JP3376010B2 - Toothpaste composition - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a dentifrice composition, and more particularly to a dentifrice composition filled in a container having an inner surface made of a synthetic resin, which is an arylpropionic acid non-steroidal anti-inflammatory agent as a medicinal agent. The present invention relates to a dentifrice composition which is capable of exhibiting the anti-inflammatory effect and the alveolar bone resorption suppressing effect of the medicinal agent for a long period of time. Therefore, the dentifrice composition of the present invention is effective for treating and preventing periodontal diseases such as gingivitis and periodontitis.

[0002]

2. Description of the Related Art Arylpropionic acid non-steroidal agents have a strong anti-inflammatory effect, and have been attempted for application to periodontal diseases such as gingivitis and periodontitis by blending them with toothpaste and the like.
(JP-A-60-61524, JP-A-52-380)
No. 30, etc.).

By the way, in general, the dentifrice composition is often filled in a so-called laminated container having an inner surface made of synthetic resin. However, such an arylpropionic acid non-steroidal agent (hereinafter sometimes simply referred to as a medicinal agent)
In the case of a dentifrice composition containing the above, since the medicinal agent has extremely high affinity for synthetic resin, it is adsorbed or permeated on the inner surface of the container during storage after filling, and as a result, the medicinal agent concentration in the composition is There is a problem that the amount decreases with time and the compounding cannot be performed stably.

[0004]

SUMMARY OF THE INVENTION The present invention has been made by paying attention to the problems of the prior art as described above.
It is an object of the present invention to provide a dentifrice composition to which an arylpropionic acid non-steroidal anti-inflammatory drug as a medicinal agent can be stably added.

[0005]

The dentifrice composition of the present invention, which has been able to solve the above-mentioned problems, is filled in a container having a synthetic resin layer at least in the innermost layer, and at least one or more arylpropionic acid non-steroids. A dentifrice composition containing an anti-inflammatory agent, wherein the polyoxyethylene-polyoxypropylene copolymer-based surfactant is contained in an amount of 15 to 80% by weight and L-menthol is added to the entire composition. It has the gist that it is a mixture of 0.05 to 2.0% by weight.

[0006]

The present inventors have conducted various studies on the composition of dentifrice in which an arylpropionic acid non-steroidal anti-inflammatory agent can be stably blended when filled in a container whose inner surface is made of synthetic resin. As a result, surprisingly, by incorporating a medicinal agent into a dentifrice base in the presence of a certain amount of polyexyethylene-polyoxypropylene copolymer and a certain amount of L-menthol, the stability over time of the medicinal agent, In particular, they have found that the stability during long-term storage of several months improves further, and have completed the present invention. The arylpropionic acid non-steroidal anti-inflammatory agent according to the present invention includes
Compounds represented by the following general formula are widely included.

[0007]

[Chemical 1]

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 above medicinal agent is
It should be appropriately determined according to the dosage form of the composition, the type of drug, etc., but when ibuprofen and / or flurbiprofen is used, the total amount thereof is preferably 0 based on the entire composition. 0.01 to 5% by weight, and more preferably 0.05 to 1.0% by weight. When the content is less than 0.01% by weight, sufficient anti-inflammatory effect and alveolar bone resorption inhibitory effect are not obtained, while when it exceeds 5% by weight, these effects are not only saturated but also irritating to oral mucosa Is present, which is a practical problem. Furthermore, the manufacturing cost also increases, which is not preferable.

The polyoxyethylene-polyoxypropylene block copolymer-based surfactant used in the present invention is a known surfactant composed of polyoxyethylene-polyoxypropylene glycol, which is known as "PLURONI" from BASF Corporation of the United States.
C) ”is commercially available. The surfactant is generally chemically defined by the weight percentage of the total molecular weight of the polyoxypropylene hydrophobic portion and the polyoxyethylene hydrophilic portion. Preferred are those in which the molecular weight of the hydrophobic group (polyoxypropylene) is 1400 to 4000 and the proportion of the hydrophilic group (polyoxyethylene) in the total molecular weight is in the range of 30 to 80% by weight.

The polyoxyethylene-polyoxypropylene block copolymer type surfactant is contained in the composition in an amount of about 15 to about 10%.
The amount is 80% by weight, preferably 20 to 50% by weight. When the blending concentration of the surfactant is less than 15% by weight, gelation is not sufficient, so that there is a problem in property stability due to solid-liquid separation. On the other hand, if it exceeds 80% by weight, gelation is too strong to obtain an appropriate viscosity as a dentifrice.

