Upadacitinib ethosomes hydrogel and its preparation method and application

Abstract

The present invention provides an upadacitinib ethosome hydrogel, a preparation method and an application thereof, relating to the technical field of pharmaceutical preparations. In the present invention, upadacitinib raw material drug is encapsulated by ethosomes and further modified with surfactants to prepare a drug that can directly act on the diseased skin of psoriasis patients through topical transdermal administration. Using the upadacitinib ethosome hydrogel can improve skin permeability, increase the accumulation at the lesion site, reduce the side effects caused by systemic absorption of the drug and improve the action efficiency of upadacitinib, and can better treat psoriasis.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to an upadacitinib ethosomal hydrogel, a preparation method thereof, and an application thereof. Background Art

[0002] Psoriasis is one of the most influential and fastest-developing autoimmune inflammatory diseases of the epidermis and dermis in the world. Hyperplasia of keratinocytes and infiltration of inflammatory cells are the main histopathological changes of psoriasis. It is characterized by epidermal hyperplasia accompanied by dilation of dermal capillaries, manifested as itchy and swollen skin, and erythema supported by silver scales. Different from normal skin, due to abnormal excessive hyperplasia, parakeratosis, and retention of the nuclei of the stratum corneum, scaly plaques will appear on the skin. At the same time, psoriasis is a chronic inflammatory disease that occurs throughout the body and requires long-term treatment. Each patient's response to treatment varies depending on factors such as the severity of the disease and comorbidities. Traditional systemic therapies for psoriasis include methotrexate, cyclosporine, and retinoids. These systemic treatment methods can cause immunosuppression and slow down the development of skin cells.

[0003] Upadacitinib (UPA) is a selective inhibitor of JAK1 developed by AbbVie Inc. in the United States. By inhibiting the JAK-STAT pathway, it can regulate the responses of various pro-inflammatory cytokines related to the pathogenesis, thereby inhibiting inflammation and regulating immunity. This drug has been approved for the treatment of psoriatic arthritis and has shown significant efficacy in clinical trials. However, upadacitinib is currently only available in tablet form for oral administration. Since the JAK-STAT pathway is widely distributed throughout the body, this administration method has side effects caused by systemic drug use, such as diarrhea, abdominal pain, nausea, and vomiting. Therefore, there is an urgent need to provide a solution to improve the above problems. Summary of the Invention

[0004] The present invention aims to provide an upadacitinib ethosomal hydrogel, a preparation method thereof, and an application thereof. The hydrogel directly acts on the diseased skin of psoriasis patients through topical transdermal administration, can better penetrate the stratum corneum, accumulate at the lesion site, and then successfully remove the skin lesions and inflammatory reactions of psoriasis to promote the recovery of skin function. At the same time, compared with injection and oral administration, it reduces the side effects caused by systemic absorption of drugs and improves the efficiency of upadacitinib.

[0005] In a first aspect, the present invention provides an upadacitinib ethosomal hydrogel, which comprises upadacitinib-loaded ethosomes and a blank gel matrix, and the mass ratio of the upadacitinib-loaded ethosomes to the blank gel matrix is 1:(1 - 2).

[0006] Optionally, the mass ratio of the upadacitinib-loaded ethosomes to the blank gel matrix is preferably 1:1.

[0007] Optionally, the upadacitinib-loaded ethosomes include upadacitinib bulk drug, nanocarriers, and surfactants.

[0008] Optionally, the nanocarriers include lipids and an alcoholic phase.

[0009] Optionally, the alcoholic phase includes ethanol and propylene glycol.

[0010] Optionally, the alcoholic phase accounts for 10%-50% of the total volume of the upadacitinib-loaded ethosomes.

[0011] Optionally, when the lipid is a natural lipid, it has a wide source and low cost, specifically including soybean lecithin.

[0012] Optionally, the volume ratio of ethanol to propylene glycol is (1-2):(1-2), preferably 1:2.

[0013] Optionally, when the surfactant is TPGS, it has a synergistic effect in the treatment of psoriasis.

[0014] Optionally, the mixing ratio of the upadacitinib bulk drug to the upadacitinib-loaded ethosomes is (2mg-5mg):1ml, preferably 4mg:1ml.

