KR20180112594A - Drug delivery system comprising bone morphogenetic protein and method for preparing the same - Google Patents

Abstract

The present invention relates to a drug deliverer including bone morphogenetic protein and a manufacturing method thereof. According to the present invention, the drug deliverer including bone morphogenetic protein is capable of reducing expenditure by minimizing a loss of drug to be delivered; reducing side effects caused by the lost drug; and conducting a treatment through bone morphogenesis by gradually leaking the drug to a local part for a long time. Moreover, according to the present invention, since a particle shape is applied as a delivery medium, the drug deliverer including bone morphogenetic protein is capable of maintaining the stability of the drug in a living body and bone morphogenesis by including the drug in the particle shape. In addition, according to the present invention, the drug deliverer including bone morphogenetic protein is capable of being applied to other protein or drug types, thereby being applied to various delivery systems.

Description

[0001] DRUG DELIVERY SYSTEM COMPRISING BONE MORPHOGENETIC PROTEIN AND METHOD FOR PREPARING THE SAME [0002]

The present invention relates to a drug delivery system comprising a bone forming protein and a method for producing the same.

Drug delivery systems are designed to increase the tissue and cell delivery efficacy and pharmacokinetic efficacy of compounds or molecules with pharmacological effects, and various forms of drug delivery systems are currently being studied. Typically, micro / nano-level particles, liposomes, transdermal patches, inhalers, implantable materials for drug retention or antibody-drug conjugates are used as drug delivery vehicles. The drug used is a protein or signaling system Drugs that can act directly on constituent molecules are mainly used.

On the other hand, it is difficult for a drug (including DNA, RNA, and protein) having various molecular weights and hydrophilic properties to spontaneously pass through the cell membrane, and overcome the intracellular defense substrate such as Multiple Drug Resistant (MDR) and Lysosomal Degradation There is a difficulty to do. In this case, the role of the drug delivery system for the maintenance and delivery of the drug is very important. In order to deliver the drug with high efficiency while maintaining the activity of the target drug in the cytoplasm, the pharmacological effect of the drug candidate having various characteristics is most directly and effectively Methods for induction and materials for various drug delivery are being studied.

Meanwhile, various types of bone grafting methods have been attempted to restore bone loss caused by fractures or injuries, and researches have been actively carried out to increase the effects by applying stem cells or growth factors together .

BMP-2 (bone morphogenetic protein-2), an essential growth factor for bone formation, can induce differentiation into bone cells by itself, and is widely used in fields such as bone grafting or bone regeneration. Currently, a method of introducing collagen sponge as a scaffold into a living body is allowed. In clinical practice, it is widely used for purposes such as spinal fusion, open tibia fracture, alveolar ridge, and sinus augmentation.

However, several shortcomings have been reported with the short half-life of BMP-2, the lack of proper delivery systems, and the use of 'off-lable' by doctors.

Currently, BMP-2 is approved by the US FDA to use collagen sponge as a scaffold. However, in this case, up to 30% of BMP-2 is lost in the initial stage, . Moreover, serious problems may arise such as excessive excretion of BMP-2 which may exert serious inflammatory reaction around the peri-operative region, side effects such as formation of bone tissue in the surrounding soft tissues, and the like. Therefore, in the case of BMP-2, the half-life of the protein is so short that the amount of bone to be regenerated and treated needs to be much larger than the actual amount required, which is another cause of side effects.

Many attempts have been made to solve these problems. For example, a technique has been proposed in which synthetic polymers such as poly (lactic acid) (PLA) and poly (lactic-co-glycolic acid) (PLGA) are used as biomaterials. However, even in the case of such a synthetic polymer, it is possible to introduce and transmit an effective protein, but problems such as toxicity or immune response which may occur in excessive use are pointed out. In order to overcome these shortcomings, a drug delivery system composed of a nontoxic natural substance such as chitosan, hyaluronan, alginate, silk fibroin and the like is attracting attention.

Among them, silk fibroin protein is a natural substance which can be extracted from Bombyx mori silkworm. It is well known that silk fibroin protein is not toxic and is biocompatible and suitable as a biomaterial.

Therefore, there is a need for a technique for a drug delivery system capable of minimizing side effects that can be manifested for a long period of time in a more localized region using the natural substance as a delivery medium. to be.

