Silica-based nanoparticles for sustained release of hydrophilic drug and manufacturing method thereof

Abstract

The present invention relates to silica-based nanoparticles for sustained release of a hydrophilic drug and a manufacturing method thereof, the nanoparticles comprising: silica-based hollow nanoparticles comprising a hollow core layer and a silica matrix shell layer infiltrated with metal; and a hydrophilic drug supported by the hollow nanoparticles.

Description

Silica-based nanoparticles for sustained release of hydrophilic drugs and method for preparing the same

[0001] The present invention relates to silica-based nanoparticles for sustained release of hydrophilic drugs and a method for producing the same.

[0002] Transdermal drug delivery systems (TDDS) have made significant strides since the first motion sickness patch received FDA approval in 1979, addressing the shortcomings of oral and parenteral administration. By delivering medication directly through the skin, TDDS eliminates the first-pass effect and the risk of gastrointestinal problems. Its noninvasive nature eliminates discomfort, pain, and the risk of embolism or sepsis.

[0003] However, paradoxically, commercial patches and ointments do not show superior performance compared to oral or parenteral administration methods in sustained release and duration, which are the greatest characteristics of TDDS. Currently, most commercial transdermal drug delivery systems are developed in the form of hydrogels, microparticles, and microspheres based on polymers such as PEG, PVA, HA, and chitosan. However, due to the nature of polymers, the particle size distribution is non-uniform, and excessive drug is released at once during the initial stage of administration due to swelling or polymer chain breakage, which raises concerns about side effects, and the duration of the drug effect is short.

[0004] The present invention provides a hollow nanoparticle comprising a hollow core layer and a metal-penetrated silica matrix shell layer; and a silica-based nanoparticle for sustained release of a hydrophilic drug, the silica-based nanoparticle comprising a hydrophilic drug loaded in the hollow nanoparticle.

[0005] 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.

[0006] The present invention provides a silica-based nanoparticle for sustained release of a hydrophilic drug, comprising a hollow nanoparticle comprising a hollow core layer and a metal-penetrated silica matrix shell layer; and a hydrophilic drug loaded in the hollow nanoparticle.

[0007] The above metal may have a different valence from the above silica.

[0008] The content of metal in the hollow nanoparticles may be 1 wt% to 30 wt%.

[0009] The above hydrophilic drug may be a solubilized form of BCS Class I; BCS Class III; BCS Class II; a solubilized form of BCS Class IV; or a BCS Class unclassified hydrophilic drug.

[0010] The size of the hollow core layer may be 200 to 600 nm, and the size of the hollow nanoparticle may be 300 to 900 nm.

[0011] In one embodiment of the present invention, a method for producing silica-based nanoparticles for sustained-release of a hydrophilic drug is provided, comprising: (a) preparing a uniform phase by stirring a solvent, a surfactant, and a swelling agent; (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; (d) adding the hollow nanoparticles produced in step (c) to a metal precursor solution, stirring, further drying, and further calcining to infiltrate the metal; and (e) impregnating the hollow nanoparticles infiltrated with the metal in step (d) into a hydrophilic drug solution to load the hydrophilic drug onto the hollow nanoparticles infiltrated with the metal.

[0012] 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; the surfactant may be at least one selected from the group consisting of cetyltrimethylammonium bromide (CTAB), Pluronic P123 (P123), and Pluronic F127 (F127); and the swelling agent may be at least one selected from the group consisting of 1,3,5-trimethylbenzene (1,3,5-TMB), benzene, and toluene.

[0013] In the above step (a), based on a total of 1 L of solvent, the content of the surfactant may be 0.5 g to 5 g, and the content of the swelling agent may be 0.05 g to 0.5 g.

[0014] In the above step (b), the silica precursor may be tetraethyl orthosilicate (TEOS) or tetramethyl orthosilicate (TMOS).

[0015] In the above step (b), the hydrothermal synthesis reaction can be performed in an autoclave at a temperature of 120 to 200°C for 24 to 168 hours.

[0016] In the above step (d), the metal precursor may be at least one selected from the group consisting of an aluminum precursor, a magnesium precursor, a zirconium precursor, and a zinc precursor.

[0017] The silica-based nanoparticle for sustained release of a hydrophilic drug according to the present invention is characterized by including a hollow nanoparticle including a hollow core layer and a metal-penetrated silica matrix shell layer; and a hydrophilic drug loaded in the hollow nanoparticle, and has the advantage of being able to enhance hydrophilicity by changing the valence of the silica matrix due to the penetration of the metal.

