JPH0238566B2 - KOKUSEIHIN - Google Patents

Description

[Detailed description of the invention]

FIELD OF THE INVENTION This invention relates to oral products, particularly oral hygiene products containing therapeutic agents. Although this specification specifically refers to the use of a fluoride-containing therapeutic agent to prevent dental caries, it is of course possible to apply the present invention to deliver other therapeutic agents into the oral cavity. It is. The inclusion of fluorine-containing water-soluble salts, such as sodium fluoride and sodium monofluorophosphate, in oral products, especially mouthwashes and dentifrices, may also reduce the risk of dental caries due to regular use of such products. It is also known that the occurrence of can be suppressed. Fluorine ion or monofluorophosphate ion is a tooth substance.
It is thought that this interacts with other acids to increase resistance to acid attack. However, since the fluoride ion level in the oral cavity decreases rapidly after use of gargles or dentifrices, the period during which the above-mentioned effective interaction is effective is short-lived. Fejerskov et al. (Acta Odontol. Scand., 1981,
(39, 241-249) mention that it is essential and necessary for fluoride ions to be present in oral fluids, even at low concentrations, in order to suppress dental caries to the maximum extent. concluded that continuous or frequent replenishment of oral fluids is essential, especially when caries is highly induced. Several proposals have been made to maintain a certain concentration of fluoride ions in the mouth for an extended period of time, such as placing a fluorine ion source in the mouth, for example as part of an orthodontic appliance. recently,
Journal of Pedodontics (1982, Spring), p.218
~228 (Williams et al.) discloses the use of guar gum to adhere fluorine-containing microcapsules to teeth in order to continuously release fluoride ions, and Int.J.Pharmaceutics, 15 , 177~184 ( 1983)
(Spooner et al.) disclose a device that includes a source of calcium fluoride particles within a membrane and is applied to a deionized enamel surface for sustained release of fluoride ions. Ogaard et al. [Caries Res., 17 ,
520-524 (see 1983) found that the sodium fluoride formed in the outer layer of tooth enamel by treatment with an aqueous sodium fluoride solution acts as an effective storage source of fluoride ions, and that the retained fluoride has a cariogenic property. It is an object of the present invention to release therapeutic agents, particularly fluoride ions, into oral fluids over an extended period of time from a specific reservoir. An object of the present invention is to provide an oral hygiene product that is suitable for use in order to retain its activity. The composition and the second composition are combined into a composite agent (a
Included as combined preparation). Said first
The composition comprises an aqueous suspension containing particles that slowly release fluoride ions into saliva, said second component comprising an aqueous solution of a cationic polymer. The present invention is based on the technical concept of sustaining therapeutic activity in oral fluids by releasing therapeutic agents from particles adhering to the oral cavity surface. According to the applicant's findings, the presence of saliva greatly inhibits the decomposition of particles on the oral cavity surface, but contacting the particles with a cationic polymer solution before or simultaneously with insertion of the particles into the mouth inhibits saliva. The effect is eliminated and particles capable of releasing therapeutic agents, particularly fluoride ions, are effectively deposited. The surface charge characteristics of particles capable of releasing therapeutic agents can be anionic, cationic, nonionic or zwitterionic. The particles constituting the fluorine ion source are preferably magnesium fluoride particles, but other slightly water-soluble salts such as calcium fluoride, strontium fluoride, and mixed salt neighborite (NaMgF ₃ ) may also be used.
You can also use Particulate fluoride ion sources such as polymer latexes that release fluoride ions can also be used. The appropriate size of the fluorine ion-releasing particles is 0.01 to 5 μm. The release rate rate of fluorine ions is a function of particle size, and it is believed that particles in the above range will provide the optimum release rate.
The preferred particle size is 0.05-0.5 μm. The particles containing the therapeutic agent must not release active molecules during storage of the product, but must release some therapeutic agent into the mouth between uses of the product, i.e., approximately 2 to 24 hours. Must be. Thus, the particles have, for example, a moderate thermodynamic solubility constant. The solubility constant (K _sp ) of divalent metal fluorides, such as magnesium fluoride, is typically about 5×10 ^-19 to 6.5×
10 ^-5 mol ³ /dm ⁹ . The actual fluorine concentration in the fluorine-containing products of the present invention may be within the conventional range normally established by local legislation. Therefore,
Typical fluorine levels are about 1500 ppm or less, but this value is not critical to the present invention. The cationic polymer has the effect of providing substantial presence on the oral cavity surface of particles capable of releasing therapeutic agents.
Various cationic polymers are commercially available. Polymers based on acrylamide or cationic monomers are suitable, e.g.
FLOC AID manufactured by Adhesives and Resins Limited
Examples include RETEN manufactured by Hercules Inc. in the United States. Among the polymers mentioned above, FLOC AID305 and
One example is RETEN220. Furthermore, the U.S.
