Ointment containing diclofenac sodium and oleic acid

Abstract

The present inventors primarily aimed to provide an ointment containing diclofenac sodium in which the formation of diclofenac analogs is suppressed. [Solution] The above problem can be solved by an ointment containing diclofenac sodium and oleic acid, wherein the oleic acid content is below a predetermined concentration.

Description

Technical Field

[0003]

[0001] The present disclosure relates to an ointment containing diclofenac sodium and oleic acid, and a method for suppressing the generation of diclofenac analogs in the ointment containing diclofenac sodium and oleic acid, etc.

Background Art

[0002] Diclofenac and its salts are classified as non-steroidal anti-inflammatory drugs (NSAIDs) and are widely used mainly for antipyretic and analgesic purposes. However, it is known that the salts of diclofenac have relatively poor stability in pharmaceutical preparations. For example, Patent Document 1 describes that in a patch containing a pharmaceutically acceptable salt of diclofenac (specifically, diclofenac sodium), a diclofenac indolinone form, which is one of the decomposition products of diclofenac, is generated. In Patent Document 1, a patch containing diclofenac free acid has been studied to suppress the generation of the diclofenac indolinone form, and it is described that a patch containing diclofenac free acid and oleic acid in a predetermined mass ratio can suppress the generation of the diclofenac indolinone form more effectively than a patch containing diclofenac sodium.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] Patent Document 1 describes how the formation of diclofenac indrinone is suppressed by using diclofenac free acid. However, in at least among diclofenac and its salts, only diclofenac sodium is permitted for use in approved drugs in Japan. In other words, since no formulations containing diclofenac free acid have been marketed in Japan, it is preferable to use diclofenac sodium rather than diclofenac free acid from the standpoint of usage history and safety. Furthermore, diclofenac sodium is more soluble in water than diclofenac free acid, making it easier to handle during manufacturing.

[0005] In view of the above circumstances, the present inventor's main objective was to provide an ointment containing diclofenac sodium in which the formation of diclofenac analogs is suppressed. More specifically, the main objective was to provide an ointment containing diclofenac sodium in which the formation of at least one diclofenac analog selected from the group consisting of diclofenac alcohol, diclofenacaldehyde, 9H-carbazole-1-acetic acid, and 8-chloro-9H-carbazole-1-acetic acid is suppressed. [Means for solving the problem]

[0006] The inventors have discovered that in an ointment containing diclofenac sodium and oleic acid, where the oleic acid content is below a predetermined concentration, the formation of diclofenac analogs may be suppressed. Further improvements have led to the completion of this disclosure.

[0007] This disclosure includes, for example, the following subjects: Section 1. It contains diclofenac sodium and oleic acid, An ointment for use on the oral mucosa, having an oleic acid content of 1.4% by mass or less. Section 2. The ointment according to item 1, wherein the oleic acid content is 0.2 to 8 parts by mass per 1 part by mass of diclofenac sodium. Section 3. An ointment according to item 1 or 2, wherein the diclofenac sodium content is 0.1 to 1.5% by mass. Section 4. An ointment according to any of items 1 to 3, which substantially contains no water. Section 5. An ointment according to any one of items 1 to 4, for use in relieving pain and / or reducing inflammation in the oral cavity caused by the wearing of dentures and / or orthodontic appliances. Section 6. A method for suppressing the formation of diclofenac analogs in an ointment containing diclofenac sodium and oleic acid, The diclofenac analog is 2-(2',6'-dichloroanilino)benzyl alcohol and / or 2-(2',6'-dichloroanilino)benzaldehyde, The process includes a step of mixing diclofenac sodium and oleic acid, A method wherein the oleic acid content in the ointment is 1.4% by mass or less. Section 7. The method according to claim 6, wherein the ointment substantially contains no water. [Effects of the Invention]

[0008] According to this disclosure, an ointment containing diclofenac sodium in which the formation of diclofenac analogs is suppressed may be provided.

