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Modified drugs for use in liposomal nanoparticles

A nanoparticle and liposome technology, applied in the field of drugs for the modification of liposome nanoparticles, can solve problems such as limiting therapeutic potential

Inactive Publication Date: 2011-06-22
THE UNIV OF BRITISH COLUMBIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

at Taxotere Pharmacokinetic variability can cause significant variability in toxicity and efficacy, as well as hematologic toxicity associated with systemic exposure to unconjugated drug
In addition, since the therapeutic activity of taxanes increases with the duration of tumor cell drug exposure, the dose-limiting toxicities of commercial taxane formulations substantially limit their therapeutic potential

Method used

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  • Modified drugs for use in liposomal nanoparticles
  • Modified drugs for use in liposomal nanoparticles
  • Modified drugs for use in liposomal nanoparticles

Examples

Experimental program
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preparation example Construction

[0313] Various methods available for preparing liposomes are described, for example, in: Szoka et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980); U.S. Pat. , ed., Marcel Dekker, Inc., New York, 1983, Chapter 1; and Hope et al. Chem. Phys. Lip. 40:89 (1986), the entire contents of which are incorporated herein by reference. In some preferred aspects, liposomes are small liposomes with a diameter of about 100 nm formed by extrusion of a hydrated lipid dispersion through a filter membrane with 100 nm pores, generally as described in Hope et al., Biochim. Biophys. Acta, 812:55-65 (1985), which is incorporated herein by reference.

[0314] In one method, heterogeneously sized multilamellar vesicles are prepared by dissolving vesicle-forming lipids in a suitable organic solvent or solvent system, and drying the mixture under vacuum (or under inert gas conditions) to form thin lipids. plasma membrane. Alternatively, lipids can be dissolved in a suitable solvent such as tert-butanol a...

Embodiment 1

[0329] Embodiment 1-chemical synthesis method

[0330] Quantification of weakly basic derivatives and unmodified drugs using ultra-performance liquid chromatography (UPLC). Use an instrument consisting of: Waters Acquity TM UPLC system with photodiode array detector (PDA) and triple-quadrupole (TQ) MS detector; Empower TM Data acquisition software version 2.0 (Waters, USA). Separation was performed as follows: using Waters Acquity TM BEH C18 column (1.7 μm, 2.1×100 mm), flow rate 0.25 mL / min, mobile phase A and B consisted of water containing 0.1% trifluoroacetic acid (TFA) and acetonitrile containing 0.1% TFA, respectively. For prednisone and etoposide derivatives and unmodified drugs, the mobile phase consisted of water with 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B). The mobile phase was delivered under a programmed linear gradient at a column temperature of 23°C.

[0331] For the docetaxel derivative and docetaxel, the separation was initiat...

Embodiment 2

[0342] Example 2 - Taxane Derivatives

[0343] At the hydroxyl group at the C-2' position, docetaxel was derivatized with N-methyl-piperazinylbutanoic acid to form the amino ester prodrug (TD1), as described below.

[0344] 2′-O-(N-methyl-piperazinylbutyrate) derivative of docetaxel (TD1)

[0345] Linker Synthesis: 4-(4-Methylpiperazin-1-yl)butyrate hydrochloride

[0346]

[0347] 1-Methylpiperazine (7.68 mL, 70 mmol, 4 equiv) was added to a stirred solution of ethyl 4-bromobutyrate (2.5 mL, 17.3 mmol) in ethyl acetate (50 mL) at room temperature. The solution was stirred at 25°C for 1 hour, a white precipitate formed and then heated to 70°C on an oil bath for 1 hour. TLC analysis (20% ethyl acetate (EtOAc) / hexanes, Rf = 0.9 (starting material), 0.1 (product), visualized with iodine (I2)) indicated complete consumption of the bromide reagent. The reaction was diluted with EtOAc (100mL), transferred to a separatory funnel, water (100mL), sodium bicarbonate (NaHCO 3 , s...

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Abstract

Drag derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drag derivatized with a weak-base moiety that facilitates active loading of the drag through a LN transmembrane pH or ion gradient into the aqueous interior of the LN. The weak-base moiety can optionally comprise a lipophilic domain that facilitates active loading of the drag to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drag derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and / or other benefits relative to the corresponding free drags.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application 61 / 055,929 (filed May 23, 2008), the entire contents of which are incorporated herein by reference. field of invention [0003] The present invention generally relates to the chemical modification of drugs that resist or cannot be encapsulated in liposomes to form derivatives that can be efficiently loaded into liposomal nanoparticles (LN) with transmembrane pH or ion gradients method. In some preferred aspects, the derivative is a prodrug that is readily converted to the free drug once released from the LN. The present invention also relates to pharmaceutical derivatives prepared according to the method of the present invention, LN preparations and pharmaceutical compositions containing such derivatives, as well as methods for their preparation and use. Background technique [0004] Many existing drug discovery strategies are based on the discovery of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K31/337A61K45/00
CPCA61K9/1278A61K9/127A61K31/337A61K31/4525A61K47/48061A61K31/5377A61K31/496A61K47/542A61P29/00A61K31/573C07D305/14C07D405/12C07D498/14C07H17/04A61K47/545C07J41/005C07K7/645A61K31/706C07J43/003
Inventor 皮特·库利斯马塞尔·巴利马科·奇厄福利尼诺伯特·莫勒伊戈·吉加尔特塞弗
Owner THE UNIV OF BRITISH COLUMBIA
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