WO2009151288A2 - Oligopeptide pour améliorer l'ostéointégration et l'oestégenèse - Google Patents

Oligopeptide pour améliorer l'ostéointégration et l'oestégenèse Download PDF

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WO2009151288A2
WO2009151288A2 PCT/KR2009/003141 KR2009003141W WO2009151288A2 WO 2009151288 A2 WO2009151288 A2 WO 2009151288A2 KR 2009003141 W KR2009003141 W KR 2009003141W WO 2009151288 A2 WO2009151288 A2 WO 2009151288A2
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oligopeptide
bone
implant
oligopeptides
seq
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PCT/KR2009/003141
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Korean (ko)
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WO2009151288A3 (fr
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강은정
엄태관
김재호
이정근
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오스템임플란트 주식회사
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Priority to CN200980000223A priority Critical patent/CN101743014A/zh
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Publication of WO2009151288A3 publication Critical patent/WO2009151288A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present invention relates to oligopeptides that promote osteoadhesion and bone formation.
  • the present invention relates to an oligopeptide used for the purpose of promoting bone adhesion and bone formation in a general implant, the present description will be described with respect to the oligopeptide applied to a dental implant.
  • the shape of the dental implant is as shown in Figure 1, the name is a fixture (referred to as an implant or a fixture) to act as an artificial root in the missing tooth area, abutment (connecting the fixture and the crown (crown), And artificial teeth (crown).
  • the implant is largely composed of a connection to the abutment and an implant surface in direct contact with the alveolar bone. In dental implants, the surface is very important as it determines the duration of bone adhesion and future function.
  • Dental implants are parts that carry the same sense and function as the original teeth by implanting a titanium artificial root into the alveolar bone without damaging the surrounding teeth at the site where the tooth is missing.
  • the dental implant is implanted in the alveolar bone and after a certain period of time, the bone is adhered to the alveolar bone, and after the bone adhesion, the abutment is connected to the artificial tooth (crown).
  • the artificial teeth After the artificial teeth are connected to the implant, they usually function normally, and after 15-20 years of bone adhesion, osteoadhesion should be maintained semipermanently.
  • the pre-fatigue life test conditions for this are mainly 5 million cycles with 250 N load.
  • One of the key performance indicators of dental implants is to shorten the period of bone adhesion. In other words, if bone adhesion does not occur within a short period of time, it is difficult to form a dental implant market as the treatment period becomes longer, and it is absolutely required to shorten the initial bone adhesion period because the normal chewing function of the implant is not smooth in the future. It is becoming.
  • TGF- ⁇ growth factor
  • IGF-1 Insulin-like growth factor-1
  • BMP bone morphogenetic protein
  • Dental implant technology is divided into design technology and surface modification technology.
  • Surface modification technology is an important factor in determining the initial bone adhesion period and the life of the implant, and is divided into 1 to 4 generations according to the development of the technology.
  • First-generation implants are machined implants developed by Branemark, Sweden, in 1965. As the first generation implants require a bone adhesion period of 4-8 months, various problems have been raised, and a second generation implant has been developed to increase the surface area of the implant for the purpose of shortening the bone adhesion period. As the surface modification method of the second generation implants, acid treatment, sand blasting, acid treatment after sand blasting, and sintering were developed, and the bone adhesion period of the second generation implant was reduced to 3 to 6 months.
  • Third-generation implants include HA (hydroxylapatite) coatings, anodization, fluorinated surfaces, and hydrophilic surfaces.
  • HA coating it is included in the second generation at the time of development, but it is classified as the third generation by the technical progress.
  • Anodization promotes bone adhesion by making the surface porous and thickening the oxide layer.
  • the fluorinated surface was developed by ASTRA, Sweden, to enhance bone adhesion by adding fluorine to the implant surface, and the surface with improved hydrophilicity was developed by ITI, Switzerland, to increase the surface energy and increase the hydrophilicity. It is shortened.
  • the third generation of implants reduced bone adhesion time to 2-4 months by adding bone forming materials, such as fluorine, calcium and phosphorus, and by making the surface porous and forming a thick oxide layer.
  • the third generation of implants takes more than three months to recover the missing teeth, and the overall success rate is slightly better than the second generation of implants, but the alveolar bone is poor. The success rate is still low, the case of alveolar bone is bad, such as elderly patients are limited use.
  • the third generation of surface modification technology is limited to shorten the bone adhesion period within three months, so the development of the fourth generation of implants is urgently required (Table 1, Types and Features of Dental Implant Surface Treatment).
