JP2011063566A - Ointment for oral cavity - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ointment for the oral cavity having excellent coating properties for affected parts, and retentivity in the initial period and with time, and excellent storage stability. <P>SOLUTION: The ointment for the oral cavity includes (a) 0.1-1.0 mass% of an alginic acid salt having a viscosity (20°C) of a 1 mass% aqueous solution of 5-100 mPa s; and (b) ≥2.0 mass% of a carboxyvinyl polymer. In the ointment, the content mass ratio represented by (b)/(a) of the ingredient (a) to the ingredient (b) is ≥5.0, and the pH is ≥3.0 and <6.00. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an oral ointment that is applied directly to an affected area.

  In oral ointments, the preparation is easily washed away by saliva, and how to keep the drug in the affected area in the mouth is important in the formulation design, and application properties to the affected area and retention in the affected area are required. Furthermore, in the ointment for oral cavity, it is important to improve the initial retention immediately after application, but the improvement in retention over time is more important because the preparation stays in the mouth for a long time. From the viewpoint of improving the retention, carboxyvinyl polymers have been proposed as a component for constructing the gel structure of the preparation (see Patent Documents 1 and 2). However, since the carboxyvinyl polymer shrinks and shrinks over time due to the salinity of saliva and liquefies, the preparation is easily washed away by saliva, and improvement in retention over time has been demanded. Moreover, although the technique using an alginate is also proposed (refer patent document 3), this is a liquid composition for oral cavity, The effect was inadequate from the point of the retention property with time.

  On the other hand, if the pH of the preparation containing alginate is less than 6.0, depending on the composition, the viscosity may decrease over time, and there is a problem in storage stability. By increasing the pH to 6.0 or more, the storage stability is improved. The technique to make it is proposed (patent document 4).

JP-A-7-126133 JP 2006-182699 A JP 2008-7413 A JP 2006-206581 A

  This invention is made | formed in view of the said situation, and it aims at providing the ointment for oral cavity which was excellent in the applicability | paintability to an affected part, the initial stage to an affected part, and the retention property with time, and excellent in storage stability.

  As a result of intensive studies to achieve the above object, the present inventors have used (a) a specific alginate and (b) a carboxyvinyl polymer in a specific amount, respectively, and represented by (b) / (a). It was found that by setting the contained mass ratio to 5 or more, the coating property to the affected area, the initial stage to the affected area, and the retention over time were excellent. Furthermore, in the above combination, by setting the pH to 3.0 or more and less than 6.00, the decrease in viscosity over time is suppressed, the storage stability is improved, and the affinity of the preparation for the oral mucosa is improved. It was found that the spreadability (including after storage) to the affected area such as ease of spreading of the drug and ease of placement on the mucous membrane was further improved. As described above, when the pH of the preparation containing alginate is less than 6.00, the problem that viscosity decreases with time, particularly storage at high temperature, is solved by a combination with a specific mass ratio with carboxyvinyl polymer, It is a new finding of the present inventors that the applicability to the affected area is improved.

Accordingly, the present invention provides the following oral ointment.
[1]. (A) 0.1 to 1.0% by mass of an alginate whose viscosity (20 ° C.) of a 1% by mass aqueous solution is 5 to 100 mPa · s;
(B) containing 2.0% by mass or more of carboxyvinyl polymer,
The mass ratio of the component (a) and the component (b) represented by (b) / (a) is 5 or more,
An oral ointment having a pH of 3.0 or more and less than 6.00.
[2]. The oral ointment according to [1], further comprising (c) 0.5-15.0% by mass of povidone.
[3]. The oral ointment according to [1] or [2], further comprising (d) 0.1 to 1.0% by mass of a cellulose polymer compound.

  ADVANTAGE OF THE INVENTION According to this invention, the ointment for oral cavity which was excellent in the applicability | paintability to an affected part, the initial stage to an affected part, and the retention property over time, and excellent in storage stability can be provided.

