JPH03271215A - Drug-containing granule and dentifrice containing the same - Google Patents

Abstract

PURPOSE:To obtain a granule having a prescribed size and strength by blending a water-insoluble inorganic binder and a drug effect ingredient for the oral cavity with other ingredients. CONSTITUTION:The objective substance obtained by blending a water-insoluble inorganic binder (e.g. colloidal silica or synthetic aluminum silicate) with a drug effect ingredient for the oral cavity (e.g. beta-glycyrrhetinic acid or vitamin E) and preparing a granule having 50-500mum grain diameter and a strength disintegrating when a load of 0.1-10g based on one granule is applied according to a spray, extrusion granulating method, etc. Although the granule can be also blended with a cream, ointment, etc., 1-50wt.% granule is preferably blended in a dentifrice to prepare a dentifrice capable of making the drug effect ingredient directly act on gaps between teeth or teeth and gingivae which are favorite localizations of dental caries or periodontosis.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a granule containing a medicinal ingredient for the oral cavity and a dentifrice containing the same. More specifically, the present invention relates to granules that can directly apply oral medicinal ingredients to the gaps between teeth and between teeth and gums, which are areas where caries and periodontal disease are most likely to occur, and to dentifrices containing the same.

[Prior Art] The technology of blending granules into dentifrices has been known in the past, and numerous patent applications have been filed for dentifrices that use organic binders such as wax, thermoplastic resins, and ethyl cellulose as binders for granules. There is. Examples of such dentifrices include those aimed at aesthetics and ease of manufacture (Japanese Patent Laid-Open No. 48
-013558 Publication JP-A-48-019738, JP-A-50-081594, JP-A-62-116
No. 506, US Pat. No. 3,929,987, US Pat. No. 4,202,878, US Pat. No. 4,376
No. 762 specification, U.S. Patent No. 4,376,763 specification,
U.S. Patent No. 4,440,877, U.S. Patent No. 466
3152 specification), the granules contain pigments, fragrances, etc.
For the purpose of an indicator when tooth brushing is completed (Japanese Patent Application Laid-Open No. 60-016913, JP-A No. 62-116506)
JP-A No. 63-250314, Belgian Patent No. 803155), granules containing medicinal ingredients to stabilize the drug (JP-A No. 48-01)
9738, JP-A-49-132249, JP-A-54080429), and the like.

On the other hand, it is known that caries and periodontal disease, which are two major diseases in the oral cavity, occur in the spaces between teeth, grooves, and gaps between teeth and gums. For example, more than 90% of caries in the molar region originates from the fissure region. It is also said that inflammation occurs in the interdental pockets between the teeth and gums.

To prevent these diseases, methods include removing dental plaque with interdental floss, inhibiting plaque accumulation with various drugs, and strengthening tooth structure and gingiva.

[Problems to be Solved by the Invention] However, interdental floss requires a certain amount of skill and time to handle, and even when using chemicals, dental plaque may accumulate in the gaps as mentioned above. Due to the unique shape of the gap, it is difficult for the drug to penetrate and the drug cannot fully exert its effect.

[Means for Solving the Problems] Under these circumstances, the present inventors have developed a method for directly applying medicinal ingredients to the spaces between teeth and between teeth and gums, which are the areas where caries and periodontal diseases often occur. As a result of intensive research into dosage forms, we discovered that a dentifrice containing granules of a certain size and strength obtained by granulating a water-insoluble binder containing medicinal ingredients satisfies these requirements. , completed the invention.

That is, the present invention provides granules that contain a water-insoluble inorganic binder and an oral medicinal ingredient, have a particle size of 50 to 500 JjM, and disintegrate when a load of 0.1 to 10 g is applied to each granule; A dentifrice containing this is provided.