  • BMP protein belonging to the TGF group has been found to play an important role in alveolar bone formation.
  • many researchers have conducted many experiments with animals. It has been reported that humans as well as animals can induce bone regeneration and strengthen bone tissue.
  • BMP was directly administered to the subject, it disappeared within a few minutes and was degraded by the enzyme present in the body, thereby confirming the loss of function.
  • a very high concentration of BMP should be administered within a short time during implantation.
  • the application of BMP to promote bone formation faces many problems in terms of stability, pharmacokinetics and cost.
  • Proteins are composed of hundreds to thousands of amino acids. As research on the structure and function of these proteins proceeds, it has been found that active sites exist in the entire amino acid sequence constituting the protein. Research into a technology that mimics the protein function of the minimum amino acid sequence that can perform the same function as is in progress.
  • a technique has been developed to produce a desired amino acid sequence in a short time using a peptide synthesizer.
  • recombinant proteins are obtained through the purification process after mass culturing by introducing a gene for producing a target protein into a gene of a microorganism or an animal cell.
  • Viral vector, cell-mediate and non-viral vector, plasmid, lipofection, etc. are used to introduce genes that produce the target protein.
  • the stability, cellular immune response and humoral immune response has shown a drawback that the expression level of the transgene is significantly reduced.
  • oligopeptides using a peptide synthesizer does not require a series of genetic manipulations, and some sequences, not the whole amino acid sequence of native proteins, are particularly important for the functioning of proteins. It is a very effective way to develop and produce oligopeptides.
  • HPLC is performed to purify the oligopeptides after the end of the synthesis, which is a much simpler and easier to purify product than the purification step of the desired product by genetic engineering.
  • the use of a synthesizer allows modification of some amino acids (eg, acetylation, amidation, phosphorylation, etc.) of the amino acid sequence of the oligopeptide according to the purpose, so that the oligopeptides that are partially different from the structure of the amino acid sequence of the natural protein are artificially modified. It has the advantage that it can be manufactured.
  • the organic synthesis method using a synthesizer is a genetic recombination to develop a stable cell line (PCR, gene cloning, clone screening, etc.) to produce the target substance, and then mass culture to isolate the target substance Compared to the refinement process, development time and costs can be reduced.
  • bioactive materials such as proteins or oligopeptides that promote bone adhesion and bone formation to the implant surface.
  • Korean Patent Application Publication No. 2006-0110190 (Bioimplants coated with bioactive materials and its coating method) forms an active layer on the outer peripheral surface of the dental implant and deposits an intermediate reactor layer on the active membrane and then forms the intermediate reactor layer.
  • the bioactive is maintained even after sterilization by coating the matrix material and the bioactive material by chemical covalent bond or by coating the polymer material in which the bioactive material is bound.
  • the present invention discloses a dental implant and a coating method thereof, which can facilitate distribution and storage, as well as secure sufficient adhesion between the dental implant and the bioactive material, thereby shortening the bone adhesion period during the dental implant procedure.
  • Korean Patent Application Publication No. 2006-0110189 is a oligopeptide that combines a peptide to a copolymer and can be treated directly on the dental implant surface to shorten bone adhesion period by promoting bone growth.
  • Korean Patent Application Publication No. 2006-0101019 (Registration No. 0676945, bone graft material coated with a tissue-enhancing peptide on the surface and support for tissue engineering) is a bone graft material coated with a cell adhesion inducing peptide and / or tissue growth factor-derived peptide on the surface and The present invention relates to a support for tissue engineering, and particularly discloses peptides derived from bone morphogenetic proteins (BMP-2, 4, 6).
  • Korean Patent Application Publication No. 2006-0082060 (Registration No.
  • BMP-2 bone morphogenetic protein
  • the present inventors have designed a new amino acid sequence having the same or more than the effect of a natural protein that promotes bone adhesion with a minimum amino acid sequence combination, analyzing the effectiveness of these substances, and selecting the best oligopeptides. While trying to apply to the surface of the implant, the present invention was completed by confirming that the oligopeptide of a specific sequence promotes initial osteoadhesion and bone formation.
  • Another object of the present invention is to chemically introduce the oligopeptides on the dental implant surface to improve initial bone adhesion, thereby shortening the implant procedure period, and in particular, increasing the success rate of the procedure for patients with low bone mass and bone mineral deficiency. To provide.
  • Another object of the present invention is to introduce the oligopeptide uniformly throughout the implant surface at low cost, and have bone regeneration and osteoadhesion properties similar to those of BMP, but have the same level of stability as that of inorganic coating materials. It is to provide an implant with less additional cost.
