KR101591587B1 - Controlled-release composition of antibiotic agent and elastomer comprising the same - Google Patents

Abstract

The present invention relates to a composition for controlling dissolution of an antimicrobial substance and an elastic body comprising the same, and is characterized in that a composition for controlling the dissolution of an antimicrobial substance is coated on an elastic body for orthodontic treatment, thereby continuously elongating the antimicrobial substance.

Description

TECHNICAL FIELD The present invention relates to a composition for controlling the dissolution of an antimicrobial substance and an elastomer containing the same,

The present invention relates to a composition for controlling dissolution of an antimicrobial substance and an elastomer containing the same.

In recent years, stainless steel ligature wire, elsatomeric ligature, or elastomeric chains have been used to draw or bind teeth when orthodontic treatment. In general, orthodontists are known to be easy to use, aesthetic, and use more of their preferred elastomeric ligatures. Accordingly, various types of orthodontic elastic products have been developed.

On the other hand, during orthodontic treatment, plaque is easily deposited around orthodontic wires and brackets, and because oral hygiene is difficult to manage due to complicated oral devices, Occurs. As a result, esthetic problems of enamel are often caused by restorative treatment accompanied by severe restoration after orthodontic treatment. Therefore, various preventive measures are proposed to prevent dental caries, one of the typical side effects of orthodontic treatment have. The most commonly used fluorine varnishes, chlorhexidine gels, and varnishes can not be used for a long period of time. In order to overcome these disadvantages, an orthodontic product in which fluorine is eluted has been developed (refer to Korean Patent Application No. 10-2004-0088081). However, the product has a problem in that fluorine is released to help enamel remineralization However, there is a limitation in the physical properties such as fluorine-containing elastomers easily colored and swelling, and in particular, there is a high risk that dental fluorosis is caused by excessive consumption of fluorine eluted from elastomers when used in children.

In this way, there is still a lack of effective methods for effectively preventing dental caries frequently occurring during orthodontic treatment. In addition, since orthodontic patients can not easily manage the accumulated dentition, the risk of periodontal disease as well as dental caries is high. All of the prophylactic methods presented in this study have limitations that focus only on dental caries. Therefore, it is required to develop an easy method for effectively preventing dental caries and periodontal disease during orthodontic treatment.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made in order to solve the above-mentioned problems in the prior art, and an object of the present invention is to provide a method for inhibiting the formation of plaque around the orthodontic appliance by effectively dissolving an effective antibacterial substance in the oral cavity for a prolonged period of time, It is an object of the present invention to provide an elastic body for orthodontics having a coating layer containing a substance and a polymer substance.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

Hereinafter, the components and technical features of the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention and are not intended to limit the scope of the invention.

Various embodiments described herein are described with reference to the drawings. In the following description, for purposes of complete understanding of the present invention, various specific details are set forth, such as specific forms, compositions, and processes, and the like. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well-known processes and techniques of manufacture are not described in any detail, in order not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "embodiment" means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Accordingly, the appearances of the phrase " in one embodiment "or" the embodiment "in various places throughout this specification are not necessarily indicative of the same embodiment of the invention. In addition, a particular feature, form, composition, or characteristic may be combined in any suitable manner in one or more embodiments.

The present invention provides a controlled-release composition for use in an orthodontic appliance for orthodontics, which comprises an antibacterial substance and a cellulosic polymer material. The composition may further comprise a tooth whitening agent, an anti-plaque agent, an anti-gingivitis agent, etc., depending on the use.

In one embodiment of the invention, the antimicrobial material may be selected from the group consisting of chlorhexidine, gentamycin, vancomycin, and tetracycline. However, it is not limited to substances having antimicrobial activity.

In another embodiment of the present invention, the cellulose-based polymer material is a cellulose ether-based material, and the cellulose ether-based material is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxyethyl methylcellulose ethyl methyl cellulose, methyl cellulose, and ethyl cellulose. In addition, polylactic-coglycolic acid (PLGA), poly (d, lactide) (PDLLA), polyurethane (PU), poly lactic acid (PLA) and poly glycolic acid (PGA) are used as biocompatible materials. But is not limited thereto.