[0018] Therefore, the hollow nanoparticles can enhance the sustained release of hydrophilic drugs by interacting with the loaded hydrophilic drugs, preventing their initial excessive release. This maximizes their efficacy while suppressing adverse effects caused by initial excessive release, such as gastrointestinal disorders.

[0019] Figures 1(a) and (b) show SEM images and SEM-EDS images, respectively, of the particle morphology of metal-infiltrated hollow nanoparticles according to Example 1.

[0020] Figure 2 shows a TEM image of the particle shape of a metal-penetrated hollow nanoparticle according to Example 2.

[0021] Figure 3 shows a TEM image of the particle shape of a metal-penetrated hollow nanoparticle according to Example 3.

[0022] Figure 4 shows a TEM image of the particle shape of hollow nanoparticles according to Comparative Example 1.

[0023] FIG. 5 is a graph showing the results of analyzing the time-dependent release amount of ibuprofen sodium (Ibuprofen-Na) as a hydrophilic drug in silica-based nanoparticles for sustained release of hydrophilic drugs according to one embodiment of the present invention.

[0024] FIG. 6 is a graph showing the results of analyzing the time-dependent release amount of diclofenac sodium (Diclofenac-Na), a hydrophilic drug, in silica-based nanoparticles for sustained release of hydrophilic drugs according to one embodiment of the present invention.

[0025] FIG. 7 is a graph showing the results of analyzing the time-dependent release amount of melatonin as a hydrophilic drug in silica-based nanoparticles for sustained release of hydrophilic drugs according to one embodiment of the present invention.

[0026] The present inventors manufactured hollow nanoparticles by hydrothermal synthesis after introducing a silica precursor, and then manufactured hollow nanoparticles infiltrated with metal by introducing a metal precursor solution, and confirmed that a hydrophilic drug could be successfully loaded and released, thereby completing silica-based nanoparticles for the sustained release of hydrophilic drugs according to the present invention.

[0027]

[0028] Hereinafter, the present invention will be described in detail.

[0029]

[0030] Silica-based nanoparticles for sustained release of hydrophilic drugs

[0031]

[0032] The present invention provides a silica-based nanoparticle for sustained release of a hydrophilic drug, comprising a hollow nanoparticle comprising a hollow core layer and a metal-penetrated silica matrix shell layer; and a hydrophilic drug loaded in the hollow nanoparticle.

[0033]

[0034] First, the silica-based nanoparticles for sustained release of a hydrophilic drug according to the present invention include hollow nanoparticles including a hollow core layer and a metal-penetrated silica matrix shell layer.

[0035] Specifically, the hollow nanoparticles include a hollow core layer and a metal-infiltrated silica matrix shell layer.

[0036] 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.

[0037] The above silica matrix shell layer is infiltrated with a metal, and the metal may have a different valence from the silica, and thus may be a monovalent metal, a divalent metal, or a trivalent metal. Specifically, the metal may be at least one selected from the group consisting of aluminum, magnesium, zirconium, and zinc, and since the ionic radius of trivalent Al is 0.39 Å, which is similar to the ionic radius of tetravalent Si, which is 0.26 Å, it is preferably aluminum, but is not limited thereto.

[0038] The size of the hollow core layer may be 200 to 600 nm, preferably 200 to 500 nm, 200 to 400 nm, or 200 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.

[0039] In addition, the size of the hollow nanoparticles may be 300 to 900 nm, preferably 300 to 800 nm, 300 to 700 nm, or 400 to 600 nm, but is not limited thereto.

[0040] Meanwhile, the hollow nanoparticles have a specific surface area of ​​100 to 1,500 m 2 / g can be 100 to 1,000 m 2 / g, 100 ~ 700 m 2 / g or 200 to 400 m 2 / g is preferred, but is not limited thereto. This specific surface area can be controlled by the amount of metal precursor introduced.

[0041] In addition, the hollow nanoparticles have a pore volume and pore size of 0.1 to 3.0 cm, respectively. 3 / g and can be 1 to 15 nm, 1.0 to 2.0 cm 3 / g and 1 to 5 nm is preferred, but is not limited thereto.

