Crosslinked polysaccharide microparticles and method for their preparation

A method for preparing crosslinked polysaccharide microparticles having an average particle diameter of 0.01 μm to 150 μm, which method comprises the following steps:

• a) preparing a dilute solution containing (1) a polysaccharide derivative having at least one crosslinkable functional group in a range of 0.1 to 5% (w/v) and (2) a crosslinking agent;
• b) dispersing the solution by spraying to form microparticulate droplets;
• and
• c) concentrating the solution contained in the droplets to facilitate a crosslinking addition reaction of the polysaccharide derivative between a mercapto group and an unsaturated C—C bond, thereby providing microparticles having an average particle diameter of 0.01 μm to 150 μm;
• wherein steps b) and c) are carried out in a spray drying procedure;
• wherein the polysaccharide derivative is a hyaluronic acid derivative comprising at least one repeating unit represented by Formula (I);
• wherein X2 represents —Y1-Q1-Y2—N(—R2)—Y3-Q2-SH, —NHCO—(CH2)4—CONH—NH—C(═NH)—(CH2)3—SH, —(CH2)2—NH—C(═NH)—(CH2)3—SH, or —(CH2)2—O—(CH2)2—O—(CH2)2—NH—C(═NH)—(CH2)3—SH,
• R1 represents a hydrogen atom, a linear or branched C1-10 alkyl group, a linear or branched C1-10 hydroxyalkyl group, a polyalkylene oxide group, a polypeptide group or a polyester group,
• Ra2, Ra3, Ra4, Ra5 and Ra6 each independently represent a hydrogen atom, a linear or branched C1-6 alkyl group, a linear or branched C2-6 alkenyl group, a linear or branched C2-6 alkynyl group, a linear or branched C1-16 alkylcarbonyl group, a linear or branched C2-6 alkenylcarbonyl group, a linear or branched C2-6 alkynylcarbonyl group or —SO2OH,
• Y1 represents a single bond, —N(—R3)CO—, —N(—R3)—, —CO— or —CH2CO—,
• Y2 represents a single bond, —CON(—R4)— or —N(—R4)—,
• Q1 represents a linear or branched C1-10 alkylene group, a linear or branched C1-10 hydroxyalkylene group, a polyalkylene oxide group, a polypeptide group or a polyester group,
• R2, R3 and R4 each independently represent a hydrogen atom, a linear or branched C1-10 alkyl group, a linear or branched C1-10 hydroxyalkyl group, a polyalkylene oxide group, a polypeptide group or a polyester group,
• Y3 represents a single bond, —CO—, —CO2—, —CH2—CH(OH)— or —CONH—, and
• Q2 represents a linear or branched C1-10 alkylene group, a linear or branched C1-10 hydroxyalkylene group, a polyalkylene oxide group, a polypeptide group or a polyester group,
• and the crosslinking agent is a compound having two or more unsaturated C—C bond-containing groups;
• or
• the polysaccharide derivative is a hyaluronic acid derivative comprising at least one repeating unit represented by Formula (II):
• wherein X3 represents —Y1-Q1-Y2—N(—R2)—Y3-Q4 or —N(—R2)—Y3-Q4,
• R1 represents a hydrogen atom, a linear or branched C1-10 alkyl group, a linear or branched C1-10 hydroxyalkyl group, a polyalkylene oxide group, a polypeptide group or a polyester group,
• Ra2, Ra3, Ra4, Ra5 and Ra6 each independently represent a hydrogen atom, a linear or branched C1-6 alkyl group, a linear or branched C2-6 alkenyl group, a linear or branched C2-6 alkynyl group, a linear or branched C1-6 alkyl carbonyl group, a linear or branched C2-6 alkenylcarbonyl group, a linear or branched C2-6 alkynylcarbonyl group or —SO2OH,
• Y1 represents a single bond, —N(—R3)CO—, —N(—R3)—, —CO— or —CH2CO—,
• Y2 represents a single bond, —CON(—R4)— or —N(—R4)—,
• Y3 represents a single bond, —CO— or —CH2CO—,
• Q1 represents a linear or branched C1-10 alkylene group, a linear or branched C1-10 hydroxyalkylene group, a polyalkylene oxide group, a polypeptide group or a polyester group,
• R2, R3 and R4 each independently represent a hydrogen atom, a linear or branched C1-10 alkyl group, a linear or branched C1-10 hydroxyalkyl group, a polyalkylene oxide group, a polypeptide group or a polyester group,
• Q4 represents a linear or branched C2-10 alkenyl group, or a linear or branched C2-10 alkynyl group, and the crosslinking agent is a compound having two or more mercapto groups;
• and
• wherein the method is performed so as to crosslink the hyaruronic acid derivative during concentration and drying.