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Publication Number
US-8642564-B2
Publication Date
2014-02-04
Expiration Date
Abstract
A composition having at least one alkyl glycoside and at least one therapeutic agent, wherein the alkylglycoside has an alkyl chain length from about 10 to about 16 carbon atoms and wherein the therapeutic agent is an oligonucleotide.
Core Innovation
The invention relates to drug-delivery compositions that include a non-irritating, non-toxic nonionic alkyl glycoside, or a saccharide alkyl ester or sucrose ester, blended with therapeutic agents including oligonucleotides such as antisense oligonucleotides and interfering RNA, including siRNA. The alkyl glycoside comprises a maltose linked by glycosidic linkage to an alkyl chain comprising between 10 to 16 carbons.
The disclosed approach increases bioavailability and stabilizes the drug at low enhancer concentrations, and the compositions are presented as suitable for oral, rectal, gastrointestinal, and mucosal routes including intranasal and ocular, including nasolacrimal, as well as CSF. The formulations are designed to enhance absorption while maintaining tolerability.
The document further describes dosage forms such as enteric or sustained-release tablet formats with coatings that become more permeable under gastrointestinal conditions. Supporting examples include long-term human intranasal tolerability with no observable irritation over weeks, improved and less variable intranasal bioavailability for salmon calcitonin, in vivo hypoglycemic effects for insulin and ocular delivery embodiments, and antibacterial activity reported for certain alkyl saccharides.
Claims Coverage
The partial content explicitly provides one independent claim and multiple dependent refinements for formulation, delivery route, alkylglycoside species, and oligonucleotide chemistry. The independent claim centers on increasing oligonucleotide bioavailability by administering an absorption increasing amount of a specified maltose-linked alkylglycoside in an oral, rectal, or gastrointestinal route context, with key inventive structure centered on a maltose-linked alkyl chain of 10 to 16 carbons.
Absorption-increasing maltose-linked alkylglycoside for oligonucleotide bioavailability
A method of increasing the bioavailability of an oligonucleotide in a subject by administering a composition comprising the oligonucleotide and an absorption increasing amount of an alkylglycoside, wherein the alkylglycoside comprises a maltose linked by glycosidic linkage to an alkyl chain comprising between 10 to 16 carbons, thereby increasing the bioavailability of the oligonucleotide in the subject.
Oral, rectal or gastrointestinal delivery route for the composition
The composition is administered to the subject via an oral, rectal or gastrointestinal delivery route.
Specified alkylglycoside concentration range
The method includes a composition wherein the alkylglycoside is present at 0.01% to 20% by weight.
Maltose-linked alkylglycoside selected as dodecyl, tridecyl, or tetradecyl maltoside
The method includes selecting the alkylglycoside from dodecyl maltoside, tridecyl maltoside, or tetradecyl maltoside.
Oral delivery route as an administering step
The method is carried out by administering the composition through the oral delivery route.
Oligonucleotide containing modified components
The method includes an oligonucleotide that comprises one or more modified components, such as a modified sugar moiety, a modified base moiety, and/or a modified sugar linking moiety.
Modified linkage chemistry for the oligonucleotide
The method includes an oligonucleotide having a modified linkage selected from the specified group, including phosphoramide, phosphorothioate, phosphorodithioate, methyl phosphonate, phosphotriester, phosphoramidate, O-methylphosphoroamidite, peptide, and combinations thereof.
Across the provided claims, the coverage is centered on increasing oligonucleotide bioavailability using an absorption increasing amount of a maltose-linked alkylglycoside with an alkyl chain of 10 to 16 carbons, administered via oral, rectal, or gastrointestinal delivery routes. Dependent claim refinements specify an alkylglycoside concentration range, particular alkylglycoside species, and oligonucleotide modifications including modified sugar, base, and linking components and enumerated modified linkage types.
Stated Advantages
Increases the bioavailability of an oligonucleotide in the subject.
Provides increased bioavailability in relation to administering the composition via an oral, rectal or gastrointestinal delivery route.
Documented Applications
Increasing the bioavailability of an oligonucleotide, including antisense oligonucleotide and interfering RNA such as siRNA, in a subject using oral, rectal, or gastrointestinal delivery routes.
Intranasal tolerability in humans for weeks with no observable irritation of nasal epithelium.
Improved and less variable intranasal bioavailability for salmon calcitonin.
In vivo hypoglycemic effects for insulin delivery using alkyl glycosides.
In vivo hypoglycemic effects for ocular delivery with alkyl glycosides.
Antibacterial activity of certain alkyl saccharides, including reported activity against Candida albicans, Aspergillus niger, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus.
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