  • the present invention is an oligopeptide having the following general structural formula; (C or K)-(I, K or P)-(I, P or K)-(K or P)-(K, P or S)-(P or S)-(A or S)-(A , P or S)-(A, P or T)-(E, P or T)-(E, L or T)-(E, L or S)-(A, L or S)-(A, I Or to promote osteoadhesion and bone formation characterized by the structure of S)-(A, I or S)-(I, M or S)-(L, M or S)-(C, L or M)- Provides oligopeptides.
  • the present invention relates to an oligopeptide applicable to a general implant, the present description will be described with respect to the oligopeptide to be applied to the dental implant.
  • the oligopeptide may add an amino acid residue having a -SH group at one end in order to be introduced in a stable state with titanium (Ti) of the implant surface.
  • Ti titanium
  • a peptide having a residue of (C, L or Y) n structure, n is 1 or 2 is more preferable, and still more preferably cysteine.
  • the oligopeptide preferably controls the distance between the oligopeptides according to the size of osteoblasts and introduces a matrix together to control the relative orientation.
  • a linker is pretreated on the titanium surface, which is a material of the implant, and the oligopeptide is introduced with an amino acid, preferably a cysteine residue, having a -SH group at the N or C terminus to bind a functional group of a linker.
  • the oligopeptide of the present invention has a free amino group or cysteine at the N-terminal of the oligopeptide in relation to the linker, so that it is easy to introduce into the implant by the linker.
  • the oligopeptide in order to introduce the oligopeptide into a stable state with titanium (Ti) on the surface of the implant, it is preferable that the oligopeptide is introduced in a silane-linker-peptide linkage relationship.
  • the oligopeptide is PEP111 (SEQ ID NO: 1), PEP121 (SEQ ID NO: 2), PEP131 (SEQ ID NO: 3), PEP112 (SEQ ID NO: 4), PEP122 (SEQ ID NO: 5 ) Is preferably an oligopeptide selected from the group consisting of PEP132 (SEQ ID NO: 6) and PEP133 (SEQ ID NO: 7), more preferably an oligopeptide selected from the group consisting of PEP111, PEP112, and PEP122, and is PEP111 or PEP122. Even more preferred is PEP111.
  • the time required for selection of an effective oligopeptide sequence is short because the synthesis time is short when the oligopeptide is produced using a peptide synthesizer to screen the oligopeptide sequence that promotes bone adhesion and bone formation. Can be shortened.
  • Oligopeptides according to the invention can be easily synthesized according to methods known to those skilled in the art.
  • the oligopeptides used in the examples of the present invention were commissioned and synthesized by Peptron Co., Ltd.
  • Oligopeptides have structurally superior stability compared to natural or recombinant proteins, and thus, may be able to secure safety against sterilization and storage. Therefore, the oligopeptide of the present invention having an effect equivalent to or greater than that of a natural protein promoting bone adhesion will play an important role in the early attachment, proliferation and differentiation of osteoblasts when applied to the implant surface. It is expected to be very useful for dramatically shortening the period of bone adhesion and to expand the treatment area, especially in low bone patients with difficult implant procedures to date.
  • the present invention when the oligopeptide is applied to the surface of the shielding membrane and the implant, the present invention preferably introduces 0.1 to 5.0 mg per unit area on the surface, and more preferably the oligopeptide has a content of 10 to 21 amino acids. It is appropriate to apply 0.1 ⁇ 3.0 mg per surface unit area of implant.
  • the oligopeptides according to the invention can be applied to the implant surface according to methods known in the art (such as the related patent applications mentioned above) or the methods of the invention. At this time, it is possible to use a matrix or a linker.
  • the conventional application describes a method of modifying the implant surface, a method of using a crosslinking agent, a method of using a matrix, a silane-linker-peptide linking method, a coating method of an oligopeptide, and the like.
  • the configuration of the preferred oligopeptide sequence used in the present invention is as follows.
  • SEQ ID NO: 1 R1-CKIPKPSSAPTELSAISMLYL-R2
  • the linker group that is pretreated on the Ti surface can be easily bonded.
  • the one-character code used in the present invention is a character code commonly used in the art, the contents of which are as follows.
  • the oligopeptides of the present invention exhibit a bone filler replacement effect, a vertical therapeutic effect in which bone formation in the vertical direction is enhanced, and a horizontal therapeutic effect in which bone formation in the horizontal direction is enhanced.
