Stable pharmaceutical topical formulations containing immunosuppressants for treating dermatological conditions

Abstract

To provide a stable yellowing-resistant topical preparation for treating dermatological conditions.SOLUTION: A stable yellowing-resistant topical preparation for treating dermatological conditions contains a JAK inhibitor in oil-in-water emulsion, white petrolatum in an amount of about 10 wt.%, butyl hydroxy toluene (BHT) of less than about 0.7 ppm in weight, oleyl alcohol in an amount of about 2 wt.%, and an antibacterial agent.

Description

[Technical Field]

[0001] The present invention relates to stable formulations for topical application creams containing immunosuppressants such as ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone, ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-propyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, or agents with similar chemical structures. [Background technology]

[0002] Dermatological conditions can be uncomfortable and embarrassing for patients, so effective and safe treatment is required.Some dermatological conditions, including psoriasis, atopic dermatitis, vitiligo, and alopecia areata, are caused by an overactive immune system and can be treated by topical application of immunosuppressants, such as topical corticosteroids, calcineurin inhibitors, cyclosporine, and phosphodiesterase-4 (PDE4) inhibitor EUCRISA (registered trademark) (crisaborole).More recently, Janus kinase (JAK) inhibitors have shown clinical efficacy as topical agents in some dermatological conditions.See, for example, U.S. Patent No. 10,463,675.

[0003] ((S)-2,2-Difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone has the chemical formula C 18 H 21 F2N7O and the following structural formula:

[0004] [ka] It has.

[0005] The synthesis of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone is described in commonly assigned U.S. Pat. No. 9,663,526, the contents of which are incorporated herein by reference in their entirety. The crystalline form of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone free base is useful as an inhibitor of protein kinases such as the enzyme Janus kinase (JAK), and is therefore therapeutically useful as an immunosuppressant for organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease (IBD), psoriasis, type 1 diabetes, and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, and other indications where immunosuppression would be desirable.

[0006] Formulations for topical delivery of immunosuppressants are generally creams or ointments containing an active pharmaceutical ingredient (API) and one or more additives. These formulations are typically light-colored or white and translucent to opaque in appearance. Squeezable tubes, pumps, bags, or other containers are filled with the immunosuppressant topical formulation, and in some cases, are provided with outer paper or cardboard packaging. The finished, packaged formulations are stored at the manufacturing site and shipped to wholesalers, pharmacies, health care clinics, hospitals, or health care providers, and ultimately to patients or end users, who then store the product during use. This journey from the manufacturing site to the patient can take a considerable amount of time. During the journey, the cream may be subjected to various temperature and humidity conditions.

[0007] Therefore, it is desirable that such topical formulations be chemically and physically stable over time over a range of storage conditions to provide manufacturers, distributors, and patients with flexibility in how they store and handle the product and to ensure that product quality is maintained throughout the product's shelf life. An important aspect of formulation stability is physical appearance, with color being one important attribute. Yellowing or darkening of the formulation over time can be perceived as an indicator of poor product quality.

[0008] Up to now, the inventors believe that this yellowing phenomenon or discoloration in such immunosuppressant medicinal creams has not been thoroughly studied or well understood.Generally, compounds that are thought to enhance chemical stability include antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbic acid (vitamin C), polyphenols, tocopherol (vitamin E) and their derivatives, and are added to additives and formulations to help maintain white or lighter color.In fact, some topical drug products have added a relatively significant amount of butylated hydroxytoluene (BHT) in the past to maintain white or lighter color, but for certain topical cream formulations, discoloration problems still persist. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 10,463,675 [Patent Document 2] US$9,663,526 [Patent Document 3] USSN63 / 047606 [Non-patent literature]

[0010] [Non-Patent Document 1] B.C. Finnin and T.M. Morgan, J.Pharm.Sci., Vol. 88, pp. 955-958, 1999 Summary of the Invention [Problem to be solved by the invention]

[0011] Thus, there is a need for stable cream formulations of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone, ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-propyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, and other topical agents that are resistant to yellowing over time. The present invention provides novel, stable topical formulations that are characterized by significantly reduced darkening or yellowing. [Means for solving the problem]

[0012] According to a first aspect of the present invention, there is provided a topical formulation for the treatment of dermatological conditions, comprising an immunosuppressant pharmaceutical agent in an oil-in-water emulsion. The immunosuppressant in this invention may comprise a JAK1, JAK2, JAK3, TYK2 or TYK2 / JAK1 inhibitor, the properties of which make it useful in the treatment of atopic dermatitis, psoriasis, vitiligo, hand eczema, uticaria and other dermatological or autoimmune conditions.

[0013] According to one aspect of the present invention, a stable topical formulation for the treatment of a dermatological condition is provided comprising a JAK inhibitor in an oil-in-water emulsion, white petrolatum in an amount of about 10% by weight, butylhydroxytoluene (BHT) in an amount of less than about 0.7 ppm by weight, oleyl alcohol in an amount of about 2% by weight, and an antibacterial agent.

[0014] In one embodiment, the JAK inhibitor is a JAK1 inhibitor. In another embodiment, the JAK inhibitor is a TYK2 / JAK1 inhibitor. For example, by way of illustration and not limitation, the JAK inhibitor includes ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone. In one embodiment, the JAK inhibitor is present in an amount of about 1% to about 3% by weight.

[0015] In another embodiment, the formulation comprises mineral oil in an amount of about 5% by weight.

[0016] In other embodiments, the formulation includes one or more other additives, such as tocopherol in an amount less than about 1.5 ppm by weight (e.g., added as a stabilizer to mineral oil in an amount between 0 and 20 ppm, or in some cases to white petrolatum in an amount of 10 ppm), polyethylene glycol 400 (PEG 400) in an amount of about 10% by weight, diethylene glycol monoethyl ether in an amount of about 15% by weight, emulsifying wax in an amount of about 10% by weight, and an antimicrobial agent including 2-phenoxyethanol in an amount of about 1% by weight.

[0017] In one embodiment, the formulation maintains its white color when stored at 40 degrees Celsius for 24 weeks with a Yellowness Index (YI) value of less than about 10. In another embodiment, the formulation maintains its white color when stored at 40 degrees Celsius for 16 weeks with a Yellowness Index (YI) value of less than about 6.

[0018] In one aspect of the present invention, yellowing of a cream formulation is minimized by ensuring that the formulation contains about 0.7 ppm or less of BHT. In one embodiment of the present invention, yellowing of a cream formulation is minimized by ensuring that white petrolatum contains about 7 ppm or less of BHT. If white petrolatum is the only source of BHT and constitutes 10% by weight of the formulation, this results in about 0.7 ppm or less of BHT in the total composition. In other embodiments, at least a portion of the about 0.7 ppm or less of BHT in the total composition does not come from white petrolatum, but may come from other ingredients, additives, or may be added separately as an additive.

[0019] While developing and optimizing various formulations of immunosuppressants, including but not limited to JAK1 modulators, more specifically TYK2 / JAK1 modulators, in topical creams for the treatment of atopic dermatitis and psoriasis, the inventors observed that drug products that initially appear white upon manufacture develop a light yellow color that increases in intensity with increasing (a) active pharmaceutical ingredient (API) concentration, (b) time, and (c) storage temperature. The inventors surprisingly and unexpectedly identified an additive that changes the color of the cream from white to light yellow. More specifically, the inventors discovered that the concentration of BHT (butylated hydroxytoluene) in the formulation has a statistically significant quadratic effect on yellowing for samples stored at 25°C, 30°C, and 40°C, and as a result, determined certain critical range limits for the amount of BHT in the drug product that minimizes yellowing.

