Sugar chain complex, drug carrier and drug delivery system

Abstract

The present invention provides a sugar chain complex having a sugar chain to which a hydroxyapatite-binding molecule is bound, the hydroxyapatite-binding molecule being an acidic peptide and / or estradiol.

Description

Technical Field

[0001] The present invention relates to a sugar chain complex, a drug carrier and a drug delivery system. Background Art

[0002] Patent Document 1 describes an ink comprising: (1) alginic acid and / or a salt thereof; (2) water; and (3) at least one compound selected from the group consisting of a compound having a peptide bond and a glycosaminoglycan. The ink is gelled by an inkjet method to form microbeads. By using this ink, both good gel forming properties and good ink discharge properties can be achieved.

[0003] It is also described that compounds having peptide bonds and glycosaminoglycans are expected to be used as scaffold materials in the field of regenerative medicine because of their excellent cell adhesion. It is described that the microbeads are used in the development of drug delivery systems and the like. Prior art literature Patent Literature

[0004] Patent Document 1: Japanese Patent Application Publication No. 2013-111401 Summary of the invention Problems to be solved by the invention

[0005] The fluidity of the gelled microbeads is lower than that of liquid ink. Therefore, when the microbeads contain drugs and are used as drug carriers, the drugs tend to stay at a predetermined location in the body, thereby increasing the local drug concentration.

[0006] However, the microbeads of Patent Document 1 increase the local drug concentration entirely due to the low fluidity of the gel. Therefore, it is not possible to fully suppress the decrease in concentration over time. When applied to a drug delivery system, there is room for improvement in appropriately increasing the local drug concentration.

[0007] In addition, the bone is not considered as a location for increasing the local drug concentration in the body in Patent Document 1. When treating bone-related diseases such as fractures and osteoporosis, locally increasing the drug concentration around the bone can help improve the treatment effect and reduce the amount of drug used.

[0008] Generally, it is known that sugar chains are easily bound to drugs such as growth factors. Therefore, it is necessary to appropriately increase the concentration of sugar chains around bones in order to use sugar chains as drug carriers in drug delivery systems. Means for solving problems

[0009] The sugar chain complex of embodiment 1 has a sugar chain to which a hydroxyapatite-binding molecule is bound, and the hydroxyapatite-binding molecule is at least one of an acidic peptide and estradiol.

[0010] Regarding embodiment 2, in the sugar chain complex of embodiment 1, the acidic peptide contains at least one selected from aspartic acid and glutamic acid. Regarding embodiment 3, in the sugar chain complex according to embodiment 1 or 2, the sugar chain contains at least one selected from the group consisting of heparin, chondroitin sulfate and hyaluronic acid.

[0011] Regarding embodiment 4, in the sugar chain complex of embodiment 3, the heparin is a low molecular weight heparin. Embodiment 5 is the sugar chain complex according to any one of Embodiments 1 to 4, wherein at least one selected from the group consisting of bone morphogenetic protein, fibroblast growth factor, vascular endothelial cell growth factor and hepatocyte growth factor is further bound to the sugar chain.

[0012] The drug carrier of embodiment 6 contains the sugar chain complex described in any one of embodiments 1 to 5. The drug delivery system of embodiment 7 uses the sugar chain complex described in any one of embodiments 1 to 5 to increase the drug concentration around bones. Effects of the Invention

[0013] According to the sugar chain complex of the present invention, the concentration of sugar chains around bones can be appropriately increased. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 It is a schematic diagram of the sugar chain complex. Figure 2 This is a reaction formula for binding an aspartic acid residue as a hydroxyapatite-binding molecule to a low-molecular-weight heparin as a sugar chain. Figure 3 The top image is a microscope photo of a rat, and the bottom image is a fluorescent image taken at the same location. Figure 4 These are microscopic photographs showing that artificial bones containing the sugar chain complex were placed around the L4 and L5 vertebrae of rats and bone healing was evaluated. DETAILED DESCRIPTION

[0015] Embodiments that embody the sugar chain complex of the present invention will be described. The sugar chain complex has sugar chains to which hydroxyapatite-binding molecules are bound. The sugar chain is described below.

[0016] <Sugar Chain> In the present invention, "sugar chain" refers to a compound formed by the connection of two or more monosaccharides. In a sugar chain, two or more monosaccharides are connected by dehydration condensation based on glycosidic bonds. Sugar chains are not limited to compounds formed by connecting only monosaccharides, but may also be compounds formed by connecting derivatives of monosaccharides. It may also be a compound formed by mixing and connecting monosaccharides and derivatives of monosaccharides. Sugar chains may be linear types in which monosaccharides and derivatives of monosaccharides are connected in a linear chain, or branched types with branches.

