Mesoporous silica, method of preparation and use thereof

Abstract

The application discloses mesoporous silica, a preparation method and application thereof. The preparation method of the mesoporous silica comprises the following steps: mixing a surfactant and water for the first time, adding a silicon source body after adjusting pH to carry out the second mixing, and adding proper cyclohexane; when the concentration of the silicate polymer reaches a critical nucleation concentration, nucleation in the water phase is carried out to form a uniform mesoporous precursor; and the precursor is washed with an organic solvent, centrifuged, dried, calcined or extracted to prepare the mesoporous silica. The mesoporous silica provided by the application has good biocompatibility and stability, has a high specific surface area, a large pore volume, adjustable pore size and particle size, has a high loading rate, can be used as a carrier of a drug, and has the advantages of safety, no pollution, high permeability, low production cost and industrialized scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of nano drug-carrying materials, and in particular to mesoporous silica, a preparation method and applications thereof. Background Art

[0002] Ibuprofen is commonly used clinically as an antipyretic and analgesic, and its therapeutic efficacy has been fully recognized. Currently, ibuprofen dosage forms include sustained-release tablets, capsules, creams, and suspensions, most of which are oral preparations. Research on topical preparations is relatively limited. Oral preparations can be very irritating to the gastrointestinal tract, necessitating the addition of certain inclusion materials to improve ibuprofen's stability and bioavailability. We have developed a silicone pressure-sensitive adhesive transdermal patch for ibuprofen that is not only convenient to use but also allows it to quickly penetrate the skin and enter the human bloodstream, thereby reducing gastrointestinal irritation and adverse drug reactions.

[0003] Currently, existing ibuprofen creams have a slow penetration rate and there is no way to determine the proper dosage.

[0004] Since the last century, nanotechnology has been applied to the local treatment of skin diseases. Recently, mesoporous nanocarriers have shown great advantages in drug delivery due to their large surface area, ordered porosity and adjustable pore volume. Ibuprofen encapsulated into nanoparticles can reduce irritation, better deliver drug efficacy and improve bioavailability.

[0005] In recent years, smart polymers have been shown to mimic living systems, sensing and responding to environmental changes. These materials undergo reversible or irreversible changes in their physical or chemical structures when the external environment undergoes even minor changes. For example, when the material is exposed to external stimuli such as temperature, light, pH, electricity, or magnetism, these changes can be induced in the material. Temperature-sensitive polymers have been the most extensively studied. When a temperature in the external environment causes a phase change, the material dissolves. Below this temperature, the polymer maintains a stable state. In drug release, due to the unique properties of temperature-sensitive materials, they can quickly sense changes in the patient's temperature, ensuring timely and quantitative drug release, avoiding frequent dosing and reducing drug toxicity and side effects.

[0006] Silicone gel is a high-end new material for medical pressure-sensitive adhesives and is often used as the basis for artificial skin. The silicone pressure-sensitive adhesive we use has excellent biocompatibility, is non-toxic and non-irritating to the skin, and most importantly, has no allergens, which expands our applicable population.

[0007] Therefore, providing a mesoporous silica particle with accurately controlled temperature is a problem that needs to be solved by those skilled in the art. Summary of the Invention

[0008] The present invention provides mesoporous silica, a preparation method, and its application. The mesoporous silica provided by the present invention has good biocompatibility and stability, a high specific surface area, a large pore volume, adjustable pore size and particle size, and a high loading rate, and can be used as a drug carrier.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0010] A method for preparing mesoporous silica comprises the following steps:

[0011] The surfactant and water are mixed for the first time, and after adjusting the pH, a silicon source is added for a second mixing, and an appropriate amount of cyclohexane is added. When the silicate polymer reaches the critical nucleation concentration, it enters the water phase for nucleation to form a uniform mesoporous precursor;

[0012] The precursor is washed with an organic solvent, centrifuged, dried, calcined or extracted to prepare mesoporous silica.

[0013] Furthermore, the surfactant includes one of cetyltrimethylammonium chloride and cetyltrimethylammonium bromide, and the molar mass ratio of the surfactant to the silicon source is (0.6-1.2): (0.08-0.15).

[0014] Furthermore, the volume ratio of the silicon source to cyclohexane is 3-45 v / v%.

[0015] Furthermore, the pH is adjusted to 9-12 using sodium hydroxide or triethanolamine.

