JP4732784B2 - Panthenol-containing oral mucosal adhesive preparation - Google Patents

Description

  The present invention relates to an oral mucosa-adhesive preparation comprising pantenol having excellent usability and excellent adhesion as an active ingredient.

Oral mucosal disorders such as stomatitis are accompanied by erythema of the mucous membranes, formation of ulcers, and sharp pain, which not only causes difficulty in speaking and taste, but also makes it difficult to eat food, and impaired salivation. It may happen. Furthermore, the damaged part of the mucous membrane serves as an entrance for various microorganisms and is exposed to the risk of secondary infection. The causes of the onset of oral mucosal damage include stress and trauma of the oral mucosa, but have not been fully elucidated. It has also been reported that oral mucosal disorders such as stomatitis frequently occur due to administration of anticancer drugs or radiation therapy.
As a method for treating such an oral mucosal disorder, topical administration of a steroid agent, azulene ointment, a mouthwash containing an antibacterial agent, and the like have been used. Furthermore, N ⁶ , 2′-O-diacyladenosine-3 ′, 5′-cyclic phosphorus, which is a liquid agent containing allopurinol known as a therapeutic agent for gout (see Patent Document 1) and a cyclic AMP derivative Preparations containing acids as active ingredients (see Patent Document 2), preparations containing basic fibroblast growth factor (bFGF) (see Patent Document 3), preparations containing serylglycine as an active ingredient (see Patent Document 4) ), Preparations containing prostaglandins in steroids (see Patent Document 5), preparations containing hyaluronic acid, glycyrrhetinic acid and polyvinylpyrrolidone as active ingredients (see Patent Document 6), biocompatible with sulfur-containing compounds as active ingredients Numerous preparation examples such as preparations containing soluble polymers (see Patent Document 7) and preparations containing intestinal trefoil peptides as active ingredients (see Patent Document 8) have been reported. Has been reported.

  Panthenol is easily oxidized in vivo to form pantothenic acid, and is therefore used as a prophylactic / therapeutic agent for pantothenic acid deficiency. Panthenol has the effect of promoting fibroblast growth and proliferation, and is known not only to promote the healing of skin inflammation, but also as a moisturizer and scalp protectant, such as cosmetics and shampoos. Has also been used. Furthermore, it has been blended in lip balms for rough lips. Panthenol was desired to be formulated as an oral preparation for the treatment of stomatitis, but panthenol easily mixes with water and easily flows out of the mouth, making it difficult to formulate into an oral mucosal preparation. Met. And, in order to perform sustained release of the drug, it is necessary to formulate panthenol with good adhesion to the oral mucosa, but by incorporating panthenol, the adhesion in the oral cavity can be improved. There was a problem that the medicinal effect was not maintained as an oral mucosa preparation.

As a method for improving the adhesion of the oral preparation to the oral mucosa, for example, a method of forming a protective film by blending a large amount of polyvinylpyrrolidone (see Patent Document 6), hydroxymethylcellulose, polyethylene glycol, gelatin, polyoxy- Method of using biocompatible polymer such as 35-castor oil (see Patent Document 7) Method of making mucoadhesive preparation using water-soluble polymer such as polyethylene glycol, acrylic acid polymer, hydroxyethyl cellulose (see Patent Document 8) A method of gelation using a metal salt of carboxymethyl cellulose or a carboxyvinyl polymer (see Patent Document 9), a sucralfate preparation (see Patent Document 10) containing an organic acid such as citric acid or tartaric acid, hydroxypropyl methylcellulose and carboxyvinyl polymer Such as the oral mucosa-adherent ointment composition containing mer (see Patent Document 11) are known.
However, these methods cannot be said to be effective for any active ingredient, and further, when an organic acid is added, the taste deteriorates, and the inflammation site of stomatitis is stimulated, which may reduce compliance. In addition, since the viscosity of the carboxyvinyl polymer decreases with a decrease in pH, there is a possibility that the adhesiveness in the oral cavity may be reduced, and it is not preferable to mix it in the oral preparation.
Thus, a method for improving the adhesion of panthenol to the oral mucosa has not been known yet.

