WO2024237645A1 - Silica-based nanoparticles for sustained release of hydrophobic drug, preparation method therefor, and transdermal drug delivery system comprising same - Google Patents

Abstract

The purpose of the present invention is to implement a hydrophobic drug as a transdermal drug delivery system (TDDS). The present invention relates to: silica-based nanoparticles for the sustained release of a hydrophobic drug, the silica-based nanoparticles comprising hollow nanoparticles that include a hollow core layer and a silica matrix shell layer, and the hydrophobic drug loaded into the hollow nanoparticles; a method for preparing same; and a transdermal drug delivery system comprising same.

Description

Silica-based nanoparticles for sustained release of hydrophobic drugs, method for preparing the same, and transdermal drug delivery system comprising the same

The present invention relates to silica-based nanoparticles for sustained release of hydrophobic drugs, a method for producing the same, and a transdermal drug delivery system comprising the same.

There are oral and parenteral methods of drug administration, such as intravenous and subcutaneous injection. Oral administration is a relatively easy way to take drugs in the form of tablets, capsules, and liquids, and it is an inexpensive and convenient method of administration because it does not require administration equipment or assistance from professional personnel. However, drugs taken orally are affected by gastric acidity and gastrointestinal motility, and the first-pass effect may cause unstable drug concentration in the bloodstream, which may reduce the therapeutic effect. An additional disadvantage is that there is a possibility of gastrointestinal diseases such as gastric ulcers and gastric perforation when nonsteroidal anti-inflammatory drugs, analgesics, narcotic analgesics, and antibiotics are administered orally.

Parenteral administration methods have the disadvantages of causing allergic reactions such as urticaria and edema, tissue damage, pain, bleeding, discomfort during administration, embolism if there are air bubbles in the syringe, and serious complications such as sepsis due to the risk of infection at the injection site or in the bloodstream.

Meanwhile, transdermal drug delivery systems (TDDS) have made great strides since the motion sickness treatment patch was first approved by the US FDA in 1979, complementing the shortcomings of oral and parenteral administration. TDDS has the advantage of eliminating the first-pass effect and the risk of gastrointestinal diseases by directly administering drugs through the skin, and as a non-invasive method, there is no discomfort or pain during administration, and no risk of embolism or sepsis.

However, paradoxically, commercial patches and ointments do not show superior performance compared to oral or parenteral administration methods in sustained release and sustainability, which can be said to be the greatest features of TDDS. Currently, most commercial transdermal drug delivery systems are developed in the form of hydrogels, microparticles, and microspheres based on polymer materials such as PEG, PVA, HA, and chitosan. However, due to the nature of polymers, the particle size distribution is uneven, and there is a concern about side effects due to the initial release of an excessive amount of drug due to swelling or polymer chain breakage, and the duration of the drug effect is short.

[Prior art literature]

[Patent Document]

(Patent Document 1) Republic of Korea Patent Publication No. 10-2020-0091682 (July 31, 2020)

The present invention is intended to provide a hollow nanoparticle including a hollow core layer and a silica matrix shell layer for implementing a hydrophobic drug as a transdermal drug delivery system (TDDS); and a silica-based nanoparticle for sustained release of a hydrophobic drug, including a hydrophobic drug loaded in the hollow nanoparticle.

However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

The present invention provides a silica-based nanoparticle for sustained release of a hydrophobic drug, comprising a hollow nanoparticle including a hollow core layer and a silica matrix shell layer; and a hydrophobic drug loaded in the hollow nanoparticle.

The above hydrophobic drug may be BCS Class II; or BCS Class IV.

The size of the hollow core layer may be 100 to 600 nm, and the size of the hollow nanoparticle may be 200 to 900 nm.

In one embodiment of the present invention, a method for producing silica-based nanoparticles for sustained-release of a hydrophobic drug is provided, comprising: (a) preparing a uniform phase by stirring a solvent and a surfactant; (b) adding a silica precursor to the uniform phase prepared in step (a), performing a first reaction, and then producing nanoparticles through a hydrothermal synthesis reaction at a temperature higher than the first reaction temperature; (c) drying and calcining the nanoparticles produced in step (b) to produce hollow nanoparticles; and (d) impregnating the hollow nanoparticles produced in step (c) in a hydrophobic drug solution to load the hydrophobic drug onto the hollow nanoparticles.

