KR100924956B1 - Method for preparing bio-inorganic organic-inorganic composite and bio-injectable organic-inorganic composite for injection - Google Patents
Method for preparing bio-inorganic organic-inorganic composite and bio-injectable organic-inorganic composite for injection Download PDFInfo
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims abstract description 28
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- 210000000988 bone and bone Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
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- -1 Apatite hydroxides Chemical class 0.000 description 2
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- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
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- 239000000945 filler Substances 0.000 description 2
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 2
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
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- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012237 artificial material Substances 0.000 description 1
- 229940062672 calcium dihydrogen phosphate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
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- 244000005700 microbiome Species 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
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- 239000004033 plastic Substances 0.000 description 1
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- 239000004626 polylactic acid Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 238000011084 recovery Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
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- Animal Behavior & Ethology (AREA)
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- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
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Abstract
본 발명은 생체 이식성 유기-무기 복합재료 제조방법 및 그에 의해 제조된 주사제용 생체 이식성 유기-무기 복합재료에 관한 것으로, 보다 상세하게는, 균일한 입자 크기를 갖는 구형 수산화아파타이트를 물에 분산시키는 단계 및 상기 수산화아파타이트 분산액에 히아루론산을 첨가하여 용해시키는 단계를 포함하여 이루어지는 생체 이식성 유기-무기 복합재료 제조방법 및 그에 의해 제조된, 균일한 입자 크기를 갖는 구형의 수산화아파타이트와 고점도의 천연 생체 고분자인 히아루론산(hyaluronic acid)을 포함하여 이루어지는 주사제용 생체 이식성 유기-무기 복합재료에 관한 것이다.The present invention relates to a method for producing a bio-inorganic organic-inorganic composite material and to a bio-injectable organic-inorganic composite material for injection prepared therein, and more particularly, to dispersing spherical apatite having a uniform particle size in water. And dissolving by adding hyaluronic acid to the apatite hydroxide dispersion. It relates to a bio-injectable organic-inorganic composite material for injection comprising a (hyaluronic acid).
수산화아파타이트, 히아루론산, 주사제, 유기-무기 복합재료, 제조방법 Apatite hydroxide, hyaluronic acid, injectables, organic-inorganic composites, manufacturing method
Description
도 1은, 실시예 1에서 제조되어 생체 이식성 유기-무기 복합재료에 포함된 수산화아파타이트의 미세구조를 나타낸 도면이다.1 is a view showing the microstructure of the apatite hydroxide prepared in Example 1 contained in the bio-inorganic organic-inorganic composite material.
본 발명은 생체 이식성 유기-무기 복합재료 제조방법 및 그에 의해 제조된 주사제용 생체 이식성 유기-무기 복합재료에 관한 것으로, 보다 상세하게는, 균일한 입자 크기를 갖는 구형 수산화아파타이트를 물에 분산시키는 단계 및 상기 수산화아파타이트 분산액에 히아루론산을 첨가하여 용해시키는 단계를 포함하여 이루어지는 생체 이식성 유기-무기 복합재료 제조방법 및 그에 의해 제조된, 균일한 입자 크기를 갖는 구형의 수산화아파타이트와 고점도의 천연 생체 고분자인 히아루론산(hyaluronic acid)을 포함하여 이루어지는 주사제용 생체 이식성 유기-무기 복합재료에 관한 것이다.The present invention relates to a method for producing a bio-inorganic organic-inorganic composite material and to a bio-injectable organic-inorganic composite material for injection prepared therein, and more particularly, to dispersing spherical apatite having a uniform particle size in water. And dissolving by adding hyaluronic acid to the apatite hydroxide dispersion. It relates to a bio-injectable organic-inorganic composite material for injection comprising a (hyaluronic acid).