  • Implant using this method induces osteoblast cell attraction and function increase due to continuous action of oligopeptides on the surface of implants, resulting in shorter initial bone adhesion period, increased success rate of low bone patients, and bone formation without bone filler Yes, it can bring down the cost of the procedure.
  • Figure 2 is a graph comparing the cell adhesion assay (cell adhesion assay) for the oligopeptide material
  • Figure 3 is a graph comparing the proliferative capacity (MTS assay) for oligopeptide material
  • Figure 4 is a graph comparing the differentiation capacity (ALP assay) for oligopeptide material
  • FIG. 5 is a schematic diagram of bone defect model (Bone defect model),
  • Figure 6 is a graph comparing bone formation ability at weeks 2 and 4 in the bone defect model (Bone defect model),
  • FIG. 7 is a picture of tissue specimens at Week 2 of the BMP-2 coated fixture (dip & dry) and oligopeptide material (dip & dry) treated groups in the bone defect model, FIG.
  • FIG. 8 is a graph comparing the differentiation capacity (ALP assay) of the oligopeptide (PEP111) of the present invention compared to the existing RGD sequence.
  • the present inventors have completed the development of TiO 2 oxide film by anodization prior to the present invention to complete the surface treatment product (GSII CellNest) by anodization.
  • the same method is known as the surface treatment method of Straumann.
  • anodization is an electrochemically formed oxide film on the surface of titanium (Ti) to form a microporous oxide film on the surface of titanium having a porous crater-shaped pores of Ra 0.8 ⁇ 1.2 of Surface roughness and surface area were increased.
  • TiO 2 As the oxide film, a surface treatment product (GSII CellNest) was used by such an anodization.
  • the present inventors found that amino acids play a key role in the proliferation and differentiation of osteoblasts in the whole amino acid sequence of BMP-2 (Bone morphogenetic protein), fibronectine, and vitronectine. Some of these sequences were modified in the sequence to prepare oligopeptides using a peptide synthesizer. The synthesized reaction was purified by HPLC to purify the desired product (oligopeptide) in a purity of 95% or more and the molecular weight was confirmed by NMR for the purified material.
  • BMP-2 Ben morphogenetic protein
  • fibronectine fibronectine
  • vitronectine vitronectine
  • oligopeptides The preparation of oligopeptides was commissioned by Peptron Co., Ltd.
  • the synthesis of peptides was carried out by Fmoc / tBu method, and purified by 95% or more purity by performing HPLC after completion of synthesis.
  • the molecular weight of the final purified material was confirmed by NMR.
  • the selected oligopeptide sequence is as follows.
  • PEP111 R1-CKIPKPSSAPTELSAISMLYL-R2
  • Cell efficacy evaluation was performed based on the differentiation capacity of osteoblast-like cell line MG63 on cell culture plates in order to analyze the effectiveness of the material prepared by introducing a cysteine residue for coating at the oligopeptide end.
  • oligopeptide solution 1 ml of oligopeptide solution at 1 uM (in DW) concentration was added to the cell culture plate (24 well culture plate), and after 3 hours at 37 ° C. in a CO 2 incubator, the oligopeptide solution was removed and the cell culture plate was replaced with PBS solution. After washing several times, it was naturally dried in a clean bench.
  • Oligopeptides and positive control group BMP-2 coated cells culture plate (24 well culture plate) was dispensed by 1 ⁇ 10 5 cells each to attach the cells for 2 hours in 37 °C, CO 2 incubator. Cell attachment was performed using DMEM medium (serum free media) except 10% fetal bovine serum. After 2 hours, the unattached cells were removed with PBS buffer (pH 7.2), and the cells were fixed by adding 1 ml of 10% formaldehyde (in PBS buffer, pH 7.2) solution. In order to quantify the cells attached to each culture plate, 0.04% cresyl violet (in 20% methanol) was added 300? L to each well, and then reacted for 30 minutes at room temperature to stain the nucleic acid of the cells attached to each well. After removing the unreacted dye solution by washing the disc three times with DW, 0.1M citric acid (in 50% ethanol) was added to 300? L, and the dye was bound to nucleic acid to measure the degree of adhesion. (Figure 2)
  • BMP-2-coated cell culture plates (24 well culture plates) were dispensed by MG63 1 ⁇ 10 5 cells and attached to the cells for 2 hours at 37 °C, CO 2 incubator.
  • Cell attachment was performed using DMEM medium (serum free media) except 10% fetal bovine serum.
