Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-08-28
2001-09-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S452000, C424S494000, C424S497000
Reexamination Certificate
active
06284271
ABSTRACT:
FIELD OF THE INVENTION.
The present invention relates to a novel pharmaceutical preparation in the form of a multiple unit effervescent dosage form comprising at least one pharmaceutically active substance, i.e. the drug(s). The effervescent dosage form comprises a drug and optionally pharmaceutically acceptable excipients in the form of individual units which units are layered with at least two coating layers providing a floating generating system. A plurality of these units with the floating generating system are mixed together with effervescent excipients and filled into a sachet or, preferably compressed into a multiple unit tableted dosage form.
More specifically, the invention relates to a new effervescent dosage forms comprising individual units, which units are coated with at least two coating layers and which layers make the individually coated units to float when they are liberated in an aqueous effervescent solution. These new effervescent dosage forms comprise for instance units of an acid susceptible substance, such as a proton pump inhibitor protected by an enteric coating layer, or comprise units of a substance which may cause irritation of the mucosal area, or comprise units of a substance covered by a film coating resulting in a controlled release profile, such as an extended release profile. Furthermore, the present invention refers to a method for the manufacture of such dosage forms and, to the use of such dosage forms in medicine.
BACKGROUND OF THE INVENTION AND PRIOR ART
Effervescent dosage forms are one possible vehicle for the administration of drugs. Effervescence may be used to provide some degree of taste-masking. Prior to administration to a patient, an effervescent composition is dissolved and/or dispersed in e.g. an aqueous medium, such as drinking water. Dissolution and/or dispersion takes place directly or rapidly, with effervescence to give an agreeable presentation of the drug in the form of a solution which is suitable to drink. Effervescent dosage forms are particularly suitable for patients finding difficulty in swallowing tablets or disliking tablets.
The dissolution upon effervescence of a multiple unit tablet that gives a dispersion of drug particles, or of individual units comprising the drug may cause problem due to the density of the units and/or the density of coating layers surrounding the units. One problem might be that a majority of the individual units are sinking to the bottom of the drinking glass during or/and after effervescence, but prior to administration. These sinking units make it difficult for the patient to drink the dispersion and to receive the complete dose because a great number of the drug containing units will remain in the glass.
A further problem with effervescent tablets is the composition of effervescent tablet excipients which might cause problem to the incorporated drug. For instance, the use of an acidic substance in the effervescent composition presents a problem, if the drug is an acid susceptible compound, such as a proton pump inhibitor. The prior art has already taught that such an acid susceptible drug is best protected by an enteric coating layer. There are different enteric coating layered preparations of for instance omeprazole as well as of other proton pump inhibitors described in the prior art, e.g. U.S. Pat. No. 4,786,505 (AB Hässle). A tableted multiple unit dosage form must also fulfill standard requirement on enteric coated articles. A suitable tableted multiple unit dosage form comprising omeprazole is described in EP 95926054.8 (Astra AB). Incorporation of such enteric coated pellets in an effervescent tablet are described in the International patent application WO97/25030 filed on Dec. 20, 1996 (Astra AB).
Other groups of drugs prepared in dosage forms with coating layer(s) are for instance substances irritating the mucosal area, e.g. NSAIDs (Non Steroidal Anti-inflammatory Drugs), and drugs formulated into controlled release dosage forms, e.g. extended release formulations.
Some examples of different effervescent tablets and systems described in the prior art are discussed below.
Effervescent tablets containing acid-sensitive agents have previously been made by coating the acid particles in the acid-base couple with the base to separate the acid-sensitive agent from the acid, see WO 94/21239 (Wehling et al.) Effervescent tablets containing the active substance without any coating layer have also been suggested by Wehling et al.
Another construction principle has been presented, wherein extended release microcapsules are incorporated in an effervescent tablet, see WO 95/27482 (Elan corp.) A further example is the above mentioned WO097/25030.
Stomach-floating hard-gelatine capsules have been described by Simone et al in Pharmacol. Res. 1995, 31(2), 115-19. However, this capsule preparation is not an effervescent dosage form, i.e. the preparation does not comprise any effervescent components.
The expandable controlled release dosage form described in EP 669 129 is using gas development in a dosage form. The tablet swells to such a size that it stays for a prolonged time in the stomach by utilising the gas generated after ingestion of the tablet.
None of the above discussed prior art document describes or discuss problems involved with dense units in an effervescent dosage form, such as an effervescent tablet comprising a plurality of individual units.
SUMMARY OF THE INVENTION
The present invention provides individually floating units comprising a pharmaceutically active substance by applying at least two coating layers, named as a floating generating system. These floating units are intended for an effervescent dosage form, and avoid the problems with units sinking during and after effervescence. The first layer of the floating generating system comprises a gas source, which reacts with an acidic aqueous solution to generate gas. The acidic aqueous solution originating from the surrounding effervescent solution penetrates through the second (outer) layer of the floating generating system. The second layer also provides a barrier to enclose the generated gas. The enclosed gas causes the density of the units to decrease, and the units will float in the effervescent solution.
More specifically, the present invention provides a multiple unit effervescent dosage form comprising individually coated units comprising a drug, and effervescent excipients. The multiple unit dosage form can be in the form of a sachet comprising the units coated according to the present invention, and the effervescent excipients, or in the form of a tableted dosage form, wherein the same coated units together with effervescent tablet excipients are compressed into a tablet.
The individually coated units containing the drug will float for a time longer than the time needed for the effervescence and liberation of the units. Thereby, the invention avoids the problem with dense units sinking to the bottom of a drinking glass during administration of the dosage form.
Further, the present invention provides a new floating generating system for effervescent dosage forms comprising a gas generating coating layer composition, and a barrier layer to enclose generated gas.
The floating effect is provided for a time long enough for the patient to complete the administration i.e. the reaction of the effervescent components with the drinking water, and to ingest the dispersion without a hurry. More specifically the floating effect is provided during approximately 5 minutes.
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patent: 9601621 (19
Lundberg Per Johan
Thune Mikael
Astrazeneca AB
Fubara Blessing
Page Thurman K.
White & Case LLP
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