Topical formulations of a TYK2 inhibitor and uses thereof

Abstract

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 involving the topical administration of such formulations.

Description

TOPICAL FORMULATIONS OF A TYK2 INHIBITOR AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 558,973, filed on February 28, 2024, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] 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.BACKGROUND OF THE INVENTION

[0003] 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.

[0004] 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.SUMMARY OF THE INVENTION

[0005] 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. Such topical pharmaceutical compositions and formulations ofCompound 1 are useful for modulating the JAK family of kinases, specifically selective inhibition of TYK2 over other JAKs, in mammals that would benefit from such activity.

[0006] In one aspect, described herein is a 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)nicotinamide (Compound 1):(Compound 1), or pharmaceutically acceptable salt, or solvate thereof;(ii) an antioxidant; and(iii) a carrier suitable for topical administration.

[0007] In some embodiments, 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.

[0008] In some embodiments, the antioxidant is butylhydroxytoluene (BHT), butylated hydroxyanisole (tert-butyl-4-hydroxy anisole, BHA), or tocopherol, or a combination thereof. In some embodiments, the pharmaceutical composition comprises from about 0.01% to about 0.50% (w / w) of the antioxidant.

[0009] In some embodiments, 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.

[0010] In some embodiments, 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.

[0011] In some embodiments, the pharmaceutical composition comprises from about 0.01% to about 1.0% (w / w) of Compound 1, or pharmaceutically acceptable salt, or solvate thereof. In some embodiments, 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.

[0012] In some embodiments, the pharmaceutical composition comprises:(i) from about 5.0% to about 20.0% (w / w) of one or more emollients;(ii) from about 5.0% to about 20.0% (w / w) of one or more emulsifiers;(iii) from about 0.0% to about 10.0% (w / w) of one or more humectants;(iv) from about 0.0% to about 0.5% (w / w) of one or more preservatives; or(v) from about 0.0% to about 1.0% (w / w) of a buffering agent; or combination thereof.

[0013] Also described herein, in some embodiments, are methods of treating a TYK2- mediated disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0014] Also described herein, in some embodiments, are methods of treating an inflammatory disease or condition or autoimmune disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0015] Also described herein, in some embodiments, are methods of treating a dermatological in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0016] Other objects, features and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.DETAILED DESCRIPTION OF THE INVENTION

[0017] 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 hereininterchangeably and, as used herein, generally refer to a composition that is pharmaceutically acceptable and that is suitable for administering Compound 1 to a subject. Such 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. In one aspect, 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.Compound 1

[0018] 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2J / -pyrazolo[4,3- c]quinolin-6-yl)amino)-7V-(methyl-t / 3)nicotinamide (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. For certain such diseases it may be desirable to administer one or more therapeutic agents topically. Developing topical formulations of Compound 1 is challenging due to, for example, its poor solubility in water and / or chemical stability.

[0019] 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

[0020] 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.

[0021] As described in the examples of this application, Compound 1 has low water solubility, with a solubility of 0.0003% (w / w) in water. However, 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. In some of the topical formulations disclosed herein Compound 1 is completely dissolved, despite its poor solubility in water. In other topical formulations disclosed herein, Compound 1 is in a suspension. As described herein, the topical formulations of Compound 1 are stable upon storage. In many of the formulations described herein, an antioxidant is added to the formulation to increase chemical stability of Compound 1.

[0022] By formulating Compound 1 as described herein, 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 pustulosis, pemphigus vulgaris, pyoderma gangrenosum, bullous pemphigoid, cutaneous lupus, or a combination thereof for which topical administration might be desired.Topical Formulations

[0023] In one aspect, described herein is 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(ii) a carrier suitable for topical administration.

[0024] In certain embodiments, the pharmaceutical composition further comprises an antioxidant. In some embodiments, the antioxidant improves the stability of the pharmaceutical composition comprising Compound 1. In some embodiments, the antioxidant improves the chemical stability of Compound 1. In some embodiments, the antioxidant is butylhydroxytoluene (BHT), butylated hydroxyanisole (tert-butyl-4-hydroxyanisole, BHA), or tocopherol, or a combination thereof.

[0025] In some embodiments, 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. In some embodiments, 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.