In the step (a), the solvent may be at least one selected from the group consisting of water, lower alcohols having C1 to C4, and ammonia water; and the surfactant may be at least one selected from the group consisting of cetyltrimethylammonium bromide (CTAB), 1,3,5-trimethylbenzene (1,3,5-TMB), Pluronic P123 (P123), Pluronic F127 (F127), benzene, and toluene.

In the above step (a), the content of the surfactant may be 0.5 g to 50 g based on 1 L of the total solvent.

In the step (b) above, the silica precursor may be tetraethyl orthosilicate (TEOS) or tetramethyl orthosilicate (TMOS).

In the above step (b), the hydrothermal synthesis reaction can be performed at a temperature of 80 to 200°C for 24 to 168 hours.

In the above step (c), drying can be performed at a temperature of 80 to 120°C for 1 to 24 hours, and calcination can be performed at a temperature of 300 to 700°C for 3 to 12 hours.

In another embodiment of the present invention, a transdermal drug delivery system comprising silica-based nanoparticles for sustained release of the hydrophobic drug is provided.

The silica-based nanoparticle for sustained release of a hydrophobic drug according to the present invention is characterized by including a hollow nanoparticle including a hollow core layer and a silica matrix shell layer infiltrated with metal; and a hydrophobic drug loaded in the hollow nanoparticle.

In the present invention, hollow nanoparticles are manufactured from silica, an inorganic material, and are used as a drug delivery platform, so that they are not easily hydrated or react with water under hydrophilic conditions, and their physical properties, such as specific surface area and pore volume, can be flexibly changed, so that a large amount of drug can be loaded.

In particular, it has the advantage of being able to implement hydrophobic drugs as transdermal drug delivery systems (TDDS) because it can improve the release sustainability while preventing initial excessive release of hydrophobic drugs.

Figures 1(a) to (c) are TEM images of silica nanoparticles of Examples 1 to 3.

Figure 2 is a schematic diagram showing the drug release pattern from the mesoporous silica particles of the present invention.

FIG. 3(a) is a graph showing the results of drug release analysis of ibuprofen as a hydrophobic drug loaded on silica nanoparticles of Examples 1 to 3, FIG. 3(b) is a graph showing the results of drug release analysis of ibuprofen salt as a hydrophilic drug loaded on silica nanoparticles of Example 1, and FIG. 3(c) is a graph showing the results of drug release analysis of loxoprofen salt as a hydrophilic drug loaded on silica nanoparticles of Example 2.

Figure 4 is a graph showing the results of drug release analysis of ketoprofen, a hydrophobic drug loaded on silica nanoparticles of Example 3.

The present inventors prepared hollow nanoparticles by introducing a silica precursor into a homogeneous phase stirred with an optimal solvent and an optimal surfactant, followed by hydrothermal synthesis, and confirmed that they could successfully support various drugs and release hydrophobic drugs in a sustained manner, thereby completing silica-based nanoparticles for sustained release of hydrophobic drugs according to the present invention.

Hereinafter, the present invention will be described in detail.

Silica-based nanoparticles for sustained release of hydrophobic drugs and transdermal drug delivery systems

The present invention provides a silica-based nanoparticle for sustained release of a hydrophobic drug, comprising a hollow nanoparticle including a hollow core layer and a silica matrix shell layer; and a hydrophobic drug loaded in the hollow nanoparticle.

In addition, the present invention provides a transdermal drug delivery system comprising silica-based nanoparticles for sustained release of the hydrophobic drug.

First, the silica-based nanoparticles for sustained release of hydrophobic drugs according to the present invention include hollow nanoparticles including a hollow core layer and a silica matrix shell layer.

Specifically, the hollow nanoparticles include a hollow core layer and a silica matrix shell layer.

The above hollow core layer may be a layer formed when a surfactant located in the core is removed during the process of drying and calcining the nanoparticles.

