Upatinib ethosome hydrogel as well as preparation method and application thereof

Abstract

The invention provides upatinib ethosome hydrogel as well as a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations. According to the invention, ethosome is used for encapsulating an upatinib raw material medicine, and a surfactant is used for further modification, so that the medicine which can directly act on the diseased skin of a psoriasis patient through local transdermal administration is prepared. By using the upatinib ethosome hydrogel, the skin permeability can be improved, the accumulation of a diseased region is increased, meanwhile, the side effect caused by systemic drug absorption is reduced, the action efficiency of upatinib is improved, and psoriasis can be better treated.

Description

Technical Field

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

[0002] Psoriasis is the world's most influential and fastest-growing autoimmune inflammatory disease of the epidermis and dermis. Keratinocyte hyperplasia and inflammatory cell infiltration are the main histopathological changes of psoriasis. It is characterized by epidermal hyperplasia, accompanied by dermal capillary dilation, manifested as itchy, swollen skin, and erythema supported by silver scales. Unlike normal skin, scaly plaques appear on the skin due to abnormal hyperproliferation of the epidermis, incomplete keratinization, and retention of stratum corneum cell nuclei. At the same time, psoriasis is a chronic inflammatory disease that occurs throughout the body and requires long-term treatment. Each patient responds differently to treatment, depending on factors such as the severity of the disease and comorbidities. Traditional systemic therapies for psoriasis include methotrexate, cyclosporine, and retinoic acid. These systemic treatments can cause immunosuppression and slow the development of skin cells.

[0003] Upadacitinib (UPA) is a selective inhibitor of JAK1 developed by AbbVie, USA. By inhibiting the JAK-STAT pathway, it can regulate the response of various pro-inflammatory cytokines related to the pathogenesis, thereby inhibiting inflammation and regulating immunity. The drug has been approved for the treatment of psoriatic arthritis and has shown significant efficacy in clinical trials, but upadacitinib is currently only available in tablets for oral administration. The JAK-STAT pathway is widely distributed throughout the body, and this method of administration has side effects caused by systemic medication, such as diarrhea, abdominal pain, nausea, vomiting, etc. Therefore, it is urgent to provide a solution to improve the above problems. Summary of the invention

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

[0005] In a first aspect, the present invention provides an upadacitinib ethosome hydrogel, wherein the hydrogel comprises upadacitinib-loaded ethosomes and a blank gel matrix, wherein 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 API, nanocarriers and surfactants.

[0008] Optionally, the nanocarrier comprises lipid and alcohol phases.

[0009] Optionally, the alcohol phase comprises ethanol and propylene glycol.

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

[0011] Optionally, the lipid is a natural lipid with wide sources and low cost, specifically including soybean lecithin.

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

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

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

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

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

[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 upadacitinib ethosome hydrogel, comprising the following steps:

[0019] The upadacitinib raw material, lipid and surfactant are dissolved in an alcohol phase, and subjected to ultrasonic treatment to obtain a mixed solution, the mixed solution is dispersed in water, subjected to ultrasonic treatment, and filtered to obtain the upadacitinib-loaded alcoholic body;

[0020] Dispersing the gel matrix on the surface of water and swelling it to obtain the blank gel matrix;

[0021] The upadacitinib-loaded ethosomes were mixed with a blank gel matrix, the pH was adjusted to 6.5-7.0, and after vacuum treatment, an upadacitinib ethosome hydrogel was obtained.

[0022] Optionally, the ultrasonic treatment includes: using a probe ultrasonic instrument at 100W-200W for 5min-10min, working for 5s and stopping for 5s every time, preferably using 150W for 7min.

[0023] Optionally, the water temperature when the mixed solution 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 sterilization filtration of drug solutions and biological preparations.

[0025] Optionally, the reagent used to adjust the pH is triethanolamine, which can neutralize the acidity of the blank gel matrix and make it thicker.

[0026] The preparation method provided by the present invention utilizes an alcohol injection-ultrasound method to prepare a nanocarrier drug, and uses an alcohol body to encapsulate upadacitinib. The alcohol body has high encapsulation rate and drug loading rate. Meanwhile, TPGS as a surfactant can improve the stability of the drug, has good targeting and biocompatibility, and is beneficial to the absorption and action of the drug. The preparation method provided by the present invention has simple steps, and is convenient and controllable to operate.

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

[0028] The upadacitinib ethosome hydrogel provided by the present invention can reduce the dosage of the drug, improve the efficacy and reduce the side effects when it is topically administered to treat psoriasis. BRIEF 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 describing the embodiments.

