Components for producing amphoteric liposomes
View Patent ↗The invention suggests amphoteric lipids wherein one or more amphoteric groups having an isoelectric point between 4 and 9 are substituted on a membranous or membrane-forming amphiphilic substance, as well as liposomes containing such compounds.
1. A compound comprising the structure shown in Formula (I):
amphoteric substance—Y—spacer—amphiphilic substance (Formula (1)), wherein:
(a) the amphoteric substance comprises a cationic portion having a pKa of from 4 to 8, and an anionic portion with a pKa of from 3 to 7, wherein
aa) the cationic portion is a substituted or unsubstituted morpholine or piperazine ring; and
bb) the anionic portion is a carboxyl group;
(b) Y is selected from the group consisting of —(C═O)—O—; —(C═O)—NH—; —NH—(C═O)—O—; —O—; —NH—; —CH═N—; —O—(O═C)—; —S—; —(O═C)—; —NH—(O═C)—; —O—(O═C)—NH— and —N═CH—;
(c) the spacer is from 1 to 8 carbon atoms; and
(d) the amphiphilic substance is selected from the group consisting of an acid group, amine containing group; a structure shown in Formula (II) and a structure shown in Formula (III), wherein
aa) the acid group is esterified with linear C 8 -C 30 alcohols, and selected from the group consisting of a dicarboxylic acid; aspartic acid; glutamic acid; malic acid; tartaric acid; citric acid; aconitic acid; citraconic acid and maleic acid;
bb) the amine group is amidated with linear C 8 -C 30 fatty acids, and selected from the group consisting 1,4-diamine; 1,5-diamine of 3-aminoalanine; diaminobutyric acid; ornithine and lysine;
cc) Formula (II) is
and;
dd) Formula (III) is
wherein X is selected from the group consisting of —O—(C═O); —NH—(C═O)—; —S—(C═O)—; —O—; —NH—; —S—; —N═CH—; —(O═C)—O—; —S—(O═C)—; —NH—(O═C)— and —N═CH—; and R 1 and R 2 are, independently, a C 8 -C 30 alkyl chain or a C 8 -C 30 acyl chain.
2. The compound of claim 1 , wherein the compound has an isoelectric point of from 5 to 7.
3. The compound of claim 1 , wherein the pKa of the cationic portion and the pKa of the anionic portion are two pH units apart.
4. The compound of claim 1 , wherein the spacer has 1 or 2 ethylenically unsaturated bonds.
5. The compound of claim 1 , wherein the spacer has from 1 to 4 hydroxyl groups.
6. The compound of claim 1 , wherein the spacer is a linear alkyl chain.
7. The compound of claim 1 , wherein the spacer is a branched alkyl chain.
8. The compound of claim 1 , wherein the spacer is a cycloalkyl ring.
9. The compound of claim 1 , wherein the dicarboxylic acid is selected from the group consisting of oxalic acid; malonic acid; succinic acid; maleic acid; fumaric acid; malic acid; tartaric acid; glutaric acid; adipic acid; caprylic acid; pimelic acid; suberic acid; cyclohexanedicarboxylic acid; cyclopentanedicarboxylic acid; citric acid, isocitric acid and ethylenediaminetetraacetic acid.
10. The compound of claim 1 , wherein the amphilphilic substance is selected from the group consisting of diacylglycerol; dialkylglycerol; phosphoglycerol; acylated 3-amino-1,2-propanediol; acylated N,N-dialkylamine; alkylated 3-amino-1,2-propanediol and alkylated N,N-dialkylamine.
11. The compound of claim 1 , wherein R 1 and R 2 are, independently, a C 8 -C 30 alkyl chain having 1 or 2 ethylenically unsaturated bonds, or a C 8 -C 30 acyl chain having 1 or 2 ethylenically unsaturated bonds.
12. The compound of claim 1 , wherein R 1 and R 2 are, independently, selected from the group consisting of lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.
13. A formulation comprising the compound of claim 1 .
14. The formulation of claim 13 further comprising a neutral lipid, anionic lipid or cationic lipid.
15. A liposome comprising the compound of claim 7 .
16. The liposome of claim 15 , further comprising an active substance.
17. The liposome of claim 16 , wherein the active substance is selected from the group consisting of a protein, peptide, genetic material, DNA molecule, RNA molecule and antisense molecule.