[0020] In a preferred embodiment, the present invention provides a formulation that uses BHT-free white petrolatum stabilized with 10 ppm tocopherol to minimize yellow color development and includes oleyl alcohol. In another embodiment, the present invention provides another formulation that provides acceptable color development, where the total cream composition contains about 0.7 ppm or less of BHT, corresponding to a BHT concentration in white petrolatum of about 7 ppm or less when the white petrolatum is about 10% by weight and the petrolatum is the only source of BHT. Additionally, the present invention surprisingly and unexpectedly provides a formulation in which various additive combinations are acceptable for product purity as long as BHT limits are maintained, such that no degradants are observed in the formulation after 24 weeks of storage at 40°C.

[0021] In one embodiment, a topical cream formulation of the present invention comprises an immunosuppressant, 15% w / w dietheylene glycol monoethyl ether, 10% w / w polyethylene glycol 400, 10% w / w emulsifier, 10% w / w petrolatum, 7% emollient, antibacterial agent, and water.

[0022] As used herein, the term "wt. %" refers to the weight % in the final formulation. In other words, if the final formulation weighs 100 grams and an ingredient is 10% by weight or 10% wt. or 10% w / w, then 10 grams of the ingredient is present in the final formulation. For ingredients described in parts per million, 1 ppm is 0.0001 wt. %.

[0023] As used herein, the term "ppm" means parts per million.

[0024] The term "storage temperature" as used herein is defined as the ambient temperature in the chamber in which the samples were stored in their primary containers - either sealed glass vials or sealed foil-laminated tubes. Relative humidity was controlled as is standard in the art. Similarly, normal atmospheric pressure conditions were utilized. Temperatures provided herein are storage temperatures unless otherwise specified and are expressed in degrees Celsius, also abbreviated herein as °C.

[0025] The term "mineral oil," as used herein, means a clear, odorless liquid comprising a mixture of refined saturated aliphatic and cyclic hydrocarbons obtained from petrolatum. The term mineral oil includes light petroleum (liquid paraffin) and mineral oils of normal or higher specific gravity or density.

[0026] The term "white petrolatum" is commonly understood in the pharmaceutical field in the United States and is also known as soft white paraffin in other parts of the world.

[0027] The term "about" is + / - 15% whether referring to wt.% or ppm values ​​described herein. For example, about 10% wt. should be understood to encompass a range of values ​​from 8.5% to 11.5%, and 10 ppm should be understood to encompass a range of values ​​from 8.5 ppm to 11.5 ppm.

[0028] The term "oil-in-water emulsion," as used herein, refers to a semi-solid mixture containing two immiscible phases, an oil phase and an aqueous phase. Oil phase droplets are suspended in the aqueous phase, and an emulsifier is used to stabilize the emulsion.

[0029] One advantage of the present invention is that it provides a white or light-colored topical delivery formulation for immunosuppressants that is more resistant to yellowing and does not yellow as severely or rapidly as previously disclosed formulations.

[0030] This and other advantages will be apparent to those skilled in the art from the figures and description that follow.

[0031] The invention will now be described, by way of example only, with reference to the following examples, tables and figures that accompany this specification. [Brief explanation of the drawings]

[0032] [Figure 1]Figure 1 displays a graph of the Yellowness Index (YI(E313-96)(D65)) of 28 cream formulation samples measured over time in glass vials (YI vials) under various storage temperatures from an initial time t0 to 24 weeks. The figure shows time (in weeks) on the lower X-axis and YI vials on the left Y-axis. The graphs of the individual sample runs are grouped according to increasing storage temperatures in °C (5, 25, 30, and 40), as shown on the upper X-axis of the figure. [Figure 2] 1 is a contour plot of Yellowness Index (YI cuvette) at 24 weeks at a storage temperature of 5° C. for one embodiment of a formulation of the present invention using the additive combination of Calumet™ white petrolatum, BASF™ oleyl alcohol, and Dow™ PEG 400, which was the best-case scenario for that storage temperature. Added tocopherol is shown on the X-axis in parts per million (ppm) and added BHT is shown on the Y-axis in parts per million (ppm). The contours for a given YI cuvette are plotted and labeled. [Figure 3] 1 is a contour plot of Yellowness Index (YI cuvette) at 24 weeks at a storage temperature of 5° C. for a less advantageous alternative embodiment of a formulation of the present invention using the additive combination of Calumet™ white petrolatum, Croda™ oleyl alcohol, and Croda™ PEG 400, which was the worst case scenario for that storage temperature. Added tocopherol is shown on the X-axis in ppm and added BHT is shown on the Y-axis in ppm. The contours for a given YI cuvette are plotted and labeled. [Figure 4] 1 is a contour plot of Yellowness Index (YI cuvette) at 24 weeks at a storage temperature of 25° C. for another embodiment of a formulation of the invention using an additive combination of Croda™ white petrolatum, Croda™ oleyl alcohol, and Dow™ PEG 400, which was the best-case scenario for that storage temperature. Added tocopherol is shown in ppm on the X-axis and added BHT is shown in ppm on the Y-axis. The contours for a given YI cuvette are plotted and labeled. [Figure 5]1 is a contour plot of Yellowness Index (YI cuvette) at 24 weeks at a storage temperature of 25° C. for an alternative, less advantageous embodiment of the present invention using an additive combination of Calumet™ white petrolatum, Croda™ oleyl alcohol, and Croda™ PEG 400, which was the worst case scenario for that storage temperature. Added tocopherol is shown on the X-axis in ppm, and added BHT is shown on the Y-axis in ppm. The contours for a given YI cuvette are plotted and labeled. [Figure 6] 1 is a contour plot of Yellowness Index (YI cuvette) at 24 weeks at a storage temperature of 30° C. for another embodiment of the invention using an additive combination of Croda™ White Petrolatum, Croda™ Oleyl Alcohol, and Dow™ PEG 400, which was the best-case scenario for that storage temperature. Added tocopherol is shown on the X-axis in ppm and added BHT is shown on the Y-axis in ppm. The contours for the constant YI cuvette are plotted and labeled. [Figure 7] 1 is a contour plot of Yellowness Index (YI cuvette) at 24 weeks at a storage temperature of 30° C. for an alternative, less advantageous embodiment of the present invention using an additive combination of Calumet™ white petrolatum, Croda™ oleyl alcohol, and Croda™ PEG 400, which was the worst case scenario for that storage temperature. Added tocopherol is shown on the X-axis in ppm, and added BHT is shown on the Y-axis in ppm. The contours for a given YI cuvette are plotted and labeled. [Figure 8-1] 1 is a contour plot of Yellowness Index (YI cuvette) at 24 weeks at a storage temperature of 40° C. for another embodiment of the invention using an additive combination of Calumet™ white petrolatum, BASF™ oleyl alcohol, and Dow™ PEG 400, which was the best-case scenario for that storage temperature. Added tocopherol is shown in ppm on the X-axis and added BHT is shown in ppm on the Y-axis. The contours for a given YI cuvette are plotted and labeled. [Figure 8-2]8 is an enlarged or zoomed-in contour plot of the YI cuvette taken from the lower left region of FIG. 8 at 24 weeks at a storage temperature of 40° C. Added tocopherol is shown on the X-axis in ppm and added BHT is shown on the Y-axis in ppm. The contours for a given YI cuvette are plotted and labeled. [Figure 9] 1 is a contour plot of Yellowness Index (YI cuvette) at 24 weeks at a storage temperature of 40° C. for an alternative, less advantageous embodiment of the present invention using an additive combination of Calumet™ white petrolatum, Croda™ oleyl alcohol, and Croda™ PEG 400, which was the worst case scenario for that storage temperature. Added tocopherol is shown on the X-axis in ppm, and added BHT is shown on the Y-axis in ppm. The contours for a given YI cuvette are plotted and labeled. [Figure 10] FIG. 1 is a graph of Yellowness Index (YI(E313-96)(D65)) or YI cuvette on the Y-axis versus storage time in weeks on the X-axis for various cream formulations containing 1% w / w API stored at 40° C. from an initial time t0 up to 16 weeks. [Figure 11] FIG. 1 is a graph of Yellowness Index (YI(E313-96)(D65)) or YI cuvette on the Y-axis versus storage time in weeks on the X-axis for various cream formulations containing 3% w / w of API stored at 40° C. from an initial time t0 up to 16 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention relates to stable formulations of compounds that are JAK modulators useful for treating diseases and conditions associated with dysregulation of JAK, particularly JAK1 and TYK2 / JAK1. The present invention further provides pharmaceutical compositions comprising such JAK enzyme modulators useful for treating and / or preventing such diseases and conditions.

