Calcipotriol complex, bifunctional monolithic hydrogel for treating psoriasis, its preparation and application

Abstract

This invention relates to calcipotriol nanocomposites, a bifunctional integrated hydrogel for treating psoriasis, and their preparation and application. The invention utilizes amino-modified mesoporous silica, onto which calcipotriol is loaded, followed by a one-pot reaction with methacrylamide gelatin, dopamine methacrylamide, sodium pyrrolidone carboxylate, and lithium phenyl (2,4,6-trimethylbenzoyl)phosphate to obtain a bifunctional integrated hydrogel. This hydrogel is a UV-responsive drug-loaded hydrogel that rapidly cross-links and adheres to the skin surface upon UV irradiation. It exhibits high light transmittance, sustained drug release, moisturizing properties, and structural stability, significantly improving the bioavailability of topical medications while meeting the clinical need for simultaneous drug treatment and UV irradiation. This achieves an organic combination and complementary mechanisms of the two treatment modalities, resulting in a more efficient treatment of psoriasis.

Description

Technical Field

[0001] This invention relates to pharmaceuticals for treating skin diseases, and more specifically, to mesoporous silica, calcipotriol nanocomposites, bifunctional integrated hydrogels for treating psoriasis, and their preparation and application. Background Technology

[0002] Psoriasis is a chronic, autoimmune skin disease characterized primarily by itchy, thick, scaly plaques. Currently, there is no cure. Clinically, psoriasis is often treated with topical medications and ultraviolet (UV) light. Topical medications can heal lesions by inhibiting immune inflammatory pathways such as Th17 / IL-17 and activating proliferative pathways such as JAK-STAT. UV light can alleviate skin lesions by promoting apoptosis of inflammatory cells, reducing local inflammation, and inhibiting excessive proliferation of keratinocytes.

[0003] Topical medications and UV irradiation are the most common and safest treatments for psoriasis. However, topical medications cannot maintain their effect on the skin for an extended period and lack sustained-release or controlled-release capabilities, resulting in low bioavailability and failing to achieve the desired therapeutic effect. To compensate for this deficiency, patients need to apply medication repeatedly every day, increasing the difficulty of treatment and reducing compliance, yet still failing to overcome the efficacy bottleneck of topical medications. On the other hand, UV irradiation is often used as an adjunct to topical medications, but because topical medications are not phototransparent, the two treatment methods cannot be performed simultaneously, increasing the treatment steps and reducing the combined treatment effect. Therefore, it is necessary to develop new treatment methods to overcome the shortcomings of treatment and meet the treatment needs.

[0004] CN104138352A discloses a composition for the local delivery of calcipotriol, comprising: (a) calcipotriol in an amount not exceeding 1 wt%, (b) ethanol, (c) propylene glycol, (d) oleic acid, (e) hydroxypropyl cellulose, (f) glycerin, and (g) water in an amount of 0-5 wt%, all amounts being based on the total weight of the composition. This composition can guide or enhance the delivery of an active drug to the skin.

[0005] CN102342914A discloses a calcipotriol solid lipid nanoparticle and its preparation method. The calcipotriol solid lipid nanoparticle is composed of 0.005%~0.5% calcipotriol, 0.1%~30% lipid material, 0.5%~10% surfactant, and water by weight percentage. The calcipotriol solid lipid nanoparticle of this invention is prepared using a high-pressure homogenization method or a microemulsion method, which is easy to industrialize. It can be further prepared into topical creams or gels for the treatment of psoriasis and ichthyosis. The advantages of this invention are: encapsulating calcipotriol in solid lipid nanoparticles allows the drug to carry through the stratum corneum, improving the drug's skin penetration ability and allowing the drug to remain in the local skin (epidermis and dermis) for a longer period, increasing the local concentration of the therapeutic drug, thereby increasing the drug's efficacy and prolonging its duration of action.

[0006] The article "Study on Skin Safety of Mesoporous Silica Nanomaterials" published by Chen Rilai et al. in *China Pharmacy* on November 5, 2014, describes the preparation method of mesoporous silica nanomaterials: Approximately 0.5 g of carbomer 934 was weighed, ground, and moistened with a small amount of purified water, then the volume was increased to 22.65 ml. After stirring evenly, the mixture was allowed to stand overnight to allow for full swelling. The pH was adjusted to 7.4 with triethanolamine to obtain a gel matrix. 0.75 g each of MSNs and NH2-MSNs were weighed, and 22.5 g of 1,2-propanediol was added to each. The mixture was subjected to high-speed shearing for 5 min (1000×g) and ultrasonication for 3 min to obtain MSNs / propylene glycol dispersions and NH2-MSNs / propylene glycol dispersions. Weigh 1.5 g each of Span 80 and polyoxyethylene stearate, and 7.25 g of liquid paraffin. Add these to the MSNs / propylene glycol dispersion and the NH2-MSNs / propylene glycol dispersion respectively, and heat in a 60°C water bath until homogeneous to obtain the oil phase. Under magnetic stirring (900 r / min), slowly add 32.50 ml of purified water to the oil phase. After stirring in a 60°C water bath for 30 min, stop heating to obtain the primary emulsion. When the temperature drops to 50°C, add the emulsion to the gel matrix in a thin stream, stir at a constant speed, and cool to obtain gels loaded with 0.75% MSNs or NH2-MSNs respectively. Using the same method, prepare gels loaded with 3% (maximum loading) MSNs or NH2-MSNs, and blank gels (without MSNs or NH2-MSNs) for later use.

[0007] However, the development of the aforementioned new agents has only partially improved the bioavailability of topical medications and cannot solve problems such as frequent application of medication and the inability to synchronize drug treatment with UV irradiation treatment. Therefore, further research and development of new formulations is needed to achieve the goal of one-time medication, long-lasting effect, and photo-drug synergistic treatment. Summary of the Invention

[0008] Topical medications and UV irradiation are two commonly used methods for treating skin diseases. However, both methods have significant limitations. Topical medications have poor moisturizing and adhesion properties, are prone to drying and peeling, and cannot maintain their effect on the lesions for long, leading to decreased drug absorption and utilization. UV irradiation alone has a slow onset of action and is often used as an adjunct to drug therapy. However, current topical medications for skin diseases, especially psoriasis, lack light transmittance, thus hindering UV irradiation and preventing simultaneous application of both treatments, resulting in a prolonged treatment cycle.

