WO2022161507A1 - Forme cristalline de tosylate de brépocitinib, son procédé de préparation et son utilisation - Google Patents

Forme cristalline de tosylate de brépocitinib, son procédé de préparation et son utilisation Download PDF

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WO2022161507A1
WO2022161507A1 PCT/CN2022/079962 CN2022079962W WO2022161507A1 WO 2022161507 A1 WO2022161507 A1 WO 2022161507A1 CN 2022079962 W CN2022079962 W CN 2022079962W WO 2022161507 A1 WO2022161507 A1 WO 2022161507A1
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brepocitinib
tosylate
crystal form
present disclosure
diffraction peaks
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PCT/CN2022/079962
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Chinese (zh)
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盛晓红
盛晓霞
彭晨玥
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杭州领业医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/42—Separation; Purification; Stabilisation; Use of additives
    • C07C303/44—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure generally relates to the field of medicinal chemistry.
  • the present disclosure relates to crystalline forms of brepocitinib tosylate and methods for their preparation and uses.
  • Brepocitinib with the development code PF-06700841, is a selective tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1) inhibitor developed by Pfizer for the treatment of psoriasis and atopic dermatitis (AD).
  • Topical therapy as well as psoriasis, psoriatic arthritis (PA), inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), vitiligo (eg active non-segmental Vitiligo), systemic lupus erythematosus (SLE), aplastic anemia (AA) and hidradenitis suppurativa (HS), etc.
  • PA psoriatic arthritis
  • IBD inflammatory bowel disease
  • CD Crohn's disease
  • UC ulcerative colitis
  • vitiligo eg active non-segmental Vitiligo
  • SLE systemic lupus
  • brepocitinib disclosed in WO2020165788A1 has been found to have problems such as high hygroscopicity, easy deliquescence, and easy gelation through research by the present inventors. Further, using a solid form with high hygroscopicity will lead to many problems after preparation, such as: opening, bottle opening stability; preparation process requirements are extremely high; affecting dissolution, it is easy to cause impurities to increase; large; and poor liquidity.
  • the purpose of the present disclosure is to provide the crystal form 1 of brepocitinib tosylate and its preparation method, pharmaceutical composition and use.
  • the brepocitinib tosylate form 1 of the present disclosure has at least one of the following advantages over known brepocitinib free forms or brepocitinib tosylate amorphous or other crystalline forms of brepocitinib tosylate : High purity and content, better stability, further reduced hygroscopicity, good particle size distribution, better solubility, meeting medicinal requirements, stable storage, and simple preparation method.
  • the crystalline form 1 of brepocitinib tosylate of the present disclosure has good druggability, is suitable for industrial production, is more conducive to preparation into a preparation product, and the prepared product is easy to store, stable in preparation, good in quality, and in dissolution. It has a better degree and is suitable for industrial production.
  • the present disclosure provides an X-ray powder diffraction pattern of brepocitinib tosylate Form 1, expressed at 2 ⁇ angles, having the following characteristic diffraction peaks: 6.3° ⁇ 0.2°, 9.4° ⁇ 0.2°, 18.7° ⁇ 0.2 °, 19.2° ⁇ 0.2° and 22.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form at 2 ⁇ angle further has at least one of the following characteristic diffraction peaks: 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.9° ⁇ 0.2°, 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form at 2 ⁇ angle further has at least 3 characteristic diffraction peaks as follows: 14.7° ⁇ 0.2°, 16.8° ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.9° ⁇ 0.2°, 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form at 2 ⁇ angle further has at least one of the following characteristic diffraction peaks: 13.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 21.2° ⁇ 0.2°, 24.9° ⁇ 0.2°, 27.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form at 2 ⁇ angle further has at least 3 characteristic diffraction peaks as follows: 13.5° ⁇ 0.2°, 14.2° ⁇ 0.2°, 21.2° ⁇ 0.2°, 24.9° ⁇ 0.2°, 27.1° ⁇ 0.2°.
  • the crystalline form has characteristic peaks and their relative intensities in an X-ray powder diffraction pattern expressed at 2 ⁇ angle as follows:
  • the brepocitinib tosylate form 1 has an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1 .