[0015] Optionally, the mixing ratio of the lipid to the upadacitinib-loaded ethosomes is (5mg-15mg):1ml, preferably 7mg:1ml.

[0016] Optionally, the mixing ratio of the surfactant to the upadacitinib-loaded ethosomes is (2mg-10mg):1ml, preferably 4mg:1ml.

[0017] Optionally, the blank gel matrix includes a gel matrix, specifically including any one of sodium alginate, HPMC, PVA, and carbomer 940, preferably 2% carbomer 940.

[0018] In a second aspect, the present invention provides a method for preparing an upadacitinib-loaded ethosome hydrogel, comprising the following steps:

[0019] Dissolve the upadacitinib bulk drug, lipid, and surfactant in the alcoholic phase, and after ultrasonic treatment, obtain a mixed solution. After dispersing the mixed solution in water and ultrasonic treatment, filter to obtain the upadacitinib-loaded ethosomes;

[0020] Disperse the gel matrix on the water surface, and after swelling, obtain the blank gel matrix;

[0021] Mix the upadacitinib-loaded ethosomes with the blank gel matrix, adjust the pH to 6.5-7.0, and after vacuum treatment, obtain the upadacitinib-loaded ethosome hydrogel.

[0022] Optionally, the ultrasonic treatment includes: treating with a probe ultrasonic instrument at 100 w - 200 w for 5 min - 10 min, stopping for 5 s every 5 s of operation, preferably treating at 150 w for 7 min.

[0023] Optionally, the water temperature when the mixture is dispersed in water is 30°C - 50°C, preferably 40°C.

[0024] Optionally, the pore size of the filter membrane during filtration is 0.22 μm, which is suitable for the sterilization filtration of liquid medicines and biological preparations.

[0025] Optionally, the reagent used for pH adjustment is triethanolamine, which can neutralize the acidity of the blank gel matrix and make it thicken.

[0026] The preparation method provided by the present invention uses the alcohol injection - ultrasonic method to prepare nano - carrier drugs, encapsulates upadacitinib with ethosomes, and the ethosome encapsulation rate and drug loading rate are high. At the same time, TPGS as a surfactant can improve the stability of the drug, has good targeting and biocompatibility, is beneficial to the absorption and action of the drug, and the preparation method provided by the present invention has simple steps, convenient and controllable operation.

[0027] In a third aspect, the present invention provides an application of upadacitinib ethosome hydrogel in the preparation of drugs for treating psoriasis.

[0028] The upadacitinib ethosome hydrogel provided by the present invention can reduce the drug dosage, improve the curative effect, and reduce side effects by locally administering drugs to treat psoriasis. Description of the Drawings

[0029] In order to more clearly introduce the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments.

[0030] Figure 1 It is the structural formula of upadacitinib;

[0031] Figure 2 -a is a photograph of the upadacitinib - loaded ethosome prepared in Example 1, Figure 2 -b is a laser irradiation diagram of the upadacitinib - loaded ethosome prepared in Example 1;

[0032] Figure 3 It is the morphological diagram of the upadacitinib - loaded ethosome prepared in Example 1 under a JEM - 2100 transmission electron microscope;

[0033] Figure 4 It is the differential scanning calorimetry analysis diagram of the sample in performance detection, where a is the upadacitinib raw material medicine, b is the physical mixture of upadacitinib and the blank ethosome, c is the blank ethosome, and d is the upadacitinib - loaded ethosome prepared in Example 1;

[0034] Figure 5 It is the X-ray diffraction analysis diagram of the sample in performance detection. Among them, a is upadacitinib raw material drug, b is the physical mixture of upadacitinib and blank ethosomes, c is blank ethosomes, and d is upadacitinib-loaded ethosomes prepared in Example 1;

[0035] Figure 6 It is the drug cumulative release percentage of upadacitinib-loaded ethosomes and upadacitinib raw material drug prepared in Example 1;

[0036] Figure 7 It is the appearance shape of upadacitinib ethosomal hydrogel prepared in Example 1;

[0037] Figure 8 It is the scanning electron microscope imaging diagram of upadacitinib ethosomal hydrogel prepared in Example 1;

[0038] Figure 9 It is the average body weight change of each group of mice within 7 days in the pharmacodynamic study;

[0039] Figure 10 It is the psoriasis lesion area and severity score of each group of mice within 7 days in the pharmacodynamic study. Detailed implementation manners

[0040] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described below in conjunction with the accompanying drawings of the specification through the following examples. However, the following examples are illustrative and are only used for specifically describing the present invention, rather than limiting the present invention.

