Preparation for Attaching to Teeth or Surrounding Part of Teeth

Abstract

The present invention provides a preparation for attaching to teeth or tooth peripheries, which comprises a malleable oral composition and an active ingredient for intra-oral delivery. Further, the present invention provides a preparation for attaching to teeth or tooth peripheries, which comprises an oral composition in a hardening ointment-phase and an active ingredient for intra-oral delivery. The preparation of the present invention may give high adhesive force to the desired site in spite of gaps between teeth or curves of teeth. The preparation of the present invention having high adhesive force increases the time of adhesion to a target site in the oral cavity, and thus may be advantageous in achieving an intended effect.

Claims

1. A preparation for attaching to teeth or tooth peripheries, which comprises: an oral composition in a hardening ointment-phase; and an active ingredient for intra-oral delivery, wherein the oral composition in the hardening ointment-phase comprises a phase transition material, a phase transition auxiliary material, and an attachment-enhancing material of a phase transition composition, wherein the phase transition material includes carrageenan, pectin, xyloglucan, gellan gum, ammonium alginate, magnesium alginate, potassium alginate, sodium alginate, lithium alginate, chitosan, poly-lactic acid (poly(D,L-lactic acid)), polylactide-co-glycolide (poly(DL-lactide-co-glycolide)), poly-caprolactone, polyacrylic acid (carbopol), polyvinylacetal diethyl aminoacetate (AEA), hydroxypropylmethyl cellulose, poly(methacrylic acid)-poly(ethylene glycol), poly(D,L-lactide)-block-poly(ethylene glycol)-block-poly(D,L-lactide), PEG-oligoglycolyl-acrylate, poly(N-isopropyl acrylamide), sucrose acetate isobutyrate, polyvinyl alcohol, glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate, or a mixture thereof, wherein the phase transition auxiliary material includes a calcium ion source of calcium sulfate, calcium carbonate, calcium phosphate dibasic (CaHPO.sub.4), barium carbonate, zinc carbonate, calcium chloride, calcium lactate, calcium citrate, calcium aspartate, calcium saccharate, calcium oxovalerate, calcium gluconate, calcium lactobionate or calcium lactogluconate; a chelating agent of barium carbonate, zinc carbonate, sodium bicarbonate, sodium carbonate, tetraborate or tripolyphosphate; acetic acid, malic acid, lactic acid, gluconic acid, ascorbic acid, boric acid or a mixture or a salt thereof; or NaOH, KOH or a mixture thereof, wherein the attachment-enhancing material of the phase transition composition includes precipitated silica for thickening, colloidal silicone dioxide, polyvinyl pyrrolidone, poly methyl vinyl ether and maleic acid copolymer, shellac, rosin, poloxamer, hyaluronic acid, acrylate copolymer, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyacrylic acid, polyethylene glycol, ethyl cellulose or a mixture thereof, or a crosslinked body thereof, wherein the active ingredient is sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate, tetrasodium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acidic sodium metaphosphate, acidic sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), aspirin, ketorolac, flurbiprofen, piroxicam, meclofenamic acid, thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, titrated extract of Zea Mays L. unsaponifiable fraction, Magnoliae Cortex, Myrrha, Rhatany, Chamomile, policresulen, titrated extract of Centella Asiatica, nutmeg extract, dexpanthenol, β-sitosterol, acetyl salicylic acid, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, ferric oxalate, vitamin E, or a mixture thereof, and wherein the preparation has the initial hardness of from 0.1 g to 20,000 g, measured at Compression mode of Texture Analyzer (TA), at the time of attachment; and has the final hardness of 40,000 g or less, measured at Compression mode of Texture Analyzer (TA), at the time of removal.

2. The preparation of claim 1, wherein the active ingredient is mixed with the oral composition in a hardening ointment-phase and contained in the preparation.

3. The preparation of claim 1, wherein the preparation becomes hardened and substantially loses its moldability in 5 minutes to 3 hours after the preparation is attached to teeth or tooth peripheries under the humidity and temperature conditions of the oral cavity.

4. The preparation of claim 3, wherein the becoming hardened and losing its moldability means that the preparation becomes to have a viscosity of 5000 cps or higher, which is measured by using Brookfield viscometer equipped with No. 6, 7 spindles at 20° C., 5 to 20 rpm, in 5 minutes to 3 hours after the preparation is attached to teeth or tooth peripheries.

5. The preparation of claim 1, wherein the time of removal is when the amount of the active ingredient released into the oral cavity is 60 wt % or more, based on the amount of the active ingredient contained in the initial preparation, after 30 minutes from the attachment of the preparation to teeth or tooth peripheries.

6. The preparation of claim 1, wherein the preparation increases its area when the preparation is pressed by applying force at the beginning of attachment.

7. The preparation of claim 1, wherein the preparation is one-formulation type; or two-formulation type consisting of the first formulation and the second formulation.

8. The preparation of claim 1, wherein the oral composition in a hardening ointment-phase further comprises a material for helping drug release, and wherein the material for helping drug release includes at least one acid and at least one base, and wherein the preparation is a two-formulation type consisting of a first formulation containing the at least acid and a second formulation containing the at least one base.

9. The preparation of claim 1, wherein water-solubility of the preparation, measured at 32° C., 1 atm after 5 minutes to 3 hours from attachment of the preparation to teeth or tooth peripheries, is 20 wt % or less.