[0017] Specific examples of sugar chains are not particularly limited, and examples thereof include glucose, galactose, mannose, fucose, xylose, N-acetylglucosamine, N-acetylgalactosamine, and derivatives thereof. Sugar chains may be decomposed products of polysaccharides, glycoproteins, proteoglycans, glycosaminoglycans, and glycolipids.

[0018] There are no particular restrictions on the derivatives of the monosaccharide, and examples of the sugar constituting the sugar chain include sugars having a carboxyl group, sugars having an amino group, deoxygenated sugars, sugars having a sulfate group, sugars having a phosphate group, etc. Alternatively, examples include substances in which the amino group, sulfate group, or phosphate group is substituted with a salt.

[0019] Specific examples of the substance having a carboxyl group include, for example, sialic acid, aldonic acids such as D-gluconic acid, iduronic acid, uronic acids such as glucuronic acid (D-glucuronic acid), and the like.

[0020] Specific examples of the substance having an amino group include D-glucosamine and D-galactosamine. Specific examples of the deoxygenated substance include 2-deoxy-D-ribose and the like.

[0021] Specific examples of the substance having a sulfate group include phosphorylated sugars and the like. The sugar chains mentioned above may be used alone or in combination of two or more. Among them, the sugar chains are preferably glycosaminoglycans.

[0022] Glycosaminoglycans are composed of linear polysaccharides and may be in the form of salts such as sodium salts. As the specific example of glycosaminoglycan, there is no particular limitation, and hyaluronic acid, chondroitin sulfate, keratinic acid, acetylated heparin acid, heparin, low molecular weight heparin etc. can be enumerated. Among these, preferably the sugar chain is hyaluronic acid, chondroitin sulfate, heparin, low molecular weight heparin. In addition, if the sugar chain is low molecular weight heparin, hydroxyapatite binding molecules are easy to combine, and drugs such as growth factors are also easy to combine, so it is preferred.

[0023] In addition, heparin generally refers to a substance having an average molecular weight of 15000 or more and 20000 or less. Low molecular weight heparin refers to low molecular weight heparin obtained by depolymerizing heparin or low molecular weight heparin obtained by chemical synthesis. The average molecular weight of low molecular weight heparin is 1000 or more and 10000 or less.

[0024] The method for measuring the average molecular weight is not particularly limited, and a known measuring method can be appropriately adopted. As a method for measuring the average molecular weight, for example, gel permeation chromatography using a standard substance with a known molecular weight can be mentioned.

[0025] The hydroxyapatite-binding molecule is described below. <Hydroxyapatite-binding molecules> The hydroxyapatite-binding molecule refers to a residue of a compound having a property of easily binding to hydroxyapatite (hereinafter also referred to as HA), which is a main constituent of bones.

[0026] In addition, the "sugar chain to which the hydroxyapatite-binding molecule is bound" of the present invention means that the residue of a compound having the property of easily binding to HA is bound to the sugar chain. And the substance formed by the binding of the HA-binding molecule to the sugar chain is called a sugar chain complex.

[0027] The compound having the property of easily binding to HA is not particularly limited, and examples thereof include acidic peptides, bisphosphonates, and estradiol. Bisphosphonates are compounds similar to pyrophosphate and are known as compounds having a high affinity for HA. Estradiol is a type of estrogen.

[0028] Among these, the HA-binding molecule is preferably an acidic peptide. Specific examples of the acidic peptide include aspartic acid and glutamic acid.

[0029] Acidic peptides are peptides having a carboxyl group on the side chain. When the HA-binding molecule is an acidic peptide, the acidic peptide binds to HA via the carboxyl group on the side chain binding to the phosphate of HA. Similarly, when the HA-binding molecule is not an acidic peptide, the HA-binding molecule binds to HA via the functional group of the HA-binding molecule binding to the phosphate of HA.

[0030] Aspartic acid and glutamic acid may be composed of one aspartic acid or one glutamic acid, or may be a substance in which a plurality of aspartic acids or a plurality of glutamic acids are linked in a chain. That is, the acidic peptide may be an acidic peptide in which a plurality of structural units are linked.

