KR20170060460A - Oral formulation comprising hardening composition having ointment form - Google Patents

Abstract

The present invention provides a tooth or tooth perimeter attachment formulation comprising a hardened ointment composition and a medicinal component for intraoral delivery. The preparation of the present invention can impart a high adhesion to a desired site despite the clearance of the teeth or the bending of the teeth and can secure a sufficient time for the drug to be delivered.

Description

[0001] The present invention relates to an oral formulation comprising a hardened ointment composition,

The present invention relates to a preparation for oral drug delivery, and more particularly, to a new oral dosage form capable of effectively delivering a pharmaceutical ingredient to a desired site in the oral cavity.

In order to deliver the oral active ingredient into the oral cavity, the time and amount of contact with the active ingredient play an important role.

A paste formulation such as a tooth paste has a disadvantage that it is difficult to provide sufficient contact time to a target site because of insufficient viscosity and high solubility, and a mouse tray for oral drug delivery has disadvantages that it is difficult to deliver a local drug . It is difficult to transmit a sufficient amount of effective ingredient, the flexibility is poor, and there is a disadvantage that it is difficult to closely contact teeth gap, gingival region and tooth boundary region.

Korean Patent No. 10-0623859 has developed a tooth whitening component delivery system using gel gelation in order to solve problems of adhesion between teeth, gaps and boundary between teeth, but when used, There is a disadvantage that it is necessary to use a separate support layer. WO 2003/037276 also discloses a formulation for oral administration in the form of a spray having a low initial viscosity. Since the difference between the normal storage temperature (in particular, in summer) and the oral temperature is small, and a very thin layer is not formed, rapid phase transition does not occur. There was a problem that it was difficult.

US Pat. No. 5,989,569 discloses the delivery of a drug by pressure on the surface of a strip, but since the drug is applied to the surface of the strip and adheres to the tooth as it is, there is an effect of temporarily releasing the active ingredient, There was a problem that strong irritation to gums and the like could be caused. In addition, the physical properties of the drug to be applied with the strip, in particular, the flexibility, are different, and it is difficult to closely contact the tooth gap.

The inventors of the present invention have studied for a long time to develop a new type of drug that can deliver drugs effectively into the oral cavity with ease of use, and as a result, the present invention has been proposed.

In order to solve the above-mentioned problems, the present invention provides a preparation for delivering an active ingredient, the properties of which are changed before and after attachment to teeth.

The present invention intends to provide a formulation in which the shape can be freely changed before use and can be adhered excellently between tooth gaps or between teeth and gums.

The present invention is to provide a new type oral preparation excellent in usability that can be conveniently used without any feeling of being touched or tacky on the hands when attached to the teeth or around the teeth.

Justice

As used herein, the term " tooth periphery " is a concept including a region generally represented by a gum, and may be used to include all portions of the mucous membrane around the teeth. The peripheral portion of the tooth may be used to mean a portion where a drug can be delivered together with the tooth when the preparation is applied to the tooth in the structure of the preparation. In this specification, a tooth or a peripheral portion of a tooth is described in combination with a 'tooth', and even if it is described only as a 'tooth', it can be understood in this specification to include both a tooth and a peripheral portion of a tooth.

As used herein, the term " hardened oral cavity composition " refers to an oral composition that does not have a certain shape before tooth contact, has an ointment shape free from deformations, and gradually loses fluidity and fixes its shape. That is, when the preparation of the present invention is applied to the periphery of teeth or teeth, the ointment is elevated until the ointment phase or close contact with the teeth, and then, when the preparation of the present invention is removed from the tooth after adhesion, ≪ / RTI > composition.

As used herein, 'applied to a tooth' may include immediately after applying the formulation of the present invention to a tooth, until the user applies pressure to the tooth to bring the preparation into close contact with the tooth. In the case of 2 formulation, 'after application of the preparation' of the present invention may mean after mixing 1 and 2 and applying to tooth.

The term "when the preparation is in close contact with the teeth" means that the user applies pressure to the tooth after a certain time has elapsed from the application of the tooth to bring the preparation into close contact with the tooth curve, the tooth gap, and between the tooth and the gum. May be understood to be about 10 minutes or less after the preparation of the present invention is applied to a tooth.

The 'cured ointment phase' formulation may be in a semi-solid ointment state such as kneading or clay after being applied, or it may be molded with an external force such as heat or pressure over time, gradually lose its possibility of forming, It can mean a formulation to be deformed.

As used herein, " curing " may include not only curing by formation of a network structure such as an ion-crosslinked structure such as an egg-box model but also degradation of fluidity accompanied with progress of polymerization reaction by light or catalyst, The degree of absorption of air, the degree of exposure to air, and the like.