[0009] In addition, Patent Document 1 describes a method for suppressing the formation of diclofenacindinone (1-(2',6'-dichlorophenyl)-2-indolinone) in a transdermal patch. However, in addition to diclofenacindinone, 2-(2',6'-dichloroanilino)benzyl alcohol (sometimes referred to as "diclofenac alcohol" or simply "alcohol" in this disclosure) and 2-(2',6'-dichloroanilino)benzaldehyde (sometimes referred to as "diclofenac aldehyde" or simply "aldehyde" in this disclosure) are also known as the main decomposition products of diclofenac or its salts. In ointments included in this disclosure, the formation of not only diclofenacindinone but also diclofenac alcohol and / or diclofenac aldehyde can be suppressed. [Brief explanation of the drawing]

[0010] [Figure 1] Test 1: The quantitative results for diclofenac quindindrinone are shown. The vertical axis represents the amount of diclofenac degradation product (diclofenac quindindrinone) produced (%), and the horizontal axis represents the amount of oleic acid added (g). [Figure 2] Test 1: The quantitative results for diclofenac alcohol and diclofenac aldehyde are shown. The vertical axis represents the amount (%) of diclofenac degradation products (diclofenac alcohol or diclofenac aldehyde) produced, and the horizontal axis represents the amount of oleic acid added (g). [Figure 3] Test 2: The quantitative results for diclofenac quindindrinone are shown. The vertical axis represents the amount (%) of diclofenac degradation products (diclofenac quindindrinone), and the horizontal axis represents the storage period (months). [Figure 4] Test 2: The quantitative results for diclofenac alcohol are shown. The vertical axis represents the amount of diclofenac degradation product (diclofenac alcohol) produced (%), and the horizontal axis represents the storage period (months). [Figure 5] Test 2: The quantitative results for diclofenacaldehyde are shown. The vertical axis represents the amount (%) of diclofenac degradation products (diclofenacaldehyde) produced, and the horizontal axis represents the storage period (months). [Figure 6]Test 3: The quantitative results of 9H-carbazole-1-acetic acid (photodegradation product 1) and 8-chloro-9H-carbazole-1-acetic acid (photodegradation product 2) are shown.

Modes for Carrying Out the Invention

[0011] Hereinafter, each embodiment included in the present disclosure will be described in more detail. The present disclosure preferably includes an ointment containing diclofenac sodium and oleic acid, and a method for suppressing the formation of diclofenac analogs in the ointment containing diclofenac sodium and oleic acid, etc., but is not limited thereto, and the present disclosure includes all that are disclosed herein and can be recognized by those skilled in the art.

[0012] 1. The ointment of the present disclosure The ointment included in the present disclosure contains diclofenac sodium and oleic acid, and the content of oleic acid is 1.4% by mass or less. Hereinafter, the said ointment included in the present disclosure may be referred to as "the ointment of the present disclosure".

[0013] The structural formula of diclofenac sodium is shown below.

Chem.

[0014] The structural formula of oleic acid is shown below.

Chem.

[0015] The amount of diclofenac sodium contained in the ointment of this disclosure is not particularly limited as long as the desired effect is obtained, and may be, for example, 0.05 to 5% by mass. The upper or lower limit of the range may be 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, or 5% by mass. The amount of diclofenac sodium contained in the ointment of this disclosure is preferably 0.05 to 2% by mass, more preferably 0.1 to 1.5% by mass, even more preferably 0.15 to 1.2% by mass, and particularly preferably 0.2 to 1% by mass.

[0016] The amount of oleic acid contained in the ointment of this disclosure is 1.4% by mass or less. The lower limit of the amount of oleic acid contained in the ointment of this disclosure is not particularly limited and may be, for example, 0.1% by mass or more. That is, the amount of oleic acid contained in the ointment of this disclosure may be, for example, 0.1 to 1.4% by mass. The upper or lower limit of the above range may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, or 1.4% by mass. The amount of oleic acid contained in the ointment of this disclosure is preferably 0.2 to 1.3% by mass, more preferably 0.3 to 1.2% by mass, even more preferably 0.4 to 1.1% by mass, and particularly preferably 0.5 to 1% by mass.