In the present invention, L-menthol is blended in order to improve the stability over time of the drug, especially the long-term stability. When the above-mentioned surfactant is blended, the flavoring due to the fragrance component is reduced, but L-menthol also has the action of preventing such a reduction in flavoring. Its content is 0.05 to 2.0% by weight, preferably 0.1 to 1.0% by weight, based on the whole composition. 0.05
If it is less than 2.0% by weight, not only the stability of the medicinal agent over time is poor but also the refreshing feeling is poor, while if it exceeds 2.0% by weight, it is not preferable because of the problem of irritation and feeling of use derived from L-menthol.

The dentifrice composition of the present invention can be made into a dosage form such as toothpaste and pasta according to a conventional method, and if necessary, an abrasive, a thickener, a fragrance, a sweetener, and other medicinal agents are used. It can be appropriately blended within a range that does not impair the effects of the invention.

The L-menthol used to improve the stability of the medicinal agent in the dentifrice composition of the present invention over time also acts as a fragrance component. Therefore, when other fragrance components are used in combination, The total amount of L-menthol is preferably 0.1 to 5.0% by weight.

In the present invention, as the active ingredient, a cationic bactericidal agent such as cetylpyridinium chloride and chlorhexidine salts, dextranase, amylase, protease, mutanase, lysozyme, enzymes such as lytic enzyme (Litech Enzyme), monofluoro, etc. Alkali metal monofluorophosphates such as sodium phosphate, potassium monofluorophosphate, sodium fluoride, fluorides such as stannous fluoride, tranexamic acid and epsilon aminocaproic acid, aluminum chlorohydroxyallantoin, dihydrocholesterol, glycyrrhizinate, glycyrrhetin One or more active ingredients such as an acid, glycerophosphate, chlorophyll, sodium chloride, caropeptide, and a water-soluble inorganic phosphate compound may be blended.

In the present invention, the container having an inner surface made of synthetic resin is composed of a synthetic resin such as polyolefin such as polyethylene and polypropylene, polyethers, Surlyn, nylon, vinyl chloride, etc., in a portion in contact with the dentifrice composition. It means a tube or other container that is used.

Specific examples of such a container include a tube made of polyethylene, paper, aluminum or the like and a laminated tube using polyethylene, polyethers, surlyn, nylon or the like in the innermost layer; polyethylene, polypropylene, nylon, Examples thereof include a poly tube made of at least one kind of vinyl chloride and the like, and a poly container made of at least one kind of polyethylene, polypropylene, nylon, vinyl chloride and the like.

[0018]

EXAMPLES Next, the present invention will be described more specifically by showing experimental examples and examples, but the present invention is not limited to these, and changes and modifications can be made without departing from the spirit of the preceding and the following. All that is included in the technical scope of the present invention. All "%" are% by weight.

Experimental Example 1 A toothpaste was prepared according to a conventional method according to the formulation shown in Table 1. The obtained toothpaste was filled in a laminate tube (innermost layer: polyethylene), and the storage stability of the medicinal agents (ibuprofen and flurbiprofen) was measured by the following method for the initial product and the product left at 40 ° C for 6 months. The sensory evaluation was also performed on the feeling of use and irritation, and a comprehensive evaluation of these was performed.

[Stability test of drug efficacy agent] (1) Preparation method of standard solution About 100 mg of dried drug efficacy standard product was precisely weighed, and methanol was added to make exactly 100 ml. 2 ml of this solution was accurately weighed and methanol was added to make exactly 100 ml, which was used as the HPLC standard solution. (2) Preparation method of sample solution About 2.0 g of toothpaste was precisely weighed, 20 ml of methanol was added thereto to disperse the mixture, and the mixture was shaken for 10 minutes, centrifuged and the supernatant 100
The mixture was placed in a ml volumetric flask and the same operation was repeated twice on the residue to add methanol to make exactly 100 ml. This solution was filtered to give an HPLC sample solution. (3) Quantitative Method of Drug Efficacy by HPLC 20 μl each of the HPLC standard solution and the sample solution were accurately taken and tested by liquid chromatography.

