Pharmaceutical composition, topical preparation and method for producing the same, use

Abstract

This invention discloses a pharmaceutical composition, a topical formulation, a method for producing the same, and its use. The pharmaceutical composition of this invention comprises the drug-active ingredient, diethylene glycol monoethyl ether, and polyethylene glycol 400, wherein the pharmaceutical composition does not contain water, and the mass ratio of diethylene glycol monoethyl ether to polyethylene glycol 400 is 1:(0.5~4.0), and the drug-active ingredient has structural formula (I). Topical formulations produced from the pharmaceutical composition provided by this invention have stable properties and do not crystallize, have a good feel, promote rapid penetration of the drug into the stratum corneum, have excellent epidermal and dermal retention ability, deliver the drug to the target on the skin, reduce systemic side effects, can achieve high local concentrations, have excellent therapeutic effects and stability, and can reduce safety risks. JPEG2026518290000036.jpg65142

Description

Technical Field

[0001] This application claims the priority of International Patent Application PCT / CN2023 / 096089 with an application date of May 24, 2023. This application incorporates the full text of the above Chinese patent application by reference.

[0002] The present invention relates to pharmaceutical compositions, topical preparations, and their manufacturing methods and uses.

Background Art

[0003] Cytokines of skin immune diseases activate various intracellular JAKs kinases via their respective receptors, control the differentiation and proliferation of related immune cells, and inhibit the secretion of cytokines. Since the JAK / STAT pathway can inhibit the activation of immune cells and inflammation mediated by T cells, it has become a major target in inflammatory diseases. Janus kinase is a family of cytoplasmic protein tyrosine kinases including JAK1, JAK2, JAK3, and TYK2.

[0004] Currently, there are multiple JAK inhibitors used in the treatment of skin damage. Oral formulations include tofacitinib, duvelisib, baricitinib, ruxolitinib, etc. Oral tofacitinib, which has completed phase III clinical trials, was temporarily suspended because the FDA required continuous provision of safety data, and it may cause serious adverse events by systemic administration. Topical administration of the active pharmaceutical ingredient has become a preferred administration method for treating skin diseases such as rheumatoid arthritis, psoriasis, alopecia areata, etc.

[0005] However, there is still room for improvement in the skin retention amount and permeability during use of current topical preparations containing active drug ingredients.

Summary of the Invention

[0006] The technical problem that this invention aims to solve is to overcome the drawbacks of prior art topical formulations, such as low skin retention and poor permeability, and to provide a pharmaceutical composition, a topical formulation, a method for producing the same, and its use. A topical formulation produced from the pharmaceutical composition provided by this invention has stable properties and does not crystallize, has a good feel when used, promotes rapid penetration of the drug into the stratum corneum, has excellent epidermal and dermal retention ability, delivers the drug to the target in the skin, reduces systemic side effects, can achieve high local concentrations, has excellent therapeutic effect and stability, and can reduce safety risks.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides a pharmaceutical composition comprising a drug-active ingredient, diethylene glycol monoethyl ether, and polyethylene glycol 400 (PEG400), wherein the pharmaceutical composition is water-free.

[0009] However, the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 400 is 1:(0.5~4.0), and the drug active ingredient has structural formula (I).

[0010] [ka]

[0011] In the present invention, the drug-active ingredient having structural formula (I) can be produced by the production method disclosed in Example 113 of CN113227074A.

[0012] In the present invention, the amount of the drug active ingredient used may be 0.001 to 10%, for example, 0.1%, 0.3%, 0.6%, 1.0%, 1.2%, 1.5%, or 2.0%, where % refers to the mass percentage of the drug active ingredient in the pharmaceutical composition.

[0013] In the present invention, diethylene glycol monoethyl ether has the effect of increasing or promoting the penetration of drugs through the skin, as well as the effect of acting as a solvent for dissolving compounds.

[0014] In the present invention, the amount of diethylene glycol monoethyl ether used may be 15 to 40%, for example, 20.0%, 23.0%, or 33.8%, where % refers to the mass percentage of diethylene glycol monoethyl ether in the pharmaceutical composition.

[0015] In the present invention, the mass ratio of the drug active ingredient to the diethylene glycol monoethyl ether is preferably 1:(10.0~250.0), for example, 1:13.33, 1:15.33, 1:16.67, 1:16.90, 1:20, 1:23, 1:33.33, 1:66.67, 1:76.67, 1:200, or 1:230.

[0016] In the present invention, the amount of polyethylene glycol 400 used may be 30 to 55%, for example, 30.4%, 38.8%, 45.3%, 52.5%, or 52.9%, where % refers to the mass percentage of polyethylene glycol 400 in the pharmaceutical composition.

[0017] In the present invention, the mass ratio of diethylene glycol monoethyl ether to polyethylene glycol 400 is preferably 1:(0.5~3.0), for example, 1:0.90, 1:1.94, 1:1.97, 1:2.63, or 2.65.

[0018] In the present invention, preferably the pharmaceutical composition further comprises polyethylene glycol 3350 (PEG3350).

[0019] Here, if the pharmaceutical composition contains polyethylene glycol 3350, the amount of polyethylene glycol 3350 used may be 25.0 to 45.0%, for example, 25.8%, 26.3%, 26.5%, 27%, 27.2%, 30%, 30.5%, 31.2%, 31.4%, 33.8%, or 40%.

[0020] Here, when the pharmaceutical composition contains polyethylene glycol 3350, the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 3350 may be 1:(0.5 to 3.6), preferably 1:(0.5 to 3.0), for example 1:1.00, 1:1.29, 1:1.30, 1:1.32, 1:1.33, 1:1.35, 1:1.36, 1:1.37 or 1:2.00.

[0021] In the present invention, preferably, the pharmaceutical composition further contains one or more of an antioxidant, a preservative, a hardening agent, and a moisturizing agent.

[0022] Here, the antioxidant may be an aromatic amine-based antioxidant, for example, dibutylhydroxytoluene.

[0023] Here, the usage amount of the antioxidant may be 0.05 to 0.2%, for example, 0.1%.

[0024] Here, the preservative may be one or more of methylparaben, sorbic acid and its salts, for example, methylparaben.

[0025] Here, the usage amount of the preservative may be 0.05 to 0.2%, for example, 0.1%.

[0026] Here, the hardening agent may be one or more of paraffin, beeswax, cetearyl alcohol, white petrolatum, glyceryl monostearate and glyceryl distearate.

[0027] Here, the usage amount of the hardening agent may be 5 to 40%, for example, 9.8%, 22.1%, 30.65% or 37.6%.

[0028] Here, the humectant may be one or more of glycerin, light liquid paraffin, soybean oil, medium-chain triglycerides, sodium hyaluronate, urea, propylene glycol, butylene glycol, panthenol, sodium pyrrolidone carboxylate, and trehalose, and is preferably propylene glycol.

[0029] Here, the amount of the humectant used may be 2 to 80%, for example, 5.0%, 9.0%, 20.0%, 37.5%, or 77.5%.

[0030] In the present invention, the pharmaceutical composition may be in the form of a solution, gel, ointment, or cream.

[0031] In the present invention, if the pharmaceutical composition is semi-solid, for example, a cream, the particle size of the drug active ingredient may be less than 180 μm.