[0017] As shown in the examples described later, if the amount of oleic acid contained in the ointment is 1.4% by mass or less, the generation of diclofenac degradation products (particularly diclofenac alcohol and / or diclofenacaldehyde) can be effectively suppressed. Furthermore, the presence of oleic acid in the ointment can effectively suppress the generation of diclofenac photodegradation products (specifically, 9H-carbazole-1-acetic acid and / or 8-chloro-9H-carbazole-1-acetic acid). Therefore, the ointment of this disclosure having an oleic acid content within the above range is preferred from the viewpoint of effectively suppressing the generation of diclofenac alcohol and diclofenacaldehyde, as well as diclofenac photodegradation products.

[0018] In the ointment of this disclosure, the amount of oleic acid per 1 part by mass of diclofenac sodium is not particularly limited as long as the desired effect is obtained. The ointment of this disclosure may contain, for example, 0.1 to 14 parts by mass of oleic acid per 1 part by mass of diclofenac sodium. The upper or lower limit of the above range may be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 parts by mass. The ointment of this disclosure preferably contains 0.2 to 10 parts by mass or 0.2 to 8 parts by mass of oleic acid per 1 part by mass of diclofenac sodium, more preferably 0.5 to 8 parts by mass, even more preferably 0.8 to 7 parts by mass, and particularly preferably 1 to 5 parts by mass.

[0019] While not particularly limited, the ointment of this disclosure preferably contains 5% by mass or less of water, more preferably 2% by mass or less, even more preferably 1% by mass or less, and is particularly preferred to contain substantially no water.

[0020] Furthermore, "substantially water-free" means that water is not used as a raw material in the preparation of the ointment according to this disclosure. However, since some raw materials contain a very small amount of water, an ointment prepared using such raw materials may contain a very small amount of water derived from those raw materials. Such an ointment containing a very small amount of water derived from the raw materials is included in the category of "substantially water-free ointment." More specifically, if water derived from the raw materials is contained in the ointment, its content is more than 0% by mass and about 0.5% by mass or less, and more preferably more than 0% by mass and about 0.4% by mass or less.

[0021] Furthermore, although not particularly limited, it is preferable that the ointment of this disclosure substantially does not contain free diclofenac acid. Substantially free of free diclofenac acid means that free diclofenac acid is not used as a raw material in the preparation of the ointment of this disclosure.

[0022] In addition to diclofenac sodium and oleic acid, the ointment of this disclosure may further contain any other components that the ointment may contain, such as surfactants, oils other than oleic acid, flavoring agents, sweeteners, humectants, binders, preservatives, colorants, pH adjusters, chelating agents, and pharmaceutically active ingredients other than diclofenac sodium, either individually or in combination of two or more.

[0023] Examples of surfactants include anionic surfactants such as polyoxyethylene alkyl ether sulfate, alkyl sulfate ester, alkyl amide ether sulfate, polyoxyethylene alkyl amide ether sulfate, α-olefin sulfonate, alkyl sulfosuccinate, polyoxyethylene alkyl ether acetate, alkyl phosphate, polyoxyethylene alkyl ether phosphate, higher fatty acid salt, N-acyl amino acid salt, N-acyl isethionate, and N-acyl methyl taurate; Cationic surfactants such as quaternary ammonium salts; Amphoteric surfactants such as amidopropyl betaine type, amidoamine oxide type, sulfobetaine type, imidazoline type, and alkylbetaine type; Examples of nonionic surfactants include polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbitan fatty acid esters, polyoxyalkylene sorbitan fatty acid esters, polyoxyalkylene glycerin fatty acid esters, polyoxyalkylene fatty acid amides, polyoxyalkylene glycol fatty acid esters, polyoxyalkylene castor oil derivatives, polyoxyalkylene hydrogenated castor oil derivatives, polyglycerin fatty acid esters, sorbitan fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, alkyl glycol fatty acid esters, alkyl polyglycosides, fatty acid alkanolamides, and others. Surfactants can be contained individually or in combination of two or more. When a surfactant has a polyoxyalkylene chain, the polyoxyalkylene chain is preferably a polyoxyethylene chain or a polyoxypropylene chain.

