WO2003094984A1 - Agent permettant d'obtenir une repousse osseuse et agent therapeutique servant a traiter l'osteoporose - Google Patents

Agent permettant d'obtenir une repousse osseuse et agent therapeutique servant a traiter l'osteoporose Download PDF

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WO2003094984A1
WO2003094984A1 PCT/JP2002/012971 JP0212971W WO03094984A1 WO 2003094984 A1 WO2003094984 A1 WO 2003094984A1 JP 0212971 W JP0212971 W JP 0212971W WO 03094984 A1 WO03094984 A1 WO 03094984A1
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bone
collagen
complex
agent
osteoporosis
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PCT/JP2002/012971
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English (en)
Japanese (ja)
Inventor
Masanori Kikuchi
Junzo Tanaka
Noriichi Ito
Yoshinobu Mandai
Hiroko Matsumoto
Yoshihisa Koyama
Kazuo Takakuda
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Japan Science And Technology Agency
National Institute For Materials Science
Nitta Gelatin Inc.
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Application filed by Japan Science And Technology Agency, National Institute For Materials Science, Nitta Gelatin Inc. filed Critical Japan Science And Technology Agency
Publication of WO2003094984A1 publication Critical patent/WO2003094984A1/fr
Priority to US10/937,732 priority Critical patent/US7229971B2/en

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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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • 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 a bioimplantable novel bone augmentation agent. More specifically, the present invention relates to a bioimplantable bone augmentation agent comprising a complex containing hydroxyapatite and collagen, and use of the bone augmentation agent as a therapeutic agent for osteoporosis.
  • Background technology relates to a bioimplantable novel bone augmentation agent. More specifically, the present invention relates to a bioimplantable bone augmentation agent comprising a complex containing hydroxyapatite and collagen, and use of the bone augmentation agent as a therapeutic agent for osteoporosis.
  • Osteoporosis is a condition in which bone loss occurs as a result of bone remodeling during the process of bone remodeling in which old bone is replaced with new bone, resulting in a loss of bone mass.
  • osteoporosis in addition to a decrease in bone mineral density, the microstructure of bone is disrupted, which weakens the bone and increases the risk of fracture. It is said that one in three menopausal women and most of the elderly suffer from osteoporosis, and many elderly patients become bedridden due to fractures.
  • the mainstream treatment for osteoporosis has been oral medications aimed at suppressing bone resorption and promoting bone formation.
  • the most widespread treatment at present is to use systemic hormones (estrogens), calcium preparations, vitamin D and its derivatives to systematically improve bone metabolism.
  • systemic hormones estrogens
  • calcium preparations calcium preparations
  • vitamin D vitamin D
  • this treatment method has a problem that a remarkable effect cannot be obtained in a short time because the dose of the drug is limited in consideration of side effects.
  • These drugs may also maintain or prevent trabeculae thinned due to osteoporosis from being absorbed any further. It is thought that the effect of slightly increasing the thickness of the trabecular bone can be expected, but the effect of newly forming trabecular bone that has been absorbed and lost cannot be expected.
  • Bone Morphogenic protein which is currently in clinical trials, is said to have an aggressive osteogenic effect, but it is expensive and has no ideal carrier. And frequent administration is required.
  • a topically applied preparation such as a biomedical implant for the treatment of osteoporosis.
  • many existing bone fillers are non-bioabsorbable and do not provide effective bone formation.
  • apatite sintered body which is a commercially available bone filler, does not have bioabsorbability, even if the granules are filled into bone, they remain permanently in the body without being replaced by bone. It is considered only.
  • a bio-implantable formulation with excellent bone augmentation activity can be developed, it can be applied to osteoporosis patients and other patients who cannot expect systemic improvement with existing drugs. It is very useful as an artificial bone augmentation agent.
  • vertebrate bone is a complex consisting of hydroxyapatite and collagen. They form a unique nanocomposite structure in which hydroxyapatite is oriented along collagen fibers in the c-axis direction in living bone, and this structure gives the bone unique mechanical properties.
  • the present inventors have conducted research to produce a hydroxyapatite nocollagen complex having a structure and composition similar to that of living bone, and to develop it as a bioabsorbable bone implant filling implant (Kikuchi et al.) , Bioomaterials 22, (2000) P 1705-171 K JP-A-7-101708, JP-A-199209, JP-A-2000-5298, etc.).