[0009] Therefore, this invention provides a UV-responsive drug-loaded hydrogel. This hydrogel can rapidly cross-link and adhere to the skin surface upon UV irradiation, and has the properties of high light transmittance (UV transmittance greater than 93%), sustained drug release (drug release rate greater than 92% within 72 hours), moisturizing and structurally stable (water content and weight reduction not exceeding 20% ​​and volume reduction not exceeding 10% within 3 days). It significantly improves the bioavailability of topical drugs while meeting the clinical need for simultaneous and integrated drug treatment and UV irradiation, realizing the organic combination and complementary mechanism of the two treatment modes. By regulating the T cell and macrophage phenotype, it reduces the release of inflammatory factors such as IL-17 and TNF-α, restores the normal proliferative state of the epidermis, and thus treats psoriasis more effectively.

[0010] In a first aspect, the present invention provides a method for preparing amino-modified mesoporous silica, characterized in that the preparation method comprises the following steps:

[0011] a. Dissolve hexadecyltrimethylammonium bromide (CTAB) in the emulsion;

[0012] b. While stirring, add dropwise a mixture of tetraethoxysilane (TEOS) and 3-aminopropyltriethoxysilane (APTES) to the product obtained in step a;

[0013] c. Add concentrated hydrochloric acid to stop the reaction;

[0014] d. Centrifugation yields a white precipitate, which is amino-modified mesoporous silica (MSN-NH2); and e. Residual template agent in the white precipitate is removed by extraction.

[0015] Preferably, according to the above-described method for preparing amino-modified mesoporous silica, the emulsion in step a is a mixture of water, ammonia, diethyl ether, and ethanol; preferably, stirring is performed during the dissolution process.

[0016] And / or, more preferably, according to the above-described method for preparing amino-modified mesoporous silica, the volume ratio of water, ammonia, diethyl ether and ethanol is (65-75):(0.6-1.0):(12-18):(3-8), more preferably (68-72):(0.7-0.9):(13-17):(4-6); and even more preferably 70:0.8:15:5.

[0017] And / or, more preferably, according to the above-described method for preparing amino-modified mesoporous silica, the ratio of hexadecyltrimethylammonium bromide (CTAB) to the emulsion in step a is (0.3-0.7) g: (85-95) ml, preferably (0.4-0.6) g: (88-92) ml, and more preferably 0.5 g: 90.8 ml.

[0018] And / or, more preferably, according to the above-described method for preparing amino-modified mesoporous silica, the stirring is characterized in that, in step a, the stirring is performed using a magnetic stirrer with a rotation speed of 800-1200 rpm; and / or, the stirring temperature is 10-20°C; and / or, the stirring time is 0.2-0.8 hr.

[0019] Preferably, the magnetic stirrer rotates at 900-1100 rpm; and / or the temperature during stirring is 13-18°C; and / or the stirring time is 0.4-0.7 hr.

[0020] And / or, more preferably, in step a, the magnetic stirrer rotates at 1000 rpm, the temperature during stirring is 15°C, and the stirring time is 0.5 hr.

[0021] And / or, more preferably, according to the above-described method for preparing amino-modified mesoporous silica, the mixture of tetraethoxysilane (TEOS) and 3-aminopropyltriethoxysilane (APTES) is added in step b in an amount of 2-3 ml; preferably 2.0-2.7 ml; more preferably 2.6 ml.

[0022] And / or, in step b, the volume ratio of tetraethoxysilane to 3-aminopropyltriethoxysilane is 20-30:1, preferably 23-27:1, and more preferably 25:1.

[0023] And / or, more preferably, according to the above-described method for preparing amino-modified mesoporous silica, characterized in that, in step b, stirring is performed using a magnetic stirrer with a rotation speed of 800-1200 rpm and a stirring time of 2-6 hours; more preferably, in step b, stirring is performed using a magnetic stirrer with a rotation speed of 1000 rpm and a stirring time of 4 hours;

[0024] And / or, in step d, the centrifugation rate is 7000-9000 rpm and the centrifugation time is 5-15 minutes; preferably, the centrifugation rate is 7500-8500 rpm and the centrifugation time is 8-12 minutes; more preferably, in step d, the centrifugation rate is 8000 rpm and the centrifugation time is 10 minutes.

[0025] And / or, more preferably, according to the above-described method for preparing amino-modified mesoporous silica, the concentration of concentrated hydrochloric acid in step c is 36% to 38% by mass, preferably 0.5-3 ml, more preferably 0.8-1.5 ml, and more preferably 1 ml.

[0026] And / or, more preferably, according to the above-described method for preparing amino-modified mesoporous silica, characterized in that, in step e, the white precipitate obtained in step d is dispersed in 120-150 ml, preferably 139-145 ml, of a solution composed of concentrated hydrochloric acid and anhydrous ethanol, extracted at 60-80°C, centrifuged, and dried; preferably, the mixture is stirred at 65-75°C, extracted, centrifuged, and dried; preferably, the precipitate is washed with pure water after centrifugation before drying.

[0027] More preferably, the volume ratio of concentrated hydrochloric acid to anhydrous ethanol is 10-20:120, preferably 15:120.

[0028] And / or, more preferably, according to the above-described method for preparing amino-modified mesoporous silica, characterized in that, in step e, the white precipitate obtained in step d is dispersed in 130-145 ml of a solution composed of concentrated hydrochloric acid and anhydrous ethanol, stirred at 65-75°C for 18-30 hours, preferably 20-28 hours, extracted, centrifuged at 75000-8500 rpm for 10-15 minutes, washed with pure water 1-5 times, and dried;

[0029] Preferably, in step e, the white precipitate obtained in step d is dispersed in 135 ml of a solution composed of concentrated hydrochloric acid and anhydrous ethanol, stirred at 70°C for 24 hours, extracted, centrifuged at 8000 rpm for 10 minutes, washed three times with pure water, and dried.

[0030] Secondly, the present invention also provides an amino-modified mesoporous silica prepared by any of the preceding methods.

[0031] Thirdly, the present invention also provides a calcipotriol silica nanocomposite (Cal@MSN-NH2), which is composed of calcipotriol (Cal) loaded on amino-modified mesoporous silica (MSN-NH2), preferably loaded on the aforementioned amino-modified mesoporous silica (MSN-NH2).

[0032] Preferably, the calcipotriol silica nanocomposite contains 0.005-0.050 mg of calcipotriol per milligram of silica, more preferably 0.007-0.040 mg.

