Conjugates of somatostatin analogues
Inventors
Schneider, Eric L. • Hearn, Brian • Ashley, Gary W. • Santi, Daniel V.
Assignees
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Publication Number
US-10413594-B2
Publication Date
2019-09-17
Expiration Date
Abstract
Conjugates of carriers and hydrogels for controlling the biological half-life of somatostatin and its analogs are disclosed.
Core Innovation
The invention provides a conjugate of the formula (1) P-(L-D)n, where D is a somatostatin or its analog and L is a moiety of formula (2). The carrier P is a hydrogel that is crosslinked with linkers that undergo beta elimination, and P is composed of 4-arm polyethylene glycols crosslinked by crosslinkers of formula (2). The somatostatin or its analog is attached to L through the Nα-amino or Nε-amino groups.
The linker moiety L includes a triazole linkage to a cyclooctyne, with defined R-group options. One of the substituent groups R1, R2, or R5 is connected to one hydrogel PEG unit, and the corresponding group is connected to another hydrogel PEG unit, thereby crosslinking the hydrogel P. The structure further specifies substituted options for R1, R2, R3, R5, and p.
The described approach targets limitations of prior depot formulations such as PLGA microspheres by providing conjugates using releasable beta-elimination linkers within hydrogel carriers to extend peptide half-life. The document also includes references to beta-elimination cleavable linkers, release kinetics, and pharmacokinetics support in exemplary contexts.
Claims Coverage
The independent claim coverage centers on a beta-elimination-cleavable somatostatin or analog conjugate within a crosslinked hydrogel PEG carrier, with inventive features defined by the linker formula (2) and a triazole/cyclooctyne coupling arrangement. Dependent claims further narrow linker substitution choices and enumerate specific somatostatin analog identities, and additional dependent claims define an associated treatment use in subjects with enumerated tumor and symptom conditions.
Beta-elimination crosslinked hydrogel conjugate with somatostatin or analog attached via Nα/Nε amino groups
A conjugate of formula (1) P-(L-D)n where P is a hydrogel crosslinked with linkers that undergo beta elimination; D is a somatostatin or its analog; n is a multiplicity; L is a moiety of formula (2); and D is attached to L through the Nα-amino or Nε-amino groups of the somatostatin or its analog.
Crosslinked PEG hydrogel carrier using formula (2) linker with triazole/cyclooctyne connection
P is composed of 4-arm polyethylene glycols crosslinked by crosslinkers of formula (2), where one of R1, R2, or R5 is connected to one hydrogel PEG unit and the corresponding group is connected to another hydrogel PEG unit, and the other R5 is connected to P via a triazole linkage to a cyclooctyne.
Defined releasable linker moiety L with substituted R-group options and parameter p
L is a moiety of formula (2) with specified substituted options for R1, R2, R3, R5, and p.
Somatostatin analog selection within the conjugate
D is one of somatostatin, octreotide, lanreotide, or pasireotide.
Treatment by administering the conjugate for a somatostatin-analog-treatable condition
A method for treating a somatostatin-analog-treatable condition by administering an effective amount of the conjugate to a subject in need.
Treatment for enumerated tumor types and associated symptom conditions
The method where the condition involves growth hormone-producing tumors, pituitary tumors that secrete thyroid stimulating hormone, diarrhea and flushing associated with carcinoid syndrome, or diarrhea in patients with vasoactive intestinal peptide-secreting tumors.
Overall claim coverage centers on a hydrogel conjugate in which somatostatin or an analog is attached via the Nα/Nε amino groups to a linker moiety L that is part of a PEG-based, 4-arm crosslinked hydrogel P. The linker is defined by a beta-elimination releasable structure with specified substituted R-group options and a triazole linkage to a cyclooctyne. Dependent claims further narrow linker substitution selections and enumerate specific analog identities, and additional dependent claims define treatment of somatostatin-analog-treatable conditions, including enumerated tumor types and associated diarrhea and flushing symptom conditions.
Stated Advantages
Extends peptide half-life using beta-elimination linkers within hydrogel carrier formulations.
Documented Applications
No documented applications found
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