KR20190129815A - Oral formulation - Google Patents

Abstract

The present invention, in a tooth or tooth peripheral attachment formulation, provides the tooth or tooth peripheral attachment formulation which contains an active ingredient, a phase transition polymer, and a polymer which is water-insoluble and soluble in ethanol, wherein the formulation contains ethanol as a solvent, is in a liquid state to be applied to teeth or teeth peripheral area, and is phase transmitted by intraoral fluid to provide adhesion to teeth or teeth peripheral area. The formulation of the present invention can impart high adhesion to a desired site despite tooth gaps or bends. The formulation having high adhesion of the present invention is advantageous to achieve a desired effect by increasing the time to adhere to a target site in the oral cavity.

Description

Oral formulation

The present invention relates to an agent for drug delivery in the oral cavity, and more particularly, a new form of drug delivery that can effectively deliver the active ingredient to the difficult to access areas, such as tooth gaps in the oral cavity, while sufficiently remaining in the target site It relates to an oral preparation.

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 the disadvantage of insufficient viscosity and high solubility, making it difficult to provide sufficient contact time to the target site. There is this. The patch or strip form has a disadvantage in that it is difficult to deliver sufficient active ingredients due to the thinness, and the flexibility is poor, and it is difficult to closely adhere to the tooth gap, the gum and the tooth boundary area.

Korea Patent No. 10-0623859 has developed a tooth whitening component delivery system using gelling in order to solve the problem of close contact between teeth gap, gum and tooth boundary area, but it has a strong flow when applied to the tooth surface during use. There was a disadvantage to use a separate support layer. In addition, WO 2003/037276 discloses a formulation that is applied in the form of a spray in the form of a spray due to its low initial viscosity, and there is a small difference in temperature between the oral cavity (especially summer) and the oral cavity. There was a problem of difficulty.

US 5,989,569 discloses the delivery of the drug by pressure by applying the drug on the surface of the strip, but by applying the drug on the surface of the strip and attaching it to the teeth as it is, there is an effect of temporarily releasing the active ingredient, around the tooth There was a problem that can cause strong irritation to the gums. In addition, the physical properties, particularly flexibility of the drug to be applied to the strip, there was a disadvantage that the close contact between the teeth gap.

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

Oral effective ingredient delivery system using a conventional phase transition, ethanol and polyol in the prescription, and intraoral saliva meet the phase transition occurs, because it can not be applied thick for rapid phase transition, apply as thin as possible to the target of gel or spray type It was characteristic to do. This phase transition property is well penetrated into the gaps of the teeth and teeth / gums, etc., it is an advantage that the drug can be delivered, but there is a problem that too thin thickness is not suitable for a sufficient amount of drug delivery.

US 5,989,569 B

In order to solve the above problems, the present invention is to provide a new type of oral attachment preparation that can be easily attached to a desired site in the oral cavity, and can secure sufficient contact time.

The present invention is to provide a formulation that can penetrate well between the tooth gap and the teeth / gums in a liquid state while applying to the teeth and the area around the teeth, to ensure sufficient close time.

The formulation of the present invention can provide excellent adhesion between the tooth surface and the gap between the tooth and the tooth as well as the tooth surface and the tooth and gum boundary at the time of initial attachment, and to provide a new type of oral preparation that is easy to remove after use.

The present invention provides a preparation for attaching a tooth or a peripheral tooth.

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

Ethanol is used as a solvent for preparing the formulation. The formulations of the present invention are not soluble in water at all or only in certain conditions (e.g., at a constant ratio of water and ethanol (e.g., at least 80% ethanol content in a mixture of ethanol and water) or only at constant pH conditions. While dissolved, ethanol includes a polymer that dissolves. The formulation may include a polymer that is water insoluble and soluble in ethanol. The water-insoluble polymer dissolved in ethanol may include a polymer that is not soluble in water at a temperature of 35 to 38 ℃, pH 7 conditions, soluble in ethanol.