As used herein, the term " preparation " means a product made by processing so as to exhibit a therapeutic effect without affecting the effect of the active ingredient.

Specific details of the invention

The present invention provides a curable ointment-based oral composition, and a tooth or tooth and gum attachment formulation comprising a medicinal ingredient for oral delivery. The inventors of the present invention have conducted studies on a drug delivery system capable of delivering the active ingredient into the oral cavity, and as a result, have come up with a new type of drug delivery system, and a new method of delivering the active ingredient into the oral cavity using such a system .

The inventors of the present invention have long studied a new drug delivery system capable of effectively delivering the active ingredient to a specific site in the oral cavity (for example, a site requiring tooth whitening, a site of inflammation in the mouth, a site of periodontal disease, etc.) . As a result, it has been developed a new type of oral preparation which can be conveniently applied to the teeth or oral mucous membrane region, and can be brought into close contact with even the bending region and the tooth gap to increase the drug reaching rate at a desired site.

An embodiment of the present invention provides a tooth or a tooth peripheral attachment agent in which a hardened ointment-based oral composition and a medicinal ingredient for intraoral administration are mixed. For example, the medicinal ingredient may be uniformly dispersed in the oral composition, and a case where the dispersion is made non-uniform may be included in the mixture of the present invention.

According to one embodiment of the present invention, the formulation of the present invention may lose the possibility of forming substantially at the time of final removal, and may lose the possibility of forming at a viscosity of more than 5000 cps at the final removal time. The viscosity of the preparation is measured at 20 ° C (room temperature), 5 to 20 rpm, and 5 to 20 rpm at the point of time when the preparation is applied to the periphery of teeth or teeth and then the drug is released. Measured by a Brookfield viscometer with a 6 or 7 spindle, may be greater than or equal to 5,000 cPs, preferably greater than or equal to 10,000 cPs, and more preferably greater than or equal to 200,000 cPs. The viscosity at the time of the final removal of the preparation may be varied depending on the type and content of the phase transfer material, phase transfer auxiliary material, and the substance that assists adhesion of the phase transfer material included in the preparation. Preferably, 5,000 cPs or more and 104,000,000 cPs or less.

According to one embodiment of the present invention, a preparation adhered to a tooth has a viscosity measured at the time of removal of 2 times or more, preferably 3 times or more, more preferably 5 times or more Can be increased.

According to another embodiment of the present invention, the formulation of the present invention may have a viscosity of 5,000 cPs or more measured at the time of removal and may have a value twice or more that of the viscosity measured at the time of application to the teeth.

The oral ointment composition contained in the formulation of the present invention may include a phase transition material, a phase transfer auxiliary substance, a substance for improving adhesion of the phase transition composition, and a substance for facilitating drug release.

The phase change material is a substance that induces curing of the oral composition of the hardened ointment, and may be selected from the group consisting of carrageenan, pectin, xyloglucan, gellan gum, ammonium alginate, magnesium alginate magnesium alginate, potassium alginate, sodium alginate, lithium alginate, chitosan, poly (L, L-lactic acid), polylactide- (DL-lactide-co-glycolide), poly-caprolactone, polyacrylic acid (carbopol), polyvinylacetal diethyl aminoacetate ), Hydroxypropylmethyl cellulose, poly (methacrylic acid) -poly (ethylene glycol), poly (D, L-lactide) -block- Poly (ethylene glycol) -block-poly (D, L-lactide)), PEG-oligoglycolyl-acrylate (PEG-L-lactide) poly (N-isopropyl acrylamide), sucrose acetate isobutyrate, polyvinyl alcohol, glyceryl monooleate, glyceryl monooleate, Glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate, and the like can be used alone or in combination of two or more, and can be used as a phase transition material in the industry. Any material can be used, and the present invention is not limited to the above examples.

The cured ointment composition may include a substance that improves adhesion of the phase transfer composition, and may include a substance having adhesion to a tooth or an adhesive retaining property and having excellent compatibility with a phase transition material. For example, it is also possible to use polyvinyl pyrrolidone, polymethyl vinyl ether and copolymers of maleic acid (poly methyl vinyl ether and maleic acid copolymers (gantrez)), shellac (polyvinylpyrrolidone, shellac, rosin, poloxamer, hyaluronic acid, acrylate copolymer (Eudragit L-100, L-100,55), hydroxypropyl methylcellulose methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyacrylic acid, polyethylene glycol, ethyl cellulose, or a mixture thereof. Preferably, hydroxypropyl methyl cellulose (HPMC) or ethyl cellulose or a mixture thereof can be used. These polymers may be used by dissolving them in water or a solvent (for example, ethanol), but crosslinked polymers may be applied. For example, crosslinked polyacrylic acid and crosslinked polyvinyl pyrrolidone may be used together with crosslinked polymer alone or crosslinked polymer. In the case of a polymer obtained by cross-linking polymers having excellent adhesion to teeth or gums, absorption of water does not dissolve in water or ethanol while exhibiting adhesive strength, thereby improving the adhesion of the composition and increasing the residue.