[0042] The content of the metal relative to the hollow nanoparticles may be 1 wt% to 30 wt%, preferably 10 wt% to 30 wt%, but is not limited thereto. By maintaining the content of the metal relative to the hollow nanoparticles within the above range, the metal can be penetrated into the silica matrix, thereby changing the valence of the silica matrix and further enhancing hydrophilicity. On the other hand, if the content of the metal relative to the hollow nanoparticles is excessively increased, the hydrophilicity of the silica matrix may actually be reduced due to the formation of metal crystals.

[0043]

[0044] Next, the silica-based nanoparticles for sustained release of a hydrophilic drug according to the present invention include a hydrophilic drug, which is characterized in that it is supported on the hollow nanoparticles.

[0045] The above hydrophilic drug may be a form having high solubility, such as a solubilized form of BCS Class I, BCS Class III, or BCS Class II; a solubilized form of BCS Class IV; or a BCS class unclassified hydrophilic drug, and is preferably a solubilized form of BCS Class I or BCS Class II having both high solubility and high permeability, but is not limited thereto. Such BCS class is a methodology for classifying drugs according to their solubility and permeability, and here, high 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 is 250 mL or less. The solubilized form of BCS Class I or BCS Class II refers to a group that has both high solubility and high permeability, the solubilized form of BCS Class III or BCS Class IV refers to a group that has high solubility but low permeability, and the BCS class unclassified hydrophilic drug refers to a group that is not classified into the BCS class but has hydrophilicity. Specifically, the hydrophilic drug may be a BCS class Ⅰ drug such as melatonin, chloroquine, diltiazem, metoprolol, paracetamol, propranolol, ketorolac, rivastigmine, or glycerin, or a BCS class Ⅲ drug such as ranitidine, cimetidine, atenolol, vancomycin, acyclovir, or metformin, or a solubilized form of a BCS class Ⅱ drug such as ibuprofen sodium or diclofenac sodium.Alternatively, the hydrophilic drug may be a water-soluble moisturizer such as urea, D-panthenol, or ceramide, and may be a BCS class unclassified hydrophilic drug.

[0046] The hydrophilic 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 hydrophilicity.

[0047]

[0048] As reviewed above, the silica-based nanoparticle for sustained release of a hydrophilic drug according to the present invention is characterized by including a hollow nanoparticle including a hollow core layer and a metal-penetrated silica matrix shell layer; and a hydrophilic drug loaded in the hollow nanoparticle, and has the advantage of being able to enhance hydrophilicity by changing the valence of the silica matrix due to the penetration of the metal.

[0049] Therefore, the hollow nanoparticles can enhance the sustained release of hydrophilic drugs by interacting with the loaded hydrophilic drugs, preventing their initial excessive release. This maximizes their efficacy while suppressing adverse effects caused by initial excessive release, such as gastrointestinal disorders.

[0050]

[0051] Method for preparing silica-based nanoparticles for sustained release of hydrophilic drugs

[0052]

[0053] The present invention comprises the steps of: (a) preparing a uniform phase by stirring a solvent, a surfactant, and a swelling agent; (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;

[0054] (d) adding the hollow nanoparticles manufactured in step (c) to a metal precursor solution, stirring, and then further drying and calcining to infiltrate the metal; and (e) impregnating the hollow nanoparticles infiltrated with the metal in step (d) into a hydrophilic drug solution to load the hydrophilic drug onto the hollow nanoparticles infiltrated with the metal.

[0055]

[0056] First, the method for manufacturing silica-based nanoparticles for sustained release of a hydrophilic drug according to the present invention includes a step [step (a)] of preparing a uniform phase by stirring a solvent, a surfactant, and a swelling agent.

[0057] The solvent is for uniformly dissolving the surfactant and the swelling agent, and may be at least one selected from the group consisting of water, a lower alcohol having C1 to C4, and ammonia water. It is preferable to include all of water, a lower alcohol having C1 to C4 (e.g., ethanol), and ammonia water, but is not limited thereto. Specifically, the volume ratio of the water, a lower alcohol 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.

[0058] In addition, the surfactant may be at least one selected from the group consisting of cetyltrimethylammonium bromide (CTAB), Pluronic P123 (P123) and Pluronic F127 (F127), and is preferably cetyltrimethylammonium bromide (CTAB), but is not limited thereto. At this time, Pluronic P123 (P123) and Pluronic F127 (F127) are a type of poloxamer, and specifically, the structural formula of Pluronic P123 (P123) is PEO 20 PPO 69 PEO 20 And, Mw is 5750Da and HLB is 7-12. In addition, the structural formula of Pluronic F127 (F127) is PEO 100 PPO 65 PEO 100 And, M w is 12600Da and HLB is 18-23.

