HK40047658B - Pharmaceutical composition - Google Patents

Description

Pharmaceutical Composition

Technical Field

This invention relates to pharmaceutical compositions comprising hyaluronic acid derivatives.

Background Technology

Osteoarthritis (hereinafter referred to as "OA" in this manual), a functional disorder caused by joint pain and degeneration, is the most common joint disease worldwide, and is one of the leading causes of physical impairment that affects the daily lives of the elderly. Similarly, rheumatoid arthritis (hereinafter referred to as "RA" in this manual), a polyarthritis known as a disease characterized by joint swelling and pain, is also known. In RA, if the condition persists and symptoms progress, cartilage and bone are destroyed, leading to degeneration and deformation, resulting in physical impairment that affects daily life, such as narrowing of the joint's range of motion.

Currently, medications for osteoarthritis, rheumatoid arthritis, and other types of arthritis utilize hyaluronic acid and its derivatives. Hyaluronic acid preparations are typically formulated as injectables to improve functional impairments and alleviate pain caused by arthritis, leveraging the lubricating, shock-absorbing, and cartilage-improving properties of hyaluronic acid. These preparations are administered directly to the affected joints, such as the knee and shoulder. Commercially available hyaluronic acid preparations include those containing purified sodium hyaluronate as the active ingredient (e.g., Artz (registered trademark), Suvenyl (registered trademark)). These preparations are typically administered once weekly for 3 to 5 consecutive weeks.

In addition, among formulations that use cross-linked hyaluronic acid as an active ingredient, there are those that are administered three times consecutively once a week (e.g., Synvisc (registered trademark)) and those that are administered once to complete the treatment (e.g., Synvisc-One (registered trademark), Gel-One (registered trademark), MONOVISC (registered trademark)).

On the other hand, steroid and non-steroidal anti-inflammatory compounds are known to be fast-acting agents and are used to treat joint pain caused by OA and RA. For example, triamcinolone acetonide, a steroid, is used to treat joint diseases such as rheumatoid arthritis, and there are commercially available intra-articular injection formulations, requiring administration every 1-2 weeks. In addition, non-steroidal anti-inflammatory compounds, such as ointments and oral formulations containing diclofenac sodium as the active ingredient, need to be administered multiple times daily to achieve their anti-inflammatory effects.

It is also known that mixtures or combinations of hyaluronic acid or its derivatives with steroid or non-steroidal anti-inflammatory compounds are used as active ingredients. For example, a mixture of cross-linked hyaluronic acid and triamcinolone acetonide (CINGAL (registered trademark)) has been commercialized as a single-dose agent. Furthermore, compounds formed by linking hyaluronic acid or its derivatives with steroid or non-steroidal anti-inflammatory compounds are also known. For example, patent documents 1 and 2 describe derivatives of hyaluronic acid to which anti-inflammatory compounds are introduced via a spacer group. These aim to provide both rapid pain relief and long-term pain relief by improving functional impairment, but are still under development and no approved drugs have been marketed to date.

In another example, development has been undertaken with the goal of both providing rapid pain relief and alleviating chronic pain by improving functional impairment. This involves introducing a conjugate of diclofenac, an anti-inflammatory compound, into the sugar chains of hyaluronic acid at a specific ratio (hereinafter sometimes referred to as "Dic-HA"). However, Dic-HA is still under development.

As a stabilization technique for hyaluronic acid, Patent Document 3 discloses a method for adding an iodine-containing reducing agent and/or a sulfur-containing reducing agent to hyaluronic acid. Additionally, Patent Document 4 discloses a method for stabilizing an aqueous composition containing hyaluronic acid using sorbitol.

Existing technical documents

Patent documents

Patent Document 1: International Publication No. 2005/066214

Patent Document 2: International Publication No. 2015/005458

Patent Document 3: Japanese Patent Application Publication No. 10-212303

Patent Document 4: International Publication No. 2017/131130

Summary of the Invention

Diclofenac, generated from Dic-HA, is a low-molecular-weight compound and therefore does not readily remain at the site of administration (e.g., the synovium within a joint), readily migrating to the lymphatic system, bloodstream, or other sites outside the administration site. Therefore, from the viewpoint of long-term efficacy, it is not preferable to generate diclofenac in the drug composition prior to administration into the body. However, the behavior of diclofenac generation from Dic-HA is unclear, and it is unclear whether simply preventing its generation is practically necessary, and if so, how to prevent it.

During development, the inventors confirmed the presence of Dic-HA decomposition products in the Dic-HA-containing composition. Furthermore, analysis of the decomposition products confirmed that molecules generated from Dic-HA are present in the composition not only in the form of diclofenac but also in the form of diclofenac lactam. Additionally, it was confirmed that the accumulation of diclofenac lactam increases depending on storage time, heat treatment, etc.

During their research, the inventors discovered that while diclofenac itself is a physiologically active substance with anti-inflammatory effects, the Cox-2 inhibitory activity of diclofenac lactam, its lactam form, is only about 1/100th that of diclofenac, and therefore it is not considered a physiologically active anti-inflammatory substance. This further clarifies the significance of providing a composition that inhibits the formation and accumulation of physiologically inactive diclofenac lactam.

As a stabilization technique for hyaluronic acid, Patent Document 3 discloses a method for adding iodine-containing reducing agents and/or sulfur-containing reducing agents to hyaluronic acid. However, these reducing agents are used to suppress the decrease in the molecular weight of hyaluronic acid, and neither the method nor the method described or disclosed any method for suppressing the formation of diclofenac from hyaluronic acid conjugates. Furthermore, Patent Document 4 discloses the stabilization of an aqueous composition containing hyaluronic acid using sorbitol, but the indicator used here is the suppression of the decrease in viscosity of the aqueous composition. The stabilization referred to here is understood as the suppression of the decrease in the molecular weight of hyaluronic acid. That is, neither the method discloses nor discloses any method for suppressing the formation of diclofenac from hyaluronic acid conjugates such as Dic-HA.

As mentioned above, while there are reports of stabilization techniques related to reducing the molecular weight of hyaluronic acid, there is no insight into techniques for inhibiting the formation of diclofenac lactam due to the degradation of Dic-HA. The inventors have discovered that, regarding the opposing issue of inhibiting the degradation of Dic-HA (inhibiting the accumulation of diclofenac lactam) in the pre-treatment stage before administration to a patient, and the desired sustained release of diclofenac with physiological anti-inflammatory activity through the sustained degradation of Dic-HA in the patient's body after administration, the current state of affairs is that no solution has been provided by existing technology.

The inventors have discovered that by allowing a certain compound to coexist in a Dic-HA-containing composition or by improving the filterability of a Dic-HA-containing aqueous composition, the accumulation of diclofenac lactam in the Dic-HA-containing composition can be suppressed.

One aspect of the present invention relates to a pharmaceutical composition comprising a compound represented by formula (1) and an ingredient (A), said ingredient (A) being at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts. This pharmaceutical composition is suitable for use as a topical therapeutic agent (e.g., an anti-inflammatory agent, an analgesic), and is particularly preferred for use as a composition for treating joint diseases such as OA and RA. Another aspect of the present invention relates to a method of manufacturing the pharmaceutical composition, comprising a step of coexisting the compound represented by formula (1) with the aforementioned ingredient (A). Yet another aspect of the present invention relates to a method of inhibiting the formation of diclofenac lactam from the compound represented by formula (1), comprising a step of coexisting the compound represented by formula (1) with the aforementioned ingredient (A). Another aspect of the present invention relates to a method for suppressing the formation of diclofenac component from the compound represented by the following formula (1), which includes a step of coexisting the compound represented by the following formula (1) with the aforementioned component (A).

Another aspect of the present invention relates to an aqueous composition comprising a compound represented by formula (1) and having a maximum throughput ( _Vmax ) of 1.0 g/ ^cm² or more.

In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, the arrangement of each disaccharide structural unit can be randomly or block-shaped, and R in each disaccharide structural unit is independently a carboxyl group or a carboxylate group.

In this specification, the compound shown in formula (1) above is sometimes referred to as a "hyaluronic acid derivative". In addition, in formula (1), the disaccharide structural unit present in a ratio of a is called a "diclofenac-derived disaccharide structural unit", and the disaccharide structural unit present in a ratio of b is called a "hyaluronic acid disaccharide structural unit" (i.e., the structure of N-acetyl-D-glucosamine and D-glucuronic acid or its salt bonded by β1,3). In addition, there is no special distinction between "diclofenac-derived disaccharide structural unit" and "hyaluronic acid disaccharide structural unit", and they are also simply referred to as "disaccharide structural unit".

In this instruction manual, ingredient (A) and the filtration improver are collectively referred to as "added ingredients".

As a more specific example, the present invention relates to the following [1] to [23].

[1] A pharmaceutical composition comprising a compound of formula (1) and component (A), wherein the aforementioned component (A) is at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

[2] The pharmaceutical composition described in [1] above is used for the treatment of joint diseases.

[3] A kit comprising a syringe into which the pharmaceutical composition described in [1] or [2] is filled.

[4] A kit comprising a vial and a syringe, the vial containing the pharmaceutical composition described in [1] or [2] above.

[5] A method for manufacturing a pharmaceutical composition containing a compound of formula (1), comprising a step of coexisting the compound of formula (1) with the aforementioned component (A).

[6] A method for inhibiting the formation of diclofenac lactam from the compound represented by formula (1), comprising a step of coexisting the compound represented by formula (1) with the aforementioned component (A).

[7] The use of component (A) in the manufacture of a pharmaceutical composition containing a compound of formula (1), comprising a step of coexisting the aforementioned component (A) with the aforementioned compound of formula (1), the aforementioned pharmaceutical composition being used for the treatment of joint diseases, wherein the aforementioned component (A) is a compound that inhibits the formation of diclofenac lactam from the compound of formula (1).

[8] A component (A) is used for treating joint diseases in humans and is used together with the compound shown in formula (1) as a component of a pharmaceutical composition for treating joint diseases.

[9] A method of treating a joint disease in a person, comprising the step of administering a pharmaceutical composition to a joint of a patient with a joint disease, the pharmaceutical composition containing an effective amount of a compound and ingredient (A) of formula (1).

[10] An aqueous composition comprising the compound shown in formula (1) and having a maximum throughput ( _Vmax ) of 1.0 g/ ^cm² or more, wherein the aforementioned maximum throughput ( _Vmax ) is as follows: the aforementioned aqueous composition at a liquid temperature of 70°C is filtered using a polyvinylidene fluoride filter membrane with a pore size of 0.22 μm under a pressure of 0.6 MPa, and the total filtration volume per unit effective filtration area is measured every 30 seconds until the flow rate is less than 1/10 of the initial flow rate at the start of filtration. The measured value obtained therefrom is then applied to the values derived in the following formulas A and B:

Formula A:

t/V = at + b

Equation B:

_{V_max} = 1/a

In the above formulas A and B, t is the filtration time (minutes), V is the total filtration capacity per unit effective filtration area (g/ ^cm2 ), a is the slope of formula A, and b is the intercept of formula A.

[11] The aqueous composition according to [10] above further comprises a filterability improver.

[12] According to the aqueous composition described above [11], wherein the aforementioned filterability improver is selected from the group consisting of polyalkylene glycols, _C1 to _C3 monohydric alcohols, hydroxyalkylated cyclodextrins and their salts.

[13] The aqueous composition according to [11] or [12] above, wherein the relative amount of diclofenac lactam, measured under the following conditions, is 0.9 or less (e.g., 0.8 or less or 0.75 or less):

The test composition containing the compound shown in formula (1) and the filterability improver, and the control composition having the same composition as above except that it does not contain the filterability improver, were stored in a constant temperature bath at 60°C for 1 week. Then, the amount of diclofenac lactam accumulated in the test composition and the control composition was determined by high performance liquid chromatography. The relative amount of diclofenac lactam accumulated in the test composition when the amount of diclofenac lactam accumulated in the control composition was set to 1 was calculated.