The formulation may provide good applicability when applied to a tooth or periphery and may adhere to the tooth or periphery after a period of time in the oral cavity.

The inventors of the present invention, while the components contained in the formulation in contact with saliva to induce phase transition, while using a polymer that is water-insoluble and soluble in ethanol together to load a large amount on the target site (load), even if the formulation is applied quickly Experiments confirmed that it could harden and have adhesion to the target site in the oral cavity for a sufficient time.

In the preparation of the present invention, a change in the solubility of the preparation occurs in a humid oral cavity, that is, it is dissolved in ethanol, which is a solvent of the preparation, and in contact with a large amount of water (acupuncture) of pH 7 or less in the oral cavity, solubility is lowered. You can stay for enough time to get the desired effect.

The formulations of the present invention are in a liquid form with good flowability immediately after application in the oral cavity, and are well permeable to tooth gaps and tooth / gum boundaries. The formulation of the present invention may react with saliva over time after application, thereby gradually hardening the formulation and gelling and attaching to a tooth or a peripheral portion of the tooth.

As used herein, "gelling" is meant to include not only the phenomenon of sol turning into a gel, but also a phenomenon involving a marked increase in elasticity or increase in viscosity of the system. The liquid phase is gradually solidified in contact with saliva, and the degree of elasticity or viscosity is not particularly limited by gelation.

The phase transfer polymer is selected from glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate, or a mixture thereof. It may include any monoglycerides (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 which induces phase transition by contact with moisture. The phase change polymer may be included in an amount of 5 to 80 wt% based on the total weight of the formulation. It is preferable for the purpose of the present invention because there is a characteristic of phase transition when contacted with a small amount of water or saliva in the above content range.

The formulation of the present invention uses a polymer that is soluble only in ethanol and hardly soluble in water, and the polymers soluble only in ethanol are also converted from a soluble phase to an insoluble phase when contacted with water. Therefore, the polymers dissolved only in the ethanol may also include a phase change polymer in the formulation in the same content range as the phase change of the other meaning occurs.

The water-insoluble and soluble polymer included in one embodiment of the present invention is a) a polymer that is soluble in ethanol but not soluble in water, or b) is typically soluble in water but is less than oral pH (pH 7). Polymers that are soluble in water at certain conditions, such as high pH, for example, may contain conventional enteric coating polymers that do not melt in acidic gastric and neutral formulations but only in basic intestine. have. For example, b) polymers that are typically not soluble in water but soluble in water under certain conditions, such as conditions higher than normal oral pH, may include polymers that are soluble in ethanol and not soluble in water below pH 7. .

Monoglycerides are characterized by phase transition according to temperature and water content, and have different characteristics in structural form and physical properties as the phase changes. When the phase transition of the monoglycerides appears, it becomes a solid structure having no fluidity and adhesion in a fluidity structure. However, since monoglycerides cannot be thickly applied for fast phase transition, they were applied to the desired target as thinly as possible in the spray type. Phase-transfer formulations using monoglycerides were too thin and inadequate for sufficient drug delivery and were only partially used in formulations that did not require drug delivery through sufficient adhesion times, such as some deodorants.

The present invention solves this problem and proposes a method for effectively delivering the drug while ensuring sufficient time for attachment.

The polymer which is not dissolved in water but dissolved in ethanol is ethyl cellulose, ethyl ester of PVM / MA copolymer, polyvinyl acetate, polyvinylacetate. Phthalate (polyvinyl acetate phthalate), shellac, rosin, methacrylic acid copolymers (e.g. EUDRAGIT ^® L100, L100-55), or mixtures thereof, preferably ethyl cellulose ), BM / EM copolymer butyl ester (Buthyl ester of PVM / MA copolymer), or a mixture thereof.