[0059] In addition, when the swelling agent is used in conjunction with the surfactant, the size of the hollow core layer and the size of the pores in the shell layer can be further optimized. The swelling agent may be at least one selected from the group consisting of 1,3,5-trimethylbenzene (1,3,5-TMB), benzene, and toluene, and is preferably 1,3,5-trimethylbenzene (1,3,5-TMB), but is not limited thereto.

[0060] Specifically, when cetyltrimethylammonium bromide (CTAB) is used as the surfactant and 1,3,5-trimethylbenzene (1,3,5-TMB) is used as the swelling agent, the weight ratio may be 5:1 to 20:1, and is preferably 8:1 to 12:1, but is not limited thereto.

[0061] At this time, based on the total amount of 1 L of the solvent, the content of the surfactant may be 0.5 g to 5 g, and the content of the swelling agent may be 0.05 g to 0.5 g. The content of the surfactant is one of the factors controlling the size of the hollow core layer.

[0062]

[0063] Next, the method for manufacturing silica-based nanoparticles for sustained release of a hydrophilic drug according to the present invention includes a step [step (b)] of introducing a silica precursor into 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.

[0064] The silica precursor may be tetraethyl orthosilicate (TEOS) or tetramethyl orthosilicate (TMOS), and the metal precursor may be at least one selected from the group consisting of an aluminum precursor (e.g., aluminum nitrate hydrate (Al(NO3)3·9H2O), aluminum sulfate (Al2(SO4)3), aluminum chloride (AlCl3), sodium aluminum oxide (NaAlO2), alum, Gibbsite, Boehmite), a magnesium precursor, a zirconium precursor, and a zinc precursor.

[0065] 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.

[0066] 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. This hydrothermal synthesis reaction can enlarge the pore size of both the hollow nanoparticles themselves and the shell layer. Therefore, nanoparticles with a stable structure can be manufactured.

[0067] After the above hydrothermal synthesis reaction, processes such as reduced pressure filtration, ethanol and distilled water washing, etc. can be added.

[0068]

[0069] Next, the method for producing silica-based nanoparticles for sustained release of a hydrophilic drug according to the present invention includes a step [step (c)] of drying and then calcining the produced nanoparticles to produce hollow nanoparticles.

[0070] Through the above drying and firing, the surfactant located in the core can be removed, thereby forming the hollow core layer.

[0071] 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.

[0072] Thereafter, the above-mentioned calcination can be performed at a temperature of 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.

[0073]

[0074] Next, the method for manufacturing silica-based nanoparticles for sustained release of hydrophilic drugs according to the present invention includes a step [step (d)] of adding the manufactured hollow nanoparticles to a metal precursor solution, stirring, and then further drying and then further calcining to infiltrate the metal.

[0075] The metal precursor may be at least one selected from the group consisting of an aluminum precursor (e.g., aluminum nitrate hydrate (Al(NO3)3·9H2O), aluminum sulfate (Al2(SO4)3), aluminum chloride (AlCl3), sodium aluminum oxide (NaAlO2), alum, gibbsite, boehmite), a magnesium precursor, a zirconium precursor, and a zinc precursor. The amount of the metal precursor added needs to be adjusted so that the metal content relative to the hollow nanoparticles is 1 wt% to 30 wt%, preferably 10 wt% to 30 wt%. For example, the molar ratio of the silica precursor and the metal precursor may be 1:0.9 to 1:0.01. By maintaining the amount of the metal precursor added in the above range, the hydrophilicity can be further enhanced by changing the valence of the silica matrix by infiltrating the metal into the silica matrix. Meanwhile, if the amount of the metal precursor is excessively increased, the hydrophilicity of the silica matrix may actually decrease due to the formation of metal crystals.

[0076] The above additional 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.

[0077] Thereafter, the above additional firing 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.

[0078]

[0079] Next, the method for manufacturing silica-based nanoparticles for sustained release of a hydrophilic drug according to the present invention includes a step [step (e)] of impregnating the metal-penetrated hollow nanoparticles with a hydrophilic drug solution to load the hydrophilic drug onto the metal-penetrated hollow nanoparticles.

