Pharmaceutical compositions containing JAK inhibitors and methods for producing and using same

Abstract

The present invention discloses a pharmaceutical composition containing a JAK inhibitor and its manufacturing method and use, specifically, a pharmaceutical composition containing a compound represented by formula I or a compound represented by formula II or a pharma- ceutical acceptable salt thereof in a mass fraction of 0.1%-3%, a solvent in a mass fraction of 35%-93%, and a permeation enhancer in a mass fraction of 5%-63%. When the pharmaceutical composition of the present invention is used as an external liniment, it has good permeability and stability. JPEG2025511939000037.jpg5837 JPEG2025511939000038.jpg4938

Description

[Technical field]

[0001] The present invention belongs to the field of medical technology, specifically to a pharmaceutical composition containing a JAK inhibitor and its preparation method and use. [Background technology]

[0002] JAK inhibitors can selectively inhibit JAK kinase and block the JAK / STAT pathway. The JAK-STAT signaling pathway is a recently discovered cytokine-stimulated signaling pathway that is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Janus kinase is a non-receptor tyrosine protein kinase with four family members, JAK1, JAK2, TYK2 and JAK3. The first three are widely present in various tissues and cells, but JAK3 is only present in the bone marrow and lymphatic system. Clinically, JAK inhibitors are mainly used to screen therapeutic drugs for blood diseases, tumors, rheumatoid arthritis and psoriasis.

[0003] Currently, several JAK inhibitors are in clinical research, but most of them have low selectivity and generally have inhibitory effects on all four kinases in the family. According to studies such as Quintas-Cardama A, selective JAK inhibitors have been used in clinical trials for rheumatoid arthritis (RA), psoriasis and other autoimmune diseases, and have been shown to significantly reduce the size of the spleen in patients, improve the clinical symptoms of patients, and improve the quality of life. Currently, the FDA has approved two types of JAK inhibitors, ruxolitinib, a product developed by the multinational pharmaceutical company Novartis, and tofacitinib, a product developed by Pfizer. Ruxolitinib mediates several cytokine and growth factor signals that are important for hematopoiesis and immune function through inhibition of the JAK pathway, and is the first oral drug approved specifically for the treatment of myelofibrosis, and tofacitinib is the first oral JAK inhibitor approved for the treatment of RA.

[0004] Alopecia areata is a common non-scarring alopecia, the cause and mechanism of its onset have not been fully elucidated, but the currently recognized mechanism is an organ-specific autoimmune disease mediated by T cells. In patients with alopecia areata, the immune structure of the anagen hair follicle is destroyed, autoimmune inflammation occurs in the hair follicle, the hair follicle cycle is altered, and hair enters the telogen phase early. Many cytokines involved in the onset mechanisms of autoimmune and inflammatory diseases all transmit intracellular signals through the JAK / STAT signaling pathway.

[0005] Atopic dermatitis (AD) is a pruritic eczematous dermatitis with long-term fluctuations in symptoms with remission and relapse.Currently, the main treatments for controlling atopic skin inflammation are topical corticosteroids and calcineurin inhibitors, but these drugs have potential safety risks and side effects such as severe skin atrophy and telangiectasia.The pathology of atopic dermatitis is an immunological dysfunction that manifests as skin barrier dysfunction and pruritus.

[0006] Clinical studies have shown that JAK inhibitors are very effective in treating autoimmune diseases, but currently, most JAK inhibitors are oral drugs, and oral drugs are systemic drugs, which may cause serious side effects.The JAK inhibitor represented by formula I or the JAK inhibitor represented by formula II (the compounds are further described in patent CN103936757A and WO2014111037A) can bind to JAK protein, thereby inhibiting JAK phosphorylation and inhibiting downstream STAT phosphorylation, inhibiting the signal transduction of related factors that depend on the JAK / STAT pathway, such as IFN-γ, IL-6 and IL-15, blocking intracellular signal transduction, and inhibiting multiple inflammatory cytokines, such as immune cell activation and T cell-mediated inflammatory diseases. [ka] JPEG2025511939000003.jpg4938 [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Chinese Patent Application Publication No. CN103936757 [Patent Document 2] International Publication No. 2014111037 Summary of the Invention [Problem to be solved by the invention]

[0008] The technical problem to be solved by the present invention is to provide a pharmaceutical composition containing a JAK inhibitor and its preparation method and use, in order to overcome the safety risk of systemic drug exposure caused by long-term oral administration of JAK inhibitors in the prior art. The pharmaceutical composition containing a JAK inhibitor of the present invention is applied locally and has the advantages of good penetration effect, good stability and few side effects. [Means for solving the problem]

[0009] The present invention mainly solves the above technical problems through the following technical solutions:

[0010] The present invention provides a JAK inhibitor-containing pharmaceutical composition comprising, as ingredients, 0.1% to 3% by mass of a compound represented by formula I or a pharma- ceutical acceptable salt thereof, 35% to 93% by mass of a solvent, and 5% to 63% by mass of a penetration enhancer, the solvent is selected from one or more of water, glycerin, polyethylene glycol 400, dimethylsulfoxide, ethyl acetate, propylene glycol, and ethanol; The penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, azone, urea, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea, isopropyl myristate, cyclodextrin, sodium dodecyl sulfate, polyoxyethylene lauryl ether, polyethylene glycol hexadecyl ether, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, glyceryl monocaprylate, caprylic / capric mono / diglycerides, propylene glycol monolaurate, propylene glycol monocaprylate, and glyceryl behenate. [ka] I