[0024] While not particularly limited, the ointments of this disclosure preferably contain polyoxyethylene hydrogenated castor oil. The average number of moles of ethylene oxide added to the polyoxyethylene hydrogenated castor oil may be, for example, about 5 to 120, preferably 10 to 80, more preferably 15 to 60, and even more preferably 15 to 40.

[0025] Furthermore, although not particularly limited, the ointment of this disclosure preferably contains polyoxyethylene alkyl ether phosphate, and more preferably contains polyoxyethylene cetyl ether sodium phosphate. From the viewpoint of formulation stability, the ointment of this disclosure is particularly preferable to contain polyoxyethylene hydrogenated castor oil and polyoxyethylene cetyl ether sodium phosphate.

[0026] Examples of oils other than oleic acid include vegetable oils, triglycerides, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, and silicone oils. These oils can be used individually or in combination of two or more.

[0027] Examples of flavoring agents include menthol, carvone, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronenyl acetate, methyl eugenol, cineole, linalool, ethyl linalool, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, d-camphor, d-borneol, fennel oil, cinnamon oil, cinnamaldehyde, peppermint oil, and vanillin. Flavoring agents can be included individually or in combination of two or more.

[0028] Examples of sweeteners include sodium saccharin, potassium acesulfamethamate, stevia, stevioside, neohesperidyl dihydrochalcone, perillartin, thaumatin, aspartylphenylalanyl methyl ester, and p-methoxycinnamic aldehyde. Sweeteners may be included individually or in combination of two or more.

[0029] Examples of wetting agents include sorbitol, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, and polyoxyethylene glycol. The wetting agent may be included individually or in combination of two or more.

[0030] Examples of binders include cellulose derivatives such as sodium carboxymethylcellulose, carboxymethyl ethylcellulose salt, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, crystalline cellulose, and crystalline cellulose-carmellose sodium; microbially produced polymers such as xanthan gum; natural polymers or natural rubbers such as tragacanth gum, karaya gum, arabic gum, carrageenan, dextrin, agar, pectin, pullulan, gellan gum, locust bean gum, and sodium alginate; synthetic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl methyl ether, and sodium polyacrylate; inorganic binders such as thickening silica and bee gum; and cationic binders such as O-[2-hydroxy-3-(trimethylammonio)propyl]hydroxyethylcellulose chloride. Binders can be used individually or in combination of two or more.

[0031] Examples of preservatives include parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, as well as benzoic acid, sodium benzoate, phenoxyethanol, and alkyldiaminoethylglycine hydrochloride. Preservatives can be used individually or in combination of two or more.

[0032] Examples of colorants include legally approved pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3, mineral pigments such as ultramarine, enhanced ultramarine, and Prussian blue, and titanium dioxide. Colorants can be used individually or in combination of two or more.

[0033] Examples of pH adjusting agents include citric acid, phosphoric acid, malic acid, pyrophosphate, lactic acid, tartaric acid, glycerophosphate, acetic acid, nitric acid, or chemically possible salts thereof, or sodium hydroxide. The pH adjusting agent may be included individually or in combination of two or more. The pH adjusting agent content may be, for example, 0.01 to 2% by mass.

[0034] Examples of chelating agents include edetic acid, pentetic acid, metaphosphoric acid, gluconic acid, etidronic acid, and chemically possible salts thereof. Chelating agents can be included individually or in combination of two or more.

