Formulations, methods, kits, and dosage forms for the treatment of atopic dermatitis and for improving the stability of active pharmaceutical ingredients.

Abstract

To disclose embodiments that relate generally to formulations, methods of treatment, kits, and dosage forms for treating inflammatory disorders, including atopic dermatitis, or cancer, the formulations comprising an active pharmaceutical ingredient.SOLUTION: A formulation provided comprises granules, where the granules comprise: micronized active ingredient; one or more granulation binders; one or more fillers; one or more disintegrants; and one or more antioxidants. In one embodiment, the methods of treatment include orally administering the active ingredient to a subject suffering from atopic dermatitis, where the active ingredient is in an amount of about 20 mg to about 80 mg.SELECTED DRAWING: Figure 10

Description

[Technical Field]

[0001] Embodiments of this disclosure relate, as a whole, to formulations, methods, kits, and dosage forms for treating atopic dermatitis and for improving the stability of active pharmaceutical ingredients. In one embodiment, the formulations, methods, kits, and dosage forms include administering an active pharmaceutical ingredient with improved stability, which can be used for the treatment of inflammatory disorders or cancer or for the treatment of atopic dermatitis. [Background technology]

[0002] Protein kinases constitute a large, structurally related family of enzymes involved in regulating various intracellular signaling processes. Almost all kinases contain a similar catalytic region of 250–300 amino acids. Kinases can be classified into several families depending on the substrates they phosphorylate.

[0003] JAK (Janus kinase, including JAK1, JAK2, JAK3, and TYK2) is a family of non-receptor tyrosine kinases found in cells. JAK is expressed in hematopoietic cells and is abundant in primary leukemia cells in children with acute lymphoblastic leukemia. Downstream substrates of JAK include signaling and transcription activator (STAT) proteins. STAT proteins function as both signaling molecules and transcription factors, ultimately binding to specific DNA sequences present in the promoters of cytokine-responsive genes. JAK / STAT signaling is involved in mediating many abnormal immune responses, such as autoimmune diseases including allergies, asthma, and transplant (allogeneic) rejection, as well as rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, in addition to solid malignancies and hematological malignancies such as leukemia and lymphoma.

[0004] Spleen tyrosine kinase (SYK) is a member of the SYK family of protein tyrosine kinases and plays a crucial role in inflammatory and allergic responses. SYK initiates IgE and IgG receptor-mediated signaling in mast cells, basophils, and macrophages, promoting degranulation and cytokine release.

[0005] Signal transduction mediated by immune receptor tyrosine activation motifs (ITAMs) is becoming increasingly clear as a major event in signal transduction pathways involved in human pathogenesis. ITAM-mediated signal transduction is involved in the relay of activation signals initiated by classical immune receptors such as T cell receptors, B cell receptors, and Fc receptors on immune cells, as well as GPVI and FcγRIIa in platelets, and transmitted to downstream intracellular molecules such as Syk.

[0006] When a ligand binds to a receptor containing ITAM, a signaling event is initiated, recruiting proteins from a non-receptor tyrosine kinase family called the Src family. These kinases phosphorylate tyrosine residues in the ITAM sequence, and this region interacts with the tandem SH2 domain of either Syk or ZAP-70. Syk's interaction with the diphosphorylated ITAM sequence induces a structural change in the kinase, enabling tyrosine phosphorylation of the kinase itself.

[0007] These kinases undoubtedly contribute to normal host defense and are also involved in disease development. Many diseases are associated with abnormal cellular responses initiated by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, and hormone-related disorders. Consequently, considerable effort has been made in medicinal chemistry to find protein kinase inhibitors for therapeutic use. In this field, in addition to compounds that act as Syk / JAK dual inhibitors, there is a need for methods to treat conditions that can benefit from such inhibition. There is also a need for formulations of Syk / JAK dual inhibitor compounds that can be used in methods to treat conditions that can benefit from such inhibition. Such formulations should optimize the efficacy of the Syk / JAK dual inhibitor compound and exhibit high stability.

[0008] Atopic dermatitis (AD) is a chronic inflammatory skin disease. It is characterized by dry, scaly, erythematous, moist, and crusted lesions, itchy, scratched skin, and lichenification. This skin condition is accompanied by intense itching and places a significant burden on the patient and their quality of life. Less than 3% of adults and 15-25% of children suffer from atopic dermatitis. Approximately 85% of cases develop in early childhood, but it can also develop later, including in adulthood.

[0009] Spleen tyrosine kinase (SYK) and Janus kinase (JAK) are tyrosine kinases that play a crucial role in the pathogenesis of various types of autoimmune and inflammatory diseases, including atopic dermatitis. SYK deregulation is involved in various human diseases, including B-cell malignancies, allergies, asthma, and other inflammatory disorders. SYK binds to the immune receptor tyrosine-dependent activation motif (ITAM) present in Fcγ-activating receptors and integrins. When SYK binds to ITAM, downstream signaling events, such as Bruton's tyrosine kinase (BTK), are activated, ultimately leading to increased release of cytokines, lipid mediators, and various proteases. These mediators contribute to B-cell overgrowth, inflammation, and tissue or cartilage damage. SYK also plays a vital role in IL-17R signaling in keratinocytes. Therefore, inhibiting SYK activity presents a promising approach for treating various types of lymphomas and inflammatory disorders.

[0010] JAK kinases (JAK1, JAK2, JAK3, and TYK2) are necessary for physiological signal transduction via cytokine and growth factor receptors that do not inherently possess kinase activity (12, 13). When JAK kinases are stimulated by factors such as erythropoetin, granulocyte-macrophage colony-stimulating factor, IL-3, IL-5, thrombopoietin, and growth hormone, they phosphorylate signaling and transcription activator (STAT1-5) family proteins, which then translocate into the nucleus and activate various downstream target genes involved in cytokine and growth factor responses. JAK kinases are particularly involved in cytokine-induced inflammatory conditions, including atopic dermatitis. [Overview of the project]

[0011] In this technological field, there is a need for therapeutic methods using compounds that act as dual inhibitors of Syk / JAK to treat inflammatory disorders such as atopic dermatitis.

[0012] In one embodiment, the present disclosure relates to a formulation, method, kit, and dosage form for treating a condition related to inhibition of Syk / JAK, such as an inflammatory disorder or a solid tumor, particularly melanoma, colorectal cancer, non-small cell lung cancer, bladder cancer, and breast cancer, and / or the following cancers: prostate, head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, rectum, stomach, uterus, cervix, ovary, vagina, testis, skin, thyroid, blood, lymph node, kidney, liver, intestine, pancreas, brain, central nervous system, adrenal gland, skin, or leukemia and / or lymphoma, etc.

[0013] In one embodiment, the present disclosure relates to a formulation, method, kit, and dosage form for treating a condition related to inhibition of Syk / JAK, such as an inflammatory disorder including atopic dermatitis.

[0014] In one embodiment, the pharmaceutical formulation described herein comprises granules, which contain a micronized active ingredient, one or more granulation binders, one or more fillers, one or more disintegrants, and one or more antioxidants. The formulation can further contain extra-granular components. The amount of the active ingredient can be about 20 mg to about 80 mg. The formulation described herein can be administered to a subject once a day for a short or long period.

[0015] The active ingredient is a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0016] In other embodiments, the present disclosure provides a dosage form comprising a pharmaceutical preparation containing the active ingredient of formula (I) in a compressed tablet, and the active ingredient of the pharmaceutical preparation maintains stability even after storage under predetermined conditions such as in an open container for a predetermined time. "Storage in an open container" in some embodiments means that the container is opened once or twice a day for a given period, for example up to 4 weeks, and remains closed otherwise. In one embodiment, the preparation can be used for the treatment of atopic dermatitis. In one embodiment, the amount of the active ingredient can be from about 20 mg to about 80 mg.

[0017] In other embodiments, the Disclosure provides a method for manufacturing or stabilizing a pharmaceutical formulation, which may be useful for the treatment of atopic dermatitis. The method comprises the steps of: mixing granular components comprising an active ingredient, one or more fillers, one or more disintegrants, and one or more antioxidants; granulating the mixed granular components until granules are formed, while adding a solution of 10% w / w one or more granulation binders dissolved in 99% v / v isopropyl alcohol; and drying and grinding the granules to produce finely ground granules, wherein the active ingredient comprises a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, and the pharmaceutical formulation may further comprise extragranular components. In the embodiments, the active ingredient in the formulation maintains stability and efficacy under predetermined conditions, including conditions under which the container may be opened once or more times for a predetermined time. In one embodiment, the formulation may contain the active ingredient in an amount of about 20 mg to about 80 mg.

[0018] In other embodiments, the Disclosure provides a kit comprising one or more dosage forms and instructions for administering those dosage forms, comprising a pharmaceutical formulation in which the dosage forms optionally contain an active ingredient in substantially compressed tablet form together with extragranular components, the active ingredient comprising a compound of formula (I), and the active ingredient in the pharmaceutical formulation maintains stability for a predetermined time and under predetermined conditions.

[0019] In other embodiments, the Disclosure provides a method for treating a condition characterized by dysregulation (e.g., abnormality or dysfunction) of the Syk / JAK pathway of a subject. In one embodiment, the Disclosure provides a method for treating a condition characterized by dysregulation (e.g., abnormality or dysfunction) of the Syk / JAK2 pathway of a subject. In other embodiments, the Disclosure provides a method for treating atopic dermatitis. The method may include administering a therapeutically effective amount of the active ingredient to a subject in one or more dosage forms, the dosage form including a pharmaceutical preparation containing the active ingredient in granular form in a compressed tablet containing optionally one or more extragranular components, the active ingredient comprising a compound of formula (I), and the active ingredient maintaining stability after the pharmaceutical preparation is stored for a predetermined time under predetermined conditions. The dosage form may contain the active ingredient in an amount of about 20 mg to about 80 mg and may be administered to the subject once daily for a short or long period of time.

[0020] In other embodiments, the Disclosure provides pharmaceutical formulations which may be useful for the treatment of atopic dermatitis. The formulations may contain the active ingredient in granular form in a compressed tablet which optionally contains one or more extragranular components, the active ingredient comprising the active ingredient of the formulation described herein, the active ingredient comprising 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimide[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile (which may be referred to herein as "Compound 1") or the active ingredient comprising 2-(1-(4-((4-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimide[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile. The amount of active ingredient can be approximately 20 mg to 80 mg. [Brief explanation of the drawing]

[0021] [Figure 1] This is an analysis report of the particle size distribution data of the active ingredients before micronization.

[0022] [Figure 2] This is an analysis report of the particle size distribution data of the active ingredients after micronization.

[0023] [Figure 3] This shows the 5-D pruritus severity scale.

[0024] [Figure 4] This is an evaluation method for the Eczema Area and Severity Index (EASI).

[0025] [Figure 5] This diagram illustrates the test design for Example 3.

[0026] [Figure 6] This chart illustrates the patient characteristics of Example 3.

