposited on said inert core (a), formed by an acid-labile benzimidazole compound, an inert, non-alkaline polymer, soluble in water, and one or more inert pharmaceutically acceptable excipients; (c) one or more intermediate layers comprising: (i) an inert non-alkaline coating, formed by an inert, non-alkaline polymer, soluble in water and one or more inert pharmaceutically acceptable excipients; and (i) a modified release system comprising an inert, non-alkaline, water-soluble polymer and an inert, non-alkaline polymer, insoluble in water; said intermediate layer or layers being disposed on said active layer (b) which covers the inert core; and (d) an outer layer disposed on said intermediate layer or layers (c) consisting of an enteric coating.

In a particular embodiment, the intermediate layer or layers (c) of the 5 pellets of the invention contain, separately: (i) one or more layers constituting said inert non-alkaline coating; and (ii) one or more layers containing said modified release system.

In this particular embodiment said inert coating and modified release layers are separated from each other and constitute independent layers. Likewise, the number of inert coating layers and the number of modified release layers is variable as well as the order of said layers, which may be interleaved with each other. In its simplest embodiment, the pellets of the invention included within this particular embodiment comprise a single inert coating layer and a single modified release layer. A representative example of this particular embodiment of the invention are gastro-resistant and modified-release pellets, containing a benzimidazole compound labile in an acidic medium as an active compound, comprising: ~ Mk ~ «> i ?? uu > > ? DHha '- ^ -ta Ma ^ M ^^ B ^^^ M ^ ia ^ aMMMaMM aM ^ ^^^ MMaHAM riliaMrt-MI (a) an inert core; (b) an active layer, deposited on said inert core (a), formed by an acid-labile benzimidazole compound, an inert, non-alkaline polymer, soluble in water, and one or more inert pharmaceutically acceptable excipients; (D) an intermediate layer is a non-alkaline inert coating disposed on said active layer (b) that covers the water soluble and one inert core, formed by an inert polymer, non-alkaline or more pharmaceutically acceptable inert excipients; (c2) a modified release intermediate layer, deposited on said intermediate inert layer (d) comprising an inert, non-alkaline polymer soluble in water and an inert, non-alkaline polymer, insoluble in water; and (d) an outer layer disposed on said modified release intermediate layer (c2) consisting of an enteric coating. In another particular embodiment, the intermediate layer or layers (c) of the pellets of the invention contain, mixed together: (i) said non-alkaline inert coating; and (ii) said modified release system.

^ -. In this particular embodiment said inert coating and modified release layers are mixed together and constitute a single layer of variable thickness. A representative example of this particular embodiment of the invention are gastroresistant and modified release pellets, which contain a benzimidazole compound labile in an acidic medium as an active compound, comprising: (a) an inert core; (b) an active layer, deposited on said inert core (a), formed by an acid-labile benzimidazole compound, an inert, non-alkaline polymer, soluble in water, and one or more inert pharmaceutically acceptable excipients; (c) an intermediate layer comprising (i) an inert non-alkaline coating formed by an inert, non-alkaline polymer, soluble in water and one or more inert pharmaceutically acceptable excipients, and (ii) a modified release system comprising a polymer inert, non-alkaline, soluble in water and an inert polymer, non-alkaline, insoluble in water, said intermediate layer being disposed on said active layer (b) which covers the inert core; and (d) an outer layer disposed on said intermediate layer (c) consisting of an enteric coating.

