KR20170065287A - Oral formulation comprising malleable oral composition - Google Patents

Abstract

The present invention provides an oral composition having malleability and a preparation for peripherally attaching a tooth or a tooth comprising a medicinal ingredient for oral delivery. The preparation of the present invention can impart a high adhesion to a desired site despite the clearance of the teeth or the bending of the teeth. The agent of the present invention having a high adhesive force may be advantageous in achieving the desired effect by increasing the time of adhering to the target site in the oral cavity.

Description

[0001] The present invention relates to oral preparations comprising malleable oral composition,

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

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

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

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

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

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

In order to solve the above-mentioned problems, the present invention provides a new type of oral cavity attachment preparation which is easy to adhere to a desired site in the oral cavity and can secure a sufficient contact time.

The present invention is intended to provide a formulation in which the shape before use can be modified and which can be adhered to the gap between the teeth and the gums with excellent adhesion.

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

Justice

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

As used herein, the term " malleability " may mean that the formulation of the present invention has formability or may be formable by external pressure. Which means that it is sufficiently flexible and permits morphological transformation to be such that it can be fully adhered to the fine gap between the teeth and gingiva when attached to the mouth.

In this specification, not only the case where the preparation is extended to the left and right but also the case where the product is deformed in four directions when it is placed on a plane and pressed with a constant force may be included in the range of the malleability, Can be included in the range. If it has malleability, the object can be compressed or its area can be widened within a certain hardness range.

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 determined by the compression test mode of the Stable Micro System TA XT Plus. After filling 20g into 50mL beaker, set 20mm diameter aluminum probe for hardness measurement, measure hardness at test speed of 1.5mm / s, target mode at distance and distance at 10mm. The hardness is understood as the peak value of the first cycle calculated. The unit can be expressed as g (g force).

As used herein, " compression force " may refer to a force applied just before a formulation is compressed, broken, cut or destroyed. The compressive 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 20g into a 50mL beaker, set a 20mm diameter aluminum probe for measuring the compression force, measure the test speed at 1.5mm / s, target mode at distance and distance at 10mm. The compressive force is understood as the area value of the first cycle calculated. The unit can be expressed as gs (g force * sec).

As used herein, " compressibility " may mean a property that the formulation can stretch without being cut or cut when subjected to a compressive force.

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 the formulation is pressed between the rollers. As used herein, the elongation can be understood to mean " plane strain " unless otherwise specified. An excellent elongation can be understood as having malleability.

As used herein, the term " applied to a tooth " may include a position of the preparation of the present invention in a tooth or a peripheral portion thereof, and then the user may pressurize the preparation to adhere the preparation to the tooth. In the case of the 2 formulation, 'after application of the preparation' of the present invention may mean immediately after mixing the 1 agent and the 2 agent and mixing them.

The term "when the preparation is in close contact with the teeth" means that the user applies pressure to the tooth after a certain time has elapsed from the application of the tooth to bring the preparation into close contact with the tooth curve, the tooth gap, and between the tooth and the gum. Can be understood to be about 5 minutes or less, preferably about 1 to 3 minutes, after the preparation of the present invention is applied to the teeth.

The 'time to remove the preparation' of the present invention may mean a time point at which the drug is released from the oral cavity after being adhered to the tissues surrounding the tooth or the teeth, and the time may be determined depending on the purpose and use of the preparation, But it may be removed within 30 minutes, more preferably within 10 minutes after adhering to the teeth from the viewpoint of convenience of use. The hardness of the preparation at the time of removal may be the same as the point of time when the preparation is applied to the teeth or close to the tooth, and the hardness of the preparation may be increased at the time of removal.

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

Specific details of the invention

The present invention provides an oral composition having malleability and a tooth or tooth comprising a medicinal ingredient for oral delivery and a preparation for gingival perimeter gingival attachment. The inventors of the present invention have conducted studies on a drug delivery system capable of delivering the active ingredient into the oral cavity, and as a result, have come up with a new type of drug delivery system, and a new method of delivering the active ingredient into the oral cavity using such a system .

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

An embodiment of the present invention provides an oral composition having malleability and a tooth or a tooth peripheral attachment agent mixed with a pharmaceutical ingredient for oral delivery. For example, the medicinal ingredient may be uniformly dispersed in the oral composition, and a case where the dispersion is made non-uniform may be included in the mixture of the present invention.

