KR102305598B1 - Oral formulation - Google Patents

Abstract

The present invention relates to a preparation for attachment to teeth or periphery of teeth, comprising an active ingredient, a phase change polymer, and a water-insoluble and ethanol-soluble polymer, and the preparation contains ethanol as a solvent, and is applied to teeth or periphery of teeth in a liquid form. , To provide a preparation for attachment to teeth or periphery of teeth, which is phase-changed by intraoral fluid and has adhesion to teeth or periphery of teeth. The formulation of the present invention can impart high adhesion to a desired site despite the gap between the teeth or the curvature of the teeth. The formulation of the present invention having high adhesion is advantageous in achieving the desired effect by increasing the time to adhere to the target site in the oral cavity.

Description

Oral formulation

The present invention relates to a formulation for intraoral drug delivery, and more particularly, to a new form of drug delivery that can effectively deliver an active ingredient to a site that is difficult to access, such as a tooth gap in the mouth, and can sufficiently stay in a target site for drug delivery. It relates to oral preparations.

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

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

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

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

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

In the conventional intraoral active ingredient delivery system using phase transition, phase transition occurs when ethanol, polyol, and saliva in the mouth meet. It was characterized by Such a phase transition characteristic is an advantage of being able to deliver a drug by permeating well in the tooth gap and the boundary between teeth/gum, but there is a problem that a too thin thickness is unsuitable for delivery of a sufficient amount of drug.

US 5,989,569 B

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

An object of the present invention is to provide a formulation capable of permeating well between teeth and teeth/gums in a liquid form and securing sufficient adhesion time while being applied to teeth and surrounding areas.

An object of the present invention is to provide an oral formulation of a new type that can be excellently adhered to the tooth surface and the boundary between teeth and gums, as well as between teeth and gaps, and is easy to remove after use at the time of initial attachment.

The present invention provides a formulation for attachment to a tooth or a tooth periphery.

The formulation according to an embodiment of the present invention includes an active ingredient, a phase change polymer, and a water-insoluble polymer that is soluble in ethanol. The formulation of the present invention may be applied to the tooth or tooth periphery in a liquid form, and after application, it may be in contact with saliva in the oral cavity to undergo a phase change to have adhesion to the tooth or tooth periphery.

Ethanol is used as a solvent for preparing the formulation. The formulation of the present invention is not soluble in water at all or only in water under certain conditions (for example, only at a certain ratio of water and ethanol (for example, the content of ethanol in a mixture of ethanol and water is 80% or more) or under certain pH conditions) As it dissolves, ethanol contains soluble polymers. The formulation may include the water-insoluble and ethanol-soluble polymer. The water-insoluble and ethanol-soluble polymer may include a polymer that is not soluble in water at a temperature of 35 to 38°C and a pH of 7 and is soluble in ethanol.

The formulation provides excellent spreadability when applied to teeth or surrounding teeth, and may have adhesion to teeth or surrounding teeth after a certain period of time has elapsed in the oral cavity.

The inventors of the present invention have found that the components contained in the formulation contact saliva to induce a phase transition, and at the same time, use a water-insoluble and ethanol-soluble polymer together to load a large amount on the target site and apply it thickly, even if the formulation is applied quickly. It was confirmed through an experiment that it can harden and have adhesion to the target area in the oral cavity for a sufficient time.

The formulation of the present invention changes the solubility of the formulation in a humid oral cavity, that is, it is dissolved in ethanol, the solvent of the formulation, and the solubility decreases while contacting with a large amount of water (saliva) with a pH of 7 or less in the oral cavity. It can stay on the skin for a sufficient amount of time to achieve the desired effect.

The formulation of the present invention is in a liquid form with excellent flowability immediately after application in the oral cavity, and can easily penetrate into the tooth gap and the tooth/gum boundary. The formulation of the present invention reacts with saliva over time after application so that the formulation gradually hardens and becomes a gel, so that it can be attached to the tooth or the tooth periphery.

As used herein, “gelation” is meant to include not only a phenomenon in which a sol is transformed into a gel, but also a phenomenon accompanied by a marked increase in elasticity or an increase in viscosity of the system. It includes a phenomenon in which the liquid gradually hardens in contact with saliva, and how much elasticity or viscosity increases by gelation is not particularly limited.

The phase change polymer is selected from glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate, or mixtures thereof. It may include any one monoglycerides, preferably glyceryl monooleate, and/or glyceryl monolinoleate may be used.