The active ingredient may include, for example, ingredients that may improve symptoms in the oral cavity, and include, for example, a tooth whitening component, a caries prevention component including a fluorine ion source, a tartar generating inhibitory component, an anti-inflammatory component, and an antibacterial component. And other vitamins and minerals. In addition, astringent may include amelioration and symptomatic ingredients. More specifically, for example, any selected from the group consisting of sodium fluoride, stannous fluoride, indium fluoride, amine fluoride, and sodium monofluorophosphate One or more fluorine ion sources; Reminerlaization agents, including hydroxyapatite; Tooth whitening ingredients include hydrogen peroxide, carbamide peroxide, calcium peroxide, perborate, percarbonate, peroxyacids, persulfates May contain calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, or mixtures thereof, and whitening effect Condensation phosphates can be used with peroxides to improve them, which may include sodium pyrophosphate (TSP), sodium pyrophosphate (SAPP), and sodium tripolyphosphate (STP). Sodium potassium pyrophosphate, tetrapotassium pyrophosphate, acidic sodium metaphosphate, acidic polyphosphate One or two or more of acidic sodium polyphosphate may be used together with the peroxide. These condensed phosphates can be used as tartar or as tartar control. They can also contribute to the improvement of whitening effect by removing metals that affect stain formation of teeth as chelating agents. Triclosan, chlorhexidine, alexidine, hextidine, sanguinarine, benzalkonium chloride, salicylanilide, domiphen bromide Antimicrobial agents, including cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), or mixtures thereof; Anti-inflammatory agents including aspirin, ketorolac, flurbiprofen, pyroxicam, meclofenamic acid, or mixtures thereof; Or thiamine, riboflavin, nicotinic acid, 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 mixtures thereof, but is not limited thereto. In addition, as drugs effective for the prevention and improvement of periodontal disease, corn unchecked quantitative extract, thick extract, myrrh, latania, chamomile, polycrezolene, centella quantitative extract nutmeg extract, dexanthenol, beta-sitosterol (β-sitosterol), acetyl salicylic acid, and the like may be included alone or in any ratio. As a symptom improving and alleviating component, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, ferric oxalate, vitamin E, or the like may be included alone or in combination.

The active ingredient may be uniformly dispersed in the oral composition, and may be included in the mixture of the present invention even when the dispersion is not uniform.

The active ingredient does not dissolve well in water, and an active ingredient dissolved only in ethanol may be particularly preferably used. In another embodiment, the active ingredient is not dissolved in water well, the active ingredient is uniformly dispersed in water may be preferably used.

Formulations according to another embodiment of the present invention may have a viscosity similar to that of conventionally flowing solutions or gels, for example, measured at speed 20 with an RV6 spindle at room temperature with a Brookfield Viscometer, preferably 10,000 or less. 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 present invention has a viscosity range before it meets saliva by way of example, and is applied to the tooth or the oral cavity, and then a phase change into a gel or a solid having adhesion to the tooth or the tissue in the oral cavity, the preparation for the tooth or tooth peripheral attachment to provide. The phase change may be preferably measured at oral temperature conditions, preferably at 36 to 38 ° C.

The viscosity can be obtained as a result of measuring the viscosity at RV6 spindle, room temperature or oral temperature conditions using a Brookfield viscometer commonly used in the industry, the viscosity means a property having a viscosity, viscosity and viscosity Can be used interchangeably. The unit can be expressed as cPs.

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

 The formulation is, in one embodiment, glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate or glyceryl monostearate A polymer selected from a mixture of; And a polymer selected from ethyl cellulose, FMB / EM-polypolymer butyl ester, polyvinylacetate, polyvinylacetate-phthalate, shellac, rosin, methacrylic acid copolymer, or mixtures thereof.

As used herein, the term "peripheral teeth" is a concept including a part that is generally represented by the gum, and may be used as a meaning including all the mucosal parts of the periphery of the tooth. The peripheral portion of the tooth may be used to encompass a site where the active ingredient for intraoral delivery may be delivered together with the tooth when the agent is applied to the tooth due to the structure of the preparation. In the present specification, the tooth or the peripheral portion of the tooth is described as being mixed with 'teeth', and although only described as the 'teeth', it may be understood in the present specification to include all the teeth or the peripheral portion of the tooth.