  • this hydroxyapatite / colla Until now, there has been no attempt to apply the I-Gen complex as a therapeutic agent for diseases associated with bone loss such as osteoporosis. Disclosure of the invention
  • An object of the present invention is to provide an implantable bone augmentation agent capable of exhibiting an effective bone augmentation action at a desired site, and a therapeutic agent for osteoporosis using the bone augmentation agent.
  • the present inventors have conducted intensive studies in order to solve the above-mentioned problems.As a result, when a complex containing hydroxyapatite and collagen was applied to the bone of an osteoporosis model animal, the bone density clearly increased around the implant. was found. That is, it was confirmed that the complex was useful as a bioimplantable osteoporosis therapeutic agent capable of forming new bone at a desired place in bone. Furthermore, they found that it is also possible to control the rate of absorption of the complex and the rate of replacement with bone by cross-linking the collagen in the complex and appropriately changing the form of the complex. Completed.
  • the present invention provides the following (1) to (6).
  • a bioimplantable bone augmentation agent comprising a complex containing hydroxyapatite and collagen.
  • the bone augmentation agent according to the present invention is a bioimplantable bone augmentation agent comprising a complex containing hydroxyapatite and collagen.
  • a bioimplantable bone augmentation agent comprising a complex containing hydroxyapatite and collagen.
  • Bioimplantable bone augmentation agent refers to a preparation (bone augmentation agent) that promotes bone turnover of a type (bioimplantation type) that is implanted and used at a target site in a living body. Shall be.
  • the general composition is Ca 5 (P0 4) 3 0H , and compounds, by non-stoichiometry of the reaction, CaHP0 4, Ca 3 ( P0 4) 2, Ca 4 0 (P0 4) 2, Ca ,. (P0 4) 6 (OH) 2, CaP 4 0 ", Ca (P0 3) 2, Ca 2 P 2 0 have Ca (H 2 P0 4) 2 - H 2 0 , etc.
  • One group of compounds referred to as calcium phosphate including.
  • hydroxyapatite has been made to Ca 5 (P0 4) 3 0H or Ca 1 () (P0 4) 6 (0H) basic ingredient a compound represented by the second set formed formula,
  • Ca a portion of the components, Sr, Ba, MG, Fe , AK Y, La, Na, K, may be substituted with one or more selected from such H.
  • a portion of (P0 4) component, V0 4 , B0 3, S0 4, C0 3, Si0 may be substituted with selection barrel (1) or more from 4 like.
  • (0H) a portion of the component, F, Cl, 0, C0 1 kind selected from 3 etc. may be substituted by or more.
  • P0 4 and of part of the Ingredients of may become a defect. biological bone Apatai Bok Because some of the OH components are replaced in the normal C0 3, during the manufacture of the composite biomaterial, some substitution of C0 3 of contamination and the components from the atmosphere (0-1 about 0 wt%) of There may be.
  • Hydroxyapatite may be an isomorphous solid solution, a substitutional solid solution, or an interstitial solid solution in addition to ordinary microcrystals / amorphous crystals, and may contain non-quantitative defects. You may.
  • the atomic ratio of calcium and phosphorus (Ca / P) is preferably in the range of 1.3 to 1.8, and more preferably in the range of 1.5 to 1.7. preferable.
  • the composition and crystal structure of apatite (calcium phosphate compound) in the product is similar to that of apatite in vertebrate bone. This is because the composition and structure can be taken, so that biocompatibility and bioabsorbability are increased.
  • the collagen constituting the bone augmenting agent of the present invention is not particularly limited, and any collagen can be used.
  • collagen obtained from the skin, bones, cartilage, tendons, organs, etc. of mammals eg, porcupine, bush, poma, magpie, mouse, etc.
  • birds eg, chicks, etc.
  • type I collagen is the most abundant and well studied. Usually, collagen simply refers to type I collagen.
  • the molecular species of collagen used in the present invention is not particularly limited, but it is preferable that collagen I be the main component.
  • collagen can be used by appropriately modifying the amino acid residues of collagen protein with appropriate chemical modification such as acetylation, succination, maleylation, phthalation, benzoylation, esterification, amidation, and guanidination. Good.
  • a method for preparing collagen for example, a method of extracting from the above-mentioned starting materials (excluding the genetic recombination technique) with a neutral buffer or a dilute acid such as hydrochloric acid, acetic acid, or citric acid may be mentioned.
