KR102324872B1 - Oral formulation comprising malleable oral composition - Google Patents

Abstract

The present invention provides an oral composition having a malleability and a preparation for attachment to a tooth or a tooth periphery comprising a pharmaceutical ingredient for intraoral delivery. The formulation of the present invention can impart high adhesion to a desired site despite the gap between the teeth or the curvature of the teeth. The formulation of the present invention having high adhesion may be advantageous in achieving the desired effect by increasing the time to adhere to the target site in the oral cavity.

Description

TECHNICAL FIELD [0001] Oral formulation comprising malleable oral composition

The present invention relates to a formulation for intraoral drug delivery, and more particularly, to a new oral formulation that can effectively deliver an active ingredient to a desired site in the oral cavity.

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

Paste formulations such as toothpaste have a disadvantage in that it is difficult to provide sufficient contact time to the target site due to insufficient viscosity and high solubility. There is this. The patch form or strip form is thin, so it is difficult to deliver sufficient active ingredients, and the flexibility is low, and there are disadvantages in that it is difficult to adhere to the tooth gap, the gum and the tooth boundary, and the like.

In order to solve the problem of adhesion between teeth gaps, gums and teeth, etc., Korean Patent Registration No. 10-0623859 developed a tooth whitening ingredient delivery system using gelation during use. There was a disadvantage of having to use a separate support layer. In addition, WO 2003/037276 discloses a formulation that is applied in the oral cavity in the form of a spray due to its low initial viscosity. The difference between the general storage temperature (especially in summer) and the oral temperature is small, and if it is not applied very thinly, a rapid phase transition does not occur, so removal is difficult. There was an annoying problem.

US 5,989,569 discloses the contents of applying a drug to the surface of the strip and delivering the drug by pressure, but since the drug is applied to the surface of the strip and attached to the teeth as it is, there is an effect of temporarily releasing the drug, and around the teeth There was a problem that it could cause strong irritation to the gums and the like. In addition, since the strip and the drug to be applied had different physical properties, especially flexibility, it was difficult to adhere to the tooth gap.

The inventors of the present invention proposed the present invention as a result of long-term research to develop a new type of formulation that is convenient to use and can effectively deliver a drug into the oral cavity.

U.S. Patent No. 5,989,569

In order to solve the above problems, the present invention is to provide a new type of formulation for oral adhesion that is easy to attach to a desired site in the oral cavity and can secure sufficient contact time.

An object of the present invention is to provide a formulation that can be deformed in shape before use and can be excellently adhered to a gap between teeth or between teeth and gums.

An object of the present invention is to provide a new type of oral preparation excellent in the feeling of use that can be used conveniently without sticking or sticking to the hand when attached to a tooth or a tooth periphery.

Justice

As used herein, the term 'periphery of a tooth' is a concept including a region generally expressed as a gum, and may be used to include all mucosal regions around the teeth. The tooth periphery may be used as a meaning encompassing a region to which an active ingredient for intraoral delivery together with the teeth can be delivered together with the teeth when the formulation is applied to the teeth due to the structure of the formulation. In this specification, a tooth or a tooth surrounding part has been described as a mixture of 'tooth', and even if it is only described as 'tooth', it may be understood in this specification to include all teeth or a tooth surrounding part.

As used herein, the term 'malleability' may mean that the formulation of the present invention may have a shape deformability or may have moldability by external pressure. It is flexible enough, and when it is attached in the oral cavity, it means that it is possible to change the shape to the extent that it can completely adhere to the tooth gap or even the minute part between the teeth and the gums.

In the present specification, not only the case where the formulation is extended from side to side, but also the case where deformation occurs in all directions when placed on a flat surface and pressed with a constant force can be included in the range of malleability, and all forms that bring about deformation of the appearance are malleable. can be included in the scope. In the case of malleability, the object may be compressed in a certain hardness range or the area may be enlarged.

As used herein, 'hardness' may mean the degree of force required to compress the formulation. The hardness of the formulation of the present invention is measured in the compression test mode of the Stable Micro System TA XT Plus. After filling 20g in a 50mL beaker, set an aluminum probe with a diameter of 20mm for hardness measurement. Hardness is understood as the peak value of the first cycle that is calculated. The unit can be expressed as g (g force).

As used herein, 'compression force' may mean a force applied until the formulation is broken, cut, or destroyed while being compressed. The compression force of the formulation of the present invention is measured in the compression test mode of the Stable Micro System TA XT Plus. After filling a 50mL beaker with 20g, set an aluminum probe with a diameter of 20mm for measuring the compression force, and measure the compression force with a test speed of 1.5mm/s, a target mode of distance and a distance of 10mm. The compression force is understood as the area value of the first cycle that is calculated. The unit can be expressed as gs(g force *sec).

As used herein, 'compressibility' may mean a property that the formulation can be stretched without being broken or cut when a compression force is applied.

As used herein, 'elongation' means the extent to which the formulation can be stretched in all directions when a load is applied, such as when a formulation is placed between rollers and compressed. Elongation as used herein may be understood to mean 'plane strain' unless otherwise specified. Excellent elongation may be understood as having malleability.

As used herein, the meaning of 'applied to the teeth' may include until the formulation of the present invention is placed on the teeth or the surrounding area and then the user applies pressure to adhere the formulation to the teeth. In the case of two formulations, 'after application of the agent' of the present invention may mean immediately after mixing the first agent and the second agent.