Another particular embodiment contemplated within the scope of the present invention comprises a mixed pellet, ie, a pellet of the invention wherein said intermediate layer or layers (c) comprise a mixture formed by (1) one or more layers of inert coating. and one or more modified release layers, and (2) a mixture constituted by said inert coating and said modified release system. The inert nucleus (a) is a pharmaceutically inert substance in relation to the active principle, that is to say, it does not react with the active principle under the conditions used so as to produce the decomposition thereof, and it can be composed of a sugar, example, sucrose, starch and their mixtures. In a particular embodiment, said inert cores are composed of a mixture of sucrose and corn starch, have an average size of between 0.3 and 1.4 mm and meet the requirements of the USP (American Pharmacopoeia) [Monograph by Sugar Spheres , USP NF 18]. In a particular embodiment, the inert cores (a) are present in the pellet of the invention in an amount comprised between 20% and 70% by weight with respect to the total pellet. Active layer (b) comprises (i) an acid-labile benzimidazole compound, preferably, a compound of formula (I), more preferably omeprazole, (i) an inert, water-soluble, non-alkaline polymer, such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC) and (iii) one or more inert pharmaceutically acceptable excipients, such as, a diluent, for example, talc. In the sense used in this description the -Ji T Í - _ ^, ^^ M ^^ MM ^^^^ M ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ The term inert, applied to a polymer or to an excipient, refers to the fact that said compounds do not react under the conditions used. In a particular embodiment, the active layer (b) is present in the pellet of the invention in an amount comprised between 10% and 50% by weight with respect to the total of the pellet. As previously mentioned, the intermediate layer or layers (c) comprise one or more inert coating layers and one or more modified release layers (ie, those containing the modified release system), separated from each other to form one or more intermediate layers or mixed together forming a single intermediate layer or a mixed system of both embodiments. In a particular embodiment, the intermediate layer or layers (c) is (are) present in the pellet of the invention in an amount between 5% and 30% by weight with respect to the total pellet. The inert coating layer or layers comprise (i) an inert polymer, non-alkaline, water soluble, such as HPMC or HPC; and (ii) one or more inert pharmaceutically acceptable excipients, such as a diluent, for example, talc, and a pigment, for example, titanium dioxide. The modified release layer (s) comprises (n) a modified release system comprising an inert, non-alkaline, water-insoluble polymer, for example, ethylcellulose (EC) or a copolymer of ammonium methacrylate [Eudragit RS and RL30D], together with an inert, non-alkaline polymer, soluble in water such as HPMC. This layer (s) provides (n) the retardant and modified release character of the active compound. The insoluble polymer: soluble polymer present in this layer (s) ratio can vary between very wide limits. By varying the amount of insoluble polymer versus that of soluble polymer a greater or lesser retarding effect is achieved [in general, increasing the amount of insoluble polymer versus the amount of soluble polymer, the release of the active principle becomes slower]. In a particular embodiment, the modified release system is present in the pellet of the invention, typically, in an amount of 10% by weight with respect to the pellet. The outer layer (d) disposed on said intermediate layer or layers (c) constitutes the enteric coating and is composed of (i) a gastroresistant polymer, such as a methacrylic copolymer, for example a copolymer formed by methacrylic acid and esters of methacrylic acid, (ii) a plasticizer, for example, triethyl citrate or the like, and (iii) one or more inert pharmaceutically acceptable excipients. , for example, talcum powder. In a particular embodiment, the outer layer (d) constituting the enteric coating is present in the pellet of the invention in an amount comprised between 10% and 15% by weight with respect to the total of the pellet. The pellets of the invention can be obtained by conventional techniques. A review of the different techniques for obtaining pellets with therapeutic applications can be found in the book Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-Sellassie, Marcel Dekker, Inc., 1989. In a particular embodiment, the pellets of the invention are obtained by applying the different layers by conventional fluid bed coating techniques using aqueous solutions or suspensions of the TheUtfaa? a £ Ce? a? l-aÉa < t. components of such layers. Briefly, in a fluid bed apparatus, the inert cores are coated with a first layer containing the labile benzimidazole compound in an acid medium, an inert, non-alkaline, water-soluble polymer, such as HPMC or HPC, and one or more excipients pharmaceutically acceptable inerts, for example, talc. Next, said active layer is coated with one or more intermediate layers containing (i) an inert non-alkaline coating, formed by an inert, non-alkaline, water-soluble polymer, such as HPMC or HPC, and one or more inert excipients pharmaceutically acceptable, for example, talc and a pigment, such as titanium dioxide; and (ii) a modified release system comprising an inert, non-alkaline, water-soluble polymer, for example HPMC, and an inert, non-alkaline, water-insoluble polymer, for example, EC or a copolymer of ammonium methacrylate. This intermediate layer may be formed by a variable number of inert coating layers and by a variable number of separate modified release layers or may be formed by a single layer constituted by a mixture of the inert coating and modified release layers or well for a mixture of both types. Finally, the enteric coating layer consisting of a gastric juice-resistant polymer or copolymer, such as that consisting of methacrylic acid methyl methacrylate, a plasticizer, for example, triethyl citrate, and one or more inert pharmaceutically acceptable excipients is applied. , for example, talcum powder. The pellets of the invention can be administered in an appropriate dosage form, such as a solid dosage form, suitable for oral administration, for example, in the form of hard gelatin capsules or can be formulated as tablets. The dosage form can contain pellets with different modified release profiles, ie, with modified release systems containing a different weight ratio (insoluble polymer: soluble polymer), for example, they can contain a mixture of (i) pellets with a rapid release profile and (i) pellets with a slow release profile, in a ratio (i) :( ii), by weight, between 10:90 and 90:10. Pellets with a slow release profile comprise an insoluble polymer ratio: soluble polymer in the higher modified release system than in the case of pellets with a rapid release profile. In the sense used in this description, the term pellets with a slow release profile refers to pellets that are released in an aqueous medium, pH 6.8, after 30 minutes [ie 150 minutes if the 2 hours are counted in acid medium (HCl) according to Monograph 724 of the USP for Drug Relay, specifically for Delayed-Release (Enteric coated Articles)] a maximum of 50% active substance. If the amount of active principle released in such conditions is greater than 50% then said pellets are considered, in this description, pellets with a rapid release profile. Example 8 shows illustrative data of pellets with slow release and quick release profiles according to the present invention. Therefore, the invention provides a solid pharmaceutical form of modified release containing as active ingredient a benzimidazole compound labile in an acid medium, suitable for oral administration, - "" - "* * ~ -" - »« «« «« * «» comprising a plurality of the pellets of the invention, with the same or different release profile, in a therapeutically effective amount. The pharmaceutical form of the invention can be obtained by conventional methods depending on the specific form of administration. A review of the different methods for obtaining pharmaceutical forms is mentioned in the Galenica Pharmacy Treaty, C. Faulí i Trillo, Luzán 5, S.A. from Editions (1993). The active ingredients can be administered in the same doses and according to the same protocols as those of the existing commercial pharmaceutical forms. In general, the dose of said active principle is comprised between approximately 1 mg / kg / day and 100 mg / kg / day, adjusted to the individual needs of the patients and according to the criteria of the specialist. The pharmaceutical form of the invention is resistant to dissolution in an acidic medium, stable in its passage through the gastric juice and allows the controlled release of the active principle in an alkaline or neutral aqueous medium, the conditions of the proximal part of the small intestine . The invention also provides a method for the prevention and treatment of disorders related to an abnormal gastric acid secretion comprising administration to a patient affected by an abnormal gastric acid secretion of a therapeutically effective amount of the pharmaceutical form of the invention. The following examples serve to illustrate the invention. The active substance release assays were performed following the protocol described in USP Monograph 724 for Drug Release, specifically for Delayed-Release (Enteric coated Articles).