The phase change polymer is preferably glyceryl monooleate for the purpose of the present invention to induce a phase change in contact with moisture. The phase change polymer may be included in an amount of 5 to 80% by weight based on the total weight of the formulation. In the above content range, it is preferable for the purpose of the present invention because it has a characteristic of a phase change when in contact with a small amount of water or saliva.

The formulation of the present invention uses a polymer soluble only in ethanol and hardly soluble in water, and the polymer soluble only in ethanol is also converted from a soluble phase to an insoluble phase upon contact with water. Therefore, since the polymers soluble only in ethanol also undergo phase change in a different sense, the phase change polymer may be included in the formulation in the same content range as described above.

The water-insoluble and ethanol-soluble polymer included in an embodiment of the present invention is a polymer that is soluble in ethanol, but a) does not dissolve in water, or b) is usually insoluble in water, but is higher than oral pH (pH 7). Polymers that are soluble in water under specific conditions such as high pH, for example, enteric coating polymers that are not soluble in acidic stomach (stomach) and neutral formulations, but dissolve only in basic (intestine) can be included. have. For example, b) polymers that are normally insoluble in water but are soluble in water under certain conditions, such as conditions higher than normal oral pH, are soluble in ethanol, and may include polymers that are not soluble in water at a pH of 7 or less. .

Monoglyceride has a characteristic of undergoing a phase transition according to temperature and moisture content, and has a characteristic of varying structural form and physical properties as the phase changes. When the monoglyceride undergoes a phase transition, it becomes a solid structure having adhesion without fluidity from a fluid structure. However, since monoglyceride cannot be applied thickly in order to rapidly undergo phase transition, it was characterized by applying it to the desired target as thinly as possible in a spray type. The phase change formulation using monoglyceride was not suitable for delivery of a sufficient amount of drug due to its too thin thickness, and was only partially used in formulations that do not require drug delivery through sufficient adhesion time, such as some deodorants.

The present invention solves this problem and proposes a method capable of effectively delivering a drug while ensuring sufficient adhesion time.

The polymer that is not soluble in water but is soluble in ethanol is ethyl cellulose, PVM / MA copolymer butyl ester (Butyl ester of PVM / MA copolymer), polyvinyl acetate (polyvinyl acetate), polyvinyl acetate It may be polyvinyl acetate phthalate, shellac, rosin, methacrylic acid copolymer (eg, EUDRAGIT ^® L100, L100-55), or a mixture thereof, preferably ethyl cellulose. ), PVM / MA copolymer butyl ester (Butyl ester of PVM / MA copolymer), or a mixture thereof.

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

The active ingredient may be uniformly dispersed in the oral composition, and even if the dispersion is made non-uniformly, it may be included in the mixture of the present invention.

The active ingredient is not readily soluble in water, and an active ingredient soluble only in ethanol may be particularly preferably used. In another embodiment, the active ingredients do not dissolve well in water and are uniformly dispersed in water may be preferably used.

The formulation according to another embodiment of the present invention may have a viscosity similar to that of a solution or gel that normally flows down, for example, 10,000 or less when measured at speed 20 with an RV6 spindle at room temperature with a Brookfield Viscometer, preferably It may have a viscosity (cPs) of 5,000 or less, more preferably 100 to 10,000, even more preferably 500 to 5,000. The invention has the above viscosity range before meeting with saliva through the embodiment, and after being applied to the teeth or oral cavity, the phase change to a gel or solid having adhesion to the teeth or oral tissue, a preparation for attachment to teeth or teeth to provide. The phase change can be preferably measured in oral temperature conditions, preferably 36 to 38 ℃ temperature conditions.

The viscosity can be obtained as a result of measuring the viscosity on the RV6 spindle, room temperature or oral temperature conditions using a Brookfield viscometer commonly used in the industry. It can be used in combination. The unit can be expressed in cPs.

The formulation may include the water-insoluble and ethanol-soluble polymer of the present invention and the phase change polymer of the present invention.

The agent in one embodiment, glyceryl monooleate (glyceryl monooleate), glyceryl monolinoleate (glyceryl monolinoleate), glyceryl monoarachidonate (glyceryl monoarachidonate), glyceryl monostearate (glyceryl monostearate) or these a polymer selected from a mixture of; and a polymer selected from ethyl cellulose, PVM/MA copolymer butyl ester, polyvinyl acetate, polyvinyl acetate-phthalate, shellac, rosin, methacrylic acid copolymer, or mixtures thereof.