[0016] The present invention also provides an application of mesoporous silica in preparing mesoporous silica-encapsulated ibuprofen thermosensitive particles, wherein the mesoporous silica-encapsulated ibuprofen thermosensitive particles comprise the following raw materials: mesoporous silica, ibuprofen, and a thermosensitive material;

[0017] The mass ratio of the mesoporous silica to ibuprofen is (0.5-1): (0.2-0.8);

[0018] The mass ratio of the ibuprofen to the temperature-sensitive material is 1:(10-20).

[0019] Furthermore, the temperature-sensitive material includes one or more of tetradecanol, docosane, eicosane, mixed fatty acid type 36, and mixed fatty acid type 38.

[0020] The present invention also provides a use of mesoporous silica-encapsulated ibuprofen-loaded thermosensitive particles as a patch system. The preparation method of the patch system comprises the following steps:

[0021] The mesoporous silica-encapsulated ibuprofen thermosensitive particles, silicone gel, a permeation enhancer, and a curing agent are mixed and stirred evenly, and then cured at room temperature to obtain a patch system.

[0022] Furthermore, the mass ratio of the silicone gel, the penetration enhancer, and the curing agent is (0.5-5): (0.1-1): (0.02-0.08).

[0023] The present invention also provides an application of a patch system in intelligent temperature control medicine for high fever patients.

[0024] Compared with the prior art, the present invention has the following technical advantages:

[0025] The present invention provides a method for preparing mesoporous silica, comprising the following steps: mixing a surfactant and water for the first time, adjusting the pH to 9-12 using sodium hydroxide / triethanolamine, adding a silicon source for a second mixing, and adding an appropriate amount of cyclohexane, so that when the silicate polymer reaches a critical nucleation concentration, it can enter the water phase for nucleation, thereby forming a uniform mesoporous precursor; washing the precursor with an organic solvent, centrifuging, drying, calcining or extracting to obtain mesoporous silica; the volume ratio of the silicon source to the cyclohexane is (3-45v / v%). The method adopted by the present invention uses a silicon source as a silicon precursor, a surfactant as a template, sodium hydroxide / triethanolamine as a pH regulator, and water and cyclohexane as solvents. During the nucleophilic substitution-polymerization reaction, the growth of the silica mesoporous structure and the regulation of spherical particles are achieved by controlling the surfactant concentration. At the same time, the pore diameter, specific surface area, and pore volume are regulated by controlling the reaction temperature and the volume ratio of the silicon source to cyclohexane. The particle diameter and uniformity are regulated by adjusting the pH value. The template is removed by calcination and extraction, thereby achieving adjustable particle diameter, specific surface area, pore volume, and pore diameter of the mesoporous silica.

[0026] The present invention provides mesoporous silica prepared by the preparation method described in the above technical solution. The mesoporous silica provided by the present invention has good biocompatibility and stability, a high specific surface area, a large pore volume, adjustable pore size and particle size, and a high loading rate, and can be used as a drug carrier.

[0027] The present invention provides mesoporous silica-encapsulated ibuprofen thermosensitive particles, which are prepared by stirring a mixture of an ibuprofen solution dissolved in anhydrous ethanol and mesoporous silica. The mesoporous silica provided by the present invention has a large specific surface area, pore diameter, and pore volume, capable of encapsulating a certain amount of ibuprofen. Furthermore, the mesoporous silica shell can be modified with a thermosensitive material, thereby releasing the encapsulated ibuprofen under certain temperature conditions. Therefore, the mesoporous silica-encapsulated ibuprofen thermosensitive particles prepared by the present invention can be used as the active substance in a patch.

[0028] The present invention provides a mesoporous silica-encapsulated ibuprofen thermosensitive particle silica gel patch. The patch is prepared by uniformly mixing the mesoporous silica-encapsulated ibuprofen thermosensitive particles with silica gel, a permeation enhancer, and a curing agent, and then curing at room temperature to obtain a patch. The patch releases the drug in vitro in a PBS buffer solution with a pH of 7.2, and the in vitro release rate can reach 100% within 24 hours. The patch can cure at room temperature, is non-irritating to the skin, and is allergen-free. The preparation method is simple, significantly reducing production costs, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is a SEM image of the mesoporous silica prepared in Example 1;

[0030] Figure 2 The nitrogen adsorption / desorption isotherm of the mesoporous silica prepared in Example 2, wherein the inset is the pore size distribution curve;

[0031] Figure 3 This is the small-angle XRD pattern of the mesoporous silica prepared in Example 3;

