KR20230040578A - Composition for Inhibiting Biofilm Formation and for Preventing or Treating Dental Disease - Google Patents
Composition for Inhibiting Biofilm Formation and for Preventing or Treating Dental Disease Download PDFInfo
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- KR20230040578A KR20230040578A KR1020210123893A KR20210123893A KR20230040578A KR 20230040578 A KR20230040578 A KR 20230040578A KR 1020210123893 A KR1020210123893 A KR 1020210123893A KR 20210123893 A KR20210123893 A KR 20210123893A KR 20230040578 A KR20230040578 A KR 20230040578A
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Abstract
Description
본 발명은 SSL25 펩타이드를 포함하는 바이오필름 형성 억제 및 구강질환 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for inhibiting biofilm formation and preventing or treating oral diseases, including an SSL25 peptide.
구강질환은 세균감염으로 인해 유발되지만 세균의 바이오필름 형성이 구강감염 질환의 진행과 악화에 직접적인 영향을 준다. 일반적으로 세균은 단독으로 분산되어 부유하기 보다는, 세균과 폴리머가 표면구조에 부착하여 구성된 복합체인 바이오필름을 이루어 존재한다. 바이오필름 형태로 증식하는 세균은 부유하고 있는 형태의 세균보다 항생제 내지 항균제에 대한 저항성이 높아진다. 뿐만 아니라 부유세균에 대한 항균력을 가진 항생제가 바이오필름을 억제할 수 없는 경우가 있어서 항생제의 과도사용과 오남용으로 인한 내성 균주가 늘어나고 있는 실정이다. Oral diseases are caused by bacterial infections, but bacterial biofilm formation directly affects the progression and aggravation of oral infections. In general, bacteria exist as a biofilm, which is a complex composed of bacteria and polymers attached to a surface structure, rather than being dispersed and suspended alone. Bacteria proliferating in the form of a biofilm have higher resistance to antibiotics or antimicrobial agents than bacteria in a floating form. In addition, there are cases where antibiotics having antibacterial activity against airborne bacteria cannot inhibit biofilm, and thus, resistant strains due to excessive use and misuse of antibiotics are increasing.
구강에는 700~1,000여종의 세균이 복잡하고 역동적인 바이오필름을 형성하고 있다. 바이오필름 형성과정은 보통 5단계 반응으로 부착단계, 응집단계, 바이오필름 형성단계, 바이오필름 성숙단계 및 마지막의 분산 단계로 구성된다. 바이오필름은 세포가 표면에 부착되고 세포와 세포가 응집하여 형성되며 미생물이 분비한 세포외고분자 물질로 이루어진 매트릭스에 둘러싸인 3차구조를 형성하고 있다. 치아에 형성된 구강 바이오필름은 치면 세균막(치태, dental plaque)이다. 치면 세균막 형성에 관여하는 세균은 바이오필름 형성 단계에 따라 차이가 나는데, 초기 치면 세균막 형성단계에는 주로 그람 양성 세균이 치아 표면에 부착되지만 이어서 그람 양성 세균이 그람 음성 세균과 응집하여 후기 치면 세균막을 만들게 된다. Between 700 and 1,000 species of bacteria form complex and dynamic biofilms in the oral cavity. The biofilm formation process is usually a five-step reaction and consists of an attachment step, an aggregation step, a biofilm formation step, a biofilm maturation step, and a final dispersal step. A biofilm is formed by cells attaching to a surface and cells aggregating together, forming a tertiary structure surrounded by a matrix composed of extracellular polymer substances secreted by microorganisms. Oral biofilm formed on teeth is a dental plaque. Bacteria involved in the formation of dental biofilms differ depending on the biofilm formation stage. In the initial stage of dental biofilm formation, mainly gram-positive bacteria adhere to the tooth surface, but then gram-positive bacteria aggregate with gram-negative bacteria to form a later dental biofilm. do.
구강내에 분포하는 미생물은 사람에 따라 차이가 있지만 그람 양성세균으로 Streptococcus mutans를 비롯하여 Lactobacillus acidophilus, Streptococcus salivarius, Staphylococcus aureus, Staphylocoocus epidermidis, Neisseria meningitidis 등이 있으며, 그람 음성세균으로는 Porphyromonas gingivalis, Escherichia coli와 Enterobacter cloacae 등이 있다. 뿐만 아니라 효모인 Candida albicans 등이 있다. 구강세균은 기회성 병원체로서 질병 발병 가능성을 가지고 있는 것으로 알려져 있는데 특히 Streptococcus mutans(스트렙토코커스 뮤탄스)는 구강질환인 충치 등 각종 구강질환을 유발하는 대표적 균이다. Microorganisms distributed in the oral cavity vary from person to person, but gram-positive bacteria include Streptococcus mutans , Lactobacillus acidophilus , Streptococcus salivarius , Staphylococcus aureus , Staphylocoocus epidermidis , and Neisseria meningitidis . Gram-negative bacteria include Porphyromonas gingivalis , Escherichia coli , and Enterobacter . cloacae , etc. In addition, there are yeasts such as Candida albica ns. Oral bacteria are known to have disease-causing potential as opportunistic pathogens. In particular, Streptococcus mutans (Streptococcus mutans) is a representative bacteria that causes various oral diseases such as tooth decay, which is an oral disease.
구강내 탄수화물이 섭취되면 Streptococcus mutans가 수크로스를 단당류인 포도당(glucose)와 과당(fructose)로 가수분해하고 포도당은 S. mutans가 분비하는 글루코실트랜스퍼라제(glucosyltransferse, GTFase)에 의해 점성을 가진 불용성 글루칸인 덱스트란(dextran)이 된다. 그리고, 덱스트란이 구강 세균과 침착되어 구강 바이오필름인 치면 세균막(치태, dental plaque)을 형성하고 치면 세균막에 칼슘이 침착되어 단단해지면 치석(dental calculus)이 되며 치석은 치아 표면에 세균을 고정하는 매트릭스 역할을 한다. 한편 가수분해된 과당은 S. mutans에 의해 젖산(lactic acid)을 생성하고 젖산은 부착성 글루칸에 포집되고 농축되어 산의 농도가 높아지게 된다. pH가 낮아지면 치아의 구성성분인 인산칼슘의 Ca2+를 용해시킴으로써 치아의 외막인 법랑질(enamel) 용해와 치아의 탈회를 유발하고 충치인 치아우식증이 생기게 된다. When oral carbohydrates are ingested, Streptococcus mutans hydrolyzes sucrose into monosaccharides, glucose and fructose, and glucose is converted into viscous and insoluble form by glucosyltransferase (GTFase) secreted by S. mutans . It becomes dextran, which is a glucan. In addition, dextran is deposited with oral bacteria to form dental plaque, which is an oral biofilm, and when calcium is deposited on the dental plaque and becomes hard, it becomes dental calculus, which fixes bacteria on the tooth surface serves as a matrix. On the other hand, hydrolyzed fructose produces lactic acid by S. mutans , and lactic acid is captured and concentrated in adherent glucan, increasing the acid concentration. When the pH is lowered, Ca 2+ of calcium phosphate, which is a component of teeth, is dissolved, causing dissolution of enamel, which is the outer layer of teeth, and demineralization of teeth, and dental caries, which is tooth decay, occurs.
스트렙토코커스 뮤탄스 억제를 통한 충치관리를 위하여 항생물질인 페니실린과 에리트로마이신, 스포라마이신(sporamycin), 반코마이신(vancomycin), 클로로헥시딘(chlorhexidine) 등을 사용하거나 금속염, 불소화합물에 의한 병원성 세균의 억제 방법 등이 이용되고 있다. 그러나, 항생물질의 지속적 사용은 미생물의 내성을 유발할 뿐만 아니라 설사, 구토 등의 부작용을 유발할 수 있으며 구강상재 균들의 생육이 저해되는 문제점도 심각하다. 또한 구강 바이오필름내 세균은 부유세균에 비해 항생제에 내한 저항성이 클 뿐만 아니라 β-lactam 계열의 항생제는 오히려 S.aureus 바이오필름 형성을 촉진시킨다고 보고된 바 있다. 따라서 충치를 비롯한 구강질환을 효과적으로 예방 및 치료하기 위해서는 부유세균의 성장억제를 나타내는 항균 효능뿐만 아니라 바이오필름의 제어력이 반드시 필요하다.For tooth decay management through suppression of Streptococcus mutans, antibiotics such as penicillin, erythromycin, sporamycin, vancomycin, and chlorhexidine are used, or pathogenic bacteria caused by metal salts and fluorine compounds suppression methods are used. However, the continuous use of antibiotics not only causes resistance to microorganisms, but also causes side effects such as diarrhea and vomiting, and the growth of oral flora bacteria is also seriously inhibited. It has also been reported that bacteria in oral biofilms are more resistant to antibiotics than airborne bacteria, and that β-lactam antibiotics promote the formation of S. aureus biofilms. Therefore, in order to effectively prevent and treat oral diseases including tooth decay, not only the antibacterial effect indicating the growth inhibition of airborne bacteria but also the controllability of the biofilm is absolutely necessary.