[0080] The hydrophilic drug solution may include a solvent capable of dissolving the hydrophilic drug (e.g., water, etc.), and the impregnation may be performed through an incipient wetness impregnation method or an excess water impregnation method known in the art.

[0081]

[0082] Hereinafter, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the following examples.

[0083]

[0084] [Example]

[0085] Example 1

[0086] 360 ml of distilled water, 140 ml of ethanol, and 15 ml of ammonia water, 0.5 g of cetyltrimethylammonium bromide (CTAB) as a surfactant, and 0.05 g of 1,3,5-trimethylbenzene (1,3,5-TMB) as a swelling agent were placed in a round-bottom flask and stirred for 1 hour to prepare a solution having a uniform phase. 10 ml of tetraethyl orthosilicate (TEOS), a silica precursor, was added, and the mixture was reacted at room temperature for 5 hours, filtered under reduced pressure, and washed with ethanol and distilled water. Next, the mixture was added to a 1 N HCl aqueous solution and hydrothermally synthesized in an autoclave at 130 °C for 48 hours. Afterwards, the solution was filtered under reduced pressure and washed with ethanol and distilled water to obtain nanoparticles. The obtained nanoparticles were dried in an oven at 100°C for 12 hours and then calcined at 600°C for 6 hours to produce hollow nanoparticles.

[0087] Next, 3.5 g of aluminum nitrate hydrate (Al(NO3)3·9H2O), an aluminum precursor, was dissolved in 200 ml of distilled water at approximately 53°C, and 1 g of the previously prepared hollow nanoparticles was added and stirred for 2 hours. After stirring, the solution was filtered using a rotary evaporation method, dried in an oven at 100°C for 12 hours, and then calcined at 550°C for 4 hours to produce hollow nanoparticles infiltrated with aluminum.

[0088]

[0089] Example 2

[0090] Hollow nanoparticles infiltrated with aluminum were prepared in the same manner as in Example 1, except that 1.5 g of aluminum nitrate hydrate (Al(NO3)3·9H2O) was added.

[0091]

[0092] Example 3

[0093] Hollow nanoparticles infiltrated with aluminum were prepared in the same manner as in Example 1, except that 0.7 g of aluminum nitrate hydrate (Al(NO3)3·9H2O) was added.

[0094]

[0095] Comparative Example 1

[0096] Hollow nanoparticles were prepared in the same manner as in Example 1, except that aluminum nitrate hydrate (Al(NO3)3·9H2O) was omitted.

[0097]

[0098] The particle size, hollow core layer size, specific surface area, pore volume, and pore size of the hollow nanoparticles manufactured in Examples 1 to 3 and Comparative Example 1 are as shown in Table 1 below, and the SEM images, SEM-EDS images, or TEM images of their shapes are shown in FIGS. 1 to 4.

[0099] ClassificationAluminum content (wt%)Particle size (nm)Hollow core layer size (nm)Shell thickness (nm)Specific surface area (m 2 / g)Pore volume (cm) 3 / g)Pore size (nm)Example 120441 ± 17252 ± 7105 ± 52991.22.7Example 210500 ± 10245 ± 5110 ± 105091.32.6Example 35485 ± 15265 ± 5107 ± 49511.62.6Comparative example 10480 ± 15255 ± 10120 ± 201,1201.72.6

[0100] As shown in Table 1 and Figures 1 to 4, the hollow nanoparticles manufactured in Examples 1 and 2 were all confirmed to have particle sizes of about 400 to 600 nm and hollow core layers of about 200 to 300 nm. After the manufacture of the hollow nanoparticles, it was confirmed that the specific surface area tended to decrease as the amount of the aluminum precursor added increased.

[0101]

[0102] Experimental Example 1: Hydrophilic Drug (1) - Ibuprofen Sodium (Ibuprofen-Na) Loading Experiment

[0103] Hollow nanoparticles loaded with a hydrophilic drug were manufactured by impregnating 0.5 g of the hollow nanoparticles manufactured in Examples 1 to 3 and Comparative Example 1 into 7 ml of an aqueous solution containing about 0.39 g of sodium ibuprofen, a hydrophilic drug, using an incipient wetness impregnation method, and then drying. As a result, the loading amount of the hydrophilic drug (1) - sodium ibuprofen (Ibuprofen-Na) is shown in Table 2 below.