[0011] In a specific embodiment of the present invention, the JAK inhibitor-containing pharmaceutical composition comprises, by mass fraction, 0.1% to 3% of a compound represented by formula I or a pharma- ceutically acceptable salt thereof, 35% to 93% of a solvent, and 5% to 63% of a penetration enhancer; the solvent is selected from one or more of water, glycerin, polyethylene glycol 400, dimethylsulfoxide, ethyl acetate, propylene glycol, and ethanol; The penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, azone, urea, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea, propyl gallate, isopropyl myristate, cyclodextrin, sodium dodecyl sulfate, polyoxyethylene lauryl ether, polyethylene glycol hexadecyl ether, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, glyceryl monocaprylate, mono- and diglycerides of capric and caprylic acids, propylene glycol monolaurate, propylene glycol monocaprylate, and glyceryl behenate. In a specific embodiment of the present invention, the mass fraction of the compound represented by formula I or a pharma- ceutically acceptable salt thereof is preferably 0.3% to 2.5%, more preferably 0.5% to 2%, for example 0.5% or 2%.

[0012] In certain embodiments of the present invention, the mass fraction of the solvent is preferably 38% to 90%, more preferably 40% to 88%, for example 40%, 45%, 69.3%, 81%, 82.5% or 87.94%, and particularly preferably 78% to 85%, for example 81% or 82.5%.

[0013] In certain embodiments of the invention, the mass fraction of the penetration enhancer is preferably 8% to 60%, more preferably 10% to 58%, for example 10.06%, 17%, 28.7%, 53% or 58%, particularly preferably 15% to 19%, for example 17%.

[0014] In certain embodiments of the invention, the solvent is preferably selected from one or more of polyethylene glycol 400, dimethyl sulfoxide, propylene glycol and ethanol, such as polyethylene glycol 400, a mixed solvent of polyethylene glycol 400 and dimethyl sulfoxide, a mixed solvent of polyethylene glycol 400, propylene glycol and ethanol, or a mixed solvent of polyethylene glycol 400, propylene glycol and dimethyl sulfoxide.

[0015] In certain embodiments of the present invention, the solvent is more preferably selected from one or more of polyethylene glycol 400, dimethyl sulfoxide, and propylene glycol, and particularly preferably a mixed solvent of polyethylene glycol 400, dimethyl sulfoxide, and propylene glycol.

[0016] In certain embodiments of the invention, the penetration enhancer is preferably selected from one or more of diethylene glycol monoethyl ether, azone, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea and propyl gallate, such as a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and oleic acid, a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and diisopropyl adipate, a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and menthol, a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and N-methylpyrrolidone, a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and imidurea, a mixed penetration enhancer of diethylene glycol monoethyl ether and azone, a mixed penetration enhancer of diethylene glycol monoethyl ether and oleic acid, or a mixed penetration enhancer of diethylene glycol monoethyl ether and menthol.

[0017] In certain embodiments of the invention, the penetration enhancer is more preferably selected from one or two of diethylene glycol monoethyl ether and oleic acid, with a mixed penetration enhancer of diethylene glycol monoethyl ether and oleic acid being particularly preferred.

[0018] In a specific embodiment of the present invention, when the solvent is a mixed solvent of polyethylene glycol 400 and dimethyl sulfoxide, the mass ratio of the polyethylene glycol 400 and dimethyl sulfoxide is preferably 6:1 to 10:1, more preferably 7:1 to 9:1, for example 8:1.

[0019] In a specific embodiment of the present invention, when the solvent is a mixed solvent of polyethylene glycol 400, propylene glycol, and ethanol, the mass ratio of the polyethylene glycol 400 and propylene glycol is preferably 2:1 to 6:1, more preferably 3:1 to 5:1, for example 4:1. The mass ratio of the propylene glycol and ethanol is preferably 1:1 to 1:3, more preferably 1:1.5 to 1:2.5, for example 1:2.

[0020] In a specific embodiment of the present invention, when the solvent is a mixed solvent of polyethylene glycol 400, propylene glycol, and dimethyl sulfoxide, the mass ratio of the polyethylene glycol 400 to dimethyl sulfoxide may be 3:1 to 10:1. The mass ratio of the propylene glycol to dimethyl sulfoxide may be 3:1 to 9:1.

[0021] In a specific embodiment of the present invention, when the solvent is a mixed solvent of polyethylene glycol 400, propylene glycol and dimethyl sulfoxide, the mass ratio of the polyethylene glycol 400 to dimethyl sulfoxide is preferably 6:1 to 10:1, more preferably 7:1 to 9:1, for example 8:1 or 8.3:1. The mass ratio of the propylene glycol to dimethyl sulfoxide is preferably 5:1 to 9:1, more preferably 6:1 to 8:1, for example 7.2:1.

[0022] In a specific embodiment of the present invention, when the solvent is a mixed solvent of polyethylene glycol 400, propylene glycol and dimethyl sulfoxide, the mass ratio of the polyethylene glycol 400 to dimethyl sulfoxide may be 4: 1. The mass ratio of the propylene glycol to dimethyl sulfoxide may be 3.794: 1.

