Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-05-30
2002-04-30
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
Reexamination Certificate
active
06379705
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new oral multi-unitary pharmaceutical preparations containing substituted benzimidazoles being inhibitors of H
+
, K
+
-ATPase (i.e. omeprazole, lansoprazole, pantoprazole, leminoprazole and pariprazole) or their pharmaceutically acceptable salts. The preparations comprise a spherical inert core, constituted by starch and sugar, coated with a layer containing at least one substituted benzimidazole in the micronized form, which is mixed with pharmaceutically acceptable inert excipients, whose proportions are suitable for allowing the disaggregation of the dosage forms and the intended dissolution of the active ingredient(s), this layer in turn being coated with an insulating layer of an exclusively polymeric nature and of suitable thickness, applying lastly an external, gastroresistant or enteric layer of suitable thickness, in order to guarantee the integrity of the product until it reaches the proximal part of the small intestine, where the formulation will be disaggregated to facilitate the absorption of the substituted benzimidazolic compounds. The pellets produced according to the invention are placed in hard gelatine capsules and administered to patients in this form. The invention does not require the stabilization of the benzimidazolic compounds using any of the strategies or processes which already belong to the state of the art. Besides, the pharmaceutical products produced in this way are free from organic solvents and/or the impurities generally associated to them, because the application of the different layers exclusively requires aqueous solvents. This aspect constitutes a technological advantage, since the manufacturing process is incomparably safer, because there is no toxicity risk to operators or explosion risks and moreover it is more ecological, because there is no possibility of environmental contamination caused by organic solvents leaking into the atmosphere. Finally, it is much safer for the patient, because there is no need to consider solvents and/or residual impurities associated to them, which is a considerable advantage in terms of public health. For the manufacture of the products, only equipment is required—a fluid bed equipment with an inner partition device (wurster). The products obtained by extrusion/spheronization, by rotogranulation or by “powder coating” are completely outside the scope of the present invention.
The products obtained are stable for a period of time compatible with pharmaceutical requirements, and they present gastroresistance and dissolution characteristics generally adapted to the period of validity established for pharmaceutical products (i.e. 3 years).
BACKGROUND OF THE INVENTION
Benzimidazolic compounds such as omeprazole (5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl-sulfinyl)1H-benzimidazole (EP-B1-0005129), lansoprazole (2-((3-methyl-4-(2,2,2-trifluoroetoxy)-2-piridyl)methyl(sulfinyl 1H-benzimidazole) (U.S. Pat. No. 4,628,098), pantoprazole (U.S. Pat. No. 4,758,579)), leminoprazole and pariprazole are anti-ulcerous substances known for decreasing gastric acid secretion (Olbe L., et al.,
Gastroenterol.,
83:193-198 (1982); Saton H. et al.,
Jpn. J. Pharmacol.
40 (suppl.), 226 (1986); Saton H, et al.,
J.Pharmacol. Exp. Ther,
248 (2), 806-815 (1989), Nagaya, H, et al.,
J.Pharmacol. Exp. Ther.,
248 (2), 799-805 (1989)) and they are used in the therapeutics of diseases related to gastric acidity in mammals and especially in humans, including gastric and duodenal ulcers, reflux oesophagitis, gastritis, duodenitis and Zollinger-Ellison syndrome.
It is also known that these substituted benzimidazoles possess a very low level of solubility in water, they solubilize easily in alkaline solutions (i.e. the t
½
of degradation of omeprazole in aqueous solutions of pH>11 is 600 days), they degrade quickly in acidic and neutral media (i.e. the t
½
of degradation of omeprazole in aqueous solutions of pH<4 is 10 minutes) (Pilbrand and Cederberg,
Scand. J. Gastroenterol,
20 (Suppl. 108), p. 113-120 (1985)) and they are stabilized in the presence of alkaline reacting compounds. The maximum stability of omeprazole solutions is reached at pH 11; for pHs lower than 7.8, degradation occurs very quickly (
Drug.Dev.Ind.Pharm.,
21(8), 965 (1995). Lansoprazole is relatively stable when exposed to the light. This compound degrades in aqueous solution, its degradation speed increasing as the pH decreases. For this reason, whenever the oral route is used it is indispensable to coat the formulations with a gastroresistant layer, in order to avoid contact between the active ingredient and gastric content with acidic characteristics. On the other hand, it is necessary that the formulations dissolved quickly in the intestine, where the benzimidazolic compounds should be absorbed, i.e. when the pH becomes higher than 6.8. Several pharmaceutical preparations containing substituted benzimidazole inhibitors of H
+
,K
+
-ATPase are already patented.
The first assays performed with classic enteric pellets containing omeprazole showed that they did not present suitable stability during a long enough period of time to be used in a satisfactory pharmaceutical dosage form, because fast degradation of the active ingredient was observed when subjected to normal conditions of storage (T=25±1° C. and HR=40-75%), with the appearance of noxious degradation products (Brandstrom A., et al.,
Acta Chemica Scandinavia,
43, 536-548 (1989)).
DE-A1-3046 559 describes a way to coat a pharmaceutical dosage form with an insoluble layer containing microcrystalline cellulose and with a second enteric layer. This preparation did not allow the desirable release of omeprazole in the small intestine.
U.S. Pat. No. 2,540,979 describes a preparation coated with an enteric layer combined with a first coating of a water-insoluble wax. This preparation was shown to be inadequate for omeprazole because the direct contact of the cellulose acetophtalate (CAP) with the omeprazole caused its degradation.
DE-A1-1 204 363 describes a pharmaceutical dosage form which has three layers but cannot be used for omeprazole because it does not allow the fast release of omeprazole in the small intestine, as is desirable. DE-A1-1 204 363 concerns a coating that allows the delivery of the active ingredient in the ileum, which is not desirable in the case of omeprazole.
DE-A1-1 617 615 describes a dosage form which likewise cannot be applied to omeprazole because it is dissolved very slowly in the intestinal juice.
GB 2 189 698 A and U.S. Pat. No. 4,786,505 propose the mixture of a mass of cellulose derivatives and disaggregants, with an appropriate amount of omeprazole and alkaline salts, in order to obtain, by extrusion, a core which is spheronized and coated with gastroresistant agents dissolved in alcoholic solutions also containing considerable percentages of acetone. However, the pellets obtained are extremely irregular in shape and dimensions, which hinders the process of filling the gelatine capsules, and this can have repercussions on a relative dispersion of the average weight of the capsules and of the respective dosage. Besides, the use of organic solvents in any of the phases of preparation of the pharmaceutical dosage forms means that the quantity thereof in the final product will have to be determined, as well as the quantity of the impurities that may be associated to them and may be potentially dangerous for the health, which makes them highly inadvisable.
U.S. Pat. No. 5,232,706 describes omeprazole dosage forms coated with one or more layers containing water-soluble alkaline excipients mixed with a second alkaline compound.
U.S. Pat. No. 5,385,739 and FR-A-2 692 146 describe pharmaceutical gastroprotected dosage forms containing omeprazole wherein the active substance is diluted with mannitol and applied to an inert core. The dosage form is prepared in a conventional coating pan, which is a slow process and requires the use of organic solvents whic
De Oliveira Maria Julia Caeiro Ramalho
Mendes Carla Patricia Goncalves
Laboratorio Mendifar-Produtos Farmaceuticos, S.A.
Pryor Alton
Sughrue & Mion, PLLC
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