EXAMPLE 1 A suspension of the active ingredient is prepared by dispersing 80.40 g of active ingredient [omeprazole or lansoprazole], 64.33 g of HPMC and 20.12 g of talc, in 642.86 g of purified (deionized) water. In a fluid bed apparatus, 563.03 g of inert, spherical, uniform 1, 0-1, 2 mm, sucrose nuclei are introduced, onto which the previously obtained suspension is sprayed. After spraying, and before applying the second layer, the spheres obtained (the inert cores coated with the active layer) are dried. In 402.86 g of purified water, 60.54 g of HPMC, 8.04 g of talc and 8.03 g of titanium dioxide are dispersed, and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying, and before applying the next layer, the spheres obtained are dried. In 631, 43 g of purified water are dispersed 36.20 g of HPMC and 44.25 g of an aqueous dispersion of ethylcellulose (EC) [ratio HPMC: EC 55:45] and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying, and before applying the next layer, the spheres obtained are dried. In 285.71 g of purified water, 88.50 g of methacrylic acid copolymer of USP / Ph.Eur quality are dispersed. (aqueous dispersion type C), 13.28 g of triethyl citrate and 13.28 g of talc, and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying and applying this enteric coating layer the resulting spheres (pellets) are dried. The pellets obtained have a slow release profile.