Japanese Patent Laid-Open No. 7-25769 JP 7-247210 A JP-A-8-27024 JP 2000-16949 A JP 2003-226644 A Special table 2004-505028 gazette See Special Table 2004-513957 JP-T-2005-503340 Japanese Patent Laid-Open No. 9-95456 JP-A-8-268895 JP-A-7-267839

  The present invention provides an oral preparation containing panthenol as an active ingredient, having excellent usability, good adhesion, maintaining the sustained efficacy of the drug, and capable of being adhered to the oral mucosa. The purpose is to provide.

  The present inventors have studied oral preparations containing panthenol as an active ingredient, but in liquids such as gargles, panthenol that easily mixes with water has poor persistence, and sufficient medicinal effects cannot be obtained. In addition, it has been difficult to form a preparation that enables sustained release of panthenol even in the case of an intraoral adhesive preparation only by the conventional adhesion improving method. This is thought to be due to the physicochemical properties peculiar to panthenol, and as a result of intensive investigations to find an oral mucosa-adhesive preparation having sufficient adhesion to the oral mucosa, an oral-adhesive preparation containing panthenol It was found that by adding polyoxyethylene hydrogenated castor oil, sorbitan monostearate, and cetanol, a panthenol-containing intraoral mucosa-adhesive preparation with excellent usability and significantly improved adhesion was obtained. Moreover, it discovered that the adhesiveness in the oral cavity was further improved by adding petrolatum to the above-mentioned preparation, and the present invention was completed.

  That is, the present invention relates to an oral mucosal adhesion preparation containing panthenol as an active ingredient. The present invention also relates to an oral mucosal adhesion preparation comprising panthenol, polyoxyethylene hydrogenated castor oil, sorbitan monostearate, and cetanol. Furthermore, the present invention relates to an oral mucosa-adhesive preparation comprising panthenol, polyoxyethylene hydrogenated castor oil, sorbitan monostearate, cetanol, and petrolatum.

The intraoral mucosa-adhesive preparation of the present invention is characterized by containing panthenol as an active ingredient, and polyoxyethylene hydrogenated castor oil as an ingredient for improving the adhesion of the panthenol to the oral mucosa, It is characterized by blending sorbitan monostearate and cetanol, preferably petrolatum.
Panthenol used as an active ingredient in the present invention has the following formula:

Which is a viscous liquid or white solid at room temperature or a mixed state thereof, dexpantenol, pantothenol, or D-pantothenyl alcohol (D-Pantothenyl Alcohol) and Sometimes called. The compounding amount of panthenol in the oral mucosa-adhesive preparation of the present invention is preferably 0.01 to 3% by weight, more preferably 0.05 to 1% by weight, particularly with respect to the total amount of the oral mucosa-adherent preparation. Preferably it is 0.1 to 0.5 weight%. If it exceeds 3% by weight, the bitterness spreads in the mouth and the feeling of use becomes worse, and if it is less than 0.01% by weight, a large amount of coating is required to obtain the effect, which is not preferable.

The polyoxyethylene hydrogenated castor oil in the oral mucosa-adhesive preparation of the present invention is obtained by adding hydrogen to castor oil to obtain a hardened oil, which is obtained by addition polymerization of ethylene oxide, and the average added mole number of ethylene oxide The range is 5 or more, preferably 5 to 100, but is not limited thereto. Specifically, for example, polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, polyoxyethylene (100) hydrogenated castor oil, etc. . Commercially available products include Nikkor HCO-5, HCO-10, HCO-20, HCO-30, HCO-40, HCO-50, HCO-60, HCO-80, HCO-100 (Nikko Chemicals), Unico Ox HC-5, HC-10, HC-20, HC-30, HC-40, HC-50, HC-60, HC-80, HC-100 (Japanese fats and oils), Emalex HC-5, HC-10 HC-20, HC-30, HC-40, HC-50, HC-60, HC-80, HC-100 (Nippon Emulsion).
The blending amount of the polyoxyethylene hydrogenated castor oil in the oral mucosa-adhesive preparation of the present invention is preferably 0.005 to 10% by weight, more preferably 0.05 to 5% by weight, particularly with respect to the total amount of the preparation. Preferably it is 0.1 to 3 weight%. If it exceeds 10% by weight, irritation to mucous membranes and ulcers becomes strong, and if it is less than 0.005% by weight, the intended effect of improving the adhesive force cannot be obtained, which is not preferable.

