WO2021060395A1

WO2021060395A1 - Sustained-release pharmaceutical composition

Info

Publication number: WO2021060395A1
Application number: PCT/JP2020/036101
Authority: WO
Inventors: 弓夫工藤; 暁劉; 勲櫻田; 二郎広瀬
Original assignee: 持田製薬株式会社
Priority date: 2019-09-25
Filing date: 2020-09-24
Publication date: 2021-04-01

Abstract

Provided is a sustained-release pharmaceutical composition that contains a NSAIDs-linked polysaccharide derivative represented by formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, and that has good physical characteristics. The present invention pertains to a sustained-release pharmaceutical composition containing a non-steroidal, anti-inflammatory compound-linked polysaccharide derivative represented by formula (I): [in formula (I), -L¹- represents a linker, (A) represents one residue of a non-steroidal, anti-inflammatory compound, (SG) represents one residue derived from a polysaccharide or a salt thereof, (A) is ester-linked, at the carboxyl group in the structure thereof, to the -O- group side of -O-L¹- or (SG) is amide-linked, at any of the carboxyl groups in the structure thereof, to the amino group or imino group on the -L¹- group side of the -O-L¹-], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Description

Sustained release pharmaceutical composition

In the present invention, an NSAIDs-binding polysaccharide derivative in which alginic acid and a non-steroidal anti-inflammatory compound (hereinafter, also referred to as NSAIDs) are bound via a linker, a pharmaceutically acceptable salt thereof, or a solvent thereof. The present invention relates to a sustained-release pharmaceutical composition containing a Japanese product.

As shown in International Publication No. 2005/66241 (Patent Document 1), NSAIDs-linked polysaccharide derivatives having a structure in which a polysaccharide or a salt thereof is covalently bonded with a linker are known. It is expected that the pharmaceutical composition containing the polysaccharide derivative can be delivered to the affected area while slowly releasing NSAIDs.

Patent Document 1 and BMC Musculoskelet Disord. 2018; 19: 157. (Non-Patent Document 1) discloses a derivative in which hyaluronic acid and NSAIDs are covalently bonded with a linker.

In WO2015 / 05458 (Patent Document 2), glycosaminoglycans in which certain drugs (for example, NSAIDs, steroids, anti-rheumatic drugs, etc.) having a controllable drug release rate are chemically introduced are introduced. Noglycan derivatives are disclosed.

US Patent Application Publication No. 2019/0184023 (Patent Document 3) was prepared with a citrate buffer (pH = 4.0 or 5.0) or a phosphate buffer (pH = 6.5). The composition of 1% (w / v) diclofenac (2-aminoethanol) -hyaluronic acid is disclosed. However, the composition disclosed in Patent Document 3 is not a composition further containing a component selected from the group consisting of a pH adjuster, an isotonic agent, a stabilizer and a surfactant.

International Publication No. 2005/66241 International Publication No. 2015-05458 U.S. Patent Application Publication No. 2019/0184023

The subject of the present invention is a sustained release property having good physical characteristics containing an NSAIDs-binding polysaccharide derivative represented by the formula (I) described in detail below, a pharmaceutically acceptable salt thereof, or a solvate thereof. To provide a pharmaceutical composition.

More specifically, the subject of the present invention is, in the sustained-release pharmaceutical composition, (1) an NSAIDs-binding polysaccharide derivative represented by the formula (I) under storage conditions, or a pharmaceutically acceptable one thereof. The sustained-release pharmaceutical composition in which the release of NSAIDs is controlled rather than a simple aqueous solution of a salt or a solvate thereof, (2) an NSAIDs-binding polysaccharide derivative represented by the formula (I) under storage conditions. Alternatively, it is to provide a method for long-term stabilization of the pharmaceutically acceptable salt thereof, or a solvate thereof.

The present inventors have conducted extensive research in order to solve the above problems. As a result, by adding a specific component, (1) under storage conditions, from the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a mixture thereof. , The sustained-release pharmaceutical composition in which the release of NSAIDs (diclofenac) is controlled, (2) NSAIDs-binding polysaccharide derivative represented by the formula (I) under storage conditions, or a pharmaceutically acceptable salt thereof. , Or their solvates and / or diclofenac-linked alginic acid derivatives represented by the formula (I-c-1), or pharmaceutically acceptable salts thereof, or amides derived from NSAIDs from their solvates. For example, the sustained-release pharmaceutical composition in which the production of diclofenacamide) is suppressed, the NSAIDs-binding polysaccharide derivative represented by the formula (3) (I), or a pharmaceutically acceptable salt thereof, or a solvent thereof. The sustained-release pharmaceutical composition in which low molecular weight of the polysaccharide is suppressed in a Japanese product (however, the polysaccharide is alginic acid, etc.), (4) the sustained-release pharmaceutical composition that is stable for a long period of time, (5) storage. Under the conditions, the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a long-term stabilization method of a mixture thereof, and represented by the formula (6) (I). The present invention is completed based on the finding of a sustained-release pharmaceutical composition containing the NSAIDs-binding polysaccharide derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a method for producing the same. It came to.

(1) "Control of NSAIDs / diclofenac release"
One aspect of the sustained-release pharmaceutical composition of the present invention is a polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or one of solvates thereof, and a buffer. It contains at least one component selected from the group consisting of pH adjusters, tonicity agents, stabilizers and surfactants. Further, one aspect of the sustained release pharmaceutical composition of the present invention has a pH range of, for example, 4.5 to 6.5. In such pharmaceutical compositions, under storage conditions, NSAIDs, especially diclofenac, can be found from the NSAIDs-binding polysaccharide derivative of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof alone. Release can be controlled.

(2) "Suppression of diclofenac amide production"
One aspect of the sustained-release pharmaceutical composition of the present invention is a polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof (where NSAIDs are diclofenac). It also contains at least one component selected from the group consisting of buffers, pH regulators, tonicity agents, stabilizers and surfactants. Further, one aspect of the sustained release pharmaceutical composition of the present invention has a pH range of, for example, 4.5 to 6.5. In such a liquid pharmaceutical composition, the production of diclofenac amide can be suppressed under storage conditions.

(3) "Suppression of low molecular weight alginic acid"
One aspect of the sustained-release pharmaceutical composition of the present invention is a polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof (provided that the polysaccharide is alginic acid). It also contains at least one component selected from the group consisting of buffers, pH regulators, tonicity agents, stabilizers and surfactants. Further, one aspect of the sustained release pharmaceutical composition of the present invention has a pH range of, for example, 4.5 to 6.5. In such a liquid pharmaceutical composition, low molecular weight alginic acid can be suppressed under storage conditions.

(4) "Long-term stable sustained-release pharmaceutical composition"
One aspect of the sustained release pharmaceutical composition of the present invention has a pH range of 4.5 to 6.5. A more specific embodiment is, for example, a group of a medical container (glass, plastic, etc. injection tube, etc.) filled with a buffer, a pH adjuster, an isotonic agent, a stabilizer, and a surfactant. A composition containing at least one component selected from the above and having a pH range of 4.5 to 6.5. In addition, a more specific embodiment comprises a group consisting of a glass or plastic medical container (injection cylinder), and a buffer, a pH adjuster, an isotonic agent, a stabilizer, and a surfactant. It contains at least one selected component and its pH range is in the range of 4.5-6.5. Such sustained release pharmaceutical compositions can be stable over the long term.

According to the present invention, NSAIDs-binding polysaccharide derivatives represented by the following formula (I), or pharmaceutically acceptable salts thereof, or solvates thereof, as well as buffers, pH adjusters, isotonic agents, and stables. Provided is a sustained-release pharmaceutical composition containing at least one component selected from the group consisting of an agent and a surfactant, which solves at least one or more of the above-mentioned problems such as long-term stability. ..

[In formula (I), -L1- represents a linker, (A) represents one residue of NSAIDs, and (SG) represents a residue derived from a polysaccharide or a salt thereof].

Preferably, a sustained release containing an NSAIDs-binding polysaccharide derivative represented by the following formulas (Ia) to (Ic-1), a pharmaceutically acceptable salt thereof, or a solvate thereof. Sustained-release pharmaceutical compositions containing pharmaceutical compositions are provided.

[In formulas (Ia) to (Ic-1), -L1- represents a linker, (A) represents one residue of NSAIDs, and (sg) represents chondroitin sulfate, dermatan sulfate, and heparin. , Heparin sulfate, keratan sulfate, or a polysaccharide selected from carboxymethyl cellulose, (HA) represents a hyaluronic acid residue, (DF) represents one residue of diclofenac, and (ALG) represents one residue. , Represents a residue of alginic acid]

In a sustained-release pharmaceutical composition of a preferred embodiment, the release of NSAIDs (such as diclofenac) is controlled under storage conditions (for example, about 2 to about 8 ° C.), and the production of diclofenac amide is suppressed when the NSAIDs are diclofenac. As a result, the reduction of molecular weight of polysaccharides, especially alginic acid, is suppressed within a certain range, and stable preparations can be obtained over a long period of time, which is highly industrially useful.

[Aspects of the present invention]
INDUSTRIAL APPLICABILITY The present invention provides a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.

Hereinafter, each aspect of the present invention will be specifically described. However, the present invention is not limited to the following embodiments, and can be implemented in any embodiment as long as the gist of the present invention is not deviated.

[1] The first aspect is the formula (I) :.

[In formula (I), (A) represents one residue of NSAIDs;
(SG) represents a residue derived from a polysaccharide or a salt thereof;
-L1- is the following formula (excluding the outside of the broken line in the formula):

Represents a linker selected from ((A) in formula (LK-B50) and formula (LK-B51) represents one residue of NSAIDs);
In (A), the carboxyl group in the structure is ester-bonded on the -O-group side of -O-L1-, and in (SG), any carboxyl group in the structure is -OL1-. -Made an amide bond with an amino group or imino group on the L1-group side]], an NSAIDs-linked polysaccharide derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as well as a buffer and pH adjustment. Provided is a sustained-release pharmaceutical composition containing at least one component selected from the group consisting of an agent, an tonicity agent, a stabilizer and a surfactant.

[1-1-1] In the above aspect [1], the formula (I) is preferably the following formula (Ia):

[In the formula (Ia), (A), and -L1- are the same as the definitions in the above aspect [1], and (sg) is chondroitin sulfate, dermatan sulfate, heparin, heparin sulfate, Represents a residue of a polysaccharide selected from keratan sulfate or carboxymethyl cellulose], an NSAIDs-linked polysaccharide derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-1-2] In the above aspect [1], the formula (I) is preferably the following formula (Ib):

[In formula (Ib), (A) and -L1- are the same as the definitions in the above aspect [1], and (HA) represents a residue of hyaluronic acid] NSAIDs binding. A hyaluronic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-1-3] In the above aspect [1], the formula (I) is preferably the following formula (Ic):

NSAIDs-linked alginic acid represented by [in formula (IC), (A), and -L1-is the same as the definition in the above aspect [1], and (ALG) represents a residue of alginic acid]. Derivatives, or pharmaceutically acceptable salts thereof, or solvates thereof.

[1-1-3-1] In the above aspect [1-1-3], the formula (I) is preferably the following formula (I-c-1):

[In the formula (I-c-1), -L1-is the same as the definition in the above-mentioned embodiment [1], (DF) represents a residue of diclofenac, and (ALG) is a residue of alginic acid. It is a diclofenac-bonded alginic acid derivative represented by [representing], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[1-2] In the above aspect [1], (SG) is preferably at least one or more polysaccharides selected from the group consisting of glycosaminoglycans, polyuronic acid, and glucan derivatives; more preferably. , Hyaluronic acid, chondroitin sulfate, dermatane sulfate, heparin, heparan sulfate, keratan sulfate, alginic acid, and at least one polysaccharide selected from the group consisting of carboxymethyl cellulose; more preferably hyaluronic acid or alginic acid. Yes; particularly preferred is alginic acid.

[1-3] In the above aspects [1] to [1-1-3], (A) is preferably propionic acid-based NSAIDs, phenylic acid-based NSAIDs, and salicylic acid-based NSAIDs.
At least one NSAIDs selected from the group consisting of; more preferably ibuprofen, furrubiprofen, ketoprofen, naproxen, planoprofen, phenoprofen, thiaprofenic acid, oxaprozine, loxoprofen sodium, aluminoprofen. , Saltoprofen, thiaprofenic acid, fervinac, diclofenac, tolmethin sodium, slindak, fenbufen, indomethacin, acemetacin, amphenac sodium, mofezolac, etdrac, alcrofenac, salicylic acid, sazapyrin, aspirin, and diflunisal. The above NSAIDs; more preferably at least one NSAID selected from the group consisting of ketoprofen, naproxen, fervinac and diclofenac; most preferably diclofenac.

[1-4] In the above aspects [1] to [1 to 3], -L1- is preferably in the following formula (excluding the outside of the broken line in the formula):

(A) in the formula (LK-B50) and the formula (LK-B51) is the same as the definition described in the above aspects [1] to [1-3]).
More preferably, the following formula (excluding the outside of the broken line in the formula):

It is a linker selected from.

[1-5] In the above aspects [1] to [1-4], the NSAIDs-binding polysaccharide derivative is preferably composed of the following formula:

[In the formula (DF) represents one residue of diclofenac, the carboxyl group in its structure and the linker moiety are ester-bonded; (ALG) represents one residue of alginate, which is more specific. ALG is an arbitrary carboxyl group in the alginic acid structure, and this carboxyl group and the linker moiety are ester-bonded; (HA) represents one residue of hyaluronic acid, and more specifically, (HA) is an arbitrary carboxyl group in the hyaluronic acid structure, and is a derivative selected from "the carboxyl group and the linker moiety have an ester bond".

[1-5-1] In the above aspect [1-5], the NSAIDs-binding polysaccharide derivative is more preferably represented by the following formula:

[In the formula (DF) represents one residue of diclofenac, more specifically, a carboxyl group within the structure of diclofenac, and this carboxyl group and the linker moiety are ester-bonded; (ALG). Represents one residue of alginic acid, and more specifically, ALG is an arbitrary carboxyl group in the alginic acid structure, and this carboxyl group and the linker moiety have an ester bond. " ..

[1-5-2] In the above aspect [1-5], the NSAIDs-binding polysaccharide derivative is more preferably represented by the following formula:

[1-5-3] In the above aspect [1-5], the NSAIDs-binding polysaccharide derivative is most preferably the following formula:

[1-6-1] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are defined in the above aspect [1]. The same as the NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a component of any one of a buffer and a pH adjuster, a stabilizer. And a sustained-release pharmaceutical composition containing any one component of a surfactant and an tonicity agent.

[1-6-2] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. The same as the NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a component of any one of a buffer and a pH adjuster, a stabilizer. , And a sustained release pharmaceutical composition containing an isotonic agent.

[1-6-3] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are defined in the above aspect [1]. The same as the NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a component of any one of a buffer and a pH adjuster, a surfactant. , And a sustained release pharmaceutical composition containing an isotonic agent.

[1-6-4] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are defined in the above aspect [1]. NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and any one component of a buffer and a pH adjuster, and isotonic. A sustained-release pharmaceutical composition containing an agent.

[1-6-5] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. The same as the NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a component of any one of a stabilizer and a surfactant, and the like. A sustained-release pharmaceutical composition containing a tensioning agent.

[1-6-6] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. The same as], an NSAIDs-binding polysaccharide derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a sustained release containing a buffer, an isotonic agent, and a stabilizer. Sexual pharmaceutical composition.

[1-6-7] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pH adjuster, an tonicity agent, and a stabilizer. Release pharmaceutical composition.

[1-6-8] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. The same as], the NSAIDs-binding polysaccharide derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a sustained release containing a buffer, an isotonic agent, and a surfactant. Sexual pharmaceutical composition.

[1-6-9] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pH adjuster, an isotonic agent, and a surfactant. Release pharmaceutical composition.

[1-6-10] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. The same as NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a sustained-release pharmaceutical composition containing a buffer and an tonicity agent. ..

[1-6-11] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. The same as the NSAIDs-binding polysaccharide derivative represented by], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a sustained-release pharmaceutical composition containing a pH adjuster and an tonicity agent. Stuff.

[1-6-12] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. The same as], an NSAIDs-binding polysaccharide derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a sustained-release pharmaceutical composition containing an tonicity agent and a stabilizer. ..

[1-6-13] In the above aspect [1], preferably, the formulas (I) [in the formula (I), (A), -L1-, and (SG) are the definitions in the above aspect [1]. The same as], an NSAIDs-binding polysaccharide derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a sustained-release pharmaceutical composition containing an tonicity agent and a surfactant. ..

[1-7-1] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], Where (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a buffer. A sustained-release pharmaceutical composition containing any one component of an agent and a pH adjuster, any one component of a stabilizer and a surfactant, and an isotonic agent.

[1-7-2] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], Where (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a buffer. A sustained-release pharmaceutical composition containing any one component of an agent and a pH adjuster, a stabilizer, and an isotonic agent.

[1-7-3] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], Where (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a buffer. A sustained-release pharmaceutical composition containing any one of an agent and a pH adjuster, a surfactant, and an isotonic agent.

[1-7-4] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], Where (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a buffer. A sustained-release pharmaceutical composition containing any one of an agent and a pH adjuster, and an isotonic agent.

[1-7-5] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and stable. A sustained-release pharmaceutical composition containing any one of an agent and a surfactant, and an isotonic agent.

[1-7-6] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a buffer. A sustained-release pharmaceutical composition containing an agent, an isotonic agent, and a stabilizer.

[1-7-7] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and pH. A sustained-release pharmaceutical composition containing a regulator, an isotonic agent, and a stabilizer.

[1-7-8] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a buffer. A sustained-release pharmaceutical composition containing an agent, an isotonic agent, and a surfactant.

[1-7-9] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and pH. A sustained-release pharmaceutical composition containing a regulator, an isotonic agent, and a surfactant.

[1-7-10] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a buffer. A sustained-release pharmaceutical composition containing an agent and an isotonic agent.

[1-7-11] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and pH. A sustained-release pharmaceutical composition containing a regulator and an isotonic agent.

[1-7-12] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and the like. A sustained-release pharmaceutical composition containing a tensioning agent and a stabilizer.

[1-7-13] In the above aspect [1], preferably, in the formulas (Ic) [formula (Ic), (A), and -L1- are the above-mentioned aspects [1-1-3]. ], And (ALG) represents a residue of alginic acid], an NSAIDs-linked alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and the like. A sustained-release pharmaceutical composition containing a tensioning agent and a surfactant.

[1-8-1] In the above aspect [1], preferably, in the formula (Ic-1) [formula (Ic-1), -L1- is the above aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. Xu containing the salt, or a solvate thereof, and any one component of a buffer and a pH adjuster, one component of a stabilizer and a surfactant, and an isotonic agent. Release pharmaceutical composition.

[1-8-2] In the above aspect [1], preferably, in the formula (I-c-1) [formula (Ic-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, and any one component of a buffer and a pH adjuster, a stabilizer, and an tonicity agent.

[1-8-3] In the above aspect [1], preferably, in the formula (I-c-1) [formula (Ic-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, and any one component of a buffer and a pH adjuster, a surfactant, and an tonicity agent.

[1-8-4] In the above aspect [1], preferably, in the formula (I-c-1) [formula (Ic-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, one of a buffer and a pH adjuster, and an tonicity agent.

[1-8-5] In the above aspect [1], preferably, in the formula (I-c-1) [formula (I-c-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, one of a stabilizer and a surfactant, and an tonicity agent.

[1-8-6] In the above aspect [1], preferably, in the formula (I-c-1) [formula (I-c-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, and a buffer, an isotonic agent, and a stabilizer.

[1-8-7] In the above aspect [1], preferably, in the formula (Ic-1) [formula (Ic-1), -L1- is the above aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, and a pH adjuster, an tonicity agent, and a stabilizer.

[1-8-8] In the above aspect [1], preferably, in the formula (I-c-1) [formula (I-c-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, and a buffer, an isotonic agent, and a surfactant.

[1-8-9] In the above aspect [1], preferably, in the formula (Ic-1) [formula (Ic-1), -L1- is the above aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, a pH adjuster, an tonicity agent, and a surfactant.

[1-8-10] In the above aspect [1], preferably, in the formula (I-c-1) [formula (I-c-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, a buffer, and an tonicity agent.

[1-8-11] In the above aspect [1], preferably, in the formula (I-c-1) [formula (I-c-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, a pH adjuster, and an tonicity agent.

[1-8-12] In the above aspect [1], preferably, in the formula (I-c-1) [formula (I-c-1), -L1- is the above-mentioned aspect [1-1-3-3]. Same as the definition in 1], where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt, a solvate thereof, and an tonicity agent and a stabilizer.

[1-8-13] In the above aspect [1], preferably, in the formula (I-c-1) [formula (I-c-1), -L1- is the above-mentioned aspect [1-1-3-1]. ], Where (DF) represents a residue of diclofenac and (ALG) represents a residue of alginic acid], a diclofenac-linked alginic acid derivative, or a pharmaceutically acceptable one thereof. A sustained-release pharmaceutical composition containing a salt or a solvate thereof, and an tonicity agent and a surfactant.

[2] The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13], which has a pH of about 4.5 to about 6.5.

[2-1] In the above aspect [2], the pH is preferably about 4.8 to about 6.0, more preferably about 5.1 to about 5.5, and even more preferably. It is about 5.3.

[3] The above-mentioned aspects [1] to [3], wherein the buffer is at least one selected from the group consisting of an acetic acid-based buffer, a citric acid-based buffer, a phosphoric acid-based buffer, and a tartaric acid-based buffer. The sustained-release pharmaceutical composition according to any one of 1-8-13].

[3-1] In the above aspect [3], the buffer is preferably acetic acid, ammonium acetate, potassium acetate, sodium acetate, sodium acetate hydrate, citrate, sodium citrate, trisodium citrate, citrate. At least one selected from the group consisting of sodium hydrate, ammonium citrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, tartrate, sodium tartrate, and ammonium tartrate. A buffer containing more than one species; more preferably at least one selected from the group consisting of acetic acid, ammonium acetate, citrate, sodium citrate, sodium dihydrogen phosphate, and disodium hydrogen phosphate. It is a buffer contained; more preferably, a sodium acetate / sodium acetate buffer, a citrate / sodium citrate buffer, or a sodium dihydrogen phosphate / disodium hydrogen phosphate buffer.

[4] Any of the above embodiments [1] to [1-8-13], wherein the pH adjuster is at least one selected from the group consisting of an acid, an acid salt, a base, and a base salt. The sustained-release pharmaceutical composition according to item 1.

[4-1] In the above aspect [4], the pH adjusting agent is preferably acetic acid, citric acid, phosphoric acid, succinic acid, gluconic acid, malic acid, tartaric acid, lactic acid, boric acid, hydrochloric acid, adipic acid, malein. Acid, sulfuric acid, or carbonic acid, ammonium acetate, sodium acetate, sodium acetate hydrate, sodium citrate, sodium citrate hydrate, sodium dihydrogen citrate, sodium monohydrogen phosphate, sodium monohydrogen phosphate, seven waters Japanese product, disodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, disodium hydrogen phosphate, disodium hydrogen phosphate dihydrate, disodium phosphate, potassium dihydrogen phosphate, phosphoric acid Disodium dihydrogen, disodium succinate, disodium succinate hexahydrate, sodium tartrate, sodium lactate, ammonium borate, sodium borate, monosodium fumarate, sodium propionate, or potassium aluminum sulfate, triethanolamine , Megrumine, monoethanolamine, diisopropanolamine, triisopropanolamine, aqueous ammonia, sodium carbonate, sodium carbonate hydrate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, or magnesium hydroxide, and tromethamole hydrochloride A pH adjuster containing at least one selected from the group;
More preferably, acetic acid, citric acid, phosphoric acid, succinic acid, gluconic acid, malic acid, tartaric acid, lactic acid, boric acid, hydrochloric acid, adipic acid, maleic acid, ammonium acetate, sodium acetate, sodium acetate hydrate, citric acid. Sodium, sodium citrate hydrate, sodium dihydrogen citrate, sodium monohydrogen phosphate, sodium monohydrogen phosphate / heptahydrate, trisodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, Disodium hydrogen phosphate, disodium hydrogen phosphate dihydrate, dipotassium phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium succinate, disodium disodium hexahydrate, sodium tartrate, A pH adjuster containing at least one selected from the group consisting of sodium phosphate solution and ammonium borate;
More preferably, it is a pH regulator containing at least one selected from the group consisting of acetic acid, ammonium acetate, sodium acetate, and sodium acetate hydrate; most preferably sodium acetate and / or sodium acetate. ..

[5] The tonicity agent is selected from the group consisting of salts, sugars, sugar alcohols, polyhydric alcohols, phosphoric acid, citric acid, aminoethyl sulfonic acid, nicotinic acid amide, benzyl alcohol, boric acid, and boric acid. The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13], wherein the sustained-release pharmaceutical composition is at least one kind.

[5-1] In the above aspect [5], the tonicity agent is preferably sodium chloride, potassium chloride, magnesium chloride, citrate hydrate, sodium citrate, sodium citrate hydrate, sodium bromide. , Potassium bromide, sodium lactate solution, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, sodium hydrogen carbonate, sodium hydrogen sulfite, benzalconium chloride , Containing at least one selected from the group consisting of anhydrous sodium citrate, glucose, fructose, lactose hydrate, trehalose hydrate, mannitol, sorbitol, xylitol, glycerin, propylene glycol, and macrogol 4000, etc. A tonic; more preferably at least one selected from the group consisting of glucose, fructose, lactose hydrate, trehalose hydrate, mannitol, sorbitol, xylitol, glycerin, propylene glycol, and macrogol 4000. Isotonic agent containing; more preferably mannitol.

[6] The sustained-release drug according to any one of the above aspects [1] to [1-8-13], wherein the stabilizer is at least one selected from the group consisting of sugar and sugar alcohol. Composition.

[6-1] In the above aspect [6], the stabilizer is preferably a stabilizer containing at least one selected from the group consisting of cyclodextrin, disaccharide, and sugar alcohol; Preferably, at least one selected from the group consisting of hydroxypropyl (HP) -β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sucrose, lactose, maltose hydrate, mannitol, sorbitol, xylitol, and glycerin. It is a stabilizer containing the above; more preferably, HP-β-cyclodextrin and / or sulfobutyl ether-β-cyclodextrin.

[7] The embodiment, wherein the surfactant is at least one selected from the group consisting of a pluronic-based surfactant, a Tween-based surfactant, a castor oil-based surfactant, and a cured castor oil-based surfactant. The sustained-release pharmaceutical composition according to any one of [1] to [1-8-13].
[7-1] In the above aspect [7], the surfactant is preferably polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, or polyoxy. Contains at least one selected from the group consisting of ethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68), polysorbate 80, and polysorbate 20. Surfactants, more preferably polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68), and / or polysorbate 80.

[8] Any of the above embodiments [1] to [1-8-13], wherein the ^{buffer is contained in an amount of about 1 × 10-5} to about 5% (w / v) based on the total amount of the sustained-release pharmaceutical composition. The sustained-release pharmaceutical composition according to item 1.
[8-1] In the above aspect [8], the content of the buffer is preferably about 1 × 10 ^-3 to about 3% (w / v), and more preferably about 1 × 10 ^-2. It is about 1% (w / v).
In the present specification, when "about" is described in the description of the content of the buffer agent, it may include a value up to ± 20% of the value, preferably up to ± 10% of the value.

[9] Any of the above embodiments [1] to [1-8-13], wherein the pH adjuster is contained in an amount of 0 to about 5 × 10 ^{-3% (w / v) based on the total amount of the sustained-release pharmaceutical composition.} The sustained-release pharmaceutical composition according to item 1.
[9'] The above-mentioned embodiments [1] to [1-8], wherein the pH adjuster is greater than 0 based on the total amount of the sustained-release pharmaceutical composition and is contained in an amount of about 5 × 10 ^{-3% (w / v) or less.} -13] The sustained-release pharmaceutical composition according to any one of the following items.
[9-1] In the above aspect [9], the content of the pH adjuster is preferably 0 to about 3 × 10 ^-3 % (w / v), and more preferably 0 to about 1 × 10. ^{It is -3} % (w / v).
In the present specification, when "about" is described in the description of the content of the pH adjuster, it may include a value up to ± 20% of the value, preferably up to ± 10% of the value.

[10] Any one of the above aspects [1] to [1-8-13], which contains about 1 to about 10% (w / v) of the tonicity agent based on the total amount of the sustained-release pharmaceutical composition. The sustained-release pharmaceutical composition according to the section.
[10-1] In the above aspect [10], the content of the tonicity agent is preferably about 1.5 to about 7% (w / v), more preferably about 2 to about 5%. (W / v).
In the present specification, when "about" is described in the description of the content of the tonicity agent, it may include a value up to ± 20% of the value, preferably up to ± 10% of the value.

[11] The stabilizer according to the above aspects [1] to [1-8-13], which contains ^{about 1 × 10 -1} to about 10% (w / v) based on the total amount of the sustained-release pharmaceutical composition. The sustained-release pharmaceutical composition according to any one of the following items.
[11-1] In the above aspect [11], the content of the stabilizer is preferably about 1.5 × 10 ^-1 to about 9% (w / v), and more preferably about 3 ×. It is 10 ^-1 to about 8% (w / v).
In the present specification, when "about" is described in the description of the content of the stabilizer, it may include a value up to ± 20% of the value, preferably up to ± 10% of the value.

[12] The above-mentioned embodiments [1] to [1-8-13], wherein the surfactant is contained in an amount of about 1 × 10 ^{-2 to about 5% (w / v) based on the total amount of the sustained-release pharmaceutical composition.} The sustained-release pharmaceutical composition according to any one of the following items.
[12-1] In the above aspect [12], the content of the surfactant is preferably about 1 × 10 ^-1 to about 3% (w / v), and more preferably about 1 × 10 ^{−. It is 1} to about 1% (w / v).
In the present specification, when "about" is described in the description of the content of the surfactant, it may include a value up to ± 20% of the value, preferably up to ± 10% of the value.

[13] The content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is about 1 × 10 ^-1 to about 20 mg / mL. The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13].
[13-1] In the above aspect [13], the content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably about 5. × 10 ^-1 to about 15 mg / mL, preferably about 5 to about 15 mg / mL, and preferably about 8 to about 12 mg / mL.
In the present specification, when "about" is described in the description of the content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, the numerical value thereof. It may include a value up to ± 20% of, preferably up to ± 10% of the value.

[14] The content of the diclofenac-linked alginic acid derivative represented by the formula (I-c-1), a pharmaceutically acceptable salt thereof, or a solvate thereof is about 5 × 10 ^-1 to about 15 mg / The above-mentioned aspects, which are mL, the above-mentioned aspects [1-1-3-1], [1-4], [1-5-2], [1-5-3], and [1-8-1] to [ The sustained-release pharmaceutical composition according to any one of 1-8-13].
[14-1] In the above aspect [14], the content of the diclofenac-linked alginic acid derivative represented by the formula (Ic-1), a pharmaceutically acceptable salt thereof, or a solvate thereof is determined. It is preferably about 5 to about 15 mg / mL, and preferably about 8 to about 12 mg / mL.
In the present specification, "about" is described in the description of the content of the diclofenac-linked alginic acid derivative represented by the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. In this case, a value up to ± 20% of the value, preferably up to ± 10% of the value may be included.

[15] The content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is about 1 × 10 ^-3 to about 6 mg / mL in terms of NSAIDs. The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13].
[15-1] In the above aspect [15], the content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof in terms of NSAIDs is determined. Preferably, it is about 5 × 10 ^-3 to about 4.5 mg / mL, more preferably about 5 × 10 ^-2 to about 4.5 mg / mL, and even more preferably about 8 × 10 ^-2 to about 3. It is 0.6 mg / mL.
In the present specification, the content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof in terms of NSAIDs is described as "about". In this case, a value up to ± 20% of the value, preferably up to ± 10% of the value may be included.

[16] The content of the diclofenac-bonded alginic acid derivative represented by the formula (I-c-1), a pharmaceutically acceptable salt thereof, or a solvate thereof is about 2.5 × 10 ^{− in terms of diclofenac. The} embodiments [1-1-3-1], [1-4], [1-5-2], [1-5-3], and [1-8-1], which are 2 to about 3 mg / mL. ] To [1-8-13] according to any one of the sustained-release pharmaceutical compositions.
[16-1] In the above aspect [16], the diclofenac-linked alginic acid derivative represented by the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof in terms of diclofenac. The content is preferably from about 2.5 × 10 ^-1 to about 3 mg / mL, more preferably from about 4 × 10 ^-1 to about 2.4 mg / mL.
In the present specification, in the description of the content of the diclofenac-linked alginic acid derivative represented by the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof in terms of diclofenac, "about , A value up to ± 20% of the value, preferably up to ± 10% of the value may be included.

[17-1] When stored under storage conditions, the NSAIDs content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a derivative of a solvate thereof The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13], which has a stability of maintaining 75% or more.
[17-1-1] In the above aspect [17-1], the storage period is preferably up to 6 months, more preferably up to 12 months, further preferably up to 24 months, and particularly preferably up to 40 months.
[17-1-2] In the above aspect [17-1], the temperature under storage conditions is preferably about 2 to about 8 ° C, more preferably about 5 ° C.
[17-1-3] In the above aspect [17-1], the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or the NSAIDs content of a solvate thereof is determined. , Preferably about 80% or more, more preferably about 85% or more.
In the present specification, "about" is used in the description of the stability of maintaining the NSAIDs content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof. When described, a value up to ± 3.0% of the value, preferably up to ± 1.0% of the value may be included.
In the present specification, the stability value for maintaining the NSAIDs content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is determined at the start of storage. It represents a value calculated from the percentage (%) of the molar concentration of maintained NSAIDs, which is obtained by subtracting the molar concentration of NSAIDs released over time with respect to the molar concentration of NSAIDs.
In the present specification, when the temperature of the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof under storage conditions is described as "about". , The value up to ± 1.0 ° C., preferably the value up to ± 0.5 ° C. may be included.

[17-2] Diclofenac-bonded alginic acid derivative represented by the formula (Ic-1), a pharmaceutically acceptable salt thereof, or a solvate thereof containing diclofenac when stored under storage conditions. The embodiments [1-1-3-1], [1-4], [1-5-2], [1-5-3], and [1-3-1], which have stability in which the amount is maintained at 75% or more. The sustained-release pharmaceutical composition according to any one of [8-1] to [1-8-13].
[17-2-1] In the above aspect [17-2], the storage period is preferably up to 6 months, more preferably up to 12 months, further preferably up to 24 months, and particularly preferably up to 40 months.
[17-2-2] In the above aspect [17-2], the temperature under storage conditions is preferably about 2 to about 8 ° C, more preferably about 5 ° C.
[17-2-3] In the above aspect [17-2], a diclofenac-linked alginic acid derivative represented by the formula (Ic-1), a pharmaceutically acceptable salt thereof, or a solvate thereof. The diclofenac content is preferably about 80% or more, more preferably about 85% or more.
In the present specification, in the description of the stability of maintaining the diclofenac content of the diclofenac-bound alginic acid derivative represented by the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. When described as "about", a value up to ± 3.0% of the value, preferably up to ± 1.0% of the value may be included.
In the present specification, the stability value for maintaining the diclofenac content of the diclofenac-bound alginic acid derivative represented by the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof is determined. It represents a value calculated from the percentage (%) of the molar concentration of maintained NSAIDs obtained by subtracting the molar concentration of diclofenac released over time with respect to the molar concentration of diclofenac at the start of storage.
In the present specification, "about" in the description of the temperature under storage conditions of the diclofenac-bonded alginic acid derivative represented by the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. When described as, it may include a value up to ± 1.0 ° C., preferably a value up to ± 0.5 ° C. of the value.

[18-1] The item according to any one of the above aspects [1] to [1-8-13], wherein the production rate of diclofenac amide is suppressed to about 30% or less when stored under storage conditions. A sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.
[18-1-1] In the above aspect [18-1], the storage period is preferably up to 6 months, more preferably up to 12 months, further preferably up to 24 months, and particularly preferably up to 40 months.
[18-1-2] In the above aspect [18-1], the temperature under storage conditions is preferably about 2 to about 8 ° C, more preferably about 5 ° C.
[18-1-3] In the above aspect [18-1], the production rate of diclofenac amide is preferably about 25% or less, more preferably about 20% or less.
In the present specification, when "about" is described in the description of the production rate of diclofenac amide, it may include a value up to ± 3.0% of the value, preferably up to ± 1.0% of the value. ..
In the present specification, the production rate of diclofenac amide represents a percentage (%) of the molar concentration of diclofenac amide released over time with respect to the molar concentration of diclofenac amide at the start of storage.
In the present specification, when the temperature of the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof under storage conditions is described as "about". , The value up to ± 1.0 ° C., preferably the value up to ± 0.5 ° C. may be included.

[18-2] The above-described embodiment [1-1-3-1], [1-4], [18-2], wherein the production rate of diclofenac amide is suppressed to about 30% or less when stored under storage conditions. 1-5-2], [1-5-3], and represented by the formula (Ic-1) according to any one of [1-8-1] to [1-8-13]. A sustained-release pharmaceutical composition containing a diclofenac-conjugated alginic acid derivative, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
[18-2-1] In the above aspect [18-2], the storage period is preferably up to 6 months, more preferably up to 12 months, further preferably up to 24 months, and particularly preferably up to 40 months.
[18-2-2] In the above aspect [18-2], the temperature under storage conditions is preferably about 2 to about 8 ° C, more preferably about 5 ° C.
[18-2-3] In the above aspect [18-2], the production rate of diclofenac amide is preferably about 25% or less, more preferably about 20% or less.
In the present specification, "about" in the description of the temperature under storage conditions of the diclofenac-bonded alginic acid derivative represented by the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. When described as, it may include a value up to ± 1.0 ° C., preferably a value up to ± 0.5 ° C. of the value.