The phase transition material may be a substance capable of controlling the phase transition or the phase transfer rate and the degree of phase transformation, and calcium ions may be used. The calcium ion is preferably water-soluble but insoluble in neutral or alkaline conditions, Can also be used. For example, calcium carbonate, calcium phosphate dibasic (CaHPO ₄ ), barium carbonate, zinc carbonate, calcium chloride, calcium lactate ), Calcium citrate, calcium aspartate, calcium saccharate, calcium oxovalerate, calcium gluconate, calcium lactobionate, Calcium carbonate, barium carbonate, zinc carbonate, sodium bicarbonate, sodium carbonate, tetraborate, calcium carbonate, and calcium carbonate of calcium lactogluconate. Tripolyphosphate, ethylenediamine tetraacetic acid, tetrasodium pyrophosphate, sodium acid pyrophosphate < RTI ID = 0.0 > A chelating agent such as sodium acid pyrophosphate or acidic sodium metaphosphate or a chelating agent such as acetic acid, malic acid, lactic acid, gluconic acid, ascorbic acid or a mixture thereof or a salt thereof, NaOH, KOH, It can be more than one.

Materials for improving the adhesion of the phase transition material, phase transfer auxiliary material, and phase transition material included in the cured ointment composition are exemplarily listed and are not necessarily limited to the above examples. According to another embodiment of the present invention, depending on the mechanism, the phase transition material, the auxiliary substance of the phase transition composition, and the substances improving the adhesion can be used without any distinction. For example, when polyvinyl alcohol is a phase transfer material, the phase transition material may be tetraborate, and the adhesion enhancing material may be alginate or colloidal silica. In another embodiment, when the phase transition material is alginate, the phase transfer aid may be calcium, and the adhesion enhancing substance may be methyl vinyl ether and maleic acid copolymers (gantrez).

The drug release aid may be used if it forms a channel, porous structure or bubble within the formulation. For example, in the case of two formulations of one agent and two agents, one type of acid contains a base in another formulation, and a bubble is formed in the formulation when the two formulations meet to form a curable ointment phase. For example, sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bicarbonate (baking soda), sodium bicarbonate ), and sodium carbonate. Preferably, the acid can be selected from acetic acid and the base can be selected from sodium carbonate. More preferably, the acid and base, sodium, which is mainly used in toothpaste, citrate and sodium bicarbonate.

The active ingredient may contain, for example, ingredients capable of improving oral symptoms, for example tooth whitening ingredients, tooth decay ingredients including fluoride ion sources, tartar formation inhibitors, anti-inflammatory ingredients, antibacterial ingredients , Other vitamins, minerals, and the like. It may also include an improving and symptom-relieving component, and the like. More specifically, for example, any one selected from the group consisting of sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, and sodium monofluorophosphate At least one fluorine ion source; A reminerization agent comprising hydroxyapatite; Tooth whitening ingredients include, but are not limited to, hydrogen peroxide, carbamide peroxide, calcium peroxide, perborate, percarbonate, peroxyacids, persulfates, It may include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, or a mixture thereof, Condensation phosphates can be used with peroxides for the improvement. Examples of condensed phosphates that can be used include tetrasodium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP) Sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acidic sodium metaphosphate, acidic sodium polyphosphate, One or more of acidic sodium polyphosphate may be used together with the peroxide. These condensed phosphates can also be used for dental calculus and for inhibiting calculus formation. They may also contribute to the improvement of the whitening effect by removing the metal which affects the stain formation of teeth as a chelating agent. But are not limited to, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide An antimicrobial agent comprising cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC) or a mixture thereof; An anti-inflammatory agent comprising aspirin, ketorolac, flurbiprofen, piroxicam, meclofenamic acid, or a mixture thereof; Or thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ), Ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K or a mixture thereof; Or mixtures thereof. ≪ RTI ID = 0.0 > In addition, drugs effective for the prevention and improvement of periodontal disease include corn-deficient quantitative extracts, extracts of myrrh, extracts of myrrh, myrrh, latinia, chamomile, polycresol, Centella extract, nutmeg extract, dexpanthenol, beta-sitosterol (β-sitosterol), acetyl salicylic acid, and the like may be contained as a single or a mixture of daily maintenance. The symptom improvement and relieving component of the symptom may include one or more of zinc chloride, potassium phosphate, potassium phosphate, calcium chloride, oxalic acid, potassium oxalate, ferric oxalate and vitamin E.

