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Composition comprising gas-filled microcapsules for ultrasound mediated delivery

a technology of ultrasound and microcapsules, which is applied in the direction of liposomal delivery, non-active genetic ingredients, disrupted materials, etc., can solve the problems of cumbersome manufacturing processes, render the whole system rather ineffective, and the release of therapeutic compounds may be less effective in the hydrophilic environment of the blood circulation or cells

Inactive Publication Date: 2009-02-12
BRACCO RES USA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0020]applying an ultrasound wave to said body part, said wave having an acoustic pressure capable of destroying a portion of said microcapsules, to effectively deliver said bioactive agent to said cell.

Problems solved by technology

This solution has however the disadvantage that the therapeutic compound has to be somehow inserted into the or attached to the gas-filled microvesicle, thus entailing cumbersome manufacturing processes.
In addition, the fact that same microvesicle carrying the therapeutic compounds shall undergo to the cavitation effects to provide the necessary cellular permeabilization renders the whole system rather ineffective.
Furthermore, as the therapeutic compound is in general hydrophobic or has to be rendered hydrophobic (e.g. in the case of genetic material) for it to be compatible with the material forming the microvesicles, the release of the therapeutic compound may be less effective in the hydrophilic environment of the blood circulation or of the cells.

Method used

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  • Composition comprising gas-filled microcapsules for ultrasound mediated delivery
  • Composition comprising gas-filled microcapsules for ultrasound mediated delivery
  • Composition comprising gas-filled microcapsules for ultrasound mediated delivery

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0121]Preparation of Thin-shell Microbubbles Filled with Air (Comparative)

[0122]A solution containing 15 mg of distearoyl phosphatidylcholine (DSPC), 15 mg of dipalmitoyl phosphatidylglycerol (DPPG) and 3 mg of palmitic acid in hexane / ethanol 8 / 2 (v / v) is prepared and the solvent evaporated to dryness. The resulting powder and 2 g of polyethylene glycol (MW4000) are dissolved in 14 g of tert-butanol at 60° C. The solution is aliquoted in 10 ml glass vials (250 μl / vial), rapidly cooled to −45° C. and lyophilised. The lyophilisate is exposed to air and then reconstituted with 5 ml of 0.9% saline solution by gentle swirling. The resulting suspension contains air-filled microbubbles (2×108 bubbles / ml, analysed by Coulter Multisizer II).

example 2

[0123]Preparation of Thin-shell Microbubbles Filled with Perfluorocarbon (Comparative)

[0124]The procedure of Example 1 is repeated except that the air in glass vial containing the lyophilisate was first evacuated by a vacuum pump and replaced by a perfluorocarbon gas (C4F10). The stiffness of the obtained microbubbles, measured according to the previously described methodology, is of about 1 N / m.

example 3

[0125]Preparation of Lipid-shell Microcapsules Filled with Air

[0126]60 mg of tripalmitin is dissolved in cyclohexane (0.6 ml). Distearoyl phosphatidylglycerol, sodium salt (DSPG.Na-40 mg) is dispersed in distilled water (30 ml) at 70° C. for 20 minutes and cooled to 45° C. The organic phase is emulsified in the aqueous phase using a POLYTRON® homogeniser (8500 rpm). The average diameter of the resulting droplets is of about 3 μm as determined with a photon correlation spectrometer (Malvern Master Sizer®).

[0127]This emulsion was added to a 500 ml glass vessel containing 200 mg of polyvinyl alcohol (PVA-MW 9000—from Aldrich) dissolved in 5 ml of distilled water. After mixing, the resulting emulsion was rapidly frozen at −40° C. and lyophilised (Christ Beta 1-8K).

[0128]The cake was resuspended in 20 ml of water. Air-containing microcapsules rose to the surface. The floating capsules were recovered, resuspended in 0.9% NaCl and analyzed with a Coulter counter Multisizer II. The stiffnes...

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PUM

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Abstract

Composition comprising gas filled microcapsules and a bioactive agent, useful for an ultrasound-mediated delivery of said bioactive agent. The microcapsules comprise a relatively stiff shell of polymeric or lipid material and have in particular a resistance to a mechanical index of at least 0.15, while the bioactive agent is substantially unbound to the shell of the microcapsules. The composition of the invention is particularly suitable for effectively delivering a genetic material into a cell, upon exposure of the composition to a level of acoustic pressure capable of destroying a portion of the microcapsules and releasing the gas contained therein.

Description

FIELD OF THE INVENTION [0001]The present invention relates to the use of a composition comprising gas filled microcapsules and a bioactive agent for preparing a formulation for ultrasound-mediated delivery of a bioactive agent and to a method for delivery of a bioactive agent which comprises administering an effective amount of said medicament to a patient in need thereof.BACKGROUND OF THE INVENTION [0002]Ultrasound contrast agents (UCA) have been widely used in diagnostic applications in medical research and clinical practice. Typically, said UCA are in the form of stabilized gas-bubbles, also known as gas-filled microvesicles. Gas-filled microvesicles are in general divided into two main categories, i.e. microbubbles and microcapsules (or microballoons).[0003]Microbubbles include aqueous suspensions in which the bubbles of gas are bounded at the gas / liquid interface by a thin envelope (film) involving a stabilizing amphiphilic material disposed at the gas to liquid interface. Micr...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K9/14A61P43/00
CPCA61K9/0009A61K47/6925A61P43/00A61K41/0028A61K48/0008
Inventor BETTINGER, THIERRYYAN, FENGMEHIER-HUMBERT, SOPHIEFRINKING, PETER
Owner BRACCO RES USA
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