[0041] The present invention provides an upadacitinib ethosomal hydrogel, and the hydrogel includes upadacitinib-loaded ethosomes and a blank gel matrix, and the mass ratio of the upadacitinib-loaded ethosomes to the blank gel matrix is 1:(1 - 2).

[0042] In some embodiments, the mass ratio of the upadacitinib-loaded ethosomes to the blank gel matrix is preferably 1:1.

[0043] In some embodiments, the upadacitinib-loaded ethosomes include upadacitinib raw material drug, a nanocarrier and a surfactant.

[0044] In some embodiments, the nanocarrier includes lipids and an alcohol phase.

[0045] In some embodiments, the alcohol phase includes ethanol and propylene glycol.

[0046] In some embodiments, the alcohol phase accounts for 10% - 50% of the total volume of the upadacitinib-loaded ethosomes.

[0047] In some embodiments, when the lipid is a natural lipid, it has a wide source and low cost, specifically including soybean lecithin.

[0048] In some embodiments, the volume ratio of the ethanol to the propylene glycol is (1 - 2):(1 - 2), preferably 1:2.

[0049] In some embodiments, when the surfactant is TPGS, it has a synergistic effect in treating psoriasis.

[0050] In some embodiments, the mixing ratio of the upadacitinib raw material drug to the upadacitinib-loaded ethosomes is (2 mg - 5 mg):1 ml, preferably 4 mg:1 ml.

[0051] In some embodiments, the mixing ratio of the lipid to the upadacitinib-loaded ethosomes is (5 mg - 15 mg):1 ml, preferably 7 mg:1 ml.

[0052] In some embodiments, the mixing ratio of the surfactant to the upadacitinib-loaded ethosomes is (2 mg - 10 mg):1 ml, preferably 4 mg:1 ml.

[0053] In some embodiments, the blank gel matrix includes a gel matrix, specifically including any one of sodium alginate, HPMC, PVA, and carbomer 940, preferably 2% carbomer 940.

[0054] The present invention also provides a method for preparing an upadacitinib-loaded ethosomal hydrogel, comprising the following steps:

[0055] S1. Dissolve the upadacitinib raw material drug, lipid, and surfactant in an alcohol phase, and after ultrasonic treatment, obtain a mixed solution. After the mixed solution is dispersed in water and ultrasonic treatment is performed, filter to obtain the upadacitinib-loaded ethosomes; Disperse the gel matrix on the water surface, and after swelling, obtain the blank gel matrix;

[0056] S2. Mix the upadacitinib-loaded ethosomes with the blank gel matrix, adjust the pH to 6.5 - 7.0, and after vacuum treatment, obtain the upadacitinib-loaded ethosomal hydrogel.

[0057] In some embodiments, when performing step S1, the ultrasonic treatment includes: treating with a probe ultrasonic instrument at 100 w - 200 w for 5 min - 10 min, stopping for 5 s every 5 s of work, preferably treating at 150 w for 7 min.

[0058] In some embodiments, when performing step S1, the water temperature when the mixed solution is dispersed in water is 30°C - 50°C, preferably 40°C.

[0059] In some embodiments, when performing step S1, the pore size of the filter membrane for filtration is 0.22 μm.

[0060] In some embodiments, when performing step S2, the reagent used for pH adjustment is triethanolamine.

[0061] In the embodiments of the present invention, upadacitinib (UPA) used is purchased from Hubei Widely Chemical Reagent Co., Ltd.; soy lecithin and TPGS used in the embodiments of the present invention are purchased from Shanghai Yuanye Bio-Technology Co., Ltd.; carbomer 940 used in the embodiments of the present invention is purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; propylene glycol and ethanol used in the embodiments of the present invention are purchased from Xilong Science Co., Ltd.