본 발명에서 사람 땀샘에서 유래된 펩타이드인 SSL25가 구강내에서 충치 등 각종 구강질환을 유발하는 구강 특이적인 스트렙토코커스 뮤탄스에 대해 항균력을 보일 뿐만 아니라 바이오필름 형성까지 억제하는 것을 확인하였다. 또한 산생성을 억제하고 글루코실트랜스퍼라제에 의한 불용성 글루칸 형성을 억제함으로써 플라크 형성이나 치아우식증을 방지한다는 것을 확인하였다. 또한 항염증 효능을 가지고 있어서 세균감염으로 인한 구강 염증을 억제하여 치아우식증, 치태, 치석, 치주질환, 치통, 시린이, 플라크, 충치, 및 구취 등의 구강질환을 안전하고 효과적으로 치료 및 예방할 수 있음을 확인하고 본 발명을 완성하였다.In the present invention, it was confirmed that SSL25, a peptide derived from human sweat glands, not only exhibits antimicrobial activity against oral-specific Streptococcus mutans, which causes various oral diseases such as tooth decay, but also inhibits biofilm formation. In addition, it was confirmed that plaque formation or dental caries is prevented by inhibiting acid production and insoluble glucan formation by glucosyltransferase. In addition, it has anti-inflammatory effect, so it suppresses oral inflammation caused by bacterial infection, so it can safely and effectively treat and prevent oral diseases such as dental caries, dental plaque, tartar, periodontal disease, toothache, cold teeth, plaque, tooth decay, and bad breath. confirmed and completed the present invention.
상기한 목적을 달성하기 위하여, 본 발명의 목적은 SSL25 펩타이드를 유효성분으로 포함하는 바이오필름 형성 억제용 조성물을 제공하는 것이다.In order to achieve the above object, an object of the present invention is to provide a composition for inhibiting biofilm formation comprising the SSL25 peptide as an active ingredient.
본 발명의 다른 목적은 SSL25 펩타이드를 유효성분으로 포함하는 항균용 구강 조성물을 제공하는 것이다.Another object of the present invention is to provide an antibacterial oral composition comprising the SSL25 peptide as an active ingredient.
본 발명의 또 다른 목적은 SSL25 펩타이드를 유효성분으로 포함하는 구강질환 예방 또는 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating oral diseases comprising SSL25 peptide as an active ingredient.
본 발명의 또 다른 목적은 SSL25 펩타이드를 유효성분으로 포함하는 구강질환 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving oral diseases comprising SSL25 peptide as an active ingredient.
본 발명의 또 다른 목적은 SSL25 펩타이드를 유효성분으로 포함하는 구강질환 예방 또는 개선용 의약외품 조성물을 제공하는 것이다. Another object of the present invention is to provide a quasi-drug composition for preventing or improving oral diseases comprising SSL25 peptide as an active ingredient.
이하 본 명세서에 대하여 더욱 상세히 설명한다.Hereinafter, the present specification will be described in more detail.
본 발명에서 개시된 각각의 설명 및 실시형태는 각각에 대한 다른 설명 및 실시형태에도 적용될 수 있다. 즉, 본 발명에 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기에 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.Each description and embodiment disclosed in the present invention can also be applied to other descriptions and embodiments for each. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited by the specific descriptions described below.
본 명세서에서 사용되는 「포함하는」과 같은 표현은, 해당 표현이 포함되는 문구 또는 문장에서 특별히 다르게 언급되지 않는 한, 다른 실시 예를 포함할 가능성을 내포하는 개방형 용어(open-ended terms)로 이해되어야 한다.Expressions such as “comprising” used in this specification are understood as open-ended terms that include the possibility of including other embodiments, unless specifically stated otherwise in a phrase or sentence in which the expression is included. It should be.
본 발명의 설명 및 청구범위에서 사용된 용어나 단어는, 통상적이거나 사전적인 의미로 한정해서 해석되어서는 아니되며, 발명자는 그 자신의 발명을 가장 최선을 방법으로 설명하기 위해 용어의 개념을 적절하게 정의할 수 있다는 원칙에 입각하여, 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야만 한다.The terms or words used in the description and claims of the present invention should not be construed as being limited to ordinary or dictionary meanings, and the inventors use the concept of terms appropriately in order to explain their invention in the best way. Based on the principle that it can be defined, it should be interpreted as meaning and concept consistent with the technical spirit of the present invention.
상기 목적을 달성하기 위한 하나의 양태로서, 본 발명은 SSL25 펩타이드를 유효성분으로 포함하는 바이오필름 형성 억제용 조성물을 제공한다.As one aspect for achieving the above object, the present invention provides a composition for inhibiting biofilm formation comprising the SSL25 peptide as an active ingredient.
본 발명에서 용어 "SSL25 펩타이드"는 덤시딘(Dermcidin, DCD)의 가수분해물로, DCD-1의 N 말단 25개의 아미노산으로 구성되어 있으며, 서열번호 1의 아미노산 서열을 가진다.In the present invention, the term "SSL25 peptide" is a hydrolyzate of Dermcidin (DCD), composed of 25 amino acids at the N terminal of DCD-1, and has the amino acid sequence of SEQ ID NO: 1.
상기 덤시딘은 땀샘에서 분비되어 땀을 통해 표피로 이동해 작용하는 펩타이드이다. 세균 막에는 음전하를 가진 인지질이 많기 때문에 대부분의 항균 펩타이드는 강한 양전하를 띄고 세균의 세포막에 결합한다. 그러나 덤시딘은 전제적으로 음전하를 띄고 있을 뿐만 아니라 helix-hinge-helix를 모티브로 한 flexible amphipathic α-helical structure로 되어 있으며 기존에 알려진 다른 항균 펩타이드와 구조적 유사성이 거의 없다. 덤시딘은 110개의 아미노산으로 이루어져 있는데 활성 형태는 단백질 분해에 의해 생산된 47개의 아미노산으로 구성된 덤시딘-1(DCD-1)이다. 또 다른 덤시딘의 가수분해물인 SSL-25는 DCD-1의 N 말단의 25개의 아미노산으로 구성되어 있다. The dermcidin is a peptide that is secreted from sweat glands and moves to the epidermis through sweat to act. Since there are many negatively charged phospholipids in bacterial membranes, most antimicrobial peptides have a strong positive charge and bind to bacterial cell membranes. However, dumcidin not only has a negative charge as a whole, but also has a flexible amphipathic α-helical structure with a helix-hinge-helix motif, and has little structural similarity with other known antimicrobial peptides. Dumcidin is composed of 110 amino acids, and the active form is Dumcidin-1 (DCD-1) composed of 47 amino acids produced by proteolysis. Another dermcidin hydrolyzate, SSL-25, is composed of 25 amino acids at the N-terminus of DCD-1.
상기 덤시딘-1의 아미노산 서열과 SSL25의 아미노산 서열은 아래와 같다.The amino acid sequence of Dumcidin-1 and the amino acid sequence of SSL25 are as follows.
