WO2025181545A1 - Formulations topiques d'un inhibiteur de tyk2 et leurs utilisations - Google Patents

Formulations topiques d'un inhibiteur de tyk2 et leurs utilisations

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Publication number
WO2025181545A1
WO2025181545A1 PCT/IB2025/000072 IB2025000072W WO2025181545A1 WO 2025181545 A1 WO2025181545 A1 WO 2025181545A1 IB 2025000072 W IB2025000072 W IB 2025000072W WO 2025181545 A1 WO2025181545 A1 WO 2025181545A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
oil
compound
combination
wax
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Pending
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PCT/IB2025/000072
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English (en)
Inventor
Anjali Pandey
D. David HENNINGS
Matthew Everett EBMEIER
Jason Michael CARBOL
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Sudo Biosciences Ltd
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Sudo Biosciences Ltd
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Publication date
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Publication of WO2025181545A1 publication Critical patent/WO2025181545A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Described herein are topical formulations of a compound that binds to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2) and methods of making such formulations. Also described herein are methods of treatment of diseases or conditions that would benefit with treatment with a compound that binds to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2) or inhibition of certain cytokine signaling, for example IL-12, IL-23, and IFN-a signaling involving the topical administration of such formulations.
  • JH2 pseudokinase domain
  • TYK2 non-receptor tyrosine-protein kinase 2
  • TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases.
  • the mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling.
  • TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g.
  • IFN-a IFN-P, IFN-K, IFN-5, IFN-s, IFN-T, IFN-CO, and IFN- (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL- 10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF).
  • the activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT3, STAT4, and STAT6.
  • Compound l is a potent and selective TYK2 inhibitor, specifically selective inhibition of TYK2 over other JAKs. There is a need to topical dosage forms of Compound 1.
  • the present disclosure relates to various topical pharmaceutical compositions or formulations of a compound that binds to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2), 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro- 2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-(methyl-tZ?)nicotinamide (Compound 1), and methods of making the same.
  • JH2 pseudokinase domain
  • TYK2 non-receptor tyrosine-protein kinase 2
  • the pharmaceutical composition is formulated as a solution, liquid, suspension, oil, gel, cream, ointment, lotion, foam, or paste. In some embodiments, the pharmaceutical composition is formulated as a suspension, gel, cream, or ointment. In some embodiments, the pharmaceutical composition is formulated as a cream. In some embodiments, the cream is a cream suspension or a dissolved cream.
  • the antioxidant is butylhydroxytoluene (BHT), butylated hydroxyanisole (tert-butyl-4-hydroxy anisole, BHA), or tocopherol, or a combination thereof.
  • BHT butylhydroxytoluene
  • BHA butylated hydroxyanisole
  • tocopherol or a combination thereof.
  • the pharmaceutical composition comprises from about 0.01% to about 0.50% (w/w) of the antioxidant.
  • the carrier suitable for topical administration comprises one or more solvents, humectants, emulsifiers, thickeners, emollients, rheology control agents, preservatives, penetration enhancers, buffering agents, or a combination thereof.
  • the pharmaceutical composition has a pH of from about 4.5 to about 6.5. In some embodiments, the pharmaceutical composition has a pH of about 4.5, about 5.0, about 5.5, about 6.0, or about 6.5.
  • the pharmaceutical composition comprises from about 0.01% to about 1.0% (w/w) of Compound 1, or pharmaceutically acceptable salt, or solvate thereof.
  • the pharmaceutical composition comprises about 0.01%, about 0.015%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.045%, about 0.05%, about 0.055%, about 0.06%, about 0.065%, about 0.07%, about 0.075%, about 0.08%, about 0.085%, about 0.09%, about 0.095%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, or about 1.0% (w/w) of Compound 1, or pharmaceutically acceptable salt, or solvate thereof.
  • the pharmaceutical composition comprises:
  • the present disclosure relates to topical pharmaceutical compositions comprising 6- (cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2J/-pyrazolo[4,3-c]quinolin-6- yl)amino)-/V-(methyl-t/3)nicotinamide (Compound 1).
  • the terms “topical pharmaceutical composition,” “topical composition,” “topical formulation,” and the like are used herein interchangeably and, as used herein, generally refer to a composition that is pharmaceutically acceptable and that is suitable for administering Compound 1 to a subject.