[0023] In certain embodiments of the present invention, when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and oleic acid, the mass ratio of the diethylene glycol monoethyl ether and oleic acid is preferably 2:1 to 5:1, more preferably 3:1 to 4:1, for example 3.57:1. The mass ratio of the propyl gallate and oleic acid is preferably 2:1 to 5:1, more preferably 3:1 to 4:1, for example 3.71:1.

[0024] In certain embodiments of the present invention, when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate, and diisopropyl adipate, the mass ratio of the diethylene glycol monoethyl ether and diisopropyl adipate is preferably 2:1 to 5:1, more preferably 3:1 to 4:1, for example 3.57:1. The mass ratio of the propyl gallate and diisopropyl adipate is preferably 2:1 to 5:1, more preferably 3:1 to 4:1, for example 3.71:1.

[0025] In certain embodiments of the present invention, when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and menthol, the mass ratio of the diethylene glycol monoethyl ether and menthol is preferably 150:1 to 430:1, more preferably 160:1 to 420:1, for example 166.67:1 or 416.67:1. The mass ratio of the propyl gallate and menthol is preferably 530:1 to 730:1, more preferably 540:1 to 720:1, for example 549:1 or 715.67:1.

[0026] In a particular embodiment of the present invention, when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and N-methylpyrrolidone, the mass ratio of the diethylene glycol monoethyl ether and N-methylpyrrolidone is preferably 2:1 to 5:1, more preferably 3:1 to 4:1, for example 3.57:1. The mass ratio of the propyl gallate and N-methylpyrrolidone is preferably 2:1 to 5:1, more preferably 3:1 to 4:1, for example 3.71:1.

[0027] In certain embodiments of the present invention, when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and imidurea, the mass ratio of the diethylene glycol monoethyl ether and imidurea is preferably 610:1 to 640:1, more preferably 620:1 to 630:1, for example 625:1. The mass ratio of the propyl gallate and imidurea is preferably 810:1 to 840:1, more preferably 820:1 to 830:1, for example 824:1.

[0028] In certain embodiments of the present invention, when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether and azone, the mass ratio of the diethylene glycol monoethyl ether and azone is preferably 4:1 to 8:1, more preferably 5:1 to 7:1, for example 6.27:1.

[0029] In certain embodiments of the present invention, when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether and oleic acid, the mass ratio of the diethylene glycol monoethyl ether and oleic acid is preferably 1.2:1 to 1.6:1, more preferably 1.3:1 to 1.5:1, for example 1.43:1.

[0030] In certain embodiments of the present invention, when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether and menthol, the mass ratio of the diethylene glycol monoethyl ether and menthol is preferably 150:1 to 180:1, more preferably 160:1 to 170:1, for example 166.67:1.

[0031] In certain embodiments of the invention, the JAK inhibitor-containing pharmaceutical composition is composed of 0.1% to 3% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 35% to 93% of a solvent, and 5% to 63% of a penetration enhancer.

[0032] In certain embodiments of the invention, the JAK inhibitor-containing pharmaceutical composition is preferably composed of components as shown in any one of the schemes below.

[0033] Scheme 1: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 26% propyl gallate and 7% oleic acid.

[0034] Scheme 2: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 26% propyl gallate and 7% diisopropyl adipate.

[0035] Scheme 3: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 32.94% propyl gallate, and 0.06% menthol.

[0036] Scheme 4: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 26% propyl gallate and 7% N-methylpyrrolidone.

[0037] Scheme 5: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 10% diethylene glycol monoethyl ether, 42.94% propyl gallate, 0.06% menthol and 5% dimethyl sulfoxide.

[0038] Scheme 6: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 32.96% propyl gallate and 0.04% imidurea.

[0039] Scheme 7: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 39.6% polyethylene glycol 400, 24.75% diethylene glycol monoethyl ether, 9.9% propylene glycol, 19.8% ethanol and 3.95% azone.

[0040] Scheme 8: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 10% diethylene glycol monoethyl ether, 36% propylene glycol, 7% oleic acid and 5% dimethyl sulfoxide.

[0041] Scheme 9: 0.5% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 41.5% polyethylene glycol 400, 10% diethylene glycol monoethyl ether, 36% propylene glycol, 7% oleic acid and 5% dimethyl sulfoxide.

[0042] Scheme 10: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 10% diethylene glycol monoethyl ether, 37.94% propylene glycol, 0.06% menthol and 10% dimethyl sulfoxide.

[0043] Scheme 11: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 32.96% propyl gallate and 0.06% imidurea.

[0044] Scheme 12: 2% of the compound of formula I or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 32.96% propyl gallate, and 3.96% imidurea.

[0045] All percentages above are by weight.

[0046] In a specific embodiment of the present invention, in the above Schemes 1 to 10, the compound represented by formula I or a pharma- ceutically acceptable salt thereof is preferably a compound represented by formula I. In a specific embodiment of the present invention, in the above Schemes 1 to 12, the compound represented by formula I or a pharma- ceutically acceptable salt thereof is preferably a compound represented by formula I.

[0047] In certain embodiments of the present invention, the JAK inhibitor-containing pharmaceutical composition is more preferably composed of the components shown in Scheme 8 or Scheme 9 above.

[0048] In certain embodiments of the invention, the pharmaceutical composition may be made into an ointment, gel, solution, spray, suspension, preferably a solution.

[0049] In each embodiment of the JAK inhibitor-containing pharmaceutical composition, the compound represented by formula I may be replaced with a compound represented by formula II. [ka]

[0050] The present invention further provides a method for preparing the JAK inhibitor-containing pharmaceutical composition, comprising the step of mixing the compound of formula I or a pharma- ceutically acceptable salt thereof, the solvent, and the penetration enhancer.

