JP3331236B2 - Oral composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to an oral composition, more specifically, an arylpropionic acid non-steroidal anti-inflammatory agent.
The present invention relates to a composition for the oral cavity which is contained in a form having excellent oral mucosal permeability and low irritation in the oral cavity. The composition for oral cavity of the present invention is excellent in anti-inflammatory effect and also has an effect of suppressing alveolar bone absorption, and is useful for treatment and prevention of periodontal diseases such as gingivitis and periodontitis.

[0002]

2. Description of the Related Art Arylpropionic acid non-steroids have a strong anti-inflammatory effect, and have been conventionally applied to periodontal diseases such as periodontitis and gingivitis by mixing them in dentifrices and the like. JP-A-60-61524, JP-A-52-38030).

By the way, when such an arylpropionic acid non-steroidal anti-inflammatory drug (hereinafter sometimes simply referred to as a pharmacologic agent) is applied to the oral cavity, it is likely that the drug will be absorbed into the oral mucosa such as the gingiva and exert its effect. It is conceivable, however, that the conventional preparations described above have poor mucosal permeability of the medicinal agent, and thus have a problem in that the compounded medicinal agent has low mucosal absorbability and low availability in the body.

On the other hand, various external preparations containing glycols have been proposed for the purpose of improving the transdermal absorbability of arylpropionic acid-based non-steroidal anti-inflammatory drugs (JP-A-60-185712; These are external preparations, and did not provide sufficient mucosal permeability when applied to the oral cavity. Furthermore, since the oral cavity is a site sensitive to irritation, it has been necessary to develop a formulation that is as mild as possible.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned problems of the prior art, and has as its object to blend an arylpropionic acid-based non-steroidal anti-inflammatory drug. An object of the present invention is to provide a composition for oral cavity which has good oral mucosal permeability and low irritation to the oral mucosa, and can sufficiently exert the therapeutic / preventive effects of the medicinal agent on periodontal disease.

[0006]

The oral composition of the present invention, which has achieved the above object, is an oral composition containing at least one or more arylpropionic acid nonsteroidal anti-inflammatory agents. And hexylene glycol in an amount of 1 to 30% by weight based on the whole composition.

[0007]

The present inventors have conducted various studies on the composition of an oral composition formulation containing an arylpropionic acid-based non-steroidal anti-inflammatory agent. As a result, surprisingly, in the presence of a certain amount of hexylene glycol, arylpropionic acid It has been found that the incorporation of a non-steroidal anti-inflammatory agent significantly improves the permeation of the oral mucosa and further alleviates the irritation to the oral mucosa, thereby completing the present invention. The arylpropionic acid non-steroidal anti-inflammatory agent according to the present invention widely includes compounds represented by the following general formula and having an anti-inflammatory action.

[0008]

Embedded image

In the formula, R represents an aryl group. Examples of such anti-inflammatory agents include, but are not limited to, ibuprofen, flurbiprofen, ketoprofen, naproxen, pranoprofen, and the like, with preference given to ibuprofen and flurbiprofen.

In the present invention, the content of the anti-inflammatory agent should be appropriately determined according to the dosage form of the composition, the type of the anti-inflammatory agent, etc., but when ibuprofen and / or flurbiprofen are used. Is contained in a total amount of preferably 0.01 to 5% by weight, more preferably 0.05 to 1.0% by weight based on the whole composition. When the content is less than 0.01% by weight, a sufficient anti-inflammatory effect and alveolar bone resorption inhibiting effect cannot be obtained. On the other hand, when the content is more than 5% by weight, these effects are not only saturated, but also the production cost is increased. Absent.

The hexylene glycol used in the present invention is incorporated in an amount of 1 to 30% by weight, preferably 1 to 10% by weight, based on the whole composition. 1% by weight
If the amount is less than the above, the mucosal permeability of the medicinal agent is not sufficient. On the other hand, if the amount exceeds 30% by weight, the effect of improving the mucosal permeability is not only saturated, but also it is not practically preferable from the viewpoint of irritation to the oral cavity.

