Drug carrier particles and method for manufacturing same

Abstract

The present application relates to drug carrier particles comprising: polymer particles comprising a complex of silk sericin and silk fibroin; and a therapeutic agent loaded within the polymer particles, wherein the polymer particles are spherical or disk-shaped.

Description

Drug carrier particles and methods for manufacturing the same

[0001] The present invention relates to drug carrier particles and a method for manufacturing the same.

[0002] Recently, silk proteins have been attracting attention as drug delivery vehicles due to their excellent biocompatibility and biodegradability. In particular, among silk proteins, silk sericin (SS) and silk fibroin (SF) each have unique characteristics; SS is water-soluble, acts as an adhesive for SF, and is involved in the cancer cell death mechanism, whereas SF accounts for 60% to 70% of the total silk and has the characteristic of being able to control biodegradability through β-sheet structural conversion.

[0003] However, most existing silk-based drug delivery systems use only SF alone, and even when SS and SF are used in combination, there is a severe lack of application cases in the form of nanoparticles or microparticles. In particular, regarding the delivery of hydrophobic drugs such as anticancer agents paclitaxel (PTX) or docetaxel (DTX), there is a need for research on the development of nano / microparticles using a combination of SS and SF and the improvement of drug delivery efficiency through this.

[0004] The technology forming the background of the present invention is disclosed in Korean Registered Patent Publication No. 10-1820574.

[0005] The present invention aims to solve the problems of the aforementioned prior art by providing a drug delivery particle comprising a biodegradable silk protein, a method for manufacturing the same, and a pharmaceutical composition comprising the same.

[0006] However, the technical problems that the embodiments of the present invention aim to solve are not limited to those described above, and other technical problems may exist.

[0007] As a technical means for achieving the above-mentioned technical problem, the first aspect of the present invention relates to a drug carrier particle, wherein the drug carrier particle comprises: a polymer particle comprising a complex of silk sericin and silk fibroin; and a therapeutic agent supported inside the polymer particle; and wherein the polymer particle is a spherical or disc-shaped particle.

[0008] According to one embodiment of the present invention, the polymer particles may contain silk sericin and silk fibroin in a mass ratio of 1:2 to 1:4, but are not limited thereto.

[0009] According to one embodiment of the present invention, the silk fibroin controls the degree of biodegradability of the polymer particles, and the silk sericin can control the bonding between the silk fibroins, but is not limited thereto.

[0010] According to one embodiment of the present invention, the particle size of the polymer particles may be 100 nm to 500 nm, or 1 μm to 5 μm, but is not limited thereto.

[0011] According to one embodiment of the present invention, the disease targeted by the drug carrier particle or the location where the drug carrier particle arrives may differ depending on the size and shape of the polymer particle, but is not limited thereto.

[0012] According to one embodiment of the present invention, when the polymer particles are spherical particles of 100 nm to 500 nm, the therapeutic agent may include a therapeutic agent targeting cervical cancer, but is not limited thereto.

[0013] According to one embodiment of the present invention, the therapeutic agent may include paclitaxel, but is not limited thereto.

[0014] According to one embodiment of the present invention, when the polymer particles are disc-shaped particles of 1 μm to 5 μm, the drug carrier particles may include a therapeutic agent targeting lung cancer, but are not limited thereto.

[0015] According to one embodiment of the present invention, the therapeutic agent may include docetaxel, but is not limited thereto.

[0016] According to one embodiment of the present invention, the therapeutic agent may be endocytosed by the polymer particles, but is not limited thereto.

[0017] According to one embodiment of the present invention, silk sericin may be disposed on the surface of the polymer particles, and silk fibroin and a therapeutic agent may be disposed inside the polymer particles, but are not limited thereto.

[0018] In addition, a second aspect of the present invention relates to a method for manufacturing drug carrier particles, comprising the steps of: mixing silk sericin and silk fibroin to form polymer particles; and loading a therapeutic agent inside the polymer particles; wherein the polymer particles are formed into spherical or disc-shaped particles.