[0051] In a particular embodiment of the present invention, the method for preparing the JAK inhibitor-containing pharmaceutical composition preferably comprises the steps of mixing the solvent and the penetration enhancer, and then dissolving the compound of formula I or a pharma- ceutically acceptable salt thereof therein to obtain the JAK inhibitor-containing pharmaceutical composition. The compound of formula I or a pharma- ceutically acceptable salt thereof is preferably the compound of formula I.

[0052] In a particular embodiment of the present invention, the dissolution method may be ultrasonic, or heating, or a combination of both. The heating is preferably water bath heating. The temperature of the heating is preferably 60°C to 70°C.

[0053] In certain embodiments of the invention, when the JAK inhibitor-containing pharmaceutical composition comprises dimethylsulfoxide (e.g., when the pharmaceutical composition is according to Scheme 5, Scheme 8, Scheme 9, or Scheme 10), the method for its preparation preferably comprises the steps of:

[0054] (1) mixing dimethyl sulfoxide and the compound represented by formula I or a pharma- ceutically acceptable salt thereof in the above-mentioned components to obtain a mixed solution; (2) mixing all the components except dimethylsulfoxide and the compound represented by formula I or a pharma- ceutically acceptable salt thereof to obtain a mixed solution; (3) mixing the mixed solution of step (1) with the mixed solution of step (2) to obtain a pharmaceutical composition containing the JAK inhibitor.

[0055] Preferably, the compound represented by formula I or a pharma- ceutically acceptable salt thereof is a compound represented by formula I above.

[0056] Preferably, in step (3), the mixing comprises adding the mixed solution of step (2) to the mixed solution of step (1).

[0057] Preferably, the mixed solution in step (1) and the mixed solution in step (2) are each uniformly mixed by stirring. The rotation speed of the stirring is preferably 1500 rpm to 2500 rpm, for example, 2000 rpm.

[0058] In certain embodiments of the invention, the prepared JAK inhibitor-containing pharmaceutical composition is preferably stored at room temperature in the dark.

[0059] In each embodiment of the method for producing a pharmaceutical composition containing a JAK inhibitor, the compound represented by formula I may be replaced with a compound represented by formula II. [ka]

[0060] The present invention further provides an external liniment which may contain the JAK inhibitor-containing pharmaceutical composition.

[0061] The present invention further provides use of the pharmaceutical composition containing a JAK inhibitor or the external liniment in the prevention, alleviation or treatment of a skin autoimmune disease associated with a JAK kinase.

[0062] In certain embodiments of the present invention, said skin autoimmune disease is preferably selected from one or more of alopecia areata, atopic dermatitis and psoriasis.

[0063] In the present invention, the solvent can promote dissolution of the active ingredient. The penetration enhancer can promote penetration of the active ingredient. In some cases, the solvent can also promote penetration of the active ingredient. The penetration enhancer can also promote dissolution of the active ingredient.

[0064] In the present invention, the term "pharmaceutical acceptable salt" refers to a pharmaceutical acceptable organic or inorganic salt of the compound of the present invention.Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, glycolate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1-1-methylene-bis(2-hydroxy-3-naphthoate)).

[0065] As long as it does not violate the common knowledge in the art, each of the above-mentioned preferable conditions can be arbitrarily combined to obtain each of the preferable embodiments of the present invention.

[0066] All of the reagents and raw materials used in the present invention are commercially available. Effect of the Invention

[0067] The positive effect of the present invention is that it provides a novel pharmaceutical composition of a JAK inhibitor-containing external liniment, which has a wide safety range and good permeability and stability. [Brief description of the drawings]

[0068] [Figure 1] Average cumulative permeability of formulations C, D and E at 2% (w / w) in an in vitro permeability study. [Diagram 2] 1 shows the mean cumulative permeability of formulations F11, A2 and E2 at 2% (w / w) in an in vitro permeability study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] This application claims priority from Chinese Patent Application No. 2022103807021, filed on April 8, 2022, and from Chinese Patent Application No. 2023103262452, filed on March 22, 2023. This application cites the above-mentioned Chinese patent application in full.

[0070] The present invention will be further described below in the form of examples, but the present invention is not limited to the scope of the examples. In the following examples, the experimental methods for which no specific conditions are described are selected according to the usual methods and conditions or product instructions.

[0071] Example 1: Saturation solubility test of the compound of formula I in different solvents [Table 1]

[0072] Example 2: Preparation of a pharmaceutical composition containing 2% (w / w) of a compound of formula I [Table 2]

[0073] Manufacturing method: (1) According to the ratios in Table 2, 9.8 g of blank formulations A, B, C, D, E and H were prepared, weighed, and then vigorously shaken and ultrasonically mixed uniformly. (2) 0.1 g of the active ingredient compound represented by formula I was weighed out in six portions and placed in clean capped vials, to which 4.9 g of the blank formulation solution prepared above was added. (3) Continue to treat with ultrasonic waves at room temperature for 30 minutes, if the sample does not dissolve and become transparent, place the sample in a water bath at 70°C and heat, the sample will completely dissolve and become transparent, and place it in the dark at room temperature for use.