[0032] Figure 4 Thermogravimetric curve of Example 7;

[0033] Figure 5 This is the EDS elemental analysis diagram prepared in Example 7;

[0034] Figure 6 This is the SEM image prepared in Example 7;

[0035] Figure 7 The particle size and zata potential diagrams prepared in Example 7 are shown;

[0036] Figure 8 The in vitro release profiles of ibuprofen prepared in Example 12 at different test times;

[0037] Figure 9 The in vitro liquid phase profiles of ibuprofen prepared in Example 12 at different test times. DETAILED DESCRIPTION

[0038] The present invention provides a method for preparing mesoporous silica, comprising the following steps:

[0039] The surfactant and water are mixed evenly, and the pH is adjusted to 9-12 using sodium hydroxide / triethanolamine. Then, a silicon source is added and mixed, and an appropriate amount of cyclohexane is added. When the silicate polymer reaches the critical nucleation concentration, it can enter the water phase for nucleation, thereby forming a uniform mesoporous precursor.

[0040] The precursor is washed with an organic solvent, centrifuged, dried, calcined or extracted to obtain mesoporous silica;

[0041] Preferably, the volume ratio of the silicon source to cyclohexane is (3-45 v / v%).

[0042] In the present invention, unless otherwise specified, all raw material components are commercially available products known to those skilled in the art.

[0043] In the present invention, the surfactant is preferably hexadecyltrimethylammonium chloride or hexadecyltrimethylammonium bromide. The molar mass ratio of the surfactant to the silicon source is (0.6-1.2):(0.08-0.15), preferably (0.9-1.1):(0.1-0.14), and more preferably (0.9-1.0):(0.1-0.12). The volume ratio of the silicon source to cyclohexane is (3-45 v / v%), preferably (4-35 v / v%), and more preferably (5-20 v / v%). The silicon source is preferably tetraethyl orthosilicate / tetrabutyl orthosilicate. In the present invention, the mass ratio of the surfactant to water is (1.0-14):(50-120), preferably (5.0-13.0):(60-100), and more preferably (9.0-12.5):(80-100). In the present invention, the mass ratio of the pH adjuster sodium hydroxide / triethanolamine to water is (0.05-1):100, preferably (0.08-0.6):100, and more preferably (0.09-0.3):100. The present invention has no specific requirements for the pH level; the pH can be adjusted to 9-12, preferably 10. By controlling the raw material ratio within the above range, the present invention produces a series of mesoporous silicas with adjustable particle size, pore size, specific surface area, pore volume, and morphology.

[0044] In the present invention, the surfactant and water are mixed for the first time, and the pH is adjusted to 9-12 by a pH regulator, and then a silicon source and a cyclohexane mixed solution are added for a second mixing. Preferably, hexadecyltrimethylammonium chloride and water are mixed for the first time to obtain a water-CTAC mixed solution. The first mixing temperature is 45-90°C, preferably 45-75°C, and more preferably 60-70°C. The first mixing temperature and the second mixing temperature are kept consistent. The mixed solution of silicon source and cyclohexane is added to the water-CATC mixed solution; the first mixing and the second mixing are preferably stirred and mixed, and the stirring mixing rate is 50-900r / min, preferably 100-500r / min, and more preferably 150-300r / min. The present invention has no special limitation on the speed of the dropwise addition, and slow dropwise addition is sufficient.

[0045] In the present invention, the time of the nucleophilic substitution-polymerization reaction is preferably 3-15 h, preferably 8-14 h, and more preferably 10-12 h.

[0046] The present invention preferably also includes solid-liquid separation of the reaction liquid of the nucleophilic substitution reaction-polymerization reaction, filtering and separating in sequence, and washing, drying and grinding the obtained solid product with anhydrous ethanol to obtain a precursor. The present invention has no special restrictions on most solid-liquid separations, and we generally use filtration and centrifugation to separate solids and liquids. The purpose of the anhydrous ethanol washing is to remove the surfactant, and the drying method is preferably vacuum drying; the vacuum drying is preferably 50-90°C, more preferably 60-75°C; the present invention has no special restrictions on the drying time, and it can be dried to constant weight. In the present invention, the grinding is preferably carried out in an agate mortar, and the particle size of the ground precursor is preferably: 100-600nm, more preferably: 150-300nm.