  • XRPD X-ray powder diffraction
  • the Fourier transform infrared spectrum (FT-IR) of the brepocitinib tosylate form 1 is at 654 ⁇ 2 cm ⁇ 1 , 682 ⁇ 2 cm ⁇ 1 , 774 ⁇ 2 cm ⁇ 1 , 820 ⁇ 2 cm -1 , 876 ⁇ 2cm -1 , 960 ⁇ 2cm -1 , 980 ⁇ 2cm -1 , 1009 ⁇ 2cm -1 , 1032 ⁇ 2cm -1 , 1086 ⁇ 2cm -1 , 1121 ⁇ 2cm -1 , 1156 ⁇ 2cm -1 , 1216 ⁇ 2cm -1 , 1234 ⁇ 2cm -1 , 1254 ⁇ 2cm -1 , 1273 ⁇ 2cm -1 , 1333 ⁇ 2cm -1 , 1364 ⁇ 2cm -1 , 1398 ⁇ 2cm -1 , 1423 ⁇ 2cm -1 , 1445
  • FT-IR Fourier transform infrared spectrum
  • the Fourier transform infrared spectroscopic characterization of the brepocitinib tosylate form 1 is substantially as shown in FIG. 7 .
  • the brepocitinib tosylate salt form 1 is anhydrous.
  • the TGA characterization of the brepocitinib tosylate form 1 is substantially as shown in FIG. 2 , before 100°C, the weight loss is 0.26%, and the decomposition temperature is about 281°C.
  • the DSC characterization of the brepocitinib tosylate crystal form 1 is substantially as shown in FIG. 3 , the Onset value is 281 ⁇ 2°C, and the peak value is 282 ⁇ 2°C.
  • the DVS characterization of the brepocitinib tosylate form 1 is substantially as shown in Figure 4, with a 0.14% weight gain at 25°C between 0% RH and 80% RH.
  • the present disclosure provides a method for preparing the crystal form, comprising:
  • the toluenesulfonic acid aqueous solution and the brepocitinib solution are mixed, stirred, and a solid is precipitated to obtain the brepocitinib tosylate crystal form 1.
  • the order in which the toluenesulfonic acid aqueous solution and the brepocitinib solution are mixed is not limited.
  • the aqueous solution of toluenesulfonic acid can be added dropwise to the brepocitinib solution (positive addition).
  • the brepocitinib solution can also be added dropwise to the aqueous toluenesulfonic acid solution (back addition).
  • the mixing manner in the preparation method is to drop the aqueous solution of toluenesulfonic acid into the brepocitinib solution.
  • the brepocitinib solution is sonicated in acetonitrile or acetone or isopropanol.
  • the aqueous solution of toluenesulfonic acid is sonicated in water.
  • the stirring means is overnight stirring at room temperature.
  • the solids are separated and dried after being precipitated in the preparation method.
  • the drying method is vacuum drying, and the time is 10-24 hours.
  • the drying operation is performed at room temperature.
  • the brepocitinib tosylate form 1 has at least one of the following beneficial effects:
  • the brepocitinib tosylate crystal form 1 of the present disclosure has good stability. Stable under high humidity conditions, its crystal form remains unchanged for at least 3 weeks.
  • the brepocitinib tosylate crystal form 1 of the present disclosure has extremely low hygroscopicity. 0.14% weight gain between 0%RH-80%RH, no or almost no hygroscopicity, while brepocitinib free state gains 5.0% weight gain between 0%RH-70%RH, has hygroscopicity, and is easy to deliquescence under high humidity conditions .
  • brepocitinib tosylate crystal form 1 of the present disclosure has better solubility.
  • brepocitinib has low solubility in free state and is easy to form a gel in water or under accelerated conditions, which will bring difficulties to the mixing step in the production process, especially it is not suitable for wet granulation, thus limiting the use of water in the production process.
