JP2023095656A - oral ointment - Google Patents

Abstract

An object of the present invention is to provide an oral ointment in which a non-steroidal anti-inflammatory agent has low elution into saliva and has high mucosal permeability.
The composition contains gelling hydrocarbon, hydroxypropylmethylcellulose having a 2% aqueous solution viscosity of 50 mPa·s or more and 20000 mPa·s or less at 20°C, and a non-steroidal anti-inflammatory agent, and contains crystalline cellulose. is 15% by mass or less.
[Selection figure] None

Description

The present invention relates to an oral ointment.

Oral ointments for the prevention and treatment of periodontitis, stomatitis, toothache, and the like are conventionally known.
US Pat. No. 5,300,000 discloses oral semi-solid formulations containing hydroxypropylmethylcellulose and polyacrylic acid.

Patent Document 2 discloses a mucosal ointment containing a mucoadhesive polymer, a sugar alcohol, and an oleaginous base that does not contain a salt of carboxymethylcellulose or sodium polyacrylate.

JP 2013-234173 A WO2014/050852

By the way, the above-mentioned oral ointment is required to remain in the affected area for a longer period of time, have an active ingredient that is less likely to be eluted into saliva in the oral cavity, and easily permeate the oral mucosa and gingival tissues.

An oral ointment for solving the above problems contains a gelling hydrocarbon, hydroxypropyl methylcellulose having a 2% aqueous solution viscosity of 50 mPa·s or more and 20000 mPa·s or less at 20° C., and a non-steroidal anti-inflammatory agent. The gist is that the content of crystalline cellulose is 15% by mass or less.

In the oral ointment, it is preferable that the 2% aqueous solution viscosity of the hydroxypropylmethylcellulose at 20°C is 3000 mPa·s or more and 5000 mPa·s or less.

The oral ointment preferably contains the crystalline cellulose at a ratio of 1% by mass or more and 15% by mass or less.
The oral ointment preferably contains polyethylene glycol and a surfactant.

The above oral ointment preferably does not substantially contain sodium polyacrylate.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to obtain an oral ointment in which a non-steroidal anti-inflammatory agent has low elution into saliva and high mucous membrane permeability.

It is a graph which shows a dissolution test result. It is a graph which shows a test result of a mucosal permeability.

An embodiment embodying the oral ointment according to the present invention will be described.
The oral ointment of this embodiment contains a gelling hydrocarbon, hydroxypropyl methylcellulose having a 2% aqueous solution viscosity of 50 mPa·s or more and 20000 mPa·s or less at 20° C., and a non-steroidal anti-inflammatory agent. Moreover, the content of crystalline cellulose is 15% by mass or less.

By containing the above components, the oral ointment can reduce the dissolution of the non-steroidal anti-inflammatory agent, which is an active ingredient, into saliva and increase its permeability to mucous membranes.

Each component constituting the oral ointment will be described below.
<Gelling hydrocarbon>
A gelled hydrocarbon is obtained by gelling a hydrocarbon, and is used as an oil-based base material. Specific examples of hydrocarbons include liquid paraffin, paraffin, isoparaffin, squalane, squalene, and polybutene. Examples of the gelled hydrocarbon include those obtained by gelling the above hydrocarbon with a polyethylene resin or the like and semi-solidifying it. In the present invention, commercially available products such as Hicol Gel (trade name) manufactured by Kaneda Corporation and Plastibase (registered trademark) manufactured by Contract Pharmaceutical Limited Canada can be used as the gelled hydrocarbon.

The content of the gelling hydrocarbon in the oral ointment is not particularly limited, but is preferably about 30 to 90% by mass. The upper or lower limit of the range is, for example, 72, 74, 76, 78, 80, 82, 84, 86, or 88% by weight. For example, the range may be 40-60% by weight.

<Hydroxypropyl methylcellulose>
Hydroxypropylmethylcellulose is a cellulose ether obtained by introducing a hydroxypropyl group into methylcellulose, and is used as a water-soluble thickening agent. In the present invention, a commercially available product such as METOLOSE (registered trademark) manufactured by Shin-Etsu Chemical Co., Ltd. can be used as hydroxypropylmethylcellulose.