[0019] According to one embodiment of the present invention, the step of encapsulating a therapeutic agent inside the polymer particles may include, but is not limited to, a step of dispersing a solution containing the polymer particles in an amount of 100 w / v% to 10 w / v% and a therapeutic agent in a solvent; and a step of centrifuging.

[0020] According to one embodiment of the present invention, the concentration of the therapeutic agent in the solvent may be 1 g / l to 20 g / l, but is not limited thereto.

[0021] Additionally, a third aspect of the present invention relates to a pharmaceutical composition comprising a drug carrier particle according to the first aspect.

[0022] According to one embodiment of the present invention, the pharmaceutical composition may be intended to treat a disease selected from the group consisting of lung cancer, cervical cancer, squamous cell carcinoma, and combinations thereof, but is not limited thereto.

[0023] The means for solving the problem described above are merely exemplary and should not be interpreted as intended to limit the present invention. In addition to the exemplary embodiments described above, additional embodiments may exist in the drawings and the detailed description of the invention.

[0024] According to the means for solving the problem of the present invention described above, the drug carrier particles according to the present invention can efficiently treat diseases occurring in specific organs because the organs reached differ depending on the particle size.

[0025] In addition, the above-mentioned drug carrier particles are formed by loading a drug within silk protein-based polymer particles containing silk sericin and silk fibroin. Since the biocompatibility and biodegradability of silk proteins can be utilized, they are suitable for drug delivery, and the accumulation and release of the drug within the affected area can be facilitated, thereby maximizing the therapeutic effect.

[0026] However, the effects obtainable from this invention are not limited to those described above, and other effects may exist.

[0027] FIG. 1 is a schematic diagram of a drug carrier particle according to one embodiment of the present invention.

[0028] Figure 2 shows the structure of silk protein.

[0029] FIG. 3 is a schematic diagram showing the process of manufacturing a drug carrier particle according to one embodiment of the present invention.

[0030] FIG. 4 is a schematic diagram of a drug carrier particle according to one embodiment of the present invention.

[0031] FIG. 5 is a schematic diagram showing the process of manufacturing a drug carrier particle according to one embodiment of the present invention.

[0032] FIG. 6a shows the size distribution of drug carrier particles according to one embodiment of the present invention, and FIG. 6b shows the Zeta Potential distribution of the drug carrier particles.

[0033] FIG. 7 is an FT-IR graph of a drug carrier particle according to one embodiment of the present invention.

[0034] FIGS. 8a and FIGS. 8b are FT-IR graphs of drug carrier particles according to one embodiment of the present invention.

[0035] FIG. 9a is a graph showing the stability of a drug carrier particle according to one embodiment of the present invention, and FIG. 9b is a graph showing the drug release ability of a drug carrier particle according to one embodiment of the present invention.

[0036] FIGS. 10a and FIGS. 10b are graphs showing the drug release ability of a drug carrier particle according to one embodiment of the present invention.

[0037] FIGS. 11a and FIGS. 11b illustrate the cytotoxicity of drug carrier particles according to one embodiment of the present invention.

[0038] FIG. 12 shows the intracellular distribution of drug carrier particles according to one embodiment of the present invention.

[0039] Figures 13 (A) to (D) are SEM and CLSM (confocal laser scanning microscopy) images of drug carrier particles according to one embodiment and a comparative example of the present invention.

[0040] FIG. 14 shows the stability of a drug carrier particle according to one embodiment of the present invention.

[0041] FIG. 15 shows the lung cancer treatment effect of a drug carrier particle according to one embodiment of the present invention.

[0042] Figures 16a and 16b illustrate the locations where drug carrier particles accumulate within the body.

[0043] Figure 17 (A) is a schematic timeline of an experiment on drug carrier particles according to one embodiment of the present invention, (B) is for lung tissue samples after treatment of the experimental group, and (C) to (F) are the results of the analysis of survival rate and average number of nodules after treatment.

[0044] FIG. 18 analyzes the accumulation of drug carrier particles in an organ according to one embodiment of the present invention.

[0045] Below, embodiments of the present invention are described in detail with reference to the attached drawings so that those skilled in the art can easily implement them.

