# US 2021/0330950 A1 · Using Alternating Electric Fields to Increase Permeability of the Blood Brain Barrier > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2021/0330950 A1 - Document ID: US20210330950A1 - Status: Published application - Kind: A1 - Application number: 17/236,487 - Filed: 2021-04-21 - Published: 2021-10-28 - Earliest claimed: 2020-04-24 - Assignees: Novocure GmbH - Applicants: Novocure GmbH - Inventors: Carsten HAGEMANN; Mario LOHR; Almuth F. KESSLER; Malgorzata BUREK; Carola FORSTER; Catherine BRAMI; Hadas Sara HERSHKOVICH; Tali VOLOSHIN-SELA - Web page: https://patentgrep.com/patent/US20210330950A1 ## CPC - A61M 37/00: Other apparatus for introducing media into the body (for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30); Percutany, i.e. introducing medicines into the body by diffusion through the skin (salt baths A61H33/04) - A61N 1/327: {for enhancing the absorption properties of tissue, e.g. by electroporation} - A61M 5/14: Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor - A61M 2037/0007: {having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents} - A61M 2210/0693: Brain, cerebrum - A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)} - A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B) ## Abstract Many drugs and other molecules cannot ordinarily traverse the blood brain barrier (BBB). However, when alternating electric fields at certain optimum frequencies (e.g., 100 kHz) are applied to the brain, the BBB becomes permeable to those molecules. When the alternating electric fields are discontinued, the BBB eventually recovers to its original impermeable state. Subsequently, re-application of alternating electric fields at the optimum frequencies will re-open the BBB. Ordinarily, many frequencies (e.g., 200 kHz) of alternating electric fields are either ineffective or less effective at inducing permeability than the optimum frequencies. But once the BBB has been opened by applying alternating electric fields at the optimum frequencies, alternating electric fields at non-optimum frequencies can maintain the permeability of a previously-opened BBB. ## Claims ### Claim 1 A method for delivering a substance across a blood brain barrier of a subject's brain, the method comprising: applying an alternating electric field to the subject's brain for a first period of time, wherein application of the alternating electric field to the subject's brain for the first period of time increases permeability of the blood brain barrier in the subject's brain; administering a first substance to the subject after the first period of time has elapsed, wherein the increased permeability of the blood brain barrier allows the first substance to cross the blood brain barrier; discontinuing the application of the alternating electric field for enough time to allow the blood brain barrier to recover; after the blood brain barrier has recovered, applying an alternating electric field to the subject's brain for a second period of time, wherein application of the alternating electric field to the subject's brain for the second period of time increases permeability of the blood brain barrier in the subject's brain; and administering a second substance to the subject after the second period of time has elapsed, wherein the increased permeability of the blood brain barrier allows the second substance to cross the blood brain barrier. ### Claim 2 (depends on 1) The method of claim 1, wherein the alternating electric field is applied at a frequency between 75 kHz and 125 kHz. ### Claim 3 (depends on 1) The method of claim 1, wherein the alternating electric field is applied at a frequency of at least 50 kHz. ### Claim 4 (depends on 1) The method of claim 1, wherein the second period of time is at least 24 hours. ### Claim 5 (depends on 1) The method of claim 1, wherein the second period of time is at least 48 hours. ### Claim 6 (depends on 1) The method of claim 1, wherein the alternating electric field has a field strength of at least 1 V/cm in at least a portion of the subject's brain. ### Claim 7 (depends on 1) The method of claim 1, wherein the alternating electric field is applied at a frequency between 75 kHz and 125 kHz, the second period of time is at least 24 hours, and the alternating electric field has a field strength of at least 1 V/cm in at least a portion of the subject's brain. ### Claim 8 (depends on 1) The method of claim 1, wherein the administering of the second substance is performed intravenously. ### Claim 9 (depends on 1) The method of claim 1, wherein the administering of the second substance is performed orally. ### Claim 10 (depends on 1) The method of claim 1, wherein the first substance and the second substance are identical. ### Claim 11 (depends on 1) The method of claim 1, wherein at least one of the first substance and the second substance comprises paclitaxel. ### Claim 12 A method for delivering a substance across a blood brain barrier of the subject's brain, the method comprising: applying a first alternating electric field at a first frequency to the subject's brain for a first period of time, wherein application of the first alternating electric field at the first frequency to the subject's brain for the first period of time increases permeability of the blood brain barrier in the subject's brain; subsequent to the first period of time, applying a second alternating electric field at a second frequency to the subject's brain for a second period of time, wherein the second frequency is different from the first frequency, and wherein the second alternating electric field at the second frequency operates to maintain permeability of the blood brain barrier; and administering the substance to the subject at least 24 hours after the first period of time has elapsed, wherein the maintained permeability of the blood brain barrier allows the substance to cross the blood brain barrier. ### Claim 13 (depends on 12) The method of claim 12, wherein the first frequency is between 75 kHz and 125 kHz. ### Claim 14 (depends on 12) The method of claim 12, wherein the first frequency is between 50 kHz and 190 kHz. ### Claim 15 (depends on 14) The method of claim 14, wherein the second frequency is at least 190 kHz. ### Claim 16 (depends on 12) The method of claim 12, wherein the first frequency is at least 50 kHz and the second frequency is higher than the first frequency. ### Claim 17 (depends on 12) The method of claim 12, wherein the first period of time is at least 24 hours. ### Claim 18 (depends on 12) The method of claim 12, wherein the second period of time comprises a single uninterrupted interval of time that is at least one week long. ### Claim 19 (depends on 12) The method of claim 12, wherein the second period of time comprises a plurality of non-contiguous intervals of time during which the second alternating electric field at the second frequency is applied to the subject's brain, wherein the plurality of non-contiguous intervals of time collectively add up to at least one week. ### Claim 20 A method for delivering a substance across a blood brain barrier of a subject's brain, the method comprising: applying an alternating electric field to the subject's brain for a period of time, wherein application of the alternating electric field to the subject's brain for the period of time increases permeability of the blood brain barrier in the subject's brain; and administering paclitaxel to the subject after the period of time has elapsed, wherein the increased permeability of the blood brain barrier allows the paclitaxel or at least one metabolite thereof to cross the blood brain barrier. ### Claim 21 (depends on 20) The method of claim 20, wherein the alternating electric field is applied at a frequency between 75 kHz and 125 kHz. ### Claim 22 (depends on 20) The method of claim 20, wherein the alternating electric field is applied at a frequency between 75 kHz and 125 kHz, the period of time is at least 24 hours, and the alternating electric field has a field strength of at least 1 V/cm in at least a portion of the subject's brain.