According to one embodiment of the present invention, the preparation of the present invention has a semi-solid property at the same time, so that it can be brought into close contact with bending or gaps.

The formulations of the present invention may have the form of dough or clay, and may be applied to the teeth or surrounding areas of the teeth in the form of ointments.

The formulation of the present invention may have an initial hardness of from 0.1 to 20,000 g, preferably from 10 g to 12,000 g, when measured in the Compression mode of the Texture Analyzer (TA). When the initial hardness is in the above-mentioned range, it is easy to adhere to the tooth gap or the bending part.

The formulation may have a final hardness of less than 40,000 g, preferably less than 30,000 g, as determined by the Texture Analyzer (TA) in the Compression mode.

The drug having the final hardness within the above range can smoothly release the drug to obtain a desired effect (for example, an effect of improving the whitening effect, a tooth whitening effect, a gingivitis-preventing effect, etc.) .

In another embodiment of the present invention, the formulation may have an initial compressibility of from 0.1 to 30,000 gs, preferably from 10 gs to 20,000 gs, when measured in a Compression mode of a Texture Analyzer (TA) Lt; / RTI > When the squeezing property is in the above range, it is easy to adhere to the tooth gap or the bending part.

The formulation may have a final compressibility of less than 50,000 gs, preferably less than 40,000 gs, when removed by a Texture Analyzer (TA) as measured in a compression mode.

The drug having the final hardness within the above range can smoothly release the drug to obtain a desired effect (for example, an effect of improving the whitening effect, a tooth whitening effect, a gingivitis-preventing effect, etc.) . The shape fixation force can secure a sufficient contact time with the site where the drug is required to reach, which can be more advantageous in achieving the desired effect.

The preparation according to one embodiment of the present invention may have a malleability, which may increase the length of the composition when pressed with a force of at least 0.5 kg / cm ² , preferably at a force of at least 1 kg / cm ² have. Specifically, the preparation is pressed at a standard relative humidity of 65% at 25 ° C with a finger, or when pressed with a pressure roller of at least 0.5 kg / cm ² , preferably at a force of at least 1 kg / cm ² It may have an elongation of 120% or more, 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 preparation of the present invention may be about 10% or less of the elongation change from the time when the preparation is applied to the tooth or the periphery of the tooth to the point where the preparation is removed. For example, in one embodiment of the present invention, the oral preparation of the present invention in which the first agent containing PVA (polyvinyl alcohol) and the second agent containing Borax are mixed, When the elution rate of the drug is 60% or more, the elongation measured according to the method of the present invention, ie, a sample of a certain weight is made 1 cm ² , and the pressure roller is pressed at a pressure of ² kg / cm ² 150%, and 150%, respectively.

The oral compositions included in the formulations of the present invention may include phase transfer materials, phase transfer aids, materials that enhance adhesion of the phase transfer composition, and materials that facilitate drug release.

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

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

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

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

The drug release aid may be used if it forms a channel, porous structure or bubble within the formulation. For example, in the case of two formulations of one agent and two agents, one type of acid contains a base in another formulation, so that when two formulations meet, a bubble is formed in the formulation when forming a viscous solder composition. Examples of the first agent include sodium acetate, lactic acid, malic acid, gluconic acid and ascorbic acid, or a water soluble salt thereof such as sodium citrate. The second agent includes sodium hydroxide (NaOH), potassium hydroxide (KOH) , Sodium bicarbonate (sodium bicarbonate), and sodium carbonate. Preferably, the acid may be selected from acetic acid and the base may be selected from sodium hydrogencarbonate, and more preferably, it is mainly used in toothpaste. Lt; RTI ID = 0.0 > sodium citrate and sodium bicarbonate. ≪ / RTI >

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

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

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

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

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

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

In the preparation of the present invention, physical properties such as hardness and compressibility may be maintained from immediately after the application to immediately before the removal, and the physical properties may be kept the same until the drug release time in the oral cavity according to the purpose, And the shape may be fixed. The time point at which the preparation of the present invention is removed may vary depending on the components contained in the preparation, but it may mean that 30 minutes have elapsed after application to the periphery of a tooth or a tooth.