The oral composition of the present invention can be prepared by a known method using toothpaste, mouthwash, pasta, powdered toothpaste,
It can be in the form of liquid dentifrice, gel, etc., and depending on the desired use and the type of composition, for example, dentifrice and gingival massage preparation, abrasives, binders, flavoring agents, viscous Ingredients such as agents and sweeteners can be blended.

For example, in the case of dentifrices, dibasic calcium phosphate dihydrate and anhydride, monobasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, calcium pyrophosphate, aluminum hydroxide, alumina, and silicic anhydride are used as abrasives. , Silica gel, aluminum silicate,
One or more of insoluble sodium metaphosphate, tribasic magnesium phosphate, magnesium carbonate, calcium sulfate, polymethyl methacrylate, bentonite, zirconium silicate, synthetic resin and the like can be compounded, and the compounding amount is usually the whole composition. 5 to 90% by weight, and 5 to 60% by weight in the case of toothpaste. Further, as a surfactant used for dentifrices, it is preferable to incorporate 0.01 to 3% by weight of an anionic surfactant such as sodium alkyl sulfate. However, considering transmucosal absorbability, lauryl sulfate is particularly preferred. It is preferable to add 0.05 to 2% by weight of sodium and N-lauroyl sarcosine sodium salt.

For example, in the case of a paste-like composition such as a pasta agent, as a binder, cellulose derivatives such as carrageenan, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, and sodium carboxymethylhydroxylethylcellulose; and alkali metal alginate such as sodium alginate. ,
Gums such as propylene glycol alginate, xanthan gum, gum tragacanth, gum karaya and gum arabic; synthetic binders such as polyvinyl alcohol, sodium polyacrylate, carboxyvinyl polymer, and polyvinylpyrrolidone; One or more binders and the like may be blended. These blending amounts are usually 0.1
~ 5% by weight.

Further, in the production of a paste or liquid oral composition, sorbit, glycerin,
Ethylene glycol, propylene glycol, 1,3-
One or more of butylene glycol, polypropylene glycol, xylit, maltitol, lactit and the like may be blended. These amounts are usually 10 to 10
70% by weight.

The oral composition of the present invention may be used alone or in combination with natural or synthetic fragrances usually used for oral preparations, in an amount of 0.01 to 10% by weight based on the whole composition.
Preferably, about 0.1 to 2% by weight can be added. Further, a sweetener such as saccharin sodium, stevioside, neoheshelidyl dihydrochalcone, dipotassium glycyrrhizinate, perillartin, soumatin, asparatyl phenylalanine methyl ester, p-methoxycinnamic aldehyde, etc. is used in an amount of 0.01 to 1 based on the whole composition. %, Preferably 0.01 to 0.5% by weight.

In the present invention, fungicides such as cetylpyridinium chloride and chlorhexidine salts, enzymes such as dextranase, amylase, protease, mutanase, lysozyme, lytic enzyme (Litech enzyme) and monofluorophosphine are further used as active ingredients. Sodium silicate, alkali metal monofluorophosphates such as potassium monofluorophosphate, sodium fluoride, fluorides such as stannous fluoride, tranexamic acid, epsilon aminocaproic acid, aluminum chlorohydroxyallantoin, dihydrocholesterol, glycyrrhizinates, glycyrrhetinic acid , Active ingredients such as glycerophosphate, chlorophyll, sodium chloride, caropeptides, and water-soluble inorganic phosphate compounds. still,
The pH of the composition is preferably 5 to 8.

[0018]

EXAMPLES Next, the present invention will be described more specifically with reference to experimental examples and examples. However, the present invention is not limited to these examples, and modifications may be made without departing from the spirit of the preceding and the following. All that is done is included in the technical scope of the present invention.
In the following, all “%” are% by weight.

