# US 10,864,219 B2 · Compositions and methods for ophthalmic and/or other applications

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- Number: US 10,864,219 B2
- Document ID: US10864219B2
- Status: Granted
- Kind: B2
- Application number: 16/221,253
- Filed: 2018-12-14
- Published: 2019-05-02
- Granted: 2020-12-15
- Earliest claimed: 2012-05-03
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Alexey Popov; Elizabeth M. Enlow; Hongming Chen; James Bourassa
- Web page: https://patentgrep.com/patent/US10864219B2

## CPC

- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 9/5115: {Inorganic compounds}
- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61K 9/10: Dispersions; Emulsions
- 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

Particles, compositions, and methods that aid particle transport in mucus are provided. The particles, compositions, and methods may be used, in some instances, for ophthalmic and/or other applications. In some embodiments, the compositions and methods may involve modifying the surface coatings of particles, such as particles of pharmaceutical agents that have a low aqueous solubility. Such compositions and methods 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 ophthalmic applications, and may be used for delivering pharmaceutical agents to the front of the eye and/or the back of the eye.

## Claims

### Claim 1

A method for treating ocular inflammation, comprising:
administering to an eye of a subject in need of treatment for ocular inflammation an effective amount of a pharmaceutical composition comprising:
(a) a plurality of coated nanoparticles, each coated nanoparticle comprising:
(i) a core particle comprising loteprednol etabonate, wherein the loteprednol etabonate constitutes at least 80% of the core particle by weight; and
(ii) a mucus penetration-enhancing coating comprising a (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, wherein the poly(propylene oxide) block has a molecular weight of about 3600 Da and the poly(ethylene oxide) blocks constitute about 70 wt % of the triblock copolymer, and wherein the triblock copolymer is non-covalently adsorbed to the core particle;
(b) about 0.5% w/v to about 3% w/v glycerin; and
(c) about 0.1% w/v to about 1% w/v sodium chloride;
wherein the topical pharmaceutical composition comprises loteprednol etabonate at about 1% w/v in total;
wherein the pharmaceutical composition is a topical suspension; and
wherein the ratio of the total weight of loteprednol etabonate to the total weight of triblock copolymer comprised in the pharmaceutical composition is about 2:1.

### Claim 2 (depends on 1)

The method of claim 1, wherein the method treats post-surgical inflammation or post-surgical pain in the subject.

### Claim 3 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition is administered to the subject twice a day.

### Claim 4 (depends on 1)

The method of claim 1, wherein the triblock copolymer is poloxamer 407.

### Claim 5 (depends on 1)

The method of claim 1, wherein the loteprednol etabonate comprises at least 90 wt % of the core particle.

### Claim 6 (depends on 5)

The method of claim 5, wherein the core particle is substantially free of a polymeric component.

### Claim 7 (depends on 6)

The method of claim 6, wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.

### Claim 8 (depends on 7)

The method of claim 7, wherein the average size is measured by dynamic light scattering.

### Claim 9 (depends on 8)

The method of claim 8, wherein the average size is as measured in Z-average diameter by dynamic light scattering.

### Claim 10 (depends on 7)

The method of claim 7, wherein the polydispersity index of the pharmaceutical composition is less than or equal to about 0.5.

### Claim 11 (depends on 7)

The method of claim 7, wherein the polydispersity index of the pharmaceutical composition is less than or equal to about 0.4.

### Claim 12 (depends on 11)

The method of claim 11, wherein the polydispersity index is measured by dynamic light scattering.

### Claim 13 (depends on 5)

The method of claim 5, wherein the coated nanoparticles have the triblock copolymer adsorbed to the core particle at an average density of at least 0.1 molecules/nm2 and less than 1 molecule/nm2.

### Claim 14 (depends on 5)

The method of claim 5, wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.

### Claim 15 (depends on 5)

The method of claim 5, wherein the pharmaceutical composition further comprises less than or equal to 0.5 wt % 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester relative to the weight of the loteprednol etabonate in the pharmaceutical composition.

### Claim 16 (depends on 15)

The method of claim 15, wherein the pharmaceutical composition is made sterile by a sterilization proves comprising gamma irradiation, and wherein the 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester is at less than or equal to 0.5 wt % relative to the weight of the loteprednol etabonate in the pharmaceutical composition after the gamma irradiation.

