Glycan complex, drug carrier, and drug delivery system

Abstract

The glycan complex has a sugar chain to which a hydroxyapatite-binding molecule is bonded. The hydroxyapatite-binding molecule is at least one of an acidic peptide and estradiol.

Description

Glycoconjugates, drug carriers, and drug delivery systems

[0001] The present invention relates to a glycoconjugate, a drug carrier, and a drug delivery system.

[0002] Patent Document 1 describes an ink containing (1) alginic acid and / or a salt thereof, (2) water, and (3) at least one compound selected from the group consisting of compounds having peptide bonds and glycosaminoglycans. Microbeads are formed by gelling this ink using an inkjet method. The use of this ink achieves both good gel-forming properties and good ink ejection properties.

[0003] Furthermore, it is described that compounds with peptide bonds and glycosaminoglycans have excellent cell adhesive properties and are therefore expected to be used as scaffolding materials in the field of regenerative medicine.It is also described that the above microbeads can be used in the development of drug delivery systems, etc.

[0004] JP 2013-111401 A

[0005] Gelled microbeads have lower fluidity than liquid ink. Therefore, when these microbeads are loaded with drugs and used as drug carriers, the drugs tend to remain in the designated locations in the body, making it possible to increase the local drug concentration.

[0006] However, the microbeads of Patent Document 1 only increase the local drug concentration by using a gel with low fluidity. Therefore, it is not possible to sufficiently suppress the decrease in concentration over time. When used in a drug delivery system, there is room for improvement in terms of appropriately increasing the local drug concentration.

[0007] Furthermore, Patent Document 1 does not consider bones as a location in the body where the concentration of a drug can be increased locally. When treating bone-related conditions such as fractures and osteoporosis, locally increasing the concentration of a drug around the bone leads to improved therapeutic effects and a reduction in the amount of drug used.

[0008] It is generally known that sugar chains easily bind to drugs such as growth factors, and therefore, it is necessary to appropriately increase the concentration of sugar chains around bones, assuming that sugar chains will be used as drug carriers in drug delivery systems.

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

[0010] Aspect 2 is the glycoconjugate of Aspect 1, wherein the acidic peptide contains at least one selected from aspartic acid and glutamic acid. Aspect 3 is the glycoconjugate of Aspect 1 or 2, wherein the glycoconjugate contains at least one selected from heparin, chondroitin sulfate, and hyaluronic acid.

[0011] Aspect 4 is the glycoconjugate of Aspect 3, wherein the heparin is a low-molecular-weight heparin. Aspect 5 is the glycoconjugate of any one of Aspects 1 to 4, wherein at least one selected from bone morphogenetic protein, fibroblast growth factor, vascular endothelial growth factor, and hepatocyte growth factor is further bound to the glycoconjugate.

[0012] A drug carrier of Aspect 6 contains the glycoconjugate according to any one of Aspects 1 to 5. A drug delivery system of Aspect 7 uses the glycoconjugate according to any one of Aspects 1 to 5 to increase the concentration of a drug around bone.

[0013] The sugar chain complex of the present invention can suitably increase the concentration of sugar chains around bones.

[0014] Figure 1 is a schematic diagram of a sugar chain complex. Figure 2 shows the reaction formula for binding low-molecular-weight heparin as a sugar chain to an aspartic acid residue as a hydroxyapatite-binding molecule. The top of Figure 3 is a micrograph of a rat, and the bottom is a fluorescent image taken at the same position. Figure 4 is a micrograph of an artificial bone containing a sugar chain complex placed around the L4 and L5 vertebrae of a rat to evaluate bone fusion.

[0015] A specific embodiment of the sugar chain complex according to the present invention will be described. The sugar chain complex has a sugar chain bound to a hydroxyapatite-binding molecule. The sugar chain will be described below.

[0016] <Sugar chain> In the present invention, the term "sugar chain" refers to a compound in which two or more monosaccharides are linked. In a sugar chain, two or more monosaccharides are linked by dehydration condensation through a glycosidic bond. The sugar chain is not limited to a compound in which only monosaccharides are linked, but may also be a compound in which monosaccharide derivatives are linked. It may also be a compound in which a mixture of monosaccharides and monosaccharide derivatives are linked. The sugar chain may be a linear type in which monosaccharides or monosaccharide derivatives are linked in a linear chain, or a branched type having branched chains.

