Benvimod solution composition, pharmaceutical preparation containing same, and preparation method and application of Benvimod solution composition

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a benvimod solution composition, a pharmaceutical preparation containing the benvimod solution composition, and a preparation method and application of the benvimod solution composition. The composition comprises benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent and water, and optionally comprises a penetration enhancer, an antioxidant, a bacteriostatic agent, a chelating agent, a pH regulator and a thickening agent. The composition disclosed by the invention can effectively relieve symptoms of inflammatory skin diseases and has an obvious improvement effect on skin injury, so that the composition has excellent drug effect and safety and can also obviously improve the compliance of patients.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a benvimod solution composition, a pharmaceutical preparation containing the same, and a preparation method and application thereof. Background Art

[0002] Psoriasis is a chronic, relapsing, inflammatory, systemic, immune-mediated disease induced by a combination of genetics and the environment. It often presents as localized or widespread scaly erythema or plaques, also known as "psoriasis." The scalp is one of the most commonly affected areas of psoriasis, affecting 45% to 80% of psoriasis patients. Typical lesions are red plaques with well-defined borders and thick scales. These lesions may occur alone on the scalp or coexist with lesions elsewhere on the body. Despite the small surface area of ​​the scalp, the pain caused by scalp psoriasis is disproportionate to the size of the lesions. Due to its intense itching, excessive scaling, and difficulty concealing the lesions, it often causes severe physical discomfort and psychological stress.

[0003] At present, topical medications are still the first-line treatment options for scalp psoriasis recommended by various guidelines and consensus. For patients with scalp psoriasis, due to the obstruction of thick scales and hair, topical medications are difficult to reach the scalp and effectively penetrate, so it is relatively stubborn and difficult to treat. Calcipotriol ointment is currently the first-line topical medication for scalp psoriasis, but it is slow to take effect during treatment and can cause adverse reactions such as skin irritation, erythema, and itching. At the same time, due to the greasy texture, inconvenience in use, and aesthetic impact of conventional topical dosage forms such as creams and ointments, patients have poor satisfaction and compliance with treatment, which brings more challenges to the topical treatment of scalp psoriasis. Therefore, it is still necessary to continuously explore topical treatment methods with excellent efficacy, less adverse effects, and good compliance.

[0004] Benvitimod (also known as benvimod) is the world's first new generation of non-hormonal small molecule chemical drugs for the treatment of inflammatory and autoimmune diseases. Its CAS number is 79338-84-4, and its chemical name is 5-[(E)-2-phenylvinyl]-2-isopropyl-1,3-benzenediol. Its structural formula is as follows:

[0005]

[0006] Benvimod, isolated from a metabolite of a symbiotic bacterium of a soil nematode, is the first therapeutic aryl hydrocarbon receptor modulating agent (TAMA). Pharmacological studies have shown that Benvimod can inhibit the activity of lymphocyte protein tyrosine kinases and has inhibitory effects on the release of inflammatory cytokines, inflammatory cell migration and infiltration, abnormal differentiation and proliferation of keratinocytes, and angiogenesis and vasodilation associated with psoriasis.

[0007] In 2019, Benvimod Cream Approved for marketing in China for the topical treatment of mild to moderate stable psoriasis vulgaris in adults. In 2022, the U.S. FDA officially approved Benvimod Cream. Marketed for the treatment of plaque psoriasis in adults. and With different prescription compositions.

[0008] CN107666902A is The corresponding formulation patent discloses a Benvimod topical medicinal emulsion composition comprising Benvimod, an oil phase, an aqueous phase, a surfactant and an antioxidant, and the composition is formulated into a cream preparation. CN113797159A discloses a Benvimod cream, which comprises Benvimod, an oil-soluble matrix, a solvent, an emulsifier, a preservative, a pH regulator, water, and an optional chelating agent and an optional antioxidant. However, the Benvimod preparations disclosed in the above-mentioned prior art and the marketed products are all cream dosage forms, with a thick texture, obvious greasy feeling, not easy to penetrate the hair stratum corneum, and a small amount of skin retention, which is not conducive to the absorption of the drug and the sustained effect of the drug. CN116723864A discloses a topical pharmaceutical composition comprising Benvimod, wherein the topical pharmaceutical composition is formulated into an aqueous gel, anhydrous gel, ointment or foam. So far, and None of them have been approved for the treatment of scalp psoriasis, and no relevant clinical trials have been conducted. There are also no reports in the art on the targeted development of benvimod into a drug that is particularly suitable for administration to the scalp.

[0009] Therefore, in view of the above-mentioned technical problems, there is an urgent need in this field to develop a stable benvimod solution preparation that is particularly suitable for effectively penetrating the thick stratum corneum of the skin and is not prone to skin irritation, so as to promote drug absorption, improve drug bioavailability, improve patient compliance, and maintain a stable and continuous effect of the drug. Summary of the Invention

[0010] Problems to be solved by the invention

[0011] The present invention aims to provide a solution composition containing benvimod, a pharmaceutical preparation containing the same, and a preparation method and application thereof. The composition is in the form of a clear and transparent aqueous solution, has good fluidity, is easy to apply, has good stability, and takes effect quickly. It has greater skin penetration and skin retention than ordinary creams and ointments, which not only improves bioavailability, but also reduces systemic exposure, effectively increasing medication safety; at the same time, it has a light greasy feeling, low irritation, does not adhere to hair, does not cause itching, is convenient for clinical use, and is particularly suitable for patients with scalp psoriasis with skin lesions such as itching and desquamation, and can significantly improve patient compliance.

[0012] Solutions for solving problems

[0013] In a first aspect, the present invention provides a pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent and water.

[0014] In one embodiment, the pharmaceutical composition of the present invention comprises benvimod, a solubilizer, a solvent and water.

[0015] In the pharmaceutical composition of the present invention, the content of benvimod or its pharmaceutically acceptable salt is 0.1%-10% based on the total weight of the composition.

[0016] In one embodiment, the content of benvimod or a pharmaceutically acceptable salt thereof is 0.1%-5% based on the total weight of the composition.

[0017] In one embodiment, the content of benvimod or its pharmaceutically acceptable salt is 0.5%-4.5% based on the total weight of the composition.

[0018] In one embodiment, the content of benvimod or a pharmaceutically acceptable salt thereof is 1%-4% based on the total weight of the composition.

[0019] In one embodiment, the content of benvimod or its pharmaceutically acceptable salt is 1%-3% based on the total weight of the composition.

[0020] In the pharmaceutical composition of the present invention, the content of the pharmaceutically acceptable salt of benvimod is based on the weight of its free base.

[0021] In one embodiment, in the pharmaceutical composition of the present invention, the content of belimumab is 0.1%-10% based on the total weight of the composition.

[0022] In one embodiment, in the pharmaceutical composition of the present invention, the content of belimumab is 0.1%-5% based on the total weight of the composition.

[0023] In one embodiment, in the pharmaceutical composition of the present invention, the content of belimumab is 0.5%-4.5% based on the total weight of the composition.

[0024] In one embodiment, in the pharmaceutical composition of the present invention, the content of belimumab is 1%-4% based on the total weight of the composition.

[0025] In one embodiment, in the pharmaceutical composition of the present invention, the content of benvimod is 1%-3% based on the total weight of the composition.

[0026] In the pharmaceutical composition of the present invention, the solubilizer is a polyoxyethylene nonionic surfactant with an HLB value of 10-30.

[0027] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene fatty alcohol ethers, polyoxyethylene glycerides, polyoxyethylene castor oil derivatives, polyoxyethylene alkylphenol ethers, polyoxyethylene fatty acid esters, vitamin E succinate polyethylene glycol esters and polyoxyethylene sorbitan fatty acid esters.

[0028] In one embodiment, the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer.

[0029] In one embodiment, the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 2,000-18,000.

[0030] In one embodiment, the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 7,500-15,000.

[0031] In one embodiment, the polyoxyethylene-polyoxypropylene block copolymer is selected from one or more of poloxamers having an average molecular weight of 7,500-10,000 and poloxamers having an average molecular weight of 9,500-15,000.

[0032] In one embodiment, the polyoxyethylene-polyoxypropylene block copolymer is selected from one or more of poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 184, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338, and poloxamer 407.

[0033] In one embodiment, the polyoxyethylene-polyoxypropylene block copolymer is selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407.

[0034] In one embodiment, the polyoxyethylene-polyoxypropylene block copolymer is selected from one or more of poloxamer 188 and poloxamer 407.

[0035] In one embodiment, the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 12-18 and a polyoxyethylene unit number of 10-60.

[0036] In one embodiment, the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 14-18 and a polyoxyethylene unit number of 10-40.

[0037] In one embodiment, the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-30.

[0038] In one embodiment, the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-25.

[0039] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene lauryl alcohol ether, polyoxyethylene oleyl alcohol ether, polyoxyethylene myristyl alcohol ether, polyoxyethylene cetyl alcohol ether, polyoxyethylene stearyl alcohol ether and polyoxyethylene cetearyl alcohol ether.

[0040] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene lauryl alcohol ether having 10-30 polyoxyethylene units, polyoxyethylene oleyl alcohol ether having 10-30 polyoxyethylene units, polyoxyethylene myristyl alcohol ether having 10-30 polyoxyethylene units, polyoxyethylene cetyl alcohol ether having 10-30 polyoxyethylene units, polyoxyethylene stearyl alcohol ether having 10-30 polyoxyethylene units, and polyoxyethylene cetearyl alcohol ether having 10-30 polyoxyethylene units.

[0041] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene lauryl alcohol ether having 10-25 polyoxyethylene units, polyoxyethylene oleyl alcohol ether having 10-25 polyoxyethylene units, polyoxyethylene myristyl alcohol ether having 10-25 polyoxyethylene units, polyoxyethylene cetyl alcohol ether having 10-25 polyoxyethylene units, polyoxyethylene stearyl alcohol ether having 10-25 polyoxyethylene units, and polyoxyethylene cetearyl alcohol ether having 10-25 polyoxyethylene units.

[0042] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene cetyl alcohol ether, polyoxyethylene stearyl alcohol ether and polyoxyethylene cetearyl alcohol ether.

[0043] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene cetyl alcohol ether having 10-30 polyoxyethylene units, polyoxyethylene stearyl alcohol ether having 10-30 polyoxyethylene units, and polyoxyethylene cetearyl alcohol ether having 10-30 polyoxyethylene units.

[0044] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene cetyl alcohol ether having 10-25 polyoxyethylene units, polyoxyethylene stearyl alcohol ether having 10-25 polyoxyethylene units, and polyoxyethylene cetearyl alcohol ether having 10-25 polyoxyethylene units.

[0045] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene stearyl alcohol ether and polyoxyethylene cetearyl alcohol ether.

[0046] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene stearyl alcohol ether having 10-30 polyoxyethylene units and polyoxyethylene cetearyl alcohol ether having 10-30 polyoxyethylene units.

[0047] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene stearyl alcohol ether having 10-25 polyoxyethylene units and polyoxyethylene cetearyl alcohol ether having 10-25 polyoxyethylene units.

[0048] In one embodiment, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether.

[0049] In one embodiment, the polyoxyethylene glyceride is selected from one or more of caprylic capric polyoxyethylene glyceride, lauroyl polyoxyethylene glyceride, linoleoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride and capric polyoxyethylene glyceride.

[0050] In one embodiment, the polyoxyethylene glyceride is selected from one or more of caprylic capric polyoxyethylene glyceride and oleoyl polyoxyethylene glyceride.

[0051] In one embodiment, the polyoxyethylene castor oil derivative is selected from one or more of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil.

[0052] In one embodiment, the polyoxyethylene castor oil derivative is selected from one or more of polyoxyethylene castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units.

[0053] In one embodiment, the polyoxyethylene castor oil derivative is polyoxyethylene hydrogenated castor oil having 30-50 polyoxyethylene units.

[0054] In one embodiment, the polyoxyethylene castor oil derivative is polyoxyethylene hydrogenated castor oil having 30-40 polyoxyethylene units.

[0055] In one embodiment, the polyoxyethylene castor oil derivative is polyoxyethylene 40 hydrogenated castor oil.