[0047] After obtaining the precursor, the precursor of the present invention is calcined or ultrasonicated to obtain mesoporous silica. In the present invention, the calcination temperature is preferably 450-600°C, more preferably 500-560°C, and most preferably 520-550°C; the heating rate from the temperature rising to the calcination temperature is preferably 1-15°C / min, more preferably 5-12°C / min, and most preferably 8-10°C / min; starting from the time the temperature rises to the calcination temperature, the calcination time is preferably 3-8h, more preferably 4-6h, and most preferably 5-6h; the calcination is preferably carried out in a muffle furnace; the calcination atmosphere is preferably air. In the present invention, the surfactant burns and decomposes during the calcination process, making the pore size and pore volume of the mesoporous silica larger. After the calcination, the present invention preferably further comprises grinding and sieving the calcined product to obtain mesoporous silica; the present invention has no special limitation on grinding, as long as the particle size of the obtained mesoporous silica can be controlled to be 50-800nm. In the present invention, the ultrasonic solvent is preferably anhydrous ethanol or methanol. During the ultrasonic process, the surfactant will react completely with the solvent, and anhydrous ethanol is more preferred. The ultrasonic process is performed in a 53 Hz high ultrasonic cleaning machine; the ultrasonic time is preferably 3-25 min, more preferably 8-20 min, and most preferably 12-16 min. The solid-liquid obtained by ultrasonication is centrifuged and dried to obtain mesoporous silica; the present invention also grinds and sieves the obtained mesoporous silica to control the particle size of the obtained mesoporous silica to 50-800 nm.

[0048] The present invention provides mesoporous silica prepared by the preparation method described in the above technical solution. In the present invention, the particle size of the mesoporous silica is 50-800nm, preferably 60-700nm, more preferably 100-400nm, and most preferably 150-300nm; the specific surface area of ​​the mesoporous silica is 450-1400m 2 / g, preferably 470-1200m 2 / g, more preferably 530-900m 2 / g, most preferably 500-840m 2 / g; the pore size of the mesoporous silica is 4-12 nm, preferably 5-10 nm, more preferably 5.5-9 nm, and most preferably 6-8 nm; the pore volume of the mesoporous silica is 0.5-3.6 cm 3 / g, preferably 0.7-3.3cm 3 / g, more preferably 0.8-3.0cm 3 / g, most preferably 1.5-2.5cm 3 / g.

[0049] The invention provides a method for preparing mesoporous silica-encapsulated ibuprofen temperature-sensitive particles, comprising particles prepared from the mesoporous silica-encapsulated ibuprofen temperature-sensitive material.

[0050] In the present invention, the ibuprofen loading is preferably 2-15 wt %, more preferably 3-12 wt %, and most preferably 5-9 wt %. The mass ratio of ibuprofen to the thermosensitive material is preferably 1:(10-25), more preferably 1:(15-23), and most preferably 1:(18-20).

[0051] The present invention provides a method for preparing the mesoporous silica-encapsulated ibuprofen thermosensitive particles described in the above technical solution, comprising the following steps:

[0052] Ibuprofen was dissolved in anhydrous ethanol, mesoporous silica was added, and the mixture was stirred at room temperature for 24 hours. The mixture was centrifuged to obtain mesoporous silica-encapsulated ibuprofen particles. The thermosensitive material was added and stirred for 3 hours to obtain mesoporous silica-encapsulated ibuprofen thermosensitive particles.

[0053] In the present invention, the temperature-sensitive material is any one of the following combinations: preferably tetradecanol + docosane, tetradecanol + heneicosane, tetradecanol + eicosane, eicosane + docosane, tetradecanol + mixed fatty acid glyceride type 36, or heneicosane + mixed fatty acid glyceride type 38. The ratio of the temperature-sensitive material combination is preferably 1:(0.5-2.1), more preferably 1:(0.6-1.7), and most preferably 1:(0.8-1.3). The melting point of the temperature-sensitive material combination is preferably 32-43°C, more preferably 35-40°C, and most preferably 37-39°C.

[0054] In the present invention, the temperature-sensitive particles are prepared by stirring and mixing. The stirring and mixing speed is preferably 100-900 r / min, more preferably 200-700 r / min, and most preferably 300-500 r / min. There is no particular limitation on the stirring and mixing time, as long as uniform coating is achieved. The stirring temperature is preferably 35-80°C, more preferably 40-70°C, and most preferably 45-65°C.