[19-1-1] For example, when 1 to 3 mL is administered, the NSAIDs-binding polysaccharide derivative represented by the formula (I) per single administration, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13], wherein the content of the substance is about 1 × 10 ^{-1 to about 60 mg.}
[19-1-2] In the above aspect [19-1-1], the NSAIDs-binding polysaccharide derivative represented by the formula (I) per single dose, or a pharmaceutically acceptable salt thereof, or a solvent thereof. The content of the Japanese product is preferably about 5 × 10 ^-1 to about 45 mg, preferably about 5 to about 45 mg, and preferably about 8 to about 36 mg.
[19-1-3] For example, when 0.5 to 5 mL is administered, the NSAIDs-binding polysaccharide derivative represented by the formula (I) per single administration, or a pharmaceutically acceptable salt thereof, or a salt thereof. The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13], wherein the content of the solvate is about 5 × 10 ^{-2 to about 100 mg.}
[19-1-4] In the above aspect [19-1-3], the NSAIDs-binding polysaccharide derivative represented by the formula (I) per single dose, or a pharmaceutically acceptable salt thereof, or a solvent thereof. The content of the Japanese product is preferably about 2.5 × 10 ^-1 to about 75 mg, preferably about 2.5 to about 75 mg, and preferably about 4 to about 60 mg.

[19-2-1] For example, when 1 to 3 mL is administered, the NSAIDs-binding polysaccharide derivative represented by the formula (I) per single administration, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13], wherein the content of the substance is about 1 × 10 ^{-3 to about 18 mg in terms of NSAIDs.}
[19-2-2] In the above aspect [19-2-1], the NSAIDs-binding polysaccharide derivative represented by the formula (I) per single dose, or a pharmaceutically acceptable salt thereof, or a solvent thereof. The NSAIDs equivalent content of the Japanese product is preferably about 5 × 10 ^-3 to about 13.5 mg, preferably about 5 × 10 ^-2 to about 13.5 mg, and preferably about 8 × 10 ^{−. 2} to about 10.8 mg.
[19-2-3] For example, in the case of administering 0.5 to 5 mL, an NSAIDs-binding polysaccharide derivative represented by the formula (I) per single administration, or a pharmaceutically acceptable salt thereof, or a salt thereof. The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13], wherein the content of the solvate is about 5 × 10 ^{-4 to about 30 mg in terms of NSAIDs.}
[19-2-4] In the above aspect [19-2-3], the NSAIDs-binding polysaccharide derivative represented by the formula (I) per single dose, or a pharmaceutically acceptable salt thereof, or a solvent thereof. The NSAIDs equivalent content of the Japanese product is preferably about 2.5 × 10 ^-3 to about 22.5 mg, preferably about 2.5 × 10 ^-2 to about 22.5 mg, and is preferably about. 4 × 10 ^-2 to about 18 mg.

In the present specification, the content of the NSAIDs-binding polysaccharide derivative represented by the formula (I) per single dose, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or the formula per single dose. When "about" is described in the description of the NSAIDs-binding polysaccharide derivative represented by (I), the pharmaceutically acceptable salt thereof, or the NSAIDs equivalent content of their solvate, ± 20% of the value. Up to, preferably, a value up to ± 10% of the value can be included.

[19-3-1] For example, in the case of administering 1 to 3 mL, a diclofenac-bound alginic acid derivative represented by the formula (Ic-1) or a pharmaceutically acceptable salt thereof per administration, or a salt thereof. The content of the solvate of the above is about 5 × 10 ^-1 to about 45 mg, the above-mentioned embodiments [1-1-3-1], [1-4], [1-5-2], [1-5]. -3], and the sustained-release pharmaceutical composition according to any one of [1-8-1] to [1-8-13].
[19-3-2] In the above aspect [19-3-1], a diclofenac-linked alginic acid derivative represented by the formula (Ic-1) per single dose, or a pharmaceutically acceptable salt thereof. Alternatively, the content of those solvates is preferably about 5 to about 45 mg, and preferably about 8 to about 36 mg.
[19-3-3] For example, in the case of administering 0.5 to 5 mL, a diclofenac-bound alginic acid derivative represented by the formula (Ic-1) or a pharmaceutically acceptable salt thereof per administration. Alternatively, the contents of those solvates are about 2.5 × 10 ^-1 to about 75 mg, the above-mentioned embodiments [1-1-3-1], [1-4], [1-5-2], and the like. The sustained-release pharmaceutical composition according to any one of [1-5-3] and [1-8-1] to [1-8-13].
[19-3-4] In the above aspect [19-3-3], a diclofenac-linked alginic acid derivative represented by the formula (Ic-1) per single dose, or a pharmaceutically acceptable salt thereof. Alternatively, the content of those solvates is preferably about 2.5 × 10 ^-1 to about 75 mg, more preferably about 2.5 to about 75 mg, and preferably about 4 to about 4 to about. It is 60 mg.

[19-4-1] For example, in the case of administering 1 to 3 mL, a diclofenac-bound alginic acid derivative represented by the formula (Ic-1) per administration, or a pharmaceutically acceptable salt thereof, or is their approximately 2.5 × ^{10 -2} ~ about 9mg content is diclofenac in terms of a solvate, wherein the aspect [1-1-3-1], [1-4], [1-5-2 ], [1-5-3], and the sustained-release pharmaceutical composition according to any one of [1-8-1] to [1-8-13].
[19-4-2] In the above aspect [19-4], a diclofenac-linked alginic acid derivative represented by the formula (Ic-1) per single dose, or a pharmaceutically acceptable salt thereof, or them. The diclofenac equivalent content of the solvate of is preferably about 2.5 × 10 ^-1 to about 9 mg, and preferably about 4 × 10 ^-1 to about 7.2 mg.

[19-4] For example, in the case of administering 0.5 to 5 mL, a diclofenac-bound alginic acid derivative represented by the formula (Ic-1) per administration, or a pharmaceutically acceptable salt thereof, or The contents of these solvates are about 12.5 × 10 ^-3 to about 15 mg in terms of diclofenac, the above-mentioned embodiments [1-1-3-1], [1-4], [1-5-2]. ], [1-5-3], and the sustained-release pharmaceutical composition according to any one of [1-8-1] to [1-8-13].
[19-4-2] In the above-mentioned embodiment [19-4], a diclofenac-linked alginic acid derivative represented by the formula (Ic-1) per single dose, or a pharmaceutically acceptable salt thereof, or them. The diclofenac-equivalent content of the solvate of is preferably about 12.5 × 10 ^-2 to about 15 mg, and preferably about 2 × 10 ^-1 to about 12 mg.

In the present specification, the content of a diclofenac-linked alginic acid derivative represented by the formula (Ic-1) or a pharmaceutically acceptable salt thereof per single dose, or a solvate thereof, or a single dose. When "about" is described in the description of the diclofenac-bound polysaccharide derivative represented by the winning formula (Ic-1), or a pharmaceutically acceptable salt thereof, or the diclofenac equivalent content of their solvate. , Up to ± 20% of the value, preferably up to ± 10% of the value may be included.

[20] A diclofenac-binding polysaccharide derivative represented by the formula (I) according to any one of the above aspects [1] to [1-8-13], which is used for intra-articular administration or near a tendon / ligament attachment site. , Or a sustained-release pharmaceutical composition containing a pharmaceutically acceptable salt thereof, or a solvate thereof.
[20-1] The above-mentioned embodiments [1-1-3-1], [1-4], [1-5-2], [1-5] for administration in the joint cavity or in the vicinity of the tendon / ligament attachment site. -3], and a diclofenac-bound alginic acid derivative represented by the formula (Ic-1) according to any one of [1-8-1] to [1-8-13], or pharmaceutically acceptable. A sustained-release pharmaceutical composition containing the salt thereof, or a solvate thereof.
[20-2] In the above aspects [20] and [20-1], preferably, for intra-elbow joint administration, intra-shoulder joint administration, intra-wrist joint administration, intra-ankle joint administration, hip joint. A sustained-release pharmaceutical composition that is at least one selected from the group consisting of intracavitary administration and intraluminal administration of the knee joint, and more preferably a sustained-release pharmaceutical composition for intracavitary administration of the knee joint. is there.

[21] The sustained-release pharmaceutical composition according to any one of the above aspects [1] to [1-8-13], which is filled in a glass or plastic medical container.
[22] A method for controlling the release of NSAIDs in a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. Therefore, the sustained-release pharmaceutical composition contains at least one component selected from the group consisting of a buffer, a pH adjuster, an tonicity agent, a stabilizer and a surfactant as an additive. How to include that.
[22-1-1] In the above aspect [22], preferably, the additive is a component of any one of a buffer and a pH adjuster, and a component of any one of a stabilizer and a surfactant. And a method of controlling the release of NSAIDs, which are isotonic agents.
[22-1-2] In the above aspect [22], preferably, the release of NSAIDs in which the additive is a component of any one of a buffer and a pH adjuster, a stabilizer, and an isotonic agent. How to control.
[22-1-3] In the above aspect [22], preferably, the release of NSAIDs in which the additive is a component of any one of a buffer and a pH adjuster, a surfactant, and an isotonic agent. [22-1-4] In the above aspect [22], preferably, the additive controls the release of NSAIDs, which is a component of any one of a buffer and a pH adjuster, and an isotonic agent. Method.
[22-1-5] In the above aspect [22], preferably, a method for controlling the release of NSAIDs, wherein the additive is a component of any one of a stabilizer and a surfactant, and an isotonic agent. ..
[22-1-6] In the above aspect [22], preferably, a method for controlling the release of NSAIDs in which the additive is a buffer, an isotonic agent, and a stabilizer.
[22-1-7] In the above aspect [22], preferably, a method for controlling the release of NSAIDs, wherein the additive is a pH adjuster, an isotonic agent, and a stabilizer.
[22-1-8] In the above aspect [22], preferably, a method for controlling the release of NSAIDs in which the additive is a buffer, an isotonic agent, and a surfactant.
[22-1-9] In the above aspect [22], preferably, a method for controlling the release of NSAIDs, wherein the additive is a pH adjuster, an isotonic agent, and a surfactant.
[22-1-10] In the above aspect [22], preferably, a method for controlling the release of NSAIDs in which the additive is a buffer and an isotonic agent.
[22-1-11] In the above aspect [22], preferably, a method for controlling the release of NSAIDs in which the additive is a pH adjuster and an isotonic agent.
[22-1-12] In the above aspect [22], preferably, a method for controlling the release of NSAIDs in which the additive is an isotonic agent and a stabilizer.
[22-1-13] In the above aspect [22], preferably, a method for controlling the release of NSAIDs in which the additive is an isotonic agent and a surfactant.

[22-2] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably used in the formulas (Ia) and (I-). b), a derivative selected from the formula (Ic), and the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. The method according to any one of [22-1-13].
[22-2-1] In the above aspect [22-2], the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is more preferable. , A derivative selected from the formulas (Ic) and (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. The method according to any one of 1-13].

[22-3] The method according to any one of the above aspects [22] to [22-2-1], wherein the pH of the sustained-release pharmaceutical composition is about 4.5 to about 6.5.
[22-3-1] In the above aspect [22-3], the pH is preferably from about 4.8 to about 6.0, more preferably from about 5.1 to about 5.5. More preferably, it is about 5.3.

[23] Contains an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof under a condition of a pH of about 4.5 to about 6.5. A method for controlling the release of NSAIDs in a sustained-release pharmaceutical composition, which is an additive to the sustained-release pharmaceutical composition, such as a buffer, a pH adjuster, an tonicity agent, a stabilizer and a surfactant. A method comprising containing one or more components selected from.
[23-1-1] In the above aspect [23], preferably, the additive is a component of any one of a buffer and a pH adjuster, and a component of any one of a stabilizer and a surfactant. And a method of controlling the release of NSAIDs, which are isotonic agents.
[23-1-2] In the above aspect [23], preferably, the release of NSAIDs in which the additive is a component of any one of a buffer and a pH adjuster, a stabilizer, and an isotonic agent. How to control.
[23-1-3] In the above aspect [23], preferably, the release of NSAIDs in which the additive is a component of any one of a buffer and a pH adjuster, a surfactant, and an isotonic agent. How to control.
[23-1-4] In the above aspect [23], preferably, the additive controls the release of NSAIDs, which is a component of any one of a buffer and a pH adjuster, and an isotonic agent. ..
[23-1-5] In the above aspect [23], preferably, a method for controlling the release of NSAIDs, wherein the additive is a component of any one of a stabilizer and a surfactant, and an isotonic agent. ..
[23-1-6] In the above aspect [23], preferably, a method for controlling the release of NSAIDs in which the additive is a buffer, an isotonic agent, and a stabilizer.
[23-1-7] In the above aspect [23], preferably, a method for controlling the release of NSAIDs in which the additive is a pH adjuster, an isotonic agent, and a stabilizer.
[23-1-8] In the above aspect [23], preferably, a method for controlling the release of NSAIDs in which the additive is a buffer, an isotonic agent, and a surfactant.
[23-1-9] In the above aspect [23], preferably, a method for controlling the release of NSAIDs, wherein the additive is a pH adjuster, an isotonic agent, and a surfactant.
[23-1-10] In the above aspect [23], preferably, a method for controlling the release of NSAIDs in which the additive is a buffer and an isotonic agent.
[23-1-11] In the above aspect [23], preferably, a method for controlling the release of NSAIDs in which the additive is a pH adjuster and an isotonic agent.
[23-1-12] In the above aspect [23], preferably, a method for controlling the release of NSAIDs in which the additive is an isotonic agent and a stabilizer.
[23-1-13] In the above aspect [23], preferably, a method for controlling the release of NSAIDs in which the additive is an isotonic agent and a surfactant.

[23-2] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably used in the formulas (Ia) and (I-). b), a derivative selected from the formula (Ic), and the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. The method for controlling the release of NSAIDs according to any one of [23-1-13].
[23-2-1] In the above aspect [23-2], the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is more preferable. , A derivative selected from the formulas (Ic) and (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. The method according to any one of 1-13].
[23-3] In the above aspects [23] to [23-2-1], the pH is preferably about 4.8 to about 6.0, more preferably about 5.1 to about 5. It is 5, and more preferably about 5.3.

[24] Xu containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof under a condition of a pH of about 4.5 to about 6.5. A method for suppressing the production of diclofenac amide in a release-release pharmaceutical composition, which is an additive to a sustained-release pharmaceutical composition, such as a buffer, a pH adjuster, an tonicity agent, a stabilizer and a surfactant. A method comprising containing at least one component selected from the group consisting of.
[24-1-1] In the above aspect [24], preferably, the additive is a component of any one of a buffer and a pH adjuster, and a component of any one of a stabilizer and a surfactant. And a method of suppressing the production of diclofenac amide, which is an isotonic agent.
[24-1-2] In the above aspect [24], preferably, the additive is diclofenac amide, which is a component of any one of a buffer and a pH adjuster, a stabilizer, and an isotonic agent. A method of suppressing generation.
[24-1-3] In the above aspect [24], preferably, the additive is diclofenac amide, which is a component of any one of a buffer and a pH adjuster, a surfactant, and an isotonic agent. A method of suppressing generation.
[24-1-4] In the above aspect [24], preferably, the additive suppresses the production of diclofenac amide, which is a component of any one of a buffer and a pH adjuster, and an isotonic agent. Method.
[24-1-5] In the above aspect [24], preferably, the additive suppresses the production of diclofenac amide, which is a component of any one of a stabilizer and a surfactant, and an isotonic agent. how to.
[24-1-6] In the above aspect [24], preferably, a method for suppressing the production of diclofenac amide, wherein the additive is a buffer, an isotonic agent, and a stabilizer.
[24-1-7] In the above aspect [24], preferably, a method for suppressing the production of diclofenac amide, wherein the additive is a pH adjuster, an isotonic agent, and a stabilizer.
[24-1-8] In the above aspect [24], preferably, a method for suppressing the formation of diclofenac amide, wherein the additive is a buffer, an isotonic agent, and a surfactant.
[24-1-9] In the above aspect [24], preferably, a method for suppressing the formation of diclofenac amide, wherein the additive is a pH adjuster, an isotonic agent, and a surfactant.
[24-1-10] In the above aspect [24], preferably, a method for suppressing the production of diclofenac amide, in which the additive is a buffer and an isotonic agent.
[24-1-11] In the above aspect [24], preferably, a method for suppressing the production of diclofenac amide, in which the additive is a pH adjuster and an isotonic agent.
[24-1-12] In the above aspect [24], preferably, a method for suppressing the production of diclofenac amide, in which the additive is an isotonic agent and a stabilizer.
[24-1-13] In the above aspect [24], preferably, a method for suppressing the formation of diclofenac amide, in which the additive is an isotonic agent and a surfactant.

[24-2] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably used in the formula (Ia), the formula (I-). b), a derivative selected from the formula (Ic), and the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. The method for suppressing the production of diclofenac amide according to any one of [24-1-13].
[24-2-1] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is more preferably used in the formula (Ic) and the formula. Any one of the above embodiments [24] to [24-1-13], which is a derivative selected from (Ic-1), a pharmaceutically acceptable salt thereof, or a solvate thereof. The method for suppressing the production of diclofenac amide according to the section.

[24-3] In the above aspects [24] to [24-2-1], the pH is preferably about 4.8 to about 6.0, more preferably about 5.1 to about 5. It is 5, and more preferably about 5.3.

[25] An NSAIDs-binding polysaccharide derivative represented by the formula (I) (wherein the polysaccharide is alginic acid), or a pharmaceutically acceptable salt thereof, under conditions where the pH is about 4.5 to about 6.5. Alternatively, it is a method for suppressing the reduction of the molecular weight of alginic acid in the sustained-release pharmaceutical composition containing those solvates, and is added to the sustained-release pharmaceutical composition as an additive such as a buffer, a pH adjuster, and isotonic. A method comprising containing one or more components selected from agents, stabilizers and surfactants.
[25-1-1] In the above aspect [25], preferably, the additive is a component of any one of a buffer and a pH adjuster, and a component of any one of a stabilizer and a surfactant. And a method of suppressing the molecular weight reduction of alginic acid, which is an isotonic agent.
[25-1-2] In the above aspect [25], preferably, the additive is a component of any one of a buffer and a pH adjuster, a stabilizer, and an isotonic agent, which is low in alginic acid. A method of suppressing molecularization.
[25-1-3] In the above aspect [25], preferably, the additive is a component of any one of a buffer and a pH adjuster, a surfactant, and an isotonic agent, which is low in alginic acid. A method of suppressing molecularization.
[25-1-4] In the above aspect [25], preferably, the additive suppresses the reduction of molecular weight of alginic acid, which is a component of any one of a buffer and a pH adjuster, and an isotonic agent. how to.
[25-1-5] In the above aspect [25], preferably, the additive suppresses the reduction of molecular weight of alginic acid, which is a component of any one of a stabilizer and a surfactant, and an isotonic agent. how to.
[25-1-6] In the above aspect [25], preferably, a method for suppressing the molecular weight reduction of alginic acid, wherein the additive is a buffer, an isotonic agent, and a stabilizer.
[25-1-7] In the above aspect [25], preferably, a method for suppressing the molecular weight reduction of alginic acid, wherein the additive is a pH adjuster, an isotonic agent, and a stabilizer.
[25-1-8] In the above aspect [25], preferably, the additive is a buffer, an isotonic agent, and a surfactant, a method for suppressing the molecular weight reduction of alginic acid.
[25-1-9] In the above aspect [25], preferably, the additive is a pH adjuster, an isotonic agent, and a surfactant, a method for suppressing the molecular weight reduction of alginic acid.
[25-1-10] In the above aspect [25], preferably, a method for suppressing the molecular weight reduction of alginic acid, wherein the additive is a buffer and an isotonic agent.
[25-1-11] In the above aspect [25], preferably, a method for suppressing the molecular weight reduction of alginic acid, wherein the additive is a pH adjuster and an isotonic agent.
[25-1-12] In the above aspect [25], preferably, a method for suppressing the molecular weight reduction of alginic acid, wherein the additive is an isotonic agent and a stabilizer.
[25-1-13] In the above aspect [25], preferably, a method for suppressing the molecular weight reduction of alginic acid, wherein the additive is an isotonic agent and a surfactant.

[25-2] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably used in the formulas (Ic) and (I). -C-1) according to any one of the above-mentioned aspects [25] to [25-1-13], which is a derivative selected from (c-1), a pharmaceutically acceptable salt thereof, or a solvate thereof. The method for suppressing the molecular weight reduction of alginic acid according to the above.
[25-3] In the above aspects [25] to [25-1-13], the pH is preferably about 4.8 to about 6.0, more preferably about 5.1 to about 5. It is 5, and more preferably about 5.3.

[26] A method for controlling the release of NSAIDs in a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. A method of setting the pH of a sustained-release pharmaceutical composition to about 4.5 to about 6.5.
[26-1-1] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably the formula (Ia), the formula ( Ib), a derivative selected from the formulas (Ic) and (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein [26] ]the method of.
[26-1-2] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is more preferably used in the formula (Ic) and the formula. The method of aspect [26] above, which is a derivative selected from (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
[26-2] A method for controlling the release of diclofenac in a sustained-release pharmaceutical composition containing a compound represented by the formula (I-c-1), wherein the pH of the sustained-release pharmaceutical composition is about 4. A method of 5 to about 6.5.
[26-3] In the above aspects [26] to [26-2], the pH is preferably about 4.8 to about 6.0, more preferably about 5.1 to about 5.5. Yes, more preferably about 5.3.

[27] In a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I) (where NSAIDs are diclofenac), a pharmaceutically acceptable salt thereof, or a solvate thereof. , A method for suppressing the production of diclofenac amide, which comprises a step of adjusting the pH of the sustained-release pharmaceutical composition to about 4.5 to about 6.5.
[27-1-1] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably the formula (Ia), the formula ( The method of aspect [27], wherein the method is at least one derivative selected from the group consisting of Ib), formula (Ic), and formula (Ic-1).
[27-1-2] In a sustained-release pharmaceutical composition containing a diclofenac-linked alginic acid derivative represented by the formula (Ic-1), a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for controlling the release of diclofenac, which comprises the step of adjusting the pH of the sustained release pharmaceutical composition to about 4.5 to about 6.5.
[27-2] In the above aspects [27] to [27-1-2], the pH is preferably about 4.8 to about 6.0, more preferably about 5.1 to about 5. It is 5, and more preferably about 5.3.

[28] In a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof (where the polysaccharide is alginic acid). , A method for suppressing the reduction of molecular weight of alginic acid, which comprises a step of adjusting the pH of the sustained-release pharmaceutical composition to about 4.5 to about 6.5.
[28-1-1] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably the formula (Ic) or the formula. The method of aspect [28] above, which is at least one derivative selected from the group consisting of (Ic-1).
[28-1-2] In a sustained-release pharmaceutical composition containing a diclofenac-linked alginic acid derivative represented by the formula (Ic-1), a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for suppressing the reduction of molecular weight of alginic acid, which comprises a step of adjusting the pH of the sustained-release pharmaceutical composition to about 4.5 to about 6.5.

[28-2] In the above aspects [28] to [28-1-2], the pH is preferably about 4.8 to about 6.0, more preferably about 5.1 to about 5. It is 5, and more preferably about 5.3.

[29] The method according to any one of [22] to [25-3], wherein the buffer is selected from the buffer according to the aspect [3].
[29-1] The above-mentioned [22] to [25-3], wherein the preferable, more preferable, or even more preferable buffer is the same as the buffer according to the aspect [3-1]. The method described.

[30] The method according to any one of [22] to [25-3], wherein the pH adjuster is selected from the pH adjusters according to the aspect [4].
[30-1] The pH adjusting agent of [22] to [25-3], wherein the preferable, more preferable, further preferable, or most preferable pH adjusting agent is the same as the pH adjusting agent according to the above aspect [4-1]. The method according to any one item.

[31] The method according to any one of [22] to [25-3], wherein the isotonic agent is selected from the isotonic agents according to the aspect [5].
[31-1] Any one of the above [22] to [25-3], wherein the preferred or more preferable isotonic agent is the same as the isotonic agent according to the above aspect [5-1]. The method described in.

[32] The method according to any one of [22] to [25-3], wherein the stabilizer is selected from the stabilizers according to the aspect [6].
[32-1] Any one of the above [22] to [25-3], wherein the preferable, more preferable, or even more preferable stabilizer is the same as the stabilizer according to the above aspect [6-1]. The method described in the section.

[33] The method according to any one of [22] to [25-3], wherein the surfactant is selected from the surfactants according to the aspect [7].
[33-1] In any one of the above [22] to [25-3], the preferred and more preferable surfactant is the same as the surfactant according to the above aspect [7-1]. The method described.

[34] A method for preserving a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a sustained-release pharmaceutical composition. The sex pharmaceutical composition is filled in a glass and / or plastic medical container, and the sustained release pharmaceutical composition comprises a buffer, a pH adjuster, an isotonic agent, a stabilizer and a surfactant as additives. A method comprising the step of containing at least one component selected from the group and the step of adjusting the pH of the sustained release pharmaceutical composition to about 4.5 to about 6.5.
[34-1-1] In the above aspect [34], preferably, the additive is a component of any one of a buffer and a pH adjuster, and a component of any one of a stabilizer or a surfactant. And a method of storage, which is an isotonic agent.
[34-1-2] In the above aspect [34], preferably, the additive is a component of any one of a buffer and a pH adjuster, a stabilizer, and an isotonic agent. ..
[34-1-3] In the above aspect [34], preferably, the additive is a component of any one of a buffer and a pH adjuster, a surfactant, and an isotonic agent. ..
[34-1-4] In the above aspect [34], preferably, the additive is a component of any one of a buffer and a pH adjuster, and an isotonic agent.
[34-1-5] In the above aspect [34], preferably, the additive is a component of any one of a stabilizer and a surfactant, and an isotonic agent, which is a method for storing.
[34-1-6] In the above aspect [34], preferably, the method of storage in which the additives are a buffer, an isotonic agent, and a stabilizer.
[34-1-7] In the above aspect [34], a method for preserving, preferably in which the additives are a pH adjuster, an isotonic agent, and a stabilizer.
[34-1-8] In the above aspect [34], a method for preserving, preferably in which the additives are a buffer, an isotonic agent, and a surfactant.
[34-1-9] In the above aspect [34], a method for preserving, preferably in which the additives are a pH adjuster, an isotonic agent, and a surfactant.
[34-1-10] In the above aspect [34], preferably, the method of storage in which the additive is a buffer and an isotonic agent.
[34-1-11] In the above aspect [34], preferably, the method of storage in which the additive is a pH adjuster and an isotonic agent.
[34-1-12] In the above aspect [34], preferably, the method of storage in which the additive is an isotonic agent and a stabilizer.
[34-1-13] In the above aspect [34], a method for preserving, preferably in which the additive is an isotonic agent and a surfactant.

[34-2] NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, preferably formulas (Ia) and (Ib). , A derivative selected from the formula (Ic), and the formula (Ic-1), or a pharmaceutically acceptable salt thereof, or a solvate thereof. 341-1-13] The storage method according to any one of the following items.
[34-2-1] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is more preferably used in the formula (Ic) and the formula. Any one of the above-described embodiments [34] to [34-1-13], which is a derivative selected from (Ic-1), a pharmaceutically acceptable salt thereof, or a solvate thereof. The storage method described in the section.
[34-3] Aspects In the above aspects [34] to [34-2-1], the pH is preferably about 4.8 to about 6.0, more preferably about 5.1 to about. It is 5.5, more preferably about 5.3.
[35] The method according to any one of [34] to [34-3], wherein the buffer is selected from the buffer according to the aspect [3].
[35-1] The above-mentioned [34] to [34-3], wherein the preferable, more preferable, or even more preferable buffer is the same as the buffer according to the aspect [3-1]. The method described.

[36] The method according to any one of [34] to [34-3], wherein the pH adjuster is selected from the pH adjusters according to the aspect [4].
[36-1] The pH adjusting agent of [34] to [34-3], wherein the preferable, more preferable, further preferable, or most preferable pH adjusting agent is the same as the pH adjusting agent according to the above aspect [4-1]. The method according to any one item.

[37] The method according to any one of [34] to [34-3], wherein the isotonic agent is selected from the isotonic agents according to the aspect [5].
[37-1] Any one of the above [34] to [34-3], wherein the preferred or more preferable isotonic agent is the same as the isotonic agent according to the above aspect [5-1]. The method described in.

[38] The method according to any one of [34] to [34-3], wherein the stabilizer is selected from the stabilizers according to the aspect [6].
[38-1] Any one of the above [34] to [34-3], wherein the preferable, more preferable, or even more preferable stabilizer is the same as the stabilizer according to the above aspect [6-1]. The method described in the section.

[39] The method according to any one of [34] to [34-3], wherein the surfactant is selected from the surfactants according to the aspect [7].
[39-1] The above-mentioned [34] to [34-3], wherein the preferable and more preferable surfactant is the same as the surfactant according to the above aspect [7-1]. The method described.

[40] The NSAIDs-binding polysaccharide derivative represented by the formula (I), or pharmaceutically acceptable, comprising the step of detecting and / or quantifying NSAIDs in the sustained-release pharmaceutical composition according to the above aspect [1]. A method for quality inspection of a sustained-release pharmaceutical composition containing a salt thereof or a solvate thereof.
[40-1] An NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutical product, comprising a step of detecting and / or quantifying diclofenac or diclofenac amide in the sustained-release pharmaceutical composition according to the above aspect [1]. A method for quality inspection of a sustained-release pharmaceutical composition containing the pharmaceutically acceptable salt thereof or a solvate thereof.
[40-1-2] The NSAIDs-binding polysaccharide derivative represented by the formula (I) is preferably the formula (Ia), the formula (Ib), the formula (Ic) and the formula (Ic-). The storage method according to any one of the above aspects [40] to [40-1], which is at least one derivative selected from the group consisting of 1).
[40-1-3] The NSAIDs-binding polysaccharide derivative represented by the formula (I) is more preferably at least one selected from the group consisting of the formula (Ic) and the formula (Ic-1). The storage method according to any one of the above aspects [40] to [40-1], which is a derivative of the above.
[40-2] Formula (I-c-1) comprising a step of detecting and / or quantifying diclofenac or diclofenac amide in the sustained-release pharmaceutical composition according to the above aspect [1-1-3-1]. A method for quality inspection of a sustained-release pharmaceutical composition containing a diclofenac-binding polysaccharide derivative represented by, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[41] A method for producing a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(1) NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, as well as a buffer, a pH adjuster, an tonicity agent, a stabilizer and a stabilizer. At least one component selected from the group consisting of surfactants is dissolved in a solvent.
(2) If necessary, a pH adjuster or buffer is added to adjust the pH of the solution to about 4.5 to about 6.5.
(3) The solution after pH adjustment is filtered using a filtration membrane having a pore size of about 5 μm or less.
Manufacturing method including the process of.

[41-1-1] In the production method of the above aspect [41], the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably used. , At least one derivative selected from the group consisting of formula (Ia), formula (Ib), formula (Ic) and formula (Ic-1).
[41-1-2] In the production method of the above aspect [41], the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is more preferable. Is at least one derivative selected from the group consisting of the formula (Ic) and the formula (Ic-1) [41-2] prepared in the production method of the above-mentioned embodiment [41]. The pH of the lysate is preferably from about 4.8 to about 6.0, more preferably from about 5.1 to about 5.5, and even more preferably from about 5.3.

[41-3] In the production method of the above aspect [41], the pore size of the filtration membrane is preferably 0.45 μm or less, more preferably about 0.22 μm or less.
[42] Derivatives selected from formula (I), formula (Ia), formula (Ib), formula (Ic), and formula (Ic-1), or pharmaceutically acceptable. In the method for producing a sustained-release pharmaceutical composition containing the salt thereof or a solvate thereof, the filtration membrane comprises polyether sulfone, PVDF, cellulose acetate, regenerated cellulose, PTFE, and a cellulose mixed ester. The method for producing a sustained-release pharmaceutical composition according to the above aspect [41], which is selected from the group.

In the present specification, when the NSAIDs-binding polysaccharide derivative represented by the formula (I) is described, unless otherwise specified, the formulas (Ia), the formula (Ib), and the formula (c-) are subordinate formulas thereof. It means that the derivative represented by 1) and the formula (Ic-1) is also included.

≪1. Polysaccharide ≫
In the present specification, the term polysaccharide means at least one polysaccharide selected from the group consisting of polysaccharides having a carboxylic acid residue in the molecule, esters thereof, and salts thereof. Specifically, it is a polysaccharide selected from glycosaminoglycans, polyuronic acid, or glucan derivatives; more preferably selected from hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, alginic acid, or carboxymethyl cellulose. Is a polysaccharide; more preferably hyaluronic acid or alginic acid; particularly preferably alginic acid.

≪2. Hyaluronic acid ≫
In the present specification, when referring to hyaluronic acid, a disaccharide unit formed by binding N-acetyl-D-glucosamine and D-glucuronic acid in a β1,3 bond is used as a basic skeleton, and the disaccharide unit is repeatedly β1. , 4, Glycosaminoglycan composed of 4 bonds, that is, hyaluronic acid that is normally available such as a commercially available product is not particularly limited. Further, those obtained by any of animal-derived, microbial-derived, chemical synthesis and the like can be used.

In the present specification, the hyaluronic acid used may be in a free state without forming a salt.
It may also be in a pharmaceutically acceptable salt (for example, sodium salt, potassium salt, magnesium salt, calcium salt, etc.).

In the present specification, the molecular weight of hyaluronic acid used is not particularly limited, and examples thereof include, for example, 10,000 to 5,000,000, preferably 500,000 to 3,000,000, as the weight average molecular weight. More preferably, 600,000 to 1,500,000 and 1,500,000 to 3,000,000 are mentioned. The molecular weight of hyaluronic acid can be measured according to the method for measuring the molecular weight of alginic acid, which will be described later.

≪3. Alginic acid ≫
Alginic acid is a kind of natural polysaccharide produced by extracting from seaweed of brown algae and purifying it, and is a polymer obtained by polymerizing D-mannuronic acid (M) and L-gluuronic acid (G). The composition ratio (M / G ratio) of alginic acid D-mannuronic acid and L-gluuronic acid, that is, the gel strength, differs mainly depending on the type of organism from which seaweed is derived, and also depends on the place of growth and season of the organism. Affected, it ranges from a high G type with an M / G ratio of about 0.2 to a high M type with an M / G ratio of about 5. The physicochemical properties of alginic acid may differ depending on the M / G ratio of alginic acid, the arrangement of M and G, etc., and the preferred use may differ. It is known that the gelling ability of alginic acids and the properties of the produced gel are affected by the M / G ratio, and that the gel strength generally increases when the G ratio is high. The M / G ratio also affects the hardness, brittleness, water absorption, flexibility, etc. of the gel. Therefore, as the alginic acid or a salt thereof used in the present invention, it is preferable to use one having an appropriate M / G ratio and an appropriate viscosity according to the final intended use.

The industrial production method of alginic acid includes an acid method and a calcium method, but in the present invention, any production method can be used. By purification, the quantitative value by the HPLC method is preferably contained in the range of 80 to 120% by mass, more preferably contained in the range of 90 to 110% by mass, and contained in the range of 95 to 105% by mass. More preferred. In the present invention, those whose quantitative values by the HPLC method are included in the above range are referred to as high-purity alginic acid. The alginic acid or a salt thereof used in the present invention is preferably high-purity alginic acid. As a commercially available product, for example, as the Kimika algin series, a product sold by Kimika Co., Ltd., preferably a high-purity food / pharmaceutical grade product can be purchased and used. It is also possible to further purify and use a commercially available product as appropriate. For example, low endotoxin treatment is preferred. As the purification method or the low endotoxin treatment method, for example, the method described in JP-A-2007-7425 can be adopted.

The salt of alginic acid in "alginic acid or a salt thereof" used in the present invention is "monovalent metal salt of alginic acid", and the hydrogen ion of D-mannuronic acid of alginic acid or carboxylic acid of L-gluuronic acid is Na + It is a salt produced by ion exchange with monovalent metal ions such as K + and K +. Specific examples of the monovalent metal salt of alginic acid include sodium alginate and potassium alginate, but sodium alginate is particularly preferable. As will be described later, the form of the alginic acid derivative of the present invention can be adjusted by utilizing the property of the solution of the monovalent metal salt of alginic acid to form a gel when mixed with a cross-linking agent.

As the alginic acid or a salt thereof used in the present invention, it is preferable to use an alginic acid having an appropriate weight average molecular weight depending on its final intended use. For example, when used as an arthritis therapeutic agent for intra-articular administration, it is preferable to use one having a weight average molecular weight of 10,000 to 10 million, more preferably 100,000 or more and 5 million or less, still more preferably 20. It is more than 10,000 and less than 3 million. More specifically, for example, any of alginic acid having the physical characteristics shown in Table 1 below or KM-A1 to KM-A4 which is a salt thereof can be used.
In the present specification, Da (Dalton) may be added as a unit in the molecular weight of alginic acid or a salt thereof.

