Paramagnetic solid lipid nanoparticles (pSLNs) containing metal amphiphilic complexes for MRI

Patent metadata

Field	Value
Publication number	US-10039843-B2
Application number	US-201314426036-A
Country	US
Kind code	B2
Filing date	Sep 6, 2013
Priority date	Sep 7, 2012
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

The present invention relates to paramagnetic solid lipid nanoparticles (pSLNs) comprising an amphiphilic paramagnetic metal chelating moiety selected from: a diazepine derivative of Formula I and a tetraazocyclododecane derivative of Formula (II): being said chelating moiety complexed to a paramagnetic metal ion selected from the group consisting of: Gd(III), Mn(II), Cr(III), Cu(II), Fe(III), Pr(III), Nd(III), Sm(III), Tb(III), Yb(III), Dy(III), Ho(III) and Er(III), or salts thereof. The invention further relates to the process for preparation of said solid lipid nanoparticles comprising amphiphilic complexes of paramagnetic metals (pSLNs) and to the use of pSLNs as MRI contrast agents in the diagnostic field.

First claim

The invention claimed is:

1. A paramagnetic Solid Lipid Nanoparticle (pSLN) comprising an inner solid lipid core and an amphiphilic component around said core, said amphiphilic component comprising a paramagnetic metal chelating moiety selected from the group consisting of a diazepine derivative of Formula I and salts thereof:

wherein:
Y is a group of formula Y′—NH— or (Y′) 2 —N—, where Y′ is selected from the group consisting of:
a linear or branched saturated or unsaturated C 8 -C 16 alkyl group; and a C 1 -C 10 alkyl group interrupted by a phosphate group —O—(HO—P═O)—O— optionally substituted by one or more groups selected from: hydroxy —OH, carboxy —COOR 1 , oxycarbonyl —(C 8 -C 16 )alkyl and oxycarbonyl —(C 8 -C 16 )alkenyl, where R 1 is hydrogen H or a C 1 -C 4 linear or branched alkyl group; and
a monophosphate ester of a substituted or partially substituted glycerol, having at least one functional group of said glycerol esterified with an aliphatic fatty acid with saturated or unsaturated carbon chains, and the phosphoric acid function is either free or salified with a alkali or earth alkali metal;

L is a bivalent linker selected from: an aliphatic C 3 -C 10 cyclic or heterocyclic group and a C 1 -C 6 alkyl, C 2 -C 6 alkenyl or alkynyl, linear or branched group optionally substituted or interrupted with an atom or group selected from the group consisting of: carbonyl —C═O, thiocarbonyl —C═S, amino —NR 1 —, carboxy —COO—, oxy-carbonyl —OCO—, amido —NR 1 CO— or —CONR 1 —, oxygen —O— and sulphur —S—, wherein R 1 is as defined above;
R I-IV and R I-III are each, independently a —(C 1 -C 3 )alkylcarboxy group,
wherein said chelating moiety is complexed with a paramagnetic metal ion selected from the group consisting of: Gd(III), Mn(II), Cr(III), Cu(II), Fe(III), Pr(III), Nd(III), Sm(III), Tb(III), Yb(III), Dy(III), Ho(III), Er(III), and a salt thereof.

2. The pSLN according to claim 1 , wherein said solid lipid core comprises at least one glyceride selected from the group consisting of: a monoglyceride, a diglyceride, a triglyceride, and mixtures thereof, having a C 12 -C 24 saturated or unsaturated linear or branched alkyl chain, where in the case of a di- and tri-glyceride, the alkyl chain can be the same or different, optionally further comprising a saturated or unsaturated fatty acid C 12 -C 22 , a fatty acid ester, or mixtures thereof.

3. The pSLN according to claim 2 , wherein said glyceride is a triglyceride.

4. The pSLN according to claim 1 , wherein said amphiphilic component further comprises at least one amphiphilic compound selected from the group consisting of: a C 6 -C 24 linear or branched, saturated or unsaturated chain phospholipid, lysolipid and sphingolipid.

5. The pSLN of claim 1 comprising:
30-45% weight/weight of a lipid component, comprising at least one glyceride selected from the group consisting of: a monoglyceride, a diglyceride, a triglyceride, and mixtures thereof, having a C 12 -C 24 saturated or unsaturated linear or branched alkyl chain, where in the case of a di- and tri-glyceride, the alkyl chain can be the same or different, optionally further comprising a saturated or unsaturated fatty acid C 12 -C 22 , a fatty acid ester, or mixtures thereof;
30-45% weight/weight of an amphiphilic component comprising a compound selected from the group consisting of: a C 6 -C 24 linear or branched saturated or unsaturated chain phospholipid, a lysolipid, and a sphingolipid; and
4-10% weight/weight of the amphiphilic paramagnetic complex of Formula I or a salt thereof.