According to one embodiment of the present invention, the preparation may be a one-part formulation or a two-part formulation consisting of one part and two parts, and more than three parts may be mixed if necessary.

The first and second agents of the two formulations are mixed and applied to the teeth or the periphery of the teeth. The viscosity measured by mixing the first agent and the second agent for application to a tooth or a tooth periphery increases as the viscosity before mixing , And may have moldability such as dough after mixing.

The formulation of the above-mentioned 2 formulation may contain the active ingredient in both of the one, two or one and two or more agents.

The formulation of the 2 formulation may optionally include a phase change material, a phase transfer auxiliary material, and a substance that improves the adhesion of the phase change material to the one, two or one and two agents.

For example, the formulation of formulation 2 may include magnesium alginate, a phase transfer material, The formulation of the 2 formulation may include hydroxypropylcellulose as a material which contains calcium chloride as a substance for assisting the curing of the phase change material in the preparation 2 and helps to adhere to a tooth or tissue surrounding the teeth. In this case, the active ingredient may be appropriately included in consideration of the compatibility with the polymer contained in the first agent and the second agent, and the characteristics thereof.

The formulation of the present invention may substantially lose the possibility of molding at the time of removal after tooth attachment. Preferably, the time point of removal may be a time point of 5 to 3 hours, preferably 8 to 90 minutes after application to a tooth or a peripheral portion of a tooth. For example, after 10 minutes, 30 minutes, or 1 hour attachment, it can be removed.

In another embodiment, the time point at which the tooth is removed may be a time point at which the active ingredient contained in the preparation becomes 30% by weight or less based on the total weight of the initial drug loaded.

The meaning of the loss of the molding ability substantially means that the product is hardened after losing its physical properties at the time of removing the formulation after application and losing formability. In one embodiment of the present invention, the water solubility of the formulation measured at 32 캜, 1 atm in a substantially lossless formability is less than 20% by weight, more preferably less than 15% by weight, even more preferably less than 10% And most preferably from 1 to 10% by weight of water solubility.

The formulation may further comprise a support layer as needed when attached to the teeth or the periphery of the teeth. The support layer may include a water-insoluble polymer generally used in oral films, and examples thereof include polyethylene (PE), polypyropylene (PP), ethylene vinyl acetate (EVA), cellulose acetate phthalate, , Polyvinyl acetate, ethylcellulose, polymethylmethacrylate, methacryloylethylbetaine / methacrylate copolymer (Yukaformer: Mitsubishi, methacryloylethyl betain / methacrylate copolymer), methacrylic acid copolymer ; Eudragit L 100, Eudragit L 12,5, Eudragit L 100-55, Eudragit L 30D-55), aminoalkyl methacrylate copolymer (Eudragit E 100, Eudragit E 12,5, Eudragit RL 100, Eudragit RL 30D) and the like can be used.

The preparation of the present invention can impart a high adhesion to a desired site despite the clearance of the teeth or the bending of the teeth.

It can be adhered well to the tooth gap and is excellent in drug delivery efficiency.

It can be used conveniently because it does not flow down when applied to teeth.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view showing a conventional oral adhesive strip (a) and a preparation (b) according to an embodiment of the present invention. Unlike the case where the active ingredient (2) and the strip (1) are made of separate layers, the preparation according to the embodiment of the present invention can take the form in which the drug is dispersed in the preparation.
FIG. 2 is an illustration showing a process of attaching the preparation 10 of the present invention to a tooth T and detaching the preparation 10 according to time. FIG.
FIG. 3 is a view illustrating an example of a process of applying a formulation according to an embodiment of the present invention to a tooth, followed by hardening the tooth, and FIG. As can be seen from FIG. 3, the preparation of the present invention can be applied even to the tooth gap.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the embodiments described below. The embodiments of the present invention are provided by way of example to facilitate a specific understanding of the present invention. Unless specifically stated otherwise, the percentages recited herein are understood to mean% by weight.

[Preparation of preparation for oral use]

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

The formulation of Example 1-3 was prepared as follows. The powder formulations of the examples were mixed using a powder mixer, and the gels of the examples were prepared by mixing the polymers at a constant rate so as not to aggregate the polymer with a mechanical mixer. In case of Example 3, the temperature was adjusted to 50 ° C, and the mixture was mixed with a mechanical mixer.

