US-12624130-B2 - Hyaluronic acid derivative composition, pharmaceutical composition and hyaluronic acid derivative-drug conjugate composition

US12624130B2US 12624130 B2US12624130 B2US 12624130B2US-12624130-B2

Abstract

Provided are: a hyaluronic acid derivative composition that comprises (A) a hyaluronic acid derivative having a steryl group introduced therein; and (B) a polar group-containing compound having at least one functional group selected from the group consisting of hydroxy group, carboxy group, amino group, amide group, carbamate group, urea group and thiol group, wherein the steryl group has been introduced at a ratio of 0.1% or more and less than 35% relative to the hyaluronic acid derivative (A); a pharmaceutical composition that contains the hyaluronic acid derivative composition as a carrier; and a hyaluronic acid derivative-drug conjugate composition wherein, in the hyaluronic acid derivative composition, one or more drugs are conjugated to the hyaluronic acid derivative (A).

Inventors

Yoshiyuki Nakagawa
Kohei YABUUCHI
Keisuke Fukumoto
Toru Katsumata
Soyeun YANG

Assignees

ASAHI KASEI KABUSHIKI KAISHA

Dates

Publication Date: 20260512
Application Date: 20210205
Priority Date: 20200205

Claims (6)

1 . A hyaluronic acid derivative composition comprising: a hyaluronic acid derivative (A) in which a steryl group is introduced; and a polar group-containing compound (B) selected from the group consisting of ethanol, isopropanol, and ethylene glycol, wherein an introduction ratio of the steryl group is 0.1% to less than 35% relative to the hyaluronic acid derivative (A), wherein an amount of the polar group-containing compound (B) relative to a mass of the hyaluronic acid derivative (A) is 0.001 ppm by mass to less than 700 ppm by mass, wherein the hyaluronic acid derivative (A) has a molecular weight of in the range of 1,000 to less than 1,000,000, and wherein the hyaluronic acid derivative (A) comprises a repeating unit of general formula (I): wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl, formyl, and C 1-6 alkylcarbonyl; Z is a direct bond or a peptide linker consisting of 2 to 30 amino acid residues; X 1 is a group selected from group consisting of: —NR b —R, —NR b —COO—R, —NR b —CO—R, —NR b —CO—NR c —R, —COO—R, —O—COO—R, —S—R, —CO—Y a —S—R, —O—CO—Y b —S—R, —NR b —CO—Y b —S—R, and —S—S—R, wherein R a , R b and R c are each independently selected from the group consisting of a hydrogen atom, C 1-20 alkyl, amino C 2-20 alkyl, and hydroxy C 2-20 alkyl; wherein a group selected from the group consisting of —O— and —NR f — may be inserted in the alkyl moiety thereof; R f is selected from the group consisting of a hydrogen atom, C 1-12 alkyl, amino C 2-12 alkyl, and hydroxyl C 2-12 alkyl; wherein a group selected from the group consisting of —O— and —NH— may be inserted in the alkyl moiety thereof; R is a steryl group; Y is a C 2-30 alkylene or —(CH 2 CH 2 O) m —CH 2 CH 2 —; and a group selected from the group consisting of —O—, —NR g — and —S—S— may be inserted in the alkylene; R g is selected from the group consisting of a hydrogen atom, C 1-20 alkyl, amino C 2-20 alkyl, and hydroxy C 2-20 alkyl; wherein a group selected from the group consisting of —O— and —NH— may be inserted in the alkyl moiety thereof; Y a is a C 1-5 alkylene; Y b is a C 2-8 alkylene or a C 2-8 alkenylene; and m is an integer of 1 to 100.
2 . The hyaluronic acid derivative composition according to claim 1 , wherein R is a cholesteryl group.
3 . A pharmaceutical composition comprising: a drug; and a carrier, wherein the carrier is a hyaluronic acid derivative composition of claim 1 .
4 . The pharmaceutical composition according to claim 3 , wherein the drug forms a complex with the hyaluronic acid derivative (A).
5 . The pharmaceutical composition according to claim 3 , wherein the drug is a pharmacologically active protein, a peptide or a nucleic acid.
6 . A hyaluronic acid derivative-drug conjugate composition comprising: the hyaluronic acid derivative composition (A) of claim 1 ; and a drug; wherein the drug is conjugated to the hyaluronic acid derivative (A) in the hyaluronic acid derivative composition.