[0032] In the present invention, after mixing each component in the pharmaceutical composition, no crystallization phenomenon occurs, and a single-phase system is formed.

[0033] In some preferred embodiments, the pharmaceutical composition comprises the drug-active ingredient, diethylene glycol monoethyl ether, polyethylene glycol 400, and polyethylene glycol 3350, and the pharmaceutical composition does not contain water. Here, the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 400 is 1:(0.5~4.0), and the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 3350 is 1:(0.5~3.6).

[0034] In some preferred embodiments, the pharmaceutical composition comprises the drug-active ingredient, diethylene glycol monoethyl ether, polyethylene glycol 400, and polyethylene glycol 3350, and the pharmaceutical composition does not contain water. Here, the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 400 is 1:(0.5~3.0), and the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 3350 is 1:(0.5~3.0).

[0035] In some preferred embodiments, the pharmaceutical composition is expressed by weight percentage as follows: Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0-33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-40.0% Includes.

[0036] In some preferred embodiments, the pharmaceutical composition is, by weight percentage, Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0-33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-40.0% Dibutylhydroxytoluene 0-0.1% Methylparaben 0-0.1% Tartrazine 0-0.001% Beeswax 0-30.65% Cetearyl alcohol 0-9.8% White petrolatum 0-22.1% Propylene glycol 0-20.2% Includes.

[0037] The present invention also provides a topical formulation comprising the above-mentioned pharmaceutical composition.

[0038] In the present invention, the topical preparation may be a liquid preparation or a semi-solid preparation.

[0039] Here, the liquid formulation may be a liniment or a tincture.

[0040] Here, the semi-solid preparation may be a cream, organic gel, ointment, or paste.

[0041] In some preferred embodiments, the ointment formulation is, by weight percentage, Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0-33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-40.0% Includes.

[0042] Preferably, the ointment formulation is as follows, by weight percentage: Drug-active ingredient 0.6-2.0% Diethylene glycol monoethyl ether 20.0-33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 26.3-40.0% Includes.

[0043] More preferably, the ointment formulation in terms of weight percentage is: 0.6% of the drug-active ingredient Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.9% Polyethylene glycol 3350 26.5% Includes.

[0044] More preferably, the ointment formulation in terms of weight percentage is: Pharmacologically active ingredient 1.2% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 26.3% Includes.

[0045] More preferably, the ointment formulation in terms of weight percentage is: Pharmacologically active ingredient 1.2% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 38.8% Polyethylene glycol 3350 40.0% Includes.

[0046] More preferably, the ointment formulation in terms of weight percentage is: Pharmacologically active ingredient 2.0% Diethylene glycol monoethyl ether 33.8% Polyethylene glycol 400 30.4% Polyethylene glycol 3350 33.8% Includes.

[0047] Preferably, the ointment formulation is as follows, by weight percentage: Drug-active ingredient 0.1-1.5% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 25.8-27.2% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Includes.

[0048] More preferably, the ointment formulation in terms of weight percentage is: 0.1% of the drug-active ingredient Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 27.2% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Includes.

[0049] More preferably, the ointment formulation in terms of weight percentage is: 0.3% of the drug-active ingredient Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 27.0% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Includes.

[0050] More preferably, the ointment formulation in terms of weight percentage is: Pharmacologically active ingredient 1.0% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 26.3% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Includes.

[0051] More preferably, the ointment formulation in terms of weight percentage is: Pharmacologically active ingredient 1.5% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 25.8% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Includes.

[0052] Preferably, the ointment formulation is as follows, by weight percentage: Drug-active ingredient 0.1-1.5% Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 30.0~31.4% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Tartrazine 0.00025~0.001% Includes.

[0053] More preferably, the ointment formulation in terms of weight percentage is: 0.1% of the drug-active ingredient Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 31.4% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Tartrazine 0.001% Includes.

[0054] More preferably, the ointment formulation in terms of weight percentage is: 0.3% of the drug-active ingredient Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 31.2% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Tartrazine 0.007% Includes.

[0055] More preferably, the ointment formulation in terms of weight percentage is: Pharmacologically active ingredient 1.0% Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 30.5% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Tartrazine 0.00025% Includes.

[0056] More preferably, the ointment formulation in terms of weight percentage is: Pharmacologically active ingredient 1.5% Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 30.0% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Includes.

[0057] Preferably, the ointment is, by weight percentage, Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0-33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-50.0% Paraffin 0-5% Beeswax 0-30.65% Cetearyl alcohol 0-9.8% White petrolatum 0-22.6% Glyceryl monostearate and glyceryl distearate 0-10% Propylene glycol 0-20.0% Dibutylhydroxytoluene 0-0.1% Methylparaben 0-0.1% Polyethylene glycol 600 0-25.0% Light liquid paraffin 0-5.0% Soybean oil 0~5.0% Medium-chain triglycerides 0-5.0% Includes.

[0058] Preferably, the ointment is, by weight percentage, Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0-33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-40.0% Dibutylhydroxytoluene 0-0.1% Methylparaben 0-0.1% Tartrazine 0-0.001% Beeswax 0-30.65% Cetearyl alcohol 0-9.8% White petrolatum 0-22.1% Propylene glycol 0-20.2% Includes.

[0059] The present invention also provides a method for producing the above-mentioned pharmaceutical composition, the method comprising the following steps: (1) Preparation of API solution: A step of mixing the drug active ingredient, diethylene glycol monoethyl ether and polyethylene glycol 400 at 50-80°C until dissolved. (2) Preparation of matrix solution: A step of heating polyethylene glycol 3350 at 50-80°C to melt it, (3) Preparation of ointment: A step of mixing the API solution and the matrix solution under stirring conditions.

[0060] In step (1), the mixing temperature is preferably 50°C or 80°C.

[0061] In step (2), preferably, the raw materials further include one or more of antioxidants, preservatives, curing agents, and humectants.

[0062] In step (2), preferably, the raw materials further include diethylene glycol monoethyl ether.

[0063] Preferably, if the raw material in step (2) contains diethylene glycol monoethyl ether, the amount of diethylene glycol monoethyl ether used in step (1) shall be 2 / 3 of the formulation amount, and the amount of diethylene glycol monoethyl ether used in step (2) shall be 1 / 3 of the formulation amount.

[0064] In one preferred embodiment, the preparation of the matrix solution comprises the following steps: methylparaben is added to diethylene glycol monoethyl ether and stirred at 50-80°C until completely dissolved; then dibutylhydroxytoluene and polyethylene glycol 3350 are added and stirred until melted.

[0065] In step (2), the heating temperature is preferably 50°C or 80°C.

[0066] In step (3), the rotational speed of the stirring may be typical in this field, and is preferably 315 rpm.

[0067] In step (3), the stirring time may be what is typical in this field, and is preferably 10 to 15 minutes.

[0068] In step (3), the mixing temperature is preferably 50°C to 60°C.

[0069] In step (3), after the mixing is complete, a cooling operation may be included.

[0070] In this case, the cooling method can be a cooling method using circulating water.

[0071] The present invention also provides the use of the above-mentioned pharmaceutical composition or topical formulation in the manufacture of pharmaceuticals for treating autoimmune diseases.

[0072] In the present invention, the autoimmune disease may be arthritis, rheumatoid arthritis, psoriasis, psoriasis vulgaris, osteoarthritis, localized suppurative disease, ankylosing spondylitis, autoimmune eye disease, dry eye, atopic dermatitis, contact dermatitis, systemic lupus erythematosus, or alopecia areata.