Further, as the alginate, the commercially available sodium alginate (sold by Mochida Pharmaceutical Co., Ltd.) shown below can also be used. Here, in the examples described later, there is also an example in which sodium alginate of A-1, A-2, A-3 and B-3 described in the table below is used as the sodium alginate. Table 2 shows the viscosity, weight average molecular weight and M / G ratio of each 1 w / w% aqueous solution of sodium alginate.

The physical property values of the sodium alginate A-1, A-2, A-3, B-1, B-2, and B-3 were measured by the method described later. The measuring method is not limited to the method, but each physical property value may differ from the above depending on the measuring method.

Alginic acid is a high molecular weight polysaccharide and it is difficult to accurately determine its molecular weight, but it generally has a weight average molecular weight of 10 to 10 million, preferably 10,000 to 8 million, and more preferably 20,000 to 3 million. Is the range of. It is known that in the measurement of the molecular weight of a polymer substance derived from a natural product, the value may differ depending on the measurement method.

When specifying the molecular weight of the alginic acid derivative of the present invention or alginic acid or a salt thereof in the present specification, it is the weight average molecular weight calculated by size exclusion chromatography (SEC) unless otherwise specified. As the alginic acid or a salt thereof used in the present invention, it is desirable to use one having an appropriate molecular weight distribution according to the final intended use.

For example, when the alginic acid derivative of the present invention is used as a therapeutic agent for arthritis for intra-articular administration, gel permeation chromatography (GPC) or gel filtration chromatography (these are combined to size exclusion chromatography) described in Examples below. Under the measurement conditions (also referred to as (SEC)), it is preferably 100,000 to 5 million, and more preferably 150,000 to 3 million. In some embodiments, it is in the range of 500,000 to 3 million, more preferably 1 million to 2.5 million, and even more preferably 1 million to 2 million.

Further, for example, according to the GPC-MALS (SEC-MALS) method, the absolute weight average molecular weight can be measured. The weight average molecular weight (absolute molecular weight) measured by the GPC-MALS method is 10,000 to 1,000,000, more preferably 50,000 to 800,000, and further preferably 60,000 to 500,000.

Normally, when the molecular weight of a high molecular weight polysaccharide is calculated by the method using SEC and SEC-MALS as described above, a measurement error of about 10% to about 30% can occur. For example, if it is 500,000, the value may fluctuate in the range of 350,000 to 650,000, and if it is 1 million, the value may fluctuate in the range of 700,000 to 1.3 million. In the present specification, when "about" is described in the description of molecular weight measurement, a value up to ± 10% of the value, and in some embodiments up to ± 20% of the value may be included.

[Viscosity measurement of sodium alginate]
It was measured using a rotational viscometer (cone plate type rotational viscometer) according to the viscosity measurement method of the Japanese Pharmacopoeia (16th edition). The specific measurement conditions are as follows. The sample solution was prepared using MilliQ water. As a measuring device, a cone plate type rotational viscometer (viscosity viscoelasticity measuring device Leostress RS600 (Thermo Haake GmbH) sensor: 35/1) was used. The rotation speed was 1 rpm when measuring the 1 w / w% sodium alginate solution. The reading time was measured for 2 minutes and used as an average value from 1 minute to 2 minutes after the start. The average value of the three measurements was taken as the measured value. The measurement temperature was 20 ° C.

[Measurement of weight average molecular weight of sodium alginate]
Measurement was performed by two types of measurement methods: (1) gel permeation chromatography (GPC) and (2) GPC-MALS. The measurement conditions are as follows.

[Pretreatment method]
An eluent was added to the sample to dissolve it, and then filtered through a 0.45 μm membrane filter to obtain a measurement solution.

(1) Gel permeation chromatography (GPC) measurement [Measurement conditions (measurement of relative molecular weight distribution)]
Column: TSKgel GMPW-XL x 2 + G2500PW-XL (7.8mm ID x 300mm x 3)
Eluent: 200 mM sodium nitrate aqueous solution Flow rate: 1.0 mL / min
Concentration: 0.05%
Detector: RI detector Column temperature: 40 ° C
Injection volume: 200 μL
Molecular weight standard: standard pullulan, glucose

(2) GPC-MALS measurement [Refractive index increment (dn / dc) measurement (measurement conditions)]
Differential Refractometer: Optilab T-rEX
Measurement wavelength: 658 nm
Measurement temperature: 40 ° C
Solvent: 200 mM sodium nitrate aqueous solution Sample concentration: 0.5 to 2.5 mg / mL (5 concentration)

[Measurement conditions (absolute molecular weight distribution measurement)]
Column: TSKgel GMPW-XL x 2 + G2500PW-XL (7.8mm ID x 300mm x 3)
Eluent: 200 mM sodium nitrate aqueous solution Flow rate: 1.0 mL / min
Concentration: 0.05%
Detector: RI detector, light scattering detector (MALS)
Column temperature: 40 ° C
Injection volume: 200 μL

The composition ratio (M / G ratio) of D-mannuronic acid and L-gluuronic acid of alginic acids differs mainly depending on the type of organism from which seaweeds are derived, and is also affected by the habitat and season of the organism. , From a high G type with an M / G ratio of about 0.2 to a high M type with an M / G ratio of about 5. It is known that the gelling ability of alginic acids and the properties of the produced gel are affected by the M / G ratio, and that the gel strength generally increases when the G ratio is high. The M / G ratio also affects the hardness, brittleness, water absorption, flexibility, etc. of the gel. The M / G ratio of the alginates and / or salts thereof used is usually 0.1-4.0, in some embodiments 0.1-3.0, and in some embodiments 0.1-2. It is .0, 0.5 to 1.8 in some embodiments, and 0.8 to 1.2 in some embodiments. In another aspect, it is 0.1 to 0.5.

In the present specification, the numerical range indicated by using "-" indicates a range including the numerical values before and after "-" as the minimum value and the maximum value, respectively.

Here, in general, a polymer substance derived from a natural product does not have a single molecular weight, but is an aggregate of molecules having various molecular weights, so that it is measured as a molecular weight distribution having a certain width. A typical measurement method is gel filtration chromatography. Typical information on the molecular weight distribution obtained by gel filtration chromatography includes weight average molecular weight (Mw), number average molecular weight (Mn), and dispersion ratio (Mw / Mn).

The weight average molecular weight emphasizes the contribution of a polymer having a large molecular weight to the average molecular weight, and is expressed by the following formula.

Mw = Σ (WiMi) / W = Σ (HiMi) / Σ (Hi)
The number average molecular weight is calculated by dividing the total weight of the macromolecules by the total number of macromolecules.

Mn = W / ΣNi = Σ (MiNi) / ΣNi = Σ (Hi) / Σ (Hi / Mi)
Here, W is the total weight of the polymer, Wi is the weight of the i-th polymer, Mi is the molecular weight at the i-th elution time, Ni is the number of molecular weight Mi, and Hi is the height at the i-th elution time. ..

In the measurement of the molecular weight of a polymer substance derived from a natural product, it is known that the value may differ depending on the measurement method (example of hyaluronic acid: Chikako YOMOTA et. Al. Bull. Natl. Health Sci., Vol. 117). , Pp135-139 (1999), Chikako YOMOTA et. Al. Bull. Natl. Inst. Health Sci., Vol. 121, pp30-33 (2003)). Regarding the measurement of the molecular weight of alginic acid, a method of calculating from the intrinsic viscosity (Intrinsic Viscosity), a method of calculating by SEC-MALLS (Size Exclusion Chromatography with Multiple Angle Laser Light Vector 2006), published by ASTM International). In the present invention, the weight average molecular weight is a value calculated by measuring the molecular weight by, for example, size exclusion chromatography (SEC) and using a calibration curve using pullulan as a standard substance by a conventional method as shown in the above literature. can do.
Further, in the present invention, the weight average molecular weight can be an absolute molecular weight measured by, for example, size exclusion chromatography (SEC) -MALS by a conventional method as shown in the above-mentioned literature.

When specifying the molecular weight of alginic acid or a salt thereof in the present specification, it is the weight average molecular weight calculated by gel filtration chromatography unless otherwise specified. As the conditions for gel filtration chromatography, for example, the conditions of this example described later can be adopted.

Further, as the alginic acid or a salt thereof used in the present invention, it is preferable to use one having an appropriate viscosity and an appropriate M / G ratio according to the final intended use.

Further, as the alginic acid or a salt thereof used in the present invention, it is preferable to use one having a lowered endotoxin level. The endotoxin value measured by the Japanese Pharmacopoeia endotoxin test is preferably less than 100 EU / g, more preferably less than 75 EU / g, still more preferably less than 50 EU / g. In the present invention, "substantially free of endotoxin" means that the endotoxin value measured by the Japanese Pharmacopoeia endotoxin test is within the above numerical range.

≪4. Linker ≫
In the present specification, in the NSAIDs-linked polysaccharide derivative represented by the formula (I), -L1-, which is a linker, can be bound to one residue derived from a polysaccharide having a carboxyl group or a salt thereof by an amide bond as described above. It has a group (amino group or imino group) at the end, and has a group (hydroxyl group) that can be bonded to one residue of NSAIDs by an ester bond at the other end, and has a structure capable of forming a polysaccharide derivative. There is. Specifically, it is a linker having a structure selected from the following formula ((A) in the formula (LK-B50) and the formula (LK-B51) represents one residue of NSAIDs).

Preferably, -L1- is the following formula:

It is a linker selected from (not including the outside of the broken line in the formula) ((A) in the formula (LK-B50) and the formula (LK-B51) represents one residue of NSAIDs);
More preferably, the following formula:

It is a linker selected from (not including the outside of the broken line in the formula).

In the present specification, in the linker-L1- in the NSAIDs-linked polysaccharide derivative represented by the formula (I), when an asymmetric carbon is present in the formula, it means that each optical isomer thereof is also included. ..

For example, in the linker-L1-, the following formula (LK-A4) in which one asymmetric carbon is present (in the formula, both outer sides of the broken line are not included):

In the case of, the following formula (LK-A4-1) in which the three-dimensional configuration is S-form and the following formula (LK-A4-2) in which the three-dimensional configuration is R-form (in either formula, both outer sides of the broken line are not included). :

It means that the linker represented by is included.

Further, when -L1- is a linker having two asymmetric carbons, for example, the following formula (LK-A5) (in the formula, both outer sides of the broken line are not included):

In the following formula (LK-A5-1), formula (LK-A5-2), formula (LK-A5-3), and formula (LK-A5-4) (in any of the formulas, both outer sides of the broken line are Not included):

It means that the linker represented by is included.

In the formula (I) of the present invention, when an asymmetric carbon is present in the linker-L1- (in the case of an optically active substance), the amine derivative (IM-A-) described later corresponding to the formula (I) is used. In the step of synthesizing 2) or (SM-B), the racemate can be separated into each optically active substance by a usual optical resolution means (separation method), and also corresponds to the formula (I). In the step of synthesizing the amine derivative (AM-1), one of the optical isomers can be selectively synthesized by using asymmetric synthesis, and each optically active substance can be synthesized. By using the obtained amine derivatives having each optically active activity, it is possible to synthesize an alginic acid derivative of the formula (I) having an asymmetric carbon (optically active).

Examples of the separation method include optical resolution methods such as a fractional recrystallization method, a diastereomer method, and a chiral column method. Hereinafter, each division method will be described in detail.

Fractional recrystallization method: An optical resolution agent is ionically bonded to a racemate to obtain a crystalline diastereomer, and then the crystalline diastereomer is separated by a fractional recrystallization method and optically resolved if desired. It is a method of obtaining an optically pure compound through a step of removing the agent. The optical resolution agent is, for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonidine. , (-)-Cinchonidine, brucine and the like.

Diastereomer method: An optical resolution agent is covalently bonded to a mixture of racemates to obtain a mixture of diastereomers, which is then subjected to conventional separation means (eg, fractional recrystallization, silica gel column chromatography, HPLC, etc.). It is a reaction in which an optically pure diastereomer is separated, and then an optically pure optical isomer is obtained through a step of removing an optical resolution agent by a chemical reaction (hydrolysis reaction or the like).

For example, when the compound or intermediate compound of the present invention has a hydroxyl group or an amino group (primary or secondary), the compound and an optically active organic acid (for example, α-methoxy-α- (trifluoromethyl) phenyl) are used. By the condensation reaction with acetic acid and (-)-mentoxyacetic acid, etc.), ester or amide diastereomers can be obtained from each. When the compound of the present invention has a carboxy group, an amide or ester diastereomer can be obtained from each of the compounds by a condensation reaction of the compound with an optically active amine or an optically active alcohol. The diastereomers obtained by the condensation reaction are separated and each diastereomer is subjected to a hydrolysis reaction with an acid or a base to be converted into an optically pure optical isomer of the original compound.

Chiral column method: A method of directly optical resolution by subjecting a racemate or a salt thereof to chromatography using a chiral column (column for separating optical isomers).

For example, in the case of high performance liquid chromatography (HPLC), a mixture of optical isomers is added to a chiral column (for example, CHIRAL series manufactured by Daicel), and an elution solvent (water, various buffers (for example, phosphate buffer)) is added. Liquid) and a single solvent such as an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) or a mixed solvent thereof) to develop the optical isomer. Separation is possible. Further, for example, in the case of gas chromatography, optical isomers can be separated by using a chiral column (for example, CP-Chirasil-DeX CB (manufactured by GL Sciences Co., Ltd.)). Further, for example, in the case of supercritical fluid chromatography (SFC), a mixture of optical isomers is added to a chiral column (for example, CHIRAL series manufactured by Daicel Co., Ltd.), and carbon dioxide and an appropriate organic solvent (for example, for example) are added to the elution solvent. , Methanol, ethanol, isopropanol, trifluoroacetic acid, diethylamine, etc.) can be used to separate the optical isomers.

The asymmetric synthesis that selectively synthesizes one of the optical isomers includes (1) an asymmetric synthesis reaction in which a racemic compound is enantioselectively reacted to lead to an optically active compound, and (2) a naturally occurring optically active compound. Examples thereof include a method of diastereoselectively synthesizing from (sugar, amino acid, etc.).

≪5. Non-steroidal anti-inflammatory compounds (NSAIDs) ≫
In the present specification, non-steroidal anti-inflammatory drugs (NSAIDs) are (1) propionic acid type, (2) phenylacetic acid type, (3) salicylic acid type, (4) fenamic acid type, (5) oxicam type, ( It is possible to select from 6) a pyrolo-pyrrole derivative or (7) a coxib system (COX-2 inhibitor). As used herein, "NSAIDs" means any non-steroidal anti-inflammatory compound, including a pharmaceutically acceptable salt thereof, which is included in one of the above structural categories.

In the present specification, the NSAIDs-linked polysaccharide derivative represented by the formula (I) is an amide with one residue derived from a polysaccharide having a carboxyl group or a salt thereof via an amino group or an imino group at the end of the linker (-L1-). NSAIDs have a carboxyl group in their chemical structure because they are bonded by a bond and are bonded to one residue of NSAIDs by an ester bond via a hydroxyl group at the end of the linker (-L1-). It becomes preferable. The NSAIDs are not particularly limited, but those that are clinically applied to arthritis are preferable.

In the present specification, examples of NSAIDs having a carboxyl group include (1) propionic acid-based NSAIDs (specifically, ibuprofen, flurubiprofen, ketoprofen, naproxen, planoprofen, phenoprofen, thiaprofenic acid, etc. Oxaprodin, loxoprofen sodium, aluminoprofen, zartprofen, thiaprofenic acid, etc.), (2) Phylolic acid-based NSAIDs (specifically, fervinac, diclofenac, tolmethin sodium, slindac, fenbufen, indomethacin, acemetacin, amphenac Sodium, mofezolac, etdrac, alcrofenac, etc.) or (3) salicylic acid-based NSAIDs (specifically, salicylic acid, sazapyrin, aspirin, diflunisal, etc.) are preferred, and exemplary embodiments of the invention. In practice, (1) ketoprofen or naproxen, which is a propionic acid derivative, or (2) fervinac or diclofenac, which is an acetic acid derivative, is more preferable, and diclofenac is particularly preferable.

≪6. Method for Producing NSAIDs-Binding Polysaccharide Derivatives >>
The method for producing an NSAIDs-binding polysaccharide derivative represented by the formula (I) is as follows: [Production method A] A compound of the formula (IM-A-2) or a salt thereof obtained by binding NSAIDs to a linker site and then deprotecting the compound or a salt thereof. Method of binding to polysaccharide (Scheme1) or [Production method B] After binding the linker site to the polysaccharide, the compound of the formula (IM-B-2) obtained by deprotection or a salt thereof is bound to NSAIDs. A method (Scheme 2) can be mentioned, and any method can be used for production. Since it may be difficult to carry out the esterification reaction using NSAIDs and a compound of the formula (IM-B-2) or a salt thereof in an aqueous solvent, [Production Method A] is preferable.

[Manufacturing method A]

[In Cheme1, -L1-, (A), and (SG) are the same as the definition of the above aspect [1], and P1 is an amino group or imino group protecting group (for example, methoxycarbonyl group, ethoxycarbonyl group). , Benzyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, allyloxycarbonyl group, methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, tosyl group, nitrobenzenesulfonyl group , Acetyl group, ethylcarbonyl group, trifluoroacetyl group, benzoyl group, etc.), and X is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.]

<Step 1> [Condensation reaction]
The compound of the formula (SM-A-1) [the compound of the formula (SM-A-1) is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature] and the formula (A) (NSAIDs). Or a salt thereof [formula (A) or a salt thereof is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature], and a method known in the literature, for example, "Experimental Chemistry Course 4th Edition". 22 Organic Synthetic IV Acids / Amino Acids / Peptides, pp. 191-309, 1992, Maruzen ”, halogen-based solvents such as dichloromethane and chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, Ether solvents such as butyl ether, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide, alcohol solvents such as methanol, ethanol, propanol, isopropanol and butanol, etc. 1,3-Dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDCI ・ HCl) in a solvent that does not participate in the reaction such as water, or a mixed solvent thereof. ), 1-Hydroxybenzotriazole (HOBt), benzotriazole-1-iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl) , 2-Chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (DMT-MM), polyphosphate (PPA), or 2- (1H-7-azabenzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methaneaminium (HATU) ) Etc., in the presence of a condensing agent selected from, etc., in the presence or absence of an organic base such as triethylamine, N, N-diisopropylethylamine, pyridine, etc. By doing so, the compound of the formula (IM-A-1) can be produced.

<Step 2> [Nucleophilic Substitution Reaction]
The compound of the formula (SM-A-2) [the compound of the formula (SM-A-2) is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature] and the Na salt of the formula (A). The compound of the formula (IM-A-1) can be produced by carrying out a nucleophilic substitution reaction according to a method known in the literature.

<Step 3> [Deprotection]
Using the compound of the formula (IM-A-1) obtained in [Production Method A] <Step 1> or [Production Method A] <Step 2>, for example, a method known in the literature, for example, "Protecting Group". Protective Groups in Organic Synthesis 4th Edition, 4th Edition, 2007, John Wiley & Sons, Greene et al. By selecting the conditions according to the type of protecting group P1, the compound of the formula (IM-A-2) or a salt thereof can be produced.

<Step 4> [Condensation reaction]
[Manufacturing Method A] Using the compound of the formula (SM-A-2) obtained in <Step 3> and the formula (SG) (polysaccharide or a salt thereof), the method of [Manufacturing Method A] <Step 1> Similarly, the compound of the formula (I) can be produced by carrying out the condensation reaction.

[Manufacturing method B]

[In Cheme2, -L1-, (A), and (SG) are the same as the definition of the above aspect [1], and P2 is a hydroxyl group-protecting group (for example, methyl, ethyl, n-propyl, isopropyl, n). -C1-6 alkyl groups typified by butyl, tert-butyl and the like; alkoxyl alkyl groups typified by methoxymethyl (MOM), methoxyethoxymethyl (MEM) and the like; tetrahydropyranyl (THP) groups; benzyl (Bn) , An aralkyl group typified by triphenylmethyl (Tr) and the like; a silyl group typified by trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) and the like. Alkyl carbonyl group typified by acetyl (Ac), ethyl carbonyl, pivaloyl (Piv), etc .; aralkyl carbonyl group typified by benzyl carbonyl, etc .; Aloyl group typified by benzoyl (Bz), etc .; methoxycarbonyl, ethoxycarbonyl, An alkoxylcarbonyl group typified by t-butoxycarbonyl (Boc) or the like; an aralkyloxycarbonyl group typified by benzyloxycarbonyl (Z) or the like can be mentioned)].

<Step 1> [Condensation reaction]
The compound of formula (SM-B) or a salt thereof [the compound of formula (SM-B) or a salt thereof is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature] and the formula (SG) ( The compound of the formula (IM-B-1) can be produced by carrying out a condensation reaction according to the method of [Production Method A] <Step 1> using a polysaccharide or a salt thereof).

<Step 2> [Deprotection]
[Manufacturing Method B] Using the compound of the formula (IM-B-1) obtained in <Step 1>, for example, a method known in the literature, for example, "Protective Groups in Organic Synthesis (Protective Groups)". in Organic Synthesis 4th Edition) 4th Edition, 2007, John Wiley & Sons, Greene et al., According to the deprotection method described in the book, depending on the type of protecting group P2. By selecting, the compound of the formula (IM-B-2) can be produced.

<Step 3> [Condensation reaction]
[Production Method B] The compound of the formula (IM-B-2) obtained in <Step 2> and the formula (A) or a salt thereof [The formula (A) or a salt thereof is known in the literature from a commercially available compound or a commercially available compound. The compound of the formula (I) can be produced by carrying out a condensation reaction according to the method of [Production Method A] <Step 1> using [A compound that can be produced by the production method of].

Further, the introduction rate of NSAIDs in the NSAIDs-bound polysaccharide derivative represented by the formula (I) in the present invention may be determined by changing the amount of the condensing agent, the condensation aid, the linker-bound NSAIDs used in the alginic acid derivative synthesis step of the present invention. It can be adjusted by. The introduction rate can be measured by measuring the absorbance or by a method using HPLC, NMR or the like. It is also possible to appropriately adjust the water solubility of the NSAIDs-binding polysaccharide derivative represented by the formula (I) depending on the structure of the linker and the introduction rate.

In the present specification, each intermediate in the method for producing an NSAIDs-linked polysaccharide derivative represented by the formula (I) can form a salt. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and a salt with an inorganic base.
Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, etc. Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid. Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvate, oxylic acid, salicylic acid, N-acetylcysteine, etc. Examples thereof include salts with organic carboxylic acids, salts with organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamate. Preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Of these, pharmaceutically acceptable salts are preferable.

The NSAIDs-linked polysaccharide derivative represented by the formula (I) can form a salt. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include monovalent metal salts, and examples thereof include sodium salts and potassium salts.

The salt is separated and collected by filtration according to a conventional method, for example, by mixing a solution containing an appropriate amount of acid or base with the compound of the present invention to form a desired salt, or distilling off the mixed solvent. Can be obtained by As a review article on salt, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermous (Wiley-VCH, 2002) have been published and are described in detail in this document.

≪7. Introduction rate of NSAIDs in NSAIDs-binding polysaccharide derivative represented by formula (I) >>
In the present specification, the NSAIDs-binding polysaccharide derivative represented by the formula (I) is less likely to cause side effects in the body, and NSAIDs capable of continuously releasing NSAIDs at a concentration capable of alleviating or analgesic arthritis, for example, have been introduced. Is preferable. For example, the introduction rate (mol%) is preferably 1.0 mol% or more. It is more preferably 2.0 mol% or more, still more preferably 4.0 mol% or more. On the other hand, when the introduction rate of NSAIDs in the NSAIDs-binding polysaccharide derivative is high, the viscosity of the solution of the sustained-release preparation may increase, which may make it difficult to handle. From this point of view, for example, the introduction rate is preferably about 1 to about 30 mol%, more preferably about 2 to about 20 mol%, and further preferably about 4 to about 15 mol%.
In the present specification, when "about" is described in the description regarding the introduction rate, it may include a value up to ± 20% of the value, preferably up to ± 10% of the value.
The introduction rate (mol%) means, for example, when NSAIDs are introduced into any carboxyl group in the structure of the polysaccharide via a linker, the introduction rate of 10 mol% means that the carboxyl group in the polysaccharide is substituted. The number of monosaccharides is 1 unit (pieces), and it is shown that NSAIDs are introduced at a ratio of 10 to 100 monosaccharides. The introduction rate of NSAIDs via the linker can be appropriately adjusted in consideration of the required amount of NSAIDs in the affected area when administered to a living body, the sustained release efficiency, and the like.

≪8. Sustained release pharmaceutical composition ≫
In one aspect, the present invention includes an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, and a buffer, a pH adjuster, and isotonicization. Provided are a sustained release pharmaceutical composition containing at least one component selected from the group consisting of agents, stabilizers and surfactants.

In one embodiment, the present invention contains an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and the pH thereof is within a predetermined range (for example, about. Provided are sustained-release pharmaceutical compositions according to 4.5-about 6.5).

Specific aspects of the present invention relating to these aspects are listed below.
(1) NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, and any one component of a buffer or a pH adjuster, stable. A sustained-release pharmaceutical composition containing any one component of an agent or a surfactant, and an tonicity agent, the pH of which is in the range of about 4.5 to about 6.5.
(2) NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and a component of any one of a buffer and a pH adjuster, stable. A sustained-release pharmaceutical composition containing an agent and an isotonic agent, the pH of which is in the range of about 4.5 to about 6.5.
(3) NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and any one of a buffer and a pH adjuster, an interface. A sustained-release pharmaceutical composition containing an activator and an tonicity agent, the pH of which is in the range of about 4.5 to about 6.5.
(4) NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, a component of any one of a buffer and a pH adjuster, and A sustained-release pharmaceutical composition containing an tonicity agent and having a pH in the range of about 4.5 to about 6.5.
(5) An NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, and a component of any one of a stabilizer and a surfactant. And a sustained-release pharmaceutical composition containing an isotonic agent and having a pH in the range of about 4.5 to about 6.5.
(6) Contains an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and its pH is in the range of about 4.5 to about 6.5. Is a sustained release pharmaceutical composition.
(7) NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and a component of any one of a buffer and a pH adjuster, stable. It contains any one component of an agent or a surfactant, and an isotonic agent, and its pH is in the range of about 4.5 to about 6.5, and is filled in a glass or plastic medical container. A sustained-release pharmaceutical composition that is substantially free of buffers.
(8) NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and a component of any one of a buffer and a pH adjuster, stable. It contains an agent and an isotonic agent, the pH of which is in the range of about 4.5 to about 6.5, and substantially contains a buffer that is filled in a glass or plastic medical container. No, sustained release pharmaceutical composition.
(9) NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and any one of a buffer and a pH adjuster, an interface. It contains an activator and an isotonic agent, the pH of which is in the range of about 4.5 to about 6.5, and substantially contains a buffer that is filled in a glass or plastic medical container. No, sustained release pharmaceutical composition.
(10) The NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, a component of any one of a buffer and a pH adjuster, and Sustained release, containing isotonic agents, pH ranges from about 4.5 to about 6.5, filled in glass or plastic medical containers, substantially free of buffers. Sex pharmaceutical composition.
(11) An NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, and a component of any one of a stabilizer and a surfactant. And an isotonic agent, the pH of which is in the range of about 4.5 to about 6.5, filled in a glass or plastic medical container, substantially free of buffer, gradual. Release pharmaceutical composition.
(12) Contains the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and the pH thereof is in the range of about 4.5 to about 6.5. A sustained-release pharmaceutical composition that is substantially free of buffer and is filled in a glass or plastic medical container.
(13) The pH range is preferably in the range of about 4.8 to about 6.0, more preferably in the range of about 5.1 to about 5.5, and even more preferably in the range of about 5.3. , The sustained-release pharmaceutical composition according to (1) to (13) above.

The sustained-release pharmaceutical composition of the present invention is a pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. The form is not particularly limited.

For example, a pharmaceutical composition for oral administration (oral preparation) or a pharmaceutical composition for parenteral administration can be mentioned, but a pharmaceutical composition for parenteral administration is preferable. Examples of the pharmaceutical composition for parenteral administration include a pharmaceutical composition for topical administration and a pharmaceutical composition for systemic administration, more preferably a pharmaceutical composition for topical administration, and further preferably for intra-articular administration and A pharmaceutical composition for administration in the vicinity of a tendon / ligament attachment site, particularly preferably for intra-elbow joint administration, intra-shoulder joint administration, intra-wrist joint administration, intra-ankle administration, intra-hip joint administration. Pharmaceutical compositions for intra-articular administration and intra-knee joint administration, most preferably pharmaceutical compositions for intra-articular administration, and the above-mentioned pharmaceutical compositions for intra-articular administration and administration near tendon / ligament attachment sites. Liquid is preferred. In addition, injection is preferable as the administration form of the pharmaceutical composition for intra-articular administration and administration near the tendon / ligament attachment site.

In the present invention, the "pharmaceutical" in the sustained-release pharmaceutical composition is not limited to humans, and for example, for mammals (humans, monkeys, horses, cows, sheep, goats, dogs, cats, rats, etc.). Means a drug used for the prevention / treatment / diagnosis of any disease.

The solvent used in the sustained-release pharmaceutical composition of the present invention is not particularly limited and may be an aqueous solvent or a non-aqueous solvent, but an aqueous solvent is preferable. That is, the sustained-release pharmaceutical composition of the present invention is preferably an aqueous sustained-release pharmaceutical composition. When the sustained-release pharmaceutical composition of the present invention is a sustained-release pharmaceutical composition for injection, it is particularly preferable that the sustained-release pharmaceutical composition of the present invention is an aqueous sustained-release pharmaceutical composition, for example, injection. It can be prepared with water for injection, distilled water for injection, physiological saline, or the like. The aqueous solvent contains at least one component selected from the group consisting of a buffer, a pH adjuster, an isotonic agent, a stabilizer and a surfactant, as long as the gist of the present invention is not deviated. You may.

The amount of the NSAIDs-binding polysaccharide derivative represented by the formula (I) contained in the sustained-release pharmaceutical composition of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof is not particularly limited, but for example, Approximately 1 × 10 ^-1 to approximately 20 mg / mL, preferably approximately 5 × 10 ^-1 to approximately 15 mg / mL, preferably approximately 5 to approximately 15 mg / mL, and preferably approximately 8 to approximately. It is 12 mg / mL.
When converted to NSAIDs, the amount thereof is, for example, about 1 × 10 ^-3 to about 6 mg / mL, preferably about 5 × 10 ^-3 to about 4.5 mg / mL, and preferably about. It is 5 × 10 ^-2 to about 4.5 mg / mL, and preferably about 8 × 10 ^-2 to about 3.6 mg / mL.

The content of the NSAIDs-binding polysaccharide derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof contained in the sustained-release pharmaceutical composition of the present invention, or a solvate thereof per single dose is particularly high. For example, but not limited to, about 1 × 10 ^-1 to about 60 mg, preferably about 5 × 10 ^-1 to about 45 mg, preferably about 5 to about 45 mg, and preferably about 8 to about. It is 36 mg.
Further, for example, it is about 1 × 10 ^-1 to about 60 mg, preferably about 5 × 10 ^-2 to about 100 mg, and preferably about 2.5 × 10 ^-1 to about 75 mg, or preferably about. It is 2.5 to about 75 mg, preferably about 4 to about 60 mg.
When converted to NSAIDs, the amount thereof is, for example, about 1 × 10 ^-3 to about 18 mg, preferably about 5 × 10 ^-3 to about 13.5 mg, and preferably about 5 × 10 ^{−. 2} to about 13.5 mg, or preferably about 8 × ^{10 -2} to about 10.8 mg.
Further, for example, it is about 1 × 10 ^-3 to about 18 mg, preferably about 5 × 10 ^-4 to about 30 mg, and preferably about 2.5 × 10 ^-3 to about 22.5 mg. It is preferably about 2.5 × 10 ⁻² to about 22.5 mg, and preferably about 4 × 10 ⁻² to about 18 mg.

The NSAIDs-binding polysaccharide derivative represented by the formula (I) contained in the sustained-release pharmaceutical composition of the present invention can be produced by the above-mentioned [Production Method A] or [Production Method B].

≪9. Additives ≫
The sustained-release pharmaceutical composition of the present invention may also contain various additives. Examples of the additive include a buffer, a pH adjuster, an tonicity agent, a stabilizer, a surfactant and the like. In addition to the above-mentioned additives, additives approved as pharmaceutical additives (for example, solubilizing agents, oxidizing agents, sustaining agents, defoaming agents, coloring agents, and mucilages) are not particularly limited. It is possible to contain a thickening agent, a preservative, a preservative, a soothing agent, a dissolving agent, a dissolving aid, a solvent, etc.).

The additives in the present specification can also be used by being dissolved in water (water for injection, distilled water for injection, physiological saline, etc.).

≪9-1. Buffer ≫
The sustained release pharmaceutical composition of the present invention, in some embodiments, is one or more buffers to control the sustained release rate of NSAIDs from the sustained release pharmaceutical composition in a specified pH range. Can have. The buffering agent regulates pH and has a buffering ability. In general, the buffering capacity must be large enough to maintain the pH of the composition for a reasonably long shelf life, but also the rapid reconstitution of the composition to physiological pH upon administration. It must be small enough to allow adjustment.
Since the buffer according to the present invention has a buffering ability, it is not particularly limited as long as it can adjust the pH of the aqueous solution and stabilize it in a specified pH range, but it is not particularly limited. Approved as is preferred. Examples of the buffer according to the present invention include an acetic acid-based buffer, a citric acid-based buffer, a phosphoric acid-based buffer, a tartaric acid-based buffer, and the like.

The buffer is preferably acetic acid, ammonium acetate, potassium acetate, sodium acetate, sodium acetate hydrate or the like as an acetic acid-based buffer, and citrate, sodium citrate, trisodium citrate as a citrate-based buffer. , Sodium citrate hydrate, ammonium citrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or dipotassium hydrogen phosphate, etc., as tartrate buffers such as tartrate, sodium tartrate, or , Ammonium tartrate, etc .; more preferably acetate, sodium acetate, citrate, sodium citrate, sodium dihydrogen phosphate, or disodium hydrogen phosphate; more preferably sodium acetate / sodium acetate buffer, citrate. Acid / sodium citrate buffer, or sodium dihydrogen phosphate / disodium hydrogen phosphate buffer.

In addition to the buffer, for example, sodium hydroxide, ammonia solution, sodium hydrogencarbonate, sodium carbonate, tromethamole, meglumin, arginine, triethanolamine, lactic acid, boric acid, bicarbonate, carbonic acid, tetraborate, and diphosphorus. It is also possible to use various salts, acids or bases such as acids, tromethamines, hydroxyethylmorpholins, etc.

The sustained-release pharmaceutical composition of the present invention may or may not contain one or more of the buffers.
In the present invention, the buffer has a pH of the sustained release pharmaceutical composition of the present invention, for example, about 4.5 to about 6.5, preferably about 4.8 to about 6.0, more preferably about 5. Based on the total volume of the sustained release pharmaceutical composition of the present invention used in an amount that can be adjusted to 1 to about 5.5, more preferably about 5.3, for example, about 1 × ^10-5 to about 5%. (W / v), preferably in the range of about 1 × 10 ^-3 to about 3% (w / v), more preferably in the range of about 1 × 10 ⁻² to about 1% (w / v). Used. It is also used at a concentration of about 1 × 10 ^-4 mg / mL to about 50 mg / mL.

In the present invention, the pH range of the buffer varies depending on the type of buffer used. For example, in the case of an acetic acid-based buffer, pH = about 4.5 to about 5.9, preferably pH = about 4.5 to about 5.5 (concentration is 20 mM or less), and more preferably acetic acid. -Sodium acetate buffer, pH = about 5.1 to about 5.5 (concentration is 10 mM).

For example, in the case of a citric acid-based buffer, pH = about 4.5 to about 6.5, preferably pH = about 4.5 to about 5.5 (concentration is 20 mM or less), and more preferably. It is a citric acid / sodium citrate buffer, and has a pH of about 5.1 to about 5.5 (concentration is 10 mM).

For example, in the case of a phosphoric acid-based buffer, pH = about 5.8 to about 6.5, preferably pH = 6.5 (concentration is 20 mM or less), and more preferably sodium dihydrogen phosphate. It is a disodium hydrogen phosphate buffer and has a pH of 6.5 (concentration is 10 mM).

For example, in the case of a tartaric acid-based buffer, pH = about 4.5 to about 5.2.

In some embodiments, the buffer is about 0.01 mM to about 100 mM, about 0.05 mM to about 100 mM, about 0.5 mM to about 100 mM, about 1 mM to about 50 mM, about 1 mM to about 40 mM, about 1 mM to. It can be present at about 30 mM, about 1 mM to about 20 mM or about 1 mM to about 10 mM. In some embodiments, the buffer is about 0.01 mM, about 0.05 mM, about 0.1 mM, about 0.2 mM, about 0.5 mM, about 1 mM, about 5 mM, about 10 mM, about 20 mM, about 30 mM. , May be present at about 40 mM, about 50 mM or about 100 mM.

When the sustained-release pharmaceutical composition of the present invention contains a salt of an NSAIDs-binding polysaccharide derivative represented by the formula (I), the salt produced by diverging from the salt of the NSAIDs-binding polysaccharide derivative represented by the formula (I) is the present invention. It is not considered to be a buffer according to the invention.