  Hereinafter, the present invention will be described in detail. The oral ointment of the present invention comprises (a) alginate having a viscosity of 1% by mass (20 ° C.) of 5 to 100 mPa · s, 0.1 to 1.0% by mass, and (b) carboxyvinyl polymer 2.0. The mass ratio of the component (a) represented by (b) / (a) to the component (b) is 5.0 or more, and the pH is 3.0 or more. It is less than 00.

(A) Alginates Specific examples of alginates include alkali metal salts such as sodium salt and potassium salt of alginic acid, triethanolamine salt, ammonium salt and the like, one kind alone or two or more kinds appropriately. They can be used in combination. The viscosity of the alginate of the present invention is 5 to 100 mPa · s from the viewpoint of storage stability, and the viscosity (20 ° C.) of a 1% by weight aqueous solution is preferably 5 to 50 mPa · s from the viewpoint of storage stability. 5-30 mPa · s is more preferable. If it is a thing outside the said viscosity range (5-100 mPa * s), storage stability will become inadequate and the retention in an oral cavity will fall because the formulation viscosity after storage falls. The viscosity was measured using a BL type rotational viscometer, rotor No. 1 to 4, measured at 60 rpm, 60 seconds after rotation.

  The content of the alginate is 0.1 to 1.0% by mass with respect to the oral ointment, preferably 0.15 to 0.7% by mass, and more preferably 0.2 to 0.4% by mass. When it exceeds 1.0 mass%, storage stability will become inadequate and the retention in the oral cavity will fall because the formulation viscosity after storage falls.

(B) Carboxyvinyl polymer The combination of (a) alginate and (b) carboxyvinyl polymer can improve the applicability to the affected area, the initial and time retention on the affected area, and the storage stability. As the carboxyvinyl polymer, the viscosity of a 0.2 mass% aqueous solution (20 ° C.) [Conditions are BH type rotational viscometer, rotor No. 6 or 7, 20 rpm, after 60 seconds], preferably 5,000 to 50,000 mPa · s, more preferably 10,000 to 40,000 mPa · s, and 16,000 to 27,000 mPa · s. s is more preferable.

  The carboxyvinyl polymer includes salts thereof. Specific examples of the carboxyvinyl polymer include Carbopol 914, 934, 934P, 940, 941, 971P, 974P, 980, 981, 2984, 5984, ETD2050, Ultrez10 (manufactured by NOVEON), Junlon PW-110, PW. -111, PW-150, PW-302, PW-310, PW-350 (manufactured by Nippon Pure Chemicals Co., Ltd.), Hibiswako 103, 104, 105 (manufactured by Wako Pure Chemical Industries, Ltd.), AQUIPECHV-501, HV-504, HV-505 (manufactured by Sumitomo Seika Co., Ltd.) and the like. A carboxy vinyl polymer can be used individually by 1 type or in combination of 2 or more types.

  (B) Content of carboxy vinyl polymer is 2.0 mass% or more with respect to oral ointment, 2.0-10.0 mass% is preferable, and 2.0-7.0 mass% is more preferable. 2.0 to 4.0% by mass is more preferable. If it is less than 2.0% by mass, the intended effect cannot be obtained, and if it exceeds 10.0% by mass, the handleability during preparation of the preparation tends to deteriorate.

  The mass ratio of the component (a) and the component (b) represented by (b) / (a) is 5 or more, and the upper limit is preferably 50 or less from the viewpoint of retention over time, and 5.0 to 40 is preferable. Preferably, 6 to 20 is more preferable, and 7 to 18 is more preferable. If the ratio is less than 5, the storage stability becomes insufficient, and the viscosity of the preparation after storage decreases, so that the retention in the oral cavity decreases or the retention over time deteriorates.

  The pH of the oral ointment of the present invention is 3.0 or more and less than 6.00. When the pH is less than 3.0, the storage stability is deteriorated, and there is a possibility that an adverse effect (dissolution) or irritation to the teeth may occur. When it is 6.00 or more, applicability to the oral mucosa and storage stability are deteriorated. The pH is preferably less than 4.0 to 6.00, more preferably less than 4.5 to 6.0, and even more preferably 5.0 to 5.9.

