KR102445889B1 - Oral formulation comprising hardening composition having ointment form - Google Patents

Abstract

The present invention provides a formulation for attachment to a tooth or a tooth periphery comprising an oral composition in the form of a hardening ointment and an active ingredient for intraoral delivery. The formulation of the present invention can provide high adhesion to a desired site despite the gap between teeth or the curvature of teeth, and can secure sufficient time for drug delivery.

Description

Oral formulation comprising hardening composition having ointment form

The present invention relates to a formulation for intraoral drug delivery, and more particularly, to a new oral formulation capable of effectively delivering 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 the 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., Republic of Korea Patent No. 10-0623859 developed a tooth whitening ingredient delivery system using gelation during use, but has strong flowability when applied to the tooth surface. 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 and thus 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 that the drug substance is temporarily released, 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.

US 5,989,569

In order to solve the above problems, the present invention is to provide a formulation for delivery of an active ingredient in which physical properties are changed before and after attachment to teeth and after time has elapsed.

An object of the present invention is to provide a formulation that can be freely deformed before use and can be excellently adhered to a tooth gap or between a tooth and a gum.

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 the teeth or the tooth periphery.

Justice

As used herein, the term 'periphery of teeth' 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 site 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 mixed with 'tooth', and even if it is only described as 'tooth', it may be understood in this specification to include all of the tooth or tooth surrounding part.

As used herein, the term 'cured ointment oral composition' refers to an oral composition that does not have a predetermined shape before tooth adhesion, but has an ointment form that can be freely deformed, gradually loses fluidity, and is fixed in shape. That is, the oral cavity in the form of an ointment is in the form of an ointment when the formulation of the present invention is applied to the teeth or around the tooth, but the viscosity rises until the point of contact after application, and then hardens when the formulation of the present invention is removed from the tooth after adhesion. It may mean a composition.

As used herein, the meaning of 'applied to the teeth' may include from immediately after applying the formulation of the present invention to the teeth until 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 after mixing the first agent and the second agent and applying the agent to the teeth.

The meaning of 'when the formulation is in close contact with the teeth' of the present invention means a point in time when the user applies pressure after a certain period of time has elapsed after applying the tooth and the formulation is in close contact with the tooth curve, the tooth gap, and between the teeth and the gums, preferably the close contact Poetry can be understood as about 10 minutes after applying the formulation of the present invention to the teeth.

The 'hardened ointment phase' formulation is in a semi-solid ointment state such as dough and clay after application, but as time passes, it is molded by external forces such as heat or pressure, and then gradually loses moldability and becomes hardened to a permanent form. It may mean a formulation that is modified.

As used herein, 'curing' may include not only curing by the formation of a network structure such as a cross-linked structure of ions, such as an egg-box model, but also a decrease in fluidity accompanying the progress of a polymerization reaction by light or a catalyst, etc. It may mean a state in which it is hardened and no longer has a shape change depending on various factors such as the degree of absorption of the material and the degree of exposure to air.

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 in the form of a hardening ointment, and a preparation for attachment to teeth or teeth and gums 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 come to propose a new type of drug delivery system and a new method for delivering a drug substance into the oral cavity using this system. .

The inventors of the present invention have studied for a long period of time on 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 inflammation in the oral cavity, a site of periodontal disease, etc.) . As a result, a new type of oral formulation has been developed that can be conveniently applied to teeth or oral mucosa, 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 a formulation for attachment to teeth or surrounding teeth in which an oral composition in the form of a hardening ointment and an active ingredient for intraoral delivery are 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 an embodiment of the present invention, the formulation of the present invention may substantially lose moldability at the time of final removal, and preferably lose moldability while having a viscosity of 5000 cps or more at the time of final removal. The viscosity measured at the time of removing the formulation after the drug was released after applying the formulation to the teeth or around the tooth was 20 °C (room temperature), 5 to 20 rpm No. It may be 5,000 cPs or more, preferably 10,000 cPs or more, more preferably 200,000 cPs or more, as measured by a Brookfield viscometer equipped with 6 or 7 spindles. The viscosity at the time of the final removal of the formulation may vary depending on the type and content of the phase change material, the phase change auxiliary material, the material that helps the phase change material to adhere, etc. included in the formulation, preferably the viscosity measured at the time of removal is 5,000 cPs or more and 104,000,000 cPs or less.