6. The pSLN according to claim 1 , characterized by a relaxivity value r 1p at 0.47 T higher than 25 mM −1 s −1 , measured in physiologic conditions.

7. The pSLN according to claim 1 , having a particle distribution from 10 to 220 nm, an average hydrodynamic diameter below 100 nm and a polydispersity index (PdI) below 0.2.

8. The pSLN according to claim 7 , wherein said average diameter is from 50-70 nm and the PdI is comprised from 0.12-0.18.

9. The pSLN according to claim 4 , wherein the amphiphilic component comprises an amphiphilic compound which comprises a C 6 -C 24 linear or branched, saturated or unsaturated chain phospholipid selected from the group consisting of: phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidyl-inositol and mixtures thereof, optionally further comprising: a bile acid or a salt thereof, a glycolipid, a fatty acid, an aliphatic alcohol, a dialkyl ether or tocopherol.

10. The pSLN according to claim 9 , wherein said phospholipid is of natural origin and is derived from soy or egg lecithin.

11. The pSLN according to claim 10 , further comprising at least one component selected from the group consisting of: a) at least one of an ionic or a non-ionic surfactant; b) a “stealth” agent optionally chemically modified with a suitable specific ligand and/or an alkyl chain or an amphiphilic component; and c) an endogenous biomolecule optionally chemically modified, wherein said specific ligand or said endogenous biomolecule is selected from the group consisting of: vitamins, peptides and polypeptides.

12. The pSLN according to claim 1 , wherein the amphiphilic paramagnetic complex is selected from the group consisting of the following compounds or salts thereof:

13. The pSLN according to claim 11 , wherein the “stealth agent” is polyethyleneglycol (PEG) optionally chemically modified with a phospholipid, a folate or a phospholipid and a folate.

14. A process for the preparation of the paramagnetic Solid Lipid Nanoparticle (pSLN) of claim 1 , comprising the following steps:
a) preparing an organic phase (O) by admixing, in a low boiling solvent immiscible in water at least the following components:
an amphiphilic complex suitable for chelating metal ions selected from a diazepine derivative of Formula I and salts thereof:

wherein:
Y is a group of formula Y′—NH— or (Y′) 2 —N—, where Y′ is selected in from the group consisting of:
a linear or branched saturated or unsaturated C 8 -C 16 alkyl group; and a C 1 -C 10 alkyl group interrupted by a phosphate group —O—(HO—P═O)—O— optionally substituted by one or more groups selected from: hydroxy —OH, carboxy —COOR 1 , oxycarbonyl —(C 8 -C 16 )alkyl and oxycarbonyl —(C 8 -C 16 )alkenyl, where R, is hydrogen H or a C 1 -C 4 linear or branched alkyl group; and
a monophosphate ester of a substituted or partially substituted glycerol, having at least one functional group of said glycerol esterified with an aliphatic fatty acid with saturated or unsaturated carbon chains, and the phosphoric acid function is either free or salified with a alkali or earth alkali metal;

L is a bivalent linker selected from: an aliphatic C 3 -C 10 cyclic or heterocyclic group and a C 1 -C 6 alkyl, C 2 -C 6 alkenyl or alkynyl, linear or branched group optionally substituted or interrupted with an atom or group selected from the group consisting of: carbonyl —C═O, thiocarbonyl —C═S, amino —NR 1 —, carboxy —COO—, oxy-carbonyl —OCO—, amido —NR 1 CO— or —CONR 1 —, oxygen —O— and sulphur —S—, wherein R 1 is as defined above;
R I-IV and R I-III are each, independently a —(C 1 -C 3 )alkylcarboxy group,

Assignees

• Bracco Imaging Spa

Inventors

• Brioschi Chiara
• Cabella Claudia
• Ghiani Simona
• Maiocchi Alessandro
• Miragoli Luigi
• Visigalli Massimo

Classifications

• A61K49/1881

  wherein the coating consists of chelates, i.e. chelating group complexing a (super)(para)magnetic ion, bound to the surface · CPC title

• A61K49/085

  conjugated systems · CPC title

• A61K49/101

  the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals · CPC title

• A61K49/106 Primary

  the complex-forming compound being cyclic, e.g. DOTA · CPC title