[0017] Specific examples of sugar chains include, but are not limited to, glucose, galactose, mannose, fucose, xylose, N-acetylglucosamine, N-acetylgalactosamine, and derivatives thereof. The sugar chain may be a polysaccharide degradation product, a glycoprotein, a proteoglycan, a glycosaminoglycan, or a glycolipid.

[0018] The monosaccharide derivatives are not particularly limited, but examples thereof include those in which the sugars constituting the sugar chain have a carboxyl group, an amino group, deoxygenated sugars, sulfate groups, or phosphate groups, etc. Alternatively, those in which the amino group, sulfate group, or phosphate group has been substituted with a salt may be used.

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

[0020] Specific examples of the amino group-containing compounds include D-glucosamine, D-galactosamine, etc. Specific examples of the deoxygenated compounds include 2-deoxy-D-ribose, etc.

[0021] Specific examples of the above-mentioned saccharides having sulfate groups include phosphorylated sugars. The above-mentioned saccharide chains may be used singly or in combination of two or more. Among these, the saccharide chain is preferably a glycosaminoglycan.

[0022] Glycosaminoglycans are composed of linear polysaccharides. Glycosaminoglycans may be in the form of salts such as sodium salts. Specific examples of glycosaminoglycans include, but are not limited to, hyaluronic acid, chondroitin sulfate, keratanic acid, heparanic acid, heparin, and low molecular weight heparin. Among these, the sugar chain is preferably hyaluronic acid, chondroitin sulfate, heparin, or low molecular weight heparin. Furthermore, low molecular weight heparin sugar chains are preferred because they are more likely to bind to hydroxyapatite-binding molecules and drugs such as growth factors.

[0023] Generally, heparin has an average molecular weight of 15,000 or more and 20,000 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 1,000 or more and 10,000 or less.

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

[0025] The hydroxyapatite-binding molecule will be described below. <Hydroxyapatite-binding molecule> The hydroxyapatite-binding molecule refers to a residue of a compound that has the property of easily binding to hydroxyapatite (hereinafter also referred to as HA), a major component of bone.

[0026] Furthermore, the term "sugar chain bound to a hydroxyapatite-binding molecule" used in the present invention means that a residue of a compound that has the property of easily binding to HA is bound to the sugar chain. The HA-binding molecule bound to the sugar chain is referred to as a sugar chain complex.

[0027] Compounds that have the property of easily binding to HA include, but are not limited to, acidic peptides, bisphosphonates, estradiol, etc. Bisphosphonates are compounds similar to pyrophosphate and are known to have 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 acidic peptides include aspartic acid and glutamic acid.

[0029] Acidic peptides are peptides with a carboxyl group in the side chain. When the HA-binding molecule is an acidic peptide, the carboxyl group in the side chain binds to the phosphate of HA, thereby binding the acidic peptide to HA. Similarly, when the HA-binding molecule is other than an acidic peptide, the functional group of the HA-binding molecule binds to the phosphate of HA, etc., thereby binding the HA-binding molecule to HA.

[0030] The aspartic acid or glutamic acid may be composed of one aspartic acid or one glutamic acid, or may be composed of multiple aspartic acids or multiple glutamic acids linked together in a chain, i.e., the acidic peptide may be composed of multiple linked structural units.

[0031] The acidic peptide may be one in which one aspartic acid and one glutamic acid are bonded together. The acidic peptide may be one in which aspartic acid and glutamic acid are bonded together, and at least one of them may be bonded in multiples. The acidic peptide may be one in which multiple aspartic acids and multiple glutamic acids are bonded together. The acidic peptide may be one in which multiple aspartic acids and multiple glutamic acids are bonded together randomly, or one in which multiple structural units are bonded together.

[0032] When a plurality of aspartic acids or a plurality of glutamic acids are bonded, it is preferable that only aspartic acids are bonded in a plurality, or only glutamic acids are bonded in a plurality.

[0033] There is no particular upper limit to the number of bonded structural units, but it is preferably 20, and more preferably 10. There is no particular lower limit to the number of bonded structural units, but it is preferably 2, and more preferably 5.

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

[0035] Below, we will explain how to bind aspartic acid residues to sugar chains as HA-binding molecules. First, a crosslinker with two amino groups is bound to the carboxyl or aldehyde group of the sugar chain. A specific example of a crosslinker is 1,11-diamino-3,6,9-trioxaundecane. A dehydration condensation reaction is carried out between the carboxyl or aldehyde group of the sugar chain and one of the amino groups of the crosslinker to form a peptide bond.