[0073] The present invention also provides a method for treating an autoimmune disease, comprising administering a therapeutically effective amount of the pharmaceutical composition or topical formulation to a subject.

[0074] In the present invention, the autoimmune disease may be arthritis, rheumatoid arthritis, psoriasis, psoriasis vulgaris, osteoarthritis, localized suppurative disease, ankylosing spondylitis, autoimmune eye disease, dry eye, atopic dermatitis, contact dermatitis, systemic lupus erythematosus, or alopecia areata.

[0075] As long as it does not violate common sense in the art, the above preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0076] In this invention, with the exception of the drug-active component, the reagents and raw materials used are commercially available.

[0077] The positive progressive effects of this invention are: Topical formulations produced from the pharmaceutical compositions provided by the present invention have stable properties, do not crystallize, have a good feel, promote rapid penetration of the drug into the stratum corneum, have excellent epidermal and dermal retention capabilities, deliver the drug to the target area of ​​the skin, reduce systemic side effects, can achieve high local concentrations, have excellent therapeutic effects and stability, and can reduce safety risks. [Brief explanation of the drawing]

[0078] [Figure 1] This is a microscopic observation of the ointment produced in Example 3, part 3A. Here, part 1(a) shows the initial conditions, and part 1(b) shows the condition after being left for 6 months under accelerated conditions. [Figure 2] These are the results of microscopic observation of the cream produced in Example 7 under initial conditions. [Figure 3] These are the microscopic observation results of the hydrogel produced in Example 10 under initial conditions. [Figure 4] These are the microscopic observation results of the organic gel produced in Example 12 under initial conditions. Here, part 4(a) shows the initial conditions, and part 4(b) shows the state after being left for 6 months under accelerated conditions. [Figure 5] This is the result of microscopic observation of the liniment manufactured in Example 13. [Figure 6] This is a square root curve diagram of the cumulative drug release per unit area-time in Effect Example 2. [Figure 7] This is a normalized emission rate curve diagram for Effect Example 2. [Modes for carrying out the invention]

[0079] The present invention will be further described below with reference to the embodiments described, but this does not limit the present invention to the scope of the embodiments described above. In the following embodiments, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or according to the product description.

[0080] In a specific embodiment of the present invention, a drug-active ingredient having structural formula (I) is produced using the production method disclosed in Example 113 of CN113227074A.

[0081] Example 1: Ointment The ointment prescription is as shown in Table 1 below.

[0082] [Table 1]

[0083] The manufacturing steps are as follows:

[0084] (1) Preparation of API solution: The prescribed amounts of the active drug, diethylene glycol monoethyl ether (Transcutol P), and polyethylene glycol 400 (PEG 400) were weighed into a container and heated in a water bath at 80°C, and stirred until completely dissolved.

[0085] (2) Preparation of matrix solution: Take the prescribed amount of polyethylene glycol 3350 (PEG3350) and heat it in a water bath at 80°C, stirring until melted.

[0086] (3) Preparation of ointment: The molten matrix solution was gradually added to the API solution while stirring, and after addition, it was stirred for 10 minutes at a stirring speed of 315 rpm, and then cooled to form the ointment.

[0087] Example 2: Ointment The ointment prescription is as shown in Table 2 below.

[0088] [Table 2]

[0089] The manufacturing steps are as follows:

[0090] (1) Preparation of API solution: The prescribed amounts of the active pharmaceutical ingredient, diethylene glycol monoethyl ether (Transcutol P), and polyethylene glycol 400 (PEG 400) were weighed into a container and heated in a water bath at 80°C, and stirred until the active pharmaceutical ingredient was completely dissolved.

[0091] (2) Preparation of matrix solution: Take the prescribed amount of polyethylene glycol 3350 (PEG3350) and heat it in a water bath at 80°C, stirring until melted.

[0092] (3) Preparation of ointment: The molten matrix solution was gradually added to the API solution while stirring. After addition, the mixture was stirred at a stirring speed of 310 rpm until it cooled to 35°C, and finally allowed to stand and cool to room temperature.

[0093] Example 3: Ointment The ointment prescription is as shown in Table 3 below.

[0094] [Table 3]

[0095] The manufacturing steps are as follows:

[0096] (1) Preparation of API solution: The prescribed amount of the active pharmaceutical ingredient, diethylene glycol monoethyl ether (Transcutol P), and 2 / 3 of the prescribed amount of polyethylene glycol 400 (PEG 400) were weighed into a container and heated at 50°C to 60°C, and stirred until completely dissolved.

[0097] (2) Preparation of matrix solution: The prescribed amount of methylparaben was weighed and added to 1 / 3 of the prescribed amount of PEG400, and stirred at 70±5°C to completely dissolve the methylparaben. Then the prescribed amounts of polyethylene glycol 3350 (PEG 3350) and dibutylhydroxytoluene were added, and stirred at 70±5°C to completely melt the PEG 3350 and dibutylhydroxytoluene. The mixture was then cooled to 50-60°C.

[0098] (3) Preparation of ointment: While maintaining a temperature of 50-60°C, pour the API solution into the matrix solution while stirring, stir for 15 minutes, then add tartrazine to adjust the color, and cool while stirring at room temperature.

[0099] A clean slide glass was taken, an appropriate amount of sample 3A (approximately 0.01g of sample was taken each time) was spread onto the slide glass, and after covering it with a coverslip, it was lightly pressed down. The ointment (in its initial state and after being stored for 6 months at 40°C and 75%RH) was first observed under a microscope with an eyepiece at 10x magnification, an objective lens at 40x magnification, and a polarization of 300°. The results are shown in Figures 1(a) and 1(b), and no crystal precipitation was observed in the ointment.

[0100] Example 4: Ointment The ointment prescription is as shown in Table 4 below.

[0101] [Table 4]

[0102] The manufacturing steps are as follows:

[0103] (1) Preparation of API solution: The prescribed amounts of the active pharmaceutical ingredient, diethylene glycol monoethyl ether (Transcutol P), and polyethylene glycol 400 (PEG 400) were weighed into a container and heated in a water bath at 80°C, and stirred until completely dissolved.

[0104] (2) Preparation of matrix solution: Take the prescribed amount of polyethylene glycol 3350 (PEG3350), curing agent, butylhydroxytoluene, methylparaben, and propylene glycol, and heat in a water bath at 80°C, stirring until melted.

[0105] (3) Preparation of ointment: The molten matrix solution was gradually added to the API solution while stirring. After adding, the mixture was stirred at a stirring speed of 315 rpm for 10 minutes, and finally allowed to stand and cool to room temperature.

[0106] Example 5: Ointment The ointment prescription is as shown in Table 5 below.

[0107] [Table 5]

[0108] The manufacturing steps are as follows:

[0109] (1) Preparation of API solution: The prescribed amounts of the active pharmaceutical ingredient, diethylene glycol monoethyl ether (Transcutol P), and polyethylene glycol 400 (PEG 400) were weighed into a container and heated in a water bath at 80°C, and stirred until completely dissolved.

[0110] (2) Preparation of matrix solution: Take the prescribed amount of polyethylene glycol 3350 (PEG3350) and heat it in a water bath at 80°C, stirring until melted.