  • compositions include, but are not limited to, solutions, liquids, suspensions, oils, gels, creams, ointments, lotions, foams, or pastes.
  • the compositions also comprise at least one solvent.
  • the compositions also comprise an antioxidant.
  • the compositions may also contain one or more additional ingredients or excipients as described herein.
  • Such topical formulations are useful in the treatment of diseases or conditions, such as rheumatoid arthritis, psoriasis including plaque psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis, and erythredermic psoriasis, psoriatic arthritis, atopic dermatitis, scleroderma, alopecia areata, hidradenitis suppurativa, lupus, systemic lupus erythematosus, lichen planus, dermatomyositis, pityriasis rubra pilaris, systemic sclerosis, palmoplantar pustulosis, pemphigus vulgaris, pyoderma gangrenosum, bullous pemphigoid, cutaneous lupus, or a combination thereof.
  • diseases or conditions such as rheumatoid
  • Compound 1 is a potent and selective TYK2 inhibitor.
  • TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases.
  • the mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling.
  • TYK2 inhibitors are useful in the treatment of diseases or conditions, such as rheumatoid arthritis, psoriasis including plaque psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis, and erythredermic psoriasis, psoriatic arthritis, atopic dermatitis, scleroderma, alopecia areata, hidradenitis suppurativa, lupus, systemic lupus erythematosus, lichen planus, dermatomyositis, pityriasis rubra pilaris, systemic sclerosis, palmoplantar pustulosis, pemphigus vulgaris, pyoderma gangrenosum, bullous pemphigoid, cutaneous lupus, or a combination thereof.
  • diseases or conditions such as rheumatoi
  • Compound 1 refers to 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H- pyrazolo[4,3-c]quinolin-6-yl)amino)-N-(methyl-t/3)nicotinamide, which has the chemical structure shown below:
  • Compound 1 and methods of making Compound 1 previously described see, WO2022175752, US Patent No. 11613548, US20230242546; each of which is incorporated by reference in its entirety). Additionally, Compound 1 can be prepared as a crystalline form as previously described (see, WO2024042363; which is incorporated by reference in its entirety).
  • the Compound 1 used to make any of the formulations described herein may comprise Compound 1 in crystalline form and/or in amorphous form.
  • Compound 1 has low water solubility, with a solubility of 0.0003% (w/w) in water.
  • water is an important component of many topical formulations, such as gels, solutions, and creams.
  • the present disclosure provides topical pharmaceutical compositions and formulations of Compound 1 that are suitable for topical administration.
  • Compound 1 is completely dissolved, despite its poor solubility in water.
  • Compound 1 is in a suspension.
  • the topical formulations of Compound 1 are stable upon storage.
  • an antioxidant is added to the formulation to increase chemical stability of Compound 1.
  • Compound 1 can be supplied in a topical dosage form such as a solution, liquid, suspension, oil, gel, cream, ointment, lotion, foam, or paste.
  • the topical fomulations described herein can be used to treat diseases or conditions, such as rheumatoid arthritis, psoriasis including plaque psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis, and erythredermic psoriasis, psoriatic arthritis, atopic dermatitis, scleroderma, alopecia areata, hidradenitis suppurativa, lupus, systemic lupus erythematosus, lichen planus, dermatomyositis, pityriasis rubra pilaris, systemic sclerosis, palmoplantar pustulo
  • a topical pharmaceutical composition comprising: (i) 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)amino)-N-(methyl-d3)ni cotinamide (Compound A): (Compound 1), or pharmaceutically acceptable salt, or solvate thereof; and
  • the pharmaceutical composition further comprises an antioxidant.
  • the antioxidant improves the stability of the pharmaceutical composition comprising Compound 1.
  • the antioxidant improves the chemical stability of Compound 1.
  • the antioxidant is butylhydroxytoluene (BHT), butylated hydroxyanisole (tert-butyl-4-hydroxyanisole, BHA), or tocopherol, or a combination thereof.
  • the pharmaceutical composition comprises from about 0.01% to about 0.50% (w/w) of the antioxidant. In some embodiments, the pharmaceutical composition comprises from about 0.10% to about 0.50% (w/w) of the antioxidant. In some embodiments, the pharmaceutical composition comprises about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, or about 0.50% (w/w) of the antioxidant. In some embodiments, the pharmaceutical composition comprises from about 0.01% to about 0.20% (w/w) of the antioxidant.