EXAMPLE 2 The procedure described in Example 1 was repeated with the exception that the suspension containing the components of the modified release intermediate layer contained 24.14 g of HPMC and 56.31 g of an aqueous dispersion of EC [ratio HPMC: EC 70:30]. The pellets obtained have a very slow release profile.

EXAMPLE 3 A suspension of the active principle is prepared by dispersing 81, 79 g of active ingredient [omeprazole or lansoprazole], 62.91 g of HPMC and 19.66 g of talc, in 629.10 g of purified (deionized) water. In a fluid bed apparatus, 547.34 g of inert, spherical, uniform 1, 0-1, 2 mm, sucrose cores are introduced, onto which the previously obtained suspension is sprayed. After spraying, and before applying the second layer, the spheres obtained (the inert cores coated with the active layer) are dried. In 393.20 g of purified water, 58.98 g of HPMC, 7.86 g of talc and 7.86 g of titanium dioxide are dispersed, and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying, and before applying the next layer, the spheres obtained are dried. In 786.40 g of purified water, 39.32 g of HPMC are dispersed and 39.32 g of an aqueous dispersion of EC [ratio HPMC: EC 50:50] and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying, and before applying the next layer, the spheres obtained are dried. In 332.20 g of purified water, 103.81 g of methacrylic acid copolymer of USP / Ph.Eur quality are dispersed. (aqueous dispersion type C) [Eudragit L30D], 15.57 g of triethyl citrate [Eudraflex], 15.59 g of talc, and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying and applying this enteric coating layer the resulting spheres (pellets) are dried.

EXAMPLE 4 The procedure described in Example 3 was repeated with the exception that the suspension containing the components of the modified release intermediate layer contained 31.46 g of HPMC and 47.18 g of an aqueous dispersion of EC [ratio HPMC: EC 60:40]. The pellets obtained have a slow release profile.

EXAMPLE 5 The procedure described in Example 3 was repeated with the exception that the suspension containing the components of the modified release intermediate layer contained 23.59 g of HPMC and 55.05 g of an aqueous dispersion of EC [ratio HPMC: EC 70:30]. The pellets obtained have a very slow release profile. 10 EXAMPLE 6 A suspension of the active ingredient is prepared by dispersing 402 g of active ingredient [omeprazole or lansoprazole], 321.65 g of HPMC and 100.6 g of talc, in 3.214.3 g of purified (deionized) water. In a fluid bed apparatus, 2.815.15 g of inert, spherical, uniform 1, 0-1, 2 mm, sucrose cores are introduced, onto which the previously obtained suspension is sprayed. After spraying, and before applying the second layer, the spheres obtained (inert cores coated with the active layer) are dried. In 2.014.3 g of purified water, 302.7 g of HPMC, 40.2 g of talc and 40.15 g of titanium dioxide are dispersed, and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying, and before applying the next layer, the obtained spheres are dried. In 3.157.15 g of purified water, 162.91 g of HPMC and 957.36 g of an aqueous dispersion of EC [HPMC: EC 70:30 ratio] are dispersed and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying, and before applying the next layer, the spheres obtained are dried. In 1,428.55 g of purified water, 1475 g of methacrylic acid copolymer of USP / Ph.Eur quality are dispersed. (aqueous dispersion type C) [Eudragit L30D], 66.4 g of triethyl citrate [Eudraflex], 66.4 g of talc, and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying and applying this enteric coating layer the resulting spheres (pellets) are dried. The pellets obtained have the core and 4 layers (active, inert coating, modified release and enteric) and a very slow release profile.

