Enteric coated tiopronin tablet
Inventors
Taylor, Jon • Smoot, Stuart • Schoenherr, Stuart • Werchan, Paul
Assignees
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Publication Number
US-11458104-B1
Publication Date
2022-10-04
Expiration Date
Abstract
A solid pharmaceutical composition is provided that includes a core, an inner coating, and an outer coating. The core includes tiopronin as an active agent. Further, the inner coating, which includes a cellulose-based polymer, surrounds the core, and the outer coating, which includes an enteric polymer, surrounds the inner coating. As a result of the specific components of the solid pharmaceutical composition, the solid pharmaceutical composition exhibits a fed state Cmax of tiopronin that is at least 70% of a 12-hour fasted state Cmax of tiopronin after oral administration of the solid pharmaceutical composition when administered as a 300 milligram dose. As such, it is possible for the solid pharmaceutical composition to be administered orally with or without food (e.g., in a fed or fasted state) while still achieving a desired maximum plasma concentration of the tiopronin in a delayed release formulation.
Core Innovation
The disclosed invention relates to an enteric-coated solid tiopronin formulation for treating cystinuria. It provides a solid pharmaceutical composition with a tiopronin core and a surrounding inner coating and outer coating, where the inner coating comprises a water soluble cellulose-based polymer and does not affect the release profile of tiopronin. The outer coating comprises an enteric polymer that prevents disintegration of the solid pharmaceutical composition in the stomach, together with an anti-tacking agent and a plasticizer.
A key aspect of the invention is oral administration with food to achieve a fed-state pharmacokinetic profile. The composition is configured so that, after oral administration of the solid pharmaceutical composition, the mean fed state Cmax of tiopronin is at least 70% of the mean 12-hour fasted state Cmax. The disclosed performance is also tied to dissolution behavior, including low dissolution in 0.1 N HCl and sufficient dissolution in PBS at pH 6.8.
The invention aims to delay absorption of tiopronin following oral administration to provide for transit out of the stomach and into the intestine before dissolution. The document describes that the solid pharmaceutical composition exhibits at least 75% dissolution after 45 minutes in PBS at pH 6.8, and it reports tiopronin content maintained under accelerated and long-term storage. Comparative discussion versus immediate-release THIOLA® supports delayed absorption consistent with stomach transit and reduced risk of nausea/eructation.
Claims Coverage
The provided claims include one independent claim directed to a cystinuria treatment method and the associated solid pharmaceutical composition, with dependent claims refining the fed-state versus fasted-state Cmax requirement and narrowing tiopronin loading ranges in the core. The inventive features center on oral administration with food, a core with specified component classes, a water soluble cellulose-based inner coating, an enteric outer coating with anti-tacking agent and plasticizer, and performance constraints for fed-state exposure and dissolution.
Cystinuria treatment by oral administration with food of a coated tiopronin solid pharmaceutical composition
A method for treating cystinuria in a patient in need thereof comprising orally administering with food a solid pharmaceutical composition comprising a core comprising tiopronin, a diluent, a binder, a disintegrant, and a lubricant; an inner coating surrounding the core comprising a water soluble cellulose-based polymer; and an outer coating surrounding the inner coating comprising an enteric polymer that prevents disintegration in the stomach, an anti-tacking agent, and a plasticizer; wherein after oral administration with food the mean fed state Cmax is at least 70% of the mean 12-hour fasted state Cmax and the solid pharmaceutical composition provides a delay in absorption to provide for transit out of the stomach and into the intestine before dissolution and exhibits at least 75% dissolution after 45 minutes in PBS at pH 6.8.
Fed-state exposure retention relative to 12-hour fasted state Cmax
After oral administration of the solid pharmaceutical composition, the mean fed state Cmax of tiopronin is at least 75% of the mean 12-hour fasted state Cmax.
Tighter fed-state Cmax comparative range
After oral administration of the solid pharmaceutical composition, the mean fed state Cmax of tiopronin ranges from 85% to 95% of the mean 12-hour fasted state Cmax.
Core tiopronin loading range
The core includes tiopronin at a concentration of 40 to 70 total wt.%.
Core tiopronin loading refinement range
The core includes tiopronin in an amount between 50 and 70 total wt.%.
Across the claims, the method relies on food-administered, enteric-coated tiopronin solids with a cellulose-based inner coating and an enteric outer coating including anti-tacking agent and plasticizer. The claims require delayed absorption to support transit before dissolution, together with at least 75% dissolution after 45 minutes in PBS at pH 6.8, and dependent claims further require higher or more specific fed/fasted Cmax thresholds and narrow tiopronin content in the core.
Stated Advantages
Delays absorption of tiopronin following oral administration to provide for transit out of the stomach and into the intestine before dissolution.
Prevents disintegration of the solid pharmaceutical composition in the stomach.
Maintains sufficient dissolution, exhibiting at least 75% dissolution after 45 minutes in PBS at pH 6.8.
Provides fed-state tiopronin exposure where mean fed state Cmax is at least 70% of mean 12-hour fasted state Cmax.
Reduced risk of nausea/eructation is described in the document.
Documented Applications
Treating cystinuria in a patient in need thereof by orally administering, with food, a coated solid pharmaceutical composition comprising tiopronin.
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