As used herein, the 'agent' refers to a product made by processing to sufficiently exhibit a therapeutic effect without affecting the effect of the active ingredient.

As used herein, the term 'applied to a tooth' may be included in the meaning of application if the agent of the present invention comes into contact with a tooth or a part of the periphery.

The inventors of the present invention have studied a drug delivery system capable of delivering an active ingredient into the oral cavity, and 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 formulation of the present invention can be removed with a brush-off at the time of removal from the teeth or around the teeth after a certain time. Formulations of the present invention may be eliminated by external stimuli or pressure, such as conventional brushing. Tools for brush-off may be used, for example, toothbrush, sponge, etc., but the type is not particularly limited.

The formulation of the present invention can impart high adhesion to a desired site despite tooth gaps or bends.

It can be closely adhered to the tooth gap, so the drug delivery efficiency is excellent.

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

In addition, the contact time between the drug reaching site and the formulation of the present invention after the application can be sufficiently secured to achieve the desired effect.

Hereinafter, the following examples and the like will be described in order to describe the present invention in more detail. However, embodiments according to the present invention can be modified in many different forms and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided by way of example in order to facilitate a specific understanding of the present invention. Unless otherwise stated,% described herein may be understood to mean weight percent.

[Production of Oral Formulations]

Oral formulations of Examples and Comparative Examples having the following compositions were prepared or purchased.

Comparative Example 4: Farodontax

Comparative Example 5: Median Intensive Whitening Gel (Polyvinyl Pyrrolidone, Ethanol, Water, etc.)

Comparative Example 6: P & G Sensi Stop

The Example and Comparative Example of Table 1 were prepared by the following method.

The temperature of the ethanol solvent is increased to around 50 degrees and the polymer stirrer is rotated at a constant rpm to help disperse and dissolve the polymer. Dissolve) first, dissolve other polymers, and add other ingredients and active ingredients to form a uniform solution or gel.

<Evaluation of Dissolution Rate and Residual Quantity>

1. Solubility evaluation in high temperature and humidity conditions without extra physical force

In order to evaluate the retention time in a hot and humid oral cavity, 0.5 g of Examples 1 to 3 and Comparative Examples 1 to 5 were loaded on the artificial teeth made of hydroxyapatite table (1 cm in diameter) and fixed with silicone molding. The temperature which melt | dissolved completely when measured in the temperature of 37 degreeC and 95% of humidity constant temperature thermostat was measured. Comparative Example 6 did not proceed separately dissolution experiment in the form of a patch.

2. Evaluation of solubility in artificial saliva caused by physical forces such as flowing saliva

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

3. Experimental Results

The results of solubility evaluation in high temperature and high humidity conditions without any physical force and the results of solubility evaluation in artificial saliva in which physical forces such as flowing saliva were applied are shown in Table 2 below.

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% conditions 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 min

As can be seen from the above Table 2, in the case of Examples, it was confirmed that not completely dissolved even after 30 minutes elapsed. However, in the case of the comparative example it was found that it was easily dissolved.

Panel Evaluation

1. Evaluation of clinical symptom or gum pain improvement survey

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

2) A survey was conducted on 15 volunteers of each group who had pain or gum pain in each group on a 5-point Liquor scale.

3) Scale criteria

5 points | pieces: The pain improvement effect lasted for 1 month in both the syringe or gum pain area to which the product was applied.

4 points | pieces: The pain improvement effect was confirmed by both the syringe and the gum pain area to which the product was applied.

3 points | pieces: The pain improvement effect was confirmed by one or more places where the product or the pain of the product which applied the product was applied.

2 points | pieces: I felt less sensitive or less gum pain for cold food than before using.

1 point | piece: There was no improvement in ache and gum pain improvement.

2. Evaluation of the whitening effect sensation questionnaire for people

1) Test Subject and Usage: Example 2, Comparative Example 2 and Comparative Example 5 were removed after application to the six teeth of the upper teeth at least 30 minutes once a day.