  In addition, pH is alkali such as sodium hydroxide, potassium hydroxide, monoethanolamine, diethanolamine, triethanolamine, triisopropanolamine, organic acids (citric acid, lactic acid, tartaric acid, malic acid, glycolic acid), inorganic It adjusts suitably with acids, such as an acid (hydrochloric acid, phosphoric acid). The pH is measured at a temperature (25 ° C.) according to the Japanese Pharmacopoeia General Test Method pH measurement method.

  The oral ointment of the present invention preferably further contains (c) povidone for the purpose of improving the initial retention. Povidone is polyvinylpyrrolidone, which can be used alone or in combination of two or more. As povidone, 5 mass% aqueous solution (25 ° C.) [Conditions are BH type rotational viscometer, rotor No. 4-7, rotation speed 20 rpm, rotation 60 seconds], preferably 1,500-60,000 mPa · s, more preferably 20,000-60,000 mPa · s, and further 50,000-60,000 mPa · s. preferable. If the viscosity is too high, the handling property during preparation of the preparation may be deteriorated (prone to remain untied).

  (C) The content of povidone is preferably 0.5 to 15.0 mass%, more preferably 0.7 to 10.0 mass%, and further preferably 0.9 to 5.0 mass% with respect to the oral ointment. preferable. The blending effect can be obtained more in the range of 0.5 to 15.0% by mass, and if the blending amount is too large, it may become sticky.

  The oral ointment of the present invention preferably further contains (d) a cellulosic polymer compound for the purpose of improving retention and coating properties. Examples of the cellulose-based polymer compound include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl ethyl cellulose, hydroxymethyl hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like. The above can be used in appropriate combination. Among these, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose are preferable, and hydroxypropyl methyl cellulose (hypromellose) is more preferable. As the cellulose-based polymer compound, a 2% by mass aqueous solution (20 ° C.) [Conditions are BL type rotational viscometer, rotor no. 1-4, rotation speed 12-30 rpm, rotation 60 seconds], 1,500-10000 mPa · s is preferable, 2500-5000 mPa · s is more preferable, and 3000-4500 mPa · s is more preferable. If the viscosity is too high, the handling property during preparation of the preparation may be deteriorated (prone to remain untied).

  (D) 0.1-1.0 mass% is preferable with respect to oral ointment, as for content of a cellulose polymer compound, 0.15-0.7 mass% is more preferable, 0.2-0. 5 mass% is more preferable. The above blending effect can be obtained more in the range of 0.1 to 1.0% by mass.

  The oral ointment of the present invention can contain a drug (active ingredient), and since the oral ointment is excellent in applicability to the affected area, initial retention in the affected area, and retention over time, the effect of the drug is further exhibited. can do. Examples of the drug include the following, which can be used singly or in appropriate combination of two or more. The following classifications include those that are duplicated due to the effect of the drug.

  Disinfectants include iodine / potassium iodide, liquid phenol / phenol, cetylpyridinium chloride, chlorhexidine chlorhexidine / chlorhexidine hydrochloride, decalinium chloride, creosote, thymol, triclocarban, benzalkonium chloride, benzethonium chloride, acrinol, oxidol, Examples include ethanol, isopropanol, mercurochrome, cresol, isopropylmethylphenol, phenyl salicylate, sulfadiazine, homosulfamine, and cinnamon oil.

  Anti-inflammatory agents include tranexamic acid, lysozyme chloride, sodium azulene sulfonate, dipotassium glycyrrhizinate / ammonium glycyrrhizinate / glycyrrhetinic acid, bromelain, serrapeptase, pranoprofen, ibuprofen piconol, presterone, sicon extract, epidihydrocholesterin , Bufexamac, ufenamate, myrrhin tincture, psycho, bukuryo, aobac, hydrocortisone acetate, prednisolone acetate, prednisolone, prednisolone, hydrocortisone, triamcinolone acetonide and the like.

