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Publication Number
US-9399017-B2
Publication Date
2016-07-26
Expiration Date
Abstract
Acid-containing oral pharmaceutical compositions are provided wherein the pharmaceutical active agents are peptide compounds (i.e., those that include a plurality of amino acids and at least one peptide bond in their molecular structures). Certain barrier layers and/or particulate coated acid are used to reduce any adverse interactions that might otherwise occur between the acid of the compositions and other components of the composition. Use of these barrier layers and/or use of particulate coated acid is believed to promote a more simultaneous release of the components of the composition than is achieved by prior art acid-protection techniques, thus enhancing, and making more consistent, the bioavailability of the active peptide compounds.
Core Innovation
The invention relates to an oral pharmaceutical composition for delivery of a physiologically active peptide agent that includes a pharmaceutically acceptable acid particle protected by a protective coating that is non-acidic. The coated acid is present in a quantity that, when the composition is added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, lowers the pH of the solution to no higher than 5.5.
A key aspect is the use of an acid resistant protective vehicle effective to transport the pharmaceutical composition through the stomach while preventing contact between the active peptide agent and stomach proteases. A water soluble barrier layer separates the coated acid from the protective vehicle, thereby controlling interactions between the acid and other formulation components, including an enteric coating and absorption enhancers.
The composition also includes an absorption enhancer, and the relationship of the barrier layer to the rest of the composition is constrained such that the barrier layer adds specified weight contributions or has specified water solubility, or alternatively the peptide agent and the acid are in the same or only layer of the composition. The documented embodiments include oral tablets with an outer layer of an acid-resistant enteric coating, a water soluble barrier layer beneath the enteric coating, and coated acid particles such as glucose-coated citric acid, together with specified excipients and performance constraints.
Claims Coverage
This document includes multiple independent claims directed to oral peptide compositions and tablets. The claims center on a stomach-protective vehicle, a water soluble barrier layer, coated acid particles engineered to lower pH to no higher than 5.5, and an absorption enhancer, with additional constraints for tablet formulation architecture and component properties.
Coated non-acidic acid particles engineered for pH lowering to no higher than 5.5
The pharmaceutical composition includes at least one pharmaceutically acceptable acid particle coated with a pharmaceutically acceptable protective coating that is non-acidic, wherein the acid quantity is sufficient to lower the pH of 0.1M aqueous sodium bicarbonate solution to no higher than 5.5 when added to 10 milliliters, and the coated acid is separated from other components.
Acid resistant protective vehicle preventing contact with stomach proteases
The composition includes an acid resistant protective vehicle effective to transport the pharmaceutical composition through the stomach of a patient while preventing contact between the active peptide agent and stomach proteases.
Water soluble barrier layer separating coated acid from protective vehicle
The composition includes a water soluble barrier layer that separates the acid from the protective vehicle, including architectures where the barrier layer is under an outer layer of acid-resistant enteric coating.
Absorption enhancer
The composition includes an absorption enhancer in combination with the peptide agent, coated acid particles, the acid resistant protective vehicle, and the water soluble barrier layer.
Barrier layer weight/solubility relationship or same-or-only-layer arrangement
The composition requires that either the barrier layer adds 3-6% to the weight, or the barrier layer comprises a material having water solubility in excess of 11 grams per 100 milliliters of water at room temperature, or the peptide agent and the acid are in the same or only layer of the composition.
Water-soluble coated acid with water solubility at least one gram per 100 milliliters
The composition includes pharmaceutically acceptable acid particles coated with a non-acidic protective coating having a solubility in water of at least one gram per 100 milliliters of water at room temperature, and the total acid quantity is sufficient to lower the pH to no higher than 5.5 in the defined sodium bicarbonate test.
Pharmaceutical tablet architecture with enteric coating and specific barrier-layer polymers
A pharmaceutical tablet includes an acid-resistant enteric coating effective to transport the tablet through the stomach while preventing contact between the active peptide agent and stomach proteases, and a water soluble barrier layer beneath the enteric coating separating the enteric coating from coated acid.
Friability-limited compressed tablet performance
The tablet is compressed into tablet form such that the maximum weight loss during friability testing is no greater than 1%.
Dry-compression tablet intermixture in a single layer
A pharmaceutical composition includes a binder for dry compression, a disintegrant, a glidant, a lubricant, an acid with non-acidic protective coating engineered for pH lowering, an acid resistant protective vehicle, and a water soluble barrier layer, wherein materials are thoroughly intermixed in a single layer.
Across the independent claims, the core claim coverage is directed to oral delivery of physiologically active peptide agents using a stomach-protective acid resistant protective vehicle, coated acid particles engineered to lower pH to no higher than 5.5 in the specified sodium bicarbonate test, and a water soluble barrier layer that separates the coated acid from the protective vehicle. The claims additionally require an absorption enhancer and impose independent-claim-specific constraints on barrier-layer properties, tablet architecture, component intermixture, and friability.
Stated Advantages
Improves and stabilizes peptide bioavailability by minimizing acid interactions with other components while promoting more simultaneous component release in the intestines.
Documented Applications
Oral delivery of physiologically active peptide agents using pharmaceutical compositions and pharmaceutical tablets configured with an acid resistant protective vehicle, coated acid particles, and a water soluble barrier layer.
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