[0026] In some embodiments, antioxidant is BHT. In some embodiments, 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. In some embodiments, the pharmaceuticalcomposition 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.

[0027] In one aspect, described herein is 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;(ii) an antioxidant; and(iii) a carrier suitable for topical administration.

[0028] In some embodiments, 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.

[0029] In some embodiments, 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.

[0030] In some instances, 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.

[0031] In some instances, ointments are innately occlusive, which can form a protective barrier on the treated skin. Additionally, this dosage form can have a high penetration profile, asthe pharmaceutical agent is dissolved in an internal phase. Thus, in some embodiments, the pharmaceutical composition is formulated as an ointment with dissolved internal phase.

[0032] 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.

[0034] In some embodiments, 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).

[0035] In some embodiments, the carrier suitable for topical administration in the topical formulations described herein comprises one or more solvents. Due to the poor solubility of Compound 1, 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. In some emboidments, 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.

[0037] In some embodiments, 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. Such excipients include, for example, humectants, emulsifiers, thickeners, emollients, rheology control agents, preservatives, penetration enhancers, buffering agents, or a combination thereof.

[0038] In certain embodiments, the 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, jojobaoil, 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);• 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.

[0039] In certain embodiments described herein, 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 pharmaceuticalcompositions 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.

[0040] In certain embodiments described herein, 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).

[0041] In certain embodiments described herein, 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.

[0042] In certain embodiments described herein, 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. In certain embodiments described herein, 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. In some embodiments, the one or more preservatives comprise methylparaben, propylparaben, or a combination thereof.

[0043] In certain embodiments described herein, 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. In some embodiments, the one or more buffering agents comprise sodium hydroxide, hydrochloric acid, sodium phosphate monobasic, sodium phosphate dibasic, sodium citrate, or a combination thereof. In some embodiments, the buffering agents comprise sodium hydroxide and / or hydrochloric acid. In some embodiments, the pharmaceutical composition hasa 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.

[0044] In certain embodiments described herein, 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. In such embodiments, one or more solvents make up the mass balance to a total of 100% (w / w).

[0045] In certain embodiments of the topical formulations described herein, the pharmaceutical composition comprises from about 0.01% to about 1.0% (w / w) of Compound 1, or pharmaceutically acceptable salt, or solvate thereof. In some embodiments, 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. In some embodiments, 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.

[0046] In certain embodiments of the topical formulations described herein, 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. In some embodiments, Compound 1 is crystalline or partially crystalline. In other embodiments, Compound 1 is amorphous.Methods of Dosing and Treatment Regimens

[0047] The present disclosure also relates to methods of administering the topical formulations comprising Compound 1 described herein.

[0048] In some aspects, 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.

[0049] In some aspects, the present disclosure provides methods of treating or preventing an inflammatory disease or condition or autoimmune disease or condition in a patient in needthereof, comprising topically administering to the patient a therapeutically effective amount of the topical pharmaceutical composition or formulation of the present disclosure.

[0050] In some embodiments, 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.

[0051] In some aspects, 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.

[0052] In some embodiments, 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.

[0053] In some embodiments described herein is a method of treating or preventing psoriasis in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein. Typically, 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. In some embodiments, the psoriasis is plaque psoriasis, guttate psoriasis, pustular psoriasis, inverse psoriasis, erythredermic psoriasis, or a combination thereof.

[0054] In some embodiments described herein is 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.

[0055] In some embodiments described herein is a method of treating or preventing 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.

[0056] In some embodiments described herein is a method of treating or preventing rheumatoid arthritis in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0057] In some embodiments described herein is a method of treating or preventing 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.

[0058] In some embodiments described herein is a method of treating or preventing scleroderma in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0059] In some embodiments described herein is a method of treating or preventing alopecia areata in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0060] In some embodiments described herein is a method of treating or preventing hi dradenitis suppurativa in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0061] In some embodiments described herein is a method of treating or preventing lichen planus in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0062] In some embodiments described herein is a method of treating or preventing dermatomyositis in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0063] In some embodiments described herein is a method of treating or preventing pityriasis rubra pilaris in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0064] In some embodiments described herein is a method of treating or preventing systemic sclerosis in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0065] In some embodiments described herein is a method of treating or preventing palmoplantar pustulosis in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0066] In some embodiments described herein is a method of treating or preventing pemphigus vulgaris in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0067] In some embodiments described herein is a method of treating or preventing pyoderma gangrenosum in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0068] In some embodiments described herein is a method of treating or preventing bullous pemphigoid in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0069] In some embodiments described herein is a method of treating or preventing cutaneous lupus in a subject, the method comprising topically administering to the skin of the subject the topical composition comprising Compound 1 as described herein.