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

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

As used herein, the meaning of 'applied to the teeth' may be included in the meaning of application if the formulation of the present invention comes into contact with the teeth or a part of the surrounding area.

As a result of repeated research on a drug delivery system capable of delivering a drug substance into the oral cavity, the inventors of the present invention have proposed a new type of drug delivery system and a new method for delivering a drug ingredient into the oral cavity using this system. .

The formulation of the present invention can be removed by brush-off at the time of removal from the tooth or the tooth periphery after a certain period of time has elapsed. The formulation of the present invention may be removed by external stimuli or pressure such as conventional brushing. A tool for brush-off may be, for example, a toothbrush or a sponge, but the type is not particularly limited.

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

The drug delivery efficiency is excellent because it can adhere well to the tooth gap.

In general, oral preparations containing a phase change material had to be applied with a thin thickness that could not secure sufficient contact time with the attachment site, but in the present invention, the solubility of the preparation is rapidly converted in a humid oral cavity even when applied thickly (soluble - > insoluble) to secure sufficient contact time.

In addition, since it is possible to sufficiently secure the contact time between the drug arrival site and the formulation of the present invention after application, it is advantageous to achieve the desired efficacy.

Hereinafter, in order to explain the present invention in more detail, the following examples and the like will be described. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the embodiments described below. The embodiments of the present invention are provided by way of example to help the specific understanding of the present invention. Unless otherwise specified, percentages in this specification may be understood to mean % by weight.

[Production of oral preparations]

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

Comparative Example 4: Parodontax

Comparative Example 5: Median Intensive Whitening Gel (polyvinyl pyrrolidone, ethanol, water, etc.)

Comparative Example 6: P&G Sensi Stop

Examples and Comparative Examples in Table 1 were prepared in the following way.

Raise the temperature of the ethanol solvent to around 50 degrees and dissolve the polymers while rotating at a constant rpm with a mechanical stirrer to help the dispersion and dissolution of the polymer. rate) first, melt other polymers, and add other ingredients and active ingredients to make a uniform solution or gel.

<Evaluation of dissolution rate and residual amount>

1. Evaluation of solubility in high temperature and high humidity oral conditions without separate physical force

In order to evaluate the retention time in a hot and humid oral cavity, 0.5 g of each of Examples 1 to 3 and Comparative Examples 1 to 5 were loaded on an artificial tooth made of a hydroxyapatite table (diameter 1 cm) fixed with silicone molding. The time for complete dissolution when placed in a constant temperature and humidity chamber at a temperature of 37 ° C. and a humidity of 95% was measured. In Comparative Example 6, a separate dissolution experiment was not performed in the form of a patch.

2. Evaluation of solubility in artificial saliva with the same physical force acting as flowing saliva

1 g each of Examples 1 to 3 and Comparative Examples 1 to 5 were loaded on top of an artificial tooth made of a hydroxyapatite table (diameter 1 cm) fixed with silicone molding, and 1 ml of artificial saliva was added to evaluate the retention time by saliva When flowing from top to bottom at a rate of /min, the time for complete dissolution was measured.

3. Experimental results

Table 2 below shows the solubility evaluation results in high-temperature and high-humidity conditions without a separate physical force and the solubility evaluation results in artificial saliva in which the same physical force as flowing saliva acts.

Complete dissolution (disintegration) time Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 37 ℃, 95% condition left >30 minutes > 30 minutes >30 minutes <6 minutes <5 minutes <5 minutes 3 minutes 2 minutes Artificial saliva 1ml/min flowing condition > 30 minutes > 30 minutes > 30 minutes 15 minutes 10 minutes 15 minutes 2 minutes 1 minute

As can be seen in Table 2, in the case of the Example, it was confirmed that it was not completely dissolved even when 30 minutes had elapsed. However, in the case of the comparative example, the experimental results showed that it was easily dissolved.

<Panel evaluation>

1. Clinical Trial or Gum Pain Improvement Questionnaire Evaluation

1) Test subject and usage: Examples 1 and 3, Comparative Examples 1, and 3-5 were applied or attached to the sore or gum pain area once a day for 10 minutes and then removed.

2) A questionnaire evaluation was conducted on a 5-point Likeard scale after 1 week of use for 15 volunteers in each group who felt a sore throat or gum pain.