[0034] According to a first aspect of the present invention there is provided a topical formulation for the treatment of a dermatological condition comprising: a JAK inhibitor in an oil-in-water emulsion; White petrolatum in an amount of about 10% by weight; less than about 0.7 ppm by weight of butylhydroxytoluene (BHT); oleyl alcohol in an amount of about 2% by weight; Antibacterial agents and A topical formulation is provided comprising:

[0035] Described below are some embodiments (E) of this first aspect of the invention, where for convenience E1 is identical thereto.

[0036] E1. A topical formulation for the treatment of a dermatological condition, comprising: a JAK inhibitor in an oil-in-water emulsion; White petrolatum in an amount of about 10% by weight; less than about 0.7 ppm by weight of butylhydroxytoluene (BHT); oleyl alcohol in an amount of about 2% by weight; Antibacterial agents and 1. A topical formulation comprising:

[0037] E2. The topical formulation of E1, wherein the JAK inhibitor is a JAK1 inhibitor.

[0038] E3. The topical formulation of E1, wherein the JAK inhibitor is a TYK2 / JAK1 inhibitor.

[0039] E4. The topical formulation of E1, wherein the JAK inhibitor is ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone.

[0040] E5. The topical formulation of any one of E1 to E4, wherein the JAK inhibitor is present in an amount of about 1% to about 3% by weight.

[0041] E6. The topical formulation of any one of E1 to E5, further comprising tocopherol in an amount less than about 6.5 ppm.

[0042] E7. The topical formulation of any one of E1 to E6, further comprising polyethylene glycol 400 in an amount of about 10% by weight.

[0043] E8. The topical formulation of any one of E1 to E7, further comprising diethylene glycol monoethyl ether in an amount of about 15% by weight.

[0044] E9. The topical formulation of any one of E1 to E8, further comprising an emulsifying wax in an amount of about 10% by weight.

[0045] E10. The topical formulation of any one of E1 to E9, wherein the antibacterial agent comprises 2-phenoxyethanol in an amount of about 1% by weight.

[0046] E11. The topical formulation of any one of E1 to E10, which maintains its white color having a Yellowness Index (YI) value of less than about 10 when stored at 40 degrees Celsius for 24 weeks.

[0047] E12. The topical formulation of any one of E1 to E11, wherein when stored at 40 degrees Celsius for 16 weeks, the formulation maintains a white color having a Yellowness Index value of less than about 6.

[0048] E13. The topical formulation of any one of E1 to E11, having a Yellowness Index value that increases by about 8 or less over 24 weeks at 40 degrees Celsius.

[0049] E14. The topical formulation of any one of E1 to E13, wherein the white petrolatum contains no more than about 7 ppm of BHT.

[0050] E15. The topical formulation of any one of E1 to E14, wherein at least a portion of the 0.7 ppm BHT does not originate from white petrolatum.

[0051] E16. The topical formulation of any one of E1 to E15, further comprising mineral oil in an amount of about 5% by weight.

[0052] E17. A topical formulation for the treatment of a dermatological condition, comprising: a JAK inhibitor as a purified oil-in-water emulsion; White petrolatum in an amount of about 10% by weight; tocopherols in an amount less than about 6.5 ppm; oleyl alcohol in an amount of about 2% by weight; Polyethylene glycol 400 in an amount of about 10% by weight; diethylene glycol monoethyl ether in an amount of about 15% by weight; mineral oil in an amount of about 5% by weight; emulsifying wax in an amount of about 10% by weight; an antimicrobial agent comprising 2-phenoxyethanol in an amount of about 1% by weight; Including, A topical formulation that is BHT-free, thereby maintaining a yellowness index of less than about 6 when stored at 40 degrees Celsius for 16 weeks, and less than or equal to about 10 when stored at 40 degrees Celsius for 24 weeks.

[0053] E18. Structural formula:

[0054] [ka] and a compound having the formula: white petrolatum having tocopherols in an amount of about 10% by weight and in an amount of less than about 10 ppm; less than about 0.7 ppm by weight of butylhydroxytoluene (BHT); oleyl alcohol in an amount of about 2% by weight; Polyethylene glycol 400 in an amount of about 10% by weight; diethylene glycol monoethyl ether in an amount of about 15% by weight; mineral oil in an amount of about 5% by weight; emulsifying wax in an amount of about 10% by weight; Antibacterial agents and 1. A topical formulation comprising:

[0055] E19. A method of treating or preventing a disease or condition selected from psoriasis, atopic dermatitis, atopic eczema, chronic hand eczema, urticaria, vitiligo, cutaneous lupus, and alopecia areata, comprising administering to a subject in need thereof a therapeutically effective amount of the topical formulation of any one of E1 to E18.

[0056] E20. The method of E19, wherein said topical formulation is administered at least once daily.

[0057] E21. The method of any one of E19 to E20, wherein the disease or condition is psoriasis.

[0058] E22. The method of any one of E19 to E20, wherein the disease or condition is atopic dermatitis.

[0059] E23. The method of any one of E19 to E20, wherein the disease or condition is hand eczema.

[0060] E24. The method of any one of E19 to E20, wherein the disease or condition is urticaria.

[0061] E25. The method of any one of E19 to E20, wherein the disease or condition is cutaneous lupus.

[0062] E26. Use of a topical formulation according to any of E1 to E18 for the manufacture of a medicament for the treatment of a disorder for which a TYK2 / JAK1 inhibitor is indicated.

[0063] E27. A topical formulation according to any of E1 to E18 for use in the treatment of a disorder in which a TYK2 / JAK1 inhibitor is indicated.

[0064] In one embodiment, the present invention includes formulations for topical dosage forms. Compositions for topical administration include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain crystalline or liquid compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dustings, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Typical additives include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, propylene glycol, and diethylene glycol monoethyl ether. Penetration enhancers may be incorporated; see, for example, B.C. Finnin and T.M. Morgan, J. Pharm. Sci., Vol. 88, pp. 955-958, 1999.