The present invention provides a drug delivery system comprising a bone forming protein and a method for producing the same.

The present invention provides a bone morphogenetic protein core and a silk fibroin covering the core, wherein the osteogenic protein core is a positively chargeable substance, and the silk fibroin provides a drug carrier which is a negatively charged substance in a particle form.

The present invention also provides a drug delivery composition comprising the drug delivery system.

The present invention also provides a method for producing a silk fibroin particle, comprising: (a) mixing a polyvinyl alcohol solution and a silk fibroin solution to prepare a silk fibroin particle solution; And (b) mixing the silk fibroin particle solution with an aqueous osteogenic protein solution to prepare a drug delivery vehicle solution.

The drug delivery system comprising the bone formation protein according to the present invention and the preparation method thereof can minimize the loss of the drug to be delivered, thereby reducing the cost, thereby reducing side effects caused by the lost drug, The drug can be slowly released locally for a long period of time to the site to be treated and the effect of treatment through the desired bone formation can be shown. In addition, since the drug delivery system including the bone formation protein according to the present invention and the method for preparing the same can be delivered including a drug to be delivered in the particle form by introducing a particle form as a delivery medium, stability of the drug in vivo And excellent bone formation ability can be maintained. In addition, the drug delivery system comprising the bone formation protein according to the present invention and the preparation method thereof can be applied to other proteins and drugs, and thus can be usefully utilized in various delivery systems.

The accompanying drawings are included to provide a further understanding of the invention to those skilled in the art, and the technical spirit of the invention is not limited thereto.
FIG. 1 is a view illustrating a process of preparing a drug delivery system comprising a bone forming protein according to an embodiment of the present invention.
FIG. 2 is a graph showing an image observed with a scanning electron microscope (SEM) according to an incorporated BMP-2 content of a drug carrier containing a bone forming protein according to an embodiment of the present invention, .
FIG. 3 is a graph illustrating the effect of the encapsulation, yield of silk fibroin particles, and the like on the drug delivery system containing bone-forming proteins according to an embodiment of the present invention, And the actual loading.
FIG. 4 is a graph showing the result of performing an experiment on the loss of BMP-2 in an in vitro environment similar to that of a drug delivery vehicle containing a bone forming protein according to an embodiment of the present invention and a stability test (b) is a graph showing the results of the stability test of BMP-2 lost in comparison with the control (control BMP-2) to be].
FIG. 5 is a graph showing the results of an experiment performed at a gene expression level in that a drug delivery system containing an osteogenic protein according to an embodiment of the present invention is excellent in bone formation ability. [(A) 2 shows the expression level of ALP mRNA according to the amount of BMP-2. Fig. 2 (b) is a graph showing the activity of ALP according to the amount of BMP-2, "BMP-2 / SF" represents the case of drug delivery containing bone-forming proteins according to the present invention, and "SF" represents the case where only silk fibroin is used as a control group ].
FIG. 6 is a graph showing the results of toxicity tests performed in vitro in a drug delivery system containing an osteogenic protein according to an embodiment of the present invention. FIG.
FIG. 7 is a graph showing the osteoforming ability of a drug delivery vehicle containing a bone forming protein according to an embodiment of the present invention using a mouse intramuscular ectopic bone model [(a) is a chart observed with soft X-ray (b) is a chart obtained by micro CT, and (c) is a bar graph obtained by digitizing it. Here, "PBS" represents a case where only phosphate buffer solution is used as a control group, "SF" BMP-2 / SF "represents the case where the drug delivery system of the present invention is used). Fig.
FIG. 8 shows a more detailed view of the bone regeneration ability of a drug delivery system comprising a bone morphogenetic protein according to an embodiment of the present invention [(a) is a diagram observed with micro CT, and (b) Quot; SF "shows the case where only silk fibroin was used as a control group, and" BMP-2 "was used as a control group as a control group BMP-2 / SF "represents the case of using the drug delivery system of the present invention).

Hereinafter, the drug delivery system comprising the bone formation protein according to the present invention and the preparation method thereof will be described in detail. However, the scope of the drug delivery system including the bone formation protein and the preparation method thereof is not limited by the following description.

The present invention relates to a drug delivery system comprising a bone forming protein. More specifically, the invention relates to a drug delivery vehicle comprising a bone forming protein core and a silk fibroin covering the core.