10. The preparation of claim 1, wherein the preparation further comprises a backing layer.

11. A preparation for attaching to teeth or tooth peripheries, which comprises: a malleable oral composition; and an active ingredient for intra-oral delivery, wherein the malleable oral composition comprises a phase transition material, a phase transition auxiliary material, and an attachment-enhancing material of a phase transition composition, wherein the phase transition material includes carrageenan, pectin, xyloglucan, gellan gum, ammonium alginate, magnesium alginate, potassium alginate, sodium alginate, lithium alginate, chitosan, poly-lactic acid (poly(D,L-lactic acid)), polylactide-co-glycolide (poly(DL-lactide-co-glycolide)), poly-caprolactone, polyacrylic acid (carbopol), polyvinylacetal diethyl aminoacetate (AEA), hydroxypropylmethyl cellulose, poly(methacrylic acid)-poly(ethylene glycol), poly(D,L-lactide)-block-poly(ethylene glycol)-block-poly(D,L-lactide), PEG-oligoglycolyl-acrylate, poly(N-isopropyl acrylamide), sucrose acetate isobutyrate, polyvinyl alcohol, glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate, or a mixture thereof, wherein the phase transition auxiliary material includes a calcium ion source of calcium sulfate, calcium carbonate, calcium phosphate dibasic (CaHPO.sub.4), barium carbonate, zinc carbonate, calcium chloride, calcium lactate, calcium citrate, calcium aspartate, calcium saccharate, calcium oxovalerate, calcium gluconate, calcium lactobionate or calcium lactogluconate; a chelating agent of barium carbonate, zinc carbonate, sodium bicarbonate, sodium carbonate, tetraborate or tripolyphosphate; acetic acid, malic acid, lactic acid, gluconic acid, ascorbic acid, boric acid or a mixture or a salt thereof; or NaOH, KOH or a mixture thereof, wherein the attachment-enhancing material of the phase transition composition includes precipitated silica for thickening, colloidal silicone dioxide, polyvinyl pyrrolidone, poly methyl vinyl ether and maleic acid copolymer, shellac, rosin, poloxamer, hyaluronic acid, acrylate copolymer, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyacrylic acid, polyethylene glycol, ethyl cellulose or a mixture thereof, or a crosslinked body thereof, wherein the active ingredient is sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate, tetrasodium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acidic sodium metaphosphate, acidic sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), aspirin, ketorolac, flurbiprofen, piroxicam, meclofenamic acid, thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, titrated extract of Zea Mays L. unsaponifiable fraction, Magnoliae Cortex, Myrrha, Rhatany, Chamomile, policresulen, titrated extract of Centella Asiatica, nutmeg extract, dexpanthenol, β-sitosterol, acetyl salicylic acid, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, ferric oxalate, vitamin E, or a mixture thereof, and wherein the preparation has the initial compressibility of 0.1 to 30,000 gs, measured at Compression mode of Texture Analyzer (TA); and has the final compressibility of 50,000 gs or less, measured at Compression mode of Texture Analyzer (TA).

12. The preparation of claim 11, wherein the active ingredient is mixed with the malleable oral composition and dispersed in the preparation.

13. The preparation of claim 11, wherein the time of removal is when the amount of the active ingredient released into the oral cavity is 60 wt % or more, based on the amount of the active ingredient contained in the initial preparation, after 30 minutes from the attachment of the preparation to teeth or tooth peripheries.

14. The preparation of claim 11, wherein the preparation increases its area when the preparation is pressed by applying force at the beginning of attachment.

15. The preparation of claim 11, wherein the malleable oral composition further comprises a material for helping drug release, and wherein the material for helping drug release includes at least one acid and at least one base, and wherein the preparation is a two-formulation type consisting of a first formulation containing the at least acid and a second formulation containing the at least one base.

16. The preparation of claim 11, wherein the preparation is one-formulation type; or two-formulation type consisting of the first formulation and the second formulation.

17. The preparation of claim 11, wherein the preparation becomes hardened and substantially loses its moldability in 5 minutes to 3 hours after the preparation is attached to teeth or tooth peripheries under the humidity and temperature conditions of the oral cavity.

18. The preparation of claim 17, wherein the becoming hardened and losing its moldability means that the preparation becomes to have a viscosity of 5000 cps or higher, which is measured by using Brookfield viscometer equipped with No. 6, 7 spindles at 20° C., 5 to 20 rpm, in 5 minutes to 3 hours after the preparation is attached to teeth or tooth peripheries.

19. The preparation of claim 11, wherein water-solubility of the preparation, measured at 32° C., 1 atm after 5 minutes to 3 hours from attachment of the preparation to teeth or tooth peripheries, is 20 wt % or less.

20. The preparation of claim 11, wherein the preparation further comprises a backing layer.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Other objects and aspects of the present invention will become apparent from the following descriptions of the embodiments with reference to the accompanying drawings in which:

[0081] The accompanying drawings illustrate a preferred embodiment of the present invention and together with the foregoing disclosure, serve to provide further understanding of the technical spirit of the present invention, and thus, the present invention is not construed as being limited to the drawing.

[0082] In the drawing, T refers to teeth, and 1 refers to the conventional strip for attaching to teeth. 2 refers to an active ingredient, and 10 refers to the oral preparation manufactured according to one embodiment of the present invention.

[0083] FIG. 1 is a drawing showing (a) the conventional strip for attaching to the oral cavity and (b) the preparation according to one embodiment of the present invention. Unlike the conventional strip wherein an active ingredient 2 and a strip 1 are in separate layers, the preparation according to one embodiment of the present invention can have the form that the drug is dispersed in the preparation.

[0084] FIG. 2 is a drawing prefiguratively showing the process of attaching the preparation of the present invention 10 to teeth T and then removing the preparation from the teeth over time.

[0085] FIG. 3 is a drawing prefiguratively showing the process of hardening the preparation according to one embodiment of the present invention after applying and adhering the preparation to teeth. As can be seen from FIG. 3, the preparation of the present invention can reach gaps between teeth.

[0086] FIG. 4 is a drawing prefiguratively showing the process of attaching the preparation 10 to teeth T and then removing the preparation from the teeth over time according to another embodiment of the present invention.

