Nanoparticles for controlled release of Sorafenib and Sorafenib derivatives

1. Nanoparticles loaded with Sorafenib (Sorafenib PBB) or Sorafenib derivatives or pharmaceutically acceptable salts thereof (Sorafenib PBB derivatives), wherein said nanoparticles are polymeric PBB nanoparticles, (PHEA-BIB-pButMA, α,β-poly(N-2-hydroxyethyl)-co-{N-2-ethylene-[2-(poly(butylmethacrylate)-isobutyrate]}-D,L-aspartamide).

2. The nanoparticles according to claim 1 , having a diameter of less than 500 nm.

3. The nanoparticles according claim 1 , having a Drug loading % (DL %) between 0.5 and 30%.

4. The nanoparticles according to claim 1 , wherein said Sorafenib derivatives are selected from the group consisting of:

Regorafenib, of formula (1)

SC-60 of formula (2)

HLC-80, of formula (3)

compounds of formula (4), where R1, R2, and R3 are as indicated in the following table:

Cpd

R 1

R 2

R 3

SC-1

1

H

H

2

H

H

3

H

H

4

H

H

5

H

H

6

H

H

7

H

H

8

H

H

9

H

H

10

H

H

11

H

H

12

H

Me

compounds of formula (5), where R1 and R2 are as indicated in the following table

Cpd

R 1

R 2

13

H

14

H

15

H

16

H

17

H

compounds of formula (6) where R1, R2 and R3 are as indicated in the following table

Cpd

R 1

R 2

R 3

18

NO 2

NH 2

19

NO 2

NH 2

20

NO 2

NH 2

21

NH 2

NH 2

22

NH 2

NH 2

23

24

compounds of formula (7) where R1 and R2 are as indicated in the following table

Compound

R 2

R 1

Sorafenib

—

—

 8a

4-Chloro-3-trifluoromethylphenyl

Phenyl

 8b

4-Chloro-3-trifluoromethylphenyl

2-Furyl

 8c

4-Chloro-3-trifluoromethylphenyl

3-Furyl

 8d

4-Chloro-3-trifluoromethylphenyl

2-Thienyl

 8e

4-Chloro-3-trifluoromethylphenyl

Pyridine-3-yl

 8f

4-Chloro-3-trifluoromethylphenyl

4-Hydroxyphenyl

 8 g

4-Chloro-3-trifluoromethylphenyl

4-Methoxylphenyl

 8 h

4-Chloro-3-trifluoromethylphenyl

4-Chlorophenyl

 8i

4-Chloro-3-trifluoromethylphenyl

4-Trifluoromethylphenyl

 8j

4-Chloro-3-trifluoromethylphenyl

4-Carbomethoxyphenyl

 8k

4-Chloro-3-trifluoromethylphenyl

3-Hydroxyphenyl

 8l

4-Chloro-3-trifluoromethylphenyl

3-Chlorophenyl

 8m

4-Chloro-3-trifluoromethylphenyl

3-Trifluoromethylphenyl

 8n

4-Chloro-3-trifluoromethylphenyl

4-Hydroxyl-3-methoxylphenyl

 8o

4-Chloro-3-trifluoromethylphenyl

3,4-Bimethoxylphenyl

 8p

4-Chloro-3-trifluoromethylphenyl

4-Acetoxy-3-methoxylphenyl

 8q

4-Chloro-3-trifluoromethylphenyl

3,4-Bifluorophenyl

 8r

4-Chloro-3-trifluoromethylphenyl

2,4-Bichlorophenyl

 8 s

4-Chloro-3-trifluoromethylphenyl

2,3,4,5,6-Pentafluorophenyl

11a

4-Chlorophenyl

4-Chlorophenyl

11b

4-Flurophenyl

4-Chlorophenyl

11c

4-Trifluoromethylphenyl

4-Chlorophenyl

11d

4-Ethoxylphenyl

4-Chlorophenyl

11e

3-Methylphenyl

4-Chlorophenyl

11f

3-Bromophenyl

4-Chlorophenyl

11g

3-Chloro-4-methylphenyl

4-Chlorophenyl

11h

2,4-Biflourophenyl

4-Chlorophenyl

compounds 12 and 13 of formula (8) and compounds 14a-k and 15a-k of formula (9) and (10), where R is as indicated in the following table

Comp. no.