[0027] [Figure 7] Figure 7A is a graph showing the percentage of subjects who achieved an EASI of 50 over time (Day 1 to Day 29) after being administered placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg, as shown in Example 3. Figure 7B is a graph showing the percentage of subjects who achieved an EASI of 75 over time (Day 1 to Day 29) after being administered placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg, as shown in Example 3.

[0028] [Figure 8] Figure 8A is a graph showing the %CFB (change from baseline) of EASI (decrease) when placebo and compound 1 were administered at doses of 20 mg, 40 mg, and 80 mg, as shown in Example 3. Figure 8B is a graph showing the %CFB when IGA (Comprehensive Assessment by the Attending Physician) was between 0 and 1, when placebo and compound 1 were administered at doses of 20 mg, 40 mg, and 80 mg, as shown in Example 3. Figure 8C is a graph showing the %CFB of BSA (decrease) when placebo and compound 1 were administered at doses of 20 mg, 40 mg, and 80 mg, as shown in Example 3.

[0029] [Figure 9] This graph shows the plasma concentrations on day 15 when compound 1 was administered at doses of 20 mg, 40 mg, and 80 mg, as shown in Example 3.

[0030] [Figure 10] The table in Example 3 shows the inhibition of JAK and Syk kinase activity by compound 1, tofacitinib, upadacitinib, and baricitinib.

[0031] [Figure 11] The table shows the inhibition of the JAK / STAT pathway by compound 1 in T cells stimulated with various cytokines, as shown in Example 3.

[0032] [Figure 12] This table shows the inhibition of IL-17-mediated CCL20 release in keratinocytes by compound 1, as shown in Example 3.

[0033] [Figure 13] As shown in Example 3, this graph shows the average weekly change in itching (NRS) when placebo and compound 1 were administered at doses of 20 mg, 40 mg, and 80 mg.

[0034] [Figure 14A-B] Figure 14A is a graph showing the improvement in skin thickness when compound 1 is administered at doses of 20 mg, 40 mg, and 80 mg. Figure 14B is a graph showing the improvement in CD3+ cells when compound 1 is administered at doses of 20 mg, 40 mg, and 80 mg.

[0035] [Figure 14C] This graph shows the improvement in CD11c+ cells when compound 1 is administered at doses of 20 mg, 40 mg, and 80 mg.

[0036] [Figure 15] As shown in Example 3, this is a table showing the adverse events (TEAEs) that occurred during treatment.

[0037] [Figure 16A] This disclosure presents data on the clinical activity, safety, and tolerability of the formulation described herein. [Figure 16B] This disclosure presents data on the clinical activity, safety, and tolerability of the formulation described herein. [Figure 16C] This disclosure presents data on the clinical activity, safety, and tolerability of the formulation described herein. [Figure 16D] This disclosure presents data on the clinical activity, safety, and tolerability of the formulation described herein. [Figure 16E] This disclosure presents data on the clinical activity, safety, and tolerability of the formulation described herein. [Figure 16F] This disclosure presents data on the clinical activity, safety, and tolerability of the formulation described herein. [Figure 16G] This disclosure presents data on the clinical activity, safety, and tolerability of the formulation described herein. [Modes for carrying out the invention]

[0038] The following detailed descriptions are illustrative and explanatory, and are intended to further illustrate the disclosures described herein. Other advantages and novel features will be readily apparent to those skilled in the art from the detailed description of the disclosures described below.

[0039] This disclosure provides one or more pharmaceutical formulations comprising an active ingredient in granular form compressed into a solid dosage form such as a tablet, methods for producing such formulations, kits, methods for treatment, and dosage forms, wherein the active ingredient is configured to modulate the Syk / JAK pathway so that such formulations can treat conditions associated with dysregulation of the Syk / JAK pathway (but not limited to cancer and inflammatory disorders, such as atopic dermatitis).

[0040] This disclosure includes novel formulations comprising pyrimido-pyridazinone compounds. The formulations described herein are useful in the treatment of patients with cancer and inflammatory disorders, such as atopic dermatitis, by administering one or more formulations to patients in need. The formulations described herein are particularly desirable due to their unexpectedly excellent stability profile and efficacy over a predetermined period of time.

[0041] In one embodiment, the pharmaceutical formulation described herein comprises finely powdered granules, the granules comprising an active ingredient, one or more granulation binders, one or more fillers, one or more disintegrants, and one or more antioxidants. The formulation may further contain extragranular components.

[0042] The active ingredient is represented by the following formula (I): [ka] (In the formula, R 1 Equation (II): [ka] (In the formula, R 3 It is a six-membered ring of H, OH, C(O)OH, C1-C6 alkyl, or (C1-C6)alkylCN; R 2 Equation (III): [ka] (In the formula, R4 is equation (IV): [ka] The formulation may contain a compound of a benzene ring (a 6-membered ring of which R5 is N or CH, and R6 is a hydroxyl group, a methyl group, or an ethyl group) or a pharmaceutically acceptable salt or prodrug thereof, and the formulation shall have a total amount of API degradation impurities of approximately 0.6% or less of the total amount of active ingredients after being stored for one week in an open container at 40°C / 75%RH.

[0043] Compounds of formula (I) have one or more chiral centers, and it is specifically envisioned that mixtures of enantiomers, in addition to each of the separate enantiomers of the compound containing the active ingredient of the Disclosure, may also be used in the Formulations and Methods. Unless otherwise indicated, as disclosed herein, any chiral, enantiomer, and racemic mixture having a certain chemical structure is intended. Methods for preparing optically active compounds containing the active ingredient of the Formulations and Methods are well known in the Art, such as the resolution of racemic mixtures or synthesis from optically active starting materials.

[0044] The active ingredients of this disclosure can be prepared, for example, according to the methods disclosed in U.S. Patent No. 8,729,079 and U.S. Patent No. 9,382,277, the entirety of which is incorporated herein by reference. In some embodiments of this disclosure, the active ingredients, including the pharmaceutical formulations of this disclosure, may be present in amounts of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% w / w.

[0045] The active ingredients for use in the formulations and methods of this disclosure include compounds that modulate the Syk / JAK pathway. The modulatory activity of the active ingredients of this disclosure makes these compounds useful in the manufacture of pharmaceutical formulations that can be used to treat inflammatory disorders such as atopic dermatitis, or cancers characterized by the presence of solid tumors, particularly melanoma, colorectal cancer, non-small cell lung cancer, bladder cancer, and breast cancer.

[0046] In certain embodiments, the active ingredient is 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile. In other embodiments, the active ingredient is 2-(1-(4-((4-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile.

[0047] Accordingly, this disclosure provides stable or stabilized pharmaceutical formulations comprising the active ingredients of this disclosure as described herein, for example, stable or stabilized formulations comprising one or more compounds of formula (I) or their enantiomers, prodrugs, pharmaceutically acceptable salts, or free bases. The stability of formulations according to this disclosure can be determined, for example, by measuring the physical state of the active ingredients. In one embodiment, the active ingredients retain their stability and efficacy after being stored for a predetermined time under predetermined conditions.

[0048] As used herein, the term "substantially granular" means that the majority of the active ingredients in the pharmaceutical compositions described herein are in granular form, preferably in the form of finely ground granules, which are compressed into tablets. In certain embodiments, "substantially granular" means that the particle size of the granules is less than about 20 microns.

[0049] As described above, the active ingredients of this disclosure are maintained in substantially granular form by combining the active ingredients with one or more stabilizing components. Stabilizing components suitable for use according to this disclosure include, as further described herein, one or more granulating binders; one or more fillers; one or more disintegrants; and one or more antioxidants.

[0050] The method of formulating the active ingredient and stabilizing ingredients can also affect stability. For example, granules suitable for incorporation into compressed tablets and maintaining long-term stability can be formed by: mixing the granular components containing the active ingredient with one or more fillers, one or more disintegrants, and one or more antioxidants; granulating the mixed granular components while adding a solution of 10% w / w of one or more granulation binders dissolved in 99% v / v isopropyl alcohol until granules are formed; and then drying and grinding the granules to produce finely powdered granules.

[0051] In some embodiments, the formulations of the Disclosure are stable after exposure to predetermined conditions for a predetermined time. For example, the pharmaceutical formulations of the Disclosure can be stored in a specified or predetermined container, for a specified or predetermined period, at various predetermined temperatures and relative humiditys, for example, in an open or closed container. In some embodiments, the formulations of the Disclosure are stable at approximately 5, 25, 30, 37, 40, or 45 degrees Celsius and approximately 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, with a maximum of at least approximately 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5. It remains stable after storage for 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 20, 25, 30, 35, 40, 45, 48, 50, 51, 52, 53, 55, or 60 hours, 1 week, 2 weeks, 3 weeks, or 4 weeks; and after storage for 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

[0052] In certain embodiments, the formulations of the present disclosure remain stable after being stored in an open or closed container for: at least about 20 hours at about 30 degrees Celsius and about 90 percent relative humidity; at least about 1, 2, or 3 weeks at about 40 degrees Celsius and about 60 percent relative humidity; at least about 1, 2, or 3 weeks at about 40 degrees Celsius and about 75 percent relative humidity; at least about 1 month at about 25 degrees Celsius and about 60 percent relative humidity; at least 1 month at about 40 degrees Celsius and about 75 percent relative humidity; at least about 3 months at about 25 degrees Celsius and about 75 percent relative humidity; or at least about 3 months at 5 degrees Celsius and an optional relative humidity. In some embodiments, “storage in an open container” means that the container was opened twice a day but kept closed for a given period, for example, up to 4 weeks.

[0053] In other embodiments, the formulation contains the active ingredient 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile or the active ingredient 2-(1-(4-((4-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile, stored in an open or closed container at approximately 30 degrees Celsius. It remains stable after being stored at approximately 20 hours at 90 degrees Celsius and 60 percent relative humidity; at approximately 1, 2, or 3 weeks at approximately 40 degrees Celsius and 60 percent relative humidity; at approximately 1, 2, or 3 weeks at approximately 75 percent relative humidity; at approximately 25 degrees Celsius and 60 percent relative humidity for at least 1 month; at approximately 40 degrees Celsius and 75 percent relative humidity for at least 1 month; at approximately 3 months at approximately 25 degrees Celsius and 75 percent relative humidity; or at 3 months at 5 degrees Celsius and any selected relative humidity.

[0054] Other physical properties of the pharmaceutical formulations of this disclosure can also be tested, for example, by exposing them to predetermined conditions, such as temperature and relative humidity, in open and closed containers and evaluating the amount of active ingredient and / or impurities in the formulation at the end of a predetermined time. Suitable methods for measuring the impurity profile of the formulations are known in the art. Exemplary methods for measuring the impurity profile of the formulations may include any suitable chromatographic separation method, such as high-performance liquid chromatography (HPLC), including the use of separation columns and gradient elution, as is known to those skilled in the art. An exemplary HPLC method for evaluating the amount of active ingredient and / or impurities in the pharmaceutical formulations of this disclosure is described below in Example 1. Furthermore, other methods, including capillary electrophoresis, electron spin resonance, gas-liquid chromatography, gravimetric analysis, solid-phase extraction, liquid-liquid extraction, ultraviolet spectroscopy, infrared spectroscopy, supercritical fluid extraction column chromatography, mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, and Raman spectroscopy, may be used instead of or in addition to HPLC separation methods.

