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Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof

a technology of benzimidazole and active ingredient, which is applied in the field of stable drug form for oral administration with benzimidazole derivatives as active ingredient and the preparation thereof, can solve the problems of destroying omeprazole, deteriorating storage stability, and not being suitable for omeprazol

Inactive Publication Date: 2005-03-24
HEESE GERD ULFERT +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this formulation is not suitable for Omeprazole because it only dissolves slowly in the intestine.
This means that the danger exists with the penetration of higher concentrations of protons that these reach the core and destroy the Omeprazole there.
This last phenomena can easily occur especially when the outer gastric juice-resistant layer possesses faults as a result of imperfections which can arise in production, physical load or through ageing manifestations in storage.
In this method, a possible reaction of the Omeprazole with the polymer is not excluded which can especially lead to a deteriorated storage stability.
Buffering and / or alkalizing additives in the intermediate layer as proposed in EP 0 247 983 are no longer necessary and can even be damaging because they increase solubility of the intermediate layer and reduce its protective function.

Method used

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  • Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof
  • Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof
  • Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

example 2

Stability of Pellet Formulations:

In a further series of experiments, the medicament according to the invention was compared with the state of the art (EP 0 247 983). For this, various colored batches were produced which have a three-layer construction: core, with the active ingredient Omeprazole in the presence of an alkaline buffering substance (Na2HPO4, according to the state of the art) and without alkaline buffering substance (according to the invention). intermediate layer either consisting of a enteric layer material partially neutralized with alkali to a pH 6.0 and / or 7.0 according to the invention or inert layer material which contains sodium acetate as a buffering substance according to the state of the art. The reference example contains non-neutralized enteric layer material and sodium acetate as a buffering substance. Outer layer of Eudragit L 100-55.

Additionally, a medicament was tested in the series of experiments in which the intermediate layer was omitted.

T...

example 3

“Self-Repair-Mechanism” of the Reactive Intermediate Layer:

Pellets with the following construction were compared: without intermediate layer (so-called pellet core) with the reactive intermediate layer according to the invention with an inert intermediate layer of HPMC (reference example)

For better judgement of the “self-repair-mechanism”, the pellets were not provided with the outer enteric coat. All pellet types were tested in artificial gastric juice (pH 1.2) in a release model of the European Pharmacopoeia (basket). The intermediate layer was partially nuetralized to pH 7.0, the upper limit of the preferred range.

The results (pellet cores without intermediate layer: not shown) are summarized in the following Table 3:

TABLE 3Intermediate layer according to the inventionReference exampleEudragit ® L100-55, pH 7.0, partially neutralized(HPMC)5% Intermediate10% Intermediate15% Intermediate20% Intermediate20% Intermediatelayer 3 alayer 3 blayer 3 clayer 3 dlayer 3 eTimePell...

example 4

Release Behaviour of Various Pellet Formulas:

Essential for the good bio-availability of the active ingredient is its release as quickly as possible in the upper small intestine region, i.e. in a weakly acid / neutral environment. To investigate the release behaviour pellets with various formulas were introduced into an aqueous medium with a pH value of 5.8 as an in vitro model for the upper small intestine (artificial intestinal fluid) and the Omeprazole released under stirring into the surroundings was determined as a function of time with HPLC (analogously to the Pharmacopia).

The examined pellet formulas and the release results are reproduced in Table 4:

TABLE 4Pellet formulaReleased Omeprazole [%]Batchrelease period30 min45 min60 minaccording to the invention4 aOmeprazole-Core + Adjuvant*,728489IL.: 3% E. L 100-55 pH 7.0gjr: 30% E. L 100-554 bOmeprazole-Core + Adjuvant*,408188IL.: 3% E. L 100-55 pH 6.0gjr: 30% E. L 100-55comparative examples4 cOmeprazole-Core + Adjuvant*, 3 5...

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Abstract

The invention relates to a stable medicament for oral administration which comprises (a) a core which contains an active ingredient selected from Omeprazole, Lansoprazole and Pantoprazole, together with customary pharmaceutical adjuvants, (b) an intermediate layer applied onto the core, and (c) a gastric juice-resistant outer layer. The intermediate layer in (b) is formed as a reactive layer in which a gastric juice-resistant polymer layer material partially neutralized with alkali with cation exchange capacity is present. Further, a method for the production of the stable medicament is disclosed.

Description

The present invention discloses a stable medicament for oral administration which comprises-one or more of the benzimidazole derivatives Omeprazole, Lansoprazole or Pantoprazole as an active ingredient as well as a method for its production. It is known from EP 0 005 129 that Omeprazole (5-methoxy-2(((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)-sulfinyl)-1H-benzimidazole functions as a potent inhibitor in the secretion of gastric acid. Omeprazole has proven itself in the therapy of duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellision syndrome. Parenteral and solid peroral medicaments are employed in this connection. The following embodiments presented for Omeprazole apply in the same manner for Lansoprazole (2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)-sulfinyl)-1H-benzimidazole) and Pantoprazole (5-difluoromethoxy-2-((3,4-dimethoxy-2-pyridyl)methyl)-sulfinyl)-1H-benzimidazole). The administration of a medicine per os is especially convenient becaus...

Claims

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Application Information

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IPC IPC(8): A61K9/32A61K9/36A61K9/50A61K9/58A61K9/62A61K31/4439
CPCA61K9/5073A61K31/4439A61K9/5084
Inventor HEESE, GERD-ULFERTJUNGER, HERBERTLAICHER, ARNIMLORCK, CLAUDIOPROFITLICH, THOMASWEISS, GERD
Owner HEESE GERD ULFERT
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