Description

TECHNICAL FIELD The present invention relates to a hyaluronic acid derivative composition, a pharmaceutical composition and hyaluronic acid derivative-drug conjugate composition. The present application claims priority based on Japanese Patent Application No. 2020-018312 filed in Japan on Feb. 5, 2020, the content of which is incorporated herein by reference. BACKGROUND ART In recent years, a bio-pharmaceutical product which is a pharmaceutical product containing protein, peptide or nucleic acid as an active ingredient thereof has been developed for practical use, and the number thereof is increasing every year. The bio-pharmaceutical product can satisfy unmet medical need which cannot be satisfied by conventional low-molecular medicines. However, there are problems in terms of difficulty in absorption from the digestive tract or the mucous membrane as well as low stability in the body and a short half-life in the blood. Thus, a bio-pharmaceutical product requires frequent administration by injection, thereby imposing excessive burdens on both patients and concerned practitioners. Therefore, there is a demand for a drug matrix (sustained-release drug delivery system matrix) which can encapsulate a bio-pharmaceutical product without impairing pharmacological activity and can release an active ingredient gradually in the living body. From such a background, a sustained-release drug delivery system matrix composed of a hyaluronic acid derivative having excellent safety has been proposed in Patent Document 1. The hyaluronic acid derivative spontaneously associates in an aqueous solution to effectively encapsulate a drug, particularly a bio-pharmaceutical product, while maintaining the biological activity thereof, and aggregates under a physiological saline concentration (or disperses under a physiological saline concentration), and the retention thereof in the blood is favorable. It is stated that, particularly when a bio-pharmaceutical product is used as an active ingredient, the hyaluronic acid derivative may be used as a carrier which can effectively encapsulate a large amount of drug while maintaining a pharmacological activity thereof, or a carrier for sustained release in the blood or a targeting carrier, which exhibits an excellent retention in the blood, and may also serve as a locally (such as subcutaneously) sustained-release carrier which can continuously release a drug. CITATION LIST Patent Literature [PTL 1] PCT International Publication No. WO 2010/053140 SUMMARY OF INVENTION Technical Problem However, since it is difficult to control the precipitation forming ability of the hyaluronic acid derivative disclosed in Patent Document 1 depending on salt concentration, and the precipitation forming ability thereof under a physiological saline concentration is not sufficient, there is a risk in which the local retention of a drug composition containing the hyaluronic acid derivative in vivo is impaired. The present invention has been made in view of the above-mentioned circumstances, and provides a hyaluronic acid derivative composition having an excellent precipitation forming ability under a physiological saline concentration, as well as a pharmaceutical composition using the hyaluronic acid derivative composition, and a hyaluronic acid derivative-drug conjugate composition. Solution to Problem The present invention encompasses the following aspects. (1) A hyaluronic acid derivative composition containing: a hyaluronic acid derivative (A) in which a steryl group is introduced; anda polar group-containing compound (B) having at least one functional group selected from the group consisting of a hydroxy group, a carboxy group, an amino group, an amide group, a carbamate group, a urea group and a thiol group,wherein the introduction ratio of the steryl group is 0.1% to less than 35% relative to the hyaluronic acid derivative (A). (2) The hyaluronic acid derivative composition according to (1), wherein the polar group-containing compound (B) is a polar group-containing compound having at least one hydroxy group. (3) The hyaluronic acid derivative composition according to (1) or (2), wherein the amount of the polar group-containing compound (B) relative to the mass of the hyaluronic acid derivative (A) is 0.001 ppm by mass to less than 1000 ppm by mass. (4) The hyaluronic acid derivative composition according to any one of (1) to (3), wherein the polar group-containing compound (B) is a compound having plural polar groups. (5) The hyaluronic acid derivative composition according to any one of (1) to (4), wherein the polar group-containing compound (B) is alcohol. (6) The hyaluronic acid derivative composition according to (5), wherein the alcohol is selected from the group consisting of ethanol, isopropanol and polyhydric alcohol. (7) The hyaluronic acid derivative composition according to (6), wherein the alcohol is polyhydric alcohol. (8) The hyaluronic acid derivative composition according to (7), wherei