[0055] In some embodiments, impurity testing includes exposing the formulation to storage conditions of 40 degrees Celsius and 75% relative humidity in open and closed containers. In other embodiments, impurity testing includes exposing the formulation to storage conditions of accelerated stress at 60 degrees Celsius in a closed container. In other embodiments, the amount of impurities can be evaluated after the formulation has been stored in an open container at 40 degrees Celsius and 75% relative humidity for one week.

[0056] The physical properties of the pharmaceutical formulations disclosed herein, such as vitamin E content, can also be tested by any appropriate analytical method, for example, by an HPLC method including isocratic elution and UV detection using water and acetonitrile as mobile phases, as described later in Example 1.

[0057] While exemplary amounts or ranges of the active ingredient and other ingredients are indicated, the pharmaceutical formulations of this disclosure may contain these ingredients in any amount suitable for the purpose of obtaining the desired pharmacological properties and stability described herein. In addition to the active ingredient, the pharmaceutical compositions of this disclosure may also contain other pharmaceutically acceptable excipients, such as adjuvants, antioxidants, binders, buffers, coatings, colorants, compression aids, diluents, disintegrants, emulsifiers, emollients, encapsulating agents, fillers, flavoring agents, fluidizers, granulators, lubricants, metal chelators, osmotic pressure modifiers, pH modifiers, preservatives, solubilizers, adsorbents, stabilizers, sweeteners, surfactants, suspending agents, thickeners, or viscosity modifiers. Suitable excipients that can be used in the pharmaceutical compositions of this disclosure are, for example, described in "Handbook of Pharmaceutical Excipients," 5th Edition, Eds.: Rowe, Sheskey, and Owen, APhA Publications (Washington, DC), December 14, 2005, the contents of which are incorporated herein by reference.

[0058] In certain embodiments, the pharmaceutical compositions of the Disclosure may be compressed into unit dosage forms, such as tablets or caplets, or added to unit dosage forms, such as compressed tablets. In further embodiments, the pharmaceutical compositions of the Disclosure may be formulated for administration as micronized granules or as a suspension of micronized granules. Pharmaceutical formulations of the Disclosure comprising micronized granules or a suspension thereof may be sprinkled or mixed into a semi-solid carrier, such as applesauce or other foods, for administration to a subject. Formulations comprising micronized granules or a suspension thereof may also be prepared by adding them to a liquid carrier suitable for administration to a subject, such as an aqueous solution of about 2% w / V hydroxypropylcellulose and about 0.1% w / V polysorbate 80 or an aqueous solution of about 0.2% hydroxypropylcellulose and 0.1% Tween 80 to create a suspension.

[0059] In one embodiment, the dosage form of the Disclosure may contain compressed tablets in, for example, about 25, 50, 75, 80, or 100 mg. In another embodiment, the dosage form of the Disclosure may contain capsules in, for example, about 25, 50, 75, 80, or 100 mg. In a further embodiment, the dosage form of the Disclosure is a tablet containing, for example, about 25, 50, 75, 80, or 100 mg of micronized granules of the active ingredient. In another embodiment, the dosage form of the Disclosure is a capsule containing, for example, about 25, 50, 75, 80, or 100 mg of micronized granules. In one embodiment, the dosage form of the Disclosure is a capsule containing, for example, about 75 mg of micronized granules.

[0060] Suitable techniques for formulating the pharmaceutical compositions of this disclosure into tablets are known in the art and may include mixing the active ingredient and stabilizing ingredient with one or more pharmaceutically acceptable tableting excipients, and compressing the mixture into tablets, for example, in a tablet press. The amount and properties of the tableting excipients used can be easily selected based on desired characteristics of the tablet, such as size, hardness, abrasion resistance, etc. Tablets containing the pharmaceutical compositions of this disclosure may also be coated with a film coating, such as Opadry White®, or with an enteric coating designed to prevent the tablet from dissolving until it passes through the stomach and / or into the upper intestines. Suitable tablet coatings and methods for applying them are known in the art.

[0061] Suitable techniques for formulating the pharmaceutical compositions of this disclosure into capsules are also known in the art, and may include mixing the active ingredient and stabilizing ingredient with one or more pharmaceutically acceptable capsule excipients, and filling the mixture into capsules. In one embodiment, the pharmaceutical formulation of this disclosure (with or without additional excipients) may be filled into capsules, for example, hard gelatin capsules. The hard gelatin capsules may be of any suitable size, for example, size "0", "0EL", "3", "4", etc. For example, in one embodiment, the capsule of this disclosure may be filled with the active ingredient in a size 4 hard gelatin capsule with an active ingredient content of 25 mg, and the target capsule filling amount may be 100 mg. In another embodiment, the active ingredient of the capsule of this disclosure may be filled with the active ingredient in a size 0el hard gelatin capsule with an active ingredient content of 100 mg, and the target capsule filling amount may be 400 mg.

[0062] This specification also provides a kit comprising at least one dosage form of the present disclosure, for example, a tablet or capsule, and instructions for administering this at least one dosage form. The kit may also include packaging or a container for housing at least one dosage form of the present disclosure, and may include instructions for storage, use, dosage, etc., and / or a package insert relating to the active ingredient. The kit may also include instructions for monitoring the blood concentration of the active ingredient (or its metabolites) after administration, and optionally, materials for performing this type of test, for example, reagents, well plates, containers, markers, labeling agents, etc. Other suitable components to be included in the kit of the present disclosure will be readily apparent to those skilled in the art by considering the desired indication, administration plan, storage conditions, and route of administration.

[0063] The pharmaceutical compositions of this disclosure can be formulated for administration in single doses or in repeated doses for continuous or intermittent, discontinuous administration. For continuous administration, the kit may optionally include instructions for administering the pharmaceutical compositions of this disclosure in individual unit dosage forms (e.g., tablets or capsules) for a predetermined period or as prescribed, for example, more than once daily, twice daily (BID), four times daily (QID), once daily, once weekly, or once monthly. If the pharmaceutical compositions of this disclosure are delivered discontinuously and regularly, the kit may include a placebo for periods when individual unit dosage forms are not delivered. In some embodiments, the formulations of this disclosure may be administered in doses of approximately 10 mg BID, approximately 20 mg BID, approximately 30 mg BID, approximately 40 mg BID, approximately 50 mg BID, approximately 75 mg BID, approximately 100 mg BID, approximately 80 mg QID, or approximately 120 mg QID. In one embodiment, the formulation of the present disclosure can be administered in a dose of approximately 75 mg BID.

[0064] Suitable packaging or containers are known in the art for containing and dispensing pharmaceuticals for regular oral use. In one embodiment, the packaging may include an indicator showing each dose period. In other embodiments, the packaging may include a marked blister pack, a graduated dispenser package, or a bottle. The kits of the present disclosure may also include means for containing any type of packaging containing unit dosage forms, such as bottles or vials, which may be held in, for example, commercial close confinements, such as injection-molded or blow-molded plastic containers.

[0065] The pharmaceutical compositions, therapeutic methods, dosage forms, and kits of this disclosure are useful for treating conditions associated with dysregulation (e.g., abnormality or dysfunction) of the Syk / JAK pathway. In one embodiment, this condition is associated with dysregulation of the Syk / JAK2 pathway. In one embodiment, the condition associated with dysregulation of the Syk / JAK pathway includes acute or chronic inflammatory disorders such as atopic dermatitis. In one embodiment, the condition associated with dysregulation of the Syk / JAK pathway includes diseases associated with abnormal cell proliferation. The term "abnormal cell proliferation" refers to the uncontrolled proliferation of cells that are naturally present in the mammalian body. In one embodiment, the disease characterized by abnormal cell proliferation is cancer, for example, cancer of the prostate, head, neck, eye, mouth, pharynx, esophagus, bronchi, larynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus, cervix, breast, ovary, vagina, testicle, skin, thyroid, blood, lymph node, kidney, liver, intestine, pancreas, brain, central nervous system, adrenal gland, skin, or leukemia or lymphoma. In one embodiment, the disease characterized by abnormal cell proliferation is prostate cancer. In another embodiment, the abnormal cell proliferation is associated with at least one type of solid tumor.

[0066] In one embodiment, the pharmaceutical compositions, therapeutic methods, dosage forms, and kits of the present disclosure are not limited to, but include, peripheral T-cell lymphoma (PTCL), chronic lymphocytic leukemia (CLL), myelofibrosis (MF), such as primary myelofibrosis (PMF), essential thrombocytopenia (ET), and polycythemia vera (PV), and mature B-cell tumors, such as active B-cell type (ABC) subtype and germinal center B-cell type (GCB) subtype. Both types of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, high-grade B-cell lymphoma (HGBL), anaplastic large cell lymphoma, marginal zone lymphoma, hairy cell leukemia, primary macroglobulinemia, monoclonal carcinoma of unknown significance (MGUS), plasma cell myeloma, Burkitt lymphoma, mature T and NK cell tumors, Hodgkin lymphoma, post-transplant lymphoproliferative disorder (PTLD), histiocytic and Dendritic cell tumors, myeloid tumors, e.g., PV, ET, primary myelofibrosis, chronic neutrophilic leukemia, chronic myeloid leukemia, atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, and acute myeloid leukemia, progenitor lymphoid tumors, e.g., B-cell acute lymphoblastic leukemia (B-ALL), acute lymphoblastic leukemia associated with Down syndrome, T-cell acute lymphoblastic leukemia (T-ALL), mature lymphocyte tumors, e.g., T-cell prolymphocytic leukemia. It is useful in the treatment of hematological conditions, including adult T-cell leukemia / lymphoma (ATLL), NK / T-cell lymphoma (NK / TCL), NK / T-cell large granular lymphocytic leukemia (NK / T-LGL), primary mediastinal large B-cell lymphoma / Hodgkin lymphoma (PBMCL / HL), and follicular lymphoma (FL), primary cutaneous lymphoma (PCL), such as mycosis fungoides / Sézary syndrome and / or peripheral T-cell lymphoma (PTCL). Other conditions, but not limited to these, include acute and chronic graft-versus-host disease (aGVHD and cGVHD) and immune-mediated complications from checkpoint inhibitors or other cancer immunotherapies.A list of hematological malignancies induced by JAK or SYK is provided in the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms; Blood 2016 127:2375-2390, which is incorporated herein by reference. Known hematological malignancies with JAK mutations are provided in Haematologica. 2015 Oct; 100(10):1240-1253, which is incorporated herein by reference.