EXAMPLES

[0087] Hereinafter, the present invention will be described in more detail through the following embodiments. However, the embodiments according to the present invention may be modified in many different forms, and the scope of the present invention shall not be construed as being limited to the embodiments described below. The embodiments of the present invention are provided for illustration to help a full understanding of the present invention. Unless stated otherwise, % used herein are understood to mean wt %.

[0088] Preparation and Test of Oral Composition in a Hardening Ointment-Phase

[0089] [Preparation of Oral Preparation]

[0090] Oral preparations of Examples and Comparative Examples having the following composition were prepared or purchased.

[0091] Preparations of Examples 1 to 3 were manufactured according to the following method. The powder preparation of Example was mixed by using a powder mixer, the gel of Example was prepared by mixing a polymer with a mechanical mixer at a constant rate without aggregation. Further, Example 3 was prepared by mixing with a mechanical mixer after adjusting temperature to 50° C.

TABLE-US-00001 TABLE 1 Example 3 Example 2 (Gel type, which is Phase Example 1 (Film coating (Dual paint type with applicator transition type type with separate backing layer) (dual syringe + mixing tip)) by saliva) First Alginate 12% First Alginate 3.8% GMO 48.0% formulation Calcium Sulfate 15% formulation Acetic Acid 2.5% EC 8.0% (powder) Sodium Phosphate 2% (gel-like) Magnoliae Cortex 0.1% Hydrogen Peroxide 6% Diatomite to 100% (active ingredient) (active ingredient) Second Gantrez 0.38% Water to 100% Ethanol 44.0% formulation Zinc Chloride 0.18% Second Alginate 3.8% (liquid-like (active ingredient) formulation Calcium Carbonate 2.0% viscosity) Water to 100% (gel-like) Sodium Carbonate 1.9% Backing layer PE film Water to 100%

[0092] Comparative Examples 1 to 5 were prepared. Comparative Example 1 used P&G SensiStop (containing active ingredient of improving sensitive teeth) and Comparative Example 2 used Parodontax (containing active ingredient of improving gingivitis).

[0093] Comparative Example 3 used Alginate Gel prescription (alginate water-soluble gel prescription, tooth whitening), Comparative Example 4 used Poloxamer prescription as a Temperature Sensitive Polymer (tooth whitening) and Comparative Example 5 used dental impression material prescription (silicone dual-syringe prescription).

TABLE-US-00002 TABLE 2 Comparative Example 5 Dental impression material Comparative Example 2 (Selection VPS Putty) (Product name: Formulation: Comparative Example 1 Parodontax ™) Comparative Example 3 Comparative Example 4 Reactive silicone gel (P&G SensiStop ™) Formulation: (Alginate Gel) (Poloxamer) (First formulation, Formulation: Strip Toothpaste Formulation: Gel Formulation: Liquid Second formulation) Water Myrrha tint Alginate 1.5% PluronicF127 20% Vinyl Polysiloxane Glycerin Rhatany tint Hydrogen Peroxide 6% Carbamide Peroxide 16% Impression Material Cellulose Gum Chamomile tint Water to 100% (H.sub.2O.sub.2 5.6%) (First formulation, Dipotassium Oxalate Water to 100% Second formulation) (active ingredient ) Carbomer Sodium Hydroxide Sodium Benzoate Potassium Sorbate PE film

[0094] [Test for Comparing Viscosity, Solubility and Convenience of Use Before Attachment or at the Beginning of Attachment and Just Before Removal]

[0095] Test Method

[0096] 1. Viscosity comparison test (Test method: Viscosity was measured by using Rotary Viscometer) [0097] Evaluation device: Brookfield Viscometer, No. 6, or 7 spindle, 5 rpm to 20 rpm, 20° C. (room temperature) [0098] Evaluation method: Viscosity of Comparative Example and Example was measured by using Brookfiled Viscometer.

[0099] As follows, i) viscosity at the first application, ii) viscosity in adhesion, iii) and viscosity just before removal were measured. But, in the case of the prescription consisting of the first formulation and the second formulation, each viscosity measured before mixing the first formulation and the second formulation was referred to as the viscosity at the time of manufacture, and in the case of consisting of only the first formulation, the viscosity at the time of manufacture was referred to the same as the viscosity before the first application.

[0100] i) Viscosity at the first application: in the case of consisting of the first formulation and the second formulation, it is the same as the viscosity right after mixing, and in the case of consisting of only the first formulation, it is the same as the viscosity at the time of manufacture.

[0101] ii) Viscosity in adhesion: in the case of consisting of the first formulation and the second formulation, the viscosity is increased from the moment of mixing, and the viscosity means the viscosity in the state where shape transformation can occur even at a small pressure. In this test, for example, in the case of a preparation whose total use time is 10 min, the preparation was adhered to the desired site at 5 min after application, and in the case of a preparation whose total use time is 30 min, the preparation was adhered to the desired site at 5 min to 10 min after application. The viscosity at this time was measured as the viscosity in adhesion.

[0102] iii) Viscosity just before removal or upon completion of drug release (the time at which about 70% to 100% of drug is released): it means the viscosity when no further viscosity increase occurs.

[0103] For example, in the case of a prescription for tooth whitening and maintaining the whitening effect, which consists of the first formulation and the second formulation, and is attached for 30 min, {circle around (1)} Viscosity at the time of manufacture means each viscosity before mixing, {circle around (2)} Viscosity at the first application means the viscosity just before application to teeth (when consisting of the first formulation and the second formulation, it means the viscosity right after mixing) {circle around (3)} Viscosity in adhesion means the viscosity at 10 min after application to teeth, {circle around (4)} Viscosity just before removal or upon completion of drug release means the viscosity at 30 min after application to teeth.