  • the brepocitinib tosylate crystal form 1 of the present disclosure has good chemical stability. Purity and content did not change significantly under long-term (normal temperature, 60%RH), accelerated (40°C, 75%RH), high temperature (50°C), high humidity (normal temperature, 92%RH) and oxidative conditions; however, the free state of brepocitinib Under the same conditions, the content is reduced, that is, the active ingredient is reduced.
  • the tablet prepared by using the brepocitinib tosylate crystal form 1 of the present disclosure has good stability. Under accelerated conditions and under high humidity conditions, the hygroscopic weighing of the tablets of brepocitinib tosylate form 1 did not change much, and there was no change in their appearance; while the tablets prepared with brepocitinib free state were under high humidity conditions. The lower tablets gained significant weight, and were yellowed, tacky, and partially collapsed under accelerated conditions and under high humidity conditions.
  • the brepocitinib tosylate crystal form 1 of the present disclosure has less solvent residue on the surface and high purity.
  • the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the brepocitinib tosylate crystal form 1 of the present disclosure or the brepocitinib tosylate crystal form obtained by the preparation method of the present disclosure, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition is selected from the group consisting of tablets, capsules, creams, transdermal patches, ointments, eye drops, lotions and gels.
  • the pharmaceutical composition may contain one or more other pharmaceutically active ingredients.
  • the other pharmaceutically active ingredient is selected from the group consisting of psoriasis drugs, lupus drugs, dermatitis drugs, and the like.
  • compositions provided by the present disclosure can be administered by a number of routes including, but not limited to: oral (enteral) administration, parenteral (injection) administration, rectal administration, topical administration, intradermal administration, intrathecal administration Administration, subcutaneous (SC), intramuscular (IM), sublingual/buccal, ocular, otic, vaginal and intranasal or by inhalation, typically, an effective amount of the Solid form of brepocitinib tosylate form 1.
  • the actual amount of brepocitinib tosylate to be administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.
  • the compounds of the present disclosure can also be administered directly into the bloodstream, into muscle, or into internal organs.
  • Suitable means of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.
  • the compounds of the present disclosure may also be applied topically to the skin or mucosa, that is, dermally or transdermally.
  • compositions of the present disclosure can take a variety of forms. These include, for example, liquid, semisolid, and solid dosage forms such as liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories.
  • liquid solutions eg, injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes, and suppositories.
  • tablets, pills, powders, liposomes, and suppositories The form depends on the intended mode of administration and therapeutic use.
  • Oral administration of solid dosage forms may, for example, be in discrete units such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure.
  • Oral administration can be in powder or granular form; oral dosage forms are sublingual, eg, lozenges.
  • the crystalline compound is usually combined with one or more adjuvants.
  • Such capsules or tablets may contain controlled release formulations.
  • the dosage form may also contain buffering agents or may be prepared with enteric coatings.
  • Oral administration can be in liquid dosage form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (eg, water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring (eg, sweetening) and/or perfuming agents.
  • the present disclosure includes parenteral dosage forms.
  • Parenteral administration includes, for example, subcutaneous injection, intravenous injection, intraperitoneal administration, intramuscular injection, intrasternal injection, and infusion.
  • Injectable preparations ie, sterile injectable aqueous or oleaginous suspensions
  • Topical administration includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams. Topical formulations may include crystalline compounds that enhance absorption or penetration of the active ingredient through the skin or other affected area.
  • administration will be accomplished using patches, either of the reservoir and porous membrane type or of the solid matrix type.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, Fibers, bandages and microemulsions, liposomes can also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol and propylene glycol, and penetration enhancers can also be incorporated.
  • topical formulations of the crystalline form of brepocitinib tosylate of the present disclosure can be administered using such formulations that encompass all conventional methods of administration across the body surface and the lining of body passages, including epithelial and mucosal tissues, including Transdermal, epidermal, oral, pulmonary, ocular, intranasal, vaginal and rectal modes of administration.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol and propylene glycol.
  • Such topical formulations can be prepared in combination with additional pharmaceutically acceptable excipients.
  • Excipients that may be essential for clinical efficacy are one or more penetration enhancers, such as one or more saturated or cis-unsaturated C10-C18 fatty alcohols.