[0031] The acidic peptide may be a substance formed by combining one aspartic acid and one glutamic acid. The acidic peptide may be a substance formed by combining aspartic acid and glutamic acid, and at least one of them may be combined with multiple aspartic acids. The acidic peptide may be a substance formed by combining multiple aspartic acids and multiple glutamic acids. It may be a substance formed by combining multiple aspartic acids and multiple glutamic acids randomly, or it may be a substance formed by combining multiple structural units.

[0032] In the case of a substance in which a plurality of aspartic acids or a plurality of glutamic acids are bonded, a substance in which only a plurality of aspartic acids are bonded or a substance in which only a plurality of glutamic acids are bonded is preferred.

[0033] The upper limit of the number of the bonded structural units is not particularly limited, but is preferably 20, and more preferably 10. The lower limit of the number of the bonded structural units is not particularly limited, but is preferably 2, and more preferably 5.

[0034] The above acidic peptides may be used alone or in combination of two or more. <Method for producing sugar chain complex> The method for binding the HA-binding molecule to the sugar chain, that is, the method for producing the sugar chain complex is not particularly limited, and a known method can be appropriately adopted.

[0035] The following describes a method for binding an aspartic acid residue as an HA-binding molecule to a sugar chain. First, a cross-linking agent having two amino groups is bonded to a carboxyl group or an aldehyde group of a sugar chain. A specific example of a cross-linking agent is 1,11-diamino-3,6,9-trioxaundecane. A dehydration condensation reaction is carried out between the carboxyl group or the aldehyde group of the sugar chain and one amino group of the cross-linking agent to form a peptide bond.

[0036] Furthermore, a divalent reagent having N-hydroxysuccinimide active ester and maleimide group with different reactivities introduced at both ends of the molecule is bonded to the other amino group of the crosslinking agent. Specific examples of the divalent reagent include Sulfo-SMCC.

[0037] The thiol (SH) biotin standard reagent to which aspartic acid is bonded is reacted with the maleimide group of the above-mentioned divalent reagent. By carrying out the above steps, a sugar chain complex having aspartic acid residues bonded to the sugar chain can be produced.

[0038] The sugar chain complex of the present invention may further be bound to a drug. The following describes drugs that bind to the sugar chain complex. <Medication> The drug that binds to the sugar chain complex is not particularly limited, and any known drug used in bone-related treatments can be used as appropriate.

[0039] Examples of the drug include growth factors, which are a general term for endogenous proteins that promote the growth and differentiation of specific cells. Specific examples of growth factors include bone morphogenetic protein, fibroblast growth factor, vascular endothelial cell growth factor, and hepatocyte growth factor.

[0040] Bone morphogenetic protein (hereinafter also referred to as BMP) is a group of proteins identified as molecules that induce or promote differentiation of bone tissue or cartilage. BMP is also called bone formation factor.

[0041] Fibroblast growth factor (hereinafter also referred to as FGF) is a group of proteins identified as molecules related to angiogenesis, wound healing, and embryonic development. FGF plays an important role in the proliferation and differentiation of a wide range of cells and tissues.

[0042] Vascular endothelial growth factor (hereinafter also referred to as VEGF) is a group of proteins identified as molecules involved in vasculogenesis and angiogenesis. VEGF is also called vascular endothelial cell proliferation factor, vascular endothelial growth factor, vascular endothelial growth factor, etc.

[0043] Hepatocyte growth factor (hereinafter also referred to as HGF) is a group of proteins identified as molecules involved in the regeneration of liver and kidney and the protection of nerves. The above drugs may be used alone or in combination of two or more. In addition, commercially available drugs may also be used.

[0044] The sugar chain complex of the present invention may be pre-bound with the above-mentioned drug. If the drug is pre-bound, when the sugar chain complex is used as a drug carrier, the operation of binding the drug to the sugar chain complex can be omitted. Therefore, it can be easily used as a drug carrier.

[0045] Alternatively, the conjugate sugar chain may be bound to the drug at the stage of use as a drug carrier instead of the above-mentioned drug. Since the conjugate sugar chain and the drug can be stored separately, it is easy to maintain the quality of each of the conjugate sugar chain and the drug in a good state.

[0046] In addition, the sugar chain complex can also be used in a state where the drug is not bound. That is, it can also be constructed in a manner such that the sugar chain complex and the drug are bound after being administered to a predetermined position in the body. In such a construction, the operation of binding the two can be omitted.

[0047] The method for binding a drug to a sugar chain complex is described below. <Method for Binding Drug to Sugar Chain Complex> The method for binding the drug to the sugar chain complex is not particularly limited, and a known method can be appropriately adopted.