R

12

—

13

—

14a

H

14b

4-F

14c

2,4-di F

14d

4-Cl

14e

4-OCH 3

14f

4-CH 3

14g

3-CH 3

14h

3-F

14i

4-CF 3

14j

4-CH 2 CH 3

14k

2,4-di CH 3

15a

H

15b

4-F

15c

2,4-di F

15d

4-Cl

15e

4-OCH 3

15f

4-CH 3

15g

3-CH 3

15h

3-F

15i

4-CF 3

15j

4-CH 2 CH 3

15k

2,4-di CH 3

compounds 2a-e, 3a-e, 4a-e of formula (11), (12) and (13), where R is as indicated in the following table

Compd.

R

2a

2b

2c

2d

2e

3a

3b

3c

3d

3e

4a

4b

4c

4d

4e

compounds of formula (14) where R is as indicated in the following table

Compd.

Substituent (R)

5a

C 6 H 4

5b

4-ClC 6 H 4

5c

3-ClC 6 H 4

5d

2-ClC 6 H 4

5e

3-CF 3 C 6 H 4

5f

4-CF 3 C 6 H 4

5g

3-FC 6 H 4

5h

4-FC 6 H 4

5i

3-F-5-FC 6 H 3

5j

3-F-4-BrC 6 H 3

5k

2-F-3-FC 6 H 3

5l

3-Cl-4-OHC 6 H 3

5m

2-OMeC 6 H 4

5n

3-OMe-4-OMeC 6 H 3

5o

4-OEtC 6 H 4

5p

2-Naphthyl

5q

4-C 6 H 5 —C 6 H 4

5r

4-MeC 6 H 4 .

5. A method for preparing Sorafenib PBB or Sorafenib PBB derivatives, wherein the method comprises:

a) providing a copolymer α,β-poly(N-2-hydroxyethyl)-co-{N-2-ethylene-[2-(poly(butylmethacrylate)-isobutyrate]}-D,L-aspartamide (PBB) and Sorafenib or salts and derivatives thereof;

b) dissolving in a solvent;

c) dialyzing against aqueous phase using a dialysis membrane with a molecular weight (MW) cut-off greater than a MW of the copolymer to obtain a colloidal dispersion; and

d) Filtering the colloidal dispersion obtained in c) to obtain Sorafenib PBB or Sorafenib PBB derivatives.

6. The method according to claim 5 , wherein said Sorafenib is Sorafenib tosylate.

7. The method according to claim 5 , wherein said Sorafenib derivatives are selected from the group comprising:

Regorafenib, of formula (1)

SC-60 of formula (2)

HLC-80, of formula (3)

compounds of formula (4), where R1, R2 and R3 are as indicated in the following table:

Cpd

R 1

R 2

R 3

SC-1

1

H

H

2

H

H

3

H

H

4

H

H

5

H

H

6

H

H

7

H

H

8

H

H

9

H

H

10

H

H

11

H

H

12

H

Me

compounds of formula (5), where R1 and R2 are as indicated in the following table

Cpd

R 1

R 2

13

H

14

H

15

H

16

H

17

H

compounds of formula (6) where R1, R2 and R3 are as indicated in the following table