[0056] In one embodiment, the polyoxyethylene alkylphenol ether is selected from one or more of nonylphenol polyoxyethylene ether, octylphenol polyoxyethylene ether, dodecylphenol polyoxyethylene ether and dinonylphenol polyoxyethylene ether.

[0057] In one embodiment, the polyoxyethylene alkylphenol ether is octylphenol polyoxyethylene ether having 4 to 50 polyoxyethylene units.

[0058] In one embodiment, the polyoxyethylene alkylphenol ether is octylphenol polyoxyethylene ether having 9 to 40 polyoxyethylene units.

[0059] In one embodiment, the polyoxyethylene alkylphenol ether is selected from one or more of octylphenol ethoxylate-9 and octylphenol ethoxylate-40.

[0060] In one embodiment, the polyoxyethylene fatty acid ester is selected from one or more of polyoxyethylene stearate and polyoxyethylene hydroxystearate.

[0061] In one embodiment, the polyoxyethylene fatty acid ester is selected from one or more of polyoxyethylene stearate having 10-50 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-50 polyoxyethylene units.

[0062] In one embodiment, the polyoxyethylene fatty acid ester is selected from one or more of polyoxyethylene stearate having 30-50 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units.

[0063] In one embodiment, the polyoxyethylene fatty acid ester is selected from one or more of polyoxyethylene 40 stearate and polyoxyethylene 15 hydroxystearate.

[0064] In one embodiment, the vitamin E polyethylene glycol succinate is a vitamin E polyethylene glycol succinate having an average molecular weight of polyethylene glycol of 400-2000.

[0065] In one embodiment, the vitamin E polyethylene glycol succinate is a vitamin E polyethylene glycol succinate having an average molecular weight of polyethylene glycol of 800-1200.

[0066] In one embodiment, the vitamin E polyethylene glycol succinate is vitamin E polyethylene glycol succinate 1000.

[0067] In one embodiment, the polyoxyethylene sorbitan fatty acid ester is a polyoxyethylene sorbitan fatty acid ester having 4 to 20 polyoxyethylene units.

[0068] In one embodiment, the polyoxyethylene sorbitan fatty acid ester is selected from one or more of Tween 20, Tween 40, Tween 60, Tween 65, Tween 80 and Tween 85.

[0069] In one embodiment, the polyoxyethylene sorbitan fatty acid ester is Tween 80.

[0070] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers.

[0071] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 12-18 and a polyoxyethylene unit number of 10-60.

[0072] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 2000-18000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 12-18 and a polyoxyethylene unit number of 10-60.

[0073] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 7500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 14-18 and a polyoxyethylene unit number of 10-40.

[0074] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamers with an average molecular weight of 7500-10000 and poloxamers with an average molecular weight of 9500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-30.

[0075] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamers with an average molecular weight of 7500-10000 and poloxamers with an average molecular weight of 9500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-25.

[0076] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 9500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-30.

[0077] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 9500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-25.

[0078] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 9500-15000, and the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene stearyl alcohol ether having 10-25 polyoxyethylene units and polyoxyethylene cetearyl alcohol ether having 10-25 polyoxyethylene units.

[0079] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, wherein the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 184, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407, and the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether.

[0080] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, wherein the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407, and the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether.

[0081] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamer 188 and poloxamer 407, and the polyoxyethylene fatty alcohol ethers are selected from one or more of polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether.

[0082] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamer 188 and poloxamer 407, and the polyoxyethylene fatty alcohol ether is polyoxyethylene 20 cetearyl alcohol ether.

[0083] In one embodiment, the solubilizer in the pharmaceutical composition of the present invention is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is poloxamer 407, and the polyoxyethylene fatty alcohol ether is polyoxyethylene 20 cetearyl alcohol ether.

[0084] In the pharmaceutical composition of the present invention, the content of the solubilizer is 1%-20% based on the total weight of the composition.

[0085] In one embodiment, the solubilizer is present in an amount of 1% to 15% by weight based on the total weight of the composition.

[0086] In one embodiment, the solubilizer is present in an amount of 2% to 13% by weight based on the total weight of the composition.

[0087] In one embodiment, the solubilizer is present in an amount of 2% to 10% by weight based on the total weight of the composition.

[0088] In the pharmaceutical composition of the present invention, the solvent is selected from one or more of monohydric alcohol, polyhydric alcohol, lower alcohol ether of polyhydric alcohol and polyethylene glycol.

[0089] In one embodiment, the monohydric alcohol is a linear or branched monohydric alcohol containing 2 to 6 carbon atoms.

[0090] In one embodiment, the monohydric alcohol is a linear or branched monohydric alcohol containing 2 to 4 carbon atoms.

[0091] In one embodiment, the monohydric alcohol is a straight chain monohydric alcohol containing 2 to 4 carbon atoms.

[0092] In one embodiment, the monohydric alcohol is selected from one or more of ethanol, isopropanol, n-butanol and tert-butanol.

[0093] In one embodiment, the monohydric alcohol is selected from one or more of ethanol and isopropanol.

[0094] In one embodiment, the polyol is a linear or branched polyol containing 2 to 6 carbon atoms.

[0095] In one embodiment, the polyol is a linear or branched polyol containing 2 to 4 carbon atoms.

[0096] In one embodiment, the polyol is a linear polyol containing 2 to 4 carbon atoms.

[0097] In one embodiment, the polyol is selected from one or more of ethylene glycol, propylene glycol, hexylene glycol, butanediol, pentanediol and glycerol.

[0098] In one embodiment, the polyol is selected from one or more of ethylene glycol, propylene glycol, butylene glycol and glycerol.

[0099] In one embodiment, the polyol is propylene glycol.

[0100] In one embodiment, the lower alcohol ether of the polyol is an ether formed by a linear or branched polyol containing 2 to 6 carbon atoms and a lower alcohol containing 1 to 4 carbon atoms.

[0101] In one embodiment, the lower alcohol ether of the polyol is an ether formed by a linear or branched polyol containing 2 to 4 carbon atoms and a lower alcohol containing 1 to 3 carbon atoms.

[0102] In one embodiment, the lower alcohol ether of the polyol is an ether formed by a linear or branched polyol containing 2 to 4 carbon atoms and a lower alcohol containing 1 to 2 carbon atoms.

[0103] In one embodiment, the lower alcohol ether of the polyol is an ether formed by a linear polyol containing 2 to 4 carbon atoms and a lower alcohol containing 1 to 2 carbon atoms.

[0104] In one embodiment, the lower alcohol ether of the polyol is diethylene glycol monoethyl ether.

[0105] In one embodiment, the polyethylene glycol is polyethylene glycol having an average molecular weight of 200-800.

[0106] In one embodiment, the polyethylene glycol is polyethylene glycol having an average molecular weight of 200-600.

[0107] In one embodiment, the polyethylene glycol is polyethylene glycol having an average molecular weight of 200-400.

[0108] In one embodiment, the polyethylene glycol is selected from one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 500, and polyethylene glycol 600.

[0109] In one embodiment, the polyethylene glycol is polyethylene glycol 400.

[0110] In one embodiment, the solvent in the pharmaceutical composition of the present invention is selected from one or more of polyols and lower alcohol ethers of polyols.

[0111] In one embodiment, the solvent in the pharmaceutical composition of the present invention is selected from one or more of a linear or branched polyol containing 2-6 carbon atoms and an ether formed by a linear or branched polyol containing 2-6 carbon atoms and a lower alcohol containing 1-4 carbon atoms.

[0112] In one embodiment, the solvent in the pharmaceutical composition of the present invention is selected from one or more of a linear or branched polyol containing 2-4 carbon atoms and an ether formed by a linear or branched polyol containing 2-4 carbon atoms and a lower alcohol containing 1-3 carbon atoms.

[0113] In one embodiment, the solvent in the pharmaceutical composition of the present invention is selected from one or more of a linear or branched polyol containing 2-4 carbon atoms and an ether formed by a linear or branched polyol containing 2-4 carbon atoms and a lower alcohol containing 1-2 carbon atoms.

[0114] In one embodiment, the solvent in the pharmaceutical composition of the present invention is selected from one or more of linear polyols containing 2-4 carbon atoms and ethers formed by linear polyols containing 2-4 carbon atoms and lower alcohols containing 1-2 carbon atoms.

[0115] In one embodiment, the solvent in the pharmaceutical composition of the present invention is selected from one or more of propylene glycol and diethylene glycol monoethyl ether.

[0116] In the pharmaceutical composition of the present invention, the content of the solvent is 2%-75% based on the total weight of the composition.

[0117] In one embodiment, the solvent is present in an amount of 5% to 75% by weight based on the total weight of the composition.

[0118] In one embodiment, the solvent is present in an amount of 6% to 65% by weight based on the total weight of the composition.

[0119] In one embodiment, the solvent is present in an amount of 10% to 65% by weight based on the total weight of the composition.

[0120] In the pharmaceutical composition of the present invention, the water that can be used in the present invention is not particularly limited and can be one or more of purified water, distilled water, deionized water and water for injection.

[0121] In the pharmaceutical composition of the present invention, the content of water is 20%-90% based on the total weight of the composition.

[0122] In one embodiment, water is present in an amount of 20% to 85% by weight of the total composition.

[0123] In one embodiment, water is present in an amount of 25% to 80% by weight of the total composition.

[0124] In one embodiment, water is present in an amount of 30% to 80% by weight of the total composition.

[0125] In one embodiment, the present invention provides a pharmaceutical composition according to any one of the following a1) to a8):

[0126] a1) A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent and water; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod or a pharmaceutically acceptable salt thereof is 0.1%-5%, the solubilizer is 1%-20%, the solvent is 2%-75% and the water is 20%-90%.

[0127] a2) A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent and water; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod or a pharmaceutically acceptable salt thereof is 0.5%-4.5%, the solubilizer is 1%-15%, the solvent is 5%-75% and the water is 20%-85%.

[0128] a3) A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent and water; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod or a pharmaceutically acceptable salt thereof is 1%-4%, the solubilizer is 2%-13%, the solvent is 6%-65% and the water is 25%-80%.

[0129] a4) A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent and water; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod or a pharmaceutically acceptable salt thereof is 1%-3%, the solubilizer is 2%-10%, the solvent is 10%-65% and the water is 30%-80%.

[0130] a5) A pharmaceutical composition in the form of a solution, comprising benvimod, a solubilizer, a solvent and water; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod is 0.1%-5%, the solubilizer is 1%-20%, the solvent is 2%-75% and water is 20%-90%.

[0131] a6) A pharmaceutical composition in the form of a solution, comprising benvimod, a solubilizer, a solvent and water; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod is 0.5%-4.5%, the solubilizer is 1%-15%, the solvent is 5%-75% and the water is 20%-85%.

[0132] a7) A pharmaceutical composition in the form of a solution, comprising benvimod, a solubilizer, a solvent and water; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod is 1%-4%, the solubilizer is 2%-13%, the solvent is 6%-65% and water is 25%-80%.

[0133] a8) A pharmaceutical composition in the form of a solution, comprising benvimod, a solubilizer, a solvent and water; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod is 1%-3%, the solubilizer is 2%-10%, the solvent is 10%-65% and water is 30%-80%.

[0134] In one embodiment, the pharmaceutical composition according to any one of a1) to a8), wherein:

[0135] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, and the solvent is selected from one or more of monohydric alcohols, polyols, lower alcohol ethers of polyols and polyethylene glycol.

[0136] In one embodiment, the pharmaceutical composition according to any one of a1) to a8), wherein:

[0137] The solubilizer is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 2000-18000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 12-18 and a polyoxyethylene unit number of 10-60; and the solvent is selected from one or more of a straight-chain or branched monohydric alcohol containing 2-6 carbon atoms, a straight-chain or branched polyhydric alcohol containing 2-6 carbon atoms, an ether formed by a straight-chain or branched polyhydric alcohol containing 2-6 carbon atoms and a lower alcohol containing 1-4 carbon atoms, and polyethylene glycol having an average molecular weight of 200-800.