The meaning of 'when the formulation is in close contact with the teeth' of the present invention means the point at which the user applies pressure after a certain period of time has elapsed after application of the tooth to bring the formulation into close contact with the tooth curve, the tooth gap, and between the teeth and gums, preferably the close contact Poetry can be understood as about 5 minutes after application of the formulation of the present invention to the teeth, preferably about 1 to 3 minutes.

The 'time of removing the formulation' of the present invention may mean a time point at which the drug is released from the oral cavity after it is in close contact with the tooth or the tissue around the tooth, and is adhered for 2 hours depending on the purpose and use of the formulation and the amount of drug released It may be removed later, but from the viewpoint of ease of use, it may be removed within 30 minutes after being in close contact with the teeth, more preferably within 10 minutes. The hardness of the formulation at the time of removal may be the same as the time at which the formulation is applied to the teeth or the time at which it is in close contact, or the hardness of the formulation may increase at the time of removal.

As used herein, the term 'formulation' refers to a product made by processing to sufficiently exert a therapeutic effect without affecting the effect of an active ingredient.

specific details of the invention

The present invention provides an oral composition having a malleability, and a formulation for attaching a tooth or a tooth and a gum around the tooth, comprising an active ingredient for intraoral delivery. As a result of repeated research on a drug delivery system capable of delivering a drug substance into the oral cavity, the inventors of the present invention have proposed a new type of drug delivery system and a new method for delivering a drug ingredient into the oral cavity using this system. .

The inventors of the present invention have developed a new drug delivery system that can effectively deliver an active ingredient to a specific site in the oral cavity (e.g., a site requiring teeth whitening, a site of irritation, an area of inflammation in the oral cavity, a site of periodontal disease, etc.) has been studied for a long time. As a result, a new type of oral formulation has been developed that can be conveniently applied to teeth or oral mucous membranes, and has excellent adhesion to curved areas and even tooth gaps, thereby increasing the drug reach to a desired area.

One embodiment of the present invention provides an oral composition having a malleability and a formulation for attachment to a tooth or a tooth periphery in which an active ingredient for intraoral delivery is mixed. For example, the active ingredient may be uniformly dispersed in the oral composition, and a case in which the dispersion is made non-uniformly may be included in the mixture of the present invention.

According to one embodiment of the present invention, the formulation of the present invention has semi-solid properties at the same time, so it may be possible to adhere to a bend or a gap.

The formulation of the present invention may have a form such as a paste or clay, and may be applied to a tooth or a region around the tooth in the form of an ointment.

The formulation of the present invention may have an initial hardness of 0.1 to 20,000 g when attached, as measured by a compression mode of a texture analyzer (TA), and preferably in a range of 10 g to 12,000 g. When the initial hardness is within the above range, it may be easy to adhere to a tooth gap or a curved portion.

The formulation may have a final hardness of 40,000 g or less upon removal as measured by the compression mode of the texture analyzer, and preferably 30,000 g or less.

A formulation having a final hardness within the above range can obtain a desired effect (for example, an effect of improving pain, whitening of teeth, preventing effect of gingivitis, etc.) due to smooth release of the drug, and can have excellent shape fixation power .

In another embodiment of the present invention, the formulation may have an initial compressibility of 0.1 to 30,000 gs at the time of attachment as measured by the compression mode of the texture analyzer, preferably 10 gs to 20,000 gs. When the compressibility is within the above range, it may be easy to adhere to a tooth gap or a curved portion.

The formulation may have a final compressibility upon removal of 50,000 gs or less, preferably 40,000 gs or less, measured in a compression mode of a texture analyzer.

A formulation having a final hardness within the above range can obtain a desired effect (for example, an effect of improving pain, whitening of teeth, preventing effect of gingivitis, etc.) due to smooth release of the drug, and can have excellent shape fixation power . This shape fixing force may be more advantageous in achieving the desired effect since it is possible to secure sufficient contact time with the site where the drug needs to be reached.

The formulation according to an embodiment of the present invention may have malleability, which may increase the length of the composition when it is pressed with a force ^{of 0.5 kg/cm 2} or more at the initial stage of attachment, preferably 1 kg/cm ^{2 or more.} have. Specifically, when the formulation is pressed with a finger at a standard relative humidity of 65% and 25° C. or with a pressure roller of 0.5 kg/cm ² or more, preferably 1 kg/cm ² or more. It may have an elongation of 120% or more when pressed, preferably an elongation of 150% or more. In another preferred embodiment, the formulation may have an elongation of 120% or more and 500% or less.

In addition, the malleability of the formulation of the present invention may be a change in elongation of about 10% from the time the formulation is applied to the tooth or the tooth periphery to the point at which it is removed. For example, in an embodiment of the present invention, the oral formulation of the present invention in which the first agent containing PVA (polyvinyl alcohol) and the second agent containing Borax are mixed has malleability and a certain time measured when it is applied to the tooth surface. is the elapsed time to be removed at the time the drug release progressed more than 60% how elongation measurement of the present invention that is, to create a sample of constant weight to 1cm ² is the measured elongation when given away by pressing at a pressure of 2kg of / cm ² by pressure roller respectively 150% and 150% can be measured equally.

The oral composition included in the formulation of the present invention may include a phase change material, a phase change auxiliary material, a material that improves adhesion of the phase change composition, and a material that helps release the drug.