The sustained-release pharmaceutical composition containing the buffer of the present invention can control the release of NSAIDs from the NSAIDs-binding polysaccharide derivative in the composition. In particular, when NSAIDs are diclofenac, it is possible to control the release of diclofenac and further suppress the production of diclofenac amide. Furthermore, when the derivative contained in the composition is a diclofenac-bonded alginic acid derivative, it is possible to control the release of diclofenac, suppress the production of diclofenac amide, and reduce the amount of alginic acid. It is possible to suppress molecularization within a certain range.

≪9-2. pH regulator ≫
The pH adjuster according to the present invention is not particularly limited as long as the composition can be stabilized by adjusting the pH, but those approved as pharmaceutical additive components are preferable. Examples of the pH adjuster include acids, acid salts, bases, base salts and the like. The pH adjuster in the present invention does not have a buffering capacity.

The pH adjuster is preferably an acid such as acetic acid, citric acid, phosphoric acid, succinic acid, gluconic acid, malic acid, tartaric acid, lactic acid, boric acid, hydrochloric acid, adipic acid, maleic acid, sulfuric acid, carbon dioxide and the like; As acid salts, ammonium acetate, sodium acetate, sodium acetate hydrate, sodium citrate, sodium citrate hydrate, sodium dihydrogen citrate, sodium monohydrogen phosphate, sodium monohydrogen phosphate / heptahydrate , Disodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, disodium hydrogen phosphate, disodium hydrogen phosphate dihydrate, dipotassium phosphate, potassium dihydrogen phosphate, dihydrogen phosphate Sodium, disodium succinate, disodium succinate hexahydrate, sodium tartrate, calcium lactate, calcium lactate hydrate, sodium lactate solution, ammonium borate, sodium borate, monosodium fumarate, sodium propionate, sulfuric acid Aluminum potassium, etc .; as bases, triethanolamine, meglumin, monoethanolamine, diisopropanolamine, triisopropanolamine, aqueous ammonia, sodium carbonate, sodium carbonate hydrate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide , Calcium hydroxide, magnesium hydroxide, etc .; as a base salt, tromethamole hydrochloride, etc.; more preferably acetic acid, citric acid, phosphate, succinic acid, gluconic acid, malic acid, tartrate acid, lactic acid, boro Acid, hydrochloric acid, adipic acid, maleic acid, ammonium acetate, sodium acetate, sodium acetate hydrate, sodium citrate, sodium citrate hydrate, sodium dihydrogen citrate, sodium monohydrogen phosphate, sodium monohydrogen phosphate・ Hexahydrate, trisodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, disodium hydrogen phosphate, disodium hydrogen phosphate dihydrate, dipotassium phosphate, potassium dihydrogen phosphate , Disodium dihydrogen phosphate, disodium succinate, disodium disodium hexahydrate, sodium tartrate, calcium lactate, calcium lactate hydrate, sodium lactate solution, or ammonium borate; more preferably acetic acid, Ammonium acetate, sodium acetate, or sodium acetate hydrate; particularly preferably acetic acid or sodium acetate.

In addition to the pH regulator, for example, glucono-δ-lactone, glycine, glycerin and the like can also be used.

The concentration of the pH adjuster according to the present invention is not particularly limited as long as the composition can be stabilized by adjusting the pH. The total volume of the sustained release pharmaceutical composition of the present invention is, for example, 0 to about 5 × 10 ^-3 % (w / v), preferably 0 to about 3 × 10 ^-3 % (w / v). , More preferably, it is used in the range of 0 to about 1 × 10 ^{-3% (w / v).} Also, for example, it is used at a content concentration of ^{0 to about 5 × 10-2 mg / mL.} Specifically, when acetic acid or sodium acetate is used as the pH adjuster, ^{a concentration of 1 × 10 -7} to 1 × 10 ^-4 % (w / v) can be mentioned.

The sustained-release pharmaceutical composition containing the pH adjuster of the present invention can control the release of NSAIDs from the NSAIDs-binding polysaccharide derivative in the composition by adjusting the pH of the composition. .. In particular, when NSAIDs are diclofenac, it is possible to control the release of diclofenac and further suppress the production of diclofenac amide. Furthermore, when the derivative contained in the composition is a diclofenac-bonded alginic acid derivative, it is possible to control the release of diclofenac, suppress the production of diclofenac amide, and reduce the amount of alginic acid. It is possible to suppress molecularization within a certain range.

≪9-3. Isotonic agent ≫
The tonicity agent according to the present invention is an agent for adjusting the osmotic pressure of the sustained-release pharmaceutical composition of the present invention, and is generally used for adjusting the osmotic pressure to the same degree as the osmotic pressure of a body fluid. The tonicity agent is not particularly limited, but those approved as pharmaceutical additive components are preferable.

Examples of the tonicity agent include salts, sugars, sugar alcohols, polyhydric alcohols, phosphoric acid, citric acid, aminoethyl sulfonic acid, nicotinic acid amide, benzyl alcohol, boric acid, borax and the like.

The tonicity agent preferably contains, as salts, sodium chloride, potassium chloride, calcium chloride (hydrate), magnesium chloride, citrate hydrate, sodium citrate, sodium citrate hydrate, sodium bromide, etc. Potassium bromide, calcium bromide, sodium lactate solution, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, sodium hydrogen carbonate, sodium hydrogen sulfite, chloride Benzarkonium, anhydrous sodium citrate, etc .; sugars include glucose, fructose, lactose hydrate, trehalose hydrate, etc .; sugar alcohols include mannitol, sorbitol, xylitol, etc.; polyhydric alcohols, etc. Glycerin, propylene glycol, Macrogol 4000 and the like; more preferably glucose, fructose, lactose hydrate, trehalose hydrate, mannitol, sorbitol, xylitol, glycerin, propylene glycol, or Macrogol 4000; more preferred. Is mannitol.

The content of the tonicity agent is not particularly limited as long as the osmotic pressure of the sustained-release pharmaceutical composition of the present invention can be adjusted to the same level as the osmotic pressure of the body fluid. The total volume of the sustained release pharmaceutical composition of the present invention is, for example, about 1 to about 10% (w / v), preferably about 1.5 to about 7% (w / v), and more preferably. It is used in the range of about 2 to about 5% (w / v). It is also used at a concentration of about 10 mg / mL to about 100 mg / mL. For example, a concentration of 4 to 5% (w / v) in the case of sugar, 4 to 5% (w / v) in the case of sugar alcohol, and 2 to 3% (w / v) in the case of polyhydric alcohol can be mentioned, which is preferable. Is 4 to 5% (w / v) in the case of mannitol.

≪9-4. Stabilizer ≫
The stabilizer according to the present invention is an agent for stabilizing the sustained-release pharmaceutical composition of the present invention, and is not particularly limited, but one approved as a pharmaceutical additive component is preferable.
Examples of the stabilizer include sugar, sugar alcohol, and the like.

The stabilizer is preferably cyclodextrin or disaccharide as a sugar, mannitol, sorbitol, xylitol, glycerin or the like as a sugar alcohol; more preferably HP-β-cyclodextrin or sulfobutyl ether-β as a cyclodextrin. -Cyclodextrin, sucrose, lactose or maltose hydrate as disaccharide, mannitol, sorbitol, xylitol, or glycerin as sugar alcohol; more preferably HP-β-cyclodextrin, or sulfobutyl ether-β-cyclodextrin Is.

The content of the stabilizer according to the present invention is not particularly limited, but in the total volume of the sustained-release pharmaceutical composition of the present invention, for example, about 1 × 10 ^-1 to about 10% (w / v), preferably. It is about 1.5 × 10 ^-1 to about 9% (w / v), and more preferably ^{used in the range of about 3 × 10 -1} to about 8% (w / v). It is also used at a concentration of about 1 mg / mL to about 100 mg / mL. For example, in the case of HP-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin, it is about 0.5 to about 5% (w / v).

When the sustained-release pharmaceutical composition contains a stabilizer, particularly HP-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin, the filtration efficiency is improved in the filtration sterilization step during the production of the composition. It is possible.

≪9-5. Surfactant ≫
The surfactant according to the present invention is an agent for improving the solubility of the sustained-release pharmaceutical composition of the present invention, and is not particularly limited, but one approved as a pharmaceutical additive component is preferable.

Examples of the surfactant include a pluronic-based surfactant (for example, Pluronic F68, etc.), a Tween-based surfactant (for example, polysolvate 80, etc.), and a castor oil-based surfactant (for example, polyoxyethylene surfactant). , Etc.), Hardened castor oil-based surfactant (for example, polyoxyethylene cured castor oil 60, etc.), and the like, preferably polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene. (54) Polyoxypropylene (39) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68), polysolvate 80, polysolvate 20. , More preferably, polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F68), or polysolvate 80.

The content of the surfactant according to the present invention is not particularly limited, but in the total volume of the sustained-release pharmaceutical composition of the present invention, for example, about 1 × ^10-2 to about 5% (w / v), preferably. It is about 1 × 10 ^-1 to about 3% (w / v), and more preferably ^{used in the range of about 1 × 10 -1} to about 1% (w / v). It is also used at a concentration of about 1 × 10 ^-1 mg / mL to about 50 mg / mL.

In addition to the above-mentioned surface activity, as an agent for improving solubility (solubility improving agent), a salt such as sodium chloride, a sugar [cyclodextrin (HP-β-cyclodextrin, etc.)), and a disaccharide (sucrose) , Etc.), etc.], sugar alcohols (mannitol, glycerin, etc.), water-soluble polymers (guagam, HA, CMC, HPMC, CVP, PVP, etc.) and the like can also be used.

Of the stabilizers, cyclodextrin and some surfactants may be classified as viscosity reducing agents (filtration efficiency improving agents).

≪9-6. Viscosity lowering agent (filtration efficiency improving agent) ≫
The viscosity reducing agent (filtration efficiency improving agent) according to the present invention is an agent for improving the viscosity or filtering efficiency of the sustained-release pharmaceutical composition of the present invention, and is not particularly limited. Those approved as pharmaceutical additive ingredients are preferable.

The viscosity reducing agent (filtering efficiency improving agent) is a substance that suppresses the hydrophobic bond between NSAIDs in the NSAIDs-binding polysaccharide derivative represented by the formula (I) contained in the sustained-release pharmaceutical composition of the present invention. For example, a compound having an inclusion action such as cyclodextrin, a compound having an amphipathic action such as a surfactant, and the like can be mentioned, and HP-β-cyclodextrin as a compound having an inclusion action is preferable. , Sulfobutyl ether-β-cyclodextrin, polyoxyethylene (160) polyoxypropylene (30) glycol (Complonic F68) as a surfactant, more preferably HP-β-cyclodextrin or Pluronic F68.

The content of the viscosity reducing agent (filtration efficiency improving agent) according to the present invention is not particularly limited, but when the viscosity reducing agent (filtration efficiency improving agent) is a surfactant, for example, about 1 × ^10-2 to about 5%. (W / v), preferably in the range of about 1 × 10 ^-1 to about 3% (w / v), more preferably in the range of about 1 × 10 ^-1 to about 1% (w / v). Used. When the viscosity reducing agent (filtration efficiency improving agent) is cyclodextrin, for example, about 1 × 10 ^-1 to about 10% (w / v), preferably about 1.5 × 10 ^-1 to about 9%. (W / v), more preferably ^{used in the range of about 3 × 10 -1} to about 8% (w / v) (w / v).

In the present specification, when the content of the viscosity reducing agent (filtration efficiency improving agent) is described as "about", it may include a value up to ± 20% of the value, preferably up to ± 10% of the value. It is a thing.

≪10. pH ≫
The pH of the sustained-release pharmaceutical composition of the present invention can control the release of NSAIDs from the NSAIDs-binding polysaccharide derivative contained in the sustained-release pharmaceutical composition of the present invention, that is, the NSAIDs and the linker (-L1-) are bound. There is a need for a pH at which the ester bond is not easily hydrolyzed and the composition can remain stable.
Further, particularly in the diclofenac-bonded polysaccharide derivative in which NSAIDs are diclofenac, the ester bond in which diclofenac and the linker (-L1-) are bonded is not easily hydrolyzed, and the formation of diclofenac amide can be suppressed. There is a need for a pH that allows the product to remain stable.
Further, when a diclofenac-bonded alginic acid derivative is contained, the ester bond to which diclofenac and the linker (-L1-) are bonded is not easily hydrolyzed, the formation of diclofenac amide can be suppressed, and the alginic acid can be further suppressed. There is a need for a pH at which low molecular weight can be suppressed within a certain range and the composition can remain stable.

The pH of the sustained release pharmaceutical composition of the present invention can be preferably acidic, preferably in the range of about 4.5 to about 6.5, preferably about 4.8 to about 6.0. It is in the range of about 5.1 to about 5.5, more preferably about 5.3.
In the present specification, when "about" is described in the pH value description, a value of ± 0.1 of the value may also be included.

On the other hand, according to a preferred embodiment of the present invention, in the sustained-release pharmaceutical composition of the present invention, by adjusting the pH range to the above-mentioned suitable range, the sustained-release pharmaceutical composition exhibiting long-term stability can be obtained. can do. As will be described later, if a specific container is used as the container for filling the sustained-release pharmaceutical composition of the present invention, it may be possible to further improve the stability.

The pH of the sustained-release pharmaceutical composition of the present invention can be adjusted by a method known per se, for example, using a buffer or a pH adjuster.

≪11. Method for producing sustained-release pharmaceutical composition ≫
The sustained-release pharmaceutical composition of the present invention can be produced by various production methods known per se. Usually, the various components (buffer, pH adjuster, tonicity agent, stabilizer, and / or surfactant) described above that can constitute the sustained-release pharmaceutical composition of the present invention are appropriately selected. It can be produced by mixing with a suitable solvent and dissolving it.

Since the sustained-release pharmaceutical composition of the present invention is preferably a sustained-release pharmaceutical composition for intra-articular administration and administration near a tendon / ligament attachment site, it can be produced as an aqueous sustained-release pharmaceutical composition. preferable.

In the case of an aqueous sustained-release pharmaceutical composition, it is preferable that the composition is sterilized at the time of production or before administration. When the sterile operation method is adopted as the sterile treatment, each of the weighed raw materials is water, an aqueous solution containing a pharmaceutically acceptable metal salt or a pH adjuster, an aqueous solvent such as a buffer solution, specifically water for injection. , Phosphate buffered saline, physiological saline and the like, and the solution can be sterilized by filtration to produce a liquid pharmaceutical composition. Water for injection is generally understood as sterile purified water that meets the exothermic substance (endotoxin) test, and water for injection produced by the distillation method is sometimes referred to as distilled water for injection.

The material of the filtration membrane for sterilizing the solution by filtration is not particularly limited, but those having a track record of use in pharmaceutical production are preferable, for example, polyether sulfone, PVDF (Polyvinylidene DiFluoride), cellulose acetate. , Regenerated cellulose, PTFE (Poly Tera Fluoro Ethylene: polytetrafluoroethylene), cellulose mixed ester, and the like, and can be appropriately selected.

Filtration of the solution can be dust-removed, sterilized, and sterilized according to the pore size of the filtration membrane. Dust removal and sterilization are possible by filtering with a filtration membrane with a pore size of about 5 μm or less, and sterilization is possible by further filtering with a filtration membrane with a pore size of about 0.45 μm or less to about 0.22 μm or less. Is also possible. In the present specification, when "about" is described in the description of the pore size of the filtration membrane, the value up to ± 0.1 μm of the value may be included.

The sustained-release pharmaceutical composition containing the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof is described in the following (1) to (3). It can be manufactured through a manufacturing process.
(1) NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, as well as a buffer, a pH adjuster, an tonicity agent, a stabilizer and a stabilizer. At least one component selected from the group consisting of surfactants is dissolved in a solvent.
(2) If necessary, a pH adjuster or buffer is added to adjust the pH of the solution to about 4.5 to about 6.5.
(3) The solution after pH adjustment is filtered using a filtration membrane having a pore size of about 5 μm or less.

In the method for producing a sustained-release pharmaceutical composition containing the NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, the formula (I) is used. The NSAIDs-conjugated polysaccharide derivative represented, or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably the formula (Ia), the formula (Ib), the formula (IC) and the like. At least one derivative selected from the group consisting of the formula (Ic-1), more preferably selected from the group consisting of the formula (Ic) and the formula (Ic-1). At least one or more derivatives.

Further, in the production method, the pH of the adjusted solution is preferably about 4.8 to about 6.0, more preferably about 5.1 to about 5.5, and even more preferably about 5.3. ..
Further, in the production method, and in the production method, the pore size of the filtration membrane is about 5 μm or less, preferably 0.45 μm or less, and more preferably about 0.22 μm or less.

This liquid pharmaceutical composition for injection can be further filled and sealed in a washed and sterilized container, and after inspection, packaging, etc., an injection prepared by filling the liquid pharmaceutical composition for injection can be produced. Here, the container is not particularly limited, and examples thereof include ampoules, vials, prefilled syringes, cartridges, and bags. The material of the container is not particularly limited, and examples thereof include glass and plastic. From the viewpoint of strength, ease of handling, safety and the like, plastic is preferable.

≪12. A method for controlling the release of NSAIDs from NSAIDs-binding polysaccharide derivatives in sustained-release pharmaceutical compositions >>
Since the sustained-release pharmaceutical composition of the present invention is intended to stably release NSAIDs for a long period of time after administration into a joint cavity or the like and deliver the NSAIDs to the affected area, storage conditions before administration (for example, about 2). ~ About 8 ° C.), when the ester bond formed by the NSAIDs and the linker (-L1-) in the structure of the NSAIDs-binding polysaccharide derivative represented by the formula (I) is hydrolyzed and released, the joint cavity. This can lead to a decrease in the amount of diclofenac that can be sustained-released internally, making it impossible to reach the affected area in an effective amount, which can be an important issue as a pharmaceutical product. Therefore, under storage conditions before administration (for example, about 2 to about 8 ° C.), it is required to be stable for a long period of time without being easily hydrolyzed.
Hydrolysis can be controlled by keeping the liquid property of the pharmaceutical composition of the present invention in the range of weakly acidic to acidic.
The pH of the sustained release pharmaceutical composition of the present invention is preferably in the range of about 4.5 to about 6.5, more preferably in the range of about 4.8 to about 6.0, and even more preferably in the range of about 5. Hydrolysis of the ester groups of NSAIDs-linked polysaccharide derivatives can be controlled by keeping in the range of .1 to about 5.5, most preferably pH = about 5.3. Specifically, the amount of NSAIDs released from the NSAIDs-binding polysaccharide derivative in the sustained-release pharmaceutical composition under storage conditions can be reduced to 25% or less.

The method for controlling the hydrolysis of the NSAIDs-binding polysaccharide derivative is particularly advantageous when preserving the sustained-release pharmaceutical composition of the present invention, and from the results of Examples described later, storage conditions (for example, about 2 to 2 to At about 8 ° C.), it can be expected that the quality can be maintained and stored for 6 months, 12 months, 36 months, 40 months, or more.

≪13. Method of suppressing the production of diclofenac amide from a diclofenac-binding polysaccharide derivative ≫
In the present specification, when NSAIDs are diclofenac in the NSAIDs-binding polysaccharide derivative represented by the formula (I), the following formula is used under certain specific conditions (for example, alkaline to neutral conditions) due to its structural properties. (DFA):

Can produce diclofenac amide represented by. For example, under alkaline conditions, in the NSAIDs-linked polysaccharide derivative represented by the formula (I) (NSAIDs are diclofenac), the aniline imino group (-NH- group) of diclofenac is intramolecular with respect to the carbonyl group of the ester bond. Diclofenac amide may be produced by the nucleophilic reaction.
Since the sustained-release pharmaceutical composition of the present invention is to be delivered to the affected area by stably releasing NSAIDs for a long period of time after administration into the joint cavity or the like, storage conditions before administration (for example, about 2 to 2 to). If diclofenac amide is formed at about 8 ° C.), it leads to a decrease in the amount of diclofenac that can be released slowly in the joint cavity, etc., and it becomes impossible to reach the affected area in an effective amount, which is an important issue as a drug. Can be. Therefore, under storage conditions before administration (for example, about 2 to about 8 ° C.), conditions under which diclofenac amide is unlikely to be formed are required.
By keeping the liquid property of the pharmaceutical composition of the present invention in the range of weakly acidic to acidic, it is possible to suppress the production of diclofenac amide.
The pH of the sustained-release pharmaceutical composition of the present invention is preferably in the range of about 4.5 to about 6.5, more preferably in the range of about 4.8 to about 6.0, and even more preferably in the range of about 5. By keeping the range from .1 to about 5.5, most preferably pH = about 5.3, the production of diclofenac amide can be suppressed more than the diclofenac-binding polysaccharide derivative. Specifically, the amount of diclofenac amide produced in the sustained-release pharmaceutical composition under storage conditions can be suppressed to about 20% or less.

The method of suppressing the production of diclofenac amide from the diclofenac-binding polysaccharide derivative is particularly effective in preserving the sustained-release pharmaceutical composition of the present invention, and the results of Examples described later (Example F5-2 (pH =). Based on the model analysis using the data of 6.5) and the Arenius plot, the amount of diclofenac amide produced was estimated to be about 18% under the storage conditions of about 5 ° C. and the storage period of 40 months). At (for example, about 2 to about 8 ° C.), it can be expected that the quality can be maintained and stored for a period of 6 months, 12 months, 36 months, 40 months, or more.

≪14. Method of suppressing the molecular weight reduction of alginic acid in NSAIDs-linked alginic acid derivative (diclofenac-linked alginic acid derivative) >>
The sustained-release pharmaceutical composition of the present invention is an NSAIDs-linked alginic acid derivative, which is one of the NSAIDs-linked polysaccharide derivatives represented by the formula (I), under storage conditions before administration (for example, about 2 to about 8 ° C.). If the molecular weight of alginic acid in the diclofenac-linked alginic acid derivative is reduced, it may lead to a decrease in the overall viscosity of the composition, which may lead to a decrease in the medicinal effect when the composition is administered into the joint cavity or the like, which is important as a pharmaceutical product. Can be a challenge. Therefore, it is required to keep the molecular weight reduction of alginic acid within a certain range under the storage conditions before administration (for example, about 2 to about 8 ° C.).

Under the conditions of 2 to 8 ° C., alginic acid is a neutral or weakly alkaline liquid and has a low molecular weight reduction rate. In addition, there is a report that the molecular weight is reduced at pH = 4.3 (Carbohydrate Polymer 73, p656-664, 2008). The composition of the present invention controls the release (hydrolysis reaction) of NSAIDs from the NSAIDs-binding polysaccharide derivative represented by the above formula (I), and also from the diclofenac-linked polysaccharide derivative represented by the formula (Ia). It is required to simultaneously satisfy the suppression of the production of diclofenac amide and the control of the molecular weight reduction of alginic acid.
This time, a specific component is added to the sustained-release pharmaceutical composition of the present invention, and the pH is in the range of about 4.5 to about 6.5, preferably in the range of about 4.8 to about 6.0. By setting it in the range of more preferably about 5.1 to about 5.5, and most preferably about 5.3, the reduction of the molecular weight (reduction of molecular weight) of alginic acid in the NSAIDs-linked alginic acid derivative or the diclofenac-linked alginic acid derivative is reduced by about 10. It became possible to keep it below%.
The method of suppressing the reduction of the molecular weight of alginic acid in the NSAIDs-linked alginic acid derivative is particularly advantageous when preserving the sustained-release pharmaceutical composition of the present invention, and from the results of Examples described later, storage conditions (for example, for example). At about 2 to about 8 ° C.), it can be expected that the quality can be maintained and stored for 6 months, 12 months, 36 months, 40 months, or more.

≪15. Sustained release of NSAIDs-binding polysaccharide derivatives >>
The NSAIDs-binding polysaccharide derivative represented by the formula (I) of the present invention alone does not bring about the anti-inflammatory effect of NSAIDs. The NSAIDs-binding polysaccharide derivative represented by the formula (I) of the present invention is ester-bonded to NSAIDs on its (HO-L1-) side via a divalent linker represented by HO-L1-H, and its (-) is bonded. Since it has a structure in which an amide bond is formed with the carboxyl group of the polysaccharide on the L1-H) side, for example, when it is made into a solution, it has the property of slowly releasing NSAIDs according to the liquid properties of the solution. .. Therefore, for example, when the NSAIDs-binding polysaccharide derivative represented by the formula (I) is administered in vivo (for example, in the joint cavity, in the human knee joint cavity, etc.), it depends on the state (liquidity) of the administration site. , The ester moiety to which the NSAIDs and the linker are bound is hydrolyzed and the NSAIDs are slowly released. Then, when the amount of NSAIDs necessary for suppressing inflammation or pain in the affected area stably reaches the affected area, it becomes possible to exert an anti-inflammatory effect and an analgesic effect for a long period of time. Due to the above properties, it is possible to form a sustained-release pharmaceutical composition using an NSAIDs-binding polysaccharide derivative.

≪16. How to save ≫
For the purpose of enhancing the storage stability of the sustained-release pharmaceutical composition of the present invention, in the process of preserving the sustained-release pharmaceutical composition, controlling the hydrolysis of the NSAIDs-binding polysaccharide derivative, diclofenac-binding polysaccharide derivative to diclofenac It is desirable to simultaneously achieve suppression of amide formation and suppression of alginic acid molecular weight reduction in NSAIDs-linked alginic acid derivatives. Therefore, for the purpose of enhancing the storage stability of the sustained-release pharmaceutical composition of the present invention, at least one selected from the group consisting of a buffer, a pH adjuster, an tonicity agent, a stabilizer and a surfactant. It is preferable to take measures such as addition of more than seed components, pH optimization, and storage temperature / humidity control.

Among the above means, it is preferable to optimize the pH of the sustained-release pharmaceutical composition of the present invention for the purpose of enhancing the storage stability. For example, the pH can be in the acidic to weakly acidic range, preferably in the range of about 4.5 to about 6.5, more preferably in the range of about 4.8 to about 6.0. More preferably, it can be in the range of about 5.1 to about 5.5, and most preferably about 5.3.

The container for storing the sustained-release pharmaceutical composition during storage is not particularly limited, but is limited to glass medical containers (glass ampoules, glass vials, glass syringes, glass cartridges, etc.) and plastic medical containers (plastic). It is preferable that the container is filled in an ample, a plastic vial, a plastic syringe, a plastic cartridge, etc.) and stored.

In the present specification, the temperature at which the sustained-release pharmaceutical composition containing the NSAIDs-binding polysaccharide derivative represented by the formula (I), the pharmaceutically acceptable salt thereof, or a solvate thereof is stored is the relevant temperature. The pharmaceutical composition can be stably stored for a long period of time (for example, (1) the release of NSAIDs from the NSAIDs-binding polysaccharide derivative in the pharmaceutical composition can be controlled, and (2) the NSAIDs-linked polysaccharide derivative (NSAIDs) in the pharmaceutical composition can be controlled. The formation of diclofenacamide from diclofenac) can be suppressed, (3) the reduction of alginic acid in the NSAIDs-linked alginic acid derivative in the pharmaceutical composition can be suppressed, etc.) The temperature is particularly limited. However, for example, room temperature (0 ° C. to about 25 ° C.) can be mentioned, preferably in the range of about 2 to about 8 ° C., and more preferably about 5 ° C.

(1) At least selected from the group consisting of a buffer, a pH adjuster, an isotonic agent, a stabilizer and a surfactant for the purpose of enhancing the storage stability of the sustained-release pharmaceutical composition of the present invention. One or more components may be included in the sustained release pharmaceutical composition. When the sustained-release pharmaceutical composition of the present invention is filled in a glass or plastic medical container, at least one selected from the group consisting of a buffer, a pH adjuster, an isotonic agent, a stabilizer and a surfactant. It is preferable to contain more than seed components. In aspects of these storage methods, the pH at the start of storage of the sustained release pharmaceutical composition of the present invention is preferably in the range of about 4.5 to about 6.5, more preferably about 4.8 to about 6. It is in the range of .0, more preferably in the range of about 5.1 to about 5.5, and most preferably in the range of about 5.3. In the aspect of these storage methods, the storage conditions of the sustained-release pharmaceutical composition of the present invention are preferably in the range of about 2 to about 8 ° C, more preferably about 5 ° C.

(2) For the purpose of enhancing the storage stability of the sustained-release pharmaceutical composition of the present invention, any one component of a buffer or a pH adjuster, any one of a stabilizer or a surfactant. Ingredients and isotonic agents may be included in the sustained release pharmaceutical composition. When the sustained-release pharmaceutical composition of the present invention is filled in a glass or plastic medical container, one component of either a buffer or a pH adjuster, or one component of a stabilizer or a surfactant. , And an isotonic agent are preferably contained. In aspects of these storage methods, the pH at the start of storage of the sustained release pharmaceutical composition of the present invention is preferably in the range of about 4.5 to about 6.5, more preferably about 4.8 to about 6. It is in the range of .0, more preferably in the range of about 5.1 to about 5.5, and most preferably in the range of about 5.3. In the aspect of these storage methods, the storage conditions of the sustained-release pharmaceutical composition of the present invention are preferably in the range of about 2 to about 8 ° C, more preferably about 5 ° C.

(3) Sustained release of any one component of a buffer or a pH adjuster, a stabilizer, and an isotonic agent for the purpose of enhancing the storage stability of the sustained-release pharmaceutical composition of the present invention. It may be contained in a pharmaceutical composition. When the sustained-release pharmaceutical composition of the present invention is filled in a glass or plastic medical container, it may contain one of a buffer or a pH adjuster, a stabilizer, and an isotonic agent. preferable. In aspects of these storage methods, the pH at the start of storage of the sustained release pharmaceutical composition of the present invention is preferably in the range of about 4.5 to about 6.5, more preferably about 4.8 to about 6. It is in the range of .0, more preferably in the range of about 5.1 to about 5.5, and most preferably in the range of about 5.3. In the aspect of these storage methods, the storage conditions of the sustained-release pharmaceutical composition of the present invention are preferably in the range of about 2 to about 8 ° C, more preferably about 5 ° C.

(4) Sustained release of any one component of a buffer or a pH adjuster, a surfactant, and an isotonic agent for the purpose of enhancing the storage stability of the sustained-release pharmaceutical composition of the present invention. It may be contained in a pharmaceutical composition. When the sustained-release pharmaceutical composition of the present invention is filled in a glass or plastic medical container, it may contain one of a buffer or a pH adjuster, a surfactant, and an isotonic agent. preferable. In aspects of these storage methods, the pH at the start of storage of the sustained release pharmaceutical composition of the present invention is preferably in the range of about 4.5 to about 6.5, more preferably about 4.8 to about 6. It is in the range of .0, more preferably in the range of about 5.1 to about 5.5, and most preferably in the range of about 5.3. In the aspect of these storage methods, the storage conditions of the sustained-release pharmaceutical composition of the present invention are preferably in the range of about 2 to about 8 ° C, more preferably about 5 ° C.

(5) For the purpose of enhancing the storage stability of the sustained-release pharmaceutical composition of the present invention, any one component of a buffer or a pH adjuster and an tonicity agent are added to the sustained-release pharmaceutical composition. It may be contained. When the sustained-release pharmaceutical composition of the present invention is filled in a glass or plastic medical container, it is preferable to contain one of a buffer or a pH adjuster and an isotonic agent. In aspects of these storage methods, the pH at the start of storage of the sustained release pharmaceutical composition of the present invention is preferably in the range of about 4.5 to about 6.5, more preferably about 4.8 to about 6. It is in the range of .0, more preferably in the range of about 5.1 to about 5.5, and most preferably in the range of about 5.3. In the aspect of these storage methods, the storage conditions of the sustained-release pharmaceutical composition of the present invention are preferably in the range of about 2 to about 8 ° C, more preferably about 5 ° C.

(6) For the purpose of enhancing the storage stability of the sustained-release pharmaceutical composition of the present invention, the sustained-release pharmaceutical composition contains any one component of a stabilizer or a surfactant and an isotonic agent. It may be contained in. When the sustained-release pharmaceutical composition of the present invention is filled in a glass or plastic medical container, it is preferable to contain one of a stabilizer or a surfactant component and an isotonic agent. In aspects of these storage methods, the pH at the start of storage of the sustained release pharmaceutical composition of the present invention is preferably in the range of about 4.5 to about 6.5, more preferably about 4.8 to about 6. It is in the range of .0, more preferably in the range of about 5.1 to about 5.5, and most preferably in the range of about 5.3. In the aspect of these storage methods, the storage conditions of the sustained-release pharmaceutical composition of the present invention are preferably in the range of about 2 to about 8 ° C, more preferably about 5 ° C.

As an index of the storage stability of the sustained-release pharmaceutical composition of the present invention, for example, when the NSAIDs-binding polysaccharide derivative represented by the formula (I) is contained, the NSAIDs released in the sustained-release pharmaceutical composition are released. The total amount of. The storage stability of the sustained-release pharmaceutical composition of the present invention can be evaluated by measuring / quantifying the total amount of NSAIDs released after storage for a certain period of time. When the diclofenac-binding polysaccharide derivative represented by the formula (Ic) is contained, the sustained-release pharmaceutical composition of the present invention is similarly measured / quantified in each amount of diclofenac or diclofenac amide. Can be evaluated for storage stability. When a diclofenac-bound alginic acid derivative represented by the formula (Ic-1) is contained, the present invention is similarly measured by measuring / quantifying each amount of diclofenac or diclofenac amide and the molecular weight of alginic acid. The storage stability of the sustained-release pharmaceutical composition can be evaluated. The amount of NSAIDs, diclofenac or diclofenac amide, and the molecular weight of alginic acid in the sustained-release pharmaceutical composition of the present invention can be detected and quantified using, for example, an analytical instrument such as LC-mass.

Examples and test examples will be given to explain the present invention in more detail, but these examples are merely examples and do not limit the present invention, and are changed without departing from the scope of the present invention. You may.

(Example A1) to (Example A24) and (Example 1) to (Example 54) are examples relating to NSAIDs-binding polysaccharide derivatives.

JEOL JNM-ECX400 FT-NMR (JEOL Ltd.) was used for the measurement of the nuclear magnetic resonance spectrum (NMR) of the examples. In 1H-NMR data, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz is hertz, and CDCl3 is heavy. Chloroform and DMSO-d6 mean deuterated dimethylsulfoxide, and CD3OD means deuterated methanol. In the 1H-NMR data, signals that cannot be confirmed due to broadband, such as hydroxyl group (OH), amino group (NH2), and carboxyl group (COOH) protons, are not described in the data.

The introduction rate (mol%) of NSAIDs in the examples is, for example, when the polysaccharide is alginic acid, 1 unit (molar) of the monosaccharide of D-mannuronic acid or L-gluuronic acid constituting alginic acid calculated from 1H-NMR. ), The ratio of the number of moles of introduced NSAIDs to 100 units (moles) of monosaccharides constituting alginic acid. When the polysaccharide is hyaluronic acid, it can be calculated in the same manner with the monosaccharide substituted by the carboxyl group of hyaluronic acid as one unit.

In the examples, the liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by the following method. Model: ZQ-2000 (waters), [UPLC] Waters AQUITY UPLC system and BEH C18 column (2.1 mm x 50 mm, 1.7 μm) (Waters), acetonitrile: 0.05% trifluoroacetic acid aqueous solution = 5: Mobile phase and gradient conditions of 95 (0 min) to 95: 5 (1.0 min) to 95: 5 (1.6 min) to 5:95 (2.0 min) were used.

The following abbreviations may be used in the examples.
Boc: tert-butoxycarbonyl CPME: cyclopentyl methyl ether DCC: N, N'-dicyclohexylcarbodiimide DIC: N, N'-diisopropylcarbodiimide DIPEA: diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DMT-MM: 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride MTBE: tert-butyl methyl ether NMP: N-methylpyrrolidone ODS: octadecylsilyl THF: tetrahydrofuran

In (Example A1) to (Example A24) and (Example 1) to (Example 54), (ALG) represents an alginic acid residue, and any carboxyl group of alginic acid is an amino group or imino group on the linker side. (HA) represents a hyaluronic acid residue, the carboxyl group of hyaluronic acid represents an amide bond with an amino group or imino group on the linker side, and (DF) represents a diclofenac residue, diclofenac. It means that the carboxyl group of the above has an ester bond with the linker.

The molecular weight of alginic acid or a salt thereof as a raw material of (Example A1) to (Example A23) was determined by the following method. Each alginic acid was weighed in consideration of drying weight loss, and ultrapure water was added to prepare a 1% aqueous solution. Then, the solution was diluted with 100 mmol / L phosphate buffer and ultrapure water so as to have a final concentration of 10 mmol / L phosphate buffer (pH 7.7) to prepare a 0.05% solution. After removing the insoluble matter with a hydrophilic PVDF filtration filter (MylexGV33 filter, Merck Millipore) having a pore size of 0.22 μm, 200 μL was subjected to gel filtration, and gel filtration was performed under the same conditions as the water-soluble alginic acid derivative according to the present invention. Carried out. The detection was carried out by a differential refractometer, and the weight average molecular weight (Mw) was determined by the same method as the water-soluble alginic acid derivative according to the present invention.

In addition, all of the following notations of "ALG" in the scheme of this example are residues derived from alginic acid or a salt thereof, and are monosaccharides of either L-gluuronic acid or D-mannuronic acid constituting alginic acid. It means a residue having a -C (= O) group, and the notation "DF" means a 2- (2,6-dichlorophenylamino) phenylacetyl group.

