Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-07-20
2004-03-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S474000, C424S485000, C424S484000, C514S394000
Reexamination Certificate
active
06706285
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an enteric coated formulation of a benzimidazole derivative and a method for preparation thereof. More specifically, the present invention relates to the enteric coated formulation of the benzimidazole derivative comprising a core and a film of an enteric coating agent on the surface thereof, the core containing a complex of the benzimidazole derivative and an ion-exchange resin, and the enteric coating agent having the degree of substitution by an acidic group of less than 30%, and the method for preparation thereof.
BACKGROUND ART
Benzimidazole derivatives have the basic skeletal structure of the following formula 1:
Representative examples of the benzimidazole derivatives are omeprazole, pantoprazole, lansoprazole, timoprazole, and picoprazole, etc., and many kinds of compounds further exist. Among the above-described compounds,
Omeprazole(5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole) has the structure as represented by the following formula 2:
Pantoprazole(5-difluoromethoxy-2[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole) has the structure as represented by the following formula 3:
Lansoprazole(2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]meth yl]sulfinyl]-1H-benzimidazole) has the structure as represented by the following formula 4:
Timoprazole(2-[[(2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole) has the structure as represented by the following formula 5:
Picoprazole(5-ethoxycarbonyl-6-methyl-2[[(3-methyl-2-pyridinyl)meth yl]sulfinyl]-1H-benzimidazole) has the structure as represented by the following formula 6:
Among the above-described benzimidazole derivatives, particularly, omeprazole suppresses strongly the secretion of acid in the stomach, and thus, is clinically very useful for the treatment of gastric or duodenal ulcer. However, it is extremely unstable under the acidic or neutral condition, and thus, is severely restricted in its formulation.
In particular, omeprazole has a half-life of less than 10 minutes under the acidic condition at a pH of 4 or less. Moreover, the product formed by degradation is also acidic, and thus, under the acidic condition, degradation of omeprazole is rapidly accelerated with the lapse of time. In contrast, the half-life of omeprazole is prolonged to about 14 hours under the neutral condition at a pH of about 7.0. As a pH becomes higher, its half-life becomes longer. It has been reported that its half-life is about 300 days at a pH of 11(Pilbrant and Cederberg, Scand. J. Gastroenterology, 1985, 20 (Suppl. 108), p113-120). Degradation of omeprazole is known as an acid-catalyzed rearrangement reaction(G. Rackur et al., Biochem, Biophys, Res. Commun. 1985; 128(1), p466-484).
Accordingly, in the case of an orally administrable formulation of a benzirnidazole derivative, the benzimidazole derivative is not allowed to be exposed to acidic gastric juice in order not to be degraded in the stomach and to reach the intestine. In particular, in the case of omeprazole, an alkaline ingredient must be contained as a stabilizing agent in a core containing omeprazole in order to improve its storage stability. Therefore, the literature [Pilbrant and Cederberg, Scand. J. Gastroenterology, 1985, 20 (Suppl. 108), p113-120] disclosed an enteric coated formulation of omeprazole, the core of which contains the alkaline ingredient and is coated with an enteric coating agent. However, since a conventional enteric coating agent has the high degree of substitution by an acidic group in order to increase acid-stability of an active ingredient, they may have undesirable effects on stability of the benzimidazole derivative. In addition, the enteric coating film of the formulation may be impaired by the alkaline ingredient as the stabilizing agent and thus, the formulation has problems that its storage stability is unsatisfactory in the long term.
Various approaches have been developed in order to solve the problems involved in formulation of a benzimidazole derivative due to its stability. For example, the Korean patent publication No. 91-4579 disclosed a method for preparing an enteric coated formulation of omeprazole using an inorganic alkalinizing agent as a stabilizing agent of omeprazole. The above-described method comprises the steps of forming a core containing omeprazole and the inorganic alkalinizing agent, forming a water-soluble inner film on the surface of the core, and subsequently forming an enteric coating film on the surface of the inner film. However, the method is very complicated because it involves the coating process consisting of two steps. In addition, if the water-soluble inner film is not or incompletely formed, the enteric coating film interacts with the alkaline core, and thus, its storage stability is severely decreased.
In order to solve the above-mentioned problems, the present inventors have repeated the extensive studies to improve the stability of a benzimidazole derivative without using an alkalinizing agent. As a result, the present inventors developed a complex of omeprazole and an ion-exchange resin which can be formulated into various dosage forms(the Korean patent No. 135736, Jan. 16, 1998). The complex has the advantage of exhibiting excellent stability in comparison with omeprazole or salts thereof as such. In the specification of the patent, it has been already described that an enteric coating film may be directly formed on the surface of the complex without forming a water-soluble inner film. However, if the water-soluble inner film is not formed on the surface thereof, even the complex still has problems that its storage stability is not satisfactory since an acidic group of the enteric coating agent has undesirable effects on the complex.
DISCLOSURE OF THE INVENTION
Accordingly, in order to solve the problems involved in the above-mentioned prior arts, an object of the present invention is to provide an enteric coated formulation of a benzimidazole derivative not only exhibiting excellent acid-stability and storage stability without a water-soluble inner film but also being rapidly disintegrated and dissolved at the absorption sites.
Another object of the present invention is to provide a method which makes it possible to simply prepare an enteric coated formulation of a benzimidazole derivative exhibiting excellent acid-stability and storage stability by omitting the step of forming a water-soluble inner film on the surface of a core.
The present invention provides an enteric coated formulation of a benzimidazole derivative comprising a core and a film of an enteric coating agent on the surface thereof, the core containing a complex of the benzimidazole derivative and an ion-exchange resin, and the enteric coating agent having the degree of substitution by an acidic group of less than 30%. The benzimidazole derivative includes, but is not limited to, omeprazole, lansoprazole, pantoprazole, timoprazole or picoprazole. In a preferable embodiment, the ion-exchange resin is an anion-exchange resin, and in a more preferable embodiment, cholestyramine resin or Dowex resin. In a preferable embodiment, the enteric coating agent has the degree of substitution by the acidic group of 27% or less. In particular, it is hydroxypropyl methylcellulose phthalate. In the most preferable embodiment, it is hydroxypropyl methylcellulose phthalate having the degree of substitution by phthalic acid of 20 to 27%.
The present invention also provides a method for preparation of an enteric coated formulation of a benzimidazole derivative, comprising the step of coating a core containing a complex of a benzimidazole derivative and an ion-exchange resin with an enteric coating agent having the degree of substitution by an acidic group of less than 30%.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be more specifically explained. According to the present invention, a complex of a
Hanms Pharm. Co., Ltd.
Page Thurman K.
Pulliam Amy E
Sherman & Shalloway
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