Pharmaceuticals for oral delivery
Inventors
Carl, Stephen M. • Vrettos, John Stanley • Stern, William
Assignees
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Publication Number
US-9526785-B2
Publication Date
2016-12-27
Expiration Date
Abstract
The present invention provides pharmaceutical compositions suitable for oral delivery and methods of treating subjects in need thereof. The pharmaceutical compositions of the present invention enhance bioavailability of at least one compound classified as BCS Class II, BCS Class III or BCS Class IV.
Core Innovation
The invention relates to solid oral dosage forms for improving oral bioavailability of aminoglycosides and other compounds. The dosage form includes a mixture containing a therapeutically effective amount of an aminoglycoside together with an absorption enhancer and coated citric acid particles, and the citric acid system is configured such that contact with aqueous sodium bicarbonate acidifies the solution to a pH no higher than 5.5.
The dosage form further includes an enteric coating and a water soluble barrier positioned between the mixture and the enteric coating to separate the mixture from the enteric coating. Oral administration is described as producing a synergistic increase in systemic bioavailability of the aminoglycoside compared with administration of a solid dosage form containing an equal dose of the aminoglycoside without the absorption enhancer and citric acid.
The described absorption enhancer system includes at least one absorption enhancer and at least one pH-lowering compound and at least one chelating agent, with citric acid identified as a preferred chelating agent and sodium citrate described as a preferred pH-lowering compound. Examples provided in the document include oral pharmaceutical compositions and treatment methods using tigecycline, zanamivir, kanamycin, and tobramycin, including coated and multilayer capsule formulations.
Claims Coverage
The independent claims are directed to solid oral dosage forms using coated citric acid particles with a water-soluble coat, a pH constraint upon contact with aqueous sodium bicarbonate, and an enteric coating with a water-soluble barrier, with synergy through inclusion of absorption enhancers; specific embodiments identify tobramycin and lauroyl carnitine.
Coated citric acid particles with water-soluble separation coat and pH acidification to no higher than 5.5
A mixture includes coated citric acid particles where the citric acid particles are coated with a water soluble coat that separates the citric acid from the aminoglycoside and, if the dosage form is added to ten milliliters of 0.1 M aqueous sodium bicarbonate solution, acidifies the solution to a pH no higher than 5.5.
Enteric coating with water soluble barrier positioned between mixture and enteric coating
The solid oral dosage form includes an enteric coating and a water soluble barrier positioned between the mixture and the enteric coating, thereby separating the mixture from the enteric coating.
Synergistic increase in systemic bioavailability versus equal-dose comparator lacking absorption enhancer and citric acid
Oral administration results in a synergistic increase in systemic bioavailability of the aminoglycoside when compared to administration of a solid dosage form containing an equal dose of the aminoglycoside without the absorption enhancer and the citric acid.
Tobramycin with lauroyl carnitine and coated citric acid particles
A mixture includes a therapeutically effective amount of tobramycin, lauroyl carnitine, and coated citric acid particles with a water soluble coat separating the citric acid from the tobramycin and acidifying to a pH no higher than 5.5 in 0.1 M aqueous sodium bicarbonate; oral administration provides about a 4-fold to about a 7-fold increase of mean systemic bioavailability of tobramycin versus an equal-dose control lacking lauroyl carnitine and the citric acid, as measured in a Beagle dog model.
Tobramycin with functional excipients including coated citric acid particles
A mixture comprises a therapeutically effective amount of tobramycin and functional excipients consisting of one or more absorption enhancer and coated citric acid particles with a water soluble coat separating the citric acid from the tobramycin, wherein acidification to a pH no higher than 5.5 occurs in 0.1 M aqueous sodium bicarbonate, and oral administration results in a synergistic increase in systemic bioavailability of the tobramycin compared with a solid dosage form containing an equal dose of tobramycin without the functional excipients.
Across the claims, the coverage is directed to solid oral dosage forms that combine coated citric acid particles with an absorption enhancer, and in some embodiments an enteric coating and a water-soluble barrier, to provide a synergistic increase in systemic bioavailability of aminoglycosides. Specific embodiments further focus on tobramycin with lauroyl carnitine and on functional excipients defined as one or more absorption enhancer alongside the coated citric acid particles.
Stated Advantages
Synergistic increase in systemic bioavailability of the aminoglycoside versus a solid dosage form containing an equal dose of the aminoglycoside without the absorption enhancer and the citric acid.
About a 4-fold to about a 7-fold increase in mean systemic bioavailability of tobramycin versus an equal-dose control lacking lauroyl carnitine and citric acid, as measured in a Beagle dog model.
Documented Applications
Treatment methods for infections, including gram-positive infection and gram-negative infection, with examples using tigecycline for systemic pharmacokinetic improvement.
Oral delivery and systemic exposure improvement for drugs including zanamivir, kanamycin, and tobramycin, supported by pharmacokinetic and bioavailability results in animal models.
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