Olaparib oral controlled-release and sustained-release pharmaceutical composition and uses thereof

Abstract

The present invention relates to an olaparib oral controlled-release and sustained-release pharmaceutical composition, which contains dissolution form improved olaparib and a matrix polymer for release rate adjustment. According to the present invention, the in vivo absorption behavior, the blood drug level and the PARP enzyme inhibition level of the pharmaceutical composition can be controlled, the pharmaceutical composition has the improved olaparib loading and / or oral absorption and / or bioavailability and / or blood drug concentration control and / or enzyme inhibition level control, and can beused as the sole preparation or can be combined with other treatment methods in the treatment of cancer.

Description

technical field [0001] The invention relates to the field of olaparib pharmaceutical preparations, in particular to an oral sustained and controlled release pharmaceutical composition of olaparib and its application. Background technique [0002] Olaparib (Olaparib), the chemical name is 1-(cyclopropylformyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2 -Fluorobenzoyl]piperazine, the molecular formula is C 24 h 23 FN 4 o 3 , with a molecular weight of 434.46 and the following chemical structure: [0003] [0004] Olaparib (trade name LYNPARZAR) is a new drug developed by AstraZeneca for the targeted therapy of hereditary advanced ovarian cancer. It was approved by the US Food and Drug Administration (FDA) in December 2014. It is currently FDA The only poly ADP transferase (PARP) inhibitor approved for marketing for tumor treatment. Polymerized ADP transferase (PARP) is a key factor in the DNA excision repair pathway, and olaparib can inhibit the activity of PRA...

AI Technical Summary

Problems solved by technology

[0007] However, in the process of R&D, production and clinical application of olaparib immediate-release capsules, there are still many limitations:

[0008] 1) Although the immediate-release capsules can quickly reach the blood drug concentration level obtained by PARP enzyme inhibition, they are eliminated quickly in the body. In order to maintain the blood drug concentration level required for effective enzyme inhibition for a long time, a higher oral dose (400mg, BID .), which leads to a large fluctuation range of the steady-state plasma concentration of olaparib, and the peak value of the steady-state plasma concentration is several times or even ten times higher than the PARP enzyme IC90 value, resulting in more serious side effects, common toxicities Side effects include nausea, fatigue, vomiting, diarrhea, taste disturbance, etc. Serious side effects include myelodysplastic syndrome, acute myeloid leukemia and pneumonia;

[0009] 2) Oral administration of 400mg BID produces higher steady-state plasma drug peaks and larger fluctuations in blood drug concentration (400mg, BID, C min，ss max,ss >6ug / mL), the side effects caused by the sudden high blood concentration have affected the long-term maintenance of the high-concentration free blood concentration required for PARP enzyme inhibition, and the effective utilization rate of olaparib for enzyme inhibition and tumor treatment Limited, which limits the full play of the curative effect of the drug;

[0010] 3) Larger oral doses of drugs (400mg dose, 8 capsules of 0#, BID), also lead to high costs in the production, packaging, storage and transportation of drugs, and poor patient compliance

[0016] According to the above patent search results, there is currently no relevant research on oral sustained-release preparations of olaparib

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