Experimental Example 1 After the components shown in Table 1 were stirred and mixed, the pH was adjusted to 6.5 with a 1 / 10N aqueous sodium hydroxide solution to prepare a test sample. Note that ibuprofen and flurbiprofen were used as arylpropionic acid-based non-steroidal anti-inflammatory agents. These were used as test agents, and the permeability of each test agent to the oral mucosa was evaluated by the following oral mucosal permeability evaluation method.

Evaluation method for oral mucosal permeability (1) Preparation of hamster cheek pouch 1.5 ml of pentobarbital (Dainippon Pharmaceutical Co., Ltd.)
A golden hamster anesthetized with / kg was tied to a fixed base, laparotomy was performed using dissecting scissors, internal organs were excised, arterial blood was collected, and the cheek pouch was pulled out with pointed tweezers and cut off with ophthalmic scissors. Next, the cheek pouch was spread, the inner white membrane was removed with round-tip tweezers, and a surgical bond was applied to the candy rubber to adhere the cheek pouch. For storage, it was immersed in a PBS (-) buffer solution and stored by cooling.

(2) Oral mucosal permeability test A slater bar was placed in the cell, and PBS was warmed to 37 ° C.
(−) The cell volume was measured with a buffer, the adjusted cheek pouch was placed on the cell, the silicone packing was hung on the neck of the cell with a clip, and the cell was placed in a thermostat at 37 ° C. for 10 minutes. The air in the cell was evacuated with a syringe, and the test solution 20 was placed on the cell donor side.
0 μl was added, sealed with parafilm, and immersed again in a thermostat. After 3 hours, 1 ml of each sample was sampled. Using this sample solution, the ibuprofen content in the solution was measured by the following HPLC method to evaluate the oral mucosal permeability.

(3) Method for Quantifying Drugs (Ibuprofen, Flurbiprofen) by HPLC About 100 mg of a dried drug standard was precisely weighed, and methanol was added to make exactly 100 ml. 5 ml of this solution was accurately weighed, and methanol was added to make exactly 100 ml. Further, 2 ml of this solution was made up with 100 ml of methanol to obtain a standard solution.

20 μl each of the standard solution and the sample solution obtained in the above (2) were accurately weighed and tested by liquid chromatography. Ibuprofen HPLC operating conditions Detector: UV absorption spectrophotometer (measuring wavelength 220 nm) Column: NUCLEOSIL 10C18 (4.6
Column temperature: constant temperature around 40 ° C Mobile phase: 10 mM sodium dihydrogen phosphate solution adjusted to pH 3.0 with phosphoric acid, and this solution and methanol mixed at a ratio of 25:75 Amount: Adjust so that the retention time of ibuprofen is about 8 minutes.

Flurbiprofen HPLC operating conditions Detector: UV absorption spectrophotometer (measuring wavelength: 246 nm) Column: INERTSILO ODS-2 (4.6 mm)
Column temperature: constant temperature around 40 ° C Mobile phase: 0.05M solution of potassium dihydrogen phosphate,
Acetonitrile and triethanolamine 65:
35: 0.02 mixture in liquid volume: 0.9ml / min

The amount of drug in the sample solution was calculated by the following equation. Amount of drug in sample solution (μg) = (A ′ / A) × C × V where A ′: peak area of drug in sample solution A: peak area of drug in standard solution C: drug concentration of standard solution (Μg / ml) V: Indicates the cell amount (ml). The oral mucosal permeability (%) was determined by the following equation.

[0026]

(Equation 1)

The final evaluation of oral mucosal permeability was evaluated according to the following criteria. Evaluation criteria ○: Oral mucosal permeability 50% or more ×: Oral mucosal permeability less than 50%

[0028]

[Table 1]

As is evident from Table 1, the examples satisfying the requirements of the present invention (samples Nos. 7 and 9), that is, the examples using hexylene glycol, have excellent oral mucosal permeability of the drug. In contrast, in the case of using glycols other than hexylene glycol (Nos. 1 to 6 and 8), the oral mucosal permeability of the drug was extremely low.