  • Such fatty alcohols include C16-C18 fatty alcohols, and are most preferably C18 fatty alcohols.
  • Examples of cis-unsaturated C16-C18 fatty alcohols include oleyl alcohol, linoleyl alcohol, gamma-linolenic alcohol, and linolenic alcohol.
  • Saturated C10-C18 fatty alcohols useful as penetration enhancers include decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, and stearyl alcohol.
  • penetration enhancers useful in preparing topical formulations include C10-C18 fatty acids, which when saturated may include capric, lauric, myristic, palmitic, stearic, and arachidic acid.
  • the penetration enhancer may be a cis-unsaturated fatty acid such as palmitoleic acid (cis-9-hexadecenoic acid), oleic acid (cis-9-octadecenoic acid), cis- Formula-Isooleic acid (cis-11-octadecenoic acid), linoleic acid (cis-9,12-octadecadienoic acid), ⁇ -linolenic acid (cis-6,9,12 -Octatrienoic acid), linolenic acid (cis-9,12,15-octadecatrienoic acid) and arachidonic acid (cis-5,8,11,14-eicosatetraene acid).
  • Penetration enhancers for example, selected from C10-C18 fatty alcohols, at about 0.1 to about 5% (w/v), more preferably 1 to about 4% (w/v), more preferably 1 Amounts in the range to about 3% (w/v) are used.
  • the present disclosure provides the brepocitinib tosylate crystal form 1 or the brepocitinib tosylate crystal form obtained according to the preparation method of the present disclosure or the pharmaceutical composition described in the present disclosure in the preparation of the treatment of TYK2 and/or Use in medicine for JAK1-related diseases.
  • the associated disease is selected from the group consisting of lupus (eg, systemic lupus erythematosus), rheumatoid arthritis (RA), psoriasis (eg, plaque psoriasis), inflammatory bowel disease (IBD) ), ulcerative colitis, Crohn's disease, vitiligo (eg, active non-segmental vitiligo), alopecia (eg, alopecia areata, alopecia areata), hidradenitis suppurativa, and atopic dermatitis.
  • lupus eg, systemic lupus erythematosus
  • RA rheumatoid arthritis
  • psoriasis eg, plaque psoriasis
  • IBD inflammatory bowel disease
  • ulcerative colitis Crohn's disease
  • vitiligo eg, active non-segmental vitilig
  • the present disclosure provides a method of treating a disease associated with TYK2 and/or JAK1, comprising administering to an individual in need of the method a therapeutically effective amount of the brepocitinib tosylate form 1 or a crystalline form according to the present disclosure
  • a therapeutically effective amount of the brepocitinib tosylate form 1 or a crystalline form according to the present disclosure The brepocitinib tosylate crystal form obtained by the preparation method or the pharmaceutical composition containing the brepocitinib tosylate crystal form 1 of the present disclosure.
  • the individual is a mammal.
  • the mammal is a human.
  • the disease is selected from lupus (eg, systemic lupus erythematosus), rheumatoid arthritis (RA), psoriasis (eg, plaque psoriasis), inflammatory bowel disease (IBD) , ulcerative colitis, Crohn's disease, vitiligo (eg, active non-segmental vitiligo), alopecia (eg, alopecia areata, alopecia areata), hidradenitis suppurativa, and atopic dermatitis.
  • lupus eg, systemic lupus erythematosus
  • RA rheumatoid arthritis
  • psoriasis eg, plaque psoriasis
  • IBD inflammatory bowel disease
  • ulcerative colitis Crohn's disease
  • vitiligo eg, active non-segmental vitiligo
  • a typical regimen is one to five oral doses per day, especially one to four oral doses.
  • each dose provides about 0.01-20 mg/kg of the solid form of brepocitinib tosylate form 1 provided by the present disclosure, with preferred doses each providing about 0.1-10 mg/kg, especially about 0.1 -5 mg/kg, depending on the specific condition being treated, the age and weight of the specific patient, and the specific patient's response to drug therapy, the exact dose is to be determined under the guidance of a physician according to standard medical principles.