  • the pharmaceutical composition comprises about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, or about 0.20% (w/w) of the antioxidant.
  • antioxidant is BHT.
  • the pharmaceutical composition comprises from about 0.01% to about 0.50% (w/w) of BHT. In some embodiments, the pharmaceutical composition comprises from about 0.10% to about 0.50% (w/w) of BHT. In some embodiments, the pharmaceutical composition comprises about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, or about 0.50% (w/w) of BHT. In some embodiments, the pharmaceutical composition comprises from about 0.01% to about 0.20% (w/w) of BHT.
  • the pharmaceutical composition comprises about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, or about 0.20% (w/w) of BHT. In some embodiments, the pharmaceutical composition comprises about 0.20% (w/w) of BHT.
  • a topical pharmaceutical composition comprising: (i) 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)amino)-N-(methyl-d3)ni cotinamide (Compound A): (Compound 1), or pharmaceutically acceptable salt, or solvate thereof;
  • the pharmaceutical composition is formulated as a solution, liquid, suspension, oil, gel, cream, ointment, lotion, foam, or paste. In some embodiments, the pharmaceutical composition is formulated as a suspension, gel, cream, or ointment.
  • the pharmaceutical composition is formulated as a gel. In some embodiments, the pharmaceutical composition is formulated as a dissolved gel. In some instances, anhydrous gels with dissolved pharmaceuticals tend to produce highly penetrating formulations. Thus, in some embodiments, the pharmaceutical composition is formulated as an anhydrous dissolved gel. In some instances, the addition of water to a formulation can improve the aesthetic properties of the formulation. Thus, in some embodiments, the pharmaceutical composition is formulated as an aqueous dissolved gel.
  • aqueous gel suspensions allow for more flexibility in formulation development, which can lead to superior stability profiles. Additionally, the inclusion of water to a formulation can improve the aesthetic properties of the formulation. Thus, in some instances, the pharmaceutical composition is formulated as an aqueous gel suspension.
  • ointments are innately occlusive, which can form a protective barrier on the treated skin. Additionally, this dosage form can have a high penetration profile, as the pharmaceutical agent is dissolved in an internal phase. Thus, in some embodiments, the pharmaceutical composition is formulated as an ointment with dissolved internal phase.
  • Dissolved cream formulations are known for having favorable aesthetic properties, but can often be more challenging with low soluble compounds. As suspension formulations allow for greater flexibility in excipient selection, cream suspensions can have better stability profiles. [0033] In some emboidments, the pharmaceutical composition is formulated as a cream. In some embodiments, the cream is a cream suspension or a dissolved cream.
  • the antioxidant in the topical formulation is butylhydroxytoluene (BHT), butylated hydroxyanisole (tert-butyl-4-hydroxyanisole, BHA), or tocopherol, or a combination thereof. In some embodiments, the antioxidant is butylhydroxytoluene (BHT).
  • the carrier suitable for topical administration in the topical formulations described herein comprises one or more solvents.
  • the solvent in some aspects comprises an organic component, or an ether component.
  • Such solvents comprise, for example, propylene glycol, hexylene glycol, isopropyl palmitate, polyoxyethylene, polyoxypropylene, diethylene glycol monoethyl ether (DGME), dimethyl isosorbide (DMI), d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), glycerin, polyethylene glycol (including PEG400), dimethyl sulfoxide (DMSO), or a combination thereof.
  • DGME diethylene glycol monoethyl ether
  • DMI dimethyl isosorbide
  • TPGS d-alpha-tocopherol polyethylene glycol 1000 succinate
  • glycerin polyethylene glycol (including PEG400), dimethyl sulfoxide (DMSO), or a combination thereof.
  • the solvent comprises hexylene glycol, DGME, PEG400, DMSO, propylene glygol, or a combination thereof. In some emboidments, the solvent comprises hexylene glycol, DGME, PEG400, propylene glygol, or a combination thereof. In some emboidments, the solvent comprises hexylene glycol, DGME, or a combination thereof. [0036] In some embodiments described herein, the solvent may also include an aqueous component. In some instances, aqueous components of topical formulations improves their aesthetic properties, such that they do not feel oily, tacky, or leave a residue on the skin. In some embodiments, the aqueous component is buffered.
