Pentosan polysulfate, pharmaceutical composition, uses of a pentosan polysulfate compound and of a pharmaceutical composition, and method for producing pentosan polysulfate.
Patent Information
- Application Number
- BR112020004787
- Authority / Receiving Office
- BR · BR
- Patent Type
- Patents
- Current Assignee / Owner
- Publication Date
- 2026-09-08
Smart Images
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Abstract
Description
/ 37 Pentosan polysulfate, pharmaceutical composition, uses of a pentosan polysulfate compound and of a pharmaceutical composition, and method for producing pentosan polysulfate. Technical Field
[001] The present invention relates to a pentosan polysulfate, and to a method for producing pentosan polysulfate. Fundamentals of the Technique
[002] Heparin has been used as a therapeutic agent for thrombosis, osteoarthritis, and similar conditions. However, since heparin is a substance derived from the organs of animals, such as cattle or pigs, it is difficult to control its quality. Furthermore, there are cases where the use of heparin in treatment causes hesitation from an ethical, religious, etc. standpoint. 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.
[003] As such, an alternative substance to heparin, pentosan polysulfate, for example, is known. Pentosan polysulfate is obtained by sulfated a plant-derived xylo-oligosaccharide. Since such pentosan polysulfate is a substance free of animal-derived components, its use as an alternative therapeutic agent to heparin was anticipated (e.g., Patent Literature (PTL) 1).
[004] Pentosan polysulfate is produced by the chemical sulfation of xylan obtained from hardwood (e.g., beech). Pentosan polysulfate is composed of a linear sulfated polysaccharide in which β-Dxylopyranose is linearly linked; and has 4-O-methylglucuronic acid, i.e., uronic acid, for approximately every 10 units of xylopyranose (Patent Literature (PTL) 1 and Patent Literature (PTL) 2). Petition 870260074260, dated 07 / 24 / 2026, page 12 / 119 / 37 Citation List Patent Literature
[005] PTL 1: WO2010 / 000013 PTL 2: JP2009-532467A Summary of the Invention Technical Problem
[006] One objective of the present invention is to provide a novel pentosan polysulfate having preferable activity for pharmaceutical applications or having stability during storage. Another objective of the present invention is to provide a cheap and efficient method for producing pentosan sulfate. Ways to Solve the Problem
[007] As a result of intensive studies to solve the above problem, the present inventors discovered a new pentosan polysulfate having superior anticoagulant activity to that of conventional pentosan polysulfates, while suppressing side effects or having stability in storage. The present inventors thus realized the present invention based on this discovery. Specifically, the present invention has the following constitution.
[008] [1] A pentosan polysulfate having a uronic acid content of 0.0 % by mass to 6.0 % by mass; a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof.
[009] [2] Pentosan polysulfate according to [1], wherein pentosan polysulfate has a uronic acid content of 0.0 % by mass to 4.0 % by mass; a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of the polysulfate of Petition 870260074260, dated 07 / 24 / 2026, page 13 / 119 3 / 37 pentosan or a pharmaceutically acceptable salt thereof.
[0010] [3] Pentosan polysulfate according to [1] or [2], wherein pentosan polysulfate has a structure represented by the Formula where each R1 independently represents a hydrogen atom, -COCH3 or -SO3X1 and at least one R1 in the molecule is SO3X1, where X1 represents 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 pentosan polysulfate or of a pharmaceutically acceptable salt thereof.
[0011] [4] Pentosan polysulfate according to any of [1] to [3], where pentosan polysulfate is represented by Formula I: where each R independently represents a hydrogen atom, -COCH3 or -SO3X and at least one R is -SO3X, where X represents a hydrogen atom or a monovalent or divalent metal; en represents an integer from 1 to 30; a pharmaceutically acceptable salt thereof; or Petition 870260074260, dated 07 / 24 / 2026, page 14 / 119 / 37 a pharmaceutically acceptable solvate of pentosan polysulfate or a pharmaceutically acceptable salt thereof.
[0012] [5] Pentosan polysulfate according to [4], where each R independently represents a hydrogen atom or -SO3X; a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof.
[0013] [6] Pentosan polysulfate according to [4] or [5], where X is sodium; a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof.
[0014] [7] A pharmaceutical composition comprising pentosan polysulfate according to any one of [1] to [6]; a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof.
[0015] [8] An anticoagulant comprising pentosan polysulfate according to any one of [1] to [6]; a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof.
[0016] [9] A method for producing pentosan polysulfate comprising: The first step involves obtaining neutral xylo-oligosaccharide from a plant-derived raw material; and the second step involves obtaining pentosan polysulfate from... Petition 870260074260, dated 07 / 24 / 2026, page 15 / 119 / 37 of neutral xylo-oligosaccharide, the first stage comprising a step of depolymerizing the plant-derived raw material and the second stage comprising a step of sulfated the neutral xylo-oligosaccharide.
[0017]
[10] The method for producing pentosan polysulfate according to [9], wherein the depolymerization step is a heat treatment step.
[0018]
[11] The method for producing pentosan polysulfate according to
[10] , wherein the heat treatment step is a heating step at 120°C or higher under non-alkaline conditions.
[0019]
[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.
[0020] From another point of view, the present invention provides: use of pentosan polysulfate according to any of [1] to [6], a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof, as an anticoagulant; use of pentosan polysulfate according to any one of [1] to [6], a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof, to produce an anticoagulant; pentosan polysulfate according to any one of [1] to [6], a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of 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 being or an animal a hydratingly effective amount of pentosan polysulfate according to any Petition 870260074260, dated 07 / 24 / 2026, page 16 / 119 / 37 one of [1] to [6], a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof; a method for treating the surface of a medical device or medical material, comprising applying to a surface of the medical device or medical material pentosan polysulfate according to any one of [1] to [6], a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of pentosan polysulfate or of a pharmaceutically acceptable salt thereof. Advantageous Effects of the Invention
[0021] The present invention provides a pentosan polysulfate having preferable activity for pharmaceutical applications or having stability during storage. The pentosan polysulfate of the present invention is useful as a pharmaceutical composition, such as an anticoagulant. The present invention further provides a cheap and efficient method for producing pentosan polysulfate. Brief Description of the Drawings
[0022] Fig. 1 is a diagram illustrating a method for producing pentosan polysulfate.
[0023] Fig. 2 is a diagram illustrating a method for producing pentosan polysulfate.
[0024] Fig. 3 is a graph showing the relationship between uronic acid content and anti-IIa or anti-Xa activity of each pentosan polysulfate.
[0025] Fig. 4 is a graph showing the relationship between uronic acid content and the anti-Xa / anti-IIa activity ratio of each pentosan polysulfate. Description of the modalities
[0026] The present invention is described in detail below. The Petition 870260074260, dated 07 / 24 / 2026, page 17 / 119 7 / 37 constituent aspects can be described below based on typical embodiments and specific examples; however, the present invention is not limited to such embodiments. Pentosan polysulfate
[0027] Pentosan polysulfate is a compound obtained by sulfating at least one hydroxyl group of a xylo-oligosaccharide. In this descriptive report, pentosan polysulfate includes pentosan polysulfate salts, pentosan polysulfate solvates, and pentosan polysulfate salt solvates. Pentosan polysulfate salts are preferably pharmaceutically acceptable salts, and examples include sodium pentosan polysulfate, potassium pentosan polysulfate, calcium pentosan polysulfate, and the like. Solvates are preferably pharmaceutically acceptable solvates. Examples of solvents include water.
