Compounds and methods for treating and / or preventing solar keratosis

Abstract

The present application relates to 17 [beta]-Huangzhou glycoside B or a pharmaceutically acceptable salt, raceme, stereoisomer, enantiomer, diastereoisomer, tautomer, metabolite, solvate, prodrug thereof, and a method of use thereof in the treatment and / or prevention of solar keratosis, which can be percutaneous permeable and can act directly on a lesion part, such as in the treatment and / or prevention of solar keratosis, such as in the treatment and / or prevention of solar keratosis, as well as in the treatment and / or prevention of solar keratosis, as well as in the treatment and / or prevention of solar keratosis. The pharmaceutical composition has higher safety while improving the curative effect.

Description

Compounds and methods for treating and / or preventing actinic keratosis

[0001] This application claims priority to and benefits of patent application 202311331585.0 filed with the State Intellectual Property Office of China on October 13, 2023, and incorporates the entire text of that application herein by reference. Technical Field

[0002] The present application belongs to the field of medical technology, and specifically relates to compounds and methods for treating and / or preventing actinic keratosis. Background Art

[0003] Reports indicate that 17β-xanthoside B can target beclin 1, inhibit the formation of LC3-associated phagosomes, and improve the development of experimental autoimmune encephalomyelitis (EAE). Patent No. CN 104736157 A records that 17β-xanthoside B can induce cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells.

[0004] Solar keratosis or actinic keratosis is a scaly, hard growth (lesion) caused by damage from the sun's ultraviolet rays. It mostly occurs on exposed areas such as the face, ears, and back of the hands. The main symptoms are red, brown, or grayish-white keratotic patches with adhesive scales on the surface. As the disease progresses, it seriously affects the patient's appearance and life safety. In recent years, the number of people suffering from AK has gradually increased, and it is of great significance to adopt safe and effective means to treat AK. Existing treatment methods include cryotherapy, surgical excision, photodynamic therapy, topical drug therapy, chemical peels, etc. Cryotherapy uses liquid nitrogen to destroy individual lesions. The main disadvantage of this treatment is that it cannot treat subclinical lesions and has a high recurrence rate of up to 96% within one year. The therapeutic effect of photodynamic therapy is affected by multiple factors such as the severity of the skin lesions, the type of irradiation light source, the time of photosensitizer encapsulation, serum vitamin D levels, etc., and there are also adverse reactions such as pain, erythema, blisters, and scabs. Drug treatment is an optional way to treat AK and can be combined with other means to improve the treatment effect of AK. Among them, 5-fluorouracil, imiquimod, butylene glycol mesylate, and nitibulin have been reported to be useful for the treatment of actinic keratosis, but the therapeutic effects are limited.

[0005] Therefore, drugs suitable for the treatment of actinic keratosis remain to be developed.

[0006] Summary of the Invention

[0007] In one aspect, the present application relates, at least in part, to a compound, which is 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof, for topical administration to treat and / or prevent actinic keratosis.

[0008] In one aspect, the present application relates, at least in part, to methods of treating and / or preventing actinic keratosis comprising administering 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof.

[0009] In one aspect, the present application relates, at least in part, to a method for treating and / or preventing actinic keratosis, comprising administering to a subject in need thereof a therapeutically effective amount of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof.

[0010] In one aspect, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof is administered to the affected area of ​​a subject at a dose of about 0.0003 mg to about 100 mg; about 0.008 mg to about 90 mg; about 0.1 mg to about 80 mg; about 0.1 mg to about 70 mg; about 0.1 mg to about 60 mg; about 0.1 mg to about 50 mg; about 0.1 mg to about 40 mg; about 0.1 mg to about 30 mg; about 0.1 mg to about 20 mg; about 0.1 mg to about 15 mg; about 0.1 mg to about 10 mg; about 0.1 mg to about 8 mg; about 0.2 mg to about 5 mg; about 0.5 mg to about 2.5 mg.

[0011] In one aspect, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof is administered to the affected area of ​​a subject at a dose of about 0.02 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 15 ... .9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 4 mg, or about 5 mg.

[0012] In one aspect, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof is administered to the affected area of ​​a subject at a dose of about 0.0003 mg / cm 2 to about 10 mg / cm 2 ; preferably about 0.001 mg / cm 2 to about 1 mg / cm 2 ; preferably about 0.002 mg / cm 2 to about 0.5 mg / cm 2 ; preferably about 0.004 mg / cm 2 to about 0.25 mg / cm 2 ; preferably about 0.008 mg / cm 2 to about 0.2 mg / cm 2 ; preferably about 0.01 mg / cm 2 to about 0.18 mg / cm 2 ; preferably about 0.016 mg / cm 2 to about 0.16 mg / cm 2 ; preferably about 0.02 mg / cm 2 to about 0.15 mg / cm 2 ; preferably about 0.025mg / cm 2 to about 0.14 mg / cm 2 ; preferably about 0.027mg / cm 2 to about 0.13 mg / cm 2 ; preferably about 0.03mg / cm 2 to about 0.125 mg / cm 2 ; preferably about 0.035mg / cm 2 to about 0.12 mg / cm 2 ; preferably about 0.04 mg / cm 2 to about 0.1 mg / cm 2 .

[0013] In one aspect, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof is administered to the affected area of ​​a subject at a dose of about 0.001 mg / cm 2 , about 0.002mg / cm 2 , about 0.003mg / cm 2 , about 0.004mg / cm 2 , about 0.005mg / cm 2 , about 0.006mg / cm 2, about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009mg / cm 2 , about 0.01mg / cm 2 , about 0.015mg / cm 2 , about 0.02mg / cm 2 , about 0.025mg / cm 2 , about 0.03mg / cm 2 , about 0.035mg / cm 2 , about 0.04mg / cm 2 , about 0.045mg / cm 2 , about 0.05mg / cm 2 , about 0.055mg / cm 2 , about 0.06mg / cm 2 , about 0.065mg / cm 2 , about 0.07mg / cm 2 , about 0.075mg / cm 2 , about 0.08mg / cm 2 , about 0.085mg / cm 2 , about 0.09mg / cm 2 , about 0.095mg / cm 2 , about 0.1mg / cm 2 , about 0.15mg / cm 2 , about 0.2mg / cm 2 , about 0.25mg / cm 2 , about 0.3mg / cm 2 , about 0.35mg / cm 2 , about 0.4mg / cm 2 , about 0.45mg / cm 2 , about 0.5mg / cm 2 , about 0.55mg / cm 2 , about 0.6mg / cm 2 , or about 0.65 mg / cm 2 .

[0014] In one aspect, the subject has an affected area of ​​about 0.01 cm 2 to about 300cm 2 ; Preferably, the affected area of ​​the subject is about 1 cm 2 to about 200cm 2 , about 1cm 2 to about 100cm 2 , about 1cm 2 to about 75cm2 , about 1cm 2 to about 50cm 2 , about 1cm 2 to about 25cm 2 ; about 10cm 2 to about 200cm 2 , about 10cm 2 to about 100cm 2 , about 10cm 2 to about 75cm 2 , about 10cm 2 to about 50cm 2 , about 10cm 2 to about 25cm 2 ; About 25cm 2 to about 200cm 2 , about 25cm 2 to about 100cm 2 , about 25cm 2 to about 75cm 2 ; About 25cm 2 to about 90cm 2 , about 25cm 2 to about 80cm 2 , or about 25cm 2 to about 70cm 2 , about 25cm 2 to about 60cm 2 , about 25cm 2 to about 50cm 2 , about 25cm 2 to about 40cm 2 , or about 25cm 2 to about 30cm 2 Preferably, the affected area of ​​the subject is about 0.2 cm 2 , about 0.5cm 2 , about 1cm 2 , about 2cm 2 , about 3cm 2 , about 4cm 2 , about 5cm 2 , about 6cm 2 , about 7cm 2 , about 8cm 2 , about 9cm 2 , about 10cm 2 , about 11cm 2 , about 12cm 2 , about 13cm 2 , about 14cm 2 , about 15cm 2 , about 16cm2 , about 17cm 2 , about 18cm 2 , about 19cm 2 , about 20cm 2 , about 25cm 2 , about 30cm 2 , about 35cm 2 , about 40cm 2 , about 45cm 2 , about 50cm 2 、approximately 55cm 2 , about 60cm 2 , about 65cm 2 , about 70cm 2 , about 75cm 2 , about 80cm 2 、approximately 85cm 2 , about 90cm 2 , about 95cm 2 , or about 100cm 2 .