The phase change material is a material that can cause viscosity in the oral composition, carrageenan (carrageenan), pectin (pectin), xyloglucan (xyloglucan), gellan gum (gellan gum), ammonium alginate (ammonium alginate), magnesium alginate (magnesium) alginate), potassium alginate, sodium alginate, lithium alginate, chitosan, poly(D,L-lactic acid), polylactide-co-cli Coride (poly(DL-lactide-co-glycolide)), poly-caprolactone (poly-caprolactone), polyacrylic acid (carbopol), polyvinylacetal diethyl aminoacetate (AEA)) , hydroxypropylmethyl cellulose, poly(methacrylic acid)-poly(ethylene glycol)(poly(methacrylic acid)-poly(ethylene glycol)), poly(D,L-lactide)-block-poly( ethylene glycol)-block-poly(D,L-lactide)(poly(D,L-lactide)-block-poly(ethylene glycol)-block-poly(D,L-lactide)), PEG-oligoglycol Colyl-acrylate (PEG-oligoglycolyl-acrylate), poly (N-isopropyl acrylamide), sucrose acetate isobutyrate, polyvinyl alcohol (polyvinyl alcohol), polyvinyl acetate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate arachidonate), glyceryl monostearate, etc. may be used alone or in combination of two or more, and any material that can be used as a phase change material in the industry may be used, and the examples are not limited thereto.

The malleable oral composition may include a material that improves the adhesion of the phase change composition, and a material having excellent compatibility with the phase change material while having adhesion to teeth or adhesion retention may be added. For example, thickened precipitated silica, colloidal silicon dioxide, polyvinyl pyrrolidone, poly methyl vinyl ether and copolymers of maleic acid (gantrez), shellac ( shellac), rosin, poloxamer, hyaluronic acid, acrylate copolymer (Eudragit L-100, L-100,55)), hydroxypropyl methyl cellulose (hydroxypropyl) methyl cellulose (HPMC)), hydroxypropyl cellulose (HPC), polyacrylic acid, polyethylene glycol, ethyl cellulose, or mixtures thereof may be included, but not necessarily limited thereto. However, preferably, hydroxypropyl methyl cellulose (HPMC) or ethyl cellulose or a mixture thereof may be used. These polymers can be used by dissolving them in water or a solvent (eg ethanol), but polymers made by crosslinking can also be applied. For example, crosslinked polyacrylic acid and crosslinked polyvinyl pyrrolidone can be used alone or in combination with non-crosslinked polymers. In the case of a polymer obtained by crosslinking polymers with excellent adhesion to teeth or gums, when water is absorbed, the polymer exhibits adhesion and is not soluble in water or ethanol, so it has the advantage of improving the adhesion of the composition as well as improving the persistence.

The phase transition auxiliary material is a material capable of inducing phase transition or controlling the rate of phase transition and adjusting the degree of phase transition, and calcium ions may be used. It can also be used that is easily converted to . 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 and calcium ion source of calcium lactogluconate, barium carbonate, zinc carbonate, sodium bicarbonate, sodium carbonate, tetraborate, tripolyphosphate, ethylenediamine tetraacetic acid, tetrasodium pyrophosphate, sodium acid pyrophosphate, acidic sodium metaphosphate, trisodium trimetaphosphate trisodium trimetaphosphate) and the like, acetic acid, malic acid, lactic acid, gluconic acid, ascorbic acid, boric acid or a mixture or salt thereof, NaOH, KOH, or a mixture thereof may be any one or more selected from the group consisting of.

The phase change material, the phase change auxiliary material, and the material for improving the adhesion of the phase change material included in the composition are listed by way of example and are not necessarily limited to the above examples. According to another embodiment of the present invention, a phase change material, an auxiliary material of the phase change composition, and a material for improving adhesion may be used without distinction according to a mechanism. For example, when polyvinyl alcohol is a phase change material, the phase change auxiliary material may be tetraborate, and the material to increase adhesion may be alginate or colloidal silica. In another embodiment, when the phase change material is alginate, the phase change auxiliary material may be calcium, and the material for increasing adhesion may be methyl vinyl ether and maleic acid copolymers (gantrez).

The substance that helps release the drug may be used as long as it creates a channel or a porous structure or a bubble (foam) in the formulation. For example, if it consists of two components, one formulation contains an acid and the other contains a base, so when the two formulations meet to form a viscous, malleable composition, a bubble is formed in the formulation. That is, the first agent contains acetic acid, lactic acid, malic acid, gluconic acid, ascorbic acid, etc. or a water-soluble salt thereof such as sodium citrate, and the second agent contains sodium hydroxide (NaOH), potassium hydroxide (KOH) , sodium bicarbonate (baking soda), may be any one selected from the group containing a base such as sodium carbonate, preferably the acid is acetic acid, the base may be selected as sodium bicarbonate, more preferably mainly used in toothpaste It may be sodium citrate and sodium hydrogen carbonate, which are acids and bases to be formed.