생체 조직의 대체용 인공 재료에는, 연조직의 대체 재료로서 고분자 재료, 경조직의 대체 재료로서 금속이나 세라믹 재료가 주로 활용되며, 유기-무기 복합재료의 경우, 그 형태 및 물성에 따라 연조직 및/또는 경조직의 대체 재료로서 폭넓게 활용이 가능하다. 연조직의 대체 재료로서 활용가능한 생체 고분자 재료로는 D,L-락트산-글리콜산 공중합체(poly(D,L-latic-co-glycolic acid), PLGA), 폴리락트산(poly lactic acid, PLA), 폴리메틸메타크릴레이트(poly methyl methcrylate, PMMA), 콜라겐(collagen), 키토산(chitosan), 히아루론산(hyaluronic acid) 등을 들 수 있다. 한편 경조직의 대체 재료로서 활용가능한 무기 재료로는 생체용 세라믹스가 주로 사용되며, 그 중에서도 인산칼슘(calcium phosphate)계 세라믹스 재료가 특히 높은 생체 적합성을 보인다.In the artificial material for replacing biological tissue, a polymer material is mainly used as an alternative material for soft tissue, and a metal or ceramic material is mainly used as an alternative material for hard tissue.In the case of an organic-inorganic composite material, soft tissue and / or hard tissue may vary depending on the form and physical properties. It can be widely used as a substitute material for. Biopolymers that can be used as a substitute for soft tissue include D, L-lactic acid-glycolic acid copolymer (poly (D, L-latic-co-glycolic acid), PLGA), polylactic acid (PLA), Poly methyl methacrylate (PMMA), collagen, collagen, chitosan, hyaluronic acid, and the like. On the other hand, as an inorganic material that can be used as an alternative material for hard tissues, bio ceramics are mainly used, and among them, calcium phosphate-based ceramic materials show particularly high biocompatibility.
생체 고분자와 생체 세라믹스를 이용한 기존의 충전제들은, 필요부위의 외과적 시술을 동반하기 때문에 시술받는 환자에게 경제적 부담과 회복 장기화의 문제를 야기시켜 왔다. 또한 수술부위의 2차 감염에 의한 별도의 질병을 유발할 가능성이 높은 것이 사실이다. 예컨대 대한민국 특허출원 제2003-0087921호에서는 생체적합성이 뛰어난 수산화아파타이트에 은(Ag) 이온을 담지시켜 충전제로 사용하므로써 수술부위의 2차 감염을 어느 정도 방지하는 방법을 제시하였으나, 그렇다 하더라도 외과적 시술을 해야 한다는 문제점은 여전히 존재한다. Existing fillers using biopolymers and bioceramics have caused problems of economic burden and prolonged recovery for patients undergoing surgery because they are accompanied by surgical procedures. It is also true that there is a high possibility of causing a separate disease due to secondary infection of the surgical site. For example, Korean Patent Application No. 2003-0087921 suggested a method of preventing secondary infection of the surgical site by supporting silver (Ag) ions on a biocompatible apatite and using it as a filler, even though it is a surgical procedure. The problem still exists.
외과적 시술을 피하기 위해서는 생체 재료를 주사제 형태로 제조하여 필요 부위에 주입하는 방법이 있으나, 생체 고분자 자체를 주사제 형태로 제조하여 주입할 경우에는 체내 잔존시간이 짧아 수시로 충전해야 하는 번거로움이 있으며, 생체 고분자 단독으로는 경조직의 결손부분을 대체하기에 부족한 점이 있다. 또한, 생체 세라믹스 단독으로는 주사기를 쉽게 빠져나오지 못하는 어려움으로 인해 시술에 많은 제약이 따르며, 따라서 주사제 형태로 제조하여 활용하기에 많은 문제가 있다.In order to avoid the surgical procedure, there is a method of preparing a biomaterial in the form of an injection and injecting it into a necessary area, but when preparing and injecting the biopolymer itself in the form of an injection, the remaining time in the body is short, and it is necessary to fill it from time to time. The biopolymer alone is insufficient to replace the defective part of the hard tissue. In addition, the biological ceramics alone has a lot of restrictions in the procedure due to the difficulty of easily exiting the syringe, and thus there are many problems in manufacturing and utilizing injectable form.