[0065] Thus, topical formulations of the presently disclosed compound of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, a JAK inhibitor, or more particularly a JAK1 inhibitor, or even more particularly a TYK2 / JAK1 inhibitor, can be administered using such preparations encompassing all conventional methods of administration across body surfaces and linings of body passages, including epithelial and mucosal tissues, including transdermal, epidermal, buccal, pulmonary, ophthalmic, intranasal, intravaginal, and rectal modes of administration.

[0066] Topical formulations containing ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone can be given to patients in need thereof in therapeutically effective amounts in daily or twice-daily doses. These amounts range from about 0.1% to about 5.0% by weight, more preferably from about 0.1% to about 3.0% by weight. [Example]

[0067] While working on the development, stability, and improvement of the above-mentioned TYK2 / JAK1 topical formulation and other similar compounds, the inventors studied the effects of both API concentration and storage temperature on formulation stability over time. The inventors observed the effect of discoloration over time on formulations containing relatively low concentration levels of the active pharmaceutical ingredient. Samples of the formulation were stored in filled foil-laminated tubes at room temperature of approximately 25°C for three (3) months and then cut open along the major central vertical plane. It was observed that tubes filled with vehicle only, with 0% or no API, exhibited minimal, if any, discoloration. At 0.1% API, some yellowing occurred. At 0.3% API, discoloration increased slightly. At more moderate, typical levels of API, such as 1%, the yellowing was more pronounced, and even more pronounced at 3% API.

[0068] We also studied the effect of different storage temperatures over time by storing and then bisecting sample-filled foil-laminated tubes as follows: 0% API at 5°C for six (6) months, and 3% API at 5°C, 25°C, 30°C for six (6) months, and 40°C for three (3) months, respectively. Yellowing significantly increased with increasing storage temperature for the 5°C, 25°C, and 30°C samples containing 3% API after they were stored for six (6) months. The 40°C / 3% API sample alone, stored for three (3) months before being cut open, was still significantly darker or yellower than any of the other samples stored longer at lower temperatures.

[0069] Because API % is often driven by efficacy, safety, and other considerations, we choose to focus on 1% to 3% of API for further experiments to understand which ingredients or excipients contribute to the yellowing phenomenon. A storage temperature of 5°C seemed to provide a reasonable reference case, as little discoloration was observed. Storage temperatures of 25°C, 30°C, and 40°C appeared to produce easily observable, and therefore measurable, variations in yellowness, facilitating our further study of the yellowing phenomenon. Regulatory agencies may request data for storage temperatures of 5°C, 25°C, and 30°C with new drug applications, with 40°C being a useful temperature for generating accelerated degradation data.

[0070] Like others attempting to formulate safe, effective, and stable medicated topical creams, the inventors had a large number of potential ingredients, stabilizers, and additives to choose from, each of which was commercially available from several different sources, sometimes with proprietary subsets of ingredients, stabilizers, and additives. This means that the possible combinations are virtually endless, and exploring them all would typically take years and require undue experimentation without a better understanding of the primary drivers of discoloration. Of course, as noted above, certain APIs can present their own unique challenges in achieving an effective and stable formulation. While not limiting the present invention, the following exemplary ingredients, stabilizers, and additives were investigated for use in JAK1 and TYK2 / JAK1 topical creams: 1. White petrolatum sold under the following trademarks: a. Calumet Super White™ petrolatum USP, which may contain up to 20 ppm BHT, available from Calumet Refining, Indianapolis, IN, USA (hereinafter more commonly Calumet™); and b. Crolatum™ V-SO, which contains 10 ppm tocopherols and is available from Croda International, Snaith, East Riding of Yorkshire, UK (hereafter more commonly Croda™). 2. Oleyl alcohol, sold under the following trademarks: a. Kollicream™ OA, which contains 250 ppm CONTROX® K SC and is available from BASF, Ludwigshafen, Germany (hereinafter more generally BASF™), and b. Super Refined™ Novol™ (hereafter more generally Croda™) by Croda International, Snaith, East Riding of Yorkshire, UK. 3. Polyethylene glycol 400 (PEG400), sold under the following trademarks: a. CARBOWAX™ (hereinafter more commonly referred to as Dow™) by Dow Chemical Company, Midland, MI, USA; and b. Croda™ Super Refined PEG400 (hereafter more commonly Croda™) by Croda International, Snaith, East Riding of Yorkshire, UK. 4. Butylhydroxytoluene (BHT) sold under the name Butylated Hydroxytoluene, Granules, NF by Spectrum Chemical Manufacturing Corporation, New Brunswick, NJ, USA. 5. DL-α-Tocopherol sold by Alfa Aesar by Thermo Fisher Scientific, 2 Radcliff, Rd., Tewksbury, MA 01876, USA. 6. Highly purified diethylene glycol monoethyl ether, EP / NF (hereafter more commonly Gattefosse™) sold under the trademark Transcutol™ HP by GATTEFOSSE SAS, 36 Chemin de Genas 69800 Saint-Priest, FRANCE. 7. Emulsifying Wax, NF (hereafter more commonly Spectrum™) sold by Spectrum Chemical Manufacturing Corporation, New Brunswick, NJ, USA. 8. Mineral oil sold under the trademark Drakeol™ 32 by Calumet Refining, Indianapolis, IN, USA, which may contain up to 20 ppm tocopherols (hereafter more commonly Calumet™). 9. An antibacterial agent such as phenoxyethanol or more specifically 2-phenoxyethanol sold under the name 2-Phenoxyethanol Multicompendial A&C Grade by A&C American Chemicals Ltd., 3010 Rue De Baene, Montreal, QC H4S 1L2, CANADA (hereafter more commonly A&C™).

[0071] With respect to JAK inhibitors, more particularly JAK1 inhibitors, and even more particularly TYK2 / JAK1 inhibitors, the present disclosure provides results and statistical conclusions for topical cream additive experiments in which the Yellowness Index according to ASTM (American Society for Testing and Materials) method E313, YI (E313-96) (D65) was measured in cuvettes ("YI cuvettes") for each sample at several storage temperatures (5°C, 25°C, 30°C, and 40°C) at 24 weeks. This DoE used a 28-run D-optimal statistical design to evaluate the effect of five factors: added BHT (0, 15, 30 ppm), added tocopherol (0, 15, 30 ppm), white petrolatum (Calumet™, Croda™), oleyl alcohol (BASF™, Croda™), and PEG400 (Dow™, Croda™) on the yellowness of the cream. Higher YI (E313-96) (D65) values ​​indicate a yellower cream. During the experiment, YI (E313-96) (D65) was measured in standard glass vials ("YI vials") from an initial time t0 through 24 weeks (weeks 0, 2, 4, 6, 8, 10, 12, and 24), as shown in FIG. 1, and in cuvettes ("YI cuvettes") at 24 weeks. Therefore, the YI cuvettes at 24 weeks at those four different storage temperatures are the DoE responses analyzed and presented in this disclosure. The goal of the experiment was to identify additive factors, levels, and compositions that would minimize the yellowness index. Using the fitted DoE model, the predicted average of the YI cuvettes at 24 weeks at 40°C could be used to select practical color-minimizing additive factors, levels, and compositions. The statistical analysis results are summarized below. 1) At 5°C, the YI vials maintained low levels from the beginning through 24 weeks. At 24 weeks, the YI cuvettes were below zero for all 28 runs. Added tocopherol had a statistically significant quadratic effect on the YI cuvettes at 24 weeks. Added BHT had a statistically significant two-way interaction effect with white petrolatum and PEG400 on the YI cuvettes at 24 weeks. 2) At 25°C, added BHT and added tocopherol had statistically significant second-order and two-way interaction effects on YI cuvettes at 24 weeks. There was also a statistically significant main effect of PEG400 and a weakly statistically significant (p=0.0538) two-way interaction effect of white petrolatum and oleyl alcohol. 3) At 30°C, added BHT and added tocopherol had statistically significant two-way and two-way interaction effects on YI cuvettes at 24 weeks. There were also statistically significant two-way interaction effects of added BHT and white petrolatum, added tocopherol and PEG 400, and white petrolatum and oleyl alcohol. 4) At 40°C, there was a statistically significant quadratic effect of added BHT and a main effect of added tocopherol and PEG400.