[0070] In some embodiments, the topical pharmaceutical composition comprising Compound 1 as described herein is administered to the skin of the patient in need thereof over the course ofone day, two days, three days, four days, five days, six days, one week, ten days, two weeks or longer. In certain embodiments, 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. In some embodiments, the composition is administered every day. In other embodiments, the composition is administered every other day.Articles of Manufacture and Kits

[0071] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more methods described herein. In some embodiments, 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. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[0072] The articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical 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.

[0073] For example, the container(s) include one or more of the crystalline or amorphous forms described herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[0074] 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.

[0075] In one embodiment, a label is on or associated with the container. In one embodiment, 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. In one embodiment, 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.Certain Terminology

[0076] Unless otherwise stated, the following terms used in this application have the definitions given below.

[0077] “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 isrelatively 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.

[0078] The term “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.

[0079] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, 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.

[0080] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary. In some instances, the number or numerical range will vary up to 10% of the stated number or numerical range.

[0081] The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0082] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0083] The term “modulate” as used herein, 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.

[0084] The term “modulator” as used herein, 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. In some embodiments, a modulator is an agonist.

[0085] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer 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] The terms “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.

[0087] The terms “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. For example, 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.

[0088] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, 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.

[0089] The term “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. a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “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. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0090] The terms “article of manufacture” and “kit” are used as synonyms.

[0091] The term “subject” or “patient” encompasses mammals. Examples of 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. In one aspect, the mammal is a human.

[0092] The terms “treat,” “treating,” or “treatment,” as used herein, 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.EXAMPLES

[0093] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.Abbreviations:Compound 1 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3- c]quinolin-6-yl)amino)-N-(methyl-t / 5)nicotinamideAPI Active pharmaceutical ingredientBHA Butylated Hydroxy anisole; tert-butyl-4-hydroxyanisoleBHT ButylhydroxytolueneBP British PharmacopeiaDGME Diethylene Glycol Monoethyl Ether DMI Dimethyl IsosorbideDMSO N,N-dimethylsulfoxideEP / Ph. Eur. European Pharmacopeia g / kg Gram(s) / kilogram(s)GLP Good Laboratory PracticeGMP Good Manufacturing PracticeGMS Glycerol MonostearateHC1 Hydrochloric AcidHPC Hydroxypropyl celluloseIVPT In Vitro Permeation TestJP Japanese PharmacopeiaMET Microbial Enumeration TestMLT Microbial limits testMol / L Moles per litreNaOH Sodium hydroxidePBS Phosphate Buffered SalineQ.S. Quantum satisRH Relative humidityUSP United States Pharmacopeia w / v Weight by volume w / w Weight by weightExample 1: Preparation of Compound 1

[0094] The preparation of Compound 1 has been previously described (see, WO2022175752, US Patent No. 11613548, US20230242546; each of which is incorporated by reference in its entirety).

[0095] Additionally, Compound 1 can be prepared as a crystalline form as previously described (see, WO2024042363; which is incorporated by reference in its entirety).Example 2: Solubility and Solvent Compatibility Study

[0096] The solubility profile of Compound 1 in a range of topically appropriate excipients, including solvents, surfactants, and oil phase excipients was evaluated. Compound 1 was added to each excipient sample until saturation was visually achieved. Solubility samples were filtered using 0.45pm PTFE syringe filters and submitted for T=0 assay. Filtered compatibility samples were stored at 50 °C for two weeks before being submitted for assay. This informationdetermined the target concentration of drug substance (DS), and the appropriate phase for dissolving Compound 1 in a multiphase system.

[0097] This solubility / compatibility study yielded the following results:Solvent did not reach saturation. The solubility capacity of the sample was capped at 5% to conserve compound.