[14] The aqueous composition according to any one of [11] to [13] above, wherein the relative amount of diclofenac is less than 1 (e.g., less than 0.95 or less) under the following conditions:

The test composition containing the compound shown in formula (1) and the filterability improver, and the control composition having the same composition as above except that it does not contain the filterability improver, were stored in a constant temperature bath at 60°C for 1 week. Then, the amount of diclofenac accumulated in the test composition and the control composition was determined by high performance liquid chromatography, and the relative amount of diclofenac accumulated in the test composition when the amount of diclofenac accumulated in the control composition was set to 1 was calculated.

[15] The aqueous composition according to any one of [10] to [14] above is used for the treatment of joint diseases.

[16] The aqueous composition according to any one of [10] to [15] above contains the compound shown in formula (1) at a concentration of 0.01 w/v% or more and 80 w/v% or less, 0.1 w/v% or more and 10 w/v% or less, 0.5 w/v% or more and 5 w/v% or less or 1 w/v%.

[17] The aqueous composition according to any one of [11] to [16] above contains a filterability improver at a concentration of 0.01 w/v% or more and 60 w/v% or less, 0.1 w/v% or more and 30 w/v% or less, 1 w/v% or more and 15 w/v% or less, or 2 w/v% or more and less than 10 w/v%.

[18] The aqueous composition according to any one of [10] to [17] above contains water at a concentration of 10 w/v% or more and 99.98 w/v% or less, 60 w/v% or more and 99.8 w/v% or less, 80 w/v% or more and 98.5 w/v% or less, or more than 89 w/v% and less than 97 w/v%.

[19] A kit comprising a syringe into which the aqueous composition described in any one of [10] to [18] is filled.

[20] A kit comprising a vial and a syringe, the vial comprising the aqueous composition described in any one of [10] to [18] above.

[21] A method for manufacturing a pharmaceutical composition containing a compound of formula (1), comprising a step of coexisting the compound of formula (1) with a filtration improver.

[22] A method for improving the filterability of a compound represented by formula (1) includes a step of coexisting the compound represented by formula (1) with a filterability improver.

[23] A method of treating joint diseases in humans, comprising the step of administering the aqueous composition described in any one of [10] to [18] above to the joints of a patient with a joint disease.

Detailed Implementation

According to the present invention, a Dic-HA-containing pharmaceutical composition is provided in which the accumulation of diclofenac lactam is inhibited.

The following examples illustrate the methods for implementing this invention.

One aspect of the present invention relates to a pharmaceutical composition comprising a compound and component (A) of formula (1), wherein component (A) is at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts:

(In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group).

Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula (1) and an additive ingredient, wherein the formation and/or accumulation of diclofenac are inhibited.

Another aspect of the present invention relates to a method for manufacturing a pharmaceutical composition containing a compound of formula (1), the method comprising the step of coexisting the compound of formula (1) with an ingredient (A) selected from at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

Another aspect of the present invention relates to a method for inhibiting the formation of diclofenac lactam from a compound of formula (1), the method comprising a step of coexisting the compound of formula (1) with at least one selected from the group consisting of a nonionic surfactant, a hydroxyalkylated cyclodextrin, a _C1 - _C3 monohydric alcohol, a _C2 - _C3 dihydric alcohol, a _C3 - _C6 trihydric alcohol, a polyalkylene glycol, a γ-lactone, a polyvinylpyrrolidone, chlorogenic acid and alkyl sulfates, and salts thereof.

Another aspect of the present invention relates to the use of at least one substance selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts, in the manufacture of a pharmaceutical composition containing a compound of formula (1), the pharmaceutical composition being used for the treatment of joint diseases, wherein the at least one substance is a compound that inhibits the formation of diclofenac lactam from the compound of formula (1).

Another aspect of the present invention relates to at least one compound for treating human joint diseases, wherein the at least one compound is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts, and is used together with the compound shown in formula (1) as a component of a pharmaceutical composition for treating joint diseases.

Another aspect of the present invention relates to a treatment method for human joint diseases, comprising the step of administering a pharmaceutical composition to the joints of a patient with a joint disease, the pharmaceutical composition comprising an effective amount of a compound of formula (1) and at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts, and inhibiting the formation of diclofenac component from the compound of formula (1).

Another aspect of the present invention relates to a method for preserving a pharmaceutical composition of formula (1), wherein the pharmaceutical composition is a pharmaceutical composition in which the formation and/or accumulation of diclofenac lactam is inhibited during preservation, and comprises a group of compounds selected from nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

Another aspect of the invention relates to a kit comprising a pharmaceutical composition and a syringe, said pharmaceutical composition containing a compound of formula (1) and at least one compound; the at least one compound being selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts, and inhibiting the formation of diclofenac components from the compound of formula (1).

According to one aspect of the invention, in a pharmaceutical composition containing a compound of formula (1), by having at least one compound selected from the group consisting of a nonionic surfactant, a hydroxyalkylated cyclodextrin, a _C1 - _C3 monohydric alcohol, a _C2 - _C3 dihydric alcohol, a _C3 - _C6 trihydric alcohol, a polyalkylene glycol, a γ-lactone, a polyvinylpyrrolidone, chlorogenic acid, an alkyl sulfate, and their salts coexist, it is possible to inhibit the accumulation of diclofenac lactam generated by the compound of formula (1) during the storage of the aforementioned pharmaceutical composition.

According to one aspect of the invention, in a pharmaceutical composition containing a compound of formula (1), by having at least one compound selected from the group consisting of a nonionic surfactant, a hydroxyalkylated cyclodextrin, a _C1 - _C3 monohydric alcohol, a _C2 - _C3 dihydric alcohol, a γ-lactone, a polyvinylpyrrolidone, chlorogenic acid and alkyl sulfates, and their salts coexist, it is possible to inhibit the accumulation of diclofenac generated by the compound of formula (1) during the storage of the aforementioned pharmaceutical composition.

According to one aspect of the invention, a pharmaceutical composition with excellent long-term stability and extended shelf life is provided. This pharmaceutical composition can be stored in a container (e.g., vial, syringe, etc.) as an aqueous composition for injection, inhibiting the accumulation of diclofenac lactam over time during storage. This allows for efficient supply of the pharmaceutical composition, reducing manufacturing/storage costs, and consequently benefiting patients who require the pharmaceutical composition.

In this specification, "carboxylate group" refers to the structure of a salt formed by a carboxylate ion [-C(=O)-O-] and a cation, and can be any pharmaceutically permissible salt form. The cation forming the carboxylate is not particularly limited as long as it can form a salt with the carboxylate ion [-C(=O)-O-], and examples include sodium ions, potassium ions, calcium ions, magnesium ions, etc. In a preferred embodiment, the carboxylate group is represented by _-CO₂Na (i.e., the cation is a sodium ion).

The term "pharmaceutically permissible salts" in this instruction manual may include, but is not limited to, metal salts such as sodium, potassium, calcium, magnesium, and barium salts; ammonium salts; amine salts such as methylamine, diethylamine, ethylenediamine, cyclohexylamine, and ethanolamine; inorganic acid salts such as hydrochloride, sulfate, hydrogen sulfate, nitrate, phosphate, hydrobromide, and hydroiodide; and organic acid salts such as acetate, phthalate, fumarate, maleate, oxalate, succinate, methanesulfonate, p-toluenesulfonate, tartrate, hydrogen tartrate, and malate.

In this specification, "diclofenac component" is used as a general term for diclofenac and diclofenac lactam, individually or collectively. The amount of diclofenac component can be determined using the high-performance liquid chromatography (HPLC) method described in the examples.

In this specification, component (A) is at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids, and alkyl sulfates, and their salts. A pharmaceutical composition is provided in which the formation and/or accumulation of diclofenac lactam is inhibited by containing component (A).

In this specification, "coexistence" means bringing the substances into contact with each other. For example, this can be done by adding component (A) to the compound shown in formula (1), or by adding the compound shown in formula (1) to component (A). Alternatively, it can be done by mixing the compound shown in formula (1) with component (A).

The salt used as ingredient (A) is not particularly limited to the "pharmaceutically permitted salts" mentioned above, and examples of pharmaceutically permitted salts as described above can be given.

In one embodiment, component (A), for example in a composition containing a compound of formula (1), has the function of inhibiting the accumulation and/or formation of diclofenac lactam.

In a preferred embodiment, component (A) further serves as an inhibitor of the accumulation and/or generation of diclofenac in a composition comprising the compound shown in formula (1).

In this specification, "inhibition" of the formation and accumulation of diclofenac means reducing the amount of diclofenac formed and/or accumulated.

The accumulation and/or formation of diclofenac can be determined by storing an aqueous composition containing the compound of formula (1) and component (A) in a constant temperature bath at 60°C for one week, and then measuring the amount of diclofenac accumulated in the aqueous composition. The accumulation inhibition effect and/or formation inhibition effect of component (A) on diclofenac is described more specifically in the examples. The amount of diclofenac in the test aqueous composition is calculated as a relative amount when the amount of diclofenac accumulated in the aqueous composition is set to 1, except that component (A) is not included. This can be evaluated (when the relative amount is less than 1, the accumulation and/or formation of diclofenac is inhibited). Using this method, it is possible to determine whether an aqueous composition containing the compound of formula (1) inhibits the accumulation and/or formation of diclofenac.

The relative amount of diclofenac lactam calculated under the above conditions is preferably 0.9 or less, more preferably 0.8 or less, and even more preferably 0.75 or less. Furthermore, the relative amount of diclofenac calculated under the above conditions is preferably less than 1, more preferably 0.95 or less, and even more preferably 0.9 or less.

The composition may contain one or more of the ingredient (A).

There are no particular limitations on the combination of components (A) containing two or more. For example, combinations of two components (A) such as polyalkylene glycol and a nonionic surfactant, or polyalkylene glycol and a hydroxyalkylated cyclodextrin, can be listed; combinations of three components (A) such as polyalkylene glycol, a nonionic surfactant, and a hydroxyalkylated cyclodextrin can also be listed. As described in the examples below, by allowing multiple components (A) to coexist, a higher inhibitory effect on diclofenac can be expected.

Furthermore, another aspect of the present invention is an aqueous composition in which the compound shown in formula (1) coexists with a component that inhibits the accumulation and/or formation of diclofenac, wherein the relative amount of diclofenac lactam after storage in a constant temperature bath at 60°C for 1 week is 0.9 or less, more preferably 0.75 or less. The aforementioned relative amount is a value when the amount of diclofenac lactam accumulated in the control composition is set to 1, provided that the same aqueous composition (control composition) other than containing the component that inhibits the accumulation and/or formation of diclofenac is stored under the same conditions.

According to the research of the inventors, it has been clarified that component (A) can also be used as an inhibitor of the formation of diclofenac component, an inhibitor of the accumulation of diclofenac lactam in the composition, or a filterability improver of an aqueous composition containing a compound represented by formula (1) as described below.

In one embodiment, the composition contains component (A) at a rate of 0.01 w/v% or more and 60 w/v% or less, preferably 0.1 w/v% or more and 30 w/v% or less, more preferably 1 w/v% or more and 15 w/v% or less, and particularly preferably 2 w/v% or more and less than 10 w/v%.

Here, diclofenac has the structure shown in formula (2) below, and diclofenac lactam has the structure shown in formula (3) below.

In this specification, "nonionic surfactant" is the nonionic surfactant as commonly understood by those skilled in the art.