The size of the hollow core layer may be 100 to 600 nm, preferably 120 to 500 nm, or 150 to 300 nm, but is not limited thereto. The size of the hollow core layer can be controlled by the type and content of the surfactant. In order to effectively prevent initial excessive release of the hydrophobic drug described below, it is most preferable that the size of the hollow core layer is controlled to 150 to 200 nm.

The above silica matrix shell layer is a layer formed through hydrothermal synthesis of a silica precursor, and a large number of pores can be formed.

The size of the above hollow nanoparticles may be 200 to 900 nm, preferably 200 to 800 nm, 200 to 700 nm, 200 to 600 nm, 200 to 500 nm or 250 to 400 nm, but is not limited thereto.

Meanwhile, the hollow nanoparticle may have a specific surface area of 100 to 1,000 m ² /g, and is preferably 100 to 300 m ² /g, but is not limited thereto. In addition, the hollow nanoparticle may have a pore volume and a pore size of 0.1 to 2.0 cm ³ /g and 1 to 15 nm, respectively, and is preferably 0.2 to 1.0 cm ³ /g and 1 to 10 nm, but is not limited thereto.

Next, the silica-based nanoparticles for sustained release of a hydrophobic drug according to the present invention are characterized in that they include a hydrophobic drug, which is supported on the hollow nanoparticles.

The above hydrophobic drug is in a form having low solubility, preferably BCS Class II; or BCS Class IV, but is not limited thereto. The BCS class is a methodology for classifying drugs according to their solubility and permeability. Here, low solubility means that the volume of an aqueous solution sufficient to dissolve a single maximum dose of a general oral solid preparation containing the same main ingredient in a pH range of 1.2 to 6.8 exceeds 250 mL. BCS Class II refers to a group having low solubility but high permeability, and BCS Class IV refers to a group having both low solubility and low permeability. Specifically, the hydrophobic drug may be a BCS class II drug such as Ibuprofen, Ketoprofen, Loxoprofen, Diclofenac, Rotigotine, Griseofulvin, Itraconazole, Ketoconazole, Tacrolimus, Nifedipine, Carbamazepine, or a BCS class IV drug such as Furosemide, Hydrochlorothiazide, Cyclosporin A, Paclitaxel, Albendazole, Azathioprine, Didanosine, etc. In the salt form of these hydrophobic drugs, they can be classified as hydrophilic drugs.

The hydrophobic drug can be efficiently loaded into the hollow nanoparticles and then have improved release duration without initial excessive release through interaction with the hollow nanoparticles with enhanced hydrophobicity.

Meanwhile, the silica-based nanoparticles for sustained release of hydrophobic drugs according to the present invention have the advantage of improving the release duration while preventing initial excessive release of hydrophobic drugs when implemented as a transdermal drug delivery system.

Specifically, the amount of the hydrophobic drug loaded relative to the silica nanoparticles may be 10 to 90 wt%, preferably 30 to 80 wt% or 40 to 60 wt%, but is not limited thereto.

When the above silica nanoparticles are subjected to a dissolution test in an SBF solution at a temperature of 32°C and a paddle speed of 600 rpm in accordance with the standards of the in vitro skin absorption test guideline (Ministry of Food and Drug Safety), the dissolution rate of the hydrophobic drug (particularly, ibuprofen, ketoprofen) after 40 hours may be 60% or less, and is preferably 10 to 50% or 20 to 40%, but is not limited thereto.

As reviewed above, the silica-based nanoparticles for sustained release of a hydrophobic drug according to the present invention are characterized by including hollow nanoparticles including a hollow core layer and a metal-penetrated silica matrix shell layer; and a hydrophobic drug loaded in the hollow nanoparticles.

In the present invention, hollow nanoparticles are manufactured from silica, an inorganic material, and are used as a drug delivery platform, so that they are not easily hydrated or react with water under hydrophilic conditions, and their physical properties, such as specific surface area and pore volume, can be flexibly changed, so that a large amount of drug can be loaded.

In particular, it has the advantage of being able to implement hydrophobic drugs as transdermal drug delivery systems (TDDS) because it can improve the release sustainability while preventing initial excessive release of hydrophobic drugs.