DCD-1: SSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSV(서열번호 2)DCD-1: SSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSV (SEQ ID NO: 2)
SSL25: SSLLEKGLDGAKKAVGGLGKLGKDA(서열번호 1)SSL25: SSLLEKGLDGAKKAVGGLGKLGKDA (SEQ ID NO: 1)
본 명세서에서 사용되는 용어, "바이오필름(biofilm, 생물막)"은 미생물에 의하여 형성된 막 모양의 구조체를 말하며, 상호 연결된 미생물 세포층 및 미생물 분비물로 이루어진 구조적 특징을 가진다. 미생물은 다당류를 생성하는 효소를 세포 외부로 분비하여 외부 환경에 존재하는 당물질로부터 수용성 또는 불용성 다당류를 형성하며, 이러한 불용성 다당류가 지속적으로 축적되면 필름 형태의 얇은 바이오필름이 형성된다. 형성된 바이오필름은 미생물 사이의 응집에 도움을 주어 결과적으로 치태, 치석이나 치아우식증, 충치와 같은 구강질환을 유발할 수 있다.As used herein, the term "biofilm" refers to a membrane-like structure formed by microorganisms, and has a structural feature consisting of interconnected microbial cell layers and microbial secretions. Microorganisms secrete polysaccharide-generating enzymes to the outside of cells to form water-soluble or insoluble polysaccharides from sugar substances present in the external environment, and when these insoluble polysaccharides are continuously accumulated, a thin film-like biofilm is formed. The formed biofilm helps in cohesion between microorganisms, and as a result, it can cause oral diseases such as plaque, dental calculus, dental caries, and tooth decay.
본 발명의 일 구체예에 따르면, 상기 바이오필름은 스트렙토코커스 뮤탄스에 의해 형성될 수 있다. According to one embodiment of the present invention, the biofilm may be formed by Streptococcus mutans.
스트렙토코커스 뮤탄스는 구강 내의 치아 표면에 부착하여 치아우식증 또는 충치 등 각종 구강질환을 유발하는 중요한 원인균으로, 포도당을 이용하여 글루칸(glucan)이라는 다당류를 합성하고, 생성된 글루칸으로 바이오필름을 형성하여 치아에 부착함으로써 외부의 물리적, 화학적 처리에 대하여 저항력을 지니게 된다.Streptococcus mutans is an important causative bacterium that attaches to the surface of teeth in the oral cavity and causes various oral diseases such as dental caries or tooth decay. By attaching to the surface, it has resistance against external physical and chemical treatment.
본 발명에서 SSL25 펩타이드가 구강내에서 충치 등 각종 구강질환을 유발하는 구강 특이적인 스트렙토코커스 뮤탄스에 대해 항균력을 보일 뿐만 아니라 바이오필름 형성까지 억제하는 것을 확인하였다. 또한 산생성을 억제하고 글루코실트랜스퍼라제에 의한 불용성 글루칸 형성을 억제함으로써 플라크 형성이나 치아우식증 등의 각종 구강질환의 치료에 적용이 가능한 것을 확인하였다(도 2, 표 1 및 표 2). In the present invention, it was confirmed that the SSL25 peptide not only exhibits antibacterial activity against oral-specific Streptococcus mutans that causes various oral diseases such as tooth decay in the oral cavity, but also inhibits biofilm formation. In addition, it was confirmed that it can be applied to the treatment of various oral diseases such as plaque formation and dental caries by inhibiting acid production and insoluble glucan formation by glucosyltransferase (FIG. 2, Tables 1 and 2).
본 발명의 SSL25 펩타이드를 포함하는 바이오필름 형성 억제용 조성물은 스트렙토코커스 뮤탄스에 의해 형성되는 바이오필름을 효과적으로 억제할 수 있으므로, 스트렙토코커스 뮤탄스의 바이오필름에 의해 유발될 수 있는 치아우식증, 충치, 구내염과 같은 각종 구강질환을 효과적으로 억제하는데 유용하게 활용될 수 있다. Since the composition for inhibiting biofilm formation comprising the SSL25 peptide of the present invention can effectively inhibit the biofilm formed by Streptococcus mutans, dental caries, tooth decay, It can be usefully used to effectively suppress various oral diseases such as stomatitis.
따라서, 본 발명의 바이오필름 형성 억제용 조성물은 항균용 구강 조성물, 구강질환 예방 또는 치료용 약학 조성물, 구강질환 예방 또는 개선용 식품 조성물, 구강질환 예방 또는 개선용 의약외품 조성물 등에 유용하게 사용될 수 있다. Therefore, the composition for inhibiting biofilm formation of the present invention can be usefully used in an antibacterial oral composition, a pharmaceutical composition for preventing or treating oral diseases, a food composition for preventing or improving oral diseases, a quasi-drug composition for preventing or improving oral diseases, and the like.
다른 하나의 양태로서, 본 발명은 SSL25 펩타이드를 유효성분으로 포함하는 항균용 구강 조성물을 제공한다.As another aspect, the present invention provides an antibacterial oral composition comprising the SSL25 peptide as an active ingredient.
본 발명에서 용어, "SSL25 펩타이드"에 대한 설명은 전술한 바와 같으며, 서열번호 1로 표시되는 아미노산 서열을 가진다. 또한, 상기 펩타이드는 스트렙토코커스 뮤탄스에 대한 항균 효과를 가지므로, 항균용 구강 조성물에 적용이 가능하다. 상기 구강 조성물은 구강질환 예방 또는 치료용 약학 조성물, 구강질환 예방 또는 개선용 식품 조성물, 구강질환 예방 또는 개선용 의약외품 조성물 등에 유용하게 사용될 수 있다. In the present invention, the description of the term "SSL25 peptide" is as described above, and has the amino acid sequence represented by SEQ ID NO: 1. In addition, since the peptide has an antibacterial effect on Streptococcus mutans, it can be applied to an antibacterial oral composition. The oral composition may be usefully used in a pharmaceutical composition for preventing or treating oral diseases, a food composition for preventing or improving oral diseases, a quasi-drug composition for preventing or improving oral diseases, and the like.
다른 하나의 양태로서, 본 발명은 SSL25 펩타이드를 유효성분으로 포함하는 구강질환 예방 또는 치료용 약학 조성물을 제공한다.As another aspect, the present invention provides a pharmaceutical composition for preventing or treating oral diseases comprising SSL25 peptide as an active ingredient.
본 발명에서 용어, "SSL25 펩타이드"에 대한 설명은 전술한 바와 같다.In the present invention, the term "SSL25 peptide" is described as described above.
본 발명에 있어서, "구강질환"이란 구강영역에서 발생하는 여러 가지 질환을 말하며, 상기 구강 영역은 앞쪽 입술부터 뒤쪽 구협에서 인두와 연결되는 입 안의 공간을 의미한다. 상기 구강질환은 구강에 발생하는 질환이라면 그 병증에 관계없이 모두 포함하는 개념이며, 상기 구강질환의 비제한적인 예로는 치아우식증, 치태, 치석, 치주질환(치주염 또는 치은염), 치통, 시린이, 충치, 플라크, 및 구취 로 이루어진 군에서 선택될 수 있으나, 이에 제한되지 않는다.In the present invention, "oral disease" refers to various diseases occurring in the oral region, and the oral region refers to the space in the mouth connected to the pharynx from the front lip to the back oral cavity. The oral disease is a concept that includes all diseases that occur in the oral cavity regardless of their symptoms, and non-limiting examples of the oral disease include dental caries, dental plaque, calculus, periodontal disease (periodontitis or gingivitis), toothache, toothache, It may be selected from the group consisting of tooth decay, plaque, and halitosis, but is not limited thereto.
본 발명에서 용어, "치아우식증(dental cavities)"은 치아면에 서식하는 세균으로 인한 감염성 질환으로서, 치아의 경조직이 침식되어 결손하는 증세를 보인다. 구체적으로 치아의 머리 부분 표면을 덮고 있고, 치아 상아질을 보호하는 유백색의 반투명하고 단단한 물질을 치아 법랑질 또는 에나멜질이라고 하는데, 입 안에 서식하는 구강병원균에 의해 설탕, 전분 등이 분해되면서 생기는 산에 의해 치아의 법랑질이 손상되어 충치가 생기는 것을 말한다. 치아 우식증을 일으키는 주요 원인으로는 치아 표면에 생성된 세균막인 치태(dental plaque, 플라크)를 들 수 있는데, 타액이 치아에 얇고 끈적한 막을 형성하고, 그 위에 스트렙토코쿠스 뮤탄스 등의 구강 미생물이 부착해 바이오필름(biofilm)을 형성함으로써 치태(dental plaque, 플라크)가 만들어지고 이후, 더욱 두꺼워져서 치석을 형성하게 된다. In the present invention, the term "dental cavities" is an infectious disease caused by bacteria inhabiting the tooth surface, and shows symptoms of tooth hard tissue erosion and loss. Specifically, the milky-white, translucent, and hard substance that covers the surface of the head of the tooth and protects tooth dentin is called tooth enamel or enamel. Tooth decay is when the tooth enamel is damaged. The main cause of dental caries is dental plaque, a bacterial film formed on the surface of teeth. By forming a biofilm, dental plaque (plaque) is created, which then becomes thicker to form tartar.