### Claim 17

A method for treating ocular inflammation, comprising:
administering to an eye of a subject in need of treatment for ocular inflammation a pharmaceutical composition comprising:
(a) a plurality of coated nanoparticles, each of the coated nanoparticles comprising:
(i) a core particle comprising a single pharmaceutical agent, wherein the single pharmaceutical agent is loteprednol etabonate, and wherein the loteprednol etabonate comprises at least 90 wt % of the core particle; and
(ii) a coating on the core particle, the coating comprising poloxamer 407 non-covalently adsorbed to the core particle; and
(b) one or more ophthalmically acceptable carriers, additives, and/or diluents;
wherein the pharmaceutical composition is a topical suspension; and
wherein the pharmaceutical composition comprises about 1% w/v loteprednol etabonate in total and about 0.5% w/v poloxamer 407 in total.

### Claim 18 (depends on 17)

The method of claim 17, wherein the method treats post-surgical inflammation in the subject.

### Claim 19 (depends on 17)

The method of claim 17, wherein the pharmaceutical composition is administered to the subject twice a day.

### Claim 20 (depends on 17)

The method of claim 17, wherein the core particle is substantially free of a polymeric component.

### Claim 21 (depends on 17)

The method of claim 17, wherein the pharmaceutical composition comprises an ionic tonicity agent.

### Claim 22 (depends on 21)

The method of claim 21, wherein the ionic tonicity agent is sodium chloride.

### Claim 23 (depends on 22)

The method of claim 22, wherein the pharmaceutical composition comprises about 0.1 to about 1% w/v sodium chloride.

### Claim 24 (depends on 22)

The method of claim 22, wherein the pharmaceutical composition further comprises about 0.5 to about 3% w/v glycerin.

### Claim 25 (depends on 17)

The method of claim 17, wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus.

### Claim 26 (depends on 17)

The method of claim 17, wherein the coated nanoparticles have poloxamer 407 adsorbed to the core particle at an average density of at least 0.01 molecules/nm2 and less than 1 molecule/nm2.

### Claim 27 (depends on 26)

The method of claim 26, wherein the average density is at least 0.1 molecules/nm2 and less than 1 molecule/nm2.

### Claim 28 (depends on 21)

The method of claim 21, wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm.

### Claim 29 (depends on 28)

The method of claim 28, wherein the average size is measured by dynamic light scattering.

### Claim 30 (depends on 29)

The method of claim 29, wherein the average size is as measured in Z-average diameter by dynamic light scattering.

### Claim 31 (depends on 28)

The method of claim 28, wherein the polydispersity index of the pharmaceutical composition is less than or equal to 0.5.

### Claim 32 (depends on 28)

The method of claim 28, wherein the polydispersity index of the pharmaceutical composition is less than or equal to 0.4.

### Claim 33 (depends on 32)

The method of claim 32, wherein the polydispersity index is measured by dynamic light scattering.

### Claim 34 (depends on 24)

The method of claim 24, wherein the pharmaceutical composition comprises less than or equal to 0.5 wt % 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester relative to the weight of the loteprednol etabonate in the pharmaceutical composition.

### Claim 35 (depends on 34)

The method of claim 34, wherein the pharmaceutical composition is made sterile by a sterilization process comprising gamma irradiation, and wherein the 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-4-ene-17-carboxylic acid chloromethyl ester is at less than or equal to 0.5 wt % relative to the weight of the loteprednol etabonate in the pharmaceutical composition after the gamma irradiation.

### Claim 36 (depends on 1)

The method of claim 1, wherein the loteprednol etabonate constitutes at least 95% of the core particle by weight.

### Claim 37 (depends on 36)

The method of claim 36, wherein the loteprednol etabonate constitutes at least 99% of the core particle by weight.

### Claim 38 (depends on 17)

The method of claim 17, wherein the loteprednol etabonate constitutes at least 95% of the core particle by weight.

### Claim 39 (depends on 38)

The method of claim 38, wherein the loteprednol etabonate constitutes at least 99% of the core particle by weight.