[0104] 2. Drug release rate comparison test (Test method: after releasing test, the concentration of an active ingredient in a solution was quantified)

[0105] A) Manipulation

[0106] 0.9% Sodium chloride solution 500 mL is poured in a test tube and a temperature of a test solution is maintained at 32±0.5° C. during drug release test. Example or Comparative Example as a sample is fixed on the upper side of a disk which can be used as a sinker without absorbing, interfering or reacting so that a target attachment surface faces outward. Then, the disk is placed in the test tube with the sample-attached side facing up, and drug release time is calculated from this point of time. The sample-attached disk is aligned parallel to the bottom of the test tube and a paddle blade. Distance between the paddle blade and the sample surface is set to 25±2 mm, and revolutions per min (rpm) is set to 25. At the time of sampling, 100 mL of sample solution is collected at a fixed position (a position 1 cm away from the wall of the test tube, between the top of the paddle blade and the test liquid surface) 30 min after the start of the test.

[0107] Drug analysis method: Depending on the drug or the content, an appropriate analysis is selected. For example, peroxides are analyzed by titration, metal salts are analyzed by ICP analysis, and natural extracts are analyzed by HPLC.

[0108] 3. Solubility comparison test: In the present invention, solubility is defined as shape retention force during artificial saliva (0.9% NaCl aqueous solution) release test. Recorded through comparative observation (Whether the shape is collapsed or maintained, or the same thickness and height are maintained or decreased in the USP drug release test was observed and recorded)

[0109] {circle around (1)} Solubility at the time of manufacture: in the case of consisting of the first formulation and the second formulation, 1 g each was taken and loaded in the same manner as the drug release test, and then solubility was observed.

[0110] {circle around (2)} In the case of consisting of the first formulation and the second formulation, solubility at the first application, in adhesion and just before removal was measured by loading the drug in the same manner as the drug release test, and observing shape transformation over time.

[0111] 4. Convenience of use comparison test (Whether wet type or dry type): The characteristics of the formulation applied to the target in the oral cavity cause the inconvenience to use because the formulation is smeared to the hands while being applied. Further, those cause the inconvenience to use because the formulation is smeared to gums or hands while applying and standing for a certain time and is smeared to the hand during removal. Wet type is characterized in that it is smeared to the hands when touched, and dry type is characterized in that it is not smeared when touched by hands because it maintains its shape.

[0112] [Efficacy/Effect Comparison Test]

[0113] 1. Clinical Survey Related to Improvement of Sensitive Teeth for Humans

[0114] 1) Test subject and instructions: Example 1 group and Comparative Example 1 group were attached to the sensitive teeth area for 10 min once a day and then removed.

[0115] 2) After 1 week use, the survey was conducted to 15 volunteers who felt sensitive teeth per each group using 3-point Likert scale.

[0116] 3) Criteria

[0117] 1 point: Compared to before use, the sensitive teeth symptoms were similar or worsened.

[0118] 2 point: Compared to before use, the sensitive teeth symptoms were slightly relieved.

[0119] 3 point: Compared to before use, the sensitive teeth symptoms were a lot relieved.

[0120] 2. Clinical Survey Related to Improvement of Gingivitis Symptoms-Relief of Gum Pain for Humans

[0121] 1) Test subject and instructions: Example 2 group and Comparative Example 2 group were attached to the gum pain area for 10 min once a day and then removed.

[0122] 2) After 1 week use, the survey was conducted to 15 volunteers who felt gum pain per each group using 3-point Likert scale.

[0123] 3) Criteria

[0124] 1 point: Compared to before use, the gum pain symptoms were similar or worsened.

[0125] 2 point: Compared to before use, the gum pain symptoms were slightly relieved.

[0126] 3 point: Compared to before use, the gum pain symptoms were a lot relieved.

[0127] 3. Evaluation of Whitening Effect by In Vitro Tooth Whitening Evaluation Method Using Artificial Teeth

[0128] (1) Preparation and Coloring of Hydroxyapatite (HAP) Tablet Sample

[0129] Artificial teeth were made by using hydroxyapatite, a component that forms 96% or more of teeth. Namely, hydroxyapatite powder was tableted with IR press or tablet machine and then sintered at 1000° C. According to Stookey method, a process of impregnating a sample in TSB (trypticase soybroth) solution in which tea, coffee, iron and mucin protein were dissolved and drying thereof was repeated for 1 week to prepare a colored artificial sample. The colored sample was washed lightly with running water using a toothbrush to remove stains that could be easily dissolved or easily removed by water, and then dried. The initial L (lightness) value was measured with a chroma meter.

[0130] (2) In Vitro Tooth Whitening Evaluation Method Using Colored Artificial Teeth

[0131] After attaching Example 3, Comparative Example 3 and Comparative Example 4 to a colored artificial teeth, respectively, the artificial teeth was allowed to stand for 30 min under conditions of the oral cavity, i.e., 37° C., 98% humidity. The sample was washed with water after removing Example and Comparative Example and then dried. Then, L value was measured. The delta L value, which is the difference between the L values before and after attachment, was calculated.

[0132] [Test for Comparing Viscosity and Solubility Before Attachment or at the Beginning of Attachment and Just Before Removal]

[0133] 1. Viscosity of Example and Comparative Example at Each Stage

[0134] (At this time, viscosity at each stage may have an error range of about +/−50 cPs.)