[0055] After the stirring, the present invention preferably further comprises freeze-drying the reaction liquid of the thermosensitive particles, and sequentially washing the obtained solid with alkali and water. The present invention does not specifically limit the method of solid-liquid separation, and the solid-liquid separation method numerically determined by those skilled in the art may be adopted, such as separation with a separatory funnel. In the present invention, washing of the thermosensitive particles is preferably performed by alkali washing, and the alkali is NaOH, and the concentration is preferably 0.1-0.3 mol / L, more preferably 0.1 mol / L, and the purpose of the alkali washing is to remove ibuprofen and impurities in the outer layer. In the present invention, the drying method is preferably freeze-drying; the present invention does not specifically limit the time for most drying, and it is sufficient to dry to constant weight.

[0056] The present invention provides mesoporous silica-encapsulated ibuprofen-containing thermosensitive particles prepared by the preparation method described in the above scheme. In the present invention, the particle size of the thermosensitive particles is 200-1000 nm, preferably 300-900 nm, more preferably 400-700 nm, and most preferably 450-650 nm; the melting point of the mesoporous silica-encapsulated ibuprofen-containing thermosensitive particles is 33-42°C, preferably 35-40°C, more preferably 36-39.5°C, and most preferably 37-39°C.

[0057] The present invention provides a preparation method for a mesoporous silica-encapsulated ibuprofen thermosensitive particle silica gel patch.

[0058] The temperature-sensitive particles are the mesoporous silica-encapsulated ibuprofen temperature-sensitive particles described in the above technical solution.

[0059] In the present invention, the mass ratio of the silicone gel: penetration enhancer: curing agent is preferably (0.5-5): (0.1-1): (0.02-0.08), more preferably (0.6-4): (0.15-0.8): (0.03-0.07), and most preferably (1-3): (0.2-0.6): (0.03-0.06).

[0060] The present invention provides a method for preparing the silicone gel patch described in the above technical solution, comprising the following steps:

[0061] The silicone gel, penetration enhancer, and curing agent are stirred and mixed until uniformly mixed. The temperature-sensitive particles prepared above are added, and the resulting mixture is evenly applied to the backing material. The present invention does not specifically limit the coating conditions; coating can be performed using coating techniques commonly used by those skilled in the art. In the present invention, the coating temperature is optimized to be 10-30°C, more preferably 15-28°C, and most preferably 20-25°C.

[0062] In the present invention, the mixing method of the silicone gel and the temperature-sensitive particles as well as the permeation enhancer and the curing agent is preferably stirring and mixing. The present invention has no special limitation on the stirring and mixing speed and time, as long as all the raw materials can be mixed evenly; the order of mixing is preferably to add the silicone gel to the permeation enhancer, and then add the temperature-sensitive particles and the curing agent in sequence.

[0063] The present invention provides the application of the patch system described in the above technical solution or the system of mesoporous silica-encapsulated ibuprofen thermosensitive particle silicone gel patch prepared by the preparation method described in the above technical solution in intelligent temperature control medicine for high fever patients.

[0064] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0065] Example 1

[0066] 100 mL of deionized water and 1.5 g of CTAB were mixed, and triethanolamine was added to adjust the pH value to 9.2. The mixture was stirred at 55°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 7.5 mL of TEOS and 67.5 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 55°C with a stirring speed of 100 r / min for 13 h. The mixture was centrifuged and the obtained solid product was washed three times with anhydrous ethanol and then vacuum-dried at 60°C to constant weight. The precursor was ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and then calcined for 5 h to obtain mesoporous silica, whose structural parameters are shown in Table 1.

[0067] Examples 2-6

[0068] Mesoporous silica was prepared according to the method of Example 1. The preparation conditions and structural parameters of the product (particle size, specific surface area SBET, pore volume VP, pore diameter DP) are shown in Table 1.

[0069] Example 2

[0070] 100 mL of deionized water and 1.3 g of CTAB were mixed, and triethanolamine was added to adjust the pH value to 10. The mixture was stirred at 55°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 5 mL of TEOS and 45 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 55°C with a stirring speed of 100 r / min for 13 h. The obtained solid product was centrifuged and washed three times with anhydrous ethanol, then vacuum-dried at 60°C to constant weight and ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and then calcined for 5 h to obtain mesoporous silica, whose structural parameters are shown in Table 1.