  • a specific unit dose can be between 5-500 mg, eg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 200 mg, 240 mg, and the like.
  • the topical formulation contains a therapeutically effective amount of brepocitinib tosylate form 1 or brepocitinib tosylate form obtained according to the preparation methods of the present disclosure, which can be administered to a patient in need thereof in doses ranging from once daily to four times daily. These amounts are in the range of about 0.1% to about 5.0% (w/v), more preferably about 0.1% to about 3.0% (w/v), such as 0.1%, 0.3%, 1%, 3%.
  • the method further comprises administering other drugs.
  • the other drug is selected from antibiotics, anti-inflammatory drugs, and contraceptives.
  • the other drug is selected from the group consisting of Itraconazole, Ethinyl estradiol, and levonorgestrel.
  • the present disclosure provides brepocitinib tosylate crystal form 1 or the brepocitinib tosylate crystal form obtained according to the disclosed preparation method or a pharmaceutical composition containing the brepocitinib tosylate crystal form 1 of the present disclosure and other Combination of drugs.
  • compositions as defined herein, wherein a crystalline compound herein or a pharmaceutically acceptable solvate of the compound is combined with one or more other therapeutic agents discussed herein used in combination.
  • “Combination" administration of two or more compounds means that all compounds are administered sufficiently close in time that the presence of one compound alters the biological effect of any other compound. Two or more compounds can be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration can be performed by admixing the compounds prior to administration, or by administering the compounds as separate dosage forms at the same time point, but at the same or different administration sites.
  • concurrent administration can be performed by admixing the compounds prior to administration, or by administering the compounds as separate dosage forms at the same time point, but at the same or different administration sites.
  • the phrases “concurrent administration”, “co-administration”, “concurrent administration” and “concurrent administration” refer to the combined administration of the compounds.
  • Root temperature in this disclosure refers to a temperature of 10°C to 30°C.
  • stirring conventional methods in the art can be used, for example, stirring methods include magnetic stirring and mechanical stirring, and the stirring speed is 50-1800 rpm. In certain embodiments, the stirring speed is 300-900 rpm.
  • Isolation can be performed by conventional methods in the art, such as centrifugation or filtration. Filtration under reduced pressure is preferred, and suction filtration is generally performed at room temperature at a pressure less than atmospheric pressure. In certain embodiments, the pressure is less than 0.09 MPa.
  • Drying can be accomplished by using conventional techniques in the art, such as drying at room temperature, air drying or drying under reduced pressure; it can be under reduced pressure or normal pressure, preferably the pressure is less than 0.09 MPa.
  • the drying apparatus and method are not limited, and can be a fume hood, a forced air oven, a spray dryer, a fluidized bed drying or a vacuum oven; it can be carried out under reduced or no reduced pressure, preferably the pressure is less than 0.09Mpa.
  • Toluenesulfonic acid means p-Toluenesulfonic acid.
  • Normal temperature refers to a temperature of 25°C ⁇ 5°C.
  • crystalline form means as evidenced by the characterization of the X-ray powder diffraction pattern shown. It is well known to those skilled in the art that the experimental errors therein depend upon instrumental conditions, sample preparation and sample purity. Spectra generally vary with instrument conditions. The relative intensities of peaks may vary with experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor; experimental errors in peak angles should also be taken into account, usually allowing an error of ⁇ 0.2°; the influence of factors such as sample height can cause The peak angle is shifted as a whole, and a certain shift is usually allowed.
  • any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present disclosure belongs to the scope of the present disclosure.
  • the "single crystal form” refers to a single crystal form detected by X-ray powder diffraction.
  • crystalline form of brepocitinib tosylate of the present disclosure is pure, single, and substantially not mixed with any other crystalline or amorphous forms.
  • substantially absent when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms or amorphous states, more particularly less than 10% by weight, especially Less than 5% by weight, especially less than 1% by weight.
  • FIG. 1 is the XRPD pattern of the brepocitinib tosylate crystal form 1 described in Example 1.
