PHARMACEUTICAL COMPOSITION CONTAINING BLOCK COPOLYMER COMPRISING BORIC ACID COMPOUND

• US 20140017192A1
• Filed: 04/02/2012
• Published: 01/16/2014
• Est. Priority Date: 03/31/2011
• Status: Active Grant

• Current Assignee: NanoCarrier Co., Ltd.
• Original Assignee: NanoCarrier Co., Ltd.
• Inventors: Kato, Yasuki, Saito, Hiroyuki, Kobayashi, Katsutoshi, Tanaka, Ryosuke, Harada, Mitsunori
• Granted Patent: US 9,561,284 B2
• Time in Patent Office: Days
• US Class Current: 424/78.17
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

A pharmaceutical composition includes a block copolymer having a hydrophilic segment, a hydrophobic segment, and a boronic acid compound bound to a side chain of the hydrophobic segment via a linker moiety that includes a heterocyclic structure. The heterocyclic structure contains a cyclic skeleton that includes a boron atom of the boronic acid compound, one or two atom(s) X bound to the boron atom and selected from an oxygen atom and a nitrogen atom, and one or two carbon atom(s) (respectively) bound to the atom(s) X. The block copolymer further includes at least one organic group bound to the carbon atom(s). The organic group(s) contain(s) an aromatic group or cyclic alkyl group that sterically protects a boronic acid ester bond and/or a boron amide bond resulting from bonding between the boron atom and the atom(s) X.

Claims

1. A pharmaceutical composition comprising a block copolymer having:

a hydrophilic segment;

a hydrophobic segment; and

a boronic acid compound bound to a side chain of the hydrophobic segment via a linker moiety that includes a heterocyclic structure, wherein;

a cyclic skeleton of the heterocyclic structure contains a boron atom of the boronic acid compound, (an) atom(s) X bound to the boron atom and selected from an oxygen atom and a nitrogen atom, and (a) carbon atom(s) bound to the atom(s) X; and

the block copolymer further comprises (an) organic group(s) bound to the carbon atom(s), the organic group(s) containing an aromatic group or cyclic alkyl group as a structure that protects a boronic acid ester bond and/or a boron amide bond resulting from bonding between the boron atom and the atom(s) X.

2. The pharmaceutical composition according to claim 1, wherein the cyclic skeleton has two atoms X¹ and X² bound to the boron atom as the atoms X.

3. The pharmaceutical composition according to claim 1, wherein the heterocyclic structure has the following chemical structure (I) or (II):

4. The pharmaceutical composition according to claim 3, wherein the heterocyclic structure comprises at least one selected from the group consisting of the following chemical structures (III) to (V):

5. The pharmaceutical composition according to claim 4, wherein an aromatic ring of the aromatic group or a cycloalkyl ring of the cyclic alkyl group is bound directly or via 1 or 2 atoms to the carbon atom(s) contained in the cyclic skeleton.

6. The pharmaceutical composition according to claim 5, wherein the boronic acid compound comprises bortezomib.

7. The pharmaceutical composition according to claim 6, wherein the hydrophilic segment is comprised of a polyethylene glycol chain and the hydrophobic segment is comprised of a polyamino acid chain.

8. The pharmaceutical composition according to claim 1, wherein the heterocyclic structure has the following chemical structure (I) or (II):

9. The pharmaceutical composition according to claim 8, wherein the heterocyclic structure comprises at least one selected from the group consisting of the following chemical structures (III) to (V):

10. The pharmaceutical composition according to claim 1, wherein an aromatic ring of the aromatic group or a cycloalkyl ring of the cyclic alkyl group is bound directly or via 1 or 2 atoms to the carbon atom(s) contained in the cyclic skeleton.

11. The pharmaceutical composition according to claim 1, wherein the boronic acid compound comprises bortezomib.

12. The pharmaceutical composition according to claim 1, wherein the hydrophilic segment is comprised of a polyethylene glycol chain and the hydrophobic segment is comprised of a polyamino acid chain.

13. A pharmaceutical composition comprising a block copolymer having:

a hydrophilic segment,

a hydrophobic segment, and

at least one boronic acid compound bound to a side chain of the hydrophobic segment via a linker moiety that includes a heterocyclic structure, wherein the heterocyclic structure has a cyclic skeleton comprising;

a boron atom of the boronic acid compound,

first and second atoms X bound to the boron atom and each independently selected from an oxygen atom and a nitrogen atom, and

first and second carbon atoms respectively bound to the first and second atoms X; and

at least one organic group bound to at least one of the first and second carbon atoms, the at least one organic group containing an aromatic group or cyclic alkyl group that sterically protects a boronic acid ester bond and/or a boron amide bond resulting from bonding between the boron atom and the first and second atoms X.

14. The pharmaceutical composition according to claim 13, wherein the aromatic group is selected from the group consisting of a phenyl group, a benzyl group, a naphthyl group, an anthracenyl group, a biphenyl group, and a triphenyl group and the cyclic alkyl group is selected from the group consisting of a cycloalkyl group having 3 to 10 carbon atoms.

15. The pharmaceutical composition according to claim 14, wherein:

two of said organic groups are respectively bound to the first and second carbon atoms.

16. The pharmaceutical composition according to claim 14, wherein the hydrophilic segment is comprised of a polyethylene glycol chain having 40-500 units and the hydrophobic segment is comprised of a polyamino acid chain having 20-80 units.

17. The pharmaceutical composition according to claim 16, wherein the boronic acid compound has the following formula (3):

18. The pharmaceutical composition according to claim 17, wherein a plurality of said block copolymers are associated in the form of a micelle.

19. A method of treating a patient in need thereof, comprising:

intraveneously administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 18.

20. A method of treating a patient in need thereof, comprising:

intraveneously administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 13.