[0071] Example 3

[0072] 100 mL of deionized water and 1.5 g of CTAB were mixed, and triethanolamine was added to adjust the pH value to 8.4. The mixture was stirred at 55°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 6 mL of TEOS and 70 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 65°C with a stirring speed of 100 r / min for 13 h. The mixture was centrifuged and the obtained solid product was washed three times with anhydrous ethanol, then vacuum-dried at 60°C to constant weight, and ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and then calcined for 4.5 h to obtain mesoporous silica, whose structural parameters are shown in Table 1.

[0073] Example 4

[0074] 100 mL of deionized water and 1.5 g of CTAB were mixed, and triethanolamine was added to adjust the pH value to 9.8. The mixture was stirred at 55°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 5 mL of TEOS and 455 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 60°C with a stirring speed of 100 r / min for 13 h. The mixture was centrifuged and the obtained solid product was washed three times with anhydrous ethanol and then vacuum-dried at 60°C to constant weight. The product was ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 2°C / min, and then calcined for 5.5 h to obtain mesoporous silica, the structural parameters of which are shown in Table 1.

[0075] Example 5

[0076] 100 mL of deionized water and 1.3 g of CTAB were mixed, and triethanolamine was added to adjust the pH value to 9.2. The mixture was stirred at 65°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 5 mL of TEOS and 455 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 62°C with a stirring speed of 100 r / min for 13 h. The mixture was centrifuged and the obtained solid product was washed three times with anhydrous ethanol and then vacuum-dried at 60°C to constant weight. The product was ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and then calcined for 5 h to obtain mesoporous silica, the structural parameters of which are shown in Table 1.

[0077] Example 6

[0078] 100 mL of deionized water and 1.5 g of CTAB were mixed, and triethanolamine was added to adjust the pH value to 8.5. The mixture was stirred at 65°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 7.5 mL of TEOS and 67.5 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 60°C with a stirring speed of 100 r / min for 13 h. The mixture was centrifuged and the obtained solid product was washed three times with anhydrous ethanol, then vacuum-dried at 60°C to constant weight, and ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 2°C / min, and then calcined for 5 h to obtain mesoporous silica, whose structural parameters are shown in Table 1.

[0079] Comparative Example 1

[0080] 100 mL of deionized water and 10 g of CTAC were mixed, and NaOH was added to adjust the pH value to 9.2. The mixture was stirred at 65°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 7.5 mL of TEOS and 67.5 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 55°C with a stirring speed of 100 r / min for 13 h. The mixture was centrifuged and the obtained solid product was washed three times with anhydrous ethanol and then vacuum-dried at 60°C to constant weight. The precursor was ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and then calcined for 5 h to obtain mesoporous silica, whose structural parameters are shown in Table 1.

[0081] Comparative Example 2

[0082] 100 mL of deionized water and 10 g of CTAC were mixed, and NaOH was added to adjust the pH value to 9.2. The mixture was stirred at 60°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 5 mL of TEOS and 45 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 55°C with a stirring speed of 100 r / min for 13 h. The obtained solid product was centrifuged and washed three times with anhydrous ethanol. It was then vacuum-dried at 60°C to constant weight and ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and calcined for 5 h to obtain mesoporous silica, whose structural parameters are shown in Table 1.

[0083] Comparative Example 3

[0084] 100 mL of deionized water and 10 g of CTAC were mixed, and NaOH was added to adjust the pH value to 10. The mixture was stirred at 55°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, a mixed solution of 7.5 mL of TEOS and 67.5 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 55°C with a stirring speed of 100 r / min for 13 h. The mixture was centrifuged and the obtained solid product was washed three times with anhydrous ethanol and then vacuum-dried at 60°C to constant weight. The product was ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and then calcined for 5 h to obtain mesoporous silica, the structural parameters of which are shown in Table 1.

[0085] Mesoporous silica was prepared according to the method of Example 1. The difference from Example 1 is that triethanolamine was replaced by NaOH and CTAB was replaced by CTAC. The preparation conditions of Comparative Examples 1-3 and the structural parameters of the products (particle size, specific surface area SBET, pore volume VP, pore diameter DP) are shown in Table 1.

[0086] Table 1 Preparation conditions of Examples 1-6 and structural parameters of mesoporous silica prepared in Comparative Examples 1-3

[0087]

[0088] Depend on Figure 1-3 As shown in Table 1, the present invention uses NaOH as a pH regulator and CTAB as a surfactant, and controls the volume ratio of cyclohexane and silicon source to prepare a pore size of 50-800nm ​​and a specific surface area of ​​450-1400m 2 / g, pore diameter of 4-12nm, pore volume of 0.5-3.6cm 3 / g of mesoporous silica; while CTAC, as a surfactant, has small particle size, specific surface area, pore volume, and pore diameter. This indicates that by changing the surfactant and adjusting the volume ratio of cyclohexane to silicon source, the particle size, specific surface area, pore diameter, and pore volume of mesoporous silica can be controlled.

