IL139894A - Stable benzimidazole composition and a method for producing it - Google Patents

Description

iitniiiiiiiiH i Ji-on1? ηο'κ/ι "ϊΐτΝτη'Τ-α v« n STABLE BENZIMIDAZOLE COMPOSITION AND A METHOD FOR PRODUCING IT Dr. D. Graeser Ltd.

Our ref. 452 STABLE BENZIMIDAZOLE FORMULATION FIELD AND BACKGROUND OF THE INVENTION The present invention relates to a novel stable formulation for an acid labile benzimidazole, and methods of preparation and administration thereof, and in particular, for a stable formulation of a benzimidazole which is suitable for oral administration.

Omeprazole, Pantoprazole, Lansoprazole and other derivatives of benzimidazole, which are active proton pump inhibitors and used conventionally for decreasing gastric secretion are known to be susceptible to degradation and transformation in acid media. Omeprazole, 5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-lH-benzimidazole, is disclosed and described in European Patent No. 5129 and European Patent No. 124495, as well as in numerous other patents and published patent applications.

The susceptibility of these active proton pump inhibitor substances to degradation and transformation in acid media increases the difficulty of preparing a pharmaceutical form designed for oral administration. If the active substance comes into contact with the stomach content, which is a highly acidic medium, these chemical substances become degraded. Thus, these benzimidazole derivatives should be protected both during storage and during their passage through the acidic environment of the stomach.

The stability of Omeprazole has been extensively studied (see for example A. Pilbrant and C. Cederberg, Scan. J. Gastroenterol., 20: 1 13-120, 1985). Omeprazole degrades with a half-life of less than 10 minutes in an environment with pH values below 4.0. At pH 6.5, the half life of Omeprazole is 18 hours and at pH 11 about 300 days. Therefore, the environment of Omeprazole should be kept at a sufficiently high pH value in order to maintain the stability of the compound, in a formulation which is suitable as a product for oral administration, for example by locating Omeprazole within a core which also contains alkaline constituents. This leads to an alkaline reaction aimed at improving stability of the active substance during manufacture thereof and during storage of the pharmaceutical formulation.

In addition, such a formulation must protect Omeprazole from the acidic environment of the stomach, since if Omeprazole is given orally without any protective coating, it will degrade in the acid environment of the stomach. European Patent No. 237,200 discloses one solution, which is to directly coat the solid core containing Omeprazole, or another benzimidazole derivative, with an enteric coating layer.

However, this apparent solution to the instability of Omeprazole caused further complications, in that the alkaline core containing Omeprazole was found to react with the enteric coating, thereby causing the enteric coating to degrade. A solution to these further complications is disclosed in United Kingdom Patent Application No. 2,189,698, in which Omeprazole is contained within a solid active core, which is coated first with a subcoating layer and then with an enteric coating layer. The enteric coating layer protects the Omeprazole during the passage through the stomach, while the subcoating layer protects the enteric coating layer from reacting negatively with the alkaline core containing Omeprazole.

The background art describes other attempts to provide formulations which are suitable for oral administration of acid-labile substances. For example, PCT Application No. WO 97/12581 discloses a composition adapted for oral administration containing Omeprazole which specifically does not include alkaline-reacting compounds. Instead, the composition features a core composed of a nuclei and Omeprazole compressed together, an intermediate layer and an enteric layer.

European Patent Application No. 519, 144 discloses a formulation for Omeprazole, which features a neutral (sugar) core. Omeprazole is sprayed onto the sugar core, after which an intermediate coating layer and an enteric coating layer are sprayed onto the core.

PCT Application No. WO 98/00114 discloses a modification to other background art formulations for Omeprazole, in which the intermediate subcoating layer is partially neutralized with an alkaline compound. However, this modified formulation still features the subcoating layer, which is a disadvantage in that it complicates the manufacturing process and increases the expense and difficulty of manufacture. Thus, the formulation disclosed in PCT Application No. WO 98/001 14, like those disclosed in European Patent Application No. 519,144 and other background art references, has the disadvantage of requiring the intermediate layer.

