Intranasal administration of active agents to the central nervous system
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Publication Number
US-8883728-B2
Publication Date
2014-11-11
Expiration Date
Abstract
Pharmaceutical compositions and methods for delivering a polypeptide to the central nervous system of a mammal via intranasal administration are provided. The polypeptide can be a catalytically active protein or an antibody, antibody fragment or antibody fragment fusion protein. The polypeptides are formulated with one or more specific agents.
Core Innovation
The invention concerns a method of delivering a therapeutic composition to the central nervous system of a mammal by intranasally administering an aqueous composition containing a therapeutic polypeptide. The method is designed to bypass the blood-brain barrier and provide central nervous system delivery of therapeutic polypeptides.
The aqueous composition includes, as a selected permeation-enhancing compound, one member of a defined group of maltopyranoside or fructopyranosyl monododecanoate compounds: 1-O-n-dodecyl-beta-D-maltopyranoside, 1-O-n-decyl-beta-D-maltopyranoside, 1-O-n-tetradecyl-beta-D-maltopyranoside, or beta-D-fructopyranosyl-alpha-glucopyranoside monododecanoate. The compound is present in the aqueous composition at a concentration between 0.125 g and 1 g per 100 ml.
The described strategy uses aqueous buffers and emphasizes nasal epithelial tight-junction permeability as a mechanistic rationale for central nervous system delivery. Documented formulations and study examples include alpha-MSH mimetibody targeting of the hypothalamus with reduced food intake, and improved central nervous system delivery of biologically active high-molecular-weight enzymes and antibody Fc fragments when formulated with selected enhancer compounds.
Claims Coverage
The independent claim covers intranasal delivery of an aqueous therapeutic polypeptide composition to the mammal central nervous system using a defined permeation-enhancing compound from a specified group at a specified concentration range. Dependent claims further refine polypeptide absorption across nasal epithelium, allow selection among named therapeutic polypeptides, specify exendin-4, and impose formulation pH and excipient concentration constraints.
Intranasal delivery to central nervous system with selected aqueous enhancer
Intranasally administering a therapeutically effective amount of an aqueous composition comprising a therapeutic polypeptide and a compound selected from the group consisting of 1-O-n-dodecyl-beta-D-maltopyranoside, 1-O-n-decyl-beta-D-maltopyranoside, 1-O-n-tetradecyl-beta-D-maltopyranoside, and beta-D-fructopyranosyl-alpha-glucopyranoside monododecanoate, wherein the compound is present in the aqueous composition at a concentration between 0.125 g to 1 g per 100 ml of the aqueous composition.
Absorbing the polypeptide across nasal epithelium
Absorbing the polypeptide across nasal epithelium.
Selecting therapeutic polypeptide from named categories
The method further includes using a selected polypeptide chosen from a group of therapeutic polypeptides comprising growth factors, hormones, neurotrophic factors, and related peptides.
Using exendin-4 as the polypeptide
The method is carried out using the polypeptide exendin-4.
Aqueous composition pH range about 4 to 8
Using the aqueous composition with a pH between about 4 and 8.
Compound concentration of 0.5 g per 100 ml
Specifying that the compound is present in the aqueous composition at a concentration of 0.5 g per 100 ml of aqueous composition.
Overall, the claim coverage centers on intranasal administration of an aqueous therapeutic polypeptide composition to the mammal central nervous system using one of the specified maltopyranoside or fructopyranosyl monododecanoate compounds at 0.125 g to 1 g per 100 ml, with dependent refinements addressing nasal epithelium absorption, particular polypeptide selections (including exendin-4), and formulation pH and excipient concentration limits.
Stated Advantages
Improved central nervous system delivery of therapeutic polypeptides, including antibody Fc fragments and biologically active high-MW enzymes.
Reduced food intake following alpha-MSH mimetibody targeting the hypothalamus.
Documented Applications
Central nervous system delivery of therapeutic compositions in a mammal via intranasal administration, including targeting the hypothalamus using an alpha-MSH mimetibody.
Delivery of antibody Fc fragments to the central nervous system.
Delivery of biologically active high-molecular-weight enzymes to the central nervous system.
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