(Example A1) Synthesis scheme 1 of diclofenac- (2-aminoethanol) -alginic acid derivative (compounds A5a to A5d)

<Step 1> Synthesis of Compound A3 Commercially available diclofenac sodium (Compound A1, 1.59 g), commercially available tert-butyl (2-bromoethyl) carbamate (Compound A2, 1.12 g), N-methylpyrrolidone (5.0 mL) The mixture was stirred at 60 ° C. for 18 hours. After cooling the reaction solution to room temperature, ethyl acetate (40 mL) and heptane (20 mL) are added, and the mixture is washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and then solvent under reduced pressure. Distilled away. The residue was purified by crystallization with ethyl acetate to give 1.19 g of compound A3.

<Step 2> Synthesis of Compound A4 A mixture of Compound A3 (1.1 g) and a 4N hydrochloric acid-ethyl acetate solution (11 mL) was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure to obtain 1.0 g of compound A4.

<Step 3-1> Synthesis of diclofenac- (2-aminoethanol) -arginic acid derivative (Compound A5a) 200 mg of sodium alginate (KM-A1 manufactured by Kimika Co., Ltd.) was dissolved in water (20 mL) and 4- (4). Add 6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (102 mg) and 1M aqueous sodium hydrogen carbonate solution (0.28 mL), and add ethanol (5 mL) of compound A4 (70 mg). ) The solution was added dropwise, and the mixture was stirred at room temperature for 20 hours. After adding ethanol (40 mL), 0.1 g / mL aqueous sodium chloride solution (2 mL) was added, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (227 mg) as a white solid. The drug introduction rate was 10.2 mol%.

<Step 3-2> Synthesis of diclofenac- (2-aminoethanol) -alginic acid derivative (Compound A5b) Using 200 mg of sodium alginate (Kimika Co., Ltd., KM-A2) (Example A1) <Step 3-1> The same procedure as in the above was carried out to obtain the title compound (194 mg) as a white solid. The drug introduction rate was 13.5 mol%.

<Step 3-3> Synthesis of diclofenac- (2-aminoethanol) -alginic acid derivative (Compound A5c) Using 200 mg of sodium alginate (Kimika Co., Ltd., KM-A3) (Example A1) <Step 3-1> The same procedure as in the above was carried out to obtain the title compound (245 mg) as a white solid. The drug introduction rate was 13.9 mol%.

<Step 3-4> Synthesis of diclofenac- (2-aminoethanol) -alginic acid derivative (Compound A5d) Using 200 mg of sodium alginate (Kimika Co., Ltd., KM-A4) (Example A1) <Step 3-1> The same procedure as in the above was carried out to obtain the title compound (239 mg) as a white solid. The drug introduction rate was 9.6 mol%.

(Example A2) Synthesis scheme 2 of diclofenac- (1-amino-2-propanol) -alginic acid derivative (Compound A9)

<Step 1> Synthesis of Compound A7 A mixture of commercially available diclofenac sodium (Compound A1, 668 mg), commercially available tert-butyl (2-bromopropyl) carbamate (Compound A6, 500 mg), and N-methylpyrrolidone (5.0 mL) is used. The mixture was stirred at 60 ° C. for 2 days. Further, compound A2 (500 mg) was added, and the mixture was stirred at 60 ° C. for 1 day. After cooling the reaction solution to room temperature, ethyl acetate (40 mL) and heptane (20 mL) are added, the mixture is washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. Distilled away. The residue was purified by silica gel column chromatography (10-15% ethyl acetate / heptane) to give compound A7 (343 mg) as a colorless gum.

<Step 2> Synthesis of Compound A8 A mixture of Compound A7 (334 mg) and a 4N hydrochloric acid-ethyl acetate solution (3 mL) was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified from ethyl acetate by crystallization to obtain Compound A8 (190 mg) as a white solid.

<Step 3> Synthesis of diclofenac- (1-amino-2-propanol) -alginic acid derivative (Compound A9) In an aqueous solution (10 g) of 1% (w / w) sodium alginate (Kimika Co., Ltd., KM-A2) Add 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (49 mg) and 1M aqueous sodium hydrogen carbonate solution (0.13 mL), and add compound A8 (52 mg). ) Was added dropwise, and the mixture was stirred at room temperature for 16 hours. After adding ethanol (15 mL), a 0.1 g / mL aqueous sodium chloride solution (1 mL) was added, and the mixture was stirred for 30 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (111 mg) as a white solid. The drug introduction rate was 9.9 mol%.

(Example A3) Synthesis scheme 3 of diclofenac- (2-aminoethoxyethanol) -alginic acid derivative (Compound A14)

<Step 1> Synthesis of Compound A12 Commercially available dichloromethane (Compound 10, 2.0 g), commercially available tert-butyl (2- (2-hydroxyethoxy) ethyl) carbamate (Compound A11, 1.39 g), N, N- A solution of N, N'-dicyclohexylcarbodiimide (1.39 g) in dichloromethane (7 mL) was added dropwise to a mixture of dimethyl-4-aminopyridine (0.17 g) and dichloromethane (7 mL) under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (60 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate / heptane) to give compound A12 (2.44 g) as a colorless gum.

<Step 2> Synthesis of Compound A13 A mixture of Compound A12 (2.4 g) and a 4N hydrochloric acid-ethyl acetate solution (24 mL) was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified from ethyl acetate by crystallization to obtain Compound A13 (1.9 g) as a white solid.

<Step 3> Synthesis of diclofenac- (2-aminoethoxyethanol) -alginic acid derivative (Compound A14) 1M carbonate in an aqueous solution (10 g) of 1% (w / w) sodium alginate (KM-A2, manufactured by Kimika Co., Ltd.) Aqueous sodium hydrogen hydrogen solution (0.13 mL), compound A13 (56 mg), ethanol (5 mL), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (4,6-dimethoxy-1,3,5-triazine-2-yl) 37 mg) was added, and the mixture was stirred overnight at room temperature. After adding ethanol (15 mL), a 0.1 g / mL aqueous sodium chloride solution (1 mL) was added, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (91.3 mg) as a white solid. The drug introduction rate was 7.0 mol%.

(Example A4) Synthesis scheme 4 of diclofenac- (serine ethyl ester) -alginic acid derivative (Compound A19)

<Step 1> Synthesis of Compound A18 1- (3-dimethylaminopropyl) -3- (3-dimethylaminopropyl) -3- at room temperature in a commercially available (tert-butoxycarbonyl) -L-serine (Compound A15, 2.0 g) ethanol (100 mL) solution. Ethylcarbodiimide hydrochloride (3.74 g) and N, N-dimethyl-4-aminopyridine (0.12 g) were added. The reaction was stirred at room temperature for 3 days. After distilling off the solvent under reduced pressure, the reaction solution was dissolved in ethyl acetate (100 mL), and the solution was mixed with a 5% aqueous citric acid solution (50 mL), a saturated aqueous sodium hydrogen carbonate solution (50 mL), and a saturated aqueous sodium chloride solution (50 mL). The mixture was washed successively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (1.08 g) of compound A16.

1- (3-Dimethylaminopropyl) -3-ethyl at room temperature in a solution of the crude product of compound A16 (1.08 g) and commercially available diclofenac sodium (compound A1, 2.95 g) in N-methylpyrrolidone (9 mL). Carbodiimide hydrochloride (2.66 g) and N, N-dimethyl-4-aminopyridine (0.11 g) were added. The reaction was stirred at room temperature for 2 days. A saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / heptane) to give a fraction (1.09 g) containing compound A17.

A mixture of a fraction containing compound A17 (1.09 g) and a 4N hydrochloric acid-ethyl acetate solution (10 mL) was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified from ethyl acetate by crystallization to obtain Compound A18 (91 mg) as a white solid.

<Step 2> Synthesis of diclophenac- (serine ethyl ester) -alginic acid derivative (Compound A19) 1M sodium hydrogen carbonate in an aqueous solution (10 g) of 1% (w / w) sodium alginate (KM-A2, manufactured by Kimika Co., Ltd.) Aqueous solution (84 μL), solution of compound A18 (30 mg) in ethanol (5 mL), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (37 mg). In addition, the mixture was stirred at room temperature for 3 days. After adding 0.1 g / mL aqueous sodium chloride solution (1 mL) and ethanol (15 mL), the mixture was stirred for 30 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (61.9 mg) as a white solid. The drug introduction rate was 13.1 mol%.

(Example A5) Synthesis scheme 5 of diclofenac- (threonine ethyl ester) -alginic acid derivative (Compound A24)

<Step 1> Synthesis of Compound A22 In an ethanol (100 mL) solution of commercially available (tert-butoxycarbonyl) -L-threonine (Compound A20, 2.14 g) at room temperature, 1- (3-dimethylaminopropyl) -3-. Ethylcarbodiimide hydrochloride (3.74 g) and N, N-dimethyl-4-aminopyridine (0.12 g) were added. The reaction was stirred overnight. After distilling off the solvent under reduced pressure, the reaction solution was dissolved in ethyl acetate (100 mL), and the solution was mixed with a 5% aqueous citric acid solution (50 mL), a saturated aqueous sodium hydrogen carbonate solution (50 mL), and a saturated aqueous sodium chloride solution (50 mL). The mixture was washed successively, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (0.96 g) of compound A21.

N, N in a solution of the crude product of compound A21 (0.96 g), commercially available diclofenac (compound A10, 1.15 g), N, N-dimethyl-4-aminopyridine (0.09 g) in dichloromethane (4 mL). A solution of ´-dicyclohexylcarbodiimide (0.8 g) in dichloromethane (4 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (60 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / heptane) to give compound A22 (0.96 g) as a colorless oily substance.

<Step 2> Synthesis of Compound A23 A mixture of Compound A22 (0.96 g) and a 4N hydrochloric acid-ethyl acetate solution (5 mL) was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified from ethyl acetate by crystallization to obtain Compound A23 (0.41 g) as a white solid.

<Step 3> Synthesis of diclofenac- (threonine ethyl ester) -arginic acid derivative (compound A24) 1% (w / w) sodium alginate (KM-A2, manufactured by Kimika Co., Ltd.) in an aqueous solution (10 g) of 4- (4) , 6-Dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (37 mg) and 2-morpholinoethanesulfonic acid monohydrate (213 mg), ethanol of compound A23 (31 mg) The (5 mL) solution was added. After 2 hours, add 0.1 M aqueous sodium hydroxide solution (0.2 mL), and after 3 hours, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride. (16 mg) was added, 0.1 M aqueous sodium hydroxide solution (0.1 mL) was added after 4 hours and 5 hours, respectively, and 4- (4,6-dimethoxy-1,3,5-triazine-2) was added after 6 hours. -Il) -4-methylmorpholinium chloride (23 mg) and 0.1 M aqueous sodium hydroxide solution (0.2 mL) were added. After 24 hours, ethanol (15 mL) and 0.1 g / mL sodium chloride aqueous solution (1 mL) were added, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (111.2 mg) as a white solid. The drug introduction rate was 5.6 mol%.

(Example A6) Synthesis scheme 6 of diclofenac-((4- (aminomethyl) phenyl) methanol) -alginic acid derivative (Compound A28)

<Step 1> Synthesis of Compound A26 Commercially available diclofenac sodium (Compound A1, 0.48 g), commercially available tert-butyl (4- (bromomethyl) benzyl) carbamate (Compound A25, 0.45 g), N-methylpyrrolidone (3) The mixture (0.0 mL) was stirred at 40 ° C. for 2 hours. After cooling the reaction solution to room temperature, ethyl acetate (40 mL) and heptane (20 mL) were added, the mixture was washed twice with water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate / heptane) to give compound A26 (0.75 g) as a white solid.

<Step 2> Synthesis of Compound A27 A mixture of Compound A26 (0.75 g) and a 4N hydrochloric acid-ethyl acetate solution (20 mL) was stirred at room temperature for 1 hour. The reaction suspension was filtered and the solid collected by filtration was washed with ethyl acetate to give compound A27 (0.36 g) as a white solid.

<Step 3> Synthesis of diclophenac-((4- (aminomethyl) phenyl) methanol) -alginic acid derivative (Compound A28) 1% (w / w) sodium alginate (KM-A2, manufactured by Kimika Co., Ltd.) aqueous solution (10 g) ), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (49 mg), 1M aqueous sodium hydrogen carbonate solution (0.16 mL), compound A27 ( A solution of 60 mg) of ethanol (5 mL) was added and stirred overnight at room temperature. After adding ethanol (20 mL), 0.1 g / mL aqueous sodium chloride solution (1 mL) was added, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (88.8 mg) as a white solid. The drug introduction rate was 5.3 mol%.

(Example A7) Synthesis scheme 7 of diclofenac- (tyramine) -alginic acid derivative (compound A32)

<Step 1> Synthesis of Compound A30 Commercially available dichloromethane (Compound A10, 0.7 g), commercially available N- (tert-butoxycarbonyl) tyramine (Compound A29, 0.56 g), N, N-dimethyl-4-aminopyridine A solution of N, N'-dicyclohexylcarbodiimide (0.49 g) in dichloromethane (2.5 mL) was added dropwise to a mixture of (0.06 g) and dichloromethane (2.5 mL) under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (15 mL) and water (15 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by crystallization from ethyl acetate to give compound A30 (0.64 g) as a white solid.

<Step 2> Synthesis of Compound A31 A mixture of Compound A30 (0.64 g) and a 4N hydrochloric acid-ethyl acetate solution (7 mL) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was washed with ethyl acetate-heptane (2: 1) to give compound A31 (0.56 g) as a white solid.

<Step 3> Synthesis of diclofenac- (tyramine) -alginic acid derivative (compound A32) 1% (w / w) sodium alginate (KM-A2, manufactured by Kimika Co., Ltd.) in an aqueous solution (10 g) of 4- (4,6) -Dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (37 mg), 1 M aqueous sodium hydrogen carbonate solution (0.11 mL), compound A31 (40 mg) in ethanol (5 mL). In addition, it was stirred overnight at room temperature. After adding ethanol (20 mL), 0.1 g / mL aqueous sodium chloride solution (1 mL) was added, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (81.0 mg) as a white solid. The drug introduction rate was 5.0 mol%.

(Example A8) Synthesis scheme 8 of diclofenac- (3-amino-2,2-difluoropropane-1-ol) -alginic acid derivative (Compound A36)

<Step 1> Synthesis of Compound A34 Commercially available dichloromethane (Compound A10, 0.7 g), commercially available tert-butyl (2,2-difluoro-3-hydroxypropyl) carbamate (Compound A33, 0.5 g), N, N A solution of N, N'-dicyclohexylcarbodiimide (0.49 g) in dichloromethane (2.5 mL) was added dropwise to a mixture of -dimethyl-4-aminopyridine (0.06 g) and dichloromethane (2.5 mL) under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (15 mL) and water (15 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (5-30% ethyl acetate / heptane) to give compound A34 (1.02 g) as a colorless gum.

<Step 2> Synthesis of Compound A35 A mixture of Compound A34 (1.0 g) and a 4N hydrochloric acid-ethyl acetate solution (10 mL) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was washed with ethyl acetate-heptane (2: 1) to give compound A35 (0.48 g) as a white solid.

<Step 3> Synthesis of diclofenac- (3-amino-2,2-difluoropropane-1-ol) -alginic acid derivative (Compound A36) 1% (w / w) sodium alginate (manufactured by Kimika Co., Ltd., KM-A2) 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (37 mg), 1 M sodium alginate aqueous solution (0.11 mL) in an aqueous solution (10 g) of , A solution of compound A35 (38 mg) in ethanol (5 mL) was added and stirred overnight at room temperature. After adding ethanol (20 mL), 0.1 g / mL aqueous sodium chloride solution (1 mL) was added, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (93.6 mg) as a white solid. The drug introduction rate was 14.9 mol%.

(Example A9) Synthesis scheme 9 of diclofenac- (N- (aminoethyl) -2-hydroxyacetamide) -alginic acid derivative (Compound A42)

<Step 1> Synthesis of Compound A39 Ice-cooled commercially available tert-butyl (2-aminoethyl) carbamate (Compound A37, 1.6 g), saturated aqueous sodium hydrogen carbonate solution (5 mL), water (20 mL), 1,2- A commercially available 2-bromoacetyl chloride (Compound A38, 1.66 mL) was added dropwise to a mixed solution of dimethoxyethane (20 mL), a saturated aqueous sodium hydrogen carbonate solution (25 mL) was further added, and the mixture was stirred for 10 minutes. The reaction solution was extracted twice with ethyl acetate (80 mL), the combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with heptane-ethyl acetate (1: 1, 10 mL) to give compound A39 (0.62 g) as a white solid.

<Step 2> Synthesis of Compound A40 A mixture of commercially available diclofenac sodium (Compound A1, 1.4 g), Compound A39 (0.62 g) and N-methylpyrrolidone (4.4 mL) was stirred at 50 ° C. for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate (40 mL) and heptane (20 mL) are added, the mixture is washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. Distilled away. The residue was purified by silica gel column chromatography (50-100% ethyl acetate / heptane) to give compound A40 (0.87 g) as a white solid.

<Step 3> Synthesis of Compound A41 A mixture of Compound A40 (0.87 g) and a 4N hydrochloric acid-ethyl acetate solution (10 mL) was stirred at room temperature for 1 hour. The reaction suspension was filtered and the solid collected by filtration was washed with ethyl acetate-heptane (2: 1) to give compound A41 (0.62 g) as a white solid.

<Step 4> Synthesis of diclofenac- (N- (aminoethyl) -2-hydroxyacetamide) -alginic acid derivative (Compound A42) 1% (w / w) sodium alginate (KM-A2, manufactured by Kimika Co., Ltd.) aqueous solution ( 10 g), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (37 mg), 1 M aqueous sodium hydrogen carbonate solution (0.11 mL), compound A41 A solution of (38 mg) in ethanol (5 mL) was added and stirred overnight at room temperature. After adding ethanol (20 mL), 0.1 g / mL aqueous sodium chloride solution (1 mL) was added, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (87.1 mg) as a white solid. The drug introduction rate was 12.3 mol%.

(Example A10) Synthesis scheme 10 of diclofenac- (N- (aminoethyl) -2-hydroxypropanamide) -alginic acid derivative (Compound A47)

<Step 1> Synthesis of Compound A45 Ice-cooled commercially available tert-butyl (2-aminoethyl) carbamate (Compound A37, 1.6 g), saturated aqueous sodium hydrogen carbonate solution (10 mL), water (20 mL), 1,2- Commercially available 2-bromopropanoyl bromide (Compound A43, 2.12 mL) was added dropwise to a mixed solution of dimethoxyethane (30 mL), a saturated aqueous sodium hydrogen carbonate solution (25 mL) was further added, and the mixture was stirred for 10 minutes. The reaction solution was extracted twice with ethyl acetate (80 mL), the combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with heptane-ethyl acetate (3: 2, 20 mL) to give a crude product of compound A44 (0.39 g).

A mixture of the crude product of compound A44 (0.39 g), commercially available sodium diclofenac (Compound A1, 0.84 g) and N-methylpyrrolidone (2.6 mL) was stirred at 50 ° C. for 1 hour and at 60 ° C. for 3 hours. .. After cooling the reaction solution to room temperature, ethyl acetate (40 mL) and heptane (20 mL) are added, the mixture is washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. Distilled away. The residue was purified by silica gel column chromatography (30-100% ethyl acetate / heptane) to give compound A45 (0.34 g) as a white solid.

<Step 2> Synthesis of Compound A46 A mixture of Compound A45 (0.34 g) and a 4N hydrochloric acid-ethyl acetate solution (4 mL) was stirred at room temperature for 1 hour. The reaction suspension was filtered and the solid collected by filtration was washed with ethyl acetate-heptane (2: 1) and tert-butyl methyl ether to give compound A46 (0.24 g) as a white solid.

<Step 3> Synthesis of diclofenac- (N- (aminoethyl) -2-hydroxypropanamide) -alginic acid derivative (Compound A47) 1% (w / w) aqueous solution of sodium alginate (Kimika Co., Ltd., KM-A2) In (10 g), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (37 mg), 1 M aqueous sodium hydrogen carbonate solution (0.11 mL), compound. A solution of A46 (40 mg) in ethanol (5 mL) was added, and the mixture was stirred overnight at room temperature. After adding ethanol (20 mL), 0.1 g / mL aqueous sodium chloride solution (1 mL) was added, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (87.0 mg) as a white solid. The drug introduction rate was 12.5 mol%.

(Example A12) Synthesis of diclofenac- (2-aminoethoxyethanol) -alginic acid derivative (Compounds A14a, A14b)

<Step 1-1> Synthesis of diclofenac- (2-aminoethoxyethanol) -alginic acid derivative (Compound A14a) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) was dissolved in water (100 mL), and ethanol (30 mL) was used. 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (456 mg) was added to the added solution at room temperature. After stirring for 30 minutes, a solution of compound A13 (346 mg) in ethanol (10 mL) -water (5 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.82 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (5 mL) and ethanol (100 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.06 g) as a white solid. The drug introduction rate was 14.0 mol%.

<Step 1-2> Synthesis of diclofenac- (2-aminoethoxyethanol) -alginic acid derivative (Compound A14b) Using 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) (Example A12) <Step 1-1 > Was carried out to obtain the title compound (1.11 g) as a white solid. The drug introduction rate was 16.4 mol%.

(Example A13) Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivatives (compounds A53a, A53b, A53c, A53d)

<Step 1> Synthesis of Compound A50 4- (4,6-dimethoxy-1) in a mixed solution of 2-aminoethanol (2.09 g) and (tert-butoxycarbonyl) glycine (5.0 g) in ethanol (30 mL) at room temperature. , 3,5-Triazine-2-yl) -4-methylmorpholinium chloride (11.4 g) was added, and the mixture was stirred for 5 hours. The reaction suspension was filtered through ethanol, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% methanol / ethyl acetate) to give compound A50 (7.3 g).

<Step 2> Synthesis of Compound A51 A mixture of commercially available diclofenac (Compound A10, 2.0 g), Compound A50 (2.2 g), N, N-dimethyl-4-aminopyridine (0.17 g), and dichloromethane (7 mL). A solution of N, N'-dicyclohexylcarbodiimide (1.39 g) in dichloromethane (7 mL) was added dropwise thereto under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (60 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to give compound A51 (2.7 g) as a white amorphous.

<Step 3> Synthesis of Compound A52 A mixture of Compound A51 (2.7 g) and a solution of 4N hydrochloric acid-1,4-dioxane (27.2 mL) was stirred at room temperature for 30 minutes. The reaction suspension was filtered and the solid collected by filtration was washed with dimethoxyethane-ethanol (1: 1) and dimethoxyethane to give compound A52 (1.73 g) as a white solid.

<Step 4-1> Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A53a) 2 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-1) was added to water (200 mL). 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (1.3 g) was added to a solution containing ethanol (60 mL) at room temperature. Added in. After stirring for 30 minutes, a solution of compound A52 (0.85 g) in ethanol (20 mL) -water (10 mL) and a 1 M aqueous sodium hydrogen carbonate solution (1.97 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (10 mL) and ethanol (200 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.80 g) as a white solid. The drug introduction rate was 19.7 mol%.

<Step 4-2> Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A53b) 2 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) was added to water (200 mL). 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (611 mg) was added at room temperature to the solution to which ethanol (60 mL) was added. It was. After stirring for 30 minutes, a solution of compound A52 (396 mg) in ethanol (20 mL) -water (10 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.92 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (10 mL) and ethanol (200 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (2.04 g) as a white solid. The drug introduction rate was 14.6 mol%.

<Step 4-3> Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A53c) Using 2 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) (implementation) Example A13) The same operation as in <Step 4-2> was carried out to obtain the title compound (1.99 g) as a white solid. The drug introduction rate was 17.0 mol%.
<Step 4-4> Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A53d) Sodium alginate (Mochida Pharmaceutical Co., Ltd., B-2) 100 mg in water (10 mL) 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (46 mg) was added at room temperature to the solution to which ethanol (3 mL) was added. It was. After stirring for 10 minutes, a solution of compound A52 (40 mg) in ethanol (2 mL) -water (1 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (20 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (108 mg) as a white solid. The drug introduction rate was 23.1 mol%.

(Example A14) Synthesis of diclofenac- (2-amino-1- (4- (hydroxymethyl) piperidine-1-yl) ethane-1-one) -alginic acid derivative (Compound A58)

<Step 1> Synthesis of Compound A55 4- (4,6-dimethoxy-1,3) in a mixed solution of 4-piperidinemethanol (0.79 g) and (tert-butoxycarbonyl) glycine (1 g) in ethanol (10 mL) at room temperature. , 5-Triazine-2-yl) -4-methylmorpholinium chloride (1.9 g) was added, and the mixture was stirred for 4 hours. Ethyl acetate was added to the reaction suspension, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% methanol / ethyl acetate) to give compound A55 (1.2 g) as a white amorphous.

<Step 2> Synthesis of Compound A56 A mixture of commercially available diclofenac (Compound A10, 0.87 g), Compound A55 (1.2 g), N, N-dimethyl-4-aminopyridine (0.07 g), and dichloromethane (5 mL). A solution of N, N'-dicyclohexylcarbodiimide (0.61 g) in dichloromethane (5 mL) was added dropwise thereto under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (5-50% ethyl acetate / heptane) to give compound A56 (1.4 g) as a white amorphous.

<Step 3> Synthesis of Compound A57 A mixture of Compound A56 (1.4 g) and a solution of 4N hydrochloric acid-1,4-dioxane (12.7 mL) was stirred at room temperature for 30 minutes. The reaction mixture was filtered under reduced pressure to obtain Compound A57 (1.3 g) as a white amorphous substance.

<Step 4> Synthesis of diclophenac- (2-amino-1- (4- (hydroxymethyl) piperidine-1-yl) ethane-1-one) -alginic acid derivative (Compound A58) Sodium alginate (Mochida Pharmaceutical Co., Ltd., B) -2) 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium in a solution prepared by dissolving 100 mg in water (20 mL) and adding ethanol (5 mL). Chloride (39 mg) was added at room temperature. After stirring for 10 minutes, a solution of compound A57 (45 mg) in ethanol (3 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (20 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (108 mg) as a white solid. The drug introduction rate was 18.4 mol%.

(Example A15) Synthesis of diclofenac- (2-amino-1- (4-hydroxypiperidine-1-yl) ethane-1-one) -alginic acid derivatives (compounds A63a, A63b)

<Step 1> Synthesis of Compound A60 4- (4,6-dimethoxy-1) in a mixed solution of 4-hydroxypiperidine (0.69 g) and (tert-butoxycarbonyl) glycine (1.0 g) in ethanol (10 mL) at room temperature. , 3,5-Triazine-2-yl) -4-methylmorpholinium chloride (1.9 g) was added, and the mixture was stirred for 4 hours. Ethyl acetate was added to the reaction suspension, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% methanol / ethyl acetate) to give compound A60 (1.0 g) as a white amorphous.

<Step 2> Synthesis of Compound A61 A mixture of commercially available diclofenac (Compound A10, 0.76 g), Compound A60 (0.99 g), N, N-dimethyl-4-aminopyridine (0.06 g), and dichloromethane (5 mL). A solution of N, N'-dicyclohexylcarbodiimide (0.53 g) in dichloromethane (5 mL) was added dropwise thereto under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (5-50% ethyl acetate / heptane) to give compound A61 (1.0 g) as a white amorphous.

<Step 3> Synthesis of Compound A62 A mixture of Compound A61 (1.0 g) and a solution of 4N hydrochloric acid-1,4-dioxane (9.3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was filtered under reduced pressure to give compound A62 (0.91 g) as a white amorphous substance.

<Step 4-1> Synthesis of diclophenac- (2-amino-1- (4- (hydroxymethyl) piperidine-1-yl) ethane-1-one) -alginic acid derivative (compound A63a) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) , A-2) 1 g was dissolved in water (100 mL), and 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmol was added to a solution containing ethanol (30 mL). Holinium chloride (370 mg) was added at room temperature. After stirring for 10 minutes, a solution of compound A62 (350 mg) in ethanol (10 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.74 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (10 mL) and ethanol (100 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.07 g) as a white solid. The drug introduction rate was 11.5 mol%.

<Step 4-2> Synthesis of diclofenac- (2-amino-1- (4- (hydroxymethyl) piperidine-1-yl) ethane-1-one) -alginic acid derivative (Compound A63b) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) , A-3) Using 1 g, the same operation as in (Example A15) <Step 4-1> was carried out to obtain the title compound (1.09 g) as a white solid. The drug introduction rate was 12.6 mol%.

(Example A16) Synthesis of diclofenac- (2-amino-N- (6-hydroxyhexyl) acetamide) -alginic acid derivative (Compound A68)

<Step 1> Synthesis of Compound A65 4- (4,6-dimethoxy-) in a mixed solution of 6-amino-1-hexanol (0.8 g) and (tert-butoxycarbonyl) glycine (1 g) in ethanol (10 mL) at room temperature. 1,3,5-Triazine-2-yl) -4-methylmorpholinium chloride (1.9 g) was added, and the mixture was stirred for 4 hours. Ethyl acetate was added to the reaction suspension, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% methanol / ethyl acetate) to give compound A65 (1.6 g) as a white amorphous.

<Step 2> Synthesis of Compound A66 A mixture of commercially available diclofenac (Compound A10, 1.0 g), Compound A65 (1.39 g), N, N-dimethyl-4-aminopyridine (0.08 g), and dichloromethane (5 mL). A solution of N, N'-dicyclohexylcarbodiimide (0.7 g) in dichloromethane (5 mL) was added dropwise thereto under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to give compound A66 (1.5 g) as a white amorphous.

<Step 3> Synthesis of Compound A67 A mixture of Compound A66 (1.5 g) and a solution of 4N hydrochloric acid-1,4-dioxane (13.6 mL) was stirred at room temperature for 30 minutes. The reaction mixture was filtered under reduced pressure to obtain Compound A67 (1.3 g) as a white amorphous substance.

<Step 4> Synthesis of diclofenac- (2-amino-N- (6-hydroxyhexyl) acetamide) -alginic acid derivative (Compound A68) 100 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., B-2) is dissolved in water (20 mL). Then, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (39 mg) was added to the solution to which ethanol (5 mL) was added at room temperature. After stirring for 10 minutes, a solution of compound A67 (45 mg) in ethanol (3 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (20 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (106 mg) as a white solid. The drug introduction rate was 18.0 mol%.

(Example A17) Synthesis of diclofenac- (2-amino-N- (2-hydroxypropyl) acetamide) -alginic acid derivatives (compounds A72a, A72b)

<Step 1> Synthesis of Compound A70 1-amino-2-propanol (0.38 g), (tert-butoxycarbonyl) glycine (0.88 g), N, N-dimethyl-4-aminopyridine (0.12 g), A solution of N, N'-dicyclohexylcarbodiimide (1.03 g) in dichloromethane (5 mL) was added dropwise to a mixture of dichloromethane (20 mL) under ice-cooling. The reaction was stirred at room temperature overnight. A solution of commercially available diclofenac (Compound A10, 1.48 g) and N, N'-dicyclohexylcarbodiimide (1.03 g) in dichloromethane (5 mL) was added dropwise to the reaction solution. The reaction was stirred at room temperature overnight. After filtering the reaction solution, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give compound A70 (0.74 g) as a white amorphous.

<Step 2> Synthesis of Compound A71 A mixture of Compound A70 (0.74 g) and a solution of 4N hydrochloric acid-1,4-dioxane (8 mL) was stirred at room temperature for 30 minutes. The reaction mixture was filtered under reduced pressure to give compound A71 (0.7 g) as a white amorphous substance.

<Step 3-1> Synthesis of diclofenac- (2-amino-N- (2-hydroxypropyl) acetamide) -alginic acid derivative (Compound A72a) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) was added to water (100 mL). 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (305 mg) was added to the solution to which ethanol (30 mL) was added at room temperature. .. After stirring for 30 minutes, a solution of compound A71 (205 mg) in ethanol (10 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.46 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (5 mL) and ethanol (100 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.04 g) as a white solid. The drug introduction rate was 13.1 mol%.

<Step 3-2> Synthesis of diclofenac- (2-amino-N- (2-hydroxypropyl) acetamide) -alginic acid derivative (Compound A72b) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) 200 mg in water (20 mL) 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (62 mg) was added to the solution to which ethanol (6 mL) was added at room temperature. .. After stirring for 10 minutes, a solution of compound A71 (41 mg) in ethanol (2 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (199 mg) as a white solid. The drug introduction rate was 14.5 mol%.

A (Example A18) Synthesis of diclofenac- (2-amino-N- (3-hydroxypropyl) acetamide) -alginic acid derivatives (compounds A76a, A76b)

<Step 1> Synthesis of Compound A74 3-amino-1-propanol (0.38 g), (tert-butoxycarbonyl) glycine (0.88 g), N, N-dimethyl-4-aminopyridine (0.12 g), A solution of N, N'-dicyclohexylcarbodiimide (1.03 g) in dichloromethane (5 mL) was added dropwise to a mixture of dichloromethane (20 mL) under ice-cooling. The reaction was stirred at room temperature overnight. A solution of commercially available diclofenac (Compound A10, 1.48 g) and N, N'-dicyclohexylcarbodiimide (1.03 g) in dichloromethane (5 mL) was added dropwise to the reaction solution. The reaction was stirred at room temperature overnight. The reaction solution was filtered, and the solvent was distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give compound A74 (1.4 g) as a white amorphous.

<Step 2> Synthesis of Compound A75 A mixture of Compound A74 (1.4 g) and a solution of 4N hydrochloric acid-1,4-dioxane (14 mL) was stirred at room temperature for 30 minutes. The reaction mixture was filtered under reduced pressure to give compound A75 (1.3 g) as a white amorphous substance.

<Step 3-1> Synthesis of diclofenac- (2-amino-N- (3-hydroxypropyl) acetamide) -alginic acid derivative (Compound A76a) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) was added to water (100 mL). 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (305 mg) was added to the solution to which ethanol (30 mL) was added at room temperature. .. After stirring for 30 minutes, a solution of compound A75 (205 mg) in ethanol (10 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.46 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (5 mL) and ethanol (100 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.03 g) as a white solid. The drug introduction rate was 13.7 mol%.

<Step 3-2> Synthesis of diclofenac- (2-amino-N- (3-hydroxypropyl) acetamide) -alginic acid derivative (Compound A76b) Using 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) (implemented) Example A18) The same operation as in <Step 3-1> was carried out to obtain the title compound (0.99 g) as a white solid. The drug introduction rate was 14.4 mol%.

(Example A19) Synthesis of diclofenac- (2-amino-N- (1-hydroxypropan-2-yl) acetamide) -alginic acid derivatives (compounds A80a, A80b)

<Step 1> Synthesis of Compound A78 3-amino-1-propanol (0.38 g), (tert-butoxycarbonyl) glycine (0.88 g), N, N-dimethyl-4-aminopyridine (0.12 g), A solution of N, N'-dicyclohexylcarbodiimide (1.03 g) in dichloromethane (5 mL) was added dropwise to a mixture of dichloromethane (20 mL) under ice-cooling. The reaction was stirred at room temperature overnight. A solution of commercially available diclofenac (Compound A10, 1.48 g) and N, N'-dicyclohexylcarbodiimide (1.03 g) in dichloromethane (5 mL) was added dropwise to the reaction solution. The reaction was stirred at room temperature overnight. The reaction solution was filtered, and the solvent was distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give compound A78 (1.4 g) as a white amorphous.

<Step 2> Synthesis of Compound A79 A mixture of Compound A78 (1.4 g) and a solution of 4N hydrochloric acid-1,4-dioxane (14 mL) was stirred at room temperature for 30 minutes. The reaction mixture was filtered under reduced pressure to give compound A79 (1.3 g) as a white amorphous substance.

<Step 3-1> Synthesis of diclofenac- (2-amino-N- (1-hydroxypropan-2-yl) acetamide) -alginic acid derivative (Compound A80a) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) 1 g. 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (305 mg) was added to a solution prepared by dissolving in water (100 mL) and adding ethanol (30 mL). Added at room temperature. After stirring for 30 minutes, a solution of compound A79 (205 mg) in ethanol (10 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.46 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (5 mL) and ethanol (100 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (0.97 g) as a white solid. The drug introduction rate was 12.2 mol%.

<Step 3-2> Synthesis of diclofenac- (2-amino-N- (1-hydroxypropan-2-yl) acetamide) -alginic acid derivative (Compound A80b) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) 1 g In the same manner as in (Example A19) <Step 3-1>, the title compound (0.99 g) was obtained as a white solid. The drug introduction rate was 14.4 mol%.

(Example A20) Synthesis of felbinac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A84)

<Step 1> Synthesis of Compound A82 A mixture of commercially available Fervinac (Compound A81, 1.0 g), Compound A50 (1.13 g), N, N-dimethyl-4-aminopyridine (0.12 g), and dichloromethane (6 mL). A solution of N, N'-dicyclohexylcarbodiimide (1.07 g) in dichloromethane (4 mL) was added dropwise thereto under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with ethanol to give compound A82 (0.80 g) as a white solid.

<Step 2> Synthesis of Compound A83 A mixture of Compound A82 (0.80 g) and a solution of 4N hydrochloric acid-1,4-dioxane (10 mL) was stirred at room temperature for 30 minutes. The reaction suspension was filtered and the solid collected by filtration was triturated with dimethoxyethane to give compound A83 (0.56 g) as a white solid.

