Topical gel for JAK inhibitors and its use

Abstract

This application discloses a topical gel comprising 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile or its crystals, a gel substrate, and its medicinal additives.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations and relates to a topical gel of a JAK inhibitor and its use.

Background Art

[0002] 2-{3-[3-Amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(isopropylsulfonyl)azetidin-3-yl}acetonitrile (Compound A) is a JAK family small molecule non-receptor tyrosine kinase inhibitor, and its JAK-STAT signaling pathway is closely related to inflammatory cytokines and tumors, and is widely involved in important biological processes such as cell proliferation, differentiation, metastasis, apoptosis, and regulation of immune responses and cell homeostasis in the process of human health and disease. TIFF2026527844000002.tif45129

[0003] As a formulation that is locally effective by topical administration, it is a great advantage of the formulation that is locally effective by topical administration that the drug can penetrate the skin, maintain its action by staying on the skin for a long time, and have little systemic exposure. At the same time, in topical formulations, gel formulations are often aqueous matrices, and after contact with clothing in clinical use, they are not greasy, easy to wash, and have excellent clinical compatibility.

Summary of the Invention

[0004] This application provides a prescription and a manufacturing method of a topical skin gel formulation, which is an excellent topical administration formulation that is non-irritating, uniform, fine, easy to apply, can quickly exert its effect, can quickly penetrate into the skin and stay locally on the skin to exert its medicinal effect.

[0005] According to one aspect, this application provides a topical gel, and the topical gel is (a) 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile, its hydrate, its pharmaceutically acceptable salt or crystalline form, (b) Gel substrate and (c) 5% to 30% of the total weight of the topical gel is propylene glycol, (d) comprising polyethylene glycol in an amount of 2% to 20% of the total weight of the topical gel.

[0006] According to some embodiments, (a) in the topical gel of the present invention is 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile hemihydrate.

[0007] According to some embodiments, the gel substrate in the topical gel of the present invention may be a carbomer. The amount of carbomer is, for example, 0.8% to 1.5% of the total weight of the topical gel, and more specifically, 1%.

[0008] According to some embodiments, the average molecular weight of polyethylene glycol in the topical gel of the present invention may be 200 to 600, for example, polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600. The amount of polyethylene glycol in the topical gel is, for example, 5% of the total weight of the topical gel.

[0009] According to some embodiments, the amount of propylene glycol in the topical gel of the present invention is approximately 15% (w / w) of the total weight of the topical gel.

[0010] In another embodiment, the present invention provides an external gel comprising (a) crystalline material of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile hemihydrate, wherein the 2θ values ​​of characteristic peaks in the powder X-ray diffraction pattern of the crystalline material are 7.93, 9.36, 11.29, 14.95, 20.96, 21.36, 21.77, 22.12, and 22.79, and the measurement error is ±0.2 degrees.

[0011] According to some embodiments, the topical gel of the present invention is (b) Gel substrate and (c) Further comprising propylene glycol in an amount of 5% to 30% of the total weight of the topical gel.

[0012] According to some embodiments, the topical gel in the present invention further comprises polyethylene glycol. The average molecular weight of the polyethylene glycol in the topical gel of the present invention may be 200 to 600, for example, polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600.

[0013] According to some embodiments, the amount of polyethylene glycol in the topical gel of the present invention is 2% to 20% of the total weight of the topical gel, for example, 5%.

[0014] According to some embodiments, the gel substrate in the topical gel of the present invention may be a carbomer. The amount of the gel substrate (e.g., carbomer) is, for example, 0.8% to 1.5% of the total weight of the topical gel, and more specifically, 1%.

[0015] According to some embodiments, the amount of propylene glycol in the topical gel of the present invention is approximately 15% (w / w) of the total weight of the topical gel.

[0016] In another embodiment, the present application provides a topical gel, the topical gel is, (a) Crystals of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile hemihydrate, (b) comprising a gel substrate, The characteristic peak 2θ values ​​in the powder X-ray diffraction pattern of the aforementioned crystal were 7.93, 9.36, 11.29, 14.95, 20.96, 21.36, 21.77, 22.12, and 22.79, with a measurement error of ±0.2 degrees. The gel substrate is, for example, carbomer, and its content may be 0.8% to 1.5% of the total weight of the topical gel, for example, 1%.