[0067] In other embodiments, conditions associated with dysregulation of the Syk / JAK pathway include acute or chronic inflammatory disorders, such as neutrophil-involved inflammation, inflammatory arthritis, inflammation of peritonitis, inflammation after myocardial infarction, or bleomycin-induced pulmonary fibrosis. Models for testing the ability of compounds to alleviate inflammation in inflammatory arthritis are known, for example, as described in Camps et al, Nature Med., 2005, 11, 936-943, which also describes a model useful for evaluating the ability of compounds to alleviate inflammation in peritonitis; a model for testing the ability of compounds to alleviate inflammation and / or enhance healing after myocardial infarction is described in Siragusa et al, Circ. Res. (2010), 106, 757-768; and models for testing the ability of compounds to prevent bleomycin-induced pulmonary fibrosis are described in Wei et al, Biochem Biophys Res Comm. 2010, 397:311-317 and Brent et al, Toxicology, 2000, 147:1-13, the entirety of these disclosures is incorporated herein by reference.

[0068] In one embodiment, the present disclosure provides formulations, methods, kits, and dosage forms for the treatment of a wide range of autoimmune diseases, including, but not limited to, atopic dermatitis, alopecia areata, eczema of the hands and feet, sweat gland abscesses, pemphigus vulgaris, psoriasis, cutaneous lupus, vitiligo, inflammatory bowel disease (UC, CD), rheumatoid arthritis, asthma, allergic rhinitis, systemic lupus erythematosus (SLE), psoriatic arthritis, and multiple sclerosis (including other autoimmune diseases).

[0069] Accordingly, this disclosure provides a method for treating a disease characterized by dysregulation (e.g., abnormality or dysfunction) of the Syk / JAK pathway of a subject, comprising administering the subject a therapeutically effective amount of an active ingredient in one or more dosage forms, wherein the dosage form comprises a pharmaceutical preparation containing the active ingredient, the active ingredient being in the form of finely ground granules formed into compressed tablets, the active ingredient comprising a compound of formula (I), and the active ingredient maintaining stability even after the pharmaceutical preparation is stored for a predetermined time under predetermined conditions.

[0070] As described herein, the therapeutically effective dose of the active ingredient herein is an amount that, when used in the treatment of cancer, is capable of, for example, reducing the number of cancer cells in a fluid (e.g., blood, peripheral cells, or lymph), reducing tumor size, inhibiting metastasis, inhibiting tumor growth, and / or improving the symptoms of one or more types of cancer. In cancer therapy, efficacy can be measured, for example, by evaluating the time to disease progression and / or determining the response rate, or by measuring the inhibition of tumor growth or metastasis. In one embodiment, administration of the formulation described herein can inhibit tumor growth by an amount of 0% to 100%, preferably more than about 50%.

[0071] As described herein, the therapeutically effective dose of the active ingredient herein is an amount that, when used to treat inflammatory disorders such as atopic dermatitis, can delay the onset of an inflammatory response, reduce its severity, shorten its duration, or alleviate one or more symptoms of an inflammatory response. When treating inflammatory disorders, efficacy can be measured, for example, by reducing physiological signs of inflammation (e.g., redness, swelling, fever, loss of function) or by measuring changes in the amount of inflammation-related cells (e.g., monocytes, macrophages, and other mononuclear cells) or molecules (e.g., pro-inflammatory cytokines). In one embodiment, the treatment of atopic dermatitis can be measured by evaluating the subject according to the Intensive Galactic Assessment (IGA) score, the 5-D pruritus scale, the Pruritus Numeric Rating Scale, or the Eczema Area and Severity Index (EASI) evaluation method, as described, for example, in Figures 3 and 4 and in Example 3 below.

[0072] The Syk / JAK pathway is known to be deregulated in various cancers due to specific mutations in different members of the pathway. For example, the recently identified JAK2 V617F Abnormalities in the Syk / JAK pathway, such as those resulting from mutations or translocations of the JAK2 gene, are underlying causes of leukemia and other myeloproliferative disorders. Such mutations can be readily detected in tumor samples using the method of Sarkar et al. (Diagn Mol Pathol. (1995) 4(4):266-73), which is known in the art. This entire disclosure is incorporated herein by reference.

[0073] Identification (also referred to herein as "preliminary determination" or "selection") of mammalian subjects, such as human patients, or populations of such subjects, who will respond favorably to treatment with the pharmaceutical formulations of the present disclosure, prior to the start of treatment, can be done by examining a sample taken from the patient (e.g., a tumor biopsy or a blood sample containing white blood cells if the condition is cancer) to detect one or more of the Syk / JAK mutations described above. After detecting a Syk / JAK mutation, the subject can be treated by administering to the subject one or more pharmaceutical formulations of the present disclosure, for example, containing a therapeutically effective amount of an active ingredient as described herein.

[0074] Suitable samples can be taken from the body of the subject and can include, for example, tissue samples, cells, extracellular substances, or cancer cells circulating in the blood or lymph. Tissue samples can be from any organ such as the skin (including the pathology of such organs), the blood circulatory system, and can be from any circulating tumor cells. Tissue samples such as tumor biopsies can be taken using known procedures. Tissue specimens can also include, for example, xenograft tumor samples from animals used in drug dosage studies or toxicity studies.

[0075] For example, a subject can be tested for the presence of a JAK2 V617F mutation. As described above, these mutations can be detected using any suitable technique known in the art, such as fluorescence in situ hybridization, sequencing based on PCR of the relevant portion of a given gene, restriction fragment length polymorphism analysis, or by monitoring the expression level of a given gene product (e.g., protein or RNA). In one embodiment, a method for treating a condition that can be treated by inhibiting the Syk / JAK pathway, comprising selecting a subject having a JAK2 V617F mutation; and administering a therapeutically effective amount of a pharmaceutical formulation of the present disclosure. In one embodiment, JAK2 v617FA method is provided for treating a patient with cancer characterized by the presence of mutations and translocations in the JAK2 gene, the method comprising the steps of identifying a patient having such mutations and administering a therapeutically effective amount of the formulation disclosed herein.

[0076] In one embodiment, the Disclosure provides a pharmaceutical formulation comprising granules, the granules comprising: a finely pulverized active ingredient; one or more granulation binders; one or more fillers; one or more disintegrants; and one or more antioxidants, wherein the active ingredient is a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, and the formulation may further comprise extragranular components. In one embodiment, the active ingredient comprises 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazine-2-yl)piperidine-4-yl)acetonitrile. In other embodiments, the active ingredient comprises 2-(1-(4-((4-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile.

[0077] In one embodiment, the antioxidant of the formulation described herein may include vitamin E or butylated hydroxytoluene; the filler may include lactose monohydrate; the disintegrant may include crospovidone or croscarmellose sodium; and the granulation binder may include polyvinylpyrrolidone or hydroxypropyl cellulose. In a particular embodiment, the granulation binder contains hydroxypropyl cellulose having a viscosity of 75 to 150 centipoise at 25°C in a 5% w / w aqueous solution. In a particular embodiment, the granulation binder contains polyvinylpyrrolidone having a number average molecular weight of about 30,000. In one embodiment, the micronized granules of the formulation described herein have a particle size of less than about 20 microns. In one embodiment, the isopropyl alcohol content of the micronized granules is less than about 5000 ppm.

[0078] In certain embodiments, the formulation may include one or more extragranular components. The extragranular components may include one or more tableting fillers, one or more disintegrants, one or more lubricants, and optionally one or more surfactants. In certain embodiments, the tableting filler may include microcrystalline cellulose, the disintegrant may include croscarmellose sodium, the surfactant may include sodium lauryl sulfate, and the lubricant may include magnesium stearate. In one embodiment, the micronized granules and extragranular components may be compressed into tablets.

[0079] The formulations of this disclosure may exist in any embodiment known to those skilled in the art. In one embodiment, the formulations may exist in the form of tablets, scored tablets, compressed tablets, coated tablets, capsules, caplets, pills, powders, and variations thereof. In one embodiment, the formulations described herein include compressed tablets.

[0080] In one embodiment, the isopropyl alcohol content of the micronized granules of the formulation is less than about 5000 ppm. The active ingredient in the embodiments described herein may be between about 5 and 50 mg, 5 mg, about 20 mg, or about 50 mg. Other embodiments of the embodiments described herein may include a tablet hardness of about 5 to 12 kP or 7 to 9 kP, and a disintegration time of less than about 5 minutes at 37°C in 0.1 N HCl, pH 6.8, and 50 mM phosphate buffer. In certain embodiments, the formulation may include tablets having an aesthetically pleasing coating; the coating may consist of hydroxypropyl cellulose, titanium dioxide, talc, and polyethylene glycol.

[0081] In one embodiment, the formulation described herein comprises a compressed tablet having micronized granules and extragranular components: the total weight of the tablet is about 150 mg; the micronized granules contain about 5 to 50 mg of an active ingredient, about 75 to 900 mg or 118.6 to 736 mg of lactose monohydrate, about 1 to 20 mg or 4.5 mg of croscarmellose sodium, about 0.1 to 5 mg or 0.15 mg of vitamin E, and about 1 to 10 mg or 4.5 mg of a granulation binder; further, the extragranular components may include about 5 to 20 mg or 11.25 mg of microcrystalline cellulose, about 1 to 10 mg or 4.5 mg of croscarmellose sodium, about 1 to 10 mg or 1.5 mg of magnesium stearate, and about 1 to 10 mg or 6 mg of enteric coating. The active ingredient in such embodiments may include 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile.

[0082] In certain embodiments of this type of compressed tablet, the granulation binder can be selected from the group consisting of polyvinylpyrrolidone and hydroxypropylcellulose, the viscosity of hydroxypropylcellulose in a 5% w / w aqueous solution at 25°C being 75 to 150 centipoise. In certain embodiments, the micronized granules contain about 75 to 150 mg or 117.1 mg to about 72.1 mg of lactose monohydrate, and the extragranular components further contain about 1 to 10 mg or 1.5 mg of sodium lauryl sulfate.

[0083] In certain embodiments, the micronized granules of the compressed tablets described herein may contain about 5 mg of the active ingredient and about 118.6 mg of lactose monohydrate, about 20 mg of the active ingredient and about 103.6 mg of lactose monohydrate, or about 50 mg of the active ingredient and about 73.6 mg of lactose monohydrate.

[0084] This specification further includes embodiments that include methods for producing the embodiments of the pharmaceutical formulations described above. It also includes methods for preparing compressed tablets, methods for stabilizing pharmaceutical formulations, and methods for preparing dosage forms, including compressing pulverized granules and extragranular components into tablets. In one embodiment, the methods, protocols, and procedures relating to the above include mixing the active ingredient with an antioxidant containing vitamin E or butylated hydroxytoluene; a filler containing lactose monohydrate; a disintegrant containing crospovidone or croscarmellose sodium; and a granulation binder containing polyvinylpyrrolidone or hydroxypropyl cellulose. In certain embodiments, the granulation binder contains hydroxypropyl cellulose having a viscosity of 75 to 150 centipoise at 25°C in a 5% w / w aqueous solution. In certain embodiments, the granulation binder contains polyvinylpyrrolidone having a number-average molecular weight of about 30,000. In one embodiment, the pulverized granules of the embodiments described herein have a particle size of less than about 20 microns. In one embodiment, the isopropyl alcohol content of the micronized granules is less than approximately 5000 ppm.