[0138] In one embodiment, the pharmaceutical composition according to any one of a1) to a8), wherein:

[0139] The solubilizer is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 7500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 14-18 and a polyoxyethylene unit number of 10-40; and the solvent is selected from one or more of a straight-chain or branched monohydric alcohol containing 2-6 carbon atoms, a straight-chain or branched polyhydric alcohol containing 2-6 carbon atoms, an ether formed by a straight-chain or branched polyhydric alcohol containing 2-6 carbon atoms and a lower alcohol containing 1-4 carbon atoms, and polyethylene glycol having an average molecular weight of 200-600.

[0140] In one embodiment, the pharmaceutical composition according to any one of a1) to a8), wherein:

[0141] The solubilizer is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 7500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-30; and the solvent is selected from one or more of a straight-chain or branched monohydric alcohol containing 2-4 carbon atoms, a straight-chain or branched polyhydric alcohol containing 2-4 carbon atoms, an ether formed by a straight-chain or branched polyhydric alcohol containing 2-4 carbon atoms and a lower alcohol containing 1-3 carbon atoms, and polyethylene glycol having an average molecular weight of 200-400.

[0142] In one embodiment, the pharmaceutical composition according to any one of a1) to a8), wherein:

[0143] The solubilizer is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 7500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-25; and the solvent is selected from one or more of a straight-chain or branched monohydric alcohol containing 2-4 carbon atoms, a straight-chain or branched polyhydric alcohol containing 2-4 carbon atoms, an ether formed by a straight-chain or branched polyhydric alcohol containing 2-4 carbon atoms and a lower alcohol containing 1-2 carbon atoms, and polyethylene glycol having an average molecular weight of 200-400.

[0144] In one embodiment, the pharmaceutical composition according to any one of a1) to a8), wherein:

[0145] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamers with an average molecular weight of 7500-10000 and poloxamers with an average molecular weight of 9500-15000, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene stearyl alcohol ether with 10-25 polyoxyethylene units and polyoxyethylene cetearyl alcohol ether with 10-25 polyoxyethylene units; and the solvent is selected from one or more of linear polyols containing 2-4 carbon atoms and ethers formed by linear polyols containing 2-4 carbon atoms and lower alcohols containing 1-2 carbon atoms.

[0146] In one embodiment, the pharmaceutical composition according to any one of a1) to a8), wherein:

[0147] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether; the solvent is selected from one or more of propylene glycol and diethylene glycol monoethyl ether.

[0148] In one embodiment, the pharmaceutical composition according to any one of a1) to a8), wherein:

[0149] The solubilizer is selected from one or more of poloxamer 188, poloxamer 407, polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether, and the solvent is selected from one or more of propylene glycol and diethylene glycol monoethyl ether.

[0150] Those skilled in the art will appreciate that the pharmaceutical composition described above is sufficient to achieve the purpose of the present invention. In the pharmaceutical composition of the present invention, in addition to bevimod or its pharmaceutically acceptable salt, solubilizer, solvent and water, the pharmaceutical composition of the present invention may also contain other pharmaceutically acceptable excipients. Other pharmaceutically acceptable excipients are not essential components of the pharmaceutical composition and are only added as needed.

[0151] In one embodiment, the other pharmaceutically acceptable excipient is a penetration enhancer.

[0152] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of fatty alcohols and fatty acid esters.

[0153] In one embodiment, the fatty alcohol is selected from one or more of a linear fatty alcohol containing 6 to 14 carbon atoms and a branched fatty alcohol containing 12 to 20 carbon atoms.

[0154] In one embodiment, the fatty alcohol is selected from one or more of octanol, decanol, octyldecanol, lauryl alcohol, and octyldodecanol.

[0155] In one embodiment, the fatty alcohol is octyldodecanol.

[0156] In one embodiment, the fatty acid ester is selected from one or more of fatty acid monoalcohol esters, fatty acid diol esters, and fatty acid glycerides.

[0157] In one embodiment, the fatty acid monoalcohol ester is a fatty acid ester formed by esterifying a monoalcohol containing 2 to 4 carbon atoms with a fatty acid containing 2 to 18 carbon atoms.

[0158] In one embodiment, the fatty acid monohydric alcohol ester is selected from one or more of ethyl oleate, isopropyl myristate, isopropyl palmitate, diisopropyl oxalate, isopropyl stearate and isopropyl laurate.

[0159] In one embodiment, the fatty acid glycol ester is a fatty acid ester formed by esterifying a glycol containing 2 to 4 carbon atoms with a fatty acid containing 2 to 18 carbon atoms.

[0160] In one embodiment, the fatty acid glycol ester is a fatty acid ester formed by esterifying a glycol containing 2 to 4 carbon atoms with a fatty acid containing 6 to 16 carbon atoms.

[0161] In one embodiment, the fatty acid glycol ester is a fatty acid ester formed by esterifying a glycol containing 2 to 4 carbon atoms with a fatty acid containing 8 to 12 carbon atoms.

[0162] In one embodiment, the fatty acid glycol ester is a fatty acid ester in which one hydroxyl group of a glycol containing 2 to 4 carbon atoms is esterified with a fatty acid containing 8 to 12 carbon atoms.

[0163] In one embodiment, the fatty acid glycol ester is selected from one or more of propylene glycol caprylate, propylene glycol monocaprylate, and propylene glycol monolaurate.

[0164] In one embodiment, the fatty acid glycol ester is selected from one or more of propylene glycol monocaprylate and propylene glycol monolaurate.

[0165] In one embodiment, the fatty acid glyceride is selected from one or more of fatty acid monoglyceride, fatty acid diglyceride and fatty acid triglyceride, and one or more hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 2-18 carbon atoms.

[0166] In one embodiment, the fatty acid glyceride is selected from one or more of fatty acid monoglyceride and fatty acid diglyceride, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 2 to 18 carbon atoms.

[0167] In one embodiment, the fatty acid glyceride is selected from one or more of fatty acid monoglyceride and fatty acid diglyceride, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 6 to 16 carbon atoms.

[0168] In one embodiment, the fatty acid glyceride is selected from one or more of fatty acid monoglyceride and fatty acid diglyceride, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 8 to 12 carbon atoms.

[0169] In one embodiment, the fatty acid glyceride is selected from one or more of monocaprylic glyceride, monocapric glyceride, dicaprylic glyceride, dicaprylic glyceride, caprylic capric glyceride, monooleic glyceride, monolinoleic glyceride, medium chain triglycerides, and caprylic capric mono- and di-glycerides.

[0170] In one embodiment, the fatty acid glyceride is selected from one or more of monocaprylic glyceride, monocapric glyceride, dicaprylic glyceride, dicapric glyceride, caprylic capric glyceride, monooleic glyceride, monolinoleic glyceride and caprylic capric mono- and di-glycerides.

[0171] In one embodiment, the fatty acid glyceride is selected from one or more of monocaprylic glyceride, monocapric glyceride, dicaprylic glyceride, dicapric glyceride, caprylic capric glyceride, and caprylic capric mono- and di-glycerides.

[0172] In one embodiment, the fatty acid glyceride is caprylic and capric mono- and di-glycerides.

[0173] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of fatty acid glycol esters and fatty acid glycerides.

[0174] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of fatty acid diol esters, fatty acid monoglycerides, and fatty acid diglycerides.

[0175] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of fatty acid diol esters and fatty acid glycerides, wherein the fatty acid diol ester is a fatty acid ester formed by esterifying a diol containing 2 to 4 carbon atoms with a fatty acid containing 2 to 18 carbon atoms, and the fatty acid glyceride is selected from one or more of fatty acid monoglyceride and fatty acid diglyceride, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 2 to 18 carbon atoms.

[0176] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of fatty acid diol esters and fatty acid glycerides, wherein the fatty acid diol ester is a fatty acid ester formed by esterifying a diol containing 2 to 4 carbon atoms with a fatty acid containing 6 to 16 carbon atoms, and the fatty acid glyceride is selected from one or more of fatty acid monoglyceride and fatty acid diglyceride, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 6 to 16 carbon atoms.

[0177] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of fatty acid diol esters and fatty acid glycerides, wherein the fatty acid diol ester is a fatty acid ester formed by esterifying a diol containing 2 to 4 carbon atoms with a fatty acid containing 8 to 12 carbon atoms, and the fatty acid glyceride is selected from one or more of fatty acid monoglyceride and fatty acid diglyceride, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 8 to 12 carbon atoms.

[0178] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of propylene glycol caprylate, propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monocaprylate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl dicaprylate, glyceryl dicaprylate, glyceryl caprylate, glyceryl monooleate, glyceryl monolinoleate and glyceryl caprylate mono- and di-caprylate.

[0179] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monocaprylate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl dicaprate, caprylic capric glyceride and caprylic capric mono- and di-glycerides.

[0180] In one embodiment, the penetration enhancer in the pharmaceutical composition of the present invention is selected from one or more of propylene glycol monocaprylate, propylene glycol monolaurate, and caprylic and capric mono- and diglycerides.

[0181] In the pharmaceutical composition of the present invention, the content of the penetration enhancer is 0-25% based on the total weight of the composition.

[0182] In one embodiment, the penetration enhancer is present in an amount of 2% to 20% by weight based on the total weight of the composition.

[0183] In one embodiment, the penetration enhancer is present in an amount of 2% to 15% by weight based on the total weight of the composition.

[0184] In one embodiment, the penetration enhancer is present in an amount of 2% to 10% by weight based on the total weight of the composition.

[0185] In one embodiment, the present invention provides a pharmaceutical composition according to any one of the following b1) to b8):

[0186] b1) A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent, water and a penetration enhancer; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod or a pharmaceutically acceptable salt thereof is 0.5%-4.5%, the solubilizer is 2%-10%, the solvent is 10%-65%, the water is 30%-80% and the penetration enhancer is 0-25%.

[0187] b2) A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent, water and a penetration enhancer; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod or a pharmaceutically acceptable salt thereof is 0.5%-4.5%, the solubilizer is 2%-10%, the solvent is 10%-65%, the water is 30%-80% and the penetration enhancer is 2%-20%.

[0188] b3) A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent, water and a penetration enhancer; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod or a pharmaceutically acceptable salt thereof is 0.5%-4.5%, the solubilizer is 2%-10%, the solvent is 10%-65%, the water is 30%-80% and the penetration enhancer is 2%-15%.

[0189] b4) A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent, water and a penetration enhancer; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod or a pharmaceutically acceptable salt thereof is 0.5%-4.5%, the solubilizer is 2%-10%, the solvent is 10%-65%, the water is 30%-80% and the penetration enhancer is 2%-10%.

[0190] b5) A pharmaceutical composition in the form of a solution, comprising benvimod, a solubilizer, a solvent, water and a penetration enhancer; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod is 0.5%-4.5%, the solubilizer is 2%-10%, the solvent is 10%-65%, the water is 30%-80% and the penetration enhancer is 0%-25%.

[0191] b6) A pharmaceutical composition in the form of a solution, comprising benvimod, a solubilizer, a solvent, water and a penetration enhancer; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod is 0.5%-4.5%, the solubilizer is 2%-10%, the solvent is 10%-65%, the water is 30%-80% and the penetration enhancer is 2%-20%.

[0192] b7) A pharmaceutical composition in the form of a solution, comprising benvimod, a solubilizer, a solvent, water and a penetration enhancer; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod is 0.5%-4.5%, the solubilizer is 2%-10%, the solvent is 10%-65%, the water is 30%-80% and the penetration enhancer is 2%-15%.

[0193] b8) A pharmaceutical composition in the form of a solution, comprising benvimod, a solubilizer, a solvent, water and a penetration enhancer; wherein, based on the total weight of the composition, the weight percentages of the components are as follows: benvimod is 0.5%-4.5%, the solubilizer is 2%-10%, the solvent is 10%-65%, the water is 30%-80% and the penetration enhancer is 2%-10%.

[0194] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0195] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the solvent is selected from one or more of monohydric alcohols, polyols, lower alcohol ethers of polyols and polyethylene glycol, and the penetration enhancer is selected from one or more of fatty alcohols and fatty acid esters.

[0196] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0197] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the solvent is selected from one or more of monohydric alcohols, polyols, lower alcohol ethers of polyols and polyethylene glycol, and the penetration enhancer is selected from one or more of fatty acid diol esters and fatty acid glycerides.