[0048] As a method for binding a drug to a sugar chain complex, for example, a liquid sugar chain complex and a liquid drug are prepared, weighed and mixed so as to achieve a predetermined mixing ratio, and then left to stand for a predetermined time, thereby binding the drug to the sugar chain complex.

[0049] Specifically, by mixing a liquid sugar chain complex with a liquid drug, functional groups such as amino and carboxyl groups of the drug protein can be bound to functional groups such as carboxyl groups, aldehyde groups, and sulfate groups of the sugar chain complex.

[0050] The standing time is not particularly limited, but is preferably 1 hour or longer, more preferably 2 hours or longer. The content ratio of the sugar chain complex and the drug is not particularly limited. When the total content ratio of the two is set to 100 mass%, the lower limit of the content ratio of the sugar chain complex is preferably 50 mass%, more preferably 60 mass%, and further preferably 70 mass%. The upper limit of the content ratio of the sugar chain complex is preferably 95 mass%, more preferably 90 mass%, and further preferably 80 mass%.

[0051] In addition, stirring may be appropriately performed after the above mixing. Instead of mixing the liquid conjugate and the liquid drug, a powdered conjugate may be mixed with a powdered drug. The powdered conjugate and the powdered drug may be prepared, for example, by freeze-drying the liquid conjugate and the liquid drug.

[0052] Alternatively, instead of simply mixing the liquid sugar chain complex and the liquid drug, the liquid sugar chain complex and the liquid drug may be mixed and then impregnated into the artificial bone formed of HA. The impregnation time is not particularly limited, but is preferably 30 minutes or more, and more preferably 1 hour or more.

[0053] By infiltrating into the artificial bone, in addition to the combination of the sugar chain complex and the drug, the sugar chain complex can also be combined with the artificial bone. By combining the sugar chain complex with the artificial bone, the sugar chain complex and the artificial bone can be applied to a specified position in the body. By combining the sugar chain complex with the artificial bone in advance, the concentration of the drug around the bone can be more appropriately increased. It is also possible to disperse the powdered sugar chain complex and the powdered drug in the artificial bone, and combine the sugar chain complex with the drug in the artificial bone.

[0054] <Other ingredients> The sugar chain complex may contain other components besides the above-mentioned ones. Examples of other components include preservatives, thickeners, dispersants, colorants, surfactants, solvents and the like. The content ratio of other components in the sugar chain complex is not particularly limited, but is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 3% by mass or less.

[0056] <Application methods, dosage forms, and uses of sugar chain complexes> The application form of the sugar chain complex is not particularly limited, and it can be used, for example, as a pharmaceutical product, a designated quasi-drug, or a quasi-drug.

[0057] The dosage form of the sugar chain complex is not particularly limited, and it can be appropriately prepared in a powdery, solid, semisolid, liquid, or the like form. The use of the sugar chain complex is not particularly limited, and the sugar chain complex can be used for known uses. Examples of the use of the sugar chain complex include drug carriers used in drug delivery systems.

[0058] <Function and Effect> The action of the sugar chain complex according to this embodiment will be described. like Figure 1 As shown, in the sugar chain complex 10, the eight aspartic acids ( Figure 1 The residue described as (Asp)8) in the sugar chain complex 10 is bound to the sugar chain 11. In addition, in the sugar chain complex 10, the bone morphogenetic protein ( Figure 1 In the example described as BMP-2) 13 binds to sugar chain 11. When sugar chain complex 10 is administered into the body, HA binding molecule 12 binds to bone, thereby making it easy for sugar chain complex 10 to remain on the bone surface. That is, the concentration of sugar chains around the bone can be appropriately increased.

[0059] In addition, bone morphogenetic protein 13 is locally present on the bone surface due to the binding of bone morphogenetic protein 13 to sugar chain 11. Compared with the prior art that increases the local drug concentration by low fluidity of gel, the decrease in drug concentration over time can be effectively suppressed. Thus, the concentration of bone morphogenetic protein 13 around the bone can be appropriately increased.

[0060] It should be noted that the above-mentioned "surroundings of the bone" are not particularly limited, and for example, refer to a range within 10 mm from the surface of the bone. The effects of the sugar chain complex according to the present embodiment will be described.

[0061] (1) The sugar chain complex has a sugar chain to which an HA-binding molecule is bound, and the HA-binding molecule is at least one of an acidic peptide and estradiol. By binding the HA-binding molecule to the bone, the sugar chain complex can be easily retained on the bone surface, thereby appropriately increasing the concentration of sugar chains around the bone.

