# US 12,178,981 B2 · Drug administration method

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- Number: US 12,178,981 B2
- Document ID: US12178981B2
- Status: Granted
- Kind: B2
- Application number: 16/958,388
- Filed: 2018-12-26
- Published: 2021-02-25
- Granted: 2024-12-31
- Earliest claimed: 2017-12-27
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: Naoyuki Murata; Shigeo Yanai
- Web page: https://patentgrep.com/patent/US12178981B2

## CPC

- A61M 37/0092: {using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis}
- A61K 41/0028: {Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds}
- A61K 41/0047: {Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent}
- A61K 49/223: {Microbubbles, hollow microspheres, free gas bubbles, gas microspheres}
- 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)}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present disclosure provides a safer novel opening system with highly broad utility for a blood-brain barrier (BBB), the opening system containing a combination of (1) nano-bubble water or nano-bubble aqueous solution containing nano-bubbles having an average diameter of not more than 200 nm, and (2) an ultrasound generating apparatus; a method for opening a BBB, including using the nano-bubble water or nano-bubble aqueous solution, and an ultrasound; and a method for increasing BBB permeability of a drug, including using the nano-bubble water or nano-bubble aqueous solution, and an ultrasound.

## Claims

### Claim 1

An opening system for a blood-brain barrier, the system comprising a combination of (a) nano-bubble water or a nano-bubble aqueous solution, said nano-bubble water or said nano-bubble aqueous solution comprising nano-bubbles having an average diameter of not more than 200 nm, and (b) an ultrasound generating apparatus, wherein the nano-bubbles consist of a gas and a non-ionic surfactant.

### Claim 2 (depends on 1)

The system according to claim 1, wherein the gas is perfluorohydrocarbon or air.

### Claim 3 (depends on 1)

The system according to claim 1, wherein the nano-bubbles have the average diameter of 50 nm-200 nm.

### Claim 4 (depends on 1)

The system according to claim 1, wherein the nano-bubbles have a d90/d10 ratio of not more than 5, wherein the d90 is a nano-bubble diameter value corresponding to cumulative 90% from a smaller diameter side of a number-based distribution of the nano-bubbles and the d10 is a nano-bubble diameter value corresponding to cumulative 10% from the smaller diameter side of the number-based distribution of the nano-bubbles.

### Claim 5 (depends on 1)

The system according to claim 1, wherein the nano-bubbles in the nano-bubble water or the nano-bubble aqueous solution have a density of not less than 2.0×108 bubbles/mL.

### Claim 6 (depends on 1)

The system according to claim 1, wherein the ultrasound generating apparatus has an ultrasound output intensity of not more than 720 mW/cm2.

### Claim 7 (depends on 1)

The system according to claim 1, wherein the ultrasound generating apparatus has an ultrasound output intensity of 50-500 mW/cm2 and an ultrasound frequency of 0.5-10 MHz.

### Claim 8 (depends on 1)

The system according to claim 1, wherein the system increases a permeability of the blood-brain barrier for a drug.

### Claim 9 (depends on 8)

The system according to claim 8, wherein the drug is a compound that is difficult to pass the blood-brain barrier.

### Claim 10 (depends on 1)

The system according to claim 1, wherein the nano-bubbles do not contain phospholipid.

### Claim 11 (depends on 1)

The system according to claim 1, wherein the nano-bubbles are not liposomes.

### Claim 12 (depends on 1)

The system according to claim 1, wherein the nanobubble water consists of water, the non-ionic surfactant and the gas.

### Claim 13

A method for opening a blood-brain barrier, the method comprising using (a) nano-bubble water or a nano-bubble aqueous solution, said nano-bubble water or said nano-bubble aqueous solution comprising nano-bubbles with an average diameter of not more than 200 nm, and (b) an ultrasound, wherein the nano-bubbles consist of a gas and a non-ionic surfactant.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the nano-bubbles do not contain phospholipid.

### Claim 15 (depends on 13)

The method according to claim 13, wherein the nano-bubbles are not liposomes.

### Claim 16 (depends on 13)

The method according to claim 13, wherein the nanobubble water consists of water, the non-ionic surfactant and the gas.

### Claim 17

A method for increasing blood-brain barrier permeability of a drug, the method comprising using (a) nano-bubble water or a nano-bubble aqueous solution, said nano-bubble water or said nano-bubble aqueous solution comprising nano-bubbles with an average diameter of not more than 200 nm, and (b) an ultrasound, wherein the nano-bubbles consist of a gas and a non-ionic surfactant.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the nano-bubbles do not contain phospholipid.

### Claim 19 (depends on 17)

The method according to claim 17, wherein the nano-bubbles are not liposomes.

### Claim 20 (depends on 17)

The method according to claim 17, wherein the nanobubble water consists of water, the non-ionic surfactant and the gas.