KR102010417B1 - Oral formulation - Google Patents
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- KR102010417B1 KR102010417B1 KR1020160004353A KR20160004353A KR102010417B1 KR 102010417 B1 KR102010417 B1 KR 102010417B1 KR 1020160004353 A KR1020160004353 A KR 1020160004353A KR 20160004353 A KR20160004353 A KR 20160004353A KR 102010417 B1 KR102010417 B1 KR 102010417B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
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Abstract
The present invention includes a phase-transfer compound and a polymer that controls the phase-transition rate, and includes an active ingredient for intraoral delivery, which provides a preparation for tooth or peripheral tooth attachment. The formulation of the present invention can impart high adhesion to a desired site despite tooth gaps or bends. Formulations of the present invention having a high adhesion may be advantageous to achieve the desired effect by increasing the time to adhere to the target site in the oral cavity. The hardness difference between the time when the tooth is applied and the time when the tooth is removed may not be easily handled and drug release may be easy.
Description
The present invention relates to a preparation for intraoral drug delivery, and more particularly to a new form of oral preparation that can effectively deliver the active ingredient in the oral cavity to the desired site, slow the initial curing rate, the rate of change of hardness is not large will be.
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 insufficient viscosity and high solubility, making it difficult to provide sufficient contact time to the target site, and mouse trays intended for intraoral drug delivery have a high foreign body feel and local drug delivery is difficult due to their shape characteristics. There is this. The patch or strip form has a disadvantage in that it is difficult to transfer sufficient active ingredients due to the thinness, and the flexibility is poor, and it is difficult to closely contact 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.
On the other hand, the impression material used for the purpose of replicating the oral tissue has the advantage that can be in close contact with the shape of the teeth, there was a problem that it is difficult to release the drug completely cured in a short time.
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 seeks to provide a formulation in a form that can be modified before use and that can be well adhered between the tooth gap or the tooth and gum.
The intraoral attachment formulation consisting of two agents has a problem that it is inconvenient to adhere to the initial tooth surface and does not have a fixed form, and that it is inconvenient to attach, and that it is inconvenient to peel off with a strong adhesive after curing. The present invention seeks to provide a formulation that can address these shortcomings.
The formulations of the present invention do not flow down during initial attachment and are able to adhere well between the tooth surface and the tooth and gum boundaries, as well as between the teeth and the gaps of the tooth, and at the time of detachment after sufficient release of the drug, there is no irritation at the teeth It is intended to provide a new form of formulation that can be eliminated.
The present invention is to provide a new type of formulation that can effectively release the drug while using a convenient to control the curing rate of the phase-transfer compound.
The present invention is to provide a new type of formulation for oral cavity with excellent usability that can be conveniently used without sticking to the hand or sticky when attached to the teeth or the peripheral area.
The present invention provides an oral preparation for tooth or tooth periphery attachment comprising a phase change compound and a polymer mixed with the phase change compound to control the curing rate of the phase change compound. The formulation may include an active ingredient that can be delivered into the oral cavity. After the formulation is attached to the tooth or the periphery of the tooth, the active ingredient included in the formulation can be released and delivered to the desired site in the oral cavity.
In general, in the case of a phase transition formulation, when a first agent and a second agent meet and a phase transition occurs, the phase transition compound is present as a fixed mass. The inventors of the present invention use a component for controlling the rate of phase transition used in the present invention together with a phase change compound. The present invention has been completed by confirming that it is possible to provide a new form of the formulation effective by controlling the curing rate of the drug release.
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.
In the case of a conventional phase change formulation, after the phase change is completed, a single mass is generally removed and removed by a peel-off method. When the phase change rate control material is used together according to an embodiment of the present invention, when removing, it may have a structure in which small lumps are united together by weak bonding, rather than one lump, so that the brush-off may be removed as if brushed with a toothbrush. Can be. That is, it is possible to give the oral neatness after use while removing the preparation of the present invention from the tooth surface through brushing.
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 tooth periphery may be used in the sense of encompassing a site where the active ingredient for intraoral delivery may be delivered together with the tooth when the preparation 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 term 'formulation' refers to a product made by processing to sufficiently exhibit a therapeutic effect without affecting the effect of the active ingredient.
