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Pharmaceutical composition comprising a campothecin derivative

A composition and drug technology, applied in the field of camptothecin derivatives, can solve the problems of unstable solubility of derivatives

Inactive Publication Date: 2010-02-17
SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] By forming a unique pharmaceutically active composition comprising a functionalized phospholipid, the present invention overcomes the problem of camptothecin derivatives, including 7-tert-butoxyiminomethylcamptothecin, when administered in their free form. Problems of instability and poor solubility of the above-mentioned derivatives

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1: 7-tert-butoxyiminomethylcamptothecin in small unilamellar, long-circulating liposomes surfaced with a polymer (e.g. PEG: polyethylene glycol Alcohol) grafting.

[0081] 7-tert-butoxyiminomethylcamptothecin in PEG-liposomes

[0082] According to the film hydration method (also known as the Bangham method (Ref. Bangham A.D. & al., J. Mol. Biol. 13, 238-252, 1965)), the sample was prepared as follows:

[0083] Step 1: Preparation of bulk drug (DS), lipid film. Dissolve excipients and DS in ethanol. The organic solvents were evaporated on a rotary evaporator (Rotavap R-210 / 215 from Büchi Switzerland) at 40°C for 4 hours to obtain a very uniform DS, lipid film. The obtained film was kept on a rotary evaporator at 55° C. and 30 mbar for 2 hours.

[0084] Step 2: DS, hydration of the lipid film. A PB-Man buffer solution (pH 7.4) was added to the DS, lipid film under magnetic stirring and kept at 40°C for 30 minutes. Obtain a milky solution: liposome solution. ...

Embodiment 2

[0092] Example 2: 7-tert-butoxyiminomethylcamptothecin in Ligand-Containing Liposomes: Surface Grafting with Certain Ligands for Drug Targeting Strategies.

[0093] 7-tert-butoxyiminomethylcamptothecin in PEG-liposomes

[0094] Samples were prepared according to the film hydration method as described in Example 1.

[0095] sample composition

[0096] Element

Concentration (mg / ml)

Volume (ml)

Phosphatidylcholine

100

-

MPEG-2000-DSPE

26

-

cholesterol

10

-

D, Lα-tocopherol

0.5

-

7-tert-butoxyiminomethylcamptothecin

0.25

-

Phosphate buffer pH5.4

-

10

[0097] analysis features

[0098] Analytical test

result

Appearance (visual inspection)

Light greenish yellow, translucent dispersion

The average particle size

122nm

Particle size distribution

99%<402nm

[0099] Stability test at 5°C and...

Embodiment 3

[0103] Example 3: 7-tert-butoxyiminomethylcamptothecin in long-circulating phospholipid micelles whose surface is grafted with a certain polymer (eg PEG2000: polyethylene glycol).

[0104] 7-tert-butoxyiminomethylcamptothecin in PEG-liposomes

[0105] Samples were prepared according to the film hydration method as described in Example 1. The only difference is that in step 4, the liposome solution was extruded through polycarbonate filters (100 and 50 nm).

[0106] sample composition

[0107] Element

Concentration (mg / ml)

Volume (ml)

Phosphatidylcholine

100

-

MPEG-2000-DSPE

26

-

cholesterol

10

-

D, Lα-tocopherol

0.5

-

7-tert-butoxyiminomethylcamptothecin

0.25

-

Phosphate buffer pH5.4

-

40

[0108] analysis features

[0109] Analytical test

result

Appearance (visual inspection)

Light greenish yellow, translucent ...

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PUM

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Abstract

The present invention relates to pharmaceutical compositions comprising a topoisomerase I inhibitor including, but not limited to, a camptothecin derivative.

Description

technical field [0001] The present invention relates to pharmaceutical compositions comprising topoisomerase I inhibitors, including but not limited to camptothecin derivatives. Background technique [0002] Camptothecin derivatives are a class of compounds described in US Patent No. 6,242,457. In general, camptothecin derivatives, such as those disclosed in U.S. Patent No. 6,242,457, present very specific challenges with regard to drug delivery, particularly the biological effects of the drug due to the low water solubility of these derivatives. The question of availability. [0003] 7-tert-butoxyiminomethylcamptothecin is a quinoline-based alkaloid that blocks cell division in rapidly dividing cells such as cancer cells by inhibiting topoisomerases. The drug substance is extremely poorly soluble in aqueous media, preventing its delivery to cancer cells in effective amounts. [0004] In addition, 7-tert-butoxyiminomethylcamptothecin is prone to hydrolysis and the lactone...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K31/4745A61K31/4741
CPCA61K9/1272A61K31/4745A61K9/1271A61K31/4741A61P35/00A61P43/00A61K9/127
Inventor G·弗朗西斯J·奥戈卡张家艾
Owner SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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