[0072] Based on the fitted DoE model (Table A3), the predicted means (and their upper limits of 95% confidence intervals) for YI cuvettes over 24 weeks at different storage temperatures are provided in Table 0 below for all eight additive combinations with 0 ppm added tocopherol (best case in terms of added tocopherol levels).

[0073] [Table 1]

[0074] The primary objective of the topical cream excipient DoE was to identify excipients and their interactions that changed the color of the cream from white to yellow. Among the five excipient factors identified as having a potential effect on color change, added BHT and added tocopherol (note: the amount added was relative to the total formulation weight) were continuous number factors, while white petrolatum, oleyl alcohol, and PEG 400 were two-level categorical factors whose levels represented different sources of the excipients. In addition to the excipients studied, Gattefosse™ Transcutol™ HP, Spectrum™ emulsifying wax, Calumet™ mineral oil, and A&C™ phenoxyethanol were used in all experimental runs.

[0075] All cream samples were manufactured using the following general procedure: Water, PEG 400, and 2-phenoxyethanol were combined in the main mixing vessel and heated to approximately 60°C (aqueous phase). In a separate vessel, mineral oil, white petrolatum, oleyl alcohol, and emulsifying wax were heated to 60°C with mixing until melted (oil phase). The oil phase mixture was added to the main mixing vessel containing the aqueous phase mixture while homogenizing. The resulting cream was cooled to approximately 35°C while homogenizing. The API was dissolved in diethylene glycol monoethyl ether at room temperature. The API solution was added to the main mixing tank while homogenizing. The resulting active cream was cooled to room temperature and filled into glass vials or foil-laminated tubes.

[0076] Cream samples for each experimental run had an active pharmaceutical ingredient (API) concentration of 30 mg / g (3 wt%) and were stored in sealed glass vials at storage temperatures of 5°C, 25°C, 30°C, and 40°C. Biweekly to monthly color measurements, including the Yellowness Index (YI) (E313-96) (D65), were performed for up to 24 weeks. Higher YI (E313-96) (D65) values ​​indicate a more yellow cream. During the experiment, YI (E313-96) (D65) was measured directly in the sealed glass vials (YI vials) from the start or initial time or t0 up to 24 weeks (weeks 0, 2, 4, 6, 8, 10, 12, and 24). Additionally, samples were removed from the glass vials at 24 weeks and transferred to disposable plastic cuvettes, referred to herein as YI cuvettes, for YI (E313-96) (D65) measurements. From this point on, the project team used the cuvette measurement method, and therefore, the YI (E313-96) (D65) measured in cuvettes (YI cuvettes) at those four different storage temperatures over 24 weeks is the DoE response analyzed and presented in this disclosure. Using the fitted DoE model, the predicted average of the YI cuvettes over 24 weeks at 40°C was used to select a practical color-minimizing additive composition.

[0077] As mentioned above, the topical cream additive DoE used a 28-run D-optimal statistical design to evaluate the main and two-way interaction effects of the five additive factors and the quadratic effects of added BHT and added tocopherol. Table 1 provides the statistical design and factor levels of the experiment.

[0078] In experimental design, a main effect is the difference between levels of an independent variable on a dependent variable averaged across levels of any other independent variables. A two-way interaction effect occurs when the effect of an independent variable on a dependent variable depends on the level of another independent variable. A second-order effect is an interaction term in which an independent variable interacts with itself. A statistically significant effect indicates that the effect is statistically significantly different from zero.

[0079] [Table 2]

[0080] Detailed data containing factor levels and responses were saved in Excel™ files for subsequent analysis. Data visualization and statistical analysis were performed with SAS JMP® 14.0.0 and Design-Expert® (v11.0.6.0).

[0081] The yellowness index YI (E313-96) (D65) measured for the samples in the vials (YI vials) from the initial time t0 up to 24 weeks (0, 2, 4, 6, 8, 10, 12, 24 weeks) is recorded in the following Tables D5, D25, D30 and D40.

[0082] [Table 3]

[0083] [Table 4]

[0084] [Table 5]

[0085] [Table 6]

[0086] The yellowness index YI (E313-96) (D65) measured by the vial method (YI vials) from an initial time t0 up to 24 weeks (weeks 0, 2, 4, 6, 8, 10, 12, and 24) from Tables DV5, DV25, DV30, and DV40 is plotted against time by storage temperature in Figure 1. It was shown that the YI vials remained at very low levels for all experimental runs at 5°C, indicating negligible color change at a storage temperature of 5°C. However, as storage temperature increased, the YI values ​​increased, as did the variation between runs or additive factor combinations.

[0087] Because we switched the Yellowness Index YI (E313-96) (D65) measurement method from vials to cuvettes at 24 weeks and used the cuvette method thereafter, only the YI cuvette data at 24 weeks at different storage temperatures is analyzed and presented as the DoE response in this disclosure. It is noteworthy that the YI vial and YI cuvette are highly correlated based on the 24-week data. The correlation coefficients between the YI vial and YI cuvette at 24 weeks are provided in Table 2 below.

[0088] [Table 7]

[0089] The yellowness index YI (E313-96) (D65) was measured at 24 weeks by the cuvette method (YI cuvette) and recorded in Table DC below.

[0090] [Table 8]

[0091] A stepwise model selection technique was used to generate candidate terms for each statistical model. To retain a model, terms had to be statistically significant at the commonly accepted 0.05 level of statistical significance (either one-tailed or two-tailed, as appropriate), unless a term was required to retain the model hierarchy when strong interaction effects were included in the model. In addition, all terms in the regression model had to be statistically significant at the commonly accepted 0.05 level of statistical significance (either one-tailed or two-tailed, as appropriate) to achieve a high R for prediction. 2 needed to be increased to a statistically significant level.

[0092] Table A1 summarizes the statistically significant factor effects for each response. All model coefficients listed in Table A1 were fitted using "-1" and "+1" coded levels instead of the actual levels for each factor. The actual levels for each coded factor are provided in Table A2.

[0093] [Table 9]

[0094] [Table 10]

[0095] The following list explains three of the key statistics included in Table A1. 1) Adjusted R 2 The values ​​represent the percentage of total variation in the data explained by the model after adjusting for the number of terms in the model compared to the number of runs in the experiment. Adjusted R 2 The closer σ approaches 1.00, the better the model fit to the data observed in this experiment. 2) R for prediction 2 ("Predicted R 2 ") estimates the percentage of total variation in new data that would be explained by a model with the same terms as the model derived in this experiment. R for prediction 2The closer to 1.00, the better the predictive power of the model. 3) The root mean square error (RMSE) is calculated from the individual differences between the observed and predicted values ​​for each experimental run. These differences are called "residuals." The RMSE can be interpreted as the standard deviation of the residuals.

[0096] The model in Table A1 is also presented using the "actual" factor values ​​in Table A3. The additive levels for each additive combination ID can be seen in Table A4.