[0098] Visual observations were performed on the solubility / compatibility samples before they were submitted for assay. Several samples displayed a marked color change following storage at 50 °C for two weeks. The samples containing oleic acid turned a slightly darker shade of yellow. Additionally, the samples containing dimethyl isosorbide started light yellow and turned hot pink over time. None of the compatibility samples showed visible precipitation.

[0099] Based on the results of this study, dimethyl sulfoxide (DMSO), diethylene glycol monoethyl ether (DGME), and dimethyl isosorbide (DMI) dissolved the greatest quantities ofCompound 1. However, DMI proved to be incompatible with Compound 1, with an 11.3% loss of Compound 1 concentration over the course of the study. Of all the solvents tested for this study, water had the worst Compound 1 solubility at 0.0003%.Example 2a: Additional Excipient Solubility

[0100] The saturated solubility of Compound 1 was assessed in a variety of excipients and binary systems which were selected based on the drug's physicochemical properties, the indication, and the FDA’s Inactive Ingredients Database. Saturated solutions of Compound 1 were stirred in each excipient / binary system for a period of 24 h in a controlled water bath at 20 °C. The samples were then centrifuged to separate the undissolved drug, and the resultant supernatant (containing the drug at saturation) was diluted and analyzed by HPLC.

[0101] Overall, DMSO, Transcutol P, PEG 400, and benzyl alcohol were shown to be the most promising solvents for inclusion in the formulation. Solvent capacity may change depending on chemical interactions, such as synergies or antagonisms, with other excipients in the formulation composition.Example 3: Water Phase Solubility Study

[0102] To develop a cream formula with dissolved Compound 1, water must be incorporated into the formulation without causing Compound 1 precipitation. As Compound 1 has very poor solubility in water, a follow up solubility study was performed to focus on solubilizing Compound 1 in a blend of DGME, DMSO, and water. A successful solvent blend will dissolve the target Compound 1 concentration while maximizing the amount of water to improve the stability and aesthetics of a cream formulation. The target Compound 1 concentration for this study was 0.50% w / w.

[0103] 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.

[0104] Based on this study, 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.Example 4: Topical Formulations

[0105] Based on the above solubility / compatibility data, six different drug product targets were selected for initial formulation development. These included a dissolved anhydrous gel, an aqueous dissolved gel, an aqueous gel suspension, an ointment with Compound 1 dissolved in an internal phase, a cream suspension, and a dissolved cream.

[0106] These batches were manufactured and stored at 40 and 50 °C to evaluate their physical stability. Active products were manufactured after suitable vehicles were identified. All products were formulated at a target Compound 1 concentration of 0.5% w / w.

[0107] All % in the following examples are given as weight ratios (%w / w).Example 4A: Anhydrous Dissolved Gel

[0108] Anhydrous gels with dissolved pharmaceuticals tend to produce highly penetrating formulations.

[0109] The anhydrous dissolved gel formulations were prepared according to the following table:

[0110] The vehicle product resulted in a clear, colorless gel. Aesthetically, this formulation applied smoothly, but resulted in a slightly tacky residue on the skin.[OHl] In the active formulation, Compound 1 (0.5% w / w) was readily dissolved and resulted in a clear, light-yellow gel.Example 4B. Aqueous Dissolved Gel

[0112] 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.

[0113] The aqueous dissolved gel formulations were prepared according to the following table:

[0114] The first vehicle product resulted in a hazy, colorless, gel that was very fluid. To address this lack of viscosity, 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.

[0115] In the active formulation, Compound 1 (0.5% w / w) was readily dissolved and resulted in a semi-translucent, light yellow, thick gel.Example 4C: Aqueous Gel

[0116] 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.

[0117] The aqueous gel suspension formulations were prepared according to the following table:

[0118] The initial vehicle formulation resulted in a semi-translucent, thick gel. Aesthetically, this formula applied smoothly and did not leave a residual tacky feeling after application.

[0119] However, when an active version of this formula was made, it was noted that Compound 1 (0.5% w / w) became flocculent after the addition of the gelling agent. The batch was homogenized at a low speed prior to pH adjustment to resuspend the API. No agglomeration was visually observed in the final batch.