In another embodiment of the present invention, there is provided a composition, wherein the weight ratio of the antimicrobial material to the cellulosic polymer material is from 0.05: 1 to 20: 1. Preferably from 0.1: 1 to 10: 1. More preferably, the composition ratio of the antibacterial substance: polymer: solvent is 10 g: 100 g: 1 mL.

In another embodiment of the present invention, the polymer material comprising the antimicrobial material is dissolved in ethanol and / or dichloromethane.

The present invention also provides a method for preparing a polymer electrolyte membrane, comprising: a) preparing a polymer solution by dissolving a cellulosic polymer material in a solvent; And b) adding an antimicrobial substance to the polymer solution.

In addition, the present invention provides a method of manufacturing an elastic body for orthodontics comprising the above-mentioned composition for controlling orthodontic treatment, and a step of coating the composition on an elastic body for orthodontic treatment.

In one embodiment of the present invention, the elastomeric ligatures for use in orthodontic brackets and orthodontic wires are applied to the elastomeric ligatures, thread and so on.

By dissolving an effective antimicrobial substance in the oral cavity for a prolonged period of time, it is possible to effectively prevent the formation of teeth around the orthodontic appliance, effectively prevent dental caries and periodontal diseases, and prevent oral diseases It is possible to shorten the treatment time of the preventive treatment to be treated in order to reduce the risk of various oral diseases that may occur after the end of orthodontic treatment. In addition, it is expected that the method of manufacturing an elastic material dissolving antimicrobial material according to the present invention can be applied to various elastic materials used in orthodontic treatment in the same manner, thereby expanding its application range.

1 shows an image of an elastic body for calibration according to an embodiment of the present invention.
FIG. 2 shows an image of an antimicrobial eluting elastomer according to an embodiment of the present invention.
(CDA) + dichloromethane (DCM); 2. chlorhexidine diacetate (CDA) + poly (methyl methacrylate); and < RTI ID = 0.0 & Methyl methacrylate (PMMA) + dichloromethane (DCM); 3. chlorhexidine diacetate (CDA) + ethyl cellulose (EC) + dichloromethane (DCM).
(CDA + EC + DCM, 3. CDA + EC + 30%). The results are shown in FIG. 4. FIG. 4 shows the result of the dissolution test of the antimicrobial material according to the solvent of the simple deposition method coating according to an embodiment of the present invention EtOH / 70% DCM 4. CDA + EC + 50% EtOH / 50% DCM 3. CDA + EC + 70% EtOH / 30% DCM).
(CDA + EC + DCM; 3. CDA + EC + 30%) in the spray coating method according to an embodiment of the present invention. EtOH / 70% DCM 4. CDA + EC + 50% EtOH / 50% DCM 5. CDA + EC + 70% EtOH / 30% DCM).
FIG. 6 shows experimental results of microscopic changes of the surface of the elastic body according to the type of polymer according to an embodiment of the present invention.
FIG. 7 shows experimental results of microscopic changes of the surface of an elastic body according to a solvent according to an embodiment of the present invention.
(CDA + DCM; 2. CDA + EC + DCM; 3. CDA + EC + 30% EtOH / 70% ethanol). FIG. 8 is a graph showing the results of experiments for confirming the antimicrobial activity of an eluting antimicrobial agent according to an embodiment of the present invention. DCM; 4. CDA + EC + 50% EtOH / 50% DCM; 5. CDA + EC + 70% EtOH / 30% DCM).

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example 1: Preparation of an elastomer coating solution

Ethyl cellulose (EC, Ethyl cellulose, SIGMA-ALDRICH, Inc., USA), poly (methyl methacrylate), and poly (methyl methacrylate) (DCM, DMC, Merck KGaA, Germany) and ethanol (SIGMA-ALDRICH, Inc., USA) were used as the polymer. ) Was used as a solvent. The composition of the antimicrobial material and the polymer of the elastomer coating solution were mixed in the same ratio as in Table 1 to prepare a coating solution.