Experimental Example 2 After the components shown in Table 2 were stirred and mixed, the pH was adjusted to 6.5 with a 1 / 10N aqueous sodium hydroxide solution to obtain a test sample. These were used as test samples, and each evaluation was performed by the above-described method for evaluating oral mucosal permeability and the following method for evaluating oral mucosal irritation.

Evaluation Method for Oral Mucosal Irritation (1) Test Animals and Breeding Conditions Seventeen-week-old Syrian hamsters, 15 males, were purchased from Japan SLC, Inc. At the time of arrival, macroscopic observation was performed to check for abnormalities, and then only normal animals were housed in cages. After breeding for 28 days and acclimatizing to the test environment, animals without any health problems were selected, and three animals (each body weight at the start of the test: 110.9 g to 159.8 g) were used for the test. Animals at room temperature 22 ± 1 ° C., relative humidity 55 ± 10
%, Light / dark cycle 12 hr. / 12 hr. (7: 0 tomorrow
(19:00 to 19:00). Samples were fed solid feed ("Lab MR Stock", manufactured by Nippon Agricultural Products Co., Ltd.), and drinking water was given tap water freely.

(2) Oral mucosal irritation test Pentobarbital (manufactured by Dainippon Pharmaceutical Co., Ltd., lot.N
o. 030741) After the hamster was anesthetized by injecting 0.1 ml / kg intraperitoneally, after confirming that no feed was contained in the cheek pouch, 0.25 ml of the test solution was administered to the right cheek pouch. On the left side, the same amount of distilled water was administered as a solvent control. This operation was performed once a day for four consecutive days. In the judgment, 24 hours after the final administration, the blood was exsanguinated and killed under ether anesthesia, and the cheek pouch was removed, and the detached state of the mucosal surface was visually observed.

Judgment Criteria in Visual Observation-: No change ±: Mild change +: Moderate change 2+: Intensity change 3+: Extreme change Finally, comprehensive evaluation was performed according to the following criteria. : The judgment result of the degree of detachment of the oral mucosa was-or ±, and the evaluation of the oral mucosal permeability was ○. ×: The judgment result of the degree of oral mucosal detachment was + or more and / or the evaluation of oral mucosal permeability was ×. Table 2 shows the results. Table 2 shows No. 7 again.

[0034]

[Table 2]

As is evident from Table 2, the oral mucosal permeability of ibuprofen and flurbiprofen was 1% by weight or more of hexylene glycol relative to the whole (sample no.
7, 11, 15 and 17 to 19) to obtain good results,
Regarding the irritancy of the oral mucosa, hexylene glycol was 30% by weight or less based on the whole (sample Nos. 7, 10-1).
4, 16 to 18), the result that the peeling action was suppressed was obtained. From these results, it was confirmed that the hexylene glycol concentration having the most excellent properties was 1 to 30% by weight of the whole composition (Sample Nos. 7, 11, 14, 17, and 18).

Example 1 In this example, a toothpaste was prepared according to a conventional method according to the following formulation. Ingredients Amounts (%) Ibuprofen 0.1 dicalcium phosphate 20.0 carboxymethyl cellulose sodium 1.5 Sorbitol solution 40.0 Sodium lauryl sulfate 1.0 Sodium saccharin 0.2 hexylene glycol 3.0 dipotassium glycyrrhizinate 0.05 allantoin aluminum chlorohydrate 0.05 Perfume 0.8 Purified water balance Total 100.0 The resulting paste Evaluation of the oral mucosa irritation and permeability of the dentifrice by the above-described methods showed that good results were obtained and excellent feeling in use was shown.

Example 2 In this example, a toothpaste was prepared according to the following formulation according to a conventional method. Ingredients Amount (%) Flurbiprofen 0.5 Silicic anhydride 20.0 Sodium polyacrylate 0.6 Xanthan gum 0.2 Glycerin 40.0 Sodium lauryl sulfate 0.5 Saccharin sodium 0.2 Hexylene glycol 5.0 Lauroyl sarcosine sodium 0.5 Chlorhexidine hydrochloride 0.05 Perfume 0.8 Purified water residue 100.0 The oral mucous membrane irritation and permeability of the resulting toothpaste were evaluated by the methods described above. As a result, good results were obtained, and excellent feeling in use was shown.