[0046] However, the present invention may be implemented in various different forms and is not limited to the embodiments described herein. Furthermore, in order to clearly illustrate the present invention in the drawings, parts unrelated to the description have been omitted, and similar parts throughout the specification have been given similar reference numerals.

[0047] Throughout this specification, when a part is described as being "connected" to another part, this includes not only cases where they are "directly connected," but also cases where they are "electrically connected" with other elements interposed between them.

[0048] Throughout the entire specification, when a component is described as being located "on," "on top," "on top," "under," "on bottom," or "on bottom" of another component, this includes not only cases where the component is in contact with the other component but also cases where another component exists between the two components.

[0049] Throughout this specification, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0050] Hereinafter, a drug carrier particle according to one embodiment and example of the present invention, a method for manufacturing the same, and a method for operating the same will be described.

[0051] As a technical means for achieving the above-mentioned technical problem, the first aspect of the present invention relates to a drug carrier particle, wherein the drug carrier particle comprises a polymer particle (110) comprising a complex of silk sericin (111) and silk fibroin (112); and a therapeutic agent (120) contained within the polymer particle, wherein the polymer particle is a spherical or disc-shaped particle.

[0052] FIGS. 1 and FIGS. 4 are schematic diagrams of drug carrier particles according to one embodiment of the present invention.

[0053] As will be described later, since the target body organs and diseases may differ depending on the size and shape of the polymer particles, the type of therapeutic agent (120) carried on the polymer particles may also differ depending on the size and shape of the polymer particles. For example, FIG. 1 is a drug carrier particle containing spherical polymer particles, intended for targeted treatment of cervical cancer, etc., and FIG. 4 is a drug carrier particle containing disc-shaped polymer particles, intended for targeted treatment of lung cancer, etc. In this case, the therapeutic agent (120) of FIG. 4 is carried on the inside of the polymer particles.

[0054] The above drug carrier particle comprises a polymer particle complex (120) composed of silk protein and a therapeutic agent (120) contained within the complex (120).

[0055] Figure 2 shows the structure of silk protein.

[0056] The silk sericin (111)(SS) according to the present invention functions as an adhesive that connects silk fibroin (112)(SF), is water-soluble, controls the mechanical properties of the drug carrier particles, and also has a cancer cell destruction mechanism, so it can have an anticancer treatment effect together with the therapeutic agent (120).

[0057] According to one embodiment of the present invention, the silk fibroin (112) controls the degree of biodegradability of the polymer particles, and the silk sericin (111) can control the bonding between the silk fibroin (112), but is not limited thereto.

[0058] Additionally, the silk fibroin (112) according to the present invention comprises 60% to 70% of the composition of ordinary silk, and includes insoluble silk II (silk II) having a structure in which a plurality of β sheets are hydrogen-bonded, and water-soluble silk I (silk I) having a random coil structure in which α helices and β sheets are mixed. The silk fibroin (112) is known to have excellent biocompatibility, and the biodegradability of the silk protein can be controlled by controlling the content of silk fibroin (112) in the silk protein.

[0059] According to one embodiment of the present invention, silk sericin (111) may be disposed on the surface of the polymer particles, and silk fibroin (112) and a therapeutic agent (120) may be disposed inside the polymer particles, but are not limited thereto.

[0060] Referring to FIG. 2, it can be seen that the structure is such that silk fibroin (112) is positioned internally in the silk protein, and silk sericin (111) is exposed externally. In the case of FIG. 4, only a complex (110) in which silk sericin (111) and silk fibroin (112) are combined is disclosed, but when the complex (110) is analyzed, it contains silk fibroin (112) and silk sericin (111) positioned on the surface of the silk fibroin (112), as in FIG. 2.

[0061] According to one embodiment of the present invention, the polymer particles may contain silk sericin (111) and silk fibroin (112) in a mass ratio of 1:2 to 1:4, but are not limited thereto.

[0062] According to one embodiment of the present invention, the therapeutic agent (120) may be endocytosed by the polymer particles, but is not limited thereto.

[0063] The above polymer particles are a composite material of silk sericin (111) and silk fibroin (112), and their biodegradability is controlled. Additionally, since the endocytosis of the above therapeutic agent (120) is promoted by the silk protein, the therapeutic effect of the therapeutic agent (120) can be assisted.