[0120] To remedy this, another active batch was made with the addition of a surfactant, Polysorbate 80, to the Water phase, prior to Compound 1 (0.5% w / w) addition, to assist in wetting out Compound 1 and prevent flocculation. This successfully aided in dispersion during processing and resulted in a smooth, light-yellow, thick gel.Example 4D: Ointment with Dissolved Internal Phase

[0121] 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.

[0122] The ointment with dissolved internal phase formulations were prepared according to the following table:

[0123] 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.

[0124] An active batch of this formulation was manufactured successfully, with Compound 1 (0.5% w / w) dissolving readily into the internal phase. This resulted in an off-white to lightyellow, thick ointment.Example 4E: Cream Suspension

[0125] 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.

[0126] The cream suspension formulations were prepared according to the following table:

[0127] 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.Example 4F: Dissolved Cream

[0129] The vehicle formulations listed below all leveraged the data produced by the water phase solubility study, which indicated that a solvent ratio of 45% DGME, 5% DMSO and 25% water would dissolve the target amount of Compound 1 while maximizing the water concentration. Each of the five initial prototype dissolved creams examined different combinations of waxes, surfactants, polymers, and types of oil phases.

[0130] The dissolved cream vehicle formulations were prepared according to the following table:

[0131] 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.

[0132] 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.

[0133] Formula 3 substituted the Pemulen TRI used in Formula 1 with 4% Sepineo P600.This resulted in a smooth, pourable, white to off-white cream that remained self supporting at all storage conditions. Aesthetically, this formula applied easily and left only minimal residue on the skin that dissipated quickly.

[0134] 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.

[0135] 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.

[0136] Active batches of both Formula 3 and Formula 5 were manufactured successfully, according to the following table:

[0137] The active of Formula 3 with Compound 1 (0.5% w / w) resulted in a batch that was comparable to the vehicle made using the same formula, while the active of Formula 5 with Compound 1 (0.5% w / w) resulted in a slightly yellower product when compared to the vehicle.

[0138] As the ionic resistance of the Sepineo P600 had yet to be investigated in either formulation, an active batch of Formula 3 was made with the inclusion of a phosphate buffer. This resulted in a product that was visually comparable to the original active Formula 3.Example 5: IVPT Study

[0139] In Vitro Permeation Testing (IVPT) was used to determine how much Compound 1 is delivered to each layer of the skin for each of the formulations.

[0140] Briefly, 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. Additionally, following the 24 hour dosing period, 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.

[0141] 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.

[0142] The penetration of each dosage form through several skin layers was evaluated. Below is a summary of the data yielded by the formulations for each skin region. Each test article is ranked based on the resulting percent penetration for the skin region when compared to the positive control sample. A positive control sample containing 0.5% w / w Compound 1 in a 2:6 DMSO / acetone solution was be prepared and tested. The results yielded by the positive control sample demonstrate the potential maximum of Compound 1 that can be delivered to each layer of the skin.IVPT Stratum Corneum EvaluationIVPT Epidermis EvaluationIVPT Dermis EvaluationIVPT Receptor Solution Evaluation

[0143] 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

[0144] Based on the initial physical stability observations and results of the IVPT study, along with the aesthetic evaluation of the prototype batches, Dissolved Cream (Formula 5) was evaluated for stability.

[0145] An accelerated stability study was run for six months on Dissolved Cream (Formula 5) at four different Compound 1 concentrations. Changes in appearance, assay, pH, and viscosity were monitored at storage conditions of 25°C and 40°C over the duration of the study. An overview of the data yielded at each temperature condition is summarized in the table below. At each timepoint, samples of the test articles were submitted for assay to determine their respective Compound 1 concentration. Each sample was mixed prior as part of sample preparation and testing was performed in duplicate. This data is reported as a percent of the label claim.

[0146] Generally, all concentrations saw a decrease in Compound 1 concentration when compared with the initial T=0 results. This change is most prominent in the 0.01% w / w concentration, particularly in the samples stored at 40 °C.

[0147] The pH of each test article did not change significantly between the timepoints and storage conditions evaluated in this study. However, 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.

[0148] The viscosity changes observed between the test articles at different timepoints are negligible.Example 7: Improved Topical Cream Formulations

[0149] A 28-day GLP toxicology study using Dissolved Cream Formula 5 resulted in a relatively high occurrence of both erythema and edema.