For the composition of the coating solution, 0.1 g of ethylcellulose or polymethyl methacrylate was sufficiently dissolved in 1 mL of dichloromethane or ethanol, and 0.01 g of chlorhexidine diacetate was added and mixed. The mixing process was carried out at room temperature.

ingredient percentage amount Chlorhexidine diacetate One % 0.01 g / mL Ethyl cellulose 10% 0.1 g / mL Polymethylmethacrylate 10% 0.1 g / mL

Example 2: Search for the composition of a coating solution capable of eluting an antimicrobial substance for a long time

2.1. Composition of Coating Solution for Simple Deposition Method

In order to ensure long-term release of the antimicrobial substance, first, the duration of the antimicrobial substance elution was searched according to the type of the polymer substance. To investigate the duration of antimicrobial dissolution, ethyl cellulose or polymethylmethacrylate was added to 1 mL of dichloromethane at a ratio as shown in Table 2 so as to be 10% W / V. (Weight / volume ratio) Diacetate 1% W / V. Was added and thoroughly mixed to prepare a coating solution.

number Antimicrobial substance
(0.01 g) Polymer
(0.1 g) menstruum
(1 mL) One Chlorhexidine
Diacetate not used Dichloromethane 2 Chlorhexidine
Diacetate Ethyl cellulose Dichloromethane 3 Chlorhexidine
Diacetate Polymethylmethacrylate Dichloromethane

In order to investigate the dissolution time of the antimicrobial substance according to the solvent, 1 mL of a solvent was prepared by mixing the ratios of ethanol and dichloromethane to each other. Ethylcellulose was added thereto in an amount of 10% W / V. 1% W / V. Of chlorhexidine diacetate was added and thoroughly mixed to prepare a coating solution (Table 3).

number Antimicrobial substance
(0.01 g) Polymer
(0.1 g) menstruum
(1 mL) One Chlorhexidine Ethyl cellulose 30% ethanol + 70% dichloromethane 2 Chlorhexidine Ethyl cellulose Ethanol 50% + dichloromethane 50% 3 Chlorhexidine Ethyl cellulose 70% ethanol + 30% dichloromethane

2.2. Composition of Coating Solution for Spray Application

In the spray coating method, the proportion of the polymer was adjusted to compensate the coating thickness of the antimicrobial material. As shown in Table 4, the dissolution period of the antimicrobial substance was determined by the solvent ratio.

Ethanol and dichloromethane were mixed in different ratios to make 1 mL of solvent. Ethylcellulose was added to the solvent to a concentration of 2% W / V. After thoroughly dissolved, 0.1% W / V of chlorhexidine diacetate was added To prepare a coating solution.

number Antimicrobial substance
(0.01 g) Polymer
(0.02 g) menstruum
(1 mL) One Chlorhexidine not used Dichloromethane 2 Chlorhexidine Ethyl cellulose Dichloromethane 3 Chlorhexidine Ethyl cellulose 30% ethanol + 70% dichloromethane 4 Chlorhexidine Ethyl cellulose Ethanol 50% + dichloromethane 50% 5 Chlorhexidine Ethyl cellulose 70% ethanol + 30% dichloromethane

Example 3: Elastic coating

3.1. Coating with simple deposition method

The elastomer was coated by a simple deposition method using the coating solution prepared by the method of Example 2.1 above. The orthodontic elastic body is used for connecting an orthodontic wire and a bracket (Fig. 1A), and is manufactured and sold in various colors (Fig. 1B). In the present invention, a transparent elastic body (TP Orthodontics, Inc., USA) was used to easily confirm the coating pattern.

Prior to coating, the elastomer was washed in distilled water and dried in a 60 ° C dry oven for 1 hour. Sixteen dried elastomers were coated and immersed in 1 mL of the prepared coating solution and dried at room temperature for 1 hour. The dried elastomers were separated one by one for application to the elution test, and an elastomer eluting the antimicrobial substance was prepared (FIG. 2).

3.2. Spray coating

The coating solution prepared by the method of Example 2.2 was used to spray the coating solution onto 16 elastomers five times. The coating was finished 5 times at a spraying interval of 5 minutes per spraying interval, followed by drying at room temperature for 30 minutes. The dried elastomers were prepared by separating one by one to be applied to the elution test.