[0062] Example 1

[0063] Embodiment 1 of the present invention provides a preparation method of upadacitinib ethosomes hydrogel (UPA@ES-TPGS-gel), including the following steps:

[0064] S1. Dissolve 80 mg of upadacitinib raw material, 140 mg of soy lecithin and 80 mg of TPGS in a mixed solvent of 2.2 mL of ethanol and 4.4 mL of propylene glycol. After ultrasonic dissolution, slowly inject the solution into 13.4 mL of water at 40 °C, stir and hydrate for 20 min, cool to room temperature, then use a probe sonicator to ultrasonicate at 150 W for 7 min, stop for 5 s every 5 s of work, and finally filter through a 0.22 μm microporous filter membrane to obtain 20 mL of upadacitinib-loaded ethosomes (UPA@ES-TPGS); weigh 2 g of carbomer 940 powder, evenly sprinkle it on the surface of 100 mL of pure water, and prepare 100 mL of blank gel matrix after sufficient swelling.

[0065] S2. Weigh 15 g of UPA@ES-TPGS and add it dropwise to 15 g of blank gel matrix while stirring. After mixing evenly, adjust the pH of the system to 7.0 with triethanolamine, and perform vacuum treatment to remove air bubbles to obtain 30 g of UPA@ES-TPGS-gel, as shown in Figure 2 -a.

[0066] The UPA@ES-TPGS prepared in step S1 is as shown in Figure 2 -a, and irradiate the UPA@ES-TPGS prepared in step S1 with a laser pointer, as shown in Figure 2 -b.

[0067] Example 2

[0068] Embodiment 2 of the present invention provides a preparation method of upadacitinib ethosomes hydrogel (UPA@ES-TPGS-gel), which is different from Embodiment 1 in that the addition amounts of ethanol, propylene glycol and water in step S1 are 2 mL, 4 mL and 14 mL respectively.

[0069] Example 3

[0070] Example 3 of the present invention provides a preparation method of upadacitinib ethosomes hydrogel (UPA@ES-TPGS-gel). The difference from Example 1 is that the temperature of water in step S1 is 35°C and the stirring hydration time is 15 min.

[0071] Example 4

[0072] Example 4 of the present invention provides a preparation method of upadacitinib ethosomes hydrogel (UPA@ES-TPGS-gel). The difference from Example 1 is that in step S1, the ultrasonic treatment is carried out with a probe ultrasonic instrument at 200 w for 5 min, stopping for 5 s every 5 s of work.

[0073] Example 5

[0074] Example 5 of the present invention provides a preparation method of upadacitinib ethosomes hydrogel (UPA@ES-TPGS-gel). The difference from Example 1 is that the amount of carbomer powder weighed in step S1 is 1 g.

[0075] Example 6

[0076] Example 6 of the present invention provides a preparation method of upadacitinib ethosomes hydrogel (UPA@ES-TPGS-gel). The difference from Example 1 is that in step S2, the addition amount of upadacitinib ethosomes is 10 g and the addition amount of blank gel matrix is 20 g.

[0077] Example 7

[0078] Example 7 of the present invention provides a preparation method of upadacitinib ethosomes hydrogel (UPA@ES-TPGS-gel). The difference from Example 1 is that in step S1, the addition amounts of upadacitinib, soybean lecithin and TPGS are 40 mg, 140 mg and 40 mg respectively, and the addition amounts of ethanol and propylene glycol are 2.2 mL and 4.4 mL respectively.

[0079] Performance detection

[0080] Perform performance detection on the UPA@ES-TPGS-gel and UPA@ES-TPGS prepared in Example 1, including:

[0081] (1) Use a dynamic laser scattering particle size analyzer to measure the average particle size, polydispersity index and Zeta potential of UPA@ES-TPGS, and measure in parallel three times. The results are shown in Table 1.

[0082] The results show that the polydispersity coefficient of UPA@ES-TPGS is less than 0.3, indicating that the particle size is uniform and the particles are evenly dispersed.