Example 1
(Film-coated type having a separate support layer) Example 2
(Dual paint type with Applicator (dual syringe + mixing tip) Example 3
(phase transition type by saliva of gel form) 1
(powder) Alginate 12%
Calcium Sulfate 15%
Sodium Phosphate 2%
Diatomaceous earth to 100% 1
(gel-like) Alginate 3.8%
Acetic Acid 2.5%
L. extract (0.1% active ingredient)
Water to 100% GMO 48.0%
EC 8.0%
Hydrogen Peroxide 6% (active ingredient)
Ethanol 44.0% 2 (liquid-like viscosity) Gantrez 0.38%
Zinc Chloride 0.18% (active ingredient)
Water to 100% 2
(gel-like) Alginate 3.8%
Calcium Carbonate 2.0%
Sodium Carbonate 1.9% Water to 100% Support layer PE film

Comparative Example 1-5 was prepared as follows. Comparative Example 1 used P & G SensiStop (containing a pharmacologically active ingredient having a silyl-improving effect), and Pharodontax (containing a pharmacologically effective ingredient for improving gingivitis) used in Comparative Example 2 was used.

Comparative Example 3 was prepared by prescribing Alginate Gel (prescription of alginate water-soluble gel, tooth whitening), Comparative Example 4 was a Poloxamer prescription (Temperature Whitening) which is a temperature sensitive polymer and Comparative Example 5 was prepared by prescribing a silicone dual-syringe Respectively.

Comparative Example 1
(P & G SensiStop ™)
Formulation: Strip
Comparative Example 2
(Product name: Paradon Tax)
Formulation: Toothpaste Comparative Example 3
(Alginate Gel)
Formulation: Gel Comparative Example 4
(Poloxamer)
Formulation: Liquid Comparative Example 5
Dental Impression
VPS Putty)
Formulation: 1 & 2 reactive silicone gel water
glycerin
Cellulose Gum
Dipotassium Oxalate
Carbomer)
Sodium Hydroxide
Sodium Benzoate
Potassium Sorbate
PE film Myrrh tint
Latania tint
Chamomile tint Alginate 1.5%
Hydrogen Peroxide 6%
Water to 100%
Pluronic F127 20%
Carbamide Peroxide 16%
(H ₂ O ₂ 5.6%)
Water to 100% Vinyl Polysiloxane Impression Material
(1 system, 2 system)

[Comparative Experiments on Viscosity, Solubility, and Convenience of Use Before Attachment or Before Attachment and Just Before Removal]

Experimental Method

1. Viscosity comparison experiment (Experimental method: viscosity measurement with rotating viscometer)

- Evaluation instrument: Brookfield Viscometer, No. 6 or 7 spindles, 5 to 20 rpm, 20 占 폚 (room temperature)

- Evaluation method: The viscosity of the comparative example and the example were measured with a Brookfiled Viscometer.

I) initial viscosity, ii) close viscosity, and iii) viscosity just before removal. However, in the case of a formulation consisting of 1 and 2, the viscosity measured before each mixing before the mixing of 1 and 2 is regarded as the viscosity at the time of manufacture, and when the composition is composed of only 1, Respectively.

i) Viscosity at the time of initial application: Viscosity immediately after mixing in the case of formulation 1 or 2, and viscosity in the case of composition 1 is the same as the viscosity in manufacturing state.

ii) Viscosity when in close contact: When composed of 1 or 2, it means the viscosity in the state where the viscosity increase starts from the moment of mixing and the shape deformation can occur even at a small pressure. In this experiment, after the application, for example, for a total use time of 10 minutes, the composition was applied to the desired site for 5 minutes. When the formulation was used for 30 minutes or more, it was closely adhered to the desired site for 5 to 10 minutes, Viscosity is measured by viscosity at close contact.

iii) Immediately before removal or completion of drug release (at about 70-100% drug release). Viscosity: The viscosity at which no further increase in viscosity occurs.

For example, in the case of a formulation consisting of a first agent and a second agent for the purpose of maintaining teeth whitening and whitening effect during the last 30 minutes, ① the viscosity in the manufacturing state refers to the respective viscosity before mixing, ② the viscosity at the time of initial coating, Viscosity before application of tooth (Viscosity immediately after mixing in case of composition of 1 and 2) ③ Viscosity after adhesion is 10 minutes after application of tooth, and ④ Viscosity immediately after removal or completion of drug release means viscosity after 30 minutes after application of tooth .