[0064] According to one embodiment of the present invention, the particle size of the polymer particles may be 100 nm to 500 nm, or 1 μm to 5 μm, but is not limited thereto.

[0065] According to one embodiment of the present invention, the disease targeted by the drug carrier particle or the location where the drug carrier particle arrives may differ depending on the size and shape of the polymer particle, but is not limited thereto.

[0066] Fine particles that enter the body may arrive at different locations depending on their size and shape. For example, it is known that particles ranging from 1 μm to 5 μm accumulate in the lungs, etc., while particles ranging from 100 nm to 500 nm accumulate in the uterus, etc.

[0067] According to one embodiment of the present invention, when the polymer particles are spherical particles of 100 nm to 500 nm, the therapeutic agent (120) may include a therapeutic agent (120) targeting cervical cancer, but is not limited thereto.

[0068] According to one embodiment of the present invention, the therapeutic agent (120) may include paclitaxel, but is not limited thereto.

[0069] Spherical particles with a size of 100 nm to 500 nm, preferably spherical particles with a radius of 250 nm to 330 nm (PDI is 0.1 to 0.35), can inject a therapeutic agent (120) into the tumor tissue within the uterus. At this time, the therapeutic agent (120) may include, in addition to paclitaxel, an anticancer agent that can be used to treat cervical cancer.

[0070] Referring to FIG. 1, the drug carrier particle for treating cervical cancer may have a structure in which silk sericin (111) is disposed on the surface and silk fibroin (112) and therapeutic agent (120) (paclitaxel) are disposed inside.

[0071] According to one embodiment of the present invention, when the polymer particles are disc-shaped particles of 1 μm to 5 μm, the drug carrier particles may include a therapeutic agent (120) targeting lung cancer, but are not limited thereto.

[0072] According to one embodiment of the present invention, the therapeutic agent (120) may include docetaxel, but is not limited thereto.

[0073] It is known that disc-shaped particles with a size of 1 μm to 5 μm, preferably with a diameter of 2.5 μm to 3 μm and a height of 1 μm to 2 μm (preferably 1 μm to 1.5 μm, more preferably 1.49 μm), accumulate in the lungs when injected into the human body. Accordingly, lung cancer can be treated through the drug carrier particles by including docetaxel for lung cancer treatment within the disc-shaped particles.

[0074] Additionally, a second aspect of the present invention relates to a method for manufacturing drug carrier particles, comprising the steps of: mixing silk sericin (111) and silk fibroin (112) to form polymer particles; and loading a therapeutic agent (120) inside the polymer particles; wherein the polymer particles are formed into spherical or disc-shaped particles.

[0075] FIGS. 3 and FIGS. 5 are schematic diagrams illustrating the process of manufacturing drug carrier particles according to one embodiment of the present invention.

[0076] Specifically, FIG. 3 illustrates a process of preparing drug carrier particles according to FIG. 1 by mixing SSSF, which is a complex (110) of silk sericin (111) and silk fibroin (112), ethanol, and paclitaxel, which is a therapeutic agent (120), stirring, and then centrifuging, wherein SSSF is related to the particle size, ethanol is related to the particle yield, and paclitaxel is related to the loading efficiency of the therapeutic agent (120).

[0077] Specifically, in the case of the spherical particles of FIG. 3, paclitaxel, an oil phase therapeutic agent (120), and ethanol, a catalyst, are mixed into a water phase SSSF mixture. When the mixed material is stirred, amphiphilic SSSF molecules aggregate around the hydrophobic (oil phase) drug, and spherical particles are formed through self-assembly in which the hydrophobic parts of the SSSF gather towards the center and the hydrophilic parts face outward. At this time, centrifugation is performed to separate the particles formed into spherical particles by the above process from the debris that did not become spherical particles.