[0035] The ointment disclosed herein may also contain, as pharmaceutically active ingredients other than diclofenac sodium, amphoteric bactericides such as dodecyldiaminoethylglycine, nonionic bactericides such as triclosan, anionic bactericides such as isopropylmethylphenol and sodium lauroyl sarcosinate, cationic bactericides such as cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, and benzethonium chloride, enzymes such as dextranase, amylase, protease, mutanase, lysozyme, and lytic enzymes (Litec enzyme), sodium monofluorophosphate, potassium monofluorophosphate, etc. It may contain alkali metal monofluorophosphates, fluorides such as sodium fluoride and stannous fluoride, tranexamic acid, epsilon-aminocaproic acid, aluminum chlorohydroxyl allantoin, allantoin, dihydrocholesterol, glycyrrhetinic acid, glycyrrhizic acid, metal salts of glycyrrhizic acid, hinokitiol, copper chlorophyllin sodium, glycerophosphate, chlorophyll, sodium chloride, caropeptide, pyridoxine hydrochloride, carbazochrome, potassium nitrate, palatinite, etc., either individually or in combination of two or more.

[0036] The ointments of this disclosure can be prepared by conventionally known methods or by methods readily conceivable from conventionally known methods. Specifically, they can be prepared, for example, by mixing diclofenac sodium, oleic acid, and an optional component until homogeneous.

[0037] 2. Action and Effects of the Ointment Disclosure Salts of diclofenac, such as diclofenac sodium, are known to have relatively poor stability in pharmaceutical formulations. The main degradation products of diclofenac are known to be 1-(2',6'-dichlorophenyl)-2-indolinone (which may be referred to in this disclosure as "diclofenac indolinone" or simply "indolinone"), 2-(2',6'-dichloroanilino)benzyl alcohol (which may be referred to in this disclosure as "diclofenac alcohol" or simply "alcohol"), and 2-(2',6'-dichloroanilino)benzaldehyde (which may be referred to in this disclosure as "diclofenac aldehyde" or simply "aldehyde").

[0038] The structure of the diclofenacindinone compound is shown below. [ka] The structure of the diclofenac alcohol is shown below. [ka] The structure of the diclofenacaldehyde compound is shown below. [ka]

[0039] Furthermore, diclofenac or its salts are known to produce 9H-carbazole-1-acetic acid and / or 8-chloro-9H-carbazole-1-acetic acid upon photodegradation. In this disclosure, diclofenac indrinone, diclofenac alcohol, diclofenac aldehyde, 9H-carbazole-1-acetic acid, and 8-chloro-9H-carbazole-1-acetic acid may be collectively referred to as "diclofenac analogs."

[0040] The structure of 9H-carbazole-1-acetic acid is shown below. [ka] The structure of 8-chloro-9H-carbazole-1-acetic acid is shown below. [ka]

[0041] As shown in the examples described later, in the ointment of this disclosure containing diclofenac sodium and oleic acid, wherein the oleic acid content is below a predetermined concentration, the formation of diclofenac analogs can be suppressed. In other words, the ointment of this disclosure exhibits excellent stability of diclofenac sodium in the formulation. Specifically, in the ointment of this disclosure, the formation of at least one diclofenac analog selected from the group consisting of diclofenac alcohol, diclofenacaldehyde, 9H-carbazole-1-acetic acid, and 8-chloro-9H-carbazole-1-acetic acid can be suppressed. In the ointment of this disclosure, the formation of diclofenac alcohol and / or diclofenacaldehyde can be suppressed particularly effectively.

[0042] Furthermore, in the ointment of the present disclosure, both the generation of diclofenac degradation products and the generation of photodegradation products can be suppressed. Specifically, in the ointment of the present disclosure, the generation of diclofenac alcohol and / or diclofenacaldehyde, as well as the generation of 9H-carbazole-1-acetic acid and / or 8-chloro-9H-carbazole-1-acetic acid can be suppressed.