[0083] Table 1 Average particle size, polydispersity index and potential value of UPA@ES-TPGS

[0084]

[0085] (2) Morphological observation

[0086] Pipette 10 μL of UPA@ES-TPGS onto a microporous copper mesh, air dry naturally, stain with 2% phosphotungstic acid for 3 min, blot off the excess stain with filter paper, air dry naturally, and observe the morphology and take pictures under a JEM-2100 transmission electron microscope. The results are as Figure 3 shown. It was found that the prepared UPA@ES-TPGS particles were regular spheres, with a relatively uniform distribution and a particle size of 100 nm - 150 nm.

[0087] (3) Determination of encapsulation efficiency (EE%) and drug loading (DL%)

[0088] Chromatographic conditions: The chromatographic workstation is an Agilent 1260 Infinity liquid chromatography system, and the chromatographic column is YMC-Triart C18 (150 mm × 3.0 mm, 3 μm). The mobile phase is water (7.5 mM dipotassium hydrogen phosphate, pH = 5.4): acetonitrile = 60:40 (v / v); the detection wavelength is 230 nm, the flow rate is 0.2 mL / min, the injection volume is 5 μL, and the column temperature is 30 °C.

[0089] Take 500 μL of UPA@ES-TPGS at the upper end of a 3KD ultrafiltration centrifugal tube, centrifuge at 10000 r / min for 20 min, then take the filtrate and make up the volume to 10 mL in a volumetric flask, mix well, filter through a 0.22 μm filter membrane, and determine the free drug concentration by HPLC. Take another 500 μL of upadacitinib ethosomes in a 10 mL volumetric flask, ultrasonically disrupt with 5 mL of methanol for 10 min, and make up the volume with the initial mobile phase, then determine the total drug concentration by HPLC. Calculate the encapsulation efficiency and drug loading according to the following formulas, and take the average value after parallel determination 3 times. The results are shown in Table 2.

[0090] EE% = (1 - m1 / m2) × 100%

[0091] DL% = (m2 - m1) / (m2 - m1 + m0) × 100%

[0092] Where: m1 is the amount of free upadacitinib; m2 is the total amount of upadacitinib; m0 is the amount of ethosomes charged.

[0093] Table 2 Encapsulation efficiency and drug loading of UPA@ES-TPGS

[0094]

[0095] (4) Differential Scanning Calorimetry (DSC)

[0096] Differential scanning calorimetry was performed on upadacitinib raw material (UPA), the physical mixture of upadacitinib raw material and blank ethosomes (UPA-ES), blank ethosomes (ES), and UPA@ES-TPGS. The results are as Figure 4 shown.

[0097] The results showed that in the DSC curves of UPA and UPA-ES, a typical endothermic peak of the drug was observed at around 204 °C, indicating its crystallinity, while ES had no endothermic peak between 30 °C and 300 °C. At the same time, it was found that the typical sharp peak of UPA@ES-TPGS at around 204 °C disappeared, indicating that UPA was successfully encapsulated in the ethosomes.

[0098] (5) X-ray Diffraction Analysis (XRD)

[0099] X-ray diffraction (XRD) analysis was performed on UPA, UPA-ES, ES, and UPA@ES-TPGS. The results are as Figure 5 shown.

[0100] The results indicated that strong characteristic diffraction peaks of the drug were present at diffraction angles of 8.0°, 9.6°, 14.1°, 14.5°, 20.5°, 23.0°, and 24.8° for UPA and UPA-ES, indicating that the drug existed in the form of a crystalline compound. No peaks appeared for ES, showing a flat diffraction curve. At the same time, it was found that the crystalline peaks at the above positions in UPA@ES-TPGS disappeared. The possible reason was that UPA was uniformly dispersed in the interior of the ethosomes in an amorphous form, indicating that the hydrophobic drug UPA was successfully encapsulated into the hydrophobic bilayer of the ethosomes.