[0017] According to some embodiments, the topical gel of the present invention further comprises polyethylene glycol and propylene glycol.

[0018] According to some embodiments, the propylene glycol in the topical gel of the present invention is 5% to 30% of the total weight of the topical gel, for example, 15%.

[0019] According to some embodiments, the polyethylene glycol in the topical gel of the present invention is 2% to 20% of the total weight of the topical gel, for example, 5%.

[0020] According to some embodiments, the average molecular weight of polyethylene glycol in the topical gel of the present invention may be 200 to 600. For example, polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600.

[0021] According to some embodiments, the topical gel of the present invention further includes one or more medicinal additives selected from the group consisting of bacteriostatic agents, antioxidants, chelating agents, and pH adjusters.

[0022] The gel substrate in this application refers to a material that is capable of forming colloids and has a spatial network structure.

[0023] In the external gel of the present application, the gel matrix includes one or more of hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, and carbomer, but is not limited thereto. Preferably, it is carbomer, and more preferably, it is one or more of carbomer homopolymer type A, carbomer homopolymer type B, and carbomer homopolymer type C.

[0024] In some embodiments, the polyethylene glycol is one or more selected from polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400, and preferably, it is polyethylene glycol 400.

[0025] In some embodiments, the chelating agent in the external gel is one or more selected from disodium edetate and calcium disodium edetate, and preferably, it is disodium edetate.

[0026] In some embodiments, the bacteriostatic agent in the external gel is one or more selected from phenoxyethanol, potassium sorbate, benzyl alcohol, methyl hydroxybenzoate, propyl hydroxybenzoate, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, chlorhexidine digluconate, chloroxylenol, chlorphenesin, dehydroacetic acid, diazolidinyl urea, DMDM hydantoin, ethyl paraben, iodopropynyl butylcarbamate, methylisothiazolinone, propyl paraben, phenoxyethanol, phenoxyisopropanol, polyaminopropyl biguanide, benzoate, and salicylic acid. Preferably, it is phenoxyethanol, potassium sorbate, benzyl alcohol, methyl hydroxybenzoate, propyl hydroxybenzoate, sodium methyl hydroxybenzoate, and sodium propyl hydroxybenzoate. More preferably, it is methyl hydroxybenzoate, propyl hydroxybenzoate, sodium methyl hydroxybenzoate, and sodium propyl hydroxybenzoate.

[0027] In some embodiments, the topical gel further comprises an antioxidant, and the antioxidant is one or more selected from dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, vitamin C, sodium bisulfite, sodium pyrosulfite, cysteine hydrochloride, preferably butylhydroxyanisole and propyl gallate.

[0028] In some embodiments, the topical gel further comprises a pH adjuster, and the pH adjuster is one or more selected from sodium hydroxide, potassium hydroxide, triethanolamine, hydrochloric acid, preferably triethanolamine or sodium hydroxide.

[0029] {3-[3-Amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(isopropylsulfonyl)azetidin-3-yl}acetonitrile (Compound A) exists in multiple crystal forms, including Crystal Form I, Crystal Form IIa, Crystal Form IIb, and Crystal Form III. Crystal Form I and Crystal Form IIa are anhydrous crystal forms, Crystal Form IIb is a hemihydrate, and Crystal Form III is amorphous. The X-ray powder diffraction data and spectra of different crystal forms are as follows.

[0030] Crystal Form IIa shows a powder X-ray diffraction pattern with characteristic peaks at 2θ = 7.61, 9.28, 12.44, 12.96, 14.28, 15.30, 17.56, 18.23, 21.05, 21.47, 22.28, 23.45, 24.87, 26.03.

[0031] Crystal Form IIb shows a powder X-ray diffraction pattern with characteristic peaks at 2θ = 7.93, 9.36, 11.29, 14.95, 20.96, 21.36, 21.77, 22.12, 22.79.