[0111] (3) Preparation of ointment: The molten matrix solution was gradually added to the API solution while stirring. After adding, the mixture was stirred at a stirring speed of 315 rpm for 10 minutes, and finally allowed to stand and cool to room temperature.

[0112] Example 6: Ointment The ointment prescription is as shown in Table 6 below.

[0113] [Table 6]

[0114] The manufacturing steps are as follows:

[0115] (1) Preparation of API solution: The prescribed amounts of the active pharmaceutical ingredient, diethylene glycol monoethyl ether (Transcutol P), polyethylene glycol 600 (PEG 600), and humectant were weighed into a container and heated in a water bath at 80°C, and stirred until completely dissolved.

[0116] (2) Preparation of matrix solution: Take the prescribed amount of polyethylene glycol 3350 (PEG3350) and heat it in a water bath at 80°C, stirring until melted.

[0117] (3) Preparation of ointment: The molten matrix solution was gradually added to the API solution while stirring, and after addition, it was stirred for 10 minutes at a stirring speed of 315 rpm, and then cooled to form the ointment.

[0118] Example 7 Cream The cream formulation is as shown in Table 7 below.

[0119] [Table 7]

[0120] The manufacturing steps are as follows:

[0121] (1) Preparation of API solution: The prescribed amount of the active drug ingredient was added to diethylene glycol monoethyl ether (Transcutol P), heated to 80°C to dissolve the drug ingredient, then the prescribed amount of propylene glycol was added and stirred for 3 minutes to mix uniformly.

[0122] (2) Preparation of the oil phase: The prescribed amounts of polyethylene glycol-7 stearate, oleoyl polyoxyethylene glyceride, glyceryl monostearate, glyceryl distearate, and medium-chain triglycerides were weighed and heated to melt them under conditions of 80°C.

[0123] (3) Cream production: While stirring, the API solution was added to the prepared oil phase and homogenization was started (rotation speed 15,000 rpm). The oil phase containing the active ingredient was then gradually added to purified water at 80°C and homogenized for 10 minutes.

[0124] The manufactured cream had a uniform texture. Following the method of Example 3, sample 7A was observed under initial conditions, and the results are shown in Figure 2. The cream showed uniform dispersion of emulsion droplets, with a particle size of approximately 10-30 μm.

[0125] Example 8: Cream The cream formulation is as shown in Table 8 below.

[0126] [Table 8]

[0127] The manufacturing steps are as follows:

[0128] (1) Preparation of API solution: Under conditions of 80°C, the prescribed amount of the active pharmaceutical ingredient was dissolved in a mixture of diethylene glycol monoethyl ether (Transcutol P) and polyethylene glycol 400 (PEG 400).

[0129] (2) Preparation of the oil phase: The prescribed amounts of polyethylene glycol-7 stearate, oleoyl polyoxyethylene glyceride, glyceryl monostearate, glyceryl distearate, and medium-chain triglycerides were weighed and heated to melt them under conditions of 80°C.

[0130] (3) Preparation of the aqueous phase: Hydroxypropyl methylcellulose solution (8A, 8B, 8C): Weigh the prescribed amount of purified water, gradually add hydroxypropyl methylcellulose while stirring, and stir until the hypromellose is completely dissolved. Carbomer solution (8D): The prescribed amount of carbomer was thoroughly dissolved in purified water.

[0131] (4) Cream production: a. Cream production (8A batch / 8B batch): The oil phase and API solution were magnetically stirred in an 80°C water bath and mixed for 5 minutes. When cooled to 50°C, the aqueous phase (hydroxypropyl methylcellulose solution) was added and vigorously stirred for 5 minutes (stirring speed: 520 rpm), then allowed to stand and cool.

[0132] b. Preparation of cream (8C batch): The oil phase and API solution were mixed by magnetic stirring for 10 minutes under 80°C water bath conditions. When cooled to 50°C, the aqueous phase (hydroxypropyl methylcellulose solution) was added and homogenization was started (homogenization rate 9.0±0.2Kr / min), and homogenization was carried out for 5 minutes, while cooling to 30°C during homogenization (homogenization rate 8.8Kr / min).

[0133] c. Preparation of cream (8D batch): The oil phase and API solution were mixed by magnetic stirring in an 80°C water bath for 10 minutes. This was then added to the aqueous phase (carbomer solution) and stirred vigorously for 5 minutes (360 rpm), and then cooled to 30°C while continuing to stir (200 rpm).

[0134] Example 9 Cream The cream formulation is as shown in Table 9 below.

[0135] [Table 9]

[0136] The manufacturing steps are as follows:

[0137] (1) Preparation of API solution: The prescribed amount of the active pharmaceutical ingredient was dissolved in a mixture of diethylene glycol monoethyl ether (Transcutol P) and polyethylene glycol 400 (PEG 400).

[0138] (2) Preparation of the oil phase: The formulation amounts of polyethylene glycol-7 stearate, cetanol (9A), monoglyceride (9B), glyceryl monostearate and glyceryl distearate (9C), light liquid paraffin, and medium-chain triglycerides were weighed and dissolved in a liquid mixture by heating under 80°C water bath conditions.

[0139] (3) Preparation of the aqueous phase: The prescribed amounts of Tween 80 and ethylparaben were dissolved in purified water at 70°C.

[0140] (4) Cream preparation: The oil phase and API solution were magnetically stirred in a 70°C water bath and mixed for 5 minutes. The aqueous phase was added at 70°C, and after high-speed cutting for 5 minutes, an appropriate amount was taken into an EP tube and allowed to stand and cool.

[0141] Example 10 Hydrogel The hydrogel formulations are as shown in Table 10 below.

[0142] [Table 10]

[0143] Note: In the table, "qs" refers to a trace amount.

[0144] The manufacturing steps are as follows:

[0145] (1) Preparation of API solution: A mixture of diethylene glycol monoethyl ether (Transcutol P) and polyethylene glycol 400 (PEG 400) was added to the prescribed amount of the active drug ingredient, and the mixture was stirred at 80°C for 10 minutes to dissolve the active drug ingredient.

[0146] (2) Preparation of carbomer solution: The prescribed amount of carbomer was weighed and fully swollen with purified water.

[0147] (3) Gel preparation: Add the API solution to the prepared carbomer solution while stirring (stirring speed 205 rpm), add a small amount of 2M sodium hydroxide solution, and after adding all of it, continue stirring for 3 minutes to fill the remaining water volume in the formula, and stir for 5 minutes (stirring speed 900 rpm).

[0148] Referencing the method of Example 3, sample 10A was observed under a microscope under initial conditions, and the results are shown in Figure 3. Under initial conditions, a small amount of crystallization was observed in the hydrogel, with a crystal grain size of approximately 15 μm.

[0149] Example 11 Hydrogel The hydrogel formulations are as shown in Table 11 below.

[0150] [Table 11]

[0151] The manufacturing steps are as follows:

[0152] (1) Preparation of API solution: The prescribed amount of the active drug was weighed, diethylene glycol monoethyl ether (or dimethyl sulfoxide) and PEG 400 were added, and the drug was dissolved by stirring at 50°C for 10 minutes.

[0153] (2) Preparation of carbomer solution: The prescribed amount of carbomer was weighed and fully swollen with purified water.