[0097] [Table 11]

[0098] [Table 12]

[0099] Using the information presented in Tables A1-A4, one can predict the 24-week YI cuvette average values ​​at different storage temperatures for a desired additive combination. For example, to predict the 24-week YI cuvette average values ​​at 40°C for additive combination #1 (Calumet white petrolatum, BASF oleyl alcohol, and Dow PEG 400) with 0 ppm added BHT and 0 ppm added tocopherol, one can use the coded values ​​of the factors (A=-1, B=-1, C=-1, D=-1, E=-1) and the model coefficients from Table A1, or the actual values ​​of the factors (A=0 ppm, B=0 ppm) and the equations from Table A3.

[0100] For example, for additive combination #1 in Table A3, the equation for a YI cuvette at 40°C for 24 weeks is: exp(1.540698+0.176473×A+0.021081×B-0.003845×A 2 )=YI#1 and substituting the actual values ​​of A=0 ppm and B=0 ppm, exp(1.540698+0.176473×0+0.021081×0-0.003845×0 2 )=4.67 can be calculated, which is the predicted median, which differs from the predicted mean on the original scale. In this case, the correction factor SD 2 / 2, and SD is the standard deviation of the prediction on the transformed scale. Therefore, the predicted mean for the YI cuvette at 40°C for 24 weeks for additive combination #1 on the original scale is exp(1.540698+0.176473×0+0.021081×0-0.003845×0 2 +SD 2 / 2)=exp(1.540698+0.2346 2 / 2) ≒ 4.80 It can be calculated as:

[0101] It is worth noting that when the predicted mean response on the transformed scale is transformed back to its original scale, the predicted mean becomes the predicted median. Design-Expert® automatically applies a correction to the back-transformed predictions, so it accurately predicts the mean rather than the median. The output in Tables 0, 3, and 4 is the corrected predicted mean.

[0102] Detailed information about each model is provided below, including contour plots in figures that allow assessment of effect size and practical importance. Added BHT and / or added tocopherol affected all four responses. These contour plots consist of "contours" (lines of constant predicted response value) with added tocopherol and added BHT as the X and Y axes, respectively.

[0103] YI cuvettes at 5°C for 24 weeks As best seen in Table DC above, at 5° C., the YI cuvette values ​​at 24 weeks were less than 0 for all 28 runs, ranging from -8.85 for run 15 to -2.93 for run 22. Added BHT, added tocopherol, oleyl alcohol, and PEG400 affected YI cuvette at 24 weeks at 5° C. There was a statistically significant quadratic effect of added tocopherol, as well as two-way interaction effects of added BHT and oleyl alcohol and added BHT and PEG400.

[0104] Using the fitted DoE model, the predicted average YI cuvettes at 24 weeks at 5°C could be used to select the best and worst color-minimizing additive compositions. Contour plots of the theoretical best and worst case scenarios in terms of the lowest and highest predicted YI cuvettes at 24 weeks at 5°C with 0 ppm added BHT and 0 ppm added tocopherol are provided in Figures 2 and 3, respectively. Under these conditions, the theoretical best case scenario, illustrated in Figure 2, was predicted for a sample containing Calumet™ white petrolatum, BASF™ oleyl alcohol, and Dow™ PEG 400. The worst case scenario, illustrated in Figure 3, was predicted for a sample containing Calumet™ white petrolatum, Croda™ oleyl alcohol, and Croda™ PEG 400.

[0105] YI cuvettes at 25°C for 24 weeks As best seen in Table DC above, the YI cuvette at 25°C and 24 weeks ranged across 28 runs from -1.19 for run 15 to 34.2 for run 20. All five factors affected the YI cuvette at 24 weeks at 25°C. Added BHT and added tocopherol had statistically significant second-order and two-way interaction effects on the YI cuvette at 24 weeks. There was also a statistically significant main effect of PEG400, and weakly statistically significant (p=0.0538) two-way interaction effects of white petrolatum and oleyl alcohol.

[0106] Using the fitted DoE model, the predicted averages for the YI cuvettes at 25°C over 24 weeks could be used to select the best and worst color-minimizing additive compositions. Contour plots of the theoretical best and worst-case scenarios in terms of the lowest and highest predicted YI cuvettes over 24 weeks at 25°C with 0 ppm added BHT and 0 ppm added tocopherol are provided in Figures 4 and 5, respectively. Under these conditions, the best-case scenario, illustrated in Figure 4, was predicted for the sample containing Croda™ white petrolatum, Croda™ oleyl alcohol, and Dow™ PEG 400. The worst-case scenario, illustrated in Figure 5, was predicted for the sample containing Calumet white petrolatum, Croda™ oleyl alcohol, and Croda™ PEG 400. The effect of variable storage temperature can be understood by comparing the entire rows of Table 0. The effect of storage temperature can also be seen by comparing the predicted averages and contour plots of Figures 2 and 3 with Figures 4 and 5.

[0107] YI cuvettes at 30°C for 24 weeks As best seen in Table DC above, the YI cuvette at 30°C for 24 weeks ranged from 0.16 for run 15 to 48.9 for run 8 across 28 runs. All five factors affected the YI cuvette at 24 weeks at 30°C. Added BHT and added tocopherol had statistically significant second-order and two-way interaction effects on the YI cuvette at 24 weeks. There were also three statistically significant two-way interaction effects: added BHT and white petrolatum, added tocopherol and PEG400, and white petrolatum and oleyl alcohol.

[0108] Using the fitted DoE model, the predicted averages for the YI cuvettes at 30°C over 24 weeks could be used to select the best and worst color-minimizing additive compositions. Contour plots of the best and worst-case scenarios in terms of the lowest and highest predicted YI cuvettes over 24 weeks at 30°C with 0 ppm added BHT and 0 ppm added tocopherol are provided in Figures 6 and 7, respectively. Under these conditions, the best scenario, illustrated in Figure 6, was predicted for the sample containing Croda™ white petrolatum, Croda™ oleyl alcohol, and Dow™ PEG 400. The worst-case scenario, illustrated in Figure 7, was predicted for the sample containing Calumet white petrolatum, Croda™ oleyl alcohol, and Croda™ PEG 400. The effect of variable storage temperature can be understood by comparing the entire rows of Table 0. The effect of storage temperature can also be seen by comparing the predicted averages and contour plots of the previous figures with Figures 6 and 7.

[0109] YI cuvettes at 40°C for 24 weeks As best seen in Table DC above, the YI cuvette at 40° C. for 24 weeks ranged from 4.48 for run 15 to 74.69 for run 22 across 28 runs. Added BHT, added tocopherol, and PEG400 affected the YI cuvette at 40° C. for 24 weeks. There was a statistically significant quadratic effect of added BHT, and a main effect of added tocopherol and PEG400.

[0110] Using the fitted DoE model, the predicted average YI cuvette at 40°C for 24 weeks could be used to select the best and worst color-minimizing additive compositions. Contour plots of the best and worst-case scenarios in terms of the lowest and highest predicted YI cuvettes at 40°C for 24 weeks with 0 ppm added BHT and 0 ppm added tocopherol are provided in Figures 8 and 9, respectively. Figure 8A shows an enlarged or zoomed-in version of Figure 8 with 0 to 2 ppm added BHT and 0 to 2 ppm added tocopherol. Under these conditions, the best-case scenario illustrated in Figure 8 was predicted for a sample containing Calumet white petrolatum, BASF™ oleyl alcohol, and Dow™ PEG 400. Figure 8A is an enlarged or zoomed-in contour plot of the yellowness index (YI cuvette) obtained from the lower left region of Figure 8, showing the low yellowness area in more detail. The worst case scenario illustrated in Figure 9 was predicted for a sample containing Calumet white petrolatum, Croda™ oleyl alcohol, and Croda™ PEG 400. By comparing the entire rows of Table 0, the effect of variable storage temperature can be seen. The effect of storage temperature can also be seen by comparing the predicted mean and contour plots of the previous figures with Figures 8 and 9.