As used herein, "applied to a tooth" may include placing the formulation of the present invention on a tooth or periphery until the user applies pressure to adhere the formulation to the tooth.
The term 'when the preparation is in close contact with the teeth' of the present invention may mean a time point at which the user applies pressure to the bend of the preparation, the gap between the teeth, the contact between the teeth and the gums after a predetermined time after tooth application.
The 'time to remove the preparation' of the present invention may mean a time when the drug is released after being adhered to the teeth or tissues around the tooth and dropped out of the oral cavity, and attached for 2 hours according to the purpose and use of the preparation and the amount of release of the drug. Although it may be removed later, in view of ease of use, it may be removed within 30 minutes, more preferably within 10 minutes after being in close contact with the teeth. The hardness of the formulation at the time of removal may be increased at the time of removal as compared to the timing at which the formulation is applied to the tooth and the time of close contact.
As used herein, 'controlling the phase transition rate' may be used in the same sense as controlling the curing rate and degree of curing of the formulation, and means that the firmness of the formulation is hardened by phase transition over time. .
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 inventors of the present invention provide a new drug delivery system that can effectively deliver the active ingredient to a specific site in the oral cavity (for example, a site requiring tooth whitening, a site of acute inflammation, a site of inflammation in the oral cavity, a site of periodontal disease, etc.). We have been studying for a long time. As a result, a new type of oral preparation can be developed that can be conveniently applied to the mucous membrane area of the tooth or oral cavity, and excellently adhered to the flexion site and the tooth gap, thereby increasing the drug arrival rate at the desired site.
Formulations which are advantageous for delivery of the drug to the tooth gap have generally been recognized and used in liquid form or in highly flowable form. However, the initial viscosity is very low, so that it flows well and is not only inconvenient to use, but also there is a problem in that sufficient contact time is not secured due to a small amount of time in close contact with the target site.
In order to solve this problem, it has been developed in the form of a dough, such as attached to the target area in the teeth and oral cavity to increase the initial adhesion but does not flow down well. Furthermore, the inventors of the present invention find that the polymer has a strong adhesiveness to gums and teeth in the oral cavity and has a property of being involved in the phase transition mechanism, so that the viscosity at the time of initial use and the viscosity at the time of removal are not large when the polymer is attached. Experiments have shown that silver can be removed easily and without irritation and has led to the development of new forms of preparations.
As used herein, "applied to a tooth" may include placing the formulation of the present invention on a tooth or periphery until the user applies pressure to adhere the formulation to the tooth.
The term 'when the preparation is in close contact with the teeth' of the present invention may mean a time point at which the user applies pressure to the bend of the preparation, the gap between the teeth, the contact between the teeth and the gums after a predetermined time after tooth application.
The 'time to remove the preparation' of the present invention may mean a time when the drug is released after being adhered to the teeth or tissues around the tooth and dropped out of the oral cavity, and attached for 2 hours according to the purpose and use of the preparation and the amount of release of the drug. Although it may be removed later, in view of ease of use, it may be removed within 30 minutes, more preferably within 10 minutes after being in close contact with the teeth. The hardness of the preparation at the time of removal may be increased at the time of removal as compared to the time of application of the preparation to the tooth, and the time of adhesion.
In one embodiment of the present invention, the formulation of the present invention may include a polymer for controlling the curing rate of the phase change compound. Formulation according to an embodiment of the present invention may have an initial hardness that is convenient to use, including a polymer for controlling the curing rate of the phase-transfer compound, and when the drug is released to remove the relatively low hardness value It is possible to provide an oral preparation that can be easily and less irritating to the attachment site.
For example, in the case of alginate powder in the phase change compound, when it comes into contact with water, it may harden initially and may increase in hardness significantly over time, thereby preventing the release of the active ingredient dispersed in the formulation. . However, in one embodiment of the present invention, a preparation prepared by mixing a polymer having a plurality of carboxyl groups, for example, PVM / MA (Gantrez) polymer, which is the same reactor as alginate, is advantageous in releasing a drug without experiencing a sudden hardness change.