The sorbitan monostearate in the oral mucosa-adhesive preparation of the present invention is obtained by esterifying the hydroxyl group of sorbitol or anhydrous sorbitol with stearic acid. Specifically, for example, Nikkor SS-10M, SS-10MV (Nikko) Chemicals) and Rheodor SP-S10V (Kao).
The blending amount of sorbitan monostearate in the oral mucosa-adhesive preparation of the present invention is preferably 0.005 to 10% by weight, more preferably 0.05 to 5% by weight, particularly preferably based on the total amount of the preparation. 0.1 to 3% by weight. If it exceeds 10% by weight, irritation to mucous membranes and ulcers becomes strong, and if it is less than 0.005% by weight, the intended effect of improving the adhesive force cannot be obtained, which is not preferable.

The blending amount of cetanol in the intraoral mucosa-adhesive preparation of the present invention is preferably 0.01 to 10% by weight, more preferably 0.05 to 5% by weight, particularly preferably 0.5 to the total amount of the preparation. ~ 3 wt%. If it exceeds 10% by weight, the feeling of use is deteriorated, and if it is less than 0.01% by weight, the intended effect of improving the adhesion cannot be obtained, which is not preferable.
Examples of petrolatum in the oral mucosa-adhesive preparation of the present invention include white petrolatum, yellow petrolatum and the like, and examples of commercially available products include Penreco Snow, Penreco Amber (Penreco), Hakuwase White (Iwaki Pharmaceutical), Examples include white petrolatum (Crompton). The blending amount of petrolatum in the oral mucosa-adhesive preparation of the present invention is preferably 0.1 to 20% by weight, more preferably 0.5 to 10% by weight, and particularly preferably 1 to 5% with respect to the total amount of the preparation. % By weight. If it exceeds 20% by weight, the feeling of use is deteriorated, and if it is less than 0.1% by weight, the desired effect of improving the adhesion cannot be obtained, which is not preferable.

The oral mucosa-adhesive preparation of the present invention may further contain other active ingredients other than panthenol, but it does not necessarily have to be added. Other active ingredients that can be blended are not particularly limited, but include, for example, potassium or ammonium salts of glycyrrhizic acid, sodium azulene sulfonate, anti-inflammatory agents such as chicone, tissue repair agents such as allantoin, dexamethasone Corticosteroids such as triamcinolone acetonide, epidihydrocholesterine, hydrocortisone acetate, iodine, potassium iodide, povidone iodine, acrinol, triclosan, piozole, sodium monofluorophosphate, sodium fluoride, isopropylmethylphenol, hinokitiol, chloride Decalinium, benzethonium chloride, cetylpyridinium chloride, alkyldiaminoethylglycine chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, methylrosaniline chloride, benzal chloride Fungicides such as chloride, and the like.
In addition to polyoxyethylene hydrogenated castor oil, sorbitan monostearate, cetanol and petrolatum, water, thickener, emulsifier, neutralizer, preservative, stabilizer, wetting Although it is possible to further mix base components such as agents, fragrances, and fats and oils, they are not necessarily blended, and are not limited to those that can be blended.