[0111] statistical conclusion Calumet™ white petrolatum and mineral oil contain BHT and tocopherol in amounts that vary from lot to lot. White petrolatum and mineral oil constitute 10% w / w and 5% w / w of the cream, respectively. Calumet™ white petrolatum is stabilized with up to 20 ppm BHT, and the lot used to prepare the DoE cream samples contained 5 ppm BHT, corresponding to 0.5 ppm BHT in the cream. Therefore, 1.5 ppm added BHT represents the worst-case scenario for a white petrolatum lot containing 20 ppm BHT. Calumet™ mineral oil is stabilized with up to 20 ppm tocopherol, and the amount in the lot used to prepare the DoE samples was not quantified; therefore, 1 ppm added tocopherol was used to represent the worst-case scenario for a mineral oil lot containing 20 ppm tocopherol. Based on the fitted model (Table A3), the predicted means (and their upper limits of 95% confidence intervals) of the YI cuvettes at 24 weeks at different storage temperatures are provided in Table 0 for all eight additive combinations. Note that for the calculations in Table 0, the added BHT was set to 0 or 1.5 ppm and the added tocopherol value was set to 0 ppm. Additionally, the predicted means (and their upper limits of 95% confidence intervals) of the YI cuvettes at 24 weeks at different storage temperatures are provided in Table 3 below for the eight additive combinations with added BHT of 0 or 1.5 ppm and added tocopherol of 1 ppm.

[0112] [Table 13]

[0113] In one embodiment where the API concentration was between about 1% and about 3% by weight, Calumet white petrolatum and Croda™ oleyl alcohol (Super Refined™ Novol™), containing 7 ppm or less of BHT, were found to be suitable replacements for the existing excipient ingredients Croda™ petrolatum (Crolatum™ V-SO) and BASF™ oleyl alcohol (Kollicream™ OA), respectively, because the change did not affect product quality. This evaluation is based on the results of a 24-week DoE that investigated the effect of several factors, including petrolatum source (Calumet™ and Croda™), oleyl alcohol source (BASF™ and Croda™), and total (intrinsic and added) BHT, on drug product appearance (color) and purity as a function of storage time and temperature.

[0114] BHT is introduced into the topical cream as an additive to white petrolatum, an additive that constitutes 10% w / w of the total cream composition. All clinical trial drug product lots manufactured to date have been made using Calumet™ Super White™ petrolatum USP, stabilized with up to 20 ppm BHT and available from Calumet Refining, Indianapolis, IN, USA. In the additive DoE, we investigated a BHT-free petrolatum, Croda™ Crolatum™ V-SO, stabilized with 10 ppm tocopherol and available from Croda International, Snaith, East Riding of Yorkshire, UK.

[0115] Based on the results of statistical analysis and additional manufacturing efficiency considerations, combination 5 in Table 4, using Crolatum™ and Kollicream™ OA, was identified as the preferred combination for minimizing yellow color development. Combinations 1 and 7 are also predicted to result in acceptable color development when the total cream formulation contains about 0.2 ppm or less of added BHT ( FIG. 8A ). The Calumet white petrolatum used in these samples contains about 5 ppm of BHT, which converts to 0.5 ppm of BHT at 10% petrolatum, and when combined with the 0.2 ppm of added BHT, provides a total of about 0.7 ppm or less of BHT in the cream. Additionally, no degradants were observed in the DoE samples stored at 40° C. for 24 weeks, indicating that various additive combinations are acceptable for product purity as long as BHT limits are maintained.

[0116] Experiments have demonstrated several limits on the amount of tocopherol in a formulation that may also be beneficial independently or in combination with the BHT limit. Figure 8A shows that, in the absence of added BHT in the formulation, acceptable color development can be achieved by limiting added tocopherol to less than about 2 ppm. Because other additives in the formulation, such as mineral oil, oleyl alcohol, and white petrolatum, may inherently contain tocopherol, an overall limit of tocopherol in the total formulation of less than about 6.5 ppm is believed to lead to acceptable color development. If less than about 0.7 ppm BHT is present throughout the formulation, the tocopherol present throughout the formulation should be limited to about 5 ppm.

[0117] [Table 14]

[0118] Formulations 5, 1, and 7 were prepared at 1% w / w and 3% API concentrations and stored in foil-laminated tubes at 40 degrees Celsius for up to 16 weeks. Formulation 4 was also prepared, packaged, and stored under the same conditions to serve as a negative control. Yellowness Index or YI (E313-96) (D65) measurements were performed at 0, 4, and 16 weeks and are recorded in Table T1. Measurements were performed by using a disposable plastic cuvette to sample the cream through the opening in the tube. Thus, the measurements were Y-cuvette measurements. Data for the 1% API concentration formulations are presented graphically in Figure 10, and data for the 3% API concentration formulation are plotted in Figure 11.

[0119] [Table 15]

[0120] As can be seen from the data, formulations 1, 5, and 7 all maintained a relatively low yellowness index or YI compared to the negative control formulation 4. At 3% API concentration, formulations 5 and 7 without BHT maintained a yellowness index of less than about 6 when stored at 40° C. for 16 weeks. The above experiments detailed in Table T are ongoing, and it is expected that the yellowness index for formulations 5 and 7 will be less than about 10 at 24 weeks at 40° C. At 1% API concentration, BHT-free formulations 5 and 7 maintained a yellowness index of less than about 3 when stored at 40° C. for 16 weeks. It is expected that the yellowness index for formulations 5 and 7 will be less than about 6 at 24 weeks at 40° C.

[0121] The chemical structure of a first JAK inhibitor for which the formulations of the present invention are useful is shown below: By way of example and not limitation, this JAK inhibitor is a JAK1, and more particularly a TYK2 / JAK1 inhibitor.

[0122] [ka]

[0123] The chemical structure of a second JAK inhibitor for which the formulations of the present invention are useful is shown below: By way of example, and not limitation, this second JAK inhibitor is a TYK2 / JAK1 inhibitor described in co-pending application USSN 63 / 047606, filed July 2, 2020, which is incorporated herein by reference in its entirety.

[0124] [ka] The chemical name of this second JAK or JAK1 / TYK2 inhibitor is ((1R,5S)-3-(2-((1-propyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((R)-spiro[2.3]hexan-1-yl)methanone.

[0125] Without being bound by the accuracy of this theory or hypothesis, it is believed that the BHT-related yellowing phenomenon occurs via reaction of BHT with the API or structurally similar species to form a conjugated species with a yellow color. In the proposed mechanism shown below for the first JAK inhibitor as an example, BHT is oxidized by reaction with air, additives, and / or additive degradants. The oxidized BHT species can then react with the API or structurally similar species to form a more highly conjugated, yellow species, as shown in the scheme below. Based on the nature of the reaction, it is reasonable to infer that APIs sharing the structural elements shown above would also be susceptible to this degradation mechanism in the presence of BHT and would therefore benefit from limiting the amount of BHT in light of the present invention.