PCT Application No. WO 83/00435 discloses a solid dosage form, such as a capsule or tablet, containing a pharmacologically active agent coated with an anionic polymer, which is insoluble in gastric juice and in intestinal juice below pH 7. The preferred anionic polymer is a partly methyl esterified methacrylic acid polymer in which the ratio of free carboxylic groups to ester groups is about 1 :2. In contrast to the present invention, Omeprazole is not disclosed as one of the active agents.

French Application No. 2,692,146 discloses stable compositions of microgranules of gastro-protected Omeprazole. The composition features a center of Omeprazole diluted in mannitol. This center is coated with an intermediate layer featuring mannitol. An enteric 139894/4 coating is then added over this intermediate layer. PCT Application No. WO 97/12581 discloses a formulation in which an intermediate layer between the core and an enteric coating contains silicium dioxide.

PCT Application No. WO 96/37195 discloses a formulation which lacks a subcoating layer, but which features a core containing titanium dioxide. Both the core containing Omeprazole and the enteric coating layer placed on top of the core include titanium dioxide as an ingredient. Unfortunately, titanium dioxide is only able to mask the discoloration caused by the reaction between Omeprazole and the enteric coating layer, but cannot prevent such an undesirable reaction. Thus, the disclosed formulation does not prevent the undesirable reaction between the benzimidazole derivative and the enteric coating, which is known in the art.

German Patent Application No. 196 26 045 Al discloses a method for stabilising Omeprazole by coating small tablets or pellets, containing large amounts of mannitol, with a subcoating of Eudragit L. The subcoating of Eudragit L is neutralized , after which a final enteric coat of non-neutralized Eudragit L is applied.

A formulation of a benzimidazole derivative, such as Omeprazole, which lacks an intermediate coating layer and yet which is stable both during storage and during the passage through the stomach, would be highly desirable. Such a formulation would be simpler to manufacture and would expose the sensitive benzimidazole derivative to fewer production steps, thereby decreasing the possibility that the active compound would degrade during production. Unfortunately, such a stable benzimidazole formulation, which lacks an intermediate layer, is not currently available.

There is thus an unmet need for, and it would be useful to have, a stable benzimidazole formulation, particularly for Omeprazole which lacks an intermediate layer and yet which is stable both during storage and during the passage through the stomach.

SUMMARY OF THE INVENTION According to some embodiments, there is provided a stable composition for a benzimidazole derivative, the composition comprising: (a) a neutral core; (b) an alkaline coating layered on said neutral core; (c) an active coating, comprising the benzimidazole derivative, layered over said alkaline coating; and (d) a single layer comprising neutralized enteric coating material having a pH value of at least 6.5 layered directly over said active coating, said neutralized enteric coating material being 139894/4 neutralized with an alkaline compound prior to applying said single layer to said active coating, with the proviso that said enteric coating material does not include HPMCP (hydroxypropyl methylcellulose phthalate).

According to some demonstrative embodiments, the enteric coating material may include at least one enteric material selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylic acid methyl methacrylate, and polymethacrylic acid ethyl methacrylate.

According to some demonstrative embodiments, the pH value of the enteric coating material may be adjusted by adding said alkaline compound to said enteric material.

According to some demonstrative embodiments, the alkaline compound may be an inorganic alkaline compound.

According to some demonstrative embodiments, the alkaline compound may be selected from the group consisting of basic sodium, potassium and ammonium hydroxide.

According to some demonstrative embodiments, the enteric coating material may be at least about 60 % neutralized by adding said alkaline compound.

According to some demonstrative embodiments, the enteric coating material may be at least about 80 % neutralized by adding said alkaline compound.

According to some demonstrative embodiments, the enteric coating material may be at least about 95 % neutralized by adding said alkaline compound.

According to some demonstrative embodiments, the pH value may be in a range of from about 7 to about 10.

According to some demonstrative embodiments, the enteric coating material may further comprise a plasticizer.

According to some demonstrative embodiments, the plasticizer may be selected from the group consisting of a citric acid ester and a phthalic acid ester.

According to some demonstrative embodiments, the benzimidazole derivative may be selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically acceptable salts thereof.

According to some demonstrative embodiments, the composition described herein may further comprise a gelatin capsule for receiving the coated cores.

According to some demonstrative embodiments, the alkaline coating may comprise one or more of sodium stearate or arginine.

According to some demonstrative embodiments, the alkaline coating may further comprise HPMC (hydroxypropyl methylcellulose).