Examples of the thickener include carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carrageenan, sodium alginate, xanthan gum, sodium polyacrylate, carboxyvinyl polymer, polyvinyl alcohol, locust bean gum, guar gum, gelatin and the like. Is mentioned.
Examples of the emulsifier include glycerin fatty acid ester, propylene glycol fatty acid ester, alkyl glyceryl ether, polyoxyethylene sorbitol fatty acid ester, polysorbate, polyoxyethylene, lauromacrogol, sodium alkyl sulfate, alkyl phosphate ester, sodium alkylbenzene sulfonate, Examples thereof include sodium N-acyl sarcosinate, N-acyl glutamate, sucrose fatty acid ester, alkyl glycosides, alkyl dimethylamine oxide, alkyl betaines and the like.
Examples of the neutralizing agent include inorganic acids such as hydrochloric acid, alkali hydroxides such as sodium hydroxide and potassium hydroxide, and amines such as triethanolamine, diethanolamine and diisopropanolamine.
Examples of the preservative include p-hydroxybenzoates, benzalkonium chloride, and the like.
Examples of the stabilizer include sodium sulfite, sodium hydrogen sulfite, dibutylhydroxytoluene, butylhydroxyanisole, edetic acid or salts thereof.
Examples of the wetting agent include polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, isopropylene glycol, and polyethylene glycol.
Examples of fragrances include spearmint oil, peppermint oil, linalool, winder green oil, sassafras oil, clove oil, peppermint oil, thyme oil, sage oil, eucalyptus oil, mayonnaise oil, cinnamon oil, lime oil, lemon oil and orange. And natural fragrances such as oil, l-menthol, dl-camphor and the like.
Examples of fats and oils include waxes such as lanolin, whale wax and carnauba wax, fatty acids, ester compounds such as octyldodecyl myristate, diisopropyl adipate, hexadecyl isostearate, decyl oleate, squalane, squalene, medium chain fatty acid triglycerides , Liquid paraffin, silicon and the like.

The pH of the intraoral mucosa-adhesive preparation of the present invention is usually preferably pH 4 to 8, more preferably pH 5 to 7, from the viewpoint of separation stability of the preparation and skin irritation. The pH is measured at 25 ° C. with a pH meter (for example, Horiba: F-24) after adding 9 parts by weight of water to 1 part by weight of the oral mucosa-adhesive preparation and shaking well.
The consistency of the intraoral adhesive preparation of the present invention is preferably 10 to 100 g, more preferably 30 to 70 g. If it is less than 10 g, the preparation is soft and flows off the coated surface, which is not preferable. On the other hand, if it exceeds 100 g, the elongation of the preparation becomes worse and the production process becomes difficult. The consistency is measured, for example, by using a rheometer (for example, Fudo Kogyo Co., Ltd .: NRM-3002D-L) to make a 1 cm diameter sphere enter 1 cm at a speed of 5 mm / second and measure the maximum load at that time.
The blending ratio of polyoxyethylene hydrogenated castor oil and sorbitan monostearate in the oral mucosa-adhesive preparation is preferably 1: 6-8: 1, more preferably 1: 3-3: 1.

  The method for producing an intraoral adhesive preparation of the present invention can be produced by an ordinary method. For example, panthenol is completely dissolved in purified water, while polyoxyethylene hydrogenated castor oil, sorbitan monostearate, cetanol and petrolatum Can be prepared by heating and dissolving at 80 ° C. or higher and then stirring and mixing both solutions at 80 ° C.

  The present invention provides a panthenol-containing intraoral mucosa-adhesive preparation that is extremely adherent to the intraoral mucosa using components that are excellent in usability. The oral mucosa-adhesive preparation of the present invention can not only continuously maintain the excellent medicinal effects of panthenol in the oral cavity, but also the adhesive preparation can cover the injured part, and physically stimulate the injured part. It is an excellent therapeutic agent for oral mucosal disorders such as stomatitis with both treatment and pain relief.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these.

0.3 g of panthenol, 25 g of concentrated glycerin and 0.1 g of Macrogol 6000 were added to 45 g of purified water and dissolved at room temperature. To this solution, 0.7 g of carboxyvinyl polymer was added and well stirred and mixed at room temperature (this is referred to as Preparation Solution A).
On the other hand, polyoxyethylene hydrogenated castor oil 60 (Nikkor HCO-60: Nikko Chemicals) 1.4 g, sorbitan monostearate (Nikkor SS-10M: Nikko Chemicals) 0.6 g, cetanol (Kao) 2 g, petrolatum (white petrolatum: Crompton) 3 g, ethyl paraoxybenzoate 0.1 g and propyl paraoxybenzoate 0.05 g were added to 13 g of light liquid paraffin and dissolved at 80 ° C. (this is referred to as Preparation B).
After adding the preparation liquid B to the preparation liquid A, stirring and mixing well at 80 ° C. and emulsifying, cooling to 60 ° C. or lower, adding 0.089 g of sodium hydroxide as a neutralizing agent to pH 5.5, Purified water was added to make a total amount of 100 g, and the mixture was well stirred and mixed to obtain an oral mucosa-adhesive preparation.