Examples of water-insoluble inorganic binders used in the granules of the present invention include colloidal silica, magnesium aluminate metasilicate, bentonite, montmorillonite, kaolin, synthetic aluminum silicate, calcium silicate, aluminum hydroxide gel, alumina sol, and magnesium carbonate. , synthetic hydrotalcite, magnesium oxide, sodium hydroxide, and the like. These can be used alone or in combination of two or more. When using these inorganic binders to produce granules by spray granulation, it is preferable that they have thixotropic properties in a slurry state.
Particularly preferred are a combination of magnesium aluminate metasilicate and colloidal silica, a combination of synthetic aluminum silicate and colloidal silica, and the like. Granules granulated with these inorganic binders, unlike those granulated with organic binders, have the characteristic that they disintegrate when a certain load is applied, such as the pressure of the bristles of a brush. This allows the drug to act efficiently locally (in spaces). Further, even if this granule contains water, it maintains enough hardness to reach the gaps, and this hardness can be changed depending on the type, combination, amount of inorganic binder, manufacturing conditions of the granule, etc. The blending amount of such an inorganic binder is influenced by other components, and if that component has a dilatant negative effect on spraying, it is preferably 30% by weight or more based on that component.

Incidentally, binders other than the water-insoluble inorganic binder described above may be added within a range that does not impair the effects of the present invention, but blending a water-soluble binder is not preferable because it causes a decrease in granule strength.

The oral medicinal ingredients contained in the granules of the present invention include:
It may be used as long as it is used in the oral cavity, and examples include anti-caries agents, antimicrobial agents, vitamins, enzymes, anti-inflammatory agents, etc., and specific examples include sodium fluoride, Tin fluoride, sodium monofluorophosphate, vitamin E1 vitamin C1 dextranase, mutanase, sodium chloride, glycyrrhetinic acid, azulene, β-glycyrrhetinic acid, dihydrocholesterol, chlorhexidine, epidihydrocholesterol, isopropylmethylphenol, trichlorocarbanilide , halocarban, hinokitiol, allantoin, tranexamic acid, propolis, cetylpyridinium chloride, etc., and these can be used alone or in combination of two or more. When blending granules containing water-soluble among these medicinal ingredients into an O/W type dentifrice, in order to prevent elution into the dentifrice base, the granules are mixed with thermoplastic resin, It is necessary to perform secondary processing using wax, etc.

Therefore, from the viewpoint of cost and the like, it is preferable to use medicinal ingredients that are insoluble or poorly soluble in water. Specific examples of such ingredients include azulene, vitamin E1β-glycyrrhetinic acid, dihydrocholesterol, chlorhexidine,
Examples include epidihydrocholesterol, isopropylmethylphenol, trichlorocarbanilide, halocarban, and hinokitiol.

The granules of the present invention can also contain water-insoluble powder materials that are commonly used as abrasives in dentifrices. Water-insoluble powder materials include dibasic calcium phosphate, tribasic calcium phosphate, insoluble sodium metaphosphate, silica,
Examples include aluminum hydroxide, magnesium phosphate, calcium carbonate, calcium pyrophosphate, zeolite, composite aluminosilicate, magnesium carbonate, red iron sulfate, and calcium sulfate.

The granules of the present invention can be produced, for example, by a spray granulation method, an extrusion granulation method, etc., but it is particularly preferably produced by a spray granulation method. When manufactured by spray granulation method,
The granule shape is almost perfectly spherical, so there is little risk of damaging teeth, and it is easy to handle after production.

When preparing the granules of the present invention, it is necessary to adjust the particle size. That is, the particle size needs to be such that it can easily enter the gaps between the teeth in the oral cavity or between the teeth and the gums. The particle size of granules is 50-500Js1, especially 100-400uIR1
Further, a range of 100 to 300 JIIR is preferred. The particle size may be measured using a scanning electron microscope. If the particle size is less than 50 JEr1, it will hardly penetrate into the above gaps, etc.
500. If it exceeds this, it will be felt as a foreign body sensation in the oral cavity, which is not desirable for the product.

In addition, the strength of the granules is also important, with 0.0% per granule.
It needs to have a strength that allows it to collapse when a load of 1 to 10 g is applied. If the granules disintegrate under a load of less than 0.1 g, they will not be able to penetrate into the dental plaque deposited in the gaps, and will disintegrate before entering the bottom of the gaps, making it impossible for the medicinal ingredients to act directly. In addition, if the granules do not disintegrate even under a load of more than 10g, they will not disintegrate after normal brushing for 1 to 5 minutes and may become stuck between teeth or between teeth and gums, preventing the medicinal ingredients from exerting their effects. I can't.

