US 12,343,396 B2
Ultrasound mediated delivery of drugs
Andrew John Healey, Moss (NO); Per Christian Sontum, Oslo (NO); and Svein Kvale, As (NO)
Assigned to EXACT THERAPEUTICS AS, Oslo (NO)
Filed by EXACT THERAPEUTICS AS, Oslo (NO)
Filed on May 14, 2021, as Appl. No. 17/302,917.
Application 17/302,917 is a division of application No. 15/024,265, abandoned, previously published as PCT/NO2014/050177, filed on Sep. 26, 2014.
Claims priority of application No. 20131293 (NO), filed on Sep. 27, 2013.
Prior Publication US 2021/0299256 A1, Sep. 30, 2021
Int. Cl. A61K 31/337 (2006.01); A61K 9/00 (2006.01); A61K 9/107 (2006.01); A61K 9/16 (2006.01); A61K 9/19 (2006.01); A61K 31/454 (2006.01); A61K 31/475 (2006.01); A61K 31/506 (2006.01); A61K 31/517 (2006.01); A61K 31/52 (2006.01); A61K 31/5377 (2006.01); A61K 31/704 (2006.01); A61K 31/7068 (2006.01); A61K 41/00 (2020.01); A61K 49/00 (2006.01); A61K 49/22 (2006.01); A61L 24/00 (2006.01); A61P 7/04 (2006.01)
CPC A61K 41/0047 (2013.01) [A61K 9/0009 (2013.01); A61K 9/1075 (2013.01); A61K 9/16 (2013.01); A61K 9/19 (2013.01); A61K 31/337 (2013.01); A61K 31/454 (2013.01); A61K 31/475 (2013.01); A61K 31/506 (2013.01); A61K 31/517 (2013.01); A61K 31/52 (2013.01); A61K 31/5377 (2013.01); A61K 31/704 (2013.01); A61K 31/7068 (2013.01); A61K 41/0028 (2013.01); A61K 49/0078 (2013.01); A61K 49/223 (2013.01); A61L 24/001 (2013.01); A61L 24/0015 (2013.01); A61P 7/04 (2018.01); A61L 2300/418 (2013.01); A61L 2300/45 (2013.01); A61L 2300/62 (2013.01); A61L 2430/36 (2013.01)] 19 Claims
 
1. A method of delivering a therapeutic agent to a mammalian subject, comprising:
administering a cluster composition and a separate therapeutic agent, the cluster composition comprising a suspension of clusters comprising a diameter in the range of 3 to 10 μm and a circularity of <0.9 in an aqueous biocompatible medium, the cluster composition formed by mixing a first component with a second component, the first component comprising a gas microbubble and a first stabilizer configured to stabilize the microbubble, the second component comprising a microdroplet comprising an oil phase and a second stabilizer comprising a phospholipid, the second stabilizer configured to stabilize the microdroplet, the oil phase comprising a diffusible component configured to diffuse into the gas microbubble so as to transiently increase the size thereof;
enlarging microbubbles of the clusters to form an enlarged bubble which is localized at a region of interest due to transient trapping in the microcirculation at the region of interest by activating a phase shift of the diffusible component by application of an activating ultrasound insonation to a region of interest within the subject, the activating ultrasound insonation comprising a frequency of between about 1 to 10 MHz and a mechanical index of 0.2 to 0.4;
oscillating the enlarged bubble to mechanically flex a vascular wall within the region of interest by application of an enhancement ultrasound insonation to the region of interest after application of the activating ultrasound, the oscillation configured to enhance uptake of the therapeutic drug, the enhancement ultrasound insonation comprising a frequency of about 200 to 1000 kHz and a mechanical index of less than about 0.4; and
wherein the gas microbubble of the first component and the microdroplet of the second component have opposite surface charges and form the clusters via attractive electrostatic interactions, and wherein the activating ultrasound insonation frequency is different than the enhancement ultrasound insonation frequency.