[0028] Pentosan polysulfate has a structure represented by Formula II. Pentosan polysulfate may contain one structure represented by Formula II or it may contain two or more structures represented by Formula II. When pentosan polysulfate contains two or more structures represented by Formula II, the structure represented by Formula II is a structure representing a repeating unit of pentosan polysulfate.
[0029] In Formula II, each R1 independently represents a hydrogen atom, -COCH3 or -SO3X1 and at least one R1 in the molecule is SO3X1, where X1 represents a hydrogen atom or a monovalent or divalent metal; and X1 is preferably a hydrogen, sodium, potassium or calcium atom, more preferably sodium, potassium or calcium and Petition 870260074260, dated 24 / 07 / 2026, p. 18 / 119 / 37 particularly preferred mode sodium. Furthermore, 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.
[0030] In Formula II, n1 + n2 is preferably from 1 to 27, more preferably from 2 to 18, and even more preferably from 3 to 10.
[0031] The portion that is an end of the structure represented by Formula II and that does not connect to a structure represented by Formula II can be -OR1. That is, -OR1 can connect to the left terminal (n1 side) of Formula II, while -R1 can connect to the right terminal (n2 side) of Formula II. It is particularly preferable that -OR1X connects to the left terminal (n1 side) of Formula II and -R1X connects to the right terminal (n2 side) of Formula II. In Formula II, R1X is a hydrogen atom or -SO3X1; X1 is a hydrogen atom or a monovalent or divalent metal; and X1 is preferably a hydrogen, sodium, potassium, or calcium atom, more preferably sodium, potassium, or calcium, and particularly preferably sodium.
[0032] R* is a hydrogen atom, -COCH3, -SO3X1 or a sulfated or non-sulfated uronic acid residue. The sulfated or non-sulfated uronic acid residue can be represented by the following formula. Formula 1
[0033] X2 represents a hydrogen atom or a monovalent or divalent metal; preferably sodium, potassium, or calcium; and particularly preferably sodium. R1 each independently represents a hydrogen atom, -COCH3 or -SO3X1, as described above. * represents a bonding position.
[0034] The pentosan polysulfate of the present invention does not include the pentosan polysulfate of Formula II wherein R* is an acid residue. Petition 870260074260, dated 07 / 24 / 2026, page 19 / 119 / 37 uronic acid or may possibly contain a small amount of such pentosan polysulfate. Specifically, the pentosan polysulfate of the present invention has a uronic acid content of 0.0% by mass to 6.0% by mass. The pentosan polysulfate of the present invention preferably has a uronic acid content of 0.0% by mass to 4.0% by mass, more preferably 0.0% by mass to 2.0% by mass, even more preferably 0.0% by mass to 2.0% by mass and even more preferably 0.0% by mass to 1.0% by mass. It is particularly preferred that the pentosan polysulfate of the present invention has a uronic acid content of substantially 0.0% by mass. The above ratio does not have to be achieved by a single molecule, but can be satisfied by pentosan polysulfate as a whole mixture of individual molecules.
[0035] That is, the pentosan polysulfate of the present invention preferably has a structure represented by Formula I. Formula 1
[0036] In Formula I, each R independently represents a hydrogen atom, -COCH3 or -SO3X, and at least one R per molecule is -SO3X, where X represents a hydrogen atom, either monovalent or divalent; and en represents an integer of 1 or more and 30 or less.
[0037] The compound represented by Formula I is preferably a compound represented by the following Formula IX. That is, it is preferable that the R terminal not be -COCH3. Formula IX Petition 870260074260, dated 07 / 24 / 2026, p. 20 / 119 / 37
[0038] In Formula IX, RX each independently represents a hydrogen atom or -SO3X.
[0039] In the pentosan polysulfate of the present invention, it is preferred that 50% or more, more preferably 70% or more, and even more preferably 90% or more, of the total number of Rs in Formula II are -SO3X; and that 8% or less, more preferably 4% or less, and even more preferably 1% or less, of the total number of Rs in Formula II are COCH3. It is particularly preferred that none of the Rs are -COCH3. More specifically, it is particularly preferred that each R independently represents a hydrogen atom or -SO3X. In other words, the pentosan polysulfate of the present invention preferably does not contain any of the acetyl groups.
[0040] The above ratio does not have to be achieved by a single molecule, but can be satisfied by pentosan polysulfate as a whole mixture of individual molecules.
[0041] X is preferably a hydrogen, sodium, potassium or calcium atom. The same is more preferably sodium, potassium or calcium and even more preferably sodium.
[0042] n is preferably 3 or more, more preferably 4 or more, and even more preferably 5 or more. On the other hand, n is preferably 30 or less, more preferably 25 or less, and even more preferably 20 or less.
[0043] The pentosan polysulfate of the present invention may be a mixture of molecules represented by Formula I that differ from each other in the value n, in the type of substituent R and / or in the degree of substitution.
[0044] Pentosan polysulfate has a structure obtained by the sulfation of xylo-oligosaccharides. Among the xylo-oligosaccharides, neutral xylo-oligosaccharides are xylo-oligosaccharides that do not contain acid. Petition 870260074260, dated 07 / 24 / 2026, page 21 / 119 / 37 uronic acid. Acidic xylo-oligosaccharides are xylo-oligosaccharides in which at least one uronic acid is attached to at least one of the xylose units in a xylo-oligosaccharide molecule. That is, acidic xylo-oligosaccharides have at least one uronic acid residue as a side chain per xylo-oligosaccharide molecule. The average number of uronic acid residues per acidic xylo-oligosaccharide molecule is preferably 1 or more and 3 or less, more preferably 1 or more and 2 or less. The number of uronic acid residues contained per xylo-oligosaccharide molecule can be measured by the carbazole-sulfuric acid method or the colorimetric method using sodium tetraborate.
[0045] The sulfur content of the pentosan polysulfate of the present invention is preferably 10.0% by mass or more, more preferably 12.0% by mass or more, even more preferably 15.5% by mass or more, and particularly preferably 16.5% by mass or more. The sulfur content of the pentosan polysulfate is preferably 20.0% by mass or less. Here, the sulfur content of the pentosan polysulfate is a value determined according to the oxygen flask combustion method described in the Japanese Pharmacopoeia.
[0046] The pentosan polysulfate of the present invention preferably has an acetyl group content of 0 to 2.0% by mass, more preferably 0 to 1.0% by mass, even more preferably 0 to 0.4% by mass, particularly preferably 0 to 0.3% by mass and even more preferably substantially 0% by mass. When the acetyl group content of the pentosan polysulfate is as described above, higher anti-Xa activity can be obtained.
[0047] The acetyl group content of pentosan polysulfate can be calculated from the integral ratio of peaks in the 1H-NMR measurement. Specifically, first, the 1H-NMR measurement is performed using a 1H-NMR measuring solution containing a specific amount of Petition 870260074260, dated 07 / 24 / 2026, page 22 / 119 / 37 pentosan polysulfate and a specific quantity of an internal standard substance. By comparing the peak for the acetyl group with the peak for a specific group of the internal standard substance in the spectrum obtained to obtain an integral ratio thereof, the molar quantity of acetyl groups in the solution is obtained. The molar quantity of acetyl groups is then multiplied by 43; and the value obtained is divided by the average molecular weight obtained separately, in order to obtain the % by mass of the acetyl groups.
[0048] The weighted average molecular weight (Mw) of the pentosan polysulfate of the present invention is not particularly limited; and may be, for example, 4000 or less, 3900 or less or 3800 or less. In this case, the lower limit of the weighted average molecular weight (Mw) of the pentosan polysulfate is preferably 1000.