  • the former is called neutral salt-soluble collagen, and the latter is called acid-soluble collagen.
  • the amount of extracted collagen is small, and most remains as insoluble collagen.
  • an enzyme solubilization method and an Alkali solubilization method are known.
  • the former is called enzyme-solubilized collagen, and the latter is so-called collagen solubilized. Both can be solubilized as molecular collagen with a yield of about 100%.
  • the method for preparing collagen (extraction type) used in the present invention is not particularly limited. However, if the molecular weight is large when the collagen is solubilized, the strength of the complex becomes insufficient due to steric hindrance. It is preferable to use a monomeric (monomolecular) collagen.
  • the enzyme-solubilized collagen and the alkali-solubilized collagen have not only a large amount of monomeric components but also a non-helical portion (telopeptide) having most of the antigenicity of collagen in the preparation stage. Since it is decomposed and removed, it is suitable for the organic-inorganic composite biomaterial of the present invention.
  • the collagen from which the non-spiral portion has been decomposed and removed is called atelocollagen.
  • the isoionic point is the pH at which the positive and negative charges originating from the dissociation group inherent in the protein molecule just cancel each other.In the case of collagen, it was solubilized when approaching the pH region of the isoionic point. It is known that things become fibrotic.
  • the isoionic point of the enzyme-solubilized collagen is pH 8-9
  • the iso-ionic point of the solubilized collagen is pH 4-5.
  • enzyme-solubilized collagen in which fibrosis of collagen proceeds in a reaction vessel in which ⁇ 1 is kept at 7 to 11 and self-organization is easy.
  • solubilizing enzyme examples include pepsin, trypsin, chymotrypsin, papain, and pronase. Pepsin and pronase are preferably used because of the ease of treatment after the enzymatic reaction.
  • the mass ratio of idoxyapatite to collagen is preferably 60:40 to 90:10, more preferably 70:30. ⁇ 85: 15 is more preferred. This is because it is necessary for the mass ratio of both to be close to the composition of living bone (75:25) for effective bioabsorption and bone formation.
  • hydroxyapatite and collagen are oriented in a self-assembled manner to form a complex similar to living bone.
  • self-organization generally means “the same or different kinds of atoms, molecules, fine particles, etc. are assembled by non-covalent interactions to form a specific tissue (Tokyo) Chemical Doujin (from "Biochemical Dictionary”).
  • calcium phosphate (hydroxyapatite) having an apatite structure has an orientation specific to living bone along collagen fibers. In other words, it means a microporous structure in which the c-axis of hydroxyapatite is oriented along the collagen fibers.
  • the complex comprising collagen and hydroxyapatite that constitutes the bone augmenting agent of the present invention is manufactured using at least three components of collagen, phosphate or phosphate, calcium hydroxide or calcium salt as starting materials. Is done.
  • the phosphate include disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and the like.
  • the calcium salt include calcium carbonate and calcium acetate.
  • the “composite containing collagen and hydroxyapatite” preferably has a microporous structure similar to a living bone, in which the c-axis of the hydroxyapatite is oriented along the collagen fibers.
  • Kikuchi et al. Kikuchi, S. et al, J., Biomater., 22 (13) (2001), 1705-1711, S. Itoh et al, J. Biomed Mater. Res, (2001), 445-453). That is, it can be obtained by simultaneously dropping a calcium hydroxide solution and a phosphate aqueous solution containing collagen into a reaction vessel, and drying the resulting precipitate.
  • the collagen to be used is not particularly limited, but if the molecular weight is large, the strength of the complex becomes insufficient due to steric hindrance. Therefore, it is preferable to use monomeric collagen.
  • pepsin-treated atelocollagen is suitable for the bone augmenting agent of the present invention because it is monomeric and has low antigenicity. 3. Evaluation of bone augmentation effect
  • the effect of the bone augmenting agent of the present invention is determined by preparing an experimental model animal reflecting the pathological condition of bone loss in humans such as osteoporosis, and implanting (implanting) the bone augmenting agent of the present invention into this model animal. It can be evaluated by confirming changes in bone mass at the application site.
