KR-102961896-B1 - Formulations, methods, kits, and dosage forms for treating atopic dermatitis and improving the stability of active pharmaceutical ingredients

Abstract

Embodiments of the present disclosure generally relate to formulations, treatment methods, kits, and dosage forms for treating inflammatory disorders including atopic dermatitis or cancer, wherein the formulations comprise an active pharmaceutical ingredient. The provided formulations comprise granules, wherein the granules comprise a micronized active ingredient; one or more granule binders; one or more fillers; one or more disintegrants; and one or more antioxidants. In one embodiment, the treatment method comprises the step of orally administering the active ingredient to a subject suffering from atopic dermatitis, wherein the amount of the active ingredient is about 20 mg to about 80 mg.

Inventors

• 라일카르 아루나
• 자리왈라 파라스
• 푸아프라디트 완타니
• 자미트 데이비드
• 데니스 루이스
• 라오 니란잔
• 우산스키 헬렌
• 굽타 산딥

Assignees

• 리버타스 바이오 인코포레이티드

Dates

Publication Date

20260508

Application Date

20180430

Priority Date

20170428

Claims (20)

1. As a pharmaceutical formulation comprising granules, The granules comprise (i) a micronized compound that is 2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazine-2-yl)piperidin-4-yl)acetonitrile, or a pharmaceutically acceptable salt thereof; (ii) hydroxypropyl cellulose; and (iii) croscarmellose sodium; and The above granules are a pharmaceutical formulation having a particle size of less than 20 microns.
2. In claim 1, A pharmaceutical formulation additionally comprising one or more antioxidants.
3. In claim 2, The above one or more antioxidants are pharmaceutical formulations comprising at least one of vitamin E or butylated hydroxytoluene.
4. In claim 3, The above-mentioned one or more antioxidants is a pharmaceutical formulation of vitamin E.
5. In claim 1, A pharmaceutical formulation comprising one or more additional fillers.
6. In claim 5, One or more of the above fillers are pharmaceutical formulations comprising lactose monohydrate.
7. In claim 1, The above granules are a pharmaceutical formulation having an isopropyl alcohol content of less than 5,000 ppm.
8. In claim 1, The above granules are a pharmaceutical formulation compressed into tablets.
9. In claim 1, A pharmaceutical formulation comprising one or more additional non-granular components.
10. In claim 9, The above-mentioned non-granular component is a pharmaceutical formulation comprising one or more tablet fillers, one or more disintegrants, one or more lubricants, and/or one or more surfactants.
11. In claim 10, A pharmaceutical formulation comprising one or more tablet fillers comprising microcrystalline cellulose, one or more disintegrants comprising croscarmellose sodium, one or more surfactants comprising sodium lauryl sulfate, and one or more lubricants comprising magnesium stearate.
12. In claim 11, The above granules and non-granular components are a pharmaceutical formulation compressed into a tablet.
13. In claim 12, The above granules are a pharmaceutical formulation having an isopropyl alcohol content of less than 5,000 ppm.
14. In claim 1, The above pharmaceutical formulation is a pharmaceutical formulation comprising 20 to 80 mg of a micronized compound.
15. In claim 14, The above pharmaceutical formulation is a pharmaceutical formulation comprising 20 mg, 40 mg, or 80 mg of a micronized compound.
16. In claim 12, The above tablet is a pharmaceutical formulation having a hardness of 7 to 9 kP and a disintegration time of less than 5 minutes in 0.1 N HCl, pH 6.8 and 50 mM phosphate buffer at 37°C.
17. In claim 12, The above tablet is a pharmaceutical formulation comprising a coating.
18. In claim 17, The above coating is a pharmaceutical formulation comprising hydroxypropylcellulose, titanium dioxide, talc, and polyethylene glycol.
19. In claim 1, The above compound is a pharmaceutical formulation of 2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazine-2-yl)piperidin-4-yl)acetonitrile hydrochloride.
20. In claim 1, The above-mentioned micronized compound is a pharmaceutical formulation having a particle size distribution D (0.9) of 13.530.

Description

Formulations, methods, kits, and dosage forms for treating atopic dermatitis and improving the stability of active pharmaceutical ingredients Embodiments of the present disclosure generally relate to formulations, methods, kits, and dosage forms for treating atopic dermatitis and also improving the stability of an active pharmaceutical ingredient. In one embodiment, the formulation, method, kit, and dosage form comprise the administration of an active pharmaceutical ingredient having improved stability and may be used for the treatment of inflammatory disorders or cancer, or for the treatment of atopic dermatitis. Protein kinases constitute a large family of structurally related enzymes involved in the control of various signaling processes within cells. Almost all kinases contain similar 250 to 300 amino acid catalytic domains. Kinases can be classified into families based on the substrates they phosphorylate. JAK (Janus kinases, including JAK1, JAK2, JAK3, and TYK2) is a family of intracellular non-receptor tyrosine kinases. JAK is abundantly expressed in hematopoietic cells and in primary leukemia cells from children with acute lymphoblastic leukemia. Downstream substrates of JAK include transcriptional signaling 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 has been suggested to be mediated in various abnormal immune responses, such as allergies, asthma, autoimmune diseases, such as graft rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, as well as solid and hematological malignancies, such as leukemia and lymphoma. Splenic tyrosine kinase (SYK) is a member of the protein tyrosine kinase SYK family and plays a pivotal role in inflammatory and allergic reactions. SYK induces IgE and IgG receptor-mediated signaling in mast cells, basophils, and macrophages, leading to degranulation and cytokine release. Immune receptor tyrosine activation motif (ITAM)-mediated signaling has emerged as a major event in signaling pathways involved in human pathology. ITAM-mediated signaling is involved in transmitting activation signals initiated by traditional immune receptors, such as T-cell receptors, B-cell receptors, and Fc receptors in immune cells, and GPVI and FcγRIIa in platelets, to downstream intracellular molecules, such as Syk. Ligand binding to ITAM-containing receptors triggers signaling events that allow for the recruitment of proteins from a family of non-receptor tyrosine kinases called the Src family. These kinases phosphorylate tyrosine residues within the ITAM sequence, which is a region interacting with the linear SH2 domain on Syk or ZAP-70. The interaction between Syk and the 2-phosphorylated ITAM sequence induces a conformation change in the kinase that allows for the tyrosine phosphorylation of the kinase itself. These kinases not only contribute to normal host defense but also participate in the pathogenesis of diseases. Various diseases are associated with abnormal cellular responses triggered 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 diseases. Consequently, significant efforts have been made in medicinal chemistry to identify protein kinase inhibitors for use as therapeutic agents. There is a demand in this field for compounds that are dual inhibitors of Syk/JAK, as well as methods to treat pathologies that can benefit from such inhibition. Furthermore, there is a demand in this field for the formulation of Syk/JAK dual inhibitor compounds that can be utilized in methods to treat pathologies that benefit from Syk/JAK inhibition. Such formulations must optimize the efficacy of Syk/JAK dual inhibitor compounds and exhibit a high level of stability. Atopic dermatitis (AD) is a chronic inflammatory skin disease. It is characterized by dry, scaly skin, erythema, lesions with oozing and crusting, abrasions caused by itching, and lichenification. The skin condition is accompanied by severe itching that places a significant burden on the subjects and their quality of life. Up to 3% of adults and 15–25% of children have atopic dermatitis. In approximately 85% of cases, it begins in early childhood, but late onset, including during adulthood, may also occur. Splenic 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. Dysregulation of SYK has been suggested in different human diseases, such as B-cell tumors, allergies, asthma, and other inflammatory disorders. SYK binds to the immune-receptor tyrosine-based activation moti