Non-limiting examples of nonionic surfactants include polysorbates (polysorbate 20, polysorbate 60, polysorbate 80, etc.), alkylphenol polyoxyethylene ethers (octylphenol polyoxyethylene ether (Triton X-100, nonylphenol polyoxyethylene ether, etc.), alkyl glucosides (decyl glucoside, lauryl glucoside, octyl glucoside, etc.), and polyoxyethylene glycol ethers (octaethylene glycol monododecyl ether, pentaethylene monododecyl ether). Polyoxyethylene alkyl ethers, polyoxyethylene dodecyl ethers, polyoxyethylene hexadecyl ethers, etc.), polyoxyethylene glycol alkylphenol ethers (polyoxyethylene glycol octylphenol ether, polyoxyethylene glycol nonylphenol ether, etc.), polyoxyethylene lauryl ether, polyoxypropylene glycol alkyl ethers, glyceryl alkyl esters, polyoxyethylene glycol sorbitol alkyl esters, monodecanoyl sucrose, cocoamide, dodecyl dimethylamine oxide, and alkoxylated alcohols (ethoxylated alcohols, propoxylated alcohols, ethoxylated propoxylated alcohols, etc.), and pharmaceutically permissible salts thereof.

In one embodiment, polysorbate 20, polysorbate 80, Triton X-100, octyl glucoside, and pharmaceutically permissible salts thereof are used as preferred nonionic surfactants.

In this specification, "hydroxyalkylated cyclodextrin" is the hydroxyalkylated cyclodextrin commonly understood by those skilled in the art.

As non-limiting examples of hydroxyalkylated cyclodextrins, hydroxyethyl-β-cyclodextrin (HE-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) can be cited. In one embodiment, HE-β-CD and HP-β-CD are used as preferred hydroxyalkylated cyclodextrins.

In this specification, " _C1 to _C3 monohydric alcohols" refers to monohydric alcohols with 1 to 3 carbon atoms, such as methanol, ethanol, n-propanol, and isopropanol.

In one embodiment, ethanol is used as a preferred _C1 to _C3 monohydric alcohol.

In this specification, " _C2 - _C3 diols" refers to diols with 2 to 3 carbon atoms, such as 1,2-ethylene glycol and propylene glycol.

In one embodiment, propylene glycol is used as a preferred _C2 - _C3 diol.

In this specification, " _C3 - _C6 triols" refers to triols with 3 to 6 carbon atoms, such as glycerol, 1,2,3-butanetriol, and D-glucose.

In one embodiment, glycerol, 1,2,3-butanetriol and D-glucose are used as preferred _C3 to _C6 triols.

In this specification, "polyalkylene glycol" refers to polymers of alkylene glycols such as polyethylene glycol and polypropylene glycol. As non-limiting examples of polyethylene glycol, PEG100 to 10000 (e.g., PEG200, PEG300, PEG400, PEG500, PEG600, PEG4000, and PEG6000) can be listed. These examples are all used as preferred polyalkylene glycols in one embodiment of the invention.

In a preferred embodiment, polyethylene glycol with a weight-average molecular weight of 200 or more and 6000 or less can be used.

In a more preferred embodiment, polyethylene glycol with a weight-average molecular weight of 400 or more and 6000 or less can be used.

In this specification, "γ-lactone" is a lactone with a 5-membered ring as commonly understood by those skilled in the art.

Examples of non-limiting γ-lactones include D-erythrolactone, sodium isoascorbate, ascorbic acid, glucuronide, and pharmaceutically permissible salts thereof.

In one embodiment, D-erythrolide, sodium isoascorbate, glucuronide, and pharmaceutically permissible salts thereof are used as preferred γ-lactones.

In this specification, "chlorogenic acid" refers to chlorogenic acid, feruloylquinic acid, dicaffeoylquinic acid, and pharmaceutically permissible salts thereof, or similar compounds.

In one embodiment, chlorogenic acid and its pharmaceutically permissible salts are used as preferred chlorogenic acids.

In this specification, "alkyl sulfate" refers to sulfates having alkyl groups such as octyl, nonyl, decyl, and dodecyl, as well as their pharmaceutically permissible salts.

Sodium dodecyl sulfate (SDS) is a representative example of alkyl sulfates.

In one embodiment, SDS is used as a preferred alkyl sulfate.

From the viewpoint of inhibiting the formation and/or accumulation of diclofenac in the composition, in a preferred embodiment, component (A) may be at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

From the viewpoint of the excellent filterability of the composition, in a preferred embodiment, component (A) may be a compound selected from the group consisting of polyalkylene glycols, _C1 to _C3 monohydric alcohols and hydroxyalkylated cyclodextrins, and their salts.

In this invention, the pharmaceutical composition is preferably used to treat joint diseases in humans. In this specification, "joint diseases" refers to various joint diseases such as those of the knee, shoulder, neck, hip, spine, jaw, fingers, elbow, wrist, and ankle. More specifically, examples of joint diseases include osteoarthritis, rheumatoid arthritis, articular cartilage damage, knee osteonecrosis, femoral osteonecrosis, shoulder arthritis, bacterial arthritis, viral arthritis, and neurogenic arthritis. The composition for treating joint diseases of this invention is preferably used for osteoarthritis or rheumatoid arthritis, and more preferably for osteoarthritis.

In this instruction manual, "treatment" can refer to treatment of the disease itself (e.g., treatment to cure or improve organic lesions in the disease), or treatment of various symptoms accompanying the disease (e.g., reductions in ADL of the joints, such as pain, stiffness, and joint function (e.g., as assessed by difficulty in daily activities, such as climbing stairs or getting in and out of a car)). Furthermore, "treatment" includes not only complete cure but also improvement of some or all of the symptoms of the disease, suppression of disease progression (including maintenance and a reduction in the rate of progression), and prevention. Prevention here includes, for example, preventing the occurrence of various symptoms associated with joint diseases, such as pain and/or stiffness, even when organic lesions are observed in the joint but no joint dysfunction is present. Additionally, prevention includes, for example, preventing the occurrence of organic lesions in joint diseases, such as pain and/or stiffness, even when no definite organic lesions are observed in the joint, and suppressing the development of non-significant symptoms among these various symptoms. The composition is preferably used to improve or cure symptoms of joint diseases or to inhibit the aggravation of joint diseases, and more preferably for the improvement or cure of symptoms. In one embodiment, the composition can be suitably used to improve, cure or inhibit the aggravation of joint pain, or to improve joint function.

In this specification, "effective amount" refers to a sufficient amount of the component that provides the desired response without excessive harmful side effects (toxicity, irritation, and allergic reactions) corresponding to a reasonable risk/benefit ratio. This "effective amount" can vary depending on various factors such as the patient's symptoms, physical condition, age, and sex. However, those skilled in the art can determine the effective amount in other situations based on the results of one or more specific trials and common technical knowledge, without needing to conduct separate tests for each combination of factors.

Hyaluronic acid comprises a glycosaminoglycan consisting of a basic backbone formed by the β1,3 bond between N-acetyl-D-glucosamine and D-glucuronic acid or their salts as a disaccharide unit (hyaluronic acid disaccharide structural unit), and the basic backbone formed by the repeated β1,4 bond of this hyaluronic acid disaccharide structural unit. Furthermore, hyaluronic acid can be obtained by any method, including purified products from animal or microbial sources, chemically synthesized products, etc.

The mass-average molecular weight of hyaluronic acid and the compound shown in formula (1) is not particularly limited, but can be 10,000 or more and 10,000,000 or less, preferably 500,000 or more and 5,000,000 or less, more preferably 600,000 or more and 3,000,000 or less, and even more preferably 600,000 or more and 1,200,000 or less. It should be noted that in this specification, the "mass-average molecular weight" of hyaluronic acid and the compound shown in formula (1) is a value measured by the intrinsic viscosity method, and has the same meaning as the "weight-average molecular weight" of these compounds.

Hyaluronic acid and the compound shown in formula (1) can be in a non-salt-forming state or in a salt-forming state. As the salts described above, pharmaceutically permissible salts as described above can be exemplified.

The compound shown in formula (1) can be obtained by covalently bonding hyaluronic acid with diclofenac using 2-bromoethylamine hydrobromide, 2-aminoethanol, etc. as spacer groups.

In the compound shown in formula (1), diclofenac is connected to the spacer group via an ester bond, and the spacer group is connected to hyaluronic acid via an amide bond.

Furthermore, in the compound shown in formula (1), each disaccharide structural unit can be randomly or block-linked in a ratio of a and b, respectively. That is, the diclofenac disaccharide structural unit and the hyaluronic acid disaccharide structural unit are linked to each other in a random or block-linked manner via β1,4 bonds.

The compound shown in formula (1) has a hydrogen atom or a hydroxyl group at the end.

In formula (1), a is the ratio of the number of diclofenac-introduced disaccharide structural units to the total number of disaccharide structural units, b is the ratio of the number of hyaluronic acid disaccharide structural units to the total number of disaccharide structural units, and a+b equals 1. When the ratio shown as a in formula (1) is expressed as a mole fraction, the value of that mole fraction is referred to as the "introduction rate" in this specification. In formula (1), a is 0.01 or more and 0.7 or less (as an introduction rate, it is 1 mol% or more and 70 mol% or less, and b is 0.3 or more and 0.99 or less), preferably 0.1 or more and 0.2 or less (10 mol% or more and 20 mol% or less, and b is 0.8 or more and 0.9 or less).

For the value of a in formula (1), the introduction rate can be adjusted by changing the reaction equivalent of condensing agent, condensing aid, spacer compound, and diclofenac in the reaction process of introducing diclofenac into hyaluronic acid.

Here, the “introduction rate” in this specification is a value calculated using the following formula 1, which can be obtained by measuring absorbance.

Equation 1:

Introduction rate (mol%) = (Number of diclofenac-introduced disaccharide structural units / Total number of disaccharide structural units) × 100

More specifically, the absorption rate is determined by the carbazole absorbance method, using a pre-prepared standard curve for diclofenac, and can be calculated according to the above formula.

In the compound shown in formula (1), n represents the total number of disaccharide structural units, which can be calculated by formula 2 or 3 below.

When determining n based on the mass-average molecular weight of the hyaluronic acid in the raw material, it can be calculated using the following formula 2.

Equation 2:

n = (weight-average molecular weight of hyaluronic acid / weight-average molecular weight of disaccharide structural unit)

When calculating n based on the mass-average molecular weight of the compound shown in Equation (1) and a and b in Equation (1), it can be calculated according to the following formula 3.

Equation 3:

n = (mass-average molecular weight of the compound represented by formula (1)) / ((mass-average molecular weight of the diclofenac disaccharide structural unit × a) + (mass-average molecular weight of the hyaluronic acid disaccharide structural unit × b))

n is an integer of 25 or more and 25,000 or less, preferably an integer of 1,250 or more and 12,500 or less, more preferably an integer of 1,500 or more and 7,500 or less, and even more preferably an integer of 1,500 or more and 3,000 or less.

The method of introducing a spacer group and diclofenac into hyaluronic acid can either introduce diclofenac into hyaluronic acid with a spacer group already introduced, or react diclofenac with hyaluronic acid that has been pre-introduced with a spacer group. This can be readily implemented by anyone skilled in the art, for example, by referring to Patent Document 1, Patent Document 2, etc.

In one embodiment, the composition contains the compound shown in formula (1) at a concentration of 0.01 w/v% or more and 80 w/v% or less. In a preferred embodiment, the composition contains 0.1 w/v% or more and 10 w/v% or less, more preferably 0.5 w/v% or more and 5 w/v% or less, and particularly preferably 1 w/v% of the compound shown in formula (1).

In addition to the compound shown in formula (1), the composition may contain a pharmaceutically permissible carrier. Examples of such a pharmaceutically permissible carrier include aqueous solvents such as water for injection, physiological saline, and Ringer's solution. In one embodiment, the pharmaceutical composition is an aqueous composition. In another embodiment, the composition is prepared by mixing the pharmaceutically permissible carrier with the compound shown in formula (1). Additives such as buffers may be added to the composition as needed. Furthermore, after mixing the components, the composition may be treated with methods such as dust removal, sterilization, or filtration.