Hydroxypropyl methylcellulose has a 2% aqueous solution viscosity at 20° C. of 50 mPa·s or more and 20000 mPa·s or less. Although the viscosity of the 2% aqueous solution at 20°C is not particularly limited, it is preferably about 100 to 10,000 mPa·s. The upper or lower limit of the range is, for example, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, or 9500 mPa s may be For example, the range may be 2000-6000 mPa·s.

The 2% aqueous solution viscosity at 20°C is measured by the following method.
(i) Method 1: Applied to hydroxypropylmethyl cellulose with a display viscosity of less than 600 mPa·s. Accurately weigh an amount corresponding to 4.0 g of dried hydroxypropyl methylcellulose into a wide-mouthed bottle, add hot water (90 to 99 ° C.) to make 200.0 g, cover the container, and use a stirrer to homogenize. Stir at 350-450 revolutions per minute for 10-20 minutes until a dispersion is formed. If necessary, the sample adhering to the wall of the container is scraped off, added to the dispersion, and then dissolved in a water bath at 10°C or less for 20 to 40 minutes with stirring. If necessary, add cold water to make 200.0 g. If bubbles are found in the solution or on the liquid surface, remove them by centrifugation, etc., and use them as the sample solution. The viscosity is measured at 20±0.1° C. for the sample solution.

(ii) Method 2: Applied to hydroxypropylmethyl cellulose with a display viscosity of 600 mPa·s or more. Accurately weigh an amount corresponding to 10.0 g of dried hydroxypropyl methylcellulose into a wide-mouthed bottle, add hot water (90 to 99 ° C.) to make 500.0 g, and then operate in the same manner as in Method 1 above to obtain a sample solution. do. The viscosity is measured at 20±0.1° C. for the sample solution.

Measurement method: Brookfield viscometer LV model is used. For display viscosities of 600 mPa·s or more and less than 1400 mPa·s, cylinder No. 3 is used, rotation speed is 60 times/min, and conversion multiplier is 20. For display viscosities of 1400 mPa·s or more and less than 3500 mPa·s, cylinder number 3 is used, rotation speed is 12 times/min, and conversion multiplier is 100. For display viscosities of 3500 mPa·s or more and less than 9500 mPa·s, cylinder No. 4 is used, rotation speed is 60 times/min, and conversion multiplier is 100. For the display viscosity of 9500 mPa·s or more and less than 99500 mPa·s, cylinder No. 4 is used, and measurement is performed at a rotation speed of 6 times/minute and a conversion multiplier of 1000. For indicated viscosities of 99,500 mPa·s or more, cylinder No. 4 is used, and measurement is performed at a rotation speed of 3 times/minute and a conversion multiplier of 2,000. When measuring, start the device and let it rotate for 2 minutes, read the viscometer reading, and stop for at least 2 minutes. The same operation is repeated twice, and the three measurements are averaged.

The content of hydroxypropylmethylcellulose in the oral ointment is not particularly limited, but is preferably about 8 to 22% by mass. The upper or lower limit of the range may be, for example, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21% by mass. For example, the range may be 10-16% by weight.

<Crystalline cellulose>
Crystalline cellulose is obtained by subjecting plant pulp fibers to acid hydrolysis or alkali hydrolysis to extract and refine the crystalline regions of cellulose.

The content of crystalline cellulose in the oral ointment is 15% by mass or less. The upper or lower limit of the range may be, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14% by weight. For example, the range may be 2-7% by weight.

When the content of crystalline cellulose is within the above numerical range, the mucosal permeability of the active ingredient in the oral ointment can be increased while the salivary elution of the active ingredient in the oral ointment is reduced.
<Non-steroidal anti-inflammatory agent>
Non-steroidal anti-inflammatory drugs are anti-inflammatory drugs not derived from glucocorticoids and are also called NSAIDs. Preferably, the non-steroidal anti-inflammatory agent is water soluble. Water-soluble non-steroidal anti-inflammatory drugs are also called water-soluble NSAIDs.