[0033] Fourthly, the present invention also provides a method for preparing the calcipotriol silica nanocomposite (Cal@MSN-NH2), wherein the calcipotriol silica nanocomposite is prepared by a method comprising the following steps:

[0034] i. Dissolve 0.1-0.3 mg of calcipotriol in 5-15 μl of anhydrous ethanol, and then add deionized water (preferably 985-995 μl of deionized water) to prepare a suspension, wherein the total volume of anhydrous ethanol and deionized water is 1 ml.

[0035] ii. Add the amino-modified mesoporous silica to the suspension obtained in step i, wherein the weight ratio of the amino-modified mesoporous silica to calcipotriol is 25-100:1.

[0036] iii. Perform an ultrasonic water bath at 30-40℃ (preferably for 1-3 hours); and

[0037] iv. The calcipotriol silica nanocomposite was obtained by filtration through a filter with a pore size of 20-25 μm.

[0038] Preferably, it is prepared by a method comprising the following steps: i. dissolving 0.2 mg of calcipotriol in 10 μl of anhydrous ethanol, and then adding 990 μl of deionized water to prepare a suspension; ii. adding 5 mg of the amino-modified mesoporous silica to the suspension prepared in step i; iii. subjecting the suspension to an ultrasonic water bath at 35°C for 2 hours; iv. filtering the suspension using a filter with a pore size of 22 μm.

[0039] Fifthly, the present invention also provides a dual-function integrated hydrogel for treating psoriasis, which is obtained by mixing methacryloyl gelatin (GelMA), dopamine methacrylamide (DMA), sodium pyrrolidone carboxylate (PCA-Na), Lap (lithium phenyl (2,4,6-trimethylbenzoyl)phosphate), and the calcipotriol silica nanocomposite described in technical solution 11 or 12;

[0040] In this bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 50-200 mg, the amount of dopamine methacrylamide is 2.5-7.5 mg, the amount of sodium pyrronyl carboxylate is 10-400 μl, the amount of Lap is 1-4 mg, and the amount of calcipotriol silica nanocomposite is 1.65-1.80 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel.

[0041] Preferably, for the aforementioned dual-function integrated hydrogel for treating psoriasis, the amount of methacrylamide gelatin is 90-110 mg, the amount of dopamine methacrylamide is 3-8 mg, the amount of sodium pyrrolidone carboxylate is 190-210 μl, the amount of Lap is 1-3 mg, and the amount of calcipotriol silica nanocomposite is 1.68-1.75 mg, and the amount of each component is scaled proportionally according to the volume of the dual-function integrated hydrogel.

[0042] More preferably, in 1 ml of the bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 100 mg, the amount of dopamine methacrylamide is 5 mg, the amount of sodium pyrrolidone carboxylate is 200 μl, the amount of Lap is 2 mg, and the amount of calcipotriol silica nanocomposite is 1.71 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel; the remainder is deionized water.

[0043] Specifically, the PCA-Na content in the bifunctional integrated hydrogel of the present invention, expressed as a volume percentage, is between 10% and 40%, which can result in strong hydrogel shaping ability, ideal ability to maintain shape, and strong ultraviolet transmittance, and is more preferably between 10% and 20%.

[0044] In a sixth aspect, the present invention also provides a method for preparing the aforementioned dual-function integrated hydrogel for treating psoriasis, comprising the following steps: mixing methacryloyl gelatin, dopamine methacrylamide, sodium pyrrolidone carboxylate, Lap and calcipotriol silica nanocomposite, and synthesizing the hydrogel under water bath conditions.

[0045] Preferably, the preparation method of the aforementioned dual-functional integrated hydrogel for treating psoriasis includes the following steps:

[0046] (1) Weigh out methacrylamide gelatin, dopamine methacrylamide, Lap and calcipotriol silica nanocomposite, mix them and dissolve them in deionized water;

[0047] (2) Then add sodium pyrrolidone carboxylate to the solution obtained in step (1);

[0048] (3) Stir in a water bath; and

[0049] (4) Remove bubbles and sterilize by filtering through a filter screen.

[0050] Preferably, the solution obtained in step (1) is magnetically stirred in a water bath before step (2).

[0051] Preferably, in step (3), the water bath conditions are a temperature of 50-60℃, preferably 55℃; and / or

[0052] Or the time is 15-45 minutes, preferably 30 minutes;

[0053] And / or, in step (4), the pore size of the filter screen is 35-45μm, preferably 40μm.

[0054] In a seventh aspect, the present invention also provides the use of the aforementioned bifunctional integrated hydrogel for treating psoriasis in the preparation of UV-responsive topical medications.

[0055] Eighthly, the present invention also provides a method for using the aforementioned dual-function integrated hydrogel for treating psoriasis in the preparation of a UV-responsive topical medication, characterized in that, after applying the dual-function integrated hydrogel to the target location, it is irradiated with UV light to crosslink and fix the dual-function integrated hydrogel; preferably, the wavelength of the UV light is 280-420 nm, more preferably 311 nm and 365 nm; and / or, the irradiation duration is 2-7 seconds, preferably 5 seconds.

[0056] The bifunctional integrated hydrogel of the present invention has the following advantages compared with existing drugs for treating psoriasis:

[0057] 1. Stronger adhesion and moisturizing / shaping ability: This hydrogel can adhere to the skin for a long time, while traditional topical medications have poor adhesion and are easily wiped off.

[0058] 2. Long-lasting high light transmittance: Traditional topical medications are opaque, preventing UV rays from penetrating and causing the medication and UV irradiation to be out of sync. The stable light transmittance of this hydrogel ensures that UV irradiation treatment can be performed at any time during the hydrogel's adhesion period.

[0059] 3. Sustained-release and prolonged effect of the drug: Topical medications cannot remain on the skin surface for an extended period, resulting in most of the active ingredients not being absorbed and low bioavailability. The hydrogel of this invention enables sustained drug release and prolonged action on the skin, significantly increasing drug bioavailability and overcoming the efficacy limitations of traditional topical medications.

