KR-20260065595-A - PHARMACEUTICAL COMPOSITION COMPRISING A CILOSTAZOL AND ROSUVASTATIN

Abstract

The present disclosure provides a pharmaceutical composition for improving symptoms in patients with peripheral arterial disease, comprising cilostazol or a pharmaceutically acceptable salt thereof; and rosuvastatin or a pharmaceutically acceptable salt thereof.

Inventors

• 최연웅
• 허현욱
• 장재상

Assignees

• 한국유나이티드제약 주식회사

Dates

Publication Date

20260508

Application Date

20260421

Claims (20)

1. As a pharmaceutical composition for improving symptoms in patients with peripheral artery disease, Cilostazol or a pharmaceutically acceptable salt thereof; and Rosuvastatin or a pharmaceutically acceptable salt thereof; A pharmaceutical composition comprising
2. In paragraph 1, A pharmaceutical composition in which the difference between the change in 100mm VAS (Visual Analog Scale) for lower extremity pain at 12 weeks from baseline of administration of the above pharmaceutical composition and the change in 100mm VAS for lower extremity pain at 12 weeks from baseline of rosuvastatin monotherapy is 3 mm or more.
3. In paragraph 1, A pharmaceutical composition in which the difference between the change in initial claudication distance (ICD) using a treadmill test at 12 weeks from baseline of administration of the above pharmaceutical composition and the change in ICD using a treadmill test at 12 weeks from baseline of rosuvastatin monotherapy is 60 m or more.
4. In paragraph 1, A pharmaceutical composition in which the difference between the change in functional claudication distance (FCD) using a counter-test at 12 weeks relative to baseline of administration of the above pharmaceutical composition and the change in FCD using a counter-test at 12 weeks relative to baseline of rosuvastatin monotherapy is 50 m or more.
5. In paragraph 1, A pharmaceutical composition in which the difference between the change in absolute claudication distance (ACD) using a counter-test at 12 weeks relative to baseline of administration of the above pharmaceutical composition and the change in ACD using a counter-test at 12 weeks relative to baseline of rosuvastatin monotherapy is 55 m or more.
6. In paragraph 1, A pharmaceutical composition in which the difference between the change in ICD using a follow-up test at 24 weeks relative to baseline of administration of the above pharmaceutical composition and the change in ICD using a follow-up test at 24 weeks relative to baseline of rosuvastatin monotherapy is 35 m or more.
7. In paragraph 1, A pharmaceutical composition in which the difference between the change in FCD using a follow-up test at 24 weeks relative to baseline of administration of the above pharmaceutical composition and the change in FCD using a follow-up test at 24 weeks relative to baseline of rosuvastatin monotherapy is 35 m or more.
8. In paragraph 1, A pharmaceutical composition in which the difference between the change in ACD using a follow-up test at 24 weeks relative to baseline of administration of the above pharmaceutical composition and the change in ACD using a follow-up test at 24 weeks relative to baseline of rosuvastatin monotherapy is 35 m or more.
9. In paragraph 1, A pharmaceutical composition in which the difference between the change in ABI (ankle brachial index) at 12 weeks from baseline of administration of the above pharmaceutical composition and the change in ABI at 12 weeks from baseline of rosuvastatin monotherapy is 0.03 points or more.
10. In paragraph 1, A pharmaceutical composition in which the difference between the change in ABI at 24 weeks from baseline of administration of the above pharmaceutical composition and the change in ABI at 24 weeks from baseline of rosuvastatin monotherapy is 0.02 points or more.
11. In paragraph 1, A pharmaceutical composition in which the difference between the rate of change in TG (Triglycerides) at 12 weeks from baseline of administration of the above pharmaceutical composition and the rate of change in TG at 12 weeks from baseline of rosuvastatin monotherapy is 10% or more.
12. In paragraph 1, A pharmaceutical composition in which the difference between the rate of change in TG at 24 weeks relative to baseline of administration of the above pharmaceutical composition and the rate of change in TG at 24 weeks relative to baseline of rosuvastatin monotherapy is 10% or more.
13. In paragraph 1, A pharmaceutical composition in which the difference between the rate of change in HDL-C (High-Density Lipoprotein Cholesterol) at 12 weeks from baseline of administration of the above pharmaceutical composition and the rate of change in HDL-C at 12 weeks from baseline of rosuvastatin monotherapy is 5% or more.
14. In paragraph 1, A pharmaceutical composition in which the difference between the rate of change in HDL-C at 24 weeks relative to baseline of administration of the above pharmaceutical composition and the rate of change in HDL-C at 24 weeks relative to baseline of rosuvastatin monotherapy is 3% or more.
15. In paragraph 1, A pharmaceutical composition in which the difference between the rate of change in non-HDL-C (non-High-Density Lipoprotein Cholesterol) at 12 weeks from baseline of administration of the above pharmaceutical composition and the rate of change in non-HDL-C at 12 weeks from baseline of rosuvastatin monotherapy is 3% or more.
16. In paragraph 1, A pharmaceutical composition in which the difference between the rate of change in non-HDL-C at 24 weeks relative to baseline of administration of the above pharmaceutical composition and the rate of change in non-HDL-C at 24 weeks relative to baseline of rosuvastatin monotherapy is 3% or more.
17. In paragraph 1, A pharmaceutical composition in which the difference between the rate of change in Apo B (Apolipoprotein B) at 12 weeks from baseline of administration of the above pharmaceutical composition and the rate of change in Apo B at 12 weeks from baseline of rosuvastatin monotherapy is 4% or more.
18. In paragraph 1, A pharmaceutical composition in which the difference between the rate of change in Apo B at 24 weeks relative to baseline of administration of the above pharmaceutical composition and the rate of change in Apo B at 24 weeks relative to baseline of rosuvastatin monotherapy is 5% or more.
19. In paragraph 1, A pharmaceutical composition in which the symptom improvement effect of a patient with peripheral artery disease administered the above pharmaceutical composition is superior to rosuvastatin monotherapy.
20. In any one of paragraphs 2 through 19, A pharmaceutical composition administered orally once a day on an empty stomach, avoiding meals.