[0078] Meanwhile, the circular particles (SSSF-DPP) of Fig. 5 (C) are manufactured by a micro-imprinting technique in which the SSSF mixed solution and the therapeutic agent (120), docetaxel, are formed into the shape of the mold using a PVA-template mold. At this time, since the PVA mold is water-soluble, when the mold filled with the SSSF mixed solution and docetaxel is dissolved in water, the PVA mold dissolves, and the micro-sized circular particles containing the SSSF and docetaxel do not dissolve in water due to hydrophobicity, so the particles can be separated and obtained through centrifugation. In addition, to prevent the SSSF from dissolving in water during the above process, the silk sericin aqueous solution and the silk fibroin aqueous solution were freeze-dried to form a powder, and the powder was dissolved in an HFIP organic solvent to use the SSSF mixed solution.

[0079] In other words, nano-sized spherical drug carrier particles containing paclitaxel internally correspond to particles created by stirring due to the properties of the material, and micro-sized disc-shaped particles containing docetaxel internally correspond to drug carrier particles whose shape is artificially formed by an containing mold.

[0080] In addition, FIG. 5 shows the process of extracting silk sericin (111)(SS) from a silkworm cocoon (A), the process of extracting silk fibroin (112)(SF) (B), and the process of mixing, stirring, and centrifuging SS, SF, and docetaxel to produce drug carrier particles according to FIG. 4.

[0081] First, silk sericin (111) and silk fibroin (112) are mixed to form polymer particles.

[0082] Next, a therapeutic agent (120) is loaded inside the polymer particles.

[0083] According to one embodiment of the present invention, the step of supporting a therapeutic agent (120) inside the polymer particles may include, but is not limited to, a step of dispersing a solution containing the polymer particles in an amount of 100 w / v% to 10 w / v% and the therapeutic agent (120) in a solvent; and a step of centrifuging.

[0084] As described above, in a solution containing the polymer particles, the higher the concentration of the polymer particles, the larger the particle size becomes. Additionally, the higher the amount of the solvent (ethanol), the higher the particle yield becomes.

[0085] According to one embodiment of the present invention, the concentration of the therapeutic agent (120) in the solvent may be 1 g / l to 20 g / l, but is not limited thereto.

[0086] In this regard, the concentration of the therapeutic agent (120) in the solvent may vary depending on the type of therapeutic agent, and it was confirmed that if the concentration of the therapeutic agent exceeds a certain level, the proportion of the therapeutic agent loaded into the polymer particles does not increase. In the case of Fig. 3, it was confirmed that when paclitaxel was 1 mg (concentration 2 g / L), the efficiency of loading paclitaxel into the polymer particles was high.

[0087] Additionally, a third aspect of the present invention relates to a pharmaceutical composition comprising a drug carrier particle according to the first aspect.

[0088] According to one embodiment of the present invention, the pharmaceutical composition may be intended to treat a disease selected from the group consisting of lung cancer, cervical cancer, squamous cell carcinoma, and combinations thereof, but is not limited thereto.

[0089] The present invention is to be explained in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0090] [Example 1]

[0091] Silk sericin and silk fibroin were mixed in water at a mass ratio of 1:3 to form an SSSF complex. Subsequently, 3 ml of water containing 12.5 w / v% of the SSSF complex, 500 μl of ethanol, and 1 mg of paclitaxel were mixed and stirred for 24 hours, followed by centrifugation at 10,000 RPM for 5 minutes and then at 13,500 RPM for 10 minutes to form spherical nanoparticles (SSSF-PTX NP) loaded with paclitaxel inside the SSSF.

[0092] [Example 2]

[0093] Aqueous silk sericin solutions and aqueous silk fibroin solutions were freeze-dried to form powders, and then SS powder and SF powder were mixed in a mass ratio of 1:3 and dissolved in an organic solvent HFIP to prepare an SSSF complex solution. Subsequently, the complex solution was poured into a water-soluble PVA mold containing a disc-shaped empty space with a diameter of 1 μm to 5 μm and a depth of 1 μm to 2 μm, and cured. Subsequently, the mold was immersed in water to dissolve the PVA mold, and centrifuged to prepare disc-shaped nanoparticles (DTX-SSSF DSP) loaded with docetaxel inside the SSSF.