[0085] In one embodiment, the formulation may further contain one or more extragranular components. The extragranular components may include one or more tableting fillers, one or more disintegrants, one or more lubricants, and optionally one or more surfactants. In certain embodiments, the tableting filler may include microcrystalline cellulose, the disintegrant may include croscarmellose sodium, the surfactant may include sodium lauryl sulfate, and the lubricant may include magnesium stearate. In one embodiment, the micronized granules and extragranular components can be compressed into tablets.

[0086] In one embodiment, the active ingredient for the above may include 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimide[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile. In another embodiment, the active ingredient may include 2-(1-(4-((4-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimide[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile.

[0087] In the above embodiment, the manufacturing and producing method may include: mixing a granular component containing the active ingredient with one or more fillers, one or more disintegrants, and one or more antioxidants; granulating the mixed granular component with a solution of 10% w / w of one or more granulation binders dissolved in 99% v / v isopropyl alcohol until granules are formed; and drying and grinding to produce finely powdered granules, wherein the active ingredient comprises a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

[0088] In further embodiments, kits are also provided that include one or more dosage forms and instructions for administering the dosage forms, the dosage forms comprising granules compressed into tablets and extragranular components. In such embodiments, the formulation may include an active ingredient comprising 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimide[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile. In other embodiments, the active ingredient may include 2-(1-(4-((4-(4-(2-hydroxyethyl)piperazine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimide[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile.

[0089] The above embodiments can be used in methods for treating a target cancer or atopic dermatitis or inflammation, comprising administering to the target a therapeutically effective amount of an active ingredient in one or more dosage forms, the dosage forms comprising micronized granules compressed into tablets and extragranular components.

[0090] The active ingredients of this disclosure can be prepared, for example, according to the methods disclosed in U.S. Patent No. 8,729,079 and U.S. Patent No. 9,382,277, the entirety of which disclosure is incorporated herein by reference. In some embodiments of this disclosure, the active ingredients constituting the pharmaceutical formulations of this disclosure may be present in amounts of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% w / w.

[0091] The active ingredients for use in this formulation and method include compounds that modulate the Syk / JAK pathway. Due to the modulating activity of the active ingredients of this disclosure, these compounds are useful in the manufacture of pharmaceutical formulations that can be used to treat inflammatory disorders, including atopic dermatitis, or cancers characterized by the presence of solid tumors, particularly melanoma, colorectal cancer, non-small cell lung cancer, bladder cancer, and breast cancer.

[0092] The therapeutically effective dose of the pharmaceutical formulations of this disclosure provided to a subject will vary depending on the purpose of administration, the patient's condition, the level of disease penetration, etc. As used herein, “subject” includes any human or non-human animal requiring treatment with the pharmaceutical formulations of this disclosure. In one embodiment, the subject is any human being (sometimes referred to herein as “patient”) requiring treatment with the formulations of this disclosure. The therapeutically effective dose of the active ingredient in the pharmaceutical formulations of this disclosure can be determined by a physician or medical professional of ordinary knowledge, taking into account the patient’s specific condition and certain variables including size, age, weight, sex, disease penetration, prior treatment, and response pattern.

[0093] In one embodiment, the pharmaceutical formulation is administered orally, for example, in the form of capsules or tablets. For example, the formulation may be provided in unit doses, for example, as compressed tablets containing a therapeutically effective dose. In one embodiment, a unit dose comprising the pharmaceutical formulation of the Disclosure may be administered once or multiple times a day, for example, 1 to 6 times at 12 or 24-hour intervals. When multiple unit doses are administered within a given time period, they may be administered at substantially equal time intervals. For example, when administering two unit doses over a 12-hour period, they may be given to the patient with a 6-hour interval between doses. Multiple unit doses may also be administered at substantially unequal time intervals within a given period. In one embodiment, a unit dose comprises the dosage form of the Disclosure in the form of orally administered tablets or capsules.

[0094] In some embodiments, the active ingredient in the pharmaceutical formulation of the Disclosure may constitute about 0.5 to 100 percent by weight, for example, about 0.5, 1, 1.5, 2, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100 percent by weight. In other embodiments, the active ingredient may constitute about 3.5 percent or about 14 percent by weight of the pharmaceutical formulation.

[0095] In some embodiments, the formulations of the Disclosure comprise the active ingredient of the Disclosure in the form of tablets, capsules, powders, suspensions, etc., formed into oral dosage forms. In these types of dosage forms of the Disclosure, the amount of the active ingredient constituting the dosage form may be any preferred amount, for example, about 0.5, 1, 1.5, 2, 2, 5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100 mg per unit dosage form. In certain embodiments, the dosage forms of the Disclosure comprise about 20 to about 80 mg of the active ingredient per dosage form.

[0096] In certain embodiments, the formulations of the Disclosure include the active ingredient of the Disclosure formed into dosage forms such as tablets, capsules, sachets, powders, suspensions, and suppositories. In such dosage forms of the Disclosure, the amount of the active ingredient constituting the dosage form may be any preferred amount, for example, about 0.5, 1, 1.5, 2, 2, 5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100 mg per unit dosage form. In certain embodiments, the dosage forms of the Disclosure contain about 25, 50, 75, 80, or 100 mg of the active ingredient per dosage form. In one embodiment, the dosage form of the Disclosure contains about 75 mg of the active ingredient per dosage form.

[0097] The preferred daily (i.e., 24-hour) doses according to the methods of this disclosure may depend on the specific treatment method and the condition being treated, regardless of whether they are administered all at once or in multiple doses. In one embodiment, the preferred daily dose, whether administered all at once or in multiple doses, is between approximately 10 and 120 mg when administered orally, for example, between approximately 20 mg to 80 mg, 25 to 75 mg, 30 mg to 70 mg, 35 mg to 65 mg, or 40 mg to 60 mg. In one embodiment, the preferred daily dose is approximately 40 mg to approximately 80 mg. In other embodiments, the preferred daily doses are approximately 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, or 120 mg. In one embodiment, a suitable daily dose is approximately 20 mg. In another embodiment, a suitable daily dose is approximately 40 mg. In yet another embodiment, a suitable daily dose is approximately 80 mg.

[0098] In other embodiments, preferred daily (i.e., 24-hour) doses by the methods of the present disclosure may depend on the specific treatment method and the condition being treated, whether administered all at once or in multiple doses. In one embodiment, preferred daily doses, whether administered all at once or in multiple doses, are between approximately 10 and 1000 mg when administered orally, for example, between approximately 20 and 500 mg, 50 mg and 250 mg, or 75 mg and 100 mg. In other embodiments, preferred daily doses are approximately 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg.

[0099] In other embodiments, preferred daily doses, whether administered all at once or in multiple doses, are approximately 0.1 mg / kg to approximately 100 mg / kg, approximately 0.5 mg / kg to approximately 75 mg / kg, approximately 0.1 mg / kg, 1 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 μg / kg, 75 μg / kg, or 100 μg / kg.

[0100] The therapeutically effective dose can be administered on a regular schedule, i.e., once daily, once weekly, once monthly, or once year, or on an irregular schedule with varying administration days, weeks, or months. Alternatively, the therapeutically effective dose to be administered can be varied. In one embodiment, the therapeutically effective dose of the initial dose is higher than the therapeutically effective dose of one or more subsequent doses. In another embodiment, the therapeutically effective dose of the initial dose is lower than the therapeutically effective dose of one or more subsequent doses. Equal doses can be administered at intervals of varying lengths, but not limited to, approximately every 2 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 1 week, 2 weeks, 3 weeks, 1 month, and 2 months. Alternatively, equal doses can be administered at uneven time intervals as recommended by the healthcare professional. The number and frequency of administrations corresponding to the entire course of treatment will be determined at the discretion of the healthcare professional. The therapeutically effective dose as described herein refers to the total amount administered over a given period. That is, if more than one active ingredient is administered, the therapeutically effective dose is equivalent to the total amount administered.

[0101] In one embodiment, the pharmaceutical formulation is administered orally once daily (QD). Administration can be short-term or long-term. For example, short-term administration may include administering the pharmaceutical formulation once daily for about one week, two weeks, three weeks, or four weeks, or for any other period longer or shorter than that. For example, long-term administration may include administering the pharmaceutical formulation once daily for at least one week, two weeks, three weeks, four weeks, 30 days, one month, two months, three months, six months, one year, two years, or five years, or for any period longer or shorter than that.

[0102] The following embodiments are provided to illustrate exemplary embodiments of the present disclosure. However, the present disclosure should not be understood as being limited to the specific conditions or details described in these embodiments. [Examples]

[0103] Example 1 Pre-formulation, formulation, and analytical data The analytical results for 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile are shown in Tables 1-3 below. Table 1 shows the results of the pH-dependent solubility profile test of HCl, Table 2 shows the results of the solubility profile of HCl in organic solvents, and Table 3 shows the results of the stress test of the HCl salt. [Table 1] [Table 2] [Table 3]

[0104] Tests were conducted to evaluate the compatibility, stability, and disintegration of excipients, including the use of Ac-Di-Sol, Polyplasdone XL-10; PVP K-30, and Crucel LF and SLS. IPA was used instead of water to avoid dissolving the granules. Tablets containing 5 / 20 / 50 mg of each substance, weighing 150 mg, were formulated using a coating containing Opadry (IPA / water, 50 / 50) (DT: <5 minutes in 0.1N HCl, pH 6.8, 50 mM PO4 buffer). Details of the components and relative weights of prototype formulations A and B are shown in Table 4 below. [Table 4]

[0105] In additional tests, residual solvent was evaluated in tablets using IPA as the granulation solvent. The results are shown in Table 5. [Table 5]

[0106] The formulation screening method included screening the first batch under accelerated storage conditions in open and closed containers at 40°C / 75%RH. The other batches were screened under accelerated stress conditions in closed containers at 60°C. Stability data are shown in Table 6. [Table 6]

[0107] The analytical procedure for content uniformity, mixing uniformity, amount of active ingredient, and associated impurities (including degradation products) of the pharmaceutical formulations of this disclosure, including tablets containing the active ingredient (containing 5 mg, 20 mg, and 50 mg), included the use of HPLC. For separation, a column with dimensions of 4.6 × 150 mm and a particle size of 3.5 microns, packed with USP-compliant L1 packing material, was used. Gradient elution was used in the HPLC method, with a mobile phase of 1 mM ammonium formate, pH 3.2, and a buffer of 0.1% formic acid in acetonitrile. The eluted fraction was detected by 275 nm UV. Detailed analytical results of the prototype formulations after one week in an open container at 40°C / 75% RH are shown in Table 7. [Table 7] [Table 8]

[0108] The above-described formulation batches were prepared by micronizing the active ingredient, mixing it with granular and extragranular components to form tablets, and finally coating the tablets.

[0109] Micronization: The general procedure for micronizing the active ingredient involved using a Micronizer 4” SDM, micronizing batches of approximately 500–550 g. The micronization parameters are as follows: Inlet air pressure: 100 PSI Grinding chamber air pressure: 40 PSI Feeder nozzle: 20 PSI Number of passes: 1

[0110] In one embodiment, 512g of raw material was added to the supply chamber, and the weight of the material obtained after pulverization was 452g.