[0015] In one aspect, the subject's affected area is skin.

[0016] In one aspect, the subject's affected area is located at one or more locations independently selected from the group consisting of: scalp, forehead, forearm, face, nose, ear, eyelid, lip, neck, arm, hand, torso, leg, and foot.

[0017] In one aspect, the subject has more than one affected area. In one aspect, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof is administered to the patient topically.

[0018] In one aspect, the 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug is prepared into a pharmaceutical composition suitable for external use.

[0019] In one aspect, based on the total weight of the pharmaceutical composition, the content of 17β-xanthoside B is about 0.025-4 weight percent, preferably about 0.05-3 weight percent, preferably about 0.2-0.8 weight percent, preferably about 0.4-0.8 weight percent, preferably about 0.075 weight percent, about 0.1 weight percent, about 0.125 weight percent, about 0.15 weight percent, about 0.175 weight percent, about 0.2 weight percent, about 0.225 weight percent, about 0.25 weight percent, about 0.275 weight percent, about 0.3 weight percent, about 0.325 weight percent, about 0.35 weight percent, about 0.375 weight percent, about 0.4 weight percent, about 0.425 weight percent, about 0.45 weight percent, about 0.475 weight percent, about 0.5 weight percent, about 0.525 weight percent, about 0.55 weight percent, about 0.575 weight percent, about 0.6 weight percent, about 0.625 weight percent, about 0.65 weight percent, about 0.675 weight percent, about 0.7 weight percent, about 0.725 weight percent, about 0.75 weight percent, about 0.775 weight percent, about 0.8 weight percent, about 0.825 weight percent, about 0.85 weight percent, about 0.875 weight percent, about 0.9 weight percent, about 0.925 weight percent, about 0.95 weight percent, about 0.975 weight percent, about 1 weight percent, about 1.25 weight percent, about 1.5 weight percent, about 1.75 weight percent, about 2.0 weight percent, about 2.25 weight percent, about 2.5 weight percent, about 2.75 weight percent.

[0020] In one aspect, the pharmaceutical composition is a gel.

[0021] In one aspect, the pharmaceutically acceptable excipients in the gel may optionally include a gel matrix. The gel matrix is ​​at least one selected from sodium carboxymethylcellulose, carbomer, gelatin, and alginate. In one aspect, the gel matrix is ​​present in an amount of about 0.5-5% by weight, preferably about 1-4% by weight, preferably about 1-3% by weight, more preferably about 1.5% by weight, about 2% by weight, about 2.5% by weight, or about 3% by weight, based on the total weight of the pharmaceutical composition.

[0022] In one aspect, the pharmaceutically acceptable excipient in the gel may optionally include a humectant. The humectant is at least one selected from alcoholic humectants; preferably, the humectant is glycerol. In one aspect, the humectant is present in an amount of about 5-35% by weight, preferably about 10-30% by weight, more preferably about 15-25% by weight, and more preferably about 15%, about 20%, about 25%, or about 30% by weight, based on the total weight of the pharmaceutical composition.

[0023] In one aspect, the pharmaceutically acceptable excipient in the gel may optionally include a solvent; preferably, the solvent is at least one of ethanol, propylene glycol, and benzyl alcohol, and the ethanol is 95% ethanol or anhydrous ethanol. In one aspect, the content of the solvent is about 20-75% by weight, preferably about 25-70% by weight, and more preferably about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, or about 65% by weight, based on the total weight of the pharmaceutical composition.

[0024] In one aspect, the pharmaceutically acceptable excipient in the gel may optionally include water, preferably purified water, distilled water or deionized water. In one aspect, the water content is about 20-75% by weight, preferably about 25-70% by weight, more preferably about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, or about 65% by weight based on the total weight of the pharmaceutical composition.

[0025] On the one hand, the pharmaceutically acceptable excipients in the gel may optionally include a penetration enhancer. On the one hand, the penetration enhancer is at least one selected from azone, borneol, Tween 80, sodium lauryl sulfate, and poloxamer, and more preferably the penetration enhancer is azone or borneol. On the one hand, based on the total weight of the pharmaceutical composition, the content of the penetration enhancer is about 0-5 weight %; preferably about 0.1-4 weight %; more preferably about 0.25 weight %; about 0.5 weight %; about 0.75 weight %; about 1 weight %; about 1.25 weight %; about 1.5 weight %; about 1.75 weight %; about 2 weight %; about 2.25 weight %; about 2.5 weight %; about 2.75 weight %; about 3 weight %; about 3.25 weight %; about 3.5 weight %; about 3.75 weight %. On the one hand, the pharmaceutically acceptable excipients may optionally include a preservative. The preservative is a paraben preservative and / or butylated hydroxytoluene; preferably, the paraben preservative is methylparaben and / or ethylparaben. In one aspect, the preservative is present in an amount of about 0-4% by weight, preferably about 0.1-3% by weight, based on the total weight of the pharmaceutical composition; more preferably about 0.25% by weight; about 0.5% by weight; about 0.75% by weight; about 1% by weight; about 1.25% by weight; about 1.5% by weight; about 1.75% by weight; about 2% by weight; about 2.25% by weight; about 2.5% by weight; about 2.75% by weight.

[0026] In one aspect, the pharmaceutical composition comprises:

[0027] About 0.2-0.8% by weight of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof; and / or

[0028] about 1.5% by weight of a gel matrix; and / or

[0029] about 40% by weight of a solvent; and / or

[0030] About 0.5% by weight of a penetration enhancer; and / or

[0031] about 20% by weight of a humectant;

[0032] and the balance of water.

[0033] In one aspect, the pharmaceutical composition is a topical composition comprising 17β-xanthoside B free base, wherein the 17β-xanthoside B free base is greater than about 90% as determined by HPLC; preferably greater than about 90.5%, greater than about 91%, greater than about 91.5%, greater than about 92%, greater than about 92.5%, greater than about 93%, greater than about 93.5%, greater than about 94%, greater than about 94.5%, greater than about 95%, greater than about 95.5%, greater than about 96%, greater than about 96.5%, greater than about 97%, greater than about 97.5%, greater than about 98%, greater than about 98.5%, greater than about 99%, greater than about 99.5%, greater than about 99.6%, greater than about 99.7%, greater than about 99.8% or greater than about 99.9%.

[0034] In one aspect, dosage forms of topical compositions include powders, sprays, ointments, emulsions, pastes, creams, lotions, gels, solutions, patches, and inhalants.

[0035] In one aspect, the dosage form of the topical composition comprises a gel.

