Methods and devices for preparation of ultrasound contrast agents

1. A method of using lipid-encapsulated gas microspheres for ultrasound imaging comprising:

placing a vial comprising an ultrasound contrast agent (UCA) lipid formulation in a shaking device comprising a holder, a detector and a processor;

determining identity of the UCA lipid formulation as either a non-aqueous UCA lipid formulation or an aqueous UCA lipid formulation based on an indicator on the vial that is read by the detector;

selecting a shaking rate and duration from pre-set options for non-aqueous and aqueous formulations using the processor;

activating the identified UCA lipid formulation to form lipid-encapsulated gas microspheres, by imparting a shaking pattern at the selected shaking rate and for the selected duration, using the shaking device;

administering the lipid-encapsulated gas microspheres to a subject; and

obtaining an ultrasound image of the subject;

wherein the aqueous UCA lipid formulation comprises DPPA, DPPC and MPEG5000-DPPE in an aqueous solvent, and a gas,

wherein the non-aqueous UCA lipid formulation comprises DPPA, DPPC and MPEG5000-DPPE in a non-aqueous solvent comprising propylene glycol and glycerol, and a gas, and having less than 5% water (w/w),

wherein the detector is an RFID reader, a barcode scanner, a color scanner, or a microchip reader, and

wherein the pre-set options comprise a shaking duration of at least 30 seconds.

2. The method of claim 1 , wherein one pre-set option comprises a shaking duration of about 45 seconds and a shaking rate of at least 4000 shaking motions per minute.

3. The method of claim 1 , wherein the shaking device comprises two or more holders.

4. The method of claim 1 , wherein the lipid-encapsulated gas microspheres have a mean diameter of about 1-2 microns.

5. The method of claim 1 , wherein the shaking device comprises a battery.

6. The method of claim 1 , wherein the holder can accommodate a 35 mm tall and 14.5 mm diameter vial.

7. The method of claim 1 , wherein one pre-set option comprises a shaking rate that is at least 4500 shaking motions per minute.

8. The method of claim 1 , wherein one pre-set option comprises a period of time that is 45 seconds and a shaking rate that is 4530 shaking motions per minute.

9. The method of claim 8 , wherein another pre-set option comprises a period of time that is 45 seconds and a shaking rate that is about 4900 shaking motions per minute.

10. The method of claim 1 , wherein the shaking device further comprises at least one storage device configured to store a look-up table that stores the pre-set options.

11. The method of claim 1 , wherein the indicator provides a method of use for the identified UCA lipid formulation.

12. A method of using lipid-encapsulated gas microspheres for ultrasound imaging comprising:

placing a vial comprising an ultrasound contrast agent (UCA) lipid formulation and associated indicator in a shaking device, wherein the device comprises a holder, a detector, one or more controllers and a processor,

reading the indicator on the vial using the detector, and identifying the vial as comprising a non-aqueous or an aqueous UCA lipid formulation based on the indicator and optionally lookup table stored in the device,

selecting a set of activation parameters for the identified UCA lipid formulation from a first set of activation parameters for a non-aqueous UCA lipid formulation and a second set of activation parameters for an aqueous UCA lipid formulation, as programmed in the device, using the processor,

activating the identified UCA lipid formulation to form lipid-encapsulated gas microspheres, using the selected set of activation parameters specific to the identified UCA lipid formulation using the one or more controllers, wherein activating comprises imparting a shaking pattern on the vial,

administering the lipid-encapsulated gas microspheres to a subject, and

obtaining an ultrasound image of the subject,

wherein the aqueous UCA lipid formulation comprises DPPA, DPPC and MPEG5000-DPPE in an aqueous solvent, and a gas,

wherein the non-aqueous UCA lipid formulation comprises DPPA, DPPC and MPEG5000-DPPE in a non-aqueous solvent comprising propylene glycol and glycerol, and a gas, and having less than 5% water (w/w),

wherein the detector is an RFID detector, a barcode scanner, a color scanner, or a microchip reader, and

wherein the first and the second set of activation parameters comprise a shaking time of at least 30 seconds.