[0198] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0199] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the solvent is selected from one or more of monohydric alcohols, polyhydric alcohols, lower alcohol ethers of polyhydric alcohols and polyethylene glycol, the penetration enhancer is selected from one or more of fatty acid diol esters and fatty acid glycerides, and the fatty acid glycerides are selected from one or more of fatty acid monoglycerides and fatty acid diglycerides.

[0200] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0201] The solubilizer is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 2000-18000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 12-18 and a polyoxyethylene unit number of 10-60; the solvent is selected from a linear or branched monohydric alcohol containing 2-6 carbon atoms, a linear or branched polyhydric alcohol containing 2-6 carbon atoms, a linear or branched polyhydric alcohol containing 2-6 carbon atoms and a polyhydric alcohol containing 1-4 carbon atoms. The invention relates to a novel nanostructured carbon nanotube-forming agent comprising: a nanostructured carbon nanotube-forming agent, a nanostructured carbon nanotube-forming agent, and a nanostructured carbon nanotube-forming agent. The nanostructured carbon nanotube-forming agent comprises ...

[0202] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0203] The solubilizer is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 7500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 14-18 and a polyoxyethylene unit number of 10-40; the solvent is selected from a linear or branched monohydric alcohol containing 2-6 carbon atoms, a linear or branched polyhydric alcohol containing 2-6 carbon atoms, a linear or branched polyhydric alcohol containing 2-6 carbon atoms and a polyhydric alcohol containing 1-4 carbon atoms. The invention relates to a novel nanostructured carbon nanotube-forming agent comprising: a nanostructured carbon nanotube-forming agent, a nanostructured carbon nanotube-forming agent, and a nanostructured carbon nanotube-forming agent. The nanostructured carbon nanotube-forming agent comprises ...

[0204] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0205] The solubilizer is selected from one or more of a polyoxyethylene-polyoxypropylene block copolymer and a polyoxyethylene fatty alcohol ether, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 7500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-30; the solvent is selected from a linear or branched monohydric alcohol containing 2-4 carbon atoms, a linear or branched polyhydric alcohol containing 2-4 carbon atoms, a linear or branched polyhydric alcohol containing 2-4 carbon atoms and a polyhydric alcohol containing 1-3 The invention relates to a novel nanostructured carbon nanotube-forming agent comprising: a nanostructured carbon nanotube-forming agent, a nanostructured carbon nanotube-forming agent, and a nanostructured carbon nanotube-forming agent. The nanostructured carbon nanotube-forming agent comprises ...

[0206] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0207] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, wherein the polyoxyethylene-polyoxypropylene block copolymer is a poloxamer having an average molecular weight of 7500-15000, and the polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-25; the solvent is selected from a linear or branched monohydric alcohol containing 2-4 carbon atoms, a linear or branched polyhydric alcohol containing 2-4 carbon atoms, a linear or branched polyhydric alcohol containing 2-4 carbon atoms and a linear or branched polyhydric alcohol containing 1-3 The invention relates to a novel nanostructured carbon nanotube-forming agent comprising: a nanostructured carbon nanotube-forming agent, a nanostructured carbon nanotube-forming agent, and a nanostructured carbon nanotube-forming agent. The nanostructured carbon nanotube-forming agent comprises ...

[0208] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0209] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamers with an average molecular weight of 7500-10000 and poloxamers with an average molecular weight of 9500-15000, the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene stearyl alcohol ethers with 10-25 polyoxyethylene units and polyoxyethylene cetearyl alcohol ethers with 10-25 polyoxyethylene units; the solvent is selected from a linear polyol containing 2-4 carbon atoms. and one or more ethers formed by a straight-chain polyol containing 2-4 carbon atoms and a lower alcohol containing 1-2 carbon atoms; the penetration enhancer is selected from one or more of fatty acid diol esters and fatty acid glycerides, wherein the fatty acid diol ester is a fatty acid ester formed by esterifying a diol containing 2-4 carbon atoms with a fatty acid containing 8-12 carbon atoms, the fatty acid glyceride is selected from one or more of fatty acid monoglyceride and fatty acid diglyceride, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 8-12 carbon atoms.

[0210] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0211] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407, and the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether; the solvent is selected from one or more of propylene glycol and diethylene glycol monoethyl ether; the penetration enhancer is selected from one or more of propylene glycol caprylate, propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monocaprylate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl dicaprylate, glyceryl dicaprylate, glyceryl caprylate, glyceryl monooleate, glyceryl monolinoleate and glyceryl caprylate mono- and di-glycerides.

[0212] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0213] The solubilizer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers, the polyoxyethylene-polyoxypropylene block copolymers are selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and poloxamer 407, and the polyoxyethylene fatty alcohol ether is selected from one or more of polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether; the solvent is selected from one or more of propylene glycol and diethylene glycol monoethyl ether; the penetration enhancer is selected from one or more of propylene glycol monocaprylate, propylene glycol monolaurate, glyceryl monocaprylate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl dicaprylate, glyceryl dicaprylate, glyceryl caprylate and glyceryl caprylate mono- and diglycerides.

[0214] In one embodiment, the pharmaceutical composition according to any one of b1) to b8), wherein:

[0215] The solubilizer is selected from one or more of poloxamer 188, poloxamer 407, polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether, the solvent is selected from one or more of propylene glycol and diethylene glycol monoethyl ether, and the penetration enhancer is selected from one or more of propylene glycol monocaprylate, propylene glycol monolaurate and caprylic and capric mono- and diglycerides.

[0216] In the pharmaceutical composition of the present invention, the other pharmaceutically acceptable excipients also include one or more of conventional mucosal adhesives, pH regulators, antioxidants, osmotic pressure regulators, antibacterial agents (or preservatives), chelating agents and thickeners in the art.

[0217] In one embodiment, the other pharmaceutically acceptable excipients further include one or more of an antioxidant, a bacteriostat, a chelating agent, a pH adjuster, and a thickener.

[0218] In one embodiment, the antioxidant in the pharmaceutical composition of the present invention is selected from one or more synthetic antioxidants such as butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, L-ascorbyl palmitate, ethoxyquinoline, sodium metabisulfite, and dilauryl thiodipropionate, and natural antioxidants such as tea polyphenols, tocopherol, cysteine, and grape seed extract.

[0219] In one embodiment, the antioxidant in the pharmaceutical composition of the present invention is selected from one or more synthetic antioxidants such as butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, L-ascorbyl palmitate, ethoxyquinoline, sodium metabisulfite, and dilauryl thiodipropionate, and natural antioxidants such as tea polyphenols, tocopherol, and grape seed extract.

[0220] In one embodiment, the antioxidant in the pharmaceutical composition of the present invention is selected from one or more of butylated hydroxyanisole and butylated hydroxytoluene, preferably butylated hydroxyanisole.

[0221] In the pharmaceutical composition of the present invention, the content of the antioxidant is 0-2% based on the total weight of the composition.

[0222] In one embodiment, the antioxidant is present in an amount of 0.01% to 1% by weight based on the total weight of the composition.

[0223] In one embodiment, the antioxidant is present in an amount of 0.05% to 0.5% by weight based on the total weight of the composition.

[0224] In one embodiment, the antioxidant is present in an amount of 0.1% to 0.2% by weight based on the total weight of the composition.

[0225] In one embodiment, the antibacterial agent in the pharmaceutical composition of the present invention is selected from one or more of benzyl alcohol, phenoxyethanol, sorbic acid or its salts (e.g., potassium sorbate), parahydroxybenzoates (also known as parabens, such as methylparaben, ethylparaben, propylparaben, butylparaben, etc.), benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salts (e.g., sodium benzoate), citric acid or its salts (e.g., sodium citrate), and ascorbic acid or its salts (e.g., sodium ascorbate).

[0226] In one embodiment, the bacteriostatic agent in the pharmaceutical composition of the present invention is benzoic acid.

[0227] In the pharmaceutical composition of the present invention, the content of the antibacterial agent is 0-2% based on the total weight of the composition.

[0228] In one embodiment, the content of the bacteriostatic agent is 0.01% to 1% based on the total weight of the composition.

[0229] In one embodiment, the content of the bacteriostatic agent is 0.1% to 0.5% based on the total weight of the composition.

[0230] In one embodiment, the content of the bacteriostatic agent is 0.2% to 0.4% based on the total weight of the composition.

[0231] In one embodiment, the chelating agent in the pharmaceutical composition of the present invention is selected from one or more of citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, edetic acid or its derivatives (preferably edetic acid or its salts, such as disodium edetate) and phosphonates.

[0232] In one embodiment, the chelating agent in the pharmaceutical composition of the present invention is edetate disodium.

[0233] In the pharmaceutical composition of the present invention, the content of the chelating agent is 0-2% based on the total weight of the composition.

[0234] In one embodiment, the chelating agent is present in an amount of 0.01% to 1% by weight of the total composition.

[0235] In one embodiment, the chelating agent is present in an amount of 0.05% to 0.5% by weight based on the total weight of the composition.

[0236] In one embodiment, the chelating agent is present in an amount of 0.1% to 0.2% by weight of the total composition.

[0237] In one embodiment, the pH adjuster in the pharmaceutical composition of the present invention is a conventional pH adjuster in the art, which is selected from one or more of inorganic or organic acids, inorganic or organic bases and buffer salts.

[0238] In one embodiment, the acid in the pharmaceutical composition of the present invention is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, citric acid, lactic acid and boric acid.

[0239] In one embodiment, the base in the pharmaceutical composition of the present invention is selected from one or more of ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide and aqueous ammonia solution.

[0240] In one embodiment, the buffer salt in the pharmaceutical composition of the present invention is selected from one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphate-sodium phosphate buffer salt, citric acid-disodium hydrogen phosphate buffer salt and acetic acid-sodium acetate buffer salt.

[0241] In one embodiment, the buffer salt in the pharmaceutical composition of the present invention is selected from one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphate-sodium phosphate buffer salt and acetic acid-sodium acetate buffer salt.

[0242] In one embodiment, the pH adjusting agent in the pharmaceutical composition of the present invention is a buffer salt.

[0243] In one embodiment, the pH adjuster in the pharmaceutical composition of the present invention is citric acid-sodium citrate buffer salt.

[0244] In the pharmaceutical composition of the present invention, the content of the pH regulator is 0-2% based on the total weight of the composition.

[0245] In one embodiment, the pH adjuster is present in an amount of 0.01% to 1% by weight based on the total weight of the composition.

[0246] In one embodiment, the pH adjuster is present in an amount of 0.1% to 0.5% by weight based on the total weight of the composition.

[0247] In one embodiment, the pH adjuster is present in an amount of 0.2% to 0.3% by weight based on the total weight of the composition.

[0248] In one embodiment, the thickening agent in the pharmaceutical composition of the present invention is selected from one or more of xanthan gum, carbomer, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium hyaluronate (also known as sodium hyaluronate), polyvinyl alcohol, xyloglucan, povidone, hydroxyethyl cellulose, gellan gum and sodium alginate.

[0249] In one embodiment, the thickening agent in the pharmaceutical composition of the present invention is selected from one or more of povidone, xanthan gum, carbomer, hydroxypropyl methylcellulose, sodium alginate and sodium hyaluronate.

[0250] In one embodiment, the thickening agent in the pharmaceutical composition of the present invention is selected from one or more of povidone, xanthan gum, carbomer, sodium alginate and sodium hyaluronate.

[0251] In one embodiment, the thickening agent in the pharmaceutical composition of the present invention is selected from one or more of xanthan gum, carbomer, sodium alginate and sodium hyaluronate.

[0252] In one embodiment, the thickening agent in the pharmaceutical composition of the present invention is selected from one or more of xanthan gum and carbomer.

[0253] In the pharmaceutical composition of the present invention, the content of the thickener is 0-5% based on the total weight of the composition.

[0254] In one embodiment, the thickener is present in an amount of 0.05% to 5% by weight based on the total weight of the composition.

[0255] In one embodiment, the thickener is present in an amount of 0.05% to 2% by weight based on the total weight of the composition.

[0256] In one embodiment, the thickener is present in an amount of 0.1% to 1.5% by weight based on the total weight of the composition.