[0060] 4. Simultaneous administration of drug therapy and UV irradiation: The simultaneous administration of the two treatment methods truly achieves complementary mechanisms and a 1+1>2 effect. The dual-function integrated hydrogel of this invention can significantly reduce the release of inflammatory factors, inhibit abnormal proliferation of epidermal cells, and reduce small blood vessel proliferation by efficiently regulating the activation state of Th17 cells, macrophages, and neutrophils, thereby significantly improving the condition of psoriasis. This is something that cannot be achieved by the traditional step-by-step administration of topical drugs and UV irradiation. Attached Figure Description

[0061] Figure 1 This is a coordinate graph showing the adhesion properties of the hydrogel of the present invention;

[0062] Figure 2a The changes in PCA-Na content of hydrogels over time;

[0063] Figure 2b The ultraviolet transmittance of hydrogels with different PCA-Na contents;

[0064] Figure 2c The water-locking and moisturizing properties of hydrogels with different PCA-Na contents at different time points;

[0065] Figure 2d A statistical graph showing the ultraviolet transmittance of hydrogels with different PCA-Na contents. Detailed Implementation

[0066] This invention provides amino-modified mesoporous silica and a bifunctional integrated hydrogel for treating psoriasis, as well as their applications. Specifically, this invention utilizes amino-modified mesoporous silica, loads calcipotriol onto it, and then reacts it in a one-pot reaction with methacrylamide gelatin, dopamine methacrylamide, sodium pyrrolidone carboxylate, and lithium phenyl (2,4,6-trimethylbenzoyl)phosphate to obtain a bifunctional integrated hydrogel. The hydrogel of this invention is a UV-responsive drug-loaded hydrogel. Upon UV irradiation, this hydrogel rapidly cross-links and adheres to the skin surface, exhibiting high light transmittance, sustained drug release, moisturizing properties, and structural stability. It significantly improves the bioavailability of topical medications while meeting the clinical need for simultaneous drug treatment and UV irradiation, achieving an organic combination and complementary mechanisms of the two treatment modalities, thus providing a more efficient treatment for psoriasis.

[0067] Specifically, the present invention provides the following technical solution.

[0068] Technical Solution 1: A method for preparing amino-modified mesoporous silica, characterized in that the preparation method includes the following steps:

[0069] a. Dissolve hexadecyltrimethylammonium bromide in the emulsion while stirring during the dissolution process;

[0070] b. While stirring, add dropwise a mixture of tetraethoxysilane and 3-aminopropyltriethoxysilane to the product obtained in step a;

[0071] c. Add concentrated hydrochloric acid to stop the reaction;

[0072] d. Centrifugation yielded a white precipitate, which is amino-modified mesoporous silica; and

[0073] e. Remove residual template agent from white precipitate by extraction.

[0074] Technical Solution 2: The method for preparing amino-modified mesoporous silica according to Technical Solution 1 is characterized in that, in step a, the emulsion is a mixture of water, ammonia, diethyl ether and ethanol; preferably, stirring is carried out during the dissolution process.

[0075] More preferably, the volume ratio of water, ammonia, ether and ethanol is (65-75):(0.6-1.0):(12-18):(3-8), even more preferably (68-72):(0.7-0.9):(13-17):(4-6); and even more preferably 70:0.8:15:5.

[0076] Technical Solution 3: The method for preparing amino-modified mesoporous silica according to Technical Solution 1 or 2 is characterized in that, in step a, the ratio of hexadecyltrimethylammonium bromide to emulsion is (0.3-0.7) g: (85-95) ml, preferably (0.4-0.6) g: (88-92) ml, and more preferably 0.5 g: 90.8 ml.

[0077] Technical Solution 4: The method for preparing amino-modified mesoporous silica according to any one of technical solutions 1-3 is characterized in that, in step b, the amount of the mixture of tetraethoxysilane and 3-aminopropyltriethoxysilane added is 2-3 ml; preferably 2.0-2.7 ml; more preferably 2.6 ml.

[0078] And / or, in step b, the volume ratio of tetraethoxysilane to 3-aminopropyltriethoxysilane is 20-30:1, preferably 23-27:1, more preferably 25:1;

[0079] And / or, in step c, the concentration of concentrated hydrochloric acid is 36% to 38% by mass, preferably 0.5-3 ml, more preferably 0.8-1.5 ml, and even more preferably 1 ml.

[0080] Technical Solution 5: A method for preparing amino-modified mesoporous silica according to any one of technical solutions 1-4, characterized in that, in step e, the white precipitate obtained in step d is dispersed in 120-150 ml, preferably 139-145 ml, of a solution composed of concentrated hydrochloric acid and anhydrous ethanol, extracted at 60-80°C, then centrifuged and dried; preferably, the mixture is stirred at 65-75°C, extracted, then centrifuged and dried; preferably, the precipitate is washed with pure water after centrifugation before drying.

[0081] Preferably, the volume ratio of concentrated hydrochloric acid to anhydrous ethanol is 10-20:120, more preferably 15:120.

[0082] Technical Solution 6: Amino-modified mesoporous silica prepared by the preparation methods described in Technical Solutions 1-5.

[0083] Technical Solution 7: A calcipotriol silica nanocomposite (Cal@MSN-NH2), which is composed of calcipotriol (Cal) loaded on amino-modified mesoporous silica (MSN-NH2) as described in Technical Solution 6.

[0084] Technical Solution 8: The method for preparing the calcipotriol silica nanocomposite as described in Technical Solution 7, wherein the calcipotriol silica nanocomposite is prepared by a method including the following steps:

[0085] i. Dissolve 0.1-0.3 mg of calcipotriol in 5-15 μl of anhydrous ethanol, and then add deionized water to make a suspension. The total volume of anhydrous ethanol and deionized water is 1 ml.

[0086] ii. Add the amino-modified mesoporous silica to the suspension obtained in step i, wherein the weight ratio of the amino-modified mesoporous silica to calcipotriol is 25-100:1.

[0087] iii. Perform an ultrasonic water bath at 30-40℃ (pre-selected ultrasonic frequency of 40-60Hz, more preferably 50Hz, 35℃); and

[0088] iv. The calcipotriol silica nanocomposite was obtained by filtration through a filter with a pore size of 20-25 μm.

[0089] Technical Solution 9: A dual-function integrated hydrogel for treating psoriasis, which is obtained by mixing methacryloyl gelatin (GelMA), dopamine methacrylamide (DMA), sodium pyrrolidone carboxylate (PCA-Na), Lap (lithium phenyl (2,4,6-trimethylbenzoyl)phosphate), and the calcipotriol silica nanocomposite described in Technical Solution 7;

[0090] In this bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 50-200 mg, the amount of dopamine methacrylamide is 2.5-7.5 mg, the amount of sodium pyrronyl carboxylate is 10-400 μl, the amount of Lap is 1-4 mg, and the amount of calcipotriol silica nanocomposite is 1.65-1.80 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel.

