JP-7857219-B2 - Pharmaceutical compositions for treating or preventing various inflammatory disorders

Inventors

• リー，ティエン－リー
• ジェン，ジェンフアン
• ニートハンマー，アンドレアス
• ティマー，アンジュリ

Assignees

• アードバーク・セラピューティクス・インコーポレイテッド

Dates

Publication Date

20260512

Application Date

20201223

Priority Date

20191224

Claims (16)

1. A pharmaceutical composition comprising a denatonium salt selected from the group consisting of denatonium acetate (DA), denatonium citrate, denatonium maleate, denatonium saccharide, and denatonium tartrate, for the treatment, prevention, and/or delaying the worsening of metabolic syndrome (METS) or hyperglycemia, which is administered orally to humans.
2. The pharmaceutical composition according to claim 1, further comprising about 0.5 g to about 5 g of acetic acid.
3. The pharmaceutical composition according to claim 2, further comprising about 1.5 g to about 3 g of acetic acid.
4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the daily dose of denatonium salt for adults is approximately 20 mg to approximately 5000 mg.
5. The pharmaceutical composition according to claim 4, wherein the daily dose of denatonium salt for adults is approximately 50 mg to approximately 1000 mg.
6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the daily dose of denatonium salt for adults is approximately 60 mg to approximately 500 mg, or a dose that achieves an intra-gastrointestinal concentration of approximately 10 ppb to approximately 50 ppm.
7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the daily dose of denatonium salt for adults is approximately 5 mg/kg (body weight) to approximately 150 mg/kg (body weight) per day.
8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the denatonium salt is denatonium acetate (DA).
9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the denatonium salt is denatonium citrate.
10. The pharmaceutical composition according to any one of claims 1 to 7, wherein the denatonium salt is denatonium maleate.
11. The pharmaceutical composition according to any one of claims 1 to 7, wherein the denatonium salt is denatonium tartrate.
12. A pharmaceutical composition according to any one of claims 1 to 8, wherein the daily dose of DA for adults is approximately 50 mg to approximately 1000 mg.
13. The pharmaceutical composition according to claim 12, wherein the daily dose of DA for adults is approximately 60 mg to approximately 500 mg, or a dose that achieves an intra-gastrointestinal concentration of approximately 10 ppb to approximately 50 ppm.
14. A pharmaceutical composition according to any one of claims 1 to 13, wherein the daily dose of denatonium salt is administered once, twice, or three times a day.
15. A pharmaceutical composition according to any one of claims 1 to 14, wherein the treatment, prevention, and/or delay of exacerbation is for metabolic syndrome (METS).
16. A pharmaceutical composition according to any one of claims 1 to 14, wherein the treatment, prevention, and/or delay of exacerbation is of hyperglycemia.

Description

This disclosure provides methods for treating, preventing and/or delaying the progression of various chronic inflammatory disorders, including (1) type 2 diabetes (metabolic syndrome (MET), obesity, hyperglycemia); (2) ARDS (acute respiratory distress syndrome); (3) chronic autoimmune inflammatory disorders (rheumatoid arthritis (RA), lupus, and psoriasis); (4) inflammatory bowel disease (IBD), e.g., Crohn's disease and ulcerative colitis; (5) metabolome-mediated disorders (atherosclerosis, hypertension, and congestive heart failure); and (6) hyperphagia, e.g., Prader-Willi syndrome, and other monogenic symptomatic obesity disorders including leptin pathway deficiency, each comprising orally administering a pharmaceutical composition comprising a denatonium salt. This disclosure is based on readouts from a series of studies tracking biomarker-level clusters to track mediators of inflammatory disorders and mediators of intestinal signaling hormones in response to orally administered denatonium salts. This disclosure further provides pharmaceutical compositions for treating and preventing various inflammatory conditions that can be tracked by pro-inflammatory biomarkers, comprising administering a pharmaceutical composition comprising a denatonium salt. Preferably, the pharmaceutical composition of the present invention, administered orally daily, comprises a denatonium salt delivered to a human adult in a total daily dose of about 20 mg to about 5000 mg by BID. Preferably, the denatonium salt is selected from the group consisting of denatonium acetate, denatonium citrate, denatonium maleate, and denatonium tartrate. Over the past 40 years, global obesity levels have more than doubled. Obesity increases the risk of metabolic syndrome and is associated with an increased risk of coronary heart disease, stroke, type 2 diabetes, certain forms of cancer, and ultimately, serious illness and death due to the coronavirus pandemic. This expanding epidemic has become one of the most critical challenges to global health today. With the emergence of this problem, our understanding of the pathological mechanisms linking obesity to disease progression has deepened. At the heart of these mechanisms lies the increased systemic inflammation resulting from obesity, which ultimately leads to numerous pathological conditions. Therefore, there is a great need for treatment and prevention to address appetite and inflammatory signaling. This disclosure addresses this need. Inflammatory Diseases Currently, various inflammatory diseases are treated with anti-tumor necrosis factor (TNF) (and anti-interleukin (IL)-6) proteins and antibodies. Such therapeutic proteins are approved for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis (JIA) in children, psoriatic arthritis, lupus, ankylosing spondylitis (AS), chronic plaque psoriasis (Ps), panuveitis, IBD including ulcerative colitis and Crohn's disease, and many other diseases. These biologics act by binding and clearing circulating TNFα (and IL-6) with antibodies or fusion proteins, such as etanercept (Embrel®). However, these anti-TNFα drugs and other biologics that indiscriminately bind and clear inflammatory cytokines have severe side effects. These side effects are caused by the inhibition of a large portion of TNF signaling. Because TNF possesses immune surveillance capabilities (which are also inhibited by these biological drugs), it increases susceptibility to infection and impaired immune surveillance, including an increased incidence of various infections and malignancies, such as leukemia and lymphoma, listed on the black-bordered warning label. Therefore, there is a need in the art for more cost-effective small molecule therapies that knock down (but not necessarily eliminate) circulating TNF. Since protein-based therapies cannot be administered orally, there is a need in the art for more sensitive or self-limiting oral small molecule agents in eliminating circulating TNF by preventing the production of TNF as a pro-inflammatory cytokine, rather than indiscriminately clearing existing and produced TNF. For example, the label on adalimumab (Humira®), approved by the US FDA, lists side effects such as an increased risk of serious infections (i.e., TB; infections caused by viruses, fungi, or bacteria), exacerbation of hepatitis B infection in virus carriers, allergic reactions, and various leukemias and lymphomas. Metabolic syndrome (METS) is a combination of factors that increase the risk of developing type 2 diabetes and cardiovascular disease. METS is a clustering of at least three of the following five conditions: (1) visceral obesity; (2) elevated blood pressure; (3) elevated blood glucose levels; (4) high serum triglycerides; and (5) low serum high-density lipoprotein (HDL). According to the International Diabetes Foundation (IDF), metabolic syndrome is characterized by central obesity and any two of the following: (1) elevated triglycerides (TG) >150 mg/d