[0257] In one embodiment, the pharmaceutical composition of the present invention comprises benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent, water, an optional penetration enhancer, an optional antioxidant, an optional bacteriostat, an optional pH adjuster, an optional chelating agent, and an optional thickening agent.

[0258] In one embodiment, the pharmaceutical composition of the present invention consists of benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent, water, an optional penetration enhancer, an optional antioxidant, an optional bacteriostat, an optional pH adjuster, an optional chelating agent and an optional thickening agent.

[0259] In the pharmaceutical composition of the present invention, the suitable pH range of the composition is 4.0-6.5.

[0260] In one embodiment, the composition has a suitable pH range of 4.5-6.5.

[0261] In one embodiment, the composition has a suitable pH range of 5.0-6.5.

[0262] In one embodiment, the composition has a suitable pH range of 4.5-5.5.

[0263] In a second aspect, the present invention provides a method for preparing the pharmaceutical composition in the form of a bevimod solution as described in the first aspect, comprising the following steps:

[0264] Benvimod or a pharmaceutically acceptable salt thereof, a solubilizer, a solvent, water, an optional penetration enhancer, an optional antioxidant, an optional antibacterial agent, an optional pH regulator, an optional chelating agent and an optional thickener are mixed uniformly to prepare a pharmaceutical composition in the form of a Benvimod solution.

[0265] In one embodiment, the order of mixing is: first mix the solubilizer, solvent, water, optional penetration enhancer, optional antioxidant, optional antibacterial agent and optional thickener, then add benvimod or its pharmaceutically acceptable salt and mix evenly, and finally add the optional pH adjuster and optional chelating agent and mix evenly to obtain a pharmaceutical composition in the form of a benvimod solution.

[0266] In one embodiment, the order of mixing is: first mix the solubilizer, solvent, optional penetration enhancer, optional antioxidant, optional antibacterial agent and optional thickener, then add benvimod or its pharmaceutically acceptable salt and mix evenly, and finally add water, optional pH adjuster and optional chelating agent and mix evenly to obtain a pharmaceutical composition in the form of benvimod solution.

[0267] In one embodiment, the mixing is performed under heating, for example, by heating in a water bath.

[0268] In one embodiment, the mixing temperature is 0-90°C, preferably 30-70°C, most preferably 40-60°C.

[0269] In one embodiment, the mixing method is stirring, ultrasonication, homogenization or microfluidization, preferably stirring.

[0270] In one embodiment, the mixing method is a stirring method under heating in a water bath at 40-60°C.

[0271] In a third aspect, the present invention further provides a pharmaceutical preparation for external use in the form of a solution, which comprises the pharmaceutical composition in the form of a solution of belimumab described in the first aspect.

[0272] The pharmaceutical composition of the present invention is directly applied to the affected area, and can also be prepared into other pharmaceutical dosage forms for external use. Therefore, the present invention also provides an external use pharmaceutical preparation comprising the aforementioned belimumab pharmaceutical composition, such as a liniment, a spray, a film, a soft patch, a cataplasm, etc.

[0273] In a fourth aspect, the present invention further provides the medical use of the pharmaceutical composition in the form of a bevimod solution described in the first aspect or the external pharmaceutical preparation in the form of a solution described in the third aspect.

[0274] First, the present invention provides the use of the pharmaceutical composition in the form of a belimumab solution described in the first aspect or the external pharmaceutical preparation in the form of a solution described in the third aspect in the preparation of a drug for preventing and / or treating inflammatory skin diseases.

[0275] Secondly, the present invention provides the pharmaceutical composition in the form of a bevimod solution described in the first aspect or the external pharmaceutical preparation in the form of a solution described in the third aspect, which is used for preventing and / or treating inflammatory skin diseases.

[0276] Again, the present invention provides a method for preventing and / or treating inflammatory skin diseases, which comprises: applying the pharmaceutical composition in the form of a belimumab solution described in the first aspect or the external pharmaceutical preparation in the form of a solution described in the third aspect to an individual in need thereof.

[0277] In one embodiment, the inflammatory skin disease of the present invention is selected from one or more of psoriasis (e.g., scalp psoriasis), eczema (e.g., childhood eczema), palmoplantar pustulosis, atopic dermatitis, contact dermatitis, seborrheic dermatitis, acne, rosacea, hair follicle syndrome, and herpes.

[0278] In one embodiment, the inflammatory skin disease of the present invention is scalp psoriasis or childhood eczema.

[0279] In one embodiment, the inflammatory skin disease of the present invention is scalp psoriasis.

[0280] Effects of the Invention

[0281] The pharmaceutical composition of the present invention in the form of a bevimod solution is clear, transparent and thermodynamically stable. The solution can improve the solubility of the drug, reduce skin irritation and promote the continuous penetration of the drug through the stratum corneum.

[0282] The pharmaceutical composition of the present invention in the form of a solution of Benvimod has excellent physical and chemical stability. The solution contains only less than 1% impurities, or less than 0.5% impurities, or less than 0.2% impurities, or less than 0.1% impurities after storage for at least 1 week, or at least 2 weeks, or at least 1 month, or at least 3 months, or at least 4 months, or at least 6 months, or at least 9 months, or at least 12 months. After storage at 60°C for at least one week, at least two weeks, at least one month, or at least 4 months, the content of a single impurity in the solution composition is less than about 0.3% by weight, or less than about 0.2% by weight, and the content of total impurities is less than about 2% by weight, or less than about 1% by weight, or less than about 0.8% by weight, or less than about 0.6% by weight, or less than about 0.4% by weight.

[0283] The pharmaceutical composition of the present invention in the form of a bevimod solution has good in vitro release effect and skin permeability, as well as extremely low systemic exposure, and therefore has excellent efficacy and safety.

[0284] The pharmaceutical composition of the present invention in the form of a bevimod solution can effectively relieve the symptoms of inflammatory skin diseases and has a significant improvement effect on skin damage. The solution composition has a PASI score of skin lesion severity in a psoriasis mouse model compared to and All showed statistical differences in efficacy and had better therapeutic effects.

[0285] The pharmaceutical composition of the present invention in the form of a bevimod solution has good fluidity, a light greasy feeling, low irritation, does not adhere to hair, does not cause itching, is convenient for clinical use, and is particularly suitable for patients with scalp psoriasis accompanied by skin lesions such as itching and desquamation, and can significantly improve patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0286] Figure 1 This is the PASI score change curve of the skin lesion severity of mice in Example 10. DETAILED DESCRIPTION

[0287] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior or preferred over other embodiments.

[0288] In addition, numerous specific details are provided in the following detailed description to better illustrate the present invention. Those skilled in the art will appreciate that the present invention can be practiced without certain specific details. In other instances, methods, means, equipment, and steps well known to those skilled in the art are not described in detail in order to highlight the main points of the present invention.

[0289] Unless otherwise stated, the units used in this specification are international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0290] In this specification, the use of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0291] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "embodiments," etc., mean that the specific elements (e.g., features, structures, properties, and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0292] the term

[0293] Unless otherwise specified, in the present invention, a numerical range expressed using "value A - value B" means a range including the endpoints A and B.

[0294] Unless otherwise stated, in the present invention, "optional" means that the listed components can be selected (if there are multiple listed components, one of them can be selected or multiple components can be selected), or the listed components can be not selected.

[0295] In the present invention, when "normal temperature" or "room temperature" is used, the temperature may be 10-40°C, or 10-30°C or 15-30°C, for example, 25°C.

[0296] Unless otherwise specified, the term "surfactant" in the present invention refers to a substance with strong surface activity that can (significantly) reduce the surface tension of a liquid. Surfactants can have properties such as solubilization, emulsification, wetting, and decontamination. The molecular structure of a surfactant is generally composed of a hydrophilic group and a hydrophobic group, wherein the hydrophilic group is usually a polar group, which can be, for example, a carboxylic acid, sulfonic acid, sulfuric acid, an amino group or an amine group and its salt, hydroxyl group, amide group, ether bond, etc.; the hydrophobic group is usually a non-polar hydrocarbon chain, generally with a length of more than 8 carbon atoms. According to the structural type, surfactants can be divided into four major categories: cationic surfactants, anionic surfactants, nonionic surfactants, and zwitterionic surfactants. Among them, nonionic surfactants will not dissociate in water, and their molecular structure includes a hydrophilic group and a hydrophobic group. The hydrophilic group can be selected from one or more of polyethylene glycol and polyols, and the hydrophobic group can be selected from one or more of fatty acids, fatty alcohols, phenols, alkylphenols, alkylamines, etc. The hydrophilic group and the hydrophobic group are bound by ester bonds or ether bonds. According to the structural type of the hydrophilic group, nonionic surfactants can be further divided into polyoxyethylene type (or polyethylene glycol type) and polyol type.

[0297] Unless otherwise indicated, the term "HLB" as used herein refers to the hydrophile-lipophile balance, which is an indicator of the degree of hydrophilicity or lipophilicity of a molecule or group. The contribution of each group in a molecule to the HLB value can be expressed numerically (i.e., group number). The HLB value of a surfactant can be considered the sum of the contributions of the various structural groups in the molecule. The HLB value of a surfactant can be obtained by consulting conventional textbooks in this field (e.g., "Pharmaceutics," edited by Bi Dianzhou, 4th edition) or technical manuals (e.g., "Handbook of Pharmaceutical Excipients," Raymond C Rowe et al., 6th edition).

[0298] Unless otherwise specified, the term "polyoxyethylene-polyoxypropylene block copolymer" or "poloxamer" in the present invention refers to a polyoxyethylene type nonionic surfactant formed by copolymerization of polyoxyethylene and polyoxypropylene, with a molecular weight of HO(C2H4O) a (C3H6O) b (C2H4O) aH, wherein the polyoxyethylene segment is hydrophilic and the polyoxypropylene segment is hydrophobic. Depending on the copolymerization ratio of polyoxyethylene to polyoxypropylene, poloxamers can have different average molecular weights and are classified into various types, including but not limited to poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 184, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338, and poloxamer 407.

[0299] Unless otherwise specified, the term "polyoxyethylene fatty alcohol ether" in the present invention refers to a polyoxyethylene nonionic surfactant formed by etherifying polyethylene glycol with a linear long-chain fatty alcohol. The number of polyoxyethylene units ranges from 2 to 100, with a typical value of 10 to 60. The long-chain fatty alcohol can be saturated (e.g., lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, etc.) or unsaturated (e.g., oleyl alcohol). The carbon chain length of the fatty alcohol portion of the polyoxyethylene fatty alcohol ether ("fatty alcohol carbon chain length") can typically be 12 to 18. Polyoxyethylene fatty alcohol ethers include, but are not limited to, one or more of polyoxyethylene stearyl alcohol ether (e.g., polyoxyethylene 2 stearyl alcohol ether, polyoxyethylene 10 stearyl alcohol ether, polyoxyethylene 20 stearyl alcohol ether, polyoxyethylene 21 stearyl alcohol ether, etc.), polyoxyethylene cetyl alcohol ether (e.g., polyoxyethylene 10 cetyl alcohol ether, polyoxyethylene 20 cetyl alcohol ether, etc.), polyoxyethylene lauryl alcohol ether (e.g., polyoxyethylene 4 lauryl alcohol ether, polyoxyethylene 9 lauryl alcohol ether, polyoxyethylene 23 lauryl alcohol ether, etc.), polyoxyethylene oleyl alcohol ether (e.g., polyoxyethylene 10 oleyl alcohol ether, polyoxyethylene 20 oleyl alcohol ether, etc.), polyoxyethylene cetearyl alcohol ether (e.g., polyoxyethylene 6 cetearyl alcohol ether, polyoxyethylene 20 cetearyl alcohol ether, polyoxyethylene 25 cetearyl alcohol ether, etc.), polyoxyethylene myristyl alcohol ether, polyoxyethylene tridecyl alcohol ether, and polyoxyethylene behenyl alcohol ether. Commercially available polyoxyethylene fatty alcohol ethers can be mixtures of polyoxyethylene fatty alcohol ethers having different fatty alcohol carbon chain lengths. For example, commercially available polyoxyethylene cetearyl alcohol ether can be a mixture of polyoxyethylene cetyl alcohol ether and polyoxyethylene stearyl alcohol ether.