<Step 3> Synthesis of felbinac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A84) 200 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) is dissolved in water (20 mL). Then, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (46 mg) was added to the solution to which ethanol (8 mL) was added at room temperature. After stirring for 10 minutes, a solution of compound A83 (32 mg) in ethanol (2 mL) -water (1 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (2 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (193 mg) as a white solid. The drug introduction rate was 10.8 mol%.

(Example A21) Synthesis of ketoprofen- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A88)

<Step 1> Synthesis of Compound A86 A mixture of commercially available ketoprofen (Compound A85, 1.0 g), Compound A50 (0.94 g), N, N-dimethyl-4-aminopyridine (0.1 g), and dichloromethane (10 mL). 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.83 g) was added to the mixture at room temperature. The reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give compound A86 (1.38 g) as a colorless gum.

<Step 2> Synthesis of Compound A87 A mixture of Compound A86 (1.38 g) and a solution of 4N hydrochloric acid-1,4-dioxane (15 mL) was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure to obtain Compound A87 (1.27 g) as a white amorphous substance.

<Step 3> Synthesis of ketoprofen- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A88) 200 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) was dissolved in water (20 mL). Then, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (46 mg) was added to the solution to which ethanol (6 mL) was added at room temperature. After stirring for 10 minutes, a solution of compound A87 (36 mg) in ethanol (2 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (2 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (201 mg) as a white solid. The drug introduction rate was 11.9 mol%.

(Example A22) Synthesis of naproxen- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A92)

<Step 1> Synthesis of Compound A90 A mixture of commercially available naproxen (Compound A89, 1.0 g), Compound A50 (1.04 g), N, N-dimethyl-4-aminopyridine (0.11 g), and dichloromethane (10 mL). 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.92 g) was added to the mixture at room temperature. The reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give compound A90 (1.39 g) as a colorless gum.

<Step 2> Synthesis of Compound A91 A mixture of Compound A90 (1.39 g) and a solution of 4N hydrochloric acid-1,4-dioxane (15 mL) was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure to obtain Compound A91 (1.28 g) as a white amorphous substance.

<Step 3> Synthesis of ketoprofen- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound A92) 200 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) was dissolved in water (20 mL). Then, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (46 mg) was added to the solution to which ethanol (6 mL) was added at room temperature. After stirring for 10 minutes, a solution of compound A91 (34 mg) in ethanol (2 mL) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added dropwise, and the mixture was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (2 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (196 mg) as a white solid. The drug introduction rate was 12.9 mol%.

(Example A24) Preparation of diclofenac- (2-aminoethanol) -hyaluronic acid (DF-HA: compound HA-1)

200 mL of water was added to and dissolved in sodium hyaluronate (Fujifilm Wako Pure Chemical Industries, Ltd., product code 089-10343) (2.0 g), 200 mL of ethanol was added, and the mixture was stirred for 30 minutes or more. Subsequently, a 50% EtOH solution (10 mL) of compound A4 (262 mg) and a 50% EtOH solution (10 mL) of DMT-MM (233 mg) were added, and the mixture was stirred overnight. A 5% aqueous NaHCO3 solution (30 mL) was added to the reaction mixture, and the mixture was stirred to confirm that the pH was 9, and then the mixture was stirred for 4 hours. Subsequently, acetic acid (800 μL) and NaCl (6 g) were added, and the mixture was stirred for 30 minutes, and then EtOH (900 mL) was added to precipitate a precipitate. After removing the supernatant by decantation, the precipitate was collected by filtration, washed twice with 90% EtOH and twice with EtOH, and the obtained precipitate was dried under reduced pressure at 40 ° C. to diclofenac- (2-amino). 1.89 g of ethanol) -hyaluronic acid (DF-HA) was obtained. As a result of determining the introduction rate by 1H-NMR, it was 19.7 mol% (ratio of hyaluronic acid to the disaccharide constituent unit).
The weight average molecular weight of (Compound HA-1) was 980,000 Da. The molecular weight was measured by the same method as in (Example A1) to (Example A23).

In (Example 1) to (Example 54), the molecular weight of the alginic acid derivative was measured by a size exclusion chromatography (SEC) method. The measurement method is as follows.

Weigh the sample, add water, stir and dissolve at room temperature for 12 hours or more, dilute with water and acetonitrile, and prepare a 0.05% solution using water: acetonitrile = 75:25 (V: V) as a solvent. did. After removing the insoluble matter from this solution by any of the pretreatment methods 1 to 3, the solution was measured under the following measurement conditions. The chromatogram of the sample was prepared by monitoring the absorbance at a wavelength of 275 nm.
[Pretreatment method 1]
Centrifuge the solution at 12000 xg for 5 minutes and collect the supernatant [pretreatment method 2].
Centrifugal filtration (12000 xg, 5 minutes) with a hydrophilic PVDF filtration filter (Ultrafree-MC-GV, Merck Millipore) with a pore size of 0.22 μm.
[Pretreatment method 3]
Filtration with a cellulose acetate filtration filter (Minisart, Sartorius) with a pore size of 0.45 μm [Measurement conditions]
Column: TSKgel guardcolum PWXL (6mm ID × 40mm, Tosoh Corporation) + TSKgel GMPWXL (7.8mm ID × 300mm, Tosoh Corporation)
Eluent: 10 mM phosphate buffer (pH 7.7): acetonitrile = 75:25
Flow rate: 1.0 mL / min
Detector: PDA detector (190nm-400nm)
Column temperature: 40 ° C
Injection volume: 10 μL

At the same time as the sample, Pluran (STANDARD P-82 (molecular weight 6.1 kDa to 642 kDa, 8 types), Showa Denko Co., Ltd.) was measured as a molecular weight standard substance by SEC measurement under the same conditions as the sample, and the absorbance at a wavelength of 230 nm was monitored. The elution time of each molecular weight standard substance was determined. For eight molecular weight standard substances, the horizontal axis was the elution time and the vertical axis was the logarithmic value of the molecular weight. Using this calibration curve, the molecular weight (Mi) at the elution time i of the chromatogram of the previously obtained sample was calculated. Next, the slope of the integral curve of the absorbance of the entire peak at the elution time i with respect to the molecular weight was calculated and used as the differential concentration fraction (Hi). From these data, the weight average molecular weight (Mw) was calculated by the following formula.

[Number 1]

The molecular weight of the raw material alginic acid was measured by the following method.

Weigh the raw material alginic acid, add water, stir and dissolve at room temperature for 12 hours or more, dilute with water and acetonitrile, and prepare a 0.1% solution using water: acetonitrile = 75:25 (V: V) as a solvent. Prepared. This was subjected to SEC measurement under the same conditions as the water-soluble alginic acid derivative according to the present invention. A chromatogram of the raw material alginic acid was prepared by monitoring the absorbance at a wavelength of 210 nm, and the weight average molecular weight (Mw) was calculated by the same method as that of the water-soluble alginic acid derivative according to the present invention.

(Example 1) Synthesis of diclofenac-((2S) -2-amino-N- (2,3-dihydroxypropyl) -3-hydroxypropanamide) -alginic acid derivative (Compound 1-5)

<Step 1> Synthesis of Compound 1-3 (2,2-dimethyl-1,3-dioxolane-4-yl) Methanol (10 mL) of methaneamine (0.64 g) and N-Boc-L-serine (1.0 g) ) DMT-MM (2.02 g) was added to the solution, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (20 mL). The mixture was washed with water (20 mL) and the aqueous layer was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. DCC (1.21 g) was added to a solution of the obtained residue (1.55 g), diclofenac (1.73 g) and DMAP (60 mg) in dichloromethane (15.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction was filtered and the filtrate was diluted with dichloromethane (50 mL). The mixture was washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 70:30) to obtain the title compound (2.58 g) as a colorless oily substance.

<Step 2> Synthesis of Compound 1-4 To a solution of Compound 1-3 (2.5 g) in THF (6.25 mL) was added 4M hydrogen chloride / dioxane (6.25 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. .. Then, water (80 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was solidified and pulverized with MTBE to obtain the title compound (1.72 g) as a white amorphous substance.

<Step 3> Synthesis of diclophenac-((2S) -2-amino-N- (2,3-dihydroxypropyl) -3-hydroxypropanamide) -alginic acid derivative (Compound 1-5) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) , A-2) Water (100 mL) was added to an ethanol suspension (30 mL) of (1.0 g), and the mixture was stirred at room temperature for 1 hour. DMT-MM (0.31 g) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (10 mL) of Compound 1-4 (0.27 g) was added, and the mixture was stirred at room temperature for 1 hour. A 1 M aqueous sodium hydrogen carbonate solution (0.5 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A 0.1 g / mL aqueous sodium chloride solution (10 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (200 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.1 g) as a white solid. The drug introduction rate was 11.0 mol%.

(Example 2) Diclofenac-((S) -2-amino-3-hydroxy-N-((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxyhexyl) propanamide) -Synthesis of alginic acid derivative (Compound 2-3)

<Step 1> Synthesis of Compound 2-2 D-glucamine (CAS number: 488-43-7, 1.0 g) and N-[(9H-fluorene-9-ylmethoxy) carbonyloxy] succinimide (1.86 g) Triethylamine (1.54 mL) was added to a mixture of methanol (10 mL), and the mixture was stirred overnight at room temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. Tert-Butyldimethylchlorosilane (2.62 g) was added to a DMF solution (10 mL) of the obtained residue (1.0 g) and imidazole (1.18 g), and the mixture was stirred at room temperature for 1 hour. Ice-cooled sewage was added to the reaction mixture, and the mixture was extracted twice with MTBE (20 mL). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 90:10). A mixture of the obtained colorless oily substance (1.8 g) and a 20% piperidine / DMF solution (6.93 mL) was stirred at room temperature for 1 hour. Water was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered and concentrated. The obtained residue (1.4 g), N-Boc-L-serine (0.42 g) and DMT-MM (0.85 g) were dissolved in methanol (10.8 mL) and stirred at room temperature for 1 hour. The reaction was concentrated and diluted with ethyl acetate. The mixed solution was washed with water (20 mL × 2) and saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 50:50). DCC (261 mg) was added to a solution of the obtained colorless oily substance (750 mg), diclofenac (344 mg) and DMAP (12.9 mg) in dichloromethane (7.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (20 mL). The mixed solution was washed with water (20 mL × 2) and saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 80:20). 4M hydrogen chloride / CPME (4.6 mL) was added to the obtained colorless oily substance under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was solidified and pulverized with MTBE to obtain the title compound (500 mg) as a white solid.

<Step 2> Diclophenac-((S) -2-amino-3-hydroxy-N-((2S, 3R, 4R, 5R) -2,3,4,5,6-pentahydroxyhexyl) propanamide)- Synthesis of Alginic Acid Derivative (Compound 2-3) Water (20 mL) was added to an ethanol suspension (5 mL) of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 2-3 (65 mg) was added, and the mixture was stirred at room temperature for 1 hour. A 1 M aqueous sodium hydrogen carbonate solution (100 μL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A 0.1 g / mL aqueous sodium chloride solution (2.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (190 mg) as a white solid. The drug introduction rate was 13.8 mol%.

(Example 3) Synthesis of diclofenac-((2S, 3R) -2-amino-N- (2,3-dihydroxypropyl) -3-hydroxybutaneamide) -alginic acid derivative (Compound 3-5)

<Step 1> Synthesis of Compound 3-2 (2,2-dimethyl-1,3-dioxolane-4-yl) Methanol (10 mL) solution of methaneamine (0.6 g) and N-Boc-L-threonine (1 g) DMT-MM (1.9 g) was added to the mixture, and the mixture was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (20 mL) and washed with water (20 mL x 2) and saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 80:20) to obtain the title compound (1.08 g) as a colorless oily substance.

<Step 2> Synthesis of Compound 3-3 DCC (1.01 g) was added to a solution of Compound 3-2 (1.08 g), diclofenac (1.44 g) and DMAP (40 mg) in dichloromethane (10.8 mL) under ice-cooling. In addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (20 mL). The mixture was washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 50:50) to obtain the title compound (1.67 g) as a colorless oily substance.

<Step 3> Synthesis of Compound 3-4 Compound 3-3 (1.67 g) was dissolved in 4M hydrogen chloride / CPME (8.35 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Then, water (50 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the obtained residue was solidified and pulverized with MTBE / heptane to obtain the title compound (1.06 g) as a white solid.

<Step 4> Diclofenac-((2S, 3R) -2-amino-N- (2,3-dihydroxypropyl) -3-hydroxybutaneamide) -alginic acid derivative (synthesis of compound 3-5 Sodium alginate (Mochida Pharmaceutical Co., Ltd.) Water (100 mL) was added to an ethanol suspension (30 mL) of A-2) (1.0 g), and the mixture was stirred at room temperature for 1 hour. DMT-MM (0.37 g) was added to this solution, and 1 After stirring for hours, an ethanol solution (10 mL) of compound 3-4 (0.28 g) was added, and the mixture was stirred at room temperature for 3 hours. A 1 M sodium alginate aqueous solution (0.6 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. 0.1 g / mL sodium chloride aqueous solution (10 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. Ethanol (200 mL) was added to the reaction solution, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration and washed with ethanol. Then, it was dried under reduced pressure to obtain the title compound (1.04 g) as a white solid. The drug introduction rate was 11.4 mol%.

(Example 4) Diclofenac-((2S, 3R) -2-amino-3-hydroxy-N- (2,5,8,11-tetraoxatridecane-13-yl) butaneamide) -alginic acid derivative (Compound 4) -5) Synthesis

<Step 1> Synthesis of Compound 4-2 DMT in a solution of 2,5,8,11-tetraoxatridecane-13-amine (100 mg) and N-Boc-L-threonine (106 mg) in methanol (1.0 mL). -MM (241 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 10:90) to obtain the title compound (200 mg) as a colorless oily substance.
<Step 2> Synthesis of Compound 4-3 DCC (121 mg) was added to a solution of compound 4-2 (200 mg), diclofenac (174 mg) and DMAP (4.8 mg) in dichloromethane (1.6 mL) under ice-cooling, and at room temperature. The mixture was stirred for 4 hours. Ethyl acetate (5 mL) was added to the reaction mixture, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 20:80) to obtain the title compound (150 mg) as an orange gum-like substance.
<Step 3> Synthesis of Compound 4-4 Compound 4-3 (150 mg) was dissolved in THF (750 μL), 4M hydrogen chloride / CPME (750 μL) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the obtained residue was purified by ODS column chromatography (0.01 M aqueous hydrochloric acid solution / acetonitrile = 100: 0 to 50:50) to obtain the title compound (55 mg) as a colorless oily substance.
<Step 4> Diclofenac-((2S, 3R) -2-amino-3-hydroxy-N- (2,5,8,11-tetraoxatridecane-13-yl) butaneamide) -alginic acid derivative (Compound 4- 5) Synthesis Water (15 mL) was added to an ethanol suspension (4 mL) of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (150 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (46 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (2 mL) of compound 4-4 (63 mg) was added, and the mixture was stirred at room temperature for 3 hours. A 1 M aqueous sodium hydrogen carbonate solution (0.1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 60 hours. A 0.1 g / mL aqueous sodium chloride solution (1.5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (150 mg) as a white solid. The drug introduction rate was 9.9 mol%.
(Example 5) Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxybutaneamide) -alginic acid derivative (Compounds 5-6a, 5-6b, 5-6c, 5-6d)

<Step 1> Synthesis of Compound 5-2 DCC (5) in a solution of N-Boc-L-threonine (5 g) and 2,3,4,5,6-pentafluorophenol (5.0 g) in ethyl acetate (50 mL). .7 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 50:50) to obtain the title compound (7.5 g) as a white solid.

<Step 2> Synthesis of Compound 5-3 DCC (6.0 g) was added to a solution of compound 5-2 (7.5 g) and diclofenac (8.7 g) in dichloromethane (75 mL), and the mixture was stirred at room temperature for 10 minutes. DMAP (0.12 g) was added to the reaction mixture, and the mixture was further stirred for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 90:10) and solidified and pulverized by MTBE to obtain the title compound (9 g) as a white solid.

<Step 3> Synthesis of Compound 5-4 A 25% aqueous ammonia solution (0.39 mL) was added to a solution of compound 5-3 (2 g) in THF (20 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was solidified and pulverized with heptane / MTBE to obtain the title compound (1.5 g) as a white solid.

<Step 4> Synthesis of Compound 5-5 Compound 5-4 (1.4 g) was dissolved in THF (7 mL), 4M hydrogen chloride / CPME (7 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the obtained residue was solidified and pulverized with MTBE. The precipitated solid was collected by filtration to give the title compound (1.2 g) as a white amorphous substance.

<Step 5-1> Synthesis of diclophenac-((2S, 3R) -2-amino-3-hydroxybutaneamide) -alginic acid derivative (Compound 5-6a) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (1) Water (150 mL) was added to an ethanol suspension (50 mL) of .5 g), and the mixture was stirred at room temperature for 1 hour. DMT-MM (0.56 g) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (10 mL) of compound 5-5 (0.36 g) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (30 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (300 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.67 g) as a white solid. The drug introduction rate was 14.2 mol%.

<Step 5-2> Synthesis of diclophenac-((2S, 3R) -2-amino-3-hydroxybutaneamide) -alginic acid derivative (Compound 5-6b) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-1) (1 g ), Water (100 mL) was added to the ethanol suspension (30 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (0.52 g) was added to this solution, and after stirring for 1 hour, an ethanol solution (10 mL) of compound 5-5 (0.34 g) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (10 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (250 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.01 g) as a white solid. The drug introduction rate was 14.0 mol%.

<Step 5-3> Synthesis of diclophenac-((2S, 3R) -2-amino-3-hydroxybutaneamide) -alginic acid derivative (Compound 5-6c) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) (200 mg) ), Water (20 mL) was added to the ethanol suspension (5 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 5-5 (50 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1.5 hours. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (189 mg) as a white solid. The drug introduction rate was 6.9 mol%.

<Step 5-4> Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxybutaneamide) -alginic acid derivative (Compound 5-6d) Sodium alginate (Mochida Pharmaceutical Co., Ltd., B-2) (200 mg) ) Was carried out in the same manner as in <Step 5-3> to obtain the title compound (189 mg) as a white solid. The drug introduction rate was 5.3 mol%.

(Example 6) Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-N- (2-hydroxyethyl) butaneamide) -alginic acid derivative (Compound 6-4)

<Step 1> Synthesis of Compound 6-2 2-Aminoethane-1-ol (55 mg) was added to a solution of Compound 5-3 (500 mg) in THF (5.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was solidified and pulverized with heptane / MTBE. The precipitated solid was collected by filtration to give the title compound (265 mg) as a white solid.

<Step 2> Synthesis of Compound 6-3 Compound 6-2 (200 mg) is dissolved in THF (1.0 mL), 4M hydrogen chloride / CPME (1.0 mL) is added under ice cooling, and the mixture is stirred at room temperature for 4 hours. did. The reaction mixture was concentrated, and the obtained residue was purified by ODS column chromatography (0.01 M aqueous hydrochloric acid solution / acetonitrile = 100: 0 to 50:50) to obtain the title compound (174 mg) as a white powder.

<Step 3> Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-N- (2-hydroxyethyl) butaneamide) -alginic acid derivative (Compound 6-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) Water (20 mL) was added to an ethanol suspension (5 mL) of (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 6-3 (53 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (220 mg) as a white solid. The drug introduction rate was 14.5 mol%.

(Example 7) Synthesis of diclofenac- (2-((2S, 3R) -2-amino-3-hydroxybutaneamide) ethane-1-sulfonic acid) -alginic acid derivative (Compound 7-3)

<Step 1> Synthesis of Compound 7-2 2-Aminoethane-1-sulfonic acid (113 mg) and DIPEA (395 μL) were added to a solution of Compound 5-3 (500 mg) in acetonitrile (5.0 mL), and the mixture was stirred at room temperature for 1 hour. did. 1M hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (10 mL). The organic layer was washed with 1M hydrochloric acid (10 mL), allowed to stand overnight at room temperature, and then concentrated under reduced pressure. The obtained residue was solidified and pulverized with MTBE, and the obtained solid was collected by filtration to obtain the title compound (160 mg) as a white solid.

<Step 2> Synthesis of diclofenac- (2-((2S, 3R) -2-amino-3-hydroxybutaneamide) ethane-1-sulfonic acid) -alginic acid derivative (Compound 7-3) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) Company, A-2) Water (20 mL) was added to an ethanol suspension (6 mL) of (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (2 mL) of compound 7-2 (56 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (220 mg) as a white solid. The drug introduction rate was 9.5 mol%.

(Example 8) Synthesis of diclofenac-((2S, 3R) -2-amino-N- (2- (dimethylamino) ethyl) -3-hydroxybutaneamide) -alginic acid derivative (Compound 8-4)

<Step 1> Synthesis of Compound 8-2 N, N-dimethylethylenediamine (98 μL) was added to a solution of compound 5-3 (500 mg) in THF (5.0 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 20:80) to obtain the title compound (380 mg) as a colorless oily substance.

<Step 2> Synthesis of Compound 8-3 Compound 8-2 (300 mg) was dissolved in THF (1.9 mL), 4M hydrogen chloride / CPME (1.9 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the obtained residue was solidified and pulverized with heptane / MTBE. The precipitated solid was collected by filtration to give the title compound (360 mg) as a white solid.

<Step 3> Synthesis of diclophenac-((2S, 3R) -2-amino-N- (2- (dimethylamino) ethyl) -3-hydroxybutaneamide) -alginic acid derivative (Compound 8-4) Sodium alginate (Mochida) Water (20 mL) was added to an ethanol suspension (6 mL) of A-2) (200 mg) of Pharmaceutical Co., Ltd., and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (2 mL) of compound 8-3 (60 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (200 mg) as a white solid. The drug introduction rate was 12.5 mol%.

(Example 9) Synthesis of diclofenac-((2S, 3R) -2-amino-N-benzyl-3-hydroxybutaneamide) -alginic acid derivative (Compound 9-4)

<Step 1> Synthesis of Compound 9-2 Benzylamine (49 μL) was added to a solution of compound 5-3 (200 mg) in THF (2.0 mL), and the mixture was stirred at room temperature for 1 hour. Heptane (4 mL) was added to the reaction solution, and the precipitated solid was collected by filtration. The resulting solid was washed with heptane / MTBE to give the title compound (195 mg) as a white solid.

<Step 2> Synthesis of Compound 9-3 Compound 9-2 (180 mg) was dissolved in THF (0.9 mL), 4M hydrogen chloride and CPME (0.9 mL) were added, and the mixture was stirred at room temperature for 4 hours. Then, the reaction solution was stirred at 35 ° C. for 1 hour and at 40 ° C. for 1 hour. The precipitated solid was collected by filtration, washed with MTBE, and dissolved in THF. The solution was concentrated to give the title compound (46 mg) as a colorless oil.

<Step 3> Synthesis of diclophenac-((2S, 3R) -2-amino-N-benzyl-3-hydroxybutaneamide) -alginic acid derivative (Compound 9-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) Water (20 mL) was added to (200 mg) ethanol suspension (5 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 9-3 (60 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 1 M aqueous sodium hydrogen carbonate solution (0.1 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hours. A 0.1 g / mL aqueous sodium chloride solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (225 mg) as a white solid. The drug introduction rate was 3.9 mol%.

(Example 10) Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-N- (pyridin-2-ylmethyl) butaneamide) -alginic acid derivative (Compound 10-4)

<Step 1> Synthesis of Compound 10-2 Pyridine-2-ylmethaneamine (34 μL) was added to a solution of Compound 5-3 (200 mg) in THF (2.0 mL), and the mixture was stirred at room temperature for 1 hour. Heptane (6 mL) was added to the reaction solution, and the precipitated solid was collected by filtration. The resulting solid was washed with heptane / MTBE to give the title compound (146 mg) as a white solid.

<Step 2> Synthesis of Compound 10-3 4M hydrogen chloride / CPME (500 μL) was added to Compound 10-2 (100 mg), and the mixture was stirred at room temperature for 1 hour. Dioxane (500 μL) was added to the reaction solution, and the precipitated solid was collected by filtration and washed with MTBE to give the title compound (71 mg) as a white solid.

<Step 3> Synthesis of diclophenac-((2S, 3R) -2-amino-3-hydroxy-N- (pyridin-2-ylmethyl) butaneamide) -alginic acid derivative (Compound 10-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) , A-2) Water (20 mL) was added to an ethanol suspension (5 mL) of (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 10-3 (62 mg) was added, and the mixture was stirred at room temperature for 3 hours. A 1 M aqueous sodium hydrogen carbonate solution (0.1 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (199 mg) as a white solid. The drug introduction rate was 4.2 mol%.

(Example 11) Synthesis of diclofenac-((2S, 3R) -2-amino-N- (2-amino-2-oxoethyl) -3-hydroxybutaneamide) -alginic acid derivative (Compound 11-4)

<Step 1> Synthesis of Compound 11-2 2-Aminoacetamide hydrochloride (37 mg) and DIPEA (61 μL) were added to a solution of compound 5-3 (200 mg) in THF (2.0 mL), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (3 mL) was added to the reaction mixture, and the mixture was washed with 1 M hydrochloric acid (2 mL) and saturated aqueous sodium chloride solution (3 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was solidified and pulverized with heptane / ethyl acetate to obtain the title compound (110 mg) as a white solid.

<Step 2> Synthesis of Compound 11-3 4M hydrogen chloride / dioxane (425 μL) was added to Compound 11-2 (85 mg), and the mixture was stirred at room temperature for 20 minutes. Methanol (2 mL) was added to the reaction solution, and the precipitated solid was collected by filtration and washed with methanol / MTBE to give the title compound (72 mg) as a white solid.

<Step 3> Synthesis of diclophenac-((2S, 3R) -2-amino-N- (2-amino-2-oxoethyl) -3-hydroxybutaneamide) -alginic acid derivative (Compound 11-4) Sodium alginate (Mochida) Water (20 mL) was added to an ethanol suspension (5.0 mL) of Pharmaceutical Co., Ltd., A-2) (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3.0 mL) of compound 11-3 (60 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (5.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (209 mg) as a white solid. The drug introduction rate was 11.6 mol%.

(Example 12) Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-1-morpholinobtan-1-one) -alginic acid derivative (Compound 12-4)

<Step 1> Synthesis of Compound 12-2 Morpholine (29 μL) was added to a solution of compound 5-3 (200 mg) in THF (2.0 mL), and the mixture was stirred at room temperature for 30 minutes. Morpholine (29 μL) was further added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Heptane (8 mL) and ethyl acetate (3 mL) were added to the reaction mixture, and the mixture was washed with 1 M hydrochloric acid (2 mL) and saturated aqueous sodium chloride solution (3 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (199 mg) as a colorless oily substance.

<Step 2> Synthesis of Compound 12-3 4M hydrogen chloride / dioxane (0.68 mL) was added to Compound 12-2 (150 mg), and the mixture was stirred at room temperature for 20 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by ODS column chromatography (0.01 M aqueous hydrochloric acid solution / acetonitrile = 80: 20 to 30:70) to obtain the title compound (77 mg) as a colorless oily substance.

<Step 3> Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-1-morpholinobtan-1-one) -alginic acid derivative (Compound 12-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A) -2) Water (20 mL) was added to an ethanol suspension (5 mL) of (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 12-3 (58 mg) was added, and the mixture was stirred at room temperature for 17 hours. A 0.1 g / mL aqueous sodium chloride solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (207 mg) as a white solid. The drug introduction rate was 10.1 mol%.

(Example 13) Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-N- (2- (methylsulfonyl) ethyl) butaneamide) -alginic acid derivative (Compound 13-4)

<Step 1> Synthesis of Compound 13-2 Compound 5-3 (200 mg) and DIPEA (74 μL) are dissolved in THF (2.0 mL) to add 2- (methylsulfonyl) ethane-1-amine hydrochloride (58 mg). In addition, it was stirred at room temperature for 1 hour. Heptane (8 mL) and ethyl acetate (3 mL) were added to the reaction mixture, and the mixture was washed with 1 M hydrochloric acid (2 mL) and saturated aqueous sodium chloride solution (3 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was solidified and pulverized with heptane / MTBE to obtain the title compound (135 mg) as a white solid.

<Step 2> Synthesis of Compound 13-3 4M hydrogen chloride / dioxane (475 μL) was added to Compound 13-2 (100 mg), and the mixture was stirred at room temperature for 20 minutes. Methanol (2.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to give the title compound (96 mg) as a colorless oily substance.

<Step 3> Synthesis of diclophenac-((2S, 3R) -2-amino-3-hydroxy-N- (2- (methylsulfonyl) ethyl) butaneamide) -alginic acid derivative (Compound 13-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) Water (20 mL) was added to an ethanol suspension (5 mL) of A-2) (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 13-3 (66 mg) was added, and the mixture was stirred at room temperature for 17 hours. A 0.1 g / mL aqueous sodium chloride solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (202 mg) as a white solid. The drug introduction rate was 9.2 mol%.

(Example 14) Synthesis of diclofenac-((S) -2-amino-3-hydroxypropanamide) -alginic acid derivative (Compound 14-5)

<Step 1> Synthesis of Compound 14-2 A mixed solution of N-Boc-L-serine methyl (2 g) and a 7M ammonia / methanol solution (10 mL) was stirred in a sealed tube at 60 ° C. overnight. The reaction mixture was concentrated to give the title compound (1.86 g) as a white solid.

<Step 2> Synthesis of Compound 14-3 DIC (0.23 mL) was added to a solution of Compound 14-2 (200 mg), diclofenac (435 mg) and DMAP (18 mg) in acetonitrile (2.0 mL), and the mixture was stirred at room temperature for 30 minutes. did. Methanol / water (2: 1) (2 mL) was added to the reaction mixture, and the mixture was stirred at 35 ° C. for 30 minutes, and the precipitated solid was collected by filtration. The filtrate was concentrated and solidified and pulverized with MTBE / heptane, and then the obtained solid was further solidified and pulverized with methanol / water. The solid precipitated after the reaction and the solid obtained by solidification pulverization were mixed to obtain the title compound (150 mg) as a white solid.

<Step 3> Synthesis of Compound 14-4 4M hydrogen chloride / dioxane (1.3 mL) was added to Compound 14-3 (130 mg), and the mixture was stirred at room temperature for 40 minutes. Ethyl acetate (2 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The precipitated solid was collected by filtration and washed with ethyl acetate to give the title compound (105 mg) as a white solid.

<Step 4> Synthesis of diclophenac-((S) -2-amino-3-hydroxypropanamide) -alginic acid derivative (Compound 14-5) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (100 mg) in ethanol suspension Water (10 mL) was added to the turbid solution (3 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (37 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (1 mL) of compound 14-4 (23 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (1 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (30 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (110 mg) as a white solid. The drug introduction rate was 16.7 mol%.

(Example 15) Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-3-phenylpropanamide) -alginic acid derivative (Compound 15-6)

<Step 1> Synthesis of Compound 15-2 (2S, 3R) Boc anhydride was added to a methanol solution (5.0 mL) of -2-amino-3-hydroxy-3-phenylpropanoic acid (500 mg), and 3 at room temperature. Stirred for days. The reaction solution was filtered and the filtrate was concentrated. The obtained residue was dissolved in methanol (6.6 mL) and THF (6.6 mL), trimethylsilyldiazomethane (0.6 M hexane solution, 5.9 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. Acetic acid (5.0 mL) was added to the reaction solution under ice-cooling, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 50:50) to obtain the title compound (734 mg) as a colorless oily substance.

<Step 2> Synthesis of Compound 15-3 A mixed solution of Compound 15-2 (734 mg) and a 7M ammonia / methanol solution (6.6 mL) was stirred in a sealed tube at 60 ° C. overnight. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 80: 20 to 70:30) to give the title compound (580 mg) as a colorless oily substance.

<Step 3> Synthesis of Compound 15-4 DIC (0.44 mL) is added to a solution of Compound 15-3 (570 mg), diclofenac (840 mg) and DMAP (35 mg) in acetonitrile (5.3 mL), and the mixture is stirred at room temperature for 1 hour. did. Methanol / water (1: 1) (10 mL) was added to the reaction mixture, and the mixture was stirred at 40 ° C. for 1 hour, and the precipitated solid was collected by filtration. The obtained solid was washed with methanol / water (3: 1) to give the title compound (900 mg) as a white solid.

<Step 4> Synthesis of Compound 15-5 4M hydrogen chloride / ethyl acetate (8.2 mL) was added to Compound 15-4 (900 mg), and the mixture was stirred at room temperature for 40 minutes. Ethyl acetate (10 mL) was added to the reaction solution, and the precipitated solid was collected by filtration to give the title compound (630 mg) as a white solid.

<Step 5> Synthesis of diclophenac-((2S, 3R) -2-amino-3-hydroxy-3-phenylpropanamide) -alginic acid derivative (Compound 15-6) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) Water (20 mL) was added to (200 mg) ethanol suspension (5 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 15-5 (55 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (220 mg) as a white solid. The drug introduction rate was 5.1 mol%.

(Example 16) Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-4-methylpentaneamide) -alginic acid derivative (Compound 16-6)

<Step 1> Synthesis of Compound 16-2 (2S, 3R) 1M aqueous sodium hydroxide solution (0) in methanol solution (2.0 mL) of -2-amino-3-hydroxy-3-4-methylpentanoic acid (200 mg) .20 mL), triethylamine (0.20 mL) and Boc anhydride (0.63 mL) were added and stirred overnight at room temperature. The reaction solution was filtered and the filtrate was concentrated. The obtained residue was dissolved in methanol (3.4 mL) and THF (3.4 mL), trimethylsilyldiazomethane (0.6 M hexane solution, 3.4 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. Acetic acid (3.0 mL) was added to the reaction solution under ice-cooling, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 30:70) to obtain the title compound (230 mg) as a colorless oily substance.

<Step 2> Synthesis of Compound 16-3 A mixed solution of Compound 16-2 (220 mg) and a 7M ammonia / methanol solution (2.2 mL) was stirred in a sealed tube at 60 ° C. overnight. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 80: 20 to 70:30) to give the title compound (110 mg) as a colorless oily substance.

<Step 3> Synthesis of Compound 16-4 DIC (104 μL) was added to a solution of Compound 16-3 (110 mg), diclofenac (198 mg) and DMAP (8.2 mg) in acetonitrile (1.1 mL), and the mixture was stirred at room temperature for 1 hour. did. Ethyl acetate was added to the reaction mixture, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate / heptane was added to the obtained residue, and the precipitated solid was removed by filtration. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 70:30) to give the title compound (165 mg) as a white amorphous substance.

<Step 4> Synthesis of Compound 16-5 4M hydrogen chloride and ethyl acetate (1.6 mL) were added to Compound 16-4 (160 mg), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (140 mg) as a white amorphous substance.

<Step 5> Synthesis of diclophenac-((2S, 3R) -2-amino-3-hydroxy-4-methylpentaneamide) -alginic acid derivative (Compound 16-6) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) Water (20 mL) was added to (200 mg) ethanol suspension (5 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 16-5 (51 mg) was added, and the mixture was stirred at room temperature for 16 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (190 mg) as a white solid. The drug introduction rate was 3.9 mol%.

(Example 17) Synthesis of felbinac-((2S, 3R) -2-amino-3-hydroxybutaneamide) -alginic acid derivative (Compound 17-5)

<Step 1> Synthesis of Compound 17-2 A mixed solution of N-Boc-L-threonine methyl (10 g) and a 7 M ammonia / methanol solution (50 mL) was stirred in a sealed tube at 60 ° C. overnight. The reaction solution was concentrated and the obtained residue was dissolved in MTBE. Seed crystals were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration to obtain the title compound (6.9 g) as a white solid.

<Step 2> Synthesis of Compound 17-3 Add DIC (157 μL) under ice-cooling to a solution of Compound 17-2 (200 mg), felbinac (214 mg) and DMAP (11 mg) in acetonitrile (2.0 mL) for 20 minutes at room temperature. Stirred. Methanol / water was added to the reaction solution, and the precipitated solid was collected by filtration to give the title compound (278 mg) as a white solid.

<Step 3> Synthesis of Compound 17-4 4M hydrogen chloride / dioxane (1.3 mL) was added to Compound 17-3 (250 mg), and the mixture was stirred at room temperature for 20 minutes. MTBE was added to the reaction solution, and the precipitated solid was collected by filtration to give the title compound (191 mg) as a white solid.

<Step 4> Synthesis of felbinac-((2S, 3R) -2-amino-3-hydroxybutaneamide) -alginic acid derivative (Compound 17-5) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg) Water (20 mL) was added to the ethanol suspension (5 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 17-4 (42 mg) was added, and the mixture was stirred at room temperature for 17 hours. A 0.1 g / mL aqueous sodium chloride solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (199 mg) as a white solid. The drug introduction rate was 9.3 mol%.

(Example 18) Synthesis of ketoprofen-((S) -2-amino-3-hydroxypropanamide) -alginic acid derivative (Compound 18-3)

<Step 1> Synthesis of Compound 18-1 Compound 14-2 (200 mg) is dissolved in acetonitrile (2.0 mL), ketoprofen (274 mg), DIC (168 μL) and DMAP (12 mg) are added, and the mixture is stirred at room temperature for 30 minutes. did. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1M hydrochloric acid and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 50: 50) to obtain the title compound (164 mg) as a white amorphous substance. It was.
..

<Step 2> Synthesis of Compound 18-2 4M hydrogen chloride / dioxane (631 μL) was added to Compound 18-1 (130 mg), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, MTBE was added to the obtained residue, and the precipitated solid was collected by filtration to give the title compound (44 mg) as a white solid.