The particle size and strength of the granules can be adjusted by selecting the type, combination and amount of the water-insoluble inorganic binder and the granule manufacturing conditions.

The granules of the present invention thus obtained can be incorporated into various water-containing compositions, such as creams and ointments, and are particularly preferably incorporated into dentifrices.

When the granules of the present invention are incorporated into toothbrushing, the amount thereof is preferably in the range of 1 to 50% by weight, particularly 3 to 30% by weight. Dentifrices are prepared according to conventional methods, and other ingredients used in normal toothpastes, such as binders, surfactants, sweeteners, fragrances, water, etc., may be added, and medicinal ingredients may also be added to the outside of the granules. can be blended. Specifically, the binder includes sodium carboxymethyl cellulose, sodium polyacrylate, hydroxyethyl cellulose, thickening silica, montmorillonite,
Carrageenan, sodium aldinate, guar gum, pectin, etc. can be used, and as surfactants, salts of acylamino acids such as sodium acylglutamate and sodium acylsarcosinate, salts of alkyl phosphoric acids such as sodium lauryl phosphate, and sucrose fatty acid esters. , sorbitan fatty acid ester, polyoxyethylene fatty acid ester, etc. can be used, and as medicinal ingredients, those that can be blended into the above-mentioned granules can be used regardless of whether they are water-soluble or water-insoluble.

[Examples] Hereinafter, the present invention will be explained in more detail by giving examples, but the present invention is not limited thereto.

Example 1 89 parts by weight of synthetic aluminum silicate as solid content,
10 parts by weight of silicic anhydride (colloidal silica) and β-
A water slurry containing 1 part by weight of glycyrrhetinic acid (water content: approximately 60%) was stirred and mixed for 120 minutes using a stirring mixer, and then granules were produced using a spray granulator. 99% of the total amount of the granules had a particle size of 50-500.

Granules in this particle size range were taken out and subjected to a load (LOAD = 2) using a thermal stress analyzer (Seiko Corporation, 5S-10).
g/m1n), the load at the time of collapse per granule was measured, and the average of 10 measurements was taken as the granule strength.

As a result, the strength of the granules was 4.15 g/piece.

Example 2 As solid contents, 60 parts by weight of calcium carbonate, 28 parts by weight of magnesium aluminate metasilicate, and silicic anhydride (
A water slurry (water content approximately 60%) containing 10 parts by weight of colloidal silica, 1 part by weight of titanium oxide, and 1 part by weight of chlorhexidine hydrochloride was mixed with a stirring mixer for 12 hours.
After stirring and mixing for 0 minutes, granules were produced using a spray granulator. 99% of the total amount of the granules had a particle size of 50-500.

Regarding this granule, the granule strength was measured in the same manner as in Example 1 and found to be 5.16 g/piece.

Example 3 98 parts by weight of synthetic aluminum silicate as solid content,
A water slurry containing 1 part by weight of a surfactant and 1 part by weight of vitamin E (water content: about 60%) was mixed for 30 minutes using a homomixer, and then granules were produced using a spray granulator. 99% of the total amount of this granule has a particle size of 100 to 300μ
Met.

Regarding this granule, the granule strength was measured in the same manner as in Example 1 and found to be 2.83 g/piece.

Comparative Example 1 As solid contents, 50 parts by weight of calcium hydrogen phosphate, 49 parts by weight of synthetic aluminum silicate, and 1 part by weight of titanium oxide
A water slurry containing parts by weight (water content: approximately 60%) was stirred and mixed for 120 minutes using a stirring mixer, and then granules were produced using a spray granulator. 99% of the total amount of the granules had a particle size of 50 to 500μ.

Regarding this granule, the granule strength was measured in the same manner as in Example 1 and found to be 2.04 g/piece.

Comparative Example 2 Solid content (97 parts by weight of synthetic aluminum silicate,
A water slurry (water content approximately 60%) containing 2 parts by weight of Metrose (organic binder) and 1 part by weight of β-glycyrrhetinic acid was stirred and mixed for 120 minutes using a stirring mixer, and then mixed using a spray granulator. Granules were produced. 99% of the total amount of the granules had a particle size of 100-300.