[0300] Unless otherwise specified, "polyoxyethylene glycerides" generally refer to glycerol monoesters, diesters, and triesters, as well as mixtures of polyethylene glycol monoesters and diesters. These can be obtained by partial alcoholysis of vegetable oils with polyethylene glycol, or by esterification of glycerol and polyethylene glycol with unsaturated fatty acids, or by mixing a condensation product of glycerol and ethylene oxide with fatty acids from vegetable oils. Depending on the type of fatty acid moiety in the polyoxyethylene glycerides, polyoxyethylene glycerides include but are not limited to caprylic capric polyoxyethylene glycerides, lauroyl polyoxyethylene glycerides, linoleoyl polyoxyethylene glycerides, oleoyl polyoxyethylene glycerides, stearoyl polyoxyethylene glycerides, and capric polyoxyethylene glycerides.

[0301] Unless otherwise specified, the term "polyoxyethylene castor oil derivative" as used herein refers to a polyoxyethylene nonionic surfactant obtained by reacting polyethylene glycol with castor oil or hydrogenated castor oil, wherein the number of polyoxyethylene units ranges from 5 to 200, with a typical value of 15 to 60. Polyoxyethylene castor oil derivatives include, but are not limited to, polyoxyethylene castor oils (e.g., polyoxyethylene 5 castor oil, polyoxyethylene 9 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, etc.) and polyoxyethylene hydrogenated castor oils (e.g., polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, and polyoxyethylene 60 hydrogenated castor oil, etc.).

[0302] Unless otherwise specified, the term "polyoxyethylene alkylphenol ether" in the present invention is a polyoxyethylene nonionic surfactant formed by the etherification of polyethylene glycol and alkylphenol, including but not limited to nonylphenol polyoxyethylene ethers having 4-10 polyoxyethylene units (for example, nonylphenol polyoxyethylene ether-4, nonylphenol polyoxyethylene ether-6, nonylphenol polyoxyethylene ether-7, nonylphenol polyoxyethylene ether-8, nonylphenol polyoxyethylene ether-10, etc.), octylphenol polyoxyethylene ethers having 4-50 polyoxyethylene units (for example, octylphenol polyoxyethylene ether-4, octylphenol polyoxyethylene ether-9, octylphenol polyoxyethylene ether-13, octylphenol polyoxyethylene ether-15, octylphenol polyoxyethylene ether-20, octylphenol polyoxyethylene ether-30, octylphenol polyoxyethylene ether-40, octylphenol polyoxyethylene ether 50, etc.), dodecylphenol polyoxyethylene ether and one or more of dinonylphenol polyoxyethylene ether.

[0303] Unless otherwise indicated, the term "polyoxyethylene fatty acid ester" in the present invention is a polyoxyethylene nonionic surfactant formed by esterification of polyethylene glycol and fatty acid (e.g., stearic acid, hydroxystearic acid, etc.), wherein the number of polyoxyethylene units varies from 2 to 150, with a typical value of 6 to 100. Polyoxyethylene fatty acid esters include, but are not limited to, polyoxyethylene stearates (e.g., polyoxyethylene 2 stearate, polyoxyethylene 4 stearate, polyoxyethylene 6 stearate, polyoxyethylene 8 stearate, polyoxyethylene 12 stearate, polyoxyethylene 20 stearate, polyoxyethylene 30 stearate, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, etc.), polyoxyethylene distearate (e.g., polyoxyethylene 8 distearate, polyoxyethylene 12 distearate, polyoxyethylene 32 distearate, polyoxyethylene 150 distearate, etc.), and polyoxyethylene hydroxystearates (e.g., polyoxyethylene 15 hydroxystearate, etc.).

[0304] Unless otherwise specified, the term "vitamin E succinate polyethylene glycol ester" in the present invention refers to a polyoxyethylene nonionic surfactant formed by esterification of the carboxyl group of D-α-tocopheryl succinic acid with polyethylene glycol. Based on the average molecular weight of the polyethylene glycol portion in the molecule, it includes but is not limited to vitamin E succinate polyethylene glycol ester 200, vitamin E succinate polyethylene glycol ester 400, vitamin E succinate polyethylene glycol ester 1000, vitamin E succinate polyethylene glycol ester 1500, vitamin E succinate polyethylene glycol ester 2000 and vitamin E succinate polyethylene glycol ester 4000, etc.

[0305] Unless otherwise specified, the term "polyoxyethylene sorbitan fatty acid ester," also known as "polyoxyethylene sorbitan fatty acid ester," "polysorbate," or "Tween" herein refers to a polyol-type nonionic surfactant (also classified as a polyoxyethylene nonionic surfactant) formed by reacting partial fatty acid esters of sorbitol and its anhydrides with polyethylene glycol, wherein the number of polyoxyethylene units ranges from 4 to 20, with typical values ​​being 4, 5, or 20, and the polyoxyethylene units may be attached to multiple hydroxyl groups of sorbitol. Polyoxyethylene sorbitan fatty acid esters include, but are not limited to, Tween 20, Tween 40, Tween 60, Tween 80, and Tween 85.

[0306] Unless otherwise specified, the term "number of polyoxyethylene units" in the present invention refers to the average degree of polymerization of the polyoxyethylene moiety (ie, polyethylene glycol moiety) in the molecule.

[0307] Unless otherwise specified, the term "polyethylene glycol average molecular weight" in the present invention refers to the average molecular weight of the polyethylene glycol portion (ie, the polyoxyethylene portion) in the defined molecule.

[0308] Unless otherwise specified, the term "polyol" in the present invention refers to an alcohol containing two or more hydroxyl groups in the molecule, which contains at least two carbon atoms (e.g., 2-6 carbon atoms), and can be a straight-chain or branched alcohol, such as a diol, a triol, etc., specifically ethylene glycol, propylene glycol, butanediol, pentanediol, hexanediol, glycerol, etc.

[0309] Unless otherwise specified, the term "lower alcohol ether of a polyol" in the present invention refers to an ether formed between a polyol and a lower alcohol containing 1-4 carbon atoms. The polyol may be a linear or branched alcohol, and the lower alcohol may be a linear or branched monohydric alcohol or polyol. The ether may be a complete ether or a partial ether. A complete ether is formed when all hydroxyl groups in a polyol molecule are etherified, and a partial ether is formed when at least one hydroxyl group in a polyol molecule is not etherified. For example, diethylene glycol is a partial ether formed when one hydroxyl group in ethylene glycol is etherified by one molecule of ethylene glycol, and diethylene glycol monoethyl ether is a complete ether formed when one hydroxyl group in ethylene glycol is etherified by one molecule of ethanol and the other hydroxyl group in ethylene glycol is etherified by one molecule of ethylene glycol.

[0310] Unless otherwise specified, the term "fatty acid ester" in the present invention refers to an ester formed by esterifying one or more hydroxyl groups in a molecule of alcohol with fatty acids. The fatty acid can be a short-chain fatty acid (with less than 6 carbon atoms), a medium-chain fatty acid (with 6-12 carbon atoms), or a long-chain fatty acid (with more than 12 carbon atoms); it can be a saturated fatty acid (such as caprylic acid, capric acid, lauric acid, etc.) or an unsaturated fatty acid (such as oleic acid, linoleic acid, etc.); it can be a monobasic acid or a polybasic acid (such as oxalic acid, succinic acid, etc.). The alcohol can be a linear or branched monohydric alcohol (such as ethanol, isopropanol, etc.) or a polyhydric alcohol (such as propylene glycol, glycerol, etc.). For polyhydric alcohols, the multiple hydroxyl groups contained in their molecules can be partially esterified or completely esterified (or fully esterified). Depending on the number of hydroxyl groups contained in the esterified alcohol, fatty acid esters can be divided into fatty acid monohydric alcohol esters, fatty acid polyhydric alcohol esters, etc. Commercially available fatty acid polyhydric alcohol esters can be a mixture of fatty acid esters in which only one hydroxyl group is esterified, some hydroxyl groups are esterified, or all hydroxyl groups are esterified. For example, commercially available propylene glycol monolaurate can be a mixture of propylene glycol monolaurate and a small amount of propylene glycol dilaurate. When multiple hydroxyl groups in a molecule of polyol are esterified, the fatty acids involved in the esterification can be the same or different.

[0311] Unless otherwise specified, the term "fatty acid glyceride" in the present invention refers to an ester formed by partial or complete esterification of one or more hydroxyl groups of glycerol with fatty acids, which is usually prepared by reacting glycerol with fatty acids. The fatty acid can be a short-chain fatty acid (with less than 6 carbon atoms), a medium-chain fatty acid (with 6-12 carbon atoms) or a long-chain fatty acid (with more than 12 carbon atoms); it can be a saturated fatty acid (such as caprylic acid, capric acid, lauric acid, etc.) or an unsaturated fatty acid (such as oleic acid, linoleic acid, etc.). When one hydroxyl group of the glycerol is esterified with fatty acid, a fatty acid monoglyceride is formed; when two hydroxyl groups of the glycerol are esterified with one or two fatty acids, a fatty acid diglyceride is formed; when all hydroxyl groups of the glycerol are esterified with one or more fatty acids, a fatty acid triglyceride is formed. Commercially available fatty acid diglyceride can contain fatty acid monoglyceride, that is, it can be a mixture of fatty acid diglyceride and a small amount of fatty acid monoglyceride.

[0312] In the present invention, fatty acid glycerol monoester, that is, one hydroxyl group of glycerol in fatty acid glycerol ester is esterified with fatty acid, wherein the esterified hydroxyl group can be the 1-hydroxyl group of glycerol or the 2-hydroxyl group of glycerol.

[0313] In the present invention, the fatty acid diglyceride, that is, the two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with fatty acids, wherein the two esterified hydroxyl groups can be the 1st and 2nd hydroxyl groups of glycerol, or the 1st and 3rd hydroxyl groups of glycerol.

[0314] The abbreviations, trade names and their meanings of some technical terms in this invention are as follows:

[0315] Abbreviation or trade name meaning API Benvimod Capryol 90 Propylene glycol monocaprylate TP Diethylene glycol monoethyl ether Labrafil M1944CS Oleoyl polyoxyethylene glycerides RH40 Polyoxyethylene 40 hydrogenated castor oil Cetomacrogol 1000 Polyoxyethylene 20 Cetearyl Ether OP-9 Octylphenol polyoxyethylene ether-9 OP-40 Octylphenol polyoxyethylene ether-40 Brij20 Polyoxyethylene 20 stearyl ether Labrasol Caprylic / capric polyoxyethylene glyceryl esters HS-15 Polyoxyethylene 15-hydroxystearate TPGS1000 Vitamin E Succinate Macrogol 1000 PEG400 polyethylene glycol 400 MCT Medium-chain triglycerides Lauroglycol 90 Propylene glycol monolaurate MCM Caprylic / capric mono- and diglycerides BHA Butylated hydroxyanisole SEPINEO P600 Hydroxyethyl Acrylate / Sodium Acryloyldimethyl Taurate Copolymer

[0316] The reagents and raw materials used in the present invention are all commercially available. Purchased from China (manufacturer: Guangdong Zhonghao Pharmaceutical Co., Ltd.), the composition is: benvimod (1%), cetyl alcohol (cetyl alcohol), white petrolatum, light liquid paraffin, mono- and distearic glyceryl, propylene glycol, Tween 80, ethylparaben and purified water; Purchased from the United States (manufacturer: Dermavant Sciences), the composition is: benvimod (1%), benzoic acid, butylated hydroxytoluene, citric acid monohydrate, diethylene glycol monoethyl ether, disodium edetate, emulsifying wax, medium chain triglycerides, polyoxyethylene 2 stearyl ether, polyoxyethylene 20 stearyl ether, Tween 80, propylene glycol, purified water and sodium citrate dihydrate.

[0317] The determination method adopted in the embodiment of the present invention is as follows:

[0318] Appearance properties test: Use the visual inspection method to observe whether the appearance of the sample is clear and transparent after preparation. Then seal the sample and place it at room temperature for 24 hours and then observe whether it is turbid or stratified. If it is still a clear and transparent aqueous solution, it meets the requirements.