  • the carrier suitable for topical administration in the topical formulations described herein comprises one or more solvents, and optionally one or more additional pharmaceutically acceptable excipients.
  • excipients include, for example, humectants, emulsifiers, thickeners, emollients, rheology control agents, preservatives, penetration enhancers, buffering agents, or a combination thereof.
  • topical formulations comprising Compound 1 as described above further include one or more of the following excipients:
  • emollients such as, for example, shea butter, cocoa butter, mineral oil, lanolin, lanolin alcohols, petrolatum, white petrolatum, paraffin, beeswax, squalene, coconut oil, jojoba oil, sesame oil, almond oil, canola oil, palm kernel oil, palm oil, safflower oil, soybean oil, sunflower oil, cetyl alcohol, cetyl palmitate, olive oil, oleyl alcohol, oleic acid, triethylhexanoin, cyclomethicone, dimethicone, sorbitol, xylitol, isopropyl palmitate, castor oil, carnauba wax, cetyl ester wax, emulsifying wax, microcrystalline wax, paraffin wax, white wax, yellow wax, polyethylene glycol, and the like, preferably white petrolatum;
  • emulsifiers such as, for example, arlacel 165, stearyl alcohol, cetearyl alcohol, cetyl alcohol, cetyl palmitate, glucoside, stearyl sulfate, sodium lauryl sulfate, cetyl sulfates, glyceryl monostearate, glyceryl laurate, isopropyl stearate, isopropyl palmitate, Sepineo P600, hydroxypropyl cellulose (HPC), hypromellose, polysorbate 60, polysorbate 80, steareth-2, steareth-21, poloxamer 407, poloxamer 188, ceteth-10 phosphate (Crodafos- CES), emulsifying wax, and the like, preferably ceteth-10 phosphate (Crodafos-CES);
  • emulsifiers such as, for example, arlacel 165, stearyl alcohol, cetearyl alcohol, cetyl
  • humectants such as, for example, mineral oil, petrolatum, white petrolatum, isopropyl palmitate, ammonium alkginate, butylene glycol, corn syrup solids, cyclomethicone, dipropylene glycol, glycerin, polydextrose, propylene glycol, sodium hyaluronate, sodium lactate, sorbitol, tagatose, trehalose, triacetin, triethanolamine, xylitol, or the like, preferably isopropyl palmitate;
  • preservatives such as, for example, benzyl alcohol, phenoxyethanol, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, methylparaben, propylparaben, benzalkonium chloride, or the like, preferably methylparaben and propylparaben;
  • rheology control agents such as, for example, carbopol, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (ELEC), carboxymethyl cellulose (CMC), carbomer, xanthan gum, carrageenan gum, sodium alginate, modified starch, Sepineo P600, or the like; and/or
  • penetration enhancers such as, for example, diethylene glycol monoethyl ether (DGME), N-methyl-2-pyrrolidone, triacetin, propylene glycol, benzyl alcohol, sodium laureth sulfate, dimethyl isosorbide, isopropyl myristate, isopropyl palmitate, isopropyl isostearate, propylene glycol monostearate, diisopropyl adipate, diethyl sebacate, oleic acid, ethyl oleate, glyceryl oleate, caprylic capric triglycerides, propylene glycol dicaprylate dicaprate, laureth-4, oleth-2, oleth-20, propylene carbonate, nonoxynol-9, nonoxynol-15, or the like, preferably di ethylene glycol monoethyl ether (DGME) and hexylene glycol.
  • DGME diethylene glyco
  • the Compound 1 topical pharmaceutical compositions or formulations comprise from about 5.0% to about 20.0% (w/w) of one or more emollients. In certain embodiments described herein, the Compound 1 topical pharmaceutical compositions or formulations comprise about 5.0%, about 10%, about 15%, or about 20.0% (w/w) of one or more emollients. In some embodiments, the one or more emollients comprise white petrolatum.
  • the Compound 1 topical pharmaceutical compositions or formulations comprise from about 5.0% to about 20.0% (w/w) of one or more emulsifiers. In certain embodiments described herein, the Compound 1 topical pharmaceutical compositions or formulations comprise about about 5.0%, about 10%, about 15%, or about 20.0% (w/w) of one or more emulsifiers. In some embodiments, the one or more emulsifiers comprise ceteth-10 phosphate (Crodafos-CES).