[0036] Furthermore, a bifunctional reagent having an N-hydroxysuccinimide activated ester and a maleimide group, which have different reactivities at both ends of the molecule, is bonded to the other amino group of the crosslinker. A specific example of the bifunctional reagent is Sulfo-SMCC.

[0037] The maleimide group of the bifunctional reagent is reacted with a sulfhydryl (SH) group biotin standard reagent to which aspartic acid is bound. By carrying out the above procedure, a glycoconjugate in which an aspartic acid residue is bound to a sugar chain can be produced.

[0038] The glycoconjugate of the present invention may further be bound to a drug. Drugs that bind to the glycoconjugate are described below. <Drug> The drug that binds to the glycoconjugate is not particularly limited, and known drugs used in bone-related treatments can be used as appropriate.

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

[0040] Bone morphogenetic proteins (BMPs) are a group of proteins that have been identified as molecules that induce and promote the differentiation of bone tissue and cartilage. BMPs are also called bone morphogenetic proteins.

[0041] Fibroblast growth factors (hereinafter referred to as FGFs) are a group of proteins identified as molecules involved in angiogenesis, wound healing, and embryonic development. FGFs play important roles in the proliferation and differentiation processes 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 growth 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 liver and kidney regeneration and neuroprotection. The above drugs may be used alone or in combination of two or more. Commercially available drugs may also be used.

[0044] The glycoconjugate of the present invention may be pre-bound to the above-mentioned drug. If the drug is pre-bound, the step of binding the drug to the glycoconjugate can be omitted when using the glycoconjugate as a drug carrier, thereby facilitating its use as a drug carrier.

[0045] Alternatively, the glycoconjugate may be pre-bound with the drug before use as a drug carrier, which allows the glycoconjugate and the drug to be stored separately, making it easier to maintain the individual qualities of the glycoconjugate and the drug in good condition.

[0046] Alternatively, the glycoconjugate may be used without a drug being bound to it. That is, the glycoconjugate and the drug may be configured to bind to each other after administration to a predetermined location in the body. In this configuration, the process of binding the two can be omitted.

[0047] The method for binding a drug to a glycoconjugate is described below. <Method for binding a drug to a glycoconjugate> The method for binding a drug to a glycoconjugate is not particularly limited, and known methods can be appropriately adopted.

[0048] For example, a method of binding a drug to a glycoconjugate involves preparing a liquid glycoconjugate and a liquid drug, weighing and mixing them to a predetermined ratio, and then leaving the mixture for a predetermined period of time, thereby binding the drug to the glycoconjugate.

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

[0050] The time for leaving the mixture to stand is not particularly limited, but is preferably 1 hour or more, and more preferably 2 hours or more. The content ratio of the glycoconjugate and the drug is not particularly limited. When the total content ratio of both is 100% by mass, the lower limit of the content ratio of the glycoconjugate is preferably 50% by mass, more preferably 60% by mass, and even more preferably 70% by mass. The upper limit of the content ratio of the glycoconjugate is preferably 95% by mass, more preferably 90% by mass, and even more preferably 80% by mass.

[0051] After the above mixing, stirring may be carried out as appropriate. Instead of mixing a liquid glycoconjugate with a liquid drug, a powdered glycoconjugate may be mixed with a powdered drug. A powdered glycoconjugate or a powdered drug can be prepared, for example, by freeze-drying a liquid glycoconjugate or a liquid drug.

[0052] Alternatively, instead of simply mixing the liquid glycoconjugate and the liquid drug, they may be mixed and then impregnated into an artificial bone made 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 impregnating the artificial bone, in addition to binding the glycoconjugate to the drug, it is possible to bind the glycoconjugate to the artificial bone. By binding the glycoconjugate to the artificial bone, it is possible to administer the glycoconjugate together with the artificial bone to a predetermined location in the body. By binding the glycoconjugate to the artificial bone in advance, it is possible to more suitably increase the concentration of the drug around the bone. The glycoconjugate and the drug in powder form may be dispersed in the artificial bone, and the glycoconjugate and the drug may be bound within the artificial bone.

[0054] <Other Components> The glycoconjugate may contain other components in addition to those described above, such as preservatives, thickeners, dispersants, colorants, surfactants, and solvents.

[0055] The content of other components in the glycoconjugate 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 Forms, Dosage Forms, and Uses of the Sugar Complex> The application form of the sugar 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 glycoconjugate is not particularly limited, and it can be prepared as appropriate into powder, solid, semi-solid, liquid, etc. The use of the glycoconjugate is not particularly limited, and it can be applied to known uses, such as drug carriers used in drug delivery systems.