[0094] [Experimental Example 1]

[0095] FIG. 6a shows the size distribution of drug carrier particles according to one embodiment of the present invention, and FIG. 6b shows the Zeta Potential distribution of said drug carrier particles. Specifically, FIG. 6a and FIG. 6b show the size distribution and Zeta Potential distribution of SSSF-PTX NP.

[0096] In addition, Table 1 below shows the particle size, PDI, Zeta Potential, and drug encapsulation efficiency of SSSF-PTX NP:

[0097] Size (d. nm)PDIZeta Potential (mV)Drug encapsulation efficiency (%)288.3±25.530.234 ±0.0993-27.21 ±2.40152.31 ±0.959

[0098] Referring to Figures 6a and 6b and Table 1, the SSSF-PTX NP exhibits a very uniform particle size of approximately 250 nm to 330 nm. Consequently, a passive targeting effect due to the enhanced permeability and retention (EPR) effect can be expected, demonstrating potential for synergy with PEMF. Furthermore, the zeta displacement represents the repulsive force between charged particles in the dispersion; particles with a displacement of -40 mV to -20 mV exhibit physical colloid stability instead of aggregating or increasing in size. [Experimental Example 2]

[0099] FIG. 7 is an FT-IR graph of a drug carrier particle according to one embodiment of the present invention, and FIG. 8a and FIG. 8b are FT-IR graphs of a drug carrier particle according to one embodiment of the present invention. In this regard, Amides A, I, II, and III of FIG. 7 are each of the following Chemical Formulas 1 to 4:

[0100] [Chemical Formula 1] (Corresponds to Amide A in Fig. 7)

[0101]

[0102] [Chemical Formula 2] (Corresponds to I in Fig. 7)

[0103]

[0104] [Chemical Formula 3] (Corresponds to II in Fig. 7)

[0105]

[0106] [Chemical Formula 4] (Corresponds to III in Fig. 7)

[0107]

[0108] Referring to FIGS. 7 to 8b, it can be seen that SSSF is a combination of SS and SF.

[0109] [Experimental Example 3]

[0110] FIG. 9a is a graph showing the stability of a drug carrier particle according to one embodiment of the present invention, FIG. 9b is a graph showing the drug release ability of a drug carrier particle according to one embodiment of the present invention, and FIG. 10a and FIG. 10b are graphs showing the drug release ability of a drug carrier particle according to one embodiment of the present invention. In this regard, FIG. 10a shows the drug release ability when the drug VEGF is used without SF (unfilled square in the graph) and the drug release ability of VEGF loaded within the SF particle (filled square in the graph), and FIG. 10b is about the drug release ability of a drug loaded in a drug carrier particle using only SS, showing the change in drug release ability according to the concentration of SS (silk sericin).

[0111] Referring to FIGS. 9a to 10b, the SSSF-PTX NP is more stable in a neutral pH environment and slowly releases the therapeutic agent (PTX) inside, and as the pH approaches acidity, it decomposes rapidly, releasing the therapeutic agent quickly. Additionally, it can be confirmed that silk sericin has strong hydrophilic properties and tends to be completely released within 8 hours.

[0112] In addition, unlike nanoparticles containing only silk sericin or silk fibroin, mixing the two controls the rate of biodegradation regardless of the ratio of silk sericin (SER) and promotes endocytosis by silk proteins.

[0113] In this regard, since drug carrier particles containing silk fibroin without silk sericin have a slow drug release rate and drug carrier particles containing silk sericin without silk fibroin have a fast drug release rate, it is necessary to develop particles with a drug release rate that falls between the two. As will be described later, it was confirmed that drug carrier particles containing both silk sericin and silk fibroin simultaneously have a drug release rate that is neither too fast nor too slow.

[0114] [Experimental Example 4]

[0115] FIGS. 11a and 11b illustrate the cytotoxicity of drug carrier particles according to one embodiment of the present invention, and FIG. 12 illustrates the intracellular distribution of drug carrier particles according to one embodiment of the present invention.

[0116] Referring to Figures 11a and 11b, no cytotoxicity was observed for SSSF NP, PTX, and SSSF PTX NP on SiHa cells, while cytotoxicity was observed for PTX and SSSF-PTX NP on HeLa cells compared to SSSF NP. This confirms the drug delivery efficiency of SSSF-NP.