<Step 3> Synthesis of ketoprofen-((S) -2-amino-3-hydroxypropanamide) -alginic acid derivative (Compound 18-3) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (150 mg) in ethanol suspension Water (15 mL) was added to the turbid solution (3.8 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (56 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (2.3 mL) of compound 18-2 (34 mg) was added, and the mixture was stirred at room temperature for 17 hours. A 0.1 g / mL aqueous sodium chloride solution (3.8 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (38 mL) was added to the reaction mixture, and the mixture was further stirred for 1.5 hours. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (163 mg) as a white solid. The drug introduction rate was 12.3 mol%.

(Example 19) Synthesis of naproxen-((S) -2-amino-3-hydroxypropanamide) -alginic acid derivative (Compound 19-3)

<Step 1> Synthesis of Compound 19-1 Compound 14-2 (200 mg) is dissolved in acetonitrile (2.0 mL), naproxen (248 mg), DIC (168 μL) and DMAP (12 mg) are added, and the mixture is stirred at room temperature for 30 minutes. did. Methanol / water was added to the reaction solution, and the precipitated solid was collected by filtration to give the title compound (251 mg) as a white solid.

<Step 2> Synthesis of Compound 19-2 4M hydrogen chloride / dioxane (970 μL) was added to Compound 19-1 (200 mg), and the mixture was stirred at room temperature for 20 minutes. MTBE was added to the reaction solution, and the precipitated solid was collected by filtration to give the title compound (130 mg) as a white solid.

<Step 3> Synthesis of naproxen-((S) -2-amino-3-hydroxypropanamide) -alginic acid derivative (Compound 19-3) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg) in ethanol suspension Water (20 mL) was added to the turbid solution (5 mL), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 19-2 (40 mg) was added, and the mixture was stirred at room temperature for 15 hours. A 0.1 g / mL aqueous sodium chloride solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (193 mg) as a white solid. The drug introduction rate was 11.5 mol%.

(Example 20) Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) -N-methylacetamide) -alginic acid derivative (Compound 20-5)

<Step 1> Synthesis of Compound 20-3 A mixture of 2- (methylamino) ethanol (0.38 g), N-Boc glycine (0.88 g), DMAP (0.12 g) and dichloromethane (20 mL) is ice-cooled. , DCC (1.03 g) in dichloromethane (5 mL) was added and the reaction was stirred at room temperature for 8 hours. Diclofenac (1.48 g) was added to the reaction solution, DCC (1.03 g) in dichloromethane (5 mL) was further added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give the title compound (0.83 g) as a white amorphous substance.

<Step 2> Synthesis of Compound 20-4 A mixture of Compound 20-3 (0.83 g) and 4M hydrogen chloride / dioxane (8 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (0.77 g) as a white amorphous substance.

<Step 3> Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) -N-methylacetamide) -alginic acid derivative (Compound 20-5) Sodium alginate at 30 ° C. (Mochida Pharmaceutical Co., Ltd., A-2) ) (200 mg), ethanol (8 mL) was added to an aqueous solution (20 mL), and the mixture was stirred for 1 hour. DMT-MM (46 mg) was added, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 20-4 (41 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added. The mixture was stirred at the same temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (2 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (219 mg) as a white solid. The drug introduction rate was 12.0 mol%.

(Example 21) Synthesis of diclofenac- (N- (2-hydroxyethyl) -2- (methylamino) acetamide) -alginic acid derivative (Compound 21-4)

<Step 1> Synthesis of Compound 21-2 A mixture of 2-aminoethanol (0.31 g), N-Boc sarcosine (0.95 g), DMAP (0.12 g) and dichloromethane (20 mL) was ice-cooled and DCC (DCC). 1.03 g) of a dichloromethane solution (5 mL) was added and the reaction was stirred at room temperature overnight. Diclofenac (1.48 g) was added to the reaction solution, DCC (1.03 g) in dichloromethane (5 mL) was further added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give the title compound (1.3 g) as a white amorphous substance.

<Step 2> Synthesis of Compound 21-3 A mixture of Compound 21-2 (1.3 g) and 4M hydrogen chloride / dioxane (13 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (1.0 g) as a white amorphous substance.

<Step 3> Synthesis of diclofenac- (N- (2-hydroxyethyl) -2- (methylamino) acetamide) -alginic acid derivative (Compound 21-4) Sodium alginate at 25 ° C (Mochida Pharmaceutical Co., Ltd., A-2) Ethanol (8 mL) was added to an aqueous solution (20 mL) of (200 mg), and the mixture was stirred for 1 hour. DMT-MM (46 mg) was added, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 21-3 (41 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added. The mixture was stirred at the same temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (2 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (191 mg) as a white solid. The drug introduction rate was 10.4 mol%.

(Example 22) Synthesis of diclofenac-((2S, 3R) -2-amino-3-hydroxy-N- (2-hydroxyethyl) butaneamide) -alginic acid derivative (Compound 22-3)

<Step 1> Synthesis of Compound 22-1 A mixture of 2-aminoethanol (0.31 g), N-Boc-L-threonine (1.1 g), DMAP (0.12 g) and dichloromethane (20 mL) is ice-cooled. , DCC (1.03 g) in dichloromethane (5 mL) was added and the reaction was stirred at room temperature overnight. Diclofenac (1.48 g) was added to the reaction solution, DCC (1.03 g) in dichloromethane (5 mL) was further added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give the title compound (0.28 g) as a white amorphous substance.

<Step 2> Synthesis of Compound 22-2 A mixture of Compound 22-1 (0.28 g) and 4M hydrogen chloride / dioxane (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.27 g) as a colorless gum-like substance.

<Step 3> Synthesis of diclofenac- (N- (2-hydroxyethyl) -2- (methylamino) acetamide) -alginic acid derivative (Compound 22-3) Sodium alginate at 25 ° C (Mochida Pharmaceutical Co., Ltd., A-2) Ethanol (8 mL) was added to an aqueous solution (20 mL) of (200 mg), and the mixture was stirred for 1 hour. DMT-MM (46 mg) was added, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 22-2 (44 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added. The reaction was stirred at the same temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (2 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (198 mg) as a white solid. The drug introduction rate was 11.1 mol%.

(Example 23) Synthesis of diclofenac-((S) -2-amino-3-hydroxy-N- (2-hydroxyethyl) propanamide) -alginic acid derivative (Compound 23-6)

<Step 1> Synthesis of Compound 23-2 tert-butyl (2-hydroxyethyl) carbamate (5 g), diclofenac (11 g) and DMAP (0.38 g) are dissolved in dichloromethane (50 mL), and DCC (7.7 g) is used. Was added under ice-cooling and stirred at room temperature for 4 hours. The reaction was filtered and washed with dichloromethane (50 mL). The filtrate was washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was solidified and pulverized with heptane / ethyl acetate to obtain the title compound (11.7 g) as a white solid.

<Step 2> Synthesis of Compound 23-3 4M hydrogen chloride / dioxane (59 mL) was added to Compound 23-2 (11.8 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was solidified and pulverized with MTBE to obtain the title compound (9.8 g) as a white solid.

<Step 3> Synthesis of Compound 23-4 Compound 23-3 (1.8 g), N-Boc-L-serine (1 g), DMT-MM (2.0 g) and 1 M aqueous sodium hydrogen carbonate solution (5.9 mL). Was dissolved in methanol (10 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), and washed with water (20 mL × 2) and saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was solidified and pulverized with MTBE to obtain the title compound (2.3 g) as a white solid.

<Step 4> Synthesis of Compound 23-5 4M hydrogen chloride / CPME (9.8 mL) was added to Compound 23-4 (2.2 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was solidified and pulverized with MTBE to obtain the title compound (1.7 g) as a white solid.

<Step 5> Synthesis of diclophenac-((S) -2-amino-3-hydroxy-N- (2-hydroxyethyl) propanamide) -alginic acid derivative (Compound 23-6) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A) -2) Water (20 mL) was added to an ethanol suspension (5 mL) of (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 23-5 (47 mg) was added, and the mixture was stirred at room temperature for 1 hour. A 1 M aqueous sodium hydrogen carbonate solution (0.10 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (180 mg) as a white solid. The drug introduction rate was 11.4 mol%

(Example 24) Diclofenac-((S) -16-amino-N- (2-hydroxyethyl) -2,5,8,11,14-pentaoxaheptadecane-17-amide) -alginic acid derivative (Compound 24) -4) Synthesis

<Step 1> Synthesis of Compound 24-2 Sodium hydride (60% oily, 15 mg) was added to a solution of N-Boc-L-serine methyl (117 mg) in DMF (2.0 mL) at 0 ° C. for 15 minutes at room temperature. Stirred. 1-Bromo-2,5,8,11,14-pentaoxapentadecane (192 mg) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. Compound 23-3 (200 mg), DMT-MM (177 mg) and water (2.0 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction was filtered, diluted with MTBE (10 mL) and washed with water (15 mL) and saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 0: 100) to obtain the title compound (110 mg) as a colorless oily substance.

<Step 2> Synthesis of Compound 24-3 4M hydrogen chloride / ethyl acetate (550 μL) was added to Compound 24-2 (110 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was neutralized with triethylamine (64 μL). The mixed solution was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate / methanol = 100: 0 to 80:20) to obtain the title compound (53 mg) as a colorless oily substance.

<Step 3> Diclofenac-((S) -16-amino-N- (2-hydroxyethyl) -2,5,8,11,14-pentaoxaheptadecane-17-amide) -alginic acid derivative (Compound 24- 4) Synthesis Water (13 mL) was added to an ethanol suspension (4 mL) of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) (130 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (48 mg) was added to this solution, and the mixture was stirred at room temperature for 1 hour. An ethanol solution (1.3 mL) of compound 24-3 (45 mg) was added to the reaction mixture, and the mixture was stirred overnight. A 0.1 g / mL aqueous sodium chloride solution (5 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (130 mg) as a white solid. The drug introduction rate was 19.8 mol%

(Example 25) Synthesis of diclofenac-((S) -2-amino-3-((2-hydroxyethyl) amino) -3-oxopropyl phosphate) -alginic acid derivative (Compound 25-6)

<Step 1> Synthesis of Compound 25-2 N-(((9H-fluorene-9-yl) methoxy) carbonyl) -O- (tert-butyl) -L-serine (5 g) and 2-aminoethane-1-ol DMT-MM (4.3 g) was added to a solution of (0.96 g) in ethanol (50 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 20:80) to obtain the title compound (5.0 g) as a colorless oily substance.

<Step 2> Synthesis of Compound 25-3 Compound 25-2 (5.0 g), diclofenac (3.5 g) and DMAP (0.14 g) are dissolved in dichloromethane (50 mL), and DCC (2.9 g) is added to ice. It was added under cooling and stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Trifluoroacetic acid (8 mL) was added to a dichloromethane solution (40 mL) of the obtained residue (8.0 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was solidified and pulverized with MTBE to obtain the title compound (5.4 g) as a white solid.

<Step 3> Synthesis of Compound 25-4 Compound 25-3 (100 mg) is dissolved in a mixed solution of dichloromethane (0.5 mL) and THF (0.5 mL), 1H-tetrazole (22 mg) is added at room temperature, and 30 Stir for minutes. Di-tert-butyldiisopropylphosphoroamidite (86 mg) was added to the reaction mixture, and the mixture was stirred at room temperature in the dark for 15 hours. 30% hydrogen peroxide solution (63 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. An aqueous sodium thiosulfate solution was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate (10 mL × 2). The organic layer was washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 70:30) to obtain the title compound (100 mg) as a colorless oily substance.

<Step 4> Synthesis of Compound 25-5 Piperidine (24 μL) was added to a solution of Compound 25-4 (100 mg) in acetonitrile (500 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate / methanol = 100: 0 to 20:80). Trifluoroacetic acid (60 μL) was added to a dichloromethane solution (240 μL) of the obtained colorless oily substance (30 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 4M hydrogen chloride and ethyl acetate (30 μL) were added to the obtained residue, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (25 mg) as a colorless oily substance (ESI-MS: 506 [M + H] +).

<Step 5> Synthesis of diclophenac-((S) -2-amino-3-((2-hydroxyethyl) amino) -3-oxopropyl phosphate) -alginic acid derivative (Compound 25-6) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) Water (10 mL) was added to an ethanol suspension (3 mL) of company A-3) (100 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (26 mg) was added to this solution, and the mixture was stirred at room temperature for 1 hour. An ethanol solution (1 mL) of compound 25-5 (25 mg) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (20 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (80 mg) as a white solid. The drug introduction rate was 5.2 mol%.

(Example 26) Synthesis of diclofenac- (2-amino-N, N-bis (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 26-4)

<Step 1> Synthesis of Compound 26-2 A mixture of tert-butylbis (2-hydroxyethyl) carbamate (3.08 g), diclofenac (2.96 g), DMAP (0.12 g) and dichloromethane (40 mL) is ice-cooled. , DCC (2.06 g) in dichloromethane (10 mL) was added and the reaction was stirred at the same temperature for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give the title compound (2.55 g) as a colorless gum.

<Step 2> Synthesis of Compound 26-3 A mixture of Compound 26-2 (2.5 g) and 4M hydrogen chloride / dioxane (25 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (2.37 g) as a colorless gum-like substance.

<Step 3> Synthesis of diclofenac- (2-amino-N, N-bis (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 26-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg) Ethanol (6 mL) was added to the aqueous solution (20 mL) of the above, and the mixture was stirred at room temperature for 30 minutes. DMT-MM (152 mg) was added, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 26-3 (77 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.18 mL) were added. The reaction was stirred at 30 ° C. for 6 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (200 mg) as a white solid. The drug introduction rate was 9.0 mol%.

(Example 27) Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) -3-phenylpropanamide) -alginic acid derivative (Compound 27-4)

<Step 1> Synthesis of Compound 27-2 Compound 23-3 (0.38 g) and 1 M in a methanol mixture (4 mL) of N-Boc-L-phenylalanine (0.32 g) and DMT-MM (0.33 g). An aqueous sodium hydrogen carbonate solution (1 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure. The residue was purified from ethyl acetate / heptane by crystallization to give the title compound (0.36 g) as a white solid.

<Step 2> Synthesis of Compound 27-3 A mixture of Compound 27-2 (0.36 g) and 4M hydrogen chloride / dioxane (6 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.36 g) as a colorless glassy substance.

<Step 3> Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) -3-phenylpropanamide) -alginic acid derivative (Compound 27-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A) -2) Ethanol (6 mL) was added to an aqueous solution (20 mL) of (200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 27-3 (72 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (199 mg) as a white solid. The drug introduction rate was 11.6 mol%.

(Example 28) Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) propanamide) -alginic acid derivative (Compound 28-4)

<Step 1> Synthesis of Compound 28-2 Compound 23-3 (0.38 g) and 1 M in a methanol mixture (4 mL) of N-Boc-L-alanine (0.23 g) and DMT-MM (0.33 g). An aqueous sodium hydrogen carbonate solution (1 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give the title compound (0.46 g) as a white solid.

<Step 2> Synthesis of Compound 28-3 A mixture of Compound 28-2 (0.46 g) and 4M hydrogen chloride / CPME (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.46 g) as a colorless gum-like substance.

<Step 3> Diclofenac-((S) -2-amino-N- (2-hydroxyethyl) propanamide) -alginic acid derivative (Compound 28-4)
Ethanol (6 mL) was added to an aqueous solution (20 mL) of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 28-3 (61 mg) and a 1M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (211 mg) as a white solid. The drug introduction rate was 13.3 mol%.

(Example 29) Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) -3-methylbutaneamide) -alginic acid derivative (Compound 29-4)

<Step 1> Synthesis of Compound 29-2 Compound 23-3 (0.38 g) and 1 M in a methanol mixture (4 mL) of N-Boc-L-valine (0.26 g) and DMT-MM (0.33 g). An aqueous sodium hydrogen carbonate solution (1 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give the title compound (0.36 g) as a white solid.

<Step 2> Synthesis of Compound 29-3 A mixture of Compound 29-2 (0.36 g) and 4M hydrogen chloride / CPME (8 mL) was stirred at room temperature for 1 hour. The reaction suspension was filtered to give the title compound (0.29 g) as a white solid.

<Step 3> Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) -3-methylbutaneamide) -alginic acid derivative (Compound 29-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A) -2) Ethanol (6 mL) was added to an aqueous solution (20 mL) of (200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 29-3 (65 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (203 mg) as a white solid. The drug introduction rate was 13.5 mol%.

(Example 30) Synthesis of diclofenac-((S) -2-amino-N1- (2-hydroxyethyl) pentandiamide) -alginic acid derivative (Compound 30-4)

<Step 1> Synthesis of Compound 30-2 DMT-MM (0.33 g) and 1 M in a methanol mixture (4 mL) of Nα-Boc-L-glutamine (0.3 g) and compound 23-3 (0.38 g). An aqueous sodium hydrogen carbonate solution (1 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. Water (8 mL) was added to the reaction suspension and the mixture was filtered to obtain the title compound (0.45 g) as a white solid.

<Step 2> Synthesis of Compound 30-3 A mixture of Compound 30-2 (0.42 g) and 4M hydrogen chloride / dioxane (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.44 g) as a white amorphous substance.

<Step 3> Synthesis of diclofenac-((S) -2-amino-N1- (2-hydroxyethyl) pentandiamide) -alginic acid derivative (Compound 30-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) ( Ethanol (6 mL) was added to an aqueous solution (20 mL) of 200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 30-3 (69 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (213 mg) as a white solid. The drug introduction rate was 17.9 mol%.

(Example 31) Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) -5-ureidopentaneamide) -alginic acid derivative (Compound 31-4)

<Step 1> Synthesis of Compound 31-2 DMT-MM (0.33 g) and 1 M in a methanol mixture (4 mL) of Nα-Boc-L-citrulin (0.33 g) and Compound 23-3 (0.38 g). An aqueous sodium hydrogen carbonate solution (1 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% methanol / ethyl acetate) to give the title compound (0.47 g) as a colorless gum-like substance.

<Step 2> Synthesis of Compound 31-3 A mixture of Compound 31-2 (0.47 g) and 4M hydrogen chloride / dioxane (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.44 g) as a white amorphous substance.

<Step 3> Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) -5-ureidopentaneamide) -alginic acid derivative (Compound 31-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A) -2) Ethanol (6 mL) was added to an aqueous solution (20 mL) of (200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 31-3 (73 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (215 mg) as a white solid. The drug introduction rate was 14.9 mol%.

(Example 32) Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) -3- (1H-indole-3-yl) propanamide) -alginic acid derivative (Compound 32-4)

<Step 1> Synthesis of Compound 32-2 DMT-MM (0.33 g) is added to a methanol mixture (4 mL) of Nα-Boc-L-tryptophan (0.37 g) and Compound 23-3 (0.38 g). , The reaction solution was stirred at room temperature for 3 hours. DMT-MM (0.33 g) and 1 M aqueous sodium hydrogen carbonate solution (1 mL) were added to the reaction mixture, and the mixture was further stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over sodium sulfate, and the filtered filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-50% ethyl acetate / heptane) to give the title compound (0.25 g) as a white amorphous substance.

<Step 2> Synthesis of Compound 32-3 A mixture of Compound 32-2 (0.25 g) and 4M hydrogen chloride / dioxane (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.26 g) as a colorless glassy substance.

<Step 3> Synthesis of diclofenac-((S) -2-amino-N- (2-hydroxyethyl) -3- (1H-indole-3-yl) propanamide) -alginic acid derivative (compound 32-4) alginic acid Ethanol (6 mL) was added to an aqueous solution (20 mL) of sodium (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 32-3 (77 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (160 mg) as a white solid. The drug introduction rate was 9.6 mol%.

(Example 33) Synthesis of diclofenac-((S) -2-amino-6- (dimethylamino) -N- (2-hydroxyethyl) hexaneamide) -alginic acid derivative (Compound 33-4)

<Step 1> Synthesis of Compound 33-2 DMT-MM (4 mL) was added to a methanol mixture (4 mL) of N2-Boc-N6, N6-dimethyl-L-lysine (0.3 g) and Compound 23-3 (0.38 g). 0.37 g) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (20-100% ethyl acetate / heptane) to obtain the title compound (0.34 g) as a colorless glassy substance.

<Step 2> Synthesis of Compound 33-3 A mixture of Compound 33-2 (0.34 g) and 4M hydrogen chloride / dioxane (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.34 g) as a white amorphous substance.

<Step 3> Synthesis of diclophenac-((S) -2-amino-6- (dimethylamino) -N- (2-hydroxyethyl) hexaneamide) -alginic acid derivative (Compound 33-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) Ethanol (6 mL) was added to an aqueous solution (20 mL) of company A-2) (200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 33-3 (78 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.27 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (151 mg) as a white solid. The drug introduction rate was 12.4 mol%.

(Example 34) Synthesis of diclofenac- (4-amino-N- (2-hydroxyethyl) tetrahydro-2H-pyran-4-carboxyamide) -alginic acid derivative (Compound 34-4)

<Step 1> Synthesis of Compound 34-2 DMT in a methanol mixture (4 mL) of 4- (Bocamino) tetrahydro-2H-pyran-4-carboxylic acid (0.27 g) and compound 23-3 (0.38 g). -MM (0.37 g) and 1 M aqueous sodium hydrogen carbonate solution (1 mL) were added, and the reaction mixture was stirred at room temperature for 2 hours. Water (8 mL) was added to the reaction suspension and the mixture was filtered to obtain the title compound (0.31 g) as a white solid.

<Step 2> Synthesis of Compound 34-3 A mixture of Compound 34-2 (0.31 g) and 4M hydrogen chloride / dioxane (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.33 g) as a colorless glassy substance.

<Step 3> Synthesis of diclofenac- (4-amino-N- (2-hydroxyethyl) tetrahydro-2H-pyran-4-carboxyamide) -alginic acid derivative (Compound 34-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A) -2) Ethanol (6 mL) was added to an aqueous solution (20 mL) of (200 mg). DMT-MM (183 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 34-3 (69 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at 50 ° C. overnight. Further, DMT-MM (0.2 g) was added, and the mixture was stirred at 60 ° C. for 6 hours. After bringing the reaction solution to room temperature, 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) were added to the reaction solution, and the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (174 mg) as a white solid. The drug introduction rate was 5.1 mol%.

(Example 35) Synthesis of diclofenac-((2S) -2-amino-6- (dimethylamino) -N- (2-hydroxy-3-methylbutyl) hexaneamide) -alginic acid derivative (Compound 35-4)

<Step 1> Synthesis of Compound 35-2 Ethanol (2 mL) of 1-amino-3-methylbutano-2-ol (0.1 g), N2-Boc-N6, N6-dimethyl-L-lysine (0.27 g) DMT-MM (0.37 g) was added to the mixture at room temperature, and the mixture was stirred for 2 hours. The reaction suspension was filtered and the filtrate was concentrated under reduced pressure. Diclofenac (0.44 g), DMAP (0.02 g) and dichloromethane (4 mL) were added to the obtained residue, and a dichloromethane solution (1 mL) of DCC (0.31 g) was added dropwise to the mixture under ice-cooling. The reaction was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (50-100% ethyl acetate / heptane) to give the title compound (0.24 g) as a colorless gum.

<Step 2> Synthesis of Compound 35-3 A mixture of Compound 35-2 (0.24 g) and 4M hydrogen chloride / dioxane (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.26 g) as a white amorphous substance.

<Step 3> Synthesis of diclophenac-((2S) -2-amino-6- (dimethylamino) -N- (2-hydroxy-3-methylbutyl) hexaneamide) -alginic acid derivative (Compound 35-4) Sodium alginate ( Ethanol (6 mL) was added to an aqueous solution (20 mL) of Mochida Pharmaceutical Co., Ltd., A-2) (200 mg). DMT-MM (73 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 35-3 (67 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.22 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (225 mg) as a white solid. The drug introduction rate was 10.3 mol%.

(Example 36) Synthesis of diclofenac-((2S) -2-amino-6- (dimethylamino) -N- (2-hydroxypropyl) hexaneamide) -alginic acid derivative (Compound 36-4)

<Step 1> Synthesis of Compound 36-2 Room temperature in a mixture of 1-aminopropane-2-ol (0.08 g), N2-Boc-N6, N6-dimethyl-L-lysine (0.27 g) in ethanol (2 mL) DMT-MM (0.37 g) was added and stirred for 2 hours. The reaction suspension was filtered and the filtrate was concentrated under reduced pressure. Diclofenac (0.44 g), DMAP (0.02 g) and dichloromethane (4 mL) were added to the obtained residue, and a dichloromethane solution (1 mL) of DCC (0.31 g) was added dropwise to the mixture under ice-cooling. The reaction was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (20-100% ethyl acetate / heptane) to give the title compound (0.18 g) as a colorless gum.

<Step 2> Synthesis of Compound 36-3 A mixture of Compound 36-2 (0.18 g) and 4M hydrogen chloride / dioxane (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.19 g) as a white amorphous substance.

<Step 3> Synthesis of diclophenac-((2S) -2-amino-6- (dimethylamino) -N- (2-hydroxypropyl) hexaneamide) -alginic acid derivative (Compound 36-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) Ethanol (6 mL) was added to an aqueous solution (20 mL) of company A-2) (200 mg). DMT-MM (73 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 36-3 (64 mg) and a 1M aqueous sodium hydrogen carbonate solution (0.22 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (218 mg) as a white solid. The drug introduction rate was 10.0 mol%.

(Example 37) Synthesis of diclofenac- (2-amino-N- (2-hydroxy-3-methylbutyl) acetamide) -alginic acid derivative (Compound 37-3)

<Step 1> Synthesis of Compound 37-1 DMT-MM (0) in a mixture of 1-amino-3-methylbutano-2-ol (0.21 g) and N-Boc glycine (0.35 g) in ethanol (4 mL) at room temperature. .73 g) was added, and the mixture was stirred for 2 hours. The reaction suspension was filtered and the filtrate was concentrated under reduced pressure. Diclofenac (0.89 g), DMAP (0.05 g) and dichloromethane (8 mL) were added to the obtained residue, and a dichloromethane solution (2 mL) of DCC (0.62 g) was added dropwise to the mixture under ice cooling. The reaction was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to give the title compound (0.75 g) as a white solid.

<Step 2> Synthesis of Compound 37-2 A mixture of Compound 37-1 (0.75 g) and 4M hydrogen chloride / dioxane (7 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.72 g) as a white amorphous substance.

<Step 3> Synthesis of diclofenac- (2-amino-N- (2-hydroxy-3-methylbutyl) acetamide) -alginic acid derivative (Compound 37-3) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg) Ethanol (6 mL) was added to the aqueous solution (20 mL) of. DMT-MM (73 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 37-2 (52 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.11 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (225 mg) as a white solid. The drug introduction rate was 15.6 mol%.

(Example 38) Synthesis of diclofenac- (2- (2- (2-aminoethoxy) ethoxy) -N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 38-5)

<Step 1> Synthesis of Compound 38-2 1- (9H-fluorene-9-yl) -3-oxo-2,7,10-trioxa-4-aza-12-dodecanoic acid (5 g) and 2-aminoethane- DMT-MM (5.2 g) was added to a solution of 1-ol (0.95 g) in ethanol (50 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, concentrated, and purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 50:50) to obtain the title compound (5.4 g) as a colorless oily substance.

<Step 2> Synthesis of Compound 38-3 DCC (3.1 g) was added to a solution of Compound 38-2 (5.4 g), diclofenac (4.5 g) and DMAP (150 mg) in acetonitrile (27 mL), and the mixture was prepared at room temperature. Stirred in the evening. The reaction mixture was filtered and concentrated, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 70:30) to obtain the title compound (1.5 g) as a colorless oily substance. Obtained.

<Step 3> Synthesis of Compound 38-4 Piperidine (0.42 mL) was added to a solution of Compound 38-3 (1.5 g) in acetonitrile (7.5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, 4M hydrogen chloride and ethyl acetate (1.5 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered, MTBE was added to the filtrate, and the supernatant was removed to obtain the title compound (1.0 g) as a colorless oily substance.

<Step 4> Synthesis of diclofenac- (2- (2- (2-aminoethoxy) ethoxy) -N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 38-5) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) Water (100 mL) was added to an ethanol suspension (30 mL) of (1.0 g), and the mixture was stirred at room temperature for 1 hour. DMT-MM (0.46 g) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (10 mL) of compound 38-4 (0.36 g) was added, and the mixture was stirred at room temperature for 1 hour. A 1 M aqueous sodium hydrogen carbonate solution (0.7 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A 0.1 g / mL aqueous sodium chloride solution (20 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (250 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.0 g) as a white solid. The drug introduction rate was 6.9 mol%.

(Example 39) Synthesis of diclofenac- (2- (methylamino) ethanol) -alginic acid derivative (Compound 39-4)

<Step 1> Synthesis of Compound 39-2 DCC in an acetonitrile solution (100 mL) of diclofenac (11 g), tert-butyl (2-hydroxymethyl) (methyl) carbamate (5 g), and DMAP (0.17 g) at 13 ° C. (8.24 g) was added, and the mixture was stirred at 14 to 21 ° C. for 4 hours. The reaction mixture was filtered through Celite, and the Celite cake was washed with ethyl acetate (150 mL). The filtrate is concentrated, dissolved in ethyl acetate (200 mL), washed with water (200 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (18.1 g). Obtained as a pale yellow oily substance.

<Step 2> Synthesis of Compound 39-3 4M hydrogen chloride and ethyl acetate (140 mL) were added to Compound 39-2 (17 g), and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration, washed with ethyl acetate (100 mL), and dried by heating under reduced pressure to give the title compound (9.42 g) as a white solid.

<Step 3> Synthesis of diclofenac- (2- (methylamino) ethanol) -alginic acid derivative (Compound 39-4) Add ethanol (30 mL) to alginic acid (Mochida Pharmaceutical Co., Ltd., A-2) (1 g) at room temperature. The mixture was stirred for two and a half hours. Water (100 mL) was added to the suspension, and the mixture was stirred at room temperature for 2 hours and 40 minutes, then DMT-MM (0.64 g) was added, and the mixture was stirred at room temperature for 55 minutes. A solution of compound 39-3 (0.45 g) in ethanol: water (1: 1) (20 mL) was added dropwise to the reaction solution over 7 minutes. The reaction mixture was stirred at room temperature for 23 hours and 30 minutes, 1 M aqueous sodium hydrogen carbonate solution (1 mL) was added, and the mixture was further stirred at room temperature for 18 hours and 15 minutes. A 0.1 g / mL aqueous sodium chloride solution (10 mL) was added to the reaction mixture and stirred for 1 hour, ethanol (200 mL) was added, and the mixture was further stirred for 2 and a half hours. The resulting solid was collected by filtration, washed with ethanol (100 mL), and dried under reduced pressure at 40 ° C. to give the title compound (1.06 g) as a white solid. The drug introduction rate was 14.8 mol%.

(Example 40) Synthesis of diclofenac- (azetidine-3-ol) -alginic acid derivative (Compound 40-4)

<Step 1> Synthesis of Compound 40-2 Diclofenac (11 g), tert-butyl 3-hydroxyazetidine-1-carboxylate (4.95 g), DMAP (0.17 g) in an acetonitrile solution (99 mL) at 18 ° C. DCC (8.26 g) was added, and the mixture was stirred at 18 to 24 ° C. for 91 hours. The reaction mixture was filtered through Celite, and the Celite cake was washed with ethyl acetate (100 mL). The filtrate was concentrated, dissolved in ethyl acetate (250 mL), washed with water (150 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1) to give the title compound (15.3 g) as a pale yellow solid.

<Step 2> Synthesis of Compound 40-3 4M hydrogen chloride / dioxane (50 mL) was added to Compound 40-2 (5 g), and the mixture was stirred at room temperature for 50 minutes and then concentrated. The resulting residue was azeotropically boiled 3 times with CPME (10 mL) to solidify and then triturated with CPME (10 mL). The solid was collected by filtration, washed with CPME (40 mL), and then dried by heating under reduced pressure to give the title compound (3.57 g) as a white solid.

<Step 3> Synthesis of diclofenac- (azetidine-3-ol) -alginic acid derivative (Compound 40-4) Add ethanol (6 mL) to alginic acid (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg) for 30 minutes at room temperature. Stirred. Water (20 mL) was added to the suspension, and the mixture was stirred at room temperature for 16 hours, DMT-MM (77 mg) was added, and the mixture was stirred at room temperature for 80 minutes. A solution of compound 40-3 (55 mg) in ethanol: water (1: 1) (4 mL) was added dropwise to the reaction solution over 2 minutes. The reaction mixture was stirred at room temperature for 6 hours and 20 minutes, 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) was added, and the mixture was further stirred at room temperature for 63 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 2 hours. Ethanol (40 mL) was added and the mixture was further stirred for 2 hours. The resulting solid was collected by filtration, washed with ethanol (40 mL), and dried under reduced pressure at 40 ° C. to give the title compound (201 mg) as a white solid. The drug introduction rate was 21.5 mol%.

(Example 41) Synthesis of diclofenac-((2S, 4R) -4-hydroxyproline ethyl ester) -alginic acid derivative (Compound 41-4)

<Step 1> Synthesis of Compound 41-2 1- (tert-butyl) 2-ethyl (2S, 4R) -4-hydroxypyrrolidin-1,2-dicarboxylic acid (1.3 g), dichloromethane (1.48 g), A mixture of DMAP (0.06 g) and dichloromethane (20 mL) was ice-cooled, a solution of DCC (1.13 g) in dichloromethane (5 mL) was added, and the reaction mixture was stirred at the same temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give the title compound (2.0 g) as a colorless gum-like substance.

<Step 2> Synthesis of Compound 41-3 A mixture of Compound 41-2 (2.0 g) and 4M hydrogen chloride / CPME (20 mL) was stirred at room temperature for 70 minutes. The reaction suspension was filtered to give the title compound (1.3 g) as a white solid.

<Step 3> Synthesis of diclophenac-((2S, 4R) -4-hydroxyproline ethyl ester) -alginic acid derivative (Compound 41-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg) aqueous solution (20 mL) ), Ethanol (6 mL) was added. DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 41-3 (65 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (187 mg) as a white solid. The drug introduction rate was 10.1 mol%.

(Example 42) Synthesis of diclofenac-((2S) -2-amino-N- (2,3-dihydroxypropyl) -4-hydroxybutaneamide) -alginic acid derivative (Compound 42-4)

<Step 1> Synthesis of Compound 42-2 (2,2-dimethyl-1,3-dioxolane-4-yl) Methanol (10 mL) solution of methaneamine (0.6 g) and N-Boc-L-homoserin (1 g) DMT-MM (1.9 g) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, the filtrate was concentrated and then diluted with ethyl acetate (20 mL). The mixture was washed twice with water (20 mL) and the aqueous layer was extracted twice with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue (1.5 g) diclofenac (2.0 g) and DMAP (60 mg) were dissolved in dichloromethane (15 mL), DCC (1.4 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 50:50) to obtain the title compound (2.1 g) as a white amorphous substance.

<Step 2> Synthesis of Compound 42-3 4M hydrogen chloride / CPME (11 mL) was added to a solution of compound 42-2 (2.1 g) in THF (11 mL) under ice-cooling, and the mixture was stirred at 30 ° C. for 1 hour. Then, water (60 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the obtained residue was purified by ODS column chromatography (0.01 M aqueous hydrochloric acid solution / acetonitrile = 100: 0 to 50:50) to obtain the title compound (630 mg) as a brown amorphous substance.

<Step 3> Synthesis of diclophenac-((2S) -2-amino-N- (2,3-dihydroxypropyl) -4-hydroxybutaneamide) -alginic acid derivative (Compound 42-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) , A-2) Water (20 mL) was added to an ethanol suspension (5 mL) of (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to the solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 42-3 (56 mg) was added, and the mixture was stirred at room temperature for 1 hour. A 1 M aqueous sodium hydrogen carbonate solution (0.1 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A 0.1 g / mL aqueous sodium chloride solution (1 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (200 mg) as a white solid. The drug introduction rate was 14.9 mol%.

(Example 43) Synthesis of diclofenac-((2S, 4R) -N- (2,3-dihydroxypropyl) -4-hydroxypyrrolidine-2-carboxyamide) -alginic acid derivative (Compound 43-4)

<Step 1> Synthesis of Compound 43-2 (2,2-dimethyl-1,3-dioxolane-4-yl) methaneamine (0.57 g) and (2S, 4R) -1-Boc-4-hydroxypyrrolidine-2 DMT-MM (1.8 g) was added to a solution of −carboxylic acid (1.0 g) in methanol (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated and diluted with ethyl acetate (10 mL). The mixture was washed with water (10 mL) and the aqueous layer was extracted twice with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue (1.5 g) diclofenac (1.9 g) and DMAP (50 mg) were dissolved in dichloromethane (15 mL), DCC (1.3 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 100: 0 to 50:50) to obtain the title compound (1.6 g) as a white solid.

<Step 2> Synthesis of Compound 43-3 Add 4M hydrogen chloride / CPME (8.0 mL) to a solution of compound 43-2 (1.6 g) in THF (8.0 mL) under ice-cooling, and stir at 30 ° C. for 1 hour. did. Then, water (50 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the obtained residue was purified by ODS column chromatography (0.01 M aqueous hydrochloric acid solution / acetonitrile = 100: 0 to 50:50) to obtain the title compound (890 mg) as a brown amorphous substance.