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

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

In an embodiment of the present invention, the drug can be easily removed by brushing at the time when the drug is released and removed, and the point of time at which the drug is removed may be the point at which 30 minutes have elapsed after the application.

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

It can be adhered well to the tooth gap and is excellent in drug delivery efficiency. In addition, since it does not flow down after being attached or diluted by the saliva, it is possible to sufficiently secure the contact time between the drug delivery site and the preparation of the present invention, which is advantageous in achieving the desired efficacy.

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

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

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

[Preparation of preparation for oral use]

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

The formulations of Examples 1-4 were prepared as follows. The powder formulations of the examples were mixed using a powder mixer, and the gels of the examples were prepared by mixing the polymers at a constant rate so as not to aggregate the polymer with a mechanical mixer. In case of Example 3, the temperature was adjusted to 50 ° C, and the mixture was mixed with a mechanical mixer. In the case of Example 1, the viscosity of each of the first and second liquids is low in liquid phase. It is confirmed that the first and second liquids are completely melted before mixing, so that a homogeneous preparation can be obtained after mixing.

Example 1 (Compression band type) Example 2 (film-coated type) Example 3 Example 4 An example having the form of a plaster Examples requiring separate support layers (dual paint type)
Applicator included (dual syringe + mixing tip) (Phase transition type by needle)
GMO + EC 1: liquid phase
2: liquid phase
1: powder
2: liquid-like viscosity
Support layer: PE film Article 1: gel-like
2: gel-like Article 1: gel-like 1: PVA 3%
Latex extract 0.1%
Ethanol 1%
Water to 100%
2: Borax 4%
Water to 100%
1: Alginate 12%
Calcium Sulfate 15%
Sodium Phosphate 2%
Diatomaceous earth to 100%
2: Gantrez 0.38%
Zinc Chloride 0.18%
Water to 100% 1: Alginate 3.8%
Aceticacid 2.5%
Latex extract 0.1%
Water to 100%
2: 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. In Comparative Example 1, P & G SensiStop ™ (containing a silymarin-enhancing active ingredient) and Comparative Example 2 was used in Pharodontax ™ (containing a gingivitis-improving active ingredient).

Comparative Example 3 was prepared by PVA Gel prescription (water soluble gel prescription, gingiva / periodontal improvement), and Comparative Example 4 was prepared by silicone dual-syringe prescription.

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

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

Experimental Method

1. Hardness comparison experiment (Experimental method: Measured by Texture Analyzer)

Evaluation instrument : Stable Micro System TA XT Plus

Evaluation method : The hardness of the comparative example and the example is measured by a texture analyzer.

The hardness is measured by a Texture Analyzer in the compression test mode of a TA (Texture Analyzer). After filling 20 g of the sample in the 50 mL beaker, the aluminum probe having a diameter of 20 mm is set for the hardness measurement. The test speed is 1.5 mm / s, the target mode is the distance, and the distance is 10 mm. The hardness, calculated mechanically, is the peak value of the first cycle.

( 1) Hardness of the preparation state: In the case of a formulation consisting of one agent and two agents, the hardness measured for each agent before mixing of agent 1 and agent 2. In the case of only one zero, the hardness of the manufactured state is interpreted to be the same as the hardness before the initial application.

② Hardness at the time of initial application: Hardness immediately after mixing in the case of formulation 1 or 2, and same as hardness in the case of composition 1.

③ Hardness in case of close contact = 1 case, 2 case From the moment of mixing The hardness starts to increase, and the hardness in the state where the shape deformation can occur even at a small pressure (the hardness when adhering to a desired site)

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

For example, the hardness of the preparation state refers to the hardness before mixing. (2) The hardness at the time of initial application is the same as that of tooth application The hardness at the time of adhesion is 10 minutes after the application of the tooth, and 4) The hardness at the time of immediately before the removal or completion of drug release means the hardness after 30 minutes after application of the tooth.

2. Crimpability  Comparative Experiment (Experimental Method: Measured by Texture Analyzer)

Evaluation instrument: Stable Micro System TA XT Plus

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

The compression test mode of the TA (Texture Analyzer) is measured by the Texture Analyzer. After filling 20 g of the sample and the comparative example into a 50 mL beaker, a 20 mm diameter aluminum probe for measuring the compression property is set, the test speed is 1.5 mm / s, the target mode is the distance, and the distance is 10 mm. The compressibility calculated mechanically is the area value of the first cycle.

