Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-08
2001-06-19
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S273700, C424S475000
Reexamination Certificate
active
06248758
ABSTRACT:
The present invention relates to stable pharmaceutical formulations, containing moisture and acid sensitive benzimidazole derivatives (e. g. omeprazole) as pharmaceutically active ingredient combined with amino acids and cyclodextrins as excipients, and to a method for preparation such pharmaceutical formulations.
Omeprazole (5-methoxy-2-2(4-methoxy-3,5-dimethyl-2-pyridinyl-methyl-sulfinyl)-1H-benzimidazol) is an effective inhibitor of gastric acid secretion and has a strong antiulcer activity. It is known, that omeprazole rapidly decomposes at acidic and neutral pH. Furthermore moisture, organic solvents and UV-irradiation accelerate the degradation of omeprazole too, causing discoloration of the substance in solution, as well as in solid form. For example, omeprazole has half-life time of 10 minutes in an aqueous solution of below a pH-value of 4, but 18 hours at pH 6,8 and about 300 days at pH 11 (M. Mathew and co-workers, Drug. Dev. Ind. Pharm., 21,965,1995). The drug has been reported to be stable under alkaline conditions [Pilbrant A° and Cederberg C. Scand. J. Gastroenterology, Suppl. 108, 113-120(1985)]. According to A. Brändström and co-workers (Acta Chem. Scand. 43,536,1989) the acid-catalyzed degradation kinetics of omeprazole is very complicated, the primary degradation is followed by rather complex secondary reactions.
Several methods for stabilizing the acid-unstable compound, in particular omeprazole have been described.
Some patent applications (U.S. Pat. No. 5,232,706, EPA-0567201 A2, EPA-0519144 A1, EPA-0496437 A2, U.S. Pat. No. 5,385,739, DEA-1204363 and EPA-0247983 B1) claim a common method to overcome this stability problem by applying an inert protective layer between the core and the enteric coating layer. The core contains the pharmaceutical active substance (omeprazole) or its salts, alkaline or acid neutralizing additives, alkaline salts or a combination thereof.
The resorption of omeprazole occurs in the upper duodenum. Therefore, a quick and complete release of the active ingredient after passage of the pylorus must be ensured in order to guarantee a sufficiently high bioavailability. For this, omeprazole is provided with a coating of enteric, i.e. gastric juice-resistant material, which is insoluble in the acid environment of the stomach (ca. pH 1 to 3) on the one hand, but dissolves in the weakly acidic to weakly alkaline region of the duodenum (pH>5,5). ordinary enteric coatings, however, are made of acidic compounds. If the core containing omeprazole will be covered with a conventional enteric coating without an subcoating, omeprazole rapidly decomposes by direct or indirect contact with the coating, with the result that the preparation become discolored.
Although the sensitivity of omeprazole against organic solvent is known, acetone and methylene-chloride (EPA-0496437 A2, EPA-0567201 A2) or acetone and ethanol (USP-5385739, EPA-0519144 A1) are used for the enteric coating of the tablets. This treatment can damage the active ingredient during the enteric coating process or during the long-term storage.
All known procedures consist of complicated multi-step operations and result in expensive final products, which must be stored under specific conditions in moisture proof packages.
DE-427785 A1, DE-3427786 A
1
, DE-3427787 A
1
intended to solve the stability problems of omeprazole by a different method. Omeprazole and &bgr;-cyclodextrin (CD) or derivatives of &bgr;-CD (hydroxypropylcyclodextrin) were reacted in 96% ethanol for 15 hours at elevated temperature. Upon cooling a white crystalline substance was isolated, which was believed to be an omeprazole/&bgr;-CD inclusion complex. However the elevated temperature through 15 hours in the presence of 96% ethanol results in ex-tensive degradation of omeprazole thus there is hardly active ingredient remained in the isolated product. It is generally known, that ethanol is a competing cyclodextrin-complex forming agent. From a 96% ethanolic system only the crystalline etha-nol/&bgr;-CD complex can be isolated by using the mentioned method (Otagiri, M. et al: Acta Pharm. Suetica 21, 357 (1984), Pitha, J. and Hoshino, T.: Int. J. Pharm 80, 234 (1992)).