[0089] Figure 2 The existence of mesopores in the mesoporous silica prepared by the present invention is proved.

[0090] Example 7

[0091] 100 mL of deionized water and 8 g of CTAC were mixed evenly, and NaOH was added to adjust the pH value to 10. The mixture was stirred at 55°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, 7.5 mL of a mixed solution of TEOS and 67.5 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 55°C with a stirring speed of 100 r / min for 13 hours. The mixture was centrifuged and the obtained solid product was washed 3 times with anhydrous ethanol, then vacuum-dried at 60°C to constant weight, and ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and then calcined for 5 hours to obtain mesoporous silica (white powder).

[0092] Thermogravimetric spectrum of the mesoporous silica prepared in this example is as follows Figure 4 shown.

[0093] The EDS elemental analysis of the mesoporous silica prepared in this example is shown in FIG. Figure 5 shown.

[0094] The SEM image of the mesoporous silica prepared in this example is as follows Figure 6 shown.

[0095] The particle size and zata potential of the mesoporous silica prepared in this example are shown in Figure 2. Figure 7 shown.

[0096] The average particle size of the mesoporous silica prepared in this example is 150 nm, the particle size distribution is narrow, and the BET specific surface area is about 850 m 2 / g, the pore diameter is about 8.5nm, and the pore volume is about 3.2cm 3 / g.

[0097] Example 8

[0098] 100 mL of deionized water and 10 g of CTAC were mixed evenly, and NaOH was added to adjust the pH value to 10. The mixture was stirred at 60°C and kept at a constant temperature to obtain a dispersion system. Under magnetic stirring, 5 mL of a mixed solution of TEOS and 40 mL of cyclohexane was added dropwise to the above dispersion system, and the mixture was reacted at 55°C with a stirring speed of 300 r / min for 13 hours. The mixture was centrifuged and the obtained solid product was washed 3 times with anhydrous ethanol, then vacuum-dried at 60°C to constant weight, and ground with an agate mortar to a particle size of 50-800 nm to obtain a precursor. The precursor was placed in a muffle furnace, heated from room temperature to 550°C at a heating rate of 1°C / min, and then calcined for 5 hours to obtain mesoporous silica (white powder).

[0099] The average particle size of the mesoporous silica prepared in this example is 170 nm, the particle size distribution is narrow, and the BET specific surface area is about 756 m 2 / g, the pore diameter is about 7.3nm, and the pore volume is about 2.8cm 3 / g.

[0100] Example 9

[0101] 1.0 g of ibuprofen was dissolved in anhydrous ethanol, 500 mg of mesoporous silica was added, and the mixture was stirred at room temperature for 24 h. The mixture was centrifuged to obtain mesoporous silica-encapsulated ibuprofen particles. 2 g of a molten mixture of thermosensitive material docosane and mixed fatty acid glyceride type 36 was added, and the mixture was stirred at 60°C for 3 h. The mixture was filtered, washed with NaOH, and freeze-dried to constant weight to obtain mesoporous silica-encapsulated ibuprofen thermosensitive particles.

[0102] The melting point of the mesoporous silica-encapsulated ibuprofen thermosensitive particles prepared in this example is 39.5°C.

[0103] Example 10

[0104] 0.5g of ibuprofen was dissolved in anhydrous ethanol, 500mg of mesoporous silica was added, and the mixture was stirred at room temperature for 24 hours. Centrifugation was performed to obtain mesoporous silica-encapsulated ibuprofen particles. 2g of a molten mixture of the thermosensitive material tetradecanol and heneicosane was added, and the mixture was stirred at 55°C for 3 hours. The mixture was filtered, washed with NaOH, and freeze-dried to a constant weight to obtain mesoporous silica-encapsulated ibuprofen thermosensitive particles. The ibuprofen loading rate was 85%.

[0105] The melting point of the mesoporous silica-encapsulated ibuprofen thermosensitive particles prepared in this example is 37°C.