Specific examples of non-steroidal anti-inflammatory agents include aspirin, actarit, acemethacin, ampiroxicam, amphenac, ibuprofen, indomethacin, etodolac, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib, tiaprofenic acid, tiaramide hydrochloride, tenoxicam, naproxen, piroxicam, felbinac, pranoprofen, flurbiprofen, mefenamic acid, medicoxib, meloxicam, mofezolac, lefecoxib, loxoprofen, lobenzarit, lornoxicam, and salts thereof.

Among these, diclofenac salts or loxoprofen salts, which are water-soluble NSAIDs, more specifically diclofenac sodium or loxoprofen sodium hydrate, are preferred. Water-soluble NSAIDs other than these can also be blended.

Non-steroidal anti-inflammatory agents may be used singly or in combination of two or more. In the following, non-steroidal anti-inflammatory agents are also simply referred to as active ingredients. Commercially available non-steroidal anti-inflammatory agents can also be used.

The content of the nonsteroidal anti-inflammatory agent in the oral ointment is not particularly limited, but is preferably about 0.01 to 10% by mass. The upper or lower limit of the range is, for example, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7. 0, 7.5, 8.0, 8.5, 9.0, or 9.5% by weight. For example, the range may be 0.05-2.0% by weight.

The oral ointment preferably contains polyethylene glycol and a surfactant. The inclusion of polyethylene glycol and a surfactant in the oral ointment can improve the dispersibility of the gelling hydrocarbon and the non-steroidal anti-inflammatory agent in the oral ointment.

<Polyethylene glycol>
Polyethylene glycol is not particularly limited, and known polyethylene glycol can be used. The polyethylene glycol is preferably polyethylene glycol that is liquid at 40° C., and preferably has an average molecular weight of about 200 to 1,500. The upper or lower limit of the range may be, for example, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, or 1400. For example, the range may be 300-600.

The content of polyethylene glycol in the oral ointment is not particularly limited, but is preferably about 1 to 20% by mass. The upper or lower limit of the range is, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19% by mass. may For example, the range may be 2-8% by weight.

<Surfactant>
Specific examples of surfactants include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants.

(Nonionic surfactant)
Specific examples of nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters and maltose fatty acid esters, sugar alcohol fatty acid esters such as maltitol fatty acid esters, sorbitans such as sorbitan monolaurate and sorbitan sesquioleate. Fatty acid esters, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitan monostearate, fatty acid alkanolamides such as lauric acid diethanolamide, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, etc. Polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters such as polyethylene glycol monooleate and polyethylene glycol monolaurate, alkyl glycosides such as lauryl glycoside and decyl glycoside, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene fatty acid esters .

(Anionic surfactant)
Specific examples of anionic surfactants include sulfuric acid ester salts such as sodium lauryl sulfate and sodium polyoxyethylene lauryl ether sulfate, polyoxyethylene alkyl ether phosphate/phosphate, sodium polyoxyethylene cetyl ether phosphate, sulfosuccinates such as sodium lauryl sulfosuccinate and sodium polyoxyethylene lauryl ether sulfosuccinate; acyl amino acid salts such as sodium cocoyl sarcosinate and sodium lauroyl methyl alanine; and sodium cocoyl methyl taurate.

(Cationic surfactant)
Specific examples of cationic surfactants include quaternary alkylammonium salts such as cetyltrimethylammonium chloride, cetylpyridinium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, stearyltrimethylammonium chloride, and gluconic acid. chlorhexidine and the like.

(Amphoteric surfactant)
Specific examples of amphoteric surfactants include amino acid-type amphoteric surfactants such as N-lauryldiaminoethylglycine and N-myristyldiethylglycine, betaine alkyldimethylaminoacetate, N-alkyl-N'-carboxymethyl-N' -hydroxyethylethylenediamine salts, and betaine amphoteric surfactants such as 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine.

One of the above surfactants may be used alone, or two or more thereof may be used in combination. Among the above surfactants, it is preferable to contain a nonionic surfactant.