[0101] (6) Study on in vitro drug release behavior

[0102] The in vitro drug release behavior of upadacitinib-loaded ethosomes (UPA@ES-TPGS) was studied. The specific operations were as follows: 2 mL of UPA@ES-TPGS was measured and placed into a pre-treated dialysis bag (cut-off molecular weight 3500 D). At the same time, 2 mL of UPA methanol solution with the same drug content as UPA@ES-TPGS was placed into another pre-treated dialysis bag. After tying both ends tightly, they were placed into a container containing 50 mL of release medium, and the temperature was maintained at 37 °C with constant stirring at 100 rpm. At predetermined time intervals (0.5, 1, 2, 4, 6, 8 h), 0.5 mL of the release medium was aspirated, and at the same time, 0.5 mL of isothermal release medium was replenished. The released release medium was filtered through a 0.22 μm microporous membrane, and the concentration of upadacitinib in the release medium was determined by HPLC. The cumulative release percentage (cumulative release, Q%) of upadacitinib was calculated according to the following formula. The results are asFigure 6 As shown, it indicates that UPA@ES-TPGS has a certain sustained-release effect compared with the UPA methanol solution, can better control drug release, and extend the action time.

[0103] Q% = W t / W total × 100% (4-1)

[0104] Where: W t is the cumulative release amount of upadacitinib in the release medium at the t-th time point; W total is the total amount of upadacitinib contained in the nanosuspension before the release experiment.

[0105] (7) Observation of appearance shape and scanning electron microscopy

[0106] The appearance shape and scanning electron microscopy were observed using UPA@ES-TPGS-gel.

[0107] The appearance shape is as Figure 7 shown. UPA@ES-TPGS-gel appears translucent, shiny, semi-solid, has good adhesiveness, is easily spread on the skin, has a slippery feeling, and is easy to clean.

[0108] Spread 0.1 g of the freeze-dried powder of UPA@ES-TPGS-gel evenly on the aluminum head with double-sided conductive tape, perform gold spraying treatment using an ion sputtering instrument, then randomly scan the coated sample for electron microscopy imaging, observe the morphological characteristics and take pictures. The results are as Figure 8 shown. It can be seen from Figure a that the hydrogel has a loose and porous structure inside, and from Figure b, it can be observed that many ethosomes are dispersed inside the hydrogel.

[0109] (8) Pharmacodynamic study

[0110] The newly purchased C57BL / 6J mice were adaptively fed for one week. The hair on the back (2 cm × 3 cm) of the mice was carefully removed completely using a razor and depilatory cream, taking care not to damage the skin of the mice. After depilation, the mice were allowed to recover for 24 h to make their skin return to normal. The mice were randomly divided into a blank group (Control), a model group (Model), a positive group (Tretinoin), a UPA gel group (UPA-gel), a UPA@ES gel group (UPA@ES-gel), and a UPA@ES-TPGS gel group (UPA@ES-TPGS-gel), with 6 mice in each group.

[0111] 62.5mg 5% imiquimod cream (IMQ) was evenly applied to the back of mice in the model group, positive group, UPA gel group, UPA@ES gel group and UPA@ES-TPGS gel group once a day, and then 0.2g of medical vaseline, 0.025% retinoic acid cream, UPA gel, UPA@ES gel and UPA@ES-TPGS gel were applied at intervals of 4 hours for 7 days; the back of mice in the blank group was only applied with an equal amount of vaseline, once a day, for 7 days. All mice were killed by cervical dislocation 4 hours after the drug administration on the 7th day.

[0112] The weight changes of mice in each group during the experiment were as follows Figure 9 The results showed that the weight of the mice in the blank group gradually increased and was generally stable, while the weight of the mice in the other groups that were smeared with IMQ showed a downward trend from 1 to 5 days, reaching the lowest weight on the 5th day, and then gradually increased, but on the last day it was still lower than the weight level before modeling. The weight loss of the remaining groups was slower than that of the model group, but the average weight level was lower than that of the blank group, indicating that IMQ inhibited the growth of mouse weight and the animal model was successfully constructed.

[0113] The skin lesions on the back of each group of mice were recorded daily and scored according to the internationally used psoriasis area and severity index (PASI) scoring standard. The specific PASI scoring standard is shown in Table 3. The results are shown in Figure 10 The total score obtained by adding up the three scores is the severity of the skin lesions (total score is 12 points). The higher the score, the more severe the skin lesions.