When pharmaceutical compositions and other compositions are used in living organisms (mammals, especially humans), dust removal and sterilization are usually required. In the case of aqueous compositions, from the viewpoint of component stability and ease of use, dust removal and sterilization processes are preferably performed by filtration. When sterilizing the composition by filtration, commercially available membrane filters, sterilized containers, sterilized syringes/cylinders, etc., can be used. For example, a membrane filter with a pore size of 0.22 μm can be used as a membrane filter. Aqueous compositions containing compounds of formula (1) have high viscosity, so according to the embodiments, there is a concern that it is difficult to prepare aqueous compositions due to low filterability, especially during filtration sterilization.

Here, the aqueous composition containing the compound shown in formula (1) has poor filterability. Patent Document 1 discloses that by alkaline treatment of a solution containing Dic-HA, a transparent solution with filter-passing properties can be obtained. However, the inventors conducted research and found that alkaline treatment of the aqueous composition containing Dic-HA promotes the formation of diclofenac. On the other hand, it was found that when the sterilization of the aqueous composition containing the compound shown in formula (1) is performed by heat sterilization instead of filter sterilization, the formation of diclofenac is still promoted.

One aspect of the present invention relates to an aqueous composition comprising a compound of formula (1), wherein the maximum throughput ( _Vmax ) in the following calculations is expressed as 1.0 g/ ^cm² or more. According to the above-described aqueous composition, filtration can be performed, thereby preventing/inhibiting the formation of diclofenac components during dust removal and sterilization processes.

The maximum throughput ( _Vmax ) is calculated more specifically as follows. That is, using a polyvinylidene fluoride (PVDF) filter membrane with a pore size of 0.22 μm, the aforementioned aqueous composition at a liquid temperature of 70°C is filtered under a pressure of 0.6 MPa. In this case, the total filtration volume (V) per unit effective filtration area of the filter membrane is measured every 30 seconds until the flow rate (Q) is less than 1/10 of the initial flow rate. The horizontal axis represents filtration time (t), and the vertical axis represents t/V. The measurement results are plotted, and the following formula A is calculated within the range of measurement points where t/V stabilizes. The maximum throughput ( _Vmax ) is obtained from the reciprocal of the slope a of formula A (i.e., formula B below). It should be noted that the flow rate (Q) is the filtration volume per unit time (i.e., Q = dV/dt).

Formula A:

t/V = at + b

Formula B:

_{V_max} = 1/a

In the above formulas A and B, t is the filtration time (minutes), V is the total filtration capacity per unit effective filtration area (g/ ^cm2 ), a is the slope of formula A, and b is the intercept of formula A.

The larger the maximum throughput ( _Vmax ) (i.e., the higher the filter's filtration efficiency), the less likely the filter will become clogged and the less time is required for filtration.

It should be noted that _Vmax itself is an evaluation index used for selecting filters and performing optimization (as needed, refer to Kobayashi Kimihiko's " _Vmax Experimental Filter Selection and Optimization Method", Bioprocess Technical Sheet Basic Technology No. 2, Millipore Japan, August 1997).

An aqueous composition containing the compound shown in formula (1) and having a maximum throughput ( _Vmax ) of 1.0 g/ ^cm² or more is useful as a pharmaceutical composition or an intermediate thereof. The maximum throughput ( _Vmax ) is preferably 6.0 g/ ^cm² or more, more preferably 8.0 g/ ^cm² or more, further preferably 10 g/cm² or more, even more preferably 15 ^g /cm² ^or more, and particularly preferably 20 g/ ^cm² or more. There is no particular upper limit to the maximum throughput ( _Vmax ), for example, it is 2000 g/ ^cm² or less (1500 g/ ^cm² or less, 1200 g/ ^cm² or less, 1000 g/cm² or less, 800 g/ ^cm² or ^less , 500 g/ ^cm² or less, 200 g/cm² or ^less ). For example, it can also be 1.0 g/ ^cm² or higher and 2000 g/ ^cm² or lower, 6.0 g/ ^cm² or ^higher and 1500 g/ ^cm² or lower, 8.0 g/ ^cm² or higher and 1000 g/cm² or ^lower , ¹⁰ g/cm² or higher and 800 g/cm² or ^lower , 15 g/ ^cm² or higher and 500 g/cm² or ^higher and 200 g/cm² or ^lower .

In one embodiment, the aqueous composition further comprises a filterability improver. In this invention, "filterability improver" is not particularly limited to anything that improves the filterability, i.e., the maximum throughput ( _Vmax ), of the aqueous composition comprising the compound shown in formula (1). Specific examples of filterability improvers may include, for example, the aforementioned component (A), but are not limited to these.

In one embodiment, the filterability improver is selected from the group consisting of polyalkylene glycols, _C1 - _C3 monohydric alcohols and hydroxyalkylated cyclodextrins as described above.

From a filterability point of view, in a preferred embodiment, PEG200-6000, methanol, ethanol, n-propanol, isopropanol, hydroxyethyl-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin are used as filterability improvers.

In a more preferred embodiment, a compound selected from the group consisting of PEG400, PEG4000, ethanol and hydroxypropyl-β-cyclodextrin can be used as a filterability improver in the composition.

As one embodiment, when PEG400 is included, it can be particularly preferred as a filtration improver from the perspective of significantly improving filtration performance.

The aqueous composition may contain one filterability improver alone or two or more.

In one embodiment, the aqueous composition may contain a filterability improver at a rate of 0.01 w/v% or more and 60 w/v% or less, preferably 0.1 w/v% or more and 30 w/v% or less, more preferably 1 w/v% or more and 15 w/v% or less, and particularly preferably 2 w/v% or more and less than 10 w/v%.

In this specification, "aqueous composition" refers to a composition containing 10 w/v or more and 99.98 w/v or less of water. The aqueous composition may also be a solution, suspension, or gel. Examples of water used to prepare the aqueous composition include, for example, water for injection, purified water, and distilled water. The water content in the aqueous composition is preferably 60 w/v or more and 99.8 w/v or less, more preferably 80 w/v or more and 98.5 w/v or less, and particularly preferably more than 89 w/v and less than 97 w/v.

In one embodiment, the maximum processing capacity ( _Vmax ) of the aqueous composition containing the compound shown in formula (1) is 1.0 g/ ^cm² or more, and the relative amount of diclofenac lactam is 0.9 or less. In a preferred embodiment, the maximum processing capacity ( _Vmax ) of the aqueous composition containing the compound shown in formula (1) is 6.0 g/ ^cm² or more, and the relative amount of diclofenac lactam is 0.8 or less. In a more preferred embodiment, the maximum processing capacity ( _Vmax ) of the aqueous composition containing the compound shown in formula (1) is 8.0 g/ ^cm² or more, and the relative amount of diclofenac lactam is 0.75 or less. It should be noted that the relative amount of diclofenac lactam is calculated as follows: the test composition containing the compound shown in formula (1) and the filterability improver, and the control composition having the same composition as described above except that it does not contain the filterability improver, are stored in a constant temperature bath at 60°C for 1 week. The amount of diclofenac lactam accumulated in the test composition and the control composition is determined by high performance liquid chromatography, and the relative amount when the amount of diclofenac lactam accumulated in the control composition is set to 1 is calculated.

The buffers that may be included in the composition can be substances known to those skilled in the art. As non-limiting examples, citrate buffer, acetate buffer, and phosphate buffer can be cited as buffers.

In one embodiment, the citrate buffer solution may be exemplified by having a final concentration of 0.1 mM to 500 mM (e.g., 1 mM to 50 mM) based on citrate. Here, the citrate buffer solution is preferably adjusted to a pH of 4.5 to 5.5. More preferred examples of the pH of the citrate buffer solution include pH 4.8 to pH 5.4, and as a further example, pH 5.1.

In one embodiment, the acetate buffer may be exemplified by having a final concentration of 0.1 mM to 500 mM (e.g., 1 mM to 50 mM) based on acetic acid. Here, the acetate buffer is preferably adjusted to a pH of 4.5 to 5.5. More preferred examples of the pH of the acetate buffer include pH 4.8 to pH 5.4, and as a further example, pH 5.1.

In one embodiment, the phosphate buffer may be exemplified by having a final concentration of 0.1 mM to 500 mM (e.g., 1 mM to 50 mM) based on phosphate. Here, the phosphate buffer is preferably adjusted to a pH of 6.0 to 7.0. More preferred examples of the pH of the phosphate buffer include pH 6.3 to pH 6.8, and as a further example, pH 6.5.

In one embodiment, the citrate buffer may be used in combination with one or more of the following as component (A): selected from _C3 - _C6 triols, polyalkylene glycols, alkyl sulfates, nonionic surfactants, _C1 - _C3 monools, γ-lactones, chlorogenic acid, _C2 - _C3 diols and polyvinylpyrrolidone, and their salts.

In one embodiment, the acetate buffer may be used in combination with one or more of the following as component (A): hydroxyalkylated cyclodextrin, polyalkylene glycol, _C1 - _C3 monohydric alcohol, nonionic surfactant, polyvinylpyrrolidone, and their salts.

In one embodiment, the phosphate buffer may be used in combination with one or more of the following as component (A): selected from γ-lactone, polyalkylene glycol and _C3 - _C6 triols, and their salts.

In one embodiment, the composition is prepared by the following steps.

(Step 1) Dissolve the specified amounts of citric acid hydrate, disodium citrate hydrate, and PEG400 in water for injection (WFI).

(Step 2) Dissolve the specified amount of the compound shown in formula (1) (introduction rate 18 mol%) in the solution of step 1. In addition, heat the dissolved solution to 70°C and degas it under reduced pressure.

(Step 3) The solution from Step 2 is filtered and sterilized using a filter with a pore size of 0.22 μm.

(Step 4) The solution from Step 3 is heated to 70°C to degas it, and then cooled to 10°C.

(Step 5) Fill the syringe with the specified amount under sterilization conditions.

Through the above steps (1) to (5), a sterile pharmaceutical composition comprising a hyaluronic acid derivative, PEG400, and citrate buffer can be prepared. Here, the concentrations of each component can be exemplified as follows: hyaluronic acid derivative; 0.5–5 w/v%, PEG400; 3–30 w/v%, and phosphate buffer; 3–30 mM (calculated as citrate), but the concentrations of each component in the pharmaceutical composition are not limited to the aforementioned ranges. Needless to say, component (A) is not limited to PEG400, and the buffer is not limited to citrate buffer. The composition of the hyaluronic acid derivative and the pore size of the membrane filter are also the same.

By making the maximum throughput ( _Vmax ) of the aqueous composition 1.0 g/ ^cm2 or higher, the suitability for filtration sterilization using a filter is improved, thereby suppressing the formation of diclofenac lactam during the sterilization process.

The prepared sterilized pharmaceutical composition can be stored at low temperatures such as 4°C or at room temperature. To inhibit the decomposition of hyaluronic acid derivatives, storage at low temperatures such as 4°C is desirable. For example, a threshold is set for the accumulation of 0.5 w/w% diclofenac lactam relative to the amount of hyaluronic acid derivative in the pharmaceutical composition. If the accumulation exceeds this threshold and the composition is deemed unsuitable for pharmaceutical quality, it can still be stored in its original, acceptable state at room temperature (25°C) for several months to about one year, provided the solution composition is suitable. The storage period is calculated based on the results of the storage tests in the following examples. By allowing component (A) to coexist, it can be extended by approximately 1 to 3 months (this calculation is based on the premise that the accumulation of diclofenac lactam is inhibited by 10 to 25% through the coexistence of component (A). This inhibition rate is at a level that can be sufficiently achieved, for example, by the results of Example 1 ((1-2)) described later). If the storage period of a qualified pharmaceutical composition with a shelf life of several months can be extended by more than 1 to 3 months, it is clear that costs can be reduced, the burden on patients can be alleviated, and a contribution to the medical economy can be achieved. In addition, it is more preferable to store the prepared sterilized pharmaceutical composition under light-protected conditions. As such conditions, storing the sterilized pharmaceutical composition in its packaged state in a refrigerator or the like is an example.