[0043] 3. Uses and Target Audience As described above, diclofenac and its salts are classified as non-steroidal anti-inflammatory drugs (NSAIDs) and are widely used primarily for antipyretic and analgesic purposes. The ointment of this disclosure containing diclofenac sodium can be used, for example, for analgesic and / or anti-inflammatory purposes. The application site of the ointment of this disclosure is not particularly limited and may be applied to the skin and / or mucous membranes, for example. The ointment of this disclosure is preferably applied to mucous membranes and particularly preferably applied to the oral cavity.

[0044] In a preferred embodiment, the ointment of the present disclosure can be used for analgesic and / or anti-inflammatory purposes for inflammation and / or periodontitis caused by physical irritation in the oral cavity. Specific examples of physical irritation in the oral cavity include, for example, irritation of the oral mucosa due to the wearing of dentures and / or orthodontic appliances, bites, tongue trauma, cheek trauma, etc. Specific examples of inflammation in the oral cavity include, for example, aphthous ulcers, mucositis, oral burns, inflammation caused by dentures, inflammation caused by orthodontic appliances, gingivitis, inflammation caused by oral surgery, temporomandibular joint disorders, Behcet's disease, mucositis caused by radiation therapy, postoperative gingivitis, traumatic stomatitis, etc.

[0045] The ointment of this disclosure may be applied to mammals, including humans (e.g., dogs, cats, mice, rats, sheep, horses, cattle, monkeys, etc.). It is particularly preferred to apply it to humans. More specifically, the target population of the ointment of this disclosure includes, for example, humans wearing dentures and / or orthodontic appliances, humans with inflammation of the oral mucosa and / or gingival tissue, and humans experiencing pain in the oral mucosa and / or gingival tissue.

[0046] 4. Method for suppressing the formation of diclofenac analogs This disclosure also includes a method for suppressing the formation of diclofenac analogs in an ointment containing diclofenac sodium and oleic acid, the method comprising the step of mixing diclofenac sodium and oleic acid, wherein the oleic acid content in the ointment is 1.4% by mass or less. The matters described in this disclosure concerning the ointment may be appropriately incorporated into the said method.

[0047] In this specification, the term “comprising” includes not only “containing” but also “essentially consisting of” and “consisting of.” Furthermore, this disclosure encompasses all combinations of the constituent elements described herein.

[0048] Furthermore, the various characteristics (properties, structure, numerical values, functions, etc.) described for each embodiment of this disclosure described above may be combined in any way to identify the subject matter covered by this disclosure. In other words, this disclosure covers all subject matter consisting of any combination of the combinable characteristics described herein. [Examples]

[0049] The embodiments of this disclosure will be described in more detail below with examples, but the embodiments of this disclosure are not limited to the examples below. Polyethylene glycol may be written as "PEG," and polyoxyethylene hydrogenated castor oil with an average number of ethylene oxide addition moles of X may be written as "HCO-X."

[0050] Test 1. Evaluation of the inhibitory effect on diclofenac sodium degradation (Evaluation in a simple system) Prior to evaluating the formulation (ointment), the inventors evaluated the amount of diclofenac degradation products produced in a simple system containing only components thought to contribute to the generation of diclofenac degradation products. Details are shown below.

[0051] 1-1. Materials and Methods 1-1-1. Sample In a simple system obtained by removing the base and powder components from the composition of an ointment containing diclofenac sodium, the oleic acid content was varied. The PEG content was adjusted in accordance with the increase or decrease in oleic acid. The concentration of each component (excluding PEG) in this simple system is equivalent to 10 times the concentration of each component in the ointment. In other words, the concentration in the formulation is equivalent to one-tenth of the concentration in the simple system.

[0052] Specifically, the samples were prepared by mixing each component according to the composition shown in the table below.

[0053] [Table 1]

[0054] 1-1-2. Determination of Diclofenac Degradation Products 1-1-2-1. Standard solution preparation Approximately 10 mg of dried diclofenac sodium for quantitative analysis was accurately weighed, and methanol was added to make exactly 100 mL. An accurate 2 mL of this solution was taken, and methanol was added to make exactly 20 mL. Another accurate 1 mL of this solution was taken, and a 50 v / v% methanol aqueous solution was added to make exactly 20 mL. The solution was filtered through a 0.2 μm aqueous filter and subjected to HPLC as a standard solution.

