Pharmaceutical composition comprising PARP inhibitor

A technology of composition and medicine, applied in the field of pharmaceutical composition containing PARP inhibitors and its preparation, capable of solving problems such as poor stability of solid dispersions

Active Publication Date: 2020-02-28
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN102238945A has described the pharmaceutical composition that comprises olaparib solid dispersion, and wherein the carrier material of solid dispersion is copovidone, and point out that the stability of solid dispersion is poor when PVP is used as carrier material

Method used

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  • Pharmaceutical composition comprising PARP inhibitor
  • Pharmaceutical composition comprising PARP inhibitor
  • Pharmaceutical composition comprising PARP inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Referring to the general test in the second part of the Chinese Pharmacopoeia 2010 edition, weigh the excess compound shown in formula I that has been ground into a fine powder in a certain amount of solvent (25°C ± 2°C), shake vigorously for 30 seconds every 5min, and observe the concentration within 30min. For drug dissolution, filter, discard the primary filtrate and take the subsequent filtrate to detect the concentration and calculate the solubility.

[0054]

[0055] As can be seen from the test results, the compound shown in formula I is slightly soluble in acetone and tetrahydrofuran, very slightly soluble in absolute ethanol, almost insoluble in conventional aqueous solvents, and the solubilizing effect of surfactants on raw materials is limited, Therefore, preparations cannot be prepared by conventional means.

Embodiment 2-3

[0057]

[0058]

[0059] Remarks: *Solvents are removed during production

[0060] Add the prescribed amount of copovidone S630 or PVP K30 to ethanol to dissolve evenly, add the prescribed amount of acetone, stir and mix evenly, add the compound shown in formula I to the above solution, heat and stir at 60°C until the compound shown in formula I completely dissolved. The above solution was spray-dried, and the obtained powder was dried at 60° C. to obtain a solid dispersion.

Embodiment 4

[0062] Investigate respectively the physical stability of embodiment 2 and 3 two kinds of solid dispersions under high temperature (40 ℃, 60 ℃) and high humidity (25 ℃, RH75 ± 5%, 25 ℃, RH90 ± 5%) conditions and accelerate Chemical stability under conditions. Compare the appearance and crystal form changes of the two placed in a watch glass. The two solid dispersions were additionally tested for solvent residues.

[0063] Residual solvent detection method: adopt gas chromatography, DB-5 capillary column (30m×0.53mm×1.0μm), flame ionization detector (FID), and use water as solvent.

[0064] Active substance content, total impurities, etc. detection method (the same below): detection by high performance liquid chromatography system, the chromatographic column is Phenomenex Luna C18 column, 4.6mm×200mm, 5μm, mobile phase: 0.02mol / L potassium dihydrogen phosphate solution / acetonitrile, detection wavelength: 254nm, 200nm.

[0065] Influencing factor test

[0066]

[0067] ...

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PUM

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Abstract

The invention relates to a pharmaceutical composition comprising a PARP inhibitor. In particular, the invention relates to a pharmaceutical composition comprising a solid dispersion of a compound shown in a formula I. The composition has a good dissolution effect and excellent stability, and can be better applied to clinic.

Description

technical field [0001] The disclosure belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing a PARP inhibitor and a preparation method thereof. Background technique [0002] PARPs (Poly(ADP-ribose) polymerases), characterized by polyadenosine diphosphate-ribosylation activity, constitute a superfamily of 18 nuclear and cytoplasmic enzymes. This poly-ADP-ribosylation can regulate the catalytic activity and protein-protein interaction of the target protein and regulate many basic biological processes, including DNA repair, cell death, and genome stability (see D'Amours et al. Biochem. J, 1999, 342, 249). [0003] PARP-1 activity accounts for about 80% of the total cellular PARP activity, and it and its closest relative PARP-2 become members of the PARP family with the ability to repair DNA damage. As a DNA damage sensor and signaling protein, PARP-1 can quickly detect and directly bind to DNA damage sites, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14A61K47/32A61K31/4985A61P35/00
CPCA61K9/146A61K31/4985A61P35/00A61K9/0019A61K9/0073A61K9/19A61K9/1652A61K31/502A61K47/32A61K9/485A61K9/4858A61K9/4866
Inventor 徐佳佳陈昊王旭
Owner JIANGSU HENGRUI MEDICINE CO LTD
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