  By the same method as Example 1, it manufactured by changing the compounding quantity of the polyoxyethylene hydrogenated castor oil 60 and the sorbitan monostearate among the components shown in Table 1, and obtained the intraoral mucosa adhesion preparation.

  In the same manner as in Example 1, the composition shown in Table 1 was produced by changing the blending amounts of polyoxyethylene hydrogenated castor oil 60 and sorbitan monostearate to obtain an oral mucosa-adhesive preparation.

  Except for petroleum jelly, the amount of purified water was increased by that amount, and the same procedure as in Example 1 was used to produce the oral mucosa-adhesive preparation using the components shown in Table 1.

Comparative Example 1
Except for the polyoxyethylene hydrogenated castor oil, the amount of purified water was increased by that amount, and the preparation shown in Table 1 was used in the same manner as in Example 1 to obtain a preparation for oral application.

Comparative Example 2
Except for sorbitan monostearate, the amount of purified water was increased by that amount, and the same procedure as in Example 1 was used to prepare the preparation for oral application, using the components shown in Table 1.

Comparative Example 3
Except for cetanol, the amount of purified water was increased by that amount, and the preparation shown in Table 1 was used in the same manner as in Example 1 to obtain a preparation for intraoral application.

Test Example The intraoral mucoadhesive preparation of the present invention prepared in Examples 1 to 4 and the oral application preparation prepared in Comparative Examples 1 to 3 were evaluated for adhesion and usability.
The adhesion force was measured by the method shown below. Two membrane filters (pore size 0.45 μm: Advantech Toyo) cut into squares (15 mm x 15 mm) are attached to two acrylic plates (55 x 30 mm, thickness 3 mm) using double-sided tape, and one filter 25 μL of purified water was dropped on the top. Further, about 50 mg of the preparation sample was uniformly applied on one of the filters, and immediately after the two acrylic plates were overlaid, they were allowed to stand for 5 minutes under a load of 100 g. One acrylic plate was fixed, and the other acrylic plate was pulled in a horizontal direction at a rate of 20 mm / min using a rheometer (FUDOH), and the maximum stress (g) at the time of peeling was measured to obtain an adhesive force.
The feeling of use is to apply 0.5 g of the oral application preparation to the oral mucosa, evaluate the ease of peeling of the oral application preparation, and the oral application preparation is one in which half of the applied amount is released in less than 60 seconds, A sample in which half of the amount remained in the oral mucosa for 60 seconds or longer was marked as ◯.
Table 1 below summarizes the blended components, blending amounts, and test results.

As a result, the oral mucosa-adhesive preparations (Examples 1 to 4) of the present invention have polyoxyethylene hydrogenated castor oil (Comparative Example 1), sorbitan monostearate (Comparative Example 2), or cetanol (Comparative Example 3). It can be seen that, compared with a preparation for oral administration which is not blended, the adhesiveness to the oral mucosa is extremely excellent, and there is no detachment into the oral cavity after application, and the usability is extremely excellent.
It can also be seen that, in order not to cause substantial detachment in the oral cavity, it is necessary to achieve an adhesion force of 15 g or more, preferably 17 g or more, more preferably 20 g or more in the adhesion test. The oral mucosa-adhesive preparations of the present invention all have an adhesive force of 15 g or more, and despite the fact that they contain panthenol that is easily mixed with water as an active ingredient, the sustained efficacy can be maintained. Is possible.

  The present invention provides a novel intraoral mucoadhesive preparation containing panthenol as an active ingredient, which is useful as a therapeutic agent for oral mucosal disorders such as stomatitis, and has industrial applicability. .

Claims (2)

  An oral mucoadhesive preparation containing panthenol, polyoxyethylene hydrogenated castor oil, sorbitan monostearate, and cetanol.   An oral mucoadhesive preparation containing panthenol, polyoxyethylene hydrogenated castor oil, sorbitan monostearate, cetanol, and petrolatum.