[0150] 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 theformulation 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.

[0151] Three formulations, at a concentration of 0.0065%, containing 25% DGME, 5% isopropyl palmitate, and 2% hexylene glycol were then compounded using multiple process parameters and assessed for stability. In these studies, Compound 1 drug substance is provided as a crystalline powder.

[0152] Stability Results

[0153] One formulation was compounded without BHT and was compounded with neutralization to the target pH after active phase addition (post-neutralization) as a control. At 25 °C, the control formulation showed continued degradation up to over 3% after 3 months. At 40 °C, the control formulation showed continued degradation of about 9% after 3 months.

[0154] 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.

[0155] 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.Example 8: IVPT Study on Improved Topical Cream FormulationsIn vitro skin permeation testing (IVPT) was conducted on the improved formulations in order to assess the effects of varied concentrations on penetration of Compound 1 into the epidermis and dermis layers of the skin. The accumulated dose of Compound 1 in the Epidermis and Dermis are shown in the following table, where all delivered doses are reported in pg / cm3:

[0156] The results of the IVPT study demonstrated a dose response over the four concentrations of Compound 1 in the selected formulation.

[0157] Formulations for the IVPT study were prepared according to the following table:

[0158] Additional excipients and ingredients can be used in the please of the exact ingredients listed in the table above to prepare suitable topical formulations.Example 9: IVPT Study on Improved Topical Cream Formulations Comparing Dissolved Cream and Suspended Creams

[0159] In vitro skin permeation testing (IVPT) was conducted on the improved formulations in order to assess the effects of varied concentrations on penetration of Compound 1 into the epidermis and dermis layers of the skin. The accumulated dose of Compound 1 in the Epidermis and Dermis are shown in the following table, where all delivered doses are reported in pg / cm3:

[0160] The results of the IVPT study demonstrated similar in vitro permiation from the two cream formulations (CR01, see below) despite a three fold in increase in the concentation of Compound 1. A similar effect was seen in the two suspended formulations (CR02) as well. The four additional dissolved cream formulations (CR05-CR08) that were also evaluated in this study did not significantly demonstrate an increased in vitro permeation.

[0161] Formulations for the IVPT study were prepared according to the following table, where all numbers are reported in % w / w of final fomulation:Example 10: Manufacturing of Improved Topical Cream Formulations

[0162] The cream manufacturing process is a sequential continuous process, consisting of multiple phases being individually prepared, and combined during final compounding.

[0163] There are three discrete phases consisting of a drug phase, water phase, and oil phase. 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.

[0164] 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. Once the emulsion has been formed, 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.

[0165] The finished product is then filled into 20 g laminate tubes.Example 11: Stability of Improved Topical Cream Formulations

[0166] Batches of final compounded formulations have been placed on stability under the long-term storage condition of 25 ± 2°C / 60 ± 5% RH and accelerated storage conditions of 40 ± 2°C / 75 ± 5% RH for 24 months. In addition, stability of these batches is also being evaluated at 5 ± 3°C / ambient RH. Analytical testing used to assess stability include tests for appearance, assay, purity / impurities, pH, viscosity and appearance by microscopy. Representative batches comprising 0.065%, 0.2%, and 0.65% of Compound 1, with BHT as an antioxidant, were found to be shelf stable for 6 months when stored in sealed laminate tubes at 5 °C, 25°C / 60% RH, and 40 °C / 75% RH.

[0167] Microbiological testing: The formulations contain two water-soluble preservatives, methylparaben at 0.2% w / w, and propylparaben at 0.05% w / w. Preservative effectiveness testing conducted on multiple batches of Compound 1 (0.0%-0.6% w / w) confirmed that the product tested according to USP <51> and European Pharmacopoeia (Ph. Eur) <5.1 3> monographs for topical products and is not prone to supporting microbial growth.

[0168] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A 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)nicotinamide (Compound 1):(Compound 1), or pharmaceutically acceptable salt, or solvate thereof;(ii) an antioxidant; and(iii) a carrier suitable for topical administration.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as a solution, liquid, suspension, oil, gel, cream, ointment, lotion, foam, or paste.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as a suspension, gel, cream, or ointment.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as a cream.