2. Experiments for comparison of drug release (Experimental method: Quantitative determination of effective ingredient concentration in solution after release experiment)

A) Operation

Pour 500 mL of a 0.9% solution of sodium chloride in the test tube and allow the test solution to maintain a temperature of 32 ± 0.5 during the drug release test. A specimen or a comparative example on a top surface of a disk which can be used as a sinker without absorbing, interfering, or reacting is fixed so that the target mounting surface faces outward, and then the surface to which the specimen is attached faces upward And the drug release time is calculated from this moment. The disk with the specimen attached is aligned parallel to the bottom of the test tube and the paddle blade. The distance between the paddle blade and the sample surface is 25 ± 2 mm and the rpm is set to 25. Take 100 mL of the sample solution at 30 minutes after the start of the test at a certain position (at a position 1 cm away from the wall of the test tube to the midpoint between the upper side of the paddle and the test liquid surface).

Drug analysis method: Depending on the drug and the content, select the appropriate analysis method. For example, titration for peroxides, ICP for metal salts, and HPLC for natural extracts.

3. Solubility comparative experiment: In the present invention, the shape retentivity is defined as the solubility during the experiment of releasing artificial saliva (0.9% NaCl solution). A comparative observation was made to observe whether the records (USP drug release experiment conditions, collapse morphology, maintain morphology, maintain the same initial thickness and height, or reduce it)

① Preparation state Solubility: When 1g and 2g are composed, 1g each is taken and loaded in the same manner as drug release experiment.

② In the case of the initial application and adhesion, if the solubility just before the removal is composed of 1 and 2, the same change as the drug release experiment after mixing is observed and then the shape change with time is observed.

4. Comparison of ease of use (wet type or dry type): Due to the nature of the formulation applied to the target in the oral cavity, it is inconvenient for the user to be handled when applying the composition. However, Bringing on the hands or on the hands when removed can cause discomfort. Wet type is characterized by sticking by hand when touched, and dry type is characterized by not retaining shape when touched by hand.

[Effectiveness / effect comparison experiment]

1. Assessment of Clinical Questionnaires on Improvement of Human Correlation

1) Subjects and Usage: The group of Example 1 and the group of Comparative Example 1 were allowed to adhere to the syringe site for 10 minutes once a day and then to be removed.

2) The questionnaire was administered to 15 volunteers who felt sylvian per group.

3) Based on the scale

1 point: Symptoms similar or worsened compared to before use

2 points: a little more severe symptoms than before use

3 points: Very severe symptoms were alleviated before use

2. Improvement of gingivitis symptoms for people - Clinical evaluation of gingival pain relief

1) Subjects and Usage: The groups of Example 2 and Comparative Example 2 were allowed to adhere to the gum pain site for 10 minutes once a day.

2) The questionnaire was administered to 15 volunteers who felt gum pain per group after using for 1 week.

3) Based on the scale

1 point: Gingival pain symptoms were similar or worsened compared to before use

2 points: A little less gum pain symptom than before use

3 points: Very relief of gum pain symptoms before use

3. Evaluation of whitening effect by in vitro tooth whitening technique using artificial teeth

(1) Preparation and coloring method of hydroxyapatite (HAP) tablets

Artificial teeth were made using hydroxyapatite, a component that forms more than 96% of teeth. That is, the hydroxyapatite powder was tableted with an IR press or a tablet machine and then sintered at 1000 ° C. Staining method was applied to TSB (trypticase soybroth) solution of tea, coffee, iron, mucine protein and dried for one week. Colored specimens were rinsed lightly with running water with a toothbrush to remove stains that could easily be dissolved or easily removed by water, then dried and the initial value of L (lightness) was measured with a chroma meter.

(2) Evaluation of in vitro tooth whitening effect using colored artificial specimens

After Example 3, Comparative Example 3 and Comparative Example 4 were respectively attached to colored artificial specimens, the specimens were washed with water after leaving the specimens for 30 minutes at 37 ° C. and 98% After giving and drying, L value was measured. The delta L value, which is the difference of the L value before and after the attachment, was calculated.

[Comparative Experiments of Viscosity and Solubility Prior to or Before the Adhesion and Immediately Before Removal]

1. Viscosity of each step of the Examples and Comparative Examples

(However, the viscosity of each step may have an error range of about +/- 50 cPs.)

Example 1 Example 2 Example 3 Comparative Example 3 Comparative Example 4 Comparative Example 5 Manufacturing Status 2 (5 cps) 1 (14,000 cps)
2 (14,000 cps) 1150 cps 13,000 cps 400 cps 1 (700,000 cps)
2 (700,000 cps) First application 30,000 cps 20,000 cps 1200 cps 13,000 cps 400 cps 700,000 cps In close contact 120,000 cps 50,000 cps 2500cps * 13,000 cps 600 cps > 2,000,000 cps Immediately before removal (upon completion of drug release) 180,000 cps > 50,000 cps > 5000 cps * 13,000 cps 600 cps Not measurable

As shown in Table 3, it was confirmed that the formulations of the invention of the present invention showed an increase in viscosity until they were brought into close contact after the initial application.