상기와 같은 문제점을 해결하기 위해 고점도의 히아루론산 용액에 골 분말을 혼합하고, 이를 고형화시키기 위해 알긴산 나트륨을 사용하는 방법이 대한민국 공개특허 제2003-0060439호에 개시되어 있으나, 이 방법을 사용하더라도 주사제 형태로 제조하기에 실질적으로 적합한 유기-무기 복합재료가 얻어지지 않을 뿐만 아니라, 그를 생체 내에 이식시 염증 반응을 일으킬 우려가 여전히 존재한다.In order to solve the above problems, a method of mixing bone powder with a high viscosity hyaluronic acid solution and using sodium alginate to solidify it is disclosed in Korean Patent Laid-Open Publication No. 2003-0060439. Not only are organic-inorganic composites practically suitable for the production of blast furnaces not obtained, but there is still a fear of causing an inflammatory response upon implantation thereof in vivo.
본 발명의 목적은, 생체 내 경조직의 결손부를 채우거나 연조직의 함몰 부위를 융기(隆起)시켜줄 때 외과적 수술이 필요 없이 치료가 가능하여, 의사는 시술이 용이하고, 환자는 수술에 대한 부담 및 고통이 감소하므로, 성형외과, 치과 그리고 정형외과 분야에 폭넓게 사용할 수 있도록, 균일한 입자 크기를 갖는 구형의 수산화아파타이트와 고점도의 천연 생체 고분자인 히아루론산(hyaluronic acid)을 포함하여 이루어지는 주사제용 생체 이식성 유기-무기 복합재료 및 그 제조방법을 제공하는 것이다.An object of the present invention is to be able to treat the surgical procedure without the need for surgery when filling in the defects of hard tissues in the living body or bulging the depressions of the soft tissues, the doctor is easy to perform the procedure, the patient is burdened for surgery and Reduced pain, biocompatible organics for injections comprising spherical apatite with uniform particle size and hyaluronic acid, a highly viscous natural biopolymer, for widespread use in plastic, dental and orthopedic applications It provides an inorganic composite material and a method of manufacturing the same.
본 발명에 따르면, 구형 수산화아파타이트를 물에 분산시키는 단계; 및 상기 구형 수산화아파타이트 분산액에 히아루론산을 첨가하여 용해시키며 혼합하는 단계를 포함하여 이루어지는 생체 이식성 유기-무기 복합재료 제조방법이 제공된다.According to the invention, the step of dispersing the spherical apatite hydroxide in water; And adding, dissolving, and mixing hyaluronic acid to the spherical apatite hydroxide dispersion to provide a method for producing a bio-inorganic organic-inorganic composite material.
본 발명에 따른 생체 이식성 유기-무기 복합재료 제조방법에 있어서, 상기 구형 수산화아파타이트는 바람직하게는 0.1㎛~100㎛, 보다 바람직하게는 1~10㎛의 평균 입자 크기를 갖는 것이 보다 용이한 시술을 가능하게 하는 주사제의 제조에 적합하다. In the method for producing a living implantable organic-inorganic composite material according to the present invention, the spherical apatite hydroxide is preferably 0.1 µm to 100 µm, more preferably 1 to 10 µm, having an average particle size. Suitable for the preparation of injectables.
본 발명에 따른 생체 이식성 유기-무기 복합재료 제조방법에 있어서, 상기 구형의 수산화아파타이트는 상기 물에 바람직하게는 5~50중량%의 함량으로, 더욱 바람직하게는 15~40중량%의 함량으로, 보다 더 바람직하게는 18~25중량%의 함량으로 분산된다. 상기 함량이 5중량% 미만이면, 복합재료의 경조직 손실 보충 효과가 부족하고, 시술 후 복합재료가 시술 부위에서 떨어질 수도 있으며, 50중량%를 초과하면, 수산화아파타이트와 히아루론산의 결합이 잘 이루어지지 않고, 주사기로 시술시 높은 압력으로 인해 환자에게 고통을 줄 수도 있어서 주사제로 제조하기에 바람직하지 않다.In the method for producing a living implantable organic-inorganic composite material according to the present invention, the spherical apatite hydroxide is preferably in the water of 5 to 50% by weight, more preferably in the content of 15 to 40% by weight, Even more preferably, it is dispersed in an amount of 18 to 25% by weight. When the content is less than 5% by weight, the hard tissue loss replenishment effect of the composite material is insufficient, the composite material may fall off the treatment site after the procedure, if more than 50% by weight, the combination of apatite hydroxide and hyaluronic acid is not well achieved However, the high pressure during the procedure with a syringe may cause pain to the patient, which is undesirable for the preparation of injections.