According to some demonstrative embodiments, the alkaline coating may further comprise sodium lauryl sulfate.

According to some demonstrative embodiments, the active coating may comprise one or more of HPMC (hydroxypropyl methylcellulose) or HPC (hydro yl propyl cellulose) or a combination thereof.

According to some demonstrative embodiments, the active coating may further comprise sodium lauryl sulfate.

According to some demonstrative embodiments, there is provided a method for producing a stable composition for a benzimidazole derivative, for example as described herein, the method comprising the steps of: (a) coating a neutral core with an alkaline coating; (b) coating said alkaline coated neutral core with an active coating, said active coating comprising the benzimidazole derivative; (c) preparing a neutralized enteric coating material having a pH value of at least about 6.5 by neutralizing with an alkaline compound; and (d) layering a single layer of said neutralized enteric coating material directly over said active layer, with the proviso that said enteric coating material does not include HPMCP (hydroxypropyl methylcellulose phthalate).

According to some demonstrative embodiments, the enteric coating material may be prepared by the steps of: (i) mixing an enteric material with water to form a mixture; and (ii) adding said alkaline compound to said mixture to form an aqueous solution having a pH value of from about 7 to about 10.

According to some demonstrative embodiments, the method described herein may further comprise the step of: (d) filling a gelatin capsule with the coated cores.

BRIEF DESCRIPTION OF THE INVENTION The formulation of the present invention contains a benzimidazole derivative, such as Omeprazole, and is able to maintain the stability of this active ingredient without a separating 139894/4 layer. Instead, the enteric coating layer is applied as a solution with a pH value of at least 6.5, and more preferably in a range of from about 7 to about 10, directly to the benzimidazole derivative substrate. This solution, with the optional addition of a plasticizer, can be directly coated onto the substrate without any necessity for an intermediate layer. Furthermore, in this pH range, the enteric coating is optionally applicable in an aqueous solution, thereby obviating the need for organic solvents for dissolving the enteric coating material.

The resultant formulation maintains the stability of the benzimidazole derivative during storage and at the same time protects the product during passage through the acidic environment of the stomach, where the acidic environment of the stomach causes a partial ionic exchange to occur within the material of the coating. This partial ionic exchange renders the coating impermeable to the acidic liquids of the stomach. On the other hand, during storage the problem of interaction between the enteric coat and the alkaline core is thus completely eliminated as the "enteric coat" is no longer acidic during the storage period..

Preferably, the benzimidazole derivative is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically acceptable salts thereof, as well as any other derivatives of benzimidazole which are proton pump inhibitors and which are conventionally used to decrease gastric secretion.

According to the present invention, there is provided a stable composition for a benzimidazole derivative, the composition comprising: (a) a substrate, the substrate featuring (i) a neutral core; (ii) an alkaline coating; and (iii) an active coating containing the benzimidazole derivative, said active coating being layered over the alkaline coating and (b) an enteric coating material layered over the substrate, the enteric coating material having a pH value of at least about 6.5, thereby obviating the need for an intermediate layer between the substrate and the enteric coating, with the proviso that the enteric material does not include hydroxypropyl methylcellulose phthalate (HPMCP).

The present application is a Patent of Addition from IL 147232 (filed June 21 , 2000), which is the National Phase of PCT Application No. WO 00/78284. Embodiments of IL 147232 include those in which the substrate is an active core, and those in which the substrate comprises a neutral core onto which is layered an active coating.

The enteric coating material optionally and preferably includes an enteric material selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinyl 139894/4 acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylic acid methyl methacrylate and polymethacrylic acid ethyl methacrylate.

More preferably, the enteric coating material further comprises an alkaline compound, such that the pH value is adjusted by adding the alkaline compound to the enteric material. Most preferably, the alkaline compound is an inorganic or organic alkaline salt compound. Even more preferably, the alkaline compound is selected from the group consisting of basic sodium, potassium or ammonium hydroxide. Also most preferably, the pH value is in a range of from about 7 to about 10. An example of a suitable organic alkaline compound includes, but is not limited to, an amino acid. More preferably, the amino acid is selected from the group consisting of arginine, histidine, lysine and tryptophan. Most preferably, the amino acid is arginine.