The formulation attached to the tooth according to an embodiment of the present invention has a viscosity measured at the time of removal of at least 2 times, preferably at least 3 times, and more preferably at least 5 times, the viscosity measured when applied to the tooth or periphery of the tooth. 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 more than doubled compared to the viscosity measured at the time of application to the teeth.

The cured ointment 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 induces curing of the oral composition in the cured ointment phase, carrageenan, pectin, xyloglucan, gellan gum, ammonium alginate, magnesium alginate (magnesium alginate), potassium alginate (potassium alginate), sodium alginate (sodium alginate), lithium alginate (lithium alginate), chitosan (chitosan), polylactic acid (poly(D,L-lactic acid)), polylactide-co -glycolide (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-oligo Glycolyl-acrylate (PEG-oligoglycolyl-acrylate), poly(N-isopropyl acrylamide), sucrose acetate isobutyrate, polyvinyl alcohol ), glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate (glyceryl monostearate) 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 cured ointment composition may include a material for improving 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 adhesive force and is not soluble in water or ethanol.

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, chelating agents, such as tripolyphosphate, ethylenediamine tetraacetic acid, tetrasodium pyrophosphate, sodium acid pyrophosphate, acidic sodium metaphosphate, acetic acid, It may be any one or more selected from the group consisting of malic acid, lactic acid, gluconic acid, ascorbic acid or a mixture or salt thereof, NaOH, KOH, or a mixture thereof.

The phase change material, the phase change auxiliary material, and the material for improving the adhesion of the phase change material included in the cured ointment composition are listed as examples, 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 acid and the other formulation contains a base, so when the two formulations meet to form a curable ointment phase, bubbles are formed in the formulation. That is, the first agent contains acetic, lactic, malic, gluconic, ascorbic acid, 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, and the base is sodium carbonate, and more preferably sodium is an acid and a base mainly used for toothpaste. It can be citrate and sodium bicarbonate.

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 production inhibitory ingredient, an anti-inflammatory ingredient, an antibacterial ingredient , and other vitamins and minerals. In addition, it may contain ingredients for improving and alleviating 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 tetrasodium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP). , sodium potassium pyrophosphate, potassium pyrophosphate (tetrapotassium pyrophosphate), acid sodium metapolyphosphate (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, as drugs effective for the prevention and improvement of periodontal disease, 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, , can have mold-like moldability after being mixed.

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 and second agents.

Formulations of the present invention may be substantially lost when they are removed after tooth attachment. Preferably, the removal time point may mean a time point after 5 minutes to 3 hours, preferably 8 minutes to 90 minutes, after application to the tooth or the tooth periphery. For example, it can be peeled off after 10 minutes, 30 minutes, or 1 hour of attachment.

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

The substantially loss of moldability means a cured state in which physical properties such as dough are lost at the time of removing the formulation after application, and shape deformation is not possible. In one embodiment of the present invention, the aqueous solubility of the formulation measured at 32° C. and 1 atm in a state of substantially losing moldability is less than 20% by weight, more preferably less than 15% by weight, even more preferably 10% by weight. It may be less than, and most preferably may have a solubility in water of 1-10% by weight.

The formulation may further include a support layer if necessary when attached to the tooth or the 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.

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.

It does not drip when applied to the teeth, making it 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.
FIG. 2 is a diagram exemplarily showing the process of attaching the formulation 10 of the present invention to the tooth T and then removing it over time.
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, the following examples and the like will be described in order to explain the present invention in more detail. 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 weight percent.

[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 1-3 were prepared in the following manner. 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 did 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.

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

Comparative Examples 1-5 were prepared as follows. Comparative Example 1 used P&G SensiStop (contains an active ingredient for improving sore throat), and Comparative Example 2 used Parodon Tax (contains an active ingredient for improving gingivitis).

Comparative Example 3 is an Alginate Gel prescription (alginate water-soluble gel prescription, teeth whitening), Comparative Example 4 is a temperature sensitive polymer, Poloxamer prescription (teeth whitening), Comparative Example 5 is a dental impression material prescription (silicone dual-syringe prescription) did.