The frequency of administration of the pharmaceutical composition can be appropriately adjusted according to the patient's symptoms, etc. From the point of view of efficacy, a frequency of once a week to once every 52 weeks can be exemplified, for example. More preferred examples include once every 2 weeks to once every 26 weeks or once every 4 weeks to once every 13 weeks. If sufficient relief can be achieved with a single dose, then of course only one dose can be administered. The composition is preferably prepared as a solution for injection (e.g., an aqueous composition). For example, when administered to affected areas such as the knee joint by injection, a longer dosing interval is desirable considering the patient's physical and psychological burden. In particular, when used as an injection, the solution is preferably colorless and clear.

In one embodiment, a syringe is provided to fill a syringe barrel with the pharmaceutical composition of the present invention. In another embodiment, a kit comprising a syringe containing a syringe barrel with the pharmaceutical composition of the present invention is also provided. The syringe is equipped with a plunger for extruding the pharmaceutical composition, etc., and is capable of extruding the composition of the present invention. In one embodiment, the composition filled in the syringe may be provided in a sterile state. In one embodiment, a single dose of the composition may be pre-filled in the syringe barrel. In addition, the kit may be made into a medical injection comprising: a solution of the compound shown in formula (1) dissolved in citrate buffer, acetate buffer, phosphate buffer, physiological saline or water for injection is filled into the syringe barrel, and sealed in a slidable manner with a plunger for extruding the pharmaceutical composition, thereby forming a medical injection. The osmotic pressure and viscosity of the solution may be adjusted as needed. It should be noted that the plunger for extruding the pharmaceutical composition may be a commonly used plunger, formed of an elastomer such as rubber or synthetic rubber, and inserted into the syringe barrel in a slidable manner in a sealed state. In addition, the kit may also include a plunger rod for extruding the pharmaceutical composition by pressing in the plunger, an instruction manual or accompanying materials, etc. In another embodiment, the pharmaceutical composition of the present invention may be provided in a vial instead of being filled into a syringe as described above. In this case, the vial is sometimes also provided together with a syringe containing a sterilized empty syringe. Alternatively, it may be provided as a kit containing the aforementioned vial and syringe.

As will be apparent to those skilled in the art, preferred properties and features of one aspect of the invention may be used independently, or in combination with another aspect of the invention.

In one embodiment, a pharmaceutical composition is provided that inhibits the formation and/or accumulation of diclofenac lactam, and the formation and/or accumulation of diclofenac are inhibited, and a method for manufacturing the same thereof.

In one embodiment, an aqueous composition and a method thereof are provided in which the formation of diclofenac lactam is inhibited, exhibiting a maximum throughput ( _Vmax ) of 1.0 g/ ^cm² or higher.

In one embodiment, an aqueous composition exhibiting a maximum throughput ( _Vmax ) of 1.0 g/cm² or ^higher and a method thereof are provided for the inhibition of diclofenac formation.

In one embodiment, an aqueous composition and a method thereof are provided that exhibit a maximum throughput ( _Vmax ) of 1.0 g/ ^cm² or more, and inhibit the formation of diclofenac lactam and diclofenac.

In one specific embodiment, a pharmaceutical composition is provided in which the formation and/or accumulation of diclofenac lactam is inhibited, and the formation and/or accumulation of diclofenac is inhibited, said pharmaceutical composition comprising a compound represented by formula (1), and at least one compound selected from the group consisting of a nonionic surfactant, a hydroxyalkylated cyclodextrin, a _C1 - _C3 monohydric alcohol, a _C2 - _C3 dihydric alcohol, a γ-lactone, a polyvinylpyrrolidone, chlorogenic acid and alkyl sulfates, and their salts.

In one specific embodiment, a pharmaceutical composition is provided in which the formation of diclofenac lactam is inhibited, the maximum throughput ( _Vmax ) is greater than 1.0 g/ ^cm2 , and the filterability is improved. The pharmaceutical composition contains a compound represented by formula (1) and at least one compound selected from the group consisting of polyalkylene glycols, _C1 to _C3 monohydric alcohols and hydroxyalkylated cyclodextrins and their salts.

In one specific embodiment, a pharmaceutical composition is provided in which the formation of diclofenac is inhibited, the maximum throughput ( _Vmax ) is greater than 1.0 g/ ^cm2 , and the filterability is improved, said pharmaceutical composition comprising a compound represented by formula (1), and at least one compound selected from the group consisting of _C1 to _C3 monohydric alcohols and hydroxyalkylated cyclodextrins and their salts.

In one specific embodiment, a pharmaceutical composition is provided in which the formation of diclofenac lactam and diclofenac is inhibited, the maximum throughput ( _Vmax ) is 1.0 g/ ^cm2 or more, and the filterability is improved. The pharmaceutical composition contains a compound represented by formula (1) and at least one compound selected from the group consisting of _C1 to _C3 monohydric alcohols and hydroxyalkylated cyclodextrins and their salts.

In one specific embodiment, a method is provided to inhibit the formation of diclofenac lactam and diclofenac from the compound represented by formula (1), the method comprising a step of coexisting the compound represented by formula (1) with at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

In one specific embodiment, a method is provided to inhibit the formation of diclofenac lactam from the compound represented by formula (1) and to improve the filterability of the compound represented by formula (1), the method comprising a step of coexisting the compound represented by formula (1) with at least one compound selected from the group consisting of polyalkylene glycols, _C1 - _C3 monohydric alcohols and hydroxyalkylated cyclodextrins and their salts.

In one specific embodiment, a method is provided to inhibit the formation of diclofenac from the compound represented by formula (1) and to improve the filterability of the compound represented by formula (1), the method comprising the step of coexisting the compound represented by formula (1) with at least one compound selected from the group consisting of _C1 to _C3 monohydric alcohols and hydroxyalkylated cyclodextrins and their salts.

In one specific embodiment, a method is provided to inhibit the formation of diclofenac lactam and diclofenac from the compound represented by formula (1) and thereby improve the filterability of the compound represented by formula (1), the method comprising a step of coexisting the compound represented by formula (1) with at least one compound selected from the group consisting of _C1 to _C3 monohydric alcohols and hydroxyalkylated cyclodextrins and their salts.

<Implementation Method>

The following examples illustrate preferred embodiments of the present invention.

[1] A pharmaceutical composition comprising a compound of formula (1) and component (A):

Ingredient (A): at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group.

[2] According to the pharmaceutical composition described above [1], wherein the aforementioned component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols.

[3] The pharmaceutical composition according to [1] or [2] above, wherein the polyalkylene glycol is polyethylene glycol.

[4] The pharmaceutical composition according to [3] above, wherein the weight average molecular weight of polyethylene glycol is 200 or more and 6000 or less.

[5] The pharmaceutical composition according to any one of [1] to [4] above contains the compound shown in formula (1) above at a concentration of 0.01 w/v% or more and 80 w/v% or less, 0.1 w/v% or more and 10 w/v% or less, 0.5 w/v% or more and 5 w/v% or less or 1 w/v%.

[6] The pharmaceutical composition according to any one of [1] to [5] above, wherein the final concentration of the aforementioned component (A) is 0.01 w/v% or more and 60 w/v% or less, 0.01 w/v% or more and 30 wt% or less, 1 w/v% or more and 15 w/v% or less, or 2 w/v% or more and less than 10 w/v.

[7] The pharmaceutical composition according to any one of [1] to [6] above further comprises a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer.

[8] The pharmaceutical composition according to any one of [1] to [7] above, wherein the pH is 4.5 to 7.0.

[9] The pharmaceutical composition according to any one of [1] to [8] above is an aqueous composition.

[10] The pharmaceutical composition according to any one of [1] to [9] above is a pharmaceutical composition for the treatment of joint diseases.

[11] The pharmaceutical composition according to [10] above, wherein the joint disease is osteoarthritis or rheumatoid arthritis.

[12] A kit comprising a syringe into which the pharmaceutical composition described in any one of [1] to [11] is filled.

[13] A kit comprising a vial and a syringe, the vial containing any of the pharmaceutical compositions described in any one of [1] to [11].

[14] A method for manufacturing a pharmaceutical composition comprising a compound of formula (1), the method comprising a step of coexisting the compound of formula (1) with component (A):

Ingredient (A): at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, the connection of each disaccharide structural unit can be randomly or blocky, and R in each disaccharide structural unit is independently a carboxyl group or a carboxylate group.

[15] According to the method described above [14], wherein the aforementioned component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols.

[16] In the method described in [14] or [15] above, the polyalkylene glycol is polyethylene glycol.

[17] According to the method described in [16] above, the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less.

[18] The method according to any one of [14] to [17] above, wherein the compound shown in the above formula (1) is added at a final concentration of 0.01 w/v% or more and 80 w/v% or less, 0.1 w/v% or more and 10 w/v% or less, 0.5 w/v% or more and 5 w/v% or less or 1 w/v%.

[19] The method according to any one of [14] to [18] above, wherein the aforementioned component (A) is added at a final concentration of 0.01 w/v% or more and 60 w/v% or less, 0.01 w/v% or more and 30 wt% or less, 1 w/v% or more and 15 w/v% or less, or 2 w/v% or more and less than 10 w/v%.

[20] The method according to any one of [14] to [19] above, wherein the compound and/or component (A) represented by formula (1) comprises a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer.

[21] The method according to any one of [14] to [20] above, wherein the pH of the pharmaceutical composition is 4.5 to 7.0.

[22] The method according to any one of [14] to [21] above, wherein the aforementioned pharmaceutical composition is an aqueous composition.

[23] A method for inhibiting the formation of diclofenac lactam from a compound represented by formula (1) below, comprising a step of coexisting the compound represented by formula (1) below with component (A):

Ingredient (A): at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group.

[24] According to the method described above [23], wherein the aforementioned component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols.

[25] In the method described above in [23] or [24], the polyalkylene glycol is polyethylene glycol.

[26] According to the method described in [25] above, the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less.

[27] The method according to any one of [23] to [26] above, wherein the aforementioned component (A) is added at a final concentration of 0.01 w/v% or more and 60 w/v% or less, 0.01 w/v% or more and 30 wt% or less, 1 w/v% or more and 15 w/v% or less, or 2 w/v% or more and less than 10 w/v%.

[28] The method according to any one of [23] to [27] above, wherein the compound represented by the aforementioned formula (1) and/or the aforementioned component (A) comprises a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer.

[29] The method according to any one of [23] to [28] above, wherein the process is carried out in the range of pH 4.5 to 7.0.

[30] The method according to any one of [23] to [29] above causes the compound shown in formula (1) to coexist with the aforementioned component (A) in an aqueous solvent.

[31] A method for inhibiting the accumulation of diclofenac lactam in a pharmaceutical composition comprising a compound of formula (1), the method comprising the step of coexisting the compound of formula (1) with ingredient (A):

Ingredient (A): at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts.

In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group.

[32] According to the method described in [31] above, wherein the aforementioned component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 to _C3 monohydric alcohols and polyalkylene glycols.

[33] In the method described in [31] or [32] above, the polyalkylene glycol is polyethylene glycol.

[34] According to the method described in [33] above, the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less.

[35] The method according to any one of [31] to [34] above, wherein the aforementioned pharmaceutical composition contains the compound shown in formula (1) at a concentration of 0.01 w/v% or more and 80 w/v% or less, 0.1 w/v% or more and 10 w/v% or less, 0.5 w/v% or more and 5 w/v% or less, or 1 w/v%.