EXAMPLE 7 A suspension of the active ingredient is prepared by dispersing 402 g of active ingredient [omeprazole or lansoprazole], 321.65 g of HPMC and 100.6 g of talc, in 3.214.3 g of purified (deionized) water. In a fluid bed apparatus, 2.815.15 g of inert, spherical, uniform 1, 0-1, 2 mm, sucrose cores are introduced, onto which the previously obtained suspension is sprayed. After spraying, and before applying the second layer, the spheres obtained (the inert cores coated with the active layer) are dried. In 5.171, 45 g of purified water disperse 465.61 g of HPMC, 40.2 g of talc, 40.15 g of titanium dioxide and 957.36 g of an aqueous dispersion of EC [ratio HPMC: EC 70:30] and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying, and before applying the next layer, the spheres obtained are dried. In 1,428.55 g of purified water, 1475 g of methacrylic acid copolymer of USP / Ph.Eur quality are dispersed. (aqueous dispersion type C) [Eudragit L30D], 66.4 g of triethyl citrate [Eudraflex], 66.4 g of talc, and the resulting aqueous suspension is sprayed onto the previously obtained spheres. After spraying and applying this enteric coating layer the resulting spheres (pellets) are dried. The pellets obtained have the core and 3 layers [active, intermediate (formed by the inert coating and the modified release system) and enteric] and a very slow release profile.

EXAMPLE 8 Release of active principle Following the methodology described in the preceding Examples, various batches of omeprazole pellets with different modified release systems have been prepared by varying only the relative amounts of HPMC and EC in order to modify the HPMC: EC ratio. The protocol used in the assay of release of the active principle is that described in Monograph 724 of the USP for Drug Relase, specifically for Delayed-Release (Enteric coated Articles). The percentage of omeprazole released at different times in an aqueous medium (pH 6.8) was determined after having previously maintained the different pellets for 2 hours in HCl medium. The results obtained are shown in Table 1.

TABLE 1 Percentage of release of Omeprazole from pellets with different release profiles This trial showed that by increasing the amount of EC compared to the amount of HPMC present in the modified release system, pellets with slower active ingredient release profiles were obtained.

Claims (19)

NOVELTY OF THE INVENTION CLAIMS

1. A sustained release, sustained release, gastro-resistant pellet, containing a labile benzimidazole compound in an acidic medium as active ingredient, comprising: (a) an inert core; (b) an active layer, deposited on said inert core (a), formed by an acid-labile benzimidazole compound, an inert, non-alkaline polymer, soluble in water, and one or more inert pharmaceutically acceptable excipients; (c) one or more intermediate layers comprising: (i) an inert non-alkaline coating, formed by an inert, non-alkaline polymer, soluble in water and one or more inert pharmaceutically acceptable excipients; and (ii) a modified release system comprising an inert, non-alkaline, water-soluble polymer and an inert, non-alkaline polymer, insoluble in water; said intermediate layer or layers being disposed on said active layer (b) which covers the inert core; and (d) an outer layer disposed on said intermediate layer or layers (c) consisting of an enteric coating.

2. Pellet according to claim 1, wherein said intermediate layer or layers (c) contain, separately: (i) one or more layers constituting said non-alkaline inert coating; and (ii) one or more layers containing said modified release system.

3. Pellet according to claim 2, comprising: (a) an inert core; (b) an active layer, deposited on said inert core (a), formed by an acid-labile benzimidazole compound, an inert, non-alkaline polymer, soluble in water, and one or more inert pharmaceutically acceptable excipients; (d) an intermediate layer constituting an inert non-alkaline coating disposed on said active layer (b) which overlies the inert core, formed by an inert, non-alkaline polymer, soluble in water and one or more inert pharmaceutically acceptable excipients; (c2) a modified release intermediate layer, deposited on said intermediate inert layer (d) comprising an inert, non-alkaline polymer, soluble in water and an inert, non-alkaline polymer, insoluble in water; and (d) an outer layer disposed on said modified release intermediate layer (c2) consisting of an enteric coating.

4. Pellet according to claim 1, wherein said intermediate layer or layers (c) contain, mixed together: (i) said non-alkaline inert coating; and (i) said modified release system.