본 발명에 따른 생체 이식성 유기-무기 복합재료 제조방법에 있어서, 상기 히아루론산은 상기 수산화아파타이트 분산액에 바람직하게는 0.1~5중량%의 농도로, 더욱 바람직하게는 0.5~1.5중량%의 농도로, 보다 더 바람직하게는 0.8~1.2중량%의 농도로 용해시킨다. 상기 농도가 0.1중량% 미만이면, 복합재료의 연조직 손실 보충 효과가 부족하고, 5중량%를 초과하면, 점도가 지나치게 증가하여 주사제로 제조하기에 바람직하지 않다.In the method for producing a living implantable organic-inorganic composite material according to the present invention, the hyaluronic acid is preferably in a concentration of 0.1 to 5% by weight, more preferably in a concentration of 0.5 to 1.5% by weight, in the apatite hydroxide dispersion. More preferably, it is dissolved at a concentration of 0.8 to 1.2% by weight. If the concentration is less than 0.1% by weight, the soft tissue loss replenishment effect of the composite material is insufficient, and if the concentration is more than 5% by weight, the viscosity is excessively increased, which is not preferable for preparing an injection.
본 발명의 제조방법의 일 구체에에 따르면, 첫번째 단계에서는, 0.1~100㎛, 바람직하게는 1~10㎛의 구형 수산화아파타이트 미립자를 정제수에 5~50중량%, 바람 직하게는 15~40중량%, 보다 바람직하게는 18~25중량%의 함량으로 혼합하고, 충분하게 분산시킨다. 다음으로 두번째 단계에서는 상기 구형 수산화아파타이트가 분산된 분산액에 히아루론산을, 그 농도가 0.1~5중량%, 바람직하게는 0.5~1.5중량%, 보다 바람직하게는 0.8~1.2중량%로 되도록 정량하여 첨가한 후 용해시키며 혼합한다. According to one embodiment of the production method of the present invention, in the first step, 5 to 50% by weight of spherical apatite hydroxide particles, preferably 1 to 10 μm, in purified water, preferably 15 to 40%, in purified water. %, More preferably in an amount of 18 to 25% by weight, and sufficiently dispersed. Next, in the second step, hyaluronic acid was added to the dispersion in which the spherical apatite was dispersed, and the concentration thereof was 0.1 to 5% by weight, preferably 0.5 to 1.5% by weight, more preferably 0.8 to 1.2% by weight. Dissolve and mix.
본 발명에 따라 상기와 같이 제조된 생체 이식성 유기-무기 복합재료는, 주사기에 충전시켜 생체 조직 결손 보충용 주사제로 제조될 수 있다. 이 복합 주사제는 인체 내의 결손 부위에 주입되어 이식될 경우, 시간의 경과에 따라 인체 내에서 분해, 흡수되며 새로운 조직으로 대체된다. The living implantable organic-inorganic composite material prepared as described above according to the present invention may be prepared as an injection for supplementing a biological tissue defect by filling a syringe. When injected into a defect site in the body, the combination injection breaks down and is absorbed and replaced by new tissue in the body over time.
본 발명에서 사용되는 상기 히아루론산은, 조직 재생과 형태 형성(morphogenesis)에서 중요한 작용을 하는 세포외 기질로서 세포막의 골형성 유도 인자와 특이적 결합을 하는 생체 적합성이 높은 천연 고분자 재료이며, 미생물을 배양하여 그로부터 추출할 수도 있고, 닭의 벼슬과 같은 천연물에서 직접 추출할 수도 있다. The hyaluronic acid used in the present invention is an extracellular matrix that plays an important role in tissue regeneration and morphogenesis, and is a highly biocompatible natural polymer material that specifically binds to bone formation inducing factors of cell membranes and cultures microorganisms. It may be extracted from it, or may be extracted directly from natural products such as chicken crest.