3. Comparison test of malleability (Test method: degree of elongation when pressing with constant force after measurement of initial length

In case of specimens which can be deformed on PET film, make 1g of the same length and length (1cm ² ), place PE film on it, set 1cm ² grid plate to be visible on PE film below, / cm ² ), the degree of elongation of the length was measured using a 1 cm ² grating plate, and the elongation was calculated by calculating the average degree of elongation in all directions. Elongation measurements were made at normal laboratory conditions and were measured at relative humidity of approximately 65% and 25 ° C.

4. Comparative experiment of drug release (Experimental method: Quantification of effective ingredient concentration in solution after release experiment)

A) Operation

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

B) Drug analysis method

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

5. Easy to use comparison test (adhesion, form retention , Adhesion, Removal power  Etc)

The characteristics of the formulation applied to the target in the oral cavity cause inconvenience to the user while being applied. However, it is inconvenient for the user to be exposed to the gums or hands while applying and leaving for a certain time, You can. Wet type can be worn when hands are touched, and dry type is not.

[Effectiveness / effect comparison experiment]

1. Assessment of Clinical Questionnaires on Improvement of Human Correlation

1) Test subject and method of use: Example 2 and Comparative Example 1 were allowed to adhere to the syringe site for 10 minutes once a day and then to be removed.

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

3) Based on the scale

1 point: Symptoms similar or worsened compared to before use

2 points: a little more severe symptoms than before use

3 points: Very severe symptoms were alleviated before use

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

1) Test Subjects and Usage: Examples 1 and 3 and Comparative Example 2 were allowed to adhere to the gum pain site for 10 minutes once a day and then to be removed.

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

3) Based on the scale

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

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

3 points: Very relief of gum pain symptoms before use

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

(One)  Preparation and coloring of hydroxyapatite (HAP) tablet samples

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

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

Example 4 and Comparative Example 3 were respectively attached to the colored artificial specimens, and then the specimens were washed with water after the Example 4 and Comparative Example 3 were removed after 30 minutes' standing at 37 ° C and 98% humidity conditions under the oral condition, After drying, L value was measured. The delta L value, which is the difference of the L value before and after the attachment, was calculated.

[Comparison of hardness before attachment or at the beginning of attachment and immediately before removal]

1. Hardness at each step of the example and comparative example

Example 1 Example 2 Example 3 Comparative Example 3 Comparative Example 4 Manufacturing Status Not measurable Not measurable Not measurable Not measurable 1 100 g
2 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 (upon completion of drug release) 150 g 12,000 g 600 g Not measurable >> not measurable

As shown in Table 3, the oral preparations of the examples of the present invention had a hardness of about 5000 g or less at the time of adhering, and the hardness was not so high that they could be deformed with a small force. Therefore, It is possible to expand to the desired length, and the softness of the preparation is advantageous in that there is little foreign body sensation in the gums or mouth. On the other hand, in Comparative Example 3, there was no hardness, so it was the same level as in Examples in terms of softness, but it was difficult to maintain shape after application with a general liquid gel, and it was dispersed when pressed by a finger. It is inconvenient to use, and it has a disadvantage that it is easily washed away in a humid mouth. 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 brought into close contact with the skin after the application, so that the hard and soft gums are liable to be burdened.

2. Compressibility of each of Examples and Comparative Examples

Example 1 Example 2 Example 3 Comparative Example 3 Comparative Example 4 Manufacturing Status Not measurable Not measurable Not measurable Not measurable 1 100 gs
2 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 (upon completion of drug release) 700 gs 16,000 gs 2000 gs Not measurable >> not measurable

As shown in Table 4, the oral preparations of the examples of the present invention do not have high compressibility when they are in close contact, that is, they do not cause a great deal of strain for a certain period of time. When lightly pressed with a finger, In other words, it is advantageous that, in addition to the size, when the teeth are uneven, it is possible to change the shape of the teeth, which can easily fill the tooth gap at the same time. On the other hand, in the case of Comparative Example 3, it is difficult to maintain the shape after application with a general liquid gel having no hardness, and it is dispersed when pressed with a finger. It is buried in the hand and easily buried in the contact with the gum, I have the disadvantage that I wash it easily. In the case of Comparative Example 4, the compression property was rapidly increased within a few minutes after the application and the value thereof was too large, so that it was difficult to use the product because of its inability to be deformed unless it was closely adhered after application.