Description

Pharmaceutical composition comprising cilostazol and rosuvastatin The present disclosure relates to a pharmaceutical composition comprising cilostazol and rosuvastatin. Cilostazol is an antithrombotic and vasodilator newly synthesized and developed by Otsuka Corporation in Japan in 1978, and is widely used to improve ischemic symptoms such as ulcers, pain, and coldness caused by chronic arterial occlusion. Cilostazol acts as a phosphodiesterase III inhibitor in the body, increasing the active form of protein kinase A (PKA) to inhibit platelet aggregation. Additionally, PKA exerts a vasodilating effect by inhibiting the activity of myosin light-chain kinase, an enzyme that contracts smooth muscle. Extended-release cilostazol formulations are currently developed and marketed in capsule and tablet forms, and as an antiplatelet agent possessing both platelet aggregation inhibition and peripheral vasodilation effects, its utility as a treatment for ischemic symptoms in patients with chronic arterial occlusion has been proven. Rosuvastatin is an inhibitor that acts selectively and competitively on HMG-CoA reductase, a reductase that catalyzes the rate-limiting step of cholesterol biosynthesis in the body. Administration of rosuvastatin inhibits cholesterol synthesis in the liver and HMG-CoA reductase, and also increases the number of LDL receptors on the surface of liver cells to promote the uptake and breakdown of LDL; these effects contribute to the pharmacological action of rosuvastatin. Since rosuvastatin is minimally metabolized in the liver and mostly excreted in the feces, it has the advantage of relatively fewer drug interactions compared to other statin drugs. Rosuvastatin is a drug used to improve hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia, and approximately 70 products are approved and sold in Korea. In a clinical trial in which cilostazol 200 mg and rosuvastatin 20 mg were administered alone or in combination to healthy adults for 7 days (Non-patent Literature 1), no significant differences were observed in adverse events, clinical laboratory tests, vital signs, electrocardiograms, or physical examinations when comparing the results of monotherapy and combination therapy. Pharmacokinetic results also confirmed that there was only a slight increase in C ss,max of cilostazol during combination therapy, and no significant interactions were observed. However, there have been no clinical trials investigating the combination therapy of cilostazol and rosuvastatin or comparing it with other treatments in patients with peripheral artery disease. According to the 2016 AHA/ACC guidelines for peripheral artery disease of the lower extremities (Non-patent Literature 2), statins are the only drugs recommended for all patients with peripheral artery disease, regardless of the presence of ischemic symptoms. Cilostazol is recommended for patients with peripheral artery disease who exhibit symptoms or claudication. Statins are not approved for the improvement of symptoms of peripheral artery disease. In other words, there is virtually no evidence that the combined administration of cilostazol and rosuvastatin to patients with peripheral artery disease offers additional benefits compared to the administration of cilostazol alone. Figure 1 is a diagram showing the change in lower extremity pain VAS at each visit time relative to the baseline for the test group and the control group. Figure 2 is a diagram showing the change in ICD using the step test at each time of visit relative to the baseline for the test group and the control group. Figure 3 is a diagram showing the change in FCD using the step test at each time of visit relative to the baseline for the test group and the control group. Figure 4 is a diagram showing the change in ACD using the step test at each time of visit relative to the baseline for the test group and the control group. Figure 5 is a diagram showing the change in ABI at each visit time relative to the baseline for the test group and the control group. Figure 6 is a diagram showing the rate of change of TG at each visit time relative to the baseline for the test group and the control group. Figure 7 is a diagram showing the rate of change in HDL-C from baseline at each visit for the test group and the control group. Figure 8 is a diagram showing the rate of change in non-HDL-C from baseline to time of visit for the test group and the control group. Figure 9 is a diagram showing the rate of change in Apo B relative to baseline at each visit for the test group and the control group. Terms or words used in this disclosure should not be interpreted as being limited to their ordinary or dictionary meanings, but should be interpreted in a meaning consistent with the technical concept of this disclosure, based on the principle that the inventor can appropriately define the meaning of terms or words to best describe his own invention. In the present disclosure, terms such as “comprisi