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Publication Number
US-8664178-B2
Publication Date
2014-03-04
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 calcitonin in which calcitonin is intermixed with coated acid particles. The coated acid particles include at least one pharmaceutically acceptable acid coated with a pharmaceutically acceptable protective coating that separates the acid from the calcitonin in the composition, while a water-soluble barrier layer separates the coated acid particles from an acid-resistant protective vehicle. The calcitonin and the coated acid particles are in the same layer of the composition.
The total acid in the pharmaceutical composition is defined by a pH-lowering condition: if the total acid is added to ten milliliters of 0.1 M aqueous sodium bicarbonate solution, it is sufficient to lower the pH of the solution to no higher than 5.5. The composition excludes an amount of base which, if released together with the acid, would prevent the pH from dropping to 5.5 or below.
The acid-resistant protective vehicle is effective to transport the pharmaceutical composition through the stomach of a patient while preventing contact between the calcitonin and stomach proteases. In use, the acid-resistant protective vehicle is breached in the intestine so the acid is released from the coated acid particles, where the acid reduces the activity of intestinal proteases and promotes more consistent peptide bioavailability.
Claims Coverage
Independent claims cover oral calcitonin formulations using coated acid particles intermixed with calcitonin and separated from an acid-resistant protective structure by a water-soluble barrier layer, together with a total-acid pH-lowering condition to no higher than 5.5 and exclusion of sufficient releasable base. The inventive features center on coated acid particles, protective transport through the stomach, barrier-layer separation, and the sodium bicarbonate pH test.
Intermixed calcitonin and coated acid particles separated by a protective coating
Calcitonin intermixed with coated acid particles, the coated acid particles comprising at least one pharmaceutically acceptable acid coated with a pharmaceutically acceptable protective coating to separate the acid from the calcitonin in the composition.
Acid-resistant protective vehicle preventing contact with stomach proteases
An acid-resistant protective vehicle effective to transport the pharmaceutical composition through the stomach of a patient while preventing contact between the calcitonin and stomach proteases.
Water-soluble barrier layer separating coated acid particles from the protective vehicle
A water-soluble barrier layer that separates the coated acid particles from the protective vehicle, wherein the calcitonin and the coated acid particles are in the same layer of the composition.
Total-acid pH-lowering to no higher than 5.5 in sodium bicarbonate
Total acid in the pharmaceutical composition is in a quantity which, if added to ten milliliters of 0.1 M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of the solution to no higher than 5.5.
No releasable base that prevents pH from dropping to 5.5 or below
The composition does not include an amount of base which, if released together with the acid, would prevent the pH of the solution from dropping to 5.5 or below.
Coated citric acid particles with acid-resistant enteric coating and underlayer barrier
Calcitonin intermixed with coated citric acid particles; an outer layer of an acid-resistant enteric coating effective to transport the pharmaceutical composition through the stomach of a patient while preventing contact between the calcitonin and stomach proteases; and a water-soluble barrier layer beneath the enteric coating that separates the enteric coating from the coated citric acid particles.
Acid-resistant enteric protective transport with underlayer separation for coated citric acid
The water-soluble barrier layer is beneath the enteric coating and separates the enteric coating from the coated citric acid particles, with total acid defined for sodium bicarbonate pH lowering and without sufficient base to prevent pH dropping to 5.5 or below.
The claim coverage centers on oral calcitonin formulations in which coated acid particles are combined with an acid-resistant protective vehicle or enteric coating and a water-soluble barrier layer, while the total acid is constrained by a defined sodium bicarbonate pH-lowering requirement and by exclusion of sufficient releasable base.
Stated Advantages
The approach is intended to minimize interactions between gastric/protecting acid components and other formulation components.
The approach is intended to promote more simultaneous release of acid and peptide into the intestine.
The approach is intended to lower local pH to 5.5 or below.
The approach is intended to reduce protease activity, including intestinal proteases.
The approach is intended to enhance and make more consistent peptide bioavailability.
Documented Applications
Oral delivery of calcitonin, including salmon calcitonin, using the described pharmaceutical compositions.
Increasing plasma calcitonin concentration by orally administering the pharmaceutical composition to a subject in need thereof.
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