As used herein, the term "core" may refer to a core in a conventional sense, that is, a core and central portion of a material, and may be understood as meaning a collective term for a centrally located material. In addition, the term "covering" in this specification can be understood to mean "surrounding a certain material. &Quot;

For example, the osteogenic protein core may be a positively chargeable material, and the silk fibroin may be a negative charge material in the form of particles.

The drug delivery system comprising the osteogenic protein according to the present invention may be prepared by forming polyvinyl alcohol (PVA), which is used in a drug delivery method described later, as a template and forming a particle-shaped silk fibroin By mixing the osteogenic protein (for example, BMP-2) in the aqueous state during the process, particles are formed by the binding force between electrostatically positively charged osteogenic proteins and negatively charged silk fibroin , A particle form containing the bone-forming protein can be formed inside the particle.

The drug delivery system comprising the bone formation protein according to the present invention can reduce the loss of drug to be delivered and reduce the cost because the drug to be delivered is contained in the silk fibroin particles and can move to the target site , Thereby reducing side effects caused by the lost drug and allowing the drug to slowly flow out locally for a long time to a site to be delivered, The in vivo stability and osteo-forming ability can be maintained excellent.

The osteogenic protein may be at least one selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-9, BMP-10, BMP- , Preferably BMP-2.

The core may further comprise a pharmaceutically active material.

More specifically, the drug delivery system according to the present invention comprises a core containing a pharmaceutically active substance, for example, a nucleic acid or a protein-based drug, which is introduced into the cell through fusion with the cell membrane to maintain the drug at a sufficient concentration To the target site.

The drug delivery vehicle may be about 30% or more, about 35% or more, or about 40% or more of drug release compared to the total drug, but it is not particularly limited that the release of more drugs out of the total drug is effectively delivered.

The diameter of the silk fibroin particles may be 100 nm to 1,000 nm, 300 nm to 900 nm, or 500 nm to 800 nm, but is not limited thereto.

The present invention also relates to a drug delivery composition comprising the above drug delivery system according to the present invention.

The composition for drug delivery comprising the drug delivery vehicle according to the present invention can also be used as a preventive or pharmacological use for a specific disease. In this case, it is possible to use a powder, granule, tablet, The composition can be formulated into various forms such as oral formulations such as emulsions, syrups and aerosols, injections of sterile injection solutions, and the like, and can be administered orally or intravenously, intraperitoneally, subcutaneously, rectally, ≪ / RTI >

Examples of suitable carriers, excipients or diluents which may further include carriers, excipients or diluents and the like include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, The present invention also relates to a method for producing a microcapsule comprising the steps of: applying an aqueous solution containing a compound selected from the group consisting of water, methylcellulose, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, .

In a preferred embodiment, the solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, for example starch, calcium carbonate, Sucrose, lactose, gelatin and the like are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used.

Examples of the oral liquid preparation include suspensions, solutions, emulsions, syrups and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, Perfumes, preservatives, and the like.

As a preferable specific example, the preparation for parenteral administration includes sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-drying agents, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.

In the case of a drug delivery composition for delivering a drug for pharmaceutical use of the present invention, the drug may be administered in a pharmaceutically effective amount. In the present invention, a "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dosage level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts.

It can also be administered to the subject via a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

In the present invention, "administration" means providing a predetermined substance to a patient in any suitable manner, and the administration route can be orally or parenterally administered through any of the usual routes as long as it can reach the target tissue. The composition of the present invention may also be administered using any device capable of delivering an effective ingredient to a target cell.

In the present invention, the term "object" includes, but is not limited to, human, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig , Preferably a mammal, more preferably a human.

The present invention also relates to a method for producing a drug delivery vehicle.

More specifically, the present invention provides a method for preparing a drug delivery vehicle, comprising: (a) mixing a polyvinyl alcohol solution and a silk fibroin solution to prepare a silk fibroin particle solution; And (b) mixing the silk fibroin particle solution with an osteogenic protein aqueous solution to prepare a drug delivery solution.

The method for manufacturing a drug delivery vehicle according to the present invention relates to a method for manufacturing the drug delivery system of the present invention described above, and a configuration similar to that described in the above-described drug delivery system according to an embodiment of the present invention will be briefly described It will be omitted.