[0126] [ka]

[0127] Based on the foregoing, it should be apparent that the present invention meets at least its stated objectives. A stable, low cost, and easy to manufacture formulation is disclosed.

[0128] The present invention has been described with reference to specific details of its embodiments. Except to the extent and unless included in the appended claims, such details are not intended to be considered limitations on the scope of the invention. For example, the formulation is not limited to the specific exemplary embodiment that uses ingredients or additives from the specific supplier identified. The formulation may include, as a substitute, ingredients or additives of equivalent grades from different suppliers, and the results would be similar in terms of color stability, as long as the amount of BHT is limited as claimed. The present invention includes, but is not limited to, the following aspects. [Aspect 1] 1. A topical formulation for the treatment of a dermatological condition, comprising: a JAK inhibitor in an oil-in-water emulsion; White petrolatum in an amount of about 10% by weight; less than about 0.7 ppm by weight of butylhydroxytoluene (BHT); oleyl alcohol in an amount of about 2% by weight; Antibacterial agents and 1. A topical formulation comprising: [Aspect 2] The topical formulation of embodiment 1, wherein the JAK inhibitor is a JAK1 inhibitor. [Aspect 3] The topical formulation of embodiment 1, wherein the JAK inhibitor is a TYK2 / JAK1 inhibitor. [Aspect 4] 2. The topical formulation of embodiment 1, wherein the JAK inhibitor comprises ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone. [Aspect 5] Aspect 5. The topical formulation of any one of aspects 1-4, wherein the JAK inhibitor is present in an amount of about 1% to about 3% by weight. [Aspect 6] 6. The topical formulation of any one of the preceding aspects, comprising tocopherol in an amount less than about 6.5 ppm. [Aspect 7] 7. The topical formulation of any one of aspects 1-6, comprising polyethylene glycol 400 in an amount of about 10% by weight. [Aspect 8] Aspect 8. The topical formulation of any one of aspects 1-7, comprising diethylene glycol monoethyl ether in an amount of about 15% by weight. [Aspect 9] Aspect 9. The topical formulation according to any one of aspects 1 to 8, comprising emulsifying wax in an amount of about 10% by weight. [Aspect 10] Aspect 10. The topical formulation of any one of aspects 1-9, wherein the antibacterial agent comprises 2-phenoxyethanol in an amount of about 1% by weight. [Aspect 11] Aspect 11. The topical formulation of any one of aspects 1-10, wherein the formulation maintains its white color having a Yellowness Index (YI) value of less than about 10 when stored at 40 degrees Celsius for 24 weeks. [Aspect 12] Aspect 12. The topical formulation of any one of aspects 1-11, wherein the formulation maintains a white color having a Yellowness Index value of less than about 6 when stored at 40 degrees Celsius for 16 weeks. [Aspect 13] 12. The topical formulation of any one of the preceding aspects, having a Yellowness Index value that increases by about 8 or less over a 24 week period at 40 degrees Celsius. [Aspect 14] Aspect 14. The topical formulation of any one of aspects 1-13, wherein the white petrolatum comprises about 7 ppm or less of BHT. [Aspect 15] 1. A topical formulation for the treatment of a dermatological condition, comprising: a JAK inhibitor as a purified oil-in-water emulsion; White petrolatum in an amount of about 10% by weight; tocopherols in an amount less than about 6.5 ppm; oleyl alcohol in an amount of about 2% by weight; Polyethylene glycol 400 in an amount of about 10% by weight; diethylene glycol monoethyl ether in an amount of about 15% by weight; mineral oil in an amount of about 5% by weight; emulsifying wax in an amount of about 10% by weight; an antimicrobial agent comprising 2-phenoxyethanol in an amount of about 1% by weight; Including, A topical formulation that is BHT-free, thereby maintaining a yellowness index of less than about 6 when stored at 40 degrees Celsius for 16 weeks, and less than or equal to about 10 when stored at 40 degrees Celsius for 24 weeks. [Aspect 16] 16. A method of treating or preventing a disease or condition selected from psoriasis, atopic dermatitis, atopic eczema, chronic hand eczema, urticaria, vitiligo, cutaneous lupus, and alopecia areata, comprising administering to a subject in need thereof a therapeutically effective amount of the topical formulation of any one of aspects 1-15. [Aspect 17] 16. Use of a topical formulation according to any of aspects 1 to 15 for the manufacture of a medicament for the treatment of a disorder in which a TYK2 / JAK1 inhibitor is indicated.

Claims

1. 1. A topical formulation comprising: a JAK inhibitor in an oil-in-water emulsion; White petrolatum in an amount of 10% by weight; less than 0.7 ppm by weight of butylhydroxytoluene (BHT); oleyl alcohol in an amount of 2% by weight; antibacterial agents wherein the JAK inhibitor comprises ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone, or ((1R,5S)-3-(2-((1-propyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)((R)-spiro[2.3]hexan-1-yl)methanone; and a topical formulation comprising:

2. 10. The topical formulation of claim 1, wherein the JAK inhibitor is present in an amount of 1% to 3% by weight.

3. 3. The topical formulation of claim 1 or 2, comprising tocopherol in an amount less than 6.5 ppm.

4. 4. A topical formulation according to any one of claims 1 to 3, comprising polyethylene glycol 400 in an amount of 10% by weight.

5. 5. A topical formulation according to any one of claims 1 to 4, comprising diethylene glycol monoethyl ether in an amount of 15% by weight.

6. 6. A topical formulation according to any one of claims 1 to 5, comprising emulsifying wax in an amount of 10% by weight.

7. 7. The topical formulation of any one of claims 1 to 6, wherein the antibacterial agent comprises 2-phenoxyethanol in an amount of 1% by weight.

8. 8. The topical formulation of any one of claims 1 to 7, which maintains its white color when stored at 40 degrees Celsius for 24 weeks, having a Yellowness Index (YI) value according to American Society for Testing and Materials (ASTM) method E313, YI(E313-96)(D65) of less than 10.

9. 9. The topical formulation of any one of claims 1 to 8, which maintains its white color when stored at 40 degrees Celsius for 16 weeks, having a Yellowness Index value according to ASTM method E313, YI(E313-96)(D65) of less than 6.

10. 10. The topical formulation of any one of claims 1 to 9, having a Yellowness Index value by ASTM method E313, YI(E313-96)(D65) that increases by no more than 8 over 24 weeks at 40 degrees Celsius.

11. 11. The topical formulation of claim 1, wherein the white petrolatum contains no more than 7 ppm of BHT.

12. The topical formulation of claim 1, further comprising: Tocopherol in an amount less than 6.5 ppm; Polyethylene glycol 400 in an amount of 10% by weight; Diethylene glycol monoethyl ether in an amount of 15% by weight; Mineral oil in an amount of 5% by weight; emulsifying wax in an amount of 10% by weight; an antimicrobial agent comprising 2-phenoxyethanol in an amount of 1% by weight; Including, A topical formulation that is BHT-free, thereby maintaining a Yellowness Index of less than 6 when stored at 40 degrees Celsius for 16 weeks, and less than or equal to 10 when stored at 40 degrees Celsius for 24 weeks.

13. 13. The topical formulation of any one of claims 1 to 12 for use in the treatment or prevention of a disease or condition selected from psoriasis, atopic dermatitis, atopic eczema, chronic hand eczema, urticaria, vitiligo, cutaneous lupus and alopecia areata.

14. 13. Use of a topical formulation according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of a disorder in which a TYK2 / JAK1 inhibitor is indicated.

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