TABLE-US-00003 TABLE 3 Comparative Comparative Comparative Example 1 Example 2 Example 3 Example 3 Example 4 Example 5 At the time of Second First formulation 1,150 cps 13,000 cps 400 cps First formulation manufacture formulation (14,000 cps) (700,000 cps) (5 cps) Second Second formulation formulation (14,000 cps) (700,000 cps) First application 30,000 cps 20,000 cps 1200 cps 13,000 cps 400 cps 700,000 cps In adhesion 120,000 cps 50,000 cps 2500 cps* 13,000 cps 600 cps >2,000,000 cps Just before 180,000 cps >50,000 cps >5000 cps* 13,000 cps 600 cps Not measurable removal (Upon completion of drug release)

[0135] As listed in Table 3, it was confirmed that after the first application of the preparation, the viscosity of the preparations of Examples of the present invention was increased until adhesion of the preparations.

[0136] 2. Drug Release Rate of Example and Comparative Example at Each Stage

TABLE-US-00004 TABLE 4 Comparative Example 1 Example 3 Example 5 After 10 min from   50%   60%   5% attachment After 30 min from >70% >80% <5% attachment

[0137] As can be seen from Table 4, when the total loaded amount of drug is referred as 100, it can be found that 70% or more of the drug was released at the time of removal of the preparation, which was 30 min after attachment. However, in the case of Comparative Example 5 corresponding to a dental impression material, it can be found that increase of the viscosity over time is the same as the preparation of the present invention showed, but drug release was not smooth.

[0138] 3. Solubility/Shape Retention Force of Preparation of Example and Comparative Example at Each Stage

TABLE-US-00005 TABLE 5 Comparative Comparative Comparative Example 1 Example 2 Example 3 Example 4 Example 5 Solubility at Second formulation First formulation Dissolved Dissolved First formulation the time of (Dissolved) (Dissolved) (Maintained shape 100%) manufacture Second formulation Second formulation (Dissolved) (Maintained shape 100%) Solubility Maintained shape Maintained shape Dissolved Partly maintained Maintained shape (100%) at first (100%) (>90%) shape (>50%) application Preparation Maintained shape Maintained shape Dissolved Partly maintained Maintained shape (100%) residue (100%) (>90%) shape (<50%) just before removal

[0139] As can be seen from Table 5, it can be found that the preparations of the present invention have excellent shape retention force just before removal. Namely, from the above results, it can be found that the preparations of the present invention can be adhered to fit to gaps between teeth after application, and its shape can be maintained just before removal.

[0140] 4. Comparison of Convenience of Use of Example and Comparative Example

TABLE-US-00006 TABLE 6 Comparative Comparative Comparative Example 1 Example 2 Example 1 Example 2 Example 4 Degree of smear Second formulation First formulation Smeared Smeared Smeared at the time of (Smeared: Wet type) (Smeared: Wet type) (Wet type) (Wet type) (Wet type) manufacture Second formulation (Smeared: Wet type) Degree of smear Almost not smeared Almost not smeared Smeared Smeared Smeared at first (Like dry type) (Like dry type) (Wet type) (Wet type) (Wet type) application Degree of smear Not smeared Not smeared Smeared Smeared Smeared just before (Wet type) (Wet type) (Wet type) removal

[0141] Table 6 shows the result of confirming convenience of use in the course of applying the preparations of the present invention. As can be seen from the above result, it was confirmed that the preparations of the present invention can be used conveniently and sanitarily because the drug was almost not smeared to the hands when applied and adhered to teeth, and there is no unnecessary loss of the drug. However, the preparations of Comparative Examples gave loss of the drug or inconvenience because the drug was smeared to the hands.

[0142] 5. Comparison of Efficacy of Example and Comparative Example

TABLE-US-00007 TABLE 7 Comparative Comparative Example 1 Example 1 Example 2 Example 2 Survey score 2.7 1.5 for sensitive teeth symptom Survey score 2.4 1.4 for gum pain

[0143] As can be seen from Table 7, it was confirmed that Example 1 had better effect of relieving sensitive teeth, compared to Comparative Example 1, and it was confirmed that Example 2 had better effect of relieving gum pain symptoms, compared to Comparative Example 2.

[0144] These results suggest that the formulations of Examples of the present invention have excellent degree of adhesion to teeth and gaps between teeth, so that active ingredient s are effectively delivered to the target site.

[0145] Further, because Comparative Examples 1 and 2 are toothpaste-type and the holding time of the drug delivered at the time of the first application (brushing) was not long, the active ingredient gradually disappeared over time. However, in the case of the preparation of Examples of the present invention providing the time for stable penetration of the active ingredient for a certain period of time, it was thought that loss rate of the active ingredient was low.

TABLE-US-00008 TABLE 8 ΔL(Use once) ΔL(Use twice) Example 3 16.54 ± 2.19  31.49 ± 3.05  Comparative Example 3 5.29 ± 1.54 9.89 ± 1.85 Comparative Example 4 7.82 ± 3.19 13.26 ± 1.99 

[0146] As can be seen from Table 8, Example 3 showed better tooth whitening effect, compared to Comparative Examples 3 and 4. It was confirmed that in the case of Comparative Examples 3 and 4, which are gel-type and liquid-type, respectively, the amount of the active ingredient delivered to teeth was smaller than the loaded amount, and the whitening effect was significantly low because the amount that flows down or disappears without being fixed after being applied to teeth was a lot.

[0147] Preparation and Test of Oral Preparation Having Malleability

[0148] Additional oral preparations, including Examples and Comparative Examples having the same composition as some of Examples 1 to 3 and Comparative Examples, were prepared and the following tests were conducted.