Cationic guar derivatives such as JAGUAR from Celanese-Stein Hall are also exemplified as suitable polymers. Desirably, the cationic polymer has a cationic charge density of at least 0.0005. Charge density is the ratio of the number of charges on a polymer unit to its molecular weight. The polymer has a molecular weight of at least about 10,000, usually at least 100,000. The cationic polymer concentration in the composite agent is approximately 3~
600 ppm is suitable, preferably 10-300 ppm. When used, the product acts like a mouth rinse. The two types of compositions are first mixed before use, or the two types of compositions are administered separately into the mouth so that they are mixed in the mouth. It is desirable to include a flavoring agent in at least one of the compositions. Flavoring agents commonly used in oral products may be used. The composition may contain other ingredients so that the composite composition can take the form of a mouthwash. Thus, one or both of the compositions can include ethanol, sorbitol or glycerin, antimicrobials, sweeteners, emulsifiers, water-soluble fluorides. The oral hygiene product in the form of a mouthwash provided by the present invention comprises a suspension of positively charged particles, preferably magnesium fluoride particles, in an aqueous or hydroalcoholic medium that gradually releases a therapeutic agent. The medium contains a dissolved cationic polymer. Compositions of the invention may also take the form of dentifrices. As one of the application forms suitable for the toothpaste product of the present invention,
An example is a method in which two or more materials are mixed together and attached to a toothbrush at the time of use. The aforementioned applications (dispensers) are, for example, USA-3290422
(American Can Co.), GB-A-1335082
(Blendax-Werke) and GB-A-1491053
(Procter & Gamble). When preparing dentifrice compositions consisting of two or more parts, contact between components of opposite charge, such as cationic polymer and anionic surfactant, should be avoided prior to application. By using the oral hygiene product of the present invention, the fluoride ion-releasing particles can be bonded and retained on the oral cavity surface, so that the fluoride ion-releasing particles can ensure that fluoride is constantly available on all tooth surfaces. It acts as a fluorine storage source that releases fluoride ions into saliva at a controlled rate. The constant bioavailability of fluorine is a guideline for preventing dental caries.
Regular use of the oral hygiene products of the present invention can help keep teeth in better health. The oral hygiene product of the present invention will be exemplified below.
Percentages are by weight. Example 1 A two-component mouthwash is illustrated. The first composition consisted of 0.2% MgF ₂ particles and balance water, and the second composition consisted of 0.01% RETEN220 and balance water. Equal amounts of the first composition and the second composition are mixed before use. The magnesium fluoride particles have an average particle size of about 0.1 μm and a particle diameter of about 0.05-0.2 μm. RETEN220 is a cationic high molecular weight copolymer based on acrylamide. 0.5 solid
The viscosity of solutions containing 1.0% and 1.0% is approximately 325 and 1.0%, respectively.
It is 750cps. (Brookfield model LVF viscometer,
spindle speed = 60 rpm, measured at 20°C). The weight average molecular weight of the copolymer is approximately 2,500,000. The positive charge density is approximately 0.001. The ratio of quaternized dimethylaminoethyl methacrylate groups/acrylamide groups is about 1:12. The first and second compositions were mixed with human saliva at a ratio of 10 parts of gargle to 1 part of total human saliva to simulate oral cavity conditions. The rate of particle deposition from this suspension onto a suitable substrate (eg, a saliva-coated glass plate) was approximately 100 times higher than in a similar experiment in which the cationic polymer was omitted. Example 2 A two-component mouthwash was prepared comprising a first composition consisting of 0.082% _MgF2 particles and balance water and a second composition consisting of 0.06% FLOC AID305 and balance water. Before use, 5 ml of the first composition and 5 ml of the second composition were mixed to prepare a gargle containing 250 ppmF. Magnesium fluoride particles have an average particle diameter of
0.06 μm, and its diameter ranged from approximately 0.04 to 0.08 μm. FLOC AID305 has a weight average molecular weight of approximately 2000000
It is a cationic copolymer mainly composed of acrylamide. The ratio of quaternized dimethylaminoethyl methacrylate groups to acrylamide groups is approximately 1:5. The positive charge density of this polymer is approximately 0.002. After putting 10 ml of the gargle in the mouth for 1 minute, the patient spit it out. Saliva samples were taken at regular intervals over several hours after gargle application. The saliva sample was treated with sodium hydroxide (10%), acetic acid (28.5%), trans-1,2-diaminocyclohexane-N,N, which are known to those skilled in the art as ionic strength adjustment buffers.
The pH was adjusted to 5 by adding 10% by weight of a buffer consisting of N',N'-tetraacetic acid (2%) and water (balance). The fluorine ion activity of the saliva sample thus buffered was measured using a special fluorine ion electrode (Orion 94-09). Measure within 5 minutes to see free fluoride ion concentration, or
Alternatively, the total fluorine ion concentration was measured after 2 days when the MgF ₂ particles suspended in saliva were left for dissolution. 0.055% so that the fluorine concentration is 250ppm
Gargle consisting of an aqueous solution containing NaF (control)
A similar operation was performed using . The results are shown in the table below.