The enteric coating material of the composition could optionally include a plasticizer. Preferably, the plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester.

According to still another embodiment of the present invention, there is provided a method for producing a stable composition for a benzimidazole derivative, the method comprising the steps of: (a) providing an inert core; (b) layering an alkaline coating on the inert core; (c) layering an active coating containing the benzimidazole derivative over the alkaline layer; (b) preparing an enteric coating material having a pH value of at least about 6.5; and (c) layering the enteric coating material over the substrate, with the proviso that the enteric coating material does not include HPMCP.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The formulation of the present invention contains a benzimidazole derivative, such as Omeprazole, and is able to maintain the stability of this active ingredient without a separating layer between the active compound and an enteric coating layer. Instead, the enteric coating layer is applied as a solution with a pH value of at least 6.5, and more preferably in a range of from about 7 to about 10, directly to a substrate comprising a neutral core, an alkaline coating and an active coating containing the benzimidazole derivative. The active coating is layered over the alkaline coating. This solution, with the addition of a plasticizer, can be directly coated onto the substrate without any necessity for an intermediate layer. Furthermore, in this pH range, the enteric coating is optionally applicable in an aqueous solution, thereby obviating the need for organic solvents for dissolving the enteric coating material. The enteric coating material does not include HPMCP. 139894/4 The resultant formulation maintains the stability of the benzimidazole derivative during storage and at the same time protects the product during passage through the acidic environment of the stomach. The problem of interaction between the enteric coat and the alkaline core is thus completely eliminated as the enteric coat at this stage is no longer acidic.

Without wishing to be limited to a single mechanism, it is hypothesized that as the formulation passes through an acidic environment, such as the acidic environment of the stomach, the outer layer of the enteric coat is converted to an' acidic form. This acidic form of the enteric coating material is insoluble in the acidic environment of the stomach. If the formulation is then placed in an environment with a more alkaline pH value, for example by moving into the small intestine, the enteric coat dissolves and releases the active substance.

The use of an enteric coating which includes HPMCP (hydroxypropylmethylcellulose phthalate) neutralized with a basic salt is disclosed in U.S. Patent No. 5,225,202 and in two scientific articles, "Enteric Film Coating Using Completely Aqueous Dissolved Hydroxypropyl Methyl Cellulose Phthalate Spray Solutions" (J.W. Stafford et al., Drug Development and Industrial Pharmacy, 8:513-530, 1982) and "The In Vitro and In Vivo Performance of Aqueous Based Enteric Coats of Neutralized Hydroxypropyl Methyl Cellulose Phthalate" (J.R. Bloor et al, Drug Development and Industrial Pharmacy, 15:2227-2243, 1989). However, the disclosed enteric coating is not taught or suggested in any of these references as a suitable direct enteric coating for substrates which contain Omeprazole. As noted previously, Omeprazole and the related benzimidazole derivatives are unusually sensitive molecules, and as such must be carefully protected. Furthermore, U.S. Patent No. 5,225,202 teaches the necessity for a subcoat between the drug-containing substrate and the enteric coating for drugs which are not compatible with the enteric coating. By contrast, the present invention has been shown to be highly effective without such a subcoat, which is particularly surprising since the background art teaches that formulations containing Omeprazole or another benzimidazole derivative must also feature a subcoat. Neither scientific article even considers the problems associated with acid-sensitive drugs, and as such cannot teach or suggest the formulation of the present invention.

As shown by both the in vitro and in vivo data given below, the formulation of the present invention has been shown to be particularly effective for the oral administration of Omeprazole as the exemplary benzimidazole derivative, a result which could not have been predicted from these references. Indeed, the article by J.R. Bloor et al. teaches away from the use of such a neutralized enteric coating for any formulation, as this article disclosed good in vitro performance of the formulation but poor in vivo performance. By contrast, as described in 139894/4 greater detail below with regard to Example 7, the formulation of the present invention shows good performance in vivo. Thus, the background art neither teaches nor suggests the direct coating of a substrate containing Omeprazole or another benzimidazole derivative with an enteric coating material having a pH value of at least about 6.5, and in fact teaches away from such a formulation.

The preparation of the benzimidazole-containing compositions of the present invention is described first with reference to the following general description and then with reference to the following non-limiting examples of the preparation and application of the compositions of the present invention.