[0049] The weighted average molecular weight (Mw) of pentosan polysulfate may be greater than 4000, 5000 or more, 7000 or more, 10000 or more, 15000 or more or 20000 or more.
[0050] The number average molecular weight (Mn) of pentosan polysulfate is not particularly limited; and may be, for example, 4000 or less, 3900 or less, 3800 or less or 3750 or less. In this case, the lower limit of the number average molecular weight (Mn) of pentosan polysulfate is preferably 300.
[0051] The number average molecular weight (Mn) of pentosan polysulfate may be 5000 or more, 7000 or more, 10000 or more, 15000 or more, or 20000 or more.
[0052] The weighted average molecular weight (Mw) and the number average molecular weight (Mn) of the pentosan polysulfate of the present invention can be measured by GPC (gel permeation chromatography). As the GPC column, a YMC-Pack Diol-300 and YMC-Pack Diol-60 (both manufactured by YMC) connected to each other can be used. The GPC conditions can be, for example, the following conditions. Petition 870260074260, dated 07 / 24 / 2026, page 23 / 119 / 37
[0053] Eluent: 25 mM potassium dihydrogen phosphate / 25 mM dipotassium hydrogen phosphate / 50 mM potassium chloride Flow rate: 0.7 mL / min Measurement temperature: 40°C. Detector: refractive index detector.
[0054] The degree of dispersion of pentosan polysulfate is preferably 1.00 or more and 1.6 or less, more preferably 1.00 or more and 1.5 or less. The degree of dispersion of pentosan polysulfate is also preferably 1.00 or more and 1.4 or more. The degree of dispersion (D) of pentosan polysulfate is calculated by the following formula. Degree of dispersion (D) = Weighted average molecular weight (Mw) / Number average molecular weight (Mn)
[0055] The pentosan polysulfate obtained by the production method of the present invention described below has high purity and tends to have a narrow molecular weight distribution. The pentosan polysulfate obtained by the production method of the present invention has excellent quality stability. Applications of Pentosan Polysulfate: Pharmaceutical Composition and Anticoagulant
[0056] The pentosan polysulfate of the present invention can be used for applications such as pharmaceuticals, food and cosmetics. For example, a pharmaceutical composition comprising, as an active ingredient, the pentosan polysulfate of the present invention (pentosan polysulfate, a pharmaceutically acceptable salt thereof or a solvate thereof) can be provided. In particular, since pentosan polysulfate has anticoagulant activity, the pharmaceutical composition described above can be used as an anticoagulant.
[0057] In general, anticoagulant activity is based on the ability to inhibit blood clotting factors. Specifically, Petition 870260074260, dated 07 / 24 / 2026, page 24 / 119 / 37 when anticoagulant activity is high, a blood clotting reaction is inhibited. Blood clotting factors mean the system of action of a series of molecules in a living body to clot blood when there is bleeding, etc. Many blood clotting factors are successively activated in order to agglutinate fibrin and stop bleeding in the bleeding area. Representative examples of blood clotting factors include factor Xa and factor IIa. Blood clotting can be inhibited by inhibiting the activity of these factors.
[0058] The factor Xa inhibitory activity (anti-Xa activity) of pentosan polysulfate is preferably 0.10 IU / mg or more and more preferably 0.12 IU / mg or more.
[0059] The inhibitory activity of pentosan polysulfate against factor IIa (anti-IIa activity) is preferably 0.50 IU / mg or less, more preferably 0.40 IU / mg or less, and even more preferably 0.30 IU / mg or less.
[0060] Here, factor Xa inhibitory activity (anti-Xa activity) can be measured using Test Team (registered trademark) Heparin S (manufactured by Sekisui Medical Co., Ltd.).
[0061] Factor IIa inhibitory activity (anti-IIa activity) can be measured using Biophen heparin anti-IIa (manufactured by Hyphen BioMed).
[0062] The ratio of factor Xa inhibitory activity (anti-Xa activity) of pentosan polysulfate to factor IIa inhibitory activity (anti-IIa activity) of pentosan polysulfate is preferably within a predetermined range. Specifically, the anti-Xa activity / anti-IIa activity ratio is preferably 0.50 or more, more preferably 1.00 or more, even more preferably 1.10 or more, and even more preferably 1.20 or more.
[0063] The pentosan polysulfate of the present invention may have anti-Xa activity, anti-IIa activity and an anti-Xa activity / anti-IIa activity ratio. Petition 870260074260, dated 07 / 24 / 2026, page 25 / 119 / 37 anti-IIa that are controlled within the ranges described above. In particular, the pentosan polysulfate of the present invention may have lower suppressed anti-IIa activity than anti-Xa activity. When the anti-Xa / anti-IIa activity ratio is controlled to fall within the range mentioned above, the anticoagulant activity can be more effectively increased; and the occurrence of side effects, such as an increased risk of bleeding or a decrease in platelets, can be suppressed.
[0064] A pharmaceutical composition comprising pentosan polysulfate of the present invention can be used, for example, as a surface treatment agent for medical devices or medical materials. The pharmaceutical composition can be used, for example, as a surface treatment agent for implantable artificial organs, blood vessels, catheters, stents, blood bags, contact lenses, intraocular lenses, and surgical auxiliary instruments. Examples of methods for immobilizing the pharmaceutical composition on the surface of a medical device or medical material include a method comprising bringing the pharmaceutical composition into contact with the medical device or medical material and irradiating the contact portion with radiation.
[0065] The pharmaceutical composition may have any dosage form and may be formed, for example, in an oral preparation, an injection or a topical preparation. Method for Producing Pentosan Polysulfate
[0066] The pentosan polysulfate of the present invention can be produced by sulfated a neutral xylo-oligosaccharide. The pentosan polysulfate of the present invention is preferably produced by sulfated a neutral xylo-oligosaccharide. The neutral xylo-oligosaccharide can be obtained by extraction from a plant-derived raw material, optionally followed by depolymerization or polymerization of D-xylose. Petition 870260074260, dated 07 / 24 / 2026, page 26 / 119 / 37
[0067] The pentosan polysulfate of the present invention can be obtained, for example, by a method for producing pentosan polysulfate, the method comprising a first step of obtaining a neutral xylooligosaccharide from a plant-derived raw material and a second step of obtaining pentosan polysulfate from the neutral xylooligosaccharide, as shown in Fig. 1. In this method, the first step includes a step of depolymerizing a plant-derived raw material. Since the method comprises the step of depolymerizing a plant-derived raw material and the sulfation step in this order, the method can efficiently produce pentosan polysulfate. The method for producing pentosan polysulfate may further include a deacetylation step. By including a deacetylation step, the method can produce a pentosan polysulfate having a low acetyl group content. Plant-derived raw material
[0068] Neutral xylo-oligosaccharides can be obtained by depolymerization of plant-derived raw materials. Examples of plant-derived raw materials include wood-derived raw materials, seed-derived raw materials, grain-derived raw materials, fruit-derived raw materials, and the like. In addition, examples of plant-derived raw materials that can be used include cottons such as cotton fibers and cotton linters; herbaceous plants such as kenaf, hemp, ramie, and rice straw; and the like. Like plant-derived raw materials, the aforementioned raw materials derived from various sources can also be used in combination.
[0069] Among these, wood-derived raw materials are preferably used as the plant-derived raw material. Examples of usable wood-derived raw materials include wood raw materials such as softwoods and hardwoods. The wood-derived raw material is preferably at least one selected from Petition 870260074260, dated 07 / 24 / 2026, p. 27 / 119 / 37 softwoods and hardwoods; and hardwoods are more preferably used. Wood-derived raw materials may be a mixture of softwood and hardwood. Bark may also be used as a wood-derived raw material.
