A stable composition with a benzimidazole derivative, such as Omeprazole, which does not contain 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 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. 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.

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)-1H-benz- imidazole, 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: 113-120, 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 98/00114, 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 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 A1 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 a 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

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. 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 the benzimidazole derivative; and (b) an enteric coating material layered over the substrate, the enteric coating material having a pH value of at least about 6.5.

The substrate can optionally have several different structures. For example, the substrate is optionally an active core containing the benzimidazole derivative, in which the core is a pellet, bead or tablet for example. The active core can be prepared by any conventional method known in the art, including but not limited to, pellets prepared by spheronisation, pellets prepared by coating an inert non pareil seed with Omeprazole, tablets prepared by granulation and compression, as well as any other methods.

The enteric coating material optionally and preferably includes an enteric material selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl 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.

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 another embodiment of the present invention, there is provided a stable composition for a benzimidazole derivative, the composition consisting essentially of: (a) a substrate, the substrate featuring the benzimidazole derivative; and (b) an enteric coating material layered over the substrate, the enteric coating material having a pH value of at least about 6.5.

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) forming a substrate with the benzimidazole derivative; (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.

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 the benzimidazole derivative substrate. 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 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. Pat. 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. Pat. 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 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. 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, this structure could be an active core containing the benzimidazole derivative. This active core could be prepared in a number of different ways which are known in the art. For example, the active core could be formed by compressing the benzimidazole derivative with an alkaline substance. As another example, the active core could be prepared by mixing the benzimidazole derivative with an alkaline substance, spheronizing the mixture and then forming cores through pelletisation. As yet another example, the active core is optionally and preferably prepared by embedding the active ingredient in a poloxamer and compressing the embedded material into tablets. The active core is also optionally formed by granulating the active ingredient with an alkaline substance and compressing the granulation into tablets.

Alternatively and optionally, 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.

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); hydroxypropyl methylcellulose phthalate (HPMCP); 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 7 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. 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."
 

Claim 1 of 33 Claims

1. A method for producing a stable tablet composition for a benzimidazole derivative, the method consisting essentially of: forming a substrate with the benzimidazole derivative; preparing a solution of an enteric polymer selected from the group consisting of HPMCAS, CAP, polyvinyl acetate phthalate, cellulose acetate trimellitate, polymethacrylic acid methacrylate, and ethyl methacrylate; neutralizing said solution by addition of an alkalizing material comprising a material selected from the group consisting of an inorganic or organic alkaline compound; and applying a single layer of said neutralized solution directly to said substrate, without an intermediate layer between said substrate and said enteric coating.
 

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