Comparative Example 1
(P&G SensiStop™)
Formulation: Strip
Comparative Example 2
(Product name: Paradontax)
Formulation: Toothpaste Comparative Example 3
(Alginate Gel)
Formulation: Gel Comparative Example 4
(Poloxamer)
Formulation: Liquid Comparative Example 5
Dental Impression Material (Selection)
VPS Putty)
Formulation: 1 agent, 2 agent reactive silicone gel water
glycerin
Cellulose Gum
Dipotassium Oxalate (drug 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%
PluronicF127 20%
Carbamide Peroxide 16%
(H ₂ O ₂ 5.6%)
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. Viscosity comparison experiment (Test method: Viscometer measurement with a rotary viscometer)

- Evaluation instrument: Brookfield Viscometer, No. 6, or 7 spindle, 5-20 rpm, 20°C (room temperature)

- Evaluation method: Viscosity of Comparative Examples and Examples was measured with a Brookfiled Viscometer.

As shown below, i) the viscosity at the time of initial application, ii) the viscosity at the time of adhesion, and iii) the viscosity immediately before removal were measured. However, in the case of a prescription consisting of one and two agents, the viscosity measured for each before mixing of the first and second agents is regarded as the viscosity during manufacture, and in the case of only one agent, the viscosity in the prepared state is the viscosity before initial application was seen to be the same as

i) Viscosity at the time of initial application: In the case of the first and second agent formulations, the viscosity is immediately after mixing, and in the case of one agent, it is the same as the viscosity of the manufacturing state.

ii) Viscosity at close contact: In case of 1st and 2nd agents, the viscosity starts to increase from the moment of mixing. In this experiment, after application, for example, in the case of a formulation using a total use time of 10 minutes, it was adhered to the desired site at about 5 minutes, and in the case of a formulation with a total use time of 30 minutes or more, it was adhered to the desired site from 5 to 10 minutes. Viscosity is measured as the viscosity at close contact.

iii) Viscosity just before removal or upon completion of drug release (at the time of drug release of about 70-100%): Viscosity at which the viscosity no longer increases.

For example, when 1 and 2 agents are prescribed for the purpose of whitening teeth and maintaining the whitening effect attached for the last 30 minutes, for example, ① Viscosity in the manufacturing state means each viscosity before mixing, ② Viscosity at the time of initial application is, Viscosity just before tooth application (viscosity immediately after mixing when 1 and 2 agents are composed) ③ Viscosity in close contact means the viscosity 10 minutes after tooth application, ④ Viscosity just before removal or when drug release is complete means the viscosity 30 minutes after tooth application. .

2. 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 keep the temperature of the test solution at 32±0.5 during the drug release test. The sample example or comparative example is fixed on the upper surface of the disk that can be used as a sinker without absorption, interference, or reaction, with the target attachment side facing outward, and then the sample attached side facing 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 of the blade of the paddle to be 25±2mm with the surface of the specimen, 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).

Drug analysis method: Select an appropriate analysis method according to the drug and its content. For example, titration for peroxides, ICP analysis for metal salts, and HPLC for natural extracts are selected for analysis.

3. Solubility comparison experiment: In the present invention, the shape retention power during the artificial saliva (0.9% NaCl aqueous solution) release experiment is defined as solubility. Record through comparative observation (Record by observing whether the shape collapses, maintains the shape, maintains the same thickness and height as the initial stage, or decreases under the USP drug release test conditions)

① Manufacturing state solubility: In the case of composition 1 and 2, take 1 g each and observe after loading in the same manner as in the drug release test.

② At the time of initial application, adhesion, and immediately before removal, if the solubility is composed of the first and second agents, after mixing, the shape change according to time is observed after loading in the same way as in the drug release experiment.

4. Convenience comparison experiment (whether wet type or dry type): Due to the nature of the formulation applied to the target in the oral cavity, staining on the hands during application also causes inconvenience, but while applying and leaving it for a certain period of time, Getting it on your hands and getting it on your hands when removing it causes discomfort. The wet type is characterized by being smeared when the formulation is touched by hand, and the dry type is characterized in that it does not come off 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: Example 1 group and Comparative Example 1 group were removed after attaching the syringe to the site for 10 minutes once a day.

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 gingivitis symptoms improvement in humans - relief of gum pain

1) Test subject and usage: Example 2 and Comparative Example 2 groups 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 made 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 and drying the Stooky method for one week. The colored specimen was lightly washed under running water with a toothbrush to remove contamination that was easily dissolved or easily removed by water, dried, and the initial value L (lightness) was measured with a chroma meter.