2. Drug release by step in the Examples and Comparative Examples

Example 1 Example 3 Comparative Example 5 After 10 minutes after attachment 50% 60% 5% After 30 minutes after attachment > 70% > 80% <5%

As can be seen from the above Table 4, when the total drug loading amount is 100, it is understood that more than 70% of the drug is released at the time of removing the preparation, which is 30 minutes after the attachment. However, in the case of Comparative Example 5 corresponding to a dental impression material, it was found that the viscosity of the dental impression material increased with time as in the case of the preparation of the present invention, but the release of the drug was not smooth.

3. Solubility of each step in the Examples and Comparative Examples /

Example 1 Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Manufacturing State Solubility 2 (melted) 1 (dissolved)
2 (melted) Melt away Melt away 1 (100% form retention)
2 (100% form retention) Solubility in initial application Shape retention (100%) Maintain shape (> 90%) Melt away Partial retention (> 50%) Shape retention (100%) Remnant residue before removal Shape retention (100%) Maintain shape (> 90%) Melt away Partial retention (<50%) Shape retention (100%)

As can be seen in Table 5, it can be seen that the formulation of the present invention is excellent in the shape retention force just before being removed. That is, from the results, it can be seen that the formulation of the present invention can be closely adhered to the clearance of the teeth after adhesion after application, and the shape thereof is maintained until just before the removal.

4. Comparison of ease of use between the embodiment and the comparative example

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 4 Degree of manufacturing state 2 (wet type) 1 (wet type)
2 (wet type) Bury
(wet type) Bury
(wet type) Bury
(wet type) Degree of initial application Like dry type Like dry type Bury
(wet type) Bury
(wet type) Bury
(wet type) Degree of burial just before removal Not buried Not buried Bury
(wet type) Bury
(wet type) Bury
(wet type)

Table 6 above shows the result of confirming the convenience of use in the process of applying the preparation of the present invention. As can be seen from the above results, when the drug of the present invention was applied to the teeth and adhered to the teeth, the drug hardly appeared on the hand, so that it could be conveniently and hygienically used and no unnecessary loss of the drug was found. However, the preparations of the comparative examples gave drugs on the hands and gave loss or inconvenience to the drugs.

5. Comparison of Efficacy Effects of Examples and Comparative Examples

Example 1 Comparative Example 1 Example 2 Comparative Example 2 Symptom scores 2.7 1.5 Gum pain symptom questionnaire score 2.4 1.4

As shown in Table 7, it was confirmed that Example 1 had a better silylation effect than Comparative Example 1, and Example 2 was found to have a better gingival pain relief effect than Comparative Example 2 .

These results suggest that the formulations of the examples of the present invention are excellent in the degree of adhesion to the gap between the teeth and the teeth, and thus the effective ingredients are effectively delivered to the intended site.

In addition, Comparative Examples 1 and 2 are similar to dentifrices, and the time for which the drug is delivered at the time of first application (brushing) is not long, so that the effective ingredient gradually disappears over time. However, Was considered to provide less time for the active ingredient to permeate stably for a certain period of time, so that the disappearance rate of the active ingredient was also lower.

ΔL (used once) ΔL (used 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

As can be seen in Table 8, Example 3 exhibited a superior tooth whitening effect as compared to Comparative Examples 3 and 4. In Comparative Examples 3 and 4, the amount of the active ingredient to be transferred to the tooth was smaller than that of the loaded amount due to a large amount of gel or liquid, which was not fixed and flowed down or lost, and the effect of tooth whitening was remarkably decreased Respectively.

T: Tooth
1: Conventional tooth attaching strip
2: active ingredient
10: Formulations containing a hardened ointment-topical oral composition

Claims (16)

