Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-09-05
2003-09-23
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S472000, C424S475000, C424S482000, C424S490000, C424S494000, C424S497000, C424S461000, C424S462000, C514S772300, C514S781000
Reexamination Certificate
active
06623759
ABSTRACT:
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 because it can be carried out by patients practically anywhere and at any time without effort and unpleasant attendant phenomena. The oral administration inevitably leads to the fact that the medicament reaches the stomach at first. However, Omeprazole and its derivatives degrade very rapidly in the acidic environment of the stomach to ineffective compounds. For example, Omeprazole has a half-life of less than ten minutes in aqueous solution at pH values under 4. Therefore, solid peroral medicines (tablets, pellets, granulates) of Omeprazole and similar active ingredients must be completely protected against gastric juice.
The resorption of Omeprazole occurs in the upper duodenum whereby this active ingredient exhibits a pronounced first-pass-effect. Therefore, an as quick and complete release as possible of the active ingredient from the medicament after passage of the pylorus must be ensured in order to guarantee a sufficiently high bio-availability.
For this, Omeprazole is provided with a coating of enteric, i.e. gastric juice-resistant materials, 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). It is known to introduce the extremely acid sensitive active ingredient Omeprazole into the core of a pellet formulation onto which one or more coating layers provided.
Frequently, Eudragit® L100 or L100-55 is used a layer material. Eudragit® L100 is a copolymer of methacrylic acid and methylmethacrylate in a certain ratio and is insoluble in an acidic environment, for example in the stomach, and therewith forms a considerably impermeable protective layer. Eudragit® L100-55 is a copolymer of methacrylic acid and ethylacrylate, whereby the ratio of the monomers is chosen in such a manner that it is insoluble at a pH<5.5, but is soluble at a pH above this. The reason for this essentially lies in the fact that the carboxyl side groups of the polymer are protonated in the acidic environment, and therewith, the polymer is non-charged as a whole. In the weakly acidic neutral and/or basic environment, for example in the intestine region, the carboxyl groups deprotonate whereby the polymer obtains negative charges. It is then water-soluble whereby the active ingredient is released.
However, Eudragit® cannot be applied directly onto the Omeprazole core because the carboxyl groups in the coating layer degrade the Omeprazole which also presents problems in the production and storage of the medicament. Even small amounts of degradation products already lead to unambiguous color changes, and therewith to loss of quality, which no longer allow administration to patients under certain conditions. The storage problems are intensified when moisture penetrates into the active ingredient-containing core through hair-line cracks and other defects in the coating layer.
Gastric juice-resistant coatings of the above-mentioned polymers which are separated from the active ingredient-containing core by an inert isolation layer are suitable for the protection of solid, peroral medicaments with Omeprazole, Lansoprazole or Pantoprazole as an active ingredient against unfavourable storage conditions and against gastric juice in oral ingestion. Additionally, it has also been proven to be appropriate to stabilize the active ingredient-containing core by addition of an alkaline reacting substance. On the other hand, a sufficiently fast release in the intestine must be ensured.
BACKGROUND ART
DE 1 204 363 describes a medicament comprising a core with various layers applied thereto. The first (inner most) layer is soluble in the stomach, but insoluble in the intestine. The second protective layer is water soluble (independent of the pH value) and the third (outer most) protective layer is a gastric juice-resistant coating. However, this formulation is not suitable for Omeprazole because it only dissolves slowly in the intestine. However, a fast dissolution in the intestine is essential for the desired bio-availability.
EP 0 247 983 discloses a pharmaceutical agent for oral administration which comprises Omeprazole as an effective component. The core material contains Omeprazole together with an alkaline reacting compound or an Omeprazole salt, optionally together with an alkaline reacting adjuvant. Intermediate layers which form a separation layer between the alkaline reacting core and an outer layer of a gastric juice-resistant coating comprise water-soluble tablet carrier mediums or tablet carrier mediums quickly disintegrating in water or polymeric, water-soluble, film-forming substance mixtures which optionally contain buffering, alkaline compounds and which should capture protons penetrating from the outside. Aside from its water-solubility, the layer material is chemically and physically inert.
However, with use of an alkaline buffering substance, such as sodium acetate for example, this freely diffuses into the intermediate layer and penetrates into the outer gastric juice-resistant layer. The increase of the pH value associated therewith can favour the penetration of moisture through the enteric layer as a result of the increasing solubility. 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.
EP 0 519 144 describes Omeprazole pellets consisting of an inert pellet core which is coded with the micronized active ingredient and is subsequently coated with a gastric juice-resistant layer. The following adjuvants, dispersed in water, are employed for coating the core with Omeprazole: hydroxymethylcellulose (HMC), water-free lactose, L-hydroxypropylcellulose (L-HPC), sodium lauryl sulfate, disodium hydrogen phosphate dihydrate. Hydroxypropylmethylcellulose phthalate (HPMCP) is used as a gastric juice-resistant coating. In this method, a possible reaction of the Omeprazole with the polymer is not excluded which can especially lead to a deteriorated storage stability.
EP 0 496 437 encompasses pellet cores and/or tablets which contain Omeprazole or an alkaline salt of Omeprazole together with an alkaline reacting compound (buffer) and which are coated with a layer of water-soluble, film-forming adjuvants which preferably react alkaline (buffer) as well as with a gastric juice-resistant outer film.
EP 0237 200 uses basic magnesium salts and/or basic calcium salts for stabilizing benzimidazole derivatives with Omeprazole as a typical representative.
According to this, numerous efforts were undertaken in the production of Omeprazole medicines which prevent the discoloration of the active ingredient, which considerably reduce the chemical degradation of Omeprazole, which prevent the degradation of the active ingredient in acidic gastric juice, but should simultaneously release the active ingredient
Heese Gerd-Ulfert
Jünger Herbert
Laicher Arnim
Lorck Claudio
Profitlich Thomas
AstraZeneca AB
Spear James M.
White & Case LLP
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