[0036] In one aspect, the amount of the pharmaceutical composition applied to the affected skin area is about 0.001 g / cm 2 Skin surface area: approximately 0.5 g / cm 2 The skin surface area is preferably about 0.0015 g / cm 2 Skin surface area: approximately 0.2 g / cm 2 Skin surface area; preferably about 0.0015 g / cm 2 Skin surface area: approximately 0.15 g / cm 2 Skin surface area; preferably about 0.002 g / cm 2 Skin surface area: approximately 0.125 g / cm 2 Skin surface area; preferably about 0.003 g / cm 2 Skin surface area: approximately 0.1 g / cm 2 Skin surface area; preferably about 0.004 g / cm 2 Skin surface area: approximately 0.005 g / cm2 Skin surface area: approximately 0.006 g / cm 2 Skin surface area: approximately 0.007 g / cm 2 Skin surface area: approximately 0.008 g / cm 2 Skin surface area: approximately 0.009 g / cm 2 Skin surface area: approximately 0.01 g / cm 2 Skin surface area: approximately 0.0125 g / cm 2 Skin surface area: approximately 0.015 g / cm 2 Skin surface area: approximately 0.0175 g / cm 2 Skin surface area: approximately 0.02 g / cm 2 Skin surface area: approximately 0.03 g / cm 2 Skin surface area: approximately 0.04 g / cm 2 Skin surface area: approximately 0.05 g / cm 2 Skin surface area: approximately 0.06 g / cm 2 Skin surface area: approximately 0.07 g / cm 2 Skin surface area: approximately 0.08 g / cm 2 Skin surface area: approximately 0.09 g / cm 2 Skin surface area.

[0037] In one aspect, 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug is administered every day, every other day, every two days, every three days, every four days, every five days, every six days, or every seven days. Typically, the administration day is one, two, three, or four times.

[0038] In one aspect, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof is administered once a week, once every six days, once every five days, once every four days, once every three days, once every two days, once a day, twice a day, three times a day, or four times a day; preferably once every two days or once a day.

[0039] In one aspect, the administration period of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof can be 1 to 100 days, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 days.

[0040] In one aspect, the frequency of administration of 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug can be once or twice a day, continued for more than one day per week, and then stopped for the rest of the week. In one aspect, it is administered every other day, once or twice a day. In one aspect, it is administered every three days, every four days, every five days, every six days, or every seven days, once or twice a day. In one aspect, it is administered every three days, every four days, every five days, every six days, or every seven days, for two consecutive days, once or twice a day. In one aspect, it is administered every four days, every five days, every six days, or every seven days, for three consecutive days, once or twice a day. In one aspect, it is administered every five days, every six days, or every seven days, for four consecutive days, once or twice a day. In one aspect, it is administered until the actinic keratosis is completely cured. In one aspect, it is administered topically.

[0041] In one aspect, the drug is maintained in contact with the skin for about 0.5 to about 24 hours per administration, optionally about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours.

[0042] In one aspect, administration of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof reduces the number and / or severity of local skin reactions or other adverse side effects in a subject compared to other treatments for actinic keratosis.

[0043] In one aspect, administration of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof reduces the number of subjects experiencing local skin reactions or other adverse side effects compared to other treatments for actinic keratosis.

[0044] In one aspect, the local skin reaction is selected from the group consisting of vesicle formation, pustule formation, erosion, ulceration, redness, swelling, flaking, scaling, lump, dryness, pus, and blister.

[0045] In one aspect, the other side effect is selected from the group consisting of application site pain, application site itching, application site irritation, application site swelling, application site burning, application site infection, edema around the eye, nasopharyngitis, chills, sore throat, ptosis, puffy eyes, hypopigmentation, hyperpigmentation, and headache.

[0046] In one aspect, the present application relates at least in part to 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof, which is used (e.g., topically) to treat and / or prevent actinic keratosis. In some aspects, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof is used as described herein at the dosage, dosing schedule, and / or in one or more diseased areas in a subject in need thereof.

[0047] In one aspect, the present application relates at least in part to the use of 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug in the treatment and / or prevention of actinic keratosis (e.g., topical use). In some aspects, 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug is used as described herein at the dosage, administration schedule, and / or in one or more diseased areas in a subject in need thereof.

[0048] In one aspect, the present application relates, at least in part, to the use of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof in the preparation of a medicament for treating and / or preventing actinic keratosis. In some aspects, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof is used as described herein at the dosage, dosing schedule, and / or in one or more diseased areas in a subject in need thereof.

[0049] In one aspect, the present application relates, at least in part, to a therapeutic agent for actinic keratosis comprising 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof. In some aspects, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof is used as described herein at the dosage, dosing schedule, and / or in one or more affected areas in a subject in need thereof.

[0050] Actinic keratosis, or "AK," is a common skin condition caused by overexposure to ultraviolet rays. AKs are rough, dry, yellow-brown, pink, or red spots (lesions) that often appear on the head, including the face, throat, neck, nose, forehead, ears, or lips. AKs may also appear on other parts of the body that are exposed to intense sunlight for extended periods of time, such as the hands, back, and other areas of the torso and legs.

[0051] As used herein, the term "torso" refers to the body of a subject other than the arms, legs, or head.

[0052] AK is most common in middle-aged or elderly people with very fair skin. Subjects with AK may have a single lesion or multiple lesions.

[0053] Clinical variants of AK include: traditional (or common) AK, hypertrophic (or hyperkeratotic) AK, atrophic AK, AK with horns, pigmented AK, actinic cheilitis, etc. Unless otherwise specifically indicated, the methods described herein are applicable to all clinical variants, including those listed herein.

[0054] Treatments for AK include cryosurgery and surgical excision and / or curettage of the affected area, photodynamic therapy, and topical preparations (e.g., creams, gels, patches, etc.) containing steroids, fluorouracil, diclofenac, imiquimod, 5-aminolevulinic acid.

[0055] An approved treatment for AK is Picato, a gel containing ingenol methylbutyrate (0.015% or 0.05%) that is applied once daily for three consecutive days (0.015%) to affected areas on the face or scalp or once daily for two consecutive days (0.05%) to affected areas on the trunk or extremities.

[0056] Skin toxicity associated with the use of other AK treatments, such as Picato, is known to produce undesirable side effects or adverse reactions, namely local skin reactions (LSRs), which include vesicle formation, pustule formation, erosion, ulceration, redness, swelling, flaking, scaling, lumps, dryness, pus, and blisters. Other side effects include application site pain, application site itching, application site irritation, application site swelling, application site burning, application site infection, peri-ocular edema, nasopharyngitis, chills, sore throat, ptosis, eye swelling, hypopigmentation, hyperpigmentation, and headache.

[0057] As used herein, the phrase "until the actinic keratosis clears" refers to a condition in which the lesions on a subject with AK are substantially or completely gone from the treated area of ​​the subject. In one embodiment, "substantially" in this context means that greater than 50% of the AK lesions have disappeared from the treated area of ​​the subject. In another embodiment, "substantially" means that greater than 60% of the AK lesions have disappeared from the treated area of ​​the subject. In another embodiment, "substantially" means that greater than 70% of the AK lesions have disappeared from the treated area of ​​the subject. In another embodiment, "substantially" means that greater than 80% of the AK lesions have disappeared from the treated area of ​​the subject. In another embodiment, "substantially" means that greater than 90% of the AK lesions have disappeared from the treated area of ​​the subject. In another embodiment, "substantially" means that greater than 95% of the AK lesions have disappeared from the treated area of ​​the subject. In another embodiment, "substantially" means that greater than 99% of the AK lesions have disappeared from the treated area of ​​the subject.

[0058] As used throughout this disclosure, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes a plurality of such methods and reference to "a dosage" includes reference to one or more dosages and equivalents thereof known to those skilled in the art, and so forth.

[0059] The term "comprising" is intended to indicate that the method includes the listed elements, but does not exclude other elements. When used to define a method, "consisting essentially of" shall mean excluding other elements that have any essential significance to the combination when used for the intended purpose. Thus, a method consisting essentially of the elements defined herein does not exclude substantial method steps. "Consisting of" means excluding multiple substantial method steps. Embodiments defined by each of these transition terms are within the scope of this application.

[0060] Unless expressly indicated otherwise, the terms "approximately" and "about" are synonymous. In one embodiment, "approximately" and "about" refer to ±5%, ±4.5%, ±4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5% ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.09%, ±0.08%, ±0.07%, ±0.06%, ±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01% of a stated amount, value, or duration. In another embodiment, "approximately" and "about" refer to ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5% of the listed amount, value, or duration. In another embodiment, "approximately" and "approximately" refer to ±1% of the listed amount, value, or duration. In another embodiment, "approximately" and "approximately" refer to ±0.5% of the listed amount, value, or duration. In another embodiment, "approximately" and "approximately" refer to ±0.1% of the listed amount, value, or duration.