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

After attaching each of Example 3, Comparative Example 3, and Comparative Example 4 to the colored artificial specimens, and leaving them for 30 minutes in oral conditions of 37 degrees and 98% humidity, after removing Examples and Comparative Examples, 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.

[Viscosity and solubility comparison experiment before attachment or at the beginning of attachment and immediately before removal]

1. Viscosity of each stage of Examples and Comparative Examples

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

Example 1 Example 2 Example 3 Comparative Example 3 Comparative Example 4 Comparative Example 5 manufacturing status 2nd agent (5 cps) 1st agent (14,000 cps)
2nd agent (14,000 cps) 1150 cps 13,000cps 400cps 1st agent (700,000cps)
2nd agent (700,000cps) first application 30,000 cps 20,000 cps 1200 cps 13,000cps 400cps 700,000cps in close contact 120,000cps 50,000 cps 2500cps* 13,000cps 600cps >2,000,000cps Immediately before removal (when drug release is complete) 180,000cps >50,000 cps >5000cps* 13,000cps 600cps not measurable

As shown in Table 3, it was confirmed that the viscosity of the formulations of the present invention increased from the time of initial application to adhesion.

*

2. Step-by-step drug release amount of Examples and Comparative Examples

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

As can be seen in Table 4, when the total drug loading is 100, it can be seen that more than 70% of the drug is released at the time of removing the formulation, which is a time point when 30 minutes have elapsed after attachment. However, in the case of Comparative Example 5 corresponding to a dental impression material, it can be seen that although the viscosity increases with time as in the formulation of the present invention, drug release is not smoothly performed.

3. Solubility of each step of Examples and Comparative Examples / Form retention of formulations

Example 1 Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Manufacturing State Solubility 2nd agent (melted) 1st agent (melted)
2nd agent (melted) melt away melt away 1st agent (shape maintenance 100%)
2nd agent (shape maintenance 100%) Solubility at first application Maintain shape (100%) Maintain shape (>90% or more) melt away Partial maintenance (>50%) Maintain shape (100%) Residual amount of agent prior to removal Maintain shape (100%) Maintain shape (>90% or more) melt away Partial maintenance (<50%) Maintain shape (100%)

As can be seen in Table 5, it can be seen that the formulation of the present invention has excellent shape retention just before removal. That is, from the above results, it can be seen that the formulation of the present invention can be closely adhered to the gap between the teeth after application and adhered, and its shape is maintained until just before removal.

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

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 4 Manufactured state 2nd agent (wet type) 1st agent (soaking: wet type)
2nd agent (wet type) buried
(wet type) buried
(wet type) buried
(wet type) Degree of smearing when first applied Almost not smeared (like 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 not smeared buried
(wet type) buried
(wet type) buried
(wet type)

Table 6 shows the results of confirming the convenience of use in the process of applying the formulation of the present invention. As can be seen from the above results, it was confirmed that the formulation of the present invention can be used conveniently and hygienically because almost no drug is smeared on the hand when it is applied to the teeth and adhered to the tooth, and there is no unnecessary loss of the drug. However, the preparations of the comparative example gave the drug loss or discomfort due to the drug on the hand.

5. Comparison of Efficacy Effects of Examples and Comparative Examples

Example 1 Comparative Example 1 Example 2 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 7, in Example 1, it was confirmed that the sirin had a better alleviating effect compared to Comparative Example 1, and Example 2 was confirmed to have a more excellent alleviating effect of gum pain symptoms compared to Comparative Example 2. . This result is considered to be the result of the effective delivery of the active ingredients to the target site because the formulations of the examples of the present invention have excellent adhesion to the teeth and the gap between the teeth.

In addition, Comparative Examples 1 and 2 correspond to the same form as toothpaste, so the retention time of the drug delivered at the time of first application (when brushing teeth) is not long, and the active ingredient is gradually lost over time, but the formulation according to the embodiment of the present invention It was thought that the loss rate of the active ingredient was also less because it provides 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 Comparative Example 4 7.82±3.19 13.26 ±1.99

As can be seen in Table 8, Example 3 exhibited a more excellent tooth whitening effect than Comparative Examples 3 and 4. Comparative Examples 3 and 4 had a large amount of flowing down or lost without being fixed after being applied to the teeth in gel and liquid form, respectively, so the amount of the active ingredient delivered to the teeth was small compared to the loaded amount, and the tooth whitening effect was also significantly reduced. confirmed to be