A hardened ointment topical oral composition; And a medicinal ingredient for intraoral delivery. The formulation according to claim 1, wherein the active ingredient is mixed with a cured ointment-based oral composition to be contained in the preparation. The method of claim 1, wherein the preparation is a tooth for being cured by the drug is lost likely molding after the after attachment 5 minutes to 3 hours in the humidity and temperature conditions mouth attached to the tooth or tooth periphery substantially to the features coming from or Preparations for attaching to the periphery of teeth. 4. The method according to claim 3, wherein the substantially unmoldable material is cured when the viscosity of the preparation is from 5 to 3 hours after application of the preparation to the peripheries of teeth or teeth, 20 rpm No. 6, and 7 spindles with a Brookfield viscometer having a viscosity of at least 5000 cps. [Claim 4] The method according to claim 3, wherein the viscosity measured at the point of 5 minutes to 3 hours after the preparation is applied to the periphery of the tooth or the teeth is 2 times or more the viscosity measured when the preparation is applied to the tooth or the periphery of the tooth Or an adhesive for attaching the peripheral portion of a tooth. The preparation for attaching a tooth or a peripheral portion of a tooth according to claim 1, wherein the hardened ointment composition comprises a phase transfer material, a phase transfer auxiliary material, a substance for improving adhesion of the phase transfer composition, and a substance for facilitating drug release. The method of claim 6, wherein the phase change material is selected from the group consisting of carrageenan, pectin, xyloglucan, gellan gum, ammonium alginate, magnesium alginate, potassium alginate, sodium alginate, lithium alginate, chitosan, poly (L, D-lactic acid), poly (lactic acid) DL-lactide-co-glycolide), poly-caprolactone, polyacrylic acid (carbopol), polyvinylacetal diethyl aminoacetate (AEA), hydroxypropylmethyl (Hydroxypropylmethyl cellulose), poly (methacrylic acid) -poly (ethylene glycol) (poly (methacrylic acid) -poly (ethylene glycol) - poly (D, L-lactide) -block-po (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 monooleate, Glyceryl monostearate, or a mixture thereof. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; 7. The method of claim 6, wherein the materials for enhancing adhesion of the phase transfer material are selected from the group consisting of incremental precipitated silica, colloidal silicon dioxide, polyvinyl pyrrolidone, polymethyl vinyl ether and poly methyl vinyl ether &lt; RTI ID = 0.0 &gt; and maleic acid copolymers, shellac, rosin, poloxamer, hyaluronic acid, acrylate copolymer, hydroxypropyl methylcellulose (HPMC ), Hydroxypropyl cellulose (HPC), polyacrylic acid, polyethylene glycol, ethyl cellulose, or a mixture thereof, or a crosslinked product thereof Wherein the tooth or the peripheral portion of the tooth is attached to the tooth. The method of claim 6, wherein the phase change auxiliary material is calcium carbonate (calcium carbonate), calcium secondary phosphate _{(calcium phosphate dibasic (CaHPO 4)} ), barium (barium carbonate), zinc carbonate (zinc carbonate), calcium chloride (calcium chloride ), Calcium lactate, calcium citrate, calcium aspartate, calcium saccharate, calcium oxovalerate, calcium gluconate, lactose, Calcium ion source of calcium lactobionate and calcium lactogluconate;
Barium carbonate, zinc carbonate, sodium bicarbonate, sodium carbonate, tetraborate, tripolyphosphate, chelating agents;
Acetic acid, malic acid, lactic acid, gluconic acid, ascorbic acid or mixtures thereof or salts thereof;
NaOH, KOH, or a mixture thereof. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; The pharmaceutical composition according to claim 1, wherein the active ingredient is selected from the group consisting of sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate, sodium pyrophosphate tetrapodassium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acid metapoly But are not limited to, acidic sodium metaphosphate, acidic sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (tetradecylpyridinium chloride) idinium 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 A), vitamin D (vitamin D), vitamin E (vitamin E), vitamin K (vitamin K), corn-deficient quantitative extracts, rose extract, myrrh, rattania, camomile, Tella fixed extract Extract of nutmeg, dexpanthenol, β-sitosterol, acetyl salicylic acid, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, iron oxalate ferric oxalate, vitamin E or a mixture thereof. A preparation for attaching to a tooth or peripheral area of teeth. 2. The pharmaceutical composition according to claim 1, wherein the preparation is one preparation; or
1 &lt; / RTI &gt; and 2 &lt; RTI ID = 0.0 &gt; agents. &Lt; / RTI &gt; 12. The method according to claim 11, wherein the first agent and the second agent of the second formulation are mixed and applied to a tooth or a peripheral portion of the tooth,
Wherein the viscosity measured by mixing the first agent and the second agent for application to the periphery of the teeth or the teeth is higher than that before the mixing, and the agent is hardened due to loss of the possibility of molding. 12. The formulation according to claim 11, wherein the formulation of the formulation for 2 comprises a pharmaceutical active ingredient in the formulation 1, formulation 2 or formulation 1 and formulation 2. 12. The formulation according to claim 11, wherein the one dosage form comprises a phase transfer composition. The formulation according to claim 1, wherein the water-solubility of the preparation is less than 20% by weight, measured at 32 캜 and 1 atm after 5 to 3 hours have elapsed from the application of the teeth or the periphery of the teeth. 2. The formulation according to claim 1, wherein the preparation further comprises a support layer.

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