[0074] Example 3: Preparation of a pharmaceutical composition containing 2% (w / w) of a compound of formula I [Table 3]

[0075] Manufacturing method: (1) 9.8 g of blank formulations F11, A2, and E2 were prepared according to the ratios in Table 3, weighed, and then vigorously shaken and ultrasonically mixed uniformly. (2) 0.1 g of the active ingredient compound represented by formula I was weighed out in three separate batches and placed in clean capped vials, to which 4.9 g of the blank formulation solution prepared above was added. (3) Formula E2 was completely dissolved by ultrasonic treatment for 30 minutes, F11 and A2 were heated in a 70°C water bath for 5 minutes, F11 was completely dissolved by ultrasonic treatment for 2 minutes, and then formula A2 was completely dissolved by continued heating for 2 minutes, and the mixture was stored in a dark place at room temperature for use.

[0076] Example 4: In Vitro Permeation Testing (IVPT) (1) Preparation before the experiment The transdermal diffusion instrument was turned on, and the parameters were set as follows: temperature: 32°C, rotation speed: 600 rpm. Clean diffusion receptor cells corresponding to the number of formulations were selected and numbered, and the standard volume was recorded in a bottle. A part of the rat's skin was selected to perform a parallel experiment with the diffusion cell using the corresponding number of formulations. After removal, the hair was shaved while still cold, and a circular rat skin was cut out with the same diameter as the supply chamber of the corresponding number of formulations. After fixing the rat skin with a clamp, a blank receptor cell solution (0.1x PBS) was added. When adding, attention was paid to removing air bubbles, and the receptor cells of the corresponding number of formulations were sequentially placed into the transdermal diffusion instrument, incubated at 32°C for 30 minutes, and the experiment was started when the temperature of the blank receptor cell solution reached 32°C.

[0077] (2) Experimental procedure The prototype formulation solution of the corresponding numbered formulation was added to the top of each receptor cell, and each formulation was added with a drop of 20 μl each, and evenly applied with a pipette tip. During the experiment, the state of the drug solution on the skin at the mouth of the top of each diffusion cell was observed. Sampling times of 18 hours, 24 hours, 36 hours, and 48 hours were set. Five minutes before sampling at each sampling point, blank receptor cell solution was added to the mouth, and the diffusion receptor cell solution was rinsed using the corresponding numbered syringe and the No. 16 rat intragastric administration needle. After rinsing was completed, 2 ml of sample was taken and placed in a 5 ml centrifuge tube and numbered. Centrifugation conditions: 12000 rpm, centrifuged at room temperature for 10 minutes, the supernatant was collected, and liquid phase detection was performed. After sampling and centrifugation were completed, blank receptor cell solution was added to the sampling port of each diffusion receptor cell, and the solution was added to the mouth to observe the transdermal state of the formulation. After 48 hours of sampling, the solution refill was stopped and the device was turned off.

[0078] After sampling at each time point, centrifuging and filtering, liquid phase detection was performed, and the liquid phase detection analysis method is as shown in the table below. [Table 4]

[0079] (3) Skin preparation of rats after the experiment After aspirating the receptor cell solution, the diffusion receptor cell device of each number was washed with a blank dilution solution (acetonitrile:water = 4:1) to remove the drug solution remaining on the rat skin. The rat skin was peeled off from each diffusion cell, and the shaved area was wiped dry with coarse filter paper. The area in contact with the receptor cell was rinsed with water, wiped dry with coarse filter paper, placed in the corresponding homogenization tube with the label number, weighed, stored in a refrigerator at -20 °C, and detected by LC-MS.

[0080] (4) Sampling detection results of receptor cells The average cumulative permeability of six formulations, C, D, E, F11, A2, and E2, at 2% (w / w) standard, was detected at each sampling point.

[0081] (5) Experimental results [Table 5]

[0082] From the results of FIG. 1 and Table 5, it was found that the average cumulative permeability at each sampling time point in the in vitro permeability test of formulations C, D, and E was in the order of D>E>C.

[0083] [Table 6]

[0084] The results of FIG. 2 and Table 6 show that the average cumulative permeability within 48 hours of the formulation A2 in the in vitro permeability test is significantly higher than those of the formulations E2 and F11.

[0085] Example 5: Stability test of formulations A2 and E (1) Preparation of stability samples of solutions of formulations A2 and E [Table 7]

[0086] Preparation of blank formulation: Each excipient was weighed according to the formulation amount, placed into a clean glass bottle with a lid, and magnetically stirred at room temperature for 30 minutes to completely dissolve the excipients and obtain a clear liquid for use.

[0087] Preparation of drug-containing formulation: The active ingredient compound of formula I was accurately weighed into a clean vial, the blank solution prepared in the above step was added according to the formulation ratio, and magnetically stirred in a water bath at 70°C for 40 minutes, and then ultrasonicated for 10 minutes until the active ingredient compound of formula I was completely dissolved, obtaining a transparent yellow solution.

[0088] (2) Stability Sampling Protocol for Formulations A2 and E Solutions [Table 8]

[0089] (3) Stability results of formulations A2 and E solutions: [Table 9] TIFF2025511939000016.tif86170

[0090] Experiments showed that formulations A2 and E were very stable, with no significant difference in stability between clear and brown bottles.

[0091] Example 6: Manufacturing process of Formulation A2 2% (w / w) standard (1) Formulation composition of formulation A2 (2% (w / w) standard [Table 10]

[0092] (2) Manufacturing steps a. Preparation of intermediate 1 [Table 11]

[0093] The prescribed amount of the compound represented by formula I, which is the drug substance, was weighed into the prescribed amount of dimethyl sulfoxide, and stirred at a rotation speed of 2000 rpm for 5 minutes to completely dissolve the compound represented by formula I, thereby obtaining intermediate 1 for use.