또한, 본 발명에서 사용되는 상기 수산화아파타이트는 인체 구성 물질인 뼈와 치아를 구성하는 무기질 성분으로서 높은 생체 적합성 및 안전성을 보인다. 또한 경조직과 직접 결합하여 신생골을 유입하고 성장시킬 뿐 아니라, 적용 조직의 세포들을 유입 및 고정시키는 역할을 하여, 새로운 자가 조직을 생성하는 특성을 가진다. 수산화아파타이트는 일반적으로 침상, 봉상, 플레이크 형태나 이들이 응집체로 많이 제조되어지고 있으나, 생체 내 이식 시 염증 반응을 일으킬 수 있으므로 구형의 수산화아파타이트를 사용하는 것이 적합하다. In addition, the apatite hydroxide used in the present invention exhibits high biocompatibility and safety as inorganic components constituting bone and teeth which are human constituent materials. In addition, it directly combines with hard tissue to introduce and grow new bone, as well as to introduce and fix cells of the applied tissue, and has the property of generating new autologous tissue. Apatite hydroxides are generally prepared in the form of needles, rods, or flakes, or aggregates. However, spherical apatite is preferable because it may cause an inflammatory response during transplantation in vivo.
이하 실시예에 의해 본 발명을 상세히 설명하나, 이에 의해 본 발명이 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.
실시예 1Example 1
구형 수산화아파타이트의 제조Preparation of Spherical Hydroxyapatite
0.5M 시트르산 수용액 1리터를 제조하고, 여기에 인산일수소칼슘무수화물 20g을 첨가하여 용해시킨 후, 1M NaOH 수용액를 첨가하여 pH를 7.0으로 조절하고, 결과물을 0.2㎛ 필터로 여과하였다. 결과 여과액을 교반하면서 열을 가하여, 그 온도가 70~80℃가 되도록 한 후, 3시간 교반하였다. 교반 후 생성된 침전물을 원심 분리와 세척을 반복하여 침전물만을 수거한 후, 얻어진 침전물을 오토클레이브에서 멸균 처리하였다. 멸균 처리한 침전물 중의 수산화아파타이트 함량은 30중량% 이었다. 멸균 처리한 침전물을 건조기에서 건조하여 구형의 수산화아파타이트를 얻었다. 얻어진 구형의 수산화아파타이트를 주사전자현미경으로 촬영한 사진을 도 1에 나타내었다.One liter of 0.5 M citric acid aqueous solution was prepared, and 20 g of calcium dihydrogen phosphate anhydride was added thereto to dissolve, and then, pH was adjusted to 7.0 by adding 1 M NaOH aqueous solution, and the resultant was filtered through a 0.2 µm filter. Heat was added while stirring the filtrate, and the temperature was 70-80 ° C, followed by stirring for 3 hours. After stirring, the resulting precipitate was centrifuged and washed repeatedly to collect only the precipitate, and then the obtained precipitate was sterilized in an autoclave. Apatite hydroxide content in the sterilized precipitate was 30% by weight. The sterilized precipitate was dried in a drier to obtain spherical apatite hydroxide. The photograph which photographed the obtained spherical apatite hydroxide with the scanning electron microscope is shown in FIG.
세포증식 저해시험Cell proliferation inhibition test
상기에서 제조한 구형 수산화아파타이트 미립자를 이용하여 세포증식 저해시험을 실시하였다. 배양 세포의 증식 저해시험은 식품의약품안전청고시 제2004-63호의 시험 방법으로 행하였다. 시험 세포로 NCTC colne 929(L-929, 섬유아세포)를 사용하였으며, 시험액으로는, 상기에서 제조한 구형 수산화아파타이트 미립자 4g에 살린(Saline) 20ml를 혼합하고, 37±2℃에서 72±2시간 동안 추출한 용출액을 필터하여 사용하였다. 배양 세포증식 저해시험 결과 세포증식 저해율은 13.78%가 나왔 다. 이는 의료용구 기준규격인 29% 미만에 해당하는 값이었다.Cell proliferation inhibition test was performed using the spherical apatite hydroxide fine particles prepared above. Proliferation inhibition test of cultured cells was carried out by the test method of 2004-63 of the Korea Food and Drug Administration. NCTC colne 929 (L-929, fibroblasts) was used as test cells, and 20 ml of saline was mixed with 4 g of the spherical apatite hydroxide particles prepared above as a test solution, and 72 ± 2 hours at 37 ± 2 ° C. The eluate extracted during the filter was used. As a result of culture cell proliferation inhibition test, cell proliferation inhibition rate was 13.78%. This was equivalent to less than 29% of medical equipment standards.