[0117] In addition, Figure 12 shows the location of the cell nucleus (DAPI) and the location of paclitaxel (Cy5.5). Referring to Figure 12, it can be seen that the efficiency of PTX delivery to the cell nucleus is enhanced by SSSF NP.

[0118] [Experimental Example 5]

[0119] Figures 13 (A) to (D) are SEM and CLSM (confocal laser scanning microscopy) images of drug carrier particles according to one embodiment and a comparative example of the present invention. In addition, Table 2 below shows the diameter, Zeta potential, loading rate, and PDI of SF disc-shaped particles, SSSF disc-shaped particles, DTX-SF disc-shaped particles, and DTX-SSSF disc-shaped particles according to Example 2. Here, Figure 13 (A) represents SF, (B) represents SSSF, (C) represents DTX-SF, and (D) represents the drug carrier particles according to Example 2, where the scale bar represents 2 μm.

[0120] Size (d. μm)PDIZeta Potential (mV)Drug encapsulation efficiency (%)(A)2.74±0.070.162-29.03±0.53(B)2.77±0.090.105-25.37±0.55-(C)2.80± 0.060.084-33.80±0.2936.16±3.37(D)2.83±0.090.118-31.60±0.2929.02±4.09

[0121] Referring to Fig. 13 and Table 2, it can be seen that SF, SSSF, DTX-SF, and DTX-SSSF discoidal particles are produced as discoidal particles of approximately 3 μm, and that there is minimal change in size even after drug loading. The zeta displacement represents the repulsive force between charged particles in the dispersion, and particles with a zeta displacement of -40 mV to -20 mV exhibit physical colloid stability instead of aggregating or increasing in particle size. [Experimental Example 6]

[0122] FIG. 14 illustrates the stability of drug carrier particles according to one embodiment of the present invention. Specifically, FIG. 14 (A) to (D) illustrates the stability of SF DSP, SSSF DSP, DTX-SF DSP, and DTX-SSSF DSP (Example 2) in an environment where the pH is 5.4 or 7.4, and (E) and (F) illustrate the drug release rates of DTX-SF DSP and DTX-SSSF DSP.

[0123] Referring to Fig. 14, the drug release rate is rapid when SSSF is in an acidic pH (5.4) environment compared to an environment with a neutral pH (7.4), which is attributed to the structural instability of SF and the hydrophilicity of SS caused by the acidic environment. Additionally, the drug release rate was relatively low in an environment with a neutral pH, which means that SF exists stably in a neutral environment.

[0124] [Experimental Example 7]

[0125] FIG. 15 illustrates the therapeutic effect of drug carrier particles on lung cancer according to one embodiment of the present invention, and FIG. 16a and FIG. 16b illustrate the locations where drug carrier particles accumulate within the body. Specifically, FIG. 15 (A) and (B) show the cell viability of A549 cells with SS, SF, SF DSP, SSSF DSP, docetaxel, DTX-SF DSP, and DTX-SSSF DSP (Example 2), and (C) and (D) are for SCC7. Additionally, FIG. 16a and FIG. 16b show drug carrier particles prepared using the fluorescent substance DiR instead of DTX.

[0126] Referring to Figure 15, it can be seen that SS causes cell damage and lowers cell viability compared to SF, and that SSSF DSP exhibits high cytotoxicity.

[0127] Also, referring to Figures 16a and 16b, when DiR-SSSF DSP particles are prepared and injected intravenously, they show a high accumulation in the lungs within 2 hours and decrease over time, which means that the particles are rapidly accumulated in the lungs and then metabolized, reducing the risk of causing adverse effects on other organs.

[0128] [Experimental Example 8]

[0129] Figure 17 (A) is a schematic timeline of an experiment on drug carrier particles according to one embodiment of the present invention, (B) is for lung tissue samples after treatment of the experimental group, and (C) to (F) are the results of the analysis of survival rate and average number of tumor nodules after treatment.