[0106] Example 11

[0107] 0.7 g of ibuprofen was dissolved in anhydrous ethanol, 500 mg of mesoporous silica was added, and the mixture was stirred at room temperature for 24 h. The mixture was centrifuged to obtain mesoporous silica-encapsulated ibuprofen particles. 2 g of a molten mixture of thermosensitive material heneicosane and mixed fatty acid glyceride type 38 was added, and the mixture was stirred at 55°C for 3 h. The mixture was filtered, washed with NaOH, and freeze-dried to constant weight to obtain mesoporous silica-encapsulated ibuprofen thermosensitive particles, in which the ibuprofen loading rate was 78%.

[0108] The melting point of the mesoporous silica-encapsulated ibuprofen thermosensitive particles prepared in this example is 40.5°C.

[0109] Example 12

[0110] Weigh 2g of silicone gel and 0.3g of menthol and stir them evenly, add 1g of mesoporous silica-encapsulated ibuprofen thermosensitive particles, continue mixing and stirring, then add 0.03g of curing agent (Ags), evenly apply it on the non-woven fabric, leave it at room temperature, and cover it with a layer of film when there is no stringing. Figure 8 and Figure 9 To correspond to the in vitro 24-hour release rate and liquid phase spectrum, the 24-hour release rate was calculated to be as high as 89.5% based on the peak area in the liquid phase spectrum.

[0111] Application Example 1

[0112] In vitro permeation experiment: According to the Chinese Pharmacopoeia, the silicone gel patch prepared in Example 12 was placed in a pH = 7.2 PBS buffer solution for in vitro permeation experiment. 1 mL of buffer solution was taken at each time point, and 1 mL of fresh PBS buffer solution was added to the dissolution cup. The sample was filtered to obtain the sample, and the release amount and release rate of ibuprofen were analyzed by peak area in the liquid phase.

[0113] The liquid phase assay conditions for in vitro release were as follows: mobile phase: 0.2% phosphoric acid: acetonitrile (30:70); detection wavelength: 220 nm; injection volume: 20 μl; column temperature: 25°C.

[0114] Table 2 shows the relationship between in vitro release rate and time

[0115]

[0116] As can be seen from Table 2, the patch release rate can reach 100% in 24 hours, indicating that this patch can achieve the ideal effect, reduce the side effects of the drug, achieve faster drug efficacy through transdermal administration, and minimize damage to the gastrointestinal tract.

[0117] The above is only a preferred embodiment of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be considered as the scope of protection of the present invention.

Claims

1. Application of mesoporous silica-encapsulated ibuprofen-loaded thermosensitive particles as a patch system, characterized in that: The preparation method of the patch system comprises the following steps: The mesoporous silica-encapsulated ibuprofen-loaded thermosensitive particles, silicone gel, a permeation enhancer, and a curing agent are mixed and stirred uniformly, and cured at room temperature to obtain a patch system; The mass ratio of the silicone gel, the penetration enhancer, and the curing agent is (0.5-5): (0.1-1): (0.02-0.08); The mesoporous silica-encapsulated ibuprofen thermosensitive particles include the following raw materials: mesoporous silica, ibuprofen and a thermosensitive material; The mass ratio of the mesoporous silica to ibuprofen is (0.5-1): (0.2-0.8); The mass ratio of the ibuprofen to the temperature-sensitive material is 1:(10-20); The preparation method of the mesoporous silica comprises the following steps: The surfactant and water are mixed for the first time, and after adjusting the pH, a silicon source is added for a second mixing, and an appropriate amount of cyclohexane is added. When the silicate polymer reaches the critical nucleation concentration, it enters the water phase for nucleation to form a uniform mesoporous precursor; washing the precursor with an organic solvent, centrifuging, drying, calcining or extracting to obtain mesoporous silica; The molar mass ratio of the surfactant to the silicon source is (0.6-1.2): (0.08-0.15); The volume ratio of the silicon source and cyclohexane is 3-20 v / v; Adjust the pH to 9-12 using sodium hydroxide or triethanolamine.

2. The use of the mesoporous silica-encapsulated ibuprofen-loaded thermosensitive particles as a patch system according to claim 1, characterized in that: The surfactant includes one of cetyltrimethylammonium chloride and cetyltrimethylammonium bromide.

3. The use of the mesoporous silica-encapsulated ibuprofen-loaded thermosensitive particles as a patch system according to claim 1, characterized in that: The temperature-sensitive material includes one or more of tetradecanol, docosane, eicosane, mixed fatty acid type 36, and mixed fatty acid type 38.

4. Use of the patch system according to any one of claims 1 to 3 in intelligent temperature control medicine for high fever patients.

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