The medicinal ingredient may include, for example, ingredients that can improve oral symptoms, for example, a tooth whitening ingredient, a tooth decay prevention ingredient including a fluoride ion source, a tartar generation inhibitory ingredient, an anti-inflammatory ingredient, an antibacterial ingredient , and other vitamins and minerals. In addition, it may contain ingredients for improving and relieving symptoms. More specifically, for example, any one selected from the group consisting of sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, and sodium monofluorophosphate one or more sources of fluorine ions; reminerlaization agents including hydroxyapatite; Teeth whitening ingredients include hydrogen peroxide, carbamide peroxide, calcium peroxide, perborate, percarbonate, peroxyacids, persulfates, may include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, or a mixture thereof, and a whitening effect Condensed phosphate can be used with peroxide for improvement. Examples of condensed phosphate that can be used include sodium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP). , sodium potassium pyrophosphate, potassium pyrophosphate (tetrapotassium pyrophosphate), acidic sodium metaphosphate (acidic sodium metaphosphate), acid sodium polyphosphate (acidic sodium polyphosphate) one or two or more of the peroxide and Can be used together. These condensed phosphates can also be used to remove calculus or to inhibit calculus formation. In addition, as chelating agents, they can contribute to improving the whitening effect by removing metals that affect the formation of stains on teeth. Triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide ), cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), or an antimicrobial agent containing a mixture thereof; anti-inflammatory agents including aspirin, ketorolac, flurbiprofen, piroxicam, meclofenamic acid, or mixtures thereof; or thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12 (vitamin B12), lipoic acid ), ascorbic acid, vitamin A, vitamin D, vitamin E, vitamin K, or mixtures thereof; or a mixture thereof, but is not limited thereto. In addition, effective drugs for the prevention and improvement of periodontal disease include corn unsaponifiable quantitative extract, husk extract, myrrh, ratania, chamomile, polycresolene, centella quantitative extract nutmeg extract, dexpanthenol, beta-sitosterol (β-sitosterol), acetyl salicylic acid, etc. may be included alone or as a mixture in a predetermined ratio. As a component for improving and alleviating symptoms of Shirin, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, ferric oxalate, vitamin E, and the like may be included alone or two or more.

According to an embodiment of the present invention, the formulation may be a single formulation or a two formulation consisting of a first agent and a second agent, and three or more agents may be mixed as needed.

The first and second agents of the two formulations are mixed and applied to the tooth or tooth periphery, and the viscosity measured by mixing the first and second agents for application to the tooth or tooth periphery increases the viscosity compared to before mixing, , may have a kneading-like formability after being mixed, and may have malleability.

The two-part formulation may include an active ingredient in the first agent, the second agent, or both the first agent and the second agent.

The two-part formulation may optionally include a phase change material, a phase change auxiliary material, and a material for improving adhesion of the phase change material in the first agent, the second agent, or both the first and second agents.

For example, a two-part formulation may include magnesium alginate, a phase change material, in the first agent. The two-part formulation may include calcium chloride as a material that helps harden the phase change material in the second agent, and hydroxypropyl cellulose as a material that helps adhere to teeth or tissues around teeth. In this case, the active ingredient may be appropriately included in consideration of compatibility and characteristics with the polymer contained in the first agent and the second agent.

The formulation of the present invention may maintain the same physical properties, such as hardness and compressibility, from immediately after attachment to just before removal, and maintain the same physical properties until the time of sufficient drug release in the oral cavity depending on the purpose, and then slightly increase the hardness at the time of removal Thus, the shape may be fixed. The time at which the formulation of the present invention is removed may vary depending on the components included in the formulation, but may mean a time point when 30 minutes have elapsed after application to the tooth or the surrounding area of the tooth.

In another embodiment, the time point at which the tooth is removed after attachment may be, for example, a time point at which the amount of drug released into the oral cavity becomes 60% by weight or more of the drug contained in the initial formulation, preferably 65% by weight, more preferably More than 70% of the drug can be released.

The formulation may further include a support layer, if necessary, when attached to a tooth or a tooth periphery. The support layer may include a water-insoluble polymer generally used in oral film, for example, polyethylene (PE), polypyrrophyllene (PP), ethylene vinyl acetate (EVA), cellulose acetate phthalate, shellac (Shellac) , polyvinyl acetate, ethyl cellulose, polymethylmethacrylate, methacryloyl ethyl betaine/methacrylate copolymer (Yukaformer: manufactured by 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) or the like may be used.

In one embodiment of the present invention, the drug of the formulation can be easily removed by brushing at the time when it is released and removed, and the time of removal may be a time point when 30 minutes have elapsed after attachment.

The formulation of the present invention can impart high adhesion to a desired site despite the gap between the teeth or the curvature of the teeth.

The drug delivery efficiency is excellent because it can adhere well to the tooth gap. In addition, since it does not flow down or diluted by saliva after attachment, it is possible to sufficiently secure the contact time between the drug arrival site and the preparation of the present invention, which is advantageous in achieving the intended efficacy.

It does not drip when applied to the teeth, so it is convenient to use.

1 is a diagram showing a conventional oral adhesive strip (a) and a formulation (b) according to an embodiment of the present invention. Unlike the active ingredient (2) and the strip (1) being composed of separate layers, the formulation according to the embodiment of the present invention may form a drug dispersed in the formulation.
2 is a diagram illustrating the process of attaching the formulation 10 of the present invention to the tooth T and then removing it over time by way of example.
3 is a diagram exemplarily showing a process of applying a formulation according to an embodiment of the present invention to teeth and then hardening after adhesion. As can be seen in FIG. 3 , the formulation of the present invention can reach even the tooth gap.

