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

A technology of recaprabib and controlled-release drugs, applied in the field of recaprabab pharmaceutical preparations, can solve the problems of drug loss, high cost, and high blood drug concentration

Inactive Publication Date: 2018-06-26
SCI RAINBOW BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, there are certain limitations in the common oral immediate-release tablet currently being studied: 1) 95% of Recaparib in the tablet is released within 15 minutes, that is, most of the drugs are quickly absorbed in the gastrointestinal tract in a short time , leading to sudden high blood drug concentration, large fluctuations in blood drug concentration, resulting in more toxic and side effects; 2) higher steady-state blood drug concentration peak, which also limits the further improvement of blood drug concentration required for efficient enzyme inhibition , which limits the full play of the drug effect of Recaprabab; 3) The effective utilization rate of the drug is not high, and the drug bioavailability is only 36%, and

Method used

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  • Rucaparib oral controlled-release and sustained-release pharmaceutical composition and uses thereof
  • Rucaparib oral controlled-release and sustained-release pharmaceutical composition and uses thereof
  • Rucaparib oral controlled-release and sustained-release pharmaceutical composition and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0148] Example 1 Fast-Slow Double-Effect Release Matrix Tablet

[0149]

[0150] Immediate-release layer: Pass the prescribed amount of Recapabu, micronized silica gel and Soluplus through a 60-mesh sieve and mix with a three-dimensional mixer at 30 rpm for 25 minutes, then slowly add to the preheated melt extruder. The extrudate was collected and crushed through a 60-mesh sieve to obtain a solid dispersion of Recapabu. After the obtained solid dispersion of Recapabril is uniformly mixed with the prescription amount of other materials (disintegrant PVPP XL) and other auxiliary materials (mannitol and magnesium stearate), it is ready for tableting.

[0151] Sustained release layer: After passing the prescribed amount of Recapabu, PVP VA64 and micronized silica gel through a 60 mesh sieve and mixing them, slowly add them to the preheated melt extruder, collect the extrudates and crush them through 60 mesh The solid dispersion of Recapabub was obtained by sieving. The obtained solid...

Example Embodiment

[0156] Comparative Example 1 Immediate-release tablets

[0157] The prescription for immediate release tablets is as follows:

[0158]

[0159] The granular active ingredient ricapabu dextrocamphorsulfonate and the auxiliary materials microcrystalline cellulose PH101, sodium mannitol starch, colloidal silicon dioxide and magnesium stearate are mixed uniformly according to the prescription ratio, sieved, and placed in a three-dimensional multidirectional mixer Mix uniformly, use 98% ethanol as a binding solvent, sieving the granules, adding the prescribed amount of intergranular auxiliary materials and mixing them, and then press the tablet to obtain an immediate-release tablet prescription.

[0160] The dissolution rate is determined by the first method device of the dissolution test method (Chinese Pharmacopoeia 2010 Edition Two Appendix XC), at 37°C, with 900mL pH 2.0 release medium, rotating speed of 75 revolutions per minute, operating in accordance with the law, , 30, 45, 60, 7...

Example

[0162] Experimental Example 1

[0163] The immediate-release tablets of Recapabu of Comparative Example 1 and the rapid-release dual-release matrix tablets of Example 1 were administered to full-bodied beagle dogs (n=3), respectively, and they were administered with 25 mL of water. After that, blood was taken at a predetermined time point. The blood sample was centrifuged at 4000 rpm for 10 min at 4°C, and the upper layer of plasma was taken for LC-MS blood concentration detection. The results are shown in Picture 10 .

[0164] Relative to C of immediate release tablet max (2750.3ng / mL) and AUC 0-h (19470h*ng / mL), C max Reduced to 1589.4ng / mL, a decrease of about 42%; AUC 0-h 20110h*ng / mL, change Picture 10 The results can still be seen, compared with the immediate-release tablets, the C max However, it can be maintained at a higher blood concentration for a long time, reducing the toxic and side effects caused by a sudden increase in the blood concentration, and at the same time,...

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Abstract

The present invention relates to a rucaparib oral controlled-release and sustained-release pharmaceutical composition, which contains dissolution form improved rucaparib and a matrix polymer for regulating release rate. 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 rucaparib loading and/or oral absorption and/or bioavailability and/or blood drug concentration control and/or enzyme inhibition level control, and canbe used as the sole preparation or can be combined with other treatment methods in the treatment of cancer.

Description

Technical field [0001] The present invention relates to the field of Recapabu drug preparations, in particular to an oral sustained and controlled release pharmaceutical composition of Recapabu and its use. Background technique [0002] Rucaparib, chemical name 8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4, 3,2-EF][2]benzazepine-6-one, the molecular formula is C 19 H 18 FN 3 O, molecular weight is 323.46, with the following chemical structure: [0003] [0004] In 2011, Pfizer stopped the development of a new drug for Recapabu and authorized Clovis Oncology to develop new drugs and markets for the compound; in 2012, the compound was used as an orphan drug in the United States and Europe for ovarian use Cancer research; in 2015, the drug was used as a third-line clinical drug for monotherapy and was used in clinical treatment research for BRCA-mutated ovarian cancer. It achieved good results and obtained the breakthrough therapy certification of the US ...

Claims

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Application Information

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IPC IPC(8): A61K9/52A61K9/24A61K31/55A61K47/32A61K47/38A61P35/00
CPCA61K9/0002A61K9/2027A61K9/2054A61K9/2086A61K9/5026A61K9/5047A61K9/5073A61K31/55A61K31/551A61K47/32A61K47/38A61P35/00
Inventor 不公告发明人
Owner SCI RAINBOW BIOPHARMA CO LTD
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