Regarding this granule, the granule strength was measured in the same manner as in Example 1 and found to be 0.07 g/piece.

Example 4 Using the granules obtained in Examples 1 to 3 or Comparative Example 1 or 2, a dentifrice having the following composition was prepared.

Granule glycerin sorbitol solution (wt%) 15.0 010 30, O Sodium carboxymethyl cellulose Sodium saccharin Methyl paraben Flavor 0 0.1 0.1 0.8 Total 100.0 Use these dentifrices to deliver medicinal ingredients locally The amount was measured by the following method.

That is, glass tubes with a diameter of 7 mm and a length of 80 mm were glued together as shown in Figure 1 to create a tooth gap model.

Then apply artificial dental plaque (lipstick with a high proportion of red pigment, Sofina 213, manufactured by Kao Corporation) to a thickness of 1.0 mm in the gap.
It was applied evenly to achieve the above results. Add this to your toothbrush (
Nylon bristles 9 bristles diameter 200. ) was used to remove artificial plaque by brushing using the scrubbing method. Next, 2 g of dentifrice was precisely weighed onto the toothbrush, and the tooth was brushed using a scrubbing method until the red color of the artificial plaque completely disappeared. Fill the gap with 100ml of distilled water
After washing with water, the remaining medicinal ingredients were extracted, and the amount was measured using high performance liquid chromatography, which was defined as the local stagnation amount (title).

In addition, the extraction was performed on the medicinal ingredient (β-
0.0025M phosphoric acid acidic methanol aqueous solution (75v/v%) for glycyrrhetinic acid), and acetonitrile 10.05M phosphate buffer containing 10mM sodium lauryl sulfate (60/40) for the medicinal ingredient of Example 2 (chlorohexidine hydrochloride). As for the medicinal ingredient (vitamin E) in Example 3, methanol was used.

The results are shown in Table 1.

Experimental Example 1 Granules having the same composition as the granules of Example 1 were produced by changing the manufacturing conditions, and by sieving, various average particle diameters (2
0Q, 501s, 100uIR, 2004, 300,
.

Granules of 400 u11 and 500 m) were obtained. A dentifrice having the composition shown in Table 1 was prepared using each of the granules, and the local retention amount of β-glycyrrhetinic acid was measured in the same manner as in Example 4.

The results are shown in Table 2.

It is possible to fully exhibit its medicinal effects.

[Brief explanation of drawings]

FIG. 1 is a drawing showing a tooth gap model used in the measurement of the local stagnation amount of medicinal ingredients in Examples. that's all

Claims (7)

[Claims] (1) Contains a water-insoluble inorganic binder and an oral medicinal ingredient, has a particle size of 50 to 500 μm, and has a particle diameter of 0.000 μm per granule.
Granules that disintegrate when a load of 1 to 10 g is applied. (2) The water-insoluble inorganic binder is colloidal silica, magnesium aluminate metasilicate, bentonite, montmorillonite, kaolin, synthetic aluminum silicate, calcium silicate, aluminum hydroxide gel, alumina sol, magnesium carbonate, synthetic hydrotalcite, oxidized The granule according to claim 1, which is one or more selected from the group consisting of magnesium and sodium hydroxide. (3) The granule according to claim 2, wherein the water-insoluble inorganic binder is a combination of synthetic aluminum silicate and colloidal silica or a combination of magnesium aluminate metasilicate and colloidal silica. (4) The granule according to claim 1, wherein the oral medicinal ingredient is water-insoluble or poorly water-soluble. (5) Oral medicinal ingredients include azulene, vitamin E, β-
The granule according to claim 4, which is one or more selected from the group consisting of glycyrrhetinic acid, dihydrocholesterol, chlorhexidine, epidihydrocholesterol, isopropylmethylphenol, trichlorocarbanilide, halocarban, and hinokitiol. (6) A dentifrice containing the granule according to claim 1. (7) Claim 6, wherein the content of the granules is 1 to 50% by weight.
Toothpaste listed.