[0154] (3) Gel preparation: Add the API solution to the prepared carbomer solution while stirring (stirring speed 205 rpm). After adding all of the solution, continue stirring for 3 minutes to fill the remaining water volume in the formulation, and stir for 5 minutes (stirring speed 900 rpm).

[0155] Example 12 Organic Gel The formulation of the organic gel is as shown in Table 12 below.

[0156] [Table 12]

[0157] The manufacturing steps are as follows:

[0158] (1) Preparation of API solution: The prescribed amounts of the active pharmaceutical ingredient and diethylene glycol monoethyl ether (Transcutol P) were weighed and stirred at 50°C for 20 minutes.

[0159] (2) Preparation of carbomer solution: The prescribed amount of carbomer was weighed and fully swollen with the prescribed amount of polyethylene glycol 400 or propylene glycol.

[0160] (3) Gel preparation: Add the API solution to the prepared carbomer solution while stirring (stirring speed 205 rpm), and after adding all of it, continue stirring for 3 minutes (stirring speed 900 rpm).

[0161] Referring to the method of Example 3, microscopic observation was performed on sample 12A (initial and accelerated conditions: 40°C, 75% RH, left for 6 months), and as shown in parts 4(a) and 4(b) of Figure 4, no crystallization phenomenon was observed in the organic gel.

[0162] Example 13: Liniment The prescription for the liniment is as shown in Table 13 below.

[0163] [Table 13]

[0164] The manufacturing steps are as follows:

[0165] The prescribed amounts of the active drug ingredient and the penetration enhancer were weighed out. After uniformly mixing the prescribed amount of the penetration enhancer, the active drug ingredient was added and stirred at 50±5°C until completely dissolved. In this example, the liniment is in solution form.

[0166] Referring to the method of Example 3, sample 13A was observed under a microscope under initial conditions, and the results are shown in Figure 5, indicating that there were no crystals in the field of view.

[0167] Comparative Example 1 Compared to Example 1, the difference lies in the formulation, as shown in Table 14 below:

[0168] [Table 14]

[0169] Comparative Example 2 Compared to sample 1A of Example 1, the difference was that the active drug component was replaced with tofacitinib citrate (batch number: HY-170-35-20200327, manufacturer: Shanghai Haoyuan Chemexpress Co., Ltd.), and the number of the manufactured sample was 2a.

[0170] Comparative Example 3 The drug-active ingredient was prepared in 50% PEG400, 10% ethoxydiglycol, and 40% PEG3350 (50% aqueous solution), and the sample number of the prepared sample was 3a.

[0171] Effect Example 1: Microscopic Observation Results Microscopic results, from parts 1(a), 4(a), and 5, confirmed that the ointment, organic gel, and liniment all showed no crystallization under initial conditions. From part 1(b), it was confirmed that the ointment remained stable over a long period without crystallization, and that the product had a uniform texture and a good feel on the skin. From part 4(b), it was found that the organic gel did not show any significant precipitation of large crystals during the stability storage process, and the particle size did not exceed 180 μm. From Figures 2 and 3, it was confirmed that the cream and hydrogel did not show any significant precipitation of large crystals even under initial conditions, and that the particle size was less than 180 μm.

[0172] Effect Example 2: Data on extracorporeal release of ointment The release amount was calculated using the external standard method, and the test method for extracorporeal release is as shown in Table 15 below.

[0173] [Table 15]

[0174] Samples 3A, 3B, 3C, and 3D were studied for extracorporeal release of ointments of different specifications using the extracorporeal release assay method described above, and the results are shown in Table 16 below:

[0175] [Table 16]

[0176] Based on Table 16, a trend line was plotted with the square root of time on the horizontal axis and the (cumulative) amount of drug released per unit area on the vertical axis (see Figure 6). The slope of the trend line represents the release rate, as shown in Table 17 below.

[0177] [Table 17]

[0178] Figure 7 shows a curve plotted with the standard on the horizontal axis and the release velocity (slope) on the vertical axis. Linear regression was performed, and the square of the correlation coefficient (R) 2 The value of ) exceeded 0.90, indicating a linear relationship between the release rates of different specifications.

[0179] The results showed that as the content of the drug-active ingredient increased, the amount and rate of ointment release also increased.

[0180] Effect Example 3: Transdermal penetration of ointment. In vitro transdermal penetration tests of the ointment were performed on samples 1C, 1D, 3A, 3B, 3C, 3D, and 1a.

[0181] The measurement method is as follows: The skin was treated with physiological saline before use, uniformly cut, and dispensed into formulations of each standard (6 samples per standard). The ointment containing the active drug component was applied to the stratum corneum of the skin using a cotton swab, and the amount used was approximately 0.2 g based on the diffusion cell diameter.

[0182] A 2 cm diameter Franz diffusion cell was used, with 10% ethanol-saline as the recipient solution, and the recipient cell volume was approximately 7 mL. Processed pig skin was fixed to the Franz diffusion cell, with the stratum corneum side facing upward as the supply cell surface and the dermis side facing downward as the recipient cell surface. Ointment was uniformly applied to the stratum corneum surface of the skin, with an application amount of 0.2 g. The recipient cell was filled with degassed recipient solution. The diffusion cell was placed in a constant temperature water bath at (32 ± 1) °C, and an electromagnetic stirrer was turned on and continuously stirred at a speed of 200 rpm. At 2, 4, 6, 8, 10, and 24 hours, the entire amount of recipient solution was removed and replenished with the same temperature and volume of recipient solution. The recipient solutions to be tested were stored at 5 °C, and the test was completed after 24 hours, after which the skin on each cup was treated.

[0183] Receptor solution preparation: After the completion of the in vitro transdermal penetration test, 200 μL of the receptor solution was precisely dispensed into a 96-well plate, 200 μL of the internal standard solution (50% methanol aqueous solution of diclofenac sodium, 92.76 ng / mL) was added, and the mixture was vortexed for 10 minutes. The mixture was centrifuged for 15 minutes (5°C, 4000 g), and 200 μL of the supernatant was accurately weighed and transferred to another 96-well plate to obtain the test sample.

[0184] Skin treatment (residual ointment on the skin surface): After the in vitro transdermal penetration test was completed, the permeation diffusion cell was removed, and the presence or absence of obvious ointment on the skin surface was observed. The liquid on the skin surface was gently aspirated using a rubber-tipped pipette, and aspirated and removed as much of the residual ointment liquid as possible, and transferred to a volumetric flask. Next, 2 mL of methanol was transferred to the supply cell using a 1 mL pipette, and the skin surface was gently scraped with a small spoon to dissolve as much of the residual drug on the skin surface as possible in methanol. The washing solution was transferred to the volumetric flask, and the above procedure was repeated 6 times. After sonication for 15 minutes, it was cooled and the volume was adjusted with methanol. The ointment collection solution was stored at 5°C. 10 μL of the ointment collection solution analysis sample was precisely aspirated, diluted with 990 μL of blank matrix, and mixed by vortexing for 3 minutes. Furthermore, more than 200 μL of the analytical sample was drawn into a 1.5 mL EP tube, 600 μL of internal standard solution (50% methanol aqueous solution of diclofenac sodium, 92.76 ng / mL) was added, and the mixture was vortexed for 10 minutes. The mixture was centrifuged for 5 minutes (5°C, 12000 rpm), and 200 μL of the supernatant was accurately weighed and transferred to a 96-well plate to obtain the test sample.