In step (a), the concentration of the polyvinyl alcohol solution may be 1% to 10%, 2.5% to 8%, or 4% to 6%, and the concentration of the silk fibroin solution may be 1% to 10% To 8% or 4% to 6%, but is not particularly limited thereto.

In addition, the method of manufacturing a drug delivery system according to the present invention may further include the step (c) of sonicating the particle solution after the step (a).

In addition, the ultrasonic processing step of the step (c) may be about 10% to 50%, about 20% to 40% or preferably about 30% of the amplitude, 50 seconds, about 20 seconds to 40 seconds, or preferably about 30 seconds.

In addition, the method of manufacturing a drug delivery system according to the present invention may further include (d) after the step (b), centrifuging the drug delivery solution.

For example, the centrifuging step (d) may be performed at a temperature of 5,000 rpm to 20,000 rpm or 10,000 rpm to 15,000 rpm at a temperature of 0 ° C to 10 ° C or 2 ° C to 8 ° C Under conditions of about 1 minute to 60 minutes or 10 minutes to 40 minutes.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.

[Example]

One. Preparation of drug delivery system

For a specific embodiment of the drug delivery system according to the present invention, the drug delivery system was prepared in the following manner.

In this regard, FIG. 1 illustrates a process for preparing a drug delivery system comprising a bone forming protein according to an embodiment of the present invention.

1 ml of silk fibroin solution (5% (w / v)) and 4 ml of polyvinyl alcohol (PVA) solution (5% (w / v)) were mixed and sonication was applied to the mixture (amplitude: 30%, 30 seconds). After that, add an appropriate amount of BMP-2 into drop-wise, vortex slightly and pour into a Patri dish (90 × 15 mm), spread evenly, and completely dry to form a film. Fully dry BMP-2 fibroin particles in film form are removed and placed in a conical tube, and 30 ml of distilled water is poured in and completely rocked. And centrifuged at 11,000 rpm and 4 ° C for 20 minutes to submerge the BMP-2 fibroin particles and extract them to prepare a drug delivery system according to the present invention.

2. Observation of morphology of drug delivery system

The morphology of drug carriers prepared by scanning electron microscopy (SEM) was observed.

FIG. 2 is a graph showing an image observed with a scanning electron microscope (SEM) according to an incorporated BMP-2 content of a drug carrier containing a bone forming protein according to an embodiment of the present invention, .

Referring to FIG. 2, it has been confirmed that almost all of the drug carriers have a spherical particle shape. In addition, the precision analysis showed a diameter of about 500 nm for silk fibroin particles without BMP-2, and a diameter of about 100 nm for particles containing BMP-2. In the case of surface charge, both silk fibroin particles (SF) and BMP-2-containing silk fibroin particles (BMP-2 / SF) exhibited similar negative charges . From these results, it can be confirmed that the BMP-2 protein having a positive charge is not attached to the particle surface but exists inside the particle. In addition, when 10 ug of BMP-2 per 1 mg of fibroin protein was used, it was confirmed that precipitation occurred.

3. Measurement of introduction efficiency and formation efficiency of drug delivery system

During the preparation of the drug delivery system, the drug delivery system according to the present invention, namely BMP-2 fibroin particles, is submerged through centrifugation, and the introduction efficiency of BMP-2 from the supernatant containing remaining unreacted BMP-2 and fibroin proteins Respectively. During the preparation of the drug delivery system, the drug delivery system according to the present invention, i.e., the submerged BMP-2 fibroin particles was lyophilized and used for measuring the particle formation efficiency through centrifugation.

More specifically, particles were prepared using 1 mg of fibroin protein, 0 ug, 2 ug, 6 ug and 10 ug of BMP-2, respectively, and the encapsulation efficiency of BMP-2 and the efficiency of silk fibroin particles. This allows us to calculate the amount of BMP-2 present per mg of actual silk fibroin.

The results are shown in FIG.

That is, FIG. 3 is a graph showing the relationship between the amount of BMP-2 introduced and the yield of silk fibroin particles in the drug delivery system containing the osteogenic protein according to an embodiment of the present invention. particle and the actual loading of the particles.

Referring to FIG. 3, it was confirmed that the efficiency with which fibroin particles are formed is about 40%, which is not influenced by the amount of BMP-2.

Subsequently, in all experiments, BMP-2 containing silk fibroin particles (BMP-2 / SF) used particles containing 12.63 ug of BMP-2 per 1 mg silk fibroin.