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

[0031] Figure 2 -a is a photo of upadacitinib-loaded ethanosomes prepared in Example 1, Figure 2 -b is a laser irradiation image of upadacitinib-loaded ethanolsomes prepared in Example 1;

[0032] Figure 3 This is a morphological picture of upadacitinib-loaded ethanosomes prepared in Example 1 under a JEM-2100 transmission electron microscope;

[0033] Figure 4 is a differential scanning calorimetry analysis diagram of the sample in the performance test, wherein a is the upadacitinib raw material, 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 is an X-ray diffraction analysis diagram of the sample in the performance test, wherein a is the upadacitinib raw material, 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;

[0035] Figure 6 The cumulative drug release percentage of the upadacitinib-loaded ethosomes and the upadacitinib bulk drug prepared in Example 1;

[0036] Figure 7 The appearance of the upadacitinib ethosome hydrogel prepared in Example 1;

[0037] Figure 8 This is a scanning electron microscope image of the upadacitinib ethosome hydrogel prepared in Example 1;

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

[0039] Fig.10 The area and severity of psoriasis lesions in each group of mice within 7 days in the pharmacodynamic study were scored. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described through the following embodiments in conjunction with the accompanying drawings. However, the following embodiments are illustrative and are only used to specifically describe the present invention rather than to limit the present invention.

[0041] The present invention provides an upadacitinib ethosome hydrogel, wherein the hydrogel 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).

[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 API, nanocarriers, and surfactants.

[0044] In some embodiments, the nanocarrier comprises a lipid and an alcohol phase.

[0045] In some embodiments, the alcoholic 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 alcoholic body.

[0047] In some embodiments, the lipid is a natural lipid that is widely available and low in cost, specifically including soy 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, there is a synergistic effect in treating psoriasis.

[0050] In some embodiments, the mixing ratio of the upadacitinib API to the upadacitinib-loaded ethanolsome 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 ethosome 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 ethanol plasmid 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 upadacitinib ethosome hydrogel, comprising the following steps:

[0055] S1. Dissolving upadacitinib API, lipids and surfactants in an alcohol phase, and subjecting the mixture to ultrasonic treatment to obtain a mixed solution. Dispersing the mixed solution in water, subjecting the mixture to ultrasonic treatment, and filtering the mixed solution to obtain the upadacitinib-loaded alcoholysomes. Dispersing a gel matrix on the surface of water, and subjecting the mixed solution to swelling to obtain the blank gel matrix.

[0056] S2. Mixing upadacitinib-loaded ethosomes with a blank gel matrix, adjusting the pH to 6.5-7.0, and vacuum treating to obtain upadacitinib ethosome hydrogel.

[0057] In some embodiments, when executing step S1, the ultrasonic treatment includes: the probe ultrasonic instrument is used for treatment at 100w-200w for 5min-10min, working for 5s and stopping for 5s every time, preferably 150w for treatment for 7min.

[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 executing step S1, the pore size of the filter membrane is 0.22 μm.

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

[0061] Upadacitinib (UPA) used in the examples of the present invention was purchased from Hubei Weideli Chemical Reagent Co., Ltd.; soybean lecithin and TPGS used in the examples of the present invention were purchased from Shanghai Yuanye Biotechnology Co., Ltd.; Carbomer 940 used in the examples of the present invention was purchased from Shanghai Yien Chemical Reagent Co., Ltd.; propylene glycol and ethanol used in the examples of the present invention were purchased from Xilong Science Co., Ltd.

[0062] Example 1

[0063] Example 1 of the present invention provides a method for preparing upadacitinib ethosome hydrogel (UPA@ES-TPGS-gel), comprising the following steps:

[0064] S1. 80 mg of upadacitinib API, 140 mg of soy lecithin and 80 mg of TPGS were dissolved in a mixed solvent of 2.2 mL of ethanol and 4.4 mL of propylene glycol. After complete dissolution by ultrasound, the solution was slowly injected into 13.4 mL of water at a constant temperature of 40° C., stirred and hydrated for 20 min, and then cooled to room temperature and ultrasonicated with a probe ultrasonicator at 150 W for 7 min, working for 5 s and stopping for 5 s each, and finally filtered through a 0.22 μm microporous filter membrane to obtain 20 mL of upadacitinib-loaded ethanol (UPA@ES-TPGS); 2 g of carbomer 940 powder was weighed and evenly sprinkled on the surface of 100 mL of pure water, and 100 mL of blank gel matrix was obtained after sufficient swelling.

[0065] S2, weigh 15g UPA@ES-TPGS and add dropwise to 15g blank gel matrix, stirring while adding, and after mixing evenly, adjust the pH of the system to 7.0 with triethanolamine, and vacuum treat to remove bubbles to obtain 30g UPA@ES-TPGS-gel, such as Figure 2 -a as shown.

