Chelate nanoemulsion for MRI

Patent metadata

Field	Value
Publication number	US-9770520-B2
Application number	US-201113995732-A
Country	US
Kind code	B2
Filing date	Dec 20, 2011
Priority date	Dec 20, 2010
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

The present invention relates to an oil-in-water nanoemulsion composition for MRI, comprising:
an aqueous phase, representing 70% to 90% by weight of the composition, advantageously 75% to 85% and more advantageously from 78% to 82% a lipid phase comprising an oil, representing 9.5% to 29.5% by weight of the composition, advantageously 14% to 25% and more advantageously 17% to 21%, a surfactant at the interface between the aqueous and lipid phases, the surfactant comprising at least one amphiphilic paramagnetic metal chelate and optionally an amphiphilic lipid; the total content of surfactant by weight relative to the oil being between 4% and 10% and advantageously between 5% and 8%; the total content of surfactant by weight relative to the composition being between 0.35% and 2.95% and advantageously between 0.5% and 2%; the oil comprising at least 70%, advantageously at least 80%, advantageously at least 95% by weight and especially at least 97% of saturated C6-C18, advantageously C6-C14 and more advantageously C6-C10 fatty acids.

First claim

The invention claimed is:

1. An oil-in-water nanoemulsion composition for MRI comprising nanodroplets, said oil-in-water nanoemulsion composition comprising:
an aqueous phase, representing 70% to 90% by weight of the composition,
a lipid phase comprising an oil, representing 9.5% to 29.5% by weight of the composition,
a surfactant at the interface between the aqueous and lipid phases, the surfactant comprising at least one amphiphilic paramagnetic metal chelate, at least one amphiphilic targeting biovector and an amphiphilic lipid, said surfactant comprising by weight:
50% to 95% of amphiphilic lipid,
5% to 50% of amphiphilic paramagnetic metal chelate, and
0.05% to 5% of amphiphilic targeting biovector;

the total content of surfactant by weight relative to the oil being between 4% and 10%;
the total content of surfactant by weight relative to the composition being between 0.35% and 2.95%;
the oil comprising at least 70% of saturated C6-C18 fatty acids,
wherein the amphiphilic paramagnetic metal chelate is a macrocyclic chelate selected from the group consisting of DOTA, DO3A, HPDO3, BTDO3A, PCTA, DOTAM, DOTMA, DOTA-GA, AAZTA, HOPO, multimers thereof and derivatives thereof in which one or more carboxylic groups are in the form of a corresponding salt, ester or amide, or in which one or more carboxylic groups are replaced with a phosphonic and/or phosphinic group, and
wherein the amphiphilic targeting biovector is of formula Bio-L-Lipo, in which:
Bio is a biological recognition part located on the outer surface of the nanodroplets selected from the group consisting of: peptides, pseudopeptides, peptidomimetics, amino acids, integrin targeting agents, glycoproteins, lectins, biotin, pteroic or aminopteroic derivatives, folic and antifolic acid derivatives, antibodies or antibody fragments, avidin, steroids, oligonucleotides, ribonucleic acid sequences, deoxyribonucleic acid sequences, hormones, proteins, which may be recombinant or muted, mono- or polysaccharides, compounds of benzothiazole, benzofuran, styrylbenzoxazole/thiazole/imidazole/quinoline or styrylpyridine backbone;
Lipo is a lipophilic group for inserting Bio into the surfactant;
L is a linking group connecting Bio and Lipo, L being:
a single bond, squarate, C 1-6 alkylene, PEG, for example CH 2 —(CH 2 —O—CH 2 )k-CH2 with k=1 to 10, (CH 2 ) 3 —NH, NH—(CH 2 ) 2 —NH, NH—(CH 2 ) 3 —NH, (CH 2 ) n , (CH 2 ) n —CO—, —(CH 2 ) n NH—CO— with n=2 to 10, (CH 2 CH 2 O) q (CH 2 ) r —CO—, (CH 2 CH 2 O)q(CH 2 ) r —NH—CO— with q=1-10 and r=2-10, (CH 2 ) n —CONH—, (CH 2 ) n —CONH-PEG, (CH 2 ) n —NH—HOOC—CH 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—CH 2 —COOH; HOOC—(CH) 2 —CO 2 —(CH 2 ) 2 —OCO—(CH 2 ) 2 —COOH; HOOC—CH(OH)—CH(OH)—COOH; HOOC—(CH 2 ) n —COOH; NH 2 —(CH 2 ) n —NH 2 , with n=0-20; NH 2 —(CH 2 ) n —CO 2 H; NH 2 —CH 2 — (CH 2 —O—CH 2 ) n —CO 2 H with n=1 to 10, or
P1-1-P2, which may be identical or different, P1 and P2 being chosen from O, S, NH, nothing, CO 2 , NHCO, CONH, NHCONH, NHCSNH, SO 2 NH—, NHSO 2 —, squarate with 1=alkyl, alkoxyalkyl, polyalkoxyalkyl (PEG), alkyl interrupted with one or more squarates or with one or more aryls, advantageously phenyls, alkenyl, alkynyl, alkyl interrupted with one or more groups chosen from —NH—, —O—, —CO—, —NH(CO)—, —(CO)NH—, —O(CO)—, or —(OC)O—.