Among the above surfactants, the HLB value, which indicates the degree of affinity between water and oil, is preferably 3 or more and 15 or less, more preferably 3.5 or more and 13 or less, and 4 or more and 11 or less. Some are even more preferred.

Examples of surfactants having an HLB value within the above numerical range include sorbitan sesquioleate (HLB: 4.0), PEG-20 hydrogenated castor oil (HLB: 10.5), and PEG-40 hydrogenated castor oil. (HLB: 12.5), PEG-60 hydrogenated castor oil (HLB: 14.0), sodium polyoxyethylene cetyl ether phosphate (HLB: 10.0) and the like.

The content of the surfactant in the oral ointment is not particularly limited, but is preferably about 0.1 to 10% by mass. The upper or lower limit of the range is, for example, 0.4, 0.7, 1.0, 1.3, 1.6, 1.9, 2.2, 2.5, 2.8, 3.1, 3.4, 3.7, 4.0, 4.3, 4.6, 4.9, 5.2, 5.5, 5.8, 6.1, 6.4, 6.7, 7. 0, 7.3, 7.6, 7.9, 8.2, 8.5, 8.8, 9.1, 9.4, or 9.7% by mass. For example, the range may be 0.4-2.5% by weight.

The oral ointment is preferably substantially free of sodium polyacrylate. Also, the oral ointment preferably does not substantially contain hydroxyethylcellulose. Here, "substantially not contained" means to allow the mode of containing at an impurity level.

Since sodium polyacrylate is a highly water-absorbent polymer, if it is contained in an oral ointment, it may deprive the oral cavity of moisture and cause discomfort to the user. In addition, as will be described later, hydroxyethyl cellulose does not easily gel by reacting with water in the oral cavity, so that the active ingredient is less likely to be eluted from the oral ointment, and there is a risk of low mucosal permeability.

<Other ingredients>
The oral ointment may contain other ingredients other than those mentioned above, such as bactericidal agents, antibacterial agents, flavors, sweeteners, coloring agents, stabilizers, etc., depending on the application purpose, form, use, and the like. As these ingredients, known ingredients that are blended in oral ointments can be used. These components may be used singly or in combination of two or more.

Specific examples of bactericides include cetylpyridinium chloride hydrate and hinokitiol.
Specific examples of antibacterial agents include parabens, sodium benzoate, triclosan, chlorhexidine hydrochloride, chlorhexidine gluconate, minocycline hydrochloride, isopropylmethylphenol, benzalkonium chloride, and benzethonium chloride. Flavors may be natural or synthetic. Further, it may be a single perfume or a mixed perfume.

Specific examples of perfumes include l-menthol, d-carvone, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineole, Linalool, ethyl linalool, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, d-camphor, d-borneol, Fennel oil, cinnamon oil, cinnamaldehyde, peppermint oil, vanillin and the like.

Specific examples of sweeteners include saccharin, saccharin sodium, sucralose, stevioside, acesulfame potassium, aspartame, xylitol, maltitol, erythritol, cycloheptaamylose, sorbitol (also referred to as sorbitol solution), and palatinit (also referred to as reduced palatinose). etc.

Specific examples of the coloring agent include legal dyes such as Green No. 1, Blue No. 1 and Yellow No. 4, and titanium oxide.
Specific examples of stabilizers include sodium edetate, sodium thiosulfate, sodium sulfite, calcium lactate, lanolin, triacetin, castor oil, magnesium sulfate and the like.

<Application form and use of oral ointment>
The application form of the oral ointment is not particularly limited, and can be used as, for example, pharmaceuticals, quasi-drugs, and cosmetics. Applications of the oral ointment include, for example, an intraoral application agent including the tongue, a gingival anti-inflammatory agent, a periodontal disease treatment agent, a denture attachment agent, an implant care agent, and the like.

The content of water in the oral ointment is preferably 3% by mass or less, more preferably 1% by mass or less, even more preferably 0.5% by mass or less, and most preferably substantially free of water.

