Hyaluronic acid derivative having amino acid and steryl group introduced thereinto

1. A hyaluronic acid derivative, comprising a repeating unit represented by formula (I):

where R 1 , R 2 , R 3 , and R 4 are independently selected from a hydrogen atom, C 1-6 alkyl, formyl, and C 1-6 alkylcarbonyl;

R 5 is a hydrogen atom, formyl, or C 1-6 alkylcarbonyl;

X 1 is hydroxy, —O-Q + , C 1-6 alkoxy, —NR 7 R 8 , or —NR 9 —Z 1 —Z 2 ;

Q + represents a counter cation;

R 6 , R 7 , R 8 , and R 9 are independently selected from a hydrogen atom and C 1-6 alkyl;

R a is a hydrogen atom, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, carboxymethyl, 2-methylpropyl, isopropyl, 2-methylthioethyl, or phenylmethyl;

Z 1 is C 2-30 alkylene or —(CH 2 CH 2 O) m —CH 2 CH 2 —, where into the alkylene 1 to 5 groups independently selected from —O—, —NR g —, and —S—S— may be inserted, and m is an integer selected from 1 to 100;

Z 2 is selected from groups represented by the following formulas:

—NR b —Z 3 ,

—NR b —COO—Z 3 ,

—NR b —CO—Z 3 ,

—NR b —CO—NR c —Z 3 ,

—COO—Z 3 ,

—CO—NR c —Z 3 ,

—O—CO—NR c —Z 3 ,

—O—COO—Z 3 ,

—S—Z 3 ,

—CO—Z a —S—Z 3 ,

—O—CO—Z b —S—Z 3 ,

—NR b —CO—Z b —S—Z 3 , and

—S—S—Z 3 ;

R b and R c are independently selected from a hydrogen atom, C 1-20 alkyl, amino C 2-20 alkyl, and hydroxy C 2-20 alkyl, where into the alkyl moieties of the groups 1 to 3 groups independently selected from —O— and —NR f — may be inserted;

R f is independently selected from a hydrogen atom, C 1-12 alkyl, amino C 2-12 alkyl, and hydroxy C 2-12 alkyl, and into the alkyl moieties of the groups 1 to 2 groups independently selected from —O— and —NH— may be inserted;

R g is independently selected from a hydrogen atom, C 1-20 alkyl, amino C 2-20 alkyl, or hydroxy C 2-20 alkyl, and into the alkyl moieties of the groups 1 to 3 groups independently selected from —O— and —NH— may be inserted;

Z 3 is a steryl group;

Z a is C 1-5 alkylene; and

Z b is C 2-8 alkylene or C 2-8 alkenylene,

wherein if the hyaluronic acid derivative comprises no repeating units represented by formula (I) in which X 1 is —NR 9 —Z 1 —Z 2 , then the hyaluronic acid derivative further comprises a repeating unit represented by formula (II):

where R 1a , R 2a , R 3a , and R 4a are independently selected from a hydrogen atom, C 1-6 alkyl, formyl, and C 1-6 alkylcarbonyl;

R 5a is a hydrogen atom, formyl, or C 1-6 alkylcarbonyl; and

X 2 is —NR 9 —Z 1 —Z 2 , where R 9 , Z 1 , and Z 2 are as defined above.

2. The hyaluronic acid derivative according to claim 1 , further comprising a repeating unit represented by formula (IIb):

where R 1b , R 2b , R 3b , and R 4b are each independently selected from a hydrogen atom, C 1-6 alkyl, formyl, and C 1-6 alkylcarbonyl;

R 5b is selected from a hydrogen atom, formyl, and C 1-6 alkylcarbonyl; and

X b is selected from hydroxy and —O-Q + , where Q + represents a counter cation.

3. The hyaluronic acid derivative according to claim 1 , wherein a percentage of the disaccharide unit comprising the group —NR 9 —Z 1 —Z 2 in existing disaccharide repeating units is 3 to 50%.

4. The hyaluronic acid derivative according to claim 1 , wherein the hyaluronic acid derivative is produced by using hyaluronic acid exclusively consisting of the disaccharide unit represented by formula (IIb)

where R 1b , R 2b , R 3b and R 4b are all hydrogen atoms, R 5b is acetyl, and X b is —O—Na + and

has a weight-average molecular weight of 3 kilo Daltons to 1,500 kilo Daltons.

5. The hyaluronic acid derivative according to claim 1 , wherein Z 1 is C 2-10 alkylene, Z 2 is —NH—COO—Z 3 , and Z 3 is a cholesteryl group.

6. The hyaluronic acid derivative according to claim 2 , wherein the hyaluronic acid derivative is obtained by reacting a hyaluronic acid derivative comprising a repeating unit represented by formula (IIb) and a repeating unit represented by formula (Ia),

where X a is selected from hydroxy, —O-Q + , C 1-6 alkoxy, and —NR 7 R 8 and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Q + , and R a are as defined in claim 1 , with a compound represented by formula below,

HNR 9 —Z 1 —Z 2 .

7. A pharmaceutical composition comprising the hyaluronic acid derivative according to claim 1 and a drug.

8. The pharmaceutical composition according to claim 7 , wherein the drug is held by forming a complex with the hyaluronic acid derivative.

9. The hyaluronic acid derivative according to claim 1 , wherein X 1 is —NR 9 —Z 1 —Z 2 in formula (I).

10. The hyaluronic acid derivative according to claim 1 , wherein a percentage of the disaccharide unit represented by formula (I) in existing disaccharide repeating units is 70 to 100%.

11. The hyaluronic acid derivative according to claim 1 , comprising no repeating units represented by formula (I) in which X 1 is —NR 9 —Z 1 —Z 2 .

12. The hyaluronic acid derivative according to claim 1 , wherein a sum of percentages of the repeating unit represented by formula (I) and the repeating unit represented by formula (II) in existing disaccharide repeating units is 70 to 100%.