[0066] The UPA@ES-TPGS prepared in step S1 is as follows Figure 2 -a, the laser pen irradiates the UPA@ES-TPGS prepared in step S1, such as Figure 2 -b as shown.

[0067] Example 2

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

[0069] Example 3

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

[0071] Example 4

[0072] Example 4 of the present invention provides a method for preparing upadacitinib ethosome hydrogel (UPA@ES-TPGS-gel), which is different from Example 1 in that the ultrasonic treatment in step S1 is 200w ultrasonication for 5 minutes with a probe ultrasonicator, working for 5 seconds and stopping for 5 seconds.

[0073] Example 5

[0074] Example 5 of the present invention provides a method for preparing upadacitinib ethosome hydrogel (UPA@ES-TPGS-gel), which is different from Example 1 in that 1 g of carbomer powder is weighed in step S1.

[0075] Example 6

[0076] Example 6 of the present invention provides a method for preparing upadacitinib ethosome hydrogel (UPA@ES-TPGS-gel), which is different from Example 1 in that the amount of upadacitinib-loaded ethosome added in step S2 is 10 g, and the amount of blank gel matrix added is 20 g.

[0077] Example 7

[0078] Example 7 of the present invention provides a method for preparing upadacitinib ethosome hydrogel (UPA@ES-TPGS-gel), which is different from Example 1 in that in step S1, the amounts of upadacitinib, soy lecithin and TPGS added are 40 mg, 140 mg and 40 mg, respectively, and the amounts of ethanol and propylene glycol added are 2.2 mL and 4.4 mL, respectively.

[0079] Performance Testing

[0080] The performance tests of UPA@ES-TPGS-gel and UPA@ES-TPGS prepared in Example 1 were performed, including:

[0081] (1) The average particle size, polydispersity index and Zeta potential of UPA@ES-TPGS were measured using a dynamic laser scattering particle size analyzer. The measurements were repeated 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] 10 μL UPA@ES-TPGS was pipetted onto the microporous copper mesh, and then naturally dried and stained with 2% phosphotungstic acid for 3 min. The excess dye was removed by filter paper. After naturally drying, the morphology was observed and photographed under a JEM-2100 transmission electron microscope. The results are shown in the figure. Figure 3 As shown, it was found that the prepared UPA@ES-TPGS particles were regular spherical, relatively evenly distributed, and had a particle size of 100nm-150nm.

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

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

[0089] 500 μL of UPA@ES-TPGS was placed on the top of a 3KD ultrafiltration centrifuge tube and centrifuged at 10000 r / min for 20 min. The filtrate was taken out and fixed to volume in a 10 mL volumetric flask. After mixing and passing through a 0.22 μm filter membrane, the free drug concentration was determined by HPLC. Another 500 μL of upadacitinib-loaded ethanol was placed in a 10 mL volumetric flask and ultrasonically crushed with 5 mL of methanol for 10 min. The initial mobile phase was fixed to volume and the total drug concentration was determined by HPLC. The encapsulation efficiency and drug loading were calculated according to the following formula. The average value was taken after three parallel measurements. The results are shown in Table 2.

[0090] EE%=(1-m1 / m2)×100%

[0091] DL%=(m2-m1) / (m2-m1+m0)×100%

[0092] Wherein: m1 is the amount of free upadacitinib; m2 is the total amount of upadacitinib; and m0 is the feed amount of the ethanolsome.

[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 using upadacitinib API (UPA), a physical mixture of upadacitinib API and blank ethosome (UPA-ES), blank ethosome (ES), and UPA@ES-TPGS. Figure 4 shown.

[0097] The results showed that in the DSC spectra of UPA and UPA-ES, the 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 ethanolsomes.

[0098] (5) X-ray diffraction analysis (XRD)

[0099] X-ray diffraction (XRD) analysis was performed using UPA, UPA-ES, ES and UPA@ES-TPGS. Figure 5 shown.

[0100] The results show that UPA and UPA-ES have strong characteristic diffraction peaks of drugs at diffraction angles of 8.0°, 9.6°, 14.1°, 14.5°, 20.5°, 23.0°, and 24.8°, indicating that the drug exists in the form of a crystalline compound. ES has no peak and presents 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 is that UPA is evenly dispersed in the alcohol body in an amorphous form, indicating that the hydrophobic drug UPA is successfully encapsulated in the hydrophobic bilayer of the alcohol body.