<Action and effect>
The action of the oral ointment of this embodiment will be described.
Since the oral ointment contains a gelatinized hydrocarbon, which is an oil-based base, as a main ingredient, it is possible to prevent the oral ointment itself from dissolving in water such as saliva in a short period of time. In addition, by containing hydroxypropylmethylcellulose, which is a water-soluble thickener that has not reacted with water, saliva can react with hydroxypropylmethylcellulose to form a gel-like film. This gel-like film allows the oral ointment to adhere to the oral mucosa and gingival tissue, and through this gel-like film, the active ingredient is eluted into the oral mucosa, gingival tissue, and saliva, which are the outside of the preparation, and the oral mucosa. and permeation of the active ingredient into the gingival tissue. This trend is particularly noticeable with water-soluble active ingredients (NSAIDs). In other words, ideally, the active ingredient should not be eluted in saliva, and should only be permeated through the oral mucosa and gingival tissues. Become. Here, if the viscosity of hydroxypropyl methylcellulose is too low, the surface of the oral ointment will be difficult to gel, so that the elution of the active ingredient in saliva will be suppressed, but the retention of the oral ointment will be poor and the active ingredient will not be absorbed. The mucosal permeability may become too low. If the viscosity of hydroxypropyl methylcellulose is too high, a strong gel-like film is formed on the surface of the oral ointment, resulting in excessive salivary dissolution of the active ingredient and low mucosal permeability of the active ingredient. There is fear. In this embodiment, a gel-like film can be selectively formed on the surface of the oral ointment by setting the viscosity of hydroxypropylmethylcellulose within a predetermined range. Therefore, the salivary dissolution of the active ingredient in the oral ointment can be suitably low, and the mucosal permeability of the active ingredient can be suitably increased.

In addition, crystalline cellulose is a material that is relatively difficult to dissolve in water or oil. Therefore, when the content of crystalline cellulose in the oral ointment is 15% by mass or less, the dissolution of the active ingredient in the oral ointment into saliva can be suitably reduced. Along with this, the mucosal permeability of the non-steroidal anti-inflammatory agent can be increased.

The effect of the oral ointment of this embodiment will be described.
(1) It contains a gelling hydrocarbon, hydroxypropylmethylcellulose having a 2% aqueous solution viscosity of 50 mPa·s or more and 20000 mPa·s or less at 20° C., and a non-steroidal anti-inflammatory agent. The content of crystalline cellulose is 15% by mass or less.

Therefore, the oral ointment can be retained in the affected area for a longer period of time, the active ingredient is less likely to be eluted into saliva in the oral cavity, and can be easily permeated through the oral mucosa and gingival tissue.
(2) The 2% aqueous solution viscosity of hydroxypropylmethylcellulose at 20°C is 3000 mPa·s or more and 5000 mPa·s or less. Therefore, the oral ointment can be retained in the affected area for a longer period of time, the active ingredient is less likely to be eluted into saliva in the oral cavity, and can be easily permeated through the oral mucosa and gingival tissue.

(3) It contains crystalline cellulose at a ratio of 1% by mass or more and 15% by mass or less. Therefore, the dissolution property of the oral ointment can be suitably lowered. In addition, the mucosal permeability of non-steroidal anti-inflammatory agents can be increased.

(4) Contains polyethylene glycol and a surfactant. Therefore, the dispersibility of the non-steroidal anti-inflammatory agent in the oral ointment can be improved.
(5) It does not substantially contain sodium polyacrylate. Therefore, it is possible to suppress discomfort caused by sodium polyacrylate depriving the oral cavity of moisture.

(6) Since hydroxypropylmethylcellulose is a water-soluble thickening agent, the gel-like film formed on the surface of the oral ointment can adhere the oral ointment to the oral mucosa and gum tissue. Through this gel-like film, the active ingredient is eluted into the oral mucosa, gingival tissue, and saliva, which are outside the formulation, and the active ingredient permeates through the oral mucosa and gingival tissue.

Examples will be given below in order to make the configuration and effects of the present invention more specific, but the present invention is not limited to these examples.
(Gelling performance evaluation test)
First, hydroxypropyl methylcellulose (hereinafter also referred to as HPMC), sodium polyacrylate, hydroxyethyl cellulose (hereinafter also referred to as HEC), Eudragit (registered trademark), and sodium alginate were prepared as water-soluble thickeners. Samples of Test Examples 1 to 5 were prepared by mixing with gelled hydrocarbons so that the content of the water-soluble thickener was 15% by mass.