2) A survey was conducted on 15 volunteers who felt that their teeth were yellowing in each group and felt the whitening effect on the five-point Richard's scale compared to the lower teeth that were not attached after one week of use. .

3) Scale criteria

5 points | pieces: The whitening effect was confirmed within 5 days compared with the lower teeth which were not attached than before use.

4 points | pieces: It felt brighter within 5 days than the lower teeth which were not attached than before use.

3 points | pieces: I felt it became brighter when used for one week compared with the lower teeth which were not attached than before use.

2 points | pieces: I felt it became brighter than the lower teeth which were not attached than before use.

1 point | piece: I do not know the difference before using.

3. Evaluation result

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 syringe 5 3 3 Whitening effect 4.5 3 2 Gingivitis 4 2 2

As can be seen in Table 3, the formulation having an embodiment composition of the present invention can facilitate the delivery of the active ingredient, ensure sufficient adhesion time can bring excellent efficacy.

Claims (8)

In preparations for attaching teeth or peripheral teeth,
The formulation includes an active ingredient, a phase-transfer polymer, and a water-insoluble and soluble polymer in ethanol, the formulation includes ethanol as a solvent,
The preparation is applied to the tooth or the periphery of the liquid, phase-shifted by saliva in the oral cavity, and has adhesion to the tooth or the periphery, preparation for the tooth or tooth peripheral attachment. The method of claim 1, wherein the phase transition polymer is glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, and glyceryl monostearate It is at least one selected from the group consisting of), the preparation for tooth or tooth peripheral attachment. According to claim 1, The phase change polymer is characterized in that 5 to 80% by weight relative to the total weight of the formulation, tooth or tooth peripheral attachment formulation. The method of claim 1, wherein the active ingredient is sodium fluoride, tin fluoride, indium fluoride, amine fluoride, sodium monofluorophosphate, sodium pyrophosphate (tetrasodium pyrophosphate (TSPP), sodium pyrophosphate (SAPP), sodium polypolyphosphate (STP), sodium potassium pyrophosphate, potassium pyrophosphate, acid metapolypoly Acidic sodium metaphosphate, acidic sodium polyphosphate, triclosan, chlorhexidine, alexidine, hexetidine, sanguinarine, benzalkonium chloride (benzalkonium chloride), salicylicanilide, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (tetradecylpyriri) dinium 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 D, vitamin E, vitamin K, corn unchecked quantitative extract, thick extract, myrrh, latania, chamomile, polycrezolene, selenium Tela quantitative extract, nutmeg extract, dexanthenol, beta-sitosterol, acetyl salicylic acid, zinc chloride, potassium phosphate, potassium diphosphate, calcium chloride, oxalic acid, potassium oxalate, oxalic acid At least one selected from the group consisting of ferric oxalate, and vitamin E Characterized in that the tooth or tooth peripheral attachment. The polymer according to claim 1, wherein the polymer which is insoluble in water and soluble in ethanol is ethyl cellulose, FMB / EM copolymer polybutyl ester, polyvinylacetate, polyvinylacetate-phthalate, shellac, rosin, and methacrylic acid copolymer. It is at least one selected from the group consisting of, teeth or tooth peripheral attachment formulation. Before contact with moisture, it has a viscosity of 10,000 cPs or less,
An agent for attachment to a tooth or tooth periphery, which is applied into the tooth or oral cavity and then phase-transforms into a gel or solid having adhesion to the tooth or intraoral tissue. The preparation of claim 6, wherein the preparation comprises a polymer and a phase-transfer polymer which are water insoluble and soluble in ethanol. According to claim 6, The formulation is glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, and glyceryl monostearate At least one polymer selected from among; And
Tooth or tooth periphery, characterized in that it comprises one or more polymers selected from ethyl cellulose, fimb / emcopolymer butyl ester, polyvinylacetate, polyvinylacetate-phthalate, shellac, rosin, and methacrylic acid copolymers. Formulation for adhesion.