[0319] Chemical stability assay: The samples were subjected to chemical stability analysis by HPLC. Column filler: octadecylsilane bonded silica gel (Shimadzu Shim-pack GIST C18, 4.6 mm × 100 mm, 3 μm or equivalent); flow rate: 0.7 mL / min; detection wavelength: 220 nm; run time: 70 minutes; mobile phase A: phosphoric acid solution (adjust the pH to 3.0 with water); mobile phase B: methanol-acetonitrile (2:1); HPLC elution gradient:

[0320] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 65 35 25 30 70 40 5 95 60 5 95 61 65 35 70 65 35

[0321] In vitro permeation: The composition of the Benvimod solution was evaluated using an in vitro skin permeation test (IVPT), ​​which aims to determine the retention of the drug in the epidermis and dermis. Method: The abdominal skin of 1-3 month old Bama miniature pigs thawed at -20°C was cut into approximately 800-1300 μm thick pieces and mounted on a Franz vertical diffusion cell using a donor block to provide a leak-proof seal, exposing 1.766 cm 2 The surface area of ​​the skin was measured by using a transepidermal water loss meter (<50 g·m -2 ·h -1The test product was applied to each skin section, and the receiving solution was collected at 1, 3, 6, 9, 12, 15 and 18 hours after application. The cumulative amount of Benvimod that permeated through the skin in the receiving solution was measured using liquid chromatography / mass spectrometry. 18 hours after application, the skin surface was wiped with a cotton swab and peeled off three times with tape to remove any residual test product. The skin layers (epidermis and dermis) were placed in separate homogenate bottles, the drug was extracted, and the cumulative amount of Benvimod in the skin layer was detected using liquid chromatography. The retention per unit area (μg / cm) was obtained by dividing the cumulative amount of Benvimod measured in the skin layer by the contact area of ​​the skin section with the drug. 2 ).

[0322] Example

[0323] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0324] Example 1: Screening of solubilizing agent types

[0325] Preparation of the Benvimod solution composition: In a glass beaker, weigh the prescribed amount of solubilizer, solvent, water, and optional penetration enhancer according to the weight percentages listed in Table 1. Stir thoroughly with a magnetic stirrer, then add the API and mix thoroughly. Then, heat in a 40-50°C water bath and stir thoroughly to prepare the Benvimod solution composition. The pH value of the solution composition was tested to be between 5.0 and 6.5. After the prepared solution composition was allowed to stand for 24 hours, its appearance was observed.

[0326] Table 1 Screening of solubilizer types

[0327]

[0328] Table 1 Screening of solubilizer types

[0329]

[0330] Table 1 Screening of solubilizer types

[0331]

[0332] Table 1 Screening of solubilizer types

[0333]

[0334] Table 1 Screening of solubilizer types

[0335]

[0336] Table 1 Screening of solubilizer types

[0337]

[0338] The results showed that when the solubilizers were poloxamer 407, poloxamer 188, Cetomacrogol 1000 and Brij20, the physical stability of the benvimod solution was good, and it remained a clear and transparent aqueous solution after standing, and the pH value remained basically unchanged; when no solubilizer was added or Labrafil M1944CS, RH40, polyoxyethylene 40 stearate, OP-9, OP-40, Labrosol, Tween 80, HS-15, TPGS1000 were added as solubilizers, the mixture formed a turbid liquid after stirring or separated after standing, and a stable solution could not be formed; it can be seen from the prescriptions 1.5-1.8, 1.13 and 1.23 that the physical stability of the benvimod solution was good when a penetration enhancer was added or not.

[0339] Example 2: Screening of compound solubilizers

[0340] The vinvelimod solution composition was prepared in the same manner as in Example 1, and the effects of different types of compound solubilizers on the physical stability of the solution were investigated. The results are shown in Table 2:

[0341] Table 2 Screening of compound solubilizers

[0342]

[0343] Table 2 Screening of compound solubilizers

[0344]

[0345] The results showed that after the solubilizers (such as polyoxyethylene 40 stearate, OP-9, Labrasol) that could not make the bevimod solution meet the physical stability requirements in Example 1 were compounded with poloxamer, the resulting solution still could not meet the physical stability requirements.

[0346] Example 3: Screening of solvent types and dosages

[0347] The same method as in Example 1 was used to prepare a belimud solution composition (pH value was between 5.0-6.5), and then allowed to stand for 24 hours to investigate the effect of the type and amount of solvent on the physical stability of the solution. The results are shown in Table 3:

[0348] Table 3 Screening of solvent types and dosages

[0349]

[0350] Table 3: Screening of solvent types and dosages

[0351]

[0352] The results showed that the benzimid solution compositions of prescriptions 3.1-3.8 all met the requirements of physical stability, remained clear and transparent aqueous solutions after standing, and the pH value remained basically unchanged.

[0353] Example 4: Screening of penetration enhancer types and dosages

[0354] The same method as in Example 1 was used to prepare a bevimod solution composition (pH value was between 5.0-6.5), and then allowed to stand for 24 hours to investigate the effect of the type and amount of the permeation enhancer on the physical stability of the solution. The results are shown in Table 4:

[0355] Table 4 Screening of penetration enhancer types and dosages

[0356]

[0357] Table 4: Screening of penetration enhancer types and dosages

[0358]

[0359] Table 4: Screening of penetration enhancer types and dosages

[0360]

[0361] The results showed that when one or more of Capryol 90, Lauroglycol 90, and MCM were used as penetration enhancers, the belimumab solution composition had good physical stability, remained a clear and transparent aqueous solution after standing, and had substantially no change in pH value.

[0362] Example 5: Comparative Example

[0363] Comparative Example 1 was prepared with reference to the prescription AG12 in patent CN116723864A (see paragraph

[0280] of CN116723864A). Comparative Example 1 is a benvimod gel composition. In order to more intuitively compare the prescription differences of the solution compositions, this example prepared Comparative Example 2 without adding the gelling agent in the prescription of Comparative Example 1, which is a benvimod solution composition. The results are detailed in Table 5:

[0364] Table 5 Comparative Example Prescription

[0365]

[0366] Example 6: Chemical Stability Study of Benvimod Solution Composition

[0367] The chemical stability of the belimumab solution compositions of Comparative Examples 1-2 of Example 5 was compared with those of Formulas 1.6, 1.8, 3.1, 1.23, 3.3, and 4.1. The samples were placed under accelerated conditions at 60°C for 10 days or 1 month, and the contents of the largest single impurity and total impurities were determined by HPLC. The compound stability test results are detailed in Table 6:

[0368] Table 6 Accelerated stability test of the vinvimod solution composition

[0369]

[0370] The results showed that the chemical stability of representative solution compositions 1.6, 1.8, 1.23, 3.1, 3.3, and 4.1 under accelerated conditions was significantly better than that of Comparative Examples 1 and 2. Moreover, among the comparative examples, the chemical stability of the solution composition without a gelling agent (Comparative Example 2) was even worse than that of the gel composition containing a gelling agent (Comparative Example 1). These results reflect that the vesimalide solution composition of the present invention has surprisingly excellent chemical stability.

[0371] Example 7: In vitro transdermal study of Benvimod solution composition

[0372] Comparative study of in vitro transdermal performance of the comparative example 1 of Example 5 and the belimumab solution compositions of prescriptions 1.8, 1.20 and 4.4 was conducted. The results are shown in Table 7.

[0373] Table 7 In vitro permeation study of the composition of the vinvimod solution

[0374]

[0375] [1] Measure the retention per unit area three times and take the average value.

[0376] *Because the transepidermal water loss value is too high and the skin integrity is poor, the test value of this time is discarded and the average of the other two test values ​​is taken.

[0377] The results showed that the skin retention effects of the solution compositions of the present invention, 1.8, 1.20 and 4.4, were significantly better than those of comparative example 1.

[0378] Example 8: Solution composition containing antioxidants, antibacterial agents, pH regulators and other excipients

[0379] Preparation of the benvimod solution composition: In a glass beaker, weigh the prescribed amount of solubilizer, solvent, optional penetration enhancer, antioxidant, antibacterial agent and thickener according to the weight percentage recorded in Table 8, stir evenly with a magnetic stirrer, add API and mix evenly, heat in a water bath at 40-50°C, add pH adjuster, chelating agent and water and stir evenly to prepare the benvimod solution composition.

[0380] Table 8 Screening of solution formulations containing other excipients

[0381]

[0382] Table 8 Screening of solution formulations containing other excipients

[0383]

[0384] Table 8 Screening of solution formulations containing other excipients

[0385]

[0386] Table 8 Screening of solution formulations containing other excipients

[0387]

[0388] The results showed that after adding antioxidants, antibacterial agents, pH regulators, chelating agents and thickeners, the physical stability of the belimumab solution composition met the requirements and remained a clear and transparent aqueous solution after standing.

[0389] Example 9: Screening of API concentration

[0390] The belimumab solution composition was prepared in the same manner as in Example 8, and the effect of API concentration on the physical stability of the solution was investigated. The results are shown in Table 9:

[0391] Table 9 Screening of API concentration

[0392]

[0393] Table 9: Screening of API concentration

[0394]

[0395] The results showed that the benvimod solution compositions of prescriptions 9.1-9.5 all met the requirements of physical stability and remained clear and transparent aqueous solutions after standing.

[0396] Example 10: In vivo pharmacodynamic study in animals

[0397] A BALB / c mouse psoriasis model was established, and the imiquimod solution composition of the present invention was administered by topical administration to investigate the therapeutic and improving effects of the test substance on imiquimod-induced psoriasis in mice.

[0398] (1) Experimental materials

[0399] Animals: SPF-grade BALB / c female mice, 9 weeks old, weighing 18 g to 22 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0400] Drugs and reagents: Test substances of the present invention (prescriptions 8.3 and 8.6), Cream, Cream and Imiquimod Cream (purchased from Sichuan Mingxin Pharmaceutical Co., Ltd.).

[0401] (2) Experimental methods

[0402] The SPF grade Balb / c mice that passed the quarantine were selected. One day before modeling, the hair of the animals in the back area of ​​about 2cm×3cm was removed with depilatory cream until the skin was completely exposed. After the experiment began, all animals were randomly divided into blank control group, model control group, positive control group ( Cream), positive control group 2 ( Cream), test substance group 1 (prescription 8.3) and test substance group 2 (prescription 8.6). On the morning of the experiment, except for the blank control group and the model control group, the mice in the other groups were smeared with the test substance 100 mg / mouse / day on the back; 6 hours after the administration, except for the blank control group, the other groups were given 5% imiquimod cream 83 mg / mouse / day, and the blank control group mice were smeared with the same dose of vaseline on the back; 4 hours after the application of imiquimod, the mice in the positive control group 1 were given the test substance 100 mg / mouse / day again; the application was continued for 7 days. The number of animals in each group was 10, and they were kept in single cages after the modeling began. The specific grouping and dosing are shown in Table 10:

[0403] Table 10 Experimental grouping and dosage design

[0404]

[0405] [1] According to The instructions for use of the cream are for use twice a day.

[0406] (3) Observation indicators

[0407] The Psoriasis Area and Severity Index (PASI) was used to score the skin lesions on the back of the mice. During the animal dosing period, each mouse was photographed with a digital camera before dosing every day. The PASI scoring method was used to score the severity of the mouse skin lesions using three indicators: erythema, scaling, and skin thickness. The PASI scoring scale ranges from 0 to 4 points, corresponding to none, mild, moderate, severe, and very severe according to the severity. The total score is the sum of the three indicator scores (0 to 12 points). The PASI scoring table is shown in Table 11:

[0408] Table 11 PASI score sheet

[0409]

[0410] (4) Data statistics

[0411] Data are presented as mean ± standard deviation (SEM). Normal distribution was tested using the one-sample Kolmogorov-Smirnov test. If normal distribution was observed, one-way ANOVA was performed. Multiple comparisons between sample means were performed using the Tukey or LSD test. A p < 0.05 was considered significant. All statistical analyses were performed using GraphPad Prism 8 statistical software.

[0412] (5) Experimental results

[0413] The female BALB / c mouse model was established by administering imiquimod. The changes in the severity scores of skin lesions in each group after treatment are shown in Table 12. The PASI score change curve of skin lesion severity is shown in Figure 1 .

