Hyaluronic acid derivative, pharmaceutical composition, and hyaluronic acid derivative-drug complex

A hyaluronic acid derivative having a steryl group introduced therein,

• wherein a ratio Mw/Mn of a weight-average molecular weight Mw to a number-average molecular weight Mn of the hyaluronic acid derivative is 1.2 or more and less than 3.0,
• wherein the Mw and the Mn are measured by size exclusion chromatography multi-angle light scattering detector, SEC-MALS, by dissolving the hyaluronic acid derivative in ultrapure water, and stirring to obtain an aqueous hyaluronic acid derivative solution of concentration 2 mg/mL;
• mixing 750 mL of a 300 mM hydroxypropyl-β-cyclodextrin (HP-β-CD) aqueous solution with 750 μL of the hyaluronic acid derivative aqueous solution to obtain a mixture;
• incubating the mixture at 37° C. for 1 hour;
• and obtaining a SEC-MALS measurement of the incubated mixture under the following conditions:
• column:
• two TSKgel GMPWXL columns
• column temperature:
• 30° C.
• eluent:
• 10 mM HP-β-CD-containing phosphate buffered saline (pH 7.4)
• flow rate:
• 1 mL/min
• injection volume:
• 200 μL
• to determine the Mw and the Mn, and
• wherein the hyaluronic acid derivative has a repeating unit represented by the following general formula (I),
• in the formula, R1, R2, R3 and R4 are each independently selected from the group consisting of a hydrogen atom, a C1-6 alkyl, a formyl and a C1-6 alkyl carbonyl;
• Z represents a single bond or a peptide linker having 2 or more and 30 or less amino acid residues;
• X1 is a group selected from the group consisting of groups represented by the following formulas:
• —NRb—R,
• —NRb—COO—R,
• —NRb—CO—R,
• -—NRb—CO—NRc—R,
• —COO—R,
• —O—COO—R,
• —S—R,
• —CO—Ya—S—R,
• —O—CO—Yb—S—R,
• —NRb—CO—Yb—S—R;
• Ra, Rb and Rc are each independently selected from the group consisting of a hydrogen atom, a C1-20 alkyl, an amino C2-20 alkyl and a hydroxy C2-20 alkyl, where an alkyl moiety of the groups may be inserted with a group selected from the group consisting of —O— and —NRf—;
• Rf is selected from the group consisting of a hydrogen atom, a C1-12 alkyl, an amino C2-12 alkyl and a hydroxy C2-12 alkyl, and an alkyl moiety of the groups may be inserted with a group selected from the group consisting of —O— and —NH—;
• R is a steryl group;
• Y is a C2-30 alkylene or —(CH2CH2O)m—CH2CH2—, where the alkylene may be inserted with a group selected from the group consisting of —O—, —NRg- and —S—S—;
• Rg is selected from the group consisting of a hydrogen atom, a C1-20 alkyl, an amino C2-20 alkyl and a hydroxy C2-20 alkyl, and an alkyl moiety of the groups may be inserted with a group selected from the group consisting of —O— and —NH—;
• Ya is a C1-5 alkylene;
• Yb is a C2-8 alkylene or a C2-8 alkenylene;
• m is an integer of 1 or more and 100 or less.