The residual ratio shown in Table 1 is shown as the residual amount when the initial drug compounding amount is 100. [Ibuprofen HPLC operating conditions] Detector: UV absorptiometer (measurement wavelength 220 nm) Column: NUCLEOSIL 10C18 (4.6
mmφ × 250 mm) Column temperature: constant temperature around 40 ° C. Mobile phase: 10 mM solution of sodium dihydrogen phosphate was adjusted to pH 3.0 with phosphoric acid, and this solution and methanol were mixed at a ratio of 25:75 Amount: The retention time of ibuprofen is adjusted to be about 8 minutes.

[Flurbiprofen HPLC operating conditions] Detector: Ultraviolet absorptiometer (measurement wavelength 246 nm) Column: INERTSIL ODS-2 (4.6 mm)
φ × 150 mm) Column temperature: constant temperature around 40 ° C. Mobile phase: 0.05 M solution of potassium dihydrogen phosphate,
65: 3 acetonitrile and triethanolamine
Mixture volume of 5: 0.02 Liquid volume: 0.9 ml / min

The amount of the medicinal agent in the sample was calculated by the following formula. Amount of medicinal agent in 100 g of toothpaste (g) = (A′x / Ax ×
K ₁ × Mx × (1 / Wt) × 2 (g) However, in the formula, K ₁ = purity of drug efficacy standard product (not required when the purity is 99.0% or more) Mx = weighed amount of drug efficacy standard product (G) A′x = peak area of drug efficacy in sample solution Ax = peak area of ibuprofen in standard solution Wt = weighed sample amount (g) The daily stability of the drug was evaluated according to the following criteria. ○… The residual rate of the drug efficacy is 95% or more △… The residual rate of the drug efficacy is 85% or more and less than 95% ×… The drug efficacy residual rate is less than 85%

[Usage test] Further, ten professional panelists were used to evaluate the feeling of use and the irritancy according to the following criteria. ○… No feeling of tingling and feeling of refreshing △… No feeling of feeling of tingling but also feeling of refreshing ×… With feeling of tingling [Comprehensive evaluation] Is ○. × ... The judgment result of aging stability was × or Δ, and / or the judgment result of feeling of use and irritation was × or Δ.

[0025]

[Table 1]

[0026]

[Table 2]

As is clear from Tables 1 and 2, the residual ratios of ibuprofen and flurbiprofen were much lower than 90% in the very common formulations such as Comparative Sample Nos. 1 and 16, and the medicinal agents were used as the basis. It was clear that it was not stably compounded in the agent.

Further, sodium carboxymethyl cellulose and sodium lauryl sulfate were removed from comparative sample Nos. 1 and 16 and a polyoxyethylene-polyoxypropylene copolymer type surfactant was added (comparative sample).
Nos. 2 to 5) also made it possible to slightly improve the residual rate of the medicinal agent. But it was inadequate. On the other hand, the present invention sample Nos. 7 to 11 and 13 to
15, 18, 19, 21-23, by blending a polyoxyethylene-polyoxypropylene copolymer based surfactant and 0.05-2.0 wt% L-menthol, ibuprofen and The residual rate of flurbiprofen could be significantly improved, and the medicinal agent could be stably compounded. In addition, when the compounding amount of L-menthol is out of the range of 0.05 to 2.0% by weight (Comparative Sample Nos. 6, 12, 17, and 20), stability over time and / or feeling of use and irritation are observed. The problem arose.

Example 1 In this example, a toothpaste was prepared by the usual method according to the following formulation and filled in a laminate tube. Ingredients Amount (%) Ibuprofen 0.1 Pluronic F 127 25.0 Average degree of polymerization: Ethylene oxide 196 Propylene oxide 67 Anhydrous calcium hydrogen phosphate 20.0 Glycerin 20.0 Sodium saccharin 0.2 L-Menthol 0.5 Fragrance (excluding L-menthol) 0.5 Cetylpyridinium chloride 0.05 Purification Water balance total 100.0 The composition of Example 1 also gave good drug stability.