본 발명의 일 실시예에서는, SSL25 펩타이드가 스트렙토코커스 뮤탄스에 대하여 우수한 항균 활성을 나타내어, 치아우식증, 충치, 치태, 플라크, 치석 등의 각종 구강질환 예방 또는 치료에 사용될 수 있음을 확인하였다(도 1).In one embodiment of the present invention, it was confirmed that the SSL25 peptide exhibits excellent antibacterial activity against Streptococcus mutans, and can be used for preventing or treating various oral diseases such as dental caries, tooth decay, plaque, plaque, tartar (Fig. One).
본 발명에서 용어, "치주질환(periodontal disease)"은 치아를 받치고 있는 치은과 치주인대 및 골조직에 염증이 생기는 질환으로서, 흔히 풍치라고도 하는데, 병의 정도에 따라 치은염(gingivitis)과 치주염(periodontitis)으로 나뉜다. 비교적 가볍고 회복이 빠른 형태의 치주질환으로 잇몸 즉, 연조직에만 국한된 형 태를 치은염이라고 하고, 이러한 염증이 잇몸과 잇몸뼈 주변까지 진행된 경우를 치주염이라고 한다. 치은(잇몸)과 치아 사이에는 V자 모양의 틈이 있는데, 이 홈(sulcus)의 잇몸 선 아래 부분을 구강병원균이 공격하면서 염증 자극원인 리포폴리사카라이드(Lipopolysaccharide, LPS)를 방출하고, 이로 인해 잇몸이 붓고 출혈이 일어나는 등 염증이 생성되며, 이로써 치주인대와 인접조직이 손상된다. 치주염이 진행되면 치주인대, 더 나아가 치조골까지 손상시키고 결국 치아가 손실된다. 또한, 치주질환의 다른 원인으로 치태 및 치석을 들 수 있다. In the present invention, the term "periodontal disease" is a disease in which the gingiva, periodontal ligament, and bone tissue supporting the teeth become inflamed, and is often referred to as periodontal disease. Depending on the severity of the disease, gingivitis and periodontitis divided into Gingivitis is a relatively mild form of periodontal disease with a rapid recovery, and the form limited to the gums, that is, soft tissues, is called gingivitis, and when this inflammation progresses to the gums and surrounding gum bones, it is called periodontitis. There is a V-shaped gap between the gingiva (gum) and the tooth, and oral pathogens attack the area below the gum line in this groove, releasing lipopolysaccharide (LPS), a inflammatory stimulus, resulting in Inflammation is created, such as swelling and bleeding of the gums, which damages the periodontal ligament and adjacent tissues. As periodontitis progresses, it damages the periodontal ligament and even the alveolar bone, eventually leading to tooth loss. In addition, other causes of periodontal disease include dental plaque and calculus.
본 발명에서 용어, "치통"이란 단 음식, 또는 아주 차갑거나 뜨거운 음식 등을 먹을 때 치아에 통증이 오는 것을 말하는데, 일반적으로는 치아 자체의 통증뿐만 아니라, 치아를 턱뼈에 지탱시키고 있는 치주조직의 통증도 포함된다. 보통 씹을 때 통증이 발생하며, 잇몸이 붓고 역한 냄새(구취)의 분비물이 나온다. 치통은 원인 질병에 따라 조금씩 다른 통증을 보이는데, 구체적으로 치아 우식증에 의한 통증은 초기에는 통증이 없으나 점차 진행되어 치아 속 신경까지 깊이 썩은 경우에 통증이 나타나고, 매복치가 있는 경우 치아 주변 조직의 염증으로 통증이 유발되며, 치아가 부서지거나 금이 간 경우, 찬 음식에 닿거나 강하게 깨물었을 때 치아가 갈라지면서 신경에 자극을 주어 통증이 생긴다. In the present invention, the term "toothache" refers to pain in the teeth when eating sweet food, or very cold or hot food. Pain is also included. It usually causes pain when chewing, swollen gums, and foul-smelling discharge (halitosis). Toothache shows slightly different pain depending on the cause disease. Specifically, the pain caused by dental caries is initially painless, but gradually progresses and causes pain when the nerves in the tooth are deeply rotted. Pain is caused, and when a tooth is broken or cracked, when it touches cold food or bites hard, the tooth splits and stimulates the nerve, causing pain.
본 발명의 일실시예에서는, SSL25 펩타이드가 LPS에 유도된 NO 생성을 억제하여 항염증 효과를 가지는 것을 확인하여, 치은염이나 치주염 등의 치주질환에 적용이 가능하다는 것을 확인하였다(도 3). 따라서 본 발명의 SSL25 펩타이드는 이러한 염증 뿐만 아니라 치아우식증, 치태, 치석, 충치 등에 의해 발생하는 구강 통증인 치통에도 적용이 가능하다.In one embodiment of the present invention, it was confirmed that the SSL25 peptide inhibits LPS-induced NO production and has an anti-inflammatory effect, confirming that it can be applied to periodontal diseases such as gingivitis and periodontitis (FIG. 3). Therefore, the SSL25 peptide of the present invention can be applied not only to such inflammation, but also to toothache, which is oral pain caused by dental caries, plaque, calculus, tooth decay, and the like.
본 발명에서 용어, "시린이"란 상아질과민증 치아(hypersensitive dentine)를 말하며, 시린이 증상이란 상아질 지각과민증(dentine hyperesthesia)을 말한다. 시린이 증상은 노출된 치아의 상아질 부분이 찬 공기나 자극적인 음식물 등에 접촉되었을 때 민감하게 느껴지는 것으로써, 치주질환을 가진 성인의 60~98 %에서 증상을 보이고 있다. 시린이 증상은 잘못된 양치 습관이나 과도한 교합력, 산에 의한 용해에 의해 잇몸쪽에 이가 패이는 경우, 구강 위생 상태가 불량한 경우, 치주 치료 후, 수복 치료를 받은 후, 산성화에 의한 치아가 용해된 경우에 나타날 수 있다. 시린이는 치아의 상아질에 존재하는 많은 세관이 외부로 노출되면서 나타나는데, 노출에 의해 모든 자극을 그대로 치수내 신경으로 전달하여 똑같은 자극에 대해서도 평소보다 민감하게 반응하게 되며 통증을 유발할 수 있다. 시린이 증상은 가벼운 증상에서 격렬하고 지속적인 통증까지 다양하게 나타날 수 있으며, 치아의 특성상 재생이 되지 않기 때문에 진통제나 소염제 등의 복용은 시린 현상의 근본적인 해결책이 되지 못한다. In the present invention, the term "cold tooth" refers to hypersensitive dentine, and the symptom of cold tooth refers to dentine hyperesthesia. Cold tooth symptoms are sensitive when the dentin part of the exposed tooth comes into contact with cold air or irritating food, and 60 to 98% of adults with periodontal disease show symptoms. Cold tooth symptoms are caused by bad brushing habits, excessive bite force, tooth decay on the gum side due to dissolution by acid, poor oral hygiene, periodontal treatment, restorative treatment, and tooth dissolution due to acidification. can appear Cold teeth appear when many tubules present in the dentin of the tooth are exposed to the outside, and through exposure, all stimuli are transmitted as they are to the nerves in the pulp, making them more sensitive than usual to the same stimuli and causing pain. Symptoms of cold teeth can vary from mild symptoms to intense and continuous pain, and because teeth do not regenerate, taking painkillers or anti-inflammatory drugs is not a fundamental solution to the pain phenomenon.