[0032] Crystal type IIb exhibits a powder X-ray diffraction pattern with more characteristic peaks at 2θ = 7.93, 9.36, 11.29, 14.69, 14.95, 15.13, 15.95, 19.93, 20.15, 20.96, 21.36, 21.77, 22.12, 22.79, 23.54, 24.14, 26.38, 28.74, and 29.15.

[0033] Crystal type I exhibits a powder X-ray diffraction pattern with characteristic peaks at 2θ = 6.48, 7.68, 9.90, 13.01, 14.81, 15.38, 16.43, 16.87, 19.61, 20.68, 23.47, 26.29, and 32.23.

[0034] TIFF2026527844000003.tif109160TIFF2026527844000004.tif135150TIFF2026527844000005.tif99150

[0035] Crystalline form IIa is converted to crystalline form IIb within 1 hour at room temperature (58.6% RH). In the manufacturing process of topical gels, gels were produced using crystalline form I and crystalline form IIb, respectively. Surprisingly, as shown in Figures 5 and 6, after 3 days, the active pharmaceutical ingredient in the gel formulations was detected to be entirely crystalline form IIb. [Brief explanation of the drawing]

[0036] [Figure 1] This is an XRPD diagram of crystal type IIa. [Figure 2] This is an XRPD diagram of crystal type IIb. [Figure 3] This is an XRPD diagram of crystal type I. [Figure 4] This is a crystal type III XRPD diagram. [Figure 5] (A) shows the XRPD results for detecting the active pharmaceutical ingredient in the formulation after producing a gel using crystal type I, (B) shows a comparison of transmission and reflection XRPD for crystal type I, and (C) shows a comparison of transmission and reflection XRPD for crystal type IIb. [Figure 6]This figure shows the XRPD results for detecting the active pharmaceutical ingredient in a formulation after producing a gel using crystalline form IIb. [Figure 7] This figure shows the cumulative penetration amount of a drug in an in vitro skin penetration test. [Figure 8] This figure shows the amount of drug retained in the epidermal layer during an in vitro skin penetration test. [Figure 9] This figure shows the amount of drug retained in the dermis layer during an in vitro skin penetration test. [Figure 10] This figure shows the cumulative penetration amounts of crystalline form I (A) and crystalline form IIb (B) in a rat skin permeability test. [Modes for carrying out the invention]

[0037] The present invention will be further described below with reference to specific examples so that those skilled in the art may better understand and implement it; however, the examples provided are not intended to limit the present invention.

[0038] Manufacturing example Topical gels were prepared according to the formulations of each example.

[0039] Examples 1 to 5: TIFF2026527844000006.tif85169TIFF2026527844000007.tif85169TIFF2026527844000008.tif78170

[0040] Manufacturing process 1. Preparation of Phase I (Carbomer Phase) A suitable amount of purified water was weighed out, and carbomer was slowly added. Stirring and dispersion were continued until swelling was complete.

[0041] 2. Preparation of Phase II (Active Ingredient Phase) Propylene glycol and polyethylene glycol 400 were weighed, methyl hydroxybenzoate and propyl hydroxybenzoate were added, and the mixture was stirred until completely dissolved. Compound A was then added, and stirring was continued until uniformly dispersed, after which the mixture was transferred to a homogenization vessel.

[0042] 3. Preparation of Phase III (Disodium Edetate Phase) An appropriate amount of purified water was weighed, disodium edetate was added, and after stirring until completely dissolved, it was transferred to a homogenization vessel.

[0043] 4, mixing homogenization The mixture was mixed and homogenized by starting the stirring and homogenization process in the homogenization kettle.

[0044] 5, pH adjustment The pH was adjusted to 5.0-7.0 using a sodium hydroxide solution.

[0045] 6. Vacuum stirring and homogenization, vacuum stirring After homogenization by stirring in a vacuum, the process is stopped and the material is discharged.