4. Safety (maintenance of activity) experiment of drug delivery system

In order to examine the safety of the drug delivery system according to the present invention, the release pattern of BMP-2 / fibroin particles in an in vitro similar environment was measured. More specifically, using a cell culture medium containing 10% fetal bovine serum (FBS), particles containing a total of 5 ug of BMP-2 were added to each tube together with the cell culture medium and reacted at 37 ° C. Thereafter, the particles were prevented from sinking using a rotator. The supernatant was stored at -80 ° C by centrifuging the sample for each time period, and the reaction was continued by adding a new culture solution. The amount of BMP-2 contained in the supernatant was measured by ELISA and the amount released for a total of 30 days was measured (see Figure 4 (a)). In order to examine whether or not the released BMP-2 retains bioactivity, the same amount of BMP-2 was reacted under the same conditions, and then the cell culture fluid containing BMP-2 was treated for 3 days in C2C12 cells , Followed by ALP staining (Fig. 4 (b)).

The results are shown in Fig.

That is, it shows the result of performing an experiment of the loss of BMP-2 in an in vitro similar condition and stability of a drug delivery vehicle containing a bone morphogenetic protein according to an embodiment of the present invention [(a (B) is a graph showing the results of the stability test of BMP-2 lost compared to the control (control BMP-2) .

4, it was confirmed that about 40% of BMP-2 was released, and that BMP-2 in the particles remained active for over 14 days, while that of normal BMP-2 remained almost constant after 11 days And the difference in the degree of staining was confirmed. Therefore, it was confirmed that BMP-2 introduced into the particle can maintain its activity for a long time while being protected from the external environment.

5. Measurement at the gene level of bone-forming ability of drug delivery system

In order to measure the osteoinductive capacity of the drug delivery system of the present invention, MC3T3-E1 cells, which are precursors of osteoblast cells, were treated with BMP-2 / SF and SF at different concentrations to determine the mRNA expression and activity Changes were observed. BMP-2 / SF containing 100 ng / ml, 300 ng / ml and 500 ng / ml of BMP-2 were treated and treated with SF at the same concentration.

The results are shown in Fig.

That is, FIG. 5 is a graph showing the result of an experiment performed at a gene expression level that a bone morphogenetic protein-containing drug delivery system according to an embodiment of the present invention is superior in osteo-forming ability [(a) (B) is a graph showing the activity of ALP according to the amount of BMP-2, and (c) shows the expression level of ALP according to the amount of BMP-2 Herein, "BMP-2 / SF" represents a case of drug delivery containing a bone forming protein according to the present invention, and "SF" represents a case where only silk fibroin is used as a control group will be].

5, it was confirmed that mRNA and activity of ALP were increased as the concentration of BMP-2 was increased in BMP-2 / SF-treated place, unlike the place where SF treatment was performed.

6. Cytotoxicity test of drug delivery system

For the cytotoxicity test of the drug delivery vehicle of the present invention, C2C12 cells were treated with different amounts of drug carriers. A maximum of 830 ug of BMP-2 / fibroin particles was treated for 24 hours and then the viable cell mass was determined using a cell viability assay.

The results are shown in Fig.

That is, FIG. 6 is a graph showing the results of toxicity tests in vitro in a drug delivery system containing bone-forming proteins according to an embodiment of the present invention.

Referring to FIG. 6, almost 100% of the cells were alive in all the groups. As a result, it was confirmed that the cytotoxicity of the drug delivery system according to the present invention was scarcely observed.

7. Measurement of bone-forming ability of drug delivery system

In order to measure the bone-forming ability of the drug delivery vehicle of the present invention, PBS, SF, BMP-2 (5 ug) and BMP-2 / SF (5 μg) were administered intramuscularly to the hindlimb muscle of female C57BL / 6 mice at 4 weeks of age using a mouse intramuscular ectopic bone model (Including 5 ug of BMP-2), and then newly formed bones were analyzed and confirmed by soft X-ray and micro CT after 8 weeks.

The results are shown in Fig.

That is, FIG. 7 is a graph showing the bone forming ability of a drug delivery vehicle containing a bone forming protein according to an embodiment of the present invention using a mouse intramuscular ectopic bone model [(a) Wherein "PBS" represents the case where only phosphate buffer solution is used as a control group, and "SF" represents a case where only phosphate buffer solution is used as a control group, and (b) BMP-2 / SF "represents the case where the drug delivery system of the present invention is used). &Quot; BMP- .