[0101] (6) In vitro drug release behavior study

[0102] The in vitro drug release behavior of upadacitinib-loaded alcohol plasmids (UPA@ES-TPGS) was studied as follows: 2 mL of UPA@ES-TPGS was measured and placed in a pretreated dialysis bag (molecular weight cutoff 3500D), and 2 mL of UPA methanol solution with the same drug content as UPA@ES-TPGS was placed in another pretreated dialysis bag. After tying both ends, the bag was placed in a container containing 50 mL of release medium, kept at a constant temperature of 37°C, and stirred at a constant speed of 100 rpm. At predetermined time intervals (0.5, 1, 2, 4, 6, and 8 hours), 0.5 mL of release medium was drawn, and 0.5 mL of isothermal release medium was added at the same time. After the taken-out release medium was filtered through a 0.22 μm microporous filter membrane, 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, and the results are shown in the figure: Figure 6 As shown, UPA@ES-TPGS has a certain sustained release effect compared with UPA methanol solution, which can better control drug release and prolong the action time.

[0103] Q%=W t / W total ×100% (4-1)

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

[0105] (7) Appearance and SEM observation

[0106] UPA@ES-TPGS-gel was used to test the appearance, shape and scanning electron microscopy observation.

[0107] Appearance shape Figure 7 As shown, UPA@ES-TPGS-gel has a translucent, glossy, semisolid appearance, good adhesion, is easy to apply on the skin, has a slippery feel, and is easy to wash.

[0108] 0.1 g of UPA@ES-TPGS-gel freeze-dried powder was spread on an aluminum head with a double-layer conductive tape, and gold was sprayed using an ion sputtering instrument. Then, the coating sample was randomly imaged by scanning electron microscopy to observe the morphological characteristics and take photos. The results are as follows: Figure 8 As shown, Figure a shows that the hydrogel has a loose and porous structure, and Figure b shows that many alcohol body particles are dispersed inside the hydrogel.

[0109] (8) Pharmacodynamic studies

[0110] The newly purchased C57BL / 6J mice were adaptively raised for one week, and the hair on the back of the mice (2cm×3cm) was carefully removed with a razor and depilatory cream without damaging the skin of the mice. After depilation, the mice recovered for 24 hours to restore their skin 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 Fig. 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 Fig.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 ethosome hydrogel provided by the present invention can improve the therapeutic efficacy of psoriasis, 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 are described in detail above, it is obvious to those skilled in the art that various modifications and variations can be made to these embodiments. However, it should be understood that such modifications and variations are within the scope and spirit of the present invention as described in the claims. Moreover, the present invention described herein may have other embodiments and may be implemented or realized in a variety of ways.

Claims

1. An upadacitinib ethosome hydrogel, characterized in that: The hydrogel 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).

2. The hydrogel according to claim 1, characterized in that The upadacitinib-loaded ethosome comprises an upadacitinib raw material, a nanocarrier and a surfactant.

3. The hydrogel according to claim 2, characterized in that The nanocarrier includes lipid and alcohol phases.

4. The hydrogel according to claim 3, 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 alcohol matrix.

5. The hydrogel according to claim 4, characterized in that The volume ratio of the ethanol to the propylene glycol is (1-2):(1-2).

6. The hydrogel according to any one of claims 2 to 3, characterized in that The mixing ratio of the upadacitinib API to the upadacitinib-loaded ethosome is (2mg-5mg):1ml; and / or, the mixing ratio of the lipid to the upadacitinib-loaded ethosome is (5mg-15mg):1ml; and / or, the mixing ratio of the surfactant to the upadacitinib-loaded ethosome is (2mg-10mg):1ml.

7. The hydrogel according to claim 1, characterized in that The blank gel matrix includes a gel matrix, specifically including any one of sodium alginate, HPMC, PVA, and Carbomer 940.

8. A method for preparing the hydrogel according to any one of claims 1 to 7, characterized in that: The following steps are involved: The upadacitinib raw material, lipid and surfactant are dissolved in an alcohol phase, and subjected to ultrasonic treatment to obtain a mixed solution, the mixed solution is dispersed in water, subjected to ultrasonic treatment, and filtered to obtain the upadacitinib-loaded alcoholic solid; Dispersing the gel matrix on the surface of water and swelling it to obtain the blank gel matrix; The upadacitinib-loaded ethosomes were mixed with a blank gel matrix, the pH was adjusted to 6.5-7.0, and after vacuum treatment, an upadacitinib ethosome hydrogel was prepared.

9. The preparation method according to claim 8, characterized in that: The ultrasonic treatment includes: a probe ultrasonic instrument with a power of 100W-200W for 5min-10min, working for 5s and stopping for 5s; 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 0.22μm; and triethanolamine is used when adjusting pH.

10. Use of the hydrogel according to any one of claims 1 to 7, or the hydrogel prepared by the preparation method according to any one of claims 8 to 9, in preparing a drug for treating psoriasis.

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