  Antihistamines include chlorpheniramine maleate, diphenhydramine salicylate, diphenylpyraline hydrochloride, mechidazine, triprolidine hydrochloride, carbinoxamine maleate, diphenhydramine hydrochloride, diphenhydramine tannate, dimenhydrinate, promethacin hydrochloride, promethazine hydrochloride, meclizine hydrochloride, isopentyl hydrochloride Etc.

  Examples of the tissue repair agent include copper chlorophyllin sodium, allantoin, aldioxa, methylmethionine sulfonium chloride, sucralfate, cetraxate hydrochloride, sofalcone, gefarnate, trimebbutin maleate, teprenone, heparin-like substances and the like.

  Examples of the local anesthetics include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, ethyl aminobenzoate, oxasecasein, and tecaine.

  Examples of herbal medicines include Keihi-Keihi oil, myrrh tincture, psychos, bukkake, abalone, clove ingredients, chamomile tincture, latania tincture, engosaku, shouma, kyoto, safflower and the like.

  Other ingredients include topical protective agents such as glycerin and concentrated glycerin, local stimulants such as l-menthol, peppermint oil, dl-menthol, tissue astringents and fungicides such as hinokitiol, hemostatic agents such as carbazochrome, ascorbic acid, ascorbine Examples include calcium acid, tocopherol acetate / calcium tocopherol calcium, pantothenol, vitamins such as pyridoxine hydrochloride, blood circulation promoters such as benzyl nicotinate, blood circulation promoters such as sodium polyethylene sulfonate, and antibiotics such as minocycline hydrochloride. .

Other optional components include wetting agents, surfactants, solvents, paraffins and the like.
Examples of the wetting agent include glycerin, propylene glycol, PEG, sorbitol, syrup, and polyhydric alcohols such as 1,3-butylene glycol.

  Although it does not specifically limit as surfactant, Nonionic surfactant is preferable. Nonionic surfactants include POE hydrogenated castor oil, (POE) sorbitan fatty acid ester, sucrose fatty acid ester, (poly) glycerin fatty acid ester, fatty acid sorbitan, (poly) propylene glycol fatty acid ester, POE glycerin fatty acid ester, POE alkyl ether , POEPOP alkyl ether, POE fatty acid ester and the like.

  Examples of the solvent include water, ethanol, glycerin, 1,3-butylene glycol and the like.

  The manufacturing method of the ointment for oral cavity of this invention is not specifically limited, For example, it can obtain by mixing (a) component and (b) component, an arbitrary component, and water (remainder). Viscosity of oral ointment (20 ° C.) [Conditions are BH type rotational viscometer, rotor no. 7, after 20 seconds of rotation, the effect of the present invention does not depend on the viscosity, but after satisfying the configuration of the present invention, it is 50 to 300 Pa · s, preferably 60 to 200 Pa · s. By adjusting the viscosity to s, it is possible to further combine suitable coating properties and retention properties.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition indicates mass%, the ratio indicates the mass ratio, and the amount of each component in the table is an amount converted into a pure component.

[Examples 1 to 24, Comparative Examples 1 to 10]
Oral ointments having the compositions shown in Tables 1 to 6 were prepared by a conventional method and evaluated as follows. The results are also shown in the table. In addition, the initial viscosity (20 degreeC) of the ointment for oral cavity of an Example [The conditions are a BH type rotational viscometer, rotor No. 7, rotation speed 20 rpm, after rotation 60 seconds] was in the range of 50 to 300 Pa · s. In the table, the viscosity of a 1% by mass aqueous solution of sodium alginate (20 ° C., BL type rotational viscometer, rotor Nos. 1 to 4, measured at 60 rpm, measured after 60 seconds) was described.

[I] Retention (initial / time), applicability to oral mucosa Take about 0.3g of sample (oral ointment) on your finger and apply to toothpaste. At this time, the following initial retention evaluation and applicability (affinity) evaluation to the oral mucosa were performed, and the following retention time evaluation was performed 20 minutes after application.