[0070] Examples of hardwoods include beech, Eucalyptus globulus, Eucalyptus grandis, Eucalyptus urograndis, Eucalyptus pellita, Eucalyptus braciana, Acacia mearnsii, and similar species. Examples of softwoods include Japanese cedar, Japanese cypress, pine, hiba, Japanese hemlock, and similar species.
[0071] The wood-derived raw material preferably has a specific gravity of 450 kg / m3 or more and 700 kg / m3 or less, and more preferably 500 kg / m3 or more and 650 kg / m3 or less. When the wood-derived raw material has a specific gravity within the range described above, the efficiency of producing neutral xylo-oligosaccharide can be further enhanced.
[0072] The wood-derived raw material is preferably wood chips obtained by grinding one or more of the woods mentioned above. When wood chips are used as a plant-derived raw material, the depolymerization of a plant-derived raw material can be efficiently carried out, and the efficiency of producing neutral xylooligosaccharide can be enhanced. First Stage Depolymerization Step
[0073] The first step involves depolymerizing a plant-derived feedstock. In the depolymerization step of a plant-derived feedstock, the plant-derived feedstock is chemically and / or physically broken down to produce a neutral xylo-oligosaccharide. Examples of the chemical and / or physical decomposition step include a heat treatment step, an alkaline treatment step, a Petition 870260074260, dated 07 / 24 / 2026, page 28 / 119 / 37 acid treatment step, an enzymatic treatment step, an ionic treatment step, a catalytic treatment step, and the like. Among these steps, the depolymerization step is either a heat treatment step or an enzymatic treatment step; and is more preferably a heat treatment step. The heat treatment step may be a heating and pressurization step.
[0074] The depolymerization step is preferably carried out under non-alkaline conditions (at pH 9 or less, and preferably pH 8 or less).
[0075] The heat treatment step is a step of heating a plant-derived raw material in the presence of a solution. Since the plant-derived raw material is hydrolyzed in such a heat treatment step, the heat treatment step is sometimes referred to as a hydrolysis treatment step or a pre-hydrolysis treatment step. The solution used in the heat treatment step is preferably water. The ratio (mass ratio) of water to plant-derived raw material is preferably in the range of 1:1 to 1:10. When the ratio of water to plant-derived raw material is adjusted within the range described above, the hydrolysis reaction can be efficiently carried out. The water used in the heat treatment step may be water added separately from the plant-derived raw material; or a portion of the water may be water originally contained in the plant-derived raw material.
[0076] In the heat treatment stage, other chemicals may also be added in addition to the plant-derived raw material and water. Examples of such other chemicals include alkalis, acids, and chelating agents. In addition, chemicals that directly or indirectly aid in the depolymerization of polysaccharides, such as scale inhibitors, pitch control agents, and ionic liquids, may also be added. Petition 870260074260, dated 07 / 24 / 2026, page 29 / 119 19 / 37
[0077] The heat treatment step is a step of heating a plant-derived raw material in the presence of water. The heating temperature (net temperature) in this step is preferably 30°C or higher, more preferably 50°C or higher, even more preferably 75°C or higher, even more preferably 90°C or higher, particularly preferably 100°C or higher, and most preferably 120°C or higher. On the other hand, the heating temperature (net temperature) is preferably 300°C or lower, more preferably 250°C or lower, and even more preferably 200°C or lower.
[0078] The treatment time in the heat treatment step can be determined, as appropriate, according to the treatment temperature. The treatment time is, for example, preferably 5 minutes or more, more preferably 10 minutes or more, and even more preferably 20 minutes or more. The P factor expressed by the following formula is a product of the heat treatment temperature and the heat treatment time. It is preferable to adjust the P factor within a preferred range.
[0079] In the formula above, P represents a P factor, T represents an absolute temperature (°C + 273.5), t represents the heat treatment time, and KHi(T) / Kioo°c represents the relative hydrolysis ratio of glycosidic bonds.
[0080] In the heat treatment stage, the P factor is preferably set to 200 or more, more preferably to 250 or more, and even more preferably to 300 or more. On the other hand, the P factor is preferably 1000 or less. In the heat treatment stage, the P factor is set as Petition 870260074260, dated 07 / 24 / 2026, page 30 / 119 / 37 appropriate so that the average degree of polymerization and the molecular weight of the neutral xylo-oligosaccharide can be within desired ranges, through which the molecular weight of the pentosan polysulfate obtained can be adjusted.
[0081] In the heat treatment step, the solution containing a plant-derived raw material preferably has a pH of 9 or less, more preferably pH 8 or less, and even more preferably pH 7 or less. That is, the heat treatment step is preferably carried out under non-alkaline conditions. The pH values described above refer to the pH of the solution before heat treatment.
[0082] In the heat treatment step, an acid derived from the raw material can be dissociated, and acid hydrolysis can proceed at least partially. Examples of acids derived from plant raw materials include organic acids such as acetic acid and formic acid. In this case, the pH of the solution containing a plant-derived raw material is further lowered after acid hydrolysis.
[0083] The method for producing pentosan polysulfate preferably comprises a heat treatment step as the first step. This can enhance the efficiency of neutral xylooligosaccharide production and further enhance the efficiency of pentosan polysulfate production. When the method includes a heat treatment step as the first step, the number of steps required to produce neutral xylooligosaccharide can be significantly reduced compared with conventional methods. By including a heat treatment under non-alkaline conditions as the first step, the method can efficiently produce neutral xylooligosaccharide with suppressed coloration because the neutral xylooligosaccharide is not replaced with hexenuronic acid.
[0084] The depolymerization step is preferably a step of Petition 870260074260, dated 07 / 24 / 2026, page 31 / 119 / 37 heat treatment; however, it may be a step other than the heat treatment step. For example, when the depolymerization step is an enzymatic treatment step, the depolymerization step includes a step of mixing a plant-derived raw material with an enzyme. Examples of usable enzymes include hemicellulase and similar enzymes. Specific examples include commercially available enzymatic preparations such as Cellulosin HC100 (trade name, manufactured by HBI Enzymes Inc.), Cellulosin TP25 (trade name, manufactured by HBI Enzymes Inc.), Cellulosin HC (trade name, manufactured by HBI Enzymes Inc.), Cartazyme (trade name, manufactured by Clariant AG), Ecopulp (trade name, manufactured by Rohm Enzyme GmbH), Sumizyme (trade name, manufactured by Shin Nihon Chemicals Corporation), Pulpzyme (manufactured by Novo Nordisk), and Multifect 720 (Genencor); and xylanase produced by microorganisms belonging to the genus Trichoderma, genus Thermomyces, genus Aureobasidium, genus Streptomyces, genus Aspergillus, genus Clostridium, genus Bacillus, genus Thermotoga, genus Thermoascus, genus Cardoceram, genus Thermomonospora, or similar organisms.
[0085] In the enzyme treatment step, an enzyme is added to a solution prepared by mixing a plant-derived raw material with water. The solution temperature during this treatment is preferably 10°C or higher and 90°C or lower, and more preferably 30°C or higher and 60°C or lower. The solution temperature is preferably close to the ideal temperature of the enzyme used. The pH of the solution is also preferably adjusted to a range in which the enzyme activity is enhanced. For example, the solution pH is preferably adjusted to a pH of 3 or higher and a pH of 10 or lower.
[0086] When the depolymerization step is an alkaline treatment step or an acid treatment step, the step of Petition 870260074260, dated 07 / 24 / 2026, page 32 / 119 / 37 Depolymerization comprises a step of mixing a plant-derived raw material with an alkaline solution or an acidic solution. In the alkaline treatment step, sodium hydroxide or potassium hydroxide are preferably added. In the acidic treatment step, hydrochloric acid, sulfuric acid, acetic acid, or the like are preferably added. In such cases, heating or pressurization may also be carried out, as appropriate.