3) Scale standard

5 points: The pain improvement effect lasted for a month in both the sore tooth and the gum pain area to which the product was applied.

4 points|pieces: The pain improvement effect was clearly felt in both the sore tooth and gum pain areas to which the product was applied.

3 points: The pain improvement effect was clearly felt in one or more areas where the product was applied, or at least one area of gum pain.

2 points: I felt that the shirin became less sensitive to cold food than before use or that the pain in the gums was reduced.

1 point|piece: The improvement effect of a sore or gum pain was not felt.

2. Evaluation of a survey on the feeling of whitening effect for humans

1) Test subject and usage: Example 2, Comparative Example 2, and Comparative Example 5 were applied to the middle 6 teeth of the upper teeth once a day for 30 minutes or more and then removed.

2) For each group, 15 volunteers who felt the need for teeth whitening because they thought their teeth were yellow on a regular basis were evaluated using a 5-point Likeard scale to evaluate the whitening effect of the sensation compared to the lower teeth that were not attached after using it for 1 week. .

3) Scale standard

5 points: A clear whitening effect was felt within 5 days compared to the lower teeth that were not attached before use.

4 points|pieces: Compared with the lower teeth which were not attached before use, it felt that it was clearly brightened within 5 days.

3 points: Compared to before use, compared to the lower teeth that were not attached, after one week of use, it was felt that the teeth were clearly brighter.

2 points|pieces: It felt a little brighter compared to the lower teeth which were not attached before use.

1 point: I don't know the difference from before use.

3. Evaluation results

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 improvement of sirin 5 3 3 whitening effect 4.5 3 2 Gingivitis improvement 4 2 2

As can be seen in Table 3, the formulation having the composition of Examples of the present invention facilitates the delivery of the active ingredient and secures sufficient adhesion time to bring excellent efficacy.

Claims (8)

In the preparation for tooth or tooth peripheral attachment,
The formulation includes an active ingredient, a phase change polymer, and a water-insoluble and ethanol-soluble polymer, and the formulation includes ethanol as a solvent,
The phase change polymer is a monoglyceride,
The water-insoluble and ethanol-soluble polymer is at least one selected from the group consisting of ethyl cellulose, PVM/MA copolymer butyl ester, polyvinyl acetate, polyvinyl acetate-phthalate, shellac, rosin, and methacrylic acid copolymer. ego,
The formulation has a viscosity of 10,000 cPs or less when measured with a Brookfield viscometer RV6 spindle speed 20 at room temperature before being applied to the tooth or tooth periphery. A formulation for attachment to a tooth or periphery of a tooth, having adhesion to the periphery. According to claim 1, wherein the monoglyceride is glyceryl monooleate (glyceryl monooleate), glyceryl monolinoleate (glyceryl monolinoleate), glyceryl monoarachidonate (glyceryl monoarachidonate), and glyceryl monostearate (glyceryl) Monostearate), characterized in that at least one selected from the group consisting of, tooth or tooth periphery attachment formulation. According to claim 1, wherein the phase-transfer polymer is 5 to 80% by weight of the total weight of the formulation, characterized in that included, tooth or tooth periphery attachment formulation. According to claim 1, wherein the active ingredient is sodium fluoride (sodium fluoride), tin fluoride (stannous fluoride), indium fluoride (indium fluoride), amine fluoride (amine fluoride), sodium monofluorophosphate (sodium monofluorophosphate), sodium pyrophosphate (tetrasodium pyrophosphate, TSPP), sodium acid pyrophosphate (SAPP), sodium tripolyphosphate (STP), sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acid metapoly acid sodium metaphosphate, acid sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride (benzalkonium chloride), salicylanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), aspirin, keto ketorolac, flurbiprofen, piroxicam, meclofenamic acid, thiamine, riboflavin, nicotinic acid, pantothenic acid , pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin Min 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, oxalic acid Iron (ferric oxalate), and vitamin E, characterized in that at least one selected from the group consisting of, teeth or tooth periphery attachment formulation. delete The method of claim 1, wherein the formulation has a viscosity of 500 to 5,000 cPs when measured with a Brookfield viscometer RV6 spindle speed 20 at room temperature before contact with moisture,
A preparation for attachment to a tooth or tooth periphery, which is applied to a tooth or oral cavity and then undergoes a phase change to a gel or solid having adhesion to the tooth or oral cavity. delete delete