[0055] 1-1-2-2. Sample Solution Preparation After storing the sample under specified conditions, approximately 0.1 g was placed in a 20 mL volumetric flask, and a 50 v / v% methanol aqueous solution was added to make exactly 20 mL of the solution. This solution was then subjected to HPLC as the sample solution.

[0056] 1-1-2-3. HPLC conditions HPLC was performed on the standard solution and each sample solution under the following conditions. • Column: Core-shell type HPLC column • Detector: UV absorbance spectrophotometer (measurement wavelength: 254 nm)

[0057] 1-1-2-4. Calculation method From the obtained HPLC data, the amount (%) of each diclofenac degradation product was calculated using the following formula. Amount of each diclofenac degradation product produced (%) = (Sim / SD) × 100 (Here, Sim: Peak area of ​​each diclofenac degradation product in the sample solution, SD: This represents the peak area of ​​diclofenac sodium in the sample solution.

[0058] 1-2. Results After storing each prepared sample at 60°C for one week, each diclofenac degradation product was quantified. The quantification results for diclofenac indrinone are shown in Figure 1, and the quantification results for diclofenac alcohol and diclofenac aldehyde are shown in Figure 2, respectively.

[0059] As shown in Figure 1, a tendency was observed for the amount of diclofenac quindindrinone compound to increase with increasing oleic acid addition. On the other hand, the amount of diclofenac alcohol compound and diclofenac aldehyde compound to increase significantly when the amount of oleic acid added exceeded 1.5 g. In other words, it was suggested that the amount of diclofenac alcohol compound and diclofenac aldehyde compound to be suppressed by reducing the amount of oleic acid added to less than 1.5 g (equivalent to 1.5% by mass in the formulation).

[0060] Test 2. Evaluation of the inhibitory effect on the degradation of diclofenac sodium (Evaluation in the formulation) Next, the inventors evaluated the amount of diclofenac degradation products produced in the formulation (ointment). Details are shown below.

[0061] 2-1. Materials and Methods 2-1-1. Sample A sample (ointment) was prepared by mixing each component according to the composition shown in the table below. The values ​​in the table represent mass percent.

[0062] [Table 2]

[0063] 2-1-2. Determination of Diclofenac Degradation Products Standard solution preparation and HPLC conditions were carried out in the same manner as in 1-1-2.

[0064] 2-1-2-1. Sample Solution Preparation After storage under specified conditions, each sample was weighed and uniformly dispersed in methanol extraction solvent. The solution was then diluted to a diclofenac sodium concentration of 0.2 mg / mL (calculated from the amount of diclofenac sodium added during sample preparation) and centrifuged. 5 mL of the supernatant was taken, and water was added to make a total volume of 10 mL. This solution was filtered through a 0.2 μm aqueous filter and subjected to HPLC as the sample solution.

[0065] 2-1-2-2. Calculation method From the obtained HPLC data, the amount (%) of each diclofenac degradation product was calculated using the following formula.

[0066] Amount of each diclofenac degradation product produced (%) =(Sim / SD)×(WS / 1000) / (WT×C×0.01)×(2 / 100)×(1 / 20)×100 (Here, Sim: Peak area of ​​each diclofenac degradation product in the sample solution, SD: Peak area of ​​diclofenac sodium in standard solution. WS: Amount of diclofenac sodium collected for quantitative analysis (mg), WT: Sample volume (g) C: This is the concentration (%) of diclofenac sodium added to the formulation.

[0067] 2-2. Results Each prepared sample was stored at 40°C and 75% RH. Sampling was performed at 1 month, 2 months, and 3 months from the start of storage to quantify each diclofenac degradation product. The quantification results for diclofenac indrinone are shown in Figure 3, the quantification results for diclofenac alcohol are shown in Figure 4, and the quantification results for diclofenac aldehyde are shown in Figure 5.