[Table] From the above results, it can be seen that in the case of the gargle of the present invention, the levels of total fluoride ions and free fluoride ions in saliva are substantially increased compared to the control gargle containing sodium fluoride. it is obvious. Example 3 A two-component gargle was prepared in the same manner as in Example 2. However, the second composition contains 0.02% FLOC.
Contains AID305. Thereafter, the procedure of Example 2 was repeated. Salivary fluoride levels in saliva obtained using the gargle of this example are as follows.

[Table] From the above results and the results of Example 2, the polymer concentration in the gargle is from 300 ppm (Example 2)
It is clear that the total fluorine content in saliva hardly changes even when reduced to 100 ppm. Example 4 A gargle was prepared from a first composition consisting of 0.15% MgF ₂ particles as in Example 1 and balance water, and a second composition consisting of 0.06% RETEN220 and balance water. A gargle containing 440 ppmF was prepared by mixing 5 ml of the first composition and 5 ml of the second composition. A gargle (control) consisting of an aqueous NaF solution with a fluorine ion concentration of 440 ppmF was also prepared. Thereafter, the procedure of Example 2 was repeated. The fluoride ion levels in saliva when using the gargle of the present invention and the control gargle are as follows.

[Table] Example 5 A gargle containing a water-soluble fluoride (sodium fluoride) is illustrated. The first composition consists of 0.10% _MgF2 particles and 0.14%
The second composition consists of NaF and the balance water, and the second composition is 0.01%
Consists of RETEN220 and the remainder water. The first composition and the second composition are mixed in equal amounts before use. Example 6 A two-component mouthwash is illustrated. The first composition consists of 0.20% _MgF2 particles and 0.14%
The second composition consists of Na ₂ HPO ₄ and the balance water.
Consists of 0.01% RETEN220 and balance water. The first composition and the second composition are mixed in equal amounts before use. The Na ₂ HPO ₄ in the first composition reverses the charge on the magnesium fluoride particles. The presence of Na ₂ HPO ₄ tends to improve the storage stability of the composition. Example 7 A two-component mouthwash composition is illustrated. The first composition consisted of 2.5% Fluoropolymer A particles and the balance glycerol, and the second composition
Consists of 0.0067% RETHN220 and balance water. One part of the first composition and three parts of the second composition are mixed before use. After being deposited in the mouth, the fluoropolymer particles undergo hydrolysis to release fluoride ions. Fluoropolymer A is a poly(methacryloxypropyl difluorohydroxysilane) stabilized by grafted poly(vinyl methyl ether) and is prepared in the form of a first composition as follows. Poly(vinyl methyl ether) (8.0 g) was dissolved in dry cyclohexane (180 c.c.) in a 250 ml flask equipped with a stirrer, condenser and nitrogen blanket. A portion of the cyclohexane (25 c.c.) was distilled off to remove traces of water, and the remainder was purged with dry nitrogen. Azobisisobutyronitrile recrystallized from ethanol (0.05
g) was dissolved in the solution. methacryloxypropyl difluorohydroxysilane (25 g) dissolved in dry cyclohexane (25 c.c.) at 85°C.
was added dropwise to the reaction vessel while stirring. A portion of the monomer solution (approximately 2 c.c.) was added very slowly over a period of 2 hours to form the grafted polymer.
After the addition, the reaction mixture became slightly cloudy, indicating that a graft polymer had formed, and the remaining monomer solution was added dropwise over a further 3 hours. Polymerization was continued for a further 2 hours, resulting in a viscous, translucent dispersion (90% conversion, based on solids content). The molar ratio of fluorosilane to vinyl methyl ether in the polymer was 1:1.33. The fluoropolymer particle dispersion was centrifuged to remove cyclohexane and washed with ethanol. The centrifuged ethanolic dispersion was then redispersed in glycerol to the desired solids content. Example 8 A two-component mouthwash composition is illustrated. The first composition consisted of 2.0% Fluoropolymer B particles, 0.66% _KH2PO4 , 0.11% _NaOH and balance water, and the second composition consisted of 0.0067% RETEN220.
