# US 10,307,372 B2 · Rapid diffusion of large polymeric nanoparticles in the mammalian brain

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,307,372 B2
- Document ID: US10307372B2
- Status: Granted
- Kind: B2
- Application number: 13/821,320
- Filed: 2011-09-12
- Published: 2013-07-18
- Granted: 2019-06-04
- Earliest claimed: 2010-09-10
- Assignees: The Johns Hopkins University
- Applicants: Justin Hanes; Graeme F. Woodworth; Elizabeth A. Nance
- Inventors: Justin Hanes; Graeme F. Woodworth; Elizabeth A. Nance
- Web page: https://patentgrep.com/patent/US10307372B2

## CPC

- A61K 9/0085: {Brain, e.g. brain implants; Spinal cord}
- A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 49/0065: {the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle}
- A61K 49/0093: {Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle}
- A61P 25/00: Drugs for disorders of the nervous system
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Non-adhesive particles as large as 110 nm can diffuse rapidly in the brain ECS, if coated with hydrophilic coatings such as PEG coatings and preferably having neutral surface charge. The ability to achieve brain penetration with larger particles will significantly improve drug and gene delivery within the CNS since larger particles offer higher drug payload, improved drug loading efficiency, and significantly longer drug release durations.

## Claims

### Claim 1

A dosage formulation for delivery of a therapeutic, prophylactic or diagnostic agent to the brain, the formulation consisting of
a. polymeric nanoparticles having a diameter of at least about 40 nm and less than about 200 nm, the nanoparticles having a hydrophobic polymeric core and being coated with a hydrophilic polymer comprising polyalkylene oxide or a block copolymer containing polyalkylene oxide blocks, in an amount effective to result in a neutral or near neutral charged surface between −10 mV and 10 mV measured as zeta-potential in phosphate buffered solution, pH 7.0 using laser Doppler anemometry and having a number density of at least 0.1 hydrophilic polymer per nm2 of nanoparticle surface, wherein the hydrophilic polymer is present in a weight percent of greater than 80% relative to the total weight of the polymeric nanoparticles,
b. an effective amount of a therapeutic, prophylactic or diagnostic agent to prevent or treat a disease or disorder of the brain, encapsulated in or on the nanoparticles, and
c. a pharmaceutically acceptable excipient for delivery into the brain,
wherein the nanoparticles have a diffusion rate at most about 60-fold slower in the brain than in water, whereas the same nanoparticles without the hydrophilic polymer coating have a diffusion rate at least about 16,000-fold slower in the brain than in water, characterized by measuring average effective diffusivities at a time scale of 1 second of respective nanoparticles in cortical tissue relative to in water (Dw/Db).

### Claim 2 (depends on 1)

The formulation of claim 1 wherein the nanoparticles are coated with polyethylene glycol or a block copolymer containing polyethylene glycol blocks.

### Claim 3 (depends on 1)

The formulation of claim 1, wherein the hydrophilic polymer has a number density of at least 0.2, 0.5, 1, 2, 5, 10, 15, 20, 25, 40, 50, 60, 75, 90, or 100 hydrophilic polymer per nm2 of nanoparticle surface.

### Claim 4 (depends on 1)

The formulation of claim 1, wherein the hydrophilic polymer has a mass of at least 9/10 of the mass of the nanoparticles.

### Claim 5 (depends on 1)

The formulation of claim 1, wherein the hydrophilic polymer has a weight percent of at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or greater relative to the total weight of the polymeric nanoparticles.

### Claim 6 (depends on 1)

The formulation of claim 1, wherein the nanoparticles are formulated for direct injection into the brain.

### Claim 7 (depends on 1)

The formulation of claim 1, wherein the polymeric core is formed of a biocompatible biodegradable polymer.

### Claim 8 (depends on 1)

The formulation of claim 1, wherein the nanoparticles have an average diameter of about 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, or 190 nm.

### Claim 9 (depends on 1)

The formulation of claim 1, wherein the therapeutic, prophylactic or diagnostic agent is loaded at a weight percent of between about 1% and about 80%, between about 1% and about 50%, between about 1% and about 40%, between about 1% and about 20%, or between about 1% and about 10%, relative to the total weight of the nanoparticles and the therapeutic, prophylactic or diagnostic agent.

### Claim 10 (depends on 1)

The formulation of claim 1 in the form of a nanoparticle suspension in an aqueous medium, wherein, following administration, the nanoparticles release an effective amount of the therapeutic, prophylactic or diagnostic agent in the brain over a period of at least 10 minutes, 20 minutes, 30 minutes, one hour, two hours, four hours, six hours, ten hours, one day, three days, seven days, ten days, two weeks, one month, or longer.

### Claim 11 (depends on 1)

A method for treating a disease or disorder of the brain, the method comprising administering to the brain the formulation of claim 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein the formulation is administered directly to the brain.

### Claim 13 (depends on 11)

The method of claim 11, wherein the formulation is administered systemically and the nanoparticles penetrate the brain by passing through the blood-brain barrier.

### Claim 14 (depends on 13)

The method of claim 13, wherein the formulation is administered in combination with one or more techniques to facilitate passage of the nanoparticles through the blood brain barrier.

### Claim 15 (depends on 14)

The method of claim 14, wherein the technique is selected from the group consisting of electron paramagnetic resonance, ultrasound, and ultrasound plus microbubbles.

### Claim 16 (depends on 11)

The method of claim 11, wherein the disease or disorder is selected from the group consisting of tumors, neurological disorders, and brain injury or trauma.

### Claim 17 (depends on 1)

The dosage formulation of claim 1, wherein the nanoparticles have an average diameter between about 60 and about 110 nm.

### Claim 18 (depends on 1)

The dosage formulation of claim 1, wherein the nanoparticles have an average diameter of at least 110 nm and less than 200 nm.

### Claim 19 (depends on 9)

The formulation of claim 9, wherein the therapeutic, prophylactic or diagnostic agent is loaded at a weight percent between about 1% and about 40% relative to the total weight of the nanoparticles and the therapeutic, prophylactic or diagnostic agent.

### Claim 20 (depends on 9)

The formulation of claim 9, wherein the therapeutic, prophylactic or diagnostic agent is loaded at a weight percent between about 1% and about 10% relative to the total weight of the nanoparticles and the therapeutic, prophylactic or diagnostic agent.