[0087] When the depolymerization step is at least one selected from an enzymatic treatment step, an alkaline treatment step, and an acid treatment step, the production method may further comprise, after the treatment step, a compression step, an extraction step, a heating step, a filtration step, a separation step, a purification step, a concentration step, a desalting step, or the like. The method may further comprise a molecular weight reduction step carried out after the treatment step. Examples of other steps include the steps described in JP 2003-183303A, the contents of which are incorporated herein by reference. Filtration Stage
[0088] The first stage may also include a filtration stage performed after the depolymerization stage described above. In the filtration stage, the reaction mixture is separated into the plant-derived feedstock solids and a solution other than the solids. More specifically, when the first stage includes a filtration stage performed after the depolymerization stage, the reaction product is separated into solids, which are used as a pulp feedstock, and a filtrate. The solids used as a pulp feedstock are subjected to a digestion or similar stage as a post-stage to provide a cellulose feedstock (dissolved pulp). Petition 870260074260, dated 07 / 24 / 2026, page 33 / 119 / 37
[0089] The recovered filtrate can be separated into a gaseous layer and a liquid layer. Since the gaseous layer contains a large amount of furfurals, these furfurals can be isolated by collecting them from the gaseous layer. On the other hand, the liquid layer contains a large amount of hemicellulose, including neutral xylo-oligosaccharide and acidic xylo-oligosaccharide. In the step described below, the neutral xylo-oligosaccharide contained in this liquid layer can be separated and purified. Separation and Purification Stage
[0090] The first stage may additionally comprise a separation and purification stage carried out after the depolymerization stage. When the first stage comprises the filtration stage described above, a separation and purification stage is preferably provided after the filtration stage.
[0091] Fig. 2 is a flowchart in which a filtration step is provided after the depolymerization step and a separation and purification step is provided after the filtration step. The first step may include a separation and purification step immediately after the depolymerization step. However, the first step preferably includes a filtration step performed after the depolymerization step; and includes a step to separate neutral xylo-oligosaccharide from the filtrate obtained and to purify the neutral xylo-oligosaccharide. The filtration step may be provided as part of the separation and purification step; or it may be provided as a step that is independent of the separation and purification step, as shown in Fig. 2. The separation and purification step is a step to separate and purify neutral xylo-oligosaccharide.Since the filtrate obtained in the filtration step contains various saccharides, such as acidic xylo-oligosaccharide, in addition to neutral xylo-oligosaccharide, the separation and purification step is also a step for removing xylo-oligosaccharides other than neutral xylo-oligosaccharide. Petition 870260074260, dated 07 / 24 / 2026, page 34 / 119 / 37
[0092] In the separation and purification step, for example, ion-exchange chromatography, affinity chromatography, gel filtration, ion-exchange treatment, NF membrane treatment, UF membrane treatment, RO membrane treatment, activated carbon treatment, or similar methods are preferably used. In the separation and purification step, it is also preferable to perform the above methods in combination. In particular, when ion-exchange chromatography is performed in the separation and purification, neutral xylo-oligosaccharide can be selectively separated and purified. In ion-exchange chromatography, acidic xylo-oligosaccharide is adsorbed; consequently, neutral xylo-oligosaccharide can be mainly obtained from the permeate. More specifically, the sugar liquid is first treated with a strong cation exchange resin to remove metal ions from the sugar liquid.Subsequently, using a strong anion exchange resin, sulfate or similar ions are removed from the sugar liquid. The resulting sugar liquid is treated with a weak anion exchange resin to adsorb the acidic xylooligosaccharide onto the resin. Concentration Stage
[0093] The first stage may also include a concentration stage. The concentration stage is preferably provided, for example, after the filtration stage and before the separation and purification stage, as shown in Figure 2. When the first stage includes such a concentration stage, the separation and purification stage can be carried out more efficiently, thus increasing the production efficiency of pentosan polysulfate.
[0094] Examples of the concentration step include a membrane treatment step using an NF membrane, an ultrafiltration membrane, a reverse osmosis membrane, or the like; a concentration step using evaporation, etc.; and the like. Petition 870260074260, dated 07 / 24 / 2026, page 35 / 119 / 37
[0095] In the concentration step, the solution is preferably concentrated so that the content of neutral xylo-oligosaccharide is 10% or more and 80% or less, and more preferably 20% or more and 60% or less, based on the total mass of the concentrate. Dehydration Stage
[0096] In the first step, neutral xylo-oligosaccharide can be obtained in the form of a neutral xylo-oligosaccharide solution; or it can be subjected to a dehydration step and thus obtained in the form of a neutral xylo-oligosaccharide concentrate or a neutral xylo-oligosaccharide powder. When a neutral xylo-oligosaccharide powder is to be produced, the production method preferably additionally comprises a pulverization step carried out after the separation and purification step. When a dehydration step is included in the present invention, the sulfation in the sulfation step described below can be carried out more efficiently.
[0097] In the pulverization stage, the neutral xylo-oligosaccharide solution obtained in the separation and purification stage is treated, for example, using a spray dryer, a freeze-drying machine, a hot air drying machine or a water-soluble organic solvent, in order to obtain a neutral xylo-oligosaccharide powder. Second Stage Sulfation Stage
[0098] The neutral xylo-oligosaccharide obtained in the first step is sulfated in a second step to obtain pentosan polysulfate. That is, the second step comprises a sulfation step.
[0099] The average degree of polymerization of the neutral xylo-oligosaccharide to be subjected to sulfation is preferably adjusted, as appropriate, according to the molecular weight of pentosan polysulfate to be obtained as a final product. Petition 870260074260, dated 07 / 24 / 2026, page 36 / 119 / 37
[00100] The average degree of polymerization of neutral xylo-oligosaccharides can be calculated by dividing the total sugar content of the neutral xylo-oligosaccharide by the amount of reducing sugar. To calculate the total sugar content, first, a solution of acidic xylo-oligosaccharide is maintained at 50°C and centrifuged at 15000 rpm for 15 minutes. Then, the total sugar content of the supernatant is quantified using the phenol-sulfuric acid method (“Kangento no Teiryo-Ho (Method for Quantifying Reducing Sugars)”; published by Gakkai Shuppan Center). The calibration curve to be used in the quantification is produced using D-xylose (Wako Pure Chemical Industries, Ltd.). The amount of reducing sugar is quantified using the Somogyi-Nelson method (“Kangento no Teiryo-Ho (Method for Quantifying Reducing Sugar)”; published by the Gakkai Shuppan Center). The calibration curve to be used in this quantification is also produced using D-xylose (Wako Pure Chemical Industries, Ltd.).
[00101] In the sulfation step, sulfuric acid or a sulfuric acid derivative is added to the neutral xylo-oligosaccharide solution to sulfate the neutral xylo-oligosaccharide. Examples of sulfuric acid derivatives include pyridine sulfur trioxide complex, chlorosulfonic acid, and the like. In this step, the concentration of the neutral xylo-oligosaccharide solution is preferably 0.1% by mass or more and 20% by mass or less, and sulfuric acid is preferably added to the neutral xylo-oligosaccharide solution having such a concentration in an amount of 0.1% by mass or more and 50% by mass or less. The neutral xylo-oligosaccharide solution after the addition of sulfuric acid preferably has a pH of 7 or more. Post-Sulfation Purification Stage
[00102] The second stage may additionally comprise a post-sulfation purification stage carried out after sulfation. When the second stage includes such a post-sulfation purification stage, a Petition 870260074260, dated 07 / 24 / 2026, page 37 / 119 / 37 high-purity pentosan polysulfate can be obtained.