Next, about 0.5 g of each sample was applied onto a metal disk made of a circular metal plate. Specifically, the metal disk is disk-shaped with a diameter of 40 mm and a thickness of 5 mm, and has a circular concave portion with a diameter of 30 mm and a depth of 0.5 mm on one side. About 0.5 g of each sample was loaded into each recess of the metal disc. About 0.5 mL of water was dropped onto each sample and left for 20 minutes. After that, water was removed from the sample, and the surface condition of the sample was visually observed. Also, about 0.5 g of each sample was taken on a finger and applied to the gums to evaluate the stickiness of the sample surface.

Gelability was evaluated according to the following evaluation criteria. Table 1 shows the results.
Evaluation Criteria for Gelling Performance ◯ (Possible): The surface of the sample is sufficiently gelled, has good shape retention, and is less sticky.

x (improper): the gelation of the sample surface was insufficient and the shape retention was poor, but the sample was less sticky.
XX (bad): The gelation of the surface of the sample is insufficient and the shape retention is poor. The surface of the sample is also sticky.

表１より、ヒドロキシプロピルメチルセルロースは、他の水溶性増粘剤に比べてゲル化性能に優れていることが確認された。

From Table 1, it was confirmed that hydroxypropylmethylcellulose is superior in gelation performance to other water-soluble thickeners.

The oral ointments of Examples 1 to 5 and Comparative Examples 1 to 3 shown in Table 2 were produced by mixing each component according to a conventional method. The mixing order of each component is not particularly limited, but polyethylene glycol and the non-steroidal anti-inflammatory agent are preferably mixed in advance. Also, when mixing the non-steroidal anti-inflammatory agent and the gelling hydrocarbon, it is preferable to mix the surfactant together. In Table 2, the number on the right side of each component means the content (% by mass) of each component, and the total amount was 100% by mass.

表２に示すように、ゲル化炭化水素は、市販品を使用した。ＨＰＭＣは、表示粘度（２０℃における２％水溶液粘度）が、４、１００、４０００、１５０００ｍＰａ・ｓである市販品を使用した。結晶性セルロースは、市販品を使用した。ポリエチレングリコールは、平均分子量が約４００である市販品を使用した。界面活性剤は、市販のＰＥＧ－６０水添ヒマシ油を使用した。非ステロイド系抗炎症剤は、市販の水溶性のＮＳＡＩＤｓであるジクロフェナクナトリウムを使用した。

As shown in Table 2, commercial products were used as gelling hydrocarbons. HPMC used was a commercial product having a display viscosity (2% aqueous solution viscosity at 20° C.) of 4, 100, 4000 and 15000 mPa·s. A commercially available crystalline cellulose was used. A commercially available polyethylene glycol having an average molecular weight of about 400 was used. Commercially available PEG-60 hydrogenated castor oil was used as the surfactant. As the non-steroidal anti-inflammatory agent, diclofenac sodium, which is a commercially available water-soluble NSAID, was used.

(Evaluation test)
The oral ointments of Examples 1 to 5 and Comparative Examples 1 to 3 were evaluated for dissolution of the oral ointments and mucosal permeability of the active ingredient. Evaluation methods and evaluation results are shown below.

(Dissolution of active ingredient in oral ointment)
Dissolution was evaluated using a dissolution tester (DT-810) manufactured by JASCO Corporation.
A metal disk identical to that used in the gelling performance evaluation was prepared. About 0.5 g of the oral ointment of each example and comparative example was filled into the concave portion of the metal disc.

As a test liquid, 500 mL of ultrapure water was prepared. After putting the test liquid into the vessel of the dissolution tester, a metal disk was submerged in the vessel. While the circular bath of the dissolution tester was kept at 37° C., the paddle was rotated at 100 rpm to stir the inside of the vessel.