[0149] [Preparation of Oral Preparation]

TABLE-US-00009 TABLE 9 Example 3 Example 4 Example 1 Example 2 (Gel type, which is (Compression band type, (Film coating type (Dual paint type with applicator Phase transition type Example having form like with separate backing layer) (dual syringe +mixing tip)) by saliva) plaster) First Alginate 12% First Alginate 3.8% First formulation: First formulation (Liquid): formulation Calcium Sulfate 15% formulation Acetic Acid 2.5% Gel-like PVA 3% (powder) Sodium Phosphate 2% (gel-like) Magnoliae Cortex extract Second formulation: Magnoliae Cortex extract Diatomite to 100% 0.1% (active ingredient) GMO 48.0% 0.1% Water to 100% EC 8.0% Ethanol 1% Hydrogen Peroxide 6% Water to 100% Second Gantrez 0.38% Second Alginate 3.8% (active ingredient) Second formulation formulation Zinc Chloride 0.18% formulation Calcium Carbonate 2.0% Ethanol 44.0% (Liquid): (liquid-like (active ingredient) (gel-like) Sodium Carbonate 1.9% Borax 4% viscosity) Water to 100% Water to 100% Backing PE film layer

[0150] Comparative Examples 1 to 3 and 5 were prepared as follows.

TABLE-US-00010 TABLE 10 Comparative Example 5 Dental impression material Comparative Example 2 (Selection VPS Putty) (Product name: Reactive silicone gel Comparative Example 1 Parodontax ™) Comparative Example 3 (Formulation: (P&G SensiStop ™) Formulation: (Alginate Gel) First formulation, Formulation: Strip Toothpaste Formulation: Gel Second formulation) Water Myrrha tint Alginate 1.5% Vinyl Polysiloxane Glycerin Rhatany tint Hydrogen Peroxide 6% Impression Material Cellulose Gum Chamomile tint Water to 100% (First formulation, Dipotassium Oxalate Second formulation) (active ingredient) Carbomer Sodium Hydroxide Sodium Benzoate Potassium Sorbate PE film

[0151] Comparative Example 1 used P&G SensiStop (containing active ingredient of improving sensitive teeth) and Comparative Example 2 used Parodontax (containing active ingredient of improving gingivitis). Comparative Example 3 used PVA Gel prescription (Water-soluble gel prescription, improving gingivitis/periodontitis) and Comparative Example 5 used dental impression material prescription (silicone dual-syringe prescription).

[0152] [Tests for Comparing Viscosity, Solubility and Convenience of Use Before Attachment or at the Beginning of Attachment and Just Before Removal]

[0153] Test Method

[0154] 1. Hardness Comparison Test (Test Method: Measured by Using Texture Analyzer) [0155] Evaluation device: Stable Micro System TA XT Plus [0156] Evaluation method: Hardness of Comparative Example and Example was measured by using Texture Analyzer.

[0157] Hardness was measured at compression test mode of TA (Texture Analyzer). After filling Example and Comparative Example into a 50 mL beaker, a 20 mm diameter aluminum probe for hardness measurement was set, and then hardness was measured with test speed of 1.5 mm/s, distance as target mode and distance of 10 mm. The hardness calculated from the device is the peak value of the first cycle.

[0158] {circle around (1)} Hardness at the time of manufacture: In the case of prescription consisting of the first formulation and the second formulation, each hardness measured before mixing the first formulation and the second formulation. In the case of consisting of only the first formulation, the hardness at the time of manufacture was referred to the same as the hardness before the first application.

[0159] {circle around (2)} Hardness at the first application: In the case of prescription consisting of the first formulation and the second formulation, hardness right after mixing. In the case of consisting of only the first formulation, the hardness was referred to the same as the hardness at the time of manufacture.

[0160] {circle around (3)} Hardness in adhesion: In the case of consisting of the first formulation and the second formulation, hardness is increased from the moment of mixing, and the hardness means the hardness in the state where shape transformation can occur even at a small pressure (Hardness when adhered to the desired site)

[0161] {circle around (4)} Hardness just before removal or upon completion of drug release: Hardness when no further hardness increase occurs. Hardness just before removal. Hardness when drug release is completed.

[0162] For example, in the case of a prescription for treating and preventing gingivitis, which consists of the first formulation and the second formulation, and is attached for 30 min, {circle around (1)} Hardness at the time of manufacture means each hardness before mixing, {circle around (2)} Hardness at the first application means the hardness just before application to teeth (when consisting of the first formulation and the second formulation, it means the hardness right after mixing) {circle around (3)} Hardness in adhesion means the hardness at 10 min after application to teeth, {circle around (4)} Hardness just before removal or upon completion of drug release means the hardness at 30 min after application to teeth.

[0163] 2. Compressibility Comparison Test (Test Method: Measured by Using Texture Analyzer)

[0164] Evaluation device: Stable Micro System TA XT Plus

[0165] Evaluation method: compressibility of Comparative Example and Example was measured by using Texture Analyzer.

[0166] Compressibility was measured at compression test mode of TA (Texture Analyzer). After filling Example and Comparative Example into a 50 mL beaker, a 20 mm diameter aluminum probe for compressibility measurement was set, and then compressibility was measured with test speed of 1.5 mm/s, distance as target mode and distance of 10 mm. The compressibility calculated from the device is the area value of the first cycle.

[0167] 3. Malleability Comparison Test (Test Method: Degree of Stretch when Pressing with a Constant Force after Measuring the Initial Length)

[0168] In the case of a sample transformable on a PET film, 1 g each of the sample was made to have the same length and breadth (1 cm.sup.2), a PE film was placed thereon, and then a 1 cm.sup.2 grid plate was to show the PE film below. Then, when pressing the sample with a constant force (2 kgf/cm.sup.2), the degree of stretch in length was measured using a 1 cm.sup.2 grid plate, and elongation percentage was calculated by calculating the average degree of elongation in all directions. The elongation percentage was measured under a general laboratory condition, i.e., under a condition of relative humidity of about 65%, 25° C.