  • PBS buffer pH 7.2
  • DMEM medium containing 10% fetal bovine serum was added, and then incubated in CO 2 incubator at 37 ° C. for 5 days. Every 2 days of culture, fresh media was replaced, and the proliferation was compared using the CellTiter 96 TM Aquous Non-Radioactive Cell Proliferation Assay Kit (Promega Co. USA) at 1, 3, and 5 days of culture. ( Figure 3)
  • oligopeptides on the differentiation of osteoblasts was compared by comparing ALP (alkaline phosphatase) activity, an early marker of osteoblast differentiation.
  • Oligonucleotide to compare the multipotential of osteogenic cell peptide and the positive control of 1 ⁇ 10 5 cells dispensed to 37 °C by per MG63 to BMP-2 the cell culture plate (24 well culture plate) for coating well, in a CO 2 incubator Incubated. Every two days of culture, fresh media was replaced and ALP activity was compared on the third and eighth days of culture. ( Figure 4)
  • Uncoated fixtures BMP-2 coated fixtures (dip & dry) were compared to control bone formation ability by oligopeptide material as a control.
  • FIG. 5 A schematic diagram of the bone defect model is shown in FIG. 5.
  • the results show that the bone regeneration effect by the PEP111 oligopeptide material is excellent.

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Abstract

La présente invention concerne un oligopeptide permettant d'améliorer l'ostéointégration et l'ostéogenèse. Plus spécifiquement, l'invention concerne des composés oligopeptidiques bioactifs représentés par la formule structurelle générale (C ou K)-(I, K ou P)-(I, P ou K)-(K ou P)-(K, P ou S)-(P ou S)-(A ou S)-(A, P ou S)-(A, P ou T)-(E, P ou T)-(E, L ou T)-(E, L ou S)-(A, L ou S)-(A, I ou S)-(A, I ou S)-(I, M ou S)-(L, M ou S)-(C, L ou M). l'oligopeptide décrit dans la présente invention est efficace pour le remplacement de l'agent de remplissage osseux, le traitement vertical et le traitement horizontal. Grâce à cette invention, l'action continue de l'oligopeptide sur la surface d'un implant treaté avec une pellicule mince de celui-ci permet de réduire le temps de ostéointégration initiale. En outre, une augmentation du taux de réussite des opérations chirurgicales sur des patients atteints d'ostéopénie peut être obtenue par induction d'une augmentation des ostéoblastes et de la fonction. Il est également possible d'obtenir une formation osseuse lorsque la masse osseuse est insuffisante, sans remplacement de l'os, ce qui permet de réduire les coûts des opérations chirurgicales.
PCT/KR2009/003141 2008-06-11 2009-06-11 Oligopeptide pour améliorer l'ostéointégration et l'oestégenèse WO2009151288A2 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2018038582A1 (fr) * 2016-08-26 2018-03-01 윤원준 Peptide favorisant l'ostéoanagenèse et l'ostéogenèse et son utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102770446B (zh) * 2010-02-26 2014-09-03 奥齿泰种植体股份有限公司 改善成骨细胞分化的寡肽
CN110551201B (zh) * 2019-08-26 2020-04-28 杭州彗搏科技有限公司 一种新型骨形成蛋白2来源的环肽、制备方法及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6344439B1 (en) * 1995-12-08 2002-02-05 Aventis Pharma S.A. Agents for promoting bone formation
US20050085623A1 (en) * 2002-02-21 2005-04-21 Gary Balian Bone targeting peptides
WO2005072403A2 (fr) * 2004-01-28 2005-08-11 The Regents Of The University Of California Peptide fixant la proteine morphogenetique osseuse
WO2008032929A1 (fr) * 2006-09-13 2008-03-20 Seoul National University Industry Foundation Greffon osseux contenant des peptides améliorant ostéogénèse

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6344439B1 (en) * 1995-12-08 2002-02-05 Aventis Pharma S.A. Agents for promoting bone formation
US20050085623A1 (en) * 2002-02-21 2005-04-21 Gary Balian Bone targeting peptides
WO2005072403A2 (fr) * 2004-01-28 2005-08-11 The Regents Of The University Of California Peptide fixant la proteine morphogenetique osseuse
WO2008032929A1 (fr) * 2006-09-13 2008-03-20 Seoul National University Industry Foundation Greffon osseux contenant des peptides améliorant ostéogénèse

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018038582A1 (fr) * 2016-08-26 2018-03-01 윤원준 Peptide favorisant l'ostéoanagenèse et l'ostéogenèse et son utilisation

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