  • Examples of such a model animal include an osteoporosis model animal (for example, a rat, a rat, or the like) produced by ovariectomy, a low calcium diet (eg, Low Ca Diet, manufactured by Nippon Clea Co., Ltd.), or a combination thereof. Mouse, etc.), or an aging-promoting mouse model produced by genetic modification, etc. (Ikuko Ezawa, Journal of the Japan Home Economics Society, vol. 38 (8) p695-703, 1987, Yamashita T. et al., J of Endocr ino l ogy 164 p239-245, 2000).
  • the change in bone mass can be confirmed, for example, by collecting tissue around the application site and performing hematoxylin and eosin staining. 4. Control of biodegradability by cross-linking of collagen
  • the bone augmenting agent of the present invention can control the rate of in vivo degradation and the rate of replacement with bone tissue by introducing crosslinks into collagen constituting the complex.
  • Crosslinking of collagen may be performed by any method such as chemical crosslinking using a crosslinking agent or a condensing agent, physical crosslinking using r-ray, ultraviolet ray, thermal dehydration, electron beam or the like.
  • the crosslinking agent include aldehyde-based crosslinking agents such as daltaraldehyde and formaldehyde; isocyanate-based crosslinking agents such as hexamethylene diisocyanate; 1-ethyl-3- (3-dimethylaminopropyl) Power Carbide-based cross-linking agents such as luposimid hydrochloride: polyepoxy-based cross-linking agents such as ethylene glycol ethyl ether; transdaltaminase; The amount of these crosslinkers used is 10 / mo per 1 g of collagen.
  • the cross-linking may be for cross-linking any part of collagen, but it is particularly preferable to cross-link carboxyl group and hydroxyl group, carboxyl group and ⁇ -amino group, and ⁇ -amino group. Further, it is preferable that at least 1% or more of the reactive functional groups are crosslinked, more preferably at least 5%. Insufficient cross-linking leads to rapid degradation in vivo, and it is not possible to expect a sufficient osteogenic effect. However, care must be taken when using an excessive amount of a cross-linking agent because it may delay absorption in vivo unnecessarily or reduce the strength of the complex and make it difficult to handle it during implantation in a living body.
  • crosslinking method using a crosslinking agent such as datalaldehyde is particularly preferable from the viewpoint of controllability of crosslinking degree and biocompatibility of the obtained composite.
  • a crosslinking method using dal aldehyde will be described.
  • a synthesis reaction of a complex containing hydroxyapatite and collagen is performed according to the method of Kikuchi et al.
  • dal ethyl aldehyde with vigorous stirring and react for 10 minutes.
  • Daltar aldehyde is added at 10 fimo 1 to 1 Ommo per 1 g of collagen in the composite biomaterial, and it is particularly preferable to add l O jLimo l to lmmo 1.
  • the temperature of the reaction solution is preferably maintained at 0 ° C to 40 ° C.
  • Filter the reaction solution immediately to separate the complex, and wash it three times with pure water to remove excess glutaraldehyde.
  • a complex in which crosslinks are introduced between collagens is obtained.
  • the obtained crosslinked complex has a slower rate of biodegradation in comparison with an uncrosslinked complex, and has sufficient indwelling properties in a living body to exhibit a sufficient osteogenic effect.
  • the cross-linking rate for obtaining a desired biodegradation rate can be evaluated, for example, by implanting the cross-linked complex into bones of experimental animals such as rats, mice, and egrets, and determining the in-vivo retention and bone formation. . If the experimental animal used is a model animal exhibiting a bone loss condition such as osteoporosis described in the preceding section, it is more suitable for evaluating the bone augmenting agent of the present invention.
  • the shape of the bone augmenting agent of the present invention is not particularly limited, and the bone augmenting agent can be formed into an arbitrary shape such as a block shape, a paste shape, a film shape, and a granule shape according to the application site and application. .
  • the composite comprising hydroxyapatite and collagen constituting the osteoprotic agent of the present invention has a sponge-like elasticity when absorbing water, and has excellent biocompatibility, osteoinductive ability or osteoconductive ability. . Therefore, when the complex is applied in a living body, it may be used after being immersed in an appropriate liquid such as physiological saline.
  • the composite biomaterial implanted in this way can quickly bond with the bone tissue and integrate with the donor-side hard tissue.
  • the bone augmentation agent of the present invention is useful for reducing bone mineral density associated with osteoporosis (including both primary and secondary), osteomalacia, osteoarthritis, rheumatoid arthritis, malignant tumors, trauma, etc. It can be used as a useful topical therapeutic. Above all, it is very suitable as a topically applied therapeutic agent for osteoporosis.
