CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage of International Application No. PCT/JP2018/033535 filed Sep. 11, 2018, claiming priority based on Japanese Patent Application No. 2017-175133 filed Sep. 12, 2017.

TECHNICAL FIELD

The present invention relates to a pentosan polysulfate, and a method for producing the pentosan polysulfate.

BACKGROUND ART

Heparin has been used as a therapeutic agent for thrombosis, osteoarthritis, and the like. However, since heparin is a substance separated from the organs of animals, such as bovines or pigs, it is difficult to control the quality thereof. Further, there are cases where the use of heparin in treatment causes hesitation from the viewpoint of religious ethics etc. Therefore, the development of an alternative therapeutic agent that is free of animal-derived components, and that can be used instead of heparin, has been desired.

As such an alternative substance for heparin, pentosan polysulfate, for example, is known. Pentosan polysulfate is obtained by sulfating a plant-derived xylooligosaccharide. Since such pentosan polysulfate is a substance free of animal-derived components, its use as an alternative therapeutic agent for heparin has been expected (for example, Patent Literature (PTL) 1).

Pentosan polysulfate is produced by chemical sulfation of xylan obtained from hardwood (e.g., beech). Pentosan polysulfate is composed of a sulfated linear polysaccharide in which β-D-xylopyranose is linearly bonded; and has 4-O-methylglucuronic acid, i.e., uronic acid, per roughly every 10 xylopyranose units (Patent Literature (PTL) 1 and Patent Literature (PTL) 2).

CITATION LIST

Patent Literature

PTL 1: WO2010/000013

PTL 2: JP2009-532467A

SUMMARY OF INVENTION

Technical Problem

An object of the present invention is to provide a novel pentosan polysulfate having activity preferable for pharmaceutical applications, or having storage stability. Another object of the present invention is to provide an inexpensive and efficient method for producing the pentosan sulfate.

Means for Solving the Problem

As a result of intensive studies to solve the above problem, the present inventors found a novel pentosan polysulfate having higher anticoagulant activity than conventional pentosan polysulfates, while suppressing side effects or having storage stability. The present inventors thus accomplished the present invention based on this finding. Specifically, the present invention has the following constitution.

[1] A pentosan polysulfate having a uronic acid content of 0.0 mass % to 6.0 mass %;

a pharmaceutically acceptable salt thereof; or

a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

[2] The pentosan polysulfate according to [1], wherein the pentosan polysulfate has a uronic acid content of 0.0 mass % to 4.0 mass %;

a pharmaceutically acceptable salt thereof; or

a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

[3] The pentosan polysulfate according to [1] or [2], wherein the pentosan polysulfate has a structure represented by Formula II:


wherein R1each independently represents a hydrogen atom, —COCH3, or —SO3X1, and at least one R1in the molecule is —SO3X1, wherein X1represents a hydrogen atom or a monovalent or divalent metal; n1 and n2 each independently represent an integer of 0 or more and 30 or less, and at least one of n1 and n2 is an integer of 1 or more; and R* represents a hydrogen atom, —COCH3, —SO3X1, or a sulfated or non-sulfated uronic acid residue;

a pharmaceutically acceptable salt thereof; or

a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

[4]

The pentosan polysulfate according to any one of [1] to [3], wherein the pentosan polysulfate is represented by Formula


wherein each R independently represents a hydrogen atom, —COCH3or —SO3X, and at least one R is —SO3X, wherein X represents a hydrogen atom or a monovalent or divalent metal; and n represents an integer of 1 to 30;

a pharmaceutically acceptable salt thereof; or

a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

[5] The pentosan polysulfate according to [4], wherein each R independently represents a hydrogen atom or —SO3X;

a pharmaceutically acceptable salt thereof; or

a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

[6] The pentosan polysulfate according to [4] or [5], wherein X is sodium;

a pharmaceutically acceptable salt thereof; or

a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

[7] A pharmaceutical composition comprising

the pentosan polysulfate according to any one of [1] to [6];

a pharmaceutically acceptable salt thereof; or

a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

[8] An anticoagulant comprising

the pentosan polysulfate according to any one of [1] to [6];

a pharmaceutically acceptable salt thereof; or

a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

[9] A method for producing pentosan polysulfate comprising:

a first step of obtaining neutral xylooligosaccharide from a plant-derived raw material; and

a second step of obtaining pentosan polysulfate from the neutral xylooligosaccharide,

the first step comprising a step of depolymerizing the plant-derived raw material, and the second step comprising a step of sulfating the neutral xylooligosaccharide.

[10] The method for producing pentosan polysulfate according to [9], wherein the depolymerization step is a heat treatment step.

[11]

The method for producing pentosan polysulfate according to [10], wherein the heat treatment step is a step of heating to 120° C. or higher under non-alkaline conditions.

[12]

The method for producing pentosan polysulfate according to any one of [9] to [11], wherein the plant-derived raw material is a wood-derived raw material.

From another point of view, the present invention provides:

use of pentosan polysulfate according to any one of [1] to [6], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof, as an anticoagulant;

use of the pentosan polysulfate according to any one of [1] to [6], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the pentosan polysulfate, or of a pharmaceutically acceptable salt thereof, for producing an anticoagulant;

the pentosan polysulfate according to any one of [1] to [6], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof, for use as an anticoagulant;

a method for inhibiting blood coagulation, comprising administering to a human or an animal a moisturizingly effective amount of the pentosan polysulfate according to any one of [1] to [6], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof;

a method for surface-treating a medical device or a medical material, comprising applying to a surface of the medical device or the medical material the pentosan polysulfate according to any one of [1] to [6], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the pentosan polysulfate or of a pharmaceutically acceptable salt thereof.

Advantageous Effects of Invention

The present invention provides a pentosan polysulfate having an activity preferable for pharmaceutical applications, or having storage stability. The pentosan polysulfate of the present invention is useful as a pharmaceutical composition, such as an anticoagulant. The present invention further provides an inexpensive and efficient method for producing the pentosan polysulfate.