[0104] Distinction Ibuprofen sodium (Ibuprofen-Na) loading amount (g (Ibuprofen-Na) / g (hollow nanoparticles)) Example 10.774 Example 20.772 Example 30.775 Comparative example 0.776

[0105] As shown in Table 2, it was confirmed that all of the hollow nanoparticles manufactured in Examples 1 to 3 and Comparative Example 1 could effectively support hydrophilic drugs.

[0106]

[0107] Experimental Example 2: Hydrophilic Drug (2) - Diclofenac Sodium (Diclofenac-Na) Loading Experiment

[0108] Hollow nanoparticles loaded with a hydrophilic drug were manufactured by impregnating 0.3 g of the hollow nanoparticles manufactured in Examples 1 to 3 and Comparative Example 1 into 7 ml of an aqueous solution containing about 0.23 g of diclofenac sodium, a hydrophilic drug, using an incipient wetness impregnation method, and then drying. As a result, the loading amount of the hydrophilic drug (2) - diclofenac sodium (Diclofenac-Na) is shown in Table 3 below.

[0109] Loading amount of diclofenac sodium (Diclofenac-Na) (g (Diclofenac-Na) / g (hollow nanoparticles)) Example 10.777 Example 20.776 Example 30.778 Comparative example 0.779

[0110] As shown in Table 3, it was confirmed that all of the hollow nanoparticles manufactured in Examples 1 to 3 and Comparative Example 1 could effectively support hydrophilic drugs.

[0111]

[0112] Experimental Example 3: Hydrophilic Drug (3) - Melatonin Loading Experiment

[0113] Example 1 and Comparative Example 1 each produced 0.3 g of hollow nanoparticles, which were impregnated with 7 ml of an aqueous solution containing about 0.41 g of melatonin, a hydrophilic drug, using an incipient wetness impregnation method, and then dried to produce hollow nanoparticles loaded with a hydrophilic drug. As a result, the loading amount of the hydrophilic drug (3) - melatonin is shown in Table 4 below.

[0114] Melatonin loading amount (g (Melatonin) / g (hollow nanoparticles)) Example 11.370 Comparative Example 1.373

[0115] As shown in Table 4, it was confirmed that both the hollow nanoparticles manufactured in Example 1 and Comparative Example 1 could effectively support hydrophilic drugs.

[0116]

[0117] Experimental Example 4: Hydrophilic Drug (1) - Ibuprofen Sodium (Ibuprofen-Na) Release Experiment

[0118] An appropriate amount of distilled water was added dropwise to 0.004 g of the hollow nanoparticles manufactured in Examples 1 to 3 and Comparative Example 1 to make a silica paste, which was then evenly applied to the upper surface of the membrane (artificial skin, area 1.13㎠). 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 37℃ 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. Ibuprofen sodium powder was used as a control. As a result, the hourly release of the hydrophilic drug (1) - ibuprofen sodium (Ibuprofen-Na) is shown in Fig. 5.

[0119] As shown in Fig. 5, in the case of ibuprofen sodium powder (control) and Comparative Example 1, it was confirmed that almost all the drug was released within 24 hours, but in the case of Examples 1 to 3 using hollow nanoparticles permeated with aluminum, it was confirmed that the drug release was sustained for more than 60 hours. In particular, it was confirmed that as the aluminum content in the hollow nanoparticles increased, the hollow nanoparticles could improve the sustained release while preventing initial excessive release through interaction with the loaded hydrophilic drug. This can be seen as the result of aluminum penetrating more into the silica matrix, changing the valence of the silica matrix and further strengthening the hydrophilicity.

[0120]

[0121] Experimental Example 5: Hydrophilic Drug (2) - Diclofenac Sodium (Diclofenac-Na) Release Experiment

[0122] The experiment was conducted in the same manner as Experimental Example 4, except that 0.001 g of the hollow nanoparticles manufactured in Examples 1 to 3 and Comparative Example 1 were used. Commercial product A and diclofenac sodium powder were used as controls (1) and (2), respectively. As a result, the hourly release amount of the hydrophilic drug (1) - diclofenac sodium (Diclofenac-Na) is shown in Fig. 6.