[0061] The term "subject" includes any living organism that has or is at risk of developing actinic keratosis. In one embodiment, the term "subject" refers to a mammal that has or is at risk of developing actinic keratosis. In one embodiment, the term subject refers to a human that has or is at risk of developing actinic keratosis. Unless expressly indicated otherwise, the term "patient" is synonymous with "subject."

[0062] As used herein, the term "therapeutically effective amount" refers to the amount of an agent, such as 17β-xanthoside B, or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof, used to treat, improve, or prevent a confirmed disease or condition, such as AK, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject depends on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experiments within the ability and judgment of a clinician.

[0063] For any compound, the therapeutically effective amount can be estimated in an animal model, typically rats, mice, rabbits, dogs or pigs. Animal models can also be used to determine suitable concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / preventive efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED50 (dose effective for 50% of the population treatment) and LD50 (dose lethal to 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio of LD50 / ED50. The dosage can vary within this range, depending on the dosage form employed and the sensitivity of the subject.

[0064] Dosage and administration are adjusted to provide sufficient levels of the active ingredient or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the location of the disease on the subject, the subject's overall health, the subject's age, weight and sex, diet, administration time and frequency, drug combination, reaction sensitivity and tolerance / response to treatment. Depending on the half-life and clearance rate, 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug can be administered daily, every other day, every three days, every four days, every five days, every six days, weekly, twice a week or once every two weeks.

[0065] For any of the methods described herein, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof can be administered topically, intradermally, intercutaneously, intragingivally, intraocularly, nasally, ocularly, transdermally, periodontally, subconjunctivally, sublingually, transmucosally, or otically. In one embodiment, 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof can be administered topically.

[0066] All percentages and ratios used herein are by weight unless otherwise specified.

[0067] The molecular formula of the term "17β-xanthoside B" used in this article is as follows:

[0068] 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug in the drug remains in a substantially dissolved form. Preferably, the drug contains at least 50% dissolved form, more preferably the drug contains at least 70% dissolved form, more preferably the drug contains at least 90% dissolved form, more preferably the drug contains 100% dissolved form. Undissolved crystals can exist in any known polymorphic form. As measured using laser diffraction, the particle size of 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug can vary between 1 micron and 100 microns (D90).

[0069] In some embodiments, the present application provides a pharmaceutical composition containing 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof.

[0070] In some embodiments, the pharmaceutical composition is made of 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug and pharmaceutically acceptable excipients, so that the pharmaceutical composition is a drug suitable for external use.

[0071] The medicine provided according to the application can be in any suitable form, in the corresponding suitable form depending on the required purposes. For example, but not limited to, the medicine can be in the form of powders, sprays, ointments, pastes, creams, lotions, solutions (such as lotions, suspensions), patches, inhalants, gels (such as hydrogels) or emulsifiable pastes for direct external use. Wherein, depending on the form of use and purposes, suitable pharmaceutically acceptable adjuvants can be selected to provide the external medicine of corresponding form, wherein, pharmaceutically acceptable adjuvants include excipients, diluents, solubilizers, emulsifiers, antioxidants, adhesives, dispersants, lubricants, preservatives, etc.

[0072] In some embodiments, the pharmaceutical composition is a gel.

[0073] In some embodiments, the pharmaceutically acceptable excipients in the gel may optionally include a gel matrix. The gel has a large drug loading capacity, flexible dosing, long-term adhesion to the administration site, a long-lasting and mild effect, good biocompatibility and stability, and is easy to apply and clean.

[0074] In some embodiments, the gel matrix is ​​at least one selected from sodium carboxymethylcellulose, carbomer, gelatin, and alginate. Among them, various types of carbomer can be used, such as carbomer 934, 940, 910 or mixtures thereof, preferably carbomer 940. Carbomer can be obtained commercially, for example, from BF Goodrich.

[0075] In some embodiments, the pharmaceutically acceptable excipients in the gel may optionally include a humectant. The humectant can increase the adhesion of the preparation, thereby improving the spreadability and viscosity of the preparation.

[0076] Penetration enhancers can increase the rate at which active ingredients penetrate the skin and deliver the active ingredients to the desired site of action in the epidermis and / or dermis. Penetration enhancers can minimize skin irritation and systemic exposure, while achieving local skin / epidermal delivery and ensuring that most of the drug remains in the skin (i.e., the site of action) to treat specific skin conditions and reduce systemic toxic side effects.

[0077] As used herein, the term "weight %" refers to the weight of a component based on the total components, unless otherwise indicated.

[0078] In the embodiments of the present application, "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or may be therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes inhibiting the disease, such as arresting the progression of the disease; or alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a drug or compound to an individual to treat, cure, alleviate, improve, mitigate or inhibit the individual's disease, including but not limited to administering a drug containing the drugs described herein to an individual in need.

[0079] To treat actinic keratosis, the pharmaceutical compositions of the present application can be applied topically to the affected area in any conventional manner known in the art, for example, by means of a dropper, applicator stick or cotton swab, by means of an intradermal or transdermal patch, or simply by applying the formulation to the skin area with the finger, sponge, pad or swab.

[0080] The pharmaceutical composition can be used in combination with one or more other methods and drugs for treating actinic keratosis. Within a certain time interval of administering the pharmaceutical composition, it can be administered to a subject simultaneously or sequentially with other drugs or treatments so that the active ingredients or agents can work together to treat or prevent actinic keratosis.

[0081] The compound contains an asymmetric center and can therefore exist as an enantiomer. The compound has multiple asymmetric centers, which can additionally exist as diastereomers. Enantiomers and diastereomers fall into the broader category of stereoisomers. All these possible stereoisomers include substantially pure resolved enantiomers, their racemic mixtures, and diastereomeric mixtures. All stereoisomers of the compound and / or their pharmaceutically acceptable salts are included. Unless otherwise stated, a reference to an isomer is applicable to any possible isomer. When an isomer component is not specifically indicated, all possible isomers are included.

[0082] Diastereomeric mixtures can be separated into individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) each diastereomer to the corresponding pure enantiomer. Enantiomers can also be separated using a chiral HPLC column.

[0083] "Pharmaceutically acceptable salts" include, but are not limited to, salts of inorganic acids selected from, for example, hydrochlorides, phosphates, hydrogenphosphates, hydrobromides, sulfates, sulfites, and nitrates; and salts of organic salts selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoates such as acetate, and salts of HOOC-(CH2)n-COOH, wherein n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium salts.

[0084] Alternatively, if the compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, consistent with conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will appreciate the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without undue experimentation.

[0085] "Prodrug" refers to a compound that is converted into a parent drug in vivo. Prodrugs are often useful because, in some cases, they can be easier to administer than the parent drug. They can be bioavailable, for example, by oral administration, whereas the parent drug cannot. The prodrug can also have improved solubility in a pharmaceutical composition than the parent drug. Examples of prodrugs are (but not limited to) compounds described herein that are administered as esters (the "prodrugs") to facilitate transport across cell membranes, where water solubility is detrimental to this transfer, but which are then metabolically hydrolyzed into carboxylic acids, active entities, which are beneficial once they enter the cell. Further examples of prodrugs can be short peptides (polyamino acids) attached to an acid group, where the peptide is metabolized to reveal an active moiety. In certain embodiments, when administered in vivo, the prodrug is chemically converted into a biological, pharmaceutical, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized into a biological, pharmaceutical, or therapeutically active form of the compound by one or more steps or methods. To produce a prodrug, a pharmaceutically active compound is modified so that it is regenerated upon in vivo administration. Such prodrugs can be designed to alter the metabolic stability or transport properties of a drug, mask side effects or toxicity, thereby improving the drug's effect or altering other characteristics or properties of the drug. Once a pharmaceutically active compound is known, those skilled in the art can design a prodrug of the compound based on knowledge of pharmacodynamics and drug metabolism in vivo.