As used herein, 'hardness' may refer to the degree of force required to compress the formulation. Hardness of the formulation of the present invention is the hardness measured by the compression test mode of Stable Micro System TA XT Plus. After filling 20g into a 50mL beaker, set a 20mm diameter aluminum probe for hardness measurement, test hardness at 1.5mm / s for test speed, distance at 10mm for target mode, and 10mm for distance. Hardness is understood as the peak value of the calculated first cycle. The unit can be expressed as g (g force).
The phase change material is a substance that can cause viscosity in the oral composition, carrageenan (carrageenan), pectin (pectin), xyloglucan (xyloglucan), gellan gum (gellan gum), ammonium alginate, magnesium alginate (magnesium) alginate, potassium alginate, sodium alginate, lithium alginate, chitosan, polylactic acid (poly (D, L-lactic acid)), polylactide-co-clinic Poly (DL-lactide-co-glycolide), poly-caprolactone, polyacrylic acid (carbopol), polyvinylacetal diethyl aminoacetate (AEA) , Hydroxypropylmethyl cellulose, poly (methacrylic acid) -poly (ethylene glycol) (poly (methacrylic acid) -poly (ethylene glycol)), poly (D, L-lactide) -block-poly ( Ethylene Glycol) -Block-Poly (D, L- Lactide) (poly (D, L-lactide) -block-poly (ethylene glycol) -block-poly (D, L-lactide)), PEG-oligoglycolyl-acrylate, Poly (N-isopropyl acrylamide), sucrose acetate isobutyrate, polyvinyl alcohol, polyvinyl acetate, glyceryl monool Latex, Glyceryl Monolinoleate, Glyceryl Monoarachidonate, Glyceryl Monostearate, etc. can be used alone or in combination of two or more. Any material that can be used may be used, and is not limited to the above examples.
Preferably, the phase transition compound may be ammonium alginate, magnesium alginate, potassium alginate, sodium alginate, sodium alginate, lithium alginate, or mixtures thereof.
The phase change compound may be included in the formulation together with a polymer having a curing rate control property of the phase change compound. The polymer having a curing rate control characteristic of the phase change compound may have the same functional group (eg, carboxyl group) as the functional group included in the phase change compound.
The polymer having a curing rate control characteristic of the phase change compound included in the formulation of the present invention may include any one or more selected from among polymers having a functional group involved in the phase transfer mechanism of the phase transfer polymer, such as a carboxyl group and a hydroxyl group. For example, when the formulation of an embodiment of the present invention is a phase-transfer reaction by alginic acid and salts thereof, the polymer may be a polymer having a carboxyl group such as polyacrylic acid, sodium polyacrylate, carbomer, carbopol, acrylate co It may be any one or more polymers selected from the group consisting of a polymer (Eudragit L-100), polyquaternium-39, a copolymer of methyl vinyl ether and maleic anhydride (PVM / MA copolymer). Preferably, the polymer may use Gantrez, which is one of methyl vinyl ether and maleic anhydride copolymer, and most preferably, Gantrez S-97, which is water-soluble and grade applicable to oral products. The polymer is excellent in adhesion to teeth and gums can be preferably used for the purpose of the present invention. On the other hand, in the case of the phase transition reaction by polyvinyl alcohol, a polymer having a hydroxy group such as polyethylene glycol, hyaluronic acid salt, microcrystalline cellulose hydroxy propyl methyl cellulose, methyl cellulose, alginic acid, carrageenan One or more of these may be used.
It is thought that a polymer having a curing rate control property of the phase-transfer compound interferes with the binding of the phase-transfer compound and the water-soluble calcium, and the carboxyl group (-COOH) contained therein binds with the water-soluble calcium, thereby preventing the hardening of the phase-transfer compound. However, the theory is not limited to this.
Preferably, the polymer having a curing rate control characteristic of the phase change compound may be water-soluble and include the same functional group as the functional group included in the phase change compound. For example, the -COOH group contained in PVM / MA binds to water-soluble calcium and can delay curing by preventing alginate from binding to water-soluble calcium.
