# US 11,298,326 B2 · Nucleic acid-containing lipid nanoparticles

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- Number: US 11,298,326 B2
- Document ID: US11298326B2
- Status: Granted
- Kind: B2
- Application number: 15/560,854
- Filed: 2016-03-24
- Published: 2018-12-13
- Granted: 2022-04-12
- Earliest claimed: 2015-03-24
- Assignees: Kyowa Kirin Co., Ltd.
- Applicants: Kyowa Kirin Co., Ltd.
- Inventors: Kentaro Hatanaka; Nobuhiro Yagi; Takeshi Kuboyama; Kaori Yagi; Shintaro Hosoe
- Web page: https://patentgrep.com/patent/US11298326B2

## CPC

- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 9/0019: {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)}
- 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 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07C 211/63: having quaternised nitrogen atoms bound to acyclic carbon atoms
- C07C 215/08: with only one hydroxy group and one amino group bound to the carbon skeleton
- 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
- C07C 219/08: having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of an acyclic unsaturated carbon skeleton
- C07C 229/06: having only one amino and one carboxyl group bound to the carbon skeleton
- C07C 229/12: to carbon atoms of acyclic carbon skeletons
- C07C 233/20: having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
- 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 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07C 271/16: to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
- C07D 207/08: with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D 207/12: Oxygen or sulfur atoms
- C07D 211/22: by oxygen atoms
- C07D 223/04: with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 295/088: to an acyclic saturated chain
- C07D 317/28: Radicals substituted by nitrogen atoms (nitro radicals C07D317/16)
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 451/14: containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12N 2320/51: modulating the chemical stability, e.g. nuclease-resistance
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention provides nucleic acid-containing lipid nanoparticles containing a lipid (lipid A) which has a hydrophilic unit having a single quaternary ammonium group, and three independent, optionally substituted hydrocarbon groups, a lipid derivative or fatty acid derivative of a water-soluble polymer, and a nucleic acid.

## Claims

### Claim 1

Nucleic acid-containing lipid nanoparticles, comprising: a lipid (lipid A), which has a hydrophilic unit having a single quaternary ammonium group and three independent, substituted and either unsubstituted or substituted hydrocarbon groups; a lipid derivative or fatty acid derivative of a water-soluble polymer; and a nucleic acid,
wherein the number of moles of the quaternary ammonium group in the lipid A is 0.1 to 10 times the number of moles of phosphorous atoms in the nucleic acid,
the average particle size is 20 nm to 65 nm, and
the lipid A is a lipid represented by:
(wherein,
R4 to R6, the same or different, are a linear or branched, and either unsubstituted or substituted C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl,
L4 to L6, the same or different, are absent or are —Z4—(CY8Y9)p4— or —Z5—(CY10Y11)p5—Z6—(CY12Y13)p6— (wherein, Y8 to Y13, the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl, Z4 to Z6, the same or different, are —O—, —NY14A—, —CO—O—, —O—CO—, —CO—NY14B—, —NY4C—CO— or (wherein, Y14A to Y14D the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl), p4 is an integer of 0 to 5, p5 is an integer of 1 to 5, and p6 is an integer of 0 to 5),
L7 is (CY15Y16)p7—, —(CY17Y18)p8—Z7—(CY19Y20)p9— —(CY21Y22)p10—Z8—(CY23Y24)p11—Z9—(CY25Y26)p12— (wherein, Y15 to Y26, the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl, Z7 to Z9, the same or different, are —O—, —NY27A—, —CO—O—, or —O—CO—, (wherein, Y27A, the same or different, is a hydrogen atom or optionally substituted C1-C4 alkyl), p7 is an integer of 1 to 5, p8 is an integer of 0 to 5, p9 is an integer of 1 to 5, p10 is an integer of 0 to 5, p11 is an integer of 1 to 5, and p12 is an integer of 1 to 5),
B1 is
(wherein, X2 and X3, the same or different, are an optionally substituted C1-C4 alkyl or are combined together to form an optionally substituted C4-C6 heterocycle with an adjacent nitrogen atom, X4 is an optionally substituted C1-C4 alkyl, X5 and X6, the same or different, are an optionally substituted C1-C4 alkyl or are combined together to form an optionally substituted C4-C6 heterocycle with an adjacent nitrogen atom, X7 is an optionally substituted C1-C4 alkyl, Y28 to Y37, the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl, Z10 and Z11, the same or different, are —O—, —NY38A—, —OO—O—, —O—CO—, —CO—NY38B, —NY38C—CO— or —NY38D—CO—O— (wherein, Y38A to Y38D, the same or different, are a hydrogen atom or optionally substituted C1-C4 alkyl), p13 is an integer of 0 to 5, and p14 to p17, the same or different, are an integer of 1 to 5), and
A2 is a pharmaceutically acceptable anion);
and a lipid (lipid B), which has a hydrophilic unit having one secondary or tertiary amino group or one substituted secondary or tertiary amino group, and a hydrophobic unit having two independent linear C8-C24 alkyl or alkenyl groups or two independent substituted linear C8-C24 alkyl or alkenyl groups;
wherein the ratio of the number of moles of lipid A to the number of moles of lipid B is 0.01 to 2;
wherein the nucleic acid has a molecular weight of 1,000 kDa or less.

### Claim 2 (depends on 1)

The lipid nanoparticles according to claim 1, wherein the lipid A is represented by formula (II), and in formula (II), one of L4 to L6 is —CO—O—(CY8Y9)p4—, —O—CO—(CY8Y9)p4— or —O—CO—(CY10Y11)p5—O—(CY12Y13)p6— or two or more of L4 to L6, the same or different, are —CO—O—(CY8Y9)p4—, —O—CO—(CY8Y9)p4— or —O—CO—(CY10Y11)p5—O—(CY12Y13)p6— and), R4 to R6 are linear or branched C15-C20 alkenyl or C9-C18 alkyl and are the same.

### Claim 3 (depends on 1)

The nucleic acid-containing lipid nanoparticles of claim 1, wherein the number of moles of lipid A is smaller than the number of moles of lipid B.