[0091] Technical Solution 10: The dual-function integrated hydrogel for treating psoriasis as described in Technical Solution 9, wherein, based on 1 ml of the dual-function integrated hydrogel, the amount of methacrylamide gelatin is 90-110 mg, the amount of dopamine methacrylamide is 3-8 mg, the amount of sodium pyrrolidone carboxylate is 190-210 μl, the amount of Lap is 1-3 mg, and the amount of calcipotriol silica nanocomposite is 1.68-1.75 mg, and the amount of each component is scaled proportionally according to the volume of the dual-function integrated hydrogel.

[0092] Technical Solution 11: The preparation method of the dual-function integrated hydrogel for treating psoriasis as described in Technical Solution 9 or 10, comprising the following steps: mixing methacryloyl gelatin, dopamine methacrylamide, sodium pyrrolidone carboxylate, Lap and calcipotriol silica nanocomposite, and synthesizing the hydrogel under water bath conditions.

[0093] Technical Solution 12: The preparation method of the dual-functional integrated hydrogel for treating psoriasis according to Technical Solution 11 includes the following steps:

[0094] (1) Weigh out methacrylamide gelatin, dopamine methacrylamide, Lap and calcipotriol silica nanocomposite, mix them and dissolve them in deionized water;

[0095] (2) Then add sodium pyrrolidone carboxylate to the solution obtained in step (1);

[0096] (3) Stir in a water bath; and

[0097] (4) Remove bubbles and sterilize by filtering through a filter screen.

[0098] Technical Solution 13: The use of the dual-function integrated hydrogel for treating psoriasis as described in Technical Solution 9 or 10 in the preparation of UV-responsive topical medications.

[0099] Summary of Terminology Abbreviations

[0100] For ease of description, the abbreviations of the substances used in this invention are summarized as follows:

[0101] CTAB: Hexadecyltrimethylammonium bromide, CAS No.: 57-09-0, Molecular Formula: C 19 H 42 BrN;

[0102] TEOS: Tetraethyl orthosilicate, CAS No.: 78-10-4, Molecular Formula: C8H20O4Si;

[0103] APTES: 3-Aminopropyl)triethoxysilane, CAS No.: 919-30-2, Molecular Formula: C9H 23 NO3Si;

[0104] GelMA: Methacrylamide gelatin;

[0105] DMA: Dopamine Methacrylamide;

[0106] PCA-Na: Sodium pyrrolidone carboxylate;

[0107] Lap: Lithium Phenyl(2,4,6-trimethylbenzoyl)phosphinate;

[0108] Cal: calcipotriol;

[0109] MSN: mesoporous silica nanoparticles;

[0110] MSN-NH2: Amino-modified mesoporous silica nanoparticles;

[0111] Cal@MSN-NH2: Calcipotriol silica nanocomposite, i.e. calcipotriol loaded on amino-modified mesoporous silica nanoparticles;

[0112] UV: Ultraviolet;

[0113] Concentrated hydrochloric acid: a hydrochloric acid solution with a concentration of 36% to 38% by mass, preferably 37.4% by mass. Example

[0114] The present invention will be specifically described below with reference to an example of preparing 1 ml of dual-function integrated hydrogel. The amount of each component in the present invention is based on preparing 1 ml of dual-function integrated hydrogel. As the volume of the dual-function integrated hydrogel to be prepared changes, the amount of each component in the present invention should be increased or decreased proportionally.

[0115] (I) Example 1: Preparation of MSN-NH2 (amino-modified mesoporous silica nanoparticles)

[0116] ① Dissolve 0.5g CTAB in 90.8ml emulsion (70ml H2O + 0.8ml NH4OH (ammonia water, concentration of 28% based on NH4OH content) + 15ml diethyl ether + 5ml ethanol), and stir with a magnetic stirrer at 1000rpm at 15℃ for 0.5h.

[0117] ② Add 2.5 ml of the TEOS + 0.1 ml of APTES mixture dropwise, and continue stirring with a magnetic stirrer at 1000 rpm at 15°C for 4 hours. Then add 1 ml of concentrated hydrochloric acid (37.4% by mass solution) to stop the reaction.

[0118] ③ Centrifuge (8000 rpm) for 10 min to obtain a white precipitate.

[0119] ④ Disperse the white precipitate obtained by centrifugation into 135 ml of solution (a solution composed of 15 ml concentrated hydrochloric acid + 120 ml anhydrous ethanol) and stir at 70 °C for 24 h. After extraction, centrifuge (8000 rpm) for 10 min, wash three times with pure water, and store in air at 60 °C to dry the resulting particles.

[0120] (II) Example 2: Preparation of Cal@MSN-NH2

[0121] ① Dissolve 0.2 mg of calcipotriol (Cal) in 10 μl of anhydrous ethanol, then add 990 μl of deionized water to prepare a calcipotriol suspension, forming a 1 ml reaction system.

[0122] ② Add 5 mg MSN-NH2 to 1 ml of suspension;

[0123] ③ Ultrasonic water bath (35℃, 40Hz), 2 hours;

[0124] ④ After filtration with a 22µm pore size and sterilization, Cal@MSN-NH2 (calcipotriol silica nanocomposite, i.e. calcipotriol loaded on amino-modified mesoporous silica nanoparticles) was obtained by storing at -20℃. ） .

[0125] Example 3:

[0126] Except for the addition of 10 mg MSN-NH2 in step ②, everything else is the same as in Example 2.

[0127] Example 4:

[0128] Except for the addition of 20 mg MSN-NH2 in step ②, everything else is the same as in Example 2.

[0129] The drug loading of the Cal@MSN-NH2 nanocomposites prepared in Examples 2-4 is shown in Table 1 below.

[0130]

[0131] (III) Preparation of bifunctional integrated hydrogels

[0132] Example 5

[0133] ① Weigh 100 mg of GelMA, 5 mg of DMA, 2 mg of Lap, and 1.71 mg of Cal@MSN-NH2 from Example 2. Mix these components and dissolve them in 800 μl of deionized water.

[0134] ② Stir magnetically for 30 minutes in a 55℃ water bath.

[0135] ③ After all components have fully dissolved, add 200 μl of PCA-Na.

[0136] ④ Stir magnetically for 30 minutes in a 55℃ water bath.

[0137] ⑤ Filter with a 40μm pore size filter to remove air bubbles and bacteria, and obtain a dual-function integrated hydrogel, which can be stored at room temperature.