[36] The method according to any one of [31] to [35] above, wherein the aforementioned component (A) is added at a final concentration of 0.01 w/v% or more and 60 w/v% or less, 0.01 w/v% or more and 30 wt% or less, 1 w/v% or more and 15 w/v% or less, or 2 w/v% or more and less than 10 w/v%.

[37] The method according to any one of [31] to [36] above, wherein the compound represented by the aforementioned formula (1) and/or the aforementioned component (A) comprises a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer.

[38] The method according to any one of [31] to [37] above, wherein the pH is in the range of 4.5 to 7.0.

[39] The method according to any one of [31] to [38] above, wherein the aforementioned pharmaceutical composition is an aqueous composition.

[40] The method according to any one of [31] to [39] above, wherein the aforementioned pharmaceutical composition is a pharmaceutical composition for treating joint diseases.

[41] The pharmaceutical composition according to [40] above, wherein the joint disease is osteoarthritis or rheumatoid arthritis.

[42] Use of component (A) in the manufacture of a pharmaceutical composition containing a compound represented by formula (1), wherein component (A) is at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts, wherein the manufacture comprises a step of coexisting component (A) with the compound represented by formula (1):

In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group.

[43] According to the application described above [42], wherein the aforementioned component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols.

[44] In the application described above in [42] or [43], the polyalkylene glycol is polyethylene glycol.

[45] In the application described above [44], the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less.

[46] The application according to any one of [42] to [45] above, wherein the aforementioned pharmaceutical composition contains the compound shown in formula (1) at a concentration of 0.01 w/v% or more and 80 w/v% or less, 0.1 w/v% or more and 10 w/v% or less, 0.5 w/v% or more and 5 w/v% or less or 1 w/v%.

[47] In any of the above [42] to [46] applications, the aforementioned component (A) is added at a final concentration of 0.01 w/v% or more and 60 w/v% or less, 0.01 w/v% or more and 30 wt% or less, 1 w/v% or more and 15 w/v% or less, or 2 w/v% or more and less than 10 w/v%.

[48] The application according to any one of [42] to [47] above, wherein the aforementioned pharmaceutical composition is a pharmaceutical composition for the treatment of joint diseases.

[49] In accordance with the application described above [48], the joint disease is osteoarthritis or rheumatoid arthritis.

[50] A component (A) for treating joint diseases in humans, wherein the component (A) is at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts, wherein the treatment is performed by using the aforementioned component (A) together with a compound represented by the following formula (1) as a constituent of a pharmaceutical composition for treating joint diseases, wherein component (A):

In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group.

[51] According to the aforementioned [50] component (A), wherein the aforementioned component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols.

[52] In the aforementioned [50] or [51] component (A), wherein the polyalkylene glycol is polyethylene glycol.

[53] According to the aforementioned [52] component (A), wherein the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less.

[54] Component (A) according to any one of [50] to [53] above, wherein the final concentration of the compound represented by the aforementioned formula (1) in the aforementioned pharmaceutical composition is 0.01 w/v% or more and 80 w/v% or less, 0.1 w/v% or more and 10 w/v% or less, 0.5 w/v% or more and 5 w/v% or less, or 1 w/v.

[55] Component (A) according to any one of [50] to [54] above, wherein the final concentration of the aforementioned component (A) in the aforementioned pharmaceutical composition is 0.01 w/v% or more and 60 w/v% or less, 0.01 w/v% or more and 30 wt% or less, 1 w/v% or more and 15 w/v% or less, or 2 w/v% or more and less than 10 w/v.

[56] Component (A) according to any one of [50] to [55] above, wherein the joint disease is osteoarthritis or rheumatoid arthritis.

[57] A method for treating a joint disease in humans, comprising the step of administering a pharmaceutical composition to a joint of a patient with a joint disease, the pharmaceutical composition containing an effective amount of a compound represented by formula (1) and component (A), wherein component (A) is at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _{C1 - C3} monohydric alcohols, C2- _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and salts thereof:

In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group.

[58] According to the method described above [57], wherein the aforementioned component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols.

[59] In the method described in [57] or [58] above, the polyalkylene glycol is polyethylene glycol.

[60] According to the method described above [59], the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less.

[61] The method according to any one of [57] to [60] above, wherein the concentration of the compound represented by the aforementioned formula (1) in the aforementioned pharmaceutical composition is 0.01 w/v% or more and 80 w/v% or less, 0.1 w/v% or more and 10 w/v% or less, 0.5 w/v% or more and 5 w/v% or less, or 1 w/v.

[62] The method according to any one of [57] to [61] above, wherein the concentration of the aforementioned component (A) in the aforementioned pharmaceutical composition is 0.01 w/v% or more and 60 w/v% or less, 0.01 w/v% or more and 30 wt% or less, 1 w/v% or more and 15 w/v% or less, or 2 w/v% or more and less than 10 w/v.

[63] The method according to any one of [57] to [62] above, wherein the joint disease is osteoarthritis or rheumatoid arthritis.

Example

The preferred embodiments of the present invention will be described in more detail below using examples, but the present invention is not limited to the following examples.

<Synthesis example>

According to the method described in the examples of International Publication No. 2005/066214, a hyaluronic acid derivative (the compound shown in formula (1)) was synthesized (a: 0.18, n: 2,000, mass-average molecular weight of hyaluronic acid: 800,000).

More specifically, it is synthesized using the following method.

2.155 g (10.5 mmol) of 2-bromoethylamine hydrobromide was dissolved in 20 mL of dichloromethane. Under ice-cold conditions, 1.463 mL (10.5 mmol) of triethylamine was added, followed by 5 mL of a dichloromethane solution containing 2.299 g (10.5 mmol) of di-tert-butyl dicarbonate ( _Boc₂O ). The mixture was stirred. After stirring at room temperature for 90 minutes, ethyl acetate was added, and the mixture was washed sequentially with 5% wt% citric acid aqueous solution, water, and saturated brine. After dehydration with sodium sulfate, the solvent was removed by vacuum distillation to obtain Boc-aminoethyl bromide.

The above-obtained Boc-aminoethyl bromide solution (2.287 g, 10.2 mmol) in 5 mL of dimethylformamide (DMF) was chilled, and then 3.255 g (10.2 mmol) of diclofenac sodium in 6 mL of DMF solution was added. The mixture was stirred overnight at room temperature. The mixture was then stirred at 60 °C for 11 hours and then overnight at room temperature. Ethyl acetate was added, and the mixture was washed sequentially with 5% (w/w) sodium bicarbonate aqueous solution, water, and saturated brine. After dehydration with sodium sulfate, the ethyl acetate was removed by vacuum distillation. The residue was purified by silica gel column chromatography (toluene:ethyl acetate = 20:1 (v/v), 0.5% (v/v) triethylamine) to obtain Boc-aminoethanol-diclofenac.

2.108 g (4.80 mmol) of Boc-aminoethanol-diclofenac obtained above was dissolved in 5 mL of dichloromethane. 20 mL of 4M hydrochloric acid/ethyl acetate was added under ice-cold conditions, and the mixture was stirred for 2.5 hours. Diethyl ether and hexane were added to precipitate the product, and the precipitate was dried under reduced pressure. This yielded aminoethanol-diclofenac acid salt. The structure was identified using ^1H -NMR.

¹ H-NMR (500MHz, CDCl ₃ ) δ (ppm) = 3.18 (2H, t, NH ₂ CH ₂ CH ₂ O-), 3.94 (2H, s, Ph-CH ₂ -CO), 4.37 (2H, t, NH ₂ CH ₂ CH ₂ O-), 6.47-7.31 (8H, m, Aromatic H, NH).

500 mg of hyaluronic acid (1.25 mmol/disaccharide unit) with a mass-average molecular weight of 800,000 was dissolved in 56.3 mL of water and 56.3 mL of dioxane. Then, hydroxysuccinimide (1 mmol)/0.5 mL of water, water-soluble carbodiimide hydrochloride (WSCI·HCl) (0.5 mmol)/0.5 mL of water, and the aforementioned aminoethanol-diclofenac acid salt (0.5 mmol)/(water:dioxane = 1:1 (v/v), 5 mL) were added sequentially, and the mixture was stirred for 24 hours. 7.5 mL of 5% sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was stirred for approximately 4 hours. After neutralization with 215 μL of 50% (v/v) acetic acid aqueous solution, 2.5 g of sodium chloride was added and the mixture was stirred. Add 400 mL of ethanol to precipitate the precipitate. The precipitate was washed twice with 85% (v/v) ethanol aqueous solution, twice with ethanol, and twice with diethyl ether. The precipitate was then dried under reduced pressure overnight at room temperature to obtain the hyaluronic acid derivative (sodium salt) (the compound shown in formula (1)). The diclofenac concentration was measured to be 18 mol% using a spectrophotometer.

Furthermore, based on the aforementioned synthesis example, a dried product of a hyaluronic acid derivative (sodium salt) with an infusion rate of 18 mol% was prepared.

<Preparation of Test Samples>

Preparation of phosphate buffer

A phosphate buffer was prepared by mixing a 75 mM sodium dihydrogen phosphate aqueous solution and a 75 mM disodium hydrogen phosphate aqueous solution at a volume ratio of 17:11. The pH of the prepared phosphate buffer was 6.5.

Preparation of citrate buffer

A citrate buffer solution was prepared by mixing a 15 mM citric acid aqueous solution and a 15 mM trisodium citrate aqueous solution at a volume ratio of 27:37. The pH of the prepared citrate buffer solution was 5.1.

Preparation of acetate buffer

Acetic acid buffer was prepared by mixing a 15 mM aqueous solution of acetic acid and a 15 mM aqueous solution of sodium acetate at a volume ratio of 1:3. The pH of the prepared acetate buffer was 5.1. Additionally, an acetate buffer with a pH of 5.1 was prepared using the same method at a concentration of 45 mM acetic acid.

Preparation of 1.5 wt% hyaluronic acid derivative solution

A 1.5 g hyaluronic acid derivative solution was prepared by mixing 1.5 g of the above-synthesized hyaluronic acid derivative with 98.5 g of the various buffer solutions prepared above and stirring in a 70°C hot water bath for 2 hours.

Preparation of aqueous solutions with various added ingredients

For the aqueous solutions of additives used in the hyaluronic acid derivative solution, various additives and WFI are prepared in such a way that they are each three times the final concentration (wt%).

• Preparation of test samples

2.0 g of the 1.5 wt% hyaluronic acid derivative solution prepared above was mixed with 1.0 g of the aforementioned aqueous solution of the additive to prepare the test sample (final concentration of hyaluronic acid derivative: 1.0 wt%). In addition, 1.0 g of WFI was mixed instead of the 1.0 g aqueous solution of the additive to prepare a control solution that did not contain the aforementioned additive.

Example 1: Effect of Added Components on the Accumulation of Diclofenac

The test samples prepared above, containing various buffer solutions (50 mM phosphate buffer, 10 mM citrate buffer, 10 mM acetate buffer, or 30 mM acetate buffer), are used for preservation testing.

After storing the test samples in a constant temperature bath at 60℃ for one week, the accumulation of diclofenac and diclofenac lactam was determined by HPLC.

For the amounts of diclofenac and diclofenac lactam, the relative values of the amounts of diclofenac and diclofenac lactam in the control solution (1 wt% hyaluronic acid derivative solution) stored at 60°C for 1 week were calculated, with the values set to 1.

The more specific steps for preserving the experiment are as follows.

<Preservation Experiment>

Various experimental samples were prepared and packed into threaded vials (AS ONE, Cat No.: 3-1599-01) and allowed to stand at 60°C for one week. The amounts of diclofenac and diclofenac lactam in the solution after standing were quantitatively analyzed by HPLC.