Hereinafter, in order to explain the present invention in more detail, the following examples and the like will be described. However, the embodiments according to the present invention may be modified in 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 help the specific understanding of the present invention. Unless otherwise specified, percentages in this specification may be understood to mean % by weight.

[Production of oral preparations]

Preparations for oral use of Examples and Comparative Examples having the following composition were prepared or purchased.

The formulations of Examples 1-4 were prepared in the following way. The powder formulation of the example was mixed using a powder mixer, and the gel of the example was prepared while mixing at a constant speed so that the polymer does not agglomerate with a mechanical mixer. In addition, in the case of Example 3, after adjusting the temperature to 50 ℃ was prepared while mixing with a mechanical mixer. In the case of Example 1, both agents 1 and 2 are liquid and have low viscosity, but before mixing, it is necessary to confirm that they are completely dissolved to obtain a uniform formulation after mixing.

Example 1 (compression band type) Example 2 (Film coating type) Example 3 Example 4 Example having a plaster-like form Examples requiring a separate support layer (dual paint type) Applicator included (dual syringe + mixing tip) (Phase transition by needle)
GMO(Glyceryl monooleate) + EC(ethyl cellulose) 1st agent: liquid 2nd agent: liquid
Part 1: power
2nd agent: liquid-like viscosity
Support layer: PE film Agent 1: gel-like
2nd agent: gel-like Agent 1: gel-like 1st agent: 3% PVA and 0.1% husk extract
Ethanol 1%
water to 100%
2nd agent: Borax 4%
Water to 100%
Agent 1: Alginate 12%
CalciumSulfate 15%
Sodium Phosphate 2%
Diatomaceous earth to 100%
2nd agent: Gantrez 0.38 %
Zinc Chloride 0.18%
Water to 100% Agent 1: Alginate 3.8 %
Aceticacid 2.5%
Peppermint Extract 0.1%
Water to 100%
2nd agent: Alginate 3.8 %
CaCO3 2.0%
Na2CO3 1.9%
Water to 100% GMO 48.0%
EC 8.0%
Hydrogen Peroxide 6%
Ethanol 44.0%

Comparative Examples 1-4 were prepared as follows. Comparative Example 1 used P&G SensiStop™ (contains an active ingredient for improving syrin), and Comparative Example 2 used Parodon Tax™ (contains an active ingredient for improving gingivitis).

Comparative Example 3 was prepared by prescription of PVA Gel (water-soluble gel prescription, gingivitis/periodontitis improvement), and Comparative Example 4 was prepared by prescription of dental impression material (silicone dual-syringe prescription).

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 (P&G SensiStop ™)Formulation: Strip (Product name: Paradontax™)
Formulation: Toothpaste (Alginate Gel)
Formulation: Gel Dental Impression Material (Selection)
VPS Putty)
Formulation: 1 agent, 2 agent reactive silicone gel water glycerin
Cellulose Gum
Dipotassium Oxalate (active ingredient)
Carbomer
Sodium Hydroxide
Sodium Benzoate
Potassium Sorbate
PE film myrrh tint
Latania Tint
Chamomile Tint Alginate 1.5%
Hydrogen Peroxide 6%
water to 100% Vinyl Polysiloxane Impression Material
(1st, 2nd)

[Comparative test for viscosity, solubility, and usability before attachment or before attachment and immediately before removal]

Experimental method

1. Hardness comparison test (Test method: Measured with Texture Analyzer)

Evaluation instrument : Stable Micro System TA XT Plus

Evaluation method : The hardness of Comparative Examples and Examples was measured with a Texture Analyzer.

Hardness is measured in compression test mode of TA (Texture Analyzer) with Texture Analyzer. After 20 g of Examples and Comparative Examples are filled in a 50 mL beaker, an aluminum probe with a diameter of 20 mm for hardness measurement is set, and the test speed is 1.5 mm/s, the target mode is the distance, and the distance is 10 mm to measure the hardness. The hardness calculated mechanically is the peak value of the first cycle.

① Hardness as manufactured: In the case of a prescription consisting of the 1st and 2nd agents, the hardness measured for each before mixing the 1st and 2nd agents. If it consists of only one agent, the hardness of the manufactured state is interpreted as the same as the hardness before the first application.

② Hardness at the time of first application: In the case of the first and second agent formulations, the hardness is immediately after mixing, and in the case of one agent, it is the same as the hardness of the manufacturing state.

③ Hardness when adhered = When composed of 1st and 2nd agents from the moment of mixing Hardness starts to increase, and hardness in a state where shape deformation can occur even with a small pressure (hardness when attached to a desired part)

④ Hardness just before removal or upon completion of drug release: Hardness when hardness no longer increases. Viscosity just before removal. hardness when drug release is complete

For example, in the case of a prescription for treatment and prevention of gingivitis that is adhered for the last 30 minutes and composed of 1 and 2 agents, ① The hardness of the manufactured state means the hardness of each before mixing, ② The hardness at the time of initial application is the tooth application. Hardness immediately before (hardness immediately after mixing in case of composition of 1st and 2nd agent) ③ Hardness in close contact means hardness after 10 minutes after tooth application, ④ Hardness just before removal or when drug release is complete means hardness 30 minutes after tooth application.

2. Compressibility comparison test (Test method: Measured with Texture Analyzer)

Evaluation instrument: Stable Micro System TA XT Plus

Evaluation method: The compressibility of Comparative Examples and Examples was measured with a Texture Analyzer.

