# US 12,178,920 B2 · Nanocrystals, compositions, and methods that aid particle transport in mucus

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- Number: US 12,178,920 B2
- Document ID: US12178920B2
- Status: Granted
- Kind: B2
- Application number: 18/529,962
- Filed: 2023-12-05
- Published: 2024-04-11
- Granted: 2024-12-31
- Earliest claimed: 2012-05-03
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Alexey Popov; Elizabeth M. Enlow; James Bourassa; Colin R. Gardner; Hongming Chen; Laura M. Ensign; Samuel K. Lai; Tao Yu; Justin Hanes; Ming Yang
- Web page: https://patentgrep.com/patent/US12178920B2

## CPC

- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 9/10: Dispersions; Emulsions
- A61K 9/5089: {Processes}
- A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 31/12: Ketones
- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61K 31/409: having four such rings, e.g. porphine derivatives, bilirubin, biliverdine (hemin, hematin A61K31/555)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 31/569: substituted in position 17 alpha, e.g. ethisterone
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 31/662: Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 49/0089: {Particulate, powder, adsorbate, bead, sphere}
- 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

Nanocrystals, compositions, and methods that aid particle transport in mucus are provided. In some embodiments, the compositions and methods involve making mucus-penetrating particles (MPP) without any polymeric carriers, or with minimal use of polymeric carriers. The compositions and methods may include, in some embodiments, modifying the surface coatings of particles formed of pharmaceutical agents that have a low water solubility. Such methods and compositions can be used to achieve efficient transport of particles of pharmaceutical agents though mucus barriers in the body for a wide spectrum of applications, including drug delivery, imaging, and diagnostic applications. In certain embodiments, a pharmaceutical composition including such particles is well-suited for administration routes involving the particles passing through a mucosal barrier.

## Claims

### Claim 1

A method of treating, diagnosing, or managing an ocular condition in a subject, the method comprising:
administering a mucus-penetrating pharmaceutical composition topically to an eye of a subject, wherein the pharmaceutical composition consists of:
A) a plurality of coated particles comprising a pharmaceutical agent, or a salt thereof, each coated particle consisting of:
1) a core particle comprising the pharmaceutical agent, wherein the pharmaceutical agent constitutes at least 80 wt % of the core particle, and
2) a mucus penetration-enhancing coating surrounding the core particle, wherein the mucus penetration-enhancing coating consists of at least one of:
a) a triblock copolymer comprising a hydrophilic block—hydrophobic block—hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer, wherein the hydrophobic block associates with the surface of the core particle, and wherein the hydrophilic block is present at the surface of the coated particle and renders the coated particle hydrophilic,
b) a synthetic polymer having pendant hydroxyl groups on the backbone of the polymer, the polymer having a molecular weight of at least about 1 kDa and less than or equal to about 1000 kDa, wherein the polymer is at least about 30% hydrolyzed and less than about 95% hydrolyzed, or
c) a polysorbate,
wherein the mucus penetration-enhancing coating is present on the outer surface of the core particle at a density of at least 0.01 molecules/nm2,
wherein the mucus penetration-enhancing coating is present in the pharmaceutical composition in an amount of between about 0.001% and about 5% by weight; and
(B) one or more ophthalmically acceptable carriers, additives, and/or diluents; and
delivering the mucus-penetrating pharmaceutical composition to a tissue in the eye of the subj ect.

### Claim 2 (depends on 1)

The method of claim 1, comprising sustaining an ophthalmically efficacious level of the pharmaceutical agent in an anterior ocular tissue selected from the group consisting of a palpebral conjunctiva, a bulbar conjunctiva, or a cornea for at least 12 hours after administration.

### Claim 3 (depends on 1)

The method of claim 1, comprising delivering the pharmaceutical agent to a tissue in the front of the eye of the subject.

### Claim 4 (depends on 1)

The method of claim 1, comprising delivering the pharmaceutical agent to a tissue in the back of the eye of the subject.

### Claim 5 (depends on 1)

The method of claim 1, wherein the tissue is a retina, a macula, a sclera, or a choroid.

### Claim 6 (depends on 1)

The method of claim 1, wherein the core particle consists of the pharmaceutical agent.

### Claim 7 (depends on 1)

The method of claim 1, wherein the pharmaceutical agent constitutes at least 85 wt % of the core particle.

### Claim 8 (depends on 1)

The method of claim 1, wherein the pharmaceutical agent constitutes at least 90 wt % of the core particle.

### Claim 9 (depends on 1)

The method of claim 1, wherein the pharmaceutical agent constitutes at least 95 wt % of the core particle.

### Claim 10 (depends on 1)

The method of claim 1, wherein the pharmaceutical agent constitutes at least 99 wt % of the core particle.

### Claim 11 (depends on 1)

The method of claim 1, wherein the polymeric carrier is polymethacrylate, polylactic acid, or polyglycolic acid, or co-polymers thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the polymeric carrier is hyaluronic acid, chitosan, or collagen.

### Claim 13 (depends on 1)

The method of claim 1, wherein the polymeric carrier is a triblock copolymer comprising a hydrophilic block—hydrophobic block—hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer.

### Claim 14 (depends on 1)

The method of claim 1, wherein the polymeric carrier is a synthetic polymer having pendant hydroxyl groups on the backbone of the polymer, the polymer having a molecular weight of at least about 1 kDa and less than or equal to about 1000 kDa, wherein the polymer is at least about 30% hydrolyzed and less than about 95% hydrolyzed.

### Claim 15 (depends on 1)

The method of claim 1, wherein the polymeric carrier is a polysorbate.