Lipid nano particles comprising cationic lipid for drug delivery system

Patent metadata

Field	Value
Publication number	US-9839616-B2
Application number	US-201213711922-A
Country	US
Kind code	B2
Filing date	Dec 12, 2012
Priority date	Dec 12, 2011
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

The present invention provides a lipid nano-particles, which allow nucleic acids to be easily introduced into cells, comprising a cationic lipid represented by formula (I)
(wherein: R 1 and R 2 are, the same or different, alkenyl, etc, and
X 3 is absent or is alkyl, etc, X 1 and X 2 are hydrogen atoms, or are combined together to form a single bond or alkylene, and Y 1 is absent or anion, L 1 is a single bond, etc, R 3 is alkyl, etc), and the like.

First claim

The invention claimed is:

1. Lipid nano particles for drug delivery comprising;
a cationic lipid of formula (l):

wherein:
R 1 and R 2 are, the same or different, each linear or branched alkyl, alkenyl or alkynyl having 10 to 24 carbon atoms,
X 1 and X 2 are hydrogen atoms, or are combined together to form a single bond or alkylene,
X 3 and Y 1 are absent,
L 1 is ,—CO— or —CO—O—, R 3 is pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl.

2. The lipid nano particles for drug delivery according to claim 1 , wherein R 1 and R 2 are dodecyl, tetradecyl, (Z)-dodec-7-enyl, (Z)-tetradec-7-enyl, (Z)-hexadec-4-enyl, (Z)-hex adec-7-enyl, (E)-hexadec-7-enyl, (Z)-hexadec-9-enyl, (7Z,10Z)-hexadec-7,10-dienyl, (7Z,10Z,13Z)-hexadec-7,10,13-trienyl, (Z)-octadec-9-enyl or (9Z,12Z)-octadec-9,12-dienyl.

3. The lipid nano particles for drug delivery according to claim 1 , wherein R 1 and R 2 are tetradecyl, hexadecyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-icos-11-enyl or (11Z,14Z)-icosa-11,14-dienyl.

4. The lipid nano particles for drug delivery according to claim 1 , wherein L 1 is —CO— or —CO—O—, R 3 is pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl.

5. The lipid nano particles for drug delivery according to claim 1 , wherein X 1 and X 2 are combined together to form a single bond or alkylene.

6. The lipid nano particles for drug delivery according to claim 1 , wherein X 1 and X 2 are combined together to form a single bond or alkylene, and
R 3 is methyl or alkyl having a carbon number of from 1 to 6 or alkenyl having a carbon number of from 3 to 6, each substituted with 1 to 3 substituent(s), which is(are), the same or different, hydroxy or carbamoyl.

7. The lipid nano particles for drug delivery according to claim 1 , wherein X 1 and X 2 are hydrogen atoms, and
R 3 is methyl or alkyl having a carbon number of from 1 to 6 or alkenyl having a carbon number of from 3 to 6, each substituted with 1 to 3 substituent(s), which is(are), the same or different, hydroxy or carbamoyl.

8. The lipid nano particles for drug delivery according to claim 1 , which comprise a nucleic acid as drug.

9. The lipid nano particles for drug delivery according to claim 8 , wherein the cationic lipid forms a complex together with the nucleic acid, or forms a complex between a combination of the cationic lipid with a neutral lipid and/or a polymer and the nucleic acid.

10. The lipid nano particles for drug delivery according to claim 8 , wherein the cationic lipid forms a complex together with the nucleic acid, or forms a complex between a combination of the cationic lipid with a neutral lipid and/or a polymer and the nucleic acid, and the composition comprises the complex and a lipid membrane for encapsulating the complex.

11. The lipid nano particles for drug delivery according to claim 8 , wherein the nucleic acid is a nucleic acid having an activity of suppressing the expression of the target gene by utilizing RNA interference (RNAi).

12. The lipid nano particles for drug delivery according to claim 11 , wherein the target gene is a gene associated with tumor or inflammation.

13. A method for introducing the nucleic acid into a cell by using the lipid nano particles for drug delivery of claim 8 .

14. The method according to claim 13 , wherein the cell is a cell at a tumor or inflammation site of a mammal.

15. The method according to claim 13 , wherein the cell is a cell in the liver, lungs, kidneys or spleen of a mammal.

16. The method according to claim 14 , wherein the method of the introduction into a cell is a method of introduction into a cell by intravenous administration.

17. A method for treating cancer or inflammatory disease, the method including administering the lipid nano particles for drug delivery of claim 1 to a mammal.

18. The method according to claim 17 , wherein the method of administration is intravenous administration.

Assignees

• Kyowa Hakko Kirin Co Ltd

Inventors

• Kuboyama Takeshi
• Era Tomohiro
• Naoi Tomoyuki

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07C211/21

  Monoamines · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• C12N15/88

  using microencapsulation, e.g. using {amphiphile} liposome vesicle · CPC title