Compressibility is measured in the compression test mode of TA (Texture Analyzer) with Texture Analyzer. After 20 g of Examples and Comparative Examples are filled in a 50 mL beaker, an aluminum probe with a diameter of 20 mm for measuring the compressibility is set, the test speed is 1.5 mm/s, the target mode is the distance, and the distance is 10 mm to measure the compressibility. The mechanically calculated compressibility is the area value of the first cycle.

3. Malleability comparison experiment (Test method: the degree of elongation when pressing with a certain force after measuring the initial length

In the case of a sample that can be deformed on PET film, make 1 g each of the same length (1 cm ² ) in width and length, put the PE film on top, set the 1 cm ² grid plate to be visible on the PE film below, and then apply a certain force (weight of 2 kg). /cm ² ) When pressed, the horizontal extension of the length was ^{measured using a 1 cm 2} grid plate, and the extent of stretching in all directions was calculated as an average to calculate the elongation. The elongation was measured under general laboratory conditions, and was measured at about 65% relative humidity and 25°C conditions.

4. Drug release amount comparison experiment (Test method: quantification of active ingredient concentration in solution after release test)

A) operation

Pour 500 mL of 0.9% sodium chloride solution into the test tube and maintain the temperature of the test solution at 32±0.5°C during the drug release test. After fixing the sample example or comparative example on the upper surface of the disc that can be used as a sinker without absorption, interference, or reaction, the target attachment side faces outward, and the sample attached side faces upward The drug release time is calculated from this moment into the test tube. The disc on which the specimen is attached is aligned parallel to the bottom of the test tube and the blade of the paddle. Set the distance between the blade of the paddle and the surface of the specimen to be 25±2mm, and set the number of revolutions per minute (rpm) to 25. When collecting the sample solution, collect 100 mL of the sample solution 30 minutes after the start of the test at a certain position (the middle position between the top of the paddle blade and the test liquid level and 1 cm away from the test tube wall).

B) Drug analysis method

Depending on the drug and the content, the appropriate analysis method is selected. For example, titration for peroxides, ICP analysis for metal salts, and HPLC for natural extracts are selected and analyzed.

5. Convenience comparison experiment (adhesion, shape retention, adhesion, removal, etc.)

Due to the nature of the formulation applied to the target in the oral cavity, it causes discomfort when applied to the hand. can cause The wet type may be smeared when the formulation is touched by hand, and the dry type may not be smeared when touched by hand because it maintains its shape.

[Efficacy/Effect Comparison Experiment]

1. Evaluation of clinical questionnaires related to human improvement

1) Test subject and usage: In Example 2 and Comparative Example 1, the syringe was attached to the site once a day for 10 minutes and then removed.

2) A questionnaire evaluation was conducted on a 3-point Likeard scale after 1 week of use for 15 volunteers who felt a tingling sensation in each group.

3) Scale standard

1 point: The pain symptoms were similar or worse compared to before use.

2 points: The soreness was slightly relieved compared to before use.

3 points: The soreness was greatly relieved compared to before use.

2. Clinical evaluation of the improvement of gingivitis symptoms in humans - relief of gum pain

1) Test subject and usage: Examples 1 and 3 and Comparative Example 2 were attached to the gum pain area once a day for 10 minutes and then removed.

2) A questionnaire evaluation was conducted on a 3-point Likeard scale after 1 week of use for 15 volunteers who felt gum pain in each group.

3) Scale standard

1 point: The symptoms of gum pain were similar or worse compared to before use.

2 points: The symptoms of gum pain were slightly relieved compared to before use.

3 points: The symptoms of gum pain were greatly relieved compared to before use.

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

(1) hydroxyapatite (HAP) tablet specimen preparation and coloring method

Artificial teeth were created using hydroxyapatite, a component that forms more than 96% of teeth. That is, the hydroxyapatite powder was sintered at 1000°C after making a tablet with an IR press or a tablet machine. A colored artificial specimen was prepared by repeating the process of impregnating tea, coffee, iron, and mucin protein in a TSB (trypticase soybroth) solution, which is the Stooky method, and repeating the drying process for one week. The colored specimen was lightly washed with a toothbrush in running water to remove contamination that was easily dissolved or easily removed by water, dried, and the initial value L (lightness) was measured with a chromameter.

(2) In vitro tooth whitening effect evaluation method using colored artificial specimens

After attaching each of Example 4 and Comparative Example 3 to the colored artificial specimens, and after allowing them to stand for 30 minutes in oral conditions of 37 degrees and 98% humidity, Example 4 and Comparative Example 3 were removed, and then the specimens were washed with water, After drying, the L value was measured. The delta L value, which is the difference between the L values before and after attachment, was calculated.