Method for preparing silica-based nanoparticles for sustained release of hydrophobic drugs

The present invention provides a method for producing silica-based nanoparticles for sustained-release of a hydrophobic drug, comprising the steps of: (a) preparing a uniform phase by stirring a solvent and a surfactant; (b) adding a silica precursor to the uniform phase prepared in step (a), performing a first reaction, and then producing nanoparticles through a hydrothermal synthesis reaction at a temperature higher than the first reaction temperature; (c) drying and calcining the nanoparticles produced in step (b) to produce hollow nanoparticles; and (d) impregnating the hollow nanoparticles produced in step (c) in a hydrophobic drug solution to load the hydrophobic drug onto the hollow nanoparticles.

First, the method for manufacturing silica-based nanoparticles for sustained release of hydrophobic drugs according to the present invention includes a step [step (a)] of preparing a uniform phase by stirring a solvent and a surfactant.

The solvent is for uniformly dissolving the surfactant, and may be at least one selected from the group consisting of water, lower alcohols having C1 to C4, and ammonia water. It is preferable that it includes all of water, lower alcohols having C1 to C4 (e.g., ethanol), and ammonia water, but is not limited thereto. Specifically, the volume ratio of the water, lower alcohols having C1 to C4 (e.g., ethanol), and ammonia water may be 10:5:1 to 50:15:1, and is preferably 20:8:1 to 30:10:1, but is not limited thereto.

In addition, the surfactant may be at least one selected from the group consisting of cetyltrimethylammonium bromide (CTAB), 1,3,5-trimethylbenzene (1,3,5-TMB), Pluronic P123 (P123), Pluronic F127 (F127), benzene and toluene, and is preferably at least two selected from the group consisting of cetyltrimethylammonium bromide (CTAB), 1,3,5-trimethylbenzene (1,3,5-TMB) and Pluronic P123 (P123), but is not limited thereto.

Specifically, when there are three types of the surfactants, such as 1,3,5-TMB, CTAB, and P123, the weight ratio of 1,3,5-TMB, CTAB, and P123 may be 1:2:10 to 1:10:30, preferably 1:2:20 to 1:3:30, but is not limited thereto. At this time, based on 1 L of the total solvent, the total content of these surfactants may be 0.5 g to 10 g. Meanwhile, when there are two types of the surfactants, such as 1,3,5-TMB and P123, the weight ratio may be 1:10 to 1:20. At this time, based on 1 L of the total solvent, the total content of these surfactants may be 10 g to 50 g.

The type and content of these surfactants can control the size of the hollow core layer and the size of the nanoparticles.

Next, the method for manufacturing silica-based nanoparticles for sustained release of a hydrophobic drug according to the present invention includes a step [step (b)] of adding a silica precursor to the prepared uniform phase, performing a first reaction, and then manufacturing nanoparticles through a hydrothermal synthesis reaction at a temperature higher than the first reaction temperature.

The above silica precursor may be tetraethyl orthosilicate (TEOS) or tetramethyl orthosilicate (TMOS).

The above first reaction can be carried out at room temperature for 1 to 10 hours, and can be carried out at room temperature for 2 to 7 hours.

After the above first reaction, the hydrothermal synthesis reaction can be performed in an autoclave, and can be performed at a temperature of 80 to 200°C for 24 to 168 hours, and is preferably performed at a temperature of 80 to 180°C, 80 to 160°C, 80 to 140°C, 80 to 130°C, 100 to 200°C, 100 to 180°C, 100 to 160°C, 100 to 140°C, 100 to 130°C, 120 to 200°C, 120 to 180°C, 120 to 160°C, 120 to 140°C, or 120 to 130°C for 36 to 72 hours, but is not limited thereto.

After the above hydrothermal synthesis reaction, processes such as reduced pressure filtration and distilled water washing can be added.

Next, the method for producing silica-based nanoparticles for sustained release of hydrophobic drugs according to the present invention includes a step [step (c)] of drying and then calcining the produced nanoparticles to produce hollow nanoparticles.

Through the above drying and calcination, the surfactant located in the core can be removed, and thus, the hollow core layer can be formed.