T: tooth
1: Conventional tooth attachment strip
2: Active ingredient
10: Formulation containing oral composition in the form of hardening ointment

Claims (13)

A gel-like hardening ointment-like oral composition before attachment; And as a preparation for attachment to teeth or surrounding teeth comprising an active ingredient for intraoral delivery,
The cured ointment oral composition is one selected from the group consisting of glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate and glyceryl monostearate. It contains more than one phase change material,
The formulation does not contain a polyol that is liquid at room temperature,
The formulation is a formulation for attachment to teeth or surrounding teeth, characterized in that after the formulation is attached to the tooth or tooth periphery, it loses moldability after attachment for 5 minutes to 3 hours under humidity and temperature conditions in the oral cavity and is hardened. The method according to claim 1, wherein the formulation is applied to the tooth or tooth periphery and after 5 minutes to 3 hours has elapsed, the aqueous solubility of the formulation measured at 32°C and 1 atm is less than 20% by weight. formulation. According to claim 1, wherein the formulation is for attachment to teeth or surrounding teeth, characterized in that after the formulation is attached to the teeth or the surrounding area of teeth, it is hardened after 8 to 90 minutes of attachment under the conditions of humidity and temperature in the oral cavity to lose moldability. formulation. According to claim 1, wherein the loss of moldability and hardening is that the viscosity value of the formulation is at a temperature of 20 °C, 5 to 20 rpm at a time point of 5 minutes to 3 hours after the formulation is applied to the teeth or around the teeth. No. Formulations for attachment to teeth or surrounding teeth, characterized in that 50,000 cps or more as a result of measurement with a Brookfield viscometer equipped with 6, 7 spindles. The method according to claim 1, wherein the viscosity measured at 5 minutes to 3 hours after application of the formulation to the teeth or periphery of the tooth is increased by more than twice the viscosity measured when the formulation is applied to the tooth or periphery of the tooth. Formulations for attachment to teeth or periphery of teeth. According to claim 1, wherein the hardening ointment oral composition further comprises a phase change material other than those described in claim 1, a phase change auxiliary material, a material for improving adhesion of the phase change composition, and a material to help release the drug. A formulation for attachment to teeth or surrounding teeth, characterized in that. 7. The method of claim 6,
- The additional phase change material is alginate, carrageenan (carrageenan), pectin (pectin), xyloglucan (xyloglucan), gellan gum (gellan gum), chitosan (chitosan), polylactic acid (poly(D,L-lactic acid) ), polylactide-co-glycolide (poly(DL-lactide-co-glycolide)), poly-caprolactone (poly-caprolactone), polyacrylic acid (polyacrylic acid (carbopol)), polyvinylacetal diethyl amino Acetate (polyvinylacetal diethyl aminoacetate (AEA)), hydroxypropylmethyl cellulose, poly(methacrylic acid)-poly(ethylene glycol), poly(D,L) -lactide)-block-poly(ethylene glycol)-block-poly(D,L-lactide)(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, or a mixture thereof,
- The material for improving the adhesion of the phase change composition is 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, chelating agent;
acetic acid, malic acid, lactic acid, gluconic acid, ascorbic acid or mixtures or salts thereof;
NaOH, KOH, or a mixture thereof; A preparation for attachment to a tooth or a tooth periphery, comprising any one or more selected from the group consisting of. 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, 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 formulation is one-pack; or
A preparation for attachment to a tooth or a tooth periphery, characterized in that it is a two-part formulation consisting of a first agent and a second agent. 10. The method of claim 9, wherein the first agent and the second agent of the two formulations are mixed and applied to the tooth or the tooth periphery,
The viscosity measured by mixing the first agent and the second agent for application to the tooth or the tooth periphery increases compared to before mixing, and the formulation loses the moldability and is hardened. [Claim 10] The preparation for attachment to teeth or surrounding teeth according to claim 9, wherein the two-part preparation contains an active ingredient in the first agent, the second agent, or both the first agent and the second agent. The method according to claim 1, wherein the formulation is removed at a temperature of 20°C, 5 to 20 rpm No. A formulation for attachment to the periphery of the tooth that has a viscosity of 5,000 cPs or more with a Brookfield viscometer equipped with 6, 7 spindles. According to claim 1, wherein the formulation further comprises a support layer, the tooth or tooth periphery attachment formulation characterized in that.

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