  • FIG. 1 is the XRPD pattern of the brepocitinib tosylate crystal form 1 described in Example 1.
  • FIG. 2 is a TGA diagram of brepocitinib tosylate crystal form 1 described in Example 1.
  • FIG. 2 is a TGA diagram of brepocitinib tosylate crystal form 1 described in Example 1.
  • FIG. 3 is a DSC chart of the brepocitinib tosylate crystal form 1 described in Example 1.
  • FIG. 4 is a DVS graph of brepocitinib tosylate Form 1 described in Example 1.
  • FIG. 4 is a DVS graph of brepocitinib tosylate Form 1 described in Example 1.
  • FIG. 5 is a 1H-NMR chart of the brepocitinib tosylate crystal form 1 described in Example 1.
  • FIG. 6 is a PLM image of brepocitinib tosylate Form 1 described in Example 1.
  • FIG. 7 is an FT-IR image of brepocitinib tosylate crystal form 1 described in Example 1.
  • FIG. 8 is a graph showing the appearance changes of the free state of brepocitinib in Experiment Example 2 under accelerated conditions into a gel and deliquescence under high humidity conditions.
  • FIG. 9 is an XRPD diagram of stability of the brepocitinib tosylate crystal form 1 in Experimental Example 3.
  • FIG. 9 is an XRPD diagram of stability of the brepocitinib tosylate crystal form 1 in Experimental Example 3.
  • X-ray powder diffraction (XRPD) test conditions are: Bruker D8, Cu-K ⁇ radiation, detection range 3°-40°2 ⁇ , step size 0.02°2 ⁇ , scan rate 0.2s.step -1 , current and voltage 40mA, 40KV.
  • Thermogravimetric analysis (TGA) test conditions are: TA Q500, 10.00°C/min from room temperature to 400°C; for the TGA chart, keep the temperature point and weight loss value.
  • DSC test conditions are: equilibrium at 0°C, rising to 350°C at 10°C/min; for the DSC chart, keep the temperature point and enthalpy value.
  • Dynamic moisture adsorption (DVS) test conditions are: taken from TA Instruments Q5000 TGA, control software Thermal Advantage, analysis software Universal Analysis; usually 1-10 mg of the sample is placed in a platinum crucible, and the TA software records the relative humidity of the sample from Weight change from 0% RH to 80% RH to 0% RH. Depending on the specific conditions of the sample, different adsorption and desorption steps can also be applied to the sample.
  • Hydrogen nuclear magnetic spectrum data (1H-NMR) were obtained from Bruker Ascend 500M HZ nuclear magnetic resonance spectrometer. Weigh an appropriate amount of sample and dissolve it into a NMR sample tube with about 0.5 mL of deuterated dimethyl sulfoxide reagent for detection.
  • Polarized light microscope (PLM) spectrum was taken from the hot stage, XP-500, eyepiece 10 times, objective lens 4 times, weigh 20 mg of the ashing sample, evenly disperse it in 50 ml of water, and take the dispersed droplets to a clean carrier. After natural drying, the slides were observed under a polarizing microscope.
  • FT-IR Fourier transform infrared spectroscopy
  • HPLC High performance liquid chromatography
  • Mobile phase A: 0.05% trifluoroacetic acid aqueous solution; B: acetonitrile solution;
  • the elution gradient is as follows:
  • the free state of Brepocitinib is prepared by the prior art, such as the method mentioned in WO2020165788A1, and can also be purchased commercially.
  • the TGA characterization data of Brepocitinib tosylate crystal form 1 is: before 100° C., the weight loss is 0.26%, the decomposition temperature is about 281° C., and it is anhydrous, as shown in FIG. 2 .
  • the DSC characterization data of Brepocitinib tosylate crystal form 1 are: the Onset value is 281 ⁇ 2°C, and the peak value is 282 ⁇ 2°C, as shown in FIG. 3 .
  • the DVS characterization data of Brepocitinib tosylate crystal form 1 is: at 25°C, the weight gain is 0.14% between 0-80% RH, as shown in FIG. 4 .