  • the Compound 1 topical pharmaceutical compositions or formulations comprise from about 0.0% to about 10.0% (w/w) of one or more humectants. In certain embodiments described herein, the Compound 1 topical pharmaceutical compositions or formulations comprise about 0.0%, about 2.5%, about 5%, aobout 7.5%, or about 10.0% (w/w) of one or more humectants. In some embodiments, the one or more humectants comprise isopropyl palmitate.
  • the Compound 1 topical pharmaceutical compositions or formulations comprise from about 0.0% to about 0.5% (w/w) of one or more preservatives. In certain embodiments described herein, the Compound 1 topical pharmaceutical compositions or formulations comprise from about 0.01% to about 0.5% (w/w) of one or more preservatives. In certain embodiments described herein, the Compound 1 topical pharmaceutical compositions or formulations comprise from about 0.05% to about 0.5% (w/w) of one or more preservatives.
  • the Compound 1 topical pharmaceutical compositions or formulations comprise about 0.05%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, or about 0.5% (w/w) of one or more preservatives.
  • the one or more preservatives comprise methylparaben, propylparaben, or a combination thereof.
  • the Compound 1 topical pharmaceutical compositions or formulations comprise from about 0.0% to about 5.0% (w/w) of one or more buffering agents. In certain embodiments described herein, the Compound 1 topical pharmaceutical compositions or formulations comprise from about 0.0% to about 1.0% (w/w) of a buffering agent.
  • the one or more buffering agents comprise sodium hydroxide, hydrochloric acid, sodium phosphate monobasic, sodium phosphate dibasic, sodium citrate, or a combination thereof.
  • the buffering agents comprise sodium hydroxide and/or hydrochloric acid.
  • the pharmaceutical composition has a pH of from about 4.5 to about 6.5. In some embodiments, the pharmaceutical composition has a pH of about 4.5, about 5.0, about 5.5, about 6.0, or about 6.5.
  • the Compound 1 topical pharmaceutical compositions or formulations comprise: about 5.0% to about 20.0% (w/w) of one or more emollients; about 5.0% to about 20.0% (w/w) of one or more emulsifiers; about 0.0% to about 10.0% (w/w) of one or more humectants; about 0.05% to about 0.5% (w/w) of one or more preservatives; or about 0.0% to about 1.0% (w/w) of a buffering agent; or combination thereof.
  • one or more solvents make up the mass balance to a total of 100% (w/w).
  • the pharmaceutical composition comprises from about 0.01% to about 1.0% (w/w) of Compound 1, or pharmaceutically acceptable salt, or solvate thereof.
  • the pharmaceutical composition comprises about 0.01%, about 0.015%, about 0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about 0.045%, about 0.05%, about 0.055%, about 0.06%, about 0.065%, about 0.07%, about 0.075%, about 0.08%, about 0.085%, about 0.09%, about 0.095%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, or about 1.0% (w/w) of Compound 1, or pharmaceutically acceptable salt
  • the pharmaceutical composition comprises about 0.01%, about 0.02%, about 0.05%, about 0.065%, about 0.20%, about 0.60%, or about 0.65% (w/w) of Compound 1, or pharmaceutically acceptable salt, or solvate thereof.
  • Compound 1, or pharmaceutically acceptable salt, or solvate thereof is at least about 90% pure, at least about 95% pure, at least about 96% pure, at least about 97% pure, at least about 98% pure, or at least about 99% pure.
  • Compound 1 is crystalline or partially crystalline. In other embodiments, Compound 1 is amorphous.
  • the present disclosure also relates to methods of administering the topical formulations comprising Compound 1 described herein.
  • the present disclosure provides methods of treating or preventing a TYK2-mediated disease or condition in a patient in need thereof, comprising topically administering to the patient a therapeutically effective amount of the topical pharmaceutical composition or formulation of the present disclosure.
  • the present disclosure provides methods of treating or preventing an inflammatory disease or condition or autoimmune disease or condition in a patient in need thereof, comprising topically administering to the patient a therapeutically effective amount of the topical pharmaceutical composition or formulation of the present disclosure.