[0062] (2) The acidic peptide contains at least one selected from aspartic acid and glutamic acid. The acidic peptide can more appropriately increase the concentration of sugar chains around bones by containing at least one selected from aspartic acid and glutamic acid.

[0063] (3) The sugar chain contains at least one selected from heparin, chondroitin sulfate and hyaluronic acid. When a drug such as a growth factor is used for bone-related treatment, the drug is easily bound to the sugar chain. Therefore, the drug concentration around the bone can be appropriately increased.

[0064] (4) Heparin is low molecular weight heparin. Low molecular weight heparin easily binds to HA-binding molecules and also easily binds to drugs such as growth factors. Therefore, the concentration of drugs such as growth factors around bones can be more appropriately increased.

[0065] (5) At least one selected from the group consisting of bone morphogenetic protein, fibroblast growth factor, vascular endothelial growth factor and hepatocyte growth factor is bound to the sugar chain. Since the concentration of these drugs around the bone can be appropriately increased, it helps to improve the therapeutic effect and reduce the amount of drugs used when performing bone-related treatments.

[0066] (6) To provide a drug carrier containing the above-mentioned sugar chain complex. Also provided is a drug delivery system for increasing the concentration of a drug around bones using the above-mentioned sugar chain complex. Therefore, the drug delivery system and the drug carrier used in the drug delivery system can appropriately increase the drug concentration in a local location such as the periphery of bones. Example

[0067] Although examples and the like are given below to more specifically describe the configuration and effects of the present invention, the present invention is not limited to these examples. Test category 1 (Preparation of sugar chain complexes) (Example 1) according to Figure 2 The sugar chain complex was prepared according to the reaction formula shown.

[0068] As the sugar chain, commercially available low molecular weight heparin was used. The average molecular weight of low molecular weight heparin was 5000. In addition, as the HA binding molecule, commercially available aspartic acid was used. Aspartic acid was formed by bonding 8 aspartic acids.

[0069] like Figure 2As shown, as step 1, low molecular weight heparin is dissolved in 2-morpholinoethanesulfonic acid (also referred to as MES) as a buffer. 1,11-diamino-3,6,9-trioxaundecane as a cross-linking agent and sodium cyanoborohydride as an imine reducing agent are mixed in the resulting solution. After shaking at room temperature for 18 hours, centrifugation is performed. After washing 3 times with phosphate buffered saline (hereinafter also referred to as PBS), the residue is diluted with PBS to obtain a diluted solution.

[0070] Next, as step 2, Sulfo-SMCC was added to the above-mentioned diluted solution as a cross-linking agent of the divalent reagent. After being kept at room temperature for 30 minutes, the solution was washed three times with PBS and further ultrafiltered. The obtained concentrated solution was dissolved in PBS to obtain a dissolved solution.

[0071] By carrying out step 1, 2,1,11-diamino-3,6,9-trioxaundecane and Sulfo-SMCC were conjugated to low molecular weight heparin. Next, as step 3, the above-mentioned solution is mixed with a thiol (SH) biotin standard reagent bound to aspartic acid. After keeping at room temperature for 30 minutes, ultrafiltration is performed. Then, it is washed three times with an acetic acid buffer. By performing the above steps 1 to 3, a liquid sugar chain complex bound to aspartic acid residues is prepared.

[0072] (Comparative Example 1) Commercially available PBS was used only without using the sugar chain complex. (Comparative Example 2) Instead of using the sugar chain complex, only commercially available bone morphogenetic protein (hereinafter also referred to as BMP-2) was used. BMP-2 is one of the above-mentioned BMPs and refers to a dimer of BMP.

[0073] Test Category 2 (Evaluation) The sugar chain concentration around the bone when the sugar chain complex of Example 1 was administered into the body was evaluated. In addition, the drug concentration around the bone when the drug was bound to the sugar chain complex of Example 1 and administered into the body was evaluated.

[0074] (Concentration of sugar chains around bones) A fluorescent labeling agent was bound to the sugar chain complex of Example 1 using a known method. Fluorescent labeling agent used was fluorescein isothiocyanate (also known as FITC). The sugar chain complex bound to the fluorescent labeling agent was subcutaneously injected into rats. After 24 hours, a microscope photo of the rat was taken. Similarly, a fluorescent image of the rat was taken. The results are shown in Figure 3It should be noted that the method of administering the sugar chain complex is not limited to subcutaneous injection (subcutaneous administration), and a known method used in a drug delivery system can be appropriately adopted. The sugar chain complex bound to a drug can also be administered by a known method used in a drug delivery system.