3. Comparison of malleability between Examples and Comparative Examples

Example 1 Example 2 Comparative Example 3 Comparative Example 4 First application
(Within 2 minutes) > 300% > 150% Can not keep form 150% In close contact
(Within 10 minutes) > 300% > 150% Can not keep form fixing Just before the removal
(After 30 minutes) > 300% 150% Can not keep form fixing

As shown in Table 5, the preparation of the present invention was able to maintain the malleability until immediately before the removal. By virtue of this malleability, the preparations of the present invention were able to be completely adhered to each other through a tooth gap, and the drug could be effectively transferred between tooth gaps and gums.

4. Drug release amounts in the Examples and Comparative Examples

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

As can be seen from the above Table 6, it was confirmed that the amount of the drug loaded in the first loading was more than 70% by weight at the time of 30 minutes after the attachment. However, in the case of the comparative example, it was confirmed that upon removal of the preparation, the hardness was increased and the release of the drug was limited.

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

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Degree of manufacturing state 1 (wet type)
2 (wet type) 1 (buried: powder type)
2 (wet type) Bury
(wet type) Bury
(wet type) Bury
(wet type) Degree of initial application Dry type Like dry type Bury
(wet type) Bury
(wet type) Bury
(wet type) Degree of burial just before removal Dry type Not buried Bury
(wet type) Bury
(wet type) Bury
(wet type)

As can be seen from the above Table 7, the comparative examples of the present invention can be conveniently used because they are hardly fused to the hands in the case of the embodiments of the present invention, .

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

As shown in Table 8, it was confirmed that Example 2 had a better silylation effect than Comparative Example 1, and Example 1 had a better gingival pain relief effect than Comparative Example 2 .

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

In addition, Comparative Example 2 and Comparative Example 3 are similar to dentifrices, and the time for which the drug is delivered at the time of first application (brushing) is not long, so that the effective ingredient gradually disappears over time. However, It is thought that the preparation through which the active ingredient is stably infiltrated for a certain period of time provides less time for the active ingredient to disappear.

ΔL (used once) ΔL (used twice) Example 3 16.54 ± 2.19 31.49 + - 3.05 Comparative Example 3 5.29 ± 1.54 9.89 ± 1.85

As can be seen from the above Table 9, the tooth whitening effect of Example 3 was superior to that of Comparative Example 3. In Comparative Example 3, the amount of the drug substance to be transferred to the teeth was smaller than the amount of the drug that was loaded because the gel was applied to the teeth and then flowed down or lost due to saliva or physical force, and the tooth whitening effect was remarkably decreased Respectively.

T: Tooth
1: Conventional tooth attaching strip
2: active ingredient
10: Malodorous preparations for oral use

Claims (17)