7, it can be confirmed that a new bone (ectopic bone) near the spherical shape was formed around the collagen sponge in the place where BMP-2 or BMP-2 / SF was inserted, unlike the experiment group in which PBS or SF was inserted (BMP-2 and BMP-2 / SF), respectively.

8. Measurement of bone regeneration ability of drug delivery system

In order to measure the bone regeneration ability of the drug delivery vehicle according to the present invention, a ciritial-sized defect having a diameter of 8 mm was induced in the skull of an 8-week-old female Sprague Dawley rats, and then a collagen sponge having a diameter of 8 mm was impregnated with PBS, SF, BMP -2 and BMP-2 / SF in the same amount as in the previous experiment (measurement of bone-forming ability of the drug delivery vehicle). After 4 weeks, the degree of defect recovery was confirmed by micro CT analysis.

The results are shown in Fig.

That is, FIG. 8 is a more detailed view of the bone regeneration ability of the drug delivery system comprising the osteogenic protein according to an embodiment of the present invention. [(A) is a view observed with micro CT, and (b) "BMP-2" represents the case where only silk fibroin is used as a control, "BMP-2" represents a control group, and " BMP-2 / SF "represents the case of using the drug delivery system of the present invention).

Referring to FIG. 8, it was confirmed that a new bone was formed from the edge of the defect at the insertion site of PBS or SF, and the degree of recovery was similarly low in the two groups. On the other hand, it was confirmed that the defect part was completely recovered in the place where BMP-2 or BMP-2 / SF was inserted. Bone volume and bone mineral contents (BMC) were 3 to 4 times higher than those of PBS and SF treatment groups. BMP-2 and BMP-2 / fibroin particles showed no significant difference Respectively.

From the results shown in the above Experiments 1 to 8 and FIGS. 1 to 8, the drug delivery system according to the present invention can minimize the loss of the drug to be delivered, gradually and locally release the drug It can be used for the delivery system of drugs and the like because it can be discharged, can not be cytotoxic, and can maintain stability and bone formation ability in vivo.

It will be understood by those of ordinary skill in the art that the foregoing description of the embodiments is for illustrative purposes and that those skilled in the art can easily modify the invention without departing from the spirit or essential characteristics thereof. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive. For example, each component described as a single entity may be distributed and implemented, and components described as being distributed may also be implemented in a combined form.

The scope of the present invention is defined by the appended claims rather than the detailed description, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be interpreted as being included in the scope of the present invention.

Claims (12)

An osteogenic protein core and a silk fibroin covering said core,
Wherein the osteogenic protein core is a positive charge material and the silk fibroin is a particle-like negative charge material. The bone morphogenetic protein of claim 1, wherein the osteogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-9, BMP-10, BMP- Wherein the drug delivery system comprises at least one selected from the group consisting of: 2. A drug delivery system according to claim 1, wherein the core further comprises a pharmaceutically active substance. The drug delivery system according to claim 1, wherein the drug delivery system has a drug release of 30% or more. The drug delivery system according to claim 1, wherein the diameter of the silk fibroin particles is 100 nm to 1,000 nm. A drug delivery composition comprising the drug delivery system according to any one of claims 1 to 5. (a) mixing a polyvinyl alcohol solution and a silk fibroin solution to prepare a silk fibroin particle solution; And
(b) mixing the silk fibroin particle solution with an aqueous osteogenic protein solution to prepare a drug delivery vehicle solution. [8] The method according to claim 7, wherein the concentration of the polyvinyl alcohol solution in step (a) is 1% to 10%, and the concentration of the silk fibroin solution is 1% to 10%. [8] The method of claim 7, further comprising the step of sonicating the particle solution after step (a). The method according to claim 9, wherein the ultrasonic treatment in step (c) is performed one or more times under conditions of an amplitude of 10% to 50% and a pulse of 10 seconds to 50 seconds. Way. [8] The method of claim 7, further comprising, after step (b), (d) centrifuging the drug delivery solution. The method of claim 11, wherein the centrifuging step (d) is performed at a temperature of 5000 rpm to 20,000 rpm, 0 캜 to 10 캜, and 1 minute to 60 minutes.

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