[0075] (Drug concentration around bone) The sugar chain complex (2 nmol) and BMP-2 (2 μg) of Example 1 were weighed and mixed in a culture dish. After standing for 2 hours, a commercially available artificial bone having a cubic shape of about 4 mm in length, width and height was placed in the culture dish, and the sugar chain complex and BMP-2 were infiltrated into the artificial bone. The infiltration was performed for 1 hour.

[0076] Next, the muscles of the back of 8-week-old Sprague-Dawley rats (hereinafter also referred to as SD rats) were divided to expose the transverse processes of L4 vertebrae and L5 vertebrae. The transverse processes of L4 vertebrae and L5 vertebrae were peeled using an electric rod. Artificial bones impregnated with sugar chain complexes and BMP-2 were configured around the transverse processes after peeling. After 8 weeks, the L4 vertebrae and L5 vertebrae of SD rats were observed under a microscope.

[0077] In Comparative Example 1, as a control, only PBS was used instead of the sugar chain complex (2 nmol / L) and BMP-2 (2 μg) of Example 1. The test was performed under the same conditions as in Example 1 except for the above.

[0078] In Comparative Example 2, only BMP-2 (2 μg) was used instead of the sugar chain complex (2 nmol / L) and BMP-2 (2 μg) in Example 1. The experiment was conducted under the same conditions as in Example 1 except for the above. The results are shown in Figure 4 .

[0079] (Evaluation results) Figure 3 The upper part is a microscope photograph of a rat 20 stained with hematoxylin-eosin (HE). The skull 21 is located on the left side, and the spine 22 is located on the right side. The sternum 23 is located below the spine 22.

[0080] Figure 3 Below is the fluorescence image of the same part as above. Figure 3 Below the , the lighter colored part means the stronger fluorescence reaction. The part with stronger fluorescence reaction means that the fluorescent labeling reagent exists in large amounts and the sugar chains bound to the fluorescent labeling reagent exist in large amounts.

[0081] according to Figure 3In the fluorescence images, in Example 1, the fluorescence reaction around the skull 21, spine 22, sternum 23 and other bones of the rat was enhanced. This confirmed that the concentration of sugar chains around the bones was appropriately increased. That is, it was confirmed that sugar chains were specifically transported to the bones (HA) by subcutaneous administration.

[0082] like Figure 4 As shown in FIG. 1 , in Comparative Examples 1 and 2, the transverse processes of the L4 and L5 vertebrae after skinning remain in the skinning state. That is, a part of the transverse process is still missing. In addition, a part of the artificial bone remains at the position separated from the L4 and L5 vertebrae. Based on these, it was confirmed that in Comparative Examples 1 and 2, bone formation was not observed between the transverse process and the artificial bone, and the bone healing was insufficient.

[0083] In contrast, in Example 1, the transverse processes of the L4 and L5 vertebrae after skinning were repaired to a certain extent. That is, artificial bone was attached around the transverse process, and a large amount of artificial bone was healed compared to Comparative Examples 1 and 2. Based on this, it was confirmed that bone healing was progressing in Example 1. In addition, it was indirectly confirmed that the concentration of BMP-2 around the bone was appropriately increased. Description of Reference Numerals

[0084] 10…sugar chain complex, 11…sugar chain, 12…HA binding molecule, 13…bone morphogenetic protein, 20…rat, 21…skull, 22…vertebra, 23…sternum.

Claims

1. A sugar chain complex, characterized in that: It has a sugar chain to which a hydroxyapatite-binding molecule is bound, and the hydroxyapatite-binding molecule is at least one of an acidic peptide and estradiol.

2. The sugar chain complex according to claim 1, wherein The acidic peptide contains at least one selected from aspartic acid and glutamic acid.

3. The sugar chain complex according to claim 1, wherein The sugar chain contains at least one selected from the group consisting of heparin, chondroitin sulfate, and hyaluronic acid.

4. The sugar chain complex according to claim 3, wherein The heparin is low molecular weight heparin.

5. The sugar chain complex according to claim 1, wherein At least one selected from the group consisting of bone morphogenetic protein, fibroblast growth factor, vascular endothelial cell growth factor and hepatocyte growth factor is further bound to the sugar chain. A drug carrier comprising the sugar chain complex according to claim 1. 7 . A drug delivery system, which uses the sugar chain complex according to claim 1 to increase the drug concentration around bones.

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