The polymer having a property of controlling the rate of the phase transfer reaction may be included in an amount of 0.01 wt% to 10 wt%, preferably 0.05 wt% to 5 wt%, based on the total weight of the formulation. When in contact with water in the above range may have a hardness range of the present invention, it can provide excellent adhesion. In addition, when the content ratio of the polymer exceeds the above range, the binding with the phase-transfer compound is strong, which may affect the release of the dispersed active ingredient and may inhibit the release of the active ingredient. The polymer having a property of controlling the rate of the phase-transfer compound and the phase-transfer reaction has a mixing ratio of phase-transfer compound: a polymer having a property of controlling the rate of the phase-transfer reaction in a weight ratio of 5: 0.01 to 0.07, preferably 5: 0.03 to It may be mixed at a weight ratio of 0.05. When it is in the said weight ratio range, the hardness of the target formulation can be achieved.
The active ingredient may include, for example, ingredients that can improve symptoms in the oral cavity, for example, tooth whitening ingredients, tooth decay prevention ingredients including fluorine ion sources, tartar production inhibitory ingredients, anti-inflammatory ingredients, antibacterial ingredients 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, including condensate phosphates, sodium pyrophosphate (TSPP), 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, 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 even if the dispersion is not uniform, it may be included in the mixture of the present invention.
According to an embodiment of the present invention, the formulation of the present invention may have semi-solid characteristics at the same time, and thus may be in close contact with a bend or a gap.
The preparation of the present invention may have a form such as dough or clay, and may be applied to the teeth or the area around the teeth in the form of an ointment.
In one embodiment of the present invention, the preparation may be used in two-part form, and may be used in three-part form as necessary. For example, i) a agent containing a phase change compound; It can be used in combination with a second agent comprising a polymer, water, an active ingredient, and other components that may be included in the formulation to control the rate of the phase transfer reaction, ii) a first agent containing a phase transfer compound; 2 agent comprising a polymer for controlling the rate of the phase transfer reaction; It is possible to use a mixture of three agents including water, the active ingredient, and other ingredients that may be included in the formulation.
The first agent and the second agent or the first agent, the second agent and the third agent may be mixed and applied to the tooth or the periphery of the tooth.
According to another embodiment of the present invention, after 1 minute of mixing the phase change compound and the phase transition compound, the hardness of the formulation reaches 140g to 350g, after 10 minutes of mixing with the phase transition compound, the hardness of the formulation is 5,200g to 13,000 It includes a polymer that reaches g, and provides a preparation for attaching teeth or peripheral teeth to deliver the active ingredient contained in the preparation to the oral cavity.
The phase change compound may be used without limitation as long as it is a substance causing viscosity included in the present specification, preferably carrageenan, pectin, xyloglucan, xyloglucan, gellan gum, ammonium alginate ( ammonium alginate, magnesium alginate, potassium alginate, sodium alginate, lithium alginate, chitosan, polylactic acid (poly (D, L-lactic acid)) , Polylactide-co-glycolide (poly (DL-lactide-co-glycolide)), poly-caprolactone, polyacrylic acid (carbopol), polyvinyl acetal diethyl aminoacetate (polyvinylacetal diethyl aminoacetate (AEA)), hydroxypropylmethyl cellulose, poly (methacrylic acid) -poly (ethylene glycol) (poly (methacrylic acid) -poly (ethylene glycol)), poly (D, L- Lacta Id) -block-poly (ethylene glycol) -block-poly (D, L-lactide) (poly (D, L-lactide) -block-poly (ethylene glycol) -block-poly (D, L-lactide) ), PEG-oligoglycolyl-acrylate, poly (N-isopropyl acrylamide), sucrose acetate isobutyrate, poly Polyvinyl alcohol, polyvinyl acetate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monoarachidonate, glyceryl monostearate ) May be used alone or in combination of two or more, and may be used as long as the material can be used as a phase change material in the industry, and is not limited to the above examples. Preferably the phase transition compound may be used alginic acid or salts thereof, preferably the alginic acid or salts thereof are ammonium alginate, magnesium alginate, potassium alginate, potassium alginate, sodium alginate ), Lithium alginate or mixtures thereof.