  • the PLM characterization data of Brepocitinib tosylate form 1 are shown in FIG. 6 .
  • the FT-IR characterization data of Brepocitinib tosylate form 1 are shown in FIG. 7 .
  • brepocitinib Under long-term, accelerated, high temperature, high humidity and oxidative conditions, the free content of brepocitinib was significantly reduced, that is, the active ingredients of the drug were reduced; the content of brepocitinib tosylate crystal form 1 did not change significantly.
  • the active ingredient and each auxiliary material were mixed according to the prescription in Table 2, and then pressed into tablets under the pressure of 20 MPa on an infrared tablet machine for 2 minutes, and the blank auxiliary materials were mixed at the same time for tableting.
  • the tablet containing brepocitinib free state had sticking phenomenon in some of the tablets during the compression process, and there was residue on the punch surface; while the tablet containing brepocitinib tosylate crystal form 1 had no sticking phenomenon.
  • the whole tablet compressed in Experimental Example 4 was placed under accelerated conditions (40°C, 75% RH) and high humidity conditions (normal temperature, 92% RH), and its weight and appearance were checked regularly.
  • Dissolution Apparatus RC12AD Tianda Tianfa Dissolution Apparatus
  • Dissolution medium pH 6.8 phosphate buffer
  • Dissolution method basket method
  • the preparation method is as follows: weigh brepocitinib tosylate crystal form 1 and various excipients according to the prescription amount and mix and press the tablet, after preparing the tablet core, then coating the aqueous solution/suspension of the coating on the tablet core to obtain 4 different specifications film-coated tablets.
  • brepocitinib tosylate crystal form 1 is mixed with lactose and microcrystalline cellulose, and then an aqueous solution of hypromellose is added.

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Abstract

L'invention concerne une forme cristalline de tosylate de brépocitinib, ainsi qu'un procédé de préparation, une composition pharmaceutique et une utilisation de celle-ci.
PCT/CN2022/079962 2021-02-01 2022-03-09 Forme cristalline de tosylate de brépocitinib, son procédé de préparation et son utilisation WO2022161507A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107074867A (zh) * 2014-08-21 2017-08-18 辉瑞公司 作为jak抑制剂的氨基嘧啶基化合物
WO2019040706A1 (fr) * 2017-08-24 2019-02-28 Aclaris Therapeutics, Inc. Compositions et méthodes de traitement du vitiligo
WO2020165788A1 (fr) * 2019-02-15 2020-08-20 Pfizer Inc. Composé de pyrimidinyl-3,8-diazabicyclo [3.2.1] octanylméthanone cristallin et son utilisation
WO2021249367A1 (fr) * 2020-06-09 2021-12-16 苏州晶云药物科技股份有限公司 Nouvelle forme cristalline de sel p-toluènesulfonate d'un composé diazabicyclique et son procédé de préparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107074867A (zh) * 2014-08-21 2017-08-18 辉瑞公司 作为jak抑制剂的氨基嘧啶基化合物
WO2019040706A1 (fr) * 2017-08-24 2019-02-28 Aclaris Therapeutics, Inc. Compositions et méthodes de traitement du vitiligo
WO2020165788A1 (fr) * 2019-02-15 2020-08-20 Pfizer Inc. Composé de pyrimidinyl-3,8-diazabicyclo [3.2.1] octanylméthanone cristallin et son utilisation
WO2021249367A1 (fr) * 2020-06-09 2021-12-16 苏州晶云药物科技股份有限公司 Nouvelle forme cristalline de sel p-toluènesulfonate d'un composé diazabicyclique et son procédé de préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANDREW FENSOME, CATHERINE M. AMBLER, ERIC ARNOLD, MARY ELLEN BANKER, MATTHEW F. BROWN, JILL CHRENCIK, JAMES D. CLARK, MARTIN E. DO: "Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S )-2,2-Difluorocyclopropyl)((1 R ,5 S )-3-(2-((1-methyl-1 H -pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841)", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 61, no. 19, 11 October 2018 (2018-10-11), US , pages 8597 - 8612, XP055688622, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b00917 *

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