Example 4: Confirmation of elution of antimicrobial substance from eluting elastomer

In order to confirm the elution of the antimicrobial substance eluted from the antimicrobial eluate prepared by the method of Example 3, 16 antimicrobial eluting elastomers were fixed to a stainless steel wire having a diameter of 2 mm and placed in the lid portion of the vial. 4 mL of distilled water was added to the 8 mL vial so that the elastic body fixed to the lid could be locked, and then replaced with fresh distilled water every predetermined time. All procedures were carried out with stirring at room temperature. The ultraviolet spectrophotometer was used to measure the elution concentration of the antimicrobial substance over time. The elution concentration of chlorhexidine was calculated from the standard curve in the range of 0.1-40 ug / mL (r = 0.98) Respectively.

In order to confirm the release of the antimicrobial substance according to the type of polymer, the release of the antimicrobial substance from the antimicrobial eluting elastomer produced by the method of Example 3.1 was measured. The results are shown in Fig.

As shown in Fig. 3, the combination (2) using polymethylmethacrylate as a polymer showed elution pattern similar to the combination (1) without using a polymer and the combination (3) using ethylcellulose showed the same amount of antimicrobial substance It was observed that the high concentration of the antimicrobial substance of 3 times or more was continuously eluted. From the above results, it was confirmed that when ethylcellulose was used as compared with the case of using polymethylmethacrylate as a polymer, the antimicrobial substance could be effectively eluted into a sustained release form.

In order to confirm the elution of the antimicrobial substance according to the solvent of the simple deposition method coating, the release of the antimicrobial substance from the elutable antimicrobial substance prepared by the method of Example 3.1 was measured. The results are shown in Fig.

As shown in FIG. 4, it was confirmed that the antimicrobial material eluted at a high concentration over a long period of time when the ratio of dichloromethane was increased as compared with that of ethanol.

In order to confirm the dissolution of the antimicrobial substance according to the solvent of the spray coating, the release of the antimicrobial substance from the antimicrobial elutable elastomer prepared by the method of Example 3.2 was measured. The results are shown in Fig.

As shown in FIG. 5, it was confirmed that the highest concentration of the antimicrobial substance was eluted when the ratio of ethanol to dichloromethane was 3: 7, and it was confirmed that there was a slight difference in the elution of the antimicrobial substance according to the other conditions I could. Also, it was confirmed that there was a difference in the elution pattern from the simple deposition, and it was confirmed that it was influenced by the coating method.

Example 5: Confirmation of fine changes in the surface of an elastic material eluting antimicrobial substance

In order to observe microscopic changes appearing on the surface of the elastomer eluting antimicrobial substance prepared by the method of Example 3, a scanning electron microscope (FE-SEM S-800, Hitachi, Japan) The condition of the coated surface was observed.

In order to confirm the microscopic change of the surface of the elastic body according to the kind of polymer, the surface of the elastic body eluting with antimicrobial substance prepared by the method of Example 3.1 was observed before and after the experiment. The results are shown in Fig.

As shown in FIG. 6, it was confirmed that all of the coating materials were removed after the completion of the experiment in Group 1, which was applied only with the antimicrobial material, and it was confirmed that all the coating groups remained in the polymer group. In the group using ethylcellulose, a small pore was observed after the end of the experiment. From the above results, it was confirmed that when the polymer was used regardless of the kind of polymer, the surface of the elastic body was effectively coated by the simple deposition method.

In order to confirm the fine changes of the surface of the elastic body according to the solvent, the surface of the elastic body dissolving the antibacterial substance prepared by the method of Example 3.1 was observed before and after the experiment. The results are shown in Fig.

As shown in Fig. 7, it was confirmed that the surface of the elastic body was smoothly coated regardless of the combination of solvents.

Example 6: Tensile test of an elastic material eluting antimicrobial substance

(Unite-O-Matic FM 20, United Calibration Corporation, Garden Grove, Calif.) Was used to check the effect of the polymer coating on the elasticity of the elastomer. The orthopedic surgeon compared the tensile forces between the groups by measuring the force in N increments at 2 mm / sec and 3 mm / sec in consideration of the operation of mounting the elastic body on the bracket to the orthodontic patient. For the tensile test, an antimicrobial eluting elastomer prepared by the method of Example 3.1 was used. The tensile force (unit: N) of the elastic material eluting the antimicrobial substance is shown in Table 5.