[0046] Production Examples 6 to 8 were manufactured according to the manufacturing methods of Examples 1 to 5. TIFF2026527844000009.tif56169TIFF2026527844000010.tif57170TIFF2026527844000011.tif57170

[0047] Using decomposed skin from 1-month-old Bamar miniature pigs, the skin penetration behavior and retention status of the active ingredients in the formulations were evaluated using Franz diffusion cells for gel samples from Examples 3, 4, and 5.

[0048] The results of the in vitro skin permeability test are as follows: TIFF2026527844000012.tif93170TIFF2026527844000013.tif59170

[0049] The results of the cumulative penetration experiment using extracorporeal release described above are shown in Figure 7, the results of the epidermal layer retention experiment are shown in Figure 8, and the results of the dermal layer retention experiment are shown in Figure 9.

[0050] In vitro skin permeability tests unexpectedly revealed that when propylene glycol and polyethylene glycol were used together, the amount of drug permeated the skin increased 4 to 11 times compared to when propylene glycol or polyethylene glycol was used alone, and the amount retained in the epidermis and dermis increased by approximately 1 time. The results of the in vitro skin permeability tests showed that the combined use of propylene glycol and polyethylene glycol significantly improved the skin permeability of the active ingredient, 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile.

[0051] Example 9: Preparation of polycrystalline 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile (A) Preparation of crystalline form I of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile In a 250 mL flask, 20.0 g of the compound 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile and 100 mL of N,N-dimethylformamide were added and stirred to dissolve. Insoluble matter was filtered off, and 250 mL of purified water was added to the filtrate. Crystallization was induced by stirring, and the resulting solid was filtered and dried. After drying, it was transferred to a 250 mL flask, and 200 mL of anhydrous ethanol was added. The mixture was heated under reflux for 3 hours, cooled, filtered, and the resulting solid was dried at 55-60°C until a constant weight was obtained, yielding 18.8 g of a white solid with a yield of 94.0% and a chemical purity of 99.62%.

[0052] (B) Preparation of crystalline form IIa of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile 5.0 g of crystals of crystalline form I of the compound 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile was added to a 100 mL flask, 100 mL of ethanol (95%) was added, the mixture was heated, stirred under reflux for 5 hours, cooled to room temperature, filtered to obtain a solid, and dried under vacuum (0.1 MPa) at 80°C for 12 hours to obtain 4.8 g of solid. The yield was 96.0%, and the purity measured by HPLC was 99.50%.

[0053] (C) Preparation of crystalline form IIb of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile In a 100 mL flask, 6.2 g of the compound 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile and 25 mL of N,N-dimethylformamide were added and stirred to dissolve. Insoluble matter was filtered off, and 50 mL of purified water was added to the filtrate. Crystallization was induced by stirring, and the mixture was filtered. The resulting solid was dried at 55-60°C until a constant weight was obtained, yielding 5.6 g of solid with a yield of 88.9%.

[0054] (D) Preparation of crystalline form III of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile 15 mg of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile was added to 3 mL of dioxane, then heated to 40°C to dissolve, clarified, filtered, and the solution was evaporated at 40°C to crystallize, yielding crystal form III. This crystal form had relatively poor crystallinity and stability, and after standing, nuclear magnetic resonance analysis showed that approximately 10% impurities had formed.

[0055] Analysis of solubility for each crystal type TIFF2026527844000014.tif36132TIFF2026527844000015.tif74129

[0056] Stability analysis of each crystal type In accordance with the Guiding Principles for Stability Studies issued by the State Food and Drug Administration, stability studies were conducted for crystal types I, IIa, and IIb. Samples were packaged in polarized low-density polyethylene bags for pharmaceutical use, and long-term stability was examined for 24 months. The results of the study are as follows.

[0057] Long-term stability of crystal type I over 24 months TIFF2026527844000016.tif99165TIFF2026527844000017.tif92165TIFF2026527844000018.tif90155

[0058] The results of the stability analysis of the different crystal forms described above indicate that crystal forms I and IIb of the compound 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile have good chemical stability. Crystal form IIa gradually absorbs water during the standing process and transforms into crystal form IIb, causing the sample to absorb water, increase in weight, and decrease in content.