[0058] <Actions and Effects> The action of the glycoconjugate of this embodiment will be described. As shown in Figure 1, the glycoconjugate 10 has eight aspartic acid residues (shown as (Asp)8 in Figure 1) as HA-binding molecules 12 bound to a glycoconjugate 11. Furthermore, the glycoconjugate 10 has a drug bone morphogenetic protein (shown as BMP-2 in Figure 1) 13 bound to the glycoconjugate 11. When the glycoconjugate 10 is administered into the body, the HA-binding molecules 12 bind to bone, making the glycoconjugate 10 more likely to remain on the bone surface. In other words, the concentration of glycoconjugates around bones can be favorably increased.

[0059] Furthermore, the binding of the bone morphogenetic protein 13 to the sugar chain 11 results in the local presence of the bone morphogenetic protein 13 on the bone surface. Compared to conventional techniques in which the local drug concentration is increased by using low gel fluidity, the decrease in drug concentration over time can be effectively suppressed. This makes it possible to suitably increase the concentration of the bone morphogenetic protein 13 around the bone.

[0060] The above-mentioned "surrounding the bone" is not particularly limited, but means, for example, a range within 10 mm from the surface of the bone. The effect of the glycoconjugate of this embodiment will be described.

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

[0062] (2) The acidic peptide contains at least one selected from aspartic acid and glutamic acid. By containing at least one selected from aspartic acid and glutamic acid, the concentration of sugar chains around the bone can be more suitably increased.

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

[0064] (4) The heparin is a low molecular weight heparin. Low molecular weight heparin is easily bound to HA-binding molecules and also easily binds to drugs such as growth factors. Therefore, it is possible to more effectively increase the concentration of drugs such as growth factors around the bone.

[0065] (5) At least one selected from bone morphogenetic factors, fibroblast growth factors, vascular endothelial growth factors, and hepatocyte growth factors is bound to the sugar chain. This makes it possible to suitably increase the concentrations of these drugs around bones, thereby contributing to improved therapeutic effects and reduced drug use in bone-related treatments.

[0066] (6) A drug carrier containing the above-mentioned glycoconjugate. Also, a drug delivery system using the above-mentioned glycoconjugate to increase the drug concentration around bone. Therefore, as a drug delivery system and a drug carrier used in a drug delivery system, it is possible to preferably increase the drug concentration in a local location, such as around bone.

[0067] Examples will be given below to more specifically explain the configuration and effects of the present invention, but the present invention is not limited to these examples. Test Section 1 (Preparation of Glycoconjugate) (Example 1) A glycoconjugate was prepared according to the reaction formula shown in Figure 2.

[0068] Commercially available low molecular weight heparin was used as the sugar chain. The average molecular weight of the low molecular weight heparin was 5,000. Commercially available aspartic acid was used as the HA-binding molecule. The aspartic acid used had eight aspartic acid units bound to each other.

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

[0070] Next, in step 2, Sulfo-SMCC was added to the diluted solution as a crosslinker for the bifunctional reagent. After being kept at room temperature for 30 minutes, the solution was washed three times with PBS and then subjected to ultrafiltration. The resulting concentrate was dissolved in PBS to obtain a solution.

[0071] By carrying out steps 1 and 2, 1,11-diamino-3,6,9-trioxaundecane and sulfo-SMCC were bound to low molecular weight heparin. Next, in step 3, the above solution was mixed with a sulfhydryl (SH) group biotin standard reagent bound to aspartic acid. After keeping it at room temperature for 30 minutes, ultrafiltration was carried out. Then, it was washed three times with acetate buffer. By carrying out the above steps 1 to 3, a liquid glycoconjugate bound to aspartic acid residues was prepared.

[0072] (Comparative Example 1) No glycoconjugate was used, and only commercially available PBS was used. (Comparative Example 2) No glycoconjugate was used, and only commercially available bone morphogenetic protein (hereinafter also referred to as BMP-2) was used. Note that BMP-2 is a type of the above-mentioned BMP, and refers to a BMP dimer.