유기-무기 복합재료의 제조Preparation of Organic-Inorganic Composites
상기에서 얻어진 침전물 100g(수산화아파타이트 함량 30중량%)에 정제수 50g을 첨가하여, 구형 수산화아파타이트의 함량이 20중량%가 되도록 혼합하였다. 이 혼합물 150g에 히아루론산 1.5g을 정량하여 첨가하므로써, 히아루론산의 농도가 1%가 되도록 하였다. 상기의 히아루론산이 용해될 때까지 흔들어 혼합하고, 완전하게 용해된 것을 확인한 후에 주사기에 1ml씩 충전하여 유기-무기 복합재료 주사제를 제조하였다. 제조된 유기-무기 복합재료 주사제 중의 구형 수산화아파타이트 분산성과, 수산화아파타이트와 히아루론산과의 결합능력 및 생체 적합성을 평가하여 표 1에 나타내었다.50 g of purified water was added to 100 g of the precipitate obtained above (30 wt% of apatite hydroxide), and the mixture was mixed so that the content of spherical apatite was 20 wt%. The concentration of hyaluronic acid was adjusted to 1% by quantitatively adding 1.5 g of hyaluronic acid to 150 g of this mixture. Shake and mix until the hyaluronic acid is dissolved, and after confirming complete dissolution, fill the syringe with 1 ml each to prepare an organic-inorganic composite injection. Dispersibility of the spherical apatite hydroxide in the prepared organic-inorganic composite injection, and the binding ability and biocompatibility of the apatite hydroxide with hyaluronic acid were evaluated in Table 1.
실시예 2Example 2
실시예 1과 같이 하여 제조된 평균 1~10㎛ 크기의 구형 수산화아파타이트 20g을 정제수 100g에 넣고 분산이 잘 되도록 충분하게 혼합하였다. 상기 혼합물에 히아루론산의 농도가 1%가 되도록 히아루론산을 1g 정량하여 넣고, 히아루론산이 완전히 용해될 때까지 흔들어 혼합하였다. 제조된 수산화아파타이트-히아루론산 복합재료를 5ml 용량의 주사기에 1ml씩 충전하여 유기-무기 복합재료 주사제를 제조하였다. 20 g of spherical apatite having a mean size of 1 to 10 μm prepared in Example 1 was added to 100 g of purified water, and the mixture was sufficiently mixed so as to be well dispersed. 1 g of hyaluronic acid was quantified in the mixture so that the concentration of hyaluronic acid was 1%, and the mixture was shaken until the hyaluronic acid was completely dissolved. The prepared inorganic hydroxide-hyaluronic acid composite material was filled in a 5 ml syringe by 1 ml to prepare an organic-inorganic composite injection.
실시예 3Example 3
실시예 1과 같이 하여 제조된 평균 50~100㎛ 크기의 구형 수산화아파타이트 25g을 정제수 100g에 넣고 분산이 잘 되도록 충분하게 혼합하였다. 상기 혼합물에 히아루론산의 농도가 1.2%가 되도록 히아루론산을 1.2g 정량하여 넣고, 히아루론산이 완전히 용해될 때까지 흔들어 혼합하였다. 제조된 수산화아파타이트-히아루론산 복합재료를 5ml 용량의 주사기에 3ml씩 충전하여 유기-무기 복합재료 주사제를 제조하였다. 25 g of spherical apatite having an average size of 50 to 100 µm prepared as in Example 1 was added to 100 g of purified water, and the mixture was sufficiently mixed so as to be well dispersed. 1.2 g of hyaluronic acid was added to the mixture so that the concentration of hyaluronic acid was 1.2%, and the mixture was shaken until the hyaluronic acid was completely dissolved. The prepared apatite hydroxide-hyaluronic acid composite material was filled in a 5 ml syringe by 3 ml each to prepare an organic-inorganic composite injection.