[0086] A "metabolite" of a compound disclosed herein is a derivative of the compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is altered by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, enzymes can produce specific structural transformations into compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphoglucuronyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.

[0087] While particular embodiments of the present disclosure have been illustrated and described, various other changes and modifications may be made without departing from the spirit and scope of the present disclosure. It is intended that the scope of the appended claims include all such changes and modifications that are within the scope of the present disclosure.

[0088] Other features and advantages of the present application are apparent from the various examples provided. The examples provided illustrate various components and methods useful in implementing the present application.

[0089] These embodiments do not limit the claimed application. Based on this disclosure, a skilled artisan can identify and adopt other components and methods that can be used to implement the present application. DETAILED DESCRIPTION

[0090] The present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the relevant invention, rather than to limit the invention.

[0091] It should be noted that, unless there is any conflict, the embodiments and features in the embodiments of this application can be combined with each other.

[0092] It should be noted that the endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed herein.

[0093] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. All reagents or instruments used without specifying the manufacturer are commercially available conventional products.

[0094] Additional aspects and advantages of the present application will be given in part in the description below, and in part will become obvious from the description below, or will be learned through practice of the present application.

[0095] Example 1

[0096] 17β-xanthoside B is poorly soluble in water, and its solubility in water is about 70μg / mL. Therefore, the solubility of 17β-xanthoside B in organic solvents of different concentrations was investigated. The experimental results are shown in the following table:

[0097] It can be seen that 17β-xanthoside B has good solubility in ethanol and propylene glycol, and can be used as solvents for dissolving 17β-xanthoside B.

[0098] Example 2

[0099] The solubility of 17β-xanthoside B in ethanol at different concentrations (20℃) was studied.

[0100] Weigh an appropriate amount of 17β-glucosidoside B raw material into a beaker, a total of 3 parts. Dissolve the first part in anhydrous ethanol first, then dilute with water to a final ethanol concentration of 20%. The sample concentration is 8 mg / g, and observe whether there is precipitation. Dissolve the second part in anhydrous ethanol first, then dilute with water to a final ethanol concentration of 75%, 66%, 50% and 40%, respectively. The corresponding sample concentrations are 50, 40, 32 and 24 mg / g, respectively, and observe whether there is precipitation. Dissolve the third part in anhydrous ethanol, then dilute with water to an ethanol concentration of 45%, and the sample concentration is 20 mg / g. Observe whether there is precipitation. The results are shown in the following table:

[0101] It can be seen that 8 mg / g of 17β-glucosidoside B can be dissolved in 20% ethanol; 20 mg / g of 17β-glucosidoside B can be dissolved in 45% ethanol.

[0102] Example 3

[0103] Compatibility test of sodium carboxymethylcellulose and carbomer with 17β-xanthoside B:

[0104] After 17β-glucosidoside B was mixed with sodium carboxymethyl cellulose and carbomer in a mass ratio of 1:5, the mixture was placed at a temperature of 60℃±2℃, a relative humidity of 90%±5% for 10 days and under conditions of cumulative total illumination greater than 1.2×106Lux·hr to investigate the effect of the gel matrix on the stability of 17β-glucosidoside B. The experimental results showed that 17β-glucosidoside B and sodium carboxymethyl cellulose had no effect on the relevant substances and content under high temperature, high humidity and light conditions, and its stability was significantly better than that of carbomer.

[0105] Compatibility test results of 17β-xanthoside B and sodium carboxymethyl cellulose.

[0106] Example 4

[0107] Weigh 17β-xanthoside B raw material, add anhydrous ethanol and stir ultrasonically to dissolve; add azone and stir evenly; add water and stir evenly; add sodium carboxymethyl cellulose and stir evenly; add glycerol and stir evenly, and swell overnight; homogenize to obtain the finished gel. The physical properties of each gel were scored. The experimental results are shown in the following table:

[0108] A total score of 1-10 indicates that the physical properties of the prepared gel are poor, which may affect the patient's medication experience. A total score of 11-15 indicates that the gel is suitable for topical administration and provides a good medication experience. A total score of 16-20 indicates that the gel has good physical properties and is easy to administer without any discomfort. It can be seen that the gel obtained when the sodium carboxymethyl cellulose content is within the range of 1.0-3.0% by weight has good physical properties.

[0109] Example 5

[0110] The gel preparation was prepared according to the method of Example 4, and the effect of different contents of moisturizer on the quality of the gel preparation of the present application was studied. The experimental results are shown in the following table:

[0111] It can be seen that when the glycerol content is in the range of 15-25 wt %, the obtained gel has good physical properties.

[0112] Example 6

[0113] Gels were prepared according to the method of Example 4, and the skin irritation of gels containing different penetration enhancers and different contents of penetration enhancers was studied.

[0114] Healthy young pigs with no back injuries were used, half male and half female. The left and right sides of the same pigs were used for drug administration. Transdermal patch administration was performed, with the test gel administered on the left side and white vaseline administered on the right side as a negative control. The administration area was 3.0 cm × 3.0 cm, and the dosage was 20 mg / cm. 2 The drug was administered once daily, with the application continued on both sides of the skin for approximately 4 hours. The application site was then cleaned with warm 0.9% sodium chloride injection. A single dose was administered. Erythema and edema at the application site were observed and recorded before administration, and 1 hour, 24 hours, 48 ​​hours, 72 hours, and 14 days after drug removal. Erythema and edema were scored according to the standard. All tests met the irritation requirements.

[0115] Among them, the test gel contains 1.2% by weight of 17β-xanthoside B, 1.5% by weight of sodium carboxymethyl cellulose, 40% by weight of anhydrous ethanol, 0.5-1.0% by weight of a permeation enhancer, 20% by weight of glycerol and the balance of water. The permeation enhancers of 0.5-1.0% by weight are 1.0% azone, 1.0% borneol, 0.75% borneol and 0.5% borneol respectively.

[0116] Example 7

[0117] The Franz diffusion cell method was used to determine the in vitro transdermal absorption, including the transdermal amount, epidermal residual amount and intradermal retention amount.

[0118] Transdermal dose: Pigskin (soaked in physiological saline for about 30 minutes before use and dried with filter paper) was fixed between the receiving cell and the dosing cell, with the stratum corneum facing the dosing cell. Approximately 200 mg of the gel of the present application was taken, accurately weighed, and evenly applied to the pigskin on one side of the dosing cell. 18 mL of 15% ethanol-physiological saline preheated to 32°C ± 0.5°C was added to the receiving cell and stirred at 200 rpm. 0.5 mL of the receptor solution was taken at 1, 2, 3, 4, and 6 hours (a blank receptor solution of the same volume and temperature was added to the receiving cell at the same time). The solution was centrifuged, the supernatant was taken, and HPLC determination was performed. The transdermal drug amount was calculated by the peak area.

[0119] Epidermal residue: Take pig skin after 6 hours of penetration of this product (note that the gel remaining on the surface has flowed out), wash it with 25 mL of saturated sodium chloride solution 5 times (5 mL each time, vortex for 0.5 minute), place the washing solution in a 100 mL volumetric flask, add 25 mL of methanol, and extract by ultrasonic for 20 minutes. Dilute to the scale with 50% methanol-saturated sodium chloride solution, shake well, filter, take the filtrate, and perform HPLC determination. The epidermal residue is calculated by the peak area.

[0120] Intradermal retention: Take the rinsed pig skin, add 25 mL of 80% methanol-saturated sodium chloride solution, heat in a 70°C water bath for 30 minutes, chop, homogenize, and centrifuge (4°C, 14000 rpm for 10 minutes), take the supernatant, filter, and take the filtrate for HPLC determination. The residual amount is calculated by the peak area.