For effective release of the active ingredient contained in the formulation containing the phase change compound and close contact with teeth, tooth gaps or tissues around the teeth, the formulation is viscous enough to be easily manipulated for one minute by mixing one agent and two agents. It should have a hardness of and preferably has a hardness of 140 g to 350 g. And, after 10 minutes of mixing the components of the formulation, the release of the drug may occur smoothly, and it may be easy to have a hardness of 5,200 g to 13,000 g in order to maintain the form fixing force and adhesion. The polyacrylic acid, sodium polyacrylate, carbomer, carbopol, acrylate copolymer (Eudragit L-100), polyquaternium-39 and methyl vinyl ether and male are preferably used to provide the hardness of the formulations for which the invention is intended. It may include any one or more selected from the group consisting of an acid anhydride copolymer (PVM / MA copolymer). Preferably, the polymer may be a copolymer of methyl vinyl ether and maleic anhydride (PVM / MA copolymer).
The form fixation force that can be achieved by the formulation of the present invention can be more advantageous to achieve the desired effect because it is possible to ensure a sufficient contact time with the site that needs to reach the drug.
The formulation according to an embodiment of the present invention may have a difference between hardness measured after 1 minute of mixing and hardness measured after 10 minutes of 5,000 g to 12,000 g, preferably 6,000 g to 10,000 g_. When the hardness range is different, it is easy to attach and easy to handle and release of the drug is effective, can be easy to remove it may be advantageous to achieve the object of the present invention.
The formulation of the present invention may further include a substance that helps release the drug, and the substance that helps release the drug may be used as long as it forms a channel, a porous structure, or a bubble (foam) in the formulation. For example, if the composition consists of two drugs, the first agent contains acid and the second agent contains base, and the two formulations form a viscous form when the two formulations meet to form a viscous form. That is, the first agent contains acetic acid, lactic acid, malic acid, gluconic acid, ascorbic acid or the like, or a water-soluble salt thereof, such as sodium citrate, and the second agent contains sodium hydroxide (NaOH) and potassium hydroxide (KOH). , Sodium hydrogen carbonate (baking soda), sodium carbonate may be any one selected from the group containing, preferably acid may be selected as acetic acid, base is sodium hydrogen carbonate, more preferably used in toothpaste And sodium citrate and sodium bicarbonate, which are acids and bases.
The formulation of the present invention is a mixture of the first agent and the second agent, the hardness of the phase transition compound is in contact with the water gradually increases, so that it is easy to adhere to the teeth, the hardness is when the normal phase transition compound and water meet when removed It is less rigid and harder than the hardness range, so it may not cause irritation of teeth and gums when removed.
The formulation may further comprise a backing film as needed when attached to a tooth or periphery. The support layer may also serve to prevent this, because when the preparation time according to an embodiment of the present invention is long, it may be buried in unwanted areas such as gums. The support layer may include a water-insoluble polymer generally used in oral films, for example polyethylene (PE), polypyrophyllene (PP), ethylene vinyl acetate (EVA), cellulose acetate phthalate, shellac (Shellac) , Polyvinyl acetate, ethyl cellulose, poly methyl methacrylate, methacryloyl ethyl betaine / methacrylate copolymer (Yukaformer: Mitsubishi, methacryloylethyl betain / methacrylate copolymer), methacrylic acid
In one embodiment of the present invention it can be easily removed by brushing at the time when the drug of the formulation is released and removed.
According to one use example, after applying the dough formulation of the present invention to the support layer, it can be attached to the target site in the oral cavity, and after a certain time (when it hardens to some extent and does not adhere to the gums, etc.), the support can be removed. have. After removing the support, it is possible to remove the preparation of the present invention by brushing with a toothbrush that was used at the time of removal. In the case of using the peel-off form, it can be removed at the time of removal without removing the support in the middle of the solidification process.
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 addition, it is advantageous to achieve the desired effect because the contact time between the drug reaching site and the agent of the present invention can be sufficiently secured since it does not flow down after dilution or dilution by saliva.