[0169] 4. Drug Release Rate Comparison Test (Test Method: After Releasing Test, the Concentration of an Active Ingredient in a Solution was Quantified)

[0170] A) Manipulation

[0171] 0.9% Sodium chloride solution 500 mL is poured in a test tube and a temperature of a test solution is maintained at 32±0.5° C. during drug release test. Example or Comparative Example as a sample is fixed on the upper side of a disk which can be used as a sinker without absorbing, interfering or reacting so that a target attachment surface faces outward. Then, the disk is placed in the test tube with the sample-attached side facing up, and drug release time is calculated from this point of time. The sample-attached disk is aligned parallel to the bottom of the test tube and a paddle blade. Distance between the paddle blade and the sample surface is set to 25±2 mm, and revolutions per min (rpm) is set to 25. At the time of sampling, 100 mL of sample solution is collected at a fixed position (a position 1 cm away from the wall of the test tube, between the top of the paddle blade and the test liquid surface) 30 min after the start of the test.

[0172] B) Drug Analysis Method

[0173] Depending on the drug or the content, an appropriate analysis is selected. For example, peroxides are analyzed by titration, metal salts are analyzed by ICP analysis, and natural extracts are analyzed by HPLC.

[0174] 5. Convenience of Use Comparison Test (Adhesive Force, Shape Retention Force, Adhesive Force, Removability and the Like)

[0175] The characteristics of the formulation applied to the target in the oral cavity cause the inconvenience to use because the formulation is smeared to the hands while being applied. Further, those cause the inconvenience to use because the formulation is smeared to gums or hands while applying and standing for a certain time and is smeared to the hand during removal. Wet type is characterized in that it is smeared to the hands when touched, and dry type is characterized in that it is not smeared when touched by hands because it maintains its shape.

[0176] [Efficacy/Effect Comparison Test]

[0177] 1. Clinical Survey Related to Improvement of Sensitive Teeth for Humans

[0178] 1) Test subject and instructions: Example 2 group and Comparative Example 1 group were attached to the sensitive teeth area for 10 min once a day and then removed.

[0179] 2) After 1 week use, the survey was conducted to 15 volunteers who felt sensitive teeth per each group using 3-point Likert scale.

[0180] 3) Criteria

[0181] 1 point: Compared to before use, the sensitive teeth symptoms were similar or worsened.

[0182] 2 point: Compared to before use, the sensitive teeth symptoms were slightly relieved.

[0183] 3 point: Compared to before use, the sensitive teeth symptoms were a lot relieved.

[0184] 2. Clinical Survey Related to Improvement of Gingivitis Symptoms-Relief of Gum Pain for Humans

[0185] 1) Test subject and instructions: Examples 1 and groups and Comparative Example 2 group were attached to the gum pain area for 10 min once a day and then removed.

[0186] 2) After 1 week use, the survey was conducted to 15 volunteers who felt gum pain per each group using 3-point Likert scale.

[0187] 3) Criteria

[0188] 1 point: Compared to before use, the gum pain symptoms were similar or worsened.

[0189] 2 point: Compared to before use, the gum pain symptoms were slightly relieved.

[0190] 3 point: Compared to before use, the gum pain symptoms were a lot relieved.

[0191] 3. Evaluation of Whitening Effect by In Vitro Tooth Whitening Evaluation Method Using Artificial Teeth

[0192] (1) Preparation and Coloring of Hydroxyapatite (HAP) Tablet Sample

[0193] Artificial teeth were made by using hydroxyapatite, a component that forms 96% or more of teeth. Namely, hydroxyapatite powder was tableted with IR press or tablet machine and then sintered at 1000° C. According to Stookey method, a process of impregnating a sample in TSB (trypticase soybroth) solution in which tea, coffee, iron and mucin protein were dissolved and drying thereof was repeated for 1 week to prepare a colored artificial sample. The colored sample was washed lightly with running water using a toothbrush to remove stains that could be easily dissolved or easily removed by water, and then dried. The initial L (lightness) value was measured with a chroma meter.

[0194] (2) In Vitro Tooth Whitening Evaluation Method Using Colored Artificial Teeth

[0195] After attaching Example 4 and Comparative Example 3 to a colored artificial teeth, respectively, the artificial teeth was allowed to stand for 30 min under conditions of the oral cavity, i.e., 37° C., 98% humidity. The sample was washed with water after removing Example 4 and Comparative Example 3 and then dried. Then, L value was measured. The delta L value, which is the difference between the L values before and after attachment, was calculated.

[0196] [Test for Comparing Hardness Before Attachment or at the Beginning of Attachment and Just Before Removal]

[0197] 1. Hardness of Example and Comparative Example at Each Stage

TABLE-US-00011 TABLE 11 Example Example Example Comparative Comparative 4 1 2 Example 3 Example 5 At the Not Not Not Not First time of measur- measur- measur- measurable formulation manu- able able able 100 g facture Second formulation 100 g First 150 g   180 g 120 g Not     300 g appli- measurable cation In 150 g   5580 g 450 g Not >33,600 g adhesion measurable Just before 150 g 12,000 g 600 g Not >>Not removal measurable measurable (Upon com- pletion of drug release)

[0198] As listed in Table 11, the oral preparations of Examples of the present invention had the hardness in adhesion of around 5,000 g or less, and those have advantages that it can be transformed by a small force due to low hardness, and therefore, when pressed lightly with a finger at the beginning, it can be stretched to the desired length, and the preparation has little feeling of foreign body in gums or oral cavity because the preparation is soft. On the contrary, in the case of Comparative Example 3, there is no hardness, so it is equivalent to Examples in terms of softness. However, it has disadvantages that it is difficult to maintain shape after application because it is a general liquid gel, it is scattered by pressing with a finger, it is inconvenient to use because it is smeared to the hands and easily smeared to the contact site to the gums, and it is easily washed out in the humid oral cavity. In the case of Comparative Example 5, there is high hardness. Thus, it has disadvantages that it may give a burden to soft gums because it is impossible to transform shape if it is not quickly adhered after application due to its hardness, and it is impossible to release a drug after the hardness is increased.