The above drying can be performed at a temperature of 80 to 120°C for 1 to 24 hours, and is preferably performed at a temperature of 90 to 110°C for 6 to 24 hours, but is not limited thereto.

Thereafter, the calcination can be performed at 300 to 700°C for 1 to 24 hours, and is preferably performed at a temperature of 400 to 600°C for 1 to 12 hours, but is not limited thereto.

Next, the method for producing silica-based nanoparticles for sustained release of a hydrophobic drug according to the present invention includes a step [step (d)] of impregnating the manufactured hollow nanoparticles into a hydrophobic drug solution to load the hydrophobic drug onto the hollow nanoparticles.

The hydrophobic drug solution may include a solvent capable of dissolving the hydrophobic drug (e.g., ethanol), and the impregnation may be performed through an incipient wetness impregnation method or an excess water impregnation method known in the art.

Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

Example 1. Preparation of silica nanoparticles (1)

125 ml of distilled water to be used as a solvent, 75 ml of ethanol, 15 ml of ammonia water (25-28%), and 0.105 g of CTAB (cetyltrimethylammonium bromide) as a surfactant, 1.045 g of P123 (Pluronic P123), and 0.042 g of 1,3,5-TMB (1,3,5-trimethylbenzene) were placed in a round bottom flask and stirred for 3 hours to prepare a solution having a uniform phase, then 10 ml of TEOS (tetraethoxysilane), a silica precursor, was added and reacted at room temperature for 5 hours, and then treated in an autoclave at 130°C for 48 hours. The treated solution was filtered under reduced pressure and washed with distilled water to obtain silica nanoparticles. The obtained silica nanoparticles were dried in an oven at 100°C for 12 hours and then calcined at 500°C for 6 hours.

Example 2. Preparation of silica nanoparticles (2)

125 ml of distilled water to be used as a solvent, 75 ml of ethanol, 15 ml of ammonia water (25-28%), and 0.3 g of CTAB, 0.85 g of P123, and 0.051 g of 1,3,5-TMB as surfactants were placed in a round bottom flask and stirred for 3 hours to prepare a solution having a uniform phase, 10 ml of TEOS as a silica precursor was added, and after reacting at room temperature for 5 hours, it was treated in an autoclave at 130°C for 48 hours. The treated solution was filtered under reduced pressure and washed with distilled water to obtain silica nanoparticles. The obtained silica nanoparticles were dried in an oven at 100°C for 12 hours and then calcined at 500°C for 6 hours.

Example 3. Preparation of silica nanoparticles (3)

125 ml of distilled water to be used as a solvent, 75 ml of ethanol, 15 ml of ammonia water (25-28%), 4.0 g of P123 as a surfactant, and 0.3 g of 1,3,5-TMB were placed in a round bottom flask and stirred for 3 hours to prepare a solution having a uniform phase, 10 ml of TEOS as a silica precursor was added, and after reacting at room temperature for 5 hours, it was treated in an autoclave at 130°C for 48 hours. The treated solution was filtered under reduced pressure and washed with distilled water to obtain silica nanoparticles. The obtained silica nanoparticles were dried in an oven at 100°C for 12 hours and then calcined at 500°C for 6 hours.

Experimental Example 1. Analysis of silica nanoparticles (1) to (3)

The particle size, hollow size, shell thickness, surface area, pore volume, and pore size of the silica nanoparticles of Examples 1 to 3 were measured and are listed in Table 1 below. In addition, TEM images were taken and are shown in Figs. 1(a) to (c).

division Particle size
(nm) Hollow size
(nm) Shell size
(nm) Surface area
(m ² /g) Pore volume
(cm ³ /g) Pore size
(nm) Example 1 374 ± 25 182 ± 20 96 ± 15 282 0.27 7 Example 2 383 ± 40 254 ± 35 64 ± 8 208 0.35 10 Example 3 285 ± 75 197 ± 60 55 ± 18 190 0.2 6