[0138] Example 6

[0139] The method is basically the same as in Example 5, except that the amounts of GelMA, DMA, Lap, PCA-Na and Cal@MSN-NH2 obtained in Example 2 are changed.

[0140] (IV) Role of each component in bifunctional integrated hydrogel

[0141] Functions of each component

[0142] 1) GelMA: Hydrogel matrix

[0143] 2) DMA: Increases the adhesion of hydrogels, increasing the adhesion shear force of ordinary GelMA hydrogels from 37.89±15 kPa to 99.13±10 kPa.

[0144] 3) PCA-Na:

[0145] ① It increases the moisturizing and shaping ability of hydrogels. Ordinary GelMA hydrogels lose about 90% of their water, shrink about 85% of their volume, and lose 80%-90% of their mass within three days. After adding PCA-Na at a ratio of 20%, the water content, volume, and mass of the hydrogel can be retained by 85% on the third day.

[0146] ② It can maintain high light transmittance of hydrogel for 3 days, ensuring that the hydrogel does not need to be replaced within 3 days for regular UV irradiation treatment.

[0147] Immediately after hydrogel synthesis, both the 2mm thick GelMA hydrogel containing PCA-Na and the ordinary GelMA hydrogel exhibited 93% UV transmittance, meeting the immediate requirements for UV irradiation therapy. By day 3, the 2mm thick GelMA hydrogel containing PCA-Na achieved a UV transmittance of 75±3%, while the ordinary GelMA hydrogel had a transmittance of only about 10%.

[0148] 4) LAP: Photoinitiator. After the hydrogel is applied to the skin surface, it is simultaneously irradiated with UV (311nm, 365nm). After UV irradiation, LAP is induced to undergo oxygen free radical coupling, which promotes photocrosslinking of the hydrogel, thereby quickly adhering to the skin and shaping it to form a stable hydrogel film.

[0149] 5) Cal: Calcipotriol is a vitamin D3 derivative that exerts its effects by acting on the vitamin D receptor (VDR). It can inhibit epidermal cell proliferation, inhibit the activation of immune cells such as T cells, and reduce the release of inflammatory factors. Calcipotriol cream (0.75mg / 15g) is commonly used in clinical practice to treat psoriasis.

[0150] 6) MSN-NH2: Amino-modified mesoporous silica is a nanoparticle and an excellent drug carrier. Calcipotriol carries a negative charge, while the amino-modified mesoporous silica carries a positive charge, resulting in a higher binding rate (the drug loading rate is 4 times higher after amino modification than before modification). Simultaneously, amino modification makes the pores of the mesoporous silica larger and more regular, which is beneficial for drug loading. Loading Cal onto MSN-NH2 gives the drug sustained-release properties, and further loading it into a hydrogel achieves two-stage sustained-release performance.

[0151] Experiments have shown that when the amount of GelMA is 50mg, the resulting hydrogel is relatively thin and has high fluidity; when the amount of GelMA is 200mg, the resulting hydrogel is relatively viscous and difficult to spread; and when the amount of GelMA is 100mg, the resulting hydrogel has a certain viscosity, similar to an ointment. Therefore, the optimal amount of GelMA is 90-110mg.

[0152] When the amount of Lap is 1 mg, gelation takes 20 seconds; when the amount of Lap is 2 mg, gelation takes 8-10 seconds; and when the amount of Lap is 4 mg, gelation takes 8-10 seconds. Therefore, the amount of Lap used is 1-4 mg, preferably 1-3 mg.

[0153] When the bifunctional integrated hydrogel of the present invention is prepared using the same method as in Example 5, except for changing the amount of DMA, the adhesiveness of the resulting hydrogel is as follows: Figure 1 As shown. In Figure 1 In the diagram, the horizontal axis represents strain, i.e., the degree of deformation, used to measure the proportion of deformation caused by external forces during the adhesion process. The formula is: Strain = Change in length after deformation / Original length. The vertical axis represents stress, representing the internal force per unit area when the material is subjected to external forces. The formula is: Stress = External force / Area subjected to force. Figure 1 It can be seen that the bifunctional integrated hydrogel prepared in Example 5 has the best adhesion.

[0154] When the bifunctional integrated hydrogel of the present invention was prepared using the same method as in Example 5, except for changing the amount of PCA-Na, the resulting hydrogel exhibited the following properties: moisturizing performance, morphology maintenance performance, and light transmittance maintenance performance. Figures 2a-2d As shown.

[0155] Figure 2a The changes in hydrogels with different PCA-Na contents over time were examined. It was found that the hydrogel without PCA-Na exhibited the most significant shrinkage, drying, and discoloration. As the PCA-Na content increased, the hydrogel's ability to maintain its shape continuously improved. Hydrogels with 20% and 40% PCA-Na contents showed the strongest shaping ability, but the 20% PCA-Na hydrogel had the best transparency. In other words, a PCA-Na content of 10%-40% in the prepared bifunctional integrated hydrogel can provide strong shaping ability and relatively ideal shape maintenance, but 10%-20% is more preferable.

[0156] Figure 2b This indicates the UV transmittance of hydrogels with different PCA-Na contents at gelation time (day 0). Purple represents the color formed on the UV colorimetric chart after UV light passes through the hydrogel; the deeper the purple, the stronger the UV transmittance. uw represents microwatts, expressed in uw / cm². 2 Quantitative analysis of irradiation intensity shows that the transmittance of the 20% PCA-Na hydrogel is slightly higher than that of the 40% hydrogel. In other words, the prepared bifunctional integrated hydrogel has a relatively high UV transmittance when the PCA-Na content is between 10% and 40%, but is more preferably between 10% and 20%.

[0157] Figure 2c The graph shows the water content. As the PCA-Na content gradually increases within the range of 0%-40%, the water-locking and moisturizing ability of the hydrogel gradually increases at different time points.

[0158] Figure 2d This is a statistical chart of ultraviolet light transmittance measured by an ultraviolet intensity meter.

[0159] (IV) Effect Verification

[0160] Animal experiments were used to verify the efficacy of the bifunctional integrated hydrogel of the present invention in treating psoriasis.

[0161] Mice were used as experimental animals, with 20 mice per group. Imiquimod 5% cream was used as an inducer for the psoriasis animal model, and it was applied topically to the mouse skin for 6 days. Various treatment experiments were conducted from day 7 to day 15 to verify the results. The hydrogel used was the bifunctional integrated hydrogel prepared in Example 5.