[Hardness comparison test before attachment or before attachment and immediately before removal]

1. Hardness of each step in Examples and Comparative Examples

Example 1 Example 2 Example 3 Comparative Example 3 Comparative Example 4 manufacturing state not measurable not measurable not measurable not measurable 1st agent 100g 2nd agent 100g first application 150 g 180 g 120 g not measurable 300 g in close contact 150 g 5580 g 450 g not measurable > 33,600 g Immediately before removal (when drug release is complete) 150 g 12,000 g 600 g not measurable >>Measurable

As described in Table 3, the oral formulations of the embodiment of the present invention have a hardness of around 5000 g or less when in close contact, and the hardness is not high and can be deformed with a small force. The advantage is that it can be extended to a desired length and the formulation is soft, so there is little feeling of foreign matter in the gums or mouth. On the other hand, in the case of Comparative Example 3, there is no hardness, so it is equivalent to the Examples in terms of softness, but it is difficult to maintain the shape after application with a general liquid gel, and it is a characteristic that it is scattered when pressed with a finger. It is inconvenient to use because it is thrown away, and it has the disadvantages of being easily washed off in a humid oral cavity. In the case of Comparative Example 4, since the hardness at the time of adhesion is too large, it is impossible to deform the shape unless it is adhered quickly after application, and it may give a burden to the hard and soft gums, and there is a disadvantage in that it is difficult to dissolve the drug after the hardness is increased.

2. Step-by-step compressibility of Examples and Comparative Examples

Example 1 Example 2 Example 3 Comparative Example 3 Comparative Example 4 manufacturing state not measurable not measurable not measurable not measurable 1st 100 gs 2nd 100gs first application 700 gs 680 gs 650 gs not measurable 1200 gs in close contact 700 gs 11,000 gs 1500 gs not measurable >55,000 gs Immediately before removal (when drug release is complete) 700 gs 16,000 gs 2000 gs not measurable >>Measurable

As shown in Table 4, the oral formulations of the embodiment of the present invention do not have high compressibility when in close contact, that is, it does not take much to deform as desired for a certain period of time. When lightly pressed with a finger, the desired deformation That is, it is advantageous not only in size, but also in that it is possible to change the shape of several teeth at the same time to easily fill the gaps between teeth when the teeth are uneven. On the other hand, in the case of Comparative Example 3, it is a general liquid gel with no hardness, and it is difficult to maintain the shape after application and is scattered when pressed with a finger. The disadvantage is that it is easily washed off. In the case of Comparative Example 4, the compressibility rapidly increases within a few minutes after application, and the value is too large.

3. Comparison of malleability of Examples and Comparative Examples

Example 1 Example 2 Comparative Example 3 Comparative Example 4 When first applied
(within 2 minutes) >300% >150% Unable to maintain shape 150% close
(within 10 minutes) >300% >150% Unable to maintain shape fix just before removal
(after 30 minutes) >300% 150% Unable to maintain shape fix

As can be seen in Table 5, the formulation of the present invention was able to maintain malleability until just before removal. Due to this malleability, the formulations of the present invention can be completely adhered to the tooth gap, and the drug can be effectively delivered between the tooth gap and the gum.

4. Drug release amount of Examples and Comparative Examples

Example 2 Example 3 Comparative Example 3 10 minutes after attachment 50% 60% 5% 30 minutes after attachment > 70% >80 % <5%

As can be seen in Table 6, in the case of Examples, it was confirmed that 70% by weight or more was released from the amount of the drug initially loaded when 30 minutes had elapsed after attachment. However, in the case of the comparative example, it was confirmed that the drug release was limited as the hardness increased when the formulation was removed.

5. Comparison of ease of use between Examples and Comparative Examples

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Manufactured state 1st agent (soaking: wet type)
2nd agent (wet type) 1st agent (stained: powder type)
2nd agent (wet type) buried
(wet type) buried
(wet type) buried
(wet type) The degree of smearing when first applied Not smeared (dry type) Almost not smeared (like dry type) Buried (wet type) buried
(wet type) buried
(wet type) The degree of smearing before removal Not smeared (dry type) not smeared Buried (wet type) buried
(wet type) buried
(wet type)

As can be seen in Table 7, in the comparative examples of the present invention, the drug was smeared on the hand in the process of attaching the formulation to the tooth surface, but in the case of the examples of the present invention, it was hardly smeared on the hand, so it was convenient to use. .

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Shirin Yi Symptom Questionnaire Score - 2.7 1.5 - Gum Pain Symptom Questionnaire Score 2.4 - - 1.4

As can be seen in Table 8, Example 2 was confirmed to have a better shirin relieving effect than Comparative Example 1, and Example 1 was confirmed to have a better gingival pain symptom relieving effect than Comparative Example 2 . These results are considered to be the result of the effective delivery of the active ingredients to the target site because the formulations of the embodiment of the present invention have excellent adhesion to the teeth and the tooth gap.

In addition, Comparative Example 2 and Comparative Example 3 correspond to the same form as toothpaste, so the retention time of the drug delivered at the time of initial application (when brushing) is not long, and the active ingredient is gradually lost over time, but the examples of the present invention It was thought that the loss rate of the active ingredient was also less because the formulation through the drug provides a time for the active ingredient to penetrate stably for a certain period of time.