[0185] Skin preparation (skin extract): After the treatment of any remaining ointment on the skin surface was completed, the skin was removed, the ointment on the surface layer was washed away, and any remaining solvent on the skin surface was absorbed with filter paper. Using scissors, the outer layer of skin that was not in direct contact with the ointment was cut off, and a skin area equivalent to the area of ​​the pool opening (i.e., approximately 3.14 cm²) was removed. 2Only the skin was kept, and after weighing the processed skin, it was sealed and stored in EP tubes. The skin was finely chopped, frozen in liquid nitrogen for more than 1 hour, then pulverized into a powder using a cryogenic pulverizer, and the pulverized balls were directly transferred to a 50 mL EP tube. The powder was then transferred to the 50 mL EP tube in small amounts several times using 25 mL methanol, sonicated, and uniformly mixed. 1 mL was then drawn into a 1.5 mL EP tube, and the resulting skin extract was sealed and stored at 5°C. 200 μL of the skin extract was precisely drawn into a 1.5 mL EP tube, 200 μL of internal standard solution (50% methanol aqueous solution of diclofenac sodium, 92.76 ng / mL) was added, and the mixture was vortexed for 10 minutes. The mixture was centrifuged for 5 minutes (5°C, 12000 rpm), and 200 μL of the supernatant was accurately weighed and transferred to a 96-well plate to obtain the test sample.

[0186] The concentrations of pharmacoactive ingredients in the recipient solution, residual ointment on the skin surface, and skin extracts were measured using LC-MS / MS. Cumulative penetration and residual amounts were calculated.

[0187] The results of the transdermal test are shown in Table 18 below:

[0188] [Table 18]

[0189] Results Analysis: In vitro skin penetration results for samples 1a, 1C, and 1D showed that the amount retained per unit area of ​​skin increased as the mass ratio of polyethylene glycol 400 / diethylene glycol monoethyl ether and polyethylene glycol 3350 / diethylene glycol monoethyl ether decreased. Results from comparative samples 3A, 3B, 3C, and 3D showed a certain correlation between the amount of ointment remaining on the skin and the drug load, and that the amount of skin remaining per unit area increased with increasing drug load. The composition of the present invention has a much larger retention / penetration rate, indicating that the amount of the composition of the present invention transferred into the bloodstream is small and the system risk is low.

[0190] Effect Example 4: Stability Test Results Stability tests were performed on samples 3B, 3C, and 3D.

[0191] The analysis method is as follows: (1) Appearance: The properties of the ointment were examined by visual inspection.

[0192] (2) pH value: The ointment was boiled again, diluted 10 times with purified water cooled to room temperature, dispersed by shaking, and the pH value was measured using a pH meter.

[0193] (3) Related substances (impurities, types are shown in Table 19 below): Related substances were measured by high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, General Rules for Four Parts 0512). The method for measuring related substances was as follows: A Waters Xselect Hss T3 C18 column (4.6 × 150 mm 3.5 μm) was used as the column, and a 10 mM aqueous solution of ammonium acetate (precisely 0.77 g of ammonium acetate was transferred to 1000 mL of pure water, mixed uniformly, and degassed) was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed according to Table 20 below, with a flow rate of 1.0 mL / min, column temperature of 15 °C, detection wavelength of 254 nm, run time of 45 min, and needle washing solution of 50% aqueous acetonitrile.

[0194] [Table 19]

[0195] [Table 20]

[0196] (3) Content: The content was measured by high performance liquid chromatography (General Rules for Pharmacopoeia of the People's Republic of China 2020 Edition, Part IV, 0512). The method for measuring the content is as follows: Disodium hydrogen phosphate dodecahydrate buffer solution (weigh 7.20 g of disodium hydrogen phosphate dodecahydrate, add 1000 mL of water and dissolve, adjust the pH to 7.80 ± 0.05 with phosphoric acid, and obtain by suction filtration through a 0.45 μm water-based filter) - acetonitrile (60:40) was used as the mobile phase, eluted at an equal concentration, column temperature: 30 °C, detection wavelength: 255 nm, flow rate: 1.0 mL per minute, injection volume: 10 μL. The detection method for the content is also applicable to the detection of the content of dibutylhydroxytoluene.

[0197] (4) Viscosity: The viscosity was measured using an American Brookfield viscometer.

[0198] (5) Microscopic examination: Take a clean slide glass, apply an appropriate amount of ointment (take about 0.01 g of sample each time) on the slide glass, cover it with a cover glass, gently press it, and first observe the ointment under the microscope under the conditions of an eyepiece magnification of 10 times, an objective lens magnification of 40 times, and a polarization of 300°.

[0199] The results are as follows: A. The results of the 30-day stability test under the conditions of a high temperature of 50 °C and light irradiation ≥ 1.2×10 6 lux·hr are shown in Table 21.

[0200]

Table 21-1

[0201]

Table 21-2

[0202]

Table 21-3

[0203] Note: "ND" indicates less than 0.05% of the reporting limit or not detected, and "-" indicates not applicable.

[0204] B. The results of the stability test for 3 months under accelerated conditions (40 °C, 75% RH) are shown in Table 22.

[0205]

Table 22-1

[0206]

Table 22-2

[0207] C. The results of the stability test for 3 months under long-term conditions (25 °C, 60% RH) are shown in Table 23.

[0208]

Table 23-1

[0209]

Table 23-2

[0210] D. The results of the stability test for 2 months during use (32 °C, 75% RH) are shown in Table 24.

[0211]

Table 24-1

[0212]

Table 24-2

[0213] The results in Tables 21-24 show that, compared to the results on day 0, pharmaceutical compositions of different specifications showed no significant changes in properties such as properties, pH, content, related substances, and viscosity when left for 30 days under influencing conditions and for 3 months under accelerated and long-term conditions. Furthermore, the results of the stability examination during use were also good. In summary, the pharmaceutical compositions of the present invention have excellent stability when used in formulations.

[0214] Effect Example 5: Pharmacokinetic (PK) Test Results Experimental method: Twenty-four female and male Bumaran miniature pigs (12 of each sex) were divided into five groups. The area of ​​ointment application was 10% of the animals' predicted body surface area.

[0215] Animals in Group 1 and Group 2 were given a single application of ointment containing sample 2A and sample 2B to the skin, respectively. In both groups, plasma, stratum corneum, epidermis, and dermis samples were collected before administration (0 hours, plasma only) and at 0.5, 1, 4, 8, 12, and 24 hours after administration.

[0216] In the third group of animals, ointment of sample 2B was applied to the skin once daily for seven consecutive days. Plasma samples were collected before administration (0) and at 0.5, 1, 4, 8, 12, and 24 hours after administration on days 1 and 7. Plasma samples were also collected before administration (0) on days 3, 4, 5, and 6. Stratum corneum, epidermal, and dermal samples were collected at 0.5, 1, 4, 8, 12, and 24 hours after administration on day 7.

[0217] In the animals of Group 4, the ointment of sample 2a was applied to the skin as a single treatment, and samples of plasma, stratum corneum, epidermis, dermis, and subcutaneous tissue were collected before administration (0, plasma only) and at 0.5, 1, 4, 8, 12, and 24 hours after administration.