5. The pharmaceutical composition of claim 4, wherein the cream is a cream suspension or a dissolved cream.

6. The pharmaceutical composition of any one of claims 1-5, wherein the antioxidant is butylhydroxytoluene (BHT), butylated hydroxyanisole (tert-butyl-4-hydroxyanisole, BHA), or tocopherol, or a combination thereof.

7. The pharmaceutical composition of any one of claims 1-6, wherein 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.

8. The pharmaceutical composition of claim 7, wherein the one or more solvents comprise propylene glycol, hexylene glycol, isopropyl palmitate, polyoxyethylene, polyoxypropylene, diethylene glycol monoethyl ether (DGME), dimethyl isosorbide(DMI), d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), polyethylene glycol (including PEG400), glycerin, dimethyl sulfoxide (DMSO), water, or a combination thereof.

9. The pharmaceutical composition of claim 7, wherein the one or more humectants comprise mineral oil, petrolatum, white petrolatum, isopropyl palmitate, ammonium alkginate, butylene glycol, com syrup solids, cyclomethicone, dipropylene glycol, glycerin, polydextrose, propylene glycol, sodium hyaluronate, sodium lactate, sorbitol, tagatose, trehalose, triacetin, triethanolamine, xylitol, sorbitol, or a combination thereof.

10. The pharmaceutical composition of claim 7, wherein the one or more emulsifiers comprise 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, or a combination thereof.

11. The pharmaceutical composition of claim 7, wherein the one or more emollients comprise 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, or a combination thereof.

12. The pharmaceutical composition of claim 7, wherein the one or more rheology control agents comprise a carbopol, hydroxypropyl methylcellulose (HPMC), hydroxy ethyl cellulose (ELEC), carboxymethyl cellulose (CMC), carbomer, xanthan gum, carrageenan gum, sodium alginate, modified starch, Sepineo P600, or a combination thereof.

13. The pharmaceutical composition of claim 7, wherein the one or more preservatives comprise benzyl alcohol, phenoxyethanol, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, methylparaben, propylparaben, benzalkonium chloride, or a combination thereof.

14. The pharmaceutical composition of claim 7, wherein the one or more buffering agents comprise sodium hydroxide, hydrochloric acid, sodium phosphate monobasic, sodium phosphate dibasic, sodium citrate, or a combination thereof.

15. The pharmaceutical composition of claim 7, wherein the the pharmaceutical composition does not contain any preservative or is preservative free.

16. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical composition has a pH of from about 4.5 to about 6.5.

17. The pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical composition has a pH of about 4.5, about 5.0, about 5.5, about 6.0, or about 6.5.

18. The pharmaceutical composition of any one of claims 1-17, wherein the pharmaceutical composition comprises from about 0.01% to about 1.0% (w / w) of Compound 1, or pharmaceutically acceptable salt, or solvate thereof.

19. The pharmaceutical composition of any one of claims 1-17, wherein 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.

20. The pharmaceutical composition of any one of claims 1-19, wherein the pharmaceutical composition comprises from about 0.01% to about 0.50% (w / w) of the antioxidant.

21. The pharmaceutical composition of any one of claims 1-19, wherein the pharmaceutical composition comprises:(i) from about 5.0% to about 20.0% (w / w) of one or more emollients;(ii) from about 5.0% to about 20.0% (w / w) of one or more emulsifiers;(iii) from about 0.0% to about 10.0% (w / w) of one or more humectants;(iv) from about 0.0% to about 0.5% (w / w) of one or more preservatives; or(v) from about 0.0% to about 1.0% (w / w) of a buffering agent; or combination thereof.

22. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition remains stable at 25±2 °C / 60% RH for 6 months or ar 40±°C / 75% RH for 3 months.