[0094] b. Preparation of mixed solvent [Table 12]

[0095] The remaining auxiliary agents were weighed into a separate container according to the ratio in the above table, and mixed thoroughly by stirring at a rotation speed of 2000 rpm for 5 minutes to prepare a mixed solvent for use.

[0096] c. Preparation of intermediate 2 The mixed solvent of step b was transferred to intermediate 1 of step a, and mixed thoroughly by stirring at a rotation speed of 2000 rpm for about 10 minutes to obtain intermediate 2.

[0097] d. Control of intermediates Mixture uniformity detection: Three samples were taken from different positions in the upper, middle, and lower layers of the intermediate 2 liquid, and approximately 1 g was taken from each position to detect the homogeneity of the mixture and calculate the RSD value.

[0098] Content detection: Approximately 1g of sample was taken from the upper, middle, and lower layers of the intermediate product 2 chemical solution, mixed into one sample, and the solution content was detected.

[0099] e.Filling After passing through the central control, intermediate 2 was filled into neutral borosilicate tubular glass vials (brown) using a liquid filling machine, and the filling amount was adjusted so that the filling amount was about 3.7 g / bottle, and the filling amount ranged from 3.7 g / bottle to 4.07 g / vial. The injections were sealed and packaged with halogenated butyl rubber stoppers (brominated) and aluminum and plastic combination caps for antibiotic bottles.

[0100] Example 7: Manufacturing process of formulation A2 0.5% (w / w) standard (1) Formulation composition of formulation A2 (0.5% (w / w) standard) [Table 13]

[0101] (2) Manufacturing steps According to the formulation of Formulation A2 at 0.5% (w / w) standard, the preparation was completed with reference to the preparation steps of Example 6.

[0102] Example 8: Stability study of the 2% (w / w) version of Formulation A2 [Table 14]

[0103] Example 9: Accelerated stability study of 2% (w / w) version of Formulation A2 [Table 15]

[0104] Example 10: Stability study of the 0.5% (w / w) version of Formulation A2 [Table 16]

[0105] Example 11: Accelerated stability study of 0.5% (w / w) version of Formulation A2 [Table 17]

[0106] The experiment demonstrated that both the 2% (w / w) and 0.5% (w / w) formulations of Formulation A2 had good stability in light, high temperature and high humidity environments.

[0107] Example 12: Preparation of a pharmaceutical composition containing 2% (w / w) of a compound of formula II [Table 18]

[0108] Manufacturing method: The same manufacturing method as in Example 2 was used except that the active ingredient was different.

[0109] Example 13: Preparation of a pharmaceutical composition containing 2% (w / w) of a compound of formula II [Table 19]

[0110] Manufacturing method: The same manufacturing method as in Example 3 was used except that the active ingredient was different.

[0111] Example 14: In Vitro Permeation Testing (IVPT) According to the experimental steps of Example 4, in vitro average cumulative permeability detection was carried out for six formulations 3, 4, 5, 7, 8 and 9 respectively, and the detection results are shown in Table 19 and Table 20.

[0112] [Table 20]

[0113] From the results in Table 19, it was found that the average cumulative permeability at each sampling time point in the in vitro permeability test for Formulations 3, 4, and 5 was in the order of 4>5>3.

[0114] [Table 21]

[0115] The results in Table 20 show that the average cumulative permeability within 48 hours of Formulation 8 in the in vitro permeability test was significantly higher than those of Formulations 9 and 7.

[0116] Example 15: Manufacturing process of Formulation 8 2% (w / w) standard (1) Formulation composition of Formulation 8 (2% (w / w) standard) [Table 22]

[0117] (2) Manufacturing steps According to the formulation of Formulation 8 at 2% (w / w) standard, the preparation was completed with reference to the preparation steps of Example 6.

[0118] Example 16: Manufacturing process of Formulation 8 0.5% (w / w) standard (1) Formulation composition of formulation 8 (0.5% (w / w) standard) [Table 23]

[0119] (2) Manufacturing steps According to the formulation of Formulation 8 at 0.5% (w / w) standard, the preparation was completed with reference to the preparation steps of Example 6.

[0120] Example 17: Stability Study of the 2% (w / w) Version of Formulation 8 [Table 24]

[0121] Example 18: Accelerated stability study of 2% (w / w) version of Formulation 8 [Table 25]

[0122] Example 19: Stability Study of 0.5% (w / w) Version of Formulation 8 [Table 26]

[0123] Example 20: Accelerated stability study of 0.5% (w / w) version of Formulation 8 [Table 27]

[0124] The experiment proved that formulation 8 standard 2% (w / w) and standard 0.5% (w / w) both have good stability in light, high temperature and high humidity environments.