본 발명에서 용어, "구취"란 구강 및 인접기관으로부터 유래되는 냄새로 구취의 85~90%가 구강에서 유래하며, 특히, 혀의 뒷쪽에서 유래하고 있다. 구취의 주요 성분은 휘발성 황화합물인데, 휘발성 황화합물의 전체량 중 90%가 시스테인으로부터 만들어지는 황화수소(hydrogen sulfide)와 메티오닌으로부터 만들어지는 메틸머캡탄 (methyl mercaptan) 및 디메틸설파이드(dimethyl sulfide)이다. 이러한 성분들은 주로 혐기성 세균이 분비하는 단백질 효소에 의해서 생성되며, 혀의 뒷쪽이 가장 중요한 서식지가 된다. 이 부위는 타액에 의해 세정작용이 잘 되지 않고, 많은 작은 함몰이 있어 세균이 지속적으로 살아가는 장소가 된다. 혐기성 세균에 의한 휘발성 황 화합물 생성이 구취의 원인으로 가장 중요하지만, 그 외 치아우식증, 치주염 등과 같은 구강질환에 의해서도 발생한다. In the present invention, the term "halitosis" is a smell derived from the oral cavity and adjacent organs, and 85 to 90% of bad breath originates from the oral cavity, particularly from the back of the tongue. The main component of bad breath is volatile sulfur compounds, 90% of which are hydrogen sulfide made from cysteine and methyl mercaptan and dimethyl sulfide made from methionine. These components are mainly produced by protein enzymes secreted by anaerobic bacteria, and the back of the tongue becomes the most important habitat. This area is not well cleaned by saliva and has many small depressions, making it a place where bacteria live continuously. The production of volatile sulfur compounds by anaerobic bacteria is the most important cause of bad breath, but it is also caused by other oral diseases such as dental caries and periodontitis.
본 발명에서 용어 "예방"이란 본 발명의 상기 SSL25 펩타이드를 포함하는 조성물의 투여로 구강질환의 발병을 억제 또는 지연시키는 모든 행위를 말한다. 본 발명에서 용어 "치료"는 본 발명의 SSL25 펩타이드를 포함하는 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경하는 모든 행위를 말한다.In the present invention, the term "prevention" refers to all activities that suppress or delay the onset of oral diseases by administering a composition containing the SSL25 peptide of the present invention. In the present invention, the term "treatment" refers to all activities that improve or beneficially change the symptoms of the disease by administering a composition containing the SSL25 peptide of the present invention.
본 발명의 약학 조성물은 구강질환을 예방하고 치료하기 위한 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있고, 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. The pharmaceutical composition of the present invention is in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods for preventing and treating oral diseases. It can be formulated and used, and may further include appropriate carriers, excipients and diluents commonly used in the preparation of compositions.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제 및 캡슐제 등이 포함되며, 이러한 고형 제제는 본 발명의 유효성분에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토오스 및 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 윤활제들도 사용될 수 있다. Solid preparations for oral administration include tablets, pills, powders, granules and capsules, etc., and these solid preparations contain at least one or more excipients such as starch, calcium carbonate, sucrose, lactose and It is prepared by mixing gelatin, etc. In addition to simple excipients, lubricants may also be used.
경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등을 들 수 있는데, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 및 보존제 등이 포함될 수 있다. Liquid formulations for oral administration include suspensions, internal solutions, emulsions and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics and preservatives are used. can be included
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
본 발명의 약학 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여할 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용을 유발하지 않으면서 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And it can be single or multiple administrations. It is important to administer the amount that can obtain the maximum effect with the minimum amount without causing side effects in consideration of all of the above factors, and can be easily determined by those skilled in the art.
본 발명에서 사용된 용어, "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 약학 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.As used herein, the term "administration" refers to introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the administration route of the composition of the present invention can be oral or parenteral as long as it can reach the target tissue. It can be administered via any route.
본 발명의 약학 조성물은 1일 투여량은 통상 0.001 ~ 150 mg/kg 체중 범위이고, 1회 또는 수회로 나누어 투여 할 수 있다. 그러나, 본 발명의 약학 조성물의 실제 투여량은 투여 경로, 환자의 연령, 성별, 체중, 및 환자의 중증도 등의 여러 관련 인자에 비추어 결정되어지는 것이므로 상기 투여량은 어떠한 측면으로든 본 발명의 범위를 제한하는 것으로 이해해서는 안된다.The daily dose of the pharmaceutical composition of the present invention is usually in the range of 0.001 to 150 mg/kg body weight, and may be administered once or divided into several times. However, since the actual dosage of the pharmaceutical composition of the present invention is determined in light of various related factors such as the route of administration, age, sex, weight, and severity of the patient, the dosage does not fall within the scope of the present invention in any aspect. It should not be understood as limiting.
본 발명의 약학 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로를 통해 투여될 수 있다. 투여의 모든 방식은 경구, 정맥, 근육 또는 피하 주사에 의해 투여될 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans through various routes. All modes of administration may be administered by oral, intravenous, intramuscular or subcutaneous injection, but are not limited thereto.
다른 하나의 양태로서, 본 발명은 SSL25 펩타이드를 유효성분으로 포함하는 구강질환 예방 또는 개선용 식품 조성물을 제공한다.As another aspect, the present invention provides a food composition for preventing or improving oral diseases comprising SSL25 peptide as an active ingredient.
본 발명에서 용어, "SSL25 펩타이드", "구강질환", "예방"에 대한 설명은 전술한 바와 같다.In the present invention, the terms "SSL25 peptide", "oral disease", and "prevention" are explained as described above.
본 발명에서 용어 "개선"은 상기 본 발명의 상기 SSL25 펩타이드를 포함하는 조성물을 이용하여 구강질환 의심 또는 발병 개체의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다.In the present invention, the term "improvement" refers to all activities that improve or benefit the symptoms of an individual suspected of or having an oral disease by using the composition containing the SSL25 peptide of the present invention.
본 발명의 구강질환의 예방 또는 개선용 식품 조성물은 환제, 분말, 과립, 침제, 정제, 캡슐 또는 액제 등의 형태를 포함하며, 본 발명의 조성물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 건강보조식품 등이 있다. The food composition for preventing or improving oral diseases of the present invention includes pills, powders, granules, precipitates, tablets, capsules or liquids, and the food to which the composition of the present invention can be added includes, for example, There are various types of food, for example, beverages, chewing gum, tea, vitamin complexes, health supplements, and the like.
본 발명의 구강질환의 예방 또는 개선용 식품 조성물에서 포함할 수 있는 필수 성분으로 유효성분인 SSL25 펩타이드 외에 다른 성분에는 특별히 제한이 없으며 통상의 식품과 같이 여러가지 생약 추출물, 식품 보조첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. As an essential ingredient that can be included in the food composition for preventing or improving oral diseases of the present invention, there are no particular restrictions on other ingredients other than the active ingredient, SSL25 peptide, and various herbal extracts, food additives, or natural carbohydrates are used as in conventional foods. It may be included as an additional ingredient.
상기 식품보조첨가제는 당업계에 통상적인 식품 보조첨가제, 예를 들어 향미제, 풍미제, 착색제, 충진제, 안정화제 등을 포함한다. The food auxiliary additives include common food auxiliary additives in the art, for example, flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like.
상기 천연 탄수화물의 예는 포도당, 과당 등의 단당류; 말토스, 수크로스 등의 이당류; 및 덱스트린, 시클로덱스트린 등의 다당류와, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이 있으며, 상기한 것 이외의 향미제로서 천연 향미제(타우마틴 등), 스테비아 추출물(레바우디오시드 Ａ, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.Examples of the natural carbohydrate include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (thaumatin, etc.), stevia extract (rebaudioside A, glycir hijin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
상기 건강보조식품은 건강기능식품 및 건강식품 등을 포함한다. The health supplements include health functional foods and health foods.
상기 건강기능(성)식품(functional food)이란, 특정보건용 식품(food for special health use, FOSHU)와 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 "기능(성)"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 식품은 당업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한없이 제조될 수 있다. 본 발명의 식품 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 식품은 구강질환의 예방 또는 개선의 효과를 증진시키기 위한 보조제로 섭취가 가능하다. The health functional food (functional food) is the same term as food for special health use (FOSHU), and is a medicine processed to efficiently display bioregulatory functions in addition to nutrient supply, and has high medical effect. means food. Here, "function (sex)" means to obtain useful effects for health purposes such as regulating nutrients for the structure and function of the human body or physiological functions. The food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and ingredients commonly added in the art during the preparation. In addition, the formulation of the food may also be prepared without limitation as long as the formulation is recognized as a food. The food composition of the present invention can be prepared in various types of formulations, and unlike general drugs, it has the advantage of not having side effects that may occur when taking drugs for a long time using food as a raw material, and has excellent portability, so that the composition of the present invention The food can be consumed as an adjuvant to enhance the effect of preventing or improving oral diseases.
다른 하나의 양태로서, 본 발명은 SSL25 펩타이드를 유효성분으로 포함하는 구강질환 예방 또는 개선용 의약외품 조성물을 제공한다.In another aspect, the present invention provides a quasi-drug composition for preventing or improving oral diseases comprising SSL25 peptide as an active ingredient.