2. The composition as claimed in claim 1 , wherein the amphiphilic targeting biovector represents 0.5% to 1% by weight of the total surfactant.

3. The composition as claimed in claim 1 , wherein the surfactant represents 5% to 8% by weight of the oil.

4. The composition as claimed in claim 1 , wherein the saturated C6-C18 fatty acids are in the form of saturated fatty acid triglycerides.

5. The composition as claimed in claim 1 , wherein the oil comprises saturated fatty acids in the following proportions:
C6-C18>70%,
or C6-C14>70%,
or C8+C10>70%.

6. The composition as claimed in claim 1 , wherein the amphiphilic paramagnetic metal chelate is a macrocyclic chelate selected from the group consisting of DOTA, DO3A, HPDO3, BTDO3A and PCTA.

7. The composition as claimed in claim 1 , wherein the amphiphilic lipid is a phospholipid.

8. The composition as claimed in claim 1 , wherein the surfactant also comprises an amphiphilic stealth agent.

9. The composition as claimed in claim 1 , wherein the paramagnetic metal of the amphiphilic paramagnetic metal chelate is selected from the group consisting of: manganese, iron, cobalt, nickel, copper, molybdenum, ruthenium, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium and ytterbium.

10. A process for preparing a composition as claimed in claim 1 , comprising the steps of:
preparation of a lipid phase comprising
optionally a first amphiphilic lipid surfactant
an oil comprising at least 70% by weight, of C6-C18 saturated fatty acids
an amphiphilic paramagnetic metal chelate
an amphiphilic targeting biovector;
dispersion of the lipid phase in an aqueous solution so as to form an oil-in-water nanoemulsion; and
recovery of the nanoemulsion composition obtained.

11. A method of diagnosing cancerous, inflammatory, neurodegenerative and/or cardiovascular diseases comprising administering a therapeutic amount of the composition as claimed in claim 1 to a patient in need thereof.

12. The composition as claimed in claim 7 , wherein the phospholipid is selected from the group consisting of phosphatidylcholine, dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylethanolamine, sphingomyelin, phosphatidylserine, phosphatidylinositol and lecithin.

13. The composition as claimed in claim 8 , wherein the amphiphilic stealth agent is a PEG derivative, a ganglioside derivative or a polysaccharide.

14. The composition as claimed in claim 9 , wherein the paramagnetic metal of the amphiphilic paramagnetic metal chelate is Gd(III), Mn(II), europium or dysprosium.

15. The composition as claimed in claim 1 , wherein the amphiphilic targeting biovector is

Assignees

• Port Marc
• Robic Caroline
• Leal Calderon Fernando
• Chadel Samy
• Guerbet Sa
• Univ Bordeaux

Inventors

• Port Marc
• Robic Caroline
• Leal Calderon Fernando
• Chadel Samy

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K49/1806 Primary

  Suspensions, emulsions, colloids, dispersions · CPC title