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

[0074] (Glycoconjugate concentration around bone) A fluorescent labeling reagent was bound to the glycoconjugate of Example 1 using a known method. Fluorescein isothiocyanate (also known as FITC) was used as the fluorescent labeling reagent. The glycoconjugate bound to the fluorescent labeling reagent was subcutaneously injected into rats. After 24 hours, microscopic photographs of the rats were taken. Similarly, fluorescent images of the rats were also taken. The results are shown in Figure 3. Note that the method of administering the glycoconjugate is not limited to subcutaneous injection (subcutaneous administration), and known methods used in drug delivery systems can be appropriately adopted. Drug-bound glycoconjugates can also be administered by known methods used in drug delivery systems.

[0075] (Drug concentration around the bone) 2 nmol of the glycoconjugate of Example 1 and 2 μg of BMP-2 were weighed and mixed in a petri dish. After leaving it for 2 hours, a commercially available artificial bone having a cubic shape with length, width, and height of approximately 4 mm was placed in the petri dish, and the artificial bone was impregnated with the glycoconjugate and BMP-2. Impregnation was carried out for 1 hour.

[0076] Next, the back muscles of 8-week-old Sprague-Dawley rats (hereinafter also referred to as SD rats) were divided to expose the transverse processes of the L4 and L5 vertebrae. The transverse processes of the L4 and L5 vertebrae were then denuded using an electric burr. Artificial bone impregnated with a glycoconjugate and BMP-2 was placed around the denuded transverse processes. After 8 weeks, the areas around the L4 and L5 vertebrae of the SD rats were observed under a microscope.

[0077] In Comparative Example 1, PBS alone was used as a control instead of 2 nmol of the glycoconjugate and 2 μg of BMP-2 used in Example 1. Except for this, the test was carried out under the same conditions as in Example 1.

[0078] In Comparative Example 2, only 2 μg of BMP-2 was used instead of 2 nmol of glycoconjugate and 2 μg of BMP-2 in Example 1. Except for this, the test was carried out under the same conditions as in Example 1. The results are shown in FIG.

[0079] (Evaluation Results) The upper part of Figure 3 is a micrograph of a rat 20 stained with hematoxylin and 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] The bottom of Figure 3 is a fluorescent image of the same area as the top. In the bottom of Figure 3, lighter colored areas indicate stronger fluorescent reactions. Areas with stronger fluorescent reactions indicate the presence of a large amount of fluorescent-labeling reagent, and therefore the presence of many glycans bound to the fluorescent-labeling reagent.

[0081] 3, in Example 1, the fluorescent reaction was strong around bones such as the rat skull 21, vertebrae 22, and sternum 23. This confirmed that the concentration of sugar chains around the bones was suitably high. In other words, it was confirmed that the sugar chains were specifically transported to the bone (HA) by subcutaneous administration.

[0082] As shown in Figure 4, in Comparative Examples 1 and 2, the transverse processes of the peeled L4 and L5 vertebrae remained peeled. That is, parts of the transverse processes were missing. In addition, parts of the artificial bone remained at a distance from the L4 and L5 vertebrae. From these findings, it was confirmed that in Comparative Examples 1 and 2, no bone formation was observed between the transverse processes and the artificial bone, and bone fusion was insufficient.

[0083] In contrast, in Example 1, the transverse processes of the denuded L4 and L5 vertebrae were repaired to a certain extent. That is, artificial bone was attached around the transverse processes, and more of the artificial bone was fused compared to Comparative Examples 1 and 2. From these findings, it was confirmed that bone fusion was progressing in Example 1. It was also indirectly confirmed that the concentration of BMP-2 around the bone was suitably elevated.

[0084] 10...glycan complex, 11...glycan, 12...HA-binding molecule, 13...bone morphogenetic protein, 20...rat, 21...skull, 22...vertebrae, 23...sternum.

Claims

1. A sugar chain complex having a sugar chain to which a hydroxyapatite-binding molecule is bound, wherein the hydroxyapatite-binding molecule is at least one of an acidic peptide and estradiol, and the sugar chain contains at least one of heparin and chondroitin sulfate.

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. (Deleted)

4. The sugar chain complex according to claim 1, wherein the heparin is low molecular weight heparin.

5. The sugar chain complex according to claim 1, further comprising at least one selected from osteogenic factors, fibroblast growth factors, vascular endothelial growth factors, and hepatocyte growth factors bound to the sugar chain.

6. A drug carrier containing a sugar chain complex having a sugar chain to which a hydroxyapatite-binding molecule is bound, wherein the hydroxyapatite-binding molecule is at least one of an acidic peptide and estradiol.

7. A drug delivery system for increasing the concentration of a drug around bone, using the drug carrier according to claim 6.