Experimental example 2. Hydrophobic drug (1) loading experiment

As a hydrophobic drug, 1 g of ibuprofen was added to ethanol to make 20 ml, and 1 g of silica nanoparticles manufactured in Example 1 or 2 were added and stirred at room temperature for 24 hours. Thereafter, the drug-loaded silica nanoparticles were filtered under reduced pressure, washed with ethanol to obtain them, and dried under reduced pressure at 60°C for 4 hours. At this time, the drug loading amount was confirmed by measuring the concentration of the drug dissolved in the washing solution using a UV measuring device. A schematic diagram of the drug release pattern is shown in Fig. 2. The drug loading amount was measured and is shown in Table 2 below.

division Amount of ibuprofen loaded per gram of silica (g) Example 1 0.408 Example 2 0.571

Experimental Example 3. Hydrophobic Drug (2) Loading Experiment

As a hydrophobic drug, 1 g of ketoprofen was added to ethanol to make 20 ml, and 1 g of silica nanoparticles manufactured in Example 3 were added thereto and stirred at room temperature for 24 hours. Thereafter, the drug-loaded silica nanoparticles were filtered under reduced pressure, washed with ethanol to obtain them, and dried under reduced pressure at 60°C for 4 hours. At this time, the drug loading amount was confirmed by measuring the concentration of the drug dissolved in the washing solution using a UV measuring device. The drug loading amounts were measured and shown in Table 2 below.

division Ketoprofen loading per gram of silica (g) Example 3 0.554

Experimental Example 4. Hydrophobic Drug (1) Release Experiment

As a hydrophobic drug, an appropriate amount of distilled water was added dropwise to about 0.004 g of the silica nanoparticles of Examples 1 to 3 loaded with ibuprofen to make a paste, which was then evenly applied to the upper surface of the membrane (artificial skin, area: 1.13 cm ² ). The membrane with the silica paste applied was placed on an FDC (Franz diffusion cell) and fixed with a clamp so that it would not move. The receptor chamber was filled with SBF (simulated body fluid) solution, and while stirring at 32°C and 600 rpm, 3 ml of the solution was taken at predetermined time intervals, and the UV absorbance was measured to confirm the concentration of the released drug. At this time, new SBF in an amount equal to the volume of the solution taken for sampling was filled into the receptor chamber.

Meanwhile, as Comparative Example 1, an experiment was performed using the silica nanoparticles of Example 1 loaded with an ibuprofen salt, which is a hydrophilic drug, in the same manner. In addition, as Comparative Example 2, an experiment was performed using the silica nanoparticles of Example 2 loaded with a loxoprofen salt, which is a hydrophilic drug, in the same manner.

As a control group, commercial products A and B (ibuprofen and loxoprofen) with the same area as the membrane (artificial skin, area: 1.13 cm ² ) were attached on the membrane. The experiment was performed in the same manner, except that the membrane with commercial products A and B attached was placed on the FDC and fixed using a clamp to prevent movement.

The drug release amount is measured and shown in Figs. 3(a) to (c). As shown in Figs. 3(a) to (c), the in-vitro release experiment results for commercial products A and B confirmed that almost all the drug was released within about 40 hours, but ibuprofen, as a hydrophobic drug supported on the hollow mesoporous silica of Examples 1 and 2 of the present invention, was confirmed to have sustained release even after hundreds of hours while undergoing an initial sustained release without an initial burst. That is, it was confirmed that ibuprofen, as a hydrophobic drug supported on the hollow mesoporous silica of Examples 1 and 2 of the present invention, exhibited both sustained-release and sustained-release.

However, in the case of Comparative Examples 1 and 2, it was confirmed that there was a problem in which an initial burst occurred rather than a commercial product A.

Experimental Example 5. Hydrophobic Drug (2) Release Experiment

As a hydrophobic drug, an appropriate amount of distilled water was added to about 0.002 g of silica nanoparticles of Example 3 loaded with ketoprofen to make a paste, which was then evenly applied to the upper surface of a membrane (artificial skin, area: 1.13 cm ² ). The membrane with the silica paste applied was placed on an FDC (Franz diffusion cell) and fixed with a clamp so that it would not move. The receptor chamber was filled with SBF (simulated body fluid) solution, and while stirring at 32°C and 600 rpm, 3 ml of the solution was taken at predetermined time intervals, and the UV absorbance was measured to confirm the concentration of the released drug. At this time, new SBF in an amount equal to the volume of the solution taken for sampling was filled into the receptor chamber.

