Polyrotaxanes bearing mixed cyclodextrin species and uses thereof

Patent metadata

Field	Value
Publication number	US-11434330-B2
Application number	US-201615768365-A
Country	US
Kind code	B2
Filing date	Oct 14, 2016
Priority date	Oct 14, 2015
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

Abstract

Various embodiments of the present invention are directed to polyrotaxanes comprising a poloxamer core and at least one cyclodextrin and methods for treating Niemann-Pick type C (NPC) and imaging (e.g., MRI) using the polyrotaxanes of the various embodiments of the present invention.

First claim

What is claimed is:

1. A polyrotaxane having the general formula:

or salts thereof,
wherein:
each m, m′, n and n is, independently, an integer from 0 to 30, with the proviso that m+m′+n+n′ is from about 4 to about 30;
C and C′ are the same or different and represent end capping groups of the formula:

wherein each L 2 is independently a bond or (C 1 -C 6 )acyl; each G 3 is a steroid group; and each s is independently an integer from 1 to 6;
B represents:

to which the endcapping groups are covalently attached to B via a (C 1 -C 6 )hydrocarbylene group;
wherein R 5 is methyl; d is an integer from about 1 to about 800; and q is an integer from about 6 to about 800; and
A and A′ each independently represent the macrocyclic host molecule of the general formula (I):

wherein:
A and A′ can be the same or different;
x is an integer from 0 to 8; Z is O or NH;
each R 1 and R 2 is, independently, hydrogen or a substituted or unsubstituted (C 1 -C 6 )hydrocarbyl group.

2. The polyrotaxane of claim 1 , wherein C and C′ are the same or different and represent end capping groups of the formula:

wherein each L 2 is independently a (C 1 -C 6 )acyl.

3. The polyrotaxane of claim 1 , wherein R 1 is a substituted (C 1 -C 6 )hydrocarbyl group.

4. The polyrotaxane of claim 1 , wherein m+m′+n+n′ is from about 5 to about 20.

5. The polyrotaxane of claim 1 , wherein A is hydroxypropyl-β-cyclodextrin (HPβCD).

6. The polyrotaxane of claim 1 , wherein A′ is 4-sulfobutylether-β-cyclodextrin (SBEβCD).

7. The polyrotaxane of claim 1 , wherein A is hydroxypropyl-β-cyclodextrin and m+n is from about 2 to about 10; and A′ is 4-sulfobutylether-β-cyclodextrin and m′+n′ is from about 2 to about 10.

8. The polyrotaxane of claim 1 , wherein the polyrotaxane is HPβCD/SBEβCD-F127 (wherein d=200 and q=65); HPβCD/SBEβCD-F68 (wherein d=151 and q=29); HPβCD/SBEβCD-L35 (wherein d=22 and q=16); HPβCD/SBEβCD-L64 (wherein d=26 and q=30); or HPβCD/SBEβCD-L81 (wherein d=6.25 and q=43), wherein:
the polyrotaxane has a weight average molecular weight of about 20,000 g/mol to about 50,000 g/mol as determined by GPC analysis;
HPβCD is a macrocyclic host of the formula (I) wherein each R′ is H, and Z is O; and
the groups C and C′ of the formula:

wherein each s is 2; each L 2 is C(O); and the steroid group is a cholesteryl group that is covalently attached to the group B of the formula:

via a C(O) group.

9. The polyrotaxane of claim 8 , wherein the polyrotaxne comprises from about 1 to about 10 HPβCD molecules and from about 1 to about 10 SBEβCD.

10. A pharmaceutical composition comprising the polyrotaxane of claim 1 and a pharmaceutically acceptable carrier.

11. A method for treating Niemann-Pick type C (NPC) comprising administering a therapeutically effective amount of a polyrotaxane as in claim 1 to a subject in need thereof.

12. The polyrotaxane of claim 1 , wherein the steroid group is a cholesteryl group.

Assignees

• Purdue Research Foundation

Inventors

• Thompson David H
• Hyun Seok-Hee
• Mondjinou Yawo
• Collins Christopher

Classifications

• C08G83/007 Primary

  Polyrotaxanes; Polycatenanes · CPC title

• A61K51/06

  Macromolecular compounds {, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules (peptides, proteins, polyamino acids A61K51/08; antibodies A61K51/10)} · CPC title

• A61K31/724

  Cyclodextrins · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K49/085

  conjugated systems · CPC title