[0218] Animals in Group 5 received a single application of sample 3a to the skin (6 mg / mL at 25 μL / m²). 2Blood and skin samples were collected at administration, before administration (0), and 0.5, 1, 3, and 6 hours after administration. Blood was collected by venous puncture and collected in a tube containing heparin sodium as an anticoagulant. After washing the exposed skin with soap and water, skin samples were collected. Perforated biopsy tissue from the epidermal layer to the muscle layer was collected at each time point in the administered skin. The epidermis, dermis, subcutaneous tissue, and subcutaneous muscle were rapidly separated, weighed, and frozen in dry ice. The epidermis and dermis were homogenized in physiological saline at a ratio of 1:3 (w / v). The homogenized samples were extracted with 3 volumes of acetonitrile and quantified against a calibration curve using an LC-MS / MS system.

[0219] The concentrations of drug-active components in plasma, stratum corneum, epidermis, and dermal samples were measured using high-performance liquid chromatography-ultraviolet detection (LC-MS / MS).

[0220] [Table 25-1]

[0221] [Table 25-2]

[0222] Note: "h × ng / mL" is the unit corresponding to plasma, and "ng × h / g" is the unit corresponding to skin tissue.

[0223] The results of skin application, comparing the results of 2A and 2B, show that the AUC in different skin layers is positively correlated with the amount used. The pharmacoactive ingredient's AUC in the epidermis and dermis 0-last The relatively high concentration suggests that the drug-active ingredients effectively penetrate the stratum corneum and remain at the therapeutic site. All plasma concentrations of the drug-active ingredients were below the lower limit of quantification, indicating low blood transfer of the drug-active ingredients. Furthermore, 12 μg / cm³ 2 After applying the ointment to the skin once daily for 7 consecutive days, the exposure levels (AUC) in the stratum corneum, epidermis, and dermis of females and males were measured. 0-last and C maxThe results showed almost no change, indicating that the drug active ingredient does not accumulate in the body.

[0224] Compared to compositions with tofacitinib (Sample 2a) and aqueous compositions (Sample 3a), the amount of the drug-active component retained in the epidermis and dermis per unit dose after application of the composition of the drug-active component of the present invention was significantly higher than that of Samples 2a and 3a, indicating that the drug of the present invention penetrates the stratum corneum more effectively to reach the site of action and has excellent permeability.

[0225] Effect Example 6: Stability Test Results A stability test was conducted on sample 3D. The analytical method is as shown in Effect Example 4 below.

[0226] The results of the 6-12 month stability test of sample 3D under long-term conditions (25°C, 60%RH) are shown in Table 26.

[0227] [Table 26]

[0228] As shown in Table 26, the pharmaceutical composition of sample 3D obtained in Example 3 showed no significant changes in properties such as properties, pH, content, related substances, and viscosity when left standing for 6 months, 9 months, and 12 months under influencing conditions. Furthermore, the results of the stability examination during use were also good. In summary, the pharmaceutical composition of the present invention exhibits excellent stability when used in formulations.

[0229] Although specific embodiments of the present invention have been described above, those skilled in the art will know that these are merely illustrative descriptions and that various changes and modifications can be made to these embodiments, provided that they do not contradict the principles of the present invention in substance. Accordingly, the scope of protection of this disclosure is defined by the appended claims.

Claims

1. It contains the drug-active ingredient, diethylene glycol monoethyl ether, and polyethylene glycol 400, and does not contain water. However, the pharmaceutical composition is characterized in that the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 400 is 1:(0.5 to 4.0), and the pharmacoactive component has structural formula (I). 【Chemistry 1】

2. The amount of the drug active ingredient used is 0.001 to 10%, for example, 0.1%, 0.3%, 0.6%, 1.0%, 1.2%, 1.5%, or 2.0%, where % refers to the mass percentage of the drug active ingredient in the pharmaceutical composition. and / or, the amount of diethylene glycol monoethyl ether used is 15 to 40%, for example, 20.0%, 23.0%, or 33.8%, where % refers to the mass percentage of diethylene glycol monoethyl ether in the pharmaceutical composition. and / or, the amount of polyethylene glycol 400 used is 30 to 55%, for example, 30.4%, 38.8%, 45.3%, 52.5%, or 52.9%, where % refers to the mass percentage of polyethylene glycol 400 in the pharmaceutical composition. and / or, the mass ratio of the drug active ingredient to the diethylene glycol monoethyl ether is 1:(10.0 to 250.0), for example 1:13.33, 1:15.33, 1:16.67, 1:16.90, 1:20, 1:23, 1:33.33, 1:66.67, 1:76.67, 1:200, or 1:

230. and / or the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 400 is 1:(0.5 to 3.0), for example 1:0.90, 1:1.94, 1:1.97, 1:2.63 or 2.

65. and / or the pharmaceutical composition further comprises polyethylene glycol 3350, and / or the pharmaceutical composition according to claim 1, further comprising one or more of antioxidants, preservatives, curing agents, and humectants.

3. When the pharmaceutical composition contains polyethylene glycol 3350, the amount of polyethylene glycol 3350 used is 25.0 to 50.0%, preferably 25.0 to 45.0%, for example 25.8%, 26.3%, 26.5%, 27%, 27.2%, 30%, 30.5%, 31.2%, 31.4%, 33.8%, or 40%. And / or, if the pharmaceutical composition contains polyethylene glycol 3350, the mass ratio of diethylene glycol monoethyl ether to polyethylene glycol 3350 is 1:(0.5 to 3.6), preferably 1:(0.5 to 3.0), for example 1:1.00, 1:1.29, 1:1.30, 1:1.32, 1:1.33, 1:1.35, 1:1.36, 1:1.37 or 1:2.

00. and / or, the antioxidant is an aromatic amine antioxidant, for example, dibutylhydroxytoluene, and / or, the amount of the antioxidant used is 0.05 to 0.2%, for example, 0.1%. and / or, the preservative is one or more of methylparaben, sorbic acid, and its salts, for example, methylparaben. and / or, the amount of preservative used is 0.05 to 0.2%, for example, 0.1%. and / or, the curing agent is one or more of paraffin, beeswax, cetearyl alcohol, white petrolatum, glyceryl monostearate, and glyceryl distearate. and / or, the amount of the curing agent used is 5 to 40%, for example, 9.8%, 22.1%, 30.65%, or 37.6%. and / or, the humectant is one or more of glycerin, light liquid paraffin, soybean oil, medium-chain triglycerides, sodium hyaluronate, urea, propylene glycol, butylene glycol, panthenol, sodium pyrrolidone carboxylate, and trehalose, preferably propylene glycol. The pharmaceutical composition according to claim 1 or 2, wherein the amount of the humectant used is 2 to 80%, for example, 5.0%, 9.0%, 20.0%, 37.5%, or 77.5%.