실시예 4Example 4
실시예 1과 같이 하여 제조된 평균 10~50㎛ 크기의 구형 수산화아파타이트 30g을 정제수 100g에 넣고 분산이 잘 되도록 충분하게 혼합하였다. 상기 혼합물에 히아루론산의 농도가 1%가 되도록 히아루론산을 1g 정량하여 넣고, 히아루론산이 완전히 용해될 때까지 흔들어 혼합하였다. 제조된 수산화아파타이트-히아루론산 복합재료를 5ml 용량의 주사기에 2ml씩 충전하여 유기-무기 복합재료 주사제를 제조하였다.30 g of the spherical apatite hydroxide having an average size of 10 to 50 µm prepared as in Example 1 was placed in 100 g of purified water and mixed well so as to be well dispersed. 1 g of hyaluronic acid was quantified in the mixture so that the concentration of hyaluronic acid was 1%, and the mixture was shaken until the hyaluronic acid was completely dissolved. The prepared apatite hydroxide-hyaluronic acid composite material was filled in a syringe of 5ml volume by 2ml to prepare an organic-inorganic composite injection.
비교예 1~3Comparative Examples 1 to 3
생체 고분자로서 각각 PLGA, 키토산 및 콜라겐을 사용하고, 생체 세라믹스로서 실시예 1에서 제조한 구형 수산화아파타이트 미립자를 사용하여 유기-무기 복합재료를 제조하였다. 제조된 유기-무기 복합재료 주사제 중의 구형 수산화아파타이트 분산성과, 수산화아파타이트와 각각의 생체 고분자와의 결합능력 및 생체 적합성을 평가하여 표 1에 나타내었다.Organic-inorganic composite materials were prepared using PLGA, chitosan and collagen as biopolymers, respectively, and spherical apatite hydroxide fine particles prepared in Example 1 as bioceramics. Dispersibility of the spherical apatite hydroxide in the prepared organic-inorganic composite injection, and the binding ability and biocompatibility of each of the biopolymers are shown in Table 1.
[표 1]TABLE 1
표 1에 있어서, 생체 고분자 중 PLGA는 물에 녹지 않기 때문에 유기 용매를 첨가해야 하는 문제점이 있었고, 키토산과 콜라겐의 경우, 산성 용매에 용해되므로 구형의 수산화아파타이트 입자의 붕괴를 초래하였다. 또한 수용성 콜라겐의 경우에는 이종 단백질로 면역 반응을 일으키기 쉬운 단점이 있으며, 저분자의 수용성 키토산의 경우도 점도가 낮기 때문에 유기-무기 복합재료에 캐리어(carrier)로 사용되기에는 부적합하였다. 결과적으로, 비교예 1~3은 모두 생체 재료로 사용되기에는 부적합하였다.In Table 1, PLGA in the biopolymer was insoluble in water, and thus, an organic solvent had to be added. Chitosan and collagen were dissolved in an acidic solvent, resulting in the collapse of spherical apatite hydroxide particles. In addition, water-soluble collagen has a disadvantage of easily causing an immune response with heterologous proteins, and low molecular weight water-soluble chitosan is also unsuitable for being used as a carrier in organic-inorganic composite materials because of its low viscosity. As a result, all of Comparative Examples 1-3 were unsuitable to be used as a biomaterial.
이상 살핀 바와 같이, 본 발명에 따라 제조된 주사제용 생체 이식성 유기-무기 복합재료를 사용하면, 의사는 시술이 보다 용이해지고, 환자들은 보다 간편하고 저렴하게 손상된 조직을 보충할 수 있는 효과를 얻을 수 있어, 성형외과, 치과 그리고 정형외과 분야에서 폭넓게 활용될 수 있다. As described above, by using the bio-injectable organic-inorganic composite material for injection prepared according to the present invention, doctors can make the procedure easier, and patients can obtain the effect of replenishing damaged tissues more simply and inexpensively. It is widely used in plastic surgery, dentistry and orthopedics.
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