[0111] The following table shows the particle sizes of the active ingredients described herein as measured in hexane. [Table 9]

[0112] Figure 1 shows the analysis report of the particle size distribution of the active ingredient before micronization. Figure 2 shows the analysis report of the particle size distribution of the active ingredient after micronization.

[0113] Formulation composition: The formulation consists of two types of tablets containing 20 mg and 50 mg. Table 8b shows the evaluation of the residual solvent amount (isopropyl alcohol or "IPA") of the 20 mg tablet, and Table 8c shows the evaluation of PVP K30-IPA as the residual solvent amount (IPA) of the 50 mg tablet. The general procedure for manufacturing the formulation involved weighing the required granular materials, mixing them, grinding them in a mortar and pestle in a powder mixer, slowly adding a 10% w / w solution of IPA-PVP K30 to the powder while continuously mixing (adding additional 99% IPA as needed until granules were formed), drying the wet material in a 40°C oven for 30 minutes, passing the dried material through a Fitzmill (hammer forward, 0040 screen, speed 2500 RPM), weighing and measuring the required non-granular materials, adding them in the following order: VivaPure 101, primelose / Polyplasone XL-10, and SLS, mixing in a cylindrical mixer for 3-5 minutes, adding magnesium stearate, mixing in a cylindrical mixer for 1 minute, and compressing the formulation into tablets using an F-Press, maintaining a target value of 150 mg and a hardness of 9 kPa. [Table 10] [Table 11]

[0114] The coating formulation is shown in Table 8d below: [Table 12]

[0115] Stability data was compiled for eight prototype formulations. Details of these test results are shown in Tables 9a (40 degrees Celsius / 75 RH) and 9b (60 degrees Celsius). Formulations 1A, 1C, 2A, and 2C showed very high stability. [Table 13] [Table 14]

[0116] Further evaluations were conducted to test the antioxidant effects of formulations 1A, 1C, 2A, and 2C.

[0117] As shown in Tables 10a and 10b, evaluations including HPLC were performed to determine the DL-α-tocopherol (vitamin E) content of specific prototype formulations. For separation, a column with dimensions of 4.6 × 150 mm and a particle size of 3.5 microns, packed with USP-compliant L1 packing material, was used. The HPLC method utilized gradient elution and isocratic elution, with water and acetonitrile (97:3 v / v) as the mobile phase, and UV detection was performed at 294 nm. [Table 15] [Table 16]

[0118] To evaluate the compatibility, stability, and disintegration of excipients, further analyses were performed using 5 mg tablets: Ac-Di-Sol and polyplasdone XL-10; PVPK-30 and Crucel LF; and SLS. In addition, tablets with higher content were evaluated for stability, tablet properties, antioxidant effect (5 mg content), and polymorphism. Formulations A, B, C, and D shown in Table 11 were selected for further evaluation. [Table 17] [Table 18]

[0119] After further analysis, the following formulations (Table 12) were selected as promising candidates. [Table 19] [Table 20] [Table 21] [Table 22]

[0120] Example 2 Immediate-release formulations The immediate-release formulations of this disclosure, containing the micronized hydrochloride of the active ingredient described herein, were prepared in two active ingredient concentrations (5 mg and 20 mg) used in clinical trials. Table 13 shows the composition and amounts of the components of the 5 mg and 20 mg tablets. [Table 23]

[0121] The formulations shown in Table 13 further contain the active ingredients shown in Table 14. Each excipient is within the potency limits listed in the latest FDA Inactive Ingredient Guide (IIG) as applicable to the oral route of administration. Table 15 shows the quantitative composition of OpaDryWhite 03F180004. [Table 24] [Table 25] The aforementioned tablets were packaged with a 1g silica gel desiccant canister, then placed in a high-density polyethylene (HDPE) bottle with induction sealing, and sealed with a pediatric safety polypropylene screw cap.

[0122] Example 3 Evaluation of the clinical efficacy and tolerability of compound 1, a SYK / JAK dual inhibitor, in patients with moderate to severe atopic dermatitis. In Example 3, the safety, tolerability, and efficacy of Compound 1, as well as the pharmacokinetic (PK) profile and pharmacodynamic / biomarkers related to evidence of drug efficacy, were evaluated in subjects with moderate to severe atopic dermatitis.

[0123] Methods and study design: This study was conducted as a randomized, double-blind, placebo-controlled, multicenter, sequential dose-escalation study in subjects with moderate to severe atopic dermatitis. The study included a screening period (within 30 days) and a 4-week treatment period, followed by a 14-day follow-up observation period, with evaluations performed at the end of the study. Three dose-escalation cohorts were examined: 20, 40, and 80 mg QD. A total of 12 subjects were enrolled for each dose; 9 subjects received compound 1, and 3 subjects received placebo.

[0124] A total of approximately 36 subjects were randomly assigned to approximately 10 research sites in the United States and Canada. After blinded safety data review by the Safety Review Committee (SRC), doses were escalated. Dose escalation continued until the maximum tolerated dose (MTD) was determined. The dose at which ≥2 subjects in the same organ system category (or ≥3 subjects in any organ system category) experienced adverse events related to the investigational drug leading to treatment discontinuation was considered to have exceeded the maximum tolerated dose (MTD).

[0125] The next lower dose will be designated as the MTD (Mean Time To Treatment). All data, including evaluations up to the end of the 28-day treatment period (Day 29) for the relevant cohort, were included in the review. The SRC will review the blinded safety data and recommend initiating the next dose cohort or discontinuing dose escalation. To further confirm the MTD determination, lower or intermediate doses and alternative dosing schedules other than these proposed doses and schedules may be explored, supported by clinical data from the next lower dose cohort. Higher doses may also be evaluated, supported by new clinical data.

[0126] After obtaining informed consent, each subject underwent screening tests between Day 30 and Day 1 prior to the start of investigational drug administration. On Day 1 (baseline), eligible subjects were randomized, and their Day 1 / baseline values ​​were tested. Depending on the cohort and randomization schedule, they were administered 20, 40, or 80 mg of compound 1 or placebo. At this visit, PK / PD samples were collected within 8 hours prior to administration (within 12 hours at selected facilities). After the first administration of the investigational drug, subjects were monitored at the medical facility for 2 hours. On Day 2, subjects were brought back to the medical facility for PK and PD samples to be collected (24 hours after administration).

[0127] PK and PD samples were collected on Day 8 and Day 29 (the last day of treatment) before administration. On Day 15, PK / PD samples were also collected before administration and within 8 hours after administration. On Day 16, subjects were brought back to the hospital for further PK and PD samples (24 hours after administration). In addition to Days 8, 22, and 29, subjects were brought back to the hospital at the end of the post-observation period (Day 43) for additional safety tests. Disease evaluations were performed on Day 1, Day 15, and Day 29.

[0128] Figure 5 illustrates the study design, including the treatment duration, post-safety observation period, initial dose, and number of subjects. In the study design shown in Figure 5, nine subjects receiving the active treatment and three subjects receiving placebo were randomly assigned to each cohort. Figure 6 illustrates the patient characteristics. In the patient characteristics shown in Figure 6, the patients were not using topical or systemic steroids and required continuous application of emollients (once or twice daily).

[0129] Diagnostic and subject selection / exclusion criteria: Selection criteria: 1. You must be able to sign a consent form before proceeding with any procedures related to the exam. 2. Must be a male or female between the ages of 18 and 75. 3. The patient must have had chronic Alzheimer's disease (AD) diagnosed according to the Hanifin & Rajka criteria for at least six months prior to the screening visit (information obtained from medical records or patient history). 4. The Eczema Area and Severity Index (EASI) score at baseline visit must be ≥16. 5. The Intensive Gathering Assessment (IGA) score by the attending physician at the baseline visit is ≥3. 6. At baseline, the area of ​​lesions due to Alzheimer's disease (AD) covers at least 10% of the body surface area (BSA). 7. The subject's body mass index (BMI) is ≤35 kg / m². 2 Being. 8. The patient has a history of insufficient response to topical corticosteroids or topical calcineurin inhibitors as treatment for Alzheimer's disease within the past year of the screening visit (information obtained from medical records or patient history). 9. Participants must apply a basic bland emollient, as recommended by the researcher, at a consistent dose once or twice daily for at least seven days prior to their baseline visit. 10. The subject has reproductive capacity *If you are sexually active (except in cases where you are sexually active only with a same-sex partner), you must agree to use medically effective contraception. Appropriate contraception is defined as consent to continue using an effective and approved method of contraception at least four weeks before baseline (Day 1) throughout the study period and up to four weeks after the last dose of the investigational drug. a. Appropriate contraception for women is defined as: hormonal contraception, intrauterine devices (IUDs), vasectomy of the partner, or double-barrier contraception (i.e., condom + diaphragm, condom or diaphragm + spermicidal gel or foam). b. Appropriate contraception for men is defined as: vasectomy, double-barrier contraception (i.e., condom + diaphragm, condom or diaphragm + spermicidal gel or foam), or the sole partner using hormonal contraception or an IUD. * Menopause in women is defined as the absence of menstruation for 24 months; if suspected, it is necessary to record that pregnancy was ruled out by follicle-stimulating hormone levels prior to the baseline visit (refer to the reference range for clinical laboratory values ​​for the confirmatory level). If applicable, hysterectomy, bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation should be recorded. 11. Women who may be pregnant must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline (Day 0). 12. Participants must be willing and capable of visiting a medical institution and following procedures related to the trial.