It doesn't flow down when applied to teeth, so it can be used conveniently.
The initial hardness is relatively high, so that it is easy to handle without falling down, and the hardness increase is relatively small at a certain time after the attachment. Therefore, it is advantageous to remove and may cause less irritation around the attached area. .
Figure 1 shows a PVM / MA corresponding to an example of a polymer that can control the curing rate of the phase-transfer compound of the present invention (left), and shows the structure of the alginate-calcium complex formed (right).
2 shows the change in hardness of the formulation identified after 1 minute by mixing the formulation. The unit of the vertical axis was represented by g. As can be seen in Figure 2, it can be seen that the hardness increases more quickly from immediately after mixing the formulation to 1 minute in the case of the embodiment, and after 1 minute the hardness has a larger value than the comparative examples. Can be. That is, one minute after mixing, it can be seen that the example is easier for the user to handle the formulation than the comparative example.
Figure 3 shows the change in hardness of the formulation confirmed 10 minutes after mixing immediately before. As can be seen in Figure 3, in the case of the Example it can be seen that the hardness of the formulation has a smaller value than the comparative example when 10 minutes have elapsed. That is, it can be seen that after a certain time elapses after the attachment, the comparative example hardens more firmly.
Figure 4 is an illustration showing a process of solidifying after applying the formulation in accordance with an embodiment of the present invention after contact with the tooth. As can be seen in Figure 3, even the tooth gap may reach the formulation of the present invention.
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.
Examples and comparative examples were prepared by the following method.
According to the following composition, the second agent was prepared while mixing with a mechanical mixer after adjusting the temperature to 50 ° C. The content of the alginate powder mixed with the second agent was 100 times the weight of the second agent.
PVM / MA 0.2%
Water to 100%
PVM / MA 0.35%
Water to 100%
PVM / MA 1.0%
Water to 100%
Water to 100%
PVA 0.35%
Water to 100%
HPMC 1.0%
Water to 100%
[Hardness Comparison Experiment (Experimental Method: Measured by Texture Analyzer)]
-Evaluation device : Stable Micro System TA XT Plus
Evaluation method : The hardness of the comparative example and the Example was measured by the Texture Analyzer.
Hardness is measured by Texture Analyzer (TA) compression test mode. After filling 20g in a 50mL beaker with Examples and Comparative Examples, a 20mm diameter aluminum probe for hardness measurement was set, and the test speed was 1.5mm / s, the target mode was distance, and the distance was 10mm. The hardness calculated mechanically is the peak value of the first cycle.
- results
The results of comparing the hardness with time after mixing the first and second agents of the Examples and Comparative Examples are shown in Table 2 below.
As can be seen in Table 2, initially after mixing, the hardness value of the embodiment was larger, so that it could be easily applied or handled on the tooth. It was easy to use. 2 and 3 show the results of a graph showing the hardness change according to the above Examples and Comparative Examples.
After attaching Feeling Test]
A feeling test was conducted using the formulation having the composition according to Table 1 above. Immediately before use, the first and second agents were mixed, and then a mixture thereof was applied to the support layer. Attached to the desired area using a support layer and then pressed with a finger to be in close contact. Although it is not necessary to remove the support layer, in this experiment, the support layer was removed two minutes after the attachment. Remove after 10 minutes of attachment time.
1. Adhesion Questionnaire
Thirty respondents were allowed to use each formulation of Comparative Example 1, Comparative Example 3, and Examples 1 to 3 according to the above method according to the group. Each group then switched to using the product and responded to a question about the tight fit between the teeth.
- Based on survey responses -
5 points | pieces: Lightly presses with a finger, and it adheres well between gums and teeth, and is easy to remove.
4 points | pieces: A light touch with a finger | toe is possible, but adhesiveness between gums is normal.
3 points | pieces: A light touch with a finger | chine is possible, but the adhesiveness of a gum is weak.
2 points | pieces: A strong adhesive force is shown to a tooth, but the adhesive force between teeth falls.
1 point | piece: It shows strong adhesive force to a tooth, but adheres to a gum.