Cpd

R 1

R 2

R 3

18

NO 2

NH 2

19

NO 2

NH 2

20

NO 2

NH 2

21

NH 2

NH 2

22

NH 2

NH 2

23

24

compounds of formula (7) where R1 and R2 are as indicated in the following table

Compound

R 2

R 1

Sorafenib

—

—

 8a

4-Chloro-3-trifluoromethylphenyl

Phenyl

 8b

4-Chloro-3-trifluoromethylphenyl

2-Furyl

 8c

4-Chloro-3-trifluoromethylphenyl

3-Furyl

 8d

4-Chloro-3-trifluoromethylphenyl

2-Thienyl

 8e

4-Chloro-3-trifluoromethylphenyl

Pyridine-3-yl

 8f

4-Chloro-3-trifluoromethylphenyl

4-Hydroxyphenyl

 8 g

4-Chloro-3-trifluoromethylphenyl

4-Methoxylphenyl

 8 h

4-Chloro-3-trifluoromethylphenyl

4-Chlorophenyl

 8i

4-Chloro-3-trifluoromethylphenyl

4-Trifluoromethylphenyl

 8j

4-Chloro-3-trifluoromethylphenyl

4-Carbomethoxyphenyl

 8k

4-Chloro-3-trifluoromethylphenyl

3-Hydroxyphenyl

 8l

4-Chloro-3-trifluoromethylphenyl

3-Chlorophenyl

 8m

4-Chloro-3-trifluoromethylphenyl

3-Trifluoromethylphenyl

 8n

4-Chloro-3-trifluoromethylphenyl

4-Hydroxyl-3-methoxylphenyl

 8o

4-Chloro-3-trifluoromethylphenyl

3,4-Bimethoxylphenyl

 8p

4-Chloro-3-trifluoromethylphenyl

4-Acetoxy-3-methoxylphenyl

 8q

4-Chloro-3-trifluoromethylphenyl

3,4-Bifluorophenyl

 8r

4-Chloro-3-trifluoromethylphenyl

2,4-Bichlorophenyl

 8 s

4-Chloro-3-trifluoromethylphenyl

2,3,4,5,6-Pentafluorophenyl

11a

4-Chlorophenyl

4-Chlorophenyl

11b

4-Flurophenyl

4-Chlorophenyl

11c

4-Trifluoromethylphenyl

4-Chlorophenyl

11d

4-Ethoxylphenyl

4-Chlorophenyl

11e

3-Methylphenyl

4-Chlorophenyl

11f

3-Bromophenyl

4-Chlorophenyl

11g

3-Chloro-4-methylphenyl

4-Chlorophenyl

11h

2,4-Biflourophenyl

4-Chlorophenyl

compounds 12 and 13 of formula (8) and compounds 14a-k and 15a-k of formula (9) and (10), where R is as indicated in the following table

Comp. no.

R

12

—

13

—

14a

H

14b

4-F

14c

2,4-di F

14d

4-Cl

14e

4-OCH 3

14f

4-CH 3

14g

3-CH 3

14h

3-F

14i

4-CF 3

14j

4-CH 2 CH 3

14k

2,4-di CH 3

15a

H

15b

4-F

15c

2,4-di F

15d

4-Cl

15e

4-OCH 3

15f

4-CH 3

15g

3-CH 3

15h

3-F

15i

4-CF 3

15j

4-CH 2 CH 3

15k

2,4-di CH 3

compounds 2a-e, 3a-e, 4a-e of formula (11), (12) and (13), where R is as indicated in the following table

Compd.

R

2a

2b

2c

2d

2e

3a

3b

3c

3d

3e

4a

4b

4c

4d

4e

compounds of formula (14) where R is as indicated in the following table

Compd.

Substituent (R)

5a

C 6 H 4

5b

4-ClC 6 H 4

5c

3-ClC 6 H 4

5d

2-ClC 6 H 4

5e

3-CF 3 C 6 H 4

5f

4-CF 3 C 6 H 4

5g

3-FC 6 H 4

5h

4-FC 6 H 4

5i

3-F-5-FC 6 H 3

5j

3-F-4-BrC 6 H 3

5k

2-F-3-FC 6 H 3

5l

3-Cl-4-OHC 6 H 3

5m

2-OMeC 6 H 4

5n

3-OMe-4-OMeC 6 H 3

5o

4-OEtC 6 H 4

5p

2-Naphthyl

5q

4-C 6 H 5 —C 6 H 4

5r

4-MeC 6 H 4 .

8. The method according to claim 5 , wherein said solvent is DMF (dimethylformamide) or DMSO (dimethyl sulfoxide) or THF (tetrahydrofuran), or mixtures thereof.

9. The method according to claim 5 , wherein after said step c), a cryoprotectant is added to said colloidal dispersion.

10. The method according to claim 5 , wherein the weight ratio of said PBB copolymer to said Sorafenib is between 10:1 and 1:1.

11. A controlled release formulation of Sorafenib or derivatives thereof comprising Sorafenib PBB or Sorafenib PBB derivatives or pharmaceutically acceptable salts.

12. The formulation according to claim 11 , further comprising an effective amount of one or more further therapeutic agents.

13. A method of treating tumor diseases of the kidney, liver, thyroid, colon, breast, pancreas, lungs, and/or of recurrent glioblastoma, the method comprising administering the formulation according to claim 11 to a patient or a subject affected by said tumor diseases.

14. The method according to claim 13 , wherein the tumor disease is hepatocellular carcinoma.

15. The nanoparticles according to claim 2 , having a diameter of less than 300 nm.

16. The nanoparticles according to claim 3 , having a DL % between about 3 and 20%.

17. The method according to claim 5 , wherein the 1 \ 4 W of the copolymer is greater than 80,000 Da.

18. The method according to claim 9 , wherein the cyroprotectant is selected from the group consisting of PVP (polyvinylpyrrolidone), PVA (polyvinyl alcohol), trehalose, mid/or lactose, and mixtures thereof.

19. The method according to claim 10 , wherein the weight ratio of said PBB copolymer to said Sorafenib is between 6:1 and 1.5:1.

20. The method according to claim 19 , wherein the weight ratio of said PBB copolymer to said Sorafenib is 2:1.