As noted previously, the formulation of the present invention includes a substrate which features the benzimidazole derivative. A solution is prepared with the enteric coating material, which has a pH value of at least 6.5 and more preferably of from about 7 to about 10.

Preferably, a pH value in the desired range is obtained by adding an alkaline compound to an enteric coating material. More preferably, the alkaline compound is selected from the group consisting of sodium, potassium or ammonium hydroxide. An example of a suitable organic alkaline compound includes, but is not limited to, an amino acid. More preferably, the amino acid is selected from the group consisting of arginine, histidine, lysine and tryptophan. Most preferably, the amino acid is arginine. This enteric coating solution is then layered directly over the substrate to form the composition of the present invention.

The term "substrate" refers to substantially any structure which features the benzimidazole derivative, such as Omeprazole.

For example, the structure could include a neutral core, such as a sugar bead which does not contain the benzimidazole derivative, over which the benzimidazole derivative is coated. The coating includes Omeprazole or other benzimidazole derivative with a suitable adhesive polymer.

Also alternatively and optionally, the structure could also include the neutral core, such as a sugar bead which does not contain the benzimidazole derivative, over which an alkaline coating is first layered to form an alkaline core. The alkaline coating features an alkaline compound, and preferably features an organic alkaline compound. Next, an active coating is then added to the alkaline core to form the active core, which is actually the substrate. The active coating includes Omeprazole or another benzimidazole derivative with a suitable adhesive polymer. An example of a suitable organic alkaline compound includes, but is not limited to, an 139894/4 amino acid. More preferably, the amino acid is selected from the group consisting of arginine, histidine, lysine and tryptophan. Most preferably, the amino acid is arginine.

Also alternatively and optionally, the substrate could be a mixture of powders, such that the substrate itself is a powder. For this embodiment, preferably the powder is not compressed, with the enteric coating being layered directly over the powder to form a granulate. The granulate is then also preferably not compressed, but rather is placed directly in capsules.

Substantially any type of neutralized suitable enteric coating material could be used in order to coat the benzimidazole substrate, including but not limited to, cellulose acetate phthalate (CAP); polyvinyl acetate phthalate; cellulose acetate trimellitate; polymethacrylic acid methyl methacrylate or ethyl methacrylate, such as the various types of Eudragit; and hydroxypropyl methylcellulose acetate succinate (HPMCAS). However, preferably the enteric coating material is prepared with the proviso that this material does not contain HPMCP alone, but only in combination with at least one of these other listed enteric coating materials. The particularly preferred enteric coating material is HPMCAS.

As used herein, the term "neutralized enteric coating material" refers to enteric coating material which has been at least partially neutralized by reaction with an alkaline compound, which is preferably a basic inorganic salt. Alternatively, the alkaline compound is preferably an organic alkaline compound. An example of a suitable organic alkaline compound includes, but is not limited to, an amino acid. More preferably, the amino acid is selected from the group consisting of arginine, histidine, lysine and tryptophan. Most preferably, the amino acid is arginine.

Preferably, the enteric coating material is at least about 60 % neutralized, more preferably the enteric coating material is at least about 80 % neutralized, and most preferably the enteric coating material is at least about 95 % neutralized.

The enteric coating optionally contains a plasticizer, such as a citric acid ester, a phthalic acid ester, or any suitable plasticizer.

The method for applying the enteric coating material to the substrate can vary.

Substantially any coating method can be used, such as pan coating or fluidized bed coating, with the solution of the enteric coat chosen. As noted previously, preferably this solution is an aqueous solution. The enteric coating materials described previously can be applied to the substrate in an aqueous solution if the pH value of the solution is adjusted to at least 6.5, and more preferably to an alkaline value, most preferably a pH value from about 7 to about 10. 139894/4 The following specific examples illustrate various aspects of the compositions of the present invention, and are not intended to be limiting in any way. Specific reference is made to Omeprazole for the purposes of description only and without intending to be limiting.

Example 1 In this example of the composition of the present invention, the substrate has three parts: a neutral core; an alkaline coating layer containing the alkaline compound which was layered over the neutral core to form the alkaline core; and an active coating layer containing the active ingredient, which was layered over the alkaline core to forai the substrate. The substrate was then coated with the enteric coating solution. Hard gelatin capsules were then filled with the resultant pellets.