2. Removal survey
Thirty respondents were allowed to use each formulation of Comparative Example 1, Comparative Example 3, and Examples 1 to 3 according to the above method according to the group. Each group then switched to using the product and responded to a question about removal.
- Based on survey responses -
5: very easy to remove and there is no tooth residue
4: It is easy to remove, but there is little residue left.
3: It is not convenient to remove and residue remains uncomfortable.
2: It is inconvenient to remove, leaving a lot of residue.
1: The removal is very inconvenient and very much residue is left.
3. Clinical trials for humans Sirin Or gum pain improvement survey
1) Test subject and usage: Examples 1 to 3 and Comparative Examples 1 to 3 were removed after attachment 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 improvement of ache or gum pain lasted for 1 month in both the attached ache and the gum pain area | region.
4 points | pieces: The adhesive or gum pain improvement effect was confirmed by both the attached syringe and the gum pain area.
3 points | pieces: The paste or gum pain area | region attached and the pain or gum pain improvement effect was confirmed clearly.
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.
4. Evaluation of the Whitening Effect Difficulty Survey for Humans
1) Test subjects and usage: Examples 1 and 4, Comparative Example 2 was removed after attaching to the six teeth of the center of the upper teeth at least once 30 minutes 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 points of 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 don't know the difference before using it.
5. Measurement result
Table 3 below shows the removal and adhesion of the comparative example and the example, the aerobic improvement effect, gingivitis improvement effect, whitening effect is shown in a table.
(peel-off)
(brush-off)
(brush-off)
(peel-off)
(peel-off)
(peel-off)
effect
effect
[Drug Release Comparison Experiment]
A) operation
Pour 500 mL of 0.9% sodium chloride solution into the test tube and keep the test solution at 32 ± 0.5 ° C during the drug release test. After fixing the sample or the comparative example to the upper surface of the disk which can be used as a sinker without absorbing, obstructing or reacting so that the target attaching surface is facing outward, the surface to which the sample is attached is facing upward. Insert the test tube into the test tube and calculate the drug release time from this moment. The sample-attached disc is aligned parallel to the bottom of the test tube and the blade of the paddle. Adjust the paddle blade to 25 ± 2mm from the sample surface and set the rpm per minute to 25 rpm. When collecting the sample, take 100 mL of the sample solution at 30 minutes after the start of the test at a certain location (1 cm away from the wall of the test tube, above the paddle blade and halfway between the test surface). The drug release experiment was carried out under conditions of a general laboratory temperature of 25 ℃, relative humidity 65%.
B) Drug analysis method
Choose the appropriate analytical method depending on the drug and also depending on the content. For example, titration for peroxides, ICP analysis for metal salts, and HPLC for natural extracts.
C) Results of active ingredient release
As can be seen in Table 4, it was confirmed that about 70% of the active ingredient can be released in the case of Example 10 minutes after the attachment. However, in the comparative example, the drug was not released smoothly due to the sharply increased hardness, and thus the degree of drug release could not be measured.
T: Tooth
10: preparations for attachment of teeth or peripheral teeth
Claims (15)
Phase transition compounds; And a semi-solid oral preparation for attachment to a tooth or tooth periphery, comprising a polymer that controls the rate of phase transition,
The phase change compound is alginic acid, alginate, or a mixture thereof,
The polymer for controlling the phase transition rate is water-soluble, a polymer containing a carboxyl group (carboxyl) as a functional group,
The phase transition compound: a polymer for controlling the phase transition rate is mixed in a weight ratio of 5: 0.01 to 0.07,
When the hardness is measured in the compression test mode of the Stable Micro System TA XT Plus after mixing the phase-transfer compound and the polymer controlling the phase transition rate, it is measured after 1 minute of mixing. A formulation, characterized in that the difference between the hardness and the hardness measured after 10 minutes is between 5,000 g and 12,000 g.
A formulation comprising a copolymer of methyl vinyl ether and maleic anhydride (PVM / MA copolymer).