[0162] The experimental results are shown in Table 2 below.

[0163]

[0164] in:

[0165] PASI 75 ratio: This refers to the proportion of psoriasis patients whose Psoriasis Area and Severity Index (PASI) score decreased by ≥75% from baseline after treatment. This indicator is used to quantitatively assess whether the treatment effect has achieved a significant improvement.

[0166] The untreated group refers to the group that did not receive any treatment.

[0167] The calcipotriol cream group refers to the group that is treated with commercially available calcipotriol cream alone, applied once a day, 1g each time;

[0168] The UV treatment group refers to the group that received treatment with UV irradiation only, once every two days, that is, on the 7th, 9th, 11th and 13th days. The UV wavelengths used covered 311nm and 365nm, and each irradiation lasted 5 seconds.

[0169] The calcipotriol cream + UV group refers to the group treated with commercially available calcipotriol cream plus UV irradiation. Calcipotriol cream is applied once a day, 1g each time, and UV irradiation is performed every two days, i.e., on the 7th, 9th, 11th and 13th days. The UV wavelengths used cover 311nm and 365nm, and each irradiation lasts for 5 seconds.

[0170] The hydrogel group refers to the group treated with the bifunctional integrated hydrogel of the present invention only, applied once on day 7 and once on day 11, that is, applied twice in total, with 1g applied each time;

[0171] The hydrogel + UV group refers to the group treated with the bifunctional integrated hydrogel of this invention plus UV irradiation. The hydrogel was applied once on day 7 and once on day 11, for a total of two applications, each time applying 1g. After each application, the hydrogel was irradiated with UV light (311nm, 365nm) for 5 seconds to promote cross-linking and shaping. This was repeated twice, for 5 seconds each time. As shown in Table 2, the PASI 75 rate in the group treated with the bifunctional integrated hydrogel of this invention reached 50% on day 4 and 95% on day 7.

[0172] The experiments above show that the hydrogel of the present invention meets the clinical need for integrated drug treatment and UV irradiation. The hydrogel can be rapidly cross-linked and adhered to the skin surface after UV irradiation, and has the properties of high light transmittance (UV transmittance greater than 93%), sustained drug release (drug release rate greater than 92% in 72 hours), moisturizing and structural stability (water content and weight reduction of no more than 20% and volume reduction of no more than 10% in 3 days), which significantly improves the bioavailability of topical drugs.

[0173] The above are merely the preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Various improvements and modifications can be made to the present invention without departing from the principles and spirit of the present invention, and all such improvements and modifications are within the scope of protection of the present invention.

Claims

1. A dual-function integrated hydrogel for treating psoriasis, which is obtained by mixing methacrylamide gelatin (GelMA), dopamine methacrylamide (DMA), sodium pyrrolidone carboxylate (PCA-Na), Lap (lithium phenyl (2,4,6-trimethylbenzoyl)phosphate), and calcipotriol silica nanocomposite; in, Based on 1 ml of this bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 50-200 mg, the amount of dopamine methacrylamide is 2.5-7.5 mg, the amount of sodium pyrrolidone carboxylate is 10-400 μl, the amount of Lap is 1-4 mg, and the amount of calcipotriol silica nanocomposite is 1.65-1.80 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel. The calcipotriol silica nanocomposite is a composite in which calcipotriol (Cal) is loaded onto amino-modified mesoporous silica (MSN-NH2).

2. The dual-functional integrated hydrogel for treating psoriasis according to claim 1, wherein, The amino-modified mesoporous silica is prepared by a method comprising the following steps: a. Dissolve hexadecyltrimethylammonium bromide in the emulsion while stirring during the dissolution process; b. While stirring, add dropwise a mixture of tetraethoxysilane and 3-aminopropyltriethoxysilane to the product obtained in step a; c. Add concentrated hydrochloric acid to stop the reaction; d. Centrifugation yielded a white precipitate, which is amino-modified mesoporous silica; and e. Remove residual template agent from white precipitate by extraction.

3. The dual-functional integrated hydrogel for treating psoriasis according to claim 2, characterized in that, In step a, the emulsion is a mixture of water, ammonia, ether, and ethanol.

4. The dual-functional integrated hydrogel for treating psoriasis according to claim 3, wherein, The volume ratio of water, ammonia, ether and ethanol in the emulsion is (65-75):(0.6-1.0):(12-18):(3-8).

5. The dual-functional integrated hydrogel for treating psoriasis according to claim 3, characterized in that, The volume ratio of water, ammonia, ether and ethanol in the emulsion is (68-72):(0.7-0.9):(13-17):(4-6).

6. The dual-functional integrated hydrogel for treating psoriasis according to claim 2, characterized in that, In step a, the ratio of hexadecyltrimethylammonium bromide to emulsion is (0.3-0.7) g : (85-95) ml.

7. The dual-functional integrated hydrogel for treating psoriasis according to claim 2, characterized in that, In step a, the ratio of hexadecyltrimethylammonium bromide to emulsion is (0.4-0.6) g : (88-92) ml.

8. The dual-functional integrated hydrogel for treating psoriasis according to any one of claims 2-7, characterized in that, In step b, the amount of the mixture of tetraethoxysilane and 3-aminopropyltriethoxysilane added is 2.0-3.0 ml; And / or, in step b, the volume ratio of tetraethoxysilane to 3-aminopropyltriethoxysilane is 20-30:1; And / or, in step c, the amount of concentrated hydrochloric acid added is 0.5-3 ml.

9. The dual-functional integrated hydrogel for treating psoriasis according to any one of claims 2-7, characterized in that, In step b, the amount of the mixture of tetraethoxysilane and 3-aminopropyltriethoxysilane added is 2.0-2.7 ml; And / or, in step b, the volume ratio of tetraethoxysilane to 3-aminopropyltriethoxysilane is 23-27:1; And / or, in step c, the amount of concentrated hydrochloric acid added is 0.8-1.5 ml.

10. The dual-functional integrated hydrogel for treating psoriasis according to any one of claims 2-7, characterized in that, In step e, the white precipitate obtained in step d is dispersed in 120-150 ml of a solution composed of concentrated hydrochloric acid and anhydrous ethanol, extracted at 60-80 °C, and then centrifuged and dried.

11. The dual-functional integrated hydrogel for treating psoriasis according to any one of claims 2-7, characterized in that, In step e, the white precipitate obtained in step d is dispersed in 139-145 ml of a solution composed of concentrated hydrochloric acid and anhydrous ethanol, extracted at 60-80 °C, and then centrifuged and dried.