  • the disease or condition is selected from rheumatoid arthritis, psoriasis including plaque psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis, and erythredermic psoriasis, psoriatic arthritis, atopic dermatitis, scleroderma, alopecia areata, hidradenitis suppurativa, lupus, and systemic lupus erythematosus, or a combination thereof.
  • the present disclosure provides methods of treating or preventing a dermotological disease or condition in a patient in need thereof, comprising topically administering to the patient a therapeutically effective amount of the topical pharmaceutical composition or formulation of the present disclosure.
  • the disease or condition is selected from lichen planus, dermatomyositis, pityriasis rubra pilaris, systemic sclerosis, palmoplantar pustulosis, pemphigus vulgaris, pyoderma gangrenosum, bullous pemphigoid, and cutaneous lupus, or a combination thereof.
  • the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • the area of skin to which the composition is administered is an area that exhibits, or is prone to exhibit, a symptom associated with psoriasis.
  • the psoriasis is plaque psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis, erythredermic psoriasis, or a combination thereof.
  • a method of treating or preventing psoriatic arthritis in a subject the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • lupus or systemic lupus erythematosus in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing rheumatoid arthritis in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • atopic dermatitis in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing scleroderma in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing alopecia areata in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing hi dradenitis suppurativa in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing lichen planus in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing dermatomyositis in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing pityriasis rubra pilaris in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing systemic sclerosis in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing palmoplantar pustulosis in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing pemphigus vulgaris in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing pyoderma gangrenosum in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing bullous pemphigoid in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • a method of treating or preventing cutaneous lupus in a subject comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.
  • the topical pharmaceutical composition comprising Compound 1 as described herein is administered to the skin of the patient in need thereof over the course of one day, two days, three days, four days, five days, six days, one week, ten days, two weeks or longer.
  • the topical pharmaceutical composition comprising Compound 1 as described herein is administered to the skin of the patient in need thereof once per day, twice per day, three times per day, or four times per day.
  • the composition is administered every day. In other embodiments, the composition is administered every other day.
  • kits and articles of manufacture for use with one or more methods described herein.
  • the kit comprises additional components, such as a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • suitable containers include, for example, bottles, vials, plates, syringes, and test tubes.
  • the containers are formed from a variety of materials such as glass or plastic.
  • the articles of manufacture provided herein contain packaging materials.
  • packaging materials include, but are not limited to, bottles, tubes, bags, cans, containers, and any packaging material suitable for a selected formulation and intended mode of use.
  • the container(s) include one or more of the crystalline or amorphous forms described herein.
  • kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich:Wiley-VCH/VHCA, 2002.
  • Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the crystalline and amorphous forms provided herein optionally exist in unsolvated as well as solvated forms.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an agonist.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. Those of skill in the art are familiar with administration techniques that can be employed with the compositions and methods described herein. In some embodiments, the compounds and compositions described herein are administered topically. [0086]
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutical combination as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term “fixed combination” means that the active ingredients, e.g.
  • non-fixed combination means that the active ingredients, e.g. a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • Compound 1 can be prepared as a crystalline form as previously described (see, WO2024042363; which is incorporated by reference in its entirety).
  • Solvent did not reach saturation.
  • the solubility capacity of the sample was capped at 5% to conserve compound.
  • DMSO dimethyl sulfoxide
  • DGME diethylene glycol monoethyl ether
  • DMI dimethyl isosorbide
  • Solvent blends were made with various amounts of DGME, DMSO, and water. The target amount of Compound 1 was added to each sample and mixed on a jar roller overnight. A visual evaluation of each blend sample was performed following mixing to determine the level of Compound 1 dissolution achieved.
  • the maximum amount of water that can be used in the final formulation is 25% (roughly 33.3% of the water phase). Based on this determination, a final water phase ratio of 25% water, 45% DGME, and 5% DMSO was selected for use in a dissolved cream formulation.
  • This dosage form utilized a similar formula as the original dissolved anhydrous gel, with the addition of water to improve the aesthetic properties of the product.
  • the first vehicle product resulted in a hazy, colorless, gel that was very fluid.