  • the bioimplantable bone augmentation agent of the present invention enables local bone augmentation at a desired site such as a femur where a fracture is a concern for osteoporosis patients who cannot expect systemic improvement by administration of existing therapeutic agents for osteoporosis. I do.
  • the bone augmenting agent of the present invention may further contain other components in addition to the essential components, hydroxyapatite and collagen, as long as the objects and effects of the present invention are not impaired.
  • Such components for example S t, Mg and C_ ⁇ 3 such as inorganic salts, Kuen acid and organic phospholipid such, BMP 2, BMP 6 and BMP 7 such osteogenic protein, bFGF, a FGF, VE GF and Growth factors such as TGF) 3.
  • the shape and size of the bone augmentation agent of the present invention are appropriately adjusted according to the application site, and implanted at a desired site in a living body.
  • the composite comprising hydroxyapatite and collagen constituting the bone augmenting agent of the present invention is bioabsorbable and has an excellent bone formation promoting effect. Therefore, the bone augmenting agent of the present invention Is gradually absorbed after application to the body, and is quickly replaced with new bone tissue.
  • FIG. 1 shows the experimental protocol of Example 1.
  • FIG. 2 shows an HE-stained image on the control side (only the hole) of the OVX Normal Ca group rat. At 6 weeks after implantation, the defect is still buried in the rats treated with 0VX, but the cortical bone thickness is thin.
  • FIG. 3 shows an HE-stained image of the HAp / Col-embedded tibia of the OVX Normal Ca group rat.
  • HAp / Col remains slightly, and new bone has begun to form around the implantation site (B: new bone, H: HAp / Col) o
  • FIG. 4 is a graph showing cancellous bone density 4 weeks after Hap / Col implantation.
  • a, b, c, and d indicate that there was a significant difference (p ⁇ 0.01 y student's t-test) between the implanted side (right limb) and the control side (left limb) in all groups.
  • FIG. 5 is a graph showing the trabecular bone density of the implanted portion. In all groups, a significant difference (p ⁇ 0.01 by student's test) was observed between the implanted side (right limb) and the control side (left limb).
  • Example 1 Hydroxyapatitano in osteoporosis model rat Bone formation by implantation of collagen (HAp / Col) complex
  • the HAp / Col complex having a structure similar to a living bone was prepared by the method of Kikuchi et al. (Kikuchi, S. et al, J., Biomater., 22 (13) (2001), 1705-1711, S. Itoh et al, J. Biomed Mater Res, (201), 445-453). 10-week-old osteoporosis model rats were implanted with the prepared complex. In the operation, a 2 mm diameter hole was made in the lateral cortical bone of the rat tibia, and HAp / Col cut to the same diameter was implanted in the right limb, while the left limb was left as a control.
  • Figure 1 shows the outline of the experimental protocol after embedding the HAp / Col complex.
  • normal diet Normal Ca Diet
  • solid animal feed for normal laboratory animals Ca: 1.11 P: 0.83, manufactured by Oriental Yeast Co., Ltd.
  • the diet was weighed and given to each rat (feed rate of 0.05 g / day per gram of body weight, feeding feed). Water was freely available.
  • the tibial bone density was measured and the tibia morphological changes were examined over time using pQCT (XCT 960A, Stratec Mediz intechnik GmbH).
  • HAp / Col was excised together with the bone tissue around the implanted site, fixed in formalin, decalcified, sliced, and subjected to hematoxylin and eosin staining (HE staining) for histological observation.
  • the HAp / Col complex was prepared according to the method of Kikuchi et al. (M. Kikuchi, et al., Biomater., 22 (13) (2001), 1705-1711). First, calcium carbonate (for alkali analysis, Wako Pure Chemical), phosphoric acid (special grade, Wako Pure Chemical), and atelocollagen (Nitta Gelatin) derived from bushu skin were prepared as starting materials. Calcium carbonate was calcined at 1050 and hydrolyzed to form a single phase of calcium hydroxide.
  • the pH in the reaction vessel was controlled to pH 9 by a controller, and the temperature was controlled to 40 by a hot water bath.
  • reaction solution was allowed to stand still for 3 hours while being suspended, and a cross-linking agent: daltaraldehyde was added with vigorous stirring, followed by a reaction for 10 minutes. After the crosslinking reaction, the complex was immediately filtered and washed three times with pure water. As a comparison, a cross-linking reaction was similarly carried out using water-soluble carbodiimide and transdalminase (both condensing agents).