[0130] Referring to Figure 17, it can be seen that the number of tumor nodules formed in the lungs decreases and survival rate improves when DTX-SSSF DSPs are administered.

[0131] [Experimental Example 9]

[0132] FIG. 18 analyzes the degree of accumulation of drug carrier particles in organs according to one embodiment of the present invention. Specifically, H&E staining was performed to analyze whether the drug carrier particles accumulate in the lungs, liver, spleen, kidneys, or heart of the body and exhibit toxicity.

[0133] Referring to Figure 18, the alveolar spaces in the lungs of the DTX-SF DSPs and DTX-SSSF DSPs treatment groups remained similar to those of the normal group, and no toxicity was observed in the liver, spleen, kidneys, or heart, which shows that the particles are safe for the lungs and other organs.

[0134] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical concept or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single unit may be implemented in a distributed manner, and components described as distributed may likewise be implemented in a combined form.

[0135] The scope of the present invention is defined by the claims set forth below rather than by the detailed description above, and all modifications or variations derived from the meaning and scope of the claims and the concept of equivalents thereof should be interpreted as being included within the scope of the present invention.

[0136] [Explanation of the symbol]

[0137] 110 : Complex

[0138] 111 : Silk Sericin

[0139] 112 : Silk fibroin

[0140] 120 : Treatment

Claims

1. Regarding drug carrier particles, The above drug carrier particles are polymer particles comprising a complex of silk sericin and silk fibroin; and A therapeutic agent supported inside the above polymer particles; Includes, The above polymer particles are spherical or disc-shaped particles, Drug carrier particles.

2. In Paragraph 1, The above polymer particles are drug carrier particles comprising silk sericin and silk fibroin in a mass ratio of 1:2 to 1:

4.

3. In Paragraph 2, A drug carrier particle in which the silk fibroin controls the degree of biodegradability of the polymer particles, and the silk sericin controls the binding between the silk fibroins.

4. In Paragraph 1, The above polymer particles have a particle size of 100 nm to 500 nm, or 1 μm to 5 μm, and are drug carrier particles.

5. In Paragraph 4, A drug carrier particle in which the disease targeted by the drug carrier particle or the location where the drug carrier particle arrives differs depending on the size and shape of the polymer particle.

6. In Paragraph 5, A drug carrier particle in which, when the polymer particle is a spherical particle of 100 nm to 500 nm, the therapeutic agent comprises a therapeutic agent targeting cervical cancer.

7. In Paragraph 6, The above therapeutic agent is a drug carrier particle containing paclitaxel.

8. In Paragraph 5, A drug carrier particle in which, when the polymer particle is a disc-shaped particle of 1 μm to 5 μm, the drug carrier particle contains a therapeutic agent targeting lung cancer.

9. In Paragraph 8, The above therapeutic agent is a drug carrier particle containing docetaxel.

10. In Paragraph 1, The above therapeutic agent is a drug carrier particle in which endocytosis is promoted by the above polymer particles.

11. In Paragraph 1, A drug carrier particle having silk sericin disposed on the surface of the polymer particle and silk fibroin and a therapeutic agent disposed inside the polymer particle.

12. In a method for manufacturing drug carrier particles, A step of forming polymer particles by mixing silk sericin and silk fibroin; and A step of loading a therapeutic agent inside the above polymer particles; Includes, The above polymer particles are formed as spherical or disc-shaped particles. Method for manufacturing drug carrier particles.

13. In Paragraph 12, A method for manufacturing a drug carrier particle, wherein the step of loading a therapeutic agent inside the polymer particle comprises: a step of dispersing a solution containing the polymer particle in an amount of 100 w / v% to 10 w / v% and the therapeutic agent in a solvent; and a step of centrifuging.

14. In Paragraph 13, A method for preparing drug carrier particles, wherein the concentration of the therapeutic agent in the above solvent is 1 g / l to 20 g / l.

15. A pharmaceutical composition comprising drug carrier particles according to claim 1 16. In Paragraph 15, The above pharmaceutical composition is intended to treat a disease selected from the group consisting of lung cancer, cervical cancer, squamous cell carcinoma, and combinations thereof.

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