[00103] In the post-sulfation purification step, for example, centrifugation, membrane filtration, dialysis, treatment with water-soluble organic solvent, treatment with activated carbon or similar methods are preferably used. Among these, treatment with water-soluble organic solvent and treatment with activated carbon are preferably used because the sulfonated pentosan polysulfate can be selectively separated and purified. Spraying stage
[00104] In the second stage, the sulfated pentosan polysulfate can be obtained in the form of a pentosan polysulfate solution; or it can be subjected to a pulverization step and thus obtained in the form of a pentosan polysulfate powder. When a pentosan polysulfate powder is to be produced, the second stage preferably additionally includes a pulverization step carried out after the post-sulfation purification step.
[00105] In the pulverization stage, the pentosan polysulfate solution obtained in the post-sulfation purification stage can be treated, for example, using a spray dryer, a freeze-drying machine, a hot air drying machine, a water-soluble organic solvent or the like, in order to obtain a pentosan polysulfate powder.
[00106] Pentosan polysulfate is obtained by carrying out the second step described above. The pentosan polysulfate thus obtained preferably has a sulfur content of 10% by mass or more to 20% by mass or less, based on the total mass of the pentosan polysulfate. The sulfur content of the pentosan polysulfate can be measured by the oxygen flask combustion method of the General Tests of the Japanese Pharmacopoeia. Petition 870260074260, dated 07 / 24 / 2026, page 38 / 119 / 37 Deacetylation Step
[00107] In the production of pentosan polysulfate, deacetylation can be performed. The deacetylation step is preferably carried out at any stage after the depolymerization step. The deacetylation step can reduce the acetyl group content of pentosan polysulfate. Specifically, the deacetylation step is a step of adding a base to a solution containing a substance obtained from a plant-derived feedstock, such as neutral xylo-oligosaccharide (also referred to herein as a “solution containing neutral xylo-oligosaccharide or similar”) in order to adjust the solution to pH 11 or higher.In the deacetylation step, the solution obtained after depolymerization, the filtrate obtained from the filtration step, the solution containing neutral xylo-oligosaccharide after the separation and purification step and before the sulfation step, the solution containing neutral xylo-oligosaccharide after the sulfation step (pentosan polysulfate), or similar solutions, can be adjusted to a pH of 11 or higher. Among these solutions, when the solution containing neutral xylo-oligosaccharide after the separation / purification step and before the sulfation step is adjusted to pH 11 or higher, a pentosan polysulfate having stable quality and a reduced acetyl group content can be obtained, and the sites where acetyl groups were attached can also be sulfated. Therefore, the sulfation efficiency and thus the efficiency of producing pentosan polysulfate can be increased.When the solution containing neutral xylo-oligosaccharide obtained after the sulfation step (pentosan polysulfate) is adjusted to pH 11 or higher, the purification step can be carried out more efficiently. The solution containing neutral xylo-oligosaccharide or similar is preferably an aqueous solution. The solution containing neutral xylo-oligosaccharide may also be referred to here as the neutral xylo-oligosaccharide solution.
[00108] The pH applied in the deacetylation step is preferably pH Petition 870260074260, dated 24 / 07 / 2026, pp. 39 / 119 / 37 to 14, and more preferably pH 12 to 13. The solution to be subjected to the deacetylation step is preferably maintained at pH 11 or higher for 0.5 hours or more, more preferably at pH 11 or higher for 1.0 hour or more, even more preferably at pH 11 or higher for 2.0 hours or more, and particularly preferably at pH 11 or higher for 3.0 hours or more. In particular, when the pH is less than 12, the solution is preferably maintained for 1.0 hour or more. Particularly preferred conditions may be, for example, conditions in which the solution is maintained at pH 12 to 13 for 3 hours or more.
[00109] While the solution is maintained within the pH range described above, the solution is preferably stirred. The temperature applied while the solution is maintained within the pH range described above is not particularly limited, but is preferably room temperature.
[00110] In the deacetylation step, a base may be added to a solution to be subjected to the deacetylation step (a solution containing neutral xylo-oligosaccharide or similar). The base to be added is not particularly limited, provided that the desired pH can be achieved. The base is preferably sodium hydroxide.
[00111] The deacetylation step may comprise a pH adjustment step of adjusting, to less than pH 11, the pH of a solution that has a pH of 11 or higher, resulting from the addition of a base after being maintained at the pH described above. In the pH adjustment step, the solution may be adjusted, for example, to pH 9 or less, pH 8 or less, pH 7 or less, pH 6 or less, pH 5 or less, or pH 4 or less. The adjustment may be carried out by adding an acid. Examples of usable acids include hydrochloric acid.
[00112] The deacetylation step preferably comprises a desalination step carried out after the pH adjustment step. Desalination may be carried out, for example, using a dialysis membrane or an NF membrane. Petition 870260074260, dated 07 / 24 / 2026, page 40 / 119 / 37
[00113] The deacetylation step may additionally comprise a step of pulverizing the product obtained for subsequent treatment. Other Steps Molecular weight adjustment step
[00114] The method for producing pentosan polysulfate may additionally comprise a molecular weight adjustment step between the first and second steps. When the method for producing pentosan polysulfate includes a deacetylation step, the molecular weight adjustment step may be performed before or after the deacetylation step. Fig. 2 is a flow diagram including a molecular weight adjustment step between the first and second steps. As shown in Fig. 2, in the molecular weight adjustment step, the molecular weight of the neutral xylo-oligosaccharide obtained in the first step is adjusted. For example, in the molecular weight adjustment step, the molecular weight of the neutral xylo-oligosaccharide may be reduced.