[0068] As shown in Figures 3-5, the amount of diclofenac degradation products—diclofenac indindrinone, diclofenac alcohol, and diclofenac aldehyde—was lower in Examples 1-3 than in the comparative examples. In particular, the amount of diclofenac alcohol and diclofenac aldehyde produced was significantly lower in Examples 1-3 than in the comparative examples.

[0069] Test 3. Evaluation of the photodegradation inhibitory effect of diclofenac sodium. Next, the inventors evaluated the amount of 9H-carbazole-1-acetic acid (sometimes referred to as "photodecomposition product 1") and 8-chloro-9H-carbazole-1-acetic acid (sometimes referred to as "photodecomposition product 2") produced upon light irradiation in a simple system similar to that used in Test 1. Details are shown below.

[0070] 3-1. Materials and Methods 3-1-1. Sample Samples were prepared by mixing each component according to the composition shown in the table below.

[0071] [Table 3]

[0072] 3-1-2. Determination of diclofenac photodegradation products After storage under specified conditions, 9H-carbazole-1-acetic acid and 8-chloro-9H-carbazole-1-acetic acid were quantified according to the method described in 1-1-2.

[0073] 3-2. Results Each prepared sample was packed into a colorless, transparent glass container and stored at 25°C for one month under 10,000 lux of light irradiation. Afterward, 9H-carbazole-1-acetic acid and 8-chloro-9H-carbazole-1-acetic acid were quantified. The results are shown in Figure 6.

[0074] As shown in Figure 6, the amount of diclofenac photodegradation products of both 9H-carbazole-1-acetic acid and 8-chloro-9H-carbazole-1-acetic acid significantly decreased upon the addition of oleic acid.

[0075] Consideration The above tests suggest that in an ointment containing diclofenac sodium and oleic acid, with an oleic acid content below a predetermined concentration, the formation of at least one diclofenac analog selected from the group consisting of diclofenac alcohol, diclofenacaldehyde, 9H-carbazole-1-acetic acid, and 8-chloro-9H-carbazole-1-acetic acid can be suppressed, and in particular, the formation of diclofenac alcohol and / or diclofenacaldehyde can be suppressed.

[0076] Furthermore, it was suggested that in ointments containing diclofenac sodium and oleic acid, where the oleic acid content is below a predetermined concentration, both the generation of diclofenac degradation products and photodegradation products can be suppressed. More specifically, it was suggested that in ointments containing diclofenac sodium and oleic acid, where the oleic acid content is below a predetermined concentration, the generation of diclofenac alcohol and / or diclofenacaldehyde, as well as the generation of 9H-carbazole-1-acetic acid and / or 8-chloro-9H-carbazole-1-acetic acid, can be suppressed.

Claims

1. It contains diclofenac sodium and oleic acid, An ointment for use on the oral mucosa, having an oleic acid content of 1.4% by mass or less.

2. The ointment according to claim 1, wherein the content of oleic acid is 0.2 to 8 parts by mass per 1 part by mass of diclofenac sodium.

3. The ointment according to claim 1, wherein the content of diclofenac sodium is 0.1 to 1.5% by mass.

4. An ointment according to any one of claims 1 to 3, which is substantially free of water.

5. An ointment according to any one of claims 1 to 3, for use in relieving pain and / or reducing inflammation in the oral cavity caused by the wearing of dentures and / or orthodontic appliances.

6. A method for suppressing the formation of diclofenac analogs in an ointment containing diclofenac sodium and oleic acid, The diclofenac analog is 2-(2',6'-dichloroanilino)benzyl alcohol and / or 2-(2',6'-dichloroanilino)benzaldehyde, The process includes a step of mixing diclofenac sodium and oleic acid, A method wherein the oleic acid content in the ointment is 1.4% by mass or less.

7. The method according to claim 6, wherein the ointment substantially contains no water.

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