Group 2㎜ Tensile strength 3㎜ Tensile strength Group 1
(CDA + DCM) 5.64 ± 1.23 6.66 ± 1.33 Group 2
(CDA + EC + DCM) 5.64 ± 0.45 6.79 ± 0.37 Group 3
(CDA + EC + 30EtOH / 70DCM) 5.62 0.30 6.81 + - 0.38 Group 4
(CDA + EC + 50EtOH / 50DCM) 4.97 + - 0.70 6.19 ± 0.64 Group 5
(CDA + EC + 70EtOH / 30DCM) 5.59 ± 0.29 6.79 ± 0.28

As shown in Table 5, it was confirmed that the coating of the polymeric material does not affect the elasticity of the elastic body.

Example 7: Confirmation of the antibacterial activity of the eluting elastomer

Streptococcus mutans , a cucumber germ, was used in order to confirm the antibacterial activity of the eluting antimicrobial substance prepared by the method of Example 3 above. Streptococcus mutans was pre-cultured in a BHI (Brain Heart Infusion) liquid medium, and then the number of bacteria was adjusted to be 10 ⁷ CFU / mL, and 100 μL of the bacterial culture was adjusted to a BHI solid medium. Then, the eight antimicrobial eluting elastomers prepared by the method of Example 3.1 were fixed on a solid medium on which the bacteria were plated and cultured at 37 ° C and 10% CO ₂ for 48 hours. Thereafter, The horizontal and vertical diameters of the inhibition zone were measured using an image program (Image-Pro ^® Plus 6.0). The results are shown in Fig.

As shown in FIG. 8, when an orthodontic elastic body was coated with an antimicrobial substance under various conditions, it was confirmed that the antimicrobial activity against specific oral bacteria appeared. In particular, the CDA + EC + 30% EtOH + 70% DCM showed that the antimicrobial region was significantly higher than the CDA + EC + 30% EtOH in FIG. 3 because the high concentration of the antimicrobial substance eluted do.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (16)

A controlled-release composition for use in a tooth-correcting elastic body, comprising a mixture of an antibacterial substance, a cellulose-based polymer, and a solvent,
Wherein the antimicrobial material is comprised between pores formed by the cellulosic polymeric material. The method according to claim 1,
Wherein the antimicrobial agent is selected from the group consisting of chlorhesidine, gentamycin, vancomycin, and tetracycline. The method according to claim 1,
Wherein the cellulosic polymer material is a cellulose ether. The method of claim 3,
The cellulose ether is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxy ethyl methyl cellulose, methyl cellulose and ethyl cellulose. Lt; / RTI > The method according to claim 1,
Wherein the weight ratio of the antimicrobial material to the cellulosic polymer material is from 0.05: 1 to 20: 1. The method according to claim 1,
Wherein the cellulosic polymer material is dissolved in ethanol or dichloromethane. The method according to claim 1,
Wherein the cellulosic polymer material is dissolved in ethanol: dichloromethane mixed in a ratio of 1: 1 to 1: 3. 8. An elastic body for orthodontic treatment, comprising the controlled-release composition according to any one of claims 1 to 7. a) preparing a polymer solution by dissolving a cellulosic polymer material in a solvent; And
and b) adding an antimicrobial substance to the polymer solution. A method for producing a controlled-release composition for use in a dental orthodontic appliance, 10. The method of claim 9,
Characterized in that the cellulosic polymeric material is a cellulose ether. 10. The method of claim 9,
The cellulose ether is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxy ethyl methyl cellulose, methyl cellulose and ethyl cellulose. How to. 10. The method of claim 9,
Wherein the antimicrobial material is selected from the group consisting of chlorhesidine, gentamycin, vancomycin, and tetracycline. 10. The method of claim 9,
Wherein the weight ratio of the antimicrobial to the macromolecular material is from 0.05: 1 to 20: 1. 10. The method of claim 9,
Characterized in that the solvent is ethanol or dichloromethane. 10. The method of claim 9,
Wherein the solvent is ethanol: dichloromethane mixed in a ratio of 1: 1 to 1: 3. A method for producing an elastic body for orthodontic treatment, comprising the step of coating a composition for oral cavity adjustment of any one of claims 1 to 7 on the elastic body for orthodontic treatment.

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