Microfluidic preparation of dual-phase nanodroplets with fluorinated compounds

Patent metadata

Field	Value
Publication number	US-2025295818-A1
Application number	US-202318864464-A
Country	US
Kind code	A1
Filing date	May 11, 2023
Priority date	May 11, 2022
Publication date	Sep 25, 2025
Grant date	—

Abstract

The present invention relates to calibrated dual-phase nanodroplets comprising an outer layer and an inner core, said outer layer comprising a biocompatible fluorinated surfactant and said inner core comprising a fluorinated compound and a biocompatible oil. The invention further relates to a method of preparation of said calibrated dual-phase nanodroplets through microfluidic technique, and to their use for in vivo or in vitro diagnostic and/or for therapy.

First claim

1 . A nanodroplet comprising an outer layer and an inner core, said outer layer comprising a biocompatible fluorinated surfactant and said inner core comprising a fluorinated compound and a triglyceride having a logP value higher than 5, wherein said biocompatible fluorinated surfactant is selected from:
(A) an amphiphilic dendrimer of generation n comprising: a hydrophobic central core of valence 2 or 3; generation chains attached to the central core and branching around the core; and a hydrophilic terminal group at the end of each generation chain; wherein n is an integer from 0 to 12; the hydrophilic terminal group comprises: a mono-, oligo- or polysaccharide residue, a cyclodextrin residue, a peptide residue, a tris(hydroxymethyl)aminomethane (Tris), or a 2-amino-2-methylpropane-1,3-diol; the hydrophobic central core being a group of formula (Ia) or (Ib):

wherein:
W is R F or a group selected from W 0 , W 1 , W 2 or W 3 :

R F is a C 4 -C 10 perfluoroalkyl,
R H is a C 1 -C 24 alkyl group,
p is 0, 1, 2, 3 or 4;
q is 0, 1, 2, 3 or 4;
L is a linear or branched C 1 -C 12 alkylene group, optionally interrupted by one or more —O—, —S—,
Z is C(═O)NH or NHC(═O),
R is a C 1 -C 6 alkyl group, and
e is at each occurrence independently selected from 0, 1, 2, 3 or 4;
(B) an amphiphilic linear oligomer of formula II

wherein:
n is the number of repeating Tris units (n-DPn is the average degree of polymerization), wherein the term Tris indicates the tris(hydroxymethyl)aminomethane unit, and
i is the number of carbon atoms in the fluoroalkyl chain
or a mixture thereof.

2 . The nanodroplet according to claim 1 , wherein said fluorinated compound is a perfluorocarbon.

3 . The nanodroplet according to claim 1 , wherein said triglyceride has a logP value higher than 7 up to 25.

4 . The nanodroplet according to claim 1 , wherein said triglyceride is tricaprilin, trilaurin, triolein, trilinolein or a mixture thereof.

5 . An aqueous suspension comprising a plurality of nanodroplets according to claim 1 , wherein said nanodroplets have a z-average diameter comprised between 100 nm and 1000 nm and a polydispersity lower than 0.25.

6 . A method for the preparation of an aqueous suspension comprising a plurality of nanodroplets, said nanodroplets comprising an outer layer and an inner core, said outer layer comprising a biocompatible fluorinated surfactant as defined in claim 1 , and said inner core comprising a fluorinated compound and a biocompatible oil having a logP value higher than 5, said method comprising the steps of:
a) preparing an aqueous phase; b) preparing an organic phase, wherein i) said aqueous phase comprises a biocompatible fluorinated surfactant as defined in claim 1 or a mixture thereof and the organic phase comprises a fluorinated compound and a biocompatible oil having a logP value higher than 5 or ii) said organic phase comprises a biocompatible fluorinated surfactant as defined in claim 1 or a mixture thereof, a fluorinated compound and a biocompatible oil having a logP value higher than 5; c) injecting said aqueous phase into a first inlet and said organic phase into a second inlet of a microfluidic cartridge, thereby mixing said aqueous phase and said organic phase in a mixing device of the microfluidic cartridge, wherein the operating pressure into said microfluidic cartridge is lower than 7000 kPa, to obtain said aqueous suspension; and d) collecting said aqueous suspension from the exit channel of the microfluidic cartridge.

7 . The method according to claim 6 , wherein said aqueous phase comprises said biocompatible fluorinated surfactant and said organic phase comprises a fluorinated compound and a biocompatible oil having a logP value higher than 5.

8 . The method according to claim 6 , wherein said fluorinated compound is a perfluorocarbon.

9 . The method according to claim 6 , wherein said biocompatible oil has a logP higher than higher than 7 up to 25.

10 . The method according to claim 6 , wherein said biocompatible oil is a triglyceride.

11 . The method according to claim 10 , wherein said triglyceride is selected from tricaprilin, trilaurin, triolein, trilinolein or a mixture thereof.

12 . The method according to claim 6 , wherein the ratio between the volume of said aqueous phase and the volume of said organic phase is comprised between 1:1 to 5:1.

13 . The method according to claim 6 , further comprising additional step e) wherein said collected aqueous suspension is diluted.

14 . The method according to claim 6 , wherein said aqueous suspension comprises a plurality of nanodroplets having a z-average diameter comprised between 100 nm and 1000 nm and a polydispersity lower than 0.25.

15 . A method of diagnostic and/or therapeutic treatment comprising administering the aqueous suspension according claim 5 to a patient.

16 . The nanodroplet according to claim 1 , wherein said triglyceride has a logP value higher than 9 up to 25.

17 . The method according to claim 6 , wherein said biocompatible oil has a logP higher than higher than 9 up to 25.

18 . The method according to claim 6 , further comprising additional step e) wherein said collected aqueous suspension is diluted with water.

Assignees

• Bracco Suisse Sa
• Avignon Univ

Inventors

• Melich Romain
• Bussat Philippe
• Cherkaoui Samir
• Contino-Pepin Christiane
• Desgranges Stéphane

Classifications

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• A61K2123/00

  Preparations for testing in vivo · CPC title

• A61K2121/00

  Preparations for use in therapy · CPC title

• A61K41/0028

  Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds · CPC title

• A61K9/5192

  Processes · CPC title