MODIFIED-RELEASE MICROPARTICLES BASED ON AMPHIPHILIC COPOLYMER AND ON ACTIVE PRINCIPLE(S) AND PHARMACEUTICAL FORMULATIONS COMPRISING THEM

1 . A liquid pharmaceutical formulation for the prolonged release of AP, comprising:

microparticles of polymer (PO), obtained by atomization of an aqueous solution or colloidal suspension of PO noncovalently associated with at least one active principle (AP), the PO being a (co)polyamino acid comprising a main chain formed by aspartic or glutamic units or a mixture thereof, part of said units carrying hydrophobic groups (HG), and

an aqueous liquid comprising polyvalent cations.

2 . The liquid pharmaceutical formulation of claim 1 , wherein the polyvalent cations are selected from the group consisting of Mg 2+ , Ca 2+ , Zn 2+ , Fe 2+ , Cu 2+ , Al 3+ , Fe 3+ and mixtures thereof.

3 . The liquid pharmaceutical formulation of claim 1 , wherein the polyvalent cations are Mg 2+ .

4 . The liquid pharmaceutical formulation of claim 1 , wherein said microparticles have a size comprised between 0.5 and 100 microns.

5 . The liquid pharmaceutical formulation of claim 1 , wherein said microparticles have a size comprised between 1 and 70 microns.

6 . The liquid pharmaceutical formulation of claim 1 , further comprising a at least one means for dispersing the PO microparticles, selected from:

a hydrophilic compound present in the suspension or colloidal solution of PO prior to atomization, and

a film of hydrophilic compound coated onto the PO microparticles.

7 . The liquid pharmaceutical formulation of claim 6 , wherein the hydrophilic compound is chosen from the group comprising:

amino acids;

polyalkylene glycols;

copolyalkylene glycols;

cellulose polymers;

hydrogenated or nonhydrogenated saccharides;

polyols;

gelatins;

nitrogenous (co)polymers;

poly(vinyl alcohol)s (PVAs);

poly(sodium glutamate);

and their mixtures.

8 . The liquid pharmaceutical formulation of claim 6 , wherein the hydrophilic compound is polyvinylpyrrolidone.

9 . The liquid pharmaceutical formulation of claim 1 , wherein PO is defined by the following general formula (I), the radical —COOR 3 including forms wherein the bond between the carboxylic and R 3 is a ionic bond —COO −+ R 3 :

in which:

R 1 represents an H, a linear C 2 to C 10 or branched C 3 to C 10 alkyl, a benzyl, or —R 4 -[HG];

NHR 1 is a terminal amino acid residue

R 2 represents an H, a linear C 2 to C 10 or branched C 3 to C 10 acyl group, or —R 4 -[HG] or a terminal pyroglutamate residue;

R 3 is an H, or

+ R 3 is selected from the group comprising:

metal cations,

organic cations,

or cationic polyamino acids;

R 4 represents a direct bond or a spacer based on 1 to 4 amino acid residues;

A independently represents a —CH 2 — radical or a —CH 2 —CH 2 — radical;

n/(n+m) is defined as the molar grafting rate and its value is sufficiently low for PO, dissolved in water at pH=7 and at 25° C., to form a colloidal suspension of submicron-sized particles of PO;

n/(n+m) is comprised between 1 and 25 mol %;

n+m is defined as the degree of polymerization and varies from 10 to 1000;

HG represents a hydrophobic group selected from the group consisting of: —OCH 2 (CH 2 —CH 2 ) 3-8 —CH 3 , oleyl, tocopheryl and cholesteryl.

10 . The liquid pharmaceutical formulation of claim 9 , wherein the molar grafting rate n/(n+m) is comprised between 10 and 25 mol %.

11 . The liquid pharmaceutical formulation of claim 1 , wherein the PO corresponds to one of the following general formulae (II), (III) and (IV), the radical —COOR 3′ including forms wherein the bond between the carboxylic and R 3′ is a ionic bond —COO −+ R 3′ :

in which:

HG represents a hydrophobic group selected from the group consisting of:

—OCH 2 (CH 2 —CH 2 ) 3-8 —CH 3 , oleyl, tocopheryl and cholesteryl;

R 30 is a linear bivalent C 2 to C 6 alkylene chain;

R 3′ is an H or,

+ R 3′ is selected from the group comprising:

metal cations,

organic cations,

or cationic polyamino acids;

R 50 is a divalent linear C 1 to C 8 alkylene chain in which one or two methylene units can be independently replaced by —O— or —NH—;

R 4 represents a direct bond or a spacer based on 1 to 4 amino acid residues;

A independently represents a —CH 2 — radical or a —CH 2 —CH 2 — radical;

n′+m′ or n″ is defined as the degree of polymerization and varies from 10 to 1000.

12 . The liquid pharmaceutical formulation of claim 1 , wherein the PO comprises at least one neutral copolyhydroxyalkylglutamine comprising a multiplicity of pendant hydrophobic groups (HGs) which are identical to or different from one another.

13 . The liquid pharmaceutical formulation of claim 1 , wherein the main chain of the (co)polyamino acid is selected from the group consisting of:

an α-L-glutamate or α-L-glutamic homopolymer,

an α-L-aspartate or α-L-aspartic homopolymer and

an α-L-aspartate/α-L-glutamate or α-L-aspartic/α-L-glutamic copolymer.

14 . A process for the preparation of a liquid pharmaceutical formulation as claimed in claim 1 , comprising the following steps:

mixing a solution of polymer (PO) with at least one AP, at pH=7.0, under isotonic conditions, the PO being a (co)polyamino acid comprising a main chain formed by aspartic or glutamic units or a mixture thereof, part of said units carrying hydrophobic groups (HG), in order to form an aqueous solution or colloidal suspension;

atomizing said colloidal suspension of PO to obtain dry solid microparticles, and

dispersing the obtained microparticles in an aqueous liquid comprising polyvalent cations.

15 . The process of claim 14 , comprising one additional step comprising:

adding at least a hydrophilic compound in the PO suspension or colloidal solution of PO prior to atomization.

16 . The process of claim 14 , comprising one additional step comprising:

coating the PO microparticles with at least a film of hydrophilic compound.

17 . A process for the preparation of a solid pharmaceutical formulation, comprising the implementation of the process according to claim 14 and a further step comprising:

lyophilizing the dispersion to obtain a dry powder of microparticles.

18 . A process for the preparation of a solid pharmaceutical formulation, comprising the implementation of the process according to claim 15 and a further step comprising:

lyophilizing the dispersion to obtain a dry powder of microparticles.

19 . A process for the preparation of a solid pharmaceutical formulation, comprising the implementation of the process according to any of claim 16 and a further step comprising:

lyophilizing the dispersion to obtain a dry powder of microparticles.

20 . A process for the preparation of a liquid pharmaceutical formulation, comprising a further step comprising:

dispersing the lyophilizate obtained by the process of claim 17 in an aqueous liquid.

21 . A process for the preparation of a liquid pharmaceutical formulation, comprising a further step comprising:

dispersing the lyophilizate obtained by the process of claim 18 in an aqueous liquid.

22 . A process for the preparation of a liquid pharmaceutical formulation, comprising a further step comprising:

dispersing the lyophilizate obtained by the process of claim 19 in an aqueous liquid.

23 . A solid pharmaceutical formulation for the release of AP, comprising a dry powder form obtained by the process of claim 17 .

24 . A solid pharmaceutical formulation for the release of AP, comprising a dry powder form obtained by the process of claim 18 .

25 . A solid pharmaceutical formulation for the release of AP, comprising a dry powder form obtained by the process of claim 19 .