Example 2 In this example, a toothpaste was prepared by the usual method according to the following formulation and filled in a laminate tube. Ingredients Amount (%) Flurbiprofen 0.05 Pluronic F 127 20.0 Average degree of polymerization: Ethylene oxide 196 Propylene oxide 67 Silic anhydride 15.0 Sorbite 40.0 Stevia extract 0.2 Allantoinchlorohydroxyaluminum 0.05 Sodium lauryl sulfate 0.5 L-Menthol 0.7 Perfume (L) -Excluding menthol) 0.5 Total purified water balance 100.0 The composition of Example 2 also provided good drug stability.

Example 3 In this example, a toothpaste was prepared by the usual method according to the following formulation and filled in a laminate tube. Ingredients (%) Ibuprofen 0.5 Pluronic F 87 35.0 Average degree of polymerization: Ethylene oxide 124 Propylene oxide 39 Sorbite 35.0 Aluminum hydroxide 15.0 Dipotassium glycyrrhizinate 0.05 L-menthol 0.3 Fragrance (excluding L-menthol) 0.7 Purified water balance 100.0 The composition of Example 3 also provided good drug stability.

Example 4 In this example, a toothpaste was prepared by the usual method according to the following formulation and filled in a laminate tube. Ingredients Amount (%) Flurbiprofen 0.5 Pluronic P-94 45.0 Average degree of polymerization: Ethylene oxide 42 Propylene oxide 47 Glycerin 20.0 Anhydrous calcium hydrogen phosphate 20.0 Sodium carboxymethylcellulose 0.5 Saccharin sodium 0.1 L-Menthol 0.3 Perfume (L-Menthol) 0.5) Total purified water balance 100.0 The composition of Example 4 also provided good drug stability.

Example 5 In this example, a toothpaste was prepared by the conventional method according to the following formulation and filled in a laminate tube. Ingredients Amount (%) Ibuprofen 0.1 Pluronic F-88 35.0 Average degree of polymerization: Ethylene oxide 194 Propylene oxide 39 Anhydrous calcium hydrogen phosphate 20.0 Glycerin 20.0 Sodium monofluoroate 0.7 Cetylpyridinium chloride 0.5 Tocopherol acetate 0.05 Saccharin sodium 0.1 L-menthol 0.7 Perfume (Excluding L-menthol) 0.3 Purified water balance 100.0 The composition of Example 5 also showed good drug stability.

Example 6 In this example, a toothpaste was prepared by the usual method according to the following formulation and filled in a laminate tube. Ingredients Amount (%) Flurbiprofen 1.0 Pluronic F-88 35.0 Average degree of polymerization: Ethylene oxide 194 Propylene oxide 39 Sorbit 40.0 Chlorhexidine hydrochloride 0.05 Silicic anhydride 15.0 Dipotassium glycyrrhizinate 0.1 L-menthol 0.3 Perfume (excluding L-menthol) ) 0.3 Total balance of purified water 100.0 The composition of Example 6 also provided good drug stability.

[0035]

EFFECTS OF THE INVENTION The present invention is configured as described above, and in a dentifrice composition filled in a container having an inner surface made of a synthetic resin, an arylpropionic acid nonsteroidal anti-inflammatory agent as a medicinal agent is used. A dentifrice composition that can be stably formulated is realized.

The dentifrice composition of the present invention can exert the anti-inflammatory effect and the effect of suppressing alveolar bone resorption possessed by the arylpropionic acid non-steroidal anti-inflammatory agent for a long period of time. Therefore, gingivitis and periodontitis. It is useful for treating and preventing periodontal diseases such as.

Continuation of the front page (56) Reference JP-A-3-218308 (JP, A) JP-A-4-159212 (JP, A) JP-A-56-110610 (JP, A) (58) Fields investigated (Int .Cl. ⁷ , DB name) A61K 7/16

Claims (3)

(57) [Claims] 1. A dentifrice composition, which is filled in a container having a synthetic resin layer as at least the innermost layer and contains at least one or more arylpropionic acid non-steroidal anti-inflammatory agent, comprising polyoxyethylene-poly The oxypropylene copolymer-based surfactant is added to the composition in an amount of 15 to 8
0% by weight and L-menthol to 0.
A toothpaste composition characterized by being blended in an amount of 05 to 2.0% by weight. 2. The dentifrice composition according to claim 1, wherein the arylpropionic acid nonsteroidal anti-inflammatory drug is ibuprofen and / or flurbiprofen. 3. The total content of ibuprofen and / or flurbiprofen is 0.01 to the total composition.
The dentifrice composition according to claim 2, which is 5% by weight.