본 발명에서 용어, "SSL25 펩타이드", "구강질환", "예방", "개선"에 대한 설명은 전술한 바와 같다.In the present invention, the terms "SSL25 peptide", "oral disease", "prevention", and "improvement" are explained as described above.
본 발명의 의약외품 조성물은 구강용 의약외품을 포함할 수 있다. 본 발명의 의약외품 조성물에 포함되는 성분은 유효성분으로서 상기 유효성분 이외에 구강용 의약외품 조성물에 통상적으로 이용되는 성분들을 포함할 수 있으며, 예컨대 연마제, 습윤제, 결합제, 기포제, 감미제, 방부제, 약효성분, 향미제, 색소, 용제, 증백제, 가용화제 또는 pH 조정제를 포함할 수 있다.The quasi-drug composition of the present invention may include a quasi-drug for oral use. Ingredients included in the quasi-drug composition of the present invention may include ingredients commonly used in oral quasi-drug compositions in addition to the above active ingredients as active ingredients, such as abrasives, wetting agents, binders, foaming agents, sweeteners, preservatives, medicinal ingredients, flavors agents, pigments, solvents, brighteners, solubilizers or pH adjusters.
본 발명의 구강용 의약외품 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 치약, 구강세정제, 구강청정제, 껌, 캔디류, 구강스프레이, 구강용 연고제, 구강용 바니쉬, 구강양치액 및 잇몸 마사지 크림 등의 제형을 가질 수 있으나 이에 제한되는 것은 아니다.The quasi-drug composition for oral use of the present invention can be prepared in any formulation commonly prepared in the art, for example, toothpaste, mouthwash, mouthwash, gum, candy, oral spray, oral ointment, and oral varnish. , oral rinse and gum massage cream, but may have formulations such as, but are not limited thereto.
하나의 예로서, 본 발명의 구강용 의약외품 조성물이 치약의 제형일 경우, 습윤제, 연마제, 결합제, 기포제, 향미제, 감미제, 착색제, 보존제, 약효성분, 용제, pH 조절제 등을 포함할 수 있다.As an example, when the oral quasi-drug composition of the present invention is a toothpaste formulation, it may contain a wetting agent, an abrasive, a binder, a foaming agent, a flavoring agent, a sweetening agent, a coloring agent, a preservative, a medicinal component, a solvent, a pH adjusting agent, and the like.
상기 습윤제는 치약제 성분 중 분말이 페이스트상이 되게 하고 치약제가 공기 중에 굳는 것을 방지하기 위한 것으로 글리세린, 솔비트액, 프로필렌글리콜, 폴리에틸렌 글리콜 등을 단독 또는 2종 이상 혼합하여 조성물 총 중량 중 1~60 중량%, 구체적으로는 10~50 중량%를 사용할 수 있다.The humectant is to make the powder of toothpaste ingredients paste and to prevent the toothpaste from hardening in the air, and glycerin, sorbitol solution, propylene glycol, polyethylene glycol, etc. alone or in combination of two or more, 1 to 60 weight of the total weight of the composition %, specifically, 10 to 50% by weight may be used.
상기 기포제는 치약제를 구강 중에 확산시켜 청소효과를 높이고, 계면활성제로서 작용하여 구강 오염을 세정하는 것으로 라우릴황산나트륨, 라우릴 사르코신산 나트륨, 알킬 설포호박산 나트륨, 자당 지방산 에스테르 등의 계면활성제를 단독 혹은 2종 이상 혼합하여 조성물 총 중량 중 0.5~10 중량%, 구체적으로는 0.5~5 중량%를 사용할 수 있다.The foaming agent diffuses the toothpaste into the oral cavity to increase the cleaning effect and acts as a surfactant to clean oral contamination. Alternatively, 0.5 to 10% by weight, specifically 0.5 to 5% by weight of the total weight of the composition may be used by mixing two or more kinds.
상기 결합제는 치약제중의 분말과 액체 성분 간의 분리를 방지하는 것으로 카복시메틸셀룰로오스나트륨, 메틸셀 룰로오스, 하이드록시 프로필셀룰로오스 등의 셀룰로오스 유도체와 알긴산나트륨, 카라기난, 잔탄검 등을 단독 혹은 2종 이상 혼합하여 조성물 총 중량 중 0.1~5 중량%, 구체적으로는 0.3~2 중량%를 사용할 수 있다.The binder prevents separation between powder and liquid components in toothpaste, and is composed of cellulose derivatives such as sodium carboxymethyl cellulose, methyl cellulose, and hydroxypropyl cellulose, sodium alginate, carrageenan, and xanthan gum alone or in combination of two or more. By mixing, 0.1 to 5% by weight, specifically 0.3 to 2% by weight of the total weight of the composition may be used.
상기 연마제는 치아표면을 상처내지 않고 치아표면의 부착물을 제거하고 치아 본래의 광택이 나도록 하는 것으로 탄산칼슘(CaCO3), 제2인산칼슘(CaHPO4, CaHPO42H2O), 무수규산(SiO22H2O), 수산화알루미늄(Al(OH)3), 피로인산칼륨, 탄산마그네슘 등을 단독 혹은 2종 이상 혼합하여 조성물 총 중량 중 1~60 중량%, 구체적으로는 10~50 중량%를 사용할 수 있다.The abrasive is calcium carbonate (CaCO3), calcium phosphate dibasic (CaHPO4, CaHPO42H2O), silicic anhydride (SiO22H2O), aluminum hydroxide (Al (OH) 3), potassium pyrophosphate, magnesium carbonate, etc. alone or in combination of two or more may be used in an amount of 1 to 60% by weight, specifically 10 to 50% by weight, based on the total weight of the composition.
상기 향미제는 치약에 상쾌감과 냄새를 부여하여 사용감을 증진시키기 위한 것으로 페퍼민트오일, 스피아민트오일, 멘톨 등을 단독 혹은 2종 이상 혼합하여 조성물 총 중량 중 0.01~60 중량%, 구체적으로는 0.01~5 중량% 를 사용할 수 있다.The flavoring agent is to enhance the feeling of use by imparting a refreshing feeling and smell to toothpaste, and peppermint oil, spearmint oil, menthol, etc. alone or in combination of two or more are used in an amount of 0.01 to 60% by weight, specifically 0.01 to 60% by weight of the total weight of the composition. 5% by weight can be used.
상기 감미제는 치약제 원료에 의한 불쾌한 맛이나 제거하고 청량감을 좋게 하기 위한 것으로 사카린산, 아스파탐, 자일리톨, 감초산 등을 단독 혹은 2종 이상 혼합하여 조성물 총 중량 중 0.01~60 중량%, 구체적으로는 0.01~5 중량%를 사용할 수 있다.The sweetener is to remove the unpleasant taste caused by raw materials for toothpaste and improve the refreshing feeling, and 0.01 to 60% by weight of the total weight of the composition by mixing saccharic acid, aspartame, xylitol, licorice acid, etc. alone or in combination of two or more, specifically 0.01 to 5% by weight can be used.
상기 SSL25 펩타이이드는 치아우식증, 치태, 치석, 치주질환, 치통, 시린이, 플라크, 충치, 또는 구취의 예방 또는 개선 등의 효과를 위한 것으로, 불화물, 염화아연, 클로르헥시딘, 아미노카프론산, 트라넥사민산, 염화세틸피리디움, 염화피리독신, 트리클로산, 초산토코페롤, 일불소인산나트륨 등을 단독 혹은 2종 이상 혼합하여 사용할 수 있다. The SSL25 peptide is for the prevention or improvement of dental caries, dental plaque, calculus, periodontal disease, toothache, toothache, plaque, tooth decay, or bad breath, and contains fluoride, zinc chloride, chlorhexidine, aminocaproic acid, Nexamic acid, cetylpyridium chloride, pyridoxine chloride, triclosan, tocopherol acetate, sodium monofluorophosphate, etc. may be used alone or in combination of two or more.
본 발명의 구강용 의약외품 조성물은 다른 구강용 의약외품 조성물과 중복하여 사용할 수 있다.The oral quasi-drug composition of the present invention can be used in combination with other oral quasi-drug compositions.
본 발명의 SSL25 펩타이드는 스트렙토코커스 뮤탄스에 의해 형성된 바이오필름 형성을 억제하며, 항균 효과를 가진다. The SSL25 peptide of the present invention inhibits the formation of a biofilm formed by Streptococcus mutans and has an antibacterial effect.