[0130] Exclusion criteria: 1. Individuals with clinically identifiable atopic dermatitis. 2. Patients who, upon their screening visit, exhibited any of the following abnormal clinical test values: a. Hemoglobin <11 g / dL b. White blood cells (WBC) <3.0×10 3 / μL c. Platelet count <125×10 3 / μL d. Neutrophils <2.50×10 3 / μL e. Lymphocytes ≤ 1.2 × 10 3 / μL f. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) > 1.5 × Upper limit of normal range (ULN) g. Total bilirubin > ULN (excluding indirect bilirubin levels associated with Gilbert's syndrome) h.Creatinine > ULN. 3. Individuals who had poorly controlled hypertension in the month immediately preceding screening, or whose blood pressure at screening was >140 mmHg systolic or >90 mmHg diastolic, and this was confirmed by re-examination. 4. Individuals whose QuantiFERON® TB test results indicate a possible tuberculosis infection, and who lack documented evidence of having completed an appropriate series of treatments for latent TB. 5. Individuals with a history of latent or active tuberculosis, or who have stayed in an endemic area within the past eight weeks. 6. Individuals for whom chest X-ray results are available at the time of screening or within three months prior to the screening visit (i.e., the interpretation report must be available), and whose results are consistent with a history of TB infection (but not limited to these, including apical scarring, apical fibrosis, multiple calcifying granulomas, etc.). This does not include non-caseating granulomas. Chest X-ray screening is not mandatory if there are no clinical signs or symptoms of active TB infection, no history of latent or active tuberculosis, and no stay in an endemic area within the past 12 months. 7. Individuals who tested positive for hepatitis B core antigen, hepatitis B surface antigen, hepatitis C antibody, and / or human immunodeficiency virus at the time of their screening visit. 8. Individuals who have used hydroxyzine or diphenhydramine within one week prior to baseline (Day 1). 9. Individuals who have used a topical product containing urea within one week prior to baseline (Day 1). 10. Individuals who received systemic antibiotics within two weeks prior to baseline (Day 1) or topical antibiotics within one week prior to baseline. 11. Treatment with any topical medication for atopic dermatitis within two weeks prior to baseline (Day 1): This includes, but is not limited to, topical corticosteroids, calcineurin inhibitors, tar, bleach, antibiotics, medical devices, bleach baths, etc. 12. Individuals who have received systemic treatment (excluding biological treatments) that may affect atopic dermatitis in less than 4 weeks prior to baseline (Day 1) (e.g., retinoids, calcineurin inhibitors, methotrexate, cyclosporine, hydroxycarbamide [hydroxyurea], azathioprine, oral / injectable corticosteroids). Note: Nasal corticosteroids, corticosteroid-containing eye drops, and inhaled corticosteroids are permitted to stabilize the condition if the subject has been using a consistent dose for at least 4 weeks prior to baseline (Day 1) and intends to continue using the same dose during the study period. 13. Individuals who have received any commercially available drug or investigational biological agent within 12 weeks or 5 half-lives (whichever is longer) prior to baseline (Day 1). 14. Individuals who are currently using or have used non-biological investigational drugs or medical devices within the four weeks prior to baseline (Day 1). 15. Individuals who are excessively exposed to sunlight, have plans to travel to areas with a mild climate, have used a tanning room within four weeks prior to baseline (Day 1), or are unwilling to minimize natural and artificial sunlight exposure during the test period. If exposure cannot be avoided, the use of sunscreen and protective clothing is recommended. 16. Individuals who have received a live attenuated vaccine within four weeks prior to baseline (Day 1), or who are scheduled to receive a live attenuated vaccine during the study period or within four weeks of the last dose of the investigational drug or within five half-lives of the investigational drug, whichever is longer. 17. Persons who are known to have immunodeficiency or who are immune-deficient. 18. Patients with a history of malignant tumors within 5 years prior to baseline visit, excluding the following: a. Cervical intraepithelial neoplasia and non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin that have been cured by treatment. 19. Patients who have a major surgical procedure scheduled during the period of participation in this study. 20. Individuals with a history of congestive heart failure classified as New York Heart Association (NYHA) Grade III or IV. 21. Individuals whose 12-lead electrocardiogram (ECG) at screening shows an abnormality that the principal investigator considers clinically significant, or whose QTc F ≥ 450 msec, regardless of clinical significance. Abnormal ECGs may be confirmed by re-examination. For individuals whose initial ECG showed QTc F ≥ 450 msec, eligibility will be determined by evaluating the average of two QTc F values. 22. Anyone who has experienced a myocardial infarction, undergone angioplasty, or had a coronary artery stent insertion within the past six months. 23. Individuals who require therapeutic use of anticoagulants or NSAIDs (non-steroidal anti-inflammatory drugs) and whose medical condition is not considered to warrant low-dose aspirin for antiplatelet effects. 24. Persons with a history of hypertrophic scarring or keloid formation at the site of a wound or suture. 25. Persons with swallowing difficulties or a history of malabsorption syndrome. 26. Individuals with a history of recurrent GERD (gastroesophageal reflux disease) requiring the use of a proton pump inhibitor within the past month. 27. Individuals with a known history of diverticulitis. 28. Individuals with poorly controlled diabetes. 29. Any person whom the principal investigator or the medical monitor of the study sponsor has determined to be at risk to the patient, unable to participate in the study, or who has a medical or mental condition that could impede the interpretation of the study results. 30. Pregnant or breastfeeding women. 31. Persons known to be hypersensitive to compound 1 or its excipients. 32. Individuals who have previously received treatment with SYK or JAK inhibitors but have not seen clinical benefit or who have experienced a relapse during treatment.

[0131] Investigational drug, dosage, and administration method: Compound 1 was administered orally in doses of 20, 40, and 80 mg qd. Compound 1 is available in 5 mg, 20 mg, and 50 mg tablets.

[0132] Exam period: The treatment period for each patient was set to a total of 4 weeks (up to day 29), and the follow-up observation period for each patient was set to a total of 14 days (up to day 43).

[0133] Evaluation criteria: Safety assessment: Safety was evaluated using adverse events (AEs), vital signs, 12-lead ECG, physical examination, and clinical laboratory tests.

[0134] PK Variable Evaluation: For compound 1, the following PK parameters (for which data were available) were derived based on the concentration-time data of compound 1 after dose administration in a fasted state on the first day and Day 15: Cmax, tmax, AUC0-∞, AUC0-t, AUC0-24, λz, t1 / 2, CL / F, and Vd / F.

[0135] Efficacy Variable Assessment: Preliminary efficacy was assessed by measuring changes in the following variables between Day 1 (baseline) and Days 15 and 29: IGA, EASI, 5-D pruritus scale, pruritus numerical rating scale, %BSA of AD lesions, and skin microbiome analysis.

[0136] Evaluation of pharmacodynamic / biomarker parameters: 1. Changes from baseline in serum inflammatory markers (including immune markers and CRP) 2. Changes from baseline in molecular skin biomarkers (inflammation and barrier function) 3. Changes in cellular markers from baseline (including a decrease in inflammatory cells) 4. Changes from baseline in epidermal thickness and barrier markers

[0137] Evaluation of effectiveness Comprehensive evaluation by the principal investigator. IGA is a five-point scale from 0 (clear) to 4 (severe) used in clinical trials to determine the severity and clinical response of Alzheimer's disease (18). IGA scores were assessed at screening, Day 1 / baseline (before administration), and Days 15, 29, 43, or early termination. [Table 26]

[0138] 5-D Itchiness Scale: The 5-D pruritus scale is a valid questionnaire used in clinical trials to assess five components of itching: intensity, duration, course, quality of life impairment, and distribution. It consists of one page and five questions (19). Each question corresponds to one of the five components of itching, and subjects rate their symptoms on a scale of 1 to 5, with 5 being the most impactful, with the past two weeks being considered "present." Subjects receive this assessment at the following visits: day 1 / baseline (before administration), and days 15, 29, 43, or at early termination. Figure 3 shows the 5-D pruritus scale.

[0139] Itchiness severity numerical evaluation scale: The Pruritus NRS is a single-item assessment tool used to evaluate the most severe itching caused by AD in a patient over the past 12 hours. Participants record patient-reported outcomes once daily. Patient compliance with the Pruritus NRS is tracked at each healthcare visit. Participants are instructed to record daily at their baseline visit and are asked about their compliance at each healthcare visit. Participants score and complete the scale shown below daily until their final trial visit. [Table 27]

[0140] Eczema Area and Severity Index: The Eczema Area and Severity Index (EASI) is an effective tool used in clinical practice and clinical trials to assess the severity and extent of Alzheimer's disease (AD). The severity of four AD characteristics is assessed by the principal investigator or contract investigator on a scale from "0" (none) to "3" (severe). Furthermore, the area of ​​AD lesions is assessed as a percentage of the body surface area of ​​the head and neck, trunk, upper extremities, and lower extremities, and converted into a score from 0 to 6. Subjects received this assessment at the following visits: at screening, day 1 / baseline (before administration), and days 15, 29, 43, or at early termination. The EASI assessment method is shown in Figure 4.

[0141] Body surface area of ​​atopic dermatitis lesions The body surface area affected by AD was assessed for each major body part (head, trunk, arms, legs), and reported as the sum of the percentages for all major body parts. Subjects were assessed at the following visits: screening, day 1 / baseline (before administration), and days 15, 29, 43, or early termination.

[0142] Skin microbiome analysis Skin microbiome sampling is a non-invasive procedure in which a cotton swab is used to trace the lesional surface, including the most aggravated eczema area, and another cotton swab is used to trace the non-lesional area of ​​skin within 5 cm of the lesion. Samples were collected from the same lesional and non-lesional areas on day 1 / baseline (before administration) and on days 29, 43, or at early termination.

[0143] Evaluation of pharmacodynamic and exploratory biomarkers Evaluation of exploratory markers Skin biopsy: Up to four skin biopsies were taken from each subject during the study period. Two punch biopsy samples were taken on Day 1 (one from lesioned skin and one from non-lesioned skin), and one punch biopsy sample was taken on Day 15 (optional by the subject) and Day 29 from the same lesioned skin (outside the scar from the previous biopsy).

[0144] Other biomarkers: A panel of biological markers was evaluated to assess the effects of compound 1 on the disease process. These included, but were not limited to, the following: • Serum cytokines and inflammatory markers • Molecular skin biomarkers (inflammation and barrier function) • Circulating and tissue-resident cell phenotypes • Epidermal thickness and epidermal barrier markers derived from skin biopsy • Other biomarkers associated with autoimmune or inflammatory diseases

[0145] result: Figure 7A is a graph showing the percentage of subjects who achieved an EASI of 50 over time (Day 1 to Day 29) when administered placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg. Figure 7B is a graph showing the percentage of subjects who achieved an EASI of 75 over time (Day 1 to Day 29) when administered placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg. Three subjects achieved an EASI of 90, and two subjects achieved 100% elimination. Figures 8A to 8C show the improvements in EASI, IGA, and BSA after 4 weeks when administered placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg. Figure 8A is a graph of %CFB (change from baseline) of EASI (decrease) when administered placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg. Figure 8B is a graph of %CFB for BSA (body surface area) (reduction) when administered with placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg. Figure 8C is a graph of %CFB for IGA0-1 (comprehensive assessment by the principal investigator) when administered with placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg. Figure 9 is a graph showing the plasma concentrations on day 15 when compound 1 was administered at doses of 20 mg, 40 mg, and 80 mg. max Furthermore, the AUC is dose-dependent, and oral absorption is rapid (T max 2~4 hours), discharge rate T 1 / 2The reaction time was mild, 10-14 hours, indicating small inter- and intra-individual variability. Figure 10 is a table showing the inhibition of JAK and Syk kinase activity by compound 1, tofacitinib, upadacitinib, and baricitinib. In Figure 10, biochemical kinase assays using purified partial-length or full-length enzymes showed IC50. 50 The values ​​were determined. Figure 11 shows the inhibition of the JAK / STAT pathway, which is stimulated by various cytokines in T cells, by compound 1. As shown in Figure 11, compound 1 strongly inhibited the JAK / STAT pathway in primary T cells stimulated by various cytokines.

[0146] Figure 12 shows that compound 1 inhibits IL-17-mediated CCL20 release in keratinocytes. As shown in Figure 12, unlike tamatinib and tofacitinib, compound 1 inhibits IL-17-SYK-mediated CCL20 release from human keratinocytes to a level comparable to that of IL-17 neutralizing antibodies. * p<0.05; *** p<0.001, compared to IL 17+DMSO control (one-way ANOVA with Dunnett's multiple comparison test), % is the percentage of reduction from IL 17+DMSO control). Each bar in Figure 12 represents the mean and SEM of three consecutive measurements (n=3) from a single donor. Figure 13 is a graph showing the mean weekly change in pruritus (NRS) when administered as placebo and compound 1 at doses of 20 mg, 40 mg, and 80 mg. As shown in Figure 13, compound 1 reduces pruritus early.