As a control, a commercial product C (ketoprofen) having the same area as the membrane (artificial skin, area: 1.13 cm ² ) was attached on the membrane. The experiment was performed in the same manner, except that the membrane with the commercial product C attached was placed on the FDC and fixed using a clamp to prevent movement.

The drug release amount is measured and shown in Fig. 4. As shown in Fig. 4, the in-vitro release experiment results for commercial product C confirmed that almost all the drug was released within about 40 hours, but ketoprofen, as a hydrophobic drug supported on the hollow mesoporous silica of Example 3 of the present invention, was confirmed to have sustained release even after hundreds of hours while undergoing an initial sustained release without an initial burst. That is, it was confirmed that ketoprofen, as a hydrophobic drug supported on the hollow mesoporous silica of Example 3 of the present invention, exhibited both sustained-release and sustained-release.

The above description of the present invention is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential characteristics of the present invention. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive. For example, each component described as a single component may be implemented in a distributed manner, and likewise, components described as distributed may be implemented in a combined form.

The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims (10)

Hollow nanoparticles comprising a hollow core layer and a silica matrix shell layer; and Silica-based nanoparticles for sustained release of a hydrophobic drug, comprising a hydrophobic drug loaded in the hollow nanoparticles. In the first paragraph, Silica-based nanoparticles for sustained release of a hydrophobic drug, characterized in that the hydrophobic drug is BCS Class II; or BCS Class IV. In the first paragraph, A silica-based nanoparticle for sustained release of a hydrophobic drug, characterized in that the size of the hollow core layer is 100 to 600 nm, and the size of the hollow nanoparticle is 200 to 900 nm. (a) a step of preparing a uniform phase by stirring a solvent and a surfactant; (b) a step of adding a silica precursor to the uniform phase prepared in step (a), performing a first reaction, and then manufacturing nanoparticles through a hydrothermal synthesis reaction at a temperature higher than the first reaction temperature; (c) a step of drying and calcining the nanoparticles manufactured in step (b) to manufacture hollow nanoparticles; and (d) A method for producing silica-based nanoparticles for sustained release of a hydrophobic drug, comprising the step of impregnating the hollow nanoparticles produced in step (c) into a hydrophobic drug solution to load the hydrophobic drug onto the hollow nanoparticles. In paragraph 4, A method for producing silica-based nanoparticles for sustained release of a hydrophobic drug, characterized in that in the step (a), the solvent is at least one selected from the group consisting of water, lower alcohols having C1 to C4, and ammonia water; and the surfactant is at least one selected from the group consisting of cetyltrimethylammonium bromide (CTAB), 1,3,5-trimethylbenzene (1,3,5-TMB), Pluronic P123 (P123), Pluronic F127 (F127), benzene, and toluene. In paragraph 4, A method for producing silica-based nanoparticles for sustained release of a hydrophobic drug, characterized in that the content of the surfactant is 0.5 g to 50 g based on 1 L of the total solvent in the step (a). In paragraph 4, A method for producing silica-based nanoparticles for sustained release of a hydrophobic drug, characterized in that in the step (b) above, the silica precursor is tetraethyl orthosilicate (TEOS) or tetramethyl orthosilicate (TMOS). In paragraph 4, A method for producing silica-based nanoparticles for sustained release of a hydrophobic drug, characterized in that the hydrothermal synthesis reaction in the step (b) is performed at a temperature of 80 to 200° C. for 24 to 168 hours. In paragraph 4, A method for producing silica-based nanoparticles for sustained release of a hydrophobic drug, wherein in the step (c) above, drying is performed at a temperature of 80 to 120°C for 1 to 24 hours, and calcination is performed at a temperature of 300 to 700°C for 3 to 12 hours. A transdermal drug delivery system comprising silica-based nanoparticles for sustained release of a hydrophobic drug according to any one of claims 1 to 3.

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