따라서, 본 발명의 SSL25 펩타이드를 포함하는 조성물은 치아우식증, 치태, 치석, 치주질환, 치통, 시린이, 플라크, 충치, 및 구취로 이루어진 군에서 선택되는 구강질환의 예방 또는 치료에 적용이 가능하므로, 약학 조성물, 식품 조성물, 의약외품 조성물에 적용이 가능하다. Therefore, the composition containing the SSL25 peptide of the present invention can be applied to the prevention or treatment of oral diseases selected from the group consisting of dental caries, dental plaque, calculus, periodontal disease, toothache, toothache, plaque, tooth decay, and halitosis. , It can be applied to pharmaceutical compositions, food compositions, and quasi-drug compositions.
도 1은 S. mutans에 대한 SSL25 펩타이드의 항균 효과를 측정한 것이다.
도 2는 S. mutans에 대한 SSL25 펩타이드의 바이오필름 억제 효과를 측정한 것이다.
도 3은, SSL25 펩타이드의 LPS에 유도된 NO 생성 억제 효과를 나타낸 것이다.1 is a measurement of the antibacterial effect of the SSL25 peptide against S. mutans .
Figure 2 is a measurement of the biofilm inhibitory effect of the SSL25 peptide on S. mutans .
3 shows the LPS-induced NO production inhibitory effect of the SSL25 peptide.
이하, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 본 발명의 실시예에 대하여 첨부한 도면을 참고로 하여 상세히 설명한다. 그러나 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되지 않는다. Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention. However, the present invention may be embodied in many different forms and is not limited to the embodiments described herein.
실시예 1. 구강질환 원인균에 대한 항균 효과 측정Example 1. Measurement of antibacterial effect on oral disease causative bacteria
구강질환의 예방 또는 치료 효과를 확인하기 위하여 항균 활성 실험을 수행하였다. 구강질환을 유발하는 대표 원인균인 스트렙토코커스 뮤탄스(Streptococcus mutans)(ATCC 25175)는 Brain heart infusion (BHI) 액체배지에서 37℃의 항온기에서 24시간 배양하여 사용하였다. 1%의 glucose가 들어 있는 BHI 액체배지에 SSL25 펩타이드를 첨가한 후 S. mutans 균을 1Х108 CFU/ml이 되게 접종하였다. 37℃에서 24시간 배양한 후 550 nm에서 흡광도를 측정한 후 항균력을 측정하였다.In order to confirm the effect of preventing or treating oral diseases, an antibacterial activity test was performed. Streptococcus mutans ( Streptococcus mutans ) (ATCC 25175), which is a representative causative agent of oral disease, was cultured in Brain heart infusion (BHI) broth for 24 hours in a thermostat at 37° C. and used. After adding the SSL25 peptide to BHI liquid medium containing 1% glucose, S. mutans was inoculated to a concentration of 1Х10 8 CFU/ml. After incubation at 37 ° C. for 24 hours, absorbance was measured at 550 nm, and then antibacterial activity was measured.
도 1은 S. mutans에 대한 SSL25 펩타이드의 항균 효과를 측정한 것이다. 그 결과, 0.05mM의 SSL25 펩타이드 농도에서 S, mutans의 생장을 47.7% 억제하는 것을 확인하였으며, 펩타이드의 농도가 증가할수록 항균 효과도 증가하는 것을 확인하였다.1 is a measurement of the antibacterial effect of the SSL25 peptide against S. mutans . As a result, it was confirmed that the growth of S. mutans was inhibited by 47.7% at a concentration of 0.05 mM SSL25 peptide, and the antibacterial effect increased as the concentration of the peptide increased.
실시예 2. 바이오필름 억제 효과 측정Example 2. Measurement of biofilm inhibitory effect
유리판인 커버글라스(cover glass)를 사용하여 S. mutans의 바이오필름 부착억제 실험을 실시하였다. 커버글라스를 넣은 시험관에 S. mutans을 배양하였으며 SSL25 펩타이드와 함께 1%의 농도가 되도록 수크로스(sucrose)를 BHI배지에 첨가하여 밤새 배양하였다. 이후 커버글라스 표면의 플라크를 크리스탈 블루(crystal blue)로 염색한후 메탄올로 추출하여 분광광도기로 590nm에서 흡광도를 측정하여 상대적 바이오필름 형성양을 측정하였다. A biofilm adhesion inhibition test of S. mutans was conducted using a cover glass, which is a glass plate. S. mutans was cultured in a test tube with a cover glass, and sucrose was added to the BHI medium to a concentration of 1% together with the SSL25 peptide and cultured overnight. Thereafter, the plaque on the surface of the cover glass was stained with crystal blue, extracted with methanol, and the absorbance was measured at 590 nm using a spectrophotometer to measure the relative amount of biofilm formation.
도 2는 S. mutans에 대한 SSL25 펩타이드의 바이오필름 억제 효과를 측정한 것이다. 그 결과, 0.1mM의 SSL25 펩타이드의 농도에서 S. mutans 바이오필름 형성을 42.7% 억제하는 것을 확인하였다.Figure 2 is a measurement of the biofilm inhibitory effect of the SSL25 peptide on S. mutans . As a result, it was confirmed that S. mutans biofilm formation was inhibited by 42.7% at a concentration of 0.1 mM SSL25 peptide.
따라서, SSL25 펩타이드를 이용하여 바이오필름 형성을 억제하는 용도로 사용할 수 있음을 알 수 있었다. Therefore, it was found that the SSL25 peptide can be used to inhibit biofilm formation.
실시예 3. glucosyltransferase 저해를 통한 비수용성 글루칸 억제 효과 측정Example 3. Measurement of water-insoluble glucan inhibitory effect through glucosyltransferase inhibition
구강내 탄수화물이 섭취되면 Streptococcus mutans가 수크로스를 단당류인 포도당(glucose)와 과당(fructose)로 가수분해하고 포도당은 S. mutans가 분비하는 글루코실트랜스퍼라제(glucosyltransferse, GTFase)에 의해 점성을 가진 불용성 글루칸인 덱스트란(dextran)이 된다. 그리고, 덱스트란이 구강 세균과 침착되어 구강 바이오필름인 치면 세균막(치태, dental plaque)을 형성하고 치면 세균막에 칼슘이 침착되어 단단해지면 치석(dental calculus)이 되며 치석은 치아 표면에 세균을 고정하는 매트릭스 역할을 한다. When oral carbohydrates are ingested, Streptococcus mutans hydrolyzes sucrose into monosaccharides, glucose and fructose, and glucose is converted into viscous and insoluble form by glucosyltransferase (GTFase) secreted by S. mutans . It becomes dextran, which is a glucan. In addition, dextran is deposited with oral bacteria to form dental plaque, which is an oral biofilm, and when calcium is deposited on the dental plaque and becomes hard, it becomes dental calculus, which fixes bacteria on the tooth surface serves as a matrix.
이에, 본 발명에서는 SSL25 펩타이드의 glucosyltransferase 저해를 통한 비수용성 글루칸 억제 효과를 측정하고자 하였다. 먼저, S. mutans를 BHI 액체배지 2 L에 배양한 후, 80% ammonium sulfate를 넣은 후 밤새 방치하였고 원심분리하여 GTFase 단백질을 회수하였다. 회수된 GTFase 단백질에 100 mM Sodium phosphate buffer (pH 6.0)을 넣고 4℃에서 24시간 동안 투석시킨 후 효소원으로 사용하였다. Accordingly, in the present invention, the effect of inhibiting water-insoluble glucan through the inhibition of glucosyltransferase by the SSL25 peptide was intended to be measured. First, after culturing S. mutans in 2 L of BHI broth, 80% ammonium sulfate was added, left overnight, and centrifuged to recover GTFase protein. 100 mM sodium phosphate buffer (pH 6.0) was added to the recovered GTFase protein, dialyzed at 4° C. for 24 hours, and then used as an enzyme source.