The HPLC conditions are as follows.

Column: TSGgel ODS-100Z (4.6mm×150mm)

Flow rate: 1 mL/min

Temperature: 35℃

Gradient: Acetonitrile (B) / 20mM Sodium Phosphate (A)

B concentration (mL/min)

0.40 (0 minutes) - 0.80 (30 minutes)

0.80 (33 minutes) - 0.40 (35 minutes)

The elution times of diclofenac and diclofenac lactam were determined in advance using standard substances.

It should be noted that storing at 60℃ for one week is equivalent to storing at 25℃ for one year.

(1-1) Preservation test using 50 mM phosphate buffer (pH 6.5)

As additives, the following were used: L-arginine hydrochloride (final concentration in the test sample: 3 wt%), L-methionine, L-lysine hydrochloride (3 wt%), α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, allyloxy-1,2-propanediol, sodium edetate (3 wt%), glycine, diglycerides, sodium thioglycolate (3 wt%), tetrakis(4-carboxyphenyl)porphyrin (1.5 wt%), nicotinamide, butylated hydroxyanisole, phlorizin hydrate (1.5 wt%), benzyl alcohol, boric acid, polyvinyl alcohol (1.5 wt%), D-erythrolide, D-glucuronide, PEG200, PEG4000, sodium isoascorbate (3 wt%), and glycerin. Additives not listed in the final concentration were used at 5 wt%.

<Results>

When L-arginine hydrochloride, L-methionine, L-lysine hydrochloride, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, allyloxy-1,2-propanediol, sodium edetate, glycine, diglyceride, sodium thioglycolate, tetrakis(4-carboxyphenyl)porphyrin, nicotinamide, butylated hydroxyanisole, phlorizin hydrate, benzyl alcohol, boric acid, and polyvinyl alcohol were used as additives, the amount of diclofenac lactam (relative value) exceeded 1. That is, compared with the control without additives, an increased amount of diclofenac lactam was observed, promoting diclofenac lactam formation. When these additives were used, except for the example of butylated hydroxyanisole, the amount of diclofenac (relative value) exceeded 1. In the case of butylated hydroxyanisole, the amount of diclofenac (relative value) was 0.99, and almost no effect on diclofenac formation was observed as an additive.

On the other hand, when D-erythrolide, D-glucuronide, PEG200, PEG4000, sodium isoascorbate, and glycerin were used as additives, the amount of diclofenac lactam (relative value) was less than 1. That is, compared with the control group without additives, the amount of diclofenac lactam formation was reduced, and the formation of diclofenac lactam was inhibited (Table 1).

Since the formation of diclofenac lactam, which is practically inactive as a COX-2 inhibitor, is inhibited, it has been determined that D-erythrolide, D-glucuronide, PEG200, PEG4000, sodium isoascorbate, and glycerol can inhibit the accumulation of diclofenac lactam. Furthermore, among these, it is known that D-erythrolide and sodium isoascorbate, with a diclofenac concentration (relative value) below 1, also inhibit diclofenac accumulation.

[Table 1]

*Lac amount; relative value of diclofenac lactam amount

**Dic amount; relative value of diclofenac amount**

(1-2) Preservation test using 10 mM citrate buffer (pH 5.1)

As additives, creatine (1 wt%), sodium deoxycholate (5 wt%), 1,2,3-butanetriol (5 wt%), PEG400 (6.3 wt% or 16.5 wt%), PEG600 (10 wt%), PEG4000 (10 wt%), PEG6000 (10 wt%), SDS (5 wt%), Triton X-100 (5 wt%), ethanol (26 wt%), octyl glucoside (5 wt%), glucuronide (0.1 wt%), chlorogenic acid (0.1 wt%), propylene glycol (10 wt%), polysorbate 20 (5 wt%), and polyvinylpyrrolidone (5 wt%) are used.

Similarly, as additives, two-component systems of PEG3350 (10.6 wt%) and polysorbate 80 (3 wt%), and PEG3350 (6.0 wt%) and hydroxypropyl-β-cyclodextrin (10 wt%), or three-component systems of PEG3350 (5.5 wt%), polysorbate 80 (1 wt%) and hydroxypropyl-β-cyclodextrin (10 wt%) were used.

<Results>

When creatine and sodium deoxycholate were used as additives, the relative amount of diclofenac lactam exceeded 1. That is, compared to the control group without additives, an increased amount of diclofenac lactam was observed, promoting its formation. When these additives were used, the relative amount of diclofenac also exceeded 1.

On the other hand, when 1,2,3-butanetriol, PEG400, PEG600, PEG4000, PEG6000, SDS, Triton X-100, ethanol, octyl glucoside, glucuronide, chlorogenic acid, propylene glycol, polysorbate 20, and polyvinylpyrrolidone were used as additives, the amount of diclofenac lactam (relative value) was less than 1. That is, compared with the control without additives, the amount of diclofenac lactam formation was reduced, inhibiting the formation of diclofenac lactam (Table 2). Table 2 also shows the properties of the solution after storage. The solution was mostly colorless and clear, and even when colored, it was only slightly yellow, and even when not clear, it was only slightly turbid. In addition, when the above two-component or three-component systems were used, the amount of diclofenac lactam (relative value) and the amount of diclofenac (relative value) were both less than 1. In addition, the solutions of these two-component and three-component systems are all colorless and clear (Table 3).

Since the formation of diclofenac lactam, which is practically inactive as a COX-2 inhibitor, is inhibited, 1,2,3-butanetriol, PEG400, PEG600, PEG4000, PEG6000, SDS, Triton X-100, ethanol, octyl glucoside, glucuronide, chlorogenic acid, propylene glycol, polysorbate 20, and polyvinylpyrrolidone can be used as inhibitors of diclofenac lactam accumulation. Furthermore, when these are used, the relative amount of diclofenac is less than 1, indicating that they also inhibit diclofenac accumulation.

[Table 2]

*Lac amount; relative value of diclofenac lactam amount

**Dic amount; relative value of diclofenac amount**

[Table 3]

*Lac amount; relative value of diclofenac lactam amount

**Dic amount; relative value of diclofenac amount**

(1-3) Preservation tests using 30 mM acetate buffer (pH 5.1)

As additives, propyl gallate (1.5 wt%), lactic anhydride (1.5 wt%), hydroxypropyl cellulose (1.5 wt%), starch (1.5 wt%), dextran (5 wt%), sucrose (5 wt%), sodium saccharin dihydrate (5 wt%), glycine (5 wt%), sodium aspartate (1.5 wt%), L-leucine (1.5 wt%), L-phenylalanine (5 wt%), L-serine (5 wt%), D-mannitol (1.5 wt%), D-sorbitol (5 wt%), hydroxypropyl-β-cyclodextrin (3 wt%, 5 wt%, 10 wt%, or 15 wt%), and ethanol (5 wt%, 10 wt%, 20 wt%, or 26.3 wt%) are used.

<Results>

When propyl gallate, lactic anhydride, hydroxypropyl cellulose, starch, dextran, sucrose, sodium saccharin dihydrate, glycine, sodium aspartate, L-leucine, L-phenylalanine, L-serine, D-mannitol, and D-sorbitol were used as additives, the relative amount of diclofenac lactam exceeded 1. That is, compared with the control group without additives, an increased amount of diclofenac lactam was observed, promoting diclofenac lactam formation. When these additives were used, the relative amount of diclofenac also exceeded 1.

On the other hand, when hydroxypropyl-β-cyclodextrin (HP-β-CD) and ethanol were used as additives, the amount of diclofenac lactam (relative value) was less than 1. That is, compared with the control without additives, a reduction in the accumulation of diclofenac lactam was observed, inhibiting the accumulation of diclofenac lactam (Table 4).

Since hydroxypropyl-β-cyclodextrin and ethanol can be used as inhibitors of diclofenac lactam accumulation because they inhibit the formation of virtually inactive diclofenac lactam as COX-2 inhibitors, their effects on diclofenac lactam accumulation have been confirmed. Furthermore, the relative amount of diclofenac used was less than 1, indicating that they also inhibit diclofenac accumulation.

[Table 4]

*Lac amount; relative value of diclofenac lactam amount

**Dic amount; relative value of diclofenac amount**

(1-4) Preservation tests using 10 mM acetate buffer (pH 5.1)

As additives, hydroxyethyl-β-cyclodextrin (5 wt%), PEG400 (7.5 wt%), PEG4000 (5 wt% or 15 wt%), ethanol (10 wt%), octyl glucoside (5 wt%), polysorbate 80 (5 wt% or 10 wt%), and polyvinylpyrrolidone (5 wt%) are used.

<Results>

When hydroxyethyl-β-cyclodextrin (HP-β-CD), PEG400, PEG4000, ethanol, octyl glucoside, polysorbate 80, and polyvinylpyrrolidone were used as additives, the amount of diclofenac lactam (relative value) was less than 1. That is, compared with the control group without additives, a reduction in the accumulation of diclofenac lactam was observed, inhibiting the accumulation of diclofenac lactam (Table 5).

Since the formation of diclofenac lactam, which is practically inactive as a COX-2 inhibitor, was inhibited, it was determined that hydroxypropyl-β-cyclodextrin, PEG400, PEG4000, ethanol, octyl glucoside, polysorbate 80, and polyvinylpyrrolidone can be used as accumulation inhibitors of diclofenac lactam. Furthermore, when these were used, the relative amount of diclofenac was less than 1, indicating that they also inhibited the accumulation of diclofenac.

[Table 5]

*Lac amount; relative value of diclofenac lactam amount

**Dic amount; relative value of diclofenac amount**

<Conclusion>

This embodiment confirms that polysorbate 20, polysorbate 80, Triton X-100, octyl glucoside, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, ethanol, glycerol, 1,2,3-butanetriol, D-glucuronide, PEG200, PEG400, PEG600, PEG4000, PEG6000, D-erythrolide, sodium isoascorbate, glucuronide, polyvinylpyrrolidone, chlorogenic acid, SDS, and propylene glycol have the effect of inhibiting the accumulation of diclofenac lactam.

Therefore, nonionic surfactants such as polysorbate 20, polysorbate 80, Triton X-100, and octyl glucoside; hydroxyalkylated cyclodextrins such as hydroxyethyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin; _C1 - _C3 monohydric alcohols such as ethanol; _C2 - _C3 dihydric alcohols such as propylene glycol; _C3 - _C6 trihydric alcohols such as glycerol, 1,2,3-butanetriol, and D-glucuronide; polyalkylene glycols such as PEG200, PEG400, PEG600, PEG4000, and PEG6000; γ-lactones such as D-erythrolide, sodium isoascorbate, and glucuronide; polyvinylpyrrolidone; chlorogenic acids such as chlorogenic acid; and alkyl sulfates such as SDS can be used as inhibitors of the formation of diclofenac lactam from hyaluronic acid derivatives; in addition, they can be used as inhibitors of the accumulation of diclofenac lactam in pharmaceutical compositions containing hyaluronic acid derivatives. In addition, the same applies to their pharmaceutically permissible salts.

Example 2 Evaluation of the filterability of the aqueous composition

The filtration of aqueous compositions containing hyaluronic acid derivatives was investigated for hydroxypropyl-β-cyclodextrin (HP-β-CD), ethanol, PEG400, and PEG4000.

<Preparation of Test Samples>

Preparation of 1.5 wt% hyaluronic acid derivative solution

The hyaluronic acid derivative prepared above was mixed with the 15 mM acetate buffer (pH 5.1) prepared above, stirred, and allowed to stand to defoam, thereby preparing a 1.5 wt% hyaluronic acid derivative solution.