[0059] Crystalline skin penetration test Crystalline forms I and IIb were selected, and topical gels were prepared according to the formulation of Example 1. Skin permeability tests were then performed immediately afterward, and the skin permeability rates of each were measured. The test results are shown in Figures 10A and 10B, indicating that crystalline form I had superior skin permeability.

[0060] Blood samples were collected 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after transdermal administration. After anesthetizing rats with isoflurane using a small animal anesthesia machine, 0.3 mL of whole blood was collected from the orbital venous plexus and placed in a heparinized anticoagulant tube. The sample was centrifuged at 4°C and 4000 rpm for 5 minutes, and the plasma was transferred to a centrifuge tube and stored at -80°C until analysis. The sample was extracted from the plasma by protein precipitation, and the extract was analyzed by LC / MS / MS. After the completion of the test, the drug was washed off the epidermis, and the skin at the administration site was peeled off. After homogenation, the drug content in the skin was analyzed by LC / MS / MS.

[0061] TIFF2026527844000019.tif37161

[0062] Crystalline forms I and IIb are characterized by high crystallinity and good stability, with crystalline form I having higher solubility than crystalline form IIb. Although crystalline form IIb has inferior transdermal absorption compared to crystalline form I, the concentration of the drug retained on the skin of animals as a topical formulation is clearly several times higher than that of crystalline form I. This unexpected characteristic makes it more suitable for topical gel formulations where penetration into the system is low but drug retention in the skin is high.

Claims

1. (a) 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile, its hydrate, its pharmaceutically acceptable salt or crystalline form, (b) Gel substrate and (c) 5% to 30% propylene glycol by weight of the topical gel, (d) 2% to 20% polyethylene glycol by weight of the topical gel, including, Topical gel.

2. The gel substrate is selected from carbomers. The topical gel according to claim 1.

3. The amount of carbomer is 0.8% to 1.5% of the total weight of the topical gel. The topical gel according to claim 2.

4. (a) Contains crystalline form of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile hemihydrate, The characteristic peak 2θ values ​​in the powder X-ray diffraction pattern of the aforementioned crystal are 7.93, 9.36, 11.29, 14.95, 20.96, 21.36, 21.77, 22.12, and 22.79, with a measurement error of ±0.20 degrees. Topical gel.

5. (b) Gel substrate and (c) 5% to 30% propylene glycol by weight of the topical gel, Further including, The topical gel according to claim 4.

6. Further containing polyethylene glycol, The topical gel according to claim 4 or 5.

7. The amount of polyethylene glycol is 2% to 20% of the total weight of the topical gel. The topical gel according to claim 6.

8. The gel substrate is selected from carbomers. The topical gel according to any one of claims 4 to 7.

9. The amount of carbomer is 0.8% to 1.5% of the total weight of the topical gel. The topical gel according to claim 8.

10. (a) Crystals of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl]-1-(isopropylsulfonyl)azetidine-3-yl}acetonitrile hemihydrate, (b) Gel substrate and Includes, The characteristic peak 2θ values ​​in the powder X-ray diffraction pattern of the aforementioned crystal are 7.93, 9.36, 11.29, 14.95, 20.96, 21.36, 21.77, 22.12, and 22.79, with a measurement error of ±0.2 degrees. The gel substrate is carbomer in an amount of 0.8% to 1.5% of the total weight of the topical gel. Topical gel.

11. Further comprising polyethylene glycol and propylene glycol, The topical gel according to claim 10.

12. The propylene glycol is present in an amount of 5% to 30% of the total weight of the topical gel. The polyethylene glycol is present in an amount of 2% to 20% of the total weight of the topical gel. The topical gel according to claim 11.

13. The average molecular weight of the polyethylene glycol is 200 to 600. The topical gel according to any one of claims 1 to 12.

14. The aforementioned topical gel further contains one or more medicinal additives selected from the group consisting of bacteriostatic agents, antioxidants, and pH adjusters. The topical gel according to any one of claims 1 to 13.

15. Use of the topical gel according to any one of claims 1 to 14 in the manufacture of a drug that inhibits JAK.

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