  • the cross-linking reaction was performed with respect to collagen lg in the complex, respectively, with dartaldehyde: 0.019 to 13.5 ol / g, water-soluble carbodiimide: 0.0191 to 8.8 mmol / g, and transglutaminase. : 19.
  • the test was performed with changing the range of 1-1910 mg / g.
  • all ⁇ - amino groups in a collagen molecule can be crosslinked theoretically at 0.191 imno l / g.
  • the crosslinked complex was dispersed in pure water and observed using a transmission electron microscope Rapid-VueR (manufactured by Beckman-Colter).
  • the crosslinked composite was subjected to dehydration molding by uniaxial pressing at 2 OMPa for 24 hours, and the three-point bending strength was measured by a universal testing machine (Autograph AGS-lkN, manufactured by Shimadzu). The measurement was performed using a crosslinked composite piece of 5 x 3 x 20 mm at a crosshead speed of 500 zm and a span of 15 mm.
  • the pressure molding was crosslinked complexes HAp / Col / H 2 0 ratio of the carbon deterrainator (LEC0 Ltd., RC - 412) was used for the measurement.
  • the amount of ⁇ -amino group was measured by the sulfo-SDTB method, and the amount of crosslinkage was determined.
  • the fiber length of the daltaraldehyde cross-linked composite was 44.8 mm on average.
  • crosslinked hydroxyapatite No macro-orientation was observed in collagen and collagen, indicating that crosslinking occurred randomly.
  • the nanoscopic structure similar to living bone (the orientation of HAp in the form of collagen monofilament) was substantially maintained.
  • concentration of daltaraldehyde increased, the color of the complex changed from dark yellow to brown. This was thought to be due to the excess dartal aldehyde cross-linking between the self-assembled fibers and increasing the composite fiber length.
  • water-soluble carbodiimide-transdaltaminase Addition was not immediately observable. This was thought to be due to the fact that water-soluble carbodiimiditol transdarinase is a condensing agent, so that cross-linking densified the complex and prevented swelling.
  • the biodegradability of the cross-linked HAp / Col composite was examined by implanting the cross-linked product (2X2X2 marauder) obtained in Example 1 with various concentrations of dartaldehyde in the tibiae of the egret.
  • bioimplantable bone augmentation agent comprising a composite containing hydroxyapatite and collagen according to the present invention enables effective bone augmentation at a desired site.
  • the bone augmentation agent is useful as a local therapeutic agent for diseases associated with bone loss such as osteoporosis.

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Abstract

L'invention concerne un agent permettant d'obtenir une repousse osseuse conçu pour être implanté dans un organisme, composé d'un matériau composite à base d'hydroxyapatite et de collagène. L'invention concerne également l'utilisation de cet agent comme agent thérapeutique pour traiter l'ostéoporose.
PCT/JP2002/012971 2002-03-11 2002-12-11 Agent permettant d'obtenir une repousse osseuse et agent therapeutique servant a traiter l'osteoporose WO2003094984A1 (fr)

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US10/937,732 US7229971B2 (en) 2002-03-11 2004-09-10 Regulation of biodegradability of composite biomaterials

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JP4968639B2 (ja) * 2005-12-15 2012-07-04 独立行政法人物質・材料研究機構 リン酸カルシウム及びアパタイト／コラーゲン複合物からなる複合体
KR20100007180A (ko) * 2008-07-11 2010-01-22 세원셀론텍(주) 뼈 재생용 콜라겐 젤 조성물의 제조방법
JP2010273847A (ja) * 2009-05-28 2010-12-09 Tokyo Institute Of Technology 高密度多孔質複合体
TWI579007B (zh) * 2010-07-02 2017-04-21 艾格諾福斯保健公司 骨再生材料之用途

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JPH10127753A (ja) * 1996-10-28 1998-05-19 Agency Of Ind Science & Technol コラーゲン繊維−リン酸カルシウム化合物複合材料及びその製造法
JPH11199209A (ja) * 1998-01-19 1999-07-27 Natl Inst For Res In Inorganic Materials 有機無機配向性複合材料の製造方法
JP2000005298A (ja) * 1998-06-17 2000-01-11 Natl Inst For Res In Inorg Mater アパタイトコーティング有機材料の製造方法
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