• Preparation of test samples

150.0 g of the 1.5 wt% hyaluronic acid derivative solution prepared above was mixed with 75.0 g of the aqueous solution of the additive to prepare the test sample (final concentration of hyaluronic acid derivative: 1.0 wt%).

In addition, a control solution was prepared by mixing 75.0 g of WFI instead of the aqueous solution of the added component.

<Test methods for filtration>

200 mL of the test sample prepared above was added to a stainless steel pressure filter holder fitted with a 0.22 μm pore size polyvinylidene fluoride (PVDF) membrane (47 mm diameter, effective filtration area: 13.8 ^cm² , manufactured by Merck). The filter was pressurized at 0.6 MPa at 70 °C. The volume of liquid passing through the filter was measured every 30 seconds, and the maximum throughput ( _Vmax ) was calculated based on the relationship between elapsed time and total filtration volume.

<Results>

With the addition of ingredients, the maximum throughput (V _max ) was confirmed to be above 1.0 g/ ^cm² (Table 6). In particular, the maximum throughput (V _max ) for PEG400 was high.

[Table 6]

<Conclusion>

If filtration is stopped before the flow rate reaches 1/10 of the initial value, the filter cannot be used effectively. If it is continued, the filtration time becomes longer, which is not optimal in terms of operational efficiency. The V90 value, calculated by multiplying the _Vmax value by 0.68 (assuming a 68% reduction in filter capacity at the point where the flow rate reaches 1/10 of the initial value), represents the throughput up to the point where the flow rate reaches 1/10 of the initial flow rate. In evaluating the filtration capacity, the V90 value is known to be empirically optimal (see, if necessary, Kobayashi Kimihiko, "Selection and Optimization Method of _Vmax Test Filters," Bioprocess Technical Sheet Basic Technology No. 2, Millipore Japan, August 1997). Water-based compositions with a maximum throughput ( _Vmax ) of 1.0 g/ ^cm² or higher, due to their high V90 value, can be considered to have excellent filterability. That is, such water-based compositions are less prone to clogging during filtration, reducing the frequency of filter replacement and cleaning, making them suitable for large-scale industrial production. Therefore, even when provided in the form of a pharmaceutical composition, heat sterilization is not required. Thus, it can be provided in the form of a composition in which the accumulation of diclofenac components, particularly the accumulation of diclofenac lactam, is inhibited.

Example 3 Preparation of the pharmaceutical composition

Component (A) is used together with a hyaluronic acid derivative in the preparation of a pharmaceutical composition. As an example, the preparation of an injectable pharmaceutical composition comprising a hyaluronic acid derivative, PEG400, and citrate buffer is shown.

(Step 1) Dissolve the specified amounts of citric acid hydrate, disodium citrate hydrate, and PEG400 in WFI.

(Step 2) Dissolve a specified amount of hyaluronic acid derivative (18 mol% hyaluronic acid content) in the solution from Step 1. Furthermore, heat the dissolved solution to 70°C and degas under reduced pressure.

(Step 3) Sterilize the solution from Step 2 by filtering it with a filter with a pore size of 0.22 μm.

(Step 4) Heat the solution from Step 3 at 70°C to degas it, and then cool it to 10°C.

(Step 5) Fill the syringe with the specified amount under sterilization conditions.

Through the above steps (1) to (5), a sterile pharmaceutical composition comprising a hyaluronic acid derivative, PEG400, and citrate buffer can be prepared. Examples of the concentrations of each component include the hyaluronic acid derivative: 0.5–5 w/v%, PEG400: 3–30 w/v%, and citrate buffer: 3–30 mM (calculated as citric acid). However, the concentrations of the various components in the pharmaceutical composition are not limited to the aforementioned ranges.

Industrial availability

The present invention provides, for example, a composition with excellent stability in which the accumulation of the physiologically inactive component diclofenac lactam is inhibited, and a composition that has a significant improving effect on joint diseases in human patients (especially patients with chronic joint diseases), and therefore has industrial applicability in the pharmaceutical industry and the like.

This invention has been described in connection with specific embodiments and various implementations, but most modifications and applications of the embodiments described herein will be readily understood by those skilled in the art without departing from the spirit and scope of the invention.

This application claims priority based on Japan Patent Application No. 2018-215867 filed with the Japan Patent Office on November 16, 2018, the contents of which are incorporated herein by reference in their entirety.

Claims (43)

1. An aqueous composition comprising the compound shown in (1) below and a filterability improver, wherein the maximum throughput _Vmax is 1.0 g/ ^cm² or more. The filterability improver is selected from the group consisting of polyethylene glycol, ethanol, hydroxyalkylated cyclodextrin and their salts, wherein the maximum throughput _Vmax is defined as follows: the aqueous composition at 70°C is filtered using a polyvinylidene fluoride filter membrane with a pore size of 0.22 μm under a pressure of 0.6 MPa, and the total filtration rate per unit effective filtration area is measured every 30 seconds until the flow rate is less than 1/10 of the initial flow rate. The measured value obtained therefrom is then applied to the values derived in the following formulas A and B: Formula A: t/V = at + b Formula B: _{V_max} = 1/a In formulas A and B above, t is the filtration time in minutes, V is the total filtration capacity per unit effective filtration area in g/ ^cm² , a is the slope of formula A, and b is the intercept of formula A. In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group. 2. The aqueous composition according to claim 1, wherein the relative amount of diclofenac lactam, measured under the following conditions, is 0.9 or less: The test composition containing the compound shown in formula (1) and the filterability improver, and the control composition having the same composition as above except that it does not contain the filterability improver, were stored in a constant temperature bath at 60°C for 1 week. Then, the amount of diclofenac lactam accumulated in the test composition and the control composition was determined by high performance liquid chromatography. The relative amount of diclofenac lactam accumulated in the test composition when the amount of diclofenac lactam accumulated in the control composition was set to 1 was calculated. 3. The aqueous composition according to claim 1, wherein the relative amount of diclofenac is less than 1 under the following conditions: The test composition containing the compound shown in formula (1) and the filterability improver, and the control composition having the same composition as above except that it does not contain the filterability improver, were stored in a constant temperature bath at 60°C for 1 week. Then, the amount of diclofenac accumulated in the test composition and the control composition was determined by high performance liquid chromatography, and the relative amount of diclofenac accumulated in the test composition when the amount of diclofenac accumulated in the control composition was set to 1 was calculated. 4. The aqueous composition according to any one of claims 1 to 3, used for the treatment of joint diseases. 5. The aqueous composition according to any one of claims 1 to 3, wherein the compound shown in formula (1) is contained at a concentration of more than 0.01 w/v% and less than 80 w/v%. 6. A kit comprising a syringe into which the aqueous composition of any one of claims 1 to 5 is filled. 7. A kit comprising a vial and a syringe, said vial comprising the aqueous composition according to any one of claims 1 to 5. 8. Use of the aqueous composition according to any one of claims 1 to 5 in the manufacture of a treatment for human joint diseases. 9. A pharmaceutical composition comprising a compound and ingredient (A) as shown in formula (1): Ingredient (A): at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts. In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group. 10. The pharmaceutical composition according to claim 9, wherein the component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols. 11. The pharmaceutical composition according to claim 9 or 10, wherein the polyalkylene glycol is polyethylene glycol. 12. The pharmaceutical composition according to claim 11, wherein the polyethylene glycol has a weight-average molecular weight of 200 or more and 6000 or less. 13. The pharmaceutical composition according to claim 9 or 10, wherein the final concentration of component (A) is 0.01 to 30 wt%. 14. The pharmaceutical composition according to claim 9 or 10, further comprising a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer. 15. The pharmaceutical composition according to claim 9 or 10, wherein the pH is 4.5 to 7.0. 16. The pharmaceutical composition according to claim 9 or 10, wherein it is an aqueous composition. 17. The pharmaceutical composition according to claim 9 or 10, wherein it is a pharmaceutical composition for the treatment of joint diseases. 18. The pharmaceutical composition according to claim 17, wherein the joint disease is osteoarthritis or rheumatoid arthritis. 19. A kit comprising a syringe into which the pharmaceutical composition of any one of claims 9 to 18 is filled. 20. A kit comprising a vial and a syringe, said vial comprising the pharmaceutical composition according to any one of claims 9 to 18. 21. A method for manufacturing a pharmaceutical composition comprising a compound of formula (1), the method comprising a step of coexisting the compound of formula (1) with component (A): Ingredient (A): at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts. In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group. 22. The method according to claim 21, wherein the component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols. 23. The method according to claim 21 or 22, wherein the polyalkylene glycol is polyethylene glycol. 24. The method according to claim 23, wherein the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less. 25. The method according to claim 21 or 22, wherein the component (A) is added at a final concentration of 0.01 to 30 wt%. 26. The method according to claim 21 or 22, wherein the compound and/or component (A) represented by formula (1) comprises a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer. 27. The method according to claim 21 or 22, wherein the pH of the pharmaceutical composition is 4.5 to 7.0. 28. The method according to claim 21 or 22, wherein the pharmaceutical composition is an aqueous composition. 29. A method for inhibiting the formation of diclofenac lactam from a compound represented by formula (1), comprising a step of coexisting the compound represented by formula (1) with component (A): Ingredient (A): at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts. In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group. 30. The method according to claim 29, wherein the component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols. 31. The method according to claim 29 or 30, wherein the polyalkylene glycol is polyethylene glycol. 32. The method according to claim 31, wherein the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less. 33. The method according to claim 29 or 30, wherein the component (A) is added at a final concentration of 0.01 to 30 wt%. 34. The method according to claim 29 or 30, wherein the compound represented by formula (1) and/or the component (A) comprises a buffer selected from the group consisting of phosphate buffer, citrate buffer and acetate buffer. 35. The method according to claim 29 or 30, wherein the process is carried out in a pH range of 4.5 to 7.0. 36. The method according to claim 29 or 30, wherein the compound represented by formula (1) is coexisted with the component (A) in an aqueous solvent. 37. The use of the compound represented by formula (1) in the manufacture of a treatment agent for human joint diseases, said treatment agent containing an effective amount of the compound represented by formula (1) and component (A), said component (A) being at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts. In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group. 38. The application according to claim 37, wherein the component (A) is selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols and polyalkylene glycols. 39. The application according to claim 37 or 38, wherein the polyalkylene glycol is polyethylene glycol. 40. The application according to claim 39, wherein the weight-average molecular weight of polyethylene glycol is 200 or more and 6000 or less. 41. The application according to claim 37 or 38, wherein the concentration of component (A) in the joint disease treatment agent is 0.01 to 30 wt%. 42. The application according to claim 37 or 38, wherein the joint disease is osteoarthritis or rheumatoid arthritis. 43. An aqueous composition comprising a compound of formula (1) coexisting with a component that inhibits the accumulation and/or formation of diclofenac, wherein the component inhibiting the accumulation and/or formation of diclofenac is at least one compound selected from the group consisting of nonionic surfactants, hydroxyalkylated cyclodextrins, _C1 - _C3 monohydric alcohols, _C2 - _C3 dihydric alcohols, _C3 - _C6 trihydric alcohols, polyalkylene glycols, γ-lactones, polyvinylpyrrolidone, chlorogenic acids and alkyl sulfates, and their salts, wherein the relative amount of diclofenac lactam after storage in a constant temperature bath at 60°C for 1 week is 0.9 or less, wherein the relative amount is a value of: a control composition containing the same aqueous composition except for the component that inhibits the accumulation and/or formation of diclofenac, stored under the same conditions, with the amount of diclofenac lactam accumulated in the control composition set to 1. In formula (1), a is greater than or equal to 0.01 and less than or equal to 0.7, a+b is 1, n is an integer greater than or equal to 25 and less than or equal to 25000, and the arrangement of each disaccharide structural unit can be randomly or block-shaped. In each disaccharide structural unit, R is independently a carboxyl group or a carboxylate group.