[0414] Table 12 Skin lesion severity scores at different time points in each group

[0415]

[0416] △: refers to There was a statistically significant difference between the two groups (P < 0.05).

[0417] *:refers to There was a statistically significant difference between the two groups (P < 0.05).

[0418] The results showed that the normal control group mice showed no skin changes such as scaling or erythema. However, the model control group mice developed fine scaling and mild wrinkling 2-3 days after applying imiquimod. On the 7th day, the skin turned dark red, covered with layered scales that easily fell off, and the skin became highly thickened and prominent. 、 On the 7th day after administration, the mental state of mice treated with cream, prescription 8.3 and prescription 8.6 was improved compared with the model control group. A few scales were seen on the skin, the skin height thickening was improved, the ridges were significantly reduced, and there were slight wrinkles. Cream and Cream, prescription 8.3 and prescription 8.6 showed a significant decrease in skin PASI scores on the 6th and 7th days of continuous application. The effects of the above prescriptions were better than Cream and Cream. With and Compared with the cream, both prescription 8.3 and prescription 8.6 showed statistical differences in efficacy. The above results show that the bevimod solution composition of the present invention can significantly improve the psoriasis-like skin lesions induced by imiquimod in BALB / c mice. Cream, Creams have better therapeutic effects.

[0419] It should be noted that, although the technical solutions of the present invention are described with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0420] While various embodiments of the present invention have been described above, the above descriptions are intended to be illustrative, non-exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is selected to best explain the principles of the embodiments, their practical applications, or technological improvements in the marketplace, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A pharmaceutical composition in the form of a solution, comprising benvimod or a pharmaceutically acceptable salt thereof (preferably benvimod), a solubilizer, a solvent and water; in, The solubilizing agent is selected from one or more of polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene fatty alcohol ethers, polyoxyethylene glycerides, polyoxyethylene castor oil derivatives, polyoxyethylene alkylphenol ethers, polyoxyethylene fatty acid esters, vitamin E succinate polyethylene glycol esters and polyoxyethylene sorbitol fatty acid esters, preferably one or more of polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene fatty alcohol ethers; The solvent is selected from one or more of monohydric alcohol, polyhydric alcohol, lower alcohol ether of polyhydric alcohol and polyethylene glycol, preferably one or more of polyhydric alcohol and lower alcohol ether of polyhydric alcohol.

2. The pharmaceutical composition according to claim 1, characterized in that The polyoxyethylene-polyoxypropylene block copolymer is a poloxamer, preferably a poloxamer with an average molecular weight of 2000-18000, more preferably a poloxamer with an average molecular weight of 7500-15000, further preferably one or more of a poloxamer with an average molecular weight of 7500-10000 and a poloxamer with an average molecular weight of 9500-15000, most preferably one or more of poloxamer 188 and poloxamer 407.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The polyoxyethylene fatty alcohol ether is a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 12-18 and a polyoxyethylene unit number of 10-60, preferably a polyoxyethylene fatty alcohol ether having a fatty alcohol carbon chain length of 16-18 and a polyoxyethylene unit number of 10-30, more preferably one or more of polyoxyethylene stearyl alcohol ether having a polyoxyethylene unit number of 10-30 and polyoxyethylene cetearyl alcohol ether having a polyoxyethylene unit number of 10-30, most preferably one or more of polyoxyethylene 20 stearyl alcohol ether and polyoxyethylene 20 cetearyl alcohol ether.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that Based on the total weight of the pharmaceutical composition, the content of the solubilizer is 1%-20%, preferably 1%-15%, more preferably 2%-13%, most preferably 2%-10%.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The polyol is a linear or branched polyol containing 2-6 carbon atoms, preferably a linear polyol containing 2-4 carbon atoms, more preferably one or more of ethylene glycol, propylene glycol, butylene glycol and glycerol, most preferably propylene glycol.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The lower alcohol ether of the polyol is an ether formed by a straight-chain or branched polyol containing 2-6 carbon atoms and a lower alcohol containing 1-4 carbon atoms, preferably an ether formed by a straight-chain or branched polyol containing 2-4 carbon atoms and a lower alcohol containing 1-2 carbon atoms, more preferably an ether formed by a straight-chain polyol containing 2-4 carbon atoms and a lower alcohol containing 1-2 carbon atoms, and most preferably diethylene glycol monoethyl ether.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that Based on the total weight of the pharmaceutical composition, the content of the solvent is 2%-75%, preferably 5%-75%, more preferably 6%-65%, most preferably 10%-65%.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that Based on the total weight of the pharmaceutical composition, the content of benvimod or its pharmaceutically acceptable salt (preferably benvimod) is 0.1%-10%, preferably 0.1%-5%, more preferably 0.5%-4.5%, further preferably 1%-4%, and most preferably 1%-3%.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that The water is one or more of purified water, distilled water, deionized water and water for injection; Furthermore, based on the total weight of the pharmaceutical composition, the water content is 20%-90%, preferably 20%-85%, more preferably 25%-80%, and most preferably 30%-80%.

10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that The pharmaceutical composition further comprises a penetration enhancer; Preferably, the penetration enhancer is selected from one or more of fatty alcohols and fatty acid esters, preferably one or more of fatty acid diol esters and fatty acid glycerides.

11. The pharmaceutical composition according to claim 10, characterized in that The fatty acid diol ester is a fatty acid ester formed by esterifying a diol containing 2 to 4 carbon atoms with a fatty acid containing 2 to 18 carbon atoms, preferably a fatty acid ester formed by esterifying a diol containing 2 to 4 carbon atoms with a fatty acid containing 8 to 12 carbon atoms, more preferably a fatty acid ester formed by esterifying one hydroxyl group in a diol containing 2 to 4 carbon atoms with a fatty acid containing 8 to 12 carbon atoms, and most preferably one or more of propylene glycol monocaprylate and propylene glycol monolaurate.

12. The pharmaceutical composition according to claim 10 or 11, characterized in that The fatty acid glyceride is selected from one or more of fatty acid glycerol monoesters and fatty acid diglycerides, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 2 to 18 carbon atoms; Preferably, the fatty acid glyceride is selected from one or more of fatty acid glycerol monoesters and fatty acid diglycerides, and one or two hydroxyl groups of glycerol in the fatty acid glyceride are esterified with a fatty acid containing 8-12 carbon atoms; More preferably, the fatty acid glyceride is selected from one or more of monocaprylic glyceride, monocapric glyceride, dicaprylic glyceride, dicapric glyceride, caprylic capric glyceride and caprylic capric mono- and diglycerides; Most preferably, the fatty acid glyceride is caprylic and capric mono- and diglycerides.

13. The pharmaceutical composition according to any one of claims 10 to 12, characterized in that Based on the total weight of the pharmaceutical composition, the content of the penetration enhancer is 0-25%, preferably 2%-20%, more preferably 2%-15%, most preferably 2%-10%.

14. The pharmaceutical composition according to any one of claims 1 to 13, characterized in that The pharmaceutical composition further comprises one or more of a mucoadhesive agent, a pH regulator, an antioxidant, an osmotic pressure regulator, a bacteriostatic agent, a chelating agent, and a thickening agent; Preferably, the pharmaceutical composition further comprises one or more of an antioxidant, an antibacterial agent, a chelating agent, a pH regulator and a thickening agent.

15. The pharmaceutical composition according to claim 14, characterized in that The antioxidant is selected from one or more of butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, L-ascorbyl palmitate, ethoxyquinoline, sodium metabisulfite, dilauryl thiodipropionate, tea polyphenols, tocopherol, cysteine ​​and grape seed extract, preferably one or more of butylated hydroxyanisole, butylated hydroxytoluene, tert-butylhydroquinone, propyl gallate, L-ascorbyl palmitate, ethoxyquinoline, sodium metabisulfite, dilauryl thiodipropionate, tea polyphenols, tocopherol and grape seed extract, more preferably one or more of butylated hydroxyanisole and butylated hydroxytoluene, further preferably butylated hydroxyanisole; Preferably, based on the total weight of the pharmaceutical composition, the content of the antioxidant is 0-2%, preferably 0.01%-1%, more preferably 0.05%-0.5%, most preferably 0.1%-0.2%.

16. The pharmaceutical composition according to claim 14 or 15, characterized in that The antibacterial agent is selected from one or more of benzyl alcohol, phenoxyethanol, sorbic acid or its salts, parahydroxybenzoates, benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salts, citric acid or its salts and ascorbic acid or its salts, preferably benzoic acid; Preferably, based on the total weight of the pharmaceutical composition, the content of the antibacterial agent is 0-2%, preferably 0.01%-1%, more preferably 0.1%-0.5%, most preferably 0.2%-0.4%.

17. The pharmaceutical composition according to any one of claims 14 to 16, characterized in that The chelating agent is selected from one or more of citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, edetic acid or its derivatives (preferably edetic acid or its salts) and phosphonates, preferably disodium edetate; Preferably, based on the total weight of the pharmaceutical composition, the content of the chelating agent is 0-2%, preferably 0.01%-1%, more preferably 0.05%-0.5%, most preferably 0.1%-0.2%.

18. The pharmaceutical composition according to any one of claims 14 to 17, characterized in that The pH regulator is one or more of an inorganic or organic acid, an inorganic or organic base, and a buffer salt, preferably a buffer salt, more preferably one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphate-sodium phosphate buffer salt, citric acid-disodium hydrogen phosphate buffer salt, and acetic acid-sodium acetate buffer salt, further preferably one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphate-sodium phosphate buffer salt, and acetic acid-sodium acetate buffer salt, most preferably citric acid-sodium citrate buffer salt; Preferably, based on the total weight of the pharmaceutical composition, the content of the pH regulator is 0-2%, preferably 0.01%-1%, more preferably 0.1%-0.5%, most preferably 0.2%-0.3%.

19. The pharmaceutical composition according to any one of claims 14 to 18, characterized in that The thickener is selected from one or more of xanthan gum, carbomer, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium hyaluronate, polyvinyl alcohol, xyloglucan, povidone, hydroxyethyl cellulose, gellan gum and sodium alginate, preferably one or more of xanthan gum and carbomer; Preferably, based on the total weight of the pharmaceutical composition, the content of the thickener is 0-5%, preferably 0.05%-5%, more preferably 0.05%-2%, most preferably 0.1%-1.5%.

20. The pharmaceutical composition according to any one of claims 1 to 19, characterized in that The pH of the pharmaceutical composition is 4.0-6.5, preferably 4.5-6.

5.

21. A method for preparing a pharmaceutical composition in solution form according to any one of claims 1 to 20, comprising the following steps: Benvimod or a pharmaceutically acceptable salt thereof (preferably Benvimod), a solubilizer, a solvent, water, an optional penetration enhancer, an optional antioxidant, an optional antibacterial agent, an optional pH regulator, an optional chelating agent and an optional thickener are uniformly mixed to obtain; Preferably, the mixing is carried out under heating, preferably under heating in a water bath; Preferably, the mixing temperature is 0-90°C, preferably 30-70°C, most preferably 40-60°C; and / or Preferably, the mixing method is stirring, ultrasonic, homogenizing or microfluidization, preferably stirring, more preferably stirring under heating in a water bath at 40-60°C.

22. A pharmaceutical preparation for external use in the form of a solution, comprising the pharmaceutical composition in the form of a solution according to any one of claims 1 to 20; Preferably, the external pharmaceutical preparation is a liniment, a spray, a film, a soft patch or a cataplasm.

23. Use of the pharmaceutical composition in solution form according to any one of claims 1 to 20 or the external pharmaceutical preparation in solution form according to claim 22 in the preparation of a medicament for preventing and / or treating inflammatory skin diseases; Preferably, the inflammatory skin disease is selected from one or more of psoriasis (preferably scalp psoriasis), eczema (preferably childhood eczema), palmoplantar pustulosis, atopic dermatitis, contact dermatitis, seborrheic dermatitis, acne, rosacea, hair follicle syndrome and herpes; More preferably, the inflammatory skin disease is scalp psoriasis or childhood eczema; Most preferably, the inflammatory skin disease is scalp psoriasis.

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