Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds
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Publication Number
US-10894087-B2
Publication Date
2021-01-19
Expiration Date
Abstract
Among other aspects, provided herein are multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds. Methods of preparing such conjugates as well as methods of administering the conjugates are also provided. Upon administration to a patient, release of the cabazitaxel-based compound is achieved.
Core Innovation
The disclosure describes cabazitaxel-based multi-arm polymeric prodrug conjugates in which cabazitaxel is linked through a releasable spacer to a water-soluble non-peptidic polymer. The conjugate is defined by formula-based structural parameters including R, Q, POLY1, and X, with R representing a polyol/polythiol/polyamine core residue bearing q arms, Q representing a linker, and X representing a spacer that is optionally associated with a releasable linkage.
The conjugate structure is characterized by substituent definitions and integer parameters, including R1 and R2 each being methyl, R3 being H, m being a positive integer from 1 to about 12, and n being a positive integer from 10 to about 400. The spacer X is defined as an optionally substituted unit including —(CH2)m— or —CH2C(O)NHCH(R3)—, and the disclosure includes pharmaceutically acceptable salts and solvates of the conjugate.
The document also describes conjugate preparation using multi-arm polymer reagents with reactive groups, and optional timing of deprotecting hydroxy groups to obtain the cabazitaxel derivatives and subsequent cabazitaxel conjugates. The formulation and composition language is tied to the fraction of conjugates in the composition that fall within the formula-defined conjugate structures, including at least 80%, 85%, or 95% of the conjugates, and the disclosure references formulations that include cabazitaxel-based conjugates and pharmaceutical carriers for administration.
Claims Coverage
The independent claim covers a defined cabazitaxel-based conjugate having specific structural substituent and integer parameter definitions, with the functional requirement of increased tumor growth delay compared to cabazitaxel. Dependent claims further scope the conjugate and compositions by specifying selected conjugate structures and quantitative constraints on the fraction of conjugates in a composition that fall within the claim-1 structure.
Cabazitaxel-based conjugate with defined spacer and substituents
A conjugate defined by the specified formula, wherein each R1 is methyl, each R2 is methyl, each X is —(CH2)m— or —CH2C(O)NHCH(R3)—, each m is a positive integer from 1 to about 12, R3 is —H, and each n is a positive integer from 10 to about 400, or pharmaceutically acceptable salts and solvates thereof.
Increased tumor growth delay compared to cabazitaxel
The conjugate is defined to have an increased tumor growth delay compared to cabazitaxel.
Selected conjugate structures
A conjugate selected from the group of conjugate structures shown in provided images, including pharmaceutically acceptable salts.
Composition with at least 80% encompassed conjugates
A composition containing multiple conjugates where at least 80% of the conjugates have a structure encompassed by claim 1.
Composition with pharmaceutically acceptable excipient
The composition further includes a pharmaceutical excipient.
Composition with at least 85% encompassed conjugates
A composition characterized by having at least 85% of its conjugates with structures encompassed by claim 1.
Composition with at least 95% encompassed conjugates
A composition in which at least 95% of the conjugates have a structure encompassed by claim 1.
Overall claim coverage requires a cabazitaxel-based conjugate with defined substituent and spacer parameters and a functional property of increased tumor growth delay compared to cabazitaxel. The scope is narrowed in dependent claims by selecting conjugates from defined structures and by imposing quantitative thresholds (80%, 85%, and 95%) on the fraction of conjugates in a composition that fall within the claim-1 encompassed structure.
Stated Advantages
Increased tumor growth delay compared to cabazitaxel.
Documented Applications
Pharmaceutical compositions and pharmaceutical carriers for administration that include the cabazitaxel-based conjugates and their pharmaceutically acceptable salts and solvates.
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