GTFase에 의한 비수용성 글루칸 합성 억제 효능을 측정하기 위하여 0.04% sodium azide를 첨가한 0.4 M phosphate buffer (pH 6.0) 0.25ml에 0.4M sucrose 0.25 ml를 첨가하였고, 이후 0.25 ml의 농도별 SSL25 펩타이드와 GTFase을 넣어 최종 1 ml이 되게 하였다. 37℃에서 3 시간 동안 반응한 후 메탄올을 첨가하여 반응을 정지시키고 원심분리로 불용성 글루칸 침전을 얻었다. 증류수와 70 % 에탄올로 순차적 세척 후 증류수 200 ㎕와 안트론 발색시약 (anthrone 200 ㎎/H2SO4 100 ㎖) 800 ㎕를 첨가하고 끓는 물에서 10 분 동안 가열하여 발색시킨 후 냉각하여 분광 광도계로 550 nm에서 흡광도를 측정하였다.To measure the inhibitory effect of water-insoluble glucan synthesis by GTFase, 0.25 ml of 0.4 M sucrose was added to 0.25 ml of 0.4 M phosphate buffer (pH 6.0) containing 0.04% sodium azide, and then 0.25 ml of SSL25 peptide and GTFase was added to make the final 1 ml. After reacting at 37° C. for 3 hours, methanol was added to stop the reaction, and insoluble glucan precipitates were obtained by centrifugation. After sequential washing with distilled water and 70% ethanol, 200 μl of distilled water and 800 μl of anthrone coloring reagent (anthrone 200 mg/
표 1은 펩타이드의 glucosyltransferase 저해를 통한 비수용성 글루칸 억제 효과를 나타낸 것이다. SSL25 펩타이드 0.1mM 농도에서 S. mutans가 분비하는 glucosyltransferse 작용에 의한 불용성 글루칸 생성을 약 38% 억제하였고 0.5mM에서는 약 67.6%억제하는 것을 확인하였다. 또한 SSL25 펩타이드의 농도가 증가할수록 불용성 글루칸 억제 효과도 증가하는 것을 확인하였다. Table 1 shows the inhibitory effect of water-insoluble glucan through inhibition of glucosyltransferase of peptides. It was confirmed that the production of insoluble glucan by the glucosyltransferase secreted by S. mutans was inhibited by about 38% at a concentration of 0.1 mM SSL25 peptide, and by about 67.6% at 0.5 mM. In addition, it was confirmed that the insoluble glucan inhibitory effect increased as the concentration of the SSL25 peptide increased.
따라서, SSL25 펩타이드가 바이오필름 형성에 관여하는 불용성 글루칸을 억제하므로, 치태, 치석 등의 구강질환 치료에 적용이 가능한 것을 알 수 있었다. Therefore, it was found that since the SSL25 peptide inhibits insoluble glucan involved in biofilm formation, it can be applied to the treatment of oral diseases such as plaque and calculus.
실시예 4. 산 생성 억제 효능 측정Example 4. Acid production inhibition efficacy measurement
1%의 glucose가 들어 있는 BHI 액체배지에 SSL25 펩타이드를 첨가한 후 S. mutans 균을 1Х108 CFU/ml이 되게 접종하였다. 37℃에서 24시간 배양한 후 산 생성 억제 효과를 pH meter로 pH를 측정하여 평가하였다. After adding the SSL25 peptide to BHI liquid medium containing 1% glucose, S. mutans was inoculated to a concentration of 1Х10 8 CFU/ml. After culturing at 37 ° C. for 24 hours, the acid production inhibitory effect was evaluated by measuring the pH with a pH meter.
표 2는 SSL25 펩타이드 첨가에 따른 S. mutans에 의한 유기산 생성 억제 효과를 나타낸 것이다. S. mutans와 SSL25 펩타이드를 넣고 24시간 배양 후에 pH meter로 pH를 측정한 결과 펩타이드를 넣지 않은 대조군에서 pH는 5.29±0.07을 나타내었고, SSL25 펩타이드 0.3 mM 농도에서 5.66±0.05, 0.5 mM에서 5.81±0.08로 pH가 증가하는 것을 확인하여, 대조군에 비하여 산생성이 억제되는 경향을 확인하였다. Table 2 shows the effect of inhibiting organic acid production by S. mutans according to the addition of SSL25 peptide. After adding S. mutans and SSL25 peptide and incubating for 24 hours, the pH was measured with a pH meter. As a result, pH was 5.29±0.07 in the control group without peptide, 5.66±0.05 at 0.3 mM SSL25 peptide, and 5.81± at 0.5 mM SSL25 peptide. By confirming that the pH increased to 0.08, it was confirmed that acid production tended to be suppressed compared to the control group.
따라서, SSL25 펩타이드가 산 생성 억제를 통하여, 치아의 외막인 법랑질(enamel) 용해와 치아의 탈회를 억제하고, 치아우식증 등 충치 생성을 억제할 수 있다는 것을 알 수 있었다.Therefore, it was found that the SSL25 peptide can suppress the dissolution of enamel, which is the outer membrane of teeth, the demineralization of teeth, and the formation of caries, such as dental caries, through inhibition of acid production.
실시예 5. 항염증 효능 측정Example 5. Measurement of anti-inflammatory efficacy
Nitric oxide (NO) 저해능 측정을 위하여 RAW 264.7 세포에서 생성되는 NO의 양은 Griess 시약을 사용하여 측정하였다. 세포를 1Х105 cells/ml가 되게 하여 24시간 동안 배양한 후 SSL25 펩타이드 시료를 농도별로 처리하여 4시간 후 lipopolysaccharide (LPS)을 대조군을 제외한 모든 well에 넣어서 4시간 동안 자극시켰다. 세포를 제외한 상층액을 Griess 시약으로 10분간 반응시킨 후 NO의 생성량은 540 nm에서 흡광도를 측정하여 확인하였다.To measure nitric oxide (NO) inhibition, the amount of NO produced in RAW 264.7 cells was measured using Griess reagent. After incubating the cells to 1Х10 5 cells/ml for 24 hours, SSL25 peptide samples were treated by concentration, and after 4 hours, lipopolysaccharide (LPS) was added to all wells except for the control group and stimulated for 4 hours. After reacting the supernatant excluding cells with Griess reagent for 10 minutes, the amount of NO produced was confirmed by measuring absorbance at 540 nm.
상기 NO는 빠르게 안정한 이산화질소, 아질산염, 질산염으로 변한다. 그리스 시약(Griess reagent)은 아질산염과 반응하여 아조염을 형성하는데 이는 NO의 농도와 일치한다. 따라서 NO의 농도는 아질산염의 표준커브로부터 계산할 수 있다. Raw 264.7 세포에 LPS를 처리하여 염증반응을 유도한 후 펩타이드를 처리하고 세포 상층액을 취해 NO생성양을 측정하였다. The NO rapidly changes to stable nitrogen dioxide, nitrite, and nitrate. Griess reagent reacts with nitrite to form azo salt, which corresponds to the concentration of NO. Therefore, the concentration of NO can be calculated from the nitrite standard curve. Raw 264.7 cells were treated with LPS to induce an inflammatory response, and then treated with peptides, and the amount of NO production was measured by taking the cell supernatant.
도 3은, SSL25 펩타이드의 LPS에 유도된 NO 생성 억제 효과를 나타낸 것이다. 그 결과, SSL25 펩타이드는 LPS에 의해 유도된 염증지표인 NO를 전 농도에서 억제하였다. LPS에 의해 생성된 NO 농도는 18.8 μM이었으나 0.5 mM의 SSL25 펩타이드 농도에서 7.6 μM 로 현저히 감소되었다. 3 shows the LPS-induced NO production inhibitory effect of the SSL25 peptide. As a result, the SSL25 peptide suppressed NO, an inflammatory marker induced by LPS, at all concentrations. The concentration of NO produced by LPS was 18.8 μM, but was significantly reduced to 7.6 μM at 0.5 mM SSL25 peptide concentration.
따라서, SSL25 펩타이드가 LPS에 유도된 NO 생성을 억제하여 항염증 효과를 가지는 것을 확인하였는 바, 치은염이나 치주염 등의 치주질환에 적용이 가능하다는 것을 알 수 있었다. Therefore, it was confirmed that the SSL25 peptide inhibits LPS-induced NO production and has an anti-inflammatory effect, and it was found that it can be applied to periodontal diseases such as gingivitis and periodontitis.
이상에서 본 발명의 바람직한 실시예에 대하여 상세하게 설명하였지만 본 발명의 권리범위는 이에 한정되는 것은 아니고 다음의 청구범위에서 정의하고 있는 본 발명의 기본 개념을 이용한 당업자의 여러 변형 및 개량 형태 또한 본 발명의 권리범위에 속하는 것이다.Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements of those skilled in the art using the basic concept of the present invention defined in the following claims are also made according to the present invention. falls within the scope of the rights of
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