  • the original formula was modified to replace 2% HPC with 4% Sepineo P600. This resulted in a semi-translucent, thick gel. Aesthetically, the optimized formula applied smoothly with relatively little residue remaining on the skin.
  • Compound 1 (0.5% w/w) was readily dissolved and resulted in a semi-translucent, light yellow, thick gel.
  • Suspension products like the aqueous gel suspension, allow for more flexibility in formulation development, which can lead to superior stability profiles. As mentioned above, the inclusion of water in the formula improves the aesthetic properties of the product.
  • aqueous gel suspension formulations were prepared according to the following table:
  • Ointments are innately occlusive, which can form a protective barrier on the treated skin. Additionally, this dosage form can have a high penetration profile, as the pharmaceutical agent is dissolved in the internal phase.
  • This ointment was designed to dissolve Compound 1 in an internal phase of DMSO and propylene glycol. To determine if this excipient ratio was suitable to dissolve the target concentration of Compound 1, a solution of 5 parts DMSO and 10 parts propylene glycol was made. When 0.5 parts Compound 1 was added to the solution, it dissolved readily. An ointment vehicle was designed and manufactured using this ratio as the internal phase. This resulted in a white to off-white, thick ointment that was aesthetically non-tacky and left a slightly greasy, occlusive barrier on the skin.
  • Cream formulations are known for having favorable aesthetic properties. As suspension formulations allow for greater flexibility in excipient selection, they can have better stability profiles.
  • a vehicle batch was manufactured first, which resulted in a soft, self supporting, white cream. Aesthetically, this formula applied smoothly and left very little residue. [0128] An active batch of this formulation was manufactured successfully with Compound 1 (0.5% w/w) and resulted in a soft, self supporting, off-white cream.
  • Formula 1 utilized a simple cream formula with the inclusion of Pemulen TRI to build the viscosity of the product. This batch separated during manufacturing and could not be completed.
  • Formula 2 substituted white petrolatum, which was the primary oil phase component of Formula 1, with mineral oil. Additionally, the Pemulen TRI was substituted for 2% Sepineo P600. This resulted in a very fluid formulation that was not self supporting. When this formula was placed in 40 and 50°C storage, the samples displayed a small amount of phase separation shortly following incubation.
  • Formula 4 substituted the original surfactant system used in Formula 1 with a combination of Polysorbate 60 and glyceryl monostearate (GMS). Additionally, 3% cetyl alcohol was included to build the overall viscosity of the product. This resulted in a smooth, thick, opaque white cream. Aesthetically, this product applied smoothly and did not leave any residue on the skin. However, when this batch was stored at 40 and 50°C, complete phase separation of the product was noted in both storage conditions.
  • Formula 5 substituted the Pemulen TRI used in Formula 4 with 4% Sepineo P600. This resulted in a cream that was visually similar to and maintained the positive aesthetic properties of Formula 4. When applied to the skin, this formula felt slightly more occlusive than Formula 3. This residue dissipated soon after application. When this batch was stored at 40 and 50°C, the samples became more pourable than the original appearance of the cream. It was noted that once the samples were removed from these storage conditions, they returned to their original appearance relatively quickly. No phase separation was observed at either storage condition.
  • IVPT In Vitro Permeation Testing
  • cadaver skin harvested from the thigh of a 75 year old female donor was dermatomed to 300 pm thickness and was used as the rate controlling membrane.
  • a solution of phosphate buffered saline (PBS) with 10% 2-hydroxypropyl-beta-cyclodextrin and 0.01% sodium azide was used as the receptor solution.
  • Samples of each test article were dosed to the donor chambers of the cells. The receptor fluid was sampled at each designated timepoint and assayed for Compound 1 content.
  • the skin membrane was tape stripped to separate the outer layers of skin, the epidermis, and the dermis. The layers of skin were assayed to determine the drug delivery of each formulation to the different regions. Each sample was tested in six replicates at seven timepoints.
  • Formulations from each of the six dosage forms discussed in Example 4 were selected for testing to evaluate permeation differences between dosage forms. Samples of both Dissolved Cream Formula 3 and Formula 5 were submitted for comparison.
  • the Anhydrous Dissolved Gel delivered the most Compound 1 to the dermis and receptor solution.
  • the Ointment, Dissolved Cream (Formula 3) and Dissolved Cream (Formula 5) could also be suitable dosage forms based on the amount of drug substance delivered to the dermis and epidermis.
