Ultrasound contrast agents and process for the preparation thereof

Inactive Publication Date: 2006-02-16
BRACCO SUISSE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] An aspect of the invention relates to an injectable contrast agent comprising gas-filled microbubbles stabilized by a stabilizing layer predominantly comprising a phospholipid in an aqueous carrier liquid, wherein at least 10% of the total volume of gas contained

Problems solved by technology

The simple dispersion of free gas bubbles in the aqueous medium is however of limited practical interest, since these bubbles are in general not stable enough to be useful as ultrasound contrast agents.
The Applicant has however observed that the amount of agitation energy applied for generating the gas microbubble dispersion in the phospholipid-containing aqueous medium may be excessively high, particularly when small diameter microbubbles are to be obtained (e.g. 23000 rpm for 10 minutes, for obtaining a dispersion of bubbles having a volume mean

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparations 1a-1n

[0210] 10 mg of DPPS are added to about 10 ml of an 10% (w / w) mannitol aqueous solution; the suspension is heated at 65° C. for 15 minutes and then cooled at room temperature (22° C.). Perfluoroheptane (8% v / v) is added to this aqueous phase and emulsified in a beaker of about 4 cm diameter by using a high speed homogenizer (Polytron T3000, probe diameter of 3 cm) for 1 minute at the speed indicated in table 1. The resulting median diameter in volume (DV50) and a mean diameter in number (DN) of microdroplets of the emulsion are shown in table 1. The emulsion is then centrifuged (800-1200 rpm for 10 minutes, Sigma centrifuge 3K10) to eliminate the excess of the phospholipid and the separated pellets (microdroplets) were recovered and re-suspended in the same initial volume of a 10% mannitol aqueous solution.

[0211] The washed emulsion is then collected into a 100 ml balloon for lyophilization, frozen and then freeze-dried according to the above standard procedure. ...

example 2

Preparations 2a-2j

[0212] The same procedure adopted for example 1 is followed, with the only difference that the phospholipid is a mixture of DPPS (20% w / w) and DSPC (80% w / w), the total amount of phospholipid remaining unchanged. The results are summarized in table 2.

TABLE 2EMULSIONGas-filled microbubblesAgitationDV50DNDV50>3 μmEx.(rpm)(μm)(μm)(μm)DV (μm)DN (μm)DV50 / DNpart. %vol. %2a60008.753.077.559.052.273.3321.811.22b100003.541.903.003.711.472.045.0511.72c120003.041.832.453.731.321.852.1519.82d125002.851.762.213.241.271.741.5724.42e130002.981.832.253.041.281.761.7623.52f135002.912.051.882.461.201.570.8733.82g140002.451.671.822.661.161.570.5736.52h145002.181.551.583.041.091.440.3846.52i150001.941.421.341.961.041.280.3161.52j160001.811.381.352.301.031.310.1459.0

example 3

Preparation 3a-3p

[0213] The same procedure adopted for examples 2 is followed, with the only difference that the DPPS / DSPC weight ratio is varied, as reported in table 3. The results are summarized in table 3.

TABLE 3EMULSIONGas-filled microbubblesDPPS / DSPCAgitationDV50DNDV50DN>3 μmEx.ratio(rpm)(μm)(μm)(μm)(μm)DV50 / DNpart. %vol. %3a80 / 20120002.441.541.681.191.410.4839.43b75 / 25120002.531.661.731.181.470.6238.33c60 / 40110003.531.862.751.451.904.0013.63d60 / 40120002.621.601.781.211.470.7235.43e60 / 40140002.361.601.591.131.410.3644.73f50 / 50120002.811.682.281.301.752.0522.63g40 / 60110003.001.722.441.321.852.3119.23h40 / 60120002.881.752.071.271.631.4525.83i40 / 60130002.611.691.761.161.520.5737.63j40 / 60140002.061.431.411.071.310.2343.83k40 / 60145002.391.671.641.151.430.4946.53l30 / 70110003.121.752.641.371.932.7616.33m30 / 70120003.081.812.381.341.782.4519.73n25 / 75110003.151.852.461.311.882.1520.73o10 / 90110003.722.263.141.472.134.6012.13p 5 / 95110004.532.234.081.542.656.357.4

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Abstract

Injectable aqueous suspension of microbubbles filled with a biocompatible gas and a method of preparation thereof. At least 10% of the total volume of gas contained in the microbubbles is contained in microbububbles with a diameter of 1.5 μm or less. The microbubbles can be obtained by preparing an emulsion comprising an aqueous medium, a phospholipid and a water immiscible organic solvent. The emulsion is then freeze-dried and then reconstituted in an aqueous suspension of gas-filled microbubbles.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of co-pending U.S. application, U.S. Ser. No. ______, filed Aug. 2, 2005, which is a national stage application of international application PCT / IB2004 / 000243, filed Feb. 3, 2004, which claims priority to and the benefit of European application EP03002375.8, filed Feb. 4, 2003, all of which are hereby incorporated by reference.FIELD OF THE INVENTION [0002] The present invention relates to a process for the preparation of a dry or lyophilized formulation useful for preparing a gas containing contrast agent usable in diagnostic imaging and to a process for preparing said gas containing contrast agent. [0003] The invention also includes dry formulations prepared by this process, which may be reconstituted to form contrast agent suspensions useful in diagnostic imaging. The invention further includes suspensions of gas filled microbubbles useful in diagnostic imaging prepared using dry formulations...

Claims

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Application Information

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IPC IPC(8): A61K49/22A61K9/19A61K49/18
CPCA61K49/223A61P43/00A61K9/19A61K49/22
Inventor SCHNEIDER, MICHELBUSSAT, PHILIPPEYAN, FENGGUILLOT, CHRISTIAN
Owner BRACCO SUISSE SA
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