and the remainder water. One part of the first composition and three parts of the second composition are mixed before use. Fluoropolymer particles held in the mouth slowly hydrolyze, releasing fluoride ions. Fluoropolymer B is a poly(methacryloyl fluoride/methyl methacrylate) with a MF/MMA molar ratio of 1:1 and was prepared in the form of a first composition as follows. A mixture (4 g) containing methacryloyl fluoride and methyl methacrylate in an equimolar ratio was dissolved in dry acetone (20 c.c.), and azobisisobutyronitrile (0.10 g) was added. The solution was purged with nitrogen and the monomers were polymerized for 12 hours at 60°C under a nitrogen blanket. The resulting polymer was precipitated in dry n-hexane and dried under nitrogen to yield a glassy powder (1.0 g; yield = 25%). A copolymer latex was prepared using an inverse emulsification method. The copolymer (3.6 g) was dissolved in a solution of oleic acid (0.4 g) in dichloromethane (36 g). Ammonium hydroxide (0.5 cc, "880" ammonium in 36 g water) was added with stirring.
After the viscosity increased to phase transition, a rapid decrease in viscosity occurred. The resulting emulsion was then subjected to ultrasonic dispersion. Removal of the dichloromethane under vacuum below 40°C yielded a stable colloidal latex, which was diluted with phosphate buffer (PH 7) to the desired solids content. The polymer particle size varied depending on the sonication time. Example 9 A two-compartment toothpaste tube suitable for simultaneously applying equal amounts of the first and second compositions is filled with the first and second compositions, respectively. The first composition consisted of 0.33% _MgF2 particles and 3.00% hydroxyethylcellulose (Natrosol
250HR) and 30.00% sorbitol syrup (70
% solution) and 0.23% disodium hydrogen phosphate
With 0.10% saccharin and 1.50% nonionic detergent
The second composition consisted of 1.00% flavoring agent and balance water, with 0.08% FLOC AID305 and 3.00% hydroxyethylcellulose (Natrosol250HR)
% sorbitol syrup (70% solution) and 0.10%
of saccharin, 1.50% nonionic detergent, 1.00% flavoring agent, and the balance water. The pH of both compositions is adjusted to 7 with sodium hydroxide. The compositions may also contain coloring agents and/or preservatives, if desired. An appropriate amount of silica abrasive may be added to the first composition to enhance the cleaning action of the dentifrice. Although the embodiments described above are examples of providing a reservoir of therapeutically active fluoride ions in the oral cavity, particles capable of gradually releasing other therapeutic agents, such as antiplaque agents in the form of microcapsules, are used. Note that it is also possible to use an agent).

Claims (1)

[Scope of Claims] 1. An oral hygiene product comprising a first composition and a second composition as a composite agent for mixing in the mouth or for mixing before insertion into the mouth, wherein the first composition is An oral hygiene product comprising an aqueous suspension of particles that gradually releases fluoride ions into saliva, the second composition comprising an aqueous solution of a cationic polymer. 2. The product according to claim 1, wherein the particles are divalent metal fluoride particles. 3. The product according to claim 1 or 2, wherein the particle size is 0.01 to 5 μm. 4. The product according to any one of claims 1 to 3, wherein the particles are magnesium fluoride particles. 5. A product according to any one of claims 1 to 4, wherein the cationic polymer has a positive charge density of at least 0.0005. 6. The product according to any one of claims 1 to 5, wherein the concentration of the cationic polymer in the mixture of the first composition and the second composition is from 3 to 600 ppm. 7. The product according to any one of claims 1 to 6, which is in the form of a gargle or a dentifrice. 8. The product of any of claims 1 to 7, wherein at least one of the first composition and the second composition comprises a flavoring agent.