[0147] The graphs in Figures 14A-C show that when compound 1 was administered at doses of 20 mg, 40 mg, and 80 mg, improvement in skin thickening and cell infiltration was observed as early as Day 15. Figure 14A is a graph showing improvement in skin thickness when compound 1 was administered at doses of 20 mg, 40 mg, and 80 mg. A decrease in overall skin thickness was observed as early as Day 15. Figure 14B is a graph showing improvement in CD3+ cells when compound 1 was administered at doses of 20 mg, 40 mg, and 80 mg. Administration of 40 and 80 mg of ASN002 reduced T cell infiltration into all layers of the skin by Day 29. Figure 14C is a graph showing improvement in CD11c+ cells when compound 1 was administered at doses of 20 mg, 40 mg, and 80 mg. Infiltration of myeloid DCs into all layers of the skin decreased as early as Day 15 when ASN002 was administered at doses of 40 and 80 mg. Figure 15 is a table showing the adverse events (TEAEs) that occurred under the treatment described in Example 3.

[0148] Conclusion: Compound 1 demonstrated clear efficacy in patients with moderate to severe atopic dermatitis (AD). Compound 1 rapidly improved symptoms, and a significant reduction in itching, as reported by patients, was observed as early as day 2 of treatment with Compound 1. Compound 1 was well-tolerated in patients with moderate to severe atopic dermatitis. Compound 1 exhibited predictable pharmacokinetics, as evidenced by dose-dependent exposure and minimal inter-individual variability and accumulation with once-daily administration. Treatment with Compound 1 downregulated inflammatory pathways, and epidermal thickening and cell infiltration showed improvement as early as day 15.

[0149] The most common adverse events were hunger-related headache and nausea, primarily reported on Day 1, and these were also reported in placebo patients. No serious infections or thromboembolic events occurred. Chemical laboratory values ​​showed no clinically significant changes, except for a transient, asymptomatic mild to moderate increase in CPK. No changes in lipid profiles were observed. Hematological laboratory values, including platelets, neutrophils, and lymphocytes, showed no clinically significant changes. Subjects in the compound 1 treatment group rapidly initiated a dose-dependent decline, with EASI 50 scores at 29%, 100%, and 88% in the 20, 40, and 80 mg cohorts, and EASI 75 scores at 0%, 63%, and 50% in the 80 mg cohorts, respectively, after 4 weeks. Baseline EASI scores were 29.0, 21.3, and 29.0, respectively. The mean declines in EASI and Numerical Rating Scale (NRS) scores at Week 4 were 21%, 79%, and 70% in the 20, 40, and 80 mg cohorts, and 15%, 47%, and 71% in the 80 mg cohorts, respectively. The 80 mg cohort showed early reduction in itching as early as Day 2 (approximately 45%), and the 40 and 80 mg cohorts also showed improvement in IGA assessment (38% achieved 0-1). These clinical improvements were accompanied by reversals in skin biomarkers (cellular infiltration, immune, and hyperplasia markers), particularly at medium and high doses.

[0150] Summary of Example 3: Background: Dysregulation of Th2 and Th22 cytokine pathways is involved in the pathogenesis of atopic dermatitis (AD). Compound 1 is a novel oral inhibitor of JAK and SYK signaling (including Tyk2) that reduces the production of Th2 and Th22 cytokines. Syk also regulates IL 17R signaling and keratinocyte differentiation in keratinocytes. Objective: The efficacy, safety, and pharmacology of Compound 1 were evaluated in patients with moderate to severe AD in a phase 1b randomized, double-blind, placebo-controlled trial (NCT03139981).

[0151] Methods: Patients were randomly assigned in a 1:3 ratio to receive either placebo or compound 1 at 20, 40, or 80 mg once daily for 4 weeks (n=36). Inclusion criteria were Eczema Area and Severity Index (EASI) ≥ 16, lesion body surface area (BSA) ≥ 10%, and Investigator's Comprehensive Assessment (IGA) ≥ 3 at baseline visits. The study objectives included safety / tolerability, efficacy, and pharmacokinetic measurements. No topical corticosteroids or other immunosuppressants were administered during or before the study.

[0152] Results: Compound 1 demonstrated very high tolerability at all dose levels. Most common adverse events were transient, mild headache and nausea, mostly limited to Day 1 of administration. Subjects in the Compound 1 treatment group showed immediate and dose-dependent response, with EASI 50 rates at 29%, 100%, and 88% in the 20, 40, and 80 mg cohorts, and EASI 75 rates at 0%, 63%, and 50% in the 80 mg cohorts, respectively, after 4 weeks. Baseline EASI scores were 29.0, 21.3, and 29.0, respectively. The mean declines in EASI and Numerical Rating Scale (NRS) at Week 4 were 21%, 79%, and 70% in the 20, 40, and 80 mg cohorts, and 15%, 47%, and 71% in the 80 mg cohorts, respectively. In the 80 mg cohort, itching reduction was observed as early as Day 2 (approximately 45%), and improvement in IGA assessment was also seen in the 40 and 80 mg cohorts (38% achieved 0-1). These clinical improvements were accompanied by a reversal of skin biomarkers (cellular infiltration, immune, and hyperplasia markers), particularly at medium and high doses.

[0153] Conclusion: This is a clinical report on the safety, efficacy, and effects of compound 1, an oral JAK / SYK inhibitor, on the lesional skin phenotype of moderate to severe Alzheimer's disease. Compound 1 showed very high tolerability, early improvement of itching, and high efficacy in EASI at 4 weeks, accompanied by reversal of inflammatory skin biomarkers.

[0154] Example 4 Clinical activity, safety, and tolerability of compound 1, a dual SYK / JAK inhibitor, in patients with non-Hodgkin lymphoma (NHL). The formulations of this disclosure, comprising 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile, contain potent inhibitors of spleen tyrosine kinase (SYK) and Janus kinase (JAK). Preclinical studies have shown that the formulations have an effective inhibitory response to SYK and JAK. 50 The low nM value suggested that it suppresses the proliferation of ibrutinib-resistant cell lines and inhibits the growth of NHL tumors and other hematological malignancies in rodent xenograft models.

[0155] Methods: In a Phase 1 / 2 clinical trial involving patients with solid tumors and hematological malignancies, the oral doses of the formulations disclosed herein were escalated to 10, 20, 30, 40, 50, 75, and 100 mg BID and 80 and 120 mg QD mg (NCT02440685). Phase 1 included patients with solid tumors or hematological malignancies; Phase 2 included only patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or mantle cell lymphoma (MCL). Endpoints included safety, tolerability, pharmacokinetics, serum inflammatory markers, and therapeutic efficacy using the RECIST or Lugano classification system.

[0156] Results: 38 patients were enrolled in a DLT phase trial with doses of 10 mg–100 mg BID and 80–120 mg QD. All patients had multiple prior treatment histories (range: 2–8). The formulation was well-tolerated. No dose-limiting adverse events were reported at these dose levels. The majority of drug-related adverse events were Gr 1 / 2 (e.g., headache, fatigue). High systemic exposure was observed at steady state (C at 40 mg BID). max , AUC (0~12h), and T 1 / 2The doses were 0.7 μM, 6.3 μM·h, and 18 h, respectively. High systemic exposure was also observed at 80 mg QD. CRP, IL-18, MIP1β, VCAM-1, and TNFR2 were significantly reduced at all doses. FL patients showed approximately 50% reduction in target lesions after 3 months (Lugano, 6 prior treatment regimens), and peripheral T-cell lymphoma patients stabilized and experienced reduced itching after 2 months of treatment (Lugano, 2 prior treatment regimens). Treatment with this formulation was continued in both lymphoma patients. Formulation-induced lymphocytosis suggestive of recompartmentalization was observed in two recently enrolled patients. Patient recruitment is ongoing. Figures 16A-16G show the clinical activity, safety, and tolerability of the formulation disclosed herein.

[0157] Conclusion: This formulation was very safe and well-tolerated. Promising preliminary evidence of efficacy in NHL patients was observed. No MTD was reached, and dose escalation is ongoing.

[0158] While this disclosure has considered specific embodiments, it should not be understood that the disclosure is limited in that respect. Embodiments described herein are illustrative examples, but many variations and other embodiments still fall within the scope of this disclosure.

Claims

1. A method for preparing a tablet formulation, the following: (A) A process to provide granular components including the following (i) a micronized compound which is 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile or a pharmaceutically acceptable salt thereof, wherein the micronized compound has a particle size distribution of about 13.530 D(0.9); and (ii) Croscarmellose sodium (B) Granulation of granular components by adding a 10% w / w solution of one or more binders consisting of hydroxypropyl cellulose in 99% v / v isopropyl alcohol until granules are formed. (C) Process of drying and grinding the granules to produce finely powdered granules. (D) A step of mixing the finely powdered granules with one or more extragranular components; and (E) A step of compressing the finely powdered granules and one or more non-granule components to form a tablet, thereby providing a tablet formulation. The method comprising, wherein one or more extragranular components include sodium lauryl sulfate.

2. The method according to claim 1, wherein the granules further comprise one or more antioxidants.

3. The method according to claim 2, wherein the one or more antioxidants include at least one of vitamin E or butylated hydroxytoluene (BHT).

4. The method according to claim 3, wherein the one or more antioxidants are vitamin E.

5. The method according to claim 1, wherein the granules further comprise one or more fillers.

6. The method according to claim 5, wherein one or more fillers contain lactose monohydrate.

7. The method according to claim 1, further comprising one or more extragranular components.

8. The method according to claim 7, wherein the extragranular component comprises one or more tablet fillers and / or one or more lubricants.

9. The method according to claim 8, wherein the one or more tablet fillers contain microcrystalline cellulose and the one or more lubricants contain magnesium stearate.

10. The method according to claim 1, wherein the tablet formulation contains about 20 mg to about 80 mg of the powdered compound.

11. The method according to claim 10, wherein the tablet formulation contains about 20 mg, about 40 mg, or about 80 mg of the micronized compound.

12. The method according to claim 10, wherein the tablet formulation contains about 5 mg of the compound.

13. The method according to claim 10, wherein the tablet formulation contains about 20 mg of the compound.

14. The method according to claim 10, wherein the tablet has a hardness of about 7 to 9 kP and disintegrates in 0.1 N hydrochloric acid (pH 6.8) and 50 mM phosphate buffer at 37°C for less than about 5 minutes.

15. The method according to claim 10, wherein the tablet includes a coating.

16. The method according to claim 15, wherein the coating comprises hydroxypropyl cellulose, titanium dioxide, talc, and polyethylene glycol.

17. The method according to claim 1, wherein the compound is 2-(1-(4-((4-(4-hydroxypiperidine-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-yl)acetonitrile hydrochloride.

18. The method according to claim 1, wherein the tablet is formulated for oral administration.

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