Example 3 A mouthwash was produced according to the following formulation according to a conventional method. Ingredients Amount (%) Ibuprofen 0.5 Ethanol 10.0 Sorbit solution 10.0 Sodium lauryl sulfate 0.5 Sodium saccharin 0.2 Hexylene glycol 5.0 Glycerin 10.0 Perfume 0.3 Remaining purified water remaining 100.0 The oral mucosal irritation and permeability of the obtained mouthwash were determined by the methods described above. When evaluated, good results were obtained,
Excellent use feeling was shown.

Example 4 A liquid dentifrice was produced according to a conventional method according to the following formulation. Ingredients Amount (%) Flurbiprofen 1.0 Glycerin 35.0 Ethanol 5.0 Sodium polyacrylate 3.0 Sodium lauryl sulfate 1.0 Saccharin sodium 0.2 Hexylene glycol 10.0 Sodium chloride 5.0 Perfume 0.2 Remainder of purified water Total 100.0 Oral mucosal irritation of the liquid dentifrice obtained As a result, good results were obtained and excellent feeling in use was shown.

Example 5 An oral pasta was produced according to the following formulation according to a conventional method. Ingredients Blended amount (%) Ibuprofen 1.0 Sorbitan monooleate 2.0 Polyoxyethylene sorbitan monooleate 4.0 Cetanol 5.0 Glycerin 15.0 Sodium carboxymethylcellulose 6.0 Hexylene glycol 8.0 Squalane 10.0 Perfume 0.6 Purified water balance total 100.0 Oral of the obtained oral pasta When the mucosal irritation and permeability were evaluated by the methods described above, good results were obtained, and excellent feeling in use was shown.

Example 6 A lubricating toothpaste was produced according to the following formulation according to a conventional method. Ingredients Amount (%) Flurbiprofen 0.05 Aluminum hydroxide 70.0 Sorbit solution 15.0 Saccharin sodium 0.1 Lauroyl sarcosinate 0.5 Hexylene glycol 1.0 Perfume 0.4 Total remaining purified water 100.0 Oral mucosal irritation and permeability of the obtained dentifrice obtained Was evaluated by the above-described method. As a result, good results were obtained, and excellent usability was exhibited.

Example 7 A gel ointment was produced according to a conventional method according to the following formulation. Ingredients Amount (%) Ibuprofen 0.1 Sorbit solution 30.0 Ethanol 20.0 Carboxyvinyl polymer 2.0 Hexylene glycol 20.0 1N-sodium hydroxide aqueous solution 5.0 Flavoring agent 0.2 Purified water remainder total 100.0 Oral mucosal irritation and permeability of the obtained gel ointment Was evaluated by the above-described method. As a result, good results were obtained, and excellent usability was exhibited.

[0043]

The present invention is configured as described above.
By adding a certain amount of hexylene glycol, the mucosal permeability of the arylpropionic acid-based non-steroidal anti-inflammatory drug was drastically increased, and an oral composition with low irritation was realized.

Since the oral composition of the present invention can fully utilize the anti-inflammatory effect and bone resorption inhibiting effect of the arylpropionic non-steroidal anti-inflammatory drug as described above, it can be used for gingivitis, periodontitis, etc. It has an excellent effect on the treatment and prevention of periodontal disease.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 7/16

Claims (3)

(57) [Claims] 1. An oral composition comprising at least one or more arylpropionic non-steroidal anti-inflammatory drugs, wherein hexylene glycol is added to the whole composition in an amount of 1%.
An oral composition characterized in that the composition is blended in an amount of about 30% by weight. 2. The oral composition according to claim 1, wherein the arylpropionic non-steroidal anti-inflammatory agent is ibuprofen and / or flurbiprofen. 3. The oral composition according to claim 2, wherein the amount of ibuprofen and / or flurbiprofen is 0.01 to 5% by weight based on the whole composition.