[0123] As shown in Fig. 6, in the case of diclofenac sodium powder (control group (1)) and Comparative Example 1, more than 90% of the drug was released within 24 hours, and in the case of commercial product A (control group (2)), most of the drug was released in 4-5 hours. However, in the case of Examples 1 to 3 using hollow nanoparticles permeated with aluminum, it was confirmed that the drug release was sustained for more than 60 hours. In particular, it was confirmed that as the aluminum content in the hollow nanoparticles increased, the hollow nanoparticles could improve the release duration while preventing initial excessive release through interaction with the loaded hydrophilic drug. This can be seen as the result of aluminum penetrating more into the silica matrix, changing the valence of the silica matrix and further strengthening the hydrophilicity.

[0124]

[0125] Experimental Example 6: Hydrophilic Drug (3) - Melatonin Release Experiment

[0126] The experiment was conducted in the same manner as Experimental Example 4, except that 0.004 g of the hollow nanoparticles manufactured in Example 1 and Comparative Example 1 were used. Melatonin was used as a control. As a result, the hourly release amount of the hydrophilic drug (3) - melatonin is shown in Figure 7.

[0127] As shown in Fig. 7, it was confirmed that Example 1 using hollow nanoparticles permeated with aluminum had a superior drug release sustained effect that could improve the sustained release while preventing initial excessive release compared to the control group (melatonin) or Comparative Example 1.

[0128]

[0129] The foregoing description of the present invention is for illustrative purposes only. Those skilled in the art will readily appreciate that modifications to other specific embodiments can be made without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. Hollow nanoparticles comprising a hollow core layer and a metal-infiltrated silica matrix shell layer; and Silica-based nanoparticles for sustained release of a hydrophilic drug, comprising a hydrophilic drug loaded in the hollow nanoparticles.

2. In paragraph 1, Silica-based nanoparticles for sustained release of a hydrophilic drug, characterized in that the metal has a different atomic number from the silica.

3. In paragraph 1, Silica-based nanoparticles for sustained release of hydrophilic drugs, characterized in that the metal content of the hollow nanoparticles is 1 to 30 wt%.

4. In paragraph 1, Silica-based nanoparticles for sustained release of a hydrophilic drug, characterized in that the hydrophilic drug is a solubilized form of BCS Class I; BCS Class III; BCS Class II; a solubilized form of BCS Class IV; or a BCS class unclassified hydrophilic drug.

5. In paragraph 1, A silica-based nanoparticle for sustained release of a hydrophilic drug, characterized in that the size of the hollow core layer is 200 to 600 nm, and the size of the hollow nanoparticle is 300 to 900 nm. 6.(a) A step of preparing a uniform phase by stirring the solvent, surfactant, and swelling agent; (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; (d) a step of adding the hollow nanoparticles manufactured in step (c) to a metal precursor solution, stirring, and then further drying and further calcining to infiltrate the metal; and (e) A method for producing silica-based nanoparticles for sustained release of a hydrophilic drug, comprising the step of impregnating the metal-penetrated hollow nanoparticles in the step (d) into a hydrophilic drug solution and loading the hydrophilic drug onto the metal-penetrated hollow nanoparticles.

7. In paragraph 6, A method for producing silica-based nanoparticles for sustained-release of a hydrophilic 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; the surfactant is at least one selected from the group consisting of cetyltrimethylammonium bromide (CTAB), Pluronic P123 (P123), and Pluronic F127 (F127); and the swelling agent is at least one selected from the group consisting of 1,3,5-trimethylbenzene (1,3,5-TMB), benzene, and toluene.

8. In paragraph 6, A method for producing silica-based nanoparticles for sustained release of a hydrophilic drug, characterized in that the content of the surfactant is 0.5 g to 5 g and the content of the swelling agent is 0.05 g to 0.5 g based on a total of 1 L of solvent in the step (a).

9. In paragraph 6, A method for producing silica-based nanoparticles for sustained release of a hydrophilic drug, characterized in that in the step (b) above, the silica precursor is tetraethyl orthosilicate (TEOS) or tetramethyl orthosilicate (TMOS).

10. In paragraph 6, A method for producing silica-based nanoparticles for sustained release of a hydrophilic drug, characterized in that the hydrothermal synthesis reaction in the step (b) is performed in an autoclave at a temperature of 120 to 200° C. for 24 to 168 hours.

11. In paragraph 6, A method for producing silica-based nanoparticles for sustained release of a hydrophilic drug, characterized in that in the step (d) above, the metal precursor is at least one selected from the group consisting of an aluminum precursor, a magnesium precursor, a zirconium precursor, and a zinc precursor.

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