  • Example 6 Stability Study
  • Dissolved Cream (Formula 5) was evaluated for stability.
  • the pH of each test article did not change significantly between the timepoints and storage conditions evaluated in this study.
  • the pH is influenced by the API concentration, with the 0.01% and 0.1% formulations having a pH of about 6.0-6.2 and the 0.5% and 0.65% formulations having a pH of about 6.3-6.6 over the course of the study.
  • Additional creams were prepared to identify formulations suitable for topical use and physical and chemical stability. As part of these studies, the addition of an antioxidant to the formulation was evaluated to prevent chemical degradation. Three antioxidants were screened for their potential use in the formulation, BHT, BHA, and tocopherol. Based on chemical analysis, BHT was selected for further evaluation.
  • One formulation was compounded without BHT and was compounded with neutralization to the target pH after active phase addition (post-neutralization) as a control.
  • the control formulation showed continued degradation up to over 3% after 3 months.
  • the control formulation showed continued degradation of about 9% after 3 months.
  • a first formulation containing BHT was compounded with neutralization to the target pH after active phase addition (post-neutralization). With BHT, the formulation showed little to no degradation after 3 months at 25 °C and minimal degradation (about 1%) at 40 °C.
  • a second formulation containing BHT was compounded with neutralization to the target pH prior to active phase addition (pre-neutralization). With BHT and a pre-neutralization step, the formulation showed no increased degradation after the initial 2 week timepoint at 25 °C, and very slow degradation at 40 °C after 3 months.
  • IVPT In vitro skin permeation testing
  • Formulations for the IVPT study were prepared according to the following table, where all numbers are reported in % w/w of final fomulation:
  • the cream manufacturing process is a sequential continuous process, consisting of multiple phases being individually prepared, and combined during final compounding.
  • the drug phase contains the API, solvents, antioxidant, and preservatives.
  • the water phase consists of purified water and sodium hydroxide.
  • the oil phase combines white petrolatum, Crodafos-CES, and isopropyl palmitate.
  • Drug phase components are combined and mixed with homogenization to facilitate the dissolution of the API, preservatives, and antioxidant.
  • the water and oil phases are heated to a target temperature of 70 ⁇ 5°C and combined with high shear mixing to ensure a homogeneous emulsion prior to adding the drug phase.
  • the drug phase is added and mixed with homogenization for a homogeneous distribution of the API, antioxidant, and preservatives.
  • the batch is then cooled to below 20 ⁇ 5°C to form the finished product.
  • the final mixture is then adjusted to the pH target (pH 5.5-6.0). In process controls have been added to the master batch records for the pH adjustment.

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Abstract

L'invention concerne des formulations topiques d'un composé qui se lie au domaine pseudokinase (JH2) de la tyrosine-protéine kinase 2 (TYK2) non réceptrice et des procédés de fabrication de telles formulations. L'invention concerne également des méthodes de traitement impliquant l'administration topique de telles formulations.
PCT/IB2025/000072 2024-02-28 2025-02-27 Formulations topiques d'un inhibiteur de tyk2 et leurs utilisations Pending WO2025181545A1 (fr)

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Citations (4)

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WO2022175752A1 (fr) 2021-02-19 2022-08-25 Sudo Biosciences Limited Inhibiteurs de tyk2 et leurs utilisations
US20230277537A1 (en) * 2020-07-17 2023-09-07 Pfizer Inc. Stable pharmaceutical topical formulation containing immunosuppressant for treating dermatological condition
CN117377669A (zh) * 2021-02-19 2024-01-09 苏多生物科学有限公司 Tyk2抑制剂及其用途
WO2024042363A1 (fr) 2022-08-24 2024-02-29 Sudo Biosciences Limited Inhibiteurs de tyk2 et leurs utilisations

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US20230277537A1 (en) * 2020-07-17 2023-09-07 Pfizer Inc. Stable pharmaceutical topical formulation containing immunosuppressant for treating dermatological condition
WO2022175752A1 (fr) 2021-02-19 2022-08-25 Sudo Biosciences Limited Inhibiteurs de tyk2 et leurs utilisations
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US20230242546A1 (en) 2021-02-19 2023-08-03 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as tyk2 inhibitors
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