Lipids and compositions for intracellular delivery of biologically active compounds

• US 9,433,681 B2
• Filed: 02/12/2014
• Issued: 09/06/2016
• Est. Priority Date: 05/17/2011
• Status: Active Grant

• Current Assignee: Axolabs GmbH
• Original Assignee: Axolabs GmbH
• Inventors: Constien, Rainer, Geick, Anke, Hadwiger, Philipp, Haneke, Torsten, Ickenstein, Ludger Markus, Hernandez Prata, Carla Alexandra, Schuster, Andrea, Weide, Timo
• Primary Examiner(s): Shterengarts, Samantha
• Assistant Examiner(s): Mauro, Matt
• Application Number:
  US14/178,538
• Publication Number:
  US 20140162962A1
• Time in Patent Office: 937 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/02 Peptides of undefined number of amino acids; Derivatives thereof
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07C 211/11 Diaminopropanes
• CPC Class Codes: C07C 211/13 Amines containing three or more amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 211/14 Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
• CPC Class Codes: C07C 211/22 containing at least two amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 217/08 the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 217/28 having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
• CPC Class Codes: C07C 217/42 having etherified hydroxy groups and at least two amino groups bound to the carbon skeleton
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 295/30 : non-acylated

Abstract

The present invention provides novel amino-lipids, compositions comprising such amino-lipids and methods of producing them. In addition, lipid nanoparticles comprising the novel amino-lipids and a biologically active compound are provided, as well as methods of production and their use for intracellular drug delivery.

Claims

1. A cyclic amino-lipid of the formula:

2. A lipid nanoparticle comprising a cyclic amino-lipid of claim 1.

3. The lipid nanoparticle of claim 2, further comprising an additional lipid selected from the group consisting of:

cationic lipid, helper lipid, and PEG-lipid.

4. The lipid nanoparticle of claim 2, further comprising a hydrophobic small molecule.

5. The lipid nanoparticle of claim 2, further comprising a biologically active compound.

6. The lipid nanoparticle of claim 5, wherein the biologically active compound is selected from the group consisting of:

a small molecule, a peptide, a protein, a carbohydrate, a nucleic acid; and

a lipid.

7. The lipid nanoparticle of claim 3, wherein the cationic lipid is a lipid comprising a quaternary amine with a nitrogen atom having four organic substituents.

8. The lipid nanoparticle of claim 3, wherein the helper lipid is a neutral zwitterionic lipid.

9. The lipid nanoparticle of claim 4, wherein the hydrophobic small molecule is selected from the group consisting of a sterol and a hydrophobic vitamin.

10. The lipid nanoparticle of claim 9, wherein the hydrophobic small molecule is cholesterol.

11. The lipid nanoparticle of claim 7, wherein the protein is selected from the group consisting of a nucleoprotein, a mucoprotein, a lipoprotein, a synthetic polypeptide, a small molecule linked to a protein, and a glycoprotein.

12. The lipid nanoparticle of claim 6, wherein the nucleic acid is in the form of a single stranded or partially double stranded oligomer or a polymer composed of ribonucleotides.

13. The lipid nanoparticle of claim 6, wherein the nucleic acid is selected from the group consisting of an miRNA, an antisense oligonucleotide, an siRNA, an immune-stimulatory oligonucleotide, an aptamer, a ribozyme, and a plasmid encoding a specific gene or siRNA.

14. A pharmaceutical composition comprising a cyclic amino-lipid according to claim 1.

15. A pharmaceutical composition comprising a lipid nanoparticle according to claim 2.

16. The pharmaceutical composition of claim 15, further comprising a biologically active compound.

17. The pharmaceutical composition of claim 16, wherein the biologically active compound is a nucleic acid.

18. The pharmaceutical composition of claim 17, wherein the nucleic acid is in the form of a single stranded or partially double stranded oligomer or a polymer composed of ribonucleotides.

19. A method of treating a disease that is caused by the over-expression of one or several proteins in a subject, said method comprising the administration of a lipid nanoparticle according to claim 5 to the subject, wherein the biologically active compound is a nucleic acid, and wherein treatment refers to alleviation of symptoms, decreasing the rate of disease progression, amelioration or palliation of the disease state, remission or improved prognosis, or slowing the progression of the disease.

20. A method of treating a disease that is caused by a reduced, suppressed or missing expression of one or several proteins in a subject, said method comprising administration of a lipid nanoparticle according to claim 5 to the subject, wherein the biologically active compound is a nucleic acid, and wherein treatment refers to alleviation of symptoms, decreasing the rate of disease progression, amelioration or palliation of the disease state, remission or improved prognosis, or slowing the progression of the disease.

21. A method for generating an immune response in a subject, said method comprising the administration of a lipid nanoparticle according to claim 5 to the subject, wherein the biologically active compound is an immune-stimulatory nucleic acid.