Claims

1. The composition comprises, by mass fraction, 0.1% to 3% of a compound represented by formula I or a compound represented by formula II or a pharma- ceutically acceptable salt thereof, 35% to 93% of a solvent, and 5% to 63% of a penetration enhancer; the solvent is selected from one or more of water, glycerin, polyethylene glycol 400, dimethylsulfoxide, ethyl acetate, propylene glycol, and ethanol; 13. The pharmaceutical composition comprising a JAK inhibitor, wherein the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, azone, urea, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea, propyl gallate, isopropyl myristate, cyclodextrin, sodium dodecyl sulfate, polyoxyethylene lauryl ether, polyethylene glycol hexadecyl ether, Tween 20, Tween 40, Tween 60, Tween 80, Span 20, Span 40, Span 60, Span 80, Span 85, deoxycholate, glycocholate, glyceryl monocaprylate, mono- and diglycerides of capric and caprylic acids, propylene glycol monolaurate, propylene glycol monocaprylate, and glyceryl behenate. 【Chemistry 5】 【change】

2. The mass fraction of the compound represented by formula I or the compound represented by formula II or a pharma- ceutically acceptable salt thereof is 0.3% to 2.5%; and / or the mass fraction of the solvent is between 38% and 90%, preferably between 40% and 88%, for example 40%, 45%, 69.3%, 81%, 82.5% or 87.94%, and / or the mass fraction of the penetration enhancer is between 8% and 60%, preferably between 10% and 58%, for example 10.06%, 17%, 28.7%, 53% or 58%, and / or the solvent is selected from one or more of polyethylene glycol 400, dimethyl sulfoxide, propylene glycol and ethanol, such as polyethylene glycol 400, a mixed solvent of polyethylene glycol 400 and dimethyl sulfoxide, a mixed solvent of polyethylene glycol 400, propylene glycol and ethanol, or a mixed solvent of polyethylene glycol 400, propylene glycol and dimethyl sulfoxide; and / or the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, azone, oleic acid, diisopropyl adipate, menthol, N-methylpyrrolidone, imidurea and propyl gallate, such as a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and oleic acid, a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and diisopropyl adipate, a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and menthol, a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and N-methylpyrrolidone, a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and imidurea, a mixed penetration enhancer of diethylene glycol monoethyl ether and azone, a mixed penetration enhancer of diethylene glycol monoethyl ether and oleic acid, or a mixed penetration enhancer of diethylene glycol monoethyl ether and menthol.

3. The mass fraction of the compound represented by formula I or the compound represented by formula II or a pharma- ceutically acceptable salt thereof is 0.5% to 2%, for example 0.5% or 2%; and / or the mass fraction of the solvent is between 78% and 85%, for example 81% or 82.5%, and / or the mass fraction of the penetration enhancer is between 15% and 19%, e.g., 17%, and / or the solvent is selected from one or more of polyethylene glycol 400, dimethyl sulfoxide, and propylene glycol, for example a mixed solvent of polyethylene glycol 400, dimethyl sulfoxide, and propylene glycol; and / or the penetration enhancer is selected from one or two of diethylene glycol monoethyl ether and oleic acid, e.g. a mixed penetration enhancer of diethylene glycol monoethyl ether and oleic acid.

4. When the solvent is a mixed solvent of polyethylene glycol 400 and dimethyl sulfoxide, the mass ratio of the polyethylene glycol 400 and dimethyl sulfoxide is 6:1 to 10:1, preferably 7:1 to 9:1, for example 8:1; and / or, when the solvent is a mixed solvent of polyethylene glycol 400, propylene glycol and ethanol, the mass ratio of the polyethylene glycol 400 and propylene glycol is 2:1 to 6:1, preferably 3:1 to 5:1, for example 4:1, and the mass ratio of the propylene glycol and ethanol is 1:1 to 1:3, preferably 1:1.5 to 1:2.5, for example 1:2; and / or, when the solvent is a mixed solvent of polyethylene glycol 400, propylene glycol and dimethyl sulfoxide, the mass ratio of the polyethylene glycol 400 and dimethyl sulfoxide is 3:1 to 10:1, preferably 6:1 to 10:1, more preferably 7:1 to 9:1, for example 8:1 or 8.3:1, and the mass ratio of the propylene glycol and dimethyl sulfoxide is 3:1 to 9:1, preferably 5:1 to 9:1, more preferably 6:1 to 8:1, for example 7.2:1; and / or when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and oleic acid, the weight ratio of the diethylene glycol monoethyl ether and oleic acid is from 2:1 to 5:1, preferably from 3:1 to 4:1, for example 3.57:1, and the weight ratio of the propyl gallate and oleic acid is from 2:1 to 5:1, preferably from 3:1 to 4:1, for example 3.71:1; and / or when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and diisopropyl adipate, the weight ratio of the diethylene glycol monoethyl ether and diisopropyl adipate is from 2:1 to 5:1, preferably from 3:1 to 4:1, for example 3.57:1, and the weight ratio of the propyl gallate and diisopropyl adipate is from 2:1 to 5:1, preferably from 3:1 to 4:1, for example 3.71:1; and / or when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and menthol, the weight ratio of the diethylene glycol monoethyl ether and menthol is from 150:1 to 430:1, preferably from 160:1 to 420:1, for example 166.67:1 or 416.67:1, and the weight ratio of the propyl gallate and menthol is from 530:1 to 730:1, preferably from 540:1 to 720:1, for example 549:1 or 715.67:1; and / or when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and N-methylpyrrolidone, the weight ratio of the diethylene glycol monoethyl ether and N-methylpyrrolidone is from 2:1 to 5:1, preferably from 3:1 to 4:1, for example 3.57:1, and the weight ratio of the propyl gallate and N-methylpyrrolidone is from 2:1 to 5:1, more preferably from 3:1 to 4:1, for example 3.71:1; and / or when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether, propyl gallate and imidurea, the weight ratio of the diethylene glycol monoethyl ether and imidurea is from 610:1 to 640:1, preferably from 620:1 to 630:1, for example 625:1, and the weight ratio of the propyl gallate and imidurea is from 810:1 to 840:1, preferably from 820:1 to 830:1, for example 824:1; and / or when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether and azone, the weight ratio of diethylene glycol monoethyl ether and azone is 4:1 to 8:1, preferably 5:1 to 7:1, for example 6.27:1; and / or when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether and oleic acid, the mass ratio of diethylene glycol monoethyl ether and oleic acid is from 1.2:1 to 1.6:1, preferably from 1.3:1 to 1.5:1, for example 1.43:1; And / or when the penetration enhancer is a mixed penetration enhancer of diethylene glycol monoethyl ether and menthol, the weight ratio of diethylene glycol monoethyl ether and menthol is 150:1 to 180:1, preferably 160:1 to 170:1, for example 166.67:

1.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the JAK inhibitor-containing pharmaceutical composition is composed of the compound represented by formula I or the compound represented by formula II or a pharma- ceutical acceptable salt thereof, the solvent and the penetration enhancer.

6. The JAK inhibitor-containing pharmaceutical composition comprises Scheme 1: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 26% propyl gallate, and 7% oleic acid; Scheme 2: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 26% propyl gallate and 7% diisopropyl adipate; Scheme 3: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 32.94% propyl gallate, and 0.06% menthol; Scheme 4: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 26% propyl gallate and 7% N-methylpyrrolidone; Scheme 5: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 10% diethylene glycol monoethyl ether, 42.94% propyl gallate, 0.06% menthol and 5% dimethyl sulfoxide; Scheme 6: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 25% diethylene glycol monoethyl ether, 32.96% propyl gallate and 0.04% imidurea; Scheme 7: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 39.6% polyethylene glycol 400, 24.75% diethylene glycol monoethyl ether, 9.9% propylene glycol, 19.8% ethanol and 3.95% azone; Scheme 8: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 10% diethylene glycol monoethyl ether, 36% propylene glycol, 7% oleic acid and 5% dimethyl sulfoxide; Scheme 9: 0.5% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 41.5% of polyethylene glycol 400, 10% of diethylene glycol monoethyl ether, 36% of propylene glycol, 7% of oleic acid, and 5% of dimethyl sulfoxide; Scheme 10: 2% of a compound of formula I or a compound of formula II or a pharma- ceutically acceptable salt thereof, 40% polyethylene glycol 400, 10% diethylene glycol monoethyl ether, 37.94% propylene glycol, 0.06% menthol and 10% dimethyl sulfoxide; The composition is composed of components shown in any one of the schemes: The pharmaceutical composition according to claim 5, characterized in that the percentages are percentages by weight.

7. 2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is an ointment, gel, solution, spray, suspension, preferably a solution.

8. A method for preparing the pharmaceutical composition of any one of claims 1 to 7, comprising the step of mixing the compound represented by formula I or formula II or a pharma- ceutically acceptable salt thereof, the solvent and the penetration enhancer.

9. 9. The method of claim 8, further comprising the step of mixing the solvent and the penetration enhancer, and then dissolving the compound of formula I or the compound of formula II or a pharma- ceutical acceptable salt thereof therein to obtain the JAK inhibitor-containing pharmaceutical composition.

10. The compound represented by formula I or the compound represented by formula II or a pharma- ceutically acceptable salt thereof is a compound represented by formula I or the compound represented by formula II, And / or the method of claim 9, characterized in that the dissolving method is ultrasonic, or heating, or a combination of both, the heating is preferably water bath heating, and the heating temperature is preferably 60°C to 70°C.

11. When the pharmaceutical composition includes dimethyl sulfoxide, the method for producing the pharmaceutical composition includes the steps of: (1) mixing dimethyl sulfoxide and a compound represented by formula I or a compound represented by formula II or a pharma- ceutically acceptable salt thereof in the above-mentioned components to obtain a mixed solution; (2) mixing all the components except for dimethyl sulfoxide and the compound represented by formula I or the compound represented by formula II or a pharma- ceutically acceptable salt thereof to obtain a mixed solution; (3) mixing the mixed solution of step (1) with the mixed solution of step (2) to obtain the pharmaceutical composition containing the JAK inhibitor; The method of claim 8, comprising:

12. The pharmaceutical composition is a pharmaceutical composition according to Scheme 5, Scheme 8, Scheme 9 or Scheme 10, And / or, the compound represented by formula I or the compound represented by formula II or a pharma- ceutically acceptable salt thereof is a compound represented by formula I or a compound represented by formula II, and / or in step (3), the mixing is adding the mixed solution of step (2) to the mixed solution of step (1); And / or the mixed solution of step (1) and the mixed solution of step (2) are mixed uniformly by stirring, respectively, and the rotation speed of the stirring is preferably 1500 rpm to 2500 rpm, for example 2000 rpm.

13. An external liniment comprising the pharmaceutical composition according to any one of claims 1 to 7.

14. 14. Use of the pharmaceutical composition according to any one of claims 1 to 7 or the external liniment according to claim 13 in the prevention, alleviation or treatment of a skin autoimmune disease associated with a JAK kinase, said skin autoimmune disease being preferably selected from one or more of alopecia areata, atopic dermatitis and psoriasis.

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