<Step 3> Synthesis of diclophenac-((2S, 4R) -N- (2,3-dihydroxypropyl) -4-hydroxypyrrolidin-2-carboxyamide) -alginic acid derivative (Compound 43-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) Water (20 mL) was added to an ethanol suspension (5 mL) of A-2) (200 mg), and the mixture was stirred at room temperature for 1 hour. DMT-MM (74 mg) was added to this solution, and the mixture was stirred for 1 hour, then an ethanol solution (3 mL) of compound 43-3 (58 mg) was added, and the mixture was stirred at room temperature for 1 hour. A 1 M aqueous sodium hydrogen carbonate solution (0.1 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A 0.1 g / mL aqueous sodium chloride solution (1 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Ethanol (50 mL) was added to the reaction mixture, and the mixture was further stirred for 1 hour. The precipitated precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (220 mg) as a white solid. The drug introduction rate was 16.0 mol%.

(Example 44) Synthesis of diclofenac- (1- (methylamino) propan-2-ol) -alginic acid derivative (Compound 44-4)

<Step 1> Synthesis of Compound 44-2 In an acetonitrile solution (16 mL) of diclofenac (1.63 g), tert-butyl (2-hydroxypropyl) (methyl) carbamate (0.8 g), and DMAP (0.03 g). DCC (1.22 g) was added at 20 ° C., and the mixture was stirred at 15-21 ° C. for 22 and a half hours. The reaction mixture was filtered through Celite, and the Celite cake was washed with ethyl acetate (40 mL). The filtrate was concentrated, dissolved in ethyl acetate (40 mL), washed with water (30 mL) and saturated aqueous sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was suspended in MTBE (10 mL) and the insoluble material was removed by filtration. The filtrate was concentrated and purified by NH silica gel column chromatography (heptane: ethyl acetate = 17: 3) to give the title compound (1.25 g) as a pale yellow oily substance.

<Step 2> Synthesis of Compound 44-3 4M hydrogen chloride and ethyl acetate (5 mL) were added to Compound 44-2 (1 g), and the mixture was stirred at room temperature for 80 minutes and then concentrated. The obtained residue was azeotropically boiled twice with ethyl acetate (5 mL), dissolved in ethyl acetate (5 mL), and then heptane (5 mL) was added to precipitate a solid for trituration. The resulting solid was collected by filtration and washed with ethyl acetate-heptane (1: 1, 10 mL). The obtained solid was triturated with ethyl acetate (3 mL), collected, washed with ethyl acetate (5 mL), and dried to obtain the title compound (0.46 g) as a white solid.

<Step 3> Synthesis of diclofenac- (1- (methylamino) propan-2-ol) -alginic acid derivative (Compound 44-4) Add ethanol (6 mL) to alginic acid (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg). In addition, the mixture was stirred at room temperature for 65 minutes. Water (20 mL) was added to the suspension, and the mixture was stirred at room temperature for 2 hours and 10 minutes, then DMT-MM (103 mg) was added, and the mixture was stirred at room temperature for 40 minutes. A solution of compound 44-3 (75 mg) in ethanol-water (1: 1) (4 mL) was added dropwise to the reaction solution over 3 minutes. The reaction mixture was stirred at room temperature for 15 hours and 40 minutes, 1 M aqueous sodium hydrogen carbonate solution (0.20 mL) was added, and the mixture was further stirred at room temperature for 24 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 70 minutes, ethanol (40 mL) was added, and the mixture was further stirred for 7 hours. The resulting solid was collected by filtration, washed with ethanol (40 mL), and dried under reduced pressure at 40 ° C. to give the title compound (221 mg) as a white solid. The drug introduction rate was 16.6 mol%.

(Example 45) Synthesis of diclofenac- (trans-4-aminotetrahydrofuran-3-ol) -alginic acid derivative (Compound 45-4)

<Step 1> Synthesis of Compound 45-2 Trans-tert-butyl (4-hydroxytetrahydrofuran-3-yl) carbamate (1.0 g), diclofenac (1.6 g), DMAP (0.06 g), dichloromethane (20 mL) The mixture was ice-cooled, DCC (1.12 g) in dichloromethane (5 mL) was added, and the reaction was stirred at the same temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-40% ethyl acetate / heptane) to give the title compound (1.9 g) as a white amorphous substance.

<Step 2> Synthesis of Compound 45-3 A mixture of Compound 45-2 (1.9 g) and 4M hydrogen chloride / dioxane (20 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (1.76 g) as a white amorphous substance.

<Step 3> Synthesis of diclofenac- (trans-4-aminotetrahydrofuran-3-ol) -alginic acid derivative (Compound 45-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (1.0 g) in ethanol suspension Water (100 mL) was added to the solution (30 mL) to prepare a solution. DMT-MM (367 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (10 mL) of compound 45-3 (230 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.55 mL) were added. The reaction was stirred at room temperature for 5 hours. After adding 0.1 g / mL sodium chloride aqueous solution (5 mL) and ethanol (100 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (1.03 g) as a white solid. The drug introduction rate was 17.5 mol%.

(Example 46) Diclofenac- (1-amino-3- (1H-1,2,3-triazole-1-yl) propan-2-ol) -alginic acid derivative (Compound 46-7) and diclofenac- (1- Synthesis of amino-3- (2H-1,2,3-triazole-1-yl) propan-2-ol) -alginic acid derivative (Compound 46-8)

<Step 1> Synthesis of Compound 46-3 and Compound 46-4 1,2,3-triazole (0.4 g), tert-butyl (oxylan-2-ylmethyl) carbamate (1.0 g), cesium carbonate (0. A mixture of 38 g) of ethanol (15 mL) was stirred at 60 ° C. overnight. The reaction mixture was concentrated under reduced pressure. Dichloromethane (20 mL) was added to the obtained residue and filtered. Diclofenac (1.88 g) and DMAP (0.14 g) were added to the filtrate. A solution of DCC (1.31 g) in dichloromethane (5 mL) was added dropwise to the mixture under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-100% ethyl acetate / heptane), and compound 46-3 (1.1 g, high polarity) and compound 46-4 (0.6 g, low polarity) were white amorphous. Obtained as.

<Step 2-1> Synthesis of Compound 46-5 A mixture of Compound 46-3 (1.1 g) and 4M hydrogen chloride / dioxane (11 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (1.14 g) as a white amorphous substance.

<Step 2-2> Synthesis of Compound 46-6 A mixture of Compound 46-4 (0.60 g) and 4M hydrogen chloride / dioxane (6 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.58 g) as a white amorphous substance.

<Step 3-1> Synthesis of diclofenac- (1-amino-3- (1H-1,2,3-triazole-1-yl) propan-2-ol) -alginic acid derivative (Compound 46-7) Sodium alginate (compound 46-7) Ethanol (6 mL) was added to an aqueous solution (20 mL) of Mochida Pharmaceutical Co., Ltd., A-2) (200 mg). DMT-MM (122 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 46-5 (84 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.18 mL) were added. The reaction was stirred at room temperature for 6 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (211 mg) as a white solid. The drug introduction rate was 16.8 mol%.

<Step 3-2> Synthesis of diclofenac- (1-amino-3- (2H-1,2,3-triazole-1-yl) propan-2-ol) -alginic acid derivative (Compound 46-8) The title compound (211 mg) was obtained as a white solid using compound 46-6 instead of compound 46-5 in the same manner as in 3-1>. The drug introduction rate was 14.8 mol%.

(Example 47) Synthesis of diclofenac- (2- (aminooxy) ethanol) -alginic acid derivative (Compound 47-4)

<Step 1> Synthesis of Compound 4-2-Boc anhydride (1.56 g) in a mixture of 2- (aminooxy) ethane-1-ol (0.50 g) and DMAP (0.08 g) in dichloromethane (10 mL) at room temperature. Dichloromethane solution (5 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. Diclofenac (2.31 g) was added to the reaction solution under ice-cooling, a dichloromethane solution (10 mL) of DCC (1.74 g) was further added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-25% ethyl acetate / heptane) to give the title compound (0.83 g) as a colorless gum.

<Step 2> Synthesis of Compound 47-3 A mixture of Compound 47.2 (0.83 g) and 4M hydrogen chloride / dioxane (9 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.77 g) as a colorless gum-like substance.

<Step 3> Synthesis of diclofenac- (2- (aminooxy) ethanol) -alginic acid derivative (Compound 47-4) In an aqueous solution (20 mL) of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) (200 mg), ethanol (20 mL) 6 mL) was added. DMT-MM (61 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 47-3 (36 mg) and a 1M aqueous sodium hydrogen carbonate solution (0.09 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (198 mg) as a white solid. The drug introduction rate was 10.9 mol%.

(Example 48) Synthesis of diclofenac- (2- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) ethanol) -alginic acid derivative (Compound 48-4)

<Step 1> Synthesis of Compound 48-2 N-Boc-PEG4-alcohol (500 mg), diclofenac (555 mg), DMAP (21 mg) in a dichloromethane (7 mL) mixture under ice-cooling, DCC (387 mg) in dichloromethane (3 mL) ) Was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to give the title compound (0.73 g) as a colorless oily substance.

<Step 2> Synthesis of Compound 48-3 A mixture of Compound 48-2 (0.73 g) and 4M hydrogen chloride / dioxane (7 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.67 g) as a colorless oily substance.

<Step 3> Synthesis of diclofenac- (2- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) ethanol) -alginic acid derivative (Compound 48-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) Ethanol (6 mL) was added to an aqueous solution (20 mL) of (200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 48-3 (70 mg) and a 1M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (204 mg) as a white solid. The drug introduction rate was 11.0 mol%.

(Example 49) Synthesis of diclofenac- (23-amino-3,6,9,12,15,18,21-heptaoxatricosan-1-ol) -alginic acid derivative (Compound 49-4)

<Step 1> Synthesis of Compound 49-2 Dichloromethane solution (2 mL) of DCC (242 mg) in a mixture of N-Boc-PEG8-alcohol (500 mg), diclofenac (347 mg) and DMAP (13 mg) in dichloromethane (3 mL) under ice cooling. ) Was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-100% ethyl acetate / heptane, 5% methanol / ethyl acetate) to give the title compound (0.64 g) as a colorless oily substance.

<Step 2> Synthesis of Compound 49-3 A mixture of Compound 49-2 (0.64 g) and 4M hydrogen chloride / dioxane (5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.56 g) as a colorless oily substance.

<Step 3> Synthesis of diclofenac- (23-amino-3,6,9,12,15,18,21-heptaoxatricosan-1-ol) -alginic acid derivative (Compound 49-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) Ethanol (6 mL) was added to an aqueous solution (20 mL) of A-2) (200 mg). DMT-MM (92 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 49-3 (94 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.14 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (217 mg) as a white solid. The drug introduction rate was 12.1 mol%.

(Example 50) Synthesis of diclofenac- (2-amino-N- (2- (2-hydroxyethoxy) ethyl) acetamide) -alginic acid derivative (Compound 50-4)

<Step 1> Synthesis of compound 50-2 2- (2-aminoethoxy) ethane-1-ol (0.53 g), N-Boc glycine (0.88 g), DMAP (0.06 g), dichloromethane (40 mL) The mixture was ice-cooled, DCC (1.03 g) in dichloromethane (5 mL) was added, and the reaction was stirred at room temperature overnight. Diclofenac (1.48 g) was added to the reaction solution, DCC (1.03 g) in dichloromethane (5 mL) was further added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-100% ethyl acetate / heptane) to give the title compound (0.84 g) as a colorless gum.

<Step 2> Synthesis of Compound 50-3 A mixture of Compound 50-2 (0.84 g) and 4M hydrogen chloride / dioxane (8 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.80 g) as a colorless gum-like substance.

<Step 3> Synthesis of diclofenac- (2-amino-N- (2- (2-hydroxyethoxy) ethyl) acetamide) -alginic acid derivative (Compound 50-4) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) ( Ethanol (6 mL) was added to an aqueous solution (20 mL) of 200 mg). DMT-MM (73 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 50-3 (52 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.11 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (204 mg) as a white solid. The drug introduction rate was 13.2 mol%.

(Example 51) Synthesis of diclofenac- (2-amino-N- (2- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl) acetamide) -alginic acid derivative (Compound 51-4)

<Step 1> Synthesis of Compound 51-2 2- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) ethane-1-ol (0.97 g), N-Boc glycine (0.88 g), DMAP A mixture of (0.06 g) and dichloromethane (40 mL) was ice-cooled, a solution of DCC (1.03 g) in dichloromethane (5 mL) was added, and the reaction was stirred at room temperature overnight. Diclofenac (1.48 g) was added to the reaction solution, DCC (1.03 g) in dichloromethane (5 mL) was further added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-100% ethyl acetate / heptane, 5% methanol / ethyl acetate) to give the title compound (1.22 g) as a colorless gum.

<Step 2> Synthesis of Compound 51-3 A mixture of Compound 51-2 (1.22 g) and 4M hydrogen chloride / dioxane (10 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1.14 g) as a colorless gum-like substance.

<Step 3> Synthesis of diclofenac- (2-amino-N- (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) ethyl) acetamide) -alginic acid derivative (Compound 51-4) Sodium alginate ( Ethanol (6 mL) was added to an aqueous solution (20 mL) of Mochida Pharmaceutical Co., Ltd., A-2) (200 mg). DMT-MM (73 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 51-3 (62 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.11 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (220 mg) as a white solid. The drug introduction rate was 16.4 mol%.

(Example 52) Synthesis of diclofenac- (1-hydroxy-3,6,9,12-tetraoxapentadecane-15-hydrazide) -alginic acid derivative (Compound 52-5)

<Step 1> Synthesis of Compound 52-3 Room temperature in a mixture of 1-hydroxy-3,6,9,12-tetraoxapentadecylic acid (0.5 g) and Boc hydrazine (0.25 g) in ethanol (4 mL). DMT-MM (0.75 g) was added and stirred for 4 hours. The reaction suspension was filtered and the filtrate was concentrated under reduced pressure. Diclofenac (0.56 g), DMAP (0.02 g) and dichloromethane (15 mL) were added to the obtained residue, and a dichloromethane solution (5 mL) of DCC (0.43 g) was added dropwise to the mixture under ice-cooling. The reaction was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-100% ethyl acetate / heptane, 5% methanol / ethyl acetate) to give the title compound (0.64 g) as a colorless gum-like substance.

<Step 2> Synthesis of Compound 52-4 A mixture of Compound 52-3 (0.64 g) and 4M hydrogen chloride / dioxane (5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.64 g) as a colorless gum-like substance.

<Step 3> Synthesis of diclofenac- (1-hydroxy-3,6,9,12-tetraoxapentadecane-15-hydrazide) -alginic acid derivative (Compound 52-5) Sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) Ethanol (6 mL) was added to an aqueous solution (20 mL) of (200 mg). DMT-MM (61 mg) was added to the solution, and after stirring for 10 minutes, an ethanol solution (2 mL) of compound 52-4 (55 mg) and a 1 M aqueous sodium hydrogen carbonate solution (0.09 mL) were added. The reaction was stirred at room temperature for 4 hours. After adding 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (40 mL) to the reaction solution, the mixture was stirred for 10 minutes. The obtained precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (212 mg) as a white solid. The drug introduction rate was 10.8 mol%.

(Example 53) Synthesis of bis (diclofenac)-(2-amino-N, N-bis (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 53-5)

<Step 1> Synthesis of Compound 53-1 DCC in an acetonitrile solution (100 mL) of diclofenac (11.5 g), tert-butyl bis (2-hydroxyethyl) carbamate (4 g), and DMAP (0.24 g) at 6 ° C. (8.85 g) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was heated to 18 ° C. and stirred at 18 to 25 ° C. for 112 hours. The reaction mixture was filtered through Celite, and the Celite cake was washed with ethyl acetate (250 mL). The filtrate was diluted with ethyl acetate (150 mL), washed with water (350 mL) and saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (11.4 g) as a white amorphous substance.

<Step 2> Synthesis of Compound 53-2 4M hydrogen chloride and ethyl acetate (74 mL) were added to Compound 53-1 (8 g), and the mixture was stirred at room temperature for 30 minutes and then concentrated. The obtained residue was azeotropically boiled twice with ethyl acetate (20 mL), triturated with MTBE (60 mL), washed with MTBE (80 mL), dried under reduced pressure, and the title compound (7.37 g) was added. Obtained as a white solid.

<Step 3> Synthesis of Compound 53-3 An ethanol solution of Compound 53-2 (1.9 g), N-Boc glycine (0.51 g), DMT-MM (1.11 g), and triethylamine (0.45 mL) ( 19 mL) was stirred at 22-24 ° C. for 18 hours. The reaction mixture was diluted with ethyl acetate (60 mL), washed with water (60 mL) and saturated aqueous sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was triturated with MTBE (15 mL), collected, washed with MTBE (15 mL), and dried under reduced pressure to give the title compound (1.67 g) as a white solid.

<Step 4> Synthesis of Compound 53-4 4M hydrogen chloride and ethyl acetate (16 mL) were added to Compound 53-3 (1.65 g), and the mixture was stirred at room temperature for 30 minutes and then concentrated. The obtained residue was dissolved in ethyl acetate (30 mL), washed with saturated aqueous sodium hydrogen carbonate solution (25 mL) and saturated aqueous sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. After adding 4M hydrogen chloride / CPME (1.5 mL), the mixture was concentrated to obtain the title compound (1.37 g) as a white solid.

<Step 5> Synthesis of bis (diclofenac)-(2-amino-N, N-bis (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 53-5) Alginic acid (Mochida Pharmaceutical Co., Ltd., A-3) ( NMP (6 mL) was added to 200 mg), and the mixture was stirred at room temperature for 10 minutes. Water (20 mL) was added to the suspension, and the mixture was stirred at room temperature for 95 minutes, then DMT-MM (52 mg) was added, and the mixture was stirred at room temperature for 25 minutes. A solution of compound 53-4 (75 mg) in NMP-water (1: 1) (4 mL) was added dropwise to the reaction solution over 5 minutes. The reaction mixture was stirred at room temperature for 62 hours and 30 minutes, 1 M aqueous sodium hydrogen carbonate solution (0.10 mL) was added, and the mixture was further stirred at room temperature for 24 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 35 minutes. Ethanol (40 mL) was added, and the mixture was further stirred for 3 hours and 50 minutes. The resulting solid was collected by filtration, washed with ethanol (40 mL), and dried under reduced pressure at 40 ° C. to give the title compound (214 mg) as a white solid. The drug introduction rate was 3.0 mol%.

(Example 54) Synthesis of bis (diclofenac)-(2-amino-N- (1,3-dihydroxypropan-2-yl) acetamide) -alginic acid derivative (Compound 54-6)

<Step 1> Synthesis of Compound 54-2 Diclofenac (14.9 g), tert-butyl (1,3-dihydroxypropan-2-yl) carbamate (4 g), DMAP (0.13 g) in an acetonitrile solution (80 mL). DCC (11.2 g) was added at 16 ° C., and the mixture was stirred at 16-21 ° C. for 5 hours and 20 minutes. The reaction mixture was filtered through Celite, and the Celite cake was washed with ethyl acetate (80 mL). The filtrate was concentrated, dissolved in ethyl acetate (300 mL), washed with water (200 mL) and saturated aqueous sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (18.1 g) as a white amorphous substance.

<Step 2> Synthesis of Compound 54-3 4M hydrogen chloride and ethyl acetate (52 mL) were added to Compound 54-2 (6 g), and the mixture was stirred at room temperature for 30 minutes and then concentrated. The obtained residue was azeotropically boiled with MTBE (20 mL) three times and dried under reduced pressure to give the title compound (5.93 g) as a white amorphous substance.

<Step 3> Synthesis of Compound 54-4 Ethanol solution (22 mL) of Compound 54-3 (3 g), N-Boc glycine (0.6 g), DMT-MM (1.29 g), and triethylamine (0.52 mL). Was stirred at 22 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (60 mL), washed with water (40 mL) and saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (heptane: ethyl acetate = 3: 2) to obtain the title compound (2.06 g) as a white amorphous substance.

<Step 4> Synthesis of Compound 54-5 4M hydrogen chloride and ethyl acetate (20 mL) were added to Compound 54-4 (2.03 g), and the mixture was stirred at room temperature for 40 minutes and then concentrated. The obtained residue was dissolved in ethyl acetate (30 mL), washed with saturated aqueous sodium hydrogen carbonate solution (25 mL) and saturated aqueous sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. After adding 4M hydrogen chloride / CPME (1.5 mL), the mixture was concentrated and dried under reduced pressure to give the title compound (1.80 g) as a white solid.

<Step 5> Synthesis of bis (diclofenac)-(2-amino-N- (1,3-dihydroxypropan-2-yl) acetamide) -alginic acid derivative (Compound 54-6) Alginic acid (Mochida Pharmaceutical Co., Ltd., A- 3) NMP (6 mL) was added to (200 mg), and the mixture was stirred at room temperature for 10 minutes. Water (20 mL) was added to this suspension, and the mixture was stirred at room temperature for 95 minutes, then DMT-MM (52 mg) was added, and the mixture was stirred at room temperature for 50 minutes. A solution of compound 54-5 (71 mg) in NMP-water (1: 1) (4 mL) was added dropwise to the reaction solution over 5 minutes. The reaction mixture was stirred at room temperature for 62 hours and 30 minutes, 1 M aqueous sodium hydrogen carbonate solution (0.10 mL) was added, and the mixture was further stirred at room temperature for 24 hours. A 0.1 g / mL aqueous sodium chloride solution (2 mL) was added to the reaction mixture, and the mixture was stirred for 35 minutes. Ethanol (40 mL) was added, and the mixture was further stirred for 4 hours and 40 minutes. The resulting solid was collected by filtration, washed with ethanol (40 mL), and dried under reduced pressure at 40 ° C. to give the title compound (199 mg) as a white solid. The drug introduction rate was 2.4 mol%.

Table 3 shows 1H-NMR data of various intermediate compounds in (Example A1) to (Example A24) and (Example 1) to (Example 54).

Tables 4 to 6 show the weights of NSAIDs-binding polysaccharide derivatives calculated from the calibration curves using pullulan as a standard substance in (Example A1) to (Example A24) and (Example 1) to (Example 54). The average molecular weight and the weight average molecular weight of the raw material alginic acid are shown.

Weight average molecular weight of NSAIDs-linked polysaccharide derivatives

Weight average molecular weight of raw material alginic acid

(Test Example F1): Contains compound A53a, compound A53b and compound A53c prepared in (Example A13), compound A72a prepared in (Example A17), and compound 39-4 prepared in (Example 39). Table 7 shows the compounds A53a, A53b and A53c prepared in the stability test of the preparation (Example A13), the compound A72a prepared in (Example A17), and the compound 39-4 prepared in (Example 39). The preparations shown in Table 8 were prepared, sterilized by filtration, dispensed, and stored under each temperature condition (25, 40, 50, 60 ° C.). Free DF (diclofenac) and DFA (diclofenac amide) concentrations were measured for samples sampled over time under the following HPLC conditions. Separately, the starting DF concentration (≈ full-binding DF concentration) was calculated from the DF introduction rate. From these values, the percentage (%) of the free DF and DFA molar concentrations over time with respect to the starting DF molar concentration of each sample solution was calculated. The results are shown in Tables 9 to 13.

HPLC condition detector: UV absorptiometer (measurement wavelength: 276 nm (DF) and 245 nm (DFA))
Column: Inertsil ODS-3 φ4.6mm × 250mm, 5μm
Column temperature: Constant temperature around 40 ° C. Mobile phase: 0.1% formic acid / methanol / acetonitrile (40: 5: 55) Solution flow rate: 1 mL / min

Percentage (%) of free DF, DFA molar concentration over time relative to starting DF molar concentration of 0.1% compound A53b solution at each temperature

0.1% Percentage (%) of free DF and DFA molar concentration over time with respect to the starting DF molar concentration at each temperature of compound A53c solution

Percentage (%) of free DF, DFA molar concentration over time relative to starting DF molar concentration of 0.1% compound A72a solution at each temperature

Percentage of free DF, DFA molar concentration over time to starting DF molar concentration at each temperature of 0.1% compound A53a solution (%)

Percentage of free DF, DFA molar concentration over time to initial DF molar concentration at each temperature of 0.1% compound 39-4 solution (%)

(Test Example F2): The table shows the compounds 5-6a and 5-6b prepared in the stability test (Example 5) of the preparation containing the compound 5-6a and the compound 5-6b prepared in (Example 5). The preparations shown in No. 14 were prepared, sterilized by filtration, dispensed, and stored under each temperature condition (25, 40, 50, 60 ° C.). Free DF and DFA concentrations were measured for samples sampled over time under the following HPLC conditions. The total DF concentration at the start (≈ full-bonded DF concentration) was measured by the absorbance method, and from these measured values, the percentage of free DF and DF molar concentration over time (%) with respect to the total DF molar concentration at the start of each compound solution. ) Was calculated. The results are shown in Tables 15 and 16.

Percentage of free DF, DFA molar concentration over time to initial DF molar concentration of 0.1% compound 5-6b solution at each temperature (%)

(Test Example F3): Stability test of a preparation containing the compound A53b prepared in (Example A13), the compound 5-6a prepared in (Example 5), and the compound 5-6b prepared in (Example 5). Preparations having the contents shown in Tables 17 and 18 were prepared for the compound A53b prepared in (Example A13), the compound 5-6a prepared in (Example 5), and the compound 5-6b prepared in (Example 5). After filtration and sterilization, the mixture was dispensed and stored under each temperature condition (25, 40, 50, 60 ° C.). Free DF and DFA concentrations were measured for samples sampled over time under the following HPLC conditions. The total DF concentration at the start (≈ full bond DF concentration) was measured by the absorptiometry, and from these measured values, the molar concentration percentage (%) of the free DF and DFA concentrations over time with respect to the total DF concentration at the start of each compound solution ) Was calculated. The results are shown in Tables 19 to 22.

HPLC condition detector: UV absorptiometer (measurement wavelength: 276 nm (DF) and 245 nm (DFA))
Column: Inertsil ODS-3 φ4.6 mm x 250 mm, 5 μm
Column temperature: Constant temperature mobile phase around 40 ° C: 0.1% formic acid / methanol / acetonitrile (40: 5: 55) Solution flow rate: 1 mL / min

(Test Example 4): Stability of the preparation containing the compound A53b prepared in (Example A13), the compound 5-6a prepared in (Example 5), and the compound 5-6b prepared in (Example 5). Test (molecular weight measurement)
The absolute molecular weight (weight average molecular weight: Mw) of the sample sampled over time in Test Example 3 was measured under the following HPLC conditions. The results are shown in Tables 23-26.

HPLC condition detector: multi-angle light scattering detector (MALS) + RI detector column: TSKgel GMPWXL 13 μm φ7.8 × 300 mm
Column temperature: 40 ° C
Mobile phase: 10 mM phosphate buffer *: acetonitrile = 80:20
Flow rate: 0.7 mL / min
The weight average molecular weight (× 10 ⁵ daltons)

(Test Example 5): Aseptic filtration examination of a preparation containing compound A53b prepared in (Example A13) and compound 5-6a prepared in (Example 5) Examples F1-11, F1-15, F1-16 , F6-8 and F6-9 preparations are prepared in 100 mL, and pressure filtration is performed at a pressure of 0.2 MPa using a Sartorius capsule filter (material: cellulose acetate, pore size: 0.2 μm, effective filtration area: 150 cm ^2). went. 10 mL of the filtrate was collected, and the filtration time per 10 mL and the DF concentration in the sample were measured by the absorbance method to calculate the recovery rate. The results are shown in Tables 27-28.

Claims

Equation (I):

[In formula (I), (A) represents one residue of NSAIDs;
(SG) represents a residue derived from a polysaccharide or a salt thereof;
-L 1- is the following formula (excluding the outside of the broken line in the formula):

Representing a linker selected from (A in formula (LK-B50) and formula (LK-B51) represents one residue of NSAIDs)], or a pharmaceutically acceptable NSAIDs-binding polysaccharide derivative. Sustained release containing at least one component selected from the group consisting of the salt, a solvate thereof, and a buffer, a pH adjuster, an tonicity agent, a stabilizer and a surfactant. Pharmaceutical composition.
The sustained-release pharmaceutical composition according to claim 1, which has a pH of about 4.5 to about 6.5.
The buffer according to claim 1 or 2, wherein the buffer is at least one selected from the group consisting of an acetic acid-based buffer, a citric acid-based buffer, a phosphoric acid-based buffer, and a tartaric acid-based buffer. Sustained-release pharmaceutical composition.
The sustained-release pharmaceutical composition according to claim 1 or 2, wherein the pH adjusting agent is at least one selected from the group consisting of an acid, a salt of an acid, a base, and a salt of a base.
At least one isotonic agent selected from the group consisting of salts, sugars, sugar alcohols, polyhydric alcohols, phosphoric acids, citric acids, aminoethylsulfonic acids, nicotinic acid amides, benzyl alcohols, boric acids, and boric acid. The sustained-release pharmaceutical composition according to claim 1 or 2, which is more than a species.
The sustained-release pharmaceutical composition according to claim 1 or 2, wherein the stabilizer is at least one selected from the group consisting of sugar and sugar alcohol.
Claim 1 or claim 1, wherein the surfactant is at least one selected from the group consisting of a pluronic-based surfactant, a Tween-based surfactant, a castor oil-based surfactant, and a cured castor oil-based surfactant. The sustained-release pharmaceutical composition according to claim 2.
The sustained-release pharmaceutical composition according to claim 1 or 2, wherein the buffer is contained in an amount of about 1 × 10 -5 to about 5% (w / v) based on the total amount of the sustained-release pharmaceutical composition.
The sustained-release pharmaceutical according to claim 1 or 2, wherein the pH adjusting agent is greater than 0 and contains about 5 × 10 -3 % (w / v) or less based on the total amount of the sustained-release pharmaceutical composition. Composition.
The sustained-release pharmaceutical composition according to claim 1 or 2, wherein the tonicity agent is contained in an amount of about 1 to about 10% (w / v) based on the total amount of the sustained-release pharmaceutical composition.
The sustained-release pharmaceutical composition according to claim 1 or 2, wherein the stabilizer is contained in an amount of about 1 × 10 -1 to about 10% (w / v) based on the total amount of the sustained-release pharmaceutical composition. ..
The sustained-release pharmaceutical composition according to claim 1 or 2, wherein the surfactant is contained in an amount of about 1 × 10 −2 to about 5% (w / v) based on the total amount of the sustained-release pharmaceutical composition. ..
Claim that the content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is about 1 × 10 -1 to about 20 mg / mL. 1 or the sustained-release pharmaceutical composition according to claim 2.
The content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof is about 1 × 10 -3 to about 6 mg / mL in terms of NSAIDs. The sustained-release pharmaceutical composition according to any one of claims 1 and 2.
NSAIDs-binding polysaccharide derivatives represented by formula (I), or pharmaceutically acceptable salts thereof, or solvates thereof, under storage conditions at a temperature of about 2 to about 8 ° C. for a storage period of at least 6 months. The sustained-release pharmaceutical composition according to claim 1 or 2, which has the stability of maintaining the NSAIDs content of the derivative in an amount of about 75% or more.
The content of the NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof per single dose is about 1 × 10 -1 to about 60 mg. The sustained-release pharmaceutical composition according to claim 1 or 2.
The first or second claim, which contains an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof for intra-articular administration. Sustained release pharmaceutical composition.
The sustained-release pharmaceutical composition according to claim 1 or 2, which is filled in a glass or plastic medical container.
A method for controlling the release of NSAIDs in a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. The sustained-release pharmaceutical composition comprises, as an additive, at least one component selected from the group consisting of a buffer, a pH adjuster, an tonicity agent, a stabilizer and a surfactant. Method.
Sustained release containing NSAIDs-binding polysaccharide derivatives represented by formula (I), pharmaceutically acceptable salts thereof, or solvates thereof under conditions of pH of about 4.5 to about 6.5. A method for controlling the release of NSAIDs in a pharmaceutical composition, which comprises a sustained-release pharmaceutical composition comprising a buffer, a pH adjuster, an isotonic agent, a stabilizer and a surfactant as additives. A method comprising containing at least one component selected from.
Sustained release containing NSAIDs-linked polysaccharide derivatives represented by formula (I), pharmaceutically acceptable salts thereof, or solvates thereof under conditions of pH of about 4.5 to about 6.5. A method for suppressing the production of diclofenac amide in a sustained-release pharmaceutical composition in which the NSAIDs are diclofenac, which is a pharmaceutical composition, and is an additive to the sustained-release pharmaceutical composition, such as a buffer and a pH adjustment. A method comprising containing at least one component selected from the group consisting of agents, tonicity agents, stabilizers and surfactants.
Sustained release containing NSAIDs-binding polysaccharide derivatives represented by formula (I), pharmaceutically acceptable salts thereof, or solvates thereof under conditions of pH of about 4.5 to about 6.5. A method for suppressing the reduction of the molecular weight of alginic acid in a sustained-release pharmaceutical composition in which the polysaccharide is alginic acid, which is a pharmaceutical composition, and is added to a sustained-release pharmaceutical composition as an additive, a buffer, and a pH. A method comprising containing at least one component selected from the group consisting of a regulator, an isotonic agent, a stabilizer and a surfactant.
A method for controlling the release of NSAIDs in a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. A method comprising the step of adjusting the pH of a sustained release pharmaceutical composition to about 4.5 to about 6.5.
A sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the NSAIDs are diclofenac. A method of controlling the release of diclofenac in a pharmaceutical composition, comprising the step of adjusting the pH of the sustained release pharmaceutical composition to about 4.5 to about 6.5.
A sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the NSAIDs are diclofenac. A method for suppressing the production of diclofenac amide in a pharmaceutical composition, comprising the step of adjusting the pH of the sustained release pharmaceutical composition to about 4.5 to about 6.5.
A sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the polysaccharide is alginic acid. A method for suppressing the reduction of molecular weight of alginic acid in a pharmaceutical composition, which comprises a step of adjusting the pH of the sustained-release pharmaceutical composition to about 4.5 to about 6.5.
Any of claims 19 to 22, wherein the buffer is at least one selected from the group consisting of acetic acid-based buffers, citric acid-based buffers, phosphoric acid-based buffers, and tartaric acid-based buffers. The method according to item 1.
The method according to any one of claims 19 to 22, wherein the pH adjusting agent is at least one selected from the group consisting of an acid, an acid salt, a base, and a base salt.
At least one isotonic agent selected from the group consisting of salts, sugars, sugar alcohols, polyhydric alcohols, phosphoric acids, citric acids, aminoethylsulfonic acids, nicotinic acid amides, benzyl alcohols, boric acids, and boric acid. The method according to any one of claims 19 to 22, which is more than a species.
The method according to any one of claims 19 to 22, wherein the stabilizer is at least one selected from the group consisting of sugar and sugar alcohol.
Claim that the surfactant is at least one selected from the group consisting of a pluronic-based surfactant, a Tween-based surfactant, a castor oil-based surfactant, and a cured castor oil-based surfactant. 19. The method according to any one of claims 22.
A method for preserving a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a sustained-release pharmaceutical composition. The product is packed in a glass / plastic medical container and is selected from the group consisting of buffers, pH regulators, isotonic agents, stabilizers and surfactants as additives in sustained release pharmaceutical compositions. A method comprising a step of containing at least one component and a step of adjusting the pH of the sustained-release pharmaceutical composition to about 4.5 to about 6.5.
The method according to claim 32, wherein the buffer is at least one selected from the group consisting of an acetic acid-based buffer, a citric acid-based buffer, a phosphoric acid-based buffer, and a tartaric acid-based buffer.
The method according to claim 32, wherein the pH adjuster is at least one selected from the group consisting of acids, acid salts, bases, and base salts.
At least one isotonic agent selected from the group consisting of salts, sugars, sugar alcohols, polyhydric alcohols, phosphoric acids, citric acids, aminoethylsulfonic acids, nicotinic acid amides, benzyl alcohols, boric acids, and boric acid. 32. The method of claim 32, which is greater than or equal to the species.
The method according to claim 32, wherein the stabilizer is at least one selected from the group consisting of sugar and sugar alcohol.
Claim that the surfactant is at least one selected from the group consisting of a pluronic surfactant, a Tween surfactant, a castor oil surfactant, and a cured castor oil surfactant. 32.
A step of detecting and / or quantifying NSAIDs in a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. , A method for quality inspection of a sustained-release pharmaceutical composition containing a derivative represented by the formula (I).
Diclofenac or diclofenac amide is detected and / or quantified in a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for quality inspection of a sustained-release pharmaceutical composition containing a table derivative of the formula (I), which comprises a step.
A method for producing a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(1) NSAIDs-binding polysaccharide derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, as well as a buffer, a pH adjuster, an tonicity agent, a stabilizer and a stabilizer. At least one component selected from the group consisting of surfactants is dissolved in a solvent.
(2) If necessary, a pH adjuster or buffer is added to adjust the pH of the solution to about 4.5 to about 6.5.
(3) The solution after pH adjustment is filtered using a filtration membrane having a pore size of about 5 μm or less.
Manufacturing method including the process of.
In the method for producing a sustained-release pharmaceutical composition containing an NSAIDs-binding polysaccharide derivative represented by the formula (I), the filtration membrane comprises polyether sulfone, PVDF, cellulose acetate, regenerated cellulose, PTFE, or a cellulose mixed ester. The method for producing a sustained-release pharmaceutical composition according to claim 40, which is selected from the group.