<Initial evaluation of retention>
The panelists were subjected to sensory evaluation of initial retention based on the following usage evaluation scores. The effect was judged from the average value of 20 people based on the following evaluation criteria.
[Usage score]
5 points: Very strong 4 points: Strongly felt 3 points: Feeling 2 points: Slightly felt 1 point: Not felt [Evaluation criteria]
A: Average 4.7 points or more B: Average 4.4 points or more and less than 4.7 points C: Average 4.0 points or more and less than 4.4 points D: Average 3.5 points or more and less than 4.0 points E: Average Less than 3.5

<Applicability to the oral mucosa (affinity)>
Twenty panelists performed sensory evaluations on the ease of spreading the drug to the oral mucosa and the ease of placing it on the mucosa (applicability) based on the following evaluation scores. The effect was judged from the average value of 20 people based on the following evaluation criteria.
[Usage score]
7 points: Very good 6 points: Pretty good 5 points: Slightly good 4 points: Not good 3 points: Slightly bad 2 points: Pretty bad 1 point: Very bad [Evaluation criteria]
A: 5.5 points or more B: 5.0 points or more and less than 5.5 points C: 4.5 points or more and less than 5.0 points D: 3.0 points or more and less than 4.5 points E: Less than 3.0 points

<Residence aging evaluation>
20 panelists performed sensory evaluation of the retention over time based on the following usage impressions. The effect was judged from the average value of 20 people based on the following evaluation criteria.
[Usage score]
5 points: Very strong 4 points: Strongly felt 3 points: Feeling 2 points: Slightly felt 1 point: Not felt [Evaluation criteria]
A: Average 3.0 points or more B: Average 2.5 points or more and less than 3.0 points C: Average 2.0 points or more and less than 2.5 points D: Average 1.5 points or more and less than 2.0 points E: Average Less than 1.5

[II] Storage stability 50 g of a sample (oral ointment) was put in a 50 mL glass bottle, and the stability after storage at 40 ° C. for 3 months was evaluated according to the following evaluation criteria.
[Evaluation criteria]
Viscosity stability (%) = Viscosity value after 3 months at 40 ° C./Initial viscosity value × 100
A: 90% or more B: 80% or more and less than 90% C: 70% or more and less than 80% D: 60% or more and less than 70% E: Less than 60%

[III] Retention property after storage The sample (oral ointment) stored in the above [II] was evaluated in the same manner as [I] retention property (initial stage / time).

In order to further confirm the staying effect of the present invention, the following staying severe test was conducted.
A pigment (Bordeaux S Wako Pure Chemical Industries, Ltd.) 0.2% was added to 99.8% of oral ointment (initial) of Example 1, Comparative Example 3 and Comparative Example 8, and about 0.1 g hairless mouse ( Each n = 3) was uniformly applied on the skin (circle having a diameter of 2.5 cm). This was placed in artificial saliva (30 mL) and gently stirred with a magnetic stirrer. Sampling was performed over time (0, 1, 3, 5, 15 minutes), and the dye concentration was measured with an absorptiometer (wavelength 520 nm) to examine the persistence of the base. The initial residual rate was 100%, and a numerical value of an absorptiometer in which 0.1 g of sample was completely dissolved in 30 mL of artificial saliva was defined as a residual rate of 0%. The results are shown in Table 7.

  In addition, the raw material used in the Example is shown below.

Claims (3)

(A) 0.1 to 1.0% by mass of an alginate whose viscosity (20 ° C.) of a 1% by mass aqueous solution is 5 to 100 mPa · s;
(B) containing 2.0% by mass or more of carboxyvinyl polymer,
The content mass ratio of the component (a) and the component (b) represented by (b) / (a) is 5 or more,
An oral ointment having a pH of 3.0 or more and less than 6.00.   Furthermore, the ointment for oral cavity of Claim 1 containing 0.5-15.0 mass% of (c) povidone.   The oral ointment according to claim 1 or 2, further comprising (d) 0.1 to 1.0% by mass of a cellulose-based polymer compound.