Granted Patent B2

US 12,622,867 · App. 17/755,221 · Granted May 12, 2026

Inventors: Per Christian Sontum (Oslo, NO); Andrew John Healey (Moss, NO); Svein Kvale (As, NO)

Assignee: EXACT THERAPEUTICS AS

A61K9/0009A61K9/1075A61K9/5015A61K31/337A61K31/4745A61K45/06A61P35/00

Abstract

Claims (33)

1 . A method of Acoustic Cluster Therapy (ACT) treatment comprising:

(i) administering a pharmaceutical composition to a mammalian subject with pancreatic cancer; wherein the pharmaceutical composition comprises:

(a) a cluster composition which comprises a suspension of clusters in an aqueous biocompatible medium, where said clusters have a mean diameter in the range 3 to 10 μm, and a circularity <0.9, and wherein the cluster concentration of clusters in the size range 3-10 μm is at least 10 million/ml, the cluster composition comprises:

(i) a first component which comprises gas microbubbles and first stabilizer to stabilize said microbubbles; and

(ii) a second component which comprises microdroplets comprising an oil phase and second stabilizer to stabilize said microdroplets, where the oil phase comprises a diffusible component capable of diffusing into said gas microbubbles so as to at least transiently increase the size thereof,

wherein the microbubbles and microdroplets of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions; and

(b) a therapeutic agent selected from the group consisting of chemotherapeutic agents, immunotherapeutic agents, and combinations thereof,

wherein when the therapeutic agent includes said chemotherapeutic agents, and wherein when said chemotherapeutic agents include paclitaxel, said paclitaxel is in an albumin-bound form,

wherein the at least one therapeutic agent is pre-, and/or co-and/or post administered separate to the cluster composition;

(ii) optionally imaging the clusters of said pharmaceutical composition using ultrasound imaging to identify a region of interest for treatment within said subject;

(iii) activating a phase shift of the diffusible component of the second component of the cluster composition from step (i) by ultrasound insonation of a region of interest within said subject; and

(iv) facilitating extravasation of the therapeutic agents administered in step (i) by further ultrasound irradiation.

2 . The method of claim 1 , wherein the step (iii) of activating the phase shift is performed with ultrasound insonation at a frequency of 1 to 10 MHz and with a mechanical index of 0.1 to 0.7.

3 . The method of claim 1 , wherein the step (iv) facilitating extravasation is performed with ultrasound insonation at a frequency of 330 to 650 kHz and with a mechanical index of 0.15 to 0.4.

4 . The method of claim 1 , wherein the steps (i) to (iv) of the ACT treatment are repeated one to four times.

5 . The method of claim 1 , wherein the insonation of step (iii) activating the phase shift starts immediately after step (i) and is immediately followed by the insonation of step (iv) facilitating extravasation.

6 . The method of claim 1 , wherein the insonation of step (iii) lasts for 30-120 seconds, followed by the insonation of step (iv) which lasts for 3-10 minutes.

7 . The method of claim 1 , wherein 1 to 5 therapeutic agents are administered simultaneously or sequentially over a certain time span wherein at least one ACT treatment is performed during the same period.

8 . The method of claim 1 , wherein a broad band or dual frequency ultrasound transducer is used in both the activating insonation of step (iii) and the further ultrasound of step (iv).

9 . A method of delivering a therapeutic agent, wherein the method comprises the steps of:

(i) administering a pharmaceutical composition to a subject with pancreatic ductal adenocarcinoma (PDAC); wherein the pharmaceutical composition comprises:

(a) a cluster composition which comprises a suspension of clusters in an aqueous biocompatible medium, where said clusters have a mean diameter in the range 3 to 10 μm, and a circularity <0.9, and wherein the cluster concentration of clusters in the size range 3-10 μm is at least 10 million/ml, the cluster composition comprises:

(i) a first component which comprises gas microbubbles and first stabilizer to stabilize said microbubbles; and

(ii) a second component which comprises microdroplets comprising an oil phase and second stabilizer to stabilize said microdroplets, where the oil phase comprises a diffusible component capable of diffusing into said gas microbubbles so as to at least transiently increase the size thereof,

wherein the microbubbles and microdroplets of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions; and

(b) a therapeutic agent selected from the group consisting of chemotherapeutic agents, immunotherapeutic agents, and combinations thereof,

wherein when the therapeutic agent includes said chemotherapeutic agents, and wherein when said chemotherapeutic agents include paclitaxel, said paclitaxel is in an albumin-bound form,

wherein the least one therapeutic agent is pre-, and/or co-and/or post administered separate to the cluster composition, and before steps ii) to iii) or after any of steps ii) to iii);

(ii) optionally imaging the clusters of said pharmaceutical composition using ultrasound imaging to identify a region of interest for treatment within said subject;

(iii) activating a phase shift of the diffusible component of the second component of the cluster composition from step (i) by ultrasound irradiation of a region of interest within said subject, such that:

(a) the microbubbles of said clusters are enlarged by said diffusible component of step (iii) to give enlarged bubbles which are localised at said region of interest due to temporary blocking of the microcirculation at said region of interest by said enlarged bubbles; and

(b) facilitating extravasation of the therapeutic agent(s) administered in step (i); and

(iv) facilitating further extravasation of the therapeutic agents administered in step (i) by further ultrasound irradiation.

Assignments (1)

Priority Claims (1)

Continuity (1)

References Cited (129)