[0121] The test gel contains 0.4 wt% of 17β-glucosidoside B, 1.5 wt% of sodium carboxymethyl cellulose, 40 wt% of anhydrous ethanol, 0.5 wt% of borneol, 20 wt% of glycerol and the balance of water, and is prepared according to the method of Example 4.

[0122] Calculations show that the drug in the gel of the present invention penetrates less than 1% of the skin within 6 hours, with an epidermal residual amount of 80-95% and an intradermal retention of approximately 10%. This indicates that the drug in the gel prepared by the present invention is essentially retained in the skin, resulting in a high local drug concentration and preventing absorption into the bloodstream, thereby reducing side effects associated with systemic drug distribution.

[0123] Example 8

[0124] Healthy, SPF-grade Hartley guinea pigs with intact dorsal skin were selected, half male and half female. A negative control (white petrolatum), a positive control (2,4-dinitrochlorophenyl petrolatum ointment), a test group (17β-xanthoside B gel, 2 mg / g of 17β-xanthoside B), a test group (17β-xanthoside B gel, 4 mg / g of 17β-xanthoside B), and a test group (17β-xanthoside B gel, 8 mg / g of 17β-xanthoside B) were set up. Each group received 0.5 g of the drug per dose, and the skin application area was 2.5 cm × 2.5 cm. Each animal in each group was exposed to the left dorsal skin for 6 hours. Skin reactions were observed and scored before drug administration and 1 and 24 hours after cleaning the residue. Sensitization was performed three times, once on the 1st, 8th, and 15th days of administration. On the 29th day of administration, the drug was placed in contact with the right side of the animal's skin for 6 hours. The skin reaction was observed and recorded before administration and 24 and 48 hours after cleaning the residue. The test results were then read.

[0125] The test gels of test group 1, group 2 and group 3 respectively contained 1.5 wt% sodium carboxymethyl cellulose, 40 wt% anhydrous ethanol, 0.5 wt% borneol, 20 wt% glycerol and the balance water, and were prepared according to the method of Example 4.

[0126] The results showed that the gel preparations of the present application did not cause allergic reactions in guinea pig skin, and the allergic reactions were all negative.

[0127] Example 9

[0128] Healthy New Zealand rabbits with no dorsal injuries were used, half male and half female. A blank gel control group and a 17β-xanthoside B gel group (17β-xanthoside B content of 2 mg / g and 4 mg / g, respectively) were set up. The test substance was administered to the left side of the rabbits, while white petrolatum was administered to the right side as a negative control. The administration area was 3.0 cm × 3.0 cm. After the application was continued for approximately 4 hours on both sides of the skin, the administration site was cleaned with warm 0.9% sodium chloride injection. A single dose was administered. Erythema and edema at the administration site were observed and recorded before administration and 1 hour, 24 hours, 48 ​​hours, 72 hours, and 14 days after drug removal. Erythema and edema were scored according to the scoring criteria. Histopathological examinations were performed on the left side of the skin at the administration site in each group 72 hours and 14 days after drug removal.

[0129] The results showed that when the blank gel control group and the 17β-xanthoside B gel group (2 mg / g, 4 mg / g) were administered percutaneously to the intact skin of New Zealand rabbits, the skin irritation reaction scores on the left and right sides of each animal were within the non-irritating range, and no abnormalities were found in the microscopic examination results, and no skin irritation reaction related to the test substance was observed.

[0130] The test gel contains 1.5 wt % sodium carboxymethyl cellulose, 40 wt % anhydrous ethanol, 0.5 wt % borneol, 20 wt % glycerol and the balance water, and is prepared according to the method of Example 4.

[0131] Example 10

[0132] A clinical study was conducted to evaluate the activity and safety of topically administered 17β-xanthoside B in subjects with actinic keratosis. 17β-xanthoside B demonstrated promising, clinically relevant activity in the treatment of actinic keratosis. Based on local tolerability and local skin reactions (LSRs), 17β-xanthoside B was safe.

[0133] This trial consists of a Phase I (single-dose ascending trial) and a Phase II (extension trial). The Phase I trial is a multicenter, open-label, dose-escalation trial that investigates the safety, tolerability, and PK characteristics of different doses of 17β-xanthoside B gel applied to the lesions in subjects with actinic keratosis, and preliminarily investigates the efficacy of 17β-xanthoside B. The Phase II trial is a multicenter, open-label trial that investigates the efficacy, safety, and PK characteristics of 17β-xanthoside B gel at the target dose in subjects with actinic keratosis.

[0134] 1. Case selection

[0135] Patients aged ≥18 years were selected. All patients cooperated with the study and provided informed consent.

[0136] 2. Inclusion criteria

[0137] Inclusion criteria: ① meet the diagnostic criteria for AK in Clinical Dermatology and are confirmed by histopathological examination or non-invasive diagnosis (dermatoscopy, skin CT, etc.); ② complete clinical data.

[0138] 3. Methods

[0139] The first phase (single ascending dose trial) included single and multiple dosing. After single dosing, DLT was observed for 3 days. On the 4th day, multiple dosing was started, with dosing every other day for 3 consecutive weeks.

[0140] Dosage: Apply the gel evenly to the affected area, avoiding rinsing and friction. Cover with a breathable, waterproof dressing and secure with a non-irritating adhesive tape. Ensure the drug remains in contact with the skin for 4 ± 0.5 hours between doses. To remove the drug, cleanse the application area with room-temperature saline.

[0141] Dosage calculation: Dosage area (cm 2 ) = square of the radius of the affected area * π

[0142] Dosage (gel) mg = current dose group per cm 2 Dosage (gel dosage)*dosage area

[0143] The conversion formula between mg and microliters is: gel weight ÷ gel density = volume (corresponding to microliters ul)

[0144] Dosing area: The dosing area is 2 treatment units (treatment unit: the area of ​​one index finger joint of each subject is one treatment unit). The total dosing area of ​​the target lesion does not exceed 25cm 2 .

[0145] Medication administration during hospitalization must be under the supervision of a physician or nurse, and the dosage and schedule must be recorded in the subject's diary card. During non-hospitalized periods, the study physician and nurse should instruct the subject to take medication according to the prescribed dosing schedule at a fixed time each day. For detailed dosing schedules, please refer to the Standard Operating Procedures for Medication Administration.

[0146] The frequency of administration of the trial drug and the setting of the interval period may be adjusted appropriately based on human safety and PK data as well as efficacy.

[0147] 4. Observation indicators

[0148] Evaluate clinical effects.

[0149] Efficacy evaluation indicators applicable to subjects with actinic keratosis:

[0150] Complete clearance rate: refers to the proportion of subjects who achieved 100% clearance of lesions;

[0151] Partial clearance rate: the proportion of subjects who achieved at least 75% clearance of lesions;

[0152] Partial clearance rate: the proportion of subjects who achieved at least 50% clearance of lesions;

[0153] Lesion-specific clearance rate: the proportion of subjects with a decrease in the number of cleared lesions from baseline to the assessment time;

[0154] Dermatology Life Quality Index: SF-36 rating scale was used to evaluate the subjects' quality of life.

[0155] Safety indicators: adverse events (including local reactions at the medication site), physical examination, vital signs, laboratory tests (including blood routine, blood biochemistry, urine routine, etc.), electrocardiogram, echocardiogram, etc.

[0156] 5. The following is a summary of the safety and efficacy data of the subjects enrolled in the first phase

[0157] A total of 29 subjects were enrolled in this study. The demographic information of the subjects is shown in the table below.

[0158] Summary demographic data – All enrolled subjects (China and Australia)

[0159] Safety results

[0160] Overall, 29 subjects received at least one topical application of 17β-xanthoside B gel, with the doses in the five groups being 0.008 mg / cm 2 , 0.016mg / cm 2 , 0.027mg / cm 2 , 0.04mg / cm 2 , 0.06mg / cm 2 , and exhibited a good safety profile. In terms of safety, 17β-xanthoside B topical gel performed similarly in Chinese and Australian subjects. According to the researchers' evaluation, drug-related adverse events were mainly skin administration site reactions.