[0114] Table 3 PASI scoring criteria

[0115]

[0116] Through continuous observation, it was found that the blank group mice did not have erythema, scales, or thickening on the back skin from day 1 to day 7. The back skin of the model group mice slightly thickened and reddened on the second day of medication, and a small amount of scales appeared in a few parts; on the third day, the erythema color further intensified, the back skin became leathery, and most of them had a small amount of white scales; on the fourth day, infiltrative plaques appeared on the back of the mice, the skin showed moderate bulges, and the erythema and scales were further aggravated; on the fifth and sixth days, the skin lesions continued to worsen; on the seventh day, it reached its peak, with obvious infiltration and thickening, and punctate bleeding was seen after scraping off the scales. The rash was similar to human psoriasis skin lesions, indicating that the model was successfully established. The erythema score, thickness score, and total score of the other groups continued to increase from day 1 to day 7, but the values were all lower than those of the model group. Among them, the UPA@ES-TPGS gel group had the most obvious improvement effect on the mouse skin.

[0117] In summary, the upadacitinib ethosomes hydrogel provided by the present invention can improve the therapeutic effect of psoriasis treatment, has a sustained-release effect and good biocompatibility, and can avoid the side effects caused by systemic administration.

[0118] Although the embodiments of the present invention have been described in detail above, it is obvious to those skilled in the art that various modifications and changes can be made to these embodiments. However, it should be understood that such modifications and changes are all within the scope and spirit of the present invention described in the claims. Moreover, the present invention described herein can have other embodiments and can be implemented or realized in various ways.

Claims

1. An upadacitinib ethosome hydrogel, characterized in that, The hydrogel comprises upadacitinib-loaded liposomes and a blank gel matrix, and the mass ratio of the upadacitinib-loaded liposomes to the blank gel matrix is 1:(1 - 2); the upadacitinib-loaded liposomes comprise upadacitinib raw material, a nano-carrier and a surfactant; the nano-carrier comprises lipids and an alcohol phase; the upadacitinib raw material, lipids and surfactant are dissolved in the alcohol phase, and after ultrasonic treatment, a mixed solution is obtained. The mixed solution is dispersed in water and then ultrasonic-treated, and filtered to obtain the upadacitinib-loaded liposomes.

2. The hydrogel according to claim 1, characterized in that, The alcohol phase comprises ethanol and propylene glycol; the alcohol phase accounts for 10% - 50% of the total volume of the upadacitinib-loaded liposomes.

3. The hydrogel according to claim 2, characterized in that, The volume ratio of the ethanol to the propylene glycol is (1 - 2):(1 - 2).

4. The hydrogel according to claim 1, characterized in that, The mixing ratio of the upadacitinib raw material to the upadacitinib-loaded liposomes is (2 mg - 5 mg):1 ml; and / or, the mixing ratio of the lipids to the upadacitinib-loaded liposomes is (5 mg - 15 mg):1 ml; and / or, the mixing ratio of the surfactant to the upadacitinib-loaded liposomes is (2mg - 10 mg):1 ml.

5. The hydrogel according to claim 1, wherein, The blank gel matrix comprises a gel matrix, specifically including any one of sodium alginate, HPMC, PVA, and carbomer 940.

6. A method for preparing the hydrogel according to any one of claims 1 to 5, characterized in that, It includes the following steps: The upadacitinib raw material, lipids and surfactant are dissolved in the alcohol phase, and after ultrasonic treatment, a mixed solution is obtained. The mixed solution is dispersed in water and then ultrasonic-treated, and filtered to obtain the upadacitinib-loaded liposomes; The gel matrix is dispersed on the water surface and swollen to obtain the blank gel matrix; The upadacitinib-loaded liposomes and the blank gel matrix are mixed, the pH is adjusted to 6.5 - 7.0, and after vacuum treatment, the upadacitinib-loaded liposome hydrogel is obtained.

7. The preparation method according to claim 6, characterized in that, The ultrasonic treatment includes: treating with a probe ultrasonic instrument at 100w - 200 w for 5 min - 10 min, stopping for 5 s every 5 s of work; and / or, the water temperature when the mixed solution is dispersed in water is 30 °C - 50 °C; the pore size of the filter membrane during filtration is 0.22 μm; triethanolamine is used when adjusting the pH.

8. Use of a hydrogel according to any one of claims 1 to 5, or a hydrogel prepared by the preparation method according to any one of claims 6 to 7, in the preparation of a medicament for treating psoriasis.

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