Substrate Neutral core Quantity per capsule Sugar spheres 20/25 ( 700-850 microns) HO mg Alkaline coating Ingredients Quantity per capsule Hydroxypropyl methylcellulose 2910 5.00 mg Sodium stearate 0.13 mg Sodium lauryl sulfate 0.50 mg Active coating Ingredients Quantity per capsule Omeprazole 20.00 mg Hydroxypropyl methylcellulose 2910 5.00 mg Hydroxypropyl cellulose 6.00 mg Sodium lauryl sulfate 0.50 mg Enteric coating layer HPMCAS 21.00 mg Triethyl citrate 6.00 mg 139894/4 The composition of the present invention was prepared according to this Example as follows. First, sugar spheres were placed in a fluid bed coating chamber, equipped with a Wurster bottom spraying device. Next, a suspension of the ingredients for the alkaline coating in water was then prepared so that the concentration was approximately 20% of the total solids in water. This alkaline coating suspension was sprayed onto the sugar spheres to form alkaline spheres.

Next, a second suspension of the ingredients in water, for the active coating, was then prepared so that the concentration was approximately 20% of the total solids in water. This active coating suspension was sprayed onto the alkaline spheres, thereby forming the substrate.

A suspension of the enteric coating was then prepared as follows. First, triethyl citrate was dissolved in water to form an aqueous solution. Sodium lauryl sulfate was then added to this aqueous solution. HPMCAS and colloidal silicon dioxide were dispersed in this solution, such that the concentration of HPMCAS was about 10% weight per volume. Arginine (3% weight per volume solution) was added to adjust the pH value of the solution to a pH value in a range of from about pH 7 to about pH 9. The enteric coating was layered over the substrate in order to form to form the finished pellets. The pellets were then placed in capsules.

Example 2 In this example of the composition of the present invention, the substrate has three parts: a neutral core; an alkaline coating layer containing the alkaline compound which was layered over the neutral core to form the alkaline core; and an active coating layer containing the active ingredient, which was layered over the alkaline core to form the substrate. The substrate was then coated with the enteric coating solution. Hard gelatin capsules were then filled with the resultant pellets.

Substrate Neutral core Quantity per capsule Sugar spheres 20/25 ( 700-850 microns) l lO mg 139894/4 Alkaline coating The composition of the present invention was prepared according to this Example as follows. First, sugar spheres were placed in a fluid bed coating chamber, equipped with a Wurster bottom spraying device. Next, a suspension of the ingredients for the alkaline coating in water was then prepared so that the concentration was approximately 20% of the total solids in water. This alkaline coating suspension was sprayed onto the sugar spheres to form alkaline spheres.

Next, a second suspension of the ingredients in water, for the active coating, was then prepared so that the concentration was approximately 20% of the total solids in water. This active coating suspension was sprayed onto the alkaline spheres, thereby forming the substrate. 139894/4 A suspension of the enteric coating was then prepared as for Example 1. The enteric coating was layered over the substrate in order to form to form the finished pellets. The pellets were then placed in capsules.

Example 3 In this example of the composition of the present invention, the substrate has three parts: a neutral core; an alkaline coating layer containing the alkaline compound which was layered over the neutral core to form the alkaline core; and an active coating layer containing the active ingredient, which was layered over the alkaline core to form the substrate. The substrate was then coated with the enteric coating solution. Hard gelatin capsules were then filled with the resultant pellets.

Substrate Neutral core Quantity per capsule Sugar spheres 20/25 (700-850 microns) l lO mg Alkaline coating Ingredients Quantity per capsule Hydroxypropyl methylcellulose 2910 5.00 mg Arginine 0.13 mg Sodium lauryl sulfate 0.50 mg Active coating Ingredients Quantity per capsule Omeprazole 20.00 mg Hydroxypropyl methylcellulose 2910 5.00 mg Hydroxypropyl cellulose 6.00 mg Sodium lauryl sulfate 0.50 mg Enteric coating layer HPMCAS 21.00 mg Triethyl citrate 6.00 mg 139894/4 The composition of the present invention was prepared according to this Example as follows. First, sugar spheres were placed in a fluid bed coating chamber, equipped with a Wurster bottom spraying device. Next, a suspension of the ingredients for the alkaline coating in water was then prepared so that the concentration was approximately 20% of the total solids in water. This alkaline coating suspension was sprayed onto the sugar spheres to form alkaline spheres.