[00115] In the molecular weight adjustment step, a pentosan polysulfate having a weighted average molecular weight of 1000 or more and 30000 or less can be obtained by performing, for example, acid treatment, alkaline treatment, enzymatic treatment, NF membrane treatment, UF membrane treatment, RO membrane treatment, gel filtration treatment, activated carbon treatment, ion exchange treatment, electrodialysis treatment or similar treatments. It is also possible to use a method of selectively collecting pentosan polysulfate having a desired weighted average molecular weight by performing membrane treatment or similar treatments in the molecular weight adjustment step. Post-Molecular Weight Adjustment Separation and Purification Step
[00116] The method for producing pentosan polysulfate may further comprise a post-molecular weight adjustment separation and purification step carried out after the molecular weight adjustment step. Examples of the post-molecular weight adjustment separation and purification step Petition 870260074260, dated 07 / 24 / 2026, page 41 / 119 / 37 may include gel filtration, ion exchange treatment, NF membrane treatment, UF membrane treatment, RO membrane treatment, electrodialysis treatment, activated carbon treatment, water-soluble organic solvent treatment, chromatographic treatment and the like. When the production method includes such a separation and purification step after molecular weight adjustment, the neutral xylo-oligosaccharide having a desired molecular weight obtained in the molecular weight adjustment step can be selectively collected and the pentosan polysulfate having a narrow molecular weight distribution can be efficiently obtained. Examples
[00117] The features of the present invention are described below in more detail with reference to the Production Examples. The materials, quantities used, proportions, treatment content, treatment procedures and the like described in the following Production Examples may be appropriately changed to the extent that such changes do not depart from the spirit of the present invention. Consequently, the scope of the present invention should not be interpreted as being limited by the following specific examples. Production of Neutral Xylo-oligosaccharide
[00118] Forty parts by mass of water were added to 10 parts by mass of wood chips (hardwood) and a heat treatment was carried out at 160°C for 3 hours. The resulting mixture was then subjected to solid-liquid separation using a screw press (manufactured by Shinryo Seisakusho: 250 x 1000 SPH-EN) and the filtrate was recovered. The filtrate was filtered through a bag filter with a micron rate of 1 μm (manufactured by ISP Filters). Then 5 parts by mass of activated carbon (PM-SX; manufactured by Mikura Kasei Kabushiki Kaisha) was added to the filtrate obtained and a treatment was allowed to proceed at 50°C for 2 hours; the reaction mixture, including the activated carbon, was filtered. Petition 870260074260, dated 07 / 24 / 2026, page 42 / 119 / 37 additionally filtered through a ceramic filter with a micron rating of 0.2 μm (manufactured by Nihon Pall Co., Ltd.) to recover a clear filtrate. The clear filtrate was then concentrated 20 times with a reverse osmosis membrane (NTR-7450; manufactured by Nitto Denko Corporation) to obtain a concentrated sugar liquid. This concentrated sugar liquid was passed through SV 1.5 via a 4-bed, 4-tower ion exchange resin system consisting of a strong cationic resin (PK-218; manufactured by Mitsubishi Chemical Corporation), a weak anionic resin (WA30; manufactured by Mitsubishi Chemical Corporation), a strong cationic resin (PK-218; manufactured by Mitsubishi Chemical Corporation), and a weak anionic resin (WA30; manufactured by Mitsubishi Chemical Corporation) to recover a neutral xylooligosaccharide solution.Sodium hydroxide was added to the neutral xylooligosaccharide solution obtained to achieve a pH of 13, and the resulting mixture was stirred at room temperature for 3 hours for deacetylation. Then hydrochloric acid was added to the solution to obtain a pH of less than 5, and the resulting salt was removed using a dialysis membrane (Spectra / Por 7, CE membrane, MWCO 100-500; manufactured by Spectrum). The resulting mixture was pulverized using a freeze-drying machine (manufactured by Eyela). Xylo-oligosaccharide Production
[00119] Forty parts by mass of water were added to 10 parts by mass of wood chips (hardwood) and a heat treatment was carried out at 160°C for 3 hours. The resulting mixture was then subjected to solid-liquid separation using a screw press (manufactured by Shinryo Seisakusho: 250 x 1000 SPH-EN) and the filtrate was recovered. The filtrate was further filtered through a bag filter with a micron rate of 1 μm (manufactured by ISP Filters). Then 5 parts by mass of activated carbon (PM-SX; manufactured by Mikura Kasei Kabushiki) were added. Petition 870260074260, dated 07 / 24 / 2026, page 43 / 119 / 37 Kaisha) were added to treat the filtrate at 50°C for 2 hours. The reaction mixture, including the activated carbon, was further filtered through a ceramic filter with a micron rate of 0.2 μm (manufactured by Nihon Pall Co., Ltd.) to recover a clear filtrate. The clear filtrate was then concentrated 20 times with a reverse osmosis membrane (NTR7450; manufactured by Nitto Denko Corporation) to obtain a concentrated sugar liquid. The concentrated sugar liquid was passed at SV 1.5 through a 4-bed 4-tower ion exchange resin system consisting of a strong cationic resin (PK-218; manufactured by Mitsubishi Chemical Corporation), a weak anionic resin (WA30; manufactured by Mitsubishi Chemical Corporation), a strong cationic resin (PK-218; manufactured by Mitsubishi Chemical Corporation), and a weak anionic resin (WA30; manufactured by Mitsubishi Chemical Corporation).Acidic xylooligosaccharide was adsorbed onto the weak anionic resin of the second and fourth towers. A 50 mM aqueous solution of sodium chloride was then passed through the second and fourth towers at SV 1.5 to recover an acidic xylooligosaccharide solution. Sodium hydroxide was added to the resulting acidic xylooligosaccharide solution to achieve a pH of 13, and the resulting mixture was stirred at room temperature for 3 hours for deacetylation. Then hydrochloric acid was added to the resulting solution to achieve a pH of less than 5, and desalting was performed using a dialysis membrane (Spectra / Por 7, CE membrane, MWCO 100-500; manufactured by Spectrum). The resulting mixture was then sprayed using a freeze-drying machine (manufactured by Eyela). Production of Sodium Pentosan Polysulfate Example 1
[00120] 25 mL of N,N-dimethylformamide, 12.4 g of pyridine sulfur trioxide complex and 1.5 g of neutral xylo-oligosaccharide powder produced by the method described above were placed in a flask. Petition 870260074260, dated 07 / 24 / 2026, page 44 / 119 / 37 separable 100 mL and a reaction was allowed to proceed at 40°C for 3 hours. After cooling, the resulting reaction mixture was added dropwise to 500 mL of ethanol. The precipitate generated was collected by filtration and 30 mL of water were added to dissolve the precipitate at this point. A sodium hydroxide solution was added to the resulting solution to achieve a pH of 10. The resulting solution was added dropwise to 500 mL of ethanol and the precipitate obtained was then collected by filtration. Next, 30 mL of water were added to dissolve the precipitate at this point; and activated carbon was added to the solution and stirred, followed by filtration. The filtrate was concentrated using an evaporator and pulverized using a freeze-drying machine (manufactured by Eyela). Example 2
[00121] Sodium pentosan polysulfate was obtained in the same manner as in Example 1, except that a mixture of 1.125 g of neutral xylo-oligosaccharide powder and 0.375 g of acidic xylo-oligosaccharide was used instead of 1.5 g of neutral xylo-oligosaccharide powder from Example 1. Example 3
[00122] Sodium pentosan polysulfate was obtained in the same manner as in Example 1, except that a mixture of 0.75 g of neutral xylo-oligosaccharide powder and 0.75 g of acidic xylo-oligosaccharide was used instead of 1.5 g of neutral xylo-oligosaccharide powder from Example 1. Comparative Example 1
[00123] Sodium pentosan polysulfate was obtained in the same manner as in Example 1, except that a mixture of 0.375 g of neutral xylo-oligosaccharide powder and 1.125 g of acidic xylo-oligosaccharide was used instead of 1.5 g of neutral xylo-oligosaccharide powder from Example 1. Comparative Example 2
[00124] Sodium pentosan polysulfate was obtained in the same manner as in Example 1, except that acid xylo-oligosaccharide powder was used in Petition 870260074260, dated 07 / 24 / 2026, page 45 / 119 / 37 place of the neutral xylo-oligosaccharide powder from Example 1. Uronic Acid Content
[00125] Approximately 10 mg of sodium pentosan polysulfate obtained from each of the Examples were weighed and dissolved in distilled water to make up the volume to exactly 25 mL. 1 mL of each solution was placed in a test tube. While the solution was cooled in ice water, 5 mL of a 0.025 M sodium tetraborate solution in sulfuric acid was added and mixed, and the resulting mixture was heated in a water bath for 10 minutes. Immediately after heating, the resulting mixture was cooled in ice, and 0.2 mL of a carbazole reagent was added and mixed. The resulting mixture was heated in a water bath for 15 minutes and then allowed to cool to obtain a sample solution. Separately, standard stock solutions of glucuronic acid at a concentration of 10 to 100 μg / mL were prepared and subjected to the same procedure as above to obtain standard solutions.1 mL of distilled water was also subjected to the same procedure, and the resulting liquid was used as a control. The absorbance at a wavelength of 530 nm was measured. Calibration curves were prepared from the absorbance of the standard solutions, and the amount of glucuronic acid (μg) was determined. The uronic acid content (% by mass) was calculated according to the following formula. When the quantitative value was negative, it was considered to be 0%. Uronic Acid Content (% by mass) = Amount of glucuronic acid (μg) / (Weighed amount of sodium pentosan polysulfate (mg) x 1 / 25) / 10 Sulfur content
[00126] The sulfur content was measured by the oxygen flask combustion method described in the Japanese Pharmacopoeia. Average Molecular Weight
[00127] The weighted average molecular weight (Mw) of polysulfate Petition 870260074260, dated 07 / 24 / 2026, page 46 / 119 / 37 pentosan was measured by GPC (gel permeation chromatography). A YMC-Pack Diol-300 and YMC-Pack Diol-60 (both manufactured by YMC) connected to each other can be used as a GPC column. The GPC was performed under the following conditions.