12. The dual-functional integrated hydrogel for treating psoriasis according to claim 10, characterized in that, In step e, the volume ratio of concentrated hydrochloric acid to anhydrous ethanol is 10-20:

120.

13. The dual-functional integrated hydrogel for treating psoriasis according to claim 11, characterized in that, In step e, the volume ratio of concentrated hydrochloric acid to anhydrous ethanol is 10-20:

120.

14. The dual-functional integrated hydrogel for treating psoriasis according to any one of claims 1-7, wherein, The calcipotriol silica nanocomposite was prepared by a method comprising the following steps: i. Dissolve 0.1-0.3 mg of calcipotriol in 5-15 μl of anhydrous ethanol, and then add deionized water to make a suspension. The total volume of anhydrous ethanol and deionized water is 1 ml. ii. Add the amino-modified mesoporous silica to the suspension obtained in step i, wherein the weight ratio of the amino-modified mesoporous silica to calcipotriol is 25-100:

1. iii. Perform ultrasonic water bath at 30-40℃; and iv. The calcipotriol silica nanocomposite was obtained by filtration through a filter with a pore size of 20-25 μm.

15. The dual-functional integrated hydrogel for treating psoriasis according to claim 8, wherein, The calcipotriol silica nanocomposite was prepared by a method comprising the following steps: i. Dissolve 0.1-0.3 mg of calcipotriol in 5-15 μl of anhydrous ethanol, and then add deionized water to make a suspension. The total volume of anhydrous ethanol and deionized water is 1 ml. ii. Add the amino-modified mesoporous silica to the suspension obtained in step i, wherein the weight ratio of the amino-modified mesoporous silica to calcipotriol is 25-100:

1. iii. Perform ultrasonic water bath at 30-40℃; and iv. The calcipotriol silica nanocomposite was obtained by filtration through a filter with a pore size of 20-25 μm.

16. The dual-functional integrated hydrogel for treating psoriasis according to claim 10, wherein, The calcipotriol silica nanocomposite was prepared by a method comprising the following steps: i. Dissolve 0.1-0.3 mg of calcipotriol in 5-15 μl of anhydrous ethanol, and then add deionized water to make a suspension. The total volume of anhydrous ethanol and deionized water is 1 ml. ii. Add the amino-modified mesoporous silica to the suspension obtained in step i, wherein the weight ratio of the amino-modified mesoporous silica to calcipotriol is 25-100:

1. iii. Perform ultrasonic water bath at 30-40℃; and iv. The calcipotriol silica nanocomposite was obtained by filtration through a filter with a pore size of 20-25 μm.

17. The dual-functional integrated hydrogel for treating psoriasis according to claim 12, wherein, The calcipotriol silica nanocomposite was prepared by a method comprising the following steps: i. Dissolve 0.1-0.3 mg of calcipotriol in 5-15 μl of anhydrous ethanol, and then add deionized water to make a suspension. The total volume of anhydrous ethanol and deionized water is 1 ml. ii. Add the amino-modified mesoporous silica to the suspension obtained in step i, wherein the weight ratio of the amino-modified mesoporous silica to calcipotriol is 25-100:

1. iii. Perform ultrasonic water bath at 30-40℃; and iv. The calcipotriol silica nanocomposite was obtained by filtration through a filter with a pore size of 20-25 μm.

18. The dual-functional integrated hydrogel for treating psoriasis according to any one of claims 1-7, in, Based on 1 ml of this bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 90-110 mg, the amount of dopamine methacrylamide is 3-7.5 mg, the amount of sodium pyrrolidone carboxylate is 190-210 μl, the amount of Lap is 1-3 mg, and the amount of calcipotriol silica nanocomposite is 1.68-1.75 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel.

19. The dual-functional integrated hydrogel for treating psoriasis according to claim 8, in, Based on 1 ml of this bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 90-110 mg, the amount of dopamine methacrylamide is 3-7.5 mg, the amount of sodium pyrrolidone carboxylate is 190-210 μl, the amount of Lap is 1-3 mg, and the amount of calcipotriol silica nanocomposite is 1.68-1.75 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel.

20. The dual-functional integrated hydrogel for treating psoriasis according to claim 10, in, Based on 1 ml of this bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 90-110 mg, the amount of dopamine methacrylamide is 3-7.5 mg, the amount of sodium pyrrolidone carboxylate is 190-210 μl, the amount of Lap is 1-3 mg, and the amount of calcipotriol silica nanocomposite is 1.68-1.75 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel.

21. The dual-functional integrated hydrogel for treating psoriasis according to claim 12, in, Based on 1 ml of this bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 90-110 mg, the amount of dopamine methacrylamide is 3-7.5 mg, the amount of sodium pyrrolidone carboxylate is 190-210 μl, the amount of Lap is 1-3 mg, and the amount of calcipotriol silica nanocomposite is 1.68-1.75 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel.

22. The dual-functional integrated hydrogel for treating psoriasis according to claim 14, wherein, Based on 1 ml of this bifunctional integrated hydrogel, the amount of methacrylamide gelatin is 90-110 mg, the amount of dopamine methacrylamide is 3-7.5 mg, the amount of sodium pyrrolidone carboxylate is 190-210 μl, the amount of Lap is 1-3 mg, and the amount of calcipotriol silica nanocomposite is 1.68-1.75 mg. The amount of each component is scaled proportionally according to the volume of the bifunctional integrated hydrogel.

23. A method for preparing the bifunctional integrated hydrogel for treating psoriasis according to any one of claims 1-22, comprising the following steps: mixing methacryloyl gelatin, dopamine methacrylamide, sodium pyrrolidone carboxylate, Lap and calcipotriol silica nanocomposite, and synthesizing the hydrogel under water bath conditions.

24. The method for preparing the bifunctional integrated hydrogel for treating psoriasis according to claim 23, comprising the following steps: (1) Weigh out methacrylamide gelatin, dopamine methacrylamide, Lap and calcipotriol silica nanocomposite, mix them and dissolve them in deionized water; (2) Then add sodium pyrrolidone carboxylate to the solution obtained in step (1); (3) Stir in a water bath; and (4) Remove bubbles and sterilize by filtering through a filter screen.

25. Use of the bifunctional integrated hydrogel for treating psoriasis according to any one of claims 1-22 in the preparation of a UV-responsive topical psoriasis medicament.

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