[0199] 2. Compressibility of Example and Comparative Example at Each Stage

TABLE-US-00012 TABLE 12 Example Example Example Comparative Comparative 4 1 2 Example 3 Example 5 At the Not Not Not Not First time of measur- measur- measur- measurable formulation manu- able able able 100 gs facture Second formulation 100 gs First 700 gs   680 gs  650 gs Not     1200 gs appli- measurable cation In 700 gs 11,000 gs 1500 gs Not >55,000 gs adhesion measurable Just before 700 gs 16,000 gs 2000 gs Not >>Not removal measurable measurable (Upon com- pletion of drug release)

[0200] As listed in Table 12, the oral preparations of Examples of the present invention have low compressibility in adhesion, and it means that those do not take much effort to make the desired transformation for a certain period of time. Those have an advantage that when pressed lightly with a finger, desired deformations can be obtained, including not only size deformation but also shape deformation, which makes it possible to easily fill teeth gaps in many teeth simultaneously even if the teeth are uneven. On the contrary, in the case of Comparative Example 3, it has disadvantages that it is difficult to maintain shape after application because it is a general liquid gel without hardness, it is scattered by pressing with a finger, it is inconvenient to use because it is smeared to the hands and easily smeared to the contact site to the gums, and it is easily washed out in the humid oral cavity. In the case of Comparative Example 5, compressibility is sharply increased within several min after application and the value is too high. Thus, it has disadvantages that it is hard to use because it is impossible to transform shape if it is not quickly adhered after application due to its hardness, and it is difficult to release a drug.

[0201] 3. Comparison of Malleability of Example and Comparative Example

TABLE-US-00013 TABLE 13 Comparative Comparative Example 4 Example 1 Example 3 Example 5 At first >300% >150% Not maintained 150% application shape (Within 2 min) In adhesion >300% >150% Not maintained Fixed (Within 10 shape min) Just before >300%   150% Not maintained Fixed removal shape (after 30 min)

[0202] As can be seen from Table 13, the preparations of the present invention could maintain the malleability just before removal. By such malleability, the preparations of the present invention could be completely adhered to gap between teeth, and effectively deliver the drug to gaps between teeth and gums.

[0203] 4. Drug Release Rate of Example and Comparative Example

TABLE-US-00014 TABLE 14 Comparative Example 1 Example 2 Example 3 After 10 min from   50%   60%   5% attachment After 30 min from >70% >80% <5% attachment

[0204] As can be seen from Table 14, in the case of Examples, it can be confirmed that 70% or more of the drug was released at the time of removal of the preparation, which was 30 min after attachment, based on the loaded amount of the drug. However, in the case of Comparative Example, it can be confirmed that removal of the preparation increased the hardness and limited the drug release.

[0205] 5. Comparison of Convenience of Use of Example and Comparative Example

TABLE-US-00015 TABLE 15 Comparative Comparative Comparative Example 4 Example 1 Example 1 Example 2 Example 3 Degree of smear at First formulation First formulation Smeared Smeared Smeared the time of (Smeared: Wet type) (Smeared: Powder type) (Wet type) (Wet type) (Wet type) manufacture Second formulation Second formulation (Smeared: Wet type) (Smeared: Wet type) Degree of smear at Not smeared Almost not smeared Smeared Smeared Smeared first application (Dry type) (Like dry type) (Wet type) (Wet type) (Wet type) Degree of smear just Not smeared Not smeared Smeared Smeared Smeared before removal (Dry type) (Wet type) (Wet type) (Wet type)

[0206] As cab be seen from Table 15, in the case of Comparative Examples of the present invention, the drug was smeared to the hands in the course of applying the preparations on the surface of teeth, but Examples of the present invention could be conveniently used because the drug was almost not smeared to the hands.

TABLE-US-00016 Comparative Comparative Example 4 Example 1 Example 1 Example 2 Survey score for — 2.7 1.5 — sensitive teeth Survey score for gum pain 2.4 — — 1.4

[0207] As can be seen from Table 16, it was confirmed that Example 1 had better effect of relieving sensitive teeth, compared to Comparative Example 1, and it was confirmed that Example 4 had better effect of relieving gum pain symptoms, compared to Comparative Example 2.

[0208] These results suggest that the formulations of Examples of the present invention have excellent degree of adhesion to teeth and gaps between teeth, so that active ingredient s are effectively delivered to the target site.

[0209] Further, because Comparative Examples 1 and 2 are toothpaste-type and the holding time of the drug delivered at the time of the first application (brushing) was not long, the active ingredient gradually disappeared over time. However, in the case of the preparation of Examples of the present invention providing the time for stable penetration of the active ingredient for a certain period of time, it was thought that loss rate of the active ingredient was low.

TABLE-US-00017 TABLE 17 ΔL (Use once) ΔL (Use twice) Example 2 16.54 ± 2.19 31.49 ± 3.05 Comparative Example 3  5.29 ± 1.54  9.89 ± 1.85

[0210] As can be seen from Table 17, Example 2 showed better tooth whitening effect, compared to Comparative Example 3. It was confirmed that in the case of Comparative Example 3, which is gel-type, the amount of the active ingredient delivered to teeth was smaller than the loaded amount, and the whitening effect was significantly low because the amount that flows down or disappears by force without being fixed after being applied to teeth was a lot.

INDUSTRIAL APPLICABILITY

[0211] The preparation of the present invention can be well adhered to gaps between teeth well, and therefore, it can effectively deliver a drug to teeth of gaps between teeth. The present invention can provide a preparation attachable in the oral cavity, which is convenient to use because it does not flow down when applied to teeth.

[0212] The present invention has been described in detail. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the scope of the disclosure will become apparent to those skilled in the art from this detailed description.