Next, a second suspension of the ingredients in water, for the active coating, was then prepared so that the concentration was approximately 20% of the total solids in water. This active coating suspension was sprayed onto the alkaline spheres, thereby forming the substrate. A suspension of the enteric coating was then prepared as in Example 1. The enteric coating was layered over the substrate in order to form to form the finished pellets. The pellets were then placed in capsules.

While the invention has been described with respect to a limited number of embodiments, it will be appreciated that many variations, modifications and other applications of the invention may be made.

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims (21)

16 139894/5 WHAT S CLAIMED IS:

1. A stable composition of a benzimidazole derivative, the composition comprising: (a) a neutral core; (b) an alkaline coating layered on said neutral core; (c) an active coating, comprising the benzimidazole derivative, layered over said alkaline coating; and (d) a single layer comprising neutralized enteric coating material having a pH value of at least 6.5 layered directly over said active coating, said neutralized enteric coating material being neutralized with an alkaline compound prior to applying said single layer to said active coating, with the proviso that said enteric coating material does not include HPMCP (hydroxypropyl methylcellulose phthalate).

2. The composition of claim 1, wherein said enteric coating material includes at least one enteric material selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylic acid methyl methacrylate, and polymethacrylic acid ethyl methacrylate.

3. The composition of claim 2, wherein the pH value of said enteric coating material is adjusted by adding said alkaline compound to said enteric material.

4. The composition of claim 3, wherein said alkaline compound is an inorganic alkaline compound.

5. The composition of claim 4, wherein said alkaline compound is selected from the group consisting of basic sodium, potassium and ammonium hydroxide.

6. The composition of claim 5, wherein said enteric coating material is at least about 60 % neutralized by adding said alkaline compound. 17 139894/4

7. The composition of claim 6, wherein said enteric coating material is at least about 80 % neutralized by adding said alkaline compound.

8. The composition of claim 7, wherein said enteric coating material is at least about 95 % neutralized by adding said alkaline compound.

9. The composition of any of claims 1-8, wherein said pH value is in a range of from about 7 to about 10.

10. The composition of claim 9, wherein said enteric coating material further comprises a plasticizer.

11. 1 1. The composition of claim 10, wherein said plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester.

12. The composition of any of claims 1-11, wherein the benzimidazole derivative is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically acceptable salts thereof.

13. The composition of any of claims 1-12, further comprising a gelatin capsule for receiving the coated cores.

14. The composition of any of claims 1-13, wherein said alkaline coating comprises one or more of sodium stearate or arginine.

15. The composition of claim 14, wherein said alkaline coating further comprises HPMC (hydroxypropyl methylcellulose).

16. The composition of claim 15, wherein said alkaline coating further comprises sodium lauryl sulfate. 18 139894/4

17. The composition of any of claims 1-16, wherein said active coating comprises one or more of HPMC (hydroxypropyl methylcellulose) or HPC (hydroxyl propyl cellulose) or a combination thereof.

18. The composition of claim 17, wherein said active coating further comprises sodium lauryl sulfate.

19. A method for producing a stable composition for a benzimidazole derivative according to any of claims 1-18, the method comprising the steps of: (a) coating a neutral core with an alkaline coating; (b) coating said alkaline coated neutral core with an active coating, said active coating comprising the benzimidazole derivative; (c) preparing a neutralized enteric coating material having a pH value of at least about 6.5 by neutralizing with an alkaline compound; and (d) layering a single layer of said neutralized enteric coating material directly over said active layer, with the proviso that said enteric coating material does not include HPMCP (hydroxypropyl methylcellulose phthalate).

20. The method of claim 19, wherein said enteric coating material is prepared by the steps of: (i) mixing an enteric material with water to form a mixture; and (ii) adding said alkaline compound to said mixture to form an aqueous solution having a pH value of from about 7 to about 10.

21. The method of claims 19 or 20, further comprising the step of: (d) filling a gelatin capsule with the coated cores. For the Applicant, Ariel Averbuch, Attorney at Law & Patent Attorney Dr. D. Graeser Ltd. Our ref. 452