4. The pharmaceutical composition comprises the drug-active ingredient, diethylene glycol monoethyl ether, polyethylene glycol 400, and polyethylene glycol 3350, and the pharmaceutical composition does not contain water. Here, the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 400 is 1:(0.5 to 4.0), and the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 3350 is 1:(0.5 to 3.6). Preferably, the pharmaceutical composition comprises the drug active ingredient, diethylene glycol monoethyl ether, polyethylene glycol 400, and polyethylene glycol 3350, and the pharmaceutical composition does not contain water. Here, the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 400 is 1:(0.5 to 3.0), and the mass ratio of the diethylene glycol monoethyl ether to the polyethylene glycol 3350 is 1:(0.5 to 3.0), More preferably, by weight percentage, the pharmaceutical composition is Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0–33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-40.0% Includes, More preferably, By weight percentage, the pharmaceutical composition is Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0–33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-40.0% Dibutylhydroxytoluene 0-0.1% Methylparaben 0-0.1% Tartrazine 0-0.001% Beeswax 0-30.65% Cetearyl alcohol 0-9.8% White petrolatum 0-22.1% Propylene glycol 0-20.0% A pharmaceutical composition according to any one of claims 1 to 3, comprising:

5. A topical preparation comprising the pharmaceutical composition described in any one of claims 1 to 4.

6. The aforementioned topical preparation is a liquid preparation or a semi-solid preparation. The liquid formulation is preferably a liniment or tincture, and the semi-solid formulation is preferably a cream, organic gel, ointment, or paste. Preferably, the ointment formulation is as follows, by weight percentage: Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0–33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-40.0% Includes, more, The composition of the ointment, expressed by weight percentage, Drug-active ingredient 0.6-2.0% Diethylene glycol monoethyl ether 20.0–33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 26.3-40.0% Does it include, Or, The composition of the ointment, expressed by weight percentage, Drug-active ingredient 0.1-1.5% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 25.8-27.2% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Does it include, Or, The composition of the ointment, expressed by weight percentage, Drug-active ingredient 0.1-1.5% Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 30.0-31.4% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Tartrazine 0.00025-0.001% Does it include, Or, By weight percentage, the ointment is, Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0–33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-50.0% Paraffin 0-5% Beeswax 0-30.65% Cetearyl alcohol 0-9.8% White petrolatum 0-22.6% Glyceryl monostearate and glyceryl distearate 0-10% Propylene glycol 0-20.0% Dibutylhydroxytoluene 0-0.1% Methylparaben 0-0.1% Polyethylene glycol 600 0-25.0% Light liquid paraffin 0-5.0% Soybean oil 0-5.0% Medium-chain triglycerides 0-5.0% Does it include, Or, By weight percentage, the ointment is, Drug-active ingredient 0.1-2.0% Diethylene glycol monoethyl ether 20.0–33.8% Polyethylene glycol 400 30.4-52.9% Polyethylene glycol 3350 25.8-40.0% Dibutylhydroxytoluene 0-0.1% Methylparaben 0-0.1% Tartrazine 0-0.001% Beeswax 0-30.65% Cetearyl alcohol 0-9.8% White petrolatum 0-22.1% Propylene glycol 0-20.0% Includes, More preferably, The composition of the ointment, expressed by weight percentage, 0.6% of the drug-active ingredient Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.9% Polyethylene glycol 3350 26.5% Does it include, Or, The composition of the ointment, expressed by weight percentage, Pharmacologically active ingredient 1.2% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 26.3% Does it include, Or, The composition of the ointment, expressed by weight percentage, Pharmacologically active ingredient 1.2% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 38.8% Polyethylene glycol 3350 40.0% Does it include, Or, The composition of the ointment, expressed by weight percentage, Drug-active ingredient 2.0% Diethylene glycol monoethyl ether 33.8% Polyethylene glycol 400 30.4% Polyethylene glycol 3350 33.8% Does it include, Or, The composition of the ointment, expressed by weight percentage, 0.1% of the drug-active ingredient Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 27.2% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Does it include, Or, The composition of the ointment, expressed by weight percentage, 0.3% of the drug-active ingredient Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 27.0% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Does it include, Or, The composition of the ointment, expressed by weight percentage, Pharmacologically active ingredient 1.0% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 26.3% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Does it include, Or, The composition of the ointment, expressed by weight percentage, Pharmacologically active ingredient 1.5% Diethylene glycol monoethyl ether 20.0% Polyethylene glycol 400 52.5% Polyethylene glycol 3350 25.8% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Does it include, Or, The composition of the ointment, expressed by weight percentage, 0.1% of the drug-active ingredient Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 31.4% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Tartrazine 0.001% Does it include, Or, More preferably, the ointment formulation in terms of weight percentage is: 0.3% of the drug-active ingredient Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 31.2% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Tartrazine 0.0007% Includes, More preferably, the ointment formulation in terms of weight percentage is: Pharmacologically active ingredient 1.0% Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 30.5% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% Tartrazine 0.00025% Does it include, Or, The composition of the ointment, expressed by weight percentage, Pharmacologically active ingredient 1.5% Diethylene glycol monoethyl ether 23.0% Polyethylene glycol 400 45.3% Polyethylene glycol 3350 30.5% Dibutylhydroxytoluene 0.1% Methylparaben 0.1% The topical formulation according to claim 5, comprising:

7. A method for producing a pharmaceutical composition according to any one of claims 1 to 6, (1) Preparation of API solution: Mix the drug active ingredient, diethylene glycol monoethyl ether and polyethylene glycol 400 at 50-80°C until dissolved. (2) Preparation of matrix solution: A step of heating polyethylene glycol 3350 at 50 to 80°C to melt it, (3) Manufacturing of ointment: step of mixing the API solution and the matrix solution under stirring conditions A method for producing a pharmaceutical composition, characterized by containing the following:

8. In step (1), the mixing temperature is 50°C or 80°C. and / or, in step (2), the raw materials further include one or more antioxidants, preservatives, curing agents and humectants, and / or, in step (2), the raw material further comprises diethylene glycol monoethyl ether, preferably, if the raw material in step (2) comprises diethylene glycol monoethyl ether, the amount of diethylene glycol monoethyl ether used in step (1) shall be 2 / 3 of the formulation amount, and the amount of diethylene glycol monoethyl ether used in step (2) shall be 1 / 3 of the formulation amount. and / or, in step (2), the heating temperature is 50°C or 80°C. and / or, in step (3), the rotational speed of the stirring is 315 rpm, and / or, in step (3), the stirring time is 10 to 15 mins. and / or, in step (3), the temperature of the mixture is 50°C to 60°C. and / or, a method for producing a pharmaceutical composition according to claim 7, further comprising a cooling operation after the mixing is completed in step (3).

9. The use of a pharmaceutical composition according to any one of claims 1 to 4, or a topical preparation according to claim 5 or 6, in the manufacture of a pharmaceutical for treating an autoimmune disease, Preferably, the autoimmune disease is arthritis, rheumatoid arthritis, psoriasis, psoriasis vulgaris, osteoarthritis, localized suppurative disease, ankylosing spondylitis, autoimmune eye disease, dry eye, atopic dermatitis, contact dermatitis, systemic lupus erythematosus, or alopecia areata.

10. The method involves administering to a subject a therapeutically effective amount of the pharmaceutical composition described in any one of claims 1 to 4, or the topical formulation described in claim 5 or 6. Preferably, the autoimmune disease is arthritis, rheumatoid arthritis, psoriasis, psoriasis vulgaris, osteoarthritis, localized suppurative disease, ankylosing spondylitis, autoimmune eye disease, dry eye, atopic dermatitis, contact dermatitis, systemic lupus erythematosus, or alopecia areata, and is a method for treating an autoimmune disease.

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