Alginic acid or salts thereof; And
When the hardness is measured in the compression test mode of the Stable Micro System TA XT Plus after mixing with the alginic acid or a salt thereof, the hardness of the formulation is 140g to 1 minute after mixing 350 g, including a polymer having a hardness of 5,200 g to 13,000 g after 10 minutes,
As the active ingredient, characterized in that the delivery to the oral cavity, the tooth or tooth peripheral attachment formulation,
The polymer mixed with the alginic acid or a salt thereof is water-soluble and includes a carboxyl group as a functional group,
The alginic acid or a salt thereof: The polymer is mixed with the alginic acid or a salt thereof is characterized in that the mixture in a weight ratio of 5: 0.01 to 0.07.
Priority Applications (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020160004353A KR102010417B1 (en) | 2016-01-13 | 2016-01-13 | Oral formulation |
| NZ745156A NZ745156A (en) | 2016-01-13 | 2017-01-12 | Preparation for oral cavity |
| CN201780006327.1A CN108472251B (en) | 2016-01-13 | 2017-01-12 | Oral preparation |
| PCT/KR2017/000409 WO2017123020A2 (en) | 2016-01-13 | 2017-01-12 | Preparation for oral cavity |
| US16/069,325 US10925830B2 (en) | 2016-01-13 | 2017-01-12 | Preparation for oral cavity |
| CN202210026652.7A CN114306214A (en) | 2016-01-13 | 2017-01-12 | Oral preparation |
| CN202210026648.0A CN114344249A (en) | 2016-01-13 | 2017-01-12 | Oral preparation |
| JP2018536506A JP6882303B2 (en) | 2016-01-13 | 2017-01-12 | Oral preparation |
| EP17738649.7A EP3403644B1 (en) | 2016-01-13 | 2017-01-12 | Preparation for oral cavity |
| AU2017206470A AU2017206470B2 (en) | 2016-01-13 | 2017-01-12 | Preparation for oral cavity |
| TW106101310A TWI776797B (en) | 2016-01-13 | 2017-01-13 | Oral formulation |
| KR1020190094738A KR102361364B1 (en) | 2016-01-13 | 2019-08-05 | Oral formulation |
| US17/148,043 US11872310B2 (en) | 2016-01-13 | 2021-01-13 | Preparation for oral cavity |
| JP2021077632A JP7254854B2 (en) | 2016-01-13 | 2021-04-30 | Oral formulation |
| JP2023053873A JP7540851B2 (en) | 2016-01-13 | 2023-03-29 | Oral Preparations |
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| KR1020160004353A KR102010417B1 (en) | 2016-01-13 | 2016-01-13 | Oral formulation |
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| KR1020190094738A Division KR102361364B1 (en) | 2016-01-13 | 2019-08-05 | Oral formulation |
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| KR20170084922A KR20170084922A (en) | 2017-07-21 |
| KR102010417B1 true KR102010417B1 (en) | 2019-08-13 |
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| KR102335985B1 (en) | 2017-07-04 | 2021-12-07 | 현대자동차주식회사 | Apparatus for controlling steering angle, lane keeping assist system having the same and method thereof |
| US20210030633A1 (en) * | 2017-08-03 | 2021-02-04 | Lg Household & Health Care Ltd. | Brush-off type tooth-attachable patch |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100662203B1 (en) * | 2005-12-05 | 2006-12-27 | 주식회사 엘지생활건강 | Delivery system for tooth whitening component using in situ gelling |
| KR100814250B1 (en) | 2006-11-01 | 2008-03-17 | 주식회사 엘지생활건강 | In-situ melting and gelling tablet composition for oral care |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR100623859B1 (en) * | 2004-09-06 | 2006-09-19 | 주식회사 엘지생활건강 | Delivery system for tooth whitening component using in situ gelling |
| KR101065612B1 (en) * | 2005-02-25 | 2011-09-19 | 주식회사 엘지생활건강 | Fast dissolving dry type tooth whitening strip |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100662203B1 (en) * | 2005-12-05 | 2006-12-27 | 주식회사 엘지생활건강 | Delivery system for tooth whitening component using in situ gelling |
| KR100814250B1 (en) | 2006-11-01 | 2008-03-17 | 주식회사 엘지생활건강 | In-situ melting and gelling tablet composition for oral care |
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