[0161] A total of 20 subjects (69%) experienced treatment-emergent adverse events (TRAEs) assessed by the investigators as drug-related. The most commonly reported TRAEs were pruritus (7 / 29, 24.1%), skin desquamation (5 / 29, 17.2%), and skin crusting (5 / 29, 17.2%), which were mainly mild local reactions at the administration site.

[0162] All AEs were grade 1 or 2 in severity, and no TEAEs of CTCAE grade 3 or above occurred.

[0163] No SAEs occurred and no DLTs were observed.

[0164] No AEs leading to death occurred.

[0165] In summary, the safety profile of 17β-xanthoside B was similar in Chinese and Australian subjects. According to the researchers' evaluation, drug-related adverse events were primarily local reactions at the skin administration site, such as pruritus, skin peeling, and skin scabs. These were all mild reactions of grade 1-2, indicating a generally good safety profile.

[0166] Effectiveness Results:

[0167] Based on the safety, tolerability, pharmacokinetic and efficacy data generated in this clinical study, the efficacy-evaluable subjects in the fifth dose group (China and Australia) included 9 patients with actinic keratosis.

[0168] In the fifth dose group (China and Australia), nine subjects with actinic keratosis were enrolled and evaluable for efficacy at Day 16, Day 24, and 28 days after the last dose. Investigator-assessed results showed that complete resolution of individual actinic keratosis lesions was observed in five subjects (55.56%) after treatment with 17β-xanthoside B topical gel.

[0169] The clearance rate of single lesion of 17β-xanthoside B in the treatment of actinic keratosis (0.06 mg / cm 2 )

[0170] Note: n represents the number of subjects

[0171] Pharmacokinetic study results:

[0172] Serum concentrations of the topical gel were measured and analyzed in Chinese and Australian patients enrolled in the dose escalation phase of the clinical study (dose levels 1-5).

[0173] The serum concentrations of 17β-xanthoside B were determined by liquid chromatography-mass spectrometry (LC / MS / MS) with a lower limit of quantification (LLOQ) of 0.02 ng / mL. 2 No increase in systemic exposure of 17β-xanthoside B was observed with increasing dose level across the dose range. Due to the low overall systemic absorption rate and sparse data, a statistically significant pharmacokinetic evaluation could not be performed (only seven Chinese subjects had plasma concentrations above the LLOQ, ranging from 0.022 to 0.106 ng / mL, and four Australian subjects had plasma concentrations above the LLOQ, ranging from 0.021 to 0.101 ng / mL).

[0174] It can be seen that the gel of the present application has a good therapeutic effect and is proven to have good safety.

[0175] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present application. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0176] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can modify, replace and vary the above embodiments within the scope of the present application.

Claims

1. A compound, which is 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof, and is used for external administration to treat and / or prevent actinic keratosis.

2. A method for treating and / or preventing actinic keratosis, comprising administering 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof.

3. The method according to claim 2, characterized in that The method comprises administering a therapeutically effective amount of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, or prodrug thereof to a subject in need thereof.

4. The method according to any one of the preceding claims, characterized in that 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug is administered to the affected area of ​​the subject at the following dosage: about 0.0003 mg to about 100 mg; about 0.008 mg to about 90 mg; about 0.1 mg to about 80 mg; about 0.1 mg to about 70 mg; about 0.1 mg to about 60 mg; about 0.1 mg to about 50 mg; about 0.1 mg to about 40 mg; about 0.1 mg to about 30 mg; about 0.1 mg to about 20 mg; about 0.1 mg to about 15 mg; about 0.1 mg to about 10 mg; about 0.1 mg to about 8 mg; about 0.2 mg to about 5 mg; about 0.5 mg to about 2.5 mg; about 0.02 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 4 mg, or about 5 mg.

5. The method according to any one of the preceding claims, characterized in that 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug is administered to the affected area of ​​the subject at the following dosage: about 0.0003 mg / cm 2 To about 10mg / cm 2 ; preferably about 0.001 mg / cm 2 About 1mg / cm 2 ; preferably about 0.002mg / cm 2 To about 0.5mg / cm 2 ; preferably about 0.004 mg / cm 2 To about 0.25mg / cm 2 ; preferably about 0.008 mg / cm 2 To about 0.2mg / cm 2 ; preferably about 0.01 mg / cm 2 To about 0.18mg / cm 2 ; preferably about 0.016mg / cm 2 To about 0.16mg / cm 2 ; preferably about 0.02mg / cm 2 To about 0.15mg / cm 2 ; preferably about 0.025mg / cm 2 To about 0.14mg / cm 2 ; preferably about 0.027mg / cm 2 To about 0.13mg / cm 2 ; preferably about 0.03mg / cm 2 To about 0.125mg / cm 2 ; preferably about 0.035mg / cm 2 To about 0.12mg / cm 2 ; preferably about 0.04mg / cm 2 To about 0.1mg / cm 2 ; about 0.001mg / cm 2 , about 0.002mg / cm 2 , about 0.003mg / cm 2 , about 0.004mg / cm 2 , about 0.005mg / cm 2 , about 0.006mg / cm 2 , about 0.007mg / cm 2 , about 0.008mg / cm 2 , about 0.009mg / cm 2 , about 0.01mg / cm 2 , about 0.015mg / cm 2 , about 0.02mg / cm 2 , about 0.025mg / cm 2 , about 0.03mg / cm 2 , about 0.035mg / cm 2 , about 0.04mg / cm 2 , about 0.045mg / cm 2 , about 0.05mg / cm 2 , about 0.055mg / cm 2 , about 0.06mg / cm 2 , about 0.065mg / cm 2 , about 0.07mg / cm 2 , about 0.075mg / cm 2 , about 0.08mg / cm 2 , about 0.085mg / cm 2 , about 0.09mg / cm 2 , about 0.095mg / cm 2 , about 0.1mg / cm 2 , about 0.15mg / cm 2 , about 0.2mg / cm 2 , about 0.25mg / cm 2 , about 0.3mg / cm 2 , about 0.35mg / cm 2 , about 0.4mg / cm 2 , about 0.45mg / cm 2 , about 0.5mg / cm 2 , about 0.55mg / cm 2 , about 0.6mg / cm 2 , or about 0.65 mg / cm 2 .

6. The method according to any one of the preceding claims, characterized in that The affected area in this subject was approximately 0.01 cm 2 About 300cm 2 Preferably, the affected area of ​​the subject is about 1 cm 2 To about 200cm 2 , about 1cm 2 To about 100cm 2 , about 1cm 2 To about 75cm 2 , about 1cm 2 To about 50cm 2 , about 1cm 2 To about 25cm 2 ; About 10cm 2 To about 200cm 2 , about 10cm 2 To about 100cm 2 , about 10cm 2 To about 75cm 2 , about 10cm 2 To about 50cm 2 , about 10cm 2 To about 25cm 2 ; About 25cm 2 To about 200cm 2 、Approx. 25cm 2 To about 100cm 2 、Approx. 25cm 2 To about 75cm 2 ; About 25cm 2 To about 90cm 2 、Approx. 25cm 2 To about 80cm 2 , or about 25cm 2 To about 70cm 2 、Approx. 25cm 2 About 60cm 2 、Approx. 25cm 2 To about 50cm 2 、Approx. 25cm 2 To about 40cm 2 , or about 25cm 2 About 30cm 2 Preferably, the affected area of ​​the subject is about 0.2 cm 2 、About 0.5cm 2 , about 1cm 2 , about 2cm 2 , about 3cm 2 、Approx. 4cm 2 、About 5cm 2 、About 6cm 2 、About 7cm 2 、Approx. 8cm 2 、About 9cm 2 , about 10cm 2 、Approx. 11cm 2 、Approx. 12cm 2 、Approx. 13cm 2 、Approx. 14cm 2 、Approx. 15cm 2 、Approx. 16cm 2 、Approx. 17cm 2 、Approx. 18cm 2 、Approx. 19cm 2 、About 20cm 2 、Approx. 25cm 2 、About 30cm 2 、Approx. 35cm 2 、Approx. 40cm 2 、Approx. 45cm 2 、Approx. 50cm 2 、Approx. 55cm 2 、Approx. 60cm 2 、Approx. 65cm 2 、Approx. 70cm 2 、Approx. 75cm 2 、Approx. 80cm 2 、Approx. 85cm 2 、Approx. 90cm 2 、Approx. 95cm 2 , or about 100cm 2 .

