# US 10,441,659 B2 · Lipids for therapeutic agent delivery formulations

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- Number: US 10,441,659 B2
- Document ID: US10441659B2
- Status: Granted
- Kind: B2
- Application number: 14/872,951
- Filed: 2015-10-01
- Published: 2016-03-17
- Granted: 2019-10-15
- Earliest claimed: 2012-06-08
- Assignees: Nitto Denko Corporation
- Applicants: Nitto Denko Corporation
- Inventors: Joseph E. Payne; John A. Gaudette; Zheng Hou; Mohammad Ahmadian; Lei Yu; Victor Knopov; Violetta Akopian; Priya Karmali; Richard P. Witte; Neda Safarzadeh; Wenbin Ying; Jun Zhang
- Web page: https://patentgrep.com/patent/US10441659B2

## CPC

- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 9/1272: comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543})
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 35/00: Antineoplastic agents
- C07C 235/08: 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
- C07C 237/08: 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
- C07C 237/16: the carbon skeleton being acyclic and unsaturated
- C07C 271/16: to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
- C07C 317/44: having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C 323/60: with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
- C07C 333/04: having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 333/40: Thiophene-2-carboxylic acid
- Y10T 428/2998: including synthetic resin or polymer
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

The description is directed to ionizable lipids useful for enhancing the delivery of therapeutic agents in liposomes.

## Claims

### Claim 1

A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:
wherein
n and m are independently 1, 2, 3, or 4;
R1 and R2 are independently C10-18alkyl-;
X is —CH2—, wherein L is —OC1-4 alkylene- or
—OC(O)C1-4 alkylene-; or
X is absent, wherein L is —C1alkylene-, —C3alkylene-, —C4alkylene-, —OC1-4 alkylene-, or —OC(O)C1-4 alkylene-; or
X is O or N, wherein L is —C1-4 alkylene-, or
—C(O)C1-4 alkylene-;
or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

### Claim 2 (depends on 1)

The composition of claim 1, comprising the compound of formula I, wherein n and m are 1 or 2.

### Claim 3 (depends on 1)

The composition of claim 1, comprising the compound of formula I, wherein X is absent.

### Claim 4 (depends on 3)

The composition compound of claim 3, comprising the compound of formula I, wherein L is —OC1-4 alkylene-, or —OC(O)C1-4 alkylene-.

### Claim 5 (depends on 3)

The composition of claim 3, comprising the compound of formula I, wherein L is —CH2—, —CH2CH2CH2—, or —CH2CH2CH2CH2—.

### Claim 6 (depends on 1)

The composition of claim 1, comprising the compound of formula I, wherein X is —CH2—.

### Claim 7 (depends on 6)

The composition of claim 6, comprising the compound of formula I, wherein L is —OC1-4 alkylene-.

### Claim 8 (depends on 7)

The composition of claim 7, comprising the compound of formula I, wherein L is —OCH2CH2— or —OCH2CH2CH2—.

### Claim 9 (depends on 6)

The composition of claim 6, comprising the compound of formula I, wherein L is —OC(O)C1-4 alkylene-.

### Claim 10 (depends on 9)

The composition of claim 9, comprising the compound of formula I, wherein L is —OC(O)CH2CH2CH2—.

### Claim 11 (depends on 1)

The composition of claim 1, comprising the compound of formula I, wherein X is O.

### Claim 12 (depends on 1)

The composition of claim 1, comprising the compound of formula I, wherein R1 and R2 are each C10-18alkyl-.

### Claim 13 (depends on 12)

The composition of claim 12, comprising the compound of formula I, wherein R1 and R2 are each C13alkyl-.

### Claim 14

A composition comprising a compound selected from the group consisting of
or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

### Claim 15 (depends on 1)

The composition of claim 1, wherein the ionizable lipid compound is 5 to 50 mol % of the total lipid molecules.

### Claim 16

A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:
wherein
n and m are independently 1, 2, 3, or 4;
R1 and R2 are independently C10-18alkyl-;
X is absent;
L is —CH2CH2—;
or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

### Claim 17 (depends on 16)

The composition of claim 16, wherein the ionizable lipid compound of formula I consists of

### Claim 18

A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:
wherein
n and m are independently 2, 3, or 4;
R1 and R2 are independently C12-18alkenyl-;
X is absent;
L is —CH2CH2—;
or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

### Claim 19

A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:
wherein
n and m are independently 2, 3, or 4;
R1 and R2 independently are a C12-18alkenyl-;
X is —CH2—, wherein L is —OC1-4 alkylene or —OC(O)C1-4 alkylene-; or
X is absent, wherein L is C1-C4alkylene, —OC1-4 alkylene, or
—OC(O)C1-4 alkylene-; or
X is O or N, wherein L is —C1-4 alkylene-, or
—C(O)C1-4 alkylene-;
or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

### Claim 20 (depends on 19)

The composition of claim 19, wherein the ionizable lipid compound of formula I consists of i-Pr-DODC

### Claim 21

A composition comprising lipid molecules comprising an ionizable lipid compound of formula I:
wherein
n and m are 1;
R1 and R2 independently are a C12-18alkenyl;
X is —CH2—, wherein L is —OC1-4 alkylene- or —OC(O)C1-4 alkylene-; or
X is absent, wherein L is —C1-4alkylene-, —OC1-4 alkylene-, or —OC(O)C1-4 alkylene-; or
X is O or N, wherein L is —C1-4 alkylene-, or
—C(O)C1-4 alkylene-;
or a pharmaceutically acceptable salt form thereof;
and a cationic lipid, wherein the cationic lipid is

### Claim 22 (depends on 21)

The composition of claim 21, wherein the ionizable lipid compound of formula I consists of C104-DO