5. Pellet according to claim 4, comprising: (a) an inert core; (b) an active layer, deposited on said inert core (a), formed by an acid-labile benzimidazole compound, an inert, non-alkaline polymer, soluble in water, and one or more inert pharmaceutically acceptable excipients; (c) an intermediate layer comprising (i) an inert non-alkaline coating formed by an inert, non-alkaline polymer, soluble in water and one or more inert pharmaceutically acceptable excipients, and (ii) a modified release system comprising a polymer inert, non-alkaline, soluble in water and an inert polymer, non-alkaline, insoluble in water, said intermediate layer being disposed on said active layer (b) which covers the inert core; and (d) an outer layer disposed on said intermediate layer (c) consisting of an enteric coating.

6. Pellet according to claim 1, wherein said intermediate layer or layers (c) comprises a mixture formed by: (1) one or more layers of inert coating and one or more layers of modified release, and (2) a mixture formed by said inert coating and said modified release system.

7. Pellet according to any of the preceding claims, wherein said acid-labile benzimidazole compound is a compound of 2 - [(2-pyridyl) methylsulfinyl] benzimidazole of formula (I) where R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy, and R4 is hydrogen or methyl.

8. Pellet according to claim 7, wherein said compound of Labile benzimidazole in acid medium is selected from the group consisting of omeprazole, lansoprazole and pantoprazole.

9. Pellet according to any of claims 1 to 6, wherein said inert water-soluble, non-alkaline polymer present in the active layer (b) is selected from hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC).

10. Pellet according to any of claims 1 to 6, wherein said water-soluble, non-alkaline inert polymer present in the intermediate layer or layers (c) is hydroxypropylmethylcellulose (HPMC).

11. Pellet according to any of claims 1 to 6, wherein said inert water-soluble, non-alkaline polymer present in the modified release layer is hydroxypropylmethylcellulose (HPMC).

12. Pellet according to any one of claims 1 to 6, wherein said inert non-alkaline water-insoluble polymer present in the modified release layer is ethylcellulose or a copolymer of ammonium methacrylate.

13. Pellet according to any of claims 1 to 6, wherein said outer layer (d) comprises a gastroresistant polymer, a plasticizer and one or more inert pharmaceutically acceptable excipients.

14. A process for obtaining a modified gastro-resistant release pellet containing as active ingredient an acid-labile benzimidazole compound according to claims 1-13, comprising: (i) applying an aqueous suspension of an aqueous suspension to an inert core; labile benzimidazole compound in an acidic medium, an inert, non-alkaline, water-soluble polymer, and one or more pharmaceutically acceptable inert excipients, to obtain an active layer that coats the inert core, (ii) applying on said active layer one or more intermediate layers, separated and / or mixed together, containing (i) an inert non-alkaline coating, formed by an inert, non-alkaline polymer, soluble in water, and one or more inert pharmaceutically acceptable excipients; and (ii) a modified release system comprising an inert, non-alkaline polymer, soluble in water and an inert, non-alkaline polymer, Nsolubie in water; separated and / or mixed; and (iii) coating said intermediate layer or layers with an aqueous suspension comprising a gastroresistant polymer, a plasticizer and one or more inert pharmaceutically acceptable excipients to create an external enteric coating layer.

15. A solid pharmaceutical form of modified release containing as active ingredient a benzimidazole compound labile in an acid medium, suitable for oral administration, comprising a plurality of modified-release and gastro-resistant pellets, containing as active ingredient a compound of labile benzimidazole in acid medium, according to claims 1-13.

16. Pharmaceutical form according to claim 15, wherein said plurality of pellets is formed by pellets having the same active ingredient release profile.

17. Pharmaceutical form according to claim 15, wherein said plurality of pellets is formed by a mixture of pellets having a different active ingredient release profile.

18. Pharmaceutical form according to claim 17, wherein said plurality of pellets is formed by a mixture of (i) pellets with a rapid release profile and (ii) pellets with a slow release profile, in a ratio (i) :( ii), by weight, between 10:90 and 90:10.

19. Pharmaceutical form according to claim 15, selected from hard gelatin capsules and tablets.