[00128] Eluent: 25 mM potassium dihydrogen phosphate / 25 mM dipotassium hydrogen phosphate / 50 mM potassium chloride Flow rate: 0.7 mL / min Measurement temperature: 40°C. Detector: refractive index detector. Table 1 Comparative Example 2 Comparative Example 1 Example 3 Example 2 Example 1 Weighted average molecular weight 2781 2487 2387 2168 2053 Uronic acid content (% by mass) 12.61 7.94 5.67 1.64 0.00 Sulfur content (% by mass) 13.28 14.33 15.12 15.09 15.34 Anti-II activity (IU / mg) 0.3361 0.2398 0.1722 0.1254 0.0301 Anti-Xa activity (IU / mg) 0.2246 0.2260 0.2563 0.2579 0.2381 Anti-Xa / anti-II activity ratio 0.668 0.942 1,488 2,056 7,910
[00129] Figs. 3 and 4 are graphs showing the relationship between uronic acid content and anti-IIa activity, anti-Xa activity or anti-Xa / anti-IIa activity ratio of each sodium pentosan polysulfate obtained in the Examples and Comparative Examples above.
[00130] As can be seen from the results shown in Table 1 and Fig. 4, the lower the uronic acid content, the higher the anti-Xa / anti-IIa activity ratio. Table 2 Comparative Example 2 Comparative Example 1 Example 3 Example 2 Example 1 Yield (g) 2.40 2.24 2.89 3.02 3.85
[00131] Table 2 shows the yields when sodium pentosan polysulfate powder was obtained from xylo-oligosaccharide powder. The results in Table 2 clearly show that, as the uronic acid content was lower, sodium pentosan polysulfate was obtained in a Petition 870260074260, dated 07 / 24 / 2026, page 47 / 119 / 37 larger quantity (with a higher yield). Stability
[00132] 2 mL of a 100 mg / mL aqueous solution of sodium pentosan polysulfate were placed in a 5 mL vial and stored at 40°C for 4 weeks. The appearance properties of the solution were confirmed. Table 3 Example 2 Example 1 Example 3 Example 2 Example 1 Solution appearance properties (initial) Transparent colorless Transparent colorless Transparent colorless Transparent colorless Transparent colorless Solution appearance properties (2 weeks of storage at 40°C) Slightly yellow transparent Slightly yellow transparent Transparent colorless Transparent colorless Transparent colorless
[00133] The results in Table 3 clearly show that aqueous solutions of sodium pentosan polysulfate having a high uronic acid content (Comparative Examples 1 and 2) turned yellow after storage at 40°C for 4 weeks; whereas aqueous solutions of sodium pentosan polysulfate having a low uronic acid content (Examples 1 to 3) showed no change and were stable. This result suggests that the pentosan polysulfate of the present invention (including pentosan polysulfate in other forms, such as a powder) is less susceptible to the adverse effects of moisture and is highly stable. Petition 870260074260, dated 07 / 24 / 2026, page 48 / 119
Claims
1 / 5 CLAIMS 1. Pentosan polysulfate having β-Dxylopyranose units, characterized in that the pentosan polysulfate has an acetyl group content of 0% by mass to 2.0% by mass and a uronic acid content of 0.0% by mass to 2.0% by mass; a pharmaceutically acceptable salt of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate.
2. Pentosan polysulfate according to claim 1, characterized in that the pentosan polysulfate has a uronic acid content of 0.0% by mass; a pharmaceutically acceptable salt of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate.
3. Pentosan polysulfate having β-D-xylopyranose units, characterized in that the pentosan polysulfate has an acetyl group content of 0% by mass to 2.0% by mass and a uronic acid content of 0.0% by mass to 6.0% by mass and a structure represented by Formula II: Formula II wherein R1 each independently represents a hydrogen atom, -COCH3 or -SO3X1 and at least one R1 in the molecule is Petition 870260074260, dated 07 / 24 / 2026, page.49 / 119 2 / 5 SO3X1, wherein X1 represents a hydrogen atom or a monovalent or divalent metal; n1 and n2 each independently represents 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 of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate.
4. Pentosan polysulfate according to claim 3, characterized in that the pentosan polysulfate is represented by Formula I: n Formula I wherein each R independently represents a hydrogen atom, -COCH3 or -SO3X and at least one R is -SO3X, wherein X represents a hydrogen atom or a monovalent or divalent metal; en is an integer from 4 to 30; a pharmaceutically acceptable salt of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate.
5. Pentosan polysulfate according to claim 4, characterized in that each R independently represents a hydrogen atom or -SO3X; a pharmaceutically acceptable salt of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate.
6. Pentosan polysulfate according to claim 4 or 5, characterized in that X is sodium; a pharmaceutically acceptable salt of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate.
7. Pharmaceutical composition, characterized in that it comprises pentosan polysulfate as defined in any one of claims 1 to 6; a pharmaceutically acceptable salt of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate.
8. Pharmaceutical composition according to claim 7, characterized in that it is an anticoagulant pharmaceutical composition.
9. Use of a pentosan polysulfate compound, characterized in that it is for the manufacture of a medicament for use in inhibiting blood coagulation, wherein the pentosan polysulfate compound is pentosan polysulfate as defined in any one of claims 1 to 6; a pharmaceutically acceptable salt of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate. Petition 870260074260, dated 24 / 07 / 2026, p. 51 / 119 4 / 5 10. Use of a pharmaceutical composition, characterized in that it is used as a surface treatment agent for medical devices or medical materials, wherein the pharmaceutical composition comprises pentosan polysulfate as defined in any one of claims 1 to 6; a pharmaceutically acceptable salt of pentosan polysulfate; or a hydrate of pentosan polysulfate or of the pharmaceutically acceptable salt of pentosan polysulfate.
11. Method for producing pentosan polysulfate as defined in any one of claims 1 to 6, characterized in that it comprises: a first step of obtaining a neutral xylo-oligosaccharide from a plant-derived raw material; and a second step of obtaining pentosan polysulfate from the neutral xylo-oligosaccharide, the first step comprising a step of depolymerizing the plant-derived raw material and the second step comprising a step of sulfatedating the neutral xylo-oligosaccharide.
12. Method for producing pentosan polysulfate, according to claim 11, characterized in that the depolymerization step is a heat treatment step.
13. Method for producing pentosan polysulfate, according to claim 12, characterized in that the heat treatment step is a heating step at 120 °C or higher under non-alkaline conditions.
14. Method for producing pentosan polysulfate, according to any one of claims 11 to 13, characterized in that the plant-derived raw material is a wood-derived raw material. Petition 870260074260, dated 07 / 24 / 2026, p. 52 / 119 5 / 5 Petition 870260074260, dated 07 / 24 / 2026, p. 53 / 119