The test solution in the vessel was sampled every time a predetermined time had passed since the start of the test. In addition, a calibration curve was prepared by measuring the absorbance of a calibration curve sample in advance. The amount of the non-steroidal anti-inflammatory agent in the sampled test solution was determined by converting from the calibration curve. The amount of non-steroidal anti-inflammatory agent eluted in the test solution relative to the content of the non-steroidal anti-inflammatory agent in the oral ointment of each example and comparative example was defined as the elution rate (%), and the dissolution property was evaluated. In addition, for comparison, dissolution was also evaluated using an aqueous gel. The aqueous gel is composed of 0.5% by mass of diclofenac sodium, 1.5% by mass of sodium polyacrylate, 20% by mass of concentrated glycerin, 15% by mass of PEG400, and 63% by mass of purified water. The results are shown in Table 2 and FIG. Table 2 shows the dissolution rate after 90 minutes from the start of the test.

(Mucous membrane permeability of active ingredient)
An artificial membrane for membrane permeability evaluation manufactured by Eko Seiki Co., Ltd. was prepared. This artificial membrane was pre-wet with phosphate buffered saline (also referred to as PBS), and then mounted on the receptor layer side of the vertical diffusion cell. After applying 100 μL of the oral ointment of each Example and Comparative Example onto the artificial membrane, the diffusion cell was filled with PBS. Receptor fluid that permeated the artificial membrane was collected at predetermined time intervals. Concentrations of non-steroidal anti-inflammatory agents in receptor fluid were quantified using high performance liquid chromatography. Mucosal permeability was evaluated using the permeation amount (μg/min) of the non-steroidal anti-inflammatory drug versus elapsed time. The results are shown in Table 2 and FIG. Table 2 shows the cumulative amount of permeation through the mucous membrane after 120 minutes. Comparative Example 1 was not evaluated for mucosal permeability.

(Evaluation results)
From FIG. 1, the dissolution rate of the water-based gel exceeds 80% 10 minutes after the start of the test, confirming that the dissolution of the active ingredient in the oral ointment is too high. In Comparative Examples 1 to 3, the dissolution rate was as low as 40% or less even after 90 minutes, confirming that the dissolution was too low. Furthermore, as shown in FIG. 2, in Comparative Examples 2 and 3, it was confirmed that the mucosal permeability was also low.

On the other hand, in Examples 1 to 5, as shown in FIG. 1, the dissolution rate 10 minutes after the start of the test was suppressed to a low level of 40% or less, and then gradually increased to reach the dissolution rate after 90 minutes. was over 60%. Further, from Table 2 and FIG. 2, it was confirmed that in Examples 1 to 5, the mucosal permeation amount after 120 minutes was 0.04 μg/min or more, indicating high mucosal permeability. Therefore, it was confirmed that the non-steroidal anti-inflammatory agent can preferably permeate the oral mucosa and gingival tissue while remaining in the affected area for a longer period of time. In addition, it was confirmed that Example 2 containing 5% by mass of crystalline cellulose had lower dissolution and higher mucosal permeability than Example 1 containing no crystalline cellulose. .

Formulation examples of the present invention are shown in Table 3 below.
In Table 3, the numerical value described on the right side of each component means the content (% by mass), which is 100% by mass when combined with the gelled hydrocarbon.

Claims (5)

A gelling hydrocarbon, hydroxypropyl methylcellulose having a 2% aqueous solution viscosity at 20°C of 50 mPa s or more and 20000 mPa s or less, and a non-steroidal anti-inflammatory agent,
An oral ointment characterized by containing 15% by mass or less of crystalline cellulose. The oral ointment according to claim 1, wherein the 2% aqueous solution viscosity of the hydroxypropylmethylcellulose at 20°C is 3000 mPa·s or more and 5000 mPa·s or less. The oral ointment according to claim 1 or 2, containing the crystalline cellulose at a ratio of 1% by mass or more and 15% by mass or less. The oral ointment according to any one of claims 1 to 3, which contains polyethylene glycol and a surfactant. The oral ointment according to any one of claims 1 to 4, which does not substantially contain sodium polyacrylate.

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