Compounds for targeting drug delivery and enhancing siRNA activity

Patent metadata

Field	Value
Publication number	US-10669229-B2
Application number	US-201815985614-A
Country	US
Kind code	B2
Filing date	May 21, 2018
Priority date	Jun 8, 2011
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

Abstract

Here described are compounds consisting of the structure

(targeting molecule) m -linker-(targeting molecule) n ,

wherein the targeting molecule is a retinoid or a fat soluble vitamin having a specific receptor on the target cell; wherein m and n are independently 0, 1, 2 or 3; and wherein the linker comprises a polyethylene glycol (PEG) or PEG-like molecule, as well as compositions and pharmaceutical formulations including these compounds which are useful for the targeting and delivery of therapeutic agents; and methods of using these compositions and pharmaceutical formulations.

First claim

What is claimed:

1. A pharmaceutical formulation, comprising a compound consisting of the structure (retinoid) m -linker-(retinoid) n ; wherein m and n are independently 1, 2 or 3, and m+n is not 2; wherein the linker is selected from the group consisting of bis-amido-PEG, tris-amido-PEG, tetra-amido-PEG, Lys-bis-amido-PEG Lys, Lys-tris-amido-PEG-Lys, Lys-tetr-amido-PEG-Lys, Lys-PEG-Lys, PEG2000, PEG1250, PEG1000, PEG750, PEG550, PEG-Glu, Glu, hexanoyl, Gly 3 , and GluNH.

2. The pharmaceutical formulation of claim 1 , wherein the retinoid is selected from the group consisting of vitamin A, retinoic acid, tretinoin, adapalene, 4-hydroxy(phenyl)retinamide (4-HPR), retinyl palmitate, retinal, saturated retinoic acid, and saturated, demethylated retinoic acid.

3. The pharmaceutical formulation of claim 1 , wherein the compound is selected from the group consisting of (retinoid) m -Lys-PEG-Lys-(retinoid) n , (retinoid) m -PEG2000-(retinoid) n , (retinoid) m -bis-amido-PEG-(retinoid) n , and (retinoid) m -Lys-bis-amido-PEG-Lys-(retinoid) n .

4. The pharmaceutical formulation of claim 3 , wherein the compound is of formula

wherein q, r, and s are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

5. The pharmaceutical formulation of claim 3 , wherein the compound is selected from the group consisting of the compounds of formulas DiVA, SatDiVA, SimDiVA, DiVA-PEG18, TriVA, 4TTNPB, and DiVA-242

6. The pharmaceutical formulation of claim 1 , in the form of a liposomal composition.

7. The pharmaceutical formulation of claim 6 , wherein the liposomal composition comprises a lipid vesicle comprising a bilayer of lipid molecules.

8. The pharmaceutical formulation of claim 7 , wherein the lipid molecules comprise one or more lipids selected from the group consisting of the compounds of formulas HEDC, DODC, HEDODC, DSPE, DOPE, and DC-6-14

9. The pharmaceutical formulation of claim 8 , wherein the lipid molecules further comprise the compound of formula S104

10. The pharmaceutical formulation of claim 7 , further comprising a nucleic acid.

11. The pharmaceutical formulation of claim 10 , wherein the composition facilitates drug delivery to a target cell.

12. A compound of formula

wherein q, r, and s are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

13. A compound selected from the group consisting of (retinoid) m -Lys-PEG-Lys-(retinoid) n , (retinoid) m -PEG2000-(retinoid) n , (retinoid) m -bis-amido-PEG-(retinoid) n , (retinoid) m -Lys-bis-amido-PEG-Lys-(retinoid) n , wherein m and n are independently 1, 2 or 3, and, and m+n is not 2.

14. The compound of claim 13 , wherein the compound is selected from the group consisting of the compounds of formulas DiVA, SatDiVA, SimDiVA, DiVA-PEG18, TriVA, 4TTNPB, and DiVA-242

15. A composition comprising the compound of claim 13 .

16. The composition of claim 15 , in the form of a liposomal composition.

17. The composition of claim 16 , wherein the liposomal composition comprises a lipid vesicle comprising a bilayer of lipid molecules.

18. The composition of claim 17 , wherein the lipid molecules comprise one or more lipids selected from the group consisting of the compounds of formulas HEDC, DODC, HEDODC, DSPE, DOPE, and DC-6-14

19. The composition of claim 17 , wherein the lipid molecules further comprise the compound of formula S104

20. The composition of claim 16 , further comprising a nucleic acid.

21. The composition of claim 17 , wherein the composition facilitates drug delivery to a target cell.

Assignees

• Nitto Denko Corp

Inventors

• Niitsu Yoshiro
• Payne Joseph E
• Gaudette John A
• Hou Zheng
• Knopov Victor
• Witte Richard P
• Ahmadian Mohammad
• Perelman Loren A
• Tanaka Yasunobu
• Akopian Violetta

Classifications

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title

• C07C235/48

  having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms · CPC title

• C07C233/21

  having the carbon atom of the carboxamide group bound to an acyclic carbon atom of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings · CPC title

• Y10S977/907

  Liposome · CPC title