The WO 93/13138 discloses a method for stabilization of acid-sensitive benzimidazoles, more specifically for the stabilization of omeprazole in drug formulations, which comprise a cyclodextrin-complex of omeprazole, a protective inert layer and an enteric coating. The omeprazole is reacted in presence of alkaline hydroxides, alkaline salts, amines or buffers with cyclodextrin and derivatives for 1 to 30 minutes at 30 to 70° C. in a homogeneous solution system. After cooling to room temperature the reacted solution is allowed to stand at 4° C. for 3 to 15 hours to form the omeprazole/cyclodextrin-complex. The isolated inclusion-complex is washed with some cooled water several times to completely remove the remaining alkaline component on the inclusion complex. Alternatively, from the reacted solution the water might be removed by spray drying, freeze drying or vacuum evaporating for isolation of the inclusion complex powder as stable compound.
In the state of the art a core made of omeprazole and an alkaline substance as well as a inclusion complex from omeprazole and cyclodextrin without an amino acid is not stable enough. A inert protective layer is necessary to guarantee the stability of omeprazole and specific moisture-proof packages were needed for storing the final product.
Main object of the invention is to guarantee a stabilization of benzimidazoles such as omeprazole as active ingredient by forming a benzimidazole/cyclodextrin inclusion complex.
It has now been found, that benzimidazoles such as omeprazole can be stabilized by complexation with a cyclodextrin such as &bgr;-cyclodextrin in the presence of an amino acid. It has further been found that in this case surprisingly no additional inert or enteric layer is needed to protect particles or a core containing the benzimidazole/cyclodextrin complex and an amino acid. Merely optionally the core may be coated directly with an enteric coating layer.
Thus, the problem underlying the invention is solved by a pharmaceutical formulation comprising or consisting of
a benzimidazole derivative as active ingredient, and as excipients
at least one cyclodextrin and
at least one amino acid.
The present invention does provide a new pharmaceutical benzimidazole formulation with improved stability features and simplified preparation process.
The benzimidazole derivative can be a compound which is decomposed in the presence of humidity and especially at a pH’11, especially ’7. Examples for these benzimidazole derivatives are omeprazole, lansoprazole, leminoprazole, rabeprazole, and pantoprazole. Omeprazole is preferred.
Further, a specific embodiment of the invention concerns a pharmaceutical formulation, wherein the inclusion complex forming agent is &bgr;-cyclodextrin, mono- or polyalkylated &bgr;-cyclodextrin, mono- or polyhydroxyalkylated &bgr;-cyclodextrin or &ggr;-cyclodextrin, preferably &bgr;-cyclodextrin.
The amino acid useful for the pharmaceutical formulation according to the invention can be an alkaline amino acid, preferably arginine, lysine or hydroxy lysine and especially L-arginine, L-lysine or L-hydroxy lysine; an alkaline dipeptide or a pharmaceutically acceptable alkaline amino acid derivate.
Further, a specific embodiment of the invention concerns a pharmaceutical formulation, wherein the molar ratio of omeprazole to cyclodextrin is 1 to 10 and preferably 1 to 2.
Further, a specific embodiment of the invention concerns a pharmaceutical formulation, wherein the molar ratio of the amino acid (preferably L-arginine) to omeprazole is 0.5 to 10 and preferably 1 to 1.
Further, a specific embodiment of the invention concerns a pharmaceutical formulation, wherein the formulation is a powdered, pelletized or granulated form, optionally processed to tablets.
The pharmaceutical formulation according to the invention can be characterized in that the particles of the powder, of the granulate
Fischer Wilfried
Klokkers Karin
Kutschera Marion
Hexal AG
Higel Floyd D.
Pitney Hardin Kipp & Szuch LLP
LandOfFree
Pharmaceutical antacid does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical antacid, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical antacid will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2539209