Pellets having a multi-layer structure for delayed release of the active substance in the distal colon
Inventors
Wilhelm, Rudolf • Proels, Markus • GREINWALD, Roland • NACAK, Tanju • BOEGERSHAUSEN, Ansgar
Assignees
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Publication Number
US-11173121-B2
Publication Date
2021-11-16
Expiration Date
Abstract
An optimized pharmaceutical formulation for the treatment of inflammatory diseases of the colon is disclosed, wherein the pharmaceutical formulation is a capsule containing pellets, which capsule is suitable for oral administration and delivers the active substance in a targeted manner to the site of action, namely the colon. This is achieved by a complex and multiple coating of pellets, which permit a modified release of active substance. The release of the active substance is at its maximum only in the colon, with at the same time low blood plasma levels. The results of the pharmaceutical tests concerning in vitro release are corroborated by the results in pharmaco-kinetic and clinical studies and the clinical efficacy demonstrated by these. The formulation according to the invention has a very good medicinal safety.
Core Innovation
The invention relates to a pellet for the delayed release of an active substance in the distal colon using a multi-layer coating. The pellet includes a starter pellet consisting only of an inert material, with the starter pellet containing no pharmaceutically active substance. An active substance layer is directly applied to the starter pellet and contains the active substance together with film-forming excipients.
A swelling layer is directly applied to the active substance layer and contains swelling materials that swell upon contact with intestinal fluid. A retard layer is directly applied to the swelling layer and does not dissolve upon contact with intestinal fluid, but rather becomes permeable for all fluids. An outermost coating is directly applied to the retard layer, where the outermost coating does not dissolve at a pH value below 5.5 and dissolves completely at a pH value greater than 6.0.
The active substance is budesonide or a pharmaceutically acceptable salt thereof. The formulation is intended to enable delayed and continuous release in the intestinal environment, including resistance to dissolution in acidic conditions and release behavior in intestinal medium. The description further addresses reduced systemic exposure through delayed pharmacokinetic behavior.
Claims Coverage
The partial content identifies one independent claim directed to a distal-colon delayed-release pellet with a multi-layer coating, with dependent claims adding further quantitative and material-specific limitations.
Distal-colon delayed-release pellet with multi-layer coating
A pellet for delayed release of an active substance in the distal colon having a starter pellet consisting only of an inert material, an active substance layer directly applied to the starter pellet, a swelling layer directly applied to the active substance layer, a retard layer directly applied to the swelling layer, and an outermost coating directly applied to the retard layer.
Budesonide active substance and pH-dependent outermost coating
The active substance is budesonide or a pharmaceutically acceptable salt thereof, the retard layer does not dissolve upon contact with intestinal fluid but becomes permeable for all fluids, and the outermost coating does not dissolve at pH below 5.5 but dissolves completely at pH above 6.0.
Overall claim coverage focuses on a multi-layer distal-colon delayed-release pellet architecture for budesonide or a salt, combining an inert starter, an active substance plus film-forming excipients, a swelling layer, a non-dissolving-but-permeable retard layer, and an outermost coating with defined pH-dependent dissolution behavior.
Stated Advantages
Enables delayed and continuous release with resistance to dissolution at low pH and dissolution at higher pH conditions.
Reduces systemic exposure through delayed pharmacokinetic behavior.
Documented Applications
Treatment context described for ulcerative colitis, including remission and safety signals, with reference to mesalazine-refractory patients and an open randomized phase I study.
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