# US 10,478,120 B2 · MRI-guided intraarterial catheter-based method for predicting territory of local blood brain barrier opening

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- Number: US 10,478,120 B2
- Document ID: US10478120B2
- Status: Granted
- Kind: B2
- Application number: 15/311,696
- Filed: 2015-05-17
- Published: 2017-03-23
- Granted: 2019-11-19
- Earliest claimed: 2014-05-17
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Piotr Walczak; Monica Pearl; Miroslaw Janowski
- Web page: https://patentgrep.com/patent/US10478120B2

## CPC

- A61B 5/4839: {combined with drug delivery}
- A61B 5/055: involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
- A61K 9/0085: {Brain, e.g. brain implants; Spinal cord}
- A61K 31/047: having two or more hydroxy groups, e.g. sorbitol
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61K 49/08: characterised by the carrier
- A61K 49/103: {the complex-forming compound being acyclic, e.g. DTPA}
- A61M 5/14: Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- 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)
- 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)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a method of administering a therapeutic agent directly to the brain parenchym through a compromised region of the blood-brain barrier in a subject having a brain disorder, that involves first disrupting the blood-brain barrier (BBB) at an isolated region by locally administering an effective amount of a hyperosmolar agent at said region using a catheter, followed by administering a therapeutically effective amount of a therapeutic agent. The step of disrupting the BBB is carried out with non-invasive MR (magnetic resonance) imaging with a contrast agent to visualize local parenchymal transcatheter perfusion at said isolated BBB region thereby indicating that the BBB region is compromised. The method of the invention allows for highly precise drug delivery to the brain through blood brain barrier disruption at specifically controlled regions.

## Claims

### Claim 1

A method of administering a therapeutic agent directly to the brain parenchyma through a compromised region of the blood-brain barrier in a subject having a brain disorder, comprising:
disrupting the blood-brain barrier (BBB) at an isolated region by locally administering an effective amount of a hyperosmolar agent at said region using a catheter,
locating an opening in the BBB using non-invasive MR (magnetic resonance) imaging with a contrast agent administered at said isolated region, and
administering a therapeutically effective amount of a therapeutic agent at the located opening in the BBB.

### Claim 2 (depends on 1)

The method of claim 1 wherein the brain disorder is a proliferative disorder.

### Claim 3 (depends on 1)

The method of claim 1, wherein the brain disorder is a neurological disorder.

### Claim 4 (depends on 3)

The method of claim 3, wherein the neurological disorder is brain damage, brain dysfunction, cranial nerve disorder, autonomic nervous system disorder, seizure disorder, movement disorder, sleep disorder, migraine, a central neuropathy, or a neuropsychiatric illness.

### Claim 5 (depends on 3)

The method of claim 3, wherein the neurological disorder is Alzheimer's disease.

### Claim 6 (depends on 1)

The method of claim 1, wherein the therapeutic agent is an agent for treating a proliferative disorder.

### Claim 7 (depends on 1)

The method of claim 1, wherein the therapeutic agent is a small molecule pharmaceutical, a protein therapeutic, a therapeutic antibody, a therapeutic nucleic acid molecule, or a composition comprising any of the same.

### Claim 8 (depends on 1)

The method of claim 1, wherein the disrupting of the BBB comprises adjusting an infusion rate of the hyperosmolar agent to control the opening in the BBB.

### Claim 9 (depends on 1)

The method of claim 1, wherein the disrupting of the BBB comprises adjusting a length of time of perfusion of the hyperosmolar agent to control the opening in the BBB.

### Claim 10 (depends on 1)

The method of claim 1, wherein the isolated region of the BBB is in the basilar artery.

### Claim 11 (depends on 1)

The method of claim 1, wherein the contrast agent used to visual local parenchymal transcatheter perfusion is gadolinium and/or Feraheme or a combination thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the contrast agent is selected from the group consisting of: gadoterate (Dotarem); gadodiamide (Omniscan); gadobenate (MultiHance); gadopentetate (Magnevist, Magnegita, Gado-MRT ratiopharm); gadoteridol (ProHance); gadoversetamide (OptiMARK); gadoxetate (Primovist); gadobutrol (Gadovist); gadoterate (Dotarem); gadodiamide (Omniscan); gadobenate (MultiHance); gadopentetate (Magnevist); gadoteridol (ProHance); gadofosveset (Ablavar, formerly Vasovist); gadoversetamide (OptiMARK); gadoxetate (Eovist); and gadobutrol (Gadavist).

### Claim 13 (depends on 1)

The method of claim 1, wherein the hyperosmolar agent is mannitol, glycerin, isosorbide, or urea.

### Claim 14 (depends on 1)

The method of claim 1, wherein the disrupting of the BBB comprises administering the hyperosmolar agent at an optimized infusion rate that is based on user-defined input data and MR imaging data.

### Claim 15 (depends on 1)

The method of claim 1 wherein the subject is a human.

### Claim 16

A method of administering a therapeutic agent to the brain parenchyma through the blood-brain barrier in a human subject, comprising:
selecting a potential opening of the blood-brain barrier by administering an effective amount of a hyperosmolar agent through an intraarterial catheter positioned at a region of the blood-brain barrier,
locating an opening in the blood brain barrier using non-invasive magnetic resonance imaging with a contrast agent administered through the intraarterial catheter positioned at the region of the blood-brain barrier, and
administering a therapeutically effective amount of a therapeutic agent through an intraarterial catheter positioned at the located, opening in the blood brain barrier.

### Claim 17 (depends on 16)

The method of claim 16 wherein the subject is a human.