ΔL (1 use) ΔL (2 uses) Example 3 16.54±2.19 31.49 ±3.05 Comparative Example 3 5.29±1.54 9.89 ±1.85

As can be seen in Table 9, Example 3 exhibited a more excellent tooth whitening effect than Comparative Example 3. Comparative Example 3 was applied to the teeth in the form of a gel, and the amount of drug substance delivered to the teeth was small compared to the amount loaded because it was not fixed and flowed down or lost by saliva or physical force, and the tooth whitening effect was also significantly reduced. was confirmed to be

T: tooth
1: Conventional tooth attachment strip
2: Active ingredient
10: malleable oral formulation

Claims (17)

oral compositions having malleability even before being attached to teeth or periphery of teeth; And a preparation for attachment to a tooth or tooth periphery having malleability comprising an active ingredient for intraoral delivery,
The formulation does not include a separate support layer,
The final hardness upon removal of the formulation is the same or greater than the initial hardness upon attachment. [Claim 3] The preparation for attachment to teeth or surrounding teeth according to claim 1, wherein the active ingredient is mixed with the oral composition having malleability and dispersed in the preparation. According to claim 1, wherein the formulation is a texture analyzer (Texture Analyzer; Compression mode) measured by the compression mode (Compression mode), the initial hardness of the formulation for attachment to teeth or surrounding teeth, characterized in that within 0.1 to 20,000 g. [Claim 2] The formulation according to claim 1, wherein the formulation has a final hardness of 40,000 g or less upon removal as measured by a compression mode of a texture analyzer. 5. The method of claim 4, wherein the removal is 30 minutes after the formulation is attached to the tooth or tooth periphery, and the amount of drug released into the oral cavity is at least 60% by weight of the drug contained in the initial formulation. Formulations for attachment to teeth or periphery of teeth. [Claim 2] The formulation according to claim 1, wherein the formulation has an initial compressibility of 0.1 to 30,000 gs at the time of attachment as measured by a compression mode of a texture analyzer. [Claim 2] The formulation for attaching to teeth or surrounding teeth according to claim 1, wherein the formulation has a final compressibility of 50,000 gs or less upon removal measured in a compression mode of a texture analyzer. [Claim 2] The formulation for attachment to a tooth or a tooth periphery according to claim 1, wherein the area of the formulation increases when it is pressed by applying a force at the initial stage of attachment. According to claim 1, wherein the oral composition having the malleability is a phase change material, a phase change auxiliary material, a material for improving the adhesion of the phase change composition, and a material for helping the release of the drug, the tooth or tooth periphery attachment formulation comprising. 10. The method of claim 9,
- The phase change material is carrageenan, pectin, xyloglucan, gellan gum, ammonium alginate, magnesium alginate, potassium alginate, Sodium alginate, lithium alginate, chitosan, poly(D,L-lactic acid), poly(DL-lactide-co) -glycolide), poly-caprolactone, polyacrylic acid (carbopol), polyvinylacetal diethyl aminoacetate (AEA), hydroxypropylmethyl cellulose , poly(methacrylic acid)-poly(ethylene glycol)(poly(methacrylic acid)-poly(ethylene glycol)), poly(D,L-lactide)-block-poly(ethylene glycol)-block-poly(D, L-lactide) (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, polyvinyl acetate, glyceryl Monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate glyceryl monostearate or a mixture thereof,
- Materials that improve the adhesion of the phase change material are thickened precipitated silica, colloidal silicon dioxide, polyvinyl pyrrolidone, poly methyl vinyl ether and maleic acid copolymers (poly methyl vinyl ether and maleic acid copolymers) , shellac, rosin, poloxamer, hyaluronic acid, acrylate copolymer, hydroxypropyl methyl cellulose (HPMC), hydroxy Propyl cellulose (hydroxypropyl cellulose (HPC)), polyacrylic acid (polyacrylic acid), polyethylene glycol (polyethylene glycol), ethyl cellulose (ethyl cellulose) or a mixture thereof, or a crosslinked product thereof,
- The phase transition auxiliary material is calcium carbonate, calcium phosphate dibasic (CaHPO ₄ ), barium carbonate, zinc carbonate, calcium chloride (calcium chloride), calcium lactate ( calcium lactate, calcium citrate, calcium aspartate, calcium saccharate, calcium oxovalerate, calcium gluconate, calcium lactobionate calcium ion source of lactobionate) and calcium lactogluconate;
Barium carbonate, zinc carbonate, sodium bicarbonate, sodium carbonate, tetraborate, tripolyphosphate, trisodium trimetaphosphate chelating agents such as;
acetic acid, malic acid, lactic acid, gluconic acid, ascorbic acid, boric acid or mixtures or salts thereof;
NaOH, KOH or mixtures thereof; A preparation for attachment to a tooth or a tooth periphery, comprising any one or more selected from the group consisting of. delete delete According to claim 1, wherein the active ingredient is sodium fluoride (sodium fluoride), tin fluoride (stannous fluoride), indium fluoride (indium fluoride), amine fluoride (amine fluoride), sodium monofluorophosphate (sodium monofluorophosphate), sodium pyrophosphate (tetrasodium pyrophosphate, TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acid metapoly acid sodium metaphosphate, acid sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride (benzalkonium chloride), salicylanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), aspirin, keto ketorolac, flurbiprofen, piroxicam, meclofenamic acid, thiamine, riboflavin, nicotinic acid, pantothenic acid , pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, non Vitamin A, vitamin D, vitamin E, vitamin K tella quantitative extract Nutmeg extract, dexpanthenol, beta-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, characterized in that the tooth or tooth periphery attachment formulation. The method of claim 1, wherein the agent is
1 formulation; or
A preparation for attachment to teeth or surrounding teeth, characterized in that it is a two-part formulation consisting of a first agent and a second agent. [Claim 15] The preparation for attachment to a tooth or a tooth periphery according to claim 14, wherein the two-part preparation contains an active ingredient in the first agent, the second agent, or both the first and second agents. 15. The formulation of claim 14, wherein the first formulation comprises a phase change composition. delete

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