7. The method according to any one of the preceding claims, characterized in that The affected area of ​​the subject was the skin.

8. The method according to any one of the preceding claims, characterized in that The subject's affected area is located at one or more locations independently selected from the following: scalp, forehead, forearm, face, nose, ear, eyelid, lip, neck, arm, hand, trunk, leg and foot.

9. The method according to any one of the preceding claims, characterized in that The 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug is prepared into a pharmaceutical composition suitable for external use.

10. The method according to any one of the preceding claims, characterized in that Based on the total weight of the pharmaceutical composition, the content of the 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug is about 0.025-4% by weight, preferably about 0.05-3% by weight, preferably about 0.2-0.8% by weight, preferably about 0.075% by weight, about 0.1% by weight, about 0.125% by weight, about 0.15% by weight, about 0.175% by weight, about 0.2% by weight, about 0.225% by weight, about 0.25% by weight, about 0.275% by weight, about 0.3% by weight, about 0.325% by weight, about 0.35% by weight, about 0.375% by weight, about 0.4% by weight, about 0.425% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight .45 weight%, about 0.475 weight%, about 0.5 weight%, about 0.525 weight%, about 0.55 weight%, about 0.575 weight%, about 0.6 weight%, about 0.625 weight%, about 0.65 weight%, about 0.675 weight%, about 0.7 weight%, about 0.725 weight%, about 0.75 weight%, about 0.775 weight%, about 0.8 weight%, about 0.825 weight%, about 0.85 weight%, about 0.875 weight%, about 0.9 weight%, about 0.925 weight%, about 0.95 weight%, about 0.975 weight%, about 1 weight%, about 1.25 weight%, about 1.5 weight%, about 1.75 weight%, about 2.0 weight%, about 2.25 weight%, about 2.5 weight%, about 2.75 weight%.

11. The method according to any one of the preceding claims, characterized in that The amount of the pharmaceutical composition applied to the affected skin area is about 0.001 g / cm 2 Skin surface area: about 0.5 g / cm 2 The skin surface area is preferably about 0.0015 g / cm 2 Skin surface area: about 0.2 g / cm 2 Skin surface area; preferably about 0.0015 g / cm 2 Skin surface area: about 0.15 g / cm 2 Skin surface area; preferably about 0.002 g / cm 2 Skin surface area: approximately 0.125 g / cm 2 Skin surface area; preferably about 0.003 g / cm 2 Skin surface area: about 0.1 g / cm 2 Skin surface area; preferably about 0.004 g / cm 2 Skin surface area: about 0.005g / cm 2 Skin surface area: about 0.006 g / cm 2 Skin surface area: about 0.007 g / cm 2 Skin surface area: about 0.008 g / cm 2 Skin surface area: about 0.009 g / cm 2 Skin surface area: about 0.01g / cm 2 Skin surface area: about 0.0125 g / cm 2 Skin surface area: about 0.015 g / cm 2 Skin surface area: about 0.0175 g / cm 2 Skin surface area: about 0.02g / cm 2 Skin surface area: about 0.03g / cm 2 Skin surface area: about 0.04g / cm 2 Skin surface area: about 0.05g / cm 2 Skin surface area: about 0.06g / cm 2 Skin surface area: about 0.07g / cm 2 Skin surface area: about 0.08g / cm 2 Skin surface area: about 0.09g / cm 2 Skin surface area.

12. The method according to any one of the preceding claims, characterized in that 17β-xanthoside B or its pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug is administered every day, every other day, every two days, every three days, every four days, every five days, every six days, or every seven days. Usually, the administration day is administered once, twice, three times, or four times.

13. The method according to any one of the preceding claims, characterized in that The pharmaceutical composition is a gel.

14. The method according to any one of the preceding claims, characterized in that The gel comprises a gel matrix, and the gel matrix is ​​preferably at least one of sodium carboxymethylcellulose, carbomer, gelatin, and alginate, and the content of the gel matrix is ​​about 0.5-5% by weight, preferably about 1-4% by weight, preferably about 1-3% by weight, preferably about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight based on the total weight of the pharmaceutical composition; and / or The gel comprises a humectant, wherein the humectant is at least one selected from alcohol humectants; preferably, the humectant is glycerol, and the content of the humectant is about 5-35% by weight, preferably about 10-30% by weight, preferably about 15-25% by weight, more preferably about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, based on the total weight of the pharmaceutical composition; and / or The gelling agent comprises a solvent; preferably, the solvent is at least one of ethanol, propylene glycol, benzyl alcohol One, more preferably ethanol is 95% ethanol or anhydrous ethanol; based on the total weight of the pharmaceutical composition, the content of the solvent is about 20-75% by weight, preferably about 25-70% by weight, more preferably about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight; and / or The gel comprises water, preferably purified water, distilled water or deionized water, and the content of the water is about 20-75% by weight, preferably about 25-70% by weight, more preferably about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight based on the total weight of the pharmaceutical composition; and / or The gel comprises a permeation enhancer, which is at least one selected from azone, borneol, Tween 80, sodium lauryl sulfate, and poloxamer, more preferably the permeation enhancer is azone or borneol, and based on the total weight of the pharmaceutical composition, the content of the permeation enhancer is about 0-5% by weight; preferably about 0.1-4% by weight; more preferably about 0.25% by weight; about 0.5% by weight; about 0.75% by weight; about 1% by weight; about 1.25% by weight; about 1.5% by weight; about 1.75% by weight; about 2% by weight; about 2.25% by weight; about 2.5% by weight; about 2.75% by weight; about 3% by weight; about 3.25% by weight; about 3.5% by weight; about 3.75% by weight.

15. The method according to any one of the preceding claims, characterized in that The pharmaceutical composition comprises a preservative, and the preservative is a paraben preservative and / or butylated hydroxytoluene; preferably, the paraben preservative is methylparaben and / or ethylparaben. Based on the total weight of the pharmaceutical composition, the content of the preservative is about 0-4 weight %; preferably 0.1-3 weight %; more preferably about 0.25 weight %; about 0.5 weight %; about 0.75 weight %; about 1 weight %; about 1.25 weight %; about 1.5 weight %; about 1.75 weight %; about 2 weight %; about 2.25 weight %; about 2.5 weight %; about 2.75 weight %.

16. The method according to any one of the preceding claims, characterized in that The pharmaceutical composition comprises: About 0.2-0.8% by weight of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof; and / or about 1.5% by weight of a gel matrix; and / or about 40% by weight of a solvent; and / or About 0.5% by weight of a penetration enhancer; and / or about 20% by weight of a humectant; and The remaining amount of water.

17. The method according to any one of the preceding claims, characterized in that Administration of 17β-xanthoside B or a pharmaceutically acceptable salt, racemate, stereoisomer, enantiomer, diastereomer, tautomer, metabolite, solvate, prodrug thereof reduces the number and / or severity of local skin reactions or other adverse side effects in a subject compared to other treatments for actinic keratosis.

18. The method according to any one of the preceding claims, characterized in that The local skin reaction is selected from the group consisting of vesicle formation, pustule formation, erosion, ulceration, redness, swelling, flaking, scaling, lumps, dryness, pus and blisters.