23. A pharmaceutical composition formulated for topical administration, comprising:(i) about 0.01% to about 1.0% (w / w) of 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl- 4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-(methyl-d3)nicotinamide (Compound 1):(Compound 1), or pharmaceutically acceptable salt, or solvate thereof;(ii) from about 0.01% to about 0.50% (w / w) of an antioxidant;(iii)one or more solvents comprising propylene glycol, hexylene glycol, polyoxyethylene, isopropyl palmitate, polyoxypropylene, diethylene glycol monoethyl ether (DGME), dimethyl isosorbide (DMI), d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS), polyethylene glycol (including PEG400), glycerin, dimethyl sulfoxide (DMSO), water, or a combination thereof; and optionally:(iv) from about 5.0% to about 20.0% (w / w) of one or more emollients;(v) from about 5.0% to about 20.0% (w / w) of one or more emulsifiers;(vi) from about 0.0% to about 10.0% (w / w) of one or more humectants;(vii) from about 0.0% to about 0.5% (w / w) of one or more preservatives; or(viii) from about 0.0% to about 1.0% (w / w) of a buffering agent; or a combination thereof; wherein the pharmaceutical composition is a cream.

24. The pharmaceutical composition of claim 23, wherein the antioxidant is butylhydroxytoluene (BHT), butylated hydroxyanisole (tert-butyl-4-hydroxyanisole, BHA), or tocopherol, or a combination thereof.

25. The pharmaceutical composition of claim 23, wherein the antioxidant is butylhydroxytoluene (BHT).

26. The pharmaceutical composition of any one of claims 23-25, wherein the one or more emollients comprise 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, or a combination thereof.

27. The pharmaceutical composition of any one of claims 23-25, wherein the one or more emollients comprise white petrolatum.

28. The pharmaceutical composition of any one of claims 23-27, wherein the one or more emulsifiers comprise 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, pol oxamer 188, ceteth-10 phosphate (Crodafos-CES), emulsifying wax, or a combination thereof.

29. The pharmaceutical composition of any one of claims 23-27, wherein the one or more emulsifiers comprise ceteth-10 phosphate (Crodafos-CES).

30. The pharmaceutical composition of any one of claims 23-29, wherein the one or more humectants comprise 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, sorbitol, or a combination thereof.

31. The pharmaceutical composition of any one of claims 23-29, wherein the one or more humectants comprise isopropyl palmitate.

32. The pharmaceutical composition of any one of claims 23-31, wherein the one or more preservatives comprise benzyl alcohol, phenoxyethanol, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, methylparaben, propylparaben, benzalkonium chloride, or a combination thereof.

33. The pharmaceutical composition of any one of claims 23-31, wherein the one or more preservatives comprise methylparaben, propylparaben, or a combination thereof.

34. The pharmaceutical composition of any one of claims 23-31, wherein the pharmaceutical composition does not contain any preservative or is preservative free.

35. The pharmaceutical composition of any one of claims 23-34, wherein the pharmaceutical composition has a pH of from about 4.5 to about 6.5.

36. The pharmaceutical composition of any one of claims 23-34, wherein the pharmaceutical composition has a pH of about 4.5, about 5.0, about 5.5, about 6.0, or about 6.5.

37. The pharmaceutical composition of any one of claims 23-36, wherein the one or more solvents comprise hexylene glycol, DGME, PEG400, DMSO, propylene glygol, or a combination thereof.

38. The pharmaceutical composition of any one of claims 23-37, wherein the one or more solvents comprise hexylene glycol, DGME, or a combination thereof.

39. The pharmaceutical composition of any one of claims 1-38, wherein 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.

40. A method of treating or preventing an inflammatory or autoimmune disease or condition in a patient in need thereof, comprising administering the pharmaceutical composition of any one of claims 1-39 to the skin of the patient in need thereof.

41. The method of claim 40 wherein the inflammatory or autoimmune disease or condition is mediated by TYK2 activity.

42. The method of claim 40 or claim 41, wherein the inflammatory or autoimmune disease or condition is selected from rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, scleroderma, alopecia areata, hidradenitis suppurativa, lupus, systemic lupus erythematosus, or a combination thereof.

43. A method of treating a dermatological disease or condition in a patient in need thereof, comprising administering the pharmaceutical composition of any one of claims 1-39 to the skin of the patient in need thereof.

44. The method of claim 43 wherein the dermatological disease or condition is mediated by TYK2 activity.

45. The method of claim 43 or claim 44, wherein the dermatological 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.

46. The method of any one of claims 40-45, wherein the pharmaceutical composition 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.

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