An oral composition having malleability; And a pharmacologically active ingredient for intraoral delivery. 2. The formulation according to claim 1, wherein the pharmacologically active ingredient is dispersed in a preparation mixed with an oral composition having malleability. The preparation according to claim 1, wherein the formulation has an initial hardness of 0.1 to 20,000 g or less when measured in a compression mode of a texture analyzer (TA). The formulation according to claim 1, wherein the preparation has a final hardness of 40,000 g or less when removed by a Texture Analyzer (TA) in a compression mode. [Claim 4] The method of claim 4, wherein the removal is performed at 30 minutes or more after the preparation is applied to the tooth or the periphery of the teeth, and the amount of the drug released into the oral cavity is 60% Or an adhesive for attaching the peripheral portion of a tooth. The formulation according to claim 1, wherein the formulation has an initial compressibility of from 0.1 to 30,000 gs when attached to a Texture Analyzer (TA) as measured in a compression mode. The formulation according to claim 1, wherein the formulation has a final compressibility of less than 50,000 gs when removed by a Texture Analyzer (TA) in a compression mode. The preparation according to claim 1, wherein an area of the preparation is increased when a force is applied to the preparation at the initial stage of adhesion. 2. The formulation according to claim 1, wherein the oral composition having malleability comprises a phase transfer material, a phase transfer auxiliary material, a substance for improving adhesion of the phase transfer composition, and a substance for facilitating drug release. The method of claim 9, wherein the phase change material is selected from the group consisting of carrageenan, pectin, xyloglucan, gellan gum, ammonium alginate, magnesium alginate, potassium alginate, sodium alginate, lithium alginate, chitosan, poly (L, D-lactic acid), poly (lactic acid) DL-lactide-co-glycolide), poly-caprolactone, polyacrylic acid (carbopol), polyvinylacetal diethyl aminoacetate (AEA), hydroxypropylmethyl (Hydroxypropylmethyl cellulose), poly (methacrylic acid) -poly (ethylene glycol) (poly (methacrylic acid) -poly (ethylene glycol) - poly (D, L-lactide) -block-po (ethylene glycol) -block-poly (D, L-lactide), PEG-oligoglycolyl-acrylate, poly (N-isopropyl acrylamide ), Sucrose acetate isobutyrate, polyvinyl alcohol, polyvinyl acetate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monooleate, Glyceryl monoarachidonate, glyceryl monostearate, or a mixture thereof. The present invention relates to a preparation for adhering a tooth or a peripheral portion of a tooth. 10. The method of claim 9, wherein the materials enhancing adhesion of the phase transfer material are selected from the group consisting of incremental precipitated silica, colloidal silicon dioxide, polyvinyl pyrrolidone, polymethyl vinyl ether and poly methyl vinyl ether &lt; RTI ID = 0.0 &gt; and maleic acid copolymers, shellac, rosin, poloxamer, hyaluronic acid, acrylate copolymer, hydroxypropyl methylcellulose (HPMC ), Hydroxypropyl cellulose (HPC), polyacrylic acid, polyethylene glycol, ethyl cellulose, or a mixture thereof, or a crosslinked product thereof Wherein the tooth or the peripheral portion of the tooth is attached to the tooth. 10. The method of claim 9, wherein the phase change auxiliary material is calcium carbonate (calcium carbonate), calcium secondary phosphate _{(calcium phosphate dibasic (CaHPO 4)} ), barium (barium carbonate), zinc carbonate (zinc carbonate), calcium chloride (calcium chloride ), Calcium lactate, calcium citrate, calcium aspartate, calcium saccharate, calcium oxovalerate, calcium gluconate, lactose, Calcium ion source of calcium lactobionate and calcium lactogluconate;
Barium carbonate, zinc carbonate, sodium bicarbonate, sodium carbonate, tetraborate, tripolyphosphate, trisodium trimetaphosphate, trisodium phosphate, Chelating agents such as;
Acetic acid, malic acid, lactic acid, gluconic acid, ascorbic acid, boric acid or a mixture thereof or a salt thereof;
NaOH, KOH, or mixtures thereof; Wherein the at least one tooth is selected from the group consisting of a tooth, a tooth, and a tooth. The pharmaceutical composition according to claim 1, wherein the active ingredient is selected from the group consisting of sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate, sodium pyrophosphate tetrapodassium pyrophosphate (TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acid metapoly But are not limited to, acidic sodium metaphosphate, acidic sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (tetradecylpyridinium chloride) idinium chloride, TPC), aspirin, ketorolac, flurbiprofen, piroxicam, meclofenamic acid, thiamine, riboflavin, , Nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, Vitamin A (vitamin A), vitamin D (vitamin D), vitamin E (vitamin E), vitamin K (vitamin K), corn-deficient quantitative extracts, rose extract, myrrh, rattania, camomile, Tella fixed extract Extract of nutmeg, dexpanthenol, β-sitosterol, acetyl salicylic acid, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, iron oxalate ferric oxalate, vitamin E or a mixture thereof. A preparation for attaching to a tooth or peripheral area of teeth. The composition according to claim 1,
1 formulation; or
1 &lt; / RTI &gt; and 2 &lt; RTI ID = 0.0 &gt; agents. &Lt; / RTI &gt; 15. The formulation according to claim 14, wherein the formulation of the formulation for 2 comprises a pharmaceutical active ingredient in both the formulation 1, formulation 2 or formulation 1 and formulation 2. 15. The formulation according to claim 14, wherein the one dosage form comprises a phase transfer composition. 2. The formulation according to claim 1, wherein the preparation further comprises a support layer.

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