13. A method of using lipid-encapsulated gas microspheres for ultrasound imaging comprising:

placing a vial comprising an ultrasound contrast agent (UCA) lipid formulation and associated indicator in a shaking device, wherein the device comprises a holder, a detector and a processor,

reading the indicator using the detector, and thereby distinguishing a non-aqueous UCA lipid formulation requiring activation for a first pre-determined period of time that is at least about 30 seconds and/or at a first pre-determined shaking rate that is at least 3000 shaking motions per minute from an aqueous UCA lipid formulation requiring activation for a different pre-determined period of time and/or a different pre-determined shaking rate;

activating the non-aqueous UCA lipid formulation, by imparting a shaking pattern using the shaking device, for the first pre-determined period of time and/or at the first pre-determined shaking rate to form lipid-encapsulated gas microspheres;

administering the lipid-encapsulated gas microspheres to a subject; and

obtaining an ultrasound image of the subject;

wherein the detector is an RFID detector, a barcode scanner, a color scanner, or a microchip reader, and

wherein the non-aqueous UCA lipid formulation comprises less than 5% water (w/w).

14. The method of claim 13 , wherein the non-aqueous UCA lipid formulation comprises DPPA, DPPC and MPEG5000-DPPE.

15. The method of claim 13 , wherein the first pre-determined period of time is about 75 seconds.

16. The method of claim 15 , wherein the first pre-determined shaking rate is about 4530 shaking motions per minute.

17. The method of claim 13 , wherein the first pre-determined shaking rate is at least 4500 shaking motions per minute.

18. The method of claim 13 , wherein the first pre-determined shaking rate is about 4900 shaking motions per minute.

19. The method of claim 13 , wherein, upon distinguishing the non-aqueous UCA lipid formulation from the aqueous UCA lipid formulation, the shaking device automatically selects the first pre-determined period of time from at least two pre-determined periods of time.

20. The method of claim 13 , wherein, upon distinguishing the non-aqueous UCA lipid formulation from the aqueous UCA lipid formulation, the shaking device automatically selects the first pre-determined shaking rate from at least two pre-determined shaking rates.

21. The method of claim 13 , wherein the shaking device comprises two or more holders.

22. The method of claim 13 , wherein the lipid-encapsulated gas microspheres have a mean diameter of about 1-2 microns.

23. The method of claim 13 , wherein the shaking device comprises a battery.

24. The method of claim 13 , wherein the holder can accommodate a 35 mm tall and 14.5 mm diameter vial.

25. The method of claim 13 , wherein the non-aqueous UCA lipid formulation is activated for 45 seconds at about 4900 shaking motions per minute.

26. The method of claim 13 , wherein the first pre-determined shaking rate is at least 5000 shaking motions per minute.

27. A method of using lipid-encapsulated gas microspheres for ultrasound imaging comprising:

placing a vial comprising an ultrasound contrast agent (UCA) lipid formulation in a shaking device comprising a holder, a detector, and a processor,

determining identity of the UCA lipid formulation as a non-aqueous UCA lipid formulation based at least in part on an indicator on the vial that is read by the detector,

selecting a shaking rate and duration from pre-set options for a non-aqueous formulation using the processor,

activating the identified UCA lipid formulation to form lipid-encapsulated gas microspheres, by imparting a shaking pattern at the selected shaking rate and for the selected duration, using the shaking device,

administering the lipid-encapsulated gas microspheres to a subject; and

obtaining an ultrasound image of the subject;

wherein the detector is an RFID detector, a barcode scanner, a color scanner, or a